Cu(II)-catalyzed intermolecular amidation of C-acylimine: A convenient access to gem-diamino acid derivatives

Article abstract of DOI:10.1021/ol2019955

C-Acylimines 1 undergo intermolecular amidation with amides 2 to produce monoacyl gem-diamino acid derivatives 3 upon treatment with Cu(OTf)₂ (20 mol %)/ PPh₃ (20 mol %) under mild conditions. This method provides an efficient access to gem-diamino acid equivalents with good to excellent yields.

Full text of DOI:10.1021/ol2019955

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4914–4917
Cu(II)-Catalyzed Intermolecular Amidation
of C-Acylimine: A Convenient Access to
gem-Diamino Acid Derivatives
Shujie Zhu, Jia Dong, Shaomin Fu, Huanfeng Jiang, and Wei Zeng*
School of Chemistry and Chemical Engineering, South China University of Technology,
No. 381, Wushan Road, Tianhe District, Guangzhou, P. R. China 510641
zengwei@scut.edu.cn
Received July 24, 2011
ABSTRACT
C-Acylimines 1 undergo intermolecular amidation with amides 2 to produce monoacyl gem-diamino acid derivatives 3 upon treatment with
Cu(OTf)2 (20 mol %)/ PPh3 (20 mol %) under mild conditions. This method provides an efficient access to gem-diamino acid equivalents with good
to excellent yields.
Transition-metal-catalyzed CÀN bond-forming reac-
tions starting from imine derivatives are among the most
straightforward strategies for constructing various nitrogen-
containing units, which could be found in many complex
natural products, synthetic biologically active compounds,
and pharmaceuticals.1 Imines have served as versatile accep-
tors of nucleophiles; their corresponding addition reactions
with carbon radicals, organometallic reagents, Mannich
donors, etc. are commonly utilized in many crucial steps.2
However, although much progress toward the transforma-
tion scope of imines has been made, the amidation of imine
derivatives has attracted much less attention because of
the poor nucleophilicity and higher pKa values (17À25)
of amides.3 Considering the wide application of nitrogen-
containing intermediates, especially for gem-diamino
carboxylic acid derivatives, which are an important
class of core structures of biological molecules,4 such
as, among others, the inhibitors of HIV-1 protease4d and
E. coli4e,g (Figure 1), the exploration of new activation
methods for imino compounds and subsequent imine
amidation reactions under mild conditions therefore is
always desirable.
Figure 1. gem-Diamino unit-containing drugs.
(1) For a review, see: Martin, S. F. Pure Appl. Chem. 2009, 81, 195
and references therein.
(2) For selective reviews, see: (a) Shimizu, M.; Hachiya, I.; Mizota, I.
Chem. Commun. 2009, 874. (b) Miyabe, H.; Yoshioka, E.; Kohtani, S. Curr.
Org. Chem. 2010, 14, 1254. (c) Bloch, R. Chem. Rev. 1998, 98, 1407.
(d) Dickstein, J. S.; Kozlowski, M. C. Chem. Soc. Rev. 2008, 37, 1166.
(e) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541.
(f) Kobayashi, S.; Ishitahi, H. Chem. Rev. 1999, 99, 1069. (g) Blay, G.;
Mo- nleon, A.; Pedro, J. R. Curr. Org. Chem. 2009, 13, 1498. For selective
recent examples, see:(h) Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2007, 129, 500. (i) Ueno, S.; Ohtsubo, M.; Kuwano, R. J. Am. Chem.
Soc. 2009, 131, 12904. (j)Qian, B.;Guo, S.;Shao, J.;Zhu, Q.; Yang, L.;Xia,
C.; Huang, H. J. Am. Chem. Soc. 2010, 132, 3650.
(4) For reviews, see: (a) Goodman, M.; Chorev, M. Acc. Chem. Res.
1979, 12, 1. (b) Chorev, M.; Goodman, M. Acc. Chem. Res. 1993, 26,
266. For selective examples, see:(c) Hernandez, J. F.; Soleihac, J. M.;
Roques, B. P.; Fournie- Zaluski, M. C. J. Med. Chem. 1988, 31, 1825. (d)
Marastoni, M.; Salvadori, S.; Bortolotti, F.; Tomatis, R. J. Peptide Res.
1997, 49, 538. (e) Kingsbury, W. D.; Boehm, J. C.; Perry, D.; Gilvary, C.
Proc. Natl. Acad. Sci. U.S.A. 1984, 81, 4573. (f) Nishimura, Y.; Shitara,
E.; Adachi, H.; Toyashima, M.; Nakajima, M.; Okami, Y.; Takeuchi, T.
J. Org. Chem. 2000, 65, 2. (g) Hwang, S. Y.; Berges, D. A.; Taggart, J. J.;
Gilvarg, C. J. Med. Chem. 1989, 32, 694. (h) Han, Y.; Giragossian, C.;
Mierke, D. F.; Chorev, M. J. Org. Chem. 2002, 67, 5085. (i) Fletcher,
M. D.; Campbell, M. M. Chem. Rev. 1998, 98, 763.
(3) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
r
10.1021/ol2019955
Published on Web 08/23/2011
2011 American Chemical Society

