Phosphine-and nitrogen-containing lewis base catalyzed highly regioselective and geometric selective cyclization of isatin derived electron-deficient alkenes with ethyl 2,3-butadienoate

Article abstract of DOI:10.1021/ol1031798

An interesting phosphine-containing Lewis base catalyzed highly regioselective [3 + 2] cycloaddition and a novel nitrogen-containing Lewis base catalyzed highly geometric selective [4 + 2] cycloaddition of isatin derived α,β-unsaturated diesters with α-al

Full text of DOI:10.1021/ol1031798

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1142–1145
Phosphine- and Nitrogen-Containing
Lewis Base Catalyzed Highly
Regioselective and Geometric Selective
Cyclization of Isatin Derived Electron-
Deficient Alkenes with Ethyl 2,3-
Butadienoate
Xiu-Chun Zhang,† Shu-Hua Cao,† Yin Wei,‡ and Min Shi*,†,‡
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China
University of Science and Technology, 130 Mei Long Road, Shanghai 200237 China, and
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032 China
*Fax: 86-21-64166128.
Mshi@mail.sioc.ac.cn
Received December 31, 2010
ABSTRACT
An interesting phosphine-containing Lewis base catalyzed highly regioselective [3 þ 2] cycloaddition and a novel nitrogen-containing Lewis base
catalyzed highly geometric selective [4 þ 2] cycloaddition of isatin derived R,β-unsaturated diesters with R-allenic ester have been disclosed to
give the corresponding cyclic products in good to excellent yields under mild conditions. A plausible reaction mechanism has also been proposed
on the basis of previous literature and our own investigation.
Recently, phosphine- and nitrogen-containing Lewis
base catalyzed cyclization reactions of allenoates have
emerged as powerful synthetic tools in the rapid construc-
tion of cyclic molecular complexity via metal-free, mild
conditions and an easy manipulation process with readily
† East China University of Science and Technology.
‡ Chinese Academy of Sciences.
(1) Selected papers on the phosphine-containing Lewis base cata-
lyzed cyclization of allenoates: (a) Zhang, C.; Lu, X. J. Org. Chem. 1995,
60, 2906. (b) Du, Y.; Lu, X.; Yu, Y. J. Org. Chem. 2002, 67, 8901. (c) Du,
Y.; Lu, X. J. Org. Chem. 2003, 68, 6463. (d) Tran, Y. S.; Kwon, O. J. Am.
Chem. Soc. 2007, 129, 12632. (e) Zhu, X.-F.; Henry, C.-E.; Kwon, O. J.
Am. Chem. Soc. 2007, 129, 6722. (f) Mercier, E.; Fonovic, B.; Henry, C.;
Kwon, O.; Dudding, T. Tetrahedron Lett. 2007, 48, 3617. (g) Dudding,
T.; Kwon, O.; Mercier, E. Org. Lett. 2006, 8, 3643. (h) Lopes, S. M. M.;
Santos, B. S.; Palacios, F.; Pinhoe Melo, T. M. V. D. ARKIVOC 2010, V,
70. (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. (k) Tran, Y. S.;
Kwon, O. Org. Lett. 2005, 7, 4289. Selected papers on the nitrogen-
containing Lewis base catalyzed cyclization of allenoates:(l) Zhao, G.-
L.; Huang, J.-W.; Shi, M. Org. Lett. 2003, 5, 4737. (m) Zhao, G.-L.; Shi,
M. J. Org. Chem. 2005, 70, 9975. (o) Shi, Y.-L.; Shi, M. Org. Lett. 2005,
7, 3057. (p) Zhao, G.-L.; Shi, M. Org. Biomol. Chem. 2005, 3, 3686. (q)
Zhao, G.-L.; Shi, Y.-L.; Shi, M. Org. Lett. 2005, 7, 4527. (r) Dai, L.-Z.;
Shi, Y.-L.; Zhao, G.-L.; Shi, M. Chem.;Eur. J. 2007, 13, 3701. (s) Shi,
M.; Dai, L.-Z.; Shi, Y.-L.; Zhao, G.-L. Adv. Synth. Catal. 2006, 348, 967.
(t) Guan, X.-Y.; Wei, Y.; Shi, M. J. Org. Chem. 2009, 74, 6343.
r
10.1021/ol1031798
Published on Web 02/08/2011
2011 American Chemical Society

available organocatalysts.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 During our on-
going investigation on phosphine- and nitrogen-contain-
ing Lewis base catalyzed cyclization reactions of
allenoates, herein, we wish to report an interesting phos-
phine-containing Lewis base catalyzed highly regioselec-
tive [3 þ 2] cycloaddition of isatin derived R,β-unsaturated
diesters with R-allenic ester as well as a novel nitrogen-
containing Lewis base catalyzed [4 þ 2] cycloaddition of
isatin derived R,β-unsaturated diesters with R-allenic ester
in good to excellent yields with high stereoselectivities
under mild conditions. Moreover, these heterocyclic pro-
ducts are the core structure motifs in a variety of natural
alkaloid derivatives such as Calabar alkaloids physostig-
mine and physovenine.4,5
We initially utilized diethyl 2-(1-(tert-butoxycarbonyl)-2-
oxoindolin-3-ylidene)malonate 1a (1.0 equiv) and allenic
ester 2 (1.5 equiv) as the substrates to investigate their
cyclization behavior in toluene at room temperature in the
presence of 20 mol % PBu3. It was found that the [3 þ 2]
cycloaddition reaction took place smoothly to give the
corresponding cyclic products 3a and 4a in 86% total yield
within 2 h and this cyclization is highly regioselective
because the ratio of 3a:4a is 13:1 (Scheme 1 and Table SI-
1 in the Supporting Information, entry 1). Subsequently, we
screened various phosphine catalysts for this reaction, and
Scheme 1. PBu3 and DMAP-Catalyzed Cyclization of 1a with 2
the results are summarized in Table SI-1 in the Supporting
Information. Sterically bulky tri(tert-butyl)phosphine
(PtBu3) and the least nucleophilic phosphine tris(4-
fluorophenyl)phosphine (P(p-FC6H4)3) did not catalyze
this reaction (Table SI-1, entries 3 and 7). Other phosphines
could smoothly promote the reaction under the standard
conditions, affording the corresponding cyclization pro-
ducts 3a and 4a in good total yields along with moderate
regioselectivities (Table SI-1, entries 2, 4-6, and 8-9). The
examination of solvent effects using PBu3 as the catalyst
revealed that, in acetonitrile, no reaction occurred and
toluene is the solvent of choice, giving the cyclic adducts
3a and 4a in higher total yield (Table SI-1, entries 10-14).
Using 10 mol % PBu3 as the catalyst produced the corre-
sponding cyclization products 3a and 4a in 80% total yield
(3a:4a = 9:1) (Table SI-1, entry 15).
Using nitrogen-containing Lewis bases as the catalysts,
we found that no reaction occurred in the presence of 1,8-
diazabicyclo[5,4,0]-7-undecene (DBU) or triethylamine in
toluene (Table SI-2 in the Supporting Information, entries
1 and 2). However, it was surprising to find that, by using
4-N,N-dimethylpyridine (DMAP) (10 mol %) as the cat-
alyst, the reaction of 1a (1.0 equiv) with 2 (2.0 equiv)
produced the corresponding [4 þ 2] cycloaddition product
5a in 70% yield as Z- and E-isomeric mixtures (Z/E = 6:1)
in toluene overnight (12 h) (Table SI-2, entry 3). Increasing
the employed amount of DMAP to 20 mol % afforded 5a
in 76% yield (Z/E = 8:1) (Scheme 1). The screening of
solvent indicated that toluene is still the best solvent,
affording 5a in higher yields (Table SI-2, entries 5-9).
Using 1,4-diazabicyclo[2,2,2]octane (DABCO) (20 mol %)
as the catalyst provided cyclic adduct 5a in 68% yield (Z/E
= 1:2) along with a double bond migrated product 6a in
31% yield (Scheme 2).
(2) For reviews: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001,
34, 535. (b) Cowen, B. J.; Miller, J. S. Chem. Soc. Rev. 2009, 38, 3102. (c)
Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. (d) Wei,
€
Y.; Shi, M. Acc. Chem. Res. 2010, 43, 1005. (e) Nising, C.; Brase, S.
Chem. Soc. Rev. 2008, 37, 1218. (f) Ye, L.-W.; Zhou, J.; Tang, Y. Chem.
