Sulfoxide-mediated oxidative cross-coupling of phenols

Article abstract of DOI:10.1039/c9sc05668h

A metal-free, oxidative coupling of phenols with various nucleophiles, including arenes, 1,3-diketones and other phenols, is reported. Cross-coupling is mediated by a sulfoxide which inverts the reactivity of the phenol partner. Crucially, the process shows high selectivity for cross-versus homo-coupling and allows efficient access to a variety of aromatic scaffolds including biaryls, benzofurans and, through an iterative procedure, aromatic oligomers.

Full text of DOI:10.1039/c9sc05668h

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DOI: 10.1039/C9SC05668H
ARTICLE
Sulfoxide-mediated oxidative cross-coupling of phenols
Zhen He,a Gregory J. P. Perrya and David J. Procter*a
Received 00th January 20xx,
Accepted 00th January 20xx
A metal-free, oxidative coupling of phenols with various nucleophiles, including arenes, 1,3-diketones and other phenols, is
reported. Cross-coupling is mediated by a sulfoxide which inverts the reactivity of the phenol partner. Crucially, the
process shows high selectivity for cross- versus homo-coupling and allows efficient access to a variety of aromatic scaffolds
DOI: 10.1039/x0xx00000x
including
biaryls,
benzofurans
and,
through
an
iterative
procedure,
aromatic
oligomers.
Introduction
Metal-catalyzed cross-coupling, involving an aryl halide and an
organometallic partner, is a powerful tool for biaryl synthesis
(Scheme 1A).1 However, oxidative, C–H/C–H couplings, involving
non-prefunctionalized partners, have recently come to the fore as
an attractive alternative (Scheme 1B).2 Their development remains
a challenge, as the reactivity of one partner must be inverted, and
known processes are compromised by the requirement for
expensive, supply risk, metal oxidants or metal catalysts.2 The
development of selective, metal-free C–H/C–H coupling reactions is,
therefore, an important goal.3
Phenols, in particular unsymmetrical phenol-derived biaryls, are
ubiquitous in nature, biomaterials and ligand collections for
catalysis.4 Approaches to these compounds generally require
multiple steps – prefunctionalization of partners or manipulation of
protecting groups – and/or the use of metals.5 Metal-free oxidative
coupling of unprotected phenols is therefore of interest, however,
avoiding homocoupling is a challenge (Scheme 1C).6 Nevertheless,
metal-free cross-coupling of phenols has been described, most
notably using electroorganic synthesis7 or hypervalent iodine
reagents,8 amongst other approaches9 (Scheme 1D).
We proposed that sulfoxides10-11 could be used to invert the
reactivity of a phenol partner, thus providing an alternative
approach to their oxidative coupling (Scheme 1E). Capture of
phenols by sulfoxides will deliver aryloxysulfonium intermediates I
that are electrophilic and capable of coupling with various
nucleophiles (e.g. Ar2).12-14 The major challenge in such an approach
is the avoidance of homocoupling.13 Furthermore, alternative
Pummerer chemistry of the sulfoxide15 and rearrangement of
sulfonium intermediates I9a,10,16 must be by-passed.
Scheme 1 (A/B) Types of cross-coupling. (C/D) Metal-free, oxidative
coupling of phenols. (E) Sulfoxide-mediated, oxidative coupling of
phenols.
Here we describe the metal-free, oxidative cross-coupling of
phenols with various carbon nucleophilic partners, including other
phenols, arenes, and 1,3-diketones (Scheme 1E). Couplings deliver
biaryls, 2-aryl 1,3-dicarbonyl compounds and benzofurans. An
iterative procedure allows selective double functionalization of
phenols and the preparation of aryl oligomers.
Results and discussion
Oxidative cross-coupling of phenols with phenols, phenol
derivatives and arenes
Guided by our previous studies, phenol 1a in CH2Cl2 was treated
with sulfoxide 4a, activated using trifluoroacetic anhydride (TFAA),
before subsequent addition of 2a (1.5 equivalents), to give the
product of cross-coupling 3a in 91% isolated yield (see the
Supporting Information for optimisation).
a. Department of Chemistry, University of Manchester, Oxford Rd, Manchester, M13
9PL, UK.
