Metal-free synthesis of N -cyano-substituted sulfilimines and sulfoximines

Article abstract of DOI:10.1055/s-0030-1258192

Starting from the corresponding sulfides, N-cyano sulfoximines can easily be accessed under metal-free conditions via the corresponding N-cyano-substituted sulfilimines. The reaction sequence involves a sulfide imination with cyanogen amide in presence of a base and N-bromosuccinimide (NBS) followed by an m-chloroperoxybenzoic acid (MCPBA) mediated oxidation of the resulting sulfilimine intermediates.

Full text of DOI:10.1055/s-0030-1258192

2922
PRACTICAL SYNTHETIC PROCEDURES
Metal-Free Synthesis of N-Cyano-Substituted Sulfilimines and Sulfoximines
N
-Cyano-Substitut
n
ed Sulfilimin
k
es and Sulfo
u
ximines r Pandey, Carsten Bolm*
Institut für Organische Chemie, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092391; E-mail: Carsten.Bolm@rwth-aachen.de
Received 8 July 2010
PSP
No192
Abstract: Starting from the corresponding sulfides, N-cyano sulfoximines can easily be accessed under metal-free conditions via the cor-
responding N-cyano-substituted sulfilimines. The reaction sequence involves a sulfide imination with cyanogen amide in presence of a base
and N-bromosuccinimide (NBS) followed by an m-chloroperoxybenzoic acid (MCPBA) mediated oxidation of the resulting sulfilimine in-
termediates.
Key words: halides, metal-free, nitriles, sulfides, sulfilimines, sulfoximines
CN
R2
H2NCN
NBS, t-BuOK
N
S
O
N CN
MCPBA, K2CO3
EtOH, 0 °C to r.t.
S
S
R1
R2
R1
R1
R2
MeOH, r.t.
1
3
2
Scheme 1 General scheme for the imination/oxidation sequence to give N-cyano sulfoximines
sulfilimines 2 in yields ranging from 75 to 95%.9 Hence,
compared to our previously reported results, the scale-up
Introduction
Sulfoximines are of interest owing to their biological (up to 24-fold) did not significantly affect the reaction
activity1 and their potential in asymmetric synthesis.2,3 outcome.
Two main routes are generally employed for their prepa-
ration. The first starts with a sulfide oxidation followed by
Table 1 Iminations of Sulfides 1
an imination of the resulting sulfoxide. Alternatively,
CN
R2
H2NCN
NBS, t-BuOK
N
S
sulfoximines can be accessed through a sulfide imination/
sulfilimine oxidation sequence.2 Most sulfur imination
methods rely on the use of metal catalysts.4,5 Recently, we
developed a metal-free approach towards N-cyano sulfil-
imines,6 which are attractive intermediates for the prepa-
ration of synthetically relevant N-cyano-substituted
sulfoximines.7 Important features of this protocol were the
use of simple cyanogen amide as nitrogen source in com-
bination with standard oxidizing agents such as N-bromo-
succinimide (NBS) or I2, which avoids the potential
dangers associated with the previously applied iodoben-
zene diacetate or related iodine reagents of higher oxida-
tion state.8 Here, we demonstrate that this approach is also
applicable for the preparation of multi-gram quantities of
N-cyano sulfoximines (Scheme 1).
S
R1
R2
R1
MeOH, r.t.
1
2
Entry
R1
Ph
Bn
Ph
R2
Product
2a
Yield of 2 (%)
1
2
3
4
5
Me
Me
Ph
93
80
95
75
89
2b
2c
4-O2NC6H4
4-MeOC6H4
Me
Me
2d
2e
Next, oxidations of sulfilimines 2 with m-chloroperoxy-
benzoic acid (MCPBA) in ethanol to provide N-cyano
sulfoximines 3 were investigated (Table 2).10 Also in this
case, the scale-up had no major influence on the yields of
the desired products, and N-cyano sulfoximines 3 were
obtained in up to 96% yield.
Scope and Limitations
As shown in Table 1, the imination of various sulfides 1
with a combination of cyanogen amide and NBS in the
presence of potassium tert-butoxide (t-BuOK) proceeded
well in methanol at room temperature, providing N-cyano
Finally it should be noted that the free NH-sulfoximines 4
can easily be prepared from the corresponding N-cyano
sulfoximines 3 by treatment with either diluted H2SO48b or
trifluoroacetic anhydride (TFAA), followed by addition
of K2CO3 (Scheme 2).6 The latter reaction sequence is a
two-step process that proceeds via the synthetically inter-
esting trifluoroacetyl-protected sulfoximines 5, which can
SYNTHESIS 2010, No. 17, pp 2922–2925
x
x.
x
x
.
2
0
1
0
Advanced online publication: 04.08.2010
DOI: 10.1055/s-0030-1258192; Art ID: Z17710SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
N-Cyano-Substituted Sulfilimines and Sulfoximines
2923
1H NMR (300 MHz, CDCl3): d = 7.82–7.77 (m, 2 H), 7.67–7.55 (m,
Table 2 Oxidation of N-Cyano Sulfilimines 2
2 H), 3.02 (s, 3 H).
CN
N
O
N
CN
13C NMR (75 MHz, CDCl3): d = 135.8 (C), 132.9 (CH), 130.1
(2 × CH), 125.7 (2 × CH), 120.5 (CN), 36.4 (CH3).
MCPBA, K2CO3
EtOH, 0 °C to r.t.
S
S
R1
R2
R1
R2
2
3
N-Cyano Benzyl Methyl Sulfilimine (2b)
a: R1 = Ph, R2 = Me
b: R1 = Bn, R2 = Me
c: R1 = R2 = Ph
d: R1 = 4-O2NC6H4, R2 = Me
e: R1 = 4-MeOC6H4, R2 = Me
Produced as for the synthesis of 2a using: benzyl methyl sulfide (7.3
mmol, 1.0 g), cyanogen amide (9.5 mmol, 0.4 g), t-BuOK (8.7
mmol, 0.8 g), MeOH (22 mL), and NBS (10.9 mmol, 1.9 g). The
product was purified by flash column chromatography (CH2Cl2–
acetone, 6:1→1:1) to give 2b.
Entry
N-Cyano sulfilimine Product
Yield of 3 (%)
1
2
3
4
5
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
76
60
86
96
77
Yield: 1.04 g (80%); white solid.
1H NMR (300 MHz, CDCl3): d = 7.47–7.42 (m, 3 H), 7.40–7.34 (m,
2 H), 4.43 and 4.19 (AB system, J = 12.8 Hz, 2 H), 2.73 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 130.1 (2 × CH), 129.6 (CH), 129.5
(2 × CH), 127.6 (C), 119.5 (CN), 55.4 (CH2), 31.2 (CH3).
N-Cyano Diphenyl Sulfilimine (2c)
Produced as for the synthesis of 2a using: diphenyl sulfide (16.1
mmol, 3.0 g), cyanogen amide (20.9 mmol, 0.9 g), t-BuOK (19.3
mmol, 2.2 g), MeOH (48 mL), and NBS (24.2 mmol, 4.3 g). The
mixture was stirred for 2 h (instead of 1.5 h). The product was puri-
fied by flash column chromatography (CH2Cl2–acetone, 9:1) to give
2c.
also be isolated in good yields.6 This reaction was demon-
strated for sulfoximine 3a, which was converted into NH-
sulfoximine 4a. In this case, both methods gave almost
identical yields (64 and 63%, respectively) in gram-scale
reactions.
Yield: 3.4 g (95%); white solid.
1H NMR (400 MHz, CDCl3): d = 7.72–7.53 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 135.7 (2 × C), 132.9 (2 × CH),
130.1 (4 × CH), 127.4 (4 × CH), 120.6 (CN).
