Cr(Salen)-catalyzed addition of 1,3-dichloropropene to aromatic aldehydes. A simple access to optically active vinyl epoxides.

Article abstract of DOI:10.1021/ol015597h

[reaction: see text]. Chiral Cr(Salen) complex (1) prepared in situ from CrCl3 promotes the enantioselective addition of 1,3-dichloropropene to aromatic aldehydes in the presence of Mn as the stoichiometric reductant and Me3SiCl as a scavenger. The result

Full text of DOI:10.1021/ol015597h

ORGANIC
LETTERS
2001
Vol. 3, No. 8
1153-1155
Cr(Salen)-Catalyzed Addition of
1,3-Dichloropropene to Aromatic
Aldehydes. A Simple Access to
Optically Active Vinyl Epoxides
,†
Marco Bandini, Pier Giorgio Cozzi,* Paolo Melchiorre, Stefano Morganti, and
Achille Umani-Ronchi*
Dipartimento di Chimica “G. Ciamician”, Via Selmi 2, 40126, Bologna, Italy
umani@ciam.unibo.it
Received January 22, 2001
ABSTRACT
Chiral Cr(Salen) complex (1) prepared in situ from CrCl3 promotes the enantioselective addition of 1,3-dichloropropene to aromatic aldehydes
in the presence of Mn as the stoichiometric reductant and Me SiCl as a scavenger. The resulting 1,2-chlorohydrins obtained in good enantiomeric
3
and diastereoisomeric excesses can be easily transformed into the corresponding chiral vinyl epoxides.
Vinyl epoxides are important starting materials for the
preparation of a variety of biologically active products and
are useful intermediates for synthesis.1 Several metal-
catalyzed ring opening reactions of vinyl epoxides were
recently described.2 Optically active vinyl epoxides can also
being employed as chiral carbonyl synthons, affording
protected alcohols in high ee’s.3 Since 1,2-halohydrines are
key intermediates for the preparation of vinyl epoxides, a
direct synthesis of optically active 1,2-chlorohydrins is highly
desirable.4 Toward this goal an enantioselective boron-
mediated stoichiometric addition of chloropropene to alde-
hydes was recently reported.5
Here we describe a catalytic diastereo- and enatioselective
approach to optically active chlorohydrins based on a
stereoselective redox process.6 Recently, we have developed
the first enantioselective Nozaki-Hiyama (NH) reaction
catalyzed by Cr(Salen) complex 1 operating at room tem-
perature (Figure 1).7a This procedure appears also to be
effective in promoting the addition of prochiral allyl bromides
† E-mail: pgcozzi@ciam.unibo.it.
(1) (a) Lindstro¨m, U. M.; Olofsson, B.; Somfai, P. Tetrahedron Lett.
1999, 40, 9276-9279. (b) Solladie´-Cavallo, A.; Boue´rat, L.; Roje, M.
Tetrahedron Lett. 2000, 41, 7309-7312.
(2) Taylor, S. K. Tetrahedron 2000, 56, 1149-1163 and references
therein.
(3) Lautens, M.; Ouellet, S. G.; Raeppel, S. Angew. Chem., Int. Ed. 2000,
39, 4079-4082.
(4) R-Halohydrines are easily converted to oxyranes, see: Marshall, J.
A. Chem. ReV. 1989, 89, 1503-1511.
Figure 1.
10.1021/ol015597h CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/24/2001

Table 1
a Isolated yield after chromatography. b The anti:syn ratio was evaluated by chiral HPLC (Chiralcel-OD) and 1H and 13C NMR. c The ee’s of the products
were evaluated by chiral HPLC (Chiralcel-OD) (see Supporting Information). d The anti diastereoisomer was not separated in the HPLC analysis. e The ee
was evaluated by chiral CG (Megadex-5) analysis performed on the corresponding epoxide (see Supporting Information).
to aromatic aldehydes.7b In particular, we have observed a
peculiar and unique switch of simple diastereoselection (anti
f syn) if an excess of Salen ligand is utilized.8 As an
extension to other prochiral substrates, the commercially
available 1,3-dichloro- and 1,3-dibromopropenes were em-
ployed.
Until now, the Nozaki-Hiyama reaction with 1,3-dihalo-
propenes was rarely employed in organic synthesis, and the
few examples reported required stoichiometric amounts of
CrCl2.9 In 1-chloro-3-bromopropene, moderate yields of the
desired γ-adduct were obtained due to the formation of side
products such as the dienes (Scheme 1). Moreover, it is
On the other hand, we found that 1,3-dichloropropene10
smoothly reacted with aromatic aldehydes in the presence
of a catalytic amount of Cr(Salen) complex (Scheme 2).11
Scheme 2. Addition of 1,3-Dichloropropene to Aromatic
Aldehydes Catalyzed by Cr(Salen)
Scheme 1. Addition of 1,3-Dihalopropene to PhCHO
Our protocol uses 10 mol % of Cr(Salen) complex
prepared in situ7a by mixing CrCl212 and Salen.13 Free Salen
ligand (10 mol %) is added7b in order to ensure a good syn
simple stereoselection. Good levels of simple stereoselection
(de 40-80%) and high enantioselectivity for the syn product
(ee up to 83% with p-F-C6H4CHO) were recorded with a
number of aromatic aldehydes as reported in Table 1.14
In contrast to the previously cited boron strategy, our
protocol adopts very mild experimental conditions5 and uses
commercially available reagents.
Mediated by CrCl2
noteworthy that commercially available 1,3-dichloropropene
is not reactive under the reported conditions.9
(9) Wender, P. A.; Wisniewski Grissom J.; Hoffmann, U.; Mah, R.
Tetrahedron Lett. 1990, 46, 6605-6609.
(10) Commercially available 1,3-dichloropropene is a 55:45 diastereo-
isomeric mixture (E/Z). However, the simple diastereoselectivity of the
reaction is not affected by the diastereoisomeric ratio of the starting halide
(see ref 7b). 1,3-Dibromopropene gave only byproducts in the Cr(Salen)-
catalyzed reaction.
(11) For applications of Cr(Salen) complexes in asymmetric catalysis,
see: Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421-431.
(12) CrCl2 is obtained by reducing anhydrous CrCl3 by the excess of
Mn in the reaction flask.
(5) Hu, S.; Jayaraman, S.; Oehlschlager, A. C. J. Org. Chem. 1996, 61,
7513-7520.
(6) Fu¨rstner, A. Chem. Eur. J. 1998, 4, 567-570.
(7) (a) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi, A.
Angew. Chem., Int. Ed. 1999, 38, 3357-3359. (b) Bandini, M.; Cozzi, P.
G.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2000, 39, 2327-2330.
(8) It is worth noting that the addition of crotyl halides to aldehydes
promoted by catalytic or stoichiometric amount of Cr salts normally gives
the anti diasteroisomer in high yields, see: Fu¨rstner, A.; Shi, N. J. Am.
Chem. Soc. 1996, 118, 12349-12357.
1154
Org. Lett., Vol. 3, No. 8, 2001

The desired γ-adducts were obtained in satisfactory
chemical yields considering the formation of byproducts
derived from process (R-adducts, eliminated products) and
from side reactions connected to the redox nature of the
catalytic cycle (such as the pinacol coupling).
The γ-adducts 3a-g, purified by flash chromatography,
were analyzed by chiral HPLC (Chiralcel-OD) and fully
characterized by spectroscopic analysis (see Supporting
Information). Relative and absolute configurations of the 1,2-
chlorohydrins were established by transforming 3a in the
corresponding vinyl epoxide 5 (Scheme 3) and comparing
(1S,2S) absolute configuration of 3a, obtained with (R,R)-
Salen, was the same as obtained by the addition of other
crotyl reagents to aromatic aldehydes,7b showing the general-
ity of our methodology. Mechanistically, this redox system
appears to be quite complex since specific cooperative effects
between different Cr(Salen) molecules seem to be involved
in this enantioselective reaction. In fact, a working model
for the catalytic redox cycle implicates the synergistic action
of one molecule of [Cr(Salen)allyl] and one of [Cr(Salen)X]
in the stereodifferentiating step of the reaction mechanism.16
In conclusion we have described a simple and effective
approach toward the synthesis of optically active 1,2-syn-
chlorohydrins, key intermediates for the preparation of cis-
vinyl epoxides. Investigations concerning the stereoselective
addition of other hetero-substituted crotyl halides to carbonyl
compounds mediated by Cr(Salen) catalyst are in progress
in our laboratory.
Scheme 3. Determination of the Absolute Configuration for
the Chlorohydrin Derived from Benzaldehyde
Acknowledgment. This work was supported by
M.U.R.S.T. (Rome), National project “Stereoselezione in
sintesi organica: metodologie and applicazioni”, C.N.R, and
the University of Bologna (Funds for selected research
topics).
Supporting Information Available: Typical reaction
procedure for the Cr(Salen)-mediated reaction and analytical
data for the isolated compounds (chlorohydrins and ep-
oxides). This material is available free of charge from the
Internet at http://pubs.acs.org.
the optical rotation value ([R]D ) -89.0, c 1, CHCl3) with
the reported value.15 The stereochemistry of the chlorohydrins
3b-g was assigned by analogy. It is worth noting that the
(13) CrCl3 (0.1 mmol) was suspended in anhydrous CH3CN; then Mn
powder (3 mmol) was added. The mixture was kept at room temperature
without stirring for 5-8 min. After that, the mixture was vigorously stirred
and a green-white precipitated was formed in 10-15 min. Salen (0.2 mmol)
and anhydrous Et3N (0.2 mmol) were added. The resulting heterogeneous
mixture was stirred at room temperature during 1 h; then 1,3-dichloropropene
(1.5 mmol) was added. The mixture turned maroon-red, and the resulting
suspension was stirred during 1 h at room temperature. After that time, the
aldehyde (1 mmol) and Me3SiCl (1.5 mmol) were added. After complete
consumption of the aldehyde (checked by GC, 24-48 h), the reaction was
quenched with a saturated solution of NaHCO3 (5 mL) and filtered over
Celite. After usual workup the crude O-protected chlorohydrin was de-
silylated under acid conditions (HCl 2 N, THF, checked by TLC). Finally
the product was purified by flash chromatography.
OL015597H
(14) Other aromatic aldehydes were screened, giving the desired product
in lower yield: p-Ph-C6H4CHO (yield 12%; syn:anti 64:36; ee syn ) 58%),
p-MeS-C6H4CHO (yield 15%; syn:anti 90:10; ee syn ) 47%), o-F-C6H4-
CHO (15% yield; syn:anti 65:35; ee syn ) 72%). Aliphatic aldehydes were
found to be unreactive. R,â-Unsaturated aldehydes furnished a complex
mixture of 1,2 and 1,4 adducts.
(15) Reported value: cis-(1R,2S)-1,2-epoxy-1-phenyl-3-butene [R]D
)
+97.4 (c 2.65, EtOH): see ref 5.
(16) An acyclic transition state has been proposed on the basis of detailed
mechanistic studies, see: Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A.
Tetrahedron 2001, 57, 835-843.
Org. Lett., Vol. 3, No. 8, 2001
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