Palladium(II)-catalyzed oxidative homo-coupling of 1,3-dimethyluracil derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.12.135

A palladium-catalyzed oxidative homo-coupling of 1,3-dimethyluracil was examined. Two types of uracil dimer, C5-C5′ linked dimer and C5-C6′ linked dimer were obtained in variable yields depending on the conditions along with a low yield of C5-C5′ and C6-C

Full text of DOI:10.1016/j.tetlet.2011.12.135

Tetrahedron Letters 53 (2012) 1323–1327
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium(II)-catalyzed oxidative homo-coupling of
1,3-dimethyluracil derivatives
⇑
Ko Hoon Kim, Hyun Seung Lee, Sung Hwan 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:
A palladium-catalyzed oxidative homo-coupling of 1,3-dimethyluracil was examined. Two types of uracil
dimer, C5–C50 linked dimer and C5–C60 linked dimer were obtained in variable yields depending on the
conditions along with a low yield of C5–C50 and C6–C50 linked uracil trimer.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 2 December 2011
Revised 21 December 2011
Accepted 21 December 2011
Available online 20 January 2012
Keywords:
Palladium
1,3-Dimethyluracil
Oxidative homo-coupling
Uracil dimer
Uracil trimer
Transition metal-based drugs have received much attention
since the finding of antitumor activity of cisplatin. Since then
numerous efforts have been devoted to the development of drugs
based on transition metals including platinum1a–d and palla-
dium.1c–f Uracil dimers and its nucleoside analogs are not the nat-
ural nucleic acid component; thus, the formation of these
compounds catalyzed by transition metal impurities or metal-con-
taining drugs in vivo may cause severe problems. With this in
mind, Lippert and co-workers have examined the preparation of
C5–C50 uracil dimers with the aid of a gold catalyst.2 Daves and
co-workers also examined the dimerization of pyrimidinylmercu-
ric salts with an equivalent amount of palladium catalyst.3
process.5 During the 6-arylation reaction with p-xylene as an ary-
lation partner, we observed the formations of a C5–C50 linked ura-
cil dimer 4a (26%) and a C5–C60 linked uracil dimer 5a (11%), albeit
in low yields,6 while the reactions of 1a and benzene, m-xylene or
o-xylene produced only trace amounts of the homo-coupled prod-
ucts, 4a and 5a, as shown in Table 1 (entries 1–4). The amounts of
uracil dimers 4a and 5a increased when the arene is sterically hin-
dered as p-xylene or mesitylene. When we used mesitylene (entry
5), cross-coupled products (2e or 3e) were not formed in any trace
amount. Instead dimer 4a was formed as a major product (52%)
along with a low yield of dimer 5a (20%).7–9 The C6–C60 linked ura-
cil dimer 6a was not formed in all entries.
In addition, various types covalently linked nucleic acids dimers
have received much attention due to their potential biological
activity, complexation properties, supramolecular self-assembly,
Watson–Crick base pair bonding models, and protein binding.4
The plausible reaction mechanism for the formations of 4a and
5a is suggested in Scheme 1.5,10 An electrophilic metalation–depro-
tonation (EMD) of 1a produced an uracilpalladium intermediate II
via the iminium ion intermediate I. Heck-type carbopalladation of
II to 1a produced an intermediate III. A subsequent epimerization
at the C50-position of III via an O-palladium enol species and the
following b-H elimination would produce a dimer 5a. When the
intermediate II reacted with 1a in an EMD process, a diuracilpalla-
dium intermediate IV could be formed. Final reductive elimination
of Pd0 from IV would produce a dimer 4a. If the first palladation of
1a occurs by a CMD process via the intermediate V, an uracilpalla-
dium intermediate VI could be generated,5 and a subsequent reac-
tion of VI and 1a in an EMD process would also produce compound
5a via a diuracilpalladium intermediate VIII. However, the dimer
6a was not formed at all presumably due to the involvement of a
congested transition state VII. Similarly, we could not observe
the formation of compound 2e.