O
N
CN
O
NH
R2
50% H2SO4
S
S
R1
R2
R1
(ref. 8b)
a: R1 = Ph, R2 = Me
3
4
N-Cyano Methyl 4-Nitrophenyl Sulfilimine (2d)
K2CO3
MeOH
TFAA
CH2Cl2
Produced as for the synthesis of 2c using: methyl 4-nitrophenyl sul-
fide (5.91 mmol, 1.0 g), cyanogen amide (7.7 mmol, 0.3 g), t-BuOK
(7.1 mmol, 0.8 g), MeOH (18 mL), and NBS (8.9 mmol, 1.6 g).
CH2Cl2 (3 × 65 mL) was used for extraction of the aqueous layer.
The product was purified by flash column chromatography
(CH2Cl2–acetone, 9:1) to give 2d.
O
N C(O)CF3
S
R1
R2
(ref. 6)
(ref. 6)
5
Scheme 2
Yield: 0.9 g (75%); pale yellow solid.
1H NMR (300 MHz, CD3OD): d = 8.53 (br d, J = 9.2 Hz, 2 H), 8.18
(br d, J = 9.2 Hz, 2 H), 3.21 (s, 3 H).
13C NMR (75 MHz, CD3OD): d = 152.1 (C), 144.5 (C), 128.8
(2 × CH), 126.3 (2 × CH), 121.9 (CN), 37.2 (CH3).
In summary, we have demonstrated gram-scale syntheses
of N-cyano-protected sulfilimines and sulfoximines using
simple and readily available reagents under straightfor-
ward reaction conditions. We expect this protocol to find
applications in the preparation of biologically relevant
products such as agrochemicals.
N-Cyano Methyl 4-Methoxyphenyl Sulfilimine (2e)
Produced as for the synthesis of 2a using: methyl 4-methoxyphenyl
sulfide (6.5 mmol, 1.0 g), cyanogen amide (8.4 mmol, 0.35 g), t-
BuOK (7.8 mmol, 0.9 g), MeOH (20 mL), and NBS (9.7 mmol, 1.7
g). CH2Cl2 (3 × 65 mL) was used for extraction of the aqueous lay-
er. The product was purified by flash column chromatography
(CH2Cl2–acetone, 9:1→2:1) to give 2e.
All starting materials were purchased from commercial suppliers
and used without further purification unless stated otherwise. The
reactions were performed in air. All products were known and their
1
full characterization was reported before.5d Here, only the H and
13C NMR data are listed.
Yield: 1.1 g (89%); light, pale yellow solid.
N-Cyano Methyl Phenyl Sulfilimine (2a)
1H NMR (300 MHz, CD3OD): d = 7.87 (d, J = 9.0 Hz, 2 H), 7.22 (d,
J = 9.0 Hz, 2 H), 3.93 (s, 3 H), 3.12 (s, 3 H).
13C NMR (75 MHz, CD3OD): d = 163.8 (C), 128.5 (2 × CH), 126.2
(C), 121.3 (CN), 115.4 (2 × CH), 55.0 (CH3), 34.8 (CH3).
A mixture of methyl phenyl sulfide (24 mmol, 3.0 g), cyanogen
amide (31 mmol, 1.3 g) and t-BuOK (29 mmol, 3.2 g) were dis-
solved in MeOH (72 mL). NBS (36 mmol, 6.4 g) was added, and the
reaction mixture was stirred for 1.5 h. The solvent was evaporated
using a rotatory evaporator, sat. sodium thiosulfate (100 mL) was
added, and the mixture was extracted with CH2Cl2 (3 × 60 mL). The
combined organic layers were washed with H2O and dried over an-
hydrous MgSO4. Evaporation of the solvent in vacuo followed by
purification by flash column chromatography (CH2Cl2–acetone,
9:1) afforded 2a.
