N-Derivatization of R-Amino Esters and Amides
extracted with CH2Cl2. The combined organic extracts were
dried over anhydrous Na2SO4. Removal of the solvent in vacuo
afforded the desired product 3a .
lyzed the compounds 10 and 10′ thus obtained by TLC
1
and by H, 13C, and 19F NMR. The chemical shift in the
19F NMR spectrum (Figure 11, Supporting Information)
for compound 10 is at -72.907, for 10′ (Figure 12,
Supporting Information) at -73.069. The analysis of
mixed sample clearly showed the difference in chemical
shifts (Figure 13, Supporting Information). In compound
10′, the presence of about 5% of 10 was detected; this is
in accordance with the enantiomeric purity of the starting
D-phenylalanine (Figure 12, Supporting Information).
TLC analysis of individual diastereomers and a mixed
sample also clearly showed the difference between dia-
stereomers 10 and 10′. All other products were assigned
Rea ction of 2a w ith Tr ieth yl P h osp h ite. To a solution
of 2a (0.62 g, 2.0 mmol) in dry CH2Cl2 (20 mL) at 0 °C were
sequentially added ZnBr2 (0.90 g, 4.0 mmol) and triethyl
phosphite (0.69 mL, 4.0 mmol). The reaction mixture was
stirred at 0 °C for 1 h and at 25 °C for 14 h. The reaction
mixture was quenched with a 10% solution of Na2CO3 and
extracted with CH2Cl2. The combined organic layers were
washed with brine and dried over anhydrous Na2SO4. After
removal of the solvent in vacuo, the residue was purified by
gradient column chromatography (silica gel) with EtOAc/
hexanes (5% of EtOAc to 50% of EtOAc, 5% step) as eluent to
afford 3b.
1
by analogy and by comparison of their H and 13C NMR
Gen er a l P r oced u r e for t h e R ea ct ion of 2a ,b w it h
Na CN. A mixture of 2a ,b (2.0 mmol) and NaCN (2.7 mmol)
in DMSO (10 mL) was stirred at 20-25 °C for 48 h. The
solution was diluted with EtOAc (20-25 mL), washed with
water, 5% Na2CO3, and brine, and dried over anhydrous Na2-
SO4. After removal of the solvent in vacuo, 3e was obtained
as a pure compound without additional purification; compound
3i was purified by gradient silica gel column chromatography
with EtOAc/hexanes (5% of EtOAc to 50% of EtOAc, step 5%)
as eluent. Compound 3e has been published previously.14
Gen er a l P r oced u r e for th e Rea ction of 2a-c w ith Allyl
Sila n es a n d Silylen ol E t h er s. N-Functionalized R-amino
esters 2 (2.0 mmol) and allylsilanes (3 mmol) or silyl enol
ethers (3 mmol) were dissolved in dry dichloromethane (12
mL). The solution was cooled to 0 °C using an ice bath, and
BF3‚Et2O (3.0 mmol) was added. The mixture was allowed to
react at 0 °C for 2 h and at 25 °C for 12 h. The reaction mixture
was quenched with a 10% aqueous solution of Na2CO3 and
extracted with dichloromethane. The combined organic layers
were dried over anhydrous Na2SO4. After removal of the
solvent in vacuo, the residue was purified by gradient column
chromatography (silica gel) with EtOAc/hexanes (5% of EtOAc
to 50% of EtOAc, 5% step) to afford 3c,d ,f-h ,j. Compounds
3g,j have been published previously.15,16
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Ben zo-
tr ia zolylm eth yl r-Am in o Am id es 7a -c. A mixture of 6 (3.0
mmol), benzotriazole (3.0 mmol), and formaldehyde (37%
aqueous solution, 3.0 mmol) in CH3OH/H2O (6 mL/3 mL) was
stirred at 25 °C for 12 h. The precipitate was filtered, washed
with cold diethyl ether, and recrystallized from appropriate
solvents to give 7a -c.
Gen er a l P r oced u r e for th e Rea ction of 7a-c w ith Allyl
Silan es an d Silylen ol Eth er s. N-Benzotriazolylmethyl R-ami-
no amides 7a -c (1.0 mmol) and allyl silanes (1.5 mmol) or
silylenol ethers (1.5 mmol) were dissolved in dry CH2Cl2 (7
mL). The solution was cooled to 0 °C using an ice bath, and
BF3‚Et2O (1.5 mmol) was added. The mixture was allowed to
react at 0 °C for 2 h and at 25 °C for 16 h. The reaction mixture
was quenched with a 10% solution of Na2CO3 and extracted
with CH2Cl2. The combined organic layers were dried over
anhydrous Na2SO4. After removal of the solvent in vacuo, the
residue was purified by gradient column chromatography
(silica gel) with EtOAc/hexanes (5% of EtOAc to 50% of EtOAc,
5% step) to afford 8a and 9a , 8c-e.
spectra.
Con clu sion s
In this paper, we disclose an efficient method for the
preparation of N-functionalized R-amino esters and
amides. Whereas previous investigations on functional-
ization of chiral R-amino esters were limited to N-
substituted 4-phenyloxazolidine-2-carboxylates and L-
proline and pipecolinic esters11 which represent cyclic
secondary amino function, the present results are now
extended to noncyclic R-amino esters and R-amino amides.
The described protocol utilizes mild conditions and
provides high yields of final compounds 3a -j, 8a -f and
intermediates 2a -c, 7a -c.
Exp er im en ta l Section
Melting points were determined using a capillary melting
point apparatus equipped with a digital thermometer and are
uncorrected. 1H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were recorded on a 300 NMR spectrometer in CDCl3
(with TMS for 1H and chloroform-d for 13C as the internal
reference). Optical rotation values were measured with the use
of the sodium D line. Column chromatography was performed
on silica gel (200-425 mesh) unless otherwise stated. All of
the reactions were carried out under N2. The HPLC system
consisted of a isocratic pump, variable-wavelength UV/vis
detector, and a computing integrator. Injector is fitted with a
20-µL loop and detection was performed at 254 nm. A 25 cm
× 4.6 mm LC-(R)-DNB-PG column was used for the chiral
separation with hexane (99.8%)/i-PrOH(0.2%) at 1.5 mL/min
flow rate as an eluent.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Ben zo-
tr ia zolylm eth yl r-a m in o Ester s 2a -c. To a solution of
benzotriazole (11.0 mmol) and the hydrochloric salt of 1a -c
(10.0 mmol) and NaOH (10.0 mmol) in MeOH/H2O (20/10 mL)
was added formaldehyde (10.0 mmol, 37% aqueous solution).
The mixture was stirred at room temperature for 4 h. For 2a ,
the obtained precipitate was filtered, washed with cold H2O
and EtOH, and recrystallized from CHCl3/hexanes. For 2b,c,
the products were extracted with diethyl ether. The organic
extracts were dried over MgSO4, and the solvent was removed
to dryness under reduced pressure to give crude compounds
2b-c, which were used in the next step without purification.
Rea ction of 7a a n d 7c w ith Na CN. A mixture of 7a or
7c (1.0 mmol) and NaCN (1.3 mmol) were dissolved in DMSO
(7 mL) and stirred at 20-25 °C for 14 h. The solution was
diluted with EtOAc, washed with water and 5% Na2CO3, and
dried over anhydrous Na2SO4. After removal of the solvent in
vacuo, the residue was purified by silica gel column chroma-
tography with EtOAc/hexanes (1/2) as eluent to afford 8b,f.
P r ep a r a tion of Com p ou n d s 10 a n d 10′. Respective
compound 3c, 3c′ (0.03 g, 0.13 mmol) and triethylamine (0.02
mL, 0.13 mmol) were added to the solution of (S)-(-)-(trifluo-
roacetyl)prolyl chloride (1.3 mL, 0.13 mmol, 0.1 M solution in
DCM) at 0 °C, and the reaction mixture was stirred at room
temperature for 12 h. After addition of water, the mixture was
R ea ct ion of 2a w it h Th iop h en ol. To a solution of
thiophenol (0.31 mL, 3.0 mmol) in dry THF (20 mL) was added
NaH (60% in mineral oil, 0.16 g, 4.0 mmol), and the reaction
mixture was stirred at 20-25 °C for 1 h. One drop of methanol
was added to quench excess NaH, and then methyl (2S)-2-
[(1H-benzotriazol-1-ylmethyl)amino]-3-phenylpropanoate 2a
(0.62 g, 2.0 mmol) was added. The mixture was stirred at
25 °C for 24 h. After removal of THF in vacuo, 10% aqueous
Na2CO3 was added to the residue, and the aqueous layer was
J . Org. Chem, Vol. 68, No. 23, 2003 9091