1,2-Migration of the thio group in allenyl sulfides: Efficient synthesis of 3-thio-substituted furans and pyrroles

Article abstract of DOI:10.1002/anie.200390064

The copper-catalyzed cycloisomerization of thioalkynyl ketones 1 a and thioalkynyl imines 1b allows the efficient synthesis of 3-thio-substituted furans 3a and pyrroles 3b, an important class of heterocyclic unit previously inaccessible by standard cycloisomerization techniques. A plausible mechanism for this unusual cascade involves a 1,2-migration of the thio group in the intermediate keto- and iminoallenyl sulfides 2. DMA=N,N-dimethylacetamide.

Full text of DOI:10.1002/anie.200390064

Communications
[7] a) S. Wang, R. M. Leblanc, Biochim. Biophys. Acta 1999, 1419,
317; b) A. Giehl, T. Lemm, O. Bartelsen, K. Sandhoff, A. Blume,
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Delapierre, F. Fotiadu, G. Buono, J. Fantini, ChemBioChem
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Smeekens, B. D. Kurijff, Biochim. Biophys. Acta 2001, 1510, 307;
for an overview of the applications of lipid monolayers, see g) H.
Brockman, Curr. Opin. Struct. Biol. 1999, 9, 438.
to the interface. These observations indicate that in the absence
of CCIs intrinsic surface activity becomes the primary contrib-
utor to Dp.
[20] Glycolipid 4 had a Dp of 2.7 mNmÀ1 at an initial pressure of
10 mNmÀ1. At all other pressures examined the Dp value was
indistinguishable from the values observed in a ™holding∫
experiment.
[8] a) C. M. Knobler, Adv. Chem. Phys. 1990, 77, 397; b) S. Heyse, T.
Stora, E. Schmid, J. H. Lakey, H. Vogel, Biochim. Biophys. Acta
1998, 85507, 319; c) C. Yuan, L. J. Johnston, Biophys. J. 2000, 79,
2768; d) J. C. Conboy, K. D. McReynolds, J. Gervay-Hague, S. S.
Saavedra, J. Am. Chem. Soc. 2002, 124, 968.
Synthesis of Pyrroles and Furans
[9] N. Kojima, B. Fenderson, M. Stroud, R. Goldberg, R. Haber-
mann, T. Toyokuni, S. Hakomori, Glycoconjugate J. 1994, 11,
238.
1,2-Migration of the Thio Group in Allenyl
Sulfides: Efficient Synthesis of 3-Thio-Substituted
Furans and Pyrroles**
[10] The glycolipids were prepared from the corresponding peracet-
ylated disaccharides by conversion into the glycosyl bromides
with HBr followed by silver triflate mediated glycosylation with
allyl alcohol. Subsequent ozonolysis, oxidation, and coupling to
tetradecylamine followed by Zemplen deacylation provided the
desired compounds. The synthetic glycolipids were characterized
by 1H and 13C NMR spectroscopy and high-resolution mass
spectrometry.
Joseph T. Kim, Alexander V. Kel©in, and
Vladimir Gevorgyan*
The 1,2-migration of the thio group is an important chemical
transformation that is extensively used in carbohydrate
chemistry for stereoselective Mitsunobu-type substitution at
the anomeric center [Eq. (1)].[1] There are also reports on
employment of a 1,2-shift of the thio group in the synthesis of
heterocycles [Eq. (2)][1a,b] Known 1,2-migrations of the thio
group can be classified as one of two types: 1) An SN2-type
attack of the lone pair of electrons of the sulfur atom at the
adjacent sp3 center in A produces the thiiranium intermediate
B, which after subsequent nucleophile-assisted ring opening
affords C, a product of 1,2-migration of the thio group
[Eq. (1)].[1] 2) The migration is triggered by attack of the
sulfur atom at the sp2 carbon atom of the iminium[2a,b] or
imine[2c] moiety of D to form the thiiranium species E. The
latter either produces sulfide F through nucleophilic attack[2c]
or gives the thioenamine G as a result of a deprotonation/
ring-opening process [R1 ¼ H, Eq. (2)].[2a,b] In all cases the
migrations of the thio group proceeded from an sp3 center to
either another sp3 [Eq. (1)][1] or to an sp2 [Eq. (2)][2] carbon
center. To the best of our knowledge, there are no reports of
1,2-migration of the thio group from an olefinic carbon atom.
