Mercury(II) chloride-mediated cyclization - Rearrangement of O-propargylglycolaldehyde dithioacetals to 3-pyranone dithioketals: An expeditious access to 3-pyranones

Article abstract of DOI:10.1021/ol047893a

(Chemical Equation Presented) O-Propargyl glycolaldehyde dithioacetals undergo a unique cyclization-rearrangement in the presence of mercuric chloride and calcium carbonate to afford 3-pyranones exclusively or along with 2,5-dihydrofuran-3-carboxaldehydes

Full text of DOI:10.1021/ol047893a

ORGANIC
LETTERS
2005
Vol. 7, No. 2
207-210
Mercury(II) Chloride-Mediated
Cyclization Rearrangement of
−
O-Propargylglycolaldehyde Dithioacetals
to 3-Pyranone Dithioketals: An
Expeditious Access to 3-Pyranones
Subir Ghorai and Anup Bhattacharjya*
Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road,
Kolkata 700032, India
anupbh@hotmail.com
Received October 12, 2004
ABSTRACT
O-Propargyl glycolaldehyde dithioacetals undergo a unique cyclization−rearrangement in the presence of mercuric chloride and calcium carbonate
to afford 3-pyranones exclusively or along with 2,5-dihydrofuran-3-carboxaldehydes via their dithioketals and dithioacetals.
Electrophilic mercury salts are important reagents in organic
synthesis. Examples of reactions involving mercury salts with
Scheme 1. Hg(II)-Mediated Reaction of an Alkyne in the
alkenes and alkynes in the presence of various nucleophiles
giving rise to varied types of products abound in the
literature.1 Intramolecular cationic cyclizations of olefinic and
acetylenic substrates having aromatic rings, alkene moieties,
and heteroatoms in the neighborhood are also well docu-
mented.1,2 The Hg(II)-mediated reaction of an alkyne 1
generally occurs via the formation of a vinylmercurial
carbonium ion 2 followed by the attack by a nucleophile
leading to the formation of the organomercury species 3
(Scheme 1). The formation of benzofurans, benzothiophenes,
and indoles from ortho-substituted arylalkynes,2a 2-methylene
tetrahydrofurans and dihydropyrans from hydroxy alkynes,2b
dihydronaphthalenes from arylalkynes,2a,c benzopyrans from
arylalkynyl ethers,2a,d-f furans from alkynyl ketones,2g and
Presence of a Nucleophile
carbocyclization of 1,6-enynes are some of the examples of
the above process.2h Although most of the Hg(II)-mediated
(2) (a) Larock, R. C.; Harrison, L. W. J. Am. Chem. Soc. 1984, 106,
4218-4227. (b) Riediker, M.; Schwartz, J. J. Am. Chem. Soc. 1982, 104,
5842-5844. (c) Nishizawa, M.; Takao, H.; Yadav, V. K.; Imagawa, H.;
Sugihara, T. Org. Lett. 2003, 5, 4563-4565. (d) Bates, D. K.; Jones, M. C.
J. Org. Chem. 1978, 43, 3775-3776. (e) Thyagarajan, B. S.; Majumdar,
K. C.; Bates, D. K. J. Heterocycl. Chem. 1975, 12, 59-66. (f) Balasubhra-
manian, K. K.; Reddy, K. V.; Nagarajan, R. Tetrahedron Lett. 1973, 14,
5003-5004. (g) Imagawa, H.; Kurisaki, T.; Nishizawa, M. Org. Lett. 2004,
6, 3679-3681. (h) Nishizawa, M.; Yadav, V. K.; Skwarczynski, M.; Takao,
H.; Imagawa, H.; Sugihara, T. Org. Lett. 2003, 5, 1609-1611. (i) Nishizawa,
M.; Skwarczynski, M.; Imagawa, H.; Sugihara, T. Chem. Lett. 2002, 12-13.
(j) Frederickson, M.; Grigg, R. Org. Prep. Proc. Int. 1997, 29, 63-116.
(1) (a) Larock, R. C. SolVomercuration/Demercuration Reactions in
Organic Synthesis; Springer-Verlag: Berlin, 1986. (b) Larock, R. C.
Tetrahedron 1982, 38, 1713-1754.
10.1021/ol047893a CCC: $30.25
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reactions involve the employment of the mercury salts in
stoichiometric quantities, in a major development in this area,
catalytic amounts of the reagent, especially Hg(II) triflate,
have been successfully used in some of the above reactions
as well as hydration of alkynes.2c,g-i
We were surprised to find that the products were the
3-pyranone 6 (38%) and the dihydrofuryl aldehyde 7 (6%)
rather than the expected aldehyde 5 (Scheme 2). The struc-
tures of 6 and 7 were secured from NMR, mass, and IR
spectral data. A simple explanation for the formation of these
compounds appeared to be a sequence of reactions consisting
of the cleavage of the dithioacetal to 5, a nonregioselective
Hg(II)-catalyzed hydration of the alkyne to give 8 and 9,
followed by the intramolecular aldol condensation and dehy-
dration to 6 and 7, respectively (Scheme 2). This possibility
was ruled out by the observation that the aldehyde 5 gen-
erated by an alternative method7 did not afford 6 and 7 under
identical conditions (Scheme 2) and was recovered un-
changed. In contrast, no such reaction occurred with the
corresponding penta-O-allyl glucose diethyldithioacetal, which
could be cleaved smoothly giving rise to the parent aldehyde.6
These observations clearly indicated that the presence of
both the dithioacetal and the alkyne functionalities was
necessary for the formation of 6 and 7. To our knowledge,
such a cyclization in an alkyne-dithioacetal system has not
been encountered previously. That the above cyclization was
not an isolated example was evident from the formation of
the pyranone 11 and the furan aldehyde 12 under identical
conditions from the structurally similar glucose-derived
dithioacetal 10. However, the cyclization failed when the
tether between the alkyne and the dithioacetal moieties was
longer than that present in 4 and 10.
Another common application of Hg(II) salts is found in
the cleavage of dithioacetals or ketals leading to carbonyl
compounds;3 in this regard, we now disclose herein a unique
carbocyclization of dithioacetals derived from O-propar-
gylglycolaldehydes in the presence of mercuric chloride,
which is apparently initiated by the electrophilic attack of
Hg(II) but takes a hitherto unknown course thereafter leading
to the formation of 6H-pyran-3-ones (3-pyranones) via their
dithioketals. It should be mentioned in this context that there
have been several synthetic exercises directed toward pyran-
3-ones due to their importance as useful synthons.4 Most of
these methods use 2-furyl alcohols, glycals, or dipropargyl
ethers as the key building blocks.
To generate the aldehyde 5 (Scheme 2) following a
common procedure of dithioacetal cleavage,5 the penta-O-
Scheme 2. Hg(II)-Mediated Reaction of 2-O-Propargyl
Glucose Diethyldithioacetals
O-Propargylsalicylaldehyde diethyldithioacetal (13), which
has one more carbon atom in the tether, underwent cleavage
rather than any cyclization, and O-propargylsalicylaldehyde
(14) was isolated as the exclusive product. These results led
to the hypothesis that the above cyclization required the
presence of an O-propargyl glycolaldehyde dithioacetal
system in the substrate.
With the dual purpose of establishing the generality of
the reaction, an alternative method for assembling the afore-
mentioned skeleton was devised as shown in Scheme 3. A
two-step method involving the reaction of an aldehyde or
ketone 15 with lithio 1,3-dithiane,8 followed by O-propar-
propargyl glucose diethyldithioacetal 4, prepared according
to a known method,6 was treated with 2.2 equiv each of
HgCl2 and CaCO3 in CH3CN-H2O (4:1) at 25 °C for 4 h.
Scheme 3. Synthesis of O-Propargyl Dithioacetals from
Aldehydes and Ketones
(3) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis; John Wiley & Sons: New York, 1999; pp 329-344.
(4) (a) Krishna, U. M.; Deodhar, K. D.; Trivedi, G. K. Tetrahedron 2004,
60, 4829-4836 and references therein. (b) Jung, M. E.; Pontillo. J. J. Org.
Chem. 2002, 67, 6848-6851. (c) Sugawara, K.; Imanishi, Y.; Hashiyama,
T. Tetrahedron: Asymmetry 2000, 11, 4529-4535. (d) van der Deen, H.;
van Oeveren, A.; Kellogg, R. M.; Feringa, B. L. Tetrahedron Lett. 1999,
40, 1755-1758 and references therein. (e) Dauben, W. G.; Kowalczyk, B.
A.; Lichtenthaler, F. W. J. Org. Chem. 1990, 55, 2391-2398 and references
therein. (f) Hepworth, J. D. In ComprehensiVe Heterocyclic Chemistry;
Boulton, A. J., McKillop, A., Eds.; Pergamon: Oxford, 1984; Vol. 3, pp
843-844.
208
Org. Lett., Vol. 7, No. 2, 2005

gylation of the resulting alcohol 16 in the presence of sodium
hydride, gave the alkyne dithioacetal 17 (Scheme 3). The
1,3-propanedithioacetals prepared in this way were subjected
to the HgCl2-mediated reaction using the conditions adopted
for 4 and 10, i.e., stirring with 2.2 equiv of each of HgCl2
and CaCO3 in CH3CN-H2O (4:1) for 4 h at 25 °C, and the
results are presented in Table 1.
was isolated in 36% yield along with a minor compound in
19% yield (entry 8). The minor compound was identified as
the dithioketal 34 by NMR and mass spectral analyses.
Additional evidence for its structure was provided by its
conversion to the parent pyranone 33 by HgCl2 and CaCO3
in CH3CN-H2O. Under similar conditions, the dithioacetal
28 and dithioketals 30 and 32 were also obtained in varying
yields from the reactions of 20, 21, and 22 respectively
(entries 5-7). Interestingly, the reaction of 23 in the presence
of 1.0 equiv each of HgCl2 and CaCO3 for 2.5 h afforded
33 and 34 in yields of 17 and 53%, respectively, whereas
under these conditions 22 gave a mixture of 32 and un-
changed starting material but no pyranone, as evident from
Table 1. Hg(II) Chloride-Mediated Reaction of O-Propargyl
Glycolaldehyde Dithioacetalsa
1
the H NMR spectrum of the product.
The optimized conditions for preparing the pyranones and
dihydrofuryl aldehydes uncontaminated with dithioacetals
involved the use of 3.0 equiv of the mercury salt and 4.0
equiv of CaCO3 in CH3CN-H2O (4:1) at 25 °C for 4 h.
The other products besides the pyranones and the dihydro-
furyl aldehydes were found to be unidentified materials
insoluble in organic solvents or water. Variation in mercury-
(II) salts, bases, and solvents either led to the formation of
intractable products or did not improve the yields (Table 2).
Table 2. Hg(II)-Mediated Cyclization of 22
entry Hg(II) (equiv) base (equiv)
solvent
yield (%)a
1
2
3
4
5
HgCl2 (3.0)
HgCl2 (2.2)
CaCO3 (4)
DIPEA (3.3) CH3CN-H2O
CH3CN-H2O
53
0
0
42
39
Hg (OTFA)2 (2.2) CaCO3 (3.3) CH3CN-H2O
HgCl2 (3.0)
HgCl2 (3.0)
CaCO3 (4)
CaCO3 (4)
THF-H2O
(CH3)2CO-H2O
a Yields refer to chromatographed material. In the cases of 0% yields,
only intractable materials were obtained.
The formation of dihydrofuryl aldehydes was not general
and was observed from some of the substrates (entries 1, 2,
and 5, Table 1) in which the carbon atoms bearing the
O-propargyl group were monosubstituted.
The above results indicate that the primary products of
this unusual cyclization are the dithioacetals or the ketals,
which are subsequently cleaved by excess mercuric chloride
to the parent aldehydes and ketones.9 An alternative structure
35 for the 3-pyranone skeleton was ruled out by an
unambiguous synthesis of 31 in 25% overall yield from 22
as shown in Scheme 4.10 The higher yield of 31 (53%)
obtained in the Hg(II)-mediated cyclization also established
its superiority over the stepwise synthesis shown in Scheme
a All reactions were performed at 25 °C in CH3CN-H2O (4:1) for 4 h
in the presence of either (A) 2.2 equiv each of HgCl2 and CaCO3 or (B)
3.0 equiv of HgCl2 and 4.0 equiv of CaCO3. b [%] denotes % yield under
conditions A, and (%) denotes % yield under conditions B.
The most noteworthy feature of the above cyclization was
discovered in the reaction of 23, in which the pyranone 33
(5) Meyers, A. I.; Comins, D. L.; Roland, D. M.; Henning, R.; Shimizu,
K. J. Am. Chem. Soc. 1979, 101, 7104-7105.
(6) Mukhopadhyay, R.; Kundu, A. P.; Bhattacharjya, A. Tetrahedron
Lett. 1995, 36, 7729-7730.
(7) Fetizon, M.; Jurion, M. J. Chem. Soc., Chem. Commun. 1972, 382-
383.
(8) Page, P. C. B.; van Niel, M. B.; Proger, J. C. Tetrahedron 1989, 45,
7643-7677.
(9) In the cases of 4, 10, 18, and 19, the intermediate dithioacetals did
not survive when 2.2 equiv each of HgCl2 and CaCO3 was used, and only
the carbonyl compounds were isolated.
Org. Lett., Vol. 7, No. 2, 2005
209

(step 2).12 After the formation of the C-C bond (step 3),
migration of the sulfur atom takes place with concomitant
expulsion of the Hg(II) (steps 4 and 5). Subsequent cleavage
of the thioketal in the presence of HgCl2 gives rise to the
pyranone 44 (step 6). An endo attack of the sulfur atom on
the alkyne-Hg(II) complex in 38 (step 1, dashed arrow)
followed by analogous steps 2-6 can explain the formation
of a dihydrofuryl aldehyde 45. We believe that the length
of the tether between the dithioacetal and the alkyne moieties
is critical for the occurrence of step 1. The cyclization itself
appears to be specific for a three-atom-tethered alkyne
dithioacetal like the O-propargyl glycolaldehyde dithioacetals
described above.
Scheme 4. Alternative Synthesis of 31 from 22
In conclusion, the work presented here describes a unique
Hg(II)-mediated reaction of O-propargyl glycolaldehyde
dithioacetals and an expedient general route to 6H-pyran-
3-ones. The application of this potentially useful reaction to
the synthesis of other heterocyclic and carbocyclic skeletons
as well as efforts toward a better understanding of its
mechanism are underway.
4. The present method provides a rapid assemblage of this
skeleton from an aldehyde or a ketone, 1,3-dithiane, and
propargyl bromide.11
A tentative mechanism for the reaction is presented in
Scheme 5. The reaction leading to a pyranone is initiated
Acknowledgment. S.G. thanks CSIR, India, for an SRF.
Thanks are due to Dr. R. Mukhopadhyay, Mr. A. Banerjee,
Mr. K. Sarkar, and Mr. S. Chowdhury for spectral analyses.
Scheme 5. Proposed Pathway for the Formation of 3-Pyranone
Dithioketals from O-Propargyl Glycolaldehyde Dithioacetals
Supporting Information Available: Experimental pro-
cedure and NMR data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL047893A
(10) 1H and 13C NMR spectra of the pyranones were consistent with the
assigned structures. In the alternative structure 35, at least one of the O-CH2
protons is expected to be vicinally coupled to the olefinic proton. No such
vicinal coupling is observed in the 1H NMR spectra. The IR and mass
spectral data also agreed well with the structures.
(11) Examples of preparing 6H-pyran-3-ones from aldehydes and ketones
are scarce. In one example, a pyranone having the same skeleton as the
ones reported in this work has been synthesized from a methyl ketone via
a multistep sequence (ref 4b).
(12) Capture of the electrophilic vinyl carbonium ion formed after
complexation with Hg(II) by a neighboring sulfur (ref 2a) as well as oxygen
atoms (refs 1, 2a, 2b, and 2g) is well precedented. In some of these instances,
a substituent attached to the heteroatom is cleaved in the next step, affording
sulfur and oxygen heterocycles.
by the exo attack of a sulfur atom on the alkyne-Hg(II)
complex in 38 (step 1, solid arrow).12 The organomercurial
species 39 then undergoes C-S bond cleavage, and the
carbocation formed is stabilized by the adjacent sulfur atom
210
Org. Lett., Vol. 7, No. 2, 2005