Steric and electronic limitations for the D?tz benzannulation of aromatic alkynes

Article abstract of DOI:10.1016/S0040-4039(02)00680-9

As part of an investigation into a new strategy for biaryl synthesis, the D?tz benzannulation of a series of substituted aryl acetylenes was undertaken to determine possible steric and electronic effects exerted by the aryl group. In the ortho position it was found that methyl, methoxy, chloro and N-amide substituents give moderate to good yields of product, whereas carbonyl derivatives and the nitro group are deleterious.

Full text of DOI:10.1016/S0040-4039(02)00680-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3849–3852
Steric and electronic limitations for the Do¨tz benzannulation of
aromatic alkynes
James C. Anderson,a,* John W. Crana and N. Paul Kingb
aSchool of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
bGlaxoSmithKline Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage,
Hertfordshire SG1 2NY, UK
Received 28 January 2002; revised 25 March 2002; accepted 5 April 2002
Abstract—As part of an investigation into a new strategy for biaryl synthesis, the Do¨tz benzannulation of a series of substituted
aryl acetylenes was undertaken to determine possible steric and electronic effects exerted by the aryl group. In the ortho position
it was found that methyl, methoxy, chloro and N-amide substituents give moderate to good yields of product, whereas carbonyl
derivatives and the nitro group are deleterious. © 2002 Published by Elsevier Science Ltd.
Hindered biaryl systems are unique molecular scaffolds
which exhibit interesting properties due, in part, to
atropisomerism around the arylꢀaryl bond. Axially chi-
ral biaryl compounds are an important constituent of
many biologically active natural and unnatural
products1 and used as chiral ligands for asymmetric
catalysis.2 Probably the most powerful method of con-
structing a biaryl axis is through the direct coupling of
two aryl groups.3 Most commonly this has been
achieved by transition metal catalysed cross coupling
between an aryl electrophile and aryl nucleophile but
the range of substrates is limited by the steric require-
ments of the system,4,5 although this problem has been
circumvented through ligand tuning by Buchwald.6 We
have been investigating an alternative and at present
unconventional strategy for biaryl synthesis which relies
upon the construction of the biaryl bond before the
construction of the final aryl group (Eq. (1)).7
substituted benzenoid compounds with good regio-
chemical control and chemical yield in one step.9 There
have been studies detailing the steric and electronic
requirements of the arylcarbene complex10 and the
alkyne,11 but none specifically looking at the character
of the aryl group of an aryl acetylene. There are only a
few examples of benzannulations of aryl acetylenes
leading to hindered biaryl systems.7c In order to investi-
gate the scope of the proposed approach we have
investigated the steric and electronic limitations with
respect to the aryl group of a series of substituted aryl
acetylenes in the Do¨tz benzannulation reaction.
(2)
Studies were carried out using readily available aryl
Fischer carbene complex 112 and a series of aryl acetyle-
nes 2 (Eq. (2)). The acetylenes were synthesised by
Sonogashira coupling reaction13 between the requisite
aryl halide and a terminal acetylene.14 We found the
water based system developed by Bumagin, Beletskaya
and co-workers15 to be superior to non-aqueous
conditions16 and to provide most of our simple aryl
acetylenes 2 in good yield. The ortho-amide substituted
2l could not be formed from the requisite halide so 2i
was treated with LDA in THF at −78°C to give 2l in
(1)
There are a number of benzannulations which could be
applied to this reaction,8 but we chose to assess the
benzannulation by Fischer carbene complexes due to
their widely reported efficiency at generating highly
Keywords: biaryls; alkynes; Do¨tz reactions; quinones.
* Corresponding author. Tel.: +44(0)115 951 4194; fax: +44(0)115 951
3564; e-mail: j.anderson@nottingham.ac.uk
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00680-9

