Phosphine-catalyzed cascade [3 + 2] cyclization-allylic alkylation, [2 + 2 + 1] annulation, and [3 + 2] cyclization reactions between allylic carbonates and enones

Article abstract of DOI:10.1021/ol102738b

The phosphine-catalyzed annulations between Morita-Baylis-Hillman adduct carbonates and enones are reported. Under the catalysis of PBu₃ (20 mol %), cascade [3 + 2] cyclization-allylic alkylation, [2 + 2 + 1] annulation, and [3 + 2] cyclization reactions chemoselectively occur depending on the substituent variation of both the carbonate and enone. These reactions provide efficient syntheses of highly functionalized cyclopentenes and cyclopentanes.

Full text of DOI:10.1021/ol102738b

ORGANIC
LETTERS
2011
Vol. 13, No. 4
580–583
Phosphine-Catalyzed Cascade [3 þ 2]
Cyclization-Allylic Alkylation, [2 þ 2 þ 1]
Annulation, and [3 þ 2] Cyclization
Reactions between Allylic Carbonates and
Enones
Rong Zhou, Jianfang Wang, Haibin Song, and Zhengjie He*
The State Key Laboratory of Elemento-Organic Chemistry and Department of
Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, P.R. China
zhengjiehe@nankai.edu.cn
Received November 12, 2010
ABSTRACT
The phosphine-catalyzed annulations between Morita-Baylis-Hillman adduct carbonates and enones are reported. Under the catalysis of PBu3
(20 mol %), cascade [3 þ 2] cyclization-allylic alkylation, [2 þ 2 þ 1] annulation, and [3 þ 2] cyclization reactions chemoselectively occur
depending on the substituent variation of both the carbonate and enone. These reactions provide efficient syntheses of highly functionalized
cyclopentenes and cyclopentanes.
Over the past decade, nucleophilic phosphine catalysis
has attracted much research effort.1 As a result, a number
of highly efficient synthetic reactions including many new
annulations to form carbocycles and heterocycles have
been developed.2 In those reactions, the most popular
substrates are electron-deficient allenes and alkynoates.
Recently, a new class of so-called modified allylic derivatives
such as halides, acetates, and tert-butyl carbonates, which
could be conveniently prepared from Morita-Baylis-
Hillman adducts,3 has emerged as complementary and
versatile substrates in nucleophilic phosphine catalysis.4
The pioneering and extensive work by Lu and colleagues
has disclosed that the modified allylic derivatives could be
(1) For leading reviews on nucleophilic phosphine catalysis, see: (a)
Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (b) Methot, J. L.;
Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. (c) Marinetti, A.;
Voituriez, A. Synlett 2010, 174. (d) Xu, S.; He, Z. Sci. Sinica Chim.
2010, 40, 856.
(2) For important reviews, see: (a) Ye, L.-W.; Zhou, J.; Tang, Y.
Chem. Soc. Rev. 2008, 37, 1140. (b) Cowen, B. J.; Miller, S. J. Chem. Soc.
Rev. 2009, 38, 3102. For representative examples, see:(c) Zhang, C.; Lu, X.
J. Org. Chem. 1995, 60, 2906. (d) Xu, Z.; Lu, X. Tetrahedron Lett. 1997,
38, 3461. (e) Cowen, B. J.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 10988.
(f) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716.
(g) Tran, Y. S.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 12632. (h) Wurz,
R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234. (i) Xu, S.; Zhou, L.;
Ma, R.; Song, H.; He, Z. Chem.;Eur. J. 2009, 15, 8698. (j) Wang, T.; Ye, S.
Org. Lett. 2010, 12, 4168.
(3) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003,
103, 811.
(4) (a) Du, Y.; Lu, X.; Zhang, C. Angew. Chem., Int. Ed. 2003, 42,
1035. (b) Du, Y.; Feng, J.; Lu, X. Org. Lett. 2005, 7, 1987. (c) Feng, J.; Lu,
X.; Kong, A.; Han, X. Tetrahedron 2007, 63, 6035. (d) Zheng, S.; Lu, X.
