Iridium – an overview | ScienceDirect Topics

3.4 Pyridines and their hydrogenated analogs

An iridium-catalyzed annulation between 1,2-diarylethanones and 3-aminopropanol leads to site specific 2,3-diarylpyridines 241a in moderate yields (2017TL3398). 3-Aminopropanol served as both a four-atom component and solvent during this procedure, releasing water as a clean by-product. In this method, sequential imine formation, alcohol oxidation and intramolecular cyclization by Knoevenagel reaction may be involved. Green synthesis of substituted pyridines 241b using an inexpensive nickel catalyst has been demonstrated by Banerjee (2018OL5587) (Scheme 67).

Scheme 67

Scheme 67. Ir- and Ni-catalyzed annulation leading to pyridines 241a,b.

Compounds 242 and 243 were obtained using heteropoly acids (H4[PMo11VO40], H4[SiW12O40], H3[PW12O40], etc.) as green, recycleable, and bifunctional (acid and redox) catalysts (Scheme 68) (2010SC1708).

Scheme 68

Scheme 68. Heteropoly acids in the synthesis of pyridines 242 and 243.

By using Ir-precatalyst 244 and different 1,3-amino alcohols as well as primary or the secondary alcohols, pyridines 245 with diverse functional groups can prepared, including challenging unsymmetrically substituted pyridines. A broad spectrum of functional groups is tolerated. In the dehydrogenative condensation steps 3 equiv. of hydrogen are liberated per formed pyridine (Scheme 69) (2013AGE6326).

Scheme 69

Scheme 69. Synthesis of polysubstituted pyridines 245.

The ruthenium complex 246 exhibits extremely high efficiency toward the coupling cyclization of γ-amino alcohols with secondary alcohols. The corresponding products, pyridine or quinoline derivatives, are obtained in good to high isolated yields. On the basis of density functional theory (DFT) calculations, the relative free energies of several possible intermediates within the formation of 2-methyl-5,6,7,8-tetrahydroquinoline 247 from 3-amino-1-butanol and cyclohexanol were proposed for a plausible reaction mechanism shown in Scheme 70. First, the dehydrogenation of the cyclohexanol forms a 4.7 kcal/mol less stable cyclohexanone 248, which further condenses with a 3-amino-1-butanol to produce the intermediate 249 (ΔG 10.5 kcal/mol) with the dissociation of a water. The dehydrogenation of 249 with a Csingle bondC coupling cyclization forms intermediate 250 (ΔG 10.6 kcal/mol), which is only 0.1 kcal/mol higher than 249 in free energy; then the dissociation of a water from 250 gives a slightly more stable intermediate 251 (ΔG 7.9 kcal/mol). The dehydrogenation of 251 for the formation of the 2-methyl-5,6,7,8-tetrahydroquinoline 247 is a 13.0 kcal/mol downhill step. Besides that, the by-product 252 was experimentally isolated, probably being formed through the dehydrogenation of 250 into intermediates 253 and a following proton transfer from carbon to nitrogen. Alternatively, 253 could also be formed through the dehydrogenation of 249 for the formation of an unstable intermediate 254 without cyclization, and the following dehydrogenation of 254 with a Csingle bondC coupling cyclization. To find direct evidence for the intermediates, the reaction solution containing 3-amino-1-butanol (1 equiv.), cyclohexanol (2 equiv.), t-BuOK (1 equiv.), 0.35 mmol% Ru-catalyst 246 in a mixture of toluene and THF (4:1) was refluxed for 24 h. The reaction was monitored by the GCMS and NMR, indicating the presence of 2-methyl-5,6,7,8-tetrahydroquinoline 247 and compounds 248, 249, 251, 252 (Scheme 70) (2016ACSC1247).

Scheme 70

Scheme 70. Plausible mechanism for the coupling cyclization of 3-amino-1-butanol with cyclohexanol on the basis of calculated relative free energies.

The Michael addition of 255 to the alkynone 256 worked well to provide the desired enamine 257 in a mixture of acetonitrile and water with the assistance of K2CO3. It was found that the reaction conditions for this step are critical, because when other solvents such as ethanol and DMF or bases were used low yields were observed. Treatment of 257 with I2/Ph3P/imidazole in DCM provided the corresponding iodide, which was refluxed in acetonitrile under the action of triethylamine to deliver the tetrahydropyridine 258 (Scheme 71) (2003TA1969, 2003JOC4400).

