A general method for the preparation of N-sulfonyl aldimines and ketimines

Article abstract of DOI:10.1021/ol048005e

(Chemical Equation Presented) A simple procedure to obtain N-sulfonyl imines involving the condensation of carbonyl compounds with p-tolyl or tert-butyl sulfinamides followed by oxidation with m-CPBA of the resulting N-sulfinylimines is reported. The meth

Full text of DOI:10.1021/ol048005e

ORGANIC
LETTERS
2005
Vol. 7, No. 2
179-182
A General Method for the Preparation of
N-Sulfonyl Aldimines and Ketimines†
Jose´ Luis Garc´ıa Ruano,* Jose´ Alema´n, M. Bele´n Cid, and Alejandro Parra
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid,
Cantoblanco, 28049-Madrid
joseluis.garcia.ruano@uam.es
Received September 30, 2004
ABSTRACT
A simple procedure to obtain N-sulfonyl imines involving the condensation of carbonyl compounds with p-tolyl or tert-butyl sulfinamides
followed by oxidation with m-CPBA of the resulting N-sulfinylimines is reported. The method is applicable to aldehydes (aliphatics and aromatics)
and ketones (diaryl, dialkyl, and aryl alkyl), even those containing enolizable protons. It also does not affect CdN or CdC double bonds and
does not epimerize -stereogenic centers.
r
The sulfonyl moiety has proven to be a powerful activating
group of imine derivatives. As a consequence, N-sulfonyl
imines have been widely used in organic synthesis.1 They
are excellent substrates in aza Diels-Alder reactions,2
nucleophilic additions,3 and reductions,4 as well as in radical5
or ene6 reactions. They have been also applied in the
synthesis of aziridines.7
A plethora of methods exists for obtaining N-sulfonyl
imines,8-16 from aromatic or nonenolizable aldehydes.9,10,15
Notwithstanding this, N-sulfonylimines derived from ali-
phatic aldehydes and ketones remain difficult to prepare
because of their kinetic instability and ease of enolization.
As a consequence, only a few of the existing published
methods can be applied. Some of the problems encountered
with existing methodology are summarized below. Although
N-sulfonylimines from enolizable aldehydes can be formed
by using Trost’s method, epimerization at the R-chiral center
† Dedicated to Professor Jose Elguero on the occasion of his 70th
birthday.
(1) (a) Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131. (b) Gohain,
M. Synlett 2003, 13, 2097. (c) Bloch, R. Chem. ReV. 1998, 98, 1407.
(2) (a) Sisko, J.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 3037. (b)
Boger, D. L; Corbett, W. L.; Curran, T. T. Kasper, A. M. J. Am. Chem.
Soc. 1991, 113, 1713. (c) Garc´ıa-Manchen˜o, O.; Go´mez-Arraya´s, R.;
Carretero, J. C. J. Am. Chem. Soc. 2004, 126, 456 and references therein.
(3) (a) Melnick, M. J.; Freyes, A. J.; Weinreb, S. M. Tetrahedron Lett.
1988, 29, 3891. (b) Yamada, K.; Fujihara, H.; Yamamoto, Y.; Miwa, Y.;
Taba, T.; Tomioka, K. Org. Lett. 2002, 4, 3509. (c) Aggarwal, V.; Alonso,
E.; Ferrar, M.; Spey, S. E. J. Org. Chem. 2002, 67, 2335. (d) Yanmaka,
M.; Nishida, A.; Nagawaka, M. Org. Lett. 2002, 2, 159. 3891. (e) Soeta,
T.; Nagai, K.; Fujihara, H.; Kuriyama, M.; Tomioka, K. J. Org. Chem.
2003, 68, 9723. (f) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem.
Soc, 2003, 125, 761. (g) Gu¨nter, M.; Gais, H.-J. J. Org. Chem, 2003, 68,
8037. (h) Yim, H.-K.; Wong, H. N. C. J. Org. Chem. 2004, 69, 2892.
(4) (a) Hojo, M.; Murakami, C.; Fujii, A.; Hosomi, A. Tetrahedron Lett.
1999, 40, 911. (b) Nisikori, H.; Yoshihara, R.; Hosomi, A. Synlett 2003, 4,
561. (c) Chen, Y.-C.; Wu, T.-F.; Deng, J.-G.; Liu, H.; Cui, X.; Zhu, J.;
Jiang, Y.-Z.; Choi, M. C. K.; Chan, A. S. C. J. Org, Chem. 2002, 67, 5301.
(5) Yamada, K.-I.; Fujihara, H.; Yamamoto, Y.; Miwa, Y.; Taga, T.;
Tomioka, K. Org. Lett. 2002, 4, 3509.
(7) (a) Hori, R. Aoayama, T.; Shoiri, T. Tetrahedron Lett. 2000, 41, 9455.
(b) Arini, L. G.; Sinclair, A.; Szeto, P.; Stockan, R. A. Tetrahedron Lett.
2004, 45, 1589.
(8) Trost, B. M.; Christopher, M. J. Org. Chem. 1991, 56, 6468.
(9) Love, B. E.; Raje, P. S.; Willimas, T. C., II. Synlett 1994, 493.
(10) Lee, K. Y.; Lee, C. C.; Kim, J. N. Tetrahedron Lett. 2003, 44, 1231
and references therein.
(11) Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 1, 75.
(12) Artman, G. D.; Bartolozzi, A.; Franck, R. W.; Weinreb, S. M. Synlett
2001, 232.
(13) Boger, D. L.; Corbett, W. L. J. Org. Chem. 1992, 57, 4777.
(14) Wolfe, J.; Ney, J. E. Org. Lett. 2003, 5, 4607.
(15) (a) Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5561. (b)
Georg, G. I.; Harriman, G. C. B.; Peterson, S. A. J. Org. Chem. 1995, 60,
7366. (c) Ram, R. N.; Khan, A. A. Synth. Commun. 2001, 31, 841. (d) Jin,
T.; Feng, G.; Yang, M.; Li, T. Synth. Commun. 2004, 34, 1277.
(16) 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.
(6) Yamanaka, M.; Nishida, A.; Nakagwa, M. Org. Lett. 2002, 2, 159.
10.1021/ol048005e CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/29/2004

is often observed.8 Likewise, although aliphatic aldehydes
can be transformed into their corresponding N-sulfonylimines
by formation of the sulfonamidosulfone intermediates and
sulfonyl elimination,11 this two-step procedure cannot be
extended to hindered or R,â-unsaturated aldehydes or to
ketones. The Hudson reaction of oximes with sulfinyl
chlorides has been used to form â-trimethylsilyl ethane-
sulfonyl and tert-butyl ketimines in moderate yields.12
N-Sulfonyl derivatives of ketimines and R,â-unsaturated
aldimines can be formed by the condensation of oximes with
sulfonyl cyanides, but this is an expensive method and
generates toxic byproducts.13 More recently, a new method
for the preparation of N-tosyl ketimines via palladium-
catalyzed isomerization of N-tosyl aziridines has been
reported.14 This method does, however, require prior prepara-
tion of the precursor aziridine and is limited to methyl
ketimines.
prepared from disulfide 8 on a multigram scale as outlined
in Scheme 2. Compound 8 was transformed into the methyl
sulfinate 9 using the procedure reported by Brownbridge and
Jowett.20 Treatment of 9 with LiHMDS21 followed by
precipitation from hexane afforded the pure sulfinamide 2
in 92% overall yield.22
Scheme 2. Multigram Scale Procedure To Obtain
Sulfinylamide 2
The condensation of aldehydes and ketones 1a-o with
p-tolylsulfinylamide 2 was accomplished using Ti(OEt)4
protocol of Davis,18 with slight modifications in the workup
(see Table 1).23 With these adjustments the desired N-
sulfinylimines 4a-o were obtained in high yields.
Therefore it seems highly desirable to find a simple,
efficient, economical, and general protocol for N-sulfonyl
aldimines and ketimines synthesis, even those containing
enolizable R-hydrogens.
In theory, the ideal procedure for obtaining N-sulfonyl-
imines would involve the condensation of carbonyl com-
pounds with sulfonamides. However, the low nucleophilicity
of the latter generally requires harsh acidic conditions to
activate the carbonyl, conditions that are usually incompatible
with the resulting unstable sulfonyl imines.9 In light of this,
we decided to focus our attention on preparing N-sulfonyl-
imines from N-sulfinylaldimines and ketimines using tech-
nologies recently introduced by the Davis and Ellman groups,
in a variety of other contexts.17 The latter compounds can
easily formed by condensation of the optically pure sulfin-
amides 218 and 319 with carbonyl compounds. Additionally,
they are stable enough to be chromatographed and stored
without significant hydrolysis. Thus, we reasoned that finding
a reagent capable of oxidizing N-sulfinyl into N-sulfonyl
imines without affecting the CdN bond could provide a
general method for the synthesis of the latter species.
We present herein a simple and general two-step procedure
for synthesizing N-sulfonylimines through the condensation
of racemic sulfinylamides with aldehydes and ketones and
oxidation with m-CPBA (Scheme 1). We have used 2 and 3
as sulfinamides because the resulting N-sulfonylimines
contain the p-Tol and t-Bu residues, which are the most
widely used in the literature.
Table 1. Preparation of N-p-Tolylsulfonylimines 6
reaction yields (%)
entry
R1
R2 s.m./prod. step a step b overall
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
H
H
H
Ph
1a/6a
1b/6b
1c/6c
1d/6d
1e/6e
1f/6f
1g/6g
1h/6h
1i/6i
93(99)18 100
93(100)8
92(- -)
3-MeOC6H4
2-Napht
2-BrC6H4
4-CNC6H4
PhCHdCH2
n-Pr
i-Pr
t-Bu
Ph
Ph
(92)18a
94(- -)
100
95
89(88)10
91(- -)
91(65)30 100
81(60)30 85b
69(- -)
76(73)32
75(78)11
(80)31a
95
78(87)18 96c
65(90)18 100c 65(53)11
9
79(89)18 96
79 (70)33 88
78(65)34 96
73(53)34 84
76(90)8
69(100)15
75(79)35
61(- -)
69(- -)
43(51)36
58(- -)
10
11
12
13
14
15
1j/6j
Me 1k/6k
4-MeOC6H4 Me 1l/6l
4-CNC6H4
t-Bu
i-Pr
Me 1m/6m 77(- -)
Me 1n/6n
Me 1o/6o
90
48(42)34 90
64(- -)
90
a Yield not recorded. b In this case the reaction time was 15 min. c To
avoid oxaziridine formation, this reaction was carried out at 45 °C.
Scheme 1. General Procedure To Prepare N-Sulfonylimines
m-CPBA has previously been used to oxidize arene
N-sulfenylimines into the corresponding N-sulfinylimines24
and N-sulfonylimines.16 Nevertheless, the conditions used
(17) (a) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. ReV. 1998, 27,
13 and references therein. (b) Ellman, J. A.; Owens, T. D.; Tang, T. P.
Acc. Chem. Res. 2002, 35, 984 (c) Zhou, P.; Chen, B.-C.; Davis, F. A.
Tetrahedron 2004, 60, 8003 and references therein.
(18) Davis, F. A.; Zhang, Y.; Andemichae, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403.
(19) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J.
Org. Chem. 1999, 64, 1278.
Our preliminary studies were carried out with the more
common p-tolyl substituent. The racemic sulfinylamide 2 was
180
Org. Lett., Vol. 7, No. 2, 2005

in the latter transformation (a two-phase system, involving
m-CPBA and aqueous NaHCO3) invariably resulted in the
formation of complex mixtures containing oxaziridines25
when this method was applied to such imines derived from
aliphatic aldehydes and ketones. On the basis of research
recently developed in our group, we suspected that these
failures and deficiencies could be related to the use of
m-CPBA in aqueous basic media.26 Therefore, we examined
the oxidation of compounds 4a-o using an equimolecular
amount of dry m-CPBA. Under these conditions S-oxidation
occurred readily at room temperature in excellent yield to
afford the pure N-sulfonylimines 6a-o without any need for
chromatography.27 The scope of the oxidation reaction can
be deduced from the results summarized in Table 1. For
comparison purposes, the yields of the N-sulfinylimines we
obtained are presented, alongside yields so far described for
N-sulfonylimines prepared by other methods.
of the sulfonyl oxaziridine, resulting from the oxidation of
6g and 6h, were observed. This side reaction can be easily
avoided by carrying out the reaction at 45 °C. Therefore,
our method to prepare N-p-tolylsulfinylimines 6 is applicable
to any kind of aldehyde or ketone, even those containing
enolizable protons and bulky substituents.
We next studied the application of our protocol to the
synthesis of the N-tert-butylsulfonyl derivatives 7 because
they have shown behavior similar to that of 6 in different
reactions and because they offer some advantages in removal
of the protecting group.28 Condensation of the commercially
available racemic N-tert-butylsulfinamide 329 with carbonyl
compounds was accomplished using the method reported by
Ellman19 but using the workup indicated in ref 23. The
resulting compounds 5 were then oxidized into 7 with
m-CPBA as previously indicated; the results are summarized
in Table 2.
Aromatic aldehydes containing both electron-withdrawing
and -donating substituents 1a-e (entries 1-5, Table 1)
afforded the corresponding sulfonylimines 6a-e in very high
yields, comparable with those of other methods; the latter
yields are shown in brackets. The lower reactivity of the
arylaldehydes containing electron-withdrawing substitu-
ents (entry 5) generally necessitates longer reaction times in
the first step. The more challenging R,â-unsaturated and
enolizable sulfonyl aldimines 6f-i (entries 6-9, Table 1)
are also easily obtained following the same protocol. It is
also posisible to prepare N-sulfinylimines derived from
ketones. Thus, benzophenone (1j, entry 10) and different
enolizable arylmethyl ketones 1k-o (entries 11-14) were
easily transformed into their corresponding N-sulfonylimines
6j-o. In these reactions, the overall yields are not as high
as those obtained from the aldehydes as a result of the lower
efficiency of the condensation step, which in the case of the
bulky pinacolone is only 48% (entry 14).
Table 2. Preparation of N-tert-butylsulfonylimines 7
reaction yields (%)
entry
R1
R2 s.m./prod.
step a
step b overall
1
2
3
4
5
6
7
8
9
Ph
H
H
H
Ph
1a/7a
1p/7p
1g/7g
1j/7j
96(91)19
63(82)19
100 96(64a)12
100 63(- -)
2-furyl
n-Pr
Ph
100(100)39 84c
84(- -)
75(- -)
63(89)19
62(- -)
100 75(61a)12
100 63(d)4c
100 62(- -)
100 73(- -)
90
78
80
Ph
Me 1k/7k
4-MeOC6H4 Me 1l/7l
4-CNC6H4 Me 1m/7m 73(- -)
-(CH2)5-
1q/7q
Me 1r/7r
Me 1s/7s
65(91)19
73b(- -)
59c(- -)
59(48a)12
57(- -)
47(- -)
The high chemoselectivity of the present oxidation method
is noteworthy, the imine and olefinic double bonds usually
being left intact. Only for aliphatic aldehydes containing the
n-butyl and isopropyl substituents (entries 7 and 8), traces
Et
10 2-pyridyl
a Yields given are calculated from the corresponding oxime. b A 4:1
mixture of the E/Z isomers was formed. c In this case the reaction time
was 15 min. d Yield not reported.
(20) Brownbridge, P.; Jowett, I. C. Synthesis 1987, 252.
(21) This procedure had been used by Davis for the synthesis of the
(S)-p-tolylsulfinamide from (S)-menthyl sulfinate.18
(22) We have checked that this procedure is also appropriate to prepare
other aliphatic or aromatic sulfinamides.
(23) The reaction mixture was treated with MeOH and some drops of
NaHCO3 until precipitation of the titanium salts. Then it was filtered through
a short pad of anhydrous Na2SO4, the solvent was evaporated, and the
residue was purified by flash chromatography.
(24) (a) Friedman, A. J.; Evans, T. R. J. Agric. Food Chem. 1983, 31,
127-134. (b) Davis, F. A.; Friedman, A. J.; Upender, N. K. J. Am. Chem.
Soc. 1978, 100, 2844.
As was the case for the p-tolyl derivatives, the N-tert-
butylsulfinylimine 5g (derived from the aliphatic aldehyde
1g) was prone to overoxidation into the N-sulfonyloxa-
ziridine, and so the amount of m-CPBA had to be precisely
measured to avoid this complication.37 It is noteworthy that
(28) (a) Sun, P.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1997, 62,
8604. (b) Schleusner, M. Koep, S.; Gu¨nter, M.; Tiwari, S. K.; Gais, H.-J.
Synthesis 2004, 967.
(29) Racemic sulfonamide 3 can be obtained according to the method
of ref 28b and references therein.
(30) Garc´ıa Ruano J. L.; Alema´n, J.; Soriano, J. F. Org. Lett. 2003, 5,
677.
(31) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll,
P. J. J. Org. Chem. 1997, 62, 2555.
(32) Raghavan, S.; Rajender, A. Tetrahedron 2004, 60, 5059.
(33) Annunziata, R.; Cinquini, M.; Cozzi, F. J. Chem. Soc., Perkin Trans.
1 1982, 2, 339.
(34) Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D. L. J. Org. Chem. 2000,
65, 8704.
(25) For leading references about oxaziridines, see: (a) Davis, F. A.;
Sheppard, A. C. Tetrahedron 1989, 45, 5703. (b) Davis, F. A.; Chen, B.-C.
Chem. ReV. 1992, 92, 919
(26) Preliminary results have been presented at the 21st International
Symposium on the Organic Chemistry of Sulfur, Madrid, July, 2004. Garc´ıa
Ruano, J. L.; Fajardo, C.; Fraile A.; Mart´ın M. R. Book of Abtracts; p 179.
(27) General Procedure for the Oxidation of Sulfinylimines 4 to
Sulfonylimines 6. Dry m-CPBA (0.4 mmol) was added in one portion to
a solution of the corresponding sulfinylimine 4 or 5 (0.4 mmol) in CH2Cl2
(2 mL) at room temperature. Once the reaction was complete (less than 1
min), the mixture was diluted with CH2Cl2 (8 mL) and washed with a
saturated solution of NaHCO3 (3 × 5 mL). The organic phase was dried
over anhydrous Na2SO4, and the solvent was evaporated to yield pure
sulfonylimines 6 or 7.
Org. Lett., Vol. 7, No. 2, 2005
181

other N-sulfonylimines were completely stable to over-
oxidation in the presence of a slight excess of m-CPBA. This
result clearly demonstrates that this procedure is applicable
to a wide variety of carbonyl compounds, even those
containing substituents that are prone to oxidation, such as
pyridine38 (entry 10), or those sensitive to acidic media, such
as furan (entry 2).
A general concern in the preparation of N-sulfonylimines
is epimerization of the stereocenter at the R-position.8
Nevertheless, no R-epimerization has been observed in the
formation of sulfinylimines.40 The smooth oxidation condi-
tions involved in our synthetic sequence to prepare N-
sulfonylimines prompted us to investigate the stability of
stereogenic centers joined to the carbonyl group. In Scheme
3 are indicated the two studied examples. Aldehyde 1t, a
second experiment, the commercially available optically pure
ketone 1u was converted into a mixture of sulfinylimines
5u and 5u′ when treated with racemic sulfonamide 3. This
mixture was oxidized to the N-sulfonyl derivative 7u with
complete regioselectivity without affecting the stereogenic
center and, remarkably, with no epoxidation of the disub-
stituted double bond, which demonstrates the high chemo-
selectivity of m-CPBA toward sulfur.
In conclusion, we have developed a simple and efficient
two-step process for obtaining N-sulfonylaldimines and
N-sulfonylketimines by reaction of the corresponding alde-
hydes or ketones with sulfinamides and further oxidation of
the resulting N-sulfinylimines with m-CPBA. The method
is applicable to aromatic and aliphatic carbonyl compounds,
even those containing enolizable protons. Additionally, it
does not affect the configuration of R-stereogenic centers
and is highly selective in the presence of CdN and CdC
(deactivated or not) double bonds.
Scheme 3. Preparation of Chiral Enolizable Sulfonylimines
Acknowledgment. We thank the Spanish Government
for financial support (Grant BQU2003-04012). J.A. and
M.B.C. thank the Ministerio de Ciencia y Tecnolog´ıa for a
predoctoral and Ramo´n y Cajal fellowship and contract,
respectively. We thank Doctor Alberto Fraile for supplying
aldehyde 1t.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 2, 4-7, and
9. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL048005E
cis-disubstituted cyclopropane, was transformed exclusively
into its corresponding N-sulfonylimine 6t, without detection
of the thermodynamically more stable trans isomer. In the
(38) In the oxidation reaction of 5s a slight excess of m-CPBA highly
favored the formation of the sulfonyl oxaziridine. This is probably due to
the pyridine ring, which makes easier the dissociation of the peracid,
increasing the concentration of the R-CO2O- that is acting as a nucleophile
at the CdN bond. This could be the reason Davis obtained large amounts
of oxaziridines in the oxidation of aliphatic sulfenylimines with the system
m-CPBA/NaHCO3 (see ref 16).
(35) Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc
2003, 125, 12996.
(36) Sugihara, Y.; Iimura, S.; Nakayama, J. Chem. Commun. 2002, 2,
134.
(39) Staas, D. D.; Savage, K. L.; Homnick, C. F.; Tsou, N. N.; Ball, R.
G. J. Org. Chem. 2002, 67, 8276.
(37) The use of a deficiency of m-CPBA produced mixtures of 7g and
5g, whereas an excess of the reagent afforded 7g and the correponding
oxaziridine.
(40) (a) Portonovo, P.; Liang, B.; Joullie´, M. M. Tetrahedron: Asymmetry
1999, 10, 1451. (b) Evans, J. W.; Ellman, J. A. J. Org. Chem. 2003, 68,
9948.
182
Org. Lett., Vol. 7, No. 2, 2005