Copper-mediated oxidative transformation of N-allyl enamine carboxylates toward synthesis of azaheterocycles

Article abstract of DOI:10.1021/ja500382c

A method for synthesis of 3-azabicyclo[3.1.0]hex-2-enes has been developed by intramolecular cyclopropanation of readily available N-allyl enamine carboxylates. Two complementary reaction conditions, CuBr-mediated aerobic and CuBr₂-catalyzed-PhIO₂-mediated systems effectively induced stepwise cyclopropanation via carbocupration of alkenes. Oxidative cyclopropane ring-opening of 5-substituted 3-azabicyclo[3.1.0]hex-2-enes was also developed for synthesis of highly substituted pyridines. In addition, diastereoselective reduction of 3-azabicyclo[3.1.0]hex-2-enes to 3-azabicyclo[3.1.0]hexanes was achieved using NaBH₃CN in the presence of acetic acid.

Full text of DOI:10.1021/ja500382c

Article
pubs.acs.org/JACS
Copper-Mediated Oxidative Transformation of N‑Allyl Enamine
Carboxylates toward Synthesis of Azaheterocycles
Kah Kah Toh, Anup Biswas, Yi-Feng Wang, Yun Yun Tan, and Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
ABSTRACT: A method for synthesis of 3-azabicyclo[3.1.0]hex-2-enes has been
developed by intramolecular cyclopropanation of readily available N-allyl enamine
carboxylates. Two complementary reaction conditions, CuBr-mediated aerobic and
CuBr2-catalyzed-PhIO2-mediated systems effectively induced stepwise cyclopropa-
nation via carbocupration of alkenes. Oxidative cyclopropane ring-opening of 5-
substituted 3-azabicyclo[3.1.0]hex-2-enes was also developed for synthesis of highly
substituted pyridines. In addition, diastereoselective reduction of 3-azabicyclo[3.1.0]hex-2-enes to 3-azabicyclo[3.1.0]hexanes was
achieved using NaBH3CN in the presence of acetic acid.
(Scheme 1a)5 or intramolecular cyclopropanation of alkenes
INTRODUCTION
■
with carboxamides using Ti(II) reagents (Scheme 1b-i),6 these
The 3-azabicyclo[3.1.0]hexane motif is an important azaheter-
ocyclic framework from the medicinal chemistry perspective.
This scaffold is prevalent in biologically active molecules,
Scheme 1. Construction of 3-Azabicyclo[3.1.0]hexane
Scaffolds
showing various potent pharmacological activities such
as bicifadine for treatment of acute and chronic pain,1 indo-
lizomycin as a bioengineered antibiotic,2 boceprevir as a protease
inhibitor for hepatitis C treatment,3 and naturally occurring
anti-tumor alkaloids like (+)-duocarmycin A (Figure 1).4
methods limit the substituent compatibility on the available
3-azabicyclo[3.1.0]hexanes. Robust variants of intramolecular
alkene cyclopropanation have recently been exploited using
nitrogen-tethered 1,5- or 1,6-enynes with transition-metal
catalysts such as Au,7 Pd,8,9 Ru,10 and Rh11 (Scheme 1b-ii).
Figure 1. Selected examples of pharmacologically active 3-
azabicyclo[3.1.0]hexanes.
The chemical synthesis of 3-azabicyclo[3.1.0]hexane scaffolds
has therefore evoked considerable interests, resulting in
development of a variety of strategies to construct them.
Although these motifs have commonly been constructed either
by intermolecular cyclopropanation of 3-pyrroline derivatives
Received: January 13, 2014
Published: April 3, 2014
© 2014 American Chemical Society
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Cyclopropanation with sulfur ylides has also been developed
(Scheme 1b-iii).12 However, these existing strategies require
long routes for the starting material preparation or the need to
use expensive noble transition metals.13 It is therefore of great
significance to develop concise and versatile methodology to
construct the 3-azabicyclo[3.1.0] frameworks from readily
available building blocks with step-, atom-, and cost-economical
fashion.
