Improved and practical procedures for the preparation of highly substituted pyridines and pyridazines via silica-mediated aromatisation

Article abstract of DOI:10.1055/s-2007-984918

A new and straightforward procedure is described for the preparation of highly substituted pyridines and pyridazines. The method involves a Diels-Alder/retro-Diels-Alder sequence leading to dihydropyridine or related intermediates, which can be aromatized

Full text of DOI:10.1055/s-2007-984918

LETTER
2217
Improved and Practical Procedures for the Preparation of Highly Substituted
Pyridines and Pyridazines via Silica-Mediated Aromatisation
Preparation of
H
ig
i
hly Sub
c
stituted Py
o
ridines
a
nd P
l
yridazi
a
nes Catozzi,a William J. Bromley,a Pierre Wasnaire,a Mairi Gibson,b Richard J. K. Taylor*a
a
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
b
Neurology & GI CEDD, GlaxoSmithKline R&D, New Frontiers Science Park, Harlow CM19 5AW, UK
Fax +44(1904)434523; E-mail: rjkt1@york.ac.uk
Received 27 April 2007
R5
Abstract: A new and straightforward procedure is described for the
preparation of highly substituted pyridines and pyridazines. The
method involves a Diels–Alder/retro-Diels–Alder sequence leading
to dihydropyridine or related intermediates, which can be aroma-
tized to pyridines and pyridazines by treatment with silica gel. The
value of this procedure has been demonstrated with a one-step
synthesis of an E-ring-modified steroid.
R1
R4
R1
R1
O
NR2
R5
R4
NR2
– N2
N
N
N
2
N
(3 equiv)
R5
N
N
R4
N
R2
R2
R2
pyrrolidine (3 equiv),
4 Å mol. sieves, ∆
H
H
R3
R3
R3
1
3
4
Key words: Diels–Alder reaction, heterocycles, pyridines, pyrid-
azines, fused-ring systems, silica-mediated aromatization
MCPBA
Method A: R5
∆
(ref. 2a)
R4
(6 equiv)
R5
R1
, MeNHCH2CH2NH2 (3 equiv),
O
The wide-ranging biological activity associated with
many pyridine derivatives, both naturally occurring and
synthetic, ensures that improved methods for the prepara-
tion of these important heterocyclic systems are of
continuing interest.1 As part of an ongoing research pro-
gramme to develop efficient and reliable methodologies
for the synthesis of heterocyclic and heteroaromatic com-
pounds, we have recently investigated routes to highly
substituted pyridine derivatives.2 Initial studies utilised
toluene, ∆
R5
R4
2
N
R2
Method B:
(ref. 2b)
R3
, pyrrolidine (1 equiv),
R4
neat, MW
O
5
2
(1 equiv)
Scheme 1
reactions between polysubstituted 1,2,4-triazines 13 and In this communication we describe an improved one-pot
enamines formed by reaction of ketones 2 with pyrroli- procedure for the synthesis of highly substituted pyridines
dine using Boger’s in situ protocol.4 Under standard ther- which simply utilises silica gel to facilitate the elimina-
mal conditions, an inverse electron-demand Diels–Alder/ tion–aromatisation of dihydropyridines 4 and which can
retro-Diels–Alder sequence, via intermediate 3, proceed- be easily adapted to larger-scale processes (Scheme 2).
ed smoothly but in situ elimination–aromatisation was not This improved procedure was discovered when trying to
observed and dihydropyridines 4 were isolated in excel- isolate dihydropyridines 4. It was found that after slow
lent yield (Scheme 1). Such observations concerning the chromatography through a column of silica gel, an ap-
difficulty of aromatising dihydropyridines 4 have been preciable quantity of pyridine 5 was obtained. Following
described before and the use of Cope elimination to this serendipitous observation, and after optimisation of
achieve aromatisation has been reported.2b,5
reaction conditions, an improved thermal approach to the
preparation of highly substituted pyridines was devel-
oped. The essence of this new route consists of the
addition of a small quantity of silica gel (Fluka, flash
chromatography silica gel 60, 220–440 mesh) to the reac-
tion mixture, made up of 1,2,4-triazine 1, 1.5 equivalents
of ketone 2, and pyrrolidine (6, Scheme 2).6
In order to overcome this limitation and to develop one-
pot routes to highly substituted pyridines, we went on to
design first a novel tethered imine–enamine (TIE) ap-
proach (Method A)2a and subsequently to develop a sol-
vent-free microwave (MW) procedure (Method B).2b The
microwave-assisted, solvent-free route proved useful for
the conversion of 1,2,4-triazines into a wide range of
highly substituted pyridines in good to excellent yield
with relatively short reaction times and stoichiometric use
of ketone and amine. However, the MW method is limited
in terms of scale.
H
N
O
R4
R1
R1
R5
R5
R4
N
N
N
6
2
N
R2
R2
toluene, ∆,
silica
R3
R3
2–10 h
SYNLETT 2007, No. 14, pp 2217–2221
Advanced online publication: 23.07.2007
0
3
.0
9
.2
0
0
7
50–99%
5
1
DOI: 10.1055/s-2007-984918; Art ID: D18507ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

2218
N. Catozzi et al.
LETTER
Table 1 Comparison of the One-Pot Methods for Pyridine Preparation
O
N
N
2a n = 1
2b n = 2
n
N
N
N
N
R2NH
n
1a
5a n = 1
5b n = 2
Entry
1
Ketone
Thermal conditionsa
TIE (method A)b
Microwave conditions
(method B)a
Silica methoda
O
4 Å mol. sieves, CHCl3,
62 °C, 48 h, 0%
4 Å mol. sieves, PhMe,
120 °C, 22 h, 74%
Neat, 120 °C, 20 min,
88%
Silica, PhMe, 120 °C, 5 h,
99%
2a
O
4 Å mol. sieves, PhMe,
120 °C, 36 h, 79%
Neat, 150 °C, 30 min,
75%
Silica, PhMe, 120 °C, 5 h,
99%
2
–
2b
a R2NH = pyrrolidine.
b R2NH = N-methylethane-1,2-diamine.
The overall effect of the silica is to increase the rate of the The scope of this improved methodology was established
aromatisation–elimination step (see Scheme 1) without by carrying out the reaction with several mono-, di- and
interfering with other phases of the cascade sequence. It trisubstituted triazines 1 in combination with cyclopen-
seems likely that the heterogeneous, slightly acidic sur- tanone (2a), cyclohexanone (2b), and valeraldehyde (2c,
face of the silica facilitates elimination–aromatisation.7,8 Table 2). In all of the examples studied, the yields were
The reaction proceeds in a range of solvents (toluene, better or comparable to those obtained using the TIE or
chloroform, dichloromethane, and ethyl acetate) and does MW approaches.2a–c The previously observed reactivities
not seem to require strictly anhydrous conditions. How- were mirrored in the silica method: 5-phenyl-3-(pyridin-
ever, anhydrous toluene is the solvent of choice. The 2-yl)-1,2,4-triazine (1a) and 5,6-di(furan-2-yl)-3-(pyri-
results collected in Table 1 provide a comparison of the dine-2-yl)-1,2,4-triazine (1d) were most reactive, while
various procedures for the one-pot conversion of triazine the 5-phenyl-1,2,4-triazine-3-carboxylic acid ethyl ester
1a into substituted pyridines 5a and 5b using cyclopen- (1b) and the 1,2,4-triazine-3-carboxylic acid ethyl ester
tanone (2a) and cyclohexanone (2b), respectively. As can (1e) were less reactive, nevertheless providing good
be seen, the silica method gives quantitative yields, even yields. It is worth noting that in some cases (entries 3, 6,
with the less reactive cyclohexanone (2b),4e with reaction 7, 8, and 9), higher reaction temperatures (160 °C) and a
times of only 5 hours. The silica reactions in Table 1 were sealed tube were necessary in order to achieve optimal
carried out on a 0.2 mmol scale but larger-scale conver- results.
sions are straightforward: thus, triazine 1a (2.5 mmol)
with cyclopentanone (2a) gave the desired pyridine 5a in
89% isolated yield.
16'
18'
15'
17'
14'
13'
O
5'
6'
18
H
12
17
1'
N
11
9
H
H
Py
9
H13
1
4
2'
9'
14
16
8'
HO
10
5
2
N
N
N
8
7
15
10'
H
H
7'
N
3
1) pyrrolidine 6,
xylene, ∆,
11'
Ph
HO
12'
6
10 h, sealed tube
2) silica, 5 h
1a
10 (67%)
Scheme 3
Synlett 2007, No. 14, 2217–2221 © Thieme Stuttgart · New York

LETTER
Preparation of Highly Substituted Pyridines and Pyridazines
2219
Table 2 Scope of Silica Method for Pyridines Synthesis
H
O
N
R5
R1
R1
+
R4
R5
R4
N
N
N
2
N
6
R2
R2
toluene, ∆,
silica
R3
R3
1
5
Entry
1
Triazine and ketone
Producta,b
Entry
6
Triazine and ketone
Producta,b
1a R1 = Py
R2 = Ph
1e R1 = CO2Et
R2 = H
Py
CO2Et
N
R3 = H
R3 = H
N
Ph
5a;d 120 °C, 5 h, 99%
(2a) Cyclopentanone
(2a) Cyclopentanone
5f;c 160 °C, 10 h, 50%
1a R1 = Py
R2 = Ph
1c R1 = Py
R2 = H
Py
N
Py
R3 = H
R3 = Ph
N
2
3
7
8
Ph
Ph
5b;d 120 °C, 5 h, 99%
(2b) Cyclohexanone
(2a) Cyclopentanone
5g;c 160 °C, 10 h, 70%
1a R1 = Py
R2 = Ph
1d R1 = Py
R2 = Fur
Py
N
Py
R3 = H
R3 = Fur
N
Fur
Ph
Fur
(2c) Valeraldehyde
5c;c 160 °C, 10 h, 72%
5h;c 160 °C, 2 h, 99%
(2a) Cyclopentanone
1b R1 = CO2Et
R2 = Ph
CO2Et
1d R1 = Py
R2 = Fur
Py
N
R3 = H
N
R3 = Fur
4
5
9
Ph
Fur
Fur
5d;d 120 °C, 10 h, 77%
(2b) Cyclohexanone
5i;c 160 °C, 5 h, 89%
(2a) Cyclopentanone
1b R1 = CO2Et
R2 = Ph
CO2Et
N
R3 = H
Ph
5e;d 120 °C, 10 h, 73%
(2b) Cyclohexanone
a Previously reported yield for TIE method (ref. 2a): 5a 74%, 5b 79%, 5c n/a, 5d 33%, 5e 61%, 5f 31%, 5g n/a, 5h 85%, 5i 82%.
b Previously reported yield for MW method (ref. 2b): 5a 77%, 5b 73%, 5c 81%, 5d 67%, 5e n/a, 5f n/a, 5g 64%, 5h 91%, 5i 64%.
c Reaction conditions: oil bath 160 °C, toluene, sealed tube.
d Reaction conditions: oil bath 120 °C, toluene, flask equipped with condenser.
Similar inverse electron-demand Diels–Alder/retro- Recently, Potter et al. reported the preparation of E-ring-
Diels–Alder–aromatisation sequences have been em- modified steroids for evaluation as inhibitors of 17b-hy-
ployed to convert tetrazines into pyridazines9 and we have droxysteroid dehydrogenase (17b-HSD) and commented
employed the TIE procedure to facilitate the aromatisa- on the inefficiency of routes to pyridine annelated
tion step.2d Table 3 illustrates that 3,6-diphenyl-1,2,4,5- analogues.10 Inspired by this work we decided to utilise
tetrazine (7a) and 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine the silica gel method to prepare a novel steroidal pyridine
(7b) can be converted into the corresponding pyridazines (Scheme 3).
8a–c using the silica variant.
Thus, triazine 1a was reacted with estrone (9) and pyrrol-
idine in a sealed tube for 10 hours, followed by treatment
with silica in order to afford the novel E-ring-modified
Synlett 2007, No. 14, 2217–2221 © Thieme Stuttgart · New York

2220
N. Catozzi et al.
LETTER
References and Notes
Table 3 Scope of Silica Method for Pyridazine Synthesis
H
(1) For recent references, see: (a) Bagley, M. C.; Glover, C.
Tetrahedron 2006, 62, 66. (b) Belhadj, T.; Nowicki, C.;
Moody, C. J. Synlett 2006, 3033. (c) Kozhevnikov, V. N.;
Kozhevnikov, D. N.; Shabunina, O. V.; Rusinov, V. L.;
Chupakhin, O. N. Tetrahedron Lett. 2005, 46, 1521.
(d) Kozhevnikov, V. N.; Kozhevnikov, D. N.; Shabunina, O.
V.; Rusinov, V. L.; Chupakhin, O. N. Tetrahedron Lett.
2005, 46, 1791. (e) Altuna-Urquijo, M.; Stanforth, S. P.;
Tarbit, B. Tetrahedron Lett. 2005, 46, 6111; and references
therein.
(2) (a) Raw, S. A.; Taylor, R. J. K. Chem. Commun. 2004, 508.
(b) Fernandez Sainz, Y.; Raw, S. A.; Taylor, R. J. K. J. Org.
Chem. 2005, 70, 10086. (c) Laphookhieo, S.; Jones, S.;
Raw, S. A.; Fernández Sainz, Y.; Taylor, R. J. K.
Tetrahedron Lett. 2006, 47, 3865. (d) See also (pyridazine
synthesis) Geyelin, P. H.; Raw, S. A.; Taylor, R. J. K.
ARKIVOC 2007, (xi), 37.
O
N
R5
R1
R1
R4
R5
R4
6
2
N
N
N
N
N
N
toluene, ∆,
silica
R3
R3
7
8
Entry
1
Tetrazine and ketone
Producta
Ph
N
N
7a R1 = Ph
R3 = Ph
Ph
(3) For recent applications of triazines, see: (a) Vzorov, A. N.;
Bhattacharyya, D.; Marzilli, L. G.; Compans, R. W.
Antiviral Res. 2005, 65, 57. (b) Wang, X.-L.; Chao, H.; Li,
H.; Hong, X.-L.; Liu, Y.-J.; Tan, L.-F.; Ji, L.-N. Inorg.
Biochem. 2004, 98, 1143. (c) Hudson, M. J.; Drew, M. G.
B.; Foreman, M. R. St. J.; Hill, C.; Huet, N.; Madic, C.;
Youngs, T. G. A. Dalton Trans. 2003, 1675. (d) Abdel-
Rahman, R. M. Pharmazie 2001, 56, 195. (e) Croot, P. L.;
Hunter, K. A. Anal. Chim. Acta 2000, 406, 289.
(4) (a) Boger, D. L.; Weinreb, S. N. Hetero Diels–Alder
Methodology in Organic Synthesis; Academic Press:
London, 1987, Chap. 10, 300. (b) Boger, D. L. Chem. Rev.
1986, 86, 781. (c) Boger, D. L. Tetrahedron 1983, 39, 2869.
(d) Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179.
(e) Boger, D. L.; Panek, J. S.; Meier, M. M. J. Org. Chem.
1982, 47, 895.
(2a) Cyclopentanone
8a; 120 °C, 10 h, 98%
Ph
N
N
7a R1 = Ph
2
R3 = Ph
Ph
(2b) Cyclohexanone
8b; 120 °C, 15 h, 82%
Py
N
N
3
7b R1 = Ph
R3 = Py
Py
(5) Chenard, B. L.; Ronau, R. T.; Schulte, G. A. J. Org. Chem.
1988, 53, 5175.
(6) Representative Procedure
(2b) Cyclohexanone
8c; 160 °C, 4 h, 50%
a Previously reported yield for TIE method (ref. 2d): 11a 93%, 11b
85%, 11c 41%.
A suspension of triazine 1a (50 mg, 0.21 mmol), pyrrolidine
(6, 26 mL, 0.31 mmol), cyclopentanone (2a, 27 mL, 0.31
mmol) and silica (Fluka, flash chromatography silica gel 60,
220–440 mesh, 200 mg) in toluene (4 mL) was heated under
reflux for 5 h. The reaction mixture was cooled to r.t., diluted
with EtOAc (6 mL), and stirred an additional 20 min at the
same temperature. The mixture was then filtered through a
Celite pad, concentrated and the residue obtained was eluted
from a column of silica (PE–EtOAc, 5:1) yielding the
desired pyridine 5a (57 mg, 99%); data were consistent with
those reported in ref. 2b.
steroid 10 in 67% yield (37% in refluxing conditions).11 It
should be noted that in this example an efficient conver-
sion was observed only when the silica gel was added
after the formation of the dihydropyridine intermediate12
(in all the other cases all components were introduced at
the commencement of the reaction).
In conclusion, a straightforward one-pot procedure for
the preparation of highly substituted pyridines and
pyridazines has been developed based on an in situ silica-
mediated elimination–aromatisation step. The effective-
ness and general applicability of this protocol has been
demonstrated, indicating that the ‘silica approach’ is the
method of choice for the preparation of highly substituted
pyridines, especially on preparative scale.
(7) Banerjee, A. K.; Laya, M. S.; Vera, W. J. Russ. Chem. Rev.
2001, 70, 971.
(8) Similar reactions were carried out in which the silica gel was
replaced by stoichiometric amounts of HCl, MeCOOH,
Et3N, or 1,5-diazabicyclo[4.3.0]non-5-ene (DBU). None of
these reactions produced pyridines 5 in significant
quantities.
(9) (a) Helm, M. D.; Moore, J. E.; Plant, A.; Harrity, J. P. A.
Angew. Chem. Int. Ed. 2005, 44, 3889. (b) Atfah, M. A.
J. Heterocycl. Chem. 1989, 26, 717.
(10) Fischer, D. S.; Allan, G. M.; Bubert, C.; Vicker, N.; Smith,
A.; Tutill, H. J.; Wood, A. P. L.; Packham, G.; Mahon, M.
F.; Reed, M. J.; Potter, B. V. L. J. Med. Chem. 2005, 48,
5749; and references therein.
(11) The structure of the cycloaddition product 10 was assigned
using NOE and HMBC NMR experiments.
Acknowledgment
We are grateful to the EPSRC (N.C. and W.J.B.), GlaxoSmithKline
(W.J.B.) and Fond Special de Recherche, Université Catholique de
Louvain (P.W.) for financial support.
(12) A solution of triazine 1a (100 mg, 0.43 mmol), pyrrolidine
(6, 52 mL, 0.64 mmol) and estrone (9) (113 mg, 0.42 mmol)
in xylene (4 mL) was heated in a screwcapped tube at 160 °C
Synlett 2007, No. 14, 2217–2221 © Thieme Stuttgart · New York

LETTER
for 10 h. The reaction mixture was cooled to r.t., silica
Preparation of Highly Substituted Pyridines and Pyridazines
2221
m, C-16¢-H), 7.29 (1 H, ddd, J = 1.0, 4.8, 7.6 Hz, C-10¢-H),
7.18 (1 H, d, J = 8.4 Hz, C-1-H), 6.63 (1 H, dd, J = 2.6, 8.4
Hz, C-2-H), 6.57 (1 H, d, J = 2.6 Hz, C-4-H), 4.80 (1 H, s,
OH), 3.45 (1 H, dd, J = 5.8, 16.1 Hz, H-12a), 3.04 (1 H, dd,
J = 11.9, 16.1 Hz, H-12b), 2.90 (2 H, m, H-6a,b) 2.47 (1 H,
m), 2.35 (2 H, m), 2.12 (1 H, m), 1.77 (4 H, m), 1.50 (1 H,
m), 1.07 (3 H, s, CH3). 13C NMR (100 MHz, CDCl3): d =
166.2, 158.6, 155.2, 153.8, 151.6, 148.5, 140.0, 138.71,
136.7, 136.4, 132.3, 128.6, 127.1, 126.3, 123.6, 122.9,
115.4, 113.3, 112.9, 56.1, 45.8, 44.3, 37.8, 34.6, 32.2, 29.6,
27.7, 26.4, 19.0. MS (EI): m/z (%) = 459.2 (100) [M + 1].
HRMS (EI): m/z calcd for C32H31N2O [M + 1]: 459.2436;
found: 459.2431 (–3.2 ppm error).
(Fluka, flash chromatography silica gel 60, 220–440 mesh)
was added and the yellow suspension obtained refluxed for
an additional 5 h. The mixture was then cooled to r.t., filtered
through a Celite pad, concentrated and the residue obtained
was eluted from a column of silica (CHCl3–EtOAc, 7:1)
yielding the desired 3-hydroxy-estra-1,3,5 (10)-triene-
[17,16-c]-(2¢-pyrid-2-yl)-(6¢-phenyl)-pyridine (10, 129 mg,
67%) as a white solid, mp 261–262 °C (toluene–hexane);
[a]D25 –50.0 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3):
d = 8.71 (1 H, ddd, J = 0.9, 1.8, 4.8 Hz, C-9¢-H), 8.43 (1 H,
ddd, J = 0.9, 1.0, 7.9 Hz, C-12¢-H), 8.13 (2 H, m, C-14¢-H,
C-18¢-H), 7.83 (1 H, ddd, J = 1.8, 7.6, 7.9 Hz, C-11¢-H), 7.56
(1 H, s, C-5¢-H), 7.49 (2 H, m, C-15¢-H, C-17¢-H), 7.41 (1 H,
Synlett 2007, No. 14, 2217–2221 © Thieme Stuttgart · New York

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