Palladium-mediated synthesis of poly-fused heterocycles from Baylis-Hillman adducts

Article abstract of DOI:10.1016/j.tet.2008.05.087

We synthesized various poly-fused heterocyclic compounds in good to moderate yields via the intramolecular Heck type reaction of Baylis-Hillman adducts modified with indole, imidazole, benzimidazole, and isatin.

Full text of DOI:10.1016/j.tet.2008.05.087

Tetrahedron 64 (2008) 7183–7190
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-mediated synthesis of poly-fused heterocycles from
Baylis–Hillman adducts
*
Hyun Seung Lee, Sung Hwan Kim, Saravanan Gowrisankar, Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 May 2008
Received in revised form 18 May 2008
Accepted 19 May 2008
Available online 21 May 2008
We synthesized various poly-fused heterocyclic compounds in good to moderate yields via the intra-
molecular Heck type reaction of Baylis–Hillman adducts modified with indole, imidazole, benzimidazole,
and isatin.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Baylis–Hillman adducts
Heck reaction
Palladium
Isatin
Benzimidazole
Indole
Imidazole
1. Introduction
moiety-containing tetracyclic compounds as NS5B inhibitors.9 They
used four-step procedure comprising of (i) bromination of indole,
Due to the abundance of medium-sized (seven-, eight- and
nine-membered) heterocyclic compounds in many natural prod-
ucts, drugs, and preclinical leads, syntheses of these compounds by
intramolecular Heck type reaction have received much attention.1
Palladium-mediated direct aryl–aryl bond-forming protocols have
also been studied extensively in this respect.2 Among the ap-
proaches of aryl–aryl bond-forming reactions, the use of hetero-
aromatic compound as one of the aryl group received special
interest due to the biological importance of many heteroaryl moi-
ety-containing compounds.1c,2a,b,3,4
(ii) Suzuki coupling with phenylboronic acid, (iii) alkylation with
allyl bromide, and (iv) ring-closing metathesis (RCM) reaction
protocol to form the target structure (Scheme 1).9 Our synthesis is
comprised of only two steps: alkylation of indole with the Baylis–
Hillman acetate 1a and the following Pd-mediated cyclization
process (Scheme 1).8 In view of the simplicity of the reaction se-
quence, the latter approach could be regarded as more efficient.
Thus we examined the generality and efficiency of our protocol8
with the modified Baylis–Hillman adducts with isatin, imidazole,
and benzimidazoles.
Although palladium-mediated syntheses of medium-sized het-
erocyclic compounds have been investigated thoroughly,1,3b,c
studies involving the Baylis–Hillman adducts5 have not been
reported much.6,7 Very recently we reported the synthesis of indole
moiety-containing tetracyclic compounds starting from the Baylis–
Hillman acetate by applying SN20 type reaction with indole and the
following Pd-mediated cyclization protocol (Scheme 2, vide infra).8
Poly-fused heterocyclic compounds were known to possess
many interesting biological activities9–12 including hepatitis C virus
(HCV) NS5B polymerase inhibitory activity.9 The chemists at Bris-
tol–Myers Squibb Company reported the synthesis of indole
2. Results and discussion
We started the synthesis of indole moiety-containing tetracyclic
compounds 4a–g and the preliminary results were reported very
recently.8 As summarized in Scheme 2, starting materials 3a–g
were synthesized by the reaction of Baylis–Hillman acetates 16b
and indole derivatives 2a–f (KOH, DMF, 0 ꢀC) in 45–95% yields. In all
cases, E-forms of 3a–g were formed as the major isomers and we
separated them easily from the minor Z-isomers (5–10%).5–8 We
have examined the optimum reaction conditions for the intra-
molecular palladium-catalyzed arylation with compound 3a and
found that the conditions comprising of Pd(OAc)2/TBAB (tetrabu-
tylammonium bromide)/K2CO3 in DMF is the best (65%).8 Under the
optimized conditions we synthesized 4a–g and the results are
* Corresponding author. Tel.: þ82 62 530 3381; fax: þ82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.087

7184
H.S. Lee et al. / Tetrahedron 64 (2008) 7183–7190
COOMe
H
N
COOMe
Br
H
Br
B(OH)2
Suzuki
N
N
R
R
R
PyHBr3
RCM
H
N
R
COOMe
7
6
OAc
Br
COOMe
N
Br
9
COOMe
(1a)
Pd(0)
1
N
R
13
R
Scheme 1. Synthesis of 7H-benzo[3,4]azepino[1,2-a]indole derivatives.
summarized in Scheme 2. Seven-membered benzoazepino[1,2-a]-
indole derivatives 4a–e were synthesized in good yields (65–82%)
from the indole derivatives 3a–e, whereas eight-membered com-
pounds 4f and 4g were obtained in moderate yields (53–60%) from
3f and 3g, which have 2-methyl substituent at the indole moiety
(R1¼Me).
The regioselective cyclization pathway was clearly demon-
strated by the results obtained from 6e and 6f. When the 2-position
of imidazole moiety was substituted with methyl group (6e), cy-
clization occurred at the 4-position of imidazole and produced
compound 7e as the sole product, whereas, cyclization occurred at
the 2-position of imidazole moiety to afford 7f when we used 6f as
the starting material, which has 4,5-diphenyl substituents. For the
substrates 6g and 6h we obtained seven-membered ring com-
pounds again. The results state that 2-position of benzimidazole is
more reactive than that of 7-position. It is interesting to note that
double bond-isomerized compound 7g0 was obtained in 8%. The
structure of 7g0 could be easily deduced from its 1H NMR spectrum
by the upfield shift of methylene protons in seven-membered ring
Encouraged by the preliminary results we examined the re-
actions of similar compounds derived from the reaction of Baylis–
Hillman acetate 1a, as the representative Baylis–Hillman adduct,
isatins (5a and 5b), benzimidazoles (5c, 5d, 5g, 5h) and imidazoles
(5e and 5f) as summarized in Scheme 3. Compounds 6a–h were
prepared in 67–89% yields under the conditions of KOH/CH3CN/0 ꢀC
or K2CO3/DMF/rt depending on the substrates (Table 1, vide infra).
The reactions of 6a–h showed the same reaction patterns as in the
previous indole-attached Baylis–Hillman adducts 3a–g in Scheme
2. Tetracyclic compounds containing eight-membered ring 7a–
d were formed from the reaction of 6a–d in 36–55% yields. For the
substrates 6a–d, formation of seven-membered ring was impossi-
ble due to the presence of carbonyl group (for 6a and 6b) and
substituent R1 (for 6c and 6d).
from
d¼5.05 ppm (7g) to
d
¼3.76 ppm (7g0). However, the combined
yield of 7g and 7g0 was very low in this case, unfortunately.
The experimental conditions for the synthesis of 6a–h and 7a–h
are summarized in Table 1 together with the yields. As compared
with the results obtained from the indole-containing substrates
3a–g, the reactions with 6a–h occurred within shorter reaction
time (15–40 min) and the yields of products were lower than those
EWG
OAc
N
EWG
R2
Br
R3
1a: EWG = COOMe
1b: EWG = COOEt
4a-e
(65-82%)
EWG
KOH, DMF
R3
+
Br
N
0 °C
R2
R3
R1
R2
R1
3a-g
N
H
(45-95%)
3a: 1a + 2a
EWG
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
3b: 1b + 2a
3c: 1a + 2b
3d: 1a + 2c
3e: 1a + 2d
3f: 1a + 2e
3g: 1a + 2f
R1
R2
N
R3
4f, 4g
(53-60%)
Scheme 2.

H.S. Lee et al. / Tetrahedron 64 (2008) 7183–7190
7185
COOMe
O
COOMe
O
N
R1
R1
O
Br
Br
N
7a: R1 = H
7b: R2 = Cl
N
O
H
O
6a: R1 = H
6b: R2 = Cl
R1
5a: R1 = H
O
COOMe
5b: R2 = Cl
COOMe
N
R1
N
R1
7c: R1 = Ph
7d: R1 = Me
N
N
N
N
H
Pd(OAc)2, TBAB
K2CO3, DMF
5c: R1 = Ph
5d: R1 = Me
6c: R1 = Ph
6d: R1 = Me
R1
conditions
1a
+
COOMe
COOMe
COOMe
R2
R2
R2
N
N
N
N
R1
R2
R1
N
N
H
Br
N
R2
R2
7f: R2 = Ph
COOMe
7e: R1 = Me
N
R1
5e: R1 = Me, R2 = H
5f: R1 = H, R2 = P h
6e: R1 = Me, R2 = H
6f: R1 = H, R2 = P h
COOMe
R
R1
R1
COOMe
1
N
N
N
R1
N
H
Br
N
N
N
N
R1
5g: R1 = H
5h: R1 = Me
6g: R1 = H
6h: R1 = Me
7g' (8%)
7g: R1 = H
7h: R1 = Me
R1
Scheme 3.
of the indole cases. When we let the reaction mixture of 6a–h for
longer reaction time we observed some decomposition of products
and the yields were reduced slightly.
moderate yields. The reaction of 6j under the same conditions
produced the corresponding 8-membered ring compound 7j in
68%. However, the purine compound 6k was decomposed com-
pletely under the same conditions. Thus we tried different condi-
tions, which were reported recently by Hocek and co-workers,4e,f
and obtained desired compound 7k albeit in low yield (23%) to-
gether with isomerized compound 7k0 (6%). The structure of 7k0
As in Scheme 4, when we used 5-methylbenzimidazole (5i) the
reaction was somewhat complex. We obtained regioisomeric
mixture of 6i in 83% yield (2:1 mixture based on 1H NMR) and the
separation was almost impossible. Thus we subjected the mixture
to the same Pd-mediated reaction conditions at 110 ꢀC for 20 min,
and we obtained desired compound 7i in 30% yield and double
bond-isomerized compound 7i0 in 9% yield, as inseparable mixtures
again.
As the final trials we also examined the reactions of carbazole-
and 6-benzylaminopurine-attached Baylis–Hillman adducts 6j and
6k (Scheme 5). The syntheses of these compounds were carried out
similarly as for the compounds 6a–i with KOH or K2CO3 in
could also be assigned by the chemical shift value (
d
¼5.14 ppm for
7k vs
d
¼3.76 ppm for 7k0), as in the case of 7g/7g0. This is the first
example of intramolecular arylation of purine system.
Although the yields of products were somewhat low in some
cases (especially for benzimidazole-attached Baylis–Hillman ad-
ducts) the protocol described herein could be used efficiently for
the synthesis of a variety of poly-fused heterocyclic compounds.
Examinations on the biological activities of prepared compounds
are currently underway and will be reported in due course.
Table 1
Synthesis of compounds 6 and 7
3. Experimental
Entry
1
Conditions
6 (%)
Conditionsa
100 ꢀC, 15 min
7 (%)þothers
7a (55)
K2CO3 (1.2 equiv),
DMF, rt, 17 h
6a (87)
3.1. General procedure
2
3
4
5
6
7
8
K2CO3 (1.2 equiv),
DMF, rt, 8 h
6b (81)
6c (67)
6d (71)
6e (84)
6f (89)
6g (80)
6h (77)
100 ꢀC, 15 min
110 ꢀC, 25 min
110 ꢀC, 20 min
110 ꢀC, 15 minb
110 ꢀC, 15 minb
110 ꢀC, 40 minb
110 ꢀC, 20 minb
7b (50)
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded in CDCl3. The signal positions are reported in parts per
million relative to TMS (d scale) used as an internal standard. IR
KOH (1.2 equiv),
CH3CN, 0 ꢀC, 5 h
KOH (1.2 equiv),
CH3CN, 0 ꢀC, 40 min
KOH (1.2 equiv),
CH3CN, 0 ꢀC, 2 h
KOH (1.2 equiv),
CH3CN, 0 ꢀC, 2 h
KOH (1.2 equiv),
CH3CN, 0 ꢀC, 1 h
KOH (1.2 equiv),
CH3CN, 0 ꢀC, 1 h
7c (48)
7d (36)
spectra are reported in cmꢁ1. Mass spectra were obtained from the
Korea Basic Science Institute (Gwangju branch). Melting points are
uncorrected. The elemental analyses were carried out at Korea
Research Institute of Chemical Technology, Taejeon, Korea. All re-
agents were purchased from commercial sources and used without
further treatment. The separations were carried out by flash col-
umn chromatography over silica gel (230–400 mesh ASTM). Or-
ganic extracts were dried over anhydrous MgSO4 and the solvents
were evaporated on a rotary evaporator under water aspirator
pressure.
7e (46)
7f (71)
7g (32)þ7g0 (8)
7h (46)
a
Conditions: Pd(OAc)2 (10 mol %), TBAB (1.0 equiv), K2CO3 (2.0 equiv), DMF.
20 mol % of Pd(OAc)2 was used.
b

7186
H.S. Lee et al. / Tetrahedron 64 (2008) 7183–7190
Me
KOH, CH3CN
0 °C, 40 min
COOMe
COOMe
Me
N
Me
1a
+
N
H
Br
N
N
Br
N
N
5i
6i (83%, 2:1)
same conditions
(110 °C, 20 min)
COOMe
COOMe
COOMe
COOMe
N
N
N
N
N
N
N
N
Me
Me
Me
Me
7i' (9%, 2:1)
7i (30%, 2:1)
Scheme 4.
3.2. Synthesis of starting materials 3a–g8
136.36, 142.22, 166.94. Anal. Calcd for C20H18BrNO2: C, 62.51; H,
4.72; N, 3.65. Found: C, 62.62; H, 4.58; N, 3.42.
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 (hex-
anes/EtOAc, 10:1) we obtained 3a (271 mg, 73%) as a white solid.
Other compounds 3b–g were synthesized similarly. The spectro-
scopic data of synthesized compounds 3b–g are as follows.
3.2.3. Compound 3d
Yield 95%; colorless oil; IR (film) 1718, 1483, 1437, 1236, 1151,
1030 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 3.76 (s, 3H), 3.82 (s, 3H),
5.00 (s, 2H), 6.35 (d, J¼3.0 Hz, 1H), 6.77 (dd, J¼9.0 and 2.4 Hz, 1H),
6.90 (d, J¼9.0 Hz, 1H), 7.03–7.35 (m, 5H), 7.69 (d, J¼7.5 Hz, 1H), 7.97
(s, 1H); 13C NMR (CDCl3, 75 MHz)
d 42.38, 52.38, 55.82, 101.13,
102.50, 110.24, 111.67, 123.88, 127.50, 128.01, 128.86, 129.59, 130.16,
130.54, 131.40, 133.12, 134.93, 142.43, 153.98, 166.85. Anal. Calcd for
3.2.1. Compound 3b
C20H18BrNO3: C, 60.01; H, 4.53; N, 3.50. Found: C, 59.78; H, 4.77; N,
3.34.
Yield 50%; white solid, mp 98–100 ꢀC; IR (film) 1718, 1459,
1101 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
1.19 (t, J¼7.2 Hz, 3H), 4.19
(q, J¼7.2 Hz, 2H), 5.03 (s, 2H), 6.43 (d, J¼3.3 Hz, 1H), 7.02–7.31 (m,
3.2.4. Compound 3e
7H), 7.56 (d, J¼7.2 Hz, 1H), 7.68 (d, J¼7.5 Hz, 1H), 7.98 (s, 1H); 13C
Yield 60%; yellow oil; IR (film) 1732, 1712, 1466, 1030 cmꢁ1 1H
;
NMR (CDCl3, 75 MHz)
d
14.03, 42.23, 61.36, 101.50, 109.57, 119.32,
NMR (CDCl3, 300 MHz)
d
1.24 (t, J¼7.2 Hz, 3H), 3.69 (d, J¼0.6 Hz,
120.70, 121.37, 123.89, 127.45, 127.46, 128.49, 129.90, 130.16, 130.45,
133.09, 135.03, 136.09, 142.22, 166.35. Anal. Calcd for C20H18BrNO2:
C, 62.51; H, 4.72; N, 3.65. Found: C, 62.25; H, 4.98; N, 3.47.
2H), 3.76 (s, 3H), 4.13 (q, J¼7.2 Hz, 2H), 5.00 (s, 2H), 6.97–7.30 (m,
7H), 7.54 (d, J¼7.5 Hz, 1H), 7.67 (d, J¼6.9 Hz, 1H), 7.96 (s, 1H); 13C
NMR (CDCl3, 75 MHz)
d 14.18, 31.40, 42.17, 52.34, 60.62, 107.57,
109.59, 118.92, 119.20, 121.66, 123.78, 126.42, 127.45, 127.78, 129.60,
130.13, 130.47, 133.04, 134.89, 136.30, 142.43, 166.80, 171.92. Anal.
Calcd for C23H22BrNO4: C, 60.54; H, 4.86; N, 3.07. Found: C, 60.33; H,
4.91; N, 2.87.
3.2.2. Compound 3c
Yield 51%; yellow oil; IR (film) 1717, 1464, 1435, 1249, 1110 cmꢁ1
;
1H NMR (CDCl3, 500 MHz)
d 2.26 (s, 3H), 3.73 (s, 3H), 4.96 (s, 2H),
6.82 (s, 1H), 6.98 (d, J¼8.0 Hz, 1H), 7.04–7.26 (m, 5H), 7.49 (d,
J¼7.5 Hz, 1H), 7.66 (d, J¼7.5 Hz, 1H), 7.96 (s, 1H); 13C NMR (CDCl3,
3.2.5. Compound 3f
125 MHz)
d
9.59, 41.97, 52.34, 109.34, 110.65, 118.61, 118.75, 121.33,
Yield 45%; white solid, mp 141–143 ꢀC; IR (film) 1717,1464,1435,
123.87, 124.92, 127.42, 128.75, 129.77, 130.16, 130.42, 133.00, 134.94,
1245, 1099 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
2.35 (s, 3H), 3.64 (s,
COOMe
Pd(OAc)2, TBAB
COOMe
K2CO3, DMF
KOH, DMF
100 °C, 30 min
0 °C, 24 h, 64%
N
Br
Br
N
N
H
5j
7j (68%)
6j
COOMe
COOMe
1a
+
Pd(OAc)2, CuI
Cs2CO3, DMF
120 °C, 60 min
NHBn
COOMe
N
K2CO3, CH3CN
rt, 48 h, 52%
N
N
N
N
N
N
N
+
N
N
N
N
N
N
H
NHBn
N
5k
N
BnNH
BnNH
6k
7k (23%)
7k' (6%)
Scheme 5.

H.S. Lee et al. / Tetrahedron 64 (2008) 7183–7190
7187
3H), 5.04 (s, 2H), 6.13 (s, 1H), 6.96–7.33 (m, 6H), 7.41 (d, J¼6.6 Hz,
1H), 7.68 (d, J¼7.8 Hz, 1H), 7.87 (s, 1H); 13C NMR (CDCl3, 75 MHz)
(m, 1H), 7.24–7.31 (m, 1H), 7.45–7.59 (m, 4H), 7.68 (d, J¼7.5 Hz, 1H),
7.85 (s, 1H), 8.01 (d, J¼7.5 Hz,1H); 13C NMR (CDCl3, 75 MHz)
d 14.22,
d
12.86, 40.31, 52.12, 100.51, 109.85, 119.17, 119.32, 120.29, 123.68,
31.62, 39.18, 52.39, 60.87, 106.17, 109.12, 119.33, 119.61, 122.44,
127.78, 128.07, 129.48, 130.96, 131.15, 131.43, 131.63, 133.56, 134.92,
136.01, 142.31, 165.89, 172.34; ESIMS m/z 376.26 (Mþþ1). Anal.
Calcd for C23H21NO4: C, 73.58; H, 5.64; N, 3.73. Found: C, 73.52; H,
5.88; N, 3.42.
127.18, 128.13, 130.34, 130.43, 130.63, 133.12, 134.76, 137.00, 137.41,
140.75, 166.56. Anal. Calcd for C20H18BrNO2: C, 62.51; H, 4.72; N,
3.65. Found: C, 62.68; H, 4.99; N, 3.54.
3.2.6. Compound 3g
Yield 62%; yellow solid, mp 111–113 ꢀC; IR (film) 1720, 1468,
3.3.5. Compound 4g
1435,1331,1251 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
2.14 (s, 3H), 2.22
Yield 60%; white solid, mp 151–153 ꢀC; IR (film) 1714, 1435,
(s, 3H), 3.63 (s, 3H), 5.02 (d, J¼1.2 Hz, 2H), 6.97–7.24 (m, 6H), 7.36
1290, 1227 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d 2.23 (s, 3H), 2.48 (s,
(d, J¼7.5 Hz,1H), 7.64 (d, J¼7.8 Hz, 1H), 7.83 (s, 1H); 13C NMR (CDCl3,
3H), 3.71 (s, 3H), 4.80 (d, J¼14.1 Hz, 1H), 4.99 (d, J¼14.1 Hz,1H), 6.77
75 MHz)
d 8.74, 10.14, 40.36, 52.07, 106.83, 109.50, 117.53, 118.49,
(dd, J¼7.2 and 0.9 Hz, 1H), 7.06–7.11 (m, 1H), 7.15 (d, J¼7.2 Hz, 1H),
120.30, 123.56, 127.01, 128.66, 130.15, 130.55, 130.80, 132.91, 133.02,
134.75, 136.22, 140.40, 166.70. Anal. Calcd for C21H20BrNO2: C,
63.33; H, 5.06; N, 3.52. Found: C, 63.12; H, 5.39; N, 3.57.
7.32–7.49 (m, 4H), 8.06 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d 8.91,
9.93, 40.93, 51.96, 106.67, 117.66, 119.38, 125.53, 125.76, 126.66,
127.37, 130.01, 130.14, 131.85, 133.38, 133.52, 134.00, 135.33, 140.48,
145.24, 166.68; ESIMS m/z 318.23 (Mþþ1). Anal. Calcd for
3.3. Synthesis of indole-containing tetracyclic compounds
4a–g8
C21H19NO2: C, 79.47; H, 6.03; N, 4.41. Found: C, 79.30; H, 6.26; N,
4.19.
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 4b–g were synthesized analogously
and the spectroscopic data of prepared compounds 4b–e and 4g are
as follows.
3.4. Synthesis of starting materials 6a and 6b
A mixture of isatin (5a, 147 mg, 1.0 mmol), Baylis–Hillman ace-
tate 1a (376 mg, 1.2 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF
(2.0 mL) was stirred at room temperature for 17 h. After the usual
aqueous workup and column chromatographic purification process
(hexanes/CH2Cl2/ether, 8:2:3) we obtained 6a (349 mg, 87%) as
a white solid. Compound 6b was synthesized similarly and the
spectroscopic data of 6a and 6b are as follows.
3.3.1. Compound 4b
Yield 82%; yellow solid, mp 166–167 ꢀC; IR (film) 1700, 1458,
3.4.1. Compound 6a
1239 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
1.36 (t, J¼7.2 Hz, 3H), 4.29
Yield 87%; white solid, mp 151–153 ꢀC; IR (film) 1739,1712,1614,
(q, J¼7.2 Hz, 2H), 4.97 (s, 2H), 6.74 (d, J¼0.6 Hz, 1H), 7.08–7.13 (m,
1H), 7.22–7.28 (m,1H), 7.34–7.47 (m, 3H), 7.56 (d, J¼8.1 Hz,1H), 7.63
(d, J¼7.5 Hz,1H), 7.85 (d, J¼8.7 Hz,1H), 7.86 (s,1H); 13C NMR (CDCl3,
1469, 1254 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 3.84 (s, 3H), 4.76 (s,
2H), 6.68 (d, J¼8.1 Hz, 1H), 7.02–7.53 (m, 7H), 7.92 (s, 1H); 13C NMR
(CDCl3, 75 MHz) d 37.45, 52.59, 111.24, 117.33,122.93, 123.57, 124.94,
75 MHz)
d
14.28, 39.16, 61.37, 101.15, 109.26, 119.74, 120.69, 121.94,
126.75, 127.46, 130.22, 130.52, 132.64, 134.37, 138.13, 143.09, 150.13,
157.71, 166.27, 182.66; ESIMS m/z 400.19 (Mþþ1), 402.33 (Mþþ3).
Anal. Calcd for C19H14BrNO4: C, 57.02; H, 3.53; N, 3.50. Found: C,
56.87; H, 3.51; N, 3.34.
127.54, 128.14, 129.64, 129.88, 130.57, 131.77, 131.88, 133.11, 136.30,
139.22, 142.38, 165.51. Anal. Calcd for C20H17NO2: C, 79.19; H, 5.65;
N, 4.62. Found: C, 79.01; H, 5.93; N, 4.40.
3.3.2. Compound 4c
3.4.2. Compound 6b
Yield 66%; yellow solid, mp 158–160 ꢀC; IR (film) 1705, 1460,
Yield 81%; white solid, mp 120–122 ꢀC; IR (film) 1745, 1712,
1251 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
2.42 (s, 3H), 3.81 (s, 3H),
1610, 1473, 1254 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
3.83 (s, 3H),
4.75 (d, J¼0.9 Hz, 2H), 6.67 (d, J¼8.4 Hz, 1H), 7.17–7.56 (m, 6H), 7.93
(s, 1H); 13C NMR (CDCl3, 75 MHz)
37.49, 52.62, 112.58, 118.16,
4.94 (s, 2H), 7.07–7.19 (m, 1H), 7.24–7.32 (m, 1H), 7.36–7.56 (m, 4H),
7.61 (d, J¼7.8 Hz, 1H), 7.69 (d, J¼7.5 Hz, 1H), 7.84 (s, 1H); 13C NMR
d
(CDCl3, 75 MHz)
d
10.17, 39.10, 52.33, 108.86, 109.06, 119.00, 119.07,
122.88, 124.74, 126.45, 127.54, 129.36, 130.18, 130.63, 132.72, 134.27,
137.44, 143.38, 148.43, 157.13, 166.14, 181.65. Anal. Calcd for
122.17, 127.13, 128.66, 129.07, 131.08, 131.19, 131.22, 132.55, 133.43,
134.40, 134.86, 142.53, 166.03; ESIMS m/z 304.18 (Mþþ1). Anal.
Calcd for C20H17NO2: C, 79.19; H, 5.65; N, 4.62. Found: C, 79.38; H,
5.93; N, 4.44.
C19H13BrClNO4: C, 52.50; H, 3.01; N, 3.22. Found: C, 52.32; H, 3.13;
N, 2.94.
3.5. Synthesis of starting materials 6c–h
3.3.3. Compound 4d
Yield 69%; yellow solid, mp 130–132 ꢀC; IR (film) 1716, 1458,
To a stirred solution of benzimidazole (5c, 194 mg, 1.0 mmol)
and KOH (79 mg, 1.2 mmol) in CH3CN (1.5 mL) was added a solution
of Baylis–Hillman acetate 1a (376 mg, 1.2 mmol) in CH3CN (0.5 mL)
at 0 ꢀC, and maintained at 0 ꢀC for 5 h with stirring. After the usual
aqueous workup and column chromatographic purification process
(hexanes/CH2Cl2/ether, 7:3:3) we obtained 6c (300 mg, 67%) as
a white solid. Other compounds 6d–h were synthesized similarly
and the spectroscopic data of 6c–h are as follows.
1243, 1216 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 3.85 (s, 3H), 3.86 (s,
3H), 4.94 (s, 2H), 6.68 (s,1H), 6.93 (dd, J¼9.0 and 2.7 Hz,1H), 7.08 (d,
J¼2.7 Hz, 1H), 7.36–7.50 (m, 4H), 7.85 (d, J¼8.1 Hz, 1H), 7.87 (s, 1H);
13C NMR (CDCl3, 75 MHz)
d 39.39, 52.44, 55.88, 100.76, 101.93,
110.11, 112.70, 127.50, 128.42, 129.60, 129.97, 130.24, 131.76, 131.87,
131.88, 133.22, 139.66, 142.67, 154.20, 166.06; ESIMS m/z 320.24
(Mþþ1). Anal. Calcd for C20H17NO3: C, 75.22; H, 5.37; N, 4.39.
Found: C, 75.05; H, 5.61; N, 4.65.
3.5.1. Compound 6c
3.3.4. Compound 4e
Yield 67%; white solid, mp 56–58 ꢀC; IR (film) 1718, 1458, 1442,
Yield 78%; yellow solid, mp 134–136 ꢀC; IR (film) 1730, 1714,
1246 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 3.58 (s, 3H), 5.32 (s, 2H),
1460, 1250 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
3.77 (s, 2H), 3.83 (s, 3H), 4.19 (q, J¼7.2 Hz, 2H), 5.04 (s, 2H), 7.12–7.17
d
1.27 (t, J¼7.2 Hz, 3H),
7.08 (dd, J¼7.8 and 1.2 Hz, 1H), 7.19–7.31 (m, 5H), 7.49–7.51 (m, 3H),
7.63 (dd, J¼7.8 and 1.2 Hz, 1H), 7.71–7.76 (m, 3H), 7.89 (s, 1H); 13C

7188
H.S. Lee et al. / Tetrahedron 64 (2008) 7183–7190
NMR (CDCl3, 75 MHz)
d
42.08, 52.24, 111.00, 119.71, 122.24, 122.65,
3.6.1. Compound 7a
123.59, 127.30, 128.55, 128.68, 129.53, 129.59, 130.03, 130.52,
130.59, 133.15, 134.25, 135.11, 142.12, 142.87, 154.32, 165.90; ESIMS
m/z 447.25 (Mþþ1), 449.27 (Mþþ3). Anal. Calcd for C24H19BrN2O2:
C, 64.44; H, 4.28; N, 6.26. Found: C, 64.76; H, 4.19; N, 6.35.
Yield 55%; white solid, mp 210–212 ꢀC (decomposed); IR (film)
1741, 1712, 1599, 1290, 1250 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d 3.81
(s, 3H), 3.93 (dd, J¼13.8 and 0.9 Hz, 1H), 5.35 (d, J¼13.8 Hz, 1H), 7.16
(dd, J¼7.8 and 7.2 Hz,1H), 7.25–7.32 (m, 3H), 7.45–7.56 (m, 2H), 7.63
(dd, J¼7.2 and 1.2 Hz, 1H), 8.22 (s, 1H); 13C NMR (CDCl3, 75 MHz)
3.5.2. Compound 6d
d 37.80, 52.49, 118.82, 124.18, 124.98, 126.89, 128.18, 128.42, 129.11,
Yield 71%; white solid, mp 124–126 ꢀC; IR (film) 1720, 1462,
130.11, 132.55, 134.43, 136.46, 143.14, 146.21, 146.38, 157.60, 165.75,
183.80; ESIMS m/z 320.25 (Mþþ1). Anal. Calcd for C19H13NO4: C,
71.47; H, 4.10; N, 4.39. Found: C, 71.54; H, 4.36; N, 4.32.
1398, 1284, 1248 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 2.53 (s, 3H),
3.66 (s, 3H), 5.07 (d, J¼1.2 Hz, 2H), 7.05–7.38 (m, 6H), 7.56–7.61 (m,
1H), 7.70 (dd, J¼7.8 and 1.2 Hz, 1H), 7.96 (s, 1H); 13C NMR (CDCl3,
75 MHz)
d
13.96, 40.56, 52.25, 109.92, 118.70, 121.56, 121.77, 123.57,
3.6.2. Compound 7b
127.39, 128.64, 130.40, 130.70, 133.28, 134.35, 134.99, 142.18, 142.34,
152.23, 165.94. Anal. Calcd for C19H17BrN2O2: C, 59.23; H, 4.45; N,
7.27. Found: C, 59.04; H, 4.81; N, 7.12.
Yield 50%; white solid, mp 166–168 ꢀC (decomposed); IR (film)
1743, 1716, 1597, 1458, 1290 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d 3.80
(s, 3H), 3.92 (d, J¼13.8 Hz, 1H), 5.33 (d, J¼13.8 Hz,1H), 7.26–7.34 (m,
3H), 7.48–7.58 (m, 3H), 8.20 (s, 1H); 13C NMR (CDCl3, 75 MHz)
3.5.3. Compound 6e
d 37.92, 52.57, 119.71, 124.69, 128.37, 128.51, 128.94, 129.05, 129.85,
Yield 84%; colorless oil; IR (film) 1716,1435,1263,1236 cmꢁ1; 1H
130.32, 132.44, 134.45, 135.20, 141.83, 144.91, 146.02, 157.12, 165.57,
182.88. Anal. Calcd for C19H12ClNO4: C, 64.51; H, 3.42; N, 3.96.
Found: C, 64.33; H, 3.67; N, 3.65.
NMR (CDCl3, 300 MHz) d 2.23 (s, 3H), 3.81 (s, 3H), 4.74 (s, 2H), 6.76
(d, J¼1.5 Hz, 1H), 6.84 (d, J¼1.5 Hz, 1H), 7.13 (dd, J¼7.5 and 1.2 Hz,
1H), 7.24–7.38 (m, 2H), 7.68 (dd, J¼7.5 and 1.2 Hz, 1H), 7.97 (s, 1H);
13C NMR (CDCl3, 75 MHz)
d
12.88, 41.92, 52.49, 118.50, 123.62,
3.6.3. Compound 7c
127.13, 127.53, 128.96, 129.73, 130.67, 133.14, 134.60, 143.04, 144.82,
166.20. Anal. Calcd for C15H15BrN2O2: C, 53.75; H, 4.51; N, 8.36.
Found: C, 53.54; H, 4.43; N, 8.21.
Yield 48%; white solid, mp 148–150 ꢀC; IR (film) 1718, 1473,
1240 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 3.39 (s, 3H), 4.94 (d,
J¼13.8 Hz, 1H), 5.31 (d, J¼13.8 Hz, 1H), 7.01 (d, J¼7.5 Hz, 1H), 7.21–
7.26 (m, 1H), 7.30–7.35 (m, 1H), 7.42–7.58 (m, 6H), 7.70–7.74 (m,
2H), 7.78 (d, J¼7.5 Hz, 1H), 8.08 (s, 1H); 13C NMR (CDCl3, 75 MHz)
3.5.4. Compound 6f
Yield 89%; white solid, mp 152–153 ꢀC; IR (film) 1716,1506,1437,
d 42.83, 51.81, 119.55, 123.01, 126.67, 126.86, 127.42, 127.74, 128.50,
1259 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
3.80 (s, 3H), 4.66 (s, 2H),
7.03–7.46 (m,13H), 7.56 (s,1H), 7.60 (dd, J¼7.5 and 1.8 Hz,1H), 7.97 (s,
1H); 13C NMR (CDCl3, 75 MHz)
41.55, 52.54,123.83,126.20,126.44,
129.43, 129.61, 130.19, 130.42, 131.06, 132.90, 134.19, 134.79, 138.63,
143.55, 145.81, 155.20, 165.62; ESIMS m/z 367.31 (Mþþ1). Anal.
Calcd for C24H18N2O2: C, 78.67; H, 4.95; N, 7.65. Found: C, 78.62; H,
5.07; N, 7.50.
d
127.47, 128.00, 128.30, 128.57, 128.60, 128.90, 129.31, 130.37, 130.64,
130.87, 133.09, 134.28, 134.48, 135.77, 138.07, 143.65, 166.17; ESIMS
m/z 473.27 (Mþþ1), 475.29 (Mþþ3). Anal. Calcd for C26H21BrN2O2: C,
65.97; H, 4.47; N, 5.92. Found: C, 66.09; H, 4.74; N, 5.89.
3.6.4. Compound 7d
Yield 36%; white solid, mp 156–158 ꢀC; IR (film) 1714, 1437,
1398, 1292, 1230 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 2.75 (s, 3H),
3.5.5. Compound 6g
3.77 (s, 3H), 4.82 (d, J¼13.8 Hz, 1H), 5.10 (d, J¼13.8 Hz, 1H), 6.95 (dd,
Yield 80%; white solid, mp 93–95 ꢀC; IR (film) 1718, 1493, 1435,
J¼7.8 and 0.9 Hz,1H), 7.20–7.27 (m, 2H), 7.39–7.55 (m, 3H), 7.63 (dd,
1284,1254 cmꢁ1;1HNMR(CDCl3, 300 MHz)
d
3.78(s, 3H), 5.10(s, 2H),
6.93–6.97 (m, 1H), 7.15–7.39 (m, 5H), 7.70–7.76 (m, 2H), 7.88 (s, 1H),
8.02 (s, 1H); 13C NMR (CDCl3, 75 MHz)
41.00, 52.55, 109.67, 120.18,
J¼7.8 and 0.9 Hz, 1H), 8.12 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d 13.69,
41.26, 52.32, 118.75, 122.43, 125.70, 126.33, 127.26, 127.97, 130.30,
130.98, 132.88, 133.29, 134.51, 138.43, 143.19, 145.94, 152.49, 166.20.
Anal. Calcd for C19H16N2O2: C, 74.98; H, 5.30; N, 9.20. Found: C,
75.22; H, 5.56; N, 9.04.
d
122.00, 122.79, 123.64, 127.63, 128.38, 129.95, 130.84, 133.33, 133.51,
134.62,143.27,143.47,143.48,166.23. Anal. Calcd forC18H15BrN2O2: C,
58.24; H, 4.07; N, 7.55. Found: C, 58.45; H, 4.08; N, 7.44.
3.6.5. Compound 7e
3.5.6. Compound 6h
Yield 46%; white solid, mp 135–137 ꢀC; IR (film) 1703, 1437,
Yield 77%; white solid, mp 98–100 ꢀC; IR (film) 1716, 1493, 1435,
1294, 1255, 1234 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 2.53 (s, 3H),
1257 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
2.26 (s, 3H), 2.32 (s, 3H),
3.87 (s, 3H), 4.74 (s, 2H), 7.16 (s, 1H), 7.32–7.46 (m, 3H), 7.65 (d,
3.78 (s, 3H), 5.06 (s, 2H), 6.57 (s, 1H), 7.24 (dd, J¼7.8 and 1.5 Hz, 1H),
J¼7.8 Hz, 1H), 7.87 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d 12.93, 40.09,
7.30–7.42 (m, 2H), 7.48 (s, 1H), 7.75 (dd, J¼7.8 and 1.5 Hz, 1H), 7.82
52.47, 125.75, 127.10, 128.12, 128.16, 130.20, 130.23, 130.76, 131.91,
132.40, 143.35, 144.40, 165.93. Anal. Calcd for C15H14N2O2: C, 70.85;
H, 5.55; N, 11.02. Found: C, 70.66; H, 5.31; N, 10.76.
(s, 1H), 7.99 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d 20.14, 20.32, 40.86,
52.49, 109.83, 120.13, 123.80, 127.63, 128.51, 130.24, 130.82, 130.83,
131.87, 132.00, 133.32, 134.82, 142.08, 142.73, 143.10, 166.25; ESIMS
m/z 399.25 (Mþþ1), 401.20 (Mþþ3). Anal. Calcd for C20H19BrN2O2:
C, 60.16; H, 4.80; N, 7.02. Found: C, 60.38; H, 4.99; N, 6.78.
3.6.6. Compound 7f
Yield 71%; white solid, mp 181–183 ꢀC; IR (film) 1709, 1471,
1442, 1292, 1255 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 3.82 (s, 3H),
3.6. Synthesis of tetracyclic compounds 7a–h
4.60 (s, 2H), 7.12–7.26 (m, 3H), 7.39–7.60 (m, 10H), 7.99 (s, 1H), 8.40
(d, J¼8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz)
d 39.55, 52.38, 126.48,
A stirred mixture of 6a (200 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 15 min. After the
usual aqueous workup and column chromatographic purification
process (hexanes/ether, 1:1) we obtained 7a (88 mg, 55%) as
a white solid. Other compounds 7b–h and 7g0 were synthesized
similarly and the representative spectroscopic data of 7a–h and 7g0
are as follows.
127.04, 128.08, 128.20 (2C), 128.46, 128.78, 128.79, 129.83, 130.01,
130.28, 130.83, 131.16, 131.32, 131.59, 134.52, 139.34, 143.56, 146.39,
165.46; ESIMS m/z 393.26 (Mþþ1). Anal. Calcd for C26H20N2O2: C,
79.57; H, 5.14; N, 7.14. Found: C, 79.45; H, 5.27; N, 7.02.
3.6.7. Compound 7g
Yield 32%; white solid, mp 110–113 ꢀC; IR (film) 1705, 1448,
1304, 1259, 1242 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 3.93 (s, 3H),

H.S. Lee et al. / Tetrahedron 64 (2008) 7183–7190
7189
5.05 (s, 2H), 7.30–7.42 (m, 2H), 7.53–7.67 (m, 4H), 7.88 (d, J¼6.9 Hz,
3.8. Synthesis of compounds 6j and 7j
1H), 7.99 (s, 1H), 8.46 (d, J¼8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz)
d
38.88, 52.68, 109.40, 119.94, 122.52, 122.98, 129.41, 129.84, 130.32,
Compound 6j was prepared according to the procedure of 6c
with KOH and the next Pd-mediated cyclization of 6j was carried
out at 100 ꢀC for 30 min.
130.34, 130.92, 131.68, 132.52, 134.86, 142.55, 143.68, 151.80, 165.67.
Anal. Calcd for C18H14N2O2: C, 74.47; H, 4.86; N, 9.65. Found: C,
74.64; H, 4.99; N, 9.62.
3.8.1. Compound 6j
3.6.8. Compound 7g0
Yield 64%; IR (film) 1720, 1597, 1485, 1458, 1435 cmꢁ1; 1H NMR
Yield 8%; white solid, mp 144–146 ꢀC; IR (film) 1714, 1456, 1273,
(CDCl3, 300 MHz)
d
3.59 (s, 3H), 5.27 (d, J¼1.2 Hz, 2H), 7.13–7.66 (m,
1259 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
3.76 (s, 2H), 3.89 (s, 3H),
10H), 7.92 (s, 1H), 7.98 (ddd, J¼7.8, 1.2, and 0.9 Hz, 2H); 13C NMR
7.38–7.52 (m, 5H), 7.57 (d, J¼7.5 Hz, 1H), 7.90 (d, J¼6.6 Hz, 1H), 8.13
(CDCl3, 75 MHz) d 40.36, 52.12, 109.62, 118.95, 119.89, 122.99,
(s, 1H), 8.24 (d, J¼6.6 Hz, 1H); 13C NMR (CDCl3, 75 MHz)
d
31.02,
123.56, 125.45, 127.15, 129.96, 130.31, 130.54, 133.05, 134.81, 140.54,
141.31, 166.70. Anal. Calcd for C23H18BrNO2: C, 65.73; H, 4.32; N,
3.33. Found: C, 65.66; H, 4.45; N, 3.17. Trace amount of Z-isomer
(<10%) was observed in 1H and 13C NMR spectra.
52.44, 110.06, 120.27, 121.20, 123.85, 124.44, 127.50, 128.40, 128.89,
130.97 (2C), 131.43, 134.62, 139.02, 142.52, 152.27, 165.86. Anal.
Calcd for C18H14N2O2: C, 74.47; H, 4.86; N, 9.65. Found: C, 74.19; H,
4.54; N, 9.36.
3.8.2. Compound 7j
3.6.9. Compound 7h
Yield 68%; white solid, mp 118–120 ꢀC; IR (film) 1714, 1458,
Yield 46%; white solid, mp 168–170 ꢀC; IR (film) 1709, 1446,
1240 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 3.63 (s, 3H), 5.00 (d,
1246 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
2.39 (s, 3H), 2.43 (s, 3H),
J¼14.1 Hz, 1H), 5.43 (d, J¼14.1 Hz, 1H), 7.10 (dd, J¼7.5 and 1.2 Hz,
1H), 7.19–7.28 (m, 3H), 7.39–7.55 (m, 4H), 7.66 (d, J¼8.4 Hz,1H), 8.05
(dd, J¼7.5 and 1.2 Hz, 2H), 8.12 (s, 1H); 13C NMR (CDCl3, 75 MHz)
3.89 (s, 3H), 4.95 (s, 2H), 7.33 (s, 1H), 7.46–7.60 (m, 4H), 7.92
(s, 1H), 8.39 (dd, J¼7.5 and 1.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz)
d
20.33, 20.62, 38.83, 52.62, 109.43, 119.82, 129.29, 129.46,
d 40.52, 52.04, 109.82, 119.15, 119.74, 119.88 (2C), 122.62, 124.44,
130.21, 130.61, 130.74, 131.46, 131.64, 132.29, 132.33, 133.46, 142.38,
125.71, 125.87, 27.04, 127.73, 130.17, 130.73, 131.40, 133.57, 135.58,
137.71, 139.97, 140.42, 145.17, 166.63. Anal. Calcd for C23H17NO2: C,
81.40; H, 5.05; N, 4.13. Found: C, 81.21; H, 5.32; N, 4.04.
142.55, 151.01, 165.77; ESIMS m/z 319.31 (Mþþ1). Anal. Calcd for
C
20H18N2O2: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.66; H, 5.92;
N, 8.71.
3.9. Synthesis of compounds 6k, 7k, and 7k0
3.7. Synthesis of compounds 6i, 7i, and 7i0
Compound 6k was prepared according to the procedure of 6a
with K2CO3 and the next Pd-mediated cyclization of 6k was carried
out at 120 ꢀC for 60 min under the influence of Pd(OAc)2/CuI/
Cs2CO3.
Compound 6i was prepared according to the procedure of 6c
with KOH and the next Pd-mediated cyclization of 6i was carried
out at 110 ꢀC for 20 min.
3.7.1. Compound 6i
3.9.1. Compound 6k
Yield 83% (major:minor¼2:1); IR (film) 1718, 1498, 1437, 1286,
Yield 52%; white solid, mp 180–182 ꢀC; IR (film) 3275, 1712,
1255 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
2.37 (s, major 3H), 2.44 (s,
1620, 1250 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d 3.81 (s, 3H), 4.86 (s,
minor 3H), 3.78 (s, major 3H, minor 3H), 5.07 (s, major 2H, minor
2H), 6.58 (s, major 1H), 6.84 (d, J¼8.1 Hz, minor 1H), 7.00 (dd, J¼8.1
and 1.5 Hz, minor 1H), 7.02 (dd, J¼8.1 and 1.2 Hz, major 1H), 7.18–
7.42 (m, major 3H, minor 3H), 7.52 (s, minor 1H), 7.59 (d, J¼8.1 Hz,
major 1H), 7.70–7.76 (m, major 1H, minor 1H), 7.82 (s, minor 1H),
7.86 (s, major 1H), 8.00 (s, major 1H, minor 1H).
2H), 5.10 (s, 2H), 6.15 (br s, NH), 7.20–7.39 (m, 7H), 7.49 (dd, J¼7.8
and 1.2 Hz, 1H), 7.63 (dd, J¼7.8 and 1.2 Hz, 1H), 7.72 (s, 1H), 8.03 (s,
1H), 8.35 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d 40.12, 44.70, 52.61,
119.38, 123.63, 127.42, 127.52, 127.69, 127.86, 128.61, 130.12, 130.62,
132.87, 134.46, 138.50, 139.81, 144.25, 149.31, 153.01, 154.56, 166.42.
Anal. Calcd for C23H20BrN5O2: C, 57.75; H, 4.21; N, 14.64. Found: C,
57.49; H, 4.34; N, 14.92.
3.7.2. Compound 7i
Yield 30% (major:minor¼2:1); IR (film) 1709, 1637, 1446, 1304,
3.9.2. Compound 7k
1242 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
2.50 (s, major 3H), 2.54 (s,
Yield 23%; white solid, mp 214–216 ꢀC; IR (film) 3259, 1714,
minor 3H), 3.88 (s, major 3H), 3.89 (s, minor 3H), 4.96 (s, major 2H,
minor 2H), 7.12 (d, J¼8.1 Hz, minor 1H), 7.16 (d, J¼8.4 Hz, major 1H),
7.36 (s, minor 1H), 7.44–7.61 (m, major 5H, minor 3H), 7.71 (d,
J¼8.1 Hz, minor 1H), 7.93 (s, major 1H, minor 1H), 8.40 (d, J¼7.5 Hz,
1616, 1259 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 3.91 (s, 3H), 4.91 (s,
2H), 5.14 (s, 2H), 6.10 (br s, NH), 7.28–7.41 (m, 5H), 7.50–7.58 (m,
3H), 7.96 (s, 1H), 8.25–8.28 (m, 1H), 8.49 (s, 1H); 13C NMR (CDCl3,
75 MHz) d 37.60, 44.78, 52.77, 120.73, 127.44, 127.77, 128.61, 129.28,
129.59, 130.08, 130.13, 130.28, 132.01, 132.38, 138.44, 142.55, 149.02,
153.13, 154.58, 165.42 (one carbon is overlapped). Anal. Calcd for
major 1H, minor 1H); 13C NMR (CDCl3, 75 MHz)
d
21.60, 21.88,
38.75, 38.88, 52.62, 52.64, 108.87, 109.15, 119.41, 119.56, 124.18,
124.51, 129.29, 129.36, 129.61, 129.65, 130.23, 130.25, 130.44, 130.47,
130.76, 130.81, 131.63, 131.65, 132.17, 132.35, 132.40, 133.02, 133.07,
135.04, 141.85, 142.50, 142.55, 143.99, 151.38, 151.66, 165.66, 165.73;
ESIMS m/z 305.22 (Mþþ1).
C23H19N5O2: C, 69.51; H, 4.82; N, 17.62. Found: C, 69.36; H, 4.99; N,
17.27.
3.9.3. Compound 7k0
Yield 6%; white solid, mp 78–80 ꢀC; IR (film) 3257, 1716, 1618,
3.7.3. Compound 7i0
1273 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
3.76 (s, 2H), 3.86 (s, 3H),
4.93 (s, 2H), 6.21 (br s, NH), 7.28–7.61 (m, 8H), 8.08 (d, J¼7.5 Hz,1H),
8.32 (s, 1H), 8.49 (s, 1H); 13C NMR (CDCl3, 75 MHz)
30.96, 44.79,
Yield 9% (major:minor¼2:1); IR (film) 1712, 1651, 1458, 1435,
1267 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
2.54 (s, major 3H), 2.55 (s,
d
minor 3H), 3.75 (s, major 2H, minor 2H), 3.88 (s, major 3H, minor
3H), 7.20–7.51 (m, major 5H, minor 5H), 7.67 (s, major 1H), 7.76 (d,
J¼8.1 Hz, minor 1H), 8.09 (s, major 1H, minor 1H), 8.22 (dd, J¼7.5
and 1.5 Hz, major 1H, minor 1H); ESIMS m/z 305.22 (Mþþ1).
52.43, 119.03, 122.04, 127.60, 127.65, 127.88, 128.65, 128.76, 128.82,
130.03, 130.31, 131.63, 138.21, 138.73, 149.08, 153.58, 154.55, 165.72
(one carbon is overlapped). Anal. Calcd for C23H19N5O2: C, 69.51; H,
4.82; N, 17.62. Found: C, 69.88; H, 4.75; N, 17.46.

7190
H.S. Lee et al. / Tetrahedron 64 (2008) 7183–7190
Lett. 2008, 49, 1670–1673; (b) Kim, J. M.; Kim, K. H.; Kim, T. H.; Kim, J. N. Tet-
Acknowledgements
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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.
8. Lee, H. S.; Kim, S. H.; Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2008, 49,
1773–1776.
This work was supported by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD, KRF-2007-
313-C00417). Spectroscopic data were obtained from the Korea
Basic Science Institute, Gwangju branch.
9. For the preparation of benzoazepino[1,2-a]indole derivatives as inhibitors of
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