Copper-catalyzed N-cyanation of sulfoximines by AIBN

Article abstract of DOI:10.1021/jo502607c

The direct copper-catalyzed N-cyanation of sulfoximines was achieved by using AIBN as a safe cyanide source. It represents a simple and environmentally benign procedure for the construction of the N-CN bond. Furthermore, some sec-amines can also be tolera

Full text of DOI:10.1021/jo502607c

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Copper-Catalyzed N-Cyanation of Sulfoximines by AIBN
Fan Teng, Jin-Tao Yu, Zhou Zhou, Haoke Chu, and Jiang Cheng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502607c • Publication Date (Web): 10 Feb 2015
Downloaded from http://pubs.acs.org on February 18, 2015
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The Journal of Organic Chemistry
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CopperꢀCatalyzed NꢀCyanation of Sulfoximines by AIBN
Fan Teng,a JinꢀTao Yu,a Zhou Zhou,a Haoke Chu,a and Jiang Cheng*,a,b
10
a
School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology,
Changzhou University, Changzhou, 213164, P. R. China. b College of Chemistry and Life Sciences, Zhejiang Normal
University, Jinhua, 321004, P. R. China.
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jiangcheng@cczu.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the
journal that you are submitting your paper to)
ABSTRACT
The direct copperꢀcatalyzed Nꢀcyanation of sulfoximines was achieved by using AIBN as a safe cyanide source. It
represents a simple and environmentally benign procedure for the construction of NꢀCN bond. Furthermore, some secꢀ
amines can also be tolerated well under this procedure.
The NꢀCN bonds are ubiquitous and frequently found in innumerable natural products, biologically active molecules
and medicinally relevant structures (Scheme 1).1ꢀ5 For example, sulfoxaflor and thiacloprid play key roles in insecticide
field.6ꢀ7 Inhibitors of cathepsin K show efficiency on bone resorption,1 while inhibitors of cathepsin C are utilized in
neutrophilꢀdominated inflammatory diseases.5 Meanwhile, cyanamides are not only employed as ligands in coordinaꢀ
tion chemistry,8ꢀ11 but also the key intermediates leading to guanidines12ꢀ16 and heterocycles.17ꢀ24 Moreover, as a safe
cyanide source, cyanamides were widely applied in the cyanation reaction.25ꢀ28
Scheme 1 Bioactive Compounds Containing NꢀCN Bonds.
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To date, several elegant approaches have been developed in CꢀCN bond formation by safe cyanide sources.29ꢀ42
However, to the best of our knowledge, the construction of NꢀCN bond was generally limited to von Braun reaction,
where XCN (X= halo) was highly toxic.43ꢀ45 Very recently, we developed the formation of NꢀCN bond via oxidative
coupling using CuCN as cyanide source.46 In view of the toxicity of CuCN, the development of safe cyanide source in
NꢀCN bond formation is still highly promising.
Scheme 2 The Employment of AIBN as “CN” Source
AIBN was widely known as a radical initiator.47ꢀ48 However, recently, Han pioneered the application of AIBN as
“CN” source in the formation of CꢀCN bonds (Scheme 2, eq 1).49 Subsequently, we described an Sꢀcyanation reaction
by AIBN (Scheme 2, eq 2).50 Herein, we wish to report the employment of AIBN in Nꢀcyanation of sulfoximines
(Scheme 2, eq 3). Importantly, N-cyano sulfoximines have attracted significant attention in crop protection as promisꢀ
ing pesticides.6ꢀ7, 51
Table 1. Optimization of the Reaction Conditions a
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entry
catalyst
solvent
base
yield (%)
1
2
CuBr2
Cu(OAc)2
CuS
CuI
MeCN
MeCN
MeCN
MeCN
MeCN
DCM
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
ꢀꢀ
65
38
3
18
10
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12
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18
19
4
90 (20%)b(< 1)c
5
ꢀꢀ
< 1
< 1
18
6
CuI
7
CuI
1,4ꢀdioxane
MeOH
MeCN
MeCN
MeCN
MeCN
8
CuI
< 1
< 1
58
9
CuI
10
11
12
CuI
NaHCO3
K3PO4
TEA
CuI
67
CuI
80
20
a
o
Reaction conditions: 1a (0.2 mmol), AIBN (0.3 mmol), Cu catalyst (0.04 mmol), base (0.4 mmol), solvent (3.0 mL) at 75 C for 24 h,
under O2. b 50 oC. c Under N2.
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Initially, the reaction of sulfonimidoyldibenzene 1a with AIBN (1.5 equiv) was tested in the presence of two equivaꢀ
o
lents of K2CO3 and 0.2 equivalent of CuBr2 in MeCN at 75 C under O2. To our delight, the Nꢀcyanation product 2a
was isolated in 65% yield (Table 1, entry 1). Among copper salts screened, such as Cu(OAc)2, CuS and CuI (Table 1,
entries 2ꢀ4), CuI was the best, providing 2a in 90% yield. The reaction became sluggish at 50 oC and could not proceed
under N2 (Table 1, entry 4). Blank reaction indicated that no cyanation product was detected at all in the absence of
catalyst (Table 1, entry 5). Other common solvents, such as DCM, MeOH and 1,4ꢀdioxane, were found to be less efꢀ
fective or ineffective for this transformation (Table 1, entries 6ꢀ8). Further investigation implied base played a crucial
role in this reaction. No cyanation reaction took place in the absence of base (Table 1, entry 9). Other inorganic bases
or organic base, such as NaHCO3, K3PO4 or TEA, was inferior to K2CO3 (Table 1, entries 10ꢀ12).
Figure 1 Substrate Scope of Sulfoximines.a
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CuI (20 mol %)
R
R'
K2CO3 (2.0 equiv)
O
1
2
3
4
O
S
NH
+
S
CN
AIBN
N
MeCN, O2, 75 o
C
R
R'
1
2
5
6
7
O
S
O
S
O
S
N
CN
N
CN
N
CN
8
9
Cl
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Cl
2b 89%
2c 88%
2a 90%
O
S
O
S
O
N
N
CN
N
CN
CN
CN
CN
S
Ph
Cl
O
2d
92%
2e 56%
2f 85%
CN
CN
N
S
N
N
S
S
O
O
O
2g
56%
2h 75%
2i 42%
CN
CN
N
S
N
N
S
O
O
Cl
S
Bu
Br
O
O
2j 45%
2l 42%
2k 73%
a Reaction conditions: sulfoximine 1 (0.2 mmol), AIBN (0.3 mmol), CuI (0.04 mmol), K2CO3 (0.4 mmol), MeCN (3.0 mL) at 75 oC for 24
h, Under O2.
With the optimal conditions established, the substrate scope of sulfoximines was tested. Both diaryl and aryl alkyl
sulfoximines are tolerated well in this procedure (Figure 1), and most of the diaryl analogues provided target products
in excellent yields (2aꢀ2f). Besides, aryl alkyl sulfoximines provided the desired products in moderate to good yields
(2gꢀ2l). For example, 4ꢀchloro (Sꢀbutylsulfonimidoyl)benzene (1k) generated the cyanation product in 73% yield (2k).
Notably, substrates with halogen groups on the aromatic rings tolerated well (2c, 2i, 2k and 2l), which make the further
functionalization possible.
Figure 2 Substrate Scope of secꢀAmines, Imine and Guanidine.a
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a Reaction conditions: secꢀamine (0.2 mmol), AIBN (0.3 mmol), CuI (0.04 mmol), K2CO3 (0.4 mmol), MeCN (3.0 mL) at 75 oC for 12 h,
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Under O2.
In addition, some cyclic secꢀamines also ran smoothly under the standard procedure leading to corresponding Nꢀ
cyanation products in good to moderate yields (4a-4d, 4h). For example, 1,2,3,4ꢀtetrahydroisoqunoline could provide
the desired product 4h in 36% yield. However, noncyclic secꢀamines could not tolerate well, and only trace amount of
products were detected by GCꢀMS. Gratifyingly, this procedure could be applicable for Nꢀcyclohexylaniline (4f). Imꢀ
portantly, the substrate scope was not limited to secꢀamines, benzophenone imine also worked well under the standard
procedure as well (4e). Although we made great efforts in order to improve the yields of 4e and 4f, the results were still
unsatisfactory. Disappointedly, other secondary anilines such as Nꢀmethylaniline, diphenylamine, Nꢀethylaniline and
lactam derivatives could not proceed under standard conditions. To our delight, 1,1,3,3ꢀtetramethylguanidine delivered
the Nꢀcyanation product in 72% yield (4g).
To test the practicality of this procedure, a 2 mmol scale reaction was conducted and 2a was isolated in an excellent
84% yield.
Further experiments were carried out to gain insight into the mechanism. Firstly, after adding 4.0 equivalents of
TEMPO, the cyanation process of 3a was completely inhibited, which implied this procedure might contain a radical
pathway. As the byproduct, acetone was detected in this process by GCꢀMS (for details, see Supporting Information).
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Moreover, the cyanide anion was detected by indicating paper even in the absence of MeCN (for details, see Supportꢀ
ing Information).52
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6
Based on the aforementioned experimental results, the proposed mechanism is outlined in Scheme 3.
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Scheme 3. Plausible Mechanism.
