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DOI: 10.1055/s-0034-1378943
Synthesis of Enantiomerically Pure 2-Heteroaromatic-Substituted 1,2-Amino Alcohols from Chiral tert-Butanesulfinyl Aldimines
Publication History
Received: 01 September 2014
Accepted after revision: 06 November 2014
Publication Date:
10 December 2014 (online)
Abstract
Nine R/S pairs of 2-heteroaromatic-substituted 1,2-amino alcohols were synthesized through 1,2-nucleophilic addition between chiral N-(tert-butylsulfinyl)imines and heteroaromatic carbanions. In most cases, the R S-isomer of N-(tert-butylsulfinyl)imines afforded the R amino alcohol from deprotection of the major diastereomer, and S S-imines afforded the S product. In general, this procedure allows for the preparation of a variety of enantiomeric pairs of 2-heteroaromatic-substituted 1,2-amino alcohols on a practical scale (>10 g) in two steps in good yields.
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Key words
amino alcohols - asymmetric synthesis - chiral auxiliaries - heterocycles - stereoselectivityThe chiral amino alcohol group has proven to be useful in drug discovery. Examples of 2-phenyl-substituted 1,2-amino alcohols include recently disclosed clinical candidates, such as implitapide,[1] [2] ERK 11E,[3] and SDZ MKS 492[4,5] (Figure [1]).
Besides 2-phenyl-substituted 1,2-amino alcohols, some pyridyl analogues have also been explored. An early example is the chiral 2-pyridyl-substituted amino ethanol (R)-1, which was synthesized in five steps using l-serine as the chiral source (Scheme [1]).[6] [7] The limitations of this method are the lack of scope to access different heterocycles, the length of the synthetic sequence, and the cost of using d-serine on large scale if the other enantiomer is required.
In 2008, Wei patented the synthesis of the pyridyl chiral amino alcohol (R)-2a from the corresponding aldehyde via a stereoselective dihydroxylation (Scheme [2]).[8] However, other 2-heteroaromatic-substituted 1,2-amino alcohols have been less explored despite being important building blocks from a drug discovery perspective.[9] [10] [11] [12] [13] The synthetic approaches in Schemes 1 and 2 were not felt to be suitable for medicinal chemists as they either only deliver one enantiomer or would require a lengthy synthetic sequence.
It is known that Ellman chiral tert-butylsulfinamides (S S)-3 and (R S)-3 (Figure [2]) have been used as convenient chiral auxiliaries for the asymmetric synthesis of amines.[14] [15] [16] [17] [18] [19] [20] [21] [22] [23]
Barrow reported the condensation of (R S)-3 with aldehyde and the reaction of the resulting imine with PhMgBr or PhLi to selectively produce chiral phenyl-substituted amino alcohols from ‘Ellman’ and ‘anti-Ellman’ intermediates (Scheme [3]).[24]
The chiral aliphatic substituted amino alcohols were synthesized using the same chemistry strategy from sulfinamide (R S)-3 under different solvents or additives to achieve good dr and yields.[25]
We have favored Barrow’s approach to explore other heteroaromatic-substituted amino alcohols as interesting building blocks for medicinal chemistry (Scheme [4]). This paper demonstrates the feasibility of the Ellman/Barrow strategy to synthesize chiral 2-heteroaromatic-substituted 1,2-amino alcohols with broad scope on >10 g scale.
In brief, condensation of tert-butanesulfinamide (S S)-3 and (R S)-3 with 2-(tert-butyldimethylsilyloxy)acetaldehyde with the aid of copper sulfate in dichloromethane provides tert-butanesulfinyl imines (S S)-4 and (R S)-4.[15] [26] The chiral tert-butanesulfinyl group activates the imine C=N towards the addition of nucleophilic reagents, such as carbanions, and its chirality serves as a directing group to provide products with generally good diastereoselectivity. Subsequent removal of the tert-butanesulfinyl group and TBS protecting group provides the desired products (S)-2a–i, (R)-2a–i.
According to a literature survey, compounds (S/R)-2a, (S/R)-2f, and (S/R)-2g are now commercially available. However, there is no reference available for their preparation except for compound (S)-2a, which was synthesized using a different approach as shown in Scheme [2]. In 2013, Eskildsen and co-workers used tert-butylsulfinamide (R S)-3 and patented the synthesis of 2-heteroaromatic-substituted 1,2-amino alcohols with a similar structure than compound (R)-2a and using a similar addition of heteroaromatic carbanions to butanesulfinimines.[27] Interestingly, none of the five-membered heterocycles has been prepared in this manner.
Nucleophilic addition between imine (S S)-4 and carbanions, in most cases, gives the S S,S (‘anti-Ellman’) diastereomers as the major isomers (Table [1, 6a–g]). When imine (R S)-4 was used, R S,R (‘anti-Ellman’) diastereomers 8a–g were obtained as the major isomers. However, both (S S)-4 and (R S)-4 have an exception: in Table [1], entry h both S S,R (‘Ellman’) and S S,S (‘anti-Ellman’) diastereomers were obtained as a 1:1 mixture (5h/6h) when (S S)-4 was used, while in entry i both R S,S (‘Ellman’) and R S,R (‘anti-Ellman’) diastereomers were obtained as a 1:1 mixture (7i/8i) when (R S)-4 was used. Fortunately, the diastereomeric mixture was easily separated by column chromatography. As we were aiming for >10 g of each enantiomer of amino alcohol, in practice only the major diastereomers 6a–g, and 8a–g for entries a–g, and both diastereomers (5h/6h, 7i/8i) for entries h,i were isolated (Table [1]).
a Yields determined by mass balance of purified material of the major diastereomers.
b Ratios determined by mass balance of isolated diastereomers (both ‘Ellman’ and ‘anti-Ellman’ products).
Among the solvents that Barrow and Ellman studied for the formation of carbanions for high diastereoselectivity,[24] [25] both dichloromethane and toluene were tested at small reaction scale in our work, and they ended up with similar results as THF. Considering THF is a good coordinating and stabilizing solvent for metal cations, we ran all subsequent experiments in anhydrous THF.
a The coefficient of HCl salts was determined by ion chromatography on Metrohm 883 with auto sampler.
b The ee was measured by chiral SFC column. When this failed, the Cbz derivatives were prepared and checked on chiral column.
c For all optical rotation: c = 1, MeOH, 20 °C.
d OR data for the demethylated by-products.
e Final compound was synthesized from the chloro derivative as shown in Scheme [5].
Successful preparation of the nucleophilic heteroaromatic carbanions was key for this chemistry. They were formed in situ through either direct Li–H exchange or Li–halogen exchange. Conditions for the formation of anions such as temperature, organometals, ratio of electrophiles, solvents, co-solvents, etc., have been examined in small scale to achieve stable carbanions and good yields for the subsequent 1,2-addition (see the scale-up synthetic details of 1,2-addition in experimental session). In many cases, n-butyllithium or tert-butyllithium works well to afford the desired carbanion. However, in Table [1], entry a, normal conditions, such as n-BuLi/THF or t-BuLi/THF were examined, but gave low conversion and complex mixtures. We succeeded by using noncryogenic conditions, as reported by Sośnicki.[28] A complex of lithium dibutyl(isopropyl)magnesate and lithium chloride was used as a halogen–magnesium exchange reagent. It can be simply prepared by mixing commercially available isopropylmagnesium chloride and n-butyllithium before use. Despite only giving 20% yield, the resulting Mg–halogen exchange process makes it possible to form the carbanion and perform the subsequent 1,2-addition at 0 °C. In some cases, co-solvents were required to stabilize the in situ formed carbanions. For instance, entry f requires 2 equivalents of tetramethylethylenediamine (TMEDA), and entry g needs 1.1 equivalents of 2,2,6,6-tetramethylpiperidine (TMP).
Entries c and d show an example of controlling the regioselectivity by blocking the C2 position on the imidazole ring. Entry c shows that the proton at C2 in 1-methyl-1H-imidazole is readily deprotonated by n-BuLi. For entry d, Cl substitution was applied to block the C2 position and switch the regioselectivity to C5.[29] The required 2-chloroimidazole (2-chloro-1-methyl-1H-imidazole) was prepared in good yield by halogen–metal exchange between the 2-lithio-1-methyl-1H-imidazole and hexachloroethane.[30]
Entries b and h demonstrate another example of controlling the regioselectivity. In entry b, the C3 carbanion was formed from the bromo precursor,[31] but for entry h the C5 carbanion was generated from Li–H exchange. Interestingly, the diastereoselectivities in entries b and h were also different, although the carbanions in both cases were synthesized at low temperature in the same solvent (THF). Entry b afforded one major diastereomer, as in most cases, while entry h produced a 1:1 diastereomeric mixture.
All diastereomers in Table [1] were treated with HCl to afford the solid amino alcohols as HCl salts (Table [2]). In entry d, the HCl salts of the chloro intermediates 6d and 8d (Table [1]) were dehalogenated with Pd/C under 1 atmosphere of hydrogen in methanol after 1 hour at 0 °C to give the final products of entry d (Scheme [5]).
The stereochemistries of diastereomers in Table [1] were assigned after the chirality of amino alcohols was confirmed. Absolute configuration of one enantiomer from each entry was determined using Mosher method,[32] [33] and the other enantiomer was tentatively assigned by analogy. For instance, the chiral substance (R)-2e was coupled with (S)-Mosher’s acid chloride (S)-(–)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride [(S)-MTPA-Cl] to afford a diastereomer of amide (R)-MTPA-2e; while when it was coupled with (R)-Mosher’s acid chloride, the amide (S)-MTPA-2e was isolated (see Supporting Information).
Protons in R1 or R2 are shielded by the phenyl ring in (S)- or (R)-Mosher amides as shown in Table [3]. The absolute configuration of the substrate 2e is deduced by interpretation of the sign of Δδ SR value, which is defined as the difference between the chemical shift of a certain proton in the (S)-MTPA amide and the chemical shift of the same proton in the (R)-MTPA derivative. All the protons shielded in the (R)-MTPA amide will present a positive Δδ SR value. Instead, those shielded in the (S)-MTPA derivative will present a negative Δδ SR value. As shown in Table [3, ]δ S (Ha) – δ R (Ha) < 0, but δ S (Hb) – δ R (Hb) > 0, so we can not conclude the orientation of R1. However, δ S (Hc) – δ R (Hc) > 0, and δ S (Hd) – δ R (Hd) > 0. Therefore, we conclude that R2 group, which contains Hc and Hd, gets oriented towards the readers. This enantiomer was therefore assigned as R-form, and the configuration of its relevant diastereomer was shown as 8e (Table [1]). The other diastereomer, which was synthesized from 1,2-addition of carbanions with imines (S S)-4 was is assumed to be 6e, and its deprotection product has S-form.
 |
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|
Proton |
δ S |
δ R |
Δδ SR = δ S – δ R |
|
Ha |
3.86 |
3.92 |
–0.06 < 0 |
|
Hb |
4.19 |
4.16 |
+0.03 > 0 |
|
Hc |
3.94 |
3.85 |
+0.09 > 0 |
|
Hd |
7.83 |
7.81 |
+0.02 > 0 |
All amino alcohols were delivered from WuXi AppTec (Shanghai) with pure 1H NMR spectra. They were stored at room temperature for several months. Unfortunately, when we ran 13C NMR experiments, we found the HCl salts of (R)-2a, (S)-2f, and (R)-2f were not stable under such storage conditions. Near full demethylation of (R)-2a happened during storage (see the Supporting Information for NMR spectra). Compounds (S)-2f and (R)-2f were mainly decomposed, which made it difficult to retrieve 13C NMR peaks from spectra. However, by comparing the pure 1H NMR spectra of (S)-2f and (R)-2f with 2D NMR spectra, we managed to report the 13C NMR spectra (see the Supporting Information for spectra). From a structural perspective, one can speculate that a HCl salt of a 2-methoxypyridine derivative may not be stable to storage at room temperature for a long time.
In summary, we have developed protocols to introduce heteroaromatic substitutions onto the α-position of amino alcohols starting from chiral tert-butanesulfinamide. In most cases, R-amino alcohols were diasteroselectively obtained from (R S)-tert-butanesulfinamide, and S-amino alcohols from (S S)-tert-butanesulfinamide, and the chemistry was performed on a practical (>10 g) scale.
Reactions were performed under N2 and with dry glassware unless otherwise stated. Reagents were used as supplied by commercial vendors without further purification or drying. Column (flash) chromatography was performed on 74–165 μm silica gel using EtOAc and petroleum ether (PE), referring to the fraction boiling in the range 30–60 °C. Melting points of final product were measured on a Büchi 510 apparatus. 1H NMR spectra were recorded at 300 or 400 MHz as indicated. 13C NMR spectra were recorded at 75 or 101 MHz as indicated. Diastereomeric ratio (dr) values were determined by mass balance of isolated diastereomers. Enantiomeric excess (ee) values of final amino alcohols were measured on chiral SFC column. If not successful on SFC column, pure chiral substances, such as (S)-2e and (R)-2e, were converted to relevant Cbz derivatives before ee analysis on chiral HPLC column (see the Supporting Information for derivation chemistry). High-resolution mass spectra (HRMS) were recorded for all final compounds, on a Waters LCTP spectrometer fitted with an electrospray (ESI) ion source. All final compounds are assessed as being >95% pure by NMR, and to be the correct mass by HRMS. Because all 1,2-addition intermediates were consumed, some of the addition products are reported with LCMS results, if available. Unfortunately, 13C NMR was not recorded on them. In this paper, synthetic details of one diastereomer of the 1,2-addition intermediates from each entry are provided, while only a general procedure of deprotection for the synthesis of final amino alcohols is given.
