Current Organic Chemistry, 2011, 15, 2897-2920 2897

Recent Advances in the Chemistry of Pyrazoles. Part 2. Reactions and N-Heterocyclic

Carbenes of Pyrazole

Andreas Schmidt* and Andrij Dreger

Clausthal University of Technology, Institute of Organic Chemistry, Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Germany

Abstract: This review article summarizes progress in N-alkylations, N-alkenylations, N-and C-arylations and hetarylations, halogena-
tions, as well as organometallic chemistry of pyrazoles mainly achieved during the last decade. In addition, the generation and chemistry
of N-heterocyclic carbenes of pyrazole (pyrazol-3-ylidenes) and remote N-heterocyclic carbenes of pyrazole (pyrazol-4-ylidenes) are de-
scribed.

Keywords: Alkylation, Alkenylation, Arylation, Halogenation, Nitration, Sulfonation, Suzuki-Miyaura reaction, Regioselectivity, Metalor-
ganic reactions, Cyclic allenes, Pyrazolium salts, Rearrangement.

1. INTRODUCTION from a substituted hydrazine as described in the first part of this

As a result of their biological, pharmacological, and technical
significance, pyrazoles (1H-pyrazoles; 1,2-diazoles) 1 form a class
of compounds of considerably growing importance (Scheme 1).
Consequently, the number of publications dealing with the chemis-
try of pyrazoles increased dramatically during the last decade.
R
N 16] and these cause elimination reactions of secondary halides. In
N
H erned by different competing parameters, and, as a consequence,
1 numerous procedures and reactions conditions have been published.
Scheme 1.
The first part of this review article [1] is concerned with pro-
gress in pyrazole chemistry made during the last decade and deals
with properties, biological activities, and syntheses of pyrazoles.
This second part summarizes reactions of pyrazoles as well as syn-
theses and reactions of N-heterocyclic carbenes of pyrazoles cover-
ing the same period of time. Thus, the two parts are complementary
and display current trends in pyrazole chemistry. Comprehensive
reports dealing with syntheses of pyrazoles appeared in Houben-
Weyl [2] and Science of Synthesis [3] covering the literature pub-
lished up to 1994 and up to the end of the 1990th, respectively. In
addition, a review on recent advances in pyrazole synthesis ap-
peared recently [4]. Many other reviews have covered portions of
this large field of ever growing importance [5-14].
2. N-ALKYLATION AND N-ALKENYLATION
Most biologically active pyrazoles possess an alkyl or aryl sub-
stituent at N-1 (cf. part 1 of this article). These can also serve as
protecting groups in syntheses of more complicated structures or
organometalic reactions (vide infra). Their syntheses can be accom-
plished in two ways: The first possibility is the preparation starting
*Address correspondence to this author at the Clausthal University of Technology,
Institute of Organic Chemistry, Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Ger-
many; Tel: +49-(0)5323-723861; Fax: +49-(0)5323-722858;
E-mail: schmidt@ioc.tu-clausthal.de
review article. The second approach consists of alkylation, alkeny-
lation, or arylation of the two tautomeric forms of pyrazoles. Even
after intense efforts in preparative pyrazole chemistry, the regiose-
lectivity of these reactions often remains a challenge. In addition,
the second method sometimes suffers from some limitations with
respect to the alkylating or arylating agent, as they are often re-
stricted to primary halides and to aromatic or heteroaromatic hal-
ides. This is due to the fact that basic conditions are necessary, [15,
summary, the regioselectivity of the alkylation of pyrazole is gov-
Among those, solvent-free conditions and microwave irradiation in
the presence of potassium carbonate [17] or sodium hydrogen car-
bonate [18] have been identified as a suited method for the prepara-
tion of N-alkylated pyrazoles. The reactions were carried out by
mixing the pyrazole with a 50% excess of the alkyl halide and a
catalytic amount of tetrabutylammonium bromide (TBAB). The
mixture was absorbed on a mixture of potassium carbonate and
potassium hydroxide, and then irradiated in an open vessel [17].
The ratio of regioisomers for the alkylation of 3(5)-methylpyrazole
2b to 3 and 4 using sodium hydrogen carbonate is similar to those
obtained under neutral conditions than to those obtained under
strongly basic conditions (Scheme 2). These reaction conditions
allowed also – for the first time – the synthesis of 1-cyclopentyl-
and 1-cyclohexylpyrazole. A detailed comparison of reaction condi-
tions (conventional heating vs. microwave irradiation) has been
presented.
The regioisomerism of pyrazole alkylation applying microwave
irradiation was also examined with respect to the leaving group, and
remarkable differences between the use of bromides and chlorides
have been shown (Scheme 3) [19]. Nineteen different alkylated
pyrazoles such as 5 and 6 have been synthesized starting by micro-
wave irradiation from benzyl, diphenylmethyl, and trityl chlorides
and bromides, respectively, and the reaction conditions have been
optimized and discussed [20]. It was shown that the three factors of
this model reaction, i) primary, secondary, tertiary carbon electro-
phile, ii) halide and iii) substitution pattern of the pyrazole, influ-
ence each other and cannot be discussed independently.

1385-2728/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.

2898 Current Organic Chemistry, 2011, Vol. 15, No. 16 Schmidt and Dreger

Ph R
Br

R N R N + N
N MW (150 W), NaHCO3, N N
H
12 min, closed teflon vessel

2a,b
Ph Ph
3 4

3a = 4a: R = H (80%)
3b: R = Me (57%); 4b: R = Me (23%)

Scheme 2.
Ph

RX
N N + N
N MW (600 W), 5 min. N N
H H
Ph
1 5 6

a: R = -CH2Ph; X = Br: 5a (21.3 %); 6a (35.3 %)

b: R = -CH2Ph; X = Cl: 5b (86.1 %); 6b (0%)
c: R = -CHPh2; X = Br: 5c (2.8%); 6c (63.0 %)
d: R = -CHPh2; X = Cl: 5d (77.0 %); 6d (0 %)

Scheme 3.

A number of publications of the last decade deals with reaction
conditions under conventional heating. Thus, the yields of the alky-
lation reaction of 3-substituted pyrazoles 7 with 1,2-dibromoethane
in the presence of potassium carbonate in acetone to 8 depends on
the nature of the substituents (Scheme 4) [21]. It was observed that
electron-withdrawing groups give higher yields.
R R
BrCH2CH2Br, K2CO3,
acetone
N N
N N
H ethanolate in ethanol was observed (Scheme 7). These compounds
7 selective human A2B adenosine receptor antagonists [25].
Br
8a: R = Me (32%)
8b: R = CN (57%)
8c: R = COOEt (72 %)
Scheme 4.
Potassium carbonate in DMF is applied as base to alkylate the
3-substituted pyrazole 9 with benzyl as well as alkyl halides to 10
(Scheme 5). Alkylation was reported to occur at N-1 in 43 – 90%
yield [22]. These compounds are interesting as histone deacetylase
inhibitors.
Alkylation of the pyrazoles 11a-c with ethylene chlorohydrine
to 12a-c was best performed in a solid-liquid system with sodium
hydroxide in dioxane under phase transfer catalysis (Scheme 6).
3(5)-Methylpyrazole, however, resulted in a 1:1-mixture of isomers
[23] Similar reactions have been carried out with 2-
chloroethylamine [24].
A 4:1-selectivity in the reaction of the pyrazol-3-yl-
carboxylates 13 with bromoacetanilides in the presence of sodium
served as starting material for the synthesis of highly potent and
The bis(pyrazol-1-yl)alkanes 16 were synthesized from 15a-c in
a superbasic medium consisting of potassium hydroxide in DMSO
(Scheme 8) [26]. Under similar conditions, substitution with vicinal
dibromides was performed [27].
1-Alkyl-3-trifluoromethyl-5-methyl-1H-pyrazoles were prefer-
entially formed on reaction of 17 effected with alkylating agents in
an ionic liquid (Scheme 9). Reaction times were shorter and yields
were better in comparison to classic solvents [28].

CN CN
S RBr (1.2 eq.), K2CO3, S
DMF, 70 °C, 16 h
N N
N N
H
R
9
10a: R = Bn
10b: R = -CH2-CH2-Ph

Scheme 5.
Recent Advances in the Chemistry of Pyrazoles Current Organic Chemistry, 2011, Vol. 15, No. 16 2899

R2 R2
Cl
OH
N R1 N
R1 N
N NaOH (s), dioxane,
H PTC OH

11a-c 12a: R1 = R2 = H (80%)

12b: R1 = Me, R2 = H (75 %; 1:1 mixture)
12c: R1 = R2 = Me (70%)

PTC = benzyltriethylammonium chloride

Scheme 6.
COOEt

O
COOEt R1 N
Br N
NHR2
N NHR2
R1
N NaOEt, EtOH, rt
H
O
13
14a:R1 = Me, R2
= Ph (65%)
14b: R1 = Me, R2 = 4-tolyl (65%)
14c: R1 = Et, R2 = 4-Cl-Ph (60%)

Scheme 7.
R
R R
X Y X
N
N N Y N
R N DMSO, KOH, R N
H
1.5 h, 80°C R
15a-c 16

16a: R = H, X = Cl, Y = -CH2- (62 %)

16b: R = Me, X = Cl, Y = -CH2OCH2- (98 %)
16c: R = Me, X = Br, Y = -CH2NHCH2- (56 %)

Scheme 8.

Me RX, [BMIM]BF4, Me CF3

KOH, 70 - 110°C, 4 - 7 h
N N + N
F3C F3C Me
N N N
H
R R

17 18 19
18a/19a: R = Bu (65 %; 4:1)
18b/19b: R = octyl (95 %; 2:1)
18c/19c: R = Bn (97 %; 3:1)
18d/19d: R = PhC(O)CH2CH2 (84 %; 2:1)
Scheme 9.

In order to avoid the aforementioned problems on using strong BnX

bases for the alkylation of pyrazoles, some basic catalysts have N N
been explored. Thus, an alternative approach to N-alkylated pyra- N MeCN, CsF-celite, N
zole 20 is the reaction with alkyl halides in acetonitrile and cesium H reflux, 2 d
Bn
fluoride – celite employed as a solid base (Scheme 10) [29]. Alter-
1 20
native base-supported catalysts are KF-Al2O3 [30, 31] and CsF- A) X = Cl (96 %)
Al2O3 and KOH-Al2O3 [31]. B) X = Br (82 %)
Basic molecular sieves have also been employed for the alkyla- Scheme 10.
tion of pyrazoles 21 under thermal conditions (Scheme 11). Al-
SBA-15 incorporating Cs+ ions and functionalized MCM-41 mate- tural properties and compositions, were studied. This method
rials with diethylaminopropyl (DEAPTS) groups, differing in tex- avoids the application of stoichiometric amounts of bases and
2900 Current Organic Chemistry, 2011, Vol. 15, No. 16 Schmidt and Dreger

tedious work-up procedures. A theoretical study of the best catalyst,
MCM-41/DEAPTS, on the reaction mechanism has been presented.
The mechanism has been calculated to involve a single step pro-
moted by the basic sites of the modified molecular sieve [32].
R1 RBr, catalyst,
MeCN or DMF
R2 N R2
N N
H vinyl ethyl ether and 3,4-dihydro-2H-pyrane by heating in tetra-
R3
21 22
a: R1 = R2 = H, R3 = -CH2Ph, method A), 353 K, 30 min, 96 % conversion
b: R1 = R2 = Me, R3 = -CH2COOEt, method B) 373 K, 3 h, 90 % conversion
method A: catalyst = (Cs)Al-SBA-15
method B: catalyst = DEAPTMS
Scheme 11.
On N-alkylation of several 4,5-dihydropyrazoles 23 aromatisa-
tion was observed which resulted in the formation of a mixture of
4,5-dihydropyrazoles 24 and pyrazoles 25 (Scheme 12). A mecha-
nism is presented in which the 2´-NO2 group acts as a hydride ac-
ceptor [33].
The selectivity of the C-5 alkylation of 1-methylpyrazole with
benzaldehyde was improved using lithium diethylamide as the base
(Scheme 13) [34]. This reaction has previously been reported to
give a mixture of products, resulting from reaction at C5 of the
pyrazole nucleus or at the methyl group attached to N-1 [35, 36].
Best results were achieved when the pyrazole was metallated by
nBuLi and was then equilibrated by a catalytic amount of diethy-
lamine. This method was also applied for the synthesis of the pyra-
zole derivative Cizolirtine (E-3710), a potent analgesic, as well as
R1
other heteroaromatics such as oxazoles and thiophenes.
Among the base-free alkylation reactions the following proce-
N
dures have been published. First, substituted pyrazoles 29 react with
chloromethane to N-alkylated pyrazoles 30 and 31a,b, respectively
(Scheme 14) [37].
Second, an N-alkylation of pyrazoles 32a-c with Mannich bases
derived from o-hydroxyacetophenones to 33a-c was also described
(Scheme 15). Equimolar amounts of Mannich base and pyrazole
offer the advantage of simple separation; excess pyrazole was with-
out influence on the yields. From a mechanistic point of view, the
reaction probably involves an elimination of the dimethylamino
group followed by a Michael addition, or proceeds via nucleophilic
substitution [38].
Photoinduced addition of alkenes to various azoles, including
pyrazole, was also described (quartz tube, 254 nm, N2, 6 – 12 h).
By this way, pyrazole 35 possessing a tertiary carbon atom at N-1 is
available (Scheme 16) [39].
Silver and zinc salts were found to efficiently catalyze the dou-
ble addition of pyrazoles to alkynes to form compounds such as 36
(Scheme 17). Single addition was achieved by silver nitrate, thus
allowing the N-alkenylation of pyrazole to 37 and 38 [40].

