Palladium-catalyzed oxidative arylation of trisubstituted olefin: An efficient synthesis of 3-(disubstituted)alkylidene-oxindoles

Article abstract of DOI:10.1016/j.tetlet.2012.10.122

A palladium-catalyzed oxidative arylation of 3-(monosubstituted)alkylidene- oxindoles with arenes afforded 3-(disubstituted)alkylidene-oxindoles in good to moderate yields.

Full text of DOI:10.1016/j.tetlet.2012.10.122

Tetrahedron Letters 54 (2013) 170–175
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
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Palladium-catalyzed oxidative arylation of trisubstituted olefin: an efficient
synthesis of 3-(disubstituted)alkylidene-oxindoles
⇑
Hyun Ju 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:
A palladium-catalyzed oxidative arylation of 3-(monosubstituted)alkylidene-oxindoles with arenes affor-
ded 3-(disubstituted)alkylidene-oxindoles in good to moderate yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 24 September 2012
Revised 22 October 2012
Accepted 29 October 2012
Available online 9 November 2012
Keywords:
Palladium
Oxidative arylation
Chelation
Oxindoles
Tetrasubstituted olefin
The palladium-catalyzed Mizoroki–Heck arylation of olefins
with aryl halides has become a well-established synthetic method
for C–C bond-formation.1 However, the normal intermolecular
Heck reaction did not work well for the synthesis of tetrasubstitut-
ed olefins due to the reluctance of trisubstituted olefins to
participate in the carbopalladation process.1 Increased steric
crowdedness during the insertion of ArPdL species to the hindered
olefin might be an important reason for the failure. As a powerful
variant of the Heck reaction, a palladium(II)-catalyzed oxidative
arylation of olefins with arenes has attracted much attention.2
The oxidative cross-coupling between olefins and arenes, com-
monly known as the Fujiwara–Moritani reaction or simply dehy-
drogenative Heck reaction, circumvents the use of preformed or
less readily accessible aryl halides. However, the reaction also did
not work well for the synthesis of highly-substituted olefins.2 Thus,
the stereo- and regioselective synthesis of highly-substituted ole-
fins is very challenging, and a very limited number of papers have
been reported.3
cyclization of N-arylpropiolamide derivatives, as shown in
Scheme 1.6,7 Zhu and co-workers have reported the synthesis of
3-(diarylmethylenyl)oxindole by a palladium-catalyzed domino
carbopalladation/C–H activation/C–C bond-forming process.6a Li
and co-workers have extended the scope of this reaction to a direct
use of arenes instead of aryl halides.6d Other research groups includ-
ing Player,6h Takemoto,6i–k and Hayashi7b have also used similar
approaches involving the use of N-arylpropiolamide derivatives.
However,
a palladium-catalyzed arylation of 3-(monosubsti-
tuted)alkylidene-oxindole derivatives has not been reported. Dur-
ing the course of our recent studies on the Pd-catalyzed oxidative
arylation of electron-deficient trisubstituted alkenes,8 we found
that the use of an electrophilic ArPd+ intermediate, generated under
the influence of AgOAc/PivOH, and the assistance of a chelation in
the alkylpalladium intermediate were crucial for the successful
arylation. We thought that the trisubstituted alkenyl moiety of
3-(monosubstituted)alkylidene-oxindoles could fulfill such
requirements, and we decided to examine their arylation, as shown
in Scheme 1.
The synthesis of 3-alkylidene-oxindoles has been extensively
studied due to their diverse biological importance.4–7 These com-
pounds could be synthesized by many ways including the Knoeve-
nagel type condensation reaction between oxindole and carbonyl
compounds; however, the yield of product was low to moderate
in most cases even under drastic conditions.4a,h,5b–d Thus, as an
alternative method, 3-(disubstituted)alkylidene-oxindoles have
At the outset of our study, we selected (E)-ethyl 2-(1-methyl-2-
oxoindolin-3-ylidene)acetate (1a) as
a model compound and
examined a palladium-catalyzed phenylation with iodobenzene,
as shown in Table 1. The reaction of 1a and iodobenzene in the
presence of Pd(OAc)2/PPh3/Et3N in DMF (entry 1) afforded very
low yield (15%) of product (2a:3a = 3:1). The yield was not im-
proved by modifying the reaction conditions including base and
solvent (entries 2–4). The yield of product increased to 65% under
the conditions of Chen and co-workers employing AgOAc in acetic
acid (entry 5);1b however, the yield was not still satisfactory. Thus
been prepared most frequently by
a
palladium-catalyzed
⇑
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.
