Highly enantioselective construction of 3-hydroxy oxindoles through a decarboxylative aldol addition of trifluoromethyl α-fluorinated gem-diols to n-benzyl isatins

Article abstract of DOI:10.1002/anie.201301443

An organocatalytic asymmetric direct aldol addition reaction that involves cleavage of a carbon-carbon bond through the release of trifluoroacetate was developed. The protocol is wide in scope, generating the desired oxindoles of biological interest in nearly quantitative yields (up to 99 %) with excellent enantioselectivities (up to 98 % ee) and diastereoselectivities (up to 99:1 d.r.). Copyright

Full text of DOI:10.1002/anie.201301443

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Angewandte
Communications
DOI: 10.1002/anie.201301443
Organocatalysis
Highly Enantioselective Construction of 3-Hydroxy Oxindoles through
a Decarboxylative Aldol Addition of Trifluoromethyl a-Fluorinated
gem-Diols to N-Benzyl Isatins**
Ibrayim Saidalimu, Xiang Fang,* Xiao-Peng He, Jing Liang, Xueyan Yang, and Fanhong Wu*
À
Owing to the stability of carbon–carbon (C C) bonds their
cleavage has long remained a great challenge for organic
chemists.[1] Decarboxylation is one of the most prevailing
methods to fulfill this purpose because of its efficiency in
forming reactive intermediates that successively promote the
bond cleavage under mild conditions.[2] Trifluoroacetate is
a functional group universally used in many reactions and the
release of which is hypothesized to be analogous to decar-
boxylation. In 1968, the first tactic in which trifluoroacetate
was released by elimination of hexafluoroacetone hydrate
fragments was reported.[3] Recently, Colby and co-workers
have demonstrated that this tactic was also applicable in
effectively furnishing a,a-difluoroenolates.[4]
the methyl ketones are sufficiently activated by a trifluoro-
methyl gem-diol group and an a-fluorine atom (Scheme 1).[11]
Scheme 1. Activation strategy for methyl ketones in aldol reactions.
The aldol reaction is among the most important protocols
À
for C C bond formation. Therefore, many asymmetric
The requisite trifluoromethyl a-fluorinated b-keto gem-
diols 1 that exist exclusively in their keto form[12] were easily
prepared with Cu(NO3)2·3H2O as catalyst from Selectfluor
and trifluoro-1,3-diones obtained by trifluoroacetylation of
methyl ketones (Table 1).[13] X-ray analysis in combination
with 13C NMR spectroscopic data of crystalline 1a supported
the formation of a gem-diol rather than of a ketone and
a water molecule.[14]
syntheses employing this reaction have been developed.[5]
A
survey of recent literature shows that significant advances in
the organocatalytic direct aldol reactions have been made.[6]
However, methyl ketones, and particularly, aryl methyl
ketones are substrates that are difficult to activate by direct
enamine formation[7] owing to the low orbital overlap
between the enamine double bond and the nitrogen lone
pair.[8] As a result, preactivation, such as the use of silyl enol
ethers,[9] of such inert ketones is often required. Recently, Lu
and co-workers reported a wise approach of using a b-
ketoacid as a surrogate of an aryl methyl ketone enolate.[10] In
an attempt to develop an effective approach for reactions
involving methyl ketones as aldol donors, we investigate here
the possibility of an enolate-mediated aldol reaction where
Asymmetric organocatalysis,[6b,c,15] which uses small mol-
ecules as catalyst surrogates of potentially toxic and costly
metals, has become a promising strategy in organic synthesis.
Therefore, with substrates 1 in hand, we sought to conduct the
decarboxylative aldol reaction of trifluoromethyl a-fluori-
Table 1: Synthesis of trifluoromethyl a-fluorinated b-keto gem-diols.[a]
[*] Dr. I. Saidalimu, Dr. X. Fang, Dr. X.-P. He, J. Liang, Dr. X. Yang
Key Laboratory for Advanced Material and Institute of Fine
Chemicals
Entry
R
Product
Yield [%][b]
School of Chemistry and Molecular Engineering
East China University of Science and Technology
130 Meilong Road, Shanghai (P.R. China)
E-mail: fangxiang@ecust.edu.cn
1
2
3
4
5
6
7
8
Ph
1a
1b
1c
1d
1e
1 f
1g
1h
1i
94 (X-ray)
3-MeC6H4
4-FC6H4
3,4-F2C6H4
4-MeOC6H4
2-MeC6H4
2-furyl
2-thienyl
4-BrC6H4
4-ClC6H4
Me
90
96
87
83
92
85
82
90
91
62
76
Prof. F. Wu
School of Chemical and Environmental Engineering
Shanghai Institute of Technology
Shanghai (P.R. China)
E-mail: wfh@sit.edu.cn
9
[**] This work is generously supported by the National Natural Science
Foundation of China (Nos. 21172148, 21202044, 21202045) and
Science and Technology Commission of Shanghai Municipality (No.
10540501300).
10
11
12
1j
1k
1l
cyclopropyl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301443.
[a] Unless otherwise noted, reactions were performed with 2.5 equiv of
Selectfluor. [b] Yields of isolated products.
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Chemie
Table 3: Optimization of the reaction conditions.[a]
nated b-keto gem-diols with isatin derivatives catalyzed by an
organic small molecule; the resulting products, 3-hydroxy-3-
substituted oxindoles, are a class of important structural
motifs in medicinal chemistry (Scheme 2).[16] The results of
the catalyst screening and condition optimization are shown
in Table 2 and Table 3, respectively.
With dichloromethane as solvent, the reaction catalyzed
by a proline derivative (Cat 1) gave the decarboxylated aldol
product 3aa in good yield, but with poor ee (Table 2, entry 1).
The use of thiourea- and squaramide-based catalysts (Cat 2–
Cat 5) led to slightly higher ee values, but lower yields
(Table 2, entries 2–5). Next, we found that among a series of
Entry
Additive
(20 mol%)
Solvent
Time
[h]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
dioxane
THF
CHCl3
DMF
DCE
MTBE
MeOH
48
48
48
48
48
48
3
48
39
54
59
53
57
98
95
–
49
52
55
61
73
84
53
97
98
88
83
88
86
99
99
85
68
66
40
80
67
78
24
66
–
54
54
86
89
83
81
69
87
92
88
94
92
91
92
91
92
8
EtOH
iPrOH
toluene
CH3CN
DMF
DMF
DMF
MeOH/DMF (20:1)
H2O/DMF (20:1)
EtOH/DMF (4:1)
iPrOH/DMF (4:1)
iPrOH/DMF (1:1)
TBA/DMF (4:1)
iPrOH/DMF (4:1)
iPrOH/DMF (4:1)
iPrOH/DMF (4:1)
iPrOH/DMF (4:1)
iPrOH/DMF (4:1)
7
–
9[d]
10
11
12
13
14
15
16
17
18
19
20
21[e]
22[f]
23
24[g]
25[f]
48
48
48
48
48
39
48
20
19
24
34
38
72
16
17
72
PhCOOH
AcOH
phenol
Scheme 2. Bioactive 3-hydroxy-3-substituted oxindoles.
Table 2: Catalyst screening and substitution effect of the nitrogen atom
of isatin for the aldol reaction (Ar=3,5-(CF3)2C6H3).[a]
AcOH
AcOH
AcOH
Entry
Catalyst
R
2
3
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Cat 1
Cat 2
Cat 3
Cat 4
Cat 5
Cat 6
Cat 7
Cat 8
Cat 9
Cat 10
Cat 11
Cat 6
Cat 6
Cat 6
Cat 6
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
H
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2j
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aj
64
48
36
43
44
42
39
54
53
44
51
39
64
trace
trace
6
21
15
25
45
69
57
48
47
45
43
57
31
-
[a] Unless otherwise indicated, all reactions were carried out with 2a
(0.2 mmol), 1a (0.3 mmol), and Cat 6 (0.02 mmol) in a solvent (2.5 mL)
at room temperature. DCE=1,2-dichloroethane; TBA=tert-butyl alco-
hol. [b] Yields of isolated products. [c] Determined by HPLC using
a chiral stationary phase. [d] 2a not fully dissolvable. [e] The reaction was
carried out at 08C. [f] 5 mol% of catalyst were used. [g] 40 mol% of acid
additive were added.
9
10
11
12
13
14
15
cinchona alkaloid derived thioureas, the quinine-derived
thiourea (Cat 6) was the most promising for the model
reaction (Table 2, entry 6). Since the substituent on the
nitrogen atom of isatin may sometimes affect the reactivity,[17]
we also employed several N-substituted isatins for the aldol
reaction. With Cat 6, N-benzyl isatin (2a) gave 3aa with
a higher ee value than N-H isatin (2j) and N-methyl isatin
(2k; Table 2, entries 12–13). However, N-Boc (2l) and N-Ts
(2m) isatins failed to react with 1a under the same conditions
(Table 2, entries 14–15).
Me
Boc
Ts
2k
2l
2m
3ak
3al
3am
-
[a] Unless otherwise indicated, all reactions were carried out with 2
(0.2 mmol), 1a (0.3 mmol), and the catalyst (0.02 mmol) in CH2Cl2
(2.5 mL) at room temperature. Boc=tert-butoxycarbonyl. [b] Yields of
isolated products. [c] Determined by HPLC using a chiral stationary
phase.
