The synthesis of 2-(Arylthio)arylcyanamides via copper-catalyzed domino intermolecular c-s cross-coupling reaction of 2-aminobenzothiazoles with aryl iodides

Article abstract of DOI:10.1080/10426507.2012.755973

A series of 2-(arylthio)arylcyanamide derivatives were obtained in excellent yields via a copper-catalyzed domino C-S cross-coupling of 2-aminobenzothiazoles with aryl iodides. This reaction occurred via an intermolecular C-S bond formation, associated with C-S bond cleavage, followed by an intermolecular S-arylation under ligand-free conditions. Their structures were unambiguously determined by the analytic tools, such as HRMS, ¹H, and ¹³C NMR analysis.

Full text of DOI:10.1080/10426507.2012.755973

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Phosphorus, Sulfur, and Silicon and the Related
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The Synthesis of 2-(Arylthio)arylcyanamides via
Copper-Catalyzed Domino Intermolecular C-S Cross-
Coupling Reaction of 2-Aminobenzothiazoles with Aryl
Iodides
Yin-Lin Shao a , Xiao-Hong Zhang a , Jiang-Sheng Han a & Ping Zhong a b
a College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, 325035,
China
b Oujiang College, Wenzhou University, Wenzhou, 325035, China
Accepted author version posted online: 02 Jan 2013.
To cite this article: Yin-Lin Shao , Xiao-Hong Zhang , Jiang-Sheng Han & Ping Zhong (2013): The Synthesis of 2-
(Arylthio)arylcyanamides via Copper-Catalyzed Domino Intermolecular C-S Cross-Coupling Reaction of 2-Aminobenzothiazoles
with Aryl Iodides, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:10.1080/10426507.2012.755973
To link to this article: http://dx.doi.org/10.1080/10426507.2012.755973
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The Synthesis of 2-(Arylthio)arylcyanamides via Copper-Catalyzed Domino Intermolecular
C-S Cross-Coupling Reaction of 2-Aminobenzothiazoles with Aryl Iodides
Yin-Lin Shao1, Xiao-Hong Zhang*1, Jiang-Sheng Han1, Ping Zhong*1,2
1 College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
2 Oujiang College, Wenzhou University, Wenzhou 325035, China
Author to whom correspondence should be addressed; E-Mail: kamenzxh@163.com;
zhongp0512@163.com;Tel.:+86-0577-86689338; Fax: +86-0577-86689338.
CN
I
NH
S
N
Cu, base
NH2
+
solvent, 80oC
S
1a
2a
3
Abstract: A series of 2-(arylthio)arylcyanamides derivatives were obtained in excellent yields via
a copper-catalyzed domino C-S cross-coupling of 2-aminobenzothiazoles with aryl iodides. This
reaction occurred via an intermolecular C-S bond formation, associated with C-S bond cleavage,
followed by an intermolecular S-arylation under ligand-free conditions. Their structures were
unambiguously determined by the analytic tools, such as HRMS, 1H and 13C NMR analysis.
Key words: 2-(Arylthio)arylcyanamides, synthesis, 2-Aminobenzothiazoles, Aryl Iodides
INTRODUCTION
It is well known that many arylthio derivatives are found to exhibit a broad range of biological
activities, including antifungal,1-4 antimicrobial,5 insecticidal activities6 and were used as the
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antagonist agents7 or inhibitors of HIV-1.8,9 Similarly, compounds containing a cyanamide
functional group have received great attention due to their special structure, reactivity and
biological activities.10-12 For example, cyanamides were used as N-donor ligands,13
dehydrogenase14 or cathepsin K15,16 inhibitors, as well as precursors for the synthesis of
biologically active heterocyclic compounds such as tetrazole17-19 or carbazide.20 Due to their great
utility, various approaches for the construction of arylthio and cyanamide scaffolds have been
reported one after another. Generally speaking, cyanamide derivatives can be obtained in good
yields from isocyanate,21 isothiocyanate,22 dithiocarbamate23,24 and amine.25-27 Among the
methods for the synthesis of arylthio derivatives, a transition-metal catalyzed cross-coupling
reaction was found to be the most efficient for the formation of C-S bond.28-37 However, the
synthesis of these two aforementioned moieties containing 2-(arylthio)arylcyanamides were
rarely reported. Only Punniyamurthy’s groups38-39 and Patel’s40 respectively demonstrated the
copper-catalyzed multistep synthesis of 2-(arylthio)arylcyanamides from the reaction of
2-(iodoaryl)thioureas with iodobenzene under ligand-assisted or ligand-free condition. However,
Punniyamurthy’s and Patel’s methods suffered from some intrinsic shortcomings, including the
commercially unavailability of starting materials (2-(iodoaryl)thioureas) and the poor atom
economy owing to the loss of iodine atom. As a continued work for the synthesis of
2-(arylthio)arylcyanamides and considering the easily available prosperity as well as the atom
economic efficiency, 2-aminobenzothiazoles were directly used as the precursors to synthesize
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2-(arylthio)arylcyanamides derivatives. Herein, the CuI-catalyzed cross-coupling of iodobenzene
with commercially available 2-aminobenzothiazoles to give 2-(arylthio)arylcyanamide
derivatives under ligand-free condition is reported in detail.
RESULTS and DISCUSSION
Our investigation started with the reaction of 2-aminobenzothiazole (1a) and iodobenzene (2a)
under N2 to screen the optimal reaction conditions (Table 1). Various bases were firstly surveyed
using CuI as catalyst, CH3CN as solvent at 80°C (entries 1-5). It can be seen that the strong base
benefits the success of the C-S cross-coupling reaction compared with the weak base. t-BuOK
proved to be the most effective (entry 2) whereas no desired 2-(phenylthio)phenylcyanamide (3)
can be obtained using NaHCO3 instead of t-BuOK (entry 4). When the experiments proceeded
under air, the corresponding yield of 3 decreased to 51% (entry 2). Subsequently, different
solvents were also screened (entries 6-10), and DMSO was shown to be most suitable, affording
the product 3 in 90% yield (entry 10). When the amount of t-BuOK was then decreased to 1 equiv,
only 69% yield of the cross-coupling product could be obtained (entry 10). Cu catalysts, such as
Cu(I) and Cu(II), such as Cu(OTf)2, Cu(OAc)2, CuSO4, CuO, CuBr2, CuBr and CuCl were tested
to give much lower yield of the cross-coupling product relative to CuI (entries 11-17). The
controlled experiment confirmed that no reaction occurred in the absence of Cu source (entry 18).
With the optimal reaction conditions, the electronic and steric effects of substituted aryl iodides
were next investigated (Table 2). As expected, various aryl iodides containing 4-CH3, 4-OCH3,
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2-OCH3, 3-CH3, 4-Cl, 2-Br, 4-F, 4-Cl-2-OCH3 moieties proceeded reactions with
2-aminobenzothiazole to give the corresponding 2-(arylthio)arylcyanamides in 51-95% yields.
These results demonstrated that the reaction seemed to be sensitive to the electronic effects in the
aromatic ring of aryl iodides. For example, aryl iodides having electron-donating substituents
(entries 1-5), such as methyl and methoxyl, gave higher yields than their chloro, fluoro and bromo
equivalents (entries 6-9). Gratifyingly, 1-iodonaphthalene was also tolerated in this process,
affording the product 12 in 75% yield (entry 10), showing that the domino cross-coupling reaction
is possible even in cases where steric hindrance from aryl iodides is increased. Nevertheless, when
2-aminobenzothiazole (1a) was reacted with bromobenzene instead of iodobenzene under the
optimal conditions, no target product can be obtained (entry 11).
Encouraged by these results, 6-methyl-2-aminobenzothiazole (1b),
5-bromo-2-aminobenzothiazole (1c), 6-nitro-2-aminobenzothiazole (1d) and
6-ethoxyl-2-aminobenzothiazole (1e) were examined with respect to various aryl iodides to
synthesize 2-(arylthio)arylcyanamides compounds (Table 3). As in previous studies, when
reacting with the identical 2-aminobenzothiazole derivatives, aryl iodides having
electron-donating groups favored the domino cross-coupling reaction over those with
electro-withdrawing substituents (entries 1-7, 8-14, 16-21). For example, more than 85% yields of
2-(arylthio)arylcyanamides compounds can be obtained using methyliodobenzenes or
methoxyliodobenzenes as the aryl iodides, whereas 74%, 75% and a trace of the targeted products
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were gained when chloroiodobenzenes reacted with 1b, 1c and 1e, respectively (entries 6, 11, 21).
The CH3 group on C-6 position of 2-aminobenzothiazole derivatives (entries 1-7) showed slightly
higher reactivity than Br group on C-5 (entries 8-14). Nevertheless, apart from
6-methyl-2-aminobenzothiazole (1b) and 5-bromo -2-aminobenzothiazole (1c),
6-ethoxyl-2-aminobenzothiazole (1e) provided the desired products in a lower yields ranging from
47-64% (entries 16-21), whereas 6-nitro-2-aminobenzothiazole (1d) remained intact during the
procedure and no trace of the corresponding product can be found (entry 15).
In summary, as
a
continued work for synthesis of 2-(arylthio)arylcyanamides,
2-aminobenzothiazoles were directly used as the precursors to afford target compounds under
ligand-free conditions. The interesting ring-open reaction was carried out via copper-catalyzed
intermolecular C-S bond formation, associated with C-S bond cleavage, followed by an
intermolecular S-arylation. And this protocol has the merits of using a commercially available
starting materials and good atom economy.
EXPERIMENTAL
Chemicals were either purchased or purified by standard techniques. The 1H NMR and 13C NMR
spectra were recorded in CDCl3 or CO(CD3)2 at 500 and 125 MHz, respectively, with TMS as the
internal standard at room temperature. The high resolution mass spectra (HRMS) were obtained on
an ESI-Q-Tof instrument.
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The general synthesis procedure of 2-(arylthio)arylcyanamides is described as follows: A mixture
of PhI (0.3 mmol), benzothiazol-2-ylamine (0.3 mmol), t-BuOK (0.6 mmol) and CuI (15 mmol%)
was stirred in DMSO (3 mL) under N2 at 80 for 10 h until complete consumption of starting
material as monitored by TLC or GC-MS analysis. After the reaction was finished, the mixture
was poured into saturated NaCl and extracted with EtOAc (310 mL). The organic layers were
dried over anhydrous MgSO4 and evaporated under vacuum. The residue was purified by flash
column chromatography (hexane/ethyl acetate) to afford the products.
2-(phenylthio)phenylcyanamide (3)40
2-(4-methylphenylthio)phenylcyanamide (4)40
2-(4-methoxylphenylthio)phenylcyanamide (5): Gummy liquid; 73 mg, 95%; 1H NMR (500
MHz, CO(CD3)2 δ ppm = 3.64 (s, 3H, OCH3), 6.76-7.38 (m, 8H, ArH), 8.43 (s, 1H, NH); 13C
NMR (125 MHz, CO(CD3)2): 55.7, 111.6, 116.0, 116.1, 121.8, 124.6, 126.0, 131.5, 132.5, 136.9,
140.6, 160.4; HRMS (ESI) Calcd for C14H13N2OS 257.0743; Found 257.0738.;
2-(2-methoxylphenylthio)phenylcyanamide (6): White solid; 72 mg, 94%; mp 106-107 oC 1H
NMR (500 MHz, CO(CD3)2) δ: 3.76 (s, 3H, OCH3), 6.51-7.45 (m, 8H, ArH), 8.41 (s, 1H, NH);
13C NMR (125 MHz, CO(CD3)2) δ: 56.3, 111.5, 111.9, 116.0, 118.3, 122.2, 124.7, 124.9, 128.3,
128.5, 132.4, 138.6, 142.2, 157.3; HRMS (ESI) Calcd for C14H13N2OS 257.0743; Found
257.0743.
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2-(3-methylphenylthio)phenylcyanamide (7): White solid; 66 mg, 92%; mp 86-87 oC; 1H NMR
(500 MHz, CO(CD3)2) δ: 2.11 (s, 3H, CH3), 6.72-7.47 (m, 8H, ArH), 8.46 (s, 1H); 13C NMR (125
MHz, CO(CD3)2) δ: 21.3, 111.5, 116.2, 119.0, 124.7, 125.4, 128.1, 128.9, 130.0, 132.5, 136.3,
138.4, 140.0, 141.8; HRMS (ESI) Calcd for C14H13N2S 241.0794; Found 241.0796.
2-(4-chlorophenylthio)phenylcyanamide (8): Light yellow solid; 68 mg, 87%; mp 106-107 oC;
1H NMR (500 MHz, CDCl3) δ: 6.93 (s, 1H, NH), 6.95-7.57 (m, 8H, ArH); 13C NMR (125 MHz,
CDCl3) δ: 109.8, 115.4, 117.0, 124.3, 128.2, 129.6, 132.0, 132.6, 133.4, 137.4, 139.7; HRMS
(ESI) Calcd for C13H10ClN2S 261.0248; Found 261.0243.
