One-pot, three-component coupling approach to the synthesis of α-iminocarboxamides

Article abstract of DOI:10.1021/ol3017337

A one-pot, three-component coupling was accomplished via the nucleophilic addition of an alkylsamarium(III) species to isocyanides and the subsequent addition of the resultant imidoyl samarium(III) species to isocyanates under mild conditions for the formation of α-iminocarboxamides. The developed sequential C-C bond-forming procedure enabled the rapid synthesis of the α-iminocarboxamides in good to excellent yields from readily available starting materials.

Full text of DOI:10.1021/ol3017337

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4090–4093
One-Pot, Three-Component Coupling
Approach to the Synthesis of
rÀIminocarboxamides
Hisashi Masui, Shinichiro Fuse, and Takashi Takahashi*
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1, Ookayama,
Meguro-ku, Tokyo 152-8552, Japan
ttak@apc.titech.ac.jp
Received June 24, 2012
ABSTRACT
A one-pot, three-component coupling was accomplished via the nucleophilic addition of an alkylsamarium(III) species to isocyanides and the
subsequent addition of the resultant imidoyl samarium(III) species to isocyanates under mild conditions for the formation of R-
iminocarboxamides. The developed sequential CÀC bond-forming procedure enabled the rapid synthesis of the R-iminocarboxamides in
good to excellent yields from readily available starting materials.
R-Iminocarboxamides have garnered much attention
in recent years because of their anti-HIV1 and anti-
convulsant2 activities and their functions as dyes3 and
as ligands of polymerization catalysts and oxida-
tion catalysts.4 R-Iminocarboxamides are also useful
as key intermediates for the synthesis of R-amino
acids.5
The most conventional method for the synthesis of R-
iminocarboxamides is the amidation of the R-keto acids
and the subsequent imination of the obtained R-ketocar-
boxamides (Figure 1a).6 Recently, we reported the con-
struction of an 87-membered combinatorial library of
R-iminocarboxamide ligands of alkene polymerization
catalysts based on this procedure.6d The limitations of this
procedure are as follows: (1) the imination usually requires
heating conditions in the presence of acid, and thus,
substrates with an acid-labile group cannot be employed,
and (2) the availability of the starting material, R-keto acid,
is somewhat limited. The convergent synthesis of R-imi-
nocarboxamides by way of a CÀC bond-forming reaction
(Figure 1b) is an elegant methodology.5e However, imidoyl
chlorides and carbamoyl silanes are not readily available
materials. The development of a divergent, high-yielding,
and mild synthetic method from readily available start-
ing materials remains important. From this point of view,
a sequential CÀC bond-forming approach7 (Figure 1c)
is ideal because R-iminocarboxamides with various
(1) Sriram, D.; Yogeeswari, P.; Gopal, G. Eur. J. Med. Chem. 2005,
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Ferreira, A. M. D. C. J. Mol. Catal. A: Chem 2004, 221, 29. (c) Rojas,
R. S.; Galland, G. B.; Wu, G.; Bazan, G. C. Organometallics 2007, 26,
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457. (b) Watthey, J. W. H.; Stanton, J. L.; Desai, M.; Babiarz, J. E.; Finn,
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Chem. 2002, 38, 1534. (b) Rojas, R. S.; Wasilke, J.-C.; Wu, G.; Ziller,
J. W.; Bazan, G. C. Organometallics 2005, 24, 5644. (c) Bou-Hamdan,
F. R.; Leighton, J. L. Angew. Chem., Int. Ed. 2009, 48, 2403. (d) Fuse, S.;
Masui, H.; Tannna, A.; Shimizu, F.; Takahashi, T. ACS Comb. Sci.
2012, 14, 17.
(7) (a) Walborsky, H. M.; Niznik, G. E. J. Am. Chem. Soc. 1969, 91,
7778. (b) Niznik, G. E.; Morrison, W. H.; Walborsky, H. M. J. Org.
Chem. 1974, 39, 600. (c) Marks, M. J.; Walborsky, H. M. J. Org. Chem.
1981, 46, 5405. (d) Marks, M. J.; Walborsky, H. M. J. Org. Chem. 1982,
47, 52. (e) Murakami, M.; Ito, H.; Ito, Y. J. Org. Chem. 1988, 53, 4158.
(f) Murakami, M.; Ito, H.; Bakar, W. A. W. A.; Baba, A. B.; Ito, Y.
Chem. Lett. 1989, 1603.
r
10.1021/ol3017337
Published on Web 08/03/2012
2012 American Chemical Society