N-Cyano Methyl Phenyl Sulfoximine (3a)
To a stirred solution of sulfilimine 2a (22.5 mmol, 3.7 g) in EtOH
(60 mL), K2CO3 (67.6 mmol, 9.3 g) and MCPBA (33.8 mmol, 5.8
g) were added at 0 °C. The reaction mixture was allowed to warm
to r.t. and stirring was continued for 1.5 h. The solvent was removed
under vacuo, and H2O (150 mL) was added. The resulting mixture
was extracted with CH2Cl2 (3 × 65 mL) and the combined organic
Yield: 3.7 g (93%); colorless oil.
Synthesis 2010, No. 17, 2922–2925 © Thieme Stuttgart · New York

2924
A. Pandey, C. Bolm
PRACTICAL SYNTHETIC PROCEDURES
phases were dried over anhydrous MgSO4 and filtered. Evaporation
of the solvent in vacuo followed by flash column chromatography
(acetone–pentane, 1:3) gave 3a.
removed under reduced pressure. Purification by flash column chro-
matography (EtOAc–acetone, 5:1) gave 4a.
Yield: 0.6 g (64%) white solid.
Yield: 3.1 g (76%); white solid.
1H NMR (300 MHz, CDCl3): d = 8.04–7.98 (m, 2 H), 7.79 (tt,
J = 7.4, 1.2 Hz, 1 H), 7.73–7.66 (m, 2 H), 3.35 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 136.0 (C), 135.5 (CH), 130.3
(2 × CH), 127.9 (2 × CH), 111.8 (CN), 44.8 (CH3).
1H NMR (300 MHz, CDCl3): d = 8.06–7.98 (m, 2 H), 7.66–7.52 (m,
3 H), 3.10 (s, 3 H, CH3), 2.86 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 132.9 (CH), 129.1 (2 × CH), 127.6
(2 × CH), 46.1 (CH3).
Method B: To a stirred solution of sulfoximine 3a (5.6 mmol, 1.0 g)
in CH2Cl2 (100 mL) at 0 °C, TFAA (2.3 mL, 16.6 mmol) was added.
The mixture was allowed to react at r.t. until most of the starting ma-
terial was consumed (monitored by TLC). Then, the reaction mix-
ture was concentrated, diluted with MeOH (40 mL) and treated with
K2CO3 (27.7 mmol, 3.8 g). The reaction was allowed to react at r.t.
until the starting material was consumed (monitored by TLC). The
solvent was then removed under reduced pressure and H2O (100
mL) was added. The resulting mixture was extracted with CH2Cl2
(3 × 50 mL) and the organic layer was then dried over anhydrous
MgSO4 and filtered. Evaporation of the solvent in vacuo followed
by flash column chromatography (EtOAc→EtOAc–acetone, 5:1)
gave 4a.
N-Cyano Benzyl Methyl Sulfoximine (3b)
Produced as for the synthesis of 3a using: sulfilimine 2b (5.8 mmol,
1.04 g), EtOH (60 mL), K2CO3 (17.5 mmol, 2.4 g) and MCPBA (8.7
mmol, 1.5 g). Flash column chromatography (EtOAc–pentane, 4:1)
gave 3b.
Yield: 0.7 g (60%); white solid.
1H NMR (300 MHz, CDCl3): d = 7.51–7.43 (m, 5 H), 4.62 (s, 2 H),
3.01 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 131.2 (2 × CH), 130.5 (CH), 129.3
(2 × CH), 125.9 (C), 112.2 (CN), 61.8 (CH2), 38.6 (CH3).
Yield: 0.5 g (63%); white solid.
N-Cyano Diphenyl Sulfoximine (3c)
Produced as for the synthesis of 3a using: sulfilimine 2c (15.0
mmol, 3.4 g), EtOH (60 mL), K2CO3 (45.1 mmol, 6.2 g) and
MCPBA (22.5 mmol, 3.9 g). The mixture was stirred for 2 h (in-
stead of 1.5 h). Flash column chromatography (EtOAc–pentane,
2:1) gave 3c.
Acknowledgment
This work was supported by the Fonds der Chemischen Industrie
and, in part, by a grant from the German-Israeli Foundation (GIF)
for scientific research and development.
Yield: 3.1 g (86%); white solid.
1H NMR (400 MHz, CDCl3): d = 8.03 (dd, J = 7.1, 1.7 Hz, 2 H),
7.69 (tt, J = 7.1, 1.4 Hz, 4 H), 7.61 (tt, J = 7.1, 1.7 Hz, 4 H).
13C NMR (100 MHz, CDCl3): d = 137.3 (2 × C), 134.7 (2 × CH),
130.0 (4 × CH), 127.9 (4 × CH), 111.9 (CN).
References
(1) For selected recent examples, see: (a) Walker, D. P.;
Zawistoski, M. P.; McGlynn, M. A.; Li, J.-C.; Kung, D. W.;
Bonnette, P. C.; Baumann, A.; Buckbinder, L.; Houser, J. A.;
Boer, J.; Mistry, A.; Han, S.; Xing, L.; Guzman-Perez, A.
Bioorg. Med. Chem. Lett. 2009, 19, 3253.
N-Cyano Methyl 4-Nitrophenyl Sulfoximine (3d)
Produced as for the synthesis of 3a using: sulfilimine 2d (4.3 mmol,
0.9 g), EtOH (60 mL), K2CO3 (12.9 mmol, 1.8 g) and MCPBA (6.5
mmol, 1.1 g). The mixture was stirred for 2.5 h (instead of 1.5 h).
Flash column chromatography (EtOAc–pentane, 1:4→EtOAc)
gave 3d.
(b) García Mancheño, O.; Dallimore, J.; Plant, A.; Bolm, C.
Adv. Synth. Catal. 2010, 352, 309. (c) Jeschke, P.; Thielert,
W.; Hungenberg, H. (Bayer CropScience AG) WO 022897
A2, 2010. (d) Jautelat, R.; Lücking, U.; Siemeister, G.;
Schulze, J.; Lienau, P. (Bayer Schering Pharma AG) 046035
A1, 2010.
Yield: 0.9 g (96%); pale yellow solid.
1H NMR (300 MHz, DMSO-d6): d = 8.55 (br d, J = 8.8 Hz, 2 H),
8.32 (br d, J = 8.8 Hz, 2 H), 3.30 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 151.3 (C), 141.8 (C), 129.6
(2 × CH), 125.1 (2 × CH), 111.6 (CN), 42.1 (CH3).
(2) For reviews, see: (a) Reggelin, M.; Zur, C. Synthesis 2000,
1. (b) Harmata, M. Chemtracts 2003, 16, 660. (c)Okamura,
H.; Bolm, C. Chem. Lett. 2004, 33, 482. (d) Bentley, R.
Chem. Soc. Rev. 2005, 34, 609. (e) Worch, C.; Mayer, A.
C.; Bolm, C. In Organosulfur Chemistry in Asymmetric
Synthesis; Toru, T.; Bolm, C., Eds.; Wiley-VCH: Weinheim,
2008, 209.
(3) For recent applications of sulfoximines as chiral ligands in
metal catalysis, see: (a) Frings, M.; Atodiresei, I.; Wang, Y.;
Runsink, J.; Raabe, G.; Bolm, C. Chem. Eur. J. 2010, 16,
4577. (b) Frings, M.; Goedert, D.; Bolm, C. Chem. Commun.
2010, DOI: 10.1039/C0CC00996B; and references therein.
(4) For Cu catalysis, see: (a) Kwart, H.; Kahn, A. A. J. Am.
Chem. Soc. 1967, 89, 1950. (b) Müller, J. F. K.; Vogt, P.
Tetrahedron Lett. 1998, 39, 4805. (c) Lacôte, E.; Amatore,
M.; Fensterbank, L.; Malacria, M. Synlett 2002, 116. For
Rh catalysis, see: (d) Okamura, H.; Bolm, C. Org. Lett.
2004, 6, 1305. For Ag catalysis, see: (e) Cho, G. Y.; Bolm,
C. Org. Lett. 2005, 7, 4983. For Fe catalysis, see: (f) Bach,
T.; Körber, C. Tetrahedron Lett. 1998, 39, 5015. (g) Bach,
T.; Körber, C. Eur. J. Org. Chem. 1999, 64, 1033.
(h) García Mancheño, O.; Bolm, C. Org. Lett. 2006, 8,
2349. (i) Bolm, C.; García Mancheño, O. Chem. Eur. J.
N-Cyano Methyl 4-Methoxyphenyl Sulfoximine (3e)
Produced as for the synthesis of 3c using: sulfilimine 2e (5.7 mmol,
1.1 g), EtOH (60 mL), K2CO3 (17.0 mmol, 2.3 g) and MCPBA (8.6
mmol, 1.5 g). Flash column chromatography (EtOAc–pentane,
1:4→EtOAc) gave 3e.
Yield: 0.9 g (77%); white solid.
1H NMR (300 MHz, CD3OD): d = 7.97 (br d, J = 9.1 Hz, 2 H), 7.23
(br d, J = 9.1 Hz, 2 H), 3.91 (s, 3 H), 3.47 (s, 3 H).
13C NMR (75 MHz, CD3OD): d = 165.3 (C), 130.1 (2 × CH), 126.8
(C), 115.1 (2 × CH), 112.7 (CN), 55.2 (CH3), 43.4 (CH3).
NH-Methyl Phenyl Sulfoximine (4a)
Method A: To sulfoximine 3a (1.0 g, 5.6 mmol), aq H2SO4 (50%,
25 mL) was added. The mixture was heated at reflux for 2 h and
then allowed to cool to r.t. After neutralization with 50% NaOH the
mixture was extracted with CH2Cl2 (3 × 50 mL), the combined or-
ganic layers were dried over anhydrous MgSO4 and the solvent was
Synthesis 2010, No. 17, 2922–2925 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
N-Cyano-Substituted Sulfilimines and Sulfoximines
2925
2007, 13, 6674. (j) Bolm, C.; García Mancheño, O.;
Dallimore, J.; Plant, A. Org. Lett. 2009, 11, 2429.
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S.; Kazaz, C.; Kilic, H.; Ulukanli, S.; Celik, A. Tetrahedron
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Chernoloz, O. V.; Yudin, A. K. ARKIVOC 2005, (iv), 26.
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Rogers, R. B.; Orr, N.; Sparks, T. C.; Gifford, J. M.; Loso,
M. R.; Zhu, Y.; Meade, T. (Dow AgroSciences) WO 149134
A1, 2007. (b) For a recent report on pesticidal combinations
containing Sulfoxaflor, see: Schade, M.; Grimm, C.;
Faerber, M.; Müller, K.; Campbell, S. (Syngenta) WO
040623, 2010.
(8) For previous syntheses of sulfilimines and sulfoximines with
N-cyano groups, see: (a) Swern, D.; Ikeda, I.; Whitfield, G.
F. Tetrahedron Lett. 1972, 2635. (b) Stoss, P.; Satzinger, G.
Tetrahedron Lett. 1973, 267. (c) Hutchins, M. G. K.; Swern,
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(e) Zhu, Y.; Rogers, R. B.; Huang, J. X. (Dow
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AgroSciences) US 0228027 A1, 2005.
(7) (a) Various N-cyano sulfoximines are of interest as
agrochemicals. A prominent example is the sap-feeding
insecticide Sulfoxaflor, which is scheduled for launch in
2012 by Dow AgroSciences. For details, see: Huang, J. X.;
(9) Using I2 instead of NBS under those conditions led to the
desired products in lower yields.
(10) Attempting to use other oxidants such as KMnO4 for the
sulfilimine oxidations led to lower sulfoximine yields.
Synthesis 2010, No. 17, 2922–2925 © Thieme Stuttgart · New York