Intramolecular Carbene C-H Insertion Reactions of 2-Diazo-2-sulfamoylacetamides

The intramolecular C-H insertions of carbenes derived from 2-diazo-2-sulfamoylacetamides were studied. 2-Diazo-2-sulfamoylacetamides were first prepared from chloroacetyl chloride and secondary amines through acylation followed by sequential treatments with sodium sulfite, phosphorus oxychloride, secondary amines, and 4-nitrobenzenesulfonyl azide. The results indicate that: (1) 2-diazo-N,N-dimethyl-2-(N,N-diphenylsulfamoyl)acetamide can take the formal aromatic 1,5-C-H insertion in its N-phenylsulfonamide moiety to afford the corresponding 1,3-dihydrobenzo[c]isothiazole-3-carboxamide 2,2-dioxide derivative; (2) no aliphatic C-H insertions occur for 2-diazo-2-(N,N-dialkylsulfamoyl)acetamides; and (3) for 2-diazo-N-phenyl-2-(N-phenylsulfamoyl)acetamides, the formal aromatic 1,5-C-H insertion in the N-phenylacetamide moiety is favorable to afford the corresponding 3-sulfamoylindolin-2-one derivatives as sole or major products. The intramolecular competitive aromatic 1,5-C-H insertion reactions of 2-diazo-2-sulfamoylacetamides with aryl groups on both amide and sulfonamide groups reveal that the N-aryl substituents on acetamide are more active than those on sulfonamide. The chemoselectivity is controlled by electronic effect of the aryl group.


Synthesis of 2-Diazo-2-sulfamoylacetamides 1
Because the carbene C-H insertion of carbamoyl diazomethanesulfonamides has not been explored previously, to confirm whether N-aryl-carbamoyl-diazomethanesulfonamides can take the aromatic 1,5-C-H insertion in their N-arylsulfonamide moiety, we first prepared N-methyl-N-phenyl and N,N-diphenyl carbamoyl-diazomethanesulfonamides 1a and 1b. The reaction of 2-chloroacetyl chloride and dimethylammonium chloride (4a·HCl) in the presence of triethylamine in dichloromethane afforded 2-chloro-N,N-dimethylacetamide (5a) in 90% yield. 2-Chloroacetamide 5a was treated with sodium sulfite in water three times to give rise to solid sodium carbamoylmethanesulfonate after removal of water. The mixture of dry crude sodium sulfonate and phosphorus oxychloride was refluxed for 3 h to afford the corresponding sulfonyl chloride 6a, which further reacted with N-methylaniline (4b) and diphenylamine (4c), respectively. However, only diphenylamine (4c) gave rise to sulfamoylacetamide 7b in a low yield of 16%. It is somewhat strange that N,N-dimethylcarbamoylmethanesulfonyl chloride (6a) failed to react with N-methylaniline (4b) (Scheme 2). To verify the results, we attempted the reaction several times, but all failed to afford sulfamoylacetamide 7a (Table 1, entry a).
The reactions of 2-chloroacetyl chloride and secondary amines 4b and 4c produced tertiary 2-chloroacetamides 5c and 5d in excellent yields. 2-Chloroacetamides 5c,d were treated with sodium sulfite in water three times to give rise to solid sodium carbamoylmethanesulfonates after removal of water. The mixtures of dry crude sodium sulfonates and phosphorus oxychloride were refluxed for 3 h to afford the corresponding sulfonyl chlorides 6c,d. To evaluate aliphatic C-H insertions of 2-diazo-2-(N,N-dialkylsulfamoyl)acetamides, sulfonyl chlorides 6c,d were reacted with N-butylbenzylamine (4d) to yield 2-(N-benzyl-N-butylsulfamoyl)-2-diazoacetamides 7c,d in satisfactory yields (Table 1, entries c and d). To investigate the intramolecular competitive aromatic 1,5-C-H insertion of N-aryl-2-(N-arylsulfamoyl)-2-diazoacetamides, sulfonyl chlorides 6c,d were further reacted with another secondary amines 4b,c to yield sulfamoylacetamides 7e-h in 30-88% yields (Table 1, entries e-h). Sulfamoylacetamides 7 were converted into 2-diazosulfamoylacetamides 1 through the diazo transformation reaction with 4-nitrobenzenesulfonyl azide (NsN 3 ) in acetonitrile with DBU as base (Scheme 2). Because the carbene C-H insertion of carbamoyl diazomethanesulfonamides has not been explored previously, to confirm whether N-aryl-carbamoyl-diazomethanesulfonamides can take the aromatic 1,5-C-H insertion in their N-arylsulfonamide moiety, we first prepared N-methyl-N-phenyl and N,N-diphenyl carbamoyl-diazomethanesulfonamides 1a and 1b. The reaction of 2-chloroacetyl chloride and dimethylammonium chloride (4aHCl) in the presence of triethylamine in dichloromethane afforded 2-chloro-N,N-dimethylacetamide (5a) in 90% yield. 2-Chloroacetamide 5a was treated with sodium sulfite in water three times to give rise to solid sodium carbamoylmethanesulfonate after removal of water. The mixture of dry crude sodium sulfonate and phosphorus oxychloride was refluxed for 3 h to afford the corresponding sulfonyl chloride 6a, which further reacted with N-methylaniline (4b) and diphenylamine (4c), respectively. However, only diphenylamine (4c) gave rise to sulfamoylacetamide 7b in a low yield of 16%. It is somewhat strange that N,N-dimethylcarbamoylmethanesulfonyl chloride (6a) failed to react with N-methylaniline (4b) (Scheme 2). To verify the results, we attempted the reaction several times, but all failed to afford sulfamoylacetamide 7a (Table 1, entry a).
On the basis of Hammett constants [33], methanesulfonyl (σ = 0.73) is a stronger electronwithdrawing group than acetyl (σ = 0.47). It should be reasonable to rationalize that the phenyl group of N-phenylamides is generally electron-richer than that of N-phenylsulfonamides, favoring the electrophilic attack of Cu-carbon ylides to the phenyl group of amides, showing higher reactivity of Proposed mechanism for the intramolecular aromatic 1,5-C-H insertion of diazosulfamoylacetamides 1. On the basis of Hammett constants [33], methanesulfonyl (σ = 0.73) is a stronger electronwithdrawing group than acetyl (σ = 0.47). It should be reasonable to rationalize that the phenyl group of N-phenylamides is generally electron-richer than that of N-phenylsulfonamides, favoring the electrophilic attack of Cu-carbon ylides to the phenyl group of amides, showing higher reactivity of N-phenylacetamides. The chemoselectivity is attributed to the different electronic effects of methanesulfonamido and acetamido groups when amides and sulfonamides possess similar steric hindrance. For example, the O=C-N(Me)-Ph and (O=) 2 S-N(Me)-Ph conjugative systems in substrate 1e can exist in the same planes or almost same planes. Thus, the electron-withdrawing conjugative effect of the methanesulfonamido group is stronger than that of the acetamido group, resulting in lower electron density of the phenyl group on sulfonamide. Thus, the aromatic 1,5-C-H insertion occurs on the phenyl group of acetamide. In N,N-diphenyl derivative 1h, both O=C-N(Ph)-Ph and O=S-N(Ph)-Ph conjugative systems cannot exist in the same planes due to steric hindrance of two phenyl groups. The phenyl group of acetamide is electron-richer than that of sulfonamide as well in 1h. The phenyl group of O=C-N(Ph)-Ph is absolutely electron-richer than that of (O=) 2 S-N(Me)-Ph in substrate 1g because the former is not in the same plane due to steric hindrance of two phenyl groups, while the latter is in the same plane. Similarly, the aromatic 1,5-C-H insertion of both substrate 1g and 1h occurs on the electron-rich phenyl group of acetamide. However, for 2-diazo-N-methyl-N-phenyl-2-(N,N-diphenylsulfamoyl)acetamide (1f), the (O=) 2 S-N(Ph)-Ph conjugative system is non-planar, showing weak electron-withdrawing conjugative effect due to steric hindrance of two phenyl groups, while the near planar O=C-N(Me)-Ph conjugative system shows strong electron-withdrawing conjugative effect to decrease the electron density of the phenyl group on the N-phenylacetamide, resulting in closer electron-densities of these two phenyl groups on both acetamide and sulfonamide. This is the reason 2-diazo-N-methyl-N-phenyl-2-(N,N-diphenylsulfamoyl)acetamide (1f) chemoselectively generated both 3-sulfamoylindolin-2-one 3f as major product and 1,3-dihydrobenzo[c]isothiazole-3-carboxamide 2,2-dioxide 2f as a minor product.

Rationale on the
The intramolecular competitive reactions of 2-diazo-N-phenyl-2-(N-phenylsulfamoyl)acetamides reveal that the chemoselectivity of the aromatic 1,5-C-H insertion is controlled by the electron density of the N-phenyl groups on amides and sulfonamides, but impacted by the steric hindrance. The results also support our proposed reaction mechanism. That is, the electrophilic attack of Cu-carbon ylides on more electron-rich phenyl group in reactants is the key step, i.e. rate-limiting step, in the aromatic carbene 1,5-C-H insertion. This result is similar to Maguire's report that the aliphatic C-H insertion of carbenes derived from 2-diazo-2-sulfonylacetamides exclusively occurred on the N-alkyl groups on amides, rather than on the alkyl groups of alkanesulfonyls [31]. These results together reveal that diazosulfonamides have more inert reactivity than their analogs diazoacetamides

Materials and Instruments
Toluene was refluxed over Na with diphenyl ketone as an indicator and freshly distilled prior to use. Melting points were obtained on a MP-500 melting point apparatus and are uncorrected. 1 H and 13 C-NMR spectra were recorded on a 400 MHz Bruker spectrometer in CDCl 3 with TMS as an internal standard and the chemical shifts (δ) are reported in parts per million (ppm). The IR spectra (KBr pellets, v (cm −1 )) were taken on a FTIR spectrometer. HRMS measurements were carried out on an Agilent LC/MSD TOF mass spectrometer. TLC separations were performed on silica gel GF254 plates, and the plates were visualized under UV light. Petroleum ether (PE, 30−60 • C) and ethyl acetate (EA) were used for column separation.
It is noteworthy that the signal of the carbon attached with diazo group in diazosulfamoylacetamides 1 cannot be displayed in their 13 C-NMR spectra. Similar observations were also reported by Novikov and Du Bios in the synthesis of diazosulfones and diazosulfonates, respectively [27,28].

General Procedure for the Preparation of Chloroacetamides 5
Dimethylammonium chloride (4.08 g, 50 mmol) and triethylamine (10.1 g, 100 mmol) were dissolved in dichloromethane (50 mL). Chloroacetyl chloride (6.78 g, 60 mmol) was added dropwise under stirring at 0 • C. The resulting solution was stirred at 0 • C for 4 h. After washing with water (30 mL × 3), drying over Na 2 SO 4 , and removing the solvent, the crude N,N-dimethyl-2-chloroacetamide was obtained and used directly in the next step [34].
To a solution of diphenylamine (8.45 g, 50 mmol) or N-methylaniline (5.35 g, 50 mmol) in dry toluene (30 mL), chloroacetyl chloride (5.65 g, 50 mmol) was added dropwise under stirring. The resulting solution was refluxed for 4 h. After removal of solvent under reduced pressure, the crude product was obtained and used directly in the next step [34].

General Procedure for the Synthesis of Sulfamoylacetamides 7
Chloroacetamide 5 (25 mmol) was added to a suspension of sodium sulfite (3.94 g, 31.25 mmol) in water (40 mL), and the mixture was stirred for 8 h at room temperature. After removal of water under reduced pressure, the crude product containing sodium chloride was obtained. To the crude product 25 mL of toluene was added, which was removed along with water under reduced pressure. The procedure was repeated three times to give the crude dry sodium sulfonate.
To the crude dry sodium sulfonate, 12.5 mL (ca. 20.5 g, 13.5 mmol) of POCl 3 was added and the mixture was refluxed for 3 h. After being dissolved in DCM (13 mL), to the mixture was added a secondary amine 4 (25 mmol) dissolved in DCM (13 mL). The resulting solution was stirred at room temperature for another 3 h. The mixture was transferred to conical flask of 250 mL, and 50 mL of water and ice mixture was added. After the pH value of the mixture was adjusted to 6-8 with 20% sodium hydroxide, the organic phase was separated and then dried over anhydrous sodium sulfate. After removal of solvent under reduced pressure, the residual oil was purified on silica gel column (EA:PE = 1:10, v/v) to yield the pure 2-sulfamoylacetamide 7.   To a suspension of Cu(acac) 2 (2 mol%, 13 mg, 0.01 mmol) in 10 mL of toluene, the corresponding diazosulfamoylacetamide 1 (0.5 mmol) was added, and the mixture was refluxed for 9 h. After removal of solvent under reduced pressure, the crude reaction mixture was purified on silica gel column (PE:EA = 10:1, v/v) to afford the desired product 2 and/or 3.

Conclusions
The intramolecular C-H insertions of carbenes derived from different diazosulfamoylacetamides were studied. The results reveal that the aromatic 1,5-C-H insertion can occur on the N-phenylsulfonamides only when they have no N-phenyl group on their acetamide. No aliphatic C-H insertions were observed for diazo(N,N-dialkylsulfamoyl)acetamides. The intramolecular competitive aromatic 1,5-C-H insertion of N-aryl-2-(N-arylsulfamoyl)-2-diazoacetamides occurs on the N-phenylacetamides predominantly rather than the phenyl group of N-phenylsulfonamides. The chemoselectivity is controlled by the electron density of the phenyl group and affected by the steric hindrance. The aromatic 1,5-C-H insertion occurs on the more electron-rich N-phenyl group because the key step (i.e, rate-determining step) is electrophilic attack (Frediel-Craft alkylation).