Scheme 3. Cu-Mediated Cyclopropanation of
N-Allylenamine Carboxylates (this work)
We have recently developed oxidative functionalization of
carbon−carbon unsaturated bonds triggered by Cu-catalyzed
reactions of N-H imines and amidines for synthesis of highly
functionalized azaheterocycles (Scheme 2).14−16
Scheme 2. Cu-Catalyzed Oxidative Functionalization of
C−C Unsaturated Bonds with N-H Imines and Amidines
atmosphere, 3-azabicyclo[3.1.0]hex-2-enes 2a was formed in
67% through intramolecular cyclopropanation (entry 1). The
examples of direct alkene cyclopropanation with nucleophilic
carbons have been limited.12,20 This discovery therefore
inspired us to optimize the reaction conditions. The yields
were improved by addition of nitrogen-ligands (2.0 equiv)
to CuBr·SMe2 (entries 2−4), in which the highest yield of
2a (93%) was obtained using 2,2′-bipyridine (entry 4). A
comparable yield of 2a was obtained with 1.1 equiv of CuBr·
SMe2 and 2,2′-bipyridine (entry 5). Use of molecular oxygen as
an atmosphere was essential as the reaction became sluggish
under an inert atmosphere (entry 6). Other types of copper(I)
such as CuCl could also mediate the reaction, albeit in a slightly
lower yield and longer reaction time (entry 7). Interestingly,
this aerobic cyclopropanation is only amenable for copper(I)
complexes, as CuBr2 failed to provide the desired product
(entry 8). The oxidation state of the Cu species during these
reaction courses is discussed in detail in the Mechanistic
Discussion section.
We next examined the reaction conditions to achieve the
catalytic conversion of this cyclopropanation. The attempts
under an O2 atmosphere gave only unsatisfactory results
(entries 9 and 10), in which the best result was 44% yield of
2a using 20 mol % of CuBr·SMe2 in the presence of 5 equiv
of DABCO (entry 10). We thus turned our attention to use
hypervalent iodine reagents as stoichiometric oxidants to
achieve the catalytic turnover.21 The hypervalent iodine(III)
reagent, PhIO22 was first tested with 20 mol % of CuBr2
(entries 11 and 12). It was found that use of 1.5 equiv of PhIO
produced 2a in 50% yield along with 29% recovery of 1a even
after stirring for 24 h (entry 11). An excess amount of PhIO
(2.5 equiv) was required to complete the reaction, giving 2a in
73% yield (entry 12). It is known that PhIO undergoes dis-
proportionation upon heating or extended storage to give PhI
and iodine(V) species, iodylbenzene (PhIO2).21f We wondered
whether PhIO2 could be the active oxidant rather than PhIO.
Indeed, the reaction with PhIO2 (0.75 equiv) was completed
within 3.5 h to deliver 87% yield of 2a (entry 13).23,24 The
catalytic loading of CuBr2 could also be reduced to 15 mol %
(entry 14), while 10 mol % of CuBr2 lowered the yield of 2a to
65% (entry 15). Other Cu(II) salts such as CuCl2 and
Cu(OAc)2 worked to give 2a in acceptable yields in spite of
slower reaction rate (entries 16 and 17). The reaction with
Cu(OTf)2, on the other hand, resulted in formation of complex
mixtures (entry 18). In this catalytic variant, CuBr·SMe2 could
also be utilized, giving slightly lower yield of 2a (74% yield) in 8
h (entry 19). The reaction with only PhIO2 yielded 13% of 2a
(entry 20),25 and the reaction with 2 equiv of CuBr2 in the
In this context, we have also studied Cu-catalyzed oxidative
transformation of N-unsaturated enamine carboxylates, which
are easily prepared by acid-mediated condensation of the
corresponding primary amines with β-keto esters or by conjugate
addition of the amines to acetylene carboxylates.17 We envisioned
that oxidative functionalization of the pendant C−C unsaturataed
bond installed on the enamine nitrogen could occur through
carbocupration with putative copper-azaenolates.18,19 This article
describes the full account of copper-mediated aerobic and copper-
catalyzed-PhIO2-mediated alkene cyclopropanation of N-allyl
enamine carboxylates for synthesis of 3-azabicyclo[3.1.0]hex-
2-enes with broad evaluation in scope, limitations, and reaction
mechanisms (Scheme 3). Facile oxidative transformations of the
resulting 3-azabicyclo[3.1.0]hex-2-enes to highly substituted
pyridines as well as diastereoselective reduction of them to
3-azabicyclo[3.1.0]hexanes are also presented.
