Iron-catalyzed cyclopropanation with glycine ethyl ester hydrochloride in water

Article abstract of DOI:10.1021/ol300688p

An iron-catalyzed cyclopropanation reaction of styrenes in aqueous media is disclosed that employs glycine ethyl ester hydrochloride in a tandem diazotization/cyclopropanation reaction. The products are accessed in good yields and good diastereoselectivity using readily available and inexpensive starting materials. Moreover, a wide range of transition metals may be used under these conditions, thus opening new opportunities for efficient carbene-transfer reactions under user-friendly conditions.

Full text of DOI:10.1021/ol300688p

ORGANIC
LETTERS
2
012
Vol. 14, No. 8
162–2163
Iron-Catalyzed Cyclopropanation with
Glycine Ethyl Ester Hydrochloride in Water
2
Bill Morandi, Amund Dolva, and E. M. Carreira*
Laboratory of Organic Chemistry, ETH-Z u€ rich, HCI H335, Wolfgang-Pauli-Strasse
1
0, 8093 Z u€ rich, Switzerland
carreira@org.chem.ethz.ch
Received March 19, 2012
ABSTRACT
An iron-catalyzed cyclopropanation reaction of styrenes in aqueous media is disclosed that employs glycine ethyl ester hydrochloride in a tandem
diazotization/cyclopropanation reaction. The products are accessed in good yields and good diastereoselectivity using readily available and
inexpensive starting materials. Moreover, a wide range of transition metals may be used under these conditions, thus opening new opportunities
for efficient carbene-transfer reactions under user-friendly conditions.
Cyclopropanation has long been recognized as an im-
1
rhodiumÀporphyrin catalyst, glycine ethyl ester hydro-
portant carbonÀcarbon bond forming reaction. The pro-
chloride, and alkenes (10 equiv) in a CH Cl /water
2
2
4
ducts are useful building blocks for organic synthesis, and
the cyclopropane motif is present in a wide range of
2
structures. Among the many cyclopropanes accessible
mixture. The products were isolated in moderate yields
after 4 days with no diastereoselectivity (1:1). Charette
later showcased a single example with Rh (CH (CH ) -
2
3
2 6
À
by metal-catalyzed carbene generation from diazoalkanes,
cyclopropyl esters have been studied extensively due to
their versatility as intermediates in synthesis. On the basis
of our recent work on the chemistry of trifluoromethyl
COO ) as a competent catalyst in the cylopropanation of
4
styrene with glycine ethyl ester hydrochloride in aqueous
5
media. In the reaction, the product was isolated as a 1.5:1
mixture of diastereomers.
3
diazomethane generated in situ via diazotization in aque-
Aiming at developing a synthetically useful protocol for
the trans-selective cyclopropanation of styrenes with gly-
cine ethyl ester hydrochloride in water, we screened a
number of transition-metal catalysts under the following
reaction conditions: p-methoxystyrene (1 equiv, limiting
reagent), glycine ethyl ester hydrochloride (2 equiv),
NaNO (2.4 equiv), and acetic acid (15 mol %) in water
2
at 40 °C in an open vial (Table 1).
Three common catalysts used in cyclopropanation re-
ous media, we sought an alternative for the preparation of
cyclopropyl esters using glycine ethyl ester hydrochloride.
This strategy would obviate the need to handle ethyl
diazoacetate and offer the possibility of performing the
reaction with an inexpensive, conveniently handled re-
agent in water. Prior to this work, case examples of similar
attempts had been published in the literature. Barrett
described the synthesis of cyclopropyl esters using a
actions (Cu(OTf) , Pd(OAc) , and Rh (OAc) ) afforded
2
2
2
4
poor results, giving low to moderate conversions with poor
diastereoselectivity (entries 1À3). The use of (Rh (CH -
(
1) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem.
Rev. 2003, 103, 977.
2) Donaldson, W. A. Tetrahedron 2001, 57, 8589 and references
therein.
2
3
(
À
4
(
CH ) COO ) and Rh (esp) gave good conversion, al-
2 6 2 2
(
3) (a) Morandi, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49,
beit with no diastereoselectivity (entries 4 and 5). The fact
that the performance of the complexes correlates with
9
4
38. (b) Morandi, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49,
294. (c) Morandi, B.; Mariampillai, B.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2011, 50, 1101. (d) Morandi, B.; Cheang, J.; Carreira, E. M. Org.
Lett. 2011, 13, 3080. (e) Morandi, B.; Carreira, E. M. Angew. Chem., Int.
Ed. 2011, 50, 9085. (f) Morandi, B.; Carreira, E. M. Org. Lett. 2011, 13,
(4) Barrett, A. G. M.; Braddock, D. C.; Lenoir, I.; Tone, H. J. Org.
Chem. 2001, 66, 8260.
(5) Wurz, R. P.; Charette, A. B. Org. Lett. 2002, 4, 4531.
5984. (g) Morandi, B.; Carreira, E. M. Science 2012, 335, 1471. (h)
K u€ nzi, S. A.; Morandi, B.; Carreira, E. M. Org. Lett. 2012, 14, 1900.
1
0.1021/ol300688p r 2012 American Chemical Society
Published on Web 04/11/2012

a
a
Table 1. Screening of Metal Catalysts
Table 2. Scope of the Cyclopropanation
b
b
dr
entry
catalyst
conversion (%)
1
2
3
4
5
6
7
8
Cu(OTf)
Pd(OAc)
2
44
25
2:1
1:1
2
Rh
Rh
Rh
2
2
2
(OAc)
4
10
1:1.5
1:1
À
(CH
(esp)
3
(CH
2
)
6
COO )
4
87
2
93
1:1
CoTPP
27
7:1
RuTPPCO
FeTPPCl
100
100
8:1
8:1
a
General procedure: catalyst (5 mol % M), EtO
2
CCH
2
NH
3
Cl
O,
0 °C. The trans/cis ratio was determined by H NMR analysis of
the unpurified reaction mixture.
(
4
2 equiv), NaNO (2.4 equiv), substrate, AcOH (15 mol %), H
2 2
b 1
ligand lipophilicity illustrates the importance of the phase
separation in the process and emphasizes the need to have
the catalyst dissolved in the substrate phase. Although
giving good diastereoselectivity (7:1), a cobaltÀporphyrin
complex gave low conversion (entry 6). To our delight, a
Ru- and Fe-porphyrin complexes performed well under
these conditions and afforded full conversion to the pro-
ductwithgoodselectivity (entries 7 and 8). The inexpensive
iron catalyst was selected for further studies due to the
good result obtained and the recent interest for this metal
6
as an alternative to noble metal catalysts. Interestingly,
the catalyst loading could be reduced to 1 mol % after
7
further optimization.
Having identified user-friendly and efficient reaction
conditions, we studied the scope of styrene derivatives that
canbetransformed tothecorrespondingtrans-cyclopropyl
esters (Table 2).
a
FeTPPCl (1 mol %), EtO CCH NH Cl (2 equiv), NaNO (2.4
2
2
2
3
b
equiv), substrate, AcOH (15 mol %), H O, 40 °C. Isolated yield of pure
trans-product. Determined by H NMR analysis of the unpurified
2
c
1
d
reaction mixture. FeTPPCl (1.5 mol %), EtO
2
CCH
NaNO2 (3.6 equiv). Isolated yield of 66% (83% purity). FeTPPCl
1 mol %), EtO CCH NH Cl (4 equiv), NaNO (4.8 equiv).
2 3
NH Cl (3 equiv),
e
f
Both electron-donating (entries 1À7) and electron-with-
drawing (entries 9 and 10) substrates gave the correspond-
ing aromatic cyclopropyl esters in good isolated yields of
pure trans-products. A diene substrate also afforded the
corresponding product, albeit in a lower yield (entry 11).
In conclusion, we have developed a new cyclopropana-
tion reaction using glycine ethyl ester hydrochloride as an
inexpensive and safe carbene precursor. The transforma-
tion produces the trans-cyclopropyl esters selectively using
a simple iron catalyst with low catalyst loading. This
synthetically useful protocol (absent inert atmosphere,
water as sole solvent) should find broad use in the pre-
paration of cyclopropanes and stimulate the design of
(
2
2
3
2
asymmetric catalysts that are active under these reaction
conditions. Development of active asymmetric catalysts
under these conditions is currently ongoing and will be
reported in due time.
Acknowledgment. We are grateful to the SSCI for a
fellowship to B.M. and the ETH-Zurich for generous
support through Grant 0-20744-11.
Supporting Information Available. Full experimental
procedures and spectral data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(
6) (a) Enthaler, S.; Junge, K.; Beller, M. Angew. Chem., Int. Ed.
2
2
008, 47, 3317. (b) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev.
004, 104, 6217.
(
7) Wolf, J. R.; Hamaker, C. G.; Djukic, J.-P.; Kodadek, T.; Woo,
L. K. J. Am. Chem. Soc. 1995, 117, 9194.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
2163