Copper-mediated aerobic synthesis of 3-azabicyclo[3.1.0]hex-2-enes and 4-carbonylpyrroles from N-allyl/propargyl enamine carboxylates

Article abstract of DOI:10.1021/ja206580j

Synthetic methods for 3-azabicyclo[3.1.0]hex-2-enes and 4-carbonylpyrroles have been developed that use copper-mediated/catalyzed reactions of N-allyl/propargyl enamine carboxylates under an O₂ atmosphere and involve intramolecular cyclopropanation and carbooxygenation, respectively. These methodologies take advantage of orthogonal modes of chemical reactivity of readily available N-allyl/propargyl enamine carboxylates; the complementary pathways can be accessed by slight modification of the reaction conditions.

Full text of DOI:10.1021/ja206580j

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pubs.acs.org/JACS
Copper-Mediated Aerobic Synthesis of 3-Azabicyclo[3.1.0]hex-2-enes
and 4-Carbonylpyrroles from N-Allyl/Propargyl Enamine Carboxylates
Kah Kah Toh,† Yi-Feng Wang,† Eileen Pei Jian Ng, and Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S Supporting Information
b
Scheme 1. Synthesis of 3-Azabicyclo[3.1.0]hex-2-enes and
4-Formylpyrroles from N-Allyl Enamine Carboxylates
ABSTRACT: Synthetic methods for 3-azabicyclo[3.1.0]
hex-2-enes and 4-carbonylpyrroles have been developed
that use copper-mediated/catalyzed reactions of N-allyl/
propargyl enamine carboxylates under an O2 atmosphere
and involve intramolecular cyclopropanation and carboox-
ygenation, respectively. These methodologies take advan-
tage of orthogonal modes of chemical reactivity of readily
available N-allyl/propargyl enamine carboxylates; the com-
plementary pathways can be accessed by slight modification
of the reaction conditions.
Table 1. Optimization of the Reaction Conditionsa
itrogen-containing heterocycles (azaheterocycles) are an
N
iconic component of numerous natural products, potent
pharmaceutical drugs, and synthons for material-based applica-
tions. Although diverse approaches to azaheterocycle synthesis
have been developed,1 there remains a demand for versatile
methodologies to construct azaheterocycles with selective con-
trol of substitution patterns from readily accessible building
blocks. Herein we report a copper-mediated/catalyzed aerobic
synthesis of 3-azabicyclo[3.1.0]hex-2-enes and 4-carbonylpyr-
roles from readily available N-allyl/propargyl enamine carbox-
ylates through cyclopropanation and carbooxygenation, respec-
tively. The different modes of reactivity may be accessed by slight
modification of the reaction conditions (see Scheme 1 for examples
using an N-allyl enamine carboxylate).
% yieldb,c
Cu salt
(equiv)
additive
(equiv)
time
(h)
entry
2a
67
3a
1
2
3
4
5
6
CuBr SMe2 (3)
ꢀ
1.5
0
0
0
0
0
0
0
0
0
0
3
CuBr SMe2 (2.1) DABCO (2 0)
0.7 (50)
3
CuBr SMe2 (2.1) DMAP (2 0)
1.5
83
88
93
89
3
CuBr SMe2 (2.1) 1,10-phenanthroline (2.1) 1.5
3
CuBr SMe2 (2.1) 2,20-bipyridine (2.0)
1.5
3
CuBr SMe2 (1.1) 2,20-bipyridine (1.1)
3
3
7d CuBr SMe2 (1.1) 2,20-bipyridine (1.1)
12 (10)e
During the course of our research program on copper-
catalyzed aerobic oxygenation/oxidation reactions,2 we became
interested in the potential chemical reactivity of N-alkenyl/
alkynyl enamine carboxylates, which are easily prepared by
acid-mediated condensation of the corresponding amines with
β-keto esters or by conjugate addition of the amines to acetylene
carboxylates.3 Aerobic oxidative functionalization of the pendant
unsaturated bonds could be envisioned to occur through the
formation of a putative copperꢀazaenolate species.4
3
8
CuCl (1.1)
2,20-bipyridine (1.1)
2,20-bipyridine (1.1)
25 (67)
9
CuBr2 (1.1)
10 Cu(OAc)2 (1.1) 2,20-bipyridine (1.1)
12
12
3
0
0
11 CuBr SMe2 (0.5) 2,20-bipyridine (0.5)
(61) (4)
3
12 CuBr SMe2 (0.2) 2,20-bipyridine (2.0)
48 (17)f (3)
3
13 CuBr SMe2 (0.2) DMAP (3.0)
7
(34) (6)
3
14 CuBr SMe2 (0.2) DABCO (5.0)
2
44 (12)
3
a All of the reactions were carried out using 0.5 mmol of N-allyl enamine
carboxylate 1a in DMSO at 60 °C under an O2 atmosphere. b Isolated
yields. c 1H NMR yields are shown in parentheses. d The reaction was
carried out under an Ar atmopshere. e 1a was recovered in 75% yield. f 1a
was recovered in 40% yield.
Our investigation commenced with copper-mediated aerobic
reactions of ethyl 3-allylamino-3-phenylacrylate (1a) (Table 1).
To our surprise, when 1a was treated with 3 equiv of CuBr SMe2
3
in DMSO at 60 °C under an O2 atmosphere, an intramolecular
cyclopropanation product, ethyl 2-phenyl-3-azabicyclo[3.1.0]
hex-2-ene-1-carboxylate (2a) was isolated in 67% yield (entry 1).
While the 3-azabicyclo[3.1.0] scaffold is found in the basic core of
several biologically active natural products5 and drug candidates,6
synthetic methods to construct this framework have been
limited.7ꢀ9 The unprecedented formation of 3-azabicyclo[3.1.0]
hex-2-ene 2a via a mechanistically intriguing cyclopropanation
reaction10 drove us to optimize the reaction conditions further.
The yield of product 2a was improved by the addition of amines
Received: July 15, 2011
Published: August 08, 2011
r
2011 American Chemical Society
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|

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Chart 1. Scope of the Synthesis of 3-Azabicyclo[3.1.0]
hex-2-enes: Substituents on the Alkenea,b
Table 2. Scope of the Synthesis of 3-Azabicyclo[3.1.0]
hex-2-enes: Substituents on the Allyl Groupa
aAll of the reactions were carried out using 0.5 mmol of N-allyl enamine
carboxylate 1 with 1.1 equiv of CuBr SMe2 and 1.1 equiv of 2,20-
3
bipyridine in DMSO at 60 °C under an O2 atmosphere for 2ꢀ3.5 h.
bIsolated yields are reported. cThe reaction was run using 1.1 equiv of
CuBr SMe2 and 1.1 equiv of DMAP.
3
(2 equiv) to CuBr SMe2 (2.1 equiv) (entries 2ꢀ5); these
3
additives may work as ligands for copper salts. The highest yield
of 2a was achieved using 2,20-bipyridine (93% yield; entry 5).
Utilization of 1.1 equiv of CuBr SMe2 with 1.1 equiv of 2,20-
3
bipyridine resulted in comparable yield of 2a (entry 6). Under an
Ar atmosphere, the reaction was sluggish and provided 2a in 10%
yield along with 75% yield recovery of 1a after 12 h (entry 7).
Although CuCl exhibited selective formation of 2a (entry 8),
Cu(II) complexes such as CuBr2 and Cu(OAc)2 failed to provide
any 2a (entries 9 and 10).11 Attempts to render this process
catalytic gave unsatisfactory results (entries 11ꢀ14). Under
these conditions, the highest yield of 2a (44%) was obtained
a All of the reactions were carried out using 0.5 mmol of N-allyl enamine
carboxylate 1 with 1.1 equiv of CuBr SMe2 and 1.1 equiv of 2,20-
3
bipyridine in DMSO at 60 °C under an O2 atmosphere for 1.5ꢀ4 h.
b Isolated yields are reported. c 1H NMR yield. d The reaction was run
using 2.1 equiv of CuCl and 1.1 equiv of 2,20-bipyridine. e The reaction
using 20 mol % CuBr SMe2 with 5 equiv of DABCO (entry 14).
