Amidation through carbamates

Article abstract of DOI:10.1016/j.tetlet.2009.03.113

N-Alkyl carbamates of primary amines are easily converted into amides under treatment with Grignard reagents. Consequently, primary amines can be converted into amides in a one-pot reaction through carbamate protection and Grignard addition.

Full text of DOI:10.1016/j.tetlet.2009.03.113

Tetrahedron Letters 50 (2009) 2653–2655
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Tetrahedron Letters
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Amidation through carbamates
*
*
Antonio Latorre, Santiago Rodríguez , Javier Izquierdo, Florenci V. González
Departament de Química Inorgànica, Universitat Jaume I, 12080 Castelló, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Alkyl carbamates of primary amines are easily converted into amides under treatment with Grignard
reagents. Consequently, primary amines can be converted into amides in a one-pot reaction through car-
bamate protection and Grignard addition.
Received 16 February 2009
Revised 11 March 2009
Accepted 16 March 2009
Available online 21 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Amides
Carbamates
Amines
1. Introduction
In all cases, starting carbamates were transformed into the cor-
responding amides6 in good to high yield. The broad availability of
Carbamates and amides are widely used protecting groups for
amines.1 While some recent reports have described the conversion
of carbamates into amides,2 more general and convenient methods
to accomplish this transformation are desirable.
Grignard reagents permitted the preparation of a wide variety of
amides, which is an advantage over similar procedures in the
literature.2
We are also glad to report a new one-pot procedure for the con-
version of amines into amides. When a primary amine was treated
with an alkoxy carbonyl chloride in the presence of triethyl amine,
followed by addition of a Grignard reagent, the corresponding
amide was obtained in good to high yield (Table 2).
During the course to the attempted preparation of diphenyl-
L-
prolinol, we reacted N-CBZ-
L
-proline methyl ester3 with phenyl
magnesium bromide. Unexpectedly, we obtained N-benzoyl-
linol 1 as the main product (Scheme 1).
L-pro-
This result prompted us to examine the reactivity of carbamates
with Grignard reagents. When carbamates of secondary amines are
treated with Grignard reagents or organolithium compounds, the
corresponding amine and ketone are obtained (Scheme 2).4 Inter-
estingly the reaction between carbamates of primary amines and
Grignard reagents has been reported before as an undesired pro-
cess.5 We are pleased to report herein that carbamates of primary
amines when treated with Grignard reagents gave rise to amides in
high yield and that primary amines can be converted into amides
in a one-pot reaction through carbamate protection and Grignard
addition (Scheme 2).
Ph
Ph
PhMgBr (8 eq.)
THF
COOMe
N
N
OH
O
O
Ph
O
1
65%
Ph
Scheme 1. Treatment of N-CBZ-
bromide.
L
-proline methyl ester with phenyl magnesium
2. Results
O
O
N-Alkyl carbamates (benzyl, methyl, and terc-butyl) of primary
amines (benzylamine, allylamine, and 3-phenylpropylamine) were
prepared according to standard procedures.1 The resulting carba-
mates were reacted with Grignard reagents in THF at room tem-
perature for 24 h (Table 1).
R"MgX
R'
R
R'
+
HN
R'
O
N
R" R"
R'
O
O
R"MgX
R
R'
R'
O
N
R"
N
H
H
* Corresponding authors. Tel.: +34 96472829156; fax: +34 964728214 (F.V.G.).
E-mail address: fgonzale@qio.uji.es (F.V. González).
Scheme 2. Treatment of carbamates of secondary and primary amines.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.113