Two types of dimers have been reported for uracil derivatives,
0
those are C5–C50 linked dimers4a–h and N3–N3 linked dimers with
a spacer.4i–k However, the synthesis of C5–C50 directly-linked di-
mers without a spacer is much limited.2,3 In these contexts, we
decided to examine the synthesis of uracil dimers in the presence
of a catalytic amount of palladium catalyst.
Recently, we reported a palladium-catalyzed regioselective
5-arylation of 1,3-dimethyluracil with bromoarenes.5 In the same
Letter, we also found a palladium-catalyzed regioselective 6-aryla-
tion with arenes via a concerted metalation–deprotonation (CMD)
⇑
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 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.135

1324
K. H. Kim et al. / Tetrahedron Letters 53 (2012) 1323–1327
Table 1
Palladium-catalyzed homo-coupling reaction of 1,3-dimethyluracil (1a)
Me
N
O
O
O
O
O
O
Me
Me
O
Me
O
Pd(TFA)2 (5 mol%)
O
Me
O
Ar
O
N
N
Me
O
N
Me
N
Me
O
N
AgOAc (3.0 equiv)
N
N
Me
O
N
Me
O
O
N
Me
N
N
Me
N
Me
N
Me
Ar
PivOH (6.0 equiv)
ArH (60 equiv)
110 oC, 20 h
N
Me
1a
O
N
N
Me
N
Me
Me
O
3
2
4a (C5-C5' dimer)
3 (%)
5a (C5-C6' dimer)
6a (C6-C6' dimer)
Entry
Arene
2 (%)
4a (%)
5a (%)
b
b
b
b
1
2
3
4
5
Benzene
2a (85)a
2b (80)a
2c (66)a
2d (52)a
2e (0)
3a (6)a
3b (11)
3c (18)
3d (<5)
3e (0)
—
—
—
—
—
—
b
m-Xylene
o-Xylene
p-Xylene
Mesitylene
b
26
52
11
20
a
Reported data (Ref. 5).
Trace amount (<5%).
b
In order to examine the dependence of yields and selectivity
results might imply that a Heck type reaction of II to form 5a re-
quired relatively lower activation energy than the second EMD
process of II to form 4a (vide supra, Scheme 1). The use of Cu(OAc)2
or AgNO3 as an oxidant was not efficient (entries 8 and 9). The use
of DMSO as a solvent was ineffective (entry 10). The reaction in the
presence of Pd(OAc)2 in CH3CN was also ineffective (entry 11).3
As described above, it is interesting to note that a C5–C50 and
C6–C50 linked uracil trimer 7a3,9 was isolated in some entries, al-
beit in low yield (see Fig. 1). The structure of 7a could be easily de-
duced from its 1H NMR spectrum by the presence of two singlets at
d = 7.12 and 7.63 ppm which correspond to the remaining H-6 pro-
tons of two uracil rings. The trimer 7a could be formed either from
(4a/5a) on the reaction conditions, we carried out the reactions
of 1a under various conditions, and the results are summarized
in Table 2. When we used PivOH as a solvent (entry 2), the result
was similar to that in mesitylene solvent (entry 1). Increasing the
amounts of PivOH decreased the yields of products (entry 3). The
reaction in mesitylene without PivOH (entry 4) provided the high-
est combined yields of products (96%). In addition, a trimeric com-
pound 7a (vide infra) was isolated in a reasonable yield (18%).3,9 It
is interesting to note that the yield of 5a increased to 46% when the
reaction was performed at 80 °C (entry 5). However, the reaction at
lower temperature (<65 °C) was so sluggish (entries 6 and 7). The
O
H
LPd
Me
O
N
O
(i) epimerization
(ii) - HPdL
Me
O
+ 1a
N
N
5a
4a
H
Heck type
Me
N
Me
III
O
O
O
N
Me
I
O
N
Me
II
H
+ 1a
- LH
Me
Pd
Me
O
Me
O
Me
O
PdL
- LH
N
N
PdL2
EMD
- Pd0
N
PdL
N
1a
EMD
O
N
N
Me
Me
IV
O
Me
N
O
O
O
- PivOH
- Pd0
O
Me
O
O
N
Me
Me
O
Pd
- PivOH
1a
CMD
PdL2
CMD
N
N
H
6a
H
1a
O
O
Me
O
N
N
Me
N
Me
VI
PdL
Pd
L
O
N
Me
V
VII (congested TS)
O
Me
O
N
O
O
N
O
O
H
Me
Me
Me
N
Me
N
O
Pd
N
Me
+ 1a
- Pd0
Me
mesitylene
CMD
- LH
O
N
Me
Pd
N
Me
5a
O
EMD
Me
N
Me
O
Me
Me
Me
IX (congested TS)
VIII
2e
Scheme 1.

