T URINE2

501
40.1.1.5.4 Substitution on the Amine Nitrogen
S. A. Lawrence
40.1.1.5.4.1 Dealkylation Reactions of Amines
Dealkylation reactions offer convenient synthetic strategies for the preparation of

amines. These strategies are commonly applied to the synthesis of secondary amines, in-
cluding cyclic amines, from tertiary amines. In addition, many natural products, particu-
larly alkaloids, contain tertiary amine groups which can be dealkylated to allow derivati-
zation. The most common route for dealkylation is the reaction with nucleophiles
(Scheme 1; see also Houben–Weyl, Vol. 11/1, p 961). However, reductive (catalytic hydro-
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genation, reduction with hydride or sodium amalgam) or oxidative [employing for exam-
ple, permanganate, manganese(IV) oxide, potassium hexacyanoferrate(III), chromic acid,
dibenzoyl peroxide, or halogens] methods are also in use (see Houben–Weyl, Vol. 11/1, p
1168, and Vol. E 16d, p 1214).
Scheme 1 Reaction of Tertiary Amines with Nucleophiles

1. Nu−
R2 R2
2. H+
+ NuMe
R1 NMe2 R1 NHMe
40.1.1.5.4.1.1 Method 1:
The von Braun Reaction with Cyanogen Bromide
The dealkylation of tertiary amines with cyanogen bromide is known as the von Braun
cyanogen bromide reaction (see Houben–Weyl, Vol. 11/1, p 982).[1,2] Cyanogen bromide
(BrCN) can be prepared from sodium cyanide and bromine in aqueous solution {see Sci-
ence of Synthesis, Vol. 18 [Four Carbon—Heteroatom Bonds: X—C”X, X=C=X, X2C=X, CX4
(Section 18.1.1.1.1)]}. It acts as a source of electrophilic cyanide, which can attack amines,
replacing alkyl groups or hydrogen with cyanide. When tertiary amines are used, dealkyl-
ation takes place and secondary amines are formed.
The initial reaction of cyanogen bromide with a tertiary amine 1 proceeds quickly to
produce a quaternary N-cyanoammonium bromide salt 2, which can then eliminate an al-
kyl bromide (or if ring opening is possible, undergo bromination at the terminal alkyl car-
bon) along with a cyanamide 3 (Scheme 2). The decomposition of the ammonium bro-
mide salt to form a cyanamide is the rate-determining factor in this part of the reaction.
Elimination of alkenes is a competing side reaction when the tertiary amine being deal-
kylated contains branched alkyl groups.[1] The cyanamide 3 is hydrolyzed under basic or
acidic conditions to give a secondary amine 4. In most instances, N-dealkylation with cya-
nogen bromide works best in solvents such as benzene, toluene, or dichloromethane. It
should be noted that in comparison with the acyl chlorides (see Section 40.1.1.5.4.1.2) the
high activity of cyanogen bromide leads to reduced selectivity, and that relatively strong
acidic conditions are required for hydrolysis of the intermediate cyanamide. Alternative-
ly, the intermediate can be cleaved using lithium tri-sec-butylborohydride (L-Selectride).[3]
for references see p 571

502 Science of Synthesis 40.1 Amino Compounds
Scheme 2 Reaction of Tertiary Amines with Cyanogen Bromide

R3 R2
R1 R2 BrCN + CN − H3O+
N R1 N Br N CN
− R3Br
R3 R2 R1
1 2 3
R2
H
N CO2H N
− CO2 R1 R2
R1
4
The ease with which alkyl groups are removed decreases in the following order: allyl <
methyl < ethyl < propyl < isopropyl < butyl.[2] This means that allylic (and also benzylic)
groups are removed most easily while higher aliphatic residues are cleaved less easily. In
any case, aryl groups are usually not cleaved.

The von Braun reaction with cyanogen bromide can cleave heterocycles [such as N-
butyl- or N-(3-methylbutyl)morpholine or -piperidine] and result in the formation of
long-chain alkylamines with a terminal bromine atom (Scheme 3, path a). However, allyl,
benzyl, and normally also methyl groups on the ring nitrogen are removed preferentially
to ring opening (Scheme 3, path b).
Scheme 3 The Reaction of Cyclic Trialkylamines with Cyanogen Bromide
path a () () R1
Br n X n N
() CN
BrCN
n
X N R1
( )n
path b ()
n
X N CN
( )n
1-Butylpyrrolidine (5) and cyanogen bromide react in benzene to afford (4-bromobutyl)bu-

tylcyanamide (6) which can be further reacted with diethylamine and then hydrolyzed us-
ing sulfuric acid to give N¢-butyl-N,N-diethylbutane-1,4-diamine (7) (Scheme 4).[4]
Scheme 4 Ring Opening of 1-Butylpyrrolidine[4]

BrCN, benzene Et2NH
35−40 oC Br Bu reflux Et2N Bu
( )3 N ( )3 N
100% 82%
N CN CN
Bu
5 6
H2SO4, H2O
reflux Et2N
80% ( )3 NHBu
Many alkaloids occur as the N-methyl derivative, which can be demethylated with cyano-
gen bromide and then used in downstream synthesis.[5] The most widely used application
of the von Braun reaction with cyanogen bromide is in the synthesis of N-methyl-3-phen-
yl-3-[4-(trifluoromethyl)phenoxy]propylamine (8, fluoxetine, Prozac) (Scheme 5).[6]
40.1.1 Alkyl- and Cycloalkylamines 503
Scheme 5 Dealkylation in the Synthesis of Fluoxetine[6]

1. BrCN, benzene, 5 oC to rt
Ph 2. KOH, ethylene glycol, reflux
Ph
54%
Ar1O NMe2 Ar1O NHMe
8
Ar1 = 4-F3CC6H4
The use of cyanogen bromide to cleave other ring systems such as aziridine[7] or nicotine[8]
derivatives has also been reported. 2-Methylindolizidine can be ring opened with cyano-
gen bromide to give a 2-substituted piperidine (Scheme 6).[9]
Scheme 6 Reaction of an Indolizidine with Cyanogen Bromide[9]

BrCN
CH2Cl2
reflux H+

N Br Br
N N
H
CN
90%
N¢-Butyl-N,N-diethylbutane-1,4-diamine (7); Typical Procedure:[4]
CAUTION: Cyanogen bromide evolves corrosive, toxic fumes on contact with water or on heat-
ing and trimerization of the crude form may occur violently. It is a severe eye and respiratory
tract irritant and a lachrymator.
A soln of BrCN (59 g, 557 mmol) in dry benzene (300 mL) (CAUTION: carcinogen) was added
slowly, over 2.5 h with stirring, to a soln of 1-butylpyrrolidine (5; 60 g, 471 mmol) in dry
benzene (300 mL). The stirred mixture reached a temperature of 35–40 8C during the reac-
tion. After the reaction was complete, the soln was left to stand overnight and then wash-
ed with 5% HCl (200 mL) and then with H2O (2 F 100 mL). The organic layer was dried
(CaCl2) and filtered, and the resulting soln was concentrated to dryness under reduced
pressure at 90 8C. The obtained product was crude (4-bromobutyl)butylcyanamide (6);
yield: 110 g (100%). This crude product (46 g, 197 mmol) was then heated with Et2NH
(110 g, 1.51 mol) for 3 h under reflux. Once the reflux period was completed, the following
step was commenced immediately: The contents of the distillation flask were mixed with
a soln of KOH (20 g, 357 mmol) in H2O (300 mL) and any unreacted Et2NH was removed by
distillation under reduced pressure. The product formed a brown oil on top of the aque-
ous layer, which was extracted with Et2O (250 mL), and the organic layer was dried
(K2CO3). The dried ethereal soln was then distilled under reduced pressure to remove the
solvent, which left a crude residue (41 g). This residue was then distilled under reduced
pressure over a column to give butyl[4-(diethylamino)butyl]cyanamide; yield: 37 g (82%).
The pure butyl[4-(diethylamino)butyl]cyanamide (20 g, 88.7 mmol) was then refluxed for
14 h with H2SO4 (40 g) in H2O (120 mL). The mixture was made alkaline and then the soln
was extracted with Et2O, dried (K2CO3), and distilled; yield: 14.2 g (80%).
rac-N-Methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylamine (8); Typical Proce-

dure:[6]
CAUTION: Cyanogen bromide evolves corrosive, toxic fumes on contact with water or on heat-
ing and trimerization of the crude form may occur violently. It is a severe eye and respiratory
tract irritant and a lachrymator.
A soln of BrCN (8.1 g, 76 mmol) in benzene (500 mL) (CAUTION: carcinogen) and toluene
(50 mL) was cooled to about 5 8C with stirring and a N2 gas sparge. A soln of N,N-dimeth-

yl-3-phenyl-3-[(4-trifluoromethyl)phenoxy]propylamine (12.146 g, 37.6 mmol) in benzene

(40 mL) was then added dropwise. The temperature of the mixture was allowed to rise
slowly to rt, and the mixture was stirred overnight whilst maintaining a N2 atmosphere.
Benzene (100 mL) was added to the mixture, which was then washed with H2O (2 F), 2 M
H2SO4 (1 F), and then with H2O until neutral. The organic layer was dried, and the solvents
were removed under reduced pressure to give methyl{3-phenyl-3-[4-(trifluorometh-
yl)phenoxy]propyl}cyanamide as an oil; yield: 9.5 g (76%).
A soln containing KOH (100 g, 1.79 mol), H2O (85 mL), ethylene glycol (400 mL), and
methyl{3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl}cyanamide (9.5 g, 28 mmol) was
prepared in a 1-L, three-necked, round-bottomed flask equipped with a magnetic stirrer
and a condenser. The mixture was heated to reflux (130 8C) for 20 h and then cooled, and
H2O (500 mL) was added. The mixture was extracted with Et2O (3 F 500 mL) and the Et2O
extracts were combined and washed with H2O. The H2O wash was discarded and the Et2O
soln was next contacted with 2 M HCl. The acidic aqueous layer was separated. A second
aqueous acidic extract with 2 M HCl was made followed by three aqueous extracts and an

extract with sat. aq NaCl. The aqueous layers were combined and made basic with 5 M aq
NaOH. The N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylamine formed was in-
soluble in the basic soln and separated. The amine was extracted into Et2O (3 F). The Et2O
extracts were combined and the combined extracts were washed with sat. aq NaCl, dried,
and concentrated under reduced pressure; yield: 6.3 g (54% overall).
40.1.1.5.4.1.2 Method 2:
Dealkylation by Acylation
Phosgene reacts with tertiary amines to form 1:1 or 1:2 metastable phosgene/amine ad-
ducts. These adducts usually decompose with the elimination of a chloroalkane to form
carbamoyl chlorides 9 {see Science of Synthesis, Vol. 18 [Four Carbon—Heteroatom Bonds:
X—C”X, X=C=X, X2C=X, CX4 (Section 18.3.5)]}. However, under forcing conditions a sec-
ondary amine 10 can be produced (Scheme 7).[10] This requires a strongly acidic medium
to hydrolyze the carbamoyl chloride 9, which limits the usefulness of the reaction. As a
result, the use of phosgene or triphosgene to dealkylate tertiary amines is limited to a few
examples such as the de-ethylation of triethylamine,[11] demethylation reactions,[12] or de-
benzylation reactions.[13,14]
Scheme 7 Reaction of Tertiary Amines with Phosgene

O O
R1 R2 COCl2
R2 + −
N N Cl Cl R12N Cl
− R2Cl
R1 R1 R1
9
hydrolysis
R12NH
− CO2
10
A better alternative is to use chloroformates or chlorothioformates as dealkylating agents

as these reagents offer the advantages of milder dealkylation conditions, are less toxic,
and also offer the possibility of selectively dealkylating amines. Methyl chloroformate
works well to demethylate opium alkaloids, particularly if lithium tri-sec-butylborohy-
dride (L-Selectride) is used to cleave the intermediate carbamate.[3]
The reaction between phosgene and acetaldehyde in the presence of triethylamine
forms 1-chloroethyl chloroformate in situ {see Science of Synthesis, Vol. 18 [Four Carbon—
Heteroatom Bonds: X—C”X, X=C=X, X2C=X, CX4 (Section 18.3.2.1.6.1)]}, which reacts
with triethylamine to give carbamate 11; this yields diethylamine upon warming in
methanol (Scheme 8).[15,16]
Scheme 8 Reaction of Triethylamine with Phosgene and Acetaldehyde[15,16]

Cl MeOH
O OMe
Et3N heat
MeCHO + COCl2 Et2NH•HCl +
− EtCl Et2N O − CO2 MeO
96%
11
Commercially available 1-chloroethyl chloroformate is widely used as a reagent for the

dealkylation of tertiary amines. The order of cleavage of groups when using this reagent
is generally the following: debenzylation > deamination of cyclohexylamines > demeth-
ylation > de-ethylation. For example, N-cyclohexyl-N-methylbenzylamine will preferen-
tially undergo debenzylation in good yield (>70%) when treated with 1-chloroethyl chlo-
roformate.[17] Methanol has been widely used at 70 8C to decompose the intermediate car-
bamate to yield the desired secondary amine.[18] 1-Chloroethyl chloroformate de-ethylates
1-ethylpiperidine to give piperidine hydrochloride (Scheme 9),[19] but the method can also
be applied to cleave the piperidine ring to produce w-chloroalkylamines.[20]

Scheme 9 De-ethylation of 1-Ethylpiperidine with 1-Chloroethyl Chloroformate[19]
O Cl
Cl O reflux
CH2Cl2, 0 oC 1h
Cl−
+
N N N Cl
Et Et O
O O O
Cl
MeOH, reflux
Cl−
45 min
+
N
H H
99%
1-Chloroethyl chloroformate can also be used to dealkylate 1,1-dimethylpiperidinium

salts, and to cleave methyl 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate (arecoline)
to give the N-demethylated derivative guvacoline in 95% yield, O-acetyltropine to give O-
acetylnortropine in 97% yield, and 6-acetylcodeine to give 6-acetylnorcodeine in 97%
yield.[18,19] A synthesis of 17-(cyclobutylmethyl)-4,5a-epoxymorphinan-3,6a,14-triol (nal-
buphine) from oxycodone has been developed using 1-chloroethyl chloroformate in one
reaction step of a five-step process.[21]
Phenyl chloroformate has been used successfully in conjunction with hydrazine to
secure efficient cleavage of the intermediate carbamate.[22] Chloroformates incorporating
unsaturation such as prop-2-ynyl chloroformate (13) can be used under mild or neutral
reaction conditions and offer better synthetic alternatives for many amine dealkylation
reactions. Prop-2-ynyl chloroformate can be prepared in the laboratory from prop-2-yn-1-
ol and diphosgene.[23] A typical amine dealkylation reaction can be performed at ambient
temperature within 2 hours. This methodology can be successfully applied to piperidi-
nones as well as simple 1-alkylpiperidines 12 (n = 2) and -pyrrolidines 12 (n = 1) to give cy-
clic secondary amines 14 (Scheme 10).[23] Similarly, vinyl chloroformate (15) can be em-
ployed with particular success (Table 1).[24]

Scheme 10 N-Dealkylation of Cyclic Tertiary Amines with Prop-2-ynyl Chloroformate[23]
O
13
Cl O rt, 0.2−2 h or
CHCl3, 0 oC reflux, 0.2−1.5 h
( )n −
+ ( )n Cl
N N − R1Cl
R1 O
R1
O
12
BnNEt3MoS4, MeCN
rt, 1−2.5 h
( )n ( )n
N N
H
O O 14

R1 n Yield (%) Ref
[23]
Me 1 50
[23]
iPr 1 59
[23]
CH2CH=CH2 1 70
[23]
Bn 1 87
[23]
Me 2 49
[23]
iPr 2 60
[23]
Bn 2 83
Table 1 Dealkylation of Cyclic Tertiary Amines Using Vinyl Chloroformate[24]

O
1. 15
Cl O
1,2-dichloroethane
R2
2. hydrolysis H
N N
R1 R3 R1 R2
Starting Material Hydrolysis Conditions Product Yield (%) Ref
[24]
1. HCl, dioxane or CH2Cl2 •HCl 90
N
2. EtOH N
Et H
MeO2C MeO2C
[24]
1. HBr, CH2Cl2 •HBr 90
2. EtOH
N N
Me H
Me H
N N
[24]
1. HCl, CH2Cl2 77
2. EtOH •HCl
OH OH
The use of O-phenyl chlorothioformate (16), which is commercially available {see Science
of Synthesis, Vol. 18 [Four Carbon—Heteroatom Bonds: X—C”X, X=C=X, X2C=X, CX4 (Sec-
tion 18.10.3)]}, is a widely used strategy for the dealkylation of amines.[25] Its reactivity
with tertiary amines is similar to 1-chloroethyl chloroformate and the intermediate dial-
kylthiocarbamates 17 are easily hydrolyzed.
Dealkylation is generally performed in dichloromethane at room temperature
within 1 hour and hydrolysis of the intermediate can be performed with 5 M ethanolic hy-
drochloric acid or with 5 M ethanolic sodium hydroxide (both at 80 8C for 16 hours). Alter-
natively, the thiocarbamates 17 can be cleaved by treatment with dimethyl sulfate fol-
lowed by water. Allylic and benzyl groups are cleaved in preference to methyl groups at-
tached to the same nitrogen atom. Phenyl chlorothioformate will demethylate 4-methyl-
morpholine without ring cleavage. Some examples of amines cleaved with O-phenyl chlo-
rothioformate are given in Table 2.[25]
Table 2 Cleavage of Amines with O-Phenyl Chlorothioformate[25]

S
16
Cl OPh
CH2Cl2 S S
R1 R3

20−45 oC, 1−2 h
N R1 + − R1
N OPh Cl − R3Cl
N OPh
R2 R2 R3 R2
17
Me2SO4
1,2-dichloroethane R1 + R2 H2O H
heat, 2 h N 100 oC, 2 h
MeSO4− R1 N
+
HSO4−
H
MeS OPh R2
Starting Amine Thiocarbamate 17 Yield (%) of 17 Ref
S
[25]
Et3N 93
Et2N OPh
S
[25]
Et2NBn 97
Et2N OPh
O S
[25]
N OPh 73
N O
Me
S
[25]
Ph NMe2
71
Me2N OPh
Cl
[25]
95
N N
PhO S
OPh
S
Me
N
N
32a [25]
OH
OH

Table 2 (cont.)
Starting Amine Thiocarbamate 17 Yield (%) of 17 Ref
OPh
Me S
N
N
[25]
>95
OAc
OAc
S
O
O
N OPh
NMe Me
O
H H O Cl
[25]
O 87

O
O
O O
O O
O
S
[25]
t-BuNMe2 36
Me2N OPh
a
The major product, obtained in >60% yield, is the thiocarbonate formed by condensation
of the chlorothioformate with the free hydroxy group of tropine.
The dealkylation reactions of amines with O-phenyl chlorothioformate have been exten-
sively reviewed.[26] The secondary amine is liberated from the intermediate thiocarbamate
by treatment with dimethyl sulfate; subsequent hydrolysis by refluxing in water gives the
hydrogen sulfate salt of the amine.[25] Chlorinated derivatives of O-phenyl chlorothio-
formate such as O-(4-chlorophenyl) chlorothioformate[27] and O-(2-chloroethyl) chlorothio-
formate[28] have also found application as amine dealkylating agents. The presence of the
chlorine substituents speeds up the hydrolysis reaction of the thiocarbamate intermedi-
ate and also allows reaction of more sterically hindered amines in the alkaloid field.[28]
Tertiary amines containing N-hydroxyethyl groups are selectively dealkylated by
treatment with thionyl chloride in tetrahydrofuran followed by potassium cyanide (in
stoichiometric excess) in tetrahydrofuran/dimethyl sulfoxide.[29]
Secondary Amines 14; General Procedure:[23]

A soln of the tertiary amine 12 (4 mmol) in dry CHCl3 (5 mL) was cooled to –23 8C and prop-
2-ynyl chloroformate (13; 5 mmol) was added dropwise under N2. Once the addition was
finished, the resulting soln was allowed to warm to rt with stirring over about 2 h. The
mixture was then diluted with Et2O (30 mL) and washed with H2O and then with brine.
The organic layer was dried (Na2SO4) to give an ethereal soln of the prop-2-ynyloxycarbon-
yl-protected amine which could be crystallized or purified by chromatography.
Benzyltriethylammonium tetrathioxomolybdate (1.2 equiv, 4.8 mmol) was added to
a soln of the carbamate (4 mmol) in MeCN (5 mL). The mixture was stirred at ambient tem-
perature for 2–2.5 h. The solvent was removed under reduced pressure and the residue
was dissolved in a mixture of CH2Cl2 (3 mL) and Et2O (10 mL). The resulting soln was fil-
tered through Celite and the filtered soln was purified by column chromatography (silica
gel) to give the dealkylated amine in almost quantitative yield.
40.1.1.5.4.1.3 Method 3:
Nitrosative Dealkylation Reactions
In very dilute nitrous acid solution (aqueous or acetic acid), tertiary amines react to form
secondary nitrosoamines with the elimination of an aldehyde or ketone.
In more concentrated nitrous acid the reaction with tertiary amines is very slow, or
may not take place at all.[30] Nitrosoamines can also be formed from the reaction between
tertiary amines and nitrosyl chloride, dinitrogen tetroxide, or nitrosonium tetrafluorobo-
rate. Secondary nitrosoamines are highly carcinogenic and potentially explosive, but they
are easily converted into secondary amines.[31] The reduction of nitrosoamines to amines
is covered in Section 40.1.1.1.5, and their reduction to hydrazines in Section 40.7.1.1.18.
The nitrosative dealkylation of amines is important in biological systems, for exam-
ple in the metabolism of trimethylamine to dimethylamine in rabbits.[32] The reagent in
vivo can be peroxynitrous acid (O=NOOH) which has a pKa of 6.8. The peroxynitrite ion
can be formed from the reaction between nitric oxide and the superoxide anion.[33]

40.1.1.5.4.1.4 Method 4:
Dealkylation by Transamination
Tertiary amines can often be dealkylated in the presence of other less substituted amines
in a formal metathesis reaction (see Houben–Weyl, Vol. 11/1, p 248, and Vol. E 16d, p 1214).
This is most common for methyl and ethyl groups, although other examples are known.
When N,N-dimethylbenzylamine is heated to 200 8C in the presence of 10 mol% ben-
zyltrimethylammonium chloride, a trace of hydrochloric acid, and boron trifluoride, ex-
change takes place to yield N,N-dibenzylmethylamine, in 73% yield, and trimethylamine
(Scheme 11).[34]
Scheme 11 Exchange of Alkyl Groups between a Tertiary Amine and a Quaternary

Ammonium Salt[34]
Me Me
Me Bn + 200 oC +
N + N Bn Cl− Me3N + N Bn Cl−
Me Me
Me Me Bn
Me Me
+ Me Bn + Me Bn
N Bn Cl− + N N Bn Cl− + N
Me Me
Bn Me Me Bn
This type of exchange reaction can be used in cyclization reactions. N4,N4-Diethylpentane-

1,4-diamine cyclizes when heated for 20 hours at 180–185 8C in the presence of its hydro-
chloride salt to give 2-methylpyrrolidine (60% yield) plus diethylamine.[35]
Similarly 1-methyl-4-phenylpiperidine-4-carbonitrile can be prepared in 79% yield
from the cyclization of the hydrochloride salt of 4-(dimethylamino)-2-[2-(dimethylami-
no)ethyl]-2-phenylbutanenitrile at 270–290 8C.[36]
However, generally these transamination reactions work best if the amino group to
be exchanged is in a benzylic position or if Mannich adducts are employed.[37] Thus, termi-
nal diamines with a carbonyl b to an amino group deaminate on heating in morpholine,
for example 3-(dimethylamino)-1-phenylpropan-1-one yields 3-morpholino-1-phenyl-
propan-1-one (78%) and dimethylamine.[38] Gramine {3-[(dimethylamino)methyl]indole}
reacts with piperidine to give a 90% yield of 3-(piperidinomethyl)indole by an elimina-
tion–addition mechanism.[39]
The transformation of a secondary amine 18 into a tertiary amine 21 is achieved by
heating with palladium black, resulting in dehydrogenation to an azomethine 19, fol-
lowed by addition of more precursor amine to give an N,N-acetal 20, and finally amine
elimination (Scheme 12). Alternatively, the intermediate azomethine can be trapped by

another added amine. Thus, N-benzylmethylamine is converted into N,N-dibenzylmethyl-

amine (24% yield) and N-butylmethylamine gives N,N-dibutylmethylamine (ca. 60%
yield).[40,41]
Scheme 12 Generation of a Tertiary Amine from a Secondary Amine[40,41]

Pd/C
120−180 oC R1 NHR2
5−20 h R1 N R1 NHR2
1
R NHR2 R2
R1 N
R2
18 19 20
R1
− R2NH2 R1 N
R2

21
Piperidin-4-one (as its hydrochloride hydrate) can be used as a substitute for ammonia in
the three-component reaction of the amine hydrochloride, an alkyne, and an aldehyde to
give tertiary propargylic amines. On treatment with ammonia or with a polymer-support-
ed scavenger amine, the N-protecting group is easily cleaved to give the primary propar-
gylic amines in good yields (Scheme 13).[42] 1,1,3-Trimethyl-4-oxopiperidinium iodide is
converted into 1-benzyl-3-methylpiperidin-4-one in 66% yield by stirring with aqueous
benzylamine for 12–15 hours.[43] The 1-benzylpiperidinone is readily debenzylated with
hydrogen using palladium/carbon in methanol. The synthetic applications of piperidin-
4-ones, including cleavage reactions, have been reviewed.[44]
Scheme 13 Asymmetric Copper-Catalyzed Synthesis of Propargylic Amines[42]
HO OH R2 O
CuBr (cat.), (R,R)-PINAP (cat.)
Et3N, 4-Å molecular sieves, CH2Cl2
R1CHO + Cl−
+ 58−88%; 83−96% ee
N N
H H
R1
R2
A: NH2, NH4Cl, EtOH, 100 oC
then HCl, MeOH NH2•HCl

B: NH3
A: 71−91% R1
R2
HN Ph
N
N
(R,R)-PINAP =
PPh2
R1 = alkyl, 2-furyl; R2 = Ph, TMS, (CH2)2Ph
In the presence of Raney nickel, alkylamines can undergo transamination reactions.

