Stereoselective rhodium-catalyzed lmination of sulfides

Article abstract of DOI:10.1021/ol802295b

(Chemical Equation Presented) The preparation of optically active sulfilimines via the catalytic diastereoselective imination of sulfides using a chiral nitrene is described. Excellent yields up to 97% and good diastereoselectivities up to 96% have been obtained. Oxidation of the sulfilimines then stereospecifically affords the corresponding sulfoximines with very good yields in the 88-96% range.

Full text of DOI:10.1021/ol802295b

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5473-5476
Stereoselective Rhodium-Catalyzed
Imination of Sulfides
Florence Collet, Robert H. Dodd,* and Philippe Dauban*
Institut de Chimie des Substances Naturelles, UPR 2301 CNRS, 1 AVenue de la
Terrasse, 91198 Gif-sur-YVette, France
robert.dodd@icsn.cnrs-gif.fr; philippe.dauban@icsn.cnrs-gif.fr
Received October 3, 2008
ABSTRACT
The preparation of optically active sulfilimines via the catalytic diastereoselective imination of sulfides using a chiral nitrene is described.
Excellent yields up to 97% and good diastereoselectivities up to 96% have been obtained. Oxidation of the sulfilimines then stereospecifically
affords the corresponding sulfoximines with very good yields in the 88-96% range.
Nitrogen is ubiquitous in Nature as evidenced by the
prevalence of alkaloids and amino acids in the world of
natural products.1 Importantly, nitrogen is even more present
in the structure of biologically active agents.2,3 The search
for its efficient and selective incorporation into various
molecules is therefore an area of intensive investigation and
a source of inspiration for synthetic chemists, who have
designed a still growing number of methodologies for this
purpose.1a,4
In this highly proliferating field, the emergence of catalytic
nitrene transfers, particularly those developed using hyper-
valent iodine reagents,5 has offered unique opportunities
culminating with the discovery of new transformations for
the direct introduction of nitrogen into various substrates.
Nitrene insertion into C-H and CdC bonds now allows an
easy and efficient access to N-protected amines and aziri-
dines, respectively.6 In parallel, their catalytic addition to
sulfides or sulfoxides affords useful sulfilimines or sulfox-
imines, respectively.
Since the discovery of methionine sulfoximine,7 these
sulfur(VI) derivatives have been extensively studied.8 The
sulfoximine moiety has been incorporated into a wide range
of biologically active compounds9 or has served as a
functional building block in materials science.10 It has also
been used as an efficient chiral auxiliary in total synthesis,8,11
while the central chirality has been often applied to the design
of chiral ligands in the field of asymmetric synthesis.12
Similarly, but to a lesser extent, sulfilimines have found
(1) (a) Kibayashi, C. Chem. Pharm. Bull. 2005, 53, 1375–1386. (b) Hili,
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Halfen, J. A. Curr. Org. Chem. 2005, 9, 657–669. (d) Dauban, P.; Dodd,
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(3) The molecular formula of Gleevec C29H31N7O is a perfect example
that illustrates the high number of nitrogen atoms in drugs.
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Synthesis to the Life Sciences; Ricci, A., Ed.; Wiley-VCH: Weinheim, 2007.
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Crabtree, R. H., Mingos, D. M. P., Eds.; Elsevier: Oxford, 2007; Vol. 10,
pp 695-724. (c) Kienle, M.; Dubbaka, S. R.; Brade, K.; Knochel, P. Eur.
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T. Nature 1949, 163, 675–676.
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347. (b) Pyne, S. Sulfur Rep. 1992, 12, 57–89. (c) Reggelin, M.; Zur, C.
Synthesis 2000, 1–64. (d) Okamura, H.; Bolm, C. Chem. Lett. 2004, 33,
482–487. (e) Gais, H. J. Heteroat. Chem. 2007, 18, 472–481.
J. Org. Chem. 2007, 4166–4176
.
(5) Dauban, P.; Dodd, R. H. Synlett 2003, 1571–1586.
10.1021/ol802295b CCC: $40.75
Published on Web 11/06/2008
2008 American Chemical Society

