Cul catalyzed N-arylation of amide as a key step for the preparation of 3-aryl β-carbolin-1-ones

Article abstract of DOI:10.1039/b406046f

An expedient synthetic route for 3-aryl β-carbolin-1-ones was developed starting from ethyl acetamidocyanoacetate and chalcone derivatives. The five- and six-membered nitrogen-containing rings in the β-carbolin-1- ones were elaborated efficiently by an in

Full text of DOI:10.1039/b406046f

View Article Online / Journal Homepage / Table of Contents for this issue
CuI catalyzed N-arylation of amide as a key step for the
preparation of 3-aryl ꢀ-carbolin-1-ones†
Shaozhong Wang,a Jianwei Sun,a Gang Yu,a Xiaoyi Hu,b Jun O Liub and Yuefei Hu*‡a
a Department of Chemistry, Nanjing University, Nanjing 210093, P. R. China.
E-mail: yfh@mail.tsinghua.edu.cn; Fax: ϩ86 10 6277 1149; Tel: ϩ86 10 6279 5380
b Department of Pharmacology and Molecular Sciences,
John Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205,
USA. E-mail: joliu@jhu.edu; Fax: ϩ01 410 955 4520; Tel: ϩ01 410 955 4619
Received 15th January 2004, Accepted 28th April 2004
First published as an Advance Article on the web 10th May 2004
Table 1 The preparation of compounds 5, 6, and 2
An expedient synthetic route for 3-aryl ꢀ-carbolin-1-ones
was developed starting from ethyl acetamidocyanoacetate
and chalcone derivatives. The five- and six-membered
nitrogen-containing rings in the ꢀ-carbolin-1-ones were
elaborated efficiently by an intramolecular ketone-nitrile
annulation and an intramolecular N-arylation of amide
respectively.
4,5,6,2
R
R1
Ar
5
6
2
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
C6H5
75
73
65
67
75
74
65
72
60
80
77
67
84
81
76
88
80
80
68
67
70
60
64
62
65
72
60
4-ClC6H4
4-MeC6H4
C6H5
4-ClC6H4
4-MeC6H4
C6H5
OCH2O
OCH2O
OCH2O
β-Carbolin-1-ones have served as important intermediates for
the preparation of complex alkaloids1 and are found to possess
potent bioactivities on the central nervous system.2 The first
report that derivatives of β-carbolin-1-one (1) with alkoxy
subsitituents on the A-ring could inhibit colon and lung tumors
appeared in patent literature in 2001.3 Subsequently, we found
that 3-aryl-β-carbolin-1-one (2) and analogues inhibit the
proliferation of HeLa cells with IC50 values in the low micro-
molar range. Moreover, aromatic substitution on C3 in 2
proved to be essential for their biological activity.4 The facile
synthetic route to various derivatives of 2 disclosed here thus
makes it possible to probe the structure and activity
relationship for the carbolin-1-one family of alkaloids (Fig. 1).
MeO
MeO
MeO
MeO
MeO
MeO
4-ClC6H4
4-MeC6H4
amide can be achieved using palladium9 and/or copper() as
catalysts.10 Herein, we report an expedient three-step synthetic
route for 3-aryl β-carbolin-1-one (2). As shown in Scheme 1,
the route starts from Michael addition of ethyl acetamido-
cyanoacetate (3) to chalcone (4) to afford a key precursor 5
with an efficient introduction of two nitrogen atoms. Then
an intramolecular ketone–nitrile annulation of 5 yields di-
hydropyridone 6. Finally, Cu() catalyzed intramolecular
N-arylation of amide 6 affords the target compound 2.
Fig. 1 β-Carbolin-1-ones with antitumor activities.
To date, two practical strategies have been adopted to
construct the skeleton of β-carbolin-1-one. One is to build
pyridone rings by using acid- or palladium-catalyzed intra-
molecular cyclization of indole-2-carboxylic acid amides,3,5 or
intramolecular Heck reaction of 3-iodoindole-2-carboxylic
acid amides.6 The other is to modify the corresponding tricyclic
precursors, such as dehydrogenation of polyhydro-β-carbolin-
1-ones,1a–b or oxidation of β-carbolins to yield the corre-
sponding N-oxides followed by a thermal rearrangement.1c–d
Since the most suitable tricyclic precursors were obtained
mainly from indole derivatives,7 both strategies rely upon, to a
great extent, the use of a few indole derivatives directly
or indirectly as common starting materials, including indole-
3-ethanamine, indole-2-carboxylic acid, 3-iodoindole-2-
carboxylic acid or 3-iodoindole-2-carboxylaldehyde. For our
purpose to synthesize 3-aryl β-carbolin-1-one (2), those
methods suffered from either inaccessible starting materials or
elaborate multi-step syntheses.
Scheme 1 The preparation of 3-aryl β-carbolin-1-ones (2). Reagents
and conditions: a. ethyl acetamidocyanoacetate (3), cat. t-BuONa, THF,
rt, 2 h; b. aq. HCl–HOAc, rt, 7 h; c. (1) CuI, NaH, DME, reflux, 7–10 h;
(2) 10% NH4OH, 2 h.
In the literature, ethyl acetamidocyanoacetate (3) has rarely
been employed as a nucleophilic donor in Michael addition
reactions and one of its nitrogen-containing groups has often
been “wasted” in other uses.11 When we treated the mixture of 3
and 4a with a catalytic amount of t-BuONa (10 mol%) at room
temperature for 2 h, the desired adduct 5a was obtained in 75%
yield. Under similar conditions, the addition of 3 to other
chalcones 4b–i yielded the corresponding adducts 5b–i in
60–75% yields (Table 1).
A number of lactams are readily prepared by the ketone–
nitrile annulation8 and the intramolecular N-arylation of
The intermediate 5 can be further elaborated by two possible
pathways. One is to build the indole ring first by an intra-
† Electronic supplementary information (ESI) available: NMR and
experimental details. See http://www.rsc.org/suppdata/ob/b4/b406046f/
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 7 3 – 1 5 7 4
1573

View Article Online
molecular N-arylation of amide, and the other is to construct
the pyridone ring by an intramolcular ketone–nitrile annul-
ation. Unfortunately, 5a did not offer any indole product in
an intramolecular N-arylation of amide catalyzed by Pd(OAc)2/
Acknowledgements
We are grateful to the National Natural Science Foundation of
China for financial support.
9b
9d
P(o-tolyl)3/Cs2CO3
or Pd(OAc)2/DPEphos/Cs2CO3
at
100 ЊC in toluene for 10 h, while the chalcone 4a was recovered
almost in quantitative yield. A control experiment revealed
that this result arose from the retro-Michael addition of 5a
catalyzed by Cs2CO3.
Notes and references
‡ Current address: Department of Chemistry, Tsinghua University,
Beijing 100084, P. R. China.
Although the acid-catalyzed ketone–nitrile annulation of 5a
8b–c
8a,d
with H3PO4–P2O5
or EtOH–H2SO4
did give 6a as white
1 (a) Atta-Ur. Rahman and M. Ghazala, Synthesis, 1980, 372;
(b) F. Bracher and D. Hildebrand, Liebigs Ann. Chem., 1992, 1315;
(c) T. Choshi, Y. Matsuya, M. Okita, K. Inada, E. Sugino and
S. Hibino, Tetrahedron Lett., 1998, 39, 2341; (d ) N. Kanekiyo,
T. Choshi, T. Kuwada, E. Sugino and S. Hibino, Heterocycles, 2000,
53, 1877; (e) T. Choshi, T. Kuwada, M. Fukui, Y. Matsuya,
E. Sugino and S. Hibino, Chem. Pharm. Bull. Jpn., 2000, 48, 108;
( f ) N. Kanekiyo, T. Kuwada, T. Choshi, J. Nohuhiro and S. Hibino,
J. Org. Chem., 2001, 66, 8793.
2 (a) T. Teshigawara, Jap Patent, 1967, 8628 (Chem. Abstr., 1968, 68,
49580g); (b) C. A. Veale, J. R. Damewood Jr., G. B. Steelman,
C. Bryant, B. Gomes and J. Williams, J. Med. Chem., 1995, 38,
86–97; (c) U. Nielsch, M. Sperzel, B. Bethe, B. Junge, F. Lieb,
R. Velten, DE 19807993/1999 (Chem. Abstr., 1999, 131, 199871m);
(d ) O. Ritzeler A. Castro L. Grenier F. Soucy, EP 1134221/2001
(Chem. Abstr., 2001, 135, 242149d).
