Generation of carbamoyl- and thiocarbamoyllithium synthons having a hydrogen(s) or an aryl group on the nitrogen and their trapping with carbonyl electrophiles

Article abstract of DOI:10.1021/ja065078f

Dimetalated amides 1 (Y = O) were generated as the synthons of carbamoyllithiums 2 (Y = O) by the reaction of isocyanates with ⁱBu₂AlTeⁿBu and a subsequent tellurium-lithium exchange reaction. A series of amide derivatives

Full text of DOI:10.1021/ja065078f

Published on Web 09/13/2006
Generation of Carbamoyl- and Thiocarbamoyllithium Synthons Having a
Hydrogen(s) or an Aryl Group on the Nitrogen and Their Trapping with
Carbonyl Electrophiles
Nobuaki Kambe,* Toru Inoue, Takanobu Takeda, Shin-ichi Fujiwara,† and Noboru Sonoda‡
Department of Applied Chemistry, Graduate School of Engineering, Osaka UniVersity, Suita,
Osaka 565-0871, Japan
Received July 17, 2006; E-mail: kambe@chem.eng.osaka-u.ac.jp
Scheme 2. Generation of Aluminum Azaenolates 5 as a
Carbamoyllithium Synthon and Their Trapping
Adding carbonyl functions into organic molecules is a signifi-
cantly important transformation in organic synthesis, and much
effort has been focused on the development of new and useful
carbonyl transfer reagents.1 Carbamoyllithium (R2NC(O)Li) is one
of the most straightforward reagents for the nucleophilic introduc-
tion of carbamoyl moieties into organic compounds, and several
methods have been developed for the generation of carbamoyl-
lithiums.2-7 Among them, we already disclosed that carbamoyl-
lithiums were generated efficiently by tellurium-lithium exchange
reaction8 of carbamotelluroates with organolithium reagents, and
many amide derivatives were obtained by the trapping with various
electrophiles.5 This reaction is of great synthetic value since one-
pot operation starting from carbamoyl chlorides in a large scale
has been established and easy isolation of the products is possible.5b
During the course of our study on the generation and synthetic
use of carbamoyllithiums, we faced two problems: (i) carbamoyl-
lithiums 1, having a hydrogen(s) on the nitrogen, rapidly rearrange
to azaenolates of the corresponding formamides;9 and (ii) carbam-
oyllithiums 2, having an aromatic substituent on the nitrogen, release
CO rapidly even at low temperatures.5b
Table 1. Conversion of Isocyanates to Carbamoyllithium Synthons
and Their Trapping with Carbonyl Electrophilesa
Scheme 1. Two Problems of Carbamoyllithiums
As the synthons of carbamoyllithiums having a hydrogen on the
nitrogen, tripropylcarbazoyllithium10a and N-methoxymethylcar-
bamoyllithium10b were reported so far; however, removal of the
protecting groups is troublesome.
To overcome these disadvantages, we examined utilization of
aluminum azaenolates of carbamoyllithiums such as 5 as a synthon
of carbamoyllithiums having a hydrogen on the nitrogen. Dianions
5 can be generated by tellurium-lithium exchange reaction of
aluminum azaenolate of carbamotelluroate 4 with organolithium
reagents; they have azaenolate structures, hence resist decarbony-
lation, and deprotection is not necessary (Scheme 2).
To prepare 3, we carried out the reaction of butyl isocyanate
with iBu2AlTenBu,11 and carbamotelluroate 4a was obtained in 88%
yield after proton quench. This shows that aluminum azaenolate
3a (R ) nBu) was formed efficiently in situ.12 Then 3a was allowed
i
a Conditions: isocyanate (1 mmol), Bu2AlTenBu (1 mmol), -23 °C,
then 0 °C, 1 h, THF (2 mL); nBuLi (1.1 mmol), -105 °C, 30 min, THF (3
mL), Et2O (4 mL); electrophile (1.5 mmol), -105 °C, then 25 °C, 2 h.
n
to react with BuLi at -105 °C for 30 min, and the mixture was
We then conducted the reaction using other electrophiles and
aryl isocyanates, and the results are also summarized in Table 1.
As for electrophiles, trapping of dianion 5a (R ) nBu) with
cyclohexanone, phenyl isocyanate, and methyl benzoate gave the
corresponding carbamoylated products in good yields (runs 2-4).
The successful result of run 3 demonstrates the utility of the present
method for the preparation of unsymmetrical oxalamides starting
from two different isocyanates. When aryl isocyanates were
trapped with benzaldehyde. As the result, R-hydroxyamide 6a was
obtained in 81% yield (Table 1, run 1).13 From this result, dianion
5 can be utilized as a useful synthon of a hydrogen possessing
carbamoyllithiums 1.
† Present address: Department of Chemistry, Osaka Dental University, Hirakata,
Osaka 573-1121, Japan.
‡ Emeritus Professor of Osaka University.
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J. AM. CHEM. SOC. 2006, 128, 12650-12651
10.1021/ja065078f CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Conversion of Isothiocyanates to Thiocarbamoyllithium
gives the corresponding amide derivatives. These results reveal that
carbamoyllithium synthons having an aryl group and/or a hydrogen
on the nitrogen, dianions 5, are generated efficiently from isocy-
anates by one-pot operation. In a similar manner, thiocarbamoyl-
lithium synthons can be generated from isothiocyanates. The present
method would provide new access to a variety of amide families,
including unsymmetrical oxalamides and their sulfur derivatives.
Synthons and Their Trapping with Carbonyl Electrophilesa
Supporting Information Available: Characterization data of all
new compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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a Similar reaction conditions employed in Table 1 were used.
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employed, R-hydroxyamides were also obtained in high yields by
trapping with benzaldehyde and cyclohexanone (runs 5-7). These
results indicate that dianions 5 (R ) aryl) served as synthons of
carbamoyllithiums having an aryl group on the nitrogen.
Removal of the p-methoxyphenyl group on the nitrogen in 6g
was then performed by the use of ceric ammonium nitrate (CAN).14
As a result, deprotected amide 7 was obtained in 81% yield (eq 1).
By combining this method, the present reaction can be employed
for nucleophilic introduction of an unsubstituted carbamoyl group
“H2NC(O)” into organic compounds.
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Kambe, N.; Inoue, T.; Sonoda, N. Org. Synth. 1995, 72, 154.
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Thiocarbamoyllithiums are also useful compounds for the
nucleophilic introduction of thiocarbamoyl moieties. However,
generation methods of them are limited to the reaction of thiofor-
mamides with LDA15 and reduction of thiocarbamoyl chloride with
lithium naphthalenide.6 There are no reports on thiocarbamoyllithi-
ums having a hydrogen on the nitrogen or their synthons. Thus,
the conversion of isothiocyanates to thiocarbamoyllithium synthons
having a hydrogen on the nitrogen was examined. As summarized
in Table 2, the reactions proceeded efficiently, and the correspond-
ing thioamides were obtained by the trapping with various carbonyl
electrophiles. Since thioamides are an important class of compounds
not only in synthetic chemistry16 but also in the biological field,17
this transformation provides a novel efficient synthetic method of
them.
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(11) Sasaki, K.; Aso, Y.; Otsubo, T.; Ogura, F. Chem. Lett. 1989, 607.
(12) The reaction of isocyanates with aluminumthioate: Hirabayashi, T.;
Imaeda, H.; Itoh, K.; Sakai, S.; Ishii, Y. J. Organomet. Chem. 1969, 19,
299.
(13) When tellurium-lithium exchange reaction and trappimg was carried out
at -78 °C, the yield of 6a dropped to 30%, although nBu2Te was obtained
nearly quantitatively.
(14) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982, 47,
2765.
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Katzenellenbogen, J. A. Bioorg. Med. Chem. 2000, 8, 1293. (b) Yu, K.-
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In summary, the reaction of isocyanates with iBu2AlTenBu affords
aluminum azaenolates of carbamotelluroates 3. Tellurium-lithium
exchange reaction of 3 and subsequent trapping with electrophiles
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