Thus, ethane-1,2-diamine (22) reacts with Raney nickel on heating to 150 8C to give first
N-(2-aminoethyl)ethane-1,2-diamine (23) followed by cyclization to piperazine (24) in 73%

yield (Scheme 14).[45]
Scheme 14 Synthesis of Piperazine from Ethane-1,2-diamine[45]

NH2 H
N
Ni Ni
NH2 HN
H2N − NH3 − NH3
N
NH2 H
22 23 24 73%
In a more general approach, terminal diamines linked by linear alkyl chains can undergo
cyclization reactions when heated with catalysts such as dichlorotris(triphenylphos-
phine)ruthenium(II) in diphenyl ether.[46] The reaction takes 5 hours at 180 8C and gives
good yields of pyrrolidine, piperidine, or hexahydro-1H-azepine (Scheme 15).[46]

Scheme 15 Synthesis of Cyclic Amines by Ruthenium-Catalyzed Transamination[46]
RuCl2(PPh3)3
Ph2O, 180 oC, 5 h ()
H2N () NH2 n
n
− NH3
N
n = 2 81% H
n = 3 90%
n = 4 78%
40.1.1.5.4.1.5 Method 5:
Acid-Mediated Dealkylation
The N-(triphenylmethyl) (N-trityl) residue and the related N-(9-phenyl-9H-fluoren-9-yl)

group are easily removed from amines by treatment with dilute acid making them conve-
nient protective groups for the amine function.[47] In a synthetic application, alkylamine
hydrochlorides 26 can be easily prepared in high yields from the reaction of alkyl halides
with tritylamine to give alkyl(trityl)amines 25, from which the trityl group is removed us-
ing trifluoroacetic acid in dichloromethane (Scheme 16).[48]
Scheme 16 Synthesis of Primary Amines via the Alkylation of Tritylamine Followed by

Cleavage of the Trityl Group[48]
1. TFA, CH2Cl2, rt
R1X H 2. HCl, MeOH, rt
TrNH2 N R1NH2•HCl
− TrNH2•HX Tr R1 − TrOMe
25 26
R1X Ratio (TrNH2/R1X) Conditions Yield (%) of 25 Ref
[48]
MeI 1:5 MeCN, 1 d, rt 90
[48]
Bu 1:10 MeCN, 10 d, rt 88
[48]
HC”CCH2Br 1:5 MeCN, 3 d, rt 90
[48]
Me(CH2)6OTs 1:2 Et3N, toluene, 10 h, reflux 80
Cl
( )2 2:1 MeCN, 2 h, 40 8Ca 90 [48]
[48]
BnBr 2:1 MeCN, 1 d, rt 90
[48]
Me(CH2)OTs 1:2 Et3N, toluene, 12 h, reflux, 78
a
KBr/acetone added to the reaction to allow halogen exchange in situ.

Primary Amines 26; General Procedure:[48]

The haloalkane (1–10 mmol) was added to a soln of TrNH2 (259 mg, 1 mmol) in MeCN
(5 mL). The resulting soln was then left at rt or refluxed as required. The precipitated
tritylamine hydrohalide was removed by filtration and the substituted tritylamine 25
was recovered by concentration of the filtrate under reduced pressure, followed by recrys-
tallization (EtOH) or column chromatography (Et2O/petroleum ether); yield: 70–90%.
The alkyl(trityl)amine 25 (1 mmol) was added to a 60% soln of TFA in CH2Cl2 (5 mL)
and stirred for 10 min at rt. MeOH (2 mL) was added at which point the yellow coloration
disappeared. The mixture was then left to stir for a further 1 h. The solvent was removed
under reduced pressure and 1 M HCl in MeOH (10 mL, 10 mmol) was added to precipitate
the amine as a hydrochloride salt. The soln was then concentrated to dryness under re-
duced pressure and the recovered primary alkylamine hydrochloride salt was washed
with anhyd Et2O and dried in a vacuum desiccator.
40.1.1.5.4.1.6 Method 6:

Photolytic Dealkylation
Direct homolytic cleavage of the C—N bond of a primary amine is energetically unfavor-
able (the energy needed for unimolecular cleavage of the C—N bond in methylamine is
59.8 kcal•mol–1).[49] For photolytic cleavage, use of a photoinitiator is required. Thus, ter-
tiary N-methylalkaloids can be demethylated to secondary amines by photooxidation in
the presence of the photosensitizer 2,7-dimethylbenzo[lmn][3,8]phenanthrolinediium
bis(tetrafluoroborate) [N,N¢-dimethyl-2,7-diazapyrenium bis(tetrafluoroborate)].[50] Co-
deine can be demethylated by singlet oxygen to give N-norcodeine in 75% yield.[51]
40.1.1.5.4.1.7 Method 7:
Cleavage of the C—N Bond Using Selenols
The relatively high acidity and strong nucleophilicity of selenols is the basis for an effi-
cient dealkylation of secondary and tertiary alkylamines (Table 3). In fact, benzeneselenol
will protonate amines and the resulting ammonium selenolate intermediates are then de-
alkylated in an SN2 process.[52] The reaction requires 150 8C and demethylation is the pre-
ferred reaction, followed by de-ethylation. Primary amines are dealkylated most slowly
and hindered tertiary amines most rapidly. In this procedure, the dealkylated amines
are isolated as their hydrochloride salts, e.g. 27.
Table 3 Dealkylation of Amines by Pyrolysis with Benzeneselenol[52]
Entry Starting Material Conditions Product Yield (%) Ref
Cl− [52]
1 1. PhSeH (2 equiv), 150 8C, 23 h + 28
N 2. HCl(g) N
Me H H
Cl− [52]
2 1. PhSeH (2 equiv), 150 8C, 23 h + 80
N 2. HCl(g) N
Me H H
Cl− [52]
3 1. PhSeH (2 equiv), 150 8C, 3 h + 100
N
N 2. HCl(g)
Me H H
Table 3 (cont.)
Entry Starting Material Conditions Product Yield (%) Ref
H +H
Me N
N
4 1. PhSeH (1.6 equiv), 150 8C, 48 h Cl− 89 [52]
2. HCl(g)
27
[52]
5 CyMeNH 1. PhSeH (3 equiv), 150 8C, 60 h CyNH2•HCl 97
2. HCl(g)
[52]
6 iPr2NEt 1. PhSeH (2.5 equiv), 96 h iPr2NH•HCl 85
2. HCl(g)
7 pyrrolidine 1. PhSeH (0.1 equiv), 150 8C, 72 h PhSe NH2•HCl 70a [52]
( )4
2. HCl(g)

a
Yield based on PhSeH.
9-Azabicyclo[3.3.1]nonane Hydrochloride (27): Typical Procedure:[52]

9-Methyl-9-azabicyclo[3.3.1]nonane (1.34 g, 9.6 mmol) and PhSeH (1.96 mL, 16 mmol) were
mixed, sealed in a thick-walled tube under N2, and heated at 150 8C for 48 h. After being
cooled, the contents of the tube were poured into Et2O (100 mL). HCl(g) was bubbled
through the soln under anhydrous conditions and a thick white precipitate formed. N2
was bubbled through the mixture for 10 min to remove excess HCl, and then the precip-
itate was collected by suction filtration and dried under high vacuum to give an off-white
powder; yield: 1.37 g (89%).
40.1.1.5.4.1.8 Method 8:
Cleavage of the C—N Bond Using Wilkinson0s Catalyst
In the protective-group chemistry of primary amines, an acid- and base-resistant unit that
is also inert to common nucleophiles is the N,N-diallyl moiety. Thus, a primary amine is
diallylated using excess allyl bromide in the presence of N,N-diisopropylethylamine (HM-
nigNs base). The allyl groups are removed under mild conditions by treatment with chlo-
rotris(triphenylphosphine)rhodium(I) (WilkinsonNs catalyst).[53] When 1-adamantyldiallyl-
amine (28) is refluxed with the rhodium catalyst for 2 hours under nitrogen in acetoni-
trile/water (84:16) with constant removal of solvent, 1-adamantylamine (29) is obtained
in 65% yield (Scheme 17).[53]
Scheme 17 Deallylation of 1-Adamantyldiallylamine[53]
N RhCl(PPh3)3 NH2
MeCN, H2O
reflux
65%
28 29
1-Adamantylamine (29); Typical Procedure:[53]

A mixture of 1-adamantyldiallylamine (28; 250 mg, 1.08 mmol) and RhCl(PPh3)3 (53 mg,
0.05 mmol) in MeCN/H2O (84:16; 25 mL) was prepared in a 50-mL round-bottomed flask
with a magnetic stirrer. A Claisen adapter fitted with a reflux condenser and an addition
funnel on one arm and with a short-path distillation head on the other was then attached

to the reaction vessel. The addition funnel was charged with excess MeCN/H2O (84:16) and
the system was flushed with N2 and brought to a vigorous boil. Fresh solvent was added to
replace the volume of liquid swept out of the distillation head and into a cooled (–70 8C)
receiver by a slow stream of N2. After 2 h, the reaction was judged complete by TLC, and
the solvents were removed under reduced pressure to leave a brownish solid (250 mg).
Flash chromatography (MeOH/CHCl3 1:1 to MeOH/NH4OH 95:5) furnished the amine after
concentration and drying under reduced pressure; yield: 106 mg (65%, as reported).
40.1.1.5.4.1.9 Method 9:
Reductive Cleavage of the C—N Bond
The C—N bond is fairly stable toward reductive cleavage. However, in tertiary benzyl-
amines debenzylation can be achieved by catalytic hydrogenation (Scheme 18).[54,55]
Scheme 18 Palladium-Catalyzed Debenzylation of Amines Using Hydrogen[54,55]

H2, Pd/C
EtOH or toluene
R 1
Bn 20−60 oC H
N N
− toluene R1 R2
R2
Instead of hydrogen, hydrazine in ethanol,[56] ammonium formate in the presence of a

trace of palladium catalyst (Scheme 19),[56,57] or cyclohexene[58] are also used to prepare
amines 31 from benzylamines 30.
Scheme 19 Palladium-Catalyzed Debenzylation of Amines Using Ammonium Formate[57]

HCO2NH4, Pd/C
R1 Bn MeOH, reflux, 10 min H
N N
R1 = (CH2)2Ph; R2 = H 90% R1 R2
R2 R1 = (CH2)2OH; R2 = H 86%
30 R1 = (CH2)2OH; R2 = Me 83% 31
R1 = (CH2)3OH; R2 = H 95%
R1 = Ph; R2 = H 76%
In a more recent method, amides (e.g., 32) can be reacted with borane to give air-stable,
usually crystalline, borane-complexed benzylamines (e.g., 33), which can be debenzylated
by palladium or Raney nickel catalyzed methanolysis (e.g., to give 34, Scheme 20). This
method works well for primary, secondary, and tertiary amines and is tolerant of a wide
range of functional groups.[59]
Scheme 20 Methanolysis of a Benzylic Borane–Amine Complex[59]
BH3•THF Pd/C
O O O O O O
THF, 0 oC to rt MeOH, rt, 12 h
83% 94%
O O +
N N − N
Bn Bn BH3 H
32 33 34
Primary or Secondary Amines 31; General Procedure:[57]

To a stirred suspension of the benzylamine 30 (3 mmol) and an equal mass of Pd/C in
anhyd MeOH (20 mL) under N2 was added HCO2NH4 (0.946 g, 15 mmol) in one portion.
The mixture was refluxed for 10 min (longer when R1 = Ph; R2 = H) and monitored by
TLC. When complete, the mixture was filtered through Celite and the Celite was washed
with CHCl3 (20 mL). Removal of the solvent gave the debenzylated amine.
cis-2,2-Dimethyltetrahydro-4H-1,3-dioxolo[4,5-c]pyrrole (34):[59]
To an ice-cold soln of cis-5-benzyl-2,2-dimethyldihydro-4H-1,3-dioxolo[4,5-c]pyrrole-
4,6(5H)-dione (32; 6.53 g, 25.0 mmol) in anhyd THF (25 mL) was added 1 M BH3•THF
(87.5 mL, 87.5 mmol). The resulting mixture was allowed to warm to rt and further stirred
for 2.5 h. The reaction was carefully quenched with MeOH (25 mL) and concentrated to
dryness. The residual crystalline material was then slurried in EtOAc/hexane (1:1;
20 mL), cooled to 0 8C, and filtered to give the borane–amine complex 33 as a white, crys-
talline solid; yield: 5.01 g (83%).
To a suspension of 10% Pd/C (600 mg, 50% wet) in MeOH (15 mL) was added a soln of
the borane–amine complex 33 (3.0 g, 12.0 mmol) in MeOH (15 mL). The reaction vessel
was immediately sealed and the mixture was stirred at rt for 12 h. The mixture was fil-
tered through cotton and carefully concentrated under reduced pressure (200 Torr). The
residue was then purified by flash chromatography (MeOH/CH2Cl2 1:1) to give a pale yel-
low oil; yield: 1.63 g (94%).

40.1.1.5.4.2 Dealkylation Reactions of Ammonium Salts
The selective dequaternization of tetraalkylammonium salts provides a convenient route

to tertiary amines. The methods include three named reactions; the Hofmann elimina-
tion, the Emde reaction, and the Stevens rearrangement. However, the Stevens rearrange-
ment is covered in Section 40.1.1.4.1.1.
40.1.1.5.4.2.1 Method 1:
Thermolytic Dealkylation
Ammonium salts are generally thermally labile and can be cleaved by heating. The gener-
al order of decreasing tendency of cleavage is: allyl > benzyl > methyl > ethyl > propyl >
butyl > phenyl.[60]
A typical example is the demethylation of 1,4-dimethyl-1,4-diazoniabicyclo[2.2.2]oc-
tane dibromide to give the demethylated product (Scheme 21).[61]
Scheme 21 Thermolysis of an Ammonium Salt[61]

Me heat
N Br + Me
Br N high vacuum N
+ 2Br−
N − 2MeBr N
N
Me Me
40.1.1.5.4.2.2 Method 2:
The Hofmann Elimination Reaction
In contrast to ammonium halides, tetraalkylammonium hydroxides show two pathways

of thermal degradation. If no alkyl substituent with a b-hydrogen is present, the hydrox-
ide anion undergoes nucleophilic attack on the carbon of an alkyl residue to give an alka-
nol and a tertiary amine, e.g. formation of methanol and trimethylamine from tetrameth-
ylammonium hydroxide (see Houben–Weyl, Vol. 11/1, p 963). However, if a b-hydrogen is
available, elimination of an alkene along with a tertiary amine is a competing process.
Normally, mixtures of alkenes and alkanols are formed (Scheme 22).[62,63]

Scheme 22 Dual Pathways in the Decomposition of Quaternary Ammonium Hydroxides[63]

R3 R4
R1 + MeOH
NMe2
2
R
R3 R4
R1 +
NMe3 OH−
R2
R1 R3
+ Me3N + H2O
R2 R4
The Hofmann elimination reaction (which is sometimes referred to as the Hofmann ex-
haustive methylation) specifically involves the reaction of alkylated trimethylamines
and proceeds with anti stereochemistry, though partial syn elimination has been ob-
served.[64] It is generally suitable for producing alkenes with one or two substituents. An
amine is reacted with excess iodomethane, followed by heating with silver(I) oxide and

water to create a tertiary amine and an alkene via a quaternary ammonium hydroxide
[see Science of Synthesis, Vol. 47 (Alkenes), and also Houben–Weyl, Vol. 11/1, p 963]. From di-
alkyldimethylammonium hydroxides with two different alkyl substituents the alkene
group eliminated is the least substituted and generally the least stable. From alkyltri-
methylammonium salts having an alkyl residue of at least four carbon atoms, the alkene
with the terminal double bond is formed; this observation is known as the Hofmann
rule.[65] This regioselectivity is due to loss of the more acidic terminal b-hydrogen giving
the product alkene with the terminal double bond. This is in direct contrast to normal
elimination reactions where the most substituted and most stable product is dominant
(ZaitsevNs rule). Methylation of sec-butylamine with iodomethane, followed by treatment
with silver(I) oxide gives but-1-ene along with trimethylamine (Scheme 23).[66]
Scheme 23 Regioselective Formation of But-1-ene by Hofmann Elimination Reaction[66]

1. MeI
NH2 2. Ag2O, H2O, heat
+ Me3N
60%
The Hofmann degradation reaction is very sensitive to reaction conditions and experi-
mental yields can vary, as shown in Scheme 24.[60,63]
Scheme 24 Alkyldimethylamines from the Thermal Decomposition of

Alkyltrimethylammonium Hydroxides[60,63]
+ pyrolysis
R1NMe3 OH− R1NMe2
− MeOH
R1 Yield (%) Ref
[63]
Bu 21
[60]
Bu 50
[63]
(CH2)4Me 23
[60]
(CH2)4Me 60
[63]
(CH2)5Me 24
[60]
(CH2)5Me 73
[63]
(CH2)6Me 26
[60]
(CH2)6Me 75
[63]
(CH2)7Me 25
[60]
(CH2)7Me 75
The differences could be due to the presence or absence of atmospheric carbon dioxide.[67]
Thus, the yield of decyldimethylamine from decyltrimethylammonium hydroxide is 30%
in the absence of carbon dioxide and 72% in the presence of atmospheric carbon diox-
ide.[67] Moreover, the use of glycerol as solvent favors alkanol formation, whereas addition
of potassium hydroxide favors the Hofmann elimination pathway.[67] Temperature also af-
fects the reaction rate. Yields of N,N,3,3-tetramethylbutan-2-amine (35) from N,N,N,3,3-
pentamethylbutan-2-ylammonium hydroxide (with concomitant elimination of meth-
anol) are 52% at 100–160 8C and 0% at 30 8C, when only alkene formation (via elimination
of trimethylamine and water) is observed (Scheme 25).[68]
Scheme 25 Temperature-Dependent Decomposition of N,N,N,3,3-Pentamethylbutan-2-

ylammonium Hydroxide[68]
30 oC
− Me3N But
− H2O
+ 100%
NMe3

OH−
But
NMe2
100−160 oC
+ But
− MeOH But
− Me3N
− H2O 35 52% 48%
If the Hofmann degradation pathway predominates, the reaction is of no interest for

amine synthesis. However, this is different for the degradation of cyclic structures where
w-(dialkylamino)alk-1-enes are formed (see Houben–Weyl, Vol. 11/1, p 964).[69] An illustra-
tive example is the formation of N,N-dimethylcycloocta-2,4-dien-1-amine (37) from the
ammonium iodide 36, which in turn is obtained from 9-methyl-9-azabicyclo[3.3.1]non-2-
ene (N-methylgranatenine) via methylation with iodomethane (Scheme 26).[70]
Scheme 26 Anion Exchange, and Thermal Decomposition in the Synthesis of

N,N-Dimethylcycloocta-2,4-dien-1-amine[70]
Me2N
Me Ag2O, H2O Me
+N Me I− +N Me OH−
96% 83%
36 37
N,N,3,3-Tetramethylbutan-2-amine (35); Typical Procedure:[68]

N,N,N,3,3-Pentamethylbutan-2-ylammonium iodide (84 g, 0.31 mol) was treated with ex-
cess Ag2O in H2O to form the quaternary hydroxide. After the reaction was complete, the
precipitated AgI was removed by filtration and the filtered soln was concentrated under a
N2 stream at atmospheric pressure. After most of the H2O had been removed by distilla-
tion, the ammonium hydroxide began to decompose and the temperature rose to around
160 8C. The tertiary amines were recovered in a cold trap filled with 6 M HCl in an ice bath.
The alkene product (8 g) was collected in a trap at –78 8C. After the reaction was complete,
the HCl soln was heated to boiling point to remove any unwanted organic impurities
(MeOH) and then neutralized with NaOH soln and fractionally distilled. Me3N (7 g) was re-
covered first followed by the less volatile N,N,3,3-tetramethylbutan-2-amine, which was
recovered as the picrate salt; yield: 17 g (42%, as reported).