http://dx.doi.org/10.1016/j.tetlet.2012.10.122

H. J. Lee et al. / Tetrahedron Letters 54 (2013) 170–175
171
R2
R2
R2
Ar
Zhu: X = H, ArI/Pd0
Li: X = H, ArH/PdII
X
ArH/PdII
O
O
Player: X = I, ArB(OH)2/Pd0
Hayashi: X = I, ArZnCl/RhI
This Work
N
N
N
O
R1
R1 = H, Me, COMe
2 = COOEt, aryl, Me
R1
R1
R
Scheme 1.
Table 1
Optimization of phenylation of 1a
Ph
EtOOC
EtOOC
COOEt
Ph
O
PhI or PhH
O
O
Conditions
N
Me
N
Me
N
Me
2a
3a
1a
Entry
Conditionsa
2a+3ab (%)
1
2
3
4
5
6
7
8
9
10
PhI (2.0 equiv), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), Et3N (2.0 equiv), DMF, 100 °C, 5 h
PhI (2.0 equiv), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), K2CO3 (2.0 equiv), DMF, 100 °C, 10 h
PhI (2.0 equiv), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), K2CO3 (2.0 equiv), CH3CN, reflux, 36 h
PhI (2.0 equiv), Pd(OAc)2 (5 mol %), TBAC (1.0 equiv), K2CO3 (2.0 equiv), DMF, 100 °C, 5 h
PhI (2.0 equiv), Pd(OAc)2 (5 mol %), AgOAc (1.1 equiv), AcOH (50 equiv), reflux, 5 h
Benzene (60 equiv), Pd(OAc)2 (5 mol %), AgOAc (2.5 equiv), PivOH (6.0 equiv), reflux, 36 h
Benzene (60 equiv), Pd(OAc)2 (5 mol %), AgOAc (4.5 equiv), PivOH (6.0 equiv), reflux, 24 h
Benzene (60 equiv), Pd(OAc)2 (10 mol %), AgOAc (3.5 equiv), PivOH (6.0 equiv), reflux, 24 h
Benzene (60 equiv), Pd(OAc)2 (10 mol %), AgOAc (2.5 equiv), PivOH (6.0 equiv), reflux, 28 h
Benzene (60 equiv), Pd(TFA)2 (5 mol %), AgOAc (2.5 equiv), PivOH (6.0 equiv), reflux, 36 h
15c
45
30d
oc
65
34e
92f
89
78
72
a
Substrate 1a (0.5 mmol) was used.
b
Isolated yield and the ratio of 2a/3a is 3:1 ꢀ 4:1 (based on 1H NMR).
c
d
e
f
Severe decomposition.
1a was recovered in 38%.
1a was recovered in 48%.
Isolated yield of 2a (74%) and 3a (18%).
we examined Pd(II)-catalyzed oxidative phenylation conditions
with benzene in the presence of AgOAc and PivOH (entries
6–10).8 Most of the entries afforded good yields of products; how-
ever, an excess use of AgOAc and/or the use of 10 mol % of Pd(OAc)2
were crucial in order to obtain satisfactory yields of products.
Although an excess amount of AgOAc was required, we selected
the condition of entry 7 as an optimum one and examined the
arylation of 1a–d,9 as shown in Table 2. The reaction of 1a and
p-xylene afforded 2b as a major product in high yield (84%) along
with a low yield (6%) of 3b (entry 2). The reaction of 1a and
o-xylene produced 2c (78%) and 3c (9%) in good combined yield
(entry 3); however, a trace amount of the corresponding regio-
isomer (2,3-dimethylphenyl derivative) was formed together. The
reactions of 5-chloro derivative 1b (entry 4), N-acetyl derivative
1c (entries 5 and 6), and even NH derivative 1d (entry 7) afforded
the corresponding products in good to moderate yields (44–93%).10
The mechanism for the formation of 2a and 3a could be
proposed, as shown in Scheme 2. The formation of the major
product 2a might follow a typical Heck mechanism, that is a
syn-carbopalladation of 1a with PhPd(OPiv) to form a C-Pd
intermediate I, rotation around the C-C single bond, and a syn
b-H elimination process. The minor compound 3a could be formed
from another C-Pd intermediate III that might be formed by an
epimerization process via an O-Pd intermediate II. Such a stereo-
mutation has been frequently observed in many examples11 and
caused the formation of a mixture of stereoisomers (vide infra).
The stereochemistry of the major isomer was confirmed, 2d as
an example (shown in Scheme 2), by NOE experiments.
In order to examine the scope of the arylation reaction we tried
the arylation of 3-arylidene and 3-alkylidene-oxindoles 1e–i,9,5e
and the results are summarized in Table 3. As shown in Table 3,
the reactions of 3-arylidene-oxindoles 1e–h (entries 1–4) required
a longer reaction time and afforded lower yields of 3-(diarylmethy-
lenyl)oxindoles than the ethoxycarbonylmethylene derivatives
1a–d. It is interesting to note that aryl–aryl coupling products 4h
and 4i were formed in low yields (entries 1 and 2). The plausible
mechanism for the formation of 4h is shownin Scheme3 (vide infra).
The corresponding aryl–aryl coupling products were also formed at
the right position on TLC in other entries (entries 3 and 4); however,
they could not be isolated in pure states because the corresponding
cis/trans isomers showed very close mobility on TLC. In the reactions
of 1g and 1h (entries 3 and 4), the minor isomers 3j and 3k were
formed in an increased amount than the ethoxycarbonylmethylene
derivatives 1a–d (Table 2) presumably due to a partial double bond
isomerization of starting material to the Z-isomer under the reaction
conditions.6g The reaction of ethylidene derivative 1i (entry 5)
showed very close reactivity to that of 1a.
The mechanism for the formation of 3-fluoren-9-ylidene-
oxindole derivatives 4h and 4i could be proposed with 4h as an
example, as shown in Scheme 3. The carbopalladation of 1e with
PhPd(OPiv) produced an alkylpalladium intermediate IV. As re-
ported by many research groups,12 1,4-palladium migration from
alkyl to aryl moiety produced an arylpalladium intermediate V. A
subsequent aryl–aryl coupling of V to form VI and the following
Pd(II)-mediated dehydrogenation13 via VII furnished the product
4h. An oxidation of Pd(0) to Pd(II) by AgOAc might carry out the

172
H. J. Lee et al. / Tetrahedron Letters 54 (2013) 170–175
Table 2
Pd-catalyzed oxidative arylation of 1a–da
Entry
Substrate
Conditions
Product (%)
EtOOC
Ph
EtOOC
COOEt
O
Ph
O
Benzene
reflux, 24 h
1
O
N
N
N
Me
Me
Me
1a
2a (74)
Ar1
3a (18)
EtOOC
COOEt
O
Ar1
O
p-Xylene
110 °C, 20 h
2
3
1a
N
N
bMe
Me
b
2b
3b
(6)
(84)
Ar2
EtOOC
COOEt
O
Ar2
O
o-Xylene
110 °C, 12 h
1a
N
N
Me
Me
2c (78)c
3c (9)c,d
EtOOC
Ar1
EtOOC
COOEt
Ar1
O
Cl
Cl
Cl
p-Xylene
110 °C, 12 h
O
4
5
6
7
O
N
Me
N
bMe
N
1b
EtOOC
bMe
Ph
O
2d
Ph
3d
(83)
(10)
EtOOC
COOEt
O
Benzene
reflux, 20 h
O
N
N
N
COMe
COMe
COMe
1c
2e (48)
Ar1
3e (12)
EtOOC
COOEt
O
Ar1
O
p-Xylene
110 °C, 12 h
1c
N
N
COMe
COMe
b
b,e
2f
3f
(-)
(69)
Ar1
EtOOC
EtOOC
COOEt
O
Ar1
O
p-Xylene
110 °C, 20 h
O
N
N
N
H
1d
b H
H
b,e
2g
3g
(-)
(44)
a
b
c
1a–d (0.5 mmol), arene (60 equiv), Pd(OAc)2 (5 mol %), AgOAc (4.5 equiv), PivOH (6.0 equiv).
Ar1 is 2,5-dimethylphenyl.
Ar2 is 3,4-dimethylphenyl.
d
e
A trace amount (<5%) of regioisomer (Ar2 = 2,3-dimethylphenyl) was contaminated.
Failed to isolate.
catalytic cycle. The reaction of 2h under the same reaction
conditions did not produce 4h at all. The result supports the
involvement of a palladium migration mechanism.
carbonyl group at the 2-position of 1a–i and 1k might facilitate
both coordination and insertion of ArPdL species to the C@C double
bond,8 as shown in Scheme 4.
The importance of a carbonyl group at the 2-position of oxin-
doles 1a–i was demonstrated by the following comparison exper-
iments with 1j9g and 1k9e (Scheme 4). The reaction of 1j and
benzene under the same conditions did not produce 2m in any
trace amount. The starting material 1j was recovered in 61% yield
after 40 h. To the contrary, the reaction of 1k afforded 2n (82%) and
4n (6%) in good combined yield. The results stated that the
In summary, an efficient synthesis of 3-(disubstituted)
alkylidene-oxindoles was carried out in good to moderate yields
by a palladium-catalyzed oxidative arylation of 3-(monosubsti-
tuted)alkylidene-oxindoles with arenes. The carbonyl group at
the 2-position of oxindoles might facilitate both coordination and
insertion of arylpalladium species to the trisubstituted C@C double
bond.

H. J. Lee et al. / Tetrahedron Letters 54 (2013) 170–175
173
EtOOC
EtOOC
EtOOC
Ph
Ph
Ph
PhPd(OPiv)
Pd(OPiv)
O
Pd(OPiv)
O
OPd(OPiv)
1a
N
Me
N
N
PhH/PdII/PivOH
Me
Me
I
II
III (C-Pd intermediate)
(C-Pd intermediate)
(O-Pd intermediate)
(i) C-C rotation
(i) C-C rotation
(ii) β-H elim.
(ii) β-H elim.
H
COOEt
O
nOe
Cl
H
2a
3a
(18%)
(74%)
N
Me
2d
Scheme 2.
Table 3
Pd-catalyzed oxidative arylation of 1e–ia
Entry
Substrate
Conditions
Product (%)
Ph
Ph
Ph
O
O
Benzene
reflux, 36 h
N
1
Me
O
1e
N
N
Me
Me
2h (57)
4h (12)
Ph
Cl
Ph
Ph
O
O
Benzene
reflux, 45 h
Cl
Cl
N
Me
2
O
1f
N
N
Me
Me
2i
4i (14)
(56)
Ar3
Ar3
Ph
Ar3
O
Ph
Benzene
reflux, 45 h
3
4
5
O
O
N
N
N
1gb
Me
Me
Me
b
b
2j
3j
(16)
(42)
Ar4
Ph
Ar4
Ar4
O
Ph
O
Benzene
reflux, 45 h
O
N
Me
N
Me
N
Me
1hc
c
3k (13)c,d
2k
(47)
Ar1
Me
Me
O
Ar1
O
O
p-Xylene
110 °C, 12 h
N
Me
N
Me
N
Me
1i
2l (73)e
3l (11)e
a
b
c
1e–h (0.5 mmol), arene (60 equiv), Pd(OAc)2 (5 mol %), AgOAc (4.5 equiv), PivOH (6.0 equiv).
Ar3 is 4-chlorophenyl.
Ar4 is 4-methoxyphenyl.
d
e
A trace amount (ca. 5%) of remaining 1h was contaminated.
Ar1 is 2,5-dimethylphenyl.

174
H. J. Lee et al. / Tetrahedron Letters 54 (2013) 170–175
Ph
Ph
1,4-Pd
Pd(OPiv)
O
migration
PhPd(OPiv)
Pd(OPiv)
O
1e
N
N
Me
IV
Me
V
- Pd0
- PivOH
aryl-aryl
coupling
Pd(OPiv)2
- PivOH
H
4h
O
- Pd0
- PivOH
Pd(OPiv)
O
N
Me
VI
N
Me
VII
Scheme 3.
Ph
Ph
Ph
COOMe
Ph
Ref. 9g
Benzene (60 equiv)
H
H
H
H
N
Pd(OAc)2, PivOH, AgOAc
was recovered in 61% after 40 h)
N
N
O
1j
(
COMe
COMe
2m
Br
1j
Ph
Ph
Benzene (60 equiv)
Pd(OAc)2, PivOH, AgOAc
reflux, 36 h
Ph
O
(i) PhCHO
(ii) Ac2O
O
O
+
N
Ref. 9e
O
N
Ph Ph
Pd
N
H
N
COMe
COMe
COMe
1k
O
2n (82%)
4n (6%)
N
COMe
Scheme 4.
3. For some selected examples on the synthesis of highly-substituted olefins,
see: (a) He, Z.; Kirchberg, S.; Frohlich, R.; Studer, A. Angew. Chem., Int. Ed. 2012,
51, 3699–3702; (b) Kandukuri, S. R.; Schiffner, J. A.; Oestreich, M. Angew.
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Yoshida, J.-i. J. Am. Chem. Soc. 2004, 126, 11778–11779; (d) Itami, K.; Kamei,
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Acknowledgments
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (2012R1A1
B3000541). Spectroscopic data were obtained from the Korea Basic
Science Institute, Gwangju branch.
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4927–4930; (b) Pinto, A.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46,
3291–3295; (c) Pinto, A.; Neuville, L.; Zhu, J. Tetrahedron Lett. 2009, 50, 3602–
3605; (d) Tang, D.-J.; Tang, B.-X.; Li, J.-H. J. Org. Chem. 2009, 74, 6749–6755; (e)
Tang, S.; Peng, P.; Zhong, P.; Li, J.-H. J. Org. Chem. 2008, 73, 5476–5480; (f) Song,
R.-J.; Liu, Y.; Li, R.-J.; Li, J.-H. Tetrahedron Lett. 2009, 50, 3912–3916; (g) Jiang, T.-
S.; Tang, R.-Y.; Zhang, X.-G.; Li, X.-H.; Li, J.-H. J. Org. Chem. 2009, 74, 8834–8837;
(h) Cheung, W. S.; Patch, R. J.; Player, M. R. J. Org. Chem. 2005, 70, 3741–3744;
(i) Yanada, R.; Obika, S.; Oyama, M.; Takemoto, Y. Org. Lett. 2004, 6, 2825–2828;
(j) Yanada, R.; Obika, S.; Kobayashi, Y.; Inokuma, T.; Oyama, M.; Yanada, K.;
Takemoto, Y. Adv. Synth. Catal. 2005, 347, 1632–1642; (k) Yanada, R.; Obika, S.;
Inokuma, T.; Yanada, K.; Yamashita, M.; Ohta, S.; Takemoto, Y. J. Org. Chem.
2005, 70, 6972–6975; (l) Balalaie, S.; Motaghedi, H.; Bararjanian, M.;
Tahmassebi, D.; Bijanzadeh, H. R. Tetrahedron 2011, 67, 9134–9141; (m)
Bararjanian, M.; Balalaie, S.; Rominger, F.; Movassagh, B.; Bijanzadeh, H. R. J.
Org. Chem. 2010, 75, 2806–2812; (n) Ueda, S.; Okada, T.; Nagasawa, H. Chem.
Commun. 2010, 46, 2462–2464.
7. For the other synthetic routes of 3-alkylidene-oxindoles, see: (a) Miura, T.;
Takahashi, Y.; Murakami, M. Org. Lett. 2008, 10, 1743–1745; (b) Shintani, R.;
Yamagami, T.; Hayashi, T. Org. Lett. 2006, 8, 4799–4801; (c) Kamijo, S.; Sasaki,
Y.; Kanazawa, C.; Schusseler, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44,
7718–7721; (d) Tang, S.; Peng, P.; Wang, Z.-Q.; Tang, B.-X.; Deng, C.-L.; Li, J.-H.;
Zhong, P.; Wang, N.-X. Org. Lett. 2008, 10, 1875–1878; (e) Tang, S.; Peng, P.; Pi,
S.-F.; Liang, Y.; Wang, N.-X.; Li, J.-H. Org. Lett. 2008, 10, 1179–1182; (f) Miura,
T.; Takahashi, Y.; Murakami, M. Org. Lett. 2007, 9, 5075–5077.
8. Lee, H. S.; Kim, K. H.; Kim, S. H.; Kim, J. N. Adv. Synth. Catal. 2012, 354, 2419–
2426. and further references cited therein on the palladium-catalyzed
chelation-assisted reactions for the purpose of stereo- and regio-control, and
multiple arylations.
ESIMS m/z 308 [M+H]+. Anal. Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56.
Found: C, 74.21; H, 5.75; N, 4.48.
Compound 2e: 48%; pale yellow solid, mp 142–144 °C; IR (KBr) 1730, 1600,
1461, 1277, 1241 cmÀ1 1H NMR (CDCl3, 300 MHz) d 1.28 (t, J = 7.2 Hz, 3H),
;
2.65 (s, 3H), 4.33 (q, J = 7.2 Hz, 2H), 6.70–6.85 (m, 2H), 7.17–7.24 (m, 1H), 7.38–
7.51 (m, 5H), 8.18 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 13.86, 26.80,
62.10, 116.63, 121.08, 122.93, 124.29, 124.50, 127.65, 129.30, 130.14, 130.77,
133.27, 140.63, 143.04, 166.53, 167.73, 170.59; ESIMS m/z 336 [M+H]+. Anal.
