Phosphine-catalyzed [4 + 2] annulation of γ-substituent allenoates: Facile access to functionalized spirocyclic skeletons

Article abstract of DOI:10.1021/ol401249e

The first phosphine-catalyzed [4 + 2] annulation of γ-substituted allenoates with 2-arylidene-1H-indene-1,3(2H)-diones is disclosed. In the reaction, the γ-substituted allenoate serves as a new type of 1,4-dipolar synthon; this broadens the application of

Full text of DOI:10.1021/ol401249e

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Phosphine-Catalyzed [4 þ 2] Annulation
of γ‑Substituent Allenoates:
Facile Access to Functionalized
Spirocyclic Skeletons
Erqing Li, You Huang,* Ling Liang, and Peizhong Xie
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, China
hyou@nankai.edu.cn
Received May 15, 2013
ABSTRACT
The first phosphine-catalyzed [4 þ 2] annulation of γ-substituted allenoates with 2-arylidene-1H-indene-1,3(2H)-diones is disclosed. In the
reaction, the γ-substituted allenoate serves as a new type of 1,4-dipolar synthon; this broadens the application of γ-substituted allenoates. This
method also offers a powerful approach to the construction of highly substituted spiro[4.5]dec-6-ene skeletons in excellent yields, and with
complete regioselectivity and high diastereoselectivity.
Spirocyclic skeletons are the structural centerpieces of a
wide variety of natural and synthetic compounds that
exhibit diverse biological activities. Consequently, ap-
proaches to the efficient synthesis of these molecules have
received considerable attention.1
Various methods such as organocatalysis2 and transition-
metal catalysis3 have previously been described in the
literature. However, drawbacks such as unsatisfactory
yields, tedious purification processes, and poor chemo-
and/or diastereoselectivities have restricted the application
of these approaches. The development of novel, straight-
forward, and flexible methods for the preparation of
spirocyclic compounds is therefore highly desirable.
Recently, because of their comparatively strong and
readily tunable nucleophilicities, phosphines have been
used as efficient catalysts in organic synthesis.4,5 A series
(1) (a) Ma, S.; Han, X. Q.; Krishnan, S.; Virgil, S. C.; Stoltz, B. M.
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47, 1560. (d) Nair, V.; Menon, R. S.; Sreekanth, A. R.; Abhilash, N.;
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r
10.1021/ol401249e
XXXX American Chemical Society

of named reactions, such as the RauhutꢀCurrier and
MoritaꢀBaylisꢀHillman reactions, have been developed.
Among these significant studies, Lu first reported the
phosphine-catalyzed [3 þ 2] cycloaddition of activated
olefins with 2,3-butadienoate for the construction of var-
ious five-membered carbocyclic compounds and hetero-
cyclic compounds [Scheme 1, (a)].6 In further investiga-
tions, Kwon and Lu independently reported new [2 þ 2 þ 2]
and [2 þ 3] annulations catalyzed by phosphines [Scheme 1,
(b) and (c)].7 At the same time, our group first reported a
novel [1 þ 4] annulation of allenoates and salicyl-N-
thiophosphinylimines using a new bifunctional phos
phine catalyst, (20-hydroxybiphenyl-2-yl)diethylphosphane
(LBBA-1), in which allenoates served as one-carbon
units participating in a domino process [Scheme 1, (d)].8
Based on these pioneering studies, Kwon et al. devel-
oped a phosphine-catalyzed [4 þ 2] cycloaddition of
compounds, further proving its synthetic efficiency.11
However, compared with the significant progress made
with allenoates and R-substituted allenoates, phosphine-
catalyzed domino reactions involving γ-substituted al-
lenoates are rare.12 In 2009, our group reported the first
example of γ-substituted allenoates acting as C2 and C3
synthons in phosphine-catalyzed [4 þ 2] and [3 þ 2]
annulations.12a Recently, Shi et al. and Nair et al. reported
novel phosphine-catalyzed reactions of γ-substituted
allenoates.13 However, to the best of our knowledge,
γ-substituted allenoates acting as a new type of 1,4-dipolar
synthon have not been reported. In this letter, we disclose
the first case of a phosphine-catalyzed [4 þ 2] annulation
of γ-substituted allenoates and activated olefins under
mild conditions (Scheme 1).
Scheme 2. Phosphine-Catalyzed Annulations of γ-Substituent
Allenoates
Scheme 1. Various Pathways for Phosphine-Catalyzed Annu-
lations
In view of our previous study of phosphine-catalyzed
domino reactions of allenoates,14 we initially used
2- benzylidene-1H-indene-1,3(2H)-dione (1a) (0.3 mmol)
and methyl 5-phenyl-2,3-pentadienoate (2a) (0.6 mmol) as
the model substrates and a catalytic amount of PPh3
(30 mol %) as the catalyst at 40 °C in CH2Cl2 to test
the reaction procedure (Scheme 2).12a Unfortunately, this
R-substituted allenoates with imides,9 and subsequent
research has shown that the [4 þ 2] cycloaddition of
R-substituted allenoates with activated olefins or ketones
is also feasible [Scheme 1, (e)].10 Kwon et al. used this
method in the synthesis of natural products and bioactive
(11) (a) Andrews, I. P.; Kwon, O. Chem. Sci. 2012, 3, 2510. (b) Villa,
R. A.; Xu, Q. H.; Kwon, O. Org. Lett. 2012, 14, 4634. (c) Jones, R. A.;
Krische, M. J. Org. Lett. 2009, 11, 1849. (d) Tran, Y. S.; Kwon, O. Org.
Lett. 2005, 7, 4289. (e) Wang, J. C.; Krische, M. J. Angew. Chem., Int. Ed.
2003, 42, 5855.
(12) (a) Meng, X.; Huang, Y.; Zhao, H.; Xie, P.; Ma, J.; Chen, R.
Org. Lett. 2009, 11, 911. (b) Ma, R.; Xu, S.; Tang, X.; Wu, G.; He, Z.
Tetrahedron 2011, 67, 1053. (c) Xu, S.; Zhou, L.; Ma, R.; Song, H.; He,
Z. Chem.;Eur. J. 2009, 15, 8698.
(13) (a) Zhang, X.-C.; Cao, S.-H.; Wei, Y.; Shi, M. Chem. Commun.
2011, 47, 1548. (b) Jose, A.; Lakshmi, K. C. S.; Suresh, E.; Nair, V. Org.
Lett. 2013, 15, 1858.
(6) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906.
(7) (a) Zhu, X.-F.; Henry, C. E.; Wang, J.; Dudding, T.; Kwon, O.
Org. Lett. 2005, 7, 1387. (b) Lu, Z.; Zheng, S.; Zhang, X.; Lu, X. Org.
Lett. 2008, 10, 3267.
(14) (a) Xie, P.; Li, E.; Zheng, J.; Li, X.; Huang, Y.; Chen, R. Adv.
Synth. Catal. 2013, 355, 161. (b) Yang, L.; Xie, P.; Li, E.; Li, X.; Huang,
Y.; Chen, R. Org. Biomol. Chem. 2012, 10, 7628. (c) Hu, C.; Geng, Z.;
Ma, J.; Huang, Y.; Chen, R. Chem.;Asian J. 2012, 7, 2032. (d) Xie, P.;
Lai, W.; Geng, Z.; Huang, Y.; Chen, R. Chem.;Asian. J. 2012, 7, 1533.
(e) Xie, P.; Huang, Y.; Chen, R. Chem.;Eur. J. 2012, 18, 7362. (f) Xie,
P.; Huang, Y.; Lai, W.; Meng, X.; Chen, R. Org. Biomol. Chem. 2011, 9,
6707. (g) Ma, J.; Xie, P.; Hu, C.; Huang, Y.; Chen, R. Chem.;Eur. J.
2011, 17, 7418. (h) Xie, P.; Huang, Y.; Chen, R. Org. Lett. 2010, 12, 3768.
(i) Meng, X.; Huang, Y.; Chen, R. Chem.;Eur. J. 2008, 14, 6852.
(8) Meng, X.; Huang, Y.; Chen, R. Org. Lett. 2009, 11, 137.
(9) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716.
(10) (a) Tran, Y. S.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 12632. (b)
Castellano, S.; Fiji, H. D. G.; Kinderman, S. S.; Watanabe, M.; de Leon,
P.; Tamanoi, F.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 5843. (c) Zh,
X.-F.; Schaffner, A.-P.; Li, R. C.; Kwon, O. Org. Lett. 2005, 7, 2977. (d)
Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234. (e) Wang, T.;
Ye, S. Org. Lett. 2010, 12, 4168.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of [4 þ 2] Annulation of γ-Substituent of
the Allenoate with 2-Benzylidene-1H-indene-1,3(2H)-dionea
cat.
t
yield
(%)b
entry
(mol %)
solvent
CH2Cl2
(h)
1
PPh3 (30)
6
trace
80
2
PPh3 (50)
toluene
CH3CN
THF
9
3
PPh3 (50)
9
53
4
PPh3 (50)
5
97
Figure 1. X-ray crystal structure of 3a.
5
PPh3 (50)
CH2ClCH2Cl
CHCl3
THF
1.5
12
14
36
9
47
6
PPh3 (50)
63
with strong electron-withdrawing or -donating groups, a
slightly higher catalyst loading (20 mol % PPh3) was
needed (Table 2, entries 10ꢀ12). When the substituent on
the benzene ring was 4-nitro, 3-bromo, 3-methyl, or
4-methoxy, high yields and diastereoselectivities were still
obtained, but a significantly longer reaction time was
required (Table 2, entries 6, 7, 10, and 11). 2-Arylidene-
1H-indene-1,3(2H)-dione 2 containing 2-naphthyl or het-
eroaryl groups could also be used in the reaction (Table 2,
entries 13 and 14). The steric properties of the esters had
7
(4-ClC6H4)3P (20)
(4-MeOC6H4)3P (20)
PPh3 (20)
91
8
THF
74
9
THF
96
10
11c
12d
PPh3 (10)
THF
9
95
PPh3 (10)
THF
20
24
89
PPh3 (20)
THF
trace
a Unless otherwise specified, all reactions were carried out using 1a
(0.3 mmol) and 2a (0.6 mmol) at 60 °C. b Yield of isolated products. c 1a
(0.3 mmol) and 2a (0.45 mmol) were used. d The reaction was carried out
at room temperature.
reaction did not show any activity, and no product was
obtained. In toluene, with a temperature of 60 °C and an
increased catalyst loading, the reaction proceeded smoothly
to give the corresponding [4 þ 2] cycloaddition adduct in
80% yield (Table 1, entry 2). It should be noted that the
[4 þ 2] cycloaddition reaction is completely regioselec-
tive and highly diastereoselective (only one isomer was
detected in all reactions). Various solvents were tested, and
THF was found to be the best, affording 3a in 97% yield
(Table 1, entries 1ꢀ6). Subsequent catalyst screening
demonstrated that PPh3 was the best choice (Table 1,
entries 6ꢀ8). On decreasing the amount of catalyst to 20
and 10 mol %, similar results were obtained (Table 1,
entries 9 and 10). However, changing the ratio of 1a to 2a
resulted in a slight decrease in the yield (Table 1, entry 11).
Furthermore, it was found that no reaction occurred in the
presence of PPh3 (20 mol %) at room temperature
(Table 1, entry 12). Based on these experimental results,
the best reaction conditions were confirmed to be PPh3
(10ꢀ20 mol %), at 60 °C in THF. The structure and
stereochemistry of 3 were determined using a combination
of NMR and HRMS spectroscopies and single-crystal
X-ray analysis (3a) (Figure 1).