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J. C. Anderson et al. / Tetrahedron Letters 43 (2002) 3849–3852
compound eliminates chromium to give a benzofuran 4
(Scheme 1). This class of compounds is known20,21 to be
unstable and can decompose if tautomerisation to give
the rearomatised product is not possible, as in our
cases. The hydrolysed product 520a was not detected in
the mixture of byproducts from our attempted benzan-
nulations. It is surprising that the benzannulation of 2i
failed as a more hindered o-CO2Me aryl acetylene has
been successfully cyclised as part of a natural product
synthesis.22 This suggests subtle steric factors may have
played a decisive role in that particular cyclisation.23
44% yield. A disubstituted acetylene was chosen so as
to render the new aromatic ring in the hindered bi-aryl
system 3 (Eq. (2)) di-ortho substituted. An oxidative
work up employing Ce(IV)/0.1 M HNO3 was employed
in all reactions to avoid any regiochemical issues. It
would be anticipated that an aryl–alkyl acetylene would
ensure good regiochemical control to position the larger
phenyl substituent adjacent to the hydroxyl function of
the initially formed phenol.10,17 In order to investigate
possible steric and electronic effects exerted by the aryl
group on the acetylene, para-substituted aromatic
groups were screened in addition to the ortho-substi-
tuted aromatic acetylenes (Table 1). The benzannula-
tions were conducted under dry state conditions18
developed by Harrity and Kerr which were found to be
generally superior to homogeneous methods. In our
reactions the remainder of the mass balance, aside from
starting material, was not accounted for as the reac-
tions were screened only for quinone formation.
An ortho-formyl group protected as its 1,3-dioxane (2k)
gave a moderate yield of the hydrolysed biaryl 3e in
42% yield. Carbonyl derivatives in the para position
(2h,j,m) gave moderate yields of biaryl 3, but the para-
From Table 1 it would seem that an ortho-methyl or
methoxy group gives good yields of benzannulated
products 3a to 3d.19 Carbonyl derivatives are unsatis-
factory in the ortho position (2e,g,i,l) yielding mixtures
of starting material and decomposition products. Hern-
don has used similar o-aldehyde/ketone aryl acetylenes
to produce isobenzofuran intermediates via intramolec-
ular cyclisation of chromium carbene species formed
from treatment with Fischer carbene complexes.20 By
analogy, the failure of our substrates (2e,g,i,l) to
undergo benzannulation could be due to a similar
alternative cyclisation pathway, whereby the carbonyl
Scheme 1. Interception of reaction intermediates by ortho-
carbonyl derivatives.
Table 1. Do¨tz benzannulations of aryl acetylenes 2
Aryl acetylene
R
R%
T (°C)
t (h)
Yield (%)a
2a
2b
2c
2d
2e
2f
2g
2h
2i
o-Me
o-OMe
o-Me
o-OMe
o-CHO
p-CHO
o-COMe
p-COMe
o-CO2Me
p-CO2Me
Ph
Ph
80
80
100
80
100
120
120
80
100
80
20
20
2
20
2
20
12
20
2
65
57
64
57
0
24
0
54
0
nBu
nBu
nBu
nBu
nBu
nBu
nBu
nBu
2j
20
56
O
2k
nBu
100
2
42b
o-
O
2l
o-CO·NiPr2
o-CO·NiPr2
o-NH2
p-NH2
o-NO2
Ph
80
100
100
100
125
100
100
100
12
2
2
2
12
2
0
44
13c,d
38d
0
0
79
71
2m
2n
2o
2p
2q
2r
nBu
nBu
nBu
nBu
nBu
nBu
nBu
p-NO2
o-Cl
p-Cl
2
2
2s
a Yield with respect to 1. Standard conditions as in Ref. 17.
b Isolated yield of biaryl aldehyde derivative recovered after hydrolysis of acetal.
c Isolated as phenol due to decomposition with CAN.
d NMR yield from inseparable mixture of quinone and unidentified byproduct.

J. C. Anderson et al. / Tetrahedron Letters 43 (2002) 3849–3852
Table 2. Do¨tz benzannulations of anilides 2
3851
(3)
Aryl acetylene
R
R%
T (°C)
t (h)
Yield (%)
2t
o-NHCOPh
p-NHCOPh
o-NMeCOPh
p-NMeCOPh
o-NtBuCOPh
nBu
nBu
nBu
nBu
nBu
100
100
100
100
100
2
2
2
2
2
44
34
50
72
0
2u
2v
2w
2x
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