Phosphine-catalyzed [4+1] annulation of 1,3-(aza)dienes with maleimides: Highly efficient construction of azaspiro[4.4]nonenes

Article abstract of DOI:10.1039/c4cc05624h

Phosphine-catalyzed [4+1] annulation of electron-deficient 1,3-dienes or 1,3-azadienes with maleimides has been successfully developed under very mild conditions, providing a convenient and highly efficient method for constructing 2-azaspiro[4.4]nonenes and 1,7-diazaspiro[4.4]nonenes. This reaction represents the first example of [4+1] cyclization between electron-deficient 4π-conjugated systems and non-allylic phosphorus ylides.

Full text of DOI:10.1039/c4cc05624h

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Phosphine-catalyzed [4+1] annulation of
1,3-(aza)dienes with maleimides: highly efficient
construction of azaspiro[4.4]nonenes†
Cite this: Chem. Commun., 2014,
50, 13506
Received 21st July 2014,
Accepted 12th September 2014
Mei Yang, Tianyi Wang, Shixuan Cao and Zhengjie He*
DOI: 10.1039/c4cc05624h
www.rsc.org/chemcomm
Phosphine-catalyzed [4+1] annulation of electron-deficient 1,3-dienes or with anticonvulsant activity.1b–d The 1,7-diazaspiro[4.4]nonane
1,3-azadienes with maleimides has been successfully developed under framework also features the molecular structures of a group
very mild conditions, providing a convenient and highly efficient method of marine alkaloids amathaspiramides possessing antiviral,
for constructing 2-azaspiro[4.4]nonenes and 1,7-diazaspiro[4.4]nonenes. cytotoxicity, and antimicrobial activities.1f Due to its structural
This reaction represents the first example of [4+1] cyclization between rigidity, the 1,7-diazaspiro[4.4]nonane core has been proven to
electron-deficient 4p-conjugated systems and non-allylic phosphorus be a key structural factor in an array of spirolactams as promising
ylides.
b-turn mimetics.1g–i Given their structural uniqueness and bio-
logical importance, syntheses of the azaspiro[4.4]nonane skeletons
Azaspiro[4.4]nonane cores like 2-azaspiro[4.4]nonane and have therefore attracted considerable interest from chemists.2 In
1,7-diazaspiro[4.4]nonane have been recognized as uniform the reported effective syntheses, the azaspirocyclic structures were
substructures in many biologically active natural and artificial generally constructed through multi-step synthetic strategies.2a–e
compounds (Scheme 1).1 For example, the 2-azaspiro[4.4]nonane Encouragingly, a couple of novel synthetic protocols have also
skeleton as a structural characteristic has been found in indolizine been realized to construct the spirocyclic core and the quaternary
alkaloid asperparaline A1a and a series of spirosuccinimides carbon centre in a one-step operation.2f–i Meanwhile, developing
a new and efficient synthetic strategy for azaspiro[4.4]nonane
skeletons remains highly desirable.
Common ylides of nitrogen, sulfur, and phosphorus can be
considered as masked carbanion nucleophiles with different
leaving groups. The ylide-initiated [4+1] annulation reaction of
electron-deficient 4p-conjugate systems provides a straight-
forward and feasible protocol to construct five-membered
cycles.3 N- and S-ylides initiated [4+1] annulation reactions of
a,b-unsaturated carbonyls, imines, and nitroalkenes have been
well documented by Tang, Xiao and other research groups,4
providing chemo- and stereoselective access to dihydrofurans,
pyrrolines, and isoxazoline N-oxides. Mechanistically, these
reactions are generally proposed to proceed through a Michael
addition-intramolecular substitution mode.3 Contrary to N- and
S-ylides, structurally analogous P-ylides have achieved little
success in similar [4+1] annulation reactions owing to the poor
leaving group ability of the phosphonium moiety.5 Recently,
a series of phosphine-catalyzed [4+1] annulations have been
successfully developed by Zhang, Shi and other groups6 from
Morita–Baylis–Hillman (MBH) derivatives and a,b-unsaturated
ketones, imines, or polar 1,3-dienes, leading to efficient syntheses
of dihydrofurans, pyrrolines, and cyclopentenes. In these reactions,
the in situ generated allylic P-ylides from MBH derivatives and
phosphines presumably effect the [4+1] annulation by a tandem
Scheme 1 Representative examples of biologically active natural and
artificial compounds containing azaspiro[4.4]nonane skeletons.
