Double intramolecular Diels-Alder reaction of α,β-unsaturated hydrazones: A new route to 2,2′-bipyridines

Article abstract of DOI:10.1039/a901641d

Heating the 1,3-diynyl bis-α,β-unsaturated hydrazones 3, 6 and 10 results in double intramolecular Diels-Alder reaction of the 1-azadienes, and after aromatisation by loss of dimethylamine, the formation of bipyridines 11-14.

Full text of DOI:10.1039/a901641d

Double intramolecular Diels–Alder reaction of a,b-unsaturated hydrazones: a
new route to 2,2A-bipyridines
Nicholas Bushby,a Christopher J. Moody,*ab David A. Riddickb and Ian R. Waldronc
a School of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD. E-mail: c.j.moody@ex.ac.uk
b Department of Chemistry, Loughborough University, Loughborough, Leicestershire, UK LE11 3TU
c
Zeneca Pharmaceuticals, Hurdsfield Industrial Estate, Macclesfield, UK SK10 2NA
Received (in Liverpool, UK) 26th February 1999, Accepted 15th March 1999
Heating the 1,3-diynyl bis-a,b-unsaturated hydrazones 3, 6
and 10 results in double intramolecular Diels–Alder reaction
of the 1-azadienes, and after aromatisation by loss of
dimethylamine, the formation of bipyridines 11–14.
The final substrate investigated was derived from hex-5-ynol
7, the homocoupling of the terminal acetylene being carried out
first (Scheme 4). Thus Glaser–Eglinton coupling of the alkyne
gave the corresponding 1,3-diyne 8; oxidation to the corre-
sponding aldehyde 9 was achieved using o-iodylbenzoic acid
(IBX) in DMSO.12 The hydrazone 10 was prepared directly by
reaction of 9 with diethoxyphosphonoethanal N,N-dimethyl-
hydrazone.8
In the 110 years since its first preparation, 2,2A-bipyridine has
been extensively used as a ligand in organometallic chemistry.1
Indeed 2,2A-bipyridine is one of the best known, and most
effective bidentate ligands for a range of metals, and in recent
years chiral bipyridine ligands have found wide use in
asymmetric synthesis.2 We now report a new route to 2,2A-
bipyridines based on the double intramolecular Diels–Alder
reaction of 1,3-diynyl bis-a,b-unsaturated hydrazones (Scheme
1).
The preparation of 6-membered ring heterocyclic compounds
by the hetero Diels–Alder reaction is now a common tactic in
organic synthesis,3 and the use of azadienes as components in
such reactions is established.4 One useful route to pyridine
derivatives is the Diels–Alder reaction of a,b-unsaturated
hydrazones with various dienophiles, and since the pioneering
work of Ghosez,5 these 1-azadienes have been used in both
inter- and intra-molecular Diels–Alder approaches to pyridine
derivatives.6–8 The intramolecular Diels–Alder (IMDA) reac-
tion of a,b-unsaturated hydrazones with alkynes, first reported
in 1988,8 is a particularly attractive route to annelated pyridines
since the initial Diels–Alder adduct readily aromatises by loss
of dimethylamine. Therefore we decided to adapt this procedure
to the direct synthesis of annelated bipyridines by the simple
incorporation of an oxidative homocoupling step giving a
1,3-diyne which would then undergo the desired double IMDA
reaction (Scheme 1).
The substrates for the double IMDA reactions were prepared
by straightforward routes (Schemes 2–4). The first route
involved the alkylation of salicylaldehyde with propargyl
chloride (prop-2-ynyl chloride) to give the corresponding
aldehyde 1. Subsequent homologation of the aldehyde with
either a,a-bis(trimethylsilyl)-N-tert-butylacetaldimine,9 or
with acetylmethylenetriphenylphosphorane gave the a,b-un-
saturated aldehydes and ketones 2. Hydrazone formation
followed by Glaser–Eglinton coupling with copper(ii) acetate10
then gave the first substrates 3 for the double IMDA reaction
(Scheme 2).
Scheme 2 Reagents and conditions: i, HC·CCH2Cl, K2CO3, EtOH; ii, (R =
H) t-BuNNCHCH(TMS)2, ZnBr2, THF, followed by aq. ZnCl2; ** (R =
Me) prepared from salicylaldehyde by reaction with Ph3PNCHCOMe
(91%), followed by HC·CCH2Cl, K2CO3, EtOH (76%); iii, Me2NNH2,
MgSO4, CH2Cl2; iv, Cu(OAc)2, pyridine, MeOH, ether.
The IMDA substrate 6 was prepared from the known
hydrazone 411 by propargylation, and oxidative homocoupling
of the alkyne (Scheme 3).
Scheme 3 Reagents and conditions: i, HC·CCH2Cl, KH, DMF; ii,
Cu(OAc)2, pyridine, MeOH, ether.
Scheme 1 (Alkynes drawn non-linear for clarity.)
Chem. Commun., 1999, 793–794
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Scheme 4 Reagents and conditions: i, Cu(OAc)2, pyridine, MeOH, ether; ii,
IBX, DMSO; iii, (EtO)2POCH2CHNNNMe2, BuLi, THF.
With a range of substrates in hand, the key double IMDA
reactions were carried out. Heating the 1,3-diyne bis-hydrazone
3a in boiling xylene gave the desired annelated 2,2A-bipyridine
as the only isolable product (yield of crude material 60–87%),
though considerable losses occurred in purification. The
substrate 3b derived from the a,b-unsaturated ketone was much
less satisfactory in the double IMDA reaction; azadiene 3b gave
only 17% of a bipyridine after prolonged heating in mesitylene,
though the product was isolated as the mono-oxidation product,
the monolactone 12 formed by oxidation at the 5-position of one
Scheme 5 (** Isolated as an oxidation product, the monolactone 12 formed
by oxidation at the 5-position of one of the benzopyrano[3,4-c]pyridine
rings.)
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of the benzopyrano[3,4-c]pyridine rings. The N-benzoyl com-
pound 6, a nitrogen analogue of 3a, underwent smooth double
IMDA on heating in xylene to give, after loss of dimethylamine,
the 4,4A-bi(benzo[c][2,7]naphthyridine) 13 in 68% yield. Fi-
nally in the series where the azadiene fragment is connected to
the alkyne dienophile by a simple alkyl chain, substrate 10
readily underwent the desired double IMDA reaction in boiling
xylene to give the 1,1A-bi(cyclopenta[c]pyridine) 14 in good
yield (Scheme 5).
We thank the EPSRC for support of this work, and the
EPSRC and Zeneca Pharmaceuticals for a CASE Award
(D. A. R.).
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Communication 9/01641D
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Chem. Commun., 1999, 793–794