Remote anionic fries rearrangement of sulfonates: Regioselective synthesis of indole triflones

Article abstract of DOI:10.1021/ol3035559

An unusual NaH-mediated remote anionic 1,5-thia-Fries rearrangement reaction was developed. This method provides an efficient approach for the regioselective synthesis of not only 2-(2-hydroxyphenyl)-3-indole triflones but also related 3-sulfonylindoles.

Full text of DOI:10.1021/ol3035559

ORGANIC
LETTERS
2013
Vol. 15, No. 3
686–689
Remote Anionic Fries Rearrangement
of Sulfonates: Regioselective Synthesis
of Indole Triflones
Xiu-Hua Xu, Misaki Taniguchi, Ayaka Azuma, Guo Kai Liu,
Etsuko Tokunaga, and Norio Shibata*
Department of Frontier Materials, Graduate School of Engineering,
Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya, 466-8555, Japan
nozshiba@nitech.ac.jp
Received December 28, 2012
ABSTRACT
An unusual NaH-mediated remote anionic 1,5-thia-Fries rearrangement reaction was developed. This method provides an efficient approach for
the regioselective synthesis of not only 2-(2-hydroxyphenyl)-3-indole triflones but also related 3-sulfonylindoles.
Over a time period of about 30 years, the anionic Fries
rearrangement has been developed as a common synthetic
concept in aromatic chemistry.1,2 This rearrangement
offers a mild and regioselective complement to a nonselec-
tive acid-catalyzed Fries rearrangement3 and photo-Fries
rearrangement.4 Since the primary work of Lloyd-Jones,5a
the anionic thia-Fries rearrangement, mainly involving a
1,3-sulfonyl migration reaction of aryl trifluoromethane-
sulfonate (triflate), has received much attention (Scheme 1a).5
This rearrangement affords aryl triflones which are an
important class of compounds used as structural units in
bioactive molecules,6 chiral catalysts,5c,d,7 and functional
(5) (a) Charmant, J. P.; Dyke, A. M.; Lloyd-Jones, G. C. Chem.
€
Commun. 2003, 380–381. (b) Zhao, Z.; Messinger, J.; Schon, U.;
€
Wartchow, R.; Butenschon, H. Chem. Commun. 2006, 3007–3009. (c)
Kargbo, R.; Takahashi, Y.; Bhor, S.; Cook, G. R.; Lloyd-Jones, G. C.;
Shepperson, I. R. J. Am. Chem. Soc. 2007, 129, 3846–3847. (d) Barta, K.;
ꢀ
Francio, G.; Leitner, W.; Lloyd-Jones, G. C.; Shepperson, I. R. Adv.
Synth. Catal. 2008, 350, 2013–2023. (e) Dyke, A. M.; Gill, D. M.;
~
Harvey, J. N.; Hester, A. J.; Lloyd-Jones, G. C.; Munoz, M. P.;
(1) (a) For the first example of an aryl ester derived anionic Fries
rearrangement, see: Miller, J. A. J. Org. Chem. 1987, 52, 322–323. (b)
For the first example of an aryl carbamate derived anionic Fries
rearrangement, see: Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48,
1935–1937. (c) For the first example of an aryl phosphate ester derived
anionic Fries rearrangement, see: Melvin, L. S. Tetrahedron Lett. 1981,
22, 3375–3376.
Shepperson, I. R. Angew. Chem., Int. Ed. 2008, 47, 5067–5070. (f) Kruck,
M.; Munoz, M. P.; Bishop, H. L.; Frost, C. G.; Chapman, C. J.; Kociok-
€
Kohn, G.; Butts, C. P.; Lloyd-Jones, G. C. Chem.;Eur. J. 2008, 14,
€
7808–7812. (g) Werner, G.; Lehmann, C. W.; Butenschon, H. Adv.
Synth. Catal. 2010, 352, 1345–1355. (h) Yoshioka, E.; Kohtani, S.;
€
Miyabe, H. Org. Lett. 2010, 12, 1956–1959. (i) Werner, G.; Butenschon,
H. Eur. J. Org. Chem. 2012, 3132–3141.
€
€
(2) For recent examples, see: (a) Neufeind, S.; Hulsken, N.; Neudorfl,
€
(6) For selected examples, see: (a) Park, C.-M.; Bruncko, M.;
Adickes, J.; Bauch, J.; Ding, H.; Kunzer, A.; Marsh, K. C.; Nimmer,
P.; Shoemaker, A. R.; Song, X.; Tahir, S. K.; Tse, C.; Wang, X.; Wendt,
M. D.; Yang, X.; Zhang, H.; Fesik, S. W.; Rosenberg, S. H.; Elmore,
S. W. J. Med. Chem. 2008, 51, 6902–6915. (b) Brown, B. S.; Keddy, R.;
Zheng, G. Z.; Schmidt, R. G.; Koenig, J. R.; McDonald, H. A.; Bianchi,
B. R.; Honore, P.; Jarvis, M. F.; Surowy, C. S.; Polakowski, J. S.; Marsh,
K. C.; Faltynek, C. R.; Lee, C.-H. Bioorg. Med. Chem. 2008, 16, 8516–
8525. (c) Sleebs, B. E.; Czabotar, P. E.; Fairbrother, W. J.; Fairlie, W. D.;
Flygare, J. A.; Huang, D. C. S.; Kersten, W. J. A.; Koehler, M. F. T.;
Lessene, G.; Lowes, K.; Parisot, J. P.; Smith, B. J.; Smith, M. L.; Souers,
A. J.; Street, I. P.; Yang, H.; Baell, J. B. J. Med. Chem. 2011, 54, 1914–
1926.
J.-M.; Schlorer, N.; Schmalz, H.-G. Chem.;Eur. J. 2011, 17, 2633–
2641. (b) Wessels, M.; Mahajan, V.; Boßhammer, S.; Raabe, G.; Gais,
H.-J. Eur. J. Org. Chem. 2011, 2431–2449. (c) Jeong, Y.-C.; Moloney,
M. G. J. Org. Chem. 2011, 76, 1342–1354. (d) Chang, C.-W.; Chein, R.-J.
J. Org. Chem. 2011, 76, 4154–4157. (e) Lin, Y.-C.; Lin, C.-H.; Chen,
C.-Y.; Sun, S.-S.; Pal, B. Org. Biomol. Chem. 2011, 9, 4507–4517. (f)
Schneider, C.; David, E.; Toutov, A. A.; Snieckus, V. Angew. Chem., Int.
Ed. 2012, 51, 2722–2726.
(3) (a) Fries, K.; Finck, G. Ber. 1908, 41, 4271–4284. (b) Chen, X.;
Tordeux, M.; Desmurs, J.-R.; Wakselman, C. J. Fluorine Chem. 2003,
126, 51–56. (c) For a recent review, see: Sartori, G.; Maggi, R. Chem.
Rev. 2011, 111, PR181–PR214.
(4) (a) Anderson, J. C.; Reese, C. B. Proc. Chem. Soc. 1960, 217. (b)
For a recent review, see: Miranda, M. A.; Galindo, F. Mol. Supramol.
Photochem. 2003, 9, 43–131.
(7) (a) Masui, M.; Ando, A.; Shioiri, T. Tetrahedron Lett. 1988, 29,
2835–2838. (b) Mouhtady, O.; Gaspard-Iloughmane, H.; Laporterie,
A.; Roux, C. L. Tetrahedron Lett. 2006, 47, 4125–4128.
r
10.1021/ol3035559
Published on Web 01/23/2013
2013 American Chemical Society

materials,8 because of the unique properties of the SO2CF3
group.9 We recently expanded the anionic ortho-Fries
rearrangement to the synthesis of several types of hetero-
aryl triflones.10 In these anionic thia-Fries rearrangement
reactions, the carbanions are generated via directed ortho
metalation (DoM).11 It is highly desirable to develop new
variations of anionic thia-Fries rearrangement under mild
conditions. In continuation of our research on heterocyclic
aryl triflones,10,12 we were next interested in 2-hydroxyaryl-
3-indole triflones 2 since 2-hydroxyaryl-3-indole is an
important structural motif frequently encountered in bio-
logically active molecules.13 We herein report the regiose-
lective synthesis of 2 by the first remote anionic thia-Fries
rearrangement of 1 (Scheme 1b).14 It should be noted that
the anionic Fries rearrangement is induced by a carbanion
generated via directed remote metalation (DreM),15 while
our rearrangement does not require powerful alkyllithium
bases since it is induced by a nitranion.
Scheme 1. Anionic Thia-Fries Rearrangement
Table 1. Optimization of Reaction Conditions
2-(1H-Indol-2-yl)phenyl triflate 1a was initially chosen
as a test substrate for remote trifluoromethanesulfonyl
(8) (a) Wolff, J. J.; Gredel, F.; Oeser, T.; Irngartinger, H.; Pritzkow,
H. Chem.;Eur. J. 1999, 5, 29–38. (b) Matsui, M.; Suzuki, M.; Hayashi,
M.; Funabiki, K.; Ishigure, Y.; Doke, Y.; Shiozaki, H. Bull. Chem. Soc.
ꢀ
Jpn. 2003, 76, 607–612. (c) Porres, L.; Mongin, O.; Katan, C.; Charlot,
yield
(%)a
M.; Pons, T.; Mertz, J.; Blanchard-Desce, M. Org. Lett. 2004, 6, 47–50.
(d) Droumaguet, C. L.; Mongin, O.; Werts, M. H. V.; Blanchard-Desce,
M. Chem. Commun. 2005, 2802–2804. (e) Mongin, O.; Porres, L.;
Charlot, M.; Katan, C.; Blanchard-Desce, M. Chem.;Eur. J. 2007,
13, 1481–1498.
(9) (a) Sheppa, W. J. Am. Chem. Soc. 1963, 85, 1314–1318. (b)
Hendrickson, J. B.; Giga, A.; Wareing, J. J. Am. Chem. Soc. 1974, 96,
2275–2276. (c) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91,
165–195. (d) Goumount, R.; Kizilian, E.; Buncel, E.; Terrier, F. Org.
Biomol. Chem. 2003, 1, 1741–1748. (e) Terrier, F.; Magnier, E.; Kizilian,
E.; Wakselman, C.; Buncel, E. J. Am. Chem. Soc. 2005, 127, 5563–5571.
(f) Guesmi, N. E.; Boubaker, T.; Goumont, R.; Terrier, F. Org. Biomol.
Chem. 2008, 6, 4041–4052.
entry
base
LDA
solvent temperature
time
2 h
ꢀ
1
THF
THF
THF
THF
DMF
DMF
DMF
DMF
DMF
THF
DMSO
DMF
À78 °C to rt
À78 °C to rt
À78 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
29
23
75
2
n-BuLi
NaHMDS
DBU
2 h
2 h
3
4
overnight trace
overnight 50
5
K2CO3
t-BuOK
NaOMe
NaH
6
2 h
78
7
overnight 18
8
2 h
2 h
4 h
2 h
2 h
87
58
22
81
80
9
LiH
(10) Xu, X.-H.; Wang, X.; Liu, G.-K.; Tokunaga, E.; Shibata, N.
Org. Lett. 2012, 14, 2544–2547.
10
11
12b
NaH
NaH
(11) For a review, see: Snieckus, V. Chem. Rev. 1990, 90, 879–933.
(12) (a) Xu, X.-H.; Liu, G.-K.; Azuma, A.; Tokunaga, E.; Shibata, N.
Org. Lett. 2011, 13, 4854–4857. (b) Kawai, H.; Sugita, Y.; Tokunaga, E.;
Shibata, N. Eur. J. Org. Chem. 2012, 1295–1298. (c) Kawai, H.; Yuan,
Z.; Tokunaga, E.; Shibata, N. Org. Lett. 2012, 14, 5330–5333.
(13) For selected examples, see: (a) Verner, E.; Katz, B. A.; Spencer,
J. R.; Allen, D.; Hataye, J.; Hruzewicz, W.; Hui, H. C.; Kolesnikov, A.;
Li, Y.; Luong, C.; Martelli, A.; Radika, K.; Rai, R.; She, M.; Shrader,
W.; Sprengeler, P. A.; Trapp, S.; Wang, J.; Young, W. B.; Mackman,
R. L. J. Med. Chem. 2001, 44, 2753–2771. (b) Mackman, R. L.; Katz,
B. A.; Breitenbucher, J. G.; Hui, H. C.; Verner, E.; Luong, C.; Liu, L.;
Sprengeler, P. A. J. Med. Chem. 2001, 44, 3856–3871. (c) Narjes, F.;
Crescenzi, B.; Ferrara, M.; Habermann, J.; Colarusso, S.; Ferreira,
M. R. R.; Stansfield, I.; Mackay, A. C.; Conte, I.; Ercolani, C.;
Zaramella, S.; Palumbi, M.-C.; Meuleman, P.; Leroux-Roels, G.;
Giuliano, C.; Fiore, F.; Marco, S. D.; Baiocco, P.; Koch, U.; Migliaccio,
G.; Altamura, S.; Laufer, R.; Francesco, R. D.; Rowley, M. J. Med.
Chem. 2011, 54, 289–301.
NaH
a Yield was determined by 19F NMR using trifluoromethoxybenzene
as an internal standard. b NaH (1.0 equiv) was added.
(triflyl) rearrangement (Table 1). When 1a was treated with
LDA, the most commonly used base for remote anionic
Fries rearrangement, the reaction was complex and the
desired compound 2a was obtained in 29% yield (Table 1,
entry 1). The low yield was probably caused by the lower
stability and better leaving ability of OSO2CF3 compared to
other directed metalation groups (DMGs). Different bases
were then screened, and NaH was proven to be the best base
giving the desired compound in 87% yield (Table 1, entries
2À9). The solvent had a significant effect on yield. Only a
22% yield was obtained when the reaction was carried out in
THF, while an 81% yield was achieved in DMSO (Table 1,
entries 10 and 11). Decreasing the amount of base from 2.0
to 1.0 equiv caused a slight drop in yield (Table 1, entry 12).
It is noteworthy that only the C(3)-Tf product was detected
from crude 19F NMR, while no N(1)-Tf product was found.
The C(3)/N(1) chemo- or regioselectivity in this intra-
molecular rearrangement reaction is opposite to that in
general sulfonylation reactions of indoles.16
(14) The present method is a nice complement to our recently
developed modified FriedelÀCrafts trifluoromethanesulfonylation
method12a for preparing 3-triflylindoles.
(15) (a) Wang, X.; Snieckus, V. Tetrahedron Lett. 1991, 32, 4879–
4882. (b) Wang, W.; Snieckus, V. J. Org. Chem. 1992, 57, 424–426. (c)
Beaulieu, F.; Snieckus, V. J. Org. Chem. 1994, 59, 6508–6509. (d) Gray,
M.; Chapell, B. J.; Taylor, N. J.; Snieckus, V. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1558–1560. (e) Chauder, B. A.; Kalinin, A. V.; Taylor,
N. J.; Snieckus, V. Angew. Chem., Int. Ed. 1999, 38, 1435–1438. (f) Reed,
M. A.; Chang, M. T.; Snieckus, V. Org. Lett. 2004, 6, 2297–2300. (g)
Macklin, T. K.; Reed, M. A.; Snieckus, V. Eur. J. Org. Chem. 2008,
1507–1509. (h) James, C. A.; Snieckus, V. J. Org. Chem. 2009, 74, 4080–
4093. (i) James, C. A.; Coelho, A. L.; Gevaert, M.; Forgione, P.;
Snieckus, V. J. Org. Chem. 2009, 74, 4094–4103. (j) Miller, R. E.;
Sommer, R.; Fan, H.; Snieckus, V.; Groth, U. Heterocycles 2012, 86,
1045–1054.
