Oxindole synthesis by direct coupling of Csp2-H and C sp3-H centers

Article abstract of DOI:10.1002/anie.200805652

(Chemical Equation Presented) An sp²/sp³ get-together: A novel and efficient method can be used to synthesize 3,3-disubstitued oxindoles by the direct intramolecular oxidative coupling of an aryl C_sp2-H and a C_sp3-H center (see scheme; DMF = N,N-dimethylformamide).

Full text of DOI:10.1002/anie.200805652

Communications
DOI: 10.1002/anie.200805652
Synthetic Methods
ꢀ
ꢀ
Oxindole Synthesis by Direct Coupling of Csp2 H and Csp3 H Centers**
Yi-Xia Jia and E. Peter Kꢀndig*
Oxindoles are common and important substructures in
natural products and biologically active molecules.[1] Numer-
ous methods have been reported for the syntheses of
oxindoles, including the derivatization of isatin and indoles,[2]
cyclization of o-aminophenylacetic acids and a-halo or a-
hydroxy acetanilides,[2a,3] radical cyclizations,[4] palladium-
catalyzed Heck reactions,[5] domino Heck/cyanation reac-
tions,[6] and cyanoamidation reactions.[7] In particular, the
methods developed by Hartwig and co-workers (Scheme 1,
A by electrophilic attack of PdII onto the acetanilide and
subsequent deprotonation. We hypothesized that by combin-
ing this method with that of the intramolecular arylation of
amides,[8] palladacycle intermediate B could be formed in situ.
ꢀ
If correct, the direct coupling of two C H bonds to give
oxindoles could be realized (Figure 1).
Scheme 1. Palladium-catalyzed oxindole synthesis from anilide deriva-
tives.
Method a, Pd-catalyzed arylation reaction),[8a,d] and Hennes-
sey and Buchwald (Scheme 1, Method b, Pd-catalyzed alkyl-
ation reaction)[9] provide very useful access to oxindoles. All
the aforementioned methods require a specifically function-
alized precursor; for example, the presence of an ortho hal-
ogen, an a-halogen or a-hydroxy group, or a preexisting ring
system. The development of new and more efficient methods
Figure 1. Initial hypothetical pathway for the catalyzed direct coupling
reaction.
The initial reaction of N-methyl-N-2-diphenylpropan-
amide (1a) was carried out in the presence of 3.0 equivalents
of tBuONa as the base and 1.2 equivalents of CuCl2 as the
oxidant, and by using 5 mol% Pd(OAc)2 as the catalyst in
toluene at 1108C. This set of conditions indeed afforded
oxindole 2a in 37% yield with 42% conversion after 20 hours
(Table 1, entry 1). Other bases were tested but tBuONa was
found to be the most efficient (Table 1, entries 1–6). The
screening of different CuII compounds (Table 1, entries 7–11)
revealed Cu(OAc)2 to give the best result. Nearly complete
conversion and a 74% yield of isolated 2a was obtained by
increasing the amount of the base and the oxidant to
5.0 equivalents and 2.2 equivalents, respectively, and by
prolonging the reaction time to 36 hours (Table 1, entry 12).
Solvent screening (Table 1, entries 13–17) showed that reac-
tions were fully suppressed in dichloroethane (DCE) and that
N,N-dimethylformamide (DMF) was the solvent of choice,
giving 2a upon isolation in 78% yield after a 5 hour reaction
time.
ꢀ
is important. Recently, C H activation has emerged as a
ꢀ
highly valuable strategy for C C coupling reactions because
of its high atom economy.[10] Accordingly, processes involving
ꢀ
direct coupling between two C H centers have received much
attention recently,[11] but examples of couplings between Csp2
ꢀ
[12]
ꢀ
H and Csp3 H centers are still scarce. Herein, we describe
our initial results for the synthesis of oxindoles by the direct
ꢀ
ꢀ
coupling of Csp2 H and Csp3 H centers (Scheme 1, Meth-
od c).[13]
Acetanilides have been recently used as substrates in
[14]
ꢀ
ortho functionalizations involving C H activation.
The
authors propose the formation of a palladacycle intermediate
[*] Dr. Y.-X. Jia, Prof. Dr. E. P. Kꢀndig
Department of Organic Chemistry, University of Geneva
30 Quai Ernest Ansermet, 1211 Geneva 4 (Switzerland)
Fax: (+41)22-379-3215
For an asymmetric version of this reaction we tested chiral
N-heterocyclic carbene (NHC) ligands, which we had suc-
cessfully used in asymmetric oxindole synthesis.[8g,h] However,
all attempts, including a change in the solvent and reaction
conditions, failed to give an enantiomerically enriched
product. These results put into question the hypothesis of
E-mail: peter.kundig@ unige.ch
[**] Support of this work by the Swiss National Foundation is gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805652.
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Angewandte
Chemie
Table 1: Oxindole synthesis by direct coupling reaction.[a]
Entry Oxidant
Base
Solvent t [h] Conv. [%][b] Yield [%][b]
1
2
3
4
5
6
7
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
BQ
tBuONa
tBuOLi
tBuOK
NaHMDS toluene 20
NaH
Cs2CO3
tBuONa
tBuONa
tBuONa
toluene 20
toluene 20
toluene 20
42
20
90
81
37
16
15
12
13
0
34
0
34
41
56
82 (74)
56
52
0
5
ꢀ
Figure 2. Revised proposed pathway for the direct C H coupling
reaction.
toluene 20
toluene 20
toluene 20
toluene 20
toluene 20
toluene 20
toluene 20
toluene 36
toluene 20
toluene 20
15
n.r.[d]
50
Different oxidants commonly used in radical chemistry
were screened and the results are listed in Table 2. CuCl2 was
the most efficient reagent, giving oxindole 2a in 93% yield
8[c]
9
K2S2O8
CuBr2
n.r.[d]
39
10
11
12
13[e]
14[e]
15
16
17
Cu(OTf)2 tBuONa
Cu(OAc)2 tBuONa
Cu(OAc)2 tBuONa
Cu(OAc)2 tBuONa
Cu(OAc)2 tBuONa
Cu(OAc)2 tBuONa
Cu(OAc)2 tBuONa
Cu(OAc)2 tBuONa
53
66
97
97
Table 2: Screening of oxidants in DMF.[a]
98
DCE
DMSO 20
DMF
20
n.r.[d]
27
5
99
85 (78)
[a] Reaction conditions: 0.4 mmol substrate in 8.0 mL solvent at 1108C
for 20 h, 1.2 equiv oxidant and 3.0 equiv base used in entries 1–11;
2.2 equiv oxidant and 5.0 equiv base used in entries 12–17. [b] Deter-
mined by GC analysis using naphthalene as an internal standard. Yield of
isolated product in parentheses. [c] Potassium peroxodisulfate. [d] No
reaction. [e] At 808C. Tf=trifluorosulfonyl, DMSO=dimethyl sulfoxide.
Entry
Oxidant
t [h]
Conv. [%][b]
Yield [%][b]
1
2
3
4
5
6
7
8
CuCl2
CuBr2
Cu(OAc)2
Cu(OTf)2
BQ
Ag2O
Mn(OAc)3
FeCl3
CAN
CuCl2
5
3
5
100
100
99
81
88
98(93)
87
85
72
35
27
42
–
10
10
10
7
10
10
24
24
84
61
n.r.[c]
n.r.[c]
48
9
–
41
48
the palladium-catalyzed sequence shown in Figure 1. Indeed,
repeating the reaction detailed in entry 17 of Table 1 in the
absence of Pd(OAc)2 afforded 2a in the same yield as
reported previously (Scheme 2). As palladium does not play a
10[d]
11[e]
CuCl2
57
[a] Reaction conditions: 0.4 mmol substrate in 8.0 mL DMF at 1108C.
[b] Determined by GC analysis using naphthalene as an internal
standard. Yield of isolated product in parentheses. [c] No reaction.
[d] 2.0 equiv CuCl2 and 3.0 equiv tBuONa were used. [e] 1.2 equiv CuCl2
and 3.0 equiv tBuONa were used.
upon isolation after 5 hours (Table 2, entry 1). Decreasing the
amount of CuCl2 and tBuONa lowered both the conversion
and yield remarkably (Table 2, entries 10 and 11). Other
oxidants such as 1,4-benzoquinone (BQ), Ag2O, and man-
ganese triacetate (Mn(OAc)3) were less efficient, and FeCl3
and ceric ammonium nitrate (CAN) did not promote this
reaction (Table 2, entries 5–9).
Scheme 2. Cu(OAc)2-mediated direct coupling reaction to give an
oxindole.
significant role in the reaction of 1a!2a, an alternative
pathway of this direct coupling, through an intramolecular
oxidative coupling reaction, is shown in Figure 2. Radical
formation by amide enolate oxidation is followed by cycliza-
tion onto the aromatic ring. The resulting cyclohexadienyl
radical readily aromatizes to the oxindole product.[15] The
alternative pathway involving a radical coupling reaction with
the second radical being formed by one-electron oxidation of
the aniline amide is deemed less probable. While it has been
shown that dimethylanilines can undergo intermolecular
oxidative coupling,[16] we find that this reaction does not
take place with acetanilides. Also, precedent for direct
oxidative coupling reactions between enolates and arenes is
limited to the electron-rich indoles and pyrroles.[17]
ꢀ
In keeping with the proposed mechanism (Figure 2), Csp2
H bond breaking is not involved in the rate-determining step
as shown by the observation of a secondary isotope effect of
0.8 in the reaction of substrate 3 (Scheme 3).
Upon exploring the scope of the reaction, a number of
substrates were tested under the optimal reaction conditions
found for 1a. The data in Table 3 show yields to be usually
good. Exceptions are reactions involving substrates having an
ortho-substituted arylacetic amide fragment (e.g. 1d and 1 f).
The reactions of 1h–j show the size of R3 to affect the
reaction. Importantly, spirooxindole 2j was obtained in good
yield, and 3-methoxy-substituted oxindole 2k could also be
obtained albeit in modest yield. Substitution within the
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Communications
In summary, we have developed a novel and efficient
method for the synthesis of 3,3-disubstitued oxindoles by the
ꢀ
direct intramolecular oxidative coupling of an aryl Csp2 H and
ꢀ
a Csp3 H center. The reaction is mediated by inexpensive
CuCl2. Additional research will focus on the development of
catalytic and asymmetric catalytic versions of this reaction.
Scheme 3. Labeling experiment using substrate 3.
Experimental Section
For full experimental and spectroscopic data, see the Supporting
Information.
Table 3: Substrate scope.[a]
Synthesis of 2a: To a dried Schlenk tube were added amide 1a
(239 mg, 1.0 mmol), CuCl2 (296 mg, 2.2 mmol), and tBuONa
(480 mg, 5.0 mmol) under N2, and then DMF (20 mL, N2 sat.) was
introduced by syringe. The resulting mixture was stirred at 1108C
for 5 h (reaction monitored by GC analysis). After cooling to room
temperature, the mixture was filtered through Celite and then brine
(100 mL) and diethyl ether (40 mL) were added. Extraction with
diethyl ether (2 ꢀ 30 mL), then drying of the combined organic
phases over MgSO4, and final evaporation of the solvent afforded a
crude product that was purified by flash chromatography (pentane/
diethyl ether 2:1) to give oxindole 2a (221 mg, 93%).
2a, 5 h, 93 %
2b, 6 h, 81 % 2c, 6 h, 96 %
2d, 24 h, 65 %
Received: November 19, 2008
Published online: January 23, 2009
Keywords: copper · oxidative coupling · oxindoles ·
radical reactions
2e, 5 h, 97 %
2I, 12 h, 92 %
2m, 8 h, 91 %
2 f, 24 h, 42 % 2g, 5 h, 91 %
2h, 12 h, 54 %
.
2j, 8 h, 78 %
2k, 5 h, 38 %
2l, 3 h, 49 %
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Scheme 4. Substrates not affording oxindole products.
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