Selective synthesis of 3-methyleneindolin-2-ones by one-pot multicatalytic processes

Article abstract of DOI:10.1016/j.tetlet.2009.04.066

A novel one-pot multicatalytic route for the synthesis of 3-methyleneindolin-2-ones has been developed involving sequential copper-catalyzed amination and palladium-catalyzed C-H functionalization processes. In the presence of CuI and Pd(OAc)₂,

Full text of DOI:10.1016/j.tetlet.2009.04.066

Tetrahedron Letters 50 (2009) 3912–3916
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Selective synthesis of 3-methyleneindolin-2-ones by one-pot
multicatalytic processes
*
Ren-Jie Song, Yu Liu, Rong-Jiang Li, Jin-Heng Li
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Ministry of Education), Hunan Normal University, Changsha 410081, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel one-pot multicatalytic route for the synthesis of 3-methyleneindolin-2-ones has been developed
involving sequential copper-catalyzed amination and palladium-catalyzed C–H functionalization pro-
cesses. In the presence of CuI and Pd(OAc)2, a variety of propiolamides underwent the reaction with
iodides to afford the corresponding 3-methyleneindolin-2-ones in moderate yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 2 March 2009
Revised 11 April 2009
Accepted 17 April 2009
Available online 22 April 2009
Keywords:
Copper
Palladium
Amination
C–H functionalization
Propiolamide
3-Methyleneindolin-2-one
The 3-methyleneindolin-2-one moieties are frequently present
in naturally occurring and biologically active compounds that dis-
play great potential utilizations in many major therapeutic areas,
such as oncology, inflammation, CNS, immunology, and endocri-
nology.1 Therefore, attention of organic chemists has been increas-
ingly drawn to the development of efficient methods for their
preparation.2–4 Among the numerous transformations, palladium-
catalyzed cyclization of N-arylpropiolamide involving an arene
C–H functionalization process displayed efficiency particularly for
the synthesis of 3-methyleneindolin-2-ones.2–6 However, only
few papers have been reported for this purpose.2,3 Zhu and co-
workers, for example, have first developed the palladium-cata-
lyzed domino carbopalladation/C–H activation/C–C bond-forming
reaction that uses an anilide sp2 C–H bond and an electrophile (aryl
iodide) as the coupling partners (Scheme 1).2 Subsequently, we
have demonstrated some new protocols for constructing the
3-methyleneindolin-2-one skeleton by palladium-catalyzed oxida-
tive C–H functionalization of an anilide sp2 C–H bond with an
nucleophile (based on amide, acid, and ArI(OAc)2).3 Due to contin-
uing interest in this area,3,4f we report here a novel one-pot multi-
catalytic route7 for the synthesis of 3-methyleneindolin-2-ones
involving sequential copper-catalyzed amination and palladium-
catalyzed C–H functionalization processes (Scheme 1).8,9
optimize the reaction conditions, and the results are summarized
in Table 1. Initially, a series of ligands L1–L7 were examined, and
the results showed that L1, N,N0-dimethylethane-1,2-diamine,
was the most efficient (entries 1–7). After treatment of amide 1a
with iodide 2a, CuI, and L1 in DMF/MeCN for 12 h, the reaction
was conducted in the same vessel for another 12 h after the addi-
tion of Pd(OAc)2 to afford the target product 3 in a 57% yield (entry
1). However, the other nitrogen-containing ligands L2–L6 were
inferior to L1 (entries 2–6). The reported effective BuchwaldꢀHar-
twig amination phosphine L7 was also examined for the one-pot
reaction, and only 34% yield of 3 was obtained (entry 7). Among
the effects of solvents examined, we found that a mixture of
DMF/MeCN (1:1) provided the best results (entries 1 and 8–14).
R3
R2
R2
R2
O
A
+
R
N
I
R
HN
R1
O
R
N
O
B
R1
3-methyleneindolin-2-one
R1
The reported works
This work
R2
R3
R2
R2
O
Pd(OAc)2
100 ºC, 12 h
CuI, L1
+
The reaction between N-(4-methoxyphenyl)-3-phenylpropiola-
mide (1a) and 1-iodo-4-methoxybenzene (2a) was investigated to
K2CO3, 100 ºC
Ar, 12 h
R
I
N
N
O
R
HN
R1
O
R
R1
R1
L1:
HN
NH
* Corresponding author. Tel.: +86 731 8872 576; fax: +86 731 8872 101.
E-mail address: jhli@hunnu.edu.cn (J.-H. Li).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.066

R.-J. Song et al. / Tetrahedron Letters 50 (2009) 3912–3916
3913
Table 1
Screening optimal conditionsa
Ph
OMe
Ph
MeO
O
(1) CuI, L, K2CO3, 100 ºC, Ar, 12 h
MeO
+
N
(2) [Pd], 100 oC, 12 h
N
H
O
MeO
OMe
I
1a
2a
3
NH2
NH2
HN
NH
O
N
N
H2N
NH2
N
N
N
N
PPh2
PPh2
L2
L1
L4
L5
L6
L7
L3
Entry
Ligand
[Pd]
Solvent
Isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20b
21c
L1
L2
L3
L4
L5
L6
L7
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(CF3CO2)2
PdBr2
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF
57
Trace
17
47
Trace
18
34
29
Trace
28
22
24
20
32
37
27
32
55
56
MeCN
Toluene
Toluene/MeCN (1:1)
DMSO/MeCN (1:1)
DMF/MeCN (1:4)
DMF/MeCN (4:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
PdCl2(PPh3)2
Pd2(dba)3
K2PdCl4
Pd(OAc)2
Pd(OAc)2
21
20
Reaction conditions: 1a (0.2 mmol), 2a (2.2 equiv), Pd(OAc)2 (10 mol %), L7 (20 mol %), K2CO3 (2.2 equiv), and DMF/MeCN (1:1, 4 mL) at 100 °C for 12 h, then Pd(OAc)2
(10 mol %) at 100 °C for 12 h.
a
Reaction conditions: 1a (0.2 mmol), 2a (2.2 equiv), CuI (10 mol %), ligand (20 mol %), K2CO3 (2.2 equiv), and solvent (4 mL) at 100 °C for 12 h, then [Pd] (10 mol %) at
100 °C for 12 h. Some side products were observed from decomposition of the C–N bonds by GC–MS analysis.
b
Both CuI (10 mol %) and Pd(OAc)2 (10 mol %) were added at the same time for 24 h.
Reaction conditions: 1a (0.2 mmol), 2a (2.2 equiv), Pd(OAc)2 (10 mol %), L7 (20 mol %), K2CO3 (2.2 equiv), and DMF/MeCN (1:1, 4 mL) at 100 °C for 12 h, then Pd(OAc)2
c
(10 mol %) at 100 °C for 12 h.
Finally, a variety of other Pd catalysts, including Pd(CF3CO2)2,
PdBr2, PdCl2(PPh3)2, Pd2(dba)3, and K2PdCl4, were evaluated (en-
tries 15–19). The screening results demonstrated that the effi-
ciency of Pd2(dba)3 or K2PdCl4 is the same as that of Pd(OAc)2,
but Pd(CF3CO2)2, PdBr2, and PdCl2(PPh3)2 were less effective. It is
noteworthy that both CuI and Pd(OAc)2 were added to the mixture
of amide 1a and iodide 2a at the same time for 24 h providing the
product 3 in a low yield (entry 20). The results demonstrated that
only a low yield was obtained without Cu catalysts by a Pd-cata-
lyzed amination/C–H functionalization process (entry 21).9,8e
With the optimal conditions in hand, the scopes of both propi-
olamides 1 and iodides 2 were examined (Table 2).10 We were
pleased to find that the reactions of amide 1a with various iodides
2b, 2c, and 2e were still conducted smoothly in moderate yields
(entries 1, 2, and 4), but the reaction of the electron-deficient ary-
liodide 2d gave a mixture of products (entry 3). Treatment of sub-
strate 1a with iodobenzene (2b), CuI, L1, and Pd(OAc)2, for
instance, selectively afforded two products 4 and 5 in 62% total
yield (entry 1). The electron-rich aryliodide 2c was also suitable
for the one-pot reaction under the standard conditions (entry 2).
Interestingly, iodomethane (2e) could undergo the reaction with
amide 1a to afford the corresponding 3-methyleneindolin-2-one
8 in 47% yield (entry 4). Subsequently, we chose both propiola-
mides 1 and iodides 2 to control the selectivity (entries 5–9).
3-Phenyl-N-p-tolylpropiolamide (1d), for instance, was reacted
with 1-iodo-4-methylbenzene (2c) to give the product 11 alone
in 53% yield (entry 7). It is noteworthy that 21% yield can still be
achieved from the reaction between the two bulk substrates, 3-
phenyl-N-o-tolylpropiolamide (1f) and 1-iodo-2-methylbenzene
(2g) (entry 9). N-Alkyl phenylpropiolamides 1g and 1h were also
investigated under the standard conditions (entries 10 and 11).
The results demonstrated that both amides 1g and 1h could under-
go the one-pot reaction selectively in 36% and 33% yields, respectively.
As shown in Scheme 2, a controlled reaction was conducted.
Treatment of N-(4-methoxyphenyl)-3-phenylpropiolamide (1a)
with 1-iodo-4-methoxybenzene (2a), CuI, and L1 afforded the cor-
responding amination product 16 in 50% isolated yield. Subse-
quently, the reaction of 16 was carried out under the Zhu’s
conditions to give the target product 3 in 48% yield.
A possible mechanism was proposed as outlined in Scheme 3 on
the basis of the previously reported mechanisms and the present
results.2,3,8,9 Reaction of amide 1 with CuIL2 affords intermediate
A with the aid of base. Intermediate A undergoes the reaction with
iodide 2 to yield the product B and to regenerate the active Cu spe-
cies.8 Subsequently, C–H functionalization of the product B occurs
after the addition of Pd catalyst to give the target 3-methylenein-
dolin-2-ones by Zhu’s process.2 We deduced that Pd-catalyzed
amination of substrate 1 with iodide 2 may take place to give the
product B in the multicatalytic processes (entry 21 in Table 1).9,8e
Based on the present results, the stereoselectivity may mainly de-
pend on the characters of both aryl group on the propiolamide
moiety and substituent R1 of iodides, such as electronic effect
and steric effect. Study of the true mechanism is in progress.
In summary, we have developed a novel one-pot protocol for
the synthesis of 3-methyleneindolin-2-ones by sequential cop-
per-catalyzed amination and palladium-catalyzed C–H functional-

3914
R.-J. Song et al. / Tetrahedron Letters 50 (2009) 3912–3916
Table 2
Selective synthesis of 3-methyleneindolin-2-ones by one-pot multicatalytic processesa
Entry
Amide 1
Iodide 2
Product/isolated yieldb (%)
O
Ph
N
Ph
Ph
OMe
Ph
N
O
1
MeO
MeO
Ph
I
2b
N
H
O
O
O
O
4 (27)
5 (35)
1a
1a
1a
1a
O
N
O
N
OMe
Ph
Ph
2
3
4
5
6
7
8
9
MeO
MeO
MeO
I
2c
N
H
OMe
6 (37; E/Z = 2 : 1)
7 (27)
NO2
Mixture
I
N
H
2d
MeO
MeI 2e
O
N
N
H
8 (47)
MeO
Ph
O
I
N
OMe
OMe
2f
N
O
MeO
H
OMe
1b
9 (32; E/Z = 1 : 1)
Ph
Ph
O
N
I
2b
N
H
O
1c
10 (45)
O
Ph
N
I
2c
N
H
O
1d
11 (53)
Ph
N
O
I
2g
N
H
O
1e
12 (55; E/Z = 2 : 1)
O
I
N
2h
N
H
O
1f
13 (21; E/Z = 3 : 1)

R.-J. Song et al. / Tetrahedron Letters 50 (2009) 3912–3916
3915
Table 2 (continued)
Entry
Amide 1
Iodide 2
Product/isolated yieldb (%)
MeO
OMe
Ph
10
MeO
O
N
Bn
Bn
I
2a
N
H
O
1g
14 (36)
OMe
OMe
Ph
11
O
I
N
2a
N
H
O
MeO
15 (33; E/Z = 3 : 1)
1h
a
Reaction conditions: 1 (0.2 mmol), 2 (2.2 equiv), CuI (10 mol %), L1 (20 mol %), and K2CO3 (2.2 equiv) in DMF/MeCN (1:1, 4 mL) at 100 °C for 12 h, then Pd(OAc)2
(10 mol %) at 100 °C for 12 h. Some side products were observed from decomposition of the C–N bonds by GC–MS analysis.
b
Ratios of Z/E isomers were determined by 1H NMR.
Ph
MeO
MeO
I
MeO
Ph
N
Ph
2a
O
Pd(OAc)2, NaOAc
N
O
CuI, L1
MeO
DMF
110 ºC, Ar, 12 h
K2CO3, DMF/MeCN
100 ºC, Ar, 12 h
MeO
N
H
O
48%
50%
1a
OMe
Zhu's Conditions
OMe
16
3
Scheme 2. A controlled reaction.
References and notes
CuL2
N
R
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Hubbard, S. R.; Schlessinger, J. Science 1997, 276, 955; (b) Sun, L.; Tran, N.;
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R1
R1I
+ Pd(0) + base
Ph
R1I
2
Ph
O
Ph
O
A
Ph
Zhu's process
N
R1
R2
N
R
O
R
B
H
CuIL2
N
R
O
R1
Pd
N
1
+
L
R
Pd(0)
CuI
base
Ph
R1I
2
O
D
Ph
R1 PdI
C
+
base
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O
1
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Hayashi, T. Org. Lett. 2006, 8, 4799; (b) Miura, T.; Takahashi, Y.; Murakami, M.
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Scheme 3. A possible mechanism.
ization reactions. In the presence of CuI and Pd(OAc)2, a variety of
propiolamides underwent the multicatalytic processes with io-
dides to afford the corresponding 3-methyleneindolin-2-ones in
moderate yields. Efforts to extend the application of the transfor-
mation in organic synthesis are underway in our laboratory.
Acknowledgments
The authors thank the New Century Excellent Talents in Univer-
sity (No. NCET-06-0711), Scientific Research Fund of Hunan Pro-
vincial Education Department (No. 08A037), and National Natural
Science Foundation of China (No. 20572020) for financial support.
Supplementary data
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2009.04.066.

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R.-J. Song et al. / Tetrahedron Letters 50 (2009) 3912–3916
7. For selected reviews on the transition metal-catalyzed multicatalytic
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10. Typical procedure: A mixture of propiolamide 1 (0.2 mmol), iodide 2 (2.2 equiv),
CuI (10 mol %), N,N0-dimethylethane-1,2-diamine L1 (20 mol %), and K2CO3
(2.2 equiv) was stirred in DMF/MeCN (v/v 1:1, 4 mL) at 100 °C for 12 h, then
Pd(OAc)2 (10 mol %) was added to the mixture, and stirred at 100 °C for
another 12 h until complete consumption of starting material which was
monitored by TLC. After the reaction was complete, the mixture was washed
with saturated NaCl, and was extracted with diethyl ether. The organic layers
were dried with Na2SO4 and were evaporated under vacuum, the residue was
purified by flash column chromatography (hexane/ethyl acetate) to afford the
pure product.
(E)-5-Methoxy-1-(4-methoxyphenyl)-3-((4-methoxyphenyl)(phenyl) methylene)-
indolin-2-one (3): Red oil; 1H NMR (500 MHz) d: 7.36–7.30 (m, 9H), 6.97 (d,
J = 4.5 Hz, 1H), 7.28 (t, J = 4.5 Hz, 3H), 7.27–7.18 (m, 4H), 7.17–7.15 (m, 1H), 7.02
(t, J = 6.5 Hz, 1H), 6.99 (t, J = 6.5 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 4.90 (s, 2H), 2.37
(s, 3H), 2.29 (s, 3H); 13C NMR (125 MHz) d: 166.5, 160.8, 158.7, 155.7, 154.9,
140.2, 137.5, 133.5, 131.6, 130.5, 129.2, 128.1, 127.8, 127.7, 124.4, 123.6, 114.6,
114.3, 114.1, 109.3, 109.2, 55.5 (2C), 55.4;IR (KBr, cmꢀ1): 1699, 1508, 1247; LRMS
(EI, 70 eV) m/z (%): 464 (33), 463 (M+, 100), 448 (13) , 420 (2), 386 (3), 340 (1), 232
(19), 195 (2); HRMS (EI) for C30H25NO4 (M+): calcd 463.1784, found 463.1783.
5-Methoxy-3-((4-methoxyphenyl)(phenyl)methylene)-1-methylindolin-2-one (15):
2E/Z = 3:1; Yellow oil, 1H NMR (500 MHz) d: 7.49 (s, 1H), 7.42–7.28 (m, 6H),
7.10 (d, J = 7.0 Hz, 2.3H), 7.06 (d, J = 7.0 Hz, 0.7H), 6.97–6.87 (m, 1H), 6.75–6.64
(m, 1H), 3.86 (s, 3H), 3.83 (s, 1H), 3.54 (s, 3H), 3.44 (s, 1H), 3.20 (s, 1H), 3.17 (s,
3H) ; 13C NMR (125 MHz) d 166.9, 160.7, 154.9, 154.7, 140.3, 137.2, 137.0,
133.3, 132.5, 131.6, 130.3, 129.7, 129.2, 129.1, 128.9, 127.7, 124.4, 123.9, 114.1,
114.0, 113.8, 113.0, 109.5, 109.2, 107.8; IR (KBr, cmꢀ1): 1684, 1507, 1490;
LRMS (EI, 70 eV) m/z (%): 372 (21), 371 (M+, 100), 356 (18), 341 (4), 328 (3), 294
(5), 264 (3), 178 (8).
9. For selected papers on Pd-catalyzed amination of amides with aryl halides, see:
(a) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35; (b) Yin, J.; Buchwald, S. L.
Org. Lett. 2000, 2, 1101; (c) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
6043; (d) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S.
L. J. Am. Chem. Soc. 2003, 125, 6653; (e) Manley, P. J.; Bilodeau, M. T. Org. Lett.
2004, 6, 2433; (f) Willis, M. C.; Brace, G. M.; Holmes, L. P. Synthesis 2005, 3229;
(g) Ligthart, G. B. W. L.; Ohkawa, H.; Sijbesma, R. P.; Meijer, E. W. J. Org. Chem.