Trimethylsilyldiazomethane as a versatile stitching agent for the introduction of aziridines into functionalized organic molecules

Article abstract of DOI:10.1021/ol102064b

A highly enantioselective route for the introduction of aziridines into functionalized organic molecules was developed via a tandem acylation and aziridination of TMSCHN₂.

Full text of DOI:10.1021/ol102064b

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4908-4911
Trimethylsilyldiazomethane as a
Versatile Stitching Agent for the
Introduction of Aziridines into
Functionalized Organic Molecules
Hong Ren and William D. Wulff*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824,
United States
wulff@chemistry.msu.edu
Received August 30, 2010
ABSTRACT
A highly enantioselective route for the introduction of aziridines into functionalized organic molecules was developed via a tandem acylation
and aziridination of TMSCHN2.
The formal addition of carbenes to Schiff bases to afford
aziridines is well-known.1 In particular, the formal transfer
of carbenes in the guise of diazo compounds to imines is
highly attractive and dates back to early observations
involving boron trifluoride etherate and zinc iodide.2 The
generality of this process with simple nonchiral Lewis acids
was not appreciated until the reports by Brookhart and
Templeton in 1996 and Jorgensen in 1997.3 In 1999 we
reported a catalytic asymmetric aziridination of imines with
diazo compounds catalyzed by a chiral spiro-boroxinate
Brønsted acid derived from VANOL or VAPOL.4-6 There
have been additional methods reported for asymmetric
catalytic synthesis of aziridines from imines and diazo
compounds with chiral Brønsted acids7,8 and chiral Lewis
acids.9 In addition, there have been a few reports of
asymmetric synthesis of aziridines induced by chiral centers
in the imine or the diazocompound.10 With a single
exception,4e these reactions involve the formation of aziri-
dines from the reactions of imines with commercially
(4) (a) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 5099–
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Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7185–7194. (g) Zhang, Y.;
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10.1021/ol102064b  2010 American Chemical Society
Published on Web 10/05/2010

available ethyl diazoacetate (EDA) or tert-butyl diazoacetate
or with corresponding amide derivatives.
synthetically convergent manner. Herein, we report a highly
enantioselective route for the introduction of aziridines into
functionalized organic molecules via a tandem acylation and
aziridination with TMSCHN2.
Our interests for the present study were directed toward
the development of the catalytic asymmetric aziridinations
with alternative diazo sources especially to those that would
allow for the straightforward introduction of a variety of
functional groups into the aziridine core (Scheme 1). The
The acylation of TMSCHN2 was first described by Shioiri
and co-workers when they introduced this reagent as a stable
and safe substitute for diazomethane in the Arndt-Eistert
synthesis of esters.11,12 In their protocol, an acid chloride
was treated with TMSCHN2 and the resulting diazomethyl
ketone heated with an alcohol to give the corresponding
homologated ester. They did demonstrate in one example
(1-naphthoyl chloride) that the diazomethyl ketone could be
isolated in good yield (74%). Shioiri’s protocol for the
Arndt-Eistert synthesis of esters with aliphatic acid chlorides
requires 2.0 equiv of TMSCHN2 to achieve optimal results.13
While TMSCHN2 is commercially available, for the sake of
efficiency, it seemed highly desirable to determine if the need
for excess TMSCHN2 was evitable. Indeed it is.
Scheme 1. Tandem Acylation/Aziridination of TMSCHN2
The yield of the diazoketone 8a is 62% with 2.0 equiv of
TMSCHN2 and 59% yield with 1.1 equiv (73% at 0 °C)
(Table 1). This stoichiometry was found to be suitable for
all of the functionalized diazoketones shown in Table 1.
We have reported evidence that suggests that the catalyst
for the catalytic asymmetric aziridination reaction is a
boroxinate-based chiral Brønsted acid of the type 3 (Scheme
2).6 Initially, the precatalyst is prepared by heating the ligand
with B(OPh)3,4g and then upon the addition of the imine the
assembly of the boroxinate catalyst is induced.6 The boroxi-
nate catalysts can be prepared from either VANOL4j or
VAPOL,6 and both catalysts were screened with the sub-
strates in Table 1. It was deemed desirable to first determine
the optimal nitrogen substituent on the imine, and thus the
reaction of the first diazo compound 8a was examined with
the benzhydryl imine 4 and the dianisylmethyl (MEDAM)
imine 5. Not unexpected from our recent studies,4h,k the
MEDAM imine 5 was found to be superior to the benzhydryl
imine 4 giving 99% vs 92% ee for the VAPOL catalyst
(Table 1, entries 3 and 1) and 94% vs 85% ee for the
VANOL catalyst (Table 1, entries 4 and 2).
goals are 2-fold: define a facile catalytic asymmetric method
for the introduction of aziridine units into functionalized
organic molecules and determine the tolerance of the
VAPOL/VANOL chiral polyborate catalyst (3 in Scheme 2)
Scheme 2. Ligands, Catalyst, and N-Protecting Groups
The scope of the tandem acylation/aziridination reactions
was examined with seven different carboxylic acids 7 and
with two different MEDAM imines 5 and 6 (Table 1). All
reactions gave excellent asymmetric inductions for all
aziridines with both VANOL and VAPOL catalysts and with
both imines. The cis-aziridines were obtained with g50:1
(10) (a) Akiyama, T.; Ogi, S.; Fuchibe, K. Tetrahedron Lett. 2003, 44,
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224. (d) Hashimoto, T.; Nakatsu, H.; Watanabe, S.; Maruoka, K. Org. Lett.
to various common organic functional groups. We were
attracted to the potential that trimethylsilyldiazomethane
(TMSCHN2) presents for realization of these goals in a
2010, 12, 1668–1671
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.
.
.
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6739. (b) Mayer, A.; Tanner, M. Biochemistry 2007, 46, 6149–6155. (c)
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Org. Lett., Vol. 12, No. 21, 2010
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Table 1. Tandem Acylation/Aziridination of TMSCHN2
a Unless otherwise specified, the acylation of TMSCHN2 was performed in MeCN at 0 °C for 24 h with 1.1 equiv of TMSCHN2. A base workup was
not used except in the preparation of 8a and 8b. All aziridinations were perfomred with 1.2 equiv of diazoketone at 0.5 M in imine in toluene at 25 °C for
24 h and went to 100% completion. The precatalyst was prepared by reaction of the ligand with 4 equiv of B(OPh)3 and 1 equiv of H2O in toluene at 80
°C for 1 h and then removal of volatiles at 80 °C (0.1 mmHg) for 0.5 h. Catalyst loading was 5 mol % for imines 4 and 5 and 10 mol % for imine 6. The
catalyst from (S)-ligands give ent-9, ent-10, and ent-11. The cis/trans selectivity is g50:1 for all reactions. b Yields in parentheses are at room temperature.
c Isolated yield after silica gel chromatography. d Determined by HPLC on a Chiralcel OD-H column. e The yield of 8a was 62% at 25 °C with 2.0 equiv
of TMSCHN2.
selectivity in all cases. Higher asymmetric inductions were
observed with the VAPOL catalysts for both imines in all
cases with the curious exception of 5-bromo-1-diazopentan-
2-one 8e (entries 19 and 20). With the diazoketone 8a as
the control, it can be seen that the boroxinate catalyst 3 is
remarkably tolerant of the presence of a variety of functional
groups with essentially no change in the asymmetric induc-
tion over the entire range of functional groups in the
diazoketones.
The most efficient method for the deprotection of MEDAM-
aziridines is treatment with triflic acid in anisole.4f,k However,
this method was optimized for simple aziridines sans
functionality. It was not clear if the functionalized aziridines
generated in the present study would be tolerant of these
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Org. Lett., Vol. 12, No. 21, 2010

conditions. As a test, aziridine 10e was subjected to 5 equiv
of triflic acid in anisole for 2 h, and to our delight, cleavage
of the MEDAM group could be achieved to give the N-H
aziridine 12e in excellent yield (Scheme 3). It was interesting
Scheme 4
.
Diastereoselective Access to Enantiomeric
Tetrahydrofurylamines
Scheme 3
.
Deprotection of the MEDAM Group from
(2R,3R)-10e
to note that this molecule could be isolated and purified on
silica gel with no evidence for intramolecular alkylation on
nitrogen.
Tetrahydrofurylamines are widely used in the synthesis
of various medical agents such as ion channel modulators,14
enzyme inhibitors,15 analgesics,16 antibiotics17 and neuotro-
pics,18 anticarcinogenic drugs,19 and antifungal agents.20 This
type of compounds are also of particular interest with regard
to ligands for asymmetric alkylation.21 Despite the broad use
and importance of tetrahydrofurylamines, a search of the
literature produced few reports for the asymmetric prepara-
tion of tetrahydrofurylamines, especially those bearing two
contiguous chiral centers. Key to the general access to all
the stereoisomers of tetrahydrofurylamines from the aziri-
dinyl ketone 10e is the ability to control the stereochemistry
in the reduction of the ketone function. The reduction was
first examined with zinc borohydride, a well-known chela-
tion-controlled reducing agent.4e Despite our concerns with
the presence of the large MEDAM group on the nitrogen
which might prevent the coordination of zinc, it proved
possible to reduce the ketone moiety with >50:1 selectivity
for diastereomer 13 (Scheme 4). Nonchelation-controlled
reduction of the ketone functionality in 10e could be effected
with L-selectride at -78 °C in 68% yield and with a 15:1
selectivity for diastereomer 16. When the reduction with
L-selectride was conducted at room temperature, the stere-
ochemistry of the reduction only dropped to 11:1, and
resulting lithium alkoxide cyclized to give the tetrahydro-
furylaziridine 17. Reductive opening of the aziridine and
reductive cleavage of the MEDAM group in the presence
of (Boc)2O afforded the tetrahydrofurylamine 18. After
cyclization of 13 with NaH, the diastereomeric tetrahydro-
furylamine 15 could be obtained from 14 with the same
protocol used in the conversion of 17 to 18.
This work has demonstrated that the Shioiri acylation of
trimethylsilyldiazomethane with aliphatic acid chlorides can
be coupled to the catalytic asymmetric aziridination of
aldimines with a chiral polyborate Brønsted acid catalyst
derived from the vaulted biaryl ligands VANOL and VA-
POL. The coupling of these methods led to a direct and
highly enantioselective method for the rapid introduction of
aziridine units into functionalized organic molecules. It is
important to note that the very high asymmetric inductions
of the boroxinate catalyst for the catalytic asymmetric
aziridination were essentially unaffected by the nature of the
functional group in the diazo component. The products of
these tandem reactions are synthetically useful intermediates,
and this was demonstrated in the stereocontrolled synthesis
of tetrahydrofuryl amines.
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Acknowledgment. This work was supported by NSF
Grant CHE-0750319.
(17) (a) Robins, M. J.; Parker, J. M. Can. J. Chem. 1983, 61, 317–322.
(b) Zimmermann, P. J.; Lee, J. Y.; Hlobilova, I.; Endermann, R.; Habich,
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Supporting Information Available: Experimental pro-
tocols, characterization procedures, and spectral data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) Tsujihara, K.; Ozeki, M.; Arai, Y. J. Med. Chem. 1982, 25, 441–
446.
(20) Ghosh, A. K.; Wang, Y. J. Org. Chem. 1998, 63, 6735–6738.
(21) Paolucci, C.; Rosini, G. Tetrahedron: Asymmetry 2007, 18, 2923–
2946.
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