Tetrahedron 60 (2004) 10039–10047

Mild and selective deprotection of carbamates with Bu4NF
Ulrich Jacquemard, Vale´rie Be´ne´teau, Myriam Lefoix, Sylvain Routier, Jean-Yves Me´rour
and Ge´rard Coudert*
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Universite´ d’Orle´ans, B.P. 6759, 45067 Orle´ans Cedex 2, France
Received 27 January 2004; revised 19 July 2004; accepted 27 July 2004

Abstract—A new mild method allowing the removal of carbamates using TBAF in THF is reported. Reactions were performed on indole,
indoline, N-methyl aniline, aniline and tryptamine derivatives. The observed selectivity according to the carbamates or the substrates is
discussed. A mechanism is postulated.
q 2004 Published by Elsevier Ltd.

1. Introduction
The selection of a protective group is often a crucial step in
organic synthesis;1 the development of new protective
groups and novel efficient methods for their introduction or
cleavage remains of prime importance in synthetic
methodology.
Many protective groups have been developed for the amino
functionality, in peptide, protein, and nucleotide syntheses
as well as in heterocyclic chemistry. Among them, may be
the most useful and popular are the carbamates. Actually,
carbamates are not only used as protective but also as
efficient directing metallation groups.2 Carbamates are
generally obtained from an amine by reaction with the
adequate chloroformate or anhydride. It is of prime interest
to dispose of a wide range of methods allowing the selective
cleavage of a definite protective group on a given nitrogen
atom in the presence of other N-protected sites.3,4 There are
a lot of conditions allowing the recovery of the free amino
group; catalytic hydrogenolysis, acidic or basic3 treatments
are generally appropriate to remove most of the different
carbamates used in organic synthesis. Nevertheless several
drawbacks constitute sometimes a limitation of the
efficiency of these methods. For instance, the presence of
a sulfur atom is commonly incompatible with a catalytic
hydrogenolysis.5 The acidic cleavage of a Boc group can
generate t-butyl cations and in some cases, scavengers have
to be used to prevent undesirable alkylation or electrophilic
additions.6 The unwanted formation of heterocycles by an
intramolecular cyclisation has been as well reported in the
course of reactions involving methyl and ethyl carbamates.7,8
Keywords: Carbamates; Deprotection; Bu4NF; Protective groups.
* Corresponding author. Tel.: C33-2-38-49-45-89.; fax: C33-2-38-41-7281; e-mail: gerard.coudert@univ-orleans.fr
0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.07.071

In some instance cleavage of phenyl carbamates led also to
undesired side-products.9–12
Tetra-n-butylammonium fluoride (Bu4NF) is a versatile and
popular reagent widely used in organic chemistry13–17 for
most fluoride-assisted reactions (deprotection of silyl
groups,3 desilylation,18 fluorination)19 and used as a base
in a variety of base-catalysed reactions.20–24 In particular
the hydrolysis of aliphatic esters25 with aqueous TBAF and
the cleavage of N-mesyl22 or N-benzenesulfonyl groups26,27
have been reported. Recently, Yasuhara prepared 2-substituted indole from 2-ethynyl anilines with TBAF22,28,29
and observed a partial or total N-dealkoxycarbonylation
during the cyclisation process. For our part we have
previously reported our own preliminary results concerning
the mild deprotection of tert-butyl carbamates (Boc) on
heteroaromatics using TBAF in refluxing THF.30
Herein we wish to extend the scope of our method to the
cleavage of various aliphatic (t-Bu, Me, Et), allylic (alloc),
benzylic (Z) and phenyl carbamates protecting different
kinds of nitrogens (Scheme 1).

Scheme 1. General scheme for Bu4NF cleavage of carbamate protective
groups in THF.

2. Results and discussion
All the studied carbamates were prepared using classical

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U. Jacquemard et al. / Tetrahedron 60 (2004) 10039–10047

conditions as indicated in the captions of Figures 1–4. The
same typical procedure was used for all deprotection assays:
the N-protected derivative was dissolved in dry THF under
argon, then the adapted amount of a 1 M solution of Bu4NF
in THF was added; the reaction was performed at rt or in
refluxing THF for the appropriate duration.
2.1. Cleavage of N-indolyl protected carbamates
We have recently reported30 the deprotection of tert-butyl
carbamate groups on pyrrole, carbazole and indole 7. The
latter was fully deprotected by Bu4NF (5 equiv) in refluxing
THF for 8 h (Table 1, entry 6a). Decreasing the amount of
the reagent affected the yield of deprotected indole but the
starting material was always recovered.30 In order to
complete these preliminary studies we prepared the other
indolyl carbamates 2–6 (Fig. 1) and examined their behavior
towards Bu4NF in different experimental conditions
(Table 1).

effective after a much longer reaction time for all the other
carbamate protective groups (entries 1b–4b). By performing
the reaction in refluxing THF, however, all the carbamates
were cleaved after 1.5 h (entries 1a–5a). Allyl and phenyl
derivatives 4 and 6 were particularly sensitive and were
cleaved in only 20 and 15 min respectively (entries 3a, 5a).
In the cases of compounds 5 and 6, were also detected
benzyl alcohol 8 and phenol 9 along with indole 1.
Decreasing the amount of reagent Bu4NF to 1.2 equiv
(instead of 5 equiv) and performing the reaction at reflux,
slowed down the rate of cleavage (entries 1c–5c), but the
order of sensitivity of the different carbamates remained
unchanged: phenyl, allylObenzyl, Me, EtOt-Bu.
The phenyl carbamate was nearly totally cleaved in 24 h at
rt, using 1.2 equiv of TBAF (entry 5d), whereas in the same
conditions the deprotection was partial with the other
derivatives, but starting material was always recovered
(entries 1d–4d, 6d).
2.2. Cleavage of amines carbamates

