Enantioselective Synthesis of Chiral 1,2-Amino Alcohols via

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Enantioselective Synthesis of Chiral 1,2-Amino Alcohols via Asymmetric Hydrogenation of α-Amino Ketones with Chiral Spiro Iridium Catalysts paper

Ming-Lei Yuan, Jian-Hua Xie,* Xiao-Hui Yang, Qi-Lin Zhou* Asymmetric Hydrogenation of α-Amino Ketones

Abstract: A highly efficient iridium-catalyzed asymmetric hydrogenation of α-amino ketones for the synthesis of chiral 1,2-amino alcohols is described. With chiral spiro iridium catalyst Ir-(R)-1c, a series of α-amino ketones were hydrogenated to chiral β-amino alcohols in excellent enantioselectivities (up to 99.9% ee) with TON up to 100 000. In addition, with this highly efficient method the chiral drugs (R)-clorpenaline and (R)-phenylephrine were prepared in very high efficiency. Key words: asymmetric hydrogenation, chiral spiro catalysts, amino ketones, amino alcohols, iridium catalysts

Catalytic asymmetric hydrogenation of ketones with chiral transition metal catalysts is one of the most powerful methods for the preparation of chiral secondary alcohols. Many efficient chiral catalysts have been developed for the ketone hydrogenations, some of them showed extremely high turnover number (TON) and enantioselectivity.1 Chiral 1,2-amino alcohols are a very common structural motif in a wide range of bioactive natural products, pharmaceuticals as well as chiral auxiliaries (Figure 1).2 The catalytic asymmetric hydrogenation of α-amino ketones is a straightforward approach to chiral 1,2-amino alcohols, and has received intensive study over the past decades.3 Several efficient catalytic methods have been developed for the asymmetric hydrogenation of α-amino ketones, and applied in the synthesis of chiral pharmaceuticals such as (R)-phenylephrine,4 an α1-adrenergic recep-

OH

H N

OH HO

Me

H N

tor agonist used as a decongestant,5 and (R)-denopamine,6 a new selective β-antagonist for the treatment of congestive heart failure.7 The chiral catalysts reported for the asymmetric hydrogenation of α-amino ketones included chiral rhodium,8 ruthenium,9 and palladium10 complexes bearing chiral diphosphine ligands. However, because of the existence of α-amino group in the substrates, most chiral catalysts showed lower efficiency in the hydrogenation of α-amino ketones than in the hydrogenation of simple ketones. Only a few catalysts provided turnover numbers as high as >10000 for the asymmetric hydrogenation of αamino ketones and have been applied in the synthesis of chiral drugs.11 Thus, the search for highly efficient and practically useful chiral catalysts for asymmetric hydrogenation of α-amino ketones to optically active 1,2-amino alcohols remains a challenge in this field. Recently, we have developed a new type of chiral iridium catalysts 1 containing chiral SpiroPAP ligands. These chiral spiro iridium catalysts showed extremely high efficiency for the hydrogenation of simple ketones, β-keto esters, and α,β-unsaturated ketones.12 Continuing our research on the development of efficient method for the preparation of chiral 1,2-amino alcohols,13 we found that the chiral spiro iridium catalysts Ir–1 has excellent enantioselectivity and high activity for the hydrogenation of αamino ketones. With Ir–(R)-1c as a catalyst, the aromatic α-amino ketones 2 were hydrogenated to the correspond-

OH Me

HO OH (R)-phenylephrine

OH iPr

HO HO

Cl (R)-adrenaline

OH HO

H N

OH

H N

HO

(R)-salbutamol

(R)-clorprenaline

OH

H N

HO

OMe

(R)-arbutamine

OMe (R)-denopamine

Figure 1 Chiral pharmaceuticals with chiral 1,2-amino alcohol unit

SYNTHESIS 2014, 46, 2910–2916 Advanced online publication: 06.08.20140039-78 1 437-210X DOI: 10.1055/s-0034-1378891; Art ID: ss-2014-h0302-op © Georg Thieme Verlag Stuttgart · New York

H N

t

Bu

Downloaded by: IP-Proxy Nankai_Uni_Tianjin, Nankai University. Copyrighted material.

State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, P. R. of China Fax +86(22)23506177; E-mail: [email protected]; E-mail: [email protected] Received: 17.05.2014; Accepted after revision: 04.07.2014

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Asymmetric Hydrogenation of α-Amino Ketones

O

R1

OH

N

R2

X

+

H2

X

EtOH, KOH, 30 °C (10–40 atm) (S/C = 5000)

R2

3 92−99% yield 97−99.9% ee TON up to 100,000

2 R1 = H, Bn R2 = Me, i-Pr, t-Bu

(R)-1a (R)-1b (R)-1c (R)-1d

PAr2 NH

R1 N

Ir–(R)-1c

N

X

Ar =

X = H (SpiroPAP) X = 3-Me X = 4-t-Bu X = 6-Me

(R)-1

ing chiral 1,2-amino alcohols 3 in up to 99.9% ee with TON as high as 100000 (Scheme 1).14 Our study began with the hydrogenation of N-benzyl-Nmethyl-α-aminoacetophenone (2a) generated in situ from the corresponding hydrochloride by the addition of one equivalent of base. When the reaction was performed in ethanol containing 0.02 mol% chiral iridium catalyst Ir– (R)-1a, generated in situ from [Ir(cod)Cl]2 and (R)-1a, and 1.2 equivalents of potassium hydroxide under 10 atm of hydrogen at 30 °C for one hour, the amino alcohol (R)-3a was obtained in 99% yield with 98% ee (Table 1, entry 1). A comparison of the chiral ligands (R)-1 showed that the ligand (R)-1c with a tert-butyl group on the para-position of the pyridine ring gave the highest enantioselectivity (99.2% ee, entry 3). Methanol and isopropanol were also suitable as solvents for this transformation, but gave lower reaction rate and slightly lower enantioselectivity (entries 5 and 6). With a strong base such as potassium tert-butoxide or sodium tert-butoxide instead of potassium hydroxide, the enantioselectivity of the reaction reached 99.2% or 99.0% ee, respectively (entries 7 and 8), but a very sluggish reaction was observed by using potassium carbonate as a base (entry 9). When the catalyst loading was lowered to 0.001 mol% (S/C = 100 000), the hydrogenation product (R)-3a was still obtained in 99% ee with 100% conversion within 24 hours under an initial hydrogen pressure of 40 atm [entry 10, TON = 100 000, turnover frequency (TOF) = 4167 h–1]. A variety of N-alkyl-N-benzyl-2-amino ketones 2a–m were hydrogenated under the optimal reaction conditions and the results are summarized in Table 2. The substituent on the phenyl ring of the α-amino ketones 2 has little effect on both reactivity and enantioselectivity of reaction. All examples gave excellent enantioselectivities (97– 99.9% ee, Table 2, entries 1–13). The substrate 2n having a secondary amino group could also be hydrogenated to the amino alcohol (R)-3n in 92% yield with 99% ee, but a longer reaction time was required for completing the reaction. The reason for this might be attributed to the chelating effect of the product (R)-3n to the metal center of the © Georg Thieme Verlag Stuttgart · New York

catalyst. It should be noted that this chiral spiro iridium catalyst can also hydrogenate 2-aminodialkyl ketones such as 1-(benzylmethylamino)propan-2-one (1 h, 100% conversion, 98% yield), but has almost no enantioselectivity (4% ee). To demonstrate the utility of this highly efficient iridiumcatalyzed asymmetric hydrogenation, (R)-clorprenaline, a β2-agonist for the treatment of diverse disease states such as bronchitis and asthma,15 was synthesized starting from the hydrogenation product (R)-3k. A one-step reaction, Table 1 Optimization of Reaction Conditions for Asymmetric Hydrogenation of 2aa O

OH

Bn N

2a

Entry Ligand

Bn

Ir–(R)-1

N

Me + H2 base, solvent, 30 °C ·HCl (10 atm) (S/C = 5000)

Base

Solvent

Me

3a

Time Conv Yield ee (h) (%)b (%)c (%)d

1

(R)-1a

KOH

EtOH

1.0 100

99

98 (R)

2

(R)-1b

KOH

EtOH

1.0 100

99

99 (R)

3

(R)-1c

KOH

EtOH

0.5 100

99

99.2 (R)

4

(R)-1d

KOH

EtOH

3.0 100

99

96 (R)

5

(R)-1c

KOH

MeOH

2.0 100

99

95 (R)

6

(R)-1c

KOH

i-PrOH

100

99

96 (R)

7

(R)-1c

KOt-Bu

EtOH

0.5 100

99

99.2 (R)

8

(R)-1c

NaOt-Bu EtOH

0.5 100

99

99.0 (R)

9

(R)-1c

K2CO3

EtOH

24

10e

(R)-1c

KOH

EtOH

24

11

2.4 – 100

99

– 99 (R)

a

Reaction conditions: Substrate (1.5 mmol scale = 0.5 M), catalyst (0.02 mol%), KOH (1.2 equiv), solvent (3.0 mL), H2 (10 atm), 30 °C. b Determined by 1H NMR spectroscopy. c Isolated yield. d Determined by HPLC by using a chiral column. e Catalyst: 0.001 mol% (S/C = 100000), H2 (40 atm). Synthesis 2014, 46, 2910–2916


Scheme 1 Asymmetric hydrogenation of aromatic α-amino ketones 2 with Ir–(R)-1c

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M.-L. Yuan et al.

of practical significance and impact from an economic perspective. A highly efficient approach to (R)-phenylephrine was established by using Ir–(R)-1c-catalyzed asymmetric hydrogenation of α-amino ketone as the key step. The substrate 4 containing an unprotected phenol group was hydrogenated on a gram-scale with catalyst Ir– (R)-1c (0.001 mol%) in ethanol in the presence of 3.0 equivalents of potassium hydroxide as a base under 15 atm of hydrogen pressure (initial) at 30 °C for 12 hours to yield (R)-5 in nearly quantitative yield with 99% ee. The (R)-phenylephrine hydrochloride was obtained in 92% yield by removing the N-benzyl group by Pd/C-catalyzed hydrogenation, followed by acidification. This process is significantly better than those reported using other catalysts.16 In conclusion, a highly efficient iridium-catalyzed asymmetric hydrogenation of α-amino ketones for the synthesis of chiral 1,2-amino alcohols was developed. With chiral spiro iridium catalyst Ir–(R)-1c a variety of chiral β-amino alcohols were produced in excellent enantioselectivities (up to 99.9% ee) with TONs up to 100000. Based on this hydrogenation reaction the chiral drugs (R)-clorpenaline and (R)-phenylephrine were prepared in very high efficiency.

Table 2 Asymmetric Hydrogenation of α-Amino Ketones 2 with Ir– (R)-1ca O

R1 N

X 2

Entry R1

R1

OH Ir–(R)-1c

N

R2 + H2 X ·HCl EtOH, KOH, 30 °C (10 atm) (S/C = 5000)

R2

3

R2

X

3

Time (h)

Yield (%)b

ee (%)c

1

Bn

Me

H

3a

0.5

99

99.2 (R)

2

Bn

Me

4-Me

3b

0.8

99

99 (–)

3

Bn

Me

4-MeO

3c

1.0

98

99 (R)

4

Bn

Me

4-Cl

3d

0.8

99

99.2 (R)

5

Bn

Me

4-Br

3e

0.8

99

>99 (R)

6

Bn

Me

3-Me

3f

0.8

99

99 (–)

7

Bn

Me

3-Cl

3g

0.8

99

99.7 (R)

8

Bn

Me

3-Br

3h

0.8

99

99.7 (R)

9

Bn

Me

2-MeO

3i

0.8

99

99.6 (–)

10

Bn

Me

2-Cl

3j

1.0

99

97 (R)

11

Bn

i-Pr

2-Cl

3k

0.5

99

99.9 (R)

12

Bn

i-Pr

H

3l

0.8

99

99.2 (R)

13

Bn

t-Bu

H

3m

0.5

99

99 (–)

14

H

t-Bu

H

3n

12

92

>99 (R)

a

Reaction conditions were the same as those listed in Table 1, entry 3. Isolated yield. c Determined by HPLC by using chiral column. b

Pd/C-catalyzed hydrogenation to remove the N-benzyl group, gave (R)-clorprenaline in 85% yield (Scheme 2). (R)-Phenylephrine is an α-adrenergic receptor agonist commonly used as a nasal decongestant,5 and various synthetic methods have been reported for the preparation of enantiopure (R)-phenylephrine.16 However, only a few are OH

OH

Bn N

i-Pr

H2 (1 atm), Pd/C (10%) AcOH, r.t., 2 h 85%

Cl (R)-3k

O

H N

i-Pr

Cl (R)-clorprenaline

Bn N

Me HCl

OH

H2 (15 atm) Ir–(R)-1c (0.001 mol%)

Bn N

KOH (3.0 equiv), EtOH 30 °C, 12 h 4.4 g scale

OH

The chiral iridium catalysts Ir–(R)-1, prepared according to our previous method,12 can be used directly or stored in the glove box (VAC DRI-LAB HE 493) for later use. Reactions or manipulations, which are sensitive to moisture or air were performed using standard Schlenk techniques (See Supporting information). H2 gas (99.999%) was purchased from Boc Gas Inc., Tianjin. i-PrOH was freshly distilled from CaH2. Anhydrous EtOH and MeOH were freshly distilled from Mg. [Ir(cod)Cl]2 was purchased from J & K Chemical Company. KOH, t-BuONa and t-BuOK were purchased from Aldrich Chemical Company. Petroleum ether (PE) used refers to the fraction boiling at 60–90 °C. Melting points were determined using an RY-I apparatus and are uncorrected. The FT-IR spectra of KBr pellets or neat samples were recorded with a Bio-Rad FTS6000 spectrophotometer. 1H and 13C NMR spectra were recorded on a Bruker AMX-300 or a Bruker AMX-400 spectrometer. Chemical shifts were reported in ppm downfield from internal TMS and external 85% H3PO4, respectively. Optical rotations were determined using a PerkinElmer 341 polarimeter. HPLC analyses were performed using Hewlett Packard Model HP1100 instruments. HRMS

4

OH (R)-5 99% ee

Me

OH

H2 (2 atm) Pd/C (10%) EtOH, r.t., 2 h then HCl 92% (2 steps)

H N

Me ·HCl

OH (R)-phenylephrine hydrochloride

Scheme 2 The synthesis (R)-clorprenaline and (R)-phenylephrine Synthesis 2014, 46, 2910–2916

© Georg Thieme Verlag Stuttgart · New York


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Asymmetric Hydrogenation of α-Amino Ketones 2; General Procedure (S/C = 5000) To a hydrogenation vessel (20 mL) was added α-amino ketone 2 (1.5 mmol as the hydrochloride), KOH (100.8 mg, 1.8 mmol), and anhydrous EtOH (2.5 mL). The vessel was then placed in an autoclave and a solution of Ir catalyst Ir–(R)-1c in anhydrous EtOH (0.5 mL, 0.6 μmol/mL, 0.3 μmol) was added via an injection port under N2 atmosphere. The autoclave was closed and quickly purged three times with H2 gas. After the autoclave was pressurized with H2 to 10 atm, the reaction solution was stirred at r.t. (30 °C) until no obvious H2 pressure drop was observed (0.5–12 h). After releasing the H2 pressure carefully, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with EtOAc–PE (1:10 → 4:1) as eluent to afford the chiral amino alcohol. The enantioselectivity was determined by chiral HPLC analysis of the chiral amino alcohol directly or of the corresponding O-acylated derivative. 18

(R)-2-[Benzyl(methyl)amino]-1-phenylethanol (3a)

Yield: 358 mg (99%); 99.2% ee; light yellow oil; [α]D20 –32.2 (c 1.0, EtOH). HPLC: Chiracel OJ column, 220 nm, 25 °C, n-hexane–i-PrOH (85:15), flow 1.0 mL/min; tR (S) = 8.1 min, tR (R) = 9.3 min. 1

H NMR (400 MHz, CDCl3): δ = 7.35–7.24 (m, 10 H), 4.74 (dd, J = 10.4, 3.6 Hz, 1 H), 3.74 (d, J = 13.1 Hz, 1 H), 3.53 (d, J = 13.1 Hz, 1 H), 2.63–2.50 (m, 2 H), 2.32 (s, 3 H). 13

C NMR (100 MHz, CDCl3): δ = 142.9, 138.9, 129.8, 129.2, 129.1, 128.2, 128.1, 126.6, 70.1, 66.2, 63.1, 42.5.

(–)-2-[Benzyl(methyl)amino]-1-(4-methylphenyl)ethanol (3b) Yield: 379 mg (99%); 99% ee (R); light yellow oil; [α]D20 –53.2 (c 1.0, EtOH). HPLC: Chiracel OJ column, 220 nm, 25 °C, n-hexane–i-PrOH (85:15), flow 1.0 mL/min; tR (minor) = 6.8 min, tR (major) = 7.5 min. IR (film): 3437, 3028, 2795, 1454, 812, 739 cm–1. 1

H NMR (400 MHz, CDCl3): δ = 7.33–7.22 (m, 7 H), 7.12 (d, J = 7.9 Hz, 2 H), 4.71 (dd, J = 10.5, 3.4 Hz, 1 H), 3.71 (d, J = 13.1 Hz, 1 H), 3.50 (d, J = 13.1 Hz, 1 H), 2.61–2.55 (m, 1 H), 2.48 (dd, J = 12.4, 3.5 Hz, 1 H), 2.31 (s, 3 H), 2.28 (s, 3 H). 13

C NMR (100 MHz, CDCl3): δ = 139.3, 138.2, 137.1, 129.2, 129.1, 128.5, 127.4, 126.0, 69.3, 65.6, 62.4, 41.8, 21.2. +

ESI-MS: m/z (%) = 256.2 (100, [M + H] ). HRMS (ESI): m/z ([M + H]+) calcd for C17H21NO: 256.1696; found: 256.1696. (R)-2-[Benzyl(methyl)amino]-1-(4-methoxyphenyl)ethanol (3c)19 Yield: 403 mg (99%); 99% ee (R); light yellow oil; [α]D20 –46.6 (c 1.0, EtOH). HPLC: Chiracel OJ column, 220 nm, 25 °C, n-hexane–i-PrOH (85:15), flow 1.0 mL/min; tR (S) = 12.5 min, tR (R) = 14.6 min.

(R)-2-[Benzyl(methyl)amino]-1-(4-chlorophenyl)ethanol (3d)20 Yield: 409 mg (99%); 99.2% ee (R); light yellow solid; mp 48– 50 °C; [α]D20 –43.0 (c 1.0, EtOH). HPLC of the acylated derivative: Chiracel AD-H column, 220 nm, 25 °C, n-hexane–i-PrOH (99:1), flow 1.0 mL/min; tR (S) = 8.9 min, tR (R) = 11.3 min. 1

H NMR (400 MHz, CDCl3): δ = 7.34–7.24 (m, 9 H), 4.70 (dd, J = 9.6, 4.4 Hz, 1 H), 3.72 (d, J = 13.1 Hz, 1 H), 3.51 (d, J = 13.1 Hz, 1 H), 2.55–2.46 (m, 2 H), 2.30 (s, 3 H).

13 C NMR (100 MHz, CDCl3): δ = 140.8, 138.0, 133.1, 129.1, 128.5, 127.5, 127.3, 120.6, 68.8, 65.3, 62.4, 41.8.

(R)-2-[Benzyl(methyl)amino]-1-(4-bromophenyl)ethanol (3e)20 Yield: 476 mg (99%); >99% ee (R); light yellow solid; mp 50– 52 °C; [α]D20 –39.2 (c 1.0, EtOH). HPLC of the acylated derivative: Chiracel AD-H column, 220 nm, 25 °C, n-hexane–i-PrOH (99:1), flow 1.0 mL/min; tR (R) = 15.5 min. 1

H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 7.4 Hz, 2 H), 7.34– 7.24 (m, 5 H), 7.20 (d, J = 8.2 Hz, 2 H), 4.67 (dd, J = 9.4, 4.5 Hz, 1 H), 3.71 (d, J = 13.0 Hz, 1 H), 3.50 (d, J = 13.0 Hz, 1 H), 2.54–2.45 (m, 2 H), 2.29 (s, 3 H). 13

C NMR (100 MHz, CDCl3): δ = 141.4, 138.0, 131.1, 129.1, 128.5, 127.7, 127.5, 121.2, 68.9, 65.2, 62.4, 41.8. (–)-2-[Benzyl(methyl)amino]-1-(3-methylphenyl)ethanol (3f) Yield: 379 mg (99%); 99% ee (R); light yellow oil; [α]D20 –51.4 (c 1.0, EtOH). HPLC: Chiracel OD-H column, 220 nm, 25 °C, n-hexane–i-PrOH (70:30), flow 1.0 mL/min; tR (minor) = 7.7 min, tR (major) = 10.7 min. IR (film): 3400, 3028, 2794, 1454, 785, 738 cm–1. 1 H NMR (400 MHz, CDCl3): δ = 7.35–7.17 (m, 7 H), 7.13 (d, J = 7.6 Hz, 1 H), 7.07 (d, J = 7.4 Hz, 1 H), 4.72 (dd, J = 10.4, 3.5 Hz, 1 H), 3.98 (br s, 1 H), 3.74 (d, J = 13.1 Hz, 1 H), 3.53 (d, J = 13.1 Hz, 1 H), 2.64–2.58 (m, 1 H), 2.52 (dd, J = 12.4, 3.5 Hz, 1 H), 2.34 (s, 3 H), 2.31 (s, 3 H). 13 C NMR (100 MHz, CDCl3): δ = 142.1, 138.1, 138.0, 129.1, 128.4, 128.3, 127.4, 126.6, 123.0, 69.4, 65.6, 62.4, 41.7, 21.5.

ESI-MS: m/z (%) = 256.3 (100, [M + H]+). HRMS (ESI): m/z ([M + H]+) calcd for C17H21NO: 256.1696; found: 256.1694. (R)-2-[Benzyl(methyl)amino]-1-(3-chlorophenyl)ethanol (3g)20 Yield: 409 mg (99%); 99.7% ee (R); light yellow oil; [α]D20 –35.0 (c 1.0, EtOH). HPLC of the acylated derivative: Chiracel AD-H column, 220 nm, 25 °C, n-hexane–i-PrOH (99:1), flow 1.0 mL/min; tR (S) = 5.8 min, tR (R) = 6.2 min. 1

H NMR (400 MHz, CDCl3): δ = 7.29–7.12 (m, 9 H), 4.64 (dd, J = 8.7, 5.3 Hz, 1 H), 3.67 (d, J = 13.1 Hz, 1 H), 3.47 (d, J = 13.1 Hz, 1 H), 2.48–2.46 (m, 2 H), 2.31 (s, 3 H).

13 C NMR (100 MHz, CDCl3): δ = 144.4, 137.9, 134.3, 129.6, 129.1, 128.5, 127.6, 127.5, 126.1, 124.0, 68.8, 65.2, 62.3, 41.7.

1

H NMR (400 MHz, CDCl3): δ = 7.34–7.24 (m, 7 H), 6.85 (d, J = 8.7 Hz, 2 H), 4.69 (dd, J = 10.5, 3.4 Hz, 1 H), 3.96 (br s, 1 H), 3.75 (s, 3 H), 3.72 (d, J = 13.1 Hz, 1 H), 3.50 (d, J = 13.1 Hz, 1 H), 2.58 (dd, J = 12.3, 10.7 Hz, 1 H), 2.46 (dd, J = 12.4, 3.5 Hz, 1 H), 2.29 (s, 3 H). 13

C NMR (100 MHz, CDCl3): δ = 159.1, 138.2, 134.3, 129.1, 128.5, 127.4, 127.2, 113.8, 69.1, 65.5, 62.4, 55.3, 41.8.

© Georg Thieme Verlag Stuttgart · New York

(R)-2-[Benzyl(methyl)amino]-1-(3-bromophenyl)ethanol (3h)20 Yield: 476 mg (99%); 99.7% ee (R); light yellow oil; [α]D20 –28.4 (c 1.0, EtOH). HPLC of the acylated derivative: Chiracel AD-H column, 220 nm, 25 °C, n-hexane–i-PrOH (99:1), flow 1.0 mL/min; tR (S) = 5.6 min, tR (R) = 6.0 min. 1 H NMR (400 MHz, CDCl3): δ = 7.51 (s, 1 H), 7.37–7.23 (m, 7 H), 7.16 (t, J = 7.8 Hz, 1 H), 4.68 (dd, J = 8.8, 5.2 Hz, 1 H), 4.04 (br s,

Synthesis 2014, 46, 2910–2916


were recorded on APEXII and ZAB-HS spectrometer. The α-amino ketones were prepared from the corresponding aryl ketones according to literature method17 (see Supporting Information).

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1 H), 3.70 (d, J = 13.1 Hz, 1 H), 3.50 (d, J = 13.1 Hz, 1 H), 2.56– 2.48 (m, 2 H), 2.28 (s, 3 H).

1

13

H NMR (400 MHz, CDCl3): δ = 7.27–7.13 (m, 10 H), 4.44 (dd, J = 10.3, 3.5 Hz, 1 H), 4.02 (br s, 1 H), 3.77 (d, J = 13.7 Hz, 1 H), 3.48 (d, J = 13.6 Hz, 1 H), 2.99–2.89 (m, 1 H), 2.52 (dd, J = 13.0, 3.6 Hz, 1 H), 2.46–2.40 (m, 1 H), 1.02 (d, J = 6.7 Hz, 3 H), 0.90 (d, J = 6.5 Hz, 3 H).

(–)-2-[Benzyl(methyl)amino]-1-(2-methoxyphenyl)ethanol (3i) Yield: 403 mg (99%); 99.6% ee (R); light yellow oil; [α]D20 –100.0 (c 1.0, EtOH).

13 C NMR (100 MHz, CDCl3): δ = 142.6, 128.8, 128.6, 128.3, 127.4, 127.3, 125.9, 69.2, 57.6, 54.8, 49.9, 20.9, 15.2.

C NMR (100 MHz, CDCl3): δ = 144.8, 138.0, 130.5, 130.0, 129.1, 129.0, 128.5, 127.5, 124.5, 122.6, 68.8, 65.3, 62.4, 41.8.

HPLC: Chiracel OJ column, 220 nm, 25 °C, n-hexane–i-PrOH (85:15), flow 1.0 mL/min; tR (minor) = 8.2 min, tR (major) = 9.2 min. IR (film): 3442, 2941, 2837, 1602, 755 cm–1. 1

H NMR (400 MHz, CDCl3): δ = 7.43 (dd, J = 7.5, 1.4 Hz, 1 H), 7.23–7.10 (m, 6 H), 6.87 (t, J = 7.2 Hz, 1 H), 6.73 (d, J = 8.13 Hz, 1 H), 5.07 (dd, J = 10.0, 3.1 Hz, 1 H), 3.68 (s, 3 H), 3.64 (d, J = 13.2 Hz, 1 H), 3.42 (d, J = 13.2 Hz, 1 H), 2.59 (dd, J = 12.3, 3.2 Hz, 1 H), 2.39 (dd, J = 12.3, 10.0 Hz, 1 H), 2.21 (s, 3 H).

13

C NMR (100 MHz, CDCl3): δ = 156.3, 138.4, 130.5, 129.2, 128.4, 128.1, 127.2, 126.5, 120.8, 110.1, 64.6, 63.5, 62.2, 55.3, 42.0. +

ESI-MS: m/z (%) = 272.1 (100, [M + H] ). HRMS (ESI): m/z ([M + H]+) calcd for C17H21NO2: 272.1645; found: 272.1649. (R)-2-[Benzyl(methyl)amino]-1-(2-chlorophenyl)ethanol (3j)20 Yield: 409 mg (99%); 97% ee (R); light yellow oil; [α]D20 –101.6 (c 1.0, EtOH). HPLC of the acylated derivative: Chiracel AS column, 214 nm, 25 °C, n-hexane–i-PrOH (90:10), flow 1.0 mL/min; tR (S) = 3.5 min, tR (R) = 3.9 min. 1

H NMR (400 MHz, CDCl3): δ = 7.52 (dd, J = 7.7, 1.4 Hz, 1 H), 7.24–7.10 (m, 7 H), 7.05 (dt, J = 7.6, 1.7 Hz, 1 H), 5.08 (dd, J = 10.2, 2.9 Hz, 1 H), 3.65 (d, J = 13.1 Hz, 1 H), 3.40 (d, J = 13.1 Hz, 1 H), 2.63 (dd, J = 12.4, 3.0 Hz, 1 H), 2.31 (dd, J = 12.4, 10.3 Hz, 1 H), 2.22 (s, 3 H).

13

C NMR (100 MHz, CDCl3): δ = 139.6, 138.3, 131.7, 129.2, 129.1, 128.4, 128.4, 127.4, 127.2, 66.5, 63.2, 62.3, 41.9.

(–)-2-[Benzyl(isopropyl)amino]-1-(2-chlorophenyl)ethanol (3k) Yield: 451 mg (99%); 99.9% ee (R); light yellow oil; [α]D20 –79.2 (c 1.0, EtOH). HPLC of the acylated derivative: Chiracel AS column, 210 nm, 25 °C, n-hexane–i-PrOH (99:1), flow 1.0 mL/min; tR (minor) = 4.0 min, tR (major) = 4.2 min. IR (film): 3444, 2965, 2931, 1444, 755 cm–1. 1

H NMR (400 MHz, CDCl3): δ = 7.57 (dd, J = 7.7, 1.4 Hz, 1 H), 7.41–7.22 (m, 7 H), 7.17 (td, J = 7.6, 1.7 Hz, 1 H), 4.94 (dd, J = 10.2, 3.1 Hz, 1 H), 4.09 (br s, 1 H), 3.86 (d, J = 13.7 Hz, 1 H), 3.57 (d, J = 13.7 Hz, 1 H), 3.08–3.01 (m, 1 H), 2.84 (dd, J = 13.0, 3.2 Hz, 1 H), 2.33 (dd, J = 13.0, 10.2 Hz, 1 H), 1.11 (d, J = 6.7 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H).

13

C NMR (100 MHz, CDCl3): δ = 140.0, 139.7, 131.7, 129.1, 128.7, 128.5, 128.2, 128.0, 127.2, 127.2, 127.1, 66.3, 55.4, 54.7, 50.1, 20.8, 15.4. ESI-MS: m/z (%) = 304.2 (100, [M + H]+).

HRMS (ESI): m/z ([M + H]+) calcd for C18H22ClNO: 304.1463; found: 304.1466. (R)-2-[Benzyl(isopropyl)amino]-1-phenylethanol (3l)18 Yield: 400 mg (99%); 99.2% ee (R); light yellow oil; [α]D20 –31.8 (c 1.0, EtOH). HPLC of the acylated derivative: Chiracel AD-H column, 220 nm, 25 °C, n-hexane–i-PrOH (90:10), flow 1.0 mL/min; tR (S) = 4.0 min, tR (R) = 4.1 min.

Synthesis 2014, 46, 2910–2916

(–)-2-[Benzyl(tert-butyl)amino]-1-phenylethanol (3m) Yield: 421 mg (99%); 99% ee (R); white solid; mp 50–52 °C; [α]D20 –2.4 (c 1.0, EtOH). HPLC of the acylated derivative: Chiracel AD-H column, 220 nm, 25 °C, n-hexane–i-PrOH (90:10), flow 1.0 mL/min; tR (minor) = 3.7 min, tR (major) = 4.0 min. IR (KBr): 3427, 2970, 2929, 1603, 1451, 730, 700 cm–1. 1 H NMR (400 MHz, CDCl3): δ = 7.94–6.93 (m, 10 H), 4.01 (m, 2 H), 3.80 (s, 1 H), 3.60 (d, J = 14.3 Hz, 1 H), 2.78–2.60 (m, 2 H), 1.20 (s, 9 H). 13 C NMR (100 MHz, CDCl3): δ = 142.9, 141.8, 128.6, 128.4, 128.2, 127.2, 127.1, 125.8, 70.6, 59.9, 55.8, 55.7, 27.6.

ESI-MS: m/z (%) = 284.2 (100, [M + H]+). HRMS (ESI): m/z ([M + H]+) calcd for C19H25NO: 284.2009; found: 284.2011. (R)-2-(tert-Butylamino)-1-phenylethanol (3n)21 Yield: 266 mg (92%); >99% ee (R); white solid; mp 78–80 °C; [α]D20 –79.8 (c 1.0, CHCl3). HPLC of the acylated derivative: Chiracel AD-H column, 220 nm, 25 °C, n-hexane–i-PrOH (90:10), flow 1.0 mL/min; tR (R) = 8.2 min. 1 H NMR (400 MHz, CDCl3): δ = 7.41–7.31 (m, 4 H), 7.30–7.24 (m, 1 H), 4.60 (dd, J = 8.8, 3.6 Hz, 1 H), 2.90 (dd, J = 11.8, 3.6 Hz, 1 H), 2.60 (dd, J = 11.8, 8.8 Hz, 1 H), 1.11 (s, 9 H). 13

C NMR (100 MHz, CDCl3): δ = 142.91, 128.35, 127.41, 125.80, 72.28, 50.38, 50.28, 29.20. (R)-Clorprenaline22 A mixture of (R)-3k (304 mg, 1.0 mmol), 10% Pd/C (30 mg) and AcOH (10 mL) in a 50 mL Schlenk tube was stirred at r.t. under an atmosphere of H2, and the reaction process was monitored by TLC (EtOAc–PE, 1:5, Rf = 0.2). After the starting material had disappeared, the solution was filtered through a pad of Celite to remove the Pd/C catalyst, and concentrated in vacuo to yield a residue. The residue was then treated with sat. aq Na2CO3 (5 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were then washed with brine (3 × 10 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by chromatography on silica gel (EtOAc–PE, 1:6, 0.5% Et3N) to afford (R)-clorprenaline; yield: 218 mg (85%); white solid; mp 79–81 °C; [α]D20 –71.8 (c 1.0, EtOH). 1

H NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 7.6 Hz, 1 H), 7.36– 7.26 (m, 2 H), 7.20 (t, J = 7.3 Hz, 1 H), 5.04 (d, J = 8.4 Hz, 1 H), 3.08 (d, J = 12.3 Hz, 1 H), 2.95–2.71 (m, 1 H), 2.54 (d, J = 12.3 Hz, 1 H), 1.09 (2 d, J = 5.3 Hz, 6 H). 13 C NMR (101 MHz, CDCl3): δ = 140.17, 131.74, 129.25, 128.35, 127.21, 127.01, 68.60, 52.27, 48.57, 23.36, 23.03.

(R)-Phenylephrine Hydrochloride4b (R)-2-[Benzyl(methyl)amino]-1-(3-hydroxyphenyl)ethanol (5) The asymmetric hydrogenation of 2-[benzyl(methyl)amino]-1-(3hydroxyphenyl)ethanone (4) for the synthesis of (R)-5 was performed at S/C = 100000 according to the similar procedure for the hydrogenation of α-amino ketones 2: amino ketone 4 (as the hydrochloride, 4.38 g, 15 mmol), KOH (2.52 g, 45 mmol), a solution of Ir-(R)-1c in anhydrous EtOH (0.5 mL, 0.6 μmol/mL, 0.3 μmol), and anhydrous EtOH (29.5 mL) at 30 °C under 15 atm of initial hydro© Georg Thieme Verlag Stuttgart · New York


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genation pressure (120 mL autoclave) for 12 h. After releasing the H2 pressure carefully, an analytical sample of the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel with EtOAc (1% Et3N) as eluent to afford (R)-5 as a white solid; yield: 3.83 g (>99 %); mp 56–58 °C; 99% ee (R); [α]D20 –49.6 (c 1.0, EtOH). HPLC: Chiracel OJ column, 220 nm, 25 °C, n-hexane–i-PrOH (80:20), flow 1.0 mL/min; tR (S) = 12.6 min, tR (R) = 18.7 min.


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1

H NMR (400 MHz, CDCl3): δ = 7.40–7.23 (m, 5 H), 7.15 (t, J = 7.8 Hz, 1 H), 6.90 (s, 1 H), 6.81 (d, J = 7.6 Hz, 1 H), 6.70 (d, J = 6.1 Hz, 1 H), 4.71 (dd, J = 10.1, 3.7 Hz, 1 H), 4.45 (br s, 2 H), 3.74 (d, J = 13.1 Hz, 1 H), 3.53 (d, J = 13.1 Hz, 1 H), 2.67–2.48 (m, 2 H), 2.31 (s, 3 H).

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13

C NMR (100 MHz, CDCl3): δ = 156.2, 143.5, 137.9, 129.5, 129.1, 128.5, 127.4, 118.0, 114.7, 112.8, 69.3, 65.2, 62.3, 41.7.

Conversion of 5 to (R)-Phenylephrine Hydrochloride To (R)-5 (3.83 g, 15 mmol), obtained as above, was added an additional amount of 10% Pd/C (386 mg), the autoclave was closed again, and purged with H2 by pressurizing to 2 atm. The reaction mixture was then stirred at r.t. until no obvious H2 pressure drop was observed (2 h). The solution was filtered through a pad of Celite to remove the catalysts, and treated with aq 6 M HCl till pH ~5. The acidified solution was then concentrated in vacuo to ~5 mL at 50– 60 °C. After slowly cooling down to r.t., (R)-phenylephrine hydrochloride separated as crystals. The crystals were collected and dried in vacuo; yield: 2.8 g (92%); white solid; mp 139–141 °C; [α]D20 –44.8 (c 1.0, H2O). 1

H NMR (400 MHz, D2O): δ = 7.31 (t, J = 7.9 Hz, 1 H), 6.95 (d, J = 7.6 Hz, 1 H), 6.91–6.84 (m, 2 H), 4.98 (dd, J = 8.1, 4.5 Hz, 1 H), 3.32–3.21 (m, 2 H), 2.73 (s, 3 H).

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Acknowledgment The project was supported by the National Natural Science Foundation of China, the National Basic Research Program of China (973 Program) (No. 2010CB833300), and the ‘111’ project (No. B06005) of the Ministry of Education of China. (13)

Supporting Information for this article is available online

at http://www.thieme-connect.com/products/ejournals/journal/ 10.1055/s-00000084.SunpmfogIritSa

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