Synthesis of 2-Boryl- and silylindoles by copper-catalyzed borylative and silylative cyclization of 2-alkenylaryl isocyanides

Article abstract of DOI:10.1021/jo101024f

(Figure Presented) We have developed a method for the synthesis of 2-borylindoles via the copper(I)-catalyzed borylative cyclization of 2-alkenylphenyl isocyanides using diboronate. The reaction proceeds at room temperature under neutral conditions and exhibits high tolerance to functional groups, such as Br, CO₂R, COR, CONMe₂, and CN. The 2-borylindoles synthesized in the present study can be elaborated into an array of indole-based derivatives, for example, through the Suzuki-Miyaura reaction. The utility of this method is demonstrated in the rapid synthesis of a kinase inhibitor, paullone. The reaction can be extended to the synthesis of 2-hydride indole and 2-silylindole by using hydroboronate (or hydrosilane) and silylboronate, respectively. Under these copper-catalyzed conditions, a quinoxaline ring system can also be constructed by using 1,2-isocyanobenzene as a substrate.

Full text of DOI:10.1021/jo101024f

pubs.acs.org/joc
Synthesis of 2-Boryl- and Silylindoles by Copper-Catalyzed Borylative
and Silylative Cyclization of 2-Alkenylaryl Isocyanides
Mamoru Tobisu,‡ Hirokazu Fujihara,† Keika Koh,† and Naoto Chatani*,†
†Department of Applied Chemistry, Faculty of Engineering and ‡Frontier Research Base for Global Young
Researchers, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
chatani@chem.eng.osaka-u.ac.jp
Received May 26, 2010
We have developed a method for the synthesis of 2-borylindoles via the copper(I)-catalyzed
borylative cyclization of 2-alkenylphenyl isocyanides using diboronate. The reaction proceeds at
room temperature under neutral conditions and exhibits high tolerance to functional groups, such as
Br, CO2R, COR, CONMe2, and CN. The 2-borylindoles synthesized in the present study can be
elaborated into an array of indole-based derivatives, for example, through the Suzuki-Miyaura
reaction. The utility of this method is demonstrated in the rapid synthesis of a kinase inhibitor,
paullone. The reaction can be extended to the synthesis of 2-hydride indole and 2-silylindole by using
hydroboronate (or hydrosilane) and silylboronate, respectively. Under these copper-catalyzed condi-
tions, a quinoxaline ring system can also be constructed by using 1,2-isocyanobenzene as a substrate.
Introduction
this heterocycle, indole-based scaffolds that can readily be
elaborated into a variety of derivatives would find widespread
utility in diversity-oriented synthesis.2 Borylated indoles should
serve as a versatile intermediate, in view of the availability of
contemporary catalytic transformation methods using organo-
boron reagents.3 Borylindoles can be synthesized via either a
protocol of lithiation/trap with boron electrophiles4 or the
catalytic direct borylation of indoles.5 However, the former
method cannot be applied to base-sensitive substrates, and the
latter suffers from susceptibility to the steric effect. A new me-
thod is therefore needed for the synthesis of a series of bory-
lated indoles that cannot be accessed by conventional methods.
One such group of compounds is 2-(2-boryl-1H-indol-3-yl)acetic
acid derivatives 1, which could be utilized as useful precur-
sors for a variety of tryptophan-derived natural and non-
natural products (Scheme 1).6 Despite their potential utility,
the synthesis of borylindoles 1 has never been reported, to
the best of our knowledge.
On the other hand, Fukuyama reported that 2-stannylin-
doles 3 can be synthesized from 2-alkenylaryl isocyanides 2
via a radical-mediated process (Fukuyama indole synthesis)
and can be elaborated into an array of derivatives through
Migita-Kosugi-Stille coupling (Scheme 2).7,8 If this reac-
tion could be extended to the synthesis of the boron analogue
4, it would lead to a nontoxic and more versatile platform
for indole-based compounds, particularly for those derived
The indole motif is a ubiquitous feature of alkaloid and
peptide natural products and represents a privileged structural
element for pharmaceutical agents.1 Due to the importance of
(1) Selected recent reviews: (a) Humphrey, G. R.; Kuethe, J. T. Chem.
Rev. 2006, 106, 2875. (b) Joucla, L.; Djakovitch, L. Adv. Synth. Catal. 2009,
351, 673.
(2) Selected reviews: (a) Schreiber, S. L. Science 2000, 287, 1964. (b)
Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46. (c) Spandl,
R. J.; Bender, A.; Spring, D. R. Org. Biomol. Chem. 2008, 6, 1149.
(3) Selected reviews: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457. (b) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829. (c) Fagnou,
K.; Lautens, M. Chem. Rev. 2003, 103, 169. (d) Miura, T.; Murakami, M.
Chem. Commun. 2007, 217. (e) Miyaura, N. Bull. Chem. Soc. Jpn. 2008, 81,
1535. (f) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461. (g)
Tobisu, M.; Chatani, N. Angew. Chem., Int. Ed. 2009, 48, 3565. (h) Goossen,
L. J.; Goossen, K.; Stanciu, C. Angew. Chem., Int. Ed. 2009, 48, 3569.
(4) Vazquez, E.; Davies, I. W.; Payack, J. F. J. Org. Chem. 2002, 67, 7551
and references therein.