O2N
O

N R
O2N EtOOC
N
O (EtO)2SO2, K2CO3,
Et
THF, 70°C, 22 h 24

N R O2N
EtOOC
N
H O

23

N R
EtOOC
N
Et
a: R = H, 24a (46%), 25a (26%) 25
b: R = Cl, 24b (37 %), 25b (27 %)
c: R = OMe, 24c (38 %), 25c ( 17 %)

Scheme 12.
1. HNEt2, nBuLi, -78°C, 5 h
2. PhCHO
N Ph N + N
N (85%) N N
Me OH Me Ph

OH

26 27 28
> 99:1

Scheme 13.
Recent Advances in the Chemistry of Pyrazoles Current Organic Chemistry, 2011, Vol. 15, No. 16 2901

R Ts

O N
N

CCl4, reflux, 2 h
O

30: R = H(CF2)3 (94 %)

R Ts

N
N
H
R Ts
29
O
N
N
CCl4, reflux, 2 h
O

31a: R = CF3 (86 %)

31b: R = H(CF2)3 (89 %)

Scheme 14.

OH O

NMe2

R2 HCl R2
R1 R1
R3
N R1 N
R1 N O OH
N EtOH, H2O, 1h
H

32a-c

R3

33a: R1 = R2 = R3 = H (75%)
33b: R1 = H, R2 = I, R3 = Me (78%)
33c: R1 = Me, R2 = NO2, R3 = Me (41%)

Scheme 15.

N
Me N Me
H N
N
PhCOOMe (sensitizer),
TfOH (20 mol %),
34 EtOAc, hn 35
(72 %)

Scheme 16.

Relatively few pieces of information on pyrazolium salts are ride 39 by HCl-catalyzed 1,4-cycloaddition of pyrazole 1 with me-
available in the literature. The synthesis of bicyclic 6-hydroxy- sityl oxide, formed from acetone, was described (Scheme 18) [41].
6,8,8-dimethyl-5-aza-1-azonia-bicyclo[3.3.0]octa-1,3-diene chlo-
2902 Current Organic Chemistry, 2011, Vol. 15, No. 16 Schmidt and Dreger

Hex R3 R3
Hex Me
AgOTf (cat.), R2 R4 R2 R4
PhCl, 130°C, 20 h
N N
N xylene, (R5)2SO4
N (81 %) N N R1 R1
H PhNO2 (cat.)
N N
R6 R6 R5
1 36 N R = Me, Et N

R7 COOEt R7 COOEt
R1 R2 42a-e 43a-e
AgNO3 (cat.), a: R1 = R2 = R4 = R7 = H, R3 = Br, R5 = R6 = Me (54 %)
PhCl, 130°C, 20 h b: R1 = COOH, R2 = R3 = R4 = R7 = H, R5 = R6 = Me (92 %)
c: R1 = R3 = R7 = H, R2 = R4 = Cl, R5 = R6 = Me (49 %)
d: R1 = R7 = H, R2 = R3 = R4 = OMe, R5 = Me, R6 = 2-thienyl (39 %)
e: R1 = R2 = R3 = R4 = H, R5 = R7 = Et, R6 = Ph (55 %)

N N Scheme 20.
N + N
Me Me
R2 R1
R1 R2

37 38
RI I
37a/38a: R1
= Hex, R2
= H (86 %; 92 : 8)
37b/38b: R1 = Ph(CH2)2, R2 = H (95 %; 84 : 16) N N
Me Me Me
37c/38c: R1 = 3-thienyl, R2 = H (56 %; 52 : 48) N N

Scheme 17.
44 45a: R = Me (25 %)
45b: R = n-octyl (58 %)
Cl
Scheme 21.
acetone, HCl
N Me According to a modified literature procedure [45], pyrazole 46
N
N N Me was reacted with benzyl bromide under microwave conditions to
(90%)
HO give the benzyl substituted pyrazolium salt 47 in good yield
H
Me (Scheme 22) [44].
1 39
Br Br
Scheme 18.
Br
The pyrazole esters 40 and 41 were methylated with dimethyl-
sulfate in the presence of nitrobenzene to give the pyrazolium salts PhCH2Br
42 and 43 in 62% and 85% yield, respectively (Scheme 19) [42].
N (60 %) N CH2Ph
This method can also be applied to highly substituted pyrazoles Me Me
N N
42 which are methylated or ethylated at N-2 to 43 (Scheme 20)
[43]. 46 47
The pyrazole 44 can be methylated using methyl iodide [43] or
octylated by n-octyliodide to 45 (Scheme 21) [44]. Scheme 22.

COOEt COOEt

2-
N N 0.5 SO4
Me N R1 N Me
1. xylene, R2
Ph
PhNO2,
40 42
140°C

2. Me2SO4,
30 min.
Me Me
2-
0.5 SO4
N N
EtOOC N EtOOC N Me
Ph Ph
41 43
Scheme 19.
Recent Advances in the Chemistry of Pyrazoles Current Organic Chemistry, 2011, Vol. 15, No. 16 2903

3. N-ARYLATIONS, N-HETARYLATIONS, AND N- However, the following example shows that different steric re-
AROYLATIONS quirements in pyrazole 50 have essentially no influence on the re-
gioselectivity under the reaction conditions applied (Scheme 24)
As described in the first part of this review on pyrazole chemis-
[51].
try [1], the most common route to N-aryl pyrazoles is the condensa-
tion of 1,3-diketones with arylhydrazines. The regioselectivity of Therefore, regioselective syntheses of unsymmetrical 3,5-
this reaction depends on the nature of the diketone and, in the pre- dialkyl-1-arylpyrazoles 54 were achieved starting from a pyrazole
sent case, this reaction lead to the undesired isomer as the major 53 possessing an oxygen atom in the side chain (Scheme 25). Due
component. N-Arylation of the pyrazoles 48a-e to 49a-e was there- to a chelation effect with the branched ether side chain which disfa-
fore accomplished with 4-fluoronitrobenzene in DMSO in the pres- voured arylation of the adjacent N-atom to 55, THF gave good re-
ence of KOtBu (Scheme 23). This reaction proceeded in excellent gioselectivities, in contrast to DMSO as solvent. A similar regio-
yields and high regioselectivities [46]. Alternative procedures ap- chemistry was obtained with tBuOLi, NaH, and EtMgBr as bases,
plying K2CO3/DMF [47], K2CO3/DMSO, [47, 48], KOH/Bu4NBr however, these bases showed sluggish reactions and gave relatively
(ultrasound, without solvent) [49], or ethanolic KOH [50] required low yields [52].
longer reaction times and gave moderate to good yields with similar Perfluoronaphthalene was reacted with pyrazoles to give oc-
regioselectivity. takis(pyrazol-1-yl)naphthalene and octakis(3,5-dimethylpyrazol-1-
yl)naphthalene, respectively. The first mentioned substitution pro-
Ar
ceeded in THF from the in situ generated sodium salt of pyrazole
with octafluoronaphthalene within 2 h at reflux temperature in 80 %
N yield, and the second in DMF within 18 h at reflux temperature in
F R N
R DMSO, KOtBu, 65 % yield [53].
70°C, 30 min. Copper-diamine-catalyzed N-arylation of pyrazoles is an alter-
N + native approach to this class of compounds. The reaction works
Ar N
well with electron-deficient as well as electron-neutral pyrazoles,
H and very electron-rich aryl halides. As a general rule, the sterically
NO2 NO2
less hindered nitrogen atom in unsymmetric pyrazoles was selec-
48a-e 49a-e
tively arylated to 57 (Scheme 26) [54].
a: Ar = Ph, R = Et (92%; 22:1) Copper-catalysis was also applied in the L-proline promoted
b: Ar = 4-CNPh, R = Et (85%; 30:1)
c: Ar = 3-pyridyl, R = Et (94%; 38:1) synthesis of 60 (Scheme 27) [54]. Coupling reactions of electron-
d: Ar = 2-furyl, R = Et (74%; 9:1) deficient aryl iodides and amines with N-methylglycine as promoter
e: Ar = Ph, R = iPr (<89%, 3.8:1) to 58 have also been reported [55]. N-Arylation to 59 was accom-
plished with arylboronic acids with copper(I) oxide [56]. In addi-
Scheme 23.

Et

Et N
NO2 N Et
N +
N tBuOK, N
DMSO, N
H 70°C
NO2
NO2
50 51 52
1 : 1.2
Scheme 24.
F
R1

R1 OTHP
R1
Me N
OTHP NO2 N
+ OTHP
Me N R2
N tBuOK, Me N
60 - 70°C N
R2 H
R2
NO2
53 NO2
54 55
a: R1 = H, R2 = H: 7:1 (THF, 71 %); 1:1 (DMSO, 93 %)
b: R1 = Me, R2 = H: 16.1 (THF, 73 %); 2:1 (DMSO, 90 %)
c: R1 = H, R2 = Me: 4:1 (THF, 74 %); 1:1 (DMSO, 94 %)
d: R1 = R2 = Me: 11:1 (THF, 80 %); 1:1 (DMSO, 91 %)
Scheme 25.
2904 Current Organic Chemistry, 2011, Vol. 15, No. 16 Schmidt and Dreger

ArX, 5 mol% CuI, ArX, Cs2CO3, Cu2O, ligand I or II,

20 mol% MeCN, 25 - 82 °C, 24 - 90 h
N
N N
N
H Ar
R R
Me NH HN Me OH
61
ligand I:
N N N a: Ar = Ph, X = I, ligand I (80 %)
N N
2.1 eq. K2CO3, toluene b: Ar = Ph, X = Br, ligand I (70 %)
H 24 h, 110°C Ar OH c: Ar = 4-CF3Ph, X = Br, ligand I (96 %)
d: Ar = 4-H2NPh, X = Br, ligand II (98 %)
56 57
e: Ar = 3-EtOOCPh, X = Br, ligand II (53 %)
ligand II: f: Ar = 3-pyridyl, X = Br, ligand II (97 %)
a: Ar = -p-C6H4-COEt, R = H, X = Br (98 %)
g: Ar = 3-thienyl, X = Br, ligand I (100 %)
b: Ar = 3-pyridyl, R = 4-COOEt, X = Br (84 %)
c: Ar = -p-C6H4OH, R = 3-Me, X = Br (78 %) N N
d: Ar = Ph, R = H, X = I (93 %)
e: Ar = Ph, R = 3-CF3 & 4-COOEt, X = I (77 %)

Scheme 26.

tion, copper(II)-mediated arylations with aryl boronic acids for the

N-derivatization of pyrazole libraries have been published [57]. Scheme 28.
CuI, K2CO3 Me
O
L-proline, Me
DMSO N N
N Br (94 %) N Me N CAN, MeCN, rt, 1 h
N N +
N Me N
H H
N
B(OH)2 MeO B(OH)2 O
1
47 % 41 %
OMe Cu(OAc)2, pyridine
60
OMe 62
CuI, K2CO3
N-methylglycine, R Scheme 29.
DMSO Cu2O
(71 %) moselectivity is explained by the wide bite angle and the formation
MeOH, rt, of a trans-chelating Xantphos-Pd(II)(Ar)Cl complex [60].
Br air, 12 h
Sodium tbutanolate and potassium tbutanolate were compared
N as bases in the coupling reaction of 2,6-dibromopyridine with pyra-
N zole 68. As an additional parameter, the molar ratios of the starting
N materials were varied. (Scheme 31) [61].
N
A systematic investigation of the regioselectivity of alkylation
and acylation reactions with substituents covering the range be-
tween electron-donating to electron-withdrawing groups and vari-
R ous reaction conditions (microwave irradiation, ultrasound irradia-
tion, conventional heating) has been carried out. Thus, aroylation of
OMe 59a: R = H (90 %) pyrazole 71 to 72 occurred regioselectively under the conditions
59b: R = Me (92 %)
58 59c: R = OMe (94 %) shown (Scheme 32). Results of X-ray single crystal analyses have
been presented [62, 63].
Scheme 27.

A copper-catalyzed N-arylation of pyrazoles to 61 was also de-
veloped, using chelating oxime-type ligands. This method is appli-
cable to a large variety of substituents (Scheme 28) [58].
In addition, a CAN dearylation of 62 and reanisylation was ex-
amined (Scheme 29) [59].
Depending on the conditions, the reaction of 4-chloro-
quinazolines 63 with aminopyrazoles 64 are chemoselective
(Scheme 30). Thus, the amination of the hetarylchloride by the
aminopyrazole to 65 (SNAr reaction) was accomplished in acid,
whereas Buchwald-Hartwig coupling to 66 was performed with
Pd(OAc)2/Xantphos/Na2CO3. Screening of the palladium source
revealed that best results were achieved with Pd2(dba)3. The che-
4. HALOGENATIONS, CYANATIONS, NITRATIONS AND
SULFONATIONS
Halogenated pyrazoles are versatile starting materials. A brief
review on 4-iodopyrazoles have been published recently [64]. The
bromination of pyrazoles using N-bromosuccinimide (NBS) and
microwave irradiation in acids gave mono-brominated pyrazoles in
good yields (Scheme 33) [65]. Under similar conditions, 1-
phenylpyrazole can be iodinated at C4 by N-iodosuccinimide in
acetic acid at 150°C in 83% yield.
4-Halo-3,5-dimethyl pyrazoles 76 have been synthesized by re-
action of 3,5-dimethyl pyrazoles 75 with N-halosuccinimides (NBS,
Recent Advances in the Chemistry of Pyrazoles Current Organic Chemistry, 2011, Vol. 15, No. 16 2905

R3

N H
Cl NH2 HN N
R1 HCl, dioxane R1
N + N
N
R3 N
N R2 N R2
H
63 64
65a: R1 = R2 = H, R3 = Me (70 %)
65b: R1 = 6-OMe, R2 = H, R3 = Me (70 %)
Pd2(dba)3, Xantphos, 65c : R1 = 7-F, R2 = Me, R3 = Me (71 %)
Na2CO3, dioxane, 70°C 65d: R1 = R2 = H = R3 = H (75 %)
65d: R1 = 7-Cl, R2 = R3 = H (80 %)

R3 H2N

N N
N NH2 N R3
R1 R1
+
N N

N R2 N R2

66 67

66a/67a: = R1 R2
= H, R3
= Me (73 % / 0 %)
66b/67b: R1 = 6-OMe, R2 = H, R3 = Me (79 % / 0%)
66c/67c : R1 = 7-F, R2 = Me, R3 = Me (70 % / 0 %)
66d/67d: R1 = R2 = H = R3 = H (15% / 73 %)
66e/67e: R1 = 7-Cl, R2 = R3 = H (21 % / 63 %)

Scheme 30.

