A facile Zn-mediated stereoselective synthesis of (E)- and (Z)-trisubstituted alkenes from Baylis-Hillman adducts in water and its application

Article abstract of DOI:10.1246/cl.2006.358

A simple and efficient stereoselective synthesis of (E)- and (Z)-trisubstituted alkenes has been accomplished by treatment of the acetyl derivatives of the Baylis-Hillman adducts with Zn in saturated aq. NH ₄C1 solution under reflux. The method has been utilized for the preparation of the two chiral insect pheromones, dominicalure-I and dominicalure-II, of the lesser grain borer Rhyzopertha dominica (F). Copyright

Full text of DOI:10.1246/cl.2006.358

358
Chemistry Letters Vol.35, No.4 (2006)
A Facile Zn-mediated Stereoselective Synthesis of (E)- and (Z)-Trisubstituted Alkenes
from Baylis–Hillman Adducts in Water and Its Application1
Biswanath Das,Ã Nikhil Chowdhury, Joydeep Banerjee, Anjoy Majhi, and Gurram Mahender
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(Received January 16, 2006; CL-060061)
A simple and efficient stereoselective synthesis of (E)- and
OAc
EWG
(Z)-trisubstituted alkenes has been accomplished by treatment
of the acetyl derivatives of the Baylis–Hillman adducts with
Zn in saturated aq. NH4Cl solution under reflux. The method
has been utilized for the preparation of the two chiral insect pher-
omones, dominicalure-I and dominicalure-II, of the lesser grain
borer Rhyzopertha dominica (F).
Zn/ aq. NH4Cl (saturated)
reflux, 1
EWG
R
R
5 h
71 96 %
R= alkyl, aryl
4 EWG = COOMe
5 EWG = CN
2 EWG = COOMe
3 EWG = CN
Scheme 1.
ucts during our earlier work on zinc-mediated reactions of 2
and 3 with unactivated alkyl halides.9 We envisaged that, with-
out applying alkyl halides in the reaction mixture the minor side
products would be emerged as desired sole products. Thus, to
our expectation, we could successfully transform the liability
of one reation into an asset in the present case. In fact, the present
reaction of 2 and 3 with Zn in saturated aq NH4Cl solution
afforded only the trisubstituted alkenes 4 and 5 in (E)- and
(Z)-forms (Table 1). The stereochemistry of the alkenes was
directed by the electron-withdrawing groups present in the
adducts. Thus, the acetyl derivatives of the adducts 2 containing
ester group produced the alkenes 4 with (E)-stereoselectivity
exclusively. On the other hand, the acetyl derivatives of the
adducts 3 with nitrile moiety afforded alkenes 5 with high (Z)-
Baylis–Hillman reaction is an important synthetic utility in
recent years.2 The adducts of the reaction, 3-hydroxy-2-methyl-
enealkanoates (derived from acrylate esters) and 3-hydroxy-2-
methylenealkanenitriles (derived from acrylonitriles) have been
utilized for the stereoselective synthesis of various polyfunction-
al molecules.2b,3 These adducts also represent useful intermedi-
ates for the synthesis of trisubstituted alkenes. Many naturally
occurring bioactive compounds including different pheromones
and antibiotics contain trisubstituted alkene moiety.4 The biolog-
ical property of these alkenes is highly dependent on their iso-
meric purity.5,6 As for an example, (S)-(+)-1-methylbutyl-(E)-
2-methyl-2-pentenoate (dominicalure-I) (1a) and (S)-(+)-1-
methylbutyl-(E)-2,4-dimethyl-2-pentenoate (dominicalure-II)
(1b), the aggregation pheromones of lesser grain borer Rhyzo-
pertha dominica (F)5 (Figure 1) contain stereodefined trans-dou-
ble bond.
Baylis–Hillman adducts have been considered as simple
synthones for stereoselective synthesis of trisubstituted alkenes.7
However, to our knowledge, there is no method reported earlier
for the synthesis of 2-methylalk-2-enoates and 2-methylalk-2-
enenitriles from Baylis–Hillman adducts or their derivatives
in aqueous medium. Moreover, the reported methods for the
conversions of the adducts into these alkenes are associated with
certain disadvantages such as utilization of expensive re-
agent,7b,7d,7f,7g limitation of applicability,7d–7g unsatisfactory
yields,7b,7d,7g weak stereoselectivity,7b,7d,7g and formation of
mixture of products.7g
1
selectivity. The Z=E ratio was determined by H NMR spectra
of the crude products and the structures and stereochemistry
of the products were derived from the spectral (IR, 1H and
13C NMR, and MS) data of the pure compounds.
Table 1. Stereoselective synthesis of (E)-2-methylalk-2-
enoates (4) and (Z)-2-methylalk-2-enenitriles (5)
E=Z
ratioc
Entry
R
Time/h Yield/%a
4a
4b
4c
4d
4e
4f
4g
4h
5a
5b
5c
5d
5e
5f
C6H5
2-Cl-C6H4
4-Cl-C6H4
4-OMe-C6H4
3,4-(MeO)2-C6H3
2,4-Cl2-C6H3
CH3-CH(CH3)-CH2
n-C7H15
2.5
1
1.5
3
3.5
2
4
4.5
4
2.5
3.5
4
91
95
96
89
75
87
78b
76b
79
83
86
77
74b
71b
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
10:90
9:91
In recent years, the application of water as a reaction medi-
um is encouraged due to economic and environmental consider-
ations.8,9 We have observed that the acetyl derivatives of the
Baylis–Hillman adducts (2 and 3) on treatment with Zn in satu-
rated aq NH4Cl solution under reflux were smoothly converted
into (E)- and (Z)-trisubstituted alkenes (4 and 5, respectively)
(Scheme 1).
C6H5
2-Cl-C6H4
4-Cl-C6H4
4-OMe-C6H4
n-C4H9
13:87
15:85
17:83
22:78
These alkenes (4 and 5) were obtained as minor side prod-
O
4.5
5
O
n-C7H15
O
O
aIsolated yield of products 4 (EWG= –COOMe) and 5
(EWG= –CN). Zn powder (4.5 equiv.) was used while in
H
H
b
1a
1b
c
other case Zn powder (3 equiv.) was required. Ratio was
determined by 1H NMR analysis.
Figure 1.
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.4 (2006)
359
Cl
alkanoates is impressive. The process has successfully been
applied for the synthesis of two chiral insect pheromones, (S)-
(+)-1-methylbutyl (E)-2-methyl-2-pentenoate (dominicalure-I)
(1a) and (S)-(+)-1-methylbutyl (E)-2,4-dimethyl-2-pentenoate
(dominicalure-II) (1b), the aggregation pheromones of lesser
grain borer Rhyzopertha dominica (F).
O
O
Zn
O
O
ZnCl
O
N
C
R'
R'
OR
A
B
Figure 2. Possible intermediates to account for the observed
stereoselectivity.
The authors thank UGC and CSIR, New Delhi for financial
assistance. They are also thankful to one of the referees for his
valuable suggestion.
O
O
OAc
1. Zn/ aq. NH4Cl (saturated)
O
reflux, 4.5 h
R
1. SOCl2
2. (S)-(+)-2-pentanol
OH
R
OMe
R
References and Notes
1
O
2. NaOH, MeOH
H
Part 72 in the series, Studies on Novel synthetic methodolo-
gies, IICT Comunication No. 060202.
(E)-2-Methylalk-2-enoic acids
2i, j
100% E
1a (74%)
1b (71%)
R = Et (2i, 6, 1a)
R = i -Pr (2j, 7, 1b)
6
7
(69%)
(64%)
2
a) A. B. Baylis, M. E. D. Hillman, German Patent 2155113,
1972; Chem. Abstr. 1972, 77, 34174q. b) D. Basavaiah,
A. J. Rao, T. Satyanarayana, Chem. Rev. 2003, 103, 811,
and references cited therein.
Scheme 2.
The regioselective reduction of 2 into 4 can possibly be ex-
plained by proposing the reaction to proceed via the formation of
the intermediates A (Figure 2). This intermediate may arise by
an initial SET to the conjugated enone moiety of 2 followed
by protonation and the second SET process. A similar mechan-
ism of the regioselective reduction of 3 into 5 can be proposed by
involving the intermediate B (Figure 2). This mechanism ex-
plains the (E)-selectivity with ester (forming a chelated reaction
intermediate, A) and (Z)-selectivity with nitriles (forming a non-
chelated intermediate, B).
We have applied the developed methodology to achieve the
synthesis of (S)-(+)-1-methylbutyl-(E)-2-methyl-2-pentenoate
(dominicalure-I) (1a) and (S)-(+)-1-methylbutyl-(E)-2,4-di-
methyl-2-pentenoate (dominicalure-II) (1b), the aggregation
pheromones of lesser grain borer Rhyzopertha dominica (F).5
The acetyl derivatives of Baylis–Hillman adducts, methyl 3-ace-
toxy-2-methylenepentanoate (2i), and methyl 3-acetoxy-2-meth-
ylene-4-methylpentanoate (2j), were treated with Zn (4.5 equiv.)
in saturated aqueous NH4Cl solution under reflux followed by
hydrolysis of the intermediate enoates10 with methanolic NaOH
in one pot to obtain (E)-2-methylpent-2-enoic acid (6), and (E)-
2,4-dimethylpent-2-enoic acid (7), respectively. These two com-
pounds (6 and 7) on treatment with SOCl2, were converted into
their corresponding acid chlorides which were then separately
reacted with (S)-(+)-2-pentanol to form (S)-(+)-1-methylbutyl
(E)-2-methyl-2-pentenoate (dominicalure-I) (1a) and (S)-(+)-
1-methylbutyl (E)-2,4-dimethyl-2-pentenoate (dominicalure-II)
(1b), respectively11 (Scheme 2).
3
4
5
a) H. M. R. Hoffman, J. Rabe, Angew. Chem., Int. Ed. Engl.
1985, 24, 94. b) R. Buchholz, H. M. R. Hoffman, Helv. Chim.
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T.-H. Chan, John Wiley & Sons, New York, 1997, and
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8
9
In conclusion, this methodology describes a convenient and
efficient stereoselective synthesis of (E)- and (Z)-trisubstituted
alkenes from acetyl derivatives of the Baylis–Hillman adducts
in eco-friendly aqueous medium. The reagents are less expen-
sive and the experimental procedure is simple. The products
are formed in high yields in short reaction times. The stereose-
lectivity of the rection, especially with 3-hydroxy-2-methylene-
10 The intermediate enoates were not isolated to avoid tedious
work-up and unwanted product loss.
11 The target molecules 1a and 1b were both obtained as color-
less oil with 74 and 71% yields, respectively with respect to
their corresponding (E)-2-methylalk-2-enoic acid. Our spec-
tral and optical data of these compounds are in agreement
with literature data.5a,5b
Published on the web (Advance View) March 11, 2006; DOI 10.1246/cl.2006.358