K. H. Kim et al. / Tetrahedron Letters 53 (2012) 1323–1327
1325
Table 2
Optimization of Pd-catalyzed homo-coupling of 1,3-dimethyluracil
Entry
1
Conditions
1a (%)a
4a (%)
5a (%)
7a (%)
b
b
b
Pd(TFA)2 (5 mol %), AgOAc (3.0 equiv)
PivOH (6.0 equiv), mesitylene (60 equiv), 110 °C, 20 h
Pd(TFA)2 (5 mol %), AgOAc (2.0 equiv)
PivOH (20 equiv), O2 balloon, 120 °C, 14 h
Pd(TFA)2 (5 mol %), AgOAc (3.0 equiv)
PivOH (60 equiv), 120 °C, 14 h
Pd(TFA)2 (5 mol %), AgOAc (3.0 equiv)
mesitylene (60 equiv), 120 °C, 4 h
Pd(TFA)2 (5 mol %), AgOAc (3.0 equiv)
mesitylene (60 equiv), 80 °C, 16 h
Pd(TFA)2 (5 mol %), AgOAc (3.0 equiv)
mesitylene (60 equiv), 55 °C, 8 h
Pd(TFA)2 (5 mol %), AgOAc (3.0 equiv)
mesitylene (60 equiv), 65 °C, 12 h
Pd(TFA)2 (5 mol %), Cu(OAc)2 (3.0 equiv)
mesitylene (60 equiv), 120 °C, 14 h
Pd(TFA)2 (5 mol %), AgNO3 (3.0 equiv)
PivOH (60 equiv), 120 °C, 14 h
10
52
20
—
—
—
2
3
9
54
39
52
38
18
11
26
46
32
0
4
18
5
0
14
b
b
c
6
90
37
75
78
74
52
—
—
—
b
7
18
29
—
b
b
c
8
—
—
—
b
b
c
9
—
—
—
b
b
c
10
11
Pd(TFA)2 (5 mol %), AgOAc (3.0 equiv)
DMSO (60 equiv), 120 °C, 14 h
Pd(OAc)2 (10 mol %), AgOAc (3.0 equiv)
CH3CN, reflux, 12 h
—
—
—
b
b
—
25
—
a
b
c
Recovered starting material.
Trace amount (<5%).
Not observed.
in a good yield (67%) along with a low yield (10%) of C5–C60 dimer
5b.9,11 We observed the formation of the corresponding trimer in a
right position on TLC; however, we failed to isolate the component
in pure state in appreciable amounts. As in the case of 1a, we car-
ried out the reaction of 1b at low temperature (see entry 5 in Table
2). Although the yield of 5b increased a little (up to 18%); however,
the ratio of 4b/5b was not reversed. The reaction of 1,3-dipropyl-
uracil (1c) showed a similar result (entry 2). A C5–C50 dimer 4c
was obtained as a major product in a good yield (72%). Although
we observed the formation of a C5–C60 dimer in a right position
on TLC; however, we failed to isolate the component in appreciable
amounts. The reaction of N1-tetrahydrofuranyl derivative 1d (entry
3) produced the corresponding C5–C50 dimer 4d in moderate yield
(52%) along with the appreciable amounts of recovered 1d (28%). It
is interesting to note that the two H-6 protons of 4d appeared as
two singlets (1:1) at d = 8.26 and 8.36 ppm in its 1H NMR spectrum
Me
N
O
5
O
O
N
Me
O
N
N
N
Me
Me
5'
5'
6
Me
O
N
Me
O
7a (C5-C5' and C6-C5' trimer)
Figure 1.
