Ring-opening reactions of 2-alkoxy-3,4-dihydropyrans with Thiols or Thiophenols

Article abstract of DOI:10.1021/ol103110q

An electrophilic ring-opening reaction of 2-alkoxy-3,4-dihydropyran with a thiophenol or thiol is developed for the first time. The generated product contains not only a 1,3-dicarbonyl moiety but also a fragment of bis(alkylthio)methane. A possible mechan

Full text of DOI:10.1021/ol103110q

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1064–1067
Ring-Opening Reactions of 2-Alkoxy-3,
4-dihydropyrans with Thiols or Thiophenols
Minghao Li,† Haoquan Li,† Tao Li,† and Yanlong Gu*,†,‡
Institute of Physical Chemistry and Industrial Catalysis, Hubei Key Laboratory of
Material Chemistry and Service Failure, School of Chemistry and Chemical Engineering,
Huazhong University of Science and Technology, 1037 Luoyu Road, Hongshan District,
Wuhan 430074, China, and State Key Laboratory for Oxo Synthesis and Selective
Oxidation, Lanzhou Institute of Chemical Physics, Lanzhou, 730000, China
*To whom correspondence should be addressed. Fax: (þ)(0)86-(0)27-87-54-45-32.
klgyl@hust.edu.cn
Received December 22, 2010
ABSTRACT
An electrophilic ring-opening reaction of 2-alkoxy-3,4-dihydropyran with a thiophenol or thiol is developed for the first time. The generated product
contains not only a 1,3-dicarbonyl moiety but also a fragment of bis(alkylthio)methane. A possible mechanism is also proposed on the basis of
postulating a ring-opening monotransthioacetalization product, which was prepared by using LiBr as catalyst as an intermediate.
Since organic sulfur compounds have become increas-
ingly useful in organic synthesis and pharmaceutical chem-
istry, convenient preparations of appropriate sulfides,
especially those which contain other functional groups,
should be important.1 Although a variety of the methods
for their synthesis are available in the literature,2 the most
convenient method should involve not only transforma-
tion of a sulfur compound but also a simultaneous intro-
duction of one or more organic functional groups into the
final product. In this regard, a ring-opening reaction of
epoxide with a thiol or thiophenol could be a typical
example, in which both formation of C-S bond and
generation of a hydroxyl group were realized at the same
time.3 Some other ring-opening reactions with thiol or
thiophenol as nucleophile showed a similar performance
on the creation of molecular complexity,4 but unfortunately,
these examples are still limited. To fit the current requirement
of pharmaceutical chemistry on molecular diversity and
(3) Some selected examples: (a) Fringuelli, F.; Pizzo, F.; Tortoioli, S.;
Vaccaro, L. Adv. Synth. Catal. 2002, 344, 379–384. (b) Pironti, V.;
Colonna, S. Green Chem. 2005, 7, 43–45. (c) Wu, J.; Xia, H.-G. Green
Chem. 2005, 7, 708–710. (d) Chen, J.; Wu, H.; Jin, C.; Zhang, X.; Xie, Y.;
Su, W. Green Chem. 2006, 8, 330–332. (e) Gao, P.; Xu, P.-F.; Zhai, H.
Tetrahedron Lett. 2008, 49, 6536–6538. (f) Dalpozzo, R.; Nardi, M.;
Oliverio, M.; Paonessa, R.; Procopio, A. Synthesis 2009, 3433–3438.
(4) (a) Cohen, T.; Ritter, R. H.; Ouellette, D. J. Am. Chem. Soc. 1982,
104, 7142–7148. (b) Adriaenssens, L. V.; Austin, C. A.; Gibson, M.;
Smith, D.; Hartley, R. C. Eur. J. Org. Chem. 2006, 4998–5001.
(c) Prasad, D. J. C.; Sekar, G. Org. Biomol. Chem. 2009, 7, 5091–5097.
(d) Larson, S. E.; Baso, J. C.; Li, G.; Antilla, J. C. Org. Lett. 2009, 11,
5186–5189. (e) Krishnaveni, N. S.; Surendra, K.; Rao, K. R. Adv. Synth.
Catal. 2006, 348, 696–700. (f) Kim, S. K.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2004, 43, 3952–3954.
† Huazhong University of Science and Technology.
‡ Lanzhou Institute of Chemical Physics.
(1) (a) Solladie, G. Synthesis of Sulfides, Sulfoxides and Sulfones. In
Comprehensive Organic Synthesis;Trost, B. M., Fleming, I., Eds.;Pergamon
Press: Oxford, UK, 1991; Vol. 6, pp 133-170. (b) Cremlyn, R. J. An
Introduction to Organo-Sulfur Chemistry; Wiley & Sons: New York, 1996.
(2) Some selected examples, see: (a) Yin, J.; Pidegon, C. Tetrahedron
Lett. 1997, 38, 5953–5954. (b) Li, C.-J.; Harpp, D. N. Tetrahedron Lett.
1992, 33, 7293–7294. (c) Harpp, D. N.; Gingras, M. J. Am. Chem. Soc.
1988, 110, 7737–7745. (d) Gingras, M.; Chan, T. H.; Harpp, D. N.
J. Org. Chem. 1990, 55, 2078–2090. (e) Ranu, B. C.; Mandal, T. J. Org.
Chem. 2004, 69, 5793–5795. (f) Ranu, B. C.; Jana, R. Adv. Synth. Catal.
2005, 347, 1811–1818.
r
10.1021/ol103110q
Published on Web 01/31/2011
2011 American Chemical Society

complexity, new and efficient reactions for the synthesis of
organic sulfur compounds are appealingly needed.
Table 1. Ring-Opening Reaction of 1a with 2a under Different
Conditionsa
Recently, the use of simple heterocycles as substrate in
organic synthesis has gained much attention because het-
erocycles displayed in organic transformations a great
productivity in creation of molecular complexicity and
diversity.5 We have reported a domino Knoevenagel/oxo
Diels-Alder reaction of olefins, formaldehyde and β-
dicarbonyl compounds, which generated a variety of
2,5,6-trisubstituted 3,4-dihydropyran derivatives in high
yields under catalyst-free conditions.6 Because the reaction
procedure is quite simple, it not only allowed an easy scale-
up of the reaction, but it also occurred to us how to use the
reaction products. In literature, reactions of such substi-
tuted dihydropyrans have been rarely explored due per-
haps to the difficulty of preparation.7 We viewed that
skeletons of the dihydropyrans involve either a semicyclic
acetal or a benzyl ether fragment that is generally unstable
in the presence of nucleophile under acidic condition.8
Particularly, semicyclic acetals (1), such as O-glycosides,
are known to react with various nucleophiles in the pre-
sence of a Lewis acid to give cyclic ether products (2) via
cyclicoxocarbenium ion intermediates (eq1).9 Onthe basis
of these results, we suspect that the substituted dihydro-
pyran 1a should be capable of reacting with a nucleophile
in the presence of Lewis acid catalyst (eq 2). However,
during our study, we found unexpectedly a highly selective
ring-opening reaction of 2-alkoxy-3,4-dihydropyran with
a thiol or thiophenol, which offers an efficient method to
link a β-dicarbonyl fragment together with the core of the
nucleophile. The optimal catalyst is manganese(II) bromide.
entry
catalyst
solvent
yield (%)
1b
2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
toluene
0
H3BO3
trace
10
3
MnCl2
NiCl2
4
12
5
Bi(OTf)3
FeCl3
trace
trace
85
6
7
InCl3
8
ZnCl2
80
9
Sc(OTf)3
Y(OTf)3
TsOH
75
10
11
12
13
14
15
16
17
18
19c
20d
21e
22f
82
78
Amberlyst-15
MnBr2
MnBr2
MnBr2
MnBr2
MnBr2
MnBr2
MnBr2
MnBr2
MnBr2
MnBr2
50
88
10
CH3CN
trace
5
DCE
1,4-dioxane
EtOH
trace
trace
54
CH3NO2
CH3NO2
CH3NO2
CH3NO2
62
96
94
a 1a: 0.25 mmol; solvent: 1 mL. b No catalyst was used. c 5 mol % of
catalyst was used. d Reaction was conducted at 60 °C. e 11 h. f Reaction
was conducted in 10 mmol scale, 11 h.
(5) For a recent review, see: Ismabery, N.; Lavila, R. Chem.;Eur. J.
2008, 14, 8444-8454 and the references cited therein.
(6) (a) Gu, Y.; De Sousa, R.; Frapper, G.; Bachmann, C.; Barrault,
ꢀ ^
J.; Jerome, F. Green Chem. 2009, 11, 1968–1972. (b) Gu, Y.; Barrault, J.;
To the best of our knowledge, only a few examples of ring-
opening reactions of dihydropyrans have been performed
sofar,10 and this typeof ring-opening reaction has not been
reported yet.
ꢀ ^
Jerome, F. Adv. Synth. Catal. 2009, 351, 3269–3278. (c) Li, M.; Chen, C.;
He, F.; Gu, Y. Adv. Synth. Catal. 2010, 352, 519–530. (d) Tan, J.-N.; Li,
M.; Gu, Y. Green Chem. 2010, 12, 908–914. (e) Tan, J.-N.; Li, H.; Gu, Y.
Green Chem. 2010, 12, 1772–1782.
(7) For oxidation: (a) Chan, Y.; Li, X.; Zhu, C.; Liu, X.; Zhang, Y.;
Leung, H. J. Org. Chem. 1990, 55, 5497–5504. (b) Chan, Y.; Zhu, C.;
Leung, H. J. Am. Chem. Soc. 1985, 107, 5274-5275. For condensation
with aldehydes: (c) Anghelova, Y.; Ivanov, C.; Metsov, S. Chem. Ber.
1977, 110, 1594–1596. (d) Armstrong, A.; Goldberg, F. W.; Sandham,
D. A. Tetrahedron Lett. 2001, 42, 4585-4587. For decarboxylative ring-
opening: (e) Jendrichovsky, J.; Jendrichovska, M.; Nevydal, J.; Rybar,
A. Czech. 1987, CS 235185 B1 19870215. (f) LaMontagne, M. P.;
Markovac, A.; Khan, M, S. J. Med. Chem. 1982, 25, 964–968. (g) Anderson,
E. P.; Crawford, J. V.; Sherrill, M. L. J. Am. Chem. Soc. 1946, 68, 1294–
1296.
(8) For the reaction between acetal and nucleophiles: (a) Bhuvaneswari,
S.; Jeganmohan, M.; Cheng, C.-H. Chem.;Eur. J. 2007, 13, 8285–8293.
(b) Chakrabarty, M.; Ghosh, N.; Basak, R.; Harigaya, Y. Tetrahedron
Lett. 2002, 43, 4075-4078. For the reaction between benzyl ether and
nucleophiles: (c) Noji, M.; Konno, Y.; Ishii, K. J. Org. Chem. 2007, 72,
5161–5167. (d) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem., Int. Ed.
2006, 45, 793–796.
Initially, a reaction of an 2-alkoxy-3,4-dihydropyran,
1a, with thiophenol, 2a, was investigated, and the results
are listed in Table 1.11 In the absence of catalyst, no
reaction occurred (entry 1). When some weak acids, such
(9) (a) Sugiura, M.; Kobayashi, S. Org. Lett. 2001, 3, 477–780.
(b) For the reactions of O-glycosides, see the following review: Du, Y.;
Linhardt, R. J. Tetrahedron 1998, 54, 9913–9959.
(11) All reactions were conducted in a 10 mL V-type flask equipped
with triangle magnetic stirring. In a typical reaction, nitromethane (1.0
mL) was mixed with 1a (60.5 mg, 0.25 mmol), 2a (68.8 mg, 0.63 mmol),
and MnBr2 (6.4 mg, 12 mol %) under air. The mixture was stirred for 6 h
at 80 °C. After reaction, the mixture was cooled to room temperature
and the desired product, 3a, was obtained by preparative TLC, using a
mixed solution of ethyl acetate and petroleum ether as eluting solvent
(the ratio of ethyl acetate/petroleum ether is 1/7). Tests for substrate
scope and experiments concerning the mechanism were all performed
according to an analogous procedure with the above mentioned.
(10) (a) Zanatta, N.; Amaral, S. S.; Esteves-Souza, A.; Echevarria,
A.; Brondani, P. B.; Flores, D. C.; Bonacorso, H. G.; Flores, A. F. C.;
Martins, M. A. P. Synthesis 2006, 2305–2312. (b) Chu, Q.; Song, L.; Jin,
G.; Zhu, S. J. Fluorine Chem. 2001, 108, 51–56. (c) Song, L.-P.; Chu,
Q.-L.; Zhu, S.-Z. J. Fluorine Chem. 2001, 107, 107–112. (d) Zhu, S. Z.;
Xu, G. L.; Qin, C. X.; Chu, Q. L.; Xu, Y. Monatsh. Chem. 1999, 130,
671–680. (e) Mellor, J. M.; Reid, G.; El-Sagheer, A. H.; El-Tamany,
E. S. H. Tetrahedron 2000, 56, 10039–10055.
Org. Lett., Vol. 13, No. 5, 2011
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Scheme 1. Substrate Scope of the Ring-Opening Reactions of
2-Butoxy-3,4-dihydropyrans with Thiophenols or Thiolsa
Scheme 2. Ring-Opening Monotransthioacetalization of 1a
with 2a and the Following Reaction of the Generated Product
with 2a
3,4-dihydropyrans and thiophenols could be applied in the
ring-opening reaction, and the corresponding products were
obtained in good to excellent yields. Thiols could also be
used instead of thiophenol, and the corresponding products
were obtained in excellent yields. It should be noted that the
skeleton of the ring-opening product has never been reported
before, and it contains not only a moiety of 1,3-dicarbonyl
compound, but also a fragment of bis(alkylthio)methane.
In view of the extensive use of the both functional groups
in various organic transformations, it would not be unrea-
sonable to expect the formed products might be valuable for
pharmaceutical synthesis. Our method thus offers the first
path for accessing this novel class of complex molecules.
The mechanism of the ring-opening reaction of the
dihydropyran, 1a, most likely involves a manganese-as-
sisted cleavage of a C-O bond of 1a. However, there are
two C-O bonds in the skeleton of 1a, so in order to shed
light on which C-O is more reactive, we then treated 1a
with LiBr, which has been reported to be a highly effective
catalyst for monothioacetalization of acetals,12 at 80 °C. In
this case, the reaction proceeded sluggishly, and after 11 h
of reaction, a product, 4a, was isolated in 81% yield without
detectable formation of any byproduct (Scheme 2). Follow-
ing treatment of 4a with 2a in the presence of MnBr2 in
nitromethane resulted in an exclusive formation of 3a.
This observation led us to postulate 4a as an intermedi-
ate of the reaction. And a plausible reaction mechanism is
thus deduced as shown in Figure 1. In the beginning of the
reaction, dihydropyran 1a was activated with the aid of
MnBr2 catalyst to form an oxonium intermediate (I). This
step was generally catalyzed by Lewis acid.13 Once I was
formed, it tended to react with 2a to generate the inter-
mediate 4a. In the presence of MnBr2, 4a underwent a
cleavageof the C-O bondtoformananotherintermediate
(II) that tended to react with the next thiophenol to
generate the final product 3a.14 It should be noted that,
in the presence of a strong acid catalyst, cleavage of the
C-O bond out of the ring is also possible, which will
a All reactions were conducted under the optimized condition of
Table 1.
as boric acid, MnCl2, and NiCl2, were used, a product, 3a,
was formed, butthe yieldsobtainedare ratherpoor(entries
2-4). Therefore, some strong acids, such as Bi(OTf)3 and
FeCl3, were then examined in this reaction, and it was
found that substrate 1a was almost completely consumed;
however, 3a were obtained only in trace amount (entries 5
and 6). In these cases, many byproducts that are difficult to
isolate were observed by TLC detection. Interestingly,
when other acids, such as Sc(OTf)3, InCl3, ZnCl2, TsOH,
and Y(OTf)3, were used ascatalysts, the yield of 3a reached
75-85% (entries 7-11). A solid acid, Amberlyst-15, was
also used, and in this case, a 50% yield was obtained (entry
12). To further improve the reaction yield, an inexpensive
catalyst, MnBr2, was used in this reaction. To our great
delight, the model reaction proceeded smoothly in this
case, and 3a was finally obtained in 88% yield (entry 13).
Further investigation revealed that the solvent also played
a key role in controlling the catalytic activity of MnBr2,
and nitromethane was proved to be an appropriate solvent
for this system (entries 14-18). In later study, the reaction
condition was optimized by using MnBr2 as catalyst. And
it was found that the best condition should be 80 °C and 12
mol % of catalyst (entries 19 and 20). Increase of reaction
time can improve the reaction yield, and finally, a max-
imum yield, 96%, was obtained with 11 h of reaction. It
should be noted that the reaction can be uneventfully
scaled up to 10 mmol, and the yield obtained is still very
high (94%, entry 22), indicating the effectiveness of this
method for practical synthesis.
(12) Ono, F.; Negoro, R.; Sato, T. Synlett 2001, 1581–1583.
(13) Cossy, J.; Rakotoarisoa, H.; Kahn, P.; Desmurs, J.-R. Tetra-
hedron Lett. 2000, 41, 7203–7205.
(14) (a) Fan, E.; Shi, W.; Lowary, T. J. Org. Chem. 2007, 72, 2917–
2928. (b) Marmsaeter, F. P.; Murphy, G. K.; West, F. G. J. Am. Chem.
Soc. 2003, 125, 14724–14725. (c) Masaki, Y.; Serizawa, Y.; Kaji, K.
Chem. Lett. 1985, 1933–1936.
With the optimized conditions in hand, we probed the
scope of the reaction withrespect toboththe dihydropyran
and thiophenol. As shown in Scheme 1, a variety of
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Org. Lett., Vol. 13, No. 5, 2011

yet. LiBr-assisted selective formation of 4a in this reaction
encouraged us to further examine the reactivity of 4a in
the presence of other nucleophiles. As shown in Scheme 3,
in the presence of an appropriate catalyst, 4a can react
smoothly with indole or 2,4-dimethylthiophenol to form
unsymmetrical double-substituted product, 6a or 7a, in
good to excellent yields. Because skeletons of the formed
products contain not only a fragment of 1,3-dicarbonyl
compound but also the core structure of two different
nucleophiles, thistype of reaction can thus be consideredas
an effective method for creation of molecular complexity
and diversity.
In conclusion, an electrophilic ring-opening reaction of
1a-type 2-alkoxy-3,4-dihydropyran with two molecules of
thiophenol or thiol was described. The generated product
contains not only a 1,3-dicarbonyl moiety but also a
fragment of bis(alkylthio)methane. By using LiBr as cat-
alyst, the dihydropyran can react selectively with thiophe-
nol to form a ring-opening monotransthioacetalization
product, which can be further converted to the final ring-
opening product. Therefore, a possible mechanism for the
ring-opening reaction of 2-alkoxy-3,4-dihydropyran with
thiophenol was proposed on the basis of postulating the
ring-opening monotransthioacetalization product as an
intermediate. In addition, the ring-opening monotrans-
thioacetalization product can further react with other
nucleophiles, such as indole and 2,4-dimethylthiophenol,
to form the corresponding unsymmetrical double-substi-
tuted product in high yields.
Figure 1. Plausible mechanism for the model reaction.
Scheme 3. Reactions of 4a with Indole and 2,4-Dimethylthio-
phenol in the Presence of Catalyst
Acknowledgment. Financial support from National
Natural Science Fundation of China (20903042), the Pro-
gram for new Century Excellent Talents in the University
of China (NCET-10-0383), and the Chutian Scholar Pro-
gram of the Hubei provincial government are acknowl-
edged. The authors are also grateful for Ms. Ping Liang
and all the other staff members in the Analytical and
Testing Center of HUST for their contributions to our
works.
generate a cyclic oxonium intermediate that can also react
with 2a. Fortunately, two different mechanisms are both
operative for the formation of 3a because all the starting
materials can finally flow the same way regardless of the
mechanism.
Supporting Information Available. Experimental de-
tails, characterization data of the products, and 1H NMR
and 13C NMR profiles of new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
It should be noted that the ring-opening monothioace-
talization of 1a-type dihydropyran has not been reported
Org. Lett., Vol. 13, No. 5, 2011
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