Pyridines: From Lab to Production

By Academic Press

Pyridines: From Lab to Production provides a synthetic armory of tools to aid the practicing chemist by reviewing the most reliable historical methods alongside new methods/ Written by scientists who have actually used these in synthesis. By emphasizing tricks and tips to optimize reactions for the best yields and purity, which are often missing from the primary literature, this book provides another dimension for the synthetic chemist. A combined academic and industrial approach evaluates the best methods for different scales of reaction and discusses practical tips (e.g. when to stop a reaction early to maximize purity or when to re-use side products). Chapters also assess whether to make or source starting materials, how to connect them and what are the best synthetic routes. The book is designed to be a stand-alone reference, but also provides cross references to leading reviews and the Comprehensive Heterocyclic Chemistry reference works for those who want to learn more.

• Reviews tried and tested practical methods to help the reader select the best method for their research
• Includes tips, tricks and hints to enable the reader to get the best yield or cleanest product out of their reaction for synthesising or transforming a pyridine derivative
• Written by both academic researchers and industry leaders this provides a unique view of how to get the most out of a reaction no matter what scale you are running this on

• Language: English
• Publisher: Academic Press
• Release date: Jan 8, 2013
• ISBN: 9780123852366

Book preview

Pyridines

from lab to production

Edited by

Eric F. V. Scriven

Department of Chemistry, University of Florida, Gainesville, United States of America

Table of Contents

Cover image

Title page

Best Synthetic Methods

Other volumes in the Series

Copyright

Preface

Contributors

Chapter 1. Introduction

1 Introduction

2 Value Chains

3 Strategic Considerations – Ring Synthesis Vs Substituent Manipulation

4 Challenges and Needs

References

Chapter 2. Ring Synthesis

1 Introduction

2 By the Formation of One Bond

3 By the Formation of Two Bonds

4 By the Formation of Three Bonds

5 Formation of Four Bonds

6 Transformations from Other Rings

7 Formal Exchange of Ring Members

8 Aromatisation

9 From Larger Molecules

References

Chapter 3. Attachment at Ring Positions

1 Introduction

2 Halogen

3 Sulphur and Selenium

4 Silicon

5 Tin

6 Phosphorus

7 Oxygen

8 Boron

9 Nitrogen

10 Carbon

11 Lithium

12 Magnesium

13 Zinc

14 Conclusion

References

Chapter 4. Substituent Modifications

1 Introduction

2 Carbon-Linked Substituents (Pyr-C)

4.3 Nitrogen-Linked Substituents (Pyr-N)

4.4 Oxygen-Linked Substituents (Pyr-O)

4.5 Sulphur-Linked Substituents (Pyr-S)

4.6 Halogen Linked to Ring (Pyr-halogen)

4.7 Substituents on the Ring Nitrogen (PyrN+-X)

References

Chapter 5. Formation of Completely or Partially Reduced Pyridines and Quinolines

1 Introduction

2 Preparation of Piperidine and Substituted Piperidines

3 Preparation of Saturated Quinolines

4 Biologically Active Piperidine and Tetrahydroquinoline compounds

References

Chapter 6. Applications to Alkaloid Synthesis

1 Introduction

2 Alkaloid Synthesis

3 Summary

References

Chapter 7. Fluorinated Pyridines

1 Fluoropyridines

2 Trifluoromethylpyridines

3 Conclusions

References

Chapter 8. Pyridine-Containing Reagents

1 Introduction

2 2-(Dimethylamino)pyridine (1)

3 4-(Dimethylamino)pyridine (12)

4 Tetrakis(pyridine-2-yloxy)silane (26) as a Coupling Reagent in the Synthesis of Carboxamides

5 2-Benzyloxy-1-methylpyridinium triflate (Dudley Reagent, 30)

6 (2S)-2-[(2-Pyridyloxy)methyl]pyrrolidine (37) as Catalyst for Enantioselective Michael Addition to Nitro Olefins

References

Chapter 9. Synthesis of Heterocyclic Compounds Using Continuous Flow Reactors

1 Introduction

2 Practical Implications in the Development of Continuous Processes

3 Heterocyclic Synthesis in Continuous Flow Reactors

4 Conclusion

References

Index

Best Synthetic Methods

Scriven: Pyridines: From Lab to Production, 2013

Other volumes in the Series

Petragnani and Stefani: Tellurium in Organic Synthesis: Second, Updated and Enlarged Edition, 2007

Gronowitz and Hörnfeldt: Thiophenes, 2004

Brandsma: Synthesis of Acetylenes, Allenes and Cumulenes: Methods and Techniques, 2004

Osborn: Carbohydrates, 2003

Jones: Quaternary Ammonium Salts: Their Use in Phase-Transfer Catalysed Reactions, 2001

Varvoglis: Hypervalent Iodine in Organic Synthesis, 1997

Grimmett: Imidazole and Benzimidazole Synthesis, 1997

Wakefield: Organomagnesium Methods in Organic Synthesis, 1995

Metzner: Sulfur Reagents in Organic Synthesis, 1994

Pearson: Iron Compounds in Organic Synthesis, 1994

Petragnani: Tellurium in Organic Synthesis, 1994

Motherwell: Free Radical Chain Reactions in Organic Synthesis, 1991

Copyright

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ISBN: 978-0-12-385235-9

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Printed and bound in Great Britain

13 14 15 16 17 10 9 8 7 6 5 4 3 2 1

Preface

The applications of new synthetic methodology developed in recent years have had a great impact on the best ways to make pyridine derivatives. This book aims to cover these advances and highlight methods that have generality with experimental procedures given. Several older methods used in industrial practice that offer good yields and are based on cheap readily available starting materials are also given. Best practices in process development are not covered as they are not usually peculiar to development of processes to manufacture pyridine chemicals. However, strategic aspects of route selection when planning the synthesis of a pyridine intermediate, whether to transform a pyridine precursor or make it by ring synthesis, is linked into pyridine value chain considerations, see Chapter 1. The next four chapters cover ring synthesis, attachments at ring reactions, modification of substituents, and reductions. This organization follows that of the Comprehensive Heterocyclic Chemistry series and should help readers to readily find more information in a specific area than contained in this short work. Three chapters deal with important developments in fluoropyridines, pyridine alkaloid synthesis, and pyridine reagents. The final chapter examines the potential for the application of flow technology in pyridine synthesis. It is hoped that the organization and content of this book will prove useful to those embarking on the synthesis of pyridine derivatives in academia and industry.

Eric F.V. Scriven

Contributors

Mohammed K. Abdel-Hamid, Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt

Ashraf M. Abdel-Megeed, Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt

Marudai Balasubramanian, R& D, Afton Chemical Corporation, Richmond, VA, USA

Daniel L. Comins, Professor Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8204 USA

William R. Dolbier Jr., Department of Chemistry, University of Florida, Gainesville, FL 32611-7200

Nilmi Fernando, Department of Chemistry, Georgia State University, Atlanta, Georgia 30302-4098, USA

Liangfeng Fu, Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA

Gordon W. Gribble, Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA

Paul A. Keller, School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia

Qi-Xian Lin, Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA

R. Murugan, Vertellus Specialties Inc, 1500 South Tibbs Avenue, Indianapolis, IN 46241, USA

Shirish Paranjpe, Department of Chemistry, Georgia State University, Atlanta, Georgia 30302-4098, USA

Eric F.V. Scriven, University of Florida, Gainesville, FL 32611, USA

Lucjan Strekowski, Department of Chemistry, Georgia State University, Atlanta, Georgia 30302-4098, USA

Sergey Tsukanov, Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8204 USA

Paul Watts, Department of Chemistry, University of Hull, Cottingham Road, Hull HU6 7RX, UK

Charlotte Wiles, Chemtrix BV, Burgemeester Lemmensstraat 358, 6163 JT Geleen, The Netherlands

Chapter 1

Introduction

R. Murugan¹ and Eric F.V. Scriven², ¹Vertellus Specialties Inc, 1500 South Tibbs Avenue, Indianapolis, IN 46241, USA., ²University of Florida, Gainesville, FL 32611, USA

1 Introduction

Pyridines were first described by Anderson in the 1840s.¹ He obtained 2-methylpyridine (beta-picoline) from bone oil distillation, and subsequently pyridine and some dimethylpyridines (lutidines).² Later (1877), Sir William Ramsey was the first to report a synthesis of pyridine that involved passing a mixture of acetylene and hydrogen cyanide through a hot tube.³ The now well-known Hantzsch synthesis appeared in 1882 (Scheme 1.1),⁴ and a vapour phase synthesis by Chichibabin in 1906.⁵

Scheme 1.1 Hantzsch pyridine synthesis.

In the first half of the last century, most pyridines used industrially came from the basic fraction obtained from coal tar distillation. Then the growth in demand for pyridine-based chemicals began to outstrip the supply from natural sources. The demand was driven by the need for 3-pyridine carboxylic acid (niacin), its amide (niacinamide), and the antituberculosis drug Isoniazid. The discovery that the addition of 2-vinylpyridine to butadiene–styrene latex binder gave a large increase in adhesion of rubber to tirecord drove a dramatic increase in demand for 2-methylpyridine, the precursor of 2-vinylpyridine. The demand created by these factors and others led to the development of a synthetic pyridine process based on Chichibabin’s early vapour phase work. This process was first developed and operated on a large commercial scale, in fluidised bed reactors, by Reilly Tar & Chemical Corporation in the early 1950s.⁶ Most processes operated today by the three major producers (Vertellus, USA; Jubilant, India; and Red Sun, China) to manufacture pyridine and methylpyridines are based on this process. Two variations are practised that involve high-temperature vapour phase processes that both yield coproducts which depend on the nature of the feed, catalyst, and conditions. A feed of acetaldehyde and ammonia gives a mixture of 2- and 4-methylpyridines (Eqn (1.1)); a feed of acetaldehyde, formaldehyde, and ammonia gives a mixture of pyridine and 3-methylpyridine (Eqn (1.2)). Only recently, by a study using labelled carbons, has the position of each of the carbons in the products been attributed precisely to the carbon in the aldehyde from which it came.⁷

(1.1)

(1.2)

The pyridine/3-picoline process is operated at greater volume driven largely by the demand for pyridine that is converted to the herbicide paraquat (demand 26,000 MTY) and the insecticide chlorpyrifos (35,000 MTY) obtained from 3-picoline in a multistep process, these volumes refer to sales in 2008. Worldwide, over 100 to 1000 tons of pyridine and products containing a pyridine ring are produced annually. The coproduct ratios in these processes can be varied to some extent by changes in feeds, operating conditions, and use of different catalysts to promote formation of one coproduct over the other. However, coproduct mixtures are always formed. Commercial success, therefore, also depends on response to demand for each of the coproducts and their downstream derivatives by low-cost synthetic routes based on best technology. Pyridine value-added chains based on the two major vapour phase coproduct reactions are illustrated (Figure 1.1).

Figure 1.1 Pyridine and picoline value-added chains.

One important liquid phase reaction is operated commercially by Lonza and provides a significant source of niacin (Scheme 1.2).⁸

Scheme 1.2 Liquid phase pyridine synthesis.

2 Value Chains

The reactions below have formed the basis for production of high-volume pyridine derivatives available commercially from the major pyridine producers or via other companies that buy pyridines, the methyl- and cyano-pyridines from the major pyridine producers. These reactions are:

1. Ammoxidation – vapour phase conversion of a methyl groups to nitriles (Eqn (1.3)). The main use of pyridine 3-carbonitrile is for production of niacinamide in a large scale commercial process that involves a controlled hydrolysis.

(1.3)

2. Reduction of nitriles to carbinols, aldehydes, and hydrolysis to amides, carboxylic acids (Scheme 1.3). Reduction of nitriles under various conditions offers a large range of products.

Scheme 1.3 Catalytic reduction of pyridine nitriles.

3. Oxidation of methyl groups to carbinols, aldehydes, and carboxylic acids (Scheme 1.4). Pyridine 3-carboxylic acid is not only an important product (niacin) in the vitamin business but it can also be converted to 2-chloropyridine-3-carboxylic acid an important intermediate for production of a number of pharmaceutical and agricultural products (Scheme 1.5).

Scheme 1.4 Oxidation of methyl pyridines.

Scheme 1.5 Some medicinal and agricultural products based on 2-chloropyridine-3-carboxylic acid.

4. Reduction of the pyridine ring to piperidines (Eqn (1.4)) or partially reduced pyridines.

(1.4)

5. Ring aminations at the 2-position by treatment of various pyridines with sodamide (Eqn (1.5)), or at positions 3- and 4- by Hofmann reaction on the respective amide (Eqn (1.6)).

(1.5)

(1.6)

Diazonium salts, formed from pyridinamines, provide an important way to functionalise pyridine ring positions, comparable with benzene chemistry. This is exemplified by a step in the synthesis of Rynaxypyr (Scheme 1.6) (and also in a route to Imidacloprid, Section 1.3) that also includes a Hofmann rearrangement step.⁹

Now other options are available for synthesis of pyridines especially those based on cross-coupling reactions. These starting materials for these reactions usually depend on the availability of chloro- or bromo-pyridines (see Chapter 3). Several dichloropyridines are available as by-products from the chlorpyrifos process (Scheme 1.7).¹⁰

Scheme 1.6 Synthesis of Rynaxypyr.

Scheme 1.7 Synthesis of Chlorpyrifos.

2.1 Routes to 3,5-Dimethyl-4-Methoxy-2-Pyridylcarbinol

The pyridine derivative, 3,5-dimethyl-4-methoxy-2-pyridylcarbinol, is an intermediate used to make Omeprazole, a proton pump acid inhibitor. Two approaches are shown (Scheme 1.8) one from 2,3,5-collidine and the other from 3,5-lutidine. The first three steps of each involve; N-oxidation, nitration, and replacement of the 4-nitro substituent by methoxide. In one case, the 2-hydroxymethyl group is installed by the reaction of 2,3,5-trimethyl-4-methoxypyridine N-oxide with acetic anhydride¹¹ to form the 3,5-dimethyl-4-methoxy-2-acetoxymethylpyridine, which on hydrolysis gives the final 2-pyridylcarbinol product. In the other route, the intermediate 3,5-dimethyl-4-methoxypyridine N-oxide on methylation with dimethyl sulphate gave the N-methoxypyridinium salt which undergoes the Minisci reaction¹² (radical substitution) to introduce the CH2OH group at the 2-positon with the elimination of the N-methoxy group. The second approach has proved more economical than the first approach.¹³

Scheme 1.8 Synthetic routes to Omeprazole.

It should be noted that of these two approaches, treatment of N-oxide with Ac2O or Minisci reaction sometimes do not work as well for less substituted pyridine N-oxides, owing to lack of regiospecificity or low yields.

3 Strategic Considerations – Ring Synthesis Vs Substituent Manipulation

When considering approaches to a target pyridine, it is important to identify a high-yield synthetic route based on the lowest cost readily available starting material which usually appears earliest in the value-added chains (Figure 1.1). Examples given of commercial routes (1 to 5 above) offer a further indication of availability of starting materials and technology involved. Then a comparison should be made of the pyridine-based route with costs of routes based on pyridine-ring synthesis from the cheapest building blocks available. It is interesting to make the above comparison for a specific case. A large volume insecticide Imidacloprid was developed by Bayer AG in the 1990s. Several synthetic routes to the key intermediate 2-chloro-5-methylpyridine, or the subsequent intermediate 2-chloro-5-chloromethylpyridine were developed (Scheme 1.9). Three of these routes have been operated commercially.

Scheme 1.9 Synthetic routes to Imidacloprid.

Two routes are based on 3-picoline, a first-generation pyridine, the lowest cost starting material. Initial work focused on chlorination of the N-oxide which always gave a mixture of 2- and 6-chlorination, and no way was found to change this to exclusively 6-chlorination.¹⁴ The Chichibabin amination of 3-picoline, similarly, favoured 2 over 6-substitution by 9:1. However, further work on this reaction proved more fruitful. It was observed that by running the amination under a high initial ammonia pressure, the product ratio was switched in the desired direction to >4:1.¹⁵ Therefore, 2-amino-5-methylpyridine became the intermediate of choice for development of a manufacturing process. Conversion to 2-chloro-5-methylpyridine was achieved by a high-yield non-aqueous diazotisation followed by chlorination with gaseous HCl. A further high-yield chlorination at the 5-methyl group, using chlorine and sodium bicarbonate, afforded 2-chloro-5-chloromethylpyridine again in high yield.¹⁶ These two chlorinations would seem to have promise of extension for chlorination of related pyridines and other heterocycles.

Two ring synthesis reactions have proved to be competitive with the above 3-picoline-based process. One involves a Vilsmeier cyclisation (Scheme 1.10)¹⁷ similar to some developed by Meth-Cohn.¹⁸ This process utilises benzylamine and the coproduct benzyl chloride is available for recycle (by conversion to benzylamine) or reuse in other ways.

Scheme 1.10 Formation of 2-chloro-5-methylpyridine by a Vilsmeier ring closure.

The third commercial process is based on reaction of acrolein with acrylonitrile; cyclopentadiene, which can be recycled, acts as a protecting group (Scheme 1.11).¹⁹

Scheme 1.11 Formation of 2-chloro-5-chloromethylpyridine from acrolein and acrylonitrile.

Another ring synthesis based on cis-pentenonitrile (a nylon by-product) has been claimed but it has never been operated commercially.²⁰

The comparative economics of the three commercial processes above is obviously very close and competitive differentiation, as it often does, depends on access to low cost raw materials and required manufacturing technology available to the competitors rather than on just synthetic chemistry considerations. Patent protection of the lowest cost process can, of course, also be the key factor in competitive differentiation. It is hoped the consideration of value chains in the section and the above case study will prove helpful for those evaluating routes to pyridine intermediates.

The application of directed ortho metallation and cross-coupling reactions have had a great influence on the best methods for synthesis of multiply substituted pyridines, particularly those of medicinal importance. Snieckus has combined in a one-pot reaction a directed ortho-metallation–boronation and a Suzuki–Miyaura coupling of a pyridine derivative (Scheme 1.12).²¹

Scheme 1.12 One pot directed-ortho-metallation, Suzuki-Miyaura coupling.

In another case, the same group combined a directed ortho metallation with a halogen dance.²² The 2-, 3-, and 4-pyridyl O-carbamates below were used to introduce electrophiles in high yields to give trisubstituted pyridines (Scheme 1.13). The electrophiles used included methanol, TMS, and iodine.

Scheme 1.13 Synthesis of trisubstituted pyridines by directed-ortho-metallation and halogen dance.

4 Challenges and Needs

Most pyridines produced commercially are required for their bioactivity. Especially, the pharmaceutical industry has stringent specifications for products, and the requirement that late-stage intermediates and final products are manufactured by FDA approved processes in FDA regulated equipment. All chemical processes developed today need to be not only lowest cost but also sustainable. This presents a challenge particularly to process development chemists. Process development techniques have become very specialised. They are not dealt with in this book as they have been well covered in a recent book.²³ Some of the successful methods used to develop the best processes for a series of products, including many pyridines continue to appear in Organic Process Research and Development. The above considerations among others have led to the study especially of catalytic reactions with a great deal of intensity and success.²⁴ This has resulted in several new reactions in pyridine chemistry that involve specific C–H activation and have the advantage of eliminating several steps, for example, halogenation and formation of a boronic ester before palladium cross coupling. A direct arylation of 2-picoline by rhodium-catalysed C–H activation is a case in point (Eqn (1.7)).²⁵

(1.7)

An interesting iron-catalysed oxidation that employs oxygen allows preferential oxidation at the benzylic CH2 rather than at the methyl group, in contrast copper-catalysed oxidation results in oxidation of both substituents (Eqn (1.8)).²⁶ It should be noted that the temperature at which these oxidations are run can have a big influence on the nature of the products formed.

(1.8)

Arylation of pyridine 2-benzylic amines using arylboronates has been achieved with ruthenium (0)- sp³ C–H bond activation, however a sterically demanding 3-substituent (methyl or phenyl) is critical for attaining high yields (Eqn (1.9)).²⁷

(1.9)

The move away from high cost toxic heavy metals to the use of base metals as alternative catalysts is illustrated by the copper-catalysed amidation of 2-phenylpyridine.

Moderate to good yields have been obtained (Eqn (1.10)).²⁸

(1.10)

The chemical processes (outlined in 1.2) and recently reported reactions (1.4), e.g. DoM,²⁹ cross-coupling,³⁰ and C–H bond activation,³¹ combined with the availability of modern flow reactor technology³² offer synthetic chemists the advantage of easier scale up from laboratory to plant and safer handling of energetic intermediates, e.g. in nitrations and Hofmann rearrangements.

Progress in pyridine chemistry over 150 years has been reviewed in a comprehensive manner.³³ Several other works deal with aspects of synthetic pyridine chemistry old³⁴,³⁵ and new.³⁶

References

1. Anderson T. Liebigs Ann. 1846;60:86.

2. Anderson T. Liebigs Ann. 1851;80:44.

3. Ramsey W. Ber. 1877;10:736.

4. Hantzsch A. Liebigs Ann. 1882;215:72.

5. Chichibabin AE. Russ J Phys Chem. 1905;37:1229.

6. Cislak, F. E.; Wheeler, W. R. US Patent 2,744,904. 1956.

7. Calvin JR, Davis RD, McAteer CH. Appl Catal. 2004;1.

8. Stocker, A.; Marti, O.; Pfammatter, T.; Schreiner, G.; Brander, S. German Patent 2,046,556 and British Patent GB 1,276,776. 1971.

9. Shapiro, R. US Patent Appl. 2007/0161797.

10. Muller K. Agrochemicals: Composition, Production, Toxicology, Applications. Toronto: Wiley-VCH; 2000; 541.

11. Boekelheide V, Linn WJ. J Am Chem Soc. 1954;76:1286.

12. Minisci, F.; Fontanna, F.; Serri, A.; Baima, R. US Patent 5,763,624. 1988.

13. Brandstrom, A. E.; Lamm, B. R. US Patent 4,544,750. 1985.

14. Gallenkamp, B.; Knops, H. US Patent 4,897,488. 1990.

15. McGill, C. K.; Sutor, J. J. US Patent 4,386,209. 1983. Lawin, P. B.; Sherman, A. R.; Grendze, M. P. US Patent 5,808,081. 1998.

16. Gunther, A. US Patent 5,198,549. 1993.

17. Jelich, K.; Lindel, H.; Mannheims, C.; Lantzsch, R.; Merz, W. US Patent 5,648,495. 1997.

18. Meth-Cohn O, Westwood KT. J Chem Soc Perkin Trans. 1984;1:1173.

19. Zhang, T. Y.; Scriven, E. F. V. US Patent 5,229,519. 1993.

20. Murugan, R.; Scriven, E. F. V.; Zhang, T. Y. US Patent 5,508,410. 1996.

21. Alessi M, Larkin AL, Ogilvie KA, et al. J Org Chem. 2007;72:1588.

22. Miller RE, Rantanen T, Ogilvie KA, Groth U, Snieckus V. Org Lett. 2010;12:2198.

23. Anderson LG. Practical Process Research and Development. 2nd ed. Amsterdam: Elsevier; 2012.

24. Busacca CA, Fandrick DR, Song JJ, Senanayake CH. Adv Synth Catal. 2011;353:1825.

25. Berman AM, Bergman RG, Ellman JA. J Org Chem. 2010;75:7863.

26. De Houwer J, Tehrani KA, Maes BUW. Angew Chem Int Ed. 2012;51:2745.

27. Dastbaravardeh N, Schnuerch M, Mihovilovic MD. Org Lett. 2012;14:1930.

28. John A, Nicholas KM. J Org Chem. 2011;76:4158.

29. Snieckus V. Chem Rev. 1990;90:879.

30. Yeung CS, Dong VM. Chem Rev. 2011;111:1215.

31. Lyons TW, Sanford MS. Chem Rev. 2010;110:1147.

32. Wiles C, Watts P. Micro Reaction Technology in Organic Synthesis. Boca Raton: CRC Press; 2011.

33. Boulton AJ, McKillop A. In: Katritzky AR, Rees CW, eds. Oxford: Pergamon; 1984; Comprehensive Heterocyclic Chemistry. Vol. 2 Boulton, A. J. Vol. Ed.; Comprehensive Heterocyclic Chemistry II, Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Eds.; Pergamon: Oxford, 1996; Vol. 6. Black, D. St.C. Vol. Ed.; Comprehensive Heterocyclic Chemistry III, Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K. Eds. Elsevier: Oxford, 2008; Vol. 7.

34. Meier-Bode H, Altpeter J. Das Pyridin und seine Derivate in Wissenschaft und Technik. Halle: Wilhelm Knapp; 1934; Ferles, M.; Jizba, J. Chemie Pyridinu, Ceskoslovenske Akademie Ved: Praha, 1955.

35. Klingsberg E, ed. Pyridine and Its Derivatives. New York: Interscience; 1960; Abramovitch, R. A., Ed., Pyridine and Its Derivatives, Wiley: New York, 1974. Newkome, G. R., Ed., Pyridine and Its Derivatives, Interscience: New York, 1984.

36. Black D StC, ed. Pyridines, Science of Synthesis. Stuttgart: Thieme; 2005.

Chapter 2

Ring Synthesis

Paul A. Keller∗, Mohammed K. Abdel-Hamid∗∗ and Ashraf M. Abdel-Megeed∗∗, ∗School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia, ∗∗Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt

1 Introduction

This chapter will present the synthesis of basic pyridines functionalised in various positions with a range of different substituents. The discussion will highlight the advantages of each synthetic strategy.

The synthesis of pyridines has a long history and the more traditional methods can still rank as some of the more reliable and favoured synthetic strategies. For example, condensation reactions are still commonly used methods with the advantages of being reliable and simple. More modern methods have emerged in the past decade for the synthesis of pyridines with great advances in the field of metal-catalysed reactions, including the use of palladium and copper. In particular, there has been much development in the use of alkyne chemistry, especially with the use of metal–alkene/alkyne chemistry.

The synthesis of pyridines by aromatisation of the partially or fully saturated 6-membered ring containing one nitrogen atom is an important synthetic strategy and, therefore, is substantially reported here as a separate section. However, often, a key sequence of reactions towards the synthesis of pyridines involves cyclic intermediates of the same type – such strategies hold equal importance in any consideration of best methods to pyridines and hence, although there may be some duplication in these aromatisation reactions, such multistep syntheses are also reported here under the appropriate headings. There is a similar overlap in classification when considering transformations from (other) ring systems to the 6-membered pyridine moiety – when the starting material ring is <6 atoms, these could also be considered under different fragment addition-type reactions. Important examples of these types of reactions are highlighted in all appropriate sections.

The parent pyridine molecule is a colourless liquid with a boiling point of 115 °C and a melting point (mp) of −42 °C. It is an irritant and has an unpleasant odour and is harmful by inhalation, by contact to the skin and if swallowed. The biological properties of pyridines, as expected, change dramatically upon substitution and the inclusion of a pyridyl moiety in compounds of biological significance is a common occurrence. There are a significant number of examples of natural products carrying the pyridine entity.

2 By the Formation of One Bond

2.1 One N–C Bond

2.1.1 Fragment N–C–C–C–C–C

2.1.1.1 Acid-Induced Cyclisations

An efficient synthesis of 3-, 5- and 6-aryl-2-chloropyridines 1 was described via the facile preparation of 5-(dimethyamino)aryl-substituted pentadienyl nitriles 1 and cyclisation with hydrochloric acid (Scheme 2.1). This approach allows for the introduction of other electron-withdrawing substituents on the pyridine ring as well as the preparation of unsubstituted arylpyridines. Some differences in the rates of cyclisation of the pentadienyl nitriles as well as the yields of chloropyridines were observed depending on the position and degree of substitution on the aryl substituent. Arylpentadienyl nitriles 1 could also be converted directly into the corresponding 2-aminopyridines 3 by treatment with ammonia in methanol.¹

Scheme 2.1 Cyclisation of pentadienyl nitriles under acid, or ammonium, induced conditions.

Using the same method, ylidenenitrile 4 was cyclised to the 2-chloronicotinonitrile 5 in excellent yield (Scheme 2.2).²

Scheme 2.2 HCl induced cyclisation of ylidenenitrile.

3-[3-(Trifluoromethyl)phenyl]-2-chloropyridine¹

A solution of (E,Z)-α-[3-(dimethylamino)-2-propenylidene]-3-(trifluromethyl)benzeneacetonitrile (9.2 g, 43 mmol) in glacial acetic acid (100 mL) was heated to 60 °C. To this solution was added dry HC1 gas at a moderate rate for 2 min. The solution was heated at 60 °C for 2 h and then poured onto ice (100 g) and CH2Cl2 (100 mL) mixture. Solid K2CO3 was added until the solution was basic and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The combined organic layers were dried (MgSO4), and the solvent was evaporated under reduced pressure to afford pink crystals (3 g). Purification via column chromatography (EtOAc/hexane (1:6)) followed by crystallisation from hexane afforded colourless crystals of the titled compound (95%).

Methyl 4-[2-(2-chloro-3-cyanopyrid-4-yl)ethyl]benzoate 5²

Methyl 4-[4,4-dicyano-3-(2-dimethylaminoethenyl)but-3-enyl]benzoate 4 (3.09 g, 10 mmol) was dissolved in glacial acetic acid (100 mL). HCl gas was bubbled through this solution at a rapid rate for 2 min. The solution was stirred at room temperature (rt) overnight and then poured onto ice (100 g). The precipitated solid was collected by filtration, washed with water and recrystallised from EtOH to yield 2.83 g (94%) of 5 as colourless needles.

Formation of the pyridine ring was achieved by reacting enamines 6 with anhydrous hydrogen chloride to afford ethyl 2-chloro-4-phenylpyridine-3-carboxylates 7 (Scheme 2.3).³

Scheme 2.3 Acid induced cyclisations enamines.

Ethyl 2-chloro-6-methyl-4-phenylnicotinate³

A solution of 4 N HCl in EtOAc (150 mL) was added to ethyl 2-cyano-5-(dimethylamino)-3-phenylhexa-2,4-dienoate (6.61 g, 81.9 mmol), and the mixture was stirred at rt for 30 h. After evaporation of the solvent, EtOAc was added to the residue. The mixture was washed successively with H2O, 1 N HCl, H2O, saturated aqueous NaHCO3, H2O and brine. The organic layer was dried and concentrated. The residue was subjected to chromatography on silica gel using hexane/EtOAc (4:1) as eluent to afford ethyl 2-chloro-6-methyl-4-phenylnicotinate as a pale yellow oil (15.4 g, 68%).

2.1.1.2 Catalytic Cyclodehydration of Bohlmann–Rahtz Aminodienone Intermediates

Recent findings have shown that the cyclodehydration of Bohlmann–Rahtz (B–R) aminodienone intermediates can be accelerated through the use of a Brønsted or Lewis acid and can be carried out in just one operation through the use of aprotic solvent or at high temperature under microwave dielectric heating. Alternative processing methods have also been reported for the cyclodehydration reaction, such as the use of continuous flow (CF) reactors to give 2,3,6-trisubstituted pyridine directly and with total regiocontrol.⁴–⁹

In a new modified reaction condition for B–R pyridine synthesis, aminoheptadienone 8 was stirred at 50 °C in toluene/acetic acid (5:1) for 6 h to generate pyridine 9 in excellent yield and without any need for further purification (Scheme 2.4).⁴

Scheme 2.4 Catalytic cyclodehydration of BohlmanneRahtz aminodienone intermediates.

Oximes 10 were converted into the substituted pyridines 11 in 60–84% yields either by azeotropic removal of water in benzene at reflux using a Dean Stark apparatus (method A, Scheme 2.5) or by stirring in a 1:1 mixture of acetic anhydride and acetic acid overnight at rt (method B).¹⁰

Scheme 2.5 Dehydration cyclisations of oximes to produce pyridines.

General Procedure for the Preparation of 2-Phenyl-2,3,4-substituted Pyridines 11 from Oximes 10¹⁰

Method A: A solution of oxime 10 (1.0 mmol) in benzene (200 mL) was heated in a Dean Stark apparatus for 4 h. Removal of the benzene under reduced pressure afforded the crude pyridines.

Method B: A solution of oxime 10 (2.0 mmol) in a 1:1 mixture of acetic anhydride and acetic acid (20 mL) was stirred overnight at rt. The reaction was quenched by the addition of ice water (150 mL) and then the remaining solution was extracted with chloroform (3 × 20 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (3 × 20 mL) and water (20 mL), dried (MgSO4) and the solvent was removed under reduced pressure. The crude pyridines 11 were purified either by column chromatography (silica gel, EtOAc) or by trituration with diisopropyl ether.

2.1.1.3 Cyclisations Under Neutral Conditions

N-Halosuccinimide-mediated processes provide complementary and efficient routes to either 2,3,5,6-tetra-substituted or 2,3,6-trisubstituted pyridines under mild conditions. The reaction of B–R intermediates with N-bromosuccinimide (NBS) provides facile access to 5-bromopyridines. Therefore, different aminodienones 12 were treated with NBS at −10 °C for 30–60 min in EtOH to give the 5-bromopyridines 13 in excellent yields (Scheme 2.6). On the other hand, cyclodehydration of B–R aminodienone intermediates using N-iodosuccinimide as a Lewis acid proceeds at low temperature under mild conditions to give the corresponding 2,3,6-trisubstituted pyridines 14 in high yield and with total regiocontrol (Scheme 2.6).⁵,⁶

Scheme 2.6 Cyclisation under neutral conditions.

General Procedure: Preparation of 2,3,4,6-tetra-substituted Pyridines 13 Using NBS⁵

A solution of aminodienone 12 (0.28 mmol, 1 equiv) and NBS (0.34 mmol, 1.2 equiv) in EtOH (5 mL) was stirred at −10 °C for 1 h followed by evaporation of the solvent under reduced pressure. Purification by silica gel column chromatography gave the 5-bromopyridines (yield: 83–98%).

General Procedure: Preparation of 2,3,6-Trisubstituted Pyridines 14 Using NIS⁶

A solution of aminodienone 12 (0.2 mmol, 1 equiv) and N-iodosuccinimide (0.25 mmol, 1.2 equiv) in EtOH (4 mL) was stirred at 0 °C for 1 h followed by evaporation of the solvent under reduced pressure. Purification by flash chromatography on silica gel, eluting with EtOAc/light petroleum, gave the pyridines 14 (yield: 84–98%).

The cyclodehydration of B–R aminodienones 15 can be also catalysed by iodine in ethanol at rt to give 2,3,6-trisubstituted pyridines 16 in excellent yield, with total regiocontrol and without the need for chromatographic purification (Scheme 2.7).⁷

Scheme 2.7 Cyclodehydration of aminodienones to pyridines.

General Procedure: Preparation of 2,3,6-Trisubstituted Pyridines 16 Using Iodine⁷

A solution of aminodienone 15 (0.2 mmol, 1 equiv) and iodine (0.04 mmol, 20 mol%) in EtOH (4 mL) was stirred at rt for 30 min and an aqueous solution of Na2S2O3 (10% w/v, 10 mL) was added. The mixture was extracted with CH2Cl2 (3 × 20 mL) and the organic extracts were combined, dried (Na2SO4) and evaporated under reduced pressure to give pyridine 16 (92–98%).

Microwave-assisted organic synthesis under CF processing has been developed as a new simple procedure for the synthesis of pyridines based upon the B–R reaction. Aminodienone 17 was cyclodehydrated with CF processing under homogeneous conditions in toluene/acetic acid (5:1) over sand to give pyridine 18 (Scheme 2.8). Results were comparable to those of experiments carried out in a sealed tube and to that of the corresponding homogeneous CF process with a Teflon heating coil.⁸,⁹

Scheme 2.8 Cyclodehydration of aminodienones to pyridines under microwave and continuos flow conditions.

Ethyl 2-methyl-6-phenylpyridine-3-carboxylate 18⁸

A solution of aminodienone 17 (80 mg, 0.3 mmol) in PhMe/AcOH (5:1) (3 mL) was irradiated for 2 min at 100 °C (150 W) in a sealed pressure-rated glass tube. The reaction mixture was cooled by a flow of compressed air then partitioned between saturated aqueous NaHCO3 and EtOAc, and the aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to give compound 18 (75 mg, 98%) as a yellow oil.

2.1.1.4 Metal-Catalysed Cyclisations

Based on metal-catalysed cyclisation reactions, various β-acetoxy-γ,δ-unsaturated O-acetoxyoximes 19 were transformed to pyridines 20 by treatment with triethylamine and a catalytic quantity of Pd(PPh3)4 in toluene at 120 °C (Scheme 2.9). The introduction of substituents on the olefin moiety or p-substituents on the aryl ketone oximes exhibited no significant effect on the product yield. Primary and secondary alkyl ketone oximes gave the corresponding pyridines in moderate yields; however, t-butyl ketone oxime did not give the pyridine product (20, R1 = t-butyl).¹¹

Scheme 2.9 Palladium catalysed cyclisation of beta-acetoxy-gamma, delta-unsaturated O -acetoxyoximes.

2-Phenylpyridine 20 (R¹ = Ph, R² = R³ = R⁴ = H)¹¹

To a solution of (E)-1-[2-(acetyloxy)imino-2-phenylethyl]prop-2-enyl acetate (87.2 mg, 0.317 mmol) in toluene (20 mL) at 50 °C was added Pd(PPh3)4 (74.7 mg, 0.070 mmol) and triethylamine (0.22 mL, 1.6 mmol), and the reaction mixture was warmed and stirred for 30 min at 120 °C. After cooling to rt, the mixture was passed through a Celite pad. The filtrate was evaporated under reduced pressure, and the red–black organic residue was purified by column chromatography (hexane/acetone 8:2) to afford 2-phenylpyridine (40.4 mg, 82%).

2.1.1.5 Reduction of Dienedinitriles

Tetra-substituted pyridines of the type 22 can be obtained by the selective reduction of the C≡N bond of dienedinitriles 21 into an imino anion using 1.0 equiv of LiAlH4 followed by 6-endo intramolecular cyclisation to afford 22 in 75% yield (Scheme 2.10).¹²

Scheme 2.10 Selective nitrile reduction using lithium aluminium hydride towards pyridines.

2,3,4,5-Tetrapropylpyridine 22¹²

LiAlH4 (1.0 mmol, 1.0 M in Et2O) was added to the conjugated enenitrile (1.0 mmol) in a solution of Et2O (5 mL) at −78 °C. The reaction mixture was stirred at −30 °C for 1 h, quenched with saturated aqueous NaHCO3 solution and extracted with Et2O. The extract was washed with brine and dried (MgSO4). The solvent was evaporated under reduced pressure to give the crude product 22, which was purified by column chromatography on silica gel using Et2O/hexane (1:10) as eluent (yield: 75%).

In 1976, Murahashi et al. reported the synthesis of pyridines by palladium-catalysed cyclisation of γ,δ-unsaturated ketone oximes or conjugated dienyl ketone oximes. Similarly, pyridines 24 were prepared by a 6-endo-type cyclisation of β-methoxy-γ,δ-unsaturated ketone oximes 23 with a catalytic use of Pd(PPh3)4 in the presence of quaternary ammonium halide (Scheme 2.11).¹³,¹⁴

Scheme 2.11 Palladium catalysed cyclisation of ketone oximes.

2.1.1.6 Cyclisation Using Ammonium Anion

Cyclisation of 2-alkylaminopentadienimine HCl salts 25 proceeded easily in the presence of ammonium acetate, at 80 °C in n-butanol, to give the corresponding 3-alkylpyridine derivatives 26 in a high yield (Scheme 2.12). The scope of this reaction is extended to long chain alkyl pyridines.¹⁵

Scheme 2.12 Cyclisation of 2-alkylaminopentadienimine HCl salts in the presence of ammonium acetate.

General Procedure: 3-Substituted Pyridines 26 from Aminopentadieneiminium Salts 25¹⁵

To a solution of aminopentadieneiminium salt 25 in n-butanol was added NH4OAc (2 equiv). The reaction mixture was heated at 80 °C overnight and then concentrated. The obtained residue was purified by column chromatography on silica gel using CH2Cl2/MeOH (95:5) as eluent to afford pyridines 26 (yield: 88–94%).

Starting from the enaminoenone 27 (X = F), 2-trifluoromethyl-5-cyanopyridine 28 was obtained in 82%, upon treatment with ammonium acetate in dimethyl formamide (DMF; Scheme 2.13). It was found that only the Z isomer reacted to produce the pyridine derivative of the bromo enaminoenone. In order to maximise the yield, small amounts (10 mol%) of triethylamine were added which had the effect of catalysing double bond isomerisation.¹⁶

Scheme 2.13 Cyclisation of enaminoenones in the presence of ammonium acetate.

2-Trifluoromethyl-5-cyanopyridine¹⁶

The enaminoenone 27 (X = F) (10.0 g, 0.0459 mol) was dissolved in DMF (50 mL), treated with ammonium acetate (5.3 g, 0.068 mol) and the resulting deep red solution stirred at 20 °C overnight. The solution was diluted with H2O (100 mL) and extracted with toluene (3 × 150 mL). The combined toluene extracts were washed with H2O (2 × 100 mL) and brine (100 mL) and then concentrated under reduced pressure to give a red oil which crystallised on standing to afford 2-trifluoromethyl-5-cyanopyridine (6.5 g, 82% yield).

An efficient procedure for the formation of N-aryl-4-pyridinamine derivatives has been described where intermediates 29 readily underwent pyridine ring closure to give compounds 30 in good to excellent yields upon treatment with two equivalents of ammonium acetate in hot DMF (Scheme 2.14).¹⁷–¹⁹

Scheme 2.14 Cyclisation of dieneamines using ammonium acetate.

General Procedure for the Synthesis of 2-(Trifluoromethyl)pyridines 30¹⁸

To a solution of the dimethylaminohexadiene-2-one 29 (2 mmol) in dry DMF (5 mL) was added ammonium acetate (0.308 g, 4 mmol) and the mixture was heated at reflux for 1.5 h. The mixture was carefully concentrated under reduced pressure, and then ice water (15 mL) was added. The resulting solid was filtered, washed with water, air-dried and then purified by recrystallisation

A convenient and practical synthetic method to prepare trifluoromethyl nicotinic acid derivatives 32 was conducted through cyclisation of the versatile precursor 31 by heating in ethanol in the presence of excess aqueous ammonium hydroxide (Scheme 2.15).²⁰

Scheme 2.15 Cyclisation of enaminoenones in the presence of ammonium acetate.

Ethyl 2-(trifluoromethyl)nicotinate²⁰

Ethyl 5-(dimethylamino)-2-(2,2,2-trifluoroacetyl)penta-2,4-dienoate (80.50 g, 303.8 mmol) was dissolved in a mixture of ethanol (700 mL) and 25% aqueous ammonia solution (240 mL). The reaction mixture was heated at 70 °C for 20 min, after which it was cooled to rt and the ethanol was removed by evaporation under reduced pressure. The residue was diluted with H2O (200 mL) and extracted with Et2O (2 × 300 mL). The organic phase was washed with brine (200 mL), dried (MgSO4) and filtered through a short silica gel plug and the filtrate was evaporated to give ethyl 2-(trifluoromethyl)nicotinate as a pale yellow oil (59.9 g, 90%).

2.1.1.7 Cyclisations in the Presence of an Alkyne

Beauchemin and co-workers reported a simple acid-catalysed intramolecular hydroamination/isomerisation/aromatisation sequence leading to various pyridines 34 starting from simple acyclic alkynyl oxime precursors 33 (Scheme 2.16). p-Toluenesulphonic acid (2 mol%) was used to catalyse these alkyne annulations. However, the reaction was almost inhibited in the presence of excess acid. The procedure proved applicable to a variety of aldoximes and ketoximes. Ester and amide groups as well as substitution on the terminal position of the alkyne were also tolerated.²¹

Scheme 2.16 Pyridines from the microwave reaction of enynes.

General Procedure: 2,3,5-Trisubstituted Pyridines 34 via Alkyne Cyclisation²¹

An oven-dried microwave tube was charged with a stir bar, capped with a septum and purged with argon for 5 min. The alkynyl oxime 33 (1.00 equiv), p-toluenesulphonic acid (0.02 equiv) and isopropanol or chlorobenzene (0.1 M) were added to the sealed tube, while keeping it under an argon atmosphere. The septum was removed and the tube was then quickly sealed with a microwave cap and heated at 160 °C for 6 h or at 180 °C for 8 h. The reaction solution was then cooled to ambient temperature and acidified using trifluoroacetic acid (TFA) (1.0 equiv). The obtained solution was concentrated under reduced pressure, cooled to 0 °C, basified using triethylamine (1.5 equiv) and directly purified by silica gel chromatography to give the corresponding pyridines 34.

The compounds 2-bromo-4,6-diaryl-N-substituted-3-pyridinecarboxamides 36 were obtained in 73–91% yield via bromination of 2-cyano-3,5-diaryl-5-oxo-N-substituted pentamides 35 in glacial acetic acid at 60–80 °C (Scheme 2.17).²²,²³

Scheme 2.17 Cyclisation via bromination of cyanooxo compounds.

2-Bromo-4,6-diaryl-N-substituted-3-pyridinecarboxamides 36²²

To a solution of the appropriate cyanoamide 35 (5 mmol) in glacial acetic acid (15 mL), heated at 60–70 °C, was added dropwise a solution of bromine (5.5 mmol) in glacial acetic acid (5 mL) with stirring, at a rate maintaining the same temperature over 15 min. After complete addition, stirring was continued for 3 h at the same temperature. The separated solid was collected and purified on preparative thin layer chromatography (TLC) plates using chloroform for elution giving the 2-bromopyridine derivative 36 as colourless crystals (yield: 73–91%).

Iminophosphoranes 37, prepared from the corresponding azides by reaction with triphenylphosphine, underwent consecutive aza-Wittig reaction–electrocyclic cyclisation with isocyanates in toluene at reflux to give 2-aminopyridine derivatives 38 (Scheme 2.18).²⁴,²⁵

Scheme 2.18 Consecutive aza-Wittig reaction-electrolcyclic cyclisation of iminophosphoranes with isocyanates to produce pyridines.

Ethyl 6-Substituted Amino-5-phenyl(styryl)pyridine-2-carboxylates 38²⁵

A solution of iminophosphorane 37 (0.49 mmol) and the appropriate isocyanate (0.49 mmol) in dry toluene (15 mL) was stirred at rt for 2 h and then heated at reflux for 48 h. After cooling, the solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography using EtOAc/hexane (1:3) as eluent to give pyridines 38 which were further crystallised from Et2O/hexane (1:1) (yield: 68–86%).

2.1.1.8 Cyano as the Source of the Pyridine Nitrogen Atom

The 2-aminodec-1-ene-1,1,3-tricarbonitrile 39 was cyclised with hydrogen bromide to the corresponding bromopyridine 40 in 90% yield (Scheme 2.19). However, cyclisation of 39 with sodium methoxide gave a mixture of 41 (69%) and its regioisomer 42 (19%).²⁶,²⁷

Scheme 2.19 Cyclisation of trinitriles with either HBr or sodium ethoxide.

4,6-Diamino-2-bromo-3-cyano-5-heptylpyridine 40²⁷

Hydrogen bromide was bubbled into a solution of 39 (0.128 g, 0.5 6 mmol) in Et2O (45 mL) over a period of 2 h. Initially, the mixture was kept at 0 °C, but as the reaction proceeded, it was allowed to gradually warm to rt. Saturated aqueous NaHCO3 (10 mL) was carefully added, followed by solid sodium carbonate, until no further gas evolution was observed. The aqueous layer was separated and extracted with EtOAc (× 3), the combined organic extract was dried (Na2SO4), and the solvent evaporated to give a yellow oil. Chromatography (0–15% EtOAc in CH2Cl2) gave bromopyridine 40 (0.155 g, 90%) as a white solid.

3-Cyano-4,6-diamino-5-heptyl-2-methoxypyridine 41 and 5-Cyano-4,6-diamino-3-heptyl-2-methoxypyridine 42²⁷

Trinitrile 39 (0.474 g, 2.06 mmol) was added to a methanolic solution of sodium methoxide prepared from sodium (0.41 g, 18 mmol) and MeOH (10 mL), and the reaction was heated at reflux for 37 h. The solution was cooled to rt and the solvent was evaporated. Water (20 mL) was added and the mixture was extracted with CH2Cl2 ( × 3). The combined organic extract was dried (MgSO4) and the solvent was evaporated to give a white solid. Chromatography (0–40% ether in hexanes) provided, in order of elution, compound 42 (0.104 g, 19%) and compound 41 (0.370 g, 69%).

Heating 43 at reflux with sodium methoxide in MeOH resulted in cyclisation to the persubstituted pyridine as well as nucleophilic substitution of the bromide with methoxy group to give 44 in 72% yield (Scheme 2.20).²⁸

Scheme 2.20 Sodium methoxide induced cyclisations of trinitriles to pyridines.

4,6-Diamino-3-cyano-2-methoxy-5-(6-methoxyhexyl)pyridine²⁸

The compound 3-amino-4-(6-bromohexyl)-2-cyanopent-2-enedinitrile (0.500 g, 1.69 mmol) was added to a solution of sodium methoxide prepared from sodium metal (0.242 g, 10.5 mmol) and MeOH (15 mL). The resulting solution was heated at reflux for 48 h. The solvent was evaporated and the residue was partitioned between pH 7 aqueous phosphate buffer (0.4 M, 20 mL) and CH2Cl2 (20 mL). The aqueous phase was extracted with additional CH2Cl2 ( × 4). The combined organic fractions were dried (Na2SO4), and the solvent was evaporated to leave an orange oil. Chromatography (40% EtOAc/hexanes) gave pyridine 4 as a white solid (0.338 g, 72%).

Enolacetals 45 undergo intramolecular Ritter reaction accompanied with 1,3-MeS shift in the presence of phosphoric acid to afford a variety of substituted 2,6-dimethylthiopyridines 46 in good yields (Scheme 2.21). Cyclisation of 45 in the presence of bromine and acetic acid yielded the corresponding 2-bromo-6-methylthio-4,5-substituted pyridines 47 in good yields where the methylthio group migration was interrupted by incorporating bromide ion as an external nucleophile.²⁹

Scheme 2.21 Intramolecular Ritter reactions of enolacetals with 1,3-MeS shift to substituted 2,6-dimethylthiopyridines.

General Procedure for Synthesis of Substituted Dimethylthiopyridines 46²⁹

Carbinoacetals 45 were treated with orthophosphoric acid (25 mL, 88%) at 130 °C for 3 h. After cooling, the reaction mixture was diluted with water (150 mL) and extracted with CHCl3 (4 × 100 mL). The combined organic phase was washed with water (100 mL), dried (Na2SO4) and evaporated to give crude dimethylthiopyridines 46 as a viscous residue which was purified by silica gel column chromatography using 5% EtOAc/hexane as eluent.

General Procedure for Substituted Bromopyridines 47²⁹

To a cold solution of carbinolacetals 45 (10 mmol), in acetic acid (25 mL), bromine (2.4 g, 15 mmol) was added dropwise and the reaction mixture was stirred for 2 h. The mixture was neutralised with a saturated solution of sodium bicarbonate, extracted with chloroform (3 × 100 mL), washed with water (100 mL), dried (Na2SO4) and evaporated to give crude bromopyridines 47, which were purified by column chromatography over silica gel using hexane as eluent.

Oxime derivatives of 5-oxoalkanenitriles 48 underwent