Preparation of trifluoromethyl-substituted aziridines with in situ generated CF3CHN2

Article abstract of DOI:10.1021/ol300539e

Direct access to trifluoromethyl-substituted aziridines through the use of a protocol in which trifluoromethyl diazomethane is generated in situ and subsequently undergoes addition to activated imines is reported.

Full text of DOI:10.1021/ol300539e

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1900–1901
Preparation of Trifluoromethyl-
Substituted Aziridines with in Situ
Generated CF3CHN2
€
Stefan A. Kunzi, Bill Morandi, and Erick M. Carreira*
Laboratorium fu€r Organische Chemie, ETH Zu€rich, CH-8093 Zu€rich, Switzerland
carreira@org.chem.ethz.ch
Received March 2, 2012
ABSTRACT
Direct access to trifluoromethyl-substituted aziridines through the use of a protocol in which trifluoromethyl diazomethane is generated in situ and
subsequently undergoes addition to activated imines is reported.
Fluorinated units are important for drug discovery
because of their ability to influence physical properties of
drug candidates.1 Consequently, there is a need for the
discovery of efficient methods to prepare fluorinated
building blocks. In line with previous work from our group
dealing with the preparation of trifluoromethyl-substi-
tuted fragments using in situ generated trifluoromethyl
diazomethane,2 we report herein the development of an
aza-Darzens reaction involving activated imines and tri-
fluoromethyl diazomethane generated in situ that affords
valuable functionalized trifluoromethylated aziridines.
The aza-Darzens is one of the most direct routes for the
preparation of aziridines.3 In this respect, the use of diazo
alkanes as nucleophiles in combination with a variety of
Brønsted or Lewis acidsascatalysts or reagentshave found
widespread use.4 Despite the rich literature on aziridine
preparation, few examples of trifluoromethyl-substituted
aziridines syntheses can be found, and these display limited
substrate scope or involve the implementation of multistep
synthesis sequences.5
Scheme 1. Strategies for Trifluoromethyl Aziridine Preparation
(1) (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3. (b) Isanbor, C.;
O’Hagan, D. J. Fluorine Chem. 2006, 127, 303. (c) Muller, K.; Faeh, C.;
Diederich, F. Science 2007, 317, 1881. (d) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
(2) (a) Morandi, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50,
9085. (b) Morandi, B.; Cheang, J.; Carreira, E. M. Org. Lett. 2011, 13,
3080. (c) Morandi, B.; Mariampillai, B.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2011, 50, 1101. (d) Morandi, B.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2010, 49, 4294. (e) Morandi, B.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2010, 49, 938. (f) Morandi, B.; Carreira, E. M. Org. Lett. 2011,
13, 5984. (g) Morandi, B; Carreira, E. M. Science 2012, 335, 1471.
(3) Sweeney, J. Eur. J. Org. Chem. 2009, 4911.
(4) For Lewis acid promoted reactions, see: (a) Casarrubios, L.;
Perez, J. A.; Brookhart, M.; Templeton, J. L. J. Org. Chem. 1996, 61,
8358. For Brønstedt acid promoted reactions, see: (b) Williams, A. L.;
Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 1612. (c) Mukherjee, M.;
Gupta, A. K.; Lu, Z.; Zhang, Y.; Wulff, W. D. J. Org. Chem. 2010, 75,
5643. (d) Akiyama, T.; Suzuki, T.; Mori, K. Org. Lett. 2009, 11, 2445.
Two distinct strategies are possible as a means of acces-
sing trifluoromethyl-substituted aziridines from imines
and diazocompounds employing the aza-Darzens reaction
(Scheme 1). The first one, reported by Akiyama and co-
workers in 2003, involves the use of trifluoroacetaldehyde
N,O-acetal 1 and a collection of diazoketones or ester
€
(5) (a) Akiyama, T.; Ogi, S.; Fuchibe, K. Tetrahedron Lett. 2003, 44,
4011. (b) Colantoni, D.; Fioravanti, S.; Pellacani, L.; Tardella, P. A.
Org. Lett. 2004, 6, 197. (c) Maeda, R.; Ooyama, K.; Anno, R.; Shiosaki,
M.; Azema, T.; Hanamoto, T. Org. Lett. 2010, 12, 2548. (d) Khomutov,
O. G.; Filyakova, V. I.; Pashkevich, K. I. Russ. Chem. Bull. 1994, 43, 261.
ꢀ
ꢀ
ꢀ
(e) Crousse, B.; Narizuka, S.; Bonnet-Delpon, D.; Begue, J.-P. Synlett
2001, 679. (f) Spanneda, M. V.; Crousse, B.; Narizuka, S.; Bonnet-
ꢀ
ꢀ
Delpon, D.; Begue, J.-P. Collect. Czech. Chem. Commun. 2002, 67, 1359.
r
10.1021/ol300539e
Published on Web 03/28/2012
2012 American Chemical Society

of trifluoromethyl-substituted dehydrobenzofuranols:2f
F3CCH2NH3Cl, NaNO2 in H2O/CH2Cl2, followed by
BF3•OEt2 and substrate. Under these conditions, the test
substrate(2-((4-methoxyphenyl)imino)-1-phenylethanone)
gavefull conversion to the product4a in 64% yield and 17:1
diastereoselectivity, as measured by analysis of the unpur-
ified product by 19F NMR spectroscopy (Table 1). The use
of other Lewis or Brønsted acids led to no reaction, slow
conversion (Cu(OTf)2, Ti(OiPr)4, TfOH, (RO)2P(O)OH),
or decomposition of the reactant or product (SnCl4, SbCl5).
With a workable protocol in hand, we studied the scope
of the reaction (Table 1). A wide range of aromatic glyoxyl
imines andan ethyl glyoxalimine (entry 4), easily prepared
from the corresponding glyoxals, afforded products in
good yields and dr. The functionalized trifluoromethyl
aziridines obtained are valuable fluorinated building
blocks for further transformations. As an example, 3-tri-
fluoromethyl-aziridine-2-carboxylates (e.g., 4d) have
been shown to undergo regio- and diastereoselective ring
opening to give trifluoromethylated β-amino acids and
β-lactams.6
Table 1. Reaction Scopea
To further establish the utility of the products generated,
aziridine 4a was subjected to deprotection using CAN
((NH4)2Ce(NO3)6) to give free aziridine 5 in an unopti-
mized 75% yield (Scheme 2).
Scheme 2. Deprotection of 4a Giving Free Aziridine 5
In conclusion, we have developed a facile one-pot
preparation of trifluoromethyl-substituted aziridines
in good yield and good diastereoselectivity starting
from trifluoroethylamine hydrochloride and PMP-
protected glyoxal imines. The cis substituted aziridine
was obtained as the major product. Deprotection of the
products is easily performed with CAN as shown on
a test substrate.
a General procedure: 3 equiv of F3CCH2NH3Cl and 3.6 equiv of
NaNO2 were stirred at 0 °C for 1 h in CH2Cl2/H2O (30:1), followed
by addition of imine (0.5 mmol, 1 equiv) and BF3 OEt2 (1.8 equiv) at
À78 °C. b Isolated yield of cis product. c Based on 19F NMR spectroscopy of
3
the crude reaction mixture. d Isolated yield of 72% (83% purity).
The functionalized trifluoromethylated aziridines de-
scribed in this work offer many opportunities for further
elaboration in the preparation of nitrogen-containing tri-
fluoromethylated compounds for drug discovery.
derivatives 2.5a A limitation of this approach is the need to
prepare and isolate the various diazoalkanes for each
aziridine. The second strategy, reported herein, involves
the use of a single diazocompound, trifluoromethyl diazo-
methane, and a variety of imine starting materials, such as
3, easily prepared from the corresponding glyoxals.
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.
We commenced our investigations with the reac-
tion conditions reported previously for the preparation
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) See ref 5e. (b) Davoli, P.; Froni, A.; Franciosi, C.; Moretti, I.;
Prati, F. Tetrahedron: Asymmetry 1999, 10, 2361. (c) Rinaudo, G.;
Narizuka, S.; Askari, N.; Crousse, B.; Delpon, D. Tetrahedron Lett.
2006, 47, 2065.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
1901