Pd-catalyzed one-pot synthesis of polysubstituted acrylamidines from isocyanides, diazo compounds, and imines

Article abstract of DOI:10.1021/ol4009552

A novel and efficient Pd-catalyzed one-pot reaction of ethyl diazoacetate, isocyanides, and imines for the synthesis of acrylamidines was developed. The multicomponent reaction may have occurred through an unpredicted ring-opening process of the ketenimine-imine [2 + 2] intermediate to form the acrylamidine products.

Full text of DOI:10.1021/ol4009552

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Pd-Catalyzed One-Pot Synthesis
of Polysubstituted Acrylamidines
from Isocyanides, Diazo Compounds,
and Imines
Xu Yan,†,‡ Jinxi Liao,‡ Yongzhi Lu,‡ Jinsong Liu,‡ Youlin Zeng,*,† and Qian Cai*,‡
College of Chemistry and Chemical Engineering, Hunan Normal University,
No. 36 Lushan Road, Changsha, Hunan, 410081, China, and Key State Laboratory of
Respiratory Disease, Guangzhou Institutes of Biomedicine and Health,
Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou Science Park,
Guangzhou, 510530, China
youlinzengcn@gmail.com; cai_qian@gibh.ac.cn
Received April 6, 2013
ABSTRACT
A novel and efficient Pd-catalyzed one-pot reaction of ethyl diazoacetate, isocyanides, and imines for the synthesis of acrylamidines was
developed. The multicomponent reaction may have occurred through an unpredicted ring-opening process of the ketenimineꢀimine [2 þ 2]
intermediate to form the acrylamidine products.
Multicomponent reactions, which involve three or more
starting materials to furnish the desired products in a one-
pot cascade reaction pattern, have been extensively applied
in organic synthesis because of their conciseness and
high efficiency.1 Ketenimines as potential intermediates
have attracted much attention in this area, and the cascade
reactions based on ketenimines are widely explored, typi-
cally by trapping the ketenimine intermediates via nucleo-
philic addition, radical addition and/or pericyclic reactions,
and so forth.2 In such reactions, the ketenimine intermedi-
ates are generally generated in situ through copper-catalyzed
azideꢀalkyne cycloaddition reaction (CuAAC)2e,3 or
other traditional methods2 such as Wittig reactions,4
elimination reactions,5 rearrangement reactions,6 and
† Hunan Normal University.
‡ Chinese Academy of Sciences.
€
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r
10.1021/ol4009552
XXXX American Chemical Society

