NaOH-Catalyzed Thiolysis of α,β-Epoxyketones in Water. A Key Step in the Synthesis of Target Molecules Starting from α,β -Unsaturated Ketones

Article abstract of DOI:10.1021/jo035804m

NaOH (0.02-0.3 molar equiv) is an efficient catalyst for the thiolysis reactions of α,β-epoxy ketones with alkyl and aryl thiols in water. Thiolysis of 3,4-epoxyheptan-2-one (1) with thiols 2a-d has been accomplished in mild conditions (30 °C and pH 6 or

Full text of DOI:10.1021/jo035804m

Na OH-Ca ta lyzed Th iolysis of r,â-Ep oxyk eton es in Wa ter . A Key
Step in th e Syn th esis of Ta r get Molecu les Sta r tin g fr om
r,â-Un sa tu r a ted Keton es
Francesco Fringuelli,* Ferdinando Pizzo, and Luigi Vaccaro*
Dipartimento di Chimica, Laboratorio di Chimica Organica, Universita` di Perugia,
CEMIN “Centro di Eccellenza Materiali INnovativi per applicazioni chimiche, fisiche e biomediche”,
Via Elce di Sotto, 8 I-06123, Perugia, Italia
frifra@unipg.it; luigi@unipg.it
Received December 10, 2003
NaOH (0.02-0.3 molar equiv) is an efficient catalyst for the thiolysis reactions of R,â-epoxy ketones
with alkyl and aryl thiols in water. Thiolysis of 3,4-epoxyheptan-2-one (1) with thiols 2a -d has
been accomplished in mild conditions (30 °C and pH 6 or 9) with complete C-R-regioselectivity and
anti-stereoselectivity, and the corresponding anti-â-carbonyl-â-hydroxysulfides 3a -d have been
prepared in excellent yields (95-98%). Compounds 3a -d , depending on their nature and pH
conditions, have undergone dehydration, C-3 epimerization reaction, and retroaldol condensation.
Dehydration of a n ti-3a -d has been chemoselectively carried out by in situ acidic treatment at
70 °C, giving stereoselectively the related (Z)-vinyl sulfides 4 in 89-94% overall yields. Under NaOH-
catalyzed thiolysis conditions, cyclic R,â-epoxyketones 6-9 have shown C-R attack only and
spontaneously dehydrated to furnish the corresponding vinyl sulfides in high yields (90-96%). The
reactions of calchone oxide (10) with thiols 2b-d have exclusively resulted in the formation of
â-carbonylsulfides 10b-d (82-93% yield), coming from the nucleophilic attack at the R-position
and retroaldol condensation. To highlight the synthetic utility of this procedure, one-pot multisteps
preparation of vinyl sulfides 7b and 7c, vinyl sulfoxides 12 and 13, and 1,5,6,7-tetrahydro-4H-
1,2,3-benzotriazol-4-one (14) starting from 2-cyclohexen-1-one (11) have also been reported.
SCHEME 1
In tr od u ction
Our research is mainly devoted to the preparation of
target molecules through one-pot multistep protocols.1
Such a strategy is a very powerful tool to attain very
simple workup procedures, to reduce costly labor and
waste production, and to improve the chemical efficiency
of a process. Water is the ideal reaction medium to
succeed in this approach because it permits the manipu-
lation of the pH of the reaction mixture allowing the
reactivity of the reagents to be finely regulated. In many
cases, both water and the contained inorganic catalysts
can be easily recovered and reused without loss in terms
of chemical efficiency.1e,g-i,2
the one-pot copper(II)-catalyzed preparation of optically
active norstatines and allonorstatines1g and paved the
route to the synthesis of 1,4-benzoxathiepinone nucleus1h
and to the chemoselective preparation of â-hydroxysul-
foxide and â-hydroxysulfones.1i Starting from 3-nitrocou-
marins, we have accomplished an original synthesis of
nitrotetrahydrobenzo[c]chromenones1j and dihydrodiben-
zo[b,d]furans via a one-pot five-step protocol.1j In all of
these examples, water has been essential for the success
of the syntheses.
Our current project has the aim to define a one-pot
protocol for the synthesis of R-carbonyl vinyl sulfides and
their sulfoxide derivatives, starting from the correspond-
ing R,â-enones in water, via (A) epoxidation, (B) thiolysis,
(C) dehydration, and (D) oxidation reactions (Scheme 1).
Our intention is to employ the resulting vinylsulfoxides
as Michael acceptors, dienophiles, or heterodienes in
Diels-Alder reactions and as 1,3-dipolarophiles in 1,3-
dipolar cycloadditions for the preparation of target
molecules in aqueous medium.
In water, following a one-pot multistep approach, we
have prepared a variety of target molecules. By using 1,2-
epoxides as building blocks, we have recently disclosed
(1) (a) Li C. J .; Chang T. H. In Organic Reactions in Aqueous Media;
Wiley: New York, 1997. (b) Fringuelli, F.; Piermatti, O.; Pizzo, F. In
Organic Synthesis in Water; Grieco P. A., Ed.; Blackie Academic and
Professional: London, 1998; pp 223-261. (c) Fringuelli F.; Matteucci
M.; Piermatti O.; Pizzo F.; Burla M. C. J . Org. Chem. 2001, 66, 4461-
4466. (d) Amantini D.; Fringuelli F.; Pizzo F.; Vaccaro L. J . Org. Chem.
2001, 66, 4463-4467. (e) Amantini D.; Fringuelli F.; Piermatti, O.;
Pizzo F.; Vaccaro L. Green Chem. 2001, 3, 229-332. (f) Amantini D.;
Fringuelli F.; Pizzo F. J . Org. Chem. 2002, 67, 7238-7243. (g)
Fringuelli F.; Pizzo F.; Rucci, M.; Vaccaro L. J . Org. Chem. 2003, 68,
7041-7045. (h) Fringuelli, F.; Pizzo, F.; Tortoioli, S.; Vaccaro, L. Green
Chem. 2003, 5, 436-440. (i) Amantini, D.; Fringuelli, F.; Pizzo, F.;
Tortoioli, S.; Vaccaro, L. Synlett 2003, 2292-2296. (j) Amantini, D.;
Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. J . Org. Chem. 2003,
68, 9263-9268.
As the first step within this project, we have recently
reported2f an efficient epoxidation of R,â-unsaturated
ketones by hydrogen peroxide catalyzed by NaOH or
10.1021/jo035804m CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/27/2004
J . Org. Chem. 2004, 69, 2315-2321
2315

Fringuelli et al.
CTAOH in water and the preparation of R-thiophenyl-
cycloxexen-2-one, in excellent yield, starting from cyclo-
hexen-2-one by one-pot epoxidation and thiolysis/dehy-
dration reactions. One of the trump cards of the process
was the recovery of both aqueous medium and base.
To our knowledge, there is no report dealing with the
reaction of thiols with R,â-epoxy ketones in sole water.
This is surprising considering that in water 1,2-epoxides
are very reactive and that a high regio- and stereoselctiv-
ity can be achieved in the nucleophilic ring-opening of
the oxirane ring. In principle, the thiolysis of R,â-epoxy
ketones in water is therefore a very promising process
for significantly improving the synthesis of R-carbonyl
vinyl sulfides and sulfoxides, providing that related regio-
and stereoselectivity problems be solved.
In this paper, we report the first study on the NaOH-
catalyzed regio- and stereoselective thiolysis of cyclic and
acyclic R,â-epoxyketones 1 and 6-10 with thiols 2a -d
in water and its application to the one-pot synthesis of a
variety of acyclic and cyclic R-carbonyl vinyl sulfides [(Z)-
4a -d , 6b, 7b-d , 8b-c, 9c,d ], â-carbonyl sulfides (10b-
d ), R-carbonyl vinyl sulfoxides (12) and (13), and 1,5,6,7-
tetrahydro-4H-1,2,3-benzotriazol-4-one (14).
The importance of vinyl sulfides in organic synthesis
is well-recognized. They have been used as acceptors in
the Michael addition and Peterson olefination sequence,3
as nucleophiles in the intramolecular attack to oxonium
ions,4 as 1,3-dipolarophiles,5 as dienophiles,6 and as a part
of diene7 or heterodiene8 systems. Their reactivity be-
comes higher when they are converted to the correspond-
ing vinyl sulfoxides and sulfones,9 and in particular,
R-carbonylvinyl sulfides and sulfoxides are of high inter-
est considering the wide spectrum of reactivity they can
display.9a,d,g
R-Carbonylvinyl sulfides are prepared by different
methods10 including Pummerer-style elimination of water
of the corresponding saturated sulfoxide10a,b and the
reaction of cycloalkanones with phenylsulfenyl chloride.10a,e
The synthesis of these molecules based on the thiolysis
R,â-epoxy ketones has been sporadically reported, e.g.,
the reaction of cyclic R,â-epoxycycloalkenones with so-
dium thiolates in organic solvents.10c,g,h This is perhaps
due to the fact that thiolysis of R,â-epoxy ketones
(especially in the case of acyclic substrates) is generally
considered to be neither regio- or stereoselective at the
C-R position.11
Resu lts a n d Discu ssion
3,4-Epoxy-heptan-2-one (1) and thiols 2a -d were
chosen to investigate the thiolysis reaction in water under
basic conditions.
Butylthiol (2a ) and phenylthiol (2b) were selected as
representative alkyl- and arylthiols. p-Carboxyphenyl-
thiol (2c) was considered an attractive substrate because
of the carboxy functionality that will imprint to the final
vinyl sulfides or sulfoxides a higher solubility in water.
This parameter could be essential to efficiently catalyze
a reaction in water by a Lewis-acid. (1S)-Camphor-10-
thiol (2d ) was chosen in view of the preparation of
optically active vinyl sulfides. The results of NaOH-
catalyzed thiolysis of 1 with 2a -d are reported in Table
1.
(2) For recent papers, see: (a) Fringuelli F.; Pizzo F.; Vaccaro L.
Synthesis 2000, 646-650. (b) Fringuelli F.; Pizzo F.; Vaccaro L. J . Org.
Chem. 2001, 66, 3544-3548. (c) Fringuelli F.; Pizzo; Vaccaro L.
Tetrahedron Lett. 2001, 42, 1131-1134. (d) Fringuelli F.; Pizzo F.;
Vaccaro L. J . Org. Chem. 2001, 66, 4719-4722. (e) Fringuelli F.; Pizzo
F.; Tortoioli, S.; Vaccaro L. Adv. Synth. Catal. 2002, 344, 379-384. (f)
Fioroni, G.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. Green Chem. 2003, 5,
425-428 (h) Fringuelli F.; Pizzo F.; Tortoioli, S.; Vaccaro L. J . Org.
Chem. 2003, 68, 8248-8251.
The pH of the reaction medium and the molar equiva-
lents of NaOH are crucial parameters for the success of
the reaction.
(3) Watanabe, S.; Mori, E.; Nagai, H.; Iwamura, T.; Iwama, T.;
Kataoka, T. J . Org. Chem. 2000, 65, 8893-8898.
Butylthiol (2a ) (pKa ) 11.40,12a 10.8812b) gave the
complete conversion of 1 to a n ti-3a at pH 9 in just 30
min while at pH 6 a 50% conversion only was reached
after 24 h (Table 1, entries 1 and 2). Phenylthiol (2b)
(pKa ) 6.513) showed a very high reactivity at pH 9 giving
a n ti-3b in 30 min while at pH 6 needed 5 h to complete
the reaction (Table 1, entries 4 and 5). p-Carboxyphe-
nylthiol (2c) (pKa ) 614) was very reactive at pH 6 giving
the complete conversion in 1 h to a n ti-3c (Table 1, entry
7) and optically active (1S)-camphorthiol (2d ) (pKa ) 9.39
( 0.215) gave the clean product a n ti-3d in 8 h at pH 9
(Table 1, entry 10).
(4) Sasmal, P. K.; Maier, M. E. J . Org. Chem. 2003, 68, 824-831.
(5) Pearson, W. H.; Hines, J . V. J Org. Chem. 2000, 65, 5785-5793.
(6) (a) Arimori, S.; Kouno, R.; Okauchi, T.; Minami, T.J . Org. Chem.
2002, 67, 7303-7308. (b) Pearson, W. H.; Mi, Y.; Young Lee, I.; Stoy,
P. J . Am. Chem. Soc. 2001, 123, 6724-6725. (c) Hayes, P.; Maignan,
C. Tetrahedron: Asymmetry 1999, 10, 1041-1050.
(7) Yoshida, T.; Ito, A.; Murase, M.; Totani, E. Chem. Pharm. Bull.
2001, 49, 1198-1202.
(8) Tietze, L. F.; Hartfiel, U.; Hu¨bsch, T.; Voss, E.; Bogdanowicz-
Szwed, K.; Wichmann, J . Liebigs Ann. Chem. 1991, 275-281.
(9) (a) Arroyo, Y.; de Paz, M.; Rodriguez, J . F.; Sanz-Tejedor, M. A.;
Garc´ıa Ruano, J . L. J . Org. Chem. 2002, 67, 5638-5643. (b) Garc´ıa
Ruano, J . L.; Tito, A.; Peromingo, M. T. J . Org. Chem. 2002, 67, 981-
987. (c) Marino, J . P.; Rubio, M. B.; Cao, G.; de Dios, A. J . Am. Chem.
Soc. 2002, 124, 13398-13399. (d) Kita, Y.; Higuchi, K.; Yoshida, Y.;
Iio, K.; Kitagaki, S.; Ueda, K.; Akai, S.; Fujioka, H. J . Am. Chem. Soc.
2001, 123, 3214-3222. (e) Carren˜o, M. C.; Herna´ndez-Sa´nchez, R.;
Mahugo, J .; Urbano, A. J . Org. Chem. 1999, 64, 1387-1390. (f)
Carreytero, J . C.; Garc´ıa Ruano, J . L.; Mart´ın Cabrejas, L. M. J . Org.
Chem. 1997, 8, 22215-2225. (g) Carren˜o, M. C. Chem. Rev. 1995, 95,
1717-1760. (h) Posner, G. H. Acc. Chem. Res. 1987, 20, 72-78.
(10) (a) Yechezkel, T.; Ghera, E.; Ostercamp, D.; Hassner, A. J . Org.
Chem. 1995, 60, 5135-5142. (b) Durman, J .; Grayson, J . I.; Hunt, P.
G.; Warren, S. J . Chem. Soc., Perkin Trans. 1 1986, 1939-1945 and
reference cited herein. (c) Abul-Hajj, Y. J . J . Med. Chem. 1986, 29,
582-584. (d) McKervey, M. A.; Ratananukul, P. Tetrahedron Lett.
1983, 24, 117-120. (e) Monteiro, H. J .; Gemal, A. L. Synthesis 1975,
437-438 and reference cited therein. (f) Mukaiama, T.; Adachi, T.;
Kumamoto, T. Bull. Chem. Soc. J pn. 1971, 44, 3155-3158. (g) Tobias,
M. A.; Strong, J . G.; Napier, R. P J . Org. Chem. 1970, 35, 1709-1711.
(h) Wilgus, H. S., III; Frauenglass, E.; Chiesa, P. P.; Nawn, G. H.;
Evans, F. J .; Gates, J . W., J r. Can. J . Chem. 1966, 44, 603-609.
(11) (a) Lauret, C. Tetrahedron: Asymmetry 2001, 12, Report No.
52, 2359-2383. (b) McElroy, A. B.; Warren, S. Tetrahedron Lett. 1985,
26, 5709-5712.
By using 0.02-0.3 molar equiv of NaOH, the thiolyses
of 1 with thiols 2a -d in water at 30 °C and at pH 6-9
were very fast (0.25-8 h) and completely R-regio- and
anti-stereoselective, exclusively giving anti-â-hydroxy
sulfides 3a -d with excellent yields (95-98%) (Table 1,
entries 2, 6, 7, and 10).16
(12) Bernasconi, C. F.; Ketner, R. J .; Brown, S. D.; Chen, X.;
Rappoport. Z. J . Org. Chem. 1999, 64, 8829-8839. (b) Yabroff, D. L.
Ind. Eng. Chem. 1940, 32, 257-262.
(13) Bordwell, F. G.; Hughes, D. L. J . Org. Chem. 1982, 47, 3224-
3232.
(14) DeCollo, T. V.; Lees, W. J . J . Org. Chem. 2001, 66, 4244-4249.
(15) The value is calculated using Advanced Chemistry Development
(ACD Software Solaris V4.76). Due to its low solubility in water, the
real pKa value is expected to be higher. (1S)-Camphorthiol is completely
soluble in water at pH g 13 in 0.5 M concentration.
2316 J . Org. Chem., Vol. 69, No. 7, 2004

NaOH-Catalyzed Thiolysis of R,â-Epoxyketones in Water
TABLE 1. Th iolysis of 3,4-Ep oxyh ep ta n -2-on e (1) by Th iols 2a -d in Wa ter a t 30 °C
a
b
d
1.05 molar equiv. The amount of NaOH reported in the table is added at once. c Reaction time relative to a conversion >99%. Ratios
evaluated by H NMR analysis. e Yield of the isolated crude product. f Reaction conversion: 50%. NaOH was added slowly maintaining
the pH around 9.0 (see the Experimental Section). Mixture of syn - and a n ti-3c, -4c, and -5c for which ratios could not be correctly
measured. Yield of the isolated pure product 5d after chromatographic purification.
1
g
h
i
SCHEME 2. P r od u cts Obta in ed fr om th e Rea ction
3,4-Ep oxyh ep ta n -2-on e (1) w ith Th iols 2
A catalytic amount of NaOH is sufficient to complete
the reaction, because while the thiolysis is proceeding,
the ring-opening of the 1,2-epoxide leads to the formation
of an alkoxide ion which is responsible for further
basification of the reaction medium.
Under more basic conditions (NaOH 0.10-2.0 molar
equiv), the thiolyses of 1 were not selective due to the
high instability of compounds a n ti-3a -d already at 30
°C that, to different extents, underwent to epimerization
reaction at the C-3, to retroaldol condensation17 and to
dehydration reaction generally giving complex mixtures
of products (syn - and a n ti-3a -d , 4a -d , and 5a -d )
(Scheme 2). Thus, while at pH 12 a n ti-3a gave only a
partial C-3 epimerization with the formation of a 4:1
mixture of a n ti-3a and syn -3a (Table 1, entry 3), the
hydroxyl sulfide a n ti-3c quickly decomposed and already
at pH 9.0 a complex mixture of products was obtained.
By 1H NMR analysis, syn - and a n ti-3c, -4c, and -5c were
identified but overcrowded signals due to additional
decomposition products hampered the correct percentage
assignment for each compound (Table 1, entries 8 and 9,
respectively). At pH 12, thiolysis of 1 with 2b (Table 1,
(16) We have also considered the possibility of a Brønsted acid
entry 6) predominantly gave dehydration of a n ti-3b to
form the olefin (Z)-4b (55%), plus syn -3b (8%) and 5b
(24%) coming from the epimerization and retroaldol
reactions respectively). Compound a n ti-3d at pH 12
evolved preferentially to give retroaldol condensation
product 5d (73%, Table 1, entry 12); the epimerization
did not occur while dehydration product (Z)-4d was only
9% of the compounds’ mixture.
catalysis and we have performed the thiolsysis of 1 with 2a and 2b at
pH 2.0. After 24 h at 30 °C 2a gave complete conversion to a n ti-3a ,
while after 72 h 2b gave 90% conversion to a n ti-3b. This result can
be justified on the basis of the higher nucleophilicity of alkylthiol with
respect to aryl ones.
(17) â-Hydroxy-R-thiophenyl cyclohexanones derivatives, upon treat-
ment with strong bases (ethylthiolate or methoxide ions or lithium
diisopropylamide) in organic solvents, give exclusive retroaldol con-
densation. It is also reported that C-R epimerization under strong base
conditions (ethylthiolate or methoxide ions) occurs via retroaldol
condensation: (a) Caine, D.; Crews, E.; Salvino, J . M. Tetrahedron Lett.
1983, 24, 2083-2086. (b) Silvermann, R. B. J . Am. Chem. Soc. 1981,
103, 3, 5939-5941.
The NaOH-adding procedure is also important. Indeed,
the reactions of 1 with thiols 2a , 2c, and 2d , were
J . Org. Chem, Vol. 69, No. 7, 2004 2317

Fringuelli et al.
TABLE 2. Ba sic Tr ea tm en t of â-Hyd r oxy Su lfid es
a n ti-3a -d
SCHEME 3. On e-P ot Syn th esis of (Z)-4a -d by
Th iolysis of 1
productsa
hydroxy
entry
sulfide
pH
T (°C)
(Z)-4
(E)-4
5
1
2
3
4
5
6
7
8
3a
3a
3b
3b
3c
3c
3d
3d
9
13
9
13
9
13
9
13
70
30b
70
30
70
30
70b
30b
26
40
67
14
9
<1
0
60
51
33
17
0
83
100c
ndd
33
0
13
13
54
50
37
a
b
Ratios evaluated by 1H NMR analysis. 24 h. c Isolated as a
d
crude product in 92% yield. Only decomposition products were
formed.
performed by adding at once the amount of NaOH (as
0.1 or 1 M aqueous solution) to the mixture of reagents
and the pH remained approximately the same during all
the reaction time. Differently, in the thiolysis of 1 with
2b better results were obtained by adding dropwise the
aqueous base (0.3 molar equiv) and maintaining the pH
around 9 for all the reaction time (Table 1, entry. 5).
We have also checked the possibility to selectively
convert the anti-R-carbonyl-â-hydroxy sulfides 3a -d ,
prepared at pH 6-9 (Table 1), into vinyl sulfides 4a -d
and R-carbonyl sulfides 5a -d by dehydration or retro-
aldol condensation, respectively.
Basic treatment of a n ti-3a -d at different tempera-
tures always gave mixtures of products except in the case
of substrate a n ti-3c, where only vinyl sulfide (Z)-4c was
formed after heating at 70 °C at pH 9.0 (Table 2). E1cb
dehydration was prevalent in the case of aryl thiols while
a slightly preferential formation of retroaldol product was
obtained for alkanethiols.
a n ti-3a -d at 70 °C under acidic conditions selectively
gave vinyl sulfides (Z)-4a-d in satisfactory yields (Scheme
3).18 This result allowed the preparation of (Z)-4a -d to
be carried out by a one-pot procedure starting from R,â-
epoxy ketone 1 (Scheme 3). The Z-configuration of the
compounds (Z)-4a -d has been confirmed by NOESY
experiments, and H1 NMR data are in agreement with
the results obtained by Warren et al.10b It must be noticed
that while under basic conditions a mixture of E/Z
alkenes were obtained, under acidic conditions a complete
Z-stereoselectivity was found. This can be justified
considering that under acidic conditions the anchimeric
assistance of sulfinyl group to form a thiiranium inter-
mediate species, is very efficient giving a resulting cis-
elimination and then a complete Z-stereoselectivity while,
under basic conditions and in the case of alkylsulfinyl
group (3a ,d ), presumably a competition of an E1cB and
E2 mechanisms acted to give a mixture of Z- and
E-alkenes.
a
From 1 after chromatography.
The investigation was then extended to the thiolysis
of R,â-epoxycycloalkenones 6-8, 2-methyl-1,4-naphtho-
quinone oxide (9) and calchone oxide (10) with thiols 2b-
d , and the results are reported in Table 2. The thiolsyses
of compounds 6-9 proceeded, again under basic condi-
tions, by using a catalytic amount of NaOH (0.1-0.3
molar equiv) at 30 °C with exclusive nucleophilic attack
at C-R, but in these cases the thiolysis reactions were
always accompanied by the dehydration of the resulting
â-hydroxy sulfides to give the corresponding vinyl sulfides
6b, 7b-d , 8b,c, and 9c,d (Table 3, entries 1-8) in
excellent yield. The only exception was the thiolysis of 8
with thiol 2b that required reflux conditions for 1 h to
have a complete dehydration.20 1,2-Epoxide 9 was almost
totally insoluble in aqueous medium, but its high reactiv-
ity allowed the products 9c and 9d to be obtained in very
short reaction times already at 30 °C.
Calchone oxide (10) showed a peculiar behavior. This
substrate is very insoluble in water and poorly reactive
at 30 °C. At 70 °C, thiolyses of 10 with 2b-d were
accomplished, but only the products 10b-d deriving from
the retroaldol reaction were isolated; thus, under aqueous
basic conditions thiols 2b-d attached the R-position of
calchone oxide (10). According to our previous experience
where CTAOH or CTABr/NaOH systems promoted the
epoxidation of highly insoluble calchone,2f we found that
using CTAOH and CTABr/NaOH (0.3 molar equiv) at 30
°C, instead of NaOH, 10b and 10c were isolated in almost
quantitative yield after 12 h (Table 3, entries 10, 11, 13,
and 14).
Then we moved to investigate the synthetic utility of
the protocol and we focused our attention to the one-pot
synthesis in water of vinyl sulfides 7b and 7c, vinyl
sulfoxides 12 and 13, and 1,5,6,7-tetrahydro-4H-1,2,3-
benzotriazol-4-one (14) starting from cyclohex-2-en-1-one
(11) (Scheme 4).
(18) The dehydration of â-hydroxy sulfides has been generally
performed under acidic conditions by using 20 mol % of p-toluensulfonic
acid (p-TsOH) in organic solvent.19 We have studied separately this
step starting from the corresponding pure â-hydroxy sulfides, by using
in water H2SO4 or HCl at 70 °C, 18 h, and in CH2Cl2 20 mol % of
p-TsOH at reflux for 10 days. H2SO4 gave lower yields due to some
carbonization, while p-TsOH gave excellent results in conditions
apparently milder than those utilizing HCl but with a very long
reaction time. In this work, we have preferred the aqueous HCl
procedure that allowed the one-pot protocol to be realized, and the use
of p-TsOH is indeed viable.
(19) Fox, D. J .; House, D.; Warren S. Angew. Chem., Int. Ed. 2002,
41 2462-2482.
(20) At 30 °C after 1 h a 3:1 mixture of hydroxy sulfide and vinyl
sulfide was isolated. After heating to reflux for an additional 1 h, only
vinyl sulfide product was obtained.
2318 J . Org. Chem., Vol. 69, No. 7, 2004

NaOH-Catalyzed Thiolysis of R,â-Epoxyketones in Water
TABLE 3. Th iolysis of r,â-Ep oxy Keton es 6-10 in Wa ter a t 30 °C
a
b
Yield of the isolated pure product. 1 h at 30 °C and 1 h at reflux. c The reaction mixture is highly heterogeneous, and the pH
measurement is hardly trustful. After 24 h at 30 °C, no conversion at all. e Reaction performed at 70 °C.
d
J . Org. Chem, Vol. 69, No. 7, 2004 2319

Fringuelli et al.
SCHEME 4. Sin gle-Step a n d On e-P ot Syn th esis of
water and we have found that NaOH can be used in
catalytic amount (0.02-0.30 molar equiv) to efficiently
promote the thiolysis of cyclic and acyclic R,â-epoxy
ketones with a variety of alkyl- and arylthiols. The use
of a catalytic amount of base avoids side reactions to be
triggered and allows a complete regio- and stereoselec-
tivity to be attained. These results make possible the use
of the thiolysis of R,â-epoxy ketones for an efficient
synthesis of R-carbonyl vinyl sulfides.
7b, 7c, a n d 12-14a
While thiolysis of cyclic R,â-epoxy ketones 6-9 gave
the corresponding vinyl sulfides directly, the hydroxyl
sulfides 3a -d coming from 3,4-epoxyheptan-2-one (1)
required an additional acidic treatment to obtain an
efficient dehydration process.
One-pot multistep protocols in water to prepare R-car-
bonyl sulfoxides and triazole 14 starting from cyclohex-
2-en-1-one (11) in very good yields have also been
reported. Water has confirmed its efficiency as reaction
medium and that its unique properties can give a very
good contribution for improving the ecocompatibility of
organic synthesis.
Exp er im en ta l Section
Typ ica l Th iolysis P r oced u r e: P r ep a r a t ion of r el-
(3R,4R)-3-Bu tylth io-4-h yd r oxyh ep ta n -2-on e (3a ). A 189
mg (2.1 mmol) portion of butylthiol (2a ) was added to 3.75 mL
of water and 0.25 mL of NaOH 0.1 M aqueous solution to
obtain a resulting pH ) 9.0. Then after 5 min, 256 mg (2.0
mmol) of 3,4-epoxyheptan-2-one (1) was added, and after an
additional 0.5 h under vigorous magnetic stirring at 30 °C,
the reaction mixture was extracted with Et2O (3 × 5 mL). The
combined organic layers were dried over Na2SO4 and evapo-
rated under vacuum to give the crude hydroxysulfide. 3a was
isolated as an oil in g98% purity by silica gel column
chromatography (Etp/AcOEt: 8:2 (gradient), silica/sample: 30:
1) in 94% yield.
a
Key: (A) H2O2/H2O, 1-3 °C, 30 min, startiong pH 12;21 (B) (i)
thiol 2b (R ) H), 30 °C, pH 9.0, 0.5 h, (ii) thiol 2c (R ) CO2H), 30
C, pH 6.0, 1 h (see Table 2); (C) Na5IO6, 30 °C, (i) 3 h (R ) H), (ii)
1 h (R ) CO2H); (D) NaNH3, pH 7.0, 30 °C, 3 h, 91%.
First, the oxidation of vinyl sulfoxides and 1,3-dipolar
cycloaddition of 12 in sole water (Scheme 4, steps C and
D) were investigated. Step A was previously reported,2f
and step B has been just defined.
Vinyl sulfides 7b and 7c, treated with sodium perio-
date in water at 30 °C, gave the corresponding vinyl
sulfoxides 12 and 13 in 85 and 81% yields, after 3 and 1
h respectively (step C, Scheme 4). Vinyl sulfoxide 12
showed a very high reactivity when treated with sodium
azide at 30 °C in water, giving the 1,3-dipolar cyclo-
addition in 3 h only and affording, after elimination of
phenylsulfenyl acid, the corresponding 1,5,6,7-tetrahydro-
4H-1,2,3-benzotriazol-4-one (14) in 91% yield (step D,
Scheme 4).
Typ ica l On e-P ot Syn th esis of a n Acyclic Vin yl Su lfid e:
Syn th esis of (Z)-3-(Bu tylth io)h ep ten -2-on e ((Z)-4a ). A 189
mg (2.1 mmol) portion of butylthiol (2a ) was added to 3.75 mL
of water and 0.25 mL of NaOH 0.1 M aqueous solution to
obtain a resulting pH ) 9.0. Then after 5 min, 256 mg (2.0
mmol) of 3,4-epoxyheptan-2-one (1) was added, and after an
additional 0.5 h under vigorous stirring at 30 °C, 0.4 mL of
concd HCl was added and the reaction mixture warmed to 70
°C. After 18 h, the reaction mixture was extracted with Et2O
(3 × 5 mL). The combined organic layers were washed with
brine (1 × 5 mL), dried over Na2SO4, and evaporated under
vacuum to give the title vinyl sulfide. (Z)-4a was isolated as
an oil in g98% purity by silca-gel column chromatography
(Etp/AcOEt: 9:1 (gradient), silica/sample: 20:1) in 90% yield:
oil; Rf ) 0.33 (Etp/AcOEt 9:1); IR (CHCl3, cm-1) 1213 (s), 1358
(w), 1461 (w), 1593 (w), 1675 (s), 2873 (w), 2933 (m), 2965 (s),
Vinyl sulfides 7b and 7c were then prepared starting
from the R,â-enone 11 via consecutive one-pot epoxidation
and thiolysis/dehydration in 93% and 91% overall yields
(Scheme 4). By submitting to sodium periodate oxidation
the reactions mixtures coming from 11 and containing
7b or 7c, vinyl sulfoxides 12 or 13 were prepared in 72%
and 63% overall yield, respectively, by a one-pot proce-
dure. When the one-pot protocol was continued, triazole
14 was obtained directly starting from cyclohex-2-en-1-
one (11) in a very good 63% overall yield (Scheme 4).
1
3019 (w); H NMR (400 MHz, CDCl3) δ 0.86 (t, 3H, J ) 7.2
Hz), 0.95 (t, 3H, J ) 7.4 Hz), 1.30-1.55 (m, 6H), 2.39 (s, 3H),
2.47 (q, 2H, J ) 7.4 Hz), 2.61 (t, 2H, J ) 7.4 Hz), 6.98 (t, 1H,
J ) 7.4 Hz); 13C NMR (400 MHz, CDCl3) δ 13.5, 13.921.7, 21.8,
27.0, 31.9, 32.8, 33.2, 137.2, 150.0, 197.3; GC-MS (EI, 70 eV)
m/z 200 (M+, 100), 157 (25), 143 (28), 115 (33), 95 (29), 67 (30),
43 (69). Anal. Calcd for C11H20OS ) C, 65.95; H, 10.06.
Found: C, 65.98; H, 10.15.
All new compounds have been fully characterized and
their structures confirmed by standard analytical and
spectroscopic methods (see the Experimental Section and
the Supporting Information).
On e-P ot Syn th esis of 1,5,6,7-Tetr a h yd r o-4H-1,2,3-ben -
zotr ia zol-4-on e (14). A 0.196 g (2.0 mmol) portion of cyclohex-
2-en-1-one (11) and 0.25 mL (0.5 molar equiv) of 2 M NaOH
aqueous solution were added to 1.62 mL of water at 0-2 °C.
After the mixture was stirred at this temperature for 10 min,
0.13 mL (1.1 molar equiv) of 35 wt % aqueous hydrogen
peroxide was added (pH ∼11). After 0.5 h, 0.215 mL (1.15
molar equiv) of thiophenol was added at 30 °C (pH ∼9), and
the stirring was continued for 30 min. At this stage, 928 mg
of powdered NaIO4 (2.0 molar equiv) was added and the
Currently, studies on the extension of this reaction and
on the applications of R-aryl- and alkylsulfenylalkenones
are ongoing in our laboratory.
In conclusion, we have reported a study on the influ-
ence of the pH on the thiolysis of R,â-epoxyketones in
2320 J . Org. Chem., Vol. 69, No. 7, 2004

NaOH-Catalyzed Thiolysis of R,â-Epoxyketones in Water
reaction mixture left under stirring at 30 °C. After 3 h, NaN3
(200 mg, 1.1 molar equiv) was added and the pH of the reaction
mixture adjusted to 7.0 by adding some drops of H2SO4 1 M
aqueous solution. After 3 h at 30 °C, the reaction mixture was
acidified to pH 2.0 and extracted with three 10 mL portions
of ethyl acetate. The combined organic layers were dried over
Na2SO4 and evaporated under reduced pressure to give the
title product in 63% overall yield. The product was recrystal-
lizated from acetone: white crystals; mp ) 226-227 °C; Rf )
0.25 (absolute AcOEt); IR (Nujol, cm-1) 3205 (m broad), 2944
(m), 2889 (m), 1666 (s), 1477 (m), 1077 (w), 992 (w), 846 (w);
1H NMR (400 MHz, DMSO-d6, 303 K) δ 2.04 (quintet, 2H, J )
6.2 Hz, H-6), 2.48 (t, 2H, J ) 6.2 Hz, H-7), 2.89 (t, 2H, J ) 6.2
Hz, H-5); 13C NMR ((400 MHz, DMSO-d6, 330 K) δ 19.8, 22.7,
38.4, 139.4, 148.1, 190.2; GC-MS (EI, 70 eV) m/z 137 (76),
109 (100), 108 (43), 80 (33), 53 (62), 52 (55). Anal. Calcd for
C6H7N3O: C, 52.55; H, 5.14; N, 30.64. Found: C, 52.59; H,
5.32; N, 30.80.
Ack n ow led gm en t. The Universita` degli Studi di
Perugia and the Ministero dell’Istruzione dell’Universita`
e della Ricerca (MIUR) are thanked for financial support
COFIN 2002; COFINLAB 2001 (CEMIN); FIRB: ”Pro-
gettazione, preparazione e valutazione biologica e far-
macologica di nuove molecole organiche quali potenziali
farmaci innovativi”.
Su p p or tin g In for m a tion Ava ila ble: Full characteriza-
tion charts (1H NMR, 13C NMR, IR, GC-MS, Rf) for compounds
a n ti-3a -d , (Z)-4a -d , 7c,d , 8b,c, 9c,d , 10c,d , 13, and 14 and
significant spectral 1H and 13C NMR signals for compounds
5a ,d and syn -3a ,b,d . This material is available free of charge
via the Internet at http://pubs.acs.org.
J O035804M
J . Org. Chem, Vol. 69, No. 7, 2004 2321