Rhodium-catalyzed borylative cyclization of 2-alkynylaryl isocyanates with bis(pinacolato)diboron

Article abstract of DOI:10.1021/ol800380t

2-Alkynylaryl isocyanates reacted with bis(pinacolato)diboron in the presence of a cationic rhodium(l) catalyst to produce borylated 3-alkylideneoxindoles stereoselectively. The carbon-boron linkage formed was further transformed via reactions such as a cross-coupling and a halogenation reaction. American Chemical society.

Full text of DOI:10.1021/ol800380t

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1743-1745
Rhodium-Catalyzed Borylative
Cyclization of 2-Alkynylaryl Isocyanates
with Bis(pinacolato)diboron
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 February 19, 2008
ABSTRACT
2-Alkynylaryl isocyanates reacted with bis(pinacolato)diboron in the presence of a cationic rhodium(I) catalyst to produce borylated
3-alkylideneoxindoles stereoselectively. The carbon-boron linkage formed was further transformed via reactions such as a cross-coupling
and a halogenation reaction.
Organoboronic acids and esters have become indispensable
reagents in organic synthesis due to their unique reactivity,
air-stability, and accessibility.1 In addition, recent studies on
organoboronic acid derivatives have demonstrated their
potential as pharmaceutical candidates.2 Thus, the develop-
ment of efficient methods for the preparation of organobo-
ronic acid derivatives is currently the subject of intense
interest. Transition-metal-catalyzed addition reactions of
diboron reagents such as bis(pinacolato)diboron (B2pin2) and
bis(catecholato)diboron (B2cat2) to unsaturated organic com-
pounds presents one of the most useful methods of forming
carbon-boron bonds.3 Not only simple alkynes,4 allenes,5
and alkenes,6 but also bifunctional substrates7,8 react with
diboron reagents. We have recently described the rhodium-
catalyzed cyclization reaction of 2-alkynylaryl isocyanates
with arylboronic acids.9 In this reaction, the aryl group on
boron is transferred regioselectively onto the alkyne moiety
to produce arylated 3-alkylideneoxindoles.10 In view of the
synthetic11 and medicinal12 importance of these heterocycles,
(6) Simple alkenes: (a) Baker, R. T.; Nguyen, P.; Marder, T. B.;
Westcott, S. A. Angew. Chem., Int. Ed. Engl. 1995, 34, 1336. (b) Dai, C.;
Robins, E. G.; Scott, A. J.; Clegg, W.; Yufit, D. S.; Howard, J. A. K.;
Marder, T. B. Chem. Commun. 1998, 1983. (c) Ram´ırez, J.; Corbera´n, R.;
Sanau´, M.; Peris, E.; Fernandez, E. Chem. Commun. 2005, 3056. (d)
Trudeau, S.; Morgan, J. B.; Shrestha, M.; Morken, J. P. J. Org. Chem.
2005, 70, 9538. Electron-deficient alkenes: (e) Ito, H.; Yamanaka, H.;
Tateiwa, J.; Hosomi, A. Tetrahedron Lett. 2000, 41, 6821. (f) Takahashi,
K.; Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2001, 625, 47. (g)
Kabalka, G. W.; Das, B. C.; Das, S. Tetrahedron Lett. 2002, 43, 2323. (h)
Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 5031. (i) Lee,
J.-E.; Yun, J. Angew. Chem. Int. Ed 2008, 47, 145. Allylic carbonates: (j)
Ito, H.; Ito, S.; Sasaki, Y.; Matsuura, K.; Sawamura, M. J. Am. Chem. Soc.
(1) Boronic acids: Preparation and Application in Organic Synthesis
and Medicine; Hall, D. G., Ed.; Wiley-VCH: Weinheim, Germany, 2005.
(2) (a) Irving, A. M.; Vogels, C. M.; Nikolcheva, L. G.; Edwards, J. P.;
He, X.-F.; Hamilton, M. G.; Baerlocher, M. O.; Baerlocher, F. J.; Decken,
A.; Westcott, S. A. New J. Chem. 2003, 27, 1419. (b) Paramore, A.; Frantz,
S. Nat. ReV. Drug DiscoVery 2003, 2, 611. (c) Rock, F. L.; Mao, W.;
Yaremchuk, A.; Tukalo, M.; Cre´pin, T.; Zhou, H.; Zhang, Y.-K.; Hernandez,
V.; Akama, T.; Baker, S. J.; Plattner, J. J.; Shapiro, L.; Martinis, S. A.;
Benkovic, S. J.; Cusack, S.; Alley, M. R. K. Science 2007, 316, 1759.
(3) For reviews, see: (a) Ishiyama, T.; Miyaura, N. Chem. Rec. 2004,
3, 271. (b) Beletskaya, I.; Moberg, C. Chem. ReV. 2006, 106, 2320. (c)
Burks, H. E.; Morken, J. P. Chem. Commun. 2007, 4717.
2007, 129, 14856
.
(7) For Pd(0)-catalyzed borylative cyclization of 1,6-enynes with
bis(pinacolato)diboron, see: Macro-Mart´ınez, J.; Lo´pez-Carrillo, V.; Bun˜uel,
E.; Simancas, R.; Ca´rdenas, D. J. J. Am. Chem. Soc. 2007, 129, 1874
.
(8) For borylative cyclization reactions with other boron reagents than
diboron compounds, see: (a) Onozawa, S.; Hatanaka, Y.; Tanaka, M. Chem.
Commun. 1997, 1229. (b) Onozawa, S.; Hatanaka, Y.; Choi, N.; Tanaka,
M. Organometallics 1997, 16, 5389. (c) Suginome, M.; Matsuda, T.; Ito,
Y. Organometallics 1998, 17, 5233. (d) Kinder, R. E.; Widenhoefer, R. A.
(4) Ishiyama, T.; Matsuda, N.; Miyaura, N.; Suzuki, A. J. Am. Chem.
Soc. 1993, 115, 11018.
(5) (a) Yang, F.-Y.; Wu, M.-Y.; Cheng, C.-H. J. Am. Chem. Soc. 2000,
122, 7122. (b) Burks, H. E.; Liu, S.; Morken, J. P. J. Am. Chem. Soc. 2007,
129, 8766.
Org. Lett. 2006, 8, 1967
.
(9) Miura, T.; Takahashi, Y.; Murakami, M. Org. Lett. 2007, 9, 5075.
10.1021/ol800380t CCC: $40.75
Published on Web 04/11/2008
2008 American Chemical Society

we next tried to incorporate a carbon-boron linkage into
the 3-alkylideneoxindole skeleton. We report herein the
stereoselective synthesis of borylated 3-alkylideneoxindoles
by the rhodium-catalyzed cyclization reaction of 2-alkynyl-
aryl isocyanates with bis(pinacolato)diboron.
Scheme 1. Proposed Reaction Pathway (I)
2-(1-Hexynyl)phenyl isocyanate (1a, 1.0 equiv) was treated
with B2pin2 (2, 1.5 equiv) in the presence of [Rh(OH)(cod)]2
(5 mol % Rh, cod ) cycloocta-1,5-diene) in 1,2-dichloro-
ethane (DCE) at 80 °C for 12 h (eq 1). 1H NMR analysis of
the reaction mixture showed that borylated 3-alkylideneox-
indole 3a was formed as a single stereoisomer (E/Z )
>20:1,13 ca.35%yield).Throughthissequence,acarbon-boron
bond and a carbon-carbon bond were formed simulta-
neously. The reaction proceeded more facilely (73% yield
by 1H NMR) when the cationic complex [Rh(cod)]2SbF6 was
employed.14 Although 3a was labile in solution, expeditious
chromatography employing Florisil as the solid phase gave
3a in 71% yield.15 Once isolated as a yellow solid, 3a was
relatively stable and could be kept at room temperature for
months without any detectable isomerization or decomposi-
tion. Whereas bis(neopentyl glycolato)diboron (B2neo2) gave
boryl-rhodium(III) species C. Finally, reductive elimination
from C affords the diboryl intermediate D along with the
starting cationic rhodium(I) species to complete the catalytic
cycle. Protonolysis of D occurs during aqueous workup to
give 3a. It should be noted, however, that another mechanism
is also conceivable, which involves oxidative addition of the
B-B bond onto a cationic rhodium(I) complex furnishing a
diboryl-rhodium(III) intermediate E,17 sequential addition
onto the alkyne moiety and the isocyanate moiety, and
reductive elimination (Scheme 2).18
1
the borylated product in a lower yield (50% by H NMR),
bis(catecholato)diboron was completely inactive under simi-
lar reaction conditions.
(1)
Scheme 2. Proposed Reaction Pathway (II)
We propose that the reaction takes place through the
pathway outlined in Scheme 1. The substrate 1a binds to
rhodium(I) to generate the chelate complex A, which then
forms the oxa-rhodacycle B by oxidative cyclization.16
A
subsequent reaction of B with B2pin2 (2) produces the
(10) For recent examples of the synthesis of 3-alkylideneoxindoles with
catalysis of transition metals, see: (a) Kamijo, S.; Sasaki, Y.; Kanazawa,
C.; Schu¨sseler, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44, 7718.
(b) D’Souza, D. M.; Rominger, F.; Mu¨ller, T. J. J. Angew. Chem., Int. Ed.
2005, 44, 153. (c) Yanada, R.; Obika, S.; Inokuma, T.; Yanada, K.;
Yamashita, M.; Ohta, S.; Takemoto, Y. J. Org. Chem. 2005, 70, 6972. (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.
(11) For oxindoles as synthetic intermediates in total synthesis, see: (a)
Lin, S.; Yang, Z.-Q.; Kwok, B. H. B.; Koldobskiy, M.; Crews, C. M.;
Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 6347. (b) Trost, B. M.;
Cramer, N.; Bernsmann, H. J. Am. Chem. Soc. 2007, 129, 3086.
(12) For biological evaluations of 3-alkylideneoxindoles, see: (a) 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. (b) 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.
(13) The stereochemistry of the exocyclic double bond was assigned
by a difference nOe study.
The use of other 2-alkynylaryl isocyanates 1 was also
examined, with the results being listed in Table 1. Primary
(16) A related rhodacycle intermediate is assumed for the Rh(I)-catalyzed
Pauson-Khand-type reaction of 2-alkynylaryl isothiocyanates: Saito, T.;
Nihei, H.; Otani, T.; Suyama, T.; Furukawa, N.; Saito, M. Chem. Commun.
2008, 172.
(14) The results with other catalysts (NMR yield/%): [Rh(cod)2]BF4
(36%), [Rh(cod)2]PF6 (35%), [Rh(cod)2]ClO4 (60%), [Rh(cod)2]BARF
(45%), [Rh(cod)(MeCN)2]SbF6 (56%), [Rh(bpy)(cod)]SbF6 (trace),
[Ir(cod)2]BARF (8%), [Ir(cod)(MeCN)2]BARF (7%).
(17) Nguyen, P.; Lesley, G.; Taylor, N. J.; Marder, T. B.; Pickett, N. L.;
Clegg, W.; Elsegood, M. R. J.; Norman, N. C. Inorg. Chem. 1994, 33,
4623.
1
(15) The borylated products 3 could be further purified by recrystalli-
zation. See the Supporting Information for details.
(18) Although the reaction in DCE-d4 was monitored by H NMR, no
possible intermediate was detected.
1744
Org. Lett., Vol. 10, No. 9, 2008

Table 1. Rh(I)-Catalyzed Cyclization Reaction of 1 with
Bis(pinacolato)diboron (2)a
Scheme 3
.
Synthetic Application of the Borylated
3-Alkylideneoxindole 3a
entry
1
R1
R2
3
yield (%)b
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
Et
H
H
H
H
H
H
H
H
3b
3c
3d
3e
3f
3g
3h
3i
74
77
86
n-Pr
i-Pr
t-Bu
Ph
4-MeOC6H4
4-BrC6H4
3-thienyl
n-Bu
31c
70c
67c
74c
54c
74
a loss of geometrical purity (E/Z ) 1:>20).19 Treatment of
3a with CuBr2 (6) resulted in the formation of brominated
3-alkylideneoxindole 7 in 96% yield again with retention of
stereochemistry (E/Z ) 1:20).20
In summary, we have developed a new borylative cycliza-
tion reaction with wide functional-group tolerance. The
sequence results in the stereoselective incorporation of a
boryl group on the exocyclic double bond of 3-alkylide-
neoxindoles. Studies addressing the synthetic scope of the
cyclization reaction and the pharmacological properties are
ongoing.
9
1j
Cl
3j
10
11
1k
1l
n-Bu
n-Bu
OMe
CO2Et
3k
3l
65
78
a Conditions: 1 (0.125 mmol), 2 (0.188 mmol), [Rh(cod)2]SbF6 (6.3 µ
mol, 5 mol %) in DCE (1.5 mL) at 80 °C for 3-6 h under Ar unless
otherwise noted. b 1H NMR yield using toluene as an internal standard; an
average of two experiments. c [Rh(cod)2]SbF6 (12.6 µmol, 10 mol %).
and secondary alkyl groups were suitable substituents on the
alkyne (entries 1-3). However, the reaction of tert-butyl-
substituted alkyne 1e failed to reach completion and the
product 3e was obtained in only 31% yield (entry 4). The
terminal alkyne substrate gave a complex mixture. Aryl- and
thienyl-substituted substrates 1f-1i successfully participated
in the reaction (entries 5-8). A range of functional groups
including chloro, methoxy ether, and ester were tolerated
on the aryl group of 1 (entries 9-11).
Acknowledgment. This work was supported in part by
the Takeda Science Foundation and the Ministry of Educa-
tion, Culture, Sports, Science and Technology of Japan (the
Global COE Program “Integrated Materials Science” B-09).
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.
The synthetic utility of the isolated borylated 3-alkylide-
neoxindole 3a (E/Z ) >20:1) was demonstrated by further
functional-group transformations shown in Scheme 3. The
Suzuki-Miyaura cross-coupling reaction with iodobenzene
(4) was executed using Pd[P(t-Bu)3]2 as the catalyst to give
the phenylated 3-alkylideneoxindole 5 in 85% yield without
OL800380T
(19) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020.
(20) Murphy, J. M.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc. 2007,
129, 15434.
Org. Lett., Vol. 10, No. 9, 2008
1745