Multistep one-pot wittig/nazarov reaction for construction of cyclopentenone with diazo compounds and acid chlorides

Article abstract of DOI:10.1021/ol901086f

A facile multistep one-pot synthesis of single or fused cyclopentenones has been developed. The sequence involves a transition metalcatalyzed ylide formation/Wittig Olefination/Nazarov Cyclization.

Full text of DOI:10.1021/ol901086f

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3048-3051
Multistep One-Pot Wittig/Nazarov Reaction
for Construction of Cyclopentenone with
Diazo Compounds and Acid Chlorides
Peng Cao,† Xiu-Li Sun,† Ben-Hu Zhu,‡ Qi Shen,‡ Zuowei Xie,§ and Yong Tang*,†
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China, School of Chemistry
and Chemical Engineering, Suzhou UniVersity, Suzhou 215123, China, and Department of
Chemistry, The Chinese UniVersity of Hong Kong, Shatin, New Territories, Hong Kong, China
tangy@mail.sioc.ac cn
Received May 18, 2009
ABSTRACT
A facile multistep one-pot synthesis of single or fused cyclopentenones has been developed. The sequence involves a transition metal-
catalyzed ylide formation/Wittig Olefination/Nazarov Cyclization.
The design and implementation of new economically sus-
tainable synthetic processes is one of the major challenges
in modern organic synthesis. The application of cascade or
domino1 and tandem2 reactions in a “one-pot” manner offers a
straightforward method for the construction of new bonds
simultaneously or in a stepwise manner without the isolation
of the intermediates, making the whole procedure economically
sustainable and environmentally conscientious. Nowadays,
multistep one-pot reactions have emerged as valuable tools in
organic synthesis for reducing operative steps, simplifying
purification procedures and enhancing synthetic efficiency,
† Chinese Academy of Sciences.
‡ Suzhou University.
(2) (a) Ho, T.-L. Tandem Organic Reactions; John Wiley & Sons, New
York, 1992. For recent reviews on tandem reactions, see: . (b) Tejedor, D.;
Gonzalez-Cruz, D.; Santos-Exposito, A.; Marrero-Tellado, J. J.; de Armas,
P.; Garcia-Tellado, F. Chem.sEur. J. 2005, 11, 3502. (c) Wasilke, J.-C.;
Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. ReV. 2005, 105, 1001. (d)
Guo, H.; Ma, J. Angew. Chem. 2006, 118, 362; Angew. Chem., Int. Ed.
2006, 45, 354. (e) Pellissier, H. Tetrahedron 2006, 62, 1619. (f) Pellissier,
H. Tetrahedron 2006, 62, 2143. (g) Nicolaou, K. C.; Edmonds, D. J.; Bulger,
P. G. Angew. Chem. 2006, 118, 7292; Angew. Chem., Int. Ed. 2006, 45,
7134. (h) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1. (i) Hussain, M. M.;
Patrick, J. W. Acc. Chem. Res. 2008, 41, 883. (j) Li, Z.; Chad, B.; He, C.
Chem. ReV. 2008, 108, 3239.
§ The Chinese University of Hong Kong.
(1) For selected reviews: (a) Tietze, L. F. Chem. ReV. 1996, 96, 115.
(b) Ikeda, S.-I. Acc. Chem. Res. 2000, 33, 511. (c) Pellissier, H. Tetrahedron
2006, 62, 2143. (d) Miyabe, H.; Takemoto, Y. Chem.sEur. J. 2007, 13,
7280. (e) Enders, D.; Grondal, C.; Matthias, H. R. M. Angew. Chem. 2007,
119, 1590; Angew. Chem., Int. Ed. 2007, 46, 1570. (f) Chapman, C. J.;
Frost, C. G. Synthesis 2007, 1. (g) Evano, G.; Blanchard, N.; Toumi, M.