R2 R1 R2 R1
(0.42 eq.)
R2 R1
Br N Br N N
R3 N R3 N
N
R3 N Pd(OAc)2, PPh3, KOtBu,
H N N
dioxane, reflux, 48 h
N
Br N
R1

68 R3
R2
69 70
69a/70a: R1
= = R2 R3
= H (29 % / 69 %)
69b/70b: R1 = R3 = Me, R2 = H (57 % / 35 %)
69c/70c: R1 = R3 = Me, R2 = Bn (66 % / 25 %)

Scheme 31.
1. p-chlorobenzoic acid,
EtOOC SMe SOCl2, 4 h EtOOC SMe
2. NaOH, CHCl3, rt
N N
Me N (89%) Me N
H
O

71 Cl
72

Scheme 32.
2906 Current Organic Chemistry, 2011, Vol. 15, No. 16 Schmidt and Dreger

R2 NBS, solvent, Br R2
MW conditions,
150°C, 10 min.
N N
R1 N R1 N
R3 R3

73a-d 74

74a: R1 = R2 = H, R3 = Ph, solvent: HOAc (84 %)

74b: R1 = Ph, R2 = COOMe, R3 = H, solvent: HOAC (89 %)
74c: R1 = 4-BrPh, R2 = COOEt, R3 = Me, solvent: HOAc (91 %)
74d: R1 = 3,4-Cl2Ph, R2 = COOMe, R3 = H, solvent: 5% HNO3 in HOAc (83 %)
Scheme 33.

NCS and NIS) under ultrasound irradiation (Scheme 34) [66]. One equivalent of bromine and iodine, respectively, converted
Identical reaction conditions were also successful using bromine, 79 into 80 (Scheme 36); the dibromo pyrazole 81 was formed from
and iodine or ICl in ethyl acetate, respectively, to prepare the corre- 80 with an additional equivalent of bromine [90].
sponding 4-halopyrazoles in good yields. 2-Alkylpyrazole-1-oxides 82, readily available on alkylation of
Me X Me 1-hydroxypyrazole and deprotonation of the OH group, are suitable
NXS, acetone, starting materials for the synthesis of 1-alkyl-5-halopyrazoles 83
6 - 90 min. ))) (Scheme 37) [67].
N N
Me N Me N
POX3, CHCl3
R R N N
N O X N
76a: R = H, X = Cl (98 %) 2.5 h, 0 - 50°C
75 76b: R = H, X = Br (98 %) R R
76c: R = H, X = I (85 %) 82 83a: R = 4-MeOC6H4CH2, X = Cl (93 %)
76d: R = Me, X = I (75 %) 83b: R = benzyl, X = Cl (98 %)
76e: R = 4-O2N-Ph, X = Br (91 %) 83c: R = allyl, X = Br (85 %)
76f: R = C6F5, X = Cl (95 %) 83d: R = Me, X = Br (78 %)

Scheme 34. Scheme 37.

Surprisingly, attempted chlorination of 77 (as a mixture with its Oxidative iodination of pyrazole 84 to 85 was also accom-
regioisomer) with N-chlorosuccimide (NCS) resulted in the forma- plished as shown in Scheme 38 [26]. The iodination of N-H or N-
tion of 4-bromopyrazole 78 (Scheme 35); the corresponding hydro- benzylpyrazoles using elemental iodine in the presence of CAN
chloride gave the expected 4-chloropyrazole [21]. proved to be a mild method to prepare 4-iodopyrazoles [68].
Cyanations of the 4-position of pyrazole can be carried out on
Me Br Me treatment of 4-dimethylphenylsilyl-1,3,5-trimethylpyrazole 86 with
NCS, MeOH, rt, 18 h chlorosulfonyl isocyanate followed by hydrolysis (Scheme 39) [90].
N HBr N
N N PhMe2Si Me 1. ClSO2N=C=O NC Me
2. HCl
Me N N
NH2 NH2 N (72 %) Me N
Me Ph
77 78 86 87

Scheme 35. Scheme 39.

Me X2, THF X Me Br2, THF Br Me

N N [80a; (96 %)] N

PhMe2Si PhMe2Si Br
N N N
Me Me Me
79 80a: X = Br (92 %) 81
80b: X = I (95 %)
Scheme 36.
I2, HIO3, H2SO4,
I
N AcOH, 100°C
N
N I
N (79 %) N N
N N
84 85
Scheme 38.
Recent Advances in the Chemistry of Pyrazoles Current Organic Chemistry, 2011, Vol. 15, No. 16 2907

1. HNO3, H2SO4 O2N 2+

3+ rt, 2h
N Co(NH3)5 N
N 3 ClO4 2. LiNO3 N Co(NH3)5 2 NO3
H 88 89
Scheme 40.
R2 R2

Cu(NO3)2 . 3 H2O, Ac2O

N N
R1 R1 N NO2
N
H
91a: R1 = H, R2 = Me (32%)
90a,b
91b: R1 = Ph, R2 = Me (61%)
Scheme 41.
O2N
N2O5, CH2Cl2 N2O5, CH2Cl2
N N N
N Faujasite N Faujasite N
H NO2 NO2
1 92 93
(80% for 2 steps)
Scheme 42.

Advances in nitropyrazole chemistry have been reviewed in H2SO4 [80]. 3,4,5-Trinitro-1H-pyrazole 97 was obtained on treat-
1998 [69]. Direct nitration, oxidation, and diazotation represent the ment of 4-amino-3,5-dinitropyrazole 96 with diperoxysulfuric acid
three general approaches to nitropyrazoles, and all of them have (Scheme 44). This interesting compound was also obtained on dia-
been applied during the last decade. Nitration of pyrazole with fum- zotation of 5(3)-amino-3(5),4-dinitropyrazole and direct nitration of
ing HNO3 and H2SO4 requires a reaction time of 40 h at 110°C to 3,5-dinitropyrazole [81].
give 4-nitropyrazole [70], as the pyrazolium cation is the reactive H2N NO2 O2N NO2
species under these strongly acidic conditions [71]. Nitration of H2S2O8
cobalt complex 88 to 89 afforded considerably milder reaction con- N
O2N N
ditions (Scheme 40). N (93 %) O2N N
Whereas the use of HNO3 or mixtures of HNO3 and H2SO4 re- H H
sults in C-nitration of pyrazoles, acetyl nitrate or trifluoroacetyl
96 97
nitrate give N-nitrated pyrazoles 91 (Scheme 41) [72, 73]. Sources
of acetyl nitrate are either mixtures of HNO3 and Ac2O in AcOH, or Scheme 44.
mixtures of Cu(NO3)2 with Ac2O [74]. It has been observed that the
Pyrazoles have also been nitrated in a continous flow reactor
use of an “acidic” mixture with excess of HNO3, Ac2O and AcOH
which is suited for large quantities of material and for use for exo-
results in nitration at N-1, whereas the nitration with the “non-
thermic electrophilic substitution reactions [82].
acidic” system (Cu(NO3)2 3 H2O / Ac2O) occurs at N-2 [75].
An effective sulfonation of pyrazoles 98a-d under relatively
Ammonium nitrate in trifluoroacetic anhydride and
mild conditions to 99a-d has been achieved in a mixture of acetic
trifluoroacetic acid converts pyrazole into 1,4-dinitropyrazole [76],
anhydride and 96 % sulphuric acid. The sulfonic acids crystallize
whereas nitration by N2O5 – generated in situ from NO2 and ozone
on cooling (Scheme 45) [83]. Oleum (20 % SO3) [84, 85] and
– gives 1-nitropyrazole only [77]. Faujasite zeolite-catalysed reac-
chlorosulfuric acid in chloroform (to avoid sulfonation of phenyl
tion of pyrazole with N2O5 yields 1-nitropyrazole immediately
substituents) [86] are alternative sulfonation reagents, although the
which is then slowly transformed into 1,4-dinitropyrazole. The
conditions are quite vigorous.
kinetics of this reaction have been explored (Scheme 42) [78].
Pyrazole on treatment with HNO3 and trifluoroacetic anhydride Me HO3S Me
gave 3,4-dinitrated derivative 95a while N-methylpyrazole gave H2SO4, Ac2O
only the 3-nitropyrazole 95b (Scheme 43) [79]. R2 N N
N rt, 3d, then reflux (30 min) R2 N
X NO2
R1 R1
(CF3CO)2O, HNO3
N 98a-d 99a: R1 = H, R2 = Me (60 %)
N
N 0°C, then 12 h at rt N 99b: R1 = Ph, R2 = Cl (93 %)
99c: R1 = p-NO2C6H4, R2 = Cl (96 %)
R R
94 99d: R1 = H, R2 = Cl (39 %)
95a: R = H, X = NO2 (41%)
95b: R = Me, X = H (65%) Scheme 45.
Scheme 43. Sulfonation of a cobalt complex of pyrazole 100 to 101 was
A convenient method to prepare 4,5-dinitropyrazoles starts found to be more facile than that of the free ligand (Scheme 46)
from 4-nitro-5-aminopyrazoles, which are oxidized by H2O2 in [87].
2908 Current Organic Chemistry, 2011, Vol. 15, No. 16 Schmidt and Dreger

1. 60% H2SO4 O3S 2+

3+
rt, 1h
N Co(NH3)5 N
N 3 ClO4 N Co(NH3)5 2 Cl
2. LiCl (50 %)
H H

100 101

Scheme 46.

Dimethylsulfate reacts with pyrazoles to give pyrazolium-4- 1. Br2, Fe, 100°C, 1 h (67 %)
sulfonates which belong to the class of cross-conjugated mesomeric 2. tBuLi, pentanes, Et2O, -75 °C HOOC
betaines (Scheme 47) [88]. 3. CO2 (88 %)
N N
F3C N F3C N
Me Me
106 107
Me2SO4, xylene H3C N CH3
H3C N N
N 1. diisopropylamine, BuLi, THF, hexanes, -75°C
O 2. crushed dry ice (70 %)
S R1
R1 O
O
Br COOH Zn, NaOH, water, COOH
102a,b 103a: R1
= H (50 %) 25 °C, 1 h
103b: R1 = Me (18 %) N N
F3C N (93 %) F3C N
Scheme 47.
Me Me

5. ORGANOMETALLIC CHEMISTRY OF PYRAZOLES 108 109

A large body of research covers metal-organic reactions of
Scheme 49.
pyrazoles and - as a consequence - Negishi, Suzuki-Miyaura, Stille
and Sonogashira reactions of pyrazoles have been summarized in a Halogen-lithium exchange and coupling with chlorosilanes or
recent microreview [89]. Therefore, this important class of reac- chlorostannanes yielded the silylated and stannylated pyrazoles
tions is described only briefly here. Bromine-lithium exchange was 111a-c, respectively, although the silanes were formed in low yields
achieved regioselectively; subsequent reaction with electrophiles (Scheme 50). A one-step procedure with lithium silylcuprates al-
then yielded 105a-g (Scheme 48) [90]. lowed to obtain 4-silylpyrazoles in good yields, and this method is
also applicable to stannylations as shown [1]. In addition, synthesis
Br Br Br E
1. nBuLi, -78°C, 2 min. and reactions of 5-tributylstannyl-4-fluoro-1H-pyrazole have been
2. electrophile described [93].
N N
Br N Br N Br Me R3M Me
1. BuLi, TMEDA, THF
2. ClMR3, -78°C - 0°C
CH2 CH2
N N
104 105a-g R N R N
Me Me
electrophile E yield (%)
a NH4Cl 110 111a: R = Me, R3M = SiMe2Ph (19 %)
H 80
b Cl6C2 Cl 82 111b: R = Me, R3M = SnBu3 (89 %)
c MeI Me 78 111c: R = Ph, R3M = SnBu3 (73 %)
R3M(Me)CuLi,
d TsCN CN 26 -78°C - 0°C
e Me2S2 SMe 84
f Ph2PCl PPh2 59
g Bu3SnCl SnBu3 R3M Me
77

Scheme 48. N
R N
Transformations in the 3-(trifluoromethyl)pyrazole series, i.e.
the formation of 4-carboxylic acid 107 and 3-pyrazolecarboxylic Me
acid 108 from 106 as shown in (Scheme 49), were not compro- 111a (78 %)
mised by any regioselectivity problems. A similar sequence of reac- 111b (81 %)
tions have also been performed starting from 1-methyl-3- 111c (62 %)
(trifluoromethyl)pyrazole and N-phenyl-trifluoromethylpyrazoles,
so that a family of isomers could be described [91]. Scheme 50.
Recent Advances in the Chemistry of Pyrazoles Current Organic Chemistry, 2011, Vol. 15, No. 16 2909

