A new thiazole synthesis by cyclocondensation of thioamides and alkynyl(aryl)iodonium reagents

Full text of DOI:10.1021/jo961681c

8004
J . Org. Chem. 1996, 61, 8004-8005
Sch em e 1
A New Th ia zole Syn th esis by
Cyclocon d en sa tion of Th ioa m id es a n d
Alk yn yl(Ar yl)Iod on iu m Rea gen ts
Peter Wipf* and Srikanth Venkatraman
Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
Received August 30, 1996
Many biologically active natural products contain
oxazole and thiazole moieties, five-membered hetero-
cycles derived from cyclodehydrated serine, threonine,
and cysteine residues.1 In spite of the long tradition in
the synthesis of these heterocycles,2 standard protocols
lack the broad range of functional group tolerance and
the stereospecificity that is required for complex natural
product synthesis. As part of our program in heterocyclic
chemistry, we have recently developed3 a modern version
of the Robinson-Gabriel synthesis for the preparation
of highly substituted oxazoles and demonstrated its
utility in total synthesis.4 We assume that in this method
after oxidation of the â-hydroxy amide 1 with Dess-
Martin reagent to give ketone 2 and exposure to tri-
phenylphosphine/iodine, a carbene is formed as the
reactive intermediate before ring closure (Scheme 1).3 In
an attempt to apply this concept to the synthesis of
thiazoles, it occurred to us that the crucial carbene
intermediate could be prepared by an addition of a
thioamide 8 to a readily available alkynyl(aryl)iodonium
salt 9 (Scheme 2). At the onset of this project, it was
not clear to us if the regioselectivity of the addition would
ultimately favor thiazoles of type 6 or 7. We now report
our preliminary data on the realization of this novel
thiazole synthesis.
Sch em e 2
Ta ble 1
Addition-elimination sequences of carbon, nitrogen,
oxygen, and some sulfur nucleophiles to alkynyliodonium
salts to form free carbenes are well documented.5,6
Instead of the more common alkynyl(phenyl)iodonium
triflates 9, we decided to use the corresponding mesylates
10 because of their, in our hands, improved tendency to
crystallize. In analogy to the method of Stang et al.,7
mesylates were prepared from commercially available
iodobenzene diacetate by sequential treatment with
NaOH, methanesulfonic anhydride, TMSCN, and alkynyl
stannanes, followed by crystallization from Et2O. The
careful purification of alkynyliodonium salt proved neces-
sary to achieve consistent yields. After mixing mesylate
a
Yields are based on alkynyl(phenyl)iodonium mesylate and
b
refer to isolated, fully characterized products. Reaction in Et2O
in the presence of K2CO3. c Reaction in MeOH in the presence of
(1) (a) Wipf, P. Chem. Rev. 1995, 95, 2115. (b) Lewis, J . R. Nat. Prod.
Rep. 1995, 135. (c) Wipf, P.; Venkatraman, S. Synlett, in press.
(2) Reviews: (a) Liebscher, J . In Heteroarenes III, Houben-Weyl, 4th
ed.; Schaumann, E., Ed.; Georg Thieme Verlag: Stuttgart, 1994; Part
2, Vol. E8b, pp 1-398. (b) Hassner, A.; Fischer, B. Heterocycles 1993,
35, 1441. (c) Lang-Fugmann, S. In Heteroarenes III, Houben-Weyl, 4th
ed.; Schaumann, E., Ed.; Georg Thieme Verlag: Stuttgart, 1993; Part
1, Vol. E8a, pp 891-1019.
Et3N. Reaction in EtOAc in the presence of Et3N. e Reaction in
d
MeOH in the presence of K2CO3.
10a with thioamide 8a in Et2O in the presence of solid
K2CO3, the desired thiazole 6a was indeed formed cleanly
after 3 h as the only significant nonpolar component in
the reaction mixture besides starting materials. Table
1 summarizes further results with this thioamide-
alkynyliodonium cyclocondensation strategy. Generally,
a range of solvents (Et2O, EtOAc, MeOH) and bases such
as carbonate or triethylamine could be used. For the
preparation of 2-aminothiazole 6b, thiourea (8b) and
(phenylacetylene)(phenyl)iodonium mesylate 10b were
reacted in methanol in the presence of 1 equiv of
triethylamine (entry 2). Synthesis of the biazole 6c was
readily accomplished from thioamide 8c and 10b in 62%
yield (entry 3). Directly linked oxazole-thiazole units
(3) Wipf, P.; Miller, C. P. J . Org. Chem. 1993, 58, 3604.
(4) (a) Wipf, P.; Lim, S. J . Am. Chem. Soc. 1995, 117, 558. (b) Wipf,
P.; Venkatraman, S. J . Org. Chem. 1995, 60, 7224. (c) Wipf, P.; Lim,
S. Chimia 1996, 50, 157. (d) Wipf, P.; Venkatraman, S. J . Org. Chem.
1996, 61, 6517.
(5) Review: Stang, P. J . Angew. Chem., Int. Ed. Engl. 1992, 31, 274.
(6) (a) Ochiai, M.; Kunishima, M.; Tani, S.; Nagao, Y. J . Am. Chem.
Soc. 1991, 113, 3135. (b) Williamson, B. L.; Tykwinski, R. R.; Stang,
P. J . J . Am. Chem. Soc. 1994, 116, 93. (c) Schildknegt, K.; Bohnstedt,
A. C.; Feldman, K. S.; Sambandan, A. J . Am. Chem. Soc. 1995, 117,
7544. (d) Feldman, K. S.; Bruendl, M. M.; Schildknegt, K. J . Org. Chem.
1995, 60, 7722 and references cited therein.
(7) (a) Zhdankin, V. V.; Crittell, C. M.; Stang, P. J .; Zefirov, N. S.
Tetrahedron Lett. 1990, 31, 4821. (b) Bachi, M. D.; Bar-Ner, N.; Crittell,
C. M.; Stang, P. J .; Williamson, B. L. J . Org. Chem. 1991, 56, 3912.
S0022-3263(96)01681-7 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 23, 1996 8005
Sch em e 3
of this type are important building blocks of cytotoxic
natural products.1c Similarly, the peptidyl thiazole 6d
was obtained from N-protected valine-alanine thioamide
8d (entry 4). Peptide-linked thiazoles such as 6d are
found in many marine natural products.8
The formation of thiazoles 6 in a single reaction step
from alkynyl(aryl)iodonium salts and thioamides can be
rationalized mechanistically by a thiophilic attack of the
hypervalent iodine atom on the sulfur atom of the
thiocarbonyl group.9 This is in contrast to the common
Michael addition-carbene formation-rearrangement re-
action pathway of these species,5,6 where addition of the
nucleophile to the carbon atom of the alkynyliodonium
compound followed by elimination of iodobenzene pro-
vides a direct route to a carbene (Scheme 3, path b). The
latter reaction course can be excluded in our case,
because it would provide thiazoles 7 of inversed C(4),C(5)-
substitution pattern.10 Therefore, we propose a novel
room-temperature polyhetero-Claisen rearrangement11 of
the primary addition product 11 that provides the N-
alkenylated thioamide 12. The groups of Ochiai and
Norton have recently reported a reductive iodonio-Claisen
rearrangement of allenyl(aryl)iodanes to yield o-propar-
gyliodoarenes,12 but no hetero-Claisen rearrangement of
the type shown in Scheme 3 has yet been noted. Sub-
sequent 1,1-elimination of 12 to give carbene 14 and
iodobenzene is expected5 to be fast and lead to the
observed heterocycle 6 after cycloaromatization.
the isolated thiazole products involves the thiophilic
attack of the iodonium atom on the thioamide, followed
by an unusual room-temperature polyhetero-Claisen
rearrangement and 1,1-elimination of iodobenzene. The
resulting carbene cyclizes to form the five-membered
heterocycle in analogy to our earlier postulated mecha-
nism for the cyclodehydration of â-keto amides to ox-
azoles. We plan to investigate the details of the poly-
hetero-Claisen rearrangement as well as further ap-
plications of this reaction concept in heterocycle synthe-
sis.
In summary, a novel thiazole synthesis based on the
cyclocondensation of hypervalent alkynyliodonium salts
and thioamides has been developed.13 Yields based on
iodonium salts as limiting reagents range from 32 to 62%,
and quite highly functionalized building blocks for natu-
ral products synthesis are readily prepared by this
convergent, single-step process. The postulated reaction
mechanism that is supported by the regiochemistry of
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (AI/GM34914). We grate-
fully acknowledge additional support from the A. P.
Sloan and the Camille Dreyfus Foundations and Merck,
Pharmacia & Upjohn, and Zeneca Co.
(8) Davidson, B. S. Chem. Rev. 1993, 93, 1771.
(9) For an example of the direct alkylation of alkynyl(aryl)iodonium
salts on iodine by organolithium reagents, see: Margida, A. J .; Koser,
G. F. J . Org. Chem. 1984, 49, 4703.
(10) The assigned regiochemistry of the thiazoles was confirmed by
comparison with commercially available 6b and independently pre-
pared 6a . An alternative, third mechanism involving the direct Michael
addition of the thioamide nitrogen on the alkynyl(aryl)iodonium
species, is unlikely since the thioamide sulfur atom is far more
nucleophilic: Walter, W.; Voss, J . In The Chemistry of Amides; Zabicky,
J ., Ed.; Wiley: New York, 1970; Part 1, pp 383-475.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and compound characterization data (13 pages).
J O961681C
(11) Blechert, S. Synthesis 1989, 71.
(12) (a) Ochiai, M.; Ito, T.; Takaoka, Y.; Masaki, Y. J . Am. Chem.
Soc. 1991, 113, 1319. (b) Gately, D. A.; Luther, T. A.; Norton, J . R.;
Miller, M. M.; Anderson, O. P. J . Org. Chem. 1992, 57, 6496. (c) Ochiai,
M.; Ito, T. J . Org. Chem. 1995, 60, 2274.
(13) The cyclocondensation of R-halocarbonyl compounds with thio-
amides is known as the Hantzsch thiazole synthesis.2 Since we also
use a thioamide as starting material, our method can be considered,
in a distant sense, as a variation of the Hantzsch synthesis.