crystals, the low yields (24–46%) were obtained due largely to
the poor solubility of both starting material and product in the
solvent used. However, we found that a good yield (80%) of 6a
can be obtained easily by standing the mixture of 5a in aqueous
HCl–HOAc at room temperature for 7 h. Using the same pro-
cedure, compounds 5b–i were converted to the corresponding
products 6b–i in 67–88% yields (Table 1).
To our disappointment, an intramolecular N-arylation of
9b
amide 6a catalyzed by Pd(OAc)2/P(o-tolyl)3/Cs2CO3 failed.
Instead of the target product 2a, it gave ethyl 4-(2-bromo-
phenyl)-2-pyridone-3-carboxylate (8) in 85% yield (Scheme 2).
Since the same result was also obtained without Pd(OAc)2
and P(o-tolyl)3, the formation of 8 must result from a Cs2CO3
promoted elimination of acetamido group, which has been
shown to be a good leaving group under basic conditions.12
3 E. Menta, N. Pescalli and S. Spinelli, WO 200109129/2001. (Chem.
Abstr., 2001, 134, 162922q).
4 S. Wang, Ph. D. Thesis, Nanjing University, China, 2002.
5 (a) J. R. Johnson, A. A. Larsen, A. D. Holley and K. Gerzon, J. Am.
Chem. Soc., 1947, 69, 2364; (b) E. M. Beccalli and G. Broggini,
Tetrahedron Lett., 2003, 44, 1919.
6 (a) E. M. Beccalli, G. A. Broggini, E. Marchesini and G. Rossi,
Tetrahedron, 2002, 58, 6673; (b) G. Abbiati, E. M. Beccalli, G. Brog-
gini and C. Zoni, J. Org. Chem., 2003, 68, 7625.
7 (a) M. Bois-Choussy, M. De Paolis and J. Zhu, Tetrahedron Lett.,
2001, 42, 3427; (b) G. Abbiati, E. M. Beccalli, A. Marchesini and
E. Rossi, Synthesis, 2001, 2477; (c) H. Zhang and R. C. Larock, Org.
Lett., 2001, 3, 3083; (d ) H. Zhang and R. C. Larock, J. Org. Chem.,
2002, 67, 7048.
Scheme 2 Cs2CO3 promoted elimination of acetamido group.
Fortunately, when compound 6a was treated under improved
Goldberg reaction conditions (CuI/NaH/DMF at 90 ЊC for 2h),
the desired product 2a was obtained in 20% yield. By varying
the reaction conditions, the best result (68%) was obtained by
refluxing the mixture of 6a/CuI/NaH (1 : 2 : 4 by mole) in DME
(ethylene glycol dimethyl ether) followed by work-up with 10%
aq. NH4OH. Under similar conditions, 6b–i were converted
into the corresponding 2b–i smoothly in moderate yields (60–
72%, Table 1).
Since 3-acetamido-4-(2-bromophenyl)-6-phenyl-2-pyridone
(9) was captured and it can be converted into 2a with CuI/NaH,
therefore, this novel one-step conversion of 6 to 2 actually was a
tandem reaction sequenced by the cleavage of the ester, a
decarboxylation–aromatization and an N-arylation of amide.
CuI played a critical role both in the initiation step to cleave the
ester and in the end step to promote the intramolecular
N-arylation of intermediate 9 to give target compound 2
(Scheme 3).
8 (a) A. I. Meyers and G. Garcia-Munoz, J. Org. Chem., 1964, 29,
1435; (b) R. Kunstmann, U. Lerch and K. Wagner, J. Heterocycl.
