Direct Conversion of Carboxylic Acids to Various Nitrogen

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Direct Conversion of Carboxylic Acids to Various Nitrogen Containing Compounds in One-Pot Exploiting Curtius Rearrangement Arun Kumar, Naveen Kumar, Ritika Sharma, Gaurav Bhargava, and Dinesh Mahajan J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01697 • Publication Date (Web): 08 Aug 2019 Downloaded from pubs.acs.org on August 8, 2019

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Direct Conversion of Carboxylic Acids to Various Nitrogen Containing Compounds in One-Pot Exploiting Curtius Rearrangement Arun Kumar1, Naveen Kumar1, Ritika Sharma2, Gaurav Bhargava2 and Dinesh Mahajan1* 1Drug Discovery Research Center, Translational Health Science and Technology Institute, Faridabad, 121001, India 2Department of Chemical Sciences, I. K. Gujral Punjab Technical University, Kapurthala, Punjab-144603, India

RECEIVED DATE (will be automatically inserted after manuscript is accepted). R= Aliphatic & (hetro)aromatic

O OH R Ph2POCl

H3 AqN

H OO

R

H N

R1

O 7 examples

R1 R

2 NH

R

1X

NaN3

OH

O HC

1C

N NH2 H 15 examples H N H R O 5 examples

R

O R

R

H N

H;

H N

R C 6H 5

O O 3 examples

H N

R2 N

H N

X

R1 O 15 examples

R X= O/

S

H2 CON C 6H 5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

R1 O 7 examples 2 Drugs

ABSTRACT: Herein we report, a single pot multi-step conversion of inactivated carboxylic acids to various Ncontaining compounds using a common synthetic methodology. The developed methodology rendered the use of carboxylic acids as direct surrogate of primary amines, for the synthesis of primary ureas, secondary/tertiary ureas, O/S-carbamates, benzoyl ureas, amides and N-formyls, exploiting Curtius reaction. This approach has a potential to provide a diversified library of N-containing compounds starting form a single carboxylic acid, based on selection of the nucleophile. Nitrogen containing compounds such as amines, amides, ureas, acyl ureas, and carbamates are ubiquitous in natural products, agrochemicals as well as pharmaceutical agents or molecules of biological and commercial interests. Hence, synthesis of these various N-containing compounds is an important objective in organic synthesis. Carboxylic acids are favorable substrates because of their broad structural diversity, ease in availability, high stability, low toxicity along with ease in storage and handling.1 Curtius rearrangement of acyl azides is a powerful method for construction of a new C-N (sp2C-N or sp3C-N) bond using azide as a source of nitrogen and carboxylic acid as source of carbon.2 The conversion of carboxylic acids to nitrogen containing compounds, avoiding use of any organic amine as a primary source of nitrogen is very alluring. In a typical Curtius reaction, an acyl azide is thermally degraded to rearrange as an isocyanate.3 The acyl azide is often synthesized in a different pot as a separate step from a pre-activated carboxylic acid and sodium azide.2-4 The isocyanate thus formed can be reacted with water, alcohol or amine as one of the nucleophile to yield corresponding amine, carbamate or urea as a final product. This makes whole process multi-pot and practically cumbersome, if one aims for conversion of carboxylic acids to N-containing compounds. One pot multi-step conversion provides an effective approach

to infuse economic and environmental efficiencies because several synthetic transformations and bond-forming steps can be carried out in a single pot.5 Yamada et al.,6 reported the first one-pot conversion of inactivated carboxylic acids to urethanes involving Curtius reaction using DPPA (diphenyl phosphoric azide). The generation of DPPA needs an additional step in a different pot involving sodium azide and diphenyl phosphoryl chloride.7 Recently, Lebel et al.8 reported one-pot conversion of carboxylic acids employing, either chloroformate or di-tert-butyl dicarbonate along with sodium azide as a replacement of DPPA. However, these methodologies are confined to conversion of carboxylic acids to corresponding amines, ureas or carbamates only. Herein, we want to report a direct, multi-step, single pot conversion of carboxylic acids to corresponding primary ureas, mixed ureas (secondary/tertiary), O-carbamates, Scarbamates, acyl ureas, N-formyls and amides exploiting a single methodology. Initial optimization efforts were focused on conversion of benzoic acid to corresponding 1-phenylurea (Table 1). Primary ureas are not only found to be bioactive molecules but they also serve as starting materials for molecules of biological and commercial interests.9 Often, primary ureas are synthesized from corresponding organic amines and ammonia involving phosgene, carbamoyl chloride or isocyanates.9 Interestingly, there is no report for direct conversion of carboxylic acids to corresponding primary ureas in one pot. This instigated us to start our optimization efforts for synthesis of 1-phenylurea (1b), as a model reaction from corresponding benzoic acid (1). In a typical procedure, benzoic acid was mixed with DPPA (entry 1, Table 1) at 0°C, using toluene as a solvent. An equivalent amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added and reaction was stirred for 30 minutes at room temperature to facilitate the formation of acyl azide. The conversion of the acyl azide was monitored as well as quantified, before heating the reaction to 90°C. Aqueous ammonium hydroxide was added to this heated solution and reaction was monitored by TLC and 1H NMR for the formation of 1-phenylurea as a final product. Use of DPPA as a reagent of choice provided 32% isolated yield of 1phenylurea, albeit corresponding benzoyl azide intermediate was formed in reasonably good amount (Entry 1, Table 1). DPPA is a commercial grade reagent which is generally obtained by vacuum distillation of the crude product obtained after a reaction of diphenyl phosphoryl chloride with sodium azide.7 We tried to replace DPPA by in situ use of diphenyl phosphoryl chloride and sodium azide (entry 2). The reaction of benzoic acid was repeated and replacement of DPPA was compensated by in situ addition of diphenyl phosphoryl chloride, sodium azide (as a solution in dry DMF) and catalytic amount of DMAP. In new reaction involving sodium azide, the conversion to corresponding benzoyl azide was less, however it was pleased to see similar isolated yield for final product 1b (entry 2 vs entry 1). As clear from data tabulated in table 1, a quick screening of few other similar reagents concluded, diphenyl phosphinic chloride (Ph2POCl) as a reagent of choice for better yields of benzoyl azide as well as 1-phenylurea (entry 3). Decent success in overall conversion with methanesulfonyl chloride (entry 5) and reaction feasibility with POCl3 (entry 4) needs special mention as these two are common reagents in organic chemistry laboratories. Ammonium chloride or ammonium formate (entry 6 and 7) were also found to be two other potential sources of ammonia for the desired conversion. Influenced by the outcome of this

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quick screening, Ph2POCl and aqueous ammonium hydroxide was used in all subsequent reactions for further studies.

donating group (3b and 5b). Presence of chemically reactive phenolic OH (9b and 10b) or labile Boc as a protecting group (7b) did not interfere with desired conversion and provided either comparable or better yields to their neutral benzoic acid (1b) counterparts. The heterocyclic (16b and 17b) as well aliphatic carboxylic acids (18b and 21b) also afforded good conversions to their respective primary ureas. The overall yields of these conversions are appreciable considering the fact that this process involves four step sequential conversions of a carboxylic acid to a corresponding primary urea exploiting sodium azide as a source of nitrogen and aqueous ammonium hydroxide as a nucleophile in one pot (scheme 1). The intermediates B, C and D were determined by mass spectrometry, 1H NMR spectroscopy and/or TLC analysis of the reaction mixture (see supporting information). Excited by the success of aqueous ammonium hydroxide as a nucleophile, we planned to evaluate other N, O and S nucleophiles. The outcome of this study is summarized in figure 2. The high isolated yields of corresponding substituted ureas, carbamates or thio-carbamates with respective N, O and S based nucleophiles was not surprising owing to historical success of these nucleophiles in classical Curtius reaction.2 Diverse class of carboxylic acids such as aromatic, aliphatic or heterocyclic carboxylic acids gave moderate to high isolated yields of respective substituted ureas using either aniline (2c to 19c) or alkyl amine (3d and 3e) as N-nucleophiles. Various alcohols such as ethanol (3f), isopropanol (3g), tert-butyl alcohol (3h) and benzyl alcohol (3i) were equally successful as Onucleophile using new protocols. Synthesis of corresponding S-carbamates (3j to 3k) marked the success of thiols as potential nucleophiles. As noticed before with aqueous ammonia, the reaction with aniline as a nucleophile also demonstrated considerable level of functional group tolerance when attempted in presence of reactive or labile functional groups (7c, 8c, 13c and 15c). Interestingly, the optimized conditions also facilitated the use of benzamide as a potential nucleophile to synthesize corresponding benzoyl ureas (3m, 4m and 19m). However, efforts to exploit primary aliphatic carboxamides resulted in messy reactions, where we struggle to isolate corresponding acyl ureas in pure form (not reported). The successful use of benzamide as a nucleophile encourages us to exploit carboxylate as a possible nucleophile for this one pot reaction with an intention to construct a new amide bond in final product.

Table 1. Reaction condition optimization for synthesis of phenyl urea O OH

1. Reagent (1.1 eq), DBU (1.1 eq),Toluene, 0oC 2. DMAP (0.1 eq), NaN3(1.1 eq solution in DMF)

O N H

3. 90oC; aq. NH4OH (2.0 eq)

1

NH2

1b

Entry

Reagent

%Yield acyl azidea

Ammonia Source

% Yield 1ba

1

DPPCl*

75

aq. NH4OH

32

2

DPPCl

61

aq. NH4OH

32

3

Ph2POCl

80

aq. NH4OH

50

4

POCl3

34

aq. NH4OH

10

5

CH3SO2Cl

58

aq. NH4OH

35

6

Ph2POCl

80

solid NH4Cl

40

7

Ph2POCl

80

solid NH2COONH4

38

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*DMAP and NaN3 was not used in this reaction; a Isolated yields are based on independent reaction conversions The scope of Ph2POCl activated reaction was studied with various carboxylic acids for the synthesis of corresponding acyl azides (Figure S1 in supporting information) along with synthesis of corresponding primary ureas as mentioned in figure 1. A set of fifteen different carboxylic acids, including diversely substituted benzoic acid analogs, aliphatic carboxylic acids as well as heterocyclic carboxylic acids were evaluated. Most of these carboxylic acids provided comparable or better yields of corresponding primary ureas in comparison to benzoic acid. Benzoic acid analogs substituted with an electron withdrawing group (11b and 12 b) gave poor conversion unlike analogs substituted with an electron

Scheme 1: Plausible route for one pot multistep conversion of carboxylic acid to N-containing compounds O Ph

Ph2POCl OH

O O Ph P NaN3 Ph O Ph B

O Ph

C

N

N

N

Ph

N D

C

O

Nu

Ph

H N

Nu

E O

Figure 1: Substrates scope of carboxylic acids for mono-substituted urea formation


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The Journal of Organic Chemistry 1. Ph2POCl (1.1 eq), DBU (1.1 eq),Toluene, 0oC 2. DMAP (0.1 eq), NaN3(1.1 eq solution in DMF)

O R

H 3C

O N H

N H

NH2

N H

2b, 56%

1b, 50% O N H

S

O N H

N H

NH2

NH2

O

NH2

N H

N H

7b, 52%

O

O

16b, 58%

12b, 25%

11b, 25%

O

O

BocHN

O

N H 5b, X=F, 75% 6b, X=Br, 69%

NH2

3b, 75%

NC NH2

X

O

NH2

N H

3. 90oC; aq. NH4OH (2.0 eq)

H3CO

O

NH2

F3C

OH

O R

HO NH2

N H

N H

17b, 61%

H N

NH2

N H

NH2

10b, 50%

O

NH2 O

21b, 48%

18b, 60%

NH2

9b, 70%

O NH2

OH O

O

22b, 51%

N H

NH2

Figure 2: Synthetic scope evaluation with other nucleophiles 1. Ph2POCl (1.1 eq), DBU (1.1 eq),Toluene, 0oC 2. DMAP (0.1 eq), NaN3(1.1 eq solution in DMF)

O R

OH

R

H N

Nu O

3. 90oC; Nucleophile (1 eq)

N-nucelophiles H N

H N

H N O

H 3C

RO

2c, 93% H N

O 2N

H N O

3c, R=CH3, 98% 4c, R=C2H5, 94%

H N

H N

O

S

15c, 62%

H N

H N

5c, X= F, 98% 6c, X=Br, 76% H N

BocHN

H N O

H N O

H3CO

O

O

OHC

H3CO

O

R

O

3g, R=H, 70% 3h, R=CH3,65%

H3CO

H N

X O

3i, X= O, 70% 3l, X= S, 40%

H3CO

H N

S O

3k, 54%

RO

O

H3CO

H N O

R N

H N

O

H N

H N

13c, 88%

H N

Benzamide-nucleophile H N

X

3f, X= O, 98% 3j, X= S, 56%

H N

19c, 68%

18c, 70%

17c, 90%

H N

8c, 95% H N

O, S-nucleophiles H N

H N HO

7c, 98% H N

H N O

O

16c, 94%

H N

O

X

O

O

H N

O

3d, R= H, 70% 3e, R=C2H5, 56% H N

O

3m, R= CH3, 52% 4m, R= C2H5, 46%

H N O

O

19m, 65%

Amide moiety is one of the most promiscuous functional exploiting benzoic acid as a nucleophile was found equally group in natural products as well as synthetic compounds. efficient when different carboxylic acids (3n, 7n, 13n, 18n and Organic chemists have deep admirations to develop new 20n) were used as amine surrogates. The reaction scope was methods to make amide bond. Historically, amide formation is also evaluated for use of formic acid as potential nucleophile one of the most exploited reactions in medicinal and process (entries 1o, 2o, 3o, 4o, 5o and 3p) resulting in the formation of chemistry.10 All reported, classical or non-classical methods of corresponding N-formyls as final product. In all the cases, amide bond formations are dependent on the use of isolated yields of corresponding amides were found to be corresponding organic amines for their condensation with moderate to good. The plausible mechanism for this newly acids.11 We envisaged that a successful use of a carboxylic developed amide bond formation reaction is summarized in acid as a nucleophile in evolved methodology can provide a scheme 2 involving labile intermediate E1 as an additional new synthetic route for amide bond formation, which will not step of scheme 1 mentioned above.12 This newly developed be dependent on use of organic amines as substrates. This amide formation reaction appears to be a unique process, contemplation was supported by limited exploitation of involving one-pot, five step sequential conversions (Scheme 1 isocyanates for amide bond formation, as reported by Crich et and 2) of two inactivated carboxylic acids to corresponding al.12 We attempted for the use of benzoic acid as a possible primary amides, using sodium azide as a source of nitrogen carboxylate nucleophile as mentioned in figure 3, entry 1n. It unlike known traditional methods. Here, one of the carboxylic was pleased to see the formation of corresponding amide 1n, acid is being exploited as a direct surrogate of a primary amine when 1 equivalent benzoic acid dissolved in DMF (pre-mixed for amide bond formation, which has never been reported with 1 equivalent of DBU) was added to reaction mixture. earlier. This process involving formation of new amide bond, Figure 3: One-pot conversion of carboxylic acids to amides



1. Ph2POCl (1.1 eq), DBU (1.1 eq),Toluene, 0oC 2. DMAP (0.1 eq), NaN3(1.1 eq solution in DMF)

O R

H N

OH

1n, 55% H N

H3CO

H N

H O

1o, 30%

H 3C

O

H N H3CO

2o, 35%

3o, 52%

O

20n, 52%

18n, 60%

H N C 2H 5O

H N O

13n, 53%

H O

H N O

OHC

7n, 58%

H O

R'

H N O

BocHN

3n, 65%

H N

3. 90 C; RCOOH (1 eq); DBU (1 eq)

H N O

R

o

H N O

Page 4 of 13

H N

H O

O

F

4o, 37%

H N

H

O

H3CO

5o, 32%

CH3

3p, 51%

Scheme 2: Plausible mechanism for amide bond formation H N O E

H N

Nu

O E1

Nu = C6H5COO-

H N

Base

O

-CO2

O

O 1n

Scheme 3: Synthesis of Sorafenib and Regorafenib R

HO

R

I Ph2POCl (1.1eq), DBU (1.1eq), Toluene, 0°C COOHII DMAP (0.1eq), NaN3 (1.1eq in DMF) II 4-chloro-3-(trifluoromethyl)aniline (1eq), 90°C HO

R H N

H N

O 23/24

CF3 (CH3)3COK (2.0 eq.), DMF, 2 hrs H K2CO3 (1.0 eq.), 80°C, 6 hrs N Cl

In conclusion, we have reinvigorated Curtius rearrangement and evolved a one-pot direct conversion of carboxylic acids to various N-containing compounds. This method facilitates the use of carboxylic acids as direct surrogates of primary amines employing sodium azide as a source of nitrogen. Both aliphatic and aromatic carboxylic acids can be transformed to various nitrogen containing compounds such as primary ureas, secondary/tertiary ureas, O/S-carbamates, benzoyl ureas, amides and N-formyls in one-pot using one common reaction condition just by altering the choice of nucleophile. The developed methodology is modular in nature, demonstrated wide product scope as well as high pot economy by providing moderate to good overall yields for multi-step conversions in single pot. Ease in availability of carboxylic acids with wide structural diversity coupled with mild reaction conditions, inexpensive reagents, functional group tolerance and broad scope in nitrogen-containing product formation can possibly make this methodology an important addition to the synthetic tool box14 of medicinal chemists for easy diversification of a given carboxylic acid to different N-containing compounds possessing different physicochemical properties.15

O O

H N

H N O

CF3 Cl

Sorafenib: R=H Regorafenib: R=F

NMR data with reported literature data and relevant reference has been provided for same along with new 1H NMR data. General Procedure for the Synthesis of Acyl Azides (1a-15a): A solution of 1 mmol carboxylic acid in 5 ml dry toluene was taken in two neck round bottom flas (rbf) under nitrogen blanket. Addition of diphenyl phosphinic chloride (210 µL, 1.1 mmol) and DBU (165 µL, 1.1 mmol) was done at 0°C. After 5 minutes of stirring, a premixed solution of 72 mg (1.1 mmol) NaN3 (12 mg, 0.1 mmol) DMAP in 0.5 ml of DMF was added to the reaction mixture. After completion of reaction as monitored by TLC, dilute aqHCl solution (1N, 20mL) was added and organic layer was extracted with diethyl ether. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford crude product. The crude product was purified by flash silica gel chromatography using increasing polarity of ethyl acetate in hexane (0:100 to 05:95) as eluent to isolate pure products. O N3

Benzoyl azide (1a).16 The title compound was synthesized from Benzoic acid (122.12 mg, 1.0 mmol) and Sodium azide (72 mg, 1.1 mmol) according to general procedure for acyl azide synthesis. Colourless oil (118 mg, 80% yield); 1H-NMR (300 MHz, CDCl3) δ (ppm) 8.01-8.04 (m, 2H), 7.59-7.65 (m, 1H), 7.43-7.49 (m, 2H). O

EXPERIMENTAL SECTION 1H

Cl O

Rxn scale 1.1 mmol; Yields: 67 % for R=H (23) and 56% for R=F (24) Rxn scale 7.24 mmol; Yield: 60% for R=H (23)

We also evaluated this methodology for the gram scale synthesis (scheme 3) of two approved oncology drugs i.e Sorafenib and Regorafenib. This is a novel synthesis of these two drugs exploiting the use of 4-hydroxybenzoic acid as a direct surrogate of 4-aminophenol, which is a required substrate for all reported synthesis of these two drugs. 13

N

H N

N

and 13C NMR spectra were recorded on Bruker 300 MHz NMR spectrometer using DMSO-d6 /CDCl3 as a solvent. Chemical shifts are given in ppm with TMS as an internal reference. J values are given in Hertz. HRMS spectra were recorded on Bruker micrOTOF Q II Mass spectrometer. All known compounds are characterized by comparison of new 1H

N3 H 3C 4-Methylbenzoyl azide (2a).16 The title compound was synthesized from p-Toluic acid (136.15 mg, 1.0 mmol) and Sodium azide (72 mg, 1.1 mmol) according to general procedure for acyl azide synthesis. Colourless oil (145


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mg, 90% yield); 1H-NMR (300 MHz, CDCl3) δ (ppm) 7.83 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 2.34 (s, 3H).

O N3

O

O 2N

4-Nitrobenzoyl azide (15a).16 The title compound was synthesized from 4-Nitrobenzoic acid (167.12 mg, 1.0 mmol) and Sodium azide (72 mg, 1.1 mmol) according to general procedure for acyl azide synthesis. Yellow solid (77 mg, 40% yield); 1H-NMR (300 MHz, CDCl3) δ (ppm) 8.30 (d, J = 9.0 Hz, 2H), 8.19-8.22 (m, 2H).

N3 H3CO

4-Methoxybenzoyl azide (3a).16 The title compound was synthesized from p-Anisic acid (152.15 mg, 1.0 mmol) and Sodium azide (72 mg, 1.1 mmol) according to general procedure for acyl azide synthesis. White solid (156 mg, 88% yield); 1H-NMR (300 MHz, CDCl3) δ (ppm) 7.98 (dd, J = 6.9 Hz, 2H), 6.92 (dd, J = 6.9 Hz, 2H), 3.87 (s, 3H).

Experimental Details for Scheme 1: A solution of 4-Anisic acid (1.0 mmol) in 5 ml dry toluene was taken in a two neck rbf under nitrogen blanket. Addition of diphenyl phosphinic chloride (210 µL, 1.1 mmol) and DBU (165 µL, 1.1 mmol) was done at 0°C. Reaction was stirred for 10 minutes and monitored by TLC. TLC analysis showed consumption of starting anisic acid and appearance of a new polar spot. An aliquot was extracted from reaction mixture, diluted with dichloromethane and washed with sodium bicarbonate solution. The organic solvent was evaporated by nitrogen flushing and remaining crude was analyse using 1H NMR spectroscopy and Mass spectrometry. A peak of M/Z [353.0, M+H+] was appeared on mass spectrum which correspond to intermediate B. Analysis of 1H NMR spectrum determine the presence of mixed anhydride (B) along with some impurity of phosphinic acid as a by-product. The synthetic procedure for intermediate C (after addition of sodium azide) has been discussed (as compound 3a) along with corresponding analytical data in above experimental section of acyl azides. Post heating using oil bath fixed at 90°C, formation of intermediate D i.e. corresponding isocyanate was confirmed by TLC comparison with authentic sample of 4methoxyphenyl isocyanate.

O N3 F 4-Fluorobenzoyl azide (5a).16 The title compound was synthesized from 4-Fluorobenzoic acid (140.11 mg, 1.0 mmol) and Sodium azide (72 mg, 1.1 mmol) according to general procedure for acyl azide synthesis. Colourless oil (149 mg, 90% yield); 1H-NMR (300 MHz, CDCl3) δ (ppm) 8.01-8.06 (m, 2H), 7.08-7.14 (m, 2H). O O O

N3 N H

tert-Butyl (4(azidocarbonyl)phenyl)carbamate (7a).17 The title compound was synthesized from N-Boc-4-aminobenzoic acid (237.25 mg, 1.0 mmol) and Sodium azide (72 mg, 1.1 mmol) according to general procedure for acyl azide synthesis. Off white solid (242 mg, 92% yield); 1H-NMR (300 MHz, CDCl3) δ (ppm) 7.91 (dd, J = 8.7 Hz, 2H), 7.40 (dd, J = 9.0 Hz, 2H), 6.69 (br, 1H), 1.48 (s, 9H). O

General Procedure for One Pot Conversion of Carboxylic Acids to Primary Ureas (1b-22b): A solution of 1.0 mmol carboxylic acid in 5 ml dry toluene was taken in a two neck rbf under nitrogen blanket. Addition of diphenyl phosphinic chloride (210 µL, 1.1 mmol) and DBU (165 µL, 1.1 mmol) was done at 0°C. After 5 minutes of stirring, a premixed solution of 72 mg (1.1 mmol) NaN3, 12 mg (0.1 mmol) DMAP in 0.5 ml of DMF was added to the reaction mixture. After complete consumption of starting material and/or formation of acyl azide (as monitored by TLC), the reaction mixture was stirred and heated using silicon oil bath having temperature fixed at 90°C followed by addition of 2.0 mmol ammonium hydroxide (28% solution in water). After the completion of reaction (based on TLC monitoring for consumption of acyl azide and formation of new spot), reaction mixture was neutralized with dilute aqHCl solution and extracted with ethyl acetate. The organic layer was washed with NaHCO3 solution and dried over anhydrous Na2SO4. Solvent was evaporated under reduced pressure, resulting crude product was purified by flash silica gel chromatography using increasing polarity of ethyl acetate in hexane (20:80 to 40:60) to isolate corresponding pure primary urea.

N3 OHC 4-Formylbenzoyl azide (13a). The title compound was synthesized from 4-Formylbenzoic acid (150.13 mg, 1.0 mmol) and Sodium azide (72 mg, 1.1 mmol) according to general procedure for acyl azide synthesis. Yellow solid (105 mg, 60% yield); m.p. 170-175 0C; 1H-NMR (300 MHz, CDCl3) δ (ppm) 10.10 (s, 1H), 8.18 (d, J = 8.28 Hz, 2H), 7.96 (d, J = 8.25 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 191.4, 139.9, 130.0, 129.7; HRMS (ESI-TOF) (m/z): [M+H]+ Calcd for C8H5N3O2H, 176.0460, Mass not found due to stability reason. O N3 H3COC 4-Acetylbenzoyl azide (14a).16 The title compound was synthesized from 4-Acetylbenzoic acid (164.16 mg, 1.0 mmol) and Sodium azide (72 mg, 1.1 mmol) according to general procedure for acyl azide synthesis. White solid (133 mg, 70% yield); 1H-NMR (300 MHz, CDCl3) δ (ppm) 8.08 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 8.7 Hz, 2H), 2.61 (s, 3H).

General Procedure for the One Pot Direct Conversion to Substituted Ureas (2c-3e), O/S Carbamates (3f-3i), Benzoyl Ureas (3m, 4m and 19m), N-formamide and Amides (1n-3p): A solution of 1.1 mmol carboxylic acid in 5 ml dry toluene

5



was taken in a two neck rbf under nitrogen blanket. Addition of diphenyl phosphinic chloride (210 µL, 1.1 mmol) and DBU (165 µL, 1.1 mmol) was done at 0°C. After 5 minutes of stirring, a premixed solution of 72 mg (1.1 mmol) NaN3, 12 mg (0.1 mmol) DMAP in 0.5 ml of DMF was added to the reaction mixture. After the conversion of carboxylic acid into acyl azide (by TLC monitoring), the reaction mixture was stirred and heated using silicon oil bath fixed at 90-100°C, followed by addition of respective nucleophile (1.0 mmol). Reaction was monitored by TLC and neutralized with dilute HCl solution followed by extraction with ethyl acetate. The organic layer was washed with aqNaHCO3 solution and dried over anhydrous Na2SO4. Solvent was evaporated under reduced pressure, and the resulting crude product was purified by flash silica gel chromatography using increasing polarity of ethyl acetate in hexane (05:95 to 20:80) as eluent to isolate pure compounds.

Br

O N H

H N

O

N H

O HO

NH2

1-(p-Tolyl)urea (2b).39 The title compound was synthesized from p-Toluic acid (136.15 mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in water, 186 µL, 2.0 mmol) according to general procedure for curtius reaction. White crystalline solid (84 mg, 56% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.38 (br, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 5.75 (br, 2H), 2.20 (s, 3H).

N H

O F3C

N H

NH2

1-(3-(trifluoromethyl)phenyl)urea (11b).19 The title compound was synthesized from 3(Trifluoromethyl)benzoic acid (190.12 mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in water, 186 µL, 2.0 mmol) according to general procedure for curtius reaction. White solid (51 mg, 25% yield); 1H-NMR (300 MHz, DMSOd6) δ (ppm) 8.87 (br, 1H), 7.94 (br, 1H), 7.39-7.50 (m, 3H), 7.20 (d, J = 7.5 Hz, 1H), 5.98 (br, 2H).

O N H

NH2

1-(2-Hydroxyphenyl)urea (10b).19 The title compound was synthesized from Salicylic acid (138.12 mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in water, 186 µL, 2.0 mmol) according to general procedure for curtius reaction. White solid (76 mg, 50% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.91 (br, 1H), 7.99 (br, 1H), 7.83 (dd, J = 7.8 Hz, 1H), 6.70-6.80 (m, 3H), 6.19 (br, 2H).

NH2

1-(4-Methoxyphenyl)urea (3b).18 The title compound was synthesized from p-Anisic acid (152.15 mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in water, 186 µL, 2.0 mmol) according to general procedure for curtius reaction. Off white solid (125 mg, 75% yield); 1HNMR (300 MHz, DMSO-d6) δ (ppm) 8.29 (br, 1H), 7.27 (d, J = 9.3 Hz, 2H), 6.79 (d, J = 9.0 Hz, 2H), 5.69 (s, 2H), 3.68 (s, 3H). F

NH2

OH O

O N H

N H

1-(3-Hydroxyphenyl)urea (9b).19 The title compound was synthesized from 3-Hydroxybenzoic acid (138.12 mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in water, 186 µL, 2.0 mmol) according to general procedure for curtius reaction. Yellow solid (107 mg, 70% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.20 (br, 1H), 8.38 (br, 1H), 6.95-7.04 (m, 2H), 6.68-6.72 (m, 1H), 6.28-6.32 (m, 1H), 5.77 (br, 2H).

O

H3CO

NH2

tert-Butyl (4-ureidophenyl)carbamate (7b). The title compound was synthesized from N-Boc-4aminobenzoic acid (237.25 mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in water, 186 µL, 2.0 mmol) according to general procedure for curtius reaction. White solid (131 mg, 52% yield); m.p. >150°C 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.10 (br, 1H), 8.36 (br, 1H), 7.22-7.30 (m, 4H), 5.73 (br, 2H), 1.46 (s, 9H) 13C{1H} NMR (75 MHz, DMSO-d6) δ 156.5, 153.3, 135.5, 133.6, 119.2, 118.7, 28.6; HRMS (ESI-TOF) (m/z): [M+Na]+ Calcd for C12H17N3O3Na 274.1168; Found 274.1182.

1-Phenylurea (1b).19 The title compound was synthesized from Benzoic acid (122.12 mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in water, 186 µL, 2.0 mmol) according to general procedure for Curtius reaction. White solid (68 mg, 50% yield); 1H-NMR (300 MHz, DMSOd6) δ (ppm) 8.49 (br, 1H), 7.38 (d, J = 7.8 Hz, 2H), 7.21 (t, J = 7.8 Hz, 2H), 6.88 (t, J = 7.2 Hz, 1H), 5.81 (br, 2H).

N H

O

O

NH2

H 3C

NH2

1-(4-Bromophenyl)urea (6b).19 The title compound was synthesized from 4-Bromobenzoic acid (201.02 mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in water, 186 µL, 2.0 mmol) according to general procedure for curtius reaction. White crystalline solid (148 mg, 69% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.67 (br, 1H), 7.37 (s, 4H), 5.91 (br, 2H).

O N H

Page 6 of 13

NH2

1-(4-Fluorophenyl)urea (5b).18 The title compound was synthesized from 4-Fluorobenzoic acid(140.11 mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in water, 186 µL, 2.0 mmol) according to general procedure for curtius reaction. White crystalline solid (116 mg, 75% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.53 (br, 1H), 7.367.41 (m, 2H), 7.01-7.07 (m, 2H), 5.82 (br, 2H).

