Copper-catalyzed aerobic [3+2]-annulation of N -alkenyl amidines

Article abstract of DOI:10.1021/ja2120629

A method for the synthesis of bi- and tricyclic amidines has been developed through copper-catalyzed aerobic [3+2]-annulation reaction of N-alkenyl amidines. These cyclic amidines could be converted into mono-benzyl-protected vicinal diamines by the reduction with aluminum hydride.

Full text of DOI:10.1021/ja2120629

Communication
pubs.acs.org/JACS
Copper-Catalyzed Aerobic [3+2]-Annulation of N-Alkenyl Amidines
Yi-Feng Wang,† Xu Zhu,† and Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
a
Table 1. Optimization of Reaction Conditions
ABSTRACT: A method for the synthesis of bi- and
tricyclic amidines has been developed through copper-
catalyzed aerobic [3+2]-annulation reaction of N-alkenyl
amidines. These cyclic amidines could be converted into
mono-benzyl-protected vicinal diamines by the reduction
with aluminum hydride.
time yield
b
entry Cu salts (equiv)
additive (equiv)
solvent (h) (%)
1
2
3
4
5
6
7
8
9
CuBr·SMe2 (1.1) 2,2′-bipyridine (1.1)
DMSO 23 29
itrogen-containing heterocycles (azaheterocycles) are an
omnipresent component of numerous natural alkaloids
CuCl (1.1)
CuI (1.1)
CuI (0.2)
CuI (0.2)
CuI (0.1)
CuI (0.1)
CuI (0.1)
CuI (0.1)
2,2′-bipyridine (1.1)
2,2′-bipyridine (1.1)
2,2′-bipyridine (0.4)
2,2′-bipyridine (0.4)
2,2′-bipyridine (0.2)
2,2′-bipyridine (0.1)
2,2′-bipyridine (0.1)
−
DMSO
DMSO
8
8
trace
51
N
and potent pharmaceutical drugs.1 Although diverse synthetic
approaches toward azaheterocycles have been exploited,2 there
remains a need for conceptually novel and versatile method-
ologies for chemical synthesis of azaheterocycles from readily
available building blocks. Herein, we report a copper-catalyzed
aerobic [3+2]-annulation of N-alkenyl amidines that includes
1,2-diamination of alkenes.
DMSO 16 55
DMF
DMF
DMF
DMF
DMF
9 38
23 80
23 87
c
d
d
23 0 (93)
30 75
10 CuI (0.1)
1,10-phenanthroline (0.1) DMF
2,2′-bipyridine (0.1) DMF
23 39
We have been interested in copper-mediated oxidative
functionalization of carbon−carbon unsaturated bonds under
aerobic conditions,3,4 and we recently reported the reactions of
N-allyl enamine carboxylates for intramolecular cyclopropana-
tion and carbooxygenation, giving 3-azabicyclo[3.1.0]hex-2-
enes and 4-formylpyrroles, respectively (eq 1).3a Amidines could
11 CuBr2 (0.1)
23 0 (53)
a
Unless otherwise noted, the reactions were carried out using 0.3−0.5
mmol of amidine 1a in solvent (0.1 M) at 60 °C under an O2
atmosphere. Isolated yields. The reaction was carried out under a N2
atmopshere. Recovery yields of 1a.
b
c
d
atmosphere, an intramolecular 1,2-diamination product, bicyclic
amidine (tetrahydro-1H-pyrrolo[1,2-c]imidazole, 2a), was iso-
lated in 29% yield (entry 1). The unprecedented 1,2-diamina-
tion reaction of the CC bond6−13 to form bicyclic amidine
2a prompted us to optimize the reaction conditions further.
While CuCl did not provide 2a at all (entry 2), the yield of
product 2a was improved to 51% by using CuI (entry 3). It was
found that the reaction could be completed even by using a
catalytic amount of CuI (entry 4), and DMF was proved to be
an optimal solvent for this transformation (entry 5). The
catalytic loading of CuI could be reduced to 10 mol %, in which
bicyclic amidine 2a was obtained in 87% yield with 10 mol %
of 2,2′-bipyridine in DMF (entry 7). Under a N2 atmosphere,
no reaction was observed along with 93% yield recovery of 1a
after 23 h (entry 8). In the absence of 2,2′-bipyridine as a
ligand, the reaction became sluggish and the yield of 2a
dropped (entry 9). The reaction with 1,10-phenanthroline
afforded amidine 2a only in 39% yield (entry 10). It is noted
that Cu(II) complexes such as CuBr2 did not afford product
2a at all (entry 11).14
be easily prepared by addition reactions of amines to the
corresponding carbonitriles or imidates.5 Stimulated by the struc-
tural analogy of amidines with enamine carboxylates, we could
envision unique oxidative amination processes to occur by copper-
mediated aerobic reactions of N-alkenyl amidines via putative
copper diazaenolates (eq 2).
We began our investigation with the copper-mediated
aerobic reactions of N-(2,2-diphenyl-4-pentenyl)amidine (1a)
(Table 1). Interestingly, when 1a was treated with 1.1 equiv of
CuBr·SMe2 and 2,2′-bipyridine in DMSO at 60 °C under an O2
Using the CuI−2,2′-bipyridine catalytic system (Table 1,
entry 7), we examined the generality of this [3+2]-annulation
Received: December 25, 2011
Published: January 31, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
of N-alkenyl amidines. By varying substituents R1 of N-4-
pentenyl amidines 1 (Chart 1), it was shown that various aro-
Table 2. Scope of the [3+2]-Annulation of N-Alkenyl
Amidines
a b
,
Chart 1. Scope of the [3+2]-Annulation of N-Alkenyl
a b
,
Amidines
a
Unless otherwise noted, the reactions were carried out using 0.3−0.5
mmol of amidine 1 using 10 mol % of CuI and 2,2′-bipyridine in DMF
b
(0.1 M) at 60 °C under an O2 atmosphere. Isolated yields were
recorded above. The reaction was run using 40 mol % of CuI and 2,2′-
bipyridine. 2j was obtained in 63% yield using 1.1 equiv of CuI
and 1.1 equiv of 2,2′- bipyridine. Unidentified complex mixtures were
c
d
e
formed.
matic rings including bromophenyl and thienyl groups (for 2g
and 2d) were tolerated, and an alkyl substituent (for 2e) could
be introduced. 4-Pentenyl tethers of amidines 1 could include
not only 2,2-diphenyl (for 2a−g) but also 2,2′-dimethyl (for
2f,g), 2,2-diallyl (for 2h), and cyclohexyl (for 2i) moieties. Even
simple N-pentenyl amidine 1j cyclized to give 2j in 58% yield,
while 40 mol % of CuI-2,2′-bipyridine was required. This method
allowed for construction of a dihydro-1H-imidazo[1,5-a]indole
structure (for 2k) in good yield. The reaction of N-5-hexenyl
amidine, however, did not afford a [3+2]-annulation product such
as 2l.
a
Unless otherwise noted, the reactions were carried out using 0.3−0.5
mmol of N-alkenyl amidines 1 with 10 mol % of CuI and 10 mol % of
b
2,2′-bipyridine in DMF at 60 °C under an O2 atmosphere. Isolated
yields were recorded above. The reaction was carried out using
40 mol % of CuI and 40 mol % of 2,2′-bipyridine. The structures were
c
d
secured by X-ray crystallographic analysis, see Supporting Information.
e
The reaction was carried out using 1.1 equiv of CuI and 1.1 equiv of
2,2′-bipyridine.
interestingly found that treatment of N-phenyl amidine 6 with
20 mol % of CuI and 40 mol % of 2,2′-bipyridine in DMSO
under an O2 atmosphere delivered sulfoxyimine 7 in 74% yield,
probably via trap of the putative nitrene species generated
during the catalytic process with DMSO (eq 4).19,20
Next, the effect of substituent on the alkenyl moiety for the
present [3+2]-annulation was examined (Table 2). The
reactions of both (E)- and (Z)-N-5-phenyl-4-pentenyl deriva-
tives 1m and 1n provided a single diastereomer of 2m and 2n,
respectively with retention of the configuration of the alkenyl
moieties (entries 1 and 2),15 which may suggest that the present
[3+2]-annulation proceeds in a concerted manner. The reaction
of N-5,5-dimethyl-4-pentenyl amidine 1o afforded no [3+2]-
annulation product even by using a stoichiometric amount of
CuI and 2,2′-bipyridine (entry 3). In this case, cyclic α-amino
ketone 3o was isolated in 31% yield through aminooxygenation
of the CC bond.16 In the case of N-4-phenyl-4-pentenyl
amidine 1p, desired bicyclic amidine 2p could be obtained in
85% yield (entry 4). The reactions of amidines 1q and 1r
bearing a cyclohexene tether proved the further potential of this
method, affording highly strained fused tricyclic amidines 2q
and 2r, respectively (entries 5 and 6).
