A facile synthesis of 1-substituted cyclopropylsulfonamides

Article abstract of DOI:10.1055/s-2006-933130

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

Full text of DOI:10.1055/s-2006-933130

LETTER
725
A Facile Synthesis of 1-Substituted Cyclopropylsulfonamides
1
-Substitu
i
ted Cy
a
lopropylsu
n
lfonamide
s
qing Li,* Daniel Smith, Henry S. Wong, Jeffrey A. Campbell, Nicholas A. Meanwell, Paul M. Scola
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA
Fax +1(203)6777702; E-mail: Jianqing.Li@bms.com
Received 28 November 2005
8 and a variety of 1-substituted cyclopropylsulfonamides
6, which are not easily accessible using the existing meth-
ods. Herein, we wish to report a practical and convenient
synthesis of 8 that is amenable to large scale and its con-
version to a series of substituted derivatives 6 as depicted
in Scheme 1.
Abstract: A practical, convenient, and high-yielding three-step
synthesis of cyclopropanesulfonamide and 1-substituted cyclopro-
panesulfonamides, starting from 3-chloropropanesulfonyl chloride,
is described.
Key words: sulfonamides, lithiation, cyclizations, cyclopropane-
sulfonamides, alkylations
Two different protecting groups for the sulfonamide NH2
moiety were examined. tert-Butylamine was selected as
the source of NH2 based on Thompson’s7 findings that the
tert-butyl group can be readily removed in acidic medium
and that its steric bulk minimizes N-alkylation or acyla-
tion. The t-Boc moiety behaves in a similar fashion, pro-
viding a protecting element that is readily installed,8
easily removed under acidic9 or thermal10 conditions and
which is not prone to N-alkylation.9 Thus, 3-chloropro-
panesulfonyl chloride 1 reacted smoothly with excess am-
monia (2a) at 0 °C to room temperature or two equivalents
of tert-butylamine (2b) in THF from –20 °C to room tem-
perature to give the 3-chloropropylsulfonamides 3a and
3b in 93% and 99% yield, respectively.11–14 Both proce-
dures are readily conducted on large scale. Conversion of
3a to the t-Boc derivative 3c was accomplished by expo-
sure to (t-Boc)2O in CH2Cl2 using Et3N as the base in the
presence of a catalytic amount of DMAP.8 Dilithiation of
3b and 3c with two equivalents of n-butyllithium at –78
°C in THF effected metallation at the sulfonamide nitro-
gen and the a-carbon atom to provide a dianion that
subsequently cyclized to form the lithiated cyclopropyl-
sulfonamides 4a and 4b, respectively, upon warming to
room temperature. Aqueous workup afforded 7a and 7b in
isolated yields of 94% and 100%, respectively. Treatment
of 7a with TFA at room temperature afforded cyclopro-
pylsulfonamide 8 in good yield.12 This three-step proce-
dure afforded cyclopropylsulfonamide 8 in a very simple
operation without resort to column chromatography for
purification, and in an economical fashion.
The cyclopropylsulfonamide moiety (Figure 1) has re-
cently emerged as an interesting structural element in
many biologically active compounds.1 Examples of mol-
ecules incorporating this functionality include antagonists
of neuropeptide Y Y5,1a CCR51b and NK11c receptors,
inhibitors of dipeptidylpeptidase IV (DPP IV),1d HCV
NS3 protease,1e factor VIIa,1f leiomyosarcoma SK-UT-1B
cell proliferation,1g farnesyl protein transferase1h and
phosphodiesterase,1i
and
antiinflammatory1j
and
antiarrhythmic1k agents.
O
R
S
N
R'
O
Figure 1
A number of methods have been reported in the literature
for the synthesis of cyclopropylsulfonamide derivatives.
The reaction of dimethylsulfonium methylide with a,b-
unsaturated sulfonamides represents a general route to
N,N-dialkyl cyclopropylsulfonamides.2 However, this
method failed to provide N- or N,N-unsubstituted deriva-
tives. N,N-Dialkyl cyclopropylsulfonamides have also
been prepared by the reaction of a-metalated N,N-dialkyl
chloromethanesulfonamides with activated olefins3 or
from the reaction of N,N-disubstituted methanesulfon-
amides with a 1,2-dihaloethane in the presence of a base.4
Base-promoted a,g-dehydrohalogenation of 3-halopro-
pylsulfonamide yields N-alkyl or N,N-dialkyl cyclopro-
pylsulfonamides.5 Although cyclopropylsulfonyl chloride
is commercially available and can readily be coupled with
amines to afford sulfonamides, it is expensive, the conse-
quence of a multistep synthesis.6
Treating 7a and 7b with 2 equivalents of a strong base (n-
BuLi for 7a and either n-BuLi or LDA for 7b) effected
formation of the N,C-dianion which reacted with a range
of electrophiles on carbon to provide a series of 1-sub-
stituted cyclopropylsulfonamides 6 after deprotection of
the sulfonamide nitrogen atom. Moreover, this process
could be telescoped into a simple and convenient one-pot
operation by treating the intermediate anions 4a and 4b
with an equivalent of n-BuLi to generate the dianion in
situ.11–14 The results compiled in Table 1 demonstrate the
scope of the electrophiles that successfully participate in
this process. The dianions reacted readily with both
activated and unactivated alkyl halides (entries 1–15),
In the course of a structure–activity survey, we required
convenient and reliable access to cyclopropylsulfonamide
SYNLETT 2006, No. 5, pp 0725–0728
1
7.
0
3.
2
0
0
6
Advanced online publication: 09.03.2006
DOI: 10.1055/s-2006-933130; Art ID: S11805ST
© Georg Thieme Verlag Stuttgart · New York

726
J. Li et al.
LETTER
O
S
O
S
O
S
n-BuLi (2 equiv)
Li
H
N
R
Cl
N
R
Cl
Cl
R
NH2
+
THF
THF
O
O
O
2a: R = H
2b: R = t-Bu
1
3
4a: R = t-Bu
4b: R = t-Boc
(t-Boc)2O, Et3N
3a: R = H: 93%
3b: R = t-Bu: 99%
3c: R = t-Boc
cat. DMAP, CH2Cl2
96%
1. n-BuLi (1 equiv)
H2O
2. electrophile
one-pot from 3b,c
O
H
R1
O
S
1. n-BuLi or
LDA (2 equiv)
H
S
N
R
N
R
2. electrophile
O
O
7a: R = t-Bu: 94%
7b: R = t-Boc: 100%
5a: R = t-Bu
5b: R = t-Boc
57–99%
TFA, r.t.
TFA, r.t.
R1
O
O
S
NH2
S
NH2
O
O
6: 47–96%
8: 91% from 7a
Scheme 1
aldehydes and ketones (entries 16–19), an ester (entry 20), lows the facile introduction of a wide array of substituents
isocyanates (entries 21 and 22), trimethylsilyl chloride at the 1-position of the cyclopropyl ring. The application
(entry 23) and halogenating agents (entries 24 and 25) to of this methodology in the synthesis of bioactive com-
produce a-substituted cyclopropylsulfonamides 5 in good pounds will be reported in due course.
to excellent isolated yields.11–14 The examples shown are
reactions performed a single time, many using the one-pot
process and the yields are unoptimized.
Acknowledgment
The authors thank Dr. Balu Balasubramanian and Dr. Bang-Chi
Chen for comments and suggestions on the manuscript.
As indicated in Table 1, in most cases the t-Bu and t-Boc
groups of the intermediates 5 can be removed by exposure
to trifluoroacetic acid at room temperature for 16 hours to
References and Notes
give the corresponding sulfonamides 6 in good yields.
The adducts derived from aldehydes and ketones provided
for complications with the cyclohexanone and acetone
adducts (entries 18 and 19) suffering dehydration under
the conditions for deprotection. The benzaldehyde adduct
(entry 17) provided a complex mixture when exposed to
trifluoroacetic acid and attempts to moderate this reaction
by diluting with CH2Cl2 merely produced an equally com-
plicated mixture at a slower rate, over four to five days.
However, heating the benzyl alcohol at reflux in xylene in
the presence of a catalytic amount of p-toluenesulfonic
acid for five hours, cooling and collecting the precipitate
afforded product that could be further purified by tritura-
tion with methanol to give product in 68% yield.
(1) A Scifinder search based on substructure A revealed more
than 90 patents claiming bioactivities of cyclosulfonamide
derivatives. See: (a) Greenlee, W. J.; Huang, Y.; Kelly, J.
M.; McCombie, S. W.; Stamford, A. W.; Wu, Y. US Patent
Appl. 2003/114517, 2003. (b) Miller, M. W.; Scott, J. D.
PCT Int. Appl. WO 2004/056770, 2004. (c) Paliwal, S.;
Reichard, G. A.; Wang, C.; Xiao, D.; Tsui, H.-C.; Shih, N.-
Y.; Arredondo, J. D.; Wrobleski, M. L.; Palani, A. PCT Int.
Appl. WO 2003/051840, 2003. (d) De Nanteuil, G.;
Portevin, B.; Benoist, A.; Levens, N.; Nosjean, O.; Husson-
Robert, B. Eur. Pat. Appl. 1245568, 2002. (e) Llinas-
Brunet, M.; Bailey, M. D. PCT Int. Appl. WO 2004/037855,
2004. (f) Glunz, P. W.; Bisacchi, G. S.; Morton, G. C.;
Holubec, A. A.; Priestley, E. S.; Zhang, X.; Treuner, U. D.
PCT Int. Appl. WO 2004/072101, 2004. (g) Walter, R.;
Heckel, A.; Roth, G. J.; Kley, J.; Schnapp, G.; Lenter, M.;
Van Meel, J. C. A.; Spevak, W.; Weyer-Czernilofsky, U.
PCT Int. Appl. WO 2002/36564, 2002. (h) Zhu, H. Y.;
Njoroge, F. G.; Cooper, A. B.; Guzi, T.; Dinanath, F. R.;
Minor, K. P.; Doll, R. J.; Girijavallabhan, V. M.; Santhanam,
B.; Pinto, P. A.; Vibulbhan, B.; Keertikar, K. M.;
In summary, we have described a convenient and efficient
methodology for the synthesis of cyclopropylsulfonamide
8 and 1-substituted cyclopropylsulfonamides 6 that takes
advantage of two N-protecting moieties. The three-step
procedure using readily available starting materials is
convenient and readily conducted on large scale and al-
Synlett 2006, No. 5, 725–728 © Thieme Stuttgart · New York

LETTER
1-Substituted Cyclopropylsulfonamides
727
Table 1 Synthesis of a-Substituted Cyclopropylsulfonamides 5 and 6
1 O
O
S
R
R1
R
S
N
NH2
H
O
O
Entry
1
Electrophile
CH3I
5a
Yield (%)b
6a
Yield (%)b
R = t-Bu; R1 = CH3
81
R1 = CH3
96
90
69
99
65
2
n-C4H9I
R = t-Boc; R1 = n-C4H9
89
R1 = n-C4H9
3
i-PrI
R = t-Boc; R1 = i-Pr
69c
55c
92
R1 = i-Pr
4
c-C4H7CH2I
c-C3H5CH2I
CH3OCH2Cl
i-PrOCH2Br
CH3OCH2CH2Br
PhCH2OCH2CH2Br
PhCH2Br
R = t-Boc; R1 = CH2(c-C4H7)
R = t-Boc; R1 = CH2(c-C3H5)
R = t-Boc; R1 = CH2OCH3
R = t-Boc; R1 = CH2Oi-Pr
R = t-Boc; R1 = CH2CH2OCH3
R = t-Boc; R1 = CH2CH2OCH2Ph
R = t-Bu; R1 = CH2Ph
R1 = CH2(c-C4H7)
R1 = CH2(c-C3H5)
R1 = CH2OCH3
5
6
77 (2 steps)
7
79
96
47
69
78
R1 = CH2Oi-Pr
98
8
R1 = CH2CH2OCH3
R1 = CH2CH2OCH2Ph
R1 = CH2Ph
45
9
85
10
11
12
13
14
15
16
17
18
66
4-CH3OC6H4CH2Cl
4-FC6H4CH2Br
2-FC6H4CH2Cl
CH2=CHCH2Br
C2H5CvCCH2Br
CH3CH2CHO
PhCHO
R = t-Boc; R1 = CH2(4-CH3OC6H4)
R = t-Boc; R1 = CH2(4-FC6H4)
R = t-Boc; R1 = CH2(2-FC6H4)
R = t-Bu; R1 = CH2CH=CH2
R = t-Bu; R1 = CH2C≡CC2H5
R = t-Bu; R1 = CH(OH)CH2CH3
R = t-Bu; R1 = CH(OH)Ph
R1 = CH2(4-CH3OC6H4)
R1 = CH2(4-FC6H4)
R1 = CH2(2-FC6H4)
R1 = CH2CH=CH2
R1 = CH2C≡CC2H5
R1 = CH(OH)CH2CH3
R1 = CH(OH)Ph
R1 = 1-Cyclohexenyl
89
25 (2 steps)
36 (2 steps)
74
97
79
61
78
84
100
47
68d
85
Cyclohexanone
R = t-Bu; R1 =
OH
19
20
21
22
23
24
25
Acetone
R = t-Boc; R1 = C(OH)(CH3)2
R = t-Bu; R1 = COPh
49
66
2-Isopropenyl
R1 = COPh
94
87
75
50
73
PhCO2CH3
PhN=C=O
n-C3H7N=C=O
(CH3)3SiCl
R = t-Bu; R1 = CONHPh
R = t-Boc; R1 = CONHn-C3H7
R = t-Bu; R1 = Si(CH3)3
57
R1 = CONHPh
R1 = CONHn-C3H7
R1 = Si(CH3)3
R1 = Cl
100
99
N-Chlorosuccinimide R = t-Boc; R1 = Cl
I2
R = t-Boc; R1 = I
67
100
78 (2 steps)
R1 = I
a All products were characterized by 1H NMR, 13C NMR, elemental analysis or HRMS.
b All yields are unoptimized and isolated yields are after purification by crystallization or column chromatography.
c LDA used as the base.
d PTSA monohydrate was used to remove the tert-butyl group.
Synlett 2006, No. 5, 725–728 © Thieme Stuttgart · New York

728
J. Li et al.
LETTER
the reaction mixture was allowed to warm to r.t. over a
Alvarez, C. S.; Baldwin, J. J.; Li, G.; Huang, C.-Y.; James,
R. A.; Bishop, W. R.; Wang, J. J.-S.; Desai, J. A. US Patent
Appl. 2004/122018, 2004. (i) Allen, D. G.; Coe, D. M.;
Cook, C. M.; Cooper, A. W. J.; Dowle, M. D.; Edlin, C. D.;
Hamblin, J. N.; Johnson, M. R.; Jones, P. S.; Lindvall, M. K.;
Mitchell, C. J.; Redgrave, A. J. PCT Int. Appl. WO 2004/
056823, 2004. (j) Breitfelder, S.; Cirillo, P. F.; Regan, J. R.
PCT Int. Appl. WO 2002/083642, 2002. (k) Brendel, J.;
Pirard, B.; Peukert, S.; Kleemann, H.-W.; Hemmerle, H.
PCT Int. Appl. WO 2002/088073, 2002.
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): d = 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):
d = 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): d = 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): d = 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.
(13) 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): d = 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): d = 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.
(2) (a) Truce, W. E.; Goralski, C. T. J. Org. Chem. 1968, 33,
3849. (b) 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.
(3) (a) Christensen, L. W.; Seaman, J. M.; Truce, W. E. J. Org.
Chem. 1973, 38, 2243. (b) Makosza, M.; Golinski, J.;
Ostrowski, S.; Rykowski, A.; Sahasrabudhe, A. B. Chem.
Ber. 1991, 124, 577.
(4) (a) Kosinski, S.; Wojciechowski, K. Eur. J. Org. Chem.
2000, 1263. (b) Meyle, E.; Schwenkkraus, P.; Zsigmondy,
M.; Otto, H.-H. Arch. Pharm. 1989, 322, 17.
(5) (a) Truce, W. E.; Goralski, C. T. J. Org. Chem. 1969, 34,
3324. (b) Neale, R. S.; Marcus, N. L. J. Org. Chem. 1969,
34, 1808.
(6) (a) Block, E.; Schwan, A.; Dixon, D. A. J. Am. Chem. Soc.
1992, 114, 3492. (b) King, J. F.; Lam, J. Y. L.; Ferrazzi, G.
J. Org. Chem. 1993, 58, 1128.
(7) Thompson, M. E. J. Org. Chem. 1984, 49, 1700.
(8) Neustadt, B. R. Tetrahedron Lett. 1994, 35, 379.
(9) Campbell, J. A.; Hart, D. J. J. Org. Chem. 1993, 58, 2900.
(10) (a) Rawal, V. H.; Cava, M. P. Tetrahedron Lett. 1985, 26,
6141. (b) Reuter, D. C.; McIntosh, J. E.; Guinn, A. C.;
Madera, A. M. Synthesis 2003, 2321.
(11) White, E. H.; Lim, H. M. J. Org. Chem. 1987, 52, 2162.
(12) 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): d = 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): d = 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.
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): d = 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): d =
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.
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
(14) For procedures on synthesis of 3a,c, 4b, 5b and removal of
t-Boc group, see: Campbell, J. A.; D’Andrea, S.; Good, A.;
Li, J.; McPhee, F.; Ripka, A.; Scola, P. M.; Tu, Y. US Patent
Appl. 2004/0077551, 2004.
Synlett 2006, No. 5, 725–728 © Thieme Stuttgart · New York