Figure 1. MeOCOCl 1.5 equiv, NaH 2 equiv, DMF, rt, 1 h, quant.; 3
EtOCOCl 1.5 equiv, NaH 2 equiv, THF, rt, 2 h, 95%; 4 AllylOCOCl
1.5 equiv, NaH 2 equiv, THF, rt, 12 h, 76%; 5 NaH 1.3 equiv, PhCH2OCOCl 3 equiv, DMF, rt, 30 min, 83%; 6 PhOCOCl 3 equiv, NaOH
3 equiv, Bu4NBr 0.03 equiv, CH2Cl2, rt, 1 h, quant. 7 Boc2O 2 equiv,
4-DMAP 1.5 equiv, THF, rt, 2 h, quant.

At rt, with 5 equiv of Bu4NF, a rapid reaction occurred in
the case of the phenyl carbamate 631 and 1 was obtained in
30 min (entry 5b). In these conditions, the deprotection was

2.2.1. Primary and secondary aromatic amines. Carbamates 14–28 were prepared from indoline 11, N-methylaniline 12 and aniline 13 using standard procedures (Fig. 2).
The Boc carbamates 18, 2332and 2833 were first submitted to
the action of TBAF (5 equiv) in refluxing THF for 8 h
(Table 2). While the protection of the secondary amines
remained intact, the Boc derivative 28 was quantitatively
deprotected (entry 10).
The indoline derivatives 1434–16,35 17 were then submitted
to TBAF (5 equiv) in the same conditions. After hydrolysis,
deprotected indoline 11 was generally isolated in low yield
and the starting material was recovered; no significant

Table 1. Reactions performed on N-indolic protected compounds 2–7
Entry
1a
b
c
d
2a
b
c
d
3a
b
c
d
4a
b
c
d
5a
b
c
d
6a
b
c
d

Reactant

Bu4NF (equiv)

Time

T (8C)

Products (yield, %)a

2

5.0
5.0
1.2
1.2
5.0
5.0
1.2
1.2
5.0
5.0
1.2
1.2
5.0
5.0
1.2
1.2
5.0
5.0
1.2
1.2
5.0
5.0
2
1.2

40 min
8 h.
2 h 15
24 h
1 h 30
8h
4 h 30
24 h
20 min
6 h 45
2h
8h
1 h 30
3h
8h
8h
15 min
30 min
15 min
24 h
8h
24 h
24 h
24 h

Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt

1 (97)
1 (90)
1 (98)
1(54), 2 (14)
1 (97)
1 (70), 3 (26)
1 (97)
1 (30), 3 (66)
1 (97)
1 (84), 4 (11)
1 (87), 4 (10)
1 (34), 4 (62)
1 (75),b 8 (ND)c
1 (76),b 8 (ND)c
1 (98),b 8 (ND)c
1 (64), 5 (36), 8 (ND)c
1 (82)b,c
1 (78),b 9 (ND)c
1 (77),b 9 (ND)c
1 (78), 6 (5), 9 (ND)c
1 (98)
7 (99)
1 (81), 7 (7)
1 (39), 7(51)

3

4

5

6

7

ND—not determined.
a
Yield given after flash chromatography.
b
Quantitative on TLC.
c 1
H NMR of the crude mixture shows an equimolar composition of compound 1 and of the liberated benzyl alcool 8 or phenol 9.

U. Jacquemard et al. / Tetrahedron 60 (2004) 10039–10047

10041

Figure 3. (a) For 30 NEt3, 1.05 equiv, PhOCOCl 1.05 equiv CH2Cl2, rt,
30 min 85%; for 31, Boc2O 1.2 equiv, 4-DMAP 1.05 equiv, CH3CN, rt, 4 h,
quant. (b) Bu4NF, THF, see text.

Figure 2. 14 EtOCOCl 1.2 equiv, NaH 1.5 equiv, THF, rt, 1 h, 88%; 15
AllylOCOCl 1.5 equiv, NaH 1.2 equiv, THF, rt, 1 h, quant.; 16 PhCH2OCOCl 1.2 equiv, NaH 1.5 equiv, DMF, rt, 2 h, 30%; 17 PhOCOCl
1.2 equiv, NaH 1.1 equiv, DMF, rt, 2 h, 72%; 20 AllylOCOCl 1.2 equiv,
NaH 1.5 equiv, THF, rt, 1 h, quant.; 21 PhCH2OCOCl 1.2 equiv, NaH
1.5 equiv, DMF, rt, 18 h, 72%; 22 PhOCOCl 1.2 equiv, NaH 1.1 equiv,
DMF, 0 8C to rt, 2 h, 83%; 23 Boc2O 1.5 equiv, 4-DMAP 1 equiv, NEt3
1.5 equiv, THF, rt, 5 h, 95%; 24 EtOCOCl 1.2 equiv, NaH 1.4 equiv, THF,
rt, 2 h, quant.; 25 AllylOCOCl 1.2 equiv, NaH 1.5 equiv, THF, rt, 6 h, 21%;
26 PhCH2OCOCl 1.2 equiv, NaH 1.5 equiv, DMF, rt, 18 h, 55%; 27
PhOCOCl 1.1 equiv, NEt3 1.2 equiv, CH2Cl2, 3 h, quant.; 18, 19, 28
commercially available.

8 h, compound 31 was only partially cleaved; the primary
amine 29 was isolated in 54% yield with recovery of the
starting material 31 in 44% yield. As expected, the phenyl
carbamate 30 was more reactive and completely cleaved
after 5 min, in refluxing THF, in the presence of 5 equiv of
TBAF.
Decreasing the amount of TBAF to 1.2 equiv just resulted in
increasing the reaction duration to 15 min. In the two cases
the primary amine 29 was quantitatively recovered from 30.
2.3. Tryptamine

difference was observed between allyl, benzyl or ethyl
carbamates (entries 1–3). One more time the phenyl
carbamate 17 was highly sensitive and the indoline was
isolated in 68% yield (entry 4). In the case of carbamates 19,
20,36 21,36 2236 and 2332 obtained from an other secondary
amine, no cleavage was observed. On the other hand, as
expected, all the carbamates 2437–26,3827,39 2833 prepared
from aniline were cleaved in no more than 8 h (entries 6–8).
The primary amine was always recovered in a quantitative
yield. The cleavage of the phenyl carbamate 27 was
extremely easy and was effective at rt, in the presence of
only 1.2 equiv of TBAF (entry 9).
The degree of substitution of the nitrogen atom of the
aromatic amine seems to be determinant. One more time the
carbamates rank in the order: phenylObenzylOallylO
ethylOt-Bu.
2.2.2. Aliphatic amine. The phenyl and t-butyl carbamates
30 and 31 were obtained from 2,3-dichlorophenylethylamine 29, a primary amine chosen as a model compound.
(Fig. 3).
When treated in refluxing THF, with 10 equiv of TBAF, for

The obvious contrast between the sensitivity of indolic
carbamates and primary amino carbamates led us to search
for conditions allowing the selective cleavage of a
protective group on a molecule bearing two protected
nitrogen atoms. Tryptamine was a good candidate for such a
study. We prepared three protected compounds (Table 3),
bearing the most sensitive (phenyl), an intermediate
(benzyl) and the less (t-Bu) reactive carbamate as leaving
groups.39–42 The selectivity of deprotection was studied
with:
– the first one, 32, bearing the same Boc group on the two
nitrogen atoms.
– the second one, 33 bearing a phenyl carbamate on the
indolic nitrogen atom and a Boc group, on the other one.
– the third one, 34, bearing a t-Boc group on the indolic
nitrogen atom and a phenylcarbamate protection on the
primary amine. The most representative assays are
reported in Table 3.
Even when a large excess of TBAF (10 equiv) was used, the
deprotection of 32 was not complete after 8 h in refluxing
THF. The cleavage occurred without surprise preferentially
on the N-indolic atom (entry 1). As expected, the phenyl

Table 2. Deprotection of aniline and indoline N-carbamates
Entry
1
2
3
4
5
6
7
8
9
10
a

Bu4NF (equiv)

Reactant
14
15
16
17
18
24
25
26
27
28

Quantitative yield in TLC and 1H NMR.

5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
1.2
5.0

Time
8h
8h
8h
8h
8h
6h
3h
2.5 h
5 min
8h

T (8C)
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
rt
Reflux

Products (%)
11 (18), 14 (79)
11 (16), 15 (57)
11 (22), 16 (74)
11 (68), 17 (35)
No reaction
13 (quant.)a
13 (quant.)a
13 (quant.)a
13 (quant.)a
13 (quant.)a

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U. Jacquemard et al. / Tetrahedron 60 (2004) 10039–10047

carbamate 33 (entry 2) was fully and selectively deprotected
on the N-indolic atom affording the monoprotected
derivative 35.43
In the presence of 1.2 equiv of TBAF, at rt, compound 34
was also completely and selectively deprotected on the
amino position affording 3644 in 83% yield. Surprisingly
when this reaction was conducted in the presence of a large
excess of TBAF, we observed the formation of an urea,
compound 37, in 25% yield, and compound 36 in 39% yield.
2.4. Other results
We showed in our previous investigations30 that aromatic
esters, aldehydes and maleimides were not affected by the
presence of a large excess of Bu4NF in anhydrous
conditions even in refluxing THF. We observed that,
under the same conditions, t-butyl and ethyl esters on
pyrrole or indole moieties were neither affected. Even the
methyl ester 4645 was selectively transformed into the Ndeprotected ester 47 in good yield (88%) (Fig. 4, assay 4).

three esters led, after work-up, to the corresponding acids
40,48 43,49 45 in quantitative yields. In these cases, the Boc
protections were never affected although TBAF was present
in large excess. These issues are in contradiction with the
result observed for 46. In order to propose an acceptable
explanation, we treated the methyl ester 4850 (Fig. 4, entry
5) in refluxing THF (5 equiv) for 7 h. This time, we isolated
quantitatively the corresponding acid 49. In fact, it seems
that the possible formation of an ammonium salt in the
medium after the first reaction of TBAF on a functional
group may induce a partial or total inhibition of the
reactivity of TBAF on a second less sensitive group. For
instance, the cleavage of a Boc group which is relatively
easy on an indole moiety (Table 1, entry 6a), is notably
slackened in the case of the tryptamine derivative 32 (Table
3, entry 1).
2.5. Mechanism
Initially we attempted this deprotection reaction on Boc
protected substrates. In this case, several proposals were
possible to explain the observed reactivity. Our investigations prompted us to consider the fluoride anion as a
nucleophile agent,24 which directly added on the carbonyl
group. A second possibility was a b-elimination. Considering the present study on carbamates, the second proposal
could be rejected because several substrates do not contain
any proton susceptible to give elimination.
A fluoride attack on the carboxyl group (Scheme 2),
generated a tetrahedral intermediate which could evolve
according two 2 ways: (a), the amide was considered as the
leaving group with formation of an alkyl fluorocarbonate
(intermediate A); (b) an alcoolate is generated as the leaving
group with formation of a fluorocarbamate (intermediate B).
The formation of the urea 37 during the deprotection of 34
(Table 3) could give some insights on the mechanism.

