Synthesis of 3-( ?3,δ-disubstituted)allylidene-2-oxindoles from isatins by Wittig reaction with Morita-Baylis -Hillman bromides

Article abstract of DOI:10.1002/bkcs.10053

Various 3-(?3,??-disubstituted)allylidene-2-oxindoles were synthesized by the Wittig reaction between isatins and the phosphorous ylide derived in situ from the Morita-Baylis -Hillman bromides. The 3-allylidene-2-oxindole could be used as an efficient syn

Full text of DOI:10.1002/bkcs.10053

Article
DOI: 10.1002/bkcs.10053
BULLETIN OF THE
H. R. Moon et al.
KOREAN CHEMICAL SOCIETY
Synthesis of 3-(γ,δ-Disubstituted)allylidene-2-Oxindoles from Isatins by
Wittig Reaction with Morita–Baylis–Hillman Bromides
*
Hye Ran Moon, Ko Hoon Kim, Junseong Lee, and Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757,
Korea. *E-mail: kimjn@chonnam.ac.kr
Received October 6, 2014, Accepted October 24, 2014, Published online January 5, 2015
Various 3-(γ,δ-disubstituted)allylidene-2-oxindoles were synthesized by the Wittig reaction between isatins
and the phosphorous ylide derived in situ from the Morita–Baylis–Hillman bromides. The 3-allylidene-2-
oxindole could be used as an efficient synthetic precursorof 1-thiacarbazole derivatives. During the conversion
of 2-oxindole moiety to 2-thiooxindole by Lawesson's reagent, 1-thiacarbazole derivative was obtained in
good yield.
Keywords: 3-Allylidene-2-oxindoles, Wittig reaction, Morita–Baylis–Hillman bromides, Isatins
Introduction
reaction was completed within 3 h at room temperature. The
desired 3-allylidene-2-oxindoles 3a-EE (51%) and 3a-ZE
(41%) were isolated, as shown in Table 1 (entry 1). The reac-
tions with 5-chloroisatin (2b), 5-methoxyisatin (2c), 5-
nitroisatin (2d), N-methylisatin (2e), and N-acetylisatin (2f)
afforded the corresponding products 3b–f (entries 2–6) in
good to moderate yields (76–94%). The EE-isomers were
formed as the major products in all cases. As an example,
the stereochemistry of 3e-EE was unequivocally confirmed
by its X-ray crystal structure (Figure 1).8
It is interesting to note that the two ortho-protons
of δ-phenyl group of 3a-EE appeared at downfield
(δ = 7.48–7.54 ppm) as compared to the remaining three
meta/para protons (δ = 7.32–7.37 ppm), while the correspond-
ing five aromatic protons of 3a-ZE appeared together as an
apparent singlet at δ = 7.41 ppm. The downfield shift of two
ortho-protons of the δ-phenyl group of 3a-EE might be due
to the anisotropic effect of the carbonyl group of 2-oxindole
moiety (see Figure 1).1c Similarly, the ortho-protons of the
δ-phenyl group of EE-isomers of 3b–f appeared at downfield
(δ = 7.44–7.63 ppm) compared to the remaining three meta/
para protons (δ = 7.30–7.44 ppm).
As a next entry, the reaction of nitrile-containing MBH bro-
mide 1b-E6 was examined, as shown in Scheme 2. The reac-
tion provided 3g-EZ in good yield (74%), and the structure of
3g-EZ was unequivocally confirmed by its X-ray crystal struc-
ture (Figure 2).9 The formation of the other isomer was
observed on thin-layer chromatography (TLC) at the right
position in trace amounts; however, the isolation failed
because of the presence of some impurity near the spot. The
proton H-4 of the isatin moiety appeared at downfield (δ =
8.13 ppm) as a result of the anisotropy of the nitrile group.10
The two ortho-protons of the phenyl moiety at the δ-position
of 3g-EZ appeared downfield (δ = 7.94–7.99 ppm) compared
to the three meta/para-protons (δ = 7.50–7.55 ppm) because of
the same anisotropy of the nitrile group. Similarly, the reaction
of 1b-E and N-methyl-5-chloroisatin (2g) showed a similar
The3-alkylidene-2-oxindole ring system representsa keysub-
structure found in many biologically important compounds.1
In this line, further functionalizations of the 3-alkylidene moi-
ety including an extension of the conjugation with C C dou-
ble bond have received much attention.2–4 Takemoto et al.
have reported the synthesis of 3-(β,δ-disubstituted)allyli-
dene-2-oxindoles via a palladium-catalyzed Heck/Heck dom-
ino reaction of alkynamide precursor, as shown in Scheme 1
(Eq. 1).2a Pontikis et al. also reported the synthesis of 3-(β,-
δ-disubstituted)allylidene-2-oxindoles via
a
palladium-
catalyzed Heck/Suzuki–Miyaura domino reaction of alkyna-
mide and styrylboronic acid.2b,c Recently, we have reported
the N,N-dimethylaminomethylenation of 3-alkylidene-2-
oxindoles with N,N-dimethylformamide dimethylacetal
(DMF-DMA) to make 3-(β,δ-disubstituted)allylidene-2-oxi-
ndoles, as shown in Scheme 1 (Eq. 2).3a
Results and Discussion
Thephosphorous ylidesderived fromMorita–Baylis–Hillman
(MBH) bromides have been used for the synthesis of functio-
nalized 1,3-dienes, which are used in many reactions such as
Diels–Alder reaction or 6π-electrocyclization.5,6 In these con-
texts, we envisaged that the Wittig reaction of isatin with phos-
phorous ylide derived from the MBH bromide could provide
3-(γ,δ-disubstituted)allylidene-2-oxindoles, as shown in
Scheme 1 (Eq. 3). To the best of our knowledge, no report
has been published for the synthesis of 3-allylidene-2-
oxindoles using the Wittig reaction.7
Thus, two representative MBH bromides 1a-Z and 1b-E
were prepared stereoselectively according to the reported
method.6 The reaction of MBH bromide 1a-Z and triphenyl-
phosphine in CH3CN afforded the corresponding phospho-
nium bromide at room temperature within 4 h. Isatin (2a)
and K2CO3 were added to the reaction mixture, and the Wittig
Bull. Korean Chem. Soc. 2015, Vol. 36, 219–225
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library
219

BULLETIN OF THE
Article
Synthesis of 3-(γ,δ-Disubstituted)allylidene-2-Oxindoles from Isatins
KOREAN CHEMICAL SOCIETY
EWG
Ph
I
Ph
O
Takemoto
Pd(0)
EWG
+
(1)
(2)
N
R
O
N
NMe2
R
Ar
Ar
CH3
O
Kim
DMF-DMA
O
N
R
N
R
δ
γ
Ph
O
E
Ph
Ph
β
PPh3
This
(3)
+
O
3(α)
E
E
K2CO3
Work
N
R
O
2
N
R
Br
Ph3P
1
MBH bromide
(E = COOMe)
Scheme 1. Synthesis of 3-allylidene-2-oxindoles.
Table 1. Synthesis of 3-allylidene-2-oxindoles 3a–f.a
O
R1
2a: R1 = H, R2 = H; 2b: R1 = Cl, R2 = H
2c: R1 = OMe, R2 = H; 2d: R1 = NO2, R2 = H
2e: R1 = H, R2 = Me; 2f: R1 = H, R2 = COMe
Z
COOMe
Br
Ph
+
3a-f
O
N
R2
1a-Z
2a-f
Entry
1
2
Product (%)
Entry
4
2
Product (%)
2a
2d
2e
2f
Ph
Ph
Ph
H
Ph
E
H
MeOOC
E
H
MeOOC
O2N
H
COOMe
E
COOMe
Z
O2N
O
O
O
O
N
N
H
N
N
H
H
3a-ZE (41)
3a-EE (51)
H
3d-ZE (11)
3d-EE (70)
2
2b
5
Ph
H
Ph
H
Ph
Ph
H
H
MeOOC
MeOOC
COOMe
COOMe
Cl
Cl
O
O
O
O
N
N
N
N
H
Me
H
Me
3b-ZE (40)
3e-ZE (42)
3b-EE (53)
3e-EE (52)
3b
2c
6
Ph
H
MeO
O
Ph
Ph
H
Ph
H
H
MeOOC
MeOOC
COOMe
COOMe
O
MeO
O
O
N
N
N
N
H
H
Ac
Ac
3c-ZE (20)
3f-ZE (39)
3c-EE (56)
3f-EE (48)
a Conditions: (i) MBH bromide 1a (1.2 equiv), PPh3 (1.2 equiv), CH3CN, room temperature, 4 h, and(ii) isatin 2a–f (1.0 equiv), K2CO3 (2.0equiv), room
temperature, 3 h.
b Reaction time for step (ii) was 5 h.
result to afford 3h-EZ in good yield (76%). Also, the
corresponding H-4 proton (δ = 8.16 ppm) and the two ortho-
protons of the phenyl moiety at the δ-position appeared down-
field (δ = 7.95–8.00 ppm).
In order to extend the conjugation of double bonds, we
examined the Wittig reaction of N-methylisatin (2e) with in
situ generated ylide from the MBH bromide 1c-ZE,6 as shown
in Scheme 3. Compound 3i-EEE was obtained in good yield
Bull. Korean Chem. Soc. 2015, Vol. 36, 219–225
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
220

BULLETIN OF THE
Article
Synthesis of 3-(γ,δ-Disubstituted)allylidene-2-Oxindoles from Isatins
KOREAN CHEMICAL SOCIETY
Figure 2. ORTEP drawing of 3g-EZ.
Figure 1. ORTEP drawing of 3e-EE.
H6'
H6'
(i) PPh3, CH3CN, rt, 4 h
(ii) 2a, K2CO3, rt, 2 h
(i) PPh3, CH3CN, rt, 4 h
(ii) 2g, K2CO3, rt, 2 h
H
Z
2' NC
H4
H
Z
2' NC
H4
E
H
H
Ph
Br
E
Cl
O
E
CN
1b-E
Cl
O
O
O
N
N
N
H
Me
3h-EZ (76%)
2g
Me
3g-EZ (74%)
H4 (δ = 8.13 ppm, d, J = 7.8 Hz)
H2' and H6' (δ = 7.94-7.99 ppm)
H4 (δ = 8.16 ppm, d, J = 1.8 Hz)
H2' and H6' (δ = 7.95-8.00 ppm)
Scheme 2. Synthesis of 3g and 3h.
(79%). The formation of the minor ZEE-isomer was observed
on TLC at the right position in trace amounts; however, we
failed to isolate the compound in appreciable amount.
As one of the synthetic applications of prepared com-
pounds, the reaction of 3e-EE and Lawesson's reagent
(LR)11 was examined, as shown in Scheme 4. The reaction
of3e-EEandLR(0.6equiv)intolueneat100 ꢀCinashorttime
(1 h) afforded 1-thiacarbazole derivative12 4 in good yield
(94%). In the reaction, the formation of a trace amount of side
product was observed. The compound was identified as a thio-
noester derivative 5.11 Actually, compound 5 was formed as a
major product (80%) by using an excess amount of LR (2.0
equiv) for 8 h. The 1-thiacarbazole 4 could be produced via
the sequential thionation of oxindole moiety to thiooxindole
I and (p-MeOPh)PS(=X)-catalyzed Michael-type cyclization
process involving the intermediates II and III.13 The forma-
tions of4 and 5 were notobserved atlower temperatures (room
temperature to 70 ꢀC); however, double-bond isomerization
of 3e-EE to 3e-ZE was observed to some extent presumably
by ArPS2.