coupling reactions of isocyanides with carbenes or diazo
compounds.7 Recently, we reported an amidation reaction
through hydrolysis of a ketenimine intermediate, which
was formed in situ through the Pd-catalyzed reaction of
isocyanides with N-tosylhydrazones.8
Scheme 2. Pd-Catalyzed One-Pot Reaction of Ethyl Diazoace-
tate, t-BuNC, and N-Benzylidene-4-methylbenzenesulfonamide
It is well documented that the reaction of ketenimines
with imines proceeds through a [2 þ 2] cycloaddition
process to produce 2-iminoazetidines,9 as in the case of
the copper-catalyzed three-component reaction10 of sulfo-
nyl azides, 1-alkynes, and imines (Scheme 1). We envi-
sioned that the same cyclic products may be obtained by
using imines to trap the ketenimine intermediates gener-
ated in situ from the Pd-catalyzed reaction of isocyanides and
diazo compounds. However, to our surprise, the Pd(OAc)2-
catalyzed one-pot reaction of ethyl diazo acetate 1, t-BuNC
2a, and N-benzylidene-4-methylbenzenesulfonamide 3a af-
forded three products at 40 °C in 1,2-dichloroethane, but no
[2 þ 2] cycloaddtion product 6a was detected (Scheme 2).
One isolated product was determined to be 5a, which was
formed through the direct reaction of ethyl diazo acetate 1
with imine 3a. The other two products were isomers, one of
which was unambiguously determined to be (E)-ethyl 2-(N-
tert-butyl-N0-tosylcarbamimidoyl)-3-phenylacrylate 4a by
X-ray crystallographic analysis.11 The other one 4a0, how-
ever, was unstable and transformed into 4a slowly in differ-
ent solvents such as ethyl acetate, chloroform, and methanol,
which we speculated to be the Z-isomer of 4a according to
the analysis of the 1H NMR and mass spectroscopic data.
The unexpected formation of the acrylamidine product
was interesting since the amidine skeleton is the key struc-
ture for many potent bioactive compounds,12 such as
NR2B subtype-selective antagonists13a and selective mus-
carinic agonists.13b Synthetic methods for such structures
are rare. The efficiency of the novel chemistry in our
Pd-catalyzed one-pot reaction for the synthesis of those
structures promoted us to optimize the reaction condi-
tions. As shown in Table 1, under the catalysis of 4 mol %
Pd(OAc)2, the three-component reaction was explored in
1,2-dichloroethane at different reaction temperatures. The
ratio of acrylamidine product 4a increased at elevated tem-
peratures, which was obtained in 70% yield at 80 °Cand75%
yield at 100 °C, respectively, accompanied by a small amount
of the unstable isomer 4a0 and byproduct 5a (Table 1, entries
2 and 3). Other solvents such as MeCN, DMF, toluene, THF,
and 1,4-dioxane were also screened, and DCE showed the
best results (Table 1, entries 4ꢀ8). Different Pd, Rh, and Cu
catalysts were also tested, and all gave inferior results by
comparison with that of Pd(OAc)2 (Table 1, entries 9ꢀ14) .
Scheme 1. Pd-Catalyzed One-Pot Reaction for the Formation of
Acrylamidines
Table 1. Condition Screeninga
t
yield (%)b yield (%)b
entry
catalyst
solvent
(°C)
4a/4a0
5a
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
DCE
40
24/34
70/9
33
13
9
2
DCE
DCE
MeCN
80
3
100
80
75/6
4
54/11
46/8
26
43
57
80
26
38
34
43
16
22
47
5
dioxane 80
6
toluene
THF
80
80
80
80
80
80
80
80
80
11/ꢀ
14/ꢀ
25/ꢀ
43/12
36/16
31/15
57/17
51/15
31/15
(7) (a) de Meijere, A.; Schirmer, H.; Duetsch, M. Angew. Chem., Int.
Ed. 2000, 39, 3964. (b) Aumann, R. Angew. Chem., Int. Ed. Engl. 1988,
7
8
DMF
DCE
DCE
DCE
DCE
ꢀ
27, 1456. (c) Fernandez, I.; Cossio, F. P.; Sierra, M. A. Organometallics
9
2007, 26, 3010. (d) Hudall, T. W.; Moorhead, E. J.; Gusev, D. G.;
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10
11
12
13
14
Pd2(dba)3
Pd(PPh3)4
c
Rh2(OAc)4
Rh(PPh3)3Clc DCE
CuId
DCE
(8) Zhou, F.; Ding, K.; Cai, Q. Chem.;Eur. J. 2011, 17, 12268.
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M.; Vidal, A.; Tovar, F.; Arrieta, A.; Lecea, B.; Cossıo, F. P. Chem.;
Eur. J. 1999, 5, 1106.
a Reagents and reaction conditions: 1 (0.6 mmol, 1.2 equiv), 2a
(1.5 mmol, 3.0 equiv), 3a (0.5 mmol, 1.0 equiv), catalyst (4 mol %), solvent
(1.5 mL), 20 h. b Isolated yield. c Catalyst (2 mol %). d Catalyst (10 mol %).
(10) Whiting, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45, 3157.
(11) See Supporting Information.
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(13) (a) Thominiaux, C.; de Bruin, B.; Bramoulle, Y.; Hinnen, F.;
Demphel, S.; Valette, H.; Bottlaender, M.; Besret, L.; Kassiou, M.;
(12) (a) Boyd, G. V. In The Chemistry of Amidines and Imidates; Patai,
S., Rappoport, Z., Eds.; Wiley: New York, 1991; Vol. 2, Chapter 8. (b)
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R. J. K., Eds.; Elsevier: New York, 2005; Vol. 5, pp 655ꢀ699.
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Durant, G. J.; Nagy, P. I.; Huzl, J. J., III; Periyasamy, S.; Ngur, D. O.;
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1996, 4, 1605.
B
Org. Lett., Vol. XX, No. XX, XXXX

With the optimized conditions in hand, we then ex-
plored the scope of substrates, and the results are shown
in Table 2. First, a series of aryl imines derived from aryl
aldehydes and TsNH2 were tested. It was found that
both electron-donating and -withdrawing substituent
groups on the aryl ring of imines were well tolerated.
In most cases, the corresponding E-acrylamidine prod-
ucts were obtained in moderate to good yields, accom-
panied by a small amount of byproduct 5 (Table 2, 4aꢀ4l).
In some cases, the unstable isomers 40 were detected.
When the imine derived from TsNH2 and the aliphatic
pivalaldehyde was explored, the reaction became com-
plicated and furnished the desired product 4m in low
yield. Further, other isocyanides were explored and
afforded the corresponding products in moderate to
good yields (e.g., 4nꢀ4q).
Scheme 3. Two Proposed Processes for the Formation of 4a
(Path II was excluded)
Based on the literature reports2 and our experimental
observations, we speculated that the acrylamidine product
4a may be formed through an unpredicted ring-opening
process of ketenimineꢀimine [2 þ 2] product 6a, which
may be unstable under the reaction conditions. As shown
in Scheme 3, two plausible mechanisms for the formation
of 4a were proposed: (1) Under the influence of the Pd
catalyst, ethyl diazoacetate 1 first reacted with isocyanide
2a to form ketenimine intermediate A (Path I). The for-
mation of such a ketenimine intermediate was confirmed
by trapping it with other nucleophiles such as TsNH2
(Scheme 4, eq 1). Ketenimine intermediate A then under-
went a [2 þ 2] reaction with imine 3a to produce the four-
membered ring intermediate 6a, which may be unstable
under the reaction conditions and undergoes a rapid ring-
opening reaction to deliver the acrylamidine products 4a
and its isomer 4a0. (2) Another possible process (Path II)
involvesethyldiazoacetate1directlyreactingwithimine3a
to deliver compound 5a, which was isolated as a stable
byproduct in the three-component reaction. Compound 5a
may act as an intermediate to react with t-BuNC 2a under
the influence of the Pd catalyst to form the ketenimine
intermediate B, which then undergoes an intramolecular
ring-closureꢀopening process to deliver the desired pro-
duct 4a. However, a controlled experiment revealed that
the reaction of 5a with 2a under the same conditions was
Table 2. Investigation of the Scope of 3-CR for the Synthesis of
E-Acrylamidinesa
Scheme 4. Some Controlled Experiments for the Understanding
of Reaction Mechanism
a Reagents and reaction conditions: 1 (0.6 mmol, 1.2 equiv), 2
(1.5 mmol, 3.0 equiv), 3 (0.5 mmol, 1.0 equiv), catalyst (4 mol %),
solvent (1.5 mL), 16ꢀ24 h. b Isolated yields.
Org. Lett., Vol. XX, No. XX, XXXX
C

amidine 7a, which was formed through direct attack of
ketenimine intermediate A by TsNH2. The benzaldehyde
did not participate in the reaction at all.
Scheme 5. A Possible Four-Component Reaction Process Was
Excluded through a Controlled Experiment
In summary, we havedeveloped a novel and efficient Pd-
catalyzed one-pot reaction of ethyl diazoacetate, isocya-
nides, and imines for the synthesis of acrylimidines, which
may be formed through an unpredicted ring-opening
process of the ketenimineꢀimine [2 þ 2] product. Further
study and application of this reaction are ongoing in our
laboratory.
Acknowledgment. The authors are grateful to the Na-
tional Natural Science Foundation of China (Grant
21202166), National S&T Major Special Project on Major
New Drug Innovation (Grant No. 2011ZX09102-010),
Guangdong Natural Science Foundation (S2012010009459),
and Key Project on Innovative Drug of Guangzhou
(11C34060759) for their financial support. We also thank
Prof. Fayang Qiu in Guangzhou Institutes of Biomedicine
and Health, Chinese Academy of Sciences for helpful
discussions.
very complicated and only afforded product 4a in less than
5% yield (Scheme 4, eq 2), which means that such a
pathway may not be responsible for the high yield of 4a
in the Pd-catalyzed three-component reaction.
Further, we still suspected that the reaction may also
proceed through another process as shown in Scheme 5.
First, the imine 3a was hydrolyzed to produce TsNH2 and
benzaldehyde. The TsNH2 would attack ketenimine inter-
mediate A to generate intermediate C, which may subse-
quently attack benzaldehyde to produce intermediate D.
This intermediate was then dehydrated to deliver the acryl-
amidine product. To exclude such a possibility, we per-
formed a four-component reaction under the same reac-
tion conditions (Scheme 4, eq 3). No acrylamidine product
4a was detected, and the only isolated product was the
Supporting Information Available. Full experimental
procedures, characterization data for all the compounds,
and crystal structure (CIF) of 4a. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX