Vinylogous N,N-dimethylaminomethylenation of 3-[(1-substituted)ethylidene]- oxindoles with N,N-dimethylformamide dimethylacetal

Article abstract of DOI:10.1016/j.tetlet.2014.02.130

An efficient stereoselective synthesis of various 3-(3-dimethylaminoprop-2- enylidene)oxindoles has been disclosed. The compounds were synthesized via a vinylogous N,N-dimethylaminomethylenation at the γ-position of 3-[(1-substituted)ethylidene]oxindoles with DMF-DMA.

Full text of DOI:10.1016/j.tetlet.2014.02.130

Tetrahedron Letters 55 (2014) 2450–2454
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Vinylogous N,N-dimethylaminomethylenation of
3-[(1-substituted)ethylidene]-oxindoles with
N,N-dimethylformamide dimethylacetal
Hyun Ju Lee a, Sangku Lee b, Jin Yu a, Jae Nyoung Kim a,
⇑
a Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
b Immune Modulator Research Center, KRIBB, Daejeon 305-806, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient stereoselective synthesis of various 3-(3-dimethylaminoprop-2-enylidene)oxindoles has
Received 26 January 2014
Revised 27 February 2014
Accepted 28 February 2014
Available online 7 March 2014
been disclosed. The compounds were synthesized via a vinylogous N,N-dimethylaminomethylenation
at the c-position of 3-[(1-substituted)ethylidene]oxindoles with DMF-DMA.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
3-Alkylideneoxindoles
Vinylogous N,N-
dimethylaminomethylenation
DMF-DMA
Stereoselective
3-Alkylideneoxindole derivatives have been received much
attention due to their diverse biological activities and synthetic
applicability.1–3 Recently, we also reported an efficient synthesis of
3-alkylideneoxindoles via Ti(OiPr)4/pyridine-mediated Knoevenagel
condensation between oxindole and various carbonyl compounds.4
In addition, the alkylidene moiety of 3-alkylideneoxindoles could be
further functionalized to make biologically potent substances.5,6 As
some examples, Michael type Cb-functionalization to b-substituted
oxindoles I,5a,b [3+2] trimethylenemethane cycloaddition to 3,3-spi-
rocyclic compounds II,2h,5c and Michael/Michael/aldol annulation
cascade to spirocycles III5a,b have been reported as depicted in
Scheme 1. Very recently, Casiraghi and co-workers have reported an
interesting vinylogous Michael addition to make IV6a,b and vinylo-
Balalaie and co-workers have also reported the synthesis via a
sequential one-pot Ugi/Heck carbocyclization, Sonogashira cou-
pling and Michael addition protocol.8c
In these contexts, we presumed that 3-(3-dimethylaminoprop-
2-enylidene)oxindole 2 (Scheme 1) could be synthesized from 3-
[(1-substituted)ethylidene]oxindole and N,N-dimethylformamide
dimethylacetal (DMF-DMA).9,10 As exemplified with 3-alkylidene-
oxindole 1a in Scheme 2, our rationale was based on the fact that
the hydrogen of a methyl group of 1a could be deprotonated easily
by a trace amount of methoxide ion, present in small amount in
DMF-DMA, to form the dienolate ion VI.6,10 Subsequently, the dien-
olate VI could react with the iminium ion to form 2a via a vinylo-
gous N,N-dimethylaminomethylenation reaction.9
Thus, the reaction of 1a-E and DMF-DMA (2.0 equiv) was exam-
ined in DMF at 80 °C for 1 h. In the reaction, a desired product 2a-E
was obtained in good yield (85%).11 The stereochemistry of 2a-E
was confirmed by comparing its 1H NMR data with the reported.4,8
The proton at the C-4 position of 2a-E appeared quite upfield
(d = 5.44 ppm) due to shielding effect of the phenyl ring. To our
surprise, the corresponding 2a-Z was not formed in any trace
amount. The favorable electrostatic interaction between the dien-
olate VI and the iminium ion might be the reason for the stereose-
lective carbonAcarbon bond formation. Accordingly, the reaction
of 1a-Z4 and DMF-DMA was examined under the same reaction
conditions. Compound 2a-E was obtained again in a slightly lower
yield (78%). The proton abstraction of 1a-Z produced a dienolate
gous Mukaiyama-type aldol reaction to V.6c The successful
c-func-
tionalization of Casiraghi group could be achieved because of the
vinylogous pro-nucleophilic character of the alkyl-group.6a
In addition, various 3-aminomethyleneoxindoles have been
known to possess many interesting biological activities.7 However,
synthesis and biological activity of
a two-carbon increased
homolog, 3-(3-aminoprop-2-enylidene)oxindoles, have not been
studied much.8 Muller and co-workers reported the synthesis of
3-(3-aminoprop-2-enylidene)oxindoles via a sequential cyclocar-
bopalladation, Sonogashira coupling, and Michael addition.8a,b
⇑
Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).
http://dx.doi.org/10.1016/j.tetlet.2014.02.130
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

H. J. Lee et al. / Tetrahedron Letters 55 (2014) 2450–2454
2451
R3
R2
R2
R3
EWG
NC
R2
R2
CHO
R4
β
α
O
O
O
N
O
N
N
R1
N
R1
R1
R1
III
I
II
R3
3
NMe2
γ
HO
R2
R3
β
R2
R2
NO2
CH3
R2
2
1
3(α)
O
O
2
R1
O
N
O
1
N
N
N
R1
R1
2
R1
IV
V
3-[(1-substituted)
3-(3-dimethylaminoprop
-2-enylidene)oxindole
ethylidene]oxindole
Scheme 1.
OMe
OMe
OMe
N
OMe
N
OMe
N
MeO
Ph
H
NMe2
- MeOH
NMe2
OMe
N
Ph
OMe
γ
δ=5.44
H
Ph
Ph
β
H
H
MeO
α
O
O
O
O
MeOH
N
N
H
N
H
N
1a-E
H
VI
H
(s-cis)
2a
-E
C-C rotation (α−β)
OMe
N
Me2N
Me2N
OMe
H
H
H
MeOH
Ph
Ph
Ph
Ph
N
MeO
MeO
O
O
O
MeOH
O
2a-Z
N
H
N
H
N
N
VII
(s-trans)
2a-Z
VIII
H
1a-Z
H
Scheme 2.
VII, but this dienolate cannot react with the iminium ion in its s-
trans form. Thus s-trans dienolate VII has to be converted to s-cis
dienolate VI via the CAC bond rotation. Otherwise, 1a-Z has to
be isomerized to 1a-E by addition/elimination mechanism of some
nucleophilic species such as methoxide ion.4 Actually, 1a-Z was
isomerized to 1a-E in the presence of DMF-DMA even at room tem-
perature within 1 h, and the formation of 2a-E was also observed
during the isomerization process, albeit in a trace amount. The
isomerization of 1a-Z to 1a-E occurred more rapidly in the pres-
ence of NaOMe in MeOH at room temperature. However, we could
not exclude the following reaction pathway for the conversion of
1a-Z to 2a-E at this stage: the formation of a dienolate VII, the reac-
tion of VII with iminium ion to form 2a-Z, and an isomerization to
2a-E via the mesomeric structure VIII.9d
of 5-chlorooxindole derivative 1d (entry 5), 1-(naphthalen-2-
yl)ethylidene derivative 1e (entry 6), and 1-(thiophen-2-yl)ethyli-
dene derivative 1f (entry 7) gave 2d–f in high yields (82–85%).
When we used the isopropylidene derivative 1g (entry 8), the yield
of 2g was somewhat low (59%) due to the formation of some side
products. The use of 1.0 equiv of DMF-DMA at 50 °C was crucial.
Otherwise, further reactions of 2g made the reaction mixture
somewhat complex. In addition, a trace amount of 2g-E was
formed together in around 10% based on its 1H NMR spectrum;
however, we cannot separate them. The reaction of an ester deriv-
ative 1h-E (entry 9) afforded the desired product 2h in good yield
(78%); however, 2h was obtained as an inseparable mixture of E/Z
isomers (1:1). The reason for the formation of E/Z mixture is not
clear at this stage.
Encouraged by the results, the reactions of various 3-alkylid-
eneoxindoles 1b–h and DMF-DMA were examined. The results
are summarized in Table 1. The reaction of N-methyl derivative
1b (entry 3) afforded 2b in good yield (89%). The reaction of N-
acetyl derivative 1c (entry 4) produced 2c in good yield (77%) along
with a low yield (8%) of N-deacetylated product 2a-E. The reactions
Unfortunately, the reaction of 1a and N,N-dimethylacetamide
dimethylacetal (DMA-DMA) failed, as shown in Scheme 3. The
reaction was sluggish and almost no reaction was observed below
80 °C. A severe decomposition to intractable side products was ob-
served at elevated temperature (>100 °C), and we could not iden-
tify nor isolate the expected compound 2i in a reasonable yield.

2452
H. J. Lee et al. / Tetrahedron Letters 55 (2014) 2450–2454
Table 1
Synthesis of 3-(3-dimethylaminoprop-2-enylidene) oxindolesa
Entry
Substrate
Product (%)
Entry
Substrate
Product (%)
Ph
NMe2
Me
O
Ph
NMe2
Me
O
1
6
O
N
N
H
1a-E
H
O
2a-E (85)
N
H
N
H
2e
-E (82)
1e-E
Me
NMe2
Ph
O
S
S
Me
O
2
3
2a-E (78)
N
O
1a-Z
H
N
H
N
H
2f-E (85)
7
Ph
Ph
NMe2
1f-E
Me
O
Ph
N
O
O
N
Me
1b-E
2b-E (89)
Me
NMe2
Me
NMe2
Me
Me
Ph
Me
O
O
O
4
5
8
9
N
O
N
2c
2a
-E (77)
-E (8)
N
N
1g
O
b
2g-Z (59)c
1c-E
O
O
Ph
NMe2
EtOOC
NMe2
Me
O
Me
O
Ph
EtOOC
Cl
Cl
O
O
N
H
N
H
N
H
N
H
1d-E
1h-E
2h (78)d
2d
-E (82)
a Conditions: 1 (0.5 mmol), DMF-DMA (2.0 equiv), DMF, 80 °C, 1 h.
b N-deacetylated product 2a-E was isolated in low yield (8%).
c DMF-DMA (1.0 equiv) was used at 50 °C for 1 h, and 2g-E (ca. 10%) was mixed together.
d E/Z mixture (1:1) based on 1H NMR.
Me
OMe
Me
O
NMe2
as shown in Scheme 4. It is interesting to note that an acetyl deriv-
ative 3 was formed, albeit in low yield (5%), presumably via an aer-
Ph
Ph
N
DMA-DMA
(2.0 equiv)
obic oxidation at the
c-position of the dienolate X, although the
reaction was carried out under N2 balloon atmosphere.12,13 Actu-
ally, the oxidation of 1i proceeded in good yield (82%) in MeOH
in the presence of NaOMe (0.3 equiv) under O2 balloon atmosphere
at 50 °C for 6 h. The aerobic oxidation proceeded even at room
temperature although somewhat slowly.
1a
-E
O
N
H
DMF
N
H
80 oC, 2 h
IX (s-cis)
2i
Scheme 3.
As a next entry, we examined the reaction of 3-[(1-unsubstitut-
ed)ethylidene]oxindole such as ethylidene derivative 1j under the
same reaction conditions, as shown in Scheme 5. Unfortunately,
we could not obtain the corresponding product in a reasonable
yield because of the formation of many side products. Casiraghi
and co-workers also did not examine such an entry in their vinylo-
gous functionalizations.6 The different reactivity of ethylidene
As shown in Scheme 3, an unfavorable steric hindrance between
the -position of IX and the iminium ion would make the reaction
difficult.
Similarly, the reaction of 1-phenylpropylidene derivative 1i
c
with DMF-DMA also failed presumably by the same steric reason,
Me
OMe
N
nOe
Me
Ph
O
NMe2
Me
Ph
Ph
Ph
γ
H
DMF-DMA
(2.0 equiv)
NaOMe
Me
(0.3 equiv)
O2
O
3
O
+
O
O
(82%)
N
H
MeOH
DMF
N
H
N
N
50 oC, 6 h
O2 balloon
80 oC, 3 h
N2 balloon
H
-E
H
1i
X
(s-cis)
3 (5%)
2j (not formed)
Scheme 4.

