Cobalt(II)-Catalyzed Isocyanide Insertion Reaction with Sulfonyl Azides in Alcohols: Synthesis of Sulfonyl Isoureas

Article abstract of DOI:10.1021/acs.joc.7b01127

A Co(II)-catalyzed isocyanide insertion reaction with sulfonyl azides in alcohols to form sulfonyl isoureas via nitrene intermediate has been developed. This protocol provides a new, environmentally friendly, and simple strategy for the synthesis of sulfonyl isourea derivatives by employing a range of substrates under mild conditions.

Full text of DOI:10.1021/acs.joc.7b01127

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Article
Cobalt(II)-Catalyzed Isocyanide Insertion Reaction with
Sulfonyl Azides in Alcohols: Synthesis of Sulfonyl Isoureas
Tian Jiang, Zheng-Yang Gu, Ling Yin, Shun-Yi Wang, and Shun-Jun Ji
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01127 • Publication Date (Web): 07 Jul 2017
Downloaded from http://pubs.acs.org on July 7, 2017
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Cobalt(II)-Catalyzed Isocyanide Insertion Reaction with Sulfonyl Azides in
Alcohols: Synthesis of Sulfonyl Isoureas
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Tian Jiang,† ZhengꢀYang Gu,† Ling Yin,†,‡ ShunꢀYi Wang,*,† and ShunꢀJun Ji*,†
†Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical
Engineering and Materials Science & Collaborative Innovation Center of Suzhou Nano Science and
Technology, Soochow University, Suzhou, 215123, P. R. China;
‡Department of Chemistry and Chemical Engineering, Jining University, Qufu, 273155, People’s
Republic of China.
E-mail: shunyi@suda.edu.cn; shunjun@suda.edu.cn
RECEIVED DATE
*CORRESPONDING AUTHOR FAX: 86ꢀ512ꢀ65880307.
ABSTRACT. A Co(II)ꢀcatalyzed isocyanide insertion reaction with sulfonyl azides in alcohols to form
sulfonyl isoureas via nitrene intermediate has been developed. This protocol provides a new,
environmentally friendly, and simple strategy for the synthesis of sulfonyl isourea derivatives by
employing a range of substrates under mild conditions.
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KEYWORDS: sulfonyl azides; alcohols; isocyanide; Co(II)ꢀcatalyzed; nitrene
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Introduction
Isourea moiety is present in various agrochemicals, pharmacologically active substances, and starting
material for the synthesis of other important molecules.1ꢀ4 For example, Isourea salt I is an important
starting material for the synthesis of fluorouracil antitumor drugs, imidazole and herbicides.1 Trimeturon
II is useful against hardꢀtoꢀkill weeds developed by Bayer.2 Isoureas III and IV are the intermediates
for the synthesis of herbicide Dinotefuran and natural product (+)ꢀbatzelladine B, respectively.3 Isoureas
V are useful polymerization iniators (Figure 1).4 The main strategy to isourea compounds is based on the
reaction of carbodiimide with alcohols with limited reaction scope.5 However, only few symmetrical
carbodiimides are commercial available. The reported methods suffer from limited substrates, longer
reaction time, toxic reagents, poor atom economy, and
Figure 1 Isoureaꢀbased bioactive molecules.
expensive catalysts, which limit their further applications. Therefore, the development of an efficient
protocol to construct isoureas directly under transition metalꢀfree and mild conditions is more desirable.
Recently, organic azides have been widely used for the C–N bond formation6 catalyzed by Rh,7 Ru,8
Fe,9 Ir,10 etc. During the past decades, Prof. Zhang’s group made a great contributions to cobaltꢀ
catalyzed nitrene chemistry utilizing porphyrin as liangds.11 However, to the best of our knowledge,
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there is no report about the cobaltꢀcatalyzed reactions of organic azides with isocyanides and alcohols
via nitrene intermediate. As important and powerful C1 synthons, isocyanideꢀbased multicomponent
reactions (IMCRs) have attracted sustainable attention for the synthesis of guanidines, thiourea
derivatives and other Nꢀheterocycles.12 Recently, we developed a Coꢀcatalyzed isocyanide insertion
reaction with amines and water to construct ureas (Scheme 1).13 As a continuation on isocyanideꢀbased
multicomponent reactions (IMCRs),14 herein, we reported a novel cobaltꢀcatalyzed isocyanide insertion
reaction with organic azides in alcohols to form sulfonyl isoureas via nitrene intermediate under mild
conditions.
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Scheme 1. Cobaltꢀcatalyzed isocyanide insertion to construct ureas and isoureas.
Results and Discussion
Initially, we tried the reaction of tꢀBuNC (2a) and tosyl azide (3a) in ethanol (1a) catalyzed by
CoC2O4 (5 mol %) at 80 °C for 8 h. To our delight, the desired product (4a) could be isolated in 90%
yield. (Table 1, entry 1). Next, we investigated the reaction utilizing different catalysts (Table 1, entry 1ꢀ
12). The reaction failed to give the desired product 4a when copper or palladium salts were employed
(Table 1, entries 6ꢀ8). Comparing with the cobalt (III) salt, cobalt (II) catalysts showed unique activities
for the transformation to form 4a (Table 1, entries 1ꢀ5). Further screening of reaction time and
temperature (Table 1, entries 13ꢀ18) showed that 4a could be observed in the highest 90% yield just
o
after 4 h at 80 C (Table 1, entry 17). It should be noted that the reaction could also lead to 4a in 50%
yield when stoichiometric ethanol was used using acetonitrile as the solvent (Table 1, entry 19).
Table 1. Optimization of the reaction conditions.a
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entry
1
Catalyst (mol %)
CoC2O4 (5)
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH3CN
Time(h)
T (oC )
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Yieldb (%)
90
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2
Co(acac)2 (5)
Cp*Co(CO)I2 (5)
Co(OAc)2·4H2O (5)
CoCl2·6H2O (5)
Pd(OAc)2 (5)
Cu(OAc)2 (5)
PdCl2 (5)
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trace
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CoC2O4 (1)
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CoC2O4 (10)
CoC2O4 (15)
CoC2O4 (20)
CoC2O4 (5)
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trace
80 (80d)
83 (83d)
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CoC2O4 (5)
CoC2O4 (5)
CoC2O4 (5)
CoC2O4 (5)
90
CoC2O4 (5)
90
CoC2O4 (5)
50
aReaction Conditions: 1a (2 ml), 2a (0.6 mmol), 3a (0.5 mmol), catalyst (5 mol%) under air atmosphere. bIsolated yield. c1.2
equiv of EtOH was used.dReaction time: 12h.
With the optimized reaction conditions in hand (Table 1, entry 17), we turned to investigate the scope
of various isocyanides (Scheme 2). Most of the reactions proceeded smoothly to afford the desired
isourea products in moderate to excellent yields. The reaction of tosyl azide 3a with adamantanyl
isocyanide and cyclohexyl isocyanide performed well under the optimal conditions and led to the
desired product 4b and 4c in 93% and 97% yields, respectively. Unfortunately, only trace amount of
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product could be detected when nꢀbutylisocyanide was applied in this reaction, perharps due to the
decomposion of isocyanide under standard conditions. The reactions of tosyl azide 3a and ethanol 1a
with substituted aryl isocyanides bearing electronꢀwithdrawing groups such as cyano, nitro, ester and
trifluoromethyl groups could furnish the desired products in 39%ꢀ90% yields. Besides, the aryl
isocyanides bearing electronꢀdonating groups also gave the desired isoureas in moderate to excellent
results (57%ꢀ99% yield). In addition, when isocyanides with substituted halogens were employed, the
desired products 4i and 4m could be isolated in 97% and 76% yields, respectively.
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Scheme 2. Substrate scope of iscyanides 2.a,b
aReaction conditions: 1 (2 ml), 2a (0.6 mmol), 3a (0.5 mmol), CoC2O4 (5 mol%), at 80 °C, 4h under air atmosphere.
bIsolated yield.
To further explore the diversity of products, we next investigated the scope of alcohols (Scheme 3).
The reactions of 2a with 3a in methanol and propanol proceeded smoothly to furnish the desired
isoureas 5a and 5b in 77% and 72% yields, respectively. Unfortunately, benzyl alcohol and bulky
alcohols such as isopropanol, 2ꢀbutyl alcohol, and isobutyl alcohol failed to afford the desired isoureas,
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perhaps due to the steric hindrance. It should be noted that the reactions of 2a with 3a in ethylene glycol
could lead to 5d in 98% yield. We also tried the reaction of 2a with 3a in water, which couldn’t led to
the corresponding urea under the optimized conditions.
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Scheme 3. Substrate scope of the alcohols 1 and water.a,b
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aReaction conditions:
bIsolated yield
1 (2 ml), 2a (0.6 mmol), 3a (0.5 mmol), CoC2O4 (5 mol%) at 80 °C, 4h under air atmosphere.
.
Then, we investigated the scope of organo azides 3 (Scheme 4). A variety of sulfonyl azides bearing
different functional groups were tested. Various kinds of substituents, such as H, OMe, F, Cl, Br and I
were well tolerated under the optimal conditions. The 4ꢀacetamidobenzenesulfonyl azide and
naphthaleneꢀ2ꢀsulfonyl azide gave the products 6g and 6h in 95% and 94% yields, respectively. Besides,
nꢀbutylsulfonyl azide and 3ꢀpyridinesulfonyl azide also exhibited good reactivities in this transformation,
delivering the target products 6j and 6i in 57% and 99% yields, respectively.
To investigate the Co intermediate species in the reaction, several electron paramagnetic resonance
(EPR) experiments were also carried out and the results are summarized in Figure 2. It was found that
the mixture of CoC2O4 in EtOH, the mixture of CoC2O4 and pꢀtoluenesulfonyl azide 3a in EtOH and the
mixture of CoC2O4 and isocyanide 2a in EtOH all failed to give EPR signals. It should be noted that a
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triplet EPR signal was obtained (g = 1.8942) from the mixture of CoC2O4, isocyanide 2a and pꢀ
toluenesulfonyl azide 3a in EtOH. This result indicates that the in situ generated cobalt nitrene species
Scheme 4. Substrate scope of the sulfonyl azides 3.a,b
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aReaction Conditions:
1 (2 ml), 2a (0.6 mmol), 3a (0.5 mmol), CoC2O4 (5 mol%) at 80 °C, 4 h under air
atmosphere. bIsolated yield.
from the mixture of CoC2O4, isocyanide and pꢀtoluenesulfonyl azide in EtOH might be involved in the
reaction.
Figure 2．EPR spectrum studies: (1) CoC2O4 (0.5 mmol) in EtOH (2 mL) at 298 K. (2) TsꢀN3 3a
(0.5 mmol), CoC2O4 (0.5 mmol) in EtOH (2 mL) at 298 K. (3) tBuꢀNC 2a (0.5 mmol), TsꢀN3 3a (0.5
mmol), CoC2O4 (0.5 mmol) in EtOH (2 mL) at 298 K. (4) tBuꢀNC 2a (0.5 mmol), CoC2O4 (0.5 mmol)
in EtOH (2 mL) at 298 K.
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(1)
(2)
(3)
(4)
G = 1.8942
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Gauss
Based on the above results and literature reports10, a plausible mechanism is described in Scheme 5.
The fast ligand exchange of CoC2O4 with isocyanides gives cobalt complex A. Complex A reacts with
sulfonyl azide in ethanol to give complex B. The dissociation of N2 from B affords Co(III)−nitrene
intermediate C. Following the coupling reaction of C with the coordinated isocyanide ligand to afford
intermediate E. In the path a, the reaction of the intermediate E with isocyanide 2 affords the
carbodiimide intermediate F and regenerates the Co catalyst A. Subsequently, the addition of ethanol to
carbodiimide intermediate F to furnish isourea 4. In the path b, the addition of EtOH to E leads to
intermediate G. Then, the intermediate G reacts with 2 via ligand exchange to furnish isourea 4 and
regenerates the Coꢀcatalyst A.
Scheme 5. Plausible Reaction Mechanism.
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CoC2O4
O
S
1
2
3
4
R-NC
R1
N3
2
O
3
[CoC2O4(R-NC)2]
A
R-NC
2
5
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9
N
O
S
R
N
N
path a
O
N
C
N
R'
S
O
R'
O
CollLn
LnColl
CollLn
EtOH
R
F
B
R
O
N
C
O
H
N
path b
O
N
C N
S
S
R'
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22
Et
O
R'
O
EtOH
E
R
O
G
HN
C
O
S
R'
N2
R
N
R-NC
O
N
R
O
4
2
N
C
C
A
R
CoIII
L
N
N
R
L
N
C
O
R
S
C
HN
C
O
C
CoIII
R'
L
R'
S
N
N
O
L
O
O
4
S
O
R'
D
CONCLUSION
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In summary, we have developed a Co(II)ꢀcatalyzed synthesis of sulfonyl isoureas by the reactions of
sulfonyl azides with isocyanides in alcohols via nitrene intermediate. This protocol provides a new,
environmentallyꢀfriendly, and simple strategy for effective synthesis of sulfonyl isourea derivatives with
a range of substrates. Further investigations of the Co(II)ꢀcatalyzed isocyanides insertion reactions
involving nitrene intermediate are currently under study in our laboratory.
EXPERIMENTAL SECTION
General Experimental Information. Unless otherwise noted, all commercially available compounds were used as provided without
further purification. Solvents for chromatography were analytical grade and used without further purification. Analytical thinꢀlayer
chromatography (TLC) was performed on silica gel, visualized by irradiation with UV light. For column chromatography, 300ꢀ400 mesh
silica gel was used. 1HꢀNMR and 13CꢀNMR were recorded on a BRUKER 400 MHz spectrometer in CDCl3 or DMSOꢀd6. Chemical shifts
(δ) were reported referenced to an internal tetramethylsilane standard or the CDCl3 residual peak (δ 7.26) or DMSOꢀd6 residual peak (δ
1
2.50) for H NMR. Chemical shifts of 13C NMR are reported relative to CDCl3 (δ 77.16) or DMSOꢀd6 (δ 39.52). Data are reported in the
following order: chemical shift (δ) in ppm; multiplicities are indicated s (singlet), bs (broad singlet), d (doublet), t (triplet), m (multiplet);
coupling constants (J) are in Hertz (Hz). Melting points were measured on an Electrothermal digital melting point apparatus and were
uncorrected. IR spectra were recorded on a BRUKER VERTEX 70 spectrophotometer and are reported in terms of frequency of absorption
(cmꢀ1). HRMS spectra were obtained by using BRUKER micrOTOFꢀQ III instrument with ESI source.
General Procedure for the construction of 4a
In a 15 mL reaction tube, tertꢀButyl isocyanide 2a (0.6 mmol, 1.2 equiv), Tosyl azide 3a (0.5 mmol, 1.0 equiv) were dissolved in 2.5 mL
o
alcohol. The system was stirred in an oil bath at 80 C under air. After 4h, it was removed from the oil bath. The reaction mixture was
charged with silica gel and concentrated. The residue was purified by silica gel column chromatography (eluent : PE/EtOAc = 4/1) to
obtain the desired product 4a as a pale white solid.
Ethyl (E)-N-(tert-butyl)-N'-tosylcarbamimidate (4a). White solid (134 mg, 90%), m.p.: 85.3ꢀ86.9 oC. IR 3323, 2978, 1603, 1334, 1301,
1122, 1072 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.75 (d, J = 8.3 Hz, 2H), 7.40 (s, 1H), 7.24 (d, J = 8.1 Hz, 2H), 4.26 (q, J = 7.1 Hz,
2H), 2.38 (s, 3H), 1.30 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 157.3, 141.9, 139.7, 128.7, 125.5, 64.0,
52.1, 29.0, 21.0, 13.7 ppm. HRMS (ESI) m/z calculated for C14H22N2O3SNa, [M+Na]+ 321.1249; found 321.1247.
Ethyl (E)-N-((3s,5s,7s)-adamantan-1-yl)-N'-tosylcarbamimidate (4b). White solid (175 mg, 93%), m.p.: 96.8ꢀ98.2 oC. IR 3309, 2905, 1605,
1508, 1486, 1385, 1332 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.79 – 7.72 (m, 2H), 7.30 (s, 1H), 7.25 (d, J = 8.0 Hz, 2H), 4.25 (q, J =
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7.1 Hz, 2H), 2.40 (s, 3H), 2.10 – 2.05 (m, 3H), 1.90 (d, J = 2.9 Hz, 6H), 1.65 (dd, J = 8.5, 4.5 Hz, 6H), 1.25 (t, J = 7.1 Hz, 3H) ppm. 13
C
1
2
NMR (100 MHz, CDCl3) δ 156.7, 141.3, 128.2, 125.0, 63.3, 52.3, 41.0, 35.1, 28.4, 20.5, 13.2 ppm. HRMS (ESI) m/z calculated for
C20H28N2O3SNa, [M+Na]+ 399.1718; found 399.1722.
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4
5
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7
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Ethyl (E)-N-cyclohexyl-N'-tosylcarbamimidate (4c). White solid (157 mg, 97%), m.p.: 74.8ꢀ75.9 oC. IR 3316, 2910, 1592, 1472, 1410,
1276, 1182, 1079, 1062 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.76 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 8.0 Hz,
2H), 4.23 (q, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.83 (d, J = 12.1 Hz, 2H), 1.73 – 1.67 (m, 2H), 1.56 (d, J = 12.1 Hz, 1H), 1.36 – 1.20 (m, 8H)
ppm. 13C NMR (100 MHz, CDCl3) δ 156.8, 141.9, 128.7, 125.5, 64.0, 50.0, 32.4, 24.8, 23.9, 21.0, 13.8 ppm. HRMS (ESI) m/z calculated
for C16H24N2O3SNa, [M+Na]+ 347.1405; found 347.1402.
Ethyl (E)-N-(4-cyanophenyl)-N'-tosylcarbamimidate (4d). Yellow solid (113 mg, 63%), m.p.: 142.8ꢀ143.6. oC. IR 2988, 2225, 1624, 1600,
1376, 1099, 1018 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 9.66 (s, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.32 (dd, J =
18.2, 8.4 Hz, 4H), 4.39 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 154.3, 142.9, 139.5,
132.8, 129.0, 125.7, 121.3, 117.9, 107.9, 65.6, 21.1, 13.6 ppm. HRMS (ESI) m/z calculated for C17H17N3O3SNa, [M+Na]+ 366.0888; found
366.0880.
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Ethyl (E)-N-(4-nitrophenyl)-N'-tosylcarbamimidate (4e). Yellow solid (124 mg, 68%), m.p.: 134.0ꢀ134.6 oC. IR 2987, 1630, 1590, 1336,
1139, 1097 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 9.78 (s, 1H), 8.21 (d, J = 9.2 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 9.2 Hz,
2H), 7.30 (d, J = 8.1 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 154.1,
143.8, 143.0, 141.2, 129.1, 125.8, 124.6, 120.8, 65.7, 21.1, 13.6 ppm. HRMS (ESI) m/z calculated for C16H17N3O5SNa, [M+Na]+
386.0787; found 386.0795.
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Ethyl (E)-N'-tosyl-N-(4-(trifluoromethyl)phenyl)carbamimidate (4f). Brown solid (175 mg, 90%), m.p.: 98.7ꢀ100.5 C. IR 2987, 1613,
1351, 1138, 1099 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 9.57 (s, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.32 (dd, J =
17.8, 8.3 Hz, 4H), 4.39 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 154.7, 142.7, 138.9,
138.5, 129.0, 126.7, 125.9,125.7, 123.4, 121.4, 65.3, 21.0, 13.5 ppm. 19F NMR (376 MHz, Chloroformꢀd) δ ꢀ62.3 ppm. HRMS (ESI) m/z
calculated for C17H17F3N2O3SNa, [M+Na]+ 409.0810; found 409.0812.
Ethyl (E)-4-((ethoxy(tosylimino)methyl)amino)benzoate (4g). Brown solid (157 mg, 80%), m.p.: 83.5ꢀ85.0 oC. IR 2982, 1606, 1573, 1281,
1142, 1130, 1067 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 9.58 (s, 1H), 8.01 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.33 – 7.27
(m, 4H), 4.37 (p, J = 7.1 Hz, 4H), 2.41 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 154.7,
142.7, 139.4, 130.3, 129.0, 126.6, 125.7, 120.7, 65.3, 60. 6, 21.1, 13.9, 13. 6 ppm. HRMS (ESI) m/z calculated for C19H22N2O5SNa,
[M+Na]+ 413.1147; found 413.1142.
Ethyl (E)-N-(p-tolyl)-N'-tosylcarbamimidate (4h). Yellow solid (158 mg, 95%), m.p.: 120.9ꢀ122.1 oC. IR 3308, 2992, 1578, 1518, 1393,
1309, 1235 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 8.69 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.14 – 7.04 (m, 3H),
4.25 (q, J = 7.1 Hz, 2H), 2.43 (s, 3H), 2.14 (s, 6H), 1.12 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 156.6, 142.3, 135.0, 132.5,
128.9, 127.7, 127.3, 125.8, 64.4, 21.0, 17.7, 13.8 ppm. HRMS (ESI) m/z calculated for C17H20N2O3SNa, [M+Na]+ 355.1092; found
355.1090.
Ethyl (E)-N-(4-chlorophenyl)-N'-tosylcarbamimidate (4i). Yellow solid (171 mg, 97%), m.p.: 119.6ꢀ122.5 oC. IR 3293, 1595, 1440, 1272,
1069 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 9.33 (s, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 8.3 Hz, 4H), 7.15 (d, J = 8.2 Hz, 2H),
4.34 (q, J = 7.0 Hz, 2H), 2.41 (s, 3H), 1.27 (t, J = 6.2 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 1545.0, 142. 6, 139.1, 133.9,
129.0, 128.7, 125.7, 123.4, 65.0, 21.1, 13.6 ppm. HRMS (ESI) m/z calculated for C16H17ClN2O3SNa, [M+Na]+ 375.0546; found 375.0562.
Ethyl (E)-N-(3-nitrophenyl)-N'-tosylcarbamimidate (4j). Yellow solid (71 mg, 39%), m.p.: 46.4ꢀ48.4 oC. IR 2988, 1528, 1340, 1300, 1237,
1100, 1067, 1021 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 9.62 (s, 1H), 8.20 (s, 1H), 8.02 (d, J = 6.6 Hz, 1H), 7.88 – 7.81 (m, 2H), 7.51
(d, J = 6.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz,
Chloroformꢀd) δ 54.5, 148.2, 142.9, 138.7, 136.6, 129.5, 129.0, 127.2, 125.7, 119.5, 116.6, 65.6, 29.2, 21.1, 13.5 ppm. HRMS (ESI) m/z
calculated for C16H17N3O5SNa, [M+Na]+ 386.0787; found 386.0784.
Ethyl (E)-N-(o-tolyl)-N'-tosylcarbamimidate (4k). White solid (165 mg, 99%), m.p.: 75.0ꢀ77.2 oC. IR 3319, 1599, 1573, 1283, 1100, 1069,
1019 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 9.13 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.26 – 7.12 (m, 4H), 4.31
(q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 2.26 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 155.9, 142.4, 139.4,
133.7, 131.6, 130.3, 128.9, 126.1, 126.1, 125.7, 124.6, 64.7, 21.0, 17.5, 13.6 ppm. HRMS (ESI) m/z calculated for C17H20N2O3SNa,
[M+Na]+ 355.1092; found 355.1090.
Methyl (E)-3-(2-(((E)-ethoxy(tosylimino)methyl)amino)phenyl)acrylate (4l). White solid (149 mg, 74%), m.p.: 113.6ꢀ115.0 oC. IR 3303,
2984, 1715, 1591, 1469, 1275, 1188, 1169, 1142, 1015, 1004 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 9.26 (s, 1H), 7.92 (d, J = 8.2 Hz,
2H), 7.77 (d, J = 16.0 Hz, 1H), 7.61 (dd, J = 7.8, 1.6 Hz, 1H), 7.42 – 7.28 (m, 5H), 6.43 (d, J = 15.9 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.82
(s, 3H), 2.45 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 166.2, 155.7, 142.5, 139.1, 138.7, 133.9, 130.1,
123.0, 129.0, 127.0, 126.8, 126.6, 125.8, 120.3, 64.8, 51.4, 21.1, 13.5 ppm. HRMS (ESI) m/z calculated for C20H22N2O5SNa, [M+Na]+
425.1147; found 425.1155.
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Ethyl (E)-N-(2-bromophenyl)-N'-tosylcarbamimidate (4m). Brown solid (152 mg, 76%), m.p.: 93.7ꢀ94.9 oC. IR 2987, 1943, 1565, 1507,
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1474 cmꢀ1. H NMR (400 MHz, Chloroformꢀd) δ 9.49 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.57 (dd, J = 8.1, 1.5 Hz, 1H), 7.43 (dd, J = 8.2,
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1.5 Hz, 1H), 7.28 (s, 1H), 7.05 (td, J = 7.7, 1.6 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.39 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100
MHz, Chloroformꢀd) δ 155.0, 142.5, 139.1, 134.0, 132.5, 128.9, 127.5, 126.7, 125.9, 125.2, 117.3, 65.0, 21.1, 13.6 ppm. HRMS (ESI) m/z
calculated for C16H17BrN2O3SNa, [M+Na]+ 419.0041; found 419.0039.
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Ethyl (E)-N-(2,6-dimethylphenyl)-N'-tosylcarbamimidate (4n). White solid (171 mg, 99%), m.p.: 120.9ꢀ122.1 oC. IR 3302, 2988, 1699,
1172, 1087, 1066 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 8.69 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.14 – 7.04
(m, 3H), 4.25 (q, J = 7.1 Hz, 2H), 2.43 (s, 3H), 2.14 (s, 6H), 1.12 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 156.6,
142.3, 135.0, 132.5, 128.9, 127.7, 127.3, 125.8, 64.4, 21.0, 17.7, 13.8 ppm. HRMS (ESI) m/z calculated for C18H22N2O3SNa, [M+Na]+
369.1249; found 369.1251.
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Ethyl (E)-N-(3,5-dimethylphenyl)-N'-tosylcarbamimidate (4o). Yellow solid (99 mg, 57%), m.p.: 120.9ꢀ122.1 oC. IR 3295, 2989, 1625,
1589, 1143, 1077, 1036 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 9.25 (s, 1H), 7.84 (d, J = 7.3 Hz, 2H), 7.28 (d, J = 7.6 Hz, 2H), 6.84 (s,
3H), 4.34 (q, J = 7.0, 6.4 Hz, 2H), 2.42 (s, 3H), 2.30 (s, 6H), 1.28 (t, J = 6.6 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 155.4,
139.4, 138.3, 135.1, 128.9, 126.9, 125.7, 119.9, 64.8, 21.0, 20.8, 13.6 ppm. HRMS (ESI) m/z calculated for C18H22N2O3SNa, [M+Na]+
369.1249; found 369.1251.
Methyl (E)-N-(tert-butyl)-N'-tosylcarbamimidate (5a). White solid (109 mg, 77%), m.p.: 71.9ꢀ73.1 oC. IR 3323, 2969, 1604, 1490, 1364,
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1278, 1141, 1116, 1076 cmꢀ1. H NMR (400 MHz, Chloroformꢀd) δ 7.78 – 7.70 (m, 2H), 7.39 (s, 1H), 7.25 – 7.20 (m, 2H), 3.77 (s, 3H),
2.36 (s, 3H), 1.27 (s, 9H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 157.8, 142.0, 139.6, 128.7, 125.5, 54.6, 52.2, 28.9, 21.0 ppm. HRMS
(ESI) m/z calculated for C13H20N2O3SNa, [M+Na]+ 307.1092; found 307.1094.
Propyl (E)-N-(tert-butyl)-N'-tosylcarbamimidate (5b). White solid (112 mg, 72%), m.p.: 56.2ꢀ57.3 oC. IR 3330, 2970, 1600, 1333, 1268,
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1122, 1075 cmꢀ1. H NMR (400 MHz, Chloroformꢀd) δ 7.77 – 7.72 (m, 2H), 7.40 (s, 1H), 7.25 – 7.21 (m, 2H), 4.15 (t, J = 6.6 Hz, 2H),
2.37 (s, 3H), 1.69 – 1.61 (m, 2H), 1.30 (s, 9H), 0.92 (t, J = 7.4 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 157.4, 141.9, 139.7,
128.7, 125.5, 69.7, 52.1, 29.0, 21.4, 21.0, 10.1 ppm. HRMS (ESI) m/z calculated for C15H24N2O3SNa, [M+Na]+ 335.1405; found 335.1404.
Butyl (E)-N-(tert-butyl)-N'-tosylcarbamimidate (5c). White solid (145 mg, 88%), m.p.: 129.6ꢀ131.3 oC. IR 3513, 3336, 2972, 1598, 1335,
1073 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.77 (d, J = 8.2 Hz, 2H), 7.42 (s, 1H), 7.25 (d, J = 7.6 Hz, 2H), 4.21 (t, J = 6.6 Hz, 2H),
2.40 (s, 3H), 1.65 – 1.59 (m, 2H), 1.39 – 1.33 (m, 2H), 1.31 (s, 9H), 0.90 (t, J = 7.4 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ
157.4, 141.9, 139.8, 128.7, 125.5, 67.9, 52.1, 30.1, 29.0, 21.0, 18.7, 13.2 ppm. HRMS (ESI) m/z calculated for C16H26N2O3SNa, [M+Na]+
349.1562; found 349.1559.
2-hydroxyethyl (E)-N-(tert-butyl)-N'-tosylcarbamimidate (5d). White solid (154 mg, 98%), m.p.: 72.3ꢀ74.2 oC. IR 3340, 2965, 1594, 1240,
1135, 1076 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.78 – 7.73 (m, 2H), 7.47 (s, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 4.37 – 4.33 (m, 2H),
3.83 – 3.79 (m, 2H), 2.40 (d, J = 2.0 Hz, 3H), 1.36 – 1.33 (m, 9H), 1.31 (d, J = 1.6 Hz, 1H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ
157.5, 142.2, 139.3, 128.8, 125.5, 69.3, 60.7, 52.5, 29.0, 21.0 ppm. HRMS (ESI) m/z calculated for C14H22N2O4SNa, [M+Na]+ 337.1198;
found 337.1197.
Ethyl (E)-N-(tert-butyl)-N'-(phenylsulfonyl)carbamimidate (6a). Yellow oil (135 mg, 95%). IR 3345, 2987, 1596, 1280, 1208, 1106, 1021
cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.85 (d, J = 6.9 Hz, 2H), 7.43 (td, J = 14.9, 14.3, 7.3 Hz, 4H), 4.24 (dd, J = 7.1, 2.1 Hz, 2H),
1.29 – 1.26 (m, 9H), 1.24 – 1.18 (m, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 157.4, 142.5, 131.4, 128.1, 125.4, 64.0, 52.2, 28.9,
13.7 ppm. HRMS (ESI) m/z calculated for C13H20N2O3SNa, [M+Na]+ 307.1092; found 307.1097.
Ethyl (E)-N-(tert-butyl)-N'-((4-fluorophenyl)sulfonyl)carbamimidate (6b). White solid (135 mg, 89%), m.p.: 46.4ꢀ48.4 oC. IR 3315, 2979,
1598, 1491, 1338, 1278, 1138, 1070 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.92 – 7.81 (m, 2H), 7.36 (s, 1H), 7.10 (t, J = 8.6 Hz, 2H),
4.24 (q, J = 7.1 Hz, 2H), 1.32 – 1.27 (m, 9H), 1.23 (d, J = 7.2 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 164.0, 157.3, 138.8,
128.1, 115.2, 64.1, 52.3, 28.9, 13.6 ppm. 19F NMR (376 MHz, CDCl3) δ ꢀ107.1 ppm. HRMS (ESI) m/z calculated for C13H19FN2O3SNa,
[M+Na]+ 325.0998; found 325.1006.
Ethyl (E)-N-(tert-butyl)-N'-((4-chlorophenyl)sulfonyl)carbamimidate (6c). White solid (106 mg, 67%), m.p.: 64.5ꢀ64.7 oC. IR 3690, 3320,
2978, 1597, 1368, 1335, 1072 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.84 – 7.79 (m, 2H), 7.45 – 7.41 (m, 2H), 7.40 (s, 1H), 4.26 (qd,
J = 7.1, 1.6 Hz, 2H), 1.32 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 157.3, 141.1, 137.6, 128.4, 127.0,
64.2, 52.3, 28.9, 13.7 ppm. HRMS (ESI) m/z calculated for C13H19ClN2O3SNa, [M+Na]+ 341.0703; found 341.0704.
Ethyl (E)-N'-((4-bromophenyl)sulfonyl)-N-(tert-butyl)carbamimidate (6d). White solid (152 mg, 84%), m.p.: 92.7ꢀ94.5 oC. IR 3676, 3334,
2976, 1596, 1340, 1140, 1073 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.71 – 7.66 (m, 2H), 7.56 – 7.51 (m, 2H), 7.34 (s, 1H), 4.20 (q, J
= 7.1 Hz, 2H), 1.26 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 157.3, 141.7, 131.4, 127.1, 126.0, 64.2,
52.3, 28.9, 13.7 ppm. HRMS (ESI) m/z calculated for C13H20BrN2O3S, [M+H]+ 363.0378; found 363.0386.
Ethyl (E)-N-(tert-butyl)-N'-((4-iodophenyl)sulfonyl)carbamimidate (6e). White solid (195 mg, 95%), m.p.: 112.6ꢀ114.5 oC. IR 3340, 2971,
1593, 1403, 1382, 1339, 1106 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.81 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.40 (s, 1H),
4.26 (q, J = 7.1 Hz, 2H), 1.32 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 157.3, 142.3, 137.3, 127.1, 98.3,
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64.2, 52.3, 29.0, 13.7 ppm. HRMS (ESI) m/z calculated for C13H19IN2O3SNa, [M+Na]+ 433.0059; found 433.0056.
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Ethyl (E)-N-(tert-butyl)-N'-((4-methoxyphenyl)sulfonyl)carbamimidate (6f). White solid (153 mg, 97%), m.p.: 77.0ꢀ78.8 oC. IR 3312, 2976,
1595, 1344, 1258, 1113, 1094, 1021 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.80 (d, J = 8.9 Hz, 2H), 7.37 (s, 1H), 6.91 (d, J = 8.9 Hz,
2H), 4.25 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 1.30 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 161.7, 157.2,
134.6, 127.5, 113.2, 63.9, 55.0, 52.1, 29.0, 13.7 ppm. HRMS (ESI) m/z calculated for C14H23N2O4S, [M+H]+ 315.1379; found 315.1381.
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Ethyl (E)-N'-((4-acetamidophenyl)sulfonyl)-N-(tert-butyl)carbamimidate (6g). White solid (162 mg, 95%), m.p.: 146.8ꢀ148.2 C. IR 3676,
3324, 2975, 1589, 1316, 1140, 1075 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 8.62 (s, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.2 Hz,
2H), 7.37 (s, 1H), 4.28 (q, J = 7.0 Hz, 2H), 2.20 (s, 3H), 1.33 (s, 9H), 1.29 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ
168.9, 157.4, 141.4, 136.8, 126.4, 118.7, 64.2, 52.3, 28.9, 24.0, 13.7 ppm. HRMS (ESI) m/z calculated for C15H23N3O4SNa, [M+Na]+
364.1299; found 364.1307.
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Ethyl (E)-N-(tert-butyl)-N'-(naphthalen-2-ylsulfonyl)carbamimidate (6h). Yellow oil (157 mg, 94%). IR 3326, 2974, 1600, 1337, 1102,
1067 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 8.42 (s, 1H), 7.92 – 7.81 (m, 4H), 7.58 – 7.47 (m, 3H), 4.26 (q, J = 7.1 Hz, 2H), 1.28 (s,
9H), 1.22 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 157.4, 139.4, 134.0, 131.5, 128.6, 128.5, 127.8, 127.3, 126.8,
125.9, 121.7, 64.1, 52.2, 29.1, 28.9, 13.7 ppm. HRMS (ESI) m/z calculated for C17H22N2O3SNa, [M+Na]+ 357.1249; found 357.1240.
Ethyl (E)-N-(tert-butyl)-N'-(pyridin-3-ylsulfonyl)carbamimidate (6i). Yellow oil (141 mg, 99%). IR 3332, 2978, 1599, 1403, 1337, 1288,
1082 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 9.01 (d, J = 2.2 Hz, 1H), 8.66 (dd, J = 4.8, 1.5 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.36 (dd,
J = 8.0, 4.9 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 1.25 (s, 9H), 1.20 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 157.4,
151.9, 146.4, 138.9, 133.2, 122.9, 64.4, 52.4, 28.8, 13.6 ppm. HRMS (ESI) m/z calculated for C12H20N3O3S, [M+H]+ 286.1225; found
286.1225.
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Ethyl (E)-N-(tert-butyl)-N'-(butylsulfonyl)carbamimidate (6j). Yellow oil (76 mg, 57%). IR 3309, 2965, 1610, 1338, 1267, 1091 cmꢀ1. H
NMR (400 MHz, Chloroformꢀd) δ 7.27 (s, 1H), 4.25 (q, J = 6.7, 6.2 Hz, 2H), 3.00 – 2.94 (m, 2H), 1.76 (p, J = 7.5 Hz, 2H), 1.44 – 1.37 (m,
2H), 1.30 (s, 12H), 0.90 (t, J = 7.3 Hz, 3H) ppm. 13C NMR (100 MHz, Chloroformꢀd) δ 157.3, 63.7, 53.9, 52.0, 28.9, 25.2, 21.0, 13.7, 13.1
ppm. HRMS (ESI) m/z calculated for C11H24N2O3SNa, [M+Na]+ 287.1405; found 287.1405.
ACKNOWLEDGMENT
We thank Prof. X. Bao (Soochow U.) for DFT calculation. We gratefully acknowledge the National Natural Science
Foundation of China (21672157, 21542015, 21372174), PAPD, the Major Basic Research Project of the Natural Science
Foundation of the Jiangsu Higher Education Institutions (No.16KJA150002), Soochow University, and State and Local Joint
Engineering Laboratory for Novel Functional Polymeric Materials for financial support.
ASSOCIATED CONTENT
Supporting Information Available.
The copies of 1H and 13C NMR spectra of the products. This material is available free of charge via the Internet at
http://pubs.acs.org.
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