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Base
Cu(II) + R1R2NH
O2
R1R2NCu(II)
AIBN
- N2
5
O2
CN
Cu(I)
R1R2NCN
6
O
O
7
CN
SET
R1R2NCu(III)CN
CN
O
8
Initially, under O2, the catalyst Cu(I) is oxidized to Cu(II). In the presence of base, the reaction between secꢀamine
and Cu(II) produces Cu(II) species 5. Meanwhile, 6 is formed by homolytic cleavage of the CꢀN bond of AIBN by libꢀ
erating one equivalent of N2. Then, in the presence of O2, intermediate 7 produces cyanide radical and extrudes one
equivalent of acetone.53 Subsequently, single electron transfer between Cu(II) intermediate 5 and the cyanide radical
takes place, and Cu(III) species 8 is formed. Finally, reduction elimination of 8 provides the desired products and reꢀ
generates Cu(I).
In conclusion, we have developed a facile approach leading to Nꢀcyanation compounds by AIBN as a safe cyanide
source. Sulfoximines, some secꢀamines as well as 1,1,3,3ꢀtetramethylguanidine are compatible with this procedure
well. In addition, the transformation employs O2 as the clean terminal oxidant under mild condition. Thus, it represents
an important and practical progress to Nꢀcyanation reaction.
EXPERIMENTAL SECTION
General Information: All chemicals were used as received without further purification unless stated otherwise. 1H
NMR and 13C NMR spectra were recorded at ambient temperature on a 300 or 400 MHz spectrometer (75 or 100 MHz
for 13C). NMR experiments are reported in δ units, parts per million (ppm), and were referenced to CDCl3 (δ 7.26 or
77.0 ppm) as the internal standard. The coupling constants J are given in Hz. Column chromatography was performed
using EM Silica gel 60 (300ꢀ400 meshes) or neutral aluminum oxide (200ꢀ300 meshes).
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General Procedure for 0.2 mmol Scale: Under O2, a 20 mL Schlenk tube equipped with a stir bar was charged
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with sulfoximine or secꢀamine (0.2 mmol), AIBN (0.3 mmol, 49.3 mg), CuI (0.04 mmol, 7.6 mg), K2CO3 (0.4 mmol,
55.3 mg) and CH3CN (3 mL), and sealed with a Teflon lined cap. The reaction mixture was stirred at 75 °C for 24 or
12 h in oil bath. After the completion of the reaction (monitored by TLC), the solvent was concentrated in vacuum and
the residue was purified by flash column chromatography on silica gel or Al2O3 with petroleum etherꢀethyl acetate as
the eluent to give the desired product.
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General Procedure for 2 mmol Scale: A 100 mL roundꢀbottom flask equipped with a stirꢀbar was charged with
sulfonimidoyldibenzene 1a (2 mmol, 434.6 mg), AIBN (3 mmol, 492.6 mg), CuI (0.4 mmol, 76 mg), K2CO3 (4 mmol,
552.8 mg) and CH3CN (30 mL). A balloon filled with oxygen gas was installed to the reaction flask. The reaction mixꢀ
ture was stirred at 75 °C for 24 h in oil bath. After the completion of the reaction (monitored by TLC), the solvent was
concentrated in vacuum and the residue was purified by flash column chromatography on silica gel with petroleum
etherꢀ ethyl acetate as the eluent to give 2a in 84% yield.
N-(Cyano) diphenyl sulfoximine (2a):46 Flash column chromatography on a silica gel (ethyl acetate: petroleum
o
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ether, 1: 6) give the product (44.0 mg, 90% yield) as a white solid; m.p.: 104ꢀ106 C (lit.: 108ꢀ110 ºC) H NMR
(CDCl3, 400 MHz) δ 7.56ꢀ7.60 (m, 4H), 7.65ꢀ7.69 (m, 2H), 7.97ꢀ7.99 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 111.9,
127.7, 129.9, 134.7, 137.1.
N-(Cyano)-4,4’-dimethyldiphenyl sulfoximine (2b): Flash column chromatography on a silica gel (ethyl acetate:
petroleum ether, 1: 6) give the product (48.2 mg, 89% yield) as a yellowish solid; m.p.: 103ꢀ105 oC. 1H NMR (CDCl3,
400 MHz) δ 2.41 (s, 6H), 7.35ꢀ7.37 (m, 4H), 7.83ꢀ7.85 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 21.5, 112.2, 127.7,
130.5, 134.4, 146.0. MS (EI): 270 (M+); HRMS (ESI) m/z calcd for C15H15N2OS (M+H)+ 271.0900, found 271.0893.
IR (KBr): 3086, 3065, 3038, 2982, 2924, 2197, 1591, 1491.
N-(Cyano)-4,4’-dichlorodiphenyl sulfoximine (2c):46 Flash column chromatography on a silica gel (ethyl acetate:
o
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petroleum ether, 1: 6) give the product (54.6 mg, 88% yield) as a white solid; m.p.: 131ꢀ134 C (lit.: 137ꢀ139 ºC). H
NMR (CDCl3, 300 MHz) δ 7.58 (d, J = 8.8 Hz, 4H), 7.92 (d, J = 8.8 Hz, 4H); 13C NMR (CDCl3, 75 MHz) δ 111.2,
129.3, 130.5, 135.3, 142.2.
N-(Cyano)-4-methyldiphenyl sulfoximine (2d): Flash column chromatography on a silica gel (ethyl acetate: petroꢀ
1
leum ether, 1: 5) give the product (47.1 mg, 92% yield) as a yellowish liquid. H NMR (CDCl3, 400 MHz) δ 2.42 (s,
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3H), 7.37ꢀ7.39 (m, 2H), 7.55ꢀ7.59 (m, 2H), 7.64ꢀ7.68 (m, 1H), 7.85ꢀ7.87 (m, 2H), 7.95ꢀ7.98 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ 21.6, 112.1, 127.6, 127.9, 129.9, 130.6, 134.0, 134.5, 137.6, 146.2. MS (EI): 256 (M+); HRMS
(ESI) m/z calcd for C14H13N2OS (M+H)+ 257.0743, found 257.0746. IR (KBr): 3088, 3063, 2922, 2850, 2197, 1593,
1475, 1446.
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N-(Cyano)-4-methoxy diphenyl sulfoximine (2e): Flash column chromatography on a silica gel (ethyl acetate:
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petroleum ether, 1: 2) give the product (30.5mg, 56% yield) as a yellowish liquid; m.p.: 99ꢀ101 oC. H NMR (CDCl3,
400 MHz) δ 3.86 (s, 3H), 7.03ꢀ7.05 (m, 2H), 7.55ꢀ7.59 (m, 2H), 7.63ꢀ7.67 (m, 1H), 7.90ꢀ7.96 (m, 4H); 13C NMR
(CDCl3, 100 MHz) δ 55.9, 112.2, 115.3, 127.5, 127.7, 129.9, 130.3, 134.4, 138.1, 164.6. MS (EI): 272 (M+); HRMS
(ESI) m/z calcd for C14H13N2O2S (M+H)+ 273.0692, found 293.0693. IR (KBr): 3096, 3065, 2943, 2843, 2197, 1591,
1494.
N-(Cyano)-4-phenyl diphenyl sulfoximine (2f): Flash column chromatography on a silica gel (ethyl acetate: peꢀ
o
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troleum ether, 1: 5) give the product (54.1 mg, 85% yield) as a yellowish solid; m.p.: 132ꢀ135 C. H NMR (CDCl3,
400 MHz) δ 7.43ꢀ7.50 (m, 3H), 7.56ꢀ7.57 (m, 2H), 7.60ꢀ7.63 (m, 2H), 7.68ꢀ7.71 (m, 1H), 7.77ꢀ7.79 (m, 2H), 8.03ꢀ8.06
(m, 4H); 13C NMR (CDCl3, 100 MHz) δ 112.0, 127.3, 127.8, 128.4, 128.5, 129.0, 129.1, 130.0, 134.7, 135.5, 137.4,
138.4, 147.8. MS (EI): 318 (M+); HRMS (ESI) m/z calcd for C19H15N2OS (M+H)+ 319.0900, found 319.0901. IR
(KBr): 3088, 3059, 3001, 2959, 2201, 1593, 1446.
N-(Cyano) methyl phenyl sulfoximine (2g):46 Flash column chromatography on a silica gel (ethyl acetate: petroleꢀ
o
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um ether, 1: 2.5) give the product (20.1 mg, 56% yield) as a white solid; m.p.: 66ꢀ69 C (lit.: 68ꢀ70 ºC). H NMR
(CDCl3, 400 MHz) δ 3.34 (s, 3H), 7.66ꢀ7.70 (m, 2H), 7.76ꢀ7.80 (m, 1H), 7.98ꢀ8.00 (m 2H); 13C NMR (CDCl3, 100
MHz) δ 44.7, 111.8, 127.8, 130.2, 135.4, 135.9.
N-(Cyano) methyl 4-methylphenyl sulfoximine (2h):46 Flash column chromatography on a silica gel (ethyl acetate:
petroleum ether, 1: 2) give the product (29.0 mg, 75% yield) as a white solid; m.p.: 78ꢀ81 oC (lit.: 84ꢀ86 ºC). 1H NMR
(CDCl3, 400 MHz) δ 2.48 (s, 3H), 3.31 (s, 3H), 7.46 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 8.3 Hz, 2H); 13C NMR (CDCl3,
100 MHz) δ 21.7, 44.8, 112.0, 127.8, 130.8, 132.7, 146.9.
N-(Cyano) methyl 4-chlorophenyl sulfoximine (2i):46 Flash column chromatography on a silica gel (ethyl acetate:
o
1
petroleum ether, 1: 2) give the product (18.0 mg, 42% yield) as a white solid; m.p.: 99ꢀ102 C (lit.: 108ꢀ110 ºC). H
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NMR (CDCl3, 400 MHz) δ 3.35 (s, 3H), 7.66 (d, J = 8.7 Hz, 2H), 7.94 (d, J = 8.6 Hz, 2H); 13C NMR (CDCl3, 100
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2
3
MHz) δ 44.8, 111.4, 129.4, 130.6, 134.4, 142.6.
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5
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N-(Cyano) methyl 4-methoxyphenyl sulfoximine (2j):51 Flash column chromatography on a silica gel (ethyl aceꢀ
o
tate: petroleum ether, 1: 2) give the product (19.0 mg, 45% yield) as a yellow solid; m.p.: 97ꢀ99 C (lit.: 102ꢀ103 ºC).
8
1H NMR (CDCl3, 400 MHz) δ 3.31 (s, 3H), 3.91 (s, 3H), 7.11 (d, J = 8.9 Hz, 2H), 7.90 (d, J = 9.0 Hz, 2H); 13C NMR
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(CDCl3, 100 MHz) δ 45.2, 56.0, 112.1, 115.5, 126.6, 130.2, 165.1.
N-(Cyano) butyl 4-chlorophenyl sulfoximine (2k): Flash column chromatography on a silica gel (ethyl acetate: peꢀ
o
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troleum ether, 1: 3) give the product (37.3 mg, 73% yield) as a yellow solid; m.p.: 89ꢀ91 C. H NMR (CDCl3, 400
MHz) δ 0.88ꢀ0.92 (m, 3H), 1.36ꢀ1.46 (m, 2H), 1.63ꢀ1.78 (m, 2H), 3.27ꢀ3.45 (m, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.88 (d,
J = 8.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 13.3, 21.1, 24.1, 56.5, 111.7, 129.9, 130.5, 133.0, 142.4. MS (EI): 256
(M+); HRMS (ESI) m/z calcd for C11H14ClN2OS (M+H)+ 257.0510, found 257.0509. IR (KBr): 3096, 2964, 2941,
2901, 2189. 1574, 1470, 1456.
N-(Cyano) methyl 4-bromophenyl sulfoximine (2l): Flash column chromatography on a silica gel (ethyl acetate:
o
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petroleum ether, 1: 2) give the product (21.7 mg, 42% yield) as a yellow solid; m.p.: 102ꢀ105 C. H NMR (CDCl3,
400 MHz) δ 3.34 (s, 3H) 7.81ꢀ7.87 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 44.7, 111.4, 129.4, 131.3, 133.6, 135.0.
MS (EI): 257 (M+); HRMS (ESI) m/z calcd for C8H8BrN2OS (M+H)+ 258.9535, found 258.9534. IR (KBr): 3086,
3022, 2999, 2916, 2195. 1570, 1466.
Octahydroquinoline-1(2H)-carbonitrile (4a):46 Flash column chromatography on an Al2O3 (ethyl acetate: petroleꢀ
um ether, 1: 10) give the product (23.1 mg, 70% yield) as a yellowish liquid. 1H NMR (CDCl3, 300 MHz) δ 0.90ꢀ1.10
(m, 2H), 1.18ꢀ1.42 (m, 4H), 1.65ꢀ1.68 (m, 5H), 1.83ꢀ1.88 (m, 1H), 2.04ꢀ2.08 (m, 1H), 2.39ꢀ2.46 (m, 1H), 2.96ꢀ3.06 (m,
1H), 3.41ꢀ3.46 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 24.7, 25.0, 25.3, 30.0, 31.0, 32.0, 40.9, 51.2, 62.3, 116.8.
4-Phenylpiperidine-1-carbonitrile (4b):46 Flash column chromatography on a silica gel (ethyl acetate: petroleum
ether, 1: 15) give the product (20.4 mg, 55% yield) as a white solid; m.p.: 69ꢀ71 oC (lit.: 68ꢀ71 ºC). 1H NMR (CDCl3,
300 MHz) δ 1.82ꢀ1.89 (m, 4H), 2.58ꢀ2.63 (m, 1H), 3.10ꢀ3.20 (m, 2H), 3.51ꢀ3.57 (m, 2H), 7.18ꢀ7.26 (m, 3H), 7.31ꢀ7.36
(m, 2H); 13C NMR (CDCl3, 75 MHz) δ 32.0, 41.2, 50.0, 118.3, 126.6, 126.7, 128.7, 144.5.
1-(Pyridin-4-yl)piperazine-1-carbonitrile (4c): Flash column chromatography on a silica gel (ethyl acetate: petroꢀ
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leum ether: triethylamine, 20: 10: 1) give the product (20.6 mg, 55% yield) as a yellowish solid; m.p.: 64ꢀ67 C. H
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NMR (CDCl3, 300MHz) δ 3.34ꢀ3.44 (m, 8H), 6.66 (q, J = 2.2 Hz, 2H), 8.31 (q, J = 2.2 Hz, 2H); 13C NMR (CDCl3,
100 MHz) δ 45.3, 48.3, 108.9, 116.8, 150.4, 154.4. MS (EI): 188 (M+). HRMS (ESI) m/z calcd for C10H13N4 (M+H)+
189.1135, found 189.1130. IR (KBr): 3049, 3009, 2976, 2868, 2214, 1603, 1516.
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Thiomorpholine-4-carbonitrile (4d):46 Flash column chromatography on a silica gel (ethyl acetate: petroleum ether,
o
1: 10) give the product (14.6 mg, 57% yield) as a white solid; m.p.: 41ꢀ43 C (lit.: 42ꢀ44 ºC).1H NMR (CDCl3, 400
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MHz) δ 2.70 (t, J = 5.1 Hz, 4H), 3.46 (t, J = 5.1 Hz, 4H); 13C NMR (CDCl3, 100 MHz) δ 26.1, 50.8, 117.3.
N-(diphenylmethylene)cyanamide (4e): Flash column chromatography on a silica gel (ethyl acetate: petroleum
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ether, 1: 20) give the product (12.4 mg, 30% yield) as a yellowish solid; m.p.: 76ꢀ78 C (lit.54: 78ꢀ79 ºC). H NMR
(CDCl3, 400 MHz) δ 7.45ꢀ7.49 (m, 2H), 7.56ꢀ7.57 (m, 4H), 7.63ꢀ7.67 (m, 2H), 7.80ꢀ7.82 (m, 2H); 13C NMR (CDCl3,
100 MHz) δ 114.6, 128.7, 131.2, 132.2, 134.4, 189.5. MS (EI): 206 (M+); HRMS (ESI) m/z calcd for C14H11N2
(M+H)+ 207.0917, found 207.0903. IR (KBr): 3085, 2920, 2856, 2176, 1595, 1581, 1549, 1446.
Cyclohexanecarbamonitrile (4f): Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:
1
80) give the product (14.5 mg, 36% yield) as a yellowish liquid. H NMR (CDCl3, 400 MHz) δ 1.17ꢀ1.28 (m, 2H),
1.32ꢀ1.42 (m, 2H), 1.64ꢀ1.72 (m, 2H), 1.89ꢀ1.93 (m, 2H), 2.07ꢀ2.10 (m, 2H), 3.52ꢀ3.60 (m, 1H), 7.07ꢀ7.11 (m, 1H),
7.14ꢀ7.16 (m, 2H), 7.34ꢀ7.38 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 25.0, 25.3, 31.0, 57.6, 112.5, 117.1, 123.7,
129.6, 140.0. MS (EI): 200 (M+); HRMS (ESI) m/z calcd for C13H17N2 (M+H)+ 201.1386, found 201.1382. IR (KBr):
3083, 3008, 2933, 2856, 2212, 1597, 1495.
2-Cyano-1,1,3,3-tetramethylguanidine (4g):46 Flash column chromatography on a silica gel (ethyl acetate: petroleꢀ
1
um ether: triethylamine, 20: 10: 1) give the product (20.3 mg, 72% yield) as a yellow liquid. H NMR (CDCl3, 400
MHz) δ 2.91 (s, 12H); 13C NMR (CDCl3, 100 MHz) δ 39.8, 117.6, 166.0.
3,4-Dihydro-2(1H)-isoquinolinecarbonitrile (4h):46 Flash column chromatography on a silica gel (ethyl acetate:
petroleum ether, 1: 10) give the product (11.4 mg, 36% yield) as a white solid; m.p.: 63ꢀ65 oC (lit.: 68ꢀ70 ºC).1H NMR
(CDCl3, 400 MHz) δ 2.96 (t, J = 5.9 Hz, 2H), 3.48 (t, J = 5.9 Hz, 2H), 4.41 (s, 2H), 7.03ꢀ7.05 (m, 1H), 7.13ꢀ7.15 (m,
1H), 7.19ꢀ7.22 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 27.5, 46.7, 49.9, 117.9, 125.9,126.6, 127.1, 129.1, 130.6,
132.5.
ACKNOWLEDGMENT
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The Journal of Organic Chemistry
We thank the National Natural Science Foundation of China (nos. 21272028 and 21202013), “Innovation & Entrepreꢀ
neurship Talents” Introduction Plan of Jiangsu Province, Jiangsu Key Laboratory of Advanced Catalytic Materials
&Technology (BM2012110), Jiangsu Province Key Laboratory of Fine Petrochemical Engineering and the Priority
Academic Program Development of Jiangsu Higher Education Institutions and Open Research Fund of Top Key Disꢀ
cipline of Chemistry in Zhejiang Provincial Colleges for financial support.
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Supporting Information:
Experimental details on the mechanism study, along with copies of 1H and 13C NMR spectra of products. This material
is available free of charge via the Internet at http://pubs.acs.org.
REFERENCES
(1) 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.
(2) Carta, F.; Akdemir, A.; Scozzafava, A.; Masini, E.; Supuran, C. T. J. Med. Chem. 2013, 56, 4691.
(3) Kumar, R.; Rai, D.; Sharma, S. K.; Saffran, H. A.; Blush, R.; Tyrrell, D. L. J. J. Med. Chem. 2001, 44, 3531.
(4) Guay, D.; Beaulieu, C.; Percival, M. D. Curr. Top. Med. Chem. 2010, 10, 708.
(5) 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.; Midgett, R.; Kmett, C.; Umbrecht, S.; Peck, B.; Davis,
A. B.; Bettoun, D. ACS Med. Chem. Lett. 2011, 2, 142.
(6) Sparks, T. C.; Watson, G. B.; Loso, M. R.; Geng, C.; Babcock, J. M.; Thomas, J. D. Pestic. Biochem. Physiol.
2013, 107, 1.
(7) Park, S. J.; Baars, H.; Mersmann, S.; Buschmann, H.; Baron, J. M.; Amann, P. M.; Czaja, K.; Hollert, H.; Bluhm,
K.; Redelstein, R.; Bolm, C. ChemMedChem 2013, 8, 217.
(8) Harb, C.; Kravtsov, P.; Choudhuri, M.; Sirianni, E. R.; Yap, G. P. A.; Lever, A. B. P.; Crutchley, R. J. Inorg.
Chem. 2013, 52, 1621.
(9) Xiang, J.; Man, W.ꢀL.; Yiu, S.ꢀM; Peng, S.ꢀM.; Lau, T.ꢀC. Chem.—Eur. J. 2011, 17, 13044.
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Page 12 of 14
(10) Lindsey, C. C.; O’Boyle, B. M.; Mercede, S. J.; Pettus, T. R. R.; Crutchley, R. J. Coord. Chem. Rev. 2001, 219,
1
2
3
125.
4
5
6
7
8
(11) Kang, L.ꢀC.; Chen, X.; Wang, X.ꢀS.; Li, Y.ꢀZ.; Song, Y.; Zuo, J.ꢀL.; You, X.ꢀZ. Dalton Trans. 2011, 40, 5200.
(12) Maestri, G.; Larraufie, M.ꢀH.; Ollivier, C.; Malacria, M.; Fensterbank, L.; Lacôte, E. Org. Lett. 2012, 14, 5538.
(13) Larraufie, M.ꢀH.; Ollivier, C.; Fensterbank, L.; Malacria, M.; Lacôte, E. Angew. Chem., Int. Ed. 2010, 49, 2178.
(14) Larraufie, M.ꢀH.; Maestri, G.; Malacria, M.; Ollivier, C.; Fensterbank, L.; Lacôte, E. Synthesis 2012, 44, 1279.
(15) Nekrasov, D. D. Russ. J. Org. Chem. 2004, 40, 1387.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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33
34
35
36
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(16) Nekrasov, D. D. Chem. Heterocycl. Compd. 2004, 40, 1107.
(17) Boñaga, L. V. R.; Zhang, H.ꢀC.; Maryanoff, B. E. Chem. Commun. 2004, 2394.
(18) Lane, T. K.; Nguyen, M. H.; D’Souza, B. R.; Spahn, N. A.; Louie, J. Chem. Commun. 2013, 49, 7735.
(19) Habibi, D.; Nasrollahzadeh, M.; Sahebekhtiari, H.; Sajadi, S. M. Synlett 2012, 23, 2795.
(20) Stolley, R. M.; Maczka, M. T.; Louie, J. Eur. J. Org. Chem. 2011, 3815.
(21) Wang, C.; Wang, D.; Xu, F.; Pan, B.; Wan, B. J. Org. Chem. 2013, 78, 3065.
