Straightforward access to enantioenriched pyrazyl alcohols using chiral organomagnesiates

Tetrahedron: Asymmetry 23 (2012) 1678–1682

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Straightforward access to enantioenriched pyrazyl alcohols using chiral organomagnesiates Olivier Payen a, Floris Chevallier b, Florence Mongin b, Philippe C. Gros a,⇑ a

Groupe SOR, UMR SRSMC, Université de Lorraine, CNRS, Bât Victor Grignard, Boulevard des Aiguillettes, 54506 Vandoeuvre-Lès-Nancy, France Équipe Chimie et Photonique Moléculaires, Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS–Université de Rennes 1, Bât. 10A, Case 1003, Campus de Beaulieu, Avenue du Général Leclerc, 35042 Rennes Cédex, France

b

a r t i c l e

i n f o

Article history: Received 22 October 2012 Accepted 8 November 2012

a b s t r a c t The clean iodine-metal exchange of iodopyrazine and subsequent enantioselective addition of the intermediate pyrazyl magnesiate to aldehydes using ((R,R)-TADDOLate)Bu2MgLi2 is reported. New chiral pyrazylalcohols were obtained in enantiomeric excesses of up to 90%. Ó 2012 Elsevier Ltd. All rights reserved.

1. Introduction

2. Results and discussion

Heteroaryl carbinols and related compounds are valuable precursors of biologically relevant molecules1 and chiral ligands for asymmetric catalysis and kinetic resolution.2 Their preparation generally involves enantioselective reduction either by hydride transfer3 or by catalytic hydrogenation4 of the corresponding heteroarylketones. Diastereoselective syntheses by trapping 2-pyridyllithium intermediates with naturally occurring optically active ketones have also been reported.5 In contrast, direct access to chiral heteroaryl alcohols via reaction between a heteroaromatic metallic derivative and a prochiral carbonyl electrophile is still an underdeveloped topic.6 In this context, the use of chiral organomagnesiates7 is a promising route that allows us to build a stabilized bimetallic reagent with saturated metal coordination sites thus avoiding side aggregation and the subsequent loss of chirality.8 Pyrazine derivatives are heterocyclic compounds of great interest but the number of derivatives synthesized via metallation processes is much lower than for pyridines due to their higher electrophilicity.9 Furthermore, the presence of two nitrogen atoms at the 1,4-positions can perturb the coordination in the chiral intermediates and thus the enantioselective process. To the best of our knowledge, no chiral pyrazyl alcohol has been synthesized yet from a pyrazyl halide and an aldehyde. In addition, only pyrazyl o-tolyl methanol has been reported using a ruthenium-catalysed asymmetric hydrogenation of pyrazyl o-tolyl ketone.4c Herein we report our investigations on the first reaction of iodopyrazine with chiral organomagnesiates and the synthesis of new enantioenriched pyrazyl alcohols.

We first investigated the reactivity of iodopyrazine10 towards a range of butylmagnesiate containing chiral ligands (Fig. 1). The chiral alcohol or diol was first deprotonated using n-BuLi (1 and 2 equiv for the alcohol and diol, respectively) in THF and the resulting alkoxide was reacted successively with n-BuMgCl (1 equiv) and n-BuLi (1 equiv). The magnesiates were then reacted with iodopyrazine under various conditions to perform the I–Mg exchange, followed by a trapping step using p-anisaldehyde as the electrophile to obtain the enantioenriched pyrazylcarbinols (Scheme 1, Table 1). In preliminary experiments, we first checked the reactivity of Bu3MgLi towards iodopyrazine. While 0.33 equiv of this reagent was reported to promote complete I–Mg exchange,11 in our hands all butyl chains could not be transferred and 0.5 equiv was necessary to complete the reaction. The same behaviour was observed with ((R,R)-TADDOLate)Bu2MgLi2. In fact, no exchange occurred using 0.5 equiv of the reagent (run 1); 1 equiv was needed for the exchange to occur cleanly after 1 h (run 2). This suggested that one butyl chain was non-transferable using both Bu3MgLi and ((R,R)-TADDOLate)Bu2MgLi2. These stoichiometries contrast with those used with 2-bromopyridine which underwent the exchange quantitatively using 0.33 equiv of Bu3MgLi7a or 0.5 equiv of ((R,R)TADDOLate)Bu2MgLi2.7 Such a difference could result from stereoelectronic features exhibited by the pyrazine nucleus. Due to its p-deficient character, pyrazyl was expected to be less coordinated to the central magnesium metal than pyridyl, thus making the transfer of the remaining magnesiate butyl chain more difficult. The quantitative exchange obtained using 1 equiv of ((R,R)-TADDOLate)Bu2MgLi2 followed by trapping with p-anisaldehyde gave the expected alcohol 2a with enantiocontrol in most cases. The enantiomeric excesses were found to be highly