Dimethylcycloocta-2,4-dien-1-amine (37):[70]
CAUTION: Inhalation, ingestion, or skin absorption of iodomethane can be fatal.
9-Methyl-9-azabicyclo[3.3.1]non-2-ene (50.3 g, 367 mmol), MeI (78 g, 550 mmol), and cyclo-
hexane (500 mL) were placed in a 1-L flask attached to a reflux condenser and heated to
40 8C for 3 h. After addition of further MeI (5 g, 35 mmol), the mixture was heated at
40 8C for another 2 h. Filtration separated a white, crystalline salt (96.5 g). The filtrate
was warmed with MeI (10 g, 70 mmol) at 40 8C for 3 h and additional ammonium iodide
(2 g) was obtained by filtration; yield: 98.5 g (96%).
Ag2O was prepared by adding a soln of NaOH (28.3 g, 708 mmol) in H2O (150 mL) to
AgNO3 (120 g, 706 mmol) in H2O (400 mL). The precipitate was washed until free from al-
kali and added to a mixture of the ammonium iodide 36 (98.5 g, 0.353 mol) and H2O
(400 mL) in a 1-L flask. After mechanical stirring and heating at 60 8C for 1 h, the mixture
was filtered, the residue of AgI and Ag2O mixture was washed with H2O and then heated
with H2O (100 mL) at 60–70 8C with intermittent shaking for 15 min. After filtering again,

the combined filtrates were concentrated under reduced pressure. Foaming could be sup-
pressed by adding a drop of silicone defoamer. The concentrate was transferred to a 250-
mL Claisen flask attached to a well-cooled receiver, and the quaternary base was decom-
posed (with some foaming) by heating in a bath (100–110 8C/15–20 Torr). The upper parts
of the flask were rinsed with H2O (10 mL) to dissolve any remaining quaternary base, and
the soln was again distilled to dryness in the same manner. The colorless oil was separat-
ed from the H2O in the distillate by extraction with portions of Et2O (50 mL and 100 mL).
The Et2O extracts were dried (MgSO4) and distilled through a column (20 cm F 1.2 cm)
packed with glass helices; yield: 44.3 g (83%); bp 80 8C/12 Torr.
40.1.1.5.4.2.3 Method 3:
Dealkylation with Ammonia, Amines, 2-Aminoethanol, or Other Bases
Generally, when a quaternary ammonium salt is heated with another amine of sufficient
nucleophilicity N-dealkylation takes place. Thus, heating alkyltrimethylammonium io-
dides in a 10- to 15-fold molar excess of 2-aminoethanol at 154 8C gives alkyldimethyl-
amines along with alkene elimination products.[71] This reaction is synthetically useful
for monodealkylation of cyclic 1,1-dialkylpiperidinium or 1,1-dimethylhexahydro-1H-
azepinium salts (Scheme 27), but ring opening can compete in the case of pyrrolidinium
salts. In any case, demethylation is particularly fast so that potentially an N-methyl group
can be substituted by a higher alkyl chain in a sequence of N-alkylation and demethyl-
ation.[72] A drawback of the use of 2-aminoethanol is the possible cleavage of methoxy
groups and of ester groups.[73]
Scheme 27 Dealkylation of Cyclic Ammonium Salts with 2-Aminoethanol[72]
OH
() 1. EtI, EtOH () H2N ()
n 2. EtOAc n n
I−
reflux
88−95% + − MeI
N N 90−97% N
Me Me Et Et
n = 1, 2
In general, when a quaternary ammonium salt is heated with a secondary amine the prod-
ucts are two tertiary amines. When benzyltrimethylammonium bromide is heated with
benzylamine the products are trimethylamine and dibenzylamine, with 90% conversion
(Scheme 28).[74] When isoindolinium bromide 38 is heated with ammonia or diethylamine
at 200 8C the ring opens at the spiro nitrogen to yield 1-[2-(aminomethyl)benzyl]- or 1-{2-
[(diethylamino)methyl]benzyl}piperidine.[75,76] Similarly, trimethyl(2-furylmethyl)ammo-
nium iodide and piperidine react to give 1-(2-furylmethyl)piperidine (39).[77]
Scheme 28 Reaction of Amines with Ammonium Salts[74–77]

+ reflux
Me3NBn Br− + BnNH2 Me3N + Bn2NH
− HBr
90%
NR12
A: NH3
+ − B: Et2NH N
N Br
A: R1 = H
B: R1 = Et
38
+
O NMe3
reflux, 3 h
I− + N
48%
N O
H

39
1-(2-Furylmethyl)piperidine (39); Typical Procedure:[77]

A mixture of (2-furylmethyl)trimethylammonium iodide (13.35 g, 50 mmol) and piperi-
dine (50 mL, 506 mmol) was gently refluxed for 3 h. After this time, the mixture was
stirred to homogeneity, and simmered to remove any evolved trimethylamine. From the
cooled mixture crystals separated, which were presumably piperidinium iodide. The mix-
ture was then made alkaline by addition of NaOH (5 g, 125 mmol) in H2O (800 mL) and ex-
tracted with Et2O (3 F 250 mL). The ethereal washings were combined and dried (KOH) and
the dried ethereal soln was fractionally distilled; yield 4.0 g (48%); bp 93–94 8C/11 Torr.
40.1.1.5.4.2.4 Method 4:
Dealkylation Reactions with Alkali Metals or Metal Hydrides
Quaternary ammonium halides with benzyl or 3-phenylprop-2-enyl (cinnamyl) residues

can be reductively cleaved using sodium amalgam in aqueous or aqueous/alcoholic solu-
tion to yield a tertiary amine and a hydrocarbon (toluene and prop-1-enylbenzene, respec-
tively). This is known as the Emde reaction. A typical example of the Emde cleavage is re-
duction of trimethyl(3-phenylprop-2-enyl)ammonium chloride to yield trimethylamine
and prop-1-enylbenzene.[78] Dibenzyl(methyl)amine is converted into allyl(benzyl)methyl-
amine by allylation to the ammonium iodide and subsequent reduction by sodium amal-
gam (Scheme 29).[79] The Emde reaction is not widely used in its original form, with the
possible exception of alkaloid degradation reactions, but can in certain cases nicely com-
plement the Hofmann degradation method.[80]
Scheme 29 Amines by Quaternization and Debenzylation with Sodium Amalgam[79]

1. I
1. PrI
2. Na/Hg, EtOH, H2O 2. Na/Hg, EtOH, H2O
Bn2NMe MeBnN MePrN
The original process discovered by Emde is not applicable to ammonium salts containing
four saturated alkyl groups. However, use of sodium or potassium in liquid ammonia has
enabled the use of the reaction to be extended.[81] Tetraethylammonium halides, when
treated with sodium in liquid ammonia, generate a mixture of ethane and ethene togeth-
er with triethylamine.[81] The ethene arises from a Hofmann-type elimination with amide
ions formed in situ between the sodium and ammonia. The order of cleavage of alkyl

groups in sodium/liquid ammonia is the following: tert-butyl >> methyl > sec-butyl > iso-
propyl > propyl > butyl » ethyl.[81]
Generally, yields for demethylation are in the high 90% range with the yield drop-
ping to 50–60% for the more difficult alkyl substituents. The alkyl cleavage reaction of tet-
raalkylammonium salts can also be achieved using a solution of sodium metal in dioxane.
The presence of sodium alkoxides formed in the reaction solution causes a Hofmann
elimination type reaction to take place.[82]
A variation on the Emde reaction is to use lithium aluminum hydride as a reductant,
especially for alkyltrimethylammonium iodides (methiodides) to give alkyldimethyl-
amines such as 40 (Scheme 30).[83–85] However, N-demethylation conditions involving the
use of lithium aluminum hydride in a refluxing high-boiling solvent such as tetrahydro-
furan or dioxane usually fail when one or more phenolic groups are present.[86]
Scheme 30 Demethylation of an Ammonium Salt Using Lithium Aluminum Hydride[85]

LiAlH4, THF
But But

+ − reflux, 96 h
NMe3 I 88% NMe2
But But
40
Instead of lithium aluminum hydride, lithium tri-sec-butylborohydride (L-Selectride) can

be applied to the reductive demethylation of alkyltrimethylammonium salts to give ter-
tiary amines (Scheme 31).[87]
Scheme 31 Demethylation of Ammonium Salts Using L-Selectride[87]

L-Selectride, toluene, THF
+ 20−65 oC, 15−120 h
R1NMe3 X− R1NMe2
R1 = (CH2)11Me; X = Br 92%
R1 = Cy; X = I 90%
R1 = ; X = I 84%
()
N O 2
2-tert-Butyl-N,N,3,3-tetramethylbutylamine (40); Typical Procedure:[85]
CAUTION: Solid lithium aluminum hydride reacts vigorously with a variety of substances, and
can ignite on rubbing or vigorous grinding.
LiAlH4 (17.4 g, 0.46 mol) was added to a soln of 2-tert-butyl-N,N,N,3,3-pentamethylbutyl-
ammonium iodide (25.1 g, 76 mmol) in THF (450 mL) in a three-necked 1-L flask under
N2. The soln was then refluxed under N2 for 96 h. Then the flask was cooled in an ice
bath and 15% aq NaOH (35.6 mL) was slowly added dropwise. Following this addition,
30% aq KOH (71.5 mL) was added. The mixture was steam distilled until the steam distil-
late tested neutral (the distillate volume was around 2.75 L). The distillate was then acidi-
fied with concd HCl (20 mL) and then concentrated to dryness under reduced pressure.
The residue after concentration was then dissolved in H2O (75 mL) and made basic by the
addition of cold 50% aq NaOH (80 mL). The resulting soln was extracted with Et2O (4 F
50 mL) followed by pentane (1 F 50 mL). The organic extracts were dried (KOH pellets)
overnight, filtered, and purified by fractional distillation; yield: 12.5 g (88%).
40.1.1.5.4.2.5 Method 5:
Dealkylation Reactions Using Sulfur Nucleophiles
Quaternary ammonium salts can be cleaved by SN2-type attack of a sulfur nucleophile on

one alkyl residue to give a tertiary amine, which acts as leaving group (Scheme 32).
Scheme 32 Alkylation/Demethylation of Cyclic Amines

1
R1X + R Nu−
N Me N X− N R1 + NuMe
Me − X−
This method can often be applied under mild conditions and is therefore particularly use-
ful for the dealkylation of sensitive alkaloid substrates such as morphine (42, R1 = H), co-
deine (42, R1 = Me), and thebaine (44), to give products 43 and 45, as well as for the syn-
thesis of simple 1-alkylpiperidines 41 (Scheme 33).[88] Moreover, the reaction usually pro-
ceeds without affecting methoxy groups and without cleavage of alkyl esters. An impor-
tant point is the group selectivity of dealkylation. Usually, the rough order of decreasing
ease of removal of groups is the following: benzyl » allyl > methyl » isopropyl > ethyl >
propyl.[73,88,89]
Scheme 33 Synthesis of 1-Alkylpiperidines by Alkylation–Demethylation[88]

PhSNa
R1X, CHCl3 MeCN/MEK
reflux, 5−6 h reflux, 24−26 h
X−
quant + − PhSMe
N N − NaX N1
Me Me R1 R1 = Pr; X = Br 75%
R
R1 = iPr; X = I 45% 41
R1 = Bu; X = I 70%
MeN OH R2N OH
1. R2X, CHCl3, reflux, 48−96 h
2. PhSNa, MeCN/MEK, 5−6 h
O 33−54% O
OR1 OR1
42 43
R1 = H, Me; R2 = Pr, iPr, Bu; X = Br, I
MeN OMe R1N OMe

1. R1I, CHCl3, reflux, 12 h
2. PhSNa, MeCN/MEK, 6−8 h
O O
R1 = Pr 67%
R1 = iPr 38%
R1 = Bu 67%
OMe OMe
44 45
Specific sulfur-based reagents include sodium benzenethiolate in methyl ethyl ketone,

methyl ethyl ketone/acetonitrile, or hexamethylphosphoric triamide;[86,88] copper(I) ben-
zenethiolate in pyridine;[73] lithium propane-1-thiolate in hexamethylphosphorous tri-
amide;[90,91] and sodium sulfide in tetrahydrothiophene 1,1-dioxide (sulfolane).[89] The
last-mentioned reagent allows an elegant one-pot dealkylation reaction that is used to de-
methylate dihydrolysergol, dextromethorphan, and laudanosine. The experimental pro-
cedure involves the dealkylation of quaternary amines (made in situ from the parent
amine and an alkyl halide) using sodium sulfide (for 46 or 48) or potassium thioacetate
(for 47 or 48) in sulfolane solution buffered with a catalytic quantity of potassium phos-
phate (Scheme 34). Yields of the products (e.g., 49) depend on the combination of alkyl
group, starting alkaloid, and sulfur nucleophile and the major side products are ring-
opened derivatives (e.g., 50), formed by a Hofmann elimination step. When benzyl bro-
mide or allyl bromide are employed for the alkylation, starting material is recovered after
treatment with the sulfur nucleophile. The use of sodium methanethiolate for the deal-
kylation of 47 leads predominantly to the Hofmann elimination products.[89]
Scheme 34 Alkylation–Demethylation of Alkaloids[89]

OH
MeO
H
NMe H
H NMe
HN
46 47
R1I, K3PO4
MeO O MeO
S + 1
NMe O N R
MeO 110 oC, 2 h MeO
Me X−
MeO MeO

MeO MeO
48
MeO MeO
A: Na2S•9H2O, 120 oC, 5 h 1

NR1 N R
B: AcSK, 120 oC, 6 h MeO MeO
+ Me
MeO OMe
MeO OMe
49 A: R1 = Et 58% 50
A: R1 = Pr 55%
A: R1 = (CH2)7Me 65%
B: R1 = Et 78%
B: R1 = Pr 82%
B: R1 = (CH2)7Me 84%
Synthetically, the main interest in sulfur-induced demethylation is in overall replace-

ment of a methyl by a higher alkyl group.[88]
Debenzylation and deallylation of N-benzyl- or N-allyl-containing ammonium salts is
also achieved by reaction with benzenethiol in aqueous sodium hydroxide.[92]
1-Alkylpiperidines 41, 43, and 45; General Procedure:[88]

A mixture of the quaternary compound (0.6 mmol), PhSNa (0.238 g, 1.8 mmol), and meth-
yl ethyl ketone/MeCN (1:1; 20 mL) was refluxed with stirring under dry N2 for 6–24 h. The
solvent was removed under reduced pressure and H2O (15 mL) was added. The product
was extracted with CHCl3 (3 F 150 mL) and with MeOH/CHCl3 (5:95; 150 mL). After evapo-
ration of the solvent, the product was purified by TLC (silica gel, EtOAc/MeOH/aq NH3
85:15:1 or 85:15:7, or EtOAc/aq NH3 100:0.3, or neutral alumina, CHCl3/MeOH). The 1-al-
kylpiperidines were purified by extraction with 10% HCl and liberating the amine with
50% aq NaOH.
2-Alkyl-1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines
49; General Procedure:[89]
The haloalkane (1.25 mmol) was added to a soln of the starting tertiary amine 48 (1 mmol)
in sulfolane (80 mL) containing K3PO4•3H2O (27 mg, 0.1 mmol) and the soln was heated at
110 8C for 2 h. Reaction completion was tested by TLC and when completion was attained,
Na2S•9H2O (240 mg, 1 mmol) was added and the mixture was heated at 120 8C for 5 h. The
mixture was poured onto ice-cold H2O (10 mL) and back-extracted with EtOAc. The organ-
ic layer was washed with H2O, dried (Na2SO4), and concentrated under reduced pressure.
Final purification by chromatography gave the N-demethylated alkaloids. In the demeth-

ylation step, Na2S•9H2O could be replaced by AcSK (9 mmol) with heating at 120 8C for 6 h.
40.1.1.5.4.2.6 Method 6:
Electrolytic Methods of Cleavage
The main feature of the electrolytic reductive cleavage of ammonium salts is the pre-
ferred removal of phenyl residues as benzene, thus allowing removal of a residue that is
difficult to remove by other methods. Yields for such reactions are up to 77%. Aqueous so-
lutions of trialkyl(aryl)ammonium iodides or tetraalkylammonium iodides are used in
electrochemical cells with lead cathodes to obtain trialkylamines as shown in Scheme
35.[93] The electrochemistry of ammonium salts has been reviewed.[94]
Scheme 35 Electrolytic Cleavage of Trialkyl(aryl)ammonium Iodides[93]

Me electrolysis (9.4 A)

R1 1 M H2SO4 Me
N+ I− N + PhH + HI
Ph R1 = R2 = Me 77% R1 R2
R2 R1 = Me; R2 = Et 69%
R1 = R2 = Et 68%
R1 = Et; R2 = Pr 47%
40.1.1.5.4.3 Replacement of Halogen Functionalities
40.1.1.5.4.3.1 Method 1:
Reaction of Ammonia with Alkyl Halides
The Hofmann amination reaction between ammonia and alkyl halides can be performed
in a sealed tube under gentle heating or in ethanol.[95] The reaction allows for the direct
formation of amines but has the disadvantage that the evolved hydrogen halide con-
sumes 1 equivalent of the amine or ammonia. In addition, since the primary amines pro-
duced from the reaction are more nucleophilic than ammonia, they preferentially attack
any excess alkyl halide and the reaction products are usually a mixture of primary, sec-
ondary, and tertiary amines, and quaternary ammonium salts (Scheme 36; see also
Houben–Weyl, Vol. 11/1, p 24). However, the reaction often works well for the preparation
of tertiary amines.
Scheme 36 The Hofmann Reaction[95]

NH3
R 1X R1NH2 + R12NH + R13N + R14NX
− HX
The reaction of bromoalkanes with aqueous ammonia at 140 8C in an autoclave to pro-

duce a range of alkylamines has been known since the 1850s.[96] Alkyl halides generally
need reaction temperatures in excess of 140 8C in an autoclave to react with ammonia al-
though activated halides can react at lower temperatures. 2-Bromo-1,1-difluoroethane re-
acts with ammonia at 125–145 8C,[97] whereas the less reactive chloroalkane 1-chloro-
2,2,2-trifluoroethane requires a reaction temperature of 185 8C.[98,99]
The alkylation of liquid ammonia by alkyl halides has been studied using alkyl bro-
mides.[100–102] The best experimental yields are obtained for 1-bromododecane, which
gives 90% of the primary dodecylamine, whereas 1-bromooctane gives only 45% of octyl-
amine.[100] The respective yields of tertiary to secondary amines is found to be 28%/18% for
1-bromohexane, 38%/12% for 1-bromooctane, and 52%/27% for 1-iodododecane.[102] Other
alkylamines also give mixtures of primary, secondary, and tertiary amines.
The alkylation of ammonia with chloroalkanes or bromoalkanes in ethanol and wa-
ter has been reported, with mixtures of primary, secondary, and tertiary amines being
formed depending on the alkyl halide to ammonia ratio being used.[103] It is difficult to

make primary and secondary amines by this route, unless multistep fractional distillation
is used for purification. However, the alkylation of ammonia to give tertiary amines is fea-
sible provided that the alkyl halides used are not sterically hindered. Generally, the less
sterically hindered the amine, the better the reaction to produce tertiary amines. Factors
important for successful reaction include the following:
(1) Low concentration of ammonia, i.e. the use of a solvent such as ethanol or water
or a two-phase system.
(2) Use of a reactive haloalkane; iodoalkanes are favored over bromoalkanes which
are, in turn, favored over chloroalkanes. Hexyl, heptyl, and octyl bromides work well,
but for nonyl and decyl groups the iodide is preferred.
(3) Liquid-phase reactions are generally preferred over vapor-phase reactions.
Some examples of typical reactions of ammonia with alkyl halides to give mixtures
of primary amines 51, secondary amines 52, and tertiary amines 53 are given in Scheme
37.

Scheme 37 Alkylation of Ammonia with Alkyl Halides[100,103–111]
NH3
R1X R1NH2 + R12NH + R13N
51 52 53
R1X Conditions Yielda (%) Ref

51 52 53
[107]
Me(CH2)7Cl EtOH, 140 8C, 20 h 11 40 22
[108]
Me(CH2)17Cl liq NH3, 50 8C, 24 h 35 n.r. 0
[100]
BnCl EtOH, 100 8C, 24 h 9 35 48
[105]
H2C=CMeCH2Cl H2O, 75 8C, 3 h n.r. n.r. 14
[106]
H2C=C=CHCH2Cl liq NH3, –50 8C, 9 h n.r. n.r. 55
[111]
NaO3S(CH2)2Cl H2O, (NH4)2CO3, 120 8C, 6 h 90 n.r. n.r.
Cl
[100]
EtOH, 100 8C, 24 h 11 39 47
Cl
[100]
liq NH3, 20 8C, 24 h 72 20 0
[103]
EtBr EtOH, 20 8C, 16 d 34 57 3
[108]
Me(CH2)15Br liq NH3, 50 8C, 24 h 45 n.r. n.r.
[110]
t-Bu(CH2)2Br liq NH3, 120 8C, 90 atm 84 n.r. 0
[105]
H2C=CHCH2Br H2O, 75 8C, 3 h n.r. n.r. 57
[100]
PhO(CH2)2Br 20 8C, 40 h 65 n.r. n.r.
[100]
PhMeN(CH)2Br 20 8C, 2 d 71 20 0
[109]
H2O3P(CH2)3Br H2O, 20 8C, 14 d 36 n.r. n.r.
[104]
EtI liq NH3, 0 8C, 15 min 46 31 17
a
n.r. = not reported.
1,2-Dichloroethane reacts with sodium sulfite to give sodium 2-chloroethanesulfonate.

When this is treated with ammonia, the product is 2-aminoethanesulfonic acid (taurine).
This reaction is catalyzed by copper(I) chloride and has been studied extensively.[111] An
alternative method for the synthesis of 2-aminoethanesulfonic acid is described in Science

of Synthesis, Vol. 39 [Sulfur, Selenium, and Tellurium (Section 39.1.3.1.5.2)].
Four-membered rings containing oxygen are cleaved in the presence of ammonia to
form adducts. For example, 3,3-bis(bromomethyl)oxetane (54) reacts with alcoholic am-
monia solution at 20 8C to form the expected diamine 55 in quantitative yield. However,
upon further treatment with 33% ammonia at 200 8C, the ring is cleaved to give 3-amino-
2,2-bis(aminomethyl)propan-1-ol (56) in 70% yield (Scheme 38).[112] The ring opening of ox-
etanes using amines to give 3-aminopropan-1-ols is further described in Science of Synthe-
sis, Vol. 36 [Alcohols (Section 36.10.2.1.2)].
Scheme 38 Cleavage of Four-Membered Oxygen Heterocycles with Ammonia[112]

H2N
Br Br NH3, R1OH H2N NH2
20 oC NH3, 200 oC NH2
HO
quant 70%
O O
NH2

54 55 56
A vapor-phase reaction using chloroalkanes 57 and ammonia over a magnesium oxide

catalyst at 310 8C gives moderate selectivity for the primary amine products 58 (Scheme
39).[113] Generally the extent of monoalkylation increases with the alkyl chain length and
the amount of secondary amine 59 and tertiary amine 60 in the product mixture decreas-
es.
Scheme 39 Amines by Vapor-Phase Reaction between Ammonia and Alkyl Halides[113]

NH3, MgO
310 oC
R1Cl R1NH2 + R12NH + R13N
57 58 59 60
R1 Yield (%) Ref

58 59 60
[113]
Bu 39.2 18.1 2.7
[113]
(CH2)5Me 45.0 13.0 2.5
[113]
(CH2)6Me 50.5 9.0 1.5
[113]
(CH2)7Me 58.0 4.2 0.8
[113]
(CH2)8Me 69.0 8.0 trace
[113]
(CH2)9Me 70.6 8.0 trace
Triallylamine (53, R1 = CH2CH=CH2); Typical Procedure:[105]

To H2O (1050 g) in a 3-L flask fitted with a stirrer, condenser, thermometer, and dropping
funnel was added 28% aq NH3 (274 g). The soln was heated to 75 8C and allyl bromide
(363 g, 3 mol) was added slowly, with stirring, via the dropping funnel at a slow rate to
maintain a steady reflux. After the addition was complete, the soln was stirred and heated
at 75 8C for a further 3 h and then allowed to cool. The upper oily layer was separated and
dried (NaOH pellets). The cold aqueous soln was then saturated with NaOH at which point
a second oily layer formed on top of the aqueous layer. This second oily layer was also sep-
arated and mixed with the first oily fraction. Triallylamine was recovered by fractional
distillation of the oily layer; yield: 57%.

