Alkyl 2,2,2-trifluoroethanesulfonates (tresylates): Elimination-addition vs bimolecular nucleophilic substitution in reactions with nucleophiles in aqueous media

Article abstract of DOI:10.1021/jo9610366

Alkyl 2,2,2-trifluoroethanesulfonate esters (tresylates), ROSO₂CH₂CF₃, react with aqueous base (pH ≥ 9) to give the (alkoxysulfonyl)acetic acid, ROSO₂CH₂COOH; with the further addition of either a primary or secondary amine or of an alkanethiol, the product is the either the corresponding amide, ROSO₂CH₂C(O)NR¹R², or a mixture in which the ketene dithioacetal, ROSO₂CH=C(SR¹)₂, or the thioorthoester, ROSO₂CH₂C(SR¹)₃, may predominate. Kinetic and product studies are consistent with the following: (a) the reaction of tresylates with water is the normal sulfonic ester hydrolysis and (b) reaction with hydroxide is an (E1cB)_rev process with loss of HF to yield the alkyl 2,2-difluoroethenesulfonate, ROSO₂CH=CF₂, which rapidly yields the observed products. Benzyl 2,2,2-trifluoroethyl sulfone reacts analogously. The relationship between these observation with small molecules and those of earlier workers with tresyl agarose is discussed.

Full text of DOI:10.1021/jo9610366

7250
J . Org. Chem. 1996, 61, 7250-7255
Articles
Alk yl 2,2,2-Tr iflu or oeth a n esu lfon a tes (Tr esyla tes):
Elim in a tion -Ad d ition vs Bim olecu la r Nu cleop h ilic Su bstitu tion in
Rea ction s w ith Nu cleop h iles in Aqu eou s Med ia 1
J ames F. King* and Manjinder S. Gill
Department of Chemistry, The University of Western Ontario, London, Ontario, Canada N6A 5B7
Received J une 3, 1996X
Alkyl 2,2,2-trifluoroethanesulfonate esters (tresylates), ROSO2CH2CF3, react with aqueous base
(pH g 9) to give the (alkoxysulfonyl)acetic acid, ROSO2CH2COOH; with the further addition of
either a primary or secondary amine or of an alkanethiol, the product is the either the corresponding
amide, ROSO2CH2C(O)NR1R2, or a mixture in which the ketene dithioacetal, ROSO2CHdC(SR1)2,
or the thioorthoester, ROSO2CH2C(SR1)3, may predominate. Kinetic and product studies are
consistent with the following: (a) the reaction of tresylates with water is the normal sulfonic ester
hydrolysis and (b) reaction with hydroxide is an (E1cB)rev process with loss of HF to yield the alkyl
2,2-difluoroethenesulfonate, ROSO2CHdCF2, which rapidly yields the observed products. Benzyl
2,2,2-trifluoroethyl sulfone reacts analogously. The relationship between these observation with
small molecules and those of earlier workers with tresyl agarose is discussed.
Esters of sulfonic acids have a long history as useful
intermediates enabling the replacement of a hydroxyl
group by a wide array of nucleophiles, as in eq 1. Among
steroid tresylate reacted at room temperature with
tetrabutylammonium fluoride to form the corresponding
mesylate ester, perhaps via the pathway shown in eq 2.
the most extensively used are p-toluenesulfonates (tosy-
lates, R′ ) p-Tol) and methanesulfonates (mesylates, R′
) CH3), and, where high reactivity is a particular
advantage, trifluoromethanesulfonates (triflates, R′ )
CF3). In 1971 Crossland, Wells, and Shiner3 introduced
2,2,2-trifluoroethanesulfonates (tresylates, R′ ) CF3CH2)
as “an easily synthesized reactive new leaving group”
typically 100 times more reactive than tosylates and 400
times less reactive than triflates in solvolytic reactions.
Tresylates have found use in solvolytic studies4 and to a
limited extent in SN2 reactions with nucleophiles such
as azide,5 thiourea,5 or thiolate anion.6
More recently still, J ennissen and co-workers8 showed
that some products derived from treatment of agarose
with tresyl chloride followed by reaction with a nucleo-
phile could not have structures of the kind proposed by
their original discoverers.9 Rather than the simple SN2
displacement products suggested by Nilsson and Mos-
bach9 (see eqs 3 and 4), J ennissen and co-workers8
Relatively recently evidence has emerged suggesting
that tresylates do not always react simply by the familiar
C-O cleavage process associated with sulfonic esters. In
1993 Choe and Katzenellenbogen7a reported that a
X Abstract published in Advance ACS Abstracts, September 15, 1996.
(1) Organic Sulfur Mechanisms. 40. For part 39, see ref 2. Presented
in part at the 78th Canadian Society for Chemistry Conference,
Guelph, Ontario, May 1995.
(2) King, J . F.; Guo, Z. R.; Lock, J . D. Phosphorus Sulfur Silicon
1994, 97, 191-197.
(3) Crossland, R. K.; Wells, W. E.; Shiner, V. J ., J r. J . Am. Chem.
Soc. 1971, 93, 4217-4219.
proposed a displacement at sulfur with cleavage of the
S-C bond (eqs 5-7).
(4) See, for example: Shiner, V. J ., J r.; Fisher, R. D. J . Am. Chem.
Soc. 1971, 93, 2553-2554. Shiner, V. J ., J r.; Seib, R. C. J . Am. Chem.
Soc. 1976, 98, 862-864. McDonald, R. N.; Curi, C. A. J . Am. Chem.
Soc. 1979, 101, 7116-7118.
(5) King, J . F.; Loosmore, S. M.; Aslam, M.; Lock, J . D.; McGarrity,
M. J . J . Am. Chem. Soc. 1982, 104, 7108-7122.
(6) McManus, S. P.; Karaman, R. M.; Sedaghat-Herati, R.; Hovanes,
B. A.; Ding, X.-T.; Harris, J . M. J . Org. Chem. 1993, 58, 6466-6469.
(7) (a) Choe, Y. S.; Katzenellenbogen, J . A. Tetrahedron Lett. 1993,
34, 1579-1580. (b) Golding, B. T.; Griffin, A. L.; Robinson, D. H.
Tetrahedron Lett. 1993, 34, 6459-6462.
(8) Demiroglou, A.; Bandel-Schlesselmann, C.; J ennissen, H. P.
