Conformation of Primary Amides in Chloroform
Esterification was performed as for the previous case and afforded
the corresponding methyl ester with 69% yield: 1H NMR 200 MHz
(CDCl3) δ 1.95 (quintet, 2H, CH2), 2.37 (t, 2H, CH2), 2.41 (t, 2H,
CH2), 2.94 (s, 3H, NCH3), 3.00 (s, 3H, NCH3), 3.66 (s, 3H, OCH3).
Ammonolysis of the crude ester (1.89 g, 11 mmol) following the
general procedure described in Supporting Information afforded 1.22
g (71%) of N,N-dimethylpentane diamide 2a as a white solid
NH), 7.15 (broad, 1H, NH). After addition of basic Al2O3 in the
sample, the amine NH wasas a broad signal at 1.45 ppm, while the
signal at 2.47 ppm was a triplet (3J ≈ 6.5 Hz). Anal. Calcd for 6b,
H2O: C, 48,64.83; H, 10,81.37; N, 18,91. Found: C, 48,32; H,
10,68; N, 18,74.
Benzylamino Propionamide (7). 3-Chloropropionamide (3.80
g; 35.3 mmol) and benzylamine (18.90 g; 177 mmol) were stirred
at room temperature in 100 mL of CH2Cl2. Next, 100 mL of 1 M
NaHCO3 was added and the mixture was stirred for 24 h. CH2Cl2
was evaporated and the aqueous phase was washed with successive
50 mL fractions of an equimolar Et2O/petroleum ether mixture until
no organic material could be further extracted. The aqueous phase
was then saturated with NaCl until the appearance of a white
suspension, which was extracted twice with 100 mL of CH2Cl2.
The combined organic layers were dried and reduced to around 50
mL. HCl was then bubbled in CH2Cl2. The hydrochloride of
compound 7 precipitated as a white powder. The powder was
dissolved in 15 mL 1 M NaHCO3. The aqueous phase was saturated
with NaCl and extracted twice with 20 mL of EtOAc. Drying of
the organic phase on Na2SO3 and evaporation afforded 7 as a white
powder, which was filtrated after trituration in Et2O (1.67 g,
26.6%): mp 96 °C; 1H NMR 500 MHz (10 mM, CDCl3) δ 2.43 (t,
J ) 5.9 Hz, 2H, CH2), 2.95 (t, J ) 5.9 Hz, 2H, CH2), 3.84 (s, 2H,
CH2), 5.35 (broad, 1H, NH), 7.30 to 7.38 (m, 5H, aromatics), 7.50
(broad, 1H, NH). Anal. Calcd: C, 67.42; H, 7.87; N, 15.73.
Found: C, 67.27; H, 7.70; N, 15.55.
1
(Et2O): mp 102-103 °C; H NMR 500 MHz (10 mM, CDCl3) δ
2.01 (quintet, J ) 7.0 Hz, 2H, CH2), 2.37 (t, J ) 7.1 Hz, 2H, CH2),
2.46 (t, J ) 6.9 Hz, 2H, CH2), 2.98 (s, 3H, NCH3), 3.04 (s, 3H,
NCH3), 5.40 (broad, 1H, NH), 6.10 (broad, 1H, NH). Anal. Calcd:
C, 53.15; H, 8.92; N, 17.71. Found: C, 52.85; H, 8.86; N, 17.48.