40.1.1.5.4.3.2 Method 2:
Reactions of Primary, Secondary, or Tertiary Amines with Alkyl Halides
The alkylation of primary, secondary, and tertiary amines with alkyl halides is simpler
and more controllable than the corresponding reaction with ammonia. Treatment of pri-
mary amines with alkyl halides yields a mixture of secondary and tertiary amines, and
quaternary ammonium salts, depending upon the reaction conditions. The reaction be-
tween tert-butylamine and iodomethane in a 2:1 ratio in xylene gives a mixture of tert-bu-
tyltrimethylammonium iodide (34%), tert-butyldimethylammonium iodide (20%) and tert-
butylmethylamine (7%).[114]
The synthesis of secondary amines by the reaction of alkyl halides with primary
amines has been reviewed.[115] Alkyl iodides have several practical advantages as alkyl-
ating agents and are also more electrophilic. Alkyl bromides are of lower reactivity and
often require elevated temperatures, although allylic bromides (and chlorides) can be
used at low temperature and pressure. Some results of alkylation reactions of primary

amines to give mixtures of secondary amines 61 and tertiary amines 62 are given in
Scheme 40.
Scheme 40 Alkylation of Primary Amines with Alkyl Halides[107,116–119]

R2
R2X H
R1NH2 N + N
R1 R2 R1 R2
61 62
R1 R2X Ratio Conditions Yield (%) Ref

(Amine/R2X) 61 62
[107]
Me BuCl 1:1 EtOH, 110 8C, 16 h 21 69
[117]
Me H2C=CMeCH2Cl 1:2 EtOH/H2O, 110 8C, 16 h 15 78
[107]
Me Me(CH2)11Cl 1:2 EtOH, 160 8C, 12 h 59 37
[118]
Et EtBr 1.3:1 100 8C, 3 h 0 51
[119]
Me Me(CH2)8I 1.6:1 MeOH, 6 h, 100 8C 18 75
a [116]
CHMeCH=CH2 EtI 1:2 KOH, reflux, 1 h – 66
a
Yield not reported.
If a secondary amine is required and the formation of a tertiary amine is to be avoided, the
traditional synthetic method has been to use a large excess of the primary amine relative
to the alkyl halide and an auxiliary base such as potassium carbonate in an aprotic solvent
such as dimethyl sulfoxide or acetonitrile. However, this method is very wasteful and un-
helpful if the starting amine is difficult to synthesize or it is a natural product that is hard
to isolate, unless there is precise control of the reaction conditions.[120]
Sodium carbonate is used as the base in the solvent-free alkylation of a range of
amines using 3-chloropropane-1,2-diol and is able to selectively give secondary amines
at reaction temperatures of 100–120 8C (Scheme 41).[121] The hydroxy groups are not at-
tacked by the amines employed, which offers the possibility of further downstream deri-
vatizations.
Scheme 41 Alkylation of Primary Amines with a Chloro Diol[121]

R1NH2 (8−12 equiv)
Na2CO3, 100−120 oC
HO Cl HO NHR1
R1 = Et 50%
OH OH
R1 = Bn 51%
R1 = (CH2)2NH2 72%
R1 = (CH2)5Me 74%
R1 = (CH2)9Me 57%
The alkylation reaction is strongly dependent on the alkyl chain length. For example, cy-
clohexylamine reacts readily with alkyl bromides in dimethyl sulfoxide solution in the
presence of potassium carbonate at 80 8C. The use of 1-bromobutane results in dialkyl-
ation giving high yields (83%) of the tertiary amine dibutyl(cyclohexyl)amine. If 1-bromo-
hexane is used, monoalkylation occurs, giving cyclohexyl(hexyl)amine in 95% yield.[122] If
N-monomethylation is required, a better synthetic option could be to use the Eschweiler–
Clarke modification of the Leuckart reaction with formic acid and formaldehyde.[123]
Benzylamine can be monoalkylated with a chiral bromide in the presence of tetrabu-

tylammonium iodide in tetrahydrofuran to give a chiral secondary amine in high
yield.[124] This experimental protocol has been applied to the preparation of a series of N-
protected optically active a-amino esters from racemic a-halo pantolactone esters.[125]
In general, the alkylation of unreactive and hindered amines has been found to be
facilitated by the use of 1,3-dimethyl-3,4,5,6-tetrahydropyrimidin-2(1H)-one (DMPU) as a
solvent. For example, treatment of (R)-1-phenylethylamine in 1,3-dimethyl-3,4,5,6-tetra-
hydropyrimidin-2(1H)-one with 2 equivalents of sodium carbonate followed by the slow
addition of bromide gives (R)-N-alkyl-1-phenylethylamines with retention of stereochem-
istry (Scheme 42).[126]
Scheme 42 Alkylation of a Chiral Amine in 1,3-Dimethyl-3,4,5,6-tetrahydropyrimidin-

2(1H)-one[126]
NH2 NHR1
R1X, Na2CO3, DMPU
Ph R1 = Bn; X = Br 95% Ph
R1 = iPr; X = I 91%
R1 = 2-PhC6H4CH2; X = Br 92%
R1 = CHPh2; X = Br 70%
R1 = CMe2Et; X = I 32%
1,1,2-Trichloroethane undergoes an anomalous reaction with ammonia when heated to

45–75 8C: instead of forming an amine adduct, it loses hydrogen chloride to form 1,1-di-
chloroethene and ammonium chloride.[127] In other cases as well, under strongly basic
conditions dehydrohalogenation can compete with N-alkylation reactions, particularly
when using lithium naphthalenide (or potassium hydroxide) as base for the selective al-
kylation of primary amines with branched alkyl halides.[128] A solution to this problem has
been proposed by utilizing primary amines as substrates in the presence of cesium hy-
droxide (Scheme 43).[129] The cesium base is effective in selectively promoting monoalkyl-
ation reactions. This method can also be used for the alkylation of diamines and poly-
amines with 2-bromoethylamine hydrobromide as the alkylating agent.[130]
Scheme 43 Alkylation of 2-Phenylethylamine with 1-Bromobutane[129]

BuBr, CsOH
molecular sieves
23 oC, 21 h
NH2 NHBu + NBu2
Ph Ph Ph
89% 10%
The use of copper catalysis has been reported in the reactions between primary amines 63
and propargylic chlorides 64 (Scheme 44).[131,132]

Scheme 44 Alkylation of Primary Amines with Propargylic Chlorides[131,132]

A: Cu, Cu2Cl2, DMF, 4 oC, 72 h
R1 R2 R1 R2
B: Cu, H2O, 40 oC, 15 h
R3NH 2 + Cl NHR3
A: R1 = R2 = Me; R3 = CMe2C CH 70%
A: R1 = R2 = Me; R3 = C(Me)(Et)C CH 62%
63 64 A: R1 = Me; R2 = Et; R3 = iPr 20%
Alkylation of secondary amines with alkyl halides is a widely used technique to prepare
tertiary amines 65 as quaternary salt formation is usually low.[133] Different alkyl groups
can be introduced onto a secondary amine and where the secondary amine is a liquid the
reaction can be run without a solvent.[133] Some typical examples of the reactions of sec-
ondary amines with alkyl halides are shown in Scheme 45.
Scheme 45 Alkylation of Secondary Amines[107,134–139]

R3
H R3X
N N

R1 R2 R1 R2
65
R1 R2 R3X Ratio Conditions Yield (%) Ref

(Amine/R3X)
[137]
Me Me Me(CH2)17Cl 3:1 autoclave, 150 8C, 12 h 100
[107]
Et Et Me(CH2)7Cl 1.5:1 EtOH, sealed tube, 160 8C, 12 h 86
[134]
Me Pr Me(CH2)9Cl 2.36:1 benzene, rt, 40 h 72
[138]
Me Me HC”C(CH2)4Cl 2.67:1 benzene, 80 8C, 13 h 60
[136]
Et Et Me(CH2)10Br 2.25:1 xylene, sealed tube, 170 8C, 6 h 78
[139]
Me Et PrBr 1:1 100 8C, 3 h 25–30
[135]
Pr Pr EtI 2:1 benzene, 20–80 8C, 5 h 56–70
Tetrahydroisoquinolines can be alkylated using alkyl halides via attachment of the amine
to a sulfonated Merrifield resin, quaternization, and cleavage. An example is illustrated in
Scheme 46.[140]
Scheme 46 Solid-Phase Alkylation of a Tetrahydroisoquinoline[140]

O O
OEt S O O
O
S
DMF O N
NH
OEt
O O Me
S
O N+ iPr2NEt, CH2Cl2
I−
MeI, DMF
OEt
OEt
NMe
The reaction of secondary allylic halides with dialkylamines often occurs with allylic in-
version to give an isomer of the expected tertiary amine. For example, upon reaction with
diethylamine, both 1-chlorobut-2-ene (66) and 3-chlorobut-1-ene (68) give N,N-diethylbut-
2-en-1-amine (67) (Scheme 47).[116] It is worth noting that these reactions give good yields
under solvent-free conditions, but when benzene is used as solvent, the yields drop con-
siderably.
Scheme 47 Reaction of Allylic Chlorides with Secondary Amines[116]

Et2NH, rt, 2 d Et2NH, reflux, 36 h Cl
Cl 85% NEt2 82%
66 67 68
In the presence of a mixed copper(0)/copper(I) catalytic system (see also Scheme 44), ter-
tiary propargyl halides alkylate secondary amines, in many instances without competing
dehydrohalogenation. For example, morpholine reacts with 3-chloro-3-methylbut-1-yne

to give the propargylic amine 69 in good yield in the presence of the copper catalyst,
whereas the uncatalyzed reaction gives poor yields even after extended reaction times
(Scheme 48).[141]
Scheme 48 Copper-Catalyzed Synthesis of a Propargylic Amine[141]

O
A: H2O, rt, 7 d
O
Cl B: Cu/CuCl, Et2O/H2O, 17−20 oC, 2 h N
+
A: 33%
N B: 79%
H
69
The palladium-catalyzed reaction of allylic chlorides with secondary amines gives allylic
tertiary amines (Scheme 49). The reaction can also be carried out without catalysis, but
higher temperatures are required. This methodology can be applied to cyclic chloroal-
kenes, and to the synthesis of secondary amines from primary amines.[142] For further cov-
erage of the palladium-catalyzed synthesis of allylic amines see Section 40.1.3.1.2.1.
Scheme 49 Synthesis of Allylic Amines from Allylic Chlorides[142]

R3 A: R42NH, Pd(PPh3)4, THF, rt R3
B: R42NH, MeCN, reflux
AcO AcO
Cl NR42
R1 R 2 R1 R2
R1 R2 R3 R4 Method Yield (%) Ref
[142]
H H H H A 87
[142]
H H H H B 75
[142]
H Me H Me B 76
a [142]
Me H Me Et A 80
Me H Me Et B 70b [142]
a
The chloride is displaced with retention of configuration.
b
The chloride is displaced with inversion of configuration.
Lithium naphthalenide has been reported to be an effective agent for the reaction be-
tween dibenzylamine and various alkyl bromides in tetrahydrofuran to give alkyldiben-
zylamines with good to excellent yields.[143] Secondary amines (diethylamine, piperidine,
and pyrrolidine) react with perhaloalkanes in the presence of sodium hydride in triethyl-

amine/dimethylformamide to give the tertiary amines in moderate to good yields.[144] An

efficient general synthesis of tertiary amines 71 by direct alkylation of secondary amines
70 with alkyl halides in N,N-diisopropylethylamine (HMnigNs base) has been reported
(Scheme 50). The formation of quaternary salts and the use of metalation reactions is
avoided.[145] The role of N,N-diisopropylethylamine in preventing quaternization is attrib-
uted to its non-nucleophilic character, limiting it to formation of a salt with the hydrogen
bromide produced in the reaction.
Scheme 50 Alkylation of Secondary Amines with Alkyl Halides[145]

R3Br, iPr2NEt (1.5 equiv)
R3
H MeCN, rt
N N
R1 R2 R1 R2
70 71
R1 R2 R3 Time (h) Yield (%) Ref

[145]
Bu Bu Bn 3 >90
[145]
(CH2)5 Bn 2 91
[145]
Bn Me Bn 3 >90
[145]
Bn Bn Pr 3 >90
[145]
(CH2)5Me (CH2)5Me Bu 24 >90
[145]
(CH2)2O(CH2)2 Bn 2 >90
Diamines with one tertiary amine and one secondary amine can be reacted with (chloro-
methyl)arenes in the presence of sodium amide or sodium carbonate to give the alkylated
amines in generally good yields (Scheme 51).[146]
Scheme 51 Base-Promoted Alkylation of Diamines[146]

Ar1
Ar1 Cl , NaNH2 or Na2CO3
NHR1 DMSO, 40 oC, 1 h N
N N R1
18−76%
R1 = Ph, Cy, 2-pyridyl, pyrimidin-2-yl, 2-thienylmethyl; R2 = 4-MeOC6H4, 2-thienyl, 5-chloro-2-thienyl, 2-furyl
N,N-Diethylbut-2-en-1-amine (62, R1 = CHMeCH=CH2; R2 = Et):[116]

EtI (135 g, 866 mmol) was added slowly to but-3-en-2-amine (30 g, 422 mmol) in a flask fit-
ted with a reflux condenser and cooled in an ice bath. The reaction was exothermic and
the ice bath was used to keep the temperature of the mixture below reflux. After the re-
action had subsided, powdered 87% KOH (27.4 g, 426 mmol) was added slowly to the soln
in small portions with cooling to maintain a gentle reflux. After the addition was com-
plete, the mixture was heated on a steam bath for 1 h after which an equal volume of
H2O was added and the resulting soln was concentrated to dryness. The free amine was
then liberated by addition of aq KOH and the flask contents were then distilled to recover
crude N,N-diethylbut-2-en-1-amine, which was then redistilled; yield: 35 g (66%).
Decyl(methyl)(propyl)amine [65, R1 = Me; R2 = Pr; R3 = (CH2)9Me]:[134]

Crude Me(CH2)9Cl (88.3 g, 0.5 mol) was dissolved in benzene (250 mL) (CAUTION: carcino-
gen) and the soln was cooled in an ice bath. PrNHMe (86 g, 1.18 mol) was then added and
the mixture was allowed to stand at rt for 40 h. Et2O (500 mL) was added and the resulting
soln was extracted with 10% HCl (2 F 250 mL). The acid wash soln was cooled and made
strongly alkaline with NaOH. The resulting basic aqueous soln was then extracted with
Et2O (3 F 200 mL) and the ethereal extracts were combined, dried overnight (KOH pellets),
concentrated, and purified by distillation; yield: 76.4 g (72%); bp 89–90 8C/1 Torr.
Tertiary Amines 71; General Procedure:[145]

The secondary amine 70 (0.5 g, 1 equiv), iPr2NEt (1.5 equiv), the alkyl bromide (1.1 equiv),
and MeCN (10 mL) were placed in a round bottomed flask and stirred at rt under N2. After
completion (monitored by TLC), the soln was concentrated to dryness under reduced pres-
sure. The residue was dissolved in CH2Cl2 (5 mL) and washed with distilled H2O (5 mL).
Both layers were retained and the aqueous layer was then washed with CH2Cl2 (2 F
5 mL). The combined organic fractions were then dried (MgSO4) and the solvent was re-
moved under reduced pressure.
40.1.1.5.4.3.3 Method 3:
Alkylation Reactions of Alkali Metal Amide Salts

Although it is possible to produce amines by the action of sodium amide on alkyl halides,
this method is extremely difficult. It works best in liquid ammonia, using iron(III) nitrate
as a catalyst, and is generally limited to the simpler amines, giving yields below 50%.[147,148]
Benzyl chloride reacts with sodium amide to give tribenzylamine.[149]
Lithiated secondary amines react with alkyl halides to form tertiary amines. General-
ly, reactions of lithium amides with alkyl chlorides are very poor (less than 5% yield) al-
though reaction of alkyl bromides can give reasonable yields (e.g., Scheme 52).[150] Howev-
er, in general this method offers little synthetic advantage over the direct alkylation of
amines.
Scheme 52 Alkylation of a Lithium Amide with an Alkyl Bromide[150]

BuBr
Et2NLi BuNEt2
53%
The in situ formation of lithium amides (from secondary amines) and their subsequent
reaction with alkyl halides to give tertiary amines is described in Science of Synthesis, Vol.
8 [Compounds of Group 1 (Li…Cs) (Section 8.3.2.3.2)].
40.1.1.5.4.3.4 Method 4:
The Gabriel Synthesis and Related Reactions of Carboxylic Acid Derivatives
The Gabriel synthesis of amines involves the reaction of a metal phthalimide, usually po-
tassium phthalimide (72), with an organic halide and subsequent cleavage of the alkyl
phthalimide 73 to release a primary amine 74 (Scheme 53; see also Houben–Weyl, Vol.
11/1, pp 79–96).[151–156] Cleavage of the N-alkylated phthalimide can be accomplished by
acid- or base-catalyzed hydrolysis or by the Ing–Manske modification, which uses hydra-
zine hydrate in methanol or ethanol.[153]
Instead of using preformed potassium phthalimide, anhydrous potassium carbonate
is often added to reactions between phthalimide and haloalkylamines to form the potas-
sium phthalimide salt in situ. For example, potassium carbonate is added to the reaction
between phthalimide and benzyl chloride to give benzylphthalimide.[153,157] Sodium car-
bonate can also be used to generate sodium phthalimide in situ.[158]

Scheme 53 Synthesis of Amines by the Gabriel Reaction[151–154,156]

O
R1X
NK
O
O
72
hydrolysis
NR1 R1NH2
O
O
73 74
R1X, M2CO3
NH

M = Na, K
R1X Alkylation Conditions Yield (%) Cleavage Conditions Yielda Ref

of 73 (%) of
74
[152]
BnCl PhthNK, 180–190 8C, 2 h ca. 50 concd HCl, 200 8C n.r.
[153]
BnCl PhthNH, K2CO3, 74–78 1. H2NNH2•H2O, EtOH, reflux 90–95
reflux, 3 h 2. HCl, reflux
3. NaOH
[154]
Me2C(OH)CH2Cl PhthNK, reflux, 4 h 60 1. H2SO4, reflux 70
2. NaOH
3. HCl
[151]
Me(CH2)15Br PhthNK, 180–190 8C, quant 1. H2NNH2•H2O, EtOH, reflux 73
24 h 2. HCl, reflux
3. NaOH
[156]
iBuBr 200 8C 60 HCl, reflux n.r.
[152]
PNBBr PhthNK, 100–130 8C 90 concd HCl, 190–200 8C n.r.
[151]
(E)-Me(CH2)7CH=CH(CH2)8Br PhthNK, 180–190 8C, 40 1. NaOH, H2O, reflux 50
24 h 2. HCl, reflux
3. NaOH
a
The use of the Gabriel synthesis has been enhanced by the use of Mitsunobu condi-
tions,[159] and also by microwave-assisted reactions in the presence of potassium carbon-
ate and tetrabutylammonium bromide as a catalyst.[160] The use of other ammonium
salts[161] or phosphonium salts[162] as catalysts has also been reported. An example of the
Gabriel reaction catalyzed by tetrabutylammonium bromide is illustrated in Science of
Synthesis, Vol. 8 [Compounds of Group 1 (Li…Cs) (Section 8.3.3.3.2)].
The Gabriel reaction can be used as a synthetic step en route to more complex mol-
ecules, with a wide range of further transformations being performed on the alkylated
phthalimide derivative before hydrolysis to the amine. Dihaloalkanes react with potassi-
um phthalimide to form an N-terminal haloalkane derivative which can then be reacted
with another reagent. Examples include reaction with an aromatic ring via a Friedel–
Crafts reaction,[163] with the sodium salt of a malonate (which after decarboxylation and
hydrolysis gives an w-aminocarboxylic acid),[164–166] or with another amine to form a di-
amine (see Houben–Weyl, Vol. 11/1, p 89). This latter reaction offers the possibility to
form unsymmetrical substituted diamines.
An unusual variation of the Gabriel reaction with 1,2-dibromoethane involves cleav-

age of the N-(2-bromoethyl) adduct 75 with potassium hydroxide at one of the N—C bonds
to form potassium 2-[(2-bromoethyl)carbamoyl]benzoate (76). This can then undergo an
intramolecular cyclization to form an eight-membered ring of bicyclic amide 77, which
cleaves in aqueous alkali to give 2-aminoethanol (ethanolamine) and phthalic acid
(Scheme 54).[167–169]
Scheme 54 Synthesis of 2-Aminoethanol by the Gabriel Reaction[167–169]

O
NK O
O KOH
Br N
Br
Br
O
75

O Br O
H
N N
H OH− OH
CO2H H2N
OK
O −
O O CO2H
76 77
As an alternative to metal phthalimides, sodium diformylamide (78) reacts with alkyl ha-
lides to give an alkyldiformamide, which is then hydrolyzed to the amine 79 (Scheme 55).
The intermediate alkyldiformamide can be isolated, but the reaction can also be per-
formed as a one-pot synthesis.[170]
Scheme 55 Gabriel-Type Synthesis Using a Diformamide Salt[170]

1. R1X, EtOH, 80−120 oC
2. HCl
OHC
3. NaOH
N Na R1NH2
67−92%
OHC
78 79
R1 = Me, Bu, (CH2)4Me, (CH2)11Me, CH2CH CH2, Bn, CH2CO2Et, CH2Bz; X = Cl, Br, I, OTs
Trifluoroacetamide (80) is alkylated at ambient temperatures using alkyl halides or meth-

anesulfonates. The intermediate N-alkylamides 81 can be converted into primary amines
82 by alkaline hydrolysis or by reduction (Scheme 56).[171] In the first step of the sequence,
alkene formation sometimes competes with acetamide alkylation; for example, in the
case of bromocyclohexane, cyclohexene is the sole product isolated (in 86% yield).[171]
The intermediate N-alkyltrifluoroacetamides can be further treated with sodium hydride
and another alkyl halide giving a dialkylacetamide. After cleavage of the amide, an un-
symmetrical dialkylamine is produced. N-Alkyltrifluoroacetamides can also be alkylated
by primary alkyl bromides or iodides in the presence of potassium hydride and 18-crown-
6 to give an N,N-disubstituted trifluoroacetamide, which can be cleaved in methanolic po-
tassium hydroxide to give an unsymmetrical secondary amine (80–95%).[172]

Scheme 56 Synthesis of Primary Amines Using Trifluoroacetamide[171]

O 1. NaH, DMF, 20 oC, 1 h O A: 20% aq KOH
2. R1X B: NaBH4, EtOH, 20 oC, 1 h
R1NH2
F 3C NH2 F3C NHR1
80 81 82
R1X Yield (%) Acetamide Yielda (%) Ref

of 81 Cleavage of 82
Methoda
[171]
Me(CH2)7Cl 20 n.r. n.r.
[171]
Me(CH2)7Br 53 A 87
[171]
Me(CH2)7I 79 A 83
[171]
BnCl 72 B 95
[171]
PhCH=CHCH2Br 57 B 94

[171]
MeO2CCH2Br 62 B 84
[171]
BnO2CCH2Br 48 B 81
[171]
Me(CH2)15I not isolated B 86
[171]
Me(CH2)5CHMeI 14 B 96
a
Benzylamine (74, R1 = Bn); Typical Procedure:[153]

An intimate mixture of phthalimide (300 g, 2.04 mol) and K2CO3 (150 g, 1.09 mol) was
treated with BnCl (300 g, 2.37 mol) and the resulting mixture was heated at reflux for
3 h. Excess BnCl was removed by distillation in a current of steam and the residue was
collected by filtration and washed with H2O to give N-benzylphthalimide (73, R1 = Bn);
yield: 360–370 g (74–78%). The benzylphthalimide could be purified by recrystallization
(AcOH).
A suspension of finely powdered benzyl phthalimide (73, R1 = Bn; 1 mol) in EtOH was
warmed with H2NNH2•H2O (1 mol). The white, gelatinous precipitate, which formed rap-
idly, was decomposed by warming with excess HCl. The precipitated phthaloyl hydrazide
was removed by filtration and washed with H2O and the filtrate and washings were par-
tially concentrated to remove EtOH. Any further precipitated phthaloyl hydrazide was re-
moved by filtration. The filtrate was then made alkaline and was extracted with Et2O. The
Et2O extracts were dried (KOH), concentrated, and distilled; yield: 90–95%.
Amines 79; General Procedure:[170]

A mixture of the alkylating agent (0.1 mol), NaN(CHO)2 (78; 11.4 g, 0.12 mol), and EtOH
(50 mL) was heated with stirring in an autoclave at 80 8C for 3 h or 100 8C for 8 h. Concd
HCl (10 mL) was added and the mixture was refluxed for 2 h. The mixture was concentrat-
ed under reduced pressure to near dryness and the residue was treated with 50% aq NaOH
with cooling, extracted with Et2O, dried (KOH), and concentrated under reduced pressure.
Purification was by distillation.
40.1.1.5.4.3.5 Method 5:
Alkylation Reactions of Nitrogen-Containing Derivatives of Carbonic Acid
Milder alternatives to the Gabriel reaction have been reported with phthalimide being re-
placed by reagents such as tert-butyl methyl imidodicarbonate[177] or di-tert-butyl imidodi-
carbonate:[178] in dimethyl sulfoxide or dimethylformamide at ambient temperatures
with specific monodeprotection under either basic or acidic conditions. Potassium bis-
(tert-butoxycarbonyl)amide in dimethylformamide reacts with alkyl halides to give high
yields of bis(tert-butoxycarbonyl)-protected amines.[178] Sodium bis(tert-butoxycarbon-

yl)amide reacts with unsaturated alkyl chlorides to give the protected alkenylamines.[179]
1-Bromobut-2-ene (crotyl bromide) reacts with urea and the alkylated urea, which is
obtained in 63% yield, can be hydrolyzed with aqueous sodium hydroxide to obtain a mix-
ture of primary (53%), secondary (26%), and tertiary crotylamines (13%).[173]
Treatment of alkyl chlorides with urea in aqueous sodium hydroxide under pressure
at 80–200 8C results in moderate to good yields of the corresponding tertiary amines 83
(Scheme 57).[174] The reaction is proposed to proceed via in situ decomposition of urea un-
der basic aqueous conditions into ammonia, isocyanate salts, and water. Both the ammo-
nia and the isocyanate can be exhaustively alkylated by the alkyl chloride to form quater-
nary ammonium salts, which undergo Hofmann degradation to provide the tertiary
amines.
Scheme 57 One-Step Conversion of Urea into Tertiary Amines[174]

O R1Cl, aq NaOH

4 atm, 40 h
R13N
H2N NH2
83
R1 Temp ( 8C) Yield (%) Ref
[174]
CH2CH=CH2 80 56
[174]
CH2CH=CHMe 80 50
[174]
CH2CMe=CH2 80 72
[174]
Bu 120 77
[174]
(CH2)7Me 200 75
[174]
Bn 120 82
In contrast to urea, guanidine reacts readily with alkyl halides in the presence of water/
ethanol to form N-alkyl adducts 84, which can then be cleaved with aqueous hydroxide
(or sodium carbonate) to generate the corresponding primary amine 85 (Scheme
58).[175,176]
Scheme 58 Synthesis of Amines from Guanidine[175,176]

NH
H2N NH2
H2O, EtOH
NH
20−78 oC, 1−40 h OH−, reflux
R1X R1NH2
R1HN NH2 52−79%
84 85
R1 = alkyl, CH2CH CH2, CH2CH CMe2, CH2CMe CH2, Bn; X = Cl, Br
Trialkylamines 83; General Procedure:[174]

Urea (30 g, 0.5 mol) was suspended in 50% w/w aq NaOH (169 mL, 3.2 mol). The alkyl halide
(3.2 mol) was added in one portion and the glass-lined 2-L Parr pressure vessel was sealed
and pressurized with N2 (4 atm) at 20 8C. The mixture was stirred and heated at the speci-
fied temperature for 40 h, then cooled to rt, and depressurized. The mixture was diluted
with H2O (1 L) and extracted with Et2O (3 F 250 mL). The combined organic layers were
washed with brine (500 mL), dried (Na2SO4), filtered, and distilled under reduced pressure
to give the tertiary amine.

In the reaction using BnCl, after heating the mixture for 40 h, the precipitated Bn3N
was collected on a glass sinter, washed with H2O (2 F 2 L) and MeOH (1 L), dried under re-
duced pressure (50 8C/0.1 Torr), and recrystallized (MeOH).
Butylamine Hydrochloride (85•HCl, R1 = Bu); Typical Procedure:[176]

A dilute aqueous soln of 95% H2SO4 (103 g, 1 mol) was added with stirring to guanidinium
carbonate (180 g, 1 mol) in H2O (400 mL). To this soln was then added Ba(OH)2•8H2O (315 g,
1 mol) in warm H2O (400 mL). The precipitated BaSO4 was removed by centrifugation to
leave a clear soln, which was titrated against dil HCl, using phenolphthalein as indicator,
to determine the guanidine concentration. This soln was kept cool.
To the prepared 10.3 M soln of guanidine in H2O (10.7 mL) was added a soln of BuBr
(13.7 g, 0.1 mol) in EtOH (25 mL) and the mixture was refluxed for 3 h. Then, 30% Na2CO3
soln (100 mL) was added. The resulting soln was distilled at atmospheric pressure and the
distillate was collected in a flask containing 6 M HCl. From time to time, H2O was added to
the distillation flask to replace that which had distilled off. After ca. 400 mL had been col-

lected, the distillate was concentrated, the residue was extracted with boiling 95% EtOH,
and NH4Cl was removed by centrifugation. The filtrate was concentrated and the residue
was then extracted with warm (80–90 8C) BuOH. Any remaining NH4Cl was removed by
centrifugation and the soln was again concentrated. The residue was treated repeatedly
with anhyd Et2O and the precipitated product was collected by suction filtration; yield:
7 g (66%).
40.1.1.5.4.3.6 Method 6:
Reactions of Alkyl Halides with Hexamethylenetetramine
Hexamethylenetetramine (86, 1,3,5,7-tetraazatricyclo[3.3.1.13,7]decane, also known as

urotropine, hexamine, or methenamine), is used to form primary amines from alkyl ha-
lides in the DelTpine reaction (see Houben–Weyl, Vol. 11/1, pp 105–107).[180–184] In the first
stage of the reaction, an alkyl halide reacts with hexamethylenetetramine to form an N-
alkylated quaternary ammonium salt 87. As is to be expected, alkyl iodides react faster
than bromides, which in turn react faster than chlorides. The alkylated hexamethylene-
tetramine salt is then hydrolyzed with hydrochloric acid/ethanol to give the salt of the re-
quired amine (Scheme 59). A wide range of alkyl halides can be employed including those
bearing ketone, amide, alkene, or alkyne functionalities.
Scheme 59 Synthesis of Primary Amines by Reaction of Alkyl Halides with

Hexamethylenetetramine[184]
N N
HCl, EtOH
R 1X + + − R1NH2•HCl
N N N N R1 X − NH4X
N N
− NH4Cl
− CH2(OEt)2
86 87
Hetarene-substituted alkyl halides are successfully converted into the corresponding

amines using hexamethylenetetramines. Thus, 2-(bromomethyl)thiophene is converted
into 2-(aminomethyl)thiophene in 80% yield[185] and 2-(bromoacetyl)furan and 2-(bromo-
acetyl)thiophene are converted into 2-(2-aminoacetyl)furan[186] and 2-(2-aminoacetyl)thio-
phene, respectively.[187]
(Z)-1,4-Dichlorobut-2-ene reacts with hexamethylenetetramine in refluxing chloro-
form to give the adduct 88 in 99% yield. This can be cleaved with hydrochloric acid in
aqueous ethanol yielding (Z)-4-chlorobut-2-en-1-amine hydrochloride (89) in greater than
95% yield (Scheme 60).[188]
Scheme 60 Synthesis of an Allylic Amine Using Hexamethylenetetramine[188]

N
N N
N
CHCl3 N HCl
Cl Cl reflux, 4 h EtOH Cl NH2•HCl
N N
+ Cl−
99% >95%
N
Cl
88 89
Another method of cleaving the alkylated hexamethylenetetramine salts 90 is with sulfur

dioxide to form the aminomethyl hydrogen sulfite 91, which can then be treated with
acid (hydrochloric, hydrobromic, acetic, oxalic, or phosphoric acid) to give the alkylam-
monium salt 92 in near quantitative yields (Scheme 61).[189] This protocol has been applied
to the synthesis of benzylic amines bearing alkyl, alkoxy, halogen, or nitro substituents

on the aromatic ring.
Scheme 61 Cleavage of Alkylated Hexamethylenetetramine Salts with Sulfur Dioxide[189]

N
SO2, H2O HCl, H2O
+ −
N N R1 X R1HN OSO2H
− 3 H2N OSO2H − SO2
N
− CH2O
− 2 HO OSO2H
90 91
R1NH2•HCl
92 R1 = Bn 88%
R1 = 4-TolCH2 100%
R1 = 3-TolCH2 100%
Hexamethylenetetramine has been applied in a procedure where alkyl chlorides or bro-

mides are converted into the corresponding iodides in situ by sodium iodide, and the
hexamethylenetetramine complex is hydrolyzed without isolating it first (Scheme 62).
The time required for the first step of the reaction varies from 2 hours for the synthesis
of benzylamine to 3 weeks for 2-phenylethylamine.[190]
Scheme 62 Synthesis of Primary Amines Using Hexamethylenetetramine[190]

1. NaI, EtOH
N 2. HCl(g)
3. NaOH
R1X + N N R1NH2
N R1 = Me 72%
R1 = Et 83%
R1 = Bn 83%
R1 = PNB 61%
R1 = (CH2)2Ph 54%
1,2-Bis(chloromethyl)benzene (93) reacts with hexamethylenetetramine at 50 8C over

6 hours to give the expected adduct 94 in 88% yield, but on cleavage of the adduct in hy-
drochloric acid/aqueous ethanol, cyclization occurs to give 2,3-dihydro-1H-isoindole (95)
in 80% yield (Scheme 63).[191]

Scheme 63 Reaction of 1,2-Bis(chloromethyl)benzene with Hexamethylenetetramine[191]

N
N
N N N N
N
CHCl3 HCl, H2O, EtOH
+N
Cl 50 oC, 6 h 20 oC, 65 h
NH
Cl 88% 80%
Cl
93 94 95
As well as alkyl halides, it is also possible to use alkyl benzenesulfonates in the reaction
with hexamethylenetetramine to generate adducts which can then be cleaved with hy-
drochloric acid to generate amine hydrochloride salts. For example, allylamine hydro-
chloride can be prepared in 63% yield from the reaction between allyl benzenesulfonate
and hexamethylenetetramine in chloroform, followed by cleavage with hydrochloric
acid/methanol.[192]

(Z)-4-Chlorobut-2-enylammonium Chloride (89):[188]
(Z)-1,4-Dichlorobut-2-ene (52.6 g, 0.41 mol) was added in one portion to a refluxing soln of
hexamethylenetetramine (57.0 g, 0.41 mol) in CHCl3 containing 1% EtOH (400 mL) and the
mixture was refluxed for 4 h. After cooling to 25 8C, the crystals of 88 were collected by
suction filtration, washed with CHCl3 (2 F 50 mL) and dried under reduced pressure (ca.
1.5 Torr); yield: 93.3 g. The filtrate was refluxed for 16 h to give further 88 (11.5 g); total
yield: 104.8 g (99%).
Salt 88 (90.0 g, 0.34 mol) was added in portions to a refluxing mixture of concd HCl
(120 mL) and EtOH (680 mL). The heating was stopped and the mixture was stirred at 22 8C
for 18 h. After cooling to 5 8C for 2 h, NH4Cl (50 g) was removed by filtration. The filtrate
was concentrated and the residue was treated with 99% EtOH (300 mL) at 40 8C. The sus-
pension was cooled to 5 8C and further NH4Cl was removed by filtration. Concentration of
the filtrate under reduced pressure gave a sticky, crystalline product; yield: 55.5 g (quant).
Benzylammonium Chloride 92 (R1 = Bn):[189]
CAUTION: Sulfur dioxide gas is a severe irritant of the eyes, skin, and mucous membranes.
Benzylammonium salt 90 (R1 = Bn; X = Cl; 50.5 g, 189 mmol) was dissolved in cold H2O
(300 mL) and the mixture was saturated with SO2. After a short time, flakes of (benzylami-
no)methyl hydrogen sulfite (91, R1 = Bn) precipitated. When the precipitation stopped,
the solid was collected by filtration and washed with cold H2O; yield: 38 g (quant).
(Benzylamino)methyl hydrogen sulfite (91, R1 = Bn; 10.5 g, 52 mmol) was stirred with
25% HCl (20 mL) and steam was passed through the mixture for 45 min keeping the total
volume constant by adding H2O. Upon cooling, benzylammonium chloride (92, R1 = Bn;
X = Cl) precipitated and was washed with acetone. The mother liquor was concentrated
and treated with acetone to precipitate further product; total yield: 6.6 g (88%).
40.1.1.5.4.3.7 Method 7:
Reaction of Alkyl Halides with Sulfonamides
Alkyl halides react with various sulfonamides, including 4-toluenesulfonamide, to give

the alkylated sulfonamides. Upon hydrolysis of the N—S bond, the alkylated amine is re-
leased (for further details see Section 40.1.1.2.3.1; see also Houben–Weyl, Vol. E 16d, pp
703–707).
In the case of trifluoromethanesulfonamides, the intermediate alkylated sulfon-
amides 96 or 98 need not be isolated and the amines, as their hydrochloride salts 97 or
99, are obtained directly by heating the reagent with the alkyl halide in the presence of
base, followed by acidic workup (Scheme 64).[193,194]
Scheme 64 Synthesis of Primary Amines from Trifluoromethanesulfonamides[193,194]
R1Br, K2CO3
CO2Et CO2Et
MeCN, reflux HCl
Tf Tf R1NH2•HCl
Ph N Ph N R1 = Bn 90%
H R1 R1 = (CH2)6Me 78%
R1 = (CH2)2Ph 65%
96 R1 = (CH2)3Ph 78% 97
R1 = CH2CH CHPh 78%
R1 = CHMePh 53%
R1Br, K2CO3
MeCN, reflux HCl
Tf Tf R1NH2•HCl

R1 = (CH2)2Ph 80%
N N
H R1 R1 = (CH2)2Ph 65%
98 99
Primary amines react with trifluoromethanesulfonic anhydride to give the corresponding

trifluoromethanesulfonamides, which can be alkylated with an alkyl halide. The trifluo-
romethylsulfonyl group can then be cleaved using lithium aluminum hydride to give the
secondary amine.[193]
40.1.1.5.4.3.8 Method 8:
Reaction of Alkyl Halides with Amides of Phosphorus Acids
N-Allylation of primary amines can be achieved by reaction of the amine with diethyl
chlorophosphonate or O,O-diethyl chlorothiophosphonate, deprotonation of the result-
ing amide, allylation (with allyl bromide), and hydrolysis.[195] N,N,N¢,N¢-Tetramethyl-N¢¢-al-
kylphosphoric triamides can be deprotonated and then alkylated on nitrogen with 3-bro-
moprop-1-yne (propargyl bromide). Direct hydrolysis of the P—N bond gives the al-
kyl(prop-2-ynyl)amine.[196] The alkyne functionality can be conveniently modified at the
intermediate phosphoric triamide stage by deprotonation of the alkyne and further alkyl-
ation prior to hydrolysis.
Primary alkylamines 100 can be methylated on nitrogen via conversion into the cor-
responding diphenylphosphinic amide 101 (using diphenylphosphinic chloride), depro-
tonation on nitrogen, reaction with iodomethane, and cleavage of the P—N bond using
4-toluenesulfonic acid. The secondary amines are isolated as the 4-toluenesulfonate salts
102 (Scheme 65).[197]

Scheme 65 Methylation of Primary Amines via Phosphinic Amides[197]

1. NaH, THF or DMF
Ph2P(O)Cl, Et3N or O 20−25 oC O
4-methylmorpholine 2. MeI
R1NH2 Ph P Ph P R1
R1 = Bn 77% NHR1 R1 = Bn 76% N
Ph Ph Me
R1 = (CH2)2Ph 70% R1 = (CH2)2Ph 60%
100 R1 = Cy 71% 101 R1 = Cy 85%
R1 = (CH2)5Me 78% R1 = (CH2)5Me 100%
TsOH, MeOH or
TsOH•H2O, benzene, Et2O H + H
N OTs−
R1 = Bn 96% R1 Me
R1 = (CH2)2Ph 96%
R1 = Cy 91% 102
R1 = (CH2)5Me 89%
Unsubstituted P,P-diphenylphosphinic amide can be alkylated on nitrogen using pri-

mary[198] or secondary[199] alkyl bromides under phase-transfer catalysis. Hydrolysis of the

alkylated phosphinic amide 103 by hydrochloric acid gives the alkylamine as its hydro-
chloride salt 104. When primary alkyl bromides are employed, depending on the number
of equivalents of alkyl bromide used, primary amines 104 or secondary amines 106 can
be synthesized in moderate to excellent yields via the intermediate phosphinic amides
103 or 105 (Scheme 66). If 1 equivalent of an amine is used initially, the monoalkylated
amide 103 can be isolated and subsequently treated with a different alkylating agent un-
der the same phase-transfer conditions to allow the synthesis of unsymmetrical phos-
phinic amides 107 and subsequently unsymmetrical secondary amines 108. When sec-
ondary alkyl bromides are used, only monoalkylation occurs regardless of the amount of
alkyl bromide, giving primary amines after hydrolysis.
If mono(tert-butoxycarbonyl)-protected P,P-diphenylphosphinic amide is used, only a
single alkylation on nitrogen is possible, to give primary amines as the sole products.[200]
Scheme 66 Synthesis of Primary and Secondary Amines from P,P-Diphenylphosphinic

Amide[198]
R1Br (1 equiv)
O NaOH, Bu4N+ HSO4− O HCl(g), THF
benzene, H2O, reflux 20−25 oC, 12 h
Ph P Ph P R1NH2•HCl
NH2 NHR1
Ph Ph
103 104
R1 Yield (%) Ref

103 104
[198]
Et 80 96
[198]
Pr 78 97
[198]
Bu 91 93
[198]
CH2CH=CH2 57 95
[198]
Bn 45 96
R1Br (2−4 equiv)

O NaOH, Bu4N+ HSO4− O HCl(g), THF
Ph P Ph P R12NH•HCl
NH2 NR12
Ph Ph
105 106
R1 Yield (%) Ref

105 106
[198]
Et 91 92
[198]
Pr 85 95
[198]
Bu 82 97
[198]
CH2CH=CH2 77 97
[198]
Bn 79 95

R2Br (2−4 equiv)
O NaOH, Bu4N+ HSO4− O HCl, THF
Ph P Ph P R1R2NH•HCl
NHR1 NR1R2
Ph Ph
103 107 108
R1 R2 Yield (%) Ref

107 108
[198]
Et Pr 93 95
[198]
Et iBu 55 93
[198]
Cy Bu 49 93
[198]
Cy CH2CH=CH2 90 94
[198]
Cy Bn 64 98
Similarly, treatment of diethyl phosphonate with primary amines in the presence of car-
bon tetrachloride or tetrabromide gives the N-alkylphosphoramidate, which can again be
alkylated using alkyl bromides under phase-transfer catalysis and hydrolyzed to give the
secondary amine hydrochloride.[201,202]
Dibromotriphenylphosphorane reacts with alkylamines to give (alkylamino)triphen-
ylphosphonium bromides. If these phosphonium salts are reacted with sodium in liquid
ammonia, (alkylimino)triphenylphosphoranes are obtained. These very moisture-sensi-
tive compounds are treated with alkyl iodides, giving alkylation on nitrogen to produce
(dialkylamino)triphenylphosphonium iodides. Only iodomethane or iodoethane can be
used for this step; higher alkyl iodides result in dehydroiodination to give alkenes. Treat-
ment of the (dialkylamino)triphenylphosphonium iodides with ethanolic potassium hy-
droxide releases the secondary amines which are isolated as their hydrochloride or hydro-
oxalate salts (Scheme 67).[203,204]

Scheme 67 Synthesis of Secondary Amines via Iminotriphenylphosphoranes[203,204]

R1NH2, Et3N, benzene NaNH2, liq NH3
0−20 oC, 3 h H −78 oC, 1 h
Ph3PBr2 + N 1 Br− N
79−93% Ph3P R 93−99% Ph3P R1
R2I (neat or in MeOH) R2 KOH, EtOH

H
reflux, 3 h
+ N 1 I− reflux, 3 h
N
68−95% Ph3P R − Ph3P O R1 R2
67−82%
R1 = t-Bu, Cy, cyclopropyl, cyclopentyl, 1-adamantyl; R2 = Me, Et
For further details of the synthesis of amines via phosphorus amides, see Section
40.1.1.2.3.2.
40.1.1.5.4.3.9 Method 9:

Reactions of Alkyl Halides with Silylamines and Silylamides
Sodium hexamethyldisilazanide reacts with primary alkyl bromides, iodides, or 4-tolu-

enesulfonates in hexamethyldisilazane or hexamethylphosphorous triamide to give N,N-
bis(trimethylsilyl)amines, which can be hydrolyzed with dilute hydrochloric acid to yield
primary amines (Scheme 68).[205]
Scheme 68 Synthesis of Primary Amines from Sodium Hexamethyldisilazanide[205]

Na
R1X R1 HCl, H2O
N N R1NH3+ Cl−
TMS TMS − NaX TMS TMS − (TMS)2O
52−79% 86−100%
R1 = Me, Et, Pr, (CH2)7Me, Bn, CH2CH CH2, CH2CH CHMe, CH2CH CMe(CH2)2CH CMe2, cyclohex-2-enyl
X = Br, I, OTs
A similar synthesis of primary amines 110 using tetramethyldisilazane (109) has also
been reported where isolation of the intermediate silylamines is not necessary (Scheme
69). This method works well for benzylic and allylic halides as well as simple alkyl ha-
lides.[206]
Scheme 69 Synthesis of Primary Amines from Tetramethyldisilazane[206]

1. KH, THF, 0 oC
2. R1Cl, THF, 0 oC to rt
3. HCl
4. NH4OH
(Me2HSi)2NH R1NH2
71−91%
109 110
R1 = (CH2)5Me, (CH)7Me, Bn, 4-ClC6H4CH2, CH2CH CH2, CH2CH CHMe, CH2CMe CH2
X = Cl, Br, I, OTs
Benzylamine (110, R1 = Bn); Typical Procedure:[206]
CAUTION: Potassium hydride ignites on exposure to air and on contact with fluorine and is
highly destructive to all tissues.
(Me2HSi)2NH (109; 8.7 mL, 50 mmol) was added dropwise to 0.5 M KH (2.2 g, 55 mmol) in
THF under argon at 0 8C and the mixture was stirred for 30 min. BnCl (5.75 mL, 50 mmol)
was added slowly and the mixture was stirred at 0 8C for 1 h and then at rt for 1 h. The re-
action was quenched with aq NH4Cl (25 mL), acidified with 0.5 M HCl (20 mL), and then
neutralized with NH4OH. The mixture was extracted with Et2O and the combined organic
layers were dried (MgSO4), concentrated, and purified by distillation; yield: 88%; bp 90 8C/
12 Torr.
40.1.1.5.4.3.10 Method 10:

Intra- and Intermolecular Cyclization Reactions
Many aliphatic amines with halide leaving groups undergo intramolecular displacement
reactions to give cyclic amines but it is often necessary to protect the amine function to
avoid further alkylation reactions. The tosyl protecting group has been widely used for
this type of reaction. The intramolecular cyclization reactions of a range of N-tosyl-w-bro-
moalkylamines in tetrahydrofuran/water (99:1) have been studied.[207] The rate of reaction
decreases in the following order: five-ring > three-ring > six-ring > seven-ring > four-ring.
Nucleophilic substitution is an effective preparative method for the synthesis of pi-
peridines. The displacement of a bromide group by a (4-nitrophenylsulfonyl)amino group

in the presence of 4-(dimethylamino)pyridine is used in the synthesis of polyhydroxylated
piperidines.[208] Stronger bases such as sodium hydride[209] or potassium tert-butoxide[210]
have also been used for cyclization reactions of phosphinamide- and sulfonamide-protect-
ed amines (Scheme 70).
Scheme 70 Synthesis of Piperidines by Intramolecular Substitution of Halides[208–210]
O O
AcO O AcO O
DMAP, CH2Cl2, rt, 3 d
R1 R1 = N3 70% R1
I HN R1 = SPh 71% N
SO2Ar1 SO2Ar1
Ar1 = 4-O2NC6H4
O Me O Me
N N
P P
Cl
MeN t-BuOK, DMF MeN
HN Ph 45−55% N Ph
Ph P Ph P
O O
Ph Ph
O
O O O
O Br O
NaH, DMF, 0 oC
78%; dr 85:15 N
O SO2Ph O SO2Ph
N
Ar1 H Ar1
Ar1 = 3,4,5-(MeO)3C6H2
1-Tosylhexahydro-1H-azepine is synthesized in 74% yield from N-(6-bromohexyl)-4-tolu-

enesulfonamide (itself formed in 65–70% yield from 1,6-dibromohexane and sodium 4-
toluenesulfonamide) by simultaneous addition of a solution of the sulfonamide in bu-
tan-1-ol and a solution of sodium butoxide in butan-1-ol to benzyl alcohol at 170 8C. The
amine can then be deprotected using aqueous hydrobromic acid.[211]
The intermolecular reaction of ammonia or primary amines with di- or trihalides is a
convenient synthetic strategy for the synthesis of cyclic amines. It is possible to prepare
four- to eight-membered rings and both monocyclic and polycyclic structures by this
method. Examples of the synthesis of a range of cyclic amines, including pyrrolidines, e.g.
111,[212] hexahydro-1H-azepines, e.g. 112,[213] 7-nitro-1,2,3,4-tetrahydroisoquinolines
113,[214] bicyclic amines 114[215] and 115,[217] and 1-azaadamantane (116)[216] are depicted
in Scheme 71.
Scheme 71 Cyclic Amines from Di- and Trihalides[212–217]

Me(CH2)11NH2, Na2CO3
Cl Cl BuOH, reflux, 1.5 h
( )4 64% N
( )11
111
MeNH2, EtOH, rt, 3 d

I I
( )6
N
Me

112
Cl
R1NH2
Cl NR1
O 2N O2N
113
Br
NH3, MeOH
Br Br N
114
Br
NH3, MeOH
Br N
Br
115
Br Br
N
NH3
116
Br
Heteroatoms in the backbone of the dihalide are tolerated. For example, when bis(2-chlo-
roethyl) ether is reacted with ammonia the product is morpholine.[218] For larger rings and
strained rings, the use of cesium carbonate[219] or cesium hydroxide[220] as a base has been
found to enhance the product yield. For the synthesis of macrocycles, high pressure is
sometimes also required.[221]
Although monocyclic amines such as pyrrolidines and piperidines can be formed
from the reaction of primary amines with 1,4-dihalobutanes and 1,5-dihalopentanes, re-
spectively, it is also possible to form ammonium salts by overalkylation of the nitrogen,
especially if there is an excess of the dihaloalkane present. If ammonia is used, these salts
contain a spiro nitrogen atom and, in the presence of base, these salts can undergo elim-
ination with ring opening to give monocyclic amines bearing a terminal alkene substitu-
ent on nitrogen.[100]
If 1,5-dibromo-3-(diphenylmethyl)pentane (117) is treated with methanolic ammonia

in a bomb at 130–140 8C, a mixture of 4-(diphenylmethyl)piperidine (118) and the spiro
product 3,9-bis(diphenylmethyl)-6-azoniaspiro[5.5]undecane bromide (119) is obtained
(Scheme 72).[222]
Scheme 72 Formation of Spiro Ammonium Salts by Alkylation of Ammonia[222]

Ph Ph
Ph Ph
Ph Ph NH3, MeOH +
130−140 oC
N
+ Br−
Br Br N
H
Ph Ph
117 118 119

34% 38%
Sodium hydride in dioxane facilitates the reaction between diethyl {2-[benzyl(meth-

yl)amino]ethyl}malonate (120) and 1,2-dibromoethane to form a piperidinium salt 121,
which on reduction with palladium/carbon and hydrogen gives diethyl 1-methyl-
piperidine-4,4-dicarboxylate (122) (Scheme 73).[223]
Scheme 73 Synthesis of a Piperidine from a Dibromoethane[223]

1. NaH, dioxane
reflux EtO2C CO2Et
CO2Et 2. Br(CH2)2Br
100 oC H2, Pd/C, rt
Bn Br−
EtO2C N 59% + 96%
Me N
Me Bn
120 121
EtO2C CO2Et
N
Me
122
1,1¢-Binaphthyl-substituted tertiary amines 124 and quaternary ammonium salts 126 are
synthesized by double alkylation of primary or secondary amines, respectively, with 2,2¢-
bis(bromomethyl)-1,1¢-binaphthyl (123). Cleavage of the resulting seven-membered ring
by reduction with lithium aluminum hydride in tetrahydrofuran gives the corresponding
2-(aminomethyl)-2¢-methyl-1,1¢-binaphthyls 125 and 127 without racemization (Scheme
74).[224] As well as simple amines, ephedrine and chiral pyrrolidines have also been em-
ployed as substrates in this reaction. The chiral amine products are of interest as ligands
in asymmetric synthesis.

Scheme 74 Synthesis of Binaphthyl-Substituted Amines[224]
Br
Br
123
R1NH2
benzene LiAlH4 NHR1
MeCN THF, reflux
NR1
R1 = Me 72% R1 = Me 72%
124 125

R1R2NH
benzene LiAlH4 NR1R2
R1 THF, reflux
MeCN +N
R1 = R2 = Me 75% R2 R1 = R2 = Me 61%
Br−
126 127
Similarly, reaction of 2,2¢-bis(dibromomethyl)biphenyl with primary and secondary

amines gives the corresponding N-alkylhexahydro-1H-azepines and N,N-dialkylhexahy-
dro-1H-azepinium salts, respectively.[225] Reaction with ammonia gives the spiro ammoni-
um salt arising from reaction of one molecule of ammonia with two molecules of the di-
bromide.
The reaction of N-benzylic N¢-tert-butyl-N-methylformimidamides 128 with butyl-
lithium in tetrahydrofuran at –78 8C followed by either 1-chloro-3-iodopropane or 1-chlo-
ro-4-iodobutane and subsequent treatment with hydrazine hydrate in acetic acid/ethanol
gives 1-methyl-2-phenylpyrrolidines 129 (n = 1) and 2-aryl-1-methylpiperidines 129
(n = 2), respectively (Scheme 75).[226]
Scheme 75 Synthesis of Cyclic Amines from Formimidamides[226]

() Cl
1. R1Li, THF, −78 oC n
2. I ( )n Cl
Ar1 NMe Ar1 NMe
−78 oC to rt EtOH/AcOH/H2NNH2 (3:1:2), rt
N N
But But
128
( )n
Ar1 N
Me
129
Ar1 R1 n Yield (%) of 129 Ref
[226]
Ph Bu 1 64
[226]
Ph Bu 2 67
[226]
4-ClC6H4 Bu 1 63
[226]
4-ClC6H4 Bu 2 67
[226]
4-MeOC6H4 t-Bu 1 67
[226]
4-MeOC6H4 t-Bu 2 61
[226]
2-pyridyl Bu 1 62
[226]
2-pyridyl Bu 2 66
[226]
3-pyridyl Bu 1 60
[226]
3-pyridyl Bu 2 62
[226]
4-pyridyl Bu 1 72
[226]
4-pyridyl Bu 2 77

A variation on this reaction with the amino nitrogen of the formimidamide being part of
a heterocyclic moiety such as pyrrolidine or piperidine allows the formation of pyrrolizi-
dine, indolizidine, and quinolizidine rings. Lithiation (using tert-butyllithium) at the 2-po-
sition of the nitrogen-containing ring and transmetalation using pent-1-ynylcopper(I) is
followed by treatment with the required dihaloalkane, then aqueous sodium sulfide and
finally potassium hydroxide, giving bicyclic amines in 70–90% yield.[227]
N-Substituted cyclic amines can be formed from haloalkyl azides with ring closure
via aminyl radicals.[228] When a haloalkyl azide is refluxed with tributyltin hydride or
tris(trimethylsilyl)silane in the presence of 2,2¢-azobisisobutyronitrile, and then 4-tolu-
enesulfonyl chloride, an alkyl radical forms that reacts intramolecularly with the azide,
releasing dinitrogen and forming an aminyl radical that is trapped as an N-tosylamine.
Thiocarbonates can be used as well as iodo- and bromo(alkyl) azides and the reaction can
be used to prepare bicyclic systems as well as both substituted and unsubstituted N-tosyl-
pyrrolidines and -piperidines.[228]
40.1.1.5.4.3.11 Method 11:

Reactions of Haloamines
The reactions of dialkylhaloamines with alkanes to give haloalkanes and secondary

amines are described in Science of Synthesis, Vol. 35 [Chlorine, Bromine, and Iodine (Sec-
tions 35.1.1.1.1.6 and 35.1.1.1.3.2)].[229] These reactions are primarily of interest as a meth-
od of introducing halogens onto an alkyl chain rather than as a way of synthesizing
amines.
The aminochlorination of alkenes to give (2-chloroalkyl)amines is covered in Science
of Synthesis, Vol. 35 [Chlorine, Bromine, and Iodine (Section 35.1.5.1.10.1)].
Cyclic tertiary amines can be formed by intramolecular reactions of N-haloamine
functions with alkanes or alkenes (the Hofmann–Lçffler–Freytag reaction).[230] These reac-
tions can be initiated in a number of ways including irradiation,[230] the use of copper(I)
salts,[230–232] samarium(II) iodide,[233] or tetrabutylammonium iodide.[234] This chemistry is
covered in Science of Synthesis, Vol. 35 [Chlorine, Bromine, and Iodine (Section
35.1.5.1.10.2)].
Cyclization reactions with ring contractions and ring expansions are known. An ex-
ample of a ring contraction is the reaction of 3-chloro-1-ethylpiperidine in the presence of
benzylamine at 65–75 8C to form 2-(benzylaminomethyl)-1-ethylpyrrolidine (73%
yield).[235]

An example of a ring expansion is the reaction of 2-chloromethyl-1-ethylpyrrolidine

hydrochloride in the presence of sodium hydroxide to form 3-chloro-1-ethyl-
piperidine.[236] Both reaction mechanisms are proposed to proceed via a chloro-
aziridinium transition state.
40.1.1.5.4.4 Replacement of Oxygen Functionalities
The reaction between ammonia and alcohols is a common way to prepare amines in in-
dustrial chemistry; reductive alkylation using aldehydes or ketones is an alternative pro-
cess. This works well on an industrial scale but is not always suitable for the laboratory if
a specific amine is required in high yield. So, in the laboratory it is more common to put a
leaving group on the alcohol to assist in the nucleophilic displacement reaction by the
attacking ammonia or amine. In any case, the reaction between the attacking nucleophile
and ammonia tends to yield a mixture of mono-, di-, and trisubstituted products, which
have to be separated by fractional distillation.

The synthetic methods available in the 1960s for N-alkylation of amines using alco-
hols and ethers have been reviewed.[237] A more recent review of the production methods
for the manufacture of lower aliphatic amines is also available.[238]
40.1.1.5.4.4.1 Method 1:
Reactions of Ammonia with Alcoholic Hydroxy Groups
The reaction of ammonia with hydroxy groups in the presence of many other functional
groups has been reported (Scheme 76; see also Houben–Weyl, Vol. 11/1, p 108).
Scheme 76 Reactions of Hydroxy Groups with Ammonia

NH3
() ()
R1 n OH R1 n NH2
R1 = OR2, NR22, NHCOR2, NHSO2R2, SO3H, SO2R2; n >−2
The reaction of ammonia with hydroxy groups is similar to the reaction with alkyl halides
(see Section 40.1.1.5.4.3.1) in that the reaction products are usually a mixture of mono-,
di-, and trisubstituted products. The reason is that mono- and dialkylamines compete
with the still-available ammonia for the alcoholic substrate giving additional alkylation
to form dialkyl- and trialkylamines, respectively. The lack of selectivity limits the useful-
ness of this method for laboratory synthesis but the N-alkylation of ammonia remains a
very important industrial method for the manufacture of many simple alkylamines.
A convenient approach to replace the alcoholic hydroxy group is by heterogeneous
catalysis using various metal oxides (see Houben–Weyl, Vol. 11/1, pp 112–120). The most
commonly encountered catalysts for this type of reaction are the oxides of thorium, alu-
minum, chromium, silicon, and tungsten. Thorium(IV) oxide (thoria) has been described
as a very active catalyst.[239–241] The reaction between ammonia and ethanol over thori-
um(IV) oxide at 350–370 8C gives a mixture of ethylamine, diethylamine, and triethyl-
amine. Pure alumina is slightly less active, but is the most widely used catalyst for direct
amination reactions. Yields can be considerably improved by using thermally activated
bauxite as the catalyst.[240] The mixture obtained from this type of catalyzed reaction de-
pends on the precise reaction conditions and is affected by temperature, pressure, feed
rates, the catalyst used, the nature of the alcohol used, and whether or not hydrogen is
added to suppress nitrile formation. Iron(III) oxide is also often added to the alumina or
bauxite support as an activator; the optimum concentration of iron oxide is about 3%.
Some results obtained for the reaction of ammonia with methanol[242–247] and butan-1-
ol,[241,248–251] respectively, using different catalyst systems are given in Tables 4 and 5. To
date, most studies of the N-alkylation of ammonia have been performed at high pressures
and temperatures. The preferred conditions for the synthesis of methylamine are 500 8C
in the presence of an alumina catalyst. The ammonia to alcohol ratio is generally in the
region of 2.4:1 to give a mixture of methylamine (54%), diethylamine (26%), and trimeth-
ylamine (20%).[240,241]
Table 4 The Vapor-Phase Reaction of Methanol and Ammonia[242–247]

catalyst
MeOH + NH3 MeNH2 + Me2NH + Me3N
Catalyst Temp ( 8C) Conversiona (%) Yielda (%) Ref

MeNH2 Me2NH Me3N
[242]
alumina 405 24 43 26 31
[243]
alumina 450 n.r. n.r. 28 57
[244]
alumina/silica 340 31 31 n.r. n.r.
[245]
kaolin 460 56 43 n.r. n.r.

[246]
AlPO4 400 n.r. 55 n.r. n.r.
[247]
Cu/Mn/alumina 380 100 83 15 2
a
Table 5 The Vapor-Phase Reaction of Butan-1-ol and Ammonia[241,244,248–251]

catalyst
BuOH + NH3 BuNH2 + Bu2NH + Bu3N + Bu2O
Catalyst Amount Temp Yielda (%) Ref

(%) of Fe2O3 ( 8C)
added Alkenes Bu2O BuNH2 Bu2NH Bu3N
bauxite 2.73 320b 13 9 21 29 9 [241]
alumina 0 320b 27 3 32 3 2 [241]
[244]
alumina/silica 0 325 n.r. n.r. 5 16 4
[249]
Cr2O3/silica/alumina 0 330 n.r. n.r. 43 32 n.r.
[249]
V2O5/silica/alumina 0 347 n.r. n.r. 30 35 n.r.
[249]
NiO/silica/alumina 0 350 n.r. n.r. 38 34 n.r.
[248]
Cr2O3/alumina 0 347 n.r. n.r. 53 20 n.r.
[250]
Ni/H2 0 181 n.r. n.r. 24 47 15
[251]
Cu/Al/Ba(OH)2 0 250 n.r. n.r. 17 52 12
a
b
Catalyst activated at 425 8C.
The reaction of cyclohexanol with ammonia in the presence of a nickel catalyst gives the
monoalkylation product 130 in excellent yield with only small quantities of the second-
ary amine 131 being formed (Scheme 77).[252]
Scheme 77 Reaction of Cyclohexanol with Ammonia[252]

NH3, Ni, 150 oC
CyOH CyNH2 + Cy2NH
130 91% 131 5%
Ammonia also reacts with some diols to form cyclic amines. For example, 2,2-dinitropro-
pane-1,3-diol (132) reacts with ammonia in aqueous solution to form 3,3-dinitroazetidine
(133) in 29% yield.[253] In other cases however, only one hydroxy group reacts as in the case

for diethylene glycol (134), which upon reaction with liquid ammonia in the presence of
nickel gives the amino alcohol 135 in 75% yield (Scheme 78).[254–256]
Scheme 78 Reaction of Diols with Ammonia[253,254]

O2N NO2 O2N NO2
NH3, H2O
29%
HO OH N
H
132 133
NH3, Ni, 220 oC

O HO NH2
HO OH 75% O
134 135
Cyclohexylamine (130); Typical Procedure:[252]

CyOH (750 g, 7.5 mol) and finely divided Ni (75 g, 1.28 mol) were placed in a stirred auto-
clave and the mixture was saturated with NH3. The autoclave was heated at 150 8C until
the internal pressure in the autoclave had dropped from 20 to 15 atm. This procedure was
repeated a further two times. The catalyst, which could be reused, was collected by filtra-
tion and the filtrate was acidified with H2SO4 and then steam distilled to remove unreact-
ed CyOH (260 g, 35%). The residue was treated with excess alkali and steam distilled. The
amine, which was separated from the distillate by addition of aq NaOH, was dried (KOH)
and fractionally distilled; yield: 442 g (91%, based on recovered starting material). Cy2NH,
which could be recovered by crystallization, was present in the distillation residue; yield:
ca. 25 g (5%, based on recovered starting material).
2-(2-Hydroxyethoxy)ethylamine (135); Typical Procedure:[254,256]

A mixture of diethylene glycol (134; 1330 g, 12.5 mol), liq NH3 (960 g, 56.5 mol), and Raney
Ni (40 g, 0.68 mol) was stirred and heated at 220 8C for 2 h in an autoclave. The pressure
reached 160–170 atm. After cooling the mixture, the excess NH3 was released, the catalyst
was removed by filtration, and the filtrate was distilled over a column. The first fraction
was H2O and a little morpholine. The desired product was then collected, while the distil-
lation residue consisted of unreacted starting material; yield: 440 g (75% with respect to
consumed starting material); bp 108–112 8C.
40.1.1.5.4.4.2 Method 2:
Reactions of Primary or Secondary Amines with Alcoholic Hydroxy Groups
Primary and secondary amines react with alkanols in a similar manner to ammonia, us-
ing a similar range of catalysts (see Section 40.1.1.5.4.4.1) to give secondary and tertiary
amines respectively (see also Houben–Weyl, Vol. 11/1, pp 112–122). Quite often, typical hy-
drogenation catalysts such as palladium metal (80–120 8C for 6–26 h),[257] copper chro-
mite,[258–260]or nickel[250,261] can also be used. Some representative examples are illustrated
in Scheme 79 and further examples are available in Houben–Weyl, Vol. 11/1, pp 126–134.
The alkylation of piperidine with propan-1-ol using tri-tert-butoxyaluminum and Raney
nickel is described in Science of Synthesis, Vol. 7 [Compounds of Groups 13 and 2 (Al, Ga,
In, Tl, Be…Ba) (Section 7.1.4.5.4)].
Scheme 79 Nickel or Copper Chromite Catalyzed Reactions between Amines and

Alcohols[250,258–261]
EtNH2, Ni, H2
150 oC
BuOH EtBuNH + EtBu2N
25% 15%
Ni, Kieselguhr, H2
100 atm, 200 oC
R1OH +
R1 = Et; R2 = H 80%
N R2 R1 = Bu; R2 = Me 78%
N R2
H R1
R1 = Cy; R2 = H 76%
CuCr2O4, 180−200 oC
R1OH + R2NH2 R1R2NH
R = Et; R2= (CH2)4Me 39%
1
R1 = Pr; R2 = Pri 61%
CuCr2O4, 200−250 oC
R1OH +
R1 = (CH2)5Me 84%
N R1 = (CH2)11Me 69%
N1
H R
BnNH2, CuCr2O4, 250 oC

HO
( )3 OH 76% N
Bn
Me(CH2)4NH2
OH
CuCr2O4, 250 oC ( )n
OH N
( )n n = 1 60%
n = 2 75% ()
4
n = 3 17%
Homogeneous catalysts that have been widely used for the reaction between secondary
amines and alcoholic hydroxy groups include ruthenium[262–264] and rhodium com-
plexes.[265] With amino alcohols, cyclization occurs to give pyrrolidines, piperidines, and
hexahydro-1H-azepines.[264] In the presence of an added alcohol, a tertiary amine is pro-
duced. The same compounds can be prepared by treating the corresponding diol (instead
of the amino alcohol) with a primary amine (Scheme 80).[264] For further examples and the
use of other catalysts see Houben–Weyl, Vol. E 16d, pp 714–725.
Scheme 80 Ruthenium-Catalyzed Cyclization Reactions of Amino Alcohols[264]

RuH2(PPh3)4
( )n
NH2 155 oC, 18−24 h
HO ( )n n = 1 79%
N
n = 2 89% H
n = 3 41%
()
5 OH
RuH2(PPh3)4
( )n
NH2 155 oC, 6−24 h
HO ( )n n = 1 58%
N
n = 2 80%
n = 3 21% ()
5
()
5 NH2
RuH2(PPh3)4
( )n
OH 155 oC, 4−24 h
HO ( )n n = 1 40%
N
n = 2 83%
n = 3 87% ()
5
Molecules containing both hydroxy and amino groups can react both intramolecularly
and intermolecularly. For example bis(2-hydroxyethyl)amine (136, diethanolamine) re-
acts at 200 8C in the presence of acetic acid to form 1,4-bis(2-hydroxyethyl)piperazine
(137) (Scheme 81).[266]

Scheme 81 Inter- and Intramolecular Reaction of an Amino Alcohol[266]
OH
N
HO OH AcOH, 200 oC
N
H − H2O
70% N
OH
136 137
The reagent mixture manganese(IV) oxide/sodium borohydride facilitates the reaction be-
tween an amine and an alcohol in a one-pot process to yield secondary and tertiary
amines (Scheme 82).[267] A variation of this process uses polymer-supported cyanoborohy-
dride to effect reduction of the intermediate imine.[268]
Scheme 82 Manganese(IV) Oxide/Sodium Borohydride Mediated Reaction between

Amines and Alcohols[267]

