Ring-closing metathesis (RCM) for the synthesis of cyclic sulfoximines

Article abstract of DOI:10.1055/s-2005-865312

Chiral heterocycles can be prepared starting from doubly unsaturated sulfoximine derivatives by ring-closing metathesis reaction in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-865312

PAPER
1421
Ring-Closing Metathesis (RCM) for the Synthesis of Cyclic Sulfoximines
RCM
for the
S
yn
a
thesis of
C
r
sfoximinesten Bolm,* Hélène Villar
Institut für Organische Chemie, RWTH Aachen, Landoltweg 1, 52056 Aachen, Germany
Fax +49(241)8092391; E-mail: carsten.bolm@oc.rwth-aachen.de
Received 9 February 2005
This paper is dedicated to Professor Dr. Bernd Giese on the occasion of his 65th anniversary
sor.10 Its deprotonation with KH in the presence of
Bu4NBr and subsequent treatment with allyl bromide (5a)
or 5-bromopentene (5b) afforded N-substituted products
6a (80%) and 6b (71%), respectively, in good yields. A
second deprotonation/alkylation sequence using n-BuLi
as base and 5-bromopentene (5b) or 4-bromobutene (5c)
gave 7–10 in yields up to 90% (Scheme 1).
Abstract: Chiral heterocycles can be prepared starting from doubly
unsaturated sulfoximine derivatives by ring-closing metathesis re-
action in good yields.
Key words: catalysis, heterocycles, macrocycles, ring-closing me-
tathesis, sulfoximines
Sulfoximines1 are useful sulfur reagents in asymmetric
synthesis2 and biological chemistry.3 Since their discov-
ery in 1946,4 cyclic sulfoximine derivatives have attracted
particular attention,5 and several methods have been de-
vised for their synthesis. For example, Harmata and co-
workers used annulation reactions of alkynes with sulfon-
imidoyl chlorides, and domino sequences involving palla-
dium catalyses followed by ring closures for the
preparation of benzothiazines 1.6 Palladium-catalyzed in-
tramolecular a-arylations of sulfoximines affording het-
erocyclic products 2 and 3 were recently introduced by us7
(Figure 1).
( )
KH, 5a or 5b,
Bu4NBr
n
HN
N
S
S
O
4
Ph
Ph
Me
Me
DME, r.t.
O
6a,b
( )n
a: n = 1; b: n = 3
c: n = 2
Br
5a–c
( )
n
N
n-BuLi, 5b or 5c
6a or 6b
S
Ph
THF, 0 °C to r.t.
( )m
O
7: n = 1, m = 3 (53%)
8: n = 1, m = 4 (68%)
9: n = 3, m = 3 (80%)
10: n = 3, m = 4 (90%)
Scheme 1 Synthesis of doubly unsaturated sulfoximines to be used
as starting materials for RCM reactions
O
Me
N
X
S
R
N
S
O
N
S
Ph
Ph
Oxidation of allyl phenyl sulfide (11) followed by stan-
dard imination of the resulting sulfoxide 12 with a mixture
of NaN3 and H2SO4 afforded the corresponding sulfox-
imine 13. Attempts to allylate 13 selectively at the sulfox-
imine nitrogen to give 14 led to a mixture of 15 and 1611
(Figure 2).
R'
O
O
2a: X = CH2
2b: X = C(O)
1
3
Figure 1 Cyclic sulfoximines obtained by palladium catalyses fol-
lowed by ring formation (see text)
We wondered, if the recently developed ring-closing me-
tathesis (RCM)8 could also be used for the preparation of
sulfoximine-containing heterocycles. With appropriately
designed starting materials macrocyclic sulfoximine de-
rivatives should result, which are difficult to prepare by
other means.9 To the best of our knowledge, RCM has
only once been employed in sulfoximine chemistry,3f and
there, its efficiency was used as indication for conforma-
tional issues of the cyclizing pseudopeptide.
NR
S
NR
S
X
S
Ph
Ph
Ph
O
O
--
15: R = H
16: R = allyl
11: X =
12: X = O
13: R = H
14: R = allyl
Figure 2 Attempted synthesis of 14 starting from allyl phenyl sul-
fide (11)
As depicted in Scheme 2, N-acylated sulfoximines 19–21
and N-allylated derivative 22 were prepared through the
intermediacy of NH-sulfoximines 13, 15, and 18. For the
synthesis of the latter compound a standard MCPBA oxi-
dation of sulfide 17 followed by rhodium-catalyzed
imination12 of the resulting sulfoxides (not shown) was
applied. Treatment of 13, 15, and 18 with acryloyl chlo-
ride in the presence of a base afforded acylated products
Various routes were developed for the synthesis of the
doubly unsaturated starting materials, which were re-
quired for the RCM. Initially, readily accessible racemic
S-methyl-S-phenyl sulfoximine (4) served as the precur-
SYNTHESIS 2005, No. 9, pp 1421–1424
x
x
.
x
x
.2
0
0
5
Advanced online publication: 12.04.2005
DOI: 10.1055/s-2005-865312; Art ID: C01205SS
© Georg Thieme Verlag Stuttgart · New York

1422
C. Bolm, H. Villar
PAPER
Table 1 RCM of Unsaturated Sulfoximines Catalyzed by 25
1. MCPBA, CH2Cl2, 0 °C
2. [Rh2(OAc)4], CF3CONH2,
MgO, PhI(OAc)2, CH2Cl2, r.t.
NH
S
Entry Starting Material
1
Product
Yield (%)a
97
S
Ph
Ph
( )n
( )n
3. K2CO3, MeOH
O
O
N
17 (n = 2)
18 (n = 2)
O
N
S
O
Ph
S
Ph
N
22
23
CH2=CHC(O)Cl,
S
13, 15
or 18
Ph
( )n
O
Et3N, DMAP,
CH2Cl2, r.t.
2
75
O
N
O
N
S
19: n = 1 (from 13)
20: n = 2 (from 18)
Ph
S
Ph
O
N
S
15
29
N
S
Ph
O
3
4
90
57
Ph
O
N
N
N
O
O
S
S
S
21
22
Ph
Ph
Scheme 2 Reaction sequence for the preparation of unsaturated
sulfoximines
7
30
N
O
O
19–21.13 N-Allylated 22 was obtained by allylation of 18
with allyl bromide (5a).
S
Ph
Ph
8
31
The investigation of the RCM reaction began with a cata-
lyst screening using sulfoximine 22 as test substrate. To
our surprise we found that only one (25, ‘2nd generation
Grubbs’) out of the five tested ruthenium carben complex-
es 24–28 was catalytically active affording 7-membered
cyclic sulfoximine 23 in reasonable yield. Thus, with 20
mol% of 25, product 23 was obtained in 65% yield. Grat-
ifyingly, the catalyst loading could be reduced to 10 and
even 5 mol% affording sulfoximine 23 in 97 and 85%
yield, respectively (Scheme 3). Toluene was the solvent
of choice, and under reflux full conversion was achieved
within 15 minutes. Use of dichloromethane proved to be
unsuitable for this catalysis.
5
6
48
61
N
O
N
N
O
S
S
S
Ph
Ph
9
32
N
S
O
O
Ph
Ph
10
33
7
8
95
86
O
O
O
O
N
N
N
S
O
S
S
Next, the substrate scope was evaluated. To our delight a
variety of cyclic sulfoximines could be prepared by the
RCM reaction (Table 1). The best results were achieved
with 20 mol% of 25, which generally led to sulfoximine-
Ph
Ph
19
34
O
O
N
S
Ru catalyst
N
S
N
S
O
Ph
toluene,
reflux, 15 min
Ph
Ph
Ph
O
O
20
35
23
22
9
75
O
O
MesN
Cl
NMes
PCy3
Ru
O
N
Cl
Cl
N
S
Ru
O
S
Ph
Cl
Ph
Ph
PCy3
PCy3
Ph
24
25
PCy3
Ru
PCy3
Ru
21
36
Cl
Cl
Cl
PCy3
Ru
Cl
Cl
O
Ph
a The yield refers to the amount of heterocycle obtained after column
chromatography. At that stage, the product still contained traces of the
metal catalyst, which could not be removed in this manner.