(5) For a review on catalytic borylation of C-H bonds, see: (a) Mkhalid,
I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem.
Rev. 2009, 110, 890. Catalytic borylation of indoles: (b) Ishiyama, T.;
Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew. Chem., Int. Ed. 2002, 41, 3056.
(c) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N. Tetra-
hedron Lett. 2002, 43, 5649. (d) Ishiyama, T.; Nobuta, Y.; Hartwig, J. F.;
Miyaura, N. Chem. Commun. 2003, 2924. (e) Mertins, K.; Zapf, A.; Beller,
M. J. Mol. Catal. A: Chem. 2004, 207, 21. (f) Tagata, T.; Nishida, M. Adv.
Synth. Catal. 2004, 346, 1655. (g) Paul, S.; Chotana, G. A.; Holmes, D.;
Reichle, R. C.; Maleczka, R. E.; Smith, M. R. J. Am. Chem. Soc. 2006, 128,
15552. (h) Kallepalli, V. A.; Shi, F.; Paul, S.; Onyeozili, E. N.; Maleczka,
R. E.; Smith, M. R. J. Org. Chem. 2009, 74, 9199. (i) Robbins, D. W.; Boebel,
T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 4068.
DOI: 10.1021/jo101024f
r
Published on Web 06/17/2010
J. Org. Chem. 2010, 75, 4841–4847 4841
2010 American Chemical Society

Tobisu et al.
JOCArticle
SCHEME 1. 2-(1H-Indol-3-yl)acetic Acid Substructure Found
in Natural and Non-natural Products
examined for their ability to promote the cyclization process,
which sheds light on the nature of the key addition reaction
to isocyanide.
Results and Discussion
On the basis of the potential electrophilic reactivity of iso-
cyanides,9 we envisioned that the cyclization of 2 to 4 could
be initiated by the addition of nucleophilic boron species10 to
the isocyano group in 2. Guided by several reports on copper-
catalyzed nucleophilic borylation of various electrophiles
(unsaturated carbonyls,11 aldehydes and ketones,12 imines,13
allylic and propargylic carbonates,14 and others15), we initially
examined the reaction of isocyanide 5a16 with diboronate 6 in
the presence of a copper catalyst (Table 1). We found that the
borylated product 7a was indeed obtained with the CuOAc/
PPh3 catalytic system at ambient temperature (entry 1). Consis-
tent with previous reports,11 protic additives improved the yield of
7a, although it was accompanied by the formation of deborylated
product 8a (entries 2-4). Finally, decreasing the amount of
MeOH to 1 equiv relative to 5a completely suppressed the
formation of 8a and afforded 7a quantitatively (entry 6).
The reaction is presumably initiated by the addition of boryl-
copper A, which can be generated in situ by the transmetalation
of CuOAc with 6 to the isocyano moiety in 5a (Scheme 3). Intra-
molecular 1,4-addition of the resultant imidoylcopper B leads to
the formation of copper enolate C. Since the transmetalation of C
with 6 is relatively slow, the addition of MeOH is required to
effectively liberate borylated product E and to generate Cu-OMe
D, which serves as a more competent precursor of A.11h
SCHEME 2. 2-Metalated Indoles from 2-Alkenylaryl Isocyanides
(10) For an excellent introduction to nucleophilic boryl species, see: (a)
Segawa, Y.; Suzuki, Y.; Yamashita, M.; Nozaki, K. J. Am. Chem. Soc. 2008,
130, 16069. (b) Dang, L.; Lin, Z.; Marder, T. B. Chem. Commun. 2009, 3987.
(11) (a) Ito, H.; Yamanaka, H.; Tateiwa, J.-i.; Hosomi, A. Tetrahedron
Lett. 2000, 41, 6821. (b) Takahashi, K.; Ishiyama, T.; Miyaura, N. Chem.
Lett. 2000, 29, 982. (c) Takahashi, K.; Ishiyama, T.; Miyaura, N. J.
Organomet. Chem. 2001, 625, 47. (d) Mun, S.; Lee, J.-E.; Yun, J. Org. Lett.
2006, 8, 4887. (e) Lee, J.-E.; Yun, J. Angew. Chem., Int. Ed. 2008, 47, 145. (f)
Lee, J.-E.; Kwon, J.; Yun, J. Chem. Commun. 2008, 733. (g) Lillo, V.; Prieto,
from tryptophan. This paper reports the catalytic synthesis
of 2-borylindole 4 through the nucleophilic addition of in
situ generated borylcopper(I) species to isocyanide 2. The
reactivity of this new family of organoboron compounds in
several catalytic reactions, such as Suzuki-Miyaura cou-
pling, is investigated, and its application to the rapid synth-
esis of paullone is also demonstrated. In addition, in situ
generated aryl-, hydride, and silylcopper(I) species are
ꢀ ꢀ
A.; Bonet, A.; Dıaz-Requejo, M. M.; Ramırez, J.; Parez, P. J.; Fernandez, E.