Figure 4. (a) Boc2O 2.0 equiv, NEt3 1 equiv, 4-DMAP 1.5 equiv, THF, rt,
12 h, 90%; (b) Bu4NF 10 equiv, THF, reflux, 6 h, quant.; (c) Boc2O
1.5 equiv, 4-DMAP 10%, THF, rt, 4 h, 83%; (d) Bu4NF 5 equiv, THF,
reflux, 7 h, quant. in TLC; (e) Bu4NF 5 equiv, THF, reflux, 5 h, quant.; (f)
Bu4NF 5 equiv, THF, reflux, 6 h, 88%; (g) Bu4NF 5 equiv, THF, reflux, 7 h,
quant.

On another hand, the hydrolysis of amino acid esters in the
presence of Bu4NF in aqueous conditions has previously
been reported.25
We prepared derivatives 39,41 42,46 and 4447 bearing both a
Boc protecting group and a methyl ester in view to examine
their behavior towards TBAF (Fig. 4). The different
experiments performed show that, actually, TBAF can be
reactive towards both carbamates and methyl esters. The
observed results are greatly dependent upon the relative
reactivities of the carbamates and the methyl esters
considered. Treated with an excess of TBAF (5 or
10 equiv) in refluxing THF, in anhydrous conditions, the

Scheme 2. Postulated mechanism.

The intermediate amide postulated in route (a) could react
with the starting material 34 to give the symmetrical urea
37; but we could not reject route (b) where the intermediate
B might react with the deprotected amine 36. In order to
choose between these two hypotheses, the phenyl carbamate
34 was reacted with Bu4NF in the presence of the primary
amine 29, which could immediately scavenge the high
reactive fluoroformate intermediate A or the carbamyl
intermediate B (Fig. 5). In this aim, compound 34 was also
reacted with 5 equiv Bu4NF at rt. After 5 min the phenyl
carbamate 34 completely disappeared (TLC) and the amine
29 was added (Fig. 5).

Table 3. Reaction of tryptamine derivatives
Entry

Reactant

Conditions

Bu4NF, 10 equiv, THF, reflux, 8 h

1

Products (yield % after purification)

35 (67), 32 (30)
35

Bu4NF, 1.2 equiv, THF, reflux, 50 min

2

35 (quant.)

33

3

35

Bu4NF, 1.2 equiv, THF, rt, 30 min

36 (83)a,b

34

36

Bu4NF, 5 equiv, THF, rt, 5 min

4

34
a
b

U. Jacquemard et al. / Tetrahedron 60 (2004) 10039–10047

32

36 (39),a,b 37 (25)b

36

37

No degradation.
Total conversion of starting material.

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U. Jacquemard et al. / Tetrahedron 60 (2004) 10039–10047

performed by the Centre Re´gional de Mesures Physiques de
l’Ouest. Analyses using Electronic Impact were performed
on a High Resolution Mass Spectrometer with double
focalisation Varian Mat 311. Analyses using Electrospray
Ionisation were performed on a Micromass MS/MS ZAB
Spec TOF with an EBE TOF geometry. Monitoring of the
reactions was performed using silica gel TLC plates silica
Merck 60 F254). Spots were visualized by UV light at 254
and 356 nm. Column chromatographies were performed
using silica gel 60 (0.063–0.200 mm, Merck). Only the nonavailable products are described (not found CAS-online).
Figure 5. Deprotection of the phenyl carbamate 34 at rt; (a) Bu4NF,
1.2 equiv 30 min; (b) Bu4NF 5 equiv, rt, 5 min then 29 1.0 equiv; (c) 29,
1.0 equiv, THF, rt, 24 h.

According to route (a) compound 29 reacted with
intermediate A giving 30 or following route (b) intermediate
B gave access to the dissymmetrical urea 50. Since
compound 50 was effectively obtained in 46% yield, this
was in favour of the route (b) (in the absence of TBAF,
compounds 34 and 29 did not react after 24 h in refluxing
THF).
In the case of indolic nitrogen carbamates, the amide
generated according to route (a) was stabilized and could be
considered as a good leaving group; this hypothesis explains
that the reactions with indolic compounds were the fastest.
Depending on the substrate, ways (a) and (b) could
(co)exist. The combination of faster leaving alcoolate
group PhO KOPhCH 2O KOallylO KOEtO KOt-BuO K
and leaving amide anion (aromaticObenzylicOaliphatic)
influence certainly the way the reaction occurs.

3. Conclusion
In this paper, we have studied the cleavage of various
aromatic and aliphatic carbamates. Whatever the amino
function (aliphatic, aromatic), the phenyl carbamate is very
easily cleaved except for secondary aromatic amine. Nprotected indolic compounds were always cleaved in the
order phenyl, allylObenzyl, Me, EtOt-Bu. The presence of
an aliphatic or vinylic methyl ester seems to inhibit the
previous reaction and aliphatic methyl esters were hydrolyzed to the corresponding acids without affecting the
protective group. All these results are useful to easily
remove various carbamates on substrates, which contain
other organic functions not compatible with acidic, basic or
catalyzed deprotections generally described in the literature.

