Facile Conversion of Thioamides into the Corresponding Amides in the Presence of Tetrabutylammonium Bromide

Abstract

Desulfurization of thioamides was accomplished using a semicatalytic amount of Bu₄NBr. The corresponding amides were obtained in high yields, with good functional group compatibility.

Amide groups occur widely in nature, and a large number of biologically active molecules, including drugs, natural products, and peptides possess amide groups. The development of methods for the efficient synthesis of amide bond containing molecules is therefore of great importance. Desulfurization of thioamides produces amides, and a number of methods for this transformation have been reported. [¹] [²] However, most of these methods suffer from several drawbacks such as harsh reaction conditions, use of a stoichiometric amount or an excess of toxic and/or expensive (metal) reagents, and a narrow substrate scope. [³] Consequently, development of more efficient methods for conversion of thioamides to amides is desirable. In this study, we report a simple, highly practical method for this conversion using Bu₄NBr as the sole reagent. Various amides are produced from the corresponding thioamides, generally in high yields, in the presence of a semicatalytic amount of Bu₄NBr, which is an inexpensive, easy-to-handle reagent of low toxicity.

First, we studied the reaction of thiobenzanilide (1) in the presence of two equivalents of Bu₄NBr in air (Table  [¹] ). Although the use of DMF, NMP, or DMSO as the sole solvent resulted in quantitative recovery of starting material 1 (entries 1-3), the NMP-DMSO solvent system surprisingly provided the desired benzanilide (2) in fairly good yield (entry 4). 2-Phenylbenzothiazole (3) was also obtained in 21% yield. [4] Interestingly, the amount of Bu₄NBr could be reduced to 0.5 equivalent without causing a reduction in the yield (entries 4 and 5 vs 6). Further studies revealed that the use of DMF as an additional co-solvent gave the best results, with formation of 77% of 2 (entry 8). [5] Bu₄NCl and Bu₄NI turned out to be much less efficient than Bu₄NBr as catalysts for the desulfurization process (entries 9 and 10), and only small amounts of product were formed in the absence of Bu₄NBr (entry 11). [6] No product was obtained when the reaction was performed under an argon atmosphere (entry 12). This suggests that oxygen is involved in this transformation. [²b] [7]

Table 1 Optimization of Reaction Parameters

Entry	Bu4NBr (equiv)	Solvent	Time (h)a	Yield (%) of 2, 3
1	2	DMF	15	0, 0 (quant)b
2	2	NMP	15	trace, 0 (quant)b
3	2	DMSO	22	0, 0 (quant)b
4	2	NMP-DMSO (1:1)	19	64, 21
5	1	NMP-DMSO (1:1)	17	61, 17
6	0.5	NMP-DMSO (1:1)	5	67, 17
7	0.2	NMP-DMSO (1:1)	5	48, <10 (16)b
8	0.5	NMP-DMSO-DMF (1:1:1)	16	77, 15
9	0.5c	NMP-DMSO-DMF (1:1:1)	12	10, 0 (82)b
10	0.5d	NMP-DMSO-DMF (1:1:1)	12	3, 0 (93)b
11	0	NMP-DMSO-DMF (1:1:1)	12	18, 0 (77)b
12	0.5e	NMP-DMSO-DMF (1:1:1)	12	0, 0 (95)b
a Reaction time was not optimized. b Yield of recovered starting material 1 in parentheses. c Bu4NCl was used instead of Bu4NBr. d Bu4NI was used instead of Bu4NBr. e Under argon atmosphere.

Once we had established the optimal reaction conditions, we examined the substrate scope of the reaction (Table  [²] ). From a series of thiobenzanilides 4 with various substituents on one or both of the benzene rings, we obtained the corresponding benzanilides 5 in good to high yields. It is worth noting that various functional groups such as cyano (entries 1, 9, and 12), nitro (entry 2), or alkoxycarbonyl (entry 3) groups, as well as halogen atoms (entries 6-8, 10), are well tolerated in the reaction. [8]

Table 2 Substrate Scope in the Desulfurization of Thioamides (continued)

Entry	4	Product	5	Yield (%)
1	R¹ = 4-CN R² = H		5a	92
2	R¹ = 4-NO2R² = H		5b	82
3	R¹ = 4-CO2Et R² = H		5c	86
4	R¹ = 4-OMe R² = H		5d	75
5	R¹ = 3-OMe R² = H		5e	13
6a	R¹ = 3-Br R² = H		5f	66
7a	R¹ = 2-F R² = H		5g	74
8	R¹ = 4-I R² = H		5h	83
9	R¹ = H R² = 4-CN		5i	59
10	R¹ = H R² = 4-Cl		5j	59
11	R¹ = H R² = 4-OMe		5k	84
12	R¹ = 4-CN R² = 4-OMe		5l	93
a Amount of Bu4NBr = 0.75 equiv.

Although thioamides 6a-c, which were derived from benzylamines, did not react at all in air, use of an oxygen atmosphere greatly enhanced the process, resulting in formation of the corresponding amides 7a-c in high yields (Scheme  [¹] ).

In conclusion, we have developed a facile method for de­sulfurization of thioamides, producing the corresponding amides, generally in high yields. The sole reagent required is 0.5 equivalent of Bu₄NBr. A solvent combination such as NMP-DMSO-DMF is crucial for this process. This reaction proceeds under metal-free, neutral, and relatively mild conditions, and has good functional group compatibility. Further studies to disclose the precise reaction mechanism, as well as to broaden the substrate scope, are under way.

All reactions were carried out under an air atmosphere unless otherwise noted. Bu₄NBr was crystallized from benzene-hexane. Anhyd 1-methyl-2-pyrrolidinone (NMP), DMSO, and DMF were purchased from Sigma-Aldrich. Thiocarbonyl compounds were prepared from the reaction of the corresponding amides with Lawesson’s reagent. Melting points were measured with a Yazawa micro melting point apparatus. ^¹H NMR spectra were recorded on JEOL JNM-AL400 (400 MHz) using TMS as an internal standard. Chemical shifts (δ) are given from TMS (0 ppm) and coupling constants are expressed in Hertz (Hz). ^¹³C NMR spectra were recorded on JEOL JNM-AL400 (100 MHz) and chemical shifts (δ) are given from ^¹³CDCl₃ (77.0 ppm). Mass spectra and high-resolution mass spectra were measured on JEOL JMS-DX303 and MS-AX500 instruments, respectively.

Desulfurization of Thioamides; General Procedure

A mixture of the respective thioamide 4 (0.23 mmol) and Bu₄NBr (36 mg, 0.11 mmol) in NMP-DMSO-DMF (1:1:1, 4.5 mL, 0.05 M) was stirred at 100 ˚C. The reaction mixture was extracted with EtOAc (3 × 10 mL) and the combined organic layers were washed with brine (3 × 10 mL), and then dried (MgSO₄). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give the desired compound. Physical and spectroscopic data for selected products are shown below.

N -(4-Cyanophenyl)benzamide (5a)

Colorless prisms: mp 164-165 ˚C (hexane-acetone) (Lit. [9] mp 170-170.5 ˚C).

IR (film): 3340, 2226, 1685, 1659, 1592, 1522, 1407, 1318 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 7.50 (t, J = 7.3 Hz, 2 H), 7.59 (t, J = 7.3 Hz, 1 H), 7.65 (d, J = 8.8 Hz, 2 H), 7.79 (d, J = 8.8 Hz, 2 H), 7.87 (d, J = 7.3 Hz, 2 H), 8.04 (br, 1 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 107.3, 118.8, 119.9, 127.1, 128.9, 132.4, 133.2, 134.0, 142.0, 165.8.

MS (EI): m/z (%) = 222 (28, [M]⁺), 105 (100).

HRMS: m/z calcd for C₁₄H₁₀N₂O: 222.0793; found: 222.0778.

N -(4-Ethoxycarbonylphenyl)benzamide (5c)

Colorless prisms; mp 147-148 ˚C (hexane-acetone) (Lit. [¹0] mp 137 ˚C).

IR (film): 3331, 1713, 1659, 1601, 1528, 1407, 1322, 1280, 1176, 1104 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 1.40 (t, J = 7.1 Hz, 3 H), 4.37 (q, J = 7.1 Hz, 2 H), 7.49 (t, J = 7.3 Hz, 2 H), 7.57 (t, J = 7.3 Hz, 1 H), 7.74 (d, J = 8.8 Hz, 2 H), 7.87 (d, J = 7.3 Hz, 2 H), 8.01 (br, 1 H), 8.06 (d, J = 8.8 Hz, 2 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 14.4, 60.9, 119.1, 126.1, 127.0, 128.8, 130.8, 132.1, 134.4, 141.9, 165.7, 166.0.

MS (EI): m/z (%) = 269 (72, [M]⁺), 105 (100).

HRMS: m/z calcd for C₁₆H₁₅NO₃: 269.1052; found: 269.1045.

N -(4-Cyanophenyl)-4-methoxybenzamide (5l)

Colorless needles; mp 155-156 ˚C (hexane-acetone).

IR (film): 3333, 2224, 1658, 1605, 1592, 1512, 1407, 1320, 1247, 1176 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 3.87 (s, 3 H), 6.97 (d, J = 8.8 Hz, 2 H), 7.62 (d, J = 8.8 Hz, 2 H), 7.78 (d, J = 8.8 Hz, 2 H), 7.84 (d, J = 8.8 Hz, 2 H), 8.06 (br, 1 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 55.5, 107.0, 114.1, 118.8, 119.8, 126.1, 129.0, 133.2, 142.2, 162.9, 165.2.

MS (EI): m/z (%) = 252 (7, [M]⁺), 135 (100).

HRMS: m/z calcd for C₁₅H₁₂N₂O₂: 252.0899; found: 252.0885.

Anal. Calcd for C₁₅H₁₂N₂O₂: C, 71.42; H, 4.79; N, 11.10. Found: C, 71.45; H, 4.81; N, 11.12.

N -(2-Bromobenzyl)benzamide (7c)

Colorless prisms; mp 135-139 ˚C (EtOH) (Lit. [¹¹] mp 141-142 ˚C).

IR (film) 3293, 1641, 1539, 1489, 1465, 1441, 1414, 1309 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 4.69 (d, J = 6.0 Hz, 2 H), 6.75 (br, 1 H), 7.15 (td, J = 7.6, 1.5 Hz, 1 H), 7.27 (td, J = 7.6, 1.4 Hz, 1 H), 7.39-7.51 (m, 4 H), 7.55 (dd, J = 7.6, 1.4 Hz, 1 H), 7.78 (d, J = 7.6 Hz, 2 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 44.3, 123.8, 127.0, 127.7, 128.6, 129.2, 130.5, 131.6, 132.8, 134.2, 137.2, 167.3.

MS (EI): m/z (%) = 289 (0.62, [M]⁺), 210 (100).

HRMS: m/z calcd for C₁₄H₁₂ ⁷⁹BrNO: 289.0102; found: 289.0085.

Anal. Calcd for C₁₄H₁₂BrNO: C, 57.95; H, 4.17; N, 4.83. Found: C, 57.93; H, 4.83; N, 4.20.

Acknowledgment

This work was supported in part by a Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science (JSPS).

References

• 1 For a review, see: Corsaro A. Pistarà V. Tetrahedron  1998,  54:  15027 
  CrossrefSearch in Google Scholar
• For selected recent reports, see:
• 2a Bahrami K. Khodaei MM. Tirandaz Y. Synthesis  2009,  369 
• 2b Shibahara F. Suenami A. Yoshida A. Murai T. Chem. Commun.  2007,  2354 
• 2c Pourali AR. Monatsh. Chem.  2005,  136:  733 
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• 2d Mohammadpoor-Baltork I. Memarian HR. Bahrami K. Monatsh. Chem.  2004,  135:  411 
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• 2e Mohammadpoor-Baltork I. Memarian HR. Hajipour AR. Bahrami K. Bull. Korean Chem. Soc.  2003,  24:  1002 
  Search in Google Scholar
• 2f Mohammadpoor-Baltork I. Khodaei MM. Nikoofar K. Tetrahedron Lett.  2003,  44:  591 
  Search in Google Scholar
• 2g Mohammadpoor-Baltork I. Sadeghi MM. Esmayilpour K. Synth. Commun.  2003,  33:  953 
  Search in Google Scholar
• 2h Movassagh B. Lakouraj MM. Ghodrati K. Synth. Commun.  2000,  30:  2353 
  Search in Google Scholar
• 4a Although the precise reaction mechanism of this cyclization affording 2-phenylbenzothiazole (3) is not clear at this point, tetrabutylammonium cation mediated Hugershoff-type reaction might be occurring, see: Metzger J. In Comprehensive Heterocyclic Chemistry   Vol. 6:  Katritzky AR. Rees CW. Pergamon Press; Oxford: 1984.  p.323 
  Search in Google Scholar
• 4b We recently reported a synthetic method for 2-arylbenzothiazoles via Pd-catalyzed C-H functionalization, see: Inamoto K. Hasegawa C. Hiroya K. Doi T. Org. Lett.  2008,  10:  5147 
  Search in Google Scholar
• 6 For previous reports on the use of Bu₄NBr in oxidation reactions of hydrocarbons, see: Harustiak M. Hronec M. Ilavsky J. React. Kinet. Catal. Lett.  1988,  37:  215 ; and references cited therein
  CrossrefSearch in Google Scholar
• The reaction mechanism of this desulfurization process is not yet clear at present. There are several reports on the desulfurization of thiocarbonyl compounds using molecular oxygen with photoirradiation, see for example:
• 7a Ramnath N. Ramesh V. Ramamurthy V. J. Org. Chem.  1983,  48:  214 
  Search in Google Scholar
• 7b Suzuki N. Sano K. Wakatsuki S. Tani N. Izawa Y. Bull. Chem. Soc. Jpn.  1982,  55:  3351 
  Search in Google Scholar
• 7c Tamagaki S. Akatsuka R. Nakamura M. Kozuka S. Tetrahedron Lett.  1979,  38:  3665 
  Search in Google Scholar
• 7d Ishibe N. Odani M. Sunami M. J. Chem. Soc., Chem. Commun.  1971,  118 
• 9 Bogert MT. Wise LE. J. Am. Chem. Soc.  1910,  32:  1494 
  CrossrefSearch in Google Scholar
• 10 Solak N. Rollas S. ARKIVOC  2006,  (xii):  173 
  Search in Google Scholar
• 11 Bowman WR. Heaney H. Jordan BJ. Tetrahedron  1991,  47:  10119 
  Search in Google Scholar

Indeed, only little is known about the functional-group compatibility of this kind of desulfurization process in previous reports.

MeCN and DMA had a yield-improving effect similar to DMF (75% and 73% yield of 2, respectively). Use of other solvents, such as 1,4-dioxane, toluene, and 2-BuOH resulted in lower yields.

Unfortunately, an aliphatic thioamide such as N-phenyl-thioacetamide did not undergo the desulfurization, the reaction of which resulted in the recovery of a large amount of the starting material.

References

• 1 For a review, see: Corsaro A. Pistarà V. Tetrahedron  1998,  54:  15027 
  CrossrefSearch in Google Scholar
• For selected recent reports, see:
• 2a Bahrami K. Khodaei MM. Tirandaz Y. Synthesis  2009,  369 
• 2b Shibahara F. Suenami A. Yoshida A. Murai T. Chem. Commun.  2007,  2354 
• 2c Pourali AR. Monatsh. Chem.  2005,  136:  733 
  Search in Google Scholar
• 2d Mohammadpoor-Baltork I. Memarian HR. Bahrami K. Monatsh. Chem.  2004,  135:  411 
  Search in Google Scholar
• 2e Mohammadpoor-Baltork I. Memarian HR. Hajipour AR. Bahrami K. Bull. Korean Chem. Soc.  2003,  24:  1002 
  Search in Google Scholar
• 2f Mohammadpoor-Baltork I. Khodaei MM. Nikoofar K. Tetrahedron Lett.  2003,  44:  591 
  Search in Google Scholar
• 2g Mohammadpoor-Baltork I. Sadeghi MM. Esmayilpour K. Synth. Commun.  2003,  33:  953 
  Search in Google Scholar
• 2h Movassagh B. Lakouraj MM. Ghodrati K. Synth. Commun.  2000,  30:  2353 
  Search in Google Scholar
• 4a Although the precise reaction mechanism of this cyclization affording 2-phenylbenzothiazole (3) is not clear at this point, tetrabutylammonium cation mediated Hugershoff-type reaction might be occurring, see: Metzger J. In Comprehensive Heterocyclic Chemistry   Vol. 6:  Katritzky AR. Rees CW. Pergamon Press; Oxford: 1984.  p.323 
  Search in Google Scholar
• 4b We recently reported a synthetic method for 2-arylbenzothiazoles via Pd-catalyzed C-H functionalization, see: Inamoto K. Hasegawa C. Hiroya K. Doi T. Org. Lett.  2008,  10:  5147 
  Search in Google Scholar
• 6 For previous reports on the use of Bu₄NBr in oxidation reactions of hydrocarbons, see: Harustiak M. Hronec M. Ilavsky J. React. Kinet. Catal. Lett.  1988,  37:  215 ; and references cited therein
  CrossrefSearch in Google Scholar
• The reaction mechanism of this desulfurization process is not yet clear at present. There are several reports on the desulfurization of thiocarbonyl compounds using molecular oxygen with photoirradiation, see for example:
• 7a Ramnath N. Ramesh V. Ramamurthy V. J. Org. Chem.  1983,  48:  214 
  Search in Google Scholar
• 7b Suzuki N. Sano K. Wakatsuki S. Tani N. Izawa Y. Bull. Chem. Soc. Jpn.  1982,  55:  3351 
  Search in Google Scholar
• 7c Tamagaki S. Akatsuka R. Nakamura M. Kozuka S. Tetrahedron Lett.  1979,  38:  3665 
  Search in Google Scholar
• 7d Ishibe N. Odani M. Sunami M. J. Chem. Soc., Chem. Commun.  1971,  118 
• 9 Bogert MT. Wise LE. J. Am. Chem. Soc.  1910,  32:  1494 
  CrossrefSearch in Google Scholar
• 10 Solak N. Rollas S. ARKIVOC  2006,  (xii):  173 
  Search in Google Scholar
• 11 Bowman WR. Heaney H. Jordan BJ. Tetrahedron  1991,  47:  10119 
  Search in Google Scholar

Indeed, only little is known about the functional-group compatibility of this kind of desulfurization process in previous reports.

MeCN and DMA had a yield-improving effect similar to DMF (75% and 73% yield of 2, respectively). Use of other solvents, such as 1,4-dioxane, toluene, and 2-BuOH resulted in lower yields.

Unfortunately, an aliphatic thioamide such as N-phenyl-thioacetamide did not undergo the desulfurization, the reaction of which resulted in the recovery of a large amount of the starting material.