N-cyclopropylation of indoles and cyclic amides with copper(II) reagent

Article abstract of DOI:10.1021/ol800376f

Copper-mediated coupling reactions of cyclopropylboronic acid with indoles and cyclic amides are described. The process utilizes catalytic or stoichiometric amounts of copper(ll) acetate, DMAP, and NaHMDS at 95 °C under an atmosphere containing oxygen. A variety of functional groups remain intact throughout the reaction.

Full text of DOI:10.1021/ol800376f

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1653-1655
N-Cyclopropylation of Indoles and
Cyclic Amides with Copper(II) Reagent
Takayuki Tsuritani,*,† Neil A. Strotman,‡ Yuhei Yamamoto,† Masashi Kawasaki,†
Nobuyoshi Yasuda,‡ and Toshiaki Mase†
Process Research, PreClinical Department, Banyu Pharmaceutical Co. Ltd., 3 Okubo,
Tsukuba, Ibaraki 300-2611, Japan, and Merck Research Laboratories, Department of
Process Research, PO Box 2000, Rahway, New Jersey 07065
takayuki_tsuritani@merck.com
Received February 18, 2008
ABSTRACT
Copper-mediated coupling reactions of cyclopropylboronic acid with indoles and cyclic amides are described. The process utilizes catalytic
or stoichiometric amounts of copper(II) acetate, DMAP, and NaHMDS at 95
groups remain intact throughout the reaction.
°C under an atmosphere containing oxygen. A variety of functional
The cyclopropyl group has received considerable attention
in the field of medicinal chemistry because of its unique
characteristics, such as its steric and electronic properties
and metabolic stability.1 Among the many cyclopropyl-
containing compounds, N-cyclopropylamides and -azoles
have attracted the most attention for the development of new
drug candidates. Some of these compounds show antiviral,2
antitumor,3 and retinoic acid receptor antagonist activity.4
Despite the importance of N-cyclopropylamine derivatives,
there are few methods to incorporate cyclopropyl groups on
nitrogen atoms. For example, cyclopropylation of simple
aniline derivatives was achieved by reductive amination with
(1-ethoxycyclopropoxy)trimethylsilane,5a-c and through mag-
nesium cyclopropylidene chemistry,5d but the yield and scope
are limited. In particular, cyclopropylation of indoles, pyr-
roles, and amides has still remained challenging chemistry.
Recently, cyclopropylation of cyclic amides and azoles was
reported by Gagnon and co-workers.6,7 This pioneering work
utilized a triscyclopropylbismuth reagent with copper(II)
acetate, and the reaction proceeded in good yields with broad
substrate scope. A few issues with this reaction are reagent
† Banyu Pharmaceutical Co. Ltd.
‡ Merck Research Laboratories.
(1) For example, see: (a) Todo, Y.; Takagi, H.; Iino, F.; Fukuoka, Y.;
Ikeda, Y.; Tanaka, K.; Saikawa, I.; Narita, H. Chem. Pharm. Bull. 1994,
42, 2049-2054. (b) Turner, W. R.; Suto, M. J. Tetrahedron Lett. 1993, 34,
281-284.
(5) (a) Kang, J.; Kim, K. S. J. Chem. Soc., Chem. Commun. 1987, 897-
898. (b) Gillaspy, M. L.; Lefker, B. A.; Hada, W. A.; Hoover, D. J.
Tetrahedron Lett. 1995, 36, 7399-7402. (c) Yoshida, Y.; Umeza, K.;
Hamada, Y.; Atsumi, N.; Tabuchi, F. Synlett 2003, 2139-2142. (d) Satoh,
T.; Miura, M.; Sakai, K.; Yokoyama, Y. Tetrahedron 2006, 62, 4253-
4261.
(2) (a) Chai, H.; Zhao, Y.; Zhao, C.; Gong, P. Bioorg. Med. Chem. 2006,
14, 911-917. (b) Zhao, C.; zhao, Y.; Chai, H.; Gong, P. Bioorg. Med.
Chem. 2006, 14, 2552-2558.
(6) Gagnon, A.; St-Onge, M.; Little, K.; Duplessis, M.; Barabe´, F. J.
Am. Chem. Soc. 2007, 129, 44-45.
(3) (a) Li, Q.; Woods, K. W.; Claiborne, A.; Gwaltney, S. L., II; Barr,
K. J.; Liu, G.; Gehrke, L.; Credo, R. B.; Hui, Y. H.; Lee, J.; Warner, R. B.;
Kovar, P.; Nukkala, M. A.; Zielinski, N. A.; Tahir, S. K.; Fitzgerald, M.;
Kim, K. H.; Marsh, K.; Frost, D.; Ng, S. C.; Rosenberg, S.; Sham, H. Bioorg.
Med. Chem. Lett. 2002, 12, 465-469. (b) Swann, E.; Barraja, P.; Oberlander,
A. M.; Gardipee, W. T.; Hudnott, A. R.; Beall, H. D.; Moody, C. J. J.
Med. Chem. 2001, 44, 3311-3319.
(4) Yoshimura, H.; Nagai, M.; Hibi, S.; Kikichi, K.; Abe, S.; Hida, T.;
Higashi, S.; Hishimura, I.; Yamanaka, T. J. Med. Chem. 1995, 38, 3163-
3173.
(7) Though there are a few reports of nucleophilic substitution of amide
nitrogen atom with cycopropyl bromide, only one or two examples are
mentioned and the yield was not clearly mentioned: (a) Liang, G.-B.; Qian,
X.; Feng, D.; Biftu, T.; Eiermann, G.; He, H.; Leiting, B.; Lyons, K.; Petrov,
A.; Sinha-Roy, R.; Zhang, B.; Wu, J.; Zhang, X.; Thornberry, N. A.; Weber,
A. E. Bioorg. Med. Chem. Lett. 2007, 17, 1903-1907. (b) Tran, T. P.;
Ellsworth, E. L.; Stier, M. A.; Domagala, J. M.; Showalter, H. D. H.;
Gracheck, S. J.; Shapiro, M. A.; Joannides, T. E.; Singh, R. Bioorg. Med.
Chem. Lett. 2004, 14, 4405-4409.
10.1021/ol800376f CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/21/2008

