Development of a Friedel-Crafts triflation

Article abstract of DOI:10.1021/ol061980g

The development of a new variant of the Friedel-Crafts reaction that yields 3-aryl enol triflates is described. The reaction is practical, is atom-economical, and works well with electron-rich arene substrates.

Full text of DOI:10.1021/ol061980g

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5429-5432
Development of a Friedel
Triflation
−Crafts
Marc A. Grundl, Anne Kaster, Ellen D. Beaulieu, and Dirk Trauner*
Department of Chemistry, UniVersity of California, Berkeley,
Berkeley, California 94720-1460
trauner@berkeley.edu
Received August 9, 2006
ABSTRACT
The development of a new variant of the Friedel−Crafts reaction that yields 3-aryl enol triflates is described. The reaction is practical, is
atom-economical, and works well with electron-rich arene substrates.
The conjugate addition of an organocuprate to an enone
followed by trapping of the resulting enolate as an enol
triflate is a powerful strategy for the regioselective installation
of double bonds (Scheme 1a).1 Although it has been widely
the other hand, which are compatible, do not lend themselves
well to triflation. In addition, the formation of the organo-
metallic species or radical usually requires prior function-
alization as a halide, which is undesirable from an atom-
economical point of view.
A solution to this problem could consist of the activation
of an enone with the highly electrophilic reagent triflic
anhydride, followed by reaction of the resultant allylic cation
with a suitable nucleophile (Scheme 1b).2 The use of triflic
anhydride for the electrophilic activation of simple carbonyl
compounds is indeed well documented.3 Somewhat surpris-
ingly, however, the ability of this reagent to activate enones
toward reaction with carbon nucleophiles remains largely
unexplored. If the attacking nucleophile was an arene, the
overall reaction would amount to a Friedel-Crafts alkylation
with concomitant formation of an enol triflate.
Scheme 1. Regioselective Formation of Enol Triflates
Our interest in this reaction initially came from a need in
total synthesis (Scheme 2). During our synthetic study toward
the haouamines, we found that treatment of enone 1 with
triflic anhydride and a sterically hindered base gave com-
(1) Perlmutter, P. In Conjugate Addition Reactions in Organic Synthesis;
Baldwin, J. E., Magnus, P. D., Eds.; Tetrahedron Organic Chemistry Series;
Pergamon Press: Oxford, 1992; Vol. 9.
(2) For activation of enones with other anhydrides, see: (a) Cooper, J.
L.; Harding, K. E. Tetrahedron Lett. 1977, 18, 3321. (b) Harding, K. E.;
Cooper, J. L.; Puckett, P. M.; Ryan, J. D. J. Org. Chem. 1978, 43, 4363.
(c) Amupitan, J.; Sutherland, J. K. J. Chem. Soc., Chem. Commun. 1980,
398.
(3) (a) Baraznanok, I. L.; Nenajdenko, V. G.; Balenkova, E. S. Synthesis
1997, 465. (b) Baraznanok, I. L.; Nenajdenko, V. G.; Balenkova, E. S.
Tetrahedron 2000, 56, 3077. (c) Liang, G.; Xu, Y.; Seiple, I. B.; Trauner,
D. J. Am. Chem. Soc. 2006, 128, 11022.
used in synthesis, this sequence is largely limited to
intermolecular cases. In the intramolecular sense, the genera-
tion of the organometallic species is normally incompatible
with the presence of an enone; in other words, Barbier
conditions cannot be easily applied. Radical additions, on
10.1021/ol061980g CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/28/2006

Scheme 2. Discovery of the Reaction
Table 1. Optimization Conditions
entry
solvent
base
6a
6b
7
1
2
3
4
5
6
7
8
DCM
PhH
Et2O
MeCN
MeNO2
MeNO2
MeNO2
MeNO2
2,6-DTBP
2,6-DTBP
2,6-DTBP
2,6-DTBP
2,6-DTBP
i-Pr2NEt
Et3N
54%
42%
59%
-
-
-
31%
30%
28%
-
-
-
-
-
64%
70%
44%
47%
45%
-
-
-
-
pound 2, representing the indeno-tetrahydropyridine core of
the natural products.4
-
Concerned that this reaction represented a specialized case
due to the very electron-rich nature of the enone moiety and
the arene, which would benefit electrophilic activation and
nucleophilic attack, respectively, we decided to map its scope
and limitations. We now report the further development of
the reaction, which proved useful for the synthesis of
polycyclic ring systems with regio-defined double bonds but
appears to be limited to relatively electron-rich arenes. We
call this reaction “Friedel-Crafts triflation” because it can
be viewed as a new variant of this venerable electrophilic
aromatic substitution.
intramolecular nucleophilic attack of the arene. Resubjection
of 6a,b to triflic acid led to clean cyclization to afford 7.
This means that trifloxy dienes can undergo protonation by
triflic acid (pKa ) -14) to afford allylic cations of type 4.
With highly polar solvents (MeCN or MeNO2), substrate
3 underwent fast cyclization to afford only the desired
cyclization product 7. Polar solvents presumably stabilize
the allylic cation, allowing it to undergo ring closure rather
than loss of a proton. Systematic variation of the base showed
that the reaction worked best with sterically demanding, non-
nucleophilic bases such as 2,6-di-tert-butyl pyridine (2,6-
DTBP). Accordingly, the combination of nitromethane or
acetonitrile as a solvent and 2,6-DTBP as a base was
subsequently used as our standard set of conditions.
Having optimized the reaction, we proceeded to explore
the substrate scope and limitations of related intramolecular
reactions (Scheme 4). To this end, substrates 8a-h were
prepared using Stork-Danheiser chemistry (see Supporting
Information).
To identify optimal conditions for the reaction and gain
insight into its mechanism, we chose dimethoxybenzyl
cyclohexenone 3 as a standard substrate (Scheme 3). This
Scheme 3. Optimization of the Friedel-Crafts Triflation
Scheme 4. Intramolecular Cyclizations
compound was prepared in a short sequence via Stork-
Danheiser alkylation (see Supporting Information).5
Treatment of 3 with triflic anhydride in different solvents
and in the presence of a variety of bases gave the desired
product 7 in variable yields. In less polar solvents, we only
isolated trifloxy dienes 6a,b (Table 1, entries 1-3). These
compounds presumably stem from deprotonation of the
cationic intermediate 4 competing with an interceding
(4) Grundl, M. A.; Trauner, D. Org. Lett. 2006, 8, 23.
(5) Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775.
5430
Org. Lett., Vol. 8, No. 24, 2006

