Sodium borohydride: A versatile reagent in the reductive N-monoalkylation of α-amino acids and α-amino methyl esters

Article abstract of DOI:10.1139/v02-083

α-Amino acids and α-amino methyl esters are easily converted to their N-monoalkyl derivatives by a reductive condensation reaction using several carbonyl compounds in the presence of sodium borohydride. This reducing agent has shown a wide versatility with minor but essential procedural variations. The reaction allows the α-monodeuterium labeling of the new N-substituent by use of sodium borodeuteride.

Full text of DOI:10.1139/v02-083

779
Sodium borohydride: A versatile reagent in the
reductive N-monoalkylation of -amino acids
and -amino methyl esters
Giancarlo Verardo, Paola Geatti, Elena Pol, and Angelo G. Giumanini
Abstract: ꢀ-Amino acids and ꢀ-amino methyl esters are easily converted to their N-monoalkyl derivatives by a
reductive condensation reaction using several carbonyl compounds in the presence of sodium borohydride. This
reducing agent has shown a wide versatility with minor but essential procedural variations. The reaction allows the ꢀ-
monodeuterium labeling of the new N-substituent by use of sodium borodeuteride.
Key words: ꢀ-amino acid, ꢀ-amino methyl esters, sodium borohydride, reductive N-monoalkylation, carbonyl com-
pounds.
Résumé : Les acides ꢀ-aminés et leurs esters peuvent facilement être transformés en leurs dérivés N-monoalkylés
par le biais d’une réaction de condensation réductrice faisant appel à divers composés carbonylés, en présence de
borohydrure de sodium. Il a été démontré que ce réactif présente une grande versatilité par rapport aux variations
mineures, mais essentielles, dans les procédures. L’utilisation de borodeutérure de sodium permet d’obtenir les dérivés
portant un atome de deutérium en position ꢀ de l’azote portant le nouveau substituant.
Mots clés : acide ꢀ-aminé, esters méthyliques d’acide ꢀ-aminé, borohydrure de sodium, N-monoalkylation réductrice,
composés carbonylés.
[Traduit par la Rédaction] Verardo et al. 788
Introduction
oxy carboxylate (8) or ꢀ-halo acids (9). The problems with
these reactions are the availability of the suitable starting
materials and, in the case of the ꢀ-halo acids, the fact that
racemization and elimination are prominent side reactions.
N-Alkylated amino acids were also prepared by acid hydro-
lysis of 2-amino nitriles, according to the Strecker synthesis
using primary amines (10) or by the oxidation of allylamines
obtained from the enantioselective reaction of an allylic sub-
strate with benzylamine in the presence of a palladium cata-
lyst bearing chiral ferrocenylphosphine ligands (11).
Examples of catalytic hydrogenation of preformed imines
obtained from the condensation reaction of amino acids and
carbonyl compounds (9, 12) or benzylamine and ꢀ-keto ac-
ids (13) were also reported.
Reductive N-alkylation of amino acids and amino esters is
a method widely used to synthesize the corresponding N-
benzyl derivatives: NaBH(OAc)3 (14), NaHTe (15),
NaBH3CN (16), and NaBH4 (12c, 17) were the reducing
agents employed. Sodium triacetoxyborohydride has also
been used to reduce imines derived from the reaction be-
tween ꢀ-keto esters and benzylamine (18). The last two re-
actants showed a larger range of applicability: in fact, they
were used with carbonyl compounds (other than benzalde-
hyde), but sodium cyanoborohydride had to be used under
inert atmosphere. Moreover, long reaction times (16–20 h)
with amino acids (19) and large excess of the carbonyl com-
pounds and the reducing agent with amides of amino acids
(20) were needed. Sodium borohydride, on the other hand,
has been used in water only on amino acids (12e) but, even
when the reaction was carried out in the presence of large
excess of reactants, yields were not satisfactory.
The use of peptides as drugs is often hampered by their
poor bioavailability because of their enzymatic degradation
by proteases (1), poor adsorption after oral ingestion, and
rapid excretion through liver and kidneys. The introduction
of modified amino acids or the use of peptidomimetics (2)
can be a solution for these drawbacks. Amino acids may be
modified by N-alkylation: peptoids (3), an important class of
peptidomimetics, express N-alkylated glycine residues.
