Phosphine-catalyzed highly diastereoselective [3+2] cyclization of isatin derived electron-deficient alkenes with α-allenic esters

Article abstract of DOI:10.1039/c0cc04289g

A novel phosphine-catalyzed highly diastereoselective [3+2] cycloaddition of isatin derived α,β-unsaturated ketones with α-allenic ester has been developed.

Full text of DOI:10.1039/c0cc04289g

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Phosphine-catalyzed highly diastereoselective [3+2] cyclization of isatin
derived electron-deficient alkenes with a-allenic estersw
Xiu-Chun Zhang,a Shu-Hua Cao,a Yin Wei*b and Min Shi*ab
Received 8th October 2010, Accepted 5th November 2010
DOI: 10.1039/c0cc04289g
A novel phosphine-catalyzed highly diastereoselective [3+2]
cycloaddition of isatin derived a,b-unsaturated ketones with
a-allenic ester has been developed.
complex product mixtures (Table S1, entries 7 and 8, ESIw).
Subsequently, we tested other alkyl phosphines such as PMe3
or PtBu3 in this reaction, but it was found that they could not
catalyze this reaction under the standard conditions (Table S1,
entries 9 and 10, ESIw). Decreasing the catalyst loading to
10 mol% slowed down the reaction rate, affording the product
3a in lower yield (Table S1, entry 11, ESIw). Based on these
experimental results, the best reaction condition has been
identified to carry out this reaction using PBu3 (20 mol%) as
the catalyst at room temperature.
Phosphine-catalyzed [3+2] or [4+2] cyclization reactions of
allenoates have been proven to be powerful synthetic tools in
the rapid formation of cyclic molecular complexity.1–3 The
synthetic utility of these cycloaddition reactions has been
largely demonstrated by the preparation of biologically active
natural products and pharmaceutically interesting substances.1k
With the aim of exploring new phosphine-catalyzed cyclization
reaction of allenoates, herein, we wish to report a novel
phosphine-catalyzed highly diastereoselective [3+2] cyclo-
addition of isatin derived a,b-unsaturated ketones with
a-allenic ester. The reaction affords the functionalized
spirocyclic oxindolic cyclopentanes, which are the core
structures in a variety of natural alkaloid derivatives,4,5 in
good to excellent yields with high regioselectivities and
diastereoselectivities.
Next, we examined the performance of commonly used
phosphines with aromatic substituents for this reaction,
and the results are summarized in Table S2 (See ESIw).
Interestingly, using the phosphines with aromatic substituents
could catalyze this reaction under the identified optimal
conditions, affording the same product 3a in similar yield,
however, the major product is the diastereoisomer (trans,
trans)-3a. Phosphine with more aromatic substituents led to
higher diastereoselectivities (Table S2, entries 1–3, ESIw).
P(MeO)Ph2 did not catalyze this reaction (Table S2, entry 4,
ESIw). Furthermore, we examined the aryl phosphines having
electron-donating groups or with electron-withdrawing groups
on their benzene rings (Table S2, entries 5–7, ESIw). It turned
out that aryl phosphine P(4-FC6H4)3 which has an electron-
withdrawing group on the benzene ring gave the best diastereo-
selectivity (Table S2, entry 7, ESIw). Subsequently, using
P(4-FC6H4)3 as the catalyst, we screened the solvent again
(Table S2, entries 8–13, ESIw). It was found that dioxane was
the most suitable solvent for this reaction, affording the
product 3a in 73% yield with excellent diastereoselectivity
(Table S2, entry 13, ESIw).
Having identified the optimal reaction conditions, we next
set out to examine the scope and limitations of this [3+2]
cycloaddition reaction catalyzed by PBu3 using various isatin
derivatives 1 with different substituents on the benzene rings,
and the results are summarized in Table 1. As shown in
Table 1, whether the electron-withdrawing or electron-donating
group at 4-, 5- or 6-position of the benzene ring of N-benzyl
isatins 1 was employed, the reactions proceeded smoothly to
give the corresponding products 3 in good total yields (up to
90%) with diastereoisomer (cis, trans)-3 as the major products
along with modest to excellent diastereoselectivities (Table 1,
entries 1–7). The major diastereoisomer was unequivocally
assigned as (cis, trans)-configuration by X-ray diffraction of
the major product of 3q (see ESIw). It is worthy noting that the
substrates having a substituent at 4-position of the benzene
ring afforded the product 3 with excellent diastereoselectivities
(cis, trans) : (trans, trans) > 20 : 1 (Table 1, entries 2 and 3).
Varying R1 from the methyl group to the phenyl group still
afforded the corresponding product 3j in 70% yield, but, along
Initially, employing (E)-1-benzyl-3-(2-oxopropylidene)indolin-
2-one 1a (1.0 equiv.) and ethyl 2,3-pentadienoate 2a
(2.0 equiv.) as the substrates, the reaction was conducted in
the presence of 20 mol% PBu3 in toluene at room temperature,
affording the [3+2] cycloaddition product 3a in 76% total
yield as a diastereoisomeric mixture of (cis, trans)-3a and
(trans, trans)-3a with a ratio of 4 : 1 (Table S1, entry 1,
see ESIw).6 It should be mentioned here that this [3+2]
cycloaddition reaction is highly regioselective because no other
regioisomers were detected. Subsequently, the solvent effects
and catalysts were investigated for this reaction, and the
results are summarized in Table S1 (ESIw). As depicted in
Table S1 (ESIw), the employed solvent had a significant
influence on the reaction outcome in which toluene and
n-Bu2O were suitable solvents for the reaction to give 3a in
good yields, presumably due to that the substrates have good
solubility in n-Bu2O (Table S1, entries 1 and 2, ESIw).
However, the solvents such as tBuOMe, dichloromethane
(DCM), Et2O, and tetrahydrofuran (THF) retarded the
reaction rate and reduced the yields of 3a (Table S1, entries
3–6, ESIw). The reaction in MeCN or DMF led to the
a Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
130 Mei Long Road, Shanghai 200237, China
b State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, China.
E-mail: weiyin@mail.sioc.ac.cn, Mshi@mail.sioc.ac.cn;
Fax: +86-21-64166128
w Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data for all compounds and X-ray
crystal data of 1n, 3j, 3q. See DOI: 10.1039/c0cc04289g
c
1548 Chem. Commun., 2011, 47, 1548–1550
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a
Table 1 Scope of the reactions catalyzed by PBu3
proceeded smoothly to give 3 in modest to good total yields
(up to 92%) with excellent diastereoselectivities (Table 2,
entries 1–9). In contrast to aforementioned reactions catalyzed
by PBu3, the reactions catalyzed by P(4-FC6H4)3 mainly
afforded the diastereoisomers (trans, trans)-3 as the major
products, which was unequivocally assigned by X-ray diffraction
of the major product of 3j (see ESIw), except for the substrates
having a substituent at the 4-position of the benzene ring,
which still gave (cis, trans) diastereoisomers as the major
products, presumably due to the steric effect (Table 2, entries 2
and 3). Varying R1 from the methyl group to the phenyl group
still afforded the corresponding product 3j in 70% yield with
excellent diastereoselectivity (cis, trans) : (trans, trans)o
1 : 20 (Table 2, entry 10). Unfortunately, when R1 = Ph
and the substituent is at the 4-position of the benzene ring of
N-benzyl isatins 1, these substrates could not undergo this
phosphine-catalyzed [3+2] cycloaddition reaction (Table 2,
entries 11 and 12). When R1 = Ph and the substituent is at the
5-, 6- or 7-position of the benzene ring of N-benzyl isatins 1,
these substrates could undergo this reaction smoothly,
affording the corresponding products in good to excellent
yields (up to >99%) with excellent diastereoselectivities
(cis, trans) : (trans, trans)o1 : 20 (Table 2, entries 13–18).
The regiochemical outcome of this reaction may be
rationalized as depicted in Scheme 1. Based on steric
considerations, this [3+2] cycloaddition reaction can take
place via the transition state A, which would be expected to
be favored over the more sterically demanding transition state
B. Thus, we obtained regioisomer A as our product.
Entry No R1
R2
H
Yieldb (%) (cis, trans) : (trans, trans)c
1
2
3
4
5
6
7
8
9d
1a
1b
1c
1d
1f
1g
1h
1j
Me
3a, 76
3b, 89
3c, 90
3d, 74
3f, 76
4 : 1
Me 4-Br
Me 4-Cl
Me 5-Br
Me 5-F
Me 5-Me 3g, 85
Me 6-Br
>20 : 1
>20 : 1
7 : 1
4 : 1
4 : 1
4 : 1
2 : 1
3h, 70
3j, 70
3q, 91
Ph
Me
H
H
1q
3 : 1
a
The reaction was carried out on a 0.1 mmol scale with 20 mol%
catalyst under Ar in toluene (1.0 ml) at rt for 8 h, and the ratio of 1/2
b
was 1.0/2.0. Isolated yield. The diastereomeric ratio of (cis, trans)/
c
(trans, trans) was determined by 1H NMR spectroscopic data. The
benzyl group was replaced by 9-anthrylmethyl group.
d
with reduced diastereoselectivity (cis, trans) : (trans, trans) =
2 : 1 (Table 1, entry 8). Changing the N-substituent from the
benzyl group to the 9-anthrylmethyl group gave the corres-
ponding product 3q in high yield along with slightly reduced
diastereoselectivity (Table 1, entry 9).
We subsequently examined the scope and limitations of this
[3+2] cycloaddition reaction catalyzed by P(4-FC6H4)3 using
various isatin derivatives 1 with different substituents on the
benzene rings, and the results are summarized in Table 2. As
shown in Table 2, whether the electron-withdrawing or
electron-donating group at 4-, 5-, 6- or 7-position of the
benzene ring of N-benzyl isatins 1 was employed, the reactions
On the basis of the above results and commonly accepted
mechanism for phosphine-catalyzed [3+2] cycloaddition
reaction,7
a
plausible mechanism for the PBu3- or
P(4-FC6H4)3-catalyzed [3+2] cycloaddition reaction between
isatin derived a,b-unsaturated ketones with a-allenic ester is
proposed in Scheme 3. The catalyst phosphine as a nucleophile
reacts with ethyl 2,3-pentadienoate 2a to produce the zwitter-
ionic intermediate I, which subsequently undergoes a Michael
addition to generate the intermediate II-1 or II-2 through
attacking the activated olefin via the re-face or si-face. The
intermediates II-1 and II-2 may be more favored than the
intermediates II-3 and II-4 due to the internal coordination of
oxygen to phosphorus atom,8 resulting in that the methyl
group and the carbonyl group on the isatin ring always possess
the trans-position in the final product. Presumably, due to the
steric reasons, the intermediate I is more favored to attack the
activated olefin via the re-face if the catalyst is PBu3; the
intermediate I is more favored to attack the activated olefin via
a
Table 2 Scope of the reactions catalyzed by P(4-FC6H4)3
Entry No R1
R2
H
Yieldb (%) (cis, trans) : (trans, trans)c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Me
3a, 73
3b, 40
3c, 40
3d, 74
3e, 78
3f, 75
3g, 78
3h, 92
o1 : 20
20 : 1
20 : 1
Me 4-Br
Me 4-Cl
Me 5-Br
Me 5-F
Me 5-Me
Me 6-Br
Me 7-Br
1 : 11
1 : 14
o1 : 20
1 : 20
o1 : 20
o1 : 20
o1 : 20
—
9
Me 7-CF3 3i, 60
H
10
11
12
13
14
15
16
17
18
1j
Ph
3j, 70
—
d
—
—
1k
1l
Ph 4-Br
Ph 4-Cl
Ph 5-Br
Ph 5-F
d
—
3k, 82
—
o1 : 20
o1 : 20
o1 : 20
o1 : 20
o1 : 20
o1 : 20
3l, >99
3m, 82
3n, >99
3o, 80
1m Ph 5-Me
1n
1o
1p
Ph 6-Br
Ph 7-Br
Ph 7-CF3 3p, 93
a
The reaction was carried out on a 0.1 mmol scale with 20 mol%
catalyst under Ar in dioxane (1.0 ml) at rt for 8 h, and the ratio of 1/2
b
was 1.0/2.5. Isolated yield. The diastereomeric ratio of (cis, trans)/
c
(trans, trans) was determined by 1H NMR spectroscopic data. No
reaction occurred.
d
Scheme 1 Rational explanation of the regioselectivity.
Chem. Commun., 2011, 47, 1548–1550 1549
c
This journal is The Royal Society of Chemistry 2011

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Natural Science Foundation of China for financial support
(20902019, 20872162, 20672127, 20821002, 20732008,
20772030 and 20702059) is greatly acknowledged.
Scheme 2 PBu3-catalyzed reaction using 2,3-butadienoate as the
Notes and references
substrate.
1 Selected papers on the phosphine-catalyzed cyclization of
allenoates. (a) C. Zhang and X. Lu, J. Org. Chem., 1995, 60,
2906; (b) Y. Du, X. Lu and Y. Yu, J. Org. Chem., 2002, 67, 8901;
(c) Y. Du and X. Lu, J. Org. Chem., 2003, 68, 6463; (d) Y. S. Tran
and O. Kwon, J. Am. Chem. Soc., 2007, 129, 12632; (e) X.-F. Zhu,
C.-E. Henry and O. Kwon, J. Am. Chem. Soc., 2007, 129, 6722;
(f) E. Mercier, B. Fonovic, C. Henry, O. Kwon and T. Dudding,
Tetrahedron Lett., 2007, 48, 3617; (g) T. Dudding, O. Kwon and
E. Mercier, Org. Lett., 2006, 8, 3643; (h) S. M. M. Lopes,
B. S. Santos, F. Palacios and T. M. V. D. Pinhoe Melo, ARKIVOC,
2010, 5, 70; (i) S. Xu, L. Zhou, R. Ma, H. Song and Z. He,
Chem.–Eur. J., 2009, 15, 8698; (j) T. Wang and S. Ye, Org. Lett.,
2010, 12, 4168; (k) Y. S. Tran and O. Kwon, Org. Lett., 2005, 7,
4289.
2 For reviews: (a) X. Lu, C. Zhang and Z. Xu, Acc. Chem. Res., 2001,
34, 535; (b) B. J. Cowen and S.J. Miller, Chem. Soc. Rev., 2009, 38,
3102; (c) J. L. Methot and W. R. Roush, Adv. Synth. Catal., 2004,
346, 1035; (d) Y. Wei and M. Shi, Acc. Chem. Res., 2010, 43, 1005.
3 Selected papers on the chiral phosphine catalyzed asymmetric
cyclization of allenoates. (a) Y.-Q. Fang and E. N. Jacobsen,
J. Am. Chem. Soc., 2008, 130, 5660; (b) G. Zhu, Z. Chen,
Q. Jiang, D. Xiao, P. Cao and X. Zhang, J. Am. Chem. Soc.,
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W. Liu, J.-K. Zhang and G. Zhao, Angew. Chem., Int. Ed., 2010, 49,
4467; (d) J. E. Wilson and G. C. Fu, Angew. Chem., Int. Ed., 2006,
45, 1426; (e) D. J. Wallace, R. L. Sidda and R. A. Reamer, J. Org.
Chem., 2007, 72, 1051; (f) Y.-K. Chung and G. C. Fu, Angew.
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Chem. Soc., 2005, 127, 12234; (h) A. Voituriez, N. Pinto, M. Neel,
P. Retailleau and A. Marinetti, Chem.–Eur. J., 2010, 16, 12541.
4 (a) T. Mugishima, M. Tsuda, Y. Kasai, H. Ishiyama, E. Fukushi,
J. Kawabata, M. Watanabe, K. Akao and J. Kobayashi, J. Org.
Chem., 2005, 70, 9430; (b) R. F. Bond, J. C. A. Boeyens,
C. W. Holzapfel and P. S. Steyn, J. Chem. Soc., Perkin Trans. 1,
1979, 175; (c) T. J. Greshock, A. W. Grubbs, P. Jiao,
D. T. Wicklow, J. B. Gloer and R. M. Williams, Angew. Chem.,
Int. Ed., 2008, 47, 3573; (d) S. Tsukamoto, T. Kawabata, H. Kato,
T. J. Greshock, H. Hirota, T. Ohta and R. M. Williams, Org. Lett.,
2009, 11, 1297.
5 For their applications in medicinal chemistry: A. Fensome,
W. R. Adams, A. L. Adams, T. J. Berrodin, J. Cohen,
C. Huselton, A. Illenberger, J. C. Kern, V. A. Hudak,
M. A. Marella, E. G. Melenski, C. C. McComas, C. A. Mugford,
O. D. Slayden, M. Yudt, Z. Zhang, P. Zhang, Y. Zhu,
R. C. Winneker and J. E. Wrobel, J. Med. Chem., 2008, 51, 1861.
6 The stereochemistry is specified by the orientation of the functional
groups which have higher priority at the C1-, C2-, C3-positions of
five-membered rings. In the case of (cis, trans)-3a, two carbonyl
groups at the C1 and C2 positions are on the same side, which is
defined as cis; one carbonyl group at the C1 position and one methyl
group at the C3 position are on the opposite side, which is defined as
trans.
Scheme 3 A plausible mechanism.
the si-face if the catalyst is P(4-FC6H4)3, which leads to a
different major product with a different spiro-configuration.
The intermediates II-1 and II-2 undergo the ring-closing
reaction to generate intermediates III-1 and III-2, respectively,
which can be converted to intermediates IV-1 and IV-2 via a
H-shift. Releasing the phosphine, the products are finally
furnished.
A
control experiment has been carried out using
2,3-butadienoate as the substrate under the standard conditions
as shown in Scheme 2. However, four diastereoisomers were
given along with the ratio of 1/0.2/1/0.4, indicating that the
methyl group on ethyl 2,3-pentadienoate is a key factor to
affect the regioselectivity (see ESIw for details).
In conclusion, we have found and developed a novel
phosphine-catalyzed highly diastereoselective [3+2] cyclo-
addition of isatin derived a,b-unsaturated ketones with
a-allenic ester, affording the functionalized spirocyclic products
in good to excellent yields, with high regioselectivities and
diastereoselectivities. The phosphine catalyst affects the final
product and was proven to be critical for controlling the
diastereoselectivity. Efforts are in progress to elucidate further
mechanistic details of these reactions and to understand their
scope and limitations.
7 For mechanistic studies of the phosphine-catalyzed Lu’s
[3+2]-cycloaddition reaction, see: (a) Y. Liang, S. Liu, Y. Xia,
Y. Li and Z.-X. Yu, Chem.–Eur. J., 2008, 14, 4361; (b) E. Mercier,
B. Fonovic, C. Henry, O. Kwon and T. Dudding, Tetrahedron Lett.,
2007, 48, 3617; (c) Y. Xia, Y. Liang, Y. Chen, M. Wang, L. Jiao,
F. Huang, S. Liu, Y. Li and Z.-X. Yu, J. Am. Chem. Soc., 2007, 129,
3470; (d) T. Dudding, O. Kwon and E. Mercier, Org. Lett., 2006, 8,
3643; (e) X.-F. Zhu, C. E. Henry and O. Kwon, J. Am. Chem. Soc.,
2007, 129, 6722.
8 (a) C.-W. Cho and M. J. Krische, Angew. Chem., Int. Ed., 2004, 43,
6689; (b) H. Park, C.-W. Cho and M. J. Krische, J. Org. Chem.,
2006, 71, 7892.
Financial support from the National Basic Research
Program of China (973)-2010CB833302 and the National
c
1550 Chem. Commun., 2011, 47, 1548–1550
This journal is The Royal Society of Chemistry 2011