Synthesis of 3-benzoyl acrylates/acrylamides via Dehydrogenation of 3-benzoyl propionates/propionamides using IBX/p-TsOH

Article abstract of DOI:10.1002/cjoc.201090225

Dehydrogenation by IBX/p-TsOH is applied to the conversion of 3-benzoyl propionates/propionamides to 3-benzoyl acrylates/acrylamides in moderate to excellent yields. The reaction time for the dehydrogenation of 3-benzoyl propionamides was remarkably short

Full text of DOI:10.1002/cjoc.201090225

NOTE
Synthesis of 3-Benzoyl Acrylates/Acrylamides via
Dehydrogenation of 3-Benzoyl Propionates/
Propionamides Using IBX/p-TsOH
Li, Ziyuan(李子元)
Wang, Yiyun(王宜运)
Tang, Changhua(唐昌华)
Yao, Hequan*(姚和权)
Xu, Jinyi(徐进宜)
Wu, Xiaoming*(吴晓明)
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University,
Nanjing, Jiangsu 210009, China
Dehydrogenation by IBX/p-TsOH is applied to the conversion of 3-benzoyl propionates/propionamides to
3-benzoyl acrylates/acrylamides in moderate to excellent yields. The reaction time for the dehydrogenation of
3-benzoyl propionamides was remarkably shorter than that for the dehydrogenation of esters.
Keywords dehydrogenation, 3-benzoyl propionate, 3-benzoyl propionamide, 3-benzoyl acrylate, 3-benzoyl
acrylamide
Introduction
dride and benzene. However, the acylation site depends
on the electronic effect of the functional groups at the
other sites on the benzene ring, resulting in poor product
diversity. We thought 3-benzoyl acrylate and their deriva-
tives bearing functional groups on benzene ring could be
achieved through a two-step sequence, in which a Stetter
reaction3 between benzaldehyde and acrylate was used to
give 3-carbonyl propionate and a subsequent dehydroge-
nation was applied to furnish the desired product in order
to improve the product diversity. Our work was then fo-
cused on the synthesis of 3-carbonyl acrylate through
dehydrogenation of 3-carbonyl propionate. It has been
reported that 3-carbonyl acrylate could be obtained from
3-carbonyl propionate through a bromination with Br2
and a subsequent elimination of HBr to generate the
It has been generally presumed that 3-carbonyl acry-
lates/acrylamides, as well as their 2,3-epoxy derivatives,
are potent Michael addition acceptors for capturing mo-
lecular targets.1,2 Particularly, 2,3-epoxy derivatives
have been extensively used as a ligand of molecular
imaging probes for cysteine proteases profiling.2
A
probable mechanism of these two categories of com-
pounds is that they serve as good electrophiles toward
internal nucleophilic groups, including cysteine or other
amino acids residues in proteins and peptides and nitro-
gen atoms in nucleotides, leading to a covalent capture
by the molecular targets (Scheme 1).
Typically, 3-benzoyl acrylate can be achieved
through a Friedel-Crafts reaction between maleic anhy-
Scheme 1 Probable mechanism of the covalent capture of the target compounds by molecular targets
*
E-mail: hyao@cpu.edu.cn; Tel.: 0086-025-83271042; Fax: 0086-025-83301606; xmwu@cpu.edu.cn; Tel.: 0086-025-83271445; Fax: 0086-025-
83301606
Received October 20, 2009; revised February 8, 2010; accepted March 23, 2010.
Project supported by the Program for New Century Excellent Talents in University by the Ministry of Education of China (No. NCET 2008), the
National Natural Science Foundation (No. 20902111) and the State Key Laboratory of Drug Research of Shanghai Institute of Materia Medica, Chi-
nese Academy of Sciences (No. SIMM0901KF-04).
Chin. J. Chem. 2010, 28, 1301— 1305
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1301

Li et al.
NOTE
double bond under basic environment.4 However, be-
sides environmental problems of bromine, potential ad-
verse reactions, such as excessive bromination at other
sites, for example, at aromatic ring or allylic position,
render only moderate total yields, generally from 50% to
60%. An alternative method to obtain 3-carbonyl acrylate
is a direct oxidation of 3-carbonyl propionate with sele-
nium dioxide as an oxidant.5 But environmental damages
caused by this oxidant as well as the low yield (only 5%
to 15%) made this approach unacceptable. Recently,
Nicolaou et. al.6 demonstrated that O-iodoxybenzoic acid
(IBX) or Dess-Martin periodinane (DMP) could directly
dehydrogenate ketone, ester, and aldehyde in DMSO to
their α,β-unsaturated derivatives, with/without being
activated by some ligands, such as N-oxides. In this let-
ter, we wish to apply this method to synthesize
3-benzoyl acrylates/acrylamides from 3-benzoyl propi-
onates/propionamides.
yield even when the reaction was carried out at 85 ℃
(Entry 4), the temperature at which Nicolaou achieved
good yields.6 As shown in Table 1, most of unconsumed
1 was recovered in these entries, which indicated that an
appropriate reagent is necessary to accelerate the reaction.
Although N-oxides were reported to efficiently pro-
mote the dehydrogenation of ketone, ester, and aldehyde
even at room temperature in excellent yields, the results
indicated that the reactions were poor when NMO was
used to promote the dehydrogenation of 1. When the re-
action was performed with 2.5 equiv. NMO at room
temperature, 40 and 65 ℃ for 48 h, 2 was obtained in
only 13%, 47% and 53% yields respectively, and most of
unconsumed 1 was recovered (Entries 5—7). TFA was
also used to promote this reaction, but only trace amount
of the desired product was achieved, and most of 1 was
recovered (Entries 8, 9).
We then tried p-TsOH to accelerate this dehydrogena-
tion. 2 was isolated only in moderate yield in the presence
of 0.3 equiv. p-TsOH at 85 ℃ for 24 h (Entry 10). Yet
no unconsumed substrate was recovered, and the hy-
drolysis of ester of 2 was observed. We reasoned that tiny
amount of water from DMSO caused the hydrolysis.
Even when the temperature was declined to 75 ℃ (Entry
11), adverse product was still obvious. Gratifyingly, hy-
drolysis of 2 was remarkably reduced and most
Results and discussion
Our investigation commenced with the screening of
reaction condition using methyl 3-(3,4-dimethoxyben-
zoyl)propionate (1) as a substrate shown in Table 1.
When 1 was treated with 2.4 equiv. IBX in DMSO with-
out ligand, no or trace desired product 2 was observed at
low temperatures (Entries 1—3). 2 was obtained in a poor
Table 1 Screening of reaction conditions of dehydrogenation of 3-benzoyl propionatea
Entry
1
Reagent
Temp./℃
r.t.
40
Time/h
48
48
48
48
48
48
48
48
48
24
48
48
48
41
36
28
28
60
Yield of 2 (recovery of 1)b/%
0 (100)
None
2
None
0 (100)
3
None
65
Trace (96)
32 (62)
4
None
85
5
2.5 equiv. NMO
2.5 equiv. NMO
2.5 equiv. NMO
0.3 equiv. TFA
0.5 equiv. TFA
0.3 equiv. p-TsOH
0.3 equiv. p-TsOH
0.3 equiv. p-TsOH
0.5 equiv. p-TsOH
1.0 equiv. p-TsOH
1.6 equiv. p-TsOH
2.0 equiv. p-TsOH
2.4 equiv. p-TsOH
1.6 equiv. p-TsOH
25
13 (80)
6
40
47 (45)
7
65
53 (36)
8
25
Trace (94)
Trace (95)
46 (0)
9
45
10
11
12
13
14
15
16
17
18
85
75
65 (0)
65
52 (39)
65
66 (26)
65
77 (16)
65
86 (Trace)
85 (0)
65
65
71 (0)
40
78 (10)
a Reactions were performed on a 0.5 mmol scale in DMSO. b Isolated yield.
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Chin. J. Chem. 2010, 28, 1301— 1305

Synthesis of 3-Benzoyl Acrylates/Acrylamides via Dehydrogenation
unconsumed substrate could be recovered (Entry 12)
when the reaction was conducted at 65 ℃ for 48 h. We
then gradually increased the amount of p-TsOH, in order
to enhance the dehydrogenation at this temperature (En-
tries 13—18). As shown in Table 1, up to 86% yield of 2
could be achieved when the reaction was performed with
1.6 to 2.0 equiv. p-TsOH at 65 ℃. It is noteworthy that 2
was obtained as a single E-isomer at C2—C3.
N-tert-butyl-3-(4-methoxyl)benzoyl propionamide (5) as
a substrate shown in Table 3. When 5 was treated at 75
℃ (Entry 1), the desired product 6 was achieved in
82%. The removal of butyl group of 6 was observed.
While at lower temperatures (Entries 4—6), the sub-
strate failed to be completely consumed after 20 h al-
though no adverse product was observed. The reaction
performed at 60—65 ℃ in the presence of 1.6 equiv.
p-TsOH gave 6 in high yields (Entries 2 and 3).7
With the condition in hand, we then explored the
substitution effects on the benzene ring as illustrated in
Table 2. A variety of functional groups on the benzene
ring were tolerated under this condition. For the sub-
strates bearing electron donating group, the dehydroge-
nation proceeded smoothly in good yields (Entries 1—3,
7, 8, 11—13). However, prolonged reaction time for the
ones bearing electron withdrawing group such as nitro-
or chloro- is needed (Entries 5, 6, 9, 10, 15), while the
substrates were still incompletely consumed, rendering
the yields relatively low.
Table 3 Dehydrogenation of 3-benzoyl propionamidea
Table 2 Dehydrogenation of 3-benzoyl propionates using IBXa
Yield of 6
Entry
Temp./℃
Time/h
(recovery of 5)b/%
82 (0)c
1
2
3
4
5
6
75
65
60
50
40
25
16
20
20
20
20
20
91 (0)
86 (6)
73 (17)
51 (42)
26 (68)
a Reactions were performed on a 0.5 mmol scale in DMSO. b Iso-
lated yield. c Trace amount of adverse product.
Entry Substrate
R1
R2
R3
Time/h Yieldb/%
1
2
3a
3b
3c
3d
3e
3f
MeO MeO PhCH2
30
54
64
81
108
95
50
70
96
96
30
43
72
72
96
82
80
Finally, we examined the application of the above
protocol for the dehydrogenation of 3-benzoyl propi-
onamides. It is noteworthy that substrates protected with
tert-butyl group are well tolerated with this protocol
affording the desired products (Entries 1—5). The re-
sults in Table 4 show similar pattern about the influence
of substitutions on the benzene ring. Interestingly, the
reaction time for this conversion was remarkably shorter
than that for esters. All substrates could be dehydroge-
nated in good to excellent yields (Entries 1—15).
H
H
MeO PhCH2
Me PhCH2
3
86
4
H
H
Cl
PhCH2
PhCH2
PhCH2
Me
81
5
H
58c
59c
82
6
O2N
H
H
7
3g
3h
3i
MeO
Me
Cl
8
H
Me
80
9
H
Me
55c
63c
89
10
11
12
13
14
15
3j
O2N
H
Me
3k
3l
MeO MeO
allyl
allyl
allyl
allyl
allyl
Conclusion
H
H
H
H
MeO
Me
H
87
In conclusion, we have applied IBX for the dehy-
drogenation of 3-benzoyl propionates/propionamides to
3-benzoyl acrylates/acrylamides. Optimized condition
has been identified under which all substrates with dif-
ferent substitutions on the benzene ring could be dehy-
drogenated efficiently in good to excellent yields.
Moreover, this process could be used for the preparation
of 3-aryl carbonyl acrylates/acrylamides and their
2,3-epoxy derivatives with good product diversity. Fur-
ther work to apply this protocol for developing cysteine
proteases inhibitors is undergoing in our laboratory and
will be reported in due course.
3m
3n
3o
84
82
51c
Cl
a
Reactions were performed on a 0.5 mmol scale with IBX (2.4
equiv.) and p-TsOH (1.6 equiv.) in DMSO (5 mL) at 65 ℃. The
reaction was quenched until TLC indicated full consumption of
the substrate, except for Entries 5, 6, 9, 10 and 15. b Isolated yield.
c Remarkably declined yields were due to incomplete consump-
tion of substrates.
In addition, we examined the dehydrogenation of
benzoyl propionamide at different temperatures using
Chin. J. Chem. 2010, 28, 1301— 1305
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Li et al.
NOTE
Table 4 Dehydrogenation of 3-benzoyl propionamides using IBXa
Entry
1
Substrate
7a
R1
MeO
H
R2
MeO
Me
H
R3
H
H
H
H
H
Et
Et
Et
Et
Et
H
H
H
H
H
R4
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Et
Time/h
12
Yieldb/%
93
86
83
81
78
92
87
86
83
80
93
93
90
87
84
2
7b
7c
20
3
H
15
4
7d
7e
H
Cl
32
5
O2N
MeO
H
H
24
6
7f
MeO
MeO
Me
Cl
14
7
7g
Et
21
8
7h
7i
H
Et
20
9
H
Et
38
10
11
12
13
14
15
7j
O2N
MeO
H
H
Et
28
7k
7l
MeO
MeO
Me
H
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
14
18
7m
7n
7o
H
19
H
20
H
Cl
28
a Reactions were performed on a 0.5 mmol scale with IBX (2.4 equiv.) and p-TsOH (1.6 equiv.) in DMSO (5 mL) at 65 ℃. The reaction
was quenched until TLC indicated full consumption of the substrate. b Isolated yield.
References and note
6
For previous application of IBX, see:
(a) Nicolaou, K. C.; Zhong, Y. L.; Baran, P. S. J. Am. Chem.
Soc. 2000, 122, 7596.
(b) Nicolaou, K. C.; Zhong, Y. L.; Baran, P. S. Angew.
Chem., Int. Ed. 2000, 39, 622.
(c) Nicolaou, K. C.; Zhong, Y. L.; Baran, P. S. Angew.
Chem., Int. Ed. 2000, 39, 625.
(d) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L.; Vega, J. A.
Angew. Chem., Int. Ed. 2000, 39, 2525.
(e) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J.
Am. Chem. Soc. 2004, 126, 5192.
(f) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L. J. Am. Chem.
Soc. 2001, 123, 3183.
(g) Nicolaou, K. C.; Baran, P. S.; Kranich, R.; Zhong, Y. L.;
Sugita, K.; Zou, N. Angew. Chem., Int. Ed. 2001, 40, 202.
(h) Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew.
Chem., Int. Ed. 2002, 41, 993.
(i) Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison,
S. T. Angew. Chem., Int. Ed. 2002, 41, 996.
(j) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L.; Sugita, K. J.
Am. Chem. Soc. 2002, 124, 2212.
(k) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L.; Sugita, K. J.
Am. Chem. Soc. 2002, 124, 2221.
(l) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L.; Sugita, K. J.
Am. Chem. Soc. 2002, 124, 2233.
(m) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L.; Sugita, K. J.
Am. Chem. Soc. 2002, 124, 2245.
1
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2
3
4
Stetter, H. Angew. Chem., Int. Ed. 1976, 15, 639.
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5
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1301— 1305

Synthesis of 3-Benzoyl Acrylates/Acrylamides via Dehydrogenation
7
Typical experimental procedure for dehydrogenation of
3-benzoyl propionates/propionamides: IBX (336 mg, 1.2
mmol) was dissolved in DMSO (5 mL). The reaction mix-
ture was then heated to 65 ℃. After IBX was completely
dissolved and the mixture was clearly transparent, N-tert-
butyl-3-(4-methoxybenzoyl)propionamide (5) (132 mg, 0.5
mmol) and p-TsOH (154 mg, 0.8 mmol) were added. The
resulting mixture was continued to stir at 65 ℃ until TLC
indicated full consumption of 6. The reaction mixture was
diluted with ethyl acetate (60 mL) and the solution was
washed with saturated sodium bicarbonate (25 mL), water
and brine, dried over sodium sulfate, and concentrated in
vacuo to give yellow residue, which was subsequently puri-
fied by flash chromatography on silica gel to afford 119 mg
(91%) of N-tert-butyl-3-(4-methoxybenzoyl)acrylamide (6)
as a white powder. m.p. 158.5—159.5 ℃; 1H NMR (CDCl3,
300 MHz) δ: 1.37 (s, 9H), 3.82 (s, 3H), 5. 70 (s, 1H), 6.82 (d,
J＝15.0 Hz, 1H), 6.90 (d, J＝8.7 Hz, 2H), 7.86 (d, J＝15.0
Hz, 1H), 7.96 (d, J＝8.7 Hz, 2H); 13C NMR (CDCl3, 75
MHz) δ: 188.2, 164.1, 163.5, 136.2, 132.5, 131.2, 130.0,
114.0, 55.5, 51.8, 28.6; IR (KBr) ν: 3357, 1643, 1588, 1524,
－1
1512, 1449, 1324, 1267, 973, 770 cm ; HRMS (ESI) calcd
for C15H20NO3 [M＋H]＋ 262.1438, found 262.1438.
(E0910209 Zhao, C.; Zheng, G.)
Chin. J. Chem. 2010, 28, 1301— 1305
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