2654
A. Latorre et al. / Tetrahedron Letters 50 (2009) 2653–2655
Table 1
N-CBZ-L-proline methyl ester could be explained by formation of
chelate 3 (Fig. 1).
Treatment of carbamates with Grignard reagents
O
O
R"MgX
R
R'
R'
4. Conclusions
O
N
H
R"
N
H
THF
In summary, we have shown that carbamates of primary
amines give rise to amides when treated with Grignard reagents.
Primary amines can then be transformed into amides through pro-
tection as a carbamate followed by Grignard treatment in a one-
pot procedure.
Entry
R
R0
Grignard (R00MgX)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
Me
t-Bu
Bn
Bn
Bn
Bn
MeMgBr
EtMgBr
PhMgBr
t-BuMgCl
MeMgBr
EtMgBr
t-BuMgCl
i-PrMgCl
MeMgBr
EtMgBr
t-BuMgCl
i-PrMgCl
MeMgBr
EtMgBr
66
70
73
74
77
72
89
62
43
43
69
99
95
71
79
83
85
PhCH2CH2CH2
PhCH2CH2CH2
PhCH2CH2CH2
PhCH2CH2CH2
CH2@CHCH2
CH2@CHCH2
CH2@CHCH2
CH2@CHCH2
PhCH2CH2CH2
PhCH2CH2CH2
PhCH2CH2CH2
PhCH2CH2CH2
PhCH2CH2CH2
5. Experimental
5.1. General experimental methods
All solvents used in reactions were freshly distilled from appro-
priate drying agents before use. 1H NMR spectra and 13C NMR spec-
tra were measured in CDCl3 (1H, 7.24 ppm; 13C 77.0 ppm) solution
at 30 °C on a 300 MHz Mercury Varian or on a 500 MHz Innova
Varian NMR spectrometer at the Serveis Centrals d’Instrumentació
Científica de la Universitat Jaume I. EM Science Silica Gel 60 was
used for column chromatography while TLC was performed with
E. Merck precoated plates (Kieselgel 60, F254, 0.25 mm). Unless
otherwise specified, all reactions were carried out under argon
atmosphere with magnetic stirring.
t-BuMgCl
i-PrMgCl
EtMgBr
Table 2
One-pot conversion of amines into amides
5.2. General experimental procedure for the protection of
amines
O
1. R'OCOCl, Et3N
R
R
NH2
N
H
R"
2. R"MgX
To an ice-bath cooled solution of the amine (1 mmol) in an
aqueous solution of 2 M sodium hydroxide (1 mL, 2 mmol) was
added the corresponding alkyl chloroformate (see Table 1)
(1 mmol). The resulting mixture, cooled with the ice-bath, was stir-
red for 1 h and then was stirred at room temperature for 45 min.
The reaction mixture was carefully neutralized using 1 M HCL solu-
tion and extracted with CH2Cl2 (3 ꢀ 30 mL). The organic layers
were washed (brine), dried (Na2SO4), and concentrated. The crude
oil was submitted to the next step without any further purification.
Entry
R
R0
R00
Yield (%)
1
2
3
4
5
6
7
8
9
PhCH2CH2CH2
PhCH2CH2CH2
PhCH2CH2CH2
CH2@CHCH2
CH2@CHCH2
CH2@CHCH2
CH2@CHCH2
CH2@CHCH2
CH2@CHCH2
PhCH2CH2CH2
Me
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
t-Bu
Et
Et
87
92
66
70
47
58
36
41
83
90
Me
Me
t-Bu
i-Pr
Et
Et
Me
Et
5.3. General experimental procedure for addition of Grignard
reagents to carbamates
10
To an ice-bath cooled solution of the carbamate (1 mmol) in
THF (6 mL) was added the corresponding Grignard reagent
(6 mmol) (see Table 1). The resulting mixture was stirred while
being cooled with an ice-bath for 10 min and then stirred at room
temperature for 24 h. The reaction was quenched with saturated
ammonium chloride solution (10 mL) and extracted with ethyl
acetate (3 ꢀ 30 mL). The organic layers were washed (brine), dried
(Na2SO4), and concentrated. The crude oil was purified by silica gel
chromatography, eluted with hexanes/EtOAc (7:3), (6:4) and EtOAc
to afford the corresponding amide (see Table 1).
This one-pot process represents a new approach to synthesizing
amides from amines.
3. Discussion
When carbamates of secondary amines are treated with Grig-
nard reagents, the corresponding amines and ketones are ob-
tained.3 However, carbamates of primary amines give amides.
Carbamates of primary amines probably react with Grignard re-
agents through an N,O-magnesium chelate 2 (Fig. 1) whilst carba-
mates of secondary amines cannot form this intermediate. The
5.4. General experimental procedure for one-pot
transformation of amines into amides
unexpected formation of the amide of diphenyl-L-prolinol from
To an ice-bath cooled solution of the amine (1 mmol) in THF
(6 mL) was added triethylamine (3 mmol) and then the corre-
sponding alkyl chloroformate (1 mmol). The resulting mixture
was stirred while being cooled by an ice-bath for 1 h and then stir-
red at room temperature for 45 min. The reaction mixture was
cooled with an ice-bath and the corresponding Grignard reagent
(6 mmol) was added (see Table 2). The resulting mixture was stir-
red while being cooled with the ice-bath for 10 min and then stir-
red at room temperature for 24 h. The reaction was cautiously
Ph
Ph
R''
O
O
Mg
O
N
R
N
R'
Mg
PhO
O
Ph
2
3
Figure 1. Chelation intermediates.

A. Latorre et al. / Tetrahedron Letters 50 (2009) 2653–2655
2655
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and extracted with ethyl acetate (3 ꢀ 30 mL). The organic layers
were washed (brine), dried (Na2SO4), and concentrated. The crude
oil was purified by silica gel chromatography, eluted with hexanes/
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Acknowledgment
This work was financed by Bancaixa-UJI foundation (P1
1A2005-14).
References and notes
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