Catalytic asymmetric cyclopropanation of heteroaryldiazoacetates

Article abstract of DOI:10.1021/jo015617t

Rh₂(S-DOSP)₄-catalyzed decomposition of heteroaryldiazoacetates in the presence of styrene results in highly diastereoselective and enantioselective cyclopropanations. Heteroaryldiazoacetates containing both electron-rich and electron-deficient heterocycles, such as thiophene, furan, pyridine, indole, oxazole, isoxazole, and benzoxazole, are effective in this chemistry. These studies broaden the range of diazo compounds containing both electron-withdrawing and electron-donating groups, which undergo highly diastereoselective cyclopropanations.

Full text of DOI:10.1021/jo015617t

J . Org. Chem. 2001, 66, 6595-6603
6595
Ca ta lytic Asym m etr ic Cyclop r op a n a tion of
Heter oa r yld ia zoa ceta tes
Huw M. L. Davies* and Robert J . Townsend
Department of Chemistry, State University of New York at Buffalo, Buffalo, New York 14260-3000
hdavies@acsu.buffalo.edu
Received March 6, 2001
Rh2(S-DOSP)4-catalyzed decomposition of heteroaryldiazoacetates in the presence of styrene results
in highly diastereoselective and enantioselective cyclopropanations. Heteroaryldiazoacetates
containing both electron-rich and electron-deficient heterocycles, such as thiophene, furan, pyridine,
indole, oxazole, isoxazole, and benzoxazole, are effective in this chemistry. These studies broaden
the range of diazo compounds containing both electron-withdrawing and electron-donating groups,
which undergo highly diastereoselective cyclopropanations.
New methods for the stereoselective synthesis of highly
functionalized cyclopropanes have been extensively stud-
ied.1 The metal-catalyzed decomposition of R-diazocar-
bonyl compounds in the presence of alkenes is a powerful
method for the synthesis of highly functionalized cyclo-
propanes.2 In this paper, we describe that various het-
eroaryldiazoacetates are capable of highly stereoselective
cyclopropanations (eq 1), which greatly broadens the
scope of this chemistry.
azoacetate 2,5 the vinyldiazoacetate 3,6 and the alkynyl-
diazoacetate 4.7 Furthermore, high asymmetric induction
can be achieved for the transformations of 2-4, when
the reactions are catalyzed by the dirhodium catalyst Rh2-
(S-DOSP)4 (5),5b,6c,7,8 again in marked contrast to the
result with ethyl diazoacetate (1) (eq 2).6b Room temper-
ature reactions of 2-4 in pentane result in cyclopropa-
nation in around 90% ee, while the cyclopropanation of
3 at -78 °C occurs in 98% ee. Considering the impressive
cyclopropanation stereoselectivity that is exhibited by
diazo compounds 2-4, the development of an even wider
range of diazo compounds with the EWG-EDG group
combination would be very worthwhile.
The most widely utilized carbenoids that have been
used for metal-catalyzed cyclopropanations are those
derived from unsubstituted diazoacetates, such as ethyl
diazoacetate (1).2a Even though various catalysts have
been developed that are capable of highly enantioselective
cyclopropanations of this class of metal-carbenoids, di-
astereocontrol has been a major challenge that has been
successfully solved in only a few systems.3 In contrast,
diazo compounds containing both electron-withdrawing
(EWG) and electron-donating groups (EDG) undergo
highly diastereoselective and chemoselective cyclopropa-
nations.4 Examples of such systems are the phenyldi-
Even though a number of heteroaryldiazoacetates are
known,9 there are no previous reports to our knowledge
* To whom correspondence should be addressed. Fax: 716-645-6547.
(1) (a) Burgess, K.; Ho, K. K.; Moye-Sherman, D. Synlett 1994, 575.
(b) Stammer, C. H. Tetrahedron 1990, 46, 2231.
(2) (a) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911. (b)
Doyle, M.; McKervey, M.; Ye, T. J ohn Wiley & Sons: New York, 1997;
pp 163-237.
(3) (a) Uchida, T.; Irie, R.; Katsuki, T. Tetrahedron 2000, 56, 3501.
(b) Niimi, T.; Uchida, T.; Irie, R.; Katsuki, T. Tetrahedron Lett. 2000,
41, 3647. (c) Uchida, T.; Irie, R.; Katsuki, T. Synlett 1999, 11, 1793.
(d) Uchida, T.; Irie, R.; Katsuki, T. Synlett 1999, 7, 1163. (e) Doyle, M.
P.; Bagheri, V.; Wandless, T. J .; Harn, N. K.; Brinker, D. A.; Eagle, C.
T.; Loh, K. L. J . Am. Chem. Soc. 1990, 112, 1906. (f) Evans, D. A.;
Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J . Am. Chem. Soc. 1991,
113, 726. (g) Nishiyama, H.; Soeda, N.; Naito, T.; Motoyama, Y.
Tetrahedron: Asymmetry 1998, 9, 2865. (h) Park, S. B.; Sakata, N.;
Nishiyama, H. Chem. A Eur. J . 1996, 2, 303.
(5) (a) Paulini, K.; Reissig, H.-U. J . Prakt. Chem./ Chem.-Ztg. 1995,
337, 55. (b) Davies, H. M. L.; Bruzinski, P. R.; Fall, M. J . Tetrahedron
Lett. 1996, 37, 4133. (c) Doyle, M. P.; Zhou, Q.-L.; Charnsangavej, C.;
Longoria, M. A.; McKervey, M. A.; Garcia, C. F. Tetrahedron Lett. 1996,
37, 4129. (d) Starmans, W. A. J .; Thijs, L.; Zwanenburg, B. Tetrahedron
1998, 54, 629. (e) Davies, H. M. L.; Rusiniak, L. Tetrahedron Lett. 1998,
39, 8811. (f) Davies, H. M. L.; Nagashima, T.; Klino, J . L. Org. Lett.
2000, 2, 823.
(6) (a) Davies, H. M. L.; Clark, T. J .; Church, L. A. Tetrahedron Lett.
1989, 30, 5057. (b) Davies, H. M. L.; Hutcheson, D. K. Tetrahedron
Lett. 1993, 34, 7243. (c) Davies, H. M. L.; Bruzinski, P. R.; Lake, D.
H.; Kong, N.; Fall, M. J . J . Am. Chem. Soc. 1996, 118, 6897. (d) Davies,
H. M. L.; Stafford, D. G.; Doan, B. D.; Houser, J . H. J . Am. Chem. Soc.
1998, 120, 3326. (e) Davies, H. M. L.; Kong, N.; Churchill, M. R. J .
Org. Chem. 1998, 63, 6586.
(4) (a) Davies, H. M. L. Tetrahedron 1993, 49, 5203. (b) Davies, H.
M. L. Curr. Org. Chem. 1998, 2, 463. (c) Davies, H. M. L.; Panaro, S.
A. Tetrahedron 2000, 56, 4871.
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(8) Davies, H. M. L. Eur. J . Org. Chem. 1945, 10, 2459.
10.1021/jo015617t CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/30/2001

6596 J . Org. Chem., Vol. 66, No. 20, 2001
Ta ble 1. Syn th esis of Meth yl Heter oa r yld ia zoa ceta tes
Davies and Townsend
a
Reference 12.
of their use in metal-catalyzed intermolecular cyclopro-
panations. The metal-catalyzed reactions of heteroaryl-
diazoacetates are limited to intramolecular capture of the
carbenoid by ylide formation,9a-d,f,g,j,k,n,p-r C-H insertion,9e,l
N-H insertion,9t or cyclopropanation9l and intermolecular
O-H insertion.9u The thermolysis of various heteroaryl-
diazoacetates has been examined.9r,s,u Heteroaryldiaz-
oacetates substituted at the 2-position of electron-rich
heteroaryl rings such as furan are of limited stability at
room temperature,9u but other heteroaryldiazoacetates
appear to have good stability and are easily handled.
(9) (a) Traulsen, T.; Friedrichsen, W. J . Chem. Soc., Perkin Trans.
1 2000, 1387. (b) Sarkar, T. K.; Ghosh, S. K.; Chow, T. J . J . Org. Chem.
2000,65, 3111. (c) Sarkar, T. K.; Basak, S.; Ghosh, S. K. Tetrahedron
Lett. 2000, 41, 759. (d) Sarkar, T. K.; Ghosh, S. K.; Nandy, S. K.; Chow,
T. J . Tetrahedron Lett. 1999, 40, 397. (e) Fernandez-Mateos, A.; Coca,
G. P.; Alonso, J . J . P.; Gonzalez, R. R.; Simmonds, M. S. J .; Blaney, W.
M. Tetrahedron 1998, 54, 14989. (f) Reck, S.; Friedrichsen, W. J . Org.
Chem. 1998, 63, 7680. (g) Reck, S.; Nather, C.; Friedrichsen, W.
Heterocycles 1998, 48, 853. (h) Preu, L.; Beiszner, A.; Moderhack, D.
J . Chem. Soc., Perkin Trans. 2 1998, 785. (i) Fernandez Mateos, A.;
Pascual Coca, G.; Perez Alonso, J . J .; Rubio Gonzalez, R.; Tapia
Hernandez, C. Synlett 1996, 1134. (j) Peters, O.; Freidrichsen, W.
Heterocycl. Commun. 1996, 2, 202. (k) Reck, S.; Bluhnm, K.; Debaer-
demaeker, T.; Declercq, J .-P.; Klenke, B.; Friedrichsen, W. Heterocycles
1996, 43, 1165. (l) Fernandez Mateos, A.; Lopez Barba, A. M. J . Org.
Chem. 1995, 60, 3580. (m) L’Abbe, G.; Luyten, I.; Vercauteren, K.;
Dehaen, W. Bull. Soc. Chim. Belg. 1993, 102, 683. (n) Nagel, J .;
Friedrichsen, W.; Debaerdemaeker, T. Z. Naturforsch., B: Chem. Sci.
1993, 48, 213. (o) L’Abbe, G.; Luyten, I.; Toppet, S. J . Heterocycl. Chem.
1992, 29, 713. (p) Assmann, L.; Debaerdemaeker, T.; Friedrichsen, W.
Tetrahedron Lett. 1991, 32, 1161. (q) Assmann, L.; Friederichsen, W.
Heterocycles 1989, 29, 1003. (r) L’Abbe, G.; Beenaerts, L. Tetrahedron
1989, 45, 749. (s) L’Abbe, G.; Dehaen, W. Tetrahedron 1988, 44, 461.
(t) Andrus, A.; Heck, J . V.; Christensen, B. G.; Partridge, B. J . Am.
Chem. Soc. 1984, 106, 1808. (u) Hoffmann, R. V.; Shechter, H. J . Am.
Chem. Soc. 1978, 100, 7934. (v) Eistert, B.; Donath, P. Chem. Ber. 1969,
102, 1725. (w) Grundmann, C.; Kober, E. J . Am. Chem. Soc. 1957, 79,
944. (x) Eistert, B.; Schade, W. Chem. Ber. 1958, 91, 1. (y) Muchall,
H. M.; Werstiuck, N. H.; Pitters, J .; Workentin, M. S. Tetrahedron
1999, 55, 3767. (z) Regitz, M. Chem. Ber. 1966, 99, 8.
In addition to the stereochemical issues, two other
issues needed to be considered in extending the rhodium-
(II)-catalyzed cyclopropanation to representative hetero-
cycles. First, Lewis basic sites on the heteroaryl ring
systems may interfere with the chemistry either by
complexation to the catalyst or by reaction with the
highly electrophilic carbenoid. Highly electron-rich het-
erocycles may also react with the carbenoid.10 Second,
certain heteroaryldiazoacetates may not be sufficiently
stable to be practical carbenoid precursors such as those
substituted at the 2-position of electron-rich heteroaryl
rings. Consequently, as the focus of this research is on
the development of practical carbenoid precursors, the
electron-rich heterocycles that were examined in this
study were limited to 3-substituted derivatives.
(10) Doyle, M.; McKervey, M.; Ye, T. J ohn Wiley & Sons: New York,
1997; p 163.

Cyclopropanation of Heteroaryldiazoacetates
J . Org. Chem., Vol. 66, No. 20, 2001 6597
The methyl naphthyl- and heteroaryldiazoacetates 13-
19 were readily prepared from the corresponding naph-
thyl and heteroarylacetates 6-12 by a diazo transfer
reaction using p-acetamidobenzenesulfonyl azide (p-
ABSA)11 and DBU in acetonitrile at room temperature
(Table 1). The methyl heteroarylacetates were synthe-
sized by esterification of the corresponding substituted
acetic acids. Some of these substituted acetic acids are
commercially available or were readily formed by one-
carbon homologation of methyl- or methanol-substituted
heteroaryl ring compounds. Experimental procedures
describing the preparation of heteroarylacetates 7-12
and heteroaryldiazoacetates 13-19 are given in the
Supporting Information. All of the heteroaryldiazoac-
etates 13-19 were easily handled and could be stored
for months at -10 °C without any apparent decomposi-
tion. Appropriate care, however, should be taken with
any new diazo compound because many compounds of
this class have the potential to be shock sensitive.
Diazo compounds 14, containing an electron-rich het-
erocycle substituted at the 3-position, were then exam-
ined (eq 4). The thiophene derivative 14a resulted in a
highly efficient cyclopropanation to form 21a , and once
again, as is typical of Rh2(S-DOSP)4-catalyzed reactions,
the highest enantioselectivity was obtained when the
reaction was carried out in hydrocarbon solvent. The
furan derivative 14b containing an electron-withdrawing
substituent also underwent a very effective cyclopropa-
nation. Under the optimized conditions, 21b was formed
in 91% yield, 96% de, and 86% ee. No side reactions due
to intramolecular ylide formation13 were observed.
The cyclopropanation chemistry of aryldiazoacetates
has been primarily focused on the parent methyl phe-
nyldiazoacetate.5 A range of substituted phenyldiazoac-
etates have been shown to be effective substrates for
rhodium-catalyzed intermolecular cyclopropanations and
C-H insertions.12 Even though the phenyl ring was
important for highly selective reactions, either electron
donating or electron withdrawing groups could be toler-
ated on the ring. Thus, it was anticipated that electron-
rich and electron-deficient heterocycles might be capable
of undergoing highly stereoselective cyclopropanations.
As an introduction to this study, the reaction of 1- and
2-naphthyldiazoacetates 13 was examined. The Rh2(S-
DOSP)4-catalyzed cyclopropanation of styrene with the
1-naphthyldiazoacetate 13a at room temperature was
very effective. The reaction at room temperature in CH2-
Cl2 gave 20a in 81% yield, 98% de, and 68% ee, while
the reaction in hexane/toluene gave 20a in 86% yield,
98% de, and 94% ee. Similarly impressive results were
obtained with the 2-naphthyldiazoacetate 13b. The rela-
tive stereochemistry of 20 is readily determined from the
The 3-indolyl derivative 15 was then examined. Rh2-
(S-DOSP)4-catalyzed cyclopropanation of 15 in CH2Cl2 to
form 22 proceeded in good yield (67%) and diastereose-
lectivity (>96% de), but the enantioselectivity was very
low (23% ee). No improvement in enantioselectivity was
obtained when the reaction was carried out in hexane
as solvent. The reason for the poor enantioselectivity with
this substrate is not well understood but there may be
interference due to the bulky N-BOC group.
1
chemical shift for the methyl group in the H NMR. In
the minor diastereomer, the methyl signal is shielded by
0.3-0.5 ppm by the cis phenyl substituent. The improved
enantioselectivity on using hexane/toluene instead of
CH2Cl2 as solvent is characteristic of Rh2(S-DOSP)4-
catalyzed cyclopropanations.6c Even higher enantioselec-
tivity would be expected if the reaction was carried out
at lower temperatures.6c
The next series of diazo compounds 16 contain electron-
deficient heterocycles (eq 6). Furthermore, compounds 16
have Lewis basic sites that could coordinate to the
catalyst or undergo reaction with the carbenoid. All three
diazo compounds under the reaction conditions caused
the color of the reaction to change from green to red, and
such a color change is indicative of coordination of the
heterocycle to the catalyst. In the reactions with CH2Cl2
at room temperature, only the 2-chloropyridin-6-yl sys-
tems 16b resulted in cyclopropanation to form 23b. The
unsubstituted pyridin-2-yl system 16a , however, did
result in a low yield of cyclopropanation to form 23a (59%
yield) under refluxing conditions with 1,2-dichloroethane
as solvent. Neither 16a nor 16b was sufficiently soluble
in hexanes for the reaction to be carried out in that
solvent. Both 23a and 23b were produced with high
diastereoselectivity and moderate enantioselectivity. No
cyclopropanation products were obtained in the reaction
(11) Baum, J . S. S., D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709.
(12) Davies, H. M. L.; Hansen, T.; Churchill, M. R. J . Am. Chem.
Soc. 2000, 122, 3063.
(13) Padwa, A.; Krumpe, K. E. Tetrahedron 1992, 48, 5385.

6598 J . Org. Chem., Vol. 66, No. 20, 2001
Ta ble 2. Asym m etr ic Cyclop r op a n a tion of 1, 1-d ip h yen yleth ylen e
Davies and Townsend
with the pyrazine derivative 16c. Even under forcing
conditions, 16c remained unchanged.
96% de, and 71% ee. This represents another example of
the remarkable solvent effect that is seen in Rh2(S-
DOSP)4-catalyzed cyclopropanations. The color of the Rh2-
(S-DOSP)4-catalyzed reaction for the benzoxazole deriva-
tive 19 was red, indicating coordination of the heterocycle
to the catalyst, and in the reaction in CH2Cl2 at room
temperature, only a 10% yield of cyclopropane 26 was
obtained (eq 9). On using more forcing conditions (re-
fluxing toluene), the yield of 26 was improved to 68%.
Even though the enantioselectivity was reasonable for
such a high-temperature reaction (71% ee), the diaste-
reoselectivity (88% de) was lower that for any of the other
heteroaryldiazoacetates.
The cyclopropanation chemistry of the heteroaryldia-
zoacetates with 1,1-diphenylethylene was also examined,
and the results are summarized in Table 2. For most of
the monocyclic heterocyclic systems, high enantioselec-
tivity (89-97% ee) was obtained. The enantioselectivity
was slightly lower for the indole 27c (67% ee), but a
similar result was also seen in the cyclopropanation of
styrene. Refluxing conditions were required for the
decomposition of the pyridinyldiazoacetate 16a and the
benzoxazolyldiazoacetate 19, and under these forcing
conditions the cyclopropanes 27d and 27h were formed
in 70-80% ee. Except for the furanyl derivative 27b, the
The final series of heteroaryldiazoacetates that were
examined were the isoxazole 17, oxazole 18, and benzox-
azole 19 derivatives. The isoxazole derivative 17 was an
exceptional system, and under the optimized conditions,
the cyclopropane 24 was formed in 84% yield, 93% de,
and 86% ee (eq 7). The standard reaction for the oxazole
in CH2Cl2 resulted in the formation of 25 in only 12% ee
(eq 8). On changing the reaction solvent, however, to a
toluene/hexane mixture 25 was formed in 81% yield,

Cyclopropanation of Heteroaryldiazoacetates
J . Org. Chem., Vol. 66, No. 20, 2001 6599
zoacetates. This model has been an excellent predictor
of the absolute stereochemistry that is obtained in these
cyclopropanations.6c,8 The drawn absolute stereochemis-
try for the cyclopropane products has not been deter-
mined but is that predicted from this model.
In summary, these studies demonstrate that a much
wider range of carbenoid intermediates can be generated
that contain both donor and acceptor groups. The cyclo-
propanation reactions of these carbenoids are highly
diastereoselective and with Rh2(S-DOSP)4 as catalyst are
highly enantioselective. Considering the aryldiazoac-
etates have been recently demonstrated to be highly
effective in catalytic asymmetric C-H activation reac-
tions,12 it is reasonable to expect that many of the
heteroaryldiazoacetates would also be effective in this
chemistry. Thus the opportunity exists for the utilization
of heteroaryldiazoacetates for the asymmetric synthesis
of aromatic heterocycles containing side chains with
multiple chiral centers.
desired cyclopropanes 27 were formed in moderate to
good yields (58-91%).
These studies demonstrate that the carbenoids derived
from methyl heteroaryldiazoacetates exhibit similar cy-
clopropanation stereoselectivity to other classes of car-
benoids containing both donor and acceptor substituents.
This stereoselectivity occurs when the heterocycle is
either electron rich or electron deficient. A similar effect
was seen with the substituted phenyldiazoacetatessthe
phenyl ring is a requirement but the effect on stereose-
lectivity of electron-donating or -withdrawing substitu-
ents is minimal. Presumably, the carbenoid center is so
electron deficient that it can be stabilized by virtually
any aromatic system, even those that would be formally
considered as electron deficient. The most serious limita-
tion with the heteroaryldiazoacetates is the use of
heterocycles that are strongly Lewis basic. With these
types of heteroaryldiazoacetates, the reactions are very
slow or fail completely, presumably because the hetero-
cycles coordinate strongly to the catalyst, inhibiting the
coordination of the diazo function, which is a prerequisite
step for the nitrogen extrusion and carbenoid formation.
The general model that has been used to explain the
stereoselectivity in these reactions is illustrated in eq
10.6c,8 The Rh2(S-DOSP)4 catalyst is viewed as if it has
D2 symmetry and can be simply considered as having two
blocking groups represented by the thick vertical lines.
The alkene approached the carbene side-on over the
electron-withdrawing group in a concerted but nonsyn-
chronous manner. Finally, rotation of the alkene away
from the catalysts would lead to the cyclopropane where
the alkene substituent is cis to the electron-donating
group of the carbenoid. This relative stereochemistry is
in agreement with that observed with the heteroaryldia-
Exp er im en ta l Section
Gen er a l In for m a tion . Reactions were performed using
heat-gun-dried glassware under an atmosphere of argon.
Tetrahydrofuran (THF) and hexanes were distilled from
sodium benzophenone ketyl prior to use. Acetonitrile (CH3CN),
toluene, diisopropylamine, dichloromethane (CH2Cl2), and 1,2-
dichloroethane (ClCH2CH2Cl) were distilled from calcium
hydride. All reaction solvents were degassed by argon gas
bubbling for about 30 min prior to use.
Gen er a l P r oced u r e for Meth yl Heter oa r yld ia zoa c-
eta te P r ep a r a tion . p-ABSA (10 mmol) was added to a
solution of the heteroaryl acetate (5 mmol) and DBU (25 mmol)
in CH3CN (30 mL) at 0 °C. The reaction mixture was allowed
to warm to room temperature over 4 h and then concentrated
in vacuo and diluted in CH2Cl2. The organic phase was washed
with water, dried (Na2SO4), and concentrated in vacuo.
Purification by silica gel chromatography (4:1 pentane/Et2O)
gave the methyl heteroaryldiazoacetate. The complete experi-
mental for the preparation of the methyl heteroaryldiazoac-
etates and their precursors is given in the Supporting Infor-
mation.
Gen er a l P r oced u r e for th e Rh od iu m (II)-Ca ta lyzed
Decom p osition of Heter oa r yld ia zoa ceta tes in th e P r es-
en ce of Alk en es. A solution of diazo (1 equiv, 0.05-0.1 M) in
hexanes, CH2Cl2, ClCH2CH2Cl, toluene, or some combination
of these solvents was added dropwise over 20 min to 3 h to a
stirred solution of alkene (5 equiv) in hexanes, CH2Cl2, ClCH2-
CH2Cl, or toluene at room temperature or heated at reflux.
After 30 min to 22 h, the reaction mixture was concentrated
in vacuo and the residue was purified by silica gel chroma-
tography. The diastereomer ratio of the cyclopropane product
was determined from the 1H NMR spectra of the crude reaction
mixture unless otherwise stated. The enantiomeric excess of

6600 J . Org. Chem., Vol. 66, No. 20, 2001
Davies and Townsend
the cyclopropane product was determined by chiral HPLC
using a Diacel Chiralcel-OD or (R,R)-Whelk-O1 analytical
column.
a solution of styrene (0.31 g, 0.35 mL, 3.0 mmol) and Rh2(S-
DOSP)4 (23 mg, 12 µmol) in CH2Cl2 (1 mL) at room temper-
ature. The reaction mixture was stirred at room temperature
for 2 h and then concentrated in vacuo to give 21a (95% de).
Purification by silica gel chromatography (97:3 pentane/Et2O)
gave the major diastereomer 21a (0.133 g, 85%): Rf 0.24 (9:1
pentane/Et2O); 78% ee (Chiralcel-OD, 0.8 mL/min, 0.6% i-
(1R,2S)-Meth yl 1-(Na p h th -1-yl)-2-p h en ylcyclop r op a n -
eca r boxyla te (20a ). A solution of 13a (0.205 g, 0.906 mmol)
in CH2Cl2 (10 mL) was added dropwise over 2.5 h to a solution
of Rh2(S-DOSP)4 (20 mg, 11 µmol) and styrene (0.47 g, 0.52
mL, 4.5 mmol) in CH2Cl2 (1 mL) at room temperature. The
reaction mixture was stirred at room temperature for 12 h and
then concentrated in vacuo to give 20a (98% de, determined
by GC-MS). Purification by silica gel chromatography (97:3
pentane/Et2O) gave the major diastereomer 20a (0.22 g,
81%): Rf 0.39 (9:1 pentane/Et2O); 68% ee (Chiralcel-OD, 1 mL/
PrOH/hexanes, tR ) 18.2 and 19.6 min); [R]25 -12.7° (c 1.04,
D
CHCl3); mp 81-83 °C; IR (film) 3105, 3028, 2950, 2847, 1717,
1
1499 cm-1; H NMR (500 MHz; CDCl3) δ 7.08 (m, 3H), 7.01
(dd, 1H, J ) 5.0, 3.0 Hz), 6.90 (dd, 1H, J ) 3.0, 1.0 Hz), 6.85
(m, 2H), 6.67 (dd, 1H, J ) 5.0, 1.0 Hz), 3.69 (s, 3H), 3.05 (dd,
1H, J ) 9.0, 7.0 Hz), 2.12 (dd, 1H, J ) 9.0, 5.0 Hz), 1.88 (dd,
1H, J ) 7.0, 5.0 Hz); 13C NMR (125 MHz; CDCl3) δ 173.9 (s),
136.1 (s), 135.6 (s), 130.3 (d), 127.9 (d), 127.7 (d), 126.4 (d),
125.2 (d), 124.3 (d), 52.5 (q), 33.4 (d), 32.4 (s), 20.5 (t); MS m/z
(relative intensity) 258 (47, M+), 226 (100), 197 (53), 165 (46),
115 (86); HRMS-EI (calcd for C15H14O2S) 258.0714, found
258.0730. Anal. Calcd for C15H14O2S: C, 69.74; H, 5.46.
Found: C, 69.64; H, 5.64.
min, 1.2% i-PrOH/hexanes, tR ) 13.3 and 15.4 min); [R]25
D
-98.2° (c 1.2, CHCl3); IR (film) 3040, 2949, 2918, 2849, 1716,
1598, 1502 cm-1; 1H NMR (500 MHz; CDCl3, -20 °C) δ (3.6:1
mixture of rotamers) 8.21 (d, 1H, J ) 8.0 Hz, minor), 7.87 (d,
1H, J ) 8.0 Hz, minor), 7.70 (d, 1H, J ) 8.0 Hz, major), 7.65-
7.5 (m, 3H + 1H major), 7.46 (t, 1H, J ) 7.6 Hz, major), 7.26-
7.10 (m, 2H), 7.04 (t, 1H, J ) 7.6 Hz, minor), 6.8-6.7 (m,
3H+1H minor), 6.59 (d, 1H, J ) 6.8 Hz, minor), 3.57 (s, 3H,
minor), 3.55 (s, 3H, major), 3.47 (dd, 1H, J ) 7.6, 9.2 Hz,
major), 3.23 (app t, 1H, J ) 8.8 Hz, minor), 2.60 (dd, 1H, J )
4.8, 9.6 Hz, minor), 2.20 (dd, 1H, J ) 4.8, 9.2 Hz, major), 2.11
(app t, 1H, J ) 6.8 Hz, major), 1.84 (dd, 1H, 1H, J ) 4.8, 7.2
Hz, minor); 13C NMR (125 MHz; CDCl3, 0 °C) δ (3.6:1 mixture
of rotamers) 174.5, 136.7, 135.5, 133.5, 132.7, 131.6, 131.3,
129.8, 128.7, 128.4, 128.0, 127.7, 127.6, 126.9, 126.3, 125.8,
124.8, 124.3, 52.5, 34.0 (minor), 32.8 (major), 23.3 (minor), 21.5
(major); MS m/z (relative intensity) 302 (100, M+), 270 (52),
240 (65), 165 (77); HRMS-EI calcd for C21H18O2 302.1307, found
302.1313.
A solution of 14a (49.5 mg, 0.271 mmol) in hexanes (4 mL)
was added dropwise over 20 min to a solution of styrene (0.14
g, 0.16 mL, 1.4 mmol) and Rh2(S-DOSP)4 (10 mg, 5.4 µmol) in
hexanes (1 mL) at room temperature. The reaction mixture
was stirred at room temperature for 1 h and then concentrated
in vacuo to give 21a (96% de). Purification by silica gel
chromatography (95:5 pentane/Et2O) gave the major diaster-
eomeric 21a (61 mg, 87%): 89% ee; [R]25 -13.2° (c 1.75,
D
CHCl3).
(1R,2S)-Meth yl 1-(3-Meth oxycar bon ylfu r an -4-yl)-2-ph e-
n ylcyclop r op a n eca r boxyla te (21b). A solution of 14b (0.101
g, 0.451 mmol) in CH2Cl2 (10 mL) was added dropwise over 1
h to a solution of styrene (0.23 g, 0.26 mL, 2.3 mmol) and Rh2-
(S-DOSP)4 (17 mg, 9.0 µmol) in CH2Cl2 (1 mL) containing 4 Å
molecular sieves (0.5 g) at room temperature. The reaction
mixture was stirred at room temperature for 8 h and then
concentrated in vacuo to give 21b (97% de). Purification by
silica gel chromatography (4:1 pentane/Et2O) gave the major
diastereomer 21b (0.109 g, 81%): Rf 0.31 (1:1 pentane/Et2O);
A solution of 13a (0.214 g, 0.946 mmol) in hexanes/toluene
(10 mL, 4:1) was added dropwise over 2.5 h to a solution of
Rh2(S-DOSP)4 (35 mg, 18.9 µmol) and styrene (0.49 g, 0.54 mL,
4.7 mmol) in hexanes (1 mL) at room temperature. The
reaction mixture was stirred at room temperature for 12 h and
then concentrated in vacuo to give 20a (98% de, determined
by GC-MS). Purification by silica gel chromatography (97:3
pentane/Et2O) gave the major diastereomer 20a (0.25 g,
81% ee (Chiralcel-OD, 1 mL/min, 1.2% i-PrOH/hexanes, tR
)
86%): 94% ee; [R]25 -134° (c 1.46, CHCl3).
22.5 and 42.0 min); [R]25D -129° (c 0.65, CHCl3); IR (film) 3147,
3086, 3028, 2951, 2852, 1724, 1602, 1549, 1500 cm-1; 1H NMR
(500 MHz; CDCl3) δ 7.72 (s, 1H), 7.11 (m, 3H), 7.02 (br s, 1H),
6.97 (m, 2H), 3.71 (s, 3H), 3.68 (s, 3H), 3.29 (dd, 1H, J ) 9.0,
7.5 Hz), 1.96 (dd, 1H, J ) 9.0, 5.0 Hz), 1.80 (dd, 1H, J ) 7.5,
5.0 Hz); 13C NMR (125 MHz; CDCl3) δ 173.4 (s), 162.9 (s), 148.4
(d), 143.3 (d), 135.6 (s), 128.3 (d), 127.6 (d), 126.6 (d), 120.6
(s), 119.1 (s), 52.4 (q), 51.2 (q), 31.9 (d), 27.7 (s), 19.7 (t); MS
m/z(relative intensity) 300 (1, M+), 268 (16), 236 (100); HRMS-
EI (calcd for C17H16O5) 300.0998, found 300.1003. Anal. Calcd
for C17H16O5: C, 67.99; H, 5.37. Found: C, 67.96; H, 5.49.
A solution of 14b (0.105 g, 0.468 mmol) in hexanes/CH2Cl2
(9 mL, 8:1) was added dropwise over 20 min to a solution of
styrene (0.24 g, 0.27 mL, 2.3 mmol) and Rh2(S-DOSP)4 (18 mg,
9.4 µmol) in hexanes (1 mL) at room temperature. The reaction
mixture was stirred at room temperature for 1 h and then
concentrated in vacuo to give 21b (96% de). Purification by
silica gel chromatography (4:1 pentane/Et2O) gave the major
D
(1R,2S)-Meth yl 1-(Na p h th -2-yl)-2-p h en ylcyclop r op a n -
eca r boxyla te (20b). A solution of 13b (0.139 g, 0.614 mmol)
in CH2Cl2 (10 mL) was added dropwise over 1.5 h to a solution
of Rh2(S-DOSP)4 (23 mg, 9.8 µmol) and styrene (0.32 g, 0.35
mL, 3.1 mmol) in CH2Cl2 (1 mL) at room temperature. The
reaction mixture was stirred at room temperature for 10 h and
then concentrated in vacuo to give 20b (98% de). Purification
by silica gel chromatography (97:3 pentane/Et2O) gave the
major diastereomeric cyclopropane 20b (0.16 g, 87%): Rf 0.29
(9:1 pentane/Et2O); 80% ee (Chiralcel-OD, 0.8 mL/min, 0.3%
i-PrOH/hexanes, tR ) 28.3 and 31.7 min); [R]25D +73.6° (c 1.62,
CHCl3); IR (film) 3055, 3025, 2950, 1717, 1602, 1500 cm-1; 1H
NMR (500 MHz; CDCl3) δ 7.70 (dd, 2H, J ) 9.5, 5.5 Hz), 7.60
(s, 1H), 7.53 (d, 1H, J ) 9.0 Hz), 7.41 (dd, 1H, J ) 9.5, 5.0
Hz), 7.39 (dd, 1H, J ) 9.5, 4.5 Hz), 7.02 (dd, 1H, J ) 8.0, 1.0
Hz), 6.99 (m, 3H), 6.80 (dd, 2H, J ) 6.5, 3.0 Hz), 3.18 (dd, 1H,
J ) 9.0, 7.5 Hz), 2.21 (dd, 1H, J ) 9.0, 5.0 Hz), 2.01 (dd, 1H,
J ) 7.5, 5.0 Hz); 13C NMR (125 MHz; CDCl3) δ 174.4, 136.1,
132.9, 132.6, 132.4, 130.5, 130.1, 128.0, 127.7, 127.6, 127.5,
127.0, 126.3, 125.8, 125.7, 52.6, 37.5, 33.2, 20.6; MS m/z
(relative intensity) 302 (100, M+), 270 (95), 241 (90), 165 (86);
HRMS-EI calcd for C21H18O2 302.1307, found 302.1333.
A solution of 13b (0.102 g, 0.451 mmol) in hexanes/toluene
(10 mL, 4:1) was added dropwise over 1.5 h to a solution of
Rh2(S-DOSP)4 (18 mg, 9.8 µmol) and styrene (0.24 g, 0.26 mL,
2.3 mmol) in hexanes (1 mL) at room temperature. The
reaction mixture was stirred at room temperature for 12 h and
then concentrated in vacuo to give 20b (90% de). Purification
by silica gel chromatography (97:3 pentane/Et2O) gave the
diastereomer 21b (0.128 g, 91%): 86% ee; [R]25 -126° (c 1.6,
D
CHCl3).
(1R,2S)-Meth yl 1-(1-ter t-Bu tyloxyca r bon ylin d ol-3-yl)-
2-p h en ylcyclop r op a n eca r boxyla te (22). A solution of 15
(0.122 g, 0.387 mmol) in CH2Cl2 (6 mL) was added dropwise
over 20 min to a solution of styrene (0.20 g, 0.22 mL, 1.9 mmol)
and Rh2(S-DOSP)4 (15 mg, 7.7 µmol) in CH2Cl2 (1 mL) at room
temperature. The reaction mixture was stirred at room tem-
perature for 2 h and then concentrated in vacuo to give 22
(97% de). Purification by silica gel chromatography (97:3
pentane/Et2O) gave the major diastereomer 22 (0.102 g,
67%): Rf 0.19 (9:1 pentane/Et2O); 23% ee (Chiralcel-OD, 0.8
major diastereomer 20b (0.106 g, 78%): 90% ee; [R]25 +100°
mL/min, 0.6% i-PrOH/hexanes, tR ) 17.2 and 28.4 min); [R]25
D
D
(c 1.4, CHCl3).
+4.22° (c 1.66, CHCl3); IR (film) 3061, 2977, 2854, 1726, 1607
1
(1R,2S)-Met h yl 2-P h en yl-1-(t h iop h en -3-yl)cyclop r o-
p a n eca r boxyla te (21a ). A solution of 14a (0.110 g, 0.387
mmol) in CH2Cl2 (12 mL) was added dropwise over 20 min to
cm-1; H NMR (500 MHz; CDCl3) δ 7.99 (br m, 1H), 7.32 (d,
1H, J ) 10.0 Hz), 7.19 (dd, 1H, J ) 9.5, 9.5 Hz), 7.09 (dd, 1H,
J ) 9.0, 9.0 Hz), 7.05-6.95 (m, 6H), 3.65 (s, 3H), 3.23 (dd, 1H,

Cyclopropanation of Heteroaryldiazoacetates
J . Org. Chem., Vol. 66, No. 20, 2001 6601
J ) 12.0, 9.0 Hz), 2.18 (dd, 1H, J ) 9.0, 6.0 Hz), 1.87 (dd, 1H,
J ) 9.0, 6.0 Hz), 1.58 (s, 9H); 13C NMR (125 MHz; CDCl3) δ
174.1 (s), 149.4 (s), 136.1 (s), 135.0 (s), 130.9 (s), 128.3 (d), 127.7
(d), 126.6 (d), 126.5 (d), 124.1 (d), 122.3 (d), 119.7 (d), 115.2
(s), 114.9 (d), 83.4 (s), 52.6 (q), 32.9 (d), 28.3 (s), 28.1 (q), 20.2
(t); MS m/z (relative intensity) 391 (11, M+), 335 (20), 291 (39),
259 (66); HRMS-EI (calcd for C24H25NO4) 391.1784, found
391.1768. Anal. Calcd for C24H25NO4: C, 73.64; H, 6.44; N,
3.58. Found: C, 73.41; H, 6.66; N, 3.39.
then cooled and concentrated in vacuo. Peaks that would be
characteristic of 23c were not evident in the 1H NMR spectrum
of the crude reaction mixture.
(1R,2S)-Meth yl 1-(3-Meth ylisoxa zol-5-yl)-2-p h en ylcy-
clop r op a n eca r boxyla te (24). A solution of 17 (90 mg, 0.50
mmol) in CH2Cl2 (10 mL) was added dropwise over 30 min to
a solution of styrene (0.26 g, 0.28 mL, 2.5 mmol) and Rh2(S-
DOSP)4 (18 mg, 9.9 µmol) in CH2Cl2 (1 mL) at room temper-
ature. The reaction mixture was stirred at room temperature
for 1 h and then concentrated in vacuo to give 24 (95% de).
Purification by silica gel chromatography (9:1 hexanes/Et2O)
gave the major diastereomer 24 (0.12 g, 79%): Rf 0.34 (1:1
pentane/Et2O); 76% ee (Chiralcel-OD, 0.8 mL/min, 0.6% i-
A solution of 15 (71 mg, 0.23 mmol) in hexanes (6 mL) was
added dropwise over 20 min to a solution of styrene (0.12 g,
0.13 mL, 1.1 mmol) and Rh2(S-DOSP)4 (9 mg, 5 µmol) in
hexanes (1 mL) at room temperature. The reaction mixture
was stirred at room temperature for 12 h and then concen-
trated in vacuo to give 22 (94% de). Purification by silica gel
chromatography (97:3 pentane/Et2O) gave the major diaste-
reomer 22 (74 mg, 82%): 12% ee; [R]25D -2.77° (c 0.65, CHCl3).
(1R,2S)-Meth yl 2-P h en yl-1-(p yr id in -2-yl)cyclop r op a n -
eca r boxyla te (23a ). A solution of 16a (56 mg, 0.32 mmol) in
ClCH2CH2Cl (6 mL) was added dropwise over 2.5 h to a
solution of styrene (0.21 g, 0.23 mL, 2.0 mmol) and Rh2(S-
DOSP)4 (12 mg, 8.1 µmol) in ClCH2CH2Cl (1 mL) heated at
reflux. The reaction mixture was heated at reflux for 22 h and
then concentrated in vacuo to give 23a (91% de). Purification
by silica gel chromatography (3:1 pentane/EtOAc) gave the
major diastereomer 23a (47 mg, 59%) and recovered 16a (5
mg, 9% recovery). 23a : Rf 0.31 (2:1 pentane/EtOAc); 47%ee
(Chiralcel-OD, 1 mL/min, 1.2% i-PrOH/hexanes, tR ) 16.6 and
PrOH/hexanes, tR ) 37.5 and 39.5 min); [R]25 -63.5° (c 1.62,
D
CHCl3); mp 70-71 °C; IR (film) 3025, 2953, 1726, 1611, 1434
cm-1; 1H NMR (500 MHz; CDCl3) δ 7.15 (m, 3H), 7.02 (m, 2H),
5.73 (s, 1H), 3.75 (s, 3H), 3.23 (dd, 1H, J ) 8.6, 8.4 Hz), 2.17
(m, 2H); 13C NMR (125 MHz; CDCl3) δ 171.1 (s), 166.0 (s), 159.4
(s), 128.2 (d), 128.1 (d), 127.3 (d), 106.4 (d), 52.8 (q), 34.6 (d),
29.1 (s), 19.8 (t), 11.3 (q). Anal. Calcd for C15H15NO3: C, 70.02;
H, 5.88, N, 5.44. Found: C, 70.08; H, 5.79; N, 5.50. A solution
of 17 (0.101 g, 0.558 mmol) in hexanes (10 mL) was added
dropwise over 1 h to a solution of styrene (0.29 g, 0.32 mL, 2.8
mmol) and Rh2(S-DOSP)4 (21 mg, 11 µmol) in hexanes (1 mL)
at room temperature. The reaction mixture was stirred at room
temperature for 3 h and then concentrated in vacuo to give
24 (93% de). Purification by silica gel chromatography (9:1
hexanes/Et2O) gave the major diastereomer 24 (0.12 g, 84%):
26.1 min). [R]25 -17.0° (c 1.05, CHCl3); IR (film) 3056, 3022,
86% ee; [R]25 -74.4° (c 1.3, CHCl3).
D
D
2951, 2852, 1720, 1589 cm-1
;
1H NMR (500 MHz; CDCl3) δ
(1R,2S)-Meth yl 1-(4,5-Dip h en yloxa zol-2-yl)-2-p h en yl-
cyclop r op a n eca r boxyla te (25). A solution of 18 (0.135 g,
0.423 mmol) in CH2Cl2 (8 mL) was added dropwise over 1 h to
a solution of styrene (0.22 g, 0.24 mL, 2.1 mmol) and Rh2(S-
DOSP)4 (16 mg, 8.5 µmol) in CH2Cl2 (1 mL) containing 4 Å
molecular sieves (0.5 g) at room temperature. The reaction
mixture was stirred at room temperature for 1 h and then
concentrated in vacuo to give 25 (97% de). Purification by silica
gel chromatography (4:1 pentane/Et2O) gave the major dias-
tereomer 25 (0.136 g, 81%): Rf 0.47 (1:1 pentane/Et2O); 12%
ee (Chiralcel-OD, 0.8 mL/min, 0.6% i-PrOH/hexanes, tR ) 18.8
8.44 (d, 1H, J ) 5.5 Hz), 7.34 (ddd, 1H, J ) 9.5, 9.5, 1.5 Hz),
7.03 (m, 4H), 6.90 (d, 1H, J ) 10.5 Hz), 6.80 (m, 2H), 3.68 (s,
3H), 3.23 (dd, 1H, J ) 11.5, 9.5 Hz), 2.36 (dd, 1H, J ) 9.5, 6.5
Hz), 2.13 (dd, 1H, J ) 11.5, 6.5 Hz); 13C NMR (125 MHz;
CDCl3) δ 173.4, 154.2, 148.5, 135.9, 135.4, 127.9, 127.7, 127.5,
126.4, 121.9, 52.6, 39.2, 33.8, 19.4; MS m/z(relative intensity)
253 (51, M+), 222 (8), 193 (100); HRMS-EI (calcd for C16H15
NO2) 253.1103, found 253.1113.
-
(1R,2S)-Met h yl 1-(2-Ch lor op yr id in -6-yl)-2-p h en ylcy-
clop r op a n eca r boxyla te (23b). A solution of diazo 16b (0.100
g, 0.473 mmol) in CH2Cl2 (10 mL) was added dropwise over 1
h to a solution of styrene (0.25 g, 0.27 mL, 2.4 mmol) and Rh2-
(S-DOSP)4 (18 mg, 9.5 µmol) in CH2Cl2 (2 mL) containing 4 Å
molecular sieves (0.5 g) at room temperature. The reaction
mixture was stirred at room temperature for 2 h and then
concentrated in vacuo to give 23b (97% de). Purification by
silica gel chromatography (4:1 pentane/Et2O) gave the major
diastereomer 23b (0.12 g, 91%): Rf 0.69 (2:1 pentane/EtOAc);
and 21.7 min) [R]25 -13.1° (c 1.22, CHCl3); IR (film) 3060,
D
3031, 2952, 2850, 1731, 1604, 1500, 1435, 1435 cm-1; 1H NMR
(500 MHz; CDCl3) δ 7.49 (d, 2H, J ) 7.0 Hz), 7.35-7.08 (br
m, 13H), 3.76 (s, 3H), 3.32 (dd, 2H, J ) 8.0, 9.1 Hz), 2.51 (dd,
1H, J ) 8.0, 5.3 Hz), 2.19 (dd, 1H, J ) 9.1, 5.3 Hz); 13C NMR
(125 MHz; CDCl3) δ 171.2 (s), 157.4 (s), 146.2 (s), 134.8 (s),
134.6 (s), 128.7 (s), 128.3 (d), 128.0 (d), 127.9 (d), 127.8 (d),
127.7 (d), 127.1 (d), 126.6 (d), 52.8 (q), 34.0 (d), 31.0 (s), 20.7
(t); MS m/z (relative intensity) 395 (100, M+), 363 (73), 335
(17), 258 (39); HRMS-EI (calcd for C26H21NO3) 395.1521, found
395.1515. Anal. Calcd for C26H21NO3: C, 78.97; H, 5.35, N,
3.54. Found: C,79.01; H, 5.55; N, 3.46.
69% ee (Chiralcel-OD, 1 mL/min, 0.8% i-PrOH/hexanes, tR
)
10.4 and 14.4 min); [R]25 +63.0° (c 1.08, CHCl3); IR (film)
D
3062, 3029, 2951, 1723, 1583, 1557 cm-1; 1H NMR (500 MHz;
CDCl3) δ 7.33 (dd, 1H, J ) 7.7, 7.7 Hz), 7.08 (m, 4H), 6.86 (m,
3H), 3.72 (s, 3H), 3.27 (dd, 1H, J ) 9.2, 7.6), 2.41 (dd, 1H, J )
7.6, 5.5 Hz), 2.16 (dd, 1H, J ) 9.2, 5.5 Hz); 13C NMR (125 MHz;
CDCl3) δ 172.8 (s), 155.1 (s), 149.9 (s), 138.0 (d), 135.4 (s), 127.9
(d), 127.8 (d), 126.3 (d), 126.0 (d), 122.4 (d), 52.6 (q), 38.8 (s),
34.2 (d), 19.4 (t); MS m/z (relative intensity) 287 (50, M+), 255
(25), 227 (100), 191 (20); HRMS-EI (calcd for C16H14ClNO2)
211.0149, found 211.0135; Anal. Calcd for C16H14ClNO2: C,
66.79; H, 4.90, N, 4.87. Found: C, 67.11; H, 5.00; N, 4.83.
A solution of 16b (28 mg, 0.13 mmol) in CH2Cl2/hexanes
(2.25 mL, 2:1) was added dropwise over 20 min to a solution
of styrene (69 mg, 76 µL, 0.66 mmol) and Rh2(S-DOSP)4 (5.0
mg, 2.6 µmol) in hexanes (0.5 mL) at room temperature. The
reaction mixture was stirred at room temperature for 2 h and
then concentrated in vacuo to give 23b (98% de). Purification
by silica gel chromatography (9:1 pentane/EtOAc) gave the
A solution of 18 (45.9 mg, 0.144 mmol) in hexanes/toluene
(2.5 mL, 3:2) was added dropwise over 20 min to a solution of
styrene (0.15 g, 0.16 mL, 1.4 mmol) and Rh2(S-DOSP)4 (9.0
mg, 4.8 µmol) in hexanes (1 mL) at room temperature. The
reaction mixture was stirred at room temperature for 14 h and
then concentrated in vacuo to give 25 (96% de). Purification
by silica gel chromatography (4:1 pentane/Et2O) gave the major
diastereomer 25 (46 mg, 81%): 71% ee; [R]25 -76.1° (c 0.92,
D
CHCl3).
(1R,2S)-Meth yl 1-(Ben zoxa zol-2-yl)-2-p h en ylcyclop r o-
p a n eca r boxyla te (26). A solution of 19 (60 mg, 0.28 mmol)
in CH2Cl2 (5 mL) was added dropwise over 20 min to a solution
of styrene (0.14 g, 0.16 mL, 1.4 mmol) and Rh2(R-DOSP)4 (10
mg, 5.5 µmol) in CH2Cl2 (2 mL) at room temperature. The
reaction mixture was stirred at room temperature for 18 h and
then concentrated in vacuo to give 26 (89% de). Purification
by silica gel chromatography (95:5 pentane/EtOAc) gave the
major diastereomer 26 (7 mg, 10%) and recovered 19 (40 mg,
67% recovery). 26: Rf 0.49 (2:1 pentane/EtOAc); 37% ee
(Chiralcel-OD, 0.8 mL/min, 0.6% i-PrOH/hexanes, tR ) 26.5
major diastereomer 23b (30 mg, 79%): 72% ee; [R]25 +64.2°
D
(c 1.3, CHCl3).
Attem p ted Cyclop r op a n a tion of Meth yl (P yr a zin -2-yl)-
d ia zoa ceta te (16c). A solution of 16c (4 mg, 22.5 µmol) in
ClCH2CH2Cl (2 mL) was added dropwise over 20 min to a
solution of styrene (47 mg, 52 µL, 0.45 mmol) and Rh2(S-
DOSP)4 (1 mg, 0.45 µmol) in ClCH2CH2Cl (0.5 mL) heated at
reflux. The reaction mixture was heated at reflux for 12 h and
and 29.9 min); [R]25 +22.0° (c 0.6, CHCl3); IR (film) 3089,
D
3061, 3031, 2953, 1732, 1613, 1573 cm-1; 1H NMR (500 MHz;
CDCl3) δ 7.60 (m, 1H), 7.30 (m, 1H), 7.06 (m, 5H), 3.76 (s, 3H),

6602 J . Org. Chem., Vol. 66, No. 20, 2001
Davies and Townsend
3.38 (dd, 1H, J ) 9.1, 8.2 Hz), 2.58 (dd, 1H, J ) 9.1, 5.2 Hz);
13C NMR (125 MHz; CDCl3) δ 170.7, 160.8, 151.1, 140.4, 134.2,
128.0, 127.7, 127.2, 124.8, 123.9, 119.8, 110.2, 82.9, 34.3, 31.9,
20.7; MS m/z (relative intensity) 293 (9, M+), 261 (14), 233 (12),
204 (7), 181 (9); HRMS-EI (calcd for C18H15NO3) 293.1052,
found 293.1061. Anal. Calcd for C18H15NO3: C, 73.71; H, 5.15,
N, 4.78. Found: C, 73.58; H, 5.36; N, 4.77.
MHz; CDCl3) δ 171.4, 149.3, 142.0, 139.8, 135.0, 130.8, 129.8,
128.8, 128.4, 127.6, 127.0, 126.7, 126.5, 124.1, 122.4, 120.5,
116.7, 114.9, 83.4, 52.2, 44.8, 34.4, 28.1, 23.4; MS m/z (relative
intensity) 467 (10, M+), 411 (8), 367 (36), 335 (54), 306 (41);
HRMS-EI (calcd for C30H29NO4) 467.2096 found 467.2051.
(1R)-Met h yl 2,2-Dip h en yl-1-(p yr id in -2-yl)cyclop r o-
p a n eca r boxyla te (27d ). A solution of 16a (56 mg, 0.32 mmol)
in ClCH2CH2Cl (6 mL) was added dropwise over 2.5 h to a
solution of Rh2(S-DOSP)4 (12 mg, 6.3 µmol) and 1,1-diphenyl-
ethylene (0.29 g, 0.28 mL, 1.6 mmol) in ClCH2CH2Cl (1 mL)
heated at reflux. The reaction mixture was heated at reflux
for 22 h and then concentrated in vacuo. Purification by silica
gel chromatography (2:1 pentane/EtOAc) gave 27d (59 mg,
58%) and recovered 18a (1 mg, 2% recovery). 27d : Rf 0.53 (2:1
pentane/EtOAc); 78% ee ((R,R)-Whelk-O1, 1 mL/min, 2.0%
i-PrOH/hexanes, tR ) 15.0 and 30.7 min); [R]25D +195° (c 0.82,
CHCl3); mp 138-139 °C; IR (film) 3083, 3057, 3024, 2948,
2928, 2850, 1720, 1588, 1567 cm-1; 1H NMR (500 MHz; CDCl3)
δ 8.35 (d, 1H, J ) 4.0 Hz), 7.58 (d, 1H, J ) 8.0 Hz), 7.50 (d,
2H, J ) 7.5 Hz), 7.42 (ddd, 1H, J ) 7.5, 7.5, 1.0 Hz), 7.31 (dd,
2H, J ) 8.0, 8.0 Hz), 7.23 (dd, 1H, J ) 7.0, 5.0 Hz), 7.04 (d,
2H, J ) 8.0 Hz), 6.95 (m, 4H), 3.32 (s, 3H), 2.95 (d, 1H, J )
5.0 Hz), 2.70 (d, 1H, J ) 5.0 Hz); 13C NMR (125 MHz; CDCl3)
δ 170.8 (s), 154.7 (s), 148.1 (d), 141.9 (s), 139.5 (s), 135.1 (d),
129.5 (d), 128.7 (d), 128.3 (d), 128.0 (d), 127.6 (d), 126.8 (d),
126.1 (d), 121.7 (d), 51.9 (q), 46.2 (s), 44.1 (s), 21.9 (t); MS m/z
(relative intensity) 329 (77, M+), 297 (14), 268 (100); HRMS-
EI (calcd for C22H19NO2) 329.1416, found 329.1425.
A solution of 19 (99.5 mg, 0.459 mmol) in toluene (6 mL)
was added dropwise over 40 min to a solution of styrene (0.24
g, 0.26 mL, 2.3 mmol) and Rh2(S-DOSP)4 (17 mg, 9.2 µmol) in
toluene (2 mL) heated at reflux. The reaction mixture was
heated at reflux for 6 h and then concentrated in vacuo to give
26 (85% de). Purification by silica gel chromatography (95:5
pentane/EtOAc) gave the major diastereomer 26 (93 mg,
68%): 71% ee; [R]25 -69.8° (c 2.15, CHCl3).
D
(1R)-Meth yl 2,2-Dip h en yl-1-(th iop h en -3-yl)cyclop r o-
p a n eca r boxyla te (27a ). A solution of 14a (46 mg, 0.25 mmol)
in hexanes (4 mL) was added dropwise over 20 min to a
solution of Rh2(S-DOSP)4 (9.5 mg, 5.0 µmol) and 1,1-diphe-
nylethylene (0.23 g, 0.22 mL, 1.3 mmol) in hexanes (1 mL) at
room temperature. The reaction mixture was stirred at room
temperature for 10 h and then concentrated in vacuo. Purifica-
tion by silica gel chromatography (4:1 pentane/EtOAc) gave
27a (61 mg, 72%): Rf 0.25 (9:1 pentane/Et2O); 97% ee (Chiral-
cel-OD, 0.8 mL/min, 0.8% i-PrOH/hexanes, tR ) 11.7 and 14.2
min); [R]25 +114° (c 1.04, CHCl3); IR (film) 3104, 3084, 3057,
D
3024, 2999, 2948, 2926, 2852, 1725, 1598 cm-1; 1H NMR (500
MHz; CDCl3) δ 7.48 (d, 2H, J ) 7.5 Hz), 7.27 (dd, 2H, J ) 7.5,
7.5 Hz), 7.18 (t, 1H, J ) 7.5 Hz), 7.13 (d, 2H, J ) 7.5 Hz),
7.07-7.00 (m, 5H), 6.98 (app t, 1H, J ) 7.5 Hz), 3.33 (s, 3H),
2.70 (d, 1H, J ) 5.5 Hz), 2.32 (d, 1H, J ) 5.5 Hz); 13C NMR
(125 MHz; CDCl3) δ 170.9, 141.9, 140.1, 136.6, 130.1, 129.3,
129.0, 128.3, 127.7, 126.8, 126.3, 124.3, 124.0, 51.9, 45.5, 38.1,
23.1; MS m/z (relative intensity) 334 (10, M+), 302 (36), 275
(100); HRMS-EI (calcd for C21H18O2S) 334.1028, found 334.1040.
Anal. Calcd for C21H18O2S: C, 75.42; H, 5.42. Found: C, 75.42;
H, 5.78.
(1R)-Meth yl 1-(2-Ch lor op yr id in -6-yl)-2,2-d ip h en ylcy-
clop r op a n e ca r boxyla te (27e). A solution of 16b (50 mg,
0.24 mmol) in CH2Cl2/hexanes (4.5 mL, 2:1) was added
dropwise over 20 min to a solution of Rh2(S-DOSP)4 (8.9 mg,
4.7 µmol) and 1,1-diphenylethylene (0.23 g, 0.22 mL, 1.3 mmol)
in hexanes (1 mL) at room temperature. The reaction mixture
was stirred at room temperature for 2 h and then concentrated
in vacuo. Purification by silica gel chromatography (4:1 pen-
tane/EtOAc) gave 27e (67 mg, 78%): 89% ee (Chiralcel-OD, 1
(1R)-Meth yl 2,2-Dip h en yl-1-(3-m eth oxyca r bon ylfu r a n -
4-yl)cyclop r op a n eca r boxyla te (27b). A solution of 14b (94
mg, 0.42 mmol) in hexanes/CH2Cl2 (10 mL, 4:1) was added
dropwise over 1 h to a solution of Rh2(S-DOSP)4 (17 mg, 8.4
µmol) and 1,1-diphenylethylene (0.38 g, 0.37 mL, 2.1 mmol)
in hexanes (2 mL) at room temperature. The reaction mixture
was stirred at room temperature for 8 h and then concentrated
in vacuo. Purification by silica gel chromatography (4:1 pen-
tane/Et2O) gave 27b (28 mg, 18%): Rf 0.31 (1:1 pentane/Et2O);
mL/min, 0.8% i-PrOH/hexanes, tR ) 11.6 and 12.5 min); [R]25
D
+284° (c 1.14, CHCl3); IR (film) 3058, 3025, 2949, 2926, 2842,
1
1722, 1580, 1439 cm-1; H NMR (500 MHz; CDCl3) δ 7.59 (d,
1H, J ) 7.5 Hz), 7.48 (d, 2H, J ) 7.5 Hz), 7.39 (t, 1H, J ) 7.5
Hz), 7.32 (t, 2H, J ) 7.5 Hz), 7.25 (dd, 1H, J ) 7.5, 6.0 Hz),
7.08 (d, 2H, J ) 8.5 Hz), 7.01-6.98 (m, 3H), 6.95 (t, 1H, J )
7.0 Hz), 3.0 (d, 1H, J ) 6.0 Hz), 2.68 (d, 1H, J ) 6.0 Hz); 13C
NMR (125 MHz; CDCl3) δ 170.5, 155.7, 149.4, 139.1, 137.8,
129.5, 128.7, 128.3, 127.8, 127.0, 126.6, 126.4, 122.1, 52.0, 47.0,
43.6, 22.2; MS m/z (relative intensity) 363 (11, M+), 331 (100),
303 (21), 267 (11); HRMS-EI (calcd for C16H14ClNO3) 287.0713,
found 287.0712. Anal. Calcd for C22H18ClNO2: C, 72.62; H,
4.99; N, 3.85. Found: C, 72.39; H,5.16; N, 3.63.
88% ee ((R,R)-Whelk-O1, 1 mL/min, 2% i-PrOH/hexanes, tR
)
12.9 and 18.3 min); [R]25 +133° (c 1.1, CHCl3); mp 156-158
D
°C; IR (film) 3150, 3059, 3025, 2950, 2838, 1725, 1599, 1545
1
cm-1; H NMR (500 MHz; CDCl3) δ 7.76 (d, 1H, J ) 2.0 Hz),
7.63 (app d, 2H, J ) 7.0 Hz), 7.30 (dd, 2H, J ) 7.5, 7.5 Hz),
7.27 (m, 2H), 7.20 (m, 1H), 7.08-7.00 (m, 3H), 6.88 (d, 1H, J
) 1.5 Hz), 3.85 (s, 3H), 3.38 (s, 3H), 2.51 (d, 1H, J ) 5.5 Hz),
2.27 (d, 1H, J ) 5.5 Hz); 13C NMR (125 MHz; CDCl3) δ 171.2,
163.4, 148.5, 143.3, 142.2, 140.3, 129.7, 128.9, 128.1, 127.7,
126.6, 126.5, 122.0, 119.5, 51.9, 51.3, 46.1, 32.4, 24.6; MS m/z
(relative intensity) 376 (1, M+), 344 (27), 312 (100); HRMS-EI
(calcd for C23H20O5) 376.1311, found 376.1299. Anal. Calcd for
(1R)-Meth yl 2,2-Dip h en yl-1-(3-m eth ylisoxa zol-5-yl)cy-
clop r op a n eca r boxyla te (27f). A solution of 17 (0.113 g,
0.624 mmol) in hexanes (10 mL) was added dropwise over 30
min to a solution of Rh2(S-DOSP)4 (24 mg, 13 µmol) and 1,1-
diphenylethylene (0.56 g, 0.55 mL, 3.1 mmol) in hexanes (1
mL) at room temperature. The reaction mixture was stirred
at room temperature for 2 h and then concentrated in vacuo.
Purification by silica gel chromatography (4:1 pentane/Et2O)
gave 27f (0.189 g, 91%): Rf 0.41 (1:1 pentane/Et2O); 95% ee
(Chiralcel-OD, 0.8 mL/min, 0.6% i-PrOH/hexanes, tR ) 35.7
C
23H20O5: C, 73.39; H, 5.36. Found: C, 73.49; H, 5.70.
(1R)-Met h yl 1-(1-ter t-Bu t yloxyca r b on ylin d ol-3-yl)-2-
d ip h en ylcyclop r op a n eca r boxyla te (27c). A solution of 15
(0.121 g, 0.384 mmol) in hexanes (6 mL) was added dropwise
over 30 min to a solution of Rh2(S-DOSP)4 (15 mg, 7.7 µmol)
and 1,1-diphenylethylene (0.35 g, 0.34 mL, 1.9 mmol) in
hexanes (1 mL) at room temperature. The reaction mixture
was stirred at room temperature for 1 h and then concentrated
in vacuo. Purification by silica gel chromatography (9:1 pen-
tane/Et2O) gave 27c (0.142 g, 79%): Rf 0.66 (1:1 pentane/Et2O);
67% ee (Chiralcel-OD, 0.8 mL/min, 0.6% i-PrOH/hexanes, tR
and 44.7 min); [R]25 +60.5° (c 1.58, CHCl3); mp 136-137 °C;
D
IR (film) 3114, 3083, 3059, 3024, 2957, 2848, 1953, 1884, 1731,
1
1688, 1607, 1581 cm-1; H NMR (500 MHz; CDCl3) δ 7.44 (d,
2H, J ) 7.5 Hz), 7.28-7.25 (m, 4H), 7.18 (t, 1H, J ) 7.5 Hz),
7.12 (t, 2H, J ) 7.0 Hz), 7.07 (t, 1H, J ) 7.0 Hz), 6.31 (s, 1H),
3.39 (s, 3H), 2.76 (d, 1H, J ) 5.5 Hz), 2.64 (d, 1H, J ) 5.5 Hz),
2.15 (s, 3H); 13C NMR (125 MHz; CDCl3) δ 168.2, 166.3, 159.4,
140.9, 139.5, 128.6, 128.5, 128.3, 128.0, 127.0, 105.0, 52.1, 48.0,
34.9, 22.8; MS m/z (relative intensity) 333 (8, M+), 304 (16),
274 (44), 250 (50), 233 (100); HRMS-EI (calcd for C21H19NO3)
333.1365, found 333.1391. Anal. Calcd for C21H19NO3: C,
75.66; H, 5.74; N, 4.20. Found: C, 75.95; H, 5.80; N, 4.26.
(1R)-Meth yl 2,2-Dip h en yl-1-(4,5-d ip h en yloxa zol-2-yl)-
cyclop r op a n eca r boxyla te (27g). A solution of 18 (54.2 mg,
0.166 mmol) in hexanes/toluene (2 mL, 3:2) was added drop-
) 17.8 and 27.7 min); [R]25 +161° (c 0.84, CHCl3); IR (film)
D
3055, 3025, 2979, 2947, 1730, 1603, 1494 cm-1; 1H NMR (500
MHz; CDCl3) δ 8.01 (br s, 1H), 7.74 (d, 1H, J ) 7.0 Hz), 7.55
(m, 2H), 7.34 (app t, 2H, J ) 7.5 Hz), 7.26-7.18 (m, 5H), 7.10
(br s, 1H), 7.00-6.93 (br m, 3H); 3.38 (s, 3H), 2.72 (d, 1H, J )
5.0 Hz), 2.34 (d, 1H, J ) 5.0 Hz), 1.57 (s, 9H); 13C NMR (125

Cyclopropanation of Heteroaryldiazoacetates
J . Org. Chem., Vol. 66, No. 20, 2001 6603
wise over 20 min to a solution of Rh2(S-DOSP)4 (8.0 mg, 3.3
µmol) and 1,1-diphenylethylene (0.30 g, 0.15 mL, 1.7 mmol)
in hexanes (1 mL) at room temperature. The reaction mixture
was stirred at room temperature for 16 h and then concen-
trated in vacuo. Purification by silica gel chromatography (4:1
pentane/Et2O) gave 27g (72 mg, 88%): Rf 0.38 (1:1 pentane/
Et2O); 92% ee (Chiralcel-OD, 0.8 mL/min, 0.6% i-PrOH/
hexanes, tR ) 26.2 and 30.3 min); [R]25D +49.6° (c 1.22, CHCl3);
mp 160-161 °C; IR (film) 3082, 3058, 3020, 2949, 2927, 2852,
1954, 1890, 1735, 1604, 1561 cm-1; 1H NMR (500 MHz; CDCl3)
δ 7.52 (d, 2H, J ) 6.5 Hz), 7.40-7.30 (m, 6H), 7.31-7.26 (m,
8H, 7.21 (t, 1H, J ) 7.0 Hz), 7.10 (t, 2H, J ) 7.0 Hz), 7.02 (t,
1H, J ) 7.0 Hz), 3.50 (s, 3H), 2.91 (d, 1H, J ) 5.5 Hz), 2.76 (d,
1H, J ) 5.5 Hz); 13C NMR (125 MHz; CDCl3) δ 168.4, 157.8.
146.5, 140.5, 139.7, 134.8, 132.3, 129.1, 128.8, 128.7, 128.4,
128.3, 127.9, 127.9, 127.2, 127.0, 126.6, 52.5, 48.0, 36.2, 24.2;
MS m/z (relative intensity) 395 (100, M+), 363 (73), 335 (17),
258 (39); HRMS-EI (calcd for C26H21NO3) 395.1521, found
395.1515. Anal. Calcd for C32H25NO3: C, 81.51; H, 5.34; N,
2.97. Found: C, 81.40; H, 5.57; N, 3.01.
allowed to cool to room temperature, and concentrated in
vacuo. Purification by silica gel chromatography (4:1 pentane/
Et2O) gave 27h (93 mg, 73%): Rf 0.60 (2:1 pentane/Et2O); 70%
ee (Chiralcel-OD, 0.8 mL/min, 0.6% i-PrOH/hexanes, tR ) 35.0
and 45.9 min); [R]25 +54.8° (c 1.42, CHCl3); mp 160-161 °C;
D
IR (film) 3084, 3058, 3026, 2950, 1736, 1611, 1564, 1494, 1454
cm-1; 1H NMR (500 MHz; CDCl3) δ 7.55 (t, 3H), 7.42 (d, 1H J
) 7.5 Hz), 7.36 (d, 2H, J ) 7.5 Hz), 7.31 (t, 2H, J ) 7.5 Hz),
7.26-7.20 (m, 3H), 7.0 (t, 2H, J ) 7.0 Hz), 6.91 (t, J ) 7.0
Hz), 3.50 (s, 3H), 2.96 (d, 1H, J ) 5.5 Hz), 2.83 (d, 1H, J ) 5.5
Hz); 13C NMR (125 MHz; CDCl3) δ 169.7, 161.3, 150.9, 140.5,
139.3, 128.8, 128.4, 127.9, 127.3, 127.0, 124.8, 124.0, 52.5, 48.6,
36.5, 24.2; MS m/z (relative intensity) 369 (35, M+), 337 (55),
310 (29); HRMS-EI (calcd for C24H19NO3) 369.1365, found
369.1359.
Ack n ow led gm en t. Financial support of this work
by the National Institutes of Health (CA85641) and the
National Science Foundation (CHE-0092490) is grate-
fully acknowledged.
(1R)-Meth yl 1-(Ben zoxa zol-2-yl)-2,2-d ip h en ylcyclop r o-
p a n eca r boxyla te (27h ). A solution of 19 (74.9 mg, 0.345
mmol) in toluene (6 mL) was added dropwise over 20 min to a
solution of Rh2(S-DOSP)4 (13 mg, 7.1 µmol) and 1,1-diphenyl-
ethylene (0.31 g, 0.30 mL, 1.7 mmol) in toluene (1 mL) heated
at reflux. The reaction mixture was heated at reflux for 2 h,
Su p p or tin g In for m a tion Ava ila ble: Experimental data
for the preparation of 6-19. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O015617T