Chromium vinylidene carbenoids: stereospecific synthesis of (Z)-2-chloroalk-2-en-1-ols.

Article abstract of DOI:10.1021/ol016935h

(Z)-2-Chloroalk-2-en-1-ols are obtained in excellent yields from a wide variety of aldehydes by addition of (E)-chromium vinylidene carbenoids, stereospecifically generated from trichloroalkanes using CrCl(2) in THF at room temperature. [reaction: see text]

Full text of DOI:10.1021/ol016935h

ORGANIC
LETTERS
2
001
Vol. 3, No. 26
237-4238
Chromium Vinylidene Carbenoids:
Stereospecific Synthesis of
4
(Z)-2-Chloroalk-2-en-1-ols
†
‡
⊥
,‡,§
D. K. Barma, Rachid Baati, Alain Valleix, Charles Mioskowski,* and
J. R. Falck*
,†
Department of Biochemistry, UniVersity of Texas Southwestern Medical Center,
Dallas, Texas 75390-9038, UniVersit e´ Louis Pasteur, Facult e´ de Pharmacie,
Laboratoire de Synth e` se Bio-Organique associe au CNRS, 67401 Illkirch, France,
and CEA de Saclay, SerVices des Molecules Marquees, Bat. 547,
91191 Gif-sur-YVette, France
j.falck@utsouthwestern.edu
Received October 18, 2001
ABSTRACT
(Z)-2-Chloroalk-2-en-1-ols are obtained in excellent yields from a wide variety of aldehydes by addition of (E)-chromium vinylidene carbenoids,
stereospecifically generated from trichloroalkanes using CrCl in THF at room temperature.
2
5
Our laboratories recently described an efficient synthesis of
terminal 2-chloropropenyl alcohols via in situ R-chloro-
vinylation of aldehydes using 1,1,1-trichloroethane and
as 3 are versatile synthetic intermediates as well as critical
structural units in a variety of biologically active natural
products of current interest. However, their accessibility
is often hampered by multistep routes and/or poor stereo-
6
1
,2
CrCl
2
.
Subsequent mechanistic investigations identified a
7
selectivity.
chromium vinylidene carbenoid as the penultimate interme-
3
The results from a panel of representative substrates are
summarized in Table 1. For simple, unactivated trichlo-
diate. Herein, we report that homologous trichloroalkanes
8
,9
1
are stereoselectively transformed to (E)-chromium vinyl-
idenes 2 which efficiently add to aldehydes affording (Z)-
(
3) Baati, R.; Barma, D. K.; Falck, J. R.; Mioskowski, C. J. Am. Chem.
Soc. 2001, 123, 9196-9197.
4) 2,2,2-Trichloroethanol derivatives also yield (Z)-2-chloroalk-2-en-
-ols accompanied by variable amounts of 1,1-dichloroalkene, (E/Z)-1-
4
2-chloroalk-2-en-1-ols 3 (eq 1). Halogenated alkenols such
(
1
chloroalkene, and 1-alkoxy-1-chloroalkene: Takai, K.; Kokumai, R.;
Nobunaka, T. Chem. Commun. 2001, 1128-1129.
(
5) (a) Taylor, R. E.; Ciavarri, J. P. Org. Lett. 2000, 1, 467-469. (b)
Dai, W.-M.; Wu, A. Tetrahedron Lett. 2001, 42, 81-83.
(
6) For example: Ueda, K.; Hu, Y. Tetrahedron Lett. 1999, 40, 6305-
6
308.
(
7) (a) Kasatkin, A.; Whitby, R. J. J. Am. Chem. Soc. 1999, 121, 7039-
7
049. (b) Kadota, J.; Komori, S.; Fukumoto, Y.; Murai, S. J. Org. Chem.
†
University of Texas.
Universit e´ Louis Pasteur.
Services des Molecules Marquees.
E-mail: mioskow@aspirine.u-strasbg.fr.
1999, 64, 7523-7527. (c) Braun, M.; Mahler, H. Liebigs Ann. 1995, 29-
40. (c) Harre, M.; Nickisch, K. Tetrahedron Lett. 1993, 34, 3123-3126.
(8) General procedure: 1,1,1-Trichloroalkane (0.4 mmol) and aldehyde
(0.4 mmol) in THF (1 mL) were added to a stirring, grayish suspension of
anhydrous CrCl2 (1.6 mmol) in THF (10 mL) under argon at ambient
temperature. After 10-12 h, the resultant reddish reaction mixture was
quenched with water and extracted thrice with ether, and the combined
ethereal extracts were evaporated in vacuo. Chromatographic purification
on SiO2 gave the (·)-chloroalkenol adducts in the indicated yields (Table
1).
‡
⊥
§
(
1) Falck, J. R.; Barma, D. K.; Mioskowski, C.; Schlama, T. Tetrahedron
Lett. 1999, 40, 2091-2094.
2) For additional examples of recent CrCl2-based methodology, see: (a)
(
Falck, J. R.; Barma, D. K.; Baati, R.; Mioskowski, C. Angew. Chem., Int.
Ed. 2001, 40, 1281-1283. (b) Baati, R.; Valleix, A.; Mioskowski, C.;
Barma, D. K.; Falck, J. R. Org. Lett. 2000, 2, 485-487.
1
0.1021/ol016935h CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/06/2001

2 2
sponding (E)-vinylidene intermediate 2 (R ) PhCH CH -)
which gave rise to 6 in excellent yield (entry 1) upon addition
of benzaldehyde (5). None of the (E)-isomer could be
detected by NMR analysis, indicating >95% stereochemical
purity. Alternatively and more conveniently, 6 could be
obtained under Barbier-type conditions in the same yield and
stereochemical purity by simultaneous addition of both 4 and
Table 1. Synthesis of (Z)-2-Chloroalk-2-en-1-ols
5
2
to a slurry of CrCl at room temperature. A catalytic
1
0
system, utilizing Mn powder to recycle chromium(III) to
chromium(II), proved disappointing, and only small amounts
of the desired adducts could be isolated.
Under the standard stoichiometric conditions, oxygenated
trichloroalkanes 7 and 9 behaved analogously with 5 furnish-
ing acetonide 8 (entry 2) and acetate 10 (entry 3), respec-
1
tively, as ∼7:3 diastereomeric mixtures based on H NMR
analysis. Conjugated versions of 2, derived from benzyl 11,
allyl 13, and cinnamyl 15 trichloromethyls, added smoothly
7b
7a
to benzaldehyde providing adducts 12 (entry 4), 14 (entry
), and 16 (entry 6), respectively. Notably, even the redox
5
sensitive R,â-unsaturated ester 17 could be induced to add
to 5 leading to diene 18, albeit in modest yield (entry 7).
A wide variety of aldehydes were suitable coupling
partners, inter alia, aliphatic 19 (entry 8), cinnamaldehyde
2
1
2
1 (entries 9, 10, and 11), and paraformaldehyde 25 (entry
2) which gave their respective (Z)-chloroalkenols 20, 22,
3, 24, and 26 free of regio- or geometric isomers.
Condensation of chiral carboxaldehyde 27 with the chromium
vinylidene derived from 11 (entry 13) evolved 28 in good
yield as a chromatographically separable ∼2:1 mixture of
syn/anti-isomers. This level of stereoinduction is typical of
vinylchromium additions to aldehydes bearing chiral R-het-
1
1
eroatoms.
In summary, we report a convergent, one-pot method for
the creation of (Z)-2-chloroalk-2-en-1-ols under mild condi-
tions from readily available trichloroalkanes and aldehydes.
Modifications to achieve synthetically useful chiral induction
are under active investigation.
Acknowledgment. The authors thank Dr. E. R. Fogel for
helpful discussions. Financial support was provided by the
Instituts de Recherche Pierre Fabre, CNRS (to R. B.), the
Robert A. Welch Foundation, NIH (GM 31278, DK38226),
and an unrestricted grant from Taisho Pharmaceutical Co.,
Ltd.
Supporting Information Available: Spectral data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.asc.org.
roalkanes, e.g., 4, stirring with 4 equiv of commercial CrCl
at room temperature for several hours generated the corre-
2
OL016935H
(
9) Additions to ketones were sluggish, even at 75-80 °C, and gave
low yields (10-15%) of the chloroalkenol adducts under the standard
reaction conditions.
(10) F u¨ rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349-12357.
(11) F u¨ rstner, A. Chem. ReV. 1999, 99, 991-1045.
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Org. Lett., Vol. 3, No. 26, 2001