1. MnO2 (2 equiv)
NaBH4 (2 equiv)
CH2Cl2, 16−21 h
2. MeOH, 40 min
R1 OH + R1NH 2 R1 NHR2
R1 R2 Yield (%) Ref
[267]
4-MeOC6H4 iBu 93
[267]
4-MeOC6H4 iPr 87
[267]
4-MeOC6H4 CH2CH=CH2 57
[267]
4-BrC6H4 iBu 86
[267]
4-O2NC6H4 iBu 85
[267]
1-naphthyl iBu 78
[267]
CH=CHPh iBu 71
[267]
C”CPh iBu 57
The palladium-catalyzed reactions of allylic alcohols with primary and secondary amines
in which the amine adds to an h2- or h3-complex have been reviewed (for the synthesis of
allylic amines see Section 40.1.3).[269,270]
40.1.1.5.4.4.3 Method 3:
The Mitsunobu and Related Reactions
The Mitsunobu reaction enables a hydroxy group to be replaced by a wide range of nucle-
ophiles.[159,271,272] Although the major application of the Mitsunobu reaction is the inver-
sion of secondary alcohols, it has also been extended to the general synthesis of amines
from alcohols.
The synthesis of amines from alcohols using the Mitsunobu reaction requires the
amines to be activated (and protected) in the form of N-alkylsulfonamides, amides,
phthalimides, or trifluoroacetamides; only in intramolecular versions of the reaction
might a protective group not be required.[273]
Scheme 83 and Table 6 show some applications of the Mitsunobu reaction using
phthalimide for the synthesis of amines 139 via alkylated phthalimides 138.[274,275]
Scheme 83 Synthesis of an Amine by Mitsunobu Reaction Using Phthalimide[275]

PhthNH
DEAD, Ph3P H2NNH2•H2O
OH NPhth NH2
THF, rt EtOH
( )5 79% ( )5 48% ( )5
Table 6 Synthesis of Allylic Amines by the Mitsunobu Reaction[274]

PhthNH
DIAD, Ph3P H2NNH2 or MeNH2
rt, 4 h MeOH
1 1
R OH R NPhth R1NH2
138 139
DIAD = diisopropyl azodicarboxylate
R1OH Yield (%) Ref

138 139

() 93 86 [274]
2 ( )2 OH
[274]
88 85
OH
OH
[274]
98 88
[274]
76 76
OH
Attempts to perform enantioselective Mitsunobu reactions of phthalimide with racemic

benzylic alcohols employing the chiral binaphthyl-based phosphorus reagent 140 in con-
junction with diethyl azodicarboxylate give moderate yields of the amines 141, with only
low enantioselectivity (£45%) (Scheme 84).[276]
Scheme 84 Enantioselective Mitsunobu Synthesis of Amines[276]

PhthNH, 140, DEAD
OH NPhth NH2
THF, reflux H2NNH2
1
R R1 R1
Ar1 36−45% Ar1 55−65%; 26−45% ee Ar1
141
O
P NMe2
O
140
Ar1 = Ph, 2,4-Cl2C6H3, 2,3,4-Cl3C6H2, 4-O2NC6H4; R1 = H, Me, Cl
The alkylations of N-methyl-4-toluenesulfonamide and N-(tert-butoxycarbonyl)-4-toluene-

sulfonamide under Mitsunobu conditions are useful synthetic strategies but they have

the disadvantage that they require relatively strong deprotection conditions (Scheme 85;
cf. Section 40.1.1.2.3.1).[277] Intramolecular reactions give 1-tosylpyrrolidine and -piperi-
dine in 95 and 85% yield, respectively, from the corresponding N-tosylamino alcohols. In
the case of N-(tert-butoxycarbonyl)-4-toluenesulfonamide selective removal of the nitro-
gen protecting groups is possible (Scheme 85). It is worth noting that 4-toluenesulfon-
amide itself is not useful in the Mitsunobu reaction since it reacts with triphenylphos-
phine to form a phosphinimine.[278]
Scheme 85 Mitsunobu Reactions Using 4-Toluenesulfonamides[277]

TsNHR2, DEAD
Ph3P, THF, rt Ts
R1OH N
R1 R2
R1 R2 Yield Ref
[277]
Bn Me 50

[277]
(CH2)2Ph Me 58
[277]
(CH2)2C”CMe Me 51
( )2
[277]
Me 80
( )2
[277]
Me 58
Br
[277]
Me 62
[277]
(CH2)2Ph Boc 97
[277]
(CH2)2C”CMe Boc 96
[277]
CHMe(CH2)2Ph Boc 92
[277]
(Z)-(CH2)2CH=CHEt Boc 88
[277]
CH2CH=CMe2 Boc 85
[277]
CHMe(CH2)2CH=CH2 Boc 75
A: DMSO, 170−180 oC
20 min NHTs
B: TFA, CH2Cl2, rt
Ts Boc
N A: 83%
H Ts
DEAD, Ph3P B: 69%
OH N
THF, rt Boc
86%
sodium naphthalenide NHBoc
DME, rt
82%
N-Tosylamino alcohol 142 cyclizes under Mitsunobu conditions to give pipecolinic acid
derivative 143 (Scheme 86).[279] Cyclization of the unprotected secondary alcohol to give
an aziridine does not occur.
Scheme 86 Synthesis of a Pipecolinic Acid Derivative by Mitsunobu Reaction[279]
O O
O OH DEAD, Ph3P O OH
THF, rt, 30 min
92%
HO HN N
CO2But Ts CO2But
Ts
142 143
In a similar manner, N-alkyl-1,1,1-trifluoromethanesulfonamides react with alcohols un-

der Mitsunobu conditions to give amines (Scheme 87).[280]
Scheme 87 Mitsunobu Reaction of Trifluoromethanesulfonamides with Alcohols[280]

TfNHMe, DEAD Me Tf
OH
Ph3P, THF N KOH, EtOH
87% 61%

OBz
OBz
H H
Me Tf N N Me Tf Me Tf
N Tf ( )7 Tf N N
80% ()
OH N 7 N
Tf Tf
1. Na, NH3, THF, t-BuOH

2. Boc2O
NHMe NHMe
3. HCl, MeOH
•4HCl
()
31% N 7 N
H H
A comparison of the reaction of N-methyl-4-toluenesulfonamide (144, X = Ts) and 1,1,1-tri-

fluoro-N-methylmethanesulfonamide (144, X = Tf) with various alcohols shows that in the
case of alkyl alcohols, the yields of the alkylated products 145 are better when the trifluo-
romethanesulfonamide is employed (Scheme 88).[280] It is interesting to note that this dif-
ference is less clear when N-phenyl-1,1,1-trifluoromethanesulfonamide and N-phenyl-4-
toluenesulfonamide are used, with the 4-toluenesulfonamide giving better yields of the
protected anilines in some cases.
Scheme 88 A Comparison of 4-Toluenesulfonamides and Trifluoromethanesulfonamides in

the Mitsunobu Reaction[280]
DEAD
Me X Ph3P, THF R1 X
R1OH + N N
H Me
144 145
R1 X Yield (%) Ref
[280]
Bn Tf 70
[280]
Bn Ts 33
[280]
iPr Tf 82
[280]
iPr Ts 53
[280]
(CH)2CH(OH)Me Tf 66
[280]
(CH)2CH(OH)Me Ts 48
The 2-nitrophenylsulfonyl group (Ns or nosyl) acts as both a protecting and activating
group for amines, and is cleaved under relatively mild conditions.[281] Both primary

amines 147 (R3 = H) and secondary amines 147 [R3 = (CH2)2Ph] can be prepared from alka-
nols via the sulfonamides 146 under Mitsunobu conditions using 2-nitrobenzenesulfon-
amide or N-alkyl-2-nitrobenzenesulfonamides, respectively, in the presence of di-tert-bu-
tyl azodicarboxylate (DBAD) and diphenyl(2-pyridyl)phosphine (Scheme 89).[282] With the
Fukuyama–Mitsunobu procedure[281] it is possible to convert a primary alcohol into a pro-
tected primary amine under particularly mild conditions.
Scheme 89 Mitsunobu Reaction of Alcohols with 2-Nitrobenzenesulfonamides[282]

NsNHR3
OH Ar1Ph2P R3 Ns NHR3
DBAD N K2CO3, PhSH
R1 R2 R1 R2
R1 R2
146 147
Ns = 2-O2NC6H4SO2; Ar1 = 2-pyridyl

R1 R2 R3 Yield (%) Ref
146 147
[282]
Bn H H 97 89
[282]
4-MeOC6H4CH2 H H 90 95
[282]
4-O2NC6H4CH2 H H 89 91
[282]
CH=CHPh H H 90 86
[282]
Bu H H 96 90
[282]
CHMePr H H 75 100
[282]
C”CEt H H 92 91
[282]
Bu Me H 70 80
[282]
Bn Me H 85 84
[282]
Bu H (CH2)2Ph 74 90
[282]
Bn H (CH2)2Ph 64 96
[282]
Bu Me (CH2)2Ph 50 96
[282]
Bn Me (CH2)2Ph 40 94
Polymer-supported 2-nitrobenzenesulfonamides, e.g. 148, have been used in sequential

Mitsunobu type reactions en route to polyamines (Scheme 90).[283,284] A variety of phos-
phines and azo compounds have been explored in this context.[283–285]
Scheme 90 Solid-Phase Mitsunobu Synthesis of Polyamines[283]

H
HO N O TMS
( )3 ( )2
O
O
() Ns ADDP, Bu3P () () ()
N 3 N N 3 N 3 N O 2 TMS
H H up to 100% H Ns H
148
ADDP = N N
N N
O
Amines can also be synthesized indirectly via the Staudinger reduction of azides (see Sec-
tion 40.1.1.1.5.4.7), which can be formed in high yields using hydrazoic acid in the Mitsu-
nobu reaction.[286] The Staudinger procedure can be combined with the Mitsunobu reac-
tion in a one-pot procedure to enable the synthesis of primary amines from primary alco-
hols via an intermediate azide in moderate to good yields. This procedure involves treat-
ing alcohols with hydrazoic acid, diisopropyl azodicarboxylate (DIAD), and triphenyl-
phosphine in tetrahydrofuran solution, followed by treatment with further triphenyl-
phosphine and then hydrolysis (Scheme 91).[287] When the reaction is applied to nonrace-
mic chiral alcohols, in some cases clean inversion of stereochemistry is observed, but
when methyl (S)-mandelate is used, racemic product is obtained. It is proposed that race-
mization occurs due to the formation of a stabilized carbanion during formation of the
intermediate azide.
Scheme 91 Synthesis of Amines from Alcohols via a Staudinger–Mitsunobu Procedure[287]

HN3, DIAD, Ph3P
benzene, THF Ph3P, THF
20 or 50 oC, 1−3 h 20 oC, 3−18 h N
1
R OH R1N 3 R1 PPh3

H2O or HCl
R1NH2
41−85%
R1 = Bn, CHMe(CH2)5Me, (CH2)2O(CH2)2OEt, CHPhCO2Me, CHMeCO2H, CH2CH2(NEt2)CO2H
CH2CH(NHCbz)CO2Me,
O O
Diphenyl phosphorazidate in conjunction with triphenylphosphine and diethyl azodicar-

boxylate has been reported as being effective in the conversion of steroids with 3-hydroxy
functions into the 3-amino derivatives with inversion of stereochemistry at this center
(Scheme 92).[288]
Scheme 92 Synthesis of Steroid-Based Amines[288]
OH
CO2R1
H
(PhO)2P(O)N3, DEAD
Ph3P, THF, rt, 4 d
R1 = Me 43%
HO OH
H R1 = Bn 40%
OH
CO2R1
H
H2N OH
H
The treatment of alcohols 149 with sodium azide and greater than 2 equivalents of tri-
phenylphosphine in a mixed solvent (carbon tetrachloride/dimethylformamide 1:4) at
90 8C enables the synthesis of a range of amines 150 (85–95%) in a one-flask reaction. Re-
actions with primary alcohols take 4–6 hours and reactions with secondary alcohols take
8–10 hours.[289] If only 1 equivalent of triphenylphosphine is used, the alkyl azide 151 is
obtained (Scheme 93).

Scheme 93 Synthesis of Amines from Alcohols via Azides[289]

Ph3P (>2 equiv)
R1NH2
NaN3 85−95%
CCl4/DMF (1:4) 150
R1OH
149 Ph3P (1 equiv)
R1 N 3
92−96%
151
R1 = alkyl, Bn, 4-HOC6H4CH2, 4-TolCH2, CH2CH CHPh, 6,7-didehydrocholestan-3-yl, menthyl
Tributyl(cyanomethylene)phosphorane (152) and 4-toluenesulfonamide react with pri-

mary and secondary alcohols in a Mitsunobu-type reaction to give sulfonamides 153,
which can be cleaved with sodium naphthalenide to give the free amines 154 (Scheme
94).[290] Alkyl alcohols give monoalkylated sulfonamides and hence primary amines, but
allylic and benzylic alcohols result in a significant amount of double alkylation on nitro-
gen and so mixtures of primary and secondary amines are obtained.

Scheme 94 Tributyl(cyanomethylene)phosphorane-Promoted Amination of Alcohols[290]
Bu3P CN 152
TsNH2, benzene sodium naphthalenide
R1OH R1NHTs R1NH2
R1 = Bu 93%
R1 = CHMe(CH2)5Me 89% 153 154
R1 = 88%
O O
Primary and secondary amines react with alcohols 155 in anhydrous tetrahydrofuran, in
the presence of triphenylphosphine and N-bromosuccinimide, to yield secondary and ter-
tiary amines 156, respectively (Scheme 95).[291] The reaction proceeds via alkoxyphosphoni-
um salt intermediates and is sensitive to steric factors, working best for primary alcohols.
Scheme 95 Triphenylphosphine–N-Bromosuccinimide-Mediated Amination of Alcohols[291]
1. Ph3P, NBS, THF R2
2. R1R3NH
R1OH N
− Ph3P O R1 R3
155 156
−O O
N
H
R1 R2 R3 Yield (%) Ref
[291]
Bn Me Me 56
[291]
Bn Et Et 60
[291]
Bn (CH2)4 60
[291]
Bn (CH2)5 58
[291]
Bn (CH2)2O(CH2)2 79
[291]
Bn t-Bu H 80
[291]
(CH)2Ph Me Me 71
[291]
CH2C”CH Bu Bu 80
[291]
(CH2)3Ac Bu Bu 19
[291]
CHEt2 Bn H 31
[291]
Bu Bu 21
O
2-Nitrobenzenesulfonamides 146; General Procedure:[282]

A mixture of 2-nitrobenzenesulfonamide (0.202 g, 1 mmol) or 2-nitro-N-(2-phenyleth-
yl)benzenesulfonamide (0.306 g, 1 mmol), diphenyl(2-pyridyl)phosphine (0.263 g,
1.0 mmol), and the alcohol (0.5 mmol) was dissolved in anhyd CH2Cl2 (10 mL) under N2.
Di-tert-butyl azodicarboxylate (0.230 g, 1.0 mmol) was added [in one portion for reactions
using 2-nitrobenzenesulfonamide, but via syringe pump over 30–45 min for reactions us-
ing 2-nitro-N-(2-phenylethyl)benzenesulfonamide] and the mixture was stirred at rt for
2 h. Then, 4 M HCl in 1,4-dioxane (5 mL) was added and, after stirring for 1 h, excess sol-
vent was evaporated. The residue was dissolved in CH2Cl2 and washed with 4 M HCl (2 F).
The organic layer was dried (MgSO4) and concentrated. The residue was purified by col-
umn chromatography (hexane/EtOAc).
Primary and Secondary Amines 147; General Procedure:[282]

A mixture of the sulfonamide 146 (0.6 mmol), PhSH (0.195 g, 1.8 mmol), and K2CO3
(0.326 g, 2.4 mmol) in MeCN (10 mL) was stirred at 50 8C for 5–12 h. Once the reaction

had been completed (TLC) the mixture was purified by flash chromatography (silica gel,
CH2Cl2/MeOH/NH3).
Amines 150; General Procedure:[289]
CAUTION: Sodium azide can explode on heating and is highly toxic. Contact of metal azides
with acids liberates the highly toxic and explosive hydrazoic acid.
A mixture of the alcohol 149 (2 mmol), NaN3 (2.4 mmol), and Ph3P (4.2 mmol) in CCl4
(CAUTION: toxic)/DMF (4:1; 10 mL) was heated to 90 8C with stirring and the reaction was
monitored by TLC. When all the alcohol had been consumed, the mixture was allowed to
cool to rt and quenched with H2O (5 mL). The quenched soln was stirred for 10 min and
then diluted with Et2O (25 mL), and the organic phase was washed thoroughly with H2O.
Trituration of the Et2O fraction at 0 8C facilitated crystallization of Ph3PO, which was re-
moved by filtration. The filtrate was dried (Na2SO4), filtered, and concentrated; yield: 85–
95%.
N-Benzyl-tert-butylamine (156, R1 = Bn; R2 = t-Bu; R3 = H); Typical Procedure:[291]

To a stirred soln of Ph3P (1.31 g, 5 mmol) and BnOH (0.54 g, 5 mmol) in anhyd THF (4 mL) at
–18 8C was added NBS (0.89 g, 5 mmol) in small portions over 2–3 min. After 5 min, t-
BuNH2 (1.2 mL, 0.88 g, 12 mmol) was added by syringe in one portion. The mixture was
stirred for a few min, and then heated at 80 8C for 1 h. The reaction was cooled and petro-
leum ether (15 mL) was added with rapid stirring. The Ph3PO and succinimide that precipi-
tated were removed by filtration. The amine was recovered from the filtrate by dil HCl/
NaOH treatments and extraction into petroleum ether followed by drying (MgSO4) and ex-
traction. Removal of solvents and Kugelrohr distillation gave the product; yield: 0.655 g
(80%).
40.1.1.5.4.4.4 Method 4:
Intermolecular Schmidt Reaction
The intermolecular Schmidt-type reaction of alkyl azides with carbocations derived from
alcohols, followed by reduction of the iminium species with sodium borohydride results
in the formation of amines. Although the reported yields are high for benzylic alcohols,
the reaction can occur with migration of hydrogen to give the expected benzylic amine,
with migration of a benzylic alkyl group to give an alternative benzylic amine, or migra-
tion of an aryl group to give an arylamine, and the regioselectivity is impossible to predict
(Scheme 96).[292] The reaction can also be applied to non-benzylic alcohols; for example 1-

methylcyclopentanol (157) reacts with butyl azide (obtained from butylamine) in dichlo-
romethane in the presence of trifluoromethanesulfonic acid, followed by reduction with
sodium borohydride in methanol to give a 95% yield of 1-butyl-2-methylpiperidine
(158).[292]
Scheme 96 Synthesis of Amines by Intermolecular Schmidt Reaction[292]

N3
1. , SnCl4 Ph Et Bn Me Ph
N N
OH
2. NaBH4 N
+ +
Ph 57%
2.5:1:2
OH 1. BuN3, TfOH
2. NaBH4
95%

N
Bu
157 158
40.1.1.5.4.4.5 Method 5:
Reactions of Ammonia and Amines with Ethers
There are several possible reaction products from the reactions between ethers and am-
monia (or amines) (Scheme 97). The reaction with symmetrical ethers can be used suc-
cessfully leading to reasonable product ratios, but the reaction with unsymmetrical
ethers is harder to control and is normally only worth considering if the two substituents
on the ether differ significantly in size and properties.
Scheme 97 The Potential Reactions of Ethers with Ammonia

R1NH2 + R2OH
R2NH2 + R1OH
NH3 (excess)
O
R1 R2
R1NH2 + R2NH2 + H2O
R1R2NH + H2 O
Ether groups are unreactive to attack by amines unless the ether exhibits ring or steric
strain or a catalyst such as alumina is used.[293] When diethyl ether is reacted with ammo-
nia at 350 8C under high pressure (22 atm) in the presence of freshly prepared alumina the
product mixture contains ethylamine (51%), diethylamine (28%), and triethylamine
(7%).[294] Tetrahydropyran reacts with ammonia over thorium(IV) oxide at 300 8C to give pi-
peridine,[295] and 2-methyltetrahydropyran reacts with ammonia at 390 8C over alumina to
give a mixture of isomers including 2-ethylpyrrolidine.[296]
When cyclic ethers react with ammonia or amines mixtures of products are often ob-
tained and, in many cases, no clear major reaction product. A summary of some of the
more successful reactions of tetrahydrofurans 159 with amines using an alumina catalyst
to give pyrrolidines 160 is shown in Scheme 98.[297–300]
Scheme 98 Reactions of Tetrahydrofurans with Ammonia or Amines[297–300]

R2NH2, alumina
400−470 oC
R1 O R1 N
R2
159 160
R1 R2 Yield (%) Ref
[297]
H H 80–85
[298]
H Et 57
[299]
H (CH2)4Me 56
[299]
H Bn 30
[299]
H cyclopentyl 40
[300]
H Cy 63

[298]
Me Me 35
Epoxides react with amines (including ammonia) with ring opening to give 2-amino alco-
hols {see also Science of Synthesis, Vol. 36 [Alcohols (Section 36.10.1.1.3)] and Houben–Weyl,
Vol. 11/1, pp 311–326}.
SAFETY: Anhydrous ammonia and amines react slowly with oxirane (ethylene oxide)
but the addition of water greatly accelerates the reaction and there is a risk of explosion.
It is recommended that the reaction is well cooled and oxirane is added to the aqueous
ammonia/amine to ensure that an excess of oxirane is never present.[301–305]
It is worth noting that depending on the reaction conditions and nature of the amine
(ammonia, primary, or secondary), more than 1 equivalent of the epoxide can react, se-
quentially replacing the hydrogen atoms attached to the nitrogen. This is illustrated in
Scheme 99 for the reaction of ammonia with oxirane.
Scheme 99 Reaction of Oxirane with Ammonia[301–305]
O HO O HO OH
NH3 NH2 N
H
HO OH
O N
OH
b-Amino alcohols 162 can be prepared by the ammonolysis of epoxides 161 using a wide
range of catalysts including metal perchlorates,[306,307] lanthanide trifluoromethanesulfo-
nates,[308,309] or calcium trifluoromethanesulfonate (Scheme 100).[310]
Scheme 100 Calcium Trifluoromethanesulfonate Catalyzed Aminolysis of Oxiranes[310]

R3R4NH
R1
Ca(OTf)2 (0.5 equiv)
R1 R2 R2
MeCN, rt
HO
O
N
R3 R4
161 162

R1 R2 R3 R4 Time (h) Yield (%) Ref
[310]
CH2OPh H iPr H 0.5 99
[310]
CH2OPh H t-Bu H 24 92
[310]
CH2OPh H Et Et 0.5 87
[310]
CH2OPh H Bn Bn 24 97
[310]
CH2OPh H 2,6-Me2C6H3 H 78 95
[310]
Me H Bn Bn 5 87
[310]
CH2Cl H Bn Bn 5 91
[310]
Ph H Bn Bn 24 80
[310]
(CH2)3 Bn H 27 91
Mild aminolysis of a range of 2-substituted epoxides with a variety of cyclic and acyclic
amines in water gives b-amino alcohols with high selectivity and in excellent yields in

the absence of any catalyst.[311] The regioselectivity of aminolysis of 2-phenyloxirane (sty-
rene oxide) depends upon the nature of the amine with anilines and benzylamine prefer-
entially attacking the substituted 2-position of the epoxide, whereas aliphatic amines
preferentially attack the unsubstituted 3-position.[311]
Enantiomerically pure diamines 165 can be prepared from (R)-2-phenyloxirane (163)
by ring opening with a cyclic secondary amine followed by mesylation and intramolecu-
lar displacement of the methanesulfonate to form an aziridinium intermediate 164. This
intermediate is then reacted in situ with a primary amine or ammonia in the presence of
an additional auxiliary base (Scheme 101).[312]
Scheme 101 Synthesis of Diamines from (R)-2-Phenyloxirane[312]
1. ( )n , EtOH
N
H
reflux, 2−3 h Ph
2. MsCl, Et3N, Et2O R1NH2, Et3N
Ph NHR1
0 oC, 30 min N+ Cl− H2O, rt, 16 h
( )n N
O ( )n
Ph
163 164 165
R1 n Yield (%) Ref
[312]
H 1 79
[312]
t-Bu 1 90
[312]
Ph 1 79
[312]
Bn 1 81
[312]
Bn 2 93
2,2-Dichlorooxiranes, formed in situ by the phase-transfer-catalyzed reaction of alde-

hydes or ketones with chloroform, react with primary or secondary amines to give inter-
mediate a-amino acid chlorides, which react with further amines to give a-amino
amides.[313]
Allyl phenyl ethers 166 react with primary and secondary amines in the presence of
sodium phenoxide and dichlorobis(triphenylphosphine)palladium(II) to give N-substitut-
ed alk-2-en-1-amines 167 (Scheme 102).[314]
Scheme 102 Reaction of Allyl Phenyl Ethers with Primary and Secondary Amines[314]
R2 R3R4NH R4 R1
PhONa, PdCl2(PPh3)2
N
PhO R3
R1 R2
166 167
R1 R2 R3 R4 Yield (%) Ref
H H t-Bu H 89a [314]
[314]
H H Et Et 100
H H (CH2)2NH(CH2)2 33b [314]
[314]
H Me Et Et 92
[314]
H (CH2)3CH=CH2 Cy H 69
[314]
Me H Me Me 89

a
A 4% yield of N,N-diallyl-tert-butylamine was also isolated.
b
Product is 1,4-diallylpiperazine.
An analogous reaction between 1-(benzyloxy)octa-2,7-diene and piperidine (85 8C for 24 h)

gives 1-(octa-2,7-dienyl)piperidine in 78% yield.[314]
Allyl ethers 168 can also react with amine-derived Grignard regents such as (diethyl-
amino)magnesium bromide in the presence of palladium(II) and triphenylphosphine in
tetrahydrofuran (Scheme 103). The reactions take 5 hours at 50 8C and give yields of the
allylic amines, e.g. 169, in excess of 60% depending on the selected reagents.[315]
Scheme 103 Reaction between Allyl Ethers and Amine-Derived Grignard Reagents[315]
Et2NMgBr
Pd(II), Ph3P
THF, 50 oC, 5 h
R 1O Et2N
R1 = Ph 78%
R1 = CH2CH CH2 96%
168 169
R1N(MgBr)2 (0.5 equiv)