Org. Lett. 2008, 10, 4481. (e) Zheng, S.; Lu, X. Tetrahedron Lett. 2009, 50,
4532. (f) Zheng, S.; Lu, X. Org. Lett. 2009, 11, 3978. (g) Ye, L.-W.; Sun,
X.-L.; Wang, Q.-G.; Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 5951.
(h) Chen, Z.; Zhang, J. Chem.;Asian J. 2010, 5, 1542. (i) Xie, P.; Huang, Y.;
Chen, R. Org. Lett. 2010, 12, 3768. (j) Cho, C.-W.; Kong, J.-R.; Krische,
M. J. Org. Lett. 2004, 6, 1337. (k) Cho, C.-W.; Krische, M. J. Angew. Chem.,
Int. Ed. 2004, 43, 6689. (l) Park, H.; Cho, C.-W.; Krische, M. J. J. Org.
Chem. 2006, 71, 7892. (m) Jiang, Y.-Q.; Shi, Y.-L.; Shi, M. J. Am. Chem.
Soc. 2008, 130, 7202.
r
10.1021/ol102738b
Published on Web 01/14/2011
2011 American Chemical Society

readily used as a C3 synthon in a series of intra- and
intermolecular phosphine-catalyzed [3 þ n] annulations
(n = 2, 3, 4, 6).4a-g Very recently, Zhang and Huang
respectively reported that the allylic carbonates underwent
[4 þ 1] annulations asa C1 component.4h,i Apart from their
use in the annulation reactions, the allylic derivatives like
acetates were also proven by Krische4j-l and Shi4m to
be effective allylic alkylating agents under nucleophilic
phosphine catalysis.5 As to their diverse reactivity patterns
and potential applications in organic synthesis, although the
above encouraging results have been achieved, the modified
allylic derivatives remain much less explored, especially by
comparison with electron-poor allenes. Further effort in this
area is still in demand.
As part of our continuous efforts on exploring phosphine-
mediated carbon-carbon bond forming reactions parti-
cularly involving in situ generated phosphorus ylide inter-
mediates,6 the allylic carbonates have also attracted our
attention as a clean and readily available source of in situ
formed allylic phosphorus ylide upon treatment with tertiary
phosphines.6d Although a few phosphine-catalyzed annu-
lations of modified allylic compounds like allylic carbo-
nates with enones were previously reported, the scope of
the enones involved was, however, very limited.4a,b,g,h Con-
sidering the successes in the phosphine-catalyzed [3 þ 2]
cycloadditions of allenoates and enones,7 and the similar-
ities in the reactivity between allenoates and modified
allylic compounds,4a-g we intended to further investigate
the phosphine-mediated reactivity of the modified allylic
compounds with enones. Herein, we wish to report the
results from such investigations.
Since the choice of allylic carbonates as the substrate
could allow the reaction to be run in a clean and homo-
geneous media, we started our study with the allylic carbon-
ate 1a and chalcone 2a (Table 1). To our delight, a new
product 3a was initially isolated from the model reaction of
1a (1.0 mmol) and 2a (1.0 mmol) under the catalysis of
PPh3 (20 mol %), albeit in only 8% yield (Table 1, entry 1).