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(S)-N-[2-(tert-Butyldimethylsilyloxy)ethylidene]-2-methylpropane-2-sulfinamide [(S S)-4]
To a solution of 2-(tert-butyldimethylsilyloxy)acetaldehyde (150 g, 0.862 mol) in CH2Cl2 (2 L) was added CuSO4 (345 g, 2.16 mol) in portions, followed by (S)-2-methylpropane-2-sulfinamide [(S S)-3; 89 g, 0.819 mol]. The mixture was stirred at r.t. overnight. TLC (PE–EtOAc, 5:1) showed the reaction was complete. The solution was filtered and the filtrate was concentrated under reduced pressure to give the crude product (180 g) as a yellow oil, which was used directly for the next step without further purification.
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(R)-N-[2-(tert-Butyldimethylsilyloxy)ethylidene]-2-methylpropane-2-sulfinamide [(R S)-4]
The title compound was synthesized from (R S)-3 in a same manner as for compound (S S)-4. It can be used directly for the 1,2-addition without further purification, but purification with flash column chromatography on silica gel (PE–EtOAc, 50:1 → 10:1) afforded the title product as a yellow oil; yield: 80 g (35%).
1H NMR (400 MHz, CDCl3): δ = 7.96 (m, 1 H), 4.44 (d, J = 3.2 Hz, 2 H), 1.11 (s, 9 H), 0.82 (s, 9 H), 0.00 (s, 6 H).
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(S)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(6-methoxypyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide (6a)
To THF (2.0 L) in a 3 L three-necked round-bottomed flask equipped with magnetic stirrer and thermometer was added a solution of n-BuLi (250 mL, 2.5 M, 625 mmol) in hexane at 0 °C under N2 with stirring. Then, a solution of i-PrMgCl (2 M, 150 mL, 300 mmol) in THF was added dropwise at 0 °C over 2 h. After the addition, a solution of 5-bromo-2-methoxypyridine (110 g, 585 mmol) in THF (0.4 L) was added dropwise at 0 °C over 1 h. The mixture was stirred for 45 min, while keeping the temperature between –2 to 0 °C. A solution of (S S)-4 (180 g, 649 mmol) in THF (0.5 L) was added dropwise to the above solution at 0 °C over 1 h. The mixture was stirred for 1 h until TLC (50% EtOAc in PE) showed the reaction was complete. The reaction mixture was quenched with sat. aq NH4Cl (1 L), extracted with EtOAc (3 × 0.5 L), and the combined extracts were dried (Na2SO4) and concentrated. The residue was purified on a silica gel column (5–10% EtOAc in PE) to give the crude product; yield: 45.7 g (20%); yellow oil; Rf = 0.35 (EtOAc–PE, 1:2).
1H NMR (300 MHz, CDCl3): δ = 8.12 (d, J = 2.0 Hz, 1 H), 7.53–7.50 (dd, J = 8.4, 2.0 Hz, 1 H), 6.70 (d, J = 8.4 Hz, 1 H), 4.49–4.47 (m, 1 H), 4.26 (m, 1 H, NH), 3.92 (s, 3 H), 3.77–3.73 (m, 1 H), 3.62–3.58 (m, 1 H), 1.22 (s, 9 H), 0.89 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3 H).
MS (ESI+): m/z = 387.2 (M + H)+.
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(R)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(6-methoxypyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide (8a)
The title compound was synthesized and purified in a same manner as for compound 6a, but using (R S)-4 for the 1,2-addition; yield: 43.9 g (20%); yellow oil; Rf = 0.35 (EtOAc–PE, 1:2).
1H NMR (300 MHz, CDCl3): δ = 8.05 (d, J = 2.1 Hz, 1 H), 7.47–7.43 (dd, J = 8.7, 2.1 Hz, 1 H), 6.65 (d, J = 8.7 Hz, 1 H), 4.41 (m, 1 H), 4.18 (m, 1 H, NH), 3.86 (s, 3 H), 3.71–3.66 (m, 1 H), 3.56–3.49 (m, 1 H), 1.18 (s, 9 H), 0.83 (s, 9 H), 0.00 (s, 3 H), –0.02 (s, 3 H).
MS (ESI+): m/z = 387.2 (M + H)+.
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(S)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]-2-methylpropane-2-sulfinamide (6b)
To a solution of 3-bromo-1-methyl-1H-pyrazole (40 g, 248 mmol) (see the Supporting Information for the synthesis) in THF (1 L) was added dropwise a solution of t-BuLi (200 mL, 1.3 M, 260 mmol) in hexane at –90 °C under N2 with stirring over 2 h. The reaction mixture was stirred at –90 °C for further 0.5 h. Then a solution of (S S)-4 (58 g, 209 mmol) in THF (0.2 L) was added dropwise to the reaction mixture at –90 °C. The mixture was stirred and warmed slowly to r.t. overnight. TLC showed the desired spot with Rf = 0.25 (EtOAc). Then the solution was quenched with sat. aq NH4Cl (1 L) and extracted with Et2O (3 × 0.8 L). The combined organic layers were dried (Na2SO4) concentrated. The crude product was purified by column chromatography over silica gel (PE–EtOAc, 20:1 → 2:1) to give the title product; yield: 22.9 g (30%); brown oil; Rf = 0.25 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.21 (d, J = 2.4 Hz, 1 H), 6.10 (d, J = 2.4 Hz, 1 H), 4.58–4.56 (m, 1 H), 4.17 (d, J = 2.8 Hz, 1 H, NH), 3.84–3.68 (m, 5 H), 1.15 (s, 9 H), 0.83 (s, 9 H), 0.00 (s, 3 H), –0.02 (s, 3 H).
MS (ESI+): m/z = 360.2 (M + H)+.
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(R)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]-2-methylpropane-2-sulfinamide (8b)
The title compound was synthesized and purified in the same manner as for compound 6b, but using (R S)-4 for 1,2-addition; yield: 42.9 g (30%); brown oil; Rf = 0.25 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.21 (br s, 1 H), 6.10 (br s, 1 H), 4.58–4.55 (m, 1 H), 4.17 (br s, 1 H, NH), 3.84–3.69 (m, 5 H), 1.15 (s, 9 H), 0.83 (s, 9 H), 0.00 (s, 3 H), –0.02 (s, 3 H).
MS (ESI+): m/z = 360. 2 (M + H)+.
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(S)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-imidazol-2-yl)ethyl]-2-methylpropane-2-sulfinamide (6c)
To a solution of 1-methyl-1H-imidazole (50.0 g, 609 mmol) in THF (1.0 L) at –78 °C under N2 atmosphere, was added a solution of n-BuLi (216 mL, 2.5 M, 540 mmol) in hexane dropwise at –78 °C with stirring over 2 h. After the addition, a solution of (S S)-4 (90.0 g, 324 mmol) in THF (0.5 L) was added dropwise to the mixture, and stirred for 3 h until TLC (PE–EtOAc, 2:1) showed the reaction was complete. The solution was quenched with sat. aq NH4Cl (1 L) at r.t., and extracted with EtOAc (3 × 0.8 L). The combined organic layers were washed with brine (1 L) and concentrated. The crude product was purified by chromatography on silica gel (eluent: PE–EtOAc, 5:1 → 2:1) to give the title compound; yield: 59.9 g (51%); colorless oil; Rf = 0.4 (EtOAc–PE, 1:2).
