Synthesis of β-iodo-α-(hydroxyalkyl)acrylates: A convenient and stereoselective reaction

Article abstract of DOI:10.1016/S0040-4039(02)01106-1

An efficient one-pot, three-component coupling reaction for the synthesis of β-iodo-α-(hydroxyalkyl) acrylates has been developed. As the iodine source as well as the Lewis acid mediator, diethyl aluminium iodide undergoes a Michael-type addition with met

Full text of DOI:10.1016/S0040-4039(02)01106-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5677–5680
Synthesis of b-iodo-a-(hydroxyalkyl)acrylates: a convenient and
stereoselective reaction
Han-Xun Wei, Joe J. Gao, Guigen Li and Paul W. Pare´*
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA
Received 15 February 2002; accepted 3 June 2002
Abstract—An efficient one-pot, three-component coupling reaction for the synthesis of b-iodo-a-(hydroxyalkyl)acrylates has been
developed. As the iodine source as well as the Lewis acid mediator, diethyl aluminium iodide undergoes a Michael-type addition
with methyl propynoate to form an active b-iodo allenolate intermediate, which in turn attacks various aldehydes or ketones to
afford b-iodo Baylis–Hillman adducts in excellent yields with high Z-selectivity. © 2002 Elsevier Science Ltd. All rights reserved.
The Baylis–Hillman type coupling is one of the most
important carbonꢀcarbon bond-forming processes in
organic synthesis.1–3 Highly functionalized Baylis–Hill-
man adducts can then be subjected to subsequent trans-
formations for the synthesis of natural products and
synthetic derivatives.4 However since b-substituted acryl-
ate olefins cannot currently undergo the Baylis–Hillman
reaction,1a,5,6 alternative methods for synthesizing b-sub-
stituted acrylate olefins are required.
Inspired by these previous studies, we and other groups
have developed several methodologies for the synthesis
of b-monosubstituted and b,b-disubstituted a-(hydroxy-
alkyl)acrylates, a-(aminoalkyl)acrylates and b-halo
Baylis–Hillman ketones.10–12 In our continuing develop-
ment of new Baylis–Hillman-type processes, we are
pleased to find that Z-b-iodo-a-(hydroxyalkyl)acrylates
were obtained by mixing aldehydes, methyl propynoate
and diethyl aluminium iodide in CH2Cl2. In this commu-
nication, we report this new procedure which is repre-
sented in Scheme 1 with results summarized in Table 1.
The synthesis of b-iodo Baylis–Hillman ketones was
initially carried out by Kishi et al.7 via a TiCl4-promoted
conjugative addition of tetrabutylammonium iodide ((n-
Bu)4NI) to a,b-acetylenic ketones followed by elec-
trophilic coupling with aldehydes. E-b-Iodo Baylis–
Hillman type ketones were also obtained by using Et2AlI
as the promoter and the halogen source.8 Afterwards, Lu
and co-workers reported a method for the synthesis of
b-iodo Baylis–Hillman esters and amides with Z-isomers
as the major products.9 The latter method also employed
(n-Bu)4NI as the halide source for the anionic conjuga-
tive addition, but used 1.2 equiv. of ZnCl4 as the Lewis
acid promoter.
We initially attempted the three-component reaction of
benzaldehyde, methyl propynoate and TiCl4 (1.2 equiv.),
but the success was very limited. However when TiCl4
was replaced by Et2AlI as the halogen source and the
Lewis acid promoter, the desired product was generated.
The reaction was carried out at 0°C by adding Et2AlI
dropwise into the mixture of aldehyde and methyl
propynoate in CH2Cl2 under argon. Most reactions went
1
to completion within 2 h as indicated by TLC or H
NMR analysis; good to high yields were realized for all
examples that were examined.
OH
O
I
COOMe
(1.2eq)
Et2AlI
CH2Cl2
( 90%)
OMe
R
RCHO
+
H
Scheme 1.
Keywords: Baylis–Hillman adducts; diethyl aluminium iodide; methyl propynoate; b-iodo-a-(hydroxyalkyl)acrylates.
* Corresponding author. Fax: (806) 742-1289; e-mail: paul.pare@ttu.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01106-1

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H.-X. Wei et al. / Tetrahedron Letters 43 (2002) 5677–5680
Table 1. Results of the Et2AlI-mediated reaction for synthesis of b-iodo Baylis–Hillman adducts13,14
Entry
Substrates
Products
Z/E selectivity (%)a
Yield (%)b
OH
H
O
I
OMe
R =
1
2
3
4
5
6
7
8
9
Benzaldehyde
Phenyl-R
94/6
91/9
95/5
95/5
95/5
94/6
93/7
95/5
86/14
88
89
85
4-Fluorobenzadehyde
4-Chlorobenzadehyde
2-Naphthaldehyde
p-Anisaldehyde
p-Tolualdehyde
Trimethylacetaldehyde
Acetophenone
4-Fluorophenyl-R
4-Chlorophenyl-R
2-Naphthyl-R
4-Methoxybenzene-R
p-Tolyl-R
tert-Butyl-R
sec-Phenethyl-R
1-Phenyl-3-methyl-1-proene-R
84
95c
90
76
75c
86c
Benzalacetone
a Estimated by crude 1H NMR determination.
b Yields after purification by column chromatography.
c Reaction for 4 h.
Dichloromethane provided the highest efficiency among
the solvents tested in terms of yield and Z/E selectivity
when using benzaldehyde as the electrophilic acceptor.
Diethyl ether gave rise to a lower yield of 65% within a
2 h reaction period, while benzene and toluene resulted
in a poorer Z/E selectivity with ratios of 80/20 and
76/24, respectively.
To explain the high Z/E stereoselectivity of this new
system, a cyclic transition state model proposed by
Kishi can be invoked.7 In their system, not only the
(n-Bu)4NI/TiCl4 combination but also Et2AlI and TiI4
were employed for the reaction. The exclusive Z
stereoselectivity of b-iodo Baylis–Hillman ketones was
obtained at −78°C, while the high E-stereoselectivity
was observed at 0°C. By using a cyclic transition state
model, they suggested the Z-stereoisomer was the
kinetically controlled product, while the E-stereoisomer
was the thermodynamically controlled product. In the
system we report here, the Z-isomer was favoured
under all reaction conditions tested. These results sug-
gest that the kinetic control plays a significant role in
determining the geometric selectivity at 0°C (Scheme 2).
This is in contrast to a previously reported TiCl4-medi-
ated reaction carried out at room temperature in which
E isomers were predominantly obtained;12 a process
believed to be under thermodynamic control.
Both aromatic and aliphatic aldehydes were suitable
electrophilic acceptors in this reaction, as shown in
Table 1. For aromatic aldehydes, substitution of an
electron-withdrawing group on the aromatic ring
resulted in no obvious effect on the reaction efficiency.
However, an electron-donating group attached to the
aromatic aldehyde reduced the reaction rate. When
p-anisaldehyde (entry 5, Table 1) was employed as the
electrophilic acceptor, the reaction needed 4 h to gener-
ate product of more than 90% yield, with only 80% of
p-anisaldehyde converted to product within 2 h. Both
aromatic ketone and aliphatic ketone substrates can be
employed as electrophilic acceptors, although they did
result in lower reaction efficiencies (entries 8 and 9,
respectively). The reaction temperature appears to
affect the Z/E selectivity as well as the rate of the
reaction. For example, when benzaldehyde was used as
the electrophilic acceptor, the reaction did not go to
completion at −78°C even when the reaction time was
extended to 24 h, however, the Z/E selectivity was
improved to 98/2.
In summary, an efficient synthetic method for b-iodo-a-
(hydroxyalkyl)acrylates has been developed. The new
OAlEt2
PhCHO
OMe
PhCHO
.
I
MeO
MeO
H
AlEt2
O
AlEt2
O
O
O
Ph
The Z/E selectivities listed in Table 1 were measured by
1H NMR spectroscopic analyses of the crude product
mixture. In all cases, the a-proton signals for Z and E
isomers were clearly distinguishable with the proton for
the Z isomer upfield relative to the proton for the E
isomer. Isomers could be readily separated by flash
chromatography and the geometries for the two iso-
mers of the benzaldehyde reaction were confirmed by
ROSEY NMR experiments. For the Z isomer, vinyl-
proton irradiation resulted in a-proton enhancement,
whereas, for the E isomer, vinyl proton irradiation
resulted in methoxyl proton enhancement.
H
Ph
I
I
H
OH
O
OH
O
Ph
OMe
Ph
OMe
H
I
I
(major)
(minor)
Scheme 2.

H.-X. Wei et al. / Tetrahedron Letters 43 (2002) 5677–5680
5679
protocol utilizes diethyl aluminium iodide as the iodine
anion source, and concurrently as a Lewis acid pro-
moter under relatively mild conditions. This new reac-
tion system provides extensive functionalization of
acrylate olefins with high chemical yields and geometric
selectivity.
bottom was flushed with nitrogen and cooled to 0°C. Into
the tube, freshly distilled dichloromethane (5.0 mL), ben-
zaldehyde (0.1 mL, 1.0 mmol) and methyl propynoate
(0.12 mL, 1.3 mmol) were added. The mixture was stirred
at 0°C for 5 min. and then a solution of diethylalu-
minium iodide in toluene (25 wt% solution in toluene, 1.2
mL, 1.2 mmol) was added dropwise via syringe in ca. 5
min. The resulting homogeneous yellow solution was
stirred for 2 h at 0°C. The reaction was quenched by
dropwise addition of 2N aqueous hydrochloric acid. The
two phases were separated, and the aqueous phase was
extracted with ethyl acetate (3×20 mL). The combined
organic layers were then washed with brine, dried over
anhydrous magnesium sulfate and concentrated. The
residue was purified by flash chromatography (hex-
ane:EtOAc, 10/1, v/v) to provide products 1Z (263 mg,
83% yield) and 1E (17 mg, 5.3% yield) (combined yields,
88%), both colourless oils.
Acknowledgements
We thank D. Purkiss for expert NMR support. Finan-
cial support was provided by the Robert A. Welch
Foundation (D-1478 and D-1361).
References
14. The physical data of all products: 1Z: 1H NMR (300
MHz, CDCl3): l 2.91 (d, J=5.5 Hz, 1H), 3.72 (s, 3H),
5.54 (dd, J=5.5, 1.5 Hz, 1H), 7.27 (d, J=1.5 Hz, 1H),
7.30–7.36 (m, 5H); 13C NMR (75 MHz, CDCl3): l 51.9,
76.0, 87.1, 126.5×2, 128.3, 218.6×2, 140.0, 145.1, 166.3;
IR (neat): wmax=3443, 3063, 2950, 1714; MS (CI, CH4):
m/z (%) 318.1 [M]+; HRMS calcd for 318.1110; found:
318.1105. 1E: 1H NMR (300 MHz, CDCl3): l 3.72 (s,
3H), 4.20 (d, J=11.4 Hz, 1H), 5.83 (d, J=11.4 Hz, 1H),
7.26–7.44 (m, 5H), 8.14 (s, 1H). Compound 2: colourless
oil (299 mg, 89% combined yields); 2Z: 1H NMR (300
MHz, CDCl3): l 2.93 (d, J=6.0 Hz, 1H), 3.72 (s, 3H),
5.52 (dd, J=6.0, 1.5 Hz, 1H), 7.00–7.06 (m, 2H), 7.28–
7.32 (m, 2H); 13C NMR (75 MHz, CDCl3): l 51.9, 73.9,
87.1, 115.4, 115.7, 128.4, 135.8, 144.9, 160.8, 164.1, 166.2;
IR (neat): wmax=3499, 3071, 2952, 1731. Compound 3:
colourless oil (300 mg, 85% combined yields); 3Z: 1H
NMR (300 MHz, CDCl3): l 3.23 (d, J=6.0 Hz, 1H), 3.72
(s, 3H), 5.48 (dd, J=6.0, 1.4 Hz), 7.22–7.32 (m, 5H); 13C
NMR (75 MHz, CDCl3): l 51.9, 75.4, 87.7, 127.8×2,
128.8×2, 134.1, 138.5, 144.6, 166.1; IR (neat): wmax=3453,
3068, 2958, 2359, 1720; MS (CI, CH4): m/z (%) 352.5
[M]+; HRMS calcd for 352.5558; found: 352.5551. Com-
pound 4: colourless oil (309 mg, 84% combined yields);
1. (a) Ciganek, E. Org. React. 1997, 51, 201; (b) Basavaiah,
D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001;
(c) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44,
4653.
2. (a) Brzezinski, L. J.; Rafel, S.; Leahy, J. M. J. Am. Chem.
Soc. 1997, 119, 4317; (b) Iwabuchi, Y.; Nakatani, M.;
Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999,
121, 10219.
3. Marko, I. E.; Giles, P. G.; Hindley, N. J. Tetrahedron
1997, 53, 1015.
4. (a) Hoffman, H. M. R.; Rabe, J. Helv. Chem. Acta 1984,
67, 413; (b) Hoffman, H. M. R.; Rabe, J. J. Org. Chem.
1985, 50, 3849.
5. Roth, F.; Gygax, P.; Frater, G. Tetrahedron Lett. 1992,
48, 6371.
6. Drewes, S. E.; Njamela, O. L.; Emslie, N. D.; Ramesar,
N.; Field, J. S. Synth. Commun. 1993, 23, 2807.
7. (a) Taniguchi, M.; Kobayashi, S.; Nakagawa, M.; Hino,
T.; Kishi, Y. Tetrahedron Lett. 1986, 34, 4763; (b)
Taniguchi, M.; Hino, T.; Kishi, Y. Tetrahedron Lett.
1986, 39, 4767.
8. Itoh, A.; Ozawa, S.; Oshima, K.; Nozaki, H. Tetrahedron
Lett. 1980, 21, 361.
9. Zhang, C.; Lu, X.-Y. Synthesis 1996, 586.
10. (a) Li, G.; Wei, H.-X.; Phelps, B. S.; Purkiss, D. W.;
Kim, S. H. Org. Lett. 2001, 3, 823; (b) Wei, H.-X.; Gao,
J. J.; Li, G. Tetrahedron Lett. 2001, 42, 9119; (c) Li, G.;
Wei, H.-X.; Gao, J. J.; Caputo, T. D. Tetrahedron Lett.
2000, 41, 1; (d) Li, G.; Wei, H.-X.; Whittlesey, B. R.;
Batrice, N. N. J. Org. Chem. 1999, 64, 1061; (e) Wei,
H.-X.; Hook, J. D.; Fitzgerald, K. A.; Li, G. Tetra-
hedron: Asymmetry 1999, 10, 661; (f) Li, G.; Wei, H.-X.;
Hook, J. D. Tetrahedron Lett. 1999, 40, 4611; (g) Li, G.;
Wei, H.-X.; Willis, S. Tetrahedron Lett. 1998, 39, 4607.
11. (a) Ramachandran, P. V.; Reddy, M. V.; Rudd, M. T.
Chem. Commun. 1999, 1979; (b) Ramachandran, P. V.;
Reddy, M. V.; Rudd, M. T. Tetrahedron Lett. 1999, 40,
627; (c) Ramachandran, P. V.; Reddy, M. V.; Rudd, M.
T.; de Alaniz, J. R. Tetrahedron Lett. 1998, 39, 8791.
12. (a) Wei, H.-X.; Kim, S. H.; Caputo, T. D.; Purkiss, D.
W.; Li, G. Tetrahedron 2000, 56, 2397; (b) Kataoka, T.;
Kinoshita, H.; Kinoshita, S.; Iwamura, T.; Watanabe, S.
Angew. Chem., Int. Ed. 2000, 39, 2358.
1
4Z: H NMR (300 MHz, CDCl3): l 3.04 (d, J=6.0 Hz,
1H), 3.70 (s, 3H), 5.69 (dd, J=6.0, 1.5 Hz, 1H), 7.29 (s,
1H), 7.47–7.50 (m, 3H), 7.80–7.84 (m, 4H); 13C NMR (75
MHz, CDCl3): l 51.9, 76.1, 87.5, 124.2, 125.6, 126.3×2,
127.6, 128.1, 128.5, 133.1×2, 137.3, 145.0, 166.3; IR
(neat): wmax=3447, 3055, 2949, 1715. Compound 5:
colourless oil (330 mg, 95% combined yields); 5Z: 1H
NMR (300 MHz, CDCl3): l 3.06 (d, J=6.0 Hz, 1H), 3.69
(s, 3H), 3.77 (s, 3H), 5.45 (dd, J=6.0, 1.5 Hz, 1H),
6.83–6.86 (d, J=6.0 Hz, 2H), 7.19–7.22 (m, 3H); 13C
NMR (75 MHz, CDCl3): l 51.9, 55.2, 75.6, 86.4, 114.0×
2, 127.9×2, 132.1, 145.4, 159.5, 166.4; IR (neat): wmax
=
3448, 3001, 2950, 2835, 1718. Compound 6: colourless oil
(399 mg, 90% combined yields); 6Z: 1H NMR (300 MHz,
CDCl3): l 2.32 (s, 3H), 3.07 (d, J=6.0 Hz, 1H), 3.68 (s,
3H), 5.46 (dd, J=6.0, 1.5 Hz, 1H), 7.11–7.20 (m, 4H);
13C NMR (75 MHz, CDCl3): l 21.1, 51.8, 75.8, 86.7,
126.4×2, 129.3×2, 137.0, 138.1, 145.2, 166.3; IR (neat):
wmax=3450, 3024, 2949, 1713. Compound 7: colourless oil
(226 mg, 76% combined yields); 7Z: 1H NMR (300 MHz,
CDCl3): l 0.89 (s, 9H), 2.68 (d, J=6.0 Hz, 1H), 3.82 (s,
3H), 4.25 (dd, J=6.0, 1.4 Hz, 1H), 7.07 (s, 1H);
13. Typical procedure (Table 1, entry 1): A dry standard-
glass test tube (150×22 mm) with a stir bar placed at the

5680
H.-X. Wei et al. / Tetrahedron Letters 43 (2002) 5677–5680
13C NMR (75 MHz, CDCl3): l 25.5×3, 36.0, 51.9, 82.5,
85.6, 145.4, 167.9; IR (neat): wmax=1716, 1614. Compound
8: colourless oil (249 mg, 75% combined yields); 8Z: H
128.3×2, 144.6, 150.1, 168.1; IR (neat): wmax=3484, 1726.
Compound 9: colourless oil (308 mg, 86% combined
1
1
yields); 9Z: H NMR (300 MHz, CDCl3): l 1.60 (s, 3H),
3.15 (s, 1H), 3.83 (s, 3H), 6.27 (d, J=18.0 Hz, 1H), 6.68
(d, J=18.0 Hz, 1H), 7.04 (d, J=0.9 Hz, 1H), 7.25–7.39 (m,
5H); IR (neat): wmax=3506, 2953, 1714.
NMR (300 MHz, CDCl3): l 1.70 (s, 3H), 3.67 (s, 3H), 3.80
(s, 1H), 7.11 (s, 1H), 7.25–7.42 (m, 5H); 13C NMR (75
MHz, CDCl3): l 28.7, 51.9, 77.8, 83.8, 125.0×2, 127.5,