Herein we wish to report a novel 1,2-migration of the thio
group from an sp2 carbon atom in allenyl sulfides. This
unprecedented migration allowed the development of an
[11] A. Chattopadhyay, E. London, Anal. Biochem. 1984, 139, 408.
[12] The Langmuir monolayer experiments were carried out on a
KSV minitrough equipped with a Wilhelmy plate and balance. A
chloroform/methanol solution of a 10% GM3/90% DPPC
mixture was deposited with a microsyringe on a subphase of
1 mm CaCl2. The solvent was allowed to evaporate over 10 min,
and the monolayer was compressed at a rate of 3 mmminÀ1 until
the desired initial monolayer pressure for the binding experi-
ment was reached. Once the monolayer was at the target
pressure the barriers were stopped, and the subphase was stirred
gently outside the barriers. The binding experiment was initiated
by injection of 1.5 mL of a concentrated glycolipid solution into
the subphase outside the Teflon barriers.
[13] Negative Dp values are indicative of either lipid loss from the
monolayers owing to the high solubility of the glycolipids and/or
rearrangements within the monolayer after compression has
ceased. See a) J. Esnault, J.-M. Mallet, Y. Zhang, P. Sin‰y, T.
LeBouar, F. Pincet, E. Perez, Eur. J. Org. Chem. 2001, 253;
b) G. L. Gaines, Insoluble Monolayers at Liquid Gas Interfaces,
Interscience Publishers, New York, 1966, p. 143.
[14] Single-site modifications can have measurable effects on CCIs.
For examples in the context of glycopolymer recognition, see
references [3c,l,m].
[15] a) W. Cook, C. Bugg, Biochim. Biophys. Acta 1975, 389, 428;
b) W. Cook, C. Bugg, J. Am. Chem. Soc. 1973, 95, 6442.
[16] Another observation consistent with this hypothesis is that the
cmc value of 3 is higher in 1 mm CaCl2 than in deionized water.
This is in contrast to 4, 5, and Tween-80,[18] all of which show
decreases in cmc values on going from water to 1 mm CaCl2, as
might be expected in a solution of greater ionic strength.
[17] The surface activities or equilibrium surface pressures for 3, 4,
and 5 are: 26, 6, and 22 mNmÀ1, respectively.
[18] Binding studies of the GM3 monolayer at 30 mNmÀ1 with
Tween-80, a nonionic hydroxy-terminated detergent, which has
an equilibrium surface pressure of 28 mNmÀ1 and a cmc of 3 mm,
also failed to show a concentration-dependent increase in Dp.
[19] When GM3 was omitted from the monolayer, injection of 25 mm
3 or 5 afforded a Dp of 8 mNmÀ1 (30 mNmÀ1 starting pressure).
The rate of increase in p was slower in the absence of GM3 which
suggests that CCIs facilitate insertion by targeting the glycolipids
[*] Prof. Dr. V. Gevorgyan, J. T. Kim, A. V. Kel©in
Department of Chemistry, University of Illinois at Chicago
845 West Taylor Street, Chicago, IL 60607-7061 (USA)
Fax: (þ1)312-355-0836
E-mail: vlad@uic.edu
[**] The support of the National Science Foundation (CHE-0096889)
and the National Institutes of Health (GM-64444) is gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angewandte
Chemie
minor isomeric furan 3 (Scheme 1, path b). Although the role
of the copper catalyst in this reaction is not completely
understood, there are some indications that it facilitates
propargyl allenyl isomerization,[3,4,8] and in some cases it is
also required for further transformations [Eq. (4)], probably
as a result of the stabilization of carbanionic intermediates.[8]
It occurred to us that if the above mechanistic proposal is
correct, then replacement of Hb in allene 4 with any other
nonmigrating group should enforce selective migration of the
thio group to produce 2,4-disubstituted furan 3 exclusively
(path b). To examine this proposal, thioallenes 7a,b were
prepared by independent methods and subjected to the
cycloisomerization conditions described above [Eq. (4)].
Remarkably, it was found that thioallenyl phenyl ketone 7a,
even in the absence of CuI, underwent quantitative thermal
transformation to 8a. In contrast, attempts to perform
analogous thermal cycloisomerization of thioallenyl alkyl
ketone 7b resulted in total decomposition of the starting
material, whereas 82% of 8b was isolated when the reaction
was performed at room temperature in the presence of CuI
(5 mol%) [Eq. (4)].
efficient method for the synthesis of 3-thio-substituted furans
and pyrroles.
During the investigation of the scope of the recently found
Cu-catalyzed transformation of alkynyl ketones and alkynyl
imines into 2,5-disubstituted furans[3] and pyrroles,[4] we
discovered that heating ketopropargyl sulfide 1 in N,N-
dimethylacetamide (DMA) in the presence of CuI
(10 mol%) not only gave the targeted 2,5-disubstituted furan
2, but also a small amount of the unexpected 2,4-disubstituted
furan 3 [Eq. (3)]. It was hypothesized that first, propargyl
allenyl isomerization[5] produces an allenic intermediate 4
(Scheme 1).
Naturally, we next attempted a selective migrative cyclo-
isomerization of substituted propargyl sulfides, undoubtedly
superior precursors when compared with allenyl sulfides from
a synthetic point of view. Accordingly, a series of alkyl-
substituted propargyl sulfides 9 were synthesized and sub-
jected to the cycloisomerization reaction [Eq. (5)].
We were very pleased to find that thiopropargyl aldehyde
9c underwent smooth and selective cycloisomerization,
producing 2-butyl-3-phenylsulfanyl-furan (8c) in 71% yield
as a single reaction product (Table 1, entry 1). Cycloisomeri-
zation of thiopropargyl ketones 9a,d,e proceeded
provided the trisubstituted furans 8a,d,e in very
good yields (Table 1, entries 2 4).[9] Cycloisomeri-
zation of phenylsulfanyl propargyl ketones pos-
sessing alkenyl (9 f), ester (9g), and protected
alcohol (9h) functionalities in the side chain
proceeded readily to afford the corresponding
trisubstituted furans 8 f h in good to very high
yields (Table 1, entries 5 7). The alkyl sulfanyl
group migrated with an efficiency comparable to
that of its phenylsulfanyl analogue to give the
corresponding furan 8i in 72% yield (Table 1,
entry 8).
Next, the allenyl sulfide 4, according to the ™standard∫
cycloisomerization scenario (Scheme 1, path a)[3] produces
the major reaction product, furan 2.[3] It was proposed that
alternatively, an intramolecular nucleophilic attack of the
lone pair of electrons of the sulfur atom at the central carbon
atom of the allene can transform it into the aromatic
thiirenium zwitterion 5.[6] The latter, either via AdN-E (5!
6) or through a direct SN2-Vin-type[7] process, affords the
Inspired by the successful synthesis of trisub-
Scheme 1. Different routes for the cyclization of the ketopropargyl sulfide 1 to give
either furan 2 or 3. Based on this mechanistic proposal, the reaction of ketoproparg-
yl sulfides in which Hb of 4 is replaced with any other nonmigrating group should ex-
clusively follow path b.
stituted furans, the cycloisomerization of thiopro-
pargyl imines was then investigated. It was found
that thiopropargyl imines 9j o in the presence of
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Communications
sulfanyl analogue (Table 1, entry 9) and the THP-protected
alcohol functionality was tolerated (Table 1, entry 14). It is
worth mentioning that all synthesized pyrroles have remov-
able groups at the nitrogen atom, for example, the tert-butyl
(8j,k, Table 1, entries 9, 10),[11] trityl (8 l, Table 1, entry 11),[12]
and 3-ethylbutyryl[4,13] (8m o, Table 1, entries 12 14) groups,
and thus can be easily functionalized further at the nitrogen
site.[14]
CuI underwent a similar transformation to give the corre-
sponding 3-thio-substituted pyrroles 8j o in very good yields
(Table 1, entries 9 14).[10] Again, the dodecyl sulfanyl group
(Table 1, entry 10) migrated comparably to the phenyl
In conclusion, a novel 1,2-migration of the thio group in
thioallenyl ketones and thioallenyl imines was discovered. An
efficient method for the synthesis of di- and trisubstituted
Table 1: Cu-catalyzed synthesis of 3-substituted furans and pyrroles.
Entry
Substrate
Product
8
Yield [%][a]
9
c
R1
R2
R3
H
X
1
2
3
4
5
6
7
8
nBu
Ph
O
71
76
89
91
95
71
93
72
d
e
a
f
nBu
Ph
Ph
Ph
Ph
Ph
Ph
Me
tBu
Ph
O
O
O
O
O
O
O
nBu
nBu
nBu
g
h
i
Me
(CH2)2CO2Me
(CH2)3OTHP
nBu
Me
Me
(CH2)11CH3
Ph
9
j
nBu
H
H
H
H
H
H
N-tBu
N-tBu
N-Tr
78
86
85
74
67
78
10
11
12
13
14
k
l
nBu
(CH2)11CH3
nBu
Ph
m
n
o
nBu
Ph
nBu
(CH2)11CH3
N-EB
N-EB
(CH2)3OTHP
Ph
[a] Yield of isolated product. THP¼ tetrahydropyran, Tr¼ trityl¼ triphenylmethyl, EB¼ ethyl butyryl.
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Angewandte
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furans and trisubstituted pyrroles that possess an aryl sulfanyl
or alkyl sulfanyl substituent at C3 has been developed.
Heterometallic Wheel Complexes
Synthesis and Characterization of Heterometallic
{Cr7M} Wheels**
Received: August 7, 2002 [Z19912]
Finn K. Larsen, Eric J. L. McInnes,
[1] a) B. D. Johnston, B. M. Pinto, J. Org. Chem. 2000, 65, 4607; b)
B. Yu, Z. Yang, Org. Lett. 2001, 3, 377; c) A. Viso, N. Poopeiko, S.
Castillon, Tetrahedron Lett. 2000, 41, 407.
[2] a) R. Plate, R. J. F. Nivard, H. C. J. Ottenheijm, Tetrahedron
1986, 42, 4503; b) P. Hamel, J. Org. Chem. 2002, 67, 2854; c) A.
Volontereo, M. Zanda, P. Bravo, G. Fronza, G. Cavicchio, M.
Crucianelli, J. Org. Chem. 1997, 62, 8031.
Hassane El Mkami, Jacob Overgaard,
Stergios Piligkos, Gopalan Rajaraman,
Eva Rentschler, Andrew A. Smith,
Graham M. Smith, Val Boote, Martin Jennings,
Grigore A. Timco,* and Richard E. P. Winpenny*
[3] A. V. Kel©in, V. Gevorgyan, J. Org. Chem. 2002, 67, 95.
[4] A. V. Kel©in, A. W. Sromek, V. Gevorgyan, J. Am. Chem. Soc.
2001, 123, 2074.
[5] For an example of propargyl allenyl isomerization, see: P. J.
Garratt, S. B. Neoh, J. Am. Chem. Soc. 1975, 97, 3255.
[6] For an example of stable thiirenium ions, see: V. Lucchini, G.
Modena, G. Valle, G. Capozzi, J. Org. Chem. 1981, 46, 4720; see
also reference [7].
[7] a) V. Lucchini, G. Modena, L. Pasquato, J. Am. Chem. Soc. 1993,
115, 4527; b) R. Destro, V. Lucchini, G. Modena, L. Pasquato, J.
Org. Chem. 2000, 65, 3367.
[8] For the cuprate-assisted transformation of propargylic thioace-
tals into allenyl copper species, see: a) H.-R. Tseng, C.-F. Lee, L.-
M. Yang, T.-Y. Luh, J. Am. Chem. Soc. 2000, 122, 4992; b) H.-R.
Tseng, C.-F. Lee, L.-M. Yang, T.-Y. Luh, J. Org. Chem. 1999, 64,
8582.
[9] Typical procedure (9d): A mixture of propargyl ketone 9d
(246 mg, 1.0 mmol), CuI (12 mg, 0.05 mmol), and anhydrous
DMA (2.0 mL) was stirred in a Wheaton microreactor (3 mL)
under an Ar atmosphere at 1308C. The reaction was monitored
by TLC and GC/MS until completion. After 12 h, the mixture
was cooled to room temperature and poured into saturated
aqueous NH4Cl (20 mL). The phases were separated, and the
aqueous phase was extracted (hexanes, 2 î 10 mL). The com-
bined organic extracts were washed (brine, 10 mL), dried
(Na2SO4, 2 g), and concentrated under reduced pressure. The
residue was purified by means of silica-gel chromatography with
hexanes to give furan 8d (187 mg, 76%).
Many beautiful cyclic metal structures have been reported
recently, for example, the giant wheels from M¸ller and co-
workers,[1] the wheels using carboxylate ligands made by,
among others, the Lippard group,[2] and the metallocoronands
reported by Saalfrank and co-workers.[3] One question that
intrigued us based on this chemistry was whether hetero-
metallic rings could be made? A recent theoretical paper by
Meier and Loss[4] suggests that such wheels may show
interesting quantum coherence phenomena. We have found
that an extensive family of such wheels can be made
straightforwardly, and in good yield, based on the fundamen-
tal chemical principle that a cation anion pair will have
different crystallization properties than a neutral molecule.
The neutral homometallic wheel, [Cr8F8(O2CCMe3)16]
(1)[5] has been widely studied, both because of its magnetic
properties[6] and because it can act as a host for small organic
molecules.[7] As we understand the chemistry of 1 thoroughly,
it seemed a good candidate for preparing heterometallic
analogues. The approach adopted was straightforward; if we
replace a single chromium(iii) center by a dication (M) the
monoanionic species [Cr7MF8(O2CCMe3)16]À will be formed.
In the presence of a suitable cation, we should then be able to
separate the salt from 1, which may also be present. Using this
[10] Cycloisomerization of 9j o to form pyrroles 8j o proceeded
under slightly different reaction conditions to those in the
synthesis of furans 8a i. See Supporting Information for details.
[11] For deprotection of N-tBu group in pyrroles, see: a) J. Leroy, C.
Wakselman, Tetrahedron Lett. 1994, 35, 8605; b) P. La Porta, L.
Capuzzi, F. Bettarini, Synthesis 1994, 3, 287.
[12] For deprotection of N-Tr group in pyrroles, see: D. J. Chadwick,
S. T. Hodgson, J. Chem. Soc. Perkin Trans. 1 1983, 93.
[13] For deprotection of analogous group in pyrroles, see: E. Roder,
H. Wiedenfeld, T. Bourauel, Liebigs Ann. Chem. 1985, 1708.
[14] It was found that EB protecting group can very easily be
removed from the pyrroles. Thus, thio-substituted pyrrole 8m
underwent a facile retro-Michael reaction in the presence of
KOtBu to give the corresponding pyrrole 8p quantitatively.
[*] Dr. G. A. Timco
Institute of Chemistry
Moldovan Academy of Sciences, Kishinev (Moldova)
Fax: (þ3732)737-133
E-mail: timg@nor.md
Prof. R. E. P. Winpenny, Dr. E. J. L. McInnes, S. Piligkos,
G. Rajaraman, A. A. Smith, V. Boote, M. Jennings
Department of Chemistry, The University of Manchester
Oxford Road, Manchester, M13 9PL (UK)
Fax: (þ44)161-275-4616
E-mail: richard.winpenny@man.ac.uk
Prof. F. K. Larsen, J. Overgaard
Department of Chemistry, University of Aarhus
8000 ärhus C (Denmark)
Dr. E. Rentschler
Max Planck Institut f¸r Strahlenchemie
M¸lheim (Germany)
Dr. H. E. Mkami, Dr. G. M. Smith
Department of Physics and Astronomy
The University of St. Andrews, St. Andrews (UK)
[**] This work was supported by the EPSRC(UK), INTAS
(Contract 00 0172) and The Royal Society.
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