5-Pentanamide Carboxylic Acid Methyl Ester (4a). Glutaric
anhydride (7 g; 61 mmol) was added carefully to 50 mL of NH3/
MeOH 40% at 0 °C. The solution was allowed to warm to room
temperature and stirred 2 h. Excess of NH3/MeOH was eliminated
under reduced pressure, and the crude residue was dissolved in 50
mL of MeOH. After cooling the solution to -10 °C, thionyl choride
(14.50 g; 122 mmol) in 80 mL of CH2Cl2 was added dropwise and
stirring was continued for 30 min. After filtration of ammonium
chloride, solvents were evaporated. The crude residue was dissolved
in CH2Cl2/H2O 50 + 50 mL. The organic layer was dried on Na2-
SO4/K2CO3 and evaporated. The crude oil was directly solubilized
in Et2O, which afforded (5.30 g, 60%) of 5-pentanamide carboxylic
1
acid methyl ester 4a as white microcrystals: mp 87-88 °C; H
NMR 500 MHz (10 mM, CDCl3) δ 2.00 (quinted, J ) 7.2 Hz, 2H,
CH2), 2.33 (t, J ) 7.3 Hz, 2H, CH2), 2.44 (t, J ) 7.1 Hz, 2H,
CH2), 3.71 (s, 3H, OCH3), 5.35 (broad, 1H, NH), 5.50 (broad, 1H,
NH). Anal. Calcd: C, 49.65; H, 7.64; N, 9.65. Found: C, 49.38;
H, 7.58; N, 9.53.
(Benzyl,tert-butoxycarbonyl-methyl) Amino Acetamide (8a).
Benzylamino acetamide 6a (1.64 g, 10 mmol) and 1.10 g (5.5
mmol) of tertiobutyl bromoacetate were stirred in 30 mL of CH2-
Cl2 for 20 h. 6a, HBr was filtrated. The organic layer was washed
with 20 mL of 1 M NaHCO3, dried, and evaporated. The residue
was triturated in petroleum ether to give 8a as white amorphous
4-Phenyl Butyramide (5). 4-Phenyl butyric acid was esterified
by SOCl2/MeOH with 91% yield. Conversion to 4-phenyl butyr-
amide 5 (83%) was performed following the general ammonolysis
procedure described in Supporting Information: mp 83 °C; 1H NMR
500 MHz (10 mM, CDCl3) δ 2.02 (quintet, J ) 7.5 Hz, 2H, CH2),
2.26 (t, J ) 7.5 Hz, 2H, CH2), 2.71 (t, J ) 7.5 Hz, 2H, CH2), 5.35
(broad, 2H, NH2), 7.21 to 7.33 (m, 5H, aromatics).
1
powder (1.20 g, 86%): mp 90-92 °C; H NMR 500 MHz (10
mM, CDCl3) δ 1.48 (s, 9H, 3xCH3), 3.30 (s, 2H, CH2), 3.31 (s,
2H, CH2), 3.83 (s, 2H, CH2), 5.45 (broad, 1H, NH), 7.30 to 7.38
(m, 5H, aromatics), 7.55 (broad, 1H, NH). Anal. Calcd: C, 64.73;
H, 7.97; N, 10.06. Found: C, 65.06; H, 8.03; N, 10.17.
(Benzyl,dimethylaminocarbamoyl-methyl) Amino Acetamide
(8b). Benzylamino acetamide 6a (1.64 g; 10 mmol) and 0.84 g
(5.5 mmol) of methyl bromoacetate were stirred in 30 mL of CH2-
Cl2 for 20 h. 6a, HBr was filtrated. The organic layer was washed
with 20 mL of 1 M NaHCO3, dried, and evaporated. Trituration of
the residue in 30 mL of Et2O afforded (benzyl,methoxycarbonyl-
methyl) amino acetamide as a white amorphous powder: mp 91
Benzylamino Acetamide (6a). Benzylamine (32 g; 300 mmol)
and 5.60 g (60 mmol) of chloroacetamide were reacted overnight
at room temperature in 100 mL of CH2Cl2. Next, 100 mL of 1 M
NaHCO3 was added and the mixture was stirred vigorously for 1
h. After evaporation of CH2Cl2 the aqueous phase was extracted
twice with 50 mL portions of Et2O, which eliminated around the
half (14 g) of the excess of benzylamine. The aqueous phase was
then gradually saturated with NaCl until a white solid appeared,
which was subsequently removed by filtration. This solid, a
benzylamine/benzylamino acetamide (1/1) complex, was dried and
dissolved in refluxing CH2Cl2. The solution was then reduced to
around 50 mL and 150 mL of Et2O was added. Benzylamino
acetamide 6a crystallized rapidly as colorless needles (5.50 g,
1
°C; H NMR 200 MHz (10 mM, CDCl3) δ 3.30 (s, 2H, CH2),
3.40 (s, 2H, CH2), 3.73 (s, 3H, OCH3), 3.81 (s, 2H, CH2), 5.45
(broad, 1H, NH), 7.30 to 7.45 (m, 5H, aromatics), 7.45 (broad,
1H, NH).