For the development of a mild synthetic method for
R-iminocarboxamides, we focused on the utilization of
samarium(III) compounds (Figure 1c, M = Sm). Ito and
Murakami et al. reported a beautiful procedure for the
preparation of imidoyl samarium(III) species from the
corresponding alkyl samarium(III) species and iso-
cyanides.10 However, the nucleophilic addition of an imi-
doyl samarium(III) species to isocyanates has not yet been
reported. Therefore, we examined this coupling reaction as
shown below.
Table 1. Optimization of the One-Pot, Three-Component
Coupling Reaction
Figure 1. Strategies for the synthesis of R-iminocarboxamides.
substituents, R1, R2, and R3, can be rapidly synthesized
from readily available starting materials.
One-pot, multicomponent reactions are powerful syn-
thetic methodologies for the rapid synthesis of complex
molecules from simple reactants. Such protocols require
neither purification nor workup of reaction intermediates,
and thus, they significantly improve synthetic efficiency. In
particular, isocyanide-based multicomponent reactions,
including Passerini and Ugi reactions,8 are highly impor-
tant because they are frequently used in organic synthesis.
We have developed and reported a one-pot, multicompo-
nent coupling approach to the synthesis of bioactive
compounds for decades.9
Herein, we wish to report a one-pot synthesis of R-
iminocarboxamides by the nucleophilic addition of an
alkyl metal species to isocyanides and the subsequent
addition of the resultant imidoyl metal species to isocya-
nates in good to excellent yields under mild conditions
(Figure 1c). The developed sequential CÀC bond-forming
procedure enabled the rapid synthesis of R-iminocarbox-
amides with various substituents, R1, R2, and R3, from
readily available starting materials: alkyl halides, isocya-
nides, and isocyanates. In addition, we also report a novel
one-pot synthesis of R,β-diiminocarboxamide and an
R-amino acid.
entry
step 1 conditions
step 2 conditions
yield (%)
1
2
3
4
HMPA, À15 °C, 3 h
À15 °C, 3 h
À78 °C, 5 min
4a, quant
no reaction
no reaction
4a, 20%
DMF, À15 °C to rt, 10 h
DMPU, À15 °C to rt, 11 h
À15 °C, 1 h
Phenethyl bromide (1), 2,6-xylyl isocyanide (2), and
phenyl isocyanate (3) were selected as substrates for the
ease of monitoring reactions (Table 1). Phenethyl bromide
(1) (3.0 equiv) was added to a mixture of 2,6-xylyl iso-
11
cyanide (2) (2.0 equiv) and SmI2 (0.1 M in THF, 6.0
equiv) under conditions 1 (Table 1). After stirring, phenyl
isocyanate (3) (1.0 equiv) was added, and the reaction
mixture was stirred using conditions 2 (Table 1). To our
delight, a one-pot, sequential CÀC bond-forming reaction
afforded the desired product 4a in a quantitative yield
under mild conditions (entry 1). The addition of HMPA
was crucial to a good yield. The desired intermediate,
imidoylsamarium(III) species, was not generated in the
absence of HMPA (entry 2) or by the addition of DMF
instead of HMPA (entry 3). When DMPU was added
instead of HMPA, the yield of the desired product was
decreased to 20% (entry 4).
€
(8) (a) Domling, A. Chem. Rev. 2006, 106, 17. (b) Passerini, M.;
Simone, L. Gazz. Chim. Ital. 1921, 51, 126. (c) Ugi, I. Angew. Chem., Int.
Ed. 1962, 1, 8. (d) Ugi, I.; Karl, R.; Lohberg, S. In Comprehensive
Organic Chemistry; Trost, B. M., Heathcock, C. H., Eds.; Pergamon:
Oxford, 1991; p 1083.
The substrate scope of the developed one-pot procedure
was explored using various alternatives (Table 2).12 In the
(9) (a) Yamada, H.; Harada, T.; Takahashi, T. J. Am. Chem. Soc.
1994, 116, 7919. (b) Takahashi, T.; Adachi, M.; Matsuda, A.; Doi,
T. Tetrahedron Lett. 2000, 41, 2599. (c) Tanaka, H.; Adachi, M.;
Tsukamoto, H.; Ikeda, T.; Yamada, H.; Takahashi, T. Org. Lett. 2002,
4, 4213. (d) Tanaka, H.; Adachi, M.; Takahashi, T. Tetrahedron Lett. 2004,
45, 1433. (e) Tanaka, H.; Adachi, M.; Takahashi, T. Chem.;Eur. J. 2005,
11, 849. (f) Tanaka, H.; Matoba, N.; Takahashi, T. Chem. Lett. 2005, 34,
400. (g) Tanaka, H.; Tateno, Y.; Nishiura, Y.; Takahashi, T. Org. Lett.
2008, 10, 5597. (h) Serizawa, T.; Miyamoto, S.; Numajiri, Y.; Fuse, S.; Doi,
T.; Takahashi, T. Tetrahedron Lett. 2009, 50, 3408. (i) Serizawa, T.;
Miyamoto, S.; Fuse, S.; Doi, T.; Takahashi, T. Bull. Chem. Soc. Jpn.
2010, 83, 942.
(10) (a) Murakami, M.; Kawano, T.; Ito, Y. J. Am. Chem. Soc. 1990,
112, 2437. (b) Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. J. Org. Chem.
1993, 58, 1458.
(11) SmI2 solution was prepared according to a literature procedure:
Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693.
The concentration of SmI2 was determined by titration according to
literature procedure: Iwamoto, T.; Ono, M. Chem. Lett. 1987, 501.
(12) It was reported that the use of hexyl isocyanide or 4-tolyl
isocyanide caused undesired reductive deisocyanation (ref 10b). There-
fore, aryl isocyanides with ortho substituents were employed as
substrates.
Org. Lett., Vol. 14, No. 16, 2012
4091

in satisfactory to excellent yields (entries 4, 5, and 10,
respectively). An acid-labile THP group was tolerated under
the coupling conditions (entry 11). The structures of all
Table 2. Synthesis of R-Iminocarboxamides
1
R-iminocarboxamides were confirmed by H NMR, 13C
NMR, IR, and HRMS.
Figure 2. Plausible mechanism for the formation of tetrahydro-
furanyl iminocarboxamide.
Wheniodobenzene(12) wasemployed asanalkylhalide,
tetrahydrofuranyl iminocarboxamide 4l was obtained in a
50% yield (Figure 2). This observation is consistent with a
Figure 3. Synthesis of (a) R,β-diiminocarboxamides and (b)
R-amino acid by changing the amount of substrate or reagent.
previous report.10b It is conceivable that phenyl radical
intermediate A was generated from iodobenzene (12) and
SmI2 abstracted hydrogen from the solvent THF. The
resultant tetrahydrofuranyl radical B was converted into
tetrahydrofuranyl samarium(III) species C, resulting in a
sequential coupling reaction with isocyanide 2 and isocya-
nate 3.
case of R1 = phenethyl or ethyl (R1Br = 1 or 9), the
desired products 4aÀj were obtained in good to excellent
yields (entries 1À10). The coupling reaction with isocya-
nides8or10, orisocyanate7, which haveeitherabulky 2,6-
diisopropyl phenyl group or a 2,4,6-tri-tert-butylphenyl
group, provided the corresponding R-iminocarboxamides
It is interesting that the product of the one-pot coupling
reaction could be switched by changing the amount of
reagent or substrate. When an excess amount (8.0 equiv
(13) Murakami, M.; Masuda, H.; Kawano, T.; Nakamura, H.; Ito,
Y. J. Org. Chem. 1991, 56, 1.
4092
Org. Lett., Vol. 14, No. 16, 2012

against isocyanate) of isocyanide was used, R,β-diimino-
carboxamide was obtained by double insertion13,14 of the
isocyanide. R,β-Diiminocarboxamide 4m was obtained in
a 54% yield (Figure 3a). Thiscoupling reaction isuseful for
the synthesis of structurally interesting vicinal tricarbonyl
compounds. When an excess amount (8.0 equiv against
isocyanate) of SmI2 was used in the one-pot reaction, the
resultant R-iminocarboxamide was reduced with SmI2 in
situ, and the corresponding R-amino acid 4n was obtained
in a quantitative yield (Figure 3b).15 This is a novel
approach for the rapid synthesis of R-amino acids.
allowed us to obtain R-iminocarboxamides with various
substituents, R1, R2, and R3, from readily available start-
ing materials: alkyl halides, isocyanides, and isocyanates in
good to excellent yields under mild conditions. In addition,
structurally diverse products, i.e., R,β-diiminocarboxa-
mides and an R-amino acid, were successfully synthesized
by changing only the amount of either the reagent or the
substrate in a one-pot reaction. The developed procedure
should be very useful for the rapid synthesis of various
iminocarboxamide-based compounds.
Inconclusion, wesuccessfullydemonstrated arapidone-
pot synthesis of various R-iminocarboxamides via the
nucleophilic addition of an alkyl samarium(III) species
to isocyanides and the subsequent nucleophilic addition of
the resultant imidoyl samarium(III) species to isocyanates.
The developed sequential CÀC bond-forming approach
(14) When phenethyl bromide was employed as R1-X, the corre-
sponding R,β-diiminocarboxamide was obtained as a mixture of dia-
stereomers with respect to the direction of the 2,6-xylyl groups in a 59%
combined yield.
Acknowledgment. We thank Dr. Akio Tannna and Dr.
Fumihiko Shimizu, Mitsubishi Chemical Group, Science
and Technology Research Center, Inc., for their fruitful
suggestions. We also thank Mitsubishi Chemical Corpora-
tion for financial support.
Supporting Information Available. Detailed experimen-
tal procedures and characterization of all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Reduction by NaBH4 after similar three-component reaction:
(a) Murakami, M.; Ito, H.; Ito, Y. J. Org. Chem. 1993, 58, 6766.
(b) Murakami, M.; Ito, H.; Ito, Y. Chem. Lett. 1996, 185.
The authors declare no competing financial interest.
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