The State Key Laboratory of Elemento-Organic Chemistry and Department of
Chemistry, Nankai University and Collaborative Innovation Center of Chemical
Science and Engineering (Tianjin), Tianjin 300071, P. R. China.
E-mail: zhengjiehe@nankai.edu.cn
† Electronic supplementary information (ESI) available: General procedures;
characterization data and NMR spectra of all new compounds; ORTEP drawings
of compounds 3a and 5a. CCDC 1013074 and 1012903. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c4cc05624h
13506 | Chem. Commun., 2014, 50, 13506--13509
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sequence of Michael addition-intramolecualr SN20 substitution.6b
By the SN20 substitution mode (also called the addition–elimination
mode), the ring-closure step can circumvent the problem arising
from the poor leaving group ability of the phosphonium moiety.7
However, to the best of our knowledge, the non-allylic P-ylide-
initiated [4+1] annulation of electron-deficient conjugated systems
has not been reported before. Herein, we wish to communicate the
phosphine-catalyzed [4+1] annulation of 1,3-(aza)dienes and
maleimides, which represents the first example of non-allylic
P-ylide-initiated [4+1] cyclization of a 4p-conjugated system. This
annulation reaction also provides a novel and efficient method
to construct azaspiro[4.4]nonane skeletons.
In our recent investigations on tertiary phosphine-mediated
annulation reactions, we found that tuning the leaving group ability
and nucleophilicity of phosphines could significantly change the
chemoselectivity of the reactions.8 Considering the fact that tri-
arylphosphines have a relatively better leaving group ability while
compared with trialkylphosphines,8b we suspected that the non-
allylic P-ylide of triarylphosphine might be able to effect the [4+1]
annulation of an electron-deficient 4p-conjugated system. Keeping
this idea in mind, we started to investigate the model reaction of
4,4-dicyano-2-methylenebut-3-enoates 1a and N-phenyl maleimide
2a (Table 1).9,10 Gratifyingly, under the co-catalysis of PPh3 (20 mol%,
relative to 1a) and benzoic acid (20 mol%), a mixture of 1a (0.2 mmol)
and 2a (0.24 mmol) in CH2Cl2 (2.0 mL) was stirred at rt for 24 h to
give an expected spirocyclic product 3a in 94% isolated yield (entry 1).
