Spiroborate esters in the borane-mediated asymmetric synthesis of pyridyl and related heterocyclic alcohols

Abstract

The effectiveness of several spiroborate ester catalysts was investigated in the asymmetric borane reduction of 2-, 3-, 4-acetylpyridines under different reaction conditions. Highly enantiomerically enriched 1-(2-, 3- and 4-pyridyl)ethanols and 1-(heterocyclic)ethanols were obtained using 1 to 10% catalytic loads of the spiroborate 5 derived from diphenylprolinol and ethylene glycol.

1. Introduction

Enantiopure secondary alcohols are key intermediaries in the synthesis of a large number of pharmaceutical products.^1,2 In particular, non-racemic alcohols (or their derived amines) containing heterocyclic fragments are known for their biological activity.^3–5 The borane-mediated reduction of prochiral ketones catalyzed by organoboranes, specifically the well known 1,3,2-oxazaborolidines,^6,7,8 have become the preferred approach to obtain non-racemic alcohols due to their high enantioselectivity, predictable absolute stereochemistry, ease of handling and operation, and low environmental impact. However, ketones containing a heteroatom can form borane complexes that not only decrease the borane source but, also, can compete with the enantioselective carbonyl reduction.⁵ Acetylpyridines were reduced with borane employing 20 mol% of B-Me CBS catalyst, but the process gave with low selectivity (< 52% ee). A stoiquiometric amount of catalyst increased the % ee only modestly.⁹ Masui and co-worker¹⁰ introduced a more reactive oxazaborolidine system generated in situ from 10% diphenyl prolinol and trimethylborate and successfully reduced 3- and 4-acetyl heteroaryl ketones with high to excellent enantioselectivity. However, to achieve good selectivity for the 2-acety analogues, a stoiquiometric amount of the amino alcohol was required. In related work, protection of the pyridine nitrogen by a methyl or allylic group significantly increased the enantioselectivity of non-enolizable diaryl- or pyridylaryl ketones.¹¹

Recently, we reported the synthesis of a series of stable spiroborate esters derived from non-racemic 1,2-aminoalcohols and ethylene glycol. These compounds, shown in Fig. 1, were fully characterized by ¹H, ¹³C and ¹¹B NMR, HRMS, IR, optical rotation and mp.¹² All exhibited high efficiency and enantioselectivity as catalysts for the borane-mediated asymmetric reduction of acetophenone.

Fig. 1.

Chiral spiroborates derived from non-racemic 1,2-aminoalcohols

Herein, we present a systematic study of the asymmetric borane-mediated reduction of acetylpyridines and related heterocyclic ketones using the spiroborate esters 1–5 as catalysts. These spiroborates are crystalline compounds that can be stored for long periods of time (> 1 y). Moreover, spiroborate 5 was exposed to moist air at 25 °C for over 24 h, without significant hydrolysis or decomposition being observable by ¹H, ¹³C and ¹¹B NMR analysis.

2. Results and discussion

Initially, we studied the asymmetric reduction of 3-acetylpyridine (6) using spiroborates 1 5. The reduction was carried out with BH₃-SMe₂ (1.6 equiv) and 10 mol % of the catalyst at room temperature. The enantiopure 1-(3-pyridyl)ethanol (7) was isolated after the reaction mixture was quenched with methanol at 0 °C, left overnight at reflux temperature, concentrated under vacuum and purified by column chromatography on deactivated aluminum oxide (method a). The results are summarized in Table 1.

Table 1.

Reduction of 3-acetylpyridine with spiroborate esters 1–5 as catalysts in THF at 25 °C using BH₃-SMe₂

Entry	Cat.	Mol %	Yield (%)	ee(%)a	Conf.
1	1	10	89	91	R (+)
2	2	10	85	96b	S (−)
3	3	10	94	96c	R (+)
4	4	10	88	92	S (−)
5	5	10	80	99	R (+)

^aBy GC of O-acetyl derivatives on a CP-Chiralsil-DexCB column.

^bBy GC on a chiral column.

^cBy ³¹P NMR of phosphonate (CDA).¹⁴

Although the catalysts 1–4 (entries 1–4) provided good enantioselectivity (i.e. >90% ee) spiroborate 5 was particularly effective, (99% ee) for the reduction of 6 (entry 5).

Several studies were carried out to determine the minimum effective catalyst loading, the best reaction temperature and solvent, as well as borane source. For these studies we chose to employ 3-acetylpyridine and the spiroborate 1 which is derived from the inexpensive and commercially available, norephedrine. The optimal amount of 1 was determined through the reduction of 3-acetylpyridine with BH₃-SMe₂ (1.6 equiv) by varying the amount of catalyst from 0.1 to 20 mol % at 25 °C. The results are shown in Table 2. The reduction of 3-acetylpyridine with 20 mol % of catalyst 1 afforded the corresponding alcohol in 91% ee and 84% isolated yield (entry 1). Decreasing the catalyst to 1 mol % slightly decreases the selectivity to 87% ee (entry 5). When smaller amounts of catalyst (>1 mol %) were used, the isolation process was more convenient by vacuum distillation in a Kugelrohr apparatus (method b), usually increasing the chemical yield.

Table 2.

Studies on the reduction of 3-acetylpyridine employing different catalytic load of 1

Entry	Catalyst 1 (mol%)	Yield (%)	eec (%)
1	20	84a	91
2	10	89a	91
3	5	94a	90
4	2.5	95a	89
5	1	93b	87
6	0.5	93b	84
7	0.25	96b	81
8	0.1	91b	65

^aPurified by column chromatography.

^bPurified by distillation.

^cBy GC of O-acetyl derivative on a CP-Chiralsil-DexCB column.

To illustrate the cut-off effect for catalyst 1, the correlation curve between the amount of catalyst and the enantiopurity of 1-(3-pyridyl)ethanol is presented in Fig 2.

Fig. 2.

Amount of catalyst 1 vs % ee of 1-(3-pyridyl)ethanol

Solvents play a key role in the degree of enantioselectivity achieved by the oxazaborolidine catalyzed borane-mediated reductions.^6,7 Therefore, we studied the 3-acetylpyridine reduction in different solvents using only 1 mol% of spiroborate ester 1 to enhance the differences in enantioselectivity. As shown in Table 3 (entry 1), THF was the most effective solvent in terms of chemical yield and enantioselectivity. Less polar solvents such as dichloromethane and toluene led to a decrease in the enantioselectivity of the reaction.

Table 3.

Solvent effects on the reduction of 3-acetylpyridine with 1 mol% of catalyst 1

Entry	Solvent	Yield (%) a	Ee (%)b
1	THF	93	87
2	Dioxane	87	84
3	t-ButylMethylEther	93	71
4	CH2Cl2	89	63
5	Toluene	65	61

^aIsolated yield.

^bBy GC of O-acetyl derivative on a CP-Chiralsil-DexCB column.

Temperature and differing borane source are also critical factors in the enantioselectivity of carbonyl and oxime reductions.^6,12,13 To amplify these changes, the reduction of 3-acetylpyridine was performed with 0.5 mol % spiroborate 1 in THF. The results are summarized in Table 4. Optimal selectivity was achieved at 25 °C in THF using BH₃-SMe₂ (entry 3, 84% ee). Use of BH₃-THF stabilized with NaBH₄ (entries 4) resulted in a dramatic decrease in the enantioselectivity.^7,15

Table 4.

Effect of temperature and different borane sources on the reduction of 3-acetylpyridine in THF with 0.5 mol % of catalyst 1

Entry	Reaction conditions	Ee (%)a
1	BH3- SMe2, 0 °C	61
2	BH3- SMe2, 50 °C	71
3	BH3- SMe2, 25 °C	84
4	BH3-THFb, 25 °C	15
5	BH3-THFc, 25 °C	65
6	BH3-DEA, 25 °C	65

^aDetermined by GC of O-acetyl derivatives.

^bBorane was stabilized with 0.005 M NaBH₄.

^cBorane was stabilized with <0.005 M N-isopropyl N-methyl-tert-butyl amine.

Further studies were extended to the reduction of the 2-, 3-and 4-acetylpyridines with catalyst 5. The results for the 3, and 4-acetylpyridines are shown in Table 5. Initially, the solvent dilution effect on the degree of selectivity was determined for the reduction of 3-acetylpyridine with 1 mol % of spiroborate ester 5. When the catalyst was diluted ten times, the enantiomeric excess dropped from 98% to 82% ee.

Table 5.

Enantioselective reduction of 3- and 4-acetylpyridine with catalyst 5

Entry	Cat. 5 (mol%)	Pyridine	Yield (%)	eea (%)
1	10	3-acetyl	80	99
2	5	3-acetyl	93	99
3	2.5	3-acetyl	91	98
4	1.0	3-acetyl	96	98
5	0.5	3-acetyl	93	94
6	10	4-acetyl	88	99
7	2.5	4-acetyl	95	99
8	1	4-acetyl	92	99

^aBy GC of O-acetyl derivatives on a chiral column.