Pd(II), Ph3P, THF, 50 oC
O 69−82% N
R1
Pyrylium salts can be reacted with methylamine under catalytic conditions [H2 (1 atm), Ni/
Ru, 100 8C, 7–10 h] to form piperidine derivatives.[316] Piperidinones can be formed from
the reaction of pyranones with primary amines, but with secondary amines the reaction
products are 5-(dialkylamino)-substituted hexanones.[317]
The presence of a carbonyl, cyano, or carboxylate group b to an ether group facili-
tates the reaction with amines. For example, the reaction of 5-methoxy-2-methylhexan-
3-one with dimethylamine in water at 70 8C gives 5-(dimethylamino)-2-methylhexan-3-
one (Scheme 104).[318] The reaction is proposed to proceed via loss of methanol from the
b-methoxy ketone, followed by addition of the amine to the intermediate enone.
Scheme 104 Displacement of a Methoxy Group by an Amine[318]

OMe O Me2NH, H2O, 70 oC
NMe2 O
Pri Pri
Similarly, b-alkoxypropanenitriles 170 react with amines at elevated temperatures to

give b-(alkylamino)propanenitriles 171 (Scheme 105).[319]

Scheme 105 Displacement of Alkoxy Groups from b-Alkoxynitriles[319]
R1O R2R3NH, 180−210 oC R 2R 3 N

CN CN
R1 = R2 = R3 = Me 88%
170 R1 = Me; R2 = Bu; R3 = H 49% 171
R1 = Me; R2,R3 = (CH2)5 80%
R1 = Et; R2,R3 = (CH2)5 58%
R1 = Me, Et, (CH2)11Me; R2 = Me, Bu; R3 = H, Me, Bu; R2,R3 = (CH2)5, (CH2)2O(CH2)2
Treatment of alkenes with ozone gives intermediate ozonides, which, without isolation,
can be partially hydrogenated and treated with amines under reductive conditions to
yield the corresponding saturated amines. Cycloalkenes undergo ring opening to give ter-
minal diamines (for further details see Houben–Weyl, Vol. E 16d, p 1232).[320]
When 2,5-dihydrofuran (172) is reacted with ozone at –50 8C in methanol and the re-
sulting ozonide is immediately reacted with sodium cyanoborohydride, then a primary
amine, and finally acetic acid, 4-substituted morpholines 173 are produced (Scheme
106).[321] Aromatic amines give better yields in this reaction than aliphatic amines. A var-

iation on this reaction in which the amine used is N,N¢-dibenzylethane-1,2-diamine gives
aza-crown ethers as reaction products.[321]
Scheme 106 Synthesis of Amines from Alkenes via Ozonides[321]

1. O3, MeOH, −50 oC
2. NaBH3CN, −50 oC
R1
3. R1NH2, −50 to 0 oC N
4. AcOH
O O
172 173
R1 Yield (%) Ref
[321]
Bu 57
[321]
s-Bu 54
[321]
t-Bu 16
[321]
Bn 44
[321]
55
Ph
OH
[321]
Ph 41
OMe
2-Amino Alcohols 162; General Procedure:[310]

To a soln of the epoxide 161 (10 mmol) and the amine (10 mmol) in MeCN (30 mL) was
added Ca(OTf)2 (81.7 g, 5 mmol) and the reaction was stirred at rt until TLC showed com-
plete consumption of starting materials. The MeCN was evaporated and H2O (20 mL) was
added to the residue, which was then extracted with CH2Cl2 (3 F 20 mL). The organic ex-
tracts were dried (Na2SO4), concentrated, and purified by chromatography (silica gel).
3-Piperidinopropanenitrile [171, R2,R3 = (CH2)5]; Typical Procedure:[319]

A mixture of piperidine (85 g, 1 mol) and 3-methoxypropanenitrile (170, R1 = Me; 85 g,
1 mol) was heated in an autoclave for 3 h at 200 8C. The resulting mixture was distilled un-
der reduced pressure; yield: 100 g (80%); bp 123.5 8C/26 Torr.
40.1.1.5.4.4.6 Method 6:
Alkylation with Sulfates
Dialkyl sulfates such as dimethyl sulfate and diethyl sulfate are effective alkylating agents
for primary and secondary amines (see also Houben–Weyl, Vol. 11/1, pp 205–212).
SAFETY: Both dimethyl and diethyl sulfate are corrosive to tissues and are probable
human carcinogens.
The reaction between primary amines 174 and dialkyl sulfates occurs at low temper-
atures to give an ammonium salt 175, which upon treatment with base (alkali metal hy-
droxides, carbonates, hydrogen carbonates, or acetates are commonly used) yields the
secondary amine 176. If the reaction is heated, a further alkylation can occur to give a ter-
tiary amine 177 (Scheme 107).
Scheme 107 Alkylation of Primary Amines with Dialkyl Sulfates

R22SO4 H H
N + 2 R2OSO3−

R1NH2
1
R R
174 175
base H
N
R1 R2
176
R2 R2
heat
R2 base
N + HSO4− N
R1 H R1 R2
177
If the amine being used forms a stable salt with the alkyl hydrogen sulfate, then the use of
an excess of amine can lead to the direct release of the alkylated amine without the need
for additional base (Scheme 108).[322,323]
Scheme 108 Alkylation of Primary Amines with Dialkyl Sulfates with No Additional Base[322]
R22SO4 H +
R1NH2 N + R1NH3 R2OSO3−
R1 R2
The alkylation of ammonia with dialkyl sulfates can lead to mixtures of primary, second-
ary, and tertiary amines and although judicious choice of molar ratios of reagents and re-
action conditions can help improve product ratios, separation of the desired product
from side products is often necessary.[324]
Alkylations with dialkyl sulfates are exothermic and are best performed in solvents
such as toluene or dichloromethane. However, water can be used if the amine substrate is
soluble.[325] Although most alkylations use diethyl or dimethyl sulfate it is possible to use
asymmetric dialkyl sulfates. The use of hexadecyl methyl sulfate has been reported for
the alkylation of 4-methyl- and 4-hexadecylmorpholine and in both cases the smaller
methyl group (rather than the hexadecyl group) is transferred to the nitrogen atom.[326]
Normally alkylation with dialkyl sulfates works best with secondary amines but pri-
mary amines can be selectively monoalkylated by first protecting them with an aldehyde
such as benzaldehyde to form an imine, e.g. 178, which is alkylated to give the iminium
salt, e.g. 179, and then hydrolyzed to give the secondary amine product, e.g. 180 (Scheme
109).[327]

Scheme 109 Selective Alkylation of a Primary Amine via an Imine[327]

PhCHO, benzene Me2SO4, benzene
reflux reflux
BuNH2 Ph NBu
178
+ Bu NaOH H
Ph N MeSO4− − PhCHO
N
Bu Me
Me
179 180 45−53%
Alkyl esters of chlorosulfonic acid (R1OSO2Cl) can also be used to alkylate amines. For fur-
ther details see Houben–Weyl, Vol. 11/1, p 213.
40.1.1.5.4.4.7 Method 7:
Alkylation with Sulfonates

As alkylating agents, sulfonates are in many instances superior to halides (see Section
40.1.1.5.4.3), because sulfonates are often better leaving groups. If primary amines such
as butylamine are reacted with 1 equivalent of a sulfonate, either one or both hydrogen
atoms attached to nitrogen can be displaced resulting in mixtures of secondary amines
181 and tertiary amines 182 (Scheme 110).[328] The choice of solvent, as well as the ratio
of amine to sulfonate can affect the product distribution (see Houben–Weyl, Vol. 11/1, p
217).[329]
Scheme 110 The Reaction of Primary Amines with Sulfonates[328]

1. R1OTs (1 equiv)
toluene, reflux, 6 h R1
2. aq NaOH H
BuNH2 N + N
R1 = (CH2)11Me 93%; (181/182) 1.2:1 Bu R1 Bu R1
R1 = (CH2)15Me 84%; (181/182) 1.5:1
181 182
The reaction of bis(sulfonyl)-substituted alkanes with primary amines leads to cyclic ter-
tiary amines, e.g. 183,[330,331] and the yields of such amines formed from bis(sulfonyl)-sub-
stituted alkyl chains with 4-methylaniline are higher than the corresponding reaction
with dihaloalkanes and have fewer side products (Scheme 111).[331]
Scheme 111 Synthesis of Cyclic Amines by Displacement of Sulfonates[330,331]

4-TolNH2
X
HMPA
R1 R1 N 4-Tol
X
R1 X Conditions Yield (%) Ref
[331]
Et OTs reflux, 16 h ~100
[331]
Me OMs 130 8C, 9 h 58
[331]
Ph OTs 130 8C, 6 h 25
[331]
Ph OMs 130 8C, 6 h 29
[331]
t-Bu OTs 130 8C, 10 h 35
[331]
t-Bu Cl 130 8C 2
4-TolNH2
OTs
HMPA, NaHCO3
( )n ( )n N 4-Tol
n = 2 77%
OTs n = 3 57%
n = 4 53%
1. R1NH2, dioxane
R1 () R1
n 2. aq NaOH ()
n
R1 R1
O O N
PhO2S SO2Ph
R2
183
n R1 R2 Yield (%) Ref
[330]
3 H Bu 50
[330]
3 H Cy 81

[330]
2 H Bn 62
[330]
2 Me Bu 39
[330]
2 Me Cy 27
Terminal bis(sulfonyloxy)alkanes 184 react with secondary amines to form symmetrical-

ly disubstituted diamines 185 with a linear alkyl chain.[332] The reaction also works for
nonterminal bis(sulfonates) (giving branched diamines) and for bis(sulfonates) containing
ether functionalities. If primary amines are reacted with bis[2-(sulfonyloxy)ethyl] ethers,
4-substituted morpholines 186 are produced (Scheme 112).[332]
Scheme 112 Synthesis of Linear Diamines and Morpholines from Bis(sulfonates)[332]

R1R2NH (20 equiv)
reflux, 20 h R1 () R1
() N n N
X n X
R2 R2
184 185
R1 R2 X n Yield (%) Ref
[332]
Cy Cy OSO2Ph 2 86
[332]
Et Et OSO2Ph 2 55
[332]
iPr iPr OTs 3 86
[332]
Ph Ph OTs 3 65
[332]
Bu Bu OTs 4 78
[332]
Me Ph OTs 4 25
[332]
Bn Bn OMs 5 10
[332]
(CH2)5 OMs 5 25
1. R1NH2, dioxane O
O O 2. aq NaOH
PhO2S O SO2Ph
R1 = Bu 70%
R2 = Bn 90%
N
R1
186
Treatment of 2-(diethylamino)ethanol with 4-toluenesulfonyl chloride followed by potas-

sium hydroxide gives 1,4-diethylpiperazine hydrochloride (188) via the corresponding
tetraethylammonium salt 187 (Scheme 113).[333]

Scheme 113 The Synthesis of 1,4-Diethylpiperazine Using 4-Toluenesulfonates[333]

Et + Et Et
TsCl, Na2CO3 KOH, EtOH N
N
benzene, reflux reflux
Et2N
OH 2OTs− •2HCl
94% 77%
N N
Et + Et Et
187 188
The macrocyclic polyamine 1,4,7,10,13,16-hexaazacyclooctadecane (189) can be synthe-

sized by a related procedure (Scheme 114).[334]
Scheme 114 Synthesis of a Polycyclic Amine by Displacement of Methanesulfonates[334]

NaOEt
() () EtOH, reflux Ts () () Ts
TsHN 2 N 2 NHTs N 2 N 2 N
Ts 87−96% − Ts −

Ts
Ts N Ts N
[MsO(CH2)2N(Ts)(CH2)2]2NTs
N N H2SO4, 100 oC
NH H HN
70−77% 49−50%
N N NH H HN
Ts N Ts N
Ts
189
Cyclic Tertiary Amines 183; General Procedure:[330]

The primary amine (1.5 mol) was added dropwise over 2 h to a soln of the bis(sulfonate) in
anhyd dioxane (500 mL). NaOH (60 g, 1.5 mol) in H2O was added and the volume of the
mixture was reduced to one-half by distillation. The residue was cooled, Et2O was added,
and the mixture was filtered and then distilled. Redistillation gave the cyclic tertiary
amine.
N,N,N¢,N¢-Tetrasubstituted Diamines 185; General Procedure:[332]

The bis(sulfonate) 184 was refluxed with the anhyd secondary amine (20 equiv) under an-
hydrous conditions for 20 h. Excess amine was removed by fractional distillation and
then excess 40% aq NaOH was added to the residue. The oily layer was collected and the
aqueous phase was extracted with Et2O. The Et2O phase and the initial oily phase were
combined and dried (K2CO3), and Et2O was removed by distillation. The residual oil was
purified by fractional distillation under reduced pressure.
1,4-Diethylpiperazine Dihydrochloride (188); Typical Procedure:[333]

TsCl (80 g, 420 mmol) and anhyd Na2CO3 (30 g, 283 mmol) were added to anhyd benzene
(250 mL) (CAUTION: carcinogen) and the mixture was stirred during the addition of 2-(di-
ethylamino)ethanol (25 g, 213 mmol) in benzene (25 mL). The mixture was refluxed on a
water bath for a further 8 h. Upon cooling, a crystalline mass precipitated, which was col-
lected by filtration. The solid was washed with benzene and Et2O and then dried. The crys-
tals were extracted with EtOH (400 mL) for 8 h to give 1,1,4,4-tetraethylpiperazinium
bis(4-toluenesulfonate) (187); yield: 55 g (94%).
1,1,4,4-Tetraethylpiperazinium bis(4-toluenesulfonate) (187; 16.3 g, 30 mmol) was
dissolved in 96% EtOH (500 mL) at reflux and 80% KOH (4.2 g, 60 mmol) in EtOH (100 mL)
was added. The mixture was stirred for a few h. After cooling, TsOK precipitated and was
removed by filtration. Addition of concd HCl to the filtrate or vigorous bubbling of HCl(g)
for 5–10 min through the filtrate followed by removal of the EtOH by distillation gave a
solid mass. EtOH was added to this residue and then removed under reduced pressure.
This process was repeated 2–3 times, after which 1,4-diethylpiperazine dihydrochloride
was obtained as a crystalline powder, which was recrystallized from EtOH; yield: 5 g (77%).
40.1.1.5.4.4.8 Method 8:
Alkylation with Nitrates
Nitric acid esters can be used to alkylate ammonia. The reaction is slower than with alkyl
halides, and reactions are often performed at 100 8C in alcoholic ammonia, but in some
cases reaction occurs at room temperature (cf. Houben–Weyl, Vol. 11/1, pp 214–216). Meth-
ylamine,[335] ethylamine,[335] and propylamine[336] have all been prepared by this route.
Diethylamine reacts with ethyl nitrate to give triethylamine, and piperidine has
been alkylated with ethyl, propyl, butyl, and 3-methylbutyl (isoamyl) nitrates.[337]
2-Nitroalkyl nitrates react with amines or ammonia to give 2-nitroalkylamines, e.g.
190 (Scheme 115), which are very unstable, but can be reduced to the corresponding 1,2-
diamines by hydrogenation (cf. Section 40.1.4.1.6.1).[338]

Scheme 115 Synthesis of 2-Nitroethylamine[338]
NH3, MeOH
O 2N NO2 −5 to 0 oC O2N
O NH2
190
2-Nitroethylamine (190); Typical Procedure:[338]

2-Nitroethyl nitrate (13.6 g, 0.1 mol) was added dropwise to a sat. soln of NH3 in MeOH
(200 mL) at –5 8C. The mixture was stirred at –5 to 0 8C for 4 h. The mixture was filtered
and the filtrate was concentrated at 40 8C under reduced pressure to give a light brown
oil; yield: 9 g (100%). The oil could not be distilled, and decomposed to a black tar within
1–2 h.
40.1.1.5.4.4.9 Method 9:
Reactions with O—P Groups
Trialkoxy(methyl)phosphonium tetrafluoroborates 191 can be used as alkylating agents

for primary and secondary amines to give secondary and tertiary amines, respectively, in
moderate to good yields (Scheme 116).[339]
Scheme 116 Alkylation of Amines Using Trialkoxy(methyl)phosphonium

Tetrafluoroborates[339]
Me3O+ BF4− R2
CH2Cl2 + R2R3NH
P(OR1) 3 MeP(OR1)3 BF4− N
− MeP(OR1)2 R1 R3
191 R1 = Me; R2 = Cy; R3 = H 75%
R1 = iPr; R2 = Cy; R3 = H 85%
R1 = Me; R2 = R3 = Pr 51%
R1 = iPr; R1 = R3 = Pr 84%
40.1.1.5.4.4.10 Method 10:

Reactions with O—Si Groups
1,2-Bis(trimethylsiloxy)cyclopentene (192) reacts with piperidine to form 2-piperidinocy-

clopentanone (193) (Scheme 117).[340] When the homologous cyclohexene 194 is treated
with piperidine under the same conditions, the sole product is 2-hydroxycyclohexanone

(195), which reacts with cyclic secondary amines to give unsaturated diamines 196 and
197.
Scheme 117 Reaction of Amines with Bis(siloxy)cycloalkenes[340]
, MeOH
O
OTMS
N
H
83%
N
OTMS
192 193
, MeOH
OTMS N O
H
OTMS OH

194 195
, benzene, H+
N N
H
66%
N
196
O
, benzene, MeOH
N N
H
+ N
N
197 34% 42%
[(1-Ethoxycyclopropyl)oxy]trimethylsilane (198) can be used for the cyclopropanation of

amines in a reductive-amination-type procedure (Scheme 118).[341]
Scheme 118 Reductive Amination of a Cyclopropanone Acetal[341]
R1NH2, NaBH3CN
MeOH, AcOH
R1 N
R1 = cyclopropyl 64%
R1 = 78%
EtO OTMS S
198
R1R2NH, NaBH3CN
R1
MeOH, AcOH
N
R1 = R2 = Pr 83%
R2
R1 = Cy; R2 = Me 75%
R1,R2 = (CH2)2N(Boc)(CH2)2 58%
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501

40.1.1.5.4 Substitution on the Amine Nitrogen

40.1.1.5.4.1 Dealkylation Reactions of Amines

Dealkylation reactions offer convenient synthetic strategies for the preparation of

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Scheme 1 Reaction of Tertiary Amines with Nucleophiles

for references see p 571

Scheme 2 Reaction of Tertiary Amines with Cyanogen Bromide

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Scheme 3 The Reaction of Cyclic Trialkylamines with Cyanogen Bromide

1-Butylpyrrolidine (5) and cyanogen bromide react in benzene to afford (4-bromobutyl)bu-

Scheme 4 Ring Opening of 1-Butylpyrrolidine[4]

Scheme 5 Dealkylation in the Synthesis of Fluoxetine[6]

Scheme 6 Reaction of an Indolizidine with Cyanogen Bromide[9]

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N¢-Butyl-N,N-diethylbutane-1,4-diamine (7); Typical Procedure:[4]

rac-N-Methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylamine (8); Typical Proce-

for references see p 571

yl-3-phenyl-3-[(4-trifluoromethyl)phenoxy]propylamine (12.146 g, 37.6 mmol) in benzene

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Scheme 7 Reaction of Tertiary Amines with Phosgene

A better alternative is to use chloroformates or chlorothioformates as dealkylating agents

Scheme 8 Reaction of Triethylamine with Phosgene and Acetaldehyde[15,16]

Commercially available 1-chloroethyl chloroformate is widely used as a reagent for the

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1-Chloroethyl chloroformate can also be used to dealkylate 1,1-dimethylpiperidinium

for references see p 571

Scheme 10 N-Dealkylation of Cyclic Tertiary Amines with Prop-2-ynyl Chloroformate[23]

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Table 1 Dealkylation of Cyclic Tertiary Amines Using Vinyl Chloroformate[24]

Starting Material Hydrolysis Conditions Product Yield (%) Ref

Table 2 Cleavage of Amines with O-Phenyl Chlorothioformate[25]

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Starting Amine Thiocarbamate 17 Yield (%) of 17 Ref

for references see p 571

Starting Amine Thiocarbamate 17 Yield (%) of 17 Ref

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Secondary Amines 14; General Procedure:[23]

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Scheme 11 Exchange of Alkyl Groups between a Tertiary Amine and a Quaternary

This type of exchange reaction can be used in cyclization reactions. N4,N4-Diethylpentane-

for references see p 571

another added amine. Thus, N-benzylmethylamine is converted into N,N-dibenzylmethyl-

Scheme 12 Generation of a Tertiary Amine from a Secondary Amine[40,41]

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Scheme 13 Asymmetric Copper-Catalyzed Synthesis of Propargylic Amines[42]

A: NH2, NH4Cl, EtOH, 100 oC

then HCl, MeOH NH2•HCl

R1 = alkyl, 2-furyl; R2 = Ph, TMS, (CH2)2Ph

In the presence of Raney nickel, alkylamines can undergo transamination reactions.

N-(2-aminoethyl)ethane-1,2-diamine (23) followed by cyclization to piperazine (24) in 73%

Scheme 14 Synthesis of Piperazine from Ethane-1,2-diamine[45]

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The N-(triphenylmethyl) (N-trityl) residue and the related N-(9-phenyl-9H-fluoren-9-yl)

Scheme 16 Synthesis of Primary Amines via the Alkylation of Tritylamine Followed by

R1X Ratio (TrNH2/R1X) Conditions Yield (%) of 25 Ref

( )2 2:1 MeCN, 2 h, 40 8Ca 90 [48]

for references see p 571

Primary Amines 26; General Procedure:[48]

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Table 3 Dealkylation of Amines by Pyrolysis with Benzeneselenol[52]

Entry Starting Material Conditions Product Yield (%) Ref

Entry Starting Material Conditions Product Yield (%) Ref