Structural determination of 3a implied that a three-
component cascade/tandem [3 þ 2] cyclization-allylic
alkylation reaction8 occurred between two molecules of
the carbonate 1a and one molecule of chalcone 2a. This
reaction represents a new reactivity pattern of the allylic
carbonates with enones, while providing a facile protocol to
Table 1. Optimization of Conditions on the Model Reactiona
time
(d)
yield of
3a (%)b
entry
phosphine
solvent
syn/antic
1
PPh3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
THF
5
4
4
3
3
2
2
2
2
4
3
2
2
8
11:1
/
2
P(4-ClPh)3
P(4-CF3Ph)3
Ph2PMe
PhPMe2
PBu3
trace
trace
40
50
64
81
89
66
30
60
24
/
3d
4
/
8:1
10:1
3:1
3:1
9:1
11:1
10:1
4:1
7:1
/
5
6
7
PBu3
8
PBu3
9
PBu3
10
11
12
13
PBu3
toluene
CH3CN
DMF
PBu3
PBu3
PBu3
ethanol
a Typical conditions: under a N2 atmosphere, a mixture of 1a (for
entries 2-6, 1.0 mmol; for entries 7-13, 1.5 mmol), 2a (0.5 mmol), and
phosphine (0.1 mmol) in solvent (2.0 mL) was stirred at rt for a
specified time. b Isolated yield. c Determined by 1H NMR of the
isolated 3a. d A [3 þ 2] cyclization product was isolated in low yield
(see ref 10).
construct highly functionalized cyclopentenes bearing one
all-carbon quaternary stereogenic center.9
Optimization of the conditions on the model reaction
was conducted (Table 1). A couple of common tertiary
phosphines were screened in the model reaction with the
adjusted molar ratio of 1a/2a (Table 1, entries 2-7).
Electron-rich PBu3 gave the best yield of 3a but in lowered
diastereoselectivity (entry 7). With PBu3 as the catalyst,
several common solvents other than CH2Cl2 were further
surveyed (entries 8-13). CHCl3 emerged as the best in
respect to the yield and diastereoselectivity of 3a (entry 8).
The reaction run in protic solvent ethanol was completely
inhibited (entry 13).
The scopes of both allylic carbonates 1 and enones 2
were examined under the optimized conditions (Table 2).
With the allylic carbonate 1a, the cascade/tandem [3 þ 2]
cyclization-allylic alkylations of a wide array of substi-
tuted chalcones 2 readily proceeded, giving the correspond-
ing cyclopentenes 3 in modest to excellent yields and good
to high diastereoselectivity (entries 1-12). The chalcones
bearing electron-donating substituents apparently were
less effective, suffering inferior yields of 3 (entries 2, 7).
2-Furyl-substituted enone 2m and phenyl-substituted die-
none 2n were also suitable substrates in the PBu3-catalyzed
cascade/tandem [3 þ 2] cyclization-allylic alkylation with
1a (Scheme 1).
(5) A series of asymmetric allylic alkylations catalyzed by chiral
amines have been developed by Chen and coworkers with allylic
carbonates. Peng, J.; Huang, X.; Cui, H.-L.; Chen, Y.-C. Org. Lett.
2010, 12, 4260 and references cited therein.
(6) (a) Xu, S.; Zhou, L.; Zeng, S.; Ma, R.; Wang, Z.; He, Z. Org. Lett.
2009, 11, 3498. (b) Xu, S.; Zhou, L.; Ma, R.; Song, H.; He, Z. Org. Lett.
2010, 12, 544. (c) Xu, S.; Zou, W.; Wu, G.; Song, H.; He, Z. Org. Lett. 2010,
12, 3556. (d) Zhou, R.; Wang, C.; Song, H.; He, Z. Org. Lett. 2010, 12,
976.
(7) (a) Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1426.
(b) Cowen, B. J.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 10988.
(c) Voituriez, A.; Panossian, A.; Fleury-Bregeot, N.; Retailleau, P.; Marinetti,
A. J. Am. Chem. Soc. 2008, 130, 14030. (d) Pinto, N.; Neel, M.; Panossian,
A.; Retailleau, P.; Frison, G.; Voituriez, A.; Marinetti, A. Chem.;Eur. J.
