Radical N-cyanation of sulfoximine through acetonitrile C-CN cleavage

Article abstract of DOI:10.1016/j.tetlet.2015.11.025

A new strategy for the N-cyanation of sulfoximine via radical process has been developed, leading to the desired products in moderate to excellent yields with good functional group tolerance. This procedure provided an alternative pathway to C-CN bond act

Full text of DOI:10.1016/j.tetlet.2015.11.025

Tetrahedron Letters 56 (2015) 7056–7058
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Radical N-cyanation of sulfoximine through acetonitrile CACN
cleavage
⇑
Weiming Hu, Fan Teng, Haibo Peng, Jintao Yu, Song Sun, Jiang Cheng, Ying Shao
School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, Advanced catalysis and Green Manufacturing Collaborative
Innovation Center, Changzhou University, Changzhou 213164, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new strategy for the N-cyanation of sulfoximine via radical process has been developed, leading to the
desired products in moderate to excellent yields with good functional group tolerance. This procedure
provided an alternative pathway to CACN bond activation of acetonitrile. In particular, 1,1,3,3-tetram-
ethylguanidine also worked well in this procedure.
Received 24 September 2015
Revised 2 November 2015
Accepted 9 November 2015
Available online 10 November 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
N-cyanation
Sulfoximine
Radical process
CACN bond activation
Acetonitrile
Sulfoximidoyl-containing derivatives have caught significant
attention in organic chemistry and have been widely applied in
crop protection and medicinal chemistry.1 Meanwhile, they have
also been proven to be successful reaction partners as chiral auxil-
iaries2 and ligands.3 Thus, pursuing N-functionalization of sulfox-
imines continues to be a front-burner issue.4 Moreover, the
NACN bonds are ubiquitous and frequently found in large numbers
of biologically active molecules, natural products, and some medic-
inal structures.5 So far, only a few studies on N-cyanation of sulfox-
imine have been conducted.6 Therefore, N-cyanation of
sulfoximine is still extremely appealing.
In the past years, it has been a challenging work to activate the
CAC bond in modern organic chemistry.7 Cleavage of CACN bond is
fascinating to serve as a cyanide source, yet challenging. In 1986,
Murahashi discovered the Pd-catalyzed decarbonylation of acyl
cyanides.8 Since then advance in CACN cleavage has been made,
which was promoted by transition metal complexes, such as Pd,9
Ni,10 Rh,11 Fe,12 and others.13 However, much attention was paid
mainly to aromatic nitriles or acyl cyanides in these cases, which
are easier to be cleaved compared to alkyl nitriles. To the best of
our knowledge, only a few examples have been reported on the
CACN cleavage of acetonitrile. In 1998, Cheng’s group reported
on the CACN bond cleavage of acetonitrile mediated by palladium
and zinc species.14 Afterward, Mascharak and co-workers discov-
ered [Cu(dmppy)(en)] (en = ethylenediamine) could activate such
a CACN bond by heterolytic cleavage to form cyano anion and
methyl cation fragments.15 Subsequently, Lu reported copper(II)
cryptate-mediated CAC bond activation of acetonitrile.16 Recently,
a Cu/Si system for the cyanation with acetonitrile has been docu-
mented by Shen.17 In 2012, Li’s group reported on the CAC bond
cleavage of acetonitrile catalyzed by copper.18 And Zhu’s group
reported cyanation of indoles using Cu/Ag system to activate the
CACN bond of acetonitrile in 2013.19 Nevertheless, there is no
report on acetonitrile serving as the radical precursor in N-cyana-
tion reaction. We are confident of initiating a study that acetoni-
trile might be a suitable cyano radical source to access N-
cyanation of sulfoximines, if the reaction conditions could be prop-
erly controlled. And that would provide an alternative option for
more efficient synthesis of N-cyanation sulfoximines. Herein we
report our success on this approach (see Scheme 1).
We used the sulfoximine 1a as a model substrate to find suit-
able reaction conditions. Initially, we examined the reaction using
1a, Cu2O, and TBHP under O2 in CH3CN at 120 °C. To our delight,
after 24 h, N-cyanation product 2a was formed in 26% yield
(Table 1, entry 1). Following this exciting result, other peroxides
were tested (Table 1, entries 2–4). Delightedly, we achieved the
desired product 2a in 85% yield when using DTBP instead of TBHP
(Table 1, entry 4). Then control experiments showed that, in the
absence of DTBP, the reaction could not take place (Table 1, entry
5). While in the absence of Cu2O, still we got the product 2a in
8% yield (Table 1, entry 6). It represented that the reaction might
⇑
Corresponding author.
E-mail address: shaoying810724@163.com (Y. Shao).
http://dx.doi.org/10.1016/j.tetlet.2015.11.025
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

W. Hu et al. / Tetrahedron Letters 56 (2015) 7056–7058
7057
Table 2
Me CN
CN
Scope of N-cyanation sulfoximinesa
radical process
O
R1
NH
R2
O
R1
N
R2
CN
O
O
Cu2O (10 mol%), DTBP (4.0 equiv)
120 oC, O2, 24h
N
CN
NH
+
S
S
+
CH3CN
S
S
C-CN bond clevage
R1
R1
R2
R2
1
2
Scheme 1. N-cyanation of sulfoximine.
O
S
O
N
CN
Cl
N
CN
CN
O
N
CN
S
Table 1
S
The optimization of reaction conditionsa
Cl
O
O
2a
2b
2c
NH
85%
82%
O
79%
N
N
CN
S
S
+
CH3CN
O
S
N
CN
O
S
N
CN
S
1a
2a
Br
OMe
CN
OMe
Entry
Catalyst
Oxidant
Temp (°C)
Yieldb (%)
2d 69%
2e 71%
2f 59%
O
S
1
2
3
4
5
6
7
8
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
—
CuF2
CuBr
CuI
CuCN
Fe(acac)2
AgF
Cu2O
Cu2O
Cu2O
TBHP
K2S2O8
BPO
DTBP
—
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
120
120
120
120
120
120
120
120
120
120
120
120
100
110
130
26
<1
<1
N
O
S
O
S
N CN
N
CN
Br
85 (80)c (<1)d
Br
Br
<1
8
2g
2h
2i
58%
72%
O
61%
48
75
40
46
<1
19
<1
41
79
O
N
CN
Ph
N
S
CN
S
O
S
N
CN
9
10
11
12
13
14
15
Ph
2j 75%
2k 81%
2l 49%
O
S
N
CN
O
S
N
CN
O
N
CN
S
a
Cl
F
Reaction conditions: 1a (0.1 mmol), oxidant (0.4 mmol), catalyst (10 mol %),
CH3CN (1.5 mL) at 120 °C for 24 h under O2 in a sealed tube. (TBHP = tert-butyl
hydroperoxide, BPO = benzoyl peroxide, DTBP = di-tert-butyl peroxide.)
2m
2n
2o
52%
51%
CN
40%
CN
b
Isolated yield.
Under air.
O
S
N
CN
N
N
c
d
N
N
Under N2.
MeO
proceed via a radical process. Thereafter, reactions were conducted
under air and N2. Sharply in contrast, N-cyanation product 2a was
formed in 80% yield under air while the reaction just did not take
place under N2 (Table 1, entry 4). Based on that, we could make a
conclusion that O2 participated in this procedure. Subsequently,
other copper(I) and copper(II) salts such as CuF2, CuBr, and CuI
were also tested in the procedure and provided the desired product
2a in 48%, 75%, and 40% yields, respectively, (Table 1, entries 7–9).
It is significant and meaningful that when CuCN was tested, pro-
duct 2a was formed only in 46% yield (Table 1, entry 10), which
ruled out the possibility that CN anion is the active compound in
this reaction. No conversion occurred when Fe(acac)2 was used
as the catalyst (Table 1, entry 11), while 2a was formed in 19%
yield in the presence of AgF (Table 1, entry 12). Different temper-
atures had also been tested in this procedure. No reaction took
place at 100 °C (Table 1, entry 13), while 2a was formed in 41%
and 79% yields at 110 °C and 130 °C, respectively, (Table 1, entries
14 and 15).
