Nucleophilic ortho allylation of aryl and heteroaryl sulfoxides

Article abstract of DOI:10.1021/ol2025197

Aryl and heteroaryl sulfoxides undergo ortho allylation upon treatment with Tf₂O and allylsilanes. The method complements the use of sulfoxides to direct ortho-metalation and reaction with electrophiles as it allows allylic carbon nucleophiles to be added ortho to the directing group in a metal-free process. The versatile sulfide adducts can be selectively manipulated using various methods including Kumada-Corriu cross-coupling of the organosulfanyl group.

Full text of DOI:10.1021/ol2025197

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5882–5885
Nucleophilic Ortho Allylation of Aryl and
Heteroaryl Sulfoxides
Andrew J. Eberhart,† Jason E. Imbriglio,‡ and David J. Procter*,†
School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL,
U.K., and Department of Medicinal Chemistry, Merck Research Laboratories,
Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065-0900, United States
david.j.procter@manchester.ac.uk
Received September 16, 2011
ABSTRACT
Aryl and heteroaryl sulfoxides undergo ortho allylation upon treatment with Tf2O and allylsilanes. The method complements the use of sulfoxides
to direct ortho-metalation and reaction with electrophiles as it allows allylic carbon nucleophiles to be added ortho to the directing group in a
metal-free process. The versatile sulfide adducts can be selectively manipulated using various methods including KumadaÀCorriu cross-
coupling of the organosulfanyl group.
The selective formation of carbonÀcarbon bonds to
aromatic and heteroaromatic rings is one of the most im-
portant synthetic objectives as an aromatic centerpiece
forms the structural basis of many active pharmaceuti-
cals, agrochemicals, and functional materials. New
methods for the metalation of aromatics and heteroaro-
matics using stoichiometric metal reagents1 and transi-
tion-metal-catalyzed activation of aromatic derivatives2
have led to a step change in the way aromatic and
heteroaromatic substrates are elaborated. These ad-
vancements have culminated in new metal-catalyzed
methods for the formation of carbonÀcarbon bonds to
unfunctionalized sites on aromatics and heteroaromatics
where only a CÀH is present.3 The use of activating
substituents that facilitate nucleophilic addition to aro-
matic systems is an underexploited approach. In recent
years, the Pummerer reaction4 of sulfoxides has been
adapted to allow activation of aromatic rings. In particu-
lar, seminal reports from Kita,5 Feldman,6 and Padwa7
have described the nucleophilic alkylation of some elec-
tron-rich heteroaryl sulfoxides and sulfilimides using Pum-
merer processes.
Inspired by the work of Kita,5a,b we here report the
first general study of the nucleophilic ortho allylation
of aryl and heteroaryl sulfoxides 1 (Scheme 1).8 The
method complements the use of sulfoxides to direct ortho-
metalation, and quenching with electrophiles, as it allows
allylic carbon nucleophiles to be added ortho to the direct-
ing group in a metal-free process with rearomatization.
Selective manipulation of the CÀS bond in the versatile
(5) (a) Akai, S.; Kawashita, N.; Wada, Y.; Satoh, H.; Alinejad, A. H.;
Kakiguchi, K.; Kuriwaki, I.; Kita, Y. Tetrahedron Lett. 2006, 47, 1881.
(b) Akai, S.; Kawashita, N.; Satoh, H.; Wada, Y.; Kakiguchi, K.;
Kuriwaki, I.; Kita, Y. Org. Lett. 2004, 6, 3793. (c) Akai, S.; Morita,
N.; Iio, K.; Nakamura, Y.; Kita, Y. Org. Lett. 2000, 2, 2279.
(6) (a) Feldman, K. S.; Vidulova, D. B. Org. Lett. 2004, 6, 1869.
(b) Feldman, K. S.; Skoumbourdis, A. P. Org. Lett. 2005, 7, 929.
(c) Feldman, K. S.; Vidulova, D. B.; Karatjas, A. G. J. Org. Chem.
2005, 70, 6429. (d) Feldman, K. S.; Karatjas, A. G. Org. Lett. 2006, 8,
4137. (e) Feldman, K. S.; Fodor, M. D. J. Org. Chem. 2009, 74, 3449.
(7) Padwa, A.; Nara, S.; Wang, Q. Tetrahedron Lett. 2006, 47, 595.
(8) Maulide has recently reported the reaction of β-ketoesters with
arylsulfoxides in an elegant, metal-free approach for the R-arylation of
carbonyl compounds. Huang, X.; Maulide, N. J. Am. Chem. Soc. 2011,
133, 8510.
† University of Manchester.
‡ Merck.
(1) Astruc, D. Modern arene chemistry; Wiley-VCH: Weinheim,
Germany, 2002; p 330.
(2) Diederich, F. N.; Stang, P. J. Metal-catalyzed Cross-coupling
Reactions; Wiley-VCH: Weinheim, Germany, 1998.
(3) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
Shul’pin, G. B. Org. Biomol. Chem. 2010, 8, 4217. Lersch, M.; Tilset,
M. Chem. Rev. 2005, 105, 2471.
(4) (a) Bur, S. K.; Padwa, A. Chem. Rev. 2004, 104, 2401. (b) Feldman,
K. S. Tetrahedron 2006, 62, 5003. (c) Akai, S.; Kita, Y. Top. Curr. Chem.
2007, 274, 35. (d) Smith, L. H. S.; Coote, S. C.; Sneddon, H. F.; Procter,
D. J. Angew. Chem., Int. Ed. 2010, 49, 5832.
r
10.1021/ol2025197
Published on Web 10/14/2011
2011 American Chemical Society

allylated sulfide adducts using Ni-catalyzed cross-coupling
of the organosulfanyl group is also described.
To assess the generality of the process we have studied
the nucleophilic ortho allylation of several arylsulfides,
activated as their sulfoxides by mCPBA oxidation. Aryl
sulfides were readily prepared by Cu13 or Pd catalyzed-
coupling14 of thiols with aryl halides and heteroaryl sulf-
oxides were prepared by metalation and quenching with
thiosulfonates or disulfides (followed by oxidation of the
sulfide).
Scheme 1. Nucleophilic Ortho Allylation of Aryl Sulfoxides
The reaction is general: neutral, electron-rich, and
electron-deficient benzene rings are allylated under our
simple reaction conditions using allylsilanes (Figure 1).
Diphenylsulfoxide underwent nucleophilic ortho allylation
using functionalized allylsilanes 5 and 6 to give 7a and 7b,
respectively, in good yield. Unsymmetrical diarylsulfox-
ides bearing an electron-rich ring gave alkylation products
7cÀg in good yields and with high selectivity for the more
electron-rich ring. Pleasingly, unsymmetrical diarylsulfox-
ides with considerable steric hindrance at sulfur underwent
efficient allylation to give 7e and 7f. Aryl alkyl sulfoxides
can also be used in the nucleophilic ortho allylation: aryl
perfluoroalkylsulfoxides(RF = C8F17)15 undergoefficient
allylation to give 7hÀm and 7p in good to excellent yields
(Figure 1). The electronic properties of the perfluoroalkyl
group facilitate aromatic substitution as n-decyl phenyl
sulfoxide underwent allylation in 19% yield. The allylation
is also compatible with substrates bearing halogen sub-
stituents although yields are lower (vide infra). Finally,
naphthyl sulfoxides underwent efficient allylation to give
7h and 7p in excellent yields. The perfluoroalkyl group also
allows fluorous solid phase extraction (FSPE)16 to be used
as a convenient alternative method for purification during
the synthesis of sulfoxide substrates and the manipulation
of sulfide products.
Although we have focused on additions to benzenes,
the ortho nucleophilic allylation of medicinally relevant
heterocycles is also possible (Figure 2). For substrates
activated by a phenylsulfinyl group, Kita’s conditions
employing TFAA17a proved optimal. Interestingly, we
found these conditions to be compatible with an indole
bearing a free NÀH, and 8e was obtained in moderate
yield.17b For a 2-thienyl perfluoroalkyl sulfoxide, the use
our Tf2O conditions with microwave heating gave excel-
lent results, and 8c and 8d were obtained in high yield.
The presenceof anelectron-withdrawing bromine on the
benzene ring leads to the formation of unallylated sulfide
byproducts (Figure 1, preparation of 7n and 7o). This
is also illustrated by comparing the efficient allylation of
In the interrupted Pummerer reaction,4 activated sulf-
oxidesreact withnucleophilesatsulfur, prior tomoreusual
thionium ion formation. Drawing on the observations of
Oshima and Yorimitsu,9 we proposed that aryl sulfoxides
would react with allylsilane nucleophiles to give sulfonium
salts that would undergo in situ thio-Claisen rearrange-
ment10 to give products of regioselective aromatic substi-
tution via an intermediate thionium ion. Optimization
studies using diphenylsulfoxide illustrated the feasibility
of the approach: treatment of diphenylsulfoxide 2 with
Tf2O11 and allylTMS, under microwave heating at 60 °C,
gave 4 in 80% yield after 1 h. No other regioisomeric pro-
ducts were obtained. Sulfonium intermediate 3 could be
isolated from thereaction and characterizedby1H NMR,12
suggesting that an alternative mechanism involving direct
allylation of the ring is not occurring (Scheme 2). Addi-
tional support for an interrupted Pummerer mechanism is
presented in Scheme 4 (vide infra).
Scheme 2. Nucleophilic Ortho Allylation of Diphenylsulfoxide
(9) (a) Kobatake, T.; Yoshida, S.; Yorimitsu, H.; Oshima, K. Angew.
Chem., Int. Ed. 2010, 49, 2340. (b) Kobatake, T.; Fujino, D.; Yoshida, S.;
Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2010, 132, 11838.
(c) Yoshida, S.; Yorimitsu, H.; Oshima, K. Org. Lett. 2009, 11, 2185.
(d) Yoshida, S.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 5573.
(10) For thio-Claisen rearrangements of sulfonium ylides and sulfo-
nium salts formed by alternative approaches, see: (a) Boyarskikh, V.;
Nyong, A.; Rainier, J. D. Angew. Chem., Int. Ed. 2008, 47, 5374. (b) Nyong,
A. M.; Rainier, J. D. J. Org. Chem. 2005, 70, 746. (c) Novikov, A. V.;
Kennedy, A. R.; Rainier, J. D. J. Org. Chem. 2003, 68, 993. (d) Novikov,
A. V.; Sabahi, A.; Nyong, A. M.; Rainier, J. D. Tetrahedron: Asymmetry
2003, 14, 911. (e) Kennedy, A. R.; Taday, M. H.; Rainier, J. D. Org. Lett.
2001, 3, 2407. (f) Furukawa, N.; Shima, H.; Ogawa, S. Heteroat. Chem.
1995, 6, 559. (g) Shima, H.; Furukawa, N. Tetrahedron 1995, 51, 12239.
(h) Plate, R.; Theunisse, A. W. G.; Ottenheijm, H. C. J. J. Org. Chem. 1987,
52, 370. (i) Plieninger, H.; Kraemer, H.-P.; Sirowej, H. Chem. Ber. 1974,
107, 3915.
(13) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517.
(14) Norris, T.; Leeman, K. Org. Process Res. Dev. 2008, 12, 869.
ꢀ
(15) Mace, Y.; Urban, C.; Pradet, C.; Blazejewski, J.; Magnier, E.
Eur. J. Org. Chem. 2009, 5313.
(16) For a discussion of fluorous tagging, see: (a) Studer, A.; Hadida,
S.; Ferritto, R.; Kim, S.-Y.; Jeger, P.; Wipf, P.; Curran, D. P. Science
1997, 275, 823. For recent reviews, see: (b) Curran, D. P. In The
ꢀ
Handbook of Fluorous Chemistry, Gladysz, J. A., Curran, D. P., Horvath,
I. T., Eds.; Wiley-VCH: Weinheim, 2004. (c) For the use of FSPE, see:
Curran, D. P.; Luo, Z. J. Am. Chem. Soc. 1999, 121, 9069.
(17) (a) Kita observed the allylation of thiophene and furan sulf-
oxides using allyltributyltin. See ref 5b. (b) Kita has reported the
allylation of the benzene ring in N-Ts 5-sulfoxy indoles using similar
conditions. Interestingly, in Kita’s work the indole bearing a free NÀH
did not undergo productive allylation. See ref 5a.
(11) Nf2O is also an efficient activator in the allylation reactions.
(12) See Supporting Information for an assigned 1H NMR of 3.
Org. Lett., Vol. 13, No. 21, 2011
5883

was obtained). This can be explained by considering pos-
sible intermediates, sulfuranes 918 and sulfonium salts 10.
Nucleophilic addition of allyl silanes tothe trifluorometha-
nesulfonylated sulfoxide may give an equilibrium mixture
of sulfuranes 9a and 9b. Allyl transfer from S to C in
sulfurane 9a is impeded by unfavorable orbital overlap.
Although allyl transfer may be possible from sulfurane 9b,
ligand coupling (reductive elimination)18 competes result-
ing in the formation of a mixture of allylated products and
byproducts 11. Electron-withdrawing substituents on the
benzene ring may disfavor formation of sulfonium ion 10
and subsequent allyl transfer (Scheme 3). Alternatively,
Scheme 3. Proposed Mechanism for the Nucleophilic Ortho
Allylation of Aryl Sulfoxides
electron-withdrawing substituents on the benzene ring
may alter the reactivity of sulfonium ion 10, disfavoring
rearrangement and promoting deallylation. Both hypoth-
eses are supported by the observation that efficient allyla-
tion of sulfur is observed in the reactions of all substrates
(1H NMR), even those that ultimately result in mixtures of
allylation products and sulfide byproducts 11.
Figure 1. Nucleophilic ortho allylation of aryl sulfoxides.
To gain additional evidence for the interrupted Pum-
merer mechanism, we prepared thiazole sulfoxide 12 con-
taining an ortho heteroatom substituent capable of inter-
cepting the carbocation intermediate resulting from
allylsilane addition to sulfur. Pleasingly, exposure of thia-
zole sulfoxide 12 to our conditions for ortho allylation gave
thiazolone 15 after interception of carbocation 13 and
hydrolysis of salt 14 (Scheme 4).
Scheme 4. Interception of an Intermediate in the Interrupted
Pummerer Reaction
Figure 2. Nucleophilic ortho allylation of heteroaryl sulfoxides.
an ortho-methyl sulfoxide (7m was obtained in 70%
yield, Figure 1) with the less successful allylation of the
corresponding ortho-trifluoromethyl sulfoxide (the sulfide
was the major productand only a trace ofallylated product
(18) For a review of hypervalent organosulfur compounds, see:
Furukawa, N.; Sato, S. Top. Curr. Chem. 1999, 205, 89.
5884
Org. Lett., Vol. 13, No. 21, 2011

reagents,20 organozinc reagents,21a arylboronic acids,21b
and organotin reagents21c,d have been reported. Exploiting
the conditions of Wenkert,20a,b ortho allyl aryl sulfides 7
have been been found to undergo efficient KumadaÀ
Corriu coupling with a range of Grignard reagents under
Ni catalysis to give adducts 16 (Figure 3). FSPE can be
used to separate nonfluorous coupling products from
fluorous disulfide, which can be recovered for reuse. Phenyl-
sulfanyl adducts could also be used in Ni-catalyzed coupling
reactions with Grignard reagents, but lower yields were
observed presumably due to insertion of Ni into the less
hindered ArS bond.22
In summary, aryl and heteroaryl sulfoxides undergo
nucleophilic ortho allylation upon treatment with allyl
silanes and Tf2O under microwave heating. The straight-
forward method complements the use of sulfoxides to
direct ortho-metalation, and quenching with electrophiles,
as it allows allylic carbon nucleophiles to be added ortho to
the directing group in a metal-free process with rearoma-
tization. The allyl substituent introduced in the nucleophi-
lic aromatic substitution is a versatile handle for further
manipulation. The sulfide substituents in the products of
allylation are precursors to arylmetals in Ni-catalyzed
cross-couplings with Grignard reagents.
Figure 3. Coupling of ortho allyl arylsulfides with Grignard
reagents under Ni catalysis.
The organylsulfanyl group in the products of nucleo-
philic ortho allylation provides further opportunities for
bond formation and decoration of the aryl or heteroaryl
template. In particular, aryl and heteroaryl sulfides are
useful partners in a range of transition-metal-catalyzed
cross-couplings.19 For example, couplings with Grignard
Acknowledgment. We thank Merck Sharp & Dohme
(CASE award to A.E.) and the EPSRC (CPhD award
to A.E.).
(19) Dubbaka, S. R.; Vogel, P. Angew. Chem., Int. Ed. 2005, 44, 7674.
(20) (a) Wenkert, E.; Ferreira, T. W.; Michelotti, E. L. J. Chem. Soc.,
Chem. Commun. 1979, 637. (b) Wenkert, E.; Shepard, M. E.; McPhail,
A. T. J. Chem. Soc., Chem. Commun. 1986, 1390. (c) Kanemura, S.;
Kondoh, A.; Yorimitsu, H.; Oshima, K. Synthesis 2008, 2659. (d) Itami,
K.; Mineno, M.; Muraoka, N.; Yoshida, J.-i. J. Am. Chem. Soc. 2004,
126, 11778.
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C spectra
and X-ray crystallographic data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(21) (a) Angiolelli, M. E.; Casalnuovo, A. L.; Selby, T. P. Synlett
2000, 905. (b) Liu, J.; Robins, M. J. Org. Lett. 2005, 7, 1149. (c) Egi, M.;
Liebeskind, L. S. Org. Lett. 2003, 5, 801. (d) Alphonse, F.-A.; Suzenet,
F.; Keromnes, A.; Lebret, B.; Guillaumet, G. Org. Lett. 2003, 5, 803.
(22) For a recent application of Wenkert’s conditions, see: Ma, J.;
Peng, L.; Zhang, X.; Zhang, Z.; Campbell, M.; Wang, J. Chem.;Asian
J. 2010, 5, 2214.
Org. Lett., Vol. 13, No. 21, 2011
5885