Subsequently, we found that the choice of solvent impacts
the yield and enantioselectivity of the model reaction
(Table 3). When DMF (dimethyl formamide) and MTBE
(methyl tert-butyl ether) were used, high enantioselectivities
but moderate yields were obtained (Table 3, entries 4 and 6).
In contrast, excellent yields but moderate enantioselectivities
were obtained in protic solvents (Table 3, entries 7–8), with
iPrOH (entry 9) as an exception owing to the poor solubility
of 2a.
In the past few years, a number of processes that involved
chiral ion pairs have become useful for the design of
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organocatalysts.[18] Jacobsen and co-workers recently discov-
ered that the Povarov reaction could be promoted effectively
by the combined use of bifunctional urea/thiourea catalysts
with a strong Brønsted acid.[19] We thus examined the model
reaction in the presence of acid additives (Table 3, entries 12–
14). AcOH (20 mol%) appeared to be the most effective
additive and gave the product with an excellent 89% ee in
a moderate yield of 61% (Table 3, entry 13). By screening
mixed solvents, we found that a mixture of iPrOH with DMF
(4:1) afforded 3aa with excellent yield (98%) and enantio-
selectivity (92%, Table 3, entry 18). Decreasing the reaction
temperature resulted in a slightly decreased yield and
prolonged reaction time (Table 3, entry 21). Furthermore,
the catalyst loading could be decreased to 5 mol% to afford
3aa in 86% yield with consistent enantioselectivity, but
prolonged reaction time (Table 3, entry 22). Further addition
of 20 or 40 mol% of AcOH to the system shortened the
reaction time (Table 3, entries 23 and 24), but not in the case
where the catalyst loading was lowered to 5 mol% (Table 3,
entry 25).
After we established the optimal reaction conditions, the
generality of this reaction was probed by using a variety of
gem-diols 1a–1l as aldol donors (Table 4). In the presence of
Cat 6 (10 mol%) and AcOH (20 mol%), the aldol reaction of
N-benzyl isatin 2a with aryl-substituted 2,4,4,4-tetrafluoro-
3,3-dihydroxy-1-butan-1-ones 1a–1h proceeded smoothly in
iPrOH/DMF (4:1) at room temperature, giving the desired
products 3aa–3ha in admirable yields (91–99%) with excel-
lent diastereoselectivities (99:1) and stereoselectivities (83–
98% ee), regardless of the positions and electronic nature of
the substituents on the phenyl rings (Table 4, entries 1–8).
Similar results were also obtained when R1 was replaced by
the heterocyclic 2-furyl and 2-thienyl groups (Table 4,
entries 9,10). The reaction could also be carried out with
aliphatic gem-diols, though more sluggishly, affording the
corresponding products in moderate yields, but still with high
diastereo- and stereoselectivities (Table 4, entries 11–12). The
absolute configuration of the major diastereomer of 3aa was
determined as 3S,1’S by X-ray analysis (Figure 1).[20]
Figure 1. X-ray crystal structure of the major diastereomer of 3aa.
Thermal ellipsoids are set at 30% probability.
Next, we probed the reaction scope with a range of N-
benzyl isatins 2b–2i as aldol acceptors (Table 5). With 1a as
the substrate, various isatins with different substituents on the
aromatic ring, including halogens and electron-donating
groups, are suitable for this reaction. Excellent yields (91–
Table 5: Generality of the reaction with aldol acceptors 2b-2i.[a]
Entry R1/R2
Time [h] Yield [%][b] d.r. [%][c] ee [%][d]
1
2
3
4
5
6
7
8
9
H (1a)/5-F (2b)
16
16
18
16
16
99 (3ab)
99 (3ac)
99 (3ad)
99 (3ae)
99 (3af)
98 (3ag)
91 (3ah)
95 (3ai)
98 (3cb)
99 (3eb)
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
92
91
92
86
92
98
91
83
83
93
H (1a)/6-Br (2c)
H (1a)/5-Br (2d)
H (1a)/7-Cl (2e)
H (1a)/5-Me (2 f)
Table 4: Generality of the aldol reaction.[a]
H (1a)/5-OMe (2g) 16
H (1a)/4-Br (2h)
H (1a)/5,7-Me2(2i)
4-F (1c)/5-F (2b)
24
24
16
10
4-OMe (1e)/5-F (2b) 19
Entry R1
Time [h] Yield [%][b] d.r. [%][c] ee [%][d]
[a] Reactions were performed with various substituted b-nitroolefins 2b–
2i (0.2 mmol) with 2,4,4,4-tetrafluoro-3,3-dihydroxy-1-arylbutan-1-one
1 (0.3 mmol) and Cat 6 (0.02 mmol) in iPrOH/DMF (4:1, 2.5 mL).