Soc. Rev. 2008, 37, 1140. (g) Marinetti, A.; Voituriez, A. Synlett 2010,
174.
(3) Selected papers on the chiral phosphine catalyzed asymmetric
cyclization of allenoates: (a) Fang, Y.-Q.; Jacobsen, E. N. J. Am. Chem.
Soc. 2008, 130, 5660. (b) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.;
Zhang, X. J. Am. Chem. Soc. 1997, 119, 3836. (c) Xiao, H.; Chai, Z.;
Zheng, C.-W.; Yang, Y.-Q.; Liu, W.; Zhang, J.-K.; Zhao, G. Angew.
Chem., Int. Ed. 2010, 49, 4467. (d) Wilson, J. E.; Fu, G. C. Angew. Chem.,
Int. Ed. 2006, 45, 1426. (e) Wallace, D. J.; Sidda, R. L.; Reamer, R. A. J.
Org. Chem. 2007, 72, 1051. (f) Chung, Y.-K.; Fu, G. C. Angew. Chem.,
Int. Ed. 2009, 48, 2225. (g) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc.
2005, 127, 12234. (h) Voituriez, A.; Pinto, N.; Neel, M.; Retailleau, P.;
Marinetti, A. Chem.;Eur. J. 2010, 16, 12541. (i) Miyamoto, H.; Okawa,
Y.; Nakazaki, A.; Kobayashi, S. Angew. Chem., Int. Ed. 2006, 45, 2274.
Paper on the chiral nitrogen-containing Lewis base catalyzed asym-
metric cyclization of allenoates:(j) Cowen, B. J.; Saunders, L. B.; Miller,
S. J. J. Am. Chem. Soc. 2009, 131, 6105.
(4) (a) Mugishima, T.; Tsuda, M.; Kasai, Y.; Ishiyama, H.; Fukushi,
E.; Kawabata, J.; Watanabe, M.; Akao, K.; Kobayashi, J. J. Org. Chem.
2005, 70, 9430. (b) Bond, R. F.; Boeyens, J. C. A.; Holzapfel, C. W.;
Steyn, P. S. J. Chem. Soc., Perkin Trans. 1 1979, 175. (c) Greshock, T. J.;
Grubbs, A. W.; Jiao, P.; Wicklow, D. T.; Gloer, J. B.; Williams, R. M.
Angew. Chem., Int. Ed. 2008, 47, 3573. (d) Tsukamoto, S.; Kawabata, T.;
Kato, H.; Greshock, T. J.; Hirota, H.; Ohta, T.; Williams, R. M. Org.
Lett. 2009, 11, 1297. (e) Marti, C.; Carreira, E. M. Eur. J. Org. Chem.
2003, 2209. (f) Toyota, M.; Ihara, M. Nat. Prod. Rep. 1998, 15, 327. (g)
Dounay, A. B.; Hatanaka, K.; Kodanko, J. J.; Oestreich, M.; Overman,
L. E.; Pfeifer, L. A.; Weiss, M. M. J. Am. Chem. Soc. 2003, 125, 6261. (h)
Miyamoto, H.; Okawa, Y.; Nakazaki, A.; Kobayashi, S. Angew. Chem.,
Int. Ed. 2006, 45, 2274 and reference therein.
Having identified the optimal reaction conditions, we
next set out to examine the scope and limitations of the
[3 þ 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 can be seen from Table 1, whether electron-with-
drawing or electron-donating groups at the 5-, 6- or 7-posi-
tion of the benzene ring of N-Boc protected isatins 1 were
employed, the reactions proceeded smoothly to give the
corresponding products 3 and 4 in good total yields along
(5) For their applications in medicinal chemistry: Fensome, A.;
Adams, W. R.; Adams, A. L.; Berrodin, T. J.; Cohen, J.; Huselton, C.;
Illenberger, A.; Kern, J. C.; Hudak, V. A.; Marella, M. A.; Melenski,
E. G.; McComas, C. C.; Mugford, C. A.; Slayden, O. D.; Yudt, M.;
Zhang, Z.; Zhang, P.; Zhu, Y.; Winneker, R. C.; Wrobel, J. E. J. Med.
Chem. 2008, 51, 1861.
Org. Lett., Vol. 13, No. 5, 2011
1143

Table 2. Substrate Scope of the Reactions Catalyzed by DMAPa
Scheme 2. DABCO-Catalyzed [4 þ 2] Cyclization of 1a with 2
yield (%)
entry
no.
PG
R
(Z/E)b
1
2
1b
1c
1d
1e
1f
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Bn
5-F
5b, 85 (8:1)
5c, 90 (4:1)
5d, 88 (5:1)
5e, 80 (5:1)
5f, 91 (Z)
5-Cl
5-Br
5-Me
5-MeO
6-Br
5,7-(Me)2
H
3
4
5
6
1g
1h
1i
5g, 80 (5:1)
5h, 87 (Z)
5i, 73 (Z)
7
a
Table 1. Substrate Scope of the Reactions Catalyzed by PBu3
8
9
1j
Me
H
5j, 78 (Z)
10
11
12
1k
1l
Cbz
allyl
PMB
H
5k, 94 (7:1)
5l, 91 (Z)
H
1m
H
5m, 58 (Z)
a The reaction was carried out on a 0.1 mmol scale with 20 mol %
catalyst under Ar in solvent (1.0 mL) at room temperature overnight,
and the ratio of 1:2 was 1.0:2.0. b Isolated total yield and these stereo-
isomers cannot be easily separated by column chromatography.
entry
no.
PG
R
yield (%)b
no.
3:4c
1
2
1b
1c
1d
1e
1f
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Bn
5-F
75
82
77
79
79
74
75
90
90
76
80
77
3b:4b
3c:4c
3d:4d
3e:4e
3f:4f
11:1
>20:1
>20:1
13:1
12:1
17:1
10:1
10:1
7:1
5-Cl
5-Br
5-Me
5-MeO
6-Br
5,7-(Me)2
H
various isatin derivatives 1 with different substituents on
the benzene rings, and the results are summarized in Table
2. All of the reactions proceeded smoothly under the
optimal conditions, producing the desired cyclic products
5b-5h in good to excellent yields (80-91%) along with
good to excellent geometric selectivities (Z/E = 4:1 to only
Z-isomer), no matter whether they had electron-withdraw-
ing or electron-donating substituents on their aromatic
rings at the 5-, 6- or 7-position (Table 2, entries 1-7).
Varying the N-protecting groups also gave the cyclic
adducts 5i-5m in good to high yields along with good
geometric selectivities (Table 2, entries 8-12). The struc-
ture and the configuration of product Z-5j was unequi-
vocally determined by X-ray diffraction, and its CIF data
are shown in the Supporting Information.7
3
4
5
6
1g
1h
1i
3g:4g
3h:4h
3i:4i
7
8
9
1j
Me
H
3j:4j
10
11
12
1k
1l
Cbz
allyl
PMB
H
3k:4k
3l:4l
11:1
3:1
H
1m
H
3m:4m
13:1
a The reaction was carried out on a 0.1 mmol scale with 20 mol %
catalyst under Ar in toluene (1.0 mL) at room temperature for 2 h, and
the ratio of 1:2 was 1.0:1.5. b Isolated total yield. c The regioisomeric
ratio of 3:4 was determined by 1H NMR spectroscopic data, and these
regioisomerscan not be easily separated by column chromatography.
We also investigated the DABCO-catalyzed cyclization
of 1i with 2in toluene, and the result is outlined in Scheme 3.
The corresponding [4 þ 2] cycloadducts 5i (Z-isomer) and
5i0 (E-isomer) were formed in 10% and 16% yields, respec-
tively along with a double bond migrated product 6i in 72%
yield (Scheme 3). The structures of 5i0 and 6i have been
established by X-ray diffraction, and their CIF data are
presented in the Supporting Information.8,9
with high regioselectivities (up to 3:4 > 20:1) (Table 1,
entries 1-7). It should also be noted that, as in the case of
other isatin derivatives 1i-1m bearing different N-protect-
ing groups, the reactions proceeded smoothly to produce
the corresponding cyclic products 3i-3m and 4i-4m in
good to high total yields (up to 90%) and moderate to high
regioselectivities (up to 13:1) (Table 1, entries 8-12). Only
in the case of a N-allylic group protected isatin derivative 1l,
the corresponding cyclization product 3l was formed in
moderate regioselectivity (3l:4l = 3:1), presumably due to
the steric effect (Table 1, entry 11). In all cases, the
cycloadducts 3 were obtained as the major products. The
structure of the major cycloaddition product 3i was un-
ambiguously assigned by X-ray diffraction, and its CIF
data are summarized in the Supporting Information.6
We next examined the scope and limitations of the
[4 þ 2] cycloaddition reaction catalyzed by DMAP using
Interestingly, we found that, in the PBu3 (10 mol %)
catalyzed cyclization of 1i with ethyl but-2-ynoate 7, the
(6) The crystal data of 3i have been deposited in the CCDC with
number 798143.
(7) The crystal data of Z-5j have been deposited in the CCDC with
number 802125.
(8) The crystal data of 5i’ have been deposited in the CCDC with
number 800399, and the crystal data of 6i have been deposited in the
CCDC with number 800400.
(9) (a) Evans, C. A.; Miller, S. J. J. Am. Chem. Soc. 2003, 125, 12394. (b)
Meng, L.-G.; Cai, P.; Guo, Q.-X.; Xue, S. J. Org. Chem. 2008, 73, 8491.
1144
Org. Lett., Vol. 13, No. 5, 2011

Scheme 3. DABCO-Catalyzed Cyclization of 1i with 2
Scheme 5. A Plausible Reaction Mechanism
Scheme 4. PBu3-Catalyzed Cyclization of 1i with Ethyl But-2-
ynoate 7
corresponding cyclization adduct 3i was formed in 77%
yield as the sole product in THF under the standard
conditions although no reaction occurred in the presence
of DMAP, presumably due to that the stronger nucleo-
philicity of a phosphine catalyst can produce the corre-
sponding alleneoate from alkynoate 7 which can
subsequently give 3i (Scheme 4; also see Scheme 5).
The mechanism for the different reaction outcome
caused by phosphine and nitrogen catalysts has not been
unequivocally established. One reasonable explanation is
shown in Scheme 5 based on the earlier reports and our
own investigations.
In the case of the PBu3-catalyzed reaction, the catalyst
reacts with the allenic ester 2 to generate a zwitterionic
intermediate A, which serves as a dipole for the subsequent
[3 þ 2] cycloaddition with 1 to give intermediate C.1a
Subsequently, the facile 1,2-proton transfer affords inter-
mediate E, and then, the elimination takes place to give the
product 3 as the major product along withthe regeneration
of the catalyst. This mechanism, as proposed by others,9
benefits from the ability ofphosphorus tostabilize the ylide
structure C. In contrast, the DMAP-catalyzed pathway
does not benefit from a similar stabilization. The zwitter-
ionic intermediate B reacts with 1 to give intermediate D,
which undergoes enolization to give intermediate F. Sub-
sequent cyclization produces cyclic adduct 5 and regener-
ates the DMAP catalyst. The cyclization step is assumed to
be the rate-determining step, accounting for the longer
reaction time required compared with the phosphine-con-
taining Lewis base catalyzed one.
functionalized spirocyclic products in good to excellent
yields along with high regioselectivities. Moreover, a novel
nitrogen-containing Lewis base catalyzed highly geometric
selective [4 þ 2] cycloaddition of isatin derived R,β-un-
saturated diesters with R-allenic ester has been disclosed,
giving the corresponding cyclic adducts in good to excel-
lent yields under mild conditions. A plausible reaction
mechanism hasalsobeenproposed on the basisofprevious
literature and our own investigation. Efforts are in pro-
gress to elucidate further mechanistic details of these
reactions and to understand their scope and limitations.
Acknowledgment. We thank the Shanghai Municipal
Committee of Science and Technology (08dj1400100-2),
National Basic Research Program of China (973)-
2009CB825300, the Fundamental Research Funds for
the Central Universities, and the National Natural Science
Foundation of China for financial support (21072206,
20472096, 20872162, 20672127, 20821002, and 20732008).
Supporting Information Available. Spectroscopic data
and NMR charts of the compounds shown in Tables 1-4,
X-ray crystal data of 3i, Z-5j, 5i0, and 6i as well as the
detailed descriptions of experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have found and developed an interest-
ing phosphine-containing Lewis base catalyzed highly
regioselective [3 þ 2] cycloaddition of isatin derived R,β-
unsaturated diesters with R-allenic ester, affording the
Org. Lett., Vol. 13, No. 5, 2011
1145