DABCO-catalyzed ring opening of activated cyclopropanes and recyclization leading to γ-lactams with an all-carbon quaternary center

Article abstract of DOI:10.1039/c4cc03392b

A novel and efficient method for the construction of γ-lactams with an all-carbon quaternary center is developed via a DABCO-catalyzed reaction of EWG-activated cyclopropanecarboxamides and electron-deficient alkenes. The process involves sequential ring-opening of activated cyclopropanes, intermolecular Michael addition and intramolecular aza-cyclization. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03392b

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DABCO-catalyzed ring opening of activated
cyclopropanes and recyclization leading to
c-lactams with an all-carbon quaternary center†
Shaoxia Lin,a Ling Li,a Fushun Liang*ab and Qun Liua
Cite this: Chem. Commun., 2014,
50, 10491
Received 6th May 2014,
Accepted 11th July 2014
DOI: 10.1039/c4cc03392b
www.rsc.org/chemcomm
A novel and efficient method for the construction of c-lactams with
an all-carbon quaternary center is developed via DABCO-
a
catalyzed reaction of EWG-activated cyclopropanecarboxamides
and electron-deficient alkenes. The process involves sequential
ring-opening of activated cyclopropanes, intermolecular Michael
addition and intramolecular aza-cyclization.
g-Lactams (pyrrolidin-2-ones) are ubiquitous structural subu-
nits in natural products and small molecules of pharmaceutical
relevance.1 Due to the biological importance and synthetic
utility, a lot of methods for the construction of g-lactams have
Fig. 1 Lewis acid versus Lewis base-catalyzed ring-opening model of
activated cyclopropanes.
been developed.2 Despite the advances, the development of DABCO-catalyzed reaction of EWG-activated cyclopropanecarbox-
novel and efficient methods for the preparation of g-lactams amides 1 and appropriate electrophiles.
with various structural features and substitution patterns,
especially those containing all-carbon quaternary center(s),3 cyclopropanecarboxamide 1a (1 mmol) and acrylonitrile (1.1 equiv.)
remains one of the hottest topics in synthetic chemistry.
as the model substrates under the Lewis base conditions (Table 1).
The initial investigation was performed with 1-acetyl-N-phenyl-
Over the past few decades, Lewis acid catalyzed ring-opening of With DABCO as the Lewis base in DMSO at 60 1C, pleasingly,
donor–acceptor cyclopropanes (which function as the source of g-lactam 2a was formed in 61% yield (Table 1, entry 1). Other
1,3-dipoles) has attracted great interest of organic chemists and solvents such as DMF, THF, DCE, MeNO2, 1,4-dioxane and MeCN
has found a wide range of applications in the construction of were tested (Table 1, entries 2–7) and MeCN was demonstrated to
various carbocycles and heterocycles.4 However, to our knowledge, be the best one, which afford 2a in 93% yield (Table 1, entry 7).
Lewis base-catalyzed ring-opening of activated cyclopropanes has Under otherwise identical conditions, lowering the reaction
been less reported till now (Fig. 1).5 In our previous study on EWG- temperature to 30 1C or cutting down the amount of DABCO to
activated cyclopropanes, we developed an efficient cascade strategy 0.1 equiv. led to decreased yields, even though the reaction time
toward aza/oxa-heterocycle construction, mainly based on the ring- was prolonged to 24 h (Table 1, entries 8 and 9). Other Lewis bases
opening and recyclization of activated cyclopropanes.6 In the were also examined. DMAP, Et3N and DBU proved to be less
continued work, we explore the feasibility of Lewis base-catalyzed effective and Ph3P inert (Table 1, entries 10–13).
ring-opening of activated cyclopropanes, as well as the potential
Having established the optimal conditions for the g-lactam
application (Scheme 1). As a result of this research, g-lactams synthesis (Table 1, entry 7), a series of DABCO-catalyzed reac-
with a quaternary carbon center were efficiently synthesized via a tions of substrates 1 and acrylonitrile were carried out (Table 2).
a Department of Chemistry, Northeast Normal University, Changchun 130024,
China. E-mail: liangfs112@nenu.edu.cn; Fax: +86-431-8509-9759
b Key Laboratory for UV-Emitting Materials and Technology of Ministry of
Education, Northeast Normal University, Changchun 130024, China
† Electronic supplementary information (ESI) available: Experimental details and
characterization of all new compounds and crystal structure data. CCDC 1001190
(2c). For ESI and crystallographic data in CIF or other electronic format see DOI:
Scheme 1 The working proposal.
10.1039/c4cc03392b
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Table 1 Screening of the reaction conditions for the synthesis of 2aa
Fig. 2 ORTEP drawing of 2c.
Entry Catalyst (equiv.) Solvent
T (1C) Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
DABCO (0.2)
DABCO (0.2)
DABCO (0.2)
DABCO (0.2)
DABCO (0.2)
DABCO (0.2)
DABCO (0.2)
DABCO (0.2)
DABCO (0.1)
DMAP (0.2)
NEt3 (0.2)
DMSO
DMF
THF
DCE
MeNO2
60
60
60
60
60
12
12
12
12
12
12
6
24
24
12
12
12
12
61
75
56
13
Trace
Trace
93
35
78
Trace
12
Trace
NR
1,4-Dioxane 60
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
60
30
60
60
60
60
60
9
10
11
12
13
DBU (0.2)
PPh3 (0.2)
Scheme 2 Reactions of N-phenylcyclopropanecarboxamides bearing
different EWGs at the C1-position.
a
Reactions were carried out with 1a (1.0 mmol), acrylonitrile (1.1 equiv.)
b
and a Lewis base (0.1 or 0.2 equiv.) in solvent (2.0 mL). Isolated yield.
1-Cyano-N-phenylcyclopropanecarboxamide (1o) afforded the
desired product 3 in 93% yield in MeCN at 80 1C for 10 h, while
1-(1-(hydroxyimino)ethyl)-N-phenylcyclopropanecarboxamide (1p)
was inefficient, with the substrate recoverable in quantitative
yield.9
We next explored the reaction by expanding the scope of the
external electrophiles. Electron-deficient olefins like acrylates
and vinylsulfone proved to be suitable for this transformation,
affording the corresponding products 4a–c and 5 in excellent
yields (Table 3, entries 1–4). N,N-dimethylacrylamide was less
efficient, giving product 6 in only 35% yield (Table 3, entry 5).
However, substituted olefins such as cinnamonitrile and ethyl
cinnamate appeared to be unreactive under the standard reac-
tion conditions,10 presumably due to the effect of steric hin-
drance. All the above results indicated the efficiency, scope and
limitations of the Lewis base activation protocol.
It was observed that all the reactions of 1a–j bearing varied electron-
donating and electron-withdrawing aryl groups or hetero-aryl
groups could proceed smoothly to afford the corresponding highly
functionalized g-lactams 2 in moderate to excellent yields (Table 2,
entries 1–10). For N-alkyl counterpart 1k (R1 = Bn), an unidentified
mixture was formed (Table 2, entry 11).7 Neither 1-acetylcyclo-
propanecarboxamide (1l, R1
= H) nor 1-benzoyl-N-phenyl-
cyclopropanecarboxamide (1m, R2 = Ph) gave satisfactory results
(Table 2, entries 11 and 12). Substrate 1n containing a methyl group
on the cyclopropyl ring afforded merely trace amounts of desired
product 2n (Table 2, entry 13). The structure of 2c was confirmed by
X-ray single crystal diffraction (Fig. 2).
Reactions of N-phenylcyclopropanecarboxamides bearing
different EWGs at the C1-position were conducted (Scheme 2).8
In order to elucidate the possible mechanism, some control
experiments were conducted (Scheme 3). In the reaction of
substrate 1a and DABCO (0.2 equiv.) in MeCN at 60 1C (no
Table 2 Synthesis of g-lactams 2 with a quaternary carbon centera
external electrophile added), zwitterion
7 was observed
(eqn (1)). When a stoichiometric amount of DABCO was used,
compound 7 was isolated in quantitative yield by simple filtration
Entry
1
R1
R2 R3 Time (h)
2
Yieldb (%)
93
Table 3 The scope of external electrophilesa
1
2
3
4
5
6
7
8
1a
Ph
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
7
12
10
10
12
12
9
12
7
7
2a
1b 4-MeC6H4
1c 4-MeOC6H4
1d 2,4-Me2C6H3
1e
1f
2b 90
2c 89
2d 82
2e
2f
2g
2h 79
2i
2j
2k
2l
4-ClC6H4
2-ClC6H4
2-Cl-5-OMeC6H3 Me
81
65
61
1g
Entry
EWG
Time (h)
Product
Yieldb (%)
1h 2-NO2C6H4
1i
1j
1k Bn
1l
1m Ph
1n Ph
Me
Me
Me
Me
Me
Ph
9
1-Naphthyl
2-Py
87
95
10
11
12
13
14
1
2
3
4
5
CO2Et
6
5
5
6
12
4a
4b
4c
5
95
97
94
98
35
c
12
12
12
—
CO2n-Bu
CO2t-Bu
SO2Ph
H
NR
2m Complex
2n Trace
Me Me 12
CONMe2
6
a
a
Reactions were carried out with 1a (1.0 mmol), acrylonitrile (1.1 equiv.)
Reactions were carried out with 1a (1.0 mmol), electron-deficient
b
and DABCO (0.2 equiv.) in MeCN (2.0 mL) at 60 1C. Isolated yield. olefin (1.1 equiv.) and DABCO (0.2 equiv.) in MeCN (2.0 mL) at 60 1C.
c
b
Unidentified mixture.
Isolated yield.
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activated cyclopropanes. We think that the hydrogen-bonding
in substrate 1 is helpful for the ring-opening to occur.12,13
Secondly, Michael addition between enolate 7 and electron-
deficient alkenes takes place, giving intermediate I with a
quaternary carbon center. Thirdly, an amide anion is generated
via proton transfer. Finally, intramolecular aza-cyclization via
nucleophilic substitution delivers product 2 with the elimina-
tion of DABCO to complete the catalytic cycle.14 Product 9 could
be generated in a similar way.15
In summary, a new and efficient organocatalyzed strategy for
the synthesis of g-lactams with an all-carbon quaternary center
is developed. The process involves DABCO-catalyzed in situ
zwitterionic salt formation, intermolecular Michael addition
and intramolecular aza-cyclization. The organocatalyzed ring-
opening of activated cyclopropanes appears to be intriguing.16
Further work on exploring the scope of 1,3-dipole species
catalyzed by a Lewis base and the cycloaddition reaction in
the construction of various carbo/heterocycles is in progress in
our laboratory.
Scheme 3 Control experiments.
Financial support from the National Natural Science Foun-
dation of China (21172034 and 21372039) is gratefully
acknowledged.
Scheme 4 Further work.
Notes and references
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(eqn (2)). No intramolecular aza-cyclization product of type 8 was
observed.11 It was thus concluded that intermolecular electrophilic
addition takes place prior to the intramolecular aza-cyclization. The
conclusion is also supported by the following reaction, i.e., the
separated zwitterion 7 may react with acrylonitrile (in the absence
of a base) to give the target molecule 2a in 95% yield (eqn (3)).
In further work, we found that, in the absence of external
electron-deficient olefins and elevated temperature, unexpected
g-lactams 9a–c were obtained in 82–91% yields via a formal
bimolecular reaction of 1 (Scheme 4).
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Scheme 5 Proposed mechanism for the formation of 2.
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a stoichiometric amount of DABCO with
N-benzylcyclopropanecarboxamide 1l in MeCN at 100 1C, ring-
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unclear.
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10494 | Chem. Commun., 2014, 50, 10491--10494
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