One-pot dehydrogenation of carboxylic acid derivatives to α,β-unsaturated carbonyl compounds under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2004.11.106

Carboxylic acid derivatives such as N-acyl-2-oxazolidones, δ-lactones, and δ-lactams were smoothly dehydrogenated to the corresponding α,β-unsaturated carbonyl compounds in one-pot manner at -78°C just by treating their lithium enolates with N-tert- butyl

Full text of DOI:10.1016/j.tetlet.2004.11.106

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 407–410
One-pot dehydrogenation of carboxylic acid derivatives to
a,b-unsaturated carbonyl compounds under mild conditions
Jun-ichi Matsuo* and Yayoi Aizawa
Center for Basic Research, The Kitasato Institute, 1-15-1-S105, Kitasato, Sagamihara, Kanagawa 228-8555, Japan
Received 12 October 2004; revised 19 November 2004; accepted 22 November 2004
Abstract—Carboxylic acid derivatives such as N-acyl-2-oxazolidones, d-lactones, and d-lactams were smoothly dehydrogenated to
the corresponding a,b-unsaturated carbonyl compounds in one-pot manner at ꢀ78 °C just by treating their lithium enolates with
N-tert-butylbenzenesulfinimidoyl chloride.
Ó 2004 Elsevier Ltd. All rights reserved.
Dehydrogenation of carboxylic acid derivatives to the
corresponding a,b-unsaturated compounds is an impor-
tant organic transformation in living organisms as well
as in organic synthesis: living organisms utilize fatty
acids to produce acetyl CoA via direct dehydrogenation
(b-oxidation) of acyl-CoA, a fatty acid derivative, to
enoyl-CoA, which is catalyzed by acyl-CoA dehydro-
genase.1 However, such direct dehydrogenation of car-
boxylic acid derivatives by nonenzymatic (chemical)
methods has not yet been studied, though several two-
step procedures are known for this transformation. That
is, dehydrogenation is usually carried out by three meth-
ods: (i) a-halogenation and subsequent elimination in
the presence of a base, (ii) preparation of a-phenyl-
sulfide2 or a-phenylselenide3 followed by elimination
of the corresponding oxides, and (iii) preparation of silyl
ketene acetals followed by treatment with palladium
acetate.4 We have recently reported a new method for
dehydrogenation of ketones to the corresponding a,b-
unsaturated ketones by using N-tert-butylbenzenesulfin-
imidoyl chloride (1),5 and the dehydrogenation was
unique in that it proceeded in a one-pot manner under
very mild conditions (ꢀ78 °C, within 30 min) (Eq. 1).
Its synthetic utility has been demonstrated in its success-
ful application to the total synthesis of several natural
products.6 In order to broaden the synthetic utility of
1, dehydrogenation of carboxylic acid derivatives such
as carboxylic esters, thioesters, amides, lactones, and
lactams were then investigated, and we would like to
report here results on one-pot and mild dehydrogena-
tion of these carboxylic acid derivatives with 1.
O
O
1) LDA
Cl
S
ð1Þ
t
2)
Bu
1
Ph
N
93%
o
THF, -78 C, 30 min
First, one-pot dehydrogenation of ethyl octanoate was
tried by generating the corresponding lithium enolate
with LDA in THF at ꢀ78 °C, followed by treatment
with 1 at the same temperature (Table 1, entry 1). It
Table 1. One-pot dehydrogenation of octanoic acid derivatives to the
corresponding a,b-unsaturated carbonyl compounds by using 1
o
1) LDA (1.1 equiv), -78
C
O
O
Cl
S
X
X
4
4
t
2)
Bu
1 (1.2 equiv)
Ph
N
o
THF, -78 C, 30 min
Entry
X
Yielda (%)
1
2
3
OEt
OPh
SPh
O
60
71
75
4
90
N
O
5b
N(Bn)SO2Ph
41
Keywords: Dehydrogenation; Amide; Ester; Lactone; Lactam.
*
Corresponding author. Tel./fax: +81 42 778 9931; e-mail: matuo@
lisci.kitasato-u.ac.jp
a Determined by 1H NMR analysis using an internal standard.
b N-Benzenesulfonyl-N-benzylbutyramide was employed.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.106

408
J. Matsuo, Y. Aizawa / Tetrahedron Letters 46 (2005) 407–410
of 1, and substituent groups on the phenyl ring of 1 were
screened. Considering the successful dehydrogenation of
ketones with 1,5 it was assumed that the efficiency of the
present dehydrogenation was influenced by the acidity
of carbonyl a-proton: that is, in the case of ethyl octano-
ate, the reaction of 1 and lithium enolate of ethyl octa-
noate was competitively inhibited by protonation of
the lithium enolate with N-tert-butylbenzenesulfenamide
(2), which was formed from 1 (Scheme 1). Therefore, the
same dehydrogenation of several octanoic acid deriva-
tives having more acidic a-protons was examined, and
it was expectedly found that the yield of the dehydro-
genation was improved to 71% and 75% when phenyl
octanoate and S-phenyl octanethioate were employed,
respectively (Table 1, entries 2 and 3). 2-Oxazolidone
derivative was dehydrogenated to the corresponding
a,b-unsaturated compound exceptionally in high yield
(90%, entry 4), while N-acyl-N-benzylbenzenesulfon-
Scheme 1. Possible mechanism for incomplete dehydrogenation of
carboxylic ester with 1.
was disappointingly found that the dehydrogenation
proceeded incompletely and the desired product was
obtained in 60% yield, though reaction conditions such
as reaction temperature, reaction time, and equivalents
Table 2. One-pot dehydrogenation of N-acyl-2-oxazolidones and carboxylic acid phenyl esters to the corresponding a,b-unsaturated compounds by
using 1
o
2
2
R
O
1) LDA (1.1 equiv), -78 C
R
O
1
1
R
O
X
Cl
S
R
X
3
t
3
2)
R
Bu
R
1 (1.2 equiv)
Ph
N
o
THF, -78 C, 30 min
Entry
1
Substrate
Product
Yielda (%)
78
O
O
O
N
O
O
N
O
O
O
O
2
3
90
67
N
O
O
N
O
O
O
4
4
O
O
N
O
N
N
O
N
O
O
O
O
O
4
5
83
87
8
8
4
4
O
O
O
O
PhO
RO
PhO
RO
N
O
N
O
O
O
R = Bn
TBS
O
O
6
7
8
9
88
92
91
91
N
O
THP
PMB
N
O
6
6
O
O
10
75
OPh
O
OPh
O
R = TBS
THP
OPh
11
12
63
72
RO
RO
OPh
a Determined by 1H NMR analysis using an internal standard.

