Stereoselective synthesis of 3-alkylideneoxindoles by rhodium-catalyzed cyclization reaction of 2-alkynylaryl isocyanates with aryland alkenylboronic acids

Article abstract of DOI:10.1021/ol7024185

The rhodium-catalyzed cyclization reaction of 2-alkynylaryl isocyanates with aryl- and alkenylboronic acids furnishes 3-alkylideneoxindoles in a stereoselective manner. The reaction allows arrangement of various substituents on the exocyclic double bond a

Full text of DOI:10.1021/ol7024185

ORGANIC
LETTERS
2
007
Vol. 9, No. 24
075-5077
Stereoselective Synthesis of
-Alkylideneoxindoles by
5
3
Rhodium-Catalyzed Cyclization Reaction
of 2-Alkynylaryl Isocyanates with Aryl-
and Alkenylboronic Acids
Tomoya Miura, 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 October 3, 2007
ABSTRACT
The rhodium-catalyzed cyclization reaction of 2-alkynylaryl isocyanates with aryl- and alkenylboronic acids furnishes 3-alkylideneoxindoles in
a stereoselective manner. The reaction allows arrangement of various substituents on the exocyclic double bond and aromatic ring with wide
functional tolerance.
The rhodium-catalyzed addition reaction of organoboron
reagents to unsaturated organic compounds has gained much
attention in organic synthesis.1 The reaction generally
proceeds via rhodium/boron transmetalation generating an
intermediate organorhodium(I) species followed by a sub-
sequent carborhodation step. It has been demonstrated by
anates are interesting bifunctional substrates with regard to
the possibility of a cascade-type cyclization reaction, for
which an alkynylpalladium species has presented a leading
6
example. We report herein the rhodium-catalyzed reaction
of 2-alkynylaryl isocyanates with organoboron reagents. This
2
scheme permits the sp carbon on boron to be transferred
2
3
us and others that multiple carborhodation steps can operate
sequentially on acceptor compounds possessing two or more
unsaturated functionalities to yield a variety of cyclic
regioselectively onto the alkyne moiety producing 3-alky-
7
8
lideneoxindoles, which are versatile synthetic intermediates
9
as well as drug candidates.
4
5
compounds. Since both alkynes and isocyanates are good
acceptors of organorhodium(I) species, 2-alkynylaryl isocy-
2
-(1-Hexynyl)phenyl isocyanate (1a, 1.0 equiv) was treated
with phenylboronic acid (2a, 1.5 equiv) in the presence of
Rh(OH)(cod)] (5 mol % Rh, cod ) cycloocta-1,5-diene)
[
2
(
1) For reviews, see: (a) Fagnou, K.; Lautens, M. Chem. ReV. 2003,
in THF (0.1 M) at room temperature for 12 h. Chromato-
1
03, 169. (b) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829.
(2) Miura, T.; Murakami, M. Chem. Commun. 2007, 217.
graphic isolation on silica gel afforded 3-alkylideneoxindole
(3) For selected examples, see: (a) Cauble, D. F.; Gipson, J. D.; Krische,
1
3
aa as a single stereoisomer (Z/E ) >20:1 by H NMR) in
M. J. J. Am. Chem. Soc. 2003, 125, 1110. (b) Shintani, R.; Tsurusaki, A.;
Okamoto, K.; Hayashi, T. Angew. Chem., Int. Ed. 2005, 44, 3909. (c) Tseng,
N.-W.; Mancuso, J.; Lautens, M. J. Am. Chem. Soc. 2006, 128, 5338. (d)
Harada, Y.; Nakanishi, J.; Fujihara, H.; Tobisu, M.; Fukumoto, Y.; Chatani,
N. J. Am. Chem. Soc. 2007, 129, 5766 and references therein.
78% yield (eq 1). The Z stereochemistry of the exocyclic
(5) (a) Koike, T.; Takahashi, M.; Arai, N.; Mori, A. Chem. Lett. 2004,
33, 1364. (b) Miura, T.; Takahashi, Y.; Murakami, M. Chem. Commun.
2007, 3577.
(6) Kamijo, S.; Sasaki, Y.; Kanazawa, C.; Sch u¨ âeler, T.; Yamamoto,
Y. Angew. Chem., Int. Ed. 2005, 44, 7718.
(4) (a) Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara, M. J. Am.
Chem. Soc. 2001, 123, 9918. (b) Murakami, M.; Igawa, H. HelV. Chim.
Acta 2002, 85, 4182. (c) Lautens, M.; Yoshida, M. Org. Lett. 2002, 4, 123.
(d) Genin, E.; Michelet, V.; Gen eˆ t, J.-P. Tetrahedron Lett. 2004, 45, 4157.
1
0.1021/ol7024185 CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/25/2007

double bond was determined by derivatization of 3aa to the
corresponding N-benzylated compound.7
the reaction of tert-butyl-substituted alkyne 1f failed to reach
completion and the product 3fa was obtained in only 18%
yield (entry 12). Interestingly, terminal alkynes successfully
participated in this process. Thus, oxindoles 3ha and 3hh
possessing Z stereochemistries for the exocyclic trisubstituted
double bonds were obtained in 70% and 74% yields,
respectively (entries 14 and 15). These results stand in
contrast to other rhodium-catalyzed reactions in which a
complex mixture often arises from a terminal alkyne via
pathways other than simple 1,2- addition, probably involving
e
The results obtained with various combinations of 2-alky-
nylaryl isocyanates 1 and organoboronic acids 2 are listed
in Table 1. Not only substituted phenylboronic acids 2b-d
1
0
a rhodium vinylidene intermediate.
The results of the reaction of functionalized aryl isocy-
anates 1 with 2a shown in Table 2 demonstrated that a wide
Table 1. Rh(I)-Catalyzed Cyclization Reaction of 1 with 2
Table 2. Reaction of Functionalized Aryl Isocyanates 1 with
2a
a
Isolated yield.
a
Isolated yield. b 2 (2.0 equiv), 40 °C. c 2 (3.0 equiv), dioxane, 100 °C.
d
2
(2.0 equiv).
range of functional groups including chloro, methoxy ether,
cyano, and ester groups were tolerated on the aryl group
of 1.
but also isomeric thienylboronic acids 2e and 2f reacted with
a to give oxindoles 3ab-3af stereoselectively in yields
ranging from 56% to 84% (entries 1-5). More forcing
conditions were applied to the reaction of 2d and 2f, which
are thought to be less nucleophilic due to steric and electronic
reasons, respectively. In addition, even alkenylboronic acids
We propose the reaction pathway depicted in Scheme 1
for the stereoselective production of oxindoles 3. Initially,
intermediate organorhodium(I) species A is generated by
transmetalation of rhodium with 2. Both alkynyl and isocy-
anato groups of 1 coordinate to the rhodium center to form
the chelate complex B, which then leads to the cyclized
rhodium(I) alkoxide C. Protonolysis of C with 2 releases
the product 3 along with a rhodium(I) boronate, which
regenerates A to promote the next catalytic cycle.11
Three mechanistic possibilities are conceivable for the
cyclization of B forming C. The first one consists of two
1
2g and 2h participated in the reaction with 1a (entries 6 and
7). Whereas primary and secondary alkyl groups were
suitable substituents at the alkyne termini of 1 (entries 8-11),
(7) For recent examples of the synthesis of 3-alkylideneoxindoles with
catalysis of transition metals, see: (a) Fielding, M. R.; Grigg, R.; Urch, C.
J. Chem. Commum. 2000, 2239. (b) Yanada, R.; Obika, S.; Oyama, M.;
Takemoto, Y. Org. Lett. 2004, 6, 2825. (c) D’Souza, D. M.; Rominger, F.;
M u¨ ller, T. J. J. Angew. Chem., Int. Ed. 2005, 44, 153. (d) Cheung, W. S.;
Patch, R. J.; Player, M. R. J. Org. Chem. 2005, 70, 3741. (e) Yanada, R.;
Obika, S.; Inokuma, T.; Yanada, K.; Yamashita, M.; Ohta, S.; Takemoto,
Y. J. Org. Chem. 2005, 70, 6972. (f) Kobayashi, Y.; Kamisaki, H.; Yanada,
K.; Yanada, R.; Takemoto, Y. Tetrahedron Lett. 2005, 46, 7549. (g)
Shintani, R.; Yamagami, T.; Hayashi, T. Org. Lett. 2006, 8, 4799. (h) Pinto,
A.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 3291.
(9) (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.
(8) For the intermediates in total synthesis, see: (a) Carroll, W. A.;
Grieco, P. A. J. Am. Chem. Soc. 1993, 115, 1164. (b) Rasmussen, H. B.;
MacLeod, J. K. J. Nat. Prod. 1997, 60, 1152. (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.
(10) For 1,1-carborhodation of terminal alkynes with organoboron
reagents through a rhodium vinylidene intermediate, see: Chen, Y.; Lee,
C. J. Am. Chem. Soc. 2006, 128, 15598.
5076
Org. Lett., Vol. 9, No. 24, 2007