† Electronic supplementary information (ESI) available: Full experimental details,
NMR spectra, CCDC numbers for X-ray structures. CCDC 1944706-1944710. For ESI
and crystallographic data in CIF or other electronic format see
DOI: 10.1039/x0xx00000x
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Journal Name
OH
H
Ar1
H
4a (1.1 equiv)
TFAA (1.7 equiv)
Me
2-Naphthols bearing bromo (3c, 3e, 3h), methoxy (3bV),iepwhAertnicylelO(3nldin)e,
cyano (3f) and ester (3g, 3i) groups at the 3-, 6- and 7-positions
OH
Ar2
DOI: 10.1039/C9SC05668H
+
Ar2
2
Ar1
CH2Cl2
S
- 40 oC to RT
were found to be compatible with the coupling (Scheme 2). The
process also embraced 1-naphthol (3j), phenols (3k-3m) and their
methyl ether derivatives (3n-3q). Of particular note, pyrene (3r)
underwent coupling with 1a to give 3r. The structure of 3r was
confirmed by X-ray crystallographic analysis.17
O
4a
1
3
Vary Ar2
OH
OH
OH
MeO
OMe
MeO
OMe
OH
MeO
OMe
OH
R
R
The phenol coupling partner (Ar1) could also be varied and
products of ortho-coupling with a range of nucleophilic partners
gave products 3s–3ac (30–90% yield). Interestingly, treatment of 4-
methoxyphenol with 1,2,4-trimethoxybenzene, under our standard
conditions, gave the product of double arylation 3ab’ in 46% yield.
The yield of 3ab’ could be increased by using 2.2 equivalent of the
sulfoxide 4a and 2.0 equivalents of 1,2,4-trimethoxybenzene (80%).
Diarylated compound 3ac’ could also be obtained. Interestingly, the
couplings could be tuned to favour products of mono- or bis-
coupling; using CH2Cl2/TFA (1:1) as solvent favoured formation of
the mono-arylated products 3ab and 3ac. Finally, the oxidative
coupling could be carried out on a gram scale; the use of 1.2 g of 4-
methoxyphenol produced 1.6 g of 3ab (55% isolated yield). In all
cross-couplings, 2-methyl benzothiophene was recovered in high
yield by chromatography and could be reused.
OH
R
3d R = Ph, 64%
3e R = Br, 61%
3f R = CN, 72%
3a R = H, 91%
3b R = OMe, 70%
3c R = Br, 83%
3h R = Br, 88%
3i R = CO2Me, 78%
3g R = CO2Me, 92%
OH
OH
OH
OH
MeO
OMe
OMe
MeO
OMe
MeO
Me
OMe
MeO
OMe
OH
Me
R
OH
OH
3m 37%
3k R = Me, 19%
3l R = OMe, 40%
3j 51%
3n 71%
OH
OH
OH
MeO
R
OMe
OMe
MeO
MeO
OMe
OMe
MeO
OMe
X-ray of 3r
Oxidative coupling of phenols with 1,3-diketones
OMe
OMe
3o 69%
3p R = H, 55%
3q R = OMe, 53%
1,3-Dicarbonyl compounds could be used as the second nucleophilic
partner (Scheme 3). For example, treatment of 1a with 1,3-
diphenylpropane-1,3-dione afforded 6a in 85% yield. The products
of ortho coupling underwent cyclization to give benzofuran
products; for example, the use of 4-methoxyphenol gave
aroyl[b]benzofuran18 6e in 55% isolated yield.
3r 43%
Vary Ar1 (and Ar2)
Me
OMe
Me
OMe
Me
OMe
Me
OMe
OH
R
OH
OH
OH
OMe
OMe
MeO
OMe
MeO
OMe
OMe
OMe
3v 51%
O
3s R = OH, 75%
3t R = OMe, 51%
O
O
4a (1.1 equiv)
TFAA (1.7 equiv)
OH
R4
R5
O
O
3u 44%
3w 53%
H
R4
R5
OH
R4
R5
+
Ar
MeO
MeO
tBu
tBu
OH
Ar
or
MeO
MeO
MeO
CH2Cl2
MeO
- 40 oC to RT
H
O
Ar
OH
1
5
6
OH
OH
OMe
OMe
OH
OH
OH
OMe
MeO
MeO
OMe
OMe
MeO
OMe
Ph
MeO
OMe
OMe
OEt
R
OMe
OMe
3x 51%
3y 90%
3z R = H, 71%
3aa R = OMe, 74%
3ab 62%a (55%)a,b
Ph
Ph
MeO
R
R
O
O
O
O
O
O
MeO
OMe
X-ray of 6b
OH
OH
6a 85%
6b 62%
6c 38%
MeO
OH
OMe
OMe
Ph
Ph
MeO
Ph
OMe
Me
O
X-ray of 3ab'
O
OMe
OMe
3ac 30%a
MeO
MeO
R = MeO, 3ab', 80%c
R = H, 3ac', 51%c
Ph
Ph
O
O
Cl
6g 75%a
R
O
O
X-ray of 6g
6e R = H, 55%a
6d 70%
Scheme 2 Oxidative cross-coupling of phenols with phenols, phenol
derivatives and arenes. Reaction conditions: To sulfoxide 4a (0.11
mmol) in CH2Cl2 (1 mL, 0.1 M) in an oven-dried tube flushed with N2
at −40 oC was added TFAA (0.17 mmol, 1.7 equiv). After 5 min,
phenol 1 (0.1 mmol in 0.5 mL CH2Cl2) was added in one portion.
Arene 2 (0.15 mmol in 0.5 mL CH2Cl2) was then added immediately.
After 15 min at −40 oC, the mixture was warmed to room
6f R = t-Bu, 67%a
Scheme
3 Oxidative coupling of phenols with 1,3-diketones.
Reaction conditions: To sulfoxide 4a (0.11 mmol) in CH2Cl2 (1 mL,
0.1 M) in an oven dried tube flushed with N2 at −40 C was added
TFAA (0.17 mmol, 1.7 equiv). After 5 min, phenol 1 (0.1 mmol in 0.5
mL CH2Cl2) was added in one portion. 1,3-Dicarbonyl 5 (0.15 mmol
in 0.5 mL CH2Cl2) was then added immediately. After 15 min at −40
oC, the mixture was warmed to room temperature and stirred for 2
h. a CH2Cl2/TFA (1:1) as solvent.
o
a
b
temperature and stirred for 2 h. CH2Cl2/TFA (1:1) as solvent.
Larger scale: (1.2 g of 1 was used). c 2 equiv of 2 and 2.2 equiv of 4a.
2 | J. Name., 2012, 00, 1-3
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ARTICLE
OH
expulsion of 3-methylbenzothiophene. The control
H
Ar3
Ar2
View Article Online
Ar3
4a (1.1 equiv)
TFAA (1.7 equiv)
experiments in Scheme 5B highlight theDiOmI:p1o0r.1t0a3n9t/Cr9oSleC0o5f66t8hHe
hydroxy group in the first partner and suggest that activation
of the phenol occurs via intermediate I. However, we were
unable to detect or isolate this intermediate and further
studies are needed to confirm the exact mechanism for phenol
activation. Scheme 5C shows that the order in which the two
nucleophilic partners are combined can be critical, suggesting
that rapid and irreversible, aryloxysulfonium salt formation
takes place between the activated sulfoxide I and the first
phenol partner, and that aryloxysulfonium salt intermediates
have very different reactivities.20
OH
Ph
Ph
Ar1
Ar2
H
O
Ar2
O
or
+
Ar1
CH2Cl2
O
O
or
- 40 oC to RT
Ar1
Ph
Ph
Ph
3
7
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
MeO
MeO
OMe
MeO
O
OH
O
HO
OMe
Ph
MeO
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
7b 52% (70%)a
7c 60%b
7a 68%
MeO
MeO
OH
OH
OH
OH
X-ray of 7d
OMe
OMe
7e 32%
7d 35%
Ph
OMe
MeO
OH
O
OH
O
Br
Ph
OMe
OMe
OMe
OH
OMe
OMe
7h 31%b
OMe
7g 72%
7f 30%
Scheme
4 Iterative coupling of three nucleophiles. Reaction
conditions: To sulfoxide 4a (0.11 mmol) in CH2Cl2 (1 mL, 0.1 M) in an
oven dried tube flushed with N2 at −40 oC was added TFAA (0.17
mmol, 1.7 equiv). After 5 min, 3 (0.1 mmol in 0.5 mL CH2Cl2) was
added in one portion. A third nucleophile (0.15 mmol in 0.5 mL
CH2Cl2) was then added immediately. After 15 min at −40 oC, the
a
mixture was warmed to room temperature and stirred for 2 h.
b
Compound 3z was used as the substrate. CH2Cl2/TFA (1:1) as
solvent.
Iterative coupling of three nucleophiles
Intrigued by the formation of the triaryl products 3ab’ and 3ac’
(Scheme 2), we considered an iterative process that would
allow the sequential, metal-free, oxidative coupling of phenols
with two different nucleophilic partners (Scheme 4). For
example, 4-methoxy phenol was first coupled with 1,2,4-
trimethoxybenzene to afford 3ab. Subsequent treatment of
3ab with 1,3-dimethoxybenzene gave the unsymmetrical,
diarylated phenol 7a in 68% yield. 1,3-Diphenylpropane-1,3-
dione could also be used as the third nucleophilic partner and
gave C7-arylated benzofurans 7c and 7h.19
Scheme 5 Proposed mechanism and support for the intermediacy
of an aryloxysulfonium salt.
Conclusions
In summary, a metal-free, sulfoxide-mediated, oxidative cross-
coupling unites phenols and various nucleophilic partners,
including phenols, 1,3-diketones and arenes. The capture and
inversion of reactivity of the first nucleophilic partner, using an
interrupted Pummerer reaction, prior to coupling with the
second nucleophile, is key to the cross-coupling.
Homocoupling is not observed and alternative Pummerer and
rearrangement processes are avoided. Iterative sulfoxide-
mediated couplings allow the construction of polyaryl
compounds.
Mechanistic Studies
Based on the above results, and our previous studies,10,13
a
possible mechanism for the oxidative cross-coupling is shown
in Scheme 5A.13 Activation of sulfoxide 4a with TFAA gives
acyloxysulfonium salt II and interrupted Pummerer reaction
with a phenol coupling partner gives aryloxysulfonium salt I.
Subsequent attack of the second partner, at the ortho or para
position of the first, results in C–C bond formation and
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Journal Name
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2017, 8, 1–8; (d) L. Bering, M. Vogt, F.DMO.I:P1a0u.1l0u3s9s/eCn9SaCn0d56A6.8PH.
Antonchick, Org. Lett., 2018, 20, 4077–4080.
We thank EPSRC (Postdoctoral Fellowship to Z.H.; Established
Career Fellowship to D.J.P.) and The University of Manchester
(Lectureship to G.J.P.P.) for their generous support.
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7
13 For the homocoupling of 2-naphthols using
a
benzothiophene catalyst, see: Z. He, A. P. Pulis and D. J.
Procter, Angew. Chem. Int. Ed., 2019, 58, 7813–7817.
14 A cross-coupling procedure was low yielding and not general,
see: K. Higuchi, T. Tago, Y. Kokubo, M. Ito, M. Tayu, S.
Sugiyama and T. Kawasaki, Org. Chem. Front., 2018, 5, 3219-
3225.
15 L. H. S. Smith, S. C. Coote, H. F. Sneddon and D. J. Procter,
Angew. Chem. Int. Ed., 2010, 49, 5832−5844.
16 T. Yanagi, K. Nogi and H. Yorimitsu, Tetrahedron Lett., 2018,
59, 2951−2959.
17 X-ray crystallographic data for 3r, 3ab’, 6b, 6g, and 7d can be
found at the Cambridge Crystallographic Data Centre (CCDC);
1944706-1944710.
18 3-Aroyl[b]benzofurans are found in bioactive molecules. (a)
T. Kalai, G. Varbiro, Z. Bognar, A. Palfi, K. Hanto, B. Bognar, E.
Osz, B. Sumegi and K. Hideg, Bioorg. Med. Chem., 2005, 13,
2629-2636; (b) C. C. Felder, K. E. Joyce, E. M. Briley, M. Glass,
8
9
K. Morimoto, K. Sakamoto, T. Ohshika, T. Dohi and Y. Kita,
Angew. Chem. Int. Ed., 2016, 55, 3652–3656.
For other selected metal-free C–H/C–H couplings of phenols,
see: (a) T. Yanagi, S. Otsuka, Y. Kasuga, K. Fujimoto, K.
Murakami, K. Nogi, H. Yorimitsu and A. Osuka, J. Am. Chem.
Soc., 2016, 138, 14582–14585; (b) S. Sharma, S. K. R.
Parumala and R. K. Peddinti, J. Org. Chem., 2017, 82, 9367–
4 | J. Name., 2012, 00, 1-3
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Chemical Science
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Journal Name
ARTICLE
K. P. Mackie, K. J. Fahey, G. J. Cullinan, D. C. Hunden, D. W.
Johnson, M. O. Chaney, G. A. Koppel and M. Brownstein, J.
Pharmacol. Exp. Ther., 1998, 284, 291-297; (c) R. C. Heel, R.
N. Brogden, T. M. Speight and G. S. Avery, Drugs, 1977, 14,
349-366.
View Article Online
DOI: 10.1039/C9SC05668H
19 In some cases, when lower yields were obtained (e.g.
formation of 7d, 7e, 7f, 7g), unreacted starting material was
recovered (10 –15% of the phenol 3 and 20–35% of the other
coupling partner
– naphthol or diketone) and some
decomposition took place (side products could not be
isolated).
20 When reversing the order of addition of the coupling
partners (Scheme 5C, bottom), the phenol could be
recovered (85% recovery), however, only a trace of the
naphthol component was observed. We have been unable to
detect any other side products and are currently
investigating possible decomposition pathways.
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