1-Phenylprazole was stannylated in position 5 by treatment with X Me 1. LDA, THF, TMEDA Me

nBuLi in THF and subsequent reaction with Bu3SnCl [94]. 5- 2. R3MCl
Unsubstituted pyrazoles were converted into 5-silyl- and 5- N N
stannylpyrazoles 112 as shown [92] (Scheme 51). N R3M N
Me R R
Me 1. LDA, THF, TMEDA
115 116a: R = Me, X = H, R3M = SiMe2Ph (79 %)
2. R3MCl
N 116b: R = Me, X = H, R3M = SnBu3 (83 %)
N R3M N
N 1. LDA, THF 116c: R = Ph, X = H, R3M = SiMe2Ph (75 %)
R 2. R3M1Cl 116d: R = Ph, X = H, R3M = SnBu3 (80 %)
R
112a: R = Me, R3M = SiMe2Ph (79 %) 3. R3M2(Me)CuLi
112b: R = Me, R3M = SnBu3 (83 %)
112c: R = Ph, R3M = SiMe2Ph (75 %) R3M2 Me
112d: R = Ph, R3M = SnBu3 (80 %)
N
Scheme 51. R3M1 N
The 5-butylstannyl-4-fluoro-1H-pyrazole can be used for the R
synthesis of 5-substituted 4-fluoropyrazoles 114 (Scheme 52) [95].
117a: R = Me, X = I, R3M1 = SiMe2Ph, R3M2 = SnBu3 (76 % / 43 %)
1. BuLi, -78°C 117b: R = Ph, X = I, R3M1 = R3M2 = SiMe2Ph (73 % / 55 %)
F F
2. RCHO or RCOMe, 117c: R = Ph, X = I, R3M1 = SnBu3, R3M2 = SnBu3 (65 % / 41 %)
-78°C rt
N N Scheme 53.
Me3Sn N R´ N
Me Me
The silylated and stannylated pyrazoles can serve as starting
113 114
materials for numerous useful transformations. Thus, reaction with
benzoylchloride gave 119 [92] (Scheme 54).
RCHO / RCOMe R´ yield
O
R3M Me Me
a PHCHO PhCH(OH) 91 %
Ph
PhCOCl, reflux
b 4-MeOC6H4CHO 4-MeOC6H4CH(OH) 87 % Me N N
N Me N
c 2-TBSOC6H4CHO 2-TBSOC6H4CH(OH) 94 % Ph Ph
Ph 119 (52 % from 118a)
d CHO PhCH=CH-CH(OH) 76 % 118a: R3M = SiMe2Ph (52 %)
118b: R3M = SnBu3 (58%) (58 % from 118b)
e Me(CH2)8CHO Me(CH2)8CH(OH) 72 %
Scheme 54.

Conditions for the metallomeric isomerisation of
-lithiated to

Scheme 52. 5-lithiated 1-benzylpyrazoles from 120 were examined. Trapping
4,5-Dimetalled pyrazoles 117 were prepared as shown in reaction with either carbon dioxide or chlorotrimethylsilane were
(Scheme 53) [92]. carried out to give 121 and 123 (Scheme 55) [96].

N N N
BuLi, THF, N 1. CO2
N N
-75°C 2. HCl
Li COOH

MeO MeO MeO

120 121

N 1. CO2 N
Li N 2. HCl HOOC N

MeO MeO
122 123

Scheme 55.
2910 Current Organic Chemistry, 2011, Vol. 15, No. 16 Schmidt and Dreger

6. C-ARYLATIONS OF PYRAZOLES A modular approach to polyfunctional pyrazoles following

Scheme 58 was also developed, where MDG is a switchable metal-
One of the most versatile CC-coupling reactions, the Suzuki-
directing group. Thus, pyrazole boronic esters obtained from
Miyaura reaction, has also been applied to pyrazoles. Thus, Suzuki
lithiated intermediates were subjected to Suzuki reactions. Halo-
coupling reactions of pyrazole triflates 124 to aryl, heteroaryl, and
genations were carried out to functionalize the 4-position.
alkenyl pyrazoles with boronic acids in the presence of palladium
catalysts [97] (Scheme 56) as well as syntheses of 1-benzyl-3- A possible sequence of reactions leading to highly substituted
heterocyclic pyrazoles [98] and 4-arylations [99] have been re- pyrazoles is shown in (Scheme 59) [101].
ported. A palladium-catalyzed alkylation / arylation sequence yielded
annulated pyrazoles such as 138 (Scheme 60) [102].
ArB(OH)2, K3PO4,
R3 R3 R2 A radical cyclisation starting from selenium compound 139 was
R2 PdCl2(dppf) / dppf,
1,4-dioxane, 100°C
applied for the synthesis of Withasomnine 140 (Scheme 61) [103].
N N Successive regioselective metalations employing TMPMgCl .
TfO N R4 N LiCl and TMP2Mg . 2 LiCl gave full functionalization of pyrazoles
R1 with various electrophiles. An example is shown in (Scheme 62)
R1
[104].

124 125a: R1 = R3 = R4 = H, R2 = Me (81 %) 7. MISCELLANEOUS REACTIONS

125b: R1 = Me, R2 = CF3, R3 = R4 = H (79 %) Diazafulvenium methides derived from the pyrazolo[1,5-
125c: R1 = Ph, R2 = Me, R3 = H, R4 = 4-OMe (76 %) c][1,3]thiazole and substituted derivatives underwent cycloaddi-
125d: R1 = Me, R2-R3 = -(CH2)4-, R4 = H (71 %) tions with dipolarophiles. Some derivatives undergo intramolecular
sigmatropic [1,8]H shifts giving vinyl-1H-pyrazoles [105]. Diaza-
Scheme 56.
fulvenium methides formed by solution pyrolysis of pyrazolo[1,5-
Vice versa, pyrazole boronic esters can be functionalized by c][1,3]thiazole-2,2-dioxides 144 undergo [8
+2
] cycloadditions
Suzuki reactions (Scheme 57) [100]. giving pyrazolo[1,5-a]pyridine derivatives 145 (Scheme 63) [106].

Cl
O
p-ClC6H4Br,
Ph B O 10% PdCl2(DPPF), K3PO4, Ph
1,4-dioxane, 85 °C, 16 h
N N
N (88 %) N
Ph Ph

126 127

Scheme 57.

1. metallate
2. functionalize switch MDG
N N N
N R1 N R1 N MDG
MDG MDG

128 129 130

1. metallate
2. functionalize

R3 R2 R2
functionalize
N N
R1 N MDG R1 N MDG

132 131

Scheme 58.
Recent Advances in the Chemistry of Pyrazoles Current Organic Chemistry, 2011, Vol. 15, No. 16 2911

BPin
1. DHP, TFA, tol. 60 °C
2. nBuLi, B(O-iPr)3, pinacol N
N N THP
N THP
(79 %)

CN
CN 133 134

1. PhBr, Pd(dba)2, PCy3, HBF4,

(83 %)
K3PO4, 1,4-dioxane, 80°C, 16 h
2. HCl, MeOH

1. NBS, EtOAc, 50°C

MeO 2. 4-MeOPhB(OH)2,
Pd(dba)2, PCy3, HBF4,
K3PO4, 1,4-dioxane, 90°C
3. HCl, MeOH
N
N (64 %)
H HCl
N
N
H HCl
CN

136 CN 135

Scheme 59.
Me
I Me
Me
N
N N
N
Pd(OAc)2, tri-2-furylphosphine,
Br Cs2CO3, norbornene, MeCN, 90 °C
(54 %)
137 138

Scheme 60.

Ph Ph Ph
Bu3SnH, ACCN,
toluene, reflux, 4h
N N N
PhSe N N N
(38%)

139 140

Scheme 61.

8. REACTIONS OF PYRAZOLIUM SALTS 9. N-HETEROCYCLIC CARBENES OF PYRAZOLE.

Friedel-Crafts-type conversions known as hydroxyalkylations
have been described. The mechanism is thought to involve protona-
tion of an aldehyde or ketone and subsequent attack of an arene by
the carboxonium ion which is a fairly weak electrophile, so that
either electron-rich arene or suitable substitution patterns of the
carboxonium ions are required for successful reactions. To over-
come these shortcomings, dicationic species 147 were generated in
the Brønsted superacid triflic acid which reacted with benzene in
condensation reactions to 148 and 149 (Scheme 64) [107].
[14]Paracyclo-bis-(1,2)pyrazolium-phanes were prepared and
structural studies were performed [108]. In addition, pyrazolium
salts serve as carbene precursors which are described in the follow-
ing chapter.
An ever-increasing research activity has been documented in
the literature dealing with N-heterocyclic carbenes as stable com-
pounds, ligands, or catalysts [109, 110]. Carbenes of pyrazoles and
its relative, indazole, [111-120] have so far stood in the shadow of
other NHCs, but some very interesting structures and reactions have
been published in the last years.
Both types of N-heterocyclic carbenes of pyrazole have been
described. Pyrazol-3-ylidene I (pyrazolin-3-ylidene) can be de-
scribed by two canonical formulae, a zwitterionic all-octet structure
and an electron-sextet structure. It contains a carbenoid center that
is - similar to the class of so-called abnormal N-heterocyclic car-
benes (aNHC) - adjacent to only one nitrogen heteroatom. By con-
trast, pyrazol-4-ylidene II (pyrazolin-4-ylidene) can be referred to
2912 Current Organic Chemistry, 2011, Vol. 15, No. 16 Schmidt and Dreger

1. TMP2Mg . 2 LiCl O
1. TMPMgCl . LiCl Br 2. CuCN . 2 LiCl Br
Ph
2. MeSO2SMe 3. PhCOCl
N N
N N
3. TMPMgCl . LiCl MeS N (75 % overall yield) MeS N
SEM 4. (BrCl2C)2
SEM SEM
(54 % overall yield)
141 142 143

TMPMgCl . LiCl: TMP2Mg . 2 LiCl:

Me Me
Me Me
Cl
N Mg Li N Mg . 2 LiCl
2
Cl
Me Me
Me Me

Scheme 62.

E E E E
E E
TMS TMS
N N
N (54%) N
N N
O2S CH2
TMS

TMS

144 E = COOEt 145

Scheme 63.

H H their point of view appeared in due course [122]. Meanwhile results

R2 R2 were published which reveal that extremely bent allenes only bear a
O HO
CF3SO3H formal relationship with classical allenes and that they share many
N N of the properties of carbenes [123].
R3 N R3 N H

R1 R1
146 147 N N
N R N R
PhH
R R
Ph H
Ph Ph I
HO R2 CF3SO3H, HO R2
PhH
N N
R3 N R3 N
N N
N R N R
R1 R1
R R
149 148 II
a: R1
= R2
= Ph, R3
= H (70 %)
b: R1 = Ph, R2 = 4-NO2Ph, R3 = H (99 %) Scheme 65.
c: R1 = Ph, R2 = Me, R3 = Cl (97 %) N-Heterocyclic carbene ligands are two electron
-donors with
d: R1 = 4-tolyl, R2 = 4-ClPh, R3 = H (81 %) little -accepting abilities and form strong bonds to metal centers. A
Scheme 64. review article on preparation and coordination of carbene ligands
derived from imidazole with pyrazole and other ligands has been
as remote N-heterocyclic carbene (rNHC), as the carbenoid C atom published recently [124]. Pyrazol-3-ylidene complexes of chro-
is not adjacent to the N-atoms. The latter mentioned species cannot mium and iron were obtained by Öfele [125] who examined their
be represented by electron sextet structures, and it has been de- fragmentation pattern in mass spectrometry [126]. A detailed topo-
scribed recently as a cyclic bent allene (vide infra) (Scheme 65). A logical analysis of theoretical charge densities of 1,3-
correspondence was published soon after the latter mentioned struc- dimethylpyrazol-3-ylidene and its chromium complex was per-
ture was published [121] and a response of the authors defending formed and results of an X-ray single crystal analysis have been
Recent Advances in the Chemistry of Pyrazoles Current Organic Chemistry, 2011, Vol. 15, No. 16 2913

reported [127]. The bond distance Cr-Ccarbene was determined to be The copper bis-carbene complex 159 was prepared starting
213.27(4) pm (Scheme 66). from a lithiated pyrazole (Scheme 69) [2].
Cr(CO)5 Fe(CO)4

N Me N Me N 1. nBuLi, THF, -80°C Cu

N N N N
N N N
Ph 2. CuO3SCF3 0.5 PhH
Me Me Ph Ph
150 151 158 159 CF3SO3

Scheme 66. Scheme 69.