4. Experimental
4.1. Chemistry
1

H and 13C NMR spectra were recorded on a Bruker 250
instrument using CDCl3 or DMSO-d6. The chemical shifts
are reported in ppm (d scale) and all J values are in Hz.
Melting points are uncorrected. IR absorption spectra were
recorded on a Perkin Elmer PARAGON 1000 PC and values
were reported in cmK1. LRMS spectra (Ion Spray) were
performed on a Perkin Elmer Sciex PI 300. HRMS were

4.1.1. 2,3-Dihydro-indole-1-carboxylic acid allyl ester
(15). A solution of indoline 11 (1 g, 8.39 mmol) in dry THF
(15 mL) was stirred under argon at 0 8C. NaH (242 mg,
10.07 mmol, 60% in oil) was added by portion. After
30 min, allyl chloroformate (1.5 g, 12.59 mmol) was added
and the reaction mixture was stirred at rt. After 1 h, water
(20 mL) was added and the aqueous phase was extracted
with EtOAc (3!50 mL). The combined organic layers were
dried over MgSO4, filtered and the solvent was removed
under reduced pressure. The crude product was purified by
flash chromatography (petroleum ether/EtOAc 8/2) to afford
compound 15 as a solid (1.703 g, quant.). Mp 50 8C; Rf
petroleum ether/EtOAc 8/2):0.45; IR (KBr, cmK1) n 3080,
3052, 2976, 2914, 1696, 1652, 1491, 1420, 1334, 1150,
1058; (CDCl3) d: 1H NMR (CDCl3) d: 3.02 (t, 2H, JZ
8.8 Hz), 3.94 (t, 2H, JZ8.6 Hz), 4.68 (s, 2H), 5.21–5.38 (m,
2H), 5.92–6.03 (m, 1H), 6.90 (t, 1H, JZ7.32 Hz), 7.07–7.16
(m, 2H), 7.85 (s, 1H); 13C NMR (CDCl3) d: 27.5 (CH2), 47.3
(CH2), 65.8 (CH2), 114.8 (CH), 117.7 (CH2), 122.6 (CH),
124.7 (CH), 127.5 (CH), 131.0 (Cq), 132.8 (CH), 142.6
(Cq), 152.8 (Cq); MS (IS) 204 (MCH)C. HRMS-EI (MC):
203.09463 calcd for C12H13NO2, found 203.0935.
4.1.2. 2,3-Dihydro-indole-1-carboxylic acid phenyl ester
(17). A solution of indoline 11 (1 g, 8.39 mmol) in dry DMF
(15 mL) was stirred under argon at 0 8C. NaH (369 mg,
9.23 mmol, 60% in oil) was added by portion. After 30 min
phenyl chloroformate (1.5 g, 12.59 mmol) was added and
the reaction mixture was stirred at rt. After 2 h, water
(20 mL) was added and the aqueous phase was extracted
with EtOAc (3!50 mL). The combined organic layers were
dried over MgSO4, filtered and the solvent was removed
under reduced pressure. The crude residue was triturated
with petroleum ether to afford compound 17 as a white solid
(1.4 g, 72%). Mp 135 8C; Rf (petroleum ether /EtOAc 7/
3):0.75; IR (KBr, cmK1) n 3058, 2982, 2916, 1717, 1600,
1487, 1459, 1408, 1336, 1225; 1H NMR (CDCl3) d: 3.22 (t,
2H, JZ8.1 Hz), 4.24 (t, 2H, JZ7.2 Hz), 7.01 (dd, 1H, JZ
J 0 Z7.5 Hz), 7.21–7.27 (m, 5H), 7.41 (dd, 2H, JZ7.5, J 0 Z
8 Hz), 7.88 (bd, 1H, JZ7.5 Hz); 13C NMR (CDCl3) d 27.5
(CH2), 47.7 (CH2), 115.0 (CH), 121.6 (2CH), 123.0 (CH),
124.6 (CH), 125.5 (CH), 127.5 (CH), 129.2 (2CH), 130.9
(Cq), 142.1 (Cq), 150.7 (Cq), 151.1 (Cq); MS (IS) 240 (MC
H)C, 262 (MCNa)C. HRMS-EI (MC): 239.09463 calcd for
C15H13NO2, found 239.0932.
4.1.3. [2-(3,4-Dichloro-phenyl)-ethyl]-carbamic acid
phenyl ester (30). A solution of 3,4-dichlorophenylethylamine 29 (500 mg, 2.64 mmol), NEt3 (385 mL 2.76 mmol)
and phenyl chloroformate (347 mL, 3.16 mmol) in CH2Cl2
(10 mL) was stirred at rt under argon. After 30 min, water