´ ´
Organometallics 2008, 28, 659. (h) Dang, L.; Lin, Z.; Marder, T. B. Organo-
metallics 2008, 27, 4443. (i) Sim, H.-S.; Feng, X.; Yun, J. Chem.;Eur. J.
2009, 15, 1939. (j) Feng, X.; Yun, J. Chem. Commun. 2009, 6577. (k) Lillo, V.;
ꢀ
Bonet, A.; Fernandez Dalton Trans. 2009, 2899. (l) Chea, H.; Sim, H.-S.;
Yun, J. Adv. Synth. Catal. 2009, 351, 855. (m) Fleming, W. J.; Muller-Bunz,
€
ꢀ
H.; Lillo, V.; Fernandez, E.; Guiry, P. J. Org. Biomol. Chem. 2009, 7, 2520. (n)
Chen, I. H.; Yin, L.; Itano, W.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
€
2009, 131, 11664. (o) Schiffner, J. A.; Muther, K.; Oestreich, M. Angew.
Chem., Int. Ed. 2010, 49, 1194.
(12) (a) Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006, 128,
11036. (b) McIntosh, M. L.; Moore, C. M.; Clark, T. B. Org. Lett. 2010, 12, 1996.
(13) Beenen, M. A.; An, C.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6910.
(14) (a) Ramachandran, P. V.; Pratihar, D.; Biswas, D.; Srivastava, A.;
Ram Reddy, M. V. Org. Lett. 2004, 6, 481. (b) Ito, H.; Kawakami, C.;
Sawamura, M. J. Am. Chem. Soc. 2005, 127, 16034. (c) Ito, H.; Ito, S.; Sasaki,
Y.; Matsuura, K.; Sawamura, M. J. Am. Chem. Soc. 2007, 129, 14856. (d) Ito,
H.; Sasaki, Y.; Sawamura, M. J. Am. Chem. Soc. 2008, 130, 15774. (e) Ito, H.;
Kosaka, Y.; Nonoyama, K.; Sasaki, Y.; Sawamura, M. Angew. Chem., Int.
Ed. 2008, 47, 7424. (f) Ito, H.; Okura, T.; Matsuura, K.; Sawamura, M.
Angew. Chem., Int. Ed. 2010, 49, 560. (g) Ito, H.; Toyoda, T.; Sawamura, M.
J. Am. Chem. Soc. 2010, 132, 5990.
(15) Styrenes: (a) Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. Organometallics
2006, 25, 2405. (b) Dang, L.; Zhao, H.; Lin, Z.; Marder, T. B. Organome-
tallics 2007, 26, 2824. (c) Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2009,
131, 3160. 1,3-Dienes: (d) Sasaki, Y.; Zhong, C.; Sawamura, M.; Ito, H. J.
Am. Chem. Soc. 2010, 132, 1226. CO2: (e) Laitar, D. S.; Muller, P.; Sadighi,
J. P. J. Am. Chem. Soc. 2005, 127, 17196. (f) Zhao, H.; Lin, Z.; Marder, T. B.
J. Am. Chem. Soc. 2006, 128, 15637. Alkynes: (g) Lee, Y.; Jang, H.;
Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 18234. (h) Kim, H. R.; Jung,
I. G.; Yoo, K.; Jang, K.; Lee, E. S.; Yun, J.; Son, S. U. Chem. Commun. 2010,
758.
(6) Selected examples: (a) Aimi, N.; Uchida, N.; Ohya, N.; Hosokawa,
€
H.; H., T.; Sakai, S.-i.; Mendonza, L. A.; Polz, L.; Stockigt, J. Tetrahedron
Lett. 1991, 32, 4949. (b) Williams, D. E.; Davies, J.; Patrick, B. O.; Bottriell,
H.; Tarling, T.; Roberge, M.; Andersen, R. J. Org. Lett. 2008, 10, 3501. (c)
Shen, T. Y.; Winter, C. A. Adv. Drug Res. 1977, 12, 90. (d) Schultz, C.; Link,
A.; Leost, M.; Zaharevitz, D. W.; Gussio, R.; Sausville, E. A.; Meijer, L.;
Kunick, C. J. Med. Chem. 1999, 42, 2909. (e) Trotter, B. W.; Quigley, A. G.;
Lumma, W. C.; Sisko, J. T.; Walsh, E. S.; Hamann, C. S.; Robinson, R. G.;
Bhimnathwala, H.; Kolodin, D. G.; Zheng, W.; Buser, C. A.; Huber, H. E.;
Lobell, R. B.; Kohl, N. E.; Williams, T. M.; Graham, S. L.; Dinsmore, C. J.
Bioorg. Med. Chem. Lett. 2001, 11, 865. (f) Yang, Z.; Reiling, S.; Nieduzak,
T. R.; Mathew, R. M.; Jackson, S.; Harris, K. J. PCT Int. Appl. WO 2008014186
Chem. Abstr. 2008, 148, 214951.
(7) A seminal report: (a) Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem.
Soc. 1994, 116, 3127A review:. (b) Tokuyama, H.; Fukuyama, T. Chem. Rec.
2002, 2, 37.
ꢀ
(8) A review of indole synthesis from isocyanides: Campo, J.; Garcia-
Valverde, M.; Marcaccini, S.; Rojo, M. J.; Torrroba, T. Org. Biomol. Chem.
2006, 4, 757.
(9) (a) Niznik, G. E.; Morrison, W. H.; Walborsky, H. M. J. Org. Chem.
1974, 39, 600. (b) Murakami, M.; Ito, H.; Ito, Y. J. Org. Chem. 1988, 53,
4158. (c) Suginome, M.; Fukuda, T.; Ito, Y. Org. Lett. 1999, 1, 1977. (d)
Tobisu, M.; Yamaguchi, S.; Chatani, N. Org. Lett. 2007, 9, 3351.
(16) The starting isocyanides used in this study can readily be prepared from
the corresponding 2-iodoanilines. See the Supporting Information for details.
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TABLE 1. Optimization of Reaction Conditionsa
TABLE 2. Copper-Catalyzed Borylation of Various Aryl Isocyanidesa
yieldb (%)
entry
additive
time (h)
7a
59
67
86
66
trace
98
8a
1
2
3
4
5
6
none
H2O
MeOH
t-BuOH
PhOH
MeOHc
24
5
5
5
5
0
13
11
6
0
trace
5
aReaction conditions: 5a (0.5mmol), 6(0.55 mmol), CuOAc (0.05 mmol),
PPh3 (0.10 mmol), additive (1.0 mmol), THF (4 mL) in a two-necked flask
under N2. bNMR yields based on 5a. cMeOH (0.5 mmol) was added.
SCHEME 3. Plausible Mechanism for the Copper-Catalyzed
Borylative Cyclization of 5a
aReaction conditions: 5(0.5mmol), 6(0.55 mmol), CuOAc (0.05 mmol),
PPh3 (0.10 mmol), MeOH (0.5 mmol), THF (4 mL) in a two-necked flask
under N2. bNMR yields based on 5.
separation,17 wesought toidentifya one-potprotocol for their
transformation. The cross-coupling product was obtained in
a yield of only 32% when the crude 2-borylindole 7a was
subjected to Suzuki-Miyaura conditions (cat. PdCl2/PPh3,
K2CO3, DME, reflux) using iodobenzene. However, the yield
was dramatically improved to 84% simply by conducting the
Suzuki-Miyaura reaction after filtration through a pad of
Florisil (entry 1, Table 3). This protocol probably removes the
residual copper salt, which would accelerate protodeborona-
tion at elevated temperature. Iodides, bromides, and triflates
all afforded 2-arylated products in moderate to good yields
without optimization of the catalytic conditions (entries 1-3),
while iodides were the most effective partner. This reactivity
difference can be utilized for the selective cross-coupling of
iodide over bromide (entry 7). Functionalized halides, such as
those containing acetyl (entry 4), cyano (entry 5), and meth-
oxy (entry 6) groups, as well as sterically demanding (entry 8)
and heteroaryl (entry 9) halides are applicable to this boryla-
tive cyclization/Suzuki-Miyaura coupling tandem. Notably,
The catalytic conditions optimized for 5a proved to be effective
for the borylative cyclization of other isocyanides (Table 2).
Ethers (entry 2), bromides (entry 3), and esters (entry 4) on the
benzene ring of isocyanide were tolerated under these catalytic
conditions. Notably, sterically congested ortho-disubstituted
isocyanide 5e was also applicable (entry 5). In agreement with
the mechanistic proposal (Scheme 3), several pendant Michael
acceptors, including metacrylate 5f and unsaturated ketone 5g,
amide 5h, and nitrile 5i, could undergo borylative cyclization to
furnish the corresponding 2-borylindoles (entries 6-9).
With a new class of 2-borylindoles in hand, we next set out
toexplore the application toSuzuki-Miyaura cross-coupling.
Since 2-borylindoles synthesized in the present study are
relatively prone to protodeboronation on chromatographic
(17) For the instability of 2-heteroarylboronic acids, see: (a) Billingsley,
K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358. (b) Knapp, D. M.;
Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961.
J. Org. Chem. Vol. 75, No. 14, 2010 4843

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TABLE 3. Tandem Borylative Cyclization/Suzuki-Miyaura Coupling
SCHEME 4. Transformations of 7aa
of 7aa
aKey: (a) 3-octyne, [Rh(OH)(cod)]2 (cat.), dioxane/H2O, 80 °C, 15 h;
(b) 3-butene-2-one, [Rh(OH)(cod)]2 (cat.), dioxane/H2O, 80 °C, 15 h;
(c) Oxone, acetone/H2O, 25 °C, 10 min.
oxidation of 7a led to oxindole 11, which constitutes an
important subclass of indole-based compounds.20
Finally, the present reaction was applied to the synthesis
of paullone, which is known as a potent inhibitor of cyclin-
dependent kinases (Scheme 5).21 By adapting the borylation/
Suzuki-Miyaura coupling sequence, paullone could be
rapidly synthesized from 5a for an overall yield of 74%.22 This
modular catalytic assembly allows straightforward access to a
range of paullone derivatives.
The present copper-catalyzed borylative cyclization is
initiated by a nucleophilic addition of borylcopper(I) spe-
cies to isocyanide. Such electrophilic reactivity of isocya-
nides is relatively unexplored,9 whereas their nucleophilic
character has been utilized in a wide range of reactions.23
Thus, a better understanding of this key nucleophilic addi-
tion to isocyanides is needed to further exploit the electro-
philic reactivity of isocyanides for organic synthesis. To
obtain qualitative insight into this process, various reagents
other than diboronate 6 were examined for their ability to
promote the cyclization of 5a (Table 4). Copper(I) hydride
generated in situ by the reaction with HB(pin) (12a)24 or
aReaction conditions: 5a (0.5 mmol), 6 (0.55 mmol), CuOAc (0.05
mmol), PPh3 (0.10 mmol), MeOH (0.5 mmol), THF (4.0 mL) in a two-
necked flask under N2 at 25 °C for 5 h; filtration and evaporation; crude
7a, RX (0.6 mmol), PdCl2 (0.025 mmol), PPh3 (0.05 mmol), K2CO3
(2.0 mmol), DME (3.0 mL) at 80 °C for 15 h. bOverall isolated yield for
two steps based on 5a.
(20) For example, see: Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int.
Ed. 2007, 46, 8748.
(21) For recent studies of biological activities of paullone families, see: (a)
Reichwald, C.; Shimony, O.; Dunkel, U.; Sacerdoti-Sierra, N.; Jaffe, C. L.;
Kunick, C. J. Med. Chem. 2008, 51, 659. (b) Stukenbrock, H.; Mussmann,
R.; Geese, M.; Ferandin, Y.; Lozach, O.; Lemcke, T.; Kegel, S.; Lomow, A.;
Burk, U.; Dohrmann, C.; Meijer, L.; Austen, M.; Kunick, C. J. Med. Chem.
2008, 51, 2196. (c) Becker, A.; Kohfeld, S.; Lader, A.; Preu, L.; Pies, T.;
Wieking, K.; Ferandin, Y.; Knockaert, M.; Meijer, L.; Kunick, C. Eur. J.
Med. Chem. 2010, 45, 335. (d) Egert-Schmidt, A.-M.; Dreher, J.; Dunkel, U.;
Kohfeld, S.; Preu, L.; Weber, H.; Ehlert, J. E.; Mutschler, B.; Totzke, F.;
vinylic sp2 (entry 10), sp (entry 11), and sp3 (entry 12) carbons
can be successfully introduced into the 2-position of indoles
under identical conditions, highlighting the utility of 2-bor-
ylindoles in diversity-oriented synthesis.
€
Schachtele, C.; Kubbutat, M. H. G.; Baumann, K.; Kunick, C. J. Med.
Chem. 2010, 53, 2433.
(22) Notes: (a) It has been reported that tin-mediated paullone synthesis
from 5a requires the use of N-protected iodoaniline and the overall yield is
The versatility of 2-borylindoles synthesized by our method
is further demonstrated by their application to other trans-
formations (Scheme 4). Rhodium-catalyzed addition of 7a to
alkynes18 and enones19 proceeded successfully to furnish 2,3-
disubstituted indoles 9 and 10, respectively. Moreover, the
ꢀ ꢀ
ꢀ
less efficient (43% from 5a). See: Henry, N.; Blu, J.; Beneteau, V.; Merour,
J.-Y. Synthesis 2006, 22, 3895. (b) Synthesis of paullone via the Suzu-
ki-Miyaura coupling of in situ prepared 2-(2-boryl-1H-indol-3-yl)-
acetonitrile has been reported, but the yield was low (25%). See: Baudoin,
O.; Cesario, M.; Guenard, D.; Gueritte, F. J. Org. Chem. 2002, 67, 1199.
(23) Suginome, M.; Ito, Y. In Science of Synthesis; Murahashi, S.-I., Ed.;
Thieme: Stuttgart, 2004; Vol. 19; pp 445-530.
(24) For representative recent reports on the catalytic reaction involving
CuH species generated from HB(pin), see: (a) Lipshutz, B. H.; Boskovic,
Z. V.; Aue, D. H. Angew. Chem., Int. Ed. 2008, 47, 10183. (b) Du, Y.; Xu,
L.-W.; Shimizu, Y.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2008, 130, 16146. (c) Noh, D.; Chea, H.; Ju, J.; Yun, J. Angew. Chem., Int. Ed.
2009, 48, 6062.
(18) A seminal report: Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara,
M. J. Am. Chem. Soc. 2001, 123, 9918. See also ref 3b-3e.
(19) Seminal reports: (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organo-
metallics 1997, 16, 4229. (b) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai,
M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579. See also ref 3b-3e.
4844 J. Org. Chem. Vol. 75, No. 14, 2010

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SCHEME 5. Rapid Synthesis of Paullone, a Kinase Inhibitor
SCHEME 6. 2-Silylindoles Synthesized by the Copper-
Catalyzed Cyclization of 5
TABLE 4. Copper-Catalyzed Cyclization of 5a Using Various Reagentsa
entry
reagents
HB(pin)c (12a)
HSiPhMe2 (12b)
(pin)B-SiMe2Ph (12c)
(pin)B-SiMePh2 (12d)
PhB(OH)2 (12e)
time (h)
R
yieldb (%)
1
2
1
5
3
3
24
H (8a)
H (8a)
SiMe2Ph (13c)
SiMePh2 (13d)
Ph (13e)
78
81
87
77
0
3d
4d
5
isocyanide 5a with silylboronate 12c under copper-cata-
lyzed conditions successfully furnished the corresponding
2-silylindole 13c (entry 3).28,29 A bulky Ph2MeSi group
could also be incorporated into the indole ring (entry 4).