4a or 5a by many possible routes, including the reaction between
4a and II in a Heck manner or 5a and II in an EMD process.
The reaction of 1,3-diethyluracil (1b) was examined under the
conditions of entry 4 in Table 2, and the results are summarized
in Table 3 (entry 1). As expected, a C5–C50dimer 4b was isolated
Table 3
Synthesis of uracil dimers 4b–e and 5ba
Entry
Substrate
Product (%)
O
O
Et
N
Et
N
Et
Et
O
O
N
6'
N
O
N
O
5'
5
Et
Et
N
O
N
Et
1b
N
N
Et
5
1
O
O
O
N
Et
Et
5b (10%, C5-C6' dimer)
(80 oC, 24 h: 4b, 60% and 5b, 18%)
4b (67%, C5-C5' dimer)
O
N
Pr
1c
Pr
N
Pr
O
O
N
O
5'
5
Pr
N
N
Pr
2
O
O
N
Pr
4c (72%, C5-C5' dimer)
(continued on next page)

1326
K. H. Kim et al. / Tetrahedron Letters 53 (2012) 1323–1327
Table 3 (continued)
Entry
Substrate
Product (%)
O
O
N
Ph
N
O
N
O
O
O
N
5'
5
O
N
Ph
Ph
N
O
3
O
1d
4d (52%, C5-C5' dimer)
O
N
O
O
5
5'
Ph
N
Ph
N
N
Ph
O
O
N
N
O
4b
BzO
BzO
OBz
O
O
O
OBz OBz
4e (43%, C5-C5' dimer)
OBz OBz
OBz OBz
1e
a
Conditions: Pd(TFA)2 (5 mol %), AgOAc (3.0 equiv), mesitylene (60 equiv), 120 °C, 4 h.
Reaction time is 12 h.
b
in CDCl3.9 The observation revealed the existence of a pair of rota-
tional isomers in a solution at room temperature presumably due
to hindered rotation around the C5–C50 single bond. When we took
the 1H NMR in DMSO-d6, the two singlets were coalesced to a
broad singlet which appeared at d = 8.24 ppm even at room tem-
perature.9 As a last entry, the reaction of N3-benzyl-20,30,50-tri-O-
benzoyluridine (1e) afforded the corresponding C5–C50 dimer 4e
in a reasonable yield (43%, entry 4). The compound 4e appeared
as a single isomer in its 1H NMR spectrum (singlet of H-6 proton
at d = 8.42 ppm). This implied that compound 4e favors only one
rotational isomer state presumably due to the presence of extre-
mely bulky sugar moieties, as compared to 4d that existed as
two restricted rotational isomers.
However, the reactions of 1,3,5-trimethyluracil (1f) or 1,3,6-
trimethyluracil (1g) failed completely. The only possible C6–C60
coupling reaction of 1f was not observed as in the case of 1,3-dime-
thylurcil. Actually, we expected the formation of a C5–C50 coupling
product in the reaction of 1g via a double EMD and/or an EMD-
Heck process; however, we did not observe the formation and
the reason might be the steric hindrance between the two 6-
methyl groups.
Padhye, S.; Afrasiabi, Z.; Sinn, E.; Fok, J.; Mehta, K.; Rath, N. Inorg. Chem. 2005,
44, 1154–1156; (f) Butour, J. L.; Wimmer, S.; Wimmer, F.; Castan, P. Chem. Biol.
Interact. 1997, 104, 165–178.
2. Zamora, F.; Amo-Ochoa, P.; Fischer, B.; Schimanski, A.; Lippert, B. Angew. Chem.,
Int. Ed. 1999, 38, 2274–2275.
