Organic reactions in water: An efficient zinc-mediated stereoselective synthesis of (E)- and (Z)-trisubstituted alkenes using unactivated alkyl halides

Article abstract of DOI:10.1021/ol048721g

(Chemical Equation Presented) Treatment of the acetyl derivatives of the Baylis-Hillman adducts 3-hydroxy-2-methylene-alkanoates and 3-hydroxy-2- methylene-alkanenitriles with unactivated alkyl halides in the presence of Zn in saturated aqueous NH₄

Full text of DOI:10.1021/ol048721g

ORGANIC
LETTERS
2
004
Vol. 6, No. 19
349-3352
Organic Reactions in Water: An
3
Efficient Zinc-Mediated Stereoselective
Synthesis of (E)- and (Z)-Trisubstituted
Alkenes Using Unactivated Alkyl Halides
Biswanath Das,* Joydeep Banerjee, Gurram Mahender, and Anjoy Majhi
Organic Chemistry DiVision-I, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
biswanathdas@yahoo.com
Received July 6, 2004
ABSTRACT
Treatment of the acetyl derivatives of the Baylis−Hillman adducts 3-hydroxy-2-methylene-alkanoates and 3-hydroxy-2-methylene-alkanenitriles
with unactivated alkyl halides in the presence of Zn in saturated aqueous NH Cl solution at room temperature afforded (2E)-2-substituted-
4
alk-2-enoates in the first case and (2Z)-2-substituted-alk-2-enenitriles with high (Z)-selectivity in the second case.
4
The Baylis-Hillman reaction involving the coupling of
activated vinylic systems with electrophiles under the
catalytic influence of a tertiary amine, usually DABCO, is a
useful carbon-carbon bond forming method in organic
of other stereospecific compounds. Thus a few methods have
4,5
been developed for the preparation of trisubstituted alkenes.
6
To our knowledge, there is only one method developed to
achieve (E)- and (Z)-selectivity involving activated Baylis-
Hillman adducts using Grignard conditions.
1
synthesis. The adducts of the reactions, 3-hydroxy-2-
methylene-alkanoates (derived from acrylate esters) and
During our efforts toward the synthesis of trisubstituted
alkenes derived from Baylis-Hillman adducts, we envisaged
7
3-hydroxy-2-methylene-alkanenitriles (derived from acryl-
onitrile), have been employed for stereoselective synthesis
that a metal-mediated alkylation in aqueous medium would
smoothly substitute the Grignard conditions. There has been
considerable recent attention in carbon-carbon bond forma-
2
of different multifunctional molecules. A trisubstituted
alkene moiety has widely been found in various naturally
occurring bioactive molecules including several important
8
9
tion in water with organometallics, particularly with zinc
3
pheromones and antibiotics. The biological activity of these
involving unactivated alkyl iodides. Although some reports
alkenes is highly dependent on their isomeric purity. Dif-
ferent trisubstituted alkenes with defined stereochemistry are
also often utilized as the key intermediates in the synthesis
(
4) Marfort, A.; McGuirk, P. R.; Helquist, P. J. Org. Chem. 1979, 44,
3
888.
(
5) (a) Masaki, Y.; Sakuma, K.; Kaji, K. J. Chem. Soc., Chem. Commun.
1
980, 434. (b) Brown, H. C.; Basavaiah, D. J. Org. Chem. 1982, 47, 5407.
(
1) (a) Baylis, A. B.; Hillman, M. E. D. German Patent 2155113, 1972;
(c) Denmark, S. E.; Amburgey, J. J. Am. Chem. Soc. 1993, 115, 10386. (d)
Navarre, L.; Darses, S.; Genet, J. P. Chem. Commun. 2004, 1108. (d) Amri,
H.; Rambaud, M.; Villieras, J. Tetrahedron 1990, 46, 3535.
(6) Basavaiah, D.; Sarma, P. K. S.; Bhavani, A. K. D. J. Chem. Soc.,
Chem. Commun. 1994, 1091.
(7) (a) Biswanath, D.; Joydeep, B.; Ravindranath, N.; Venkataiah, B.
Tetrahedron Lett. 2004, 45, 2425. (b) Biswanath, D.; Joydeep, B.;
Ravindranath, N. Tetrahedron 2004 In press.
Chem. Abstr. 1972, 77, 34174q. (b) Basavaiah, D.; Rao, A. J.; Satya-
narayana, T. Chem. ReV. 2003, 103, 811 and references therein.
(2) (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985,
2
1
4, 94. (b) Buchholz, R.; Hoffmann, H. M. R. HelV. Chim. Acta 1991, 74,
213. (c) Basavaiah, D.; Bakthadoss, M.; Pandiaraju, S. J. Chem. Soc.,
Chem. Commun. 1998, 1639.
3) (a) Bradshaw, J. W. S.; Baker, R.; Howse, P. E. Nature 1975, 258,
30. (b) Rossi, R.; Carpita, A.; Messari, T. Synth. Commun. 1992, 22, 603.
c) Garson, M. J. Chem. ReV. 1993, 93, 1699.
(
2
(
(8) Li, C. J.; Chan, T. H. Organic Reactions in Aqueous Media; John
Wiley & Sons: New York, 1997 and references therein.
1
0.1021/ol048721g CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/24/2004

Table 1. Optimization of the Reaction Conditionsa
entry
metal (equiv)
alkyl halide (equiv)
solvent
yield (%)b
side product (%)c
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
Zn (1.5)
Zn (1.5)
Zn (1.5)
Zn (1.5)
Zn (1.5)
Zn (1.5)
Zn (1.5)
Zn (1.5)
Zn (1.5)
Zn (1.5)
Zn (3)
i-PrI (1.5)
i-PrI (1.5)
i-PrI (1.5)
i-PrI (1.5)
i-PrI (1.5)
i-PrI (1.5)
i-PrI (1.5)
i-PrI (1.5)
i-PrI (1.5)
i-PrBr (1.5)
i-PrBr (4)
i-PrI (2)
CH2Cl2
dioxane
MeOH
H2O
0.1 M aq NH4Cl
0.5 M aq NH4Cl
0
2
5
0
0
0
0
tr
8
38
58
63
72
68
52
56
75
86
0
tr
5
1 M aq NH4Cl
saturated aq NH4Cl
saturated aq NH4Cl/dioxane (1:1)
saturated aq NH4Cl
saturated aq NH4Cl
saturated aq NH4Cl
saturated aq NH4Cl
saturated aq NH4Cl
saturated aq NH4Cl
saturated aq NH4Cl
15
17
24
20
10
<2
0
1
1
1
1
1
1
1
Zn (2)
Zn (3)
In (3)
Sm (3)
i-PrI (4)
i-PrI (4)
i-PrI (4)
i-PrI (4)
0
85
0
<2
Zn (3)/Yb(OTf)3
a
Treatment of 1b with isopropyl halide and metal at room temperature for 12 h. b Isolated yield of product 3biii. c Isolated yield of the reduced side
product.
on alkylation in aqueous conditions9a are known, there is
still a need to develop a method for stereoselective synthesis
of (E)- and (Z)-trisubstituted alkenes with unactivated alkyl
2 2
isopropyl iodide (i-PrI) in the presence of Zn in CH Cl
afforded no product even after 12 h. Only a trace amount of
the product was formed during the same period of time when
the similar reaction was conducted in methanol, dioxane, or
water. However, the rate and yield of the products were
10
halides in water. The fact is that a highly reactive metal is
required to break the C-X bond of an unactivated alkyl
halide. Even if the desired organometallic intermediate is
successfully generated by this reaction, various competing
side reactions may occur. For examples, reduction of starting
materials and the hydrolysis of an organometallic intermedi-
ate may be mentioned. Essentially, these difficulties have
prevented the further development of aqueous organic
reaction onto simple alkyl halides. Hence, there must be a
fair balance between metal reactivity and side product
conversion without severely compromising the yield of the
desired alkylated product. Herein we wish to report an
efficient alkylation on activated Baylis-Hillman adducts to
produce trisubstituted alkenes in water. In the presence of
improved by the addition of aqueous solution of NH
4
Cl, and
the concentration of NH Cl was found to have a prominent
4
effect. Thus the dry conditions of the reaction are not
required. The role of water is significant here as the addition
of NH Cl in other dry solvents such as dioxane and MeOH
4
yielded only the trace quantity of the product. The yield of
the trisubstituted olefin 3biii was good (72%) in 12 h when
saturated aqueous NH
iodide were used. However, a larger side product (15%, Table
) led us to further optimize the conditions. To our
4
Cl solution and 1.5 equiv of alkyl
1
expectation, increasing the amount of alkyl iodide (entry 13,
Table 1) led to the formation of the alkylated product (3biii)
almost exclusively (side product <2%). Thus, 4 equiv of
4
zinc and saturated aqueous NH Cl, simple alkyl iodides
reacted with activated Baylis-Hillman adducts at room
temperature to yield (E)- and (Z)-trisubstituted alkenes with
moderate to high yield and excellent stereoselectivity.
To achieve the suitable conditions of the above transfor-
mation, a series of experiments was carried out (Table 1).
alkyl iodide were used for R
2
4
1
) aryl (3a-c, 4a-b, Table
), whereas 5 equiv was needed when R ) alkyl (3d-e,
c, Table 2). It may be noted that the extended conjugation
1
provided by the aromatic ring stabilizes the alkene and hence
formed the products in high yield even with only a slight
excess of the nucleophile. Metal reactivity toward the reaction
was also studied and zinc (3 equiv entry 13, Table 1) was
found to be the best choice. Samarium and indium, metals
of current interest, failed to produce the product (Table 1).
Treatment of 1b (R
1
6 4
) 2-Cl-C H ; EWG ) -COOMe) with
(
9) (a) Li, C. J.; Wei, C.; Keh, C. C. K. J. Am. Chem. Soc. 2003, 125,
062. (b) Organozinc Reagents: A Practical Approach; Knochel, P., Jones,
P., Eds. Oxford University Press: New York, 1999.
10) Synthesis of amino acid derivatives and amines has been reported
4
(
before utilizing zinc in aqueous medium: Huang, T. S.; Keh, C. C. K.; Li,
C. J. Chem. Commun. 2002, 2440. Miyabe, H.; Ueda, M.; Nishimura, A.;
Naito, T. Org. Lett. 2002, 4, 131.
3
Addition of a lanthanide triflate [e.g.,Yb(OTf) ] along with
4
saturated aqueous NH Cl did not effect the yield of the
3350
Org. Lett., Vol. 6, No. 19, 2004

Table 2. Stereoselective Synthesis of (2E)-2-Substituted
Alk-2-enoates (3) and (2Z)-2-Substituted Alk-2-ene-nitriles (4)
Figure 1. Possible intermediates to account for the observed
stereoselectivity.
entry
R1
R2
time (h) yield (%)a
Z/Eb
3
3
3
a
b
c
C6H5
(i) n-Bu
10
10
10
12
12
12
12
12
12
14
14
14
14
12
12
12
12
12
12
14
14
74
77
84
73
78
86
70
75
85
54
63
65
62
78
76
80
76
73
77
58
60
0:100
0:100
0:100
0:100
0:100
0:100
0:100
0:100
0:100
0:100
0:100
0:100
0:100
88:12
90:10
94:6
(
(
ii) n-Hex
iii) i-Pr
whereas when â-substituted acrylonitriles were present in
the adduct (2), the olefins (4) were formed with high (Z)-
stereoselectivity. The Z/E ratio was determined by H NMR
2-Cl-C6H4
(i) n-Bu
1
(
(
ii) n-Hex
iii) i-Pr
spectra of the crude products, and the structures and
stereochemistry of the products were established from the
4-OMe-C6H4 (i) Et
1
13
spectral (IR, H and C NMR, and MS) data of the pure
compounds.
(
(
ii) n-Bu
iii) i-Pr
1
1,13
Thus the present method can be utilized for
3
3
4
d
e
a
n-C5H11c
2-C4H9c
C6H5
(i) Et
ii) n-Pr
the preparation of both the (E)- and (Z)-trisubstituted alkenes.
The regioselective alkylation can be explained by a 1,4-
(
(i) i-Pr
ii) n-Hex
(i) n-Bu
addition type of mechanism involving a â-acetoxy elimina-
5d,14
tion.
In the present case the reaction possibly involves
the activation of the C-I bond of the alkyl iodide to form
an alkylzinc species, which then undergoes the above
mechanism on the acetyl derivatives of the Baylis-Hillman
adducts. This mechanism explains the (E)-selectivity with
ester (forming a chelated reaction intermediate, A, Figure
(
(
ii) n-Hex
iii) i-Pr
4
4
b
c
2-Cl-C6H4
n-C3H7c
(i) n-Bu
89:11
90:10
95:5
80:20
82:18
(
(
ii) n-Hex
iii) i-Pr
(i) n-Bu
ii) n-Hex
1
) and (Z)-selectivity with nitriles (forming a nonchelated
(
intermediate, B, Figure 1). However, an alternative mecha-
a
Isolated yield of products 3 (EWG ) COOMe) and 4 (EWG ) CN).
nism for the reaction involving a single-electron transfer
b
1
c
Ratio was determined by H NMR analysis. Zn (4 equiv) and alkyl iodide
5 equiv) were used.
15
(
SET) process could not be excluded. The methodology
(
Scheme 1
product. When using alkyl bromide instead of alkyl iodide,
a much lower yield of the product was observed (Table 1).
During the current studies several 3-acetoxy-2-methylene-
alkanoates (1) and 3-acetoxy-2-methylene-alkanenitriles (2)
1
1
were treated with various alkyl iodides in the presence of
Zn in saturated aqueous NH Cl solution at room temperature
to generate efficiently different trisubstituted alkenes (Tables
4
2
). The stereochemistry of the trisubstituted alkenes derived
1
b,12
from Baylis-Hillman adducts is well-documented.
The
electron-withdrawing groups present in the adducts direct
the stereochemistry of the products. When â-substituted
acrylate esters were present in the adduct (1), the conversion
afforded the olefins (3) with (E)-stereoselectivity exclusively,
was successfully applied to the synthesis of (2E)-2-butyloct-
3a,16
2-enal (6),
an alarm pheromone component of the African
weaver ant, Oecophylla longinoda. Reduction of (2E)-
(
11) General Experimental Procedure. A suspension of a 3-acetoxy-
2
-methylene-alkanoate or a 3-acetoxy-2-methylene-alkanenitrile (3 mmol),
(13) (a) Larson, G. L.; deKaifer, C. F.; Seda, R.; Torres L. E.; Ramirez,
J. R. J. Org. Chem. 1984, 49, 3385. (b) Baraldi, P. G.; Guarneri, M.; Pollini,
G. P.; Simoni, D.; Barco, A.; Benetti, S. J. Chem. Soc., Perkin Trans. 1
1984, 2501. (c) Boche, G.; Buckl, K.; Martens, D.; Schneider, D. R.
Tetrahedron Lett. 1979, 4967. (d) Minami, I.; Yuhara, M.; Shimizu, I.; Tsuji,
J. J. Chem. Soc., Chem. Commun. 1986, 118.
(14) For similar examples, see: (a) Sorek, Y.; Cohen, H.; Meyerstein,
D. J. Chem. Soc., Faraday Trans. 1 1986, 82, 3431. (b) Kondo, T.; Kaneko,
Y.; Tsunawaki, F.; Okada, T.; Shiotsuki, M.; Morisaki, Y.; Mitsudo, T.
Organometallics 2002, 21, 4564.
alkyl iodide (12 mmol), and Zn powder (588 mg, 9 mmol) in saturated
aqueous NH4Cl solution (6 mL) was stirred for 10-14 h at room
temperature. After the reaction was completed (monitored by TLC), EtOAc
(
15 mL) was added and shaken. The organic layer was separated and the
aqueous layer extracted with EtOAc (3 × 10 mL). The combined organic
portion was washed with brine (3 × 10 mL) followed by water (3 × 10
mL), dried, filtered, and concentrated. The residue was subsequently
subjected to column chromatography over silica gel to afford pure
trisubstituted alkene.
(
12) Trisubstituted alkenes derived from Baylis-Hillman adducts having
(15) Chan, T. H. Pure Appl. Chem. 1996, 52, 5643.
(16) Basavaiah, D.; Suguna hyma, R. Tetrahedron 1996, 52, 1253 and
references therein.
EWG ) CN and R2 ) alkyl never produced (Z)-isomer solely. For example,
see ref 6.
Org. Lett., Vol. 6, No. 19, 2004
3351

methyl-2-butyl-3-pentyl-propenoate (3dii) yielded the cor-
responding alcohol (5) in 92%. Upon oxidation with PDC
the product 6 was furnished in 87% yield.
Supporting Information Available: Analytical and
spectral data of all prepared new compounds and experi-
mental procedure for the synthesis of compound 6. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank CSIR and UGC, New
Delhi, for financial assistance.
OL048721G
3352
Org. Lett., Vol. 6, No. 19, 2004