The substrate scope of this strategy was investigated under the
optimized reaction conditions. Initially, diphenylsulfoximine
derivatives were tested. Generally, various substituted groups
(such as methyl, methoxy, chloro, and bromo groups) were all tol-
erated well and provided the corresponding N-cyanation products
in moderate to excellent yields as shown in Table 2 under the stan-
dard procedure. For instance, 2b, 2c, 2e, and 2k were isolated in
82%, 79%, 71%, and 81% yields, respectively. To our delight,
alkylphenylsulfoximines, arylimine, and guanidine also worked
smoothly under the standard procedure delivering the N-cyanation
products. For example, (S-methylsulfonimidoyl)benzene derivative
provided the 2l in 49% yield and (S-ethylsulfonimidoyl)benzene
2p 54%
2q 73%
2r 31%
aReaction conditions: 1a (0.1 mmol), DTBP (0.4 mmol), Cu2O (10 mol %), CH3CN
(1.5 mL) at 120 °C for 24 h under O2 in a sealed tube.
derivative provided the N-cyanation product 2m in 52% yield.
Meanwhile, we are glad to emphasize that substrates containing
halogen also run smoothly (2n, 2o), which provided an efficient
route for further functionalizations. Interestingly, 1,1,3,3-tetram-
ethylguanidine also worked well in this procedure, and gave the
N-cyanation product in 73% yield (2q). Besides, benzophenone
imine in this reaction led to the desired product in 31% yield
(2r), which further extended the substrate scope.
More experiments were conducted to study the potential mech-
anism. Initially, the radical scavenger TEMPO (2,2,6,6-tetramethyl-
1-piperidinyloxyl) was added to this procedure, no desired product
2a was formed, and the adduct TEMPO-CN was observed by GC–
MS (Figs. S1 and S2 in Supplementary data). Meanwhile, product
2a was not provided either when adding BHT (2,6-di-tert-butyl-
4-methylphenol) to the reaction, and the adduct between BHT
and cyanide was also detected by GC–MS (Figs. S3 and S4 in Sup-
plementary data). These indicate that a radical pathway may be
involved in this transformation (Scheme 2).
Based on the aforementioned experimental results, the possible
mechanism is proposed shown in Scheme 3. Firstly, the catalyst Cu
(I) is oxidized to Cu(II) by O2. Then, the reaction between sulfox-
imines 4 and Cu(II) species 3 produces another Cu(II) species 5.
At the same time, cyano radical is formed via CACN bond cleavage
of acetonitrile promoted by catalyst copper and DTBP. Subse-

7058
W. Hu et al. / Tetrahedron Letters 56 (2015) 7056–7058
Agric. Food Chem. 2011, 59, 2950; (b) Lücking, U. Angew. Chem., Int. Ed. 2013, 52,
O
O
standard condition
NH
NH
N
9337.
+
+
S
CH3CN
CH3CN
S
CN
+
+
N
O
eq 1
2. (a) Johnson, C. R. Acc. Chem. Res. 1973, 6, 341; (b) Pyne, S. Sulfur Rep. 1992, 12,
57; (c) Reggelin, M.; Zur, C. Synthesis 2000, 1.
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2004, 32, 482.
Ph
2 eq TEMPO Ph
Ph
Ph
CN
1a
2a, <1%
detected by GC-MS
4. For some examples: (a) Dong, W.-R.; Wang, L.; Parthasarathy, K.; Pan, F.-F.;
Bolm, C. Angew. Chem., Int. Ed. 2013, 52, 3478–3480; (b) Priebbenow, D. L.;
Bolm, C. Org. Lett. 2014, 16, 1650; (c) Wang, L.; Priebbenow, D. L.; Dong, W.-R.;
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Parthasarathy, K.; Bolm, C. Org. Lett. 2000, 2014, 16.
O
S
O
N
standard condition
3 eq BHT
CN
S
eq 2
Ph
Ph
2a, <1%
Ph
Ph
O
CN
detected by GC-MS
1a
5. (a) Deaton, D. N.; Hassell, A. M.; McFayden, R. B.; Miller, A. B.; Miller, L. R.;
Shewchuk, L. M.; Tavares, F. X.; Willard, D. H., Jr.; Wright, L. L. Bioorg. Med.
Chem. Lett. 2005, 15, 1815; (b) Carta, F.; Akdemir, A.; Scozzafava, A.; Masini, E.;
Supuran, C. T. J. Med. Chem. 2013, 56, 4691; (c) Kumar, R.; Rai, D.; Sharma, S. K.;
Saffran, H. A.; Blush, R.; Tyrrell, D. L. J. J. Med. Chem. 2001, 44, 3531; (d) Guay,
D.; Beaulieu, C.; Percival, M. D. Curr. Top. Med. Chem. 2010, 10, 708; (e) Lainé, D.;
Palovich, M.; McCleland, B.; Petitjean, E.; Delhom, I.; Xie, H.; Deng, J.; Lin, G.;
Davis, R.; Jolit, A.; Nevins, N.; Zhao, B.; Villa, J.; Schneck, J.; McDevitt, P.;
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(b) Teng, F.; Yu, J.-T.; Zhou, Z.; Chu, H.; Cheng, J. J. Org. Chem. 2015, 80, 2822.
7. Some reviews for CAC bond activation, see: (a) Park, Y. J.; Park, J.-W.; Jun, C.-H.
Acc. Chem. Res. 2008, 41, 222; (b) Jun, C.-H. Chem. Soc. Rev. 2004, 33, 610; (c)
Rybtchinski, B.; Milstein, D. Angew. Chem., Int. Ed. 1999, 38, 870; (d) Halpern, J.
Acc. Chem. Res. 1982, 15, 238.
8. Murahashi, S. I.; Naota, T.; Nakajima, N. J. Org. Chem. 1986, 51, 898.
9. Selected examples for Pd-promoted CACN cleavage, see: (a) Nozaki, K.; Sato,
N.; Takaya, H. J. Org. Chem. 1994, 59, 2679; (b) Kobayashi, Y.; Kamisaki, H.;
Yanada, R.; Takemoto, Y. Org. Lett. 2006, 8, 2711; (c) Sundermeier, M.; Zapf, A.;
Beller, M. Angew. Chem., Int. Ed. 2003, 42, 1661; (d) Wen, Q.-D.; Jin, J.-S.; Hu, B.-
B.; Lu, P.; Wang, Y.-G. RSC Adv. 2012, 2, 6167.
10. Selected examples for Ni-promoted CACN cleavage, see: (a) Miller, J. A.;
Dankwardt, J. W. Tetrahedron Lett. 2003, 44, 1907; (b) Nakao, Y.; Oda, S.;
Hiyama, T. J. Am. Chem. Soc. 2004, 17, 13904; (c) Nakao, Y.; Yada, A.; Ebata, S.;
Hiyama, T. J. Am. Chem. Soc. 2007, 129, 2428; (d) Nakao, Y.; Yada, A.; Hiyama, T.
J. Am. Chem. Soc. 2010, 132, 10024; (e) Wu, M.-S.; Rayabarapu, D. K.; Cheng, C.-
H. J. Am. Chem. Soc. 2003, 125, 12426; (f) Watson, M. P.; Jacobsen, E. N. J. Am.
Chem. Soc. 2008, 130, 12594; (g) Yu, D.-G.; Yu, M.; Guan, B.-T.; Li, B.-J.; Zheng,
Y.; Wu, Z.-H.; Shi, Z.-J. Org. Lett. 2009, 11, 3374; (h) Nakai, K.; Kurahashi, T.;
Matsubara, S. J. Am. Chem. Soc. 2011, 133, 11066; (i) Patra, T.; Agasti, S.;
Akanksha, ; Maiti, D. Chem. Commun. 2013, 69.
11. Selected examples for Rh-promoted CACN cleavage, see: (a) Taw, F. L.; White,
P. S.; Bergman, R. G.; Brookhart, M. J. Am. Chem. Soc. 2002, 124, 4192; (b) Taw, F.
L.; Mueller, A. H.; Bergman, R. G.; Brookhart, M. J. Am. Chem. Soc. 2003, 125,
9808; (c) Tobisu, M.; Kita, Y.; Chatani, N. J. Am. Chem. Soc. 2006, 128, 8152; (d)
Taw, F. L.; Mellows, H.; White, P. S.; Hollander, F. J.; Bergman, R. G.; Brookhart,
M.; Heinekey, D. M. J. Am. Chem. Soc. 2002, 124, 5100.
12. For Fe-promoted CACN cleavage, see: (a) Nakazawa, H.; Kawasaki, T.; Miyoshi,
K.; Suresh, C. H.; Koga, N. Organometallics 2004, 23, 117; (b) Nakazawa, H.;
Kamata, K.; Itazaki, M. Chem. Commun. 2005, 4004.
13. For other metal-promoted CACN cleavage, see: (a) Ochiai, M.; Hashimoto, H.;
Tobita, H. Angew. Chem., Int. Ed. 2007, 46, 8192; (b) Li, X.-Y.; Sun, H.-J.; Yu, F.-L.;
Flörke, U.; Klein, H.-F. Organometallics 2006, 25, 4695; (c) Xu, H.-W.; Williard, P.
G.; Bernskoetter, W. H. Organometallics 2012, 31, 1588; (d) Churchill, D.; Shin, J.
H.; Hascall, T.; Hahn, J. M.; Bridgewater, B. M.; Parkin, G. Organometallics 1999,
18, 2403; (e) Liu, Q.-X.; Xu, F.-B.; Li, Q.-S.; Song, H.-B.; Zhang, Z.-Z.
Organometallics 2004, 23, 610.
Scheme 2. Preliminary mechanistic studies.
O
R1
N
R2
CN
O2
O
R1
NH
R2
S
Cu(I)
S
7
Cu(II)
4
3
Cu Catalyst
CH3CN
tBuO-
CN
CN
N
Cu(III)
DTBP
N
Cu(II)
O
R1
S
R2
O
R1
6
S
R2
5
Scheme 3. Proposed mechanism.
quently, cyano radical reacts with 5 and formed Cu(III) species 6.
Finally, reduction elimination of 6 provides the desired products
7 and regenerates Cu(I).
In conclusion, we have developed an alternative strategy for the
N-cyanation of sulfoximines, which represents a significant and
practical progress to N-cyanation reaction. The procedure featured
a free-radical process, safe and cheap cyanide source, and good
functional group tolerance.
Acknowledgments
We thank the National Natural Science Foundation of China
(No. 21302015), the Natural Science Foundation for Colleges and
Universities of Jiangsu Province (No. 12KJB150005), Jiangsu
Planned Projects for Postdoctoral Research Fund No. 1501094B,
China Postdoctoral Science Foundation funded project, the Priority
Academic Program Development of Jiangsu Higher Education Insti-
tutions (PAPD) and Changzhou University (ZMF10020010) for
financial support.
Supplementary data
14. Luo, F.-H.; Chu, C.-I.; Cheng, C.-H. Organometallics 1998, 17, 1025.
15. Marlin, D. S.; Olmstead, M. M.; Mascharak, P. K. Angew. Chem., Int. Ed. 2001, 40,
4752.
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L.-Y.; Li, Y.; Zhuang, X.-M.; Jiang, L.; Chen, J.-M.; Luck, R. L.; Lu, T. Chem. Eur. J.
2009, 15, 12399.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.11.
025.
17. (a) Kou, X.; Zhao, M.; Qiao, X.; Zhu, Y.; Tong, X.; Shen, Z. Chem. Eur. J. 2013, 19,
16880; (b) Zhu, Y.; Zhao, M.; Lu, W.; Li, L.; Shen, Z. Org. Lett. 2015, 17, 2602.
18. Song, R.-J.; Wu, J.-C.; Liu, Y.; Deng, G.-B.; Wu, C.-Y.; Wei, W.-T.; Li, J.-H. Synlett
2012, 2491.
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