Decarboxylative alkylation of β-keto Acids with isochromans under oxidative conditions

Article abstract of DOI:10.1002/cjoc.201200994

An unprecedented decarboxylative alkylation reaction of β-keto acids with isochromans has been developed under oxidative conditions. A range of β-keto acids smoothly undergo decarboxylative alkylation with isochromans in the presence of 2,2,6,6-tetramethylpiperdine-1-oxoammonium hexafluorophosphate to give structurally diverse 1-acylmethylisochromans in moderate to excellent yields with extremely high regioselectivity. A range of β-keto acids smoothly undergo decarboxylative alkylation with isochromans in the presence of 2,2,6,6-tetramethylpiperdine-1-oxoammonium hexafluorophosphate to give structurally diverse 1-acylmethylisochromans in moderate to excellent yields. Copyright

Full text of DOI:10.1002/cjoc.201200994

COMMUNICATION
DOI: 10.1002/cjoc.201200994
Decarboxylative Alkylation of β-Keto Acids with Isochromans
under Oxidative Conditions
Yan Chena and Shi-Kai Tian*,a,b
a Joint Laboratory of Green Synthetic Chemistry, Department of Chemistry, University of Science and Technology
of China, Hefei, Anhui 230026, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, China
An unprecedented decarboxylative alkylation reaction of β-keto acids with isochromans has been developed
under oxidative conditions. A range of β-keto acids smoothly undergo decarboxylative alkylation with isochromans
in the presence of 2,2,6,6-tetramethylpiperdine-1-oxoammonium hexafluorophosphate to give structurally diverse
1-acylmethylisochromans in moderate to excellent yields with extremely high regioselectivity.
Keywords β-keto acids, isochromans, 2,2,6,6-tetramethylpiperdine-1-oxoammonium salts, decarboxylation, al-
kylation
Introduction
fluorophosphate (145 mg, 0.48 mmol) in 1,2-dichloro-
ethane (2.0 mL) were added isochroman 2 (0.40 mmol)
and β-keto acid 1 (0.48 mmol). The mixture was stirred
at 70 ℃ for 45 min, cooled to room temperature, and
concentrated to dryness under reduced pressure. The
residue was purified by column chromatography on sil-
ica gel, eluting with petroleum ether/ethyl acetate (20∶
1), to give compound 3.
In sharp contrast to many other active methylene
compounds, β-keto acids have rarely been employed as
carbon nucleophiles in chemical synthesis for the form-
ation of carbon-carbon bonds due to their instability to
heat, acids, and bases. It constitutes a formidable chal-
lenge to fine tune reaction conditions for β-keto acids to
form carbon-carbon bonds with carbon electrophiles
prior to their decomposition through decarboxylation. In
this context, sporadic examples have shown that some
appropriate conditions allow β-keto acids to undergo
decarboxylative carbon-carbon bond-forming reactions
with carbon electrophiles such as aldehydes,[1] ketones,[2]
imines,[3] activated alkenes,[4] allylic electrophiles,[5]
N-benzylic sulfonamides,[6] and benzylic alcohols.[7] In
these biomimetic reactions, β-keto acids serve as surro-
gates of ketones but with higher reactivity and regiose-
lectivity for the formation of carbon-carbon bonds. Thus,
it is highly desirable to extend the synthetic utilities of
β-keto acids by exploring their reactions with other
types of carbon electrophiles. Here we report an un-
precedented decarboxylative alkylation reaction of β-
keto acids with isochromans under oxidative conditions.
Results and Discussion
Although it is known that isochromans can be con-
verted to the corresponding oxonium ions under oxida-
tive conditions,[8] care should be taken in the selection
of appropriate oxidants to minimize the decomposition
of β-keto acids to ketones and the overoxidation of
isochromans to isochroman-1-ones during the desired
alkylation reaction. Therefore, at the outset we focused
our attention on 2,2,6,6-tetramethylpiperdine-1-oxoam-
monium salts (TEMPO salts, T＋Y−), mild oxidants that
are stable, nontoxic, and readily accessible.[9] To our
delight, the model reaction of β-keto acid 1a with
isochroman (2a) occurred in the presence of 1.2 equiv.
of T＋PF－ in 1,2-dichloroethane at 30 ℃ and 1-ben-
6
zoylmethylisochroman (3a) was obtained in 54% yield
(Table 1, Entry 1). The yield was improved to 82% by
elevating the temperature to 70 ℃ (Table 1, Entry 2).
We further examined several other TEMPO salts, but
failed to enhance the yield (Table 1, Entries 3－5). It is
noteworthy that TEMPO itself could not promote the
Experimental
General procedure for the decarboxylative alkylation
of β-keto acids with isochromans: To a solution of
2,2,6,6-tetramethylpiperdine-1-oxoammonium
hexa-
*
E-mail: tiansk@ustc.edu.cn; Tel.: +86 551-3600871
Received October 13, 2012; accepted November 27, 2012; published online December 27, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200994 or from the author.
Dedicated to the Memory of Professor Weishan Zhou.
†
Chin. J. Chem. 2013, 31, 37—39
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
37

Chen & Tian
COMMUNICATION
reaction under oxygen (Table 1, Entry 6). Other than
TEMPO derivatives, a few readily accessible organic
oxidants, such as 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ), N-bromosuccinimide (NBS), and tert-butyl
peroxide (DTBP), were examined, and the reaction gave
a much lower yield or even resulted in no desired prod-
uct at all (Table 1, Entries 7－9). Finally, the efforts to
further enhance the yield proved fruitless by screening a
range of common solvents (Table 1, Entries 10－20).
eric product was obtained from the reaction with β-keto
acids 1i and 1j (Table 2, Entries 9 and 10). In a sharp
contrast, very low regioselectivity was reported previ-
ously by Li et al. in the synthesis of similar compounds
by using the alkylation reaction of unsymmetric dialkyl
ketones with isochromans under oxidative conditions.[8c]
While the reaction with an α,β-disubstituted β-keto acid
gave excellent diastereoselectivity (Table 2, Entry 12),
poor diastereoselectivity was observed in the reaction
with a 3- or 4-substituted isochroman (Table 2, Entries
14－15).[10]
Table 1 Optimization of the reaction conditionsa
O
O
O
O
Table 2 Decarboxylative alkylation of β-keto acids with
oxidant
+
isochromansa
Ph
Ph
OH
O
R3
5
4
O
O
O
O
R3
-
1a
2a
3a
T+PF6, DCE
6
3
R1
R1
+
OH
70 oC, 45 min
O
Yieldb/%
R2
R2
Entry
1
Oxidant
T＋PF－
T＋PF－
T＋BF－
Solvent
Temp/℃
30
1
2
3
DCE
54
82
71
40
15
0
6
Entry
1, R1, R2
1a, Ph, H
1b, 4-MeC6H4, H
2, R3
2a, H
Product Yieldb/%
2
DCE
DCE
70
6
1
2
3a
3b
3c
3d
3e
3f
82
85
90
78
65
69
81
65
61
69
56
3
70
4
4
T＋ClO－4 DCE
70
2a, H
5
6c
T＋OTf−
TEMPO
DDQ
DCE
70
3
1c, 4-MeOC6H4, H 2a, H
4
1d, 4-FC6H4, H
1e, 4-BrC6H4, H
1f, 2-furyl, H
1g, 2-thienyl, H
1h, Me, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
DCE
70
5
7
DCE
70
40
Trace
0
6
8
NBS
DCE
70
7
3g
3h
3i
9
DTBP
T＋PF－
T＋PF－
T＋PF－
T＋PF－
T＋PF－
T＋PF－
T＋PF－
T＋PF－
T＋PF－
T＋PF－
T＋PF－
DCE
70
8
10
11
12
13
14
15
16
17
18
19
20
CHCl3
Toluene
EtOAc
THF
70
Trace
0
6
9
1i, Me(CH2)2, H
1j, Me2CH, H
1k, Me3C, H
70
6
10
11
3j
70
Trace
Trace
0
6
3k
70
6
DME
MeCN
MeNO2
DMF
70
6
12c
2a, H
3l
51
,
1l
70
63
73
0
6
13d
14e
15
1a, Ph, H
2b, 3-Me
2c, 4-Me
2d, 5-Me
2e, 6-OMe
2f, 6-F
3m
3n
3o
3p
3q
70
80
78
50
67
70
6
70
1a, Ph, H
1a, Ph, H
1a, Ph, H
1a, Ph, H
6
DMSO
EtOH
Water
70
0
6
70
0
16
6
70
0
17
6
a Reaction conditions: β-keto acid 1a (0.48 mmol), isochroman
(2a) (0.40 mmol), oxidant (0.48 mmol), solvent (2.0 mL), 30 or
70 ℃, 45 min. b Isolated yield. c 10 mol% TEMPO was used
under oxygen.
a
Reaction conditions: β-keto acid 1 (0.48 mmol), isochroman 2
(0.40 mmol), T＋PF－ (0.48 mmol), DCE (2.0 mL), 70 ℃, 45
min. b Isolated yield. c 91∶9 dr. d 63∶37 dr. e 54∶46 dr.
6
Atmospheric pressure chemical ionization (APCI)
mass spectroscopic analysis of the reaction mixture of
β-keto acid 1a and isochroman (2a) allowed us to iden-
tify two intermediates, oxonium ion 4a in the presence
A variety of β-keto acids smoothly underwent de-
carboxylative alkylation with isochromans under oxida-
tive conditions to give structurally diverse 1-acylmethyl-
isochromans in moderate to excellent yields (Table 2).
Relatively lower yields were obtained in some cases
owing to the consumption of the starting materials
through the decomposition of β-keto acids to ketones
and/or the overoxidation of isochromans to isochroman-
1-ones. The β-positions of β-keto acids could bear sub-
stituents such as aryl, heteroaryl, or alkyl groups, and
the reaction tolerated electron-rich and electron-poor
aromatic moieties. It is noteworthy that no regioisom-
of T＋PF－ [HRMS (APCI) calcd for C9H9O＋ (M)＋
6
133.0648, found 133.0645] and β-keto acid/isochroman
adduct 5a [HRMS (APCI) calcd for C18H17O4 (M＋H)＋
＋
297.1121, found 297.1118] according to the high resolu-
tion mass data (Figure 1). The isolation of adduct 5a
was not successful by chromatography on silica gel due
to rapid decomposition. Although acetophenone was
detected in a significant amount in the reaction mixture,
it underwent oxidative alkylation with isochroman (2a)
38
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 37—39

Decarboxylative Alkylation of β-Keto Acids with Isochromans under Oxidative Conditions
under the standard conditions to give compound 3a in
only 9% yield, which is much lower than that obtained
from the reaction with β-keto acid 1a (Table 2, Entry 1).
These results clearly indicate that the oxidative forma-
tion of carbon-carbon bonds between β-keto acids and
isochromans occurs prior to decarboxylation.
Acknowledgement
We are grateful for the financial support from the
National Natural Science Foundation of China
(21232007 and 21172206), the National Basic Research
Program of China (973 Program 2010CB833300), and
the Program for Changjiang Scholars and Innovative
Research Team in University (IRT1189).
O
O
References
Ph
HO
O+
O
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Figure 1 Intermediates 4a and 5a.
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the following reaction pathway for the decarboxylative
alkylation of β-keto acids with isochromans (Scheme 1).
Oxidization of isochroman 2 by T＋PF－ gives oxon-
6
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Scheme 1 Proposed reaction pathway
O
O
OH O
O
O
- HPF6
R3
R1
OH
R1
OH
R1
O
R2
OH
R2
R2
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1
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- CO2
R3
R3
O
O
R3
O
O
R1
-
2
4
PF6
R2
3
HPF6
N
O
N
N
H
-
PF6
-
OH
OH
PF6
Conclusions
We have developed, for the first time, an efficient
decarboxylative alkylation reaction of β-keto acids with
isochromans under oxidative conditions. A range of
β-keto acids smoothly undergo decarboxylative alkyla-
tion with isochromans in the presence of 2,2,6,6-
tetramethylpiperdine-1-oxoammonium hexafluorophos-
phate to give structurally diverse 1-acylmethylisochro-
mans in moderate to excellent yields with extremely
high regioselectivity. Preliminary mechanistic studies
indicate that the oxidative formation of carbon-carbon
bonds between β-keto acids and isochromans occurs
prior to decarboxylation.
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[10] The standard reaction conditions were not applicable to acyclic
ethers. For example, no alkylation product was obtained from the
reaction of dibenzyl ether with β-keto acid 1a in the presence of 1. 2
equiv. of T＋PF－ . In this case, dibenzyl ether was consumed com-
6
pletely and benzaldehyde was obtained in 20% yield.
(Pan, B.; Fan, Y.)
Chin. J. Chem. 2013, 31, 37—39
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
39