3
In these cases, 4-formylpyrrole 3a was formed as a minor product
was run using 1.1 equiv of CuBr SMe2 and 1.1 equiv of DMAP.
via carbooxygenation of the alkene.
3
Using the CuBr SMe2ꢀ2,20-bipyridine system (Table 1, en-
3
try 6), we examined the generality of the synthesis of substituted
3-azabicyclo[3.1.0]hex-2-enes 2. Varying the substituent R1 of
N-allyl enamines 1 (Chart 1) showed that benzene rings bearing
either an electron-donating group (MeO in 2b and 2c) or an
electron-withdrawing group (CF3 in 2f) were tolerated and that
the CꢀBr bond remained intact when a bromine substituent (2d
and 2e) was introduced. 3-Azabicyclo[3.1.0]hexenes 1 bearing
naphthyl (2g and 2h), thienyl (2i), and benzofuranyl (2j) groups
as well as alkyl groups (2kꢀm) were all formed in good yields.
Interestingly, the reaction of N-allyl enamine 1m bearing an
additional pendant alkene as R1 revealed that the cyclization
reaction exclusively selects the alkene tethered to the nitrogen
atom, furnishing 3-azabicyclo[3.1.0]hex-2-ene 2m in 77% yield.
Next, the effect of the substituent on the allyl moiety in
the synthesis of 3-azabicyclo[3.1.0]hexenes 2 was examined
(Table 2). The reactions of both (Z)- and (E)-N-3-phenylallyl
derivatives 1n provided nearly 1:1 mixtures of 2n12 and 2n0 in
good combined yields (entry 1), suggesting that the present
cyclopropanation proceeds in a stepwise manner. The reaction of
N-3,3-dimethylallyl enamine 1o under the standard reaction
conditions afforded the corresponding azabicyclo[3.1.0]hexene
2o in 36% yield along with bromomethyl dihydropyrrole 4o-Br
(X = Br) in 13% yield. Using CuCl as the copper source with 2,20-
bipyridine provided 2o and 4o-Cl (X = Cl) in 58 and 23% yield,
respectively. Using DMAP as the additive improved the yield of
Scheme 2. Proposed Reaction Pathway for the Formation of
3-Azabicyclo[3.1.0]hexenes
2o to 63% yield and suppressed the formation of 4o-Br to <5%
(entry 2). Subjecting chloromethyl dihydropyrrole 4o-Cl to the
standard reaction conditions resulted in a sluggish reaction that
generated a complex mixture of products (see the Supporting
Information). This indicates that halomethyl dihydropyrroles 4o
likely are not involved in the second CꢀC bond-forming step of
the cyclopropanation. In the case of 2-phenylallyl enamine 1p,
3-azabicyclo[3.1.0]hexene 2p and trisubstituted pyridine 5p were
formed in 43 and 25% yield, respectively (entry 3). Diastereoselective
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Scheme 3. Selective Formation of 4-Formylpyrroles
Scheme 5. Synthesis of 4-Benzoylpyrroles
Scheme 4. Proposed Reaction Pathway for the Formation
4-Formylpyrroles
possible reaction pathway for the 4-formylpyrrole formation. After
formation of organocopper peroxide intermediate C (see Scheme 2
for details), subsequent isomerization gives peroxide E. Elimination
of [CunꢀOH] then affords dihydropyrrole F bearing the formyl
group.2,16 Further oxidation establishes aromatic pyrrole 3a. Inter-
estingly, the reaction of N-3,3-dimethylallyl enamine 1o provided
ethyl 2-phenylpyrrole-3-carboxylate (3o) in 24% yield via cleavage
of the particular CꢀC bond between the carbons marked in blue
and green. This result suggests the presence of a peroxide inter-
mediate such as 1o-E, which undergoes fragmentation to give 3o
along with elimination of acetone and [Cunꢀ1ꢀOH].
This carbonylative pyrrole formation, however, could not be
applied to the synthesis of 4-benzoylpyrrole 3n from N-3-phenylallyl
enamine (E)-1n under the present conditions, producing instead a
complex mixture of products (eq 1 in Scheme 5). It was found that
the use of N-3-phenylpropargyl enamines 1t in place of N-allyl
enamines overcame this drawback (eq 2 in Scheme 5). Treatment of
1t with 20 mol % CuCl and 2 equiv of DABCO in DMSO at 80 °C
under an O2 atmosphere gave 4-benzoylpyrrole 3t (the same as
pyrrole 3n) in 60% yield.17,18 The reactions of several N-propargyl
enamines 1uꢀy afforded the corresponding 3-benzoylpyrroles
3uꢀy in good to moderate yields.
cyclization was observed from 1-phenylallyl enamine 1q, affording
R- and β-phenyl 2q12 in 77 and 5% yield, respectively (entry 4). The
further potential of this method was probed by the reactions of cyclic
N-allyl enamines 1r and 1s, which delivered highly strained fused
tricyclic compounds (entries 5 and 6).
On the basis of these results, a mechanistic proposal is outlined
in Scheme 2. In this senario, CuIBr reacts first with molecular
oxygen to form a CuII peroxo species in either monomeric or
dimeric form.13 The reaction of N-allyl enamine 1a with the
resulting CuII peroxo species forms copper azaenolates (A and B),
which may then undergo intramolecular carbocupration of the
tethered alkene moiety to generate organocopper intermediate
C. Presumably, formation of metallacyclobutane D followed by a
CꢀC bond-forming reductive elimination14 would complete the
cyclopropanation to deliver 3-azabicyclo[3.1.0]hexene 2a. This
process would allow the construction of sterically congested and
highly strained molecules (e.g., 2o, 2r, and 2s).
In summary, intriguing chemical reactivities of N-allyl/pro-
pargyl enamine carboxylates have been exploited to synthesize
3-azabicyclo[3.1.0]hex-2-enes and 4-carbonylpyrroles under Cu-
mediated/catalyzed aerobic oxidation conditions. Slight modifi-
cation of the reaction conditions allowed for a complete reversal
of product selectivity. Further investigation of the scope, detailed
mechanisms, and synthetic applications of the present processes
to other types of molecules is currently underway.
Futher exploration into reaction optimization revealed that
4-formylpyrroles 3 could be generated selectively over 3-azabicyclo
[3.1.0]hex-2-enes 2 simply by adding K2CO3 (Scheme 3). In this
case, ethyl 4-formyl-2-phenylpyrrole-3-carboxylate (3a)12 was
formed as a single product from N-allyl enamine 1a with both
Cu(I) and Cu(II) complexes.15 The best result (56% yield) was
obtained using Cu(OAc)2 (20 mol %) with 50 mol % DABCO
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, char-
b
acterization of all new compounds, complete ref 6a, NMR spectra,
and crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
and 2 equiv of K2CO3. Conversely, using CuBr SMe2 (20 mol %)
3
’ AUTHOR INFORMATION
with 20 mol % DABCO and 2 equiv of K2CO3 lowered the yield
of 3a to 41%. Several 2-aryl-4-formylpyrroles could be synthe-
sized in yields of 52ꢀ56%, while the yield of 2-cyclopropyl-4-
formylpyrrole 3l was moderate (31%).
Corresponding Author
shunsuke@ntu.edu.sg
Although the role of K2CO3 in influencing the product
selectivity remains uncertain, we propose in Scheme 4 one
Author Contributions
†These authors contributed equally.
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’ ACKNOWLEDGMENT
H.; Li, H. Angew. Chem., Int. Ed. 2009, 48, 1417. (b) Villalobos, J. M.; Srogl,
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This work was supported by funding from Nanyang Techno-
logical University and the Singapore Ministry of Education
(Academic Research Fund Tier 2: MOE2010-T2-1-009). We
thank Dr. Yongxin Li (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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