The reduction of 3-, and 4-acetylpyridines with spiroborate 5 was successfully performed with less than 5 mol % providing the enantiopure pyridyl ethanols (> 98% ee, Table 5, entries 4 and 8) in excellent yield. Remarkably, the reduction of 4-acetyl pyridine at 25 °C in THF using BH₃-SMe₂ afforded 99% ee even with 1 mol% of catalyst. In addition, using 10% catalyst 3 for the reduction of 3-, and 4-acetylpyridine, afforded also high enantioselectivity: 97.2% ee and 96.4% ee, respectively, determined by ³¹P NMR analysis of the phosphonate derivatives, which were prepared by the Alexakis method.¹⁴

The asymmetric borane reduction of 2-substituted heteroaryl ketones is more challenging since borane complexed to the pyridyl nitrogen can reduce the carbonyl group through an intramolecular process, thereby decreasing the enantioselectivity of the reaction. Initially, 2-acetylpyridine (9) was reduced with 0.1 equiv of catalyst 1 and 2 equiv of borane-SMe₂ in THF at room temperature.

Quenching the reaction mixture with methanol (procedure a) for the isolation of 1-(2-pyridyl) ethanol (10) was not effective, perhaps, due to the formation of the stable alkoxyborane complexes. The product was successfully obtained after acid hydrolysis and continuous extraction from the aqueous phase for 3 days with diethyl ether. Nevertheless, the isolated yield was modest. The selectivity was also low, even when 1 equiv of spiroborate 1 was used (entry 1–3, Table 6). Several electrophiles, such as TMSCl, BF₃, B(OMe)₃ and BEt₃, were employed to protect the pyridyl nitrogen. The enantioselectivity, however, was not improved and other side products were observed. The reduction of 2-acetyl pyridine with 1equiv of catalyst 5 and 2 equiv of borane- SMe₂ achieved 93% ee (entry 7). An attempt was made to use the catalyst 5 more efficiently by adding a second load of 2-acetylpyridine after the initial asymmetric reduction was performed, before quenching the reaction. Unfortunately, the enantioselectivity dropped from an initial 93% ee to 58% ee. Borane DEA and catalyst 5 afforded 78% ee (entry 8). Surprisingly, when the reducing reagent was BH₃-DEA, the absolute configuration of product was (S), the opposite compared to the obtained with borane-SMe_2. Since alcohol 10 is water-soluble, the chemical yield was improved by its isolation as its acetyl ester (entries 6 and 7).

Table 6.

Enantioselective reduction of 2-acetylpyridine using spiroborates 1 and 5 as catalysts

Entry	Catalyst	Mol % catalyst	Reagent	Yield %	% eea, (Conf)
1	1	10	BH3-SMe2	59	8 (R)
2	1	25	BH3-SMe2	54	16 (R)
3	1	100	BH3-SMe2	58	40 (R)
4	5	10	BH3-SMe2	-	10 (R)
5	5	50	BH3-SMe2	56	58 (R)
6	5	100	BH3-SMe2	82b	93 (R)
7	5	100	BH3-DEA	79b	78 (S)

^aBy GC on a chiral column (CP-Chiralsil-DexCB) of O-acetate.

^bThe product was isolated as O-acetate derivative.

Other important heteroaryl ketones were reduced with borane employing the spiroborate 5 catalyst to expand the scope of the reaction. The results are presented in Table 7. The 5-acetyl-2-methoxypyridine was effectively reduced with only 1 mol% of catalyst 5 (98% ee, entry 1). Initial reduction of 2-acetylphenothiazine using 1 mol % of catalyst 5 afforded 94% ee, but with 10 mol % of catalyst provided highly enantiopure alcohol 12 (> 99% ee). Interestingly, spiroborate ester 3 derived from (S)-diphenyl valinol also provided 12 with similarly high selectivity. In the reduction of 4′-(imidazol-1-yl) acetophenone with 10 mol % of catalyst 5, the enantiomeric excess of alcohol 13 increased slightly to 92%. The solubility of these large heterocyclic compounds play a crucial role since they require more dilute solutions which affects the effectiveness of the catalyst. The reduction of 3-benzoylpyridine with 10 mol % of 5 produced (R)-phenyl pyridyl methanol (14) in good yield with 83% ee (entry 7).

Table 7.

Enantioselective reduction of other heterocyclic ketones using spiroborates 3 and 5 as catalysts

Entry	Substrate	Cat.	Prod	Mol %	Yield (%)	eea (%)
1	5-acetyl-2-methoxy pyridine	5	11	1	77	98b
2	2-acetylphenothiazine	5	12	1	94	94
3	2-acetylphenothiazine	5	12	10	97	>99
4	2-acetylphenothiazine	3	12	10	95	>99
5	4′-(Imidazol-1-yl) acetophenone)	5	13	1	85	90
6	4′-(Imidazol-1-yl) acetophenone	5	13	10	76	92
7	3-benzoylpyridine	5	14	10	83	83

^aBy ³¹P NMR of phosphonate (CDA) derivative.¹⁴

^bBy GC of O-acetyl derivatives on a chiral column.

3. Conclusion

Prochiral ketones containing heteroaromatic fragments undergo asymmetric reduction with a high degree of enantioselectivity using the novel spiroborates derived from non-racemic 1,2-amino alcohols. This work demonstrates that these crystalline spiroborates can be successfully used as highly efficient chiral transfer reagents employing less than 1 mol % of the catalyst in some cases. The synthesis of important enantio-pure alcohols with heterocyclic groups was also achieved in high chemical yield by a rapid and practical procedure for small and potential large-scale industrial use.

4. Experimental

All reactions were performed in oven-dried glassware (120 °C) under N₂ atmosphere. Air- and moisture sensitive reagents and solvents were transferred via syringe. All reagents were obtained commercially unless otherwise noted. Common solvents were dried and distilled by standard procedures. Anhydrous borane reagents were purchased from Aldrich and used directly from the sealed bottle. Chromatographic purification of products was accomplished using flash chromatography on a Merck silica gel, Si 60^® (200–400 mesh) or Fisher, Activity I, 60–325 mesh acid alumina oxide deactivated by 3% of water, 25–30 g; hexane AcOEt 100:1 to 1:1 using HPLC grade solvents. Thin layer chromatography (TLC) was performed on Merck silica gel plates. Spots were made visible with an UV lamp and/or I₂ vapors. Infrared analyses were performed in a Termo Nicolet 670 FT-IR. ¹H, ¹³C and ¹¹B NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer with standard pulse sequences operating at 400.152 MHz, 100.627 MHz, 128.384 MHz and and 161.992 MHz for ¹H, ¹³C, ¹¹B and ³¹P respectively, in CDCl₃. Chiral gas chromatography analysis was processed on a Hewlett Packard GC 5890 equipped with a Chrompack Chiralsil-Dex-CB column (30 m × 0.25 mm × 0.25μm). GC-MS analysis was processed on a Finnigan Trace GC/Polaris Q Mass detector using a Restek RTX-5MS column. A Perking Elmer Polarimeter Model 341 was used for optical rotation analysis.

4.1 (±)-1-(6-Methoxypyridin-3-yl)-ethanol (11)

To 1-(6-methoxypyridin-3-yl)ethanone (151 mg, 1 mmol) in THF (5 mL) and MeOH (1 mL) was added solid sodium borohydride (38 mg, 1 mmol) at 25 °C. After the reaction mixture was stirred over 1h, the solvents were evaporated and the residue dissolved in water (10 mL). Solid NaCl was added, followed by ammonia hydroxide solution (30% in water, 1 mL). The product was extracted with ether (5×10 mL) and dried over Na₂SO₄. The solvents were removed under vacuum; the residue was distilled in a Kugelrohr apparatus under vacuum to give the final product as colorless oil (133 mg, 87%).

4.2 General preparation of O-acetyl derivatives for GC-analysis of pyridyl ethanols

To a solution of the racemic or enantio-enriched alcohol (20 mg, 0.16 mmol) in dry dichloromethane (1 mL,) in a 2 mL vial was added neat triethylamine (0.1 mL, 0.72 mmol), acetic anhydride (0.1 mL, 1.06 mmol ) and a small crystal of DMAP (5 mg, 0.04 mmol ). The mixture was left at 25 °C for 5 min. After the reaction was complete (followed by TLC, hexane/AcOEt, 1:1), the mixture was transferred to a second 10 mL vial with H₂O (2.5 mL) and shaken for 5 min. Solid Na₂CO₃ (2 g) was carefully added by small portions and left for 5 min, shaking from time to time. Extreme evolution of gas was observed. The O-acetyl derivative was extracted with diethyl ether (4 mL) and the organic phase was transferred with a Pasteur pipette to another vial and analyzed by chiral GC.

4.3 Synthesis of Chiral Derivatizing Agent (CDA) 18 for enantiomeric analysis of alcohols by ³¹P NMR¹⁴

4.3.1 Dicarbamate (16)

In a 250 mL round flask, a solution of (R,R)-(−)-cyclohexane-1,2-diamine (10 g, 88 mmol) in toluene (130 mL) was stirred and cooled to 0 °C. Ethyl chloroformate (18.1 mL, 190 mmol) and NaOH (7.6 g, 190 mmol) in water (8.3 mL) were added simultaneously. Temperature should not reach more than 10 °C during the addition. The mixture was then stirred overnight and the precipitate was filtered and rinsed with CH₂Cl₂. The solid was continuously extracted in a soxhlet system overnight with CH₂Cl₂ (150 mL). The solutions were then mixed, dried over MgSO₄ and concentrated under vacuum. The dicarbamate 17 was obtained as a white solid (89% yield). ¹H NMR (400 MHz, CDCl₃): δ 1.23 (m, CH₃); 1.72 (d, CH₂); 2.0 (d, CH₂); 3.33 (m, CH₂), 4.09 (m, CH), 4.97 (N-H); ¹³C NMR (100 MHz, CDCl₃): δ 14.6 (OCH₂CH₃), 24.8, 32.9, 55.4 (NCH), 60.7 (OCH₂CH₃) and 157.0 (C=O).

4.3.2 (R,R)-N,N′-Dimethyl-cyclohexane-1,2-diamine (17)

To a solution of LiAlH₄ (14.89 g, 392.5 mmol) in dry THF (300 mL) was slowly added compound 16 (20.29 g, 78.5 mmol) in dry THF (50 mL) at 25 °C. The mixture was stirred for 18 h at reflux temperature and cooled to 0 °C. Ethylenediamine (20 mL) was slowly added to the mixture, followed by a 15% NaOH aqueous solution (20 mL) during 1 h. The precipitate was removed through celite pad, and the filtrate was concentrated under vacuum. The celite was then extracted overnight with ethyl ether using a Soxhlet apparatus. The ether solutions were combined, dried over K₂CO₃, filtered and concentrated. After vacuum distillation through a 10 cm Vigreux column, the colorless diamine 17 was obtained in a 61% yield. Bp 83 °C (20 mm Hg); ¹H NMR (400 MHz, CDCl₃): δ 0.98 (m, 1H, CH); 1.25 (m, 1H, CH); 1.51 (s, 1H, N-H); 1.75 (m, 1H, CH); 2.04 (m, 1H, CH); 2.12 (m, 1H, CH); 2.42 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃): δ 25.0 (NHCH₃), 30.8, 33.6, 63.2 (NHCH).

4.3.3 Chloro-1,3-dimethyl-octahydro-benzo[1,3,2] diazaphosphole (CDA 18)

To a solution of the chiral diamine 17 (0.50 g, 3.50 mmol) in CH₂Cl₂ (10 mL) in 25 mL round flask was added triethylamine (2.44 mL, 17.5 mmol), followed by the addition of PCl₃ (1.22 mL, 14.0 mmol). The mixture was concentrated under vacuum to eliminate the excess of PCl₃. The CDA 18 in CDCl₃ (10 mL) was prepared as a standard solution (0.35 M) for further diastereoisomeric analyses.

CDA (18) preparation in a NMR tube

In a dried NMR tube were placed the chiral alcohol (0.02 g, 0.141 mmol) and CDCl₃ (0.4 mL). The tube was shaken until complete dissolution. Et₃N (0.1 mL, 0.717 mmol) was added with a micro syringe, followed by the addition of PCl₃ (0.05 mL, 0.573 mmol). The NMR tube was carefully shaken as an exothermic reaction takes place. The mixture is concentrated under vacuum. The same amounts of CDCl₃ and triethylamine were added again to the NMR tube. The in situ solution of CDA 18 was immediately used. A ³¹P NMR spectrum was recorded to check the reagent; ³¹P NMR (161.992 MHz, CDCl₃); δ 182.

4.3.4 General procedure for derivatization for ³¹P NMR analysis

To the CDA 18 (0.141 mmol) in a NMR tube was added triethylamine (0.1 mL) and diamine 17 (8 to 10 μL). The solution was shaken and the ³¹P NMR spectrum was recorded and analyzed. The conversion of 19 to the corresponding thiophosphoramidates with sulfur (S₈) powder were carried out in the same NMR tube for a second ³¹P NMR determination in cases where the signals were not resolved. A racemic sample of each alcohol was used to identify the relevant signals before each non-racemic derivative was analyzed. This was also necessary to insure that the alcohol enantiomers react at the same rate with the CDA. ³¹P NMR (161.992 MHz, CDCl₃); δ (ppm) derivative of (±)-1-(4-pyridyl)ethanol (8), 141.23 and 140.13 (Δ δ = 1.10); (±)-1-(3-pyridyl)ethanol (7), 141.58 and 140.32 (Δ δ = 1.26); (±)-1-(2-pyridyl)ethanol (10), 141.11 and 138.23 (Δ δ = 2.88).

4.4 (R)-(+)-1-(3-Pyridyl)-ethanol (7) using 1 mol% of catalyst 5

Borane-SMe₂ complex (10 M, 1.6 mL, 16.0 mmol) was added to a solution of (S)-2-[(1,3,2-dioxaborolan-2-yloxy)diphenylmethyl]pyrrolidine (5)¹² (32 mg, 0.10 mmol) in dry THF (5 mL) at 25 °C and the mixture was stirred for 1h. A solution of 3-acetylpyridine (1.21 g, 10.0 mmol) in THF (5 mL) was added for 5 h using an infusion pump. The reaction mixture was stirred at rt over 1 h, then cooled at 0 °C and quenched with methanol (10 mL). After refluxing for 12 h, the solvents were removed under vacuum; the residue was distilled in a Kugelrohr apparatus under vacuum to give the final product as colorless oil (1.18 g, 96%). ¹H NMR (400 MHz, CDCl₃): δ 1.47 (d, J = 6.5 Hz, 3H, Me), 4.88 (q, J = 6.5 Hz, CHMe), 6.02 (br. s, 1H, OH), 7.22 (m, 1H, CH_Ar), 8.29 (m, 1H, CH_Ar), 8.41 (m, 1H, CH_Ar); ¹³C NMR (100 MHz, CDCl₃): δ 25.3, 67.1, 123.6, 133.7, 142.2, 146.9, 147.6. Chiral GC of O-acetyl derivative (Rt 12.05 min) indicated 98.2% ee. [α]²³_D = +41.1° (c 3.6, CHCl₃). Lit.¹⁶ [α]²⁰_D = +52.4° (c 1.40, CHCl₃) for > 95% ee.

4.5 (R)-(+)-1-(4-Pyridyl)-ethanol (8) using 1 mol% of catalyst 5

Borane-SMe₂ complex (10M, 1.6 mL, 16.0 mmol) was added to a solution of (S)-2-[(1,3,2-dioxaborolan-2-yloxy)diphenylmethyl]-pyrrolidine (5)¹² (32 mg, 0.10 mmol) in dry THF (5 mL) at 25 °C. A solution of 4-acetylpyridine (1.21 g, 10.0 mmol) in THF (5 mL) was added for 5 h using an infusion pump. The reaction mixture was stirred at 25 °C over 1h, cooled at 0 °C and quenched with methanol (10 mL). After refluxing for 4 h, the mixture was analyzed by ¹¹B NMR and the N-BH₃ complex signal was observed at −13.28 ppm. More MeOH (10 mL) was added and refluxed for 12 h. The solvents were removed under vacuum and the residue was distilled in a Kugelrohr apparatus under vacuum to give pure (R)-1-(4-pyridyl)ethanol as a white crystalline material (1.13 g, 92%); (mp: 55–58 °C). ¹H NMR (400 MHz, CDCl₃): δ1.39 (d, J = 6.4Hz, 3H); 4.80 (q, J = 6.4Hz, 1H); 5.1 (s, 1H); 7.22 (d, J = 6.0 Hz, 2H); 8.31 (d, J = 5.6Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 25.0 (CH₃); 68.2 (C-H(OH); 120.6 (CH_Ar); 149.0 (CH_Ar); 156.0. Chiral GC of O-acetyl derivative (Rt 12.39 min) indicated 99% ee. [α]²³_D = +49.0 (c 2.5, CHCl₃). Lit.¹⁶ [α]²⁰_D = +42.5° (c 1.04, MeOH) for > 95% ee.

4.6 (R)-(+)-1-(2-Pyridyl)-ethanol (10) using 100 mol % catalyst 5

Borane-SMe₂ complex (10M, 0.5 mL, 5.00 mmol) was added to a solution of (S)-2-((1,3,2-dioxaborolan-2-yloxy)diphenylmethyl)pyrrolidine (5)¹² (808 mg, 2.50 mmol) in dry THF (5 mL) at rt for 4h. A solution of 2-acetylpyridine (303 mg, 2.50 mmol) in THF (2 mL) was added for 1h using an infusion pump. The reaction mixture was stirred 1h at 25 °C, cooled to 0 °C, quenched with methanol (5 mL) and refluxed for 12 h. The solvents were removed under vacuum and the residue dissolved in CH₂Cl₂ (10 mL). Acetic anhydride (2 mL) and triethylamine (2 mL) were added followed by DMAP (5 mg). After stirring at 25 °C for 1 h, the reaction mixture was added to water (15 mL) and quenched with solid Na₂CO₃ (10 g). The organic phase was separated and the product was extracted with ethyl ether (5 × 10 mL). The combined organic extracts were dried with MgSO₄ and concentrated in vacuum. The product was purified by column chromatography (Al₂O₃ deactivated by 3% of water, 35 g; hexane and hexane AcOEt 100:1 to 10:1). The main fractions were concentrated under vacuum and the residue was distilled in Kugelrohr apparatus under vacuum to give the final product as colorless oil (338 mg, 82%). ¹H NMR (400 MHz, CDCl₃): δ 1.61 (d, J = 6.8 Hz, 3H, CHMe), 2.13 (s, 3H, OAc), 5.91 (q, J = 6.8 Hz, 1H, CHMe), 7.20 (m, 1H, CH_Ar), 7.33 (d, J = 8Hz, 1H, CH_Ar), 7.68 (m, 1H, CH_Ar), 8.58 (m, 1H, CH_Ar); ¹³C NMR (100 MHz, CDCl₃): δ 20.7, 21.3, 73.1, 120.5, 122.7, 136.7, 149.4, 160.3, 170.3. Chiral GC of O-acetyl derivative indicated 92.9 % ee. [α]²³_D= +90.1° (c 2.5, CHCl₃). Lit.¹⁶ [α]²⁰_D = +102.3° (c 1.27, CHCl₃) for > 95% ee.

4.7 (R)-(+)-1-(6-Methoxy-pyridin-3-yl)-ethanol (11) using 1 mol % of catalyst 5

Borane-SMe₂ complex (10M, 0.99 mL, 9.9 mmol) was added to a solution of (S)-2-[(1,3,2-dioxaborolan-2-yloxy)diphenylmethyl]pyrrolidine (5)¹² (19.9 mg, 0.06 mmol) in dry THF (3 mL) at rt and the mixture was stirred for 1h. A solution of 1-(6-methoxypyridin-3-yl)ethanone (930 mg, 6.16 mmol) in THF (5 mL) was added for 5h using an infusion pump. The reaction mixture was stirred at 25 °C over 1 h, then cooled to 0 °C and quenched with methanol (5 mL). After refluxing for 12 h, the solvents were removed under vacuum and the product was purified by column chromatography (Al₂O₃ deactivated by 3% of water, 25 g; hexane AcOEt 100:1 to 1:1). The main fractions were concentrated under vacuum and the residue was distilled in a Kugelrohr apparatus (oven temperature 210 °C) under vacuum (1 mm Hg) to give the final product as colorless oil (726 mg, 77%). IR (CaF₂, film, cm⁻¹): 3355 (br, OH), 2974, 2948, 1609, 1496, 1325, 1286, 1253, 1094, 1029. ¹H NMR (400 MHz, CDCl₃): δ 1.45(d, J = 6.5 Hz, 3H, CHMe), 3.16 (br. s, 1H, OH), 3.89 (s, 3H, OMe), 4.81 (q, J = 6.5, 1H, CHMe), 6.70 (d, J = 8.6 Hz, 1H, CH_Ar), 7.60 (m, 1H, CH_Ar), 8.01 (m, 1H, CH_Ar); ¹³C NMR (100 MHz, CDCl₃): δ 24.8, 53.5, 67.6, 110.8, 133.7, 136.5, 144.1, 163.7. Chiral GC of O-acetyl derivative indicated 98.0 % ee. [α]²³_D= +33.7° (c 2.7, CHCl₃).

4.8 (R)-(+)1-(10H-Phenothiazin-2-yl)-ethanol (12) using 10 mol % catalyst 5

Borane-SMe₂ complex (10.0 M, 2.0 mL, 20 mmol) was added to a solution of spiroborate 5 (0.323g, 1.0 mmol) in dry THF (30 mL) at 25 °C and the mixture was stirred for about 15 min. A solution of 2-acetyl-1-phenothiazine (2.413 g, 10.0 mmol) in dry THF (40 mL) was added to the reaction mixture during 1 h using an infusion pump. The mixture was allowed to react overnight. The reaction was cooled to 0 °C, quenched with MeOH (20 mL) and heated to reflux for 2 h. The solvent was removed in vacuo. The crude product was purified by washing the solid 1-(10H-phenothiazin-3-yl)ethanol with dichloromethane (50 mL) several times to remove traces of impurities and dried overnight under high vacuum obtaining pure (R)-1-(10H-phenothiazin-2-yl)-ethanol (2.375 g, 97.6% yield). Mp 134–136 °C.¹⁸ IR (cm⁻¹): 3396 (NH), 3314 (OH), 1091 (C-O). ¹H NMR (400 MHz, (DMSO): δ 1.27 (d, J = 6.4 Hz, 3H, CH₃); 4.57 (m, 1H, C-HOH); 5.10 (d, J = 4.0 Hz 1H, -OH); 6.7–7.0 (m, 7H, Ar); 8.55 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO): δ 26.2, 68.1, 112.0, 114.6, 114.9, 117.0, 119.4, 122.1, 126.2, 126.7, 127.9, 142.4, 142.7, 147.6. ³¹P NMR (162 MHz, CDCl₃): (Racemic Derivative): δ (ppm) 141.02 and 137.91 (Δδ = 3.11). (Chiral Alcohol): δ (ppm) 137.91 (>99% ee). [α ]²³_D = +24.0° (c 1.0, MeOH).

4.9 (R)-(+)-4′-(Imidozol-1-yl)-phenyl ethanol (13) using 10 mol % catalyst 5

Borane-SMe₂ complex (10M, 2.0 mL, 20.0 mmol) was added to catalyst 5 (323 mg, 0.10 mmol) in dry THF (20 mL) at rt. A solution of 4′-(imidazol-1-yl) acetophenone (1.86 g, 10.0 mmol) in THF (20 mL) was added for 5 h using an infusion pump. The reaction mixture was stirred at 25 °C overnight and then, cooled to 0 °C and quenched with methanol (10 mL). After refluxing overnight, the solvents were removed under vacuum. The crude was purified by flash column chromatography on a silica column (40 g) using ethyl acetate to give the pure 13 as a white crystalline material (1.40 g, 76%), mp: 118–120 °C; ¹H NMR (400 MHz, CDCl₃): δ1.53 (d, J = 6.4Hz, 3H), 3.7. (br s, 1H), 4.96 (q, J = 6.4Hz, 1H), 7.14 (s, 1H); 7.24 (s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.8 (d, J = 8.4 Hz, 2H), 7.69 (s, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 24.5 (CH₃); 69.3 (C-H(OH), 118.3, 121.4, 127.0 (CH_Ar), 130.0, 135.5, 136.2(CH_Ar), 146.0. The product was analyzed by ³¹P NMR with small amount of sulfur; the diastereomers signals at 86.1 ppm (3.5 %) and 85.8 ppm (96%) provided 92.5% ee. [α]²³_D = +31.7 ° (c 0.40, CHCl₃). Lit.¹⁹ [α ]¹⁷_D = −33 (c 0.48, CHCl₃) for >98% (by HPLC) for (S) enantiomer.

4.10 (S)-(+)-Phenyl(pyridin-3-yl)methanol (14) with 10 mol% catalyst 5

Borane-SMe₂ complex (10.0 M, 1.0 mL, 10 mmol) was added to a solution of spiroborate 5 (0.323 g, 1.0 mmol) in dry THF (30 mL) at 25 °C and the mixture was stirred for about 15 min. A solution of 3-benzoylpyridine (1.832 g, 10.0 mmol) in dry THF (10 mL) was added to the reaction mixture during 1 h. The mixture was allowed to react overnight. The reaction mixture was cooled to 0 °C, then MeOH (20 mL) was added and the mixture was heated to reflux for 8 h. Decomposition of N-BH₃ complex was confirmed by ¹¹B NMR and the mixture was concentrated to colorless oil. The residue was distilled under high vacuum in the Kugelrohr oven (140 °C/0.7 mmHg) obtaining pure phenyl (pyridin-3-yl)methanol (1.53 g, 83 % yield). ¹H NMR (400 MHz, CDCl₃): δ 4.20 (s, 1H, OH); 5.84 (s, 1H, C-H); 7.23 (m, 1H, C-H), 7.27 7.38 (m, 5H); 7.71 (m, J = 7.6 Hz, 1H); 8.36 (dd, J = 4.4 Hz, 1H); 8.50 (d, J = 2.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 73.9, 123.5, 126.6, 127.9, 128.7, 134.4, 139.7, 143.2, 148.0, 148.3. Using the in situ CDA solution a diastereomeric sample was prepared and analyzed by ³¹P NMR (161.992 MHz, CDCl₃); the enantio-purity was 83% ee. [α]²³_D = +12.0 (c 1.6, CHCl₃). Lit.²⁰ [α ]²⁰_D = −19.0 (c 1.20, CHCl₃) for 75% ee (by HPLC).