(22) Lane, T. K.; D’Souza, B. R.; Louie, J. J. Org. Chem. 2012, 77, 7555.
(23) Wong, B.; Stumpf, A.; Carrera, D.; Gu, C.; Zhang, H. Synthesis 2013, 45, 1083.
(24) Katla, V. R.; Syed, R.; Kuruva, C. S.; Kuntrapakam, H. K.; Chamarthi, N. R. Chem. Pharm. Bull. 2013, 61, 25.
(25) Wang, R.; Falck, J. R. Chem. Commun. 2013, 49, 6516.
(26) Gong, T.ꢀJ.; Xiao, B.; Cheng, W.ꢀM.; Su, W.; Xu, J.; Liu, Z.ꢀJ.; Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013, 135,
10630.
(27) Chaitanya, M.; Yadagiri, D.; Anbarasan, P. Org. Lett. 2013, 15, 4960.
(28) Han, J.; Pan, C.; Jia, X.; Zhu, C. Org. Biomol. Chem. 2014, 12, 8603.
(29) Zhang, G.; Ren, X.; Chen, J.; Hu, M.; Cheng. J. Org. Lett. 2011, 13, 5004.
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(30) Liu, B.; Wang, J.; Zhang, B.; Sun, Y.; Wang, L.; Chen, J.; Cheng, J. Chem. Commun. 2014, 50, 2315.
(31) Jin, J.; Wen, Q.; Lu, P.; Wang, Y. Chem. Commun. 2012, 48, 9933.
(32) Ding, S.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374.
1
2
3
4
5
6
7
8
9
(33) Ren, X.; Chen, J.; Chen, F.; Cheng, J. Chem. Commun. 2011, 47, 6725.
(34) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 10272.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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48
49
50
51
52
53
54
55
56
57
58
59
60
(35) Zhang, G.; Chen, S.; Fei, H.; Cheng, J.; Chen, F. Synlett 2012, 2247.
(36) Kou, X.; Zhao, M.; Qiao, X.; Zhu, Y.; Tong, X.; Shen, Z. Chem.—Eur. J. 2013, 19, 16880.
(37) Wen, Q.; Jin, J.; Mei, Y.; Lu, P.; Wang Y. Eur. J. Org. Chem. 2013, 4032.
(38) Zhang, L.; Wen, Q.; Jin, J.; Wang, C.; Lu, P.; Wang Y. Tetrahedron 2013, 69, 4236.
(39) Pan, C.; Jin, H.; Xu, P.; Liu, X.; Cheng, Y.; Zhu, C. J. Org. Chem. 2013, 78, 9494.
(40) Song, R.ꢀJ.; Wu, J.ꢀC.; Liu, Y.; Deng, G.ꢀB.; Wu, C.ꢀY. Wei, W.ꢀT.; Li, J.ꢀH. Synlett 2012, 2491.
(41) Chen, X.; Hao, X.ꢀS.; Goodhue, C. E.; Yu, J.ꢀQ. J. Am. Chem. Soc. 2006, 128, 6790.
(42) Kou, X.; Zhao, M.; Qiao, X.; Zhu, Y.; Tong, X.; Shen, Z. Chem. Eur. J. 2013, 19, 16880ꢀ16886.
(43) von Braun, J. Ber. 1907, 40, 3914.
(44) Hageman, H. A. Org. React. 1953, 7, 198.
(45) Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279.
(46) Teng, F.; Yu, J.ꢀT.; Jiang, Y.; Yang, H.; Cheng, J. Chem. Commun. 2014, 50, 8412.
(47) Oba, T.; Tateno, Y.; Ihara, M.; Fukusumi, T.; Takei, N.; Ito, S. Tetrahedron Lett. 2014, 55, 725.
(48) Schröder, K.; Konkolewicz, D.; Poli, R.; Matyjaszewski, K. Organometallics 2012, 31, 7994.
(49) Xu, H.; Liu, P.ꢀT.; Li, Y.ꢀH.; Han, F.ꢀS. Org. Lett. 2013, 15, 3354.
(50) Teng, F.; Yu, J.ꢀT.; Jiang, Y.; Yang, H.; Cheng, J. Chem. Commun. 2014, 50, 12139.
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(51) Mancheño, O. G.; Bistri, O.; Bolm, C. Org. Lett. 2007, 9, 3809.
1
2
3
4
5
6
7
8
9
(52) For the cyanation reaction using MeCN as cyanide source, please see refs 39, 41 and 42.
(53) Janzen, E. G.; Krygsman, P. H.; Lindsay, D. A.; Haire, D. L. J. Am. Chem. Soc. 1990, 112, 8279.
(54) Jochims, J. C.; Rahman, M. A. Chem. Ber. 1984, 117, 502.
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