2010, 16, 1033.
n-Butyl (1ab) and tert-butyl (1ac) analogues of the allylic
carbonate 1a were also explored (Table 2). With the chosen
(8) For most recent examples of phosphine-catalyzed multicompo-
nent cascade/tandem annulations, see: (a) Liu, H.; Zhang, Q.; Wang, L.;
Tong, X. Chem. Commun. 2010, 46, 312. (b) Cai, L.; Zhang, B.; Wu, G.;
Song, H.; He, Z. Chem. Commun. 2011, 47, 1045.
(9) For reviews on the construction of quaternary carbon center, see:
(a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5363. (b) Bella, M.; Gasperi, T. Synthesis 2009, 1583.
Org. Lett., Vol. 13, No. 4, 2011
581

Table 2. PBu3-Catalyzed Cascade [3 þ 2] Cyclization-Allylic
Alkylation and [2 þ 2 þ 1] Annulation of 1 and 2a
Scheme 1. Cascade [3 þ 2] Cyclization-Allylic Alkylation
between 1a and Other Enones
R2
in Ar1
R3
in Ar2
time
(d)
3 (%)b,
drc
entry
1
4 (%)b
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1ab
H
H (2a)
2
2
1
2
3
2
2
3
3
1
3
3
2
3
4
3
2
2
3
2
3
3
3a, 89, 9:1
3b, 49, 11:1
3c, 80, 10:1
3d, 91, 7:1
3e, 83, 7:1
3f, 76, 10:1
3g, 29, 7:1
3h, 81, 7:1
3i, 68, 7:1
3j, 77, 7:1
3k, 62, 8:1
3l, 77, 7:1
3o, 80, 8:1
3p, 94, 7:1
/
2
4-MeO H (2b)
/
/
/
/
/
/
/
/
/
/
/
/
/
3
4-F
H (2c)
H (2d)
4
4-Cl
5
3-NO2 H (2e)
4-NO2 H (2f)
Table 3. PBu3-Catalyzed [3 þ 2] Cyclization of 1 and 2a
6
7
4-Me
H
4-MeO (2g)
8
4-Cl (2h)
4-Cl (2i)
4-Br (2j)
4-Br (2k)
4-Br (2l)
H (2a)
9
4-CF3
H
10
11
12
13
14
15
16
17
18
19d
20d
21d
22d
4-F
4-Cl
H
time
entry
R1 in 1
Ph (1b)
Ar1 in 2
Ar2 in 2
Ph (2a)
(d)
5 (%)b
1ab 4-Cl
1ac 4-F
1ac 4-Cl
H (2d)
1
2
3
4
5
6
Ph
1
1
1
1
1
2
5b, 68
5c, 89
5d, 84
5e, 59
5f, 65
5g, 78
H (2c)
3q, 70, 20:1 4a, 5
3r, 64, 14:1 4b, 11
3s, 15, 20:1 4c, 74
3t, 12, 14:1 4d, 65
Ph (1b)
Ph (1b)
4-CF3Ph Ph (2q)
4-ClPh 4-NO2Ph (2p)
Ph (2d)
4-CF3Ph Ph (2q)
4-ClPh Ph (2d)
H (2d)
1a
H
4-NO2 (2o)
4-NO2 (2p)
4-NO2 (2o)
4-NO2 (2p)
4-NO2 (2o)
4-NO2 (2p)
4-MeO-Ph (1c) 4-ClPh
1a
4-Cl
H
4-ClPh (1d)
2-furyl (1e)
1ab
/
/
/
/
4e, 60
4f, 62
4g, 71
4h, 56
1ab 4-Cl
1ac
1ac 4-Cl
a Reaction conditions: a mixture of allylic carbonates 1 (0.6 mmol),
chalcones 2 (0.5 mmol), and PBu3 (0.1 mmol) in CHCl3 (2 mL) was
stirred at rt. b Isolated yield based on 2.