⇑ Corresponding author. Tel.: +33 383684979; fax: +33 383684785. E-mail address: [email protected] (P.C. Gros). 0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetasy.2012.11.003

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LH* =

OH

OH

OH

OH

OH HO OH

(R)-BINOL

Ar

(R)-BIPHEN H2

Ar

Me

(R,R)-TADDOL, Ar= Ph

O

OH

O

OH

T1, Ar=

Ar

(-)-menthol

(S,S)-hydrobenzoin

T2, Ar=

Ar

Me Figure 1. Chiral ligands used herein.

Li 1) n-BuLi (2 equiv) solvent 1, -5°C, 20 min

OH *

LH*

Mg

*

2) n-BuMgCl (1 equiv) -5°C, 20 min 3) n-BuLi (1 equiv) -5°C, 20 min

OH

Bu

O

Bu

O Li L*Bu2MgLi2

N 1) N L*Bu2MgLi2 (n equiv, prepared in solvent 1)

I N

solvent 2, -10 °C, 1 h 2) p-anisaldehyde (n' equiv) -100°C, 1 h 3) Hydrolysis

OMe

N 2a

OH

Scheme 1. Preparation of chiral organomagnesiates and reaction with iodopyrazine.

H O

N

Ar attack of Re face

O O

O

O

Mg

Li

(S)

Ar

N OH major

N

N

Scheme 2. Proposed intermediate for enantioselective addition of pyrazylmagnesiate.

dependent on the aldehyde stoichiometry and solvent employed. Increasing of the organometallic/aldehyde ratio improved the enantioselectivity. Indeed, ee’s ranging from 40% to 80% (runs 2–4) (however with a yield decrease from 51% to 8%) were obtained by decreasing the amount of aldehyde from 1.5 to 1 equiv. An increase in the aldehyde amount (2.5 equiv) was found to be detrimental for both the ee and the yield (run 5). Good ee (76%)

was obtained in a THF-toluene mixture (magnesiate prepared in THF and iodopyrazine added in toluene) but a poor yield was obtained (run 6). Performing the whole reaction in toluene and keeping 1.5 equiv of aldehyde gave 2a in 60% ee with an acceptable 33% yield. Other chiral ligands were screened in this solvent. Substitution of the (R,R)-TADDOL phenyl groups by a para-tertbutyl or two (3,5-) methyls (runs 9 and 10) ensured a less efficient

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Table 1 LH⁄ (n equiv)

Run 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 a b c d e

Solvent 1

(R,R)-TADDOL (0.5) (R,R)-TADDOL (1) (R,R)-TADDOL (1) (R,R)-TADDOL (1) (R,R)-TADDOL (1) (R,R)-TADDOL (1) (R,R)-TADDOL (1) (R,R)-TADDOL (1) T1 (1) T2 (1) (R)-BINOL (1) (R)-BIPHEN H2 (1) (S,S)-Hydrobenzoin (1) ()-Menthol (1) (R,R)-TADDOL (1)

Solvent 2

THF THF THF THF THF THF THF Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene

THF THF THF THF THF Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene

N

N

I

1) ((R,R)-TADDOLate)Bu2MgLi2 (1 equiv), toluene -30 to -10°C, 1 h

N

2) RCHO (2.5 equiv) -100°C, 1 h 3) Hydrolysis

N

R OH 2a-i

Run

Product, yielda (%)

R

eeb (%)

1

OMe

2a, 22

72

2

NMe2

2b, 17

86

3

CF3

2c, 14

12

2d, 25

80

2e, 10

90

2f, 40

64

2g, 13

46

2h, 11

78

2i, 15

rac

MeO 4

Me2N 5

Me 6

Cl 7

8

MeO 9 b

1.5 1.5 1.2 1.0 2.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 2.5

2aa,b (%) e

— 51 11 8 7 8 26 33 35 27 26 23 27 7 22

eec (%) — 40 74 80 66 76 32 60 48 40 4 32d rac 8 72

I–Mg exchange complete unless stated otherwise. Yield after column chromatography. Determined by chiral GC. The opposite enantiomer was obtained. No exchange, starting material recovered.

