Catalytic decarboxylative alkylation of β-keto acids with sulfonamides via the cleavage of carbon-nitrogen and carbon-carbon bonds

Article abstract of DOI:10.1039/c1cc12790j

An efficient decarboxylative alkylation reaction of β-keto acids with N-benzylic or N-allylic sulfonamides has been developed, for the first time, through sequential cleavage of carbon-nitrogen and carbon-carbon bonds in the presence of 10 mol% of FeCl₃.

Full text of DOI:10.1039/c1cc12790j

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COMMUNICATION
Catalytic decarboxylative alkylation of b-keto acids with sulfonamides
via the cleavage of carbon–nitrogen and carbon–carbon bondsw
Cui-Feng Yang, Jian-Yong Wang and Shi-Kai Tian*
Received 12th May 2011, Accepted 7th June 2011
DOI: 10.1039/c1cc12790j
An efficient decarboxylative alkylation reaction of b-keto acids
with N-benzylic or N-allylic sulfonamides has been developed,
for the first time, through sequential cleavage of carbon–nitrogen
and carbon–carbon bonds in the presence of 10 mol% of FeCl3.
While b-keto esters have been widely employed as carbon
nucleophiles to couple with a broad range of carbon electro-
philes in carbon–carbon bond-forming reactions, the corres-
ponding b-keto acids have received relatively little attention in
Scheme 1 Proposed decarboxylative alkylation of b-keto acids with
this respect. Sporadic examples show that under appropriate
electron-withdrawing group-activated alkylamines.
conditions b-keto acids are capable of undergoing decarboxyl-
ative carbon–carbon bond-forming reactions with carbon
electrophiles such as aldehydes,1 imines,2 electron-deficient
the formation of neutral byproducts would slow down the
alkenes,3 allylic acetates,4 and 1,3-diene monoepoxides.5 Such
biomimetic reactions allow b-keto acids to be employed as
attractive surrogates of ketones for a-alkylation in a highly
regioselective manner because, in general, direct alkylation of
ketones suffers from unsatisfying reactivity and regioselectivity.
Nevertheless, for a long time further exploration of the
synthetic utility of b-keto acids has been hampered by their
instability to heat, acids, and bases.1c,d Herein, we wish
to disclose an unprecedented decarboxylative alkylation of
b-keto acids with sulfonamides via catalytic cleavage of
carbon–nitrogen and carbon–carbon bonds.
decomposition of b-keto acids through decarboxylation
(Scheme 1). However, it is a formidable challenge to fine tune
reaction conditions for the purpose to cleave the carbon–
nitrogen bonds in activated alkylamines prior to the carbon–
carbon bonds in b-keto acids.
The decarboxylative alkylation of b-keto acid 1a with an
activated benzhydrylamine was selected as a model reaction to
test our hypothesis (Table 1). Initially, the acidity of b-keto
acid 1a itself was attempted to catalyze its reaction with
p-toluenesulfonyl-activated benzhydrylamine (sulfonamide 2a)
in 1,2-dichloroethane at room temperature (Table 1, entry 1).
However, no alkylation product was obtained, and b-keto acid
1a was found to decompose slowly to give acetophenone.
Gratifyingly, the employment of 10 mol% of FeCl3 to catalyze
the reaction resulted in the formation of ketone 3a in 29%
yield (Table 1, entry 2). More excitingly, the yield was drama-
tically improved up to 98% simply by elevating the tempera-
ture to 60 1C (Table 1, entry 4). Lowering the catalyst loading
to 5 mol% or switching the catalyst to other Lewis acids just
led to diminished yields or even no desired product at all
(Table 1, entries 5–12). A Brønsted acid such as sulfuric acid
was also capable of catalyzing this reaction, but provided a
much lower yield (67%, Table 1, entry 13). Replacement of
1,2-dichloroethane with a few other organic solvents drama-
tically reduced the yield (Table 1, entries 14–18). More-
over, the reaction efficiency was significantly affected by the
electron-withdrawing groups on the amine nitrogen atoms,
and no better yield was obtained when replacing the
p-toluenesulfonyl group with another sulfonyl group, a phos-
phoryl group, an acyl group, or an alkoxycarbonyl group
(Table 1, entries 19–24).
Electron-withdrawing group-activated alkylamines have
emerged as useful sp3 carbon electrophiles to couple with a
range of nucleophiles through acid-catalyzed carbon–nitrogen
bond cleavage.6,7 Significantly, the formation of nonacidic
byproducts is beneficial to reduce undesired side reactions,
such as overalkylation and elimination, when compared to
similar reactions with alkyl halides, which are commonly
employed as alkylating agents and inevitably leads to the
generation of hydrogen halides as strongly acidic byproducts.8
In this context, we envisioned that it would be possible to
develop a decarboxylative alkylation of b-keto acids with
electron-withdrawing group-activated alkylamines under
appropriate acidic conditions based on the assumption that
Joint Laboratory of Green Synthetic Chemistry, Department of
Chemistry, University of Science and Technology of China, Hefei,
Anhui 230026, China. E-mail: tiansk@ustc.edu.cn;
Fax: +86 551-360-1592; Tel: +86 551-360-0871
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, and copies of 1H and 13C NMR
spectra for products. See DOI: 10.1039/c1cc12790j
c
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Chem. Commun., 2011, 47, 8343–8345 8343

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Table 1 Optimization of reaction conditionsa
Table 2 Decarboxylative alkylation of b-keto acids with sulfonamide 2aa
Yieldb
Solvent Temp/1C (%)
Yieldb
Time/h (%)
Entry 2a–ah, EWG
Catalyst
Entry b-Keto acids
Product
1
2
3
2a, Ts
2a, Ts
2a, Ts
2a, Ts
2a, Ts
2a, Ts
2a, Ts
2a, Ts
2a, Ts
2a, Ts
2a, Ts
2a, Ts
2a, Ts
2a, Ts
2a, Ts
2a, Ts
2a, Ts
2a, Ts
None
FeCl3
FeCl3
FeCl3
FeCl3
DCE
DCE
DCE
DCE
DCE
25
25
45
60
60
60
60
60
60
60
60
60
60
0
29
88
98
75
56
27
0
0
0
62
0
67
64
33
12
66
21
94
67
91
0
4
5c
6
1
2
1a, R = H
1b, R = OMe
3a, R = H
3b, R = OMe
1.5
2
98
92
FeCl3ꢀ6H2O DCE
7
8
9
ZnCl2
DCE
DCE
DCE
DCE
Cu(OTf)2
La(OTf)3
Bi2(SO4)3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
SnCl4ꢀ5H2O DCE
3
1c
3c
2
74
TMSCI
H2SO4
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
DCE
DCE
CHCl3 60
EtOAc 60
THF
MeNO2 60
MeCN 60
DCE
DCE
DCE
DCE
DCE
DCE
60
4
5
6
7
1d, R = Me 3d, R = Me
1e, R = (CH2)2Me 3e, R = (CH2)2Me
2
2
2
1.5
77
92
90
79
1f, R = CHMe2
1g, R = CMe3
3f, R = CHMe2
3g, R = CMe3
2ab, 4-O2NC6H4SO2 FeCl3
2ac, 2-O2NC6H4SO2 FeCl3
2ad, n-C8H17SO2
2ae, (PhO)2PO
2af, PhCO
60
60
60
60
60
60
FeCl3
FeCl3
FeCl3
FeCl3
0
52
2ag, BnOCO
a
8
1h
3h
2
56
Reaction conditions: b-keto acid 1a (0.24 mmol), activated benz-
hydrylamine 2a–ag (0.20 mmol), catalyst (if any, 10 mol%), solvent
b
(1.0 mL), 1.5 h. Isolated yield. 5 mol% of FeCl3 was used.
c
9
1i
3i
2
39
In the presence of 10 mol% of FeCl3, a range of b-keto acids
smoothly underwent decarboxylative alkylation with sulfonamide
2a to afford structurally diverse unsymmetric ketones in good
to excellent yields (Table 2, entries 1–7). This reaction well
tolerated electron-rich aromatic moieties (Table 2, entries 2
and 3), and moreover, no regioisomeric alkylation product
was obtained from the reaction with b-keto acids 1e and 1f
(Table 2, entries 5 and 6). a-Alkyl b-keto acids were also
examined in the iron-catalyzed decarboxylative alkylation
reaction, and the corresponding unsymmetric ketones were
obtained in moderate yields (Table 2, entries 8 and 9).
a
Reaction conditions: b-keto acid 1 (0.24 mmol), sulfonamide 2a
b
(0.20 mmol), FeCl3 (10 mol%), DCE (1.0 mL), 60 1C. Isolated yield.
1a (Table 3, entries 13 and 14).9 Nevertheless, this reaction was
not applicable to less reactive sulfonamides such as N-benzyl-
p-toluenesulfonamide, N-allyl-p-toluenesulfonamide and
N-(1-adamantyl)-p-toluenesulfonamide.
The decarboxylative alkylation reaction was found to work
well with a p-toluenesulfonyl-activated secondary benzylic
amine. For example, ketone 3a was obtained in a good yield
from the reaction of b-keto acid 1a with sulfonamide 4a or 4b
in the presence of 10 mol% of FeCl3 (eqn (1)). It is noteworthy
that the other carbon–nitrogen bond of sulfonamide 4a or 4b
was not cleaved at all.
A variety of N-bisbenzylic sulfonamides were smoothly
reacted with b-keto acid 1a in the presence of 10 mol% of
FeCl3 to afford the corresponding 2,2-diarylethyl phenyl
ketones in good yields (Table 3, entries 1–5). It is noteworthy
that both electron-withdrawing and electron-donating groups
were successfully introduced into the ketone products by
employing the sulfonamides bearing such groups on the
aromatic rings. The carbon–nitrogen bonds of N-mono-
benzylic sulfonamides were successfully cleaved under the
same reaction conditions and coupled with b-keto acid 1a to
afford the desired ketones in moderate to good yields (Table 3,
entries 6–9). To our delight, no rearrangement was observed
for the carbon–carbon multiple bonds in the reaction with
N-(a-alkynylbenzyl)- or N-(a-alkenylbenzyl)-p-toluenesulfon-
amides (Table 3, entries 10–12). Moreover, N-allylic sulfon-
amides served as suitable substrates to couple with b-keto acid
ð1Þ
The reaction of b-keto acid 1a with optically active sulfon-
amide (R)-2h (93% ee) proceeded smoothly in the presence of
10 mol% of FeCl3 to afford ketone 3p in nearly racemic form
(1% ee) (Table 3, entry 7). This result suggests that a benzyl
cation intermediate is involved in the reaction.6d,g,7e,f To gain
c
8344 Chem. Commun., 2011, 47, 8343–8345
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Table 3 Decarboxylative alkylation of b-keto acid 1a with sulfon-
supported the reaction pathway proposed in Scheme 1, and
the sequential SN1 alkylation/decarboxylation accounts for
the extremely high regioselectivity observed in the reaction
(Table 2, entries 5 and 6).
amidesa
Time/h Yieldb (%)
ð2Þ
Entry Sulfonamides
Product
1c
2
2b, R = OMe
2c, R = Cl
3j, R = OMe
3k, R = Cl
6
1.5
87
83
ð3Þ
In summary, a range of b-keto acids smoothly undergo
decarboxylative alkylation with N-benzylic or N-allylic sulfon-
amides in the presence of 10 mol% of FeCl3 to afford
structurally diverse unsymmetric ketones in good to excellent
yields and with extremely high regioselectivity. Preliminary
mechanistic studies indicate that the reaction proceeds
through SN1 alkylation followed by decarboxylation.
3d
4
2d, X = CH2CH2 3l, X = CH2CH2
2e, X = S
2f, X = O
1
1.5
2
83
65
72
3m, X = S
3n, X = O
5
We are grateful for the financial support from the National
Natural Science Foundation of China (20972147 and
20732006), the National Basic Research Program of China
(2010CB833300), and the Chinese Academy of Sciences.
6
7
8
2g, R = H
2h, R = 4-OMe
2i, R = 2-Me
3o, R = H
3p, R = 4-OMe
3q, R = 2-Me
3
1.5
1.5
52
59
65
Notes and references
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9
2j
3r
2
58
10
11
2k, R = Ph
2l, R = n-Bu
3s, R = Ph
3t, R = n-Bu
2
1
83
71
5 T. Tsuda, M. Tokai, T. Ishida and T. Saegusa, J. Org. Chem., 1986,
51, 5216.
6 For examples with Brønsted acids, see: (a) K. H. Chung, J. N. Kim
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H. J. Lee and J. N. Kim, Tetrahedron Lett., 1998, 39, 6219;
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12
13
2m, R = Ph
2n, R = Me
3u, R = Ph
3v, R = Me
1
1.5
73
54
14
2o
3w
3
45
a
Reaction conditions: b-keto acid 1a (0.24 mmol), sulfonamide 2
(0.20 mmol), FeCl3 (10 mol%), 1,2-dichloroethane (1.0 mL), 60 1C.
Isolated yield. The reaction was run at room temperature.
b
c
d
0.30 mmol of b-keto acid 1a was used.
more insights into the reaction mechanism, we carried out 1H
NMR spectroscopic analysis of a mixture of b-keto acid 1a,
sulfonamide 2a, and 10 mol% of sulfuric acid in deuterated
chloroform at room temperature and identified b-keto acid 5
as an intermediate, which was confirmed by ESI-HRMS
spectroscopic analysis (eqn (2)). Although acetophenone was
detected in a significant amount in this mixture, it could not be
effectively alkylated with sulfonamide 2a under the conditions
as illustrated in eqn (3). These experiments substantially
9 No regioisomer of product 3v was obtained probably due to
maintaining a maximum degree of conjugation.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 8343–8345 8345