Scheme 71

Scheme 71. I2/Ph3P/imidazole-mediated synthesis of tetrahydropyridine 258.

The piperidine derivative 259 was obtained as a minor product by Ru-catalyzed cyclization of 260 (2014T2134). Similar piperidines were also synthesized from N-protected amino alcohol 261. Under mildly acidic conditions (pyridinium p-toluenesulfonate (PPTS) in DCM at room temperature) the two ethoxy groups of acetal 261 exchanged with the alcohol and carbamate groups to give bicyclic N,O-acetal 262 and piperidine derivative 263 (Scheme 72) (2009JOC9460).

Scheme 72

Scheme 72. Synthesis of bicyclic piperidines 259 and 262.

The N-protected racemic substrate 264 was subjected to the key Pd(II)/CuCl2-catalyzed N,O-bicyclization under various reaction conditions to furnish the corresponding 6-oxa-2-azabicyclo[3.2.1]octane 265 (2005CC3948). The NHBoc group deprotection in carbinol 266 followed by 6-endo-trig cyclization using Et3N as base provided a separable mixture of unsaturated azasteroids 267a and 267b in 1.2:1 ratio (Scheme 73) (2017EJMC139).

Scheme 73

Scheme 73. Synthesis of compounds 265 and 267a,b.

Сomparative reactivity of 1,3-, 1,4-, and 1,5-amino alcohol moieties presented within one structure has been investigated (2015JA7915, 2003CC582). Mitsunobu and Appel cyclizations lead to five- and six-membered azaheterocycles, e.g., 268 and 269. In both cases the 1,3-amino alcoholic fragment remains unchanged. Similarly, the compound 270 is configured for intramolecular an aza-Michael addition reaction, which was successfully achieved by the treatment of 270 with 1% HCl in isopropanol to afford 2,4,6-trisubstituted piperidine 271 (Scheme 74) (2009TL5686).

Scheme 74

Scheme 74. Mitsunobu, Appel, and aza-Michael cyclizations leading to piperidines 268, 269, and 271.

During the total synthesis of coccinellid alkaloids Snyder and coworkers performed a series of interesting transformations starting with the key intermediate 272 (2014JA9743). They converted the hydroxy group in 272 to a reactive bromide 273 through the intermediacy of its N-deprotected TFA salt. They then dissolved this material 273 in i-PrOH and treated it with Et3N in the hope that its enamine could be isomerized to its less stable, exocyclic counterpart 274, thereby inducing a terminating cyclization. Pleasingly, this conjecture proved true, affording (−)-propyleine 275 and (−)-isopropyleine 276 as an equilibrating 1:3 mixture in 43% yield (Scheme 75).

Scheme 75

Scheme 75. Synthesis of intermediates to coccinellid alkaloids.

An aza-Achmatowicz reaction with meta-chloroperbenzoic acid (m-CPBA) of the γ-amino alcohols 277 afforded the intended hemiaminals, which, due to the anticipated lability, were directly converted with CH(OEt)3 and BF3·Et2O into the N,O-acetals 278 in moderate to good yields (Scheme 76) (2014OL2038).

Scheme 76

Scheme 76. Synthesis of N,O-acetals 278 by aza-Achmatowicz reaction.

Treatment of the bishomoallylic amine 279 with I2 and NaHCO3 in MeCN followed by the addition of TsNCO (4.5 equiv.) to the reaction mixture after 16 h (i.e., omitting the addition of AgBF4) gave a 76:19:5 mixture of 280, 281, and 282, respectively, in addition to N-(α-methylbenzyl)acetamide (which resulted from loss of the N-α-methylbenzyl group in a Ritter-type process) (Scheme 77) (2016JOC6481).

Scheme 77

Scheme 77. Synthesis of compounds 280–282.

Two new approaches for forming 1,2,3,6-tetrahydropyridines have been reported (2015OL4030). Both reactions employ a strategic phosphate substituent on the nitrogen atom. In the presence of an additional phosphate substituent (X = P(= O)(OEt)2) an anionic cascade can be triggered upon treatment with base. Alternatively, when X = H the same 1,2,3,6-tetrahydropyridine 283 can be accessed via an acid-catalyzed cyclization (Scheme 78).

Scheme 78

Scheme 78. Synthesis of 1,2,3,6-tetrahydropyridine 283.