A concise approach to the preparation of 2-hydroxydiarylketones by an intramolecular acyl radical ipso substitution

Article abstract of DOI:10.1016/S0040-4039(00)01746-9

Substituted 2-hydroxydiarylketones have been simply prepared using an intramolecular acyl radical [1,6] ipso substitution reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01746-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9667–9671
A concise approach to the preparation of
2-hydroxydiarylketones by an intramolecular acyl radical
ipso substitution†
William B. Motherwell* and Santiago Va´zquez
Department of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street,
London WC1H 0AJ, UK
Received 8 August 2000; revised 13 September 2000; accepted 5 October 2000
Abstract
Substituted 2-hydroxydiarylketones have been simply prepared using an intramolecular acyl radical
[1,6] ipso substitution reaction. © 2000 Elsevier Science Ltd. All rights reserved.
The 2-hydroxydiarylketone unit occurs in many target molecules of importance for organic
synthesis, encompassing both natural products such as cotoin, balanol and daunomycinone as
well as purely synthetic biologically active drugs.1 It also functions as an ultraviolet screen in
products such as dioxybenzone, mexenone and oxybenzone and has also found use in this context
within the paints and plastics industry (e.g. benzophenone-6, benzoresorcinol).1 Although a
variety of methods for the construction of this moiety have been developed as a direct
consequence of these varied properties, the most often used strategies are firmly rooted in the
ionic tradition with reactions such as Friedel–Crafts acylation2 or the Fries rearrangement.3
Within the last few years, we have developed a novel approach for the synthesis of biaryls by
using an intramolecular free radical ipso substitution reaction of a suitably constituted sulphonyl
substituted aromatic derivative by a second ortho substituted s aryl radical.4 This concept of
intramolecular free radical arylation for biaryl construction has been skilfully extended by several
groups in recent times.5–9 To date however, our work has always centred around the initial
generation of an aryl radical as the trigger for carbonꢀcarbon bond formation to the second
sulphonyl substituted aromatic acceptor. In the present communication, we wish to describe a
new synthesis of 2-hydroxydiarylketones using a similar strategy but involving the substitution
of those sulphonyl derivatives by an aromatic acyl radical as the key step (Scheme 1).
* Corresponding author.
†
Dedicated with respect and admiration to Professor Harry Wasserman, an exemplary scholar, gentleman and
enthusiast for organic chemistry on the occasion of his 80th birthday.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01746-9

9668
O
O
R'
O
O
R'
O
O
S
S
O
O
Initiator
H
R
R
[1,6] Ipso
substitution
O
O
R'
O
O
S
O
- SO2
R'
O
R
R
H-atom
abstraction
OH
O
R'
R
Scheme 1.
While acyl radicals have been known for nearly a century, they have only recently emerged as
an important tool for organic synthesis.10 However, their reactions with aromatic11 and
heteroaromatic12 compounds have been little studied.
Although acyl radicals can be generated from many precursors, most notably by the reductive
stannane protocol from acyl selenides,10a we elected to generate our required intermediate by
simple hydrogen atom abstraction from an aldehyde since the starting materials, 3a–o, were all
readily prepared in a single step from inexpensive and commercially available o-hydroxyben-
zaldehydes (Scheme 2).
R'
O
R'
O
O
OH
ClO2S
S
2
CHO
CHO
2 N NaOH, H2O,
CH2Cl2, r.t., overnight
3
R
1
R
OH
O
Chlorobenzene, 24 h, ∆
R'
di-tert-butyl peroxide
4
R
Scheme 2.

9669
Thus, the reaction of 1a–o with the appropriate arylsulphonyl chloride in a two-phase system
of aqueous sodium hydroxide and dichloromethane at room temperature furnished the desired
sulphonates 3a–o in high yields.13,14
In an initial experiment, we studied the reaction of a solution of 3a in chlorobenzene at reflux
for 24 h in the presence of one equivalent of di-tert-butyl peroxide as initiator. Examination of
the reaction mixture at this time revealed a 4:1 ratio of 3a:4a in favour of the starting material
although the desired ketone was isolated, after column chromatography in 15% yield. Neither
the conversion nor the yield in this experiment could be improved by using longer reaction
times.
This result indicated to us that any putative chain propagation step involving abstraction of
the aldehydic hydrogen atom by the aryloxy radical formed on loss of sulphur dioxide was
clearly inefficient although each of the steps is formally favoured in terms of polar effects. In the
event, the most practical and expedient solution proved to be the addition of ten equivalents of
initiator whereupon 4a was isolated in 80% yield.15 A non chain radical reaction is certainly
involved. It was of further interest to note that products arising from decarbonylation or [1,7]
addition to the sulphonyl substituted acceptor ring were not detected.
Our attention was then directed towards a study of the series of substituted derivatives shown
in Table 1. Examination of the results reveals that both electron donating and electron
withdrawing groups are generally well tolerated in the aromatic sulphonyl acceptor ring (Entries
a–i), although, as expected, incorporation of the radicophilic cyano group (Entry k) led to a
much lower yield. In stark contrast to our studies in the biaryl series, where increasing steric
hindrance actually favours the reaction by virtue of an orthogonal approach,4d the conforma-
tional constraints imposed by such substituents are clearly unfavourable in the present [1,6] ipso
substitution process, as witnessed by the case of the mesityl derivative (Entry j).
Table 1
Synthesis of 2-hydroxydiarylketones 4a–o
Entry
Substrate 3 (yield %)
Product 4 (yield %)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
R=H, R%=4-CH3 (71%)
R=H, R%=4-F (70%)
R=H, R%=2-F (63%)
80%
53%
57%
68%
56%
49%
40%
52%
76%
38%
30%
Traces
37%
28%
33%
R=H, R%=2,4-diF (61%)
R=H, R%=4-OCH3 (64%)
R=H, R%=3,4-diOCH3 (78%)
R=H, R%=2-NO2 (76%)
R=H, R%=4-NO2 (73%)
R=H, R%=3-CH3 (70%)
R=H, R%=2,4,6-triCH3 (56%)
R=H, R%=2-CN (80%)
R=3-OCH3, R%=4-CH3 (46%)
R=6-OCH3, R%=4-CH3 (78%)
R=5-OCH3, R%=4-CH3 (71%)
R=4-OCH3, R%=4-CH3 (84%)

9670
It was also of mechanistic interest to note that the incorporation of even a single methoxy
group in the donor ring (Entries l–o), led to a significant decrease in the yield, irrespective of its
position, and indeed, in the case of the 3-methoxy derivative (Entry l) to complete destruction
of the starting material. It has not escaped our attention that the production of a phenolic free
radical inhibitor as the product of a radical reaction is somewhat unusual and the above
observation is in accord with the trend that the more electron rich phenols are highly efficient
antioxidants. Competitive hydrogen atom abstraction from the methoxy groups may also, of
course be problematic.
Finally, as shown in Scheme 3, we have also extended this approach to the synthesis of
heterocyclic systems, with the preparation of the sulphonates 5 and 6 in 73 and 76% yield,
respectively, from their corresponding sulphonyl chlorides. The reactions of 5 and 6 under the
conditions stated above afforded the unsymmetrical heterodiarylketones 7 and 8 in 48 and 34%
yield, respectively, thus confirming once again the sensitivity of the reaction to steric hindrance.
S
O
O
O
OH
O
S
Chlorobenzene, 24 h, ∆
S
CHO
di-tert-butyl peroxide
5
7
48%
O
S
N
O
OH
O
O
Chlorobenzene, 24 h, ∆
O
N
OHC
di-tert-butyl peroxide
O
6
8
34%
Scheme 3.
In summary, the foregoing results provide a simple, inexpensive and experimentally conve-
nient two step method for the construction of the 2-hydroxydiaryl ketone unit which bypasses
the more commonly employed Lewis acidic conditions used for carbonꢀcarbon bond formation.
Acknowledgements
We are grateful to the European Community for the Award of a Fellowship under the MRT
Programme to S.V.
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9671
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14. Satisfactory analytical (combustion and/or high-resolution mass) and spectral (IR, NMR and MS) data were
obtained for all new compounds. Yields refer to purification by crystallisation or flash chromatography on silica
gel.
15. Typical procedure for the synthesis of 2-hydroxydiarylketones: To a refluxing solution of 6 (2.81 g, 10 mmol), in
chlorobenzene (50 ml) was added di-tert-butylperoxide (19 ml, 100 mmol). The solution was refluxed for 24 h
under nitrogen. The solvent was evaporated giving a dark oil that was purified by column chromatography on
silica gel eluted with petrol and dichloromethane furnishing (2-hydroxyphenyl)-(3,5-dimethylisoxazol-4-yl)-
1
methanone, 8, as a yellow solid (742 mg, 34%), mp 106–108°C (diethyl ether). H NMR (400 MHz, CDCl3): l
2.29 (s, 3 H, CH3), 2.39 (s, 3 H, CH3), 6.90 (ddd, 1 H, J=8.0, J%=7.2 and J¦=0.7 Hz, 5%-H), 7.04 (dd, 1 H,
J=8.6 and J%=0.7 Hz, 3%-H), 7.41 (dd, 1 H, J=8.0 and J%=1.7 Hz, 6%-H), 7.52 (ddd, 1 H, J=8.6, J%=7.0 and
J¦=1.7 Hz, 4%-H), 11.7 (s, 1 H, OH); 13C NMR (100.6 MHz, CDCl3): l 10.9 (CH3), 13.0 (CH3), 115.8 (C), 118.6
(CH), 119.1 (CH), 119.8 (C), 132.2 (CH), 137.1 (CH), 158.9 (C), 162.7 (C), 170.6 (C), 194.3 (C); IR (KBr): 2930,
1612, 1592, 1482, 1425, 1247, 1150, 1110, 918, 767 cm−1; MS (FAB): 218 (M+1, 100), 217 (M+, 23), 200 (8), 177
(8), 161 (4). HRMS C12H12NO3 requires: 218.0817; found: 218.0822. C12H12NO3 (217.22) calcd: C, 66.35; H, 5.11;
N, 6.45. Found: C, 66.09; H, 5.21; N, 6.18.
.