Radical reactions in esters with alkoxy functionality chemistry an unusual alcohol moiety hydrogen abstraction

Article abstract of DOI:10.1016/j.tetlet.2004.02.158

Various geometrically pure (E)-alkenes have been synthesized by radical substitution of alcohol moieties generated via hydrogen abstraction within ethyl esters. These reactions occurred with high regioselectivity and gave a new access to 1-methyl-3-aryl-allyl esters.

Full text of DOI:10.1016/j.tetlet.2004.02.158

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3685–3687
Radical reactions in esters with alkoxy functionality chemistry an
unusual alcohol moiety hydrogen abstraction
Ming-Chung Yan, Yeong-Jiunn Jang, Jhenyi Wu, Yung-Feng Lin and Ching-Fa Yao*
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei, Taiwan 116, ROC
Received 8 January 2004; revised 9 February 2004; accepted 27 February 2004
Abstract—Various geometrically pure (E)-alkenes have been synthesized by radical substitution of alcohol moieties generated via
hydrogen abstraction within ethyl esters. These reactions occurred with high regioselectivity and gave a new access to 1-methyl-3-
aryl-allyl esters.
Ó 2004 Elsevier Ltd. All rights reserved.
This last decade has witnessed an increased interest in
the radical chemistry of b-nitrostyrenes 1, especially in
how to enlarge the diversity of functional groups
belonged to the radical donors.1 It is known from the
literature that 3-aryl-allyl ester units are often used as
precursors in synthesizing important fused aromatic
compounds such as benzofurans, benzothiophenes.2 In
addition, these substrates are valuable for stereochemi-
cal studies on the transition metal-catalyzed allylic
alkylation,3 and they have found wide application in
organic synthesis as versatile active intermediates.
However, examples of radical designs for the prepara-
tion of these units have been limited. In connection
with our ongoing program related to the utilities of
b- nitrostyrenes 1, we here describe an efficient synthesis
of 1-methyl-3-aryl-allyl ester derivatives based on regio-,
and stereoselective substitution reactions of b-nitrosty-
renes 1 with simple ethyl esters using a common radical
initiator––benzoyl peroxide.
Therefore, this leads to more electrophilic radicals,
which preferentially react with electron-rich alkenes.5
Against the background presented above, we assume
our starting materials (b-nitrostyrenes 1) are electron-
poor nitroalkenes and have high potential for trapping
electron-rich radicals. Thus an extraordinary design for
preparing 1-methyl-3-aryl-allyl esters involving the alk-
oxy moiety C–H abstraction followed by radical sub-
stitution is build.
First, we began our studies with the benzoyl peroxide
mediated reactions shown in Eq. 1 and Table 1. When
(E)-b-nitrostyrene 1a was treated with 2.5 equiv of
benzoyl peroxide in ethyl acetate 2f under refluxing
condition for 6 h, (E)-1-methyl-3-phenyl-allyl acetate 3af
was obtained as the sole product in 50% yield (Table 1,
entry 1). The mechanism of this reaction is presumably
similar to our previous study in the radical addition–
elimination reaction of b-nitrostyrenes 1 and different
alkyl radicals.1 Initiation occurs with the alkoxy moiety
C–H abstraction of 2f with the benzoyl or phenyl radical
species generated from benzoyl peroxide. The resulting
radical species undergo intermolecular addition to Åthe
b-nitrostyrene 1a followed by elimination of NO2 to
yield (E)-alkene because the product stability of (E)-
alkene is much stable than (Z)-alkene in energy. In addi-
tion to (E)-1a, a series of (E)-nitroalkenes with various
aromatic parts owning different electron demand were
examined, and the results revealed the tendency toward
the higher electrophilic ability of the functional group in
nitroalkenes the higher reactivity of it (Table 1, entries
1–5). This phenomenon led us to believe that our
starting substrates (b-nitrostyrenes 1) were excellent
It is well known that with carboxylic esters and lactones,
radical hydrogen abstraction can occur either a to the
carbonyl or at the alkoxy group, but generally esters
have been predominately alkylated at the a-position of
the acid moiety.4 For high regioselectivities and yields at
the position next to the carbonyl, esters with an addi-
tional electron-withdrawing substituent should be used.
* Corresponding author. Tel.: +886-2-29309092; fax: +886-2-293242-
49; e-mail: cheyaocf@scc.ntnu.edu.tw
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.158

3686
M.-C. Yan et al. / Tetrahedron Letters 45 (2004) 3685–3687
radical acceptors and had great capacity for trapping
electron-rich radicals.
the carbonyl group and promote the opportunities of
abstraction at the alkoxy moiety.
Ar
O
Ar
O
Bz2O2
R
After successfully establishing the desired C–H
abstraction preferentially on alkoxy moiety, attention
was given to the difference between the alkoxy and acid
moiety in regioselectivity. It is well known that the
degree of the carbon radical center always plays
important roles in different radical reactions. To study
this selectivity for more precisely, the substrates, which
generate radical centers with equal degree (‘secondary’
radicals) must be employed. Toward this purpose, we
decided to investigate in more detail the reactions with
the ester 4 in similar conditions (Eq. 2). As shown,
products 6 were obtained as minor products together
with the predicted products 5 in moderated yields. Not
beyond our expectations, no matter what kind electron
demand of substituents in the benzene ring the C–H
abstraction at the alkoxy moiety always slightly pre-
dominated over the acid moiety. At this stage, we believe
the nature of nitroalkenes 1 are mainly influenced by the
NO2-group, making these substrates good electron-rich
radical trappers.
+
O
reflux
R
O
NO2
1
2
3
1 , 3 a. Ar = Ph
b. Ar = p-Cl-Ph
2 , 3 f. R = methyl
g. R = iso-propyl
h. R = tert-butyl
ð1Þ
c. Ar = p-MeO-Ph
d. Ar = 2-thienyl
e. Ar = 2-furyl
Table 1. The preparation of 1-methyl-3-aryl-allyl ester 3 from the
reaction of b-nitrostyrenes 1, ethyl ester 2, and benzoyl peroxide under
refluxing condition
Entry
1
2, R
Bz2O2
[equiv]
Time
[h]
3 Isolated
yield [%]
1
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
Methyl
Methyl
2.5
6
6
6
6
6
6
6
6
5
5
5
6
5
5
5
50
61
47
43
33
55
69
49
48
33
60
74
48
50
33
2
2.25
2.75
2.75
2.5
3
Methyl
Methyl
Methyl
4
5
6
iso-Propyl
iso-Propyl
iso-Propyl
iso-Propyl
iso-Propyl
tert-Butyl
tert-Butyl
tert-Butyl
tert-Butyl
tert-Butyl
2.5
7
2.25
2.5
To expand the versatility and synthetic value of the
reaction for the preparation of geometrically pure (E)-
styryl esters, we used the conditions resembled in
Eq. 2 to examine substitutions of the NO2-group
with the other ester containing longer alkoxy chain (Eq.
3).
8
9
2.5
2.5
10
11
12
13
14
15
2.5
2.25
2.75
2.5
2.5
Ar
Ar
O
O
Ar
O
Bz2O2
O
O
+
+
reflux
O
NO2
1
4
5
6
ð2Þ
a. Ar = Ph
b. Ar = p-Cl-Ph
c. Ar = p-MeO-Ph
2.5 equiv., 5h
2.25 equiv., 5h 5b. 39% Yield
2.5 equiv., 5h
5c. 27% Yield
5a. 37% Yield
6a. 33% Yield
6b. 31% Yield
6c. 24% Yield
In view of the above results, we decided to examine
generality of this radical NO2-substitution procedure, by
replacing 2f with other esters 2, since the acetic acid
moiety can be introduced first, increasing the likelihood
that the chemistry of the new introduced acid moiety in
2 can be analyzed (Table 1, entries 6–15). Ethyl isobu-
tyrate 2g and ethyl trimethylacetate 2h were chosen as
readily available models for this purpose. As expected,
not only similar products were obtained from these two
bulkier esters, but NO2-substitution with them were also
found to proceed slightly efficiently than 2f without loss
of configurational integrity at the double bond as indi-
cated by their yields. The success of these two reactions
could be attributed to the fact that the boiling points of
these two esters are higher than that of 2f, thus facili-
tating the hydrogen abstraction and NO2-substitution
reaction; moreover, the increase of alkyl groups on the
acid moiety would inhibit the hydrogen abstraction a to
Not only the reaction of the ethyl ester proceeded in nice
yields, but also that of the propyl ester resulted in good
yields. The reaction of b-nitrostyrene 1a and propyl
acetate 7 in analogous conditions gave the correspond-
ing propyl acetate derivative isomers 8a as well as
unexpected 9a in 33% and 26% yields, respectively (Eq.
3). This special type of regioselectivity about the C–H
functionalized radical reaction of ester was never seen
before,6 and we presumed that it resulted from the
reasons: [1] the difference in the rate of hydrogen
abstraction on the alkoxy moiety between a- and b-
positions to oxygen; [2] the preeminent radical trapping
ability of b-nitrostyrenes 1. Owing mainly to the excel-
lent electron-rich radical trapping ability of our accep-
tors as mentioned above, once a radical formed (no
matter a- or b-radicals) after hydrogen abstraction, it
added to the very reactive b-nitrostyrenes 1, so that the
regioselectivity of hydrogen abstraction process led to

M.-C. Yan et al. / Tetrahedron Letters 45 (2004) 3685–3687
3687
the present selectivity of the reactions. On the other
hand, the b-hydrogen abstraction rate factor was so
small in ethyl ester 2 series that we cannot observe any
b-products in the crude GC–MS analysis.
styrenes 1 in the presence of a common radical
initiator––Bz2O2. Further studies on the application of
this method to synthesize other valuable compounds are
under investigation.
Ar
O
O
Ar
O
Ar
O
Bz2O2
O
+
+
reflux
O
NO2
1
7
8
9
a. Ar = Ph
2.5 equiv., 6h
2.5 equiv., 6h
2.5 equiv., 6h
2.5 equiv., 6h
8a. 33% Yield
8b. 42% Yield
8c. 32% Yield
8d. 33% Yield
9a. 26% Yield
b. Ar = p-Cl-Ph
c. Ar = p-MeO-Ph
d. Ar = 2,6-di-MeO-Ph
9b. 30% Yield
9c. 15% Yield
9d. 15% Yield
0.2M LiOH
ð3Þ
THF, 0°C → rt
3h, 99% Yield
10
Acknowledgements
O
O
O
O
O
O
O
H
H
Financial support of this work by the National Science
Council of the Republic of China is gratefully
acknowledged.
H
H
HO
HO
O
O
O
OH
(-)-Cabenegrin A-I
OH
OH
(-)-Cabenegrin A-II
10
References and notes
Scheme 1.
1. (a) Liu, J.-T.; Jang, Y.-J.; Shih, Y.-K.; Hu, S.-R.; Chu,
C.-M.; Yao, C.-F. J. Org. Chem. 2001, 66, 6021; (b) Jang,
Y.-J.; Shih, Y.-K.; Liu, J.-Y.; Kuo, W.-Y.; Yao, C.-F.
Chem. Eur. J. 2003, 9, 2123.
Pterocarpans are naturally occurring plant products
carrying a cis-fused benzofuranyl-benzopyran ring sys-
tem, and many of them exhibit various biological effects,
most particularly antifungal, antibacterial, and anti-
HIV activity.7 In 1982, Darko had demonstrated that
two representatives of these natural products, cabene-
grin A-I and A-II (Scheme 1) are the active components
of a Brazilian folk medicine used against snake venoms.8
Although the pharmacophore of these two molecules
and the synthetic route to some structural analogues
were established by Gulacsi and co-workers, the yields
of these multistep procedures are too low to be suitable
for industrial production: for instance, the structural
analogue 10 possessing similar inhibitory effects to
cabenegrin A-I on the LPS-induced TNF-a production
in the plasma because of carrying a phenylbutenol side
chain with E-geometry was prepared only in trace yield
after five steps (less than 3%).9
2. Iwasaki, M.; Kobayashi, Y.; Li, J.-P.; Matsuzaka, H.;
Ishii, Y.; Hidai, M. J. Org. Chem. 1991, 56, 1922.
€
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ꢀ
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Akad. Nauk 1961, 136, 1326; (b) Allen, J. C.; Cadogan, J. I.
G.; Harris, B. W.; Hey, D. H. J. Chem. Soc. 1962, 4468; (c)
Cazaux, M.; Lalande, R. Bull. Soc. Chim. Fr. 1971, 2, 461.
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Engler, T. A.; LaTessa, K. O.; Iyengar, R.; Chai, W.;
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Tetrahedron Lett. 1982, 23, 3855.
The above results10 prompted us to investigate the syn-
thesis of 10 via propyl acetate mediated substitution and
subsequent hydrolysis of the resulting b-form ester 9d
based on the present methodology (Eq. 3). Then, a
simple two-steps procedure has been developed in which
4-(2,6-dimethoxy-phenyl)-2-methyl-but-3-en-1-ol 10 was
synthesized from cheap and easily accessible materials in
greatly increasing yield by comparison.
9. Gulacsi, K.; Litkei, G.; Antus, S.; Szantay, C.; Darko, L.
L.; Szelenyi, J.; Hasko, G.; Vizi, S. E. Arch. Pharm.
Pharm. Med. Chem. 2001, 334, 53.
10. General procedure for the reaction of esters with
b-nitrostyrene––preparation of (E)-3af, (E)-1-methyl-3-
phenyl-allyl acetate: b-Nitrostyrene 1a (149.2 mg,
1.0 mmol) and benzoyl peroxide (605.6 mg, 2.5 mmol)
were placed in ethyl acetate 2f (10 mL). The mixture
was stirred for 5 h under refluxing condition and then
concentrated in vacuo. After the solvent evaporated, the
residue was purified by column chromatography on
silica gel and yielded the desired product (E)-3af in 50%
yield.
In conclusion, we demonstrated a variety of simple alkyl
esters were regioselectively and stereoselectively con-
verted to (E)-styryl esters by the reaction with b-nitro-