RESULTS AND DISCUSSION
■
Optimization of Reaction Conditions. Our studies began
with copper-mediated aerobic reactions of ethyl 3-allylamino-
3-phenyl acrylate (1a) (Table 1). When 1a was treated with
3.0 equiv of CuBr·SMe2 in DMSO at 60 °C under an O2
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a
degree of chemoselectivity inherent in these present methods.
The ethoxy carbonyl group on R2 could be replaced with a
cyano group, giving 2n in 60−62% yields for the both systems
(entry 13). However, enamine 1o bearing a benzoyl group as
R2 did not work well to afford 2o only in 15% and 45% yields
under the CuBr·SMe2/O2 and the CuBr2/PhIO2 conditions,
respectively (entry 14).
Table 1. Optimization of Reaction Conditions
oxidants
time
[h] yield [%]
b
Next, the effects of the substituents on the alkene tether were
investigated (Table 3). The reactions of both (Z)- and (E)-N-3-
phenylallyl derivatives 1p under the CuBr·SMe2/O2 conditions
afforded nearly 50:50 diastereo-mixtures of 2p and 2p′ (entries 1
and 2). In contrast, the CuBr2/PhIO2 system delivered the
product 2p as the major product (2p:2p′ = 85:15) regardless of
the original stereochemistry of enamine 1p along with the
formation of 4-benzoylpyrrole 3p as a side product. The present
cyclopropanation likely proceeds via the stepwise C−C bond
formation as the stereochemistry of the double bond was not
retained in both of the reactions. However, the structure of the
intermediates involved in the cyclopropanation might be different
under the CuBr·SMe2/O2 and the CuBr2/PhIO2 conditions,
resulting in the dissimilar diastereoselectivity (see Scheme 7 for
more details). The present methods are capable of constructing
the C−C bond between quaternary carbons starting from N-3,3-
disubstituted allyl enamines 1q and 1r, in which the CuBr·SMe2/
O2 conditions performed better (entries 3 and 4). The reaction of
N-3,3-dimethylallyl enamine 1q under the CuBr·SMe2/O2
conditions (entry 3) afforded the corresponding azabicyclo[3.1.0]-
hexene 2q in 36% yield along with the formation of bromomethyl
dihydropyrrole 4q-Br (X = Br) in 13% yield. Using CuCl as a
copper source with 2,2′-bipyridine provided 2q and 4q-Cl (X =
Cl) in 58% and 23% yields, respectively. Using DMAP as an
additive improved the yield of 2q to 63% yield with minimizing
the formation of 4q-Br to less than 5%. Putting a substituent on
the α-position of the enamine nitrogen (for 1s and 1t) rendered
the process diasteroselective in both of the reaction conditions,
affording the corresponding α-2s and α-2t as the major products,
respectively (entries 5 and 6). The present cyclopropanation is
robust to construct highly strained fused azatricyclic cyclopropane
compounds 2u and 2v by the reactions of cyclic N-allyl enamines
1u and 1v, respectively, although 2v could not be accessed under
the CuBr2/PhIO2 conditions (entries 7 and 8). N-Butenyl
enamine carboxylate 1w showed poor reactivity toward the
present cyclopropanation, in which only the CuBr2/PhIO2
conditions could construct the desired azabicyclic cyclopropane
2w albeit in low yield (entry 9).
Mechanistic Discussion. On the basis that the present
cyclopropanation under the CuBr·SMe2/O2 system could only
be mediated by Cu(I) complexes (see Table 1, entries 8),26 we
postulated that Cu(II)-O2 complexes play a vital role to realize
the process.27 On the contrary, only a trace amount of 2a was
observed using 2.0 equiv of CuBr2 without PhIO2 (Table 1,
entry 21), indicating that the CuBr2/PhIO2 system likely
involves a higher oxidation state copper(III) species.
To gain more detailed mechanistic information for the
present cyclopropanation, the reactions of tetrasubstituted
enamine 1x, which is not able to form the cyclopropane ring,
were tested under the present reaction conditions (Scheme 4).
