Mercuric chloride and iodide mediated cyclization of tethered alkynedithioacetals as a general route to five- and six-membered rings: Tuning of regioselectivity by alkyne substitution

Article abstract of DOI:10.1021/ol0527274

Mercuric chloride mediated cyclization of tethered alkynedithioacetals has been established as a general route to five- and six-membered carbocycles and heterocycles. Substitution at the alkyne terminus leads to preferential formation of five-membered rings, whereas unsubstituted alkynedithioacetals give six-membered rings as the major products. Mercuric iodide interrupts the reaction at the intermediate dithioacetal stage.

Full text of DOI:10.1021/ol0527274

ORGANIC
LETTERS
2006
Vol. 8, No. 2
313-316
Mercuric Chloride and Iodide Mediated
Cyclization of Tethered
Alkynedithioacetals as a General Route
to Five- and Six-Membered Rings:
Tuning of Regioselectivity by Alkyne
Substitution
Goutam Biswas, Subir Ghorai, and Anup Bhattacharjya*
Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road,
Kolkata 700032, India
anupbhattacharjya@iicb.res.in
Received November 10, 2005
ABSTRACT
Mercuric chloride mediated cyclization of tethered alkynedithioacetals has been established as a general route to five- and six-membered
carbocycles and heterocycles. Substitution at the alkyne terminus leads to preferential formation of five-membered rings, whereas unsubstituted
alkynedithioacetals give six-membered rings as the major products. Mercuric iodide interrupts the reaction at the intermediate dithioacetal
stage.
The use of mercury compounds as reagents in organic
synthesis is well established.1 Apart from different mercu-
ration reactions involving alkenes and alkynes, Hg(II)
compounds have been extensively used in a variety of
carbocyclization and heterocyclization reactions.1,2 The ma-
jority of these ring-forming reactions have led to the
formation of five- and six-membered rings. Recently we
reported a unique reaction of O-propargylglycolaldehyde
dithioacetals 1 (X ) O, Scheme 1) in the presence of
mercuric chloride, CaCO3 in CH3CN-H2O, which results
in the formation of 6H-pyran-3-ones 3 (3-pyranones, X )
O, R3 ) H, R4 ) H, Scheme 1) along with dihydrofuran-
3-aldehydes 4 (X ) O, R3 ) H, R4 ) H) in some cases
(Scheme 1).3 The most noteworthy feature of this cyclization
was the intermediacy of the 3-pyranone dithioacetals 2
(X ) O, R3 ) H, R4 ) H) during the reaction. The utility of
this novel reaction lies in the fact that the end result is
intramolecular carbon-carbon bond formation leading to six-
and five-membered rings. The reaction attains greater
significance if it can accommodate substrates having all
(1) (a) Larock, R. C. SolVomercuration/Demercuration Reactions in
Organic Synthesis; Springer-Verlag: Berlin, Germany, 1986. (b) Larock,
R. C. Tetrahedron 1982, 38, 1713-1754.
(2) (a) Imagawa, H.; Iyenaga, T.; Nishizawa, M. Org. Lett. 2005, 7, 451-
453. (b) Imagawa, H.; Kurisaki, T.; Nishizawa, M. Org. Lett. 2004, 6, 3679-
3681. (c) Nishizawa, M.; Yadav, V. K.; Skwarczynski, M.; Takao, H.;
Imagawa, H.; Sugihara, T. Org. Lett. 2003, 5, 1609-1611. (d) Nishizawa,
M.; Takao, H.; Yadav, V. K.; Imagawa, H.; Sugihara, T. Org. Lett. 2003,
5, 4563-4565. (e) Nishizawa, M.; Skwarczynski, M.; Imagawa, H.;
Sugihara, T. Chem. Lett. 2002, 12-13. (f) Frederickson, M.; Grigg, R. Org.
Prep. Proc. Int. 1997, 29, 63-116. (g) Larock, R. C.; Harrison, L. W. J.
Am. Chem. Soc. 1984, 106, 4218-4227. (h) Riediker, M.; Schwartz, J. J.
Am. Chem. Soc. 1982, 104, 5842-5844. (i) Bates, D. K.; Jones, M. C. J.
Org. Chem. 1978, 43, 3775-3776. (j) Thyagarajan, B. S.; Majumdar, K.
C.; Bates, D. K. J. Heterocycl. Chem. 1975, 12, 59-66. (k) Balasubhra-
manian, K. K.; Reddy, K. V.; Nagarajan, R. Tetrahedron Lett. 1973, 14,
5003-5004.
(3) Ghorai, S.; Bhattacharjya, A. Org. Lett. 2005, 7, 207-210.
10.1021/ol0527274 CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/14/2005

Scheme 1. General HgCl2 Mediated Carbocyclization of
Table 1. Generalized HgCl2 Mediated Cyclization of Tethered
Alkynedithioacetals Containing Terminal Alkynesa
Three-Atom Tethered Alkynedithioacetals
carbon tethers or tethers containing other heteroatoms such
as nitrogen resulting in the formation of both carbocyclic
and heterocyclic rings. Moreover the reaction depicted in
Scheme 1 was also observed to afford five-membered rings
as minor products in some cases.3 The scope of the reaction
could be expected to increase if the regioselectivity could
be tuned so as to preferentially afford either six- or five-
membered rings. The realization of the aforementioned two
goals would greatly expand the scope of the reaction and
increase the diversity in the products obtained. We report
herein that the reaction is indeed applicable to alkynedithio-
acetals 1 (Scheme 1) having tethers comprising all carbon
atoms or containing heteroatoms such as nitrogen and
oxygen. Also described below is an interesting and useful
tuning of the regioselectivity by substitution at the alkyne
terminus, which makes the reaction preferentially favor the
five-membered ring-systems 4 (Scheme 1).
It was observed earlier that the mercuric chloride induced
reaction of these tethered alkyne dithioacetals did not occur
when the tether contained more than three atoms.3 The
necessity of a three-atom tether was evident from the
hydrolytic cleavage of the dithioacetal 5 with a two-atom
tether under the aforementioned conditions; this led to the
aldehyde 64 (Scheme 2) rather than the anticipated cyclization
product.
a All reactions were performed at 25 °C in CH3CN-H2O (4:1) for 4 h
in the presence of 3.0 equiv of HgCl2 and 4.0 equiv of CaCO3. b Preparation
of the starting materials is described in the Supporting Information.
c Chromatographically isolated yields. d Compounds 7, 8, and 9 are dia-
stereomerically pure; however, their stereochemistry could not be estab-
lished.
CN-H2O at 25 °C, resulted in the formation of cyclohex-
2-enone (11) as the exclusive product in 42% isolated yield.
The 1H NMR spectrum of 11 was identical with the reported
1H NMR spectrum of cyclohex-2-enone.5 The malonate
derivative 12 (entry 3, Table 1) under similar conditions gave
rise to the cyclohexenone 13 in 45% yield. No five-
membered compound was detected in these reactions. The
nitrogenous substrate 14 (entry 4, Table 1) also successfully
underwent cyclization, affording a mixture of the 2,3-
dihydro-1H-pyridin-4-one 15 (41%) and the 2,5-dihydro-1H-
pyrrole-3-carbaldehyde 16 (7%). Formation of five-mem-
bered rings as minor components was also previously
observed with oxygen analogues.3 The results cited in Table
1 established that the mercuric chloride mediated cyclization
of tethered alkynedithioacetals containing an unsubstituted
alkyne moiety is a general reaction giving rise primarily to
six-membered rings. The structures of the aforementioned
compounds were established on the basis of IR, NMR, and
mass spectral analyses. The results presented in Table 1
established that the HgCl2 mediated alkynedithioacetal cy-
clization is generally applicable for the construction of six-
and five-membered carbocycles and heterocycles.
Scheme 2. HgCl2 Mediated Reaction of a Two-Atom
Tethered Alkynedithioacetal
The applicability of the reaction to chiral substrates was
demonstrated by the cyclization of the diastereomerically
pure 7 (entry 1, Table 1; stereochemistry unknown), which
afforded 3-pyranone 8 (28%) along with the dihydrofuran
aldehyde 9 (14%) (Table 1), both as single diastereomers.
The simplest all carbon tethered alkynedithioacetal 10 (entry
2, Table 1), on treatment with HgCl2 and CaCO3 in CH3-
The reaction of substrates, in which the terminal alkyne
moieties are substituted, showed a drastic change in regio-
selectivity. In this regard, our results are presented in Table
2. The substituted alkyne substrates 17, 19, 21, and 23
(entries 1-4, Table 2) all gave exclusively five-membered
(5) Handbook of Proton-NMR Spectra & Data; Edited by Asahi Research
Centre, Academic Press: Orlando, FL, 1985; Vol. 2, p 67, compound
number 929.
(4) Kulkarni, B. A.; Sharma, A.; Gamre, S.; Chattopadhyay, S. Synthesis
2004, 595-599.
314
Org. Lett., Vol. 8, No. 2, 2006

the dihydropyridone 26 (27%) and the pyrrolidine 276 (31%).
The aldehyde 286 (13%) formed via the cleavage of the
dithioacetal was also obtained from this reaction albeit in
poor yield. The pyrrolidine 306 (38%) was the exclusive
product of cyclization from 29 (entry 6, Table 2), along with
deprotected aldehyde 316 (16%), which was obtained as a
minor product. The all-carbon tethered malonate 32 (entry
7, Table 2) gave exclusively the cyclopentene 336 (52%).
Substitution at the dithioacetal carbon atom did not lead to
any change in the regioselectivity as is evident from the
reactions of 34 and 36 (entries 8 and 9, Table 2), which gave
rise to the six-membered rings 35 (46%) and 37 (51%),
respectively, as exclusive products.
Table 2. Effect of Substitution on the HgCl2 Mediated
Cyclization of Tethered Alkynedithioacetalsa
The results (entries 1-7) in Table 2 indicate that a useful
and interesting tuning of the regioselectivity of the cyclization
can be achieved with alkyne substitution. The reasons for
this change in regioselectivity are not known. Although the
exact mechanism of mercuration reactions is not known,1 it
is proposed that Hg(II) reacts with a terminal alkyne to form
a vinyl carbonium ion or complex, in which the Hg is
attached to the terminal carbon atom. The situation is more
complex for a disubstituted alkyne where the carbonium ion
may be formed at any of the two alkyne carbon atoms. This
is probably why mixtures of products are formed from such
reactions,1 although there are cases where the preferential
formation of one product has been observed.1,2h In our earlier
study 1,3-propanedithioketals of the corresponding 3-pyra-
nones were isolated as intermediates in some reactions of
O-propargylgylcolaldehyde dithioacetals.3 In the present
work a related but different intermediate 38 was isolated from
the reaction of alkyne diethyldithioacetal 14 with 1.0 equiv
of HgCl2. The structure of 38 was secured by NMR and mass
spectral data, and it was found that the ketone 15 could be
generated from 38 by treatment with excess HgCl2. A
tentative mechanism for the formation of 38 is presented in
Scheme 4. It should be mentioned that this mechanism has
Scheme 3. Formation of Vinylsulfide Intermediate during
Hg(II) Reaction of Alkyne Ethanedithioacetal 14
close similarity with the one proposed earlier for the
formation of pyranones.3
The yields of the HgCl2 mediated reactions are not
particularly high, although it should be mentioned that
alternative routes to the products would require multistep
synthesis. It is possible that a substantial part of the starting
material undergoes polymerization, because appreciable
quantities of insoluble residues are obtained in all the
reactions.
a All reactions were performed at 25 °C in CH3CN-H2O (4:1) for 4 h
in the presence of 3.0 equiv of HgCl2 and 4.0 equiv of CaCO3. b Preparation
of the starting materials is described in the Supporting Information.
c Chromatographically isolated yields.
3-acyl-2,5-dihydrofurans 18, 20, 22, and 24 on treatment with
HgCl2 under the standard conditions, which stood in sharp
contrast to our earlier reported reactions, which afforded the
six-membered enones exclusively or as the major products.3
The dithioacetal 25 (entry 5, Table 2) gave a 1:1 mixture of
A remarkable observation was made when HgI2 was used
as the reagent in the reaction of the O-propargylglycolalde-
(6) Rhee, J. U.; Krische, M. J. Org. Lett. 2005, 7, 2493-2495.
Org. Lett., Vol. 8, No. 2, 2006
315

ability of HgI2 to interrupt the reaction at the intermediate
stage is expected to be useful, because the dithioacetals can
undergo further transformations such as desulfurization
giving rise to unsaturated rings. So far all attempts to catalyze
the above-mentioned reactions by mercuric triflate, which
has been successfully used for other mercuration reactions,2a-e
have so far proven unsuccessful. Treatment of 43 with
Hg(OTf)2 in CH3CN-H2O resulted in hydration of the alkyne
without affecting the thioacetal group, and this observation
was in agreement with the reported hydration of alkynes in
the presence of Hg(OTf)2.2e
Scheme 4. Tentative Mechanism for the Formation of 38
In conclusion, HgCl2 has been established as an effective
reagent for mediating the general cyclization of tethered
alkynedithioacetals to obtain five- and six-membered rings.
A remarkable aspect of this reaction is the tuning of the
regioselectivity of the reaction by alkyne carbon atom
substitution. In addition, HgI2 has been found to interrupt
the reaction so that the intermediate dithioacetal is formed
exclusively. Future work on this potentially important
reaction will focus on the dependence of the mechanism on
the nature of dithioacetals as well as its application to the
synthesis of complex ring systems.
hyde dithioacetal 42 (Scheme 5). The known3 intermediate
dithioacetal 44 was isolated as the exclusive product even
when excess HgI2 was used. Similar behavior of HgI2 was
also encountered in the reaction of the dithioacetal 43, where
a mixture of the known3 3-pyranone dithioacetal 45 and the
dithioacetal 46 was obtained (Scheme 5). The particular
Acknowledgment. The award of Senior Research Fel-
lowships to G.B. and S.G. by CSIR, India, is gratefully
acknowledged. Thanks are due to Dr. R. Mukhopadhyay,
Dr. P. K. Datta, Mr. A. Bannerjee, Mr. K. Sarkar, Mr. S.
Chowdhury, and Mr. S. Samaddar for spectral analyses.
Scheme 5. HgI2 Mediated Cyclization of Alkynedithioacetals
Supporting Information Available: Experimental pro-
cedure and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
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