Table 1. Optimization of Reaction Conditions for Amidation of
C-Acyliminea
Scheme 1. Catalytic Amidation of Imines
entry
catalyst
ligand
yield (%)b
1
Cu(OAc)2. H2O
Cu(OAc) 2
CuCl2
5
2
6
3
15
4
CuBr2
27
5
Cu(OTf) 2
Cu(OTf) 2
Cu(OTf)2
Cu(OTf)2
Cu(OTf) 2
Cu(OTf) 2
Cu(OTf) 2
32
6
tracec
61
7
L1
L2
L3
L4
L5
L5
L6
L7
L8
L5
L5
L5
L5
8
55
9
62
Among the different types of CÀN bond-forming reac-
tions, aza-Michael addition of amides to enones provides
a convenient approach to make β-amido carbonyl com-
pounds in the presence of transition metal salts that act as
Lewisacidcatalysttoactivateenone.5 Recently, the Antilla
group found that a Brønsted acid could efficiently cata-
lyze intermolecular amidation of N-acylimines to give
N,N-aminals in good to excellent yields (see Scheme 1a).
There are only a few reports about imine amidation up to
present,6 and transition-metal-catalyzed imine amidation
was also previously unknown. Unfortunately, when we
tried to use Antilla’s method to make gem-diamino acid
derivative 3a via Brønsted acid catalyzed amidation of
C-acylimine 1a, only traces of target product 3a was
formed (see Scheme 1b).7 The above combined results
about transition-metal-catalyzed aza-Michael addition
and Brønsted acid catalyzed imine amidation encouraged
us to envision that transition metal salts could possibly
activate the carbonÀnitrogen double bond of C-acylimine
via the coordination with carbonyl oxygen and imine
nitrogen and then enhanced addition of amide nitrogen
nucleophile to C-acylimine carbon to produce R-amido-R-
amino acid derivates (3) (see Scheme 1c). Although differ-
ent methods to make gem-diamino acid derivatives via
Curtius- or Hoffman-type rearrangements of protected
10
11
12
13
14
15
16
17
18
19
66
84
trace
66
Cu(OTf) 2
Cu(OTf) 2
Cu(OTf) 2
Cu(OTf) 2
Cu(OTf) 2
Cu(OTf) 2
Cu(OTf) 2
72
58
41d
49e
61f
67g
a Reaction conditions: unless stated otherwise, all reactions were
carried out with C-acylimine 1a (0.2 mmol), amide 2a (0.3 mmol),
catalyst (20 mol %), ligand (20 mol %), and toluene (2.0 mL) under
Ar atmosphere at 25 °C for 6 h. b Isolated yield. c Substrate 2b (0.3 mol)
was used. d Reaction temperature 10 °C. e Reaction temperature 50 °C.
f 10 mol % Cu(OTf)2 and 10 mol % PPh3 were used. g 30 mol %
Cu(OTf)2 and 30 mol % PPh3 were used.
amino acid equivalents4a,b or a benzotriazole-mediated
approach8 were developed successively, these synthetic
methods suffer from disadvantages of multistep proce-
dures (more than three steps) and low overall yield.8,9
Herein we report an efficient synthetic method of gem-
diamino residues via copper(II)-catalyzed amidation of
C-acylimine.
(5) For selective examples, see: (a) Gaunt, M. J.; Spencer, J. B. Org.
Lett. 2001, 3, 25. (b) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org.
Lett. 2002, 4, 1319. (c) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003,
68, 2109. (d) Hamashima, Y.; Somei, H.; Shimura, Y.; Tamura, T.;
Sodeoka, M. Org. Lett. 2004, 6, 1861. (e) Wabnitz, T. C.; Yu, J. Q.;
Spencer, J. B. Chem.;Eur. J. 2004, 10, 484. (f) Palomo, C.; Oiarbide,
ꢀ
M.; Halder, R.; Kelso, M.; Gomez- Bengoa, E.; Garcıa, J. M. J. Am.
Chem. Soc. 2004, 126, 9188. (g) Chen, Y. K.; Yoshida, M.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2006, 128, 9328.
(6) (a) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni,
S.;Wang, Y.;Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696. (b) Liang, Y.;
Rowland, E. B.; Rowland, G. B.; Perman, J. A.; Antilla, J. C. Chem.
Commun. 2007, 4477.
(7) When we also tried to use some stronger acids such as H3PO4 and
HOTf as catalyst using Antilla’s reaction conditions, the best yield was
only up to 15% (see Supporting Information for more details).
(8) Katritzky, H. R.; Urogdi, L.; Mayence, A. J. Org. Chem. 1990, 55,
2206.
(4-Methoxy-phenylimino)-acetic acid ethyl ester (1a)
was first used as the model substrate to screen the reaction
conditions for the optimization of the catalyst, ligand, sol-
vent, and temperature under Ar atmosphere. As shown in
Table 1, when 1a (0.1 mmol), which formed from ethyl
(9) Chorev, M.; Willson, C. G.; Goodman, M. J. Am. Chem. Soc.
1977, 99, 8075.
Org. Lett., Vol. 13, No. 18, 2011
4915

