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Recent advances in the synthesis of N-acyl sulfonamides

Michelle O'Driscollabc, Gangireddy Sujeevan Reddyabc and Timothy P. O'Sullivan*abc
aSchool of Chemistry, University College Cork, Cork, T12 YN60, Ireland. E-mail: tim.osullivan@ucc.ie
bSchool of Pharmacy, University College Cork, Cork, T12 YN60, Ireland
cAnalytical and Biological Chemistry Research Facility, University College Cork, Cork, T12 YN60, Ireland

Received 17th July 2025 , Accepted 25th August 2025

First published on 8th September 2025


Abstract

The N-acyl sulfonamide group is widespread in pharmaceutically active compounds. This is partly due to the ability of N-acyl sulfonamides to act as bioisosteric equivalents of carboxylic acids. Accordingly, methods for the efficient preparation of N-acyl sulfonamides are of considerable interest to medicinal chemists. In this review, we summarise developments in the synthesis of this pharmaceutically relevant functional group across a broad range of methodologies.


1. Introduction

The N-acyl sulfonamide is a widely explored moiety in drug discovery, primarily due to its ability to act as a bioisostere of carboxylic acids.1–4 Unlike sulfonamides, the acidity of N-acyl sulfonamides is comparable to carboxylic acids with pKa values of 3.5–4.5.5–7 The comparable distances between the two sulfonyl oxygens to that of a carboxylate offers similar hydrogen bonding geometries and increased hydrogen bonding capabilities over carboxylic acids. In addition, N-acyl sulfonamides display increased hydrolytic and enzymatic stability compared to their carboxylic acid surrogates.8 The incorporation of an N-acyl sulfonamide permits the introduction of a wide range of structural modifiers at the carbon or sulfur atom unlike simple carboxylic acids.9 A judicious choice of substituents can provide access to additional regions of an enzyme receptor, allowing for control over both physicochemical properties and biological activity, a feature we have exploited in our own work on the development of novel sulfonamide-based quorum sensing inhibitors.10,11

Therapeutics containing N-acyl sulfonamides are being continually developed for various indications. Examples include treatments for Alzheimer's disease,12 diabetes,13 osteoporosis,14 hypertension,15,16 cancer,17–20 reperfusion,21 asthma,6,22 antibacterial23 and antiviral infections.24,25 As an example, several N-acyl sulfonamide-based protease inhibitors of hepatitis C have been developed by Bristol-Myers Squibb,26,27 Abbott Laboratories28 and Array Biopharma29 and were subsequently approved by the FDA (Asunaprevir, Paritaprevir and Danoprevir). The N-acyl sulfonamide group is present in a variety of FDA-approved drugs and drug candidates and sample of these have been shown in Fig. 1.


image file: d5ra05157f-f1.tif
Fig. 1 N-Acyl sulfonamides of clinical interest.

N-Acyl sulfonamides have also found application in asymmetric organocatalysis. Ley and co-workers synthesised N-acyl sulfonamide-containing organocatalysts for asymmetric Mannich, nitro-Micheal and Aldol reactions.30 The catalyst afforded good to excellent yields and enantioselectivities and required lower catalytic loadings and shorter reaction times than their original proline lead. Likewise, Bellis and co-workers prepared and evaluated a series of prolyl sulfonamides for organocatalysed aldol reactions.31 4-Benzyloxyprolyl and 4-hydroxyprolyl sulfonamides were the most promising alternatives to proline and resulted in increased enantiomeric excess of up to 20%. Additionally, acyl sulfonamides have been employed as ‘‘safety-catch” linkers in solid-phase reactions.32

While N-acyl sulfonamides are common in medicinal chemistry and organocatalysis, reviews dedicated to their synthesis are somewhat limited. Most existing reports mention this motif only briefly, typically within a broader discussion on amide bioisosteres or sulfonamide chemistry in drug design. Reviews on bioisosterism often cite N-acyl sulfonamides as a carboxylic acid replacement, but focus on drug design and biology.33 Similarly, broader surveys of sulfonamide-containing compounds usually mention N-acyl sulfonamides but with little in-depth coverage of their preparation.34 Synthetic methodology reviews may address amide bond formation or sulfonylation chemistry, but rarely integrate the two to highlight the unique challenges in accessing N-acyl sulfonamides.35

Herein, we review recent developments in the synthesis of this important functional group. This review has been subdivided based on the different reagents and approaches as follows:

(1) Acid anhydrides.

(2) Acid chlorides, bromides and benzotriazoles.

(3) Carboxylic acids and esters.

(4) Thio acids.

(5) Aldehydes and ketones.

(6) Pd-catalysed aminocarbonylations.

(7) Sulfonyl fluorides, chlorides and benzotriazoles.

(8) Alkynes.

2. Acid anhydrides

N-Acyl sulfonamides are most commonly obtained by treating a sulfonamide with an acid anhydride or acid chloride in the presence of base. A methodology to acylate aryl sulfonamides under acidic conditions was developed by GlaxoSmithKline.36 A catalytic amount of sulfuric acid (3 mol%) in acetonitrile was sufficient for this transformation (Table 1). Reaction of primary aliphatic sulfonamides proceeded in excellent yields (entries 1–6) as did the N-acylation of a secondary sulfonamide (entry 7). Trifluoromethyl and tert-butyl anhydrides were successfully coupled to both aliphatic and aromatic sulfonamides (entries 8–12). These conditions were also suitable for unsubstituted aromatic anhydrides (entries 13 and 14).
Table 1 N-Acylation of sulfonamides with anhydrides in the presence of sulfuric acid

image file: d5ra05157f-u1.tif

Entry R1 R2 R3 Yield
1 Me H Me 92%
2 Me H tBu 86%
3 Me H Ph 95%
4 Me H 4-MeOC6H4 91%
5 Me H 4-O2NC6H4 98%
6 Me H 2,4,6-iPr3C6H2 90%
7 Me Me Ph 96%
8 CF3 H Ph 60%
9 tBu H Me 94%
10 tBu H tBu 61%
11 tBu H Ph 94%
12 tBu H 2,4,6-iPr3C6H2 90%
13 Ph H Me 44%
14 Ph H Ph 77%
15 4-F3CC6H4 H Ph n.r.
16 4-MeOC6H4 H Ph n.r.


Samant and co-workers found that Fe-exchanged montmorillonite was an effective catalyst for the N-acylation of sulfonamides.37 The K10–FeO catalyst was prepared by treating montmorillonite K10 clay with anhydrous iron(III) chloride in acetonitrile. Under the optimised conditions of K10–FeO catalyst in acetonitrile at 60 °C, several primary and secondary sulfonamides were treated with acetic anhydride, benzoic anhydride and trifluoroacetic anhydride respectively (Table 2). Acetic anhydride was the superior acylating agent affording excellent yields and shorter reaction times (entries 1–6). The use of benzoic anhydride resulted in slower reaction times and moderate yields (entries 7–11). Even after 5 cycles, the activity of the catalyst was unaffected.

Table 2 N-Acylation of sulfonamides under K10–FeO catalysis

image file: d5ra05157f-u2.tif

Entry R1 R2 R3 Time (min) Yield
1 Me Ph H 15 92%
2 Me 4-MeC6H4 H 15 95%
3 Me 4-MeOC6H4 H 15 91%
4 Me 4-ClC6H4 H 5 98%
5 Me Me H 15 82%
6 Me 4-MeC6H4 Me 15 92%
7 Ph Ph H 120 74%
8 Ph 4-MeC6H4 H 120 72%
9 Ph 4-MeOC6H4 H 120 67%
10 Ph 4-ClC6H4 H 120 78%
11 Ph Me H 120 62%
12 Ph 4-MeC6H4 Me 120
13 CF3 Ph H 30 62%
14 CF3 4-ClC6H4 H 30 66%


A range of Lewis acids were screened by Reddy et al. for the N-acylation of benzenesulfonamide.38 As the cheapest and easiest catalyst to handle, zinc chloride was subsequently selected for the N-acylation of a series of sulfonamide compounds under solvent-free conditions (Table 3). Reaction of benzenesulfonamide with different aliphatic anhydrides proceeded efficiently and in high yields (entries 1–5). Toluene sulfonamide was successfully converted to the N-acetyl and N-trifluoro derivatives in 97% (entry 7) and 93% yields (entry 8). The presence of an electron-withdrawing nitro group did not hinder transformation to the desired products (entries 9 and 10). Alkyl sulfonamides were likewise converted in excellent yields (entries 11 and 12). N-Substitution of a secondary sulfonamide with benzyl/methyl groups was successful (entries 13–17). This protocol was also expanded to the acylation of carboxylic acid substrates via a mixed anhydride (see Scheme 10).

Table 3 N-Acylation of sulfonamides under zinc chloride catalysis

image file: d5ra05157f-u3.tif

Entry R1 R2 R3 Time (min) Yield
1 Me H Ph 2 97%
2 Et H Ph 4 96%
3 nPr H Ph 7 95%
4 tBu H Ph 60 90%
5 CF3 H Ph 10 94%
6 Ph H Ph 240 88%
7 Me H 4-MeC6H4 2 97%
8 CF3 H 4-MeC6H4 10 93%
9 Me H 4-O2NC6H4 3 95%
10 nPr H 4-O2NC6H4 5 94%
11 Me H Me 2 98%
12 nPr H Me 3 96%
13 Me Bn 4-MeC6H4 5 94%
14 Et Bn 4-MeC6H4 8 93%
15 Me Bn Me 5 95%
16 Et Bn Me 7 92%
17 Me image file: d5ra05157f-u4.tif Me 2 96%


The catalytic effects of magnetic Fe3O4 diatomite earth (Fe3O4@DE) was investigated by Kowsari and co-workers (Table 4).39 Fe3O4@DE easily outperformed other iron-based heterogeneous catalysts and equalled or surpassed acetic acid (entries 1–10). Notably, Fe3O4@DE is effective under solvent-free conditions, can be easily recovered by application of a magnetic field and withstands five reaction cycles without loss of activity. This catalyst system has also been successfully applied to benzoyl chloride-mediated N-acylations (see Scheme 3).

Table 4 N-Acylation of sulfonamides using acetic anhydride and Fe3O4@DE

image file: d5ra05157f-u5.tif

Entry R Yield
Fe3O4@DE CH3COOH
1 4-AcHNC6H4 93% 95%
2 Ph 95% 90%
3 4-ClC6H4 95% 85%
4 4-MeC6H4 93% 85%
5 4-MeOC6H4 95% 80%
6 3-O2NC6H4 95% 85%
7 3-HO2CC6H4 95% 75%
8 4-BrC6H4 90% 85%
9 4-O2NC6H4 88% 80%
10 Me 97% 95%


Bougheloum and co-workers described the use of H6P2W18O62, a Wells–Dawson type heteropolyacid catalyst, for the conversion of sulfamides to N-acyl sulfamides (Table 5).40 Addition of 1 mmol% H6P2W18O62 in acetonitrile efficiently catalysed the conversion of aliphatic and aromatic sulfamides to the corresponding N-acyl sulfamide in excellent yields (entries 1–5).

Table 5 N-Acylation of sulfamides under H6P2W18O62 catalysis

image file: d5ra05157f-u6.tif

Entry R Time (min) Yield
1 image file: d5ra05157f-u7.tif 15 95%
2 nPrNH 22 92%
3 tBuNH 20 93%
4 PhCH2NH 25 94%
5 3-FC6H4NH 20 94%


Bougheloum adapted this chemistry into a green synthesis of N-acylsulfonamides.41 A cesium salt of the Wells–Dawson heteropolyacid, which offered good recoverability, was assessed using several acid anhydrides in water (Table 6). Under these conditions, acetic anhydride reacted with sulfonamides in good to excellent yields and more rapidly than acetyl chloride (entries 1–9). Cyclic anhydrides, including succinic anhydride (entries 10–17), maleic anhydride (entry 19), 2,3-dichloro maleic anhydride (entry 20), glutaric anhydride (entry 21) and phthalic anhydride (entry 22), were similarly compatible with this protocol.

Table 6 N-Acylation of primary sulfonamides in water using Cs5HP2W18O62

image file: d5ra05157f-u8.tif

Entry Anhydride R1 R2 Time (min) Yield
1 image file: d5ra05157f-u9.tif Me nBuNH 20 91%
2 image file: d5ra05157f-u10.tif Me tBuNH 20 92%
3 image file: d5ra05157f-u11.tif Me Cl(CH2)2NH 30 79%
4 image file: d5ra05157f-u12.tif Me PhNH 25 92%
5 image file: d5ra05157f-u13.tif Me PhCH2NH 25 85%
6 image file: d5ra05157f-u14.tif Me 3-FC6H4NH 30 76%
7 image file: d5ra05157f-u15.tif Me image file: d5ra05157f-u16.tif 30 88%
8 image file: d5ra05157f-u17.tif Me image file: d5ra05157f-u18.tif 30 85%
9 image file: d5ra05157f-u19.tif Me 4-MeC6H4 20 92%
10 image file: d5ra05157f-u20.tif HO2CCH2CH2 nBuNH 20 89%
11 image file: d5ra05157f-u21.tif HO2CCH2CH2 tBuNH 20 90%
12 image file: d5ra05157f-u22.tif HO2CCH2CH2 PhNH 25 88%
13 image file: d5ra05157f-u23.tif HO2CCH2CH2 PhCH2NH 30 86%
14 image file: d5ra05157f-u24.tif HO2CCH2CH2 3-FC6H4NH 30 74%
15 image file: d5ra05157f-u25.tif HO2CCH2CH2 image file: d5ra05157f-u26.tif 30 85%
16 image file: d5ra05157f-u27.tif HO2CCH2CH2 image file: d5ra05157f-u28.tif 30 84%
17 image file: d5ra05157f-u29.tif HO2CCH2CH2 4-MeC6H4 35 90%
18 image file: d5ra05157f-u30.tif Ph 4-MeC6H4 90 65%
19 image file: d5ra05157f-u31.tif HO2CCH[double bond, length as m-dash]CH 4-MeC6H4 35 79%
20 image file: d5ra05157f-u32.tif HO2CC(Cl)[double bond, length as m-dash]C(Cl) 4-MeC6H4 45 75%
21 image file: d5ra05157f-u33.tif HO2C(CH2)2CH2 4-MeC6H4 45 80%
22 image file: d5ra05157f-u34.tif 2-HO2CC6H4 4-MeC6H4 50 55%


The acylation of secondary sulfonamides with acetic anhydride was effectively catalysed by the same catalyst in water, furnishing the target N-acyl sulfonamides in 75–88% yields (Scheme 1). In general, the conversion of primary sulfonamides (Table 6) was faster and higher yielding than their secondary sulfonamide counterparts (Scheme 1). By increasing the catalyst loading from 5 mmol% to 10 mmol%, comparable yields to the primary sulfonamides were achieved.


image file: d5ra05157f-s1.tif
Scheme 1 N-Acylation of secondary sulfonamides in water using Cs5HP2W18O62.

Ghazviniyan and co-workers established a procedure for obtaining N-acyl sulfonamides under functionalised graphene oxide@ZIF-90-supported sulfuric acid (GO@ZIF-90@NCH2CH2NH3+HSO4 or GZAH) catalysis.42 A small number of sulfonamides were successfully acylated with acetic anhydride in acetonitrile at 50 °C in excellent yields of 85–95% (Table 7). The GZAH catalyst could be recycled in five sequential reactions without significant loss of efficacy.

Table 7 N-Acylation of sulfonamides under GZAH catalysis

image file: d5ra05157f-u35.tif

Entry R Yield
1 Ph 95%
2 4-MeOC6H4 93%
3 4-MeC6H4 85%
4 4-ClC6H4 85%
10 4-BrC6H4 92%


Bouasla and colleagues demonstrated how ultrasonic irradiation could be exploited for the preparation N-acyl sulfonamides under green conditions (Table 8).43 Several sulfonamides were acetylated using an ultrasonic bath at 40 kHz, without the requirement of a catalyst or solvent. The products were obtained in 60–96% yields over 15–60 minutes (entries 1–10). The accelerating effect of ultrasound likely results from cavitation, whereby bubbles implode, generating sites of high temperatures and pressures in the reaction mixture, thus driving the reaction forward.

Table 8 Catalyst- and solvent-free acylation under ultrasonic irradiation

image file: d5ra05157f-u36.tif

Entry R Time (min) Yield
1 Cy–NH 30 94%
2 nPrNH 15 90%
3 tBuNH 15 95%
4 PhCH2NH 30 96%
5 3-FC6H4NH 30 93%
6 image file: d5ra05157f-u37.tif 40 90%
7 image file: d5ra05157f-u38.tif 60 60%
8 4-MeOC6H4NH 35 80%
9 image file: d5ra05157f-u39.tif 20 85%
10 image file: d5ra05157f-u40.tif 30 83%


Atropoisomerism is form of chirality which results from restricted rotation around a bond axis.44 Ong and co-workers developed an isothiourea-catalysed atroposelective N-acylation of sulfonamides in good to high enantiopurities (Table 9).45 Three different isothiourea catalysts were screened, with commercially available isothiourea (S)-homobenzotetramisole or (S)-HBTM in cyclopentyl methyl ether proving optimal. Electron-rich and electron-poor anhydrides performed equally well (entries 2 and 3). Bicyclic (entry 4), aliphatic (entries 5 and 9) and heteroaromatic (entry 6) unsaturated anhydrides were equally well tolerated, achieving yields of 73–93% and enantioselectivities of 65–99%.

Table 9 Isothiourea-catalysed atroposelective N-acylation with various anhydrides

image file: d5ra05157f-u41.tif

Entry R Yield ee
a 20 mol% (S)-HBTM used.b 96 h reaction time.
1 (E)-PhCH[double bond, length as m-dash]CH 73% 85%
2 (E)-2-MeOC6H4CH[double bond, length as m-dash]CH 59%a 82%
3 (E)-4-FC6H4CH[double bond, length as m-dash]CH 78% 85%
4 (E)-1-NapthylC6H4CH[double bond, length as m-dash]CH 88% 82%
5 (E)-nPrCH[double bond, length as m-dash]CH 90% 65%
6 (E)-2-FurylCH[double bond, length as m-dash]CH 93% 72%
7 Ph 73%b 82%
8 PhCH2CH2 86% 80%
9 Et 86%a 88%


The same authors next investigated the scope of the sulfonamide substrates (Table 10). Replacing the para-methyl for a phenyl, chloride, bromide or iodide substituent gave similar yields but reduced enantioselectivities of 71–79% (entries 1–4). An ortho-methyl was required for good enantioselectivity as replacing an ortho-methyl with an ortho-ethyl was associated with a significant reduction in enantioselectivity to 49% (entry 5). Swapping the ortho-iodo for an ortho-bromo was beneficial, affording the acylated products in up to 94% yield and achieving enantioselectivities of 81–84% (entries 6 and 7). By contrast, substituting the iodine with a chlorine did not furnish the desired atropoisomer, likely due to the chlorine atom being too small to provide an adequate rotation barrier along the C–N axis (entry 11). Replacing the 4-nosyl protecting group with either a 3-nosyl (entry 8), 4-chlorophenyl (entry 9) or methyl (entry 10) produced comparable yields and stereoselectivities. Finally, no atropoisomerism was observed in the absence of an ortho-alkyl substituent (entries 12 and 13).

Table 10 Isothiourea-catalysed atroposelective N-acylation of various sulfonamides

image file: d5ra05157f-u42.tif

Entry R1 R2 R3 X Yield ee
a 20 mol% (S)-HBTM used.b N.A.: no atropoisomerism.
1 4-O2NC6H4 Me Ph I 83% 79%
2 4-O2NC6H4 Me Cl I 81% 73%
3 4-O2NC6H4 Me Br I 78% 72%
4 4-O2NC6H4 Me I I 63% 71%
5 4-O2NC6H4 Et I I 52% 49%
6 4-O2NC6H4 Me Me Br 94% 84%
7 4-O2NC6H4 Me H Br 73% 81%
8 3-O2NC6H4 Me Me I 82% 88%
9 4-ClC6H4 Me Me I 83% 78%a
10 Me Me Me I 78% 84%
11 4-O2NC6H4 Me Me Cl N.A.b
12 4-O2NC6H4 H H I N.A.b
13 4-O2NC6H4 H H I N.A.b


In a series of papers, Massah and co-workers investigated several catalysts (P2O5/SiO2,46 H3PO4/SiO2,47 SiO2–Cl,48 Bi(OTf)3,49 BiCl3,49 Al(HSO4)3[thin space (1/6-em)]50 and Zr(HSO4)4)50 for the N-acylation of sulfonamides using common acid anhydrides under both homogeneous and heterogeneous conditions (Table 11). Acetylation catalysed by Bi(OTf)3 at 5 mol% loading was exceptionally rapid, yielding products in as little as 1–2 minutes in yields of up to 96% (entry 11). Methyl, benzene and ortho-methylbenzene sulfonamides were N-acylated with methanoic, ethanoic, n-propanoic, i-propanoic, n-butanoic, n-pentanoic, benzoic and 4-nitrobenzoic anhydrides (entries 1–23). Several of these reactions were also carried out using acid chlorides (see Acid chlorides section).

Table 11 Comparison of the effect of selected catalysts on the N-acylation of primary sulfonamides

image file: d5ra05157f-u43.tif

Entry R1 R2 P2O5/SiO246[thin space (1/6-em)] H3PO4/SiO2[thin space (1/6-em)]47 SiO2–Cl48 Bi(OTf)3[thin space (1/6-em)]49 BiCl3[thin space (1/6-em)]49 Al(HSO4)3[thin space (1/6-em)]50 Zr(HSO4)4[thin space (1/6-em)]50
Time (min) Yielda Time (min) Yieldb Time (min) Yieldc Time (min) Yieldd Time (min) Yielde Time (min) Yieldf Time (min) Yieldg
a Sulfonamide: 2 mmol; acid anhydride: 2 mmol; catalyst: 0.35 g; CH2Cl2: 5 mL; reflux.b Sulfonamide: 1 mmol; acid anhydride: 2 mmol (in two portions); H3PO4/SiO2: 0.3 g; n-hexane: 5 mL; reflux.c Sulfonamide: 1 mmol; acid anhydride: 2 mmol; SiO2–Cl: 0.3 g; n-hexane: 5 mmol; reflux.d Sulfonamide: 1 mmol; acid anhydride: 2 mmol; Bi(OTf)3: 5 mol%; CHCl3: 5 mL; reflux.e Sulfonamide: 1 mmol; acid anhydride: 2 mmol; BiCl3: 10 mol%; CHCl3: 5 mL; reflux.f Sulfonamide: 1 mmol; acid anhydride: 1.1–1.5 mmol; Al(HSO4)3: 5 mol%; CH2Cl2: 5 mL; r.t.g Sulfonamide: 1 mmol; acid anhydride: 1.1–1.5 mmol; Zr(HSO4)4: 5 mol%; CH2Cl2: 5 mL; r.t.
1 Me Me 40 85% 60 80% 72 88% 2 90% 10 90% 5 86% 7 85%
2 Et Me 15 80% 20 82% 18 85% 2 91% 12 88%        
3 nPr Me 25 75% 20 80% 24 80% 1 91% 10 88%        
4 iPr Me 25 96% 20 96% 15 95% 2 91% 13 91% 5 89% 7 85%
5 nBu Me     30 80%     5 90% 13 90%        
6 nPent Me                     5 89% 7 85%
7 Ph Me 180 82%     300 85% 30 91% 60 87%        
8 Me Ph 45 85% 55 80% 90 80% 2 94% 15 90% 7 91% 15 90%
9 Et Ph 25 85% 25 85% 30 85% 2 92% 17 89%        
10 nPr Ph 30 80% 30 80% 36 90% 2 95% 17 90% 7 88% 15 91%
11 iPr Ph 35 95% 25 95% 24 95% 1 96% 20 92% 7 85% 15 81%
12 nBu Ph     35 80%     3 92% 20 90%        
13 Ph Ph 105 90%     360 80% 35 90% 70 85% 25 72% 70 70%
14 4-O2NC6H4 Ph             600 10% 720 10%        
15 Me 4-MeC6H4 60 75% 90 95% 72 74% 2 94% 20 90% 5 86% 7 90%
16 Et 4-MeC6H4 45 83% 30 80% 36 85% 2 93% 20 92% 5 88% 7 89%
17 nPr 4-MeC6H4 35 78% 35 85% 36 93% 3 90% 20 90%        
18 iPr 4-MeC6H4 30 97% 25 97% 30 95% 1 91% 20 89%        
19 nBu 4-MeC6H4             3 96% 20 88% 5 88% 7 88%
20 nPent 4-MeC6H4                     5 89% 7 85%
21 Ph 4-MeC6H4 160 80%     420 60% 30 88% 80 82%        
22 Et 4-O2NC6H4 80 78%                        
23 nPr 4-O2NC6H4 90 75%                        


This methodology was also compatible with secondary sulfonamides (Table 12).50 Increasing the steric bulk on the nitrogen substituent from iPr (entry 1) to nBu (entry 5) did not impact upon reaction efficiency. The desired products were recovered in as little as 5 minutes and in yields of up to 96% (entries 1–8). The incorporation of a phenyl ring was associated with slower reaction rates and reduced yields of 70–75% (entries 9–13).

Table 12 N-Acylation of secondary sulfonamides under metal hydrogen sulfate catalysis

image file: d5ra05157f-u44.tif

Entry R1 R2 Al(HSO4)3 Zr(HSO4)4
Solvent-free CH2Cl2 Solvent-free CHCl3
Time (min) Yield Time (min) Yield Time (min) Yield Time (min) Yield
1 Me nPr 5 93% 7 90% 10 82% 15 80%
2 nPr nPr 5 95% 7 94% 10 80% 15 85%
3 nBu nPr 5 96% 7 93% 10 78% 15 82%
4 iPr nPr 5 85% 7 83% 10 71% 15 70%
5 Me nBu 5 90% 7 88% 10 82% 15 78%
6 Et nBu 5 92% 7 89% 10 80% 15 81%
7 nPr nBu 5 92% 7 90% 10 78% 15 80%
8 nBu nBu 5 89% 7 85% 10 85% 15 82%
9 Et Ph 15 75% 20 75% 30 72% 45 72%
10 nPr Ph 15 75% 20 71% 30 70% 45 70%
11 nBu Ph 15 74% 20 70% 30 70% 45 70%
12 iPr Ph 15 72% 20 70% 30 71% 45 70%
13 nPent Ph 15 70% 20 70% 30 71% 45 70%


Massah also reported the first examples of the preparation of bis-N-acyl sulfonamides (Scheme 2).50 Several bis-sulfonamides were initially prepared via sulfonylation of an appropriate diamine. N-Acylation of these substrates was subsequently conducted in the presence of Al(HSO4)3 or Zr(HSO4)4 in refluxing acetonitrile. Excellent yields (88–95%) of bis-N-acyl sulfonamides of varying chain lengths and increasing steric bulk were obtained in less than 10 minutes.


image file: d5ra05157f-s2.tif
Scheme 2 N-Acylation of bis-sulfonamides under metal hydrogen sulfate catalysis.

3. Acid chlorides, bromides and benzotriazoles

A one-pot sequential sulfonylation and acylation of amines in the presence of ZnO was described by Tamaddon and colleagues (Table 13).51 An initial one hour stir time of the sulfonyl chloride, amine and 20 mol% ZnO, followed by the addition of the acid chloride, generated the N-acyl sulfonamides in excellent yields (entries 1–10). Type I ZnO nanoparticles were found to outperform both ZnO and type II ZnO nanoparticles, as well as the recovered ZnO catalyst (entries 3 and 6–8).
Table 13 One-pot sequential sulfonylation/acylation

image file: d5ra05157f-u45.tif

Entry R1 R2 R3 Time (h) Yield
a 0.3 mmol (30 mol%) of type I nanoZnO used.
1 H Me Me 0.5 95%
2 H Me Ph 0.5 92%
3 H Ph Ph 1 90%, 91%a
4 H 4-MeC6H4 Me 0.5 92%
5 H 4-MeC6H4 Ph 0.5 90%
6 Ph Me Ph 0.75 89%, 91%a
7 Ph Ph Me 0.75 93%, 93%a
8 Ph 4-MeC6H4 Me 0.5 93%, 91%a
9 Bu 4-MeC6H4 Me 0.5 92%
10 Bu 4-MeC6H4 Ph 1 93%


Fe3O4@DE, developed by Kowsari as an N-acylation catalyst for anhydrides (see Table 4), is equally applicable to acid chlorides (Scheme 3).39 In most cases, benzoyl chloride was a better coupling partner, affording higher yields than acetic anhydride in the presence of either Fe3O4@DE or acetic acid.


image file: d5ra05157f-s3.tif
Scheme 3 N-Acylation of sulfonamides under Fe3O4@DE catalysis.

Williams explored the utility of iodide salts as activating agents for acid chlorides.52 Potassium iodide in acetonitrile at 60 mol% was optimal and proved superior to both lithium and sodium iodide. Various sulfonamides and acid chlorides were employed to probe the reaction scope with yields of 54–97% being recorded (Table 14). Partial racemisation was observed when (S)-2-phenylpropanoyl chloride was employed, suggesting that the reaction does not proceed solely via a ketene intermediate (entry 12). The mechanism likely involves conversion of the acid chloride to the more reactive acid iodide, which is characterised by greater polarizability and reduced overlapping of the iodine's lone pairs with image file: d5ra05157f-t1.tif

Table 14 Use of potassium iodine to generate acid iodides

image file: d5ra05157f-u46.tif

Entry R1 R2 Yield
1 Ph 4-MeC6H4 89%
2 nBu 4-MeC6H4 88%
3 4-BrC6H4 4-MeC6H4 67%
4 2-MeC6H4 4-MeC6H4 92%
5 PhCH2CH2 4-MeC6H4 91%
6 tBu 4-MeC6H4 80%
7 4-MeOC6H4 4-MeC6H4 97%
8 Ph Ph 96%
9 Ph 4-MeOC6H4 83%
10 Ph 2,4,6-Me3C6H2 73%
11 Ph Me 83%
12 image file: d5ra05157f-u47.tif 4-MeC6H4 54% (80% ee)


Massah expanded his study of anhydride catalysts (see Table 11), and found that acid chlorides were even more reactive in the presence of P2O5/SiO2, Bi(OTf)3 or BiCl3 (Table 15). Equimolar equivalents of acid chloride proved sufficient for smooth conversion whereas at least two equivalents of the anhydride were required. Bi(OTf)3 produced remarkably fast and efficient reactions, generating products in 1–45 min (entries 1–9). Contrastingly, reactions were generally slower (35–240 min) and lower yielding (60–85%) with the H3PO4/SiO2 system (entries 1–9). Secondary sulfonamides underwent successful acylation in the presence of metal hydrogen sulfate catalysts (entries 10–12).

Table 15 N-Acylation of sulfonamides in the presence of different acid catalysts

image file: d5ra05157f-u48.tif

Entry R1 R2 R3 P2O5/SiO2[thin space (1/6-em)]46 H3PO4/SiO2[thin space (1/6-em)]47 SiO2–Cl48 Bi(OTf)3[thin space (1/6-em)]49 BiCl3[thin space (1/6-em)]49 Al(HSO4)3[thin space (1/6-em)]50 Zr(HSO4)4[thin space (1/6-em)]50
Time (min) Yielda Time (min) Yieldb Time (min) Yieldc Time (min) Yieldd Time (min) Yielde Time (min) Yieldf Time (min) Yieldg
a Sulfonamide: 2 mmol; acid chloride: 2 mmol; catalyst: 0.35 g; CH2Cl2: 5 mL; reflux.b Sulfonamide: 1 mmol; acid chloride: 2 mmol (in two portions); H3PO4/SiO2: 0.3 g; n-hexane: 5 mL; reflux.c Sulfonamide: 1 mmol; acid chloride: 2 mmol; SiO2–Cl: 0.3 g; n-hexane: 5 mmol; reflux.d Sulfonamide: 1 mmol; acid chloride: 2 mmol; Bi(OTf)3: 5 mol%; CHCl3: 5 mL; reflux.e Sulfonamide: 1 mmol; acid chloride: 2 mmol; BiCl3: 10 mol%; CHCl3: 5 mL; reflux.f Sulfonamide: 1 mmol; acid chloride: 1.1–1.5 mmol; Al(HSO4)3: 5–10 mol%; CH2Cl2: 5 mL; r.t.g Sulfonamide: 1 mmol; acid chloride: 1.1–1.5 mmol; Zr(HSO4)4: 5–10 mol%; CH2Cl2 or CHCl3: 5 mL; r.t.
1 Me H Me 60 80% 60 85% 72 90% 5 95% 12 88% 15 92% 30 83%
2 Et H Me 120 70% 60 80% 60 80% 1 94% 10 90%        
3 Ph H Me 45 85% 35 80% 138 85% 25 93% 35 88%        
4 Me H Ph 90 75% 130 80% 90 85% 5 91% 17 87% 15 83% 30 75%
5 Et H Ph 120 85% 110 80% 108 80% 5 96% 15 90% 15 83% 30 80%
6 Ph H Ph 60 87% 40 82% 150 90% 40 95% 45 85%        
7 Me H 4-MeC6H4 120 78% 240 60% 90 78% 5 86% 12 90% 15 85% 30 82%
8 Et H 4-MeC6H4 240 70% 90 75% 90 75% 5 92% 10 89%        
9 Ph H 4-MeC6H4 90 82% 120 80% 420 75% 45 85% 55 83%        
10 Me nPr 4-MeC6H4                     15 85% 20 84%
11 Et nBu 4-MeC6H4                     15 80% 20 75%
12 Me Ph 4-MeC6H4                     30 70% 60 70%


A series of pyrimidone-containing acyl sulfonamides was evaluated by Bochet et al. for their anti-cancer properties.53 Pyrimidone-derived adduct 5 was prepared over two steps: 2-bromoacetyl bromide 1 was first combined with methanesulfonamide 2 under reflux to afford 2-bromo-N-(methylsulfonyl)acetamide 3 in 81% yield (Scheme 4). Intermediate 3 was then treated with 2-mercapto-6-methylpyrimidin-4(3H)-one 4 to produce target acyl sulfonamide 5. The rationale for employing an acid bromide is not provided, but is presumably due to the higher reactivity afforded by the bromide leaving group.


image file: d5ra05157f-s4.tif
Scheme 4 Synthesis of a pyrimidone-containing acyl sulfonamide.

The use of N-acyl benzotriazoles has been pioneered by Katritzky.54–56 N-Acyl benzotriazoles represent a viable alternative to acid chlorides, which can be difficult to prepare and handle.57 Reaction of N-acyl benzotriazoles with primary sulfonamides in the presence of sodium hydride in THF proceeded in good to excellent yields (Table 16).58 Aryl- (entries 1–5) and heteroaryl-containing (entries 6–11) substrates were readily transformed. However, 4-diethylaminophenyl and 4-pyridyl derivatives (entries 5–7) proved difficult to isolate, likely due to the increased aqueous solubility. Coupling of Cbz-protected amino acid-based benzotriazoles was also possible under these conditions (entries 12–14). Acylation of an acetazolamide-containing sulfonamide with both aromatic N-acyl derivatives (entries 15–17) and amino acid benzotriazole (entry 18) was similarly successful.

Table 16 Synthesis of N-acyl sulfonamides using N-acyl benzotriazoles and sulfonamides

image file: d5ra05157f-u49.tif

Entry R1 R2 Yield
1 4-MeC6H4 Me 85%
2 4-MeC6H4 4-MeC6H4 95%
3 4-MeOC6H4 Me 85%
4 4-MeOC6H4 4-MeC6H4 98%
5 4-(Et2N)C6H4 4-MeC6H4 98%
6 4-Pyridyl 4-MeC6H4 97%
7 4-Pyridyl Me 98%
8 2-Furyl 4-MeC6H4 95%
9 4-Pyrrolyl Me 80%
10 4-Pyrrolyl 4-MeC6H4 76%
11 2-Indolyl 4-MeC6H4 83%
12 Cbz–Ala Me 78%
13 Cbz–Ala 4-MeC6H4 87%
14 Cbz–Phe 4-MeC6H4 90%
15 4-MeC6H4 image file: d5ra05157f-u50.tif 88%
16 4-Pyridyl image file: d5ra05157f-u51.tif 100%
17 4-O2NC6H4 image file: d5ra05157f-u52.tif 81%
18 Cbz–Ala image file: d5ra05157f-u53.tif 96%


The same group later expanded this methodology to encompass N-(α,β-unsaturated acyl)-benzotriazoles (Table 17).59 Two methods for coupling the benzotriazoles were established, employing either potassium tert-butoxide at 0 °C to room temperature (method A, entries 1–4) or sodium hydride at room temperature/reflux (method B, entries 5–12). β-Heteroarylacroyl benzotriazoles treated with substituted aromatic sulfonamides and potassium tert-butoxide generated the desired product in excellent yields (entries 2, 3 and 5), with the exception of a 2-thienyl acyl benzotriazole substrate (entry 4). Incorporation of methyl or phenyl groups at the α-position was not a barrier to successful coupling (entries 9 and 10).

Table 17 Synthesis of N-acyl sulfonamides from N-(α,β-unsaturated acyl)-benzotriazoles

image file: d5ra05157f-u54.tif

Entry R1 R2 R3 R4 Method Yield
1 Ph H H 4-MeC6H4 A 80%
2 2-Furyl H H 4-MeC6H4 A 89%
3 2-Thienyl H H 4-MeC6H4 A 91%
4 2-Thienyl H H Ph A 48%
5 2-Thienyl H H 2,4,6-Me3C6H2 B 87%
6 Ph H H 2,4,6-Me3C6H2 B 65%
7 3,4,5-(MeO)3C6H2 H H 3-F3CC6H4 B 84%
8 3,4,5-(MeO)3C6H2 H H 4-tBuC6H4 B 56%
9 Ph H Me 4-tBuC6H4 B 84%
10 Ph H Ph Me B 60%
11 Ph H H Me B 63%
12 Me Me H 4-tBuC6H4 B 70%


4. Carboxylic acids and esters

Solid-phase organic synthesis is a widely used method for the generation of peptides and small molecule libraries.60 A polymer-supported version of EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) was employed by Sturino to prepare various N-acyl sulfonamides (Table 18).61 This methodology was compatible with methanesulfonamide (entry 1) and a wide range of aromatic sulfonamides (entries 2–24). Coupling of heteroaryl sulfonamides was also possible under these conditions (entry 25).
Table 18 Application of polymer-supported EDC in the synthesis of N-acyl sulfonamides

image file: d5ra05157f-u55.tif

Entry R1 Yield
1 Me 66%
2 image file: d5ra05157f-u56.tif 75%
3 Ph 56%
4 2-MeC6H4 75%
5 3-MeC6H4 73%
6 2,5-Me2C6H3 76%
7 4-MeOC6H4 68%
8 2,5-(MeO)2C6H3 78%
9 2-FC6H4 79%
10 2-ClC6H4 81%
11 3-ClC6H4 63%
12 4-ClC6H4 62%
13 3-BrC6H4 68%
14 2,4-Cl2C6H3 67%
15 2,5-Cl2C6H3 73%
16 2-Cl-6-MeC6H3 76%
17 3,4,5-Cl3C6H2 74%
18 C6F5 73%
19 2-O2NC6H4 63%
20 4-O2NC6H4 63%
21 2-F3CC6H4 63%
22 4-F3CC6H4 76%
23 Bn 64%
24 2-PhC6H4 73%
25 5-Br-2-Thienyl 57%


In 2013, Bach and co-workers discovered a novel series of ethyl 6-aminonicotinate acyl sulfonamides as P2Y12 receptor antagonists.62 Ethyl 6-azetidinylnicotinate acyl sulfonamides were synthesized via the initial reaction of ethyl 6-chloronicotinates with azetidine-3-carboxylic acids to afford azetidinylpyridine derivatives, which were subsequently coupled with various sulfonamides to yield the desired acyl sulfonamides (Table 19). Similarly, ethyl 6-piperidinylnicotinate acyl sulfonamides were prepared from the reaction of ethyl 6-chloronicotinates with piperidine-4-carboxylic acids, followed by sulfonamide coupling. Acyl sulfonamides with thienyl moiety were prepared in low to moderate yields (entries 1 and 2). Synthesis of acyl sulfonamides containing 2-phenylethyl and cyclohexyl was also successful. Treatment of carboxylic acids with benzene sulfonamides afforded the desired products in good yields (entry 5). Reaction with various benzyl sulfonamides proceeded in low to high yields (entries 6–16).

Table 19 Synthesis of ethyl-6-azetidinyl/piperidinyl nicotinate acyl sulfonamides

image file: d5ra05157f-u57.tif

Entry R1 R2 R3 Yield
n = 1 n = 2
1 H Cl 5-Cl-2-Thienyl 56% 24%
2 Me CN 5-Cl-2-Thienyl 15% 45%
3 Me CN PhCH2CH2 39%  
4 Me CN CyCH2 11%  
5 Me CN Ph 70% 49%
6 Me CN Bn 54% 83%
7 Me CN 2-MeBn 2%  
8 Me CN 3-F3CBn 39%  
9 Me CN 3-MeBn 15%  
10 Me CN 4-ClBn 48%  
11 Me CN 4-FBn 43% 80%
12 Me CN 4-MeBn 15% 45%
13 Me CN 4-CH2OHBn 19%  
14 Me CN 4-OMeBn   45%
15 Me CN 4-iPrBn   56%
16 Me CN 2,4-F2Bn   34%


Ellis described a racemisation-free pathway for the synthesis of the endothelin-A antagonist acyl sulfonamide 11.63 Initial attempts at coupling enantiopure 6 using EDC/HOAt and DMAP (stoichiometric or catalytic) resulted in complete racemisation. However, when enantiopure acid 6 was treated with EDC and HOAt, the corresponding configurationally stable HOAt ester 7 was successfully isolated (Scheme 5). Subsequent treatment with saturated aqueous ammonia afforded enantiomerically pure amide 8. Reaction of amide 8 with sulfonyl chloride 9 in the presence of NaHMDS in THF at low temperature, afforded protected acyl sulfonamide 10 which was subsequently hydrogenolysed to provide enantiomerically pure acyl sulfonamide 11.


image file: d5ra05157f-s5.tif
Scheme 5 Preparation of enantiopure acyl sulfonamides.

Rad et al. described the use of cyanuric chloride (2,4,6-trichloro-1,3,5-triazine or TCT) for the one-pot synthesis of N-acyl sulfonamides from carboxylic acids.64 A combination of alumina and triethylamine in anhydrous acetonitrile afforded high yields and short reaction times (Table 20). Coupling of aliphatic and aromatic carboxylic acids with sulfonamides was successful under these conditions (entries 1–16). Conversion of carboxylic acids containing electron-withdrawing substituents (entries 5 and 16) necessitated longer reaction times. Moderate yields were noted when a benzamide moiety was incorporated into the acid substrate (entries 10–12).

Table 20 Cyanuric acid-mediated coupling of sulfonamides and carboxylic acids

image file: d5ra05157f-u58.tif

Entry R1 R2 Time (min) Yield
1 Ph Ph 60 92%
2 Ph 4-MeC6H4 40 85%
3 Ph Me 60 65%
4 4-ClC6H4 Ph 50 85%
5 4-ClC6H4 Me 100 76%
6 4-MeOC6H4 Ph 50 86%
7 4-O2NC6H4 Ph 90 75%
8 4-MeOC6H4CH2 Ph 90 65%
9 (E)-PhCH[double bond, length as m-dash]CH Ph 120 62%
10 BzNHCH2 Ph 75 60%
11 BzNHCH2 4-MeC6H4 70 55%
12 BzNHCH2 Me 70 60%
13 Me Ph 80 74%
14 Me 4-MeC6H4 75 70%
15 Me Me 75 68%
16 3-Pyridyl Ph 120 70%


The mechanism likely proceeds via an SN-Ar type reaction between the carboxylic acid I and cyanuric chloride II in the presence of triethylamine, resulting in the formation of an active carboxylate cyanuric ester intermediate III (Scheme 6). The chemoselectivity arises from the fact that sulfonamides remain unreactive toward cyanuric chloride under the reaction conditions, whereas carboxylic acids readily form carboxylate anions, which are significantly more nucleophilic than sulfonamides. Consequently, cyanuric chloride reacts exclusively with the carboxylate species to produce the active ester. The ester then combines with a sulfonamide to form N-acyl sulfonamide product IV, with the concomitant liberation of cyanuric acid V.


image file: d5ra05157f-s6.tif
Scheme 6 Proposed mechanism for cyanuric acid couplings.

A one-pot methodology for coupling carboxylic acids and sulfonamides using the Mukaiyama reagent (2-chloro-1-methylpyridinium iodide or CMPI) was developed by Chen and Luo.65 A 2[thin space (1/6-em)]:[thin space (1/6-em)]1 ratio of sulfonamide to carboxylic acid, with triethylamine as base and catalytic DMAP in dichloromethane, proved optimum (Table 21). Coupling of methanesulfonamide with aromatic (entries 1–7), heteroaromatic (8–10), and aliphatic (entries 11–13) acids was successful. The sulfonamide partner could also be varied, ranging from aliphatic (entries 1–13, 15 and 16) to aromatic (entries 14 and 17–19).

Table 21 Coupling of carboxylic acids and sulfonamides using the Mukaiyama reagent

image file: d5ra05157f-u59.tif

Entry R1 R2 Yield
1 4-ClC6H4 Me 81%
2 3-ClC6H4 Me 82%
3 2-ClC6H4 Me 73%
4 3-MeOC6H4 Me 89%
5 2-MeC6H4 Me 91%
6 2-F3CC6H4 Me 78%
7 4-O2NC6H4 Me 78%
8 image file: d5ra05157f-u60.tif Me 72%
9 image file: d5ra05157f-u61.tif Me 78%
10 image file: d5ra05157f-u62.tif Me 58%
11 image file: d5ra05157f-u63.tif Me 75%
12 image file: d5ra05157f-u64.tif Me 71%
13 image file: d5ra05157f-u65.tif Me 77%
14 image file: d5ra05157f-u66.tif Ph 36%
15 Ph iPr 83%
16 Ph Cyclopropyl 89%
17 Ph Ph 83%
18 Ph 3-ClC6H4 84%
19 Ph 2-ClC6H4 87%


Manabe et al. reported the successful exploitation of sulfonyl isocyanates to access N-acyl sulfonamides from carboxylic acid (Table 22).66 Carboxylic acids containing functional groups such as esters (entry 1), alkenes (entry 2), halides (entry 3), acetals (entries 7 and 8), and ethers (entries 5 and 9) were transformed in excellent yields. Notably, reaction of N-Cbz-L-glutamic acid α-benzyl afforded the N-acyl sulfonamide in quantitative yield (entry 6) without the formation of pyroglutamate side products previously reported.67 This strategy was adapted to the preparation of biologically active nucleoside derivatives (entry 8), as well as anti-tumor agents (entry 10), both in high yields.

Table 22 Preparation of N-acyl sulfonamides using sulfonyl isocyanates

image file: d5ra05157f-u67.tif

Entry R1 R2 Yield
a Reaction was performed at 50 °C in 5 min.
1 image file: d5ra05157f-u68.tif 4-MeC6H4 97%
2 image file: d5ra05157f-u69.tif 4-MeC6H4 85%
3 image file: d5ra05157f-u70.tif 4-MeC6H4 96%
4 image file: d5ra05157f-u71.tif 4-MeC6H4 100%
5 image file: d5ra05157f-u72.tif 4-MeC6H4 83%
6 image file: d5ra05157f-u73.tif 4-MeC6H4 100%
7 image file: d5ra05157f-u74.tif 4-MeC6H4 81%
8 image file: d5ra05157f-u75.tif 4-MeC6H4 89%
9 image file: d5ra05157f-u76.tif Me 90%
10 2,4-Cl2C6H3 4-ClC6H4 93%a


Ashfeld and colleagues described a chlorophosphite-mediated Staudinger-like acylation of sulfonyl azides as a route to N-acyl sulfonamides.68 This approach, which relies on a Staudinger-type ligation of the C–N bond, was initially optimised for the preparation of amides and later adapted to N-acyl sulfonamides (Table 23). The best outcomes were obtained with ClP(pin), or 2-chloro-4,4,5,5-tetramethyl-1,3,2-dioxaphospholane, and triethylamine with a 1.3[thin space (1/6-em)]:[thin space (1/6-em)]1 ratio of acid to azide. Aromatic carboxylic acids (entries 1–6), ranging from electron-rich to electron-poor, in addition to heteroaromatic substrates (entry 7), reacted with tosyl azide in good to excellent yields. This transformation was highly chemoselective with para-substituted alcohol (entry 8), aldehyde (entry 9) and ketone (entry 10) functional groups well tolerated. Conversion of aliphatic substrates was also successful (entries 15–17), albeit in low yields for sterically encumbered pivalic acid (entry 17). This utility of this methodology was exemplified by the synthesis of anti-tumor agent LY573636 in excellent 97% yield (entry 18).69

Table 23 Direct Staudinger-like acylation of carboxylic acids with sulfonyl azides

image file: d5ra05157f-u77.tif

Entry R1 R2 Yield
1 Ph 4-MeC6H4 93%
2 4-MeOC6H4 4-MeC6H4 96%
3 4-F3CC6H4 4-MeC6H4 81%
4 4-NCC6H4 4-MeC6H4 96%
5 4-ClC6H4 4-MeC6H4 91%
6 2-IC6H4 4-MeC6H4 83%
7 2-Pyrrolyl 4-MeC6H4 81%
8 4-(HOCH2)C6H4 4-MeC6H4 64%
9 4-(OHC)C6H4 4-MeC6H4 60%
10 4-(MeCO)C6H4 4-MeC6H4 82%
11 2-(PhCO)C6H4 Bn 34%
12 (E)-PhCH[double bond, length as m-dash]CH 4-MeC6H4 93%
13 (E)-PhCH[double bond, length as m-dash]CH Me 76%
14 Bn 4-MeC6H4 94%
15 nHept 4-MeC6H4 91%
16 Cy 4-MeC6H4 80%
17 tBu 4-MeC6H4 56%
18 2,4-Cl2C6H3 5-Br-2-Thienyl 97%


Following initial formation of phosphite ester II, subsequent reaction with the azide generates a common phosphazide intermediate III (Scheme 7). The mechanism can then plausibly proceed by two different pathways. Path A involves acyl substitution and elimination of nitrogen gas to generate an ester azaylide IV, which undergoes [1,3]-acyl migration to the phosphorimide VI. Subsequent hydrolysis liberates the acyl sulfonamide target. Path B proceeds by formation of phosphoryl triazine V which then rearranges to produce the same phosphorimide VI as path A.


image file: d5ra05157f-s7.tif
Scheme 7 Proposed reaction pathways.

A novel, cobalt-catalysed process for the preparation of N-acyl sulfonamides from carboxylic acids has been developed by Ji and colleagues.70 During a study of insertion reactions of isocyanides, the authors serendipitously observed how a cobalt catalyst promoted the formation of N-tosylbenzamide from benzoic acid and tosyl azide.71 5 mol% dicobalt octacarbonyl in acetonitrile at 80 °C proved optimum (Table 24). This chemistry was compatible with aromatic (entries 1–14), trans-cinnamic acid (entry 15), aliphatic (entry 16) and heteroaromatic acids (entries 17 and 18). Other azides, ranging from electron-rich (entries 19 and 20) to electron-poor (21–23) and aliphatic examples (entries 25–27), were also well tolerated. Anti-tumor agent LY573636 could be prepared on a gram scale under these conditions (entry 28).

Table 24 Co-catalysed coupling of carboxylic acids and sulfonylazides

image file: d5ra05157f-u78.tif

Entry R1 R2 Yield
1 Ph 4-MeC6H4 96%
2 2-MeC6H4 4-MeC6H4 97%
3 3-MeC6H4 4-MeC6H4 98%
4 4-MeC6H4 4-MeC6H4 96%
5 4-MeOC6H4 4-MeC6H4 71%
6 2-FC6H4 4-MeC6H4 85%
7 2-ClC6H4 4-MeC6H4 80%
8 2-BrC6H4 4-MeC6H4 79%
9 3-ClC6H4 4-MeC6H4 81%
10 3-BrC6H4 4-MeC6H4 83%
11 3-IC6H4 4-MeC6H4 85%
12 4-ClC6H4 4-MeC6H4 80%
13 4-BrC6H4 4-MeC6H4 76%
14 4-F3CC6H4 4-MeC6H4 70%
15 (E)-PhCH[double bond, length as m-dash]CH 4-MeC6H4 86%
16 Cyclobutyl 4-MeC6H4 74%
17 3-Furyl 4-MeC6H4 91%
18 2-Thienyl 4-MeC6H4 93%
19 Ph Ph 93%
20 Ph 4-MeOC6H4 89%
21 Ph 4-CNC6H4 71%
22 Ph 4-BrC6H4 80%
23 Ph 4-IC6H4 94%
24 Ph 2-Naphthyl 93%
25 Ph Et 83%
26 Ph nPr 69%
27 Ph nBu 72%
28 2,4-Cl2C6H3 5-Br-2-Thienyl 60%


The proposed catalytic cycle begins with generation of intermediate I via ligand exchange from Co2(CO)8 in acetonitrile, which then reacts with tert-butyl isocyanide to form active complex II (Scheme 8). Reaction of II with a sulfonyl azide affords complex III which dissociates to liberate nitrogen gas and intermediate IV. A subsequent coupling reaction with the coordinated isocyanide molecule furnishes VI which is attacked by the carboxylic acid forming VII. Rearrangement of VII leads to intermediate VIII which decomposes to generate the target acyl sulfonamide.


image file: d5ra05157f-s8.tif
Scheme 8 Proposed catalytic cycle.

Williams et al. developed an effective methodology for transforming amino acids into acyl sulfonamides via a thio acid intermediate.72 This approach involves the initial conversion of a protected amino acid into a mixed anhydride and subsequent reaction with trimethylsilyl thiolate to form a thioester (Table 25). The thioester rearranges to a thionoester and forms a thio acid upon methanolysis. Addition of sulfonyl azide generates the acyl sulfonamide product. Coupling of either base- (entries 1–3) or acid-sensitive (entries 3–5) substrates was equally successful.

Table 25 Synthesis of acyl sulfonamides from amino acids and sulfonyl azides

image file: d5ra05157f-u79.tif

Entry R1 R2 Yield
1 image file: d5ra05157f-u80.tif 4-(HO2C)C6H4 86%
2 image file: d5ra05157f-u81.tif 4-(HO2C)C6H4 83%
3 image file: d5ra05157f-u82.tif 4-(HO2C)C6H4 98%
4 image file: d5ra05157f-u83.tif (TMS)CH2CH2 96%
5 image file: d5ra05157f-u84.tif (TMS)CH2CH2 94%


In an effort to discover novel anti-cancer agents, Sławiński and co-workers pioneered a novel approach to acyl sulfonamides from carboxylic acids and N-[4-chloro-5-methyl-2-(R1-methylthio)benzenesulfonyl]cyanamide potassium salts (Table 26).73 Cyanamide potassium salts containing alkene (entry 1) or amide (entry 3) moieties produced high yields, in contrast to alkyne substrates (entry 2). Aryl/heteroaryl derivatives of cyanamide potassium salts afforded moderate to excellent yields (entries 4–15). Variation of the acid component from propanoic acid (entries 16–25), to isobutyric (entry 26) and 3-cyclohexenepropanoic acid (entry 27) proved similarly successful. Coupling of solid acid reagents, such as benzoic acid (entry 28) or trans-cinnamic acid (entries 29 and 30), were conducted in water or toluene, in contrast to solvent-free conditions for other acids.

Table 26 N-Acyl sulfonamides from carboxylic acids and cyanamide potassium salts

image file: d5ra05157f-u85.tif

Entry R1 R2 Solvent Time (h) Yield
1 Me H2C[double bond, length as m-dash]CH   15 72%
2 Me HC[triple bond, length as m-dash]C   17 35%
3 Me H2NCO   4.5 60%
4 Me Ph   2 54%
5 Me 3-F3CC6H4   2 84%
6 Me 4-F3CC6H4   1.5 50%
7 Me 4-ClC6H4   2 50%
8 Me 4-MeOC6H4   1 51%
9 Me 4-Pyridyl   1.5 45%
10 Me 1-Naphthyl   1.5 54%
11 Me 2-Naphthyl   2 50%
12 Me 2-Quinolinyl   2 52%
13 Me image file: d5ra05157f-u86.tif   1 55%
14 Me image file: d5ra05157f-u87.tif   1.5 59%
15 Me image file: d5ra05157f-u88.tif   1.5 62%
16 Et Ph   1 86%
17 Et 3-F3CC6H4   2 68%
18 Et 4-F3CC6H4   1 93%
19 Et 4-ClC6H4   2 68%
20 Et 4-MeOC6H4   1 85%
21 Et 4-Pyridyl   2 65%
22 Et 2-Naphthyl   1.5 86%
23 Et image file: d5ra05157f-u89.tif   1.75 87%
24 Et image file: d5ra05157f-u90.tif   1 81%
25 Et image file: d5ra05157f-u91.tif   1.5 68%
26 (CH3)2CH Ph   2 95%
27 Cy–CH2CH2 Ph   1.5 81%
28 Ph Ph Water 144 72%
29 (E)-PhCH[double bond, length as m-dash]CH Ph Water 96 76%
30 (E)-PhCH[double bond, length as m-dash]CH 1-Naphthyl Toluene 120 50%


The reaction is initiated by protonation of the nitrile nitrogen by the carboxylic acid (Scheme 9). Simultaneously, the carboxylate anion accepts the lone pair from the nitrile, activating the nitrile for nucleophilic attack. The carboxylic acid serves dual roles as a proton donor and a stabilizing agent for the nitrile activation. This is followed by a subsequent attack of the sulfonamide nitrogen anion on the carbonyl, leading to C–O cleavage. Elimination of cyanate produces the required acyl sulfonamide.


image file: d5ra05157f-s9.tif
Scheme 9 Proposed mechanism for the coupling of cyanamide potassium salts with carboxylic acids.

Reddy and co-workers expanded their methodology for the N-acylation of sulfonamides from acid anhydrides (Table 3) to carboxylic acids via a mixed anhydride intermediate (Scheme 10).38 Treating sulfonamides with trans-cinnamic, 3,4-dimethoxyphenylacetic acid, levulinic acid and (±)-ibuprofen furnished the corresponding N-acyl sulfonamide products in up to 85% yield.


image file: d5ra05157f-s10.tif
Scheme 10 ZnCl2-catalysed N-acylation via mixed anhydrides.

Sagar outlined a procedure for synthesising orthogonally protected N-acyl sulfonamide-tethered peptides from commercially available amino acids via a selenocarboxylate intermediate.74 Initially, the selected amino acid was converted to its mixed anhydride and subsequently selenated with NaBH2Se3 (Table 27). This methodology allowed for the preparation of sulfonamide-linked peptides (entries 1–7), N-acyl sulfonamide-derived dipeptide substrates (entries 8 and 9), as well as aryl sulfonamide-derived peptides (entries 10–17), all in excellent yields. Epimerisation studies involving optically pure Cbz–(L)-Phg–OH and Cbz–(D)-Phg–OH confirmed that racemisation was not observed over the course of the reaction.

Table 27 Synthesis of orthogonally protected N-acyl sulfonamide tethered dipeptides

image file: d5ra05157f-u92.tif

Entry R1 R2 Yield
1 image file: d5ra05157f-u93.tif image file: d5ra05157f-u94.tif 91%
2 image file: d5ra05157f-u95.tif image file: d5ra05157f-u96.tif 86%
3 image file: d5ra05157f-u97.tif image file: d5ra05157f-u98.tif 93%
4 image file: d5ra05157f-u99.tif image file: d5ra05157f-u100.tif 89%
5 image file: d5ra05157f-u101.tif image file: d5ra05157f-u102.tif 93%
6 image file: d5ra05157f-u103.tif image file: d5ra05157f-u104.tif 92%
7 image file: d5ra05157f-u105.tif image file: d5ra05157f-u106.tif 90%
8 image file: d5ra05157f-u107.tif Ph 82%
9 image file: d5ra05157f-u108.tif Ph 85%
10 image file: d5ra05157f-u109.tif Ph 94%
11 image file: d5ra05157f-u110.tif Ph 86%
12 image file: d5ra05157f-u111.tif 4-MeC6H4 90%
13 image file: d5ra05157f-u112.tif 4-MeC6H4 92%
14 image file: d5ra05157f-u113.tif 4-MeC6H4 95%
15 image file: d5ra05157f-u114.tif 4-MeC6H4 94%
16 image file: d5ra05157f-u115.tif Dansyl 88%
17 image file: d5ra05157f-u116.tif 2,4-F2C6H3 90%
18 image file: d5ra05157f-u117.tif image file: d5ra05157f-u118.tif 82%
19 image file: d5ra05157f-u119.tif image file: d5ra05157f-u120.tif 85%


The authors suggest that the mechanism proceeds via the formation of selenocarboxylate I by in situ selenation of the corresponding acid (Scheme 11). This intermediate then reacts with sulfonyl azide II through stepwise linear coupling, followed by intramolecular cyclisation to form a five-membered heteroaromatic ring IV. This decomposes through retro-[3 + 2] reaction, expelling nitrogen and selenium to furnish the N-acyl sulfonamide.


image file: d5ra05157f-s11.tif
Scheme 11 Possible mechanism for N-acyl sulfonamide formation.

Hu et al. reported an efficient, one-pot amidation of carboxylic acids via selenocarboxylate intermediates.75 While the major focus of the paper is on the preparation of amides, one example is provided of an N-acyl sulfonamide 15 obtained from carboxylic acid 12 and sulfonyl azide 14 in 98% overall yield (Scheme 12).


image file: d5ra05157f-s12.tif
Scheme 12 One-pot amidation of carboxylic acids.

Two pathways have been proposed by which selenatriazoline intermediate IV can be generated (Scheme 13). Path A is a stepwise mechanism in which the terminal nitrogen of the electron-deficient azide combines with the selenium of selenocarboxylate I followed by an intramolecular cyclisation to form intermediate II. Electron-withdrawing groups help stabilise the transition state by delocalising the negative charge on the nitrogen. Alternatively, the reaction may proceed via electron-rich azides (path B), which involves a slower, concerted [3 + 2] cyclisation.


image file: d5ra05157f-s13.tif
Scheme 13 Proposed mechanism for selenocarboxylate/azide amidation.

Zeng et al. investigated several metal-based Lewis acid catalysts for the inter- and intramolecular N-acylation of sulfonamides with esters.76 A catalytic loading of 1.5 equivalents of TiCl4 in 1,1,2,2-tetrachloroethane at 115–160 °C in a sealed tube proved optimal (Table 28). This protocol was suitable for aliphatic (entries 1–10), aromatic (entries 11–13 and 16), and heteroaromatic (entry 14) esters, in addition to both aromatic (entries 1–15) and aliphatic sulfonamides (entry 16). The group postulated that the 4-methoxy derivative was obtained in poor yield (30%) due to the formation of an unreactive oxonium salt (entry 5). To prevent this, addition of 1.5 equivalents of triethylamine saw the yield increase by 24%. Bulky esters returned lower yields (entries 9 and 10). Varying the electronic nature of the ester substituents did not significantly impact upon reactivity (entries 11–14). An interesting intramolecular transformation of 2-sulfamoyl benzoic acid ethyl ester to saccharin proceeded in 82% yield at 115 °C (entry 15).

Table 28 TiCl4-mediated N-acylation of sulfonamides with esters

image file: d5ra05157f-u121.tif

Entry R1 R2 R3 Time (h) Yield
a 1.5 equiv. triethylamine was added.b 3 equiv. ethyl isobutyrate was added.c Reaction carried out at 160 °C.
1 Me Et 4-MeC6H4 18 76%
2 Me Et 4-ClC6H4 30 81%
3 Me Et 4-BrC6H4 55 77%
4 Me Et 4-O2NC6H4 48 48%
5 Me Et 4-MeOC6H4 36 30% (54%)a
6 Me Et Ph 24 70%
7 Me Et 4-MeC6H4 24 69%
8 Me nBu 4-MeC6H4 24 72%
9 Me tBu 4-MeC6H4 24 56%
10 iPr Et 4-MeC6H4 24 51%b
11 Ph Et 4-MeC6H4 24 97%c
12 4-MeC6H4 Et 4-MeC6H4 24 55%c
13 4-ClC6H4 Et 4-MeC6H4 24 46%c
14 2-Pyridyl Et 4-MeC6H4 24 45%c
15 image file: d5ra05157f-u122.tif 48 82%
16 Ph Et Me 24 94%c


5. Thio acids

Williams et al. discovered that reaction of a benzylazide with thioacetic acid produced N-benzyl acetamide which could be applied to sulfonyl azides. Accordingly, reaction of thio acids with various sulfonyl azides in the presence of 2,6-lutidine provided easy access to N-acyl sulfonamides (Table 29).77 Thiobenzoic acid and thioacetic acid readily combined with tosyl azide (entries 1 and 2) or 4-carboxysulfonyl azide in excellent yields (entries 3 and 4). α-Aminoacyl sulfonamide derivatives could be obtained from the corresponding 2,4,6-trimethoxybenzyl (2,4,6-TMOB) thioesters by initial liberation of the thio acid, followed by reaction with the sulfonyl azide (entries 5–9).
Table 29 Preparation of acyl sulfonamides from thio acids/esters and sulfonyl azidesa

image file: d5ra05157f-u123.tif

Entry R1 R2 R3 Method Time Yield
a Method A: 2,6-lutidine, methanol, r.t.; method B: 2,6-lutidine, water, r.t.; method C: TFA/DCM (40–80% v/v), HSiEt3, r.t. for 1–3 h, then 2,6-lutidine, MeOH, r.t.
1 Ph H Ph A 15 min 98%
2 Me H Ph A 15 min 96%
3 Ph H 4-(HO2C)C6H4 B 1 h 93%
4 Me H 4-(HO2C)C6H4 B 1 h 98%
5 image file: d5ra05157f-u124.tif 2,4,6-TMOB Ph C 12 h 91%
6 image file: d5ra05157f-u125.tif 2,4,6-TMOB 4-MeC6H4 C 12 h 87%
7 image file: d5ra05157f-u126.tif 2,4,6-TMOB 4-MeC6H4 C 12 h 72%
8 image file: d5ra05157f-u127.tif 2,4,6-TMOB image file: d5ra05157f-u128.tif C 12 h 73%
9 image file: d5ra05157f-u129.tif 2,4,6-TMOB image file: d5ra05157f-u130.tif C 12 h 73%


The mechanism is outlined in Scheme 14 and proceeds via the formation of thiatriazoline intermediate III. Reaction of the thio acid with sulfonyl azide forms a thiatriazoline intermediate through either a stepwise diazo transfer-like mechanism or a [3 + 2] cycloaddition. Decomposition of thiatriazoline intermediate III via a retro [3 + 2] cycloelimination ultimately yields the acyl sulfonamide, with the concomitant release of nitrogen and sulfur.


image file: d5ra05157f-s14.tif
Scheme 14 Reaction mechanism of thio acids with sulfonyl azides.

Liskamp exploited a similar methodology for the preparation of N-β-protected acyl sulfonamides (Table 30).78 Both Fmoc- and Cbz-protected derivatives of glycine (entries 1–4), phenylalanine (entries 5–8), valine (entries 9 and 10), and serine (entries 11 and 12) were coupled to either thioacetic or thiobenzoic acid in excellent yields. While chloroform was suitable for glycine substrates (entries 1–4), DMF was required for less soluble starting materials (entries 5–12). Significantly, this approach also facilitated chemical ligation, allowing access to (α-amino)acyl sulfonamides (entry 13) or peptidyl sulfonamides (entry 14).

Table 30 Synthesis of N-β-protected acyl sulfonamides

image file: d5ra05157f-u131.tif

Entry Protecting group R1 R2 Solvent Yield
1 Fmoc Me H CHCl3 90%
2 Fmoc Ph H CHCl3 100%
3 Cbz Me H CHCl3 100%
4 Cbz Ph H CHCl3 100%
5 Fmoc Me Bn DMF 91%
6 Fmoc Ph Bn DMF 87%
7 Cbz Me Bn DMF 95%
8 Cbz Ph Bn DMF 96%
9 Fmoc Me iPr DMF 95%
10 Fmoc Ph iPr DMF 96%
11 Fmoc Me tBuO-CH2 DMF 93%
12 Fmoc Ph tBuO-CH2 DMF 94%
13 Fmoc image file: d5ra05157f-u132.tif H DMF 81%
14 Cbz image file: d5ra05157f-u133.tif Bn DMF 99%


6. Aldehydes and ketones

Ma et al. designed a protocol for the direct N-acylation of sulfonamides using aldehydes and azolium salts (Table 31).79 A combination of azolium salt 16 (2-mesityl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium chloride), oxidant DPQ (3,3′,5,5′-tetra-tert-butyldiphenoquinone) and potassium tert-butoxide facilitated the coupling of selected aldehydes to tosylamide to generate the desired N-tosylcarboxamides in excellent yields (entries 1–11). Aromatic (entries 1–5), thiophenic (entry 6) and naphthalic (entry 7) aldehydes reacted readily, in addition to enals (entry 8) and ynals (entries 9–11). Changing the sulfonamide substituent to phenyl (entry 12), 3-nitrophenyl (entry 13), 2-chlorophenyl (entry 14) or methyl (entry 15) was similarly successful.
Table 31 Oxidative N-acylation of sulfonamides using aldehydes

image file: d5ra05157f-u134.tif

Entry R1 R2 Yield
a 2.0 equiv. tBuOK used.
1 4-ClC6H4 4-MeC6H4 97%
2 Ph 4-MeC6H4 97%
3 2-FC6H4 4-MeC6H4 94%
4 3-MeOC6H4 4-MeC6H4 90%
5 3-O2NC6H4 4-MeC6H4 87%
6 2-Thienyl 4-MeC6H4 87%
7 2-Naphthyl 4-MeC6H4 91%
8 (E)-Ph–CH[double bond, length as m-dash]CH 4-MeC6H4 82%
9 Heptyne 4-MeC6H4 87%
10 Cy–C[triple bond, length as m-dash]C 4-MeC6H4 79%
11 Ph–C[triple bond, length as m-dash]C 4-MeC6H4 71%
12 4-ClC6H4 Ph 95%
13 4-ClC6H4 3-O2NC6H4 93%
14 4-ClC6H4 2-ClC6H4 96%
15 4-ClC6H4 Me 92%
16 2,3-Cl2C6H3 5-Br-2-Thienyl 87%a


The catalytic cycle starts with carbene 16a which undergoes nucleophilic addition to the aldehyde to afford Breslow intermediate I (Scheme 15). This intermediate is then oxidised by DPQ to generate acylazolium species II. In tandem, tBuOK deprotonates the sulfonamide which then attacks the carbonyl forming adduct III. Subsequent fragmentation of the azolium intermediate regenerates carbene 16a and furnishes the target N-acyl sulfonamide.


image file: d5ra05157f-s15.tif
Scheme 15 Catalytic cycle.

Chang and Chan developed the first chemoselective ruthenium-catalysed amidation of aldehydes using N-(para-tolylsulfonyl)imino phenyliodinane (PhI[double bond, length as m-dash]NTs) as the nitrogen source (Table 32).80 The procedure was compatible with tertiary carbon-containing substrates, with C–N bond formation occurring selectively at the aldehyde functional group (entries 1, 2, 7 and 8). Competitive side reactions were not observed in the presence of benzylic (entries 10 and 11) or vinylic (entries 12 and 13) alkene bonds. Aromatic (entries 15–18) and heteroaromatic (entries 19 and 20) aldehydes were readily transformed to their corresponding N-acyl sulfonamides.

Table 32 [Ru(TTP)(CO)]-catalysed amidation

image file: d5ra05157f-u135.tif

Entry R1 Yield
1 iBu 94%
2 iPr 86%
3 Et 97%
4 nHex 97%
5 tBu 60%
6 Br(CH2)4 96%
7 Cyclopropyl 91%
8 Cyclopentyl 99%
9 Cy 97%
10 Ph–CH2 86%
11 Ph–(CH2)2 68%
12 image file: d5ra05157f-u136.tif 99%
13 image file: d5ra05157f-u137.tif 91%
14 image file: d5ra05157f-u138.tif 99%
15 Ph 93%
16 4-MeC6H4 92%
17 4-MeOC6H4 96%
18 1-Naphthyl 68%
19 2-Thienyl 76%
20 2-Furyl 93%


To elucidate the mechanism, deuterium-labelling experiments were performed using α-[D]-benzaldehyde. N,N-[D]-Tosylbenzamide was isolated in 90% yield with 76% deuterium incorporation at the nitrogen atom (Scheme 16). The reaction likely proceeds initially via a high-oxidation-state metal complex [Ru(TTP)(NTs)2], with subsequent transfer of the imido/nitrene group either by direct insertion (route A) or by H-atom abstraction/radical rebound (route B) to generate the sulfonamide adduct.


image file: d5ra05157f-s16.tif
Scheme 16 Proposed mechanism for Ru-catalysed amidation.

Johann Chan and co-workers established a mild method for preparing N-sulfonylcarboxamides from aldehydes under rhodium(II) catalysis (Table 33).81 The best yields were obtained using a Rh2(esp)2 catalyst in isopropyl acetate with PhI(OC(O)tBu)2 as the oxidant. The procedure had excellent functional group tolerability with successful coupling to halo- (entries 4–7, 9 and 12) and nitro-containing (entry 8, 10 and 11) aryl sulfonamides. Similarly, good results were recorded with heterocyclic (entries 7 and 8) and activated olefinic aldehydes (entry 12). Lower temperatures were required for some electron-rich sulfonamides to reduce their tendency to degrade (entries 1–3).

Table 33 Rh(II)-catalysed oxidative sulfamidation of aldehydes

image file: d5ra05157f-u139.tif

Entry R1 R2 T (°C) Yield
1 Ph Ph 0 94%
2 Ph 4-MeC6H4 0 90%
3 Mesityl Me 0 90%
4 Ph 2-Cl-4-BrC6H3 50 80% (99%)
5 4-MeOC6H4 2-Cl-4-BrC6H3 50 98%
6 4-NCC6H4 2-Cl-4-BrC6H3 50 85% (99%)
7 image file: d5ra05157f-u140.tif 3-F3CC6H4 50 72%
8 image file: d5ra05157f-u141.tif 3-O2NC6H4 50 72%
9 tBu 2-Cl-4-BrC6H3 50 67%
10 Cyclopropyl 3-O2NC6H4 50 62%
11 nPr 3-O2NC6H4 50 85%
12 image file: d5ra05157f-u142.tif 3-BrC6H4 50 63%


To determine the most likely mechanistic pathway, the authors carried out several rate experiments (Scheme 17). Reaction of a sulfonamide with an equimolar mixture of benzaldehyde and benzaldehyde-d6 was accompanied by a primary isotope effect (kH/kD = 2.5), indicating that C–H bond cleavage was occurring during the rate determining step. Given this and other supporting evidence, the most plausible route is path C which proceeds via a concerted asynchronous nitrene insertion into an aldehyde hydrogen.


image file: d5ra05157f-s17.tif
Scheme 17 Potential pathways for Rh catalysed sulfamidation of aldehydes.

A catalyst-free process for the sulfamidation of aldehydes has been described by Phukan and co-workers employing N,N-dibromo-p-toluene sulfonamide (TsNBr2) as a nitrene transfer source (Table 34).82 A series of aromatic (entries 1–11) and aliphatic (entries 12–14) aldehydes were treated with TsNBr2 and potassium carbonate to generate the corresponding N-acyl sulfonamides in excellent yields (79–90%) in 4 hours or less. The mechanism proceeds via base-mediated abstraction of Br+ ions with subsequent loss of KBr to form a sulfonyl nitrene intermediate which undergoes C–H σ-insertion to generate the final product.

Table 34 Sulfamidation of aldehydes using TsNBr2

image file: d5ra05157f-u143.tif

Entry R Time (h) Yield
1 Ph 3 85%
2 4-ClC6H4 3 84%
3 4-BrC6H4 3 80%
4 4-MeOC6H4 3 88%
5 2-BrC6H4 3 78%
6 2-FC6H4 3 80%
7 2-MeOC6H4 3 88%
8 3-ClC6H4 3 84%
9 3-BrC6H4 3 80%
10 4-MeC6H4 3 89%
11 2-Naphthyl 3 90%
12 CH3(CH2)6 3 89%
13 iPr 4 79%
14 Ph(CH2)2 4 87%


Phukan subsequently extended this protocol to α-nitroketones (Table 35).83 Higher yields were obtained from para- and meta-substituted aryl ketones (entries 2–8), whereas ortho-substituted ketones were less reactive (entries 9–11). The transformation of aliphatic ketones was also successful, albeit in lower yields (entries 13 and 14). Typically, α-nitroketones are stable in the β-hydroxy nitroolefin form due to stabilisation by intramolecular hydrogen bonding during enolization. Treatment with base effects the abstraction of Br+ from TsNBr2, leading to nucleophilic attack of the nitrogen on the α-nitroketone. Subsequent protonation-deprotonation in water results in elimination of nitromethane and formation of the tosyl amide product.

Table 35 Sulfamidation of nitroketones using TsNBr2

image file: d5ra05157f-u144.tif

Entry R1 Yield
1 Ph 76%
2 4-BrC6H4 71%
3 4-ClC6H4 74%
4 4-MeC6H4 76%
5 4-MeOC6H4 72%
6 3-ClC6H4 68%
7 3-BrC6H4 66%
8 3-O2NC6H4 65%
9 2-MeOC6H4 53%
10 2-FC6H4 57%
11 2-BrC6H4 56%
12 2-Naphthyl 70
13 Ph(CH2)2 65%
14 nHeptyl 61%


7. Pd-catalysed aminocarbonylations

In pioneering work on Pd-catalysed carbonylations, Indolese and Schnyder demonstrated how aminocarbonylation of aryl bromides with sulfonyl azides could provide access to acyl sulfonamides.84 Reaction of 1-bromo-3-methylbenzene with benzenesulfonamide in the presence of PdCl2(PPh3)2, PPh3 and triethylamine in a carbon monoxide atmosphere afforded 3-methyl-N-(phenylsulfonyl)benzamide in 70% conversion and 69% yield (Scheme 18). By increasing the equivalents of triethylamine from 1.1 to 2, 100% conversion was achieved.
image file: d5ra05157f-s18.tif
Scheme 18 Pd-catalysed aminocarbonylation of 1-bromo-3-methylbenzene.

A robust Pd-catalysed aminocarbonylation method for the preparation of N-acyl sulfonamides using molybdenum hexacarbonyl, which generates carbon monoxide in situ, has been developed by Larhed and co-workers (Table 36).85 With the appropriate sulfonamide and aryl iodide in the presence of Mo(CO)6, 10 mol% palladium acetate, and DBU in a sealed tube, carbonylations reached completion in 15 minutes under microwave irradiation (method A). Various aryl iodides were coupled to tosyl azide in high yields (entries 1–7, 10 and 11). Heteroaryl halides were also compatible substrates (entries 10 and 11). Coupling to other primary aromatic and aliphatic sulfonamides (entries 12–15) was similarly successful, while reactions with secondary sulfonamides was likewise possible, although in reduced yields (entry 16). The reduced reactivity of aryl bromides necessitated a switch to Herrmann's palladacycle86 in combination with [(tBu)3 PH]BF4[thin space (1/6-em)]87 at higher temperature (method B). Gratifyingly, the resulting yields were higher than those obtained from the matching aryl iodides (entries 1–5, 7, 10, 14 and 15).

Table 36 Pd catalysed carbonylation of aryl halides with sulfonamides in the presence of Mo(CO)6

image file: d5ra05157f-u145.tif

Entry R1 R2 R3 Yield
Method A Method B
1 4-MeOC6H4 H 4-MeC6H4 88% 93%
2 4-MeC6H4 H 4-MeC6H4 87% 91%
3 2-MeC6H4 H 4-MeC6H4 88% 93%
4 Ph H 4-MeC6H4 80% 95%
5 1-Naphthyl H 4-MeC6H4 74% 96%
6 4-PhCO–C6H4 H 4-MeC6H4 70%  
7 4-F3CC6H4 H 4-MeC6H4 76% 95%
8 2-MeOC6H4 H 4-MeC6H4   94%
9 4-NCC6H4 H 4-MeC6H4   83%
10 2-Thienyl H 4-MeC6H4 65% 79%
11 3-Thienyl H 4-MeC6H4 79%  
12 4-MeC6H4 H Ph 88%  
13 4-MeC6H4 H 4-BrC6H4 84%  
14 4-MeC6H4 H Me 72% 88%
15 4-MeC6H4 H CF3 71% 80%
16 4-MeC6H4 Me Ph 47%  
17 image file: d5ra05157f-u146.tif H Me   52%


Odell et al. demonstrated a mild method for the regioselective Pd-catalysed aminocarbonylation of substituted indoles and pyrroles with sulfonyl azides in the presence of Mo(CO)6 (Table 37).88 Carbonylation of differently substituted indoles in anhydrous acetonitrile proceeded mostly in high yields (entries 1–17), apart from electron-poor substrates, such as acyl- (entry 4), nitro- (entry 16) and nitrile-containing (entry 17) derivatives. Attempted transformation of 7-aza indole failed, even under forcing conditions. Both electron-rich (entries 18–22) and electron-poor (entries 23–27) sulfonyl azides reacted readily, with two exceptions. The steric bulk of two ortho-isopropyl blocked reaction completely (entry 20), while a para-brominated sulfonyl azide (entry 23) was also unreactive. N-Acyl sulfonamides were accessible from heteroaromatic sulfonyl azides (entries 28–30) but not in the case of pyridinesulfonyl azide (entry 31). Furthermore, pyrroles reacted with tosyl azide 14 under the same conditions to afford the corresponding N-acyl sulfonamides 2022 in good yields, while carbonylation of ambident nucleophile 2-(1H-pyrrol-1-yl)aniline 23 resulted in the formation of N-carbamoyl sulfonamide 24 (Scheme 19).

Table 37 Regioselective Pd-catalysed aminocarbonylation of heteroaromatics

image file: d5ra05157f-u147.tif

Entry R1 R2 R3 R4 Yield
1 Me H H 4-MeC6H4 95%
2 Bn H H 4-MeC6H4 89%
3 Ph H H 4-MeC6H4 68%
4 Ac H H 4-MeC6H4 n.r.
5 H H H 4-MeC6H4 95%
6 H H 4-Me 4-MeC6H4 70%
7 Me Me H 4-MeC6H4 89%
8 Me H 4-Me 4-MeC6H4 90%
9 Me H 5-Me 4-MeC6H4 91%
10 Me H 6-Me 4-MeC6H4 90%
11 Me H 7-Me 4-MeC6H4 78%
12 Me Ph H 4-MeC6H4 84%
13 Me H 5-MeO 4-MeC6H4 77%
14 Me Me 4-MeO 4-MeC6H4 76%
15 Me H 6-Cl 4-MeC6H4 79%
16 Me H 5-NO2 4-MeC6H4 38%
17 Me H 5-NC 4-MeC6H4 26%
18 Me H H 3,4-(MeO)2C6H3 75%
19 Me H H 4-MeOC6H4 71%
20 Me H H 2,4,6-iPr3C6H2 n.r.
21 Me H H 4-NHAcC6H4 56%
22 Me H H 3-MeOC6H4 77%
23 Me H H 4-BrC6H4 Trace
24 Me H H 2,3,4-Cl3C6H2 73%
25 Me H H 3-F3CC6H4 92%
26 Me H H 4-NCC6H4 89%
27 Me H H 4-NO2C6H4 79%
28 Me H H image file: d5ra05157f-u148.tif 81%
29 Me H H 2-Thienyl 89%
30 Me H H image file: d5ra05157f-u149.tif 44%
31 Me H H 3-Pyridyl Trace
32 Me H H iPr 73%
33 Me H H nBu 70%
34 Me H H image file: d5ra05157f-u150.tif 73%
35 Me H H Bn 93%



image file: d5ra05157f-s19.tif
Scheme 19 Regioselective aminocarbonylation of pyrroles.

According to the proposed mechanism (Scheme 20), the Pd(II) precatalyst is reduced in situ to Pd(0) active complex I under carbon monoxide. The active Pd(0) species I undergoes oxidative addition into the sulfonyl azide, generating a Pd-bound sulfonyl nitrene intermediate II with the release of nitrogen gas. Coordination of carbon monoxide to intermediate II facilitates migratory insertion, leading to the formation of sulfonyl isocyanate intermediate III. Finally, nucleophilic attack by the indole or pyrrole affords the N-acyl sulfonamide product.


image file: d5ra05157f-s20.tif
Scheme 20 Proposed mechanism for heteroaryl aminocarbonylation.

More recently, Xia et al. demonstrated that C–H aminocarbonylation could be conducted on unactivated alkenes.89 Screening of reaction parameters showed that 5 mol% palladium acetate in acetonitrile at 80 °C with a carbon monoxide atmosphere was optimal (Table 38). A range of N-acyl sulfonamides were initially prepared by treating alkenes with tosyl azide, affording the corresponding products in moderate to good yields (entries 1–19). Interestingly, aminocarbonylation of an E-/Z-mixture of 1-ethoxy-1-propene furnished the E-isomeric product exclusively in 76% yields (entry 13). Subsequently, the scope of the sulfonyl azide component was investigated by reaction with 3,4-dihydro-2H-pyran (entries 20–34). Electron-rich (entries 20–22) and electron-poor (entries 23–26) starting materials displayed good reactivity, as did naphthyl (entries 27 and 28), heteroaryl (entry 29) and aliphatic (entries 31–34) sulfonyl azides. Complex substrates, such as 3,4,6-tri-O-benzyl-D-glucal (entry 35) and stigmasterol derivatives (entry 36) produced the corresponding N-acyl sulfonamides in good yields. This strategy was also applied to the synthesis of an analogue of glibenclamide (entry 37).90

Table 38 Pd-catalysed aminocarbonylation of alkenes

image file: d5ra05157f-u151.tif

Entry R1 R2 Yield
1 image file: d5ra05157f-u152.tif 4-MeC6H4 82%
2 image file: d5ra05157f-u153.tif 4-MeC6H4 80%
3 image file: d5ra05157f-u154.tif 4-MeC6H4 86%
4 image file: d5ra05157f-u155.tif 4-MeC6H4 61%
5 image file: d5ra05157f-u156.tif 4-MeC6H4 54%
6 image file: d5ra05157f-u157.tif 4-MeC6H4 59%
7 image file: d5ra05157f-u158.tif 4-MeC6H4 44%
8 image file: d5ra05157f-u159.tif 4-MeC6H4 52%
9 image file: d5ra05157f-u160.tif 4-MeC6H4 82%
10 image file: d5ra05157f-u161.tif 4-MeC6H4 70%
11 image file: d5ra05157f-u162.tif 4-MeC6H4 63%
12 image file: d5ra05157f-u163.tif 4-MeC6H4 76%
13 image file: d5ra05157f-u164.tif 4-MeC6H4 87%
14 image file: d5ra05157f-u165.tif 4-MeC6H4 47%
15 image file: d5ra05157f-u166.tif 4-MeC6H4 76%
16 image file: d5ra05157f-u167.tif 4-MeC6H4 79%
17 image file: d5ra05157f-u168.tif 4-MeC6H4 83%
18 image file: d5ra05157f-u169.tif 4-MeC6H4 87%
19 image file: d5ra05157f-u170.tif 4-MeC6H4 91%
20 image file: d5ra05157f-u171.tif Ph 73%
21 image file: d5ra05157f-u172.tif 4-MeOC6H4 82%
22 image file: d5ra05157f-u173.tif 2,4,6-Me3C6H2 81%
23 image file: d5ra05157f-u174.tif 4-F3CC6H4 82%
24 image file: d5ra05157f-u175.tif 4-FC6H4 71%
25 image file: d5ra05157f-u176.tif 4-ClC6H4 75%
26 image file: d5ra05157f-u177.tif 4-BrC6H4 83%
27 image file: d5ra05157f-u178.tif 1-Naphthyl 52%
28 image file: d5ra05157f-u179.tif 2-Naphthyl 80%
29 image file: d5ra05157f-u180.tif 2-Thienyl 65%
30 image file: d5ra05157f-u181.tif Bn 83%
31 image file: d5ra05157f-u182.tif nPr 65%
32 image file: d5ra05157f-u183.tif nBu 70%
33 image file: d5ra05157f-u184.tif iPr 76%
34 image file: d5ra05157f-u185.tif image file: d5ra05157f-u186.tif 44%
35 image file: d5ra05157f-u187.tif 4-MeC6H4 67%
36 image file: d5ra05157f-u188.tif 4-MeC6H4 53%
37 image file: d5ra05157f-u189.tif image file: d5ra05157f-u190.tif 78%


The active Pd(0) species is generated by the reaction of palladium acetate with carbon monoxide and is stabilized by an acetonitrile ligand (Scheme 21). This Pd(0) species, containing a coordinated CO ligand, reacts with the sulfonyl azide to generate intermediate I. CO then undergoes migratory insertion into the azide, forming II. The release of nitrogen gas generates palladium-coordinated isocyanate intermediate III. The formation of the isocyanate intermediate was confirmed by a control experiment in which Pd-catalyzed carbonylation of tosyl azide under carbon monoxide furnished tosyl isocyanate. The palladium-coordinated isocyanate intermediate (III) then undergoes alkene coordination, and regioselective migratory insertion affords intermediate IV. This is followed by β-H elimination, leading to the formation of intermediate V. Finally, reductive elimination affords the desired N-acyl sulfonamide, while regenerating the Pd(0) catalyst, thereby completing the catalytic cycle.


image file: d5ra05157f-s21.tif
Scheme 21 Catalytic cyclic for the aminocarbonylation of alkenes.

A Pd-catalysed carbonylation strategy was exploited by Roberts and colleagues to produce acylsulfamides.91,92 Two different approaches were developed, using either carbon monoxide, triethylamine and catalytic [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex [PdCl2 (dppf)·CH2Cl2] (Table 39, method A) or Mo(CO)6 and DBU in combination with [Pd(OAc)(P(o-tolyl)3)]2 and [(tBu)3PH]BF4 (method B). The latter method is more advantageous as it does not require access to specialised carbonylation apparatus and is more readily adaptable to parallel synthesis. Using these methods, a range of aryl (entries 1–20) and heteroaryl (21–33) bromides were coupled to pyrrolidine-1-sulfonamide in high yields. Variation of the sulfonamide partner from other cyclic (entries 34–37) to acyclic (entries 38–48) substrates did not negatively impact on outcomes.

Table 39 Pd-catalysed carbonylation of sulfamides with aryl/heteroaryl bromides

image file: d5ra05157f-u191.tif

Entry R1 R2 Yield
Method A Method B
1 Ph Pyrrolidinyl 92% 78%
2 2-MeC6H4 Pyrrolidinyl 83% 60%
3 3-MeC6H4 Pyrrolidinyl 83% 72%
4 4-MeC6H4 Pyrrolidinyl 75%  
5 2-MeOC6H4 Pyrrolidinyl 73% 68%
6 3-MeOC6H4 Pyrrolidinyl 82% 88%
7 4-MeOC6H4 Pyrrolidinyl 80% 88%
8 2-FC6H4 Pyrrolidinyl 76% 78%
9 2-ClC6H4 Pyrrolidinyl 61% 56%
10 3-ClC6H4 Pyrrolidinyl 76% 90%
11 4-ClC6H4 Pyrrolidinyl 90% 77%
12 2-CyC6H4 Pyrrolidinyl 36%  
13 4-tBuC6H4 Pyrrolidinyl   53%
14 3-MeO2CC6H4 Pyrrolidinyl 70%  
15 4-Me2NC(O)C6H4 Pyrrolidinyl   86%
16 3-NCC6H4 Pyrrolidinyl 78% 74%
17 4-NCC6H4 Pyrrolidinyl 80% 50%
18 3-F3CC6H4 Pyrrolidinyl   68%
19 4-F3CC6H4 Pyrrolidinyl   73%
20 2-Naphthyl Pyrrolidinyl   70%
21 3-Furyl Pyrrolidinyl   84%
22 2-Thienyl Pyrrolidinyl 70% 58%
23 3-Thienyl Pyrrolidinyl 75% 51%
24 2-Pyridyl Pyrrolidinyl 66%
25 3-Pyridyl Pyrrolidinyl 56% 74%
26 4-Pyridyl Pyrrolidinyl 58% 46%
27 5-Pyrimidyl Pyrrolidinyl 78%  
28 image file: d5ra05157f-u192.tif Pyrrolidinyl 50%  
29 image file: d5ra05157f-u193.tif Pyrrolidinyl 86% 76%
30 image file: d5ra05157f-u194.tif Pyrrolidinyl 72%  
31 image file: d5ra05157f-u195.tif Pyrrolidinyl   52%
32 image file: d5ra05157f-u196.tif Pyrrolidinyl   87%
33 image file: d5ra05157f-u197.tif Pyrrolidinyl   55%
34 4-NCC6H4 Piperidinyl 84%  
35 4-MeOC6H4 Piperidinyl 66%  
36 4-NCC6H4 4-Morpholinyl 72%  
37 4-MeOC6H4 4-Morpholinyl 69%  
38 Ph image file: d5ra05157f-u198.tif 50%  
39 Ph image file: d5ra05157f-u199.tif 85% 91%
40 4-NCC6H4 image file: d5ra05157f-u200.tif 75%  
41 4-NCC6H4 image file: d5ra05157f-u201.tif 70%  
42 4-NCC6H4 image file: d5ra05157f-u202.tif 69%  
43 Ph image file: d5ra05157f-u203.tif   59%
44 4-NCC6H4 image file: d5ra05157f-u204.tif 67%  
45 4-MeOC6H4 image file: d5ra05157f-u205.tif 84%  
46 4-NCC6H4 image file: d5ra05157f-u206.tif 75%  
47 Ph image file: d5ra05157f-u207.tif   72%
48 4-NCC6H4 image file: d5ra05157f-u208.tif 50%  


8. Sulfonyl fluorides, chlorides and benzotriazoles

We have previously described the application of the benzotriazole group in the N-acylation of sulfonamides (see Table 16). This approach was also adapted to the acylation of amides using the corresponding N-sulfonyl benzotriazoles (Table 40).58 A small substrate scope study was undertaken where 4-tolyl or 4-pyridyl amides were treated with mesyl or 4-tosyl benzotriazole in the presence of sodium hydride in refluxing THF. The N-acyl sulfonamide products were obtained in yields ranging from 34% to 91%, with entries 2–4 comparable to the previous methodology, albeit with longer reaction times. This protocol was extended to α,β-unsaturated amides with the expected N-(α,β-unsaturated acyl) sulfonamides recovered in 25–71% yields (entries 5–9).59 While these reaction times were relatively short, the average yields were significantly lower than those obtained from the matching N-acyl benzotriazoles (see Table 17).
Table 40 Coupling of amides and sulfonyl benzotriazoles

image file: d5ra05157f-u209.tif

Entry R1 R2 T (°C) Time (h) Yield
1 4-MeC6H4 Me Reflux 24 34%
2 4-MeC6H4 4-MeC6H4 Reflux 24 83%
3 4-Pyridyl Me Reflux 24 77%
4 4-Pyridyl 4-MeC6H4 Reflux 24 91%
5 image file: d5ra05157f-u210.tif 4-MeC6H4 r.t. 2 71%
6 image file: d5ra05157f-u211.tif Me r.t. 2 25%
7 image file: d5ra05157f-u212.tif 2,4,6-Me3C6H2 r.t. 2 30%
8 image file: d5ra05157f-u213.tif 4-MeC6H4 r.t. 2 30%
9 image file: d5ra05157f-u214.tif 2,4,6-Me3C6H2 r.t. 2 30%


A route to N-acyl sulfamates from fluorosulfates was developed by Borggraeve and co-workers.93 Fluorosulfates have gained popularity in recent years through Sharpless' sulfur fluoride exchange (SuFEx) chemistry94 and in cross coupling reactions.95 The protocol demonstrated wide functional group tolerability, with halogen (entries 2, 5, 8 and 10), ester (entry 3) and nitrile (entry 7) substituents withstanding sodium hydride in THF (Table 41). This chemistry was also compatible with more complex natural products (entries 14 and 15). Various amide coupling partners were explored, with butyramide (entry 16), methyl acrylamide (entry 17) and Boc-prolinamide (entry 18) returning similar yields. Unsubstituted (entry 19) and para-substituted benzamides (entries 20–22) were less reactive coupling partners, requiring 24 h or elevated temperatures to achieve desirable yields.

Table 41 Synthesis of N-acyl sulfamates from fluorosulfamates

image file: d5ra05157f-u215.tif

Entry R1 R2 Yield
a 24 h.
1 Me 3,5-Me2C6H3 85%
2 Me 3-F3CC6H4 60%
3 Me 4-EtO2CC6H4 70%
4 Me 4-MeOC6H4 80%
5 Me 3-IC6H4 68%
6 Me 4-MeSO2C6H4 62%
7 Me 3-NCC6H4 72%
8 Me 4-BrC6H4 78%
9 Me 2,6-Me2C6H3 76%
10 Me 2-BrC6H4 69%
11 Me 2-Naphthyl 83%
12 Me image file: d5ra05157f-u216.tif 82%
13 Me image file: d5ra05157f-u217.tif 69%
14 Me image file: d5ra05157f-u218.tif 69%
15 Me image file: d5ra05157f-u219.tif 73%
16 nPr 3,5-Me2C6H3 69%
17 image file: d5ra05157f-u220.tif 3,5-Me2C6H3 69%
18 image file: d5ra05157f-u221.tif 3,5-Me2C6H3 50%
19 Ph 3,5-Me2C6H3 79%a
20 4-FC6H4 3,5-Me2C6H3 62%a
21 4-O2NC6H4 3,5-Me2C6H3 63%a (79% at 50 °C)a
22 4-MeOC6H4 3,5-Me2C6H3 25%a (70% at 50 °C)a
23 Me image file: d5ra05157f-u222.tif 67%


The unusual reactivity of 4-carboxylamido-2-oxazoline systems was reported by Cossu and co-workers.96 The team intended to synthesise 4-nitrile derivatives of various 4-carboxyamido-2-oxazolines using a well-known procedure (i.e. reaction with p-toluenesulfonyl chloride in pyridine).97 However, only the N-sulfonylated derivatives were isolated in excellent yields (Table 42). The authors suggest that an equilibrium between two species exists, whereby a hydrogen bond might form between the amidic proton and the carboxylic oxygen. This allows for the amidic nitrogen to attack the electrophilic sulfur, owing to the decreased nucleophilicity of the oxygen atom and is likely due to the presence of α-exocyclic protons (entries 2–5). Notably, racemic 2-phenyl-4-carboxyamido-2-oxazoline treated with p-toluenesulfonyl chloride exclusively generated the 4-nitrile derivative, demonstrating the importance of the α-exocyclic proton in this transformation.

Table 42 Synthesis of N-acyl sulfonamides from 4-carboxylamido-2-oxazoline derivatives

image file: d5ra05157f-u223.tif

Entry R1 R2 R3 Yield
1 Ph H 4-MeC6H4 80%
2 Ph(CH2)3 H 4-MeC6H4 80%
3 PhCH2 H 2-Napthyl 90%
4 PhCH2 H image file: d5ra05157f-u224.tif 85%
5 Ph(CH2)3 Me 4-MeC6H4 85%


Patel and co-workers developed a series of novel sulfonamide–quinoxaline derivatives 26 and 27 in their search for anti-cancer agents (Scheme 22).98 Different primary amides were refluxed with 2,3-diphenylquinoxaline-6-sulfonyl chloride 25 in 10% aqueous sodium hydroxide solution to afford the N-acyl sulfonamides in moderate yields.


image file: d5ra05157f-s22.tif
Scheme 22 Novel sulfonamide–quinoxaline derivatives.

In their investigation of novel antimicrobial agents, Rehman et al. treated nicotinamide 28 with tosyl chloride 29 in the presence of sodium carbonate to afford N-tosylnicotinamide 30 in 76% yield (Scheme 23).


image file: d5ra05157f-s23.tif
Scheme 23 Synthesis of N-tosylnicotinamide.

Caddick et al. established a new route to sulfonamides and N-acyl sulfonamides via intramolecular radical addition to pentafluorophenyl vinylsulfonate 33 with subsequent aminolysis (Scheme 24).99 Initially, pentafluorophenyl vinylsulfonate intermediate 33 was synthesised using pentafluorophenol (31) and 2-chloro-ethane-1-sulfonyl chloride (31). Next, 6-iodo-D-galactose (34) was coupled to pentafluorophenyl vinylsulfonate intermediate 33 via a tin-mediated radical addition. Subsequent aminolysis of substrate 35 with benzamide 36 and sodium hydride furnished the corresponding N-acyl sulfonamide 37. The authors suggest that pentafluorophenyl vinylsulfonate 33 acts as a bifunctional acceptor which is highly susceptible to radical attack, in addition to nucleophilic attack by amines with simultaneous displacement of the pentafluorophenol species. This chemistry has several advantages over sulfonyl chlorides, such as an increased ability to withstand column chromatography or more basic reaction condition.


image file: d5ra05157f-s24.tif
Scheme 24 Synthesis of N-acyl sulfonamides from pentafluorophenyl vinylsulfonate esters.

The authors suggest that the reaction proceeds by the deprotonation of the sulfonate group with rapid extrusion of pentafluorophenol, generating sulfene intermediate III (Scheme 25). This was previously shown by King et al. to be the preferred pathway for the hydrolysis of sulfonyl halides at high pH.100


image file: d5ra05157f-s25.tif
Scheme 25 Proposed mechanism for amine displacement.

9. Alkynes

Building upon their previous research on copper-catalysed coupling of sulfonyl azides, alkynes, and amines,101 Chang et al. later adapted this chemistry to the synthesis of N-acyl sulfonamides.102 Initial optimisation of the coupling of phenylacetylene and tosyl azide saw isolation of the product in 94% yield using catalytic copper(I) iodide and triethylamine in chloroform (Table 43, entry 1). Other aromatic (entries 2 and 3) and aliphatic (entries 4–10) alkynes reacted in high yields, while functional groups such as alkenes (entry 11), esters (entry 12) and internal alkynes (entry 13) were also tolerated. In the case of propargylic ether (entry 10), swapping triethylamine for lutidine was accompanied by a dramatic increase in yields (34% to 74%). Additionally, phenylacetylene reacted with sulfonyl azides to afford the corresponding acyl sulfonamides in good yields (entries 14–17).
Table 43 Copper-catalysed hydrative coupling of terminal alkynes and sulfonyl azides

image file: d5ra05157f-u225.tif

Entry R1 R2 Yield
a Lutidine used in place of triethylamine.b CuI (3 mol%) was used.
1 Ph 4-MeC6H4 94%
2 4-MeC6H4 4-MeC6H4 82%
3 4-F3CC6H4 4-MeC6H4 83%
4 nBu 4-MeC6H4 78%
5 tBu 4-MeC6H4 87%
6 3-Thienyl 4-MeC6H4 84%
7 image file: d5ra05157f-u226.tif 4-MeC6H4 83%
8 image file: d5ra05157f-u227.tif 4-MeC6H4 75%
9 image file: d5ra05157f-u228.tif 4-MeC6H4 84%
10 image file: d5ra05157f-u229.tif 4-MeC6H4 34% (74%)a
11 image file: d5ra05157f-u230.tif 4-MeC6H4 75%
12 image file: d5ra05157f-u231.tif 4-MeC6H4 89%
13 image file: d5ra05157f-u232.tif 4-MeC6H4 77%
14 Ph Bn 74%
15 Ph nBu 87%
16 Ph (CH3)3Si(CH2)2 97%
17 Ph image file: d5ra05157f-u233.tif 77%
18 BocNHCH2 4-MeC6H4 81%b


A similar strategy was explored by Fokin et al. (Table 44).103 A range of alkynes were treated with aryl sulfonyl azides in the presence of 2 mol% [Cu(MeCN)4]PF6 and tris(benzyltriazolylmethyl)amine (TBTA), sodium ascorbate and sodium bicarbonate in t-butanol/water at room temperature. TBTA was found to have an accelerating effect while sodium ascorbate prevented formation of oxidation byproducts. Coupling of 4-acetamidobenzenesulfonyl azide with terminal alkynes bearing alcohol (entry 1), carboxylic acid (entries 2 and 8), carbamate (entry 4) and ether (entry 6) functional groups proceeded in good yields. Transformation of complex substrates, such as ethynyl estradiol (entry 9), was similarly successful.

Table 44 Copper(I)-catalysed synthesis of N-acyl sulfonamides from alkynes and sulfonyl azides

image file: d5ra05157f-u234.tif

Entry R1 R2 Yield
a TBTA/[Cu] resin (2 mol%) used as catalyst.
1 image file: d5ra05157f-u235.tif NHAc 60%
2 image file: d5ra05157f-u236.tif NHAc 67%
3 image file: d5ra05157f-u237.tif NHAc 74%
4 BocNHCH2 NHAc 83%
5 Ph NHAc 64%
6 image file: d5ra05157f-u238.tif NHAc 83%a
7 image file: d5ra05157f-u239.tif NHAc 54%
8 HO2C NHAc 75%
9 image file: d5ra05157f-u240.tif NHAc 68%
10 image file: d5ra05157f-u241.tif NHAc 62%a
11 Ph NO2 27%
12 Ph Me 69%a


Mechanistically, the copper(I) acetylide reacts with a sulfonyl azide to afford (1,2,3-triazol-5-yl)copper intermediate I (Scheme 26). This species undergoes nitrogen elimination to form an alkynamide intermediate II. Protonation of II leads to the formation of a highly reactive ketenimine III, which subsequently undergoes hydrolysis to yield the N-acyl sulfonamide. An alternative ring-opening pathway, similar to the Dimroth rearrangement, is also possible where the triazolyl copper species rearranges via a diazoimine intermediate IV to form the ketenimine III.


image file: d5ra05157f-s26.tif
Scheme 26 Proposed mechanism for copper-catalysed coupling of alkynes and sulfonyl azides.

10. Conclusion

The presence of an N-acyl sulfonamide in wide range of pharmaceutical ingredients and bioactive compounds underlines its significance as a key functional group. The ability to efficiently prepare N-acyl sulfonamides remains an important goal in medicinal chemistry. As demonstrated in this review, while traditional routes involving acid chlorides and anhydrides are the mainstay methods to accessing N-acyl sulfonamides, an increasing array of novel chemistries are being employed which offer advantages such as increased reactivity, reduced waste or higher selectivity. To our knowledge, no dedicated review on the synthesis of N-acyl sulfonamides has been recently published. This review seeks to fill that gap by presenting a comprehensive, reagent-based survey of recent advances in the preparation of N-acyl sulfonamide, including assessments of reaction scope, functional group tolerance, and potential for late-stage diversification. This review should act as practical resource for both synthetic chemists and drug discovery teams, facilitating the informed selection of the most efficient routes to this important functional group.

Conflicts of interest

There are no conflicts of interest to declare.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Acknowledgements

Michelle O'Driscoll is grateful for funding by way of a Government of Ireland Postgraduate Research Scholarship [GOIPG/2021/227] provided by Taighde Éireann – Research Ireland. GSR is grateful for funding by way of a Government of Ireland Postdoctoral Fellowship [GOIPD/2023/1218] provided by Taighde Éireann – Research Ireland.

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