Chem., 1981, 18, 1437; (c) R. Kunstmann, U. Lerch, H. Gerhards,
M. Leven and U. Schacht, J. Med. Chem., 1984, 27, 432;
(d ) K. Hattori and R. B. Grossman, J. Org. Chem., 2003, 68, 1409.
9 For selected recent reports, see: (a) J. P. Wolfe, R. A. Rennels
and S. L. Buchwald, Tetrahedron, 1996, 52, 7525; (b) S. Wagaw,
R. A. Rennels and S. L. Buchwald, J. Am. Chem. Soc., 1997, 119,
8451; (c) F. He, B. M. Foxman and B. B. Snider, J. Am. Chem. Soc.,
1998, 120, 6417; (d ) B. H. Yang and S. L. Buchwald, Org. Lett.,
1999, 1, 35; (e) J. Yin and S. L. Buchwald, Org. Lett., 2000, 2, 1101;
( f ) W. C. Shakespeare, Tetrahedron Lett., 1999, 40, 2035;
(g) J. Madar, H. Kopecka, D. Pireh, J. Pease, M. Pliushchev,
R. J. Sciotti, P. E. Wiedeman and S. W. Djuric, Tetrahedron Lett.,
2001, 42, 3681; (h) J. Yin and S. L. Buchwald, J. Am. Chem. Soc.,
2002, 124, 6043.
10 For selected recent reports, see: (a) W. Schlecker, A. Huth, E. Ottow
and J. Mulzer, Tetrahedron, 1995, 51, 9531; (b) P. Molina, P. M.
Fresneda and S. Delgado, Synthesis, 1999, 326; (c) R. J. Hall,
J. Marchant, A. M. F. Oliveira-Campos, M.-J. R. P. Queiroz and
P. V. R. Shannon, J. Chem. Soc., Perkin Trans. 1, 1992, 3439;
(d ) A. Klapars, J. C. Antilla, X. Huang and S. L. Buchwald, J. Am.
Chem. Soc., 2001, 123, 7727; (e) A. Klapars, X. Huang and
S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 7421; ( f ) S. Cacchi,
G. Fabrizi and L. M. Parisi, Org. Lett., 2003, 5, 3843; (g) K. Okano,
H. Tokuyama and T. Fukuyama, Org. Lett., 2003, 5, 4987;
(h) K. Yamada, T. Kurokawa, H. Tokuyama and T. Fukuyama,
J. Am. Chem. Soc., 2003, 125, 6630.
Scheme 3 CuI initialized tandem reaction.
11 For selected recent reports, see: (a) L. Cheng, C. A. Goodwin,
M. F. Schully, V. V. Kakkar and G. Claeson, J. Med. Chem., 1992,
35, 3364; (b) C. Wang and H. I. Mosberg, Tetrahedron Lett., 1995,
36, 3623; (c) D. Choi, J. P. Stables and H. Kohn, J. Med. Chem.,
1996, 39, 1907; (d ) R. J. Smith, S. Bratovanov and S. Bienz, Tetra-
hedron, 1997, 53, 13695; (e) M. Kiuchi, K. Adachi, T. Kohara,
M. Minoguchi, T. Hanano, Y. Aoki, T. Mishina, M. Arita,
N. Nakao, M. Ohtsuki, Y. Hoshino, K. Teshima, K. Chiba, S. Sasaki
and T. Fujita, J. Med. Chem., 2000, 43, 2946.
In summary, a novel preparation of 3-aryl β-carbolin-1-one
was developed. Ethyl acetamidocyanoacetate (3) was employed
as a nucleophilic donor in a Michael addition reaction for
efficient introduction of two nitrogen-containing functional
groups to the adduct 5. Then a very mild intramolecular
ketone–nitrile annulation of 5 gave the desired pyridone
intermediate 6 conveniently. Finally, the indole ring was
assembled efficiently by an intramolecular N-arylation of
amide 6 catalyzed by CuI to yield target compound 2.
12 S. Wang, G. Yu, J. Lu, K. Xiao, Y. Hu and H. Hu, Synthesis, 2003,
487.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 7 3 – 1 5 7 4
1574