[b] Yields of isolated products. [c] Determined by 19F NMR spectroscopic
analysis of unpurified reaction products. [d] Determined by HPLC using
a chiral stationary phase.
1
Ph (1a)
16
16
16
16
99 (3aa)
97 (3ba)
99 (3ca)
95 (3da)
96 (3ea)
91 (3 fa)
99 (3ga)
97 (3ha)
99 (3ia)
99 (3ja)
43 (3ka)
67 (3la)
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
92
93
91
83
95
93
88
91
92
98
83
83
2
3
3-MeC6H4 (1b)
4-FC6H4 (1c)
4
3,4-F2C6H4 (1d)
5
4-MeOC6H4 (1e) 36
6
7
8
9
2-MeC6H4 (1 f)
4-BrC6H4 (1g)
4-ClC6H4 (1h)
2-furyl (1i)
36
20
20
28
28
60
60
99 %), high diastereoselectivities (99:1) and stereoselectivi-
ties (83–98% ee) were obtained (Table 5, entries 1–8).
Furthermore, we investigated the reaction of (4-fluoro-
phenyl)-(1c) and (4-methoxyphenyl)-3,3-dihydroxybutan-1-
one (1e) with isatin 2b and found that the electronic
properties of the substituents had a negligible impact on the
reactivity (Table 5, entries 9–10).
To study the plausible mechanism of the reaction, we
further synthesized two substrates to verify that the asym-
metric aldol addition is not a stepwise process in which release
10
11
12
2-thienyl (1j)
Me (1k)
cyclopropyl (1l)
[a] Reactions were performed with 2a (0.2 mmol) with various substi-
tuted 2,4,4,4-tetrafluoro-3,3-dihydroxy-1-butan-1-ones 1a–1l (0.3 mmol)
and Cat 6 (0.02 mmol) in iPrOH/DMF (4:1, 2.5 mL). [b] Yields of
isolated products. [c] Determined by 19F NMR spectroscopic analysis of
unpurified reaction products. [d] Determined by HPLC using a chiral
stationary phase.
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Received: February 19, 2013
Published online: April 15, 2013
Keywords: aldol reaction · carbon–
.
carbon bond cleavage · organocatalysis ·
reaction mechanisms · trifluoroacetate release
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Scheme 3. a) No reaction of 4 or 5 with 2a was observed under the optimized
conditions. b) Plausible mechanism of tandem asymmetric aldol reaction/trifluoroace-
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dihydroxy-1-phenylbutan-1-one 4 and 2-fluoro-1-phenyletha-
none 5 did not react with isatin 2a under the optimized
conditions (Scheme 3a). On the basis of the above results, we
propose a plausible reaction mechanism, which is shown in
Scheme 3b for the addition of 1a to 2a in the presence of
Cat 6. After the initial formation of a primary asymmetric
aldol adduct bearing a 3R configuration, the amino group of
the catalyst deprives a proton from the addition product,
releasing the trifluoroacetate group. Subsequently the enol
anion retrieves the proton from the amino group of the
catalyst to provide the decarboxylated product 3aa.
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In summary, we have developed a new and efficient direct
aldol reaction of gem-diols to isatins catalyzed by a bifunc-
tional thiourea derived from a cinchona alkaloid. The key step
of this protocol is the release of trifluoroacetate for the
À
cleavage of a C C bond by making use of gem-diols as
a synthetic equivalent of fluorinated aryl/alkyl methyl ketone
enolates. The resulting decarboxylated products were
obtained almost quantitatively with excellent selectivities.
We believe that this strategy would complement the existing
asymmetric fluorinations, thereby facilitating the synthesis of
chiral fluorinated molecules for the development of 3-
hydroxy-3-phenacyloxindoles of medicinal interest.
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exist exclusively in the enol form for this aldol reaction is not
sufficient. For example, 4,4,4-trifluoro-3-hydroxy-1-phenylbut-2-
en-1-one did not react with isatin 2a even after stirring for three
days.
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Experimental Section
General procedure for the decarboxylative aldol reaction: To
a solution of N-benzyl isatin 2 (0.2 mmol) in iPrOH/DMF (4:1,
2.5 mL) Cat 6 (0.02 mmol) and trifluoromethyl a-fluorinated b-keto
gem-diols 1 (0.3 mmol) were added. Upon complete consumption of
isatin (monitored by TLC), the reaction mixture was concentrated
and purified by column chromatography to afford the adducts.
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