Ph
Ph
N
N
SPh
PCy3
28
27
26
(Ciba 6015)
(Ciba 6033)
(Ciba 606)
Scheme 3 RCM reaction of 22 to give heterocyclic sulfoximine 23
catalyzed by ruthenium carben complexes 24–28
Synthesis 2005, No. 9, 1421–1424 © Thieme Stuttgart · New York

PAPER
RCM for the Synthesis of Cyclic Sulfoximines
1423
Hz), 3.81 (ddd, 1 H, J = 17.9, 5.8, 1.9 Hz), 3.70 (ddd, 1 H,
J = 14.3, 11.2, 2.2 Hz), 3.27 (ddd, 1 H, J = 14.3, 7.7, 2.2 Hz), 2.54–
2.43 (m, 1 H), 2.37–2.27 (m, 1 H).
13C NMR: d = 137.6, 132.3, 131.9, 127.9, 127.2, 126.2, 57.1, 41.5,
21.4.
based heterocycles in good to excellent yields. For exam-
ple, 8- and 11-membered cyclic products 30 and 33 were
obtained in 90 and 61% yield, respectively (Table 1, en-
tries 3 and 6). Also, acryloated sulfoximines 19–21 react-
ed well affording the corresponding cyclic products 34–
36 in high yields (entries 7–9).
MS: m/z (%) = 207.9 ([M + H]+, 4 ), 206.8 ([M]+, 2).
As indicated by the 13C NMR spectra, the 9- to 11-mem-
bered ring products 31–33 were obtained as E/Z mixtures,
and we are currently exploring the selective formation of
those compounds as well as derivatives thereof.
HRMS (EI): m/z cald for C11H13NOS: 207.0718; found: 207.0718.
Acknowledgment
We gratefully acknowledge the Deutsche Forschungsgemeinschaft
(SFB 380) and the Fonds der Chemischen Industrie for financial
support. H. V. thanks the Alexander von Humboldt-Foundation for
a postdoctoral stipend. We also appreciate receiving samples of
compounds 26–28, which were provided by Dr. van der Schaaf
from Ciba Specialty Chemicals Inc.
In summary, we investigated the RCM reactions of dou-
bly unsaturated sulfoximines and prepared novel hetero-
cycles in this manner. Ruthenium-benzylidene complex
25 proved to be the most active catalyst for the ring clo-
sure providing cyclic sulfoximines in good to excellent
yields.
References
All reactions were carried out under argon using standard Schlenk
techniques. Toluene was distilled over sodium/benzophenone and
stored under argon. NH-Sulfoximines were prepared according to
the literature. All other starting materials were obtained from com-
mercial suppliers and used without further purification. NMR spec-
tra were recorded in CDCl3 with TMS as internal standard on a
(1) Reviews: (a) Reggelin, M.; Zur, C. Synthesis 2000, 1.
(b) Mikolajczk, M.; Drabowicz, J.; Kielbasinski, P. Chiral
Sulfur Reagents; CRC Press: Boca Raton, 1997. (c) Pyne,
S. Sulfur Reports 1992, 12, 57. (d) Haake, M. In Houben-
Weyl, Vol. E11; Klamann D., Thieme: Stuttgart, 1985,
1299. (e) Johnson, C. R. Acc. Chem. Res. 1973, 6, 341.
(f) Johnson, C. R. Aldrichimica Acta 1985, 18, 3.
(2) For the use of sulfoximines as chiral ligands in asymmetric
catalysis, see (reviews): (a) Okamura, H.; Bolm, C. Chem.
Lett. 2004, 33, 482. (b) Harmata, M. Chemtracts - Org.
Chem. 2003, 16, 660.
Varian Gemini 300 spectrometer (300 and 75 MHz for 1H and 13
C
NMR spectra, respectively) or an Innova 400 spectrometer (400 and
100 MHz for 1H and 13C NMR spectra, respectively), FTIR spectra
on a Perkin-Elmer PE-1760 FT apparatus and MS spectra on a Vari-
an MAT 212 using chemical ionization technique.
(3) (a) Mock, W. L.; Tsay, J.-T. J. Am. Chem. Soc. 1989, 111,
4467. (b) Mock, W. L.; Zhang, J. Z. J. Biol. Chem. 1991,
266, 6393. (c) Bolm, C.; Kahmann, J. D.; Moll, G.
Tetrahedron Lett. 1997, 38, 1169. (d) Bolm, C.; Moll, G.;
Kahmann, J. D. Chem. Eur. J. 2001, 7, 1118. (e) Tye, H.;
Skinner, C. L. Helv. Chim. Acta 2002, 85, 3272. (f) Bolm,
C.; Müller, D.; Hackenberger, C. P. R. Org. Lett. 2002, 4,
893. (g) Bolm, C.; Müller, D.; Dalhoff, C.; Hackenberger, C.
P. R.; Weinhold, E. Bioorg. Med. Chem. Lett. 2003, 13,
3207.
(4) (a) Mellanby, E. Br. Med. J. 1946, 2, 885. (b) Mellanby, E.
Br. Med. J. 1947, 3, 288. (c) Bentley, H. R.; McDermott, E.
E.; Moran, T.; Pace, J.; Whitehead, J. K. Proc. Roy. Soc. B
1950, 137, 402.
Compound 22 was obtained by allylation of 18 with allyl bromide
(5a).
N-Allyl-S-but-3-enyl-S-phenylsulfoximine (22)
Yield: 80%.
IR (CHCl3): 3075, 1642, 1444, 1412, 1266, 1222, 1139, 1086, 997,
917, 747, 692 cm–1.
1H NMR: d = 7.92–7.88 (m, 2 Harom), 7.67–7.55 (m, 3 Harom), 6.01–
5.90 (m, 1 H), 5.77–5.66 (m, 1 H), 5.32–5.25 (md, 1 H, J = 16.8
Hz), 5.10–4.98 (m, 3 H), 3.70–3.62 (md, 1 H, J = 15.4 Hz), 3.54–
3.46 (md, 1 H, J = 15.4 Hz), 3.36–3.18 (m, 2 H), 2.62–2.49 (m, 1
H), 2.47–2.35 (m, 1 H).
13C NMR: d = 137.9, 137.8, 134.0, 132.9, 129.4, 129.3, 116.9,
114.5, 55.8, 46.1, 27.1.
(5) For examples, see: (a) Williams, T. R.; Cram, D. J. J. Org.
Chem. 1973, 38, 20. (b) Stoss, P.; Satzinger, G. Chem. Ber.
1972, 105, 2575. (c) Williams, T. R.; Cram, D. J. J. Am.
Chem. Soc. 1971, 93, 7333.
MS: m/z = 234.2 (M+, 3%).
Anal. Calcd for C13H17NOS: C, 66.34; H, 7.28; N, 5.95. Found: C,
66.11; H, 7.70; N, 5.61.
(6) (a) Harmata, M.; Kahraman, M.; Jones, D. E.; Pavri, N.;
Weatherwax, S. E. Tetrahderon 1998, 54, 9995.
Ring-Closing Metathesis Reactions; 1-Phenyl-1l4-[1,2]thiaz-
epine-1-oxide (23); Typical Procedure
(b) Harmata, M.; Pavri, N. Angew. Chem. Int. Ed. 1999, 38,
2419. (c) Harmata, M.; Ghosh, S. K. Org. Lett. 2001, 3,
3321. (d) Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003,
125, 5754. (e) Harmata, M.; Rayanil, K.-O.; Gomes, M. G.;
Zheng, P.; Calkins, N. L.; Kim, S.-Y.; Fan, Y.; Bumbu, V.;
Lee, D. R.; Wacharasindhu, S.; Hong, X. Org. Lett. 2005, 7,
143; and references cited therein.
To refluxing toluene (200 mL) was rapidly added the doubly unsat-
urated sulfoximine 22 (0.1 mmol), followed by the ruthenium cata-
lyst 25 (5 mol%). After 15 min at reflux, the mixture was cooled to
r.t. and concentrated in vacuo. Column chromatography (silica gel,
pentane–EtOAc, 1:1) afforded the 23 as a brown oil. NMR spectros-
copy indicated the presence of traces of remaining catalyst, which
could not be removed by chromatographical means; yield: 97%.
Commonly, 20 mol% of the catalyst were used. In this case, 23 was
obtained in 65% yield.
IR (CHCl3): 3016, 2962, 2927, 1264, 1219, 1145, 1122, 760 cm–1.
1H NMR: d = 8.06–8.03 (m, 2 Harom), 7.58–7.46 (m, 3 Harom), 5.83–
5.77 (m, 1 H), 5.732–5.66 (m, 1 H), 4.31–4.23 (md, 1 H, J = 17.9
(7) (a) Bolm, C.; Martin, M.; Gibson, L. Synlett 2002, 832.
(b) Bolm, C.; Okamura, H.; Verrucci, M. J. Organomet.
Chem. 2003, 687, 444.
(8) (a) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl.
1997, 36, 2036. (b) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413. (c) Fürstner, A. Angew. Chem. Int. Ed.
2000, 39, 3012. (d) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18. (e) Armstrong, S. K. J. Chem. Soc.,
Synthesis 2005, No. 9, 1421–1424 © Thieme Stuttgart · New York

1424
C. Bolm, H. Villar
PAPER
Perkin Trans. 1 1998, 371. (f) Schrock, R. R.; Hoveyda, A.
H. Angew. Chem. Int. Ed. 2003, 42, 4592. (g) Yet, L. Chem.
Rev. 2000, 100, 2963. (h) Handbook of Metathesis; Grubbs
R. H., Wiley-VCH: Weinheim, 2003, and references cited
therein.
key references describing the preparation of enantiopure 4,
see: (a) Fusco, R.; Tericoni, F. Chem. Ind. (Milan) 1965, 47,
61. (b) Johnson, C. R.; Schroeck, C. W. J. Am. Chem. Soc.
1973, 95, 7418. (c) Johnson, C. R.; Schroeck, C. W.;
Shanklin, J. R. J. Am. Chem. Soc. 1973, 95, 7424.
(d) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8,
909.
(9) For other recent summaries of RCM reactions affording
sulfur-containing heterocycles, see: (a) Karsch, S.; Freitag,
D.; Schwab, P.; Metz, P. Synthesis 2004, 1696.
(11) These products are shown with defined stereochemistry at
the double bond, although it was not determined if an E or Z
olefin was formed.
(b) McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R.
Chem. Rev. 2004, 104, 2239.
(10) In this study racemic sulfoximine 4 was used. However,
since the preparation of 4 in both enantiomeric forms is well
established, a ‘chiral switch’ should be easy to achieve. For
(12) Okamura, H.; Bolm, C. Org. Lett. 2004, 6, 1305.
(13) (a) Bolm, C.; Hackenberger, C. P. R.; Simic, O.; Verrucci,
M.; Müller, D.; Bienewald, F. Synthesis 2002, 879.
(b) Hackenberger, C. P. R.; Raabe, G.; Bolm, C. Chem. Eur.
J. 2004, 10, 2942.
Synthesis 2005, No. 9, 1421–1424 © Thieme Stuttgart · New York