The First Nonthiolic, Odorless 1,3-Propanedithiol Equivalent and Its Application in Thioacetalization

Article abstract of DOI:10.1021/jo034702t

2-[2-Chloro-1-(1-chlorovinyl)allylidene]-1,3-dithiane 1 was synthesized by the chlorination of 3-(1,3)-dithianylidenepentane-2,4-dione 2 using the Vilsmeier-Haack reagent in 99% yield. As a novel nonthiolic, odorless 1,3-propane-dithiol equivalent, 1 was investigated in the thioacetalization reaction. Various types of aldehydes and ketones 3 were converted to the corresponding dithianes 4 in the presence of 1 in high yields (79-97%). Moreover, 1 exhibited obvious chemoselectivity between aldehyde and ketone in this thioacetalization reaction. A mechanism for this thioacetalization reaction is proposed.

Full text of DOI:10.1021/jo034702t

Th e F ir st Non th iolic, Od or less
,3-P r op a n ed ith iol Equ iva len t a n d Its
Ap p lica tion in Th ioa ceta liza tion
synthesis and application of various ketene dithioac-
etals.1
3,14
As part of the further investigations, we report
1
herein a novel ketene dithioacetal, 2-[2-chloro-1-(1-chlo-
rovinyl)allylidene]-1,3-dithiane 1, and its application in
a thioacetalization reaction as a nonthiolic, odorless
substitute for 1,3-propanedithiol.
Qun Liu,* Guangbo Che, Haifeng Yu, Yingchun Liu,
J ingping Zhang, Qian Zhang, and Dewen Dong
Department of Chemistry, Northeast Normal University,
Changchun, 130024, P. R. China
liuqun@nenu.edu.cn
Received May 23, 2003
Abstr act: 2-[2-Chloro-1-(1-chlorovinyl)allylidene]-1,3-dithiane
1
was synthesized by the chlorination of 3-(1,3)-dithianyli-
denepentane-2,4-dione 2 using the Vilsmeier-Haack reagent
in 99% yield. As a novel nonthiolic, odorless 1,3-propane-
dithiol equivalent, 1 was investigated in the thioacetalization
reaction. Various types of aldehydes and ketones 3 were
converted to the corresponding dithianes 4 in the presence
of 1 in high yields (79-97%). Moreover, 1 exhibited obvious
chemoselectivity between aldehyde and ketone in this thio-
acetalization reaction. A mechanism for this thioacetaliza-
tion reaction is proposed.
Through the Vilsmeier-Haack reaction,15 compound
1 was synthesized from 3-(1,3)-dithian-2-ylidenepentane-
2
,4-dione 2 in 99% yield. It is worth noting that the
odorless 1 could be stored in a desiccator for several
months without any chemical change, namely, it is quite
stable. Compound 2 was prepared from acetylacetone,
carbon disulfide, and 1,3-dibromopropane in nearly quan-
titative yield following the procedure described in the
literature.16
The thioacetalization reaction between 1 and selected
aldehydes/ketones 3 was carried out via a simple proce-
dure. The preparation of dithiane 4d is described below
as an example. Piperonal 3d (2.0 mmol), compound 1 (2.2
mmol), and methanol (99%, 15 mL) were added to a flask
equipped with a condenser. The mixture was heated at
Thioacetalization is well-known as a reaction that
1
protects carbonyl groups of aldehydes and/or ketones.
Recently, extensive work has been focused on its applica-
tions, such as the unparalleled dithiane carbanion lynch-
pin strategy in natural and/or complex molecule synth-
esis,2 the new approach to titanium-alkylidene chem-
-4
5
istry to form a C-C bond, and the dithiane-/trithiane-
2
reflux and stirred under N . Once the aldehyde had been
based photolabile scaffolds in molecular recognition.6
Unfortunately, most of the above work related to the
thioacetalization reaction has involved the use of flam-
mable, harmful, and obnoxious odor producing thiols or
sulfides, which can lead to serious environmental and
,7
consumed, as indicated by TLC, the resulting mixture
was worked up and separated via silica gel chromatog-
raphy (eluent: petroleum ether) to afford 4d in 97% yield
(mp 86-87 °C). Various types of aromatic aldehydes with
electron-donating and electron-withdrawing groups were
converted to the corresponding dithianes 4 in the pres-
ence of 1. Similarly, aliphatic aldehydes, cycloketones,
and aromatic ketones also gave high yields of the corre-
sponding dithianes 4. The structures of the starting
materials and the products, along with the reaction
conditions and product yields, are given in Table 1.
From Table 1, 1 exhibited generality in the thioacetal-
ization reaction since it worked very well with both
aldehydes and ketones. It was noted, however, that the
thioacetalization of aldehydes proceeded more easily with
the shorter reaction time and higher yields than that of
1
-7
safety problems.
To circumvent these problems, the
development of odorless substitutes for these obnoxious
thiols and sulfides is therefore of great merit.8
-12
In our
previous work, much effort has been devoted to the
(
1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; J ohn Wiley & Sons: New York, 1999.
2) Bulman Page, P. C.; Van Niel, M. B.; Prodger, J . C. Tetrahedron
989, 45, 7643.
3) Smietana, M.; Valleix, A.; Mioskowski, C. Tetrahedron Lett. 2003,
4, 213.
4) (a) Smith, A. B., III; Pitram, S. M.; Gaunt, M. J .; Kozmin, S. A.
(
1
(
4
(
J . Am. Chem. Soc. 2002, 124, 14516. (b) Smith, A. B., III; Lin, Q.;
Doughty, V. A.; Zhuang, L.; McBriar, M. D.; Kerns, J . K.; Brook, C. S.;
Murase, N.; Nakayama, K. Angew. Chem., Int. Ed. 2001, 40, 196. (c)
Tyrrell, E.; Skinner, G. A.; J anes, J .; Milsom, G. Synlett 2002, 1073.
(9) (a) Brown, H. C.; Zaidlewicz, M.; Dalvi, P. V.; Biswas, G. K. J .
Org. Chem. 2001, 66, 4795. (b) Crich, D.; Neelamkavil, S. Org. Lett.
2002, 4, 4175.
(10) Manabe, K.; Iimura, S.; Sun, X. M.; Kobayashi, S. J . Am. Chem.
Soc. 2002, 124, 11971.
(11) Bertini, V.; Lucchesini, F.; Pocci, M.; De Munno, A. J . Org.
Chem. 2000, 65, 4839.
(12) Wan, Y. Q.; Kurchan, A. N.; Barnhurst, L. A.; Kutateladze, A.
G. Org. Lett. 2000, 2, 1133.
(13) Zhang, Q.; Zhao, Y. L.; Shi, Y.; Wang, L. X.; Liu, Q. Synth.
Commun. 2002, 32, 2369.
(14) Wang, M.; Xu, X. X.; Liu, Q.; Xiong, L.; Yang, B.; Gao, L. X.
Synth. Commun. 2002, 32, 3437.
(15) Thomas, A. D.; Asokan, C. V. Tetrahedon Lett. 2002, 43, 2273.
(16) Choi, E. B.; Youn, I. K.; Pak, C. S. Synthesis 1988, 792.
(
5) (a) Horikawa, Y.; Watanabe, M.; Fujiwara, T.; Takeda, T. J . Am.
Chem. Soc. 1997, 119, 1127. (b) Breit, B. Angew. Chem., Int. Ed. 1998,
7, 453. (c) Takeda, T.; Kuroi, S.; Yanai, K.; Tsubouchi, A. Tetrahedron
Lett. 2002, 43, 5641.
6) (a) Wan, Y. Q.; Angleson, J . K. Kutateladze, A. G. J . Am. Chem.
Soc. 2002, 124, 5610. (b) Kurchan, A. N.; Kutateladze, A. G. Org. Lett.
002, 4, 4129.
7) (a) Sasson, R.; Hagooly, A.; Rozen, S.Org. Lett. 2003, 5, 769. (b)
Chiba, K.; Uchiyama, R.; Kim, S.; Kitano, Y.; Tada, M. Org. Lett. 2001,
, 1245.
8) (a) Crich, D.; Neelamkavil, S. J . Am. Chem. Soc. 2001, 123, 7449.
b) Crich, D.; Neelamkavil, S. Tetrahedron 2002, 58, 3865. (c) Nishide,
K.; Ohsugi, S. I.; Fudesaka, M.; Kodama, S. Node, M. Tetrahedron Lett.
3
(
2
(
3
(
(
2
002, 43, 5177.
1
0.1021/jo034702t CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/17/2003
9
148
J . Org. Chem. 2003, 68, 9148-9150

SCHEME 1. In ter m ed ia tes Obta in ed in th e Th ioa ceta liza tion Rea ction
SCHEME 2. P r op osed Mech a n ism for th e Th ioa ceta liza tion Rea ction
ketones, compare 3a with 3n and 3i with 3q. The fact
that aldehydes appear to be more reactive than ketones
in this thioacetalization reaction is attributed to steric
effects. For further comparison, two more thioacetaliza-
tion reactions were carried out using 3a /3n /1 (mole ratio
TABLE 1. Th ioa ceta liza tion of Selected Ald eh yd es/
Keton es 3 w ith Com p ou n d 1
1
:1:1) and 3i/3q/1 (mole ratio 1:1:1). Products 4a and 4i
were obtained in 81% (reaction time: 150 min) and 91%
yield (reaction time: 110 min), respectively, and no
production arising from reaction with the ketone was
detected. This indicates that 1, as a thioacetalization
reagent, is chemoselective for aldehydes over ketones.
In an attempt to optimize the reaction conditions,
the thioacetalization reaction with 1 was carried out in
dried, absolute solvents, including MeOH, EtOH, THF,
R1
R2
yielda (%)
entry
time (min)
3
3
a , 4a
b, 4b
3c, 4c
d , 4d
e, 4e
f, 4f
3g, 4g
h , 4h
i, 4i
j, 4j
k , 4k
3l, 4l
m , 4m
n , 4n
o, 4o
3p , 4p
q, 4q
Ph
H
H
H
H
H
H
H
H
H
H
H
H
150
145
160
160
160
160
120
120
120
150
150
120
350
300
300
350
400
95
96
95
97
92
85
92
91
93
79
79
81
91
91
90
86
85
2-Furyl
PhCHdCH
3,4-O2CH2C6H3
4-MeOC6H4
4-CHOC6H4
4-FC6H4
3
3
3
3
3
3
3
4-Me2NC6H4
4-NO2C6H4
2-CHOC6H4
4-HOC6H4
n-C6H13
2 2
CH Cl , t-BuOH, and i-PrOH. Unfortunately, there was
no evidence that the thioacetalization reaction had taken
place at either room or reflux temperature. It appears
that the small amount of water present in the solvent
plays an important role in the reaction.
To investigate the mechanism of this thioacetalization
reaction, several supporting experiments were carried
out. In one experiment, a mixture of 1 (2.2 mmol) and 3i
3
3
3
-(CH2)6-
Ph
Ph
Me
Ph
Me
Me
4-NH2C6H4
4-NO2C6H4
3
(
2.0 mmol) in methanol (99%, 20 mL) was stirred at room
a
Isolated yields after column chromatography on silica gel.
temperature for 20 min; the final pH value of the reaction
J . Org. Chem, Vol. 68, No. 23, 2003 9149

mixture was approximately 3.5. Dimethylacetal 5i (struc-
ture see Scheme 1) and ketene dithioacetal 2 were
obtained in 97% and 10% yields, respectively, with 90%
of 1 remaining in the system. This indicates that the
thioacetalization reaction does not occur at room tem-
perature. Obviously, 5i is the acetalized product of 3i,
and 2 has resulted from the hydrolysis of 1. In another
experiment, a mixture of 1 (2.2 mmol) and 3i (2.0 mmol)
in methanol (99%, 20 mL) was heated at reflux for 70
min. The pH of the reaction mixture fell to 2.5 prior to
being quenched with aqueous NaOH. Consequently,
dimethylacetal 5i, dithio ortho ester 6, monothioacetal
Although it was not separated from the reaction
system, 10 was prepared by the deacylation of 2 using
HCl as the catalyst. Both compounds 2 and 10 were
applied to the above thioacetalization reaction. Replacing
1 with compounds 2 and 10 in the above thioacetalization
reaction and under similar conditions as described in
Table 1 unfortuantely proved unsuccessful. However, 4a
was obtained from experiments with 3a /1/ 2 (mole
ratio: 2:1:1) and 3a /1/ 10 (mole ratio: 2:1:1) in 75% and
77% yields, respectively. The experiments reveal that
both compounds 2 and 10 could act as suitable thioac-
etalization reagents only when the appropriate catalyst
is used. Therefore, the reaction between 1 and aldehyde/
ketone is actually an acid-assisted, self-catalyzed trans-
thioacetalization reaction.
7
a i, and dithiane 4i, as shown in Scheme 1, were
obtained from the resulting reaction mixture in 14%, 9%,
1%, and 45% yields, respectively. Obviously, the tem-
1
perature plays another important role in the thioacetal-
ization reaction and the change of pH indicates that the
reaction proceeds with the release of acid. The experi-
ment suggests that 6, as an intermediate of the thioac-
etalization reaction, might result from 2 and the dithiane
In summary, a novel ketene dithioacetal, compound 1,
as a nonthiolic, odorless, stable thioacetalization reagent
has been developed. Various types of aldehydes and
ketones have been converted to the corresponding
dithianes in the presence of this reagent in high yield
(79-97%). Meanwhile, the thioacetalization reaction with
its associated mild reaction conditions, high yields, and
chemoselectivity between aldehydes and ketones has
been demonstrated as an acid-assisted, self-catalyzed
trans-thioacetalization reaction. Further investigations
on the applications of this novel thioacetalization reagent
are in progress.
4
would be potentially formed via a trans-thioacetaliza-
tion between 6 and the acetal 5.
On the basis of the above experimental results, a
mechanism for this thioacetalization reaction is proposed
as shown in Scheme 2. With the strong nucleophilicity
from the electron-donating alkylthio groups,17 1 is easily
hydrolyzed by water from the solvent and subsequently
releases HCl to form 2. With the released HCl as catalyst,
Ack n ow led gm en t. Financial support of this work
by the NNSFC (29862004 and 20272008) is greatly
acknowledged.
2
then undergoes deacylation. The solvent, methanol,
then can add to the deacylated product 10 to give 6. This
can further react with methanol to give 11, which can
then add to intermediate 5 to generate the mixed acetal
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and analytical data for 1, its thioacetalization products
7
. Further reaction of 7 will then lead to the dithiane 4.
4
, and the synthetic intermediates. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) (a) Okuyama, T. Acc. Chem. Res. 1986, 19, 370. (b) Chou, W.
C.; Fang, J . M. J . Org. Chem. 1996, 61, 1473.
J O034702T
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150 J . Org. Chem., Vol. 68, No. 23, 2003