Copper(II)-Catalyzed Reactions of Î±-Keto Thioesters with Azides via

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Copper(II)-Catalyzed Reactions of #-Keto Thioesters with Azides via C-C and C-S Bond Cleavages: Synthesis of N-Acylureas and Amides Rajib Maity, Sandip Naskar, and Indrajit Das J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03054 • Publication Date (Web): 02 Feb 2018 Downloaded from http://pubs.acs.org on February 3, 2018

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The Journal of Organic Chemistry

Copper(II)-Catalyzed Reactions of α-Keto Thioesters with Azides via C-C and C-S Bond Cleavages: Synthesis of N-Acylureas and Amides Rajib Maity, Sandip Naskar, and Indrajit Das* Organic and Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata 700 032, India. E-mail: [email protected]

ABSTRACT

Cu(II)-catalyzed reaction of α-keto thioesters with trimethylsilyl azide (TMSN3) proceeds with the transformation of the thioester group into urea through C-C and C-S bond cleavages, constituting a practical and straightforward synthesis of N-acylureas. When diphenyl phosphoryl azide (DPPA) is used instead as the azide source in an aqueous environment, primary amides are formed via substitution of the thioester group. The reactions are proposed to proceed through Curtius rearrangement of the initially formed α-keto acyl azide to generate an acyl isocyanate intermediate, which reacts further with an additional amount of azide or water and rearranges to afford the corresponding products. To demonstrate the potentiality of the

method,

one-step

syntheses

of

pivaloylurea

and

anticonvulsant activities, have been carried out.

ACS Paragon Plus Environment

isovaleroylurea,

displaying

The Journal of Organic Chemistry 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

INTRODUCTION The N-acylurea moiety is a functional group commonly found in a broad spectrum of medicinal and therapeutic agents.1-2 For example, some are known to possess promising anticonvulsant, anti-inflammatory, analgesic, anti-fungal, anti-tumor, and antiproliferative activities,1 or are used in agriculture as insecticides.2 N-Acylureas are also important building blocks in organic syntheses.3 Various synthetic strategies have been developed for accessing N-acylureas.4-9 Traditionally, these are synthesized by coupling activated carboxylic acids such as acid chlorides, anhydrides, esters, and carbodiimides with ureas4 or by the condensation of amines with acyl isocyanates/S-allyl N-acylmonothiocarbamates.5 Other methods starting from ureas include arylboronic acid-catalyzed direct condensation with carboxylic acids6a and acylation with alk1-en-2-yl esters.6b Recently, the syntheses of N-acylureas have also been accomplished via microwave-assisted Pd-catalyzed carbonylation of aryl or heteroaryl halides with urea nucleophiles using CO gas/Mo(CO)6,7 Rh(III)-catalyzed C-H functionalization of indolines with aryl and alkyl isocyanates,8 or NHC-catalyzed oxidative coupling of aldehydes with N, Nʹ-disubstituted carbodiimides under aerobic conditions.9a Solid-phase synthesis of Nacylureas or cinnamoyl ureas from resin-bound ureas and acyl chlorides has also been reported.9b Despite these different approaches, most of the published methods require either ureas or suitably activated carboxylic acids in the form of labile compounds such as the acyl chlorides, which can, in some cases, be difficult to handle or synthesize. Consequently, development of efficient routes to synthesize N-acylureas from readily accessible starting materials continues to captivate organic chemists. Continuing our efforts for the exploration of α-keto thioesters as building blocks for accessing diverse heterocycles,10 we investigated their reactivity with different azides.11 This revealed that with TMSN3 in the presence of Cu(OAc)2 as a catalyst they delivered N-


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acylureas, N-cinnamoyl ureas, and N-aroylureas;

the results provided a practical and

straightforward synthesis of the products. The substrates possibly underwent Curtius rearrangement,12 the in situ generated acyl isocyanate intermediate reacting further to deliver the products (Scheme 1). The reaction seems to proceed with the transformation of the thioester group into a urea moiety via cleavage of the C-C and C-S bonds with retention of the thioester carbonyl group. Furthermore, use of DPPA instead of TMSN3 as the azide source and carrying out the reaction in an aqueous milieu provided an alternative procedure to generate primary amides from α-keto thioesters via removal of the thioester group (Scheme 1). Scheme 1. Proposed synthesis of N-acylureas 3 and primary amides 4 from α-keto thioesters and azides

RESULTS AND DISCUSSION To optimize the reaction conditions for cinnamoyl urea, we initiated model studies with γphenyl substituted β,γ-unsaturated α-keto methylthioesters 1a, different azide sources 2, dry DMF, and 3 Å MS under 30 mol% copper catalysis at 80 oC (Table 1). We were pleased to observe that CuCl could catalyze this transformation in the presence of TMSN3 to afford 3a in 66% yield (entry 1). Though other Cu(I) and Cu(II) salts such as CuBr, Cu2O, CuCl2,



CuBr2, Cu(acac)2, and Cu(OTf)2 proved inferior (entries 2-7), utilization of Cu(OAc)2 as a catalyst could significantly improve the yield to 89%, and the reaction proceeded to Table 1. Optimization studies for accessing cinnamoyl urea 3aa,b

completion within 1 h (entry 8). Subsequent attempts with commercially available azide sources such as tetrabutylammonium azide (TBAA), NaN3, and p-toluenesulfonyl azide (TsN3) proved discouraging (entries 9-11). The use of diphenylphosphoryl azide (DPPA) as an azide source failed to deliver 3a (entry 12), furnishing 4a instead in 78% yield (Table 5, vide infra). The reaction did not work well either with 3.0 equiv. TMSN3 (entry 13) or 10 mol% Cu(OAc)2 (entry 14), generating only moderate yields. Different solvents such as DMSO and MeCN were also screened (entries 15-16), but without success. The yield of the product 3a also went down when the reaction was conducted at 60 oC or 100 oC (entries 17-


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18). Only moderate yields were achieved in the absence of any catalyst or solvent, as side reactions were observed (entries 19-20). With the optimal reaction conditions (entry 8, Table 1), the substrate scope and generality for this transformation was investigated using various γ-substituted β,γ-unsaturated α-keto methylthioesters 1 and TMSN3 2a, the results of which are given in Table 2. The reaction Table 2. Substrate scope of the Cu(OAc)2/TMSN3-mediated synthesis of N-acylureas from γ-substituted β,γunsaturated α-keto methylthioestersa



tolerates a wide range of γ-substituted α-keto methylthioesters. Substrates containing an aromatic ring at the γ-position of thioesters with electron-rich (1b-j) or electron-poor 1k-n) substituents delivered the corresponding substituted cinnamoyl ureas in moderate to good yields (3b-n).9b,13 The p-bromo substituted phenyl derivative (1o) gave the expected product (3o) in low yield, perhaps due to the competitive coupling reaction,14 though no aromatic azide was isolated. The reaction with a strong electron-withdrawing substituent (-CN) on the aromatic ring also turned out to be rather sluggish (3p), ostensibly owing to the poor migratory aptitude during Curtius rearrangement. However, it proceeded uneventfully in the presence of a heteroaromatic substituent, delivering the product in moderate yield (3q). Even thioesters 1r and 1s containing γ-naphthyl substituents yielded the corresponding products (3r-s). Moreover, α-keto thioesters with an alkyl group at the γ-position (1t-v) also furnished the desired products 3t-v in moderate yields. The structures of 3a and 3l were established by single crystal X-ray diffraction analysis (Table 2).15 Subsequently, we extended the scope of the reaction with aryl rather than styryl substituted αketo thioesters (Table 3). Under the standard reaction conditions shown in Table 2, substrates containing electron-neutral (1aa), electron-donating (1ab-1ad), and electron-withdrawing (1ae) substituents in the aromatic ring or with a fused aromatic ring (1af) or a biphenyl Table 3. Substrate scope of the Cu(OAc)2/TMSN3-mediated synthesis of N-aroylureas from α-keto thioestersa


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substituent (1ag) at the α-position of the α-keto thioesters delivered the corresponding Naroylureas in moderate yields (3aa-ag).9b,16 The synthetic versatility of this developed methodology was established by single-step syntheses of pivaloylurea (PVU) 3ah, isovaleroylurea (IVU) 3ai, 2-methylbutanoylurea 3aj, and n-butyrylurea 3ak from the corresponding α-keto thioesters 1ah-1ak (Scheme 2).1b,17 Scheme 2. Syntheses of pivaloylurea, isovaleroylurea, 2-methylbutanoylurea, and n-butyrylureaa

Based on the experimental results, we propose a plausible mechanistic pathway as detailed in Scheme 3. We presume that Cu(II) may form a complex I by coordinating with the sulphur atom of the thioesters, increasing their electrophilicity. Nucleophilic substitution by azide followed by elimination of thiolate anion could then lead via intermediate II to intermediate III. This in turn undergoes Curtius rearrangement via elimination of nitrogen to generate an acyl isocyanate intermediate IV, which reacts with TMSN3 by pathway a or b. Pathway a envisages cycloadduct formation with intermediate IV to produce silylated tetrazole V, which expels molecular nitrogen to generate intermediate VI.18 VI could exist in equilibrium with an acyl nitrene species VII, which undergoes reduction with thiolate anion catalyzed by copper, as described in the literature, to yield product 3.19 Alternatively (pathway b), IV could react with TMSN3 to produce the carbamoyl azide VIII (a 1,4-adduct), which undergoes similar reduction with [Cu]-thiolate via elimination of nitrogen to form 3.19 Attempts to isolate any of the proposed intermediates in Scheme 3 were unsuccessful. It is



Scheme 3. Proposed mechanism for the formation of N-acylureas from γ-substituted β,γ-unsaturated α-keto methylthioesters or α-keto thioesters

TMSN3 O

O O

R S

O

TMSN3 Cu(OAc)2, DMF, 3 Å MS, 80 oC

R1

R

R S

[Cu]

R1

N3

N

R

N

N

O

II

- N2

O

- [Cu] [SR1]

O

Me 3Si

I

1

R1

S

O

[ -keto acyl azide] III Intermediate VI or VII

[Cu] [-SR1] "reduction" R1SSR 1

[Curtius rearrangement]

O R

N2

path a

N

R

path b

C O

O

Me3SiO

TMSN3

O

N

N

N

N

R

[Carbamoyl azide]

[acyl isocyanate] IV

O N H

NH2

N-acylurea 3

VIII

TMSN3

H3O "reduction"

O

SiMe 3 O

O N

N R

N

R

O N

C

N

V silylated tetrazole

N2

VI

SiMe 3 N

O R

SiMe 3 N

C

[Cu] [-SR1] N

O VII acyl nitrene

R1SSR1

noteworthy that a large excess of TMSN3 (5 equiv.) is critical to obtain N-acylureas in moderate to high yields. In order to support our proposed mechanistic model, we next decided to use ESI-HRMS (LTQ Orbitrap) studies as a means of probing the proposed intermediates from the reaction mixtures. α-Keto thioester 1aa was chosen to study the reaction under the standard conditions. An aliquot was taken from the reaction mixture after 5 min, diluted with acetonitrile and analysed by ESI-HRMS (Figure 1). The spectrum showed [M + Na] peaks corresponding to the desilylated product of the intermediates silylated tetrazole or carbamoyl azide V or VIII (m/z 213.0396) and for acyl nitrene VI or VII (m/z 185.0332). This experiment supports the formation of the intermediates V or VIII and VI or VII, as described in our proposed mechanism. However, acyl isocyanate intermediate IV was hardly detectable, perhaps due to its high reactivity towards azide in solution. Interestingly, the spectrum showed peaks at m/z 215.0804 and 202.0487, attributed to the [M + Na] peak of PhCONHCONMe2 [derived by the addition of NMe2 (from DMF)] and [M – CO + Na] peak


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of PhCONHCOOAc [derived by the addition of OAc from Cu(OAc)2] to intermediate IV (Figure 1), which indirectly supports the formation of a short-lived acyl isocyanate intermediate derived via Curtius rearrangement. It must be mentioned here that a thiocarbamate should be formed if the thiolate anion, released in the first step, acts as a nucleophile to intermediate IV. But we neither encountered such product nor detected the corresponding mass spectral peak during ESI-HRMS studies. However, we isolated diphenyl disulfide (Ph2S2) in 10-12% yield during all the reactions discussed above.

Figure 1. ESI-HRMS (LTQ Orbitrap) spectrum of the crude reaction mixture after 5 min. Aliquot taken was diluted with MeCN.



In order to gain further evidence for the intermediacy of the acyl isocyanate IV, we performed control experiments (Scheme 4). DMSO was preferred as a solvent over DMF to slow down the reaction. When 1aa was treated with 3 equiv. TMSN3 and Cu(OAc)2 in DMSO at room temperature, and the reaction was quenched either with MeOH or piperidine after 5 min, the carbamate 5a or urea 5b derivative was obtained, as expected, along with the desired N-acylurea 3aa. These two parallel experiments support the formation of the intermediate IV. Moreover, the formation of primary amides 4 (Table 6, vide infra) from αketo thioesters 1 in the presence of water provides direct evidence for the generation of acyl isocyanate IV intermediate via Curtius rearrangement.

Scheme 4. Control Experiments

Furthermore, to clarify the mechanism of the reduction of azide to amine via nitrene intermediate, carbamoyl azide VIII was prepared independently from the literature precedent,19a and subjected to reductions in the presence of different reducing agents. However, no expected product was ever observed even after heating the reaction mixtures for prolonged periods; the starting materials either underwent degradation or were recovered. Parallely, commercially available benzoyl isocyanate IV was treated with TMSN3 and different reducing agents, but only carbamoyl azide VIII was isolated. However, the pathway by which the reduction of nitrenes to amines take place is uncertain at this point, and further investigations are going on to find it out.19b-c,20 ACS Paragon Plus Environment

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The utility and practical usefulness of the protocol were further investigated by carrying out the reactions on scale-up batches to isolate 3a, 3b, and 3s without any significant decrease in the yields (Table 4).

Table 4. Scale-up batches for N-acylureasa,b

Interestingly, during the optimization studies for accessing cinnamoyl urea, we observed that DPPA in the presence of 30 mol% Cu(OAc)2 provided the cinnamamide in 78% yield (vide supra, Table 1, entry 12). However, the reason behind this unusual behaviour of DPPA is not very clear at present. Perhaps the acyl isocyanate intermediate formed via Curtius rearrangement undergoes hydrolysis during work-up process to produce the cinnamamide. Formation of the primary amide as the exclusive product led us to consider whether this method could provide a general access to this valuable scaffold as a complement to the existing procedures.21,22 After optimization with different conditions, use of 2.0 equiv. DPPA and 30 mol% Cu(OTf)2 in DMF/H2O (9.5:0.5) proved to be optimal (entry 4, Table 5). Next, the scope of α-keto thioesters 1 was explored, as shown in Table 6. Various γ-substituted β,γunsaturated α-keto methylthioesters or α-substituted α-keto thioesters were successfully converted to their corresponding primary amides in moderate to good yields (4a-s).22 It is noteworthy that the α-keto thioesters having an alkyl group at the α-position were also found to be compatible under the reaction conditions (4t-u).22h



Table 5. Optimization studies for accessing cinnamamide 4aa

Table 6. Substrate scope of the Cu(OTf)2/DPPA-mediated synthesis of primary amidesa

O R

Cu(OTf)2 (30 mol%), 2 mL DMF-H2O (v/v 9.5:0.5), 100 oC, 2.5-4 h

O

SR1

PhO P OPh N3

O 1 (1.0 equiv.)

- N2

O R

- CO2

R = (Het)Ar, Alk; R1 = Alk, Ar O

O

O NH2

NH2

O NH2

Me 4a, 3 h, 90%

NH2

4 Yield up to 92% 20 entries

2b (2 equiv.)

Me

NH2

MeO

4b, 3.5 h, 87%

OMe 4d, 3.5 h, 80%

4c, 4 h, 57%

O

O NH2

O NH2

Cl

NH2

Br Cl (X-ray of 4e)b

4e, 3 h, 77%

Cl

O

O

Br

O

Cl

Br

Br

O NH2

4k, 3 h, 57% O

NH2

O

O

O NH2

O

O NH2

NH2

NH2

Cl

MeO 4p, 3 h, 72%

NH2 4o, 4 h, 57%

4n, 3 h, 65%

4m, 3.5 h, 83%

4l, 2.5 h, 78%

O NH2

S

NC

NH2

O2 N

4j, 2.5 h, 92%

4i, 3.5 h, 81% O

O NH2

NH2

NH2

4h, 4 h, 53%

4g, 3 h, 63%

4f, 3 h, 74%

4q, 3 h, 43%

4r, 3 h, 60%

4s, 3 h, 72%

O NH2

4t, 2.5 h, 66%

NH2 4u, 3 h, 54%c

a

Reaction conditions: -Substituted , -unsaturated -keto methylthioesters or -keto thioesters 1 (0.05 g, 1 equiv.), Cu(OTf) 2 (30 mol%), and DPPA 2b (2 equiv./mmol) in 2 mL DMF/H2O (v/v 9.5:0.5 mL) at 100 oC. bThe thermal ellipsoids are shown in 50% probability level. cAlong with 4u, some inseparable mixtures were present.


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In analogy with the mechanism outlined in Scheme 3, the formation of primary amides 4 could be explained (Scheme 5) by invoking in situ generation of an acyl isocyanate intermediate IV, which on subsequent reaction with water and elimination of carbon dioxide could lead to 4 via the unstable intermediate acyl carbamic acid IX. Scheme 5. Proposed mechanism for the formation of primary amides 4 from γ-substituted β,γ-unsaturated αketo methylthioesters or α-keto thioesters 1

CONCLUSIONS In summary, we have developed a new and efficient route to N-acylureas from α-keto thioesters, TMSN3, and catalytic Cu(II). C-C and C-S bond cleavages with retention of the keto group in α-keto thioester are thereby achieved. Examples of the cleavage of these bonds in a single transformation are still rare. The introduction of DPPA instead of TMSN3 as the azide source in presence of water provides an alternative synthesis of primary amides via removal of thioester group from α-keto thioesters. Both the reactions are proposed to proceed through Curtius rearrangement leading to the formation of an acyl isocyanate intermediate, which then reacts with an additional amount of azide or water and rearranges to afford the corresponding products. The formation of the reactive intermediates in the proposed mechanism has been supported by ESI-HRMS studies and control experiments. To exhibit the potentiality of the developed method for N-acylureas, single-step syntheses of pivaloylurea and isovaleroylurea are reported. EXPERIMENTAL SECTION General Information. Melting points were determined in open-end capillary tubes and are uncorrected. TLC was performed on silica gel plates (Merck silica gel 60, f254), and the spots



were visualized with UV light (254 and 365 nm) or by charring the plate dipped in 5% H2SO4-MeOH or vanillin charring solution. 1H and 13C NMR spectra were recorded in CDCl3 or DMSO-d6 solvent using TMS as the internal standard. HRMS (m/z) were measured using EI (magnetic sector, positive ion), ESI (Q-TOF or LTQ Orbitrap, positive ion) techniques. Infrared (IR) spectra were recorded on Fourier transform infrared spectroscopy, only intense peaks were reported. General procedure for the synthesis of 3. Cu(OAc)2 (30 mol %) and 3 Å MS (0.05 g) were taken in a 25 mL flame-dried, two-neck, round-bottomed flask, equipped with a magnetic stirring bar and a condenser, under an argon atmosphere and dried by heating in vacuum. β,γUnsaturated α-keto methylthioester or α-keto thioester 1 (0.05 g, 1.0 equiv) was added into the mixture. Dry DMF (2.0 mL) and TMSN3 2a (5.0 equiv./mmol) were introduced successively, and the resulting reaction mixture was stirred at 80 oC, employing time as mentioned. After completion of the reaction (TLC), saturated NH4Cl solution was added, and the mixture was extracted with dichloromethane (10 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to get a residue. The crude residue was purified by silica gel column chromatography [230–400; eluent: ethyl acetate/n-hexane] to obtain 3. General procedure for the synthesis of 4. A mixture of β,γ-Unsaturated α-keto methylthioesters or α-keto thioester 1 (0.05 g, 1.0 equiv.), Cu(OTf)2 (30 mol%), 2 mL DMFH2O (v/v 9.5:0.5), and diphenyl phosphoryl azide 2b (2 equiv./mmol) was heated at 100 oC, employing time as mentioned. After completion of the reaction (TLC), saturated NH4Cl solution was added, and the mixture was extracted with dichloromethane (10 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to get a residue. The crude residue was purified by silica gel column chromatography [230–400; eluent: ethyl acetate/n-hexane] to obtain 4.


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N-Carbamoylcinnamamide 3a:9b Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (45%); white solid (0.041 g, 89% yield); mp 204206 oC (lit.9b 202-204 oC); solvent of crystallization: dichloromethane/methanol. Spectral data are consistent with previously reported values. 1H NMR (300 MHz, d6-DMSO): δ = 10.33 (br. s., 1 H), 7.92 (br. s., 1 H), 7.66 (d, J = 15.9 Hz, 1 H), 7.59 - 7.62 (m, 2 H), 7.44 - 7.46 (m, 3 H), 7.33 (br. s., 1 H), 6.81 ppm (d, J = 15.9 Hz, 1 H); 13C{1H} NMR (75 MHz, d6-DMSO): δ = 166.3, 154.2, 143.0, 134.2, 130.5, 129.1 (2 CH), 128.1 (2 CH), 120.4 ppm. (E)-N-Carbamoyl-3-(2,4,5-trimethylphenyl)acrylamide 3b: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (45%); white solid (0.039 g, 83% yield); mp 214-216 oC. 1H NMR (600 MHz, d6-DMSO): δ = 10.26 (br. s., 1 H), 7.92 (br. s., 1 H), 7.79 (d, J = 15.6 Hz, 1 H), 7.29 (s, 2 H), 7.03 (br. s., 1 H), 6.66 (d, J = 15.6 Hz, 1 H), 2.30 (s, 3 H), 2.19 ppm (s, 6 H);

13

C{1H} NMR (150 MHz, d6-DMSO): δ =

167.0, 154.7, 140.8, 139.4, 135.4, 134.6, 132.6, 130.7, 127.7, 120.5, 19.7, 19.4, 19.2 ppm; IR (KBr): ṽmax = 3379, 3318, 3223, 1667, 1618, 1417, 1189, 1097 cm-1; HRMS (EI): m/z calcd for C13H16N2O2 [M]+: 232.1212; found: 232.1203. (E)-N-Carbamoyl-3-(3,5-dimethylphenyl)acrylamide 3c: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (45%); white solid (0.033 g, 71% yield); mp 213-215 oC. 1H NMR (300 MHz, d6-DMSO): δ = 10.27 (br. s., 1 H), 7.92 (br. s., 1 H), 7.58 (d, J = 15.9 Hz, 1 H), 7.32 (br. s., 1 H), 7.20 (s, 2 H), 7.08 (br. s., 1 H), 6.78 (d, J = 15.6 Hz, 1 H), 2.29 ppm (s, 6 H); 13C{1H} NMR (75 MHz, d6-DMSO): δ = 166.3, 154.2, 143.2, 138.1 (2 CH), 134.1, 132.0, 125.9 (2 CH), 120.1, 20.8 (2 x CH3) ppm; IR (KBr): ṽmax = 3421, 3316, 1679, 1625, 1405, 1192, 1098 cm-1; HRMS (EI): m/z calcd for C12H14N2O2 [M]+: 218.1055; found: 218.1056. (E)-N-Carbamoyl-3-(p-tolyl)acrylamide 3d:13b Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (45%); white solid (0.028 g, 60% yield);



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mp 219-221 oC. Spectral data are consistent with previously reported values. 1H NMR (600 MHz, d6-DMSO): δ = 10.28 (br. s., 1 H), 7.91 (br. s., 1 H), 7.61 (d, J = 15.6 Hz, 1 H), 7.47 (d, J = 7.2 Hz, 2 H), 7.30 (br. s., 1 H), 7.24 (d, J = 7.2 Hz, 2 H), 6.73 (d, J = 15.6 Hz, 1 H), 2.31 ppm (s, 3 H);

13

C{1H} NMR (150 MHz, d6-DMSO): δ = 166.9, 154.7, 143.4, 140.9,

131.9, 130.1 (2 CH), 128.5 (2 CH), 119.7, 21.5 ppm. (E)-N-Carbamoyl-3-(o-tolyl)acrylamide 3e: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (45%); white solid (0.027 g, 58% yield); mp 209-211 oC. 1H NMR (300 MHz, d6-DMSO): δ = 10.37 (br. s., 1 H), 7.93 (br. s., 1 H), 7.87 (d, J = 15.9 Hz, 1 H), 7.53 (d, J = 6.9 Hz, 1 H), 7.27 - 7.35 (m, 4 H), 6.71 (d, J = 15.9 Hz, 1 H), 2.39 ppm (s, 3 H); 13C{1H} NMR (75 MHz, d6-DMSO): δ = 166.7, 154.6, 140.8, 137.9, 133.4, 131.3, 130.6, 126.9, 126.7, 122.0, 19.8 ppm; IR (KBr): ṽmax = 3375, 3322, 1697, 1603, 1388, 1183, 1100 cm-1; HRMS (ESI): m/z calcd for C11H12N2O2Na [M + Na]+: 227.0797; found: 227.0799. (E)-N-Carbamoyl-3-(2,3,4-trimethoxyphenyl)acrylamide 3f: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (50%); white solid (0.033 g, 70% yield); mp 190-192 oC. 1H NMR (300 MHz, d6-DMSO): δ = 10.30 (br. s., 1 H), 7.96 (br. s., 1 H), 7.72 (d, J = 15.9 Hz, 1 H), 7.30 (d, J = 8.7 Hz, 2 H), 6.92 (d, J = 8.7 Hz, 1 H), 6.77 (d, J = 15.9 Hz, 1 H), 3.84 (s, 3 H), 3.83 (s, 3 H), 3.76 ppm (s, 3 H);

13

C{1H}

NMR (75 MHz, d6-DMSO): δ = 166.8, 155.5, 154.4, 152.8, 141.9, 137.9, 123.5, 120.5, 119.1, 108.6, 61.3, 60.5, 56.1 ppm; IR (KBr): ṽmax = 3428, 3135, 1690, 1572, 1492, 1286, 1176, 1100, 783 cm-1; HRMS (EI): m/z calcd for C13H16N2O5 [M]+: 280.1059; found: 280.1049. (E)-N-Carbamoyl-3-(3,4-dimethoxyphenyl)acrylamide 3g: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (50%); white solid (0.029 g, 62% yield); mp 210-212 oC. 1H NMR (300 MHz, d6-DMSO): δ = 10.17 (br. s., 1


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H), 7.94 (br. s., 1 H), 7.60 (d, J = 15.6 Hz, 1 H), 7.29 (br. s., 1 H), 7.17 - 7.19 (m, 2 H), 7.02 (d, J = 9.0 Hz, 1 H), 6.69 (d, J = 15.6 Hz, 1 H), 3.80 ppm (s, 6 H); 13C{1H} NMR (75 MHz, d6-DMSO): δ = 166.6, 154.3, 151.0, 148.9, 143.1, 126.9, 122.2, 118.0, 111.8, 110.5, 55.6, 55.5 ppm; IR (KBr): ṽmax = 3372, 3312, 1668, 1599, 1516, 1262, 1182, 1147 cm-1; HRMS (EI): m/z calcd for C12H14N2O4 [M]+: 250.0954; found: 250.0946. (E)-N-Carbamoyl-3-(3-methoxyphenyl)acrylamide 3h: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (50%); white solid (0.031 g, 66% yield); mp 157-159 oC. 1H NMR (300 MHz, d6-DMSO): δ = 10.29 (br. s., 1 H), 7.91 (br. s., 1 H), 7.63 (d, J = 15.9 Hz, 1 H), 7.37 - 7.40 (m, 1 H), 7.34 (br. s., 1 H), 7.15 - 7.19 (m, 2 H), 7.01 (dd, J = 2.1, 8.1 Hz, 1 H), 6.81 (d, J = 15.6 Hz, 1 H), 3.79 ppm (s, 3 H); 13C{1H} NMR (75 MHz, d6-DMSO): δ = 166.6, 160.0, 154.6, 143.2, 136.0, 130.6, 121.2, 120.6, 116.5, 113.7, 55.6 ppm; IR (KBr): ṽmax = 3364, 3221, 1680, 1578, 1382, 1255, 1175 cm-1; HRMS (EI): m/z calcd for C11H12N2O3 [M]+: 220.0848; found: 220.0842. (E)-N-Carbamoyl-3-(4-hydroxyphenyl)acrylamide 3i:13c Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (50%); white solid (0.025 g, 54% yield); mp 232-234 oC. Spectral data are consistent with previously reported values. 1H NMR (300 MHz, d6-DMSO): δ = 10.20 (br. s., 1 H), 10.06 (br. s., 1 H), 7.95 (br. s., 1 H), 7.56 (d, J = 15.6 Hz, 1 H), 7.44 (d, J = 8.7 Hz, 2 H), 7.26 (br. s., 1 H), 6.82 (d, J = 8.4 Hz, 2 H), 6.58 ppm (d, J = 15.9 Hz, 1 H); 13C{1H} NMR (75 MHz, d6-DMSO): δ = 166.7, 159.9, 154.4, 143.3, 130.1 (2 CH), 125.2, 116.5, 116.0 (2 CH) ppm. (E)-3-(4-(tert-Butyl)phenyl)-N-carbamoylacrylamide 3j: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (45%); white solid (0.037 g, 79% yield); mp 197-199 oC. 1H NMR (300 MHz, d6-DMSO): δ = 10.30 (br. s., 1 H), 7.93 (br. s., 1 H), 7.63 (d, J = 15.6 Hz, 1 H), 7.53 (d, J = 8.7 Hz, 2 H), 7.47 (d, J = 8.7 Hz, 2 H), 7.31 (br. s., 1 H), 6.77 (d, J = 15.9 Hz, 1 H), 1.29 ppm (s, 9 H);


13

C{1H} NMR (75 MHz, d6-


Page 18 of 36

DMSO): δ = 166.4, 154.2, 153.4, 142.8, 131.4, 127.9 (2 CH), 125.9 (2 CH), 119.5, 34.6, 30.9 ppm (3 CH3); IR (KBr): ṽmax = 3386, 2961, 1683, 1579, 1381, 1179 cm-1; HRMS (EI): m/z calcd for C14H18N2O2 [M]+: 246.1368; found: 246.1364. (E)-N-Carbamoyl-3-(4-chlorophenyl)acrylamide 3k:13b Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (45%); white solid (0.027 g, 58% yield); mp 234-236 oC. Spectral data are consistent with previously reported values. 1H NMR (600 MHz, d6-DMSO): δ = 10.33 (br. s., 1 H), 7.88 (br. s., 1 H), 7.63 (d, J = 15.6 Hz, 1 H), 7.60 (d, J = 8.4 Hz, 2 H), 7.50 (d, J = 8.4 Hz, 2 H), 7.33 (br. s., 1 H), 6.78 ppm (d, J = 15.6 Hz, 1 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 166.5, 154.6, 142.0, 135.3, 133.5, 130.2 (2 CH), 129.6 (2 CH), 121.6 ppm. (E)-N-Carbamoyl-3-(3-chlorophenyl)acrylamide 3l: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (45%); white solid (0.037 g, 79% yield); mp 186-188 oC; solvent of crystallization: dichloromethane/acetone.

1

H NMR

(600 MHz, d6-DMSO): δ = 10.32 (br. s., 1 H), 7.87 (br. s., 1 H), 7.65 (s, 1 H), 7.63 (d, J = 16.2 Hz, 1 H), 7.55 (d, J = 7.2 Hz, 1 H), 7.45 - 7.48 (m, 2 H), 7.35 (br. s., 1 H), 6.83 ppm (d, J = 15.6 Hz, 1 H);

13

C{1H} NMR (150 MHz, d6-DMSO): δ = 166.4, 154.5, 141.7, 136.9,

134.2, 131.4, 130.5, 128.2, 126.8, 122.6 ppm; IR (KBr): ṽmax = 3389, 3338, 3209, 1668, 1626, 1418, 1188, 1093 cm-1; HRMS (EI): m/z calcd for C10H9ClN2O2 [M]+: 224.0353; found: 224.0349. (E)-N-Carbamoyl-3-(2,5-dichlorophenyl)acrylamide 3m:13c Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (45%); white solid (0.032 g, 68% yield); mp 209-211 oC. Spectral data are consistent with previously reported values. 1H NMR (600 MHz, d6-DMSO): δ = 10.37 (br. s., 1 H), 7.83 (br. s., 1 H), 7.79 (d, J = 15.6 Hz, 1 H), 7.70 (d, J = 2.4 Hz, 1 H), 7.59 (d, J = 9.0 Hz, 1 H), 7.52 (dd, J = 2.4, 9.0 Hz, 1


Page 19 of 36 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


H), 7.40 (br. s., 1 H), 6.88 ppm (d, J = 15.6 Hz, 1 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 165.9, 154.3, 136.9, 134.3, 132.9, 132.7, 132.3, 131.8, 127.8, 125.7 ppm. (E)-N-Carbamoyl-3-(2,4-dichlorophenyl)acrylamide 3n: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (45%); white solid (0.024 g, 51% yield); mp 200-202 oC. 1H NMR (600 MHz, d6-DMSO): δ = 10.44 (br. s., 1 H), 7.82 7.85 (m, 2 H), 7.74 (d, J = 1.8 Hz, 1 H), 7.68 (d, J = 8.4 Hz, 1 H), 7.54 (dd, J = 1.8, 9.0 Hz, 1 H), 7.38 (br. s., 1 H), 6.85 ppm (d, J = 15.6 Hz, 1 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 166.0, 154.4, 137.1, 135.9, 135.0, 131.5, 130.1, 129.5, 128.7, 124.6 ppm; IR (KBr): ṽmax = 3392, 3329, 1667, 1622, 1477, 1187, 1098 cm-1; HRMS (ESI): m/z calcd for C10H8Cl2N2O2Na [M + Na]+: 280.9861; found: 280.9854. (E)-3-(4-Bromophenyl)-N-carbamoylacrylamide 3o: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (45%); white solid (0.019 g, 40% yield); mp 250-252 oC. 1H NMR (600 MHz, d6-DMSO): δ = 10.34 (br. s., 1 H), 7.88 (br. s., 1 H), 7.61 - 7.66 (m, 3 H), 7.53 (d, J = 8.4 Hz, 2 H), 7.34 (br. s., 1 H), 6.80 ppm (d, J = 16.2 Hz, 1 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 166.5, 154.6, 142.1, 133.9, 132.6 (2 CH), 130.4 (2 CH), 124.2, 121.7 ppm; IR (KBr): ṽmax = 3376, 1739, 1692, 1585, 1397, 1326, 1185 cm-1; HRMS (ESI): m/z calcd for C10H9BrN2O2Na [M + Na]+: 292.9725; found: 292.9725. (E)-N-Carbamoyl-3-(3-cyanophenyl)acrylamide 3p: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (50%); white solid (0.019 g, 41% yield); mp 236-238 oC. 1H NMR (600 MHz, d6-DMSO): δ = 10.37 (br. s., 1 H), 8.05 (br. s., 1 H), 7.91 (d, J = 7.8 Hz, 1 H), 7.88 (d, J = 7.8 Hz, 2 H), 7.68 (d, J = 15.6 Hz, 1 H), 7.65 (d, J = 7.2 Hz, 1 H), 7.36 (br. s., 1 H), 6.87 ppm (d, J = 15.6 Hz, 1 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 166.3, 154.5, 141.0, 135.9, 134.0, 132.4 (2 CH), 130.8, 123.3, 118.8,



Page 20 of 36

112.7 ppm; IR (KBr): ṽmax = 3367, 3330, 3215, 2231, 1665, 1618, 1403, 1184, 1101 cm-1; HRMS (EI): m/z calcd for C11H9N3O2 [M]+: 215.0695; found: 215.0689. (E)-N-Carbamoyl-3-(thiophen-2-yl)acrylamide 3q: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (45%); white solid (0.0282 g, 61% yield); mp 203-205 oC. 1H NMR (600 MHz, d6-DMSO): δ = 10.26 (br. s., 1 H), 7.89 (br. s., 1 H), 7.81 (d, J = 15.0 Hz, 1 H), 7.69 (d, J = 4.8 Hz, 1 H), 7.47 (d, J = 3.6 Hz, 1 H), 7.30 (br. s., 1 H), 7.13 (t, J = 4.8 Hz, 1 H), 6.54 ppm (d, J = 15.0 Hz, 1 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 166.5, 154.6, 139.6, 136.4, 133.0, 130.1, 129.1, 119.1 ppm; IR (KBr): ṽmax = 3378, 3332, 1690, 1613, 1388, 1169, 1105 cm-1; HRMS (EI): m/z calcd for C8H8N2O2S [M]+: 196.0306; found: 196.0300. (E)-N-Carbamoyl-3-(naphthalen-2-yl)acrylamide 3r: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (40%); white solid (0.032 g, 68% yield); mp 179-181 oC. 1H NMR (600 MHz, d6-DMSO): δ = 10.36 (br. s., 1 H), 8.13 (br. s., 1 H), 7.92 - 7.98 (m, 4 H), 7.81 (d, J = 15.6 Hz, 1 H), 7.69 (d, J = 9.0 Hz, 1 H), 7.56 - 7.57 (m, 2 H), 7.34 (br. s., 1 H), 6.92 ppm (d, J = 15.6 Hz, 1 H);

13

C{1H} NMR (150 MHz, d6-

DMSO): δ = 166.7, 154.7, 143.4, 134.2, 133.4, 132.2, 130.5, 129.2, 129.0, 128.2, 127.9, 127.4, 123.7, 121.2 ppm; IR (KBr): ṽmax = 3386, 3321, 3204, 1684, 1628, 1479, 1180 cm-1; HRMS (EI): m/z calcd for C14H12N2O2 [M]+: 240.0899; found: 240.0895. (E)-N-Carbamoyl-3-(naphthalen-1-yl)acrylamide 3s: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (40%); white solid (0.033 g, 70% yield); mp 210-212 oC. 1H NMR (300 MHz, d6-DMSO): δ = 10.45 (br. s., 1 H), 8.42 (d, J = 15.3 Hz, 1 H), 8.22 (d, J = 7.8 Hz, 1 H), 7.97 - 8.04 (m, 3 H), 7.79 (d, J = 7.2 Hz, 1 H), 7.55 - 7.65 (m, 3 H), 7.36 (br. s., 1 H), 6.86 ppm (d, J = 15.3 Hz, 1 H); 13C{1H} NMR (75 MHz, d6-DMSO): δ = 166.2, 154.2, 139.4, 133.4, 131.2, 130.8, 130.6, 128.8, 127.2, 126.4,


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125.8, 125.1, 123.3, 123.2 ppm; IR (KBr): ṽmax = 3373, 1742, 1687, 1585, 1389, 1181, 782 cm-1; HRMS (EI): m/z calcd for C14H12N2O2 [M]+: 240.0899; found: 240.0895. (E)-N-Carbamoyl-3-cyclohexylacrylamide 3t: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (30%); white solid (0.0216 g, 47% yield); mp 189-191 oC. 1H NMR (300 MHz, d6-DMSO): δ = 10.17 (br. s., 1 H), 7.88 (br. s., 1 H), 7.25 (br. s., 1 H), 6.84 (dd, J = 6.6, 15.3 Hz, 1 H), 6.04 (d, J = 15.3 Hz, 1 H), 2.09 - 2.18 (m, 1 H), 1.61 - 1.72 (m, 5 H), 1.03 - 1.34 ppm (m, 5 H); 13C{1H} NMR (75 MHz, d6-DMSO): δ = 166.4, 154.3, 152.8, 120.8, 39.6, 31.2 (2 CH2), 25.5 (CH2), 25.2 ppm (2 CH2); IR (KBr): ṽmax = 3381, 3338, 2925, 2112, 1674, 1616, 1406, 1101 cm-1; HRMS (ESI): m/z calcd for C10H16N2O2Na [M + Na]+: 219.1110; found: 219.1130. (E)-N-Carbamoyl-4-methyl-5-phenylpent-2-enamide 3u: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (40%); white solid (0.020 g, 43% yield); mp 140-142 oC. 1H NMR (600 MHz, d6-DMSO): δ = 10.15 (br. s., 1 H), 7.81 (br. s., 1 H), 7.16 - 7.32 (m, 6 H), 6.71 - 6.76 (m, 1 H), 6.02 (d, J = 15.0 Hz, 1 H), 2.85 - 2.89 (m, 1 H), 2.42 - 2.53 (m, 2 H), 1.18 ppm (d, J = 6.6 Hz, 3 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 166.3, 154.7, 146.9, 146.4, 128.9 (2 CH), 127.3 (2 CH), 126.6, 124.6, 40.4 (CH2), 38.9, 22.3 ppm; IR (KBr): ṽmax = 3360, 2123, 1734, 1693, 1398, 1207 cm-1; HRMS (ESI): m/z calcd for C13H16N2O2Na [M + Na]+: 255.1110; found: 255.1124. (E)-N-Carbamoyl-5-methylhex-2-enamide 3v: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (60%); white solid (0.019 g, 41% yield); mp 174-176 oC. 1H NMR (600 MHz, d6-DMSO): δ = 10.17 (br. s, 1 H), 7.87 (br. s., 1 H), 7.25 (br. s., 1 H), 6.82 - 6.87 (m, 1 H), 6.05 (d, J = 15.6 Hz, 1 H), 2.05 (t, J = 7.2 Hz, 2 H), 1.65 - 1.74 (m, 1 H), 0.86 (s, 3 H), 0.85 ppm (s, 3 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 166.5, 154.7, 147.4, 124.5, 41.1, 27.7, 22.6 ppm (2 CH3); IR (KBr): ṽmax = 3377, 2120,



1703, 1686, 1402, 1107 cm-1; HRMS (ESI): m/z calcd for C8H14N2O2Na [M + Na]+: 193.0953; found: 193.0960. N-Carbamoylbenzamide 3aa:9b,16a Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (35%); white solid (0.019 g, 56% yield); mp 213215 oC (lit.9b 210-211 oC). Spectral data are consistent with previously reported values. 1H NMR (600 MHz, d6-DMSO): δ = 10.53 (br. s., 1 H), 8.04 (br. s., 1 H), 7.93 (d, J = 7.8 Hz, 2 H), 7.60 (t, J = 7.2 Hz, 1 H), 7.48 (t, J = 7.8 Hz, 2 H), 7.39 ppm (br. s., 1 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 168.6, 154.7, 133.2, 133.1, 129.0 (2 CH), 128.6 (2 CH) ppm. N-Carbamoyl-3-methoxybenzamide 3ab:16g Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (40%); white solid (0.023 g, 64% yield); mp 165-167 oC. 1H NMR (600 MHz, d6-DMSO): δ = 10.54 (br. s., 1 H), 8.03 (br. s., 1 H), 7.52 (d, J = 7.8 Hz, 1 H), 7.49 (br. s., 1 H), 7.37 - 7.40 (m, 2 H), 7.15 (d, J = 7.8 Hz, 1 H), 3.80 ppm (s, 3 H);

13

C{1H} NMR (150 MHz, d6-DMSO): δ = 168.3, 159.6, 154.6, 134.5,

130.1, 120.9, 119.5, 113.2, 55.8 ppm; IR (KBr): ṽmax = 3366, 3319, 1706, 1667, 1593, 1382, 1233, 1091 cm-1; HRMS (EI): m/z calcd for C9H10N2O3 [M]+: 194.0691; found: 194.0690. N-Carbamoyl-4-methoxybenzamide 3ac:16a Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (50%); white solid (0.0218 g, 61% yield); mp 214-216 oC (lit.16a 214-216 oC). Spectral data are consistent with previously reported values. 1H NMR (300 MHz, d6-DMSO): δ = 10.39 (br. s., 1 H), 8.10 (br. s., 1 H), 7.98 (d, J = 9.0 Hz, 2 H), 7.34 (br. s., 1 H), 7.02 (d, J = 8.7 Hz, 2 H), 3.83 ppm (s, 3 H); 13C{1H} NMR (75 MHz, d6-DMSO): δ = 167.4, 162.8, 154.4, 130.3 (2 CH), 124.6, 113.8 (2 CH), 55.5 ppm. N-Carbamoyl-3,4-dimethylbenzamide 3ad: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (30%); white solid (0.02 g, 56% yield); mp 186-188 oC. 1H NMR (600 MHz, d6-DMSO): δ = 10.37 (br. s., 1 H), 8.06 (br. s., 1 H), 7.77 (s, 1 H), 7.69 (d, J = 6.6 Hz, 1 H), 7.35 (br. s., 1 H), 7.24 (d, J = 7.2 Hz, 1 H), 2.26 (s, 3


Page 22 of 36

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H), 2.25 ppm (s, 3 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 168.5, 154.7, 142.2, 137.0, 130.5, 130.0, 129.6, 126.1, 19.9, 19.8 ppm; IR (KBr): ṽmax = 3373, 3331, 1687, 1600, 1383, 1260, 1106 cm-1; HRMS (EI): m/z calcd for C10H12N2O2 [M]+: 192.0899; found: 192.0888. N-Carbamoyl-4-chlorobenzamide 3ae:16c,d Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (35%); white solid (0.014 g, 39% yield); mp 231-233 oC (lit16d 252-253 oC). Spectral data are consistent with previously reported values. 1H NMR (300 MHz, d6-DMSO): δ = 10.64 (br. s., 1 H), 7.98 (br. s., 1 H), 7.97 (d, J = 8.7 Hz, 2 H), 7.58 (d, J = 8.4 Hz, 2 H), 7.44 ppm (br. s., 1 H); 13C{1H} NMR (150 MHz, d6DMSO): δ = 167.6, 154.5, 138.0, 132.0, 130.6 (2 CH), 129.0 (2 CH) ppm. N-Carbamoyl-2-naphthamide 3af:16e,f Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (35%); white solid (0.02 g, 55% yield); mp 226-228 oC (lit16f 207-208 oC). 1H NMR (600 MHz, d6-DMSO): δ = 10.67 (br. s., 1 H), 8.63 (s, 1 H), 8.09 (br. s., 1 H), 8.03 (d, J = 7.8 Hz, 1 H), 7.98 - 8.01 (m, 2 H), 7.95 - 7.97 (m, 1 H), 7.65 (t, J = 7.8 Hz, 1 H), 7.60 (t, J = 7.8 Hz, 1 H), 7.44 ppm (br. s., 1 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 168.7, 154.7, 135.2, 132.3, 130.4, 129.7, 129.7, 128.9, 128.6, 128.1, 127.4, 124.7 ppm. N-Carbamoyl-[1,1'-biphenyl]-4-carboxamide 3ag: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (35%); white solid (0.018 g, 48% yield); mp 232-234 oC. 1H NMR (600 MHz, d6-DMSO): δ = 10.59 (br. s., 1 H), 8.07 (br. s., 1 H), 8.05 (d, J = 8.4 Hz, 2 H), 7.80 (d, J = 7.8 Hz, 2 H), 7.74 (d, J = 7.8 Hz, 2 H), 7.49 (t, J = 7.2 Hz, 2 H), 7.41 ppm (t, J = 7.2 Hz, 2 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 168.2, 154.7, 144.6, 139.3, 131.9, 129.6 (2 CH), 129.3 (2 CH), 128.8, 127.4 (2 CH), 127.1 (2 CH) ppm; IR (KBr): ṽmax = 3381, 3333, 1702, 1668, 1597, 1385, 1265, 1097 cm-1; HRMS (EI): m/z calcd for C14H12N2O2 [M]+: 240.0899; found: 240.0895.



N-Carbamoylpivalamide 3ah:17a,c Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (30%); white solid (0.0144 g, 44% yield); mp 149151 oC (lit17c 145-147 oC). 1H NMR (300 MHz, d6-DMSO): δ = 9.68 (br. s., 1 H), 7.90 (br. s., 1 H), 7.20 (br. s., 1 H), 1.15 ppm (s, 9 H);

13

C{1H} NMR (75 MHz, d6-DMSO): δ = 180.0,

154.5, 38.9, 26.4 ppm (3 x CH3). N-Carbamoyl-3-methylbutanamide 3ai:1b Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (30%); white solid (0.0126 g, 39% yield); mp 191-193 oC (lit17d 206-208 oC). 1H NMR (300 MHz, d6-DMSO): δ = 10.11 (br. s., 1 H), 7.79 (br. s., 1 H), 7.20 (br. s., 1 H), 2.15 (d, J = 7.5 Hz, 2 H), 1.92 - 2.06 (m, 1 H), 0.88 ppm (d, J = 6.6 Hz, 6 H); 13C{1H} NMR (75 MHz, d6-DMSO): δ = 174.3, 154.0, 44.8, 25.2 (CH2), 22.2 ppm (2 x CH3). N-Carbamoyl-2-methylbutanamide 3aj:17e Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (40%); white solid (0.0134 g, 41% yield); mp 180-182 oC (lit17e 178-180 oC). Spectral data are consistent with previously reported values. 1H NMR (600 MHz, d6-DMSO): δ = 10.13 (br. s., 1 H), 7.81 (br. s., 1 H), 7.21 (br. s., 1 H), 2.37 (sxt, J = 6.6 Hz, 1 H), 1.52 (dquin, J = 7.2, 15.0 Hz, 1 H), 1.32 (dquin, J = 7.2, 13.8 Hz, 1 H), 0.99 (d, J = 7.2 Hz, 3 H), 0.79 ppm (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 178.7, 154.5, 41.9, 26.8 (CH2), 17.3, 11.9 ppm. N-Carbamoylbutyramide 3ak:17f Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (40%); white solid (0.0117 g, 37% yield); mp 176178 oC (lit17f 173-174 oC). 1H NMR (600 MHz, d6-DMSO): δ = 10.10 (br. s., 1 H), 7.76 (br. s., 1 H), 7.19 (br. s., 1 H), 2.22 (t, J = 7.2 Hz, 2 H), 1.51 (sxt, J = 7.2, 14.4 Hz, 2 H), 0.84 ppm (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 175.2, 154.4, 38.0 (CH2), 18.3 (CH2), 13.9 ppm.


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Cinnamamide 4a:22a Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (60%); white solid (0.032 g, 90% yield); mp 146-148 oC (lit.22a 144 o

C). Spectral data are consistent with previously reported values. 1H NMR (300 MHz, d6-

DMSO): δ = 7.55 - 7.57 (m, 3 H), 7.37 - 7.45 (m, 4 H), 7.13 (br. s., 1 H), 6.61 ppm (d, J = 15.9 Hz, 1 H); 13C{1H} NMR (75 MHz, d6-DMSO): δ = 166.8, 139.3, 134.9, 129.5, 129.0 (2 CH), 127.6 (2 CH), 122.3 ppm. (E)-3-(o-Tolyl)acrylamide 4b:22b Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (60%); white solid (0.032 g, 87% yield); mp 172174 oC (lit.22i 176-178 oC). Spectral data are consistent with previously reported values. 1H NMR (600 MHz, d6-DMSO): δ = 7.62 (d, J = 16.2 Hz, 1 H), 7.57 (br. s., 1 H), 7.51 (d, J = 7.2 Hz, 1 H), 7.21 - 7.25 (m, 3 H), 7.13 (br. s., 1 H), 6.49 (d, J = 15.6 Hz, 1 H), 2.35 ppm (s, 3 H);

13

C{1H} NMR (150 MHz, d6-DMSO): δ = 167.2, 137.2, 137.1, 134.1, 131.1, 129.7,

126.8, 126.4, 123.9, 19.9 ppm. (E)-3-(p-Tolyl)acrylamide 4c:22b Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (60%); white solid (0.021 g, 57% yield); mp 190192 oC (lit22j 190-191 oC). Spectral data are consistent with previously reported values. 1H NMR (600 MHz, d6-DMSO): δ = 7.49 (br. s., 1 H), 7.43 (d, J = 7.8 Hz, 2 H), 7.36 (d, J = 15.6 Hz, 1 H), 7.20 (d, J = 7.8 Hz, 2 H), 7.06 (br. s., 1 H), 6.53 (d, J = 16.2 Hz, 1 H), 2.30 ppm (s, 3 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 167.3, 139.7, 139.6, 132.6, 130.0 (2 CH), 128.0 (2 CH), 121.7, 21.4 ppm. (E)-3-(3,4-Dimethoxyphenyl)acrylamide 4d:22a Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (90%); white solid (0.031 g, 80% yield); mp 163-165 oC (lit.22a 166 oC). Spectral data are consistent with previously reported values. 1

H NMR (600 MHz, d6-DMSO): δ = 7.43 (br. s., 1 H), 7.33 (d, J = 15.6 Hz, 1 H), 7.14 (s, 1

H), 7.08 (d, J = 7.8 Hz, 1 H), 7.00 (br. s., 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 6.47 (d, J = 15.6 Hz,



1 H), 3.78 (s, 3 H), 3.76 ppm (s, 3 H);

13

C{1H} NMR (150 MHz, d6-DMSO): δ = 167.5,

150.5, 149.3, 139.8, 128.1, 121.9, 120.4, 112.1, 110.3, 56.0, 55.9 ppm. (E)-3-(4-Chlorophenyl)acrylamide 4e:22b Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (60%); white solid (0.029 g, 77 % yield); mp 207-209 oC (lit22j 210-211 oC); solvent of crystallization: dichloromethane/acetone. Spectral data are consistent with previously reported values. 1H NMR (600 MHz, d6-DMSO): δ = 7.57 (d, J = 8.4 Hz, 3 H), 7.45 (d, J = 7.2 Hz, 2 H), 7.38 (d, J = 15.6 Hz, 1 H), 7.14 (br. s., 1 H), 6.60 ppm (d, J = 15.6 Hz, 1 H);

13

C{1H} NMR (150 MHz, d6-DMSO): δ = 166.9,

138.3, 134.3, 134.3, 129.7 (2 CH), 129.4 (2 CH), 123.6 ppm. (E)-3-(3-Chlorophenyl)acrylamide 4f:22c Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (60%); white solid (0.028 g, 74% yield); mp 122-124 oC. Spectral data are consistent with previously reported values. 1H NMR (600 MHz, CDCl3): δ = 7.59 (d, J = 15.6 Hz, 1 H), 7.50 (s, 1 H), 7.37 (d, J = 7.2 Hz, 1 H), 7.29 7.34 (m, 2 H), 6.47 (d, J = 15.6 Hz, 1 H), 5.93 (br. s., 1 H), 5.83 ppm (br. s., 1 H); 13C{1H} NMR (150 MHz, CDCl3): δ = 167.5, 141.2, 136.3, 134.9, 130.2, 129.9, 127.5, 126.4, 120.8 ppm. (E)-3-(4-Bromophenyl)acrylamide 4g:22a Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (60%); white solid (0.025 g, 63% yield); mp 211-213 oC (lit.22a 214 oC). Spectral data are consistent with previously reported values. 1

H NMR (300 MHz, d6-DMSO): δ = 7.61 (d, J = 8.4 Hz, 3 H), 7.51 (d, J = 8.4 Hz, 2 H), 7.38

(d, J =15.6 Hz, 1 H), 7.15 (br. s., 1 H), 6.62 ppm (d, J = 16.2 Hz, 1 H); 13C{1H} NMR (75 MHz, d6-DMSO): δ = 166.5, 138.0, 134.2, 131.9 (2 CH), 129.6 (2 CH), 123.2, 122.6 ppm. (E)-3-(2-Bromophenyl)acrylamide 4h:22e Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (60%); white solid (0.021 g, 53% yield); mp 172-174 oC. Spectral data are consistent with previously reported values. 1H NMR (600


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MHz, d6-DMSO): δ = 7.68 (d, J = 7.8 Hz, 3 H), 7.63 - 7.64 (m, 1 H), 7.43 (t, J = 7.8 Hz, 1 H), 7.30 (t, J = 7.8 Hz, 1 H), 7.25 (br. s., 1 H), 6.61 ppm (d, J = 15.6 Hz, 1 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 166.5, 137.6, 134.9, 133.7, 131.6, 128.8, 128.1, 126.0, 124.6 ppm. (E)-3-(2,5-Dibromophenyl)acrylamide 4i: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (60%); white solid (0.034 g, 81% yield); mp 189-191 oC. 1H NMR (600 MHz, d6-DMSO): δ = 7.84 (d, J = 2.4 Hz, 1 H), 7.63 (d, J = 9.0 Hz, 1 H), 7.56 (br. s., 1 H), 7.55 (d, J = 15.6 Hz, 1 H), 7.49 (dd, J = 1.8, 8.4 Hz, 1 H), 7.31 (br. s., 1 H), 6.68 ppm (d, J = 15.6 Hz, 1 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 166.2, 137.2, 136.1, 135.5, 134.0, 130.5, 127.6, 123.4, 121.7 ppm; IR (KBr): ṽmax = 3373, 3177, 1671, 1618, 1389, 1022 cm-1; HRMS (EI): m/z calcd for C9H7Br2NO [M]+: 302.8894; found: 302.8899. (E)-3-(2,6-Dichlorophenyl)acrylamide 4j:22a Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (60%); white solid (0.036 g, 92% yield); mp 159-161 oC (lit.22a 164 oC). Spectral data are consistent with previously reported values. 1

H NMR (600 MHz, CDCl3): δ = 7.74 (d, J = 16.2 Hz, 1 H), 7.35 (d, J = 8.4 Hz, 2 H), 7.18 (t,

J = 7.8 Hz, 1 H), 6.62 (d, J = 16.2 Hz, 1 H), 5.88 (br. s., 1 H), 5.74 ppm (br. s., 1 H); 13C{1H} NMR (150 MHz, CDCl3): δ = 166.9, 136.1, 135.0, 132.2, 129.7, 128.8 (3 CH), 128.0 ppm. (E)-3-(4-Nitrophenyl)acrylamide 4k:22b Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (70%); light yellow solid (0.022 g, 57% yield); mp 220-222 oC (lit22j 216-217 oC). Spectral data are consistent with previously reported values. 1H NMR (600 MHz, d6-DMSO): δ = 8.24 (d, J = 7.8 Hz, 2 H), 7.82 (d, J = 7.8 Hz, 2 H), 7.68 (br. s., 1 H), 7.50 (d, J = 16.2 Hz, 1 H), 7.29 (br. s., 1 H), 6.78 ppm (d, J = 15.6 Hz, 1 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 166.4, 148.0, 142.0, 137.3, 129.1 (2 CH), 127.1, 124.6 (2 CH) ppm.



(E)-3-(4-Cyanophenyl)acrylamide 4l:22b Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (60%); white solid (0.029 g, 78% yield); mp 182-184 oC. Spectral data are consistent with previously reported values. 1H NMR (600 MHz, d6-DMSO): δ = 7.86 (d, J = 7.8 Hz, 2 H), 7.73 (d, J = 8.4 Hz, 2 H), 7.63 (br. s., 1 H), 7.45 (d, J = 15.6 Hz, 1 H), 7.24 (br. s., 1 H), 6.73 ppm (d, J = 15.6 Hz, 1 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 166.5, 140.0, 137.8, 133.3 (2 CH), 128.7 (2 CH), 126.3, 119.2, 111.9 ppm. (E)-3-(Thiophen-2-yl)acrylamide 4m:22b Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (50%); white solid (0.03 g, 83% yield); mp 162-163 oC (lit22k 152-153 oC). Spectral data are consistent with previously reported values. 1H NMR (600 MHz, d6-DMSO): δ = 7.76 (br. s., 1 H), 7.58 (t, J = 4.2 Hz, 1 H), 7.47 (br. s., 1 H), 7.39 (d, J = 15.6 Hz, 1 H), 7.33 (d, J = 4.8 Hz, 1 H), 7.03 (br. s., 1 H), 6.40 ppm (d, J = 15.6 Hz, 1 H); 13C{1H} NMR (150 MHz, d6-DMSO): δ = 167.4, 138.3, 133.7, 128.1, 127.9, 125.6, 122.2 ppm. (E)-3-(Naphthalen-1-yl)acrylamide 4n:22f Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (60%); white solid (0.025 g, 65% yield); mp 172-174 oC (lit.22f 177 oC). Spectral data are consistent with previously reported values. 1

H NMR (300 MHz, d6-DMSO): δ = 8.18 - 8.23 (m, 2 H), 7.97 - 7.99 (m, 2 H), 7.79 (d, J =

6.9 Hz, 1 H), 7.70 (br. s., 1 H), 7.58 - 7.65 (m, 2 H), 7.55 (d, J = 7.5 Hz, 1 H), 7.22 (br. s., 1 H), 6.67 ppm (d, J = 15.9 Hz, 1 H); 13C{1H} NMR (75 MHz, d6-DMSO): δ = 167.1, 136.1, 133.8, 132.4, 131.3, 130.0, 129.1, 127.3, 126.7, 126.2, 125.8, 124.9, 123.7 ppm. (E)-3-Cyclohexylacrylamide 4o:22d Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (55%); white solid (0.0207 g, 57% yield); mp 138140 oC. Spectral data are consistent with previously reported values. 1H NMR (300 MHz, d6DMSO): δ = 7.34 (br. s., 1 H), 6.88 (br. s., 1 H), 6.55 (dd, J = 6.6, 15.6 Hz, 1 H), 5.80 (dd, J


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= 0.9, 15.6 Hz, 1 H), 2.02 - 2.12 (m, 1 H), 1.60 - 1.71 (m, 5 H), 1.01 - 1.33 ppm (m, 5 H); 13

C{1H} NMR (75 MHz, d6-DMSO): δ = 166.9, 148.0, 122.1, 39.2, 31.6 (2 CH2), 25.6 (CH2),

25.3 ppm (2 CH2). Benzamide 4p:22c Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (30%); white solid (0.018 g, 72% yield); mp 122-124 oC (lit.22c 128129 oC). Spectral data are consistent with previously reported values. 1H NMR (300 MHz, d6DMSO): δ = 7.98 (br. s., 1 H), 7.86 - 7.88 (m, 2 H), 7.39 - 7.55 (m, 3 H), 7.37 ppm (br. s., 1 H); 13C{1H} NMR (75 MHz, CDCl3, with few drops of d6-DMSO): δ = 168.9, 133.2, 130.9, 127.6 (2 CH), 126.9 ppm (2 CH). 4-Methoxybenzamide 4q:22c Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (50%); white solid (0.012 g, 43% yield); mp 164-166 oC (lit22c 167-168 oC). Spectral data are consistent with previously reported values. 1H NMR (300 MHz, d6-DMSO): δ = 7.84 (d, J = 8.4 Hz, 3 H), 7.18 (br. s., 1 H), 6.97 (d, J = 8.4 Hz, 2 H), 3.80 ppm (s, 3 H);

13

C{1H} NMR (75 MHz, CDCl3; with few drops of d6-DMSO): δ =

168.2, 161.4, 128.8 (2 CH), 125.4, 112.7 (2 CH), 54.6 ppm. 4-Chlorobenzamide 4r:22c Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (30%); white solid (0.0169 g, 60% yield); mp 180-182 oC (lit.22c 178-179 oC). Spectral data are consistent with previously reported values. 1H NMR (300 MHz, d6-DMSO): δ = 8.05 (br. s., 1 H), 7.88 (d, J = 8.4 Hz, 2 H), 7.52 (d, J = 8.4 Hz, 2 H), 7.47 ppm (br. s., 1 H); 13C{1H} NMR (75 MHz, CDCl3; with few drops of d6-DMSO): δ = 167.8, 136.9, 131.7, 128.6 (2 CH), 127.8 ppm (2 CH). 2-Naphthamide 4s:22c Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (50%); white solid (0.021 g, 72% yield); mp 200-202 oC (lit.22c 196-197 oC). Spectral data are consistent with previously reported values. 1H NMR (300 MHz, d6-DMSO): δ = 8.49 (s, 1 H), 8.15 (br. s., 1 H), 7.97 - 8.02 (m, 4 H), 7.56 - 7.63 (m, 2



H), 7.48 ppm (br. s., 1 H);

13

C{1H} NMR (75 MHz, d6-DMSO): δ = 168.0, 134.2, 132.2,

131.7, 128.9, 127.9, 127.8, 127.6 (2 CH), 126.7, 124.4 ppm. Pivalamide 4t:22h Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (50%); white solid (0.015 g, 66% yield); mp 148-150 oC (lit.22h 154157 oC). Spectral data are consistent with previously reported values. 1H NMR (300 MHz, d6DMSO): δ = 7.01 (br. s., 1 H), 6.69 (br. s., 1 H), 1.06 ppm (s, 9 H); 13C{1H} NMR (75 MHz, d6-DMSO): δ = 179.9, 37.9, 27.5 ppm (3 x CH3). 2-Methylbutanamide 4u: Prepared according to the general procedure discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (50%); white solid (0.0123 g, 54% yield); mp 109-111 oC (lit.17a 112-114 oC). Spectral data are consistent with previously reported values. 1H NMR (600 MHz, d6-DMSO): δ = 7.21 (br. s., 1 H), 6.67 (br. s., 1 H), 2.07 - 2.12 (m, 1 H), 1.42 - 1.49 (m, 1 H), 1.22 - 1.29 (m, 1 H), 0.94 (d, J = 6.6 Hz, 3 H), 0.79 ppm (t, J = 7.2 Hz, 3 H); 13

C{1H} NMR (150 MHz, d6-DMSO): δ = 178.1, 41.5, 27.1 (CH2), 18.0, 12.3 ppm.

General procedure for the control experiments: Cu(OAc)2 (0.011 g, 0.062 mmol, 30 mol %) and 3 Å MS (0.05 g) were taken in a 25 mL flame-dried, two-neck, round-bottomed flask, equipped with a magnetic stirring bar, under an argon atmosphere and dried by heating in vacuum. α-Keto thioester 1aa (0.05 g, 0.206 mmol, 1.0 equiv.) was added into the mixture. Dry DMSO (2.0 mL) and TMSN3 2a (0.01 mL, 0.62 mmol, 3.0 equiv.) were introduced successively, and the resulting reaction mixtures was stirred at room temperature. The reaction was quenched after 5 min either with MeOH (0.02 mL, 0.41 mmol, 2.0 equiv.) or piperidine (0.04 mL, 0.41 mmol, 2.0 equiv.), and stirring was continued for another 30 min at the same temperature. Saturated NH4Cl solution was added, and the mixture was extracted with dichloromethane (10 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to get a residue.


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The crude residue was purified by silica gel column chromatography [230–400; eluent: ethyl acetate/n-hexane] to obtain the products. For MeOH addition: After purification, we isolated 5a, PhCONHCONH2 3aa (0.010 g, 14%), and trace amounts of Ph2S2 and PhCOCOOMe. The analytical data of 3aa exactly matched with our previously reported values. Methyl benzoylcarbamate 5a:23 Eluent, EtOAc/n-hexane (25%); white solid (0.010 g, 15% yield); mp 118-120 oC (lit.23b 120 oC). Spectral data are consistent with previously reported values. 1H NMR (600 MHz, CDCl3): δ = 8.18 (br. s., 1 H), 7.82 (d, J = 7.2 Hz, 2 H), 7.59 (t, J = 7.8 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 2 H), 3.87 ppm (s, 3 H); 13C{1H} NMR (150 MHz, CDCl3): δ = 164.7, 151.7, 133.1, 132.9, 128.9 (2 CH), 127.6 (2 CH), 53.3 ppm. For piperidine addition: After purification, we isolated 5b, PhCONHCONH2 3aa (0.010 g, 14%), and trace amounts of Ph2S2 and PhCOCOOMe. The analytical data of 3aa exactly matched with our previously reported values. N-Benzoylpiperidine-1-carboxamide 5b:7 Eluent, EtOAc/n-hexane (25%); white solid (0.014 g, 27% yield); mp 168-170 oC (lit.7 172174 oC). Spectral data are consistent with previously reported values. 1H NMR (600 MHz, d6DMSO): δ = 10.93 (br. s., 1 H), 8.65 (d, J = 7.8 Hz, 2 H), 8.38 (t, J = 7.8 Hz, 1 H), 8.28 (t, J = 7.2 Hz, 2 H), 4.18 (br. s., 4 H), 2.37 (br. s., 2 H), 2.30 ppm (br. s., 4 H);

13

C{1H} NMR

(150 MHz, d6-DMSO): δ = 167.3, 153.7, 134.6, 133.4, 129.7 (2 CH), 129.2 (2 CH), 26.8 (2 CH2), 25.1 ppm (3 CH2).

AUTHOR INFORMATION Corresponding Author *Email: [email protected] ORCID ID Indrajit Das: 0000-0002-5731-0232 Notes



The authors declare no competing financial interest.

ACKNOWLEDGMENTS I.D. thanks DST-SERB (EMR/2016/001720) for financial support and Drs. Basudeb Achari and Ramalingam Natarajan for valuable discussions. R.M. and S.N. thank UGC-India for fellowships.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Copies of 1H, 13C{1H}, and DEPT-135 NMR spectra (PDF) Crystallographic data for the compounds 3a, 3l, and 4e (CIF)

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