This copper-catalyzed silylative cyclization proved to be
applicable to a wide range of isocyanides (Scheme 6). It
should also be noted that, in contrast to 2-borylindoles 7,
2-silylindoles synthesized in this study were all sufficiently
stable to be isolated by chromatography. On the other
hand, the phenylcopper(I) species generated by transmeta-
lation from phenylboronic acids30 failed to form indole
products (entry 5).
Lin and Marder investigated the magnitude of the trans
influence of a series of ligands in trans-[PtL(Cl)(PMe3)2],
based on the calculated bond lengths, and determined the
following order: SiMe3 > B(pin)> H > Ph.31 This order
reflects the strong σ-donating ability of the silyl32 and boryl10b,33
ligands. Although the corresponding data for copper(I) com-
plexes are unavailable, the order reported above is in good
agreement with the reactivity trend observed in Table 4. Thus,
the present cyclization reaction requires the use of copper(I)
species with highly nucleophilic ligands, including boryl, silyl,
and hydride, which allow for nucleophilic attack toward
isocyanides.
aReaction conditions: 5a (0.5 mmol), 12 (0.6 mmol), CuOAc (0.05
mmol), PPh3 (0.10 mmol), MeOH (0.5 mmol), THF (4.0 mL) in a two-
necked flask under N2 at 25 °C. bIsolated yield based on 5a unless
c
otherwise noted. 12a (1.0 mmol) was used. dRun with CuOAc (0.025
mmol) and PPh3 (0.05 mmol) at 0 °C.
HSiMe2Ph (12b)25 was also capable of initiating the cycliza-
tion to afford indole 8a (entries 1 and 2). We next turned our
attention to the reactivity of the corresponding silylcopper-
(I) species. In view of reports on the copper-catalyzed
nucleophilic silylation of R,β-unsaturated carbonyl com-
pounds using disilane,26 we initially examined (PhMe2Si)2
as a silicon source. However, the desired 2-silylindole was
not formed under these catalytic conditions. We then
envisioned that silylboronate (R3SiB(OR0)2) would be an-
other candidate for a silyl-transferring reagent in copper
catalysis, by analogy with the generation of silylrhodium(I)
species from this reagent.27 As expected, the reaction of
(25) For representative recent reports on the catalytic reaction involving
ꢀ
CuH species generated from HSiR3, see: (a) Welle, A.; Dıez-Gonzalez, S.;
´
Tinant, B.; Nolan, S. P.; Riant, O. Org. Lett. 2006, 8, 6059. (b) Deutsch, C.;
Lipshutz, B. H.; Krause, N. Angew. Chem., Int. Ed. 2007, 46, 1650. (c) Yoo,
K.; Kim, H.; Yun, J. Chem.;Eur. J. 2009, 15, 11134. (d) Zhong, C.; Sasaki,
Y.; Ito, H.; Sawamura, M. Chem. Commun. 2009, 5850. (e) Rupnicki, L.;
Saxena, A.; Lam, H. W. J. Am. Chem. Soc. 2009, 131, 10386.
(26) (a) Ito, H.; Ishizuka, T.; Tateiwa, J.-i.; Sonoda, M.; Hosomi, A.
J. Am. Chem. Soc. 1998, 120, 11196. (b) Clark, C. T.; Lake, J. F.; Scheidt,
K. A. J. Am. Chem. Soc. 2003, 126, 84.
(29) During the preparation of this manuscript, a report on copper-
catalyzed 1,4-addition of a silyl group in silylboronates to unsaturated
carbonyls was published: Lee, K.-s.; Hoveyda, A. H. J. Am. Chem. Soc.
2010, 132, 2898.
(30) For representative recent reports on the catalytic reaction involving
ArCu species generated from ArB(OH)2, see: (a) Uemura, T.; Chatani, N. J.
Org. Chem. 2005, 70, 8631. (b) Villalobos, J. M.; Srogl, J.; Liebeskind, L. S. J.
Am. Chem. Soc. 2007, 129, 15734. (c) Zheng, H.; Zhang, Q.; Chen, J.; Liu, M.;
Cheng, S.; Ding, J.; Wu, H.; Su, W. J. Org. Chem. 2008, 74, 943. (d) Rao, H.;
Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009, 48, 1114.
(31) Zhu, J.; Lin, Z.; Marder, T. B. Inorg. Chem. 2005, 44, 9384.
(32) (a) Dioumaev, V. K.; Procopio, L. J.; Carroll, P. J.; Berry, D. H. J. Am.
Chem. Soc. 2003, 125, 8043 and references therein. (b) Takaya, J.; Iwasawa, N.