The synthesis of N-alkylated amino acids and amino
esters has been extensively studied and a number of proce-
dures are available. One interesting approach is the alkyl-
ation of sulfonamides (Mitsunobu reaction) both in solution
using, e.g., 2,4-dinitrobenzenesulfonyl (4) or 2,2,5,7,8-penta-
methylchroman-6-sulfonyl (5) as protecting groups, and in
the solid phase with 2-nitrobenzenesulfonyl (6) as the pro-
tecting group. These methods require long reaction times,
three or more reaction steps, and occasional racemization is
observed. The alkylation of N-unprotected amino acids and
esters was also reported (7), but is limited to N-benzylation.
Alternatively, the desired amino function can be directly in-
troduced by a SN2 reaction with appropriate ꢀ-substituted
carboxylic acid derivatives e.g., ꢀ-trifluoromethanesulfonyl-
Received 8 January 2002. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 18 June 2002.
G. Verardo,1 P. Geatti, E. Pol, and A.G. Giumanini.
Department of Chemical Sciences and Technologies,
University of Udine, I-33100 Udine, Italy.
1Corresponding author (e-mail: gverardo@tin.dstc.uniud.it).
Can. J. Chem. 80: 779–788 (2002)
DOI: 10.1139/V02-083
© 2002 NRC Canada

780
Can. J. Chem. Vol. 80, 2002
Scheme 1.
O
O
O
R2
R3
1
1
MeOH or THF-MeOH/
(AcOH)/10 min, r.t.
R
OR
NaBH , 1-2h,
4
R
OR
R
OR1
O
0 °C
+
N
R2
N
R2
70-95%
H
NH2
R3
R3
1
, R1 = H
, R1 = Me
3
2
4
5
, R1 = H
, R1 = Me
6
, R1 = H
7
, R1 = Me
1
R
H
2
R
3
R2
R3
a
b
c
d
e
f
h
i
j
a
b
c
d
e
f
H
a
b
c
d
e
H
H
H
H
Et
Pr
tert-Bu
Ph
Me2CH
Ph
4-HO-C6H4
indolyl
CH2CO2H
imidazolyl
CH2CONH2
CH2SMe
Me2CH
Ph
4-HO-C6H4
indolyl
CH2CO2Me
Me
Me
R
R2
R3
7
R
R2
R3
6
ab
bb
cb
cc
cd
ce
dd
eb
ec
ed
fb
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
Pr
Pr
Pr
tert-Bu
Ph
Me
Ph
Pr
tert-Bu
Ph
Pr
Ph
Et
Pr
Ph
Pr
Pr
ad
bb
bd
ca
cb
cc
cd
ce
db
dd
ea
ec
ed
ee
fa
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
Me
H
H
H
Me
Ph
Pr
Ph
Et
Pr
tert-Bu
Ph
Me
Pr
Ph
Et
tert-Bu
Ph
Me
Et
tert-Bu
Ph
Me2CH
Ph
Ph
Ph
Ph
4-HO-C6H4
Indolyl
Indolyl
Indolyl
CH2CO2H
CH2CO2H
imidazolyl
imidazolyl
imidazolyl
CH2CONH2
CH2Sme
Me2CH
Me2CH
Ph
Ph
Ph
Ph
Ph
4-HO-C6H4
4-HO-C6H4
indolyl
indolyl
indolyl
indolyl
CH2CO2Me
CH2CO2Me
CH2CO2Me
CH2CO2Me
fd
ha
hb
hd
ib
fc
fd
fe
jb
Me
agent in the reductive alkylation of both 1 and 2, the
physical form (pellets or granular) of the reductant and mi-
nor but essential procedural variations were found to be very
important.
Results and discussion
On the basis of the knowledge we have acquired on the
applications of sodium borohydride as reducing agent in the
reductive N-alkylation of amines (21), we have now ex-
tended its use to ꢀ-amino acids (1) and ꢀ-amino methyl es-
ters (2) in combination with several carbonyl compounds (3)
(Scheme 1).
