Pyridines Substituted with Five Different Elements

Abstract

By stepwise and regioselective installation of functional groups, we have synthesized and characterized two pyridines, 3-fluoro-5-iodo-2-(methylthio)-6-(trimethylsilyl)isonicotinonitrile and 3-fluoro-5-iodo-2-methoxy-6-(trimethylsilyl)isonicotinonitrile, substituted with five different elements, not including hydrogen, using known and newly developed methods. Novel methodology for dehalocyanation of iodopyridines and rapid, high-yielding microwave-assisted acidic hydrolysis of 2-fluoropyridines to their corresponding 2-pyridones are disclosed.

Heavily substituted pyridines with varying functional groups in defined positions have become increasingly important over the last few decades, largely because of their value as building blocks and scaffolds in medicinal chemistry, a discipline which greatly relies on rapid, high-yielding, and selective synthetic protocols. Pyridines are key substructures of many drugs on the market, [¹] of natural products, [²] and also of advanced materials such as organic electrophosphorescent light-emitting diodes (OLEDs) [³] and dye-sensitized solar cells. [4] Synthesis of pyridines with complex substitution patterns - ‘regioexhaustive functionalizations’ - is a field pioneered by Schlosser et al. [5]

During recent work we needed multi-functionalized pyridines with diverse chemical handles in defined positions. Among the features we wanted were functional groups suitable for nucleophilic aromatic substitution (fluorides), [6] addition of organolithium and Grignard reagents (nitriles), [7] catalytic cross-coupling reactions (iodides), [8] protection-deprotection (trimethylsilyls), [5e] [f] and possibly also for selective palladium catalyzed cross-couplings with organozinc reagents (thioethers). [9] Alternatively, direct cross-couplings between trimethylsilylated pyridines and aryl halides [¹0] and between fluoropyrdines and aromatic Grignard reagents [¹¹] have recently been reported and could be envisaged.

Herein, we illustrate the synthesis of two pyridines, title compounds 1 and 2 (Figure  [¹] ), substituted with five different elements, not including hydrogen. Both compounds are derived from commercial 2,3-difluoropyridine (3), by a linear, stepwise, and regioselective installation of functional groups, in five and six steps, respectively (Scheme  [¹] ). To the best of our knowledge, these are the first isolated and characterized pyridines of this kind.

The iodination of commercially available 2,3-difluoropyridine (3) was performed according to a literature procedure to give iodopyridine 4. [5d] This was converted to the corresponding nitrile 5 by a newly developed procedure employing copper(I) cyanide in propionitrile under focused microwave (MW) irradiation, in excellent yield. The usual microwave protocol for the Rosenmund-von Braun reaction with N-methyl-2-pyrrolidone as solvent [¹²] gave only 10% conversion at the same temperature and reaction time, which is why we chose to explore more exotic solvents. We first observed that the reaction seemed to proceed better in acetonitrile, but to avoid high pressures at 160 ˚C in the microwave cavity, we then settled with propionitrile, which has a higher boiling point. (Caution: propionitrile is much more acutely poisonous than acetonitrile and is also a suspected carcinogen!) [¹³] Compound 5 reacted rapidly and with complete regioselectivity with sodium methanethiolate to give compound 9 in quantitative yield. Curiously, our attempts to analogously react 5 with sodium methoxide to get compound 7 were unsuccessful. No selectivity between the 2- and 3-positions was achieved under any of the conditions attempted and the reaction was surprisingly slow. Instead we discovered that it was possible to transform 5 into pyridone 6 by mixing it with aqueous 2 M hydrochloric acid, without co-solvents or any other phase-transfer agents and heating the mixture to 150 ˚C for five minutes via microwave irradiation to give the product in high yield. The microwave assisted acidic hydrolysis of this 2-fluoropyridine is remarkably fast compared to traditional literature procedures which call for reflux conditions for 6 to 50 hours. [¹4]

Pyridone 6 was then O-alkylated with methyl iodide using silver carbonate as base to give methoxypyridine 7. Iodination of 7 and 9 was effected by the same protocol, using freshly prepared lithium 2,2,6,6-tetramethylpiperidide (LiTMP) to give the corresponding 5-lithiopyridines, which were then reacted with elemental iodine to yield compounds 8 and 10, respectively.

It should be noted that the literature is quite inconsistent regarding how many equivalents of LiTMP one should use to achieve ortho-lithiation followed by electrophile trapping of aromatic nitriles in general and cyanopyridines in particular. Some authors report that 1.2 equivalents [¹5] work well while others stipulate the need for 2 equivalents. [¹6] It is assumed that the lithiation proceeds by initial addition of LiTMP over the nitrile triple bond, but whether this intermediate is in equilibrium with the desired ring-lithiated species or not is debated. In our case and in this particular step, 1.2 equivalents consistently gave higher yields and purities of the desired iodides 8 and 10, but this is likely highly substrate dependent (vide infra­).

In the final steps, compounds 8 and 10 were lithiated at the last vacant ring positions and quenched with trimethylsilyl chloride to give title compounds 1 and 2. Conversely, this last step required 2 equivalents of amide base, as 1.2 equivalents generated only trace amounts of the desired products. This may be explained by the fact that both ortho positions relative to the nitrile are already occupied and that the first equivalent base yields an intermediate that cannot be in equilibrium with the desired 6-lithiated species.

In pure form as solids at room temperature, compounds 1 and 2 appear remarkably stable. No degradation could be detected either qualitatively by appearance, or quantitatively by NMR and GC-MS after several weeks under ambient atmosphere, unprotected from light.

Attempts to perform chemoselective reactions on the title compounds 1 and 2, such as cross-couplings, additions and substitutions, are in progress and will be reported in separate publications. Nevertheless, we would like to briefly mention some preliminary findings. We first speculated that compounds 1 and 2 reacted spontaneously with methanol (nucleophilic aromatic substitution on the fluoride) without base or other activating agent, since we repeatedly observed this unwanted side-reaction, often with full conversion, when we diluted the GC-MS samples from the reaction mixture with methanol. This difficulty in preparing an analytical sample was eventually resolved by switching to less reactive solvents such as pentane or dichloromethane. Interestingly, during a controlled experiment in which purified 1 and 2 were dissolved in methanol, no reaction was observed by GC-MS after a period of 15 minutes. We could thereby also conclude that this side-reaction is not an analysis instrument artifact.

However, subsequent addition of a catalytic amount of 2,2,6,6-tetramethyl-piperidine (TMP) to the methanol solution of 2 gave full consumption after only 15 minutes at room temperature and three new products, in roughly a 1:1:1 ratio, whose molecular weights correspond to structures 11, 12, and 10 were detected by GC-MS (Figure  [²] ). It thus appears that under these conditions substitution of the fluoride and desilylation occur at comparable rates. On the other hand, when TMP was added to the methanol solution of 1, only low conversion (20%) back to desilylated compound 8 was observed after 2 hours and no substitution product could be detected. The methylthio substituent in the 2-position thus appears far more activating to the whole system compared to its methoxy counterpart. In summary, it is also likely that our initial observations of methanol-fluoride exchange can be explained by the presence of residual base in the crude reaction mixture.

In conclusion, we have shown a stepwise synthesis of two pyridines, title compounds 1 and 2, substituted with five different elements, not including hydrogen, using known and newly developed methods. The novel microwave assisted cyanation and hydrolysis methods could likely be useful for many chemists, both in academia and industry, working with pyridine synthesis. Subsequent reactions of the final compounds are in progress and will be reported in due course.

All operations were, unless otherwise indicated, performed at r.t. without any special care being taken for the exclusion of air and moisture. Microwave reactions were carried out on a Biotage Initiator Sixty. Gradient column chromatography was performed on a CombiFlash Companion, ISCO Inc. ^¹H NMR and ^¹³C NMR spectra were recorded at 400 MHz or 100 MHz, respectively, on a Bruker DPX 400 spectrometer using the solvent residual peak as reference. GC-MS was performed on a system supplied by Agilent Technologies, consisting of a 6890N G1530N GC, a G2614A auto-sampler, G2613A injector and a G2589N mass spectrometer. The mass spectrometer was equipped with a chemical ionization (CI) ion source. High-resolution mass spectra were recorded on a Waters (Micromass) GCT Time of Flight mass spectrometer coupled to an Agilent Technologies Gas Chromatograph 6890N series. Commercial solvents and reagents were used as received.

2,3-Difluoroisonicotinonitrile (5)

A mixture of 2,3-difluoro-4-iodopyridine (4; 16.87 g, 70 mmol), CuCN (7.52 g, 84.00 mmol) and propionitrile (68 mL) was equally distributed between 6 vials and heated for 3.5 h at 160 ˚C via microwave irradiation. The combined mixtures were concentrated, diluted with CH₂Cl₂ (70 mL), filtered, and again concentrated. The resulting residue was purified by gradient column chromatography (120 g silica gel column, elution with 0-40% EtOAc in heptane) to give an oil (9.86 g, quant.).

^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.30 (dd, J = 5.0, 1.0 Hz, 1 H), 7.97 (dd, J = 4.8, 4.2 Hz, 1 H).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 152.1 (dd, ^¹ J _C,F = 242.6 Hz, ^² J _C,F = 12.8 Hz, 1 C), 146.2 (dd, ^¹ J _C,F = 276.2 Hz, ^² J _C,F = 30.7 Hz, 1 C), 142.6, 124.0, 112.4, 110.7.

CI-MS: m/z (%) = 141.0 ([M + 1]⁺, 100).

3-Fluoro-2-oxo-1,2-dihydropyridine-4-carbonitrile (6)

A mixture of 2,3-difluoroisonicotinonitrile (5; 9.54 g, 68.10 mmol) and aq 2 M HCl (85 mL) was equally distributed between 6 vials and heated for 5 min at 150 ˚C via microwave irradiation. After cooling to r.t., the mixtures were combined (the vials rinsed with MeOH), concentrated, and dried in a vacuum oven overnight at 50 ˚C to give a solid (8.86 g, 94%).

^¹H NMR (400 MHz, DMSO-d ₆): δ = 12.78 (br s, 1 H), 7.44 (dd, J = 6.8, 1.3 Hz, 1 H), 6.48 (dd, J = 6.8, 5.1 Hz, 1 H).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 154.9 (d, J _C,F = 264.2 Hz, 1 C), 154.3 (d, J _C,F = 23.8 Hz, 1 C), 132.5, 112.2, 107.0, 102.7.

CI-MS: m/z (%) = 139 ([M + 1]⁺, 100).

HRMS: m/z calcd for C₆H₃FN₂O: 138.0229; found: 138.0232.

3-Fluoro-2-methoxyisonicotinonitrile (7)

To a slurry of pyridone 6 (8.86 g, 64.16 mmol) and Ag₂CO₃ (26.5 g, 96.24 mmol) in CHCl₃ (200 mL) at r.t. under N₂ was added MeI (4.80 mL, 76.99 mmol). The resulting mixture was stirred at r.t. for 2 d and then filtered through Celite and concentrated. The resulting residue was purified by gradient column chromatography (80 g silica gel column, elution with 0-30% EtOAc in heptane) to give an oil that solidified on standing (2.78 g, 29%).

^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.20 (d, J = 5.1 Hz, 1 H), 7.50 (dd, J = 5.3, 3.8 Hz, 1 H), 4.01 (s, 3 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 153.8, 148.0 (d, J _C,F = 276.0 Hz, 1 C), 142.1, 117.5, 111.8, 108.7, 54.5.

CI-MS: m/z (%) = 153 ([M + 1]⁺, 100).

3-Fluoro-5-iodo-2-methoxyisonicotinonitrile (8)

A 2.5 M hexane solution of n-BuLi (1.380 mL, 3.45 mmol) was added to a solution of 2,2,6,6-tetramethylpiperidine (509 mg, 0.611 mL, 3.60 mmol) in THF (15 mL) at 0 ˚C under N₂. The resulting mixture was stirred for 10 min and then cooled to -78 ˚C. A solution of compound 7 (456 mg, 3 mmol) in THF (5 mL) was added. After 30 min at -78 ˚C, a solution of I₂ (761 mg, 3.00 mmol) in THF (5 mL) was added. The reaction mixture was stirred for 5 min at -78 ˚C, then the cooling bath was removed, and the mixture stirred at r.t. for 1 h. The mixture was quenched with 10% aq Na₂S₂O₃ (5 mL) and the THF was removed in vacuo. CH₂Cl₂ (5 mL) was added to the residue, the organic phase was separated, concentrated and purified by gradient column chromatography (12 g silica gel column, elution with 0-30% EtOAc in heptane) to give a white solid (435 mg, 52%).

^¹H NMR (400 MHz DMSO-d ₆): δ = 8.50 (s, 1 H), 3.97 (s, 3 H).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 153.4, 148.7, 147.37, 116.3, 112.6, 81.7, 54.8.

CI-MS: m/z (%) = 279 ([M + 1]⁺, 100).

HRMS: m/z calcd for C₇H₄FIN₂O: 277.9352; found: 277.9347.

3-Fluoro-5-iodo-2-methoxy-6-(trimethylsilyl)isonicotinonitrile (1)

A 2.5 M hexane solution of n-BuLi (0.151 mL, 0.38 mmol) was added to a solution of 2,2,6,6-tetramethylpiperidine (53.3 mg, 0.064 mL, 0.38 mmol) in anhyd THF (2 mL) at 0 ˚C under N₂. The resulting mixture was stirred for 15 min and then cooled to -78 ˚C. A solution of compound 8 (50 mg, 0.18 mmol) in THF (1 mL) was added dropwise to produce an orange solution. The reaction mixture was stirred for 20 min. A solution of Me₃SiCl (0.046 mL, 0.36 mmol) in THF (1 mL) was added. After 45 min at -78 ˚C, the cooling bath was removed and the mixture allowed to attain r.t. The mixture was evaporated directly on silica gel (0.5 g) and purified by gradient column chromatography (4 g silica gel column, elution with 0-10% EtOAc in heptane) to give a white solid (14 mg, 22%).

^¹H NMR (400 MHz, CDCl₃): δ = 4.05 (s, 3 H), 0.62 (s, 9 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 151.9, 148.3, 134.8, 115.3, 113.9, 111.7, 55.1, 1.6.

CI-MS: m/z (%) = 351 ([M + 1]⁺, 100).

HRMS: m/z calcd for C₁₀H₁₂FIN₂OSi: 349.9748; found: 349.9762.

3-Fluoro-2-(methylthio)isonicotinonitrile (9)

NaSMe (841 mg, 12.00 mmol) was slurried in MeCN (8 mL). A mixture of 2,3-difluoroisonicotinonitrile (5; 1401 mg, 10 mmol) in pentane (10 mL) was added in one portion. The biphasic mixture was stirred vigorously at r.t. for 15 min, during which time a rise in temperature was noted. The mixture was transferred to a separating funnel with H₂O (50 mL) and EtOAc (20 mL). The organic phase was separated and the aqueous phase extracted with EtOAc (2 × 25 mL). The combined organic phases were washed with H₂O (20 mL), dried (MgSO₄), and concentrated to an oil that solidified on standing (1680 mg, quant.).

^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.22 (dd, J = 5.0, 1.0 Hz, 1 H), 7.43 (dd, J = 5.0, 1.0 Hz, 1 H), 2.64 (d, J = 1.8 Hz, 3 H).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 162.4 (d, J _C,F = 240.0 Hz, 1 C), 146.2, 127.1, 124.9, 124.5, 114.3, 17.7.

CI-MS: m/z (%) = 169 ([M + 1]⁺, 100).

HRMS: m/z calcd for C₇H₅FN₂S: 168.0157; found: 168.0161.

3-Fluoro-5-iodo-2-(methylthio)isonicotinonitrile (10)

2,2,6,6-Tetramethylpiperidine (339 mg, 0.407 mL, 2.40 mmol) was dissolved in anhyd THF (10 mL) under argon and cooled to 0 ˚C. A 1.6 M hexane solution of n-BuLi (1.440 mL, 2.30 mmol) was added dropwise over 1 min to produce a yellow solution. After 10 min, the solution was cooled to -78 ˚C. A solution of compound 9 (336 mg, 2 mmol) in anhyd THF (3 mL) was added dropwise over 2 min. After 30 min, a solution of I₂ (508 mg, 2.00 mmol) in anhyd THF (2 mL) was added dropwise. After 30 min, the cooling bath was removed and the mixture allowed to attain r.t. over 1 h. Aq 10% Na₂S₂O₃ (1 mL) was added and most of the THF evaporated in vacuo. The residue was partitioned between Et₂O (25 mL) and H₂O (20 mL). The organic phase was separated, dried (MgSO₄), and evaporated to an oil. The crude product was purified by gradient column chromatography (25 g silica gel column, elution with 0-30% EtOAc in heptane) to give a white solid (451 mg, 77%).

^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.49 (s, 1 H), 2.66 (d, J = 1.8 Hz, 3 H).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 162.1 (d, J _C,F = 241.0 Hz, 1 C), 153.0, 133.3, 127.5, 115.4, 91.8, 17.8.

CI-MS: m/z (%) = 295 ([M + 1]⁺, 100).

HRMS: m/z calcd for C₇H₄FIN₂S: 293.9124; found: 293.9134.

3-Fluoro-5-iodo-2-(methylthio)-6-(trimethylsilyl)isonicotinonitrile (2)

A 2.5 M hexane solution of n-BuLi (0.420 mL, 1.05 mmol) was added to a solution of 2,2,6,6-tetramethylpiperidine (148 mg, 0.178 mL, 1.05 mmol) in anhyd THF (3 mL) at 0 ˚C under argon. The resulting mixture was stirred for 15 min and then cooled to -78 ˚C. A solution of compound 10 (147 mg, 0.5 mmol) in THF (1 mL) was added dropwise to produce a dark-green solution. The reaction mixture was stirred for 25 min. A solution of Me₃SiCl (0.127 mL, 1.00 mmol) in THF (1 mL) was added. After 45 min at -78 ˚C, the cooling bath was removed and the mixture allowed to attain r.t. The mixture was concentrated and purified on a silica gel column by eluting with 0-20% EtOAc in heptane to give an oil, which solidified on standing (115 mg, 63%).

^¹H NMR (400 MHz, DMSO-d ₆): δ = 2.60 (d, J = 1.8 Hz, 3 H), 0.65 (s, 9 H).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.6 (d, J _C,F = 245.5 Hz, 1 C), 143.3, 132.6, 128.9, 125.1, 118.8, 114.3, 17.8, 1.9.

CI-MS: m/z (%) = 367 ([M + 1]⁺, 100).

HRMS: m/z calcd for C₁₀H₁₂FIN₂SSi: 365.9519; found: 365.9503.

Acknowledgment

Dr. Fernando Huerta is gratefully acknowledged for encouragement and inspiration. Dr. Colin Ray and Mr. Alexander Munro are thanked for their wholehearted proof-reading of the manuscript. Dr. Krzysztof Laniewski kindly assisted us with high-resolution mass spectrometry analysis.

References

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For example: the proton pump-inhibitor omeprazole, the hypnotic agent zopiclone, the antidepressant mirtazepine, the anti-inflammatory agent sulfasalazine, and the antiarrhythmic agent disopyramid.

For example: nicotine from tobacco, ricinine from castor bean, pyridoxine (vitamin B₆) from milk or meat products, and epibatidine from the skin of a neotropical poisonous frog, Epipedobates tricolor.

References

• 3a Su S.-J. Chiba T. Adv. Mater.  2008,  20:  2125 
  Search in Google Scholar
• 3b Su S.-J. Sasabe H. Takeda T. Kido J. Chem. Mater.  2008,  20:  1691 
  Search in Google Scholar
• 4 Wu J. Hao S. Lan Z. Lin J. Huang M. Huang Y. Li P. Yin S. Sato T. J. Am. Chem. Soc.  2008,  130:  11568 
  CrossrefSearch in Google Scholar
• 5a Schlosser M. Mongin F. Chem. Soc. Rev.  2007,  36:  1161 
  Search in Google Scholar
• 5b Schlosser M. Rausis T. Bobbio C. Org. Lett.  2005,  7:  127 
  Search in Google Scholar
• 5c Schlosser M. Bobbio C. Rausis T. J. Org. Chem.  2005,  70:  2494 
  Search in Google Scholar
• 5d Bobbio C. Schlosser M. J. Org. Chem.  2005,  70:  3039 
  Search in Google Scholar
• 5e Marzi E. Bobbio C. Cottet F. Schlosser M. Eur. J. Org. Chem.  2005,  2116 
• 5f Cottet F. Schlosser M. Eur. J. Org. Chem.  2004,  3793 
• 5g Bobbio C. Rausis T. Schlosser M. Chem. Eur. J.  2005,  11:  1903 
  Search in Google Scholar
• 5h Cottet F. Marull M. Mongin F. Espinosa D. Schlosser M. Synthesis  2004,  1619 
• 6a Dyker G. Muth O. Eur. J. Org. Chem.  2004,  4319 
• 6b Chambers RD. Hassan MA. Hoskin PR. Kenwright A. Richmond P. Sandford G. J. Fluorine Chem.  2001,  111:  135 
  Search in Google Scholar
• 6c DuPriest MT. Schmidt CL. Kuzmich D. Williams SB. J. Org. Chem.  1986,  51:  2021 
  Search in Google Scholar
• 7 Miller JA. Tetrahedron Lett.  2001,  42:  6991 
  CrossrefSearch in Google Scholar
• 8a Sase S. Jaric M. Metzger A. Malakhov V. Knochel P. J. Org. Chem.  2008,  73:  7380 
  Search in Google Scholar
• 8b Feurerstein M. Doucet H. Maurice S. J. Organomet. Chem.  2003,  687:  327 
  Search in Google Scholar
• 9a Takahiro K. Miyazaki T. Tokuyama H. Fukuyama T. Heterocycles  2009,  77:  233 
  Search in Google Scholar
• 9b Liebeskind LS. Srogl J. Org. Lett.  2002,  4:  979 
  Search in Google Scholar
• 10 Pierrat P. Gros P. Fort Y. Org. Lett.  2005,  7:  697 
  Search in Google Scholar
• 11 Mongin F. Mojovic L. Guillamet B. Trécourt F. Quéguiner G. J. Org. Chem.  2002,  67:  8991 
  CrossrefPubMedSearch in Google Scholar
• 12 Cai L. Liu X. Tao X. Shen D. Synth. Commun.  2004,  34:  1215 
  CrossrefSearch in Google Scholar
• 13 Ahmed AE. Farooquim MYH. Toxicol. Lett.  1982,  12:  157 
  CrossrefSearch in Google Scholar
• For example, see:
• 14a Sutherland A. Gallagher T. J. Org. Chem.  2003,  68:  3352 
  Search in Google Scholar
• 14b Bradlow HL. Vander W. Calvin A. J. Org. Chem.  1949,  14:  509 
  Search in Google Scholar
• 14c Rodgers JD, Robinson DJ, Arvanitis AG, Maduskuie TP, Shepard S, Storace L, Wang H, Rafalski M, Jalluri RK, Combs AP, and Crawley ML. inventors; PCT Int. Appl. WO  2005105814.  ; Chem. Abstr. 2005, 143, 460175
• 15 For example, see: Hansen HM. Lysén M. Begtrup M. Kristensen JL. Tetrahedron  2005,  61:  9955 
  CrossrefSearch in Google Scholar
• 16a Cailly T. Fabis F. Lemaître AB. Rault S. Tetrahedron Lett.  2005,  46:  135 
  Search in Google Scholar
• 16b Cailly T. Fabis F. Bouillon A. Lemaître S. Sopkova J. de Santos O. Rault S. Synlett  2006,  53 

For example: the proton pump-inhibitor omeprazole, the hypnotic agent zopiclone, the antidepressant mirtazepine, the anti-inflammatory agent sulfasalazine, and the antiarrhythmic agent disopyramid.

For example: nicotine from tobacco, ricinine from castor bean, pyridoxine (vitamin B₆) from milk or meat products, and epibatidine from the skin of a neotropical poisonous frog, Epipedobates tricolor.