This solid was directly poured into 40 mL of dimethylamine 40
wt % solution in water, 0.027 g of NaCN (0.55 mmol) was added,
and the mixture was stirred for 3 days at room temperature. The
solution was reduced to around 5 mL, saturated with NaCl, and
extracted twice with 30 mL of CH2Cl2. After drying over Na2SO4,
evaporation yielded a thick oil, which was dissolved in EtOAc /Et2O
(1/5). 8b slowly precipitated as white globular colonies (0.76 g,
55% for the two steps): mp 105-110 °C (waxy fusion); 1H NMR
500 MHz (10 mM, CDCl3) δ 2.89 (s, 3H, NCH3), 2.96 (s, 3H,
NCH3), 3.33 (s, 2H, CH2), 3.42 (s, 2H, CH2), 3.83 (s, 2H, CH2),
5.45 (broad, 1H, NH), 7.29 to 7.37 (m, 5H, aromatics), 8.05 (broad,
1H, NH). Anal. Calcd: C, 62.63; H, 7.68; N, 16.85. Found: C,
62.61; H, 7.61; N, 16.79.
1
56%): mp 92 °C; H NMR 500 MHz (10 mM, CDCl3) δ 3.35 (s,
2H, CH2), 3.83 (s, 2H, CH2), 5.45 (broad, 1H, NH), 7.05 (broad,
1H, NH), 7.30 to 7.39 (m, 5H, aromatics). After addition of basic
Al2O3 in the sample, the amine NH appeared as a broad triplet at
1.83 ppm while signals at 3.35 and 3.83 ppm were doublets (3J )
3
5.7 Hz and J ) 6.5 Hz, respectively). Anal. Calcd: C, 65.83; H,
7.37; N, 17.06. Found: C, 65.39; H, 7.28; N, 16.87.
Isobutylamino Acetamide (6b). Isobutylamine (11 g; 150 mmol)
and 2.80 g (30 mmol) of chloroacetamide were reacted overnight
in 50 mL of CH2Cl2. Next, 30 mL of 1 M NaHCO3 was added and
the mixture was stirred vigorously for 2 h. The organic layer was
dried on Na2SO4 and evaporation afforded a colorless oil that
solidified on standing. This crude compound was dissolved in
boiling Et2O and the solution was cooled by addition of cold
pentane, which led rapidly to the crystallization of isobutylamino
acetamide 6b as pearlescent microcrystals (1.91 g, 49%): mp 50-
55 °C (waxy); 1H NMR 500 MHz (10 mM, CDCl3) δ 0.96 (d, J )
6.7 Hz, 6H, 2xCH3), 1.75 (multiplet, J ) 6.7 Hz, 1H, CH), 2.47
(d, J ) 6.7 Hz, 2H, CH2), 3.30 (s, 2H, CH2), 5.40 (broad, 1H,
(Dicarbamoyl-methyl) Benzylamine (8c). Compound 8c was
prepared following the same procedure as 8b except that the final
step was the general ammonolysis procedure described in Support-
1
ing Information (78%): mp (EtOAc) 157 °C; H NMR 200 MHz
(10 mM, CDCl3) δ 3.30 (s, 4H, 2 × CH2), 3.82 (s, 2H, CH2), 5.45
(broad, 2H, 2 × NH), 6.65 (broad, 2H, 2 × NH), 7.30 to 7.45 (m,
5H, aromatics). Anal. Calcd: C, 64.73; H, 7.97; N, 10.06. Found:
C, 65.06; H, 8.03; N, 10.17.
J. Org. Chem, Vol. 71, No. 1, 2006 157