Insertion of arynes into carbon-halogen σ-bonds: Regioselective acylation of aromatic rings

Article abstract of DOI:10.1039/b701581j

Arynes were found to insert into carbon-halogen σ-bonds of various acid halides, enabling acyl and halogen moieties to be introduced simultaneously into adjacent positions of aromatic rings. The Royal Society of Chemistry.

Full text of DOI:10.1039/b701581j

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Insertion of arynes into carbon–halogen s-bonds: regioselective
acylation of aromatic rings{
Hiroto Yoshida,* Yasuhiro Mimura, Joji Ohshita and Atsutaka Kunai*
Received (in Cambridge, UK) 1st February 2007, Accepted 21st February 2007
First published as an Advance Article on the web 9th March 2007
DOI: 10.1039/b701581j
We first carried out the reaction of benzyne with 3-methoxy-
benzoyl chloride (2a) in THF at 0 uC and observed that insertion
into the carbonyl–chlorine s-bond took place smoothly by simply
mixing benzyne precursor 1a,4 2a and a fluoride ion (KF/18-
crown-6), giving 2-chloro-39-methoxybenzophenone (3aa) in 70%
yield (Table 1, entry 1). Benzoyl chloride (2b) could also be applied
to the reaction to afford a 68% yield of 3ab (entry 2), and
moreover, the reaction with substituted benzoyl chlorides posses-
sing electron-neutral (2c), -withdrawing (2d) or -donating groups
(2e–2i) produced the respective insertion products (3ac–3ai) in
good to moderate yields (entries 3–9). Worthy to note is high
functional group-compatibility of the reaction: treatment of
bromo- (2j), cyano- (2k) or methoxycarbonyl-substituted benzoyl
chloride (2l) with benzyne yielded the products (3aj–3al), leaving
these functional groups intact (entries 10–12).
Arynes were found to insert into carbon–halogen s-bonds of
various acid halides, enabling acyl and halogen moieties to be
introduced simultaneously into adjacent positions of aromatic
rings.
Friedel–Crafts acylation reactions have been extensively studied
and have been the most important method for the synthesis of
aromatic ketones.1 Owing to relatively large size of acyl moieties,
the reactions of aromatic compounds bearing such ortho-para-
directing groups as alkyl, alkoxy and halogen afford mainly or
solely para-substituted products (Scheme 1, A). Hence, search for
novel acylation reactions, in which acyl moieties are introduced
regioselectively into an ortho-position of ortho-para-directing
groups, has been a challenging and urgent subject in synthetic
organic chemistry. In the course of our ongoing studies on
insertion reactions of arynes into element–element s-bonds,2,3
which enable two functional groups to be introduced simulta-
neously into the contiguous positions of the aromatic rings, we
have found that acid halides add across arynes at their carbonyl–
halogen s-bonds under extremely mild conditions. We report
herein a new method for ortho-selective acylation of aromatic rings
depending upon the aryne insertion into carbonyl–halogen
s-bonds, in which acyl and halogen moieties are incorporated
into 1,2-positions of the aromatic rings all at once (Scheme 1, B).
Besides benzoyl chloride derivatives, the reaction with other acid
halides was also examined (Table 2). Thus, when 2-naphthoyl-
(2m) or (E)-cinnamoyl chloride (2n) was allowed to react with
benzyne, 3am or 3an5 was formed in 50 or 58% yield (entries 1 and
2). Aliphatic acid chlorides (2o–2s) could participate in the reaction
irrespective of the size of an alkyl group (entries 3–7), and a
carbonyl–bromine s-bond of benzoyl- (2t) or isobutyryl bromide
Table 1 Insertion of benzyne into substituted benzoyl chloridesa
Entry
R in 2
Time/h
3
Yieldb (%)
1
2
3
4
5
6
7
8
3-MeO (2a)
H (2b)
4-Ph (2c)
4-CF3 (2d)
4-Me (2e)
2-Me (2f)
2,5-Me2 (2g)
2,4-Me2 (2h)
4-MeO (2i)
4-Br (2j)
4-CN (2k)
4-CO2Me (2l)
9
8.5
11.5
10
9
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
70
68
61
60
55
52
52
43
42
61
54
51
9
9
8.5
9
10
11
11.5
Scheme 1 Regioselectivities in acylation reactions.
9
10
11c
12
a
3aj
3ak
3al
Department of Applied Chemistry, Graduate School of Engineering,
Hiroshima University, Higashi-Hiroshima, 739-8527, Japan.
E-mail: yhiroto@hiroshima-u.ac.jp; Fax: +81-82-424-5494;
Tel: +81-82-424-7724
{ Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b701581j
The reaction was carried out in THF (2 mL) at 0 uC using 1a
(0.30 mmol), (0.33 mmol), KF (0.60 mmol) and 18-crown-6
(0.60 mmol). Isolated yield based on 1a. 4 eq. of KF.
2
b
c
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Table 2 Insertion of benzyne into various acid halidesa
Entry Acid halide
Time/h
3
Yieldb (%)
1
2
3
4
5
6
7
8
R9: 2-naphthyl, X: Cl (2m)
R9: (E)-cinnamyl, X: Cl (2n)
R9: t-Bu, X: Cl (2o)
R9: 1-adamantyl, X: Cl (2p)
R9: Cy, X: Cl (2q)
R9: i-Pr, X: Cl (2r)
R9: pentadecyl, X: Cl (2s)
R9: Ph, X: Br (2t)
R9: i-Pr, X: Br (2u)
R9: PhO, X: Cl (2v)
R9: EtO, X: Cl (2w)
R9: 9-carbazoyl, X: Cl (2x)
10
9.5
10
22
33.5
23
90
4.5
6
3am 50
3an
3ao
3ap
3aq
3ar
3as
3at
3au
3av
58
57
48
59
46
39
54
43
64
9
10
11
12
a
8
11.5
11
3aw 56
3ax 53
The reaction was carried out in THF (2 mL) at 0 uC using 1a
(0.30 mmol), (0.33 mmol), KF (0.60 mmol) and 18-crown-6
(0.60 mmol). Isolated yield based on 1a.
2
b
(2u) readily underwent the insertion of benzyne, enabling acyl and
bromo moieties to be introduced into the adjacent positions as well
(entries 8 and 9). Furthermore, a chloroformate (2v or 2w) or a
carbamoyl chloride (2x) was found to react with benzyne at their
carbonyl–chlorine s-bonds exclusively to provide 3av–3ax in
moderate yields, where the respective carbonyl–oxygen or
carbonyl–nitrogen s-bonds remained unchanged (entries 10–12).
The versatility of the present acylation can be further enhanced
by employing variously substituted arynes. As depicted in
Scheme 2, facile insertion of 4,5-dialkylated arynes (from 1b or
1c) or 2,3-naphthalyne (from 1d) into 2a was observed to give the
corresponding polysubstituted diaryl ketones (3ba–3da). Despite
the steric hindrance around the triple bond, the reaction of 3,6-
dimethylbenzyne (from 1e) or 3,6-dimethoxybenzyne (from 1f)
also proceeded, furnishing 3ea or 3fw in 69 or 41% yield. In
addition, an unsymmetrical aryne, 4-methylbenzyne (from 1g)
efficiently reacted with 2w to afford a mixture of two regioisomers
(3gw : 39gw = 1 : 1),6 whereas the reaction using 3-methoxybenzyne
(from 1h) produced solely 3hw bearing the chloro moiety at the
meta position to the methoxy moiety, which implies that a halogen
atom in an acid halide acts as a nucleophilic site in the present
reaction (vide infra).7
Scheme 2 Insertion of substituted arynes.
In view of salient electrophilicity of arynes8 and the observed
regioselectivity in the reaction of 3-methoxybenzyne, the insertion
reaction would be initiated by a nucleophilic attack of a halogen
atom in an acid halide (Scheme 3). The resulting zwitterion (4) then
produces the insertion product by an intramolecular nucleophilic
substitution at the carbonyl group.
In conclusion, we have disclosed the convenient acylation of
aromatic rings via the novel insertion reaction of arynes into
carbonyl–halogen s-bonds, where the acyl moieties are incorpo-
rated into the ortho-positions to the halogen moieties with perfect
regioselectivities. Based upon the present reaction, halogenated
aryl ketones of structural diversity, whose regioselective synthesis
by conventional Friedel–Crafts acylation would be difficult, can
Scheme 3 Reaction pathway for the insertion reaction.
2406 | Chem. Commun., 2007, 2405–2407
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A. Kunai, Chem. Commun., 2005, 3454; H. Yoshida, M. Watanabe,
J. Ohshita and A. Kunai, Chem. Commun., 2005, 3292; H. Yoshida,
J. Ikadai, M. Shudo, J. Ohshita and A. Kunai, Organometallics, 2005, 24,
156; J. Ikadai, H. Yoshida, J. Ohshita and A. Kunai, Chem. Lett., 2005,
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A. Kunai, Chem. Commun., 2004, 1980; H. Yoshida, J. Ikadai, M. Shudo,
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4 Y. Himeshima, T. Sonoda and H. Kobayashi, Chem. Lett., 1983, 1211.
5 (E)-Configuration of the cinnamyl group in 2n is retained in 3an.
6 This result confirms that the present reaction indeed proceeds through an
aryne intermediate.
7 Owing to an electron-withdrawing inductive effect and a steric effect of
the methoxy moiety, 3-methoxybenzyne generally accepts a nucleophilic
attack at the meta position to the methoxy moiety.
readily be fabricated in a straightforward manner. Further studies
on expansion of reaction scope are in progress.
We thank Central Glass Co Ltd. for a generous gift of
trifluoromethanesulfonic anhydride.
Notes and references
1 Reviews: G. A. Olah, Friedel–Crafts and Related Reactions, Wiley, New
York, 1964; P. H. Gore, Chem. Ind. (London), 1974, 727. Recent
examples: Y. Matsushita, K. Sugamoto and T. Matsui, Tetrahedron Lett.,
2004, 45, 4723; M. J. Earle, U. Hakala, B. J. McAuley,
M. Nieuwenhuyzen, A. Ramani and K. R. Seddon, Chem. Commun.,
2004, 1368; M. J. Earle, U. Hakala, C. Hardacre, J. Karkkainen,
B. J. McAuley, D. W. Rooney, K. R. Seddon, J. M. Thompson and
K. Waehaelae, Chem. Commun., 2005, 903.
2 D. Pen˜a, D. Pe´rez and E. Guitia´n, Angew. Chem., Int. Ed., 2006, 45, 3579.
3 H. Yoshida, K. Tanino, J. Ohshita and A. Kunai, Chem. Commun., 2005,
5678; H. Yoshida, M. Watanabe, J. Ohshita and A. Kunai, Chem. Lett.,
2005, 34, 1538; H. Yoshida, M. Watanabe, J. Ohshita and A. Kunai,
Tetrahedron Lett., 2005, 46, 6729; H. Yoshida, T. Minabe, J. Ohshita and
8 A review on electrophilic coupling of arynes: S. V. Kessar, in
Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming,
Pergamon Press, Oxford, 1991, vol. 4, pp. 483–515.
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