Palladium-Catalyzed Arylation of Aryl Sulfenate Anions with Aryl Bromides under Mild Conditions: Synthesis of Diaryl Sulfoxides

Article abstract of DOI:10.1021/acs.orglett.6b00073

A palladium-catalyzed arylation of aryl sulfenate anions generated from aryl 2-(trimethylsilyl)ethyl sulfoxides and CsF has been developed. This protocol is effective for the synthesis of diaryl sulfoxides and heteroaryl aryl sulfoxides under mild conditions employing aryl bromides. Various functional groups, including those with acidic protons, are well tolerated.

Full text of DOI:10.1021/acs.orglett.6b00073

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Arylation of Aryl Sulfenate Anions with Aryl
Bromides under Mild Conditions: Synthesis of Diaryl Sulfoxides
Hui Jiang,†,‡ Tiezheng Jia,‡ Mengnan Zhang,‡ and Patrick J. Walsh*,‡
†Department of Applied Chemistry, China Agricultural University, 2 West Yuanmingyuan Road, Beijing 100193, P. R. China
‡Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry,
University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: A palladium-catalyzed arylation of aryl sulfenate
anions generated from aryl 2-(trimethylsilyl)ethyl sulfoxides
and CsF has been developed. This protocol is effective for the
synthesis of diaryl sulfoxides and heteroaryl aryl sulfoxides
under mild conditions employing aryl bromides. Various
functional groups, including those with acidic protons, are well
tolerated.
ryl sulfoxides are important structural motifs in natural
retro-Michael reaction of β-sulfinyl esters to generate sulfenate
anions followed by palladium-catalyzed arylation with aryl
iodides and bromides to prepare aryl sulfoxides (Scheme 1a).9
An enantioselective version of this reaction has also been
introduced.10 Subsequently, the same group reported a
palladium-catalyzed C−O bond cleavage of allylic sulfenate
esters by a Mislow−Braverman−Evans rearrangement of the
allyic sulfoxides. The resulting aryl sulfenate anion underwent
palladium-catalyzed coupling with aryl iodides or bromides to
yield diaryl sulfoxides (Scheme 1b).11
bioactive compounds,2 and marketed ther-
apeutics, such as Nexium3 and Provigil.4 They are also used as
ligands in transition-metal catalysis.5 The two classic methods
for sulfoxides synthesis are the oxidation of sulfides and
nucleophilic substitution of sulfinate amides or esters.6 Despite
the utility of these two methods, they leave room for
improvement. These approaches use either strong oxidants or
reactive organolithium and Grignard reagents, which can limit
their functional group compatibility.
1
Aproducts,
In 2015, Perrio and co-workers utilized the thermal
fragmentation of tert-butyl sulfoxides to generate sulfenate
anions that underwent Pd-catalyzed arylation (Scheme 1c).12
These reactions all employed Pd(XANTPHOS)-based cata-
lysts. In 2013, Nolan and co-workers developed an N-
heterocyclic carbene (NHC)-ligated palladium catalyst for the
synthesis of diaryl sulfoxides from aryl methyl sulfoxides and
aryl bromides or chlorides (Scheme 1d).13 Simultaneously, our
group reported a general, high-yielding method for the
synthesis of diaryl sulfoxides from benzyl aryl sulfoxides
(Scheme 1e).14 In these latter two cases, the sulfoxide
substrates undergo an initial α-arylation.
In recent years, transition-metal-catalyzed reactions have
been employed in the formation of sulfoxide C−S bonds
(Scheme 1) via the arylation of sulfenate anions, [RSO]−.7 In
pioneering work, Poli and Madec8 reported a KOH-promoted
Scheme 1. Palladium-Catalyzed Arylation of Sulfenate
Anions with Aryl Halides
In general, the generation of alkyl sulfenate anions with β-
hydrogens, RCH2CH2SO−, under the basic conditions
employed in Scheme 1, is challenging due to the instability of
the precursors,15 intermediates,16 and/or products.7a−c,16b,17
For these reasons, we recently developed a palladium-catalyzed
arylation of alkyl sulfenate anions, which afforded alkyl aryl
sulfoxides in high yield (Scheme 2a).18 Key to success of this
process was a fluoride-triggered elimination strategy with alkyl
2-(trimethylsilyl)ethyl sulfoxides15,19 to liberate the requisite
alkyl sulfenate anion intermediates. Given the mildly basic
conditions that can be used with 2-(trimethylsilyl)ethyl
Received: January 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00073
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Letter
Scheme 2. Arylation of (a) Alkyl Sulfenate Anions and (b)
Aryl Sulfenate Anions
Table 1. Optimization of Palladium-Catalyzed Diaryl
Sulfoxide Formation from 1a and 2a
a
entry
ligand
[Pd]/ligand (mol %) concn (M) 3a (%)
1
2
3
4
5
NIXANTPHOS
RuPhos
5/7.5
2/4
2/4
2/4
2/4
2/4
1/2
2/4
2/4
2/4
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.5
67
57
71
75
92
<5
62
64
32
sulfoxides, we envisioned that this approach would also be
useful for the synthesis of diaryl sulfoxides. Herein, we present
the palladium-catalyzed arylation of sulfenate anions with aryl
bromides initiated with aryl 2-(trimethylsilyl)ethyl sulfoxides
under mild conditions (Scheme 2b).
We initiated our studies using NIXANTPHOS/Pd(dba)2 to
catalyze cross-coupling of phenyl 2-(trimethylsilyl)ethyl sulf-
oxides (1a) and 4-tert-butylbromobenzene (2a, see Figure 1 for
SPhos
P(tBu)2(CH2tBu)
sSPhos
sSPhos
sSPhos
sSPhos
sSPhos
sSPhos
b
6
7
c
8
d
9
e
10
96 (93 )
a
Assay yields determined by 1H NMR using 0.1 mmol (7 μL) CH2Br2
b
c
d
as internal standard. 50 °C. 1.5 equiv of 2a. 2.0 equiv of CsF.
e
Isolated yield.
Scheme 3. Substrate Scope of Aryl Bromides in Pd-Catalyzed
a
Diaryl Sulfoxides Formation with 1a
Figure 1. Ligand structures.
ligand structures). We previously used this catalyst for the
arylation outlined in Scheme 1e.14a Four fluoride sources (LiF,
NaF, KF, and CsF) and six commonly used solvents [THF,
toluene, 2-Me-THF, DME (dimethoxyethane), CPME (cyclo-
pentyl methyl ether), and dioxane] were screened (see the
Supporting Information for details). The leading hit was CsF in
2-Me-THF with 67% assay yield (0.1 mmol scale, Table 1,
entry 1). We next examined 44 sterically and electronically
diverse mono- and bidentate ligands on microscale. Along with
NIXANTPHOS (L1), RuPhos (L2), SPhos (L3), di-tert-
S
butylneopentylphosphine·HBF4 (L4), and SPhos (L5) were
the most promising hits. With 5 mol % of Pd(dba)2 and 10 mol
% of ligand loading (L2−L5), the microscale reactions were
successfully translated to laboratory scale with similar high assay
yields (>90%). When the palladium loading was reduced to 2
mol %, however, SSPhos outperformed the other ligands (entry
2−4 vs entry 5) and was, therefore, used for the duration of
these studies. Attempts to decrease the temperature, catalyst
loading, equivalents of aryl bromide (2a) or CsF led to
diminished assay yields of 3a (entries 6−9). Increasing the
reaction concentration from 0.1 to 0.5 M increased assay yield
to 96% with 93% isolated yield after purification (entry 10).
With optimized conditions for the arylation of sulfenate
anions (Table 1, entry 10), we examined the scope of aryl
bromides with trimethyl(2-(phenylsulfinyl)ethyl)silane (1a,
Scheme 3). Aryl bromides bearing electron-donating groups,
such as 4-tert-butyl and 4-methoxy, were well tolerated,
providing 3a and 3b in 93% and 94% yield, respectively.
Electron-withdrawing groups on the aryl bromides also
exhibited good reactivity. 4-Fluorobromobenzene (2c) and 4-
a
Reaction conditions: 1a (0.5 mmol), 2a−l (1.0 mmol), CsF (1.5
s
mmol), Pd(dba)2 (0.01 mmol), SPhos (0.02 mmol), 2-Me-THF (1
b
c
s
mL), 80 °C, 24 h. 5 mol % of Pd(dba)2, 10 mol % of Sphos. 48 h.
d
e
2 mL of 2-Me-THF. 32 h.
trifluoromethyl bromobenzene (2e) afforded the corresponding
products in 79% and 78% yield, respectively. We were pleased
that good chemoselectivity in coupling at bromide over
chloride was achieved with 4-chlorobromobenzene, affording
3d in 92% yield. Further studies indicated that, although sSPhos
B
DOI: 10.1021/acs.orglett.6b00073
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Letter
has been used in coupling of aryl chlorides,20 these substrates
are not viable under our conditions. Sterically hindered aryl
bromides, such as 2-bromotoluene (2f) and 1-bromonaph-
thalene (2g), furnished the products 3f and 3g in 92% and 90%
yield, respectively.
sulfoxide underwent the coupling reaction, but the isolated
yield was only 52%.
To demonstrate the synthetic utility of this approach, we
performed the coupling of 2-(trimethylsilyl)ethyl sulfoxide 1a
(6 mmol) with 4-chlorobromobenzene (2d) in 85% yield (1.20
g, Scheme 5).
Heterocycle-containing sulfoxides exhibit a broad range of
biological activities. Our protocol is effective for their synthesis.
Thus, 3-(phenylsulfinyl)pyridine (3h), 5-quinoline phenyl
sulfoxide (3i), 3-quinoline phenyl sulfoxide (3j), 3-thiophene
phenyl sulfoxide (3k), and 2-thiophene phenyl sulfoxide (3l)
were generated in 73−88% yields. Under the optimized
conditions, 5-bromo-1H-indole (2m) afforded products 3m in
Scheme 5. Gram-Scale Synthesis of 3d via Palladium-
Catalyzed Diaryl Sulfoxide Generation
S
70% yield. It is noteworthy that the SPhos-ligated catalyst
successfully promoted C−S bond formation faster than C−N
bond formation (Buchwald−Hartwig coupling21), leaving the
N−H intact. 4-Bromobenzaldehyde and 4-bromoacetophenone
were also good substrates, providing the coupling products 3n
and 3o in 70 and 72% yield, respectively.
Next, we turned our attention to the substrate scope of aryl
2-(trimethylsilyl)ethyl sulfoxides (Scheme 4). In general,
In summary, we introduce a palladium-catalyzed route to
prepare diaryl sulfoxides from aryl 2-(trimethylsilyl)ethyl
sulfoxides and aryl bromides. The aryl sulfenate anions were
generated in situ by a fluoride-triggered elimination strategy
under mildly basic conditions, enabling the synthesis of a wide
range of functionalized diaryl sulfoxides.
Scheme 4. Substrate Scope of Aryl 2-(Trimethylsilyl)ethyl
Sulfoxides in Pd-Catalyzed Diaryl Sulfoxide Formation with
a
ASSOCIATED CONTENT
Bromobenzene
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00073.
Procedures and characterization data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: pwalsh@sas.upenn.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE-1464744)
for financial support. H.J. thanks the China Scholarship Council
(201406350156) for financial support.
a
REFERENCES
Reaction conditions: 1 (0.5 mmol), 2q (1.0 mmol), CsF (1.5 mmol),
■
s
Pd(dba)2 (0.01 mmol), SPhos (0.02 mmol), 2-Me-THF (1 mL), 80
(1) (a) Dini, I.; Tenore, G. C.; Dini, A. J. Nat. Prod. 2008, 71, 2036.
(b) El-Aasr, M.; Fujiwara, Y.; Takeya, T.; Tsukamoto, S.; Ono, M.;
Nakamo, D.; Okawa, M.; Kinjo, J.; Yoshimitsu, H.; Nohara, T. J. Nat.
Prod. 2010, 73, 1306. (c) Wyche, T. P.; Piotrowski, J. S.; Hou, Y.;
Braun, D.; Deshpande, R.; McIlwain, S.; Ong, I. M.; Myers, C. L.;
Guzei, I. A.; Westler, W. M.; Andes, D. R.; Bugni, T. S. Angew. Chem.,
Int. Ed. 2014, 53, 11583. (d) Nohara, T.; Fujiwara, Y.; Komota, Y.;
Kondo, Y.; Saku, T.; Yamaguchi, K.; Komohara, Y.; Takeya, M. Chem.
Pharm. Bull. 2015, 63, 117.
(2) (a) Rinehart, K. L.; Sakai, R. US2004/59112 A1, 2004. (b)
Amira Pharmaceuticals, Inc. US/2010/4331 A1, 2010. (c) Amira
Pharmaceuticals, Inc. Hutchinson, J. H.; Seiders, T. J.; Arruda, J. M.;
Roppe, J. R. WO2010/42652 A2, 2010. (d) Combinatorx (Singapore)
Pte. Ltd. US2010/9970 A1, 2010. (e) ACHAOGEN, Inc. WO2009/
137130A2, 2009.
b
°C, 24 h. 1 (0.1 mmol), 2q (0.2 mmol), CsF (0.3 mmol), Pd(dba)2
(0.005 mmol), sSPhos (0.01 mmol), 2-Me-THF (0.5 mL), 100 °C, 24
h.
various substituents on the aryl sulfoxide were compatible,
affording the desired diaryl sulfoxides in high yields. Aryl 2-
(trimethylsilyl)ethyl sulfoxides coupled with bromobenzene
(2q) to give the parent diphenyl sulfoxide (3q) in 92% yield. 2-
(Trimethylsilyl)ethyl sulfoxides bearing electron-donating
groups such as 4-Me (1r) and 4-OMe (1b) both provided
the products in 95% yield. 2-(Trimethylsilyl)ethyl sulfoxides
bearing 4-F (1c) and 4-Cl (1d) furnished products in 92% and
94% yield, respectively. Hindered 1-naphthyl (1g) and 2-tolyl
(1f) 2-(trimethylsilyl)ethyl sulfoxides provided the expected
products in 90 and 80% yield, respectively. The 3-OMe
derivative (1p) could also be used as a coupling partner,
affording 3p in 96% yield. 2-Pyridyl 2-(trimethylsilyl)ethyl
(3) Astra Aktiebolag. U.S. Patent US5877192 A, 1998.
(4) Laboratoire L. Lafon. U.S. Patent US4927855A, 1990.
(5) For reviews, see: (a) Trost, B. M.; Rao, M. Angew. Chem., Int. Ed.
2015, 54, 5026. (b) Mellah, M.; Voituriez, A.; Schulz, E. Chem. Rev.
2007, 107, 5133. For recent examples, see: (c) Trost, B. M.; Ryan, M.
C
DOI: 10.1021/acs.orglett.6b00073
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
C.; Rao, M.; Markovic, T. Z. J. Am. Chem. Soc. 2014, 136, 17422.
(d) Stang, E. M.; White, M. C. J. Am. Chem. Soc. 2011, 133, 14892.
(e) Dornan, P. K.; Leung, P. L.; Dong, V. M. Tetrahedron 2011, 67,
4378. (f) Chen, J.; Chen, J.; Lang, F.; Zhang, X.; Cun, L.; Zhu, J.;
Deng, J.; Liao, J. J. Am. Chem. Soc. 2010, 132, 4552.
́ ́
(6) (a) Wojaczynska, E.; Wojaczynski, J. Chem. Rev. 2010, 110, 4303.
(b) O’Mahony, G. E.; Kelly, P.; Lawrence, S. E.; Maguire, A. R.
ARKIVOC 2011, 1, 1. (c) Bolm, C. Coord. Chem. Rev. 2003, 237, 245.
(7) For reviews, see: (a) O’Donnell, J. S.; Schwan, A. L. J. Sulfur
Chem. 2004, 25, 183. (b) Maitro, G.; Prestat, G.; Madec, D.; Poli, G.
Tetrahedron: Asymmetry 2010, 21, 1075. (c) Schwan, A. L.; Soderman,
̈
S. C. Phosphorus, Sulfur Silicon Relat. Elem. 2013, 188, 275. For
sulfenate anions as catalyst, see: (d) Zhang, M.; Jia, T.; Yin, H.;
Carroll, P. J.; Schelter, E. J.; Walsh, P. J. Angew. Chem., Int. Ed. 2014,
53, 10755. (e) Zhang, M.; Jia, T.; Wang, C. Y.; Walsh, P. J. J. Am.
Chem. Soc. 2015, 137, 10346. (f) Zhang, M.; Jia, T.; Sagamanova, I. K.;
Pericas, M. A.; Walsh, P. J. Org. Lett. 2015, 17, 1164. For sulfenate
anions in enantioselective alkylation, see: (g) Zong, L.; Ban, X.; Kee,
C. W.; Tan, C. H. Angew. Chem., Int. Ed. 2014, 53, 11849.
(8) Aversa, M. C.; Bonaccorsi, P.; Madec, D.; Prestat, G.; Poli, G.
The Fabulous Destiny of Sulfenic Acids. In Innovative Catalysis in
Organic Synthesis: Oxidation, Hydrogenation, and. C-X Bond Fanning
Reactions; Andersson, P. G., Ed.; Wiley−VCH, 2012.
(9) Maitro, G.; Vogel, S.; Prestat, G.; Madec, D.; Poli, G. Org. Lett.
2006, 8, 5951.
(10) Maitro, G.; Vogel, S.; Sadaoui, M.; Prestat, G.; Madec, D.; Poli,
G. Org. Lett. 2007, 9, 5493.
(11) Bernoud, E.; Le Duc, G.; Bantreil, X.; Prestat, G.; Madec, D.;
Poli, G. Org. Lett. 2010, 12, 320.
(12) Gelat, F.; Lohier, J.-F.; Gaumont, A.-C.; Perrio, S. Adv. Synth.
Catal. 2015, 357, 2011.
(13) Izquierdo, F.; Chartoire, A.; Nolan, S. P. ACS Catal. 2013, 3,
2190.
(14) (a) Jia, T.; Bellomo, A.; Montel, S.; Zhang, M.; El Baina, K.;
Zheng, B.; Walsh, P. J. Angew. Chem., Int. Ed. 2014, 53, 260. (b) Jia, T.;
Zhang, M.; Sagamanova, I. K.; Wang, C. Y.; Walsh, P. J. Org. Lett.
2015, 17, 1168.
̀
(15) Foucoin, F.; Caupene, C.; Lohier, J.-F.; de Oliveira Santos, J. S.;
Perrio, S.; Metzner, P. Synthesis 2007, 2007, 1315.
(16) (a) Soderman, S. C.; Schwan, A. L. Org. Lett. 2011, 13, 4192.
(b) Jia, T.; Bellomo, A.; EL Baina, K.; Dreher, S. D.; Walsh, P. J. J. Am.
Chem. Soc. 2013, 135, 3740.
(17) For reviews, see: (a) Field, L. Synthesis 1972, 1972, 101.
(b) Field, L. Synthesis 1978, 1978, 713. (c) Trost, B. M.; Salzmann, T.
N.; Hiroi, K. J. Am. Chem. Soc. 1976, 98, 4887. (d) Trost, B. M. Acc.
Chem. Res. 1978, 11, 453. (e) Trost, B. M. Chem. Rev. 1978, 78, 363.
For recent examples, see: (f) Cubbage, J. W.; Guo, Y.; McCulla, R. D.;
Jenks, W. S. J. Org. Chem. 2001, 66, 8722. (g) Aversa, M. C.;
Barattucci, A.; Bilardo, M. C.; Bonaccorsi, P.; Giannetto, P. Synthesis
2003, 2241. (h) Latorre, A.; Lop
́
ez, I.; Ramírez, V.; Rodríguez, S.;
Izquierdo, J.; Gonzalez, F. V.; Vicent, C. J. Org. Chem. 2012, 77, 5191.
́
(18) Jia, T.; Zhang, M.; Jiang, H.; Wang, C. Y.; Walsh, P. J. J. Am.
Chem. Soc. 2015, 137, 13887.
́ ́ ́
(19) For a review, see: (a) Chambert, S.; Desire, J.; Decout, J.-L.
Synthesis 2002, 2319. For pioneering works, see: (b) Oida, T.;
Ohnishi, A.; Schimamaki, T.; Hayashi, Y.; Taniomoto, S. Bull. Chem.
Soc. Jpn. 1991, 64, 702. (c) Oida, T.; Nakamura, M.; Takashima, Y.;
Hayashi, Y. Bull. Inst. Chem. Res. Kyoto Univ. 1992, 70, 295.
(d) Schwan, A. L.; Dufault, R. Tetrahedron Lett. 1992, 33, 3973.
For recent works, see: (e) Schwan, A. L.; Strickler, R. R.; Dunn-
Dufault, R.; Brillon, D. Eur. J. Org. Chem. 2001, 2001, 1643.
(20) (a) Molander, G. A.; Ryu, D. W.; Hosseini-Sarvari, M.;
Devulapally, R.; Seapy, D. G. J. Org. Chem. 2013, 78, 6648.
(b) Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2005,
44, 6173.
(21) (a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13.
(b) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27. (c) Hartwig, J.
F. Acc. Chem. Res. 2008, 41, 1534. (d) Evano, G.; Blanchard, N.;
Toumi, M. Chem. Rev. 2008, 108, 3054.
D
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