Synthesis of Heterocyclic and Carbocyclic Fluoro-olefins by Ring-Closing Metathesis

Article abstract of DOI:10.1021/ol035065w

(Equation presented) Ring-closing metathesis (RCM) of vinyl fluoride-containing dienes in the presence of ruthenium alkylidene carbene complex 11 proceeded efficiently to give six- and seven-membered cyclic vinyl fluorides. The RCM reaction was used to pr

Full text of DOI:10.1021/ol035065w

ORGANIC
LETTERS
2003
Vol. 5, No. 19
3403-3406
Synthesis of Heterocyclic and
Carbocyclic Fluoro-olefins by
Ring-Closing Metathesis
Sofia S. Salim,† Richard K. Bellingham,‡ Vachiraporn Satcharoen,† and
,†
Richard C. D. Brown*
Department of Chemistry, UniVersity of Southampton, Highfield,
Southampton SO17 1BJ, U.K., and Synthetic Chemistry Department,
Chemical DeVelopment, GlaxoSmithKline Pharmaceuticals, Old Powder Mills,
Tonbridge, Kent TN11 9AN, U.K.
rcb1@soton.ac.uk.
Received June 12, 2003
ABSTRACT
Ring-closing metathesis (RCM) of vinyl fluoride-containing dienes in the presence of ruthenium alkylidene carbene complex 11 proceeded
efficiently to give six- and seven-membered cyclic vinyl fluorides. The RCM reaction was used to prepare amine- and sulfamide-linked cyclo-
olefins, as well as carbocyclic systems, from a simple commercial fluoro-olefin.
Fluoro-olefins have been recognized as hydrolytically stable,
nonclassical isosteric replacements for the carboxamide
group.1 In contrast to simple double bonds, which are
generally considered to behave as noninteracting conforma-
tionally constrained spacers,2 fluoro-olefins have been sug-
gested as superior isosteric replacements and are therefore
of considerable interest in the synthesis of peptidomimetics
and other biologically active molecules.3 Consequently, mild
and general methods that allow the straightforward introduc-
tion of fluorinated double bonds into acyclic and cyclic
systems would constitute valuable synthetic methods.4 Here
we describe our preliminary studies concerning the ring-
closing metathesis (RCM) reactions of monofluorinated
dienes linked by various carbon and heteroatom-containing
chains to provide cyclic vinyl fluorides.5
Initial investigations focused on the RCM reactions of
sulfamide-linked diene substrates, as these provided the
seven-membered cyclic scaffold present in a series of highly
potent HIV protease inhibitors (Figure 1).6 Indeed, Hanson
† University of Southampton.
‡ GlaxoSmithKline Pharmaceuticals.
(1) For fluoro-olefin isosteres: Zhao, K.; Lim, D. S.; Funaki, T.; Welch,
J. T. Bioorg. Med. Chem. 2003, 11, 207. Bartlett, P. A.; Otake, A. J. Org.
Chem. 1995, 60, 3107. Veenstra, S. J.; Hauser, K.; Felber, P. Bioorg. Med.
Chem. Lett. 1997, 7, 351. Welch, J. T.; Lin, J. Tetrahedron 1996, 52, 291.
Allmendinger, T.; Felder, E.; Hungerbu¨hler, E. Tetrahedron Lett. 1990, 31,
7297. Allmendinger, T.; Furet, P.; Hungerbu¨hler, E. Tetrahedron Lett. 1990,
31, 7301. Abraham, R. J.; Ellison, S. L. R.; Schonholzer, P.; Thomas, W.
A. Tetrahedron 1986, 42, 2101.
(2) Gardner, R. R.; Liang, G.-B.; Gellman, S. H. J. Am. Chem. Soc. 1999,
121, 1806. Wipf, P.; Henningger, T. C.; Geib, S. J. J. Org. Chem. 1998,
63, 6088. Cox, M. T.; Gormley, J. J.; Hayward, C. F.; Petter, N. N. Chem.
Commun. 1980, 800. Cox, M. T.; Heaton, D. W.; Horbury, J. Chem.
Commun. 1980, 799. Hann, M. M.; Sammes, P. G.; Kennewell, P. D.;
Taylor, J. B. Chem. Commun. 1980, 234.
Figure 1. Structure of sulfamide fluoro-olefin RCM products and
related small-molecule HIV protease inhibitors.
10.1021/ol035065w CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/26/2003

et al. had previously demonstrated that analogues of the
cyclic sulfamide protease inhibitors could be prepared
efficiently by a RCM-based approach,7,8 and we felt that
extension of the method to fluoro-olefins might provide
access to novel analogues with potentially interesting proper-
ties. Impetus for the synthesis of fluorinated seven-membered
sulfamides was augmented further by the fact that previous
efforts to interconvert hydroxyl groups to halogens in cyclic
HIV protease inhibitors 3 had been complicated by ring-
contraction reactions.9
Scheme 2. RCM Reactions of Sulfamides
Sulfamide-linked RCM precursors were prepared using
established procedures,10 the only point of note being the
relatively low reactivity of 1-chloro-2-fluoroprop-2-ene as
an alkylating agent (Scheme 1). This minor complication in
a heated bath at 100 °C, retaining CH2Cl2 as the solvent. It
is noteworthy that no special high-dilution conditions were
required to avoid cross-metathesis, and all of the desired
N,N′-disubstituted sulfamides were obtained in good to
excellent yields.11 The difference in reaction rates between
the Boc-, H-, and alkyl-substituted sulfamides is not im-
mediately apparent but may be a consequence of conforma-
tional preferences of the intermediate ruthenium alkylidene
complexes.
Scheme 1a
During the course of this work, literature searches failed
to reveal any previously successful examples of RCM of
fluoro-olefins to give cyclic vinyl fluorides. However,
(6) For a review of cyclic HIV protease inhibitors: De Lucca, G. V.;
Erickson-Viitanen, S.; Lam, P. Y. S. Drug DiscoVery Today 1997, 2, 6.
Cyclic ureas 3 (X ) CO): Lam, P. Y. S.; Jadhav, P. K.; Eyermann, C. J.;
Hodge, C. N.; Ru, Y.; Bacheler, L. T.; Meek, J. L.; Otto, M. J.; Rayner, M.
M.; Wong, N. Y.; Chang, C. H.; Weber, P. C.; Jackson, D. A.; Sharpe, T.
R.; Erickson-Viitanen, S. Science 1994, 263, 380. Sulfamides 3 (X ) SO2),
see ref 10 and: Hulte´n, J.; Bonham, N. M.; Nillroth, U.; Hansson, T.;
Zuccarello, G.; Bouzide, A.; Åqvist, J.; Classon, B.; Danielson, U. H.;
Karle´n, A.; Kvarnstro¨m, I.; Samuelsson, B.; Hallberg, A. J. Med. Chem.
1997, 40, 885. Ba¨ckbro, K.; Lo¨wgren, S.; O¨ sterlund, K.; Atepo, J.; Unge,
T.; Hulte´n, J.; Bonham, N. M.; Schaal, W.; Karle´n, A.; Hallberg, A. J.
Med. Chem. 1997, 40, 898. Triazacyclic ureas 2: Sham, H. L.; Zhao, C.;
Stewart, K. D.; Betebenner, D. A.; Lin, S.; Park, C. H.; Kong, X.-P.;
Rosenbrook, W. Jr.; Herrin, T.; Madigan, D.; Vasavanonda, S.; Lyons, N.;
Molla, A.; Kempf, D. J.; Plattner, J. J.; Norbeck, D. W. J. Med. Chem.
1996, 39, 392.
(7) For olefin RCM approaches to sulfamides: Dougherty, J. M.; Probst,
D. A.; Robinson, R. E.; Moore, J. D.; Klein, T. A.; Snelgrove, K. A.;
Hanson, P. R. Tetrahedron 2000, 56, 9781.
(8) For olefin RCM approaches to related (S)-heterocycles: Cyclic
sulfonamides (sultams): (a) Hanson, P. R.; Probst, D. A.; Robinson, R. E.;
Yau, M. Tetrahedron Lett. 1999, 40, 4761. (b) Brown, R. C. D.; Castro, J.
L.; Moriggi, J. D. Tetrahedron Lett. 2000, 41, 3681. (c) Long, D. D.; Termin,
A. P. Tetrahedron Lett. 2000, 41, 6743. Sultones: (d) Karsch, S.; Schwab,
P.; Metz, P. Synlett 2002, 2019.
a Reagents: (a) t-BuOH, CH2Cl2, Et3N, then allylbenzylamine;
(b) CH2dCFCH2Cl, NaI, t-BuOK, THF; (c) TFA, CH2Cl2; (d)
t-BuOK, THF, BnBr/MeI/EtBr, rt.
the synthesis was readily resolved by conversion of the
chloride to the corresponding allylic iodide, either in situ or
prior to the reaction.
RCM was first carried out on the Boc-protected sulfamide
6, which cyclized smoothly (3 h) in refluxing CH2Cl2 with
6 mol % ruthenium complex 11 (Scheme 2). The monosub-
stituted sulfamide 7 also underwent ring-closure in refluxing
CH2Cl2 (7 h), whereas the N-alkyl sulfamides 8-10 were
slower to cyclize and required higher temperatures. We found
it convenient to use sealed, crimped-cap vials immersed in
(9) De Lucca, G. V. J. Org. Chem. 1998, 63, 4755.
(10) See ref 7 and: Dewynter, G.; Aouf, N.; Criton, M.; Montero J. L.
Tetrahedron 1993, 49, 65.
(3) For general reviews of peptidomimetics: Hanessian, S.; Mc-
Naughton-Smith, G.; Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997,
53, 12789. Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699. Gainnis,
A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244.
(4) For reviews on the synthesis of fluoro-olefins: Gouverneur, V.;
Greedy, B. Chem. Eur. J. 2002, 8, 766. Taylor, S. D.; Kotoris, C. C.; Hum,
G. Tetrahedron 1999, 55, 12431. Silvester, M. J. Aldrichimica Acta 1995,
28, 45. See also ref 1 for selected examples.
(5) For general reviews of olefin metathesis: (a) Grubbs, R. H.; Miller,
S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446. (b) Schuster, M.; Blechert
S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2037. (c) Armstrong, S. K. J.
Chem. Soc., Perkin Trans. 1 1998, 371. (d) Phillips, A. J.; Abell, A. D.
Aldrichimica Acta 1999, 32, 75. (e) Fu¨rstner A. Angew. Chem., Int. Ed.
2000, 39, 3012. (f) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003,
42, 1900.
(11) Procedure for the Preparation of Compound 12. To a stirring
solution of the sulfamide 6 (60 mg, 0.16 mmol) in CH2Cl2 (5 mL) was
added Grubbs’ ruthenium complex 11 (8.0 mg, 0.009 mmol). The reaction
mixture was stirred for 5 h at reflux. The solvent was removed under reduced
pressure to afford a brown oil, which was purified by column chromatoraphy
(Et2O/hexane, 1:4) to yield the title compound 12 as a pale yellow oil (50.0
mg, 0.14 mmol, 90%). 1H NMR (400 MHz, CDCl3): δ 1.56 (9H, s, CH3),
3.78 (2H, t, J ) 5.0 Hz, NCH2), 4.46 (2H, s, NCH2), 4.48 (2H, d, JH-F
)
11.3 Hz, NCH2), 5.31 (1H, td, J ) 5.0, 17.8 Hz, dCH), 7.38-7.33 (5H,
m, Ar). 13C NMR (67.9 MHz, CDCl3): δ 28.1 (CH3), 41.2 (d, JC-F ) 11
Hz, CH2), 45.3 (d, JC-F ) 42 Hz, CH2), 52.1 (CH2), 85.0 (C), 102.8 (d,
JC-F ) 20 Hz, CH), 128.5 (CH), 128.6 (CH), 129.1 (CH), 135.0 (C), 151.3
(CO), 161.9 (d, JC-F ) 264 Hz, CF). IR (CCl4): υmax 2978, 2935, 2864,
1725, 1370, 1327, 1130 cm-1. HRMS (C16H21FN2O4S): calcd, 379.1098;
found, 379.1099.
3404
Org. Lett., Vol. 5, No. 19, 2003

Blechert et al. and Grubbs had reported on the cross-
metathesis of perfluoroalkyl-substituted olefins,12-14 attribut-
ing their success to the use of later-generation ruthenium
N-heterocyclic carbene complexes.15 In the same work,
Grubbs et al. noted that vinyl halides had failed to give cross-
metathesis products.13,14 Given the dearth of examples of
RCM involving halo-olefins, we set out to establish if the
RCM of fluoro-olefins could be more widely applicable
(Scheme 3).
17, deallylation occurred rather than the desired ring closure.
Recently, Cadot et al. have reported that allyl and homoallyl
groups can undergo isomerization in the presence of the
ruthenium alkylidene complex 11.17 It therefore seems likely
that isomerization of allylic amine 17, followed by in situ
hydrolysis of the resulting enamine, accounts for the forma-
tion of 18. However, the structure of the ruthenium species
mediating the isomerization remains unknown. Gratifyingly,
the homologous amine 19 provided the six-membered vinyl
fluoride 20 in good yield.
In the carbocyclic series, RCM also proceeded smoothly
to provide the six- and seven-membered products 25 and
26, respectively. However, we were unable to close the five-
membered ring 24, and in this case starting material was
recovered.
Scheme 3. Further RCM Reactions of Vinyl Fluorides
RCM of the ether-linked diene 27 required more forcing
conditions and did not proceed as cleanly as the above
examples. The characteristic signals of the desired seven-
membered product 28 were observed in the 1H NMR spectra
of the crude reaction mixture, and a partially purified sample
(40%, see Supporting Information) was obtained after
chromatography. Unfortunately, isolation of a pure sample
of the product was not possible due to its instability and
volatility.18
A general observation made on the work described here
is that RCM reactions of fluoro-olefins are typically slower
than their nonfluorinated analogues. We therefore suggest
that the first step along a productive reaction pathway would
be reaction at the more electron-rich olefin to form a
ruthenium alkylidene complex A (Figure 2). Coordination
A variety of monofluorinated dienes, with carbon and
heteroatoms in the linking chain, were prepared. Amine and
ether substrates 17, 19, and 27 were obtained by fluoro-
allylation of N-benzylallylamine, N-benzyl-4-aminobutene,
and 2-allyl-phenol, respectively. The malonate derivatives
21-23 were synthesized by alkylation of the sodium salt of
diethyl (2-fluoro-allyl)malonate in DMF at 100 °C in the
presence of NaI.
RCM reactions of the amines 17 and 19 were carried out
on both the free 3° amines and their corresponding am-
monium salts with similar results.16 We were surprised to
observe that in the case of the five-membered ring precursor
Figure 2. Proposed reaction pathway for the RCM of fluoro-olefin-
containing dienes
of the poorer σ-donor fluoro-olefin and formal [2 + 2]
(12) Imhof, S.; Randl, S.; Blechert, S. Chem. Commun. 2001, 1692.
(13) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 3783. See also: Kirkland, T. A.; Grubbs, R. H. J.
Org. Chem. 1997, 62, 7310.
(14) RCM of chloro-olefins has recently been realized using the
ruthenium complex 11 to provide five- to seven-membered products. Chao,
W.; Weinreb, S. M. Org. Lett. 2003, 5, 2505.
(16) Early reports in the literature suggested that RCM reactions of
substrates containing free basic nitrogen atoms could be problematic,
whereas the corresponding ammonium salts could be cyclized. Fu, G. C.;
Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856. Felpin,
F.-X.; Girard, S.; Vo-Thanh, G.; Robins, R. J.; Villie´ras, J.; Lebreton, J. J.
Org. Chem. 2001, 66, 6305. In the current work, we initially formed TFA
salts of 17 and 19 prior to submission to the RCM conditions but
subsequently found that the reactions of free amines 17 and 19 with
ruthenium complex 11 gave similar results.
(15) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168.
Org. Lett., Vol. 5, No. 19, 2003
3405

