6
J. Schulz et al. / Journal of Organometallic Chemistry xxx (2015) 1e8
1610 w, 1583 w, 1544 s, 1503 m, 1476 m, 1470 m, 1449 m, 1389 m,
1329 s, 1287 m, 1254 m, 1201 vs, 1159 vs, 1042 vs, 1009 m, 854 m,
749 s, 740 mw, 662 m, 611 m, 528 s, 501 m cmꢁ1. MS (ESIꢁ): m/z
485.9 ([M ꢁ HNEt3]ꢁ). Anal. Calcd. for C32H49PO4N2S,½AcOEt: C
64.53, H 8.44, N 4.43%. Found: C 64.16, H 8.33, N 4.48%.
layer was analyzed by NMR spectroscopy. For isolation of the
coupling product, the aqueous layer was extracted with ethyl ac-
etate (2 ꢂ 5 mL) and the combined organic layers were washed
with brine (10 mL), dried over MgSO4 and evaporated under
reduced pressure. The products were purified by column chro-
matography over silica gel column using dichloromethane-
methanol (20:1 v/v) as the eluent and, following evaporation
under reduced pressure, were isolated as white solids. Amino
acids 6 often tend to retain traces of dichloromethane used during
the chromatography, which cannot be removed even upon pro-
longed evacuation. The amount of the residual solvent was always
verified by NMR analysis.
Synthesis of racemic N-Boc-4-chlorophenylalanine (4a)
Racemic 4-chlorophenylalanine (10.0 g, 50 mmol) and sodium
hydroxide (6.0 g, 150 mmol) were dissolved in distilled water
(150 mL) in a round-bottom flask equipped with a stirring bar and a
dropping funnel. The reaction mixture was cooled in ice and a so-
lution of di-tert-butyl dicarbonate (13.1 g, 60 mmol) in tetrahy-
drofurane (150 mL) was slowly introduced from the dropping
funnel. The resulting mixture was allowed to warm to room tem-
perature and then stirred overnight. The resulting solution was
transferred into a separatory funnel and washed twice with diethyl
ether (100 mL). The aqueous phase was acidified with 3 M aqueous
citric acid to pH 4e5 and the obtained suspension was extracted
with dichloromethane (3 ꢂ 150 mL). The combined organic extracts
were washed with brine, dried over anhydrous MgSO4, filtered and
evaporated under reduced pressure to give 4a as a white solid.
Yield: 13.8 g (92%).
Analytical data for the cross-coupling products 6
Rac-2-{[(tert-butyloxy)carbonyl]amino}-3-(biphenyl-4-yl)propionic
acid (6a)
White solid. 1H NMR (DMSO-d6):
d 1.33 (s, 9H, CH3), 2.78e3.09
(m, 2H, CH2), 4.01e4.17 (m, 1H, CH), 7.14 (d, 3JHH ¼ 8.4 Hz, 1H, NH),
7.33e7.37 (m, 3H, C12H8), 7.43e7.47 (m, 2H, C12H8); 7.57e7.59 (m,
2H, C12H8), 7.63e7.65 (m, 2H, C12H8), 12.62 (br s, 1H, CO2H). 13C{1H}
NMR (DMSO-d6):
d 28.1, 36.0, 55.1, 78.1, 126.4, 126.5, 127.2, 127.3,
1H NMR (DMSO-d6):
d 1.32 (s, 9H, CMe3), 2.74e3.05 (m, 2H,
128.9, 129.7, 134.5, 137.3, 138.2, 140.0, 155.5, 173.6. MS (ESIꢁ): m/z
340.0 ([M ꢁ H]ꢁ). The data are in accordance with the literature
[21].
CH2), 3.97e4.12 (m, 1H, CH), 7.11 (d, 3JHH ¼ 8.5 Hz, 1H, NH), 7.27 (d,
3JHH ¼ 8.4 Hz, 2H, C6H4); 7.33 (d, 3JHH ¼ 8.4 Hz, 2H, C6H4),12.64 (br s,
1H, CO2H). 13C{1H} NMR (DMSO-d6):
d 28.03 (9C, CMe3), 35.66
(CH2), 54.84 (CH), 77.98 (CMe3), 127.94 (2C), 130.90 (2C), and 136.99
(C6H4); 155.33 (C]O), 173.27 (CO2H). One of the C6H4 carbons was
not found. MS (ESIꢁ): m/z 299.1 ([M ꢁ H]ꢁ). Anal. Calcd. for
Rac-2-{[(tert-butyloxy)carbonyl]amino}-3-(20-methylbiphenyl-4-
yl)propionic acid (6b)
Colorless viscous oil. 1H NMR (DMSO-d6):
d 1.33 (s, 9H, CH3),
C
14H18ClNO4: C 56.09, H 6.05, N 4.67%. Found: C 55.99, H 6.07, N
2.22 (s, 3H, CH3), 2.78e3.12 (m, 2H, CH2), 4.03e4.21 (m, 1H, CH),
7.12e7.19 (m, 2H, C12H8 and NH), 7.20e7.36 (m, 7H, C12H8),12.65 (br
4.60%.
s, 1H, CO2H). 13C{1H} NMR (DMSO-d6):
d 20.15 (CH3), 28.13 (9C,
Synthesis of racemic N-Boc-4-bromophenylalanine (4b)
CH3), 36.19 (CH2), 55.00 (CH), 78.00 (CMe3), 125.88, 127.14, 128.67,
128.95, 129.45, 130.29, 134.66, 136.66, 139.22, 141.11 (C12H8); 155.45
(C]O),173.60 (CO2H). MS (ESIꢁ): m/z 354.0 ([M ꢁ H]ꢁ). Anal. Calcd.
for C21H25NO4,0.1CH2Cl2: C 69.64, H 6.98, N 3.85%. Found: C 69.62,
H 7.05, N 3.64%.
Compound 4b was prepared similarly to 4a starting from
racemic 4-bromophenylalanine (5.0 g, 20.4 mmol) and sodium
hydroxide (2.5 g, 61.2 mmol) in distilled water (75 mL), and di-tert-
butyl dicarbonate (5.4 g, 24.7 mmol) in tetrahydrofurane (75 mL),
and was isolated as a white solid. Yield 6.1 g (87%).
1H NMR (DMSO-d6):
d 1.32 (s, 9H, CH3), 2.70e3.04 (m, 2H, CH2),
Rac-2-{[(tert-butyloxy)carbonyl]amino}-3-(30-methylbiphenyl-4-
3
3.97e4.12 (m, 1H, CH), 7.11 (d, JHH ¼ 8.4 Hz, 1H, NH), 7.21 (d,
yl)propionic acid (6c)
3JHH ¼ 8.3 Hz, 2H, Ph), 7.47 (d, 3JHH ¼ 8.3 Hz, 2H, Ph); 12.64 (br s, 1H,
White solid. 1H NMR (DMSO-d6):
d 1.33 (s, 9H, CH3), 2.37 (s, 3H,
CO2H). 13C{1H} NMR (DMSO-d6):
d 28.02 (9C, CH3), 35.70 (CH2),
CH3), 2.78e3.08 (m, 2H, CH2), 4.01e4.16 (m, 1H, CH), 7.09e7.18 (m,
2H, C12H8 and NH), 7.29e7.37 (m, 3H, C12H8), 7.39e7.47 (m, 2H,
54.77 (CH), 77.98 (CMe3), 119.4, 130.86 (2C), 131.3 (2C), 137.4 (C6H4),
155.3 (C]O), 173.2 (CO2H). MS (ESIꢁ): m/z 343.0 ([M ꢁ H]ꢁ). Anal.
Calcd. for C14H18BrNO4: C 48.85, H 5.27, N 4.07%. Found: C 48.81, H
5.19, N 3.85%.
C
12H8), 7.53e7.59 (m, 2H, C12H8), 12.64 (br s, 1H, CO2H). 13C{1H}
NMR (DMSO-d6):
d 21.07 (CH3), 28.09 (9C, CH3), 36.00 (CH2), 55.09
(CH), 78.01 (CMe3), 123.57, 126.35, 127.13, 127.81, 128.72, 129.58,
137.18, 137.93, 138.27, 139.91 (C12H8); 155.42 (C]O), 173.51 (CO2H).
MS (ESIꢁ): m/z 354.0 ([M
21H25NO4,0.05CH2Cl2: C 70.29, H 7.03 N 3.90%. Found: C 70.53, H
7.07, N 3.77%.
ꢁ
H]ꢁ). Anal. Calcd. for
SuzukieMiyaura cross-coupling of protected amino acids 4a and 4b
with boronic acids 5
C
The respective palladium precursor (5
mmol of Pd) and ligand 3
(2.9 mg, 5 mol; unless noted otherwise) were placed into a
Schlenk tube and dissolved in dichloromethane (0.5 mL). The
mixture was stirred for 15 min and then evaporated under vac-
m
Rac-2-{[(tert-butyloxy)carbonyl]amino}-3-(40-methylbiphenyl-4-
yl)propionic acid (6d)
uum. The appropriate protected halogenated amino acid
4
White solid. 1H NMR (DMSO-d6):
d 1.32 (s, 9H, CH3), 2.33 (s, 3H,
(0.50 mmol), boronic acid (0.55 mmol) and base (2.0 mmol) were
added to the Schlenk tube, and the reaction vessel was degassed
by three vacuumeargon cycles, filled with argon and sealed with a
rubber septum. Degassed solvent (3 mL) was introduced and the
reaction vessel was placed into a pre-heated oil bath. After stirring
for 4 h, the reaction was terminated by cooling in ice and simul-
taneous addition of 3 M aqueous HCl (3 mL), ethyl acetate (3 mL)
and mesitylene (0.50 mmol; an internal standard). The organic
CH3), 2.76e3.08 (m, 2H, CH2), 4.01e4.16 (m, 1H, CH), 7.12 (d,
3JHH ¼ 8.3 Hz, 1H, NH), 7.24e7.26 (m, 2H, C12H8), 7.30e7.32 (m, 2H,
C
12H8), 7.51e7.56 (m, 4H, C12H8), 12.63 (br s, 1H). 13C{1H} NMR
(DMSO-d6):
d 20.64 (CH3), 28.14 (9C, CH3), 36.05 (CH2), 55.16 (CH),
78.05 (CMe3), 126.14, 126.31, 129.48, 129.64, 136.48, 136.99, 137.10,
138.11 (C12H8); 155.47 (C]O), 173.57 (CO2H). MS (ESIe): m/z 354.0
([M ꢁ H]ꢁ). Anal. Calcd. for C21H25NO4: C 70.96, H 7.09, N 3.94%.
Found: C 71.23, H 7.31, N 3.51%.
j.jorganchem.2015.01.020