availability and atom efficiency: the triscyclopropylbismuth
reagent is not commercially available and not stable for
extended periods of storage, and two of the three cyclopropyl
groups on bismuth do not participate in the coupling reaction.
Therefore, we searched for a more facile method to
introduce cyclopropyl groups on nitrogen atoms of azoles
and amides. Transition-metal-catalyzed reactions between
organohalides and amines constitute the most common
strategy for N-alkylation and N-arylation.8,9 Accordingly, we
initially attempted the coupling reactions of indole with
cyclopropyl bromide using a palladium, nickel, or copper
catalyst. However, no desired coupling product was obtained,
and only the N-allylated product derived from cyclopropane
ring opening was observed, together with unreacted starting
material (Scheme 1).
Table 1. Conditions for the N-Cyclopropylation of Indole
entry
amine
x
additive
y
yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13c
0
7
40
9
36
10
20
20
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
Et3N
lutidine
DMAP
DMAP
1.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3
4
5
6
0.1
0.1
0.1
0.2
Scheme 1. Palladium-, Nickel-, or Copper-Catalyzed Reaction
of Indoles with Cyclopropyl Bromide
21
45 (43)b
NaHMDS
NaHMDS
1.0
1.0
65 (62)b
0
3
DMAP
3.0
a HPLC assay yield. b Isolated yield. c Trialkoxyborate 7 was employed
instead of cyclopropylboronic acid.
Because of this vulnerability of cyclopropyl bromide to
ring opening, we next turned our attention to the copper-
mediated oxidative coupling reaction, a well-established
reaction between arylmetals and amines. Thus far, arylmetals
such as aryllead triacetate,10 arylbismuth,6,11 aryltrimethoxy-
silanes,12 diaryl iodonium salts,13 arylstannanes,14 and aryl-
boronic acid15,16 have been reported to be efficient coupling
partners for N-arylation. In particular, the coupling reactions
with arylboronic acids have been studied extensively since
the initial work by Chan and Lam.15,16 We decided to focus
on N-cyclopropylation with cyclopropylboronic acid since
it is a commercially available reagent17 and began our study
with indole as a model substrate. The initial results are shown
in Table 1.
We were pleased to find that the desired coupling product
was obtained in 40% assay yield under standard reaction
conditions (entry 3) : Cu(OAc)2 (10 mol %), pyridine (3.0
equiv), dry air, and toluene at 95 °C. DMAP and pyridine
were found to be suitable amines (entries 3 and 8-10). The
effect of additives was explored, and it was found that
addition of an equimolar amount of NaHMDS improved the
yield (entries 10 and 11), while addition of a catalytic amount
(0.1 equiv) of amine ligands (entries 4-6) or addition of
decanoic acid16b,d (0.2 equiv) did not improve the yields. This
was plausibly due to the increased nucleophilicity of the
indole anion. The reaction without pyridine or DMAP did
not proceed at all (entries 1 and 12). Trialkoxyborate reagent
7 (see Table 1), which was recently developed by Miyaura’s
group as an efficient reagent for C-N bond formation as
well as for Suzuki-Miyaura couplings,18 did not work well
(entry 13). Molecular oxygen was of importance in this
reaction. When the reaction was conducted under a nitrogen
atmosphere, no coupling product was obtained.
(8) For reviews, see: Kienle, M.; Dubbaka, S. R.; Brade, K.; Knochel,
P. Eur. J. Org. Chem. 2007, 4166-4176.
(9) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382-2384. (b)
Goodbrand, H. B.; Hu, N.-X. J. Org. Chem. 1999, 64, 670-674. (c) Lindley,
J. Tetrahedron 1984, 40, 1433-1456. (d) Kiyomori, A.; Marcoux, J.-F.;
Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657-2640.
(10) Elliott, G. I.; Konopelski, J. P. Org. Lett. 2000, 2, 3055-3057 and
references cited therein.
(11) Sorenson, R. J. J. Org. Chem. 2000, 65, 7747-7749 and references
cited therein.
(12) (a) Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.;
DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600-7601. (b)
Song, R.-J.; Deng, C.-L.; Xie, Y.-X.; Li, J.-H. Tetrahedron Lett. 2007, 48,
7845-7848.
(13) Kang, S.-K.; Lee, S.-H.; Lee, D. Synlett 2000, 1022-1024.
(14) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K.
M.; Chan, D. M. T.; Combs, A. Synlett 2000, 674-676.
(15) (a) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters,
M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-
2944. (b) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933-2936.
With these optimized conditions in hand, the scope and
limitations of this reaction were examined (Table 2).
The reaction tolerated a variety of functional groups, such
as chloride (entries 5 and 8), ester (entries 6), ketone (entry
7), nitrile (entry 3), and nitro (entry 4) groups. Although the
reactions with electron-deficient substrates were not sufficient
(17) Suzuki-Miyaura coupling reactions of cyclopropylboronic acid and
aryl halides had already been reported. Wallace, D. J.; Chen, C. Tetrahedron
Lett. 2002, 43, 6987-6990.
(18) Yamamoto, Y.; Takizawa, M.; Yu, X.-Q.; Miyaura, N. Angew.
Chem., Int. Ed. 2008, 47, 928-931.
(16) (a) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233-1236. (b)
Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077-2079. (c) Quach,
T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397-4400. (d) Txschucke, C. C.;
Murphy, J. M.; Hartwig, J. F. Org. Lett. 2007, 9, 761-764.
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Org. Lett., Vol. 10, No. 8, 2008

Table 2. N-Cyclopropylation of Indole Derivatives
Table 3. N-Cyclopropylation of Amides
a Reaction conditions are the same as those mentioned in Table 2.
b Isolated yield
Cyclic amides and benzamide worked well (entries 1, 2,
and 5), but acyclic amide did not afford the coupling product
and starting material was recovered (entry 6). The poor
reactivity of the acyclic amide might be due to its strong
preference for the Z-conformation since all cyclic amides
are forced to adopt the E-conformation. In addition, the
coupling reaction proceeded well for a carbamate and imide
(entries 3 and 4).
a Isolated yield. b Trialkoxy borate 7 was employed instead of cyclo-
propylboronic acid without NaHMDS.
In summary, we have established a copper-mediated
cyclopropylation of indoles and amides with cyclopropyl-
boronic acid. Further development of this chemistry is
currently under investigation in our laboratories.
(entries 3, 4, 6, 7, 9 and 11), the yields could be improved
by using a stoichiometric amount of copper(II) acetate.
However, surprisingly, stoichiometric reactions gave worse
results in the case of electron rich substrates (entries 1 and
2),19 and stoichiometric reactions with trialkoxyborate reagent
7 in the absence of NaHMDS furnished the desired coupling
product in good yield.
Acknowledgment. We thank Dr. Kurihara H. for his
helpful discussions and Drs. H. Ohsawa, M. Matsuda, and
J. Sakai, Merck & Co. Inc., for HRMS measurements.
We next applied this system to the cyclopropylation of
amides (Table 3).
Supporting Information Available: Detailed experi-
mental procedures and characterization data of each com-
pound. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) In the case of indole and 5-methoxyindole, starting material was
consumed completely, while starting material remained in the case of other
substrates. An insoluble black tar emerged during the extractive operation
in the former case.
OL800376F
Org. Lett., Vol. 10, No. 8, 2008
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