A brief survey of the reaction conditions was then conducted
(Table 1). Acetic acid was also a good acid additive (entry 2). Without
the acid additive, the annulation reaction could not occur at all
(entry 3). A screening of the phosphine catalysts unveiled that
relatively electron-deficient triarylphosphines were all good for the
reaction but electron-richer (4-MeOC6H4)3P and alkylphosphines
Table
2
Phosphine-catalyzed [4+1] annulation of 1,3-dienes 1 and
maleimides 2a
Entry R1 in 1
R2 in 2
Time (h) 3, Yieldb (%)
1
2
3
4
5
6
7
8
Ph (1a)
Ph
Ph
Ph
Ph
Ph
4-ClC6H4 (1b)
4-FC6H4 (1c)
4-MeOC6H4 (1d) Ph
4-MeC6H4 (1e)
4-CF3C6H4 (1f)
2-MeC6H4 (1g)
2-MeOC6H4 (1h) Ph
2-BrC6H4 (1i)
3-BrC6H4 (1j)
Ph (2a)
24
36
12
48
48
24
48
48
48
48
48
48
48
48
48
48
48
24
48
3a, 94
3b, 99
3c, 88
3d, 89
3e, 81
3f, 59
3g, 80
3h, 88
3i, 76
3j, 99
3k, 73
3l, 99
3m, 58
3n, 62
3o, 48
3p, 99
3q, 87
3r, 99
3s, 99
4-MeC6H4 (2b)
4-NO2C6H4 (2c)
Bn (2d)
n-Bu (2e)
Boc (2f)
Ph
Ph
9
10
11
12c
13
14d
15
16
17
18
19
Ph
Ph
Ph
Ph
Ph
3-MeOC6H4 (1k) Ph
3-FC6H4 (1l)
3-MeC6H4 (1m)
3,4,5-(MeO)3
C6H2 (1n)
Ph
Ph
Ph
20
21
22
2-Naphthyl (1o)
2-Furyl (1p)
2-Thienyl (1q)
Ph
Ph
Ph
48
24
48
3t, 99
3u, 99
3v, 94
a
Typical conditions: under a N2 atmosphere, a mixture of diene 1
(0.2 mmol), maleimide 2 (0.24 mmol), benzoic acid (0.04 mmol) and
Ph3P (0.04 mmol) in CH2Cl2 (2.0 mL) was stirred at rt for a specified time.
b
c
Isolated yield. Product 3l was obtained as a diastereomeric mixture of
d
dr 2 : 1. Product 3n was obtained as a diastereomeric mixture with dr
3 : 1.
were much less effective (entries 4–9). With Ph3P employed as the catalyst, a couple of common solvents including toluene, THF,
acetonitrile and ethanol were also examined, giving product 3a in
Table 1 A brief survey of the model reaction conditionsa
modest to good yields (entries 10–13).
With the optimized conditions in hand, we then examined the
substrate scope of this [4+1] annulation reaction, and the results
are summarized in Table 2. With dicyano-2-methylenebut-3-enoate
1a used as a representative partner, a series of N-substituted
maleimides 2 were firstly surveyed. Both N-aryl and N-alkyl
maleimides 2 all worked well, giving the corresponding annulation
products 3 in high yields (entries 1–5). N-(tert-Butoxycarbonyl)
maleimide 2f also readily delivered its annulation product in a
moderate yield (entry 6). With N-phenyl maleimide 2a chosen as
one reactant, a series of different aryl-substituted dienes 1 was
proven to be effective, giving the corresponding products 3 in
moderate to excellent yields (Table 2, entries 7–22). Apart from
products 3l and 3n, all of the annulation products 3 were obtained
as single racemates. Products 3l and 3n were isolated as diastereo-
meric mixtures since the steric hindrance of the ortho-substituents
at the benzene rings results in axis chirality in their structures
(entries 12 and 14). Thus, the results in Table 2 indicate that the
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
1
Ph3P
Ph3P
Ph3P
(4-FC6H4)3P
(4-ClC6H4)3P
(4-CF3C6H4)3P
(4-MeOC6H4)3P
MePh2P
n-Bu3P
Ph3P
Ph3P
Ph3P
Ph3P
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
24
24
48
24
24
24
48
48
48
72
72
72
72
94
88
0
2c
3d
4
93
89
87
19
14
Trace
85
52
46
53
5
6
7
8
9
10
11
12
13
CH3CN
Ethanol
a
Typical conditions: under a N2 atmosphere, a mixture of 1a (0.2 mmol), phosphine-catalyzed [4+1] annulation reaction of electron-deficient
2a (0.24 mmol), benzoic acid (0.04 mmol) and a phosphine catalyst
1,3-dienes 1 and maleimides 2 has a wide substrate scope and
accordingly provides a convenient and efficient method to
construct highly functionalized 2-azaspiro[4.4]nonane skeletons.
b
(0.04 mmol) in solvent (2.0 mL) was stirred at rt. Isolated yield based on
c
d
1a. Acetic acid (0.04 mmol) was used instead of benzoic acid. Without
the acid additive.