Org. Lett., Vol. 15, No. 3, 2013
687

According to the above results, we proposed the follow-
ing reaction mechanism (Scheme 3). Compound 1a was
treated with NaH giving intermediate A, which underwent
intramoleculartriflyl migration toproduce intermediateB.
Protonation and aromatic isomerization of intermediate
B afforded the final product 2a. Accordingly the direct
generation of carbanion C from 1a is not a feasible process.
Hence, the present remote anionic thia-Fries rearrange-
ment induced by nitranion is fundamentally different from
the conventional thia-Fries rearrangement which gener-
ates a carbanion directly by strong alkyllithiums.
Scheme 2. NaH-Mediated Remote Anionic Rearrangement of
Various Aryl Triflatesa
Scheme 3. Plausible Reaction Mechanism
a All reported reaction yields are isolated yields by silica-gel column
chromatography.
To further prove the reaction mechanism, a 1:1 mixture
of compounds 1a and 3c was treated withNaH (Scheme 4).
After analysis, one single peak was found from the crude
19F NMR, and after column chromatography compound
Under optimized reaction conditions, the scope of the
triflyl rearrangement of various 2-(1H-indol-2-yl)phenyl
triflates 1aÀm was investigated (Scheme 2). Since the
present method does not require strong alkyllithium bases,
a variety of functional groups, including Cl and Br, are
well tolerated. All the phenyl triflates 1bÀj bearing either
electron-donating or -withdrawing substituents in different
positions underwent remote triflyl rearrangement giving
desired products 2bÀj in moderate to excellent yields.
Notably, the rearrangement of 1-(1H-indol-2-yl)naphthalen-
2-yl triflates 1kÀm also proceeded efficiently, giving the
desired products 2kÀm in excellent yields. When N-methy-
lindole derivative 3a and 3-methylindole derivative 3b were
treated under the same optimized reaction conditions, no
rearrangement was observed (Figure 1).
Scheme 4. Crossover Experiment between 1a and 3c
Scheme 5. Reaction of 4a and 4b under Optimized Reaction
Conditions
Figure 1. N-Methylindole 3a and 3-methylindole 3b.
(16) For selected examples, see: (a) Liu, W.; Lim, H. J.; RajanBabu,
T. V. J. Am. Chem. Soc. 2012, 134, 5496–5499. (b) Rueeger, H.; Lueoend,
€
R.; Rogel, O.; Rondeau, J.-M.; Mobitz, H.; Machauer, R.; Jacobson, L.;
Staufenbiel, M.; Desrayaud, S.; Neumann, U. J. Med. Chem. 2012, 55,
3364–3386. (c) Blessley, G.; Holden, P.; Walker, M.; Brown, J. M.;
Gouverneur, V. Org. Lett. 2012, 14, 2754–2757.
688
Org. Lett., Vol. 15, No. 3, 2013

2a was obtained in good yield. Compound 1a was triflylated
but not compound 3c, which could demonstrate that triflyl
migration is an intramolecular process.
are well accepted under these conditions, since the reaction
does not require strong alkyllithium bases.
Finally, this rearrangement reaction was applied on
methanesulfonate 4a and perfluorobutanesulfonate 4b
(Scheme 5). To our delight, the migration process pro-
ceeded well and the desired compounds 5a and 5b were
obtained in moderate yields.
Acknowledgment. This study was financially supported in
part by the Platform for Drug Discovery, Informatics, and
Structural Life Science from the Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan. We are grateful
to Central Glass Co., Ltd. for the gift of triflic anhydride.
Inconclusion, we developed a novel remote anionic thia-
Fries rearrangement reaction. To the best of our knowl-
edge, this is the first example of remote anionic thia-Fries
rearrangement. It provides an efficient method for the
synthesis of not only biologically attractive 3-indole tri-
flones but also various 2-(2-hydroxyphenyl)-3-sulfonyl-
1H-indoles. Bromo- and chloro-substituted substrates
Supporting Information Available. Experimental pro-
cedures, full characterization of new products, and copies
of NMR spectra. This material is available free of charge
via the Internet http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 3, 2013
689