Two Practical and Efficient Approaches to Fluorinated and Nonfluorinated Chiral β-Imino Sulfoxides

Article abstract of DOI:10.1021/jo980336f

Reaction of fluorinated and nonfluorinated N-substituted imidoyl chlorides 1 with lithium derivatives of enantiopure methyl p-tolyl sulfoxide 2a (or racemic methyl phenyl sulfoxide 2b) gave a wide variety of chiral N-substituted β-imino sulfoxides 4 in good to excellent yields. The title compounds (R)-4 were also prepared by aza-Wittig reaction of γ-fluoro-β-keto sulfoxides (R)-5 and N-aryl iminophosphoranes 6. The imino - enamino equilibrium was studied, showing, in all instances, the imino form as the predominant tautomer independent of the nature of the N-substituent. The configuration of the C=N double bond was found to be Z for both N-alkyl and N-aryl derivatives on the basis of ¹H NMR NOE difference experiments performed over several compounds. Ab initio calculations (HF/6-31G*) carried out on several representative examples of 1 and 4 are, in general, consistent with the experimental results.

Full text of DOI:10.1021/jo980336f

6210
J . Org. Chem. 1998, 63, 6210-6219
Tw o P r a ctica l a n d Efficien t Ap p r oa ch es to F lu or in a ted a n d
Non flu or in a ted Ch ir a l â-Im in o Su lfoxid es
Santos Fustero,* Antonio Navarro, Bele´n Pina, and Amparo Asensio
Departamento de Quı´mica Orga´nica, Facultad de Farmacia, Universidad de Valencia,
46100-Burjassot (Valencia), Spain
Pierfrancesco Bravo, Marcello Crucianelli, Alessandro Volonterio, and Matteo Zanda*
C.N.R.-Centro di Studio per le Sostanze Organiche Naturali, Dipartimento di Chimica del Politecnico,
via Mancinelli 7, I-20131 Milano, Italy
Received February 23, 1998
Reaction of fluorinated and nonfluorinated N-substituted imidoyl chlorides 1 with lithium derivatives
of enantiopure methyl p-tolyl sulfoxide 2a (or racemic methyl phenyl sulfoxide 2b) gave a wide
variety of chiral N-substituted â-imino sulfoxides 4 in good to excellent yields. The title compounds
(R)-4 were also prepared by aza-Wittig reaction of γ-fluoro-â-keto sulfoxides (R)-5 and N-aryl
iminophosphoranes 6. The imino-enamino equilibrium was studied, showing, in all instances,
the imino form as the predominant tautomer independent of the nature of the N-substituent. The
configuration of the CdN double bond was found to be Z for both N-alkyl and N-aryl derivatives
on the basis of 1H NMR NOE difference experiments performed over several compounds. Ab initio
calculations (HF/6-31G*) carried out on several representative examples of 1 and 4 are, in general,
consistent with the experimental results.
In tr od u ction
Among the easily accessible fluoro-amino building
blocks, perfluoroalkyl imidoyl halides,5 particularly the
trifluoromethyl derivative, have recently emerged as
promising and valuable synthetic intermediates that can
be converted into a variety of useful nitrogen hetero-
cycles5b,6 and other functionalized acyclic compounds
including trifluoromethyl ketimines,5b R,â-unsaturated
trifluoromethyl ketones,7 amidines, and imidates.6b,8 Fol-
lowing an efficient modification of the methodology
previously developed by Appel,9 perfluoroalkyl imidoyl
halides have recently been synthesized in a high-yielding
The development of new and efficient methods for the
regio- and stereoselective approach to compounds of high
synthetic and pharmacological interest is one of the most
active areas of research in modern organic chemistry.1
In the search for new strategies for the preparation of
biologically active molecules, we focused our attention on
fluorine-containing acyclic nitrogen compounds.
Organofluorine chemicals are finding increasing utility
in various fields including medicinal, biological, agricul-
tural, and analytical chemistry.2 Although most applica-
tions involve fluorinated oxygen derivatives,2,3 the syn-
thesis and reactivity of fluorine-containing amino
compounds have received a great deal of attention in
recent years owing to their peculiar biological behavior,
arising mainly from the fact that fluorine substituents
weaken the basicity, in turn modifying solubility, desol-
vation, and binding properties. In particular, fluorine-
containing amino acids4a-e and amino alcohols4f are
compounds which exhibit unique biological properties.2,4
(4) A number of fluorine-containing amino acids have been synthe-
sized and studied as potential enzyme inhibitors. Amino acids contain-
ing the trifluoromethyl group are also potential antimetabolites
because of the relatively nontoxic and stable nature of this group. See
for example: (a) Fluorine-containig Amino Acids: Synthesis and
Properties; Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley: Chichester,
1994. (b) Sakai, T.; Yan, F.; Kashino, S.; Uneyama, K. Tetrahedron
1996, 52, 233. (c) Osipov, S. N.; Golubev, A. S.; Sewald, N.; Michel, T.;
Kolomiets, A. F.; Fokin, A. V.; Burger, K. J . Org. Chem. 1996, 61, 7521.
(d) Bravo, P.; Capelli, S.; Meille, S. V.; Viani, F.; Zanda, M.; Kukhar,
V. P.; Soloshonok, V. A. Tetrahedron: Asymmetry 1994, 5, 2009. (e)
Soloshonok, V. A.; Fokina, N. A.; Rybakova, A. V.; Shishkina, I. P.;
Galushko, S. V.; Sorochinsky, A. E.; Kukhar, V. P. Tetrahedron:
Asymmetry 1995, 7, 1601. (f) Be´gue´, J .-P.; Bonnet-Delpon, D. Trifluo-
romethylated Amino Alcohols: New Synthetic Approaches and Me-
dicinal Targets. In Biomedical Frontiers of Fluorine Chemistry; Ojima,
I., McCarthy, J . R., Welch, J . T., Eds.; American Chemical Society:
Washington, DC, 1996; pp 59-72.
(1) Helmchen, G.; Hoffmann, R. W., Mulzer, J .; Schaumann, E.
Stereoselective Synthesis; Houben-Weyl Methods of Organic Chemistry;
Georg Thieme Verlag: Stuttgart, 1996, Workbench Edition E21, Vols.
1-10.
(2) (a) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991. (b) Filler, R.; Kobayashi, Y.;
Yagupolskii, L. M. Biomedical Aspects of Fluorine Chemistry; Elsevi-
er: Amsterdam, 1993. (c) Banks, R. E.; Tatlow, J . C.; Smart, B. E.
Organofluorine Chemistry: Principles and Commercial Applications;
Plenum Press: New York, 1994. (d) Welch, J . T. Selective Fluorination
in Organic and Bioorganic Chemistry, ACS Symposium Series 456;
American Chemical Society: Washington, DC, 1991. (e) For a review
see also: Resnati, G. Tetrahedron 1993, 49, 9385. (f) Resnati, G.;
Soloshonok, V. A. Tetrahedron Symposia-in Print-no. 58. Tetrahedron
1996, 52, 1, 319.
(3) See for example: (a) Arnone, A.; Bravo, P.; Frigerio, M.; Viani.
F.; Cavicchio, G.; Crucianelli, M. J . Org. Chem. 1994, 59, 3459. (b)
Arnone, A.; Bravo, P.; Frigerio, M.; Salani, G.; Viani. F.; Zappala`, C.;
Cavicchio, G.; Crucianelli, M. Tetrahedron 1995, 51, 8289. (c) Hui-
Ping, G.; Chang-Ming, H. Synthesis 1996, 1363.
(5) (a) Kantlehner, W.; Mergen, W. W. In Comprehensive Organic
Functional Group Transformations; Katritzky, A. R., Meth-Cohn, O.,
Rees, C. W., Eds.; Pergamon: 1995; Vol. 5, Chapter 17. (b) Uneyama,
K.; Morimoto, O.; Yamashita, F. Tetrahedron Lett. 1989, 30, 4821.
(6) (a) Uneyama, K.; Yamashita, F.; Sugimoto, K.; Morimoto, O.
Tetrahedron Lett. 1990, 31, 2717. (b) Uneyama, K.; Kobayashi, M.
Tetrahedron Lett. 1991, 32, 5981. (c) Uneyama, K.; Sugimoto, K. J .
Org. Chem. 1992, 57, 6014. (d) Kobayashi, M.; Sadamune, K.; Mi-
zukami, H.; Uneyama, K. J . Org. Chem. 1994, 59, 1909. (e) Watanabe,
H.; Yan, F.; Sakai, T.; Uneyama, K. J . Org. Chem. 1994, 59, 758. (f)
Sakamoto, T.; Kikugawa, Y. J . Org. Chem. 1994, 59, 929.
(7) Huang, W. S.; Yuan, C. Y. J . Chem. Soc., Perkin Trans. 1 1995,
741.
(8) Uneyama, K.; Kobayashi, M. J . Org. Chem. 1994, 59, 3003.
(9) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801 and
references therein.
S0022-3263(98)00336-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/11/1998

Fluorinated and Fluorine-Free Chiral â-Imino Sulfoxides
J . Org. Chem., Vol. 63, No. 18, 1998 6211
one-pot procedure by Uneyama10 starting from perfluo-
roalkyl carboxylic acids and primary amines. In this
context we have studied the reactivity of imidoyl chlorides
toward azaenolates derived from 2-alkyl-2-oxazolines and
2-alkyl-2-thiazolines and report a simple route to masked
N-substituted â-enamino acid derivatives.11 These com-
pounds can be regarded as precursors of â-amino acids.
Chiral sulfoxides and, particularly, â-keto sulfoxides,
are very interesting compounds widely used in asym-
metric synthesis.12,13 These reagents are usually ob-
tained by simple acylation of R-metalated chiral sulfox-
ides with esters.14 The fluorinated version was developed
in a similar way, in the laboratories of Politecnico of
Milan,15 and the utility of γ-fluoro-â-keto sulfoxides has
been demonstrated in the preparation of several chiral
fluorinated oxygen compounds of synthetic and biological
interest.16
In contrast with â-keto sulfoxides, the corresponding
imino derivatives have received relatively little attention.
Although â-imino sulfoxides and their enamine tau-
tomers, including a few containing fluorine examples,17
have been known for a reasonable time, their utility in
asymmetric synthesis had not been demonstrated until
recently.17,18 These compounds were used, mainly through
selective reduction processes, for preparing analogues of
biologically active molecules such as optically active
amines,17b,19 amino alcohols,17b amino acids,17b and alka-
loid precursors.20 A limited number of synthetic methods
have been developed in recent years for preparing â-imino
sulfoxides using approaches which can be classified into
the following four categories:
(i) The condensation between â-keto sulfoxides and
amines,18a,21 which is the most, a priori, simple synthetic
strategy. However, this reaction is not satisfactory for
the preparation of γ-fluoro-â-imino sulfoxides and is
progressively less efficient with increasing fluorination
level.17 For these reasons we have developed an alterna-
tive route to some R-(fluoroalkyl)-â-sulfinyl enamines 4
(R2 ) Cbz or H and R1 ) RF) based on an aza-Wittig
reaction of imino phosphoranes (Ph3PNR2, R2 ) Cbz or
SiMe3) with fluorinated â-keto sulfoxides17 (see retrosyn-
thetic scheme, eq 1). A similar methodology had been
applied to the synthesis of â-enamino esters.22,23
(ii) Andersen-type syntheses,24 which involve the
reaction of metalated alkyl imines with chiral sulfinic
esters. This procedure has been applied with success to
acyclic,21d,25 endocyclic,20 and exocyclic imines.18b The
major limitation of this procedure is the need to keep a
strict control of the reaction conditions in order to avoid
undesired competing reactions such as epimerization of
the sulfinyl stereocenter.21d
(iii) Michael-type addition of primary and secondary
amines to either allenyl25a,26 or alkynyl chiral sulfox-
ides.27,28 Owing to their relative inaccessibility, allenyl
sulfoxides have been used only for specific cases when
the aforementioned strategies (i and ii) have failed.25a
(iv) Reaction of sulfinyl carbanions with nitriles of
which only a few examples have been described, the best
results being obtained with aromatic nitriles.19,29
Since all the existing approaches to â-imino sulfoxides
possess several limitations in their general applicability,
the development of new and general methodologies for
the synthesis of these useful derivatives is highly desir-
able. In this paper we report in detail two practical and
efficient strategies for the synthesis of fluorinated and
nonfluorinated â-imino sulfoxides (4) (retrosynthetic
scheme, eq 1): the reaction of chiral lithiated aryl methyl
sulfoxides (2) with imidoyl chlorides (1) (route A)30 and
the extension of the “aza-Wittig approach” to the syn-
thesis of N-aryl γ-fluoro-â-imino sulfoxides (R)-4 (route
(10) Uneyama, K.; Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe,
H. J . Org. Chem. 1993, 58, 32.
(11) Fustero, S.; Navarro, A.; D´ıaz, D.; de la Torre, M. G.; Asensio,
A.; Sanz, F.; Liu Gonza´lez, M. J . Org. Chem. 1996, 61, 8849.
(12) (a) Posner, G. H. In The Chemistry of Sulphones and Sulphox-
ides; Patai, S., Rappoport, Z., Stirling, C. J . M., Eds.; Wiley: New York,
1988. (b) Solladie´, G. Synthesis 1981, 185. (c) Solladie´, G. Pure Appl.
Chem. 1988, 60, 1699. (d) Posner, G. H. Acc. Chem. Res. 1987, 20, 72.
(d) Walker, A. J . Tetrahedron: Asymmetry 1992, 3, 961. (e) Carren˜o,
M. C. Chem. Rev. 1995, 95, 1717.
(13) See for example: Solladie´, G.; Colobert, F. In Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 1995; Vol.
5, pp 3606 and 3235 and references therein.
(14) (a) Solladie´, G.; Fre´chou, C.; Demailly, G.; Greck, C. J . Org.
Chem. 1986, 51, 1912. (b) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Rubio,
A. Tetrahedron Lett. 1987, 28, 4861. (c) Solladie´, G.; Ghiatou, N.
Tetrahedron: Asymmetry 1992, 3, 33.
(15) (a) Bravo, P.; Piovosi, E.; Resnati, G. Synthesis 1986, 579. (b)
Bravo, P.; Zanda, M. Asymmetric Synthesis of Fluoro-Organic Com-
pounds via Chiral Sulfoxide Chemistry. In Enantiocontrolled Synthesis
of Fluoro-Organic Compounds: Stereochemistry, Challenges and Bio-
medicinal Targets; Soloshonok, V. A., Ed.; Wiley: Chichester, in press.
(16) See for example: (a) Bravo, P.; Frigerio, M.; Resnati, G. J . Org.
Chem. 1990, 55, 4216. (b) Bravo, P.; Pregnolato, M.; Resnati, G. J .
Org. Chem. 1992, 57, 2726.
(21) (a) Kawecki, R.; Kozerski, L. Tetrahedron 1986, 42 1469. (b)
Ogura, K.; Ishida, M.; Tomori, H.; Fujita, M. Bull. Chem. Soc. J pn.
1989, 62, 3531. (c) Baldenius, K.-U.; Kagan, H. B. Tetrahedron:
Asymmetry 1990, 1, 597. (d) Garc´ıa Ruano, J . L.; Lorente, A.;
Rodriguez, J . H. Tetrahedron Lett. 1992, 33, 5637. (e) Ogura, K.;
Tomori, H.; Fujita, M. Chem. Lett. 1991, 1407.
(17) (a) Bravo, P.; Crucianelli, M.; Zanda, M. Tetrahedron Lett. 1995,
36, 3043. (b) Arnone, A.; Bravo, P.; Capelli, S.; Fronza, G.; Meille, S.
V.; Zanda, M.; Cavicchio, G.; Crucianelli, M. J . Org. Chem. 1996, 61,
3375. Corrigenda: J . Org. Chem. 1996, 61, 9635. (c) Arnone, A.; Bravo,
P.; Bruche´, L.; Crucianelli, M.; Vichi, L.; Zanda, M. Tetrahedron Lett.
1995, 36, 7301.
(18) (a) Kawecki, R.; Kozerski, L.; Urbanczyk-Lipkowska, Z.; Bocelli,
G. J . Chem. Soc., Perkin Trans. 1 1991, 2255. (b) Carren˜o, M. C.;
Dominguez, E.; Garc´ıa Ruano, J . L.; Pedregal, C.; Rodriguez, J . H.
Tetrahedron 1991, 47, 10035. (c) Bravo, P.; Crucianelli, M.; Fronza,
G.; Zanda, M. Synlett 1996, 249. (d) Volonterio, A.; Zanda, M.; Bravo,
P.; Fronza, G.; Cavicchio, G.; Crucianelli, M. J . Org. Chem. 1997, 62,
8031.
(22) Kloeck, J . A.; Leschinsky, K. L. J . Org. Chem. 1978, 43, 1460.
(23) Shen, Y.; Gao, S. J . Fluorine Chem. 1996, 76, 37.
(24) Andersen, K. K.; Gaffield, W.; Papanikolaou, N. E.; Foley, J .
W.; Perkins, R. I. J . Am. Chem. Soc. 1964, 86, 5637.
(25) (a) Annunziata, R.; Cinquini, M.; Restelli, A.; Cozzi, F. J . Chem.
Soc., Perkin Trans. 1 1982, 1183. (b) See ref 18a and references therein.
(26) Truce, W. E.; Markley, L. D. J . Org. Chem. 1970, 35, 3275.
(27) (a) McMullen, C. H.; Stirling, C. J . M. J . Chem. Soc. B 1966,
1217. (b) Lee, A. W. M.; Chan, W. H.; Lee, Y.-K. Tetrahedron Lett. 1991,
32, 6861. (c) Lee, A. W. M.; Chan, W. H.; Tao, Y.; Lee, Y. K. J . Chem.
Soc., Perkin Trans. 1 1994, 477. (d) Chan, W.; Lee, A. W. M.; J iang, L.
Tetrahedron Lett. 1995, 36, 715.
(28) For synthesis of chiral alkynyl sulfoxides, see: (a) Kosugi, H.;
Kitaoka, M.; Tagami, K.; Takahashi, A.; Uda, H. J . Org. Chem. 1987,
52, 1078. (b) See ref 27b.
(19) Tsuchihashi, G.-I.; Iriuchijima, S.; Maniwa, K. Tetrahedron Lett.
1973, 14, 3389.
(20) (a) Hua, D. H.; Bharathi, S. N.; Takusagawa, F.; Tsujimoto,
A.; Panangadan, J . A. K.; Hung, M.-H.; Bravo, A. A.; Erpelding, A. M.
J . Org. Chem. 1989, 54, 5659. (b) Hua, D. H.; Bharathi, S. N.; Robinson,
P. D.; Tsujimoto, A. J . Org. Chem. 1990, 55, 2128. (c) Hua, D. H.;
Bharathi, S. N.; Panangadan, J . A. K.; Tsujimoto, A. J . Org. Chem.
1991, 56, 6998. (d) Hua, D. H.; Park, J .-G.; Katsuhira, T.; Bharathi,
S. N. J . Org. Chem. 1993, 58, 2144. (e) Bravo, P.; Crucianelli, M.;
Farina, A.; Meille, S. V.; Volonterio, A.; Zanda, M. Eur. J . Org. Chem.
1998, 435.
(29) (a) Yokoyama, M.; Takeshima, T. Tetrahedron Lett. 1978, 19,
147. (b) Annunziata, R.; Cinquini, M.; Colonna, S.; Cozzi, F. J . Chem.
Soc., Perkin Trans. 1 1981, 614. (c) Alternatively, fluorinated N-
unsubstituted â-enamino sulfoxides have been prepared by using
N-trimethylsilyl iminophosphoranes as already indicated (see ref 17b).
(30) For preliminary communications, see: (a) Bravo, P.; Cavicchio,
G.; Crucianelli, M.; Markovsky, A. L.; Volonterio, A.; Zanda, M. Synlett
1996, 887. (b) Fustero, S.; Navarro, A.; Asensio, A. Tetrahedron Lett.
1997, 38, 4891. Corrigenda: Tetrahedron Lett. 1997, 38, 6477.

6212 J . Org. Chem., Vol. 63, No. 18, 1998
Fustero et al.
Sch em e 1
stage, ultimately furnishing the corresponding N-unsub-
stituted derivative by standard procedures.4b,33
Although the reaction between imidoyl chlorides 1 and
lithiated sulfoxides 2 (route A) has rather general ap-
plicability, its particular importance is in the synthesis
of fluorinated derivatives (R1 ) RF).34 In fact, fluorinated
N-alkyl (Table 1, entries 4, 6, 9, 12, 17, 18, and 19) as
well as N-aryl (Table 1, entries 1, 2, 3, 5, 7, 8, 10, 11, 13,
14, 15, and 16) â-imino sulfoxides (4) were always
obtained in good to excellent yields. All these reactions
were very fast (less than 20 min) and proceeded well
under mild conditions (-78 to -50 °C) (see Experimental
Section).35
Fluorine-free â-imino sulfoxides 4b,c,p (Table 1, en-
tries 2, 3, and 16) were obtained by employing imidoyl
chlorides (1) derived from aromatic amines (R2 ) aryl)
and bulky aliphatic, aromatic, and heteroaromatic car-
boxylic acids (R1 ) tert-butyl, phenyl, and pyridyl). In
these cases the protocol also worked well, although higher
temperatures (-78 to 0 °C) and longer reaction times
(∼3-5 h) were required. In general, results were better
when fluorinated N-aryl imidoyl chlorides (1) (R1 ) RF)
were used, a feature ascribed to the higher electrophi-
licity of the iminic carbon in these derivatives. Moreover,
it must be noted that, in contrast with those examples
described in the literature,36 this method also produced
high yields when it was applied to the synthesis of
derivatives 4b,c,n ,p (Table 1, entries 2, 3, 14, and 16),
which are not activated by fluoroalkyl residues.
B).30a The results of an ab initio (HF/6-31G*) study
carried out in order to establish, or predict, the configu-
rational stability of tautomers and geometric isomers of
â-imino sulfoxides (4), as well as of imidoyl chlorides (1),
are also presented, and comparisons are made, wherever
possible, with the accompanying experimental evidence.
(1)
(33) See for example: Cimarelli, C.; Palmieri, G. J . Org. Chem. 1996,
61, 5557. Of particular synthetic interest is the chemoselective cleavage
of the N-PMP group of â-aminosulfoxides, obtained by hydride-
promoted reduction of â-iminosulfoxides
4 with ceric ammonium
nitrate, which does not affect the stereogenic sulfinyl group. See ref
30a.
(34) We have not applied this methodology to the synthesis of
fluorine-free â-imino sulfoxides 4 where R1 and R2 are aliphatic groups.
The thermal instability of the N-alkyl imidoyl chlorides 1 derived from
aliphatic carboxylic acids (see refs 9 and 10) and their, in general, lower
reactivity coupled with the fact that these systems have already been
successfully prepared by condensation or Andersen-type reactions, as
described by Garc´ıa Ruano et al. (see ref 21d), are some of the reasons
for our choice.
Resu lts a n d Discu ssion
Rou te A. The synthesis of â-imino sulfoxides 4 via
imidoyl chlorides 1 is outlined in Scheme 1. Com-
mercially available (+)-(R)- and (-)-(S)-methyl p-tolyl
sulfoxides 2a 24,31 and (()-methyl phenyl sulfoxide 2b
were lithiated with LDA in THF. Subsequently, the
appropriate N-alkyl or N-aryl imidoyl chloride 110 was
slowly added at -78 °C, affording the corresponding
â-imino sulfoxides 4 in high yields (Table 1). The
reactions were accomplished either by using 1.0 equiv of
sulfoxide 2 and 2 equiv of LDA, mixed at -40 °C (method
1), or by using 2.0 equiv of lithiated methyl p-tolyl
sulfoxide (R)-2a prepared at -70 °C (method 2).32a In
almost all instances (method 1 or 2) the reactions
proceeded to completion,32b as indicated by TLC (for
details see Experimental Section).
(35) In one case this reaction was accompanied by an unexpected
side reaction. Addition of (2-methoxycarbonylphenyl)imino trifluoro-
acetimidoyl chloride 1s to lithiated (R)-(+)-2a produced the N-(2-
hydroxycarbonyl-phenyl)imino derivative 4s, as
a nearly unique
product. Hydrolysis of the methyl ester functionality may be explained
by postulating that the intermediate lithiated â-sulfinyl enamine 3s
undergoes an intramolecular Dieckmann-type cyclization, producing
the unstable cyclic derivative A. Under aqueous workup conditions,
the final product 4s can be produced by retro-condensation. Neverthe-
less, it cannot be ruled out that the carboxylic acid might also emerge
by simple hydrolysis of the ester under alkaline conditions as suggested
by one of the referees.
Most of the cases reported in Table 1 relate to imidoyl
chlorides (1) bearing p-methoxyphenyl and R-phenylethyl
groups as R2 substituents. This choice was made because
both these R2 groups can be readily cleaved at a later
(31) These compounds can also be synthesized on a large scale by
using the DAG methodology. See for example: (a) Guerrero de la Rosa,
V.; Ordon˜ez, M.; Llera, J . M.; Alcudia, F. Synthesis 1995, 761. (b) El
Ouazzani, H.; Khiar, N.; Ferna´ndez, I.; Alcudia, F. J . Org. Chem. 1997,
62, 287.
(32) (a) When method 2 was employed, the excess of sulfoxide (R)-2
could be recovered quantitatively by flash chromatography (FC). (b)
The use of only 1 equiv of LDA (or, alternatively, lithiated sulfoxide
2) led, in all cases, to yields lower than 50%. See also ref 11 and
literature cited therein.
(36) Very poor yields were always obtained for these derivatives (0-
30%) (refs 21a,c and 25a).

Fluorinated and Fluorine-Free Chiral â-Imino Sulfoxides
J . Org. Chem., Vol. 63, No. 18, 1998 6213
Ta ble 1. N-Su bstitu ted â-Im in o Su lfoxid es 4 Obta in ed fr om Ar yl Meth yl Su lfoxid es 2 a n d Im id oyl Ch lor id es 1 (Rou te A)
Imidoyl chlorides (1)
entry
2a
R1
R2
product
(RS)-4a
yield (%)b
method
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
(+)-2a
(+)-2a
(+)-2a
(+)-2a
(+)-2a
(+)-2a
(+)-2a
(+)-2a
(+)-2a
(+)-2a
(+)-2a
(-)-2a
(-)-2a
(-)-2a
(-)-2a
(-)-2a
(-)-2a
(-)-2a
(()-2b
CF3
p-MeOC6H4
85 (>99)
65
93
82
82
80
90
>99
80
74
76
97
92
87
72
80
72
1 (2)
1
1
1
1
1
2
2
2
2
2
1
1
1
1
1
1
t-Bu
p-MeC6H4
Ph
(RS)-4b
(RS)-4c
(R,RS)-4d
(RS)-4e
(R,RS)-4f
(RS)-4g
(RS)-4h
(RS)-4i
Ph
CF3
(R)-(+)-C6H5(Me)CH
p-MeOC6H4
(R)-(+)-C6H5(Me)CH
Ph
m-MeOC6H4
n-hexyl
CF3CF2
CF3CF2
CF3
CF3
CF3
CF2Cl
CF2Cl
CF3
CF3(CF2)6
p-FC6H4
CF2Cl
3-Pyridyl
CF3
Ph
(RS)-4j
m-MeOC6H4
(S)-(+)-c-C6H11(Me)CH
p-MeOC6H4
p-MeC6H4
p-MeOC6H4
p-MeOC6H4
c-C6H11
(RS)-4k
(S,SS)-4l
(SS)-4m
(SS)-4n
(SS)-4o
(SS)-4p
(SS)-4q
(R,SS)-4d
(S,R/SS)-4r
CF3
CF3
(R)-(+)-C6H5(Me)CH
(S)-(+)-c-C6H11(Me)CH
83
85
1
1
a
b
2a : (R)-(+)-methyl p-tolyl sulfoxide and (S)-(-)-methyl p-tolyl sulfoxide. 2b: (()-methyl phenyl sulfoxide. Yield after purification.
Ta ble 2. N-Ar yl γ-F lu or o â-Im in o Su lfoxid es (RS)-4
Sch em e 2
Obta in ed via Aza -Wittig (Rou te B)
entry
RF
CF3
Ar
product
yield (%)
1
2
3
4
5
6
7
p-MeOC6H4
(RS)-4a
(RS)-4g
(RS)-4j
(RS)-4o
(RS)-4t
(RS)-4u
(RS)-4v
93
85
82
97
76
90
ca. 30
CF3
Ph
Ph
CF2Cl
CF2Cl
CF2CF3
CF2H
CFH2
p-MeOC6H4
Ph
Ph
Ph
The “aza-Wittig method” is particularly useful for the
preparation of â-imino sulfoxides (4) bearing an activat-
ing group in the â-position. In fact â-keto sulfoxides (5)
which have a fluorine-free alkyl chain in the â-position
(for example, a methyl group) are unreactive at room
temperature toward N-aryl iminophosphoranes (6).
Monofluorinated â-keto sulfoxide (RS)-5e is poorly reac-
tive, demonstrated by the fact that after 30 h at 50 °C
only ca. 30% of (RS)-5e was transformed into the desired
product (RS)-4v. In contrast, difluoro â-keto sulfoxide
(RS)-5d and â-perhaloalkylated â-keto sulfoxides (RS)-
5a -c are very reactive, even at room temperature. This
finding correlates well with our previous studies on
the behavior of â-keto sulfoxides as substrates of the
aza-Wittig reaction with N-Cbz and N-SiMe3 imino
triphenylphosphoranes.17a,b
Rou te B. The synthesis of some N-aryl â-imino
sulfoxides (R)-4 via aza-Wittig reaction37 of γ-fluoro-â-
keto sulfoxides (R)-5 with N-aryl imino triphenylphos-
phoranes 6 is reported in Scheme 2. The starting
N-phenyl imino phosphorane 6a was prepared by reac-
tion of Ph3PBr2 and aniline with triethylamine as base
(Kirsanov reaction).38a,b The N-p-methoxyphenyl imino
phosphorane 6b was prepared by reaction of p-methox-
yphenyl azide with triphenylphosphine (Staudinger
reaction).37,38c
An equimolar amount of N-aryl iminophosphorane 6
and γ-fluoro-â-keto sulfoxide [(RS)-5a -d ], in dry benzene,
was reacted overnight at room temperature affording the
corresponding N-aryl γ-fluoro â-imino sulfoxides [(RS)-
4a ,g,j,o,t,u ,v], in high yield (Table 2).
There was no evidence of racemization in either
synthetic route. Reaction of chiral N-(S)-[1-cyclohexyl-
ethyl]-2,2,2-trifluoroacetimidoyl chloride 1l with enan-
tiopure (S)-methyl p-tolyl sulfoxide 2a provided only one
diastereoisomer (S,SS)-4l (entry 12, Table 1), based on
NMR analysis (1H and 19F) of the crude reaction mixture.
As expected, reaction of (S)-1l with racemic (()-methyl
phenyl sulfoxide provided equal diastereomeric quantities
of the â-imino sulfoxide 4r (entry 19, Table 1), again
estimated on the basis of NMR experiments.39
(37) The term “aza-Wittig reaction” is adopted in this paper for
reasons of clarity, due to its widespread use in the literature. The name
“aza-Wittig” arises from the similarity between this reaction, involving
iminophosphoranes, and the true Wittig reaction, which makes use of
carbon-phosphorus ylides. However, it must be recognized that the
former reaction was discovered by Staudinger: (a) Staudinger, H.;
Meyer, J . Helv. Chim. Acta 1919, 2, 635. (b) Staudinger, H.; Hauser,
E. Helv. Chim. Acta 1921, 4, 861. We thank Dr. Vadim A. Soloshonok,
National Industrial Research Institute of Nagoya, J apan, for pointing
this out. The fact that “Staudinger reaction”, which would be more
appropriate, is the well-established name for two other important
processes, namely, the reaction between azides and triphenylphos-
phine, as well as the reaction between ketenes and imines, leading to
â-lactams, led us to use the term “aza-Wittig reaction” to avoid
confusion. For recent reviews see: (c) Molina, P.; Vilaplana, M. J .
Synthesis 1994, 1197. (d) J ohnson, A. W.; Kasha, W. C.; Starzewsky,
K. A. O.; Dixon, D. A. Ylides and Imines of Phosphorus; J ohn Wiley:
New York, 1993; Chapter 13.
P u r ifica tion of â-Im in o Su lfoxid es. Purification of
â-imino sulfoxides (4) was carried out in most cases by
flash chromatography (FC) or, alternatively, by medium-
pressure liquid chromatography (MPLC) on silica gel.
(38) (a) Kirsanov, A. V. Izv. Akad. Nauk SSSR 1950, 426; Chem.
Abstr. 1951, 45, 1503. (b) Horner, L.; Oediger, H. Liebigs Ann. Chem.
1959, 627, 142. (c) Leffler, J . E.; Temple, R. D. J . Am. Chem. Soc. 1967,
89, 5235.
(39) To date we have not been able to obtain the pure single
diastereoisomers by chromatography (FC or MPLC).

6214 J . Org. Chem., Vol. 63, No. 18, 1998
Fustero et al.
Ch a r t 1
F igu r e 1. Representative NOE results.
obtained via route A as a 9:1 mixture of Z/ E iminic
tautomers) (entries 3 and 14, Table 1). In contrast, for
fluoroalkyl N-alkyl derivatives, such as 4d (entries 4 and
18, Table 1), the freshly prepared homogeneous Z iminic
tautomer underwent slow isomerization upon standing
neat at room temperature, to form the corresponding
enamino tautomer.45 The original situation was restored
when the enaminic tautomers were redissolved in CDCl3
and allowed to stand in solution for a few hours.
All this experimental evidence, in conjuntion with the
computational studies (see below), point to the fact that
the Z iminic configuration is the thermodynamically more
stable tautomeric form for â-imino sulfoxides.
Some partial hydrolysis to the corresponding â-keto
sulfoxides was occasionally observed, but this could be
avoided by pre-elution with a 2% triethylamine/hexanes
solution.40 Chemically pure fluorinated â-imino sulfox-
ides (4) are stable compounds which can be stored at 0
°C for a long time and handled at room temperature
without any deterioration.
