Microwave-assisted synthesis of sodium sulfonates precursors of sulfonyl chlorides and fluorides

Article abstract of DOI:10.1016/j.tetlet.2009.09.167

We describe the use of a microwave reaction for the conversion of various bromides to sodium sulfonates that have been further elaborated to sulfonyl chlorides. This new approach leads to much improved yields and shorter reaction times. Representative sul

Full text of DOI:10.1016/j.tetlet.2009.09.167

Tetrahedron Letters 50 (2009) 7028–7031
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted synthesis of sodium sulfonates precursors of sulfonyl
chlorides and fluorides
*
Shakiru O. Alapafuja, Spyros P. Nikas , Vidyanand G. Shukla, Ioannis Papanastasiou,
*
Alexandros Makriyannis
Center for Drug Discovery, Northeastern University, 116 Mugar Life Sciences Building, 360 Huntington Avenue, Boston, MA 02115, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe the use of a microwave reaction for the conversion of various bromides to sodium sulfonates
that have been further elaborated to sulfonyl chlorides. This new approach leads to much improved
yields and shorter reaction times. Representative sulfonyl chlorides serve as precursors for the respective
sulfonyl fluorides that are potent inhibitors of the fatty acid amide hydrolase.
Received 20 August 2009
Revised 26 September 2009
Accepted 28 September 2009
Available online 2 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Sodium sulfonates
Microwave
Sulfonyl chlorides
Sulfonyl fluorides
1. Introduction
thioacetates, and isothioureas,.). However, many of these proce-
dures involve stepwise oxidation followed by chlorination leading
Sulfonyl chlorides are important intermediates for the synthesis
of a range of organic compounds including industrial and agricul-
tural chemicals. For example, these are used in the preparation of
sulfonic acid amides and esters as well as in the production of her-
bicides, detergents, dyes, elastomers, ion exchange resins, and
pharmaceuticals.1–10
to low yields, and are not convenient and safe due to the use of haz-
ardous and noxious reagents. Recently developed oxidizing agents
such as N-chlorosuccinimide,39,40 as well as the iodosobenzene/
42
HCl41 and the chloro-trimethysilane/KNO3 systems are more
effectivewhen used with aryl and benzyl thiols and thiol derivatives.
Non oxidative approaches for the synthesis of alkyl sulfonyl chlo-
rides involve: (a) formation of Grignard or organolithium reagents
from alkyl halides and subsequent addition to sulfuryl chlo-
ride;18,43,44 and (b) refluxing of bromides with sodium or ammo-
nium sulfite in water45–49 to give the corresponding sulfonates
that upon treatment with a chlorinating agent45–51 (e.g., SOCl2/
DMF, POCl3, PCl5, and cyanuric chloride,.) lead to sulfonyl chlorides.
However, use of organometallic reagents involves tedious proce-
dures and results in poor and at best moderate yields, while conver-
sion of bromides to sulfonates requires refluxing for many hours.
While seeking to improve the method which employs sodium
sulfite in refluxing water,45–47,49 we found that use of microwave
irradiation remarkably decreases the time required for the conver-
sion of bromides to sodium sulfonates and enhances the yield of
the respective sulfonyl chlorides. Optimal conditions involve
microwave heating (160 °C) of bromide and sodium sulfite in a
mixture of THF/EtOH/H2O for 15 min. We report here details of this
work and include the synthesis of the hitherto unknown sulfonyl
fluorides 9b, 9m, and 9n (Scheme 2). A full structure–activity
relationship (SAR) study for all sulfonyl fluorides synthesized11,12
as FAAH inhibitors will be reported elsewhere.
In the course of our program aiming at developing potent and
selective inhibitors for the endocannabinoid deactivating en-
zymes,11–17 we were faced with the synthesis of substituted and
unsubstituted phenylalkyl and phenoxyalkyl sulfonyl chlorides
(Scheme 1) that serve as precursors for the respective sulfonyl flu-
orides. In general, sulfonyl fluorides (e.g., AM 374,14 3, Fig. 1) are
capable of inhibiting12–14,18 fatty acid amide hydrolase (FAAH),19–
21
an intracellular membrane-bound enzyme that degrades and
inactivates bioactive lipid amides including the endocannabinoid
anandamide22 (1a, Fig. 1) and the sleep-inducing agent oleamide23
(2a, Fig. 1). Some sulfonyl fluorides act as FAAH inhibitors and ex-
hibit therapeutic potential for the treatment of pain, inflammation,
cancer, anxiety, and sleep disorders.24–26
A general approach for the preparation of sulfonyl chlorides in-
volves oxidative chlorination of the precursor sulfur deriva-
tives9,27–38 (e.g., thiols, sulfides, thiocyanates, thiocarbamates,
* Corresponding authors. Tel.: +1 617 373 4200; fax: +1 617 373 7493 (A.M.).
E-mail addresses: spyridonnikas@yahoo.com (S.P. Nikas), a.makriyannis@neu.
edu (A. Makriyannis).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.167

S. O. Alapafuja et al. / Tetrahedron Letters 50 (2009) 7028–7031
7029
a
b
R
Br
R
SO2Cl
R
SO3Na
3
4
5
a: R =
BnO
(CH2)4
b: R =
c: R =
O
(CH2)4
(CH2)3
,
,
,
d
h
e
f
: R =
,
g
: R =
,
: R =
: R =
: R =
,
(CH2)4
(CH2)8
(CH2)5
(CH2)6
(CH2)7
,
i
j
k
,
: R =
: R =
: R =
BnO
(CH2)7
,
(CH2)7
(CH2)7
OBn
,
,
BnO
,
l: R =
m: R =
n: R =
BnO
O
(CH2)4
O
(CH2)4
O (CH2)4
,
,
Cl
o: R =
r: R =
p: R =
q: R =
F
O
(CH2)4
MeO
O
(CH2)6
( )3
,
,
,
MeO
s: R =
(CH2)2
,
,
O
a
b
Br
Br
NaO3S
SO3Na
ClO2S
SO2Cl
7
8
6
Scheme 1. Reagents and conditions: (a) Na2SO3, THF/EtOH/H2O (1:2:2), MW, 160 °C, 15 min; (b) SOCl2, benzene/DMF, 50 °C, 3 h, 44–65% from 3.
O
a
R
SO2Cl
R
SO2F
OH
N
H
5
9
Anandamide (1a)
O
b: R =
NH2
O
(CH2)4
(CH2)4
Oleamide (2a)
m: R =
O
O
FAAH
O
Cl
OH
n: R =
(CH2)4
Arachidonic acid (1b)
Oleic acid (2b)
O
OH
Scheme 2. Reagents and conditions: (a) NH4F, acetone, reflux, 2 h, 90–92%.
benzyloxyphenyl)butane (3a) was synthesized in five steps from
4-phenoxybutyl bromide and 4-anisaldehyde following our dis-
closed procedures.12
SO2F
Bromides 3a and 3b were heated with sodium sulfite using
reaction conditions shown in Table 1, and the crude sodium sulfo-
nates 4a and 4b were treated with thionyl chloride in the presence
of catalytic amounts of DMF, under standard conditions,12,46,49 to
give the respective sulfonyl chlorides 5a and 5b. As seen in Table
1, heating of 3a and sodium sulfite in refluxing water for 36 h led
to sulfonyl chloride 5a in 18% isolated yield (entry 1). The yield
of this conversion was improved significantly (37%) and the heat-
ing time was reduced to 24 h when the solvent was changed to a
mixture of EtOH/H2O (2:1 ratio, entry 2). Replacement of the con-
ventional heating method with microwave irradiation resulted in
improved yield for sulfonyl chloride 5a (41%) while the reaction
time was remarkably reduced to 10 min (entry 3). Further
improvement in the yield of 5a (47–50%) was accomplished by
AM 374 (3)
Figure 1. Substrates (1a, 2a) and inhibitor (3) of fatty acid amide hydrolase (FAAH).
2. Results and discussion
In order to identify optimal reaction conditions for the conver-
sion of substituted and unsubstituted phenylalkyl and pheno-
xyalkyl bromides 3a–3p to the respective sodium sulfonates 4a–
4p (Scheme 1) we have chosen 3a and 3b as representative starting
materials for a screening process where a number of reaction con-
ditions were explored (Table 1). The required 4-phenoxybutyl bro-
mide (3b) was commercially available while 4-bromo-1-(4-

7030
S. O. Alapafuja et al. / Tetrahedron Letters 50 (2009) 7028–7031
Table 1
Reaction conditions for the conversion of bromides 3a and 3b to sodium sulfonates 4a and 4b and yields of the final products sulfonyl chloridesa 5a and 5b, respectively
Entry
Bromide
Product sulfonyl
chloride
Solvent (equiv
of Na2SO3)
Heating (temp.)
Time of heating for the conversion
of bromides to sodium sulfonates
Yieldb of sulfonyl
chloride (%)
1
2
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
H2O
(1.4)
EtOH/H2O = 2:1
(1.4)
EtOH/H2O = 2:1
(1.4)
THF/EtOH/H2O = 1:2:2
(1.4)
THF/EtOH/H2O = 1:2:2
(1.4)
THF/EtOH/H2O = 1:2:2
(1.4)
EtOH/H2O = 2:1
(1.4)
EtOH/H2O = 2:1
(1.4)
EtOH/H2O = 2:1
(1.6)
THF/EtOH/H2O = 1:2:2
(1.6)
CHc
36 h
18
37
41
47
50
48
58
61
62
65
(reflux)
CHc
24 h
(reflux)
MWd
3
10 min
10 min
15 min
20 min
24 h
(120 °C)
4
MWd
(120 °C)
MWd
5
(160 °C)
6
MWd
(160 °C)
CHc
7
(reflux)
8
MWd
10 min
15 min
15 min
(150 °C)
MWd
9
(160 °C)
10
MWd
(160 °C)
a
b
c
Sulfonyl chlorides were produced from the intermediate sodium sulfonates 4a and 4b using standard conditions (Scheme 1).12
Isolated yields of spectroscopically pure compounds.
CH = conventional heating inside a thermostated oil bath under magnetic stirring.
d
MW = microwave irradiation using a CEM Discover microwave devise in closed vessels and under magnetic stirring.
Table 2
microwave heating at 160 °C for 15 min using a mixture of THF/
EtOH/H2O (1:2:2 ratio) as the reaction solvent (entries 4–6).
Similar trends were observed in the conversion of 4-pheno-
xybutyl bromide (3b) to the respective sulfonyl chloride 5b (Table
1). Conventional heating for 24 h is required to produce 5b in 58%
yield, while microwave irradiation for 15 min using 1.6 equiv of so-
dium sulfite, led to 62% yield for 5b (entries 7–9). Again, use of a
mixture of THF/EtOH/H2O (1:2:2 ratio) as the reaction solvent, en-
hances the yield of the two step procedure (entry 10). In summary,
optimal reaction conditions for the conversion of bromides 3a and
3b to the respective sodium sulfonates 4a and 4b (Scheme 1) in-
volve microwave irradiation (160 °C) of 3a or 3b and 1.6 equiv of
sodium sulfite in a mixture of THF/EtOH/H2O (1:2:2 ratio).
With these results in hand, the scope of our microwave ap-
proach was explored with a variety of substituted and unsubstitut-
ed phenylalkyl and phenoxyalkyl bromides as well as with alkyl,
alkenyl, and substituted alkyl bromides52 (Scheme 1 and Table
2). The required starting materials 3c–3h, 3m–3s, and 6 were com-
mercially available while bromides 3i, 3j, and 3k were synthesized
in five steps from 6-phenoxyhexyl bromide and 4- or 3- or 2-anis-
aldehyde following our previously disclosed procedures.12 Starting
bromide 3l was prepared by etherification12 of commercially avail-
able 4-hydroxyphenol with 1,4-dibromobutane.
Examples of synthesized sulfonyl chlorides using the microwave-assisted approacha
Entry
Bromide
Sulfonyl chloride
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
3a
3b
3c
3d
3e
3f
3g
3h
3i
5a
5b
5c
5d
5e
5f
5g
5h
5i
50
65
61
65
65
63
60
61
52
51
50
51
63
65
52
53
55
57
51
44
3j
3k
3l
5j
5k
5l
3m
3n
3o
3p
3q
3r
3s
6
5m
5n
5o
5p
5q
5r
5s
8
a
Reagents and conditions: (a) Na2SO3, THF/EtOH/H2O (1:2:2), MW, 160 °C,
15 min; (b) SOCl2, benzene/DMF, 50 °C, 3 h.
b
Isolated yields of spectroscopically pure compounds.
We have previously synthesized phenylalkyl sulfonyl chlorides
5c–5h (Scheme 1) from the respective iodides using a low temper-
ature lithium–iodine exchange53 and treatment of the resulting
organolithium reagent with sulfuryl chloride.12 This approach gave
5c–5h in only 19–23% yields12 while following our optimized
microwave-assisted method the yield was increased to 60–65%
(Table 2, entries 3–8). In addition, the benzyloxy-substituted phe-
nylheptyl sulfonyl chlorides 5i–5k (Scheme 1) were previously
synthesized by us in 38–40% yields using conventional heating
for 24 h,12 whereas microwave irradiation for 15 min increased
the yields to 50–52% (Table 2, entries 9–11). In a similar fashion,
sulfonyl chlorides 5l–5s and the 1,5-disulfonyl chloride 8 were
synthesized in 44–65% yield (Table 2, entries 12–20). Treatment
of 5b, 5m, and 5n with ammonium fluoride in refluxing acetone
gave the respective sulfonyl fluorides 9b, 9m, and 9n in 90–92%
yield54 (Scheme 2).
3. Conclusion
In summary, we found that the use of microwave irradiation
remarkably decreases the time required for the conversion of bro-
mides to sodium sulfonates and enhances the yield of the respec-
tive sulfonyl chlorides. Representatives of the latter serve as
precursors for the corresponding sulfonyl fluorides that are potent
inhibitors of the fatty acid amide hydrolase.
Acknowledgments
This work was supported by grants from the National Institute on
Drug Abuse, PO1-DA009158, R37-DA003801, and RO1-DA007215.

S. O. Alapafuja et al. / Tetrahedron Letters 50 (2009) 7028–7031
7031
heated for 15 min at 160 °C under microwave irradiation (300 W) using a CEM
Discover system. The reaction mixture was cooled to room temperature and
volatiles were removed under reduced pressure. The residue was scrupulously
dried under high vacuo and the crude product 4, (a pale yellow solid) was used
in the next step without further purification.
Sulfonyl chlorides (5). To a stirred suspension of sulfonate 4 in anhydrous
benzene (7 mL)/DMF (0.1 ml), was added thionyl chloride (2.6 mmol) and the
mixture was heated at 50 °C for 3 h under argon. The reaction was quenched by
dropwise addition of water at room temperature and extracted with diethyl
ether. The organic layer was washed with brine, dried (MgSO4), and the solvent
was evaporated under reduced pressure. Purification by flash column
References and notes
1. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Chemistry, 3rd ed.;
Wiley-Interscience: New York, 1999.
2. Kociensky, P. J. Protecting Groups; Thieme: New York, 1994.
3. Levitt, G. In Synthesis and Chemistry of Agrochemicals II; Baker, D. R., Fenyes, J. G.,
Moberg, W. K., Eds.; American Chemical Society: Washington, DC, 1991; pp 16–
31.
4. Theodoridis, G. Tetrahedron 2000, 56, 2339.
5. Moore, J. D.; Herpel, R. H.; Lichtsinn, J. R.; Flynn, D. L.; Hanson, P. R. Org. Lett.
2003, 5, 105.
6. Blotny, G.; Biernat, J. F.; Taschner, E. Liebigs Ann. Chem. 1963, 663, 195.
7. Dubbaka, S. R.; Vogel, P. J. Am. Chem. Soc. 2003, 125, 15292.
8. Brewster, J. H.; Ciotti, C. J. J. Am. Chem. Soc. 1955, 77, 6214.
9. Kvrn, L.; Werder, M.; Hauser, H.; Carreira, E. M. Org. Lett. 2005, 7, 1145.
10. Lassalle, G.; Galtier, D.; Galli, F. Application: EU 643047 A1, 1995, p 12.
11. Makriyannis, A.; Nikas, S. P.; Alapafuja, S. O.; Shukla, V. G. Application: WO
2009052319 A1, Northeastern University: USA, 2009, p 209.
12. Makriyannis, A.; Nikas, S. P.; Alapafuja, S. O.; Shukla, V. G. Application: WO
2008013963 A2, University of Connecticut: USA, 2008, p 123.
13. Makriyannis, A.; Lin, S.; Hill, W. A. Application: WO 97/45407, University of
Connecticut: USA, 1997, p 34.
chromatography on silica gel (diethyl ether in hexane) gave
shown on Table 2.
5 in yields
Selected data of synthesized sulfonyl chlorides: 4-phenoxybutanesulfonyl
chloride (5b). IR (neat) 2935, 1513, 1371 (s), 1164 (s); 1H NMR (500 MHz,
CDCl3) d 7.29 (t, J = 8.2 Hz, 2H, 3-H, 5-H, –OPh), 6.97 (t, J = 8.2 Hz, 1H, 4-H, –
OPh), 6.89 (d, J = 8.2 Hz, 2H, 2-H, 6-H, –OPh), 4.04 (t, J = 5.7 Hz, 2H, –CH2–OPh),
3.80 (m as t, J = 8.0 Hz, half of an AA‘XX’ system, 2H, –CH2SO2Cl), 2.29 (m as qt,
J = 7.0 Hz, 2H, –CH2CH2SO2Cl), 2.01 (qt, J = 6.0 Hz, 2H, –CH2CH2CH2SO2Cl);
mass spectrum m/z (relative intensity) 250 (M++2, 7), 248 (M+, 21), 155 (16),
107 (22), 94 (100), 77 (21), 65 (15); exact mass calcd for C10H13ClO3S,
248.0274; found, 248.0276.
4-(2-Chlorophenoxy)butanesulfonyl chloride (5m). IR (neat) 2927, 1512, 1371 (s),
1163 (s); 1H NMR (500 MHz, CDCl3) d 7.39 (dd, J = 8.0 Hz, J = 1.5 Hz, 1H, 3-H, –
O–Ph–Cl), 7.24 (td, J = 8.0 Hz, J = 1.5 Hz, 1H, 5-H, –O–Ph–Cl), 6.94 (td, J = 8.0 Hz,
J = 1.5 Hz, 1H, 4-H, –O–Ph–Cl), 6.93 (dd, J = 8.0 Hz, J = 1.5 Hz, 1H, 6-H, –O–Ph–
Cl), 4.13 (t, J = 5.8 Hz, 2H, –CH2–O–Ph–Cl), 3.95 (m as t, J = 7.3 Hz, half of an
AA‘XX’ system, 2H, –CH2SO2Cl), 2.35 (m as qt, J = 7.5 Hz, 2H, –CH2CH2SO2Cl),
2.10 (qt, J = 6.0 Hz, 2H, –CH2CH2CH2SO2Cl); mass spectrum m/z (relative
intensity) 286 (M++4, 2), 284 (M++2, 13), 282 (M+, 19), 183 (5), 155 (31), 141
(15), 128 (100), 111 (6), 99 (7), 83 (8); exact mass calcd for C10H12Cl2O3S,
281.9884; found, 281.9887.
4-(3-Methylphenoxy)butanesulfonyl chloride (5n). IR (neat) 2943, 1513, 1372 (s),
1164 (s); 1H NMR (500 MHz, CDCl3) d 7.19 (t, J = 7.5 Hz, 1H, 5-H, –O–Ph–Me),
6.81 (d, J = 7.5 Hz, 1H, 4-H, –O–Ph–Me), 6.73 (s, 1H, 2-H, –O–Ph–Me), 6.71 (d,
J = 7.5 Hz, 1H, 6-H, –O–Ph–Me), 4.04 (t, J = 5.5 Hz, 2H, –CH2–O–Ph–Me), 3.81
(m as t, J = 7.3 Hz, half of an AA‘XX’ system, 2H, –CH2SO2Cl), 2.35 (s, 3H, –Me),
14. Deutsch, D. G.; Lin, S.; Hill, W. A. G.; Morse, K. L.; Salehani, D.; Arreaza, G.;
Omeir, R. L.; Makriyannis, A. Biochem. Biophys. Res. Commun. 1997, 231, 217.
15. Gifford, A. N.; Magalie, B.; Lin, S.; Goutopoulos, A.; Makriyannis, A.; Volkow, N.
D.; Gatley, J. S. Eur. J. Pharmacol. 1999, 383, 9.
16. Zvonok, N.; Pandarinathan, L.; Williams, J.; Johnston, M.; Karageorgos, I.;
Janero, D. R.; Krishnan, S. C.; Makriyannis, A. Chem. Biol. (Cambridge, MA, United
States) 2008, 15, 854.
17. Karanian, D. A.; Karim, S. L.; Wood, J.-A. T.; Williams, J. S.; Lin, S.; Makriyannis,
A.; Bahr, B. A. J. Pharmacol. Exp. Ther. 2007, 322, 1059.
18. Segall, Y.; Quistad, G. B.; Nomura, D. K.; Casida, J. E. Bioorg. Med. Chem. Lett.
2003, 13, 3301.
19. Cravatt, B. F.; Giang, D. K.; Mayfield, S. P.; Boger, D. L.; Lerner, R. A.; Gilula, N. B.
Nature 1996, 384, 83.
20. Giang, D. K.; Cravatt, B. F. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 2238.
21. Bracey, M. H.; Hanson, M. A.; Masuda, K. R.; Stevens, R. C.; Cravatt, B. F. Science
2002, 298, 1793.
22. Devane, W. A.; Hanus, L.; Breuer, A.; Pertwee, R. G.; Stevenson, L. A.; Griffin, G.;
Gibson, D.; Mandelbaum, A.; Etinger, A.; Mechoulam, R. Science 1992, 258,
1946.
23. Boger, D. L.; Henriksen, S. J.; Cravatt, B. F. Curr. Pharm. Des. 1998, 4, 303–314.
24. Cravatt, B. F.; Lichtman, A. H. Curr. Opin. Chem. Biol. 2003, 7, 469.
25. Lambert, D. M.; Fowler, C. J. J. Med. Chem. 2005, 48, 5059.
26. Di Marzo, V. Nat. Rev. Drug Disc. 2008, 7, 438.
2.29 (m as qt, J = 7.1 Hz, 2H, –CH2CH2SO2Cl), 2.02 (qt, J = 6.9 Hz, 2H,
–
CH2CH2CH2SO2Cl); mass spectrum m/z (relative intensity) 264 (M++2, 3), 262
(M+, 9), 162 (21), 147 (12), 131 (19), 119 (42), 108 (100), 91 (95), 77 (22), 64
(43); exact mass calcd for C11H15ClO3S, 262.0430; found, 262.0429.
53. Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404.
54. Typical procedure for the conversion of sulfonyl chlorides 5b, 5m, and 5n to
fluorides 9b, 9m, and 9n.
To a stirred solution of sulfonyl chloride 5 (1 equiv) in dry acetone, was added
anhydrous NH4F (2.3 equiv) and the mixture refluxed for 2 h under argon. The
solvent was evaporated under reduced pressure and the residue was dissolved
in diethyl ether. The ethereal solution was washed with water and brine, dried
(MgSO4), and evaporated in vacuo. Purification by flash column
chromatography on silica gel (diethyl ether in hexane) gave sulfonyl fluoride
9 as a white solid in 90–92% yield.
27. Sandler, S. R.; Karo, W.. In Organic Functional Group Preparations; Academic
Press: New York, 1983; Vol. I.
28. Sprague, J. M.; Johnson, T. B. J. Am. Chem. Soc. 1937, 59, 1837.
29. Johnson, T. B. Proc. Natl. Acad. Sci. U.S.A. 1939, 25, 448.
30. Meinzer, A.; Breckel, A.; Thaher, B. A.; Manicone, N.; Otto, H.-H. Helv. Chim. Acta
2004, 87, 90.
4-Phenoxybutanesulfonyl fluoride (9b). IR (neat) 2940, 1513, 1398 (s), 1194 (s);
1H NMR (500 MHz, CDCl3) d 7.30 (td, J = 8.5 Hz, J = 1.0 Hz, 2H, 3-H, 5-H, –OPh),
6.97 (td, J = 8.5 Hz, J = 1.0 Hz, 1H, 4-H, –OPh), 6.89 (dd, J = 8.5 Hz, J = 1.0 Hz, 2H,
2-H, 6-H, –OPh), 4.03 (t, J = 5.6 Hz, 2H, –CH2–OPh), 3.50 (m as dt, J = 11.0 Hz,
J = 4.5 Hz, 2H, –CH2SO2F), 2.20 (m as qt, J = 7.5 Hz, 2H, –CH2CH2SO2F), 2.00 (qt,
J = 7.0 Hz, 2H, –CH2CH2CH2SO2F); 13C NMR (100 MHz, CDCl3) d 158.48, 129.58,
121.11, 114.41, 66.52, 50.65 (d, J = 16.4 Hz, –CH2SO2F), 27.43, 20.91; mass
spectrum m/z (relative intensity) 232 (M+, 25), 139 (9), 107 (6), 94 (100), 77
(13); exact mass calcd for C10H13FO3S, 232.0569; found, 232.0572. Anal. Calcd
(C10H13FO3S): C, 51.71; H, 5.64. Found: C, 52.09; H, 5.75.
4-(2-Chlorophenoxy)butanesulfonyl fluoride (9m). IR (neat) 2929, 1511, 1394 (s),
1197 (s); 1H NMR (500 MHz, CDCl3) d 7.40 (dd, J = 8.0 Hz, J = 1.5 Hz, 1H, 3-H, –
O–Ph–Cl), 7.24 (td, J = 8.0 Hz, J = 1.5 Hz, 1H, 5-H, –O–Ph–Cl), 6.94 (td, J = 8.0 Hz,
J = 1.5 Hz, 1H, 4-H, –O–Ph–Cl), 6.93 (dd, J = 8.0 Hz, J = 1.5 Hz, 1H, 6-H, –O–Ph–
Cl), 4.12 (t, J = 6.0 Hz, 2H, –CH2–O–Ph–Cl), 3.64 (m as dt, J = 11.0 Hz, J = 3.5 Hz,
2H, –CH2SO2F), 2.26 (m as qt, J = 8.0 Hz, 2H, –CH2CH2SO2F), 2.08 (qt, J = 6.0 Hz,
2H, –CH2CH2CH2SO2F); mass spectrum m/z (relative intensity) 268 (M++2, 7),
266 (M+, 21), 238 (9), 196 (10), 149 (12), 139 (14), 128 (100), 99 (6); exact mass
calcd for C10H12FClO3S, 266.0180; found, 266.0178.
31. Piatek, A.; Chapuis, C.; Jurczak, J. Helv. Chim. Acta 2002, 85, 1973.
32. Humljan, J.; Gobec, S. Tetrahedron Lett. 2005, 46, 4069.
33. Monnee, M. C.; Marijne, M. F.; Brouwer, A. J.; Liskamp, R. M. Tetrahedron Lett.
2000, 41, 7991.
34. Schindler, W. Helv. Chim. Acta 1957, 40, 2148.
35. Park, Y. J.; Shin, H. H.; Kim, Y. H. Chem. Lett. 1992, 1483.
36. Langler, R. F. Can. J. Chem. 1976, 54, 498.
37. Langler, R. F.; Marini, Z. A.; Spalding, E. S. Can. J. Chem. 1979, 57, 3193.
38. Douglass, I. B. J. Org. Chem. 1974, 39, 563.
39. Kim, D. W.; Ko, Y. K.; Kim, S. H. Synthesis 1992, 1203.
40. Nishiguchi, A.; Maeda, K.; Miki, S. Synthesis 2006, 4131.
41. Sohmiya, H.; Kimura, T.; Fujita, M.; Ando, T. Tetrahedron 1998, 54, 13737.
42. Prakash, G. K. S.; Mathew, T.; Panja, C.; Olah, G. A. J. Org. Chem. 2007, 72, 5847.
43. Gilbert, E. E. Synthesis 1969, 3.
44. Quast, H.; Kees, F. Synthesis 1974, 489.
45. King, J. F.; Harding, D. R. K. J. Am. Chem. Soc. 1976, 98, 3312.
46. Castang, S.; Chantegrel, B.; Deshayes, C.; Dolmazon, R.; Gouet, P.; Haser, R.;
Reverchon, S.; Nasser, W.; Hugouvieux-Cotte-Pattat, N.; Doutheau, A. Bioorg.
Med. Chem. Lett. 2004, 14, 5145.
47. Johnston, T. P.; Kussner, C. L.; Holum, L. B. J. Org. Chem. 1960, 25, 399.
48. Markgraf, H. J.; Hess, A. B., Jr.; Nichols, C. W.; King, R. W. J. Org. Chem. 1964, 29,
1499.
49. Abramovitch, R. A.; Holcomb, W. D.; Thompson, W. M.; Wake, S. J. Org. Chem.
1984, 49, 5124.
50. Erman, W. F.; Kretschmar, H. C. J. Org. Chem. 1961, 26, 4841.
51. Blotny, G. Tetrahedron Lett. 2003, 44, 1499.
4-(3-Methylphenoxy)butanesulfonyl fluoride (9n). IR (neat) 2954, 1515, 1398
(s), 1192 (s); 1H NMR (500 MHz, CDCl3) d 7.19 (t, J = 7.5 Hz, 1H, 5-H, –O–Ph–
Me), 6.81 (d, J = 7.5 Hz, 1H, 4-H, –O–Ph–Me), 6.73 (s, 1H, 2-H, –O–Ph–Me),
6.71 (d, J = 7.5 Hz, 1H, 6-H, –O–Ph–Me), 4.04 (t, J = 6.0 Hz, 2H, –CH2–O–Ph–
Me), 3.52 (m as dt, J = 11.0 Hz, J = 3.5 Hz, 2H, –CH2SO2F), 2.36 (s, 3H, –Me),
2.21 (m as qt, J = 7.6 Hz, 2H, –CH2CH2SO2F), 2.00 (qt, J = 6.7 Hz, 2H,
–
CH2CH2CH2SO2F); mass spectrum m/z (relative intensity) 246 (M+, 31), 139
(8), 128 (9), 108 (100), 91 (12), 77 (6); exact mass calcd for C11H15FO3S,
246.0726; found, 246.0729.
52. Typical procedure for the conversion of bromides 3 to sulfonyl chlorides 5 via
sodium sulfonates 4.Sulfonic acid sodium salts (4). A mixture of bromide 3
(1 mmol) and Na2SO3 (1.6 mmol) in THF/EtOH/H2O (1:2:2 mixture, 5 mL) was