Scheme 1
Scheme 2
If the stepwise mechanism operates in a way that the initial
carborhodation occurs on one functionality without coordi-
native participation of the other functionality, the selective
production of 3 contradicts the lack of chemoselectivity
observed in the intermolecular competitive reaction. How-
ever, the stepwise pathway via D cannot be ruled out if it is
taken into consideration that the reactivity order of two
functionalities toward carborhodation can change when
chelating coordination is possible. A detailed computational
study would help differentiating between the possibilities
mentioned above.
To conclude, the rhodium-catalyzed reaction of 2-alky-
nylaryl isocyanates 1 with organoboronic acids 2 permits
the stereoselective placement of various kinds of substituents
on the exocyclic double bonds of the resulting 3-alkylide-
neoxindoles with wide functional group tolerance. Aryl,
heteroaryl, and alkenyl groups are delivered cis to the
carbonyl group from the boron compounds 2, and hydrogen,
primary alkyl, and secondary alkyl groups are placed trans
to the carbonyl group.
sequential carborhodation steps, initially operating on the
alkyne moiety and next on the isocyanato moiety (D) in a
6
stepwise manner, as in the palladium-catalyzed case.
Another mechanistic possibility is a more concerted one as
12
schematized in E. Formation of two carbon-carbon bonds
and a rhodium-oxygen bond occurs simultaneously. The last
possibility involves an oxidative cyclization step to form a
13
carbon-carbon bond furnishing rhodacycle F and subse-
2
quent reductive elimination to install the R group.
The following control experiments were carried out to gain
some mechanistic insight (Scheme 2). A mixture of 1-hexy-
nylbenzene (4, 1.0 equiv) and phenyl isocyanate (5, 1.0
equiv) was reacted with 3-thienylboronic acid (2e, 1.0 equiv).
Both substrates 4 and 5 competed for reaction with 2e to
give the corresponding adducts 614 and 7 in 28% and 20%
yield, respectively. In addition, R,â-unsaturated amide 8 was
obtained in 9% yield, suggesting that some part of intermedi-
ate alkenylrhodium(I) species immediately underwent inter-
molecular addition to 5. When 2 equiv of 2e was employed,
the yields of the products 6-8 nearly doubled.
Acknowledgment. This work was supported by the
Takeda Science Foundation and the Ministry of Education,
Culture, Sports, Science, and Technology, Japan (Grant-in-
Aids for Young Scientists (B) 18750084 and Scientific
Research on Priority Areas 18032040).
(11) Zhao, P.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2007,
1
29, 1876.
(12) Kurahashi, T.; Shinokuba, H.; Osuka, A. Angew. Chem., Int. Ed.
Supporting Information Available: Experimental details
and spectra data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
2
006, 45, 6336.
(13) For intermolecular oxidative cyclization with the CtC triple bond
of an alkyne and the NdC double bond of an isocyanate, see: Yu, R. T.;
Rovis, T. J. Am. Chem. Soc. 2006, 128, 12370.
1
(14) A high regioselectively (ca. 20:1) was observed by H NMR.
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