cycloaddition can then occur to provide the intermediate
metallacyclobutane C when a suitable linking group is
present. We believe that the failure of the RCM reactions to
give five-membered rings is a reflection of the lower
reactivity of the fluoro-olefin double bond, combined with
a greater ring strain energy developing in the formation of
an intermediate such as B or the transition state en route to
C. Thus, competing side-reactions (deallylation of 17) or
recovered starting material are observed.
using a commercially available fluoro-olefin fragment.
Current effort in our laboratory is focused on the develop-
ment of solid-phase cyclization-cleavage approaches to
fluoro-olefins.8b
Acknowledgment. We thank GlaxoSmithKline for a
CASE award (S.S.S.), the Royal Society (R.C.D.B.) for a
University Research Fellowship, and Merck Sharp and
Dohme, Syngenta, AstraZeneca, and Pfizer for unrestricted
grants. We also thank Professor S. Weinreb for helpful
discussions during the preparation of this manuscript.
In conclusion, we have shown that RCM of fluoro-olefins
provided a convenient approach to a variety of carbocyclic
and heterocyclic vinyl fluorides in good to excellent yields
Supporting Information Available: Experimental pro-
cedures, data for 7-10, 13-23, and 25-27, and copies of
1H NMR spectra for 6-10, 12-23, and 25-28. This material
is available free of charge via the Internet at http://pubs.acs.org.
(17) Cadot, C.; Dalko, P. I.; Cossy, J. Tetrahedron Lett. 2002, 43, 1839.
(18) Partial purification of 28 was possible on base-washed (Et3N) SiO2,
although some decomposition still occurred. An NMR sample enriched in
28 also underwent substantial decomposition on standing in CDCl3 overnight
(see Supporting Information).
OL035065W
3406
Org. Lett., Vol. 5, No. 19, 2003