Table 2. Scopes of the Phosphine-Catalyzed [4 þ 2] Annulation
a
of γ-Substituent Allenoates in the Presence of PPh3
t
yield
(%)b
entry
Ar
C6H5
R
(h)
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
9
95 (3a)
92 (3b)
98 (3c)
86 (3d)
88 (3e)
88 (3f)
89 (3g)
96 (3h)
89 (3i)
82 (3j)
96 (3k)
92 (3l)
64 (3m)
88 (3n)
98 (3o)
98 (3p)
92 (3q)
2
4-MeC6H5
4-BrC6H5
4-ClC6H5
4-FC6H5
3-BrC6H5
3-MeC6H5
2-BrC6H5
2-MeC6H5
4-NO2C6H5
4-MeOC6H5
2.4-Cl2C6H3
2-thienyl
1-naphthyl
C6H5
10
10
16
16
36
36
12
12
16
16
10
36
36
9
3
4
5
6
7
8
9
10c
11c
12c
13c
14c
15
16
17
With the optimized conditions in hand, we next explored
the substrate scope of the new phosphine-catalyzed [4 þ 2]
cycloaddition; the results are listed in Table 2. The position
of the substituent on the aromatic ring of substrate 2 had
no significant influence on the yields and diastereoselec-
tivities. Phenyl groups with electron-withdrawing or
-donating groups worked well as substituents (Table 2,
entries 1ꢀ9). When the substituents were phenyl groups
C6H5
t-Bu
Bn
9
C6H5
9
a Unless otherwise noted, all reactions were carried out with 1
(0.3 mmol) and 2 (0.6 mmol) in THF (3.0 mL) at 60 °C. b Yield of
isolated product. c The reactions were carried out with 1 (0.3 mmol) and 2
(0.6 mmol) in the presence of PPh3 (20 mol %) in THF (3.0 mL) at 60 °C.
Org. Lett., Vol. XX, No. XX, XXXX
C

only a slight influence on the yield (Table 2, entries 1,
15ꢀ17).
reaction at large scale (ꢁ10). The reaction of 2-benzyl-
idene-1H-indene-1,3(2H)-dione (1a) and methyl 5-phe-
nyl-2,3- pentadienoate (2a) was carried out under the
optimal conditions; the domino reaction proceeded
smoothly and afforded the desired adduct 3a at the
gram scale, without loss of reactivity and diastereo-
selectivity (Scheme 4).
Based on our experimental results and previous studies,15
we proposed a possible mechanism for the formation of
spiro[4.5]dec-6-ene and the stereochemistry of this domino
reaction (Scheme 3). Conceivably, the first step is nucleo-
philic addition of triarylphosphine to the allene ester, giving
1,3-dipolar zwitterion A or B. Intermediate A or B under-
goes a reversible equilibrium overall proton shift, giving
intermediate C. The allylic carbanion C then undergoes a
Michael addition with 2, enabling the formation of inter-
mediate D; in this step, the steric effect of the large
substituent on substrates will enable good product dia-
stereoselectivity. Then, D followed by an isomerization to
give intermediate E, an umpolung addition, and a proton
shift forms intermediate G. Finally, elimination of the phos-
phine catalyst gives 3 and completes the catalytic cycle.
Scheme 4. Large Scale [4 þ 2] Annulation between 1a and 2a
In conclusion, we have developed a novel method for the
synthesis of spiro[4.5]dec-6-ene through a phosphine-cat-
alyzed [4 þ 2] annulation, with excellent yields and high
diastereoselectivities. More importantly, we have disclosed
the first example of γ-benzyl allenoates acting asa new type
of C4 synthon and participating in a phosphine-catalyzed
domino reaction. Further investigations will focus on
designing new domino reactions using these new 1,4-
dipolar synthons and on performing asymmetric versions
of the annulation.
Scheme 3. Possible Mechanism for the Formation of 3
Acknowledgment. This work was supported financially
by the National Natural Science Foundation of China
(21172115, 20972076) and the Natural Science Foundation
of Tianjin (10JCYBJC04000).
In order to demonstrate the practicality of the strategy,
we performed the phosphine-catalyzed [4 þ 2] annulation
(15) For mechanistic studies of the phosphine-catalyzed cycloaddi-
tion reaction, see: (a) Liang, Y.; Liu, S.; Xia, Y.; Li, Y.; Yu, Z.-X.
Chem.;Eur. J. 2008, 14, 4361. (b) Mercier, E.; Fonovic, B.; Henry, C.;
Kwon, O.; Dudding, T. Tetrahedron Lett. 2007, 48, 3617. (c) Xia, Y.;
Liang, Y.; Chen, Y.; Wang, M.; Jiao, L.; Huang, F.; Liu, S.; Li, Y.; Yu,
Z.-X. J. Am. Chem. Soc. 2007, 129, 3470. (d) Dudding, T.; Kwon, O.;
Mercier, E. Org. Lett. 2006, 8, 3643. (e) Zhu, X.-F.; Henry, C. E.; Kwon,
O. J. Am. Chem. Soc. 2007, 129, 6722.
Supporting Information Available. Detailed experimen-
tal procedures, spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX