Highly substituted pyridines via tethered imine-enamine (TIE) methodology

Article abstract of DOI:10.1039/b316107b

A tethered imine-enamine methodology has been developed for the direct conversion of 1,2,4-triazines into highly substituted pyridines via the inverse electron demand Diels-Alder reaction which avoids the need for a discrete aromatisation step. This TIE methodology has also been applied in one pot reaction cascades involving 1,2,4-triazines and utilising MnO ₂-mediated tandem oxidation processes (TOPs).

Full text of DOI:10.1039/b316107b

Highly substituted pyridines via tethered imine–enamine (TIE)
methodology
Steven A. Raw* and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York, UK YO10 5DD. E-mail: sar113@york.ac.uk.
E-mail: rjkt1@york.ac.uk; Fax: +44(0)1904 434 523; Tel: +44(0)1904 432 606
Received (in Cambridge, UK) 10th December 2003, Accepted 22nd December 2003
First published as an Advance Article on the web 27th January 2004
A tethered imine–enamine methodology has been developed for
the direct conversion of 1,2,4-triazines into highly substituted
pyridines via the inverse electron demand Diels–Alder reaction
which avoids the need for a discrete aromatisation step. This
TIE methodology has also been applied in one pot reaction
cascades involving 1,2,4-triazines and utilising MnO2-mediated
tandem oxidation processes (TOPs).
as zwitterion 2d, which resembles the N-oxide 4. We anticipated
that 2d would undergo elimination in situ, leading directly to the
pyridine 3.
The substituted pyridine motif is found in many biologically active
compounds,1 both naturally occurring and synthetic. As part of an
ongoing research programme into the synthesis of heterocyclic and
heteroaromatic compounds,2 we were interested in the formation of
highly substituted pyridines 3. The inverse electron demand Diels–
Alder reaction of 1,2,4-triazines with enamines appeared to be the
method of choice (Scheme 1).3
Scheme 3 Tethered imine as a mimic of a Cope elimination intermediate.
N-Methylethylenediamine was chosen for several reasons: it is
commercially available; the two carbon tether allows a 6-mem-
bered transition state (2d) and it provides the least hindered
enamine possible. Hence, triazine 1a in CHCl3 was treated with
cyclopentanone, N-methylethylenediamine and powdered 4A mo-
lecular sieves and heated to 55 °C or to reflux. Unfortunately, no
reaction was observed by chromatographic analysis. However,
when the reaction was repeated in toluene at reflux, the desired
pyridine 3a was obtained in an isolated yield of 74%.
Scheme 1 Inverse demand Diels–Alder reaction of 1,2,4-triazines.
The tethered imine–enamine concept vindicated, we went on to
investigate the scope of this methodology, first with respect to the
ketone (Table 1). As can be seen, cyclic ketones comprising small
to medium-sized rings (from cyclopentanone to cyclooctanone)
reacted with triazine 1a to give the pyridines 3a–d in good to
quantitative yields (entries i–iv). Much larger rings, such as
cyclododecanone, gave none of the desired pyridine even after
extended reaction times, presumably due to steric factors.
The scope of this methodology was also explored in terms of the
1,2,4-triazine component. A range of triazines (1b,5 1c,6 1d5 and
1e) was synthesised according to literature procedures and all
shown to be good substrates for this chemistry (entries v–ix). The
use of trisubstituted triazine 1b is of particular note in that the
pentasubstituted pyridines 3e (88%) and 3f (82%) were formed
with great efficiency (entries v and vi). The less active 3-heptade-
cyl-5-phenyl-1,2,4-triazine 1e showed no conversion to the pyr-
idine 3j by chromatographic and spectroscopic analysis of the
reaction mixture (entry x). Most interesting amongst these results,
however, is the fact that cyclohexanone proved to be a useful
substrate for the TIE methodology (entries ii, vi, viii), despite the
intermediate dihydropyridines normally being reluctant to undergo
aromatisation.3c–e,4
This methodology, widely used, has two main limitations,
namely the requirement for a preformed enamine and the unusual
stability of the intermediates 2 when using enamines derived from
cyclohexanone.3d Boger et al.3c–e circumvented these difficulties
for 1,2,4-triazine or 3-substituted-1,2,4-triazines: 4A molecular
sieves allow in situ enamine formation and catalyse the elimination
step forming pyridine 3 from dihydropyridine 2, though yields
remain low (19–66%). We found, however, that for our more
substituted 1,2,4-triazines (e.g. 1a), this procedure gave only the
dihydropyridine intermediates (e.g. 2a and 2b), albeit in excellent
yields (Scheme 2). No pyridine was observed in the 1H NMR
spectrum of the crude reaction products. Neither were pyridines 3a
or 3b formed when the reactions were repeated in THF or toluene
at reflux. Aromatisation of 2a to 3a was finally accomplished via
Cope elimination of the corresponding N-oxide.3a,4
This TIE methodology also offers the possibilty of a catalytic
variant.3d,e Thus, when 1b was reacted under the standard
conditions with just 20 mol% diamine for 72 h, pyridine 3e was
produced in a yield of 52% with 24% of 1b being recovered. We are
currently optimising this catalytic procedure.
We have recently published a MnO2-mediated TOP (Tandem
Oxidation Process) for the synthesis of nitrogen containing
heterocyclic and heteroaromatic compounds.2a We were interested
Scheme 2 Reaction of substituted 1,2,4-triazines with enamines.
Ideally, we required a procedure that could be applied to these
more substituted 1,2,4-triazines 1 to allow the formation of the
pyridines 3 in one transformation. We envisaged that the use of a
tethered imine–enamine should provide an intermediate that
mimics the N-oxide 4 (Scheme 3). The dihydropyridine 2c can exist
508
C h e m . C o m m u n . , 2 0 0 4 , 5 0 8 – 5 0 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 1 Synthesis of highly substituted pyridines from 1,2,4-triazines7,8
Entry Triazine
i
Ketone Time
22 h
Product
Yield
Entry
Triazine
Ketone
Time
21 h
Product
Yield
82%
1a
1a
3a
3b
74% vi
79% vii
1b
1c
3f
ii
36 h
22 h
21 h
5 h
6 h
16 h
16 h
36 h
3g
33%
iii
iv
v
1a
1a
1b
3c 100% viii
1c
3h 61%
3d
77% ix
1d
3i
31%
a
3e
88%
x
1e
3j
–
a 1H NMR spectroscopy and chromatographic analysis of the crude reaction product showed only the triazine substrate in the aromatic region.
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365; (c) J. C. McManus, T. Genski, J. S. Carey and R. J. K. Taylor,
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3 (a) H. Neunhoeffer, in Comprehensive Heterocyclic Chemistry II, vol. 6,
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S. Panek and M. M. Meier, J. Org. Chem, 1982, 47, 895; (e) D. L. Boger
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to examine whether such chemistry could be adapted to the TOP
synthesis of 1,2,4-triazines 3 and, in particular, extended protocols
which would allow the production of dihydropyridines (e.g. 2a) and
pyridines (e.g. 3a) in situ from the corresponding amidrazone (e.g.
6a) and a-hydroxyketone (e.g. 5a). We are currently optimising
this TOP–TIE chemistry but now disclose our preliminary results
(Scheme 4). As can be seen, we have obtained good yields for these
cascade reactions, the longest sequence being oxidation; double-
condensation; Diels–Alder; retro-Diels–Alder; aromatisation to
form 3a in an overall yield of 46% from 5a.
4 B. L. Chenard, R. T. Ronau and G. A. Schulte, J. Org. Chem., 1988, 53,
5175.
5 D. J. Hennessy, G. R. Reid, F. E. Smith and S. L. Thompson, Can. J.
Chem., 1984, 62, 721.
6 S. C. Benson, J. L. Gross and J. K. Snyder, J. Org. Chem., 1990, 55,
3257.
Scheme 4 TOP–TIE approaches to dihydropyridines and pyridines.
In conclusion, we have developed an improved protocol for the
direct conversion of 1,2,4-triazines 1 into highly substituted
pyridines 3 which eliminates the need for a second, discrete
aromatisation step. The methodology is operationally simple and
affords the pyridines 3 in good to quantitative yields. We have also
adapted existing TOP methodology from our laboratories to the
direct synthesis of dihydropyridine 2a and pyridine 3a from the
amidrazone 6a and the a-hydroxyketone 5a in situ in good overall
yields. We are currently employing the TIE methodology in target
synthesis.
7 Representative procedure: Synthesis of 3-phenyl-1-(2-pyridyl)-
5,6,7,8-tetrahydroisoquinoline 3b.8 To a solution of 3-(2-pyridyl)-
5-phenyl-1,2,4-triazine 1a (0.10 mmol, 0.023 g) in toluene (1.0 mL) was
added powdered 4A molecular sieves (0.100 g), cyclohexanone (0.60
mmol, 0.062 mL) and N-methylethylenediamine (0.30 mmol, 0.026 mL)
and the mixture heated at reflux for 36 h. It was then cooled, filtered
through a cotton wool plug and concentrated in vacuo, to furnish the
crude product. Purification by column chromatography on silica gel (9 :
1 petrol ether : ethyl acetate) gave the title compound, 3b (0.023 g, 79%)
as a colourless oil: Rf 0.40 (3 : 1 petrol ether : ethyl acetate); nmax (film)
3060, 2932, 2859, 1585, 1566, 1555, 1472, 1416, 1137, 799, 776, 746,
695 cm21; dH (CDCl3) 1.64–1.85 (4 H, m), 2.78–2.92 (4 H, m), 7.17–7.42
(5H, m), 7.69–7.84 (2 H, m), 7.88–8.01 (2 H, m), 8.59 (1 H, dt, J 4.5 Hz,
J 1.5 Hz, pyr-H6); dC (CDCl3) 22.3 (CH2), 23.3 (CH2), 26.9 (CH2), 30.0
(CH2), 120.8 (CH), 122.6 (CH), 124.8 (CH), 126.9 (CH), 128.5 (CH),
128.7 (CH), 130.8. (C), 136.7 (CH), 139.7 (C), 148.2 (C), 148.3 (CH),
153.4 (C), 156.3 (C), 159.8 (C); m/z (CI) 287 (MH+) [HRMS (CI) calcd.
for C20H19N2 287.1548. Found 287.1544 (1.4 ppm error)].
8 All new compounds were fully characterised spectroscopically and by
HRMS.
We are grateful the EPSRC for postdoctoral support (ROPA
fellowship, S. A. R)
Notes and references
1 For examples see: M. S. Puar, A. K. Ganguly, A. Afonso, R. Brambilla,
P. Mangiaracina, O. Sarre and R. D. MacFarlane, J. Am. Chem. Soc.,
1981, 103, 5231; G. Beck, K. Kesseler, E. Baader, W. Bartmann, A.
Bergmann, E. Granzer, H. Jendrella, B. v. Kerekjarto, R. Krause, E.
C h e m . C o m m u n . , 2 0 0 4 , 5 0 8 – 5 0 9
509