First Carbamates Conversion to Amides by Simple Alkyl Group Transfer from Trialkylalanes

Article abstract of DOI:10.1021/ol036234f

(Equation presented) N-Monosubstituted carbamates are cleanly converted to amides under treatment with trialkylaluminum. This reaction involves an aluminum-assisted internal delivery of alkyl groups. It can be applied to new and mild protecting group strategies for alcohols.

Full text of DOI:10.1021/ol036234f

ORGANIC
LETTERS
2004
Vol. 6, No. 3
381-383
First Carbamates Conversion to Amides
by Simple Alkyl Group Transfer from
Trialkylalanes
Laurent El Kaim,* Laurence Grimaud, Anabelle Lee, Yannick Perroux, and
Cornelia Tirla
Laboratoire Chimie et proce´de´s, Ecole Nationale Supe´rieure de Techniques AVance´es,
32 Bd Victor, 75739 Paris Cedex 15, France
elkaim@ensta.fr
Received November 14, 2003
ABSTRACT
N-Monosubstituted carbamates are cleanly converted to amides under treatment with trialkylaluminum. This reaction involves an aluminum-
assisted internal delivery of alkyl groups. It can be applied to new and mild protecting group strategies for alcohols.
Adding a nucleophile to an ester or an amide without
touching a ketone either present or formed in the medium
has been a challenging problem for chemists in the past
decades.1 Most solutions proposed have dealt with the
stabilization of the ketones through tetrahedric adducts stable
in the reaction medium. The overall transformation represents
a formal reactivity inversion between ketones and esters.
Similar conversion of carbamates into amides is less well
documented; it has been mostly performed with lithium
anions or dianions whose nucleophilicity does not allow the
presence of sensitive groups.2 Furthermore, these lithium
anions are all characterized by the presence of a proximal
chelating function (ketone,2a oxazol,2b sulfone,2c phosphonate2d)
associated with the stabilization of the adducts. There is still
a need for a simple and mild conversion of carbamates.
interested in the reactions of trialkylaluminum compounds
with carbamates. We expected that easy formation of
N-aluminated complexes from monosubstituted carbamates
may promote vicinal alkyl group delivery under mild
conditions.
When AlMe3 (3 equiv) was added to a solution of 1a in
1,2-dichloroethane at -30 °C, fast gas evolution was
observed; the solution was then heated to 65 °C forming
after 2 days acetamide 2a in good yield (Scheme 1).
Scheme 1
Following our recent study on the interaction of trialkyl-
aluminums with hydrazones and aldehydes,3 we became
Several N-monoalkyl and -monoaryl carbamates gave
similar results with various alkylaluminum derivatives as
shown in Table 1. Trimethylaluminum was the most reactive
alane giving faster and higher yielding reactions for all
carbamates tested (Table 1). In the case of carbamate 1e,
benzyl alcohol could be recovered in good isolated yield
(80%) along with expected amide 2h.
(1) For typical examples see: (a) Nahm, S.; Weinreb, S. Tetrahedron
Lett. 1981, 22, 3815-3818. (b) Hlasta, D.; Court, J. Tetrahedron Lett. 1989,
30, 1773-1776. (c) Chung, E.; Cho, C. W.; Ahn, K. J. Org. Chem. 1998,
63, 7590-7591.
(2) (a) Hubbard, J. S.; Harris, T. M. J. Org. Chem. 1981, 46, 2566-
2570. (b) Shono, T.; Kise, N.; Sanda, F.; Ohi, S.; Tsubata, K. Tetrahedron
Lett. 1988, 29, 231-234. (c) White, J. D.; Blakemore, P. R.; Milicevic, S.;
Choudhry, S. C.; Cupano, J.; Serico, L. Org. Lett. 2002, 4, 1803-1806.
(d) Tay, M. K.; About-Jaudet, E.; Savignac, P. Tetrahedron 1989, 45, 4415-
4430.
This reaction represents one of the first straightforward
transformations of carbamates into simple alkylamides (ac-
(3) El Kaim, L.; Grimaud, L.; Perroux, Y.; Tirla, C. J. Org. Chem. 2003,
68, 8733-8735.
10.1021/ol036234f CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/07/2004

