A Facile Synthesis of 1-Substituted Cyclopropylsulfonamides

Abstract

A practical, convenient, and high-yielding three-step synthesis of cyclopropanesulfonamide and 1-substituted cyclopropanesulfonamides, starting from 3-chloropropanesulfonyl chloride, is described.

sulfonamides - lithiation - cyclizations - cyclopropanesulfonamides - alkylations

References and Notes

A Scifinder search based on substructure A revealed more than 90 patents claiming bioactivities of cyclosulfonamide derivatives. See:

<A NAME="RS11805ST-1A">1a</A> Greenlee WJ, Huang Y, Kelly JM, McCombie SW, Stamford AW, and Wu Y. inventors; US Patent Appl.  2003/114517. 

<A NAME="RS11805ST-1B">1b</A> Miller MW, and Scott JD. inventors; PCT Int. Appl. WO  2004/056770. 

<A NAME="RS11805ST-1C">1c</A> Paliwal S, Reichard GA, Wang C, Xiao D, Tsui H.-C, Shih N.-Y, Arredondo JD, Wrobleski ML, and Palani A. inventors; PCT Int. Appl. WO  2003/051840. 

<A NAME="RS11805ST-1D">1d</A> De Nanteuil G, Portevin B, Benoist A, Levens N, Nosjean O, and Husson-Robert B. inventors; Eur. Pat. Appl.  1245568. 

<A NAME="RS11805ST-1E">1e</A> Llinas-Brunet M, and Bailey MD. inventors; PCT Int. Appl. WO  2004/037855. 

<A NAME="RS11805ST-1F">1f</A> Glunz PW, Bisacchi GS, Morton GC, Holubec AA, Priestley ES, Zhang X, and Treuner UD. inventors; PCT Int. Appl. WO  2004/072101. 

<A NAME="RS11805ST-1G">1g</A> Walter R, Heckel A, Roth GJ, Kley J, Schnapp G, Lenter M, Van Meel JCA, Spevak W, and Weyer-Czernilofsky U. inventors; PCT Int. Appl. WO  2002/36564. 

<A NAME="RS11805ST-1H">1h</A> Zhu HY, Njoroge FG, Cooper AB, Guzi T, Dinanath FR, Minor KP, Doll RJ, Girijavallabhan VM, Santhanam B, Pinto PA, Vibulbhan B, Keertikar KM,
Alvarez CS, Baldwin JJ, Li G, Huang C.-Y, James RA, Bishop WR, Wang JJ.-S, and Desai JA. inventors; US Patent Appl.  2004/122018. 

<A NAME="RS11805ST-1I">1i</A> Allen DG, Coe DM, Cook CM, Cooper AWJ, Dowle MD, Edlin CD, Hamblin JN, Johnson MR, Jones PS, Lindvall MK, Mitchell CJ, and Redgrave AJ. inventors; PCT Int. Appl. WO  2004/056823. 

<A NAME="RS11805ST-1J">1j</A> Breitfelder S, Cirillo PF, and Regan JR. inventors; PCT Int. Appl. WO  2002/083642. 

<A NAME="RS11805ST-1K">1k</A> Brendel J, Pirard B, Peukert S, Kleemann H.-W, and Hemmerle H. inventors; PCT Int. Appl. WO  2002/088073. 

<A NAME="RS11805ST-2A">2a</A> Truce WE. Goralski CT. J. Org. Chem.  1968,  33:  3849 

<A NAME="RS11805ST-2B">2b</A> Brienne M.-J. Varech D. Leclercq M. Jacques J. Radembino N. Dessalles M.-C. Mahuzier G. Gueyouche C. Bories C. Loiseau P. Gayral P. J. Med. Chem.  1987,  30:  2232 

<A NAME="RS11805ST-3A">3a</A> Christensen LW. Seaman JM. Truce WE. J. Org. Chem.  1973,  38:  2243 

<A NAME="RS11805ST-3B">3b</A> Makosza M. Golinski J. Ostrowski S. Rykowski A. Sahasrabudhe AB. Chem. Ber.  1991,  124:  577 

<A NAME="RS11805ST-4A">4a</A> Kosinski S. Wojciechowski K. Eur. J. Org. Chem.  2000,  1263 

<A NAME="RS11805ST-4B">4b</A> Meyle E. Schwenkkraus P. Zsigmondy M. Otto H.-H. Arch. Pharm.  1989,  322:  17 

<A NAME="RS11805ST-5A">5a</A> Truce WE. Goralski CT. J. Org. Chem.  1969,  34:  3324 

<A NAME="RS11805ST-5B">5b</A> Neale RS. Marcus NL. J. Org. Chem.  1969,  34:  1808 

<A NAME="RS11805ST-6A">6a</A> Block E. Schwan A. Dixon DA. J. Am. Chem. Soc.  1992,  114:  3492 

<A NAME="RS11805ST-6B">6b</A> King JF. Lam JYL. Ferrazzi G. J. Org. Chem.  1993,  58:  1128 

<A NAME="RS11805ST-7">7</A> Thompson ME. J. Org. Chem.  1984,  49:  1700 

<A NAME="RS11805ST-8">8</A> Neustadt BR. Tetrahedron Lett.  1994,  35:  379 

<A NAME="RS11805ST-9">9</A> Campbell JA. Hart DJ. J. Org. Chem.  1993,  58:  2900 

<A NAME="RS11805ST-10A">10a</A> Rawal VH. Cava MP. Tetrahedron Lett.  1985,  26:  6141 

<A NAME="RS11805ST-10B">10b</A> Reuter DC. McIntosh JE. Guinn AC. Madera AM. Synthesis  2003,  2321 

<A NAME="RS11805ST-11">11</A> White EH. Lim HM. J. Org. Chem.  1987,  52:  2162 

<A NAME="RS11805ST-12">12</A>

Procedure for the Synthesis of 8.
tert-Butylamine (2a, 3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to -20 °C and
3-chloropropanesulfonyl chloride (1, 1.5 mol, 182.4 mL) was added slowly. The reaction mixture was allowed to warm to r.t. and stirred for 24 h. The mixture was filtered, and the filtrate concentrated in vacuo. The residue was dissolved in CH₂Cl₂ (2.0 L), washed with 1 N HCl (1.0 L), H₂O (1.0 L) and brine (1.0 L) before being dried over Na₂SO₄. The solution was filtered and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to afford the product 3b as a white solid (316.0 g, 99%). Mp 70-72 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.37 (s, 9 H, 3 × CH₃), 2.25-2.30 (m, 2 H, CH₂), 3.21 (t, J = 7.5 Hz, 2 H, CH₂), 3.67 (t, J = 7.5 Hz, 2 H, CH₂), 4.36 (br s, 1 H, NH). ¹³C NMR (125 MHz, CDCl₃): δ = 27.4, 30.4, 42.9, 53.4, 54.9. Anal. Calcd for C₇H₁₆NO₂S: C, 39.33; H, 7.54; N, 6.55. Found: C, 39.37; H, 7.33; N, 6.49.
To a stirred solution of compound 3b (0.75 mol, 160 g) in dry THF (2 L) at -78 °C under N₂ was added slowly a solution of n-BuLi (2.5 M in hexane, 2.1 equiv, 1.575 mol, 630 mL). After addition, the dry ice bath was removed and the reaction mixture was allowed to warm to r.t. over a period of 2 h. The reaction mixture was cooled to 0 °C and quenched with sat. NH₄Cl solution (500 mL). The THF was removed in vacuo and the residue partitioned between EtOAc (1.5 L) and H₂O (1 L). The organic phase was separated, washed with brine (1 L) and dried over MgSO₄ before being filtered and concentrated in vacuo to give a white solid which was recrystallized from hexane to give the product 7a as white needles (125.0 g, 94%). Mp 81-83 °C. ¹H NMR (500 MHz, CDCl₃): δ = 0.96-1.00 (m, 2 H, CH₂), 1.16-1.19 (m, 2 H, CH₂), 1.38 (s, 9 H, 3 × CH₃), 2.43-2.47 (m, CH), 4.23 (br s, 1 H, NH). ¹³C NMR (125 MHz, CDCl₃): δ = 6.5, 30.7, 33.6, 54.3. Anal. Calcd for C₇H₁₅NO₂S: C, 47.43; H, 8.52; N, 7.90. Found: C, 47.53; H, 8.49; N, 7.74.
A solution of compound 7a (0.62 mol, 110.0 g) in TFA (500 mL) was stirred at r.t. under N₂ for 16 h. The TFA was removed in vacuo to give a yellow oil which was crystallized from EtOAc-hexane (1:3, 300 mL) to afford product 8 as white needles (68.5 g, 91%). Mp 106-107 °C. ¹H NMR (500 MHz, DMSO): δ = 0.87-0.93 (m, 4 H, 2 × CH₂), 2.49-2.54 (m, 1 H, CH), 6.76 (br s, 2 H, NH₂). ¹³C NMR (125 MHz, DMSO): δ = 4.90, 32.0. Anal. Calcd for C₃H₇NO₂S: C, 29.74; H, 5.82; N, 11.56. Found: C, 30.02; H, 5.61; N, 11.37.

<A NAME="RS11805ST-13">13</A>

Typical Procedure Exemplified by the Preparation of 1-Methylcyclopropylsulfonamide (Table, Entry 1).
To a solution of 3b (20 mmol, 4.3 g) in dry THF (100 mL) under N₂ was added a solution of n-BuLi (2.5 M in hexane, 2.1 equiv, 44 mmol, 17.6 mL) at -78 °C. The reaction mixture was allowed to warm to r.t. over a period of 1.5 h and then was cooled to -78 °C. Another equivalent of
n-BuLi (8 mL) was added, the mixture warmed to r.t. over a period of 1.5 h and then recooled to -78 °C. The MeI (2 equiv, 40 mmol, 2.5 mL) was added and the reaction mixture was allowed to warm to r.t. over a period of 12 h. The mixture was quenched with a solution of sat. NH₄Cl (100 mL) and extracted with EtOAc (100 mL). The organic extract was washed with brine (100 mL), dried over MgSO₄, filtered and concentrated in vacuo to give a yellow oil which was crystallized from hexane to afford the product as slightly yellow needles (3.1 g, 81%). Mp 77-78 °C. ¹H NMR (500 MHz, CDCl₃): δ = 0.77-0.80 (m, 2 H, CH₂), 1.38-1.41 (m, 2 H, CH₂), 1.36 (s, 9 H, 3 × CH₃), 1.51 (s, 3 H, CH₃), 4.07 (br s, 1 H, NH). ¹³C NMR (125 MHz, CDCl₃): δ = 13.8, 19.0, 30.9, 37.3, 54.4. Anal. Calcd for C₈H₁₇NO₂S: C, 50.23; H, 8.95; N, 7.32. Found: C, 50.05; H, 8.80; N, 7.32.
Treatment of this material (10 mmol, 1.91 g) with TFA (30 mL) using the same procedure described above for 8 gave the product as a white solid (1.25 g, 96%). Mp 103-104 °C. ¹H NMR (500 MHz, DMSO): δ = 0.74 (dd, J = 6.1, 4.0, 2 H, CH₂), 1.13 (dd, J = 6.1, 4.0, 2 H, CH₂), 1.44 (s, 3 H, CH₃), 6.72 (br s, 2 H, NH₂). ¹³C NMR (125 MHz, DMSO): δ = 12.1, 17.6, 36.4. Anal. Calcd for C₄H₉NO₂S: C, 35.54; H, 6.71; N, 10.36. Found: C, 35.67; H, 6.80; N, 10.40.

<A NAME="RS11805ST-14">14</A> Campbell JA, D’Andrea S, Good A, Li J, McPhee F, Ripka A, Scola PM, and Tu Y. inventors; US Patent Appl.  2004/0077551. For procedures on synthesis of 3a,c, 4b, 5b and removal of t-Boc group, see: