10.1002/adsc.201900179
Advanced Synthesis & Catalysis
were combined, dried over Na2SO4 and filtered-off. The
solvent was distilled under reduced pressure and the
analysed by GC or/and HPLC (see Electronic Supporting
Information).
resulting
reaction
crude
purified
by
column
chromatography on silica gel (10% EtOAc/hexane),
yielding ketones 2a-i as oil products.
General procedure for the synthesis of 1-arylpropan-
amines 8a-i through
a chemoenzymatic cascade
i
1-Phenylpropan-2-one (2a) Colourless oil (29 mg,
85% yield). 1H NMR (300.13 MHz, CDCl3): δ 2.15 (s, 3H),
3.70 (s, 2H), 7.17-7.24 (m, 2H), 7.26-7.38 (m, 3H) ppm.
13C NMR (300.13 MHz, CDCl3): δ 29.3 (CH3), 51.1 (CH2),
127.1 (CH), 128.8 (2CH), 129.5 (2CH), 134.3 (C), 206.7
(C) ppm.
sequence using PrNH2 as amine donor. A solution of
allylbenzene 1a-i (0.0625 mmol) in acetonitrile (125 µL)
was added under inert atmosphere to a Schlenk flask
containing a mixture of Pd(TFA)2 (2.5 mol%, 0.5 mg),
NaTFA (0.0125 mmol, 1.7 mg) and the corresponding
Fe(III) salt (37.5 mM) in water (2.4 mL). The reaction was
stirred (see main manuscript for temperature and reaction
times), and after this time isopropyl ammonium phosphate
(0.25 M, 172 mg) and isopropylamine (0.15 M, 31 µL) for
a final amine donor concentration of 0.9 M and pH 8.5,
PLP (1 mM) and the ATA (1:1 w/w enzyme:allylbenzene
ratio) were successively added. This suspension was
shaken at 250 rpm at 30 ºC for 24 h, quenching the
reaction by acidification with a HCl 0.5 M aqueous
solution, which was extracted with EtOAc (2 x 2.5 mL).
The aqueous phase was collected, basified with a NaOH 4
M aqueous solution (1 mL) and extracted with EtOAc (3 x
2.5 mL). The organic phases were combined, dried over
Na2SO4 and filtered-off, finally distilling the solvent under
reduced pressure, yielding optically active 1-arylpropan-2-
amines 8a-j as colourless oils.
1-(2-Methylphenyl)propan-2-one (2b). Colourless oil
1
(36 mg, 96% yield). H NMR (300.13 MHz, CDCl3): δ
2.14 (s, 3H), 2.25 (s, 3H), 3.71 (s, 2H), 7.09-7.23 (m, 4H)
ppm. 13C NMR (300.13 MHz, CDCl3): δ 19.8 (CH3), 29.4
(CH3), 49.3 (CH2), 126.4 (CH), 127.5 (CH), 130.5 (CH),
130.6 (CH), 133.3 (C), 137.0 (C), 206.6 (C) ppm.
1-(3-Methylphenyl)propan-2-one (2c). Colourless oil
1
(35 mg, 95% yield). H NMR (300.13 MHz, CDCl3): δ
2.16 (s, 3H), 2.35 (s, 3H), 3.67 (s, 2H), 6.98-7.12 (m, 2H),
7.09 (d, JHH = 7.5 Hz, 1H), 7.23 (t, JHH = 7.4 Hz, 1H) ppm.
13C NMR (300.13 MHz, CDCl3): δ 21.5 (CH3), 29.4 (CH3),
51.1 (CH2), 126.5 (CH), 128.0 (CH), 128.8 (CH), 130.3
(CH), 134.1 (C), 138.6 (C), 207.5 (C) ppm.
1-(4-Methylphenyl)propan-2-one (2d). Colourless oil
1
(35 mg, 94% yield). H NMR (300.13 MHz, CDCl3): δ
2.14 (s, 3H), 2.34 (s, 3H), 3.65 (s, 2H), 7.06-7.19 (m, 4H)
ppm. 13C NMR (300.13 MHz, CDCl3): δ 21.2 (CH3), 29.3
(CH3), 50.8 (CH2), 129.4 (2CH), 129.6 (2CH), 131.3 (C),
136.8 (C), 206.9 (C) ppm.
1-Phenylpropan-2-amine (8a). Colourless oil (26 mg,
78% yield). 1H NMR (300.13 MHz, CDCl3): δ 1.12 (d, JHH
= 6.2 Hz, 3H), 1.54 (brs, 2H), 2.44 (dd, JHH = 13.5, 8.0 Hz,
1H), 2.65 (dd, JHH = 13.5, 5.4 Hz, 1H), 3.10-3.23 (m, 1H),
7.14-7.35 (m, 5H) ppm. 13C NMR (300.13 MHz, CDCl3): δ
23.5 (CH3), 46.6 (CH2), 48.6 (CH), 126.3 (CH), 128.5
(2CH), 129.3 (2CH), 139.7 (C) ppm. []D20= +45.0 (c 0.2,
CHCl3, >99% ee (S)-8a), lit. []D20= +40.0 (c 1.0, CHCl3,
98% ee).14c
1-[4-(Trifluoromethyl)phenyl]propan-2-one
(2e).
Colourless oil (39 mg, 78% yield). 1H NMR (300.13 MHz,
CDCl3): δ 2.20 (s, 3H), 3.78 (s, 2H), 7.31 (d, 3JHH = 8.0 Hz,
3
2H), 7.60 (d, JHH = 8.1 Hz, 2H) ppm. 13C NMR (300.13
3
MHz, CDCl3): δ 29.7 (CH3), 50.4 (CH2), 125.7 (q, JCF
=
1
2
3.8 Hz, 2CH), 124.2 (q, JCF = 271.7 Hz, C), 129.6 (q, JCF
= 32.6 Hz, C), 130.0 (2CH), 138.1 (C), 206.2 (C) ppm. 19F
NMR (282.35 MHz, CDCl3): –62.57 ppm.
1-(2-Methylphenyl)propan-2-amine (8b). Colourless
1
oil (8 mg, 85% yield). H NMR (300.13 MHz, CDCl3): δ
2.32 (s, 3H), 2.42 (brs, 2H), 2.62 (dd, JHH = 13.5, 7.8 Hz,
1H), 2.74 (dd, JHH = 13.5, 6.0 Hz, 1H), 3.14-3.27 (m, 1H),
7.08-7.23 (m, 4H) ppm. 13C NMR (300.13 MHz, CDCl3): δ
19.7 (CH3), 23.2 (CH3), 43.4 (CH2), 47.6 (CH), 126.0 (CH),
126.5 (CH), 130.2 (CH), 130.5 (CH), 136.5 (C), 137.6 (C)
ppm. []D20= +23.3 (c 0.35, MeOH, >99% ee (S)-8b).
1-(3-Methylphenyl)propan-2-amine (8c). Colourless
1-(2-Methoxyphenyl)propan-2-one (2f). Colourless oil
1
(39 mg, 94% yield). H NMR (300.13 MHz, CDCl3): δ
2.14 (s, 3H), 3.67 (s, 2H), 3.81 (s, 3H), 6.88 (d, JHH = 8.1
Hz, 1H), 6.93 (td, JHH = 7.4, 1.0 Hz, 1H), 7.13 (dd, JHH
=
7.3, 1.6 Hz, 1H), 7.26 (td, JHH = 7.8, 1.8 Hz, 1H) ppm. 13C
NMR (300.13 MHz, CDCl3): δ 29.4 (CH3), 45.6 (CH2),
55.4 (CH3), 110.5 (CH), 120.8 (CH), 123.7 (C), 128.7
(CH), 131.2 (CH), 157.4 (C), 207.2 (C) ppm.
1
oil (9 mg, 92% yield). H NMR (300.13 MHz, CDCl3): δ
1.13 (d, JHH = 6.3 Hz, 3H), 1.83 (brs, 2H), 2.33 (s, 3H),
2.49 (dd, JHH = 13.3, 8.1 Hz, 1H), 2.69 (dd, JHH = 13.3, 5.3
Hz, 1H), 3.10-3.24 (m, 1H), 6.95-7.06 (m, 3H), 7.19 (t, JHH
= 7.4 Hz, 1H) ppm. 13C NMR (300.13 MHz, CDCl3): δ
21.5 (CH3), 23.5 (CH3), 46.5 (CH2), 48.6 (CH), 126.4 (CH),
127.1 (CH), 128.4 (CH), 130.1 (CH), 138.1 (C), 139.6 (C)
ppm. []D20= +29.4 (c 0.2, MeOH, >99% ee (S)-8c).
1-(4-Methoxyphenyl)propan-2-one (2g). Colourless
1
oil (38 mg, 92% yield). H NMR (300.13 MHz, CDCl3): δ
2.15 (s, 3H), 3.65 (s, 2H), 3.81 (s, 3H), 6.83-6.90 (m, 2H),
7.08-7.15 (m, 2H) ppm. 13C NMR (300.13 MHz, CDCl3): δ
29.2 (CH3), 50.2 (CH2), 53.4 (CH3), 114.3 (2CH), 126.4
(C), 130.5 (2CH), 158.8 (C), 207.1 (C) ppm.
1-(1,3-Benzodioxol-5-yl)propan-2-one
(2h).
1-(4-Methylphenyl)propan-2-amine (8d). Colourless
Colourless oil (41 mg, 91% yield). 1H NMR (300.13 MHz,
CDCl3): δ 2.15 (s, 3H), 3.61 (s, 2H), 5.95 (s, 2H), 6.66 (m,
2H), 6.78 (d, JHH = 7.9 Hz, 1H) ppm. 13C NMR (300.13
MHz, CDCl3): δ 29.2 (CH3), 50.6 (CH2), 101.1 (CH2),
108.5 (CH), 109.8 (CH), 122.6 (CH), 127.9 (C), 146.7 (C),
148.0 (C), 206.6 (C) ppm.
1
oil (9 mg, 90% yield). H NMR (300.13 MHz, CDCl3): δ
1.11 (d, JHH = 6.3 Hz, 3H), 1.50 (brs, 2H), 2.32 (s, 3H),
2.47 (dd, JHH = 13.3, 8.1 Hz, 1H), 2.68 (dd, JHH = 13.2, 5.2
Hz, 1H), 3.06-3.21 (m, 1H), 7.03-7.16 (m, 4H) ppm. 13C
NMR (300.13 MHz, CDCl3): δ 19.4 (CH3), 22.9 (CH3),
42.0 (CH2), 49.6 (CH), 129.3 (2CH), 129.5 (2CH), 133.8
(C), 136.7 (C) ppm. []D20= +37.3 (c 0.2, MeOH, >99% ee
(S)-8d), lit. []D20= +35.0 (c 1.6, MeOH, 96% ee).14d
1-(3,4-Dimethoxyphenyl)propan-2-one
(2i).
Colourless oil (40 mg, 83% yield). 1H NMR (300.13 MHz,
CDCl3): δ 2.12 (s, 3H), 3.60 (s, 2H), 3.84 (s, 6H), 6.68 (d,
JHH = 2.0 Hz, 1H), 6.72 (dd, JHH = 8.1, 2.0 Hz, 1H), 6.81 (d,
JHH = 8.1 Hz, 1H) ppm. 13C NMR (300.13 MHz, CDCl3): δ
29.1 (CH3), 50.6 (CH2), 55.9 (CH3), 55.9 (CH3), 111.4
(CH), 112.4 (CH), 121.6 (CH), 126.7 (C), 148.2 (C), 149.1
(C), 206.9 (C) ppm.
1-[4-(Trifluoromethyl)phenyl]propan-2-amine (8e).
1
Colourless oil (9 mg, 70% yield). H NMR (300.13 MHz,
CDCl3): δ 1.18 (d, JHH = 6.3 Hz, 3H), 2.79 (d, JHH = 6.8 Hz,
2H), 3.29 (h, JHH = 6.5 Hz, 1H), 3,64 (brs, 2H), 7.32 (d,
JHH = 8.0 Hz, 2H), 7.56 (d, JHH = 8.0 Hz, 2H) ppm. 13C
NMR (300.13 MHz, CDCl3): δ 21.5 (CH3), 23.5 (CH3),
46.5 (CH2), 48.6 (CH), 126.4 (CH), 127.1 (CH), 128.4
(CH), 130.1 (CH), 138.1 (C), 139.6 (C) ppm. 19F NMR
(282.35 MHz, CDCl3): –62.41 ppm. []D20= +33.5 (c 0.4,
CHCl3, >99% ee (S)-8e), lit. []D20= +22.2 (c 1.1, CHCl3,
90% ee).14d
General procedure for the biotransamination of
ketones 2a-j. In a 1.5 mL Eppendorf tube with a phosphate
i
buffer (100 mM, pH 7.5, 500 µL) containing PrNH2 (1.0
M) and PLP (1 mM), 1-arylpropan-2-one (2a-i, 0.01
mmol) was added. Then the ATA (10.0 mg of those
overexpressed in E. coli or 2.0 mg of the commercially
available ATAs) was added, and the mixture was shaken at
30 °C and 250 rpm for 24 h. The reaction was quenched by
addition of a NaOH 4 M aqueous solution (200 µL) and
extracted with EtOAc (3 x 500 µL). The combined organic
phases were washed with H2O (500 µL), dried over
Na2SO4, filtered-off and the resulting solution was
1-(2-Methoxyphenyl)propan-2-amine (8f). Colourless
1
oil (18 mg, 87% yield). H NMR (300.13 MHz, CDCl3): δ
1.17 (d, JHH = 6.4 Hz, 3H), 2.44 (dd, JHH = 13.1, 7.6 Hz,
1H), 2.78 (dd, JHH = 13.0, 5.8 Hz, 1H), 2.79 (brs, 2H),
3.23-3.36 (m, 1H), 3.83 (s, 3H), 6.85 (d, JHH = 7.8, 1H),
6.90 (td, JHH = 7.4, 1.2 Hz, 1H), 7.15 (dd, JHH = 7.3, 1.6 Hz,
1H), 7.23 (td, JHH = 7.8, 1.7 Hz, 1H) ppm. 13C NMR
(300.13 MHz, CDCl3): δ 22.7 (CH3), 40.4 (CH2), 47.4
9
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