3. Arai, I.; Hanna, R.; Daves, G. D., Jr. J. Am. Chem. Soc. 1981, 103, 7684–7685.
4. For the leading references on nucleic acids dimers, see: (a) Sniady, A.; Sevilla,
M. D.; Meneni, S.; Lis, T.; Szafert, S.; Khanduri, D.; Finke, J. M. Dembinski Chem.
Eur. J. 2009, 15, 7569–7577. and further references cited therein; (b) Murata, S.;
Mizumura, Y.; Hino, K.; Ueno, Y.; Ichikawa, S.; Matsuda, A. J. Am. Chem. Soc.
2007, 129, 10300–10301; (c) Semenov, V. E.; Galiullina, L. F.; Lodochnikova, O.
A.; Kataeva, O. N.; Gubaidullin, A. T.; Chernova, A. V.; Efremov, Y. Y.; Latypov, S.
K.; Reznik, V. S. Eur. J. Org. Chem. 2007, 4578–4593; (d) Accetta, A.; Corradini,
R.; Sforza, S.; Tedeschi, T.; Brognara, E.; Borgatti, M.; Gambari, R.; Marchelli, R. J.
Med. Chem. 2009, 52, 87–94; (e) Semenov, V. E.; Akamsin, V. D.; Reznik, V. S.;
Chernova, A. V.; Dorozhkina, G. M.; Efremov, Y. Y.; Nafikova, A. A. Tetrahedron
Lett. 2002, 43, 9683–9686; (f) Kumar, S.; Malik, V.; Kaur, N.; Kaur, K.
Tetrahedron Lett. 2006, 47, 8483–8487; (g) Das, S.; Thakur, A. J. Eur. J. Org.
Chem. 2011, 2301–2308; (h) Spacilova, L.; Dzubak, P.; Hajduch, M.; Krupkova,
S.; Hradil, P.; Hlavac, J. Bioorg. Med. Chem. Lett. 2007, 17, 6647–6650; (i) Ono, T.;
Yoshida, K.; Saotome, Y.; Sakabe, R.; Okamoto, I.; Ono, A. Chem. Commun. 2011,
47, 1542–1544; (j) Li, G.-R.; Liu, J.; Pan, Q.; Song, Z.-B.; Luo, F.-L.; Wang, S.-R.;
Zhang, X.-L.; Zhou, X. Chem. Biodiversity 2009, 6, 2200–2208; (k) Nakane, M.;
Ichikawa, S.; Matsuda, A. J. Org. Chem. 2008, 73, 1842–1851.
5. Kim, K. H.; Lee, H. S.; Kim, J. N. Tetrahedron Lett. 2011, 52, 6228–6233. and
further references cited therein.
6. Unreported results.
7. For the synthesis of a C5–C50 uracil dimer, see: (a) Park, B. R.; Kim, K. H.; Kim, T.
H.; Kim, J. N. Tetrahedron Lett. 2011, 52, 4405–4407; (b) Senga, K.; Ichiba, M.;
Nishigaki, S. J. Org. Chem. 1978, 43, 1677–1683; (c) Kruger, O.; Wille, U. Org. Lett.
2001, 3, 1455–1458.
In summary, we examined a Pd (II)-catalyzed oxidative homo-
coupling reaction of 1,3-dimethyluracil and related derivatives.
Based on the experimental results we proposed a mechanistic sce-
nario in detail. Further studies on the synthesis of un-protected
nucleoside dimers and the conformational characteristics are cur-
rently underway.
8. For the C5–C60 uracil dimer, see: (a) Brown, D. J.; Strekowski, L. Aust. J. Chem.
1981, 34, 1157–1160; (b) Arai, I.; Lee, T. D.; Hanna, R.; Daves, G. D., Jr.
Organometallics 1982, 1, 742–747.