U. Jacquemard et al. / Tetrahedron 60 (2004) 10039–10047

(20 mL) was added and the aqueous phase was extracted
with CH2Cl2 (3!20 mL). The combined organic layers
were dried over MgSO4, filtered and the solvent was
removed under reduced pressure. The crude product was
purified by flash chromatography (petroleum ether/EtOAc
8/2) to afford compound 30 as a white solid (698 mg, 85%).
Mp 74 8C; Rf (petroleum ether/EtOAc 8/2): 0.15; IR (KBr,
cmK1) n 3321, 3050, 2950, 2882, 1707, 1537, 1493, 1292,
1249, 1205; 1H NMR (CDCl3) d 2.85 (t, 2H, JZ7 Hz), 3.52
(q, 2H, JZ6.5 Hz), 5.1 (bs, 1H), 7.04–7.41 (m, 8H); 13C
NMR (CDCl3) d?35.1 (CH2), 42.0 (CH2), 121.5 (2CH),
125.4 (CH), 128.2 (CH), 129.3 (2CH), 130.6 (CH), 130.7
(CH), 132.5 (Cq), 138.8 (Cq), 150.8 (Cq), 154.5 (Cq); MS
(IS) 310/312 (MCH)C, 332/334 (MCNa)C. HRMS-EI
(MC): 309.03233 calcd for C15H13Cl2NO2, found 309.0318.
4.1.4. [2-(3,4-Dichloro-phenyl)-ethyl]-carbamic acid tertbutyl ester (31). A solution of 3,4-dichlorophenylethylamine 29 (500 mg, 2.64 mmol), 4-DMAP (322 mg
2.64 mmol) and Boc2O (690 mg, 3.16 mmol) in acetonitrile
(15 mL) was stirred at rt under argon. After 4 h, water
(20 mL) was added and the aqueous phase was extracted
with EtOAc (3!20 mL). The combined organic layers were
dried over MgSO4, filtered and the solvent was removed
under reduced pressure. The crude product was purified by
flash chromatography (petroleum ether then petroleum
ether/ EtOAc 6/4) to afford compound 31 as white solid
(762 mg, quant.). Mp 86 8C. Rf (petroleum ether/EtOAc 5/
5): 0.54; IR (KBr, cmK1) n 3338, 2979, 2925, 1687, 1534,
1283, 1168; 1H NMR (CDCl3) d: 1.44 (s, 9H), 2.79 (t, 2H,
JZ6.7 Hz), 3.39 (m, 2H), 4.57 (s, 1H), 7.02 (d, 1H, JZ
8.3 Hz), 7.29 (s, 1H), 7.36 (d, 1H, JZ8.3 Hz); 13C NMR
(CDCl3) d 28.7 (CH3), 35.7 (CH2), 41.8 (CH2), 79.9 (Cq),
128.6 (CH), 130.8 (CH), 131.2 (CH), 132.8 (Cq), 139.6
(Cq), 156.2 (Cq); MS (IS) 290/292 (MCH)C. HRMS-ESI
(MCNaC): 312.05340 calcd for C13H17NO2Cl2Na, found
312.0539.
4.1.5. 3-(2-tert-Butoxycarbonylamino-ethyl)-indole-1carboxylic acid tert-butyl ester (32). A solution of
tryptamine hydrochloride (1.38 g, 7.57 mmol), 4-DMAP
(1.11 g, 9.08 mmol) and Boc2O (3.46 g, 15.89 mmol) in
acetonitrile (20 mL) was stirred at rt under argon. After
12 h, water (50 mL) was added and the aqueous phase was
extracted with EtOAc (3!50 mL). The combined organic
layers were dried over MgSO4, filtered and the solvent was
removed under reduced pressure. The crude product was
purified by flash chromatography (petroleum ether then
petroleum ether/ EtOAc 8/2) to afford compound 32 as a
waxy solid (2.45 g, 90%). Rf (petroleum ether/EtOAc 9/1):
0.24; IR (KBr, cmK1) n 3374, 2976, 2930, 1724, 1722, 1545,
1254, 1160, 1091; 1H NMR (CDCl3) d: 1.44 (s, 9H), 1.66 (s,
9H), 2.89 (t, 2H, JZ7.0 Hz), 3.46 (m, 2H), 4.63 (s, 1H),
7.23 (m, 2H), 7.41 (s, 1H), 7.53 (d, 1H, JZ7.8 Hz), 8.13 (d,
1H, JZ8.0 Hz); 13C NMR (CDCl3) d 26.0 (CH2), 28.6
(CH3), 28.8 (CH3), 40.7 (CH2), 79.5 (Cq), 83.8 (CH3), 115.7
(CH), 118.2 (Cq), 119.4 (CH), 122.8 (CH), 123.5 (CH),
124.8 (CH), 130.8 (Cq), 135.9 (Cq), 150.1 (Cq), 156.4 (Cq);
MS (IS) 361 (MCH)C. HRMS-ESI (MCNaC): 383.19468
calcd for C20H28N2O4Na, found 383.1948.
4.1.6. 3-(2-tert-Butoxycarbonylamino-ethyl)-indole-1carboxylic acid phenyl ester (33). A solution of compound

