A highly efficient thiourea catalyzed dehydrative nucleophilic substitution reaction of 3-substituted oxindoles with xanthydrols

Article abstract of DOI:10.1039/c3ra44520h

We report a highly efficient thiourea catalyzed dehydrative nucleophilic substitution reaction. The Schreiner's thiourea catalyst A₁ catalyzed the alkylation of 3-substituted oxindoles with xanthydrols well, to furnish quaternary oxindoles in high yield. The ESI-MS analysis confirms the interaction of 3-substituted oxindole 1 with the thiourea, which might facilitate the oxindole-hydroxindole tautomerization for the alkylation. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra44520h

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A highly efficient thiourea catalyzed dehydrative
nucleophilic substitution reaction of 3-substituted
Cite this: RSC Adv., 2013, 3, 19880
oxindoles with xanthydrols†
Received 5th July 2013
*
*
Long Chen, Feng Zhu, Cui-Hong Wang and Jian Zhou
Accepted 29th August 2013
DOI: 10.1039/c3ra44520h
www.rsc.org/advances
We report a highly efficient thiourea catalyzed dehydrative nucleo- in improving its efficiency by using catalytic amount of acids.8
philic substitution reaction. The Schreiner's thiourea catalyst A1 Noticeably, the combination of a chiral amine catalyst with an
catalyzed the alkylation of 3-substituted oxindoles with xanthydrols acid co-catalyst emerges as a powerful strategy for the devel-
well, to furnish quaternary oxindoles in high yield. The ESI-MS opment of asymmetric version of this reaction,9 since Cozzi's
analysis confirms the interaction of 3-substituted oxindole 1 with the pioneering work.9a Nevertheless, there still has ample room for
thiourea, which might facilitate the oxindole–hydroxindole tauto- further studies: (1) identify new catalysts for this green meth-
merization for the alkylation.
odology. Generally, the use of a Lewis acid or a specic Brønsted
acid catalyst is necessary.8,9 To the best of our knowledge, the
general acid catalyzed variant is largely unexplored, although
recently Cozzi reported a remarkable cataꢀlyst-free “on water”
nucleophilic substitution of alcohols at 80 C.10a In the studies
of triuoroacetic acid (TFA) catalyzed alkylation of oxazolones
using Michler's hydrols, Rios et al. found that thiourea could
also work, but the yield of the desired product was not given.10b
The potential and the advantages of (thio)urea catalysis have
not been explored in this important C–C bond forming reaction.
(2) Enable the construction of quaternary carbons. While the
arylation of tertiary alcohols has been studied,8f–l few attention
is paid to the alternative strategy which relies on the alkylation
at the tertiary carbon of nucleophiles.8f,9e,10b Herein, we wish to
report a highly efficient thiourea-catalyzed dehydrative nucleo-
philic substitution of unprotected both 3-aryl and 3-alkyl oxin-
doles using xanthydrols.
Recently, there is an ever-increasing interest in the diverse
synthesis of 3,3-disubstituted oxindoles,11 a type of privileged
scaffolds in natural products and pharmaceutically active
compounds, as the substituents at the C3 position of oxindole
framework greatly inuenced their bioactivity. Of all the
methods available, the direct functionalization of 3-substituted
oxindoles proves to be very useful, and N-Boc protected 3-
substituted oxindoles, which are so reactive that could even be
elaborated under base-free phase transfer condition,12 are the
most popular substrates for reaction design. Unfortunately,
their synthesis needs three steps from isatins, with the sacrice
of one more equivalent of (Boc)2O.13 Therefore, the use of less
reactive but easily accessible unprotected 3-substituted oxin-
doles 1 for reaction design is challenging but worth of
exploration.14
Since Hine and co-workers discovered that biphenylenediol can
catalyze the epoxide-opening reaction,1 hydrogen-bonding
donor catalysts have found widespread applications in organic
synthesis.2 In particular, (thio)urea derivatives, a type of dual
hydrogen-bond donors, proved to be very useful.3 In 1994,
Curran and Kuo reported for the rst time that ureas could
serve as catalysts for some organic reactions.4 Schreiner et al.
further developed a remarkable array of thiourea catalysts, and
N,N0-bis-[3,5-bis-(triuoromethyl)phenyl]-thiourea A1 proved to
be a powerful organocatalyst.5 The most important advances in
this eld were made by the Jacobsen laboratory,6 whose studies
fueled the development of asymmetric chiral (thio)urea catal-
ysis.3 Later, inspired by Takemoto's work,7 bifunctional (thio)
urea-tertiary amine catalysts opened up new synthetic oppor-
tunities of urea catalysis. Despite signicant achievements, it is
still highly desirable to extend urea catalysis to new types of
reactions.5–7
The dehydrative nucleophilic substitution of alcohols is an
important atom economical C–C bond forming reaction.8 Apart
from electron-rich aromatics and heteroatom based nucleo-
philes, active methylene compounds such as malonates,
b-ketoesters and 2,4-diketones are also viable substrates for this
reaction. During the past decade, much progress has been made
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of
Chemistry, East China Normal University, 3663 N. Zhongshan Road, Shanghai
200062, P. R. China. E-mail: chwang@chem.ecnu.edu.cn; jzhou@chem.ecnu.edu.cn;
Fax: +86-21-6223-4560; Tel: +86-21-6223-4560
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra44520h
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In this context, we have reported that bifunctional (thio)urea decreased yield for 3a (entry 9). When the reaction was run
derivatives could catalyze the direct amination15a and Michael under nitrogen, the yield of 3a could be improved to 81%
addition15b using unprotected oxindole 1.15 To increase the (entry 10), and further to 88% by increasing the usage of 2a from
structural diversity of quaternary oxindoles, we considered the 1.2 to 2.0 equivs (entry 12). Based on these studies, the optimal
direct coupling of oxindole 1 with xanthydrols. Accordingly, the condition was determined to run the reaction at 50 ꢀC using
reaction of unprotected 3-phenyl oxindole 1a and 2a was chosen CH3CN as the solvent, in the presence of 10 mol% of urea A1 as
for condition optimization, and some typical results were the catalyst.
shown in Table 1. Based on our previous studies in the acid
Under the optimized condition, the scope of the reaction
catalyzed functionalization of tertiary alcohols,16 various Lewis with respect to different substituted oxindoles was examined
acids were rst evaluated. Very surprisingly, the use of Lewis (Table 3). The effects of substituent on the phenyl ring of
acids generally led to the deterioration of 2a. For example, in the oxindoles were rst examined (entries 1–4), and it turned out
presence of 10 mol% of In(OTf)3, no desired product 3a was that the electron-withdrawing substituents slowed down the
obtained, but 4 and 5 were isolated in 73% and 21% yield,17 reaction, but the corresponding products 3b–c were still
respectively (entry 1). While Xiao reported that the use of CuCl obtained in high yield (entries 2 and 3). 3-Monosubstituted
beneted the a-alkylation of aldehydes using 2, it mediated the oxindoles 1e–j with different aromatic substituents at C3 posi-
reaction to give 3a in only 14% yield, with 56% of 4 (entry 2). tion all worked well to give the desired products in high to
Brønsted acids were then tried. Unexpectedly, when HOTf or excellent yield (entries 5–10). To our delight, unprotected 3-alkyl
p-TsOH was used, no product 3a was obtained (entries 3 and 4), oxindoles 1k–l were also viable substrates, giving products 3k–l
but benzoic acid as the catalyst afforded 3a in 36% yield (entry in good yield (entries 11 and 12). The 9H-thioxanthen-9-ol 2b
5). These results suggested that strong acids might result in the could readily react with both 3-aryl and alkyl oxindoles to give
deterioration of 2a, which encouraged us to try H-bonding the desired products 3m–o in good yield (entries 13–15).
donor catalysts. Indeed, better yield for 3a was obtained when
It should be noted that although Rios et al. reported the TFA
1,10-binaphthyl-2,20-diol (BINOL) or urea A1 was used (entries 6 catalyzed alkylation of 3-alkyl oxindoles using Michler's hydrols,
and 7). Particularly, A1 provided 3a in 59% yield. These results and Liu et al. reported a nice asymmetric reaction of N-Boc
encouraged us to optimize other thioureas A2–A6, pyridine 3-alkyl oxindoles and Michler's hydrols catalyzed by the
based thioureas B1–B2 and bisthioureas C1–C2, but no further combination of a bis-cinchona alkaloid and methylsulfonic acid
improvement was observed (entries 8–16).
(1 : 1), our protocol was distinct from their research in that it
In the following, other reaction parameters were studied by enabled both unprotected 3-aryl and 3-alkyl oxindoles to be
using 10 mol% of urea A1 as the catalyst at 50 ꢀC. The study of alkylated by xanthydrols, and most importantly, H-bonding
solvent effects revealed that CH3CN was the best, which could donor catalysts such as thiourea A1 turned out to be more effi-
improve the yield of product 3a to 77% (entries 1 to 8, Table 2). cient in this reaction than Lewis acids and commonly used
Raising the reaction temperature to 70 ꢀC resulted in the strong Brønsted acids for this SN1 type reaction. The result
prompted us to study the corresponding catalytic asymmetric
Table 1 Catalyst screening
Table 2 Solvent screening and condition optimization
Entrya
Solvent
X
Temp. (ꢀC)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
ClCH2CH2Cl
THF
Toluene
DMF
CH3CO2Et
Acetone
CH3NO2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
2.0
50
50
50
50
50
50
50
50
70
50
50
50
15
15
15
15
15
15
2
6
4
6
5
65
63
65
11
78
66
68
77
70
81
85
88
Entrya
Catalyst
Yieldb (%)
Entrya
Catalyst
Yieldb (%)
1c
2d
3
4
5
6
7
8
In(OTf)3
CuCl
Trace
14
Trace
Trace
36
52
59
23
9
10
11
12
13
14
15
16
A3
A4
A5
A6
B1
B2
C1
C2
31
44
45
33
50
50
31
49
HOTf
p-TsOH
PhCO2H
BINOL
A1
9
10c
11c
12c
A2
5
a
On a 0.1 mmol scale. b Isolated yield. c 4 and 5 were obtained in 73%
and 21% yield, respectively. d 56% of 4 and trace amount of 5.
a
On a 0.1 mmol scale. b Isolated yield. c Under N2 atmosphere.
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Table 3 Substrate scope
Entrya
1
2
Time (h)
5
3
Yieldb (%)
1
2
3
4
5
6
7
8
1a: R1 ¼ H, R2 ¼ Ph
1b: R1 ¼ 5-F, R2 ¼ Ph
1c: R1 ¼ 5,7-Br, R2 ¼ Ph
2a
2a 22
2a 22
3a 81
3b 76
3c 83
3d 80
3e 89
3f 75
3g 86
3h 91
3i 65
3j
3k 65
3l 85
3m 79
3n 63
3o 79
1d: R1 ¼ 5,7-methyl, R2 ¼ Ph 2a 12
1e: R1 ¼ H, R2 ¼ 4-FC6H4
1f: R1 ¼ H, R2 ¼ 4-BrC6H4
1g: R1 ¼ H, R2 ¼ 4-MeC6H4
1h: R1 ¼ H, R2 ¼ 4-CF3C6H4
2a 18
2a 18
2a 18
2a
9
9
1i: R1 ¼ H, R2 ¼ 2-thiophenyl 2a 24
1j: R1 ¼ 5-Br, R2 ¼ 2-naphthyl 2a 12
10
11
12
13
14
15
82
1k: R1 ¼ H, R2 ¼ Bn
1l: R1 ¼ 5-Br, R2 ¼ Me
1a: R1 ¼ H, R2 ¼ Ph
1k: R1 ¼ H, R2 ¼ Bn
1l:R1 ¼ 5-Br, R2 ¼ Me
2a 22
2a 24
2b 18
2b 24
2b 24
a
On a 0.25 mmol scale. b Isolated yield.
process by using some typical chiral thiourea catalysts, but no
enantiomeric excess was observed.18
Fig. 1 (A) ESI-MS spectrum (positive mode) of the interaction between 3-phenyl
oxindole 1a and thiourea A5. (B) ESI-MS/MS spectrum for CID of [1a + A5 + Na]+ at
m/z 460 with a collision energy of 10 eV.
To investigate the role of thioureas to catalyze this reaction,
the ESI-MS analysis of the reaction process was undertaken.19
Interestingly, the interaction of thioureas with 3-phenyl oxin-
dole 1a was conrmed by ESI-MS/MS analysis. For example, a
characteristic signal [1a + A5 + Na]+ consistent with the complex
of oxindole 1a and thiourea A5 was observed at m/z 460
(A, Fig. 1), which was further conrmed by the CID fragmen-
tation pattern of the ion m/z 460 obtained from an ESI-MS/MS
(positive mode) experiment (B, Fig. 1). The high resolution mass
data of the detected complex was as follows: calculated for
thiourea with 3-substituted oxindole, which might facilitate the
oxindole–hydroxindole tautomerization for the alkylation. The
scope and limitation of this methodology, the mechanism study
and the development of asymmetric version is now in progress
in our laboratory.
The nancial support from NSFC (21172075, 21222204),
Ministry of Education (NCET-11-0147), Program of Shanghai
Subject Chief Scientist (13XD1401600) and Innovation Program
of SMEC (12ZZ046).
C
27H23N3Na1O1S1 460.1454; found 460.1439; with an error of
3.25 ppm. Considering the role of thiourea catalysts is generally
believed to activate the electrophilic reaction partners through
the hydrogen-bonding interaction, this nding is very inter-
esting, suggesting that the thiourea might activate the nucleo-
phile for the reaction, which is rarely reported.3
Based on this information, we initially proposed a dual role
of the thiourea catalyst to promote this reaction, as shown in
Scheme 1. The interaction of 3-substituted oxindole 1 with
thiourea A5 lead to the oxindole–hydroxindole tautomerization,
which might form a reactive intermediate (i); on the other hand,
the interaction of the thiourea and xanthydrols might facilitate
the formation of carbocation intermediate (ii). Accordingly,
both intermediates (i) and (ii) readily reacted with each other to
give the desired product 3 and regenerate the thiourea catalyst.
In conclusion, we have reported a highly efficient thiourea
catalyzed alkylation of both unprotected 3-aryl and 3-alkyl
oxindoles using xanthydrols. Initial investigation of the reaction
mechanism by ESI-MS analysis reveals the interaction of the Scheme 1 Proposed reaction mechanism.
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Y.-L. Liu, X.-P. Zeng and J. Zhou, Chem.–Asian J., 2012, 7,
1759; (g) C.-B. Ji, Z.-Y. Cao, X. Wang, D.-Y. Wu and J. Zhou,
Chem.–Asian J., 2013, 8, 877; (h) X.-P. Zeng, Y.-L. Liu,
C.-B. Ji and J. Zhou, Chin. J. Chem., 2012, 30, 2631.
19 For selected references on detecting the reaction
intermediates by mass spectrometry: (a) W. Schrader,
P. P. Handayani, J. Zhou and B. List, Angew. Chem., Int.
Ed., 2009, 48, 1463; (b) L. Zhang, R. Qian, X. Zhang,
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(c) H. Guo, R. Qian, Y.-X. Liao, S.-M. Ma and Y.-L. Guo, J.
Am. Chem. Soc., 2005, 127, 13060; (d) H.-L. Bao, J. Zhou,
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Soc., 2008, 130, 10116; (e) S. Meyer, R. Koch and
J. O. Metzger, Angew. Chem., Int. Ed., 2003, 42, 4700; (f)
R. Qian, H. Guo, Y.-X. Liao, Y.-L. Guo and S.-M. Ma, Angew.
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17 The same phenomenon has been reported: (a) Z. Zhu and
J. H. Espenson, J. Org. Chem., 1996, 61, 4324; (b)
ˇ
M. Prashad, Y. Lu and O. Repic, J. Org. Chem., 2004, 69, 584.
18 We chose the reaction of 1a and 2a to initiate the asymmetric
study. Aer screening several typical chiral thiourea catalyst,
we found that only chiral thiourea catalyst A7 could give
product 3a in 3% ee when using dichloromethane as the
19884 | RSC Adv., 2013, 3, 19880–19884
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