Tributylphosphine-catalyzed Stetter reaction of N,N-dimethylacrylamide: Synthesis of N,N-dimethyl-3-aroylpropionamides

Article abstract of DOI:10.1016/S0040-4039(01)02344-9

The reaction of arylaldehydes 1 and N,N-dimethylacrylamide in the presence of tributylphosphine afforded N,N-dimethyl-3-aroylpropionamides 2 in moderate yields. The reaction might involve the formation of α-oxo ylide A.

Full text of DOI:10.1016/S0040-4039(01)02344-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1247–1251
Tributylphosphine-catalyzed Stetter reaction of
N,N-dimethylacrylamide: synthesis of
N,N-dimethyl-3-aroylpropionamides
Ji Hyeon Gong, Yang Jin Im, Ka Young Lee and Jae Nyoung Kim*
Department of Chemistry and Institute of Basic Science, Chonnam National University, Kwangju 500-757, South Korea
Received 29 August 2001; revised 5 December 2001; accepted 7 December 2001
Abstract—The reaction of arylaldehydes 1 and N,N-dimethylacrylamide in the presence of tributylphosphine afforded N,N-
dimethyl-3-aroylpropionamides 2 in moderate yields. The reaction might involve the formation of a-oxo ylide A. © 2002 Elsevier
Science Ltd. All rights reserved.
The Baylis–Hillman reaction is well known as a cou-
pling reaction of aldehydes and activated alkenes cata1-
lyzed by tertiary amines or tertiary phosphines.
Activated alkenes involve ethyl acrylate, acrylonitrile,
dimethylacrylamide in THF in the presence of Bu3P
and phenol as our continuing program on the Baylis–
Hillman reaction. However, no expected Baylis–Hill-
4
man adduct was obtained in the reaction. Instead, we
1
alkyl vinyl ketone, aryl vinyl sulfone, etc. However,
could isolate N,N-dimethyl-3-benzoylpropionamide
5
acrylamides cannot be used as a electrophile in the
Baylis–Hillman reaction in usual reaction conditions
due to the diminished electrophilicity of the b-position
(2a) in 52% yield as an oil. The reaction could also be
conducted without phenol (Scheme 1).
1
,2
of acrylamides. The Baylis–Hillman adduct of acryl-
amide was obtained in low yield in certain reaction
conditions such as under high pressure or under
The reaction mechanism could be suggested as follows
6
as Stetter have proposed in a similar reaction. Tri-
butylphosphine attacked benzaldehyde to generate the
2
7
microwave irradiation conditions.
tautomeric betaine-ylide species A, which was added to
N,N-dimethylacrylamide in a 1,4-fashion to give the
Recently, mild cooperative catalytic activity of phenol
product after elimination of Bu P (pathway (i) in
3
derivatives in the Baylis–Hillman reaction with tri-
Scheme 2). The catalyzed nucleophilic addition of alde-
hyde to electrophilic double bond, known as Stetter
reaction, is a rapid and efficient method for the prepa-
3
butylphosphine (Bu P) was reported. Phenol acts as a
3
Brfnstead acid to activate the carbonyl group of an
aldehyde and a polarized alkene in the reaction. Thus,
we envisioned that the use of phenol in the Baylis–Hill-
man reaction of N,N-dimethylacrylamide and benzalde-
hyde could afford the Baylis–Hillman adduct. We
examined the reaction of benzaldehyde (1a) and N,N-
6
ration of 1,4-dicarbonyl compounds. Cyanide ion and
thiazolium salt were used as the catalyst in the Stetter
reaction. Although almost all of the electrophilic dou-
ble bonds have been used in the Stetter reaction, the
reaction of acrylamides was not mentioned in the litera-
O
O
CH =CH-CONMe
2
NMe2
H
2
Bu P
O
3
THF, reflux
1a
2a
Scheme 1.
Keywords: tributylphosphine; Stetter reaction; Baylis–Hillman reaction; acrylamide.
*
Corresponding author. Fax: 82-62-530-3381; e-mail: kimjn@chonnam.chonnam.ac.kr
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02344-9

1
248
J. H. Gong et al. / Tetrahedron Letters 43 (2002) 1247–1251
6
ture. Moreover, Bu P catalyzed Stetter reaction have
reversible, while the conjugate addition to N,N-
dimethylacrylamide leading to 2 is irreversible as
3
not been reported.
6
reported. Moreover, it seemed that the sterically hin-
The other possible reaction pathways in the reaction
conditions were also depicted in Scheme 2. The
dered A could not attack the carbonyl carbon of benz-
aldehyde. In order to clarify the reaction mechanism we
examined the reaction with benz(aldehyde-d) (1a–D)
and obtained the expected deuterium-labeled 2a–D in
41% yield (see entry 2 in Table 1).
reversible addition reactions of Bu P either to aldehyde
3
(
1,2-fashion, pathway (i) and (iii) in Scheme 2) or
N,N-dimethylacrylamide (1,4-fashion, pathway (ii) in
Scheme 2) might be a competition. In our reaction
conditions, neither the Baylis–Hillman products nor the
benzoin condensation products were observed. The b-
position of N,N-dimethylacrylamide is less electrophilic
than the other normally used activated alkenes in the
Baylis–Hillman reaction such as ethyl acrylate, acrylo-
As shown in Table 1 various aromatic aldehydes 1a–g
gave the corresponding Stetter type products 2a–g in
reasonable yields. Replacement of Bu P to Ph P did not
3
3
give the products at all. The use of DABCO was also
ineffective. The use of catalytic amounts of Bu3P
required long reaction time to obtain appreciable
amounts of products. It is interesting to note that the
use of cyanide ion or thiazolium salt (3-benzyl-5-(2-
hydroxyethyl)-4-methyl thiazolium chloride) in the
reaction was ineffective for the synthesis of 2. By using
4-acryloylmorpholine the corresponding product 2a%
1,2
nitrile, alkyl vinyl ketone or aryl vinyl sulfone. Thus,
we could not obtain the Baylis–Hillman adducts.
Instead, 1,2-addition of Bu P toward benzaldehyde
3
occurred predominantly in our reaction conditions. The
initially formed oxyanion (betaine form) was in equi7-
librium with the tautomeric carbanion (ylide form).
The ylide form resembled the carbanion in the benzoin
condensation. However, to our disappointment, there
was no benzoin condensation product in the reaction
mixtures as mentioned before even in the absence of
N,N-dimethylacrylamide. This might be explained as
follows. Addition of the carbanion to benzaldehyde
leading to the benzoin condensation product is
5e,5f
was obtained similarly (entry 9).
However, when we
used sterically hindered aldehydes such as 1h and 1i, the
formation of intermediate A was inhibited and we
could not obtain the desired compounds 2h and 2i.
Instead, we could isolate the allylic alcohol derivatives
8
3h and 3i in moderate yields (Scheme 3). The plausible
mechanism for the formation of these compounds was
O
(i) Stetter reaction
NMe2
OH
Bu P
O
3
R-CHO
R
H
R
PBu3
PBu3
betaine
α-oxo ylide
A
H
O
O
O
- Bu P
3
NMe2
R
NMe2
R
PBu3
O
2
(ii) Baylis-Hillman reaction
O
O
O
OH O
O
H
-
Bu3P
Bu P
R-CHO
3
NMe2
R
NMe2
PBu3
R
NMe2
NMe2
PBu3
(
not formed)
B
(iii) benzoin condensation reaction
benzoin
condensation
O
O
Bu P
OH
3
R
R-CHO
R
H
R
R
PBu3
OH
PBu3
(not formed)
betaine
α-oxo ylide
A
Scheme 2.

J. H. Gong et al. / Tetrahedron Letters 43 (2002) 1247–1251
Table 1. Synthesis of N,N-dimethyl-3-aroylpropionamides 2
1249
yield (%)a
product (2)
entry
aldehyde (1)
conditions
O
CHO CH =CHCONMe (1.5 equiv)
NMe2
2a
2
2
5
2
1
Bu P (1.0 equiv)
3
(oil)
O
1a
THF, reflux, 2 h
O
D
CDO CH =CHCONMe (1.0 equiv)
NMe2
2
2
1b
4
2
3
Bu P (1.0 equiv)
3
O 2a-D
(oil)
1
a-D THF, reflux, 3 h
O
CHO
1b
NMe2
CH2=CHCONMe2 (1.5 equiv)
Bu3P (1.0 equiv)
THF, reflux, 2 h
6
1
O
(59-61)
Me
Me
Cl
2b
O
O
O
CHO
NMe2
CH2=CHCONMe2 (0.5 equiv)
Bu3P (0.5 equiv)
4
9c
101-102)
4
5
6
O
O
O
(
Cl
1c
2c
o
THF, 40-50 C, 3 h
CHO CH =CHCONMe (0.7 equiv)
NMe2
2
2
8c
5
Bu P (0.7 equiv)
3
(
69-70)
MeO
Me
1d THF, refulx, 4 h
MeO
Me
2d
CHO
NMe2
CH2=CHCONMe2 (0.5 equiv)
Bu3P (0.5 equiv)
3c
5
(oil)
1e
THF, reflux, 4 h
2e
O
CHO CH2=CHCONMe2 (1.0 equiv)
NMe2
58
7
8
Bu3P (1.0 equiv)
O
(69-71)
o
THF, 40-50 C, 3 h
2f
1f
O
O
CHO
CH2=CHCONMe2 (1.0 equiv)
NMe2
6
(oil)
8
Bu P (1.0 equiv)
3
O
O
N
THF, reflux, 2 h
N
2g
1g
O
O
CHO
(1.0 equiv)
N
N
61
9
O
(71-73)
Bu3P (1.0 equiv)
THF, reflux, 2 h
2a'
1a
a
b
Isolated yield based on aldehyde, mp was written below. Small amounts of 2a was contaminated,
which might be produced due to trace amounts of moisture in the reaction mixture.8 cBased on N,
N-dimethylacrylamide.
shown for 3i. For the sterically hindered aldehydes,
Bu P (405 mg, 2.0 mmol) and N,N-dimethylacrylamide
3
addition of Bu P occurred firstly in a 1,4-fashion to
(297 mg, 3.0 mmol) in THF (10 mL) was heated to
reflux for 2 h. After the usual workup process and
column chromatographic purification (CH Cl /ether,
3
give the intermediate B (pathway (ii) in Scheme 2). The
reaction of B and 1i gave 3i after elimination of Bu P.
3
2
2
However, the reaction with other aliphatic aldehydes
such as hexanal and isobutyraldehyde shows complex
mixtures on TLC. The reaction with other acrylamides
such as N-tert-butylacrylamide and acrylamide shows
sluggish reaction. Thus, we could isolate neither the
Stetter type products nor the allylic alcohol derivatives
in reasonable yields.
2:1) pure 2a was isolated as a colorless oil, 214 mg
5,8
(52%).
In conclusion, we disclosed the facile synthesis of N,N-
dimethyl-3-aroylpropionamides in moderate yields by
the tributylphosphine catalyzed Stetter type reaction for
the first time. The studies on the general applicability of
the reaction with various acrylamides and the
intramolecular version of the reaction are currently
underway.
The reaction of benzaldehyde (entry 1 in Table 1) is
typical: A mixture of benzaldehyde (212 mg, 2.0 mmol),

1
250
J. H. Gong et al. / Tetrahedron Letters 43 (2002) 1247–1251
Cl
O
Cl OH
NMe2
CH2=CH-CONMe2 (1.0 equiv)
H
O
Bu3P (1.0 equiv)
THF, reflux, 12 h
Cl
h
Cl
1
3h (32%)
O
OH
CH2=CH-CONMe2 (1.0 equiv)
NMe2
H
Bu3P (1.0 equiv)
THF, reflux, 24 h
O
3i (54%)
1i
O
OH
O
NMe2
NMe2
PBu3
NMe2
PBu3
PBu3
B
O
H
-
Bu3P
NMe2
PBu O
3
Scheme 3.
Acknowledgements
K. Y.; Chung, Y. M.; Lee, H. J.; Kim, J. N. Tetrahedron
Lett. 2000, 41, 2613; (e) Lee, H. J.; Kim, H. S.; Kim, J. N.
Tetrahedron Lett. 1999, 40, 4363; (f) Lee, H. J.; Seong, M.
R.; Kim, J. N. Tetraherdon Lett. 1998, 39, 6223.
This work was supported by Korea Research Founda-
tion Grant (KRF-2001-015-DP0326).
5. For the synthesis of N,N-dialkyl-3-aroylpropionamides by
different approaches, see: (a) Pouilhes, A.; Thomas, S.
Tetrahedron Lett. 1989, 30, 2285; (b) Tishchenko, I. G.;
Kulinkovich, O. G.; Masalov, N. V. Synthesis 1982, 268;
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(
g) Basavaiah, D.; Kumaragurubaran, N. Tetrahedron
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Isaacs, N. S. Tetrahedron Lett. 1986, 27, 5007. For the
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J. H. Gong et al. / Tetrahedron Letters 43 (2002) 1247–1251
1251
2
a: 214 mg (52%); colorless oil; IR (KBr) 2925, 1685, 1647
171.58 (C), 199.21 (C); mass (70 eV) m/z (rel. intensity) 72
(53), 101 (23), 105 (100), 134 (17), 162 (43), 206 (M , 19).
−
1
1
+
cm ; H NMR (CDCl ) l 2.77 (t, J=6.6 Hz, 2H), 2.95 (s,
3
3
H), 3.09 (s, 3H), 3.35 (t, J=6.6 Hz, 2H), 7.42–8.03 (m, 5H);
3h: white solid; mp 119–120°C; IR (KBr) 3259, 2927, 1657,
1
3
−1 1
C NMR (CDCl ) l 27.23, 33.68, 35.62, 37.22, 128.12,
1591 cm ; H NMR (CDCl ) l 3.00 (s, 3H), 3.08 (s, 3H),
3
3
1
28.53, 133.09, 136.75, 172.02, 199.37; mass (70 eV) m/z (rel.
3.55 (d, J=9.5 Hz, 1H, D O exchangeable), 6.14 (ddd,
2
+
intensity) 77 (47), 105 (100), 133 (29), 161 (87), 205 (M , 31).
2
J=6.5 Hz, 1H), 2.96 (s, 3H), 3.10 (s, 3H), 3.35 (d, J=6.5
J=9.5, 4.2 and 2.1 Hz, 1H), 6.57 (dd, J=15.2 and 2.1 Hz,
1H), 6.99 (dd, J=15.2 and 4.2 Hz, 1H), 7.17 (t, J=7.9 Hz,
1
a–D: colorless oil; H NMR (500 MHz, CDCl ) l 2.78 (t,
3
13
1H), 7.30 (d, J=7.9 Hz, 2H); C NMR (CDCl ) l 35.75,
3
Hz, 2H), 7.46 (t, J=7.5 Hz, 2H), 7.55 (t, J=7.5 Hz, 1H),
37.45, 70.91, 120.62, 129.33, 129.62, 134.63, 135.63, 143.03,
13
8
.02 (d, J=7.5 Hz, 2H); C NMR (125 MHz, CDCl ) l
166.23; mass (70 eV) m/z (rel. intensity) 72 (49), 100 (100),
3
+
2
6.89 (t, J=19.6 Hz, CH), 33.50 (CH ), 35.40 (CH ), 37.00
173 (84), 175 (55), 201 (16), 244 (18), 273 (M , 10), 275
2
3
+
(
CH ), 127.99 (CH), 128.41 (CH), 132.90 (CH), 136.79 (C),
(M +2, 7).
3