A new general method for the preparation of N-sulfonyloxaziridines

Article abstract of DOI:10.1021/ol052250w

(Chemical Equation Presented) A simple procedure to obtain N-alkylsulfonyl- and N-arylsulfonyloxaziridines from the corresponding N-sulfinylimines involving a one-pot, two-step oxidation process with m-CPBA (1 equiv) and m-CPBA/KOH (1.1 equiv) is reported

Full text of DOI:10.1021/ol052250w

ORGANIC
LETTERS
2005
Vol. 7, No. 24
5493-5496
A New General Method for the
Preparation of N-Sulfonyloxaziridines
Jose´ Luis Garc´ıa Ruano,* Jose´ Alema´n, Cristina Fajardo, and Alejandro Parra
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid,
Cantoblanco, 28049 Madrid, Spain
joseluis.garcia.ruano@uam.es
Received September 16, 2005
ABSTRACT
A simple procedure to obtain N-alkylsulfonyl- and N-arylsulfonyloxaziridines from the corresponding N-sulfinylimines involving a one-pot,
two-step oxidation process with m-CPBA (1 equiv) and m-CPBA/KOH (1.1 equiv) is reported. The method is applicable to N-sulfinylimines
derived from aldehydes (aliphatic and aromatic) and ketones (dialkyl and aryl alkyl) and preserves CdC-conjugated double bonds. Almost
quantitative yields, very mild conditions (usually less than 5 min at room temperature), and easy purification by filtration are the main features
of this new procedure, which can be performed at a gram scale.
Oxaziridines1 have proven to be interesting reagents2 with
multiple and diverse applications as oxidizing and electro-
philic amination reagents. In particular, N-sulfonyloxaziri-
dines3 have been the most widely used probably due to their
stability and easy handling.4 The first general method for
synthesizing these compounds, reported by Davis in 1980,5
involved the oxidation of N-sulfonyliminessprepared by
condensation of the aldehyde’s diethyl acetal with the
N-sulfonamide at 130-180 °Csfollowed by a m-CPBA two-
phase oxidation system (HCCl3/NaHCO3-H2O). After these
initial results, the use of other oxidizing reagents that improve
the yields, shorten the reaction times, and facilitated the
purification processes have been reported. The most popular
reagent for oxidizing the CdN bond at N-sulfonylimines is
Oxone buffered with KHCO3 or K2CO3,6 which was also
(3) For oxidation of double bonds, see: (a) Davis, F. A.; Jenkins, R. H.;
Awad, S. B.; Stringer, O. D.; Watson, H. W.; Galloy, J. J. Am. Chem. Soc.
1982, 104, 5412. (b) Davis, F. A.; Harakal, M. E.; Awad S. B. J. Am. Chem.
Soc. 1983, 105, 3123. (c) Davis, F. A.; Abdul-Malik N. F.; Jenkins, L. A.
J. Org. Chem. 1983, 48, 5128. For oxidation of sulfur atom, see: (d) Davis,
F. A.; Billmers, J. M. J. Org. Chem. 1983, 48, 2672. (e) Davis, F. A.;
McCauley, J. P., Jr.; Harakal, M. E. J. Org. Chem. 1984, 49, 1467. (f)
Davis, F. A.; Billmers, J. M.; Gosciniak, D. J. Towson, J. C. J. Org. Chem.
1986, 51, 4240. (g) Davis, F. A.; McCauley, J. P.; Chattopadhyay S.; Harkal,
M. E.; Towson, J. C.; Watson, W. H.; Tavanaiepour, I. J. Am. Chem. Soc.
1987, 109, 3370. (h) Davis, F. A.; Lal, S. G. J. Org. Chem. 1988, 53, 5004.
(i) Davis, F. A. ThimmaReddy, R.; Weismiller, M. C. J. Am. Chem. Soc.
1989, 11, 5964. (j) Davis, F. A.; Reddy, T.; Han, W.; Carroll, P. J. J. Am.
Chem. Soc. 1992, 14, 1428. (k) Davis, F. A.; Weismiller, K. M.; Reddy, R.
T.; Chen, B.-C. J. Org. Chem. 1992, 57, 7274. (l) Schoumacker, S.; Hamelin,
O.; Te´ti, S.; Pe´caut, J.; Fontecave, M. J. Org. Chem. 2005, 70, 301. For
R-oxidation of the carbonyl group, see: (m) Davis, F. A.; Chen, B.-C. Chem.
ReV. 1992, 92, 919 and references therein. (n) Davis, F. A.; Kumar, A.;
Reddy, R.; Chen, B.-C.; Wade, P. A.; Shah, S. W. J. Org. Chem. 1993, 58,
7591. (o) Davis, F. A.; Reddy, R. E.; Kasu, P. V. N.; Portonovo, S. P.;
Carroll, P. J. J. Org. Chem. 1997, 62, 3625.
(1) (a) Emmons, W. D. J. Am. Chem. Soc. 1956, 78, 6208. (b) Emmons,
W. D. J. Am. Chem. Soc. 1957, 79, 5739. (c) Horner, L.; Jrgens, E. Chem.
Ber. 1957, 90, 2184. (d) Krimm, H. Chem. Ber. 1958, 91, 1057.
(2) (a) Page, P. C. B.; Heer, J. P.; Bethell, D.; Collington, E. W.;
Andrews, D. M. Tetrahedron: Asymmetry 1995, 6, 2911. (b) Wolfe, M.
S.; Dutta, D.; Aube´, J. J. Org. Chem. 1997, 62, 654. (c) Vidal, J.; Hannachi,
J.-C.; Hourdin, G.; Mulatier, J.-C.; Collet, A. Tetrahedron Lett. 1998, 39,
8845. (d) Choong, I. C.; Ellman, J. A. J. Org. Chem. 1999, 64, 6528. (e)
Bonnet, D.; Rommes, C.; Gras-Masse, H.; Melnyk O. Tetrahedron 1999,
40, 7315. (f) Page, P. C. B.; Heer, J. P.; Bethell, D.; Lund, A.; Collington,
E. W.; Andrews. D. M. J. Org. Chem. 1997, 62, 6093. (g) Messina, F.;
Botta, M.; Corelli, F.; Paladino, A. Tetrahedron: Asymmetry 2000, 11, 4895.
(h) Messina, F.; Botta, M.; Corelli, F.; Paladino, A. Tetrahedron: Asymmetry
2000, 11, 4895. (i) Armstrong, A.; Edmods, I. D.; Swarbric, M. E.
Tetrahedron Lett. 2003, 44, 5335. (j) Washington, I.; Houk, K. N. J. Org.
Chem. 2003, 68, 6597. (k) Hannachi, J.-C.; Vidal, J.; Mulatier, J.-C.; Collet,
A. J. Org. Chem. 2004, 69, 2367. (l) Armstrong, A.; Jones, L. H.; Knight,
J. D.; Kelsey R. D. Org. Lett. 2005, 7, 713.
(4) For a compiled use of N-sulfonyloxazidines, see: Mishra, J. K. Synlett
2005, 3, 543.
(5) Davis, F. A.; Lamendola, J. Jr.; Nadir, U.; Kluger, E. W.; Sedergran,
T. C.; Panunto, T. W.; Billmers, R.; Jenkins, R., Jr.; Turchi, I. J.; Watson,
W. H.; Chen, J. S.; Kimura, M. J. Am. Chem. Soc. 1980, 102, 2000.
10.1021/ol052250w CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/02/2005

reported by Davis, but other oxidants7 (peroximidic acid)
have also been used.
affords instantaneously oxaziridine 2a, which can be isolated
in an almost quantitative yield (entry 4, Table 1) by simple
The main limitations of all of these methods are related
to the difficulties associated with the synthesis of the starting
N-sulfonylimines by condensation of N-sulfonamides with
the proper carbonyl compounds.5,8 It does not give good
results for compounds derived from aliphatic aldehydes and
ketones containing tautomerizable protons or for N-alkyl-
sulfonylamides derivatives, giving low yields in the con-
densation step. As a consequence, the structural diversity of
the N-sulfonyloxaziridines reported so far is rather limited,
being restricted to those derived from aromatic aldehydes
and some bicyclic ketones and in most cases only concerning
the N-arylsulfonyl derivatives.
Table 1. Results Obtained in the Conversion of 1a into 2a
Using Relevant Methods
reaction yield
entry
1
conditions
time
(%)
isolation
m-CPBA two-phase
oxidation system
(HCCl3/NaHCO3-H2O)
and PTC11
4-5 h
92 extraction +
crystallization
We have recently published a new method to prepare
N-sulfonylimines9 consisting of the condensation of the
carbonyl compounds with N-sulfinamides and further oxida-
tion of the resulting N-sulfinylimines with m-CPBA. As this
condensation step lacks the limitations indicated for N-
sulfonamides, the scope of our method in the synthesis of
N-sulfonylimines is much wider, which suggests that the
structural diversity of the oxaziridines would be now also
larger. Moreover, we have just reported the usefulness of
m-CPBA/KOH as a nucleophilic epoxidizing reagent of
highly deficient double bonds able to act as very good
Michael acceptors (gem-disubstituted by two electron-
withdrawing groups).10 The two main advantages of this
reagent, with respect to the peroxidessthe most commonly
used to obtain epoxidessare its higher reactivity toward the
CdC bonds and the higher stability of the resulting epoxide
2
3
Oxone, KHCO3-H2O6
2 h
95 extraction +
crystallization
85 extraction +
silica gel
peroximidic acid (H2O2,
TBAB, CCl3CN, CH2Cl2,
H2O, NaHCO3)7
0.5 h
chromatography
4
this paper (m-CPBA, KOH) <1 min 100 filtration
filtration. Significant advantages of using this procedure can
be inferred by comparing these results with those obtained
with the best methods previously reported for preparing 2a
(see Table 1). This comparison demonstrates that, in terms
of reaction times, experimental procedures simplicity, and
yields, m-ClC6H4COOO- is the most efficient oxaziridinating
reagent so far reported for N-sulfonylimines. The much
shorter reaction times required for our reagent must be due
to its use as a suspension in a dry solvent. The absence of
water substantially increases the reactiVity of m-ClC6H4CO-
OO- with respect to the preViously used reagents, all of them
requiring the use of water as cosolVent, which solVates the
oxygen, substantially reducing their nucleophilic reactiVity.
As the N-sulfinylimines12 are much more stable than their
corresponding N-sulfonylimines13 and the latter compounds
can be instantaneously obtained from the former ones by
reaction with m-CPBA,9 we reasoned that the use of the
N-sulfinylimines as the starting products for synthesizing
N-sulfonyloxaziridines could be made following a two step
one pot oxidation, by successive reactions with m-CPBA and
m-CPBA/KOH, without isolating the N-sulfonylimine 1
intermediate (Scheme 1).
-
to the anion formed as byproduct (m-ClC6H4CO2 instead
of RO-). Therefore, we reasoned that both these features
could be very useful in the synthesis of the oxaziridines if
the m-CPBA/KOH system is reactive enough to oxidize the
CdN of N-sulfonylimines. In this paper, we report a new
procedure for preparing N-sulfonyloxaziridines consisting in
the one-pot, two-step oxidation of N-sulfinylimines with
m-CPBA (1 equiv) and m-CPBA/KOH (1.1 equiv). It allows
the synthesis of N-alkyl- and N-arylsulfonyloxaziridines with
a large structural variety including those derived from
aldehydes and ketones containing enolizable protons. This
method provides higher yields, requires much shorter reaction
times (usually less than 5 min), and involves a simpler
purification process (filtration) than the methods reported so
far. Moreover it can be used at a gram scale.
Scheme 1
We first studied the reaction of m-CPBA/KOH with N-p-
tolylsulfonylbenzylideneimine 1. The addition at room tem-
perature of this imine to a 1:1 mixture of KOH and m-CPBA
(6) Davis, F. A.; Chattopadhyay, S.; Towso, J. C.; Lal, S.; Reddy, T. J.
Org. Chem. 1988, 53, 2087.
(7) (a) Kra¨ıem, J.; Othman, R. B.; Hassine, B. B. C. R. Chimie 2004, 7,
1119. (b) Davandi, J. A. Karami, B.; Zolfigol, M. A. Synlett 2002, 933.
(8) See, for example: (a) Trost, B. M.; Christopher, M. J. Org. Chem.
1991, 56, 6468. (b) Lee, K. Y.; Lee, C. C.; Kim, J. N. Tetrahedron Lett.
2003, 44, 1231 and references therein. (c) Wolfe, J.; Ney, J. E. Org. Lett.
2003, 5, 4607. (d) Jin, T.; Feng, G.; Yang, M.; Li, T. Synth. Commun.
2004, 34, 1277.
(9) Garc´ıa Ruano, J. L.; Alema´n, J.; Cid, M. B.; Parra, A. Org. Lett.
2005, 7, 179.
(10) Garc´ıa Ruano, J. L.; Fajardo, C.; Fraile, A.; Martin, R. J. Org. Chem.
2005, 70, 4300.
This prompted us to study the direct transformation of 3a
into 2a. After several trials in different conditions, we found
(11) Davis, F. A.; Stringer, O. D. J. Org. Chem. 1982, 7, 1774. This is
a improved synthesis of their previous first synthesis (ref 5).
(12) (a) For p-tolylsulfinylimines, see: Zhou, P.; Chen, B.-C.; Davis, F.
A. Tetrahedron 2004, 60, 8003 and references therein. (b) For tert-butyl-
N-sulfinylmines, see: Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem.
Res. 2002, 35, 984 and references therein.
5494
Org. Lett., Vol. 7, No. 24, 2005

that reaction of 3a with m-CPBA (1 equiv) followed by
treatment with a mixture of m-CPBA (1.1 equiv) and KOH
(3 equiv) at room temperature yielded the desired oxaziridine
2a in 94% isolated yield. Worthy of notice are the simplicity
of the experimental procedure14 and the easy purification15
(filtration) of the resulting oxaziridine.
Table 2. Preparation of N-p-Tolylsulfonyloxaziridines 2a-i
from N-p-Tolylsulfinylimines 3a-i
We then prepared N-sulfinylimines 3a-s by condensation
of the N-sulfinamides 5a-d with the corresponding carbonyl
compounds (Scheme 2) according to the Davis’ protocol16
starting
entry material
yield
(%)
R1
R2
products
1
2
3
4
5
6
7
8a
9
3a
3b
3c
3d
3e
3f
3g
3h
3ib
Ph
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
94
89
97
96
99
97
99
89
80
3-MeOC6H4
4-NO2C6H4
4-CNC6H4
PhCHdCH2
Me
i-Pr
Ph
Ph
Scheme 2
Me 2g
Me 2h (74)/2′h (26)c
Me 2i (86)/2′i (14)c
slightly modified in the work up, which allowed the
improvement of the yields.17 N-Sulfinamides 5a-d were
obtained by reaction of disulfides with NBS/MeOH18 and
further treating with LiHMDS19 (for more details, see the
Supporting Information).
The results obtained in the reactions of the N-p-tolylsulfi-
nylimines 3a-i, derived from aromatic or aliphatic aldehydes
and ketones, with m-CPBA and m-CPBA/KOH according
to the procedure indicated above, are summarized in Table
2.
As we can see, reactions are very efficient in all cases.
Aromatic N-sulfinylaldimines 3a-d, containing electron-
donating or electron-withdrawing groups, afford oxaziridines
2a-d in very high yields. Less than 5 min are required for
the whole process. The simplicity of the experimental
procedure prompted us to check the multigram scale. It was
performed by reaction of 2.4 g of N-p-tolylsulfinylimine 3a
(0.01 mol) with the reagents, obtaining pure oxazidirine 2a
in a yield (97%) even better than that obtained at a lower
a Similar results were obtained at -40 °C. b N-tert-Butylsulfonyl deriva-
tive was used. c Diastereoisomeric ratio.
scale, which suggests that this transformation is almost
quantitative.
The conjugated double bonds are not affected by the
reagents, as suggested by the easy transformation of N-
sulfinylimine 3e into 2e (entry 5, Table 2). Similarly, an
excellent result was obtained with the enolizable aldimine
3f, which indicates that under the basic conditions used in
these reactions the possible enolization does not decrease
the reactivity of the process (entry 6, Table 2).
Also remarkable are the results obtained from enolizable
N-p-toluenesulfinylketimines 3g-i (entries 7-9, Table 2).
Starting from 3g, the evolution of the reaction is identical
to that of the sulfinylaldimines and 2g, with the sulfonyl
group in an anti arrangement with respect to the isopropyl
group, allowing us to obtain diastereomerically pure N-p-
tolylsulfonyloxaziridine 2g (entry 7, Table 2). On the
contrary, starting from ketimine 3h (entry 8, Table 2), a 3:1
mixture of anti- and syn-oxaziridines (2h and 2h′) was
obtained, whereas this ratio is even higher (anti/syn ) 86:
14) starting from the N-tert-butylsulfinylketimine 3i. Con-
sidering the low energy required for the syn-anti isomer-
ization of N-arylsulfonyloxaziridines,20 the composition of
the reaction mixtures must be dependent only on the relative
stability of the oxaziridines (thermodynamic control) pre-
sumably associated with the relative value of the almost
eclipsed interactions of the SO2Tol group with the substituent
adopting a cis arrangement.
(13) N-Sulfinylimines derived from aliphatic aldehydes or ketones are
stable for months at -20 °C, whereas their corresponding sulfonylimines
only can usually be stored for less than 1 day.
(14) General Procedure for the Synthesis of N-Sulfonyloxaziridines
from N-Sulfinylimines. Dry m-CPBA (0.40 mmol) is added in one portion
to a solution of the corresponding N-sulfinylimine (0.40 mmol) in CH2Cl2
(2 mL) at room temperature. Once the reaction is completed (usually it is
instantaneous; see the text), the reaction crude is added over a white
suspension of m-CPBA (0.44 mmol) and powdered KOH (1.4 mmol) in 1
mL of CH2Cl2 (previously prepared and maintained for 5 min at room
temperature). When this second reactionswhich is also instantaneous and
can be easily followed by TLCsis finished, the reaction crude is filtered
and the solvent evaporated to yield pure N-sulfonyloxaziridine.
(15) The use of an excess of KOH is required for transforming the
m-chlorobenzoic acid generated in the first step in its corresponding insoluble
carboxylate, removable by filtration. The use of an alternative procedure
involving the reaction of the N-sulfinylimine with a 2:1 mixture of m-CPBA/
KOH in only one step, is also efficient to form the N-sulfonyloxazididines,
but their isolation is not so simple because m-CPBA remains solved in the
organic layer.
(16) Davis, F. A.; Zhang, Y.; Andemichae, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403.
(17) The reaction mixture was treated with MeOH, and some drops of
NaHCO3 were added until precipitation of the titanium salts. Then, it was
filtered trough a short pad of anhydrous Na2SO4, the solvent evaporated,
and the residue purified by flash chromatography.
(18) Brownbridge, P.; Jowett, I. C. Synthesis 1987, 252.
(19) This procedure has been used by Davis for synthesizing (S)-p-
tolylsulfinamide from (S)-menthyl sulfinate. See ref 16.
Finally we have also prepared oxaziridines 2j-s bearing
different residues at the sulfur atom (Table 3). The interest
in the N-o-methoxyphenylsulfonylimines 2l and 2m is related
to their possible usefulness in asymmetric processes involv-
ing the formation of stable metal chelates with the nitrogen
(20) A thermodynamic control was detected (anti/syn 1/3). See: (a)
Jennings, W. B.; Watson, S. P.; Tolley, M. S. J. Am. Chem. Soc. 1987,
109, 8099. (b) Jennings, W. B.; Watson, S.; Boyd, D. R. J. Chem. Soc.,
Chem. Commun. 1988, 931.
Org. Lett., Vol. 7, No. 24, 2005
5495

with especially good results being obtained for the interesting
tert-butyl derivatives 2l and 2m (entries 3 and 4, Table 3).
The only substrates producing less satisfactory results were
3r and 3s (entries 9 and 10, Table 3), bearing a p-
nitrophenylsulfonyl group at nitrogen. The problems ob-
served derive from the already expected difficulty of
oxidizing the highly deficient p-nitrosulfinyl group into the
p-nitrosulfonyl one during the first step with m-CPBA. This
requires much longer reactions times (several hours) for this
step, resulting in the decomposition of the starting N-
sulfinylimines which is especially significant for the less
stable alkylimine 3s (entry 10, Table 3). These reactions were
not performed following the general protocol14 but rather
by treating the N-sulfinylimines 3r and 3s with a 6:4 mixture
of m-CPBA/KOH for 4 and 12 h, respectively.
In conclusion, we have developed a simple and efficient
two-step process for obtaining N-sulfonyloxaziridines starting
from N-sulfinylaldimines consisting of their successive
reaction with m-CPBA and m-CPBA/KOH. It is applicable
to aromatic and aliphatic aldimines and ketimines, regardless
of the presence of enolizable protons, allows the synthesis
of N-sulfonyloxaziridines containing different residues at the
sulfur atom, and can be performed on a multigram scale.
Additionally, it can be applied on substrates containing cyano
groups and conjugated CdC bonds.
Table 3. Synthesis of Different N-Alkyl- and
N-Arylsulfonyloxaziridines
entry starting material R1
R3
product yield (%)
1
2
3
3j
3k
3l
Ph o-MeOC6H4
i-Pr o-MeOC6H4
Ph t-Bu
2j
2k
2l
2m
2n
2o
2p
2q
2rb
2s
99
93
99
99
91
83
99
93
4
5
6
7
8
9a
10a
3m
3n
3o
3p
3q
3r
3s
i-Pr t-Bu
Ph i-Pr
i-Pr i-Pr
Ph n-Pr
i-Pr n-Pr
Ph p-NO2C6H4
i-Pr p-NO2C6H4
57
(32)c
a Reactions were performed in only one step with a 6:4 mixture of
m-CPBA/KOH for longer reaction times (4-12 h). b Oxaziridine 2r was
purified by chromatography. c Conversion measured by H NMR.
1
and oxygen atoms. The behavior of 3j and 3k in their
successive reactions with m-CPBA and m-CPBA/KOH was
identical to that of the tolylsulfonyl derivatives (entries 1
and 2, Table 3).21 N-Alkylsulfonyl-oxaziridines were easily
obtained under the conditions of our protocol, from the
corresponding N-alkylsulfinylimines (entries 3-8, Table 3)
Acknowledgment. We thank the Spanish Government
for financial support (Grant No. BQU2003-04012). J.A. and
A.P. thank the Ministerio de Ciencia y Tecnolog´ıa and
Ministerio de Educacio´n y Ciencia, respectively, for pre-
doctoral fellowships.
(21) We have also tried the synthesis of the p-methoxyphenyl derivative
(p-MeOC6H4CdNSO-o-MeOC6H4.) The reaction works, but the low
stability of the resulting oxaziridine in the basic medium used precludes its
isolation. This behavior had already been observed by Davis with the
p-MeOC6H4 derivatives (ref 5). As it must be presumably due to the high
stability of the benzylcarbacation resulting from the ring opening, which
immediately would react with the basic medium, we performed the reaction
without using excess of KOH in the second step (the isolation of compound
was now different). Nevertheless, under these conditions, we obtained
similarly bad results.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL052250W
5496
Org. Lett., Vol. 7, No. 24, 2005