1H NMR (400 MHz, DMSO-d 6): δ = 7.10 (d, J = 1.2 Hz, 1 H), 6.88 (d, J = 1.2 Hz, 1 H), 5.30 (d, J = 2.8 Hz, 1 H, NH), 4.50 (m, 1 H), 4.02 (d, J = 7.2 Hz, 2 H), 3.68 (s, 3 H), 1.13 (s, 9 H), 0.86 (s, 9 H), 0.06 (s, 3 H), 0.00 (s, 3 H).
MS (ESI+): m/z = 360.2 (M + H)+.
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(R)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-imidazol-2-yl)ethyl]-2-methylpropane-2-sulfinamide (8c)
The title compound was synthesized and purified in the same manner as for compound 6c, but using (R S)-4 for the 1,2-addition; yield: 56.9 g (49%); colorless oil; Rf = 0.4 (EtOAc–PE, 1:2).
1H NMR (400 MHz, DMSO-d 6): δ = 7.04 (d, J = 1.2 Hz, 1 H), 6.81 (d, J = 1.2 Hz, 1 H), 5.26 (d, J = 2.8 Hz, 1 H, NH), 4.43 (m, 1 H), 3.96 (d, J = 6.8 Hz, 2 H), 3.62 (s, 3 H), 1.07 (s, 9 H), 0.80 (s, 9 H), 0.00 (s, 3 H), –0.07 (s, 3 H).
MS (ESI+): m/z = 360.2 (M + H)+.
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(S)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(2-chloro-1-methyl-1H-imidazol-5-yl)ethyl]-2-methylpropane-2-sulfinamide (6d)
To a solution of 2-chloro-1-methyl-1H-imidazole (92.8 g, 796 mmol) (see the Supporting Information for the synthesis) in anhydrous THF (1.8 L) was added dropwise a solution of t-BuLi (336 mL, 2.5 M, 840 mmol) in hexane at –60 °C with stirring over 2 h. After the addition, a solution of (S S)-4 (221.6 g, 799 mmol) in anhydrous THF (1.0 L) was added dropwise to the above solution over 1 h at the same temperature. The resulting mixture was warmed from –60 °C to r.t. with stirring overnight. TLC (PE–EtOAc, 1:1) showed the expected spot (Rf = 0.3). The mixture was poured into sat. aq NH4Cl (1 L) and extracted with EtOAc (3 × 0.8 L). The organic layers were combined, washed with brine (1 L), dried (Na2SO4), and concentrated. The crude product was purified by flash column chromatography on silica gel (PE–EtOAc, 10:1 → 2:1) to give the title compound; yield: 189.9 g (60%); yellow solid; Rf = 0.3 (EtOAc–PE, 1:1).
1H NMR (400 MHz, CDCl3): δ = 6.82 (s, 1 H), 4.35 (m, 1 H), 4.07 (d, J = 4.8 Hz, 1 H, NH), 3.80 (m, 2 H), 3.49 (s, 3 H), 1.12 (s, 9 H), 0.81 (s, 9 H), 0.00 (s, 6 H).
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(R)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(2-chloro-1-methyl-1H-imidazol-5-yl)ethyl]-2-methylpropane-2-sulfinamide (8d)
The title compound was synthesized and purified in a same manner as for compound 6d, but using (R S)-4 for the 1,2-addition; yield: 99.9 g (67%); yellow solid; Rf = 0.3 (EtOAc–PE, 1:1).
1H NMR (400 MHz, CDCl3): δ = 6.91 (s, 1 H), 4.47 (m, 1 H), 4.20 (d, J = 4.8 Hz, 1 H, NH), 3.89–3.95 (m, 2 H), 3.62 (s, 3 H), 1.25 (s, 9 H), 0.93 (s, 9 H), 0.13 (s, 6 H).
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(S)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-2-methylpropane-2-sulfinamide (6e)
To a solution of 1-methyl-1H-[1,2,4]triazole (38.4 g, 462 mmol) in THF (1.2 L) at –78 °C under N2 atmosphere was added a solution of n-BuLi (185 mL, 2.5 M, 462.5 mmol) in hexane dropwise at –78 °C with stirring over 2 h. After the addition, the mixture was stirred at this temperature for 30 min. A solution of (S S)-4 (106.8 g, 385 mmol) in THF (1.2 L) was added dropwise to the mixture, and stirred for 3 h until TLC (PE–EtOAc, 2:1) showed the reaction was complete. The solution was quenched with sat. aq NH4Cl (1 L) at r.t. and extracted with EtOAc (3 × 0.5 L), and the combined organic layers were washed with brine (1 L) and concentrated. The crude product was purified by chromatography on silica gel (eluent: PE–EtOAc, 20:1 → 3:1) to give the title compound; yield: 99.8 g (72%); yellow oil; Rf = 0.3 (EtOAc–PE, 1:5).
1H NMR (400 MHz, CDCl3): δ = 7.87 (s, 1 H), 4.73 (m, 1 H), 4.25 (d, J = 6.4 Hz, 1 H, NH), 4.16–4.20 (m, 1 H), 3.98 (s, 3 H), 3.85–3.90 (m, 1 H), 1.22 (s, 9 H), 0.85 (s, 9 H), 0.05 (s, 3 H), 0.00 (s, 3 H).
MS (ESI+): m/z = 361.2 (M + H)+.
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(R)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-2-methylpropane-2-sulfinamide (8e)
The title compound was synthesized and purified in a similar manner as for compound 6e, but using (R S)-4 for the 1,2-addition; yield: 15.9 g (55%); colorless oil; Rf = 0.3 (EtOAc–PE, 1:5).
1H NMR (400 MHz, CDCl3): δ = 7.87 (s, 1 H), 4.73 (m, 1 H), 4.24 (d, J = 6.4 Hz, 1 H, NH), 4.16–4.20 (m, 1 H), 3.98 (s, 3 H), 3.86–3.90 (m, 1 H), 1.22 (s, 9 H), 0.85 (s, 9 H), 0.05 (s, 3 H), 0.00 (s, 3 H).
MS (ESI+): m/z = 361.2 (M + H)+.