Chem. ReV. 2008, 108, 3054. (h) de Meijere, A.; von Zezschwitz, P.; Bra¨se,
S. Acc. Chem. Res. 2005, 38, 413. (i) Yu, X.; Wang, W. Org. Biomol. Chem.
2008, 6, 2037. (j) Crone, B.; Kirsch, S. F. Chem.sEur. J. 2008, 14, 3514.
(k) Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516.
10.1021/ol901086f CCC: $40.75
Published on Web 06/12/2009
 2009 American Chemical Society

which saves solvents and resources. However, it is difficult to
efficiently and chemoselectively control one-pot, multistep
reactions, due to the mutual interference among various
components. Herein, we report a successful example of mul-
tistep one-pot synthesis of ꢀ-methylenecyclopentenones through
the Wittig/Nazarov reactions using unsaturated diazocarbonyl
compounds and acyl chloride as the precursors of vinyl allenes.
As our ongoing research project on ylide chemistry,3 we
recently developed a novel efficient method of allene
synthesis via transition metal-catalyzed reaction of diazo-
carbonyl compounds with phosphines and ketenes4 in which
a variety of di- and trisubstituted allenes can be obtained by
olefination of ketenes with EDA in the presence of Ph3P and
tetra(p-chlorophenyl)porphyrin iron chloride (Fe(TCP)Cl).
Allenes, owing to their unique chemical properties, are
demonstrated as important synthetic building blocks in
various reactions such as cycloadditions, cycloisomerizations,
cross-coupling reactions and the Nazarov reaction.5-10 The
first Nazarov cyclization of an allenyl ketone was reported
by Tius and Nagao independently.6 In 1998, Hashmi
extended this reaction to allenyl vinyl ketones, which
delivered the products on silica gel.7 In addition, indol-2-yl
allenyl ketones were cleanly converted to the corresponding
cyclopenta[b]-indole derivatives under mild conditions.8 A
variant type of Nazarov cyclization was reported by de Lera
et al. in which divinylallene acetals underwent cyclization
almost quantitatively under mild conditions (TsOH).9 The
cationic cyclopentannulation of allenyl ethers has been
widely studied by Tius and constitutes a very efficient
construction of R-methylenecyclopentenones.10 We reasoned
that allenyl vinyl ketones could be synthesized from the
Wittig reaction of unsaturated carbonyl ylide with ketenes
and might undergo cyclization efficiently in one pot.
Initial attempts were made using unsaturated carbonyl
ylide 1 and ketene 2 in toluene at 0 °C. The intermediate
1
vinyl allenyl ketone 3, detected by H NMR, subsequently
underwent cyclization under acidic conditions. Among
several acids (TfOH, HCl, AcOH, FeCl3 and silica gel)
examined, TFA (40 equiv) was found to be the best giving
the product in 79% yield with Z/E ratio of 11/1 (Scheme 1).
Scheme 1. One-Pot Reactions of Ylide 1 with Ketene 2
Although Hashmi7 and Forest10f have shown that silica gel
can serve as an excellent catalyst for Nazarov cyclizations
of allenyl vinyl ketones, it was not the optimal in the current
case probably due to the interference of the in situ produced
Ph3PO. Considering the synthetic difficulty of pure unsatur-
ated carbonyl ylide 1, we discovered that the in situ generated
1 via Fe(TCP)Cl-catalyzed reaction of diazocarbonyl com-
pounds 4 with Ph3P reacted with ketene 2 as well as pure 1.
As shown in Table 1, the reactions proceeded better in ether
(3) (a) Sun, X.-L.; Tang, Y. Acc. Chem. Res. 2008, 41, 937. (b) Deng,
X.-M.; Cai, P.; Ye, S.; Sun, X.-L.; Liao, W.-W.; Li, K.; Tang, Y.; Wu,
Y.-D.; Dai, L.-X. J. Am. Chem. Soc. 2006, 128, 9730. (c) Cao, P.; Sun,
X.-L.; Li, C.-Y.; Kang, Y.-B.; Xie, Z.; Tang, Y. J. Org. Chem. 2007, 72,
6628. (d) Ye, L.-W.; Sun, X.-L.; Wang, Q.-G.; Tang, Y. Angew. Chem.
2007, 119, 6055; Angew. Chem., Int. Ed. 2007, 46, 5951. (e) Wang, Q.-G.;
Deng, X.-M.; Zhu, B.-H.; Ye, L.-W.; Sun, X.-L.; Tang, Y. J. Am. Chem.
Soc. 2008, 130, 5408.
Table 1. Effect of Reaction Conditions on the One-Pot Wittig/
Nararov Cyclizationa
(4) Li, C.-Y.; Wang, X.-B.; Sun, X.-L.; Tang, Y.; Zheng, J.-C.; Xu,
Z.-H.; Zhou, Y.-G.; Dai, L.-X. J. Am. Chem. Soc. 2007, 129, 1494.
(5) For recent reviews: (a) Zimmer, R.; Reissig, H.; Modern Allene
Chemistry; Krause, N., Hashmi, A. S. K., Eds.; WILEY-VCH: Weinheim,
2004; Vol. 2, p 847. (b) Horvath, A.; Baeckvall, J. E. Modern Allene
Chemistry; Krause, N., Hashmi, A. S. K., Eds.; WILEY-VCH: Weinheim,
2004; Vol. 2, pp 973-994. (c) Ma, S. Chem. ReV. 2005, 105, 2829. (d)
Shen, H. C. Tetrahedron 2008, 64, 3885. For recent examples: (e) Ma, S.;
Lu, P.; Lu, L.; Hou, H.; Wei, J.; He, Q.; Gu, Z.; Jiang, X.; Jin, X. Angew.
Chem. 2005, 117, 5409; Angew. Chem., Int. Ed. 2005, 44, 5275. (f) Trillo,
B.; Lopez, F.; Gulias, M.; Castedo, L.; Mascarenas, J. L. Angew. Chem.
2008, 120, 965; Angew. Chem., Int. Ed. 2008, 47, 951. (g) Cheong, P. H.;
Morganelli, P.; Michael, M. R.; Houk, K. N.; Toste, F. D. J. Am. Chem.
Soc. 2008, 130, 4517. (h) Lu, Z.; Zheng, S.; Zhang, X.; Lu, X. Org. Lett.
2008, 10, 3359. (i) Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2008, 130,
15254. (j) Osborne, J. D.; Randell-Sly, H. E.; Currie, G. S.; Cowley, A. R.;
Willis, M. C. J. Am. Chem. Soc. 2008, 130, 17232. (k) Yudha, S. S.;
Yoichiro, Y. T.; Takai, K. Angew. Chem. 2008, 120, 9458; Angew. Chem.,
Int. Ed. 2008, 47, 9318. (l) Alexander, S. D.; Anna, W. S.; Marina, R.;
Joseph, T. K.; Alexander, V. K.; Vladimir, G. J. Am. Chem. Soc. 2008,
entry
solvent
equiv of TFA
Z/Eb
yieldc (%)
1
2
3
4
5
6
7
8
EtOH
CH3CN
CH2Cl2
Et2O
THF
DME
Et2O
Et2O
Et2O
Et2O
Et2O
40
40
40
40
40
40
10
20
30
80
40
11/1
20/1
8/1
13/1
9/1
7/1
5/1
8/1
11/1
8/1
81
72
63
93
88
91
78
79
84
69
95
130, 1440
.
9
(6) (a) Nagao, Y.; Lee, W.-S.; Kim, K. Chem. Lett. 1994, 389. (b) Nagao,
Y.; Lee, W.-S.; Kim, K. Chem. Lett. 1994, 597. (c) Tius, M. A.; Kwok,
10
11d
12/1
C.-K.; Gu, X.-Q.; Zhao, C. Synth. Commun. 1994, 24, 871
(7) Hashmi, A. S. K.; Bats, J. W.; Choi, J. H.; Schwarz, L. Tetrahedron
Lett. 1998, 39, 7491
.
a Conditions: a solution of diazo compound in toluene (2 mL) was slowly
added in 2 h via a syringe pump to a solution of Ph3P (1.2 equiv) and 1.0
mol % Fe(TCP)Cl in toluene (0.5 mL), 2 h at 0 °C and then quenched with
the solution of TFA. b Determined by 300 MHz 1H NMR. c Isolated yield.
d Ketene was prepared in situ from acid chloride and Et3N in 2 h at room
temperature. For detailed procedure, see Supporting Information.
.
(8) (a) Ishikura, M.; Matsuzaki, Y.; Agata, I. Chem. Commun. 1996,
2409. (b) Ishikura, M.; Uchiyama, H.; Matsuzaki, N. Heterocycles 2001,
55, 1063
.
(9) (a) de Lera, A. R.; Rey, J. G.; Hrovat, D.; Iglesias, B.; Lopez, S.
Tetrahedron Lett. 1997, 38, 7425. (b) Iglesias, B.; de Lera, A. R.; Rodriguez-
Otero, J.; Lopez, S. Chem.sEur. J. 2000, 6, 4021
Org. Lett., Vol. 11, No. 14, 2009
.
3049

solvents, particularly in Et2O (entry 4). On the other hand,
the amount of TFA also had some effects on the yields
and Z/E ratios of the cyclization. Furthermore, ketene 2
prepared in situ from 2-phenylbutanoyl chloride and Et3N
also worked extremely well in such a tandem Wittig/
Nazarov cyclization to afford the product in nearly
quantitative yield with a similar stereoselectivity, implying
no interference of byproducts Et3N•HCl or Ph3PO to the
reaction (entry 11). Subsequent investigation showed that
the aforementioned method was applicable to various aryl
alkyl ketenes. As indicated in Table 2, the nature of alkyl
bonyl substrates were prepared to further investigate the
reaction scope. As shown in Table 3, a wide range of vinyl
Table 3. Tandem Wittig/Nazarov Cyclization with Alkenyl
Diazoketonesa
entry
products
R3
Z/Eb
yield (%)c
1
2
3
4
5j
p-MeOC6H4
C6H5
p-ClC6H4
2-furyl
C6H4CHdCH
C5H11
Cyclohexyl
10/1
12/1
17/1
15/1
24/1
15/1
11/1
87
95
82
80
71
90
63
Table 2. One-Pot Synthesis of ꢀ-Methylenecyclopentenones
5a-i from 4 and Acid Chloridesa
5k
5L
5m
5n
5o
5p
5
6
7d
a Conditions: a solution of diazo compound in toluene (2 mL) was slowly
added in 2 h via a syringe pump to a solution of Ph3P (1.2 equiv.) and 0.55
mol % of Fe(TCP)Cl in toluene (0.5 mL). Ketene was generated in situ
from acid chloride and Et3N within 2 h at room temperature, 2 h at 0 °C
and then quenched with the solution of 40 equiv of TFA in 2.5 mL Et2O.
b Determined by 300 MHz 1H NMR. c Isolated yield. d 1.1 mol % of
Fe(TCP)Cl, diazo compound was slowly added in 3 h via a syringe pump.
entry product
R1
R2
Z/Eb yield (%)c
1
2
5a
5b
5c
5d
5e
5f
5g
5h
5i
C6H5
C6H5
C6H5
C6H5
Me
2.5/1
12/1
10/1
90
86
88
n-Pr
n-Bu
homoallyl 40/1
3
4d
5
76
p-MeO-C6H4 Et
10/1
18/1
9/1
23/1
-
84
93
65
59
6
p-Cl-C6H4
p-Br-C6H4
1-naphthyl
Ph
Et
Et
Et
Ph
diazoketones underwent cyclization smoothly in good yields
with high Z/E ratios. Such method can also be used to prepare
fused carbocyclic rings from 1-cyclohexenyl-2-diazoethanone
in excellent yields with very good stereoselectivity, which
adds to the versatility of the process (Scheme 2).
7e
8f
9
68
10
-
cyclohexyl
-
trace
a Conditions: a solution of diazo compound in toluene (2 mL) was slowly
added within 2 h via a syringe pump to a solution of Ph3P (1.2 equiv) and
0.55 mol % of Fe(TCP)Cl in toluene (0.5 mL). Ketene was generated in
situ from acid chloride and Et3N in 2 h at room temperature, 2 h at 0 °C
and then quenched with the solution of 40 equiv of TFA in 2.5 mL Et2O.
b Determined by 300 MHz 1H NMR. c Isolated yield. d Ketene was generated
in situ in 40 min. e Ketene was generated in situ in 1 h. f Ketene was
generated in situ within 5 h at 40 °C.
Scheme 2
.
One-Pot Synthesis of Hexahydroindenone from
1-Cyclohexenyl-2-diazoethanone
substituents on ketenes had little influence on the yields
(entries 1-3). Ketene with homoallyl group reacted
smoothly to give alkenyl cyclopentenone in good yield
(entry 4). The steric and electronic effects of substituents
on aryl ring had some influence on the yields (entries
5-8). Diaryl substituted ketene also gave good yield (entry
9). Ketene derived from cyclohexanecarboxylic acid did
not work (entry 10). High Z/E ratios of the exocyclic
alkene were observed in all products, except for 5a (entry
1).
Encouraged by the successful tandem Wittig/Nazarov
reaction of 4, a serious of conjugate unsaturated diazocar-
(10) (a) Hu, H.; Smith, D.; Cramer, R. E.; Tius, M. A. J. Am. Chem.
Soc. 1999, 121, 8985. (b) Harrington, P. E.; Tius, M. A. Org. Lett. 2000,
2, 2447. (c) Harrington, P. E.; Tius, M. A. J. Am. Chem. Soc. 2001, 123,
8509. (d) Harrington, P. E.; Murai, T.; Chu, C.; Tius, M. A. J. Am. Chem.
Soc. 2002, 124, 10091. (e) Tius, M. A. Acc. Chem. Res. 2003, 36, 284. (f)
Forest, J.; Bee, C.; Cordaro, F.; Tius, M. A. Org. Lett. 2003, 5, 4069. (g)
Tius, M. A. Eur. J. Org. Chem. 2005, 2193. (h) Banaag, A. R.; Tius, M. A.
J. Am. Chem. Soc. 2007, 129, 5328. (j) Banaag, A. R.; Tius, M. A. J. Org.
Chem. 2008, 73, 8133.
Attempts to determine the Z/E selectivity of the cyclization
products by H NMR techniques were unsuccessful due to
the invisible NOE. Fortunately, the molecular structures of
the major isomers of products 5f and 5q were established
by single-crystal X- ray analyses (Figure 1), which showed
that the Nazarov cyclization reactions favored Z selectivity.11
1
3050
Org. Lett., Vol. 11, No. 14, 2009

Scheme 3. Proposed Stereochemical Model
tation ring closure. Since the produced intermediate I is more
stable than intermediate II due to the steric effect, Z-product
were obtained as the major ones.12
In conclusion, we have developed a novel Wittig/Nazarov
cyclization reaction, which offers a straightfoward method
for the construction of ꢀ-methylenecyclopentenones in a
multistep one-pot manner without the isolation of intermedi-
ates. The high yield, excellent stereoselectivity, mild reaction
conditions as well as simple purification procedures make
this method very attractive to the synthesis of cyclopentenone
derivatives.
Acknowledgment. We are grateful for the financial
support from the National Natural Science Foundation of
China (Grant No. 20821002 and 20672131) and the Major
State Basic Research Development Program (Grant No.
2006CB806105).
Supporting Information Available: Detailed experimen-
tal procedures and characterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 1. X-ray structures of the major isomers of 5f and 5q.
OL901086F
(11) CCDC 714457 (5f) and CCDC 714458 (5q) contain the supple-
mentary crystallographic data.
(12) E-5k didn’t isomerize into Z-5k under the reaction conditions.
The high stereoselectivity can be explained very well as
shown in Scheme 3. The cyclization proceeded via conro-
Org. Lett., Vol. 11, No. 14, 2009
3051