Synthesis of 2,2c-6-trisubstituted and 2,2c-,6,6--tetrasubstituted diaryl sulfides and diaryl sulfones by copper-promoted coupling and/or ortholithiation

Article abstract of DOI:10.1055/s-0029-1217986

Stoichiometric copper(I) iodide, in the presence of potassium carbonate and ethylene glycol, promotes the coupling of even highly sterically encumbered 2,6-disubstituted thiophenols and aryl iodides to form hindered diarylsulfides. Hindered diarylsulfones

Full text of DOI:10.1055/s-0029-1217986

LETTER
2769
Synthesis of 2,2¢,6-Trisubstituted and 2,2¢,6,6¢-Tetrasubstituted Diaryl Sulfides
and Diaryl Sulfones by Copper-Promoted Coupling and/or Ortholithiation
Synthesis
o
of Tri- and T
n
etrasubstitut
a
e
d
D
iaryl
S
t
ulfides
hand Sulfonesan Clayden,* James Senior
School of Chemistry, University of Manchester, Oxford Rd., Manchester M13 9PL, UK
Fax +44(161)2754612; E-mail: clayden@man.ac.uk
Received 15 June 2009
transformation in all the but the most hindered systems,
such as 5c, for which MCPBA was required to ensure ox-
idation of the intermediate sulfoxide (Scheme 1).
Abstract: Stoichiometric copper(I) iodide, in the presence of potas-
sium carbonate and ethylene glycol, promotes the coupling of even
highly sterically encumbered 2,6-disubstituted thiophenols and aryl
iodides to form hindered diarylsulfides. Hindered diarylsulfones
may be made in a complementary fashion by ortholithiation of the
sulfone oxidation products of less hindered diarylsulfides.
R
R
R
method A:
NaBO3⋅H2O,
AcOH, 50 °C
CuI (20 mol%)
K2CO3
ethylene glycol
Key words: copper, Ullmann, coupling, sulfide, sulfone, lithiation
SH
I
3
O2S
S
or method B:
MCPBA,
CH2Cl2,
t-amyl alcohol
120 °C, 16 h
In connection with studies on the stereochemical
properties1 of potentially atropisomeric sulfur com-
pounds,2 we required a supply of various hindered (i.e. tri
or tetra-ortho-substituted) diarylsulfides 1 and diarylsul-
fones 2 (Figure 1). A recently reported method3 employs
Cu(I) to catalyse the Ullmann-style coupling of thiophe-
nols (and other thiols) with aryl halides.4 However, this
method was used only to make relatively unhindered sul-
fides bearing one or two groups ortho to the sulfur atom,
and no examples were reported with either coupling part-
ner being 2,6-disubstituted. In this paper we report an ex-
tension of Buchwald’s method to the synthesis of more
heavily substituted diarylsulfides and diarylsulfones ei-
ther by increasing the quantity of metal used or by oxida-
tion of the sulfide coupling products to sulfones and
subsequent directed ortholithiation.5 The only previous
synthesis of a 2,2¢,6,6¢-tetraalkyl (in fact, tetramethyl) di-
aryl sulfide by direct coupling employed the sodium thi-
olate with CuI in the presence of toxic HMPA.4n
R
R
20 °C, 18 h
R
6
5
4
5a R = Et 96%
6a R = Et 86% (method A)
5b R = i-Pr 91%
6b R = i-Pr 85%, 85% (method A, B)
6c R = t-Bu 0%b, 65% (method A, B)
6d R = 2,3-benzoa 83% (method A)
5c R = t-Bu 88%
5d R = 2,3-benzoa 90%
Scheme 1 Synthesis of 2,2¢disubstituted sulfones by coupling and
oxidation. a 1-Naphthyl; b Method A gave the sulfoxide in 90% yield
The 2,2¢-bis-t-butyl sulfone 6c was successfully mono-
lithiated and quenched with a range of electrophiles6–8 to
give 2,2¢,6-tri-orthosubstituted sulfones 7a–d as shown in
Scheme 2. Yields were good in all cases.
Further attempted lithiations of 7 were unsuccessful, as
was the attempted one-pot double lithiation of either 6c or
6d. Even the use of excess sec-BuLi with 6b gave a singly
quenched product 8 when acetone was used as the electro-
phile. However, after methylation to yield 9, further lithi-
ation was possible and, in the presence of cyclobutanone,
the tetra-ortho-substituted sulfone 10 was obtained, which
has the property of being atropisomeric.2
Martin showed8 that substituted diarylsulfones may be
made by lithiating the cyclic sulfone 12, which is conve-
niently made from diphenylsulfone 11. We used a related
strategy for the synthesis of tetrasubstituted diaryl ethers.9
Attempted double lithiation of 128 returned a mixture of
13 and 14, both of which were converted into alkenes 15
and 16 on attempted reduction with triethylsilane
(Scheme 3). Hydrogenation of 15 gave the diisopropyl-
substituted cyclic sulfone 17.
R1
R1
O2S
S
R2
R4
R2
R4
R3
R3
1
2
Figure 1 Hindered diarylsulfides 1 and diarylsulfones 2
Precursors for lithiation in the form of less hindered 2,2¢-
disubstituted diarylsulfides 5 were made from thiols 3 and
iodides 4 by the method of Buchwald et al.3 and oxidised
to the corresponding sulfones 6. Sodium perborate in ace-
tic acid at 50 °C6 was found to be a reliable reagent for the
Although lithiation of the sulfones provided some useful-
ly hindered sulfones,2 it was not general enough for our
purposes, so we returned to the synthesis of 2,2,6,6¢-tetra-
substituted diarylsulfides by Cu-promoted coupling of
2,6-disubstituted thiophenols and 2,6-disubstituted aryl
halides. Buchwald’s original publication3 did not detail
SYNLETT 2009, No. 17, pp 2769–2772
x
x
.x
x
.2
0
0
9
Advanced online publication: 24.09.2009
DOI: 10.1055/s-0029-1217986; Art ID: D15909ST
© Georg Thieme Verlag Stuttgart · New York

2770
J. Clayden, J. Senior
LETTER
1. s-BuLi,
–78 °C, THF
2. E+
7a E = Me 78%a
7b E = I 82%b; 66%c
7c E = CH(OH)Ph 77%d
7d E = Sp-Tol 73%e
O2S
O2S
E
6c
1. s-BuLi,
1. s-BuLi,
–78 °C, THF
–78 °C, THF
2. acetone
O2S
RO O2S
MeO O2S
HO
2.
43%
O
6b
8 (R = H)
9 (R = Me)
10 57%
NaH, MeI, THF
97%
Scheme 2 Functionalisation of diarylsulfones by lithiation. a E+ = MeI; b E+ = I2; c E+ = (CH2I)2; d E+ = PhCHO; e E+ = p-Tol2S2
OH
OH
1. s-BuLi,
THF
O2S
HO O2S
O2S
R1
18
R2
+
CuI (100 mol%)
K2CO3
ethylene glycol
SiMe2
SiMe2
2. acetone
SiMe2
SH
I
S
R1
R2
12
13 35%
14 52%
t-amyl alcohol
120 °C, 16 h
Et3SiH,
BF3OEt2
Et3SiH,
BF3OEt2
20
19
H2, Pd/C
EtOH
Scheme 4 Tetra-ortho-substituted diarylsulfides by Cu-promoted
coupling
O2S
O2S
O2S
93%
SiMe2
SiMe2
SiMe2
17
Table 1 Synthesis of 2,2¢,6,6¢-Tetrasubstituted Diarylsulfides by
the Coupling Method of Scheme 4
15 65%
16 76%
Scheme 3 Functionalisation of a thiasilaanthracene-S,S-dioxide 12
Entry
Thiol 18 (R1)
18a (Me)
18a (Me)
18b (Br)
Iodide 19 (R2)
19a (Me)
19c (Br)
Product 20, Yield (%)
20a (79)
the direct synthesis of such tetrasubstituted diarylsulfides
by coupling, but we found that 2,6-disubstituted thiophe-
nols 18 and the related aryl iodides 19 nonetheless made
suitable coupling partners (Scheme 4). Both of the start-
ing materials were made from readily made aryl bromides
by the methods shown in Scheme 5. Thus, bromide 21b
(made by bromination of available 3,5-di-tert-butyltolu-
ene 21a) was converted into the corresponding aryllithi-
um by bromine-lithium exchange. Trapping with iodine
gave the iodide 19a in 87% yield; trapping with dimeth-
yldisulfide yielded methylsulfide 21f (93%), which was
demethylated using sodium 2-propanethiolate10 to yield
thiophenol 18a in 93% yield. Bromination and oxidation11
of 21b yielded aldehyde 21d, which was protected and
converted into the iodide 19b similarly. Both the 2-bro-
mo-substituted iodide 19c and thiophenol 18b were made
by iodination (I2, Selectfluor12) of 21g, followed by (io-
dide-selective13) copper-catalysed coupling3 with 4-meth-
oxybenzylthiol (to give 21h) and acid-catalysed
deprotection.
1
2
3
20b (76)
19c (Br)
20c (30)
O
O
4
5
18a (Me)
18b (Br)
20d (55)
20e (40)
19b
O
O
19b
Optimal yields for the hindered couplings shown in
Scheme 4 were obtained by using equimolar amounts of
each of the coupling partners 18 and 19, along with one
equivalent of copper(I) iodide and two equivalents of ethy-
lene glycol. Heating this mixture with base (potassium
carbonate) in tert-amyl alcohol at 120 °C for 16 hours
Synlett 2009, No. 17, 2769–2772 © Thieme Stuttgart · New York

LETTER
Synthesis of Tri- and Tetrasubstituted Diaryl Sulfides and Sulfones
2771
(3) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517.
(4) Other recent methods for C–S bond formation in less
hindered systems have been described, see: (a) Fernandez-
Rodriguez, M.-A.; Shen, O.; Hartwig, J. F. J. Am. Chem.
Soc. 2006, 128, 2180. (b) Correa, A.; Carril, M.; Bolm, C.
Angew. Chem. Int. Ed. 2008, 47, 2880. (c) Zhang, H.; Cao,
W.; Ma, D. Synth. Commun. 2007, 37, 25. (d) Xu, H. J.;
Zhao, X. Y.; Deng, J.; Fu, Y.; Feng, Y.-S. Tetrahedron Lett.
2009, 50, 434. (e) Lee, J.-Y.; Lee, P. H. J. Org. Chem. 2008,
73, 7413. (f) For a review, see: Kondo, T.; Mitsudo, T.
Chem. Rev. 2000, 100, 3205. For further representative
examples, see: (g) Palomo, C.; Oiarbide, M.; López, R.;
Gómez-Bengoa, E. Tetrahedron Lett. 2000, 41, 1283.
(h) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett.
2000, 2, 2019. (i) McWilliams, J. C.; Fleitz, F. J.; Zheng, N.;
Armstrong, J. D. Org. Synth. 2002, 79, 43. (j) Li, G. Y.
Angew. Chem. Int. Ed. 2001, 40, 1513. (k) Li, G. Y. J. Org.
Chem. 2002, 67, 3643. (l) Schopfer, U.; Schlapbach, A.
Tetrahedron 2001, 57, 3069. (m) Bates, C. G.; Gujadhur,
R. K.; Venkataraman, D. Org. Lett. 2002, 4, 2803. (n) Only
one previous report, a coupling method employing HMPA as
solvent, addresses a 2,2¢,6,6¢-tetraalkyl diarylsulfide, see:
Fujihara, H.; Chiu, J.; Furukawa, N. J. Am. Chem. Soc. 1988,
110, 1280.
R1
R1
H
R2
Compound
21a
21b
R2
Me
a
b
c
Br
Br
Br
Br
I
Me
e
f
21c
CH2Br
CHO
diox
Me
21d
d
e
21e
19a
19b
21f
I
diox
Me
SMe
SH
H
g
18a
Me
Br
21g
19c
h
i
I
Br
21h
18b
SPMB Br
SH
Br
j
Scheme 5 Preparation of the starting materials for the hindered cou-
pling. Reaction conditions: (a) Br2, Fe, CHCl3; (b) NBS, (PhCO2)2,
CCl4, 16 h, D (94%); (c) 2-nitropropane, NaOEt, EtOH, 4 h (61%); (d)
ethylene glycol, p-TsOH, toluene, 18 h, D (97%); (e) 1. t-BuLi, THF,
–78 °C; 2. I2 (88% 19a; 87% 19b); (f) 1. t-BuLi, THF, –78 °C; 2.
Me2S2 (93%); (g) t-BuSNa, DMF, D, 18 h (93%); (h) Selectfluor, I2,
MeCN, D, 5 h (44%); (i) CuI, K2CO3, ethylene glycol, t-amyl alcohol,
120 °C, 18 h (73%); (j) CF3CO2H, PhOMe (82%).
generally returned moderate to high yields of the coupled
sulfides 20 (Scheme 4 and Table 1).14 Notably, the selec-
tivity for insertion of Cu into even a hindered C–I bond al-
lowed sulfides containing bromo-substituents to be made
– substituents which, in principle, allow further function-
alisation to more elaborate derivatives.
(5) For recent reviews of directed lithiation, see: (a) Clayden, J.
Organolithiums: Selectivity for Synthesis; Pergamon:
Oxford, 2002. (b) Clayden, J. Directed Metallation of
Aromatic Compounds. In Chemistry of Organolithium
Compounds, Vol. 1; Rappoport, Z.; Marek, I., Eds.; Wiley:
Chichester, 2004, 495. (c) Whisler, M. C.; MacNeil, S.;
Snieckus, V.; Beak, P. Angew. Chem. Int. Ed. 2004, 43,
2206.
In summary, highly hindered sulfides may be formed by
copper-promoted coupling of thiols with aryl iodides;14
comparably hindered sulfones may be formed either by
oxidation of these sulfides or by lithiation/electrophilic
quenching of simpler sulfones.
(6) Clayden, J.; Cooney, J. J. A.; Julia, M. J. Chem. Soc., Perkin
Trans. 1 1995, 7.
(7) Iwao, M.; Iihama, T.; Mahalanabis, K. K.; Perrier, H.;
Snieckus, V. J. Org. Chem. 1989, 54, 24.
(8) Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105,
6155.
(9) Betson, M. S.; Clayden, J. Synlett 2006, 745.
(10) Pinchart, A.; Dallaire, C.; Van Bierbeek, A.; Gingras, M.
Tetrahedron Lett. 1999, 5479.
Acknowledgment
We are grateful to the ESPRC for support.
(11) Kimura, S.; Bill, E.; Bothe, E.; Weyhermller, T.; Wieghardt,
K. J. Am. Chem. Soc. 2001, 123, 6025.
(12) Stavber, S.; Kralj, P.; Zupan, M. Synthesis 2002, 1513.
(13) For examples of selectivity of I over Br in related reactions,
see: Deng, W.; Zou, Y.; Wang, Y.-F.; Liu, L.; Guo, Q.-X.
Synlett 2004, 1254.
(14) Copper-Promoted Coupling; Typical Procedure for (2,4-Di-
tert-butyl-6-bromophenyl)-(2,4-di-tert-butyl-6-methylphenyl)
sulfane (20b)
References and Notes
(1) For examples of atropisomerism and discussions on the
conformational properties of non-biaryl systems, see:
(a) Clayden, J.; Turner, H.; Helliwell, M.; Moir, E. J. Org.
Chem. 2008, 73, 4415. (b) Adler, T.; Bonjoch, J.; Clayden,
J.; Font-Bardía, M.; Pickworth, M.; Solans, X.; Solé, D.;
Vallverdú, L. Org. Biomol. Chem. 2005, 3, 3173.
(c) Clayden, J.; Worrall, C. P.; Moran, W.; Helliwell, M.
Angew. Chem. Int. Ed. 2008, 47, 3234. (d) Betson, M. S.;
Clayden, J.; Worrall, C. P.; Peace, S. Angew. Chem. Int. Ed.
2006, 45, 5803. (e) Clayden, J.; Fletcher, S. P.; McDouall,
J. J. W.; Rowbottom, S. J. M. J. Am. Chem. Soc. 2009, 131,
5331. (f) For an overview of this area, see: Clayden, J.
Chem. Commun. 2004, 127.
(2) For studies of conformational interconversions in
diarylsulfides and sulfones, see: (a) Kessler, H.; Rieker, A.;
Rundel, W. Chem. Commun. 1968, 475. (b) Lam, W. Y.;
Martin, J. C. J. Org. Chem. 1981, 46, 4458. (c) Grilli, S.;
Lunazzi, L.; Mazzanti, A. J. Org. Chem. 2001, 4444.
(d) Lunazzi, L.; Mazzanti, A.; Minzoni, M. Tetrahedron
2005, 61, 6782. (e) Clayden J., Senior J., Helliwell M.;
Angew. Chem. Int. Ed.; in press
Thiophenol 18a (574 mg), copper(I) iodide (462 mg) and
potassium carbonate (560 mg) were charged to a flask fitted
with a reflux condenser, which was evacuated/back-filled
with nitrogen (×3). A solution of iodide 19c (800 mg) and
ethylene glycol (0.23 mL) in tert-amyl alcohol (6 mL) was
added via syringe and the reaction mixture was heated to
reflux for 24 h. The reaction mixture was allowed to cool to
r.t., diluted with ethyl acetate (40 mL) and filtered through a
glass sinter. The filtrate was washed with water (3 × 50 mL)
and brine (50 mL), dried over MgSO4 and the solvents were
removed under reduced pressure. The crude product was
purified by flash chromatography (petroleum ether) to yield
the title compound as a white solid that was recrystallised
from acetone (1.27 g, 76%); mp 125–129 °C(acetone); Rf =
0.69 (petroleum ether); 1H NMR (400 MHz, CDCl3): d =
7.45 (d, J = 2 Hz, 1 H, ArH), 7.36 (d, J = 2 Hz, 1 H, ArH),
Synlett 2009, No. 17, 2769–2772 © Thieme Stuttgart · New York

2772
J. Clayden, J. Senior
LETTER
7.33 (d, J = 2 Hz, 1 H, ArH), 6.93 (d, J = 2 Hz, 1 H, ArH),
1.75 (s, 3 H, ArCH3), 1.65 (s, 9 H, CMe3), 1.64 (s, 9 H,
CMe3), 1.30 (s, 9 H, CMe3), 1.28 (s, 9 H, CMe3); 13C NMR
(100 MHz, CDCl3): d = 150.8, 150.2, 149.0, 148.5, 139.0,
133.1, 131.8, 129.7, 127.0, 126.1, 123.6, 122.5, 38.3, 37.5,
34.7, 34.5, 31.3, 31.3, 31.1, 30.9, 23.0; MS (CI): m/z (%) =
502 (40) [79Br M]+, 504 (40) [81Br M]+, 503 (50) [79BrM +
H]+, 505 (50) [81BrM + H]+; HRMS: m/z calcd for
C29H43BrS: 502.2263; found: 502.2264.
Synlett 2009, No. 17, 2769–2772 © Thieme Stuttgart · New York

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