The reaction of 1x under the CuBr·SMe2/O2 system afforded
bromomethyl dihydropyrrole 4x and azabicyclic lactone 5x in
30% and 11% yields, respectively (Scheme 4a). Similarly, the
CuBr2−PhIO2 system delivered 4x and 5x in 7% and 20%
yields, respectively, while another azaheterocycle 6x having
entry Cu salts [equiv]
[equiv]
additive [equiv]
Reactions with a Stoichiometric Amount of Copper Salts
1
2
3
4
5
6
7
8
CuBr·SMe2 (3.0) O2 (1 atm)
CuBr·SMe2 (2.1) O2 (1 atm)
CuBr·SMe2 (2.1) O2 (1 atm)
−
1.5
0.7
1.5
67
c
DABCO (2.0)
50
83
93
89
DMAP (2.0)
CuBr·SMe2 (2.1) O2 (1 atm) 2,2′-bipyridine (2.0) 1.5
CuBr·SMe2 (1.1) O2 (1 atm) 2,2′-bipyridine (1.1)
3
d
c
e
e
CuBr·SMe2 (1.1)
−
2,2′-bipyridine (1.1) 12
10 (75)
c
CuCl (1.1)
O2 (1 atm) 2,2′-bipyridine (1.1) 25
O2 (1 atm) 2,2′-bipyridine (1.1) 48
67
CuBr2 (1.1)
0
Reactions with a Catalytic Amount of Copper Salts
c
9
CuBr·SMe2 (0.2) O2 (1 atm) 2,2′-bipyridine (2.0) 12
17 (40)
f
10 CuBr·SMe2 (0.2) O2 (1 atm)
DABCO (5.0)
2
24
3
44
d
e
11
12
13
14
15
16
17
18
CuBr2 (0.2)
CuBr2 (0.2)
PhIO (1.5)
PhIO (2.5)
MS 4A
50 (29)
73
d
d
d
d
d
d
d
d
MS 4A
CuBr2 (0.2) PhIO2 (0.75)
−
−
−
−
−
−
−
−
−
3.5
5
87
CuBr2 (0.15) PhIO2 (0.75)
88
CuBr2 (0.1)
CuCl2 (0.2)
PhIO2 (0.75)
PhIO2 (0.75)
6
65
c
7.5
20
20
8
72
c
Cu(OAc)2 (0.2) PhIO2 (0.75)
Cu(OTf)2 (0.2) PhIO2 (0.75)
65
c
14
c
19 CuBr·SMe2 (0.2) PhIO2 (0.75)
74
d
20
21
−
PhIO2 (0.75)
24
3
13
0
d
CuBr2 (2.0)
−
a
The reactions were carried out using 0.3 mmol of N-allyl enamine
b
carboxylate 1a in DMSO at 60 °C unless otherwise stated. Isolated
c
d
yields. 1H NMR yields. The reaction was carried out under an Ar or
e
f
N2 atmosphere. Recovery of 1a. 12% of ethyl 4-formyl-2-phenyl-1H-
pyrrole-3-carboxylate was also obtained. DABCO = 1,4-diazabicyclo-
[2.2.2]octane; DMAP = 4-dimethylaminopyridine.
absence of PhIO2 did not give 2a at all (entry 21). These results
suggested that the combination of copper salts and PhIO2 is
indispensable in this catalytic cyclopropanation.
Scope and Limitation. With the optimized reaction
conditions for the stoichiometric CuBr·SMe2/O2 system
(Table 1, entry 5) as well as the catalytic CuBr2/PhIO2 system
(Table 1, entry 13), the scope of this oxidative synthesis of 3-
azabicyclo[3.1.0]hex-2-enes 2 was investigated (Table 2). Both
the CuBr·SMe2/O2 and CuBr2/PhIO2 systems performed
comparably when R1 of the N-allyl enamines 1 was varied.