Ph
(i) PPh3, CH3CN, rt, 4 h
(ii) 2e, K2CO3, rt, 3 h
E
Z
COOMe
Br
H
MeOOC
Ph
O
1c-ZE
N
Me
3i-EEE (79%)
Scheme 3. Synthesis of 3 i.
Conclusion
In summary, various 3-(γ,δ-disubstituted)allylidene-2-
oxindoles have been synthesized by the Wittig reaction
between isatins and the phosphorous ylide derived in situ from
the MBH bromides. Further studies on the biological
activity and chemical transformations of prepared compounds
are under progress and the results will be released in due
course.
Bull. Korean Chem. Soc. 2015, Vol. 36, 219–225
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
221

BULLETIN OF THE
Article
Synthesis of 3-(γ,δ-Disubstituted)allylidene-2-Oxindoles from Isatins
KOREAN CHEMICAL SOCIETY
S
Ph
OMe
COOMe
H
H
MeOOC
H
thionation
Ph
Ph
S
S
O
N
N
N
Me
Me
Me
5
4
3e-EE
LR (0.6 equiv), 1 h: 4 (94%) + 5 (trace)
LR (2.0 equiv), 8 h: 4 (9%) + 5 (80%)
S
P
LR/toluene
thionation
-
X
Ar
Ph
Ph
H
COOMe
H
X
X
S
P
S
MeOOC
MeOOC
P
Ar
addition
S
rotation
Ar
Ph
S
S
S
X
Ar
P
N
N
N
(X = S or O)
Me
Me
Me
I
III
II
S
P
S
P
S
S
S
2 Ar
2 Ar
S
MeO
P
S
OMe
P
S
(Ar is p-methoxyphenyl)
Lawesson's reagent
Scheme 4. The reaction of 3e and Lawesson's reagent.
Experimental Section
128.59, 128.80, 129.79, 129.85, 130.68, 130.81, 135.00,
140.86, 142.86, 167.68, 168.15; ESIMS m/z 306 [M + H]+.
Anal. calcd for C19H15NO3: C, 74.74; H, 4.95; N, 4.59; found:
C, 74.71; H, 4.82; N, 4.41.
Typical Procedure for the Synthesis of 3a. A mixture of
MBH bromide 1a-Z (306 mg, 1.2 mmol) and PPh3 (315 mg,
1.2 mmol) in CH3CN (3.0 mL) was stirred at room tempera-
ture for 4 h. The corresponding phosphonium salt, monitored
by TLC, was formed quantitatively. To the reaction mixture,
isatin (2a, 147 mg, 1.0 mmol) and K2CO3 (276 mg, 2.0 mmol)
were added, and the reaction mixture was stirred at room tem-
perature for 3 h. After the usual aqueous extractive work-up
and column chromatographic purification process (hexanes/
EtOAc, 2:1), compounds 3a-EE (156 mg, 51%) and 3a-ZE
(125 mg, 41%) were obtained as yellow solids. Other com-
pounds were synthesized similarly, and the spectroscopic data
of 3a–i (see Supporting Information) are as follows:
Compound3b-EE:53%; yellow solid, mp208–210 ꢀC;IR
(KBr) 3173, 1709, 1613, 1453, 1265 cm−1; 1H NMR (CDCl3,
300 MHz) δ 3.82 (s, 3H), 6.77 (d, J = 8.1 Hz, 1H), 7.06 (d, J =
1.8 Hz, 1H), 7.14 (dd, J = 8.1 and 1.8 Hz, 1H), 7.31–7.38 (m,
3H), 7.45–7.52 (m, 2H), 7.63 (d, J = 1.5 Hz, 1H), 8.01 (d, J =
1.5 Hz, 1H), 8.48 (br s, 1H); 13C NMR (CDCl3, 75 MHz) δ
52.73, 110.76, 123.13, 124.46, 125.65, 127.46, 128.81,
129.53, 129.61, 130.52, 130.54, 131.55, 134.16, 139.66,
145.03, 166.50, 168.92; ESIMS m/z 340 [M + H]+, 342 [M
+ H + 2]+. Anal. calcd for C19H14ClNO3: C, 67.16; H, 4.15;
N, 4.12; found: C, 67.02; H, 4.37; N, 4.04.
Compound 3a-EE: 51%; yellow solid, mp 162–164 ꢀC; IR
Compound 3b-ZE: 40%; yellow solid, mp 162–164 ꢀC; IR
(KBr) 3261, 1722, 1615, 1472, 1259 cm−1; 1H NMR (CDCl3,
300 MHz) δ 3.80 (s, 3H), 6.83 (d, J = 8.1 Hz, 1H), 7.22 (dd,
J = 8.1 and 2.1 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 7.37–7.45
(m, 6H), 7.83 (d, J = 1.8 Hz, 1H), 8.43 (br s, 1H); 13C NMR
(CDCl3, 75 MHz) δ 52.32, 110.99, 120.81, 124.72, 127.56,
128.42, 128.71, 129.47, 129.81, 130.07, 130.80, 134.82,
139.13, 143.67, 167.39, 167.73, one carbon was overlapped;
ESIMS m/z 340 [M + H]+, 342 [M + H + 2]+.
(KBr) 3200, 1709, 1614, 1465, 1255, 1205 cm−1; H NMR
1
(CDCl3, 300 MHz) δ 3.76 (s, 3H), 6.84–6.92 (m, 2H), 7.14
(d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.32–7.37 (m,
3H), 7.48–7.54 (m, 2H), 7.59 (d, J = 1.8 Hz, 1H), 7.98 (d,
J = 1.8 Hz, 1H), 8.78 (br s, 1H); 13C NMR (CDCl3, 75
MHz) δ 52.61, 110.04, 121.91, 122.15, 124.12, 126.10,
128.74, 129.88, 129.97, 130.33, 130.72, 130.90, 134.24,
141.39, 144.29, 166.99, 169.43; ESIMS m/z 306 [M + H]+.
Anal. calcd for C19H15NO3: C, 74.74; H, 4.95; N, 4.59; found:
C, 74.96; H, 5.07; N, 4.34.
Compound 3c-EE: 56%; yellow solid, mp 166–168 ꢀC; IR
(KBr) 3230, 1708, 1483, 1259, 1203 cm−1; 1H NMR (CDCl3,
300 MHz) δ3.67 (s, 3H), 3.79(s, 3H), 6.73(d, J = 8.1 Hz, 1H),
6.74 (s, 1H), 6.79 (d, J = 8.1 Hz, 1H), 7.30–7.38 (m, 3H),
7.49–7.57 (m, 2H), 7.60 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 1.8
Hz, 1H), 9.09 (br s, 1H); 13C NMR (CDCl3, 75 MHz) δ
52.63, 55.70, 110.22, 110.49, 115.63, 122.57, 125.98,
128.75, 130.12, 130.38, 130.65, 131.32, 134.19, 135.34,
144.13, 155.27, 166.98, 169.76; ESIMS m/z 336 [M + H]+.
Compound 3a-ZE: 41%; yellow solid, mp 158–160 ꢀC; IR
(KBr) 3287, 1717, 1615, 1269, 1258, 1203 cm−1; H NMR
1
(CDCl3, 300 MHz) δ 3.81 (s, 3H), 6.91 (d, J = 7.8 Hz, 1H),
7.03 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 1.8 Hz, 1H), 7.26 (t, J
= 7.8 Hz, 1H), 7.41 (s, 5H), 7.47 (d, J = 7.8 Hz, 1H), 7.80
(d, J = 1.8 Hz, 1H), 8.52 (br s, 1H); 13C NMR (CDCl3, 75
MHz) δ 52.28, 110.04, 120.60, 121.99, 123.29, 128.53,
Bull. Korean Chem. Soc. 2015, Vol. 36, 219–225
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
222

BULLETIN OF THE
Article
Synthesis of 3-(γ,δ-Disubstituted)allylidene-2-Oxindoles from Isatins
KOREAN CHEMICAL SOCIETY
Anal. calcd for C20H17NO4: C, 71.63; H, 5.11; N, 4.18; found:
C, 71.48; H, 5.35; N, 4.17.
(t, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.8
Hz, 1H), 7.32–7.43 (m, 3H), 7.44–7.55 (m, 2H), 7.64 (s,
1H), 8.01 (s, 1H), 8.28 (d, J = 7.8 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) δ 26.80, 52.65, 116.58, 122.06, 123.33,
124.82, 125.75, 128.82, 129.29, 130.26, 130.58, 130.71,
131.20, 134.12, 140.12, 144.97, 166.57, 167.76, 170.75;
ESIMS m/z 348 [M + H]+. Anal. calcd for C21H17NO4: C,
72.61; H, 4.93; N, 4.03; found: C, 72.87; H, 5.20; N, 3.94.
Compound 3f-ZE: 39%; yellow solid, mp 156–158 ꢀC; IR
Compound 3c-ZE: 20%; yellow solid, mp 178–180 ꢀC; IR
(KBr) 3271, 1718, 1487, 1260, 1202 cm−1; 1H NMR (CDCl3,
300 MHz) δ 3.79 (s, 3H), 3.80 (s, 3H), 6.81 (apparent d, J =
1.5 Hz, 2H), 7.03 (dd, J = 1.5 and 1.2 Hz, 1H), 7.19 (d, J =
1.8 Hz, 1H), 7.41 (s, 5H), 7.79 (d, J = 1.8 Hz, 1H), 8.57 (br
s, 1H); 13C NMR (CDCl3, 75 MHz) δ 52.28, 55.92, 106.88,
110.56, 115.30, 124.14, 128.60, 128.63, 128.75, 129.80,
130.81, 131.21, 134.83, 134.99, 142.86, 155.45, 167.69,
168.38; ESIMS m/z 336 [M + H]+.
1
(KBr) 1733, 1713, 1465, 1373, 1282, 1163 cm−1; H NMR
(CDCl3, 300 MHz) δ 2.70 (s, 3H), 3.83 (s, 3H), 7.23 (t, J =
7.8 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 7.36–7.45 (m, 6H),
7.55 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 2.1 Hz, 1H), 8.30 (d,
J = 7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 26.74,
52.38, 116.88, 119.79, 123.17, 124.92, 128.40, 128.71,
129.07, 129.95, 130.12, 130.29, 130.85, 134.81, 139.58,
143.70, 166.57, 167.29, 170.82; ESIMS m/z 348 [M + H]+.
Compound 3g-EZ: 74%; yellow solid, mp 190–192 ꢀC; IR
Compound3d-EE:70%; yellow solid, mp246–248 ꢀC;IR
1
(KBr) 3177, 1714, 1615, 1517, 1333, 1252, 1202 cm−1; H
NMR (DMSO-d6, 300 MHz) δ 3.77 (s, 3H), 7.00 (d, J = 8.7
Hz, 1H), 7.32–7.44 (m, 3H), 7.45–7.63 (m, 3H), 7.75 (s,
1H), 8.07 (s, 1H), 8.13 (d, J = 8.7 Hz, 1H), 11.35 (br s, 1H);
13C NMR (DMSO-d6, 75 MHz) δ 52.73, 109.98, 118.90,
121.18, 125.53, 126.61, 128.29, 128.78, 130.43, 130.72,
131.88, 133.93, 141.63, 144.70, 148.35, 165.85, 168.20;
ESIMS m/z 351 [M + H]+. Anal. calcd for C19H14N2O5: C,
65.14; H, 4.03; N, 8.00; found: C, 65.35; H, 4.20; N, 7.81.
Compound 3d-ZE: 11%; yellow solid, mp 172–174 ꢀC; IR
1
(KBr) 3149, 2220, 1707, 1605, 1464, 1325, 1201 cm−1; H
NMR (CDCl3, 300 MHz) δ 6.90 (d, J = 7.8 Hz, 1H), 7.06 (t,
J = 7.8 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.35 (s, 1H),
7.50–7.55 (m, 3H), 7.65 (s, 1H), 7.94–7.99 (m, 2H), 8.08
(br s, 1H), 8.13 (d, J = 7.8 Hz, 1H); 13C NMR (CDCl3, 75
MHz) δ 106.03, 110.12, 117.24, 120.69, 122.44, 126.79,
128.17, 129.26, 130.20, 130.64, 131.75, 132.27, 132.84,
141.84, 153.01, 169.24; ESIMS m/z 273 [M + H]+. Anal.
calcd for C18H12N2O: C, 79.39; H, 4.44; N, 10.29; found:
C, 79.43; H, 4.29; N, 10.12.
1
(KBr) 3271, 1724, 1621, 1523, 1338, 1260 cm−1; H NMR
(CDCl3, 300 MHz) δ 3.81 (s, 3H), 7.04 (d, J = 8.7 Hz, 1H),
7.37–7.50 (m, 6H), 7.91 (d, J = 2.1 Hz, 1H), 8.22 (dd, J =
8.4 and 2.1 Hz, 1H), 8.34 (d, J = 2.1 Hz, 1H), 9.23 (br s,
1H); 13C NMR (CDCl3, 75 MHz) δ 52.44, 109.88, 116.36,
123.68, 126.07, 127.91, 128.75, 128.87, 130.52, 130.84,
132.29, 134.52, 143.24, 144.95, 145.65, 167.16, 168.11;
ESIMS m/z 351 [M + H]+.
Compound 3h-EZ: 76%; red solid, mp 196–198 ꢀC; IR
1
(KBr) 2213, 1707, 1607, 1484, 1370, 1111 cm−1; H NMR
Compound 3e-EE: 52%; yellow solid, mp 112–114 ꢀC; IR
(CDCl3, 300 MHz) δ 3.27 (s, 3H), 6.77 (d, J = 8.1 Hz, 1H),
7.31 (dd, J = 8.1 and 1.8 Hz, 1H), 7.42 (d, J = 0.9 Hz, 1H),
7.48–7.56 (m, 3H), 7.64 (d, J = 0.9 Hz, 1H), 7.95–8.00 (m,
2H), 8.16 (d, J = 1.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ
26.45, 105.73, 109.05, 117.22, 121.32, 126.76, 126.95,
127.69, 129.30, 130.07, 130.30, 132.52, 132.71, 133.05,
143.16, 153.91, 167.72; ESIMS m/z 321 [M + H]+, 323 [M
+ H + 2]+. Anal. calcd for C19H13ClN2O: C, 71.14; H, 4.08;
N, 8.73; found: C, 71.40; H, 4.23; N, 8.71.
1
(KBr) 3056, 2950, 1711, 1610, 1469, 1254 cm−1; H NMR
(CDCl3, 300 MHz) δ 3.27 (s, 3H), 3.75 (s, 3H), 6.79 (d, J =
7.5 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 7.15 (d, J = 7.5 Hz,
1H), 7.24 (t, J = 7.5 Hz, 1H), 7.30–7.37 (m, 3H), 7.48–7.54
(m, 2H), 7.60 (d, J = 1.5 Hz, 1H), 7.95 (d, J = 1.5 Hz, 1H);
13C NMR (CDCl3, 75 MHz) δ 26.09, 52.56, 108.01,
121.31, 122.11, 123.76, 126.18, 128.72, 129.67, 129.77,
130.26, 130.52, 130.73, 134.26, 144.00, 144.06, 167.03,
167.58; ESIMS m/z 320 [M + H]+. Anal. calcd for
C20H17NO3: C, 75.22; H, 5.37; N, 4.39; found: C, 75.19; H,
5.43; N, 4.22.
Compound 3i-EEE: 79%; yellow solid, mp 122–124 ꢀC;
IR (KBr) 2950, 1712, 1609, 1469, 1375, 1275, 1235 cm−1;
1H NMR (CDCl3, 300 MHz) δ 3.31 (s, 3H), 3.81 (s, 3H),
6.79 (dd, J = 15.3 and 11.7 Hz, 1H), 6.82 (d, J = 7.8 Hz,
1H), 6.87 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 15.3 Hz, 1H), 7.17
(d, J = 7.8 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.26 (s, 5H),
7.61 (s, 1H), 7.69 (d, J = 11.7 Hz, 1H); 13C NMR (CDCl3,
75 MHz) δ 26.15, 52.34, 107.94, 120.75, 122.15, 124.55,
124.67, 125.81, 127.51, 128.74, 129.29, 129.55, 129.56,
129.73, 135.85, 142.93, 143.71, 144.26, 166.74, 167.79 ;
ESIMS m/z 346 [M + H]+. Anal. calcd for C22H19NO3: C,
76.50; H, 5.54; N, 4.06; found: C, 76.42; H, 5.71; N, 3.93.
Synthesis of 1-Thiacarbazole Derivatives 4 and 5.
Compounds 4 and 5 were prepared from 3e-EE and LR in tol-
uene (100 ꢀC), and the spectroscopic data are as follows:
Compound 4: yellow solid, mp 166–168 ꢀC; IR (KBr)
Compound 3e-ZE: 42%; yellow solid, mp 118–120 ꢀC; IR
1
(KBr) 3056, 2948, 1705, 1610, 1470, 1257 cm−1; H NMR
(CDCl3, 300 MHz) δ 3.23 (s, 3H), 3.83 (s, 3H), 6.83 (d, J =
7.8 Hz, 1H), 7.05 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 1.8 Hz,
1H), 7.32 (t, J = 7.8 Hz, 1H), 7.39 (s, 5H), 7.47 (d, J = 7.8
Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H); 13C NMR (CDCl3, 75
MHz) δ 25.84, 52.27, 108.08, 120.21, 121.93, 122.51,
128.11, 128.52, 128.94, 129.64, 129.73, 130.37, 130.75,
135.03, 142.29, 143.45, 166.21, 167.60; ESIMS m/z 320
[M + H]+. Anal. calcd for C20H17NO3: C, 75.22; H, 5.37; N,
4.39; found: C, 75.41; H, 5.50; N, 4.47.
Compound 3f-EE: 48%; yellow solid, mp 142–144 ꢀC; IR
1
(KBr) 2950, 1743, 1714, 1602, 1459, 1371, 1302 cm−1; H
1
NMR (CDCl3, 300 MHz) δ 2.77 (s, 3H), 3.74 (s, 3H), 7.08
1692, 1598, 1485, 1228 cm−1; H NMR (CDCl3, 300 MHz)
Bull. Korean Chem. Soc. 2015, Vol. 36, 219–225
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
223

BULLETIN OF THE
Article
Synthesis of 3-(γ,δ-Disubstituted)allylidene-2-Oxindoles from Isatins
KOREAN CHEMICAL SOCIETY
Pelosi, A. Sartori, L. Battistini, F. Zanardi, G. Casiraghi, Angew.
Chem. Int. Ed. 2012, 51, 6200; (b) G. Rassu, V. Zambrano, L.
Pinna, C. Curti, L. Battistini, A. Sartori, G. Pelosi, F. Zanardi,
G. Casiraghi, Adv. Synth. Catal. 2013, 355, 1881; (c) G. Rassu,
V. Zambrano, R. Tanca, A. Sartori, L. Battistini, F. Zanardi, C.
Curti, G. Casiraghi, Eur. J. Org. Chem. 2012, 466;(d) B. Ranieri,
A. Sartori, C. Curti, L. Battistini, G. Rassu, G. Pelosi, G. Casir-
aghi, F. Zanardi, Org. Lett. 2014, 16, 932; (e) G. Bencivenni, L.-
Y. Wu, A. Mazzanti, B. Giannichi, F. Pesciaioli, M.-P. Song, G.
Bartoli, P. Melchiorre, Angew. Chem. Int. Ed. 2009, 48, 7200;(f )
K. Jiang, Z.-J. Jia, S. Chen, L. Wu, Y.-C. Chen, Chem. Eur. J.
2010, 16, 2852; (g) B. M. Trost, N. Cramer, S. M. Silverman,
J. Am. Chem. Soc. 2007, 129, 12396; (h) B. M. Trost, N. Cramer,
H. Bernsmann, J. Am. Chem. Soc. 2007, 129, 3086; (i) Z.-J. Jia,
H. Jiang, J.-L. Li, B. Gschwend, Q.-Z. Li, X. Yin, J. Grouleff, Y.-
C. Chen, K. A. Jorgensen, J. Am. Chem. Soc. 2011, 133, 5053; (j)
F. Pesciaioli, P. Righi, A. Mazzanti, G. Bartoli, G. Bencivenni,
Chem. Eur. J. 2011, 17, 2842; (k) I. Allous, S. Comesse, M. San-
selme, A. Daich, Eur. J. Org.Chem. 2011, 5303;(l)Q. Wei, L.-Z.
Gong, Org. Lett. 2010, 12, 1008; (m) X.-H. Chen, Q. Wei, S.-W.
Luo, H. Xiao, L.-Z. Gong, J. Am. Chem. Soc. 2009, 131, 13819;
(n) T. Fukuyama, G. Liu, J. Am. Chem. Soc. 1996, 118, 7426; (o)
D. B. Ramachary, C. Venkaiah, P. M. Krishna, Org. Lett. 2013,
15, 4714; (p) X.-F. Huang, Z.-M. Liu, Z.-C. Geng, S.-Y. Zhang,
Y. Wang, X.-W. Wang, Org. Biomol. Chem. 2012, 10, 8794; (q)
N. R. Ball-Jones, J. J. Badillo, A. K. Franz, Org. Biomol. Chem.
2012, 10, 5165; (r) B. Viswambharan, K. Selvakumar, S. Mad-
havan, P. Shanmugam, Org. Lett. 2010, 12, 2108; (s) W. A. Car-
roll, P. A. Grieco, J. Am. Chem. Soc. 1993, 115, 1164; (t) G.
Wang, X. Liu, T. Huang, Y. Kuang, L. Lin, X. Feng, Org. Lett.
2013, 15, 76; (u) L. Yang, F. Wang, P. J. Chua, Y. Lv, L.-J.
Zhong, G. Zhong, Org. Lett. 2012, 14, 2894; (v) H. Lv, X.-Y.
Chen, L.-H. Sun, S. Ye, J. Org. Chem. 2010, 75, 6973.
δ 3.61 (s, 3H), 3.79 (s, 3H), 5.51 (s, 1H), 7.16–7.25 (m, 6H),
7.31–7.38 (m, 2H), 7.63–7.71 (m, 1H), 8.25 (s, 1H); 13C NMR
(CDCl3, 75 MHz) δ 30.79, 43.13, 51.89, 109.09, 110.08,
111.75, 117.04, 121.30, 121.89, 126.38, 126.77, 127.84,
128.52, 132.23, 136.45, 138.53, 141.48, 167.15; ESIMS m/
z 336 [M + H]+. Anal. calcd for C20H17NO2S: C, 71.62; H,
5.11; N, 4.18; found: C, 71.55; H, 5.32; N, 4.06.
Compound 5: orange solid, mp 171–173 ꢀC; IR (KBr)
1582, 1557, 1482, 1263, 1230 cm−1; 1H NMR (CDCl3, 300
MHz) δ 3.60 (s, 3H), 4.18 (s, 3H), 6.17 (s, 1H), 7.15–7.25
(m, 6H), 7.33–7.39 (m, 2H), 7.67–7.74 (m, 1H), 8.49 (s,
1H); 13C NMR (CDCl3, 75 MHz) δ 30.94, 45.39, 58.53,
109.23, 111.33, 117.29, 120.54, 121.57, 122.29, 126.83,
126.95, 127.64, 128.36, 129.38, 138.88, 138.99, 141.23,
208.43; ESIMS m/z 352 [M + H]+. Anal. calcd for
C20H17NOS2: C, 68.34; H, 4.88; N, 3.99; found: C, 68.60;
H, 4.81; N, 3.87.
Acknowledgments. This researchwassupported bytheBasic
Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Educa-
tion, Science and Technology (2014R1A1A2053606). The
spectroscopic data were obtained from the Korea Basic Sci-
ence Institute, Gwangju branch.
SupportingInformation. Additionalsupportinginformation
is available in the online version of this article.
References
1. For the synthesis of 3-alkylidene-2-oxindoles and their biologi-
cal activity, see: (a) A. Millemaggi, R. J. K. Taylor, Eur. J. Org.
Chem. 2010, 4527, and further references cited therein; (b) C. R.
Prakash, P. Theivendren, S. Raja, Pharmacol. Pharm. 2012, 3,
62; (c) L. Sun, N. Tran, F. Tang, H. App, P. Hirth, G. McMahon,
C. Tang, J. Med. Chem. 1998, 41, 2588.
5. For the general reviews on MBH reaction, see: (a) D. Basavaiah,
A. J. Rao, T. Satyanarayana, Chem. Rev. 2003, 103, 811; (b) D.
Basavaiah, B. S. Reddy, S. S. Badsara, Chem. Rev. 2010, 110,
5447; (c) V. Singh, S. Batra, Tetrahedron 2008, 64, 4511; (d)
J. N. Kim, K. Y. Lee, Curr. Org. Chem. 2002, 6, 627; (e) K.
Y. Lee, S. Gowrisankar, J. N. Kim, Bull. Korean Chem. Soc.
2005, 26, 1481; f ) S. Gowrisankar, H. S. Lee, S. H. Kim,
K. Y. Lee, J. N. Kim, Tetrahedron 2009, 65, 8769; (g) M. Shi,
F.-J. Wang, M.-X. Zhao, Y. Wei, The Chemistry of the
Morita–Baylis–Hillman Reaction, RSC Publishing, Cambridge,
2011.
6. For the synthesis and synthetic applications of the ylides derived
from MBH bromides, see: (a) R. M. Crist, P. V. Reddy, B. Bor-
han, Tetrahedron Lett. 2001, 42, 619; (b) C. G. Lee, K. Y. Lee, S.
J. Kim, J. N. Kim, Bull. Korean Chem. Soc. 2007, 28, 719; (c) M.
M. Sa, L. Meier, Heteroat. Chem. 2013, 24, 384; (d) R. Zhou, C.
Wang, H. Song, Z. He, Org. Lett. 2010, 12, 976; (e) C. Muthiah,
K. S. Kumar, J. J. Vittal, K. C. K. Swamy, Synlett 2002, 1787; (f )
K. H. Kim, C. H. Lim, J. W. Lim, J. N. Kim, Adv. Synth. Catal.
2014, 356, 697; (g) C. H. Lim, K. H. Kim, J. W. Lim, J. N. Kim,
TetrahedronLett. 2013, 54, 5808;(h)C. H. Lim, S. H. Kim, K. H.
Kim, J. N. Kim, Tetrahedron Lett. 2013, 54, 2476; (i) C. H. Lim,
S. H. Kim, K. H. Park, J. Lee, J. N. Kim, Tetrahedron Lett. 2013,
54, 387; (j) S. H. Kim, J. W. Lim, J. Yu, J. N. Kim, Bull. Korean
Chem. Soc. 2013, 34, 2915.
2. For the synthesis of conjugated alkylidene-2-oxindole deriva-
tives, see: (a) R. Yanada, S. Obika, T. Inokuma, K. Yanada,
M. Yamashita, S. Ohta, Y. Takemoto, J. Org. Chem. 2005, 70,
6972; (b) M. Arthuis, R. Pontikis, J.-C. Florent, Tetrahedron Lett.
2007, 48, 6397; (c) M. Arthuis, R. Pontikis, G. G. Chabot, J.
Seguin, L. Quentin, S. Bourg, L. Morin-Allory, J.-C. Florent,
ChemMedChem 2011, 6, 1693; (d) D. M. D'Souza, C. Muschel-
knautz, F. Rominger, T. J. J. Muller, Org. Lett. 2010, 12, 3364;
(e) C. Muschelknautz, B. Mayer, F. Rominger, T. J. J. Muller,
Chem. Heterocycl. Compd. 2013, 49, 860; (f ) M. Bararjanian,
S. Balalaie, F. Rominger, B. Movassagh, H. R. Bijanzadeh, J.
Org. Chem. 2010, 75, 2806; (g) T. Miura, T. Toyoshima, Y. Taka-
hashi, M. Murakami, Org. Lett. 2008, 10, 4887; (h) T. Miura, Y.
Takahashi, M.Murakami,Org.Lett.2007,9,5075;(i)H. Asahara,
T. Kida, T. Hinoue, M. Akashi, Tetrahedron 2013, 69, 9428.
3. For our recent synthesis of 3-alkylidene-2-oxindoles and their
derivatizations, see: (a) H. J. Lee, S. Lee, J. Yu, J. N. Kim, Tet-
rahedron Lett. 2014, 55, 2450; (b) H. J. Lee, J. W. Lim, J. Yu, J.
N. Kim, Tetrahedron Lett. 2014, 55, 1183; (c) H. J. Lee, K. H.
Kim, S. H. Kim, J. N. Kim, Tetrahedron Lett. 2013, 54, 170.
4. Forthe synthetic applications of 3-alkylidene-2-oxindolederiva-
tives, see: (a) C. Curti, G. Rassu, V. Zambrano, L. Pinna, G.
7. For the Wittig-type reactions of isatin derivatives, see: (a) W.
Yan, D. Wang, J. Feng, P. Li, D. Zhao, R. Wang, Org. Lett.
2012, 14, 2512; (b) Y.-L. Liu, J. Zhou, Chem. Commun. 2013,
Bull. Korean Chem. Soc. 2015, Vol. 36, 219–225
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
224

BULLETIN OF THE
Article
Synthesis of 3-(γ,δ-Disubstituted)allylidene-2-Oxindoles from Isatins
KOREAN CHEMICAL SOCIETY
49, 4421; (c) E. Wenkert, S. Liu, Synthesis 1992, 323; (d) Z.
10. For the stereochemical assignment of nitrile derivatives, see: (a)
X. Zhou, T. Xiao, Y. Iwama, Y. Qin, Angew. Chem. Int. Ed.
2012, 51, 4909; (b) J. R. Suresh, U. K. Syam Kumar, H. Ila,
H. Junjappa, Tetrahedron 2001, 57, 781.
11. For the thionation with Lawesson's reagent, see: (a) T. Ozturk,
E. Ertas, O. Mert, Chem. Rev. 2007, 107, 5210; (b) M. P. Cava,
M. I. Levinson, Tetrahedron 1985, 41, 5061; (c) M. Jesbeger,
T. P. Davis, L. Barner, Synthesis 2003, 1929; (d) R. S. Varma,
D. Kumar, Org. Lett. 1999, 1, 697.
12. For the synthesis and biological activity of 1-thiacarbazole deri-
vatives, see: (a) F. Cochard, M. Laronze, E. Prost, J.-M. Nuzil-
lard, F. Auge, C. Petermann, P. Sigaut, J. Sapi, J.-Y. Laronze,
Eur. J. Org. Chem. 2002, 3481; (b) A. M. Nyong, J. D. Rainier,
J. Org. Chem. 2005, 70, 746; (c) S. Singh, A. Srivastava, S.
Samanta, Tetrahedron Lett. 2012, 53, 6087; (d) F. M. Moghad-
dam, B. K. Foroushani, M. Sobhani, N. Masoud, M. R. Khoda-
bakhshi, N. S. Weng, Tetrahedron 2013, 69, 8169; (e) K. C.
Majumdar, S. Alam, Org. Lett. 2006, 8, 4059; (f ) S. Majumder,
P. J. Bhuyan, Tetrahedron Lett. 2012, 53, 762.
Chen, J. Fan, A. S. Kende, J. Org. Chem. 2004, 69, 79; (e) N.
A. Meanwell, H. R. Roth, E. C. R. Smith, D. L. Wedding, J. J.
K. Wright, J. Org. Chem. 1991, 56, 6897; (f ) E. N. Koz'minykh,
E. S. Berezina, V. O. Koz'minykh, Russ. J. Gen. Chem. 1996,
66, 1100.
8. Crystal data of compound 3e-EE: solvent of crystal growth (hex-
anes/CH2Cl2, 10:1); empirical formula C20H17NO3, Fw = 319.4,
crystal dimensions 0.17 × 0.15 × 0.12 mm3, Monoclinic, space
group P21/n, a = 13.504(3) Å, b = 8.2246(18) Å, c = 15.246(3)
Å, α = 90.00ꢀ, β = 91.678(5)ꢀ, γ = 90.00ꢀ, V = 1692.6(6) Å3,
Z = 4, Dcalcd = 1.253 mg/m3, F000 = 672, MoKα (λ = 0.71073
Å), R1 = 0.0461, wR2 = 0.1150, GOF = 1.058 (I > 2σ(I)). The
X-ray data have been deposited in CCDC with number 1013579.
9. Crystal data of compound 3g-EZ: solvent of crystal growth
(EtOH); empirical formula C18H12N2O, Fw = 272.3, crystal
dimensions0.20 × 0.11 × 0.09 mm3, Orthorhombic, space group
P212121, a = 4.4968(13) Å, b = 12.156(4) Å, c = 25.162(8) Å, α
= 90.00ꢀ, β = 90.00ꢀ, γ = 90.00ꢀ, V = 1375.4(7) Å3, Z = 4, Dcalcd
= 1.315 mg/m3, F000 = 568, MoKα (λ = 0.71073 Å), R1 =
0.0544, wR2 = 0.1156, GOF = 1.029 (I > 2σ(I)). The X-ray data
have been deposited in CCDC with number 1013826.
13. For the similar Michael-type cyclizations of thioamides, see: (a)
S. Bhowmik, A. Mishra, S. Batra, RSC Adv. 2011, 1, 1464; (b) C.
Gimbert, A. Vallribera, Org. Lett. 2009, 11, 269.
Bull. Korean Chem. Soc. 2015, Vol. 36, 219–225
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
225