Calcd for C20H17NO4: C, 71.63; H, 5.11; N, 4.18. Found: C, 71.87; H, 5.36; N,
4.03.
Compound 3e: 12%; pale yellow solid, mp 154–156 °C; IR (KBr) 1723, 1600,
1463, 1285, 1241 cmÀ1 1H NMR (CDCl3, 300 MHz) d 1.28 (t, J = 7.2 Hz, 3H),
;
2.51 (s, 3H), 4.35 (q, J = 7.2 Hz, 2H), 7.11 (td, J = 7.8 and 1.2 Hz, 1H), 7.27–7.47
(m, 7H), 8.23 (d, J = 8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 13.91, 26.95, 62.43,
116.70, 121.24, 122.11, 123.43, 124.88, 128.30, 128.40, 129.75, 130.84, 133.09,
139.91, 142.83, 166.15, 167.35, 170.73; ESIMS m/z 336 [M+H]+. Anal. Calcd for
C
20H17NO4: C, 71.63; H, 5.11; N, 4.18. Found: C, 71.92; H, 5.47; N, 4.16.
Compound 2g: 44%; pale yellow oil; IR (film) 3271, 1728, 1615, 1467,
1241 cmÀ1 1H NMR (CDCl3, 300 MHz) d 1.30 (t, J = 7.2 Hz, 3H), 2.22 (s, 3H),
;
2.27 (s, 3H), 4.30 (q, J = 7.2 Hz, 2H), 6.15 (d, J = 7.8 Hz, 1H), 6.62 (td, J = 7.8 and
1.2 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 7.04–7.17 (m, 4H), 8.91 (s, 1H); 13C NMR
(CDCl3, 75 MHz) d 13.92, 18.94, 20.91, 61.80, 110.02, 121.64, 122.22, 123.60,
126.78, 127.56, 130.06, 130.28, 130.59, 132.78, 133.11, 136.32, 141.34, 141.80,
167.86, 167.92; ESIMS m/z 322 [M+H]+. Anal. Calcd for C20H19NO3: C, 74.75; H,
5.96; N, 4.36. Found: C, 74.58; H, 6.12; N, 4.19.
Compound 2h:6e,7b 57%; pale yellow solid, mp 160–162 °C; IR (KBr) 1701, 1607,
1470, 1258 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.11 (s, 3H), 6.34 (d, J = 7.5 Hz,
;
1H), 6.59 (td, J = 7.5 and 1.2 Hz, 1H), 6.67 (d, J = 7.5 Hz, 1H), 7.08 (td, J = 7.5 and
1.2 Hz, 1H), 7.18–7.40 (m, 10H); ESIMS m/z 312 [M+H]+.
Compound 4h: 12%; reddish solid, mp 156–158 °C; IR (KBr) 1691, 1606, 1471,
1261 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.25 (s, 3H), 6.76 (d, J = 7.8 Hz, 1H),
;
6.89 (td, J = 7.8 and 1.2 Hz, 1H), 7.08 (td, J = 7.8 and 1.2 Hz, 1H), 7.14–7.33 (m,
4H), 7.47–7.55 (m, 2H), 8.06 (d, J = 7.8 Hz, 1H), 8.31 (d, J = 7.8 Hz, 1H), 9.03 (dd,
J = 7.8 and 1.2 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 26.10, 108.25, 119.31,
119.97, 121.25, 122.82, 125.11, 126.56, 126.94, 127.46, 128.10, 129.16, 130.22,
131.18, 131.23, 137.48, 137.84, 141.51, 143.11, 144.07, 148.87, 167.64; ESIMS
m/z 310 [M+1]+. Anal. Calcd for C22H15NO: C, 85.41; H, 4.89; N, 4.53. Found: C,
85.23; H, 5.02; N, 4.37.
9. For the synthesis of starting materials and their synthetic applications, see: (a)
Cao, S.-H.; Zhang, X.-C.; Wei, Y.; Shi, M. Eur. J. Org. Chem. 2011, 2668–2672 (For
1a and 1d); (b) Palumbo, C.; Mazzeo, G.; Mazziotta, A.; Gambacorta, A.; Loreto,
M. A.; Migliorini, A.; Superchi, S.; Tofani, D.; Gasperi, T. Org. Lett. 2011, 13,
6248–6251 (For 1a and 1b); (c) Tan, B.; Zeng, X.; Leong, W. W. Y.; Shi, Z.;
Barbas, C. F., III; Zhong, G. Chem. Eur. J. 2012, 18, 63–67 (For 1c); (d) Teichert, A.;
Jantos, K.; Harms, K.; Studer, A. Org. Lett. 2004, 6, 3477–3480 (For 1e and 1h);
(e) Voituriez, A.; Pinto, N.; Neel, M.; Retailleau, P.; Marinetti, A. Chem. Eur. J.
2010, 16, 12541–12544 (For 1e and 1k); (f) Lopez-Alvarado, P.; Avendano, C.
Synthesis 2002, 104–110 (For 1i); (g) Kim, H. S.; Lee, H. S.; Kim, S. H.; Kim, J. N.
Tetrahedron Lett. 2009, 50, 3154–3157 (For 1j). The starting materials were
prepared according to the reported methods, and 1a–e and 1g–k were
known9,5e and the spectroscopic data of unknown compound 1f are as follows
Compound 1f: pale yellow solid, mp 140–142 °C; IR (KBr) 1703, 1608, 1482,
Compound 2l: 73%; pale yellow oil; IR (film) 1700, 1607, 1470, 1254 cmÀ1 1H
;
NMR (CDCl3, 300 MHz) d 2.02 (s, 3H), 2.25 (s, 3H), 2.67 (s, 3H), 3.19 (s, 3H),
5.83 (d, J = 7.8 Hz, 1H), 6.56 (td, J = 7.8 and 1.2 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H),
6.79 (s, 1H), 7.00–7.14 (m, 3H); 13C NMR (CDCl3, 75 MHz) d 18.32, 20.91,
21.97, 25.59, 107.26, 121.68, 122.32, 122.69, 123.46, 126.15, 127.94, 128.70,
129.98, 130.53, 136.29, 142.06, 142.09, 154.75, 167.96; ESIMS m/z 278
[M+H]+. Anal. Calcd for C19H19NO: C, 82.28; H, 6.90; N, 5.05. Found: C,
82.34; H, 6.68; N, 4.94.
Compound 3l: 11%; pale yellow oil; IR (film) 1709, 1607, 1469, 1255 cmÀ1 1H
;
NMR (CDCl3, 300 MHz) d 2.08 (s, 3H), 2.25 (s, 3H), 2.48 (s, 3H), 3.06 (s, 3H),
6.72–6.80 (m, 2H), 6.94–7.10 (m, 3H), 7.23 (td, J = 7.8 and 1.2 Hz, 1H), 7.60 (d,
J = 7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 18.88, 21.09, 24.61, 25.58, 107.68,
121.61, 123.09, 123.74, 123.98, 126.18, 128.11, 128.37, 129.83, 130.10, 135.15,
142.90, 143.36, 152.84, 166.02; ESIMS m/z 278 [M+H]+. Anal. Calcd for
1270 cmÀ1
;
1H NMR (CDCl3, 300 MHz) d 3.15 (s, 3H), 6.62 (d, J = 8.4 Hz, 1H),
C
19H19NO: C, 82.28; H, 6.90; N, 5.05. Found: C, 82.41; H, 7.05; N, 5.12.
Compound 4n: 6%; reddish solid; mp 212–214 °C (dec.); IR (KBr) 1717, 1598,
1460, 1276 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.72 (s, 3H), 7.00–7.12 (m, 2H),
7.11 (dd, J = 8.4 and 2.1 Hz, 1H), 7.31–7.43 (m, 3H), 7.45–7.54 (m, 3H), 7.78 (s,
1H); 13C NMR (CDCl3, 75 MHz) d 26.25, 108.96, 122.42, 122.76, 126.28, 127.09,
128.80, 129.21, 129.33, 129.99, 134.39, 138.80, 142.66, 168.04; ESIMS m/z 270
[M+H]+, 272 [M+H+2]+. Anal. Calcd for C16H12ClNO: C, 71.25; H, 4.48; N, 5.19.
Found: C, 71.41; H, 4.33; N, 5.08.
;
7.14–7.38 (m, 4H), 7.40–7.54 (m, 2H), 8.10 (d, J = 8.1 Hz, 1H), 8.23 (d,
J = 8.1 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H), 8.69 (d, J = 7.8 Hz, 1H); 13C NMR (CDCl3,
75 MHz)
d 27.09, 116.71, 119.64, 120.15, 124.02, 124.05, 124.70, 125.75,
10. Typical procedure for the synthesis of 2a and 3a: A stirred mixture of 1a (116 mg,
0.5 mmol), Pd(OAc)2 (5.6 mg, 5 mol %), AgOAc (377 mg, 2.25 mmol), and PivOH
(307 mg, 3.0 mmol) in benzene (2.7 mL, 60 equiv) was heated to reflux for 24 h
under N2 balloon atmosphere. After the aqueous extractive workup and
column chromatographic purification process (hexanes/Et2O, 2:1) compounds
2a (114 mg, 74%) and 3a (28 mg, 18%) were obtained as pale yellow oils. Other
compounds were synthesized similarly, and the selected spectroscopic data of
2a, 3a, 2e, 3e, 2g, 2h, 4h, 2l, 3l, and 4n are as follows.
126.08, 127.29, 128.18, 129.36, 130.61, 131.82, 132.00, 137.17, 137.42, 139.96,
142.08, 143.12, 150.56, 167.28, 171.05; ESIMS m/z 338 [M+H]+. Anal. Calcd for
C
23H15NO2: C, 81.88; H, 4.48; N, 4.15. Found: C, 81.74; H, 4.66; N, 4.01.
11. For the stereo-mutation via an O-Pd intermediate, see: (a) Ikeda, M.; El Bialy, S.
A. A.; Yakura, T. Heterocycles 1999, 51, 1957–1970. and further references cited
therein; (b) Cropper, E. L.; White, A. J. P.; Ford, A.; Hii, K. K. J. Org. Chem. 2006,
71, 1732–1735. When we subjected the reaction mixture of 1a for a longer
time (48 h) the ratio between 2a and 3a was not changed. In addition, we could
not observe the formation of 3a in any trace amount when we subjected 2a to
the palladium-catalyzed arylation reaction conditions. The results stated that
the possibility for the Pd-catalyzed isomerization between 2a and 3a would be
low.
12. For the alkyl to aryl 1,4-palladium migration, see: (a) Huang, Q.; Fazio, A.; Dai,
G.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 7460–7461; (b)
Wang, L.; Pan, Y.; Jiang, X.; Hu, H. Tetrahedron Lett. 2000, 41, 725–727; (c) Ma,
S.; Gu, Z. Angew. Chem., Int. Ed. 2005, 44, 7512–7517. and further references
cited therein.
Compound 2a: 74%; pale yellow oil; IR (film) 1712, 1609, 1470, 1256,
1230 cmÀ1 1H NMR (CDCl3, 300 MHz) d 1.28 (t, J = 7.2 Hz, 3H), 3.15 (s, 3H),
;
4.32 (q, J = 7.2 Hz, 2H), 6.62–6.74 (m, 3H), 7.11–7.18 (m, 1H), 7.37–7.45 (m,
3H), 7.45–7.52 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 13.90, 25.91, 61.94, 108.15,
120.54, 121.83, 123.36, 125.42, 127.91, 129.05, 129.75, 130.32, 133.66, 141.47,
144.39, 166.18, 168.03; ESIMS m/z 308 [M+H]+. Anal. Calcd for C19H17NO3: C,
74.25; H, 5.58; N, 4.56. Found: C, 74.51; H, 5.63; N, 4.36.
Compound 3a: 18%; pale yellow oil; IR (film) 1713, 1607, 1470, 1262 cmÀ1 1H
;
NMR (CDCl3, 300 MHz) d 1.28 (t, J = 7.2 Hz, 3H), 3.08 (s, 3H), 4.34 (q, J = 7.2 Hz,
2H), 6.73 (d, J = 7.8 Hz, 1H), 6.94 (td, J = 7.8 and 1.2 Hz, 1H), 7.25 (td, J = 7.8 and
1.2 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.32–7.38 (m, 3H), 7.40–7.48 (m, 2H); 13C
NMR (CDCl3, 75 MHz) d 13.95, 25.83, 62.15, 108.16, 120.60, 122.16, 122.76,
124.85, 128.14, 128.53, 129.36, 130.43, 133.23, 141.26, 143.79, 165.97, 167.70;
13. For Pd(II)-catalyzed oxidation of a,b-position of carbonyl compounds, see: (a)
Muzart, J. Eur. J. Org. Chem. 2010, 3779–3790. and further references cited
therein; (b) Giri, R.; Maugel, N.; Foxman, B. M.; Yu, J.-Q. Organometallics 2008,
27, 1667–1670.