The reactions could install both electron-donating (MeO,
entries 1 and 2) and electron-withdrawing groups (CF3, entry 3)
on the benzene ring. In addition, a C−Br bond was kept
untouched in the present process (entries 4 and 5). Naphthyl
(entries 6 and 7), benzofuranyl (entry 8), and thienyl (entry 9) as
well as alkyl groups (entries 10−12) could be introduced as R1
under both the CuBr·SMe2/O2 and CuBr2/PhIO2 conditions,
while the Cu(II)/PhIO2 system furnished poor yields of 2l and
2m when isopropyl and butenyl groups were utilized as R1
(entries 12 and 13). Of particular importance is the observation
that N-allyl enamine 1m bearing an additional pendant alkene
on R1 cyclized exclusively with the alkene tethered to the
nitrogen atom, providing 3-azabicyclo[3.1.0]hex-2-enes 2m in
77% and 30% under the CuBr·SMe2/O2 and CuBr2/PhIO2
systems, respectively. The finding highlights the pronounced
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a
Table 2. Scope of the Synthesis of 3-Azabicyclo[3.1.0]hex-2-enes 2: Substituents on the Alkene
a
Unless otherwise stated, the reactions were carried out under either condition A or B. Condition A: 0.5 mmol of N-allyl enamine carboxylate 1 with
1.1 equiv of CuBr·SMe2 and 1.1 equiv of 2,2′-bipyridine in DMSO at 60 °C under O2 atmosphere. Condition B: 0.3 mmol of N-allyl enamine
b
c
carboxylate 1 with 0.2 equiv of CuBr2, 0.75 equiv of PhIO2 in DMSO at 60 °C under N2 atmosphere. Isolated yields. The reaction was run using
1.1 equiv of CuBr·SMe2 and 1.1 equiv of DMAP.
tetrahydro-1H-benzo[f]isoindole skeleton was also isolated in
17% yield (Scheme 4b).
organocopper tether in cis-orientation undergoes cyclization to
deliver 6x either via ionic or radical pathway (Scheme 5d).
Based on these observations, the proposed mechanistic
possibilities of the present cyclopropanation are illustrated in
Schemes 6 and 7, which are categorized according to the
substitution patterns of alkenes of enamines 1. The cyclo-
propanation of terminal alkene (for the reactions of enamines
1a−o, 1s, 1t, and 1w) involves the first C−C-bond-forming
intramolecular carbocupration30 (formation of the imine
C/enamine D mixture) followed by the second C−C bond
formation via a intramolecular SN2-type substitution reaction of
organocopper with enamine moiety D (Scheme 6a). On the
other hand, carbocupration of enamines 1q and 1r bearing the
3,3-disubstituted allylic tether provides the tertiary organo-
copper moieties (E and F), which might not undergo an SN2-
type substitution reaction. Instead, prior elimination of Cun−2
The formation of these azaheterocyles 4x−6x suggested the
presence of organocopper intermediates B/B′ (as a diastereo-
meric mixture), which are formed presumably via carbocupra-
tion of the putative copper-azaenolates A/A′ onto the tethered
alkene (Scheme 5a). As shown in Scheme 5b, the C−Cu bond
of B/B′ is substituted by a present bromide anion to give
bromomethyl dihydropyrrole 4x (ionic path). Alternatively,
bromination via a carbon-radical intermediate generated via
homolytic cleavage of the C−Cu bond is not ruled out (radical
path).28 The intermediate B bearing the ethoxycarbonyl group
at the same side with the organocopper tether undergoes intra-
molecular C−O bond forming ionic cyclization,29 followed by
de-ethylation to afford azabicyclic lactone 5x (Scheme 5c). On
the other hand, diastereomer B′ having the benzyl moiety and
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a
Table 3. Scope of the Synthesis of 3-Azabicyclo[3.1.0]hex-2-enes 2: Substituents on the Allyl Group
a
Unless otherwise stated, the reactions were carried out under either conditions A or B. Condition A: 0.5 mmol of N-allyl enamine carboxylate
1 with 1.1 equiv of CuBr·SMe2 and 1.1 equiv of 2,2′-bipyridine in DMSO at 60 °C under O2 atmosphere. Condition B: 0.3 mmol of N-allyl enamine
b
c
carboxylate 1 with 0.2 equiv of CuBr2, 0.75 equiv of PhIO2 in DMSO at 60 °C under N2 atmosphere. Isolated yields. Ethyl 4-benzoyl-2-phenyl-1H-
d
e
pyrrole-3-carboxylate 3p was formed as a coproduct (see the figure below). 1H NMR yields. CuCl (2.1 equiv) was used instead of CuBr·SMe2.
f
The reaction was run using 1.1 equiv of CuBr·SMe2 and 1.1 equiv of DMAP.