applications in synthesis,13 catalysis,14 and medicinal chem-
istry.15
Table 1. Catalytic Imination of Methyl p-Tolyl Sulfide 3a
Several synthetic strategies have been developed for the
preparation of these chiral sulfur derivatives, and among
these, direct oxidative imination is by far the most studied
methodology.8d Various nitrogen sources16 such as
chloramines16a-c and azides16d-f can be used for these
transformation, but the most significant achievements have
been realized starting from iminoiodanes in combination with
a transition metal catalyst.17 Copper salts have been found
to be optimal in this context,17a-d but manganese,17e
rhodium,17f,i silver,17g,i or iron17h,i complexes are also
efficient catalysts. Surprisingly, a limited number of studies
have been dedicated to the stereoselective imination of
sulfides and sulfoxides using hypervalent iodine
entry
temp (°C)
solvent
yield (%)
dea
1
2
3
4
5
6
7
8
-35
-78
-50
25
-35
-35
-35
-35
(CH2Cl)2/MeOH 3:1
(CH2Cl)2/MeOH 3:1
(CH2Cl)2/MeOH 3:1
(CH2Cl)2/MeOH 3:1
(CH2Cl)2
(CH2Cl)2/MeOH 1:1
(CH2Cl)2/MeOH 3:1
(CH2Cl)2/MeOH 3:1
93
92
92
94
75
88
88
93
70
62
66
50
40
48
b
80c
a Determined by 1H NMR. b Three days at -35 °C without the
rhodium(II) catalyst 1. c Using 10 mol % of catalyst 1 and adding
hypervalent iodine reagent via syringe pump over 1 h.
(9) (a) Mock, W. L.; Tsay, J.-T. J. Am. Chem. Soc. 1989, 111, 4467–
4472. (b) Koizumi, M.; Hiratake, J.; Nakatsu, T.; Kato, H.; Oda, J. J. Am.
Chem. Soc. 1999, 121, 5799–5800. (c) Bolm, C.; Moll, G.; Kahmann, J. D.
Chem. Eur. J. 2001, 7, 1118–1128. (d) Kahraman, M.; Sinishtaj, S.; Dolan,
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Weinheim, 2008; pp 209-229.
reagents,17d,e,18,19 and in all cases the combined yields and
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We have recently reported the use of sulfonimidamides
for the generation of chiral nitrenes and their subsequent
metal-catalyzed insertion into CdC20a and C-H bonds.20b,c
In all cases, high yields were obtained starting from
stoichiometric amounts of alkenes and alkanes as a conse-
quence of the high reactivity of the nitrene species. More
importantly, the matched combination of the sulfonimidamide
and a chiral rhodium catalyst proved optimal to induce
selective benzylic and allylic C-H aminations with stereo-
selectivities generally above 90%.20b,c Thus, these results
combined with previous observations convinced us to explore
the stereoselective imination of sulfides using chiral nitrenes
derived from sulfonimidamides.
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3220.
Application of the previously determined optimal condi-
tions for C-H amination to methyl p-tolyl sulfide 3a, i.e.,
combining 3 mol % of Rh2{(S)-nta}4 1 with 1.2 equiv of
(S)-N-(p-toluenesulfonyl)-p-toluenesulfonimidamide 2 in the
presence of 1.4 equiv of PhI(OCOt-Bu)2 in a 3:1 mixture of
1,1,2,2-tetrachloroethane/methanol at -35 °C for 3 days,20c
allowed us to isolate the corresponding sulfilimine 4a with
a very good yield of 93% and a diastereoselectivity of 70%
(Table 1, entry 1).
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NMR studies indicated that consumption of starting
material was in fact complete after only 5 h, 4a being isolated
with the same yield and de as before. This shorter reaction
time encouraged us to screen the reaction temperature in
(17) (a) Mu¨ller, J. F. K.; Vogt, P. Tetrahedron Lett. 1998, 39, 4805–
4806. (b) Lacoˆte, E.; Amatore, M.; Fensterbank, L.; Malacria, M. Synlett
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Catal. 2005, 347, 641–645. (e) Nishikori, H.; Ohta, C.; Oberlin, E.; Irie,
R.; Katsuki, T. Tetrahedron 1999, 55, 13937–13946. (f) Okamura, H.; Bolm,
C. Org. Lett. 2004, 6, 1305–1307. (g) Cho, G. Y.; Bolm, C. Org. Lett.
2005, 7, 4983–4985. (h) Garcia Mancheno, O.; Bolm, C. Org. Lett. 2006,
8, 2349–2352. (i) Garcia Mancheno, O.; Bolm, C. Chem. Eur. J. 2007, 13,
6674–6681.
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Sparey, T. J.; Taylor, P. C. J. Org. Chem. 1997, 62, 6512–6518
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Org. Lett., Vol. 10, No. 23, 2008

order to improve the selectivity.21 However, decreasing the
temperature down to -78 °C induced a slight drop in
selectivity (entries 2 and 3 vs entry 1) while the yield
remained unchanged. Changing the solvent ratios also did
not improve results (entries 5 and 6). While testing the
reaction in the absence of the rhodium catalyst, we observed,
as did Bolm in a recently reported study,22 that the racemic
sulfilimine 4a is indeed isolated in 88% yield after 3 days at
-35 °C (entry 7). Such non-catalyzed imination clearly
operates in parallel to the stereoselective rhodium-mediated
process and is probably the main reason for the lower
diastereoselectivities observed when compared to those
obtained in our previously described C-H amination. In
order to circumvent this side reaction, we increased the
amount of catalyst while adding the hypervalent iodine
reagent very slowly, but this led to only a modest 10%
increase of the diastereoselectivity (entry 8 vs entry 1).
Various sulfides were then screened using the conditions
described for compound 3a in entry 1 of table 1 (Table 2).
Aryl alkyl sulfides 3a-j were transformed under stoichio-
metric conditions into the corresponding sulfilimines 4a-j
in very good yields, generally above 80% and up to 97%
(entries 1-10). High yields in the 91-95% range were also
observed with dialkyl sulfides 3k-n (entries 11-14), thereby
confirming the superior reactivity of sulfonimidamide-derived
nitrenes when compared to that of nitrenes generated from
sulfonamides.20 The reaction is also chemoselective since
neither aziridines nor a benzylic C-H amination product
were isolated in the case of, respectively, vinylic sulfides
3g,m and benzylic sulfide 3j. Another noteworthy feature
of this reaction is the total absence of the sulfoxide often
formed as a byproduct in sulfide imination.16c,19
Table 2. Catalytic Oxidative Imination of Sulfides 3
As far as diastereoselectivity is concerned, despite the
occurrence of the undesirable non-catalyzed imination, aryl
alkyl sulfilimines 4a-j were isolated with moderate to
excellent diastereoisomeric excesses of up to 96% while
imination of dialkyl sulfides 3k-m proved to be poorly
diastereoselective. Once more, these selectivities have been
found to be the consequence of a matched effect between
the sulfonimidamide (S)-2 and the catalyst Rh2{(S)-nta}4.
Then, use of Rh2(OAc)4 with (S)-2 in the presence of sulfide
3a affords the corresponding sulfilimine 4a in 89% yield but
with a low de of 10%, while the mismatched combination
of (S)-2 and Rh2{(R)-nta}4 leads to 4a in 88% yield and a
de of only 32%.
All of these results indicate that this methodology is as
efficient17e or even better17d,18 than known published ste-
reoselective preparations of sulfilimines using iminoiodanes.
Moreover, our results demonstrate more convincingly than
the previous report by Fensterbank, Lacote, and Malacria19
that use of a chiral nitrene is likely to induce efficient
diastereoselective imination of sulfides.
a
Determined by H NMR. b Using 10 mol % of catalyst 1 and adding
1
hypervalent iodine reagent via syringe pump over 1 hour.
Sulfilimines 4 were then transformed into their corre-
sponding sulfoximines 5 by oxidation under standard condi-
tions using m-CPBA (Table 3). The expected sulfur(VI)
products 5a-f and 5i were isolated in very good yields in
the 88-96% range and with diastereoisomeric excesses
similar to those obtained for sulfilimines 4, thereby indicating
that the oxidation proceeds stereospecifically. The diastere-
(21) Further experiments confirmed the optimization of the reaction
parameters. Use of the more crowded catalyst [Rh2{(S)-nttl}4] afforded
compound 4a in 90% yield but with a lower de of 62%. The p-nitro analog
of 4a was isolated in 76% yield and 70% de starting from N-(p-
toluenesulfonyl)-p-nitrobenzenesulfonimidamide. Finally, use of the less
soluble PhIdO led to a decrease of the reactivity and the selectivity (69%
yield and 60% de).
(22) Cho, G. Y.; Bolm, C. Tetrahedron Lett. 2005, 46, 8007–8008.
Org. Lett., Vol. 10, No. 23, 2008
5475

Table 3. Oxidation of Sulfilimines 4a
Scheme 1. Deprotection of Sulfoximine 5a
entry substrate
R1
R2 product yield (%) deb
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
p-MeC6H4
p-MeOC6H4 Me
p-NO2C6H4 Me
2-Py
Ph
Ph
Me
5a
5b
5c
5d
5e
5f
91
94
90
94
96
92
88
72
70
20
44
64
72
52
In conclusion, rhodium(II)-catalyzed transfer of a chiral
nitrene generated from (S)-N-(p-toluenesulfonyl)-p-toluene-
sulfonimidamide 2 in the presence of a hypervalent iodine
reagent allows the mild chemo- and diastereoselective
imination of sulfides used in stoichiometric amounts. Opti-
cally active sulfilimines were isolated with excellent yields
up to 97% and good diastereoselectivities up to 96%. They
can in turn be stereospecifically transformed into the corre-
sponding sulfoximines with excellent yields. This study
demonstrates that use of a sulfonimidamide-derived chiral
nitrene for sulfide imination is more efficient, albeit of
comparable selectivity, than that involving the combination
of a sulfonamide and a chiral transition metal catalyst. Work
is now in progress to optimize the design of the chiral nitrene
precursor.
Me
Me
Et
4i
2-Naph
Me
5i
a Reaction conditions: sulfilimine 4 (1 equiv), m-CPBA (1.5 equiv),
K2CO3 (3 equiv) in CH2Cl2 at room temperature for 1 h. b Determined by
1H NMR.
oisomeric sulfoximines 5 can be easily separated by simple
flash chromatography on silica gel.
The preparation of sulfoximines 5 allowed determination
of the sense of the stereoinduction for the imination of
sulfides 3. Thus, stereospecific imination of optically pure
(S)-methyl p-tolylsulfoxide by application of the same
conditions used for sulfides 3 affords the sulfoximine (S)-
5a in 85% yield and 99% ee. Comparison of the optical
rotation of this enantiomerically pure compound with that
of the product obtained from sulfilimine 4a then allowed us
to determine that the latter has the same absolute configu-
ration. Therefore, the combination of (S)-2 and the rhodium
catalyst Rh2{(S)-nta}4 1 induces the formation of the (R)-
sulfilimines 4.23
Acknowledgment. We wish to thank the Institut de
Chimie des Substances Naturelles for financial support and
fellowships (F.C.). We also thank Paul Mu¨ller (Department
of Organic Chemistry, University of Geneva) for fruitful
discussions. Support and sponsorship concerted by COST
Action D40 “Innovative Catalysis: New Processes and
Selectivities” are kindly acknowledged.
Finally, it was found that free NH sulfoximines could be
obtained by removal of the sulfonimidoyl group under
reductive conditions. Thus, treatment of 5a with 10 equiv
of magnesium under sonication in methanol20c,24 afforded
the deprotected product 6 with a non-optimized yield of 41%
(Scheme 1).25
Supporting Information Available: Experimental details,
characterization data, and spectra (1H and 13C NMR) for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL802295B
(23) On the basis of this result, sulfides 4 have always been drawn with
this (R)-configuration in each previous scheme.
(25) It should be mentioned that this procedure cannot be applied to
sulfilimines of type 4 because use of magnesium in methanol under
sonication leads to the starting sulfide 3.
(24) Xu, Y. M.; Shi, M. J. Org. Chem. 2004, 69, 417–425
.
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Org. Lett., Vol. 10, No. 23, 2008