J. Am. Chem. Soc. 2008, 130, 15254.
(27) (a) Walter, C.; Auer, G.; Oestreich, M. Angew. Chem., Int. Ed. 2006,
45, 5675. (b) Walter, C.; Oestreich, M. Angew. Chem., Int. Ed. 2008, 47,
€
3818. (c) Walter, C.; Frohlich, R.; Oestreich, M. Tetrahedron 2009, 65, 5513.
(d) Ohmiya, H.; Ito, H.; Sawamura, M. Org. Lett. 2009, 11, 5618.
(28) Silylindoles via catalytic C-H bond silylation: (a) Ishiyama, T.;
Sato, K.; Nishio, Y.; Saiki, T.; Miyaura, N. Chem. Commun. 2005, 5065. (b)
Lu, B.; Falck, J. R. Angew. Chem., Int. Ed. 2008, 47, 7508. Preparation and
cross-coupling of 2-indolylsilanols: (c) Denmark, S. E.; Baird, J. D. Org.
Lett. 2004, 6, 3649. (d) Denmark, S. E.; Baird, J. D. Org. Lett. 2006, 8, 793. (e)
Denmark, S. E.; Baird, J. D.; Regens, C. S. J. Org. Chem. 2008, 73, 1440. (f)
Denmark, S. E.; Baird, J. D. Tetrahedron 2009, 65, 3120.
(33) Segawa, Y.; Yamashita, M.; Nozaki, K. Angew. Chem., Int. Ed.
2007, 46, 6710 and references therein.
J. Org. Chem. Vol. 75, No. 14, 2010 4845

Tobisu et al.
JOCArticle
SCHEME 7
On the other hand, when silylboronates 12c and 12d were
used instead of diboronate 6, the expected 2-silylquinoxa-
lines 22c and 22d were obtained (Scheme 8). In addition to
the tolerance of 2-silyquinoxaline 22c,d toward protodesily-
lation, the greater σ-donating nature of a silyl ligand, as
compared with boryl, might be an important factor for the
achievement of efficient cyclization.
Conclusions
In summary, we have developed the copper-catalyzed
borylative cyclization of 2-alkenylphenyl isocyanides, lead-
ing to the formation of otherwise inaccessible 2-borylated
indoles under very mild conditions (room temperature and
neutral pH). The 2-borylated indoles thus obtained serve as
versatile platforms for a diverse range of indole derivatives
via a boron-based transformation such as the Suzuki-
Miyaura reaction. The utility of the method was further
demonstrated in the rapid synthesis of paullone. The cycliza-
tion process was initiated by the nucleophilic attack of the
borylcopper(I) species toward an isocyanide moiety. The
cyclization reactions also proceeded when silylboronate and
hydroboronate (or hydrosilane) were used to generate silyl-
copper(I) and hydride copper(I) species, respectively. The
strong σ-donating ability of boryl, silyl, and hydride ligands
was key to this successful development. Further develop-
ment of catalytic transformation of isocyanides is ongoing in
our laboratory.37
SCHEME 8
Experimental Section
As described in Scheme 3, the present reaction is initiated
by the nucleophilic borylation (or silylation) of isocyanide to
form imidoylcopper, as in B, which is subsequently inter-
cepted by R,β-unsaturated carbonyls through intramolecular
1,4-addition, leading to the construction of an indole skele-
ton. If the intermediate imidoylcopper species could react
with other tethered electrophiles, the reaction would be
extended to access different ring systems.34 We found that
an isocyanide moiety could be employed for such a purpose.
The reaction of 1,2-diisocyanobenzene 2035 with diboronate
6 in the presence of a copper(I) catalyst afforded the cyclized
products (Scheme 7). However, the expected 2-borylquino-
xaline 21a was not observed, but hydride 21b was obtained
instead, along with 2-methoxyquinoxaline 21c.36 Compound
21b is presumably formed through the protodeboronation of
21a. The yield of 21b was only moderate, even when the
reaction was conducted at 60 °C.
Typical Procedure for a Cu-Catalyzed Borylative Cyclization/
Suzuki-Miyaura Coupling Tandem. An oven-dried, N2-purged,
10 mL, two-necked flask was charged with 6(139.7 mg, 0.55 mmol),
5a (93.6 mg, 0.5 mmol), PPh3 (26.2 mg, 0.1 mmol), Cu(OAc)
(6.1 mg, 0.05 mmol), THF (4 mL), and methanol (20 μL, 0.5
mmol). The system was immersed in an oil bath at 25 °C. After
5 h, it was removed from the oil bath. The contents were passed
through a short Florisil pad. Evaporation of the solvent afforded
crude 7a as a colorless oil.
A N2-purged, 10 mL, two-necked flask was charged with
K2CO3 (276.4 mg, 2.0 mmol), PPh3 (13.1 mg, 0.05 mmol),
palladium(II) chloride (4.4 mg, 0.025 mmol), iodobenzene
(122.4 mg, 0.6 mmol), and a solution of 2-borylindole 7a obtained
as above in DME (3 mL). The system was immersed in an oil bath
at 80 °C. After 15 h, it was removed from the oil bath and cooled to
room temperature. The contents were transferred to a round-
bottom flask, and volatiles were removed in vacuo. The residue
was subjected to column chromatography on silica gel (eluent;
hexane/EtOAc = 5/1) to give (2-phenyl-1H-indol-3-yl)acetic acid
methyl ester (111.4 mg, 84% yield) as a white solid.
