Stereoselective synthesis of methyl (Z)-α-methoxyacrylates via two-carbon homologation of aldehydes

Article abstract of DOI:10.1016/j.tetlet.2008.11.027

Methyl (Z)-α-methoxyacrylates are generated in good yields by a mild, stereospecific two-carbon homologation of a wide variety of aldehydes utilizing commercial methyl 2,2-dichloro-2-methoxyacetate and CrCl₂ under Barbier conditions at room tem

Full text of DOI:10.1016/j.tetlet.2008.11.027

Tetrahedron Letters 50 (2009) 402–405
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Tetrahedron Letters
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Stereoselective synthesis of methyl (Z)-a-methoxyacrylates
via two-carbon homologation of aldehydes
Rachid Baati a, , Charles Mioskowski a,z, Dhurke Kashinath a, Sanjeevarao Kodepelly a, Biao Lu b, J. R. Falck b,
*
*
a Laboratoire de Synthèse Bio-Organique, UMR 7175-LC1, Faculté de Pharmacie, Université Louis Pasteur de Strasbourg, 74 Route du Rhin, B.P. 24, 67401 Illkirch, France
b Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Methyl (Z)-a-methoxyacrylates are generated in good yields by a mild, stereospecific two-carbon homo-
Received 17 September 2008
Revised 31 October 2008
Accepted 7 November 2008
Available online 13 November 2008
logation of a wide variety of aldehydes utilizing commercial methyl 2,2-dichloro-2-methoxyacetate and
CrCl2 under Barbier conditions at room temperature. A rational mechanism based upon a Reformatsky-
type addition pathway or an in situ generated (E)-trioxo-chromium vinylidene carbenoid is proposed.
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to the memory of Dr. Charles
Mioskowski
2-Alkoxyacrylic moieties are present in many natural and semi-
synthetic products,1 and have been used as key intermediates for
the preparation of biologically active compounds.2 The derivatives
of arylalkadienes are useful in the treatment of osteoporosis and
other diseases.3 Moreover, the C–C double bond present in these
compounds can be used for diverse transformations such as Claisen
rearrangement,4 Diels–Alder,2a,5 and Heck reactions.2b,6 Several
methods are available in the literature for the preparation of
commercial methyl 2,2-dichloro-2-methoxy acetate (1) and CrCl2
at room temperature (Scheme 1).
The reaction parameters were optimized with equimolar 1 and
p-tolualdehyde (2). Utilizing 4 equivalents of anhydrous CrCl2 at rt
in THF under Barbier conditions, (Z)-a-methoxyacrylate 3
(Z/E > 97:3)14 was obtained in 54% yield. The yield of 3 increased
proportionately to a maximum of 88% with the application of 6
equivalents of CrCl2 (Table 1, entry 1).15 No further improvements
were realized if more equivalents of CrCl2 were used.
2-alkyloxy-
a
,b-unsaturated alkenoates, and most of them rely
-alkoxy phos-
either on Horner–Emmons condensations using
a
Homologations were also observed in EtOAc, benzene, and diox-
ane, but yields were inferior.16 Likewise, attempts to utilize cata-
lytic amounts of CrCl2 regenerated in situ by excess Fe(0) or
Mn(0) proved unsatisfactory, even at elevated temperatures.
With suitable reaction conditions in hand, the scope of our
methodology was then investigated using a panel of structurally
representative aliphatic and aromatic aldehydes. Aromatic alde-
hydes bearing electron-donating substituents, for example,
4-methoxybenzaldehyde (4, entry 2) and piperonal (6, entry 3),
as well as electron-withdrawing groups, for example, methyl 4-
formylbenzoate (8, entry 4) and 4-trifluoromethyl benzaldehyde
(10, entry 5) underwent smooth condensations to give stereoselec-
tively Z-configured adducts 5, 7, 9, and 11, respectively, in good
yields (70–80%). Significantly, our two-carbon homologation is also
compatible with a variety of functional groups as demonstrated by
phono acetates,2e–g,3,7 or on reactions of aldehydes with alkyl
esters under basic conditions.1d,2j,8 Other methods used for this
purpose are palladium cross-coupling with vinylic electrophiles9
via alkenyl metallic species10 and phosphine-catalyzed addition
of arylpropiolates to oxygen nucleophiles.11 However, some of
these methods present quite often serious drawbacks such as
multistep transformations, low yields, and more importantly low
selectivity. Moreover, some reaction conditions are not compatible
with common functional groups.
During the past few years we have been engaged with the stud-
ies of organochromium compounds for stereoselective C–C bond
forming reactions.12 In this connection, recently we reported the
preparation of (Z)-methyl 2-methoxy-3-phenylacrylate by the
reaction of benzaldehyde and 2,2-dichloro-2-methoxy acetate in
presence of CrCl2.13 With this background and considering the
importance of methoxyacrylates, we report herein, the generality
of the reaction for the preparation of (Z)-a-methoxyacrylates via
two-carbon homologation of a large panel of aldehydes utilizing
O
O
O
Cl
+ Cl
OCH3
CrCl2
R
OCH3
R
H
* Corresponding authors. Fax: +33 390 244 306 (R.B.); fax: +1 214 648 6455
(J.R.F.).
OCH3
1
OCH3
THF, rt, 10 h
E-mail addresses: baati@bioorga.u-strasbg.fr (R. Baati), j.falck@utsouthwestern.
edu (J. R. Falck).
Scheme 1. Stereoselective synthesis of (Z)-
esters.
a
-methoxy-a,b-unsaturated alkenoic
z
Deceased on 2nd June 2007.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.027

R. Baati et al. / Tetrahedron Letters 50 (2009) 402–405
403
Table 1
Various functionalized alkenoic esters
Entry
Aldehyde
Alkenoate
Yield (%)
88
O
O
H
OCH3
1
OCH3
H3C
H3C
2
3
O
O
OCH3
H
2
70
OCH3
H3CO
H3CO
4
5
O
O
O
O
O
OCH3
OCH3
H
3
4
75
77
O
6
7
O
O
OCH3
H
OCH3
H3CO2C
H3CO2C
8
9
O
O
H
OCH3
5
6
80
85
OCH3
F3C
F3C
10
11
O
O
H
OCH3
OCH3
H3COC
H3COC
13
12
O
O
OCH3
H
7
8
84
70
OCH3
O
Br
Br
14
15
O
O
OCH3
H
16
OCH3
17
O
OCH3
9
77
H
OCH3
18
19
O
O
OCH3
H
10
11
69
71
O
21
OCH3
O
20
O
O
OCH3
H
23
OCH3
22
O
O
12
13
62
62
H
OCH3
OCH3
25
24
O
O
H
OCH3
OCH3
H3CO
H3CO
26
27

404
R. Baati et al. / Tetrahedron Letters 50 (2009) 402–405
O
OCr(III)
OCr(III)
OMe
CrCl2
H3CO
RCHO
pathway a
O
H3CO
H3CO
R
OMe
H3CO
Cl
Cl
O
OCr(III)
29
O
30
Cr(III)
Cl
CrCl2
H3CO
R
OMe
31
1
OCH3
Cr(III)
28
OCr(III)
OMe
Cr(III)
Cr(III)
OCH3
pathway b
H3CO
RCHO
Cr(III)
32
33
O
R
O
OCr(III)
OCr(III)
MeO2C
H
MeO
H
CO2Me
OMe
H3CO
H3CO
R
31
R
R
OMe
OMe
(Z)-acrylate
Cr(III)
31a
Cr(III)
31b
(E)-acrylate
Figure 1. Mechanism for stereoselective Z-alkenoic ester formation.
5617–5620; (c) Bosch, J.; Salas, M.; Amat, M.; Alvarez, M.; Morgó, I.; Adrover, B.
Tetrahedron 1991, 47, 5269–5276; (d) Hanessian, S.; Ma, J.; Wang, W. J. Am.
Chem. Soc. 2001, 123, 10200–10206.
the selective transformations of an aromatic ketoaldehyde
(12?13, entry 6) and an aromatic bromide (14?15, entry 7).
It is noteworthy that aliphatic aldehydes like n-hexanal (16)
and hydrocinnamaldehyde (18) were well tolerated and led to
(Z)-acrylates 17 (entry 8) and 19 (entry 9), respectively, without
complications. Heterocyclic aldehyde furfural (20, entry 10) was
also a suitable substrate, and furnished the corresponding (Z)-acry-
late 21 in modest yield (69%) along with recovered starting mate-
2. (a) Duvelleroy, D.; Perrio, C.; Parisel, O.; Lasne, M.-C. Org. Biomol. Chem. 2005, 3,
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Willard, A. K. J. Org. Chem. 1976, 41, 986–996; (g) Ireland, R. E.; Müller, R. H.;
Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868–2877; (h) Daniewski, A. R.;
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L.; Rivier, M. WO 2007049158, 2007; Chem. Abstr. 2007, 146, 481812.
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8. Houpis, I. N.; Patterson, L. E.; Alt, C. A.; Rizzo, J. R.; Zhang, T. Y.; Haurez, M. Org.
Lett. 2005, 7, 1947–1950.
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3042.
10. Fuchibe, K.; Iwasawa, N. Tetrahedron 2000, 56, 4907–4915.
11. Gabillet, S.; Lecerclé, D.; Loreau, O.; Dézard, S.; Gomis, J.-M.; Taran, F. Synthesis
2007, 515–522.
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9196–9197; (b) Barma, D. K.; Baati, R.; Valleix, A.; Mioskowski, C.; Falck, J. R.
Org. Lett. 2001, 3, 4237–4238; (c) Barma, D. K.; Kundu, A.; Zhang, H.;
Mioskowski, C.; Falck, J. R. J. Am. Chem. Soc. 2003, 125, 3218–3219; (d) Baati,
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rial (22%). Extension of the homologation procedure to
a,b-
unsaturated aldehydes (entries 11–13) was satisfactory in terms
of reactivity and stereoselectivity (Z/E ꢀ 97:3), although slightly
lower yields were obtained.
In concert with prior mechanistic studies,12,13 we propose that
reaction of 1 with CrCl2 initially generates 2-chloro-2-methoxy-
2-chromium carbenoid 28 (Fig. 1). Addition of this species to the
aldehyde results in a Reformatsky-type adduct 30 (pathway a),
which upon further reduction affords 31. Alternatively, pathway
b could also be invoked for the formation of the intermediate 31,
via the possible formation of a nucleophilic trioxo-vinylidene carb-
enoid 33. Subsequent anti-periplanar E2 elimination through the
less congested conformer 31a preferentially delivers Z-olefin. The
high selectivity observed for the a-methoxyacrylates might be as-
cribed to the high steric hindrance in conformer 31b, which favors
the elimination from the more stable conformer 31a predom-
inantly. At this stage of our investigations, the most probable path-
way a or b is not settled, and attempts to trap the intermediates are
underway in our laboratories.
In conclusion, we have demonstrated and established the scope
and the functional group compatibility of the stereospecific syn-
thesis of (Z)-a-methoxyacrylates via a CrCl2-promoted conden-
sation of methyl 2,2-dichloro-2-methoxy acetate with various
aldehydes. We believe that the modular strategy outlined here will
be a convenient general way to prepare this useful class of highly
functionalized, trisubstituted alkenes.
13. Falck, J. R.; Bejot, R.; Barma, D. K.; Bandyopadhyay, A.; Joseph, S.; Mioskowski,
C. J. Org. Chem. 2006, 71, 8178–8182.
14. The Z/E ratio was determined by quantitative integration of the vinyl proton of
both isomers in the 1H NMR of the crude reaction mixture. The stereochemistry
of the major Z acrylate was assigned by NOE experiments.
15. Procedure for the preparation of alkenoic ester 3: To a solution of methyl 2,2-
dichloro-2-methoxy acetate 1 (100 mg, 0.57 mmol) in dry THF (5 mL) was
added 4-methyl benzaldehyde
2 (69 mg, 0.57 mmol)) followed by CrCl2
(6 equiv). The mixture was allowed to stir at rt for 10 h. After completion of
the reaction (TLC), it was quenched with water (10 mL) and extracted with
ether (2 Â 25 mL). Combined organic layers were washed with brine, water,
and concentrated under reduced pressure to give crude product, which was
purified by silica gel column chromatography. Elution of the column with
cyclohexane/EtOAc (98/2) mixture gave desired alkenoic ester 3 (104 mg, 88%).
1H NMR (300 MHz, CDCl3) d 2.52 (s, 3H), 3.92 (s, 3H), 4.00 (s, 3H), 7.14 (s, 1H),
7.34 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 21.8,
52.5, 59.5, 124.3, 129.7, 130.1, 130.9, 139.7, 145.2, 165.4.; MS (EI) 206.1.
Spectral data for compound 5: 1H NMR (300 MHz, CDCl3) d 3.76 (s, 3H), 3.83 (s,
3H), 3.84 (s, 3H), 6.91 (d, J = 9.03 Hz, 2H), 6.98 (s, 1H), 7.72 (d, J = 8.43 Hz, 2H).;
13C NMR (75 MHz, CDCl3) d 52.4, 55.6, 59.4, 114.4, 124.6, 132.2, 144.2, 160.6,
165.5. Compound 7: 1H NMR (300 MHz, CDCl3) d 3.76 (s, 3H), 3.84 (s, 3H), 5.99
Acknowledgments
We thank the CNRS, the ANR (DK and SK fellowships), the
Robert A. Welch Foundation, and NIH (GM31278, DK38226) for
financial support.
References and notes
1. (a) Shigemori, H.; Miyoshi, E.; Shizuri, Y.; Yamamura, S. Tetrahedron Lett. 1989,
30, 6389–6392; (b) Estendorfer, S.; Ledl, F.; Severin, T. Tetrahedron 1990, 46,

R. Baati et al. / Tetrahedron Letters 50 (2009) 402–405
405
(s, 2H), 6.80 (d, J = 8.1 Hz, 1H), 6.92 (s, 1H), 7.12 (d, J = 8.1 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 52.4, 59.5, 101.7, 108.7, 109.9, 114.4, 124.5, 125.9, 127.9,
132.1, 144.4, 148.2, 148.6, 165.3. Compound 9: 1H NMR (200 MHz, CDCl3,): d
3.81 (s, 3H), 3.86 (s, 3H), 3.92 (s, 3H), 6.96 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 8.02–
8 (d, J = 8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3): d 52.2, 52.3, 59.4, 122.2, 129.7,
52.0, 60.1, 126.2, 128.0, 128.5, 141.2, 146.5, 164.3. ESI:(M+H)+ = 221.
Compound 21: 1H NMR (200 MHz, CDCl3): d 3.81 (s, 3H), 3.83 (s, 3H), 6.50–
6.47 (m, 1H), 6.90–6.92 (d, J = 3.4 Hz, 2H), 6.99 (s, 1H), 7.46–7.47 (d, J = 6 Hz,
1H); 13C NMR (75 MHz, CDCl3): d 52.2, 59.3, 112.4, 113.7, 114.1, 143.2, 143.4,
149.4, 164.5. GC–MS: (M)+ = 182. Compound 27: 1H NMR (200 MHz, CDCl3) d
3.77 (s, 3H), 3.81 (s, 3H), 3.82 (s, 3H), 6.76 (d, J = 15.4 Hz, 1H), 6.88 (d,
J = 9.02 Hz, 2H), 7.00 (d, J = 10.54 Hz, 1H), 7.08 (d, J = 11 Hz, 1H), 7.43 (d,
J = 8.8 Hz, 2H).; 13C NMR (50 MHz, CDCl3) d 53.3, 55.7, 61.1, 114.6, 119.7, 127.2,
128.9, 129.8, 137.8, 144.5, 160.5, 164.9.
129.90, 129.97, 137.8, 147.0, 164.4, 166.6. ESI: (M+H)+ = 251. Compound 13: 1
H
NMR (200 MHz, CDCl3): d 2.60 (s, 3H), 3.81 (s, 3H), 3.86 (s, 3H), 6.95 (s, 1H),
7.80 (d, J = 6.4 Hz, 2H), 7.97 (d, J = 6 Hz, 2H); 13C NMR (75 MHz, CDCl3): d 27.2,
52.6, 59.6, 122.3, 128.7, 130.3, 138.2, 147.4, 164.6, 197.5. ES+: (M+H)+ = 235.
Compound 19: 1H NMR (CDCl3, 200 MHz): d 2.58–2.66 (t, J = 8.4 Hz, 2H), 2.75–
2.82 (t, J = 8.2 Hz, 2H), 3.58 (s, 3H), 3.81 (s, 3H), 6.29–6.36 (t, J = 14.8 Hz, 1H),
7.20–7.24 (m, 2H), 7.30–7.38 (m, 3H). 13C NMR (CDCl3, 75 MHz): d 27.4, 34.9,
16. The use of other solvents, under otherwise identical conditions, was not
satisfactory: EtOAc, benzene, and dioxane afforded 3 in 18%, 5%, and 38% yield,
respectively.