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Synlett 2012(4): 595-600  
DOI: 10.1055/s-0031-1290332
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

TiCl4-Mediated Direct N-Alkylation of Sulfonamides with Inactive Ethers

Jiayan Chen, Ling Dang, Qiang Li, Yong Ye, Shaomin Fu, Wei Zeng*
School of Chemistry and Chemical Engineering, South China University of Technology, 381 Wushan Road, Guangzhou 510641,P. R. of China
Fax: +86(20)22236337; e-Mail: zengwei@scut.edu.cn;

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Publication History

Received 18 November 2011
Publication Date:
06 February 2012 (online)

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Abstract

A TiCl4-mediated intermolecular or intramolecular direct N-alkylation reaction of sulfonamides with inactive ethers as alkylating agents was successfully achieved. This method provides a novel approach towards N-alkyl sulfonamides from inactive ethers via an easy workup procedure.

Key words

N-alkylation - Lewis acid - N-alkyl sulfonamide - dialkyl ether - titanium tetrachloride

The development of new methodologies for the formation of carbon-nitrogen bonds is a challenging area of organic synthesis. [¹] In this context, N-alkylation reactions of sulfonamides have attracted significant attention, because N-alkyl sulfonamides exhibit a wide range of biological activities, such as antibacterial, anticancer and antiviral functions, and they serve as antiviral HIV protease inhibitors. [²] Generally, the classical method for the synthesis of N-alkylated sulfonamides are performed by the reaction of amines with sulfonyl halides, [³] and transition-metal-­catalyzed cross-coupling of sulfonamides with organic halides or olefins. [4] Recently, N-alkylation of sulfonamide using alcohol as alkylating agent has attracted particularly interest due to the easy activation of the hydroxyl group by transition metal salts or small organic molecules. For example, Beller and Williams et al. found transition metals Ru(III) or Cu(II) could efficiently catalyze the N-alkylation of sulfonamide using borrowing hydrogen methodology (Scheme  [¹] , a). [5] Of course, besides Fukuyama-Mitsunobu N-alkylation, [6] much progress on acid-catalyzed direct N-alkylation with alcohol has also been achieved. Various Lewis acids and Brønsted acids have been employed to realize this transformation via a carbocation mechanism (Scheme  [¹] , b). [7] Considering the widespread application of N-alkylated sulfonamide in the synthesis of pharmaceuticals and agrochemicals, the exploration of new direct N-alkylation of sulfonamides using various alkylating agents under mild conditions is always desirable.

As we know, compared with alcohol alkylating agent, the activation of sp³ C-O bond in aliphatic ether is much more challenging which is arising from the high bond energy, [8] and the N-alkylation of amides with ethers are rarely studied. [9] Nevertheless, we think that a suitable catalyst could also possibly activate the carbon-oxygen single bond of an ether via the coordination with the ether oxygen atom, then enhance the nucleophilic attack of the amide nitrogen at the ether carbon atoms to produce N-alkylating sulfon­amides 3 (Scheme  [¹] , c). In connection with our interest in the development of N-acylation and N-alkylation of sulfonamide, [¹0] we report herein a novel TiCl4-promoted N-alkylation of sulfonamides using inactive ethers as alkyl­ating reagents.

Scheme 1 N-alkylation of sulfonamide

N-Alkylation of 4-toluene sulfonamide (0.5 mmol) with ether was first succeeded with boron trifluoride diethyl etherate (BF3˙OEt2, 2.0 equiv) in dry toluene (1.0 mL) at 110 ˚C. It is believed that the coordination of the ether oxygen to the boron atom activates the carbon-oxygen bonds of ether for the nucleophilic attack. To our delight, we found BF3 could promote the N-alkylation of sulfon­amide with diethyl ether to form N-alkyl sulfonamide 3a (38% yield) and N,N-dialkyl sulfonamide 3aa (11% yield, Table  [¹] , entry 1). Inspired by this positive result, we further investigated other reaction conditions to define the reaction parameters, and found that a reaction time of 48 hours and 6.0 equiv of BF3˙OEt2 gave 3a and 3aa in a total yield of 95% (Table  [¹] , entry 6). Increasing the promoter loading further did not improve the yields (Table  [¹] , compare entries 6, 7, and 8). When the reaction temperature was lowered to 90 ˚C or increased to 130 ˚C, the yield decreased due to the incomplete reaction or tedious workup, respectively (Table  [¹] , compare entries 6 and 9, 10). The effect of the solvent was also investigated, toluene and ethyl acetate were the better solvents, with 1,1,2,2-tetrachloroethane (TCE) being the best (Table  [¹] , compare entries 6 and 11-15).

Table 1 BF3-Promoted N-Alkylation of p-Toluenesulfonamide (1a) with Diethyl Ether as Alkylating Agenta

Entry BF3˙OEt2 (equiv) Temp (˚C) Solvent Product (%)b
3a 3aa Total yield
 1 2 110 toluene 38 11 49
 2 3 110 toluene 40 37 77
 3 4 110 toluene 40 36 76
 4 6 110 toluene 45 46 91
 5 6 110 toluene 54c 34c 88
 6 6 110 toluene 39d 56d 95
 7 7 110 toluene 48 31 79
 8 8 110 toluene 44 40 84
 9 6  90 toluene 40  7 47
10 6 130 toluene 46 41 87
11 6 120 TCE 38 56 94
12 6  80 EtOAc 41 36 77
13 6  90 DCE 54 10 64
14 6 150 DMSO - - -
15 6 110 MeCN trace trace trace
a Reaction conditions: all reactions were carried out under an Ar atmosphere in a sealed tube, sulfonamide (0.5 mmol), solvent (1.0 mL), 24 h.
b Isolated yield after purification.
c Reaction time: 18 h.
d Reaction time: 48 h.

Unfortunately, when we attempted to extend this reaction to other dialkyl ethers such as di-n-butyl ether using BF3˙OEt2 (6.0 equiv) as promoter, only 36% yield of N-n-butyl p-toluene sulfonamide (3b) was obtained due to a possible weak complexation between BF3 and di-n-butyl ether (Table  [²] , entry 11), so we turned our efforts to screen other Lewis acid promoters including AlCl3, FeCl3, TiCl4, ZrCl4, MgO, etc. to get satisfying conversion, and the corresponding results are summarized in Table  [²] . As shown in Table  [²] , among the tested Lewis acids, TiCl4 showed the most effective promotion of mono-N-alkylation of sulfonamide with di-n-butyl ether in 60% yield (Table  [²] , entry 5), and basically other Lewis acids could not afford good yields of the desired product 3b (Table  [²] , entries 1-11). We tried to use an excess amount of dialkyl ether with respect to sulfonamide and extended the reaction time (48 h) in order to further improve the yield of the transformation, and finally the best yield of 3b (78%) was achieved in the presence of TiCl4 (6.0 equiv) at 120 ˚C for 48 hours when the ratio of 2b/1a is 12:1(Table  [¹] , compare entries 12-14). Noteworthy, if the reaction time was further extended to 72 hours, the yield of monoalkylation product 3b would decrease to some degree due to the formation of N,N-dialkylated product (Table  [²] , entry 14).

Table 2 Catalyst Screening for Mono-N-alkylation of p-Toluene Sulfonamide with Di-n-butyl Ether as Alkylating Agenta

Entry Catalyst Reaction time (h) Yield (%)b,c
 1 AlCl3 24 24
 2 FeCl3 24 23
 3 Fe2O3 24 n.r.
 4 ZrCl4 24  9
 5 TiCl4 24 60
 6 MgO 24 n.r.
 7 Cu(OAc)2˙H2O 24 n.r.
 8 FeCl2˙4H2O 24 n.r.
 9 CdCl2˙2.5H2O 24 n.r.
10 NiCl2˙6H2O 24 n.r.
11 BF3˙OEt2 24 36
12 TiCl4 24 69d
13 TiCl4 48 78d
14 TiCl4 72 70e
a Reaction conditions: p-toluene sulfonamide (0.5 mmol), di-n-butyl ether (6.0 equiv, 3.0 mmol), Lewis acid (6.0 equiv), TCE (1.0 mL), the reaction was carried out at 120 ˚C at the given reaction time in sealed tube.
b Isolated yield after purification.
c n.r. = no reaction
d Conditions: 12.0 equiv of di-n-butyl ether were used.
e Conditions: 24.0 equiv of di-n-butyl ether were used.

Accordingly, the substrate scope for the mono-N-alkylation of sulfonamides was further extended to various ethers using the optimized reaction conditions. [¹¹] As shown in Table  [³] , the alkylating reagents examined could be performed smoothly in moderate to good yields. Analysis of the efficiency in which our substrates are N-alkyl­ated indicates that both electronic and steric effects govern the N-alkylation system. Increasing the electronic density of the sulfonamide nitrogen enhance the N-alkylation performance (Table  [³] , entries 1-5), while electronic-deficient substrates leads to decreased product yield (Table  [³] , entry 6), and the similar electronic effect of substituents on the dibenzyl ethers was also observed (Table  [³] , entries 7-9). Steric-hindrance effects also play a key role in this reaction system, as increasing the steric hindrance of the ether at Ca leads to a substantial decrease in product yield, while decreasing the steric hindrance at Ca leads to an improved N-alkylating yield (Table  [³] , compare entries 1 and 11, 12), but for the N-substituted sulfonamide 1g, no significant steric effect was observed (Table  [³] , compare entries 1 and 15). It is interesting to note that when we employed diethyl ether as alkylating agent using BF3˙OEt2 as promoter, the N-alkylation product of N-phenyl-p-toluene sulfonamide (1h) is toluene-4-sulfonic acid ethyl ester (3p, 69% yield) instead of N-ethyl-N-phenyl-4-methyl-benzenesulfonamide (Table  [³] , entry 16), possibly due to the large steric hindrance effect from N-substituted amide that favors esterlysis of sulfon­amide. Changing the substrate from an aryl sulfonamide to an alkyl sulfonamide, such as methanesulfonamide, also gave the desired alkylated product 3q in 56% yield (Table  [³] , entry 17). Moreover, if p-toulene sulfonamide (1a) was treated upon the unsymmetrical ether methoxymethylbenzene (2f), the alkylation reaction would only afford N-benzyl-4-methyl-benzensulfonamide (3h, 40% yield) without detectable byproducts N-methyl-4-methyl-benzensulfonamide (Table  [³] , entry 10). Although TiCl4 could promote 2-(ethoxymethyl) benzenesulfon­amide to form 2,3-dihydro-benzo[d]isothiazole 1,1-dioxide (3r) via intramolecular N-alkylation, the corresponding yield is poor (Table  [³] , entry 18).

To our satisfaction, TiCl4 could enhance 2-sulfamonyl-benzoic acid ethyl ester (1k) to form unexpected cyclic N-alkylation product 2-n-butyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[d] isothiazo-3-one (3s) and 2-benzyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[d] isothiazo-3-one (3t) in good yield (Table  [³] , entries 19 and 20). A possible reaction pathway for 3s is depicted in Scheme  [²] . The ester carbonyl group was activated by an initial coordination of the carbonyl oxygen with Ti(IV), and suffered an intramolecular nucleophilic attack from sulfonamide nitrogen to generate the N-acylation product 3u, [¹0] and the corresponding amide nitrogen continued to attack the ether-­oxygen bond activated by Ti(IV) via SN2 displacement, and led to the formation of N-alkylation product 3s. During the N-alkylation reaction of 1k, the rearranged product 3v was not detected using GC-MS method, so the SN1 transformation pathway was excluded.

Scheme 2 Mechanistic proposal for the TiCl4-promoted cascade N-acylation/N-alkylation of sulfonamide 1k

In conclusion, we have demonstrated that the direct intermolecular or intramolecular N-alkylation of sulfonamides with inactive esters is possible using TiCl4 as promoter for the first time. This transformation may be of interest in the synthesis of complex cyclic polyfunctionalized sulfon­amides.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.

Table 3 TiCl4-Catalyzed N-Alkylation of Sulfonamides with Ethers (continued)

Entry Sulfonamide Ether Time (h) Product Yield (%)a,b
 1

1a

2b 		48

3b 		78
 2

1b

2b 		24

3c 		73
 3

1c

2b 		48

3d 		75
 4

1d

2b 		72

3e 		79
 5

1e

2b 		48

3f 		80
 6

1f

2b 		48

3g 		39
 7

1a

2c 		48

3h 		69
 8

1a

2d 		24

3i 		49
 9

1a

2e 		48

3j 		-
10

1a

2f 		48

3h 		40
11

1a

2g 		48

3k 		40
12

1a

2h 		48

3l 		33
13

1a

2i 		48

3m 		61
14

1a

2j 		48

3a 		79
15

1g

2b 		48

3o 		77
16

1h

2k 		48

3p 		69c
17

1i

2c 		48

3q 		56d
18

1j 		- 48

3r 		18e
19

1k

2b 		48

3s 		64
20

1k

2c 		24

3t 		69
a Isolated yields, average of 2 runs.
b Reaction conditions: p-toluene sulfonamide (0.5 mmol), ether (12.0 equiv, 6.0 mmol), Lewis acid (6.0 equiv, 3.0 mmol), TCE (2.0 mL), the reaction was carried out at 120 ˚C at the given reaction time in sealed tube.
c BF3˙OEt2 (6.0 equiv) was used.
d The reaction was carried out at 90 ˚C.
e Lowering the reaction temperature (≤120 ˚C) or increasing the reaction temperature (≥120 ˚C) resulted in poorer yield.

Acknowledgment

The financial supports for this work from the Program for New Century Excellent Talents in University by Ministry of Education (No. NCET-10-0371), the FRFCU (No. 2009ZM0262), the NSFC (No. 21072063), RFDP (No. 20100172120020), and the FRFCU (No. 2009ZM0262, 2009ZM0126) are gratefully acknowledged.

11

General Procedure for the Transformation
Sulfonamide (0.50 mmol), ether (12.0 equiv, 6.0 mmol) and Cl2CHCHCl2 (2.0 mL) were combined in a pressure tube equipped with a stir bar, the mixture was stirred about 10 min, then TiCl4 (6.0 equiv, 3.0 mmol) was added, and the reaction mixture was heated to 120 ˚C for the given time. After the starting material has disappeared (monitored by TLC), the reaction mixture was cooled to r.t. and treated with H2O (5.0 mL) to decompose the exceed TiCl4, then filtered, and the filtrate was extracted with EtOAc (3 × 10 mL).
The combined organic layers was dried over Na2SO4 and concentrated in vacuo, the corresponding residue was purified by flash column chromatography (silica gel) to furnish the target product. All the products are known compounds and are identified using ¹H NMR, LRMS, and
IR by comparison with previously reported data (see Supporting Information for complete details).

11

General Procedure for the Transformation
Sulfonamide (0.50 mmol), ether (12.0 equiv, 6.0 mmol) and Cl2CHCHCl2 (2.0 mL) were combined in a pressure tube equipped with a stir bar, the mixture was stirred about 10 min, then TiCl4 (6.0 equiv, 3.0 mmol) was added, and the reaction mixture was heated to 120 ˚C for the given time. After the starting material has disappeared (monitored by TLC), the reaction mixture was cooled to r.t. and treated with H2O (5.0 mL) to decompose the exceed TiCl4, then filtered, and the filtrate was extracted with EtOAc (3 × 10 mL).
The combined organic layers was dried over Na2SO4 and concentrated in vacuo, the corresponding residue was purified by flash column chromatography (silica gel) to furnish the target product. All the products are known compounds and are identified using ¹H NMR, LRMS, and
IR by comparison with previously reported data (see Supporting Information for complete details).

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Scheme 1 N-alkylation of sulfonamide

Scheme 2 Mechanistic proposal for the TiCl4-promoted cascade N-acylation/N-alkylation of sulfonamide 1k