Ta u tom er ism of â-Im in o Su lfoxid es. Almost all the
â-imino sulfoxides 4 obtained by either route were single
iminic tautomers (Chart 1).41 However, the exact tau-
tomeric composition appeared to be sensitive to the
structural features of the â-imino sulfoxides. NMR
analysis (1H, 19F, and 13C) in CDCl3 at room temperature
showed that fluorinated N-aryl derivatives 4 exist only
as the Z iminic tautomers (4R) (Chart 1) (see below).42
However, fluorinated N-alkyl and fluorine-free deriva-
tives (4) contain detectable amounts (10-20%) of the
other three tautomeric forms shown (4â,γ,δ). Under the
same conditions, a significant amount of the E iminic
form was observed only in the case of 4b (R1 ) t-Bu)
(Table 1, entry 2) (78/22 Z/E). Monofluorinated â-imino
sulfoxide (RS)-4v (Table 2, entry 7) was produced via
route B as an almost equimolar mixture of Z (4R) and E
(4â) iminic tautomers although, in this case, we were not
able to obtain chemically pure samples, only mixtures of
(RS)-4v with the corresponding starting â-keto sulfoxide
(RS)-5e (see Experimental Section).
Str u ctu r e Deter m in a tion . The structure and ster-
eochemistry of the â-imino sulfoxides (4) prepared by
routes A and B were deduced on the basis of their NMR
(1H, 13C, and 19F) spectra and elemental and HRMS
1
analyses. Thus, for instance, the H NMR spectrum of
the chlorodifluoro derivative 4o (entry 15, Table 1)
displays characteristic signals at δ 3.71 (d, J ) 12.7 Hz,
1H) and 4.03 (d, J ) 12.7 Hz, 1H) corresponding to the
AB system of CH2S*O. In the 19F NMR spectrum the
2
CClF2 group resonates at δ -59.2 (dAB, J FF ) 163.5 Hz,
2
1F) and -60.0 (dAB, J FF ) 163.5 Hz, 1F). Finally, the
three main features of the 13C NMR spectrum are the
signals corresponding to the CH2S*O, CClF2, and CdN
groups which appear at δ 55.7, 123.2 (t, 1J CF ) 292.8 Hz),
2
and 152.3 (t, J CF ) 28.5 Hz), respectively. These data
confirm unequivocally the iminic structure proposed for
4o.
A study of the thermal stability of these derivatives
was addressed next. When fluoroalkyl N-aryl deriva-
tives, for example, compound 4a (entry 1, Table 1), were
heated at 50 °C in a CDCl3 solution for 5 days their
original homogeneous Z iminic structure (see below) was
completely preserved, as confirmed by NMR. The same
stability was observed for N-aryl â-imino sulfoxides not
bearing a fluoroalkyl residue,43 such as 4c44 and 4n (both
Further corroboration for the correct configuration
assignment to the tautomers 4R and 4â41 was obtained
1
by H NMR NOE difference experiments performed on
4a (entry 1, Table 1 and Figure 1), as well as by ab initio
calculations (see below). These studies showed that
â-imino sulfoxides 4 exist mainly in the Z iminic config-
uration. Thus, irradiation of the singlet at δ 6.87 (4H)
of the aromatic ring of the p-anisidine group of 4a led to
a 3.0% and 2.7% enhancement of the signals correspond-
ing to CHHS*O (δ 4.09, d) and ortho hydrogens of the
p-tolyl sulfinyl (δ 7.28, d) groups, respectively. Cor-
respondingly, irradiation of the signal at δ 7.28 showed
only a small interaction (0.4%) with the hydrogens (δ
6.87) of the p-anisidine ring. Unfortunately, the proxim-
ity and overlapping of some of the aromatic signals of
compounds 4c (entry 3, Table 1) and 4n (entry 14, Table
(40) Meyers, A. I.; Novachek, K. A. Tetrahedron Lett. 1996, 37, 1747.
(41) 4R: Z imino configuration. 4â: E imino configuration. 4γ: Z
enamino configuration. 4δ: E enamino configuration.
(42) On one occasion, for compound 4n (entry 14, Table 1), small
amounts of other tautomers were observed by 19F NMR spectroscopy.
(43) Only compound 4p (entry 16, Table 1) underwent a very slow
Z f E imine isomerization by heating in CDCl3 solution at 50 °C for
3 weeks. The peculiar behavior of 4p may be explained by assuming
the presence of a charge-transfer interaction between the π-electron-
deficient pyridine and the π-electron-rich p-anisidine aromatic rings,
which should stabilize the E iminic isomer.
(44) In contrast with this result, it has been reported in the
literature (see ref 25a) that compound 4c, initially obtained only as
an Z imino tautomer, undergoes a complete Z f E imine isomerization
by standing at room temperature for several days. For comparison,
we have also used the methodology described in ref 25a for preparing
4c (29%). We found that both methods afforded the same 9:1 mixture
of Z/ E imino tautomers. In any case we could not observe Z f E imine
isomerization.
(45) This could be observed by 1H and 19F NMR since the initial AB
system of the CH2S*O group in (R,SS)-4d (entry 18, Table 1) was slowly
converted to a singlet corresponding to the dCHS*O group of the Z
enaminic structure and the quartet of the NCHCH3 group appeared
as a multiplet due to the additional coupling with the NH of the
enaminic form. Moreover, the CF3 group signal moved upfield from δF
-72.1 to -62.1 ppm. Similar isomerizations have also been observed
for related compounds (see ref 17b).

Fluorinated and Fluorine-Free Chiral â-Imino Sulfoxides
J . Org. Chem., Vol. 63, No. 18, 1998 6215
Ch a r t 2
By comparing the relative energies of the N-aryl
derivatives 4a , 4c, and 4v (Table 3) for the several
tautomers shown in Chart 1, it can be seen that the Z
imino tautomer (4R) is predicted to be more stable than
the other three tautomeric forms (4â, 4γ, and 4δ), in
agreement with the experimental evidence.48,50
The situation is somewhat more complicated for N-
alkyl derivatives. Thus, for example, for the fluorine-
free N-alkyl â-imino sulfoxide 4A,21d the Z enamino
tautomer is known to be preferred. According to our
calculations, the energy difference between the Z enam-
ino form (4γ) and the Z and E imino structures (4R and
4â) (1.3 and 0.8 kcal/mol, respectively) is in clear ac-
cordance with the experimental results.21d Subsequently,
we performed the calculations on derivatives 4C21a and
4D producing energy differences of only 0.9 and 0.5 kcal/
mol in favor of the E imine form (4â). This suggests that
compounds 4C and 4D should exist as an imino-enamino
mixture, in agreement with experimental findings.21a In
the case of N-alkyl fluoroalkyl derivatives, such as 4d ,
the Z iminic tautomer is 1.8 and 1.9 kcal/mol more stable
than the E imino and Z enamino isomers, respectively,
in accord with N-aryl fluoroalkyl derivatives. This ten-
dency has also been observed for all fluorinated N-alkyl
derivatives synthesized in this work (see Table 1).
1) made selective irradiation difficult; therefore observed
NOE values were not meaningful.
Similarly, N-alkyl derivatives such as compound 4q
(entry 17, Table 1 and Figure 1) showed an NOE
enhancement (5.5 and 4.0%) for the diastereotopic hy-
drogens (CH2SO) at δ 3.69 and 3.92 respectively through
irradiation of the multiplet at 3.21 ppm corresponding
to the methine cyclohexyl moiety proton. An additional
NOE (1.6%) was observed with the ortho-hydrogens of
the p-tolyl ring at δ 7.51.46
Finally, from the data listed in Table 3, it can also be
inferred that for the N,N′-disubstituted fluorine-free
derivatives the E enamino configuration is found to be
more stable than the corresponding Z enamino configu-
ration, as expected.21a,51
Com p u ta tion a l Stu d ies. To gain further insight into
the relative stabilities of the Z and E iminic and enaminic
tautomers of compounds 4 (Chart 1) we have carried out
semiempirical (AM1) and ab initio (HF/3-21G and HF/
6-31G*) molecular orbital calculations involving full
optimizations using the Gaussian94 series of programs.47
Representative compounds synthesized in this work, such
as 4a , 4c, 4d , and 4v were first examined. Next, the
study was extended to other selected examples taken
from the literature, for instance 4A,21d 4B,48 4C,21a and
4E,21a as well as the simple derivative 4D (Chart 2),
considered as a model. The HF/6-31G* optimized geom-
etries of the most stable tautomer for some representative
compounds 4 are shown in Figure 2, while their total and
relative energies at the HF/6-31G* level of theory are
summarized in Table 3.49 Preliminary examination of
these data reveals that calculations closely match the
experimental results.
Furthermore, we performed a computational study on
the relative stabilities of the Z and E geometries of the
starting fluorinated imidoyl chlorides 1, for example, 1a
(R1 ) CF3; R2 ) p-MeOC6H4, entry 1, Table 1) and 1q
(R1 ) CF3; R2 ) c-C6H11, entry 17, Table 1) (Scheme 3).
It must be pointed out that, although these compounds
were always obtained as a single isomer,5b,6d to our
knowledge the exact geometry of the CdN double bond
has not yet been established.
Semiempirical (AM1) and ab initio (HF/3-21G and HF/
6-31G*) results for fluorinated imidoyl chlorides 1 were
in good agreement with the experimental results. Thus,
these derivatives appear to exist exclusively in the Z
geometry, 1a being 5.6 kcal mol-1 (4.1 at AM1 and 5.3
at 3-21-G) more stable than the E geometry at HF/6-31G*
level, and 1q being 5.9 kcal mol-1 (3.0 at AM1 and 4.1 at
HF/3-21G) more stable than the E geometry at HF/6-
31G* level.
In conclusion, two new and efficient approaches (routes
A and B) to fluorinated chiral â-imino sulfoxides 4 have
been developed. The first methodology (route A) has also
been extended to nonfluorinated N-aryl â-imino sulfox-
ides. The “aza-Wittig method” (route B) is an alternative
and complementary approach, particularly attractive for
the preparation of â-imino sulfoxides bearing perhaloge-
(46) It must be emphasized that certain ambiguities exist in the
literature regarding the stereochemistry of the double bond of the
iminic and enaminic tautomers of derivatives 4 (see ref 21). Thus, for
example, Ogura assigned an
E enamino configuration to N-alkyl
â-enamino sulfoxides resulting from condensations of â-ketosulfoxides
with aliphatic amines (see ref 21e), while the same author proposed
the opposite Z enamino configuration for related compounds obtained
in a similar manner (see ref 21b). This, and other contradictory results
(see refs 21a,c), can be explained by assuming that the reaction
conditions, as well as the methodology used to prepare the target
â-imino sulfoxides, are critical in obtaining one or the other tautomer.
(47) Gaussian 94, Revision C.3; Frisch, M. J .; Schlegel, Trucks, G.
W.; H. B.; Gill, P. M. W.; J ohnson, B. G.; Robb, M. A.; Cheeseman, J .
R.; Keith, T.; Petersson, G. A.; Montgomery, J . A.; Raghavachari, K.;
Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.;
Cioslowski, J .; Stefanov, B. B.; Nanayakkara, A.; Challacombe, N.;
Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. W.; Andre´s, J . L.;
Replogle, E. S.; Gomperts, R.; Mart´ın, R. L.; Fox, D. J .; Binkley, J . S.;
Defrees, D. J .; Baker, J .; Stewart, J . J . P.; Head-Gordon, M.; Gonza´lez,
C.; Pople, J . A.; Gaussian Inc., Pittsburgh, PA, 1995.
(49) It must be pointed out that good agreement between theory
and experimental exists only for the highest level of theory (HF/6-
31G*// HF/6-31G*).
(50) A different result was found in the case of the N-aryl fluorine-
free derivative 4B (Chart 2 and Table 3). HF/6-31G* calculations for
4B predict the E imino (4â) configuration as the most stable tautomer.
Accordingly, this compound has been obtained by Garc´ıa Ruano et al.
(see ref 48) as an E imino/Z imino/Z enamino (50/10/40) mixture from
the N-PMP imine of acetone, following an Andersen-like method.
(51) Kozerski, L.; Kawecki, R.; Bednarek, E. Magn. Reson. Chem.
1987, 25, 712.
(48) Lorente, A., Ph.D. Thesis, Universidad Auto´noma de Madrid,
1997. See also ref 21d.

6216 J . Org. Chem., Vol. 63, No. 18, 1998
Fustero et al.
F igu r e 2. HF/6-31G* optimized structures of compounds 4a R, 4cR, 4d R, 4vR, 4Aγ, and 4Bâ.
Ta ble 3. Ca lcu la ted Tota l (h a r tr ee) a n d Rela tive
En er gies (k ca l m ol-1) of th e Op tim ized Str u ctu r es 4a , 4c,
4d , 4v, a n d 4A-E Usin g Molecu la r Or bita l Ca lcu la tion s
(HF /6-31G*//6-31G*)
Sch em e 3
compd
tautmr
Etot
Erel
4a
R
â
-1553.000 11
-1552.997 22
-1552.995 99
-1552.984 29
-1333.059 95
-1333.055 79
-1333.053 94
-1333.049 38
-1517.187 40
-1517.190 19
-1517.187 16
-1517.173 43
-1241.394 11
-1241.387 16
-1241.383 54
-1241.384 06
-1181.575 43
-1181.576 26
-1181.577 54
-1181.565 54
-1256.423 36
-1256.425 47
-1256.423 48
-1256.413 22
-1256.416 05
-952.027 35
-952.031 89
-952.030 45
-952.019 71
-952.023 40
-722.480 53
-722.484 94
-722.484 12
-722.474 80
-761.498 15
-761.490 71
0.0
1.8
2.6
9.9
0.0
2.6
3.8
6.6
0.0
1.8
1.9
10.5
0.0
4.4
6.6
6.3
1.3
0.8
0.0
7.5
1.3
0.0
1.2
7.7
5.9
2.9
0.0
0.9
7.6
4.4
2.8
0.0
0.5
6.4
0.0
4.7
γ
δ1
R
â
sulfoxides 4 has been studied on the basis of their
spectral properties (NOE experiments) and additionally
by ab initio calculations at the HF/6-31G* level of theory.
The results of this study have allowed us to predict that
fluorinated derivatives appear, almost independent of
their structural nature, in the Z imino configuration
predominantly, while, for the fluorine free derivatives,
either a Z enamino or an E imino/Z enamino mixture is
preferred. This study has also permitted us to establish
that the starting imidoyl chlorides 1 should exist in a Z
configuration. Further studies on the reduction of the
CdN bond of 4, as well as the exploitation of â-imino
sulfoxides for the stereoselective synthesis of biologically
important fluoro-amino compounds, are in progress.
4c
γ
δ2
R
â
4d
4v
4A
4B
γ
δ1
R
â
γ
δ2
R
â
γ
δ1
R
â
γ
Exp er im en ta l Section
δ1
δ2
R
â
Gen er a l Meth od s. All reactions were performed on a dual
manifold vacuum/argon system. General details concerning
the treatment of solvents and reagents are provided in the
Experimental Section of our earlier publications.11,18d (+)-(R)-
and (-)-(S)-methyl p-tolyl sulfoxide and (()-methyl phenyl
sulfoxide were purchased from Aldrich Co. and used without
further purification. Alternatively, (+)-(R)-methyl p-tolyl sul-
foxide was prepared by the Andersen protocol from (-)-
menthyl sulfinate and methylmagnesium iodide.24 Imidoyl
chlorides were prepared according to the methods described
in the literature.9,10 N-Phenyl iminotriphenylphosphorane 6a
was prepared by Kirsanov reaction of aniline with Ph3PBr2.38a,b
N-p-Methoxyphenyl iminotriphenylphosphorane 6b was pre-
pared by Staudinger reaction of p-methoxyphenyl azide with
4C
γ
δ1
δ2
R
â
4D
4E
γ
δ1
E
Z
nated and gem-difluorinated â-alkyl residues, the latter
being difficult to synthesize via imidoyl halides. Fur-
thermore, the imino-enamino equilibrium of â-imino

Fluorinated and Fluorine-Free Chiral â-Imino Sulfoxides
J . Org. Chem., Vol. 63, No. 18, 1998 6217
triphenylphosphine.37,38c All other reagents were of the best
commercial grade available and were used without further
purification. Reaction progress was monitored by analytical
thin-layer chromatography (TLC) on UV active silica gel 60
142.7, 149.0 (q, 2J CF ) 34.7), 158.3; 19F NMR (235 MHz) -71.2
(CFCl3 as standard) or -72.1 (C6F6 as standard); IR (KBr)
1502, 1250, 1053; HRMS (FAB) calcd for (M+ + 1) C17H17NO2-
SF3 356.0932, found 356.0930. Anal. Calcd for C17H16NO2-
SF3: C, 57.46; H, 4.54; N, 3.94; S, 9.02. Found: C, 57.55; H,
4.38; N, 3.92; S, 8.95.
F
254 and visualization was achieved using UV illumination and
iodine. Column chromatography methods, flash chromatog-
raphy, and medium pressure liquid chromatography (MPLC)
were carried out as previously reported.11,17b Melting points
are uncorrected. All NMR spectra were recorded in CDCl3
solution. 1H and 13C nuclei were determined using TMS (0
ppm) and the center line of the chloroform-d triplet (77.0 ppm)
as internal standard, while CFCl3 (0 ppm) (compounds pre-
pared by route A, method 1) or C6F6 (compounds prepared by
route A, method 2, and route B) were used as external
(RS)-2-(Z)-p -Tolylim in o-3,3-d im et h ylb u t h yl-1-p -t olyl-
su lfoxid e (4b). MPLC [n-hexanes-EtOAc (20:1)] on silica gel
(Rf ) 0.4) gave 4b (65%; route A, method 1) as an orange oil:
[R]25 +4.8 (c 0.56, CHCl3); 1H NMR (250 MHz) (major
D
tautomer) 1.30 (s, 9H), 2.34 (s, 3H), 2.35 (s, 3H), 3.69-3.65
(m, 2H), 6.60 (d, J ) 8.2, 2H), 7.03-7.19 (m, 6H); (minor
tautomer) 1.18 (s, 9H), 1.29 (s, 3H), 3.70 (m, 2H), 6.47 (d, J )
8.2, 2H); 13C NMR (75 MHz) (major tautomer) 21.2 (q), 28.1
(q), 28.7 (q), 40.4 (s), 58.1 (t), 118.9 (d), 123.3 (d), 129.5 (d),
129.6 (d), 132.7 (s), 141.6 (s), 148.0 (s), 171.1 (s), 176.8 (s);
(minor tautomer) 20.7 (q), 20.6 (q), 21.2 (q), 57.9 (t), 118.4 (d),
123.2 (d), 129.1 (d), 129.1 (d), 131.8 (s), 140.9 (s), 142.4 (s),
148.6 (s), 171.0 (s), 176.8 (s); IR (KBr) 1636, 1514, 1500, 1042;
HRMS calcd for (M+) C20H25NOS 327.1657, found 327.1651.
Anal. Calcd for C20H25NOS: C, 73.35; H, 7.69; N, 4.28; S, 9.79.
Found: C, 73.50; H, 7.48, N, 4.22; S, 9.70.
standards for 19F nuclei.
J values are reported in hertz.
Composition of tautomeric mixtures was quantitatively estab-
lished on the basis of 19F NMR analysis. Infrared spectra are
reported in cm-1. High-resolution mass spectra (HRMS) were
obtained at 70 eV by electron impact. FAB mass spectra were
obtained using Cs+ as reagent ions with a m-nitrobenzyl
alcohol (NOBA) matrix. Elemental analyses were performed
by the Microanalytical Service of the University of Zaragoza
and by Redox SNC, Cologno M. (Milano).
Com p u ta tion a l Meth od s. Ab Initio molecular orbital
calculations were performed with the GAUSSIAN 94 package
of programs.47 For further details regarding instrumentation
and others see ref 11.
Gen er a l P r oced u r e for th e Syn th esis of N-Su bstitu ted
â-Im in o Su lfoxid es 4 via Im id oyl Ch lor id es (Rou te A).
Rou te A. Meth od 1. To a stirred solution of diisopropy-
lamine (0.6 mL, 4 mmol) in THF (10 mL) at -40 °C was added
n-butyllithium (2.5 M in hexanes, 1.6 mL, 4 mmol) dropwise.
After stirring for 30 min, (R)- or (S)-methyl-p-tolylsulfoxide 2
(0.31 g, 2 mmol) in THF (10 mL) was slowly added. The yellow
solution was slowly warmed (20 min) to 0 °C and was then
cooled to -78 °C. A solution of the desired imidoyl chloride 1
(2 mmol) in THF (10 mL) was added dropwise, and the reaction
mixture was monitored by TLC analysis. After the total
disappearance of the starting material the reaction was
quenched by addition of methanol (0.5 mL) and the solution
was allowed to reach rt. The solvents were removed under
reduced pressure. Methylene chloride (50 mL) was poured
onto the crude mixture, and the solution was washed with
brine. Drying (MgSO4), filtration, and evaporation furnished
the crude product 4.
Meth od 2. In this case 2 equiv of (R)-methyl p-tolyl
sulfoxide 2 was lithiated by 2 equiv of LDA at -70 °C for 10
min, following the procedure described above. The reactions
were quenched with an excess of a saturated aqueous solution
of ammonium chloride at -78 °C. The resulting mixture was
allowed to warm to room temperature under stirring. The
unreacted equivalent of (R)-methyl p-tolyl sulfoxide 2 was
always recovered almost quantitatively by flash chromatog-
raphy.
Gen er a l P r oced u r e for th e Syn th esis of N-Ar yl â-Im i-
n o Su lfoxid es (R)-4 via Aza -Wittig (Rou te B). To a stirred
mixture of â-keto sulfoxide (R)-5a -d (1 equiv) in dry benzene
(5 mL) at room temperature, solid iminophosphorane 6 (1
equiv) was added in one portion. The resulting solution was
stirred overnight at room temperature, and the solvent was
removed under reduced pressure. In the case of monofluori-
nated derivative (R)-5e the reaction mixture was stirred for
30 h at 50 °C.
Purification was carried out as indicated in each case.
(RS)-2-(Z)-p-An isylim in o-3,3,3-tr iflu or op r opyl-1-p-tolyl-
su lfoxid e (4a ). Recrystallization [n-hexane-CCl4 (5:1) or
i-Pr2O] gave a pale-yellow solid, which soon became orange
upon standing in the presence of air (route A, 85% with method
1, quantitative yield with method 2; route B, 93%): Rf ) 0.4
(n-hexanes-EtOAc 8:2); [R]25D -327.7 (c 0.50, CHCl3); mp 97-
99 °C [from n-hexane-CCl4 (5:1)], 92-93 °C (from i-Pr2O); 1H
NMR (250 MHz) 2.41 (s, 3H), 3.75 (d, J ) 12.6, 1H), 3.82 (s,
3H), 4.09 (d, J ) 12.6, 1H), 6.87 (s, 4H), 7.28 (d, J ) 8.0, 2H),
7.45 (d, J ) 8.0, 2H); 13C NMR (62.8 MHz) 21.4, 55.4, 55.9,-
114.2, 119.1 (q, 1J CF ) 277.2), 121.4, 123.8, 130.2, 138.9, 140.1,
(RS)-2-(Z)-P h en ylim in o-2-p h en yleth yl-1-p-tolylsu lfox-
id e (4c). Recrystallization (n-hexanes-EtOAc (1:10)) afforded
a white solid (93%; route A, method 1): [R]25 -78.8 (c 0.65,
D
CHCl3); mp 110-112 °C; 1H NMR (250 MHz) (major tautomer)
2.37 (s, 3H), 4.05 (d, J ) 12.7, 1H), 4.32 (d, J ) 12.7, 1H), 6.56
(d, J ) 8.0, 2H), 7.05-7.41 (m, 10H), 7.98 (d, J ) 8.0, 2H);
(minor tautomer) 4.26 (d, J ) 12.7, 1H), 4.47 (d, J ) 12.7, 1H),
6.58 (d, J ) 8.0, 2H), 7.20-7.70 (m, 10H), 7.89 (d, J ) 8.0,
2H); 13C NMR (62.8 MHz) (major tautomer) 21.3 (q), 58.0 (t),
119.6 (d), 123.8 (d), 123.9 (d), 128.0 (d), 128.5 (d), 129.3 (d),
129.8 (d), 131.1 (d), 137.4 (s), 139.9 (s), 142.1 (s), 149.9 (s),
158.8 (s); (minor tautomer) 68.0 (t); IR (KBr) 1623, 1588, 1294,
1041; HRMS calcd for (M+) C21H19NOS 333.1187 found,
333.1177. Anal. Calcd for C21H19NOS: C, 75.65; H, 5.75; N,
4.20; S, 9.60. Found: C, 75.95; H, 5.70; N, 4.11; S, 9.43.
(R,RS)-2-(Z)-(N-1-P h en yleth ylim in o)-3,3,3-tr iflu or op r o-
p yl-1-p-tolylsu lfoxid e (4d ). Flash chromatography (n-hex-
anes-EtOAc (3:1)) on silica gel (Rf ) 0.3) furnished 4d (82%;
route A, method 1) as a clear yellow oil: [R]25 +206.1 (c 0.68,
D
CHCl3); 1H NMR (250 MHz) 1.33 (d, J ) 6.5, 3H), 2.41 (s, 3H),
3.79 (d, J ) 13.0, 1H), 4.03 (d, J ) 13.0, 1H), 4.81 (q, J ) 6.5,
1H), 7.25-7.38 (m, 7H), 7.50 (d, J ) 8.1, 2H); 13C NMR (62.8
1
MHz) 21.4, 24.2, 54.5, 61.2, 119.2 (q, J CF ) 261.9), 123.9,
2
126.6, 127.4, 128.6, 129.8, 130.2, 139.5, 142.9, 147.3 (q, J CF
) 40.3); 19F NMR (235 MHz) -72.1; IR (neat) 1608, 1533, 1186,
1149, 1028; HRMS (FAB) calcd for (M+ + 1) C18H19NOSF3
354.1139, found 354.1143. Anal. Calcd for C18H18NOSF3: C,
61.18; H, 5.13; N, 3.97; S, 9.07. Found: C, 61.25; H, 5.05; N,
3.83; S, 8.98.
(R,SS)-2-(Z)-(N-1-P h en yleth ylim in o)-3,3,3-tr iflu or op r o-
p yl-1-p-tolylsu lfoxid e (4d ). Flash chromatography [n-hex-
anes-EtOAc (3:1)] on silica gel (Rf ) 0.4) furnished (R,SS)-4d
(83%; route A, method 1) as a clear yellow solid: [R]25D +169.4
1
(c 1.08, CHCl3); mp 138-140 °C; H NMR (250 MHz) 1.46 (d,
J ) 6.5, 3H), 2.28 (s, 3H), 3.57 (d, J ) 13.0, 1H), 4.00 (d, J )
13.0, 1H), 4.74 (q, J ) 6.5, 1H), 7.11-7.28 (m, 7H), 7.46 (d, J
) 8.1, 2H); 13C NMR (62.8 MHz) 21.4, 25.2, 54.9, 60.9, 119.3
(q, 1J CF ) 261.9), 123.6, 126.2, 127.2, 128.5, 130.3, 139.9, 142.7,
2
143.1, 147.5 (q, J CF ) 40.3); 19F NMR (235 MHz) -71.9; IR
(neat) 1608, 1533, 1186, 1149, 1028; HRMS (FAB) calcd for
(M+ + 1) C18H19NOSF3 354.1139, found 354.1131. Anal. Calcd
for C18H18NOSF3: C, 61.18; H, 5.13; N, 3.97; S, 9.07. Found:
C, 61.32; H, 5.11; N, 3.92; S, 9.02.
(RS)-2-(Z)-(p-An isylim in o)-4,4,4,3,3-p en ta flu or obu tyl-1-
p-tolylsu lfoxid e (4e). Flash chromatography (n-hexanes-
EtOAc (3:1)) on silica gel (Rf ) 0.5) furnished 4e (82%; route
A, method 1) as a clear yellow solid: [R]25 -398.52 (c 0.81,
D
1
CHCl3); mp 58-60 °C; H NMR (250 MHz) 2.41 (s, 3H), 3.76
(d, J ) 12.7, 1H), 3.82 (s, 3H), 4.11 (d, J ) 12.7, 1H), 6.90 (m,
4H), 7.29 (d, J ) 8.2, 2H), 7.45 (d, J ) 8.2, 2H); 13C NMR (62.8
1
2
MHz) 21.4, 55.5, 56.2, 110.2 (tq, J CF ) 260.5, J CF ) 36.9),
114.2, 118.4 (qt, 1J CF ) 286.4, 2J CF ) 40.5), 121.5, 123.8, 130.2,
139.0, 140.2, 142.7, 150.0 (t, 2J CF ) 27.7), 158.4; 19F NMR (235

6218 J . Org. Chem., Vol. 63, No. 18, 1998
Fustero et al.
MHz) -50.6 (s, 3F), -83.8 (d, 2J FF ) 286.3, 1F), -85.3 (d, 2J FF
) 286.3, 1F); IR (KBr) 1500, 1242, 1054; HRMS (FAB) calcd
for (M+) C18H16NO2SF5 405.0822, found 405.0825. Anal. Calcd
for C18H16NO2SF5: C, 53.32; H, 3.98; N, 3.46; S, 7.91. Found:
C, 53.10; H, 3.45; N, 3.46; S, 8.38.
119.0, 123.0 (t, 1J CF ) 294.6), 123.8, 125.8, 129.0, 130.2, 140.2,
142.6, 146.0, 153.4 (t, 2J CF ) 29.3); 19F NMR (235 MHz) δ -60.0
(s); IR (NaCl) 1670, 1590, 1480, 1390, 1285, 1150, 1120, 1075,
1050, 1035. Anal. Calcd for C16H14NOSF2Cl: C, 56.22; H,
4.13; N, 4.10. Found: C, 56.12; H, 4.18; N, 4.06.
(R,RS)-2-(Z)-(N-1-P h en ylet h ylim in o)-4,4,4,3,3-p en t a -
flu or obu tyl-1-p-tolylsu lfoxid e (4f). Flash chromatography
(n-hexanes-EtOAc (3:1)) on silica gel (two spots were detected
by TLC, Rf ) 0.4, 0.1) furnished 4f (80%; route A, method 1)
(RS)-2-(Z)-m -An isylim in o-3-ch lor o-3,3-d iflu or op r op yl-
1-p-tolylsu lfoxid e (4k ). Flash chromatography (n-hexane/
EtOAc 3:1) on silica gel (Rf ) 0.50, n-hexane/EtOAc 7:3), gave
4k (76%; route A, method 2), which was recrystallized (n-
as a yellow oil: [R]25 +2.75 (c 0.87, CHCl3); 1H NMR (200
hexane/i-Pr2O) to give a white solid: mp 68-69 °C; [R]25
D
D
MHz) 1.52 (d, J ) 6.4, 3H), 2.35 (s, 3H), 3.67 (d, J ) 13.0,
1H), 4.07 (d, J ) 13.0, 1H), 4.84 (q, J ) 6.4, 1H), 7.19-7.36
(m, 7H), 7.53 (d, J ) 8.1, 2H); 1H NMR (400 MHz) a small
amount of the minor tautomer is observed 5.18 (s); 13C NMR
-168.2 (c 0.40, CHCl3); 1H NMR (250 MHz) δ 2.41 (s, 3H),
3.80 (d, J ) 12.9, 1H), 3.83 (s, 3H), 4.06 (d, J ) 12.9, 1H), 6.39
(m, 2H), 6.72 (m, 1H), 7.25-7.35 (m, 3H), 7.38 (d, J ) 8.2,
2H); 13C NMR (50.3 MHz) δ 21.3, 55.3, 56.0, 104.8, 111.0, 111.7,
122.9 (t, 1J CF ) 294.7), 123.7, 129.9, 130.2, 140.2, 142.7, 147.1,
1
2
(62.8 MHz) 21.4, 25.6, 54.9, 61.4, 110.0 (tq, J CF ) 255.8, J CF
1
2
2
) 36.4), 118.4 (qt, J CF ) 283.6, J CF ) 40.5), 123.6, 126.0,
153.5 (t, J CF ) 29.2), 160.2; 19F NMR (235 MHz) δ -60.0 (s);
2
127.2, 128.5, 130.3, 139.7, 142.8, 143.2, 148.3 (t, J CF ) 27.7);
IR (NaCl) 1660, 1590, 1475, 1375, 1350, 1130; HRMS calcd
for (M+) C17H16NO2SF2Cl 371.0558, found 371.0568. Anal.
Calcd for C17H16NO2SF2Cl: C, 54.98; H, 4.35; N, 3.77.
Found: C, 54.75; H, 4.20; N, 3.44.
19F NMR (235 MHz) -81.1, -115.8; IR (neat) 1669, 1491, 1222,
1058; HRMS (FAB) calcd for (M+ + 1) C19H19NOSF5 404.1108,
found 404.1093. Anal. Calcd for C19H18NOSF5: C, 56.57; H,
4.50; N, 3.47; S, 7.95. Found: C, 56.30; H, 4.42; N, 3.41; S,
7.83.
(S,SS)-2-(Z)-(N-1-Cycloh exyleth ylim in o)-3,3,3-tr iflu or o-
p r op yl-1-p-tolylsu lfoxid e (4l). Flash chromatography (CH2-
Cl2) on silica gel (two spots were detected by TLC, Rf ) 0.5,
(RS)-2-(Z)-P h en ylim in o-3,3,3-tr iflu or op r op yl-1-p-tolyl-
su lfoxid e (4g). Flash chromatography (n-hexane/EtOAc 3:1)
on silica gel (Rf ) 0.55, n-hexane/EtOAc 7:3), gave 4g (route
0.2) gave 4l (97%; route A, method 1) as a clear yellow oil:
1
[R]25 -129.2 (c 1.05, CHCl3); H NMR (250 MHz) 0.85-1.83
D
A, 90% with method 2; route B, 85%) as a yellow oil: [R]25
(m, 13H), 2.44 (s, 3H), 3.47 (m, 1H), 3.73 (t, J ) 12.3, 1H),
3.96 (d, J ) 12.3, 1H), 7.38 (d, J ) 8.0, 2H), 7.59 (d, J ) 8.0,
2H); 13C NMR (62.8 MHz) 17.9, 21.4, 26.1, 26.2, 26.3, 29.0,
D
-72.7 (c 0.33, CHCl3); 1H NMR (250 MHz) δ 2.40 (s, 3H), 3.74
(d, J ) 12.6, 1H), 4.01 (d, J ) 12.6, 1H), 6.75 (m, 2H), 7.17-
7.40 (m, 7H); 13C NMR (50.3 MHz) δ 21.3, 55.9, 119.0, 119.1
(q, 1J CF ) 280.0), 123.9, 125.9, 129.0, 130.2, 139.9, 142.7, 145.9,
150.4 (q, 2J CF ) 34.9); 19F NMR (235 MHz) -72.4 (s); IR (NaCl)
1670, 1590, 1485, 1480, 1330, 1220, 1175, 1130; HRMS calcd
for (M+) C16H14NOSF3 325.0748, found 325.0740. Anal. Calcd
for C16H14NOSF3: C, 59.07; H, 4.34; N, 4.31. Found: C, 58.82;
H, 4.71; N, 4.22.
1
29.4, 43.8, 54.6, 62.2, 119.1 (q, J CF ) 277.7), 123.9, 130.2,
2
140.1, 142.7, 147.0 (q, J CF ) 33.9); 19F NMR (235 MHz) four
tautomers, -71.7 (87%), -67.2 (4%), -63.7 (3%), -61.8 (6%);
IR (neat) 1449, 1338, 1140; HRMS (FAB) calcd for (M+ + 1)
C
C
18F25NOSF3 360.1609, found 360.1601. Anal. Calcd for
18F24NOSF3: C, 60.15; H, 6.73; N, 3.90; S, 8.92. Found: C,
59.95; H, 6.57; N, 3.80; S, 9.10.
(RS)-2-(Z)-m-An isylim in o-3,3,3-tr iflu or opr opyl-1-p-tolyl-
su lfoxid e (4h ). Flash chromatography (n-hexane/EtOAc 3:1)
on silica gel (Rf ) 0.50, n-hexane/EtOAc 7:3), gave 4h
(SS)-2-(Z)-(p-An isylim in o)-(2-p er flu or oh ep tyl)eth yl-1-
p-tolylsu lfoxid e (4m ). Flash chromatography [n-hexanes-
EtOAc (3:1)] on silica gel (Rf ) 0.5) afforded 4m (92%; route
(quantitative; route A, method 2) as a yellow oil: [R]25 -76.2
A, method 1) as a clear yellow solid: [R]25 +269.4 (c 1.00,
D
D
1
1
(c 0.46, CHCl3); H NMR (250 MHz) δ 2.40 (s, 3H), 3.76 (d, J
CHCl3); mp 62-64 °C; H NMR (200 MHz) 2.33 (s, 3H), 3.68
) 12.6, 1H), 3.80 (s, 3H), 4.03 (d, J ) 12.6, 1H), 6.34 (m, 2H),
6.74 (m, 1H), 7.19-7.32 (m, 3H), 7.40 (d, J ) 8.3, 2H); 13C
NMR (50.3 MHz) δ 21.4, 55.3, 56.0, 104.8, 111.0, 111.7, 119.1
(q, 1J CF ) 279.2), 123.8, 129.9, 130.2, 139.9, 142.8, 147.0, 150.5
(q, 2J CF ) 35.0), 160.2; 19F NMR (235 MHz) -72.3 (s); IR (NaCl)
1665, 1590, 1575, 1475, 1325, 1270, 1255, 1195, 1175, 1130
(br); HRMS calcd for (M+) C17H16NO2SF3 355.0854, found
355.0840. Anal. Calcd for C17H16NO2SF3: C, 57.46; H, 4.54;
N, 3.94. Found: C, 57.72; H, 4.54; N, 3.77.
(d, J ) 12.5, 1H), 3.74 (s, 3H), 4.04 (d, J ) 12.5, 1H), 6.83 (s,
4H), 7.21 (d, J ) 8.2, 2H), 7.37 (d, J ) 8.2, 2H); 13C NMR (62.8
MHz) 21.4, 55.5, 56.9, 106.0-116.1 (m, C7F15), 114.3, 121.4,
2
123.8, 130.3, 139.3, 140.3, 142.7, 150.5 (t, J CF ) 26.7), 158.5;
19F NMR (235 MHz) -81.1 (t, 3J FF ) 9.8, 3F), -111.6 (dt, 2J FF
) 280.5, 3J FF ) 12.3, 1F), -113.2 (d, 2J FF ) 280.5, 3J FF ) 12.3,
1F), -120.9 (m, 4F), -122.3 (m, 2F), -123.0 (m, 2F), -126.4
(m, 2F); IR (neat) 1604, 1508, 1242, 1057; HRMS (FAB) calcd
for (M+) C23H16NO2SF15 656.0741, found 656.0732. Anal.
Calcd for C23H16NO2SF15: C, 42.13; H, 2.46; N, 2.14; S, 4.88.
Found: 42.04; H, 1.99; N, 2.12; S, 4.76.
(RS)-2-(Z)-n -Hexylim in o-3,3,3-tr iflu or op r op yl-1-p-tolyl-
su lfoxid e (4i). Flash chromatography (n-hexane/EtOAc 3:1)
on silica gel (three spots were detected by TLC, Rf ) 0.60, 0.55,
0.25, n-hexane/EtOAc 7:3), gave 4i (80%; route A, method 2)
(SS)-2-(Z)-(p -Tolylim in o)-2-(p -flu or op h en yl)et h yl-1-p -
tolylsu lfoxid e (4n ). Recrystallization (n-hexanes-EtOAc (5:
as a yellow oil: [R]25 +75.53 (c 0.17, CHCl3); major imine
1)) gave 4n as a white solid (87%; route A, method 1): [R]25
D
D
isomer (ca. 90% of the mixture) 1H NMR (250 MHz) δ 0.88
(m, 3H), 1.20-1.40 (m, 6H), 1.49-1.69 (m, 2H), 2.44 (s, 3H),
3.15-3.28 (m, 1H), 3.34-3.54 (m, 1H), 3.71 (d, J ) 13.1, 1H),
4.04 (d, J ) 13.1, 1H), 7.36 (d, J ) 8.0, 2H), 7.56 (d, J ) 8.0,
2H); 13C NMR (50.3 MHz) δ 13.8, 21.2, 22.3, 26.7, 29.8, 31.3,
+62.0 (c 0.71, CHCl3); mp 241-243 °C; H NMR (250 MHz)
1
2.34 (s, 3H), 2.39 (s, 3H), 4.05 (d, J ) 12.8, 1H), 4.29 (d, J )
12.8, 1H), 6.50 (d, J ) 8.0, 2H), 7.09-7.26 (m, 8H), 7.97 (dd,
J 1 ) 8.6, J 2 ) 5.4, 2H); 13C NMR (62.8 MHz) 20.8, 21.4, 57.7,
115.3, 115.7, 119.2, 124.2, 129.3, 129.6, 130.1, 133.5, 139.8,
142.2, 155.2, 162.5, 166.5; 19F NMR (235 MHz) -109.3 (m, 1F);
IR (KBr) 1635, 1514, 1224, 1043; HRMS calcd for (M+ + 1)
1
52.7, 54.3, 119.0 (q, J CF ) 278.8), 123.7, 130.1, 139.7, 142.6,
2
148.6 (q, J CF ) 34.2); 19F NMR (235 MHz) δ -73.1 (s); minor
1
enamine isomers (both ca. 5% of the mixture) H NMR (250
C
C
22H21NOSF 366.1328, found 366.1325. Anal. Calcd for
22H20NOSF: C, 72.30; H, 5.52; N, 3.83; S, 8.77. Found: C,
MHz) δ 5.16 and 5.41 (s, SCHdC); 19F NMR (235 MHz) δ -69.1
and -62.9 (s); IR (NaCl) 3300, 1690, 1620, 1550, 1510, 1470
(br), 1350, 1210, 1150 (br); HRMS calcd for (M+) C16H22NOSF3
333.1374, found 333.1376. Anal. Calcd for C16H22NOSF3: C,
57.64; H, 6.65; N, 4.20. Found: C, 58.01; H, 6.43; N, 3.65.
(RS)-2-(Z)-P h en ylim in o-3-ch lor o-3,3-d iflu or op r op yl-1-
p-t olylsu lfoxid e (4j). Flash chromatography (n-hexane/
EtOAc 3:1) on silica gel (Rf ) 0.55, n-hexane/EtOAc 7:3) gave
4j (route A, 74% with method 2; route B, 82%), which was
72.11; H, 5.42; N, 3.85; S, 8.50.
(SS)-2-(Z)-(p-An isylim in o)-3-ch lor o-3,3-d iflu or op r op yl-
1-p-tolylsu lfoxid e (4o). Flash chromatography [n-hexanes-
EtOAc (3:1)] on silica gel (Rf ) 0.6) gave 4o (72%; route A,
method 1) as a brown solid: [R]25D +391.5 (c 1.02, CHCl3); mp
59-61 °C; 1H NMR (250 MHz) 2.32 (s, 3H), 3.71 (d, J ) 12.7,
1H), 3.74 (s, 3H), 4.03 (d, J ) 12.7, 1H), 6.80-6.83 (m, 4H),
7.20 (d, J ) 8.2, 2H), 7.36 (d, J ) 8.2, 2H); 13C NMR (62.8
1
recrystallized (n-hexane) to give a white solid: mp 63-65 °C;
MHz) 21.4, 55.4, 55.7, 114.2, 121.4, 123.2 (t, J CF ) 292.8),
1
2
[R]20 -146.7 (c 0.21, CHCl3); H NMR (250 MHz) δ 2.41 (s,
123.8, 130.2, 138.9, 140.3, 142.6, 152.3 (t, J CF ) 28.5), 158.2;
D
3H), 3.78 (d, J ) 12.8, 1H), 4.05 (d, J ) 12.8, 1H), 6.79 (m,
2H), 7.15-7.40 (m, 7H); 13C NMR (50.3 MHz) δ 21.4, 55.9,
19F NMR (235 MHz) -59.2 (d, 2J FF ) 163.5, 1F), -60.0 (d, 2J FF
2
) 163.5, 1F) (CFCl3 as standard) or -59.2 (d, J FF ) 163.5,

Fluorinated and Fluorine-Free Chiral â-Imino Sulfoxides
J . Org. Chem., Vol. 63, No. 18, 1998 6219
2
1F), -59.9 (d, J FF ) 163.5, 1F) (C6F6 as standard); IR (neat)
138.9, 142.6, 155.4 (q, 2J CF ) 37.7), 195.8; 19F NMR (235 MHz)
-77.44 (s); HRMS calcd for (M+) C17H14NO3SF3 369.0647,
found 369.0651. Anal. Calcd for C17H14NO3SF3: C, 55.28; H,
3.82; N, 3.79. Found: C, 55.34; H, 3.90; N, 3.78.
1603, 1503, 1251, 1047; HRMS (FAB) calcd for (M+ + 1) C17H17
NOSF2Cl 372.0637, found 372.0624. Anal. Calcd for C17H16
NOSF2Cl: C, 54.98; H, 4.35; N, 3.77; S, 8.62. Found: 54.48;
-
-
H, 4.15; N, 3.78; S, 8.94. The enantiomer (RS)-(Z)-4o was
(RS)-2-(Z)-(P h en ylim in o)-4,4,4,3,3-p en ta flu or obu tyl-1-
p-tolylsu lfoxid e (4t). Flash chromatography [n-hexanes-
EtOAc (3:1)] on silica gel (Rf ) 0.60, n-hexanes-EtOAc 7:3)
furnished 4t (76%; route B), which was recrystallized (i-Pr2O)
obtained by aza-Wittig reaction in 97% yield (route B): [R]25
D
-344.6 (c 0.95, CHCl3); Rf and 1H, 13C, and 19F spectra were
identical to those of enantiomeric compound (SS)-(Z)-4o.
(SS)-2-(Z)-(p-An isylim in o)-2-(3-p yr id yl)eth yl-1-p-tolyl-
su lfoxid e (4p ). Flash chromatography (EtOAc) on silica gel
to give a white solid: [R]25 -133.4 (c 1.0, CHCl3); mp 96-98
D
1
°C; H NMR (250 MHz) 2.41 (s, 3H), 3.76 (d, J ) 12.6, 1H),
4.03 (d, J ) 12.6, 1H), 6.78 (m, 2H), 7.15-7.43 (m, 7H); 13C
NMR (100.6 MHz) 21.5, 56.4, 109.9 (tq, J ) 258.3 and 37.1),
118.4 (qt, J ) 286.8 and 35.7), 119.0, 123.8, 126.05, 129.05,
130.2, 140.1, 142.7, 146.0, 151.5 (t, 2J CF ) 28.1); 19F NMR (235
(Rf ) 0.3) gave 4p (80%; route A, method 1) as a dense yellow
1
oil: [R]25 +21.3 (c 1.05, CHCl3); H NMR (250 MHz) (major
D
isomer) 2.28 (s, 3H), 3.72 (s, 3H), 3.98 (d, J ) 13.0, 1H), 4.00
(d, J ) 13.0, 1H), 6.60 (d, J ) 8.8, 2H), 6.79 (d, J ) 8.8, 2H),
7.05-7.32 (m, 5H), 8.15 (m, 1H), 8.54 (m, 1H), 9.06 (m, 1H);
13C NMR (75 MHz) 22.2 (q), 56.4 (q), 57.9 (t), 115.1 (d), 121.6
(d), 124.2 (d) 124.8 (d), 130.9 (d), 134.2 (s), 136.2 (d), 140.5 (s),
143.3 (d), 149.7 (s), 152.2 (d), 157.6 (s), 157.8 (s), 179.7 (s); IR
2
2
MHz) -117.3 (d, J FF ) 313, 1F), -116.0 (d, J FF ) 313, 1F),
-82.3 (s, 3F); HRMS calcd for (M+) C17H14NOSF5 375.0716,
found 375.0704. Anal. Calcd for C17H14NOSF5: C, 54.40; H,
3.76; N, 3.73. Found: C, 54.53; H, 3.77; N, 3.72.
(neat) 1634, 1585, 1241, 1035; HRMS (FAB) calcd for (M+
1) C21H21N2O2S 365.1324, found 365.1334. Anal. Calcd for
21H20N2O2S: C, 69.21; H, 5.53; N, 7.69; S, 8.80. Found:
+
(RS)-2-(Z)-(P h en ylim in o)-3,3-d iflu or op r op yl-1-p-tolyl-
su lfoxid e (4u ). Flash chromatography [cyclohexanes-EtOAc
(7:3)] on silica gel (Rf ) 0.35) furnished 4u (90%; route B), as
C
a red oil: [R]25 +76.34 (c 0.87, CHCl3). Imine tautomer (ca.
69.05; H, 5.22; N, 7.55; S, 8.68.
D
90% of the mixture): 1H NMR (250 MHz) 2.41 (s, 3H), 3.74
(d, J ) 12.4, 1H), 3.96 (d, J ) 12.4, 1H), 6.23 (t, J CF ) 54.8,
1H), 6.67 (m, 2H), 7.22-7.42 (m, 7H); 13C NMR (62.8 MHz)
21.5, 54.95, 113.95 (t, 1J CF ) 244.6), 119.1, 123.9, 125.5, 129.0,
130.2, 140.3, 142.5, 146.8, 155.6 (t, 2J CF ) 27.7); 19F NMR (235
(SS)-2-(Z)-Cycloh exylim in o-3,3,3-t r iflu or op r op yl-1-p -
tolylsu lfoxid e (4q). Flash chromatography [n-hexanes-
EtOAc (5:1)] on silica gel (Rf ) 0.2) gave 4q (72%; route A,
method 1) as a clear yellow oil: [R]25 -158.2 (c 1.15, CHCl3);
D
1H NMR (250 MHz) 1.09-1.79 (m, 10H), 2.35 (s, 3H), 3.21 (m,
1H), 3.69 (d, J ) 12.6, 1H), 3.92 (d, J ) 12.6, 1H), 7.30 (d, J )
8.0, 2H), 7.51 (d, J ) 8.0, 2H); 13C NMR (62.8 MHz) 21.2 (q),
23.7 (t), 23.8 (t), 25.0 (t), 32.5 (t), 32.7 (t), 54.2 (t), 61.0 (d),
119.0 (CF3, q, 1J CF ) 277.5), 123.8 (d), 130.1 (d), 139.6 (s), 142.7
2
2
MHz) -121.8 (dd, J FF ) 317 and J FH ) 54.9, 1F), -120.4
2
2
(dd, J FF ) 317 and J FH ) 54.9, 1F). Enamine tautomer (ca.
10% of the mixture): 1H NMR (250 MHz) 2.39 (s, 3H), 5.83
(d, J ) 3, 1H), 6.21 (br signal, 1H), 7.13 (d, J ) 8, 2H), 7.23 (t,
J ) 54, 1H), 7.16-7.34 (m, 5H), 7.47 (d, J ) 8, 2H); 19F NMR
2
(s), 146.0 (CdN, q, J CF ) 34.7); 19F NMR (235 MHz) -72.0
(235 MHz) -114.9 (dd, 2J HF ) 54 and J FF ) 305), -125.7 (dd,
2
(81.0%), -68.1 (8.0%), -64.2 (1.5%), -61.8 (9.5%); IR (KBr)
1669, 1595, 1198, 1056; HRMS (FAB) calcd for (M+ + 1) C16H21
NOSF3 332.1296, found 332.1293. Anal. Calcd for C16H20
-
-
2J HF ) 54 and J FF ) 305); HRMS calcd for (M+) C16H15NOSF2
2
307.0842, found 307.0844.
NOSF3: C, 57.99; H, 6.08; N, 4.23; S, 9.67. Found: C, 57.72;
H, 5.87; N, 4.19; S, 9.58.
(RS)-2-(Z)-(P h en ylim in o)-3-flu or op r op yl-1-p -t olylsu l-
foxid e (4v). The aza-Wittig reaction was carried out at 50
°C for 30 h. Flash chromatography [n-hexanes-EtOAc (7:3)]
on silica gel (Rf ) 0.25) furnished 4v (ca. 30%; route B), as a
red oil, and as a mixture with ca. 30% of starting monofluoro
â-ketosulfoxide (R)-5a . (R)-4v in an almost equimolar ratio
of two iminic tautomers. Overall yield ca. 30%: 1H NMR (250
MHz) 2.41 (s, 3H) and 2.43 (s, 3H), 3.66 (dd, J ) 2.1 and 12.5,
1H) and 3.82 (dd, J ) 2.1 and 12.5, 1H), 4.07 (d, J ) 1.1, 1H),
4.08 (d, J ) 1.1, 1H), 4.77 (d, J ) 46.6, 2H), 4.79 (d, J ) 46.6,
2H), 5.12 (dd, J HH ) 13.4 and J HF ) 46.6, 1H) and 5.19 (dd,
J HH ) 13.4 and J HF ) 46.6, 1H); 19F NMR (235 MHz) -225.25
(t, J ) 46.6), -224.3 (t, J ) 46.6).
(()-(S,R/SS)-2-(Z)-(N-1-Cycloh exyleth ylim in o)-3,3,3-tr i-
flu or op r op yl-1-p h en ylsu lfoxid e (4r ). MPLC [n-hexanes-
EtOAc (3:1)] on silica gel (two spots were detected by TLC, Rf
) 0.7, 0.3) gave 4r (85%; route A, method 1) as a clear yellow
oil: diastereomeric mixture (ca. 1:1) 1H NMR (250 MHz) (S,SS),
0.85-1.83 (m, 13H), 3.34-3.48 (m, 1H), 3.71 (t, J ) 12.3, 1H),
3.89 (d, J ) 12.3, 1H), 7.45-7.69 (m,4H); (S,RS), 0.85-1.83
(m, 13H), 3.34-3.48 (m, 1H), 3.57 (t, J ) 12.3, 1H), 3.99 (d, J
) 12.3, 1H), 7.45-7.69 (m, 4H); 13C NMR (50 MHz) (both
diastereomers) 17.7 (q), 18.7 (q), 25.9 (t), 26.0 (t), 26.1 (t), 26.2
(t), 29.2 (t), 29.3 (t), 43.3 (d), 43.7 (d), 54.3 (t), 54.5 (t), 62.1
1
(d), 62.5 (d), 119.4 (CF3, q, J CF ) 274.2), 123.6 (d), 123.7 (d),
129.5 (d), 131.9 (d), 131.9 (d), 143.2 (s), 143.4 (s), 146.8 (CdN,
Ack n ow led gm en t. The authors are grateful to the
Direccio´n General de Investigacio´n Cient´ıfica y Te´cnica
for their financial support of this research (DGICYT,
PB94-1313-C02-02 and PB97-0760-C02-01) and also the
CIEMAT (Ministerio de Industria y Energ´ıa) for com-
puter time. A predoctoral fellowship from the Univer-
sidad de Valencia to A.N. and from the Generalitat
Valenciana to B.P. are also gratefully acknowledged.
2
q, J CF ) 33.9); 19F NMR (235 MHz) four isomers each
diastereoisomer, -71.8 (85.3%), -67.2 (3.9%), -63.7 (2.3%),
-61.8 (8.5%); -71.6 (87.0%), -67.4 (4.3%), -63.5 (2.2%), -61.8
(6.5%); IR (neat) 1669, 1443, 1334, 1139, 1086, 1049; HRMS
(FAB) calcd for (M+ + 1) C17H23NOSF3 346.1452, found
346.1446. Anal. Calcd for C17H22NOSF3: C, 59.11; H, 6.42;
N, 4.05; S, 9.28. Found: C, 58.95; H, 6.34; N, 4.08; S, 9.22.
(RS)-(Z)-2-(2-h yd r oxyca r b on ylp h en ylim in o)-3,3,3-t r i-
flu or op r op yl-1-p-tolylsu lfoxid e (4s). The reaction between
2-methoxycarbonylphenyltrifluoroacetimidoyl chloride 1s and
lithiated methyl p-tolyl sulfoxide (R)-2a , according to the
general procedure, directly provided 4s (71%, route A, method
2), purified by flash chromatography [n-hexanes-EtOAc (1:
1)] on silica gel (Rf ) 0.45) and recrystallized (i-Pr2O) to give
a white solid: [R]25D +125.9 (c 0.068, CHCl3); mp 152-155 °C;
1H NMR (250 MHz) 2.40 (s, 3H), 4.33 (d, J ) 13.5, 1H), 4.56
(d, J ) 13.5, 1H), 7.26-7.34 (m, 3H), 7.50 (d, J ) 7.7, 2H),
Su p p or tin g In for m a tion Ava ila ble: Calculated relative
energies (kcal mol-1) at semiempirical (AM1) and ab initio (HF/
3-21G) calculations (Table 4) and copies of optimized structures
at the HF/6-31G* level corresponding to compounds 1a , 1q,
4a , 4c, 4d , 4v, and 4A-E (41 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
7.69 (m, 1H), 7.90 (d, J ) 8.1, 1H), 8.66 (d, J ) 8.5, 1H), 10.25
1
(br s, 1H); 13C NMR (50.3 MHz) 21.3, 66.6, 115.4 (q, J CF
)
288.6), 121.0, 122.4, 124.0, 124.8, 130.0, 132.5, 136.3, 138.4,
J O980336F