The pyrazol-3-ylidene complexes 154 were synthesized from Herrmann´s group described the one-pot synthesis of rhodium
terminal alkynes 152, hexacarbonyl chromium, triethyloxonium complex 161 of pyrazol-3-ylidene in 1997 [132]. Later, an X-ray
tetrafluoroborate, and 1,2-dimethylhydrazine [128, 129]. Transfer structure of 161 and its conversion into the air stable carbonyl com-
of the carbene ligand to gold was accomplished by [AuCl(SMe2)] plex 162 - which decomposes in solution under air - was presented
and H[AuCl4], respectively, and to palladium by [PdCl2(NCPh)2]. [133]. The X-ray analysis of 161 shows a slightly disturbed square-
Some of these complexes have been tested in Mizoroki-Heck reac- planar coordination sphere of the rhodium center. The rhodium-
tions. Modest activity was found in Suzuki-Miyaura and Stille reac- carbon bond length [203.4(5) pm] is not indicative for the strength
tions (Scheme 67) [125]. of this bond, as it does not differ considerably from other rhodium-
1. nBuLi, -78°C, THF NHC complexes. IR and NMR spectroscopy prove the cis-
2. [Cr(CO)6] conformation of both carbonyl ligands in 161, and the IR spectra
OEt display two strong (CO) bands. According to the CO-stretching
3. [Et3O]BF4, CH2Cl2
R H (CO)5Cr frequencies, recorded in CH2Cl2, the pyrazole ligands belong to the
strongest -donors in comparison with 1,3-dimethylimidazol-2-
152 153 ylidene, 1,3-dimethylimidazolidine-2-ylidene, or tetrazol-2-ylidene.
R In 13C NMR spectroscopy, the carbene carbon atom of complex 161
appears at
= 187.5 ppm in CD2Cl2, and the 1J(Rh-Ccarbene) cou-
H(Me)N-NH(Me) pling constant is 43.2 Hz (Scheme 70).
- EtOH
The iridium complex 164 was prepared and its catalytic activi-
ties in the reactions I – III was tested. This complex had good cata-
a: R = Ph (67 %) Cr(CO)5 lytic acidities in reaction I, but an analogous complex with 1,3-
b: R = C6H4NMe2 (75 %) bis(n-butyl)imidazol-2-ylidene displayed a better performance in
c: R = (C5H4)Fe(C5H5) (94 %) the reactions II and III (Scheme 71) [134].
N Me
R N 1,3-Dimethylpyrazolium iodide reacted also via a transmetala-
Me tion reaction of the silver carbene complex to form 165 or 166 in
dependence on the amounts of Ru(p-cymene) added. The metalated
154
carbon of 165 and 166 appear at
= 180.3 ppm and
= 175.1 ppm
Scheme 67. in the 13C NMR spectra, respectively. The structure of 165 was also
elucidated by an X-ray single crystal analysis. The Ru-C carbene bond
In this context, the preparation of complex 157 starting from
length was determined to be 208.4(7) pm. The complexes were
precursor 156 should be mentioned. On protonation with trifluoro-
sulfonic acid the resonance frequency of the carbene carbon atom tested in two catalytic reactions, the -alkylation of secondary alco-
shift from
= 145.6 ppm to 164.7 ppm. Results of X-ray single hols with primary alcohols and the dimerization of phenylacetylene,
crystal analyses are presented (Scheme 68) [130]. and both complexes displayed good activities (Scheme 72) [135].
Oxidative addition of 3-chlorotetramethylpyrazolium chloride
cp
167a and 3-chloro-1,5-dimethyl-2,4-diphenylpyrazolium chloride
1. nBuLi, THF, -80°C N
N Fe N 167b to the palladium(0) complex shown in Scheme 73 lead to the
OC
N 2. formation of palladium pyrazol-3-ylidene complexes 168a,b. Com-
cp Cl CO Ph
Ph plex 168a could not be isolated. The carbene carbon atoms ap-
Fe 156 peared between
= 161.1 ppm and 163.7 ppm as double doublets in
155 OC CO the 13C NMR spectra with 2JCP coupling constants between 7.3 and
10.5 Hz. The bond lengths Pd-Ccarbene was determined by a single
1. CF3SO3H, CH2Cl2 crystal X-ray analysis to be 198.0(2) pm. The diphenyl derivatives
-20°C, 30 min. had excellent catalytic activities in Heck reactions (Scheme 73)
[136].
cp Pyrazol-3-ylidene 171 was generated by thermal decarboxyla-
N tion of the pseudo-cross-conjugated heterocyclic mesomeric betaine
Fe N H
OC 170 which gives the pyrazolium salt 172 on trapping with protons.
CO Ph The N-heterocyclic carbene was examined by electrospray ioniza-
157 tion mass spectrometry, and the process of decarboxylation by
Scheme 68. NMR spectroscopy. The in situ generated carbene can induce aldol
2914 Current Organic Chemistry, 2011, Vol. 15, No. 16 Schmidt and Dreger

Et
O
Rh Rh
I O
Et
N N
N Me EtOH (56 %) LxRh N Me
Me Me
160 161
I
Rh CO
RhLx = -COD

OC
OC Rh N
N Me
I Me
162

Scheme 70.

Me Me
Me
Me
Me
I 1. Ag2O, MeCN, rt, 2 h Ir Cl
2. [{IrCl2Cp*}2], reflux, 3 h Cl
N N
N Me (40 %) N Me
Me Me
163 130°C 164
(I) PhCH2OH + nBuOH PhCH2OnBu

(II) PhNH2 + nHexNH2 150°C (Ph)(nHex)NH

(III) PhCH2OH + tBuNH2 110°C (PhCH2)(tBu)NH

Scheme 71.

Me
Me
1. Ag2O, CH2Cl2, rt, 2 h Me
2. [RuCl2(p-cymene)]2, reflux, 3 h
0.5 eq. Ru Cl
Cl
(60 %) N
N Me
Me

I 165

N
N Me Me
Me
Me Me
PF6
163 1. Ag2O, CH2Cl2, rt, 2 h Ru N
N Me
2. [RuCl2(p-cymene)]2, reflux, 3 h Cl
0.5 eq. N Me
N Me
(35 %) Me
166

Scheme 72.
Recent Advances in the Chemistry of Pyrazoles Current Organic Chemistry, 2011, Vol. 15, No. 16 2915

Ph Me Ph Me
Cl Ph3P Cl N
R Cl N
Pd(PPh3)4, 2 h, R Pd
N -CO2 N
90°C, CH2Cl2 PPh3 Me
Cl Me
N N
Me N R (70 %)
Me N R O O
Me
Me
167a: R = Me 168a,b 170
167b: R = Ph toluene,
1 h, 120°C
Ph Me Ph Me
N H2O N
Ph3P Cl
R Pd N N
Me Me
Cl - OH
H
N
Me N R 172 171
Me Scheme 74.
169a,b
Pseudo-cross-conjugated heterocyclic mesomeric betaines of
Scheme 73. pyrazole 173a-e which possess an aromatic ring in position 1 un-
dergo decarboxylation on heating to N-heterocyclic carbenes. These
additions, Knoevenagel reactions, and redox esterifications NHC of pyrazole rearrange spontaneously to 4-aminoquinolines
(Scheme 74) [137]. 174a-e which are of interest as potential anti-malarials (Scheme 75)

R3
R2 R4
R5
R4 HN
R1 R3 R7

R6 N R5
N -CO2
R2 N R6
R1
R7 O
O 174a-e
173a-e

R1-4 R1-4

N N
R5 R5
N N
R6,7 A R6,7

R1-4 R1-4
R5
R5 N
R5 N H
N R1-4
C
N R6,7
N
N
R6,7 R6,7 D
B
a: R1 = R2 = R4 = R7 = H, R3 = Br, R5 = R6 = Me (84 %)
b: R1 = COOH, R2 = R3 = R4 = R7 = H, R5 = R6 = Me (0 %)
c: R1 = R3 = R7 = H, R2 = R4 = Cl, R5 = R6 = Me (51 %)
d: R1 = R7 = H, R2 = R3 = R4 = OMe, R5 = Me, R6 = 2-thienyl (55 %)
e: R1 = R2 = R3 = R4 = H, R5 = R7 = Et, R6 = Ph (94 %)

Scheme 75.
2916 Current Organic Chemistry, 2011, Vol. 15, No. 16 Schmidt and Dreger

[43, 44]. The mechanism can be depicted as follows: Ring-cleavage I

of NHC A results in the formation of an intermediate which can be 2
Ph3P Pd PPh3
represented by the zwitterionic formula B or the neutral formula C.
Ring-closure to D can either be regarded as electrophilic aromatic Me Me
substitution (from B) or 6-electrocyclization (from C). Tautomeri- 2 BF4
N N
sation then gives the 4-aminoquinoline. DFT calculations indicate Me
( )3
the ring transformation to proceed via a sequence of intramolecular Me
elimination, imine inversion and 6-electrocyclization steps [44]. N N
Likewise, pyrazolium salts 175 rearrange to 4-aminoquinolines
Me Me
176a,b via the NHC of pyrazole (Scheme 76) [43, 44].
Ph3P Pd PPh3
Me
I
182
R2
I HN
KOtBu, toluene 2 BF4
R1 I [Pd2(dba)3]
N Me
Me
N
4 PPh3, CH2Cl2, reflux
Me Me
N Me
N N n=3
175 176a (47 %) Me
176b (31 %) ( )n
Me
N N
Scheme 76. [Pd2(dba)3]
Concerning pyrazol-4-ylidene, oxidative addition of the ligand Me 4 PPh3, CH2Cl2, reflux
Me
precursors 177 to [Pd2(dba)3]/PPh3 (dba = dibenzylideneacetone) n=1
I
lead to the neutral PdII(rNHC) complexes 178a,b [138, 139]. The in
181 4
situ deprotonation of 1,2,3,5-tetrasubstituted pyrazolium salts with PPh3
Ph3P I
basic metal precursors such as Pd(OAc)2 or Ag2O was unsuccess- Me Me
ful, probably because of the low acidity of the pyrazolium C-4 pro- Pd Pd
ton. The 4-iodopyrazolium triflates reacted to monocationic
Me N I N Me
bis(phosphine) complexes (X-ray analyses). The 1H NMR reso- 4 BF4
N N
nance frequencies are shifted upfield in comparison to the signals of Me Me
their precursors. The 13C NMR signals of the carbenoid C atoms of
the cationic complexes appear at
= 128.2 and 127.8 ppm as trip- Me Me N
N
lets, respectively, because of heteronuclear coupling with constants N Me
Me N I
of 2J(C,P) = 7.3 Hz. All complexes were subjected to Suzuki-
Miyaura and Mizoroki-Heck reactions [140] to test their catalytic Pd Pd
Me Me
activities. The cationic complexes showed better results (Scheme Ph3P I PPh3
77). 183
Pyrazole-derived remote dicarbenes 182 and 183 have also been
Scheme 78.
described (Scheme 78) [141].

I PPh3
I
I Me 0.5 [Pd2(dba)3] Pd Me
PPh3, CH2Cl2, reflux I
N N
Me N Et Me N Et
R R
177 178a: R = Ph (70 %)
178b: R = Me (60 %)

OTf PPh3
I
OTf
I Me 0.5 [Pd2(dba)3] Pd Me
2 PPh3, CH2Cl2, reflux PPh3
N N
Me N Et Me N Et
R R

180 179a: R = Ph (80 %)

179b: R = Me (73 %)
Scheme 77.
Recent Advances in the Chemistry of Pyrazoles Current Organic Chemistry, 2011, Vol. 15, No. 16 2917

The 3,5-diamino-substituted pyrazolium salt 185 was used as ligands. Pyrazol-3-ylidene is a stronger donor than pyrazol-4-
precursors for the synthesis of remote N-heterocyclic carbenes of ylidene [143], and both are stronger than all the other carbenes ex-
pyrazoles which have been described as five-membered ring allenes amined.
with four -donor amino groups. As already mentioned above, this
structure seems still to be under debate. As a matter of fact, treat- CONCLUSIONS
ment of precursor 186 with BuLi resulted in the formation of com-
Not only as a result of their biological significance, pyrazoles
pound 187 (X-ray analysis) (Scheme 79). [142]
form a class of compounds of growing importance. Progress made
during the last decade cover the range from classical electrophilic
BF4 BF4 substitution reactions such as nitration and sulfonation to metal-
Cl N N organic transformations. In addition, several members of this class
H of compounds such as abnormal N-heterocyclic carbenes and re-
Cl N N mote N-heterocyclic carbenes / 5-membered allenes have been ob-
Ph N Ph
N N tained for the first time. We hope that this review serves as a stimu-
Ph Ph lus for ongoing research in the area of pyrazole chemistry.