H. J. Lee et al. / Tetrahedron Letters 55 (2014) 2450–2454
2453
Andersson, C. J. Med. Chem. 2005, 48, 5412–5414; (i) Singh, P.; Kaur, M.; Holzer,
W. Eur. J. Med. Chem. 2010, 45, 4968–4982.
4. For the synthesis of 3-alkylideneoxindole derivatives by Ti/pyridine, see: Lee,
H. J.; Lim, J. W.; Yu, J.; Kim, J. N. Tetrahedron Lett. 2014, 55, 1183–1187. and
further references cited therein.
Me
DMF-DMA
(1.0-2.5 equiv)
complex
O
DMF, 50-80 oC
N
5. For the selected examples on the functionalizations at the a- and b-positions of
Me
3-alkylideneoxindole derivatives, see: (a) Bencivenni, G.; Wu, L.-Y.; Mazzanti,
A.; Giannichi, B.; Pesciaioli, F.; Song, M.-P.; Bartoli, G.; Melchiorre, P. Angew.
Chem., Int. Ed. 2009, 48, 7200–7203; (b) Jiang, K.; Jia, Z.-J.; Chen, S.; Wu, L.;
Chen, Y.-C. Chem. Eur. J. 2010, 16, 2852–2856; (c) Trost, B. M.; Cramer, N.;
Bernsmann, H. J. Am. Chem. Soc. 2007, 129, 3086–3087; (d) Jia, Z.-J.; Jiang, H.; Li,
J.-L.; Gschwend, B.; Li, Q.-Z.; Yin, X.; Grouleff, J.; Chen, Y.-C.; Jorgensen, K. A. J.
Am. Chem. Soc. 2011, 133, 5053–5061; (e) Pesciaioli, F.; Righi, P.; Mazzanti, A.;
Bartoli, G.; Bencivenni, G. Chem. Eur. J. 2011, 17, 2842–2845; (f) Allous, I.;
Comesse, S.; Sanselme, M.; Daich, A. Eur. J. Org. Chem. 2011, 5303–5310; (g)
Wei, Q.; Gong, L.-Z. Org. Lett. 2010, 12, 1008–1011.
1j-E
Scheme 5.
N
Ph
piperidine (6.0 equiv)
6. For the vinylogous Michael addition of 3-alkylideneoxindoles to nitroolefins,
see: (a) Curti, C.; Rassu, G.; Zambrano, V.; Pinna, L.; Pelosi, G.; Sartori, A.;
Battistini, L.; Zanardi, F.; Casiraghi, G. Angew. Chem., Int. Ed. 2012, 51, 6200–
6204; (b) Rassu, G.; Zambrano, V.; Pinna, L.; Curti, C.; Battistini, L.; Sartori, A.;
Pelosi, G.; Zanardi, F.; Casiraghi, G. Adv. Synth. Catal. 2013, 355, 1881–1886; Z-
Alkylidene product was formed selectively in the reactions. For the vinylogous
Mukaiyama-type aldol reaction between aromatic aldehyde and 3-alkenyl-2-
silyloxyindoles, see: (c) Rassu, G.; Zambrano, V.; Tanca, R.; Sartori, A.; Battistini,
L.; Zanardi, F.; Curti, C.; Casiraghi, G. Eur. J. Org. Chem. 2012, 466–470; Very
iPrOH/DMF (1:1), 90 oC, 5 h
- Me2NH
2a-E
+ 2a-E (14%)
O
N
H
4 (78%)
Scheme 6.
recently, vinylogous Mukaiyama-type Mannich reaction on
c-enolizable 3-
alkylideneoxindoles has been reported, (d) Ranieri, B.; Sartori, A.; Curti, C.;
Battistini, L.; Rassu, G.; Pelosi, G.; Casiraghi, G.; Zanardi, F. Org. Lett. 2014, 16,
932–935.
derivative 1j as compared to that of 3-[(1-substituted)ethyli-
dene]oxindoles 1a–h is not clear at this stage.
7. For the synthesis and biological activity of 3-aminomethyleneoxindoles, see:
(a) Cantagrel, G.; de Carne-Carnavalet, B.; Meyer, C.; Cossy, J. Org. Lett. 2009, 11,
4262–4265; (b) Bararjanian, M.; Hosseinzadeh, S.; Balalaie, S.; Bijanzadeh, H.
R.; Wolf, E. Tetrahedron Lett. 2011, 52, 3329–3332; (c) Sarges, R.; Howard, H. R.;
Koe, B. K.; Weissman, A. J. Med. Chem. 1989, 32, 437–444; (d) Kumar, S. P.; Gut,
J.; Guedes, R. C.; Rosenthal, P. J.; Santos, M. M. M.; Moreira, R. Eur. J. Med. Chem.
2011, 46, 927–933; (e) Bouchikhi, F.; Rossignol, E.; Sancelme, M.; Aboab, B.;
Anizon, F.; Fabbro, D.; Prudhomme, M.; Moreau, P. Eur. J. Med. Chem. 2008, 43,
2316–2322; (f) Park, S.-J.; Cho, C.-G.; Lee, K.-I. Bull. Korean Chem. Soc. 2004, 25,
349–350; (g) Pedras, M. S. C.; Jha, M. J. Org. Chem. 2005, 70, 1828–1834.
8. For the synthesis and applications of 3-(3-aminoprop-2-enylidene)oxindoles,
see: (a) D’Souza, D. M.; Muschelknautz, C.; Rominger, F.; Muller, T. J. J. Org. Lett.
2010, 12, 3364–3367; (b) Muschelknautz, C.; Mayer, B.; Rominger, F.; Muller, T.
J. J. Chem. Heterocycl. Compd. 2013, 49, 860–871; (c) Bararjanian, M.; Balalaie, S.;
Rominger, F.; Movassagh, B.; Bijanzadeh, H. R. J. Org. Chem. 2010, 75. 2806–
2012; (d) Beccalli, E. M.; Clerici, F.; Marchesini, A. Tetrahedron 2001, 57, 4787–
4792.
As a last entry, we examined the synthesis of piperidinyl deriv-
ative 4 from N,N-dimethyl derivative 2a and piperidine, as shown
in Scheme 6. The reversible reaction afforded 4 in good yield
(78%) when we used 6.0 equiv of piperidine, along with recovered
starting material in 14% yield.7d–f
In summary, an efficient and stereoselective synthesis of vari-
ous 3-(3-dimethylaminoprop-2-enylidene)oxindoles has been car-
ried out by the vinylogous N,N-dimethylaminomethylenation at
the c-position of 3-alkylideneoxindoles with DMF-DMA.
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
(2012R1A1B3000541). Spectroscopic data were obtained from
the Korea Basic Science Institute, Gwangju branch.
9. For some selected examples on aminomethylenation of active methyl or
methylene compounds, see: (a) Villemin, D.; Belhadj, Z.; Cheikh, N.;
Choukchou-Braham, N.; Bar, N.; Lohier, J.-F. Tetrahedron Lett. 2013, 54, 1664–
1668; (b) Cartier, D.; Valla, A.; Guillou, R. L.; Labia, R.; Potier, P. Eur. J. Org. Chem.
2003, 2250–2253; (c) Ishichi, Y.; Ikeura, Y.; Natsugari, H. Tetrahedron 2004, 60,
4481–4490; (d) Hvala, A.; Sorsak, L. J.; Sorsak, G.; Bratusek, U.; Svete, J.; Lah, N.;
Leban, I.; Stanovnik, B. Heterocycles 2002, 57, 791–809; (e) Conreaux, D.;
Bossharth, E.; Monteiro, N.; Desbordes, P.; Balme, G. Tetrahedron Lett. 2005, 46,
7917–7920; (f) Melikyan, G.; Piroyan, A. ARKIVOC 2006, iv, 234–239.
10. For our related papers involving the use of DMF-DMA, see: (a) Lee, K. Y.; Lee, M.
J.; Gowrisankar, S.; Kim, J. N. Tetrahedron Lett. 2004, 45, 5043–5046; (b) Kim, T.
Y.; Kim, H. S.; Lee, K. Y.; Kim, J. N. Bull. Korean Chem. Soc. 1999, 20, 1255–1256;
(c) Lee, H. J.; Kim, H. S.; Kim, J. N. Tetrahedron Lett. 1999, 40, 4363–4366.
11. The starting materials 1a–j were prepared according to the reported
methods.3,4
References and notes
1. For the synthesis of 3-alkylideneoxindoles and their biological activity, see: (a)
Millemaggi, A.; Taylor, R. J. K. Eur. J. Org. Chem. 2010, 4527–4547. and further
references cited therein; (b) Prakash, C. R.; Theivendren, P.; Raja, S. Pharmacol.
Pharm. 2012, 3, 62–71; (c) Sun, L.; Tran, N.; Tang, F.; App, H.; Hirth, P.;
McMahon, G.; Tang, C. J. Med. Chem. 1998, 41, 2588–2603.
2. For the synthetic applications of 3-alkylideneoxindole derivatives, see: (a) Lin,
S.; Yang, Z.-Q.; Kwok, B. H. B.; Koldobskiy, M.; Crews, C. M.; Danishefsky, S. J. J.
Am. Chem. Soc. 2004, 126, 6347–6355; (b) Fukuyama, T.; Liu, G. J. Am. Chem. Soc.
1996, 118, 7426–7427; (c) Ramachary, D. B.; Venkaiah, C.; Krishna, P. M. Org.
Lett. 2013, 15, 4714–4717; (d) Huang, X.-F.; Liu, Z.-M.; Geng, Z.-C.; Zhang, S.-Y.;
Wang, Y.; Wang, X.-W. Org. Biomol. Chem. 2012, 10, 8794–8799; (e) Ball-Jones,
N. R.; Badillo, J. J.; Franz, A. K. Org. Biomol. Chem. 2012, 10, 5165–5181; (f)
Viswambharan, B.; Selvakumar, K.; Madhavan, S.; Shanmugam, P. Org. Lett.
2010, 12, 2108–2111; (g) Chen, X.-H.; Wei, Q.; Luo, S.-W.; Xiao, H.; Gong, L.-Z. J.
Am. Chem. Soc. 2009, 131, 13819–13825; (h) Trost, B. M.; Cramer, N.; Silverman,
S. M. J. Am. Chem. Soc. 2007, 129, 12396–12397; (i) Carroll, W. A.; Grieco, P. A. J.
Am. Chem. Soc. 1993, 115, 1164–1165; (j) Lee, H. J.; Kim, K. H.; Kim, S. H.; Kim, J.
N. Tetrahedron Lett. 2013, 54, 170–175.
3. For the synthesis of 3-alkylideneoxindole derivatives under the influence of a
base including amines, see: (a) Du, T.-P.; Zhu, G.-G.; Zhou, J. Lett. Org. Chem.
2012, 9, 225–232; (b) Villemin, D.; Martin, B. Synth. Commun. 1998, 28, 3201–
3208; (c) Obase, H.; Nakamizo, N.; Takai, H.; Teranishi, M.; Kubo, K.; Shuto, K.;
Kasuya, Y.; Shigenobu, K.; Hashikami, M. Chem. Pharm. Bull. 1983, 31, 3186–
3197; (d) Chen, L.; Feng, L.; Huang, M.; Li, J.; Nan, F.; Pang, T.; Yu, L.; Zhang, M.
WO 2011/033099; Chem. Abstr. 2011, 154, 360857.; (e) Bouerat, L. M. E.;
Fensholdt, J.; Nielsen, S. F.; Liang, X.; Havez, S. E.; Andersson, E. C.; Jensen, L.;
Hansen, J. R. WO 2005/058309, 2005; Chem. Abstr. 2005, 143, 97259.; (f)
Asahara, H.; Kida, T.; Hinoue, T.; Akashi, M. Tetrahedron 2013, 69, 9428–9433;
(g) Zhang, W.; Go, M.-L. Bioorg. Med. Chem. 2009, 17, 2077–2090; (h) Bouerat,
L.; Fensholdt, J.; Liang, X.; Havez, S.; Nielsen, S. F.; Hansen, J. R.; Bolvig, S.;
Typical procedure for the synthesis of 2a-E:
A mixture of 1a-E (118 mg,
0.5 mmol) and DMF-DMA (120 mg, 1.0 mmol) in DMF (1.0 mL) was heated to
80 °C for 1 h under N2 balloon atmosphere. After the aqueous extractive
workup and column chromatographic purification process (CH2Cl2/EtOAc, 2:1)
compound 2a-E was obtained as an orange solid, 123 mg (85%). Other
compounds 2b–h were synthesized analogously and the selected
spectroscopic data of 2a, 2b, 2e, 2f, 3, and 4 are as follows. It is interesting
to note that the 13C NMR peak of the carbon atom of N,N-dimethylamino group
was not observed due to severe line-broadening effect.14
Compound 2a-E: 85%; orange solid, mp 266–268 °C; IR (KBr) 1646, 1620, 1515,
1409 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.97 (s, 6H), 5.44 (d, J = 7.8 Hz, 1H),
;
6.39 (d, J = 13.2 Hz, 1H), 6.51 (t, J = 7.8 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 6.89 (t,
J = 7.8 Hz, 1H), 7.20–7.30 (m, 2H), 7.44–7.54 (m, 3H), 7.62 (d, J = 13.2 Hz, 1H),
7.72 (br s, 1H); 13C NMR (CDCl3, 75 MHz) d 100.52, 108.27, 109.69, 120.36,
120.79, 124.00, 125.98, 127.96, 128.65, 128.88, 136.95, 138.90, 153.23, 156.42,
169.74; ESIMS m/z 291 [M+H]+. Anal. Calcd for C19H18N2O: C, 78.59; H, 6.25; N,
9.65. Found: C, 78.37; H, 6.46; N, 9.51.
Compound 2b-E: 89%; orange solid, mp 174–176 °C; IR (KBr) 1649, 1615, 1528,
1336 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.96 (s, 6H), 3.33 (s, 3H), 5.47 (d,
;
J = 7.5 Hz, 1H), 6.37 (d, J = 13.2 Hz, 1H), 6.54 (t, J = 7.5 Hz, 1H), 6.74 (d,
J = 7.5 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 7.22–7.30 (m, 2H), 7.45–7.53 (m, 3H),
7.71 (d, J = 13.2 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 25.46, 100.47, 106.69,
109.81, 120.34, 120.51, 124.03, 124.95, 127.87, 128.67, 128.81, 138.94, 139.85,
152.84, 155.71, 168.43; ESIMS m/z 305 [M+H]+. Anal. Calcd for C20H20N2O: C,
78.92; H, 6.62; N, 9.20. Found: C, 78.86; H, 6.80; N, 8.99.

2454
H. J. Lee et al. / Tetrahedron Letters 55 (2014) 2450–2454
Compound 2e-E: 82%; orange solid, mp 244–246 °C; IR (KBr) 1649, 1618, 1514,
1263 cmÀ1 1H NMR (DMSO-d6, 300 MHz) d 2.89 (s, 6H), 5.11 (d, J = 7.5 Hz, 1H),
6.20 (t, J = 7.5 Hz, 1H), 6.38 (d, J = 13.2 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 6.74 (t,
J = 7.5 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.52–7.64 (m, 2H), 7.63 (d, J = 13.2 Hz,
1H), 7.77 (s, 1H), 7.94–8.12 (m, 3H), 10.23 (br s, 1H); 13C NMR (DMSO-d6,
142.05, 151.65, 168.46, 204.00; ESIMS m/z 264 [M+H]+. Anal. Calcd for
17H13NO2: C, 77.55; H, 4.98; N, 5.32. Found: C, 77.80; H, 5.21; N, 5.27.
Compound 4: 78%; orange solid, mp 250–252 °C; IR (KBr) 1654, 1601, 1520,
1243 cmÀ1 1H NMR (DMSO-d6, 300 MHz) d 1.55 (br s, 6H), 3.22 (br s, 4H), 5.21
(d, J = 7.5 Hz, 1H), 6.30 (d, J = 13.5 Hz, 1H), 6.34 (t, J = 7.5 Hz, 1H), 6.66 (d,
J = 7.5 Hz, 1H), 6.78 (t, J = 7.5 Hz, 1H), 7.10–7.30 (m, 2H), 7.40–7.65 (m, 3H),
7.73 (d, J = 13.5 Hz, 1H), 10.19 (br s, 1H); 13C NMR (DMSO-d6, 75 MHz) d 23.51,
25.23, 98.76, 108.11, 109.00, 119.28, 119.80, 123.70, 125.34, 127.98, 128.13,
129.03, 138.08, 138.51, 151.59, 155.32, 168.92; ESIMS m/z 331 [M+H]+. Anal.
Calcd for C22H22N2O: C, 79.97; H, 6.71; N, 8.48. Found: C, 79.82; H, 6.94; N,
8.39.
;
C
;
75 MHz)
d 99.64, 108.19, 109.04, 119.29, 119.67, 123.73, 125.36, 126.42,
126.52, 126.74, 126.84, 127.92, 128.16, 128.70, 132.40, 133.17, 136.06, 138.13,
152.91, 154.94, 168.92; ESIMS m/z 341 [M+H]+. Anal. Calcd for C23H20N2O: C,
81.15; H, 5.92; N, 8.23. Found: C, 80.97; H, 5.97; N, 8.04.
Compound 2f-E: 85%; orange solid, mp 254–256 °C; IR (KBr) 1649, 1619, 1508,
1403 cmÀ1 1H NMR (DMSO-d6, 300 MHz) d 2.95 (s, 6H), 5.42 (d, J = 7.8 Hz, 1H),
;
6.48 (t, J = 7.8 Hz, 1H), 6.65 (d, J = 13.2 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 6.84 (t,
J = 7.8 Hz, 1H), 6.97 (dd, J = 3.6 and 0.9 Hz, 1H), 7.24 (dd, J = 5.1 and 3.6 Hz, 1H),
7.51 (d, J = 13.2 Hz, 1H), 7.77 (dd, J = 5.1 and 0.9 Hz, 1H), 10.21 (br s, 1H); 13C
NMR (DMSO-d6, 75 MHz) d 100.24, 108.21, 110.40, 119.59, 120.02, 124.10,
124.95, 126.90, 127.16, 127.78, 138.16, 138.55, 146.58, 152.52, 168.50; ESIMS
m/z 297 [M+H]+. Anal. Calcd for C17H16N2OS: C, 68.89; H, 5.44; N, 9.45. Found:
C, 69.08; H, 5.73; N, 9.36.
12. The starting material 1i-E was recovered (67%) in the reaction (80 °C, 3 h). For
the similar aerobic oxidation of oxindole derivatives, see: (a) Lee, H. S.; Kim, K.
H.; Kim, Y. M.; Kim, J. N. Bull. Korean Chem. Soc. 2010, 31, 1761–1764; (b) Lee, H.
J.; Lee, S.; Lim, J. W.; Kim, J. N. Bull. Korean Chem. Soc. 2013, 34, 2446–2450.
13. The stereochemistry of
experiment.
3 was confirmed as cis-form based on the NOE
14. For the peak-broadening of similar compounds, see: (a) Steinhardt, S. E.;
Silverston, J. S.; Vanderwal, C. D. J. Am. Chem. Soc. 2008, 130, 7560–7561; (b)
Wypych, J.-C.; Nguyen, T. M.; Benechie, M.; Marazano, C. J. Org. Chem. 2008, 73,
1169–1172; (c) Lee, K. Y.; Lee, C. G.; Na, J. E.; Kim, J. N. Tetrahedron Lett. 2005,
46, 69–74.
Compound 3: 82%; yellow solid, mp 172–174 °C; IR (KBr) 1706, 1613, 1465,
1229 cmÀ1 1H NMR (DMSO-d6, 300 MHz) d 2.40 (s, 3H), 6.47 (d, J = 7.5 Hz, 1H),
;
6.70 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.44–7.51
(m, 2H), 7.52–7.62 (m, 3H), 10.76 (br s, 1H); 13C NMR (CDCl3, 75 MHz) d 29.08,
110.29, 121.33, 121.95, 123.53, 124.27, 127.79, 129.32, 129.89, 130.18, 132.87,