Tandem thia-Fries rearrangement-cyclisation of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate benzyne precursors

Article abstract of DOI:10.1039/c3cc44529a

A novel transformation of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate aryne precursors is described. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc44529a

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Tandem thia-Fries rearrangement – cyclisation of
2-(trimethylsilyl)phenyl trifluoromethanesulfonate
benzyne precursors†‡
Cite this: Chem. Commun., 2013,
49, 7602
Received 17th June 2013,
Accepted 9th July 2013
Catherine Hall, Jaclyn L. Henderson, Guillaume Ernouf and Michael F. Greaney*
DOI: 10.1039/c3cc44529a
www.rsc.org/chemcomm
A novel transformation of 2-(trimethylsilyl)phenyl trifluoromethane-
sulfonate aryne precursors is described.
The introduction of 2-(trimethylsilyl)phenyl trifluoromethane-
sulfonate as a precursor to ortho-benzyne has fueled a renaissance
in aryne chemistry.1 Discovered in 1983 by Kobayashi,2 the
precursor generates benzyne under the notably mild conditions
of simple fluoride treatment at room temperature. The initial
conditions of CsF in MeCN have been expanded to include a
variety of fluoride sources and solvent combinations, confer-
ring a degree of control on the rate of benzyne generation and
thus opening up new areas of chemistry that were previously
inaccessible using classical aryne precursors.
Fig. 1 X-ray structure of 2a. Thermal ellipsoids at 50% probability.
In the course of developing new transformations of ortho- yield along with a small amount of the triflone 3a (Table 1,
benzyne,3 we observed that fluoride treatment of bromo-substituted entry 1). Isolation of 3a is significant as it suggests that it, or a
precursor 1a led to the unexpected formation of phenoxathiin-dioxide related species, may be a precursor to the final phenoxathiin-
2a in 51% yield (Scheme 1). The heterocycle was isolated as a single dioxide product 2a. The methyl group in 1a was not a require-
regio-isomer and characterised by single crystal X-ray diffraction4 ment for reaction (entry 2), with the bromo-compound 1b
(Fig. 1). This intriguing reaction is without precedent in aryne providing 2b in 21% yield at room temperature along with
chemistry, prompting us to conduct further investigations to try small amounts of uncyclised triflone. The yield of the process
and understand the mechanistic pathway leading to 2a. In addition, could be improved by raising the temperature to 60 1C
phenoxathiin-dioxides are a scarcely studied class of heterocycle, and (47% yield, entry 3), or by adding toluene to the solvent system,
novel methods for their synthesis could prove useful.5
with a 3 : 1 MeCN : toluene mix providing 2b in 60% yield at
We began our study by repeating the reaction at room room temperature (entry 4). Addition of a less polar solvent
temperature, observing the formation of 2a in slightly lower would be expected to slow the rate of reaction of CsF with the
silane starting material 1a. Adding an additional bromine atom
to the substrate reduced the reaction efficiency (entry 5), but the
chloro derivative 1c proved successful in the reaction, providing
2d in 60% yield (entry 6).
Moving away from halogens at the ortho-position to the
trifluoromethanesulfonate, however, immediately shut down
the reaction. Phenyl, methoxy, methyl and simple hydrogen-
substitution all gave intractable mixtures from which no
phenoxathiin dioxide could be isolated (entry 7). The ortho-
nitro substrate 1i, however, reacted to give the rearranged
phenol 4a in 68% yield (entry 8).
Collectively, these results point to a mechanism involving
an anionic thia-Fries rearrangement. Fluoride treatment of 1
results in C–Si bond cleavage as the first step in the mechanism,
Scheme 1 Phenoxathiin-dioxide synthesis.
School of Chemistry, University of Manchester, Oxford Rd, Manchester M13 9PL,
UK. E-mail: michael.greaney@manchester.ac.uk
† Celebrating 300 years of Chemistry at Edinburgh.
‡ Electronic supplementary information (ESI) available: Data for new compounds
and experimental procedures. CCDC 945230. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c3cc44529a
c
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Table 1 Phenoxathiin-dioxide synthesis
Entry Substrate
Conditions
Productsa
MeCN, CsF, rt,
4 h
1
MeCN, CsF, rt,
4 h
2
3
4
1b
1b
MeCN, CsF,
60 1C, 4 h
MeCN : toluene
(3 : 1), CsF, rt,
24 h
2b (47%)
2b (60%)
Scheme 2 Proposed mechanism for phenoxathiin-dioxide formation.
aryltricarbonylchromium complexes as substrates.8,9 Our sub-
strate scope in Table 1 is in line with literature reports on
the thia-Fries rearrangement of trifluoromethanesulfonates.
Electron withdrawing groups ortho to the trifluoromethane-
sulfonate, halogens in particular, activate this pathway and
subsequent phenoxathiin-dioxide formation. Moving away from
this substitution pattern results in the reaction shutting down,
in line with literature precedent. The nitro-containing substrate
1i clearly demonstrates the thia-Fries pathway in operation,
providing the rearranged phenol 4a as the only product.9a
It appears that the strongly electron withdrawing nitro group
deactivates 1i to benzyne formation, providing no aryne 7 for
further reaction to the heterocyclic products 2. Indeed, we were
unable to find any reports of 6-nitro-2-(trimethylsilyl)phenyl
trifluoromethanesulfonates being successfully used as aryne
precursors in the literature. Halo-substituted compounds, how-
ever, can generate arynes and undergo further reaction to give
the adduct 8. Protonation of this anion affords the triflones 3
isolated as side-products. In contrast to Lloyd-Jones’ reaction
system in the cryogenic regime, where thia-Fries rearrangement
was orthogonal to aryne generation depending on reaction
MeCN, CsF,
rt, 6 h
5
6
MeCN : toluene
(3 : 1), CsF, rt,
24 h
MeCN, CsF,
rt, 24 h
7
Complex mixtures
MeCN, CsF,
rt, 24 h
8
a
Isolated yields.
followed by thia-Fries reaction of the resulting anion.6 conditions, here we require the substrate 1 to bifurcate between
The phenolate 6 can then react with an aryne molecule 7, both thia-Fries and aryne generation in the same reaction. The
formed from 5 via trifluoromethanesulfonate elimination in final cyclisation of anion 8 involves displacement of CF3 anion
the established aryne generation pathway. Cyclisation of the from the triflone, a process precedented for Grignard addition
resultant phenyl anion 8 onto the trifluoromethanesulfonate in sulfone synthesis.9b,10
group gives the heterocyclic phenoxathiin-dioxide products
(Scheme 2).
Further experiments were carried out to test this mecha-
nistic conjecture. We prepared the halo-phenol 4b separately
The anionic thia-Fries rearrangement was first reported by and reacted it with benzyne under the reaction conditions.
Lloyd-Jones and co-workers (also working in the context of Successful cyclisation to the phenoxathiin-dioxide product
aryne generation).7 Treatment of 2-(chloro)phenyl trifluoro- 2f was observed, (along with formation of 3c), establishing
methanesulfonate 9 with LDA at À78 1C led to either thia- phenol-aryne addition as a viable step in the mechanism
Fries rearrangement (to compound 4b) or aryne generation, (Scheme 3). Re-subjection of triflones such as 3c to the reaction
a dichotomy that could be controlled by the amount of conditions did not result in cyclisation to the heterocyclic
DIPA present in the reaction. Subsequent elucidation of the products 2. This indicates that the neutral molecule is insuffi-
reaction mechanism revealed the degree of metalation to be the ciently nucleophilic to undergo intramolecular attack at the
critical factor in partitioning the reaction between thia-Fries triflone group, and reaction through the anionic intermediate 8
and aryne generation.6 The reaction has also been demonstrated is necessary to displace CF3 at the sulfur centre. The formation of
to occur for 2-(trimethylsilyl)phenyl trifluoromethanesulfonates, small amounts of 3 in the reaction is likely due to competitive
¨
with Butenschon and co-workers reporting examples using protonation from the MeCN solvent, a common side-product
c
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and we thank the EPSRC mass spectrometry service at the
University of Swansea.
Notes and references
1 (a) P. M. Tadross and B. M. Stoltz, Chem. Rev., 2012, 112, 3550–3577;
(b) C. M. Gampe and E. M. Carreira, Angew. Chem., Int. Ed., 2012, 51,
3766–3778; (c) A. Bhunia, S. R. Yetra and A. T. Biju, Chem. Soc. Rev.,
2012, 41, 3140–3152; (d) A. V. Dubrovskiy, N. A. Markina and
R. C. Larock, Org. Biomol. Chem., 2013, 11, 191–218.
2 Y. Himeshima, T. Sonoda and H. Kobayashi, Chem. Lett., 1983,
1211–1214.
3 (a) T. Pirali, F. Z. Zhang, A. H. Miller, J. L. Head, D. McAusland and
M. F. Greaney, Angew. Chem., Int. Ed., 2012, 51, 1006–1009;
(b) D. McAusland, S. Seo, D. G. Pintori, J. Finlayson and M. F.
Greaney, Org. Lett., 2011, 13, 3667–3669; (c) K. Biswas and M. F.
Greaney, Org. Lett., 2011, 13, 4946–4949; (d) A. A. Cant, L. Roberts
and M. F. Greaney, Chem. Commun., 2010, 46, 8671–8673;
(e) A. A. Cant, G. H. V. Bertrand, J. L. Henderson, L. Roberts and
M. F. Greaney, Angew. Chem., Int. Ed., 2009, 48, 5199–5202.
4 CCDC 945230 contains the crystallographic data for 2a. ORTEP-3
was used to produce the thermal ellipsoid plots: L. J. Farrugia,
J. Appl. Crystallogr., 1997, 30, 565.
5 For the development of phenoxathiin-dioxides as monoamine
oxidase inhibitors, see: M. Harfenist, D. P. C. Mcgee and H. L.
White, J. Med. Chem., 1991, 34, 2931–2933.
Scheme 3 Mechanistic studies.
6 Intramolecular OAr - CAr sulfone transfer has been established in
the anionic thia-Fries rearrangement by Lloyd-Jones and co-workers,
using a crossover experiment with labelled substrates: A. M. Dyke,
D. M. Gill, J. N. Harvey, A. J. Hester, G. C. Lloyd-Jones, M. P.
Munoz and I. R. Shepperson, Angew. Chem., Int. Ed., 2008, 47,
5067–5070.
in aryne couplings involving silyl-trifluoromethanesulfonate
precursors 1.3e
Finally, we conducted cross-over experiments with two different
aryne precursors in the same pot, 1b and 1d. A statistical
mixture of hetero- and homo-coupled phenoxathiin-dioxides
were observed on GC-MS analysis, supporting the dual reaction
mode of the trifluoromethanesulfonate starting materials with
respect to thia-Fries rearrangement and free benzyne formation
in the same pot.
7 J. P. H. Charmant, A. M. Dyke and G. C. Lloyd-Jones, Chem. Commun.,
2003, 380–381.
¨
¨
8 (a) Z. Zhao, J. Messinger, U. Schon, W. Rudolf and H. Butenschon,
Chem. Commun., 2006, 3007–3009; (b) G. Werner, C. W. Lehmann
¨
and H. Butenschon, Adv. Synth. Catal., 2010, 352, 1345–1355;
¨
(c) G. Werner and H. Butenschon, Eur. J. Org. Chem., 2012,
3132–3141.
In conclusion, we have discovered a new reaction of 2-(tri-
methylsilyl)aryl trifluoromethanesulfonate benzyne precursors,
where they bifurcate between thia-Fries rearrangement and
aryne generation on simple fluoride treatment. Subsequent
union and cyclisation affords novel phenoxathiin-dioxides. This
pathway will be relevant to the design of new aryne reaction
systems in general, where it may manifest when halogen or
nitro-containing aryne precursors are used to explore substrate
scope.11 Finally, the reaction affords phenoxathiin-dioxides by a
new route that does not require the preparation of a phenoxathiin
and subsequent oxidation.
9 Other examples of the anionic thia-Fries rearrangement: (a) I. R.
Hardcastle, PhD thesis, University of Manchester, 1990; (b) R. Kargbo,
Y. Takahashi, S. Bhor, G. R. Cook, G. C. Lloyd-Jones and I. R. Shepperson,
J. Am. Chem. Soc., 2007, 129, 3846–3847; (c) X. H. Xu, X. Wang, G. K. Liu,
E. Tokunaga and N. Shibata, Org. Lett., 2012, 14, 2544–2547;
(d) E. Yoshioka and H. Miyabe, Tetrahedron, 2012, 68, 179–189;
(e) X. H. Xu, M. Taniguchi, A. Azuma, G. K. Liu, E. Tokunaga and
N. Shibata, Org. Lett., 2013, 15, 686–689.
10 R. W. Steensma, S. Galabi, J. R. Tagat and S. W. McCombie,
Tetrahedron Lett., 2001, 42, 2281–2283.
11 For examples of 6-halo-2-trimethylsilyl(phenyl) trifluoromethane-
sulfonates used with fluoride to generate arynes, see: (a) J. D. Kirkham,
P. M. Delaney, G. J. Ellames, E. C. Row and J. P. A. Harrity, Chem.
Commun., 2010, 46, 5154–5156; (b) B. Lakshmi, U. K. Wefelscheid
and U. Kazmaier, Synlett, 2011, 345–348; (c) D. Rodriguez, A. Cobas,
We thank the University of Manchester and the EPSRC for
funding (Leadership fellowship to M.F.G.). Dr Anna Collins
(University of Edinburgh) is thanked for X-ray crystallography
˜
D. Pena, D. Perez and E. Guitian, Org. Lett., 2012, 14, 1363–1365;
(d) Y. Zeng, L. Zhang, Y. Zhao, C. Ni, J. Zhao and J. Hu, J. Am. Chem.
Soc., 2013, 135, 2955–2958.
c
7604 Chem. Commun., 2013, 49, 7602--7604
This journal is The Royal Society of Chemistry 2013