Enantioselective Cyclopropanation of Allylic Alcohols. The Effect of Zinc Iodide

Article abstract of DOI:10.1021/jo9702397

The effect of zinc iodide on the catalytic, enantioselective cyclopropanation of aliylic alcohols is examined with bis(iodomethyl)zinc as the reagent and bis-methanesulfonamide 7 as the catalyst. Significant rate enhancement was observed when 1 equiv of zinc iodide was present, but more importantly, the enantiomeric excess of the product cyclopropane increased from 80% to 89% for the substrate cinnamyl alcohol. Reaction studies and spectroscopic investigations show that this remarkable influence is the result of reagent modification via a Schlenk equilibrium that produces the more reactive and selective species (iodomethyl)zinc iodide.

Full text of DOI:10.1021/jo9702397

3390
J . Org. Chem. 1997, 62, 3390-3401
En a n tioselective Cyclop r op a n a tion of Allylic Alcoh ols. Th e Effect
of Zin c Iod id e
Scott E. Denmark* and Stephen P. O’Connor
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801
Received February 10, 1997X
The effect of zinc iodide on the catalytic, enantioselective cyclopropanation of allylic alcohols is
examined with bis(iodomethyl)zinc as the reagent and bis-methanesulfonamide 7 as the catalyst.
Significant rate enhancement was observed when 1 equiv of zinc iodide was present, but more
importantly, the enantiomeric excess of the product cyclopropane increased from 80% to 89% for
the substrate cinnamyl alcohol. Reaction studies and spectroscopic investigations show that this
remarkable influence is the result of reagent modification via a Schlenk equilibrium that produces
the more reactive and selective species (iodomethyl)zinc iodide.
In tr od u ction
In 1958, Simmons and Smith reported a simple method
for the cyclopropanation of olefins using a zinc-copper
couple and diiodomethane in refluxing diethyl ether.1
This paper was to herald an era of ready access to three-
membered carbocycles. Furukawa later found that the
zinc-copper couple could be replaced by diethylzinc,
which provided better reproducibility, greater substrate
variety, and faster reactions.2 Wittig independently
described an alternative process that uses zinc iodide and
diazomethane.3 The nature of the cyclopropanating
reagents in these reactions has been addressed but was
never clearly established.4 However, the Lewis basic
nature of the reagents was suggested by the strong
directing effects of suitably placed hydroxyl groups or
derivatives thereof.5
The obvious importance of enantiopure cyclopropanes
as end products or synthetic intermediates led to the
development of enantioselective versions of this reaction.
There are numerous auxiliary-based methods such as
the tartrate-derived acetal 1 pioneered by Yamamoto
that illustrate the high levels of diastereoselectivity that
can be obtained (Figure 1).6 The use of stoichiometric
quantities of chiral additives to modify the reagent has
also met with considerable success.7 Perhaps the best
example of this type of reaction is that described by
Charette wherein the dioxaborolane 2 is used. A third
means of effecting an enantioselective process is that of
catalysis, using substoichiometric amounts of a chiral
modifier. Unfortunately, to date, catalytic methods have
not been as selective. Both Kobayashi8 and our own
group9 have reported enantioselective cyclopropanation
procedures for allylic alcohols using bis-sulfonamides
such as 3. However, the enantiomeric excesses are in
general 10-15% lower than the auxiliary-based or sto-
F igu r e 1. Reagents for stereoselective cyclopropanation with
methylene transfer agents.
ichiometric reagent methods. A very recent addition to
the catalytic procedures currently available for enanti-
oselective cyclopropanation has been reported by
Charette.10 When 25 mol % of the TADDOL reagent 4
was used, the cyclopropanation of cinnamyl alcohol was
affected in 90% ee. However, substrate generality was
limited as seen in the cyclopropanation of prenyl alcohol,
which proceeded in only 60% ee.
(6) (a) Yamamoto, H.; Arai, I.; Mori, A. J . Am. Chem. Soc. 1985,
107, 8254. (b) Mash, E. A.; Hemperly, S. B.; Nelson, K. A.; Heidt, P.
C.; Van Deusen, S. J . Org. Chem. 1990, 55, 2045. (c) Hanessian, S.;
Andreotti, D.; Gomtsyan, A. J . Am. Chem. Soc. 1995, 117, 10393. (d)
Charette, A. B.; Turcotte, N.; Marcoux, J .-F. Tetrahedron Lett. 1994,
35, 513. (e) Tai, A.; Sugimura, T.; Yoshikawa, M.; Futagawa, T.
Tetrahedron 1990, 46, 5955. (f) Kang, J .; Lim, G. J .; Yoon, S. K.; Kim,
M. Y. J . Org. Chem. 1995, 60, 564. (g) Taguchi, T.; Morikawa, T.;
Sasaki, H.; Hanai, R.; Shibuya, A. J . Org. Chem. 1994, 59, 97. (h)
Bernabe, M.; de Frutos, M. P.; Fernandez, M. D.; Fernandez-Alvarez,
E. Tetrahedron Lett. 1991, 32, 541. (i) Imai, T.; Mineta, H.; Nishida,
S. J . Org. Chem. 1990, 55, 4986. (j) Seebach, D.; Stucky, G. Angew.
Chem., Int. Ed. Engl. 1988, 27, 1351. (k) Horton, D.; Albano, E. L.;
Lauterbach, J . H. J . Chem. Soc., Chem. Commun. 1968, 357.
(7) (a) Charette, A. B.; J uteau, H. J . Am. Chem. Soc. 1994, 116, 2651.
(b) Denmark, S. E.; Edwards, J . P. Synlett 1992, 229. (c) Fujisawa, T.;
Ukaji, Y.; Nishimura, M. Chem. Lett. 1992, 61. (d) Ukaji, Y.; Sada, K.;
Inomata, K. Chem. Lett. 1993, 1227. (e) Sawada, S.; Inouye, Y. Bull.
Chem. Soc. J pn. 1969, 42, 2669. (f) Furukawa, J .; Kawabata, N.;
Nishimura, J . Tetrahedron Lett. 1968, 3495.
X Abstract published in Advance ACS Abstracts, April 15, 1997.
(1) (a) Simmons, H. E.; Smith R. D. J . Am. Chem. Soc. 1958, 30,
5323. (b) Simmons, H. E.; Smith, R. D. J . Am. Chem. Soc. 1959, 81,
4256. (c) Simmons, H. E.; Cairns, T. L.; Vladuchick, S. A.; Hoiness, C.
M. Org. React. 1972, 20, 1.
(2) (a) Furukawa, J .; Kawabata, N.; Nishimura, J . Tetrahedron Lett.
1966, 3353. (b) Furukawa, J .; Kawabata, N.; Nishimura, J . Tetrahedron
Lett. 1968, 3495.
(3) (a) Wittig, G.; Schwarzenbach, K. Angew. Chem. 1959, 71, 652.
(b) Wittig, G.; Schwarzenbach, K. Liebigs Ann. Chem. 1961, 650, 1.
(4) (a) Simmons, H. E.; Blanchard, E. P. J . Am. Chem. Soc. 1964,
86, 1337. (b) Furukawa, J .; Nishimura, J .; Kawabata, N.; Kitayama,
M. Tetrahedron 1971, 27, 1799. (c) Wittig, G.; Wingler, F. Chem. Ber.
1964, 97, 2146.
(8) (a) Kobayashi, S.; Imai, N.; Sakamoto, K.; Takahashi, H.
Tetrahedron Lett. 1994, 35, 7045. (b) Kobayashi, S.; Takahashi, H.;
Yoshioka, M.; Ohno, M. Tetrahedron Lett. 1992, 33, 2575.
(9) (a) Denmark, S. E.; Christenson, B. L.; Coe, D. M.; O’Connor, S.
P. Tetrahedron Lett. 1995, 36, 2215. (b) Denmark, S. E.; Christenson,
B. L.; O'Connor, S. P. Tetrahedron Lett. 1995, 36, 2219.
(5) Winstein, S.; Sonnenberg, J .; DeVries, L. J . Am. Chem. Soc. 1959,
81, 6523.
(10) Charette, A. B.; Brochu, C. J . Am. Chem. Soc. 1995, 117, 11367.
S0022-3263(97)00239-9 CCC: $14.00 © 1997 American Chemical Society

Enantioselective Cyclopropanation of Allylic Alcohols
J . Org. Chem., Vol. 62, No. 10, 1997 3391
Sch em e 1
Sch em e 2
Metal carbenes also react with olefins to yield cyclo-
propanes and in the presence of chiral ligands are highly
selective and catalytic. However, the delivery of meth-
ylene (CH2) is not enantioselective with these systems
as diazo esters or diazo ketones must be used.11
Despite its widespread application as the premier
methylene transfer agent, the exact composition of the
Simmons-Smith reagent has never been unambiguously
demonstrated. Our interest in a more precise formula-
tion of reagent structure and deeper understanding of
its mechanism of action derive from the belief that such
information is crucial for the design of improved ligands
for enantioselective cyclopropanation. Our studies on the
chiral bis-sulfonamide-promoted cyclopropanation of al-
lylic alcohols have uncovered some remarkable effects of
added zinc iodide when used in conjunction with bis-
(iodomethyl)zinc. We report herein our studies, which
suggest that this is the result of reagent modification by
a Schlenk equilibrium. Both reaction studies and spec-
troscopic investigations indicate that, in the presence of
zinc iodide, bis(iodomethyl)zinc is rapidly converted to
(iodomethyl)zinc iodide. We believe that this species is
a more reactive and more selective reagent under these
reaction conditions.
allylic alcohols suggested that the complex between bis-
(iodomethyl)zinc and zinc iodide [Zn(CH2I)2‚ZnI2] was the
actual reagent. The disparity between these conclusions
reveals the difficulty in establishing reagent structure.
Sp ectr oscop ic In sigh ts. In 1984, Mitchell and Fa-
bisch15 reported a spectroscopic study on bromo analogs
of the Simmons-Smith reagent. They reported that, in
THF-d8, the treatment of zinc metal or a zinc-copper
couple with 1 equiv of dibromomethane produced a
compound that they assigned as (bromomethyl)zinc
bromide (BrCH2ZnBr). However, upon standing, two
new sets of signals appeared. Comparison of the relative
peak positions to those reported for the corresponding
mercury compounds BrCH2HgBr and Hg(CH2Br)2 led the
authors to propose that one of the new species was
Zn(CH2Br)2. It was concluded that the Schlenk equilib-
rium shown in eq 1 for the corresponding bromo analogs
lies to the left.
Related studies from these laboratories16 have also
addressed the question of the Schlenk equilibrium for
ICH2ZnI. The formation of Zn(CH2I)2 under Furukawa
conditions (1 equiv of Et2Zn + 2 equiv of CH2I2) in
acetone-d6 followed by in vacuo removal of the solvent
resulted in the formation of compounds that had lost
∼50% of the original ZnCH2I units as determined iodo-
metrically. Furthermore, if this process is carried out
in the presence of 1 equiv of the bis-ether 5 (Scheme 2),
the solid obtained after evaporation gave the correct
elemental analysis for the compound of empirical formula
5‚ICH2ZnI. However, 1H and 13C spectra of the com-
plexes both before and after removal of the volatiles
indicated a single ICH2Zn-containing entity that ap-
peared to be the same as 5‚Zn(CH2I)2. Our original
interpretation was that the ICH2ZnI formed by vacuum
treatment underwent equilibration to Zn(CH2I)2 and zinc
iodide, but the similarity of NMR signals for related
carbenoid reagents has already been noted.
In a previous paper, we reported that zinc iodide had
a beneficial effect on the rate and enantioselectivity of
the bis-sulfonamide-catalyzed cyclopropanation of allylic
alcohols with Zn(CH2I)2.9b In light of the studies men-
tioned above, the potential effect of zinc iodide on a
Schlenk process under these reaction conditions was
obvious. We were intrigued by the opportunity to use a
combination of rate and selectivity data together with
additional spectroscopic studies to elucidate the role of
zinc iodide. We describe herein the results of that
investigation in full and provide evidence that the actual
cyclopropanating agent under these conditions is indeed
ICH2ZnI.
Ba ck gr ou n d
Ch em ica l In sigh ts. In 1929, Emschwiller12 first
reported the reaction of a zinc-copper couple with
diiodomethane. The organozinc species formed by heat-
ing these reagents in Et2O decomposed slowly at room
temperature over several days with the concomitant
evolution of ethylene, presumably the result of a coupling
process. In addition, it was observed that methyl iodide
was liberated upon hydrolysis while diiodomethane was
regenerated by the addition of iodine (Scheme 1). These
observations led Emschwiller to propose that (iodometh-
yl)zinc iodide had been formed.
In their landmark studies, Simmons and Blanchard4a
examined cyclopropanation of olefins with Zn-Cu/CH2I2
in the presence of alcohols and have interpreted the
results in terms of a Schlenk equilibrium (eq 1). In the
Zn(CH2I)2 + ZnI2 h 2 ICH2ZnI
(1)
Schlenk process, (iodomethyl)zinc iodide (ICH2ZnI) dis-
proportionates to bis(iodomethyl)zinc (Zn(CH2I)2) and
zinc iodide. Dauben and Berezin have addressed this
question as well but arrived at a conclusion supporting
(iodomethyl)zinc iodide as the reagent.13 In similar
studies, Rickborn and Chan14 have examined cyclopro-
panation of cis- and trans-5-methyl-2-cyclohexenols under
the conditions of Simmons and Smith. The relative rates
for the cyclopropanation of the two diastereomeric, cyclic
(11) (a) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M.
J . Am. Chem. Soc. 1991, 113, 726. (b) Pfaltz, A. Acc. Chem. Res. 1993,
26 , 339. (c) Masamune, S.; Lowenthal, R. E.; Akibo, A. Tetrahedron
Lett. 1990, 31, 6005. (d) Doyle, M. P.; Duatkin, A. B.; Protopopova, M.
N.; Yang, C. I.; Miertschin, C. S. Winchester, W. R.; Simonsen, S. H.;
Lynch, V.; Ghosh, R. Recl. Trav. Chim. Pays-Bas 1995, 114, 163.
(12) Emschwiller, G. C. R. Acad. Sci. Paris 1929, 188, 1555.
(15) Mitchell, T. N.; Fabisch, B. J . Organomet. Chem. 1984, 269,
219.
(16) (a) Denmark, S. E.; Edwards, J . P.; Wilson, S. R. J . Am. Chem.
Soc 1991, 113, 723. (b) Denmark, S. E.; Edwards, J . P. J . Org. Chem
1991, 56, 6974. (c) Denmark, S. E.; Edwards, J . P.; Wilson, S. R. J .
Am. Chem. Soc. 1992, 114, 2592.
(13) Dauben, W. G.; Berezin, G. H. J . Am. Chem. Soc. 1963, 85, 468.
(14) Rickborn, B.; Chan, J . H.-H. J . Am. Chem. Soc. 1968, 90, 6406.

3392 J . Org. Chem., Vol. 62, No. 10, 1997
Denmark and O’Connor
Sch em e 3
While this paper was in preparation, Charette and
Marcoux reported the results of a similar study on the
existence and position of the Schlenk equilibrium in eq
1.17 Reaction studies on the chiral, racemic compound
4-phenyl-3-butenol and also on a chiral, nonracemic allyl
ether of a glucose-derived auxiliary were carried out.
These investigations showed that reagent stoichiometries
were critical in obtaining the highest diastereomeric
excesses. The combination of equimolar amounts of
diethylzinc and diiodomethane provided the highest
diastereomeric excesses, suggesting that EtZnCH2I was
the most selective reagent. Reagent combinations that
should provide Zn(CH2I)2 and ICH2ZnI led to succes-
sively lower de’s. Utilizing the same bis-ether 5 that
was used in our own work (vide infra), VT NMR studies
verified the presence of these compounds using the
appropriate reagent combinations. Unfortunately, the
species EtZnCH2I, the putatively more selective reagent,
was revealed by NMR to coexist with substantial amounts
of the Zn(CH2I)2 and Et2Zn complexes, presumably the
result of another Schlenk equilibrium (eq 2).
F igu r e 2. Yield and enantiomeric excess as a function of
conversion without ZnI2.
5‚EtZnCH2I h 1/2 [5‚Zn(CH2I)2 + 5‚Et2Zn] (2)
Of more relevance to this report, the authors showed
spectroscopically that the complex of 5 with bis(iodo-
methyl)zinc undergoes reaction with the corresponding
zinc iodide complex to yield the iodomethylzinc iodide
complex 5‚ICH2ZnI (eq 3).18
F igu r e 3. Yield and enantiomeric excess as a function of
conversion with ZnI2.
induction period, followed by a rapid appearance of the
product 8. This behavior was exhibited at various
temperatures with and without chiral catalysts. We
surmised that this profile resulted from the slow forma-
tion of an active cyclopropanating species different from
bis(iodomethyl)zinc. Once the reaction begins, a byprod-
uct caused the formation of a more active cyclopropana-
ting reagent leading to faster reaction. Thus, an auto-
catalytic process (with characteristic sigmoidal kinetics)
was postulated. The only necessary byproduct of the
cyclopropanation is zinc iodide (eq 4), and in our previous
1/2 [5‚Zn(CH2I)2 + 5‚ZnI2] h 5‚ICH2ZnI
(3)
Although the reactions investigated therein were dia-
stereoselective cyclopropanations as opposed to the cata-
lytic, enantioselective ones described here, the conclu-
sions concerning reagent composition and the Schlenk
equilibria are in agreement with our results. While the
reagent ICH2ZnI was the least selective for the diaste-
reoselective cyclopropanations examined, we have found
it to be far superior to Zn(CH2I)2 in catalytic, enantiose-
lective cyclopropanations of allylic alcohols using chiral
bis-sulfonamides as the promoters. The ability of zinc
iodide to promote the formation of this reagent from bis-
(iodomethyl)zinc is examined in this report using both
reaction selectivities and spectroscopy studies.
olefin + 1/2 Zn(CH2I)2 f cyclopropane + 1/2 ZnI2
(4)
paper we noted the significant rate-enhancing effects of
this salt if it is present at the beginning of the reaction.
Indeed, the kinetic profile of an identical cyclopropana-
tion of cinnamyl alcohol in the presence of zinc iodide
(Figure 3, solid line) shows no induction period and a
rapid appearance of product.
Additional evidence in support of the hypothesis of an
autocatalytic process was forthcoming for the conversion-
dependent enantioselectivity of the reaction. The dashed
lines in Figures 2 and 3 depict the enantiomeric composi-
tion of the product as a function of reaction conversion.
In the absence of zinc iodide, the enantiomeric excess of
the product changes over the time course of the reaction
from 46 to 76% ee. However, in the presence of zinc
iodide, the enantiomeric excess is high (81-86%) and
constant throughout the reaction time span.
Resu lts
Zin c Iod id e a n d En a n tioselective Cyclop r op a n a -
tion . In the course of our studies on the optimization of
the catalytic, enantioselective cyclopropanation of cin-
namyl alcohol with bis(iodomethyl)zinc and 79 (Scheme
3), we noted an unusual kinetic profile (Figure 2, solid
line). Specifically, the reaction displayed a marked
(17) Charette, A. B.; Marcoux, J .-F. J . Am. Chem. Soc. 1996, 118,
4539.
(18) Charette has recently described the solid-state structure of
ICH2ZnI as complex with 18-crown-6: Charette, A. B.; Marcoux, J .-
F.; Be´langer-Garie´py, F. J . Am. Chem. Soc. 1996, 118, 6792.

Enantioselective Cyclopropanation of Allylic Alcohols
J . Org. Chem., Vol. 62, No. 10, 1997 3393
Sch em e 4
Ta ble 1. Cyclop r op a n a tion of Cin n a m yl Alcoh ol Usin g
Va r iou s Ad d itives
entry
additivea
t1/2,b min
ee (8),c %
1
2
3
4
5
6
7
8
9
10
11
12
13
8
<3
<3
4
80
86
80
76
72
45
83
75
23
72
32
39
d
ZnI2
ZnBr2
ZnCl2
ZnF2
Zn(OAc)2
CdCl2
CdI2
MgI2
PbI2
MnI2
HgI2
10
10
11
11
50e
8
F igu r e 4. Dependence of rate and enantioselectivity of
cyclopropanation of cinnamyl alcohol on loading of catalyst 7
(10 mol % zinc iodide added).
12e
15
d
GaI3
a
b
1.0 equiv. Estimated half-lives from GC analysis of reaction
progress. c Determined by chiral HPLC. Decomposition of start-
d
ing material. e Reaction faster than without 7.
experiments, we chose to establish if this behavior is
unique to zinc iodide or if it is general for other metal
salts. To do so, we developed a set of reaction conditions
that have been found to give good, reproducible results
(Scheme 4).19 First, as noted before, it was necessary to
form the ethylzinc alkoxide of the substrate allylic
alcohols prior to reaction to obtain high selectivities.9
Furthermore, contrary to our previously reported conclu-
sions, the formation of the zinc complex of promoter 7
was important for high enantioselectivities. The protocol
shown in Scheme 4 was used to survey other metal salts
in the cyclopropanation reaction. A number of such
additives were selected, and reactions were run using 1
equiv of the anhydrous solids in each case, Table 1.
Rates and enantiomeric excesses were measured both
with (10 mol %) and without promoter 7. Shown in Table
F igu r e 5. Zinc-containing species in the reaction mixture.
Another perplexing facet of the asymmetric cyclopro-
panations provides additional indirect evidence that zinc
iodide is somehow incorporated into the catalytic com-
plex. As part of the overall optimization, we examined
the effect of catalyst loading on the rate and enantiose-
lectivity of the cyclopropanation. This provided the
astonishing results that are combined in Figure 4 (10 mol
% zinc iodide added; see Scheme 3, n ) 0.1). First, we
discovered that the rate of reaction was inversely related
to the loading of the catalyst 7! With 1-5 mol % of 7,
we observed no induction period, and with 50-100 mol
% of 7, the reactions were actually slower than in the
absence of the catalyst. Even more striking was the
dependence of enantioselectivity on catalyst loading,
which also decreased steadily beyond the 10% loading.
We surmised that the zinc complex Zn(7-2H) (see Figure
5) was acting as a zinc iodide scavenger preventing the
salt from generating whatever active species is actually
responsible for the enantioselective cyclopropanation.
This hypothesis was supported by an experiment identi-
cal to that with 25 mol % of 7 but with 1.25 equiv of zinc
iodide added as well. The reaction rate and selectivity
were restored (no induction period, 78% ee). Taken
together, these three studies provide strong evidence that
zinc iodide is necessary for the formation of the catalyti-
cally active species.
1 are the times to 50% conversion (t
1/2) and enantiomeric
excesses where cinnamyl alcohol was the model sub-
strate. The results shown are for those reactions run in
the presence of 7. Duplicate reactions were also run with
each metal salt but in the absence of promoter, and in
all cases except for magnesium iodide and manganese
iodide (Table 1, entries 9 and 11, respectively) the
promoted reactions were faster. Only zinc bromide and
cadmium chloride (Table 1, entries 3 and 7, respectively)
provided enantiomeric excesses equal to or greater than
that which was obtained in the absence of an additive
(Table 1, entry 1). However, zinc iodide was unique in
providing not only the best selectivity but also a very high
reaction rate (t1/2 ) <3 min). Our attention was therefore
focused on zinc iodide as the ideal additive.
Su r vey of Met a l Ha lid es. Clearly, understanding
the origin of the remarkable zinc iodide effect is critical
for an accurate mechanistic picture of this process.
However, before embarking on more detailed mechanistic
(19) Denmark, S. E.; O’Connor, S. P. J . Org. Chem. 1997, 62, 584.

3394 J . Org. Chem., Vol. 62, No. 10, 1997
Denmark and O’Connor
Sch em e 6
Sch em e 5
tion is not favorable. At this stage of our investigation
we chose to concentrate on the role of zinc iodide in
reagent composition.
The combination of zinc iodide with bis(iodomethyl)-
zinc represents the Schlenk equilibrium of eq 1. If this
process does occur, (iodomethyl)zinc iodide would be
formed, which could serve as the active cyclopropanation
reagent. Our approach to the question of reagent com-
position has been two-fold involving both reagent studies
and spectroscopic investigations.
In situ Gen er a tion of Zin c Iod id e. Having dem-
onstrated the critical role played by zinc iodide, we
became concerned about reproducibility due to the hy-
groscopic nature of this salt and the extreme moisture
sensitivity of organozinc reagents. Indeed, repeated use
of zinc iodide from the same container led to progressively
lower enantiomeric excesses in the cyclopropanation of
cinnamyl alcohol, eventually approaching 70% ee. Fur-
thermore, a control experiment in which 1 equiv of water
was added to the reaction mixture led to a slow reaction
in which the product was obtained in only 31% ee.
A possible solution to this problem is to generate zinc
iodide in situ from nonhygroscopic reagents. The route
envisioned involved the addition of 1 equiv of diethylzinc
to a suspension of 2 equiv of iodine in dichloromethane
(eq 5). A three-flask protocol was developed to incorpo-
Rea gen t Stu d ies. To address the question of reagent
composition, specifically Zn(CH2I)2 vs ICH2ZnI, we chose
to independently generate (iodomethyl)zinc iodide by four
distinct reactions and use it under our standard condi-
tions for the cyclopropanation of cinnamyl alcohol in the
presence of promoter 7. Shown in Scheme 6 are the four
proposed routes to make (iodomethyl)zinc iodide. Route
1 is the Schlenk process in question. Routes 2 and 3 are
simple permutations of the same conceptual approach
that is founded on the lability of the zinc-carbon bonds
in diethylzinc. The addition of 1 equiv of iodine to
diethylzinc followed by the addition of 1 equiv of di-
iodomethane should yield the desired product (iodo-
methyl)zinc iodide by the sequential replacement of the
reactive ethyl groups (route 2). Likewise, reversal of
reagent addition order, namely 1 equiv of diiodomethane
first and then 1 equiv of iodine to diethylzinc, should also
give (iodomethyl)zinc iodide (route 3). A fourth route was
envisioned whereby bis(iodomethyl)zinc, generated from
2 equiv of diiodomethane and 1 equiv of diethylzinc,
undergoes iodinolysis with 1 equiv of iodine to yield
(iodomethyl)zinc iodide.22
Since the proposed Schlenk equilibrium of eq 1 and
route 1 would give 2 equiv of (iodomethyl)zinc iodide, the
stoichiometries for routes 2-4 were adjusted accordingly;
i.e., reagents were used such that 2 equiv of ICH2ZnI
would be produced in each case. The reagent mixtures
were all heterogeneous, containing either white precipi-
tate or a slurry of purple hue indicating residual iodine.
We note this to illustrate the difficulty of performing
spectroscopic investigations of such compounds (vide
infra). Our standard procedure for the individual steps
of each route was to wait 5 min at 0 °C after the addition
of each reagent before continuing with the sequence. The
four reagents were used under a standard set of reaction
conditions similar to that shown in Scheme 4 for the
promoted cyclopropanation of cinnamyl alcohol. How-
ever, for routes 2-4 the reactions taking place in the B
and C flasks are carried out in one flask (B) to generate
the reagent (iodomethyl)zinc iodide as shown in Scheme
7. The progress of the reactions was monitored by GC
and the enantiomeric excess of the cyclopropanes was
established after workup by chiral HPLC. The results
are shown in Figure 6.
Et2Zn + 2 I2 f ZnI2 + 2 EtI
(5)
rate this modification (Scheme 5). The allylic alcohol and
promoter 7 (0.1 equiv) were treated with 1.1 equiv of
diethylzinc in flask A, zinc iodide was generated in flask
B, and bis(iodomethyl)zinc was prepared in flask C. The
contents of flask A were added to flask B, and this
mixture then transferred to flask C. As a further
improvement, we chose to distill the diethylzinc prior to
use.20 The benefits became apparent when the cyclopro-
panation of cinnamyl alcohol using this new procedure
gave the product reproducibly in 89% enantiomeric
excess. These results should be contrasted to those
obtained when 1 equiv of solid zinc iodide was used,
where the selectivities ranged from 86% ee at best down
to a low of 70% ee.21
Zin c Iod id e a n d th e Sch len k Equ ilibr iu m . In a
multicomponent system such as that shown in Scheme
4, there is a multitude of interactions possible for zinc
iodide. Zinc iodide could influence any or all of the three
main components of the reaction, which not coinciden-
tally are all present as zinc-containing species. As shown
in Figure 5, these are the substrate (ethylzinc alkoxide),
the catalyst (zinc-sulfonamide complex), and the reagent
(bis(iodomethyl)zinc). The interaction of zinc iodide with
the oligomeric ethylzinc alkoxide could form a mixed
aggregate that is highly reactive. In addition, we cannot
rule out an interaction of zinc iodide with the zinc
promoter, although the inverse dependence of rate and
selectivity on catalyst loading suggest that this interac-
(20) While neat diethylzinc is a highly pyrophoric liquid, the in vacuo
distillation of 5 mL quantities was uneventful. From the slightly yellow
commercial material was obtained a clear and colorless distillate that
was superior by 1H-NMR analysis.
(21) It should also be noted that while we have been able to
regenerate the “dry” solid ZnI2 by slow sublimation at 200 °C/0.1 mm
(as shown by the 86% ee obtained when using this material), the use
of Et2Zn and I2 to generate ZnI2 in situ avoids this tedious procedure.
(22) A fifth route was attempted following the method of Wittig3
(diazomethane and zinc iodide) but proved impractical due to the
difficulty of obtaining dry diazomethane.

Enantioselective Cyclopropanation of Allylic Alcohols
J . Org. Chem., Vol. 62, No. 10, 1997 3395
Sch em e 7
F igu r e 7. Diagnostic 13C resonances for 5 and its complexes
6 and 9-12 (CDCl3, 0.6 M, -70 °C).
perature NMR studies allowed us to reduce the equili-
bration of the bound and unbound zinc-ether complexes
such that the two diastereotopic zinc-bound methylenes
could be observed as separate signals in the 13C spectrum
at -70 °C while still maintaining complete solubility even
at 0.6 M. We thus undertook the spectroscopic examina-
F igu r e 6. Rate and selectivity data for the four routes to
(iodomethyl)zinc iodide.
The reactions with reagents formed using route 1 (the
Schlenk process) and route 2 had essentially the same
rates and gave the product 8 in the same enantiomeric
excess (86% ee). This suggests that the same species
must be formed by these two procedures and that the
Schlenk equilibrium lies on the side of (iodomethyl)zinc
iodide (eq 1). However, the reagents from routes 3 and
4 were both slower and less selective (73% and 23% ee,
respectively). Since our initial assumption was that
routes 2-4 should all give (iodomethyl)zinc iodide, the
discrepancy in the reaction results necessitated investi-
gations of the actual species formed under each set of
conditions. This was addressed by the spectroscopic
studies described below. Not only should this support
our contention that zinc iodide and bis(iodomethyl)zinc
react to form (iodomethyl)zinc iodide by showing that the
species formed with routes 1 and 2 are the same, but it
should also provide insights into reasons for the lower
reaction rates and selectivities observed with routes 3
and 4.
Sp ectr oscop y Stu d ies. The insolubility as well as
instability of the zinc-containing compounds of interest
in CDCl3 necessitated the use of solubilizing and stabiliz-
ing agents. It had previously been shown that some of
the organozinc species under investigation were solubi-
lized and stabilized in benzene-d6 and acetone-d6 when
ether-type ligands were present.16 Unfortunately, for the
purposes at hand, neither dimethoxyethane, THF, nor
diethyl ether provided sufficient solubilization in either
CHCl3 or CH2Cl2. However, these same studies revealed
that equimolar amounts of the bis-methyl ether 5 allowed
significant solubilization (0.8-1.0 M) of bis(iodomethyl)-
zinc at room temperature in benzene-d6.16 We were
gratified to discover that this compound solubilized bis-
(iodomethyl)zinc in CDCl3 at a concentration adequate
for our purposes (0.6 M). Furthermore, variable-tem-
1
tion of the processes shown in Scheme 6 by both H and
13C NMR using 1 equiv of 5 per zinc. Our goal was to
establish what species were formed with each route and
to determine the reasons for the differences in rates and
selectivities.
The 1H NMR spectra were found to be useful for
determining the extent of some of the reactions examined.
However, the broadness of the peaks at low temperatures
as well as the presence of many overlapping signals made
interpretation difficult. The 13C NMR spectra were much
more informative. Thus, analysis of each of the compo-
nents formed using the four routes shown in Scheme 6
was carried out in CDCl3 at -70 °C in the presence of 5
(1.0 equiv).
Some of the diagnostic 13C resonances for the various
compounds of interest when complexed with 5 are col-
lected in Figure 7. The peaks for the bornane carbons
did not vary by much more than 1-2 ppm for all of the
compounds examined. The signals for the carbons at-
tached to zinc were more diagnostic as shown by the wide
range of chemical shifts. Once each of the complexes for
starting materials (Et2Zn, ZnI2) and intermediates
(EtZnI, EtZnCH2I, Zn(CH2I)2) were assigned and estab-
lished to be distinguishable, we felt that the complexes
of the reagents formed by each of the four routes in
Scheme 6 would then be examined.
The spectra for the first intermediates in each of the
four routes revealed important information. For routes
1 and 4 the clean and quantitative formation of complex
6 was observed as had been previously reported.16
However, it was also clear that the expected products
from routes 2 and 3 were not being formed exclusively.
1
The H and 13C NMR spectra for the expected complexes
of EtZnI (10) and EtZnCH2I (11) contained multiple sets

3396 J . Org. Chem., Vol. 62, No. 10, 1997
Denmark and O’Connor
F igu r e 9. Complex 13 (5‚ICH2ZnI).
F igu r e 8. Partial 13C-spectra for the four routes to (iodo-
methyl)zinc iodide and of bis(iodomethyl)zinc as complexes
with 5 in CDCl3 at -70 °C.
of resonances. For 10, it was conceivable that the Zn-
epimeric complexes of EtZnI with 5 were not intercon-
verting at the temperature of acquisition (-70 °C). While
the spectrum indicated that the two diastereomeric EtZnI
complexes were the major species present, minor species
were also detected.
For 11, the situation was not as easily explained.
Examination of the 1H and 13C spectra indicated the
presence of both the diethylzinc complex 9 and the bis-
(iodomethyl)zinc complex 6, in addition to the signals that
have tentatively been assigned to 11. The overall
transformation for the first step of route 3 therefore
appeared to be as follows (stoichiometries of products not
indicated):
F igu r e 10. Variable temperature studies of 6 (5‚Zn(CH2I)2)
and 13 (5‚ICH2ZnI) in CDCl3.
of approximately equal intensity at approximately -14.9
ppm and approximately -17.1 ppm. Clearly, a new and
unique species was formed from each of the four routes.
We suspected this new species was 13, the complex of 5
and (iodomethyl)zinc iodide, and that the two signals
were due to the Zn-epimeric complexes (Figure 9). In
support of this hypothesis, we demonstrated that the
signals corresponded to two species in equilibrium. By
raising the temperature to 0 °C and then recooling to -70
°C the two peaks at -17.2 and -19.6 ppm coalesced and
then reappeared (Figure 10). Likewise, the coalescence
of the bis(iodomethyl)zinc complex was observed, albeit
at a lower temperature (approximately -45 °C), as one
might expect for a less Lewis acidic species. Why one
diastereomer should so heavily predominate was not
obvious, and no attempt to assign the individual isomers
was made.
Full examination of the spectra for the end products
of each route provided further insights. The use of route
1 (the Schlenk equilibrium) and route 2 provided the
cleanest spectra with near-quantitative formation of the
new species, which we have assigned as 13 (Figure 9).
This supported our contention that the addition of zinc
iodide to bis(iodomethyl)zinc leads to (iodomethyl)zinc
iodide via a Schlenk process. While we were initially
concerned with additional peaks in the spectrum for the
first step of route 2, this was simply due to the presence
of both diastereomeric complexes. Thus, we have sup-
ported the notion that the effect of zinc iodide on the
enantioselective cyclopropanation of allylic alcohols was
one of reagent modification.
Et2Zn + CH2I2 f EtZnCH2I + Zn(CH2I)2 + Et2Zn
(6)
This was obviously not the intended outcome, namely
the unique formation of EtZnCH2I as indicated by a clean
spectrum of 11. It was apparent that the addition of 1
equiv of iodine, the second step of route 3, to this reagent
mixture would not yield the complex between (iodo-
methyl)zinc iodide and 5 as the exclusive product. The
reason for the lower reaction rate and selectivity (73%
ee) with route 3 was likely a manifestation of incomplete
reagent formation and inhomogeneity.
Spectroscopic analysis of the end product from each of
the four routes provided a wealth of information. We first
analyzed the diagnostic region of the 13C spectrum where
the ZnCH2I signals appeared. Shown in Figure 8 are the
13C spectra (-5 to -25 ppm) for the compounds made by
each of the four routes to (iodomethyl)zinc iodide (the
spectrum of the bis(iodomethyl)zinc complex (6) is shown
for comparison). All four routes appeared to give the
same species. Two signals were visible in all of the
spectra: a small peak at approximately -17.2 ppm and
a larger one at approximately -19.6 ppm. These were
different from those for 6, which displayed resonances
The spectra for the reagent formed using route 3 were
much more complicated. As described above, the mixture
from the first step of route 3 contained EtZnCH2I along
with diethylzinc and bis(iodomethyl)zinc. When reacted
with 1 equiv of iodine (per zinc) in the second step it also

Enantioselective Cyclopropanation of Allylic Alcohols
J . Org. Chem., Vol. 62, No. 10, 1997 3397
yielded a number of species. Two major complexes were
evident, and we have assigned these as the desired
(iodomethyl)zinc iodide complex 13 and, tentatively, the
zinc iodide complex 12. Surprisingly, there were no
signals for ethylzinc species in the 1H NMR spectrum and
no evidence in the 13C spectrum for any residual bis-
(iodomethyl)zinc.
In route 4, the addition of 1 equiv of iodine to bis-
(iodomethyl)zinc clearly produced (iodomethyl)zinc iodide
as shown in Figure 8. However, there appeared to be at
least one other major zinc-containing complex present as
evidenced by a second set of 13C signals as well as
multiple resonances in the 1H spectrum. We have
tentatively assigned these additional peaks to the zinc
iodide complex 12.
-70 °C but the half-life was on the order of 30-40 min.
Thus, while the Schlenk equilibration of 6 and 12 to give
13 does occur at -70 °C, it is slow enough that it might
be possible to assess what effect the bis-ether 5 has on
this process.
Despite the technical difficulties we nonetheless made
an attempt to determine if the Schlenk equilibrium could
be established in the absence of 5. Thus, suspensions of
bis(iodomethyl)zinc and zinc iodide were prepared at 0
°C in CDCl3 (0.6 M). They were then combined and
maintained for 5 min at 0 °C following which the white
slurry was cooled to -70 °C. Two equivalents of the bis-
ether 5 (1 equiv for each zinc equiv) was then added.
Unfortunately, only minimal solubilization occurred at
this reduced temperature as large amounts of precipitate
still remained. An acquisition time of 60 min was
required to obtain 13C spectra with a signal-to-noise ratio
of only ∼3:1. As observed above, this was sufficient time
for the Schlenk equilibrium to have occurred by at least
50% at this temperature (t1/2 ) ∼30-40 min). Between
-10 and -25 ppm in the 13C spectrum, a single peak at
approximately -19 ppm was discernible above the noise,
indicative of the presence of 13. The time required for
data acquisition as well as the poor signal-to-noise ratio
make interpretation of this result very questionable.
However, it does suggest that even in the absence of 5,
the Schlenk process of eq 1 lies on the side of (iodometh-
yl)zinc iodide.
Our initial hypothesis for the poor selectivity observed
with route 4 (23% ee) related to diiodomethane, the
byproduct, which should be formed upon iodinolysis of
Zn(CH2I)2. It could conceivably convert the ethylzinc
alkoxide of cinnamyl alcohol (EtZnOR) into the corre-
sponding (iodomethyl)zinc alkoxide (ICH2ZnOR).23 How-
ever, subsequent spectroscopic investigations revealed
that metathesis of the ethylzinc alkoxide with di-
iodomethane to yield the (iodomethyl)zinc alkoxide does
not occur. The addition of 1 equiv of CH2I2 to the
preformed ethylzinc alkoxide of cinnamyl alcohol in
1
CDCl3 at room temperature showed no change in the H
NMR spectrum after 20 min. This result as well as the
spectroscopic studies for route 4 described above suggests
that the reason for poor selectivity with this procedure
is the production of byproduct(s) that interfere with the
reaction between bis(iodomethyl)zinc and iodine.
The spectroscopic studies for routes 1 and 2 clearly
showed that the Schlenk equilibrium lies on the side of
(iodomethyl)zinc iodide. However, all of the NMR inves-
tigations on reagent composition described above were
conducted using equimolar amounts of 5. We were very
cognizant of the influence of ligands and solvents on
Schlenk equilibria,24 and attempts were made to assess
if the bis-ether 5 was responsible for shifting the equi-
librium of eq 1 in favor of (iodomethyl)zinc iodide over
bis(iodomethyl)zinc and zinc iodide.
Solutions of complexes 6 (5‚Zn(CH2I)2) and 12 (5‚ZnI2)
were prepared separately in CDCl3, cooled to -70 °C, and
then combined. At -70 °C, spectra were acquired at 15,
45, and 150 min after mixing (see the Supporting
Information). The two peaks in the 13C spectrum for 6
(at -14.9 and -17.1 ppm) were slowly replaced by those
assigned to 13, the (iodomethyl)zinc iodide complex (at
-17.2 and -19.6 ppm). The immediate appearance of
complex 13 showed that equilibration occurred even at
Discu ssion
Rea ction Stu d ies w ith Zin c Iod id e a n d Oth er
Meta l Sa lts. The graphs in Figures 2-4 clearly estab-
lish that zinc iodide improves the enantiomeric excess
for the cyclopropanation of allylic alcohols by making the
process highly selective throughout the entire course of
the reaction. Thus, while zinc iodide accelerates the
reaction for the promoted and unpromoted events, the
enantiomeric excess is increased not by making the
promoted reaction faster but by making it consistently
more selective.
The presence of a substantial background reaction,
which occurs in the absence of promoter, has been a
limiting factor in improving the enantiomeric excesses
under these conditions. As mentioned above, the rate
acceleration observed upon the addition of 1 equiv of zinc
iodide manifests itself in the presence of promoter 7 but
unfortunately also in its absence. Obviously, if the
difference in rate between the promoted and unpromoted
reactions can be increased, the reaction should become
more selective.
Indeed, the effect of zinc iodide on the enantioselective
pathway is dramatic. With as little as 1 mol % of 7, the
product cyclopropane 8 is obtained quantitatively in less
than 30 min with 50% ee. Raising the amount of 7 slows
down the reaction and decreases the enantioselectivity
by sequestering the zinc iodide produced throughout the
reaction. Without zinc iodide available, the formation
of (iodomethyl)zinc iodide from bis(iodomethyl)zinc is a
much slower process. Clearly, the zinc species added at
the outset of the reaction are not uniquely responsible
for the high rates and enantioselectivities observed.
The results in Table 1 show clearly the benefits of the
use of zinc iodide over the other metal salts examined.
Both rate and enantiomeric excess were optimal with zinc
iodide. Each of the additives in Table 1 may enter into
a Schlenk equilibrium process with bis(iodomethyl)zinc
(23) Independent generation of the iodomethylzinc alkoxide of
cinnamyl alcohol followed by cyclopropanation under standard condi-
tions using 10 mol % of 7 led to 8 in a very unselective manner (2%
ee). This suggested that the reason route 4 was so poorly selective
resulted from the formation of diiodomethane and that this compound
reacted with the ethylzinc alkoxide of cinnamyl alcohol to form the
(iodomethyl)zinc alkoxide.
(24) For the Schlenk equilibrium between Et2Zn + ZnI2 and EtZnI,
in the presence of coordinating solvents such as THF or ether the
following references support EtZnI as the more stable species: (a)
Abraham, M. H.; Rolfe, P. H. J . Chem. Soc., Chem. Commun. 1965,
325. (b) Evans, D. F.; Wharf, I. J . Organomet. Chem. 1966, 5, 108. (c)
Evans, D. F.; Wharf, I. J . Chem. Soc. A 1968, 783. (d) Abraham, M.
H.; Rolfe, P. H. J . Organomet. Chem 1967, 7, 35. (e) Evans, D. F.;
Fazakerley, G. V. J . Chem. Soc. A 1971, 182. In the absence of
coordinating solvents, the following references suggest that the equi-
librium favors Et2Zn + ZnI2: (f) Boersma, J .; Noltes, J . G. J .
Organomet. Chem. 1967, 8, 551. (g) Boermsa, J .; Noltes, J . G.
Tetrahedron Lett. 1966, 1521. (h) Evans, D. F.; Maher, J . P. J . Chem.
Soc. 1962, 5125.

3398 J . Org. Chem., Vol. 62, No. 10, 1997
Denmark and O’Connor
Sch em e 8
that the presence of a halogen, whether iodine, bromine,
or chlorine, on the zinc atom, when coupled with the
internally activated ICH2Zn unit, is responsible for the
faster reactions compared to Zn(CH2I)2.
We propose that the first three additives, ZnI2, ZnBr2,
and ZnCl2, increase reaction rates by forming highly
reactive cyclopropanating reagents ICH2ZnX (X ) I, Br,
Cl). However, in the presence of 10 mol % of chiral
sulfonamide 7, the different reagents afford the product
cyclopropane with different enantiomeric excesses of
(Table 1): ZnI2 (86% ee), ZnBr2 (80% ee), ZnCl2 (76% ee).
It is obvious that the reagents become less sensitive to
the influence of the chiral promoter 7 in the order I > Br
> Cl. Thus, while the proposed reagents ICH2ZnI, ICH2-
ZnBr, and ICH2ZnCl all contain the (iodomethyl)zinc
unit, the nature of the halogen attached directly to the
zinc atom is obviously critical for an effective interaction
with the promoter. Since the promoter is present as the
zinc derivative (formed by prior treatment with 1 equiv
of diethylzinc), it is reasonable to propose that X in ICH2-
ZnX coordinates to the zinc of the promoter complex. The
ability of the atom X to do this must decrease in the
direction I > Br > Cl. The larger size, longer zinc-iodine
bond lengths, and increased polarizability of iodine
relative to bromine and chlorine are factors that may
contribute to this phenomenon. As Simmons and Smith
showed that iodine is the best X group of I-, Br-, and
Cl- in XCH2Zn for cyclopropanation, we suggest that
iodine in the ZnX portion of the reagent is the best
halogen for interacting with the promoter.4a,25
Rea gen t Stu d ies of th e Sch len k Equ ilibr iu m . Of
the four routes examined for the independent production
of (iodomethyl)zinc iodide (Scheme 6), only routes 1 and
2 gave clearly interpretable results regarding the Schlenk
equilibrium. Since both the rate and enantioselectivity
of cyclopropanation with the reagent prepared by route
1 were essentially identical to those obtained with route
2, we suggest that the Schlenk equilibrium does exist and
that ICH2ZnI is the active agent.
The results for routes 3 and 4 were not as straightfor-
ward. Both the rates of reaction and the enantiomeric
excesses of the products were much lower. As all four
routes were actually heterogeneous mixtures of highly
reactive organometallic reagents, it was impossible to
assess the degree of completion for each step in these
processes as well as to establish how cleanly the desired
reagents were made. Given these limitations, we offer
the tentative conclusion that while ICH2ZnI is formed
in each route (vide infra), there are other species present
that reduce the effective concentration or interfere with
the cyclopropanation process.
as shown in eq 7. In the case where M ) Zn, 2 equiv of
Zn(CH2I)2 + MXn h ICH2ZnX + ICH2MXn-1 (7)
the species ICH2ZnX would be formed. For the reaction
where 1 equiv of a metal iodide MIn is used 1 equiv each
of ICH2ZnI and ICH2MIn-1 would be produced. The
assumption that the Schlenk process for each metal salt
lies to the right may not necessarily be true, but our
results support this contention. If this were not the case,
then the metal salts should all have had no effect on rate
and selectivity. As can be seen from Table 1, each metal
salt provided results different from the case where no
additive was used (entry 1).
Simmons and Blanchard have examined the species
ClCH2ZnI formed by the reaction of zinc-copper couple
and chloroiodomethane.4a Initial insertion of zinc into
the carbon-iodine bond is assumed to occur since the
analogous reaction with dichloromethane does not lead
to a reagent capable of olefin cyclopropanation. Further-
more, if ClCH2ZnCl is formed using the method of Wittig
(diazomethane and zinc chloride),3 cyclopropanation of
olefins does occur. Thus, since ClCH2ZnCl is an active
cyclopropanation reagent but zinc-copper couple and
dichloromethane do not lead to a species capable of
adding methylene to olefins, it can safely be concluded
that zinc does not readily insert into carbon-chlorine
bonds. It was therefore not unreasonable for Simmons
and Blanchard to propose that ClCH2ZnI is formed from
zinc-copper couple and chloroiodomethane by zinc inser-
tion into the carbon-iodine bond. However, upon hy-
drolysis of this putative species, methyl iodide was
formed with only trace quantities of methyl chloride in
evidence. An equilibrium such as that shown in Scheme
8 must be occurring whereby ClCH2ZnI is converted to
ICH2ZnCl by an intramolecular or intermolecular pro-
cess. Thus, while ClCH2ZnI is formed initially, the
thermodynamically more stable isomer is probably ICH2-
ZnCl. Conceivably, the longer carbon-iodine vs carbon-
chlorine bond as well as the fact that iodide is a better
bridging group than chloride may make the (iodomethyl)-
zinc chloride species more favorable. It may also be that
the (iodomethyl)zinc chloride species is more reactive
than the corresponding (chloromethyl)zinc iodide both
toward hydrolysis as well as methylene delivery to
olefins. These events may be activated by a zinc-iodine
interaction of either an inter- or intramolecular nature.
The conclusion one draws is that the species ICH2ZnX
(X ) Cl or Br), obtained by the Schlenk process (eq 7)
from Zn(CH2I)2 and ZnX2, are stable relative to the
corresponding compounds XCH2ZnI, due to the greater
ability of iodine to coordinate with zinc in an intramo-
lecular manner. The nature of the X group in ICH2ZnX
must have little influence on the reactivity of the reagent
since reactions in the presence of ZnI2, ZnBr2, and ZnCl2
proceed at approximately the same rate yet significantly
faster than the case when no additive is used. It appears
Sp ectr oscop y Stu d ies. From the partial 13C spectra
NMR provided in Figure 8 it could be seen that each of
the four routes shown in Scheme 6 produced the same
new species characterized by the signals at -17.2 and
-19.6 ppm. That these two resonances were observed
in this region of the 13C spectrum suggested that they
are for methylenes bonded to both iodine and zinc.
Further, their temperature-dependent line shape sug-
gested that they are interconverting species present in
unequal amounts that belong to the two diastereomeric
(iodomethyl)zinc iodide complexes 13 shown in Figure 9.
The observation that the Schlenk mixture Zn(CH2I)2/ZnI2
also gave these two peaks (route 1) was a strong indica-
(25) For
a discussion of transition structure proposals for the
cyclopropanation see ref 19.

Enantioselective Cyclopropanation of Allylic Alcohols
J . Org. Chem., Vol. 62, No. 10, 1997 3399
tion that the effect of zinc iodide under the standard
reaction conditions for the cyclopropanation of allylic
alcohols was to drive the equilibrium process to the
reagent (iodomethyl)zinc iodide. The nearly identical
spectra for the reagents obtained with both routes 1 and
2 is the strongest support for this contention.
The full spectra for routes 3 and 4 revealed the
presence of 13 for both of these routes, albeit compro-
mised by other species. The observation of these other
species helped us rationalize why reactions using the
reagents produced with route 3 and 4 were not as
selective. The active agent (iodomethyl)zinc iodide was
formed but in reduced amounts leading to slower and less
effective catalysis.
iodide upon the reagent bis(iodomethyl)zinc. Further-
more, it is concluded that (iodomethyl)zinc iodide is the
actual cyclopropanation reagent both with and without
chiral promoters. While complications due to instability
and insolubility of many of the zinc compounds were
encountered and potentially compromising modifications
were required to perform the spectroscopic studies, the
combination of all of the results obtained lead us to
conclude that the Schlenk equilibrium of eq 1 lies
predominantly if not exclusively on the side of (iodo-
methyl)zinc iodide. We have further demonstrated that,
for allylic alcohols, in situ zinc iodide generation under
the conditions of bis-sulfonamide 7-promoted cyclopro-
panation leads to a highly selective reaction (89% ee).
In the case of route 3, the lower yield of (iodomethyl)-
zinc iodide could be due to poor chemical selectivity in
both steps. In the first step, 1 equiv of CH2I2 is added to
Et2Zn, and three species were detected spectroscopically
(Et2Zn, EtZnCH2I, Zn(CH2I)2). It is likely that EtZnCH2I
is produced but undergoes Schlenk equilibration itself to
form a mixture containing Et2Zn and Zn(CH2I)2 (eq 8).
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR and 2D NMR spectra
were recorded at field strengths of 400 or 500.1 MHz (1H) and
100 or 125.8 MHz (13C). Data are reported in the following
order: chemical shifts in ppm (δ); multiplicities are indicated
(bs (broadened singlet), s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet)); coupling constants, J , are reported
in hertz; integration is given; and assignment is indicated.
Elemental analyses were performed by the University of
Illinois Microanalytical Service Laboratory. Optical rotations
are reported as follows: [R]tempD (solvent, concentration in g/100
mL). Diiodomethane (Aldrich) was washed with Na2S2O3 (aq),
dried (MgSO4), distilled from CaH2 (88 °C/40 Torr), stored over
copper, and protected from light. Neat diethylzinc was used
as purchased from Strem in protocol A. In protocol B,
diethylzinc was distilled (0 °C/0.03 Torr). Zinc iodide (Aldrich)
of 99.99+% and 99.999% grades was stored over P2O5. Iodine
was obtained from Mallinckrodt and used as is. Reagent-grade
dichloromethane was distilled from P2O5 prior to use in the
reactions. Analytical TLC was performed on Merck silica gel
plates with QF-254 indicator. Visualization was accomplished
with UV light, iodine, or phosphomolybdic acid solution (5%
in ethanol). Column (flash) chromatography was performed
using 32-63 mm silica gel. Solvents for extraction and
chromatography were technical grade and distilled from the
indicated drying reagents: hexane (CaCl2), dichloromethane
(CaCl2), ethyl acetate (K2CO3). Analytical gas chromatography
was performed on a Hewlett-Packard 50 m Ultra Phenyl
Methyl Silicone (U2) or a Hewlett Packard 50 m phenyl methyl
silicone (HP-5) column. Analytical high-pressure liquid chro-
matography (HPLC) was performed using Daicel Chiralcel OJ
column with the detector wavelength at 254 nm. The flow rate
and solvent system were as denoted. The syntheses of 516c
and 79a,19 have been previously described. Cinnamyl alcohol
was obtained from Aldrich and recrystallized from pentane/
ether.
NMR Stu d ies. Gen er a l P r oced u r e for th e P r ep a r a tion
of Sa m p les. All of the NMR tubes used were Wilmad 528,
dried for 2 h at 125 °C, and then allowed to cool to rt over
P2O5. The septum-capped NMR tubes were evacuated and
then filled with argon. All additions of liquids were performed
with gas-tight syringes or with cannulas. Solid zinc iodide was
added to NMR tubes while in a glovebox. Where noted,
degassing involved three freeze-pump-thaw cycles. Chloro-
form-d1 was distilled from P2O5 and then passed through basic
alumina immediately prior to sample preparation.
NMR Sp ectr a of (R)-(1l,2l,3u ,4u )-2,3-Dim eth oxy-4,7,7-
tr im eth ylbicyclo[2.2.1]h ep ta n e (5). A sample of 5 (60 mg,
0.30 mmol) in a septum-capped NMR tube under argon was
dissolved in CDCl3 (0.5 mL). The sample was degassed, the
tube was sealed with Teflon and parafilm, cooled to -70 °C,
and the spectra were acquired. Data for 5: 1H NMR (500
MHz, CDCl3, -70 °C) 3.38 (s, 3 H, H3C(12)), 3.33 (s, 3 H, H3C-
(11)), ∼3.34 (HC(2), this signal was obscured by the C-11
methyl signal), 3.13 (d, J ) 6.7, 1 H, HC(3)), 1.79 (d, J ) 5.1,
1 H, HC(1)), 1.58 (tt, J ) 9.0, 12.4, 1 H, HC(6x)), 1.37 (dt, J )
3.4, 12.4, 1 H, HC(5x)), 0.97 (s, 3 H, H3C(8)), 0.90 (dt, J ) 3.9,
11.2, 1 H, HC(5n)), 0.83 (s, 3 H, H3C(10)), 0.83 (HC(6n), this
EtZnCH2I h 1/2 [Et2Zn + Zn(CH2I)2]
(8)
It is also possible that the reaction of EtZnCH2I with
CH2I2 is faster than the reaction of Et2Zn with CH2I2.
This would produce the same three species. Whichever
the case, subsequent addition of I2 does not cleanly
produce ICH2ZnI as we could detect the ZnI2 complex 12
as an additional major component. Thus, for route 3, an
unproductive side reaction gives ZnI2 and removes this
zinc equiv from the potential for methylene delivery.
Route 4 also led to lower than expected quantities of
(iodomethyl)zinc iodide complex 13. It was apparent
from the spectra that the problem was in the iodinolysis
step, namely the addition of 1 equiv of iodine to the bis-
(iodomethyl)zinc complex 6. While 13 was formed, it
appeared that substantial amounts of the zinc iodide
complex 12 had also been produced. Again, a puzzling
observation was that none of the bis(iodomethyl)zinc
complex 6 remained. Since equimolar quantities of
iodine and the complex of Zn(CH2I)2 were reacted, it is
difficult to rationalize the production of ICH2ZnI and ZnI2
while completely consuming the Zn(CH2I)2.
A major caveat in these spectroscopic studies is the role
of the bis-ether 5 in the position of the Schlenk equilib-
rium. While 5 is essential for solubilization and stabi-
lization to allow spectroscopic observation of the various
zinc species, it is well known that the position of the
Schlenk equilibrium is strongly medium dependent.24 An
attempt to address what effect the bis-ether 5 had on the
Schlenk equilibrium was thwarted by low solubility of
the species at -70 °C. The evidence obtained supported
the hypothesis that the zinc equilibrium, even in the
absence of the bis-ether 5, favored (iodomethyl)zinc iodide.
However, the low signal-to-noise level in the 13C spectrum
(∼3/1) resulting from the limited low-temperature solu-
bility of the species present make this conclusion less
than firm.
Su m m a r y
The results presented here have served to clarify the
favorable effect of zinc iodide in the bis-sulfonamide-
promoted cyclopropanation of allylic alcohols. It has been
proposed and the supporting evidence provided that
(iodomethyl)zinc iodide is formed by the action of zinc

3400 J . Org. Chem., Vol. 62, No. 10, 1997
Denmark and O’Connor
signal was obscured by the C-10 methyl signal), 0.68 (s, 3 H,
H3C(9)); 13C NMR (125.8 MHz, CDCl3, -70 °C) 89.91 (C(3)),
86.19 (C(2)), 60.68 (C(12)), 58.26 (C(11)), 48.83 (C(4)), 46.72
(C(1)), 46.21 (C(7)), 33.19 (C(5)), 23.77 (C(6)), 20.90 (C(9)), 20.07
(C(8)), 11.42 (C(10)).
J ) 6.7, 1 H, HC(3)), 3.60 (s, 3 H, H3C(11)), 2.11 (d, J ) 3.9,
1 H, HC(1)), 1.74 (b, 1 H, HC(6x)), 1.48 (d, J ) 9.3, 1 H, HC-
(5x)), 1.05 (s, 3 H, H3C(8)), 0.99 (s, 3 H, H3C(10)), 0.77 (s, 3 H,
H3C(9)); 13C NMR (125.8 MHz, CDCl3, -70 °C) 89.97 (C(3)),
85.41 (C(2)), 62.59 (C(12)), 58.38 (C(11)), 49.86 (C(4)), 47.17
(C(1)), 44.01 (C(7)), 32.33 (C(5)), 22.68 (C(6)), 20.85 (C(9)), 20.01
(C(8)), 12.17 (C(10)).
NMR Sp ectr a of ((R)-(1l,2l,3u ,4u )-2,3-Dim eth oxy-4,7,7-
tr im eth ylbicyclo[2.2.1]h ep ta n e)d ieth ylzin c (9). To a sep-
tum-capped NMR tube containing 5 (60 mg, 0.30 mmol) in
CDCl3 (0.5 mL) at 0 °C was added Et2Zn (31 µL, 0.30 mmol).
The sample was degassed, the tube was sealed with Teflon
and parafilm and cooled to -70 °C, and the spectra were
acquired. Data for 9: 1H NMR (500 MHz, CDCl3, -70 °C) 3.41
(s, 3 H, H3C(12)), ∼3.41 (HC(2), this signal was obscured by
the C-12 methyl signal), 3.33 (s, 3 H, H3C(11)), 3.22 (d, J )
7.6, 1 H, HC(3)), 1.86 (d, J ) 4.8, 1 H, HC(1)), 1.61 (m, 1 H,
HC(6x)), 1.39 (dt, J ) 4.3, 12.3, 1 H, HC(5x)), 1.05 (t, J ) 8.5,
3 H, CH3CH2Zn), 0.99 (s, 3 H, H3C(8)), 0.90 (s, 3 H, H3C(10)),
0.70 (s, 3 H, H3C(9)), -0.49 (q, J ) 8.2, 2 H, H2CZn); 13C NMR
(125.8 MHz, CDCl3, -70 °C) 89.92 (C(3)), 86.16 (C(2)), 60.43
(C(12)), 57.39 (C(11)), 49.20 (C(4)), 46.39 (C(1)), 45.61 (C(7)),
33.05 (C(5)), 23.57 (C(6)), 20.97 (C(9)), 19.85 (C(8)), 11.78, 11.64
(C(10), CH3CH2Zn)), 3.64 (CH2Zn).
NMR Sp ectr a of ((R)-(1l,2l,3u ,4u )-2,3-Dim eth oxy-4,7,7-
tr im eth ylbicyclo[2.2.1]h eptan e)eth ylzin c Iodide (10). The
contents of a septum-capped NMR tube containing 9 (0.30
mmol) in CDCl3 (0.5 mL) at 0 °C was tranferred via cannula
to a second septum-capped NMR tube containing I2 (76 mg,
0.30 mmol) at 0 °C. After being mixed at 0 °C for 1 min, the
sample became clear and colorless. It was allowed to warm
to rt for 30 min and then cooled to -70 °C for acquisition of
the spectra. Only partial spectral assignments are given for
10 due to complexities arising from the presence of diastere-
omeric complexes. Data for 10: 1H NMR (500 MHz, CDCl3,
-70 °C) 0.11 (q, J ) 8.0, CH2Zn); 13C NMR (125.8 MHz, CDCl3,
-70 °C) 61.78 (C(12)), 57.78 (C(11)), 2.09 (CH2Zn).
NMR Sp ectr a of ((R)-(1l,2l,3u ,4u )-2,3-Dim eth oxy-4,7,7-
tr im eth ylbicyclo[2.2.1]h ep ta n e)(iod om eth yl)zin c Iod id e
(13) via Rou te 1. To a septum-capped NMR tube containing
a solution of 6 in CDCl3 (0.6 M) at -78 °C was added via
cannula an equimolar solution of 12 also in CDCl3 (0.6 M) at
-78 °C. The sample was placed in the NMR probe precooled
to -70 °C, and spectra were acquired at 8, 48, and 150 min
from mixing. At 48 min approximately 50% of 6 and 12
remained while by 150 min the conversion to 13 was complete.
Data for 13: 1H NMR (500 MHz, CDCl3, -70 °C) 3.78 (s, 3H,
H3C(12)), 3.71 (s, 3H, H3C(11)), 3.12 (q, J ) 7.6, CH3CH2I),
2.02 (d, J ) 5.0, 1 H, HC(1)), 1.745 (t, J ) 7.6, CH3CH2I), 1.35
(bs, 2 H, ZnCH2I), 1.00 (s, 3 H, H3C(8)), 0.91 (s, 3 H, H3C(10)),
0.73 (s, 3 H, H3C(9)); 13C NMR (125.8 MHz, CDCl3, -70 °C)
89.49 (C(3)), 85.37 (C(2)), 63.00 (C(12)), 59.21 (C(11)), 49.52
(C(4)), 46.90 (C(1)), 43.94 (C(7)), 32.27 (C(5)), 22.61 (C(6)), 20.70
(C(9)), 20.28 (CH3CH2I), 20.11 (C(8)), 12.06 (C(10)), 1.14
(CH3CH2I), -17.19, -19.56 (ZnCH2I).
NMR Sp ectr a of ((R)-(1l,2l,3u ,4u )-2,3-Dim eth oxy-4,7,7-
tr im eth ylbicyclo[2.2.1]h ep ta n e)(iod om eth yl)zin c Iod id e
(13) via Rou te 2. To a septum-capped NMR tube containing
10 (0.30 mmol) in CDCl3 (0.6 M) at -78 °C was added CH2I2
(24 µL, 0.30 mmol). Three hours at room temperature was
required for complete conversion to 13. Spectra (1H and 13C
NMR) were then acquired at -70 °C and were essentially the
same as those obtained with route 1.
NMR Sp ectr a of ((R)-(1l,2l,3u ,4u )-2,3-Dim eth oxy-4,7,7-
tr im eth ylbicyclo[2.2.1]h ep ta n e)(iod om eth yl)zin c Iod id e
(13) via Rou te 3. The sample of 11 (0.30 mmol) from above
at 0 °C was added via cannula to a septum-capped NMR tube
under argon containing I2 (76 mg, 0.30 mmol) at 0 °C.
Complete dissolution of the I2 required ∼5 min at 0 °C, at
which point the sample was cooled to -70 °C for the acquisition
NMR Sp ectr a of ((R)-(1l,2l,3u ,4u )-2,3-Dim eth oxy-4,7,7-
tr im eth ylbicyclo[2.2.1]h ep ta n e)bis(iod om eth yl)zin c (6).
To a septum-capped NMR tube containing 9 (0.30 mmol) in
CDCl3 (0.5 mL) at 0 °C was added CH2I2 (48 µL, 0.60 mmol).
The tube was sealed with Teflon and parafilm and placed in
the NMR probe at 0 °C. Observation of the 13C spectrum
indicated that ∼60 min were required for complete formation
of the bis(iodomethyl)zinc species. The probe was then cooled
to -70 °C, and the spectra were acquired. Only partial
1
of H and 13C NMR spectra. These indicated the presence of
both 11 and 13.
NMR Sp ectr a of ((R)-(1l,2l,3u ,4u )-2,3-Dim eth oxy-4,7,7-
tr im eth ylbicyclo[2.2.1]h ep ta n e)(iod om eth yl)zin c Iod id e
(13) via Rou te 4. The sample of 6 (0.30 mmol) from above
at -78 °C was added via cannula to a septum-capped NMR
tube under argon containing I2 (76 mg, 0.30 mmol) at -78 °C.
The contents of the tube were warmed to 0 °C and mixed for
2-3 min, at which point complete dissolution of the I2 occurred.
After 5 min at 0 °C, the tube was placed in the NMR probe at
-70 °C, and the spectra were acquired. While 13 was present,
the was an appreciable amount of 12 as well as a small
quantity another compound which was not assignable.
(1R,2R)-2-P h en ylcyclop r op a n em eth a n ol (8). In Situ
Gen er a tion of Zin c Iod id e. To a flame-dried, 15 mL, two-
necked, round-bottom flask (flask A) equipped with a stir bar,
septum, and argon inlet were added cinnamyl alcohol (134 mg,
1.00 mmol) and promoter 7 (27 mg, 0.10 mmol, 0.10 equiv).
Vacuum (∼0.1 mm) was applied for ∼30 s, and then the flask
was put under an atmosphere of argon. This was repeated
twice followed by the addition of CH2Cl2 (3 mL). The solution
was cooled under argon to 0 °C, and diethylzinc (113 µL, 1.10
mmol, 1.10 equiv) was added. The solution was stirred at 0
°C for 10 min. To a flame-dried, 25 mL, two-necked, round-
bottom flask (flask B) equipped with a stir bar, septum, and
argon inlet were added iodine (508 mg, 2.00 mmol, 2.00 equiv)
and CH2Cl2 (10 mL). The suspension was cooled under argon
to 0 °C, and diethylzinc (103 µL, 1.00 mmol, 1.00 equiv) was
added. A thick, white precipitate immediately formed, occa-
ssionally exhibiting a purple tint. The slurry was stirred at 0
°C for 10 min. To a flame-dried, 100 mL, two-necked, round-
bottom flask (flask C) equipped with a stir bar, septum, and
argon inlet were added diiodomethane (161 µL, 2.00 mmol,
2.00 equiv) and CH2Cl2 (24 mL). The solution was cooled to 0
°C, and diethylzinc (103 µL, 1.00 mmol, 1.00 equiv) was added
with subsequent stirring for 5 min (white precipitate formed
1
spectral assignment could be made for the H NMR spectrum
at -70 °C due to the broadness of the signals. Data for 6: 1H
NMR (500 MHz, CDCl3, -70 °C) 1.20 (bs, 2 H, H2CZn); 13C
NMR (125.8 MHz, CDCl3, -70 °C) 90.37 (C(3)), 86.87 (C(2)),
61.28 (C(12)), 58.28 (C(11)), 49.48 (C(4)), 46.73 (C(1)), 44.18
(C(7)), 32.45 (C(5)), 23.02 (C(6)), 20.86 (C(9)), 20.32 (CH3CH2I),
19.63 (C(8)), 11.88 C(10), 1.17 (CH3CH2I), -14.85, -17.05
(ICH2Zn).
NMR Sp ectr a of ((R)-(1l,2l,3u ,4u )-2,3-Dim eth oxy-4,7,7-
t r im et h ylb icyclo[2.2.1]h ep t a n e)et h yl(iod om et h yl)zin c
(11). To a septum-capped NMR tube containing 9 (0.30 mmol)
in CDCl3 (0.5 mL) at -78 °C was added CH2I2 (24 µL, 0.30
mmol), and the tube sealed with Teflon and parafilm. After
the contents were mixed at -78 °C, the tube was warmed to
0 °C for 5 min and then cooled back to -70 °C for the
acquisition of the spectra. The spectra indicated the presence
of both 9 and 6 along with the complex of EtZnCH2I (11).
Partial assignment of the spectra for 11 are given. Data for
11: 1H NMR (500 MHz, CDCl3, -70 °C) -0.03 (q, J ) 7.8, 1
H, CH3CH2Zn), -0.10 (q, J ) 8.1, 1 H, CH3CH2Zn); 13C NMR
(125.8 MHz, CDCl3, -70 °C) -1.09 (CH3CH2Zn), -12.37 (ICH2-
ZnEt), -15.0, -17.2 (Zn(CH2I)2).
NMR Sp ectr a of ((R)-(1l,2l,3u ,4u )-2,3-Dim eth oxy-4,7,7-
tr im eth ylbicyclo[2.2.1]h ep ta n e)zin c Iod id e (12). To a
septum-capped NMR tube containing ZnI2 (96 mg, 0.30 mmol)
were added CDCl3 (0.5 mL) and 5 (60 mg, 0.30 mmol). The
sample was degassed and the tube sealed with Teflon and
parafilm. Approximately 1 h at room temperature with
occassional mixing was required to affect complete solution.
The sample was then cooled to -70 °C for the acquisition of
the spectra. Data for 12: 1H NMR (500 MHz, CDCl3, -70 °C)
3.82 (d, J ) 6.81, 1 H, HC(2)), 3.74 (s, 3 H, H3C(12)), 3.68 (d,

Enantioselective Cyclopropanation of Allylic Alcohols
J . Org. Chem., Vol. 62, No. 10, 1997 3401
after ∼2 min). The contents of flask A were added via cannula
over ∼30 s to flask B. The resulting thick, white slurry was
stirred at 0 °C for 2 min and was transferred in like manner
to flask C. The mixture was a thick white slurry and was
maintained at 0 °C. Reaction progress was monitored periodi-
cally as follows: an aliquot (5-10 drops) was removed via
cannula into a precooled (0 °C) solution of CH2Cl2 (0.5 mL)
containing TMEDA (5 drops); after washing with 2 N HCl (0.5
mL), this solution was passed through a small plug of Florisil
(∼1/8 in.), followed by EtOAc (0.5 mL); this solution was then
assayed by GC (U2, isothermal 180 °C, tR 5.9 min). The
reaction was quenched at 0 °C after 45 min with 2 N NaOH
(13 mL). The organic layer was removed, the aqueous layer
was extracted with CH2Cl2 (2 × 20 mL), and the organic layers
were combined, dried (MgSO4), and concentrated in vacuo. The
product was then purified by flash chromatograpy (hexane/
EtOAc, 3/1) followed by bulb-to-bulb distillation to yield 136
mg (92%) of product as a clear, colorless liquid. Data for 8:
was quenched, the product isolated and purified, and the
enantiomeric excess determined. Data for 8: HPLC tR (1R,2R)-
8, 21.8 min (93.4%); tR (1S,2S)-8, 28.4 min (6.6%) (86% ee)
(Daicel OJ , hexane/i-PrOH, 98/2, 1.0 mL/min).
(1R,2R)-2-P h en ylcyclop r op a n em eth a n ol (8). Rou te 2.
The contents of flask A were prepared as described above for
route 1. To a second 25 mL, two-necked, round-bottom flask
(flask B) similarly equipped were added iodine (152 mg, 0.60
mmol, 2.00 equiv) and CH2Cl2 (7 mL) and the contents cooled
under argon to 0 °C. Diethylzinc (62 µL, 0.60 mmol, 2.00
equiv) was added to give a white slurry. After 5 min at 0 °C,
diiodomethane (49 µL, 0.60 mmol, 2.00 equiv) was added, again
producing a white slurry. After an additional 5 min at 0 °C,
the contents of flask A were transferred via cannula over ∼30
s to flask B. The mixture was a thick white slurry and was
maintained at 0 °C with periodic assays as described above in
the procedure for In Situ Generation of Zinc Iodide. After 30
min at 0 °C, as described above in the procedure for In Situ
Generation of Zinc Iodide, the reaction was quenched, the
product isolated and purified, and the enantiomeric excess
determined. Data for 8: HPLC tR (1R,2R)-8, 21.6 min (93.1%);
tR (1S,2S)-8, 28.1 min (6.9%) (86% ee) (Daicel OJ , hexane/i-
PrOH, 98/2, 1.0 mL/min).
(1R,2R)-2-P h en ylcyclop r op a n em eth a n ol (8). Rou te 3.
The contents of flask A were prepared as described above for
route 1. To a second 25 mL, two-necked, round-bottom flask
(flask B) similarly equipped were added CH2Cl2 (7 mL) and
diiodomethane (49 µL, 0.60 mmol, 2.00 equiv) and the contents
cooled under argon to 0 °C. Diethylzinc (62 µL, 0.60 mmol,
2.00 equiv) was added. After 5 min at 0 °C, at which point a
small amount of white precipitate had formed, iodine (152 mg,
0.60 mmol, 2.00 equiv) was added to give a thick slurry with
a slight purple tint. After an additional 5 min at 0 °C, the
contents of flask A were transferred via cannula over ∼30 s
to flask B. The mixture was a thick white slurry and was
maintained at 0 °C with periodic assays as described above in
the procedure for In Situ Generation of Zinc Iodide. After 30
min at 0 °C, as described above in the procedure for In Situ
Generation of Zinc Iodide, the reaction was quenched, the
product isolated and purified, and the enantiomeric excess
determined. Data for 8: HPLC tR (1R,2R)-8, 21.8 min (86.9%);
tR (1S,2S)-8, 28.0 min (13.1%) (73% ee) (Daicel OJ , hexane/i-
PrOH, 98/2, 1.0 mL/min).
(1R,2R)-2-P h en ylcyclop r op a n em eth a n ol (8). Rou te 4.
The contents of flask A were prepared as described above for
route 1. To a second 25 mL, two-necked, round-bottom flask
(flask B) similarly equipped was added CH2Cl2 (7 mL) and
diiodomethane (98 µL, 1.20 mmol, 4.00 equiv) and the contents
cooled under argon to 0 °C. Diethylzinc (62 µL, 0.60 mmol,
2.00 equiv) was added to produce a thick white slurry in 1-2
min. After 5 min at 0 °C, iodine (152 mg, 0.60 mmol, 2.00
equiv) was added to give a thick slurry with a purple tint. After
an additional 5 min at 0 °C, the contents of flask A were
transferred via cannula over ∼30 s to flask B. The mixture
was a thick white slurry and was maintained at 0 °C with
periodic assays as described above in the procedure for In Situ
Generation of Zinc Iodide. After 30 min at 0 °C, as described
above in the procedure for In Situ Generation of Zinc Iodide,
the reaction was quenched, the product isolated and purified,
and the enantiomeric excess determined. Data for 8: HPLC
tR (1R,2R)-8, 22.4 min (61.8%); tR (1S,2S)-8, 27.8 min (38.2%)
(23% ee) (Daicel OJ , hexane/i-PrOH, 98/2, 1.0 mL/min).
1
(see ref 19 for full characterization of 8) H NMR (400 MHz,
CDCl3) 7.30-7.24 (m, 2 H), 7.20-7.14 (m, 1 H), 7.10-7.06 (m,
2 H), 3.67-3.56 (ddd, J ) 6.8, J ) 11.2, J ) 18.1, 2 H), 1.86-
1.79 (td, J t ) 4.6, J d ) 9.3, 1 H), 1.84-1.79 (t, J ) 4.5, 1 H),
1.50-1.42 (m, 1 H), 1.01-0.90 (m, 2 H); HPLC tR (1R,2R)-8,
23.1 min (94.9%); tR (1S,2S)-8, 29.8 min (5.1%) (89% ee) (Daicel
OJ , hexane/i-PrOH, 98/2, 1.0 mL/min). Anal. Calcd for
C10H12O (148.21): C, 81.04; H, 8.16. Found: C, 80.74; H, 8.26.
(1R,2R)-2-P h en ylcyclop r op a n em eth a n ol (8). Gen er a l
P r oced u r e for Use w ith a n d w ith ou t Ad d itives. In a
flame-dried, 25 mL, two-necked, round-bottom flask (flask A)
equipped with a stir bar, septum, and argon inlet were
combined cinnamyl alcohol (41 mg, 0.30 mmol), promoter 7 (9
mg, 0.03 mmol, 0.10 equiv), and 1.00 equiv of an anhydrous
solid from Table 1. The corresponding reaction was also run
in the absence of any additive. Vacuum (∼0.1 mm) was
applied for ∼30 s, and then the flask was put under an
atmosphere of argon. This was repeated twice followed by the
addition of CH2Cl2 (4 mL). The suspension was cooled under
argon to 0 °C, and diethylzinc (34 µL, 0.33 mmol, 1.10 equiv)
was added and the mixture maintained at 0 °C for 30 min. To
a second 25 mL, two-necked, round-bottom flask (flask B)
similarly equipped were added CH2Cl2 (7 mL) and di-
iodomethane (49 µL, 0.60 mmol, 2.00 equiv) and the contents
cooled under argon to 0 °C. Diethylzinc (31 µL, 0.30 mmol,
1.00 equiv) was added to give a white slurry after 1-2 min.
After 5 min at 0 °C, the contents of flask A were transferred
via cannula over ∼30 s to flask B. The mixture was a thick
slurry and was maintained at 0 °C with periodic assays as
described above in the procedure for In Situ Generation of Zinc
Iodide. After 30 min at 0 °C, as described above in the
procedure for In Situ Generation of Zinc Iodide, the reaction
was quenched, the product isolated and purified, and the
enantiomeric excess determined. (See Table 1 for results).
(1R,2R)-2-P h en ylcyclop r op a n em eth a n ol (8). Rou te 1.
In a flame-dried, 25 mL, two-necked, round-bottom flask (flask
A) equipped with a stir bar, septum, and argon inlet were
combined cinnamyl alcohol (41 mg, 0.30 mmol) and promoter
7 (9 mg, 0.03 mmol, 0.10 equiv). Vacuum (∼0.1 mm) was
applied for ∼30 s, and then the flask was put under an
atmosphere of argon. This was repeated twice followed by the
addition of CH2Cl2 (4 mL). The suspension was cooled under
argon to 0 °C, and diethylzinc (34 µL, 0.33 mmol, 1.10 equiv)
was added to give a clear, colorless solution which was
maintained at 0 °C for 30 min. To a second 25 mL, two-necked,
round-bottom flask (flask B) similarly equipped were added
iodine (152 mg, 0.60 mmol, 2.00 equiv) and CH2Cl2 (7 mL) and
the contents cooled under argon to 0 °C. Diethylzinc (31 µL,
0.30 mmol, 1.00 equiv) was added to give a slurry with a slight
purple tint. After 10 min at 0 °C, an additional quantity of
diethylzinc (31 µL, 0.30 mmol, 1.00 equiv) was added followed
by diiodomethane (40 µL, 0.60 mmol, 2.00 equiv). After an
additional 5 min at 0 °C, the contents of flask A were
transferred via cannula over ∼30 s to flask B. The mixture
was a thick white slurry and was maintained at 0 °C with
periodic assays as described above in the procedure for In Situ
Generation of Zinc Iodide. After 30 min at 0 °C, as described
above in the procedure for In Situ Generation of Zinc Iodide,
the reaction
Ack n ow led gm en t. We are grateful to Pharmacia
and the Upjohn Company for financial support.
Su p p or tin g In for m a tion Ava ila ble: The experimental
procedures along with the 1H and 13C NMR spctra for the
various complexes and exchange experiments are provided (52
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead for ordering information.
J O9702397