H
a For entries 1-16, the molar ratio of 1/2 was 3:1; for entries 17-22,
the molar ratio of 1/2 was 1:1; for more experimental detail, see
Supporting Information. b Isolated yield based on 2. c Referring to
syn-/anti-3, determined by 1H NMR of isolated 3. d Other unidentified
stereoisomers of 4 were isolated in 3-10% yields.
reoptimized conditions (Table 3). It was found that, under
the catalysis of PBu3 (20 mol %), the aryl-substituted
allylic carbonates 1 readily gave the [3 þ 2] cyclization
products 5 as a single diastereomer in satisfactory yields
(entries 1-6). This result definitely broadens the substrate
scope for the phosphine-catalyzed [3 þ 2] cyclization
reactions between the allylic derivatives and enones.4a,b,g,h
It also provides an efficient synthesis for differently sub-
stituted cyclopentenes which could not be accessed by the
phosphine-catalyzed [3 þ 2] cycloaddition of allenoates
and enones.7 However, an alkyl such as methyl and
n-propyl-substituted allylic carbonates 1 (R1 = Me, n-Pr)
were not suitable substrates; under the same conditions,
their reactions with the chalcone 2a all resulted in a complex
mixture.
chalcones (2a, 2c, or 2d) employed, the allylic carbonates
1ab (R=n-Bu) and 1ac (R=t-Bu) readily gave the cor-
responding cyclopentenes 3o-r in good yields and stereo-
selectivity (entries 13-16). In cases of 1ac, however, a
minor product 4a or 4b was isolated in low yield as a single
diastereomer (entries 15, 16). 4a and 4b were identified as
the [2 þ 2 þ 1] annulation products which were generated
from two molecules of the chalcone 2 and one molecule of
the allylic carbonate 1ac. Further survey unveiled that,
under accordingly optimized conditions (1/2 molar ratio
1:1; 20 mol % of PBu3 relative to 2), the electron-deficient
chalcones (2o, 2p) bearing a 4-nitrophenyl at the car-
bonyl all gave the [2 þ 2 þ 1] annulation products 4 as the
major in medium yields in the reactions with the allylic
carbonates 1a, 1ab, or 1ac (entries 17-22). Thus, this
PBu3-catalyzed [2 þ 2 þ1] annulation reaction between
allylic carbonates 1 and electron-poor chalcones 2 repre-
sents a facile synthesis for highly functionalized cyclo-
pentanes 4.
The structures of compounds 3, 4, and 5 were identified
1
by H, 13C NMR and HRMS-ESI measurements. Re-
presentative compounds were further confirmed by a
combination of HMBC, HMQC, NOESY, and X-ray
crystallographic analyses (for detail, see Supporting Infor-
mation).
To better understand the PBu3-catalyzed annulations
in this study, the following experiments were deliberately
conducted (Scheme 2). The isolated [3 þ 2] cyclization
product 5a from the allylic carbonate 1a and chalcone
The substituted allylic carbonates 1 were further tested
in the reactions with representative chalcones 2 under the
582
Org. Lett., Vol. 13, No. 4, 2011

Scheme 2. Experiments for Mechanistic Investigations
Scheme 3. Proposed Mechanism for Formation of 3, 4, and 5
2a10 was treated with1aunder the same conditions asthose
shown in Table 2, and the allylic alkylation product 3a was
readily collected in 69% yield and a 9:1 syn/anti ratio. This
result implies that the cyclopentenes 3 from the allylic
carbonates 1 and enones 2 are most likely generated in a
[3 þ 2] cyclization-allylic alkylation sequence. To evaluate
the competition relationship between the formation of 3
and 4 in the PBu3-catalyzed reaction of the allylic carbo-
nates 1and enones 2, the reactions of 1a and 2o with different
1a/2o ratios were run in CDCl3 and monitored by 1H NMR
(Scheme 2). Results indicated that the ratio between the
corresponding products 3s and 4c nearly remained constant
in the course of the monitored processes. This fact implies
that, under the given conditions, the ratio between 3 and 4
solely depends on the reactivity of the substrates 1 and 2.
On the basis of the experimental results in this work, a
proposed mechanism to account for the formation of 3, 4,
and 5 is depicted in Scheme 3. Initially, upon treatment
with PBu3, the allylic carbonate 1 gives the allylic phos-
phorus ylide intermediate 6 via an addition-elimination-
deprotonation process.11 Subsequent γ-addition of the
ylide 6 to the enone 2 generates the enolate 7. When R1 is
an aryl group in 7, the enolate 7 is prone to a ring-closure
via an intramolecular Michael addition, followed by an
elimination of PBu3 to produce the [3 þ 2] cyclization
product 5. On the other hand, when R1 is hydrogen in 7,
consequently the intramolecular ring-closure of 7to generate
the intermediate 9 (path A) will compete with the Michael
addition of 7 to the enone 2 leading to the formation of
the intermediate 11 (path B). When the enone 2 is
relatively less electron-deficient, the intermediate 9 is pre-
dominantly formed. 9 then undertakes a direct addition-
elimination (an SN20 process)12 with the carbonate 1,
followed by the release of the catalyst PBu3 under the aid
of the in situ generated tert-butoxide anion to accomplish
the formation of the cascade [3 þ 2] cyclization-allylic
alkylation product 3.13 When the enone 2 is more elec-
tron-deficient, particularly attached with a 4-nitrophenyl
group at its carbonyl, the conversion of 7 into 11 via path
B is favored. The intermediate 11 subsequently under-
goes a double-bond migration, followed by an intramo-
lecular Michael addition and elimination of PBu3 to
furnish the cascade [2 þ 2 þ 1] annulation product 4
(Scheme 3).
In conclusion, the PBu3-catalyzed cascade [3 þ 2]
cyclization-allylic alkylation, [2 þ 2 þ 1] annula-
tion, and [3 þ 2] cyclization reactions between allylic
carbonates and enones have been demonstrated, which
provide efficient accesses to highly functionalized cyclo-
pentenes and cyclopentanes. Together with the previous
reports,4a,b,g,h this work offers a clear profile about the
phosphine-mediated diverse reactivity of the modified
allylic derivatives with a broad array of enones. Future
efforts in our laboratory will be directed toward further
expanding the scope and developing asymmetric ver-
sions of these annulations.
Acknowledgment. Financial support from National Nat-
ural Science Foundation of China (Grant Nos. 20872063,
21072100) is gratefully acknowledged.
Supporting Information Available. Experimental details;
characterization data; 1H and 13C NMR spectra for 3, 4,
and 5; NOESY, HMBC, and HMQC spectra for repre-
sentative compounds; X-ray crystallographic data (CIF files)
and ORTEP drawings for 3r and 4c. This material is available
free of charge via the Internet at http://pubs.acs.org.
(10) A [3 þ 2] cycloaddition product 5a was obtained in 6% yield in
the P(4-CF3Ph)3-catalyzed model reaction (Table 1, entry 3).
(13) Although a stepwise synthesis of 3a was realized from the [3 þ 2]
addition product 5a and 1a (Scheme 2), it is believed that the stepwise
synthesis of 3a probably proceeds via the same intermediate 9 (Scheme 3)
which can be generated from the nucleophilic attack of PBu3 to 5a.
Hence, the formation of 3 is most likely via a cascade sequence, although
a tandem one (see Supporting Information) could not be completely
ruled out. For the definition of a cascade/tandem reaction, see:
Chapman, C. J.; Frost, C. G. Synthesis 2007, 1.
(11) Reference 6d and references cited therein.
(12) Ramachandran, P. V; Madhi, S.; Bland-Berry, L.; Reddy,
M. V. R.; O’Donnell, M. J. J. Am. Chem. Soc. 2005, 127, 13450 and
references cited therein.
Org. Lett., Vol. 13, No. 4, 2011
583