Diastereoselective synthesis of CF3-substituted, epoxide-fused heterocycles with β-(trifluoromethyl)vinylsulfonium salts

Article abstract of DOI:10.1021/ol303200n

CF₃-substituted vinyl diphenylsulfonium triflate is an effective annulation reagent for the formation of α-CF₃ substituted, epoxide-fused heterocycles (pyrrolidines, piperidines, and tetrahydrofurans). This simple method affords a variety of valuable heterocyclic building blocks in a highly diastereoselective manner (dr >20:1).

Full text of DOI:10.1021/ol303200n

ORGANIC
LETTERS
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Vol. XX, No. XX
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Diastereoselective Synthesis of
CF3‑Substituted, Epoxide-Fused
Heterocycles with
β‑(Trifluoromethyl)vinylsulfonium Salts
Sven P. Fritz,† Thomas H. West,† Eoghan M. McGarrigle,*,†,‡ and
Varinder K. Aggarwal*,†
School of Chemistry, University of Bristol, Cantock’s Close, BS8 1TS Bristol, U.K., and
Centre for Synthesis and Chemical Biology, UCD School of Chemistry and Chemical
Biology, University College Dublin, Belfield, Dublin 4, Ireland
V.Aggarwal@bristol.ac.uk; Eoghan.McGarrigle@ucd.ie
Received November 20, 2012
ABSTRACT
CF3-substituted vinyl diphenylsulfonium triflate is an effective annulation reagent for the formation of R-CF3 substituted, epoxide-fused
heterocycles (pyrrolidines, piperidines, and tetrahydrofurans). This simple method affords a variety of valuable heterocyclic building blocks in a
highly diastereoselective manner (dr >20:1).
Fluorinated and especially CF3-substituted compounds
are of considerable contemporary interest,1 due to the
development of biologically active compounds containing
this functionality.2 Combined into heterocyclic frameworks,
this often leads to the creation of superior pharmacophores.3
Despite this high interest, efficient methods, starting from
simple materials, for the introduction of the trifluoromethyl
group into saturated heterocycles are still scarce.4,5 We
recently reported the synthesis of epoxide- and aziridine-
fused five-, six-, and seven-membered heterocycles from
unsubstituted vinylsulfonium triflates6,7 and explored
alternative modes of reactivity with these reagents for the
construction ofothermonocyclicfour- to seven-membered
heterocycles such as morpholines.8,9 We envisioned that we
could combine our advances on the Michael-type-addition/
annulation sequence for fused ring systems with CF3-
substituted vinylsulfonium salts reported by others10 to
produce useful heterocyclic building blocks (Scheme 1).
† University of Bristol.
‡ University College Dublin.
(1) (a) Yale, H. L. J. Med. Pharmaceut. Chem. 1959, 1, 121. (b)
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Diederich, F. Science 2007, 317, 1881. (d) O’Hagan, D. Chem. Soc. Rev.
2008, 37, 308.
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Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992. (c) Purser, S.;
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J.-L. Eur. J. Org. Chem. 2006, 3421. (f) Lin, P.; Jiang, J. Tetrahedron
2000, 56, 3635.
(5) For recent examples on the formation of sp3 CÀCF3 bonds
leading to building blocks for similar heterocycles, see: (a) Kieltsch, I.;
Eisenberger, P.; Togni, A. Angew. Chem., Int. Ed. 2007, 46, 754. (b)
Pham, P. V.; Nagib, D. A.; MacMillan, D. W. C. Angew. Chem., Int. Ed.
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2012, 51, 9567 and references therein.
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10.1021/ol303200n
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Table 1. Substrate Scope of the Annulation Reaction
Scheme 1. Context of Presented Work
Screening of reaction conditions using aminoketone 2a
and β-trifluoromethylvinyl sulfonium salt 1 led to an
optimized method that produced 3a in 81% yield and in
>20:1 dr (please see Supporting Information for optimi-
zation details). The scope of the reaction (Table 1) was
shown to extend to the synthesis of other N-tosyl pyrroli-
dines 3aÀd, giving good yields and excellent diastereoselec-
tivity. Sulfonamide 3e bearing the easier-to-cleave p-Ns11
also worked well. Furthermore, the synthesis of fused
(6) For initial studies, see: (a) Wang, Z.; Jimenez, L. S. J. Am. Chem.
Soc. 1994, 116, 4977. (b) Wang, Z.; Jimenez, L. S. Tetrahedron Lett.
1996, 37, 6049. (c) Dong, W. T.; Jimenez, L. S. J. Org. Chem. 1999, 64,
2520. (d) Wang, Y. F.; Zhang, W. H.; Colandrea, V. J.; Jimenez, L. S.
Tetrahedron 1999, 55, 10659. (e) Kim, K. H.; Jimenez, L. S. Tetrahedron:
Asymmetry 2001, 12, 999.
(7) For our work, see: (a) Unthank, M. G.; Hussain, N.; Aggarwal, V. K.
Angew. Chem., Int. Ed. 2006, 45, 7066. (b) Kokotos, C. G.; McGarrigle,
E. M.; Aggarwal, V. K. Synlett 2008, 219. (c) Unthank, M. G.; Tavassoli, B.;
Aggarwal, V. K. Org. Lett. 2008, 10, 1501. (d) Yar, M.; Unthank, M. G.;
McGarrigle, E. M.; Aggarwal, V. K. Chem.;Asian. J. 2011, 6, 372. (e) Fritz,
S. P.; Ali, Z.; Unthank, M. G.; McGarrigle, E. M.; Aggarwal, V. K. Helv.
Chim. Acta 2012, in press, doi:10.1002/hlca.201200455.
(8) For further vinylsulfonium mediated annulation reactions, see:
(a) Matsuo, J.; Yamanaka, H.; Kawana, A.; Mukaiyama, T. Chem. Lett.
2003, 32, 392. (b) Yamanaka, H.; Matsuo, J.; Kawana, A.; Mukaiyama,
T. Chem. Lett. 2003, 32, 626. (c) Yamanaka, H.; Mukaiyama, T. Chem.
Lett. 2003, 32, 1192. (d) Yamanaka, H.; Matsuo, J.; Kawana, A.;
Mukaiyama, T. ARKIVOC 2004, 42. (e) Yar, M.; McGarrigle, E. M.;
Aggarwal, V. K. Angew. Chem., Int. Ed. 2008, 47, 3784. (f) Hansch, M.;
Illa, O.; McGarrigle, E. M.; Aggarwal, V. K. Chem.;Asian. J. 2008, 3,
1657. (g) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Org. Lett. 2009,
11, 257. (h) Xie, C. S.; Han, D. Y.; Liu, J. H.; Xie, T. Synlett 2009, 3155.
(i) Bornholdt, J.; Felding, J.; Kristensen, J. L. J. Org. Chem. 2010, 75,
7454. (j) Catalan-Munoz, S.; Muller, C. A.; Ley, S. V. Eur. J. Org. Chem.
2010, 183. (k) Xie, C. S.; Han, D. Y.; Hu, Y.; Liu, J. H.; Xie, T. A.
Tetrahedron Lett. 2010, 51, 5238. (l) Chen, J. R.; An, J.; Chang, N. J.;
Song, L. D.; Jin, Y. Q.; Ma, Y.; Xiao, W. J. Chem. Commun. 2011, 47,
1869. (m) Fritz, S. P.; Mumtaz, A.; Yar, M.; McGarrigle, E. M.;
Aggarwal, V. K. Eur. J. Org. Chem. 2011, 3156. (n) McGarrigle,
E. M.; Fritz, S. P.; Favereau, L.; Yar, M.; Aggarwal, V. K. Org. Lett.
2011, 13, 3060. (o) Yar, M.; Fritz, S. P.; Gates, P. J.; McGarrigle, E. M.;
Aggarwal, V. K. Eur. J. Org. Chem. 2012, 160. (p) Fritz, S. P.; Moya,
J. F.; Unthank, M. G.; McGarrigle, E. M.; Aggarwal, V. K. Synthesis
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2012, 48, 9927.
a Isolated yield after purification. b From polymeric aldehyde 2b. c 36 h
reaction time. d A weaker (pyridine) or stronger (NaH) base did not change
the outcome of the reaction, but led to much lower conversion. e Combined
yield of 5a and 5b, 5a:5b = 2.9:1.
(9) For reviews, see: (a) Fritz, S. P. Synlett 2012, 23, 480. (b) Yar, M.;
McGarrigle, E. M.; Aggarwal, V. K. Sulfonium, Ethenyldiphenyl-, 1,1,1-
Trifluoromethanesulfonate. In Encyclopedia of Reagents for Organic Synthe-
sis, eEROS; Paquette, L. A., Crich, D., Fuchs, P. L., Molander, G. A., Eds.; John
Wiley & Sons Ltd.: 2012; doi: 10.1002/047084289X.rn01409.
piperidines 3f,g was possible, as long as enolizable protons
were not present, otherwise competing elimination occurred.12
B
Org. Lett., Vol. XX, No. XX, XXXX

Epoxide-fused tetrahydrofuran 3h was synthesized in good
yield and excellent diastereoselectivity, but the attempted
synthesis of six-membered oxygen heterocycles was domi-
nated by competing elimination, forming enol ether 4.12
Thiol 2j, with increased acidity adjacent to the CF3 group,
also resulted in elimination giving rise to products 5a/5b.
Evidently, in cases of slow cyclization or increased acidity
ofthe CHCF3, competing elimination dominates.13 The cis
relative stereochemistry of the product from 2a was con-
firmed from a crystal structure of 3a (Figure 1).
Based on our experience with unsubstituted vinylsulfo-
nium salts,7 we propose that, after initial addition of the
nucleophile 2a to vinyl sulfonium salt 1 to form sulfur ylide
6, two possible pathways (A and B) leading to cis and trans
products should be considered (Scheme 2). Betaine 7 would
suffer less from steric strain than 8 and has more favorable
dipole interactions than 8. Pathway A with a transition state
leading from conformer 6A to betaine 7 would be expected
to be lower in energy than pathway B (with a transition state
leading from conformer 6B to betaine 8) as the transition
states will experience similar steric and dipole interactions as
the betaines. This accounts for the preferred formation of
the cis-epoxide 3a.
The strength of the diastereocontrol provided by the CF3
group (reagent control) was probed using the chiral sub-
strates derived from alanine, 9a,b. Out of four possible
products, only two were obtained, 10 and 11, in a 1:1 ratio
(Scheme 3a). Unsurprisingly, the stereogenic center in 9 does
not influence which face of the vinyl sulfonium salt is
attacked. The chiral substrate 9a shows an inherent prefer-
ence for formation of the epoxide cis to the methyl group
(Scheme 3b).7c Thus, product 10, with the epoxide cis to both
theMeandCF3 groups, is “doubly matched” and expected to
be easily formed. In contrast, compound 11 has the epoxide
cis to the CF3 group but trans to the Me group and so is
mismatched. Despite the inherent bias of a 4.6:1 ratio against
its formation imposed by the Me group, it was still formed
with complete exclusion of the other mismatched isomer 12
[with the epoxide cis to the Me group (matched) but trans to
the CF3 group (mismatched)], showing that the CF3 group
appears to induce a selectivity of >92:1 (>20:1 Â 4.6:1).14
Figure 1. X-ray crystal structure of 3a, showing cis configura-
tion of epoxide to CF3 (thermal ellipsoids are drawn at the 50%
probability level).
Scheme 2. Proposed Reaction Pathway for the
Diastereoselective Formation of 3a
Scheme 3. Reactions of R-Substituted Aminoketones 9
Finally, to give an example of how this method enables
rapid access to functionalized building blocks with diverse
options for elaboration, a regioselective opening15 of
(10) (a) Maeda, R.; Ooyama, K.; Anno, R.; Shiosaki, M.; Azema, T.;
Hanamoto, T. Org. Lett. 2010, 12, 2548. (b) Lin, H.; Shen, Q. L.; Lu, L.
J. Org. Chem. 2011, 76, 7359. (c) Kasai, N.; Maeda, R.; Furuno, H.;
Hanamoto, T. Synthesis 2012, 44, 3489. Sulfonium salt 1 can be synthesized
in two steps from 2-bromo-3,3,3-trifluoroprop-1-ene (ref 10c).
(11) (a) Kocienski, P. J. Protecting Groups; Thieme: New York, 1994.
(b) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,
3rd ed.; Wiley-Interscience: New York, 1999.
Org. Lett., Vol. XX, No. XX, XXXX
C

Through probing matched and mismatched stereoisomers,
it was found that the diastereoselectivities are >20:1 and
could be higher than >90:1. The methodology has been
extended toanarray of different classes of CF3 substituted,
epoxide-fused heterocycles (N-, O-, five and six rings),
which are useful intermediates in synthesis.
Scheme 4. Ring Opening of 3b with NaN3
Acknowledgment. S.P.F. thanks EPSRC (Engineering
and Physical Sciences Research Council) for a studentship.
V.K.A. thanks EPSRC for a Senior Research Fellowship.
E.M.M. thanks Science Foundation Ireland and Marie-
Curie COFUND for a SIRG award (Grant Number
11/SIRG/B2154). We thank Dr. Craig Butts (University
of Bristol) and Dr. Mairi Haddow (University of Bristol)
for NMR and X-ray assistance, respectively.
epoxide 3bwith NaN3 wascarried out togiveazido alcohol
14 in 61% yield (Scheme 4).
In conclusion, we have demonstrated an easy and effi-
cient synthesis of CF3-substituted heterocyclic building
blocks in good yields and very high diastereoselectivities.
(12) Substrates with an enolizable proton are prone to a competing
elimination reaction. We note that with unsubstituted vinyldiphenyl-
sulfonium salts the conjugate addition/annulation sequence was suc-
cessful but it was a problem with hindered chiral vinylsulfonium salts;
see ref 7a.
Supporting Information Available. Experimental pro-
cedures, compound characterization, spectra, and X-ray
crystallographic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) If, for example, the CF3 group exerted a selectivity of 50:1, then
in the mismatched case we would expect to see an 11:1 ratio of 11:12,
which would be observable by 1H NMR. The absence of 12 shows that
the CF3 group exerts very high selectivity and probably >90:1.
(13) If cyclization towards the betaine is slow, competing elimination
dominates. Related competing eliminations were also observed by
Hanamoto et al. (ref 10c).
€
(15) (a) Herdeis, C.; Aschenbrenner, A.; Kirfel, A.; Schwabenlander,
F. Tetrahedron: Asymmetry 1997, 8, 2421. (b) Curtis, K. L.; Evinson,
E. L.; Handa, S.; Singh, K. Org. Biomol. Chem. 2007, 5, 3544. (c) Rives,
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A.; Genisson, Y.; Faugeroux, V.; Zedde, C.; Lepetit, C.; Chauvin, R.; Saffon,
N.; Andrieu-Abadie, N.; Colie, S.; Levade, T.; Baltas, M. Eur. J. Org. Chem.
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The authors declare no competing financial interest.
D
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