185 186 REFRENCES

[1] Schmidt, A.; Dreger, A. Recent advances in the chemistry of pyrazoles.
BuLi, THF, -78°C (26 %) properties, biological activities, and syntheses. Curr. Org. Chem., 2010, 15,
1423-1463.
[2] Kirschke, K. In: Houben-Weyl, Methoden der organischen Chemie; Schau-
BF4 mann, E. Ed.; Thieme Verlag, 1994; Vol. E8b, pp. 399-763.
BF4 [3] Stanovnik, B.; Svete, J. In: Science of Synthesis, R. Neier, Ed.; Thieme
Verlag: Stuttgart, 2002; Vol. 12, pp. 15-225.
Li
N Li N [4] Fustero, S.; Simón-Fuentes, A.; Sanz-Cervera, J.F. Recent Advances in the
Synthesis of Pyrazoles. A Review. Org. Prep. Proc. Int., 2009, 41(4), 253-
290.
N N Ph N [5] Grimmett, M.R. In: Comprehensive Organic Chemistry, D. H. R. Barton, W.
N N Ph
N D. Ollis, Eds.; Pergamon: Oxford 1979, 4, pp. 357-410.
[6] Jacobs, T.L. In: Heterocyclic Compounds, R. C. Elderfield, Ed.; Wiley: New
Ph Ph York 1957, 5, pp. 45-162.
[7] Kost, A.N.; Grandberg, I.I. Progress in Pyrazole Chemistry. Adv. Heterocycl.
187 Chem., 1966, 6, 347-429.
[8] Behr, L.C.; Fusco, R.; Jarboe, C.H. In: The Chemistry of Heterocyclic Com-
Scheme 79. pounds, Interscience: New York, 1967, 22, pp. 10-64.
[9] Elguero, J. In: Comprehensive Heterocyclic Chemistry, A. R. Katritzky, C.
In order to avoid the formation of C-Li bonds, 188 was depro- W. Rees, Eds.; Pergamon: Oxford 1984, 5, pp. 167-303.
tonated by KHMDS to give species 189, the ligand properties of [10] Elguero, J. In: Comprehensive Heterocyclic Chemistry II, A. R. Katritzky, E.
which were assessed by infrared analysis of the rhodium(I) dicar- F. V. Scriven, Eds.; Elsevier: Oxford 1996, 3, pp. 1-75.
[11] Makino, K.; Kim, H.S.; Kurasawa, Y. Synthesis of pyrazoles and condensed
bonyl chloride 190. They appear to be stronger donor ligands than pyrazoles. J. Heterocycl. Chem., 1999, 36(2), 321-332.
phosphines, five-membered NHCs and bis(diisopropylamino)car- [12] Makino, K.; Kim, H.S.; Kurasawa, Y. Synthesis of pyrazoles. J. Heterocycl.
bene. The carbene carbon atoms of 187 (Scheme 79) and 189 were Chem., 1998, 35(3), 489-497.
[13] Takagi, K.; Hubert-Habart, M. Ring transformation of 5-acylpyrimidines and
detected at
= 114.4 ppm and 115.5 ppm, respectively (Scheme 5-acyluracils into pyrazoles with hydrazines in acidic medium. J. Heterocycl.
80). Chem., 1996, 33(4), 1003-1015.
[14] Elnagdi, M.H.; Elgemeie, G.E.H.; Abd-Elaal, F. A.-E. Recent Developments
in the Synthesis of Pyrazole Derivatives. Heterocycles, 1985, 23(12), 3121-
I 3153.
O Ar OAr OAr [15] Benjes, P.A.; Grimmett, M.R., in N-Alkylation of Nitrogen Azoles, Advances
Ar KHMDS in Detailed Reaction Mechanisms, 1994, 3, 199, JAI Press Inc.: UK.
O N Ph N Ph [16] Begtrup, M.; Larsen, P. Alkylation, Acylation, and Silyation of Azoles. Acta
N ArO ArO N Ph
N N Chem. Scand., 1990, 44, 1050-1057.
Ph [17] Bogdal, D.; Pielichowski, J.; Jaskot, K. Remarkable fast N-alkylation of
Ph Ph azaheterocycles under microwave irradiation in dry media. Heterocycles,
Ar = 2,6-Me2C6H3 189 1997, 45(4), 715-722.
188 [18] Almena, I.; Díez-Barra, E.; de la Hoz, A.; Ruiz, J.; Sánchez-Migallón, A.;
Elguero, J. Alkylation and arylation of pyrazoles under solvent-free condi-
[{Rh(CO)2Cl}2] tions: Conventional heating versus microwave irradiation. J. Heterocycl.
Chem. 1998, 35(6), 1263-1268.
(CO)2ClRh OAr [19] Blanco, M.; Claramunt, R.M.; Escolástico, C.; Sanz, D. A study of the re-
gioisomerism in pyrazole alkylation using environmental friendly microwave
irradiation. 10th International Electronic Conference on Synthetic Organic
ArO N Ph
N Chemistry (ECSOC-10), 1-30 November 2006;
www.usc.es/congresos/ecsoc/10/MAS/e007/e007.pdf
Ph [20] Escolástico, C.; Blanco, M.; Claramunt, R. M.; Sanz, D.; Elguero, J. Micro-
wave synthesis of arylmethyl substituted pyrazoles. Open Org. Chem. J.,
190
2008, 2, 10-16.
Scheme 80. [21] Saulnier, M. G.; Frennesson, D.B.; Wittman, M.D.; Zimmermann, K.; Vela-
parthi, U.; Langley, D.R.; Struzynski, C.; Sang, X.; Carboni, J.; Li, A.; Greer,
The ligand donor strength of N-heterocyclic carbenes including A.; Yang, Z.; Balimane, P.; Gottardis, M.; Attar, R.; Vyas, D. 2-(1H-
Imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl)ethanamine side chain
pyrazol-3-ylidene and pyrazol-4-ylidene has been determined by variants of the IGF-1R inhibitor BMS-536924. Bioorg. Med. Chem. Lett.,
13
C NMR spectroscopy employing trans-[PdBr2(iPr2-bimy)L]n- 2008, 18(5), 1702-1707.
i [22] Price, S.; Bordogna, W.; Bull, R.J.; Clark, D. E.; Crackett, P.H.; Dyke, H.J.;
( Pr2-bimy = 1,3-diisopropylbenzimidazolin-2-ylidene; L = NHC).
Gill, M.; Harris, N.V.; Gorski, J.; Lloyd, J.; Lockey, P.M.; Mullett, J.; Roach,
The method is based on the sensitivity of the iPr2-bimy carbene A.G.; Roussel, F.; White, A.B. Identification and optimization of a series of
resonance frequency to the donor strength of the varying co- substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids as potent his-
2918 Current Organic Chemistry, 2011, Vol. 15, No. 16
tone deacetylase (HDAC) inhibitors. Bioorg. Med. Chem. Lett., 2007, 17(2),
370-375.
[23] Baltayan, A.O.; Rstakyan, V.I.; Ananosyan, S.K.; Kinoyan, F.S.; Attaryan,
O.S.; Asratyan, G.V. Alkylation of pyrazole with ethylene chlorohydrins un-
der phase transfer catalysis. Russ. J. Gen. Chem., 2009, 79(11), 2417-2419.
[24] Attaryan, O.S.; Baltayan, A.O.; Sgatelyan, R.E.; Takmazyan, K.T. Synthesis
of 1-(2-aminoethyl)pyrazoles under phase-transfer catalysis. Russ. J. Gen.
Chem., 2008, 78(1), 136-138.
[25] Tabrizi, M.A.; Baraldi, P.G.; Preti, D.; Romagnoli, R.; Saponaro, G.; Baraldi,
S.; Moorman, A.R.; Zaid, A.N.; Varani, K.; Borea, P.A. 1,3-Diproyl-8-(1-
phenylacetamide-1H-pyrazol-3-yl)-xanthine derivatives as highly potent and
selective human A2B adenosine receptor antagonists. Bioorg. Med. Chem.,
2008, 16(5), 2419-2430.
[26] Potapov, A.S.; Domina, G.A.; Khlebnikov, A.I.; Ogorodnikov, V.D. Facile
Synthesis of Flexible Bis(pyrazol-1-yl)alkane and Related Ligands in a Su-
perbasic Medium. Eur. J. Org. Chem., 2007, (30), 5112-5116.
[27] Nudnova, E.A.; Potapov, A.S.; Khlebnikov, A.I.; Ogorodnikov, V.D. Syn-
thesis of ditopic ligands containing bis(1H -pyrazol-1-yl)-methane fragments.
Russ. J. Org. Chem., 2007, 43(11), 1698-1702.
[28] Frizzo, C.P.; Moreira, D.N.; Guarda, E.A.; Fiss, G.F.; Marzari, M.R.B.;
Zanatta, N.; Bonacorso, H.G.; Martins, M.A.P. Ionic liquid as catalyst in the
synthesis of N-alkyl trifluoromethyl pyrazoles. Catal. Commun., 2009, 10(8),
1153-1156.
[29] Hayat, S.; Atta-ur-Rahman, Choudhary, M.I.; Khan, K.M.; Schumann, W.;
Bayer, E. N-Alkylation of anilines, carboxamides and several nitrogen het-
erocycles using CsF-celite/alkyl halides/CH3CN combination. Tetrahedron,
2001, 57(50), 9951-9957.
[30] Moghaddam, F.M.; Dokht Taimoory, S.M.; Ismaili, H.; Bardajee, G.R.
KF/Al2O3-Mediated N-Alkylation of Amines and Nitrogen Heterocycles and
S-Alkylation of Thiols. Synth. Commun., 2006, 36(23), 3599-3607.
[31] Branco, M.W.; Cao, R.Z.; Liu, L.Z.; Ege, G. Regioselective Benzylation of
an Indazolyl-substituted Pyrazole under the Influence of Inorganic Solid
Supported Bases. J. Chem. Res. (S), 1999, (4), 274-275.
[32] Matos, I.; Pérez-Mayoral, E.; Soriano, E.; Zukal, A.; Martín-Aranda, R.M.;
López-Peinado, A.J.; Fonseca, I.; ejka, J. Experimental and theoretical
study of pyrazole N-alkylation catalyzed by basic modified molecular sieves.
Chem. Eng. J., 2010, 161(3), 377-383.
[33] López-Cara, L.C.; Camacho, E. M.; Carrión, M.D.; Gallo, M.A.; Espinosa,
A.; Entrena, A. An unexpected aromatization during the N-alkylation reac-
tion of 3,4-dihydro-1H-pyrazole derivatives: insight into the reaction mecha-
nism. Tetrahedron Lett., 2006, 47(35), 6239-6242.
[34] Smith, T.E.; Mourad, M.S.; Velander, A.J. Effects of base, electrophile, and
substrate on the selective alkylation of heteroaromatic systems. Heterocycles,
2002, 57(7), 1211-1217.
[35] Butler, D.E.; Alexander, S.M. Lithiation of substituted pyrazoles. Synthesis
of isomerically pure 1,3-, 1,3,5-, and 1,5-substituted pyrazoles. J. Org.
Chem., 1972, 37(2), 215-220.
[36] Katritzky, A.R.; Jayaram, C.; Vassilatos, S. Alpha-lithiation of n-alkyl
groups in pyrazoles. Tetrahedron, 1983, 39(12), 2023-2029.
[37] Kanishchev, O.S.; Timoshenko, V.M.; But, S.A.; Chernega, A.N.; Sher-
molovich, Y.G.; Regioselectivity of alkylation of polyfluoroalkyl-substituted
NH-pyrazoles and NH-1,2,3-triazoles by olefins. Zh. Org. Farm. Khimii,
2008, 6(4), 65-70.
[38] Roman, C.; Comanita, E.; Comanita, B. N-Alkylation of pyrazoles with
mannich bases derived from ortho-hydroxyacetophenones. Chem. Hetero-
cycl. Compd., 2002, 38(9), 1072-1076.
[39] Moran, J.; Cebrowski, P.H.; Beauchemin, A.M. Intermolecular Hydroamina-
tions via Strained (E)-Cycloalkenes. J. Org. Chem., 2008, 73(3), 1004-1007.
[40] Tsuchimoto, T.; Aoki, K.; Wagatsuma, T.; Suzuki, Y. Lewis Acid Catalyzed
Addition of Pyrazoles to Alkynes: Selective Synthesis of Double and Single
Addition Products. Eur. J. Org. Chem., 2008, (23), 4035-4040.
[41] Mayboroda, A.; Rheinwald, G.; Lang, H. 1,4-Cycloaddition of pyrazole with
mesityl oxide; solid-state structure of bicyclic [C6H5Me3N2(OH)]Cl. Tetra-
hedron Lett., 2003, 44(10), 2129-2131.
[42] Schmidt, A.; Habeck. T.; Kindermann, M.K.; Nieger, M. New Pyrazolium-
carboxylates as Structural Analogues of the Pseudo-Cross-Conjugated Betai-
nic Alkaloid Nigellicine. J. Org. Chem., 2003, 68(15), 5977-5982.
[43] Schmidt, A.; Münster, N.; Dreger, A. Functionalized 4-Aminoquinolines by
Rearrangement of Pyrazole N-Heterocyclic Carbenes. Angew. Chem. Int.
Ed., 2010, 49(15), 2790-2793.
[44] Dreger, A.; Cisneros Camuña, R.; Münster, N.; Rokob, T.A.; Pápai, I.;
Schmidt, A. Rearrangements of N-Heterocyclic Carbenes of Pyrazole to 4-
Aminoquinolines and Benzoquinolines. Eur. J. Org. Chem., 2010, (22),
4296-4305.
[45] Guillou, S.; Bonhomme, F.J.; Janin, Y.L. Nitrogen's reactivity of various 3-
alkoxypyrazoles. Tetrahedron, 2009, 65(13), 2660-2668.
[46] Wang, X.-J.; Tan, J.; Grozinger, K.; Betageri, R.; Kirrane, T.; Proudfoot, J.R.
Practical synthesis of 1,3-diaryl-5-alkylpyrazoles by a highly regioselective
N-arylation of 3,5-disubstituted pyrazoles with 4-fluoronitrobenzene. Tetra-
hedron Lett., 2000, 41(28), 5321-5324.
[47] Park, K.H.; Cho, S.Y.; Yum, E.K.; Yu, C.M.; Hwang, K.J. Novel migration
of aryl group in 3-trifluoromethylpyrazolyl aryl ether. Bull. Korean Chem.
Soc., 1995, 16(9), 799-801.
[48] Luo, Y.; Potvin, P.G.; Chelation-Controlled Regioselectivity in the Synthesis
of Substituted Pyrazolylpyridine Ligands. 1. Bidentates. J. Org. Chem.,
1994, 59(7), 1761-1765.
Schmidt and Dreger
[49] Cerrada, M.L.; Elguero, J.; De La Fuente, J.; Pardo, C.; Ramos, M. Synthesis
of p-Nitrophenylazoles by Phase Transfer Catalysis Without Solvent. Synth.
Commun., 1993, 23(14), 1947-1952.
[50] Finar, I.L.; Hurlock, R.J. The preparation of some trinitrophenylpyrazoles. J.
Chem. Soc., 1957, 3024-3027.
[51] Malhotra, N.; Falt-Hansen, B.; Becher, J. Selective N-1 alkylation of un-
symmetrically substituted pyrazoles. J. Heterocycl. Chem., 1991, 28(8),
1837-1839.
[52] Wang, X.-J.; Tan, J.; Zhang, L. Regioselective Synthesis of Unsymmetrical
3,5-Dialkyl-1-arylpyrazoles. Org. Lett., 2000, 2(20), 3107-3109.
[53] Escolastico, C.; Torres, M. A.; Santa Maria, M. D.; Claramunt, R. M.;
Jagerovic, N.; Elguero, J.; Sastre, R. Spectroscopic properties of two highly
substituted PAH heteroanalogs: octakis(pyrazol-1-yl)naphthalene and oc-
takis(3,5-dimethylpyrazol-1-yl)naphthalene. ARKIVOC 2000, iv, 612-626.
[54] Antilla, J.C.; Baskin, J.M.; Barder, T.E.; Buchwald, S.L. CopperDiamine-
Catalyzed N-Arylation of Pyrroles, Pyrazoles, Indazoles, Imidazoles, and
Triazoles. J. Org. Chem., 2004, 69(17), 5578-5587.
[55] Zhang, H.; Cai, Q.; Ma, D. Amino Acid Promoted CuI-Catalyzed CN Bond
Formation between Aryl Halides and Amines or N-Containing Heterocycles.
J. Org. Chem., 2005, 70(13), 5164-5173.
[56] Sreedhar, B.; Venkanna, G.T.; Kumar, K.B.S.; Balasubrahmanyam, V.
Copper(I) Oxide Catalyzed N-Arylation of Azoles and Amines with Arylbo-
ronic Acid at Room Temperature under Base-Free Conditions. Synthesis,
2008, (5), 795-799.
[57] Rossiter, S.; Woo, C.K.; Hartzoulakis, B.; Wishart, G.; Stanyer, L.; Labadie,
J.W.; Selwood, D.L. Copper (II)-Mediated Arylation with Aryl Boronic Ac-
ids for the N-Derivatization of Pyrazole Libraries. J. Comb. Chem., 2004,
6(3), 385-390.
[58] Cristau, H.-J.; Cellier, P.P.; Spindler, J.-F.; Taillefer, M. Mild Conditions for
Copper-Catalysed N-Arylation of Pyrazoles. Eur. J. Org. Chem., 2004, (4),
695-709.
[59] Butler, R.N.; Hanniffy, J.M.; Stephens, J.C.; Burke, L.A. A Ceric Ammo-
nium Nitrate N-Dearylation of N-p-Anisylazoles Applied to Pyrazole, Tria-
zole, Tetrazole, and Pentazole Rings: Release of Parent Azoles. Generation
of Unstable Pentazole, HN5/N5-, in Solution. J. Org. Chem., 2008, 73(4),
1354-1364.
[60] Shen, Z.; Hong, Y.; He, X.; Mo, W.; Hu, B.; Sun, N.; Hu, X. Switching the
chemoselectivity in the amination of 4-chloroquinazolines with aminopyra-
zoles. Org. Lett., 2010, 12(3), 552-555.
[61] Sun, X.; Yu, Z.; Wu, S.; Xiao, W.-J. Base effect and inhibition of catalytic
activity in palladium-catalysed N-heteroarylation of pyrazoles with 2,6-
dibromopyridine. Organometallics, 2005, 24(12), 2959-2963.
[62] Wen, L.R.; Zhao, G.L.; Li, M.; Qi, W.Y.; Zhang, X.L.; Yang, H.Z. A new
approach to ethyl 1-aroyl/arolymethyl-5-methyl-3-methylthiopyrazole-4-
carboxylates: High regioselectivity in alkylation and acylation reactions be-
tween N-1 and N-2 of a pyrazole derivative. Chin. Chem. Lett., 2005, 16(9),
1161-1164.
[63] Wen.; L.-R.; Wang, S.-W.; Li. M.; Qi, W.-Y.; Zhang, X.-L.; Yang, H.-Z., An
unexpected and green synthetic protocol for ethyl 1-aroyl/aroylmethyl5-
methyl-3-methylthiopyrazole-4-carboxyltes: High regioselectivity in alkyla-
tion and acylation reactions between N-1 and N-2 of a pyrazole ring. J. Chin.
Chem. Soc., 2005, 52(5), 1021-1028.
[64] Perreira, C. M. P.; Quina, F. H.; Silva, F. A. N.; Emmerich, D. J.; Machulek,
Jr., A. Synthesis of 4-iodopyrazoles. A brief review. Mini-Rev. Org. Chem.
2008, 5, 331-335.
[65] Li, G.; Kakarla, R.; Gerritz, S.W. A fast and efficient bromination of isoxa-
zoles and pyrazoles by microwave irradiation. Tetrahedron Lett., 2007,
48(26), 4595-4599.
[66] Stefani, H.A.; Pereira, C.M.P.; Almeida, R.B.; Braga, R.C.; Guzen, K.P.;
Cella, R. A mild and efficient method for halogenations of 3,5-dimethyl
pyrazoles by ultrasound irradiation using N-halosuccinimides. Tetrahedron
Lett., 2005, 46(40), 6833-6837.
[67] Eskildsen, J.; Vedsø, P.; Begtrup, M. Synthesis of 2-Alkylpyrazole-1-oxides:
A Facile Access to 1-Alkyl-5-halopyrazoles. Synthesis, 2001, (7), 1053-
1056.
[68] Rodriguez-Franco, M. I.; Dorronsoro, I.; Hernández-Higueras, A.I.; Ante-
quera, G. A mild and efficient method for the regioselective iodination of
pyrazoles. Tetrahedron Lett., 2001, 42(5), 863-865.
[69] Shevelev, S. A.; Dalinger, I. L. Advances in the nitropyrazole chemistry.
Russ. J. Org. Chem., 1998, 34(8), 1071-1080.
[70] Boyer, J.H.; in Nitroazoles: the C-nitro derivatives of five-membered N- and
N,O-heterocycles, VCH, Weinheim, 1986, p. 186.
[71] Austin, M.W.; Blackborow, J.R.; Ridd, J.H., Smith, B.V., The kinetics and
mechanism of heteroaromatic nitration. Part II. Pyrazole and imidazole. J.
Chem. Soc., 1965, 1051-1057.
[72] Shevelev, S.A.; Vinogradov, V.M.; Dalinger, I.L.; Cherkasova, T.I. Nitro-
pyrazoles .8. 3(5)-Amino-4-Nitropyrazole – Convenient Synthesis and Study
of Nitration. Russ. Chem. Bull., 1993, 42(11), 1861-1864.
[73] Janssen, J.W.A.M.; Koeners, H.J.; Kruse, C.G.; Habraken, C.L.; Pyrazoles.
XII. Preparation of 3(5)-nitropyrazoles by thermal rearrangement of N-
nitropyrazoles. J. Org. Chem., 1973, 38(10), 1777-1782.
[74] Buchanan, J.G.; Stobie, A.; Wightman, R.H. C-Nucleoside studies. Part XI.
Cine-substitution in 1,4-dinitropyrazoles; application to the synthesis of
formycin via nitropyrazole derivatives. Can. J. Chem., 1980, 58(23), 2624-
2627.
Recent Advances in the Chemistry of Pyrazoles
[75] Dalinger, I.L.; Litosh, V.A.; Shevelev, S.A. Nitropyrazoles. 10. N-Nitration
of 3(5)-substituted pyrazoles. Russ. Chem. Bull., 1997, 46(6), 1149-1153.
[76] Buchanan, J.G.; Harrison, M.; Wightman, R.H.; Harnden, M.R. C-
Nucleoside studies. Part 20. Synthesis of some pyrazolo[4,3-d]pyrimidine
acyclonucleosides related to (S)-(2,3-dihydroxypropyl)adenine; a direct
method for double functionalization of the pyrazole ring. J. Chem. Soc.,
Perkin Trans 1, 1989, 925-930.
[77] Suzuki, H.; Nonoyama, N, Ozone-mediated nitration of pyrazole, imidazole
and uracil with nitrogen dioxide. J. Chem. Res. (S), 1996, (5), 244-245.
[78] Claridge, R.P.; Lancaster, N.L.; Millar, R.W.; Moodie, R.B.; Sandall, J. P.B.
Faujasite catalysis of aromatic nitrations with dinitrogen pentoxide. The ef-
fect of aluminium contents on catalytic activity and regioselectivity. The ni-
tration of pyrazole. J. Chem. Soc., Perkin Trans 2, 2001, 197-200.
[79] Katritzky, A.R.; Scriven, E.F.V.; Majumder, S.; Akhmedova, R.G.; Akhme-
dov, N.G.; Vakulenko, A.V. Direct nitration of five membered heterocycles.
ARKIVOC, 2005, iii, 179-191.
[80] Katritzky, A.R.; Vakulenko, A.V.; Sivapackiam, J.; Draghici, B.;
Damavarapu, R. Synthesis of Dinitro-Substituted Furans, Thiophenes, and
Azoles. Synthesis, 2008, (5), 699-706.
[81] Hervé, G.; Roussel, C.; Graindorge, H. Selective Preparation of 3,4,5-
trinitro-1H-pyrazole: A stable all-carbon-nitrated arene. Angew. Chem. Int.
Ed., 2010, 49(18), 3177-3181.
[82] Pelleter, J.; Renaud, F. Facile, fast and safe process development of nitration
and bromination reactions using continuous flow reactors. Org. Proc. Res.
Dev., 2009, 13(4), 698-705.
[83] Grandberg, I.I.; Nam, N. L. Sorokin, V.I., New method for the sulfonation of
pyrazoles. Chem. Heterocycl. Compd., 1997, 33(5), 532-534.
[84] Mezei, G.; Raptis, R.G. Pyrazole-4-sulfonate networks of alkali and alkaline-
earth metals. Effect of cation size, charge, H-bonding and aromatic interac-
tions on the three-dimensional supramolecular architecture. New. J. Chem.,
2003, 27(9), 1399-1407.
[85] Rondestvedt, Jr. C.S.; Chang, P.K. Unsaturated sulfonic acids. V. Additions
of diazomethane and phenyl azide to derivatives of ethylenesulfonic acid and
its homologs. J. Am. Chem. Soc., 1955, 77, 6532-6540.
[86] Barry, W.J.; Finar, I.L.; Khatkhate, G.V. Sulphonation of arylpyrazoles. Part
II. Some 1-phenylpyrazolesulphonic acids and their derivatives. J. Chem.
Soc. C, 1968, 1120-1122.
[87] Matthews, H.R.; Bucke, L.C.; Blackman, A.G. Electrophilic substitution of
metal-coordinated pyrazole: nitration, sulfonation and bromination of
[Co(NH3)5(pyzH)]3+ (pyzH = pyrazole). Inorg. Chim. Acta, 1998, 227(1), 89-
97.
[88] Dreger, A.; Münster, N.; Schmidt, A.; Gjikaj, M. unpublished results.
[89] Schnürch, M.; Flasik, R.; Khan, A.F.; Spina, M.; Mihovilovic, M.D.; Sta-
netty, P. Cross-Coupling Reactions on Azoles with Two and More Heteroa-
toms. Eur. J. Org. Chem., 2006, (15), 3283-3307.
[90] Iddon, B.; Tønder, J.E.; Hosseini, M.; Begtrup, M. The N-vinyl group as a
protection group of the preparation of 3(5)-substituted pyrazoles via bro-
mine–lithium exchange. Tetrahedron, 2007, 63(1), 56-61.
[91] Schlosser, M.; Volle, J.-N.; Leroux, F.; Schenk, K. Switchable reactivity: the
site-selective functionalization of trifluoromethyl-substituted pyrazoles. Eur.
J. Org. Chem., 2002, (17) 2913-2920.
[92] Calle, M.; Cuadrado, P.; González-Nogal, A.M.; Valero, R. Synthesis and
Reactions of Silylated and Stannylated 1,2-Azoles. Synthesis, 2001, (13),
1949-1958.
[93] Hanamoto, T.; Suetake, T.; Koga, Y.; Kawanami, T.; Furuno, H.; Inanaga, J.
Synthesis and reactions of 5-tributylstannyl-4-fluoro-1H-pyrazole. Tetrahe-
dron, 2007, 63(23), 5062-5070.
[94] De la Hoz, A.; Díaz-Ortiz, A.; Elguero, J.; Martínez, L. J.; Moreno, A.;
Sánchez-Migallón, A. Solvent-free preparation of tris-pyrazolyl-1,3-5-
triazines. Tetrahedron, 2001, 57, 4397-4403.
[95] Hanamoto, T.; Hashimoto, E.; Miura, M.; Furuno, H.; Inanaga, J. Reaction of
N-Methyl-5-tributylstannyl-4-fluoro-1H-pyrazole and its Application to N-
Methyl-chromeno[2,3-d]pyrazol-9-one Synthesis. J. Org. Chem., 2008,
73(12), 4736-4739.
[96] Ondi, L.; Schlosser, M. Metalated 1-(p-methoxybenzyl)pyrazole: a structural
chameleon. Eur. J. Org. Chem., 2006, (10), 2417-2422.
[97] Dragovich, P.S.; Bertolini, T.M.; Ayida, B.K.; Li, L.-S.; Murphy, D.E.;
Ruebsam, F.; Sun, Z.; Zhou, Y. Regiospecific synthesis of 1,5-disubstituted-
1H-pyrazoles containing differentiated 3,4-dicarboxylic acid esters via Su-
zuki coupling of the corresponding 5-trifluoromethane sulfonates. Tetrahe-
dron, 2007, 63(5), 1154-1166.
[98] Curtis, M.P.; Sammons, M.F.; Piotrowski, D.W. A convenient and rapid
approach for the synthesis of 1-benzyl-3-heterocyclic pyrazoles. Tetrahedron
Lett., 2009, 50(39), 5479-5481.
[99] Guillou, S.; Nesmes, O.; Ermolenko, M.S.; Janin, Y.L. 4-Arylation of 3-
alkoxypyrazoles. Tetrahedron, 2009, 65(17), 3529-3535.
[100] Browne, D.L.; Helm, M.D.; Plant, A.; Harrity, J.P.A. A sydnone cycloaddi-
tion route to pyrazole boronic esters. Angew. Chem., 2007, 119(45), 8810-
8812; A sydnone cycloaddition route to pyrazole boronic esters. Angew.
Chem. Int. Ed., 2007, 46, 8656-8658.
[101] McLaughlin, M.; Marcantonio, K.; Chen. C.-Y.; Davies, I.W. A Simple,
Modular Method for the Synthesis of 3,4,5-Trisubstituted Pyrazoles. J. Org.
Chem., 2008, 73(11), 4309-4312.
[102] Blaszykowski, C.; Aktoudianakis, E.; Bressy, C.; Alberico, D.; Lautens, M.
Preparation of Annulated Nitrogen-Containing Heterocycles via a One-Pot
Current Organic Chemistry, 2011, Vol. 15, No. 16 2919
Palladium-Catalyzed Alkylation/Direct Arylation Sequence. Org. Lett., 2006,
8(10), 2043-2045.
[103] Allin, S.M.; Barton, W.R.S.; Bowman, W.R.; McInally, T. Radical cyclisa-
tion onto pyrazoles: synthesis of withasomnine. Tetrahedron Lett., 2002,
43(23), 4191-4193.
[104] Despotopoulou, C.; Klier, L.; Knochel, P. Synthesis of Fully Substituted
Pyrazoles via Regio- and Chemoselective Metalations. Org. Lett., 2009,
11(15), 3326-3329.
[105] Pinho e Melo, T. M. V. D.; Nunes, C. M.; Soares, M. I. L.; Paixão, J. A.;
Beja, A. M.; Silva, M. R. Chemistry of Diazafulvenium Methides in the Syn-
thesis of Functionalized Pyrazoles. J. Org. Chem., 2007, 72(12), 4406.
[106] Pinho e Melo, T. M. V. D.; Soares, M. I. L.; d`a Rocha Gonsalves, A. M.
New chemistry of diazafulvenium methides: one way to pyrazoles. Tetrahe-
dron Lett., 2006, 47(5), 791-794.
[107] Klumpp, D. A.; Kindelin, P. J.; Li, A. Superacid-promoted reactions of
pyrazolecarboxaldehydes and the role of dicationic electrophiles. Tetrahe-
dron Lett., 2005, 46(16), 2931-2935.
[108] Cabildo, P.; Sanz, D.; Claramunt, R. M.; Bourne, S. A.; Alkorta, I.; Elguero,
J. Synthesis and Structural Studies of Some [14]Paracyclo-bis-
(1,2)pyrazolium- and (1,3)imidazolium-phanes. Tetrahedron 1999, 55, 2327-
2340.
[109] Hahn, F.E.; Jahnke, M.C. Heterocyclic Carbenes: Synthesis and Coordina-
tion Chemistry. Angew. Chem. Int. Ed., 2008, 47(17), 3122-3172.
[110] Melaimi, M.; Soleilhavoup, M.; Bertrand, G. Stable cyclic carbenes and
related species beyond diaminocarbenes. Angew. Chem. Int. Ed. 2010, 49,
8810-8849.
[111] Schmidt, A.; Snovydovych, B.; Casado, J.; Quirante, J.J.; López Navarrete,
J.T.; Ramírez, F.J. Quantum mechanical study and vibrational spectra of in-
dazolium-3-carboxylate and its decarboxylation product, the N-heterocyclic
carbene indazol-3-ylidene. Phys. Chem. Chem. Phys., 2009, 11(2), 341-348.
[112] Lindner, A.S.; Schmidt, A. N-Heterocyclic carbenes of indazole as reagents:
Indazol-3-ylidene-mediated syntheses of amidines from thiolactams of pyr-
rolobenzodiazepines. Synlett, 2008, (19), 2961-2964.
[113] Schmidt, A.; Snovydovych, B.; Gjikaj, M. N-Heterocyclic Carbenes of
Indazole: Ring Enlargement Reactions by
-Halo Ketones and Dehalogena-
tions of Vicinal Dihalides. Synthesis, 2008, (17), 2798-2804.
[114] Schmidt, A.; Snovydovych, B.; Hemmen, S. N-Heterocyclic Carbene In-
duced Cycloaddition Reactions of Indazoles with Acetylenes To Form a New
Ring System. Eur. J. Org. Chem., 2008, (25), 4313-4319.
[115] Schmidt, A.; Snovydovych, B.; Habeck, T.; Dröttboom, P.; Gjikaj, M.;
Adam, A. N-Heterocyclic Carbenes of 5-Haloindazoles Generated by Decar-
boxylation of 5-Haloindazolium-3-carboxylates. Eur. J. Org. Chem., 2007,
(29), 4909-4916.
[116] Schmidt, A.; Habeck, T.; Snovydovych, B.; Eisfeld, W. Addition Reactions
and Redox Esterifications of Carbonyl Compounds by N-Heterocyclic Car-
benes of Indazole. Org. Lett., 2007, 9(18), 3515-3518.
[117] Schmidt, A.; Habeck, T.; Lindner, A.S.; Snovydovych, B.; Namyslo, J.C.;
Adam, A.; Gjikaj, M. Translation of Pseudo-Cross-Conjugation into Chemis-
try: Cycloadditions of Mesomeric Betaines to the New Ring System
Spiro[indazole-3,3‘-pyrrole]. J. Org. Chem., 2007, 72(6), 2236-2239.
[118] Schmidt, A.; Beutler, A.; Habeck, T.; Mordhorst, T.; Snovydovych, B.
Pseudo-Cross-Conjugated Mesomeric Betaines and N-Heterocyclic Carbenes
of Indazole. Synthesis, 2006, (11), 1882-1894.
[119] Schmidt, A.; Habeck, T.; Merkel, L.; Mäkinen, M.; Vainiotalo, P. Electros-
pray ionization mass spectrometric studies of nucleophilic carbenes derived
from pyrazolium and indazolium carboxylates. Rapid Comm. Mass Spec-
trom., 2005, 19(16), 2211-2216.
[120] Schmidt, A.; Merkel, L.; Eisfeld, W. Nucleophilic Carbenes and Pseudo-
Cross-Conjugated Mesomeric Betaines of Indazole Starting from Analogues
of the Alkaloid-Betaine Nigellicine. Eur. J. Org. Chem., 2005, (10), 2124-
2130.
[121] Christl, M.; Engels, B. Stable Five-Membered-Ring Allenes with Second-
Row Elements Only: Not Allenes, But Zwitterions. Angew. Chem. Int. Ed.,
2009, 48(9), 1538-1539.
[122] Lavallo, V.; Dyker, C.A.; Donnadieu, B.; Bertrand, G. Are Allenes with
Zwitterionic Character Still Allenes? Of Course!. Angew. Chem. Int. Ed.,
2009, 48(9), 1540-1542.
[123] Hänninen, M.M.; Peuronen, A.; Tuononen, H.M. Do extremely bent allenes
exist? Chem. Eur. J., 2009, 15(30), 7287-7291.
[124] Lee, H.M.; Lee, C.-C.; Cheng, P.-Y., Recent Development of Functionalized
N-Heterocyclic Carbene Ligands:Coordination Chemistry and Catalytic Ap-
plications. Curr. Org. Chem., 2007, 11(17), 1491-1524.
[125] Öfele, K.; Roos, E.; Herberhold, M. Isomerisierungsreaktionen von cis- und
trans-Dicarben-Komplexen des Typs M(CO)4L2 (M = Cr, Mo, W). Z. Natur-
forsch., 1976, 31B(8), 1070-1077.
[126] Müller, J.; Öfele, K.; Krebs, G., Mass spectroscopic decomposition of penta-
carbonylchromium and tetracarbonyliron complexes with heterocyclic car-
bene ligands. J. Organomet. Chem., 1974, 82(3), 383-395.
[127] Tafipolsky, M.; Scherer, W.; Öfele, K.; Artus, G.; Pedersen, B.; Herrmann,
W.A.; McGrady, G. S. Electron Delocalization in Acyclic and N-
Heterocyclic Carbenes and Their Complexes: A Combined Experimental and
Theoretical Charge-Density Study. J. Am. Chem. Soc., 2002, 124(20), 5865-
5880.
[128] Aumann, R.; Jasper, B.; Fröhlich, R.; Organic Syntheses via Transition Metal
Complexes. 78. Hydrazinolysis of Alkynylcarbene Complexes of Chromium
2920 Current Organic Chemistry, 2011, Vol. 15, No. 16
and Tungsten. Formation of Hydrazinocarbene, Imidate, Pyrazolidinylidene,
and Nitrile Complexes. Organometallics, 1995, 14(5), 2447-2455.
[129] Kessler, F.; Szesni, N.; Maaß, C.; Hohberger, C.; Weibert, B.; Fischer, H.
Transfer of heterocyclic carbene ligands from chromium to gold, palladium
and platinum. J. Organomet. Chem., 2007, 692(14), 3005-3018.
[130] Raubenheimer, H.G., Desmet, M.; Olivier, P.; Kruger, G.J. Preparation and
characterization of carbene complexes of iron from azolyl and thienyl pre-
cursors. J. Chem. Soc., Dalton Trans., 1996, 4431-4438.
[131] Raubenheimer, H.G.; Desmet, M.; Lindeque, L. Bis(carbene) complexes of
copper prepared from lithiated azoles. J. Chem. Res (S), 1995, (5), 184-185.
[132] Köcher, C.; Herrmann, W.A. Heterocyclic carbenes. Part 11. One-pot syn-
thesis of rhodium and iridium carbene complexes. J. Organomet. Chem.,
1997, 532(1-2), 261-265.
[133] Herrmann, W.A.; Schütz, J.; Frey, G. D.; Herdtweck, E. N-Heterocyclic
Carbenes: Synthesis, Structures, and Electronic Ligand Properties. Or-
ganometallics, 2006, 25(10), 2437-2448.
[134] Prades, A.; Corberán, R.; Poyatos, M.; Peris, E. [IrCl2Cp*(NHC)] Com-
plexes as Highly Versatile Efficient Catalysts for the Cross-Coupling of Al-
cohols and Amine. Chem. Eur. J., 2008, 14(36), 11474-11479.
[135] Prades, A.; Viciano, M.; Sanaú, M.; Peris, E. Preparation of a Series of
“Ru(p-cymene)” Complexes with Different N-Heterocyclic Carbene Ligands
for the Catalytic -Alkylation of Secondary Alcohols and Dimerization of
Phenylacetylene. Organometallics, 2008, 27(16), 4254-4259.
Received: 10 November, 2010 Revised: 14 December, 2010
Schmidt and Dreger
[136] Schütz, J.; Herdtweck, E.; Herrmann, W.A. Synthesis and Catalytic Applica-
tion of Palladium Pyrazolin-3-ylidene Complexes. Organometallics, 2004,
23(26), 6084-6086.
[137] Schmidt, A.; Habeck, T. Nucleophilic carbenes of pyrazoles starting from
pseudo-cross-conjugated mesomeric betaines. Lett. Org. Chem., 2005, 2(1),
37-39.
[138] Han, Y.; Huynh, H.V. Preparation and characterization of the first pyrazole-
based remote N-heterocyclic carbene complexes of palladium(II). Chem.
Commun., 2007, (10), 1089-1091.
[139] Han, Y.; Huynh, H.V.; Tan, G.K. Palladium(II) Pyrazolin-4-ylidenes: Re-
mote N-Heterocyclic Carbene Complexes and Their Catalytic Application in
Aqueous Suzuki
Miyaura Coupling. Organometallics, 2007, 26(26), 6581-
6585.
[140] Han, Y.; Lee, L.J.; Huynh, H.V. Palladium(II) Pyrazolin-4-ylidenes: Sub-
stituent Effects on the Formation and Catalytic Activity of Pyrazole-Based
Remote NHC Complexes. Organometallics, 2009, 28(9), 2778-2786.
[141] Han, Y.; Lee, L. J.; Huynh, H.V. Pyrazole-derived remote dicarbenes: Versa-
tile ligands for di- and tetranuclear complexes. Chem. Eur. J., 2010, 16(3),
771-773.
[142] Lavallo, V.; Dyker, C.A.; Donnadieu, B.; Bertrand, G. Synthesis and Ligand
Properties of Stable Five-Membered-Ring Allenes Containing Only Second-
Row Elements. Angew. Chem. Int. Ed., 2008, 47(29), 5411-5414.
[143] Huynh, H.V.; Han, Y.; Jothibasu, R.; Yang, J.A. 13C NMR Spectroscopic
Determination of Ligand Donor Strengths Using N-Heterocyclic Carbene
Complexes of Palladium(II). Organometallics, 2009, 28(18), 5395-5404.
Accepted: 11 January, 2011