A New, Mild Synthesis of N-Sulfonyl Ketimines via the Palladium-Catalyzed Isomerization of Aziridines

Article abstract of DOI:10.1021/ol0357651

(Matrix presented) A new method for the synthesis of N-tosylketimines via the palladium-catalyzed isomerization of N-tosylaziridines is described. The mild reaction conditions tolerate the presence of a variety of functional groups including ketones, este

Full text of DOI:10.1021/ol0357651

ORGANIC
LETTERS
2003
Vol. 5, No. 24
4607-4610
A New, Mild Synthesis of N-Sulfonyl
Ketimines via the Palladium-Catalyzed
Isomerization of Aziridines
John P. Wolfe* and Joshua E. Ney
Department of Chemistry, UniVersity of Michigan, 930 N. UniVersity AVenue,
Ann Arbor, Michigan 48109-1055
jpwolfe@umich.edu
Received September 12, 2003
ABSTRACT
A new method for the synthesis of N-tosylketimines via the palladium-catalyzed isomerization of N-tosylaziridines is described. The mild
reaction conditions tolerate the presence of a variety of functional groups including ketones, esters, and acetals. The reactions are believed
to proceed via the oxidative addition of the aziridine to Pd(0) and represent the first examples of transformations involving Pd(0)-mediated
oxidative additions of aziridines that do not proceed through allylpalladium intermediates.
Sulfonyl imines are versatile intermediates in organic
synthesis.1 For example, they are used as substrates in hetero
Diels-Alder reactions2 and trimethylenemethane cycload-
ditions,3 which provide a useful route to nitrogen hetero-
cycles. They are also employed as electrophiles in a wide
variety of addition4 and reduction5 reactions.
As a result of the broad synthetic utility of sulfonylimines,
a large number of methods have been developed for their
preparation.1 Although the formation of sulfonyl aldimines
can be achieved through several methods, synthesis of sulfo-
nyl ketimines remains a serious challenge.1 For example, in
contrast to N-alkyl imines, N-sulfonyl imines are difficult
to prepare via condensation reactions.1 Typically the conden-
sation of primary sulfonamides with aldehydes and ketones
requires harsh reaction conditions and is usually limited to
the preparation of nonenolizable sulfonyl aldimines.1,6,7
Many other strategies have been developed for the con-
version of aldehydes to N-sulfonyl imines,8-10 including
methods for the in situ generation of sulfonyl imines.2a,4e,f
However, these protocols are usually limited to the synthesis
of nonenolizable sulfonylimines derived from aldehydes; the
use of these methods for sulfonyl ketimine synthesis is rare
and is limited to preparation of diaryl ketimine derivatives.9
The most general methods for the synthesis of sulfonyl-
ketimines involve the condensation of oximes with sulfinyl
chlorides11 or sulfonyl cyanides.12 However, sulfinyl chlo-
(1) Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131-184.
(2) (a) Sisko, J.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 3037-
3040. (b) Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A. M. J.
Am. Chem. Soc. 1991, 113, 1713-1729. (c) Abramovitch, R. A.; Shinkai,
I.; Mavunkel, B. J.; More, K. M.; O’Connor, S.; Ooi, G. H.; Pennington,
W. T.; Srinivasan, P. C.; Stowers, J. R. Tetrahedron 1996, 52, 3339-3354.
(d) McFarlane, A. K.; Thomas, G.; Whiting, A. Tetrahedron Lett. 1993,
34, 2379-2382.
(6) (a) Lee, K. Y.; Lee, C. G.; Kim, J. N. Tetrahedron Lett. 2003, 44,
1231-1234 and references therein. (b) Love, B. E.; Raje, P. S.; Williams,
T. C., II. Synlett 1994, 493-494. (c) Jennings, W. B.; Lovely, C. J.
Tetrahedron 1991, 47, 5561-5568. (d) Vishwakarma, L. C.; Stringer, O.
D.; Davis, F. A. Org. Synth. 1987, 66, 203-208.
(7) For preparation of enolizable tosyl aldimines using condensation
methodology, see: Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000,
75-77.
(8) Trost, B. M.; Marrs, C. J. Org. Chem. 1991, 56, 6468-6470.
(9) Georg, G. I.; Harriman, G. C. B.; Peterson, S. A. J. Org. Chem. 1995,
60, 7366-7368.
(10) For synthesis of enolizable tosyl aldimines via photochemical
rearrangement of naphtho[1,8-de]-dithiin-1-N-tosylsulfilimines, see: Fujii,
T.; Kimura, T.; Furukawa, N. Tetrahedron Lett. 1995, 36, 1075-1078.
(11) (a) Artman, G. D.; Bartolozzi, A.; Franck, R. W.; Weinreb, S. M.
Synlett 2001, 232-233 and references therein. (b) Brown, C.; Hudson, R.
F.; Record, K. A. F. J. Chem. Soc., Perkin Trans. 2 1978, 822-828.
(3) (a) Trost, B. M.; Marrs, C. M. J. Am. Chem. Soc. 1993, 115, 6636-
6645. (b) Shigeru, Y.; Yanagawa, M.; Nakamura, E. Chem Lett. 1999, 879-
880.
(4) (a) Miyabe, H.; Ueda, M.; Naito, T. Chem. Commun. 2000, 2059-
2060. (b) Yamada, K.-i.; Fujihara, H.; Yamamoto, Y.; Miwa, Y.; Taga, T.;
Tomioka, K. Org. Lett. 2002, 4, 3509-3511. (c) Aggarwal, V. K.; Alonso,
E.; Ferrara, M.; Spey, S. E. J. Org. Chem. 2002, 67, 2335-2344. (d)
Yamanaka, M.; Nishida, A.; Nakagawa, M. Org. Lett. 2000, 2, 159-161.
(e) Sisko, J.; Weinreb, S. M. J. Org. Chem. 1990, 55, 393-395. (f) Melnick,
M. J.; Freyer, A. J.; Weinreb, S. M. Tetrahedron Lett. 1988, 29, 3891-
3894.
(5) Charette, A. B.; Giroux, A. Tetrahedron Lett. 1996, 37, 6669-6672.
10.1021/ol0357651 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/31/2003

rides are often unstable and highly reactive. The analogous
sulfonyl cyanides are easier to manipulate but are quite
expensive and generate toxic byproducts.
Table 1. Ligand Effectsa
Because of the limitations of the above transformations,
the development of a new method for the synthesis of
sulfonyl ketimines under mild conditions would be desirable.
An ideal method would be general, atom economical,
catalytic, and tolerant of a wide range of functional groups
and would not require toxic or otherwise hazardous reagents.
During the course of our studies on the reactivity of
transition metal complexes toward aziridines13 we found that
treatment of 2-butyl-N-tosylaziridine (1) with a stoichiometric
mixture of Pd2(dba)3/PCy3 in C6D6 at 70 °C led to the clean
formation of N-tosylketimine 2 (eq 1).14,15 The transformation
entry
metal complex
ligand
P(o-tol)3
Cy2P(o-biphenyl)
PCy3
reaction timeb
1
2
3
4
5
6
7
8
9
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd[P(t-Bu)3]2
Pd[PCy)3]2
Pd[P(t-Bu)2Me]2
Pd[P(t-Bu)2Cy]2
Pd[P(t-Bu)Cy2]2
no reaction
no reaction
8 h
no reaction
no reaction
1 h
25 min
no reaction
>72 hc
PCy3
a Conditions: 1.0 equiv of substrate, 1.0 equiv of metal complex, C6D6
1
(0.015 M). All reactions provided a single product as judged by H NMR
analysis. b Time required for the complete conversion of substrate to product.
c The reaction was stopped after 72 h and was found to have proceeded to
66% completion.
of 1 to 2 was found to proceed effectively with only a
catalytic amount (5 mol %) of palladium. Given the mild
nature of these reaction conditions and the essentially
quantitative conversion of aziridine to imine, we reasoned
that the palladium-catalyzed isomerization of aziridines could
potentially be employed as a very mild synthesis of N-tosyl
ketimines that would tolerate a wide variety of functional
groups. Our preliminary studies on the efficacy of this
transformation are described herein.
In contrast to 2-vinyl-N-tosylaziridines, which readily
undergo oxidative addition to Pd(0),16 the oxidative addition
of 2-alkyl or -aryl aziridines to Pd(0) has not been previously
described.13 Thus, to maximize the kinetic efficiency of this
process, we examined the stoichiometric reaction of 1 with
a number of palladium/phosphine complexes. Mixtures of
Pd2(dba)3 and triarylphosphines such as PPh3, P(o-tol)3,
BINAP, and dppf did not provide active catalysts for this
reaction. In contrast, palladium complexes supported by
electron-rich trialkylphosphines promoted the isomerization
(Table 1). In general, preformed L2Pd complexes were more
reactive than catalysts generated in situ from Pd2(dba)3 or
Pd(OAc)2.17 The steric properties of the ligand had a dramatic
impact on reactivity. For example, both Pd[PCy3]2 (3) and
Pd[P(t-Bu)2Me]2 (4) were sufficiently reactive to promote
the isomerization at room temperature, whereas Pd[P(t-Bu)3]2
did not catalyze the reaction even at 80 °C. Although 4 was
more reactive than 3, most reactions were conducted with
commercially available 3.
As shown in Table 2, a number of N-tosylaziridines are
isomerized to N-tosylketimines in good yield in the presence
of 2-4 mol % 3. The reaction conditions are sufficiently
mild to tolerate a variety of functional groups including esters
(entry 3), olefins (entry 3), acetals (entry 4), and ketones
(entry 5). The isomerization of these functionalized substrates
is particularly noteworthy, as highly functionalized N-
tosylketimines would be difficult to prepare using existing
methods and have not been previously described. In contrast
to the related isomerization of styrene oxide to 2-phenylacetal-
dehyde,14b 2-phenyl N-tosylaziridine 5 reacts at the less
hindered carbon rather than the activated benzylic position,
to afford sulfonyl ketimine 6 (entry 2). We also observed
that N-acylaziridine 8 was converted to N-acylenamine 9 in
47% yield (entry 7).18 At present, this method is limited to
the isomerization of terminal aziridines; 1,2-disubstituted
aziridines did not react under our standard conditions (entry
6). We are currently pursuing the development of other
catalysts that may be capable of transforming more highly
substituted substrates.
(12) Boger, D. L.; Corbett, W. L. J. Org. Chem. 1992, 57, 4777-4780.
(13) (a) Hillhouse has recently reported the synthesis of an azanickela-
cyclobutane via oxidiative addition of 2-butyl-N-tosylaziridine to (bipy)-
NiEt2 or (bipy)Ni(COD). See: Lin, B. L.; Clough, C. R.; Hillhouse, G. L.
J. Am. Chem. Soc. 2002, 124, 2890-2891. (b) The oxidative addition of
ethyleneimine to Pt(II) under acidic conditions has been previously
described. See: Mitchenko, S. A.; Slinkin, S. M.; Vdovichenko, A. N.;
Zamashchikov, V. V. Metallorg. Khim. 1991, 4, 1031-1035.
(14) The palladium-catalyzed isomerization of epoxides to ketones has
been previously reported. See: (a) Suzuki, M.; Watanabe, A.; Noyori, R.
J. Am. Chem. Soc. 1980, 102, 2095-2096. (b) Kulasegaram, S.; Kulawiec,
R. J. J. Org. Chem. 1997, 62, 6547-6561 and references therein.
(15) Control experiments demonstrated that the aziridine did not isomer-
ize when heated for 15 h at 70 °C in C6D6 with 1 equiv of tricyclohexyl-
phosphine in the absence of Pd.
(16) For recent examples in catalytic reactions, see: (a) Butler, D. C.
D.; Inman, G. A.; Alper, H. J. Org. Chem. 2000, 65, 5887-5890. (b)
Fugami, K.; Morizawa, Y.; Ishima, K.; Nozaki, H. Tetrahedron Lett. 1985,
26, 857-860. (c) Aoyagi, K.; Nakamura, H.; Yamamoto, Y. J. Org. Chem.
2002, 67, 5977-5980. (d) Trost, B. M.; Fandrick, D. R. J. Am. Chem. Soc.
2003, 125, 11836-11837.
In most cases the isolation of analytically pure N-
tosylimines was achieved by rapid chromatography on silica
gel. In some cases (Table 2, entries 4 and 5) the isolated
products were contaminated with small amounts (ca. 5-15%)
of byproducts resulting from partial hydrolysis of the imine
by silica gel. However, we found the metal-catalyzed
(17) Mixtures of Pd2(dba)3/PCy3 did effectively catalyze the isomerization
of 1. However, chromatographic separation of the imine product from dba
was very difficult.
(18) Aziridines bearing N-benzyl or N-diphenylphosphoryl groups did
not react under our standard conditions. The reaction of an N-boc aziridine
proceeded very slowly, requiring 1 equiv 3 and >24 h at 80 °C to reach
completion.
4608
Org. Lett., Vol. 5, No. 24, 2003

Table 2. Palladium-Catalyzed Isomerization of Aziridinesa
Scheme 1. Proposed Catalytic Cycle
dines to Ni(0)13 we propose the following mechanism for
the isomerization reactions (Scheme 1). Oxidative addition
of the N-tosylaziridine to Pd[PCy3]2 presumably occurs in
an SN2 fashion19 to afford either zwitterion A or azametal-
lacyclobutane B. Intermediate A or B could then undergo
â-hydride elimination to afford hydrido-palladium amido
species C. Reductive elimination of C would provide an
N-tosylenamine, which could tautomerize to afford the
observed products. The fact that the tosylaziridine substrates,
including 2-phenylaziridine, react at the less hindered carbon
is supportive of a nucleophilic (SN2) mechanism of oxidative
addition rather than a mechanism involving Lewis acid
mediated activation of the aziridine, which would most likely
result in ring opening at the benzylic position.20 It is not
clear if azametallacyclobutane B is formed under our reaction
conditions; however, it seems likely that â-hydride elimina-
tion occurs from an acyclic species such as A. Examination
of models suggests that â-hydride elimination from B would
be stereoelectronically unfavorable.21
a Conditions: 1.0 equiv of substrate, 2-4 mol % Pd[PCy3]2 (3), toluene
(0.25 M), 70 °C. b The yields reported in this table are average isolated
yields obtained from two or more runs. c This material contained ∼15% of
7,7-diethoxy-heptan-2-one resulting from partial imine hydrolysis during
chromatographic purification. d This material contained ∼5% of p-toluene-
sulfonamide resulting from partial imine hydrolysis during chromatographic
purification.
In conclusion, we have developed a new method for the
synthesis of N-tosylketimines via a palladium-catalyzed
isomerization of N-tosylaziridines. These reactions represent
the first examples of transformations involving oxidative
addition of aziridines to Pd(0) that do not proceed through
allylpalladium intermediates. The reactions exhibit excellent
functional group tolerance and are amenable to use in one-
pot sequential reactions. Further studies to expand the scope
of this reaction and to ascertain the nature of the intermedi-
ates in the catalytic cycle are currently underway.
isomerization of aziridines is amenable to use in “one-pot”
addition processes. For example, aziridine 1 was treated with
a catalytic amount of 3 for 7 h at 70 °C until all of the starting
material had been consumed as judged by 1H NMR analysis.
At this point the reaction mixture was cooled to room
temperature, and methylmagnesium bromide was added. The
resulting amine product 10 was isolated in 66% yield (eq
2). Substrate 7 was converted into 11 in an analogous manner
(eq 3). These processes provide a three-step (two-pot)
procedure for the conversion of a terminal olefin into a
substituted tert-butylamine derivative.
Acknowledgment. The authors thank the University of
Michigan for financial support of this work. J.P.W. thanks
the Camille and Henry Dreyfus Foundation for a new faculty
(19) Hillhouse has shown that oxidative addition of Ni(0) to N-tosyl-
aziridines proceeds with inversion of configuration, which suggests that
oxidative addition occurs via an SN2 mechanism. See ref 13a.
(20) Lewis acid mediated nucleophilic ring-opening reactions of N-tosyl-
2-phenylaziridine typically afford products resulting from substitution at
the benzylic position or mixtures of regioisomers. For recent examples,
see: (a) Ungureanu, I.; Bologa, C.; Chayer, S.; Mann, A. Tetrahedron Lett.
1999, 40, 5315-5318. (b) Schneider, M. -R.; Klotz, P.; Ungureanu, I.;
Mann, A.; Wermuth, C. -G. Tetrahedron Lett. 1999, 40, 3873-3876. (c)
Sabitha, G.; Babu, R. S.; Rajkumar, M.; Reddy, C. S.; Yadav, J. S.
Tetrahedron Lett. 2001, 42, 3955-3958.
On the basis of our observations and Hillhouse’s elegant
mechanistic studies on the oxidative addition of N-tosylaziri-
(21) Zhang, L.; Zetterberg, K. Organometallics 1991, 10, 3806-3813.
Org. Lett., Vol. 5, No. 24, 2003
4609

award, and Research Corporation for an innovation award.
J.E.N. acknowledges the University of Michigan for a Re-
gents Fellowship. Additional unrestricted support was pro-
vided by Eli Lilly and 3M. The authors also thank Professors
E. Vedejs and M. S. Sanford for their helpful comments on
this manuscript.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0357651
4610
Org. Lett., Vol. 5, No. 24, 2003