Novel rearrangements of 2,3-dimercapto-1-propanol derivatives: Formation of dialkyl sulfide, dialkyl disulfide, and 1,2,3-tris(alkylthio)propane

Article abstract of DOI:10.1021/jo960784s

The base alkylation of 2,3-dimercapto-1-propanol with alkyl halides leads in good yield to 2,3-bis(alkylthio)-1-propanol and dialkyl sulfide. The reaction of 2,3-bis(alkylthio)-1-propanol with catalytic concentrated sulfuric acid proceeds with rearrangement to give 1,2,3-tris(alkylthio)propane and dialkyl disulfide. The rearrangement reaction takes place through a common intermediate thiaranium intermediate 8.

Full text of DOI:10.1021/jo960784s

8
244
J . Org. Chem. 1996, 61, 8244-8247
Novel Rea r r a n gem en ts of 2,3-Dim er ca p to-1-p r op a n ol Der iva tives:
F or m a tion of Dia lk yl Su lfid e, Dia lk yl Disu lfid e, a n d
1
,2,3-Tr is(a lk ylth io)p r op a n e
Chi Wi Ong,* Yi Meen Chou, and J unn Nan Wang
Department of Chemistry, National Sun Yat Sen University, Kaoshiung, Taiwan 804
Received April 29, 1996X
The base alkylation of 2,3-dimercapto-1-propanol with alkyl halides leads in good yield to 2,3-bis-
(alkylthio)-1-propanol and dialkyl sulfide. The reaction of 2,3-bis(alkylthio)-1-propanol with catalytic
concentrated sulfuric acid proceeds with rearrangement to give 1,2,3-tris(alkylthio)propane and
dialkyl disulfide. The rearrangement reaction takes place through a common intermediate
thiaranium intermediate 8.
In tr od u ction
The chemical compound 2,3-dimercapto-1-propanol is
Ta ble 1. Ba se Alk yla tion of 2,3-Dim er ca p to-1-p r op a n ol
w ith Alk yl Ha lid es To Give 2,3-Bis(a lk ylth io)-1-p r op a n ol
a n d Dia lk yl Su lfid e
1
well known for its ability to serve as a ligand for metals.
It has been used an antidote for heavy metal poisoning
because it forms stable complexes with the mercapto
groups and thus facilitates excretion from the body. 2,3-
Dimercapto-1-propanol is also effective in reactivating
enzymes that have been deactivated by thiol reagents.
Recently, 2,3-dimercapto-1-propanol has been found to
inhibit transactivation directed by tat protein, which is
a metal-containing transcriptional transactivating factor
in HIV.2
In the course of developing the synthesis of new metal-
sequestering agents based on 2,3-dimercapto-1-propanol
derivatives, we have uncovered a series of novel rear-
rangement reactions that lead to the formation of dialkyl
sulfide, dialkyl disulfide, and 1,2,3-tris(alkylthio)propane.
We report herein a detailed study of these amazingly
diverse rearrangement reactions of 2,3-dimercapto-1-
propanol with a view of establishing the generality of this
process and the influence of substituent on the product
distributions. There have been no previous reports on
this type of rearrangement, although it has been known
that commercially available 2,3-dimercapto-1-propanol
3
contains a minute trace of 1,2,3-tris(alkylthio)propane.
Resu lts a n d Discu ssion
The conversion of 2,3-dimercapto-1-propanol to the
corresponding S,S′-dialkyl derivatives proceeded smoothly
upon the addition of alkyl bromide in the presence of
sodium bicarbonate and ethanol/water mixture as sol-
vent.4 In this manner, 2,3-bis(ethylthio)-1-propanol (1)
and 2,3-bis(isopropyl)-1-propanol (2) were obtained as the
sole products in good yields. In contrast, the reaction
with benzyl bromide was found to give both 2,3-bis-
undergoes elimination of dialkyl sulfide and thiaranium
intermediate 5. We noted that the same thiaranium
intermediate 5 was formed irrespective of the regiose-
lectivity in S-alkylation (Scheme 1). This was confirmed
by reacting pure 3 with benzyl bromide, which was found
to give 4 as the major product. When pure 3 was heated
with sodium bicarbonate in ethanol/water, only the
starting material was recovered. We thus postulate that
the reactions with ethyl bromide and isopropyl bromide
also must have afforded the corresponding dialkyl sul-
fides, which were removed during evaporation under
vacuo due to their low boiling points. Thus, the reaction
with hexyl bromide was found to give 2,3-bis(hexylthio)-
1-propanol (6) and dihexyl sulfide (7).
(benzylthio)-1-propanol (3) and dibenzyl sulfide (4) as the
major products (Table 1). The observation of 4 as the
major product can be explained by the initial attack of a
sulfur atom in 3 with another molecule of benzyl bromide
to give the alkylsulfonium intermediate, which then
X
Abstract published in Advance ACS Abstracts, October 1, 1996.
(
1) Randell, R. V.; Seeler, A. O. Med. Progr.: BAL N. Eng. J . Med.
948, 239, 1004.
2) Kubota, S.; El-Farrah, M. A.; Maki, M.; Harada, S.; Hatanaka,
M. AIDS Res. Hum. Retroviruses 1990, 6, 919.
3) White, L. B.; Torosian, G.; Becker, C. H. Anal. Chem. 1974, 46,
43.
4) Ong, C. W.; Yen, F. W.; Chou, Y. M.; Chao, Y. K.; Chen, C. F.
Biorg. Med. Lett. 1993, 4, 607.
1
(
(
In the course of this work, the 2,3-bis(alkylthio)-1-
propanol prepared above was treated with phenol in the
presence of catalytically concentrated sulfuric acid in
1
(
S0022-3263(96)00784-0 CCC: $12.00 © 1996 American Chemical Society

Rearrangements of 2,3-Dimercapto-1-propanol Derivatives
J . Org. Chem., Vol. 61, No. 23, 1996 8245
Sch em e 1
Ta ble 2. Rea ction of 2,3-Bis(a lk ylth io)-1-p r op a n ol in th e
P r esen ce of Ca ta lytic Con cen tr a ted Su lfu r ic Acid To
Give 1,2,3-Tr is(a lk ylth io)p r op a n e a n d Dia lk yl Disu lfid e
a
refluxing toluene aimed at synthesizing phenyl ether
derivatives. Surprisingly, two totally different products
were obtained, and these were characterized as 1,2,3-
tris(alkylthio)propane and dialkyl disulfide derivatives.
The exact structure of the dialkyl disulfide, in particular,
the differentiation from the dialkyl sulfide counterpart,
1
was difficult to ascertain from the H NMR. This
structure was confirmed by two independent syntheses:
(i) dihexyl sulfide from sodium sulfide with hexyl bromide
and (ii) dihexyl disulfide from sodium hydrogen sulfide
5
with hexyl bromide, followed by oxidation. Dihexyl
1
sulfide was found to exhibit an H NMR signal at δ 2.50
and dihexyl disulfide at δ 2.70 for the methylenethio
1
group. In general, the H NMR chemical shifts for the
disulfides are at a lower field as compared with the
sulfides. The rearrangements of compounds 1, 2, 3, and
6
were summarized in Table 2. To our knowledge, the
a
rearrangement of 2,3-bis(alkylthio)-1-propanol to 1,2,3-
tris(alkylthio)propane and dialkyl disulfide is unprec-
edented. The observed formation of 1,2,3-tris(alkylthio)-
propane and dialkyl disulfide is interesting and can be
explained by protonation of the sulfur or oxygen atoms.
Protonation of the sulfur atom readily eliminates a
molecule of alkylmercaptan with the formation of thia-
ranium intermediate 5 as proposed in Scheme 1, ir-
respective of which sulfur atom is protonated. The
thiaranium intermediate 5 can then undergo further
transformation leading to another molecule of alkylm-
ercaptan and acrolein. The alkylmercaptan formed will
subsequently lead to the formation of dialkyl disulfide
The yields of products were based on theoreticel yield.
(
benzylthio)-1-propanol (3), which rearranged under these
conditions to give dibenzyl disulfide 9 as the major
product (50%), together with 1,2,3-tris(benzylthio)pro-
pane 10 (30%). On changing to 2,3-bis(alkylthio)-1-
propanol, we observed a decreasing amount of disulfide,
and 1,2,3-tris(alkylthio)propane was obtained as the
major product. In this manner, 1, 2, and 6 gave the
corresponding 1,2,3-tris(ethylthio)propane (11) (86%),
1
(
,2,3-tris(isopropylthio)propane (12) (87%), and 1,2,3-tris-
hexylthio)propane (13) (40%), in excellent yields. In the
case of 6, some dihexyl disulfide (14) (7.5%) was isolated.
After the reaction, a polymeric gum was found at the
bottom of the reaction vessel. This can be attributed to
the proposed formation of acrolein during the reactions,
which undergoes polymerization readily under acidic
conditions.
5
due to oxidation through prolonged reaction time. Al-
ternatively, the protonation of the oxygen atom will
readily eliminate a molecule of water with the formation
of thiaranium intermediate 8. Because of the strain in
this thiaranium group, it can undergo a ring-opening
reaction with the alkyl mercaptan produced by elimina-
tion regioselectively at the less substituted position to
give 1,2,3-tris(alkylthio)propane (Scheme 2). The ring
opening of the thietanium group has also been observed
previously.6 A summary of these results is given in
Table 2. Ultimately, the ratio of dialkyl disulfide and
In order to increase the potential of thioethers to serve
as ligands for metal ions, we next examined the syn-
8
thesis of 1,2,3-tris[(2-aminoethyl)thio]propane, using the
above methodology. Reaction of 1,2-dimercapto-1-pro-
panol afforded 2,3-bis[(2-phthalimidoethyl)thio]-1-pro-
panol (15) in a 44% yield. This was again smoothly
rearranged under concentrated sulfuric acid in refluxing
toluene to give 1,2,3-tris[(3-phthalimidoethyl)thio]pro-
pane (16) (56%) and bis(2-phthalimidoethyl) disulfide (17)
23%). The versatility was further extended to the
synthesis of 2,3-bis[(carbethoxymethyl)thio]-1-propanol
18), which again undergoes rearrangement smoothly
,7
1
,2,3-tris(alkylthio)propane will be controlled by the ease
of disulfide formation. It is known that benzyl mercaptan
has a higher pK , and it will react slower with electro-
a
(
philes such as the thiaranium intermediate 8 and thus,
favors the formation of disulfide after oxidative self-
coupling.6 This is consistent with the result of 2,3-bis-
(
under acidic conditions to 1,2,3-tris[(carbethoxymethyl)-
thio]propane (19).
(
(
5) Khurana, J . M.; Sahoo, P. K. Synth. Commun. 1992, 22, 1691.
6) Vriesema, B. K.; Lemaire, M.; Buter, J .; Kellog, R. M. J . Org.
Chem. 1986, 51, 5169.
7) Adams, R. D.; Fallon, S. B. J . Am. Chem. Soc. 1994, 116, 10540.
(8) Murray, S. G.; Hartley, F. R. Chem. Rev. 1981, 365 and
references cited therein.
(

8
246 J . Org. Chem., Vol. 61, No. 23, 1996
Ong et al.
Sch em e 2
(d, J ) 8.6 Hz, 2H), 2.75 (m, 1H), 3.61 (s, 2H), 3.68 (s, 2H),
+
3
2
3
.70 (m, 2H), 7.23-7.27 (m, 10H); LRMS (EI) m/z 304 (M ),
+
13, 122, 91; HRMS (EI) (M - 1) calcd for C17
H
19OS
2
03.0877, found 303.0881.
Diben zyl su lfid e (4): light yellow oil, 45%; IR (CHCl
3
) υ
-
1 1
)
(
3
3100, 2880 cm ; H NMR (CDCl ) δ 3.58 (s, 4H), 7.22-7.31
+
+
m, 10H); LRMS (EI) m/z 214 (M ), 123, 91; HRMS (EI) (M )
calcd for C14
H
14S 214.0816, found 214.0812.
2
,3-Bis(h exylth io)-1-p r op a n ol (6): light yellow oil, 28%;
-
1 1
IR (CHCl
3
) υ ) 3500, 2900, cm ; H NMR (CDCl ) δ 0.89 (t,
3
J ) 6.8 Hz, 6H), 1.25-1.50 (m, 12H), 1.59 (m, 4H), 2.50-3.00
+
(
2
2
m, 7H), 3.75 (qq, J ) 5 Hz, 2H); LRMS (EI) m/z 292 (M ),
+
07, 175; HRMS (EI) (M ) calcd for C15 292.1895, found
H
32OS
2
92.1897. Anal. Calcd for C15 32OS C, 61.64; H, 10.96.
H
2
Found: C, 61.38; H, 10.93.
Dih exyl su lfid e (7): light yellow oil, 25.8%; 1H NMR
CDCl ) δ 0.89 (t, J ) 6.7 Hz, 6H), 1.25-1.50 (m, 12H), 1.59
(
(
3
+
m, 4H), 2.50 (t, J ) 7.5 Hz, 4H); LRMS (EI) m/z 202 (M ),
+
1
2
17, 85; HRMS (EI) (M ) calcd for C12
02.1913.
H26S 202.1755, found
Rea ction s of 2,3-Bis(th io-d er iva tive)-1-p r op a n ol w ith
Con cen tr a ted Su lfu r ic Acid in Reflu xin g Tolu en e. To a
solution of the 2,3-bis(thio-derivative)-1-propanol in toluene
was added a few drops of concentrated sulfuric acid and the
mixture refluxed under azeotropic conditions overnight. Tolu-
ene was then removed under reduced pressure and the crude
product treated with dilute NaOH followed by extraction with
3
CHCl . The crude product obtained was then chromatographi-
cally separated.
3
Diben zyl d isu lfid e (9): light yellow oil, 50%; IR (CHCl )
-
1
1
υ ) 3100, 2880 cm ; H NMR (CDCl ) δ 3.58 (s, 4H), 7.22-
3
+
7
.31 (m, 10H); LRMS (EI) m/z 246 (M ), 123, 91; HRMS (EI)
+
(
M ) calcd for C14
14 2
H S 246.0537, found 246.0542.
1
,2,3-Tr is(ben zylth io)p r op a n e (10): yellow oil, 31%; IR
-
1
1
(
(
(
CHCl
3
) υ ) 3100, 2850 cm ; H NMR (CDCl ) δ 2.50-3.00
3
m, 5H), 3.62 (s, 4H), 3.74 (s, 2H), 7.22-7.42 (m, 15H); LRMS
+
+
EI) m/z 319 (M ) 410), 195, 91; HRMS (EI) (M) calcd for
C
24
H
26
S
3
410.1196, found 410.1179.
,2,3-Tr is(eth ylth io)p r op a n e (11): light yellow oil, 86%;
H NMR (CDCl ) δ 1.27 (t, J ) 7.2 Hz, 9H), 2.57 (q, J ) 7.2
1
1
3
Hz, 4H), 2.90 (m, 5H); 1 C NMR δ 14.2, 15.0, 25.0, 27.1, 36.2,
3
In conclusion, we have demonstrated that 2,3-dimer-
+
+
4
5.8; LRMS (EI) m/z 224 (M ), 195, 163; HRMS (EI) (M ) calcd
for C 224.0727, found 224.0725.
,2,3-Tr is(isop r op ylth io)p r op a n e (12): yellow oil, 87%;
capto-1-propanol derivatives can undergo a wide array
of rearrangement reactions. These reactions provide an
easy entry to 1,2,3-tris(mercapto)propane derivatives,
useful as new metal chelators and of potential therapeu-
tic interest.
9
20 3
H S
1
-1
1
IR (CHCl
3
) υ ) 2880 cm ; H NMR (CDCl ) δ 1.28 (m, 18H),
3
+
2.80-3.20 (m, 8H), LRMS (EI) m/z 266 (M ), 223, 191, 137,
+
89; HRMS (EI) (M ) calcd for C12
66.1196.
,2,3-Tr is(h exylth io)p r op a n e (13): yellow oil, 37.2%; IR
26 3
H S 266.1197, found
2
1
Exp er im en ta l Section
-
1
1
(
CHCl
3
) υ ) 2950 cm ; H NMR (CDCl ) δ 0.88 (t, J ) 6.6
3
1H NMR spectra were recoded at 300 MHz in chloroform-d
solutions unless otherwise stated. All column chromatography
operations were conducted using Kieselgel 60.
Gen er a l P r oced u r e for th e S,S′-Dia lk yla tion of 2,3-
Dim er ca p to-1-p r op a n ol. To a solution of 2,3-dimercapto-
Hz, 9H), 1.25-1.50 (m, 18H), 1.59 (m, 6H), 2.55 (m, 6H), 2.88
+
(m, 5H); LRMS (EI) m/z 392 (M ), 307, 275, 131; HRMS (EI)
+
(M ) calcd for C21
H
44
S
3
392.2605, found 392.2596. Anal. Calcd
: C, 64.29; H, 11.22. Found: C, 64.28; H, 11.27.
Dih exyl d isu lfid e (14): light yellow oil, 7.5%; IR (CHCl
44 3
for C21H S
3
)
-
1
1
1
-propanol (0.1 M) in a water-ethanol mixture (300 mL:30
υ ) 2950 cm ; H NMR (CDCl
1.25-1.50 (m, 12H), 1.67 (m, 4H), 2.68 (t, J ) 7.5 Hz, 4H);
LRMS (EI) m/z 234 (M ), 150, 117, 85; HRMS (EI) (M ) calcd
for C12 234.1476, found 234.1482.
2,3-Bis[(2-ph th alim idoeth yl)th io]-1-pr opan ol (15): light
yellow oil, 44%; IR (CHCl
(CDCl ) δ 2.80-3.10 (m, 7H), 3.90 (m, 6H), 7.72 (m, 4H), 7.83
(m, 4H); LRMS (FAB) m/z 470 (M ), 296, 263, 174, 160; HRMS
3
) δ 0.89 (t, J ) 6.7 Hz, 6H),
mL) was added sodium bicarbonate (0.2 M) and the mixture
left to stir at room temperature for 1 h under 1 atm of nitrogen.
After this period, the appropriate halide (0.2 M) was added
and the mixture refluxed for 3 days. The solution was
concentrated to approximately one-third of its volume and
extracted with chloroform, dried over magnesium sulfate, and
evaporated to dryness. The crude product obtained was
chromatographed on a silica gel column to afford the products.
+
+
26 2
H S
-1 1
3
) υ ) 3500, 1770, 1710 cm ; H NMR
3
+
+
(FAB) (M ) calcd for C23
22 2 5 2
H N O S 470.0970, found 470.0968.
2
,3-Bis(eth ylth io)-1-p r op a n ol (1): colorless oil, 72%; IR
1,2,3-Tr is[(2-p h th a lim id oeth yl)th io]p r op a n e (16): yel-
-
1
1
-1 1
(
CHCl
3
) υ ) 3500 cm ; H NMR (CDCl
3
) δ 1.28 (t, J ) 7.4
low oil, 56%; IR (CHCl
3
3
) υ ) 1774, 1708 cm ; H NMR (CDCl )
Hz, 6H), 2.60 (m, 4H), 2.77-2.93 (m, 3H), 3.80 (m, 2H); LRMS
δ 3.00 (m, 10H), 3.23 (m, 1H), 3.97 (m, 6H), 7.73 (m, 6H), 7.86
+
+
+
(
C
EI) m/z 180 (M ), 151, 119, 105; HRMS (EI) M calcd for
180.0643, found 180.0638.
,3-Bis(isop r op ylth io)-1-p r op a n ol (2): colorless oil, 65%;
(m, 6H); LRMS (FAB) m/z 659 (M ), 485, 452, 206; HRMS
+
7
H
2
16OS
2
(FAB) (M ) calcd for C33
H
29
N
3
O
6
S
3
659.1218, found 659.1218.
Bis(2-p h th a lim id oeth yl) d isu lfid e (17): yellow oil, 23%;
-
1
1
-1 1
IR (CHCl
3
) υ ) 3480 cm ; H NMR (CDCl
3
) δ 1.28 and 1.33
IR (CHCl
3
) υ ) 1775, 1710 cm ; H NMR (CDCl
3
) δ 3.04 (t, J
(
(
dd, J ) 2.4 Hz, 12H), 2.90-3.05 (m, 5H), 3.76 (m, 2H); LRMS
) 7 Hz, 2H), 4.04 (t, J ) 7 Hz, 4H), 7.74 (m, 4H), 7.85 (m,
+
+
+
+
EI) m/z 208 (M ), 165, 133; HRMS (EI) M calcd for C
208.0955, found 208.0949.
,3-Bis(ben zylth io)-1-p r op a n ol (3): colorless oil, 22%; IR
9
H
20
-
4H); LRMS (EI) m/z 412 (M ), 206; HRMS (FAB) (M ) calcd
for C20 412.0552, found 412.0548.
2,3-Bis[(ca r beth oxym eth yl)th io]-1-p r op a n ol (18): col-
OS
2
16 2 4 2
H N O S
2
-
1
1
-1 1
(CHCl
3
) υ ) 3500, 3100, 2850 cm ; H NMR (CDCl
3
) δ 2.59
3
orless oil, 62%; IR (CHCl ) υ ) 3500, 2900, 1750 cm ; H NMR

Rearrangements of 2,3-Dimercapto-1-propanol Derivatives
J . Org. Chem., Vol. 61, No. 23, 1996 8247
(
CDCl
3
) δ 1.26 (t, J ) 7.5 Hz, 6H), 2.94 (d, J ) 5 Hz, 2H), 3.10
grant studentship grant to Y.M.C. (Ph.D.) and J .N.W.
(
m, 1H), 3.24 (s, 2H), 3.30 (s, 2H), 3.75 (m, 2H), 4.14 (q, J )
(
M.Sc.). We thank National Tsing Hua University for
+
7
.2 Hz, 4H); LRMS (EI) m/z 296 (M ), 279, 223, 177. Anal.
Calcd for C11 : C, 44.59; H, 6.76. Found: C, 44.54; H,
.87.
,2,3-Tr is[(ca r beth oxym eth yl)th io]p r op a n e (19): color-
assistance in obtaining the high-resolution mass spec-
tra.
20 5 2
H O S
6
1
Su p p or tin g In for m a tion Ava ila ble: Copies of proton
NMR spectra of compounds 1-4, 6, 7, and 9-19 (17 pages).
This material is contained in libraries on microfiche, im-
mediately 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.
-
1
1
less oil, 41%; IR (CHCl
1
)
3
) υ ) 1750 cm ; H NMR (CDCl
3
) δ
.30 (t, J ) 7.2 Hz, 9H), 3.10 (m, 4H), 3.34 (m, 7H), 4.23 (q, J
7.2 Hz, 6H); LRMS (EI) m/z 398 (M ), 278, 238, 160.
+
Ack n ow led gm en t. We would like to thank the
National Science Council of Taiwan for the research
J O960784S