Double α-addition reaction of ortho -hydroxyacetophenones to ethyl propiolates mediated by Ph3P: Synthesis of functionalized 1,4-pentadienes

Article abstract of DOI:10.1055/s-0030-1258093

A new way of synthesizing functionalized 1,4-pentadienes by double -addition reaction of ortho-hydroxyacetophenones to ethyl propiolate mediated by Ph₃P in moderate yields is described. On the other hand, other ortho-hydroxyphenyl ketones resulted in the single α-addition products in moderate to good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258093

LETTER
1833
Double a-Addition Reaction of ortho-Hydroxyacetophenones to Ethyl
Propiolates Mediated by Ph3P: Synthesis of Functionalized 1,4-Pentadienes
S
ynthesis of Fun
i
ctiona
n
lized 1,4-Pen
g
tadienes -Guo Meng,b Kai Tang,b Hui-Fang Liu,a Jiang Xiao,a Song Xue*a
a
Department of Applied Chemistry, Tianjin University of Technology, Tianjin 300191, P. R. of China
Fax +86(22)60214252; E-mail: xuesong@ustc.edu.cn
b
Department of Chemistry, University of Science and Technology of China, Hefei 230026, P. R. of China
Received 9 April 2010
alkynoates in the presence of Ph3P. Herein we reported
that functionalized 1,4-pentadienes was formed via dou-
ble a-addition reaction step when the ortho-acylphenols
used were ortho-hydroxyacetophenones.
Abstract: A new way of synthesizing functionalized 1,4-penta-
dienes by double a-addition reaction of ortho-hydroxyaceto-
phenones to ethyl propiolate mediated by Ph3P in moderate yields
is described. On the other hand, other ortho-hydroxyphenyl ketones
resulted in the single a-addition products in moderate to good
yields.
Table 1 Optimization of the Double a-Addition Reaction Condi-
tions
Key words: a-addition, functionalized 1,4-pentadienes, Ph3P,
ortho-acylphenols, ethyl propiolates
OH
O
OH
O
O
Ph3P (50 mol%)
solvent, r.t., 16 h
COOEt
COOEt
+
OEt
Functionalized 1,4-pentadienes are important intermedi-
ate in organic synthesis. They serve as key building blocks
in the preparation of various interesting molecules.1
Moreover, they are important structural units present in
several biologically active molecules.2 Consequently,
some useful and new methodologies were developed for
their synthesis.3 The comparatively simple method to ob-
tain a 1,4-diene framework is the Baylis–Hillman reac-
tion, which was developed by Basavaiah.4 However, the
development of simple and mild methods for the synthesis
of functionalized 1,4-pentadienes is strongly desirable.
1a
2a
3a
Entry
1a (mmol) 2a (mmol) Solvent
Yield (%)a
21b
43
1
2
0.3
0.3
0.3
0.3
0.3
0.3
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.9
0.6
0.6
0.6
0.6
0.6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
EtOAc
acetone
DMF
3
37c
4
23d
43e
5
6
45
The a-addition reaction is one of the most fundamental
carbon–carbon bond-forming reactions in organic synthe-
sis. In recent years, electron-deficient alkynes are often
used as nucleophile precursors for the formation of car-
bon–carbon bonds and recent studies on the chemistry of
organocatalysts via conjugate addition of N and P nucleo-
philes have uncovered a number of interesting reactions.5
Trost, Taran, and our group have reported various phos-
phine-catalyzed a-addition reactions by using electron-
deficient alkynes as substrates.6,7 Most recently, we re-
ported Ph3P-catalyzed a-addition reactions of 1-(o-hy-
droxyaryl)-1,3-diketones to ethyl propiolates to give
multifunctional vinylesters (Scheme 1).8 In order to fur-
ther develop new addition reactions, we investigated the
a-addition reactions of ortho-acylphenols to terminal
7
53
8
20
9
27
10
11
15
<10
a Isolated yields.
b 20 mol% Ph3P was used.
c 100 mol% Ph3P was used.
d At 0 °C.
e At reflux.
O
OH
O
O
R1
O
O
O
R1
Ph3P (30 mol%)
CH2Cl2, r.t., 12 h
+
OEt
CO2Et
Scheme 1
SYNLETT 2010, No. 12, pp 1833–1836
x
x
.x
x
.2
0
1
0
Advanced online publication: 14.06.2010
DOI: 10.1055/s-0030-1258093; Art ID: W05710ST
© Georg Thieme Verlag Stuttgart · New York

1834
L.-G. Meng et al.
LETTER
Table 2 Reaction of ortho-Acylphenols 1 with Terminal
Alkynoates for the Synthesis of 1,4-Pentadienes (continued)
Our studies were initiated by addition of 0.5 equivalents
of Ph3P to a solution of 2-hydroxyacetophenone (1a) and
2.0 equivalents ethyl propiolate (2a) in CH2Cl2. A 43%
yield of the functionalized 1,4-pentadiene product 3a was
formed from the double a-addition reaction of ortho-
acylphenol to ethyl propiolate when the reaction was
stirred at room temperature for 16 hours (entry 2,
Table 1). Its structure was determined by NMR and
HRMS spectra. The amount of Ph3P has an obviously ef-
fect on this reaction. The desired product 3a was obtained
in only 21% yield when 20 mol% Ph3P were used. The
yield of the product was slightly decreased by further
increasing the amount of Ph3P. The yield of the double
a-addition reaction could not be improved under reflux
conditions and decreased when the reaction was stirred at
0 °C. The ratio of 1a and 2a also had an effect on the re-
action, and the desired product 3a was afforded in 53%
yield when the amount of 2-hydroxyacetophenone was in-
creased (entry 7, Table 1). Ph3P as a catalyst was crucial
for this reaction. A complex mixture was formed when
tributylphosphine or tricyclohexylphosphine, in place of
Ph3P, was used. The use of other organic bases, such as
1,4-diazabicyclo-[2,2,2]-octane, 4-dimethylaminopyri-
dine, Et3N, and pyridine, did not give the desired prod-
ucts.
Entry Substrate
Product, yield (%)a
O
R
OH
O
OH
O
COOEt
COOEt
5
EtO
OMe
OH
OMe
OH
1e
3e 56
O
O
COOEt
COOEt
6
7
EtO
EtO
MeO
3f 45
OH
MeO
1f
O
OH
O
COOEt
COOEt
Cl
Cl
1g
3g 48
OH
O
OH
OH
OH
O
COOEt
COOEt
8
9
EtO
EtO
Cl
Cl
Table 2 Reaction of ortho-Acylphenols 1 with Terminal
Alkynoates for the Synthesis of 1,4-Pentadienes
1h
3h 50
O
OH
O
Entry Substrate
Product, yield (%)a
O
COOEt
COOEt
R
1i
3i 40
OH
O
O
OH
OH
O
OH
O
O
COOEt
COOEt
1
2
EtO
EtO
COOEt
COOEt
10
EtO
Me
Me
1a
3a 53
OH
Me
OH
Me
OH
O
1j
3j 45
O
O
COOEt
COOEt
COOEt
11
12
EtO
Br
Br
COOEt
1b
1c
1d
3b 47
OH
Me
O
Me
O
OH
O
O
O
1k
3k 51
COOEt
COOEt
OH
OH
3
4
EtO
EtO
COOMe
MeO
OMe
OH
OMe
COOMe
3c 54
OH
1a
a Isolated yields.
3l 46
O
COOEt
COOEt
Further investigations conducted with various solvents
were also performed. When shifting the solvent to CHCl3
or ethyl acetate, the desired product 3a was obtained in
20% and 27%, respectively. With acetone or DMF as sol-
vents, the yield of reaction was even worse.
OEt
OEt
3d 40
Synlett 2010, No. 12, 1833–1836 © Thieme Stuttgart · New York

LETTER
Synthesis of Functionalized 1,4-Pentadienes
1835
1-phenylprop-2-yn-1-one, failed to react under the same
conditions. It was also noted that the yield of the double
a-addition products were moderate (40–56%), this was
due to the formation of other byproducts during the reac-
tion.
Table 3 Reaction of Ketones 4 with Ethyl Propiolates Mediated by
Ph3P (50 mol%)
Entry
1
Substrate
Product, yield (%)a
OH
O
O
O
OH
O
To further evaluate the scope of this reaction, substituted
ketones 4, in which the methyl group were replaced by a
longer alkyl group, were synthesized and tested under
above standard conditions. The results are summarized in
Table 3. In these occasions, the desired double a-addition
products 3 were not formed, but single a-addition prod-
ucts were afforded in moderate to good yields, which
might be due to steric hindrance of the substitutent. For
example, exposure of substrate 1-(2-hydroxyphenyl)pro-
pan-1-one (4a) and 1-(2-hydroxy-phenyl)butan-1-one
(4b) to 2a in the presence of Ph3P (50 mol%) at room tem-
perature for 16 hours afforded the corresponding single
a-addition products 5a and 5b in 54% and 44% yields,
respectively. Furthermore, 1-(2-hydroxyphenyl)-2-phe-
nylethanone (4c) substituted by phenyl group could be
transformed into the corresponding product 5c in 74%
yield. Other substrates 4d,e also gave good yields of the
corresponding products. However, no desired product
was detected when 1-(2-hydroxyphenyl)-2-methylpro-
pan-1-one (4f) was submitted to this reaction, which
might be due to steric hindrance of the isopropyl group.
COOEt
COOEt
COOEt
4a
4b
5a 54
OH
OH
O
O
2
3
5b 44
OH
OH
OH
4c
5c 74
OH
O
O
COOEt
4
5d 75
4d
OH
O
OH
O
O
On the basis of these results and previous investigations,7,8
a mechanistic pathway for the unexpected a-addition
reaction is proposed in Scheme 2. The first step of the re-
action begins with conjugate addition of Ph3P to ethyl pro-
piolate to produce a zwitterion 6, which then deprotonates
the ketone 1 or 4 to generate 7 and 8. The intermediate 8
could be converted to enolate 9 through proton transfer.
The enolate 9 then undergoes a-C addition to the interme-
diate 7 to give 10. When R2 = H, the intermediate 10
would be followed by proton transfer and elimination of
Ph3P to generate 11. The product 3 is formed through a
second reaction process from steps B to F. On the other
hand, when R2 is an alkyl or phenyl group, the intermedi-
ate 10 will afford the single a-addition product 5 through
proton transfer and elimination of Ph3P. The compound 5
cannot be further converted into the double a-addition
product due to the presence of alkyl or phenyl group,
which prevents reacting with ethyl propiolate. Higher
yield of product 5 was obtained when R2 is a phenyl
group, which might be ascribed to the carbanion of inter-
mediate 9 well stabilized by phenyl ring. Our attempts to
isolate 11 were not successful. The results imply that a
second a-addition of 11 to ethyl propiolate proceeds faster
than that of substrate 1.
COOEt
5
6
Cl
Cl
4e
4f
5e 66
OH
n.d.b
Cl
a Isolated yields.
b No desired product was detected.
Under these optimized conditions,9 we next explored the
scope of the double a-addition reaction, As shown in
Table 2, a variety of ortho-hydroxyacetophenones 1 was
employed as the reaction substrate and the corresponding
functionalized 1,4-pentadienes were obtained in moderate
yields. Clearly, substituents on the aromatic ring had no
obviously effect on the yield of the double a-addition
reactions. The naphthyl substrate 1i also reacted smoothly
with ethyl propiolate to give the desired product 3i in 40%
yield. Notably, when multisubstituted ortho-hydroxyace-
tophenones, such as 1-(2-hydroxy-4,5-dimethylphenyl)-
ethanone (1j) and 1-(4-bromo-2-hydroxy-5-methyl-
phenyl)ethanone (1k), could also be converted to the cor-
responding products in moderate yields. As expected,
methyl propiolate could also be used as a substrate to react
with 1a to afford the desired product 3l in 46% yield.
However, acetylenic ketones, such as but-3-yn-2-one and
In order to elucidate the key effect of the hydroxyl group
in the substrate, acetophenone and 2-acetylphenyl ben-
zoate were subjected to the reaction with ethyl propiolate
mediated by Ph3P in CH2Cl2 at room temperature, but no
reactions occurred. Furthermore, in the presence of phe-
nol, acetophenone, and 2-acetylphenyl benzoate also pro-
vided no a-addition product under the typical conditions.
The reaction of para-acylphenol, in place of ortho-
Synlett 2010, No. 12, 1833–1836 © Thieme Stuttgart · New York

1836
L.-G. Meng et al.
LETTER
O
O
O
B
Ph3P
A
OEt
2a
Ph3P
OEt
OH
Ph3P
OEt
–
7
D
O–
O
6
O
OH
O
R2
R2
R2
C
–
R1
R1
R1
8
9
1 or 4
E
PPh3
OEt
–
OH
O
OH
O
OH
O
OEt
– Ph3P
2 = H
B–F
COOEt
COOEt
R2
10
– Ph3P
O
O
R
R1
R1
11
R1
F
3
OH
O
OEt
R2
O
R1
5
R
2 = Alk or Ph
Scheme 2 Plausible mechanism for a-addition reactions
Perkin Trans. 1 2000, 253. (c) Andrey, O.; Glanzmann, C.;
Landais, Y.; Parra-Rapado, L. Tetrahedron 1997, 53, 2835.
acylphenol, with ethyl propiolate only gave b-addition
product ethyl 3-(4-acetylphenoxy)acrylate. These results
show that hydroxyl group in ortho-acylphenol plays an
important role in the a-addition reaction.
(3) (a) Matsuhashi, H.; Hatanaka, Y.; Kuroboshi, M.; Hiyama,
T. Tetrahedron Lett. 1995, 36, 1539. (b) Matsushita, H.;
Negishi, E. J. Am. Chem. Soc. 1981, 103, 2882. (c) Agrios,
K. A.; Srebnik, M. J. Org. Chem. 1994, 59, 5468.
(d) Klaps, E.; Schmid, W. J. Org. Chem. 1999, 64, 7537.
(e) Hara, R.; Nishihara, Y.; Landré, P. D.; Takahashi, T.
Tetrahedron Lett. 1997, 38, 447.
(4) (a) Basavaiah, D.; Kumaragurubaran, N.; Sharada, D. S.
Tetrahedron Lett. 2001, 42, 85. (b) Basavaiah, D.; Sharada,
D. S.; Kumaragurubaran, N.; Reddy, R. M. J. Org. Chem.
2002, 67, 7135.
(5) For review, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem.
Res. 2001, 34, 535. (b) Valentine, D. H. Jr.; Hillhouse, J. H.
Synthesis 2003, 317. (c) Methot, J. L.; Roush, W. R. Adv.
Synth. Catal. 2004, 346, 1035. (d) Ye, L.-W.; Zhou, J.;
Tang, Y. Chem. Soc. Rev. 2008, 37, 1140. (e) Nair, V.;
Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T.
Acc. Chem. Res. 2006, 39, 520.
In conclusion, we have described an unexpected double
a-addition reaction of ortho-hydroxyacetophenones to
terminal alkynoates mediated by Ph3P. The reaction af-
forded functional 1,4-pentadienes in moderate yields un-
der mild conditions. Meanwhile, single a-addition
reaction was occurred when substituted ketones 4, in
place of ortho-hydroxyacetophenones, were used as sub-
strates. The hydroxyl group in substrate was important to
form the a-addition products.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(6) (a) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997, 119,
7595. (b) Meunier, S.; Siaugue, J.-M.; Sawichi, M.; Calbour,
F.; Dézard, S.; Taran, F.; Mioskowski, C. J. Comb. Chem.
2003, 5, 201. (c) Hanédanian, M.; Loreau, O.; Taran, F.;
Mioskowski, C. Tetrahedron Lett. 2004, 45, 7035.
(d) Hanédanian, M.; Loreau, O.; Sawicki, M.; Taran, F.
Tetrahedron 2005, 61, 2287.
Acknowledgment
We are grateful to the National Natural Science Foundation of Chi-
na (20772116) and the Tianjin Natural Science Foundation
(09JCZDJC24400) for financial supports.
(7) (a) Xue, S.; Zhou, Q.-F.; Zheng, X.-Q. Synth. Commun.
2005, 35, 3027. (b) Meng, L.-G.; Tang, K.; Guo, Q.-X.;
Xue, S. Tetrahedron Lett. 2008, 49, 3885.
(8) Meng, L.-G.; Hu, B.; Wu, Q.-P.; Liang, M.; Xue, S. Chem.
Commun. 2009, 6089.
(9) General Reaction Procedure
References and Notes
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To a solution of ortho-acylphenols (0.6 mmol) with terminal
alkynoates (0.6 mmol) in dry CH2Cl2 (2 mL) was added Ph3P
(79 mg, 0.3 mmol), and the resulting mixture was stirred at
r.t. for 16 h. The solvent was removed in vacuo, and the
residue was purified by column chromatography on silica
gel (PE–EtOAc = 20:1) to give the desired product.
(2) (a) Nicolaou, K. C.; Ramphal, J. Y.; Petasis, N. A.; Serhan,
C. N. Angew. Chem., Int. Ed. Engl. 1991, 30, 1100.
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Synlett 2010, No. 12, 1833–1836 © Thieme Stuttgart · New York

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