Cu(II)-Catalyzed Ortho

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Cu(II)-Catalyzed Ortho C-H Nitration of Aryl Ureas By C-H Functionalization Chun-Meng Wang, Kai-Xiang Tang, Tian-Hong Gao, Lin Chen, and Li-Ping Sun J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01016 • Publication Date (Web): 03 Jul 2018 Downloaded from http://pubs.acs.org on July 3, 2018

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The Journal of Organic Chemistry

Cu(II)-Catalyzed Ortho C-H Nitration of Aryl Ureas By C-H Functionalization Chun-Meng Wang, Kai-Xiang Tang, Tian-Hong Gao, Lin Chen, Li-Ping Sun* Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China

H

R2 N

H N

R1

NO2 R3

O

+ Fe(NO3)3•9H2O

CuCl2•2H2O, p-TSA toluene, 110 oC

R1

R2 N

H N

R3

O

17 examples, up to 92% yield gram scale ABSTRACT: A novel protocol for the aromatic ortho C-H nitration of aryl ureas with Fe(NO3)3·9H2O is developed. The reaction utilizes CuCl2·2H2O as catalyst and p-TSA as additive, showing good functional group tolerance and furnishing the desired products in moderate to excellent yields.

Introduction Urea derivatives are widely used in many roles, including those used as biologically active compounds, as pharmaceuticals, as agricultural pesticides and as antioxidants in gasoline1 (Figure 1). Additionally, urea derivatives are also important units in organic synthesis. A quite important application of them is served as excellent ortho-directing functional groups in the activation of C-H bonds by transition metal catalysts. With their utilization, methods have been established for the implementation of direct ortho C-C bond formation such as arylation2, carbonylation3, alkenylation4 and other reactions5. However, in comparison with the well-established chelation-assisted transition metal catalyzed C−C bond formation, the direct C−N bond formation by using ureas as directing groups is unknown. O CH3

H N

HN

H N

N

N H

O CH3

S

Antiarrhythmic drug

N

Signal transduction modulators HN N

H3CO

N H

N H

OCF3

O

O N

N H

N H

N

ROCK inhibitor N

N

P2Y1 antagonist

Figure 1. Bioactive compounds containing urea scaffolds examples.

Aromatic nitro compounds are widely used as raw materials in many disciplines of the chemical industry and also are essential constituents in some therapeutic and pharmaceutically relevant molecules6. Up to now, numerous useful methods

for their preparation have been developed. In these methods, the electrophilic nitration of arenes have long been the classic and practical synthetic approach. However, the poor selectivity and imperfect functional group tolerance restrict their appliance7. To overcome these drawbacks, several approaches have been explored including the nitration of aryl halides, pseudohalides, and organometallic compounds8. However, they still suffer from the requirement of prefunctionalized substrate precursors. The direct transformations of C−H bond to C−NO2 bond have drawn the attention because they could improve the atom economy and simplify the operation. In the past decades, transition-metal-catalyzed chelation assisted C−H functionalization have been widely explored and extensively employed in organic synthesis. In 2010, Xu and Liu9a reported the first example of a palladium-catalyzed direct ortho-nitration of aryl C-H bonds by using azaarenes as the directing functional groups. Since then, the chelation-directed strategy was explored by using transition metals such as palladium9, copper10, ruthenium11 and so on12 with various nitro sources. Despite the advances, most of these reactions suffered from the use of Nheterocycles as the directing groups, which are difficult to be removed, thus having some limitation in substrate scopes. Besides, some of them need harsh reaction conditions which hamper the further application. Therefore, an easily available nitro source, convenient reaction conditions and good regioselectivity are still the long-standing goal for the nitration. Herein, we report the ortho-C−H nitration of ureas by using ureas as the directing groups, which proceeds under convenient conditions in the presence of CuCl2·2H2O as catalyst with Fe(NO3)3·9H2O utilized as nitro source. Results and Discussion In our initial investigation, the reaction was performed by using N, N-dimethyl-N’-(4-methylphenyl)urea (1a) as a model substrate with CuCl2·2H2O (0.4 equiv), Fe(NO3)3·9H2O (0.35 equiv) and p-TSA (1 equiv) in 1,2-dichloroethane (DCE) at 80 o C under air. To our delight, the reaction occurred at the orthoposition of the N-aryl ring and gave product 2a in 77% yield (Table 1，entry 1). Sequentially, we conducted the reaction under O2 atmosphere and N2 atmosphere, respectively, to ex-

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plore whether the atmosphere was able to improve the yield of the product. However, the yields were not increased (entries 23). Then additives were taken into consideration. Some other Table 1. Optimization Studies for the Cu-Catalyzed Nitration of Ureasa

entry

catalyst

nitro source

additive

solvent

yield(%)b

1

CuCl2.2H2O

Fe(NO3)3.9H2O

p-TSA

DCE

77

2

CuCl2.2H2O

Fe(NO3)3.9H2O

p-TSA

DCE

78c

3

CuCl2.2H2O

Fe(NO3)3.9H2O

p-TSA

DCE

52d

4

.

not lead to the formation of 2a in a drastically decreased yield (entry 18). However, the yield decreased to 74% when the amount of p-TSA was controlled to 0.5 equiv (entry 19). Finally, the standard reaction conditions for the synthesis was identified as follows: 0.2 equiv CuCl2·2H2O as the catalyst, 0.35 equiv Fe(NO3)3·9H2O as the nitro source, 1 equiv p-TSA as the additive and toluene as the solvent under an air atmosphere at 110 oC. Scheme 1. Substrate Scope of the Nitrationa

NO2

CuCl2 2H2O

.

Fe(NO3)3 9H2O

HOAc

DCE

60

5

CuCl2.2H2O

Fe(NO3)3.9H2O

TFA

DCE

80

6

CuCl2.2H2O

Fe(NO3)3.9H2O

TfOH

DCE

80

7

CuCl2.2H2O

Fe(NO3)3.9H2O

PivOH

DCE

68

8

.

CuCl2 2H2O

Cu(NO3)2 3H2O

p-TSA

DCE

57

9

CuCl2.2H2O

AgNO2

p-TSA

DCE

N.D.e

10

CuCl2.2H2O

Fe(NO3)3.9H2O

p-TSA

toluene

89

11

.

CuCl2 2H2O

12

.

CuCl2 2H2O

13

CuBr2

14

Cu(OTf)2

.

.

p-TSA

CH3CN

54

.

Fe(NO3)3 9H2O

p-TSA

THF

60

Fe(NO3)3.9H2O

p-TSA

toluene

84

Fe(NO3)3 9H2O

.

Fe(NO3)3 9H2O

p-TSA

toluene

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F

O

NO2 N O

H3COOC

2h, 35%

O

15

Cu(OAc)2 H2O

.

90

Fe(NO3)3 9H2O

p-TSA

toluene

88

p-TSA

toluene

78

16

Cu(NO3)2 3H2O

Fe(NO3)3.9H2O

17

--

Fe(NO3)3.9H2O

p-TSA

toluene

N.D.e

18

CuCl2.2H2O

Fe(NO3)3.9H2O

p-TSA

toluene

84f

19

CuCl2.2H2O

Fe(NO3)3.9H2O

p-TSA

toluene

74g

.

a

Reaction conditions: N,N-dimethyl-N’-(4-methylphenyl)urea (1a) (0.11 mmol, 1 equiv), Fe(NO3)3·9H2O (0.0385 mmol, 0.35 equiv), Cu salt (0.044 mmol, 0.4 equiv), additive (0.11 mmol, 1 equiv), solvent (3 mL), reflux. bIsolated yield. cReaction was carried out under N2 using a N2 balloon assembly. d Reaction was carried out under O2 using a O2 balloon assembly. eN.D. = not detected. fCuCl2·2H2O (0.022 mmol, 0.2 equiv). gp-TSA(0.055mmol, 0.5equiv.)

acids such as HOAc, TFA, TfOH and PivOH were used, and the best result of them was at the same level compared with pTSA (entries 4-7). Next, among the nitro sources examined, Fe(NO3)3·9H2O gave the best result, whereas Cu(NO3)2·3H2O and AgNO2 afforded the target product in less than 60% yield (entries 8-9). For the solvents, toluene was found to be the optimum choice, which gave the highest yield (89%) at reflux temperature (entries 10-12). Afterwards, a screening of copper sources showed that no obviously increased yield was exhibited (entries 13−16). Control experiment confirmed that no reaction was observed without the Cu source (entry 17). Additionally, lowering the amount of the Cu source (20 mol %) did

NO2

NO2

NO2

H N O

H3C

H3C

NO2

H3C

N O

NO2 N Cl

H N

N

Cl

O

2p, trace

H N

H N O

2r, trace

2q, 78%

H N

OCH3

OCH3 2o, N.D.c

H N

N

Br

O

Cl 2n, 33%

H N

2m, 59%

H N

O

F

NO2

NO2 O

H3CO

2g, 92%

N

2l, 55% N

N

O OCH3 2j, 50%

OCH3

H N

H N O

N

H N

H3CO

2k, 50% .

O

NO2

H N O

N

OCH3

H3CO

N

2d, 68%

N

2i, 38% NO2

H N

H N

NO2

H N

O 2f, 60%

2e, 65%

NO2

Br

2c, 66%

N

H N

N O

NO2

H N

NO2

H N

Cl

2b, 63%b

NO2

F3C

N O

NO2

I

NO2

H N

NO2 OCH3 H3C

H N

N O

2s, 90%

O

H N

N O

2t, 87%

a

Reaction conditions: ureas 1 (0.11 mmol, 1 equiv), Fe(NO3)3·9H2O (0.0385 mmol, 0.35 equiv), CuCl2·2H2O (0.022 mmol, 0.2 equiv), p-TSA (0.11 mmol, 1 equiv), toluene (3 mL), reflux. bIsolated yield. cN.D. = not detected.

With the optimized reaction conditions established, the scope and functional groups compatibility of this protocol was explored (Scheme 1). For the N,N-dimethyl-N’-arylureas, the urea containing unsubstituted phenyl ring reacted smoothly to form the product 2f in a yield of 60%. A substrate bearing an electron-donating functional group (1g) produced the product


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The Journal of Organic Chemistry in excellent yield (2g), whereas 1j, 1k having ortho-methoxy and meta-methoxy substituents were less reactive giving the products in less than 60% yield. Slightly electron-withdrawing groups furnished the desired products in moderate yields (2b2e), which could offer platforms for further functionalization as they contain halogens. The strong electron-withdrawing groups, –CF3 and –COOCH3, drastically decreased the yields and the expected product 2h and 2i were obtained in 35% and 38% yields, respectively. Disubstituted substrates bearing methoxy and bromo groups at the 3- and 4-positions provided the products (2l and 2m) in good yields (55 and 59%). Besides, a disubstituted substrate bearing fluoro and chloro groups at the 4- and 3-positions also provided the orthonitrated product (2n) in 33% yield. However, substrate that the 2- and 4-positions were occupied by chloro groups offered the product in trace yield. Interestingly, when methoxy substituted the 3- and 5-positions, the substrate (1o) did not give the corresponding product (2o). Next, we investigated the application of ureas equipped with different alkyl substituents on the nitrogen atom. Changing the dimethylamino moiety to cyclic diamines had no influence on the reaction, and thereby piperidine and morpholine urea derivatives reacted excellently to provide 2s and 2t in 90% and 87% yields. At the same time, ureas which were constituted by primary amines were also studied. We found that N-ethyl urea could be transformed smoothly under the catalytic conditions to 2q. Nevertheless, N-methoxy urea was restricted to provide the product 2r. Scheme 2. Gram Scale Reaction and Nitroarenes Transformation

Given the operational simplicity of this method, we performed a gram scale reaction (Scheme 2, a), and the nitration product was obtained in 60% yield. To demonstrate the utility of this method, we carried out a few transformations using the nitration products as starting materials. Hydrogenation of 2a under Pd/C and H2 condition provided aniline in excellent yield (Scheme 2, b), which could be conveniently converted to other functional groups (e.g., Cl, Br, I, CN...) via Sandmeyer reactions. To gain insights into the reaction pathway, additional experiments were performed. Radical scavenger TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was added under the standard reactions (Scheme 3, a) to figure out whether a radical intermediate was involved in the reaction. Although the yield was decreased, the reaction was not completely suppressed, suggesting that a radical pathway might not be involved. Then we performed an intermolecular competition experiment between an electron-rich substrate (1g) and electron-deficient substrate (1i) under the optimized conditions. The products 2g and 2i were isolated in equal yields, which indicated that C–H activation was not involved in the rate-

limiting step of this transformation. Next, when phenyl dimethylcarbamate (4) was used as a substrate, the nitration product 5 was not obtained, indicating that the NH group of ureas is indispensable for the regioselective nitration. Scheme 3. Control Experiments

Although details about the mechanism remained to be ascertained, on the basis of these observations and earlier precedents10d, a plausible mechanism for this reaction was depicted in Scheme 4. The substrate 1 may first bind with CuCl2·2H2O to give an intermediate 6 that may undergo reaction with Fe(NO3)3·9H2O to afford the intermediate 7. The subsequent intramolecular ortho-nitration via an aromatic electrophilic substitution can give the intermediate 8, which can afford the target product 2 and the hydrated CuCl2 to complete the catalytic cycle. Scheme 4. Proposed Catalytic Cycle

Conclusion In summary, we have developed a novel and efficient copper-catalyzed, highly regioselective, direct C−H nitration of ureas with iron nitrate as a nitro source by utilizing ureas as directing groups. The present method tolerates a variety of functional groups and allows the synthesis of diverse nitrated urea derivatives in moderate to excellent yields. This therefore represents an important extension of the chemistry of urea compounds. Experimental Section General Information Unless otherwise noted, all chemical reagents were commercially purchased and used without further purification. Analytical TLC was carried out by using pre-254 coated plates and visualized with UV light. Melting points (uncorrected) were determined on a RY-1 MP apparatus. 1H and 13C NMR



spectra were recorded on a Bruker AV-300 spectrometer at 300 MHz and 75 MHz, respectively. Chemical shifts are reported in δ (ppm), relative to the internal standard of TMS. The signals observed are described as: s (singlet), d (doublet), t (triplet), q (quartet), m (multiple). Coupling constants are reported as J values in units of Hz. Mass spectrometry was obtained by using a Q-TOF high-resolution mass spectrometer. Flash column chromatography was performed over silica gel 200-300 m. General Procedure for the Substrates 1a-1t All the starting substrates (1a-1t) for nitration were prepared according to literature reported methods4c, 5a. Method a: aniline derivatives (500 mg, 4.67 mmol) and triethylamine (1.3 mL, 9.34 mmol) were dissolved in a two neck round bottom flask followed by drop wise addition of chlorofomic acid dimethyl amide (1.8 mL, 20 mmol) using a syringe. The reaction mixture was stirred at room temperature. After completion, the reaction was diluted with DCM (30 mL), washed by 2N HCl (15×3 mL), brine (15×3 mL). After being dried over Na2SO4, the organic solvent was removed by evaporation. Then the crude mixture was purified by flash column chromatography (DCM/EA 50:1) to give 1a-1q. Method b: a solution of triphosgene (0.59 g, 2 mmol) in dry DCM (10 mL) was prepared under an N2 atmosphere in a two neck dried round-bottom flask and cooled to 0 °C. A solution of aryl amine (5.0 mmol) and triethylamine (1.38 mL, 10 mmol) in DCM (10 mL), which was prepared in a dried roundbottom flask, was added slowly via cannula. After 15 minutes, the ice bath was removed and the reaction mixture was allowed to stir at room temperature until the TLC analysis indicated conversion of the amine. In a separate dried flask, dry triethylamine (1.52 mL, 11 mmol) was added under an N2 atmosphere to a solution of corresponding amine (5.5 mmol) in dry DMF (10 mL) at room temperature. The resulting white suspension was cooled to 0 °C and the solution containing the isocyanate was added via cannula. The ice bath was removed and the reaction mixture was stirred for 10-12 hours. The solvent was removed under vacuum and the residue suspended in DCM and filtered to remove the non-soluble triethylammoniumchloride salt. Then 1q-1t were obtained by flash column chromatography (DCM/EA 50:1). General Procedure for the Products 2a-2t To a mixture of substituted ureas 1 (0.25 mmol, 1 equiv.), CuCl2·2H2O (0.05 mmol, 0.2 equiv.) and Fe(NO3)3·9H2O (0.0875 mmol, 0.35 equiv) in toluene (3 mL) was added pTSA (0.25 mmol, 1 equiv), then round-bottom flask was stirred at 110 oC temperature until TLC indicated the total consumption of the ureas. Upon completion, the mixture was treated with saturated NaHCO3 (10 mL) solution and extracted with DCM (3 × 10 mL). The combined organic phase was dried over Na2SO4 and then evaporated of the solvent under reduced pressure. Next, purification of the crude residue by flash column chromatography on silica gel (PE/EA) afforded the desired products 2. Characterization Data of Products 2 1,1-dimethyl-3-(4-methyl-2-nitrophenyl)urea (2a): Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 54 mg, yield: 84%. mp: 102-103 oC. 1H NMR (300 MHz, CDCl3) δ 10.10 (s, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.43 (d, J = 8.3 Hz, 1H), 3.12 (s, 6H), 2.37 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 154.7, 137.1, 135.4, 135.1, 131.3, 125.3, 121.2, 36.4,

Page 4 of 8

20.4. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C10H13N3O3 224.1035; found 224.1033. 3-(4-fluoro-2-nitrophenyl)-1,1-dimethylurea (2b): Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 70 mg, yield: 63%. mp: 99-100 oC. 1H NMR (300 MHz, CDCl3) δ 9.96 (s, 1H), 8.63 (dd, J = 9.6, 5.4 Hz, 1H), 7.81 (dd, J = 8.4, 2.4 Hz, 1H), 7.19-7.31 (m, 1H), 3.02 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 155.8 (d, J = 243.7 Hz), 154.6, 134.1 (d, J = 2.3 Hz), 123.8 (d, J = 22 Hz), 123.2 (d, J = 7 Hz), 111.7 (d, J = 27 Hz), 36.4. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C9H10FN3O3 228.0784; found 228.0779. 3-(4-chloro-2-nitrophenyl)-1,1-dimethylurea (2c): Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 22 mg, yield: 61%. mp: 95-96 oC. 1H NMR (300 MHz, CDCl3) δ 10.15 (s, 1H), 8.73 (d, J = 9.3 Hz, 1H), 8.21 (t, J = 2.2 Hz, 1H), 7.57 (dd, J = 2.3, 9.3 Hz, 1H), 3.13 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 154.3, 136.2, 136.0, 135.5, 126.3, 125.1, 122.6, 36.5. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C9H10ClN3O3 244.0489; found 244.0481. 3-(4-bromo-2-nitrophenyl)-1,1-dimethylurea (2d): Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 54 mg, yield: 76%. mp: 103-105 oC. 1H NMR (300 MHz, CDCl3) δ 10.16 (s, 1H), 8.68 (d, J = 9.2 Hz, 1H), 8.36 (t, J = 2.3 Hz, 1H), 7.70 (dd, J = 2.2, 9.2 Hz, 1H), 3.13 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 154.3, 138.8, 136.6, 135.7, 128.0, 122.8, 113.1, 36.5. HRMS (ESI-QTOF) m/z [M + H]+ calcd for C9H10BrN3O3 287.9984; found 287.9977. 3-(4-iodo-2-nitrophenyl)-1,1-dimethylurea (2e): Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 68 mg, yield: 65%. mp: 145-146 oC. 1H NMR (300 MHz, CDCl3) δ 10.17 (s, 1H), 8.54 (d, J = 9.1 Hz, 2H), 7.86 (d, J = 8.3 Hz, 1H), 3.13 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 154.2, 144.4, 137.2, 135.8, 133.9, 122.9, 82.2, 36.5. HRMS (ESI-QTOF) m/z [M + H]+ calcd for C9H10IN3O3 335.9845; found 335.9839. 1,1-dimethyl-3-(2-nitrophenyl)urea (2f): Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 69 mg, yield: 60%. mp: 78-79 oC. 1H NMR (300 MHz, CDCl3) δ 10.2 (s, 1H), 8.69 (d, J = 8.6 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.60 (t, J = 8.5, 7.3 Hz, 1H), 7.05 (t, J = 8.1, 7.6 Hz, 1H), 3.12 (s, 6H). 13 C NMR (75 MHz, CDCl3) δ 154.6, 137.4, 136.0, 135.5, 125.7, 121.3, 36.4. HRMS (ESI-QTOF) m/z [M + H]+ calcd for C9H11N3O3 210.0879; found 210.0874. 3-(4-methoxy-2-nitrophenyl)-1,1-dimethylurea (2g): Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 100 mg, yield: 92%. mp: 120-121 oC. 1H NMR (300 MHz, CDCl3) δ 9.97 (s, 1H), 8.60 (d, J = 9.4 Hz, 1H), 7.65 (d, J = 2.6 Hz, 1H), 7.24 (dd, J = 2.7, 9.4 Hz, 1H), 3.85 (s, 3H), 3.11 (s, 6H). 13 C NMR (75 MHz, CDCl3) δ 154.9, 153.6, 135.9, 131.6, 124.5, 123.0, 107.6, 55.8, 36.4. HRMS (ESI-QTOF) m/z [M + H]+ calcd for C10H13N3O4 240.0984; found 240.0985. 1,1-dimethyl-3-(2-nitro-4(trifluoromethyl)phenyl)urea (2h): Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 25 mg, yield: 35%. mp: above 300 oC. 1H NMR (300 MHz, CDCl3) δ 10.27 (s, 1H), 8.80 (d, J = 8.9 Hz, 1H), 8.38 (s, 1H), 7.68 (d, J = 9.2 Hz, 1H), 3.02 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 154.0, 140.2, 134.4, 132.1 (d, J = 3.2 Hz), 124.8, 123.5 (t, J = 4.2 Hz), 122.1 (t, J = 138 Hz), 121.8, 36.5. HRMS (ESI-QTOF) m/z [M + H]+ calcd for C10H10F3N3O3 278.0753; found 278.0749. methyl 4-(3,3-dimethylureido)-3-nitrobenzoate (2i): Eluent: petroleum ether: ethyl acetate (12:1). Yellow solid, 37


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The Journal of Organic Chemistry mg, yield: 38%. mp: 152-153 oC. 1H NMR (300 MHz, CDCl3) δ 10.48 (s, 1H), 8.92 (s, 1H), 8.85 (d, J = 9.1 Hz, 1H), 8.23 (d, J = 9.1 Hz, 1H), 3.96 (s, 3H), 3.16 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 165.0, 154.0, 140.8, 136.3, 127.8, 123.0, 120.7, 52.5, 36.5. HRMS (ESI-QTOF) m/z [M + H]+ calcd for C11H13N3O5 290.0753; found 290.0749. 3-(2-methoxy-6-nitrophenyl)-1,1-dimethylurea (2j): Eluent: petroleum ether: ethyl acetate (16:1). Yellow solid, 90 mg, yield: 50%. mp: 126-127 oC. 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.7 Hz, 2H), 7.71 (s, 1H), 7.38 (s, 1H), 3.98 (s, 3H), 3.07 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 154.4, 146.6, 141.6, 118.1, 116.7, 104.9, 56.4, 36.4. HRMS (ESI-QTOF) m/z [M + H]+ calcd for C10H13N3O4 240.0984; found 240.0981. 3-(5-methoxy-2-nitrophenyl)-1,1-dimethylurea (2k): Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 59 mg, yield: 50%. mp: 151-153 oC. 1H NMR (300 MHz, CDCl3) δ 10.72 (s, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 9.6 Hz, 1H), 6.58 (dd, J = 2.3, 9.7 Hz, 1H), 3.93 (s, 3H), 3.14 (s, 6H). 13 C NMR (75 MHz, CDCl3) δ 165.8, 154.8, 140.5, 128.7, 128.0, 110.2, 102.1, 56.0, 36.4. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C10H13N3O4 240.0984; found 240.0983. 3-(4,5-dimethoxy-2-nitrophenyl)-1,1-dimethylurea (2l): Eluent: petroleum ether: ethyl acetate (12:1). Yellow solid, 67 mg, yield: 55%, mp: 172-173 oC. 1H NMR (300 MHz, CDCl3) δ 10.72 (s, 1H), 8.51 (s, 1H), 7.69 (s, 1H), 4.03 (s, 3H), 3.94 (s, 3H), 3.14 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 156.3, 155.0, 143.4, 135.2, 127.4, 106.7, 101.8, 56.6, 56.2, 36.4. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C11H15N3O5 270.1090; found 270.1086. 3-(4-bromo-5-methoxy-2-nitrophenyl)-1,1dimethylurea (2m): Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 35 mg, yield: 59%. mp: 159-160 oC. 1H NMR (300 MHz, CDCl3) δ 10.66 (s, 1H), 8.57 (s, 1H), 8.48 (s, 1H), 4.03 (s, 3H), 3.15 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 161.8, 154.5, 139.6, 130.4, 128.8, 103.7, 101.7, 57.1, 36.5. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C10H12BrN3O4 318.0089; found 318.0083. 3-(3-chloro-4-fluoro-2-nitrophenyl)-1,1-dimethylurea (2n): Eluent: petroleum ether: ethyl acetate (16:1). Yellow solid, 20 mg, yield: 33%, mp: 145-146 oC. 1H NMR (300 MHz, CDCl3) δ 10.14 (s, 1H), 8.96 (d, J = 7.1 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 3.11 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 154.2, 151.4 (d, J = 246 Hz), 134.4 (d, J = 2.7 Hz), 130.6 (d, J = 18 Hz), 122.8, 112.7 (d, J = 26 Hz), 36.4. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C9H9ClFN3O3 262.0395; found 262.0390. 1-ethyl-3-(4-methyl-2-nitrophenyl)urea (2q): Eluent: petroleum ether: ethyl acetate (6:1). Yellow solid, 49 mg, yield: 78%, mp: 170-171 oC. 1H NMR (300 MHz, CDCl3) δ 9.70 (s, 1H), 8.54 (d, J = 8.7 Hz, 1H), 7.99 (s, 1H), 7.43 (d, J = 8.6 Hz, 1H), 5.02 (s, 1H), 3.40-3.36 (m, 2H), 2.37 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 154.3, 137.0, 135.2, 134.9, 131.3, 125.2, 121.5, 34.5, 20.3, 15.1. HRMS (ESIQTOF) m/z: [M + H]+ calcd for C10H13N3O3 224.1035; found 224.1029. N-(4-methyl-2-nitrophenyl)pyrrolidine-1-carboxamide (2s): Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 55 mg, yield: 90%, mp: 148-149 oC. 1H NMR (300 MHz, CDCl3) δ 9.96 (s, 1H), 8.65 (d, J = 8.7 Hz, 1H), 8.0 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 3.58-3.54 (m, 4H), 2.37 (s, 3H),

2.03(s, 4H). 13C NMR (75 MHz, CDCl3) δ 153.0, 137.1, 135.2, 134.7, 131.1, 125.2, 121.1, 45.9, 25.6, 20.4, 15.1. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C12H15N3O3 250.1192; found 250.1179. N-(4-methyl-2-nitrophenyl)morpholine-4carboxamide (2t): Eluent: petroleum ether: ethyl acetate (4:1). Yellow solid, 52 mg, yield: 87%, mp: 145-146 oC. 1H NMR (300 MHz, CDCl3) δ 10.14 (s, 1H), 8.52 (d, J = 8.7 Hz, 1H), 8.02 (s, 1H), 7.45 (d, J = 8.6 Hz, 1H), 3.79 (t, J = 4.5, 5.0 Hz, 3H), 3.59 (t, J = 4.5, 4.9 Hz, 3H), 2.38 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 153.9, 137.2, 135.5, 134.7, 131.8, 125.4, 121.4, 66.5, 44.1, 20.4, 15.1. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C12H15N3O4 266.1141; found 266.1130. The Procedure for the Reduction of Compound 2a To a solution of compound 2a (100 mg, 0.446 mmol) in MeOH (10 ml) was added 5% palladium-carbon catalyst (20 mg). The reaction mixture was allowed to stir at room temperature under H2. After 6 h, the mixture was filtered, concentrated in vacuo and purified by column chromatography (petroleum ether: ethyl acetate 1:2) to give 74 mg (86%) of compound 3a as a purple solid. The Data of Compound 3a 3-(2-amino-4-methylphenyl)-1,1-dimethylurea: Purple solid, 74 mg, yield: 86%, mp: 42-43 oC. 1H NMR (300 MHz, CDCl3) δ 6.82 (d, J = 7.7 Hz, 1H), 6.49 (s, 1H), 6.47 (d, J = 7.7 Hz, 1H), 5.98 (s, 1H), 3.82 (s, 2H), 2.91 (s, 6H), 2.14 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 156.5, 141.5, 136.4, 125.7, 123.0, 120.2, 118.5, 36.6, 21.0. HRMS (ESIQTOF) m/z: [M + H]+ calcd for C10H16N3O 194.1293; found 194.1284. Controlled Experiments: Reaction in the Presence of Radical Quencher TEMPO To a mixture of substituted ureas 1 (0.25 mmol, 1 equiv.), CuCl2·2H2O (0.05 mmol, 0.2 equiv.), Fe(NO3)3·9H2O (0.0875 mmol, 0.35 equiv) and TEMPO (0.25 mmol, 1 equiv) in toluene (3 mL) was added p-TSA (0.25 mmol, 1 equiv), then round-bottom flask was stirred at 110 oC temperature. Upon completion, the mixture was treated with saturated NaHCO3 (10 mL) solution and extracted with DCM (3 × 10 mL). The combined organic phase was dried over Na2SO4 and then evaporated of the solvent under reduced pressure. Next, purification of the crude residue by flash column chromatography on silica gel (petroleum ether: ethyl acetate 8:1) afforded the desired product 2a in a yield of 53%. Intermolecular Competition Reaction between 1g and 1i To a mixture of urea 1g (0.15 mmol), 1i (0.15 mmol), CuCl2·2H2O (0.06 mmol, 0.2 equiv.) and Fe(NO3)3·9H2O (0.105 mmol, 0.35 equiv) in toluene (3 mL) was added p-TSA (0.3 mmol, 1 equiv), then round-bottom flask was stirred at 110 oC temperature. Upon completion, the mixture was treated with saturated NaHCO3 (10 mL) solution and extracted with DCM (3 × 10 mL). The combined organic phase was dried over Na2SO4 and then evaporated of the solvent under reduced pressure. Next, the mixed products 2g and 2i were separate through the purification of the crude residue with flash column chromatography on silica gel (petroleum ether: ethyl acetate 8:1). The ratio of 2g and 2i was determined by 1H-NMR, which showed the result was 1:1. The Preparation of Phenyl Dimethylcarbamate 4



The substrate 4 was prepared according to literature reported method13. The Nitration of Phenyl Dimethylcarbamate 4 To a mixture of compound 4 (41 mg, 0.25 mmol, 1 equiv.), CuCl2·2H2O (0.05 mmol, 0.2 equiv.) and Fe(NO3)3·9H2O (0.0875 mmol, 0.35 equiv) in toluene (3 mL) was added p-TSA (0.25 mmol, 1 equiv), then round-bottom flask was stirred at 110 oC temperature for 10 h and there was no reaction proceeding.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website Copies of 1H and 13C NMR spectra

AUTHOR INFORMATION Corresponding Author * Email: [email protected]; [email protected]

ACKNOWLEDGMENT We are grateful to the funds supported by the National Natural Science Foundation (NO. 21472243), Jiangsu Provincial Natural Science Foundation, the National College Students Innovation Training Program and Technology Innovation Team of Jiangsu Province in 2015 China.

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