A New Approach for the Synthesis of Highly Substituted Aromatic Rings: The Alkyne-Mediated Approach

Article abstract of DOI:10.1002/chem.201504421

Pentasubstituted aromatic rings serve as templates for drug design and can be conveniently prepared by the thermolysis of suitably substituted alkynes under microwave conditions. Rings in the microwave! Pentasubstituted aromatic rings serve as templates for drug design and can be conveniently prepared by the thermolysis of suitably substituted alkynes under microwave conditions.

Full text of DOI:10.1002/chem.201504421

DOI: 10.1002/chem.201504421
Communication
&
Synthetic Methods
A New Approach for the Synthesis of Highly Substituted Aromatic
Rings: The Alkyne-Mediated Approach
[
a]
[a]
[a]
[a]
Philip J. Parsons,* Daniel R. Jones, Alex C. Padgham, Lewis A. T. Allen,
[
a]
[b]
[a]
Clive S. Penkett, Robert A. Green, and Andrew J. P. White
Dedicated to Dr. Alfred Bader on the occasion of his 91st birthday and in memory of Oxana Bennett
Abstract: Pentasubstituted aromatic rings serve as tem-
plates for drug design and can be conveniently prepared
by the thermolysis of suitably substituted alkynes under
microwave conditions.
Scheme 1. Ley’s synthesis of a tricycle using microwave conditions. Reagents
and conditions: a) DMF, 2008C, MW (81%).
[
10]
The discovery of cascade reactions added a new dimension to
the science of organic synthesis. Such reactions have allowed
new architectures to be synthesised, as well as providing more
concise syntheses of biologically important molecules and nat-
ural products in general. Cascade sequences can proceed by
clic compounds without the use of metal catalysis. Further, it
was found that in general, ene-diynes can cyclise to afford
[
1]
furans and dihydrofurans.
Danheiser and co-workers showed that intermolecular cas-
cade reactions could efficiently yield bicycles and tricycles (de-
[
1]
[11]
invoking a number of mechanisms including thermal, photo-
pending on the nature of the dienophile). The diyne species
[
2]
[3]
[4]
[5]
chemical, radical, metal-catalysed and organocatalysis.
The synthesis of polysubstituted aromatic rings can be chal-
(3) undergoes an intramolecular propargylic ene reaction to
form an intermediate allene followed by the concomitant inter-
molecular Diels–Alder reaction in the presence of a dienophile
to yield the polycyclic product (Scheme 2). Parsons and co-
workers have also demonstrated that an intra/intermolecular
[6]
lenging by traditional methods. In view of the importance of
these polysubstituted aromatic rings, particularly in the phar-
maceutical and agrochemical industries, we elected to design
and carry out new and shorter methods for the preparation of
these highly desirable molecules without the use of transition-
metal-catalyzed cyclisation. Many syntheses of polysubstituted
aromatic rings rely on transition-metal-catalyzed cyclisation re-
actions including gold-, palladium- and cobalt-catalyzed se-
[
12]
reaction can take place.
[
7]
quences.
Ley and co-workers published an elegant methodology
paper, which uses a [2+2+2] cyclisation. A triyne or ene/diyne
precursor undergoes a thermal cyclisation when subjected to
microwave radiation to afford a tricycle with a tetrasubstituted
[8]
benzene core (Scheme 1). Sakai and Danheiser extended this
work to include the use of nitriles, hence forming a pyridine
[
9]
derivative.
Scheme 2. Danheiser’s intermolecular cascade reaction. Reagents and condi-
tions: a) i) PhMe, 1608C; ii) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 258C
(72%).
Parsons and co-workers have demonstrated that a thermal
intramolecular cyclisation can be used to form the lactonamy-
cin core and other interesting fused heterocyclic and carbocy-
Our initial studies focused on a palladium mediated cyclisa-
tion, because we envisaged that a pentasubstituted benzene
ring could be formed in one synthetic operation (Scheme 3).
To our delight, the cyclisation outlined in Scheme 3 gave rise
to the pentasubstituted benzene derivative (8) albeit in 28%
isolated yield. To avoid the use of metals in our cyclisation re-
actions and to attempt to improve the yields of the cyclized
products, we investigated the chemistry of propargyl ethers
(Scheme 4).
[
a] Prof. P. J. Parsons, D. R. Jones, A. C. Padgham, L. A. T. Allen, Dr. C. S. Penkett,
Dr. A. J. P. White
Department of Chemistry, Imperial College London
South Kensington, London, SW7 2AZ (UK)
E-mail: p.parsons@imperial.ac.uk
[
b] R. A. Green
School of Chemistry, University of Southampton
Southampton, SO17 1BJ (UK)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504421.
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Communication
With the ether (9) in hand, we carried out a microwave-as-
sisted cyclisation, and to our delight, the tricycle (10) was
formed in 45% isolated yield (Scheme 4). Alternatively, when
water was used as the reaction solvent, the yield of 10 in-
creased to 50% when subjected to microwave irradiation.
A series of analogues of the furan 9 were prepared (Table 1).
Of particular note is the conversion of the nitrile (35 and 39)
into the pyridines (36 and 40) with loss of the propanone
moiety. The mechanism proposed for this cyclisation is shown
in Scheme 6.
Scheme 3. Palladium-assisted cyclisation of furans. Reagents and conditions:
Pd(OAc) ], PPh , K CO , MeCN (28%).
[
2
3
2
3
Thermal cyclisation of furan 35 resulted in the formation of
