In situ generation of zinc carbenoids from diazo compounds and zinc salts: Asymmetric synthesis of 1,2,3-substituted cyclopropanes

Article abstract of DOI:10.1021/ja9074776

(Chemical Equation Presented) The first enantioselective cyclopropanation of alkenes using zinc carbenoids generated in situ from diazo compounds and zinc salts is reported. This new method allows the highly enantioand diastereoselective synthesis of 1,2,

Full text of DOI:10.1021/ja9074776

Published on Web 10/13/2009
In Situ Generation of Zinc Carbenoids from Diazo Compounds and Zinc Salts:
Asymmetric Synthesis of 1,2,3-Substituted Cyclopropanes
Se´bastien R. Goudreau and Andre´ B. Charette*
Department of Chemistry, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
Received September 3, 2009; E-mail: andre.charette@umontreal.ca
The Simmons-Smith reaction has proven to be a very
powerful tool for the synthesis of cyclopropanes.1 Since the
seminal report,2 many methods have been reported to generate
zinc carbenoids. Among them, the reaction of gem-dihaloalkanes
with diethyl zinc has proven to be the most efficient.3 However,
to the best of our knowledge, no Simmons-Smith reaction using
a catalytic amount of zinc has proven to be efficient in the
synthesis of enantioenriched cyclopropanes.1
1,2,3-Substituted cyclopropanes are naturally occurring sub-
units that not only have potential biological activity but also
are powerful intermediates in the synthesis of complex
molecules.1,4 Many approaches have been used to prepare these
compounds, notably by the cyclopropanation of alkenes1 or by
carbometalation of cyclopropenes.5 Although zinc carbenoids
have been successfully used to synthesize these cyclopropanes
in highly enantioenriched form,6-8 the preactivation of the
cyclopropane ring is generally required to introduce the desired
functionality (Scheme 1).
development of suitable conditions to generate zinc carbenoids
in situ from different precursors. We envisioned that zinc iodide
and diazo reagents could be used as carbenoid precursors and
should be compatible with enantioselective procedures (Scheme
2). Although diazo compounds occupy a vast area of research
in cyclopropanation, there are only a few reports on their use in
Simmons-Smith cyclopropanation reactions.10
Herein we report the first enantioselective cyclopropanation
of alkenes using zinc carbenoids generated in situ from diazo
compounds and a zinc salt (Scheme 2). This new method allows
the highly enantio- and diastereoselective synthesis of 1,2,3-
substituted cyclopropanes via aryl-substituted carbenoids. We
also report the first Simmons-Smith reaction using a catalytic
amount of zinc salt to generate an enantioenriched cyclopropane.
Table 1. Reaction Conditions Optimizationa
Scheme 1. Synthesis of 1,2,3-Substituted Cyclopropanes Using
Zinc Carbenoids
reagent 1
(1.0 equiv)
reagent 2
(1.0 equiv)
entry
T (°C)
convb (%)
drb
eec (%)
1d
2
3
NaH
NaH
KH
EtZnI
EtZnI
EtZnI
ZnI2
ZnI2
ZnI2
-
-20
-20
-20
-20
0
>95
5
34
52
72
78
88:12
nd
>95:5
>95:5
>95:5
>95:5
0
nd
94
95
94
93
4
5e
6
-
-
20
a Reactions were performed using 2.5 equiv of phenyldiazomethane.
b Determined by 1H NMR. c Determined by SFC analysis on chiral
stationary phase. d Performed without the ligand 3. e 1.1 equiv of 3 was
used
An alternative approach would employ substituted zinc
carbenoids, introducing the substituent and the three-membered
ring in the same step. However, to date, there is no enantiose-
lective method using aryl-substituted zinc carbenoids to directly
produce aryl-substituted cyclopropanes.9 According to literature
precedents,10e,11 and to our preliminary investigations, the
unstable aryl-substituted carbenoids have to be formed in situ
to obtain the desired cyclopropane. However the independent
preformation of carbenoids is crucial in enantioselective
Simmons-Smith cyclopropanation reactions,12,13 and this is
generally achieved by treating an organozinc reagent with a gem-
diiodoalkane in a separate reaction vessel (Scheme 2).1
We began our investigation using the allylic alcohol 1h as a
test substrate for the nonasymmetric process. Our preliminary
optimization showed that when the alcohol 1h is treated at -20
°C in CH2Cl2 with 1.0 equiv of NaH, 1.0 equiv of ZnI2, and 2.5
equiv of phenyldiazomethane, >95% conversion is obtained
(Table 1, entry 1). These conditions proved to be general for a
variety of allylic alcohols and diazo reagents (Table 2). However,
when 1.2 equiv of the chiral ligand 36b,7c,8,14 were used under
the same conditions, the conversion decreased drastically to 5%
(entry 2). To our delight, using KH to deprotonate the alcohol
afforded 34% conversion with >95:5 dr and 94% ee (entry 3),
proving the compatibility of this method with ligand 3. It is
noteworthy that preforming the carbenoid led to no product
because of its rapid degradation. After screening multiple bases
and zinc sources, we determined that using EtZnI afforded 52%
conversion with >95:5 dr and 95% ee (entry 4). Increasing the
Scheme 2. Synthesis of Aryl-Substituted Carbenoids
In addition to the low stability of aryl-carbenoids, their gem-
diiodide precursors are unstable compounds and not easily
accessible. Facing these challenging problems, we sought the
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C O M M U N I C A T I O N S
reaction temperature to 0 °C and lowering the amount of ligand
3 to 1.1 equiv provided the best compromise between the
conversions, the dr’s, and ee’s (entry 5).
reacted with good yields, good dr’s, and excellent enantiose-
lectivities (entries 8-12). The reaction tolerated primary alkyls
(entries 8,10), secondary alkyls (entry 9), and functionalized alkyl
groups (entry 11). Other aryl diazo reagents also proved to be
efficient in these conditions (entries 13-15). Good yields,
excellent enantioselectivities, and only one diastereomer were
obtained. Remarkably, in this transformation two new C-C
bonds and three contiguous strereocenters are formed.
Table 2. Scope Study
Scheme 3. Proposed Mechanism
The proposed mechanism for this reaction begins by the
deprotonation of the alcohol by EtZnI followed by the com-
plexation of the dioxaborolane ligand to the zinc alkoxide after
its addition (Scheme 3). Phenyldiazomethane reacts with the zinc
iodide salt to generate the phenyl-substituted carbenoid. This
carbenoid is then delivered selectively to one of the two faces
of the alkene by the dioxaborolane. The diastereoselectivity
observed is explained by favorable π-stacking when R1 is an
aryl and by the steric repulsion of the directing group. The latter
is consistent with the higher dr’s obtained when ligand 3 was
used (entries 8-12) as observed in our previous reports.7c,8
Interestingly, the carbenoid can react with either the alkene
or the diazo reagent, and in both cases the zinc iodide salt is
regenerated. Indeed, the entire diazo reagent (2.5 equiv) is
degraded by the zinc iodide salt (1.0 equiv), which demonstrated
its catalytic activity. Based on these observations, we investigated
the possible catalytic use of zinc salts.15 We envisaged that ZnI2
could react with phenyldiazomethane to form the carbenoid,
which would react with an allylic alkoxide to form the
cyclopropane and ZnI2. The latter could then be released to
achieve another catalytic cycle (Scheme 4). We were pleased to
note that using only 5 mol % of zinc iodide in CH2Cl2 and NaH
(1.0 equiv) allowed the cyclopropanation of cinnamyl alcohol
in good yield.16,17
a Isolated yield. b Determined by 1H NMR of the crude mixture.
c Determined by SFC analysis on chiral stationary phase. d 1.25 equiv of
phenyldiazomethane was used.
With these conditions in hand, we next investigated the scope
of the enantioselective reaction (Table 2). Performing the reaction
on cinnamyl alcohol derivatives with phenyldiazomethane led
to complete conversion and excellent ee’s, and only one
diastereomer was detected in all cases (Table 2, entries 1-7).
The reaction conditions were compatible with para or ortho
aromatic halogens resulting in excellent yields and enantiose-
lectivities (entries 1-4). Using the electron-poor 4-CF3-Ph
allylic alcohol (1e) led to 98% yield, >95:5 dr, and 99% ee.
Excellent results were also obtained with 4-Me-Ph allylic alcohol
(1f) (entry 6) and with the hindered 2,6-Me2-Ph allylic alcohol
(1g) (entry 7). Less reactive alkyl-substituted allylic alcohols
We then envisioned that these conditions could be applied in
a diastereoselective Simmons-Smith reaction. We previously
reported that the diastereoselective cyclopropanation of (3E)-
4-phenylbut-3-en-2-ol using Zn(CH2I)2 gives the corresponding
1,2-disustituted cyclopropane with 3.2:1 dr, which represents
one of the less selective substrates.18 To test the limits of our
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C O M M U N I C A T I O N S
Scheme 4. Catalytic Cycle of the ZnI2-Catalyzed Simmons-Smith
Cyclopropanation
Supporting Information Available: Experimental procedure for
the preparation of compounds and spectroscopic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
References
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system, we performed the cyclopropanation on a similar alkene.
We were pleased to find that treating allylic alcohol 5 with 5
mol % of ZnI2 and only 1.25 equiv of phenyldiazomethane
furnished the cyclopropane 6 in 95% yield, 4:1 dr (Scheme 5).
This similar level of diastereoselectivity demonstrated the
potential of the reaction for diastereoselective cyclopropanation
reactions.
(9) For leading references on enantioselective cyclopropanation by transfer of
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Fieldhouse, R. Chem. Commun. 1997, 1785–1786. (b) Aggarwal, V. K.;
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J. Chem. Soc., Perkin Trans. 1 2000, 3267–3276. (c) Aggarwal, V. K.;
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Scheme 5. ZnI2-Catalyzed Simmons-Smith Cyclopropanation
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In summary, we developed the first enantioselective cyclo-
propanation of alkenes using zinc carbenoids generated in situ
from diazo compounds and zinc salts. This new method allows
the highly enantio- and diastereoselective synthesis of 1,2,3-
substituted cyclopropanes via aryl-substituted carbenoids. The
first Simmons-Smith reaction using a catalytic amount of zinc
to generate enantioenriched cyclopropane was also reported. The
development of the catalytic enantioselective cyclopropanation
reaction will be reported in due course.
(11) Groth, U.; Scho¨llkopf, U.; Tiller, T. Liebigs Ann. Chem. 1991, 1991, 857–
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Acknowledgment. This work was supported by NSERC
(Canada), the Canada Foundation for Innovation, the Canada
Research Chair Program, and the Universite´ de Montre´al. We
also thank Jad Tannous (Universite´ de Montre´al) for SFC
separations. S.R.G. thanks NSERC (PGS D) for a postgraduate
fellowship as well as L.E. Zimmer and L.-P. Beaulieu for the
syntheses of starting materials.
(15) For seminal work on Simmons-Smith reaction using a catalytic amount
of zinc, see ref 10e.
(16) See Supporting Information.
(17) Performing the reaction with the dioxaborolane ligand 3 and a catalytic
amount of zinc led to low conversion. This is probably due to the Lewis
basic amides present in 3 that can coordinate to the zinc, thereby preventing
its release and catalytic turnovers.
(18) Charette, A. B.; Lebel, H. J. Org. Chem. 1995, 60, 2966–2967.
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