Stereoselective synthesis of 3-alkylideneoxindoles by palladium-catalyzed cyclization reaction of 2-(alkynyl)aryl isocyanates with organoboron reagents

Article abstract of DOI:10.1021/ol801844w

(Chemical Equation Presented) A palladium(0)/monophosphine catalyst promotes a cyclization reaction of 2-(alkynyl)aryl isocyanates with organoboron reagents to produce stereodefined 3-alkylideneoxindoles. The alkynyl and isocyanato groups undergo oxidativ

Full text of DOI:10.1021/ol801844w

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4887-4889
Stereoselective Synthesis of
3-Alkylideneoxindoles by
Palladium-Catalyzed Cyclization
Reaction of 2-(Alkynyl)aryl Isocyanates
with Organoboron Reagents
Tomoya Miura, Takeharu Toyoshima, Yusuke Takahashi, and
Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto UniVersity,
Katsura, Kyoto 615-8510, Japan
murakami@sbchem.kyoto-u.ac.jp
Received August 25, 2008
ABSTRACT
A palladium(0)/monophosphine catalyst promotes a cyclization reaction of 2-(alkynyl)aryl isocyanates with organoboron reagents to produce
stereodefined 3-alkylideneoxindoles. The alkynyl and isocyanato groups undergo oxidative cyclization with Pd(0) to form an oxapalladacycle
intermediate. Subsequent transmetalation and reductive elimination afford the product.
The 3-alkylideneoxindole ring system represents a key
substructure found in a number of biologically active
compounds.1 In addition, 3-alkylideneoxindoles are valuable
intermediates in the synthesis of naturally occurring alka-
loids2 and drug candidates.3 Although Knoevenagel conden-
sation between oxindole derivatives and carbonyl compounds
is one of the most reliable procedures for their preparation,
a mixture of both stereoisomers is often formed with regard
to the resulting carbon-carbon double bond.1a,2a-c Therefore,
the development of a method for the stereoselective synthesis
of these important molecules is needed, and several transi-
tion-metal-mediated procedures have been developed.4 We
have previously described the rhodium(I)-catalyzed cycliza-
tion reaction of 2-(alkynyl)aryl isocyanates with aryl- and
alkenylboronic acids.5 This reaction permits the sp2 carbon
(1) (a) Sun, L.; Tran, N.; Tang, F.; App, H.; Hirth, P.; McMahon, G.;
Tang, C. J. Med. Chem. 1998, 41, 2588. (b) Vieth, M.; Cummins, D. J.
J. Med. Chem. 2000, 43, 3020. (c) Woodard, C. L.; Li, Z.; Kathcart, A. K.;
Terrell, J.; Gerena, L.; Lopez-Sanchez, M.; Kyle, D. E.; Bhattacharjee, A. K.;
Nichols, D. A.; Ellis, W.; Prigge, S. T.; Geyer, J. A.; Waters, N. C. J. Med.
Chem. 2003, 46, 3877. (d) Pandit, B.; Sun, Y.; Chen, P.; Sackett, D. L.;
Hu, Z.; Rich, W.; Li, C.; Lewis, A.; Schaefer, K.; Li, P.-K. Bioorg. Med.
Chem. 2006, 14, 6492. (e) Andreani, A.; Burnelli, S.; Granaiola, M.; Leoni,
A.; Locatelli, A.; Morigi, R.; Rambaldi, M.; Varoli, L.; Kunkel, M. W.
J. Med. Chem. 2006, 49, 6922.
(4) For recent examples of the synthesis of 3-alkylideneoxindoles with
catalysis of transition metals, see: (a) Kamijo, S.; Sasaki, Y.; Kanazawa,
C.; Schu¨ꢀeler, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44, 7718.
(b) Yanada, R.; Obika, S.; Inokuma, T.; Yanada, K.; Yamashita, M.; Ohta,
S.; Takemoto, Y. J. Org. Chem. 2005, 70, 6972. (c) Cheung, W. S.; Patch,
R. J.; Player, M. R. J. Org. Chem. 2005, 70, 3741. (d) Shintani, R.;
Yamagami, T.; Hayashi, T. Org. Lett. 2006, 8, 4799. (e) Pinto, A.; Neuville,
L.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 3291. (f) Tang, S.; Yu, Q.-F.;
Peng, P.; Li, J.-H.; Zhong, P.; Tang, R.-Y. Org. Lett. 2007, 9, 3413. (g)
Tang, S.; Peng, P.; Pi, S.-F.; Liang, Y.; Wang, N.-X.; Li, J.-H. Org. Lett.
2008, 10, 1179. (h) Miura, T.; Takahashi, Y.; Murakami, M. Org. Lett.
2008, 10, 1743. (i) Tang, S.; Peng, P.; Wang, Z.-Q.; Tang, B.-X.; Deng,
C.-L.; Li, J.-H.; Zhong, P.; Wang, N.-X. Org. Lett. 2008, 10, 1875.
(5) Miura, T.; Takahashi, Y.; Murakami, M. Org. Lett. 2007, 9, 5075.
(2) (a) Carroll, W. A.; Grieco, P. A. J. Am. Chem. Soc. 1993, 115, 1164.
(b) Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426. (c) Lin, S.;
Yang, Z.-Q.; Kwok, B. H. B.; Koldoskiy, M.; Crews, C. M.; Danishefsky,
S. J. J. Am. Chem. Soc. 2004, 126, 6347. (d) Trost, B. M.; Cramer, N.;
Bernsmann, H. J. Am. Chem. Soc. 2007, 129, 3086.
(3) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.; Gao,
W.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Tomita, Y.; Parrish, D. A.;
Deschamps, J. R.; Wang, S. J. Am. Chem. Soc. 2005, 127, 10130.
10.1021/ol801844w CCC: $40.75
Published on Web 10/07/2008
2008 American Chemical Society

on boron to be transferred regioselectively onto the alkyne
moiety to produce arylated and alkenylated 3-alkylideneox-
indoles in a stereoselective manner. In this paper, we report
that palladium(0) catalysts promote an analogous type of
cyclization reaction with greater efficiency. The palladium-
catalyzed system not only expands the substrate scope for
the substituents at the alkyne termini but also permits the
installation of sp3 and sp carbons on the exocyclic double
bond.
species C.10 Reductive elimination from C then affords
arylated intermediate D and regenerates the palladium(0)
catalyst.11 Protonolysis of D occurs during aqueous workup
to give 3aa.
To compare the Rh- and Pd-catalyzed reactions, we
examined the arylative cyclization reaction of 2-(2-phenyl-
ethynyl)phenyl isocyanate (1a). When 1a was treated with
4-methylphenylboronic acid (2a) in the presence of [Rh-
(OH)(cod)]2 (5 mol % of Rh) at 50 °C for 12 h, 3-alkylide-
neoxindole 3aa was obtained in only 13% yield.5 Remark-
ably, the use of readily available Pd(PPh3)4 (5 mol % of Pd)
provided 3aa in 99% yield as a single stereoisomer (Z/E )
>20:1,6 eq 1) at 50 °C. No base is required to promote the
catalytic cycle unlike the Suzuki-Miyaura cross-coupling
reaction.7 Palladium(II) catalysts such as PdCl2(PPh3)2,
Pd(OAc)2, and Pd(OAc)2/dppe failed to promote the present
reaction or gave a complex mixture of products.8,9 We
propose that the reaction proceeds through the pathway
outlined in Scheme 1. Substrate 1a binds to a palladium(0)
The results obtained with various combinations of 2-(alky-
nyl)aryl isocyanates 1 and organoboronic acids 2 are listed
in Table 1. Not only arylboronic acids 2b-2d but also
Table 1. Pd(0)-Catalyzed Cyclization Reaction of 1 with 2
t
yield
(%)a
entry
1
R1
2
R2
X
(°C)
3
Scheme 1. Proposed Reaction Pathway
1
2
3
4
5
6
7
8
9
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
2b 4-CF3C6H4 1.5 80 3ab 89b
2c 4-MeOC6H4 1.5 50 3ac 99
2d 2-MeC6H4
2e 3-thienyl
2f ꢀ-styryl
1.5 50 3ad 87
1.5 rt 3ae 91
1.5 50 3af 97
2g (E)-pentenyl 2.0 rt 3ag 99
2h cyclopropyl 2.0 80 3ah 76b,c
2i Me
2j n-Bu
2.0 80 3ai 95b,c
3.0 100 3aj 49b,d
1.5 50 3bk 98
10 1b 4-MeC6H4 2k Ph
11 1c 4-CF3C6H4 2k Ph
12 1d 4-MeOC6H4 2k Ph
13 1e 2-MeC6H4 2k Ph
1.5 rt 3ck 99
1.5 50 3dk 99
1.5 50 3ek 97
14 1f 3-thienyl
15 1g n-Bu
16 1g n-Bu
17 1h n-Pr
18 1i i-Pr
2k Ph
2k Ph
2i Me
2k Ph
2k Ph
2.0 rt 3fk 99
1.5 50 3gk 98 (78)
2.0 80 3gi 68b,c (13)
1.5 rt 3hk 88 (79)
1.5 rt 3ik 92 (85)
1.5 80 3jk 99b,e (76)
2.0 100 3kk 55b,f (70)
19 1j cyclopropyl 2k Ph
20 1k H 2k Ph
a Isolated yield (stereoisomer ratio ) >20:1) unless otherwise noted.
The yield using the Rh(I) catalyst was in parenthesis; see Supporting
Information for details. b 1,4-Dioxane was used. c 3 h. d Pd2(dba)3·CHCl3
(5 mol % of Pd) and P(2-furyl)3 (10 mol %) were used. e 2 h. f E/Z )
15:1∼20:1.
catalyst to generate the chelate complex A, which then forms
the oxapalladacycle B by oxidative cyclization. Subsequent
transmetalation of B with 2a produces the alkenylpalladium
(6) The ratio of stereoisomers was determined by 1H NMR. The Z
configuration of the exocyclic double bond of 3aa was assigned by an NOE
study.
heteroaryl- and alkenylboronic acids 2e-2g reacted with 1a
to give the corresponding 3-alkylideneoxindoles 3ab-3ag
stereoselectively in yields ranging from 87% to 99% (entries
1-6). In contrast to the rhodium system with which only an
sp2 carbon on boron could be introduced efficiently, even
(7) (a) Miyaura, N. In Metal-Catalyzed Cross-Coupling Reaction;
Diederich, F., de Meijere, A., Eds.; Wiley-VCH: New York, 2004; Chapter
2. (b) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 15, 2419.
(8) For a Pd(II)-catalyzed addition reaction of arylboronic acids, see:
(a) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Angew. Chem., Int. Ed. 2003,
42, 2768. (b) Lautens, M.; Dockendorff, C. Org. Lett. 2003, 5, 3695
.
(9) For a Pd(II)-catalyzed cyclization reaction of alkynones with
arylboronic acids, see: (a) Song, J.; Shen, Q.; Xu, F.; Lu, X. Org. Lett.
2007, 9, 2947. (b) Tsukamoto, H.; Kondo, Y. Org. Lett. 2007, 9, 4227. (c)
(10) Tsukamoto, H.; Suzuki, T.; Uchiyama, T.; Kondo, Y. Tetrahedron
Lett. 2008, 49, 4174.
Yang, M.; Zhang, X.; Lu, X. Org. Lett. 2007, 9, 5131
.
4888
Org. Lett., Vol. 10, No. 21, 2008

alkylboronic acids 2h-2j participated in the reaction with
1a (entries 7-9). A wide range of aryl groups 1b-1e and a
heteroaryl group 1f proved to be suitable as the substituents
at the alkyne termini of 1 (entries 10-14). With primary
and secondary alkyl-substituted substrates 1g-1j, the pal-
ladium(0)-catalyzed reaction gave higher yields than the
rhodium(I)-catalyzed reaction (entries 15-19). However,
terminal alkyne 1k, which was an appropriate substrate for
the rhodium system, required heating at 100 °C using the
current conditions and was accompanied by isomerization
of product 3kk to the thermally stable (E)-isomer (entry
20).12
Table 3. Cyclization Reaction of 1a with Alkynylboronates 2
entry
2
R2
Ph
TMS
n-Pr
t (°C)
3
yield (%)a
(Z/E)b
1
2
3
2l
2m
2n
50
50
rt
3al
3am
3an
76
61
48
(92:8)
(89:11)
(91:9)
The results in Table 2 show that a variety of functional
groups including chloride, ether, and ester are tolerated on
the aryl group of 1. The palladium system gave consistently
better yields (over 90% yield) than the rhodium system.
a Isolated yield. b The ratio of stereoisomers was determined by 1H NMR.
pin ) pinacolato.
of phenyl-substituted alkyne 1a with alkynylboronate 2l in
the presence of Pd2(dba)3·CHCl3 and P(2-furyl)3 afforded the
desired oxindole 3al in 76% yield as a mixture of stereoi-
somers16 (Z/E ) 92:8, entry 1). Alkynylboronates 2m17 and
2n bearing trimethylsilyl and n-propyl groups also reacted
with 1a to produce the Z-isomers preferentially (entries 2
and 3). Yamamoto and co-workers reported a palladium-
catalyzed cyclization reaction of 2-(alkynyl)aryl isocyanates
with terminal alkynes, which afforded the corresponding
alkynylated 3-alkylideneoxindoles.4a However, phenyl-
substituted alkyne 1a was an inappropriate substrate, giving
a complex mixture of unidentified products. Therefore, the
present reaction provides a complementary alkynylative
approach to the 3-alkylideneoxindoles.
Table 2. Reaction of Functionalized Aryl Isocyanates 1 with 2k
In summary, an efficient cyclization reaction of 2-(alky-
nyl)aryl isocyanates with organoboron reagents has been
developed using a palladium(0) catalyst. The palladium
system shows a remarkably broad substrate scope and also
achieves the stereoselective incorporation of various sub-
stituents on the exocyclic double bond of 3-alkylideneox-
indoles.
a Isolated yield (stereoisomer ratio ) >20:1) unless otherwise noted.
The yield using the Rh(I) catalyst was in parenthesis; see Supporting
Information for details.
Acknowledgment. This work was supported in part by
the Mizuho Foundation for the Promotion of Sciences and
the Ministry of Education, Culture, Sports, Science and
Technology of Japan (Grant-in-Aids for Scientific Research
on Priority Areas 18032040 and Young Scientists (B)
20750078).
We next examined the alkynylative cyclization reaction
using alkynylboronates13 and P(2-furyl)3 as the phosphine
ligand,14,15 with the results being listed in Table 3. Treatment
(11) At this time, it is not possible to rule out a mechanism involving
sequential carbopalladation steps, initially operating on the alkyne moiety
and next on the isocyanate moiety in a stepwise manner. For oxidative
addition of arylboronic acids to Pd(0), see: (a) Cho, C. S.; Uemura, S. J.
Organomet. Chem. 1994, 465, 85. (b) Moreno-Man˜as, M.; Pe´rez, M.;
Pleixats, R. J. Org. Chem. 1996, 61, 2346.
Supporting Information Available: Experimental details
and spectral data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) Villemin, D.; Martin, B. Synth. Commun. 1998, 28, 3201.
(13) For a Pd(0)-catalyzed alkynylation reaction of aryl halides with
alkynylboronates or alkynylborates, see: (a) Castanet, A.-S.; Colobert, F.;
Schlama, T. Org. Lett. 2000, 2, 3559. (b) Torres, G. H.; Choppin, S.;
Colobert, F. Eur. J. Org. Chem. 2006, 1450.
OL801844W
(15) Pd(PPh3)4 was less effective, and its use under the same reaction
conditions gave 3al in 42% yield (Z/E ) 56/44)
(16) As reported in ref 4a, the E/Z isomerization of alkynylated
3-alkylideneoxindoles was caused by the phosphine ligand
.
(14) (a) Kagawa, N.; Malerich, J. P.; Rawal, V. H. Org. Lett. 2008, 10,
2381. For a review of P(2-furyl)3 as ligand, see: (b) Andersen, N. G.; Keay,
.
B. A. Chem. ReV. 2001, 101, 997
.
(17) Alkynylboronate 2m was so labile that it was handled in a glovebox.
Org. Lett., Vol. 10, No. 21, 2008
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