Intramolecular palladium-catalyzed direct arylation of alkenyl triflates

Article abstract of DOI:10.1021/ol702044z

A catalyst generated from Pd(OAc)₂ and dppp is effective for the direct intramolecular arylatlon of alkenyl triflates. Conjugated alkene-arene-containing carbocycles are produced in good yield. The process tolerates a variety of aryl substituen

Full text of DOI:10.1021/ol702044z

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4391-4393
Intramolecular Palladium-Catalyzed
Direct Arylation of Alkenyl Triflates
Ana C. F. Cruz,† Neil D. Miller,‡ and Michael C. Willis*,§
Department of Chemistry, UniVersity of Bath, Bath, BA2 7AY, U.K., Department of
Chemistry, Chemical Research Laboratory, UniVersity of Oxford, Mansfield Road,
Oxford, OX1 3TA, U.K., and GlaxoSmithKline, New Frontiers Science Park,
Third AVenue, Harlow, Essex, CM19 5AW, U.K.
michael.willis@chem.ox.ac.uk
Received August 20, 2007
ABSTRACT
A catalyst generated from Pd(OAc)2 and dppp is effective for the direct intramolecular arylation of alkenyl triflates. Conjugated alkene−arene-
containing carbocycles are produced in good yield. The process tolerates a variety of aryl substituents as well a simple heteroaryl groups.
Electron-deficient aryl rings deliver faster reactions.
Palladium-catalyzed cross-coupling reactions are some of the
most reliable and widely used transformations available to
synthetic chemists and, in particular, represent a standard
method for biaryl synthesis.1 Traditional cross-coupling
reactions rely on the union of two activated aryl units, usually
an aryl halide together with an aryl organometallic. However,
recent reports have described how one of the two activating
groups, usually the organometallic component, can be
replaced with a simple C-H unit of an arene.2,3 These direct
functionalization methods offer significant advantages, not
least the far simpler preparation of the C-H-containing
arene.4 Although originally limited to the use of electron-
rich arenes and heteroarenes,5 more recent reports have
shown that electron-poor6 and neutral7 arenes can also be
effective in direct arylation reactions.8 Activated alkenes, in
the form of alkenyl halides (or pseudohalides), are also used
extensively in cross-coupling chemistry,1 although to date,
reports of their use in direct functionalization methods are
limited.9 Given the diverse range of transformations available
with alkene-containing compounds, the direct arylation of
activated alkenes would provide an attractive entry to these
synthetically valuable products. In this Letter, we detail an
(4) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107,
174. (b) Campeau, L.-C.; Stuart, D. R.; Fagnou, K. Aldrichimica Acta 2007,
40, 35. (c) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2005, 1253.
(5) Selected examples: (a) Ames, D. E.; Opalko, A. Synthesis 1983, 234.
(b) Hennings, D. D.; Iwasa, S.; Rawal, V. H. J. Org. Chem. 1997, 62, 2.
(c) Li, W. J.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.: Javadi, G. J.;
Cai, D.; Larsen, R. D. Org. Lett. 2003, 5, 4835. (d) Toure´, B. B.; Lane, B.
S.; Sames, D. Org. Lett. 2006, 8, 1979.
(6) (a) LaFrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 8754. (b) LaFrance, M.; Shore, D.; Fagnou Org.
Lett. 2006, 8, 5097.
(7) (a) Campeau, L.-C.; Thansandote, P.; Fagnou, K. Org. Lett. 2005, 7,
1857. (b) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 581. (c) LaFrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006,
128, 16496.
† University of Bath.
‡ GlaxoSmithKline.
§ University of Oxford.
(1) General reviews: (a) Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E.-I., Ed.; Wiley: New York, 2002. (b) Metal-
Catalysed Cross-Coupling Reactions; de Meijere, A., Deidrich, F., Eds.;
Wiley-VCH: Weinheim, Germany, 2004.
(2) For general reviews on C-H functionalization, see: (a) Handbook
of C-H Transformations; Dyker, G., Ed.; Wiley-VCH: Weinheim,
Germany, 2005. (b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002,
102, 1731. (c) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077.
(3) For recent examples of Pd-catalyzed cross-coupling processes in
which both activating groups are absent, see: (a) Stuart, D. R.; Fagnou, K,
Science 2007, 316, 1172. (b) Dwight, T. A.; Rue, N. R.; Charyk, D.;
Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137.
(8) Directed arylation reactions have been achieved with a variety of
electronically varied arenes. For a discussion of directed arylation systems,
as well as the use of alternative metal catalysts, see ref 4a.
10.1021/ol702044z CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/13/2007

efficient intramolecular direct arylation of alkenyl triflates.
The process employs readily available substrates, uses
relatively low loadings of a palladium catalyst, and delivers
synthetically useful alkene-containing carbocyclic products
(eq 1).
explore this system. Alternative bases were explored; al-
though NEt3 and Hu¨nigs base delivered product, they were
less effective than NBu3 (entries 7 and 8). The strong
inorganic base, NaOtBu, delivered the ketone corresponding
to triflate 1 as the only product, while the weaker Cs2CO3
was poorly effective (entries 9 and 10). Finally, the use of
nonpolar or protic solvents proved to be ineffective; however,
the use of the polar nonprotic solvent NMP provided
quantitative conversion to product after only 8 h reaction
(entries 11-13). These last seven experiments were all
performed using 2 mol % of palladium.
We focused reaction development on the cyclization of
the triflate 1 (Table 1).10 Our choice of reaction conditions
With efficient conditions for the conversion of 1 into 2
established, we explored the scope of the method (Table 2).
Table 1. Reaction Development for the Conversion 1 f 2a
Table 2. Scope of the Intramolecular Palladium-Catalyzed
Direct Functionalization of Alkenyl Triflatesa
time
entry
ligand
PPh3
PPh3
dppb
dppp
catalyst
base
solvent (h) conversionb
1
2
3
4
5
6
5 mol % NBu3
3 mol % NBu3
3 mol % NBu3
3 mol % NBu3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
24
48
48
48
48
48
30
24
2
99%
82%
90%
99%
89%
88%
81%
16%
0%d
21%
4%
DPEphos 3 mol % NBu3
PCy3
3 mol % NBu3
2 mol % NEt3
2 mol % NiPr2Et DMF
2 mol % NaOtBu DMF
2 mol % Cs2CO3 DMF
2 mol % NBu3
2 mol % NBu3
2 mol % NBu3
7c dppp
8c dppp
9c dppp
10c dppp
11c dppp
12c dppp
13c dppp
25
48
PhMe
tBuOH 24
14%
99%
NMP
8
a Conditions: triflate 1 (1.0 equiv), base (3.0 equiv), 60 °C. b Measured
using 1H NMR. c At 80 °C. d Ketone corresponding to only product 1, 99%.
was guided by a related study we had undertaken11 and
involved treatment of triflate 1 with Pd(OAc)2, PPh3, and
NBu3 in DMF. We were pleased to observe quantitative
conversion to the desired product when the reaction was
performed at 60 °C for 24 h using a 5 mol % loading of
palladium (entry 1). When the catalyst loading was reduced
to 3 mol %, the conversion fell to 82% (entry 2). A number
of alternative phosphine ligands were evaluated using this
loading, and although several, including both mono- and
diphosphines, were successful, the use of dppp proved to be
most effective (entries 3-6). The high reaction efficiency
combined with the low cost of dppp prompted us to further
a Conditions: triflate 1 (1.0 equiv), base (3.0 equiv), 80 °C. b Isolated
yields. c A 1.7:1 mixture of regioisomers; major shown. d With 5 mol % of
Pd and dppp employed. e A 2.5:1 mixture of regioisomers; major shown.
f A 10:1 mixture of regioisomers; major shown.
(9) (a) Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41,
1569; Angew. Chem., Int. Ed. 2002, 41, 2227 (erratum). (b) Hughes, C. C.;
Trauner, D. Tetrahedron 2004, 60, 9675. (c) Fishwick, C. W. G.; Grigg,
R.; Sridharan, V.; Virica, J. Tetrahedron 2003, 59, 4451. (d) Ackermann,
L.; Althammer, A. Angew. Chem., Int. Ed. 2007, 46, 1627.
(10) See Supporting Information for details.
(11) (a) Willis, M. C.; Powell, L. H. W.; Claverie, C. K.; Watson, S. J.
Angew. Chem., Int. Ed. 2004, 42, 1249. (b) Willis, M. C.; Claverie, C. K.;
Mahon, M. F. Chem. Commun. 2002, 832.
All of the cyclization substrates were readily prepared by
alkylation of the parent ketone followed by triflate forma-
tion.10 Although the conversion for triflate 1 to carbocycle
2 was excellent, the isolated yield was poor due to volatility
(entry 1). Adding substituents to the aryl ring remedied this
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Org. Lett., Vol. 9, No. 21, 2007

problem and also allowed the effect of electronically different
groups to be explored.
Scheme 1. Functionalization of alkene 3
Both resonance and inductively electron-withdrawing
substituents resulted in smooth conversion to the desired
products (entries 2-7). The introduction of electron-donating
substituents resulted in significantly slower reactions, and
in order to achieve good yields, in reasonable reaction times,
the catalyst loading was increased to 5 mol %. Using these
conditions, both methoxy and silyloxy substituents were
tolerated well (entries 8-11). The use of the O-TIPS
substrate demonstrated that good levels of regioselection
(10:1) could be achieved by steric control (entries 9 and 10).
The aryl group could also be exchanged for simple heteroaryl
variants without adversely effecting the process and provides
a further class of functionalized products (entries 12 and 13).
Entries 14, 15, and 16 demonstrate that the starting substrates
are not limited to cyclopentene systems, that the second alkyl
substituent can be varied from methyl, and finally, that the
presence of a second alkyl substituent is not necessary to
achieve efficient cyclization.
bicyclic alkane 5, respectively. The latter transformation
demonstrates that the net result of an alkenyl triflate direct
arylation-alkene hydrogenation combination is the formation
of an alkyl-substituted arene, a sequence equivalent to direct
alkyl functionalization of the arene.
In conclusion, we have demonstrated that the Pd-catalyzed
direct functionalization of alkenyl triflates represents an
efficient route to a variety of conjugated bicyclic alkene-
arene systems. The process tolerates a variety of electroni-
cally varied aryl substituents and simple heteroarenes. A full
mechanistic study of these transformations is underway and
will be reported in due course.
A number of mechanistic models have been proposed to
rationalize the efficiencies and selectivities observed in direct
functionalization biaryl syntheses.12 An electrophilic aromatic
substitution (SEAr) mechanism is most often invoked for
electron-rich substrates,13 and either σ-bond metathesis14 or
proton-abstraction pathways15 are attributed to the more
recently reported electron-poor substrates. The rate differ-
ences we observed with variation of the substituents in the
substrates used in Table 2 seem to rule out a SEAr mechanism
in the present system, as the electron-rich substrates displayed
consistently slower rates. We also compared the reactivity
of unfunctionalized triflate 1 and its pentadeuterated coun-
terpart and measured an intermolecular kinetic isotope effect
kH/kD ) 5.0 (80 °C).10 Although we have not performed a
detailed mechanistic study, these results are consistent with
either σ-bond metathesis or proton-abstraction mechanisms.
One of the drivers for this study was that an efficient route
to synthetically useful alkene-containing products would be
achieved. The reactions shown in Scheme 1 serve to demon-
strate the potential utility of the products; both dihydroxy-
lation and hydrogenation of alkene 3 proceeded efficiently
and with high levels of diastereocontrol to deliver diol 4 and
Acknowledgment. This work was supported by the
EPSRC and GlaxoSmithKline. The EPSRC Mass Spectrom-
etry Service at the University of Wales Swansea is also
thanked.
Noted Added after ASAP Publication. There were errors
in the structures in the Abstract graphic and entries 5 and 6
of Table 2 in the version published ASAP September 13,
2007; the revised version was published ASAP September
18, 2007.
Supporting Information Available: Experimental pro-
cedures and full characterization for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL702044Z
(13) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan,
V. Org. Lett. 2004, 6, 1159.
(14) Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
12084.
(15) (a) Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren,
A. M. J. Am. Chem. Soc. 2006, 128, 1066. (b) Garcia-Cuadrado, D.; de
Mendoza, P.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem.
Soc. 2007, 129, 6880. See also ref 7c.
(12) Echavarren, A. M.; Go´mez-Lor, B.; Gonza´lez, J. J.; de Frutos, OÄ .
Synlett 2003, 58. See also ref 4a.
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