A facile one-pot stereoselective synthesis of trisubstituted (E)-2-methylalk-2-enoic acids from unactivated Baylis-Hillman adducts and a simple access to some important insect pheromones

Article abstract of DOI:10.1016/j.tetlet.2006.07.014

An efficient one-pot stereoselective synthesis of trisubstituted (E)-2-methylalk-2-enoic acids has been accomplished by treatment of unactivated Baylis-Hillman adducts, 3-hydroxy-2-methylenealkanoates, with Al-NiCl₂·6H₂O in methanol at room temperature followed by hydrolysis. The method has been applied to the synthesis of three important insect pheromones, (4S,2E)-2,4-dimethyl-2-hexenoic acid, (+)-(S)-manicone and (+)-(S)-normanicone.

Full text of DOI:10.1016/j.tetlet.2006.07.014

Tetrahedron Letters 47 (2006) 6615–6618
A facile one-pot stereoselective synthesis of trisubstituted
(E)-2-methylalk-2-enoic acids from unactivated
Baylis–Hillman adducts and a simple access to some
important insect pheromonesI
Biswanath Das,* Nikhil Chowdhury, Joydeep Banerjee and Anjoy Majhi
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 9 May 2006; revised 27 June 2006; accepted 6 July 2006
Available online 31 July 2006
Abstract—An efficient one-pot stereoselective synthesis of trisubstituted (E)-2-methylalk-2-enoic acids has been accomplished by
treatment of unactivated Baylis–Hillman adducts, 3-hydroxy-2-methylenealkanoates, with Al–NiCl2Æ6H2O in methanol at room
temperature followed by hydrolysis. The method has been applied to the synthesis of three important insect pheromones,
(4S,2E)-2,4-dimethyl-2-hexenoic acid, (+)-(S)-manicone and (+)-(S)-normanicone.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The Baylis–Hillman reaction is a versatile carbon–
carbon bond forming reaction, which provides function-
alized adducts.1 These adducts have been utilized in
various synthetic transformations and also in stereose-
lective syntheses of several naturally occurring bioactive
compounds.1b,2 In continuation of our work2c,3 on
Baylis–Hillmann chemistry, we have recently observed
that treatment of unactivated Baylis–Hillman adducts,
acids 3 via formation of the intermediate esters 2
(Scheme 1). The core structure of the acids 3 is present
in various bioactive a-methylcinnamic acids4 (for exam-
ple, in LK 903, a hypolipidemic agent) and in several
insect pheromones5,6 (such as (4S,2E)-2,4-dimethyl-2-
hexenoic acid) (Fig. 1). The present method is a simple
access to these important compounds.
that is, 3-hydroxy-2-methylenealkanoates
1
with
Initially we treated 1a (R = C6H5) with various reducing
systems in different solvents under different reaction
conditions (Table 1). Al–NiCl2Æ6H2O proved to be best
reducing system at room temperature in methanol
Al–NiCl2Æ6H2O in methanol at room temperature
followed by hydrolysis with KOH/MeOH produced
the corresponding trisubstituted (E)-2-methylalk-2-enoic
O
O
MeOH
r. t., 2 h
Al-NiCl2.6H2O
MeOH
O
KOH
i)
OH
R
OH
OMe
R
OMe
R
r.t., 1-2h
crystallization
or
chromatography
ii)
R= aryl, alkyl
3
2
1
71-88%
( overall yield )
100 %
E
Scheme 1.
Keywords: Baylis–Hillman adduct; Al–NiCl2Æ6H2O; (E)-2-Methylalk-2-enoic acid; Stereoselectivity; Pheromone.
q Part 94 in the series, ‘Studies on novel synthetic methodologies’. IICT Communication No. 060710.
*
Corresponding author. Tel./fax: +91 40 7160512; e-mail: biswanathdas@yahoo.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.014

6616
B. Das et al. / Tetrahedron Letters 47 (2006) 6615–6618
O
OH
O
OH
O
H
OH
n-C14H29O
(4S,2E)-2,4-dimethyl-2-hexenoic acid
LK 903
Figure 1.
Table 1. Reaction of 1a (R = C6H5) with different reducing systems
Table 2. Synthesis of trisubstituted (E)-2-methylalk-2-enoic acids 3
using Al–NiCl2Æ6H2O
Entry Reagent
Solvent
Time (h) Isolated
Yield(%)
Entry
R
Time (h)a Isolated yieldb,c,d (%)
a
b
c
d
e
f
g
h
Zn–NH4Cl
H2O
CH2Cl2
EtOH–H2O (1:1)
MeOH
MeOH–H2O (3:1)
18
5
9
3
4
1
1
1
58a,b
41c
19a
17
38a,d
99e
98e
0
a
b
c
d
e
f
g
h
i
C6H5
1
1
1.5
1
1
2
2
2
2
88
84
83
81
86
71
78
77
75
74
72
Zn–AcOH
In–NH4Cl
Mg
Zn–Cu
Al–NiCl2Æ6H2O MeOH
Al–NiCl2Æ6H2O THF
4-MeC6H4
4-EtC6H4
4-ClC6H4
2,4-Cl2C6H3
3,4,5-(MeO)3C6H2
4-C14H29OC6H4
C2H5
i-Pr
n-C5H11
n-C7H15
Al–NiCl2
MeOH
a Reaction mixture was refluxed.
j
k
2
2
b An unidentified side product was obtained.
c,d,e E/Z ratio was 58:42, 60:40, and 100:0, respectively (determined
from 1H NMR spectra of the crude products).
a Time required for reduction of the adduct. The time required for
hydrolysis is 2 h in each case and is not included here.
b The acids were purified by column chromatography using hexane–
EtOAc (4:1) when R = alkyl or by crystallization from hexane–
EtOAc (1:1) when R = aryl.
c All products were characterized by 1H and 13C NMR, MS, and IR
data.
d E/Z ratio was 100:0.
affording 2a in 1 h in a very high yield (99%) and with
complete E-selectivity. THF was also found to be a suit-
able solvent for the reaction. However, as we intended
to hydrolyze the intermediate ester 2a without isolation,
the reaction was carried out in MeOH.
models A and B (Fig. 2). Transition state A is more
favored than B- and (E)-products are thus formed
solely.
A series of (E)-2-methylalk-2-enoic acids were subse-
quently prepared in one-pot from Baylis–Hillman
adducts, 1 (derived from both aromatic and aliphatic
aldehydes) by treatment with Al–NiCl2Æ6H2O in metha-
nol at room temperature and hydrolyzing the intermedi-
ate esters with KOH–MeOH (Table 2).7 The final
products were purified by crystallization or column
chromatography. The yields of the products were high
(71–88% with respect to the adducts 1) and were formed
solely with (E)-stereoselectivity. The structures and ste-
reochemistries of the products were confirmed from
their spectral (IR, 1H, and 13C NMR and MS) and
microanalytical data.7 In the 1H NMR spectrum of a tri-
substituted alkene, the b-vinylic protons, cis and trans to
the ester group are known to resonate at d 7.5 and 6.5,
respectively, when R is an aryl group.8 The same proton
cis and trans to an ester group appears at d 6.8 and 5.7,
respectively, when R is alkyl.8 These values were useful
in determining the stereochemistry of the products.
The present method is useful for the synthesis of (E)-a-
methylcinnamic acids (R = aryl in 3) and insect phero-
mones (R = alkyl in 3). Unmodified adducts can directly
be used for the preparation of these compounds. The
present methodology was also successfully employed
for the synthesis of (4S,2E)-2,4-dimethyl-2-hexenoic
acid 4 (a caste-specific compound of the mandibular
glands of male carpenter ants of the genus Camponotus)5
from the adduct10 5 derived from (S)-2-methylbutyral-
dehyde11 (Scheme 2). Adduct 5 was formed as an insep-
arable mixture of syn- and anti-isomers in a 70:30
ratio.10 Reduction of 5 with migration of the double
bond and subsequent elimination of the hydroxyl group
OH
Al–NiCl2Æ6H2O was initially used for the reduction of
a,b-unsaturated carbonyl compounds to produce the
corresponding saturated carbonyl compounds.9 The
proposed mechanism involves the interaction of Al with
NiCl2 to form Ni(0), which then loses electrons. How-
ever, in the present case, isomerization of the exocyclic
double bond with concomitant loss of C-3–OH took
place. The stereochemistry of the reaction can possibly
be explained2b,d,3a,b by considering the transition state
O
H
R
Me
Me
COOMe
COOMe
R
H
O
OH
A
B
Figure 2.

B. Das et al. / Tetrahedron Letters 47 (2006) 6615–6618
6617
OH
O
Al-NiCl . 6H O
1.
2
2
O
MeOH, r. t., 2 h
DABCO, Dioxane
CHO
OMe
OMe
+
2. KOH, MeOH / H2O
r, t., 10 h
0 ºC, 20 h
H
H
71%
73%
5
O
O
O
R2CuLi
Et2O
SOCl2
benzene
R
OH
Cl
reflux, 2 h
100%
H
-78 ºC, 15 min
H
H
4
R = Et (84%)
R = Me (80%)
6
7
(
4S,2E)-2,4-dimethyl-2-hexenoic acid
Scheme 2.
would lead to loss of the stereogenic centre at C-3.
Hence, no attempt was made to separate the diastereo-
mers of 5. Acid 4 was subsequently converted into
(+)–(S)-manicone 6 and (+)-(S)-normanicone 7 (the
mandibular gland alarm pheromone substances of the
ants of the genus Manica)6 by treating the correspond-
ing acid chlorides with Et2CuLi and Me2CuLi separately
in ether solution at À78 ꢁC.11 The optical and spectral
properties (1H and 13C NMR and MS) of 4, 6, and 7
were in good agreement with those reported earlier.11,12
Acknowledgement
The authors thank CSIR and UGC, New Delhi, for
financial assistance.
References and notes
1. (a) Baylis, A. B.; Hillman, M. E. D. German Patent
2155113, 1972; Chem. Abstr. 1972, 77, 34174q; (b)
Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem.
Rev. 2003, 103, 811–891, and references cited therein.
2. (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed.
Engl. 1985, 24, 94–110; (b) Buchholz, R.; Hoffmann, H.
M. R. Helv. Chim. Acta 1991, 74, 1213–1220; (c) Das, B.;
Banerjee, J.; Mahender, G.; Majhi, A. Org. Lett. 2004, 6,
3349–3352; (d) Chandrasekhar, S.; Chandrasekhar, G.;
Vijeender, K.; Reddy, M. S. Tetrahedron Lett. 2006, 47,
3475–3478.
3. (a) Das, B.; Banerjee, J.; Ravindranath, N. Tetrahedron
2004, 60, 8357–8361; (b) Das, B.; Banerjee, J.; Majhi, A.;
Mahender, G. Tetrahedron Lett. 2004, 45, 9225–9227; (c)
Das, B.; Majhi, A.; Banerjee, J.; Chowdhury, N.; Ven-
kateswarlu, K. Tetrahedron Lett. 2005, 46, 7913–7915; (d)
Das, B.; Holla, H.; Majhi, A.; Venkateswarlu, K. Tetra-
hedron Lett. 2005, 46, 8895–8897.
Alternative methods for the synthesis of 2-methylalk-2-
enoic acids are the Wittig reaction and the Horner–
Wadsworth–Emmons reaction. The latter method is an
improved protocol of the former and more advanta-
geous as the phosphate by-product can be extracted into
water.13 2-Methylalk-2-enoic acids and related com-
pounds including manicone (6) were prepared earlier
employing the Horner–Wadsworth–Emmons method.14a
However, the required a-branched diethylcarboxylic
methane phosphonates are not commercially available
and the preparation of these compounds involved com-
plex experimental steps.14b The reactions between phos-
phonates and aldehydes required a low temperature
(À60 ꢁC). In the present method for the preparation of
2-methylalk-2-enoic acids, all the reagents were directly
available and the reactions were conducted at room
temperature. Using the Horner–Wadsworth–Emmons
method, the 2-methylalk-2-enoic acids derived from ali-
phatic aldehydes were mixtures of (E)- and (Z)-isomers.
Manicone, prepared by this method, was also obtained
as a mixture of (E)- and (Z)-isomers. In the present
method the products were formed solely as the (E)-iso-
mers. Thus, the present method is superior to classical
alternatives.
4. Basavaiah, D.; Krishnamacharyulu, M.; Hyma, R. S.;
Sarma, P. K. S.; Kumaragurabaran, N. J. Org. Chem.
1999, 64, 1197–1200.
5. Brand, J. M.; Duffield, R. M.; MacConnell, J. G.; Blum,
M. S.; Fales, H. M. Science 1973, 179, 388–389.
6. (a) Fales, H. M.; Blum, M. S.; Crewe, R. M.; Brand, J.
M. J. Stored. Prod. Res. 1972, 18, 1077; (b) Bestmann, H.
J.; Attygalle, A. B.; Glasbrenner, J.; Reimer, R.;
Vostrowsky, O. Angew. Chem., Int. Ed. Engl. 1987, 26,
784.
7. General experimental procedure: To a mixture of fresh Al
powder (20 mmol) and NiCl2Æ6H2O (20 mmol) was added
the Baylis–Hilmann adduct 1 (2 mmol) dissolved in freshly
distilled MeOH (10 mL). A vigorous reaction took place
within a few seconds, which subsided after 20 min. The
reaction was monitored by TLC. After completion, 60%
KOH (3 g) in MeOH (5 mL) was added and the reaction
stirred for 2 h at room temperature. MeOH was removed
under reduced pressure and the reaction mixture was
diluted with water (100 mL) and filtered. The filtrate was
acidified with dilute HCl (1 N) and extracted with ether
(2 · 50 mL). The ether extract was dried over Na2SO4 and
In conclusion, we have developed a simple and efficient
method for the synthesis of trisubstituted (E)-2-meth-
ylalk-2-enoic acids from unmodified Baylis–Hillman
adducts by treatment with Al–NiCl2Æ6H2O at room
temperature followed by hydrolysis with KOH–MeOH.
The high yields and excellent stereoselectivity are advan-
tages of this method. The method has successfully been
applied to the synthesis of some important insect
pheromones.

6618
B. Das et al. / Tetrahedron Letters 47 (2006) 6615–6618
concentrated. The crude product was purified by crystal-
(d) Tanaka, K.; Yamagishi, N.; Tanikaga, R.; Kaji, A.
Bull. Chem. Soc. Jpn. 1979, 52, 3619–3625.
9. (a) Hazarika, M. J.; Barua, N. C. Tetrahedron Lett. 1989,
30, 6567–6570; (b) Sarmah, B. K.; Barua, N. C. Tetra-
hedron 1991, 47, 8587–8600.
lization from hexane–EtOAc (1:1) (when 1 was derived
from an aromatic aldehyde) or by column chromatogra-
phy over silica gel using 10% EtOAc in hexane as eluent
(when 1 was derived from an aliphatic aldehyde).
The spectral (IR, 1H and 13C NMR and MS) and
analytical data of the novel (E)-2-methylalk-2-enoic acids
are given below.
10. Preparation of Baylis–Hillman adduct
5 (methyl-3-
hydroxy-4-methyl-2-methylene-2-hexenoate): A solution
of (S)-2-methylbutyraldehyde (1.08 mL, 10 mmol) and
methyl acrylate (2.68 mL, 30 mmol) in dioxane (10 mL)
was cooled to 0 ꢁC and DABCO (50 mol %, 0.56 g,
10 mmol) was added. After completion (20 h), the reaction
was partitioned with tert-butylmethyl ether (75 mL) and
5% aqueous HCl solution (25 mL). The organic extracts
were collected, dried over anhydrous Na2SO4, filtered, and
concentrated. The resulting residue was purified by column
chromatography (5% EtOAc in hexane) to give adduct 5
(1.22 g, colorless oil) as an inseparable mixture of syn/anti
isomers (70:30, 71% combined yield). The ratio was
Product 3c: IR (KBr): mmax 3417, 1682, 1617 cmÀ1 1H
;
NMR (200 MHz, CDCl3): d 7.81 (1H, s), 7.37 (2H, d,
J = 8.0 Hz), 7.21 (2H, d, J = 8.0 Hz), 2.69 (2H, q,
J = 7.0 Hz), 2.15 (3H, s), 1.28 (3H, t, J = 7.0 Hz); 13C
NMR (50 MHz, CDCl3): 174.8, 142.2, 141.5, 133.1, 130.2,
128.3, 126.9, 28.3, 15.4, 14.2; FABMS: m/z 191 [M+H]+Å.
Anal. Calcd for C12H14O2: C, 75.79; H, 7.37. Found: C,
75.86; H, 7.31.
Product 3f: IR (KBr): mmax 2962, 1688, 1612 cmÀ1 1H
;
NMR (200 MHz, CDCl3): d 7.73 (1H, s), 6.62 (2H, s), 3.88
(9H, s), 2.16 (3H, s); 13C NMR (50 MHz, CDCl3): 174.3,
153.6, 136.8, 132.3, 107.7, 55.8, 14.6; FABMS: m/z 253
[M+H]+Å, Anal. Calcd for C13H16O5: C, 61.91, 6.35.
Found: C, 61.82, 6.41.
1
assigned from the H NMR chemical shifts and coupling
constant values of the C3-H and C4-H. See: Heathcock,
C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic: Orlando, 1984; Vol. 3, pp 111–118. IR (KBr):
Product 3j: IR (KBr): mmax 3412, 1688, 1612 cmÀ1
;
1H
m
max 3485, 2965, 2932, 2880, 1726, 1631 cmÀ1; 1H NMR: d
NMR (200 MHz, CDCl3): d 11.92 (1H, br s), 6.88 (1H, t,
J = 7.0 Hz), 2.21 (2H, q, J = 7.0 Hz), 1.89 (3H, s), 1.52–
1.40 (2H, m), 1.39–1.26 (4H, m), 0.87 (3H, t, J = 7.0 Hz);
FABMS: m/z 157 [M+H]+Å. Anal. Calcd for C9H16O2: C,
69.23; H, 10.26. Found: C, 69.31; H, 10.22.
0.80–0.96 (6H, m), 1.15 (1.4H, m, syn), 1.43 (0.6H, m,
anti), 1.68 (1H, m), 2.60 (0.7H, d, J = 6.5 Hz, syn), 2.83
(0.3H, d, J = 8.0 Hz, anti), 3.76 (3H, s), 4.08 (0.3H, t,
J = 8.0 Hz, anti), 4.30 (0.7H, t, J = 6.5 Hz, syn), 5.74
(0.3H, s, anti), 5.79 (0.7H, s, syn), 6.24 (0.3H, s, anti), 6.27
(0.7H, s, syn); 13C NMR: syn d 11.9, 13.4, 26.8, 39.0, 52.0,
74.7, 125.6, 142.3, 167.3; anti d 11.5, 16.0, 24.5, 39.5, 52.0,
76.8, 126.3, 141.9, 167.5; m/z 173 (M+Å+1). Anal. Calcd for
C9H16O3: C, 62.79; H, 9.30. Found: C, 62.70; H, 9.34.
11. Rossi, R.; Carpita, A.; Cossi, P. Tetrahedron 1992, 48,
8801–8824.
Product 3k: IR (KBr): mmax 3418, 1689, 1642 cmÀ1 1H
;
NMR (200 MHz, CDCl3): 6.89 (1H, t, J = 7.0 Hz), 2.20
(2H, q, J = 7.0 Hz), 1.81 (3H, s), 1.50–1.42 (2H, m), 1.39–
1.22 (8H, m), 0.88 (3H, t, J = 7.0 Hz); FABMS: m/z 185
[M+H]+Å. Anal. Calcd for C11H20O2: C, 71.74; H, 10.87.
Found: C, 71.68; H, 10.92.
8. (a) Larson, G. L.; de Kaifer, C. F.; Seda, R.; Torres, L. E.;
Ramirez, J. R. J. Org. Chem. 1984, 49, 3385–3388; (b)
Basavaiah, D.; Sarma, P. K. S.; Bhavani, A. K. D. J.
Chem. Soc., Chem. Commun. 1994, 1091–1092; (c) Baraldi,
P. G.; Guarneri, M.; Pollini, G. P.; Simoni, D.; Barco, A.;
Benetti, S. J. Chem. Soc., Perkin Trans. 1 1984, 2501–2505;
12. Martischonok, V.; Melikyan, G. G.; Mineif, A.; Vostrow-
sky, O.; Bestmann, H. J. Synthesis 1991, 560–564.
13. Li, J. J. Name Reactions, 2nd ed.; Springer: New Delhi,
2003; pp 198–199.
14. (a) Coutrot, P.; Ghribi, A. Synthesis 1986, 790–792; (b)
Coutrot, P.; Ghribi, A. Synthesis 1986, 661.