Table 2 Synthesis of chiral pyrazyl alcohols

a

n0 equiv

t-Bu

Yield after column chromatography. Determined by chiral GC.

enantiocontrol (48 and 40% ee, respectively). (R)-BINOL gave 2a in almost racemic form (run 11) as did (S,S)-hydrobenzoin (run 13)

and ()-menthol (run 14). Interestingly, BIPHEN H2 gave the other enantiomer in 32% ee (run 12). Finally, 72% ee could be obtained by using ((R,R)-TADDOLate)Bu2MgLi2 and 2.5 equiv of aldehyde (run 15). A larger excess (5 equiv) did not improve the results. In order to investigate the scope of the new enantioselective process, the conditions determined in Table 1, run 15 were applied to the preparation of various chiral pyrazyl alcohols (Table 2). The effect of the stereoelectronic features of the aldehydes was found to be critical. The substitution of the ring with electron-donating groups markedly improved the ee’s which increased as a function of the donating ability. Indeed, ee’s increased from 72% to 86% when p-dimethylamino was used instead of the p-methoxy group (runs 1 and 2). In contrast, the electron withdrawing p-CF3 group led to much lower enantiocontrol (12% ee, run 3). The introduction of a substituent at the ortho position gave even better results with methoxy and dimethylamino groups. o-Anisaldehyde and o-dimethylaminobenzaldehyde led to alcohols 2d and 2e in very good ee’s of 80% and 90% (runs 4 and 5). It is worthy of note that the enantioselectivity of the magnesiate procedure is comparable to that of hydrogenation since 2d was obtained in 84% ee via asymmetric hydrogenation of the corresponding ketone.4c Non-coordinating and less electron-donating methyl and chloro substituents gave lower ee’s (64% and 46%, respectively, runs 6 and 7). The enantiocontrol was also efficient in the naphthalene series since 2-methoxy-1-naphthaldehyde gave alcohol 2h in 78% ee (run 8). Finally, pivalaldehyde led to a racemic alcohol, which indicated that the aromatic part of the aldehyde was essential to ensure enantiodiscrimination (run 9). A coordination intermediate explaining the enantiocontrol upon the addition of pyrazylmagnesiates to aldehydes is depicted in Scheme 2. After the reaction of iodopyrazine with ((R,R)TADDOLate)Bu2MgLi2, a butyl group is transferred and replaced by a pyrazyl ligand on magnesium. In agreement with the model proposed by Seebach and co-workers,12 the pseudo axially oriented phenyl group of (R,R)-TADDOL sterically forces the aldehyde to preferentially display its Re-face for attack of the carbonyl by the pyrazyl ligand.13 A major enantiomer with the the S configuration is then expected. This was verified by 1H NMR of the corresponding Mosher esters.14 The increase in enantiomeric excess when coordinating substituents are present ortho to the carbonyl of the aldehyde could be explained by an additional chelation of the lithium cation. The consequence is a decrease of rotational freedom and a better enantiocontrol. This interaction is expected to be highly favoured in a non-coordinating solvent like toluene used

O. Payen et al. / Tetrahedron: Asymmetry 23 (2012) 1678–1682

here. It can be also be seen that the stability of the chiral intermediate should be dependent on the electronic character of the aldehyde. The reaction of the chiral pyrazyl intermediate is expected to be slower with an electron rich aldehyde (e.g. bearing a methoxy group) thus allowing the depicted coordination to occur and formation of the adequate complex. 3. Conclusion We have achieved the first synthesis of enantioenriched pyrazyl alcohols using a chiral organomagnesiate. ((R,R)TADDOLate)Bu2MgLi2 performed a clean iodine–magnesium exchange while transferring its chiral ligand to pyrazine organometallics, then inducing enantioselective addition. Despite moderate yields, due to the low temperature of the aldehyde trapping step, a range of new chiral pyrazyl alcohols have been prepared with up to 90% enantiomeric excess. The best results were obtained with electron rich aromatic aldehydes. This concomitant generation of a sensitive pyrazyl organometallic under non-cryogenic conditions and the enantioselective addition to carbonyl derivatives using an all-in-one reagent is a promising concept for the synthesis of chiral heterocyclic compounds. 4. Experimental section 4.1. General All reactions were carried out under an argon atmosphere. All glassware were flame-dried before use. All reagents, ligands and aldehydes were commercially available and used as received, except for 2-iodopyrazine15 and 2-dimethylamino-benzaldehyde.16 THF and toluene were purified by a solvent purification device. Column chromatography was performed on silica gel Si 60 (63–200 lm). Solvents were used as purchased. Thin-layer chromatography (TLC) was performed on silica gel 60 with fluorescent indicator UV254 (0.2 mm) with UV detection. 1H and 13C NMR spectra were obtained on a 200 MHz spectrometer. Coupling constants are reported in Hertz (Hz). For reactions performed in the asymmetric version, enantiomeric ratios were measured with a gas chromatograph equipped with a CP-Chirasil-DexCB column (5 m  0.25 mm) using nitrogen as the carrier gas (Injection port temperature: 250°C, detector temperature: 275°C). Optical rotations of the enantiomers (k = 589 nm, c 1.0 g/100 mL, CHCl3) were measured by a MCP 300 Anton Paar Polarimeter. 4.2. Procedure for the I–Mg exchange reaction using ((R,R)-TADDOLate)Bu2MgLi2 and the synthesis of enantioenriched pyrazylcarbinols In a Schlenk tube, flushed under argon, (R,R)-TADDOL (0.340 g, 0.728 mmol, 1.0 equiv) was dissolved in anhydrous toluene (C = 0.08 M). Next, n-BuLi (1.4 M in hexanes, 2.0 equiv) was slowly added at 10°C. After stirring at this temperature for 20 min, n-BuMgCl (2.0 M in THF, 1.0 equiv) was added at 10°C and the resulting solution was stirred for additional 20 min at the same temperature. n-BuLi (1.4 M in hexanes, 1.0 equiv) was added at 10°C and the mixture was stirred for 20 min at 10°C. 2-Iodopyrazine (0.150 g, 1.0 equiv) was then added at 30°C. The mixture was stirred for 1 h between 30 and 10°C. The reaction was monitored by TLC (eluent: ethyl acetate/cyclohexane 8/2). The medium was then cooled to 100°C and the aldehyde (1.82 mmol, 2.5 equiv) was added. The mixture was left at 100°C and stirred for 2 h. The reaction was quenched with a saturated aqueous solution of NH4Cl. The aqueous layer was extracted with ethyl acetate and acidified (pH = 3–4) using a sulphuric acid aqueous solution. The aqueous solution was then extracted with ethyl

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acetate. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was then purified by column chromatography over silica gel and analysed by chiral GC to determine enantiomeric ratios. 4.2.1. (S)-(4-Methoxyphenyl)(pyrazin-2-yl)methanol 2a11 2-Iodopyrazine (0.150 g, 0.728 mmol, 1.0 equiv), p-anisaldehyde (0.221 mL, 1.82 mmol, 2.5 equiv). Yield: 25% (40 mg). Pale yellow oil. Rf = 0.38 (ethyl acetate/cyclohexane: 8/2). ee = 72%. ½a27:5 ¼ þ43:9 (c 1.0, CHCl3). Chiral GC conditions: (135 °C, presD sure = 60 kPa, flow rate: 120 mL/min), tR1 = 20.22 min (major enantiomer), tR2 = 22.92 min. 1H NMR (200 MHz, CDCl3) d 3.81 (s, 3H), 4.49 (s, 1H), 5.84 (s, 1H), 6.90 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 8.48 (s, 1H), 8.52 (s, 1H), 8.60 (s, 1H) ppm. 13C NMR (62.5 MHz, CDCl3) d 55.2, 73.7, 114.2 (2C), 128.2 (2C), 134.0, 142.8, 143.2, 143.4, 157.2, 159.5 ppm. HRMS calcd for C12H12N2NaO2 [M+Na]: 239.0791. Found: 239.0790. 4.2.2. (S)-(4-Dimethylaminophenyl)(pyrazin-2-yl)methanol 2b 2-Iodopyrazine (0.150 g, 0.728 mmol, 1.0 equiv), 4-(dimethylamino)benzaldehyde (0.272 g, 1.82 mmol, 2.5 equiv) as a toluene solution (2 mL). Yield: 17% (0.028 g). Yellow oil. Rf = 0.34 (ethyl acetate/cyclohexane: 8/2). ee: 86%. ½a29 D ¼ þ72:9 (c 1.0, CHCl3). Chiral GC conditions: (140 °C, pressure = 60 kPa, flow rate: 120 mL/min), tR1 = 40.02 min (major enantiomer), tR2 = 43.27 min. 1H NMR (200 MHz, CDCl3) d 2.93 (s, 6H), 4.25 (s, 1H), 5.78 (s, 1H), 6.69 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 8.44 (s, 1H), 8.49 (s, 1H), 8.59 (s, 1H) ppm. 13C NMR (62.5 MHz, CDCl3) d 40.5 (2C), 74.0, 112.5 (2C), 127.9 (2C), 129.6, 142.7, 142.9, 143.4, 150.4, 157.6 ppm. HRMS calcd for C13H15N3NaO [M+Na]: 252.1107. Found: 252.1106. 4.2.3. (Pyrazin-2-yl)(4-(trifluoromethyl)phenyl)methanol 2c 2-Iodopyrazine (0.150 g, 0.728 mmol, 1.0 equiv), p(trifluoromethyl)benzaldehyde (0.249 mL, 1.82 mmol, 2.5 equiv). Yield: 14% (0.026 g). Orange oil. Rf = 0.43 (ethyl acetate/cyclohexane: 8/2). ee: 12%. ½a27 D ¼ þ2:0 (c 1.0, CHCl3). Chiral GC conditions: (135 °C, pressure = 60 kPa, flow rate: 120 mL/min), tR1 = 8.06 min (major enantiomer), tR2 = 9.73 min. 1H NMR (200 MHz, CDCl3) d 4.53 (s, 1H), 5.93 (s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 8.52 (s, 2H), 8.59 (s, 1H) ppm. 13C NMR (62.5 MHz, CDCl3) d 73.5, 125.8 (q, JCF = 4.4 Hz), 127.1 (4C), 130.5 (d, JCF = 40 Hz), 143.0, 143.3, 143.8, 145.6, 155.9 ppm.19F NMR (235 MHz, CDCl3) d 62.6 (s) ppm. HRMS calcd for C12H10F3N2O [M+H]+: 255.0740. Found: 255.0748. 4.2.4. (S)-(2-Methoxyphenyl)(pyrazin-2-yl)methanol 2d 2-Iodopyrazine (0.150 g, 0.728 mmol, 1.0 equiv), o-anisaldehyde (0.248 g, 1.82 mmol, 2.5 equiv) as a toluene solution (2 mL). Yield: 25% (0.039 g). Orange paste. Rf = 0.38 (ethyl acetate/cyclohexane: 8/2). ee: 80%. ½a29 D ¼ þ98:4 (c 1.0, CHCl3). Chiral GC conditions: (130 °C, pressure = 60 kPa, flow rate: 120 mL/min), tR1 = 13.32 min, tR2 = 15.01 min (major enantiomer). 1H NMR (200 MHz, CDCl3) d 3.85 (s, 3H), 4.60 (s, 1H), 6.23 (s, 1H), 6.89–7.03 (m, 2H), 7.27–7.41 (m, 2H), 8.46 (s, 1H), 8.50 (s, 1H), 8.70 (s, 1H) ppm. 13C NMR (62.5 MHz, CDCl3) d 55.3, 69.2, 110.7, 120.9, 127.6, 129.2, 130.0, 142.8, 143.0, 143.6, 156.3, 157.1 ppm. HRMS calcd for C12H12N2NaO2 [M+Na]: 239.0791. Found: 239.0794. 4.2.5. (S)-(2-Dimethylaminophenyl)(pyrazin-2-yl)methanol 2e 2-Iodopyrazine (0.150 g, 0.728 mmol, 1.0 equiv), 2-(dimethylamino)benzaldehyde (0.272 g, 1.82 mmol, 2.5 equiv) as a toluene solution (4 mL). Yield: 10% (0.017 g). Orange oil. Rf = 0.46 (ethyl acetate/cyclohexane: 8/2). ee: 90%. ½a23 D ¼ þ5:3 (c 1.0, CHCl3). Chiral GC conditions: (125 °C, pressure = 60 kPa, flow rate: 120 mL/min), tR1 = 16.66 min (major enantiomer), tR2 = 18.81 min.

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1

H NMR (200 MHz, CDCl3) d 2.65 (s, 6H), 3.65 (s, 1H), 6.17 (s, 1H), 7.15 (m, 2H), 7.29 (m, 2H), 8.45 (s, 1H), 8.49 (s, 1H), 8.83 (s, 1H) ppm. 13C NMR (62.5 MHz, CDCl3) d 45.9 (2C), 74.4, 121.9, 125.5, 128.8, 129.1, 136.4, 142.9, 143.1, 143.4, 151.9, 158.6 ppm. HRMS calcd for C13H15N3NaO [M+Na]: 252.1107. Found: 252.1111.

(major enantiomer). HRMS calcd for C12H12N2NaO2 [M+Na]: 239.0791. Found: 239.0793.

4.2.6. (S)-(Pyrazin-2-yl)(o-tolyl)methanol 2f4c 2-Iodopyrazine (0.150 g, 0.728 mmol, 1.0 equiv), o-tolualdehyde (0.210 mL, 1.82 mmol, 2.5 equiv). Yield: 40% (0.059 g). Pale yellow oil. Rf = 0.47 (ethyl acetate/cyclohexane: 8/2). ee: 64%. ½a30 D ¼ þ41:7 (c 1.0, CHCl3). Chiral GC conditions: (120 °C, pressure = 60 kPa, flow rate: 120 mL/min), tR1 = 18.15 min (major enantiomer), tR2 = 20.93 min. 1H NMR (200 MHz, CDCl3) d 2.35 (s, 3H), 4.71 (s, 1H), 6.08 (s, 1H), 7.20–7.22 (m, 3H), 7.29–7.33 (m, 1H), 8.44 (s, 1H), 8.50 (s, 2H) ppm. 13C NMR (62.5 MHz, CDCl3) d 19.4, 71.7, 126.3, 127.3, 128.1, 130.9, 135.9, 139.5, 142.9, 143.0, 143.3, 157.1 ppm. HRMS calcd for C12H13N2O [M+H]+: 201.1022. Found: 201.1020.

The alcohol was dissolved in dry CH2Cl2 (Concentration equal to 0.033 M). (R)-Methoxyphenylacetic acid [(R)-MPA] (3.0 equiv), DMAP (0.2 equiv) and dicyclohexylcarbodiimide (2.0 equiv) were then added to the solution in a Schlenk tube under argon. The resulting mixture was stirred for 15 h at room temperature. After the solvent was removed, the crude residue was directly analysed by NMR. It consisted of a mixture of (R,S)- and (R,R)-diastereoisomers. The 1H NMR in CDCl3 showed a specific chemical shift for the H3 proton of pyrazine in each diasteroisomer, the most shielded corresponding to the (R,R) form.4b For each ester, the absolute configuration of the major diastereoisomer was (R,S). It is deduced for each alcohol that the configuration of the major enantiomer was (S). The chemical shifts of the H-3 protons in the diastereoisomers are given in chiral product characterization. Data for the (R)-MPA ester of (S)-(4-methoxyphenyl)(pyrazin-2-yl) methanol 2a. 1H NMR (200 MHz, CDCl3) d H3 8.06 (R,R), 8.53 (R,S) ppm. Data for the (R)-MPA ester of (S)-(2-chlorophenyl)(pyrazin-2-yl) methanol 2g. 1H NMR (200 MHz, CDCl3) d H3 8.22 (R,R), 8.55 (R,S) ppm.

4.2.7. (S)-(2-Chlorophenyl)(pyrazin-2-yl)methanol 2g 2-Iodopyrazine (0.150 g, 0.728 mmol, 1.0 equiv), 2-chlorobenzaldehyde (0.205 mL, 1.82 mmol, 2.5 equiv). Yield: 13% (0.021 g). Yellow oil. Rf = 0.56 (ethyl acetate/cyclohexane: 8/ 1 2). ee: 46%. ½a29 D ¼ þ61:6 (c 1.0, CHCl3). H NMR (200 MHz, CDCl3) d 4.69 (s, 1H), 6.37 (s, 1H), 7.29 (t, J = 3.5 Hz, 2H), 7.40–7.51 (m, 2H), 8.53 (s, 1H), 8.56 (s, 1H), 8.64 (s, 1H) ppm. 13C NMR (62.5 MHz, CDCl3) d 70.2, 127.4, 128.6, 129.4, 129.7, 132.6, 139.1, 143.0, 143.6 (2C), 155.7 ppm. HRMS calcd for C11H9ClN2NaO [M+Na]: 243.0296. Found: 243.0307. 4.2.8. (S)-(2-Methoxy-1-naphthyl)(pyrazin-2-yl)methanol (2h) 2-Iodopyrazine (0.150 g, 0.728 mmol, 1.0 equiv), 2-methoxy-1-naphthaldehyde (mL, 1.82 mmol, 2.5 equiv). Yield: 11% (0.021 g). Yellow oil. Rf = 0.37 (ethyl acetate/cyclohexane: 8/ 2). ee: 78%. ½a21 D ¼ þ61:0 (c 1.0, CHCl3). Chiral GC conditions: (145 °C, pressure = 60 kPa, flow rate: 120 mL/min), tR1 = 65.41 min (major enantiomer), tR2 = 73.54 min. 1H NMR (200 MHz, CDCl3) d 3.93 (s, 3H), 6.93 (s, 1H), 7.29–7.45 (m, 3H), 7.82 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 8.45 (s, 1H), 8.56 (s, 2H) ppm. 13C NMR (62.5 MHz, CDCl3) d 56.6, 67.7, 113.2, 121.5, 123.7 (2C), 126.9, 128.7, 129.7, 130.9, 132.2, 142.5, 142.6, 143.1, 155.2, 158.1 ppm. HRMS calcd for C16H14N2NaO2 [M+Na]: 289.0947. Found: 289.0937. 4.2.9. 2,2-Dimethyl-1-(pyrazin-2-yl)-1-propanol 2i17 2-Iodopyrazine (0.150 g, 0.728 mmol, 1.0 equiv), trimethylacetaldehyde (0.198 mL, 1.82 mmol, 2.5 equiv). Yield: 8% (0.010 g). Yellow oil. Rf = 0.49 (ethyl acetate/cyclohexane: 8/2). Racemic product. Chiral GC conditions: (80 °C, pressure = 60 kPa, flow rate: 120 mL/min), tR1 = 15.71 min, tR2 = 19.24 min. 1H NMR (200 MHz, CDCl3) d 0.94 (s, 9H), 3.66 (s, 1H), 4.45 (s, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.54 (s, 1H), 8.56 (s, 1H) ppm. 13C NMR (62.5 MHz, CDCl3) d 25.7 (3C), 36.5, 78.9, 142.9, 143.4, 144.4, 155.8 ppm. HRMS calcd for C9H15N2O [M+H]+: 167.1179. Found: 167.1178. 4.3. Preparation of (R)-(4-methoxyphenyl)(pyrazin-2-yl)methanol (R)-2a using (R)-BIPHEN H2 The procedure used with (R,R)-TADDOL was repeated using (R)-BIPHEN H2 (0.258 g, 0.728 mmol, 1.0 equiv), 2-iodopyrazine (0.150 g, 0.728 mmol, 1.0 equiv), p-anisaldehyde (0.133 mL, 1.09 mmol, 1.5 equiv). Yield: 32% (0.051 g). ee% = 32. ½a26 D ¼ 19:35 (c 1.0, CHCl3). Chiral GC conditions: (135 °C, pressure = 60 kPa, flow rate: 120 mL/min), tR1 = 21.32 min, tR2 = 23.90 min

4.4. General procedure for esterification of chiral pyrazylcarbinols with (R)-MPA4b,7b

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