The carbonyl compound (3) was added at room tempera-
ture to a methanolic solution of 1 or a hydrochloride of 2 af-
ter its neutralization in situ with a slight excess of finely
powdered NaOH. After 10 min, a time sufficient to form
imine 4 or 5, the reaction mixture was cooled to 0°C and
solid NaBH4 was added. GC–MS analysis of the reaction
mixture before the addition of NaBH4 indicated that higher
temperatures and (or) longer contact times between 2 and 3
did not improve the formation of 5; moreover, the conver-
sion into the corresponding N-alkylated compounds 7 was
lower. Since our goal was the use of NaBH4 as the reducing
The reaction between the amino acids (1) and all the car-
bonyl substrates (3) was carried out in MeOH using NaBH4
pellets (Method A). Unlike water (12e), this solvent, was
able to solubilize all the species initially present and the spe-
cies eventually forming in the process, and it also made the
NaBH4 reactive enough to reduce the imine 4. The meth-
anolic mixture obtained was acidified with 37% aqueous
HCl up to the isoelectric point of the starting amino acid (1)
and, after removal of the solvent and addition of acetone, a
solid was obtained composed of a mixture of the N-alkyl
amino acids (6) and NaCl as determined by 1H and 13C
NMR and by qualitative analysis. To eliminate NaCl, the
solid was washed with water, but unfortunately, all the N-
alkyl derivatives of glutamic acid (1f) and, particularly,
histidine (1h) were found to be widely soluble in water. For
© 2002 NRC Canada

Verardo et al.
781
Table 1. Yields and some properties of N-alkyl amino acids (6).
Isolated
mp
Lit. mp
(°C)
[ꢀ]D
(1 M HCl)
Product
yield (%)a (°C)
Anal. calcd. (found)
6ab C7H15NO2
6bb C10H21NO2
6cb C13H19NO2
6cb-d C13H18DNO2
6cc C14H21NO2
6cd C16H17NO2
6ce C12H17NO2
6dd C16H17NO3
6eb C15H20N2O2
6ec C16H22N2O2
6ed C18H18N2O2
6fb C9H17NO4
6fd C12H15NO4
6ha C9H15N3O2
6hb C10H17N3O2
6hd C13H15N3O2
6ib C9H18N2O3
6jb C9H19NO2S
82
86
85
80
83
91
63
92
82
90
94
73 (91)
78 (89)
73 (92)
75 (90)
84 (90)
89
>260
>260
>260
>260
205
286 (12a)
267 (12a)
C 57.90 (57.88) H 10.41 (10.40) N 9.65 (9.67) +19.0 (c 1.0)
C 64.13 (64.16) H 11.30 (11.28) N 7.48 (7.47) +33.0 (c 1.0)
C 70.56 (70.58) H 8.65 (8.68) N 6.33 (6.36)
C 70.23 (70.20) H 8.16 (8.18) N 6.30 (6.28)
C 71.46 (71.48) H 8.99 (8.98) N 5.95 (5.96)
+44.0 (c 1.0)
+43.8 (c 1.0)
+68.7 (c 0.8)
+44.0 (c 1.0)
+58.7 (c 1.0)
+68.7 (c 0.7)
245
243 (19), 225–227 (9) C 75.27 (75.25) H 6.71 (6.74) N 5.49 (5.46)
260 dec. 260–263 (19)
259 dec.
248 dec.
234 dec.
249 dec. 248–250 (9)
185
165
198
166
191
C 69.54 (69.55) H 8.27 (8.25) N 6.76 (6.78)
C 70.83 (70.85) H 6.32 (6.35) N 5.16 (5.18)
C 69.20 (69.23) H 7.74 (7.75) N 10.76 (10.78) +48.0 (c 2.0)
C 70.04 (70.01) H 8.08 (8.05) N 10.21 (10.25) +34.5 (c 2.0)
C 73.45 (73.48) H 6.16 (6.15) N 9.52 (9.55)
C 53.19 (53.18) H 8.43 (8.45) N 6.89 (6.86)
C 60.75 (60.77) H 6.37 (6.35) N 5.90 (5.89)
+48.0 (c 0.9)
+31.3 (c 2.0)
+19.6 (c 1.0)
156–157 (19)
C 54.81 (54.78) H 7.67 (7.65) N 21.30 (21.33) +49.0 (c 1.0)
C 56.85 (56.88) H 8.11 (8.14) N 19.89 (19.91) +48.2 (c 0.9)
C 63.66 (63.68) H 6.16 (6.14) N 17.13 (17.11) +39.0 (c 1.0)
C 53.45 (53.48) H 8.97 (8.94) N 13.85 (13.88) +22.7 (c 1.5)
205
260 dec.
198–199 (12e)
90
C 52.65 (52.68) H 9.33 (9.34) N 6.82 (6.80)
+52.0 (c 1.0)
1
aAll the reactions were carried out according to Method A; yields in parentheses were determined by H NMR using phenylacetic acid as internal
standard.
Table 2. Yields and some properties of N-alkyl amino acid methyl ester hydrochlorides (7).
Isolated
yield (%) Method (°C)
mp
Lit. mp
(°C)
[ꢀ]D
(MeOH)
Product
Anal. calcd. (found)
184
83
7ad C11H16NO2Cl
7bb C11H24ClNO2
7bd C14H22ClNO2
7ca C13H20ClNO2
7cb C14H22ClNO2
7cc C15H24ClNO2
7cd C17H20ClNO2
7cd-d C17H19ClDNO2
7ce C13H20ClNO2
7db C14H22ClNO3
7dd C17H20ClNO3
7ea C15H21ClN2O2
7ec C17H25ClN2O2
7ed C19H21ClN2O2
7ee C15H21ClN2O2
7fa C10H20ClNO4
7fc C12H24ClNO4
7fd C14H20ClNO4
7fe C10H20ClNO4
70
91
89
97
90
72
87
82
87
88
85
95
87
82
93
74
89
83
78
C
B
C
B
B
C
C
C
D
B
C
B
C
C
D
B
C
C
D
C 57.52 (57.48) H 7.02 (7.00) N 6.10 (6.15)
C 55.57 (55.58) H 10.17 (10.09) N 5.89 (5.91) +16.0 (c 1.5)
+27.3 (c 1.0)
169 167–168 (17b) C 61.87 (61.83) H 8.16 (8.13) N 5.15 (5.11)
128
104
143
+25.4 (c 1.0)
+47.5 (c 2.0)
+46.0 (c 2.0)
+61.0 (c 1.0)
+39.0 (c 1.0)
+39.6 (c 1.0)
+60.4 (c 1.2)
+43.8 (c 2.0)
+57.3 (c 0.8)
+22.5 (c 2.0)
+16.5 (c 2.0)
+23.3 (c 1.5)
+40.0 (c 1.5)
+20.0 (c 2.0)
+25.5 (c 1.8)
+19.5 (c 2.0)
+57.8 (c 1.0)
C 60.58 (60.55) H 7.82 (7.83) N 5.43 (5.43)
C 61.87 (61.85) H 8.16 (8.18) N 5.15 (5.13)
C 63.04 (63.05) H 8.46 (8.48) N 4.90 (4.93)
C 66.77 (66.75) H 6.59 (6.58) N 4.58 (4.55)
C 66.55 (66.57) H 6.24 (6.26) N 4.57 (4.55)
C 60.58 (60.57) H 7.82 (7.80) N 5.43 (5.41)
C 58.43 (58.45) H 7.71 (7.70) N 4.87 (4.89)
C 63.45 (63.45) H 6.26 (6.28) N 4.35 (4.33)
C 60.70 (60.72) H 7.13 (7.15) N 9.44 (9.43)
C 62.86 (62.83) H 7.76 (7.75) N 8.62 (8.63)
C 66.18 (66.16) H 6.14 (6.15) N 8.12 (8.10)
C 60.70 (60.71) H 7.13 (7.12) N 9.44 (9.45)
C 47.34 (47.35) H 9.95 (9.98) N 5.52 (5.53)
C 51.15 (51.16) H 8.58 (8.56) N 4.97 (4.99)
C 55.72 (55.75) H 6.68 (6.68) N 4.64 (4.63)
C 47.34 (47.37) H 9.95 (9.94) N 5.52 (5.50)
153 151–152 (7b)
150
154
96
195
109
>260
101
105
121
122
103
116
this reason the yield of N-butyl- (6fb), N-benzyl- (6fd) glu-
tamic acid, N-propyl- (6ha), N-butyl- (6hb), and N-benzyl
histidine (6hd) were also determined by 1H NMR using
phenylacetic acid as internal standard (Table 1). This acid,
as sodium salt in D2O–NaOH, exhibited a singlet at ꢁ = 3.54,
which was far away from all the other signals.
The use of acetone during the work-up of the reaction
provided a solid that, freed from unreacted 3 and (or) the
corresponding alcohol, happened to be less soluble in water
during the elimination of NaCl.
N-Isopropyl phenylalanine (6ce) was obtained only in
63% isolated yield; however, a large excess (3 mol equiv) of
acetone (3e) was used.
When propanal (3a) or butanal (3b) were used in combi-
nation with 2, Method A was followed but granular NaBH4
was added (Method B). These aldehydes reacted very
quickly with 2; therefore excess granular NaBH4 was used to
promote the reduction of 3a or 3b, which in turn caused the
N,N-dialkylation of 2 as shown by the GC–MS analysis of
the reaction mixture.
© 2002 NRC Canada

782
Table 3. Infrared, H and 13C NMR spectra, and EI-MS spectra of N-alkyl amino acids (6).
Can. J. Chem. Vol. 80, 2002
1
1H NMR (D2O–NaOH–DSS)
ꢁ (J in Hz)
13C NMR (D2O–NaOH–DSS)
ꢁ (J in Hz)
Product
IR (KBr) ꢂ (cm–1
)
EI-MS (70eV) m/z (%)
145 (M+, 2), 111 (1), 102
(19), 100 (100), 74 (6), 56
(11), 44 (20)
3200–2000, 1570, 1460,
1383, 1360, 1280, 1210,
1142, 1100, 1090, 1052,
980, 890, 835, 774, 670
0.82 (t, J = 7.1, 3H, CH3), 1.31 (sext,
J = 7.1, 2H, CH3CH2), 1.37 (d, J = 7.1,
3H, *CHCH3) 1.46–1.67 (m, 2H, CH2),
2.81–3.03 (app t, 2H, NCH2), 3.55 (q,
J = 7.1, 1H, *CH)
6ab
15.3, 17.6, 21.7, 30.3, 48.5,
60.3, 177.5
6bb
6cb
3300–2000, 1580, 1165,
1390, 1294, 1273, 1230,
1150, 1130, 1063, 1009,
885, 849, 805, 782, 742,
683
0.82–0.95 (m, 9H, 3×CH3), 1.15–1.65
(m, 7H, 3×CH2 + CH), 2.30–2.52 (m, 2H, 33.4, 40.1, 49.3, 65.0, 185.9
NCH2), 3.05 (dd, J1 = 8.3, J2 = 6.6, 1H,
*CH)
15.8, 22.3, 24.2, 25.2, 27.3,
187 (M+, 2), 172 (1), 143
(12), 142 (100), 130 (11),
88 (30), 86 (8)
3300–2000, 1578, 1460,
1390, 1361, 1305, 1087,
1060, 851, 788, 752,
707, 680, 530
0.82 (t, J = 7.1, 3H, CH3), 1.11–1.48
(m, 4H, 2×CH2), 2.28–2.54 (m, 2H,
NCH2), 2.81 and 2.86 (AB of ABX,
JAB = 13.5, JAX = 7.5, JBX = 6.1, 2H,
*CHCH2), 3.24 (dd, J1 = 7.5, J2 = 6.1,
15.9, 22.3, 33.3, 41.5, 49.3,
67.7, 129.1, 131.0, 131.8,
140.7, 183.9
222 ([M+1