(34) Synthesis of pyridine derivatives via cyclization of isocyanides: (a)
Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1991, 113, 2127. (b) Curran, D. P.;
Liu, H.; Josien, H.; Ko, S. B. Tetrahedron 1996, 52, 11385. (c) Josien, H.; Ko,
S. B.; Bom, D.; Curran, D. P. Chem.;Eur. J. 1998, 4, 67. (d) Rainier, J. D.;
Kennedy, A. R. J. Org. Chem. 2000, 65, 6213. (e) Curran, D. P.; Du, W. Org.
Lett. 2002, 4, 3215. (f) Lu, X.; Petersen, J. L.; Wang, K. K. Org. Lett. 2003, 5,
3277. (g) Mitamura, T.; Tsuboi, Y.; Iwata, K.; Tsuchii, K.; Nomoto, A.;
Sonoda, M.; Ogawa, A. Tetrahedron Lett. 2007, 48, 5953. (h) Liu, L.; Wang,
Y.; Wang, H.; Peng, C.; Zhao, J.; Zhu, Q. Tetrahedron Lett. 2009, 50, 6715. (i)
Mitamura, T.; Iwata, K.; Ogawa, A. Org. Lett. 2009, 11, 3422. See also refs 9c
and 35.
Methyl 2-(2-(4-acetylphenyl)-1H-indol-3-yl)acetate (entry 4 in
Table 3): Rf 0.23 (hexane/EtOAc = 2/1); yellow solid; mp =
159 °C; 1H NMR (CDCl3, 270.05 MHz) δ 2.65 (s, 3H), 3.74 (s,
3H), 3.88 (s, 2H), 7.16-7.26 (m, 3H), 7.40 (d, J = 7.8 Hz, 1H),
7.69 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 8.07 (d, J =
8.1 Hz, 1H), 8.29 (s, 1H); 13C NMR (CDCl3, 67.80 MHz) δ 26.6,
30.9, 52.2, 106.9, 111.1, 119.3, 120.3, 123.2, 127.9, 128.8, 128.9,
(35) Suginome and Ito reported that a thermal reaction of 1,2-diisocya-
nobenzene with (iPr2N)2BSiMe2Ph affords 2-boryl-3-silylquinoxaline. See:
(a) Suginome, M.; Fukuda, T.; Ito, Y. J. Organomet. Chem. 2002, 643-644,
508. For related polymerization, see: (b) Ito, Y.; Miyake, T.; Hatano, S.;
Shima, R.; Ohara, T.; Suginome, M. J. Am. Chem. Soc. 1998, 120, 11880.
(36) The mechanism for the formation of 21c is currently unclear. Since
21c was not observed when the reaction was conducted in the absence of
Cu(OAc), 21c is formed through copper catalysis.
(37) For our work on catalytic reactions using isocyanides, see: (a)
Chatani, N.; Oshita, M.; Tobisu, M.; Ishii, Y.; Murai, S. J. Am. Chem.
Soc. 2003, 125, 7812. (b) Oshita, M.; Yamashita, K.; Tobisu, M.; Chatani, N.
J. Am. Chem. Soc. 2005, 127, 761. (c) Yoshioka, S.; Oshita, M.; Tobisu, M.;
Chatani, N. Org. Lett. 2005, 7, 3697. (d) Tobisu, M.; Kitajima, A.; Yoshioka,
S.; Hyodo, I.; Oshita, M.; Chatani, N. J. Am. Chem. Soc. 2007, 129, 11431. (e)
Tobisu, M.; Ito, S.; Kitajima, A.; Chatani, N. Org. Lett. 2008, 10, 5223. See
also ref 9d.
4846 J. Org. Chem. Vol. 75, No. 14, 2010

Tobisu et al.
JOCArticle
134.7, 135.9, 136.1, 136.8, 172.5, 197.8; IR (KBr) 3359 m, 2949
w, 1726 s, 1674 s, 1601 s, 1547 w, 1506 w, 1450 m, 1435 m, 1404
w, 1360 m, 1342 m, 1327 m, 1282 s, 1261 s, 1236 m, 1196 m, 960
m, 835 m, 739 s, 642 w, 621 w, 596 m, 567 w, 536 w, 492 w, 436 w;
MS m/z (relative intensity) 307 (Mþ, 56), 248 (63), 206 (62), 205
(38), 204 (41), 43 (100); HRMS calcd for C19H17NO3 307.1208,
found 307.1209.
Coordination Funds for Promoting Science and Techno-
logy, Ministry of Education, Culture, Sports, Science and
Technology (MEXT), Japan. We also thank the Instrumen-
tal Analysis Center, Faculty of Engineering, Osaka Univer-
sity, for assistance with the MS, HRMS, and elemental
analyses.
Acknowledgment. This work was carried out, in part, by
the Program of Promotion of Environmental Improvement
to Enhance Young Researchers’ Independence, the Special
Supporting Information Available: Detailed experimental
procedures and characterization of products. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 14, 2010 4847