Pd-Mediated synthesis of 7H-benzo[3,4]azepino[1,2-a]indole-6-carboxylic acid derivatives from indole-containing Baylis-Hillman adducts

Article abstract of DOI:10.1016/j.tetlet.2008.01.058

We synthesized novel tetracyclic fused indole derivatives via the intramolecular Heck reaction of indole-containing Baylis-Hillman adducts in good to moderate yields.

Full text of DOI:10.1016/j.tetlet.2008.01.058

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1773–1776
Pd-Mediated synthesis of
7H-benzo[3,4]azepino[1,2-a]indole-6-carboxylic acid derivatives
from indole-containing Baylis–Hillman adducts
Hyun Seung Lee a, Sung Hwan Kim a, Taek Hyeon Kim b, Jae Nyoung Kim a,*
a Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
b Department of Applied Chemistry and Center for Functional Nano Fine Chemicals, College of Engineering, Chonnam National University,
Gwangju 500-757, Republic of Korea
Received 4 December 2007; revised 10 January 2008; accepted 11 January 2008
Available online 15 January 2008
Abstract
We synthesized novel tetracyclic fused indole derivatives via the intramolecular Heck reaction of indole-containing Baylis–Hillman
adducts in good to moderate yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Baylis–Hillman adducts; Benzoazepino[1,2-a]indole; Heck reaction; Palladium
Due to the abundance of medium-sized heterocyclic
compounds in many natural products, drugs, and preclini-
cal leads, syntheses of these compounds by intramolecular
Heck type reaction have received much attention.1 Palla-
dium-mediated direct aryl–aryl bond-forming protocols
have also been studied extensively in this respect.2 Among
the approaches of aryl–aryl bond-forming reactions, the
use of indole moiety as one of the aryl group received
special interest due to the biological importance of indole
moiety-containing heterocyclic compounds.1c,2a,b,3
Although palladium-mediated synthesis of medium-
sized heterocyclic compounds has been investigated,1 stud-
ies involving the Baylis–Hillman adducts have not been
reported much.4,5 Lamaty and co-workers reported the
synthesis of benzazepines starting from the aza-Baylis–Hill-
man adducts.4a,b Vasudevan and co-workers examined the
cyclization of sulfonamide derivatives of Baylis–Hillman
adducts and prepared seven-membered heterocyclic
compounds.4c Very recently, we reported the synthesis of
pentacyclic benzoazepino[2,1-a]isoindole compounds via
consecutive carbopalladation using enamides of Baylis–
Hillman adducts.5
During the continuous studies we reasoned that indole-
containing Baylis–Hillman adducts could be used efficiently
for the synthesis of poly-fused heterocyclic compounds
including benzo[3,4]azepino[1,2-a]indoles6 by applying
intramolecular palladium-catalyzed arylation. Poly-fused
heterocyclic compounds having indole moiety were known
to possess many interesting biological activities6–8 including
hepatitis C virus (HCV) NS5B polymerase inhibitory activ-
ity,6 thus we decided to examine the intramolecular Heck
reaction with indole-containing Baylis–Hillman adducts as
shown in Scheme 1.
Required starting materials 3a–g were synthesized by the
reaction of Baylis–Hillman acetates 14d and indole deriva-
tives 2 (KOH, DMF, 0 °C)9 in 45–95% yields. In all cases,
E-forms of 3a–g were formed as the majors and we sepa-
rated them easily from the minor Z-isomers (5–10%).4,5
We examined the optimum reaction conditions for the
intramolecular palladium-catalyzed arylation with com-
pound 3a, and the results are summarized in Table 1.
Although all the conditions examined afforded desired
product 4a in variable yields (24–65%), the conditions
*
Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J. N. Kim).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.058

1774
H. S. Lee et al. / Tetrahedron Letters 49 (2008) 1773–1776
EWG
OAc
Br
N
EWG
R2
4a-e
R3
1a: EWG = COOMe
1b: EWG = COOEt
EWG
KOH, DMF
R3
+
Br
N
0 oC
R2
R3
R1
3a-g
R2
R1
N
H
EWG
N
2a: R1 = H, R2 = H, R3 = H
2b: R1 = H, R2 = Me, R3 = H
2c: R1 = H, R2 = H, R3 = OMe
2d: R1 = H, R2 = CH2COOEt, R3 = H
2e: R1 = Me, R2 = H, R3 = H
2f: R1 = Me, R2 = Me, R3 = H
R1
R2
4f, 4g
Scheme 1.
Table 1
Optimization of the reaction conditions for the synthesis of 4a
Entry
Conditions
Time (h)
4aa (%)
3aa (%)
1
2
3
4
5
6
a
Pd(OAc)2 (10 mol %), TBAB (1.0 equiv), K2CO3 (2.0 equiv), DMF, 100 °C
Pd(OAc)2 (10 mol %), PPh3 (20 mol %), K2CO3 (2.0 equiv), DMF, 100 °C
Pd(OAc)2 (10 mol %), TBAB (1.0 equiv), KOAc (2.0 equiv), DMF, 100 °C
Pd(OAc)2 (10 mol %), TBAB (1.0 equiv), K2CO3 (2.0 equiv), CH3CN, reflux
Pd(OAc)2 (10 mol %), TBAB (1.0 equiv), NaHCO3 (2.0 equiv), DMF, 100 °C
Pd(OAc)2 (10 mol %), PPh3 (20 mol %), Et3N (2.0 equiv), DMF, 100 °C
1
1
1
1
8
65
61
58
54
45
24
0
0
0
8
5
18
32
Isolated yield.
Table 2
Pd-mediated cyclizations of indole moiety-containing Baylis–Hillman adducts
Entry
Substratea (%)
Time (min)
60
Productb (%)
COOMe
COOMe
1
Br
N
N
3a (73)
4a (65)
COOEt
COOEt
N
2
60
N
N
Br
Br
3b (50)
4b (82)
COOMe
COOMe
N
3
30
3c (51)
4c (66)

H. S. Lee et al. / Tetrahedron Letters 49 (2008) 1773–1776
1775
Table 2 (continued)
Entry
Substratea (%)
COOMe
Time (min)
Productb (%)
COOMe
4
120
OMe
Br
N
N
3d (95)
4d (69)
OMe
COOMe
COOMe
N
Br
N
5
6
30
3e (60)
4e (78)
COOEt
EtOOC
COOMe
N
COOMe
N
60
Br
Br
3f (45)
3g (62)
4f (53)
COOMe
N
COOMe
N
7
300
4g (60)
a
Conditions: 1 (1.2 equiv), 2 (1.0 equiv), KOH (1.2 equiv), DMF, 0 °C, 30 min to 4 h. The stereochemistry of 3a–g was confirmed as E by their chemical
shifts of vinyl protons (d = 7.83–7.98 ppm).
b
Conditions: 3 (1.0 equiv), Pd(OAc)2 (10 mol %), TBAB (1.0 equiv), K2CO3 (2.0 equiv), DMF, 100 °C, 30 min to 5 h.
using Pd(OAc)2/TBAB (tetrabutylammonium bromide)/
K2CO3 in DMF (entry 1) was the best (65%). Under the
optimized conditions we examined the reactions of 3b–g
and the results are summarized in Table 2.10 For the indole
derivatives 3a–e, the reactions produced seven-membered
benzoazepino[1,2-a]indole derivatives 4a–e in good yields
(65–82%). However, 2-methyl group in compounds 3f
and 3g rendered the formation of seven-membered ring
impossible, and aryl–aryl bond-formation occurred to form
the eight-membered compounds 4f and 4g in moderate
yields (53–60%).10 The extreme selectivity between seven-
and eight-membered ring-formation could be used for
further elaboration of this strategy.
References and notes
1. For the synthesis of medium-sized ring by Heck type cyclization, see:
(a) Arnold, L. A.; Luo, W.; Guy, R. K. Org. Lett. 2004, 6, 3005–3007;
(b) Gibson, S. E.; Guillo, N.; Tozer, M. J. Chem. Commun. 1997, 637–
638; (c) Avila-Zarraga, J. G.; Lujan-Montelongo, A.; Covarrubias-
Zuniga, A.; Romero-Ortega, M. Tetrahedron Lett. 2006, 47, 7987–
7989; (d) Soderberg, B. C. G.; Hubbard, J. W.; Rector, S. R.; O’Neil,
S. N. Tetrahedron 2005, 61, 3637–3649; (e) Donets, P. A.; Van der
Eycken, E. V. Org. Lett. 2007, 9, 3017–3020; (f) Rigby, J. H.; Hughes,
R. C.; Heeg, M. J. J. Am. Chem. Soc. 1995, 117, 7834–7835; (g)
Joucla, L.; Popowycz, F.; Lozach, O.; Meijer, L.; Joseph, B. Helv.
Chim. Acta 2007, 90, 753–763.
2. For the examples of palladium-mediated intramolecular aryl–aryl
couplings, see: (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev.
2007, 107, 174–238 and further references cited therein; (b) Lane, B.
S.; Sames, D. Org. Lett. 2004, 6, 2897–2900; (c) Campeau, L.-C.;
Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581–
590; (d) Campeau, L.-C.; Parisien, M.; Leblanc, M.; Fagnou, K. J.
Am. Chem. Soc. 2004, 126, 9186–9187; (e) Campeau, L.-C.; Than-
sandote, P.; Fagnou, K. Org. Lett. 2005, 7, 1857–1860; (f) Parisien,
M.; Valette, D.; Fagnou, K. J. Org. Chem. 2005, 70, 7578–7584; (g)
Gomez-Lor, B.; Echavarren, A. M. Org. Lett. 2004, 6, 2993–2996; (h)
Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173–
1193.
In summary, we synthesized tetracyclic indole deriva-
tives via the palladium-mediated intramolecular Heck reac-
tion from indole-containing Baylis–Hillman adducts.
Acknowledgments
This work was supported by the Korea Research Foun-
dation Grant funded by the Korean Government
(MOEHRD, KRF-2006-311-C00384). Spectroscopic data
was obtained from the Korea Basic Science Institute,
Gwangju branch.
3. For the examples of Heck type cyclization involving indole moiety,
see: (a) Routier, S.; Merour, J.-Y.; Dias, N.; Lansiaux, A.; Bailly, C.;
Lozach, O.; Meijer, L. J. Med. Chem. 2006, 49, 789–799; (b) Putey,
A.; Joucla, L.; Picot, L.; Besson, T.; Joseph, B. Tetrahedron 2007, 63,
867–879; (c) Kozikowski, A. P.; Ma, D. Tetrahedron Lett. 1991, 32,

1776
H. S. Lee et al. / Tetrahedron Letters 49 (2008) 1773–1776
3317–3320; (d) Grigg, R.; Sridharan, V.; Stevenson, P.; Sukirthalin-
gam, S.; Worakun, T. Tetrahedron 1990, 46, 4003–4018.
Y.; Noguchi, T.; Ando, I.; Ogura, N.; Ikeda, S.; Hashimoto, H. J.
Med. Chem. 2006, 49, 6950–6953; (c) Faust, R.; Garratt, P. J.; Jones,
R.; Yeh, L.-K.; Tsotinis, A.; Panoussopoulou, M.; Calogeropoulou,
T.; Teh, M.-T.; Sugden, D. J. Med. Chem. 2000, 43, 1050–1061; (d)
Rivara, S.; Mor, M.; Silva, C.; Zuliani, V.; Vacondio, F.; Spadoni, G.;
Bedini, A.; Tarzia, G.; Lucini, V.; Pannacci, M.; Fraschini, F.; Plazzi,
P. V. J. Med. Chem. 2003, 46, 1429–1439.
4. For the Pd-mediated reactions involving Baylis–Hillman adducts, see:
(a) Ribiere, P.; Declerck, V.; Nedellec, Y.; Yadav-Bhatnagar, N.;
Martinez, J.; Lamaty, F. Tetrahedron 2006, 62, 10456–10466; (b)
Declerck, V.; Ribiere, P.; Nedellec, Y.; Allouchi, H.; Martinez, J.;
Lamaty, F. Eur. J. Org. Chem. 2007, 201–208; (c) Vasudevan, A.;
Tseng, P.-S.; Djuric, S. W. Tetrahedron Lett. 2006, 47, 8591–8593; (d)
Coelho, F.; Veronese, D.; Pavam, C. H.; de Paula, V. I.; Buffon, R.
Tetrahedron 2006, 62, 4563–4572.
5. Gowrisankar, S.; Lee, H. S.; Lee, K. Y.; Lee, J.-E.; Kim, J. N.
Tetrahedron Lett. 2007, 48, 8619–8622 and further references cited
therein on the synthesis and biological activities of benzoazepino[2, 1-a]
isoindole moiety-containing compounds. For the general review on
Baylis–Hillman reaction, please see: (a) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. Rev. 2003, 103, 811–891; (b) Ciganek, E.. In
Organic Reactions; Paquette, L. A., Ed.; John Wiley & Sons: New
York, 1997; Vol. 51, pp 201–350; (c) Basavaiah, D.; Rao, P. D.;
Hyma, R. S. Tetrahedron 1996, 52, 8001–8062; (d) Kim, J. N.; Lee, K.
Y. Curr. Org. Chem. 2002, 6, 627–645; (e) Lee, K. Y.; Gowrisankar,
S.; Kim, J. N. Bull. Korean Chem. Soc. 2005, 26, 1481–1490 and
further references cited therein.
6. (a) For the preparation of benzoazepino[1,2-a]indole derivatives as
inhibitors of hepatitis C virus (HCV) replication, see: Hudyma, T. W.;
Zheng, X.; He, F.; Ding, M.; Bergstrom, C. P.; Hewawasam, P.;
Martin, S. W.; Gentles, R. G. WO 2007092000, 2007; Chem. Abstr.
2007, 147, 277782; (b) Meanwell, N. A.; Gentles, R. G.; Ding, M.;
Bender, J. A.; Kadow, J. F.; Hewawasam, P.; Hudyma, T. W.; Zheng,
X. U.S. Patent 2,007,184,024, 2007; Chem. Abstr. 2007, 147, 257667.
7. For the synthesis and biological importance of 1,7-annulated indole
derivatives, see: (a) Al-awar, R. S.; Ray, J. E.; Hecker, K. A.; Huang,
J.; Waid, P. P.; Shih, C.; Brooks, H. B.; Spencer, C. D.; Watkins, S.
A.; Patel, B. R.; Stamm, N. B.; Ogg, C. A.; Schultz, R. M.; Considine,
E. L.; Faul, M. M.; Sullivan, K. A.; Kolis, S. P.; Grutsch, J. L.;
Joseph, S. Bioorg. Med. Chem. Lett. 2004, 14, 3217–3220; (b) Zhu, G.;
Conner, S. E.; Zhou, X.; Chan, H.-K.; Shih, C.; Engler, T. A.;
Al-awar, R. S.; Brooks, H. B.; Watkins, S. A.; Spencer, C. D.;
Schultz, R. M.; Dempsey, J. A.; Considine, E. L.; Patel, B. R.; Ogg, C.
A.; Vasudevan, V.; Lytle, M. L. Bioorg. Med. Chem. Lett. 2004, 14,
3057–3061; (c) Van Wijngaarden, I.; Hamminga, D.; van Hes, R.;
Standaar, P. J.; Tipker, J.; Tulp, M. Th. M.; Mol, F.; Olivier, B.; de
Jonge, A. J. Med. Chem. 1993, 36, 3693–3699; (d) Toscano, L.;
Grisanti, G.; Fioriello, G.; Seghetti, E.; Bianchetti, A.; Bossoni, G.;
Riva, M. J. Med. Chem. 1976, 19, 208–213.
9. (a) Bodwell, G. J.; Li, J. Org. Lett. 2002, 4, 127–130; (b) Caddick, S.;
Shering, C. L.; Wadman, S. N. Tetrahedron 2000, 56, 465–473.
10. Typical procedure for the synthesis of 3a and 4a: To a stirred solution
of indole (2a, 117 mg, 1.0 mmol) and KOH (79 mg, 1.2 mmol) in
DMF (1.5 mL) was added a solution of Baylis–Hillman acetate 1a
(376 mg, 1.2 mmol) in DMF (0.5 mL) at 0 °C, and maintained at 0 °C
for 4 h with stirring. After the usual aqueous workup and column
chromatographic purification process (hexanes/EtOAc, 10:1), we
obtained 3a (271 mg, 73%) as a white solid. A stirred mixture of 3a
(185 mg, 0.5 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), TBAB (161 mg,
0.5 mmol), and K2CO3 (138 mg, 1.0 mmol) in DMF (2 mL) was
heated to 100 °C for 1 h. After the usual aqueous workup and column
chromatographic purification process (hexanes/ether, 10:1), we
obtained 4a (95 mg, 65%) as a pale yellow solid. Other compounds
3b–g and 4b–g were synthesized similarly and the representative
spectroscopic data of compounds 3a, 4a, and 4f are as follows:
Compound 3a: 73%; white solid, mp 95–97 °C; IR (film) 1717, 1463,
1435, 1248 cmÀ1; 1H NMR (CDCl3, 300 MHz) d 3.74 (s, 3H), 5.03 (s,
2H), 6.43 (d, J = 3.3 Hz, 1H), 6.99–7.30 (m, 7H), 7.56 (d, J = 6.9 Hz,
1H), 7.68 (d, J = 7.5 Hz, 1H), 7.98 (s, 1H); 13C NMR (CDCl3,
75 MHz) d 42.26, 52.36, 101.54, 109.52, 119.36, 120.72, 121.41,
123.87, 127.47, 127.48, 128.50, 129.51, 130.14, 130.53, 133.10, 134.90,
136.04, 142.48, 166.81; ESIMS m/z 370.09 (M++H).
Compound 4a: 65%; yellow solid, mp 142–144 °C; IR (film) 1705,
1457, 1242 cmÀ1; 1H NMR (CDCl3, 300 MHz) d 3.84 (s, 3H), 4.97 (s,
2H), 6.74 (s, 1H), 7.08–7.13 (m, 1H), 7.20–7.28 (m, 1H), 7.35–7.48 (m,
3H), 7.57 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.85 (d,
J = 8.1 Hz, 1H), 7.86 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 39.19,
52.41, 101.23, 109.27, 119.78, 120.71, 122.00, 127.58, 128.16, 129.66,
129.98, 130.22, 131.82 (2C), 133.15, 136.33, 139.21, 142.71, 166.03;
ESIMS m/z 290.19 (M++H). Anal. Calcd for C19H15NO2: C, 78.87;
H, 5.23; N, 4.84. Found: C, 78.67; H, 5.47; N, 4.76.
Compound 4f: 53%; white solid, mp 179–181 °C; IR (film) 1714, 1438,
1
1225 cmÀ1; H NMR (CDCl3, 300 MHz) d 2.57 (d, J = 0.6 Hz, 3 H),
3.73 (s, 3H), 4.82 (d, J = 14.1 Hz, 1H), 5.01 (d, J = 14.1 Hz, 1H), 6.21
(d, J = 0.6 Hz, 1H), 6.77 (dd, J = 7.2 and 0.6 Hz, 1H), 7.05–7.10 (m,
1H), 7.18 (d, J = 7.2 Hz, 1H), 7.35–7.52 (m, 4H), 8.10 (s, 1H); 13C
NMR (CDCl3, 75 MHz) d 12.65, 40.91, 52.03, 100.52, 119.47, 119.98,
125.76, 125.78, 126.74, 127.39, 129.47, 130.08, 131.65, 133.48, 134.62,
135.23, 137.72, 140.25, 145.46, 166.62; ESIMS m/z 304.18 (M++H).
Anal. Calcd for C20H17NO2: C, 79.19; H, 5.65; N, 4.62. Found: C,
79.05; H, 5.78; N, 4.53.
8. For the synthesis and biological importance of tetracyclic indole
derivatives, see: (a) Bressy, C.; Alberico, D.; Lautens, M. J. Am.
Chem. Soc. 2005, 127, 13148–13149 and further references cited
therein; (b) Ikegashira, K.; Oka, T.; Hirashima, S.; Noji, S.;
Yamanaka, H.; Hara, Y.; Adachi, T.; Tsuruha, J.-I.; Doi, S.; Hase,