Highly selective copper-catalyzed ring expansion of vinyl thiiranes: Application to synthesis of biotin and the heterocyclic core of plavix

Article abstract of DOI:10.1021/ja069059h

We report herein a new, highly selective, mild copper-catalyzed vinyl thiirane ring-expansion protocol for the formation of 2,5-dihydrothiophenes. Preliminary substrate scope and applications of this new synthetic disconnection to the formal racemic total synthesis of biotin and the synthesis of the antiplatelet blockbuster pharmaceutical agent Plavix are described. Copyright

Full text of DOI:10.1021/ja069059h

Published on Web 02/16/2007
Highly Selective Copper-Catalyzed Ring Expansion of Vinyl Thiiranes:
Application to Synthesis of Biotin and the Heterocyclic Core of Plavix
Erik Rogers, Hiroshi Araki, Lindsay A. Batory, Christine E. McInnis, and Jon T. Njardarson*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell UniVersity,
Ithaca, New York 14853-1301
Received December 18, 2006; E-mail: jn96@cornell.edu
Thiophenes and tetrahydrothiophenes are valuable synthetic
building blocks which are essential components of a variety of
products, ranging from pharmaceuticals to materials. While much
effort has been devoted to the synthesis of thiophenes1 and tetrahy-
drothiophenes,2 dihydrothiophenes have received much less atten-
tion even though they are more amenable to further functionaliza-
tion.3 Despite new methods using olefin metathesis4 and gold
catalysis,5 the earliest reductive approach by Birch still remains
the most common approach.6 We envisioned that vinyl thiiranes
could serve as very attractive synthons for accessing 2,5-dihydro-
thiophenes, and in this Communication, we report on the develop-
ment and study of the first formation of 2,5-dihydrothiophenes from
vinyl thiiranes using readily available copper catalysts.
Vinyl thiiranes are underutilized synthons in organic chemistry.7
Although direct thiiranation of olefins still remains a challenge,8
vinyl thiiranes can be easily accessed from vinyl oxiranes9 or by
the reduction of enone thiophosphates.10 There are very few reported
ring expansions of vinyl thiiranes (1) in the literature (Scheme 1),
which is perhaps not surprising given how readily they undergo
desulfurization to form conjugated dienes (5) when heated.11 The
work of Adams12 and Alper13 is most relevant to our pursuit. Adams
has shown that vinyl thiiranes can be converted to dihydrodithiins
(6) along with equimolar amount of dienes (5) using a tungsten
catalyst, and Alper has used palladium catalysts to ring expand vinyl
thiiranes to several four-membered vinyl-substituted heterocycles.
To the best of our knowledge, there are no successful examples of
the ring expansion of vinyl thiiranes to 2,5-dihydrothiophenes (2).14
The products of such a reaction are particularly attractive synthetic
intermediates since it is well-established that they can be readily
oxidized or reduced to thiophenes (3) and tetrahydrothiophenes (4),
respectively.
philic sulfide addition to the metal activated thiirane and resulting
intramolecular disulfide formation to form 6, as observed by Adams,
was also of significant concern.
Vinyl thiirane 7 was chosen as a model substrate, and it was
determined that the nucleophilic dihydrothiin (9) formation and
extrusion of sulfur as the pathways (both of which lead to diene
10) in competition with the rearrangement to a 2,5-dihydrothiophene
(8). Further studies revealed that the product distribution of these
three pathways was also affected by the catalyst electronics (Table
1). Of catalysts studied to date, only copper catalysts have been
shown to rearrange vinyl thiirane 7 to 2,5-dihydrothiophene 8.
Competing dihydrodithiine (9) formation turns also out to be a major
challenge, but we were able to suppress this intermolecular reaction
by using lower concentration. As expected, suppressing the
undesired desulfurization (10) pathway proved to be the main
obstacle we needed to overcome. Most copper catalysts did not
facilitate the formation of 8 to any appreciable extent (entries 2-9).
Our studies revealed that fluorinated copper(II) acetylacetonate
(acac) catalysts improved formation of 2,5-dihydrothiophene 8 as
the major product (entries 10-11), and copper(II) hexafluoroacetyl-
acetonate in particular proved to be superior by successfully
suppressing both diene (10) and dihydrodithiine (9) formation while
favoring the catalytic ring expansion of 7-8 (entry 11).
Table 1. Copper-Catalyzed Ring Expansion of Vinyl Thiiranes
entry
catalyst
time (h)a
8/9/10b
1
none
12
12
2
0:0:1
0:0:1
1:9:10
0:1:3
0:1:1
0:2:3
1:4:8
1:3:4
1:6:8
2:0:3
11:0:1
2
Cu
3
CuBr
Cu(OAc)2
Cu(TFA)2
Cu(thiophene 2-carboxylate)
Cu(cyclohexanebutyrate)2
Cu(2-ethylhexanoate)2
Cu(acac)2
Scheme 1. Vinyl Thiirane Ring Expansions
4
2
5
2
6
2
7
2
8
2
9
3
10
11
Cu(tfacac)2
Cu(hfacac)2
3
1
a For a 100% conversion at 5 mol % catalyst, 120 °C and 0.01 M in
toluene. b Ratio determined by analyzing 1H NMR spectra of unpurified
mixture.
Encouraged by our recent success in the rearrangement of vinyl
oxiranes, we proposed that an analogous reaction might occur with
a vinyl thiirane.15 We realized three main obstacles would need to
be overcome for this ring expansion to be successful. Since vinyl
thiiranes readily fragment to form dienes (5) when heated, the ring
expansion would need to occur at lower temperatures than for vinyl
oxiranes (150 °C) in order to outcompete undesired sulfur extrusion.
Turning over the catalyst, exchanging a 2,5-dihydrothiophene (2)
for a vinyl thiirane (1), might also prove to be particularly
challenging since thioethers coordinate to metal catalysts much
stronger compared to their ether counterparts. Competing nucleo-
This ring expansion is not only limited to vinyl thiirane 7, but
also proves to be tolerant of many substitution patterns. Several
monosubstituted vinyl thiiranes are shown to be competent (entries
1-6), and as can be seen from entries 1-4, regioisomeric vinyl
thiiranes can be used to access the same 2,5-dihydrothiophene
product.16(Table 2). The substrate shown in entry 1 was used to
study the effects of catalyst loading and temperature. We were able
to use a catalyst loading of 0.1 mol % to achieve full conversion
in less than 2 h. At room temperature, the reaction was found to
9
2768
J. AM. CHEM. SOC. 2007, 129, 2768-2769
10.1021/ja069059h CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Copper-Catalyzed Synthesis of 2,5-Dihydrothiophenes*
12 rearranged to give the desired 2-substituted 2,5-dihydrothiophene
(13), which then underwent a chemoselective and substrate
controlled dihydroxylation18 affording diol 14, an intermediate in
Ohrui’s synthesis19 of biotin, in only four steps from ester 11.
Plavix is an antiplatelet medication used to reduce the risk of
heart attack and stroke.20 Our copper catalyzed vinyl thiirane
rearrangement can be used to access its fused heterocyclic core
(21) in a few steps as illustrated in Scheme 3. The amino group of
1721 was first protected, and the aldehyde was then converted in a
single step to epoxide 18, which was then thiiranated using
potassium thiocyanate. Thiirane 19 ring expanded to 2,5-dihy-
drothiophene 20 in the presence of Cu(tfacac)2. Oxidation using
sulfuryl chloride22 proceeded smoothly to a fused thiophene product,
which upon deprotection afforded 21. This synthetic building block
has been utilized to access Plavix in one additional step.23
In summary, we have demonstrated that vinyl thiiranes can be
selectively converted to 2,5-dihydrothiophenes in excellent yields
using commercially available electrophilic copper(II) catalysts. This
new methodology provides a mild new entry into the thiophene
framework as illustrated by our synthetic approaches to biotin and
Plavix. Further studies on the mechanism and scope of this new
catalytic ring expansion are currently underway.
*Conditions: Cu(hfacac)2, C6H6, 0.1 M. a Isolated yield. b Yield based
on molar ratios from 1H NMR integration c Concentration ) 0.01 M.
d Toluene. e Cu(tfacac)2. f Volatile product.
Acknowledgment. We would like to thank Cornell University
for financial support.
Scheme 2. Formal Racemic Total Synthesis of Biotin
Supporting Information Available: Experimental details and
physical data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) Russell, R. K.; Press, J. B. In ComprehensiVe Heterocyclic Chemstry;
Katritsky, A. R., Rees, C. W., Scriven, E. F., Eds.; Pergamon: Oxford,
1996; Vol. 7, pp 679-729.
(2) For a recent approach, consult: Brandau, S.; Maerten, E.; Jorgensen, K.
A. J. Am. Chem. Soc. 2006, 128, 14986-14991 and references cited
therein.
(3) (a) Blenderman, W. G.; Joullie, M. M. Heterocycles 1982, 19, 111-147.
(b) Shevkhgeimer, M.-G. A. Chem. Heterocycl. Compd. 1998, 34, 1101-
1122.
Conditions: (a) 16, Grubbs second, CH2Cl2, 40 °C, 70%; (b) NaBH4,
MeOH, 10 °C, 83%; (c) 5% Cu(hfacac)2, benzene, 120 °C, 1.5 h, 0.01 M,
80%; (d) AD-mix R, t-BuOH, H2O, room temp, 50% (80% based on
recovered starting material).
(4) Spagnol, G.; Heck, M.-P.; Nolan, S. P.; Mioskowski, C. Org. Lett. 2002,
4, 1767-1770.
Scheme 3. Synthesis of the Thiophene Core of Plavix
(5) Morita, N.; Krause, N. Angew. Chem., Int. Ed. 2006, 45, 1897-1899.
(6) (a) Birch, S. F.; McAllan, D. T. Nature 1950, 165, 899. (b) Blenderman,
W. G.; Joullie, M. M. Tetrahedron Lett. 1979, 20, 4985-4988.
(7) (a) Dittmer, D. C. In ComprehensiVe Heterocyclic Chemstry; Katritsky,
A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 7, pp 131-184.
(b) Chew, W.; Harpp, D. N. Sulfur Rep. 1993, 15, 1-39.
(8) Adam, W.; Bargon, R. M. Chem. ReV. 2004, 104, 251-262.
(9) (a) Bordwell, F. G.; Andersen, H. M. J. Am. Chem. Soc. 1953, 75, 4959-
4962. (b) Price, C. C.; Kirk, P. F. J. Am. Chem. Soc. 1953, 75, 2396-
2400.
Conditions: (a) TFA, CH2Cl2, room temp then TrCl, Et3N, room temp,
93%; (b) ClCH2I, n-BuLi, THF, -78 °C to room temp; (c) KSCN, Et3N,
CH2Cl2-MeOH, room temp, (40%, two steps); (d) 5 mol % Cu(tfacac)2,
C6H6, 100 °C, 52%; (e) SO2Cl2, Et3N, CH2Cl2, 0 °C, then 1 M HCl, THF,
room temp, 65%.
(10) Maciagiewicz, I.; Dybowski, P.; Skowronska, A. Tetrahedron Lett. 1999,
40, 3791-3794.
(11) Vollhardt, K. P. C.; Bergman, R. G. J. Am. Chem. Soc. 1973, 95, 7538-
7539.
(12) (a) Adams, R. D.; Long, J. W., IV; Perrin, J. L. J. Am. Chem. Soc. 1998,
120, 1922-1923. (b) Adams, R. D. Acc. Chem. Res. 2000, 33, 171-178.
(13) Larksarp, C.; Sellier, O.; Alper, H. J. Org. Chem. 2001, 66, 3502-3506.
(14) Lautenschlaeger, F. J. Org. Chem. 1969, 34, 3998-4002. In a single
example, it was shown that oxidation of butadiene episulfide with hydrogen
peroxide afforded 2,5-dihydrothiophene-1-oxide in a 25% yield.
(15) Batory, L. A.; McInnis, C. E.; Njardarson, J. T. J. Am. Chem. Soc. 2006,
128, 16054-16055.
proceed in 2 days with 10 mol % catalyst. Furthermore, entry 8
was found to proceed best with the less electrophilic Cu(tfacac)2
catalyst. Similarly, disubstituted vinyl thiiranes (entries 7-10) are
also excellent substrates for this reaction. The synthetic utility of
this new method has been demonstrated in the synthesis of biotin
and Plavix, as detailed in Schemes 2 and 3.
Biotin (vitamin H) is an important biocatalyst involved in carbon
dioxide transport, which has remained a synthetic challenge since
its isolation 70 years ago.17 Our synthetic method can be used to
access the tetrahydrothiophene moiety from commercially available
ethyl 6-heptenoate (11, Scheme 2). Although attempts to form vinyl
thiirane 12 in a single step by cross metathesis of 11 with 15 were
unsuccessful, cross metathesis with enone thiophosphate 16 fol-
lowed by a selective reduction with NaBH4 and in situ cyclization
did afford 12 in good yield. In our key synthetic step, vinyl thiirane
(16) In a preliminary study, we have independently subjected the two
enantiomers of 2- styrilthiirane (entry 5) to the reaction conditions (see
Supporting Information). Our results, for this particular substrate, indicate
that there is some erosion of chirality during the course of the reaction.
(17) De Clercq, P. J. Chem. ReV. 1997, 97, 1755-1792.
(18) Walsh, P. J.; Ho, P. T.; King, S. B.; Sharpless, K. B. Tetrahedron Lett.
1994, 35, 5129-5132.
(19) Diol 14 was previously accessed in 11 synthetic steps, see Ohrui, H.;
Emoto, S. Tetrahedron Lett. 1975, 16, 2765-2766.
(20) Herbert, J. M.; Frehel, D.; Valee, E.; Kieffer, G.; Gouy, D.; Berger, Y.;
Necciari, J.; Defreyn, G.; Maffrand, J. P. CardioVasc. Drug ReV. 1993,
11, 180-198.
(21) Wohl, A.; Losanitsch, M. S. Chem. Ber. 1908, 40, 4685-4698.
(22) Rossy, P. A.; Hoffmann, W.; Muller, N. J. Org. Chem. 1980, 45, 617-620.
(23) Bouisset, M.; Radisson, J. U.S. Patent 5036156 A, 1991.
JA069059H
9
J. AM. CHEM. SOC. VOL. 129, NO. 10, 2007 2769