The importance of N-aluminated complex type A in the
vicinal delivery of the alkyl group from the alane can be
further substantiated by the following competitive experiment
using an equimolar mixture of carbamate 1a and ethylben-
zoate 4. With 3 equiv of trimethylaluminum and after
complete conversion of carbamate 1a into amide 2a, the
starting ester was recovered in low yield along with alcohol
5 resulting from double addition of the alane to the ester.
Though slower, the reaction is still effective with 1.5 equiv
of alane, leaving now the ester unaffected after complete
conversion of the starting carbamate (Scheme 3).
Table 1. Trialkylaluminum-Induced Reaction of Carbamate 1
To Form Amide 2
entry
1
2 (yield %)
Ra
R′
Me
R′′
Et
timeb (h)
1
2
3
4
6
7
8
1a 2b (67)
1a 2c (63)
1b 2d (66)
1b 2e (67)
1c 2f (73)
1d 2g (71)
1e 2h (73)
4-ClPh
4-ClPh
CH2Ph
CH2Ph
72
168
72
Me
Me
Me
i-Bu
Et
Me
Et
48
96
72
Ar(CH2)2 Me
Ar(CH2)2 Ph
Et
Scheme 3
Ar(CH2)2 CH2Ph Et
84
a Ar ) 3,4-dimethoxyphenyl. b To a solution of 1 (2 mmol) in dry 1,2-
dichloroethane (10 mL) at -30 °C is added AlR′′3 (6 mmol as a 2 M solution
in toluene). After removal of the cold bath, the mixture is stirred at 65 °C
for the time given in the table. Addition of a saturated aqueous solution of
dipotassium L-(+)-tartrate followed by usual workup and column chroma-
tography afford amides 2.
This reaction opens the way for new protection/deprotec-
tion strategies using carbamates. Besides the usual benzyl
or BOC-type carbamates amenable to easy degradation
through hydrogenolysis or acidic treatments, carbamate
deprotection usually suffers from the need for harsh basic
conditions.
Taking into account the very easy carbamate formation
by HCl-catalyzed addition of alcohol to isocyanate,7 this new
alkylaluminum cleavage of carbamates brings a very efficient
way to recover unprotected alcohols. This strategy was
applied successfully using tert-butyl isocyanate and various
alcohols, as shown in Table 2. Most noteworthy is the ability
etamides, propionamides, ...); besides several one-pot con-
versions limited to specific carbamates,4 the synthesis of
amides from carbamates usually requires a two-step proce-
dure with intermediate conversion to amine under strong
basic medium.5
The mechanism of the reaction probably involves an
activation of the carbamate through N,O-aluminated chelate
A6 followed by alkoxy migration to give isocyanate B and
amide C (Scheme 2); the latter remains unreactive under the
Scheme 2
Table 2. Trialkylaluminum-Induced Reaction of Carbamate 1
To Form Amide 2 and Alcohol 6a
reaction conditions, forming the final amide 2 after hydroly-
sis. The absence of reaction observed with carbamate 1f, 1g
and urethane 1h is consistent with an activation of the
reaction through intermediates related to A.
a
Notes as follows: (*) To a solution of 6 in CH2Cl2 (1 M) was added
t-BuNCO (1 equiv) and a 37% solution of HCl in water (0.05 equiv, 1j,1k)
or DBU (0.05 equiv, 1i). (**) To a solution of carbamate 1 (2 mmol) in
dry 1,2-dichloroethane (10 mL) at -30 °C is added AlMe3 (3 mmol) as a
solution in toluene. After removal of the cold bath, the mixture was let for
15 min at room temperature and then stirred at 65 °C for the time given in
the table. Usual treatment affords alcohol 6.
(4) (a) Li, W. R.; Yo, Y. C.; Lin, Y. S. Tetrahedron 2000, 56, 8867-
8875. (b) Nazih, A.; Heissler, D. Synthesis 2002, 203-206. (c) Ihara, M.;
Hirabayashi, A.; Taniguchi, N.; Fukumoto, K. Heterocycles 1992, 33, 851-
858.
(5) For typical examples of carbamates conversion to acetamides, see:
(a) Masatshi, K.; Kunitomo, A.; Toshiyuki, K.; Masanori, H.; Tokushi, H.;
Yoshiyuki, A.; Tadashi, M.; Masafuni, A.; Noriyoshi, N.; Makio, O.; Yukio,
H. J. Med. Chem. 2000, 43, 2946-2961. (b) Tanida, H.; Tsuji, T.; Irie, T.
J. Org. Chem. 1966, 31, 3941-3947.
to protect tertiary alcohol 6b without formation of elimination
compounds during carbamate synthesis and cleavage.
In summary, we have disclosed a mild cleavage reaction
of carbamates that can find uses in new protection, depro-
382
Org. Lett., Vol. 6, No. 3, 2004

tection strategies for alcohols. This reaction represents to our
knowledge the first formation of amides by simple alkyl
group additions to carbamates. This was made possible by
an activation of the carbamate through the formation of an
N-aluminated complex. Further activations of NH acidic
compounds using alkylaluminum chemistry are under study
in our research group.
(6) Though adducts between alanes and carbamates have been described
as solids and shown to exhibit a reversible Al shift from N to O (carbonyl),
the lack of reactivity of 1g makes us believe that adducts type A could be
the reactive intermediate in this reaction: Hirabayashi, T.; Sakakibara, T.;
Ishii, Y. J. Organomet. Chem. 1971, 32, C5-C6.
(7) These additions are described using an ether solution of HCl as
catalyst. A few drops of concentrated HCl in water gives also satisfying
results: Benalil, A.; Roby, P.; Carboni, B.; Vaultier, M. Synthesis 1991,
787-788.
Supporting Information Available: Synthetic procedures
for carbamate formation and cleavage to amides along with
analytical data for unknown carbamatesand amides. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL036234F
Org. Lett., Vol. 6, No. 3, 2004
383