The Bohlmann-Rahtz route to functionalised pyridine scaffolds and their use in library synthesis

Article abstract of DOI:10.1016/S0040-4039(03)00034-0

The Bohlmann-Rahtz reaction has been used to prepare 2,3,6-trisubstituted pyridines suitable for use in library synthesis. The synthesis of piperidine substituted nicotinic acid derivative 9 has been optimised and carried out on a large scale to give ca. 500 g of scaffold which was used in the generation of the pyridine library 11.

Full text of DOI:10.1016/S0040-4039(03)00034-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1627–1629
The Bohlmann–Rahtz route to functionalised pyridine scaffolds
and their use in library synthesis
Katherine E. Bashford,a Matthew B. Burton,b Stuart Cameron,b Anthony L. Cooper,b
Rebecca D. Hogg,b Peter D. Kane,b David A. MacManus,b Christopher A. Matrunola,b
Christopher J. Moody,a,* Avril A. B. Robertsonb,* and Mark R. Warneb
aSchool of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
bTripos Receptor Research Ltd., Bude-Stratton Business Park, Bude, Cornwall EX23 8LY, UK
Received 9 December 2002; accepted 20 December 2002
Abstract—The Bohlmann–Rahtz reaction has been used to prepare 2,3,6-trisubstituted pyridines suitable for use in library
synthesis. The synthesis of piperidine substituted nicotinic acid derivative 9 has been optimised and carried out on a large scale
to give ca. 500 g of scaffold which was used in the generation of the pyridine library 11. © 2003 Elsevier Science Ltd. All rights
reserved.
The wide ranging biological activity associated with
many pyridine derivatives, both naturally occurring and
synthetic, ensures that the synthesis of this important
ring system remains a topic of current interest.1,2 In
addition, simple low molecular weight heterocyclic
molecules make ideal scaffolds on which to base the
high throughput synthesis of libraries of drug-like com-
pounds. Recent examples include the use of 1,2,5-thia-
diazolidin-3-one-1,1-dioxide and pyrimidine scaffolds in
the synthesis of serine proteinase and kinase inhibitors
respectively,3,4 and the use of simple pyridine scaffolds
to generate libraries of inhibitors of HIV-1 protease
and Factor Xa.5,6 In a programme designed to develop
new heterocyclic scaffolds for library synthesis, the
trisubstituted pyridines 1 (Fig. 1) containing three
points of potential diversity seemed particularly
attractive.
Although many synthetic routes to pyridines already
exist, the synthesis of 2,3,6-trisubstituted derivatives
first reported by Bohlmann and Rahtz in 1957 is partic-
ularly versatile,7 although surprisingly it has been little
used. We have applied it to the synthesis of the pyridine
core of the promothiocin antibiotics,8,9 and Baldwin
and co-workers have used similar chemistry in the
synthesis of novel heterocyclic substituted a-
aminoacids.10,11 Most recently Bagley and co-workers
have modified the original reaction conditions and
applied them to the synthesis of various pyridine based
heterocyclic systems.12–17 We now report the applica-
tion of the Bohlmann–Rahtz reaction to the synthesis
of the 2,3,6-trisubstituted pyridines, and their subse-
quent use in the generation of libraries based on the
general structure 1.
Three initial targets 2–4 containing just two points of
diversity and different types of linker L were chosen to
exemplify the methodology, although only one (the
piperidine derivative 4) was used in library generation
(q.v.). The pyridines were successfully obtained on a
small scale (0.5–1.0 mmol) by reacting the correspond-
ing enamine 5 with the alkynone 6 (5 equiv.) under the
Figure 1. R1, R2, R3 points of diversity; X=O, NH; L=
linker.
* Corresponding authors. Fax: +44 1392 263434 (C.J.M.); fax: +44
1288 359222 (A.A.B.R.); e-mail: c.j.moody@ex.ac.uk; aroberts@
tripos.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00034-0

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K. E. Bashford et al. / Tetrahedron Letters 44 (2003) 1627–1629
has been carried out on a large scale to give ca. 500 g
of the pyridine scaffold 9.
Adopting
a product-based, reagent-biased library
design approach and utilising both ChemSpace™ and
ChemCore™,19 a diverse selection of drug-like products
were computationally selected for use as a general
screening library. Reagent biasing was applied to the
virtual library by implementing filters from a knowl-
edge base maintained in ChemCore™, removing
reagents containing competing functionality and chemi-
cal substructures classified as undesirable in drug-like
molecules. Following reagent filtering, the virtual
library was filtered to include products with physical
property criteria in the spirit of ‘drug-like’ molecules as
described by Lipinski.20 In particular products were
constrained to have a molecular weight below 550 and
a C log P56.0. Finally, to reduce the virtual library to
a size that was practical for synthesis, a selection
algorithm utilising both Unity 2D fingerprints and
Topomers was applied to the virtual library.21–23
Scheme 1.
Following from this design process, the acid 9 was
coupled to a range of amines24 to provide 14 protected
intermediates in 61–87% yield on a 100 mmol scale.
Subsequent treatment with HCl in dioxan removed the
tert-butoxycarbonyl protecting group for further cou-
pling reactions. Coupling of the deprotected intermedi-
ates 10 with various active species was performed on a
0.22 mmol scale and all products were analysed (after
aqueous work-up but no further purification) by LC-
MS at 254 nm. The scope of the library was firstly
exemplified by reaction of 10 (R1=benzyl) with two
carboxylic acids [two amides, 93 and 95% purity], two
acid chlorides [two amides, 85 and 98% purity], two
sulfonyl chlorides [two sulfonamides, 95 and 97%
purity], two isocyanates [two ureas, 85 and 98% purity],
two isothiocyanates [two thioureas, both 91% purity],
and two aldehydes under reductive amination condi-
tions [two tertiary amines, 83 and 94% purity] to give
12 example library compounds 11 (Scheme 3). A larger
library was then constructed with all 14 R1 intermedi-
ates 10 reacted with 148 carboxylic acids [2072 amides,
1140 compounds were ]70% purity] and 11 isothio-
cyanates [154 thioureas, 86 compounds were ]70%
purity].
Scheme 2.
original Bohlmann–Rahtz conditions in ethanol at
room temperature, followed by heating neat to a higher
temperature (Scheme 1).
The synthesis of the pyridine 4 was then optimised for
use on a large scale (Scheme 2). Thus N-Boc-
isonipecotic acid was converted into the b-ketoester 7
by coupling to Meldrum’s acid followed by
ethanolysis18 in excellent yield. Reaction with ammo-
nium acetate in ethanol gave the enamine 8 in high
yield and purity. In order to reduce the number of
equivalents of alkynone needed, we, like others,12–17
have modified the conditions for the Bohlmann–Rahtz
reaction, and found that the enamine 8 reacted with
butynone in boiling ethanol to give the pyridine 4 in
77% yield. Finally hydrolysis of the ester 4 gave the
acid 9 for use in library synthesis. Using the modified
conditions described in Scheme 2, the whole sequence
In summary, we have developed an efficient large scale
synthesis of the pyridine scaffold 9 containing two
points of diversity and demonstrated its use in library
synthesis.
Scheme 3.

K. E. Bashford et al. / Tetrahedron Letters 44 (2003) 1627–1629
1629
Acknowledgements
Pritchard, G. J.; Tang, L. T. J. Chem. Soc., Perkin Trans.
1 2000, 2311–2316.
12. Bagley, M. C.; Dale, J. W.; Bower, J. Synlett 2001,
1149–1151.
We thank the EPSRC and Tripos Receptor Research
Ltd for a CASE award (to K.E.B.), and the EPSRC
Mass Spectrometry Service at Swansea for mass spec-
tra. We also thank Janet Dawson, Sandra Dumas,
Grahame Harden, Veronica O’Connor, Martin Smith
and Mike Webb for providing analytical data in sup-
port of this paper.
13. Bagley, M. C.; Dale, J. W.; Hughes, D. D.; Ohnesorge,
M.; Phillips, N. G.; Bower, J. Synlett 2001, 1523–1526.
14. Bagley, M. C.; Brace, C.; Dale, J. W.; Ohnesorge, M.;
Phillips, N. G.; Xiong, X.; Bower, J. J. Chem. Soc.,
Perkin Trans. 1 2002, 1663–1671.
15. Bagley, M. C.; Dale, J. W.; Bower, J. Chem. Commun.
2002, 1682–1683.
16. Bagley, M. C.; Lunn, R.; Xiong, X. Tetrahedron Lett.
2002, 43, 8331–8334.
References
17. Bagley, M. C.; Dale, J. W.; Ohnesorge, M.; Xiong, X.;
Bower, J. J. Comb. Chem. 2003, 5, 41–44.
18. Oikawa, Y.; Sugano, K.; Yonemitsu, O. J. Org. Chem.
1978, 43, 2087–2088.
19. ChemSpace™ and ChemCore™ are Tripos’ proprietary
library-design technology and cheminformatics solution
providing critical tracking of the chemistry process inside
the laboratory.
1. Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1999,
2849–2866.
2. Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 2001,
2491–2515.
3. Groutas, W. C.; Kuang, R. Z.; Ruan, S. M.; Epp, J. B.;
Venkataraman, R.; Truong, T. M. Bioorg. Med. Chem.
1998, 6, 661–671.
20. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney,
P. J. Adv. Drug Deliv. Rev. 1997, 23, 3–25.
21. Cramer, R. D.; Poss, M. A.; Hermsmeier, M. A.;
Caulfield, T. J.; Kowala, M. C.; Valentine, M. T. J. Med.
Chem. 1999, 42, 3919–3933.
4. Ding, S.; Gray, N. S.; Wu, X.; Ding, Q.; Schultz, P. G. J.
Am. Chem. Soc. 2002, 124, 1594–1596.
5. Bouras, A.; Boggetto, N.; Benatalah, Z.; de Rosny, E.;
Sicsic, S.; Reboud-Ravaux, M. J. Med. Chem. 1999, 42,
957–962.
22. Clark, R. D.; Patterson, D. E.; Soltanshahi, F.; Blake, J.
F.; Matthew, J. B. J. Mol. Graphics Mod. 2000, 18,
404–411.
6. Phillips, G.; Davey, D. D.; Eagen, K. A.; Koovakkat, S.
E.; Liang, A.; Ng, H. P.; Pinkerton, M.; Trinh, L.;
Whitlow, M.; Beatty, A. M.; Morrissey, M. M. J. Med.
Chem. 1999, 42, 1749–1756.
7. Bohlmann, F.; Rahtz, D. Chem. Ber. 1957, 90, 2265–
2272.
8. Moody, C. J.; Bagley, M. C. Synlett 1998, 361–362.
9. Bagley, M. C.; Bashford, K. E.; Hesketh, C. L.; Moody,
C. J. J. Am. Chem. Soc. 2000, 122, 3301–3313.
10. Adlington, R. M.; Baldwin, J. E.; Catterick, D.;
Pritchard, G. J.; Tang, L. T. J. Chem. Soc., Perkin Trans.
1 2000, 303–305.
23. Clark, R. D. J. Chem. Inf. Comput. Sci. 1997, 37, 1181–
1188.
24. Amines used in the synthesis of R1 intermediates: 4-(imi-
dazol-1-yl)aniline; 1,2,5,6-tetrahydropyridine; thiazo-
lidine; ethyl piperazine-1-carboxylate; 3-(2-aminoethyl)-
indole;
methylfurfurylamine;
2-amino-5-(tert-butyl)-1,3,4-thiadiazole;
2-(2-aminoethyl)thiophene;
N-
2-
ethoxybenzylamine; isoindoline; 2-N-propoxyethylamine;
1-(3-aminopropyl)imidazole; 3-(aminomethyl)pyridine; 2-
(furfurylthio)ethylamine.
11. Adlington, R. M.; Baldwin, J. E.; Catterick, D.;