the imine 41. The azadiene then underwent a [4+2] cycloaddi-
tion with the pendant furan to give the intermediate tetracycle
42. Fragmentation of 42 resulted in the formation of the
enone 43, which in turn lost acetone to give the pyridine 36.
The aldehyde 30 is also an interesting product, because it
would be difficult to synthesise by other means. The mecha-
nism of the formation of 30 relies on Diels–Alder/fragmenta-
tion chemistry (Scheme 7).
Scheme 4. Thermal cyclisation of alkynes. Reagents and conditions: DMF,
008C, MW, 3 h (45%) or H O, 2008C, MW, 1 h (50%).
2
2
Synthesis of the ether (9) proved to be very straightforward
Scheme 5).
Attempted cyclisation using a palladium-mediated cascade
failed to give the aldehyde (48; Scheme 8).
(
Table 1. Analogues synthesised by using new cyclisation methodology. Reagents and conditions: MeCN, 2008C, MW, 1–6 h.
Entry Starting material
Product
Yield [%] Entry Starting material
Product
Yield [%]
31
1
50
61
8
9
2
3
4
23
32
42
62
62
10
11
5
50
12
13
65
48
6
7
99
32
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Communication
Scheme 8. Attempted palladium-mediated cyclisation to for the aldehyde
derivative. Reagents and conditions: a) [Pd(OAc) ], PPh , K CO , MeCN.
2 3 2 3
The highest yields in the cyclisation reactions were observed
with those starting materials containing either a gem-dimethyl
group, which demonstrates the Thorpe–Ingold effect to en-
hance cyclisation or with oxygen atoms present in the side-
[
13]
chain with appended lone pairs, as an example 25. Entry 6
Table 1) is very interesting due to the high yield of the prod-
Scheme 5. Reagents and conditions: a) AcOH, HOC
6 4 2
H OH, H O, 1308C,
(
3
0 min (93%); b) ethynylmagnesium bromide (83%); c) tert-butyldimethylsil-
uct 26 and the fact that aromatic furan ring formation is fav-
oured in preference of benzene-ring production. This observa-
tion can be explained, because the oxygen atom at position
nine of the chain appended to the furan moiety becomes the
yl chloride (TBSCl), imidazole, 4-dimethylaminopyridine (DMAP; 92%);
d) i) nBuLi; ii) para-formaldehyde (84%); e) i) NaH, THF; ii) propargyl bromide
(
88%).
3
,4-disubstituted furan 26. The suggested mechanism of this
reaction is shown in Scheme 9.
Scheme 6. Proposed mechanism for the formation of the pyridine derivative.
Scheme 9. Proposed mechanism for the formation of the furan derivative.
Cyclisation of the ether 25 gave 26 in very high yield (99%).
The reaction proceeded by an ene reaction followed by
a Diels–Alder reaction to afford a tetracyclic intermediate 50.
The furan 26 was formed, because simple proton loss from 51
gave rise to the aromatic furan rather than the oxidative pro-
cess, which would form a benzene ring. Further, oxidation of
26 would give a highly strained 10p ring system, which is un-
favourable. In the other examples quoted, a carbon atom is
present at position nine, and hence aromatic ring formation is
not possible in a five-membered ring system.
The cyclisation of 9 to 10 was also attempted using a ther-
mal flow technique. The initial results of which are very en-
couraging (these experiments were carried out with colleagues
at the University of Southampton). However, isolated yields
were modest compared with the batch microwave technique.
Scheme 7. Proposed mechanism for the formation of the aldehyde deriva-
tive.
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Communication
Most recently, this methodology has been extended to in-
clude the formation of hexasubstituted benzene rings (38;
entry 12, Table 1). This was achieved by using a substituted
alkyne (37) in place of a terminal alkyne and made little differ-
ence to the yield for the cyclisation step. Its structure was de-
termined by X-ray crystallography (Figure 1) and showed that
the newly appended phenyl ring is orthogonal to the tricycle
giving potential applications in the area of molecular switches,
which may be enhanced by substitution of the ortho or meta
Acknowledgements
Drs. Alfred and Isabel Bader are gratefully acknowledged for
their generous support of this work. An Imperial College stu-
dentship to D.R.J. is also acknowledged. A Professor Parsons
award to A.C.P. has also been donated. We thank Professor
W.B. Motherwell for his interest in this work and his scholarly
contributions over the years. An Oxana Bennett award is also
gratefully acknowledged from Davox Consulting as this was
made available upon her untimely death. We thank Professors
Richard Brown and David Harrowven for their help with the
flow technique and their keen interest in this work. Finally,
Peter Haycock and Lisa Haigh are acknowledged for their help
with NMR and mass spectroscopy, respectively.
[
14]
positions. This also greatly expands the scope of this reac-
tion for the synthesis of drugs templates.
Keywords: alkynes · aromatic rings · cyclization · furan ·
microwave chemistry · thermolysis
[
[
[
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containing a furan group can cyclise in one step to give tricy-
clic compounds. Although the yields of 28, 30, 32 and 34 are
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involve multi-step sequences, and yields would be lower than
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Received: November 3, 2015
Published online on February 11, 2016
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