2-(2-bromophenylthio)phenylcyanamide (9): Light yellow solid; 70 mg, 77%; mp 92-93 oC; 1H
NMR (500 MHz, CDCl3) δ ppm = 6.49-6.51 (m, 1H, ArH), 6.94 (s, 1H, NH), 7.02-7.60 (m, 7H,
ArH); 13C NMR (125 MHz, CDCl3): 109.8, 115.5, 116.4, 121.3, 124.4, 126.7, 127.4, 128.3, 132.4,
133.2, 136.4, 138.0, 140.2; HRMS (ESI) Calcd for C13H10BrN2S 304.9743; Found 304.9741.
2-(4-fluorophenylthio)phenylcyanamide (10): Gummy liquid; 37 mg, 51%; 1H NMR (500
MHz, CDCl3) δ ppm = 6.96(s, 1H, NH), 6.97-7.56 (m, 8H, ArH);13C NMR (125 MHz, CDCl3) δ
ppm = 114.3, 115.6 (J = 21.25 Hz), 117.1, 123.2, 127.8, 128.5 (d, J = 7.5 Hz), 129.9, 130.7, 136.1,
138.4, 160.9 (J = 237.5 Hz); HRMS (ESI) Calcd for C13H10FN2S 245.0543; Found 245.0542.
2-(5-chloro-2-methoxylphenylthio)phenylcyanamide (11): Light yellow solid; 54 mg, 62%; mp
55-57 oC; 1H NMR (500 MHz, CDCl3) δ ppm = 3.91 (s, 3H, OCH3), 6.77 (s, 1H, NH), 6.80-7.59
(m, 7H, ArH),. 13C NMR (125 MHz, CDCl3) δ ppm = 56.4, 111.9, 115.3, 117.0, 124.2, 125.0,
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126.6, 128.2, 129.0, 132.0, 132.3, 137.7, 140.1, 155.2; HRMS (ESI) Calcd for C14H12ClN2OS
291.0353; Found 291.0348.
2-(1-naphthylthio)phenylcyanamide (12): White solid; 62 mg, 75%; mp 83-85 oC; 1H NMR
(500 MHz, CDCl3) δ ppm = 6.85 (m, 1H, ArH), 6.87 (s, 1H, NH), 7.12-8.29 (m, 10H, ArH),; 13C
NMR (125 MHz, CDCl3): 108.9, 114.4, 116.3, 122.6, 123.3, 123.7, 124.9, 125.7, 125.8, 126.3,
127.8, 130.0, 130.6, 130.7, 133.0, 136.2, 138.6; HRMS (ESI) Calcd for C17H13N2S 277.0794;
Found 277.0784.
2-(phenylthio)-4-methylphenylcyanamide (13)40
2-(4-methylphenylthio)-4-methylphenylcyanamide (14)40
2-(4-methoxylphenylthio)-4-methylphenylcyanamide (15)38
2-(2-methoxylphenylthio)-4-methylphenylcyanamide (16)38
2-(3-methylphenylthio)-4-methylphenylcyanamide (17): White solid; 71 mg, 93%; mp 98-100
oC; 1H NMR (500 MHz, CDCl3) δ ppm = 2.28, (s, 3H, CH3), 2.33 (s, 3H, CH3), 6.80-6.81 (m, 2H,
ArH), 6.87 (s, 1H, NH), 6.98-7.39 (m, 7H, ArH); 13C NMR (125 MHz, CDCl3): 19.5, 20.3, 109.4,
114.1, 116.2, 123.0, 126.4, 126.6, 128.3, 131.3, 132.9, 133.8, 136.1, 136.7, 138.4; HRMS (ESI)
Calcd for C15H15N2S 255.0950; Found 255.0939.
2-(4-chlorophenylthio)-4-methylphenylcyanamide (18)38
2-(1-naphthylthio)-4-methylphenylcyanamide (19): White solid; 75 mg, 86%; mp 122-123 oC;
1H NMR (500 MHz, CDCl3) δ ppm = 2.32 (s, 3H, CH3), 6.73 (s, 1H, NH), 6.82-8.27 (m, 10H,
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ArH); 13C NMR (125 MHz, CDCl3) δ: 20.5, 110.3, 115.3, 116.8, 123.6, 124.4, 125.9, 126.7, 126.8,
127.0, 128.8, 131.0, 132.0, 132.2, 134.0, 134.1, 137.2, 137.6; HRMS (ESI) Calcd for C18H15N2S
291.0950; Found 291.0938.
2-(4-methylphenylthio)-5-bromophenylcyanamide (20): White solid; 81 mg, 85%; mp 101-102
oC; 1H NMR (500 MHz, CDCl3) δ ppm = 2.30 (s, 3H, CH3), 6.92 (s, 1H, NH), 6.97-7.49 (m, 7H,
ArH). 13C NMR (125 MHz, CDCl3) δ ppm = 21.0, 109.3, 117.8, 118.4, 125.3, 127.4, 128.0, 130.3,
130.4, 137.4, 138.0, 140.0. HRMS (ESI) Calcd for C14H12BrN2S 318.9899; Found 318.9896.
2-(4-methoxylphenylthio)-5-bromophenylcyanamide (21): Gummy liquid; 90 mg, 90%; 1H
NMR (500 MHz, CDCl3) δ ppm = 3.78 (s, 3H, OCH3), 6.82-6.84 (m, 2H, ArH), 7.00 (s, 1H, NH),
7.10-7.46 (m, 5H, ArH). 13C NMR (125 MHz, CDCl3) δ ppm = 55.4, 115.4, 118.4, 119.2, 124.0,
124.8, 127.3, 132.3, 137.2, 139.9, 159.5, 167.7; HRMS (ESI) Calcd for C14H12BrN2OS 334.9848;
Found 335.0488.
2-(3-methylphenylthio)-5-bromophenylcyanamide (22): Light yellow solid; 82 mg, 86%; mp
95-96 oC; 1H NMR (500 MHz, CDCl3) 1H NMR (500 MHz, CDCl3) δ ppm = 2.29 (s, 3H, CH3),
6.82-6.88 (m, 2H, ArH), 6.93 (s, 1H, NH), 7.01-7.51 (m, 5H, ArH). 13C NMR (125 MHz, CDCl3)
δ ppm =20.3, 116.0, 117.4, 123.4, 124.6, 126.4, 126.9, 127.8, 128.4, 129.9, 131.3, 137.3, 138.6,
139.6. HRMS (ESI) Calcd for C14H12BrN2S 318.9899; Found 318.9909.
2-(4-chlorophenylthio)-5-bromophenylcyanamide (23): White solid; 76 mg, 75%; mp 86-88
oC; 1H NMR (500 MHz, CDCl3) δ ppm = 6.96-7.42 (m, 7H, ArH), 7.52 (s, 1H, NH). 13C NMR
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(125 MHz, CDCl3) δ ppm = 116.3, 118.6, 126.1, 128.5, 128.9, 130.9, 132.3, 132.7, 133.1, 138.4,
140.7. HRMS (ESI) Calcd for C13H9BrClN2S 338.9353; Found 338.9337
2-(2-bromophenylthio)-5-bromophenylcyanamide (24): Light yellow solid; 72 mg, 63%; mp
87-89 oC; 1H NMR (500 MHz, CDCl3) δ ppm = 6.53-6.55 (m, 2H, ArH), 6.95 (s, 1H, NH),
7.06-7.57 (m, 5H, ArH);13C NMR (125MHz, CDCl3) δ ppm = 115.6, 118.7, 121.5, 126.6, 127.0,
127.8, 128.4, 128.9, 132.3, 133.4, 135.6, 138.9, 141.2. HRMS (ESI) Calcd for C13H9Br2N2S
382.8848; Found 382.8845.
2-(4-fluorophenylthio)-5-bromophenylcyanamide (25): White solid; 70 mg, 70%; mp 86-88
oC; 1H NMR (500 MHz, CDCl3) δ ppm = 6.96 (s, 1H, NH), 6.97-7.50 (m, 7H, ArH). 13C NMR
(125 MHz, CDCl3) δ ppm =115.8 (J = 22.5 Hz ), 117.5, 124.7, 126.5, 127.8, 128.8 (J = 12.5 Hz),
129.9, 131.3, 137.0, 139.4, 161.0 (J = 250.0Hz). HRMS (ESI) Calcd for C13H9BrFN2S 322.9648;
Found 322.9645.
2-(4-fluorophenylthio)-5-bromophenylcyanamide (26): White solid; 94 mg, 85%; mp 95-97
oC; 1H NMR (500 MHz, CDCl3) δ ppm = 3.91 (s, 3H, OCH3), 6.81-7.24 (m, 4H, ArH), 7.37 (s, 1H,
NH), 7.43-7.49 (m, 2H, ArH). 13C NMR (125MHz, CDCl3) δ ppm =65.6, 112.2, 116.6, 118.4,
124.0, 125.9, 126.7, 127.4, 128.9, 130.0, 132.3, 138.5, 141.2, 155.5. HRMS (ESI) Calcd for
C14H11BrClN2OS 368.9459; Found 368.9445.
2-phenylthio-4-methoxylphenylcyanamide (27): Gummy liquid; 38 mg, 47%; 1H NMR (500
MHz, CDCl3) δ: 1.39 (t, J = 10.0 Hz, 3H, CH2CH3), 3.99 (q, J = 10.0 Hz, 2H, CH2CH3), 6.64 (s,
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1H, NH), 7.01-7.28 (m, 8H, ArH); 13C NMR (125 MHz, CDCl3) δ: 13.7, 63.2, 109.7, 115.3, 117.2,
117.4, 121.5, 125.6, 126.2, 128.5, 131.7, 133.8, 154.3. HRMS (ESI) Calcd for C15H15N2OS
271.0900; Found 271.0903.
2-(4-methylphenylthio)-4-methoxylphenylcyanamide (28): Light yellow solid; 46 mg, 54%;
mp 107-108 oC; 1H NMR (500 MHz, CDCl3) δ ppm = 1.39 (t, J = 10.0 Hz, 3H, OCH2CH3), 2.30 (s,
3H, CH3), 3.98 (q, J = 10.0 Hz, 2H, OCH2CH3), 6.63 (s, 1H, NH), 6.98-7.24 (m, 7H, ArH); 13C
NMR (125MHz, CDCl3): δ ppm = 13.7, 19.9, 63.1, 109.8, 115.3, 116.7, 118.4, 121.1, 127.0,
129.3, 130.0, 131.4, 136.0, 154.2. HRMS (ESI) Calcd for C16H17N2OS 285.1056; Found
285.1049.
2-(4-methoxylphenylthio)-4-methoxylphenylcyanamide (29): Light yellow solid; 54 mg, 60%;
mp 122-123 oC; 1H NMR (500 MHz, CDCl3) δ: 1.38 (t, J = 10.0 Hz, 3H, OCH2CH3), 3.78 (s, 3H,
OCH3), 3.96 (q, J = 10.0 Hz, 2H, OCH2CH3), 6.63. (s, 1H, NH), 6.82-7.21 (m, 7H, ArH). 13C
NMR(125 MHz, CDCl3) δ: 13.7, 54.4, 63.1, 114.2, 115.3, 116.1, 120.1, 120.3, 123.5, 127.8, 129.9,
130.7, 154.2, 158.3. HRMS (ESI) Calcd for C16H17N2O2S 301.1005; Found 301.1010.
2-(2-methoxylphenylthio)-4-methoxylphenylcyanamide (30): Gummy liquid; 57 mg, 63%; 1H
NMR (500 MHz, CDCl3) δ ppm = 1.39 (t, J = 7.5 Hz, 3H, OCH2CH3), 3.93 (s, 3H, OCH3), 3.98 (q,
J = 10.0 Hz, 2H, OCH2CH3), 6.85-6.99 (m, 4H, ArH), 7.09 (s, 1H, NH), 7.13-7.24 (m, 3H, ArH);
13C NMR (125 MHz, CDCl3) δ ppm = 13.7, 55.0, 63.1, 110.0, 115.0, 116.9, 118.0, 120.8, 121.6,
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121.7, 129.2, 130.0, 132.1, 154.1, 155.7. HRMS (ESI) Calcd for C16H17N2O2S 301.1005; Found
301.1001.
2-(3-methylphenylthio)-4-methoxylphenylcyanamide (31): White solid; 54 mg, 64%; mp 83-84
; 1H NMR (500 MHz, CDCl3) δ ppm = 1.39 (t, J = 7.5 Hz, 3H, OCH2CH3), 2.28 (s, 3H, CH3),
3.99 (q, J = 10.0 Hz, 2H, OCH2CH3), 6.64 (s, 1H, NH), 6.83-7.24 (m, 7H, ArH); 13C NMR (125
MHz, CDCl3) δ ppm = 14.7, 21.4, 64.2, 110.8, 116.3, 118.0, 118.6, 122.4, 124.3, 127.6, 127.9,
129.3, 132.6, 134.4, 139.5, 155.2 HRMS (ESI) Calcd for C16H17N2OS 285.1056; Found
285.1052.
Acknowledgment
The authors thank the National Natural Science Foundation of China (No. 20972114), Zhejiang
Provincial Natural Science Foundation of China (Y4100578).
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Table 1 Reaction-Condition Optimization.a
CN
I
NH
S
N
Cu, base
NH2
+
solvent, 80oC
S
1a
2a
3
Entry Cu source
base
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
Yieldb(%)
62
76 (51c)
1
2
CuI
CuI
K3PO4.3H2O
t-BuOK
NaOH
3
CuI
70
4
CuI
NaHCO3
Cs2CO3
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
-
25
-
5
CuI
6
CuI
7
CuI
(CH3)3COH
CH3COOC2
CHCl3
21
22
-
8
CuI
9
CuI
10
11
12
13
14
15
16
17
18
CuI
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
90 (69d)
75
73
69
70
74
79
77
-
Cu(OTf)2
Cu(OAc)2
CuO
CuBr2
CuBr
CuCl
CuSO4
-
a Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), Cu (15
mol%), base (2 equiv), solvent (3 mL) under N2 b Isolated yields
c Using air instead of N2 d 1 equiv t-BuOK was used.
Table 2. Reaction of 2-aminobenzothiazole with various substituted aryl iodidesa
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CN
NH
CuI (15 mol%)
I
S
t-BuOK (2.0 equiv)
DMSO, 80oC, N2
NH2
+
R1
N
S
R1
1a
2a-j
3-12
Entry
2-Aminobenzothiazole
Aryl iodides
Product(yield %b)
I
S
NH2
1
3 (90)
N
1a
2a
I
2
3
4
1a
1a
1a
4 (93)
5 (95)
6 (94)
H3C
2b
I
H3CO
2c
I
OCH3
2d
I
5
1a
7 (92 )
CH3
2e
I
6
7
8
9
1a
1a
1a
1a
8 (87)
9 (77)
Cl
2f
Br
I
2g
I
10 (51)
11 (62)
F
2h
I
OCH3
Cl
2i
I
10
1a
12 (75)
2j
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Br
11
-
1a
a Reaction conditions: 1a (0.3 mmol), 2 (0.3 mmol), CuI (15 mol%),
t-BuOK (2 equiv), DMSO (3 mL) under N2 b Isolated yields
Table 3. Reaction of substituted 2-aminobenzothiazoles with different substituted aryl
iodidesa
CN
CuI (15 mol%)
I
NH
S
N
t-BuOK (2.0 equiv)
DMSO, 80oC, N2
NH2
+
R2
S
R1
R2
2a-j
R1
1b-e
13-31
Entry
2-Aminobenzothiazole
Aryl iodides
Product(yield % b)
I
S
NH2
1
13 (94)
N
1b
2a
I
2
3
4
1b
1b
1b
14 (93)
15 (90)
16 (84)
H3C
2b
I
H3CO
2c
I
OCH3
I
2d
5
1b
17 (93 )
CH3
2e
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I
6
7
8
1b
1b
18 (74)
19 (86)
20 (85)
Cl
2f
2j
I
S
NH2
2b
N
Br
1c
9
1c
2c
2e
2f
21(90)
22 (86)
23 (75)
24 (63)
25 (70)
26 (85)
10
11
12
13
14
1c
1c
1c
1c
1c
2g
2h
2i
O2N
O
S
NH2
NH2
15
16
2a
2a
-
N
S
N
1d
1e
27 (47)
17
18
19
20
21
1e
2b
2c
2d
2e
2f
28 (54)
29 (60)
30 (63)
31 (64)
trace
1e
1e
1e
1e
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a Reaction conditions: 1 (0.3 mmol), 2 (0.3 mmol), CuI (15 mol%), t-BuOK (2
equiv), DMSO (3 mL) under N2 b Isolated yields
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