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(S)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(2-methoxypyridin-4-yl)ethyl]-2-methylpropane-2-sulfinamide (6f)
To a mixture of 4-bromo-2-methoxypyridine (50 g, 0.245 mol) and TMEDA (80 mL, 532 mmol) in anhydrous THF (1.0 L) at –80 °C under N2 was added a solution of n-BuLi (170 mL, 2.5 M, 425 mmol) in hexane. After the addition, the mixture was stirred for 10 min at –80 °C. A solution of (S S)-4 (80 g, 288 mmol) in anhydrous THF (200 mL) was added dropwise below –80 °C. After the addition, TLC (EtOAc–hexane, 1:4) showed the reaction was complete. The mixture was quenched with sat. aq NH4Cl (1 L). The organic layer was separated, dried (Na2SO4), and concentrated under reduced pressure. The residue (ca. 135 g) was purified by flash column chromatography on silica gel (EtOAc–PE, 1:6 → 1:2) to give the expected diastereomer as a yellow oil; yield: 30.9 g (28%); Rf = 0.2 (EtOAc–hexane, 1:4).
1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 5.2 Hz, 1 H), 6.79 (m, 1 H), 6.67 (s, 1 H), 4.43 (m, 1 H), 4.18 (d, J = 2.0 Hz, 1 H, NH), 3.88 (s, 3 H), 3.74–3.78 (m, 1 H), 3.54–3.58 (m, 1 H), 1.19 (s, 9 H), 0.83 (s, 9 H), 0.01 (s, 3 H), –0.03 (s, 3 H).
MS (ESI+): m/z = 387.2 (M + H)+.
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(R)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(2-methoxypyridin-4-yl)ethyl]-2-methylpropane-2-sulfinamide (8f)
The title compound was synthesized and purified in a same manner as for compound 6f, but using (R S)-4 for the 1,2-addition; yield: 39.0 g (41%); yellow oil; Rf = 0.2 (EtOAc–hexane, 1:4).
1H NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 6.4 Hz, 1 H), 6.79 (m, 1 H), 6.69 (s, 1 H), 4.43 (m, 1 H), 4.20 (d, J = 2.4 Hz, 1 H, NH), 3.89 (s, 3 H), 3.76–3.80 (m, 1 H), 3.55–3.60 (m, 1 H), 1.24 (s, 9 H), 0.85 (s, 9 H), 0.03 (s, 3 H), –0.01 (s, 3 H).
MS (ESI+): m/z = 387.2 (M + H)+.
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(S)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(pyrazin-2-yl)ethyl]-2-methylpropane-2-sulfinamide (6g)
To a stirred solution of 2,2,6,6-tetramethylpiperidine (92.7 g, 656 mmol) in THF (1.0 L) was added a solution of n-BuLi (266.7 mL, 2.5 M, 667 mmol) in hexane at –65 °C under N2. The mixture was stirred for 30 min, and then a solution of pyrazine (44.4 g, 554 mmol) in THF (0.3 L) was added dropwise at –65 °C within 30 min at –65 °C. After stirring for another 1 h, a solution of (S S)-4 (160 g, 577 mmol) in THF (0.2 L) was added at –65 °C under N2. The mixture was warmed to r.t. by removing the cooling bath, and the mixture was continuously stirred for 24 h at r.t. until TLC (33% EtOAc in PE) showed (S S)-4 was completely consumed. The mixture was quenched with sat. aq NH4Cl (1 L), extracted with CH2Cl2 (3 × 0.8 L), and the combined organic extracts were dried (Na2SO4). Evaporation of the solvent gave the crude product, which was purified by flash column chromatography on silica gel (PE–EtOAc, 4:1) to give the title product; yield: 41.0 g (20%); yellow oil; Rf = 0.3 (EtOAc–PE, 1:3).
1H NMR (400 MHz, CDCl3): δ = 8.64 (d, J = 1.2 Hz, 1 H), 8.53 (m, 1 H), 8.48 (d, J = 2.8 Hz, 1 H), 4.66 (m, 1 H), 4.45 (d, J = 2.4 Hz, 1 H, NH), 4.00–4.07 (m, 1 H), 3.87–3.97 (m, 1 H), 1.25 (s, 9 H), 0.80 (s, 9 H), –0.04 (s, 3 H), –0.09 (s, 3 H).
MS (ESI+): m/z = 358.2 (M + H)+.
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(R)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(pyrazin-2-yl)ethyl]-2-methylpropane-2-sulfinamide (8g)
The title compound was synthesized and purified in a same manner as for compound 6g, but using (R S)-4 for the 1,2-addition; yield: 47.9 g (22%); brown oil; Rf = 0.3 (EtOAc–PE, 1:3).
1H NMR (300 MHz, CDCl3): δ = 8.69 (br s, 1 H), 8.58 (m, 1 H), 8.53 (m, 1 H), 4.70 (m, 1 H), 4.49 (d, J = 2.4 Hz, 1 H, NH), 4.05–4.20 (m, 1 H), 3.90–4.03 (m, 1 H), 1.29 (s, 9 H), 0.84 (s, 9 H), 0.00 (s, 3 H), –0.05 (s, 3 H).
MS (ESI+): m/z = 358.2 (M + H)+.
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(S)-N-[(R)-2-(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-pyrazol-5-yl)ethyl]-2-methylpropane-2-sulfinamide (5h) and (S)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-pyrazol-5-yl)ethyl]-2-methylpropane-2-sulfinamide (6h)
To a solution of 1-methyl-1H-pyrazole (82.1 g, 1.0 mol) in THF (1.5 L) was added dropwise a solution of n-BuLi (440 mL, 2.5 M, 1.1 mol) in hexane at –65 °C under N2. The reaction mixture was stirred at –65 °C for a further 0.5 h. Then a solution of (S S)-4 (277.5 g, 1.0 mol) in THF (0.5 L) was added dropwise to the mixture at –65 °C over 1 h. The mixture was stirred and warmed to r.t. by removing the cooling bath until TLC showed one desired spot with Rf = 0.3 (PE–EtOAc, 1:2) and the second expected spot with Rf = 0.25 (EtOAc). Then the solution was quenched with sat. aq NH4Cl (1 L) and extracted with Et2O (3 × 1.0 L). The combined organic layers were dried (Na2SO4), and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (PE–EtOAc, 20:1 → 2:1) to give 5h in the first fraction and 6h in the second fraction.
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5h
First fraction; yield: 60.0 g (17%); yellow oil; Rf = 0.3 (PE–EtOAc, 1:2).
1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 1.6 Hz, 1 H), 6.21 (d, J = 1.6 Hz, 1 H), 4.49 (m, 1 H), 3.93–4.07 (m, 1 H, NH), 3.86 (s, 1 H), 3.76–3.80 (m, 2 H), 1.15 (s, 9 H), 0.82 (s, 9 H), 0.00 (s, 3 H), –0.02 (s, 3 H).
MS (ESI+): m/z = 360.2 (M + H)+.
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6h
Second fraction; yield: 60.0 g (17%); yellow oil; Rf = 0.25 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.33 (d, J = 1.6 Hz, 1 H), 6.11 (d, J = 1.6 Hz, 1 H), 4.54 (m, 1 H), 4.11 (d, J = 3.6 Hz, 1 H, NH), 3.82 (s, 1 H), 3.69–3.80 (m, 2 H), 1.12 (s, 9 H), 0.82 (s, 9 H), 0.00 (s, 6 H).
MS (ESI+): m/z = 360.2 (M + H)+.
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(R)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(1,4-dimethyl-1H-pyrazol-5-yl)ethyl]-2-methylpropane-2-sulfinamide (7i) and (R)-N-[(R)-2-(tert-Butyldimethylsilyloxy)-1-(1,4-dimethyl-1H-pyrazol-5-yl)ethyl]-2-methylpropane-2-sulfinamide (8i)
To a solution of 1,4-dimethyl-1H-pyrazole (52 g, 541 mmol) in anhydrous THF (1.0 L) was added dropwise n-BuLi (0.22 L, 2.5 M, 550 mmol) at –78 °C with stirring over 2 h. Then, a solution of (R S)-4 (110 g, 396 mmol) in anhydrous THF (1.0 L) was added dropwise to the above solution over 1 h at the same temperature. The resulting mixture was stirred at –78 °C for 1.5 h. TLC (PE–EtOAc, 1:2) showed (R S)-4 was completely consumed. The mixture was poured into sat. aq NH4Cl (1 L) and extracted with EtOAc (3 × 0.8 L). The combined organic extracts were washed with brine (1 L), dried (Na2SO4), and concentrated to give the crude product. Purification by column chromatography on silica gel (PE–EtOAc, 20:1 → 5:1) gave 8i as a yellow oil, and 7i as a yellow solid when the column was continuously eluted with PE–EtOAc (5:1 → 2:1).
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7i
Second fraction; yield: 40.7 g (28%); yellow solid; Rf = 0.25 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.29 (s, 1 H), 4.71 (m, 1 H), 4.03–4.07 (m, 1 H, NH), 3.91 (s, 3 H), 3.87–3.81 (m, 2 H), 2.13 (s, 3 H), 1.23 (s, 9 H), 0.87 (s, 9 H), 0.04 (s, 3 H), 0.00 (s, 3 H).
MS (ESI+): m/z = 374.6 (M + H)+.
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8i
First fraction; yield: 33.3 g (23%); colorless oil; Rf = 0.3 (PE–EtOAc, 1:2).
1H NMR (400 MHz, CDCl3): δ = 7.15 (s, 1 H), 4.62 (m, 1 H), 4.08 (s, 1 H, NH), 3.86 (s, 3 H), 3.81–3.85 (m, 4 H), 3.61–3.70 (m, 1 H), 1.98 (s, 3 H), 1.13 (s, 9 H), 0.83 (s, 9 H), 0.00 (s, 6 H).
MS (ESI+): m/z = 374.6 (M + H)+.
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Chiral Amino Alcohols; General Procedure
To a solution of diastereomer 5h, 6a–h, 7i, 8a–g, or 8i (1 equiv) in MeOH or EtOAc (1–5 mL/mmol) was added a solution of HCl (8–10 equiv) in an organic solvent (MeOH or EtOAc; 4 M, 2–2.5 mL/mmol) at 0 °C. The total concentration of the substrate was 0.2–0.5 M. The mixture was stirred at r.t. for 20 min or longer time, such as overnight, until TLC (for instance 33% EtOAc in PE) showed the starting material was consumed. The reaction mixture was concentrated under reduced pressure. The residue was triturated and washed with EtOAc to give the HCl salt of the chiral amino alcohol. Typically the deprotection yield was >80% (Table [2]). The coefficient of HCl salts was determined by ion chromatography on Metrohm 883 with autosampler at WuXi AppTech.
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(S)-2-Amino-2-(6-methoxypyridin-3-yl)ethanol Dihydrochloride[8] [(S)-2a]
Yield: 17.9 g (85%); yellow solid.
1H NMR (400 MHz, DMSO-d 6): δ = 8.74 (br s, 3 H), 8.31 (d, J = 2.3 Hz, 1 H), 7.99 (dd, J = 8.7, 2.3 Hz, 1 H), 6.93 (d, J = 8.7 Hz, 1 H), 4.22–4.34 (m, 1 H), 3.86 (s, 3 H), 3.68–3.80 (m, 2 H).
13C NMR (101 MHz, DMSO-d 6): δ = 163.3, 146.0, 139.6, 125.0, 110.3, 62.3, 53.8, 53.2.
HRMS (ESI+): m/z calcd for C8H12N2O2 (M + H)+: 169.0977; found: 169.0975.
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(R)-2-Amino-2-(6-methoxypyridin-3-yl)ethanol Dihydrochloride [(R)-2a]
Yield: 7.6 g (84%); yellow solid.
1H NMR (400 MHz, DMSO-d 6): δ = 8.60 (br s, 3 H), 8.27 (d, J = 2.4 Hz, 1 H), 7.91–7.88 (dd, J = 8.4, 2.4 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 4.26 (m, 1 H), 3.84 (s, 3 H), 3.71 (m, 2 H).
13C NMR: Not available, as the compound was demethylated during storage. Please see the Supporting Information for the NMR results of the demethylated by-product.
HRMS (ESI+): m/z calcd for C8H12N2O2 (M + H)+: 169.0977; found: 169.0981.
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(S)-2-Amino-2-(1-methyl-1H-pyrazol-3-yl)ethanol Hydrochloride [(S)-2b]
Yield: 26.9 g (99%); syrupy brown solid.
1H NMR (400 MHz, DMSO-d 6): δ = 8.49 (br s, 3 H), 7.70 (d, J = 2.0 Hz, 1 H), 6.40 (d, J = 2.0 Hz, 1 H), 4.15–4.26 (m, 1 H), 3.81 (s, 3 H), 3.64–3.79 (m, 2 H).
13C NMR (101 MHz, DMSO-d 6): δ = 146.3, 132.0, 104.2, 62.0, 51.0, 38.5.
HRMS (ESI+): m/z calcd for C6H11N3O (M + H)+: 142.0980; found: 142.0988.
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(R)-2-Amino-2-(1-methyl-1H-pyrazol-3-yl)ethanol Hydrochloride [(R)-2b]
Yield: 25.9 g (99%); syrupy brown solid.
1H NMR (400 MHz, DMSO-d 6): δ = 8.44 (br s, 3 H), 7.71 (d, J = 2.0 Hz, 1 H), 6.39 (d, J = 2.0 Hz 1 H), 4.15–4.30 (m, 1 H), 3.84 (s, 3 H), 3.65 – 3.79 (m, 2 H).
13C NMR (101 MHz, DMSO-d 6): δ = 146.2, 132.0, 104.1, 62.0, 51.0, 38.5.
HRMS (ESI+): m/z calcd for C6H11N3O (M + H)+: 142.0980; found: 142.0986.
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(S)-2-Amino-2-(1-methyl-1H-imidazol-2-yl)ethanol Hydrochloride [(S)-2c]
Yield: 26.3 g (89%); off-white solid; mp 153–155 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 9.39 (br s, 3 H), 7.76 (s, 2 H), 4.94 (t, J = 6.3 Hz, 1 H), 3.97–4.06 (m, 2 H), 3.95 (s, 3 H).
13C NMR (101 MHz, DMSO-d 6): δ = 141.1, 124.3, 119.9, 59.8, 46.1, 35.0.
HRMS (ESI+): m/z calcd for C6H11N3O (M + H)+: 142.0980; found: 142.0976.
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(R)-2-Amino-2-(1-methyl-1H-imidazol-2-yl)ethanol Hydrochloride [(R)-2c]
Yield: 26.1 g (93%); off-white solid; mp 153–155 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 9.32 (br s, 3 H), 7.73 (s, 2 H), 4.92 (t, J = 6.3 Hz, 1 H), 3.95–4.09 (m, 2 H), 3.94 (s, 3 H).
13C NMR (101 MHz, DMSO-d 6): δ = 141.1, 124.2, 120.1, 59.9, 46.2, 34.9.
HRMS (ESI+): m/z calcd for C6H11N3O (M + H)+: 142.0980; found: 142.0982.
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(S)-2-Amino-2-(1-methyl-1H-imidazol-5-yl)ethanol Hydrochloride [(S)-2d]
Deprotection of diastereomer 6d (58.0 g, 147.2 mmol) afforded the chlorinated product of the title compound as an intermediate (30.5 g, 143.8 mmol, 98%). The resulting crude was dissolved in MeOH (300 mL), and 10% Pd/C (10.0 g) powder was added. The mixture was stirred at 50 °C under 3 atm of H2 for 2 h. The mixture was filtered and the solvent was concentrated under reduced pressure to give the title compound; yield: 25.0 g (98%); off-white solid; mp 263–264 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 9.12 (s, 1 H), 9.02 (br s, 3 H), 7.83 (s, 1 H), 4.55 (t, J = 5.8 Hz, 1 H), 3.94 (s, 3 H), 3.69–3.91 (m, 2 H).
13C NMR (101 MHz, DMSO-d 6): δ = 136.0, 129.7, 120.0, 60.9, 45.5, 33.8.
HRMS (ESI+): m/z calcd for C6H11N3O (M + H)+: 142.0980; found: 142.0977.
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(R)-2-Amino-2-(1-methyl-1H-imidazol-5-yl)ethanol Hydrochloride [(R)-2d]
Prepared in a similar manner to (S)-2d from the chloro-blocked addition intermediate 8d; yield: 16.8 g (75%); off-white solid; mp 263–264 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 9.17 (s, 1 H), 9.03 (br s, 3 H), 7.86 (s, 1 H), 4.56 (t, J = 5.8 Hz, 1 H), 3.94 (s, 3 H), 3.73–3.92 (m, 2 H).
13C NMR (101 MHz, DMSO-d 6): δ = 135.9, 129.8, 119.7, 60.9, 45.5, 33.8.
HRMS (ESI+): m/z calcd for C6H11N3O (M + H)+: 142.0980; found: 142.0984.
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(S)-2-Amino-2-(1-methyl-1H-1,2,4-triazol-5-yl)ethanol Dihydrochloride [(S)-2e]
Yield: 30.9 g (89%); off-white solid; mp 145–146 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 8.84 (br s, 3 H), 8.00 (s, 1 H), 4.65 – 4.74 (m, 1 H), 3.90 (s, 3 H), 3.86–3.89 (m, 1 H), 3.72 (dd, J = 11.0, 6.5 Hz, 1 H).
13C NMR (101 MHz, DMSO-d 6): δ = 150.8, 150.0, 61.1, 47.2, 35.7.
HRMS (ESI+): m/z calcd for C5H10N4O (M + H)+: 143.0933; found: 143.0934.
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(R)-2-Amino-2-(1-methyl-1H-1,2,4-triazol-5-yl)ethanol Dihydrochloride [(R)-2e]
Yield: 22.9 g (~100%); off-white solid; mp 143–145 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 8.79 (br s, 3 H), 8.00 (s, 1 H), 4.65–4.74 (m, 1 H), 3.90 (s, 3 H), 3.83–3.89 (m, 1 H), 3.73 (dd, J = 11.0, 6.5 Hz, 1 H).
13C NMR (101 MHz, DMSO-d 6): δ = 150.7, 150.0, 61.0, 47.2, 35.6.
HRMS (ESI+): m/z calcd for C5H10N4O (M + H)+: 143.0933; found: 143.0932.
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(S)-2-Amino-2-(2-methoxypyridin-4-yl)ethanol Dihydrochloride [(S)-2f]
Yield: 15.7 g (96%); yellow solid, but material was partially demethylated during storage.
1H NMR was recorded at WuXi AppTech, and 13C NMR and other 2D NMR were recorded at Mölndal (AstraZeneca). 13C NMR was reported based on 2D NMR study (please see the Supporting Information).
1H NMR (400 MHz, DMSO-d 6): δ = 8.79 (br s, 3 H), 8.18 (d, J = 5.3 Hz, 1 H), 7.13 (dd, J = 5.3, 1.3 Hz, 1 H), 7.01 (s, 1 H), 4.28 (m, 1 H), 3.85 (s, 3 H), 3.65–3.79 (m, 2 H).
13C NMR (101 MHz, DMSO-d 6): δ = 163.6, 147.9, 146.9, 116.1, 109.4, 62.3, 54.6, 53.4.
HRMS (ESI+): m/z calcd for C8H12N2O2 (M + H)+: 169.0977; found: 169.0973.
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(R)-2-Amino-2-(2-methoxypyridin-4-yl)ethanol Dihydrochloride [(R)-2f]
Yield: 23.1 g (98%); yellow solid; product was partially demethylated during storage.
1H NMR (400 MHz, DMSO-d 6): δ = 8.78 (br s, 3 H), 8.18 (d, J = 5.3 Hz, 1 H), 7.12 (dd, J = 5.3, 1.3 Hz, 1 H), 7.00 (s, 1 H), 4.27 (m, 1 H), 3.85 (s, 3 H), 3.61–3.82 (m, 2 H).
13C NMR (101 MHz, DMSO-d 6): δ = 163.6, 147.9, 146.9, 116.1, 109.4, 62.3, 54.7, 53.4.
HRMS (ESI+): m/z calcd for C8H12N2O2 (M + H)+: 169.0977; found: 169.0975.
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(S)-2-Amino-2-(pyrazin-2-yl)ethanol Hydrochloride [(S)-2g]
Yield: 20.6 g (~100%); brown solid; mp 154–156 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 8.84 (d, J = 1.5 Hz, 1 H), 8.74 (br s, 3 H), 8.69–8.71 (m, 1 H), 8.67 (d, J = 2.6 Hz, 1 H), 4.48–4.61 (m, 1 H), 3.78–3.94 (m, 2 H).
13C NMR (101 MHz, DMSO-d 6): δ = 150.7, 144.4, 144.3, 143.8, 61.8, 54.2.
HRMS (ESI+): m/z calcd for C6H9N3O (M + H)+: 140.0824; found: 140.0821.
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(R)-2-Amino-2-(pyrazin-2-yl)ethanol Hydrochloride [(R)-2g]
Yield: 21.3 g (90%); brown solid; mp 154–156 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 8.84 (d, J = 1.5 Hz, 1 H), 8.77 (br s, 3 H), 8.68–8.71 (m, 1 H), 8.66 (d, J = 2.6 Hz, 1 H), 4.46–4.61 (m, 1 H), 3.78–3.95 (m, 2 H).
13C NMR (101 MHz, DMSO-d 6): δ = 150.7, 144.4, 144.3, 143.8, 61.8, 54.3.
HRMS (ESI+): m/z calcd for C6H9N3O (M + H)+: 140.0824; found: 140.0827.
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(S)-2-Amino-2-(1-methyl-1H-pyrazol-5-yl)ethanol Hydrochloride [(S)-2h]
Yield: 28.0 g (~100%); yellow solid; mp 185–187 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 8.69 (br s, 3 H), 7.41 (d, J = 2.0 Hz, 1 H), 6.52 (d, J = 2.0 Hz, 1 H), 4.45–4.6 (m, 1 H), 3.86 (s, 3 H), 3.67–3.81 (m, 2 H).
13C NMR (101 MHz, DMSO-d 6): δ = 137.5, 137.5, 105.4, 61.6, 47.6, 36.7.
HRMS (ESI+): m/z calcd for C6H11N3O (M + H)+: 142.0980; found: 142.0984.
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(R)-2-Amino-2-(1-methyl-1H-pyrazol-5-yl)ethanol Hydrochloride [(R)-2h]
Yield: 25.0 g (84%); yellow solid; mp 185–187 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 8.69 (br s, 3 H), 7.41 (d, J = 2.0 Hz, 1 H), 6.52 (d, J = 2.0 Hz, 1 H), 4.45–4.6 (m, 1 H), 3.86 (s, 3 H), 3.67–3.83 (m, 2 H).
13C NMR (101 MHz, DMSO-d 6): δ = 137.5, 137.5, 105.4, 61.7, 47.6, 36.7.
HRMS (ESI+): m/z calcd for C6H11N3O (M + H)+: 142.0980; found: 142.0981.
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(S)-2-Amino-2-(1,4-dimethyl-1H-pyrazol-5-yl)ethanol Hydrochloride [(S)-2i]
Yield: 25.0 g (84%); off-white solid; mp 165–167 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 8.68 (br s, 3 H), 7.22 (s, 1 H), 4.37–4.60 (m, 1 H), 3.89–3.96 (m, 1 H), 3.85 (s, 3 H), 3.74–3.82 (m, 1 H), 2.10 (s, 3 H).
13C NMR (101 MHz, DMSO-d 6): δ = 138.6, 132.9, 115.4, 60.1, 47.8, 37.4, 9.2.
HRMS (ESI+): m/z calcd for C7H13N3O (M + H)+: 156.1137; found: 156.1143.
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(R)-2-Amino-2-(1,4-dimethyl-1H-pyrazol-5-yl)ethanol Hydrochloride [(R)-2i]
Yield: 23.6.0 g (96%); off-white solid; mp 165–167 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 8.70 (br s, 3 H), 7.23 (s, 1 H), 4.37–4.57 (m, 1 H), 3.88–3.96 (m, 1 H), 3.85 (s, 3 H), 3.75–3.81 (m, 1 H), 2.10 (s, 3 H).
13C NMR (101 MHz, DMSO-d 6): δ = 138.6, 133.0, 115.4, 60.1, 47.8, 37.4, 9.3.
HRMS (ESI+): m/z calcd for C7H13N3O (M + H)+: 156.1137; found: 156.1143.
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Acknowledgment
The authors thank Structure Analysis & Separation Science group, AstraZeneca R & D Mölndal for HRMS measurement.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0034-1378943.
- Supporting Information
-
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- 15 Liu G, Cogan DA, Owens TD, Tang TP, Ellman JA. J. Org. Chem. 1999; 64: 1278
- 16 Cogan DA, Liu G, Ellman J. Tetrahedron 1999; 55: 8883
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- 18 Tang TP, Ellman JA. J. Org. Chem. 1999; 64: 12
- 19 Ferreira F, Botuha C, Chemla F, Perez-Luna A. Chem. Soc. Rev. 2009; 38: 1162
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- 13 Morris WJ, Muppalla KK, Cowden C, Ball RG. J. Org. Chem. 2013; 78: 706
- 14 Cogan DA, Liu G, Kim K, Backes BJ, Ellman JA. J. Am. Chem. Soc. 1998; 120: 8011
- 15 Liu G, Cogan DA, Owens TD, Tang TP, Ellman JA. J. Org. Chem. 1999; 64: 1278
- 16 Cogan DA, Liu G, Ellman J. Tetrahedron 1999; 55: 8883
- 17 Cogan DA, Ellman JA. J. Am. Chem. Soc. 1999; 121: 268
- 18 Tang TP, Ellman JA. J. Org. Chem. 1999; 64: 12
- 19 Ferreira F, Botuha C, Chemla F, Perez-Luna A. Chem. Soc. Rev. 2009; 38: 1162
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- 21 Li Y, Ma Y, Lu Z, Wang L, Ren X, Sun Z. Tetrahedron Lett. 2012; 53: 4711
- 22 Davis FA, McCoul W. J. Org. Chem. 1999; 64: 3396
- 23 Spitz C, Khoumeri O, Terme T, Vanelle P. Synlett 2013; 24: 1725
- 24 Barrow JC, Ngo PL, Pellicore JM, Selnick HG, Nantermet PG. Tetrahedron Lett. 2001; 42: 2051
- 25 Tang TP, Volkman SK, Ellman JA. J. Org. Chem. 2001; 66: 8772
- 26 Ellman JA. Pure Appl. Chem. 2003; 75: 39
- 27 Eskildsen J, Sams AG, Pueschl A. PCT Int. Appl WO2013/007621, 2013 ; Chem. Abstr. 2013, 158, 187339.
- 28 Struk Ł, Sośnicki JG. Synthesis 2012; 44: 735
- 29 Primas N, Mahatsekake C, Bouillon A, Lancelot J, Oliveira Santos JS, Lohier J, Rault S. Tetrahedron 2008; 64: 4596
- 30 Mani NS, Jablonowski JA, Jones TK. J. Org. Chem. 2004; 69: 8115
- 31 Pavlik JW, Kurzweil EM. J. Org. Chem. 1991; 56: 6313
- 32 Dale JA, Mosher HS. J. Am. Chem. Soc. 1973; 95: 512
- 33 Seco JM, Quiñoá E, Riguera R. Chem. Rev. 2004; 104: 17