Generally, we observed that the Friedel-Crafts triflation
proceeded well with highly nucleophilic arenes. Dimethoxy-
benzenes 8a,b reacted rapidly to afford the cis-fused products
9a,b. Within the cyclohexenone series, yields increased with
the electron-donating nature of the enone substituent. This
trend presumably reflects the stability of intermediary allylic
cations of type 4.
In addition to intramolecular reactions, we explored
intermolecular cases (Scheme 6). These were found to work
Scheme 6. Intermolecular Reactions
Other ring systems were investigated as well. Substrate
8c gave indole 9c as a single diastereomer, whose relative
stereochemistry could not be determined by NMR spectros-
copy. Dimethoxybenzyl cyclopentenone 8d afforded benzobi-
cyclo[3.3.0]octadiene 9d. Vinyl cyclohexenone 8e cleanly
underwent 7-endo trig instead of 5-endo trig attack to afford
the diene triflate 9e. Related [6-7-6] ring systems are
relatively rare but are found in several natural products.6
Electronically less-activated substrates failed to undergo
direct cyclization under our standard conditions (Scheme 5).
Scheme 5. Two-Step Procedures
in slightly better yields with acetonitrile as a solvent. Anisole
reacted with cyclohexenone to afford a mixture of regio-
isomeric enol triflates 15a,b in synthetically useful yields.
Resorcinol dimethyl ether cleanly gave enol triflate 16.
Methyl indole gave the corresponding 3-substituted enol
triflate 17. Sylvan reacted with cyclohexenone and 3-methyl
cyclohexenone to give enol triflates 18 and 19, respectively.
The formation of a quaternary center in the latter reaction is
remarkable, despite its low yield. It should be noted though
that sterically congested quaternary carbons were routinely
formed in the intramolecular reactions (Scheme 4).
In summary, we have described a new variant of the
Friedel-Crafts reaction that generates enol triflates through
triflic anhydride promoted conjugate addition of an arene to
an enone. The reaction appears to work well if three
conditions are met: (a) a substituted enone that yields a
stabilized allylic cation after activation with triflic anhydride
is present; (b) a polar solvent that further increases the
lifetime of this cation is used; and (c) the arene is nucleophilic
enough to compete with deprotonation.
The Friedel-Crafts triflation is operationally simple and
atom-economical because triflic acid is the only byproduct.
It provides a useful alternative to cuprate conjugate additions
followed by interception of the resulting metal enolate with
phenyl triflimide or Commins’ reagent. The method does
not require prior functionalization of the arene and could be
especially advantageous in cases where the organometallic
Benzyl cyclohexenone 8f7 afforded trifloxy dienes 10a and
10b. Resubjection of this mixture to triflic acid did not afford
a cyclized product but resulted in almost full conversion of
the mixture to 10b. By contrast, m-methoxybenzyl cyclo-
hexenone 8g and iodomethoxybenzyl cyclohexenone 8h
initially gave a mixture of dienes, which could be cyclized
to afford tricyclic enol triflates 12a,b and 14, respectively.
(6) For synthetic approaches toward the [6-7-6] ring system, see: (a)
Majetich, G.; Zhang, Y. J. Am. Chem. Soc. 1994, 116, 4979. (b) Majetich,
G.; Hicks, R.; Zhang, Y.; Tian, X.; Feltman, T. L.; Fang, J.; Duncan, S. J.
Org. Chem. 1996, 61, 8169. (c) Simmons, E. M.; Sarpong, R. Org. Lett.
2006, 8, 2883.
(7) Kim, S.; Jon, S. Y. Bull. Korean Chem. Soc. 1995, 16, 472.
Org. Lett., Vol. 8, No. 24, 2006
5431

species cannot be generated easily in the presence of the
enone, as is generally the case in intramolecular reactions.
The extension of the method toward other unsaturated
carbonyl compounds, nucleophiles, and electrophilic activa-
tors is currently under investigation.
postdoctoral fellowship. A.K. thanks the Deutsche Studien-
stiftung for a fellowship. E.D.B. thanks the National Science
Foundation for a Graduate Research Fellowship.
Supporting Information Available: Spectroscopic and
analytical data for compounds 3, 7-9, 10b, 12a,b, 14-19,
and 22a-f. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. Financial support by Novartis and the
Alfred P. Sloan Foundation is gratefully acknowledged.
M.A.G. thanks the Deutsche Forschungsgemeinschaft for a
OL061980G
5432
Org. Lett., Vol. 8, No. 24, 2006