Fast Synthesis of Aryl Triflates with Controlled Microwave Heating

Article abstract of DOI:10.1021/ol025701a

matrix presented Synthesis of aryl triflates from phenols using N-phenyltriflimide requires only 6 min for completion when conducted with controlled microwave heating. The methodology was applied to both solution- and solid-phase conditions. Ten different

Full text of DOI:10.1021/ol025701a

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1231-1233
Fast Synthesis of Aryl Triflates with
Controlled Microwave Heating
Anna Bengtson, Anders Hallberg, and Mats Larhed*
Department of Organic Pharmaceutical Chemistry, Uppsala UniVersity, BMC,
Box-574, SE-751 23 Uppsala, Sweden
mats@orgfarm.uu.se
Received February 11, 2002
ABSTRACT
Synthesis of aryl triflates from phenols using N-phenyltriflimide requires only 6 min for completion when conducted with controlled microwave
heating. The methodology was applied to both solution- and solid-phase conditions. Ten different aryl triflates were synthesized and isolated
in good yields. Applications in high-throughput chemistry are suggested.
In high-throughput chemistry there is a need to decrease the
reaction times as well as effectuate the purification proce-
dures. Conceptual and technological solutions to these issues
have been the subjects of intensive research. Automated and
focused microwave flash heating was recently proven to
improve the preparative efficiency and to dramatically reduce
reaction times for several different types of organic trans-
formations.1
conditions for the reduction of the reaction time in order to
make the triflation more adoptable to high-throughput
chemistry. A general method was desired, although primarily
we were interested in making triflates from salicylic alde-
hydes for further use as precursors for annulation reactions.
Herein we describe the first protocol for fast microwave-
promoted triflatation of phenols (Scheme 1).
Aryl triflates are useful starting materials in many types
of palladium- and nickel-catalyzed coupling reactions.2 The
most common procedure for the preparation of aryl triflates
is to react triflic anhydride with a phenol in the presence of
a base.3 Triflic anhydride is, however, a low temperature,
nonselective reagent, and consequently its use in high-
throughput synthesis of functionalized aryl triflates is limited.
An alternative route to aryl triflates is to use N-phenyltri-
flimide, a stable and crystalline triflating agent that often
results in improved selectivity.4
Scheme 1a
a Reagents and conditions: (a) Tf2NPh (1.0 equiv), K2CO3 (3.0
equiv), THF, 120 °C (microwave heating), 6 min.
In most cases, reaction times between 3 and 8 h are needed
when employing N-phenyltriflimide.5 We aimed at finding
Nine different phenols (1a-i) were selected as starting
materials. The selection was made to include both electron-
donating and electron-withdrawing substituents. K2CO3 was
chosen due to its ability to act as a drying agent as well as
a base.
(1) Recent reviews: (a) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman,
J. Tetrahedron 2001, 57, 9225-9283. (b) Larhed, M.; Hallberg, A. Drug
DiscoVery Today 2001, 6, 406-416. (c) Lew, A.; Krutzik, P. O.; Hart, M.
E.; Chamberlin, A. R. J. Comb. Chem. 2002, 4, 95-105.
(2) Ritter, K. Synthesis 1993, 735-762.
(3) Baraznenok, I. L.; Nenajdenko, V. G.; Balenkova, E. S. Tetrahedron
2000, 56, 3077-3119.
(4) Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 46, 4607-
4610.
(5) (a) Crisp, G. T.; Turner, P. D. Tetrahedron 2000, 56, 407-415. (b)
Wentworth, A. D.; Wentworth, P., Jr.; Mansoor, U. F.; Janda, K. D. Org.
Lett. 2000, 2, 477-480.
10.1021/ol025701a CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/15/2002

Aryl triflates have proven to be surprisingly stable at high
temperatures.6 Thus, the heating was not foreseen to cause
any serious decomposition problems. Despite that, we
decided not to conduct the reaction above 120 °C, to make
it compatible with more thermosensitive functional groups.
The results from the study are outlined in Table 1. Using
controlled microwave heating we succeeded in reducing the
reaction time to 6 min.7 The reactions were found not to be
sensitive to air or moisture; hence there was no need for an
inert atmosphere. All the phenols were smoothly converted
to triflates in isolated yields between 69 and 91%.
to any extent. The highly electron-poor 5-nitrosalicylic
aldehyde and the sterically hindered 3-formyl-5-methylsali-
cylic aldehyde (not reported) could also be triflated with this
method, as deduced from GC-MS and crude NMR, but the
formed products were very insoluble and for this reason
difficult to fully purify. It is notable that, employing only 1
equiv of the triflimide, all reactions delivered full conversion
of the starting phenol. This nonexcess stoichiometry results
in less demanding purification and good atom economy.
4-Hydroxybenzoic acid (1j), coupled to a 2-chlorotrityl
linker, was chosen for solid-phase triflate synthesis (Scheme
2). Liquid Et3N was used as base instead of K2CO3, and
There was no clear correlation between the reaction
outcome and the electron density of the substituents, and a
formyl group in the ortho-position did not reduce the yield
Scheme 2. Fast Solid-Phase Synthesisa
Table 1. Synthesis of Aryl Triflates
a Reagents and conditions: (a) Tf2NPh (1.0 equiv), Et3N (3.0
equiv), THF, 120 °C (microwave heating), 6 min; (b) 1% TFA/
CH2Cl2, rt, 1 h.
2-chlorotrityl polystyrene resin was utilized due to the mild
cleaving conditions required.8
Rewardingly, the fast methodology was easily transferred
to the solid-phase conditions and compound 2j was isolated
in 80% yield after cleavage (Table 1, entry 10). No hydrolysis
of the liberated triflate was detected.
a >95% pure according to GC-MS. Compounds 2a-h were purified with
flash chromatography. Compound 2i was purified through washing with
hot THF. b Synthesized on solid support.
Figure 1. Temperature and pressure profiles for a representative
triflation reaction (entry 2).
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Org. Lett., Vol. 4, No. 7, 2002

THF is not an ideal solvent for rapid microwave heating
in sealed reaction vessels. This has been attributed to the
relatively low boiling point and a low tan δ of the solvent.9
Despite that, the reaction mixture could be heated to 120 °C
in less than 1 min and the pressure did not exceed 5 bar in
any of the reactions (Figure 1).
In summary, we have developed a convenient microwave-
assisted, high-speed method for synthesis of aryl triflates.
One successful example of solid-phase synthesis is given,
which indicates that the method easily can be adopted for
use on solid support.
Acknowledgment. The authors acknowledge the financial
support from the Swedish Research Council and from the
Knut and Alice Wallenberg Foundation. We also thank
PersonalChemistry AB for providing us with the Smith-
Synthesizer.
Supporting Information Available: Complete Experi-
mental Section with full analytical characterization of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(6) Subramanian, L. R.; Hanack, M.; Chang, L. W. K.; Imhoff, M. A.;
Schleyer, P. v. R.; Effenberger, F.; Kurtz, W.; Stang, P. J.; Dueber, T. E.
J. Org. Chem. 1976, 41, 4099-4103.
(7) General experimental procedure: The phenol (2.0 mmol), N-phenyl-
bis(trifluoromethane-sulfonimide) (2.0 mmol, 710 mg), K2CO3 (6.0 mmol,
830 mg), and 3.0 mL of THF were mixed in a septum-capped tube. The
reaction mixture was heated to 120 °C for 6 min in a SmithSynthesizer.
(8) Barlos, K.; Chatzi, O.; Gatos, D.; Stavropoulos, G. Int. J. Peptide
Protein Res. 1991, 37, 513-520.
OL025701A
(9) Tan δ ) 0.047 at room temperature; Gabriel, C.; Gabriel, S.; Grant,
E. H.; Halstead, B. S. J.; Mingos, D. M. P. Chem. Soc. ReV. 1998, 27,
213-224.
Org. Lett., Vol. 4, No. 7, 2002
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