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Table 3 Phosphine-catalyzed [4+1] annulation of 1,3-azadienes 4 and
maleimides 2a
Entry R1 in 4
R2 in 2
Time (h) 5, Yieldb (%)
1
2
3
4
5
6
7
8
Ph (4a)
Ph
Ph
Ph
Ph
Ph (2a)
4-MeC6H4 (2b)
4-NO2C6H4 (2c) 48
Bn (2d)
n-Bu (2e)
Boc (2f)
48
72
5a, 82
5b, 69
5c, 87
5d, 49
Trace
5e, 32
5f, 76
5g, 45
Scheme 3 A proposed mechanism for formation of 3 and 5.
96
96
48
48
48
Ph
spirocyclic product 3u in 88% yield (Scheme 2, a). However, a
methylated analogous ylide 2ab failed to bring about a similar
product (Scheme 2, b).
Based on the above experimental results and closely related
reports,3,8c a plausible mechanism is depicted in Scheme 3 to
account for the formation of 3 or 5. A phosphorus ylide B is
in situ generated via the nucleophilic attack of phosphine at
4-MeOC6H4 (4b) Ph
4-ClC6H4 (4c) Ph
a
Typical conditions: under a N2 atmosphere, a mixture of azadiene 4
(0.2 mmol), maleimide 2 (0.24 mmol), benzoic acid (0.04 mmol) and
Ph3P (0.04 mmol) in CH2Cl2 (2.0 mL) was stirred at rt for a specified time.
b
Isolated yield.
Structurally similar a,b-unsaturated imines 4 as electron- maleimide 2 followed by benzoic acid-aided proton transfer.8c
deficient 1,3-azadienes were also explored under the standard The ylide B then undergoes a Michael addition to electron-
conditions (Table 3). With phenyl-substituted azadiene 4a used deficient diene 1 or azadiene 4 to generate intermediate C,
as a reactant, a series of N-substituted maleimides 2 were which subsequently cyclizes by an intramolecular SN2 mode to
examined (entries 1–6). Except N-butyl maleimide 2e, N-aryl, furnish spirocyclic product 3 or 5 and regenerate the phosphine
N-benzyl, and N-(tert-butoxycarbonyl) maleimides 2 were good catalyst.
substrates in the [4+1] annulations with 4a, readily affording the
In conclusion, we have successfully developed a novel
corresponding products 5 in modest to good yields. Representa- phosphine-catalyzed [4+1] annulation reaction of electron-deficient
tive aryl-substituted 1,3-azadienes 4b and 4c were also examined 1,3-dienes or 1,3-azadienes with maleimides, which provides a
in the reactions with maleimide 2a, smoothly giving the expected convenient and highly efficient method to construct important
azaspirocyclic products 5 in moderate yields (entries 7 and 8). azaspiro[4.4]nonane skeletons. This reaction also represents the
Therefore, 1,3-azadienes 4 were proven to be effective candidates first example of the [4+1] annulation between electron-deficient
in the phosphine-catalyzed [4+1] annulation reaction with 4p-conjugated systems and non-allylic phosphorus ylides by the
maleimides 2, which provided efficient access to highly functiona- Michael addition-intramolecular substitution mode. Further
lized 1,7-diazaspiro[4.4]nonane skeletons.
expanding its scope and developing its asymmetric version are
The structures of products 3 and 5 were well identified by NMR currently under investigation in our laboratory.
(1H, 13C) and HRMS. Representative compounds 3a (CCDC
Financial support from National Natural Science Foundation of
1013074) and 5a (CCDC 1012903) were further confirmed by X-ray China (Grant no. 21121002; 21272119) is gratefully acknowledged.
crystallographic analyses. For detailed spectroscopic data, see ESI.†
To glean some mechanistic insights into the annulation
reaction, the following experiments were deliberately conducted
Notes and references
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