Angew. Chem., Int. Ed. Engl. 1994, 33, 120-123.
(9) Nilsson, K.; Mosbach, K. Biochem. Biophys. Res. Commun. 1981,
102, 449-457.
S0022-3263(96)01036-5 CCC: $12.00 © 1996 American Chemical Society

Alkyl 2,2,2-Trifluoroethanesulfonates
J . Org. Chem., Vol. 61, No. 21, 1996 7251
Sch em e 1a
neopentyl mesylate (4a ) on refluxing with aqueous base
and (b) its synthesis by partial hydrolysis of dineopentyl
sulfoacetate (6a ) which was in turn prepared from
(chlorosulfonyl)acetyl chloride and neopentyl alcohol.14
Also shown in Scheme 1 are the reactions of 1a with
butylamine to give 3a (R1 ) Bu, R2 ) H), and with
diethylamine to form the corresponding diethylamide (3a ,
R1 ) R2 ) Et) in 30% and 80% yields, respectively. The
structures follow from spectra and their syntheses from
2a via the acid chloride (5a ). These results and those
recently reported by Gais and Ruppert13 are in complete
accord.
Shown in Scheme 2 are the reactions of 1 with sodium
hydroxide with added phenylmethanethiol. With equimo-
lar amounts of 1a and thiol, a 3:4:3:1 mixture of 2a , the
stereoisomeric fluoro monosulfides (7a), the ketene dithio-
acetal (8a ), and the benzyl thioester (9a ) was obtained;
with a 3-fold excess of the thiol the product was entirely
8a (80% yield). The structure of 8a is assigned from
spectra, mode of synthesis, and its conversion into a
mixture of 4a and 1,1,2-tris((phenylmethyl)thio)ethene
(11), on refluxing with 4.5 M NaOH in H2O:dioxane for
39 h.15 The trisulfide (11) was synthesized independently
from phenylmethanethiol, sodium ethoxide, and trichlo-
roethene, following the general procedure of Truce and
Kassinger.16 The structures of the fluoro sulfides (7a )
followed also from their spectra, mode of synthesis, and
further reactions; the latter included (a) conversion of one
isomer to 8a with aqueous sodium hydroxide and phen-
ylmethanethiol under mild conditions and (b) transfor-
mation of the other isomer slowly with aqueous NaOH
into a mixture of 2a and 8a containing a small amount
of the thioester (9a ). The geometry of the fluoro sulfides
(7a ) was deduced from the hydrogen-fluorine coupling
constants; that with the 28.6 Hz coupling was assigned
the trans H-F arrangement as in E-7a , and the isomer
with the 16.5 Hz coupling the cis H-F geometry as in
Z-7a . The thioester (9a ) was not isolated in pure form
from either of the reaction products above; its presence
in the mixture was deduced from the observation of
a
(a ) R ) Me3CCH2; (b) R ) Me2CHCH2; (c) R ) Et; (d ) R )
Me(CH2)7.
The suggested reactions of J ennissen and co-workers,
however, have no parallel that we are aware of in the
chemistry of sulfonic esters, nor there is any known or
readily imagined mechanism that would satisfactorily
account for the formation of acetic acid and sulfuric,
thiosulfuric, or sulfamic esters under these conditions.
It therefore seemed to us that another reaction pathway
would be much more likely. In our view such a route
might be an elimination-addition process following the
pattern demonstrated initially for substitution â to a
sulfonyl group by Stirling and co-workers10 and closely
related to that suggested for the reactions of tresylates
with fluoride or acetate7 ions, and also for transforma-
tions observed by Eleev, Sokol’skii, and Knunyants with
tresyl fluoride.11 To obtain information on the matter,
we have carried out a study of the reactions of some
simple alkyl tresylates with aqueous sodium hydroxide
in the presence of some simple amines and thiols, and
now report our results. A preliminary report describing
some of these experiments has appeared;12 essentially the
same conclusion for the reaction of butylamine in a
related model system has been independently reported
by Gais and Ruppert.13
1
characteristic H NMR signals at δ 3.90, 4.22, and 4.25
found with an authentic 9a prepared from the acid
chloride (6a ) and phenylmethanethiol. Interestingly,
treatment of a sample of 9a under conditions comparable
to those that yield 8a and 10a led only to partial (10%)
hydrolysis to 2a , with most (90%) of the 9a recovered
unchanged.
Resu lts a n d Discu ssion
Replacement of the neopentyl group in 1a with other
alkyl groups (1b-1d ) led to relatively small changes in
the reactions in Schemes 1 and 2. With isobutyl tresylate
(1b) the reaction with 3 equivs of phenylmethanethiol
(and reaction time of 40 min) gave principally the ketene
dithioacetal (8b) along with a smaller amount of the
thioorthoester (10b) (ratio 4:1). With 7 equivs of thiol
(reaction time 260 min) or 20 equivs (reaction time 75
min) the thioorthoester was the major product (3:1 ratio
of 10b to 8b). The formation of 8a from 1a without any
sign of any 10a would appear to arise at least partly from
the low solubility of 8a which leads to its spontaneous
precipitation from the reaction mixture. This does not
occur with the isobutyl and ethyl esters, and the corre-
Rea ction s a n d P r od u cts. Neopentyl tresylate (1a )
was chosen as the substrate for our first experiments,
because it would be expected to show minimal rates of
simple alkyl transfer resulting from attack of nucleo-
philes with C-O cleavage, while at the same time being
well setup to undergo reactions at the trifluoroethyl
group. The reactions of 1a and other esters with hy-
droxide and amines are summarized in Scheme 1. With
0.5 M NaOH in 1:1 H2O-dioxane 1a gave ((neopentyl-
oxy)sulfonyl)acetic acid (2a ) in 90% yield. The structure
of 2a follows from (a) its conversion (in 60% yield) to
(10) Stirling, C. J . M. Chem. Ind. (London) 1960, 933. Kader, A. T.;
Stirling, C. J . M. J . Chem. Soc. 1962, 3686-3692 and later papers in
this series.
(14) Cf. R. Vieillefosse, Bull. Soc.Chim. Fr. 1947, 351-356.
(15) The survival under these conditions of (a considerable portion
of) the neopentyl mesylate (4a ) formed emphasizes the slowness of the
SN2 reactions of neopentyl sulfonic esters.
(16) Truce, W. E.; Kassinger, R. J . Am. Chem. Soc. 1958, 80, 1916-
1919.
(11) Eleev, A. F.; Sokol’skii, G. A.; Knunyants, I. L. Izv. Akad. Nauk
SSSR Ser. Khim. 1978, 2084-2090 (Engl. Transl. 1837-1842).
(12) King, J . F.; Gill, M. S. Angew. Chem., Int. Ed. Engl. 1995, 34,
1612-1613.
(13) Gais, H.-J .; Ruppert, S. Tetrahedron Lett. 1995, 36, 3837-3838.

7252 J . Org. Chem., Vol. 61, No. 21, 1996
King and Gill
Sch em e 2a
a
(a ) R ) Me3CCH2; (b) R ) Me2CHCH2; (c) R ) Et; (d ) R ) Me(CH2)7.
arises more from reaction of the thiolate anion with 8d
and (or) 10d than with 1d .
Ra te Stu d ies. The pH-rate profile of the hydrolysis
of 1c was obtained by the pH-stat method and is shown
in Figure 1 (circles); this yields the rate law kobs ) kw
+
1
k
OH[OH-]. The H NMR spectrum of the products of the
deuterolysis at pD e 8.0 showed the presence of CH3-
CH2OD and CF3CH2SO3-, but at pD 13.7 the product
consisted of CH3CH2OSO2CD2COO- along with a small
amount of the monodeuterated material, CH3CH2-
OSO2CHDCOO-. In an experiment in which NaOD in
D2O was added to a solution of 1a in CD3CN:D2O, the
19F NMR signal due to neopentyl 2,2,2-trifluoroethane-
sulfonate changed from a triplet to mixtures of a triplet,
doublet, and singlet (due to a mixture of the CH2, CHD,
and CD2 isotopomers) and finally to a product consisting
mostly of CF3CD2SO2OCH2CMe3 along with some of the
solvolysis product (chiefly CF3CD2SO3-). It would appear
that the reaction of water (kw term) is exclusively the
conventional solvolysis usual with sulfonic esters, whereas
the reaction of hydroxide anion is clearly consistent with
the reversible E1cB reaction shown below. The subse-
quent Michael-type reactions of 15 with amines or
phenylmethanethiolate anion would appear to be fast
since there is no sign of any buildup of 15 in the reaction
mixture.
F igu r e 1. pH-rate profile for the hydrolysis of ethyl tresylate
(1c) (circles) and for the reaction of 1c with aniline (0.05 M)
in water, at 25.0 °C. The lines are calculated from the
equations kobs ) kw + kOH[OH-] (solid line) and kobs ) kw
+
kOH[OH-] + kN[PhNH2] (dashed line) using kw ) 1.85 × 10-4
s-1, kOH ) 75 M-1 s-1, and kN ) 5.5 × 10-3 M-1 s-1; the points
are experimental.
sponding thioorthoesters (10b and 10c) are formed in the
reactions with the relatively higher proportions of phen-
ylmethanethiol. Butanethiol (3 equiv, 15 min) gave the
ketene dithioacetal (12) with no sign of the thioorthoester;
ethane-1,2-dithiol also yielded only the dithioacetal (13).
The pH-rate profile for the reaction of 1c with aqueous
aniline is also shown in Figure 1 (triangles) and corre-
sponds to the rate expression kobs ) kw + kOH[OH-] +
kN[PhNH2]. Examination of the product of the reaction
at pH 6 showed the presence of N-ethylaniline (21%
yield), as expected if the kN term is a simple SN2
displacement at carbon by aniline. At the high pH end
of the reaction range studied, kOH[OH-] . kN[PhNH2] and
the formation of 15 and its subsequent reactions become
the major processes.
An unexpected feature of the reactions of the ethyl and
octyl esters (1c and 1d ) is the comparative insignificance
of the direct SN2 reaction at carbon with loss of the
tresylate anion. Our limited study of the octyl ester (1d )
A reversible E1cB process is specific base catalyzed and
is therefore not expected to show any acceleration with
added amines, provided they act only as bases and not
as nucleophiles. With dibutylamine (0.01 M total amine
concentration, at pH 9.5) the pseudo-first-order rate
constant was found to be 2.5 × 10-3 s-1 as compared to
2.8 × 10-3 s-1 without the amine; analogously, diethyl-
amine (0.1 M, pH 9.0) gave kobs ) 12.2 × 10-4 s-1 vs 9.1
× 10-4 s-1 for the reaction at pH 9.0 without the amine.
These results are thus in good agreement with an
(E1cB)rev mechanism with very little or no direct nucleo-
1
showed no sign of any SN2 reaction, while the H NMR
spectrum of the products of the reaction of the ethyl ester
(1c) with PhCH2SH indicated the presence of perhaps
5% of the SN2 product, PhCH2SEt. In another experi-
ment using less phenylmethanethiol (2.2 equiv, 15 min)
the ratio of 8d :10d :PhCH2SEt was found to be 77:22:1.
The 19F NMR spectrum of the aqueous phase showed the
fluorine to be present almost entirely as fluoride anion
(g99.5%) with only a trace of tresylate anion (e0.5%); it
would appear that the benzyl ethyl sulfide probably

Alkyl 2,2,2-Trifluoroethanesulfonates
J . Org. Chem., Vol. 61, No. 21, 1996 7253
philic attack of the amine on the ester (1c). The reaction
of the thiolate anion is presumably similar.
regard this picture, perhaps with further modifications
as noted in the paragraph above, as sufficient to account
for the available information.
Rea ction s of Ben zyl 2,2,2-Tr iflu or oeth yl Su lfon e.
Virtually all of the reactions shown in Schemes 1 and 2
do not require the sulfonic ester function and would be
expected to appear in appropriately modified form in the
reactions of other substrates bearing the 2,2,2-trifluoro-
ethylsulfonyl group. Accordingly benzyl 2,2,2-trifluoro-
ethyl sulfone (16) was found to react with aqueous NaOH
with and without phenylmethanethiol to yield 18 and 17,
respectively; also shown is the formation of the orthoester
(19) by the reaction of sodium ethoxide in ethanol.
In our view it is unlikely that our model reactions and
those of the solid phase system will be either (a) quali-
tatively very different or (b) quantitatively identical. The
local environment (especially steric aspects) of any
tresylate ester in tresyl agarose will differ one from
another depending on its location in the solid phase
polymer, and it is unlikely that many of these will have
environments identical to those of the alkyl tresylate
models (1a to 1d ). In the reaction of alkyl tresylates with
a thiolate anion, the model system is clearly complex and
it is unreasonable to expect the solid phase reactions to
show the same subtle balance of competing influences
leading to the same balance of productsseven though the
products are in all likelihood derived from fundamentally
the same chemistry.
Exp er im en ta l Section
Instrumentation and general procedures are the same as
described elsewhere,18 except as noted below. 19F chemical
shifts are relative to CFCl3; IR spectra were obtained using a
Perkin Elmer 2000 FT-IR spectrometer. Melting points were
determined using either a Kofler Hot Stage or a Gallenkamp
melting point apparatus and are uncorrected. Kieselgel, silica
gel for TLC (containing 5% CaSO4, purchased from Inter
Science, Markham, Ontario), was used for thin-layer chroma-
tography and thick-layer preparative plates. Workup refers
to (a) addition of 1 M H2SO4 to pH 1-2, (b) extraction with
dichloromethane, (c) drying of the organic extract with anhy-
drous magnesium sulfate, and (d) evaporation of the solvent
using a Bu¨chi rotary evaporator connected to a water aspirator.
(Chlorosulfonyl)acetyl chloride was prepared by the procedure
Rea ction s of Tr esyl Aga r ose. As is noted in the
introduction, the present study was prompted by the
report by J ennissen and co-workers8 putting forward
what appeared to us to be highly suspect structures for
the products of the solid phase reactions of tresyl agarose
with nucleophiles in the presence of base. It is our view
that the study of solid phase polymer reactions should
be informed by a thorough knowledge of the analogous
solution phase chemistry, and hence we set out to do the
experiments described in this paper. In our communica-
tion12 we suggested that our model studies and the
evidence of J ennissen et al. published at that point were
consistent with the products being not those shown in
eqs 5-7 but rather, respectively, agarose-CH2OSO2CH2-
COOH (20), agarose-CH2OSO2CH2C(O)NHBu (21), and
a mixture of 20 and agarose-CH2OSO2CHdC(SBu)2 (22).
In reviewing our paper Professor J ennissen provided
some unpublished information (notably a set of CP/MAS
13C NMR spectra) from which one might conclude that
butyl-SS-agarose (the product from the reaction with
butanethiol) could well be more complex than we had
indicated. Accordingly we simply suggested that in view
of the complexity of the products from 1, butyl-SS-
agarose could well have a complex composition, with
components corresponding to any (or all) of the (seven)
structures encountered in our model studies, i.e., in
addition to 20 and 22, ROSO2CHdCFSBu (E and Z
isomers), ROSO2CH2C(SBu)3, ROSO2CH2CO-SBu, and
even RSBu. In addition there are the further possibilities
of (a) simple hydrolysis to give back the agarose unit and
(b) a reaction of the analogue of 15 with one or more of
the hydroxyl groups of the carbohydrate; the formation
of the orthoester (19) from 16 suggests one possible mode.
In a Comment on our paper, J ennissen17a announced
his conclusion that he concurred with our structures 20
and 21, but took issue with our initial suggestion for the
structure for butyl-S,S-agarose. In our Reply we
reiterated17b our proposal that butyl-S,S-agarose may
have a complex structure, as previously mentioned; we
1
of Hinman et al.19 in 30% yield, as a clear liquid, H NMR δ
5.07 (s); reported 1H NMR δ 5.06 (s).20 Dichloromethane was
distilled from calcium hydride prior to use; otherwise reagent
grade chemical and solvents were used as received. pD ) pH
meter reading + 0.37.
Preparation of, spectrometric data for, and interconversions
among 1a , 2a , 3a , 5a , E-7a , Z-7a , 8a , and 11 are given
elsewhere.12
Ma ter ia ls a n d Au th en tic Sp ecim en s. Tr esyla tes (1b -
1d ) were obtained by the procedure of Crossland et al.3
Isobu tyl 2,2,2-tr iflu or oeth a n esu lfon a te (1b): clear liquid,
74% yield; IR (CHCl3) νmax 2967 (w), 1387 (s), 1325 (s), 1275
(s), 1259 (s), 1186 (s), 1138 (s), 1081 (s), 960 (s), 947 (s) cm-1
;
1H NMR δ 1.00 (d, J ) 7 Hz, 6H), 2.07 (nonet, 1H), 3.90 (q, J
) 8.8 Hz, 2H), 4.12 (d, J ) 7 Hz, 2H); 13C NMR δ 18.3, 28.2,
53.4 (q, J ) 32.2 Hz), 78.0, 121.0 (q, J ) 277.5 Hz); 19F NMR
δ -62.64 (t, J ) 8.4 Hz). Eth yl 2,2,2-tr iflu or oeth a n e-
su lfon a te (1c): clear liquid, 55% yield; IR (CHCl3) νmax 1384
(s), 1326 (s), 1275 (s), 1259 (s), 1185 (vs), 1139 (s), 1090 (s),
1
997 (s), 929 (vs) cm-1; H NMR δ 1.46 (t, J ) 7 Hz, 3H), 3.89
(q, J ) 8.8 Hz, 2H), 4.43 (q, J ) 7 Hz, 2H); 13C NMR δ 14.9,
52.6 (q, J ) 33 Hz), 69.0, 121.0 (q, J ) 277.5 Hz); 19F NMR δ
-63.67 (t, J ) 9 Hz), reported 1H NMR δ 1.40 (t, J ) 7 Hz,
3H), 3.90 (q, J ) 9 Hz, 2H), 4.40 (q, J ) 7 Hz, 2H) and 19F
NMR (CF3COOH) δ 16.0 (t, J ) 9 Hz).21 Oct yl 2,2,2-
1
tr iflu or oeth a n esu lfon a te (1d ): clear liquid, 80% yield; H
NMR δ 0.88 (t, 3H), 1.28 (br s, 10H), 1.78 (m, 2H), 3.88 (q, J
) 8.7 Hz, 2H), 4.35 (t, J ) 7 Hz, 2H). Authentic 4 was
(18) King, J . F.; Rathore, R.; Lam, J . Y. L.; Guo, Z. R.; Klassen. D.
F. J . Am. Chem. Soc. 1992, 114, 3028-3033.
(19) Hinman, R. L.; Locatell, L., J r. J . Am. Chem. Soc. 1959, 81,
5655-5658.
(20) Pouchert, C. J .; Behnke, J . Aldrich Library of 13C and 1H FT
NMR Spectra. 1 (1), 1415C.
(17) (a) J ennissen, H. P. Angew. Chem., Int. Ed. Engl. 1995, 34,
2495. (b) King, J . F.; Gill, M. S. Angew. Chem., Int. Ed. Engl. 1995,
34, 2495.
(21) Ohta, Y.; Kohda, K.; Kimoto, H.; Okano, T.; Kawazoe, Y. Chem.
Pharm. Bull. 1988, 36, 2410-2416.

7254 J . Org. Chem., Vol. 61, No. 21, 1996
King and Gill
prepared from neopentyl alcohol and MsCl22 (84% yield): IR
unreacted phenylmethanethiol. The product mixture was
separated on a thick-layer preparative plate, eluting with ethyl
acetate:petroleum ether (35-60 °C) (1:8), to give 8b (white
solid, 65 mg, 50.5%) as the lower band and 10b (liquid, 21
mg, 15%) as the upper band. 8b: mp 69-70 °C; IR (CHCl3)
νmax 3032 (w), 2969 (w), 1496 (s), 1355 (vs), 1179 (vs), 976 (s),
(neat) νmax 1480 (m), 1354 (vs), 1176 (vs), 967 (vs), 846 (s) cm-1
;
1H NMR δ 0.99 (s, 9H), 3.00 (s, 3H), 3.87 (s, 2H); 13C NMR δ
1
25.8, 31.5, 36.7, 78.9; reported H NMR δ 0.98 (s, 9H), 2.98 (s,
3H), 3.82 (s, 2H).23
Neop en tyl ((Neop en tyloxy)su lfon yl)a ceta te (6a ).
A
1
943 (s), 852 (w) cm-1; H NMR δ 0.90 (d, J ) 9 Hz, 6H), 1.90
solution of neopentyl alcohol (194 µL, 2.2 mmol) and (chloro-
sulfonyl)acetyl chloride (214 mg, 1.2 mmol) in dichloromethane
(7 mL) was stirred at rt for 30 min and then cooled in an ice
bath; triethylamine (87 µL, 1.2 mmol) was added and the
mixture stirred for 15 min in ice bath and for 30 min at rt.
Workup gave 6a (214 mg, 69.5%) as an oil purified on a thick-
layer preparative plate by eluting with toluene:diethyl ether
(10:1) and extracting with dichloromethane (112 mg, 36.4%):
IR (CHCl3) νmax 2965 (s), 1742 (s), 1497 (s), 1370 (vs), 1292 (s),
(nonet, 1H), 3.67 (d, J ) 7 Hz, 2H), 4.06 (s, 2H), 4.27 (s, 2H),
6.02 (s, 1H), 7.25-7.38 (m, 10H); 13C NMR δ 18.7, 28.0, 37.5,
39.0, 76.1, 113.9, 127.7, 128.1, 128.6, 128.9, 128.93, 129.2,
133.6, 135.5, 156.8. 10b: IR (CHCl3) νmax 3032 (w), 2966 (w),
1602 (w), 1495 (s), 1454 (s), 1368 (vs), 1175 (vs), 1162 (vs),
1
971 (vs), 947 (vs), 818 (w) cm-1; H NMR δ 0.93 (d, J ) 7 Hz,
6H), 1.96 (sept, 1H), 3.78 (s, 2H), 3.91 (d, J ) 7 Hz, 2H), 4.08
(s, 6H), 7.21-7.38 (m, 15H); 13C NMR δ 18.6, 28.3, 36.5, 60.2,
65.2, 76.6, 127.5, 128.7, 129.4, 135.8. (ii) 1b (130 mg, 0.6
mmol) in dioxane (5 mL) and phenylmethanethiol (485 µL, 4.13
mmol) in 1 M NaOH (5 mL, 5 mmol) at rt showed a precipitate
after 5 min; 2 mL of dioxane was added and worked up after
260 min at rt to give an oil, TLC of which showed 10b and 8b
present in a 3:1 ratio. Further purification on thick-layer
preparative plates as above gave 10b (150 mg, 48%) and 8b
(36 mg, 15%). (iii) 1b (46.6 mg, 0.21 mmol) in THF (0.5 mL)
and phenylmethanethiol (497 µL, 4.2 mmol) in 1 M NaOH (4.5
mL, 4.5 mmol), under nitrogen when stirred at rt for 75 min,
gave an oil, the 1H NMR spectrum of which showed signals
due to 10b and 8b (3:1 ratio) and unreacted phenylmethaneth-
iol.
1
1178 (s), 1119 (s), 962 (vs) cm-1; H NMR δ 0.98 (s, 9H), 1.0
(s, 9H), 3.92 (s, 2H), 4.0 (s, 2H), 4.12 (s, 2H); 13C NMR δ 25.9,
26.2, 31.4, 31.8, 54.6, 75.8, 80.9, 162.1. 6a (18.9 mg, 0.07
mmol) in 1 M NaOH (1 mL, 1 mmol) was stirred at rt for 18
h. Workup gave 2a (8.8 mg, 62%) as a clear liquid with 1H
and 13C NMR spectra identical to those of the previously
prepared 2a .12
Ben zyl ((Neop en tyloxy)su lfon yl)th ioa ceta te (9a ). 5a
(20 mg, 0.087 mmol) was treated with excess phenylmethaneth-
iol in an NMR tube in CDCl3; after a week 9 was isolated and
purified on a thick-layer preparative plates eluting with ethyl
acetate:petroleum ether (35-60 °C) to give a white solid (21
mg, 75%), which was recrystallized from diethyl ether:petro-
leum ether (bp 35-60 °C), mp 47-48 °C: IR (CHCl3) νmax 3032
(w), 2966 (w), 1688 (s), 1368 (w), 1177 (s), 1020 (w), 957 (vs),
Rea ction of 1b w ith Excess Eth a n e-1,2-d ith iol a n d
Aqu eou s Na OH. 1b (106 mg, 0.5 mmol) dissolved in dioxane
(0.5 mL) was added to a solution of ethane-1,2-dithiol (121 µL,
0.14 mmol) in 1 M NaOH (1.5 mL, 1.5 mmol); the flask was
flushed with nitrogen and the reaction mixture was stirred at
rt for 25 min. Workup gave a yellowish oil, which was purified
on a thick-layer preparative plate, eluting with ethyl acetate:
petroleum ether (bp 35-60 °C) (1:8) and extracting with
dichloromethane to give 2-(((isobutyloxy)sulfonyl)methylene)-
1,3-dithiolane (13) (62 mg, 50%), as a light yellow liquid: IR
(CHCl3) νmax 3030 (w), 2996 (w), 1530 (s), 1345 (s), 1161 (vs),
893 (w), 839 (w) cm-1 1H NMR δ 0.96 (s, 9H), 3.90 (s, 2H),
;
4.22 (s, 2H), 4.25 (s, 2H), 7.25-7.31 (m, 5H); 13C NMR δ 25.9,
31.9, 34.3, 60.7, 81.1, 127.7, 128.7, 128.9, 135.9, 185.8. 9 (19
mg, 0.6 mmol) was dissolved in 1 M NaOH (0.2 mL, 0.2 mmol)
and dioxane (0.25 mL) and stirred at rt for 25 min. Workup
gave a clear liquid, the 1H NMR spectrum of which showed
signals due to 2a (10%) and unreacted 9a (90%).
Rea ction of 1a w ith Na OD/D2O. To a solution of 1a (20
mg, 0.09 mmol) in CD3CN (0.3 mL) in an NMR tube was added
an NaOD/D2O solution (pD 12.07) dropwise, and the reaction
was monitored by 19F NMR. In a series of five spectra over
an 80 min interval the initial triplet at -62.20 ppm due to 1a
was replaced by (an initially larger) a doublet at -62.29 and
a singlet at -62.38 ppm due to the CHD and CD2 isotopomers,
respectively; the final trace showed the doublet and the singlet
(ratio ∼1:10) along with signals at -62.73 (d) and -62.51 (s)
ppm assigned to the CHD and CD2 isotopomers of the tresylate
anion.
1
978 (s), 928 (w), 858 (s) cm-1; H NMR δ 0.94 (d, J ) 6.5 Hz,
6H), 1.99 (nonet, 1H), 3.43-3.55 (m, 4H), 3.85 (d, J ) 6.5 Hz,
2H), 6.23 (s, 1H); 13C NMR δ 18.7, 28.1, 37.0, 39.5, 76.0, 105.1,
164.3; exact mass calcd for C8H14O3S3 254.0105, found 254.0093.
Rea ction of 1b w ith Excess Bu ta n eth iol a n d Aqu eou s
Na OH. 1b (56.8 mg, 0.26 mmol) in THF (0.5 mL) was added
to a solution of butanethiol (83 µL, 0.77 mmol) in 1 M NaOH
(1 mL, 1 mmol), the reaction flask was flushed with nitrogen,
and the reaction mixture was stirred at rt for 15 min. Workup
gave a yellowish liquid (67.6 mg), the 1H NMR spectrum of
which showed signals appropriate to 1-((isobutyloxy)sulfonyl)-
2,2-bis(butylthio)ethene (12). Purification of the reaction
mixture on a thick-layer preparative plate, eluting with ethyl
acetate:petroleum ether (35-60 °C) (1:9), and extracting with
dichloromethane gave 12 (32 mg, 37%) as a clear liquid: 1H
NMR δ 0.94 (m, 6H), 0.99 (d, J ) 7 Hz, 6H), 1.46 (sept, 4H),
1.61-1.74 (m, 4H), 2.04 (sept, 1H), 2.85 (t, J ) 7 Hz, 2H), 3.04
(t, J ) 7 Hz, 2H), 3.91 (d, J ) 7Hz, 2H), 5.93 (s, 1H); 13C NMR
δ 13.5, 18.8, 21.8, 22.0, 28.2, 29.4, 31.5, 32.4, 33.8, 76.0, 110.0,
159.4.
((Isobu tyloxy)su lfon yl)a cetic Acid (2b). 1b (32 mg, 0.01
mmol) in 1 M NaOH (0.5 mL, 0.5 mmol) and dioxane (0.25
mL), reacted at rt for 30 min and then made acidic and
extracted with CDCl3 (1 mL), gave 2b (17 mg, 60%), as a clear
liquid: IR (CHCl3) νmax 3031 (w), 2968 (s), 1741 (s), 1370 (vs),
1175 (s), 972 (s), 949 (s), 912 (W) cm-1 1H NMR δ 0.99 (d,
;
6H), 2.07 (1H), 4.14 (d, 2H), 4.16 (s, 2H), 8.55 (br s, 1H); 13C
NMR δ 18.5, 28.3, 54.2, 78.1, 165.8. ((Octyloxy)su lfon yl)-
a cetic Acid (2d ). 1d (49 mg, 0.18 mmol) similarly gave 2d
(27 mg, 60%) as a clear liquid: 1H NMR δ 0.88 (t, 2H), 1.28
(br s, 10H), 1.77 (m, 2H), 4.15 (s, 2H), 4.36 (t, J ) 6.5 Hz, 2H).
(E t h oxysu lfon yl)a cet ic Acid (2c). 1c (20 mg, 0.1 mmol)
similarly gave 2c (10 mg, 57%) as a clear liquid: 1H NMR δ
1.45 (t, 3H), 4.14 (s, 2H), 4.44 (q, 2H), 5.12 (br s, 1H); 13C NMR
δ 15.1, 54.5, 68.9, 165.1.
Rea ction of 1d w ith Excess P h en ylm eth a n eth iol a n d
Aqu eou s Na OH. 1d (51.7 mg, 0.19 mmol) in dioxane (0.5
mL) and phenylmethanethiol (66 µL, 0.56 mmol) in 1 M NaOH
(0.47 mL, 0.47 mmol) at rt for 20 min gave an oil (75.5 mg),
Rea ction of 1b w ith Excess P h en ylm eth a n eth iol a n d
Aqu eou s Na OH. (i) 1b (58.8 mg, 0.27 mmol) in dioxane (0.3
mL) and phenylmethanethiol (94 µL, 0.8 mmol) in 1 M NaOH
(0.67 mL, 0.67 mmol) at rt for 40 min gave an oil, shown by
1H NMR to be a mixture of 1-((isobutyloxy)sulfonyl)-2,2-bis-
((phenylmethyl)thio)ethene (8b ), 1-((isobutyloxy)sulfonyl)-
2,2,2-tris((phenylmethyl)thio)ethane (10b ) (4:1 ratio), and
1
the H NMR spectrum of which showed 8d as the only major
product; chromatography on a thick-layer preparative plate
eluting with ethyl acetate:petroleum ether (35-60 °C) (1:8)
gave 8d (56 mg, 64%) as a broad band: 1H NMR δ 0.90 (t,
3H), 1.28 (br s, 10H), 1.55-1.65 (m, 1H), 3.89 (t, 2H), 4.60 (s,
2H), 4.27 (s, 2H), 6.03 (s, 1H), 7.23-7.40 (m, 10H).
Reaction of 1d with Dieth ylam in e an d Aqu eou s NaOH.
Diethylamine (73 µL, 0.7 mmol) and 1 M NaOH (0.59 mL, 0.59
mmol) and 1d (65 mg, 0.24 mmol) in dioxane (0.5 mL) at rt
for 15 min gave N,N-diethyl((octyloxy)sulfonyl)acetamide (3d ,
R1,R2 ) Et) (54 mg, 75%), as a low-melting solid: 1H NMR δ
(22) Crossland, R. K.; Servis, K. L. J . Org. Chem. 1970, 35, 3195-
3196.
(23) (a) Berkessel, A.; Voges, M. Chem. Ber. 1989, 122, 1147-1151.
(b) Truce, W. E.; Vrencur, D. J . J . Org. Chem. 1970, 35, 1226-1227.

Alkyl 2,2,2-Trifluoroethanesulfonates
J . Org. Chem., Vol. 61, No. 21, 1996 7255
0.88 (t, J ) 7 Hz, 3H), 1.39-1.50 (m, 16H), 1.71-1.82 (m, 1H),
3.37-3.52 (m, 2H), 4.18(s, 2H), 4.36 (t, J ) 7 Hz, 2H).
aniline, 230 µL (0.252 mmol); (ii) butylamine, 490 µL (4.96
mmol); (iii) diethylamine, 520 µL (5.03 mmol); and (iv) mor-
pholine, 220 µL (2.52 mmol).
Rea ction of 1c w ith Excess P h en ylm eth a n eth iol a n d
Aqu eou s Na OH. 1c (37.2 mg, 0.19 mmol) in THF (0.5 ML)
and phenylmethanethiol (70 µL, 0.6 mmol) in 1 M NaOH (0.5
mL, 0.5 mmol) under N2 at for 15 min gave an oil (82.5 mg),
the 1H NMR spectrum of which showed signals due to
1-(ethoxysulfonyl)-2,2,2-tris((phenylmethyl)thio)ethane (10c)
and 1-(ethoxysulfonyl)-2,2-bis((phenylmethyl)thio)ethene (8c)
and signals at δ 1.23 (t, J ) Hz, 3H), 2.44 (q, J ) Hz, 2H),
Ben zyl 2,2,2-Tr iflu or oeth yl Su lfon e (16). Benzyl 2,2,2-
trifluoroethyl sulfide25 (3.03 g, 14.7 mmol) was dissolved in
glacial acetic acid (15 mL) in a 100 mL flask placed in a water
bath and stirred. To the above stirred solution was added 30%
hydrogen peroxide (10 mL) dropwise over a period of 1 h. The
reaction mixture was stirred for 67 h. The precipitate was
filtered and washed with a small amount of water. Recrys-
tallization from methanol gave 16 (2.32 g, 67%) as a white
solid: mp 150 °C; IR (CHCl3) νmax 3034 (w), 1495 (w), 1457
(w), 1401 (w), 1348 (vs), 1313 (s), 1272 (s), 1238 (w), 1159 (w),
1
and 3.72 (s, 2H) assigned to benzyl ethyl sulfide (reported H
NMR δ 1.23 (t, J ) Hz, 3H), 2.44 (q, J ) Hz, 2H), 3.72 (s, 2H),
7.21-7.33 (m, 5H),24 in a 53:41:6 ratio. The reaction mixture
was purified on a thick-layer plate, eluting with ethyl acetate:
petroleum ether (bp 35-60 °C) (1:7), to give 10c (44 mg, 45%)
as a white solid and 8c (22 mg, 30%) as a clear liquid. 10c:
1H NMR δ 1.35 (t, J ) 7.1 Hz, 3H), 3.81 (s, 2H), 4.09 (s, 6H),
4.25 (q, J ) 7.1 Hz, 2H), 7.23-7.38 (m, 15H); 13C NMR δ 15.2,
36.5, 60.3, 65.3, 67.5, 127.5, 128.7, 129.5, 135.8. Anal. Calcd
for C25H28O3S4: C, 59.51; H, 5.60; S, 25.37. Found: C, 59.70;
H, 5.73; S, 25.15. 8c: 1H NMR δ 1.26 (t, J ) 7.1 Hz, 3H),
3.97 (q, J ) 7.1 Hz, 2H), 4.07 (s, 2H), 4.28 (s,2H), 6.03 (s, 1H),
7.24-7.40 (m, 10H); 13C NMR δ 14.8, 37.6, 39.0, 66.6, 114.2,
127.7, 128.1, 128.6, 128.9, 129.2, 133.6, 135.5, 156.8; exact
mass calcd for C18H20O3S3 380.0575, found: 380.0580.
1
1129 (vs), 1079 (w) cm-1; H NMR δ 3.58 (q, J ) 9.3 Hz, 2H),
4.40 (s, 2H), 7.26-7.46 (m, 5H); 13C NMR δ 52.6 (q, J ) 31.8
Hz), 61.2, 121.3 (q, J ) 277.4 Hz), 126.7, 129.4, 129.7, 130.7;
19F NMR δ -61.12 (t, J ) 8.8 Hz).
((P h en ylm eth yl)su lfon yl)a cetic Acid (17). 16 (100 mg,
0.42 mmol) was dissolved in 1 M NaOH (2 mL, 2 mmol) and
dioxane (2 mL). The reaction mixture was stirred at rt for 30
min. Workup gave 17 (84 mg, 93%) as a white solid, which
was recrystallized from dichloromethane: mp 134-136 °C; IR
(CHCl3) νmax 3027 (s), 1735 (s), 1603 (w), 1331 (vs), 1156 (w),
1
1125 (s), 904 (w), 874 (w) cm-1; H NMR (acetone-d6) δ 4.02
Rea ction s of 1c w ith Na OD/D2O. Below p D 8. 1c (10
mg, 0.05 mmol) was dissolved in CD3CN (0.2 mL) in an NMR
tube, and to this was added D2O (0.5 mL). The reaction was
followed by 1H NMR and after 9 days it showed signals due to
ethanol-d and trifluoroethanesulfonate anion (1:1 ratio) and
traces of unreacted 1c (4%). NMR spectra run after addition
of authentic specimens of ethanol and CF3CH2SO3- confirmed
the identity of the products ethanol-d (1H NMR (D2O/CD3CN/
DSS) δ 1.14 (t, 3H), 3.59 (q, 2H); 13C NMR δ 19.6, 59.8) and
trifluoroethanesulfonate (1H NMR δ 3.75 (q, J ) 10 Hz, 2H);
13C NMR δ 55.0 (q, J ) 30 Hz), 125.5 (q, J ) 275.7 Hz)).
Above p D 10. 1c (7 mg, 0.036 mmol) was dissolved in 0.48
N NaOD/D2O solution (0.5 mL). The 19F NMR spectrum after
10 min showed signals only due to fluoride anion (-122.0
(s, 2H), 4.62 (s, 2H), 7.36-7.54 (m, 5H); 13C NMR (acetone-d6)
δ 56.4, 59.8, 129.3, 129.5, 129.6, 132.1, 164.9.
1-((P h en ylm eth yl)su lfon yl)-2,2-bis(p h en ylm eth ylth io)-
eth en e (18). 16 (72 mg, 0.3 mmol) dissolved in dioxane (1
mL) was added to a solution of phenylmethanethiol (89 µL,
0.76 mmol) and 1 M NaOH (1 mL, 1 mmol), and the reaction
mixture was stirred at rt for 40 min. Workup gave 18 (91 mg,
70%), as a white solid, which was recrystallized from dichlo-
romethane:diethyl ether: mp 108.5-109 °C; IR (CHCl3) νmax
3025 (s), 1603 (w), 1495 (s), 1455 (w), 1314 (s), 1141 (w), 1115
1
(vs), 934 (w), 882 (w), 828 (w) cm-1; H NMR δ 3.89 (s, 2H),
4.26 (s, 2H), 4.27 (s, 2H), 5.82 (s, 1H), 7.04-7.44 (m, 10H); 13
C
1
ppm); the H NMR spectrum after 20 min showed signals due
NMR δ 37.8, 39.1, 60.5, 118.5, 127.9, 128.2, 128.4, 128.5, 128.8,
129.3, 130.9, 133.6, 136.2, 157.1.
to ethanol-d and (ethoxysulfonyl)acetate anion-d2 in a 3:97
ratio. (Eth oxysu lfon yl)a ceta te: 1H NMR (D2O/DSS) δ 1.39
(t, 3H), 4.41 (q, 2H).
2-((P h en ylm eth yl)su lfon yl)-1,1,1-tr ieth oxyeth a n e (19).
To a solution of sodium ethoxide (2.17 mmol, 0.87 M) in dry
ethanol (1.5 mL) was added a solution of 16 (93.6 mg, 0.4
mmol) in dry ethanol (1 mL), and the reaction mixture was
stirred at rt for 15 min. Excess ethanol was removed on rotary
evaporator and under vacuum to give a white solid which upon
extraction with anhydrous diethyl ether gave 19 (solid, 108
mg, 86%): IR (CHCl3) νmax 3024 (w), 2984 (w), 2934 (w), 2904
(w), 1597 (w), 1456 (w), 1323 (vs), 1279 (w), 1235 (s), 1122 (s),
Rea ction of 1c w ith An ilin e a t p H 6. 1c (22.8 mg, 0.12
mmol) in THF (100 µL) and aniline (230 µL, 2.52 mmol) in
water (50 mL), set at pH 6 with addition of dilute NaOH and
HCl, at rt for 270 min with the pH was maintained at pH 6
by adding NaOH (0.1 M), was extracted with CDCl3 (1 mL).
1H NMR showed weak signals ascribable to N-ethylaniline;
an authentic sample of N-ethylaniline (1 µL) was added to the
NMR tube and the spectrum was run again to confirm the
identity of product and estimate the amount originally present
(21%).
1
1072 (s), 1041 (w) cm-1; H NMR δ 1.25 (t, J ) 7.1 Hz, 9H),
3.37 (s, 2H), 3.65 (q, J ) 7.1 Hz, 6H), 4.41 (s, 2H), 7.37-7.48
(m, 5H); 13C NMR δ 14.9, 53.9, 58.3, 59.9, 110.7, 127.9, 128.6,
128.7, 131.1.
Kin et ic St u d ies w it h E t h yl Tr esyla t e (1c). Gen er a l
P r oced u r e. The rate of hydrolysis of 1c and kinetics of
reaction of 1c with amines were determined using the pH-
stat technique as previously described.18 Hyd r olysis:
A
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council of Canada for finan-
cial support of this work.
solution of 1c (50 µL) (0.013-0.024 mmol) in THF was injected
into water (50 mL) at 25 °C, which had been previously
adjusted to the desired pH value with aqueous sodium
hydroxide (1 M) or aqueous hydrochloric acid (1 M). The
reaction mixture was vigorously stirred and the pH of the
solution kept constant with a sodium hydroxide solution (0.1
M). The rate of hydrolysis was monitored by recording the
volume (mL) of the titrant (sodium hydroxide) added with time.
Plots of -ln(v∞ - vt) vs time were constructed from the volume
of sodium hydroxide titrant added. The pseudo-first-order rate
constants were then obtained from the slopes of straight lines;
the results are listed in Table 1 (supporting information).
Hyd r olysis-Am in olysis. A solution of 40 or 50 µL of 1c in
THF was injected into a solution of the amine in water (50
mL) set at the desired pH and the reaction was followed as
above: the quantities of the amines were, respectively, (i)
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of new
compounds and of reaction products characterized primarily
by NMR and a table of pseudo-first-order rate constants for
hydrolysis and aminolysis of ethyl tresylate (1c) at 25 °C (67
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O9610366
(25) Bunyagidj, C.; Piotrowska, H.; Aldridge, M. H. J . Org. Chem.
1981, 46, 3335-3336.
(24) Toyota, S.; Oki, M. Bull. Chem. Soc. J pn. 1991, 64, 1563-1569.