Table 2. Copper(II)-Catalyzed Intermolecuar Amidation of C-Acyliminea
a Unless otherwise noted, all reactions were performed under argon at 25 °C for the given time; C-acylimine, 0.2 mmol; amide, 0.3 mmol; Cu(OTf)2, 20mol%;
PPh3, 20 mol %; solvent, toluene (2.0 mL). b Isolated yield. c Reaction temperature 45 °C. d K2CO3(1.0 equiv) was added. e 3.0 equiv of amide was used. f 30 mol %
Cu(OTf)2 and 30 mol % PPh3 were used.
4916
Org. Lett., Vol. 13, No. 18, 2011

oxoacetate and 4-methoxyaniline, was treated with 1.5
equiv of benzamide (2a) in toluene (2.0 mL) at room tem-
perature (25 °C) for 6 h in the presence of copper salts
carboxamide could also be used in this transformation and
gave the corresponding monoacyl gem-diamino acid
derivates in moderate yields (entries 18À20). The
structure of 3n was unambiguously assigned by single
crystal X-ray analysis (see Supporting Information for
more details).
Esteryl 2-benzimidazole and its corresponding deriva-
tives belong to an important precursor for assembling
biological molecules.12 Cu(II)-catalyzed intramolecular
(20 mol %) such as Cu(OAc)2, CuCl2, CuBr2, Cu(OAc)2
3
H2O, and Cu(OTf)2 (entries 1À5), the use of Cu(OTf)2
provided a 32% yield of the desired product, monoacyl
gem-diamino acid derivative (3a) (entry 5).10 No desired 3a
was detected byTLC and 1H NMR methods in the absence
of copper salts even after 24 h. When we switched substrate
benzamide to 4-toluenesulfonamide (2b), the sulfonamida-
tion of C-acylimine 1a did not take place due possibly to
less nucleophilic property of sulfonamide compared with
carbonamide 2a (entry 6).3 Subsequently, we investigated
the effect of ligand on the copper(II)-catalyzed amidation
of C-acylimine in order to improve the reaction yield, we
soon found nitrogen- or phosphate-containing ligands
(L1ÀL8) significantly improved yield of 3a (compare en-
tries 5 and 7À15); among the tested ligands, PPh3 (L5)
showed the best cocatalyzed activity (entry 11). Notably,
PPh3 could not enhance efficiently the transformation
to occur in absence of Cu(OTf)2 (entry 12). Encouraged
by these positive results, we further investigated
other reaction conditions to define the reaction parameters.
When the reaction temperature was lowered to 10 °C or
increased to 50 °C, the yield decreased due to incomplete
reaction or decomposition of C-acylimine, respectively
(compare entries 11, 16, and 17). A catalyst loading of
20 mol % was found to be effective to achieve satisfied yield
(compare entries 11, 18, and 19). The effect of the solvent
was also investigated, and THF, dioxane, and ethyl acetate
were the better solvents, with toluene being the best (see
Supporting Information for more details).
amidation/dehydrogenation of C-acylimine
5 could
occur and gave the N-protected 2-esteryl benzimidazole 6
in 87% yield. When Pd(II)/PhI(OAc)2 system was em-
ployed in this reaction, N-unprotected 2-esteryl benzimi-
dazole 7 was produced in 78% yield via one-pot cascade
intramolecular amidation/oxidation/desulfonylation. This
two-step reaction process starting from o-phenylenedia-
mine derivative 4 has an overall yield of 48À54% (see
Scheme 2).
Scheme 2. Synthesis of Esteryl 2-Benzoimidazole via Transition-
Metal-catalyzed Intramolecular Amidation of C-Acylimine
In conclusion, we have developed the first copper(II)-
catalyzed intermolecular amidation of C-acylimine under
mild conditions. A range of electron-rich and electron-
poor C-acylimine and amide derivatives participate. The
protocol uses readily available C-acylimines (synthesized
by the reaction of ethyl oxoacetate with amines) and
amides as the starting material and provides the corre-
sponding monoacyl gem-diamino acid derivatives in
moderate to excellent yields. The further studies about
transition-metal-catalyzed intramolecular amidation of
C-acylimine are underway in our laboratory.
With the optimized reaction conditions in hand, the
scope of this transformation was subsequently investi-
gated. As shown in Table 2, this new method could be
applied to a wide range of substrates. The catalysis pro-
ceeded well with benzamide irrespective of the electronic
effects of substituent at the iminoaromatic ring. Thus,
C-acylimine with methyl, methoxyl, chloro, bromo, esteryl,
and nitro substituents at the 4-position or 3-position of
phenyl ring reacted to afford the corresponding R-amido-
R-amino acid derivates in yields up to 98% (entries 1À7).
On the contrary, significant substituent effect for
benzamide substrate was observed, and the reaction with
4-nitro- benzamide gave only 31% yield of the target com-
pound 3l (entries 1, 10À13). In the case of 1-naphthylamide,
lower reactivity was observed possibly due to steric influence
of naphthyl group (entry 17). Moreover, N-alkyl C-acyli-
mine, aliphatic amide, and acrylamide were also investi-
gated, and the corresponding target compounds were ob-
tained in moderate to good yields (entries 8, 9, 14À16).11
It is worth noting that heterocyclic amide such as 2-pyr-
idinecarboxamide, 2-furancarboxamide, and 2-thiophene-
Acknowledgment. The authors thank the NCET
(Grant No. NCET-10-0371), the FRFCU (Grant No.
2009ZM0262), the NSFC (No. 21072063), RFDP (No.
20100172120020), and GNSF (No. 10351064101000000)
for financial support. The authors are also grateful to Prof.
Yuanfu Deng (School of Chemistry and Chemical Engineer-
ing, SCUT) for the X-ray single-crystal analysis.
Supporting Information Available. Details for experi-
ments conditions, characterization data, copies of 1H and13C
NMR spectra for all isolated compounds, and crystallo-
graphic data for 3n in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
(10) The compound 3a was found to be stable in air atmosphere even
under heat treatment condition (100 °C) for 12 h.
(11) It should be noted that the amidation of C-alkyl or C-arylimines
with 2a is limited possibly due to the poor electrophilicity of imine
carbon, and also the amidation of 1a with N-phenyl-acetamide or
N-ethyl-benzamide did not proceed smoothly even at 45 °C for 24 h.
(12) (a) Baraldi, P. G.; Romagnoli, R.; Beria, I.; Cozzi, P.; Geroni, C.;
Mongelli, N.; Bianchi, N.; Mischiati, C.; Gambari, R. J. Med. Chem.
2000, 43, 2675. (b) Chezal, J. M.; Papon, J.; Labarre, P.; Lartigue, C.;
Galmier, M. J.; Decombat, C.; Chavignon, O.; Maublant, J.; Teulade,
J. C.; Madelmont, J. C.; Moins, N. J. Med. Chem. 2008, 51, 3133.
Org. Lett., Vol. 13, No. 18, 2011
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