Based on these results, a proposed mechanistic possibility is
outlined in Scheme 1. In this senario, CuII is first oxidized by
molecular oxygen to form a higher oxidation state CuII super-
oxo or peroxo species (described as [CuII]).21 One-electron
oxidation of N-alkenyl amidine 1 with the resulting CuII species
The reaction of N-allyl amidine 4 was also examined (eq 3).17
In this case, bicyclic aziridine 5 was isolated in 33% yield,
although a stoichiometric use of CuBr·SMe2 and 2,2′-bipyridine
in DMSO was required to complete the reaction.18 It was
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Communication
a
Scheme 1. Proposed Reaction Mechanism for the [3+2]-
Chart 2. Reductive Transformation of Cyclic Amidines
Annulation of N-Alkenyl Amidines
through copper diaza-enolate A proceeds to give 1,3-diazaallyl
radical B, which may be further oxidized by another CuII
species to generate nitrene intermediate (copper nitrene
complex) C.22,23 Presumably, nitrene intermediate C could
potentially possess chemical reactivity as a 1,3-dipole with
resonance form D, which would induce the concerted [3+2]-
cycloaddition with an intramolecular alkenyl moiety to give
cyclic amidine 2 with retention of the configuration of the
alkene (for Table 2, entries 1 and 2). The results in eqs 3
(aziridination) and 4 (sulfoxyimine formation) also implied
generation of the putative nitrene species like C. The catalytic
cycle could be maintained by oxygen oxidation of the resulting
CuI species to the CuII.
Vicinal diamine functionalities are privileged as the structual
elements in biologically active molecules as well as ligands
for transition metal catalysts.24 Having developed a
preparation method of bi- and tricyclic amidines, we finally
explored concise reductive transformation of them to vicinal
diamines.25,26 It was found that reduction by aluminum
hydride (AlH3, prepared in situ from LiAlH4 and AlCl3)27
proceeded smoothly to give monobenzyl-protected vicinal
diamines, in which the benzyl group was attached exclusively
on the tethered nitrogen (marked in red) along with formation of
another secondary amine on the pyrrolidine ring (marked in blue)
(Chart 2). By using this reductive transformation, mono-
cyclic pyrrolidines 8a and 8p, azaspiro[4,5]decanes 8i and 8r,28
dihydro-1H-indole 8k, and octahydro-1H-indole (bicyclic pyrroli-
dines) 8q with the vicinal diamine moiety could be efficiently
constructed.
In summary, unprecedented chemical reactivity of N-alkenyl
amidines under copper-catalyzed aerobic conditions have been
exploited for the synthesis of bi- and tricyclic amidines. The
reaction might be characterized as a concerted [3+2]-annula-
tion via putative nitrene species, which might be generated
under the mild oxidative reaction conditions with molecular
oxygen. Moreover, concise reductive conversion of the bi- and
tricyclic amidines into mono-benzyl-protected vicinal diamines
has been demonstrated using aluminum hydride. Further
investigation of the scope, detailed mechanisms, and synthetic
applications of the present strategy to other azaheterocycles as
well as development of asymmetric intermolecular diaminations
is currently underway.
a
Unless otherwise noted, the reactions were carried out by first
treatment of AlCl3 (1 equiv) in THF with LiAlH4 (3 equiv) at 0 °C
followed by addition of cyclic amidines 2 and stirring at room
temperature. See Supporting Information for more details. Isolated
yields were recorded above. The reaction were carried out using
b
c
3 equiv of AlCl3 and 9 equiv of LiAlH4 for 48 h.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
shunsuke@ntu.edu.sg
Author Contributions
†These authors contributed equally to this paper.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by funding from Nanyang Tech-
nological University and the Singapore Ministry of Education.
We thank Dr. Yongxin Li and Dr. Rakesh Ganguly (Division of
Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University) for
assistance in X-ray crystallographic analysis.
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