Palladium-catalyzed synthesis of benzo[c]pyrimido[1,6-a]azepine scaffold from Morita-Baylis-Hillman adducts: Intramolecular 6-arylation of uracil nucleus

Article abstract of DOI:10.1016/j.tetlet.2011.11.085

Palladium-catalyzed intramolecular arylation at the C-6 position of uracil moiety was examined. Morita-Baylis-Hillman adducts bearing an uracil moiety at the primary position served an efficient way to a benzo[c]pyrimido[1,6-a]azepine scaffold.

Full text of DOI:10.1016/j.tetlet.2011.11.085

Tetrahedron Letters 53 (2012) 497–501
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Tetrahedron Letters
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Palladium-catalyzed synthesis of benzo[c]pyrimido[1,6-a]azepine scaffold from
Morita–Baylis–Hillman adducts: intramolecular 6-arylation of uracil nucleus
⇑
Hyun Seung Lee, Ko Hoon Kim, Se Hee Kim, 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:
Palladium-catalyzed intramolecular arylation at the C-6 position of uracil moiety was examined. Morita–
Baylis–Hillman adducts bearing an uracil moiety at the primary position served an efficient way to a
benzo[c]pyrimido[1,6-a]azepine scaffold.
Received 24 October 2011
Revised 11 November 2011
Accepted 11 November 2011
Available online 1 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Benzo[c]pyrimido[1,6-a]azepine
Morita–Baylis–Hillman adducts
Palladium
Uracil
6-Arylation
Recently various tetracyclic fused indole derivatives have been
synthesized via a palladium-catalyzed cyclization of indole-con-
taining Morita–Baylis–Hillman adducts in our group.1 As a contin-
uous study, we were interested in the synthesis of benzoazepine
derivatives2 fused with a uracil moiety, because these compounds
have a potential hepatitis C virus (HCV) NS5B polymerase inhibi-
tory activity.3
The arylation of uracil ring was carried out most frequently by
palladium-catalyzed cross-coupling reactions of 5-halouracils with
arylboronic acids4 or arylstannanes.5 Very recently, a palladium-
catalyzed direct arylation of uracil derivatives with aryl halides
has been reported.6,7 We also reported a regioselective palla-
dium-catalyzed direct arylation of uracil derivatives.8
In these respects, we decided to check the feasibility of the Pd-
catalyzed intramolecular arylation to the 6-position of uracil moi-
ety in order to synthesize benzoazepine derivatives as shown in
Scheme 1. The reaction of Morita–Baylis–Hillman acetate 1a and
uracil (2a) in the presence of K2CO3 in DMF afforded the starting
material 3a in a good yield (80%). However, a palladium-catalyzed
cyclization of 3a failed completely under various reaction condi-
tions.9 Literature survey revealed that a Pd-catalyzed C-arylation
of free (N–H)-containing heterocycles is a difficult task.6,10 Thus
we decided to protect the N3-position of 3a with a benzyl group
to prepare 4a (94%). To our delight, a Pd-catalyzed cyclization of
4a provided 5a in a good yield (78%) in a short time (30 min) in
the presence of Pd(OAc)2, TBAB (tetrabutylammonium bromide)
and KOAc in DMF.1,7a,11
Encouraged by the successful results, we prepared starting mate-
rials 4b–f by the selective N1-alkylation of uracil derivatives 2a–d
with Morita–Baylis–Hillman acetates 1a–c and a subsequent N3-
protection with benzyl bromide, as shown in Table 1. All entries
showed good to moderate yields (73–89% for the first cinnamylation
at N1-position, 79–96% for the second benzylation at N3-position).
During the preparation of 3a–f, the corresponding Z-isomers were
formed in trace amounts; however, we separated E-isomers of 3a–
f and used for the next benzylation. As uracil derivatives, we used
uracil (2a), thymine (2b), 5-fluorouracil (2c), and 5-ethyluracil
(2d). With these starting materials 4b–f we examined the palla-
dium-catalyzed cyclization, and the results are summarized in Table
1. 5-Substituted uracil derivatives 4b–d with methyl, fluoro, and
ethyl groups afforded the corresponding benzo[c]pyrimido[1,6-
a]azepine derivatives 5b–d in moderate yields (62–83%). Naphtha-
lene derivative 4e and dimethoxyphenyl derivative 4f also produced
the corresponding products 5e and 5f in reasonable yields (59–78%).
The reaction mechanism could be proposed as shown in Scheme
2. An oxidative addition of C–Br bond of 4a to Pd0 produced an
arylpalladium intermediate I. A subsequent 7-exo-carbopallada-
tion of I to form II, and the following epimerization at C-5 position
of the uracil moiety via a corresponding O-palladium intermediate
III gave IV, which produced 5a by a syn b-H elimination process.12
However, the Pd-catalyzed cyclization reaction with 5-nitroura-
cil derivative 4g failed, as shown in Scheme 3. Expected compound
5g was not formed in any trace amount. Instead, rearranged MBH
acetate 6 was isolated in 62% along with many intractable side
⇑
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 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.085

498
H. S. Lee et al. / Tetrahedron Letters 53 (2012) 497–501
COOMe
O
COOMe
OAc
Br
O
O
Pd(OAc)2
TBAB, KOAc
COOMe
H
O
1. K2CO3, DMF
R
O
N
N
+
Br
N
N
DMF, 120 oC, 30 min
2. PhCH2Br
K2CO3, DMF
N
H
2a
N
Bn
1a
3a (80%, R = H)
4a (94%, R = Bn)
O
5a (78%)
Scheme 1.
Table 1
Preparation of starting materials 4a–f and Pd-catalyzed synthesis of 5a–f
OAc
OAc
Br OAc
MeO
MeO
COOMe
COOMe
COOMe
Br
Br
1c
1b
1a
1. 2a-d, K2CO3, DMF (to 3a-f)
Pd(OAc)2, TBAB
1a-c
4a-f
5a-f
KOAc, DMF, 120 oC
2. PhCH2Br, K2CO3, DMF
Entry
1
1+2
Substrate 4a (%)
Product 5b (%)
COOMe
COOMe
O
Bn
O
Br
N
N
N
N
N
N
1a+2a
O
4a (80/94)
N
5a (78)
Bn
O
O
O
O
COOMe
COOMe
O
Bn
O
Br
N
N
2
3
4
5
6
1a+2b
1a+2c
1a+2d
1b+2a
1c+2a
O
4b (89/89)
Me
N
5b (83)
Me
COOMe
Bn
COOMe
O
Bn
O
Br
N
N
O
4c (88/95)
F
N
5c (62)
F
Bn
COOMe
COOMe
O
Bn
O
Br
N
N
O
4d (84/86)
Et
N
5d (79)
Et
Bn
COOMe
COOMe
O
Bn
O
Br
N
N
N
O
N
5e (78)
4e (78/96)
MeO
MeO
Bn
O
COOMe
COOMe
O
MeO
MeO
Bn
O
Br
4f (73/79)
N
N
N
O
N
Bn
5f (59)
O
a
Conditions: (i) 1 (1.0 mmol), 2 (1.5 equiv), K2CO3 (2.0 equiv), DMF, rt, 5 h (3a–f); (ii) 3 (0.8 mmol), PhCH2Br (1.5 equiv), K2CO3 (2.0 equiv), DMF, rt, 5 h (4a–f). Yields were
noted in the parenthesis as follows (3a–f/4a–f).
b
Conditions: 4 (0.5 mmol), Pd(OAc)2 (10 mol %), TBAB (1.0 equiv), KOAc (3.0 equiv), DMF, 120 °C, 30 min (for 5a–e) and 80 min (for 5f).
products. Compound 6 could be formed via the nucleophilic
displacement of 5-nitro-3-benzyluracil moiety with an acetate
ion. Compound 5g was not formed also when we use K2CO3 or
Cs2CO3 instead of KOAc in order to suppress the formation of 6.
Thus, we turned our attention to a functionalization at the 5-po-
sition of the uracil moiety of 5a, in order to synthesize a variety of
similar benzoazepine derivatives including a 5-nitro derivative 5g.
The results are summarized in Table 2. As shown in entry 1,

H. S. Lee et al. / Tetrahedron Letters 53 (2012) 497–501
499
COOMe
COOMe
COOMe
O
COOMe
- HBr
- Pd0
O
Pd0
7-exo
Bn
O
5a
N
4a
N
N
Pd
Br
N
N
H
R
O
H
O
H
Pd
R
Br
R
N
N
N
Pd
Bn
Bn
Bn
R
Br
O
O
O
I
BrPd
II
IV
III
Scheme 2.
COOMe
O
Pd(OAc)2 (10 mol%)
TBAB (1.0 equiv)
COOMe
COOMe
O
N
Bn
O
KOAc (3.0 equiv)
DMF, 90 oC, 20 min
Br
N
N
Br OAc
6 (62%)
O2N
N
Bn
O
NO2
4g
5g (not formed)
Scheme 3.
Table 2
Various functionalization at the 5-position of uracil moiety in 5a
Entry
Conditions
Product 5 (%)
COOMe
N
N
N
1
Cu(NO3)2 (2.0 equiv), Ac2O, rt, 8 h
O
O2N
N
5g (54)
5h (80)
Bn
O
O
O
COOMe
2
3
I2 (1.5 equiv), Ce(NH4)2(NO3)6 (1.0 equiv) CH3CN, reflux, 10 h
O
I
N
Bn
COOMe
LiCl (1.2 equiv), Ce(NH4)2(NO3)6 (2.0 equiv) CH3CN/AcOH, 80 °C, 1 h
O
Cl
N
5i (70)
Bn
COOMe
N
4
Ethyl acrylate (30 equiv), Pd(TFA)2 (10 mol %) AgOAc (4.0 equiv), PivOH (6.0 equiv), 100 °C, 18 h
O
EtOOC
N
Bn
5j (51)
O
COOMe
N
O
MeOOC
MeO
MeOOC
5
Dimethyl malonate (6.0 equiv) Ce(NH4)2(NO3)6 (6.0 equiv) CH3CN/MeOH (3:1), rt, 3 h
N
Bn
5k (65)
O
nitration of 5a under the influence of Cu(NO3)2/Ac2O afforded
product 5g in moderate yields (54%).13 Iodination of 5a with iodine
in the presence of ammonium cerium nitrate (CAN) afforded 5h
(entry 2) in a good yield (80%).14 Chlorination of 5a was carried
out to form 5i (70%) by LiCl/CAN according to the reported meth-
od.15 In addition, a palladium-catalyzed Fujiwara–Moritani reac-
tion16 of 5a with ethyl acrylate afforded the corresponding
compound 5j in a reasonable yield (51%). As a last entry (entry
5), an introduction of a malonate moiety was performed according
to the literature method to form 5k in a moderate yield (65%).17

500
H. S. Lee et al. / Tetrahedron Letters 53 (2012) 497–501
2.0 mmol) in DMF (2.0 mL) was stirred at room temperature for 5 h. After
the usual aqueous extractive workup and column chromatographic
purification process (hexanes/ether, 1:2) compound 3a was obtained as a
Although the yields were moderate in some entries (entries 1 and
4), we could prepare variously functionalized benzoazepine
derivatives.
white solid, 293 mg (80%).
A solution of 3a (292 mg, 0.8 mmol), benzyl
bromide (205 mg, 1.2 mmol), and K2CO3 (221 mg, 1.6 mmol) in DMF (2.0 mL)
was stirred at room temperature for 5 h. After the usual aqueous extractive
workup and column chromatographic purification process (hexanes/ether, 1:2)
In summary, a palladium-catalyzed intramolecular arylation at
the C-6 position of the uracil moiety was examined. Morita–Bay-
lis–Hillman adducts bearing an uracil moiety at the primary posi-
tion provided an efficient way to a novel benzo[c]pyrimido[1,6-
a]azepine scaffold. In addition, various functionalizations of the
synthesized benzoazepine derivative were successfully carried
out. Further studies on the biological activities are underway and
the results will be published in due course.
compound 4a was obtained as colorless oil, 343 mg (94%).
A mixture of
compound 4a (228 mg, 0.5 mmol), Pd(OAc)2 (11 mg, 10 mol %), TBAB (161 mg,
0.5 mmol), and KOAc (147 mg, 1.5 mmol) in DMF (2.0 mL) was heated to
120 °C for 30 min. After the usual aqueous extractive workup and column
chromatographic purification process (hexanes/ether, 1:1) compound 5a was
obtained as a white solid, 146 mg (78%). Other compounds were synthesized
similarly, and the selected spectroscopic data of 4a and 5a–k are as follows.
Compound 4a: 94%; colorless oil; IR (film) 1710, 1663, 1449, 1230 cmÀ1 1H
;
NMR (CDCl3, 300 MHz) d 3.77 (s, 3H), 4.68 (s, 2H), 5.02 (s, 2H), 5.60 (d,
J = 8.1 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 7.15–7.30 (m, 6H), 7.42 (d, J = 8.1 Hz,
2H), 7.58 (d, J = 7.2 Hz, 1H), 7.93 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 44.05,
45.00, 52.44, 101.24, 123.17, 127.32, 127.36, 127.82, 128.13, 128.96, 129.56,
130.39, 132.69, 134.54, 136.66, 141.68, 143.98, 151.05, 162.61, 166.24; ESIMS
m/z 455 (M++H), 457 (M++H+2). Anal. Calcd. For C22H19BrN2O4: C, 58.04; H,
4.21; N, 6.15. Found: C, 58.33; H, 4.42; N, 6.08.
Acknowledgments
This work was supported by the National Research Foundation
of Korea Grant funded by the Korean Government (2011-0002570).
Spectroscopic data were obtained from the Korea Basic Science
Institute, Gwangju branch.
Compound 5a: 78%; white solid, mp 118–120 °C; IR (KBr) 1718, 1658, 1460,
1433 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.45 (d, J = 13.5 Hz, 1H), 3.89 (s, 3H),
;
5.08 (d, J = 13.5 Hz, 1H), 5.24 (d, J = 13.5 Hz, 1H), 5.79 (s, 1H), 6.01 (d,
J = 13.5 Hz, 1H), 7.23–7.34 (m, 3H), 7.45 (d, J = 7.5 Hz, 1H), 7.50–7.62 (m, 4H),
7.69 (d, J = 7.5 Hz, 1H), 7.93 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 40.20, 44.62,
52.66, 102.64, 127.59, 128.30, 129.29, 129.74, 130.36, 130.77, 130.87, 132.26,
133.38, 134.39, 136.73, 142.00, 150.52, 152.20, 161.97, 165.22; ESIMS m/z 375
(M++H). Anal. Calcd. For C22H18N2O4: C, 70.58; H, 4.85; N, 7.48. Found: C, 70.37;
H, 4.93; N, 7.37.
References and notes
1. For our recent synthesis of indole-containing polycyclic compounds from
Morita–Baylis–Hillman adducts, see: (a) Lee, H. S.; Kim, S. H.; Kim, T. H.; Kim, J.
N. Tetrahedron Lett. 2008, 49, 1773–1776; (b) Lee, H. S.; Kim, S. H.; Gowrisankar,
S.; Kim, J. N. Tetrahedron 2008, 64, 7183–7190.
Compound 5b: 83%; white solid, mp 100–102 °C; IR (KBr) 1718, 1697, 1643,
2. For the synthesis of various benzoazepine derivatives, see: (a) Dumoulin, D.;
Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron: Asymmetry
2009, 20, 1903–1911; (b) Ozeki, M.; Muroyama, A.; Kajimoto, T.; Watanabe, T.;
Wakabayashi, K.; Node, M. Synlett 2009, 1781–1784; (c) Fantauzzi, S.; Gallo, E.;
Caselli, A.; Piangiolino, C.; Ragaini, F.; Re, N.; Cenini, S. Chem. Eur. J. 2009, 15,
1241–1251; (d) Novak, T.; Mucsi, Z.; Balazs, B.; Keresztely, L.; Blasko, G.;
Nyerges, M. Synlett 2010, 2411–2414; (e) Gowrisankar, S.; Lee, H. S.; Lee, K. Y.;
Lee, J.-E.; Kim, J. N. Tetrahedron Lett. 2007, 48, 8619–8622; (f) Gowrisankar, S.;
Lee, K. Y.; Kim, J. N. Bull. Korean Chem. Soc. 2005, 26, 1112–1116; (g) Sajitz, M.;
Frohlich, R.; Salorinne, K.; Wurthwein, E.-U. Synthesis 2006, 2183–2190.
3. (a) For the similar poly-fused compounds showing a hepatitis C virus NS5B
polymerase inhibitory activity, 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. US
2007184024, 2007; Chem. Abstr. 2007, 147, 257667.; (c) Habermann, J.; Capito,
E.; del Rosario Rico Ferreira, M.; Koch, U.; Narjes, F. Bioorg. Med. Chem. Lett.
2009, 19, 633–638; (d) Ding, M.; He, F.; Poss, M. A.; Rigat, K. L.; Wang, Y.-K.;
Roberts, S. B.; Qiu, D.; Fridell, R. A.; Gao, M.; Gentles, R. G. Org. Biomol. Chem.
2011, 9, 6654–6662. and further references cited therein.
4. For the palladium-catalyzed synthesis of 5-aryluracil derivatives with
arylboron reagents, see: (a) Kalachova, L.; Pohl, R.; Hocek, M. Synthesis 2009,
105–112; (b) Western, E. C.; Daft, J. R.; Johnson, E. M., II; Gannett, P. M.;
Shaughnessy, K. H. J. Org. Chem. 2003, 68, 6767–6774; (c) Crisp, G. T.; Macolino,
V. Synth. Commun. 1990, 20, 413–422; (d) Pomeisl, K.; Holy, A.; Pohl, R.; Horska,
K. Tetrahedron 2009, 65, 8486–8492; (e) Pomeisl, K.; Holy, A.; Pohl, R.
Tetrahedron Lett. 2007, 48, 3065–3067; (f) Coelho, A.; Sotelo, E. J. Comb. Chem.
2005, 7, 526–529; For recent 6-arylation of uracil derivatives, see: (g) Shih, Y.-
C.; Chien, T.-C. Tetrahedron 2011, 67, 3915–3923.
5. For the palladium-catalyzed synthesis of 5-aryluracil derivatives with
arylstannane reagents, see: (a) Gutierrez, A. J.; Terhorst, T. J.; Matteucci, M.
D.; Froehler, B. C. J. Am. Chem. Soc. 1994, 116, 5540–5544; (b) Sadler, J. M.;
Ojewoye, O.; Seley-Radtke, K. L. Nucleic Acids Symp. Ser. 2008, 52, 571–572; (c)
Wigerinck, P.; Pannecouque, C.; Snoeck, R.; De Clercq, E.; Herdewijn, P. J. Med.
Chem. 1991, 34, 2383–2389; (d) Herdewijn, P.; Kerremans, L.; Wigerinck, P.;
Vandendriessche, F.; Aerschot, A. V. Tetrahedron Lett. 1991, 32, 4397–4400.
6. For the palladium-catalyzed intermolecular arylation of uracil derivatives, see:
(a) Cernova, M.; Pohl, R.; Hocek, M. Eur. J. Org. Chem. 2009, 3698–3701; (b)
Cernova, M.; Cerna, I.; Pohl, R.; Hocek, M. J. Org. Chem. 2011, 76, 5309–5319.
7. For the palladium-catalyzed intramolecular arylation of uracil derivatives, see:
(a) Majumdar, K. C.; Sinha, B.; Maji, P. K.; Chattopadhyay, S. K. Tetrahedron
2009, 65, 2751–2756; (b) Majumdar, K. C.; Debnath, P.; Taher, A.; Pal, A. K. Can.
J. Chem. 2008, 86, 325–332.
1459, 1439 cmÀ1 1H NMR (CDCl3, 300 MHz) d 1.80 (s, 3H), 3.37 (d, J = 14.4 Hz,
;
1H), 3.88 (s, 3H), 5.13 (d, J = 13.5 Hz, 1H), 5.27 (d, J = 13.5 Hz, 1H), 6.02 (d,
J = 14.4 Hz, 1H), 7.23–7.34 (m, 3H), 7.44–7.58 (m, 6H), 7.92 (s, 1H); 13C NMR
(CDCl3, 75 MHz) d 14.24, 40.18, 44.87, 52.55, 109.58, 127.50, 128.24, 128.66,
129.39, 129.66, 130.00, 131.89, 132.12, 132.80, 135.65, 136.90, 141.82, 146.69,
149.91, 163.34, 165.28; ESIMS m/z 389 (M++H). Anal. Calcd. For C23H20N2O4: C,
71.12; H, 5.19; N, 7.21. Found: C, 71.34; H, 5.02; N, 7.12.
Compound 5c: 62%; white solid, mp 146–148 °C; IR (KBr) 1719, 1660, 1275,
1262 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.42 (d, J = 14.1 Hz, 1H), 3.89 (s, 3H),
;
5.10 (d, J = 13.5 Hz, 1H), 5.28 (d, J = 13.5 Hz, 1H), 6.02 (d, J = 14.1 Hz, 1H), 7.25–
7.35 (m, 3H), 7.48–7.62 (m, 5H), 7.69–7.74 (m, 1H), 7.93 (s, 1H); 13C NMR
(CDCl3, 75 MHz) d 40.20, 45.19, 52.66, 127.02 (d, JC–F = 3.5 Hz), 127.88, 128.38,
129.48, 129.56, 130.71, 130.94, 131.91 (d, JC–F = 7.5 Hz), 132.17, 135.17, 136.17
(d, JC–F = 29.3 Hz), 136.10, 137.59 (d, JC–F = 223.2 Hz), 141.92, 148.52, 156.86 (d,
JC–F = 26.3 Hz), 165.11; ESIMS m/z 393 (M++H). Anal. Calcd. For C22H17FN2O4: C,
67.34; H, 4.37; N, 7.14. Found: C, 67.55; H, 4.39; N, 7.02.
Compound 5d: 79%; white solid, mp 128–130 °C; IR (KBr) 1720, 1697, 1645,
1454, 1438 cmÀ1 1H NMR (CDCl3, 300 MHz) d 0.98 (t, J = 7.2 Hz, 3H), 2.03–2.39
;
(m, 2H), 3.35 (d, J = 14.1 Hz, 1H), 3.87 (s, 3H), 5.10 (d, J = 13.5 Hz, 1H), 5.29 (d,
J = 13.5 Hz, 1H), 6.01 (d, J = 14.1 Hz, 1H), 7.23–7.34 (m, 3H), 7.44–7.58 (m, 6H),
7.93 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 13.75, 21.20, 40.22, 44.74, 52.55,
115.58, 127.47, 128.26, 128.72, 129.38, 129.55, 130.00, 130.82, 132.28, 133.00,
135.65, 136.99, 141.73, 146.83, 149.88, 162.79, 165.30; ESIMS m/z 403 (M++H).
Anal. Calcd. For C24H22N2O4: C, 71.63; H, 5.51; N, 6.96. Found: C, 71.38; H, 5.82;
N, 6.93.
Compound 5e: 78%; white solid, mp 164–166 °C; IR (KBr) 1718, 1656, 1450,
1262 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.51 (d, J = 14.4 Hz, 1H), 3.91 (s, 3H),
;
5.12 (d, J = 13.8 Hz, 1H), 5.29 (d, J = 13.8 Hz, 1H), 5.81 (s, 1H), 6.05 (d,
J = 14.4 Hz, 1H), 7.26–7.37 (m, 3H), 7.45 (d, J = 8.4 Hz, 1H), 7.50–7.62 (m, 4H),
7.89 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 8.29 (d, J = 7.5 Hz,
1H); 13C NMR (CDCl3, 75 MHz) d 40.70, 44.62, 52.66, 105.52, 126.19, 126.60,
127.62, 127.87, 128.33 (2C), 129.41, 130.64, 131.03, 131.27, 133.05, 133.24,
133.96, 136.72, 142.03, 148.47, 150.75, 161.55, 165.14 (one carbon was
overlapped); ESIMS m/z 425 (M++H). Anal. Calcd. For C26H20N2O4: C, 73.57; H,
4.75; N, 6.60. Found: C, 73.81; H, 4.78; N, 6.43.
Compound 5f: 59%; white solid, mp 198–200 °C; IR (KBr) 1714, 1656, 1518,
1454, 1440 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.45 (d, J = 14.4 Hz, 1H), 3.88 (s,
;
3H), 3.95 (s, 3H), 3.96 (s, 3H), 5.08 (d, J = 13.8 Hz, 1H), 5.24 (d, J = 13.8 Hz, 1H),
5.77 (s, 1H), 6.01 (d, J = 14.4 Hz, 1H), 6.88 (s, 1H), 7.13 (s, 1H), 7.21–7.35 (m,
3H), 7.54 (d, J = 8.1 Hz, 2H), 7.86 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 40.45,
44.58, 52.54, 56.13, 56.20, 101.45, 111.95, 112.65, 126.73, 127.53, 128.05,
128.28, 129.20, 130.49, 136.78, 141.94, 150.38, 150.55, 150.94, 152.02, 162.13,
165.31; ESIMS m/z 435 (M++H). Anal. Calcd. For C24H22N2O6: C, 66.35; H, 5.10;
N, 6.45. Found: C, 66.41; H, 5.37; N, 6.23.
8. Kim, K. H.; Lee, H. S.; Kim, J. N. Tetrahedron Lett. 2011, 52, 6228–6233. and
further references cited therein.
Compound 5g: 54%; white solid, mp 208–210 °C; IR (KBr) 1726, 1669, 1528,
9. The reactions of 3a under the following conditions were all ineffective: (i)
Pd(OAc)2, TBAB, K2CO3, DMF, 120 °C;1 (ii) Pd(OAc)2, PPh3, CuI, Cs2CO3, DMF,
150 °C;6 (iii) Pd(OAc)2, TBAB, KOAc, DMF, 120 °C;7 (iv) Pd(OAc)2, TBAC, PivOH,
K2CO3, DMF, 130 °C;8 (v) Pd(OAc)2, PPh3, PivOH, K2CO3, DMF, 130 °C.8
10. For the difficulty in the Pd-catalyzed C-arylation of free (N–H)-containing
heterocycles including free (N–H)-indoles and pyrroles, see: Wang, X.; Gribkov,
D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476–1479. In addition, the failure of C-
arylation of uracil derivatives was also noted in Ref. 6.
1465, 1434 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.37 (d, J = 14.4 Hz, 1H), 3.91 (s,
;
3H), 5.09 (d, J = 13.5 Hz, 1H), 5.29 (d, J = 13.5 Hz, 1H), 6.08 (d, J = 14.4 Hz, 1H),
7.30–7.37 (m, 3H), 7.47–7.70 (m, 6H), 8.01 (s, 1H); 13C NMR (CDCl3, 75 MHz) d
40.66, 45.79, 52.86, 127.97, 128.23, 128.54, 128.91, 129.89, 130.38, 130.46,
130.81, 132.41, 132.80, 135.20, 135.45, 141.63, 147.42, 148.23, 154.98, 164.65;
ESIMS m/z 420 (M++H). Anal. Calcd. For C22H17N3O6: C, 63.01; H, 4.09; N, 10.02.
Found: C, 63.33; H, 4.29; N, 9.89.
Compound 5h: 80%; white solid, mp 218–220 °C; IR (KBr) 1718, 1649, 1579,
11. Typical procedure for the synthesis of 4a and 5a: A solution of MBH acetate (1a,
313 mg, 1.0 mmol), uracil (2a, 168 mg, 1.5 mmol), and K2CO3 (276 mg,
1447, 1430 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.40 (d, J = 14.4 Hz, 1H), 3.88 (s,
;

H. S. Lee et al. / Tetrahedron Letters 53 (2012) 497–501
1455, 1438 cmÀ1
501
3H), 5.17 (d, J = 13.5 Hz, 1H), 5.30 (d, J = 13.5 Hz, 1H), 6.08 (d, J = 14.4 Hz, 1H),
7.26–7.35 (m, 3H), 7.44–7.62 (m, 5H), 7.84 (d, J = 7.8 Hz, 1H), 7.94 (s, 1H); 13C
NMR (CDCl3, 75 MHz) d 41.77, 46.56, 52.66, 109.68, 127.84, 128.36, 128.74,
129.38, 129.72, 131.03, 132.93, 133.40, 134.60, 135.02, 136.30, 141.75, 149.72,
152.59, 160.14, 165.01; ESIMS m/z 523 (M++Na). Anal. Calcd. For C22H17IN2O4:
C, 52.82; H, 3.43; N, 5.60. Found: C, 52.95; H, 3.71; N, 5.73.
;
1H NMR (CDCl3, 300 MHz) d 3.19 (s, 3H), 3.30 (d, J = 14.4 Hz,
1H), 3.61 (s, 3H), 3.65 (s, 3H), 3.89 (s, 3H), 5.07 (d, J = 13.8 Hz, 1H), 5.25 (d,
J = 13.8 Hz, 1H), 6.04 (d, J = 14.4 Hz, 1H), 7.24–7.34 (m, 3H), 7.43–7.65 (m, 6H),
7.96 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 40.24, 45.23, 52.57, 53.02, 53.10,
53.47, 83.57, 109.60, 127.68, 128.27, 128.84 (2C), 129.33, 130.75, 131.43,
131.93, 133.24, 136.22, 141.75, 149.14, 153.93, 162.44, 164.91, 166.28, 167.51
(one carbon was overlapped); ESIMS m/z 557 (M++Na). Anal. Calcd. For
Compound 5i: 70%; white solid, mp 198–200 °C; IR (KBr) 1720, 1657, 1452,
1433 cmÀ1
;
1H NMR (CDCl3, 300 MHz) d 3.39 (d, J = 14.4 Hz, 1H), 3.88 (s, 3H),
C28H26N2O9: C, 62.92; H, 4.90; N, 5.24. Found: C, 63.10; H, 4.96; N, 5.15.
5.14 (d, J = 13.5 Hz, 1H), 5.30 (d, J = 13.5 Hz, 1H), 6.03 (d, J = 14.4 Hz, 1H), 7.25–
7.35 (m, 3H), 7.46–7.62 (m, 5H), 7.80 (d, J = 7.8 Hz, 1H), 7.94 (s, 1H); 13C NMR
(CDCl3, 75 MHz) d 41.01, 45.91, 52.67, 109.07, 127.88, 128.37, 128.75, 129.70,
129.81, 130.28, 130.87, 132.56, 132.64, 135.41, 136.16, 141.82, 147.19, 148.97,
159.05, 165.00; ESIMS m/z 431 (M++Na), 433 (M++2+Na). Anal. Calcd. For
12. For the formal anti b-H elimination Ikeda, M.; El Bialy, S. A. A.; Yakura, T.
Heterocycles 1999, 51, 1957–1970. and further references cited therein. Most of
the intramolecular Heck reactions involving a formal anti-elimination process
could be understood actually by syn b-H elimination after the epimerization of
a carbopalladation intermediate via a palladium enolate or the epimerization
of b-H.
13. Giziewicz, J.; Wnuk, S. F.; Robins, M. J. J. Org. Chem. 1999, 64, 2149–2151.
14. Janeba, Z.; Balzarini, J.; Andrei, G.; Snoeck, R.; De Clercq, E.; Robins, M. J. Can. J.
Chem. 2006, 84, 580–586.
15. Asakura, J.-i.; Robins, M. J. J. Org. Chem. 1990, 55, 4928–4933.
16. For some examples of Fujiwara–Moritani oxidative Heck reaction, see: (a)
Hirota, K.; Isobe, Y.; Kitade, Y.; Maki, Y. Synthesis 1987, 495–496; (b) Miyasaka,
M.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2010, 75, 5421–5424; (c) Li, Z.;
Ma, L.; Tang, C.; Xu, J.; Wu, X.; Yao, H. Tetrahedron Lett. 2011, 52, 5643–5647;
(d) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem.,
Int. Ed. 2005, 44, 3125–3129.
C
22H17ClN2O4: C, 64.63; H, 4.19; N, 6.85. Found: C, 64.70; H, 4.42; N, 6.81.
Compound 5j: 51%; white solid, mp 150–152 °C; IR (KBr) 1719, 1657, 1459,
1436 cmÀ1 1H NMR (CDCl3, 300 MHz)
1.23 (t, J = 7.2 Hz, 3H), 3.39 (d,
;
d
J = 14.1 Hz, 1H), 3.89 (s, 3H), 4.05–4.20 (m, 2H), 5.15 (d, J = 13.5 Hz, 1H), 5.29
(d, J = 13.5 Hz, 1H), 6.08 (d, J = 14.1 Hz, 1H), 6.79 (d, J = 15.6 Hz, 1H), 7.12 (d,
J = 15.6 Hz, 1H), 7.24–7.36 (m, 3H), 7.47–7.67 (m, 6H), 7.96 (s, 1H); 13C NMR
(CDCl3, 75 MHz) d 14.16, 40.51, 45.03, 52.68, 60.06, 108.42, 120.87, 127.75,
128.36, 128.84, 129.52, 129.81, 130.76, 131.36, 133.00, 133.42, 135.99, 136.48,
137.22, 141.73, 149.07, 152.39, 160.85, 164.93, 167.88; ESIMS m/z 473 (M++H).
Anal. Calcd. For C27H24N2O6: C, 68.63; H, 5.12; N, 5.93. Found: C, 68.74; H, 5.03;
N, 5.68.
Compound 5k: 65%; white solid, mp 126–128 °C; IR (KBr) 1744, 1721, 1649,
17. Kim, Y. H.; Lee, D. H.; Yang, S. G. Tetrahedron Lett. 1995, 36, 5027–5030.