Epoxides and aziridines from diazoacetates via ylide intermediates.

Article abstract of DOI:10.1021/ol015600x

An effective methodology is reported for stereospecific epoxidation and aziridination via carbonyl ylide intermediates using rhodium(II) acetate catalyzed reactions of phenyl- and styryldiazoacetates with aldehydes, ketones, or imines.

Full text of DOI:10.1021/ol015600x

ORGANIC
LETTERS
2001
Vol. 3, No. 6
933-935
Epoxides and Aziridines from
Diazoacetates via Ylide Intermediates
Michael P. Doyle,* Wenhao Hu, and Daren J. Timmons
Department of Chemistry, UniVersity of Arizona, Tucson, Arizona 85721
mdoyle@u.arizona.edu
Received January 22, 2001
ABSTRACT
An effective methodology is reported for stereospecific epoxidation and aziridination via carbonyl ylide intermediates using rhodium(II) acetate
catalyzed reactions of phenyl- and styryldiazoacetates with aldehydes, ketones, or imines.
In the long history of catalyst-directed entry to carbonyl
ylides from diazocarbonyl compounds, there have been very
few examples of epoxide formation.1 Huisgen reported the
formation of oxirane from the reaction of dimethyl diaz-
omalonate with benzaldehyde, but in only 7% yield when
the reaction was performed at 125 °C in the presence of 1
mol % of Cu(acac)2;2 the same compound was not reported
in reactions performed with Rh2(OAc)4 or CuOTf at lower
temperatures and might have been due to thermolysis. Maas
reported epoxidation of benzaldehyde with R-diazo(trimeth-
ylsilyl)acetates, but only when CuOTf was used and only in
competition with 1,3-dipolar addition;3 the epoxidation
product was not observed with catalysis by dirhodium(II)
perfluorobutyrate. Instead, the initially formed carbonyl ylide
1 undergoes proton transfer, 1,3-dipolar cycloaddition, or
internal reactions that are specific to the diazo compound
employed (Scheme 1).4 With ethyl diazoacetate (R1 ) H,
R2 ) Et), for example, catalytic diazo decomposition in the
presence of benzaldehyde resulted in dioxolane formation
(2) and in 3 when performed in the presence of an alternative
dipolarophile.5 As a result of the apparent inability of diazo
compounds to form epoxides directly via this methodology,
Aggarwal has devised a clever alternative whereby an organic
sulfide intercepts the metal carbene, and epoxidation of
aldehydes takes place via a sulfur ylide.6
If one recognizes the absence of 4 from catalytic reactions
of diazo compounds with aldehydes as a function of the
relative rates for ring closure of 1 and reactions with
dipolarophiles, then increasing the stability of the intermedi-
ate ylide might be expected to reverse the preference for
dipolar cycloaddition. Indeed, some early photochemical
results with diazo compounds did produce products from
carbene addition to ketones,7 but these results were not
elaborated beyond means for detection of carbonyl ylide
intermediates. We now report that catalytic diazo decomposi-
Scheme 1
(1) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; John Wiley and Sons, Inc.:
New York, 1998; Chapter 7. Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998,
98, 911. Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Chem. Soc.
ReV. 2001, 30, 50.
(2) de March, P.; Huisgen, R. J. Am. Chem. Soc. 1982, 104, 4952.
(3) Alt, M.; Maas, G. Tetrahedron 1994, 50, 7435.
(4) Padwa, A.; Hornbuckle, S. F. Chem. ReV. 1991, 91, 263.
10.1021/ol015600x CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/02/2001

tion of phenyl- and styryldiazoacetates in the presence of
arylaldehydes and aryl ketones results in stereospecific
epoxidation and that when these reactions are performed with
arylimines stereospecific addition occurs to produce a single
aziridine product.
Table 1. Isolated Yields of Epoxides 5 from Reactions of
Diazoacetate with Aldehydes or Ketonea
R1
Ar
R2
yield 5, %b
Ph
Ph
Ph
Ph
Ph
C6H5
H
H
H
H
Me
H
H
66
81
80
86
38 (72)c
50
75
p-MeOC6H4
p-NO2C6H4
t-PhCHdCHd
C6H5
C6H5
t-PhCHdCHd
t-PhCHdHd
t-PhCHdHd
a Reactions performed in CH2Cl2 heated at reflux with 1.0 mol % of
rhodium(II) acetate. b Isolated yield of product following chromatographic
purification. c Yield obtained with 20-fold excess of acetophenone. d t )
trans.
Addition of aryldiazoacetate or styryldiazoacetate to an
equivalent amount of aldehyde in the presence of Rh2(OAc)4
resulted in the production of epoxide 5 (eq 1) as a single
isomer in good yield. Product stereochemistry was estab-
lished as Z by correlation of the product from epoxidation
of the alkene corresponding to 5 (R1 ) Ph, R2 ) H, Ar )
Ph) and from the X-ray structure of the product from reaction
of methyl phenyldiazoacetate with p-anisaldehyde (Figure
1).8,9 Complex mixtures were obtained with aliphatic alde-
ratio. Attempts to achieve enantiocontrol using chiral dirhod-
ium azetidinone catalysts10 were not successful; products
obtained were racemic.
In a typical procedure, a solution of methyl phenyldiaz-
oacetate (0.351 g, 2.0 mmol) in 5 mL of CH2Cl2 was added
via syringe pump (5.0 mL/h) over 1 h to a solution of Rh2-
(OAc)4 (8.8 mg, 0.02 mmol) and trans-cinnamaldehyde (0.29
g, 2.2 mmol) in 10 mL of CH2Cl2 heated at reflux. After
complete addition, the reaction mixture was cooled to room
temperature and then passed through a short silica plug,
which was subsequently washed with CH2Cl2 (20 mL). The
solvent was removed, and a portion of the crude product
1
was subjected to H NMR analysis for determination of
Figure 1. Crystal structure of 5 (R1 ) Ph, R2 ) H, Ar )
p-MeOC6H4) with selected bond lengths [Å] and angles [deg]: O1-
C2 1.442(3), O1-C3 1.435(3), C2-C3 1.482(3); C3-O1-C2
62.03(15), O1-C2-C3 58.76(15), O1-C3-C2 59.21(15); C20-
C2-C3-C30 154.8(2).
chemo- and diastereoselectivity. None of the cyclopropane
1
or trans-epoxidation product was observed in the crude H
(8) Crystal data for 5 (R1 ) Ph, R2 ) H, Ar ) p-MeOC6H4): C17H16O4,
Mr ) 284.30, orthorhombic, space group Pbca with a ) 11.8237(12), b )
8.4569(8), c ) 28.946(3) Å, volume ) 2894.4(5) Å3, Z ) 8, Fcalc ) 1.305
g/cm3, F(000) ) 1200. Colorless rectangular block (0.12 × 0.13 × 0.25
mm3). Data were collected out to 2θ ) 56° by an ω-scan technique (0.2°
ωscan) and an exposure time of 20 s on a Bruker SMART 1000 CCD
detector X-ray diffractometer at 170(2) K system using graphite mono-
chromated Mo KR radiation (λ ) 0.71073 Å). A total of 25430 reflections
were integrated and retained, of which 3576 were unique (<redundancy>
) 7.11, Rint ) 9.4%, Rsig ) 6.8%). Of the unique reflections, 1855 (52%)
were observed >2σ(I). Solution was achieved utilizing direct methods
followed by Fourier synthesis with anisotropic displacement parameters for
the non-hydrogen atoms. Conventional refinement indices using the 1855
reflections with F > 4σ(F) are R1 ) 0.0601, wR2 ) 0.1408. The structure
was solved using SHELXS in the Bruker SHELXTL (version 5.0) software
package.
hydes, but acetophenone gave 5 in modest yield, which could
be increased by increasing the relative amount of ketone
employed. Results are reported in Table 1. To determine
relative reactivity, reaction between methyl phenyldiazoac-
etate and 5-fold molar excesses of benzaldehyde and styrene
relative to methyl phenyldiazoacetate (eq 2) resulted in the
formation of epoxide and cyclopropane products in a 2.1:1
(5) Doyle, M. P.; Forbes, D. C.; Protopopova, M. N.; Stanley, S. A.;
Vasbinder, M. M.; Xavier, K. R. J. Org. Chem. 1997, 62, 7210. Doyle, M.
P.; Forbes, D. C.; Xavier, K. R. Russ. Chem. Bull. 1998, 47, 932.
(6) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. ReV. 1997, 97, 2341.
Aggarwal, V. K. Synlett 1998, 329.
(7) Scino, J. C.; McGimpsey, W. G.; Casal, H. L. J. Am. Chem. Soc.
1985, 107, 7204. Becker, R. S.; Bost, R. O.; Kolc, J.; Bertoniere, N. R.;
Smith, R. L.; Griffin, G. W. J. Am. Chem. Soc. 1970, 92, 1302.
(9) Crystallographic data (excluding structure factors) for 5 (R1 ) Ph,
R2 ) H, Ar ) p-MeOC6H4) and 7 (R1 ) R2 ) H) have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC-151857 and CCDC-151858. Copies of the data can
be obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 IEZ, U.K. (fax: (+44) 1223-336-033; e-mail: deposit@
ccdc.cam.ac.uk).
(10) Doyle, M. P.; Davies, S. B.; Hu, W. Org. Lett. 2000, 2, 1145.
934
Org. Lett., Vol. 3, No. 6, 2001

NMR spectrum. Column chromatography on silica gel
(hexanes/ethyl acetate ) 20:1) yielded 0.48 g of cis-
epoxidation product 5 as a viscous colorless oil in 86%
yield.11
Addition to selected imines occurred in a similar fashion
to furnish aziridine products in good yield. Methyl phenyl-
diazoacetate underwent Rh2(OAc)4-catalyzed reaction with
arylimines 6 (eq 3) to produce a single isomer 7 (79% yield
Figure 2. Crystal structure of 7 (R1 ) R2 ) H) with selected bond
lengths (Å) and angles [deg]: N1-C2 1.450(2), N1-C3 1.469(2),
C2-C3 1.524(2), N1-C3 1.469(2), C2-C20 1.488(2), C3-C30
1.498(2); C3-N1-C2 62.96(9), N1-C2-C3 59.13(9), N1-C3-
C2 57.91.
between Ar and R1 favor 8. The N-aryl group controls
stereochemical preference in 9 that results in the exclusive
formation of 7. In any case, only one diastereoisomer was
observed for either epoxide or aziridine formation. These
observations and interpretations suggest a broad versatility
of this methodology for epoxidation and aziridination that
has not been realized previously.
with R1 ) R2 ) H, 64% yield with R1 ) NO2, R2 ) H, and
84% yield with R1 ) H, R2 ) NO2). In contrast to that of 5,
product stereochemistry for 7 was E, as determined by single-
crystal X-ray diffraction studies (Figure 2).12 With 7c
catalytic hydrogenation followed by ceric ammonium nitrate
oxidation gave the NH-aziridine in good yield. There have
been several recent reports of catalytic aziridination using
ethyl diazoacetate but none using aryldiazoacetates, and in
these cases the stereochemistry that predominates is opposite
to that reported here.13
Acknowledgment. We are grateful to the National
Science Foundation and to the National Institutes of Health
(GM 46503) for their support of this research. We also
acknowledge the Molecular Structure Laboratory at the
University of Arizona, the NSF grant CHE9610374, which
provided the diffractometer, and Dr. Michael Carducci for
his assistance.
The results reported here are consistent with the interven-
tion of ylide intermediates 8 and 9. Steric interactions
(11) Methyl (2R/S,3R/S)-2,3-epoxy-2-phenyl-3-styrylpropionate (5): 1H
NMR (CDCl3, 500 MHz) δ 7.62-7.59 (comp, 2H), 7.45-7.29 (comp, 8H),
6.90 (d, J ) 16.0 Hz, 1H), 6.08 (dd, J ) 16.0, 7.9 Hz, 1H), 3.82 (s, 3H),
3.73 (d, J ) 7.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 168.1, 137.3,
135.7, 134.8, 128.7, 128.5, 128.4, 126.7, 126.6, 121.8, 65.7, 65.4, 52.7;
HRMS calcd for C18H17O3 281.1178, found 281.1177.
OL015600X
(12) Crystal data for 7 (R1 ) R2 ) H): C22H19NO2, Mr ) 329.38,
triclinic, space group P-1 with a ) 8.2351(6), b ) 10.7043(8), c ) 11.2999-
(9) Å, R ) 69.9100(10), â ) 77.619(2), γ ) 70.7020(10), volume ) 877.19-
(12) Å3, Z ) 2, Fcalc ) 1.247 g/cm3, F(000) ) 348. Colorless rectangular
block (0.08 × 0.16 × 0.33 mm3) cut from larger crystal. Data were collected
and refined as described for 5. Conventional refinement indices using the
2856 reflections with F > 4σ(F) are R1 ) 0.0484, wR2 ) 0.1117.
(13) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 5099.
Gunnoe, T. B.; White, P. S.; Templeton, J. L.; Casarrubios, L. J. Am. Chem.
Soc. 1997, 119, 3171. Rasmussen K. G.; Jørgensen, K. A. J. Chem. Soc.,
Perkin Trans. 1 1997, 1287. Nagayama S.; Kobayashi, S. Chem. Lett. 1998,
685. Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. Angew. Chem., Int. Ed.
Engl. 1995, 34, 676.
Org. Lett., Vol. 3, No. 6, 2001
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