6


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NC

O N H

O

NH2

1-(4-Cyanophenyl)urea (12b).19 The title compound was synthesized from 4-Cyanobenzoic acid (147.13 mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in water, 186 µL, 2.0 mmol) according to general procedure for curtius reaction. White solid (41 mg, 25% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.09 (br, 1H), 7.61-7.66 (m, 2H), 7.55-7.58 (m, 2H), 6.11 (br, 2H). S

NH2

1-(Thiophen-3-yl)urea The title compound was synthesized from 3-Thiophenecarboxylic acid (128.14 mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in water, 186 µL, 2.0 mmol) according to general procedure for curtius reaction. Off white solid (83 mg, 58% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.76 (br, 1H), 7.35 (dd, J = 5.1 Hz, 1H), 7.13-7.15 (m, 1H), 6.94 (dd, J = 5.1 Hz, 1H), 5.77 (br, 2H). O

(16b).40

N H

H N O

1-Phenyl-3-(p-tolyl)urea (2c).20 The title compound was synthesized from p-Toluic acid (150 mg, 1.1 mmol) and Aniline (92 µL, 1.0 mmol) according to general procedure for curtius reaction. Off white solid (211 mg, 93% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.54-8.60 (br, 2H), 7.44 (d, J = 7.8 Hz, 2H), 7.24-7.34 (m, 4H), 7.08 (d, J = 8.1 Hz, 2H), 6.96-6.98 (m, 1H), 2.24 (s, 3H). H N

NH2

1-(Benzo[d][1,3]dioxol-5-yl)urea (17b). The title compound was synthesized from Piperonylic acid (166.13 mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in water, 186 µL, 2.0 mmol) according to general procedure for curtius reaction. White solid (110 mg, 61% yield); m.p. 165-170ºC; 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.38 (br, 1H), 7.16 (d, J = 2.1 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.60 (dd, J = 8.4 Hz, 1H), 5.92 (s, 2H), 5.74 (br, 2H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 156.5, 147.5, 141.8, 135.5, 110.7, 108.4, 101.0, 100.9; HRMS (ESI-TOF) (m/z): [M+Na]+ Calcd for C8H8N2O3Na 203.0433; Found 203.0431.

O

1-(4-Methoxyphenyl)-3-phenylurea (3c).20 The title compound was synthesized from p-Anisic acid (168 mg, 1.1 mmol) and Aniline (92 µL, 1.0 mmol) according to general procedure for curtius reaction. Off white solid (238 mg, 98% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.56 (br, 1H), 8.45 (br, 1H), 7.43 (dd, J = 8.7 Hz, 2H), 7.35 (dd, J = 6.9 Hz, 2H), 7.23-7.28 (m, 2H), 6.92-6.97 (m, 1H), 6.86 (dd, J = 6.9 Hz, 2H) 3.71 (s, 3H). H N

H N O

C 2H 5O

1-(4-Ethoxyphenyl)-3-phenylurea (4c). The title compound was synthesized from 4Ethoxybenzoic acid (183 mg, 1.1 mmol) and Aniline (92 µL, 1.0 mmol) according to general procedure for curtius reaction. White solid (241 mg, 94% yield); m.p. 165-170°C; 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.55 (br, 1H), 8.43 (br, 1H), 7.43 (dd, J = 8.7 Hz, 2H), 7.33 (dd, J = 6.9 Hz, 2H), 7.26 (t, J = 7.8 Hz, 2H), 6.94-6.96 (m, 1H), 6.84 (dd, J = 6.9 Hz, 2H), 3.95-3.98 (m, 2H), 1.30 (m, 3H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 154.1, 153.2, 140.3, 133.0, 129.2, 122.0, 120.5, 118.5, 115.0, 63.5, 31.1; HRMS (ESI-TOF) (m/z): [M+Na]+ Calcd for C15H16N2O2Na 279.1104; Found 279.1088.

NH2

1-Cyclohexylurea (18b).19 The title compound was synthesized from Cyclohexanecarboxylic acid (128.17 mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in water, 186 µL, 2.0 mmol) according to general procedure for curtius reaction. White solid (85 mg, 60% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 5.79-5.81 (br, 1H), 5.27 (br, 1H), 3.23-3.30 (m, 1H), 1.59-1.74 (m, 4H), 1.48-1.53 (m, 1H), 1.02-1.26 (m, 5H). H N

H N

H3CO

O N H

H N H 3C

O

O

NH2

1-(4-isopropylphenyl)urea (22b).19 The title compound was synthesized from 4-Isopropylbenzoic acid (164.20 mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in water, 186 µL, 2.0 mmol) according to general procedure for curtius reaction. White solid (91 mg, 51% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.37 (br, 1H), 7.28 (d, J = 8.46 Hz, 2H), 7.07 (d, J = 8.46 Hz, 2H), 5.74 (br, 2H), 2.74-2.83 (m, 1H), 1.15 (d, J = 6.9 Hz, 6H).

O N H

N H

NH2

H N

O

1-Benzylurea (21b).19 The title compound was synthesized from Phenylacetic acid (136.15 mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in water, 186 µL, 2.0 mmol) according to general procedure for curtius reaction. White solid (72 mg, 48% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 7.29-7.34 (m, 2H), 7.19-7.26 (m, 3H), 7.38-6.42 (br, 1H), 5.51 (br, 2H), 4.17 (d, J = 6.3 Hz, 2H).

H N O

1-(4-Fluorophenyl)-3-phenylurea The title compound was synthesized from 4Fluorobenzoic acid (154 mg, 1.1 mmol) and Aniline (92 µL, 1.0 mmol) according to general procedure for curtius reaction. Off white crystalline solid (226 mg, 98% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.67 (br, 1H), 8.63 (br, 1H), 7.42-7.47 (m, 4H), 7.27 (t, J = 7.8 Hz, 2H), 7.11 (t, J = 8.7 Hz, 2H), 6.96 (t, J = 7.5 Hz, 1H). F

(5c).21

7



H N

Nitrobenzoic acid (183.83 mg, 1.1 mmol) and Aniline (92 µL, 1.0 mmol) according to general procedure for curtius reaction. Off white solid (160 mg, 62% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.43 (br, 1H), 8.91 (br, 1H), 8.19 (dd, J = 7.2 Hz, 2H), 7.67-7.71 (m, 2H), 7.47 (dd, J = 8.7 Hz, 2H), 7.28-7.33 (m, 2H), 6.99-7.04 (m, 1H).

H N O

1-(4-Bromophenyl)-3-phenylurea The title compound was synthesized from 4Bromobenzoic acid (221 mg, 1.1 mmol) and Aniline (92 µL, 1.0 mmol) according to general procedure for curtius reaction. Off white crystalline solid (221 mg, 76% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.79 (br, 1H), 8.68 (br, 1H), 7.40-7.45 (m, 6H), 7.27 (t, J = 7.8 Hz, 2H), 6.97 ((t, J = 7.5 Hz, 1H). Br

(6c).22

H N

O

H N

H N

O

tert-Butyl (4-(3phenylureido)phenyl)carbamate (7c). The title compound was synthesized from N-Boc-4-aminobenzoic acid (261 mg, 1.1 mmol) and Aniline (92 µL, 1.0 mmol) according to general procedure for curtius reaction. White solid (321 mg, 98% yield); m.p. >200ºC; 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.17 (br, 1H), 8.56 (br, 1H), 8.49 (br, 1H), 7.43 (dd, J = 8.7 Hz, 2H), 7.23-7.33 (m, 6H), 6.94-6.97 (m, 1H), 1.46 (s, 9H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 153.3, 153.0, 140.2, 134.6, 134.3, 129.2, 122.1, 119.2, 118.5, 79.2, 28.6; HRMS (ESI-TOF) (m/z): [M+Na]+ Calcd for C18H21N3O3Na 350.1475; Found 350.1446. H N HO

H N

O

H N O

O

1-(Benzo[d][1,3]dioxol-5-yl)-3phenylurea (17c).24 The title compound was synthesized from Piperonylic acid (182.74 mg, 1.1 mmol) and Aniline (92 µL, 1.0 mmol) according to general procedure for curtius reaction. Off white crystalline solid (231 mg, 90% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.58 (br, 1H), 8.53 (br, 1H), 7.43 (dd, J = 8.4 Hz, 2H), 7.20-7.29 (m, 3H), 6.93-6.98 (m, 1H), 6.73-6.84 (m, 2H), 5.97 (s, 2H).

H N O

1-(4-Hydroxyphenyl)-3-phenylurea (8c).23 The title compound was synthesized from 4Hydroxybenzoic acid (152 mg, 1.1 mmol) and Aniline (92 µL, 1.0 mmol) according to general procedure for curtius reaction. Off white solid (217 mg, 95% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.05 (br, 1H), 8.50 (br, 1H), 8.29 (br, 1H), 7.42 (dd, J = 8.4 Hz, 2H), 7.19-7.27 (m, 4H), 6.93-6.95 (m, 1H), 6.68 (dd, J = 6.9 Hz, 2H). H N

H N

1-Cyclohexyl-3-phenylurea (18c).20 The title compound was synthesized from Cyclohexanecarboxylic acid (140.98 mg, 1.1 mmol) and Aniline (92 µL, 1.0 mmol) according to general procedure for curtius reaction. White solid (153 mg, 70% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.33 (br, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.20 (t, J = 7.8 Hz, 2H), 6.87-6.89 (m, 1H), 6.09-6.11 (br, 1H), 3.39-3.47 (m, 1H), 1.77-1.81 (m, 2H), 1.63-1.69 (m, 2H), 1.51-1.55 (m, 1H), 1.36 (m, 5H).

H N

1-(4-Formylphenyl)-3-phenylurea (13c). The title compound was synthesized from 4Formylbenzoic acid (165 mg, 1.1 mmol) and Aniline (92 µL, 1.0 mmol) according to general procedure for curtius reaction. Brown solid (212 mg, 88% yield); m.p. 140-145ºC; 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.85 (s, 1H), 9.20 (br, 1H), 8.85 (br, 1H), 7.83 (dd, J = 6.9 Hz, 2H), 7.65-7.68 (m, 2H), 7.47 (dd, J = 8.7 Hz, 2H), 7.30 (t, J = 7.8 Hz, 2H), 6.98-7.03 (m, 1H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 191.8, 152.5, 146.1, 139.6, 131.5, 130.5, 129.3, 122.8, 118.9, 118.0; HRMS (ESI-TOF) (m/z): [M+Na]+ Calcd for C14H12N2O2Na 263.0791; Found 263.0771. H N

H N O

O

OHC

O 2N

H N

O S 1-Phenyl-3-(thiophen-3-yl)urea (16c). The title compound was synthesized from 3Thiophenecarboxylic acid (140.96 mg, 1.1 mmol) and Aniline (92 µL, 1.0 mmol) according to general procedure for curtius reaction. White solid (205 mg, 94% yield); m.p. 205-215°C; 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.91 (br, 1H), 8.61 (br, 1H), 7.42-7.46 (m, 3H), 7.24-7.29 (m, 3H), 7.04 (dd, J = 5.1 Hz, 1H), 6.96-6.98 (m, 1H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 152.8, 140.2, 137.7, 129.2, 125.0, 122.2, 121.7, 118.6, 106.1; HRMS (ESI-TOF) (m/z): [M+H]+ Calcd for C11H10N2OSH 219.0592; Found 219.0616.

O

HN

Page 8 of 13

H N

H N O

1-Phenyl-3-propylurea (19c).25 The title compound was synthesized from Butyric acid (100 µL, 1.1 mmol) and Aniline (92 µL, 1.0 mmol) according to general procedure for curtius reaction. Yellowish solid (121 mg, 68% yield); 1H-NMR (300 MHz, CDCl3) δ (ppm) 7.20-7.24 (m, 4H), 6.97-7.01 (m, 1H), 6.86 (br, 1H), 5.15 (br, 1H), 3.08-3.15 (m, 2H), 1.41-1.48 (m, 2H), 0.84-0.87 (m, 3H). H N

H N

H3CO

H N O

1-Ethyl-3-(4-methoxyphenyl)urea (3d). The title compound was synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and Ethylamine hydrochloric salt (81.55 mg, 1.0 mmol) according to general procedure for

O

1-(4-Nitrophenyl)-3-phenylurea (15c).20 The title compound was synthesized from 4-

8


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curtius reaction. White solid (136 mg, 70% yield); m.p. 125130°C; 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.16 (br, 1H), 7.26 (dd, J = 6.6 Hz, 2H), 6.79 (dd, J = 6.9 Hz, 2H), 5.93-5.96 (br, 1H), 3.68 (s, 3H), 3.03-3.12 (m, 2H), 1.03 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 155.8, 154.3, 134.2, 119.8, 114.3, 55.6, 34.4, 16.0; HRMS (ESITOF) (m/z): [M+H]+ Calcd for C10H14N2O2H 195.1134; Found 195.1151. H N

H N

Benzyl (4methoxyphenyl)carbamate (3i).26 The title compound was synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and Benzyl alcohol (100 µL, 1.0 mmol) according to general procedure for curtius reaction. Off white solid (180 mg, 70% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.57 (br, 1H), 7.35-7.41 (m, 7H), 6.86 (d, J = 9.0 Hz, 2H), 5.12 (s, 2H), 3.70 (s, 3H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 155.2, 153.9, 137.2, 132.5, 128.9, 128.5, 128.4, 120.2, 114.4, 66.0, 55.6.

N

1,1-Diethyl-3-(4methoxyphenyl)urea (3e).31 The title compound was synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and Diethylamine (103.45 µL, 1.0 mmol) according to general procedure for curtius reaction. Colourless oil (124 mg, 56% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 7.99 (br, 1H), 7.34 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 9.0 Hz, 2H), 3.70 (s, 3H), 3.27-3.34 (m, 4H), 1.07 (t, J = 6.9 Hz, 6H). H N

H N

S-ethyl (4methoxyphenyl)carbamothioate (3j). The title compound was synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and Ethanethiol (74 µL, 1.0 mmol) according to general procedure for Curtius reaction. Brown solid (119 mg, 56% yield); m.p. 60-65ºC; 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 10.07 (br, 1H), 7.39 (d, J = 9.0 Hz, 2H), 6.84-6.88 (m, 2H), 3.70 (s, 3H), 2.80-2.87 (m, 2H), 1.20-1.25 (m, 4H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 164.8, 155.7, 132.6, 121.1, 120.3, 114.4, 55.6, 23.7, 16.2; HRMS (ESI-TOF) (m/z): [M+H]+ Calcd for C10H13NO2SH 212.0740; Found 212.0722.

O

Ethyl (4-methoxyphenyl)carbamate (3f).26 The title compound was synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and Ethanol (58 µL, 1.0 mmol) according to general procedure for curtius reaction. Brownish oil (192 mg, 98% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.37 (br, 1H), 7.34 (d, J = 9 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 4.08-4.10 (m, 2H), 3.70 (s, 3H), 1.22 (m, 3H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 154.15, 154.16, 132.7, 120.2, 114.3, 60.3, 55.5, 15.0. H N

H N

S-allyl (4methoxyphenyl)carbamothioate (3k). The title compound was synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and 2Propene-1-thiol (82.56 µL, 1.0 mmol) according to general procedure for curtius reaction. Brown solid (121 mg, 54% yield); m.p. 65-70°C; 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 10.16 (br, 1H), 7.40 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 9.3 Hz, 2H), 5.75-5.93 (m, 1H), 5.21-5.27 (m, 1H), 5.06-5.10 (m, 1H), 3.71 (s, 3H), 3.55 (d, J = 6.9 Hz, 2H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 165.2, 156.0, 134.5, 131.8, 121.6, 118.0, 114.5, 55.6, 36.5, 32.0; HRMS (ESI-TOF) (m/z): [M+Na]+ Calcd for C11H13NO2SNa 246.0559; Found 246.0534.

Isopropyl (4methoxyphenyl)carbamate (3g).27 The title compound was synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and 2Propanol (77 µL, 1.0 mmol) according to general procedure for curtius reaction. Yellowish oil (147 mg, 70% yield); 1HNMR (300 MHz, DMSO-d6) δ (ppm) 9.31 (br, 1H), 7.34 (d, J = 9.0 Hz, 2H), 6.83 (dd, J = 6.6 Hz, 2H), 4.81-4.90 (m, 1H), 3.69 (s, 3H), 1.23 (d, J = 6.3 Hz, 6H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 155.0, 153.7, 132.8, 120.1, 114.3, 67.5, 55.6, 22.4.

H N H3CO

S O

H3CO

O O

H3CO

S O

H3CO

O

H3CO

O

H3CO

O

H3CO

O

H N

O O

H3CO

S O

S-benzyl (4methoxyphenyl)carbamothioate (3l). The title compound was synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and Benzyl mercaptan (117.39 µL, 1.0 mmol) according to general procedure for curtius reaction. Yellowish crystalline solid (110 mg, 40% yield); m.p. 40-45ºC 1H-NMR (300 MHz, DMSOd6) δ (ppm) 7.90 (dd, J = 6.9 Hz, 2H), 7.27-7.39 (m, 5H), 7.07 (d, J = 9.0 Hz, 2H), 4.30 (s, 2H), 3.84 (s, 3H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 189.2, 164.2, 138.2, 129.6, 129.3, 129.0, 127.6, 114.7, 56.1, 32.7; HRMS (ESI-TOF) (m/z): [M-

tert-Butyl (4methoxyphenyl)carbamate (3h).28 The title compound was synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and Tert-butanol (96 µL, 1.0 mmol) according to general procedure for curtius reaction. Colourless oil (145 mg, 65% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.10 (br, 1H), 7.34 (d, J = 8.7 Hz, 2H), 6.82 (dd, J = 6.9 Hz, 2H), 3.69 (s, 3H), 1.46 (s, 9H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 154.9, 153.4, 133.0, 120.1, 114.2, 79.1, 55.5, 28.6.

9



CH3+Na]+ Calcd for C14H12NO2SNa 281.0481; Found 281.0519. H N

H N O

H3CO

N-(4-methoxyphenyl)benzamide (3n).29 The title compound was synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and Benzoic acid (122.12 mg, 1.0 mmol) according to general procedure for curtius reaction. White crystalline solid (148 mg, 65% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 10.12 (br, 1H), 7.94 (d, J = 6.6 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.49-7.58 (m, 3H), 6.92 (d, J = 9.0 Hz, 2H), 3.74 (s, 3H).

H N O

H3CO

O

N-((4methoxyphenyl)carbamoyl)benzamide (3m).38 The title compound was synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and Benzamide (121.14 mg, 1.0 mmol) according to general procedure for curtius reaction. White solid (141 mg, 52% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 10.97 (br, 1H), 10.67 (br, 1H), 8.004-8.033 (m, 2H), 7.63-7.65 (m, 1H), 7.48-7.56 (m, 4H), 6.93 (dd, J = 6.9 Hz, 2H), 3.74 (s, 3H).

H N O

HN H N

H N O

C 2H 5O

O

O

tert-Butyl (4benzamidophenyl)carbamate (7n).34 The title compound was synthesized from N-Boc-4-aminobenzoic acid (261 mg, 1.1 mmol) and Benzoic acid (122.12 mg, 1.0 mmol) according to general procedure for curtius reaction. White solid (181 mg, 58% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 10.14 (br, 1H), 9.30 (br, 1H), 7.92-7.95 (m, 2H), 7.64 (d, J = 9.0 Hz, 2H), 7.52-7.58 (m, 3H), 7.41 (d, J = 9.0 Hz, 2H), 1.48 (s, 9H).

O

N-((4ethoxyphenyl)carbamoyl)benzamide (4m). The title compound was synthesized from 4-Ethoxybenzoic acid (182.79 mg, 1.1 mmol) and Benzamide (121.14 mg, 1.0 mmol) according to general procedure for curtius reaction. Off white solid (131 mg, 46% yield); m.p. 150-155°C; 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 10.99 (br, 1H), 10.68 (br, 1H), 8.02 (d, J = 9.0 Hz, 2H), 7.47-7.66 (m, 5H), 6.92 (d, J = 9.0 Hz, 2H), 3.98-4.05 (q, J = 13.5 Hz, 2H), 1.32 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 169.1, 155.4, 151.6, 133.4, 132.8, 130.9, 129.0, 128.7, 122.0, 115.0, 63.6, 15.1; HRMS (ESI-TOF) (m/z): [M+Na]+ Calcd for C16H16N2O3Na, 307.1053; Found 307.1029. H N

Page 10 of 13

H N O

N-(4-formylphenyl)benzamide (13n).35 The title compound was synthesized from 4-Formylbenzoic acid (165.14 mg, 1.1 mmol) Benzoic acid (122.12 mg, 1.0 mmol) according to general procedure for curtius reaction. Off white solid (120 mg, 53% yield); 1H-NMR (300 MHz, DMSOd6) δ (ppm) 10.45 (br, 1H), 10.11 (br, 1H), 8.13 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.7 Hz, 2H), 7.77-7.80 (m, 2H), 7.37 (t, J = 7.8 Hz, 2H), 7.13 (t, J = 7.5 Hz, 1H). OHC

H N

O O N-(propylcarbamoyl)benzamide (19m). The title compound was synthesized from Butyric acid (100 µL, 1.1 mmol) and Benzamide (121.14 mg, 1.0 mmol) according to general procedure for curtius reaction. Off white solid (134 mg, 65% yield); m.p. 60-65ºC; 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 10.66 (br, 1H), 8.66-8.70 (br, 1H), 7.947.97 (m, 2H), 7.59-7.64 (m, 1H), 7.48-7.53 (m, 2H), 3.16-3.23 (m, 2H), 1.49-1.56 (m, 2H), 0.90 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 168.7, 153.9, 133.1, 133.0, 128.9, 128.5, 41.2, 22.9, 11.7; HRMS (ESI-TOF) (m/z): [M+Na]+ Calcd for C11H14N2O2Na 229.0953; Found 229.0968.

H N O

N-cyclohexylbenzamide (18n).36 The title compound was synthesized from Cyclohexanecarboxylic acid (140.98 mg, 1.1 mmol) and Benzoic acid (122.12 mg, 1.0 mmol) according to general procedure for curtius reaction. White solid (122 mg, 60% yield); 1H-NMR (300 MHz, CDCl3) δ (ppm) 7.73 (dd, J = 8.1 Hz, 2H), 7.37-7.47 (m, 3H), 5.94 (br, 1H), 3.98 (m, 1H), 1.99-2.04 (m, 2H), 1.70-1.77 (m, 4H), 1.35-1.45 (m, 2H), 1.17-1.28 (m, 3H).

H N O

N-phenylbenzamide (1n).30 The title compound was synthesized from Benzoic acid (134.33 mg, 1.1 mmol) and Benzoic acid (122.12 mg, 1.0 mmol) according to general procedure for curtius reaction. White crystalline solid (109 mg, 55% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 10.25 (br, 1H), 7.95 (dd, J = 8.1 Hz, 2H), 7.78 (dd, J = 8.7 Hz, 2H), 7.50-7.60 (m, 3H), 7.36 (t, J = 7.8 Hz, 2H), 7.087.13 (m, 1H).

H N O

N-ethylbenzamide (20n).37 The title compound was synthesized from Propionic acid (82 µL, 1.1 mmol) and Benzoic acid (122.12 mg, 1.0 mmol) according to general procedure for curtius reaction. White solid (78 mg, 52% yield); 1H-NMR (300 MHz, CDCl3) δ (ppm) 8.05-8.08 (m, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 4.364.43 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H).

10


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H N

H N

H O

N-phenylformamide (1o).33b The title compound was synthesized from Benzoic acid (134.33 mg, 1.1 mmol) and Formic acid (38 µL, 1.0 mmol) according to general procedure for curtius reaction. Brownish solid (36 mg, 30% yield); 1H-NMR (300 MHz, CDCl3, mixture of two rotamers) δ (ppm) 8.62 (d, J = 11.43 Hz, 1H), 8.32 (d, J = 1.14 Hz, 1H), 7.46-7.48b (br, 1H), 7.47 (d, J = 7.71 Hz, 2H), 7.25-7.32 (m, 4H), 7.00-7.15 (m, 5H). H N

O

H3CO

N-(4-methoxyphenyl)acetamide (3p).32 The title compound was synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and acetic acid (57 µL, 1.0 mmol) according to general procedure for curtius reaction. Off white solid (85 mg, 51% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.77 (br, 1H), 7.47 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 3.71 (s, 3H), 2.00 (s, 3H). H N

H O

H 3C

Cl 1-(4-Chloro-3(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (23).41 The title compound was synthesized from 4-Hydroxybenzoic acid (151.93 mg, 1.1 mmol) and 4-Chloro-3(trifluoromethyl)aniline (195.57 mg, 1.0 mmol) according to general procedure for curtius reaction. White solid (222 mg, 67% yield); m.p. 210-215°C; 1H-NMR (300 MHz, DMSOd6) δ (ppm) 9.13 (br, 1H), 9.03 (br, 1H), 8.49 (br, 1H), 8.09 (s, 1H), 7.60 (d, J = 3.3 Hz, 2H), 7.22 (d, J = 9.0 Hz, 2H), 6.69 (d, J = 8.7 Hz, 2H). F

O

H3CO N-(4-methoxyphenyl)formamide (3o).33a The title compound was synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and Formic acid (38 µL, 1.0 mmol) according to general procedure for curtius reaction. Colourless oil (79 mg, 52% yield); 1H-NMR (300 MHz, CDCl3, mixture of two rotamers) δ (ppm) 8.48 (d, J = 11.6 Hz, 1H), 8.32 (s, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 6.846.90 (m, 4H), 3.78/3.79 (2s, 6H).

H

F F

O

H N

N

H N

O

H N O

F

F F

Cl

4-(4-(3-(4-chloro-3(trifluoromethyl)phenyl)ureido)phenoxy)-Nmethylpicolinamide (Sorafenib).42 The title compound was synthesized from O-alkylation of compound 8 q (300 mg 0.907 mmol) with 4-chloro-N-methylpicolinamide (86 mg, 0.503 mmol). Off white solid (210 mg, 50% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.49 (br, 1H), 9.24 (br, 1H), 8.83 (d, J = 6.0 Hz, 1H), 8.51 (d, J = 6.0 Hz, 1H), 8.11 (s, 1H), 7.58-7.64 (m, 4H), 7.43 (d, J = 3.0 Hz, 1H), 7.17 (dd, J = 9.0 Hz, 3H). O

H O

N-(4-fluorophenyl)formamide (5o).33b The title compound was synthesized from 4-Fluorobenzoic acid (154.12 mg, 1.1 mmol) and Formic acid (38 µL, 1.0 mmol) according to general procedure for curtius reaction. White solid (32 mg, 32% yield); 1H-NMR (300 MHz, CDCl3) δ (ppm) 8.58 (d, J = 11.4 Hz, 1H), 8.38 (d, J = 1.32 Hz, 1H), 7.88 (br, 1H), 7.50-7.55 (m, 2H), 7.02-7.10 (m, 6H). F

F

H N

Cl 1-(4-Chloro-3(trifluoromethyl)phenyl)-3-(2-fluoro-4-hydroxyphenyl)urea (24). The title compound was synthesized from 2-Fluoro-4Hydroxybenzoic acid (262.26 mg, 1.68 mmol) and 4-Chloro3-(trifluoromethyl)aniline (300 mg, 1.53 mmol) according to general procedure for curtius reaction. Off white solid (300 mg, 56% yield); m.p. 195-200ºC; 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.68 (br, 1H), 9.32 (br, 1H), 8.26 (br, 1H), 8.11 (s, 1H), 7.58-7.64 (m, 3H), 6.56-6.66 (m, 2H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 155.0, 154.8, 139.9, 132.4, 127.3, 125.0, 123.2, 118.1, 117.9, 116.9, 116.9, 111.4, 103.2, 102.9; HRMS (ESI-TOF) (m/z): [M+Na]+ Calcd for C14H9ClF4N2O2Na 371.0186; Found 371.0170.

N-(4-ethoxyphenyl)formamide (4o).33a The title compound was synthesized from 4-Ethoxybenzoic acid (183 mg, 1.1 mmol) and Formic acid (38 µL, 1.0 mmol) according to general procedure for curtius reaction. White solid (61 mg, 37% yield); 1H-NMR (300 MHz, CDCl3, mixture of two rotamers) δ (ppm) 8.49 (d, J = 11.52 Hz, 1H), 8.30 (d, J = 1.59 Hz, 1H), 8.07-8.10 ( br, 1H), 7.42 (d, J = 8.94 Hz, 2H+1NH), 7.01 (d, J = 8.85 Hz, 2H),6.85 (t, J = 8.41 Hz, 4H), 3.96-4.04 (m, 4H), 1.38-1.43 (m, 6H). H N

H N

HO

O

C 2H 5O

F F

O

H

H N

F

H N

HO

N-p-tolylformamide (2o).33a The title compound was synthesized from p-Toulic acid (150 mg, 1.1 mmol) and Formic acid (38 µL, 1.0 mmol) according to general procedure for curtius reaction. White solid (47 mg, 35% yield); 1H-NMR (300 MHz, CDCl3, mixture of two rotamers) δ (ppm) 8.55 (d, J = 11.46 Hz, 1H), 8.26 (d, J = 1.59 Hz, 1H), 7.46 (br, 1H), 7.34 (d, J = 8.37 Hz, 2H), 7.06 (t, J = 8.41 Hz, 4H), 6.91 (d, J = 8.31 Hz, 2H), 2.25/2.24(2s, 6H). H N

CH3

ASSOCIATED CONTENT

Supporting Information Figure S1 to S4 and analytical spectral

11



data of all reported compounds is available as supporting information

116, 12029-12122. (b) Pattabiraman, V. R.; Bode, J. W. Rethinking amide bond synthesis. Nature. 2011, 480, 471-479. (c) Valeur, E.; Bradley, M. Amide bond formation: beyond the myth of coupling reagents. Chem. Soc. Rev. 2009, 38, 606-631. (d) Lanigan, R. M.; Sheppard, T. D. Recent Developments in Amide Synthesis: Direct Amidation of Carboxylic Acids and Transamidation Reactions. Eur. J. Org. Chem. 2013, 2013, 7453-7465.

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

(12) Sasaki, K.; Crich, D. Facile Amide Bond Formation from Carboxylic Acids and Isocyanates. Org. Lett. 2011, 13, 2256-2259.

ACKNOWLEDGMENT

(13) (a) Raoul, J. L.; Kudo, M.; Finn, R. S; Edeline, J.; Reig, M.; Galle, P. R. Systemic therapy for intermediate and advanced hepatocellular carcinoma: Sorafenib and beyond. Cancer Treat. Rev. 2018, 68, 16-24. (b) Finn, R. S. Review of Regorafenib for the Treatment of Hepatocellular Carcinoma. Gastroenterology & Hepatology. 2017, 13, 492-495. (c) Bankston, D.; Dumas, J.; Natero, R.; Riedl, B.; Monahan, M. K.; Sibley, R. A Scaleable Synthesis of BAY 43-9006: A Potent Raf Kinase Inhibitor for the Treatment of Cancer. Org. Proc. Res. Dev. 2002, 6, 777-781

Authors acknowledged the support of THSTI for lab facility. AK and NK acknowledge the support of DBT-BIRAC for research fellowship under BIRAC CRS scheme, BT/CRS0200/CRS -10/16. Authors also acknowledge the support of GNDU Amritsar, for HRMS analysis and kind facilitation by Prof Palwinder Singh for same. REFERENCES (1)

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Direct Conversion of Carboxylic Acids to Various Nitrogen

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