10045

3543 (559 mg, 2.15 mmol), phenyl chloroformate
(0.432 mL, 3.44 mmol) in CH2Cl2 containing NaOH
(258 mg, 6.45 mmol) and a catalytic amount of tetrabutyl
ammonium bromide (21 mg, 0.06 mmol) was stirred at rt
under argon. After 12 h water (20 mL) was added and the
aqueous phase was extracted with EtOAc (3!20 mL). The
combined organic layers were dried over MgSO4, filtered
and the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography
(petroleum ether then petroleum ether/EtOAc 8/2) to afford
compound 33 as a white solid (579 mg, 71%). Mp 132 8C;
Rf (petroleum ether/EtOAc 7/3):0.68; IR (KBr, cmK1) n
3306, 3053, 3004, 2977, 2899, 1754, 1692, 1535, 1457,
1383; 1H NMR (CDCl3) d: 1.44 (s, 9H), 2.92 (t, 2H, JZ
6.6 Hz), 3.48 (q, 2H, JZ6.3 Hz), 4.76 (bs, 1H), 7.23–7.47
(m, 6H), 7.57–7.59 (m, 2H), 8.22 (bd, 1H, JZ7.5 Hz); 13C
NMR (CDCl3) d: 25.6 (CH2), 28.3 (3CH3), 40.0 (CH2), 79.2
(Cq), 115.3 (CH), 119.1 (CH), 119.5 (Cq), 121.4 (2CH),
122.6 (CH), 123.2 (CH), 125.0 (CH), 126.3 (CH), 129.5
(2CH), 130.6 (Cq), 135.7 (Cq), 149.0 (Cq), 150.2 (Cq),
155.8 (Cq); MS (IS) 281 (MCHKBoc)C, 381 (MCH)C,
398 (MCNH4)C. HRMS-ESI (MCNaC): 403.16338 calcd
for C22H24N2O4Na, found 403.1635.
4.1.7. 3-(2-Phenoxycarbonylamino-ethyl)-indole-1-carboxylic acid tert-butyl ester (34). A solution of 3-(2phenoxycarbonylamino-ethyl)-indole40 (150 mg, 0.53 mmol)
in a mixture of THF (2 mL) and DMF (2 mL) was treated
with 4-(dimethylamino)pyridine (6 mg, 0.05 mmol),
triethylamine (74 mL, 0.53 mmol) and di-tert-butyl dicarbonate (128 mg, 0.59 mmol). Stirring was continued overnight. After addition of water (20 mL), the crude product
was extracted with ethyl acetate (2!10 mL). The combined
organic layers were then washed twice with brine.
Purification of the crude product by flash chromatography
(petroleum ether/EtOAc 8/2) afforded compound 34
(104 mg, 51%). Colorless oil; Rf (petroleum ether/EtOAc
6/4):0.88; IR (NaCl, cmK1) n 3355, 2974, 2940, 1731, 1527,
1491, 1454, 1256, 1207, 1159, 1091; 1H NMR (CDCl3) d:
1.67 (s, 9H), 2.99 (t, 2H, JZ6.8 Hz), 3.60 (q, 2H, JZ
6.6 Hz), 5.14 (bs, 1H), 7.09–7.38 (m, 6H), 7.46 (s, 1H), 7.58
(d, 1H, JZ7.6 Hz), 8.14 (bd, 1H, JZ7.6 Hz); 13C NMR
(CDCl3) d: 25.0 (CH2), 27.8 (CH3!3), 40.6 (CH2), 83.2
(Cq), 115.0 (CH), 117.3 (Cq), 118.7 (CH), 121.3 (CH!2),
122.2 (CH), 122.8 (CH), 124.2 (CH), 124.9 (CH), 128.9
(CH!2), 130.1 (Cq), 135.2 (Cq), 149.4 (Cq), 150.8 (Cq),
154.5 (Cq); MS (IS) 381 (MCH)C, 403 (MCNa)C.
403.16338
calcd
for
HRMS-ESI
(MCNa C):
C22H24N2O4Na, found 403.1635.
4.1.8. 3-(2-Amino-ethyl)-indole-1-carboxylic acid tertbutyl ester (36). A solution of 34 (89 mg, 0.234 mmol)
and TBAF (0.28 mL, 1 M in THF, 0.281 mmol) in dry THF
(2.5 mL) was stirred under argon at rt. After 30 min water
(5 mL) was added and the aqueous phase was extracted with
EtOAc (3!5 mL). The combined organic layers were dried
over MgSO4, filtered and the solvent was removed under
reduced pressure. The crude product was purified by flash
chromatography (CH2Cl2/MeOH 9/1) to afford compound
36 as colorless oil (50 mg, 83%). Rf (CH2Cl2/MeOH 9/1):
0.22; IR (NaCl, cmK1) n 3404, 2976, 2922, 1731, 1454,
1369, 1250, 1157; 1H NMR (CDCl3) d: 1.66 (s, 9H), 2.62
(bs, 2H), 2.89 (t, 2H, JZ6.4 Hz), 3.07 (bs, 2H), 7.23 (dd,

10046

U. Jacquemard et al. / Tetrahedron 60 (2004) 10039–10047

1H, JZJ 0 Z7.3 Hz), 7.32 (dd, 1H, JZJ 0 Z7.3 Hz), 7.44 (s,
1H), 7.53 (d, 1H, JZ7.0 Hz), 8.13 (bd, 1H, JZ7.6 Hz); 13C
NMR (CDCl3) d: 28.3 (3CH3), 29.8 (CH2), 41.3 (CH2), 83.6
(Cq), 115.4 (CH), 117.9 (Cq), 119.1 (CH), 122.6 (CH),
123.4 (CH), 124.5 (CH), 129.8 (Cq), 135.5 (Cq), 149.7 (Cq);
MS (IS) 261 (MCH)C, 161 (MCHKBoc)C. HRMS-ESI
(MCH C): 261.16030 calcd for C15 H21 N2 O2, found
261.1611.
4.1.9. 1,3-Bis-[2-(1H-indol-1- carboxylic acid tert-butyl
ester-3-yl)-ethyl]-urea (37). A solution of 34 (202 mg,
0.53 mmol) and TBAF (2.65 mL, 1 M in THF, 0.265 mmol)
in dry THF (5 mL) was stirred under argon at rt. After 5 min
water (5 mL) was added and the aqueous phase was
extracted with EtOAc (3!5 mL). The combined organic
layers were dried over MgSO4, filtered and the solvent was
removed under reduced pressure. The crude product was
purified by flash chromatography using petroleum ether/
EtOAc 5/5 to afford compound 37 (36 mg, 25%) as yellow
oil and MeOH to afford compound 36 (54 mg, 39%). Rf
(petroleum ether/EtOAc 5/5):0.46; IR (NaCl, cmK1) n 3319,
3046, 1716, 1599, 1532, 1491, 1443, 1318, 1224, 1202,
1023; 1H NMR (CDCl3) d: 1.64 (s, 18H), 2.86 (t, 4H, JZ
6.5 Hz), 3.47 (q, 4H, JZ6.5 Hz), 4.42 (t, 2H, JZ5.8 Hz),
7.16–7.33 (m, 4H), 7.39 (s, 2H), 7.50 (d, 2H, JZ7.6 Hz),
8.10 (d, 2H, JZ7.9 Hz); 13C NMR (CDCl3) d: 25.8 (CH2),
28.1 (3CH3), 40.0 (CH2), 83.5 (Cq), 115.2 (CH), 117.9 (Cq),
118.9 (CH), 122.4 (CH), 123.0 (CH), 124.4 (CH), 130.4
(Cq), 135.4 (Cq), 149.6 (Cq), 158.1 (Cq); MS (IS) 547.5
(MCH)C. HRMS-ESI (MCNaC): 569.27399 calcd for
C31H38N4O5Na, found 569.2743.
4.1.10. 4-(tert-Butoxy-hydroxy-methyl)-4H-benzo[1,4]
oxazine-2-carboxylic acid (45). A solution of compound
4447 (110 mg, 0.36 mmol) in dry THF (4 mL) was stirred at
rt under argon. Bu4NF (1.8 mL, 1 M in THF) was added and
the reaction mixture was refluxed for 5 h. After cooling, a
solution of NH4Cl satd. (10 mL) was added and the aqueous
phase was extracted with EtOAc (3!10 mL). The combined organic layers were dried over MgSO4, filtered and
the solvent was removed under reduced pressure. Compound 45 was obtained as a white solid (99 mg, quant.). Mp
184 8C dec. Rf (CH2Cl2/MeOH 9/1): 0.12; IR (KBr, cmK1) n
3386, 2975, 2771, 1581, 1731, 1682, 1495, 1151, 755; 1H
NMR (CDCl3) d: 1.51 (s, 9H), 6.84 (m, 3H), 7.27 (s, 1H),
7.83 (d, 1H, JZ8.3 Hz), 10.3 (s, 1H, exchange D2O); 13C
NMR (CDCl3) d 28.6 (CH3), 83.1 (Cq), 116.9 (CH), 117.2
(CH), 119.7 (CH), 121.1 (CH), 127.2 (CH), 134.6 (Cq),
147.9 (Cq) 150.2 (Cq), 164.6 (Cq); MS (IS) 278 (MCH)C.
HRMS-ESI (MKHC2Na C): 322.06674 calcd for
C14H14NO5Na2, found 322.0669.
4.1.11. 3-(2-{3-[2-(3,4-Dichloro-phenyl)-ethyl]-ureido}ethyl)-indole-1-carboxylic acid tert-butyl ester (50). A
solution of 34 (173 mg, 0.455 mmol) and TBAF (2.27 mL,
1 M in THF, 0.265 mmol) in dry THF (5 mL), amine 29
(86 mg, 0.455 mmol) was stirred under argon at rt for 5 min.
Water (5 mL) was added and the aqueous phase was
extracted with EtOAc (3!5 mL). The combined organic
layers were washed with a saturated aqueous solution of
NaCl (5 mL) and dried over MgSO4, filtered and the solvent
was removed under reduced pressure. The crude product
was purified by flash chromatography (petroleum ether/

EtOAc 55/45) to afford compound 48 (105 mg, 48%) as a
pale yellow oil. Rf (CH2Cl2/MeOH 9/1): 0.78; IR (NaCl,
cmK1) n 3334, 2977, 2933, 1731, 1634, 1573, 1474, 1453,
1380, 1256; 1H NMR (CDCl3) d: 1.66 (s, 9H), 2.71 (t, 2H,
JZ6.8 Hz), 2.88 (t, 2H, JZ6.5 Hz), 3.35 (q, 2H, JZ
6.6 Hz), 3.48 (q, 2H, JZ6.4 Hz), 4.35 (t, 1H, JZ5.8 Hz),
4.45 (t, 1H, JZ5.7 Hz), 6.97 (dd, 1H, JZ8.2, J 0 Z2 Hz),
7.19–7.35 (m, 4H), 7.41 (s, 1H), 7.52 (d, 1H, JZ7.1 Hz),
8.10 (d, 1H, JZ8.0 Hz); 13C NMR (CDCl3) d: 25.8 (CH2),
28.1 (3CH3), 35.5 (CH2), 39.9 (CH2), 41.1 (CH2), 83.6 (Cq),
115.2 (CH), 117.9 (Cq), 118.9 (CH), 122.4 (CH), 123.0
(CH), 124.4 (CH), 128.2 (CH), 130.1 (Cq), 130.3 (CH),
130.4 (Cq), 130.6 (CH), 132.2 (Cq), 135.4 (Cq), 139.5 (Cq),
149.7 (Cq), 158.2 (Cq); MS (IS) 476/478 (MCH)C, 376/
378 (MCHKBoc)C. HRMS-ESI (MCNaC): 498.13272
calcd for C24H27N3O3Cl2Na, found 498.1328.

Acknowledgements
We thanks La fondation pour la Recherche Me´dicale (FRM)
and La Ligue contre le Cancer Re´gion Centre for their
financial support.

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