J. Matsuo, Y. Aizawa / Tetrahedron Letters 46 (2005) 407–410
409
Table 3. One-pot dehydrogenation of lactones and lactams with 1
amide gave the desired product in low yield (entry 5). It
was then revealed that N-acyl-2-oxazolidone was a
suitable carboxylic acid derivative for dehydrogenation
with 1.
O
O
o
1) LDA (1.1 equiv), -78
C
X
X
Cl
S
R
R
t
n
n
2)
Bu
1 (1.2 equiv)
Next, the scope and limitations of the present dehydro-
genation of N-acyl-2-oxazolidones and carboxylic acid
phenyl esters were investigated (Table 2). The dehydro-
genation of N-acyl-2-oxazolidones proceeded more effi-
ciently than that of carboxylic acid phenyl esters (entries
1–9 vs entries 10–12), and linear N-acyl-2-oxazolidones
were smoothly dehydrogenated at ꢀ78 °C within 30 min
to afford the corresponding a,b-unsaturated compounds
in high yields. Only (E)-isomers were stereoselectively
formed by this reaction. The dehydrogenation of a b-
branched N-acyl-2-oxazolidone gave the desired product
in moderate yield (entry 3), probably because the reaction
between sterically hindered lithium enolate and 1 took
place slowly. It should be noted that protecting groups
such as benzyl, TBS, THP, and PMB, and an isolated
double bond were not damaged nor oxidized at all under
the present dehydrogenation conditions. Even a long
carboxylic acid derivative was smoothly dehydrogenated
by the present method (entry 4).
Ph
N
o
THF, -78 C, 30 min
Entry
1
Substrate
Product
Yielda (%)
O
O
O
O
72
5
5
R = Bz
2
3
4
5
6
7
70
80
79
45
44
57
O
SO2Ph
Boc
Bn
BOM
Tf
O
R
N
R
N
O
O
O
O
O
N
O
N
8
44
6
6
The one-pot dehydrogenation of lactones and lactams
was also investigated by the same procedure (Table 3).
Dehydrogenation of d-lactone gave the corresponding
a,b-unsaturated d-lactone in good yield (entry 1), and
d-lactams were also dehydrogenated effectively when
lactam-nitrogen was protected by appropriate electron-
withdrawing groups such as benzenesufonyl and Boc
groups (entries 2–4). On the other hand, the dehydroge-
nation of N-benzyl-2-piperidone and N-BOM-2-piper-
idone gave the dehydrogenated compounds in 45%
and 44% yields, respectively (entries 5 and 6) presum-
ably due to competitive protonation of their lithium
enolates with 2, which was described before. Contrary
to the dehydrogenation of six-membered lactone and
lactams, five-membered cyclic compounds and a seven-
membered lactam were dehydrogenated in low yields.
SO Ph
SO Ph
2
n = 1
n = 2
9
10
53
15
2
n
n
a Determined by 1H NMR analysis using an internal standard.
enolates with 1 at ꢀ78 °C afforded the corresponding
a,b-unsaturated carbonyl compounds in high yields.
The formed a,b-unsaturated N-acyl-2-oxazolidones are
useful synthetic intermediates in organic synthesis,
especially for stereoselective Michael addition reactions7
and Diels–Alder reactions,8 and the method for remov-
ing the 2-oxazolidone moiety has already been estab-
lished.9 This method has the possibility of being
applied not only to the synthesis of molecular building
blocks but also to introduction of a,b-unsaturation
to natural products for derivatizing them to more
interesting compounds because of its mild reaction
conditions.
A typical experimental procedure is as follows (Table 2,
entry 2): a solution of n-butyllithium (1.51 N in hexane,
0.23 mL, 0.35 mmol) was added to a solution of diiso-
propylamine (38 mg, 0.38 mmol) in THF (1.7 mL)
at ꢀ78 °C. A solution of N-octyryl-2-oxazolidone
(67.5 mg, 0.32 mmol) in THF (1 mL) was then added
to the reaction mixture, followed by adding a solution
of 1 (82.6 mg, 0.38 mmol) in THF (0.5 mL). After
the reaction mixture was stirred at ꢀ78 °C for 30 min,
the reaction was quenched with saturated NaHCO3.
The mixture was extracted with AcOEt, and extracts
were washed with brine, dried over Na2SO4, filtered,
and concentrated. The yield of dehydrogenated com-
pound (90%) was determined by 1H NMR analysis
using triphenylmethane as an internal standard.
Acknowledgements
The authors thank Professor Teruaki Mukaiyama and
ꢀ
Professor Satoshi Omura for their kind and generous
help. The present work was partially supported by
Grant-in-Aids for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology,
Japan.
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Commercially available from Tokyo Kasei Kogyo Co., Ltd. (TCI).

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