species generates stable tertiary carbocation G,31 which is
readily trapped by the enamine moiety to give 2q and 2r
(Scheme 6b). Subjection of chloromethyl dihydropyrrole 4q-Cl
(Table 3, entry 3) to the CuBr·SMe2/O2 conditions resulted in
formation of cyclopropane 2q only in 13% yield along with a
complex mixture of unidentified products. The reaction of
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Scheme 4. Reactions of Enamine 1x
Scheme 6. Proposed Mechanisms for the Cyclopropanation
Scheme 5. Proposed Mechanisms for the Formation of
Compounds 4x−6x
4q-Cl under the CuCl2/PhIO2 system did not provide
cyclopropane 2q but generates 4-propenylpyrrole 3q in 22%
yield (Scheme 6-c). These results indicate that halomethyl
dihydropyrroles 4 are not likely involved in the second C−C
bond forming step of the cyclopropanation. Nonetheless, the
possibility of the reaction pathway including electrophilic
activation of the alkene with halonium ions is ruled out as the
reactions could be performed in the absence of halide anions
(i.e., the reactions with Cu(OAc)2 in Table 1, entry 17).
In the reactions of 3-phenylallyl enamines (Z)- and (E)-1p,
the reaction conditions interestingly varied the diastereoselec-
tivity of the cyclopropanation, in which the CuBr·SMe2/O2
conditions provided almost 50:50 ratio of 2p and 2p′, whereas
the CuBr2/PhIO2 system rendered the reaction more selective
for the formation of 2p (2p:2p′ = 85:15) (Table 3, entries 1
and 2). The CuBr·SMe2/O2 system generates a diastereomeric
mixture of organocopper(II) intermediates H and H′, which are
likely under equilibrium through homolytic dissociation and
recombination of the C-radical I and Cu(I) species (Scheme 7-a).32
These organocopper(II) intermediates H and H′ might keep
covalent-bond character through the C−Cu bond, resulting in
the formation of them in nearly 50:50 ratio due to the steric
repulsion between the phenyl group with the ethoxy carbonyl
part for H and between the copper moiety ([Cu]) with the
ethyoxy carbonyl part for H′ (see the Newman projections).
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Scheme 7. Proposed Mechanisms for Enamine 1p
Scheme 8. Reactions of 2-Phenylallyl Enamine 1y
only 3-azabicyclo[3.1.0]hex-2-ene 2y but also trisubstituted
pyridine 7y in 43% and 25% yields, respectively, while prolonging
the reaction time to 22 h lowered the mass balance. Similarly, the
reaction of 1y under the CuBr2/PhIO2 system for 6 h provided
both 2y and 7y in 49% and 30% yields, respectively. In contrast,
the longer reaction time (for 22 h) provided pyridine 7y as a single
product in 70% yield. This implied that 3-azabicyclo[3.1.0]hex-2-
ene 2y is oxidatively transformed into pyridine 7y during the
reaction course.34 It is proposed that single-electron oxidation of
2y by the higher valent copper species [Cun] generates cation
radical, that undergoes ring-expansion via C−C bond homolytic
cleavage of the cyclopropane ring followed by oxidative
aromatization to afford 7y.
We next examined the scope and limitation of the direct
oxidative conversion of N-2-phenylallyl enamines 1 to pyridines
7 under the CuBr2−PhIO2 conditions.35 Various 2-phenylallyl
enamines 1 were transformed to the corresponding pyridines 7
Scheme 9. Scope of Oxidative Synthesis of Trisubstituted
Pyridines 7 from 2-Phenylallyl Enamines 1
Presumably, successive intramolecular nucleophilic substitution
of H and H′ produces 2p and 2p′, respectively. On the other
hand, in the CuBr2/PhIO2 system, the higher valent
organocopper(III) intermediate J bearing more ionic C−
Cu(III) bond is likely involved, that is readily converted into
benzylic carbocation species K and K′ by elimination of
copper(I) species (Scheme 7-b). The steric repulsion between
the phenyl group on the tethered carbocation and the
dihydropyrrole ring rendered the carbocation K more stable,
resulting in the selective formation of 2p. The presence of
benzylic carbocation K and K′ could be supported by the
formation of 4-benzoylpyrrole 3p that was generated
presumably by oxygenation of K and K′ with the DMSO
solvent.33 The cyclopropanation reactions under the CuBr·
SMe2/O2 conditions should generate Cu(0) species along with
formation of the products, that might render it difficult to
realize the catalytic process with molecular oxygene (see Table 1,
entries 9 and 10).
a,b
a
Pyridine Formation. The generality of this copper-mediated/
catalyzed synthesis of 3-azabicyclo[3.1.0]hex-2-enes 2 was
further explored using 2-phenylallyl enamine 1y (Scheme 8).
The reaction under the CuBr·SMe2/O2 system for 4 h yielded not
The reactions were carried out using 0.2 mmol of 2-phenylallyl
enamine carboxylate 1 with 0.2 equiv of CuBr2 and 0.75 equiv of
b
PhIO2 in DMSO at 60 °C under a N2 atmosphere. Isolated yields
were reported.
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by stirring the reaction mixture for 22 h (Scheme 9). Enamines
1 bearing naphthyl and thienyl groups as R1 worked smoothly
to give the corresponding pyridines 7z and 7aa in good yields,
while installation of a cyclopropyl group as R1 (for 7ab) and
replacement of an ethoxycarbonyl group to cyano group (for 7ac)
resulted in moderate yields.
This oxidative pyridine synthesis was then investigated using
2-methallyl enamine 1ad that provided exclusively 3-azabicyclo-
[3.1.0]hex-2-ene 2ad under both of the reaction conditions
A and B in shorter reaction time (3.5−5.5 h) (Scheme 10).
26% yields, respectively. Further screening of the reaction conditions
(see the Supporting Information) revealed that successive treatment
of the crude mixture of 3-azabicyclo[3.1.0]hex-2-ene 2ad with
CuBr2 under an O2 atmosphere in DMSO at 60 °C could complete
the conversion to afford pyridine 7ad in 69% yield as two-step yield
from enamine 1ad (condition C).
Diastereoselective CN Reduction. Finally, we investigated
reduction of the imine CN bond of 3-azabicyclo[3.1.0]hex-2-
enes 2 for synthesis of saturated 3-azabicyclo[3.1.0]hexanes 8.36
Assuming that a hydride approaches the CN bond from the
opposite side of the cyclopropane ring, diastereoselective
reduction is anticipated (Scheme 11). As expected, reduction
of 2a with NaBH3CN in the presence of acetic acid provided
3-azabicyclo[3.1.0]hexane 8a in 88% yield as a single stereo-
isomer.37 This stereoselective reduction could be applied to a
range of substrates 2 with different substitutents on R1−R5 to
give the corresponding 3-azabicyclo[3.1.0]hexanes 8 in good to
excellent yields.
Scheme 10. Reactions of 2-Methallyl Enamine 1ad
CONCLUSION
■
In summary, we have successfully established a novel
cyclopropanation protocol for accessing 3-azabicyclo[3.1.0]-
hex-2-enes from readily available N-allyl enamine derivatives.
Two complementary reaction conditions, CuBr-mediated aerobic
and CuBr2-catalyzed-PhIO2-mediated systems, effectively induced
cyclopropanation for a variety of N-allyl enamines. Oxidative
cyclopropane ring-opening of 5-substituted 3-azabicyclo[3.1.0]hex-
2-enes to form highly substituted pyridines was also developed. In
addition, diastereoselective reduction of 3-azabicyclo[3.1.0]hex-2-
enes to 3-azabicyclo[3.1.0]hexanes was achieved using NaBH3CN
in the presence of acetic acid. We anticipate that the present
molecular transformation of N-allyl enamine carboxylates is
capable of offering a new synthetic approach to biologically and
medicinally important azaheterocycles.
Scheme 11. Diastereoselective Reduction of 3-
Azabicyclo[3.1.0]hex-2-enes 2
a b
,
ASSOCIATED CONTENT
* Supporting Information
■
S
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
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by funding from Nanyang
Technological University and Singapore Ministry of Education
(Academic Research Fund Tier 2: MOE2012-T2-1-014). 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. Y.-F.W. thanks Lee
Kuan Yew postdoctoral fellowship (the LKY PDF).
a
The reactions were carried out using 0.1−0.3 mmol of 2 with 3 equiv
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■
b
Isolated yields were recorded.
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