9. Typical procedure for the synthesis of 4a, 5a and 7a: A stirred mixture of 1,3-
dimethyluracil (1a, 140 mg, 1.0 mmol), Pd(TFA)2 (17 mg, 5 mol %), and AgOAc
(501 mg, 3.0 mmol) in mesitylene (8.3 mL, 60 equiv) was heated to 120 °C for
4 h. After cooling to room temperature, the reaction mixture was diluted with
CH2Cl2 and filtered through a pad of Celite. The solvent was removed and the
residue was purified by column chromatography (hexanes/EA, 1:1) to afford 4a
(73 mg, 52%), 5a (36 mg, 26%), and 7a (25 mg, 18%) as white solids. Other
compounds were prepared similarly, and the selected spectroscopic data of
compounds 4a,2,3,7 5a,3,8 7a,3 4b, 5b, and 4c–e are as follows.
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.
Dimer 4a:2,3,7 52%; white solid, mp 278–279 °C (lit.7b 286 °C); IR (KBr) 1702,
1661, 1482, 1452, 1344 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 3.41 (s, 6H), 3.48 (s,
;
6H), 8.41 (s, 2H); ESIMS m/z 301 [M++Na]. Anal. Calcd for C12H14N4O4: C, 51.80;
H, 5.07; N, 20.13. Found: C, 51.93; H, 5.12; N, 20.02.
References and notes
Dimer 5a:3,8 26%; white solid, mp 291–292 °C (lit.3 295 °C); IR (KBr) 1707, 1650,
1483, 1443, 1347 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 3.29 (s, 3H), 3.37 (s, 3H),
;
1. For the leading references on transition metal-containing drugs including Pt
and Pd, see: (a) Klein, A. V.; Hambley, T. W. Chem. Rev. 2009, 109, 4911–4920;
(b) Wheate, N. J.; Walker, S.; Craig, G. E.; Oun, R. Dalton Trans. 2010, 39, 8113–
8127; (c) Ali, M. A.; Mirza, A. H.; Butcher, R. J.; Tarafder, M. T. H.; Keat, T. B.; Ali,
A. M. J. Inorg. Biochem. 2002, 92, 141–148; (d) Castan, P.; Colacio-Rodriguez, E.;
Beauchamp, A. L.; Cros, S.; Wimmer, S. J. Inorg. Biochem. 1990, 38, 225–239; (e)
3.41 (s, 3H), 3.51 (s, 3H), 5.65 (s, 1H), 7.42 (s, 1H); 13C NMR (CDCl3, 75 MHz) d
28.07, 28.38, 33.56, 37.58, 103.69, 108.28, 143.13, 147.59, 151.00, 152.13,
160.34, 162.31; ESIMS m/z 301 [M++Na]. Anal. Calcd for C12H14N4O4: C, 51.80;
H, 5.07; N, 20.13. Found: C, 51.56; H, 5.34; N, 19.94.
Trimer 7a:3 18%; white solid, mp >290 °C (lit.3 >350 °C); IR (KBr) 2956, 1701,

K. H. Kim et al. / Tetrahedron Letters 53 (2012) 1323–1327
1327
1647, 1452, 1349 cmꢀ1
;
1H NMR (CDCl3, 600 MHz) d 3.29 (s, 3H), 3.33 (s, 3H),
J = 16.2 Hz, 2H), 6.01–6.18 (m, 2H), 7.18–7.49 (m, 10H), 8.24 (br s, 2H); 13C
NMR (DMSO-d6, 75 MHz) d (23.51, 23.53), (31.95, 31.98), 43.85, 69.67, (87.60,
87.62), (104.38, 104.47), 127.20, 127.64, 128.35, 136.94 (138.01, 138.03),
149.56, (161.31, 161.32); ESIMS m/z 565 [M++Na]. Anal. Calcd for C30H30N4O6:
C, 66.41; H, 5.57; N, 10.33. Found: C, 66.54; H, 5.72; N, 10.14.
3.35 (s, 3H), 3.36 (s, 3H), 3.39 (s, 3H), 3.40 (s, 3H), 7.12 (s, 1H), 7.63 (s, 1H); 13
C
NMR (CDCl3, 150 MHz) d 28.33, 28.34, 28.66, 33.44, 37.29, 37.37, 105.77,
105.93, 108.06, 143.31, 144.22, 146.86, 150.93, 151.36, 151.60, 160.63, 162.32,
163.22; ESIMS m/z 439 [M++Na]. Anal. Calcd for C18H20N6O6: C, 51.92; H, 4.84;
N, 20.18. Found: C, 52.06; H, 4.71; N, 20.11.
Dimer 4e: 43%; white solid, mp 174–176 °C; IR (KBr) 1730, 1659, 1447,
Dimer 4b: 67%; white solid, mp 174–176 °C; IR (KBr) 2975, 1690, 1639, 1445,
1265 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 4.60 (dd, J = 12.6 and 3.3 Hz, 2H), 4.73
;
1255 cmꢀ1
;
1H NMR (CDCl3, 300 MHz)
d
1.25 (t, J = 7.2 Hz, 6H), 1.37 (t,
(d, J = 13.8 Hz, 2H), 4.75–4.82 (m, 2H), 4.93 (d, J = 13.8 Hz, 2H), 4.90–4.98 (m,
2H), 5.87 (dd, J = 5.1 and 5.1 Hz, 2H), 5.98 (dd, J = 5.1 and 5.1 Hz, 2H), 6.39 (d,
J = 5.1 Hz, 2H), 7.16–7.23 (m, 6H), 7.28–7.47 (m, 18H), 7.52–7.64 (m, 4H), 7.92–
7.97 (m, 4H), 7.98–8.06 (m, 8H), 8.42 (s, 2H); 13C NMR (CDCl3, 75 MHz) d 44.71,
63.96, 70.90, 74.60, 80.45, 88.64, 105.57, 127.64, 128.33, 128.37, 128.50,
128.59, 129.07, 129.27, 129.48, 129.81, 129.97, 133.38, 133.72, 133.81, 136.04,
136.92, 149.56, 160.88, 165.18, 165.26, 165.76 (two carbons were overlapped);
HRMS (ESI+) m/z Calcd for C74H59N4O18 [M++H]: 1291.3825, Found: 1291.3839.
Anal. Calcd for C74H58N4O18: C, 68.83; H, 4.53; N, 4.34. Found: C, 68.67; H, 4.71;
N, 4.18.
J = 7.2 Hz, 6H), 3.90 (q, J = 7.2 Hz, 4H), 4.07 (q, J = 7.2 Hz, 4H), 8.40 (s, 2H); 13C
NMR (CDCl3, 75 MHz) d 12.74, 14.04, 36.92, 45.27, 104.36, 141.99, 149.79,
162.18; ESIMS m/z 357 [M++Na]. Anal. Calcd for C16H22N4O4: C, 57.47; H, 6.63;
N, 16.76. Found: C, 57.76; H, 6.86; N, 16.49.
Dimer 5b: 10%; pale yellow solid, mp 120–122 °C; IR (KBr) 2980, 1700, 1658,
1449, 1340 cmꢀ1 1H NMR (CDCl3, 600 MHz) d 1.20 (t, J = 7.2 Hz, 3H), 1.24 (t,
;
J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.38 (t, J = 7.2 Hz, 3H), 3.48 (br s, 1H), 3.89
(q, J = 7.2 Hz, 2H), 4.01 (br s, 1H), 4.02 (q, J = 7.2 Hz, 2H), 4.06 (q, J = 7.2 Hz, 2H),
5.61 (s, 1H), 7.36 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 12.70, 12.72, 14.24, 14.41,
36.53, 37.14, 42.11, 45.40, 104.65, 108.45, 141.97, 147.07, 150.17, 151.22,
160.19, 162.01; ESIMS m/z 357 [M++Na]. Anal. Calcd for C16H22N4O4: C, 57.47;
H, 6.63; N, 16.76. Found: C, 57.61; H, 6.67; N, 16.52.
10. For the transition metal-catalyzed oxidative coupling of heteroaromatic
compounds and their proposed reaction mechanisms, see: (a) Cho, S. H.;
Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068–5083. and further
references cited therein; (b) Li, Y.; Wang, W.-H.; Yang, S.-D.; Li, B.-J.; Feng, C.;
Shi, Z.-J. Chem. Commun. 2010, 46, 4553–4555; (c) Li, Y.; Jin, J.; Qian, W.; Bao,
W. Org. Biomol. Chem. 2010, 8, 326–330; (d) Xi, P.; Yang, F.; Qin, S.; Zhao, D.;
Lan, J.; Gao, G.; Hu, C.; You, J. J. Am. Chem. Soc. 2010, 132, 1822–1824; (e) Li, Z.;
Wang, Y.; Huang, Y.; Tang, C.; Xu, J.; Wu, X.; Yao, H. Tetrahedron 2011, 67,
5550–5555; (f) Liang, Z.; Zhao, J.; Zhang, Y. J. Org. Chem. 2010, 75, 170–177; (g)
Xia, J.-B.; Wang, X.-Q.; You, S.-L. J. Org. Chem. 2009, 74, 456–458; (h) Truong, T.;
Alvarado, J.; Tran, L. D.; Daugulis, O. Org. Lett. 2010, 12, 1200–1203; (i) Do, H.-
Q.; Daugulis, O. J. Am. Chem. Soc. 2009, 131, 17052–17053; (j) Monguchi, D.;
Yamamura, A.; Fujiwara, T.; Somete, T.; Mori, A. Tetrahedron Lett. 2010, 51,
850–852; (k) Takahashi, M.; Masui, K.; Sekiguchi, H.; Kobayashi, N.; Mori, A.;
Funahashi, M.; Tamaoki, N. J. Am. Chem. Soc. 2006, 128, 10930–10933; (l)
Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2004, 126, 5074–5075.
11. One of the methylene (–CH2–) moiety among the four ethyl groups of 5b
appeared in 1H NMR as two broad singlets presumably due to a restricted
rotation.9
Dimer 4c: 72%; white solid, mp 154–155 °C; IR (KBr) 2961, 1687, 1649, 1446,
1350, 1240 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 0.97 (t, J = 7.5 Hz, 6H), 0.98 (t,
;
J = 7.5 Hz, 6H), 1.61–1.72 (m, 4H), 1.73–1.84 (m, 4H), 3.79 (t, J = 7.5 Hz, 4H),
3.96 (t, J = 7.5 Hz, 4H), 8.40 (s, 2H); 13C NMR (CDCl3, 75 MHz) d 10.89, 11.31,
20.81, 22.41, 43.34, 51.72, 104.06, 142.44, 150.18, 162.34; ESIMS m/z 413
[M++Na]. Anal. Calcd for C20H30N4O4: C, 61.52; H, 7.74; N, 14.35. Found: C,
61.39; H, 7.92; N, 14.21.
Dimer 4d: 52%; white solid, mp 212–214 °C; IR (KBr) 2957, 1690, 1650, 1442,
1268 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 1.95–2.20 (m, 6H), 2.28–2.49 (m, 2H),
;
4.01 (dd, J = 14.7 and 7.5 Hz, 2H), 4.26–4.35 (m, 2H), 5.13 (d, J = 15.6 Hz, 2H),
5.18 (d, J = 15.6 Hz, 2H), 6.08–6.12 (m, 2H), 7.20–7.35 (m, 6H), 7.40–7.51 (m,
4H), 8.26 (s, 1H), 8.36 (s, 1H); 13C NMR (CDCl3, 75 MHz) d (23.74, 23.79), (32.97,
33.07), 44.46, (70.33, 70.38), (88.14, 88.23), (104.31, 104.33), 127.56, (128.36,
128.37), (128.91, 128.97), (136.66, 136.67), (137.58, 137.60), 149.82, (161.94,
161.97); 1H NMR (DMSO-d6, 300 MHz) d 1.84–2.20 (m, 6H), 2.25–2.48 (m, 2H),
3.85–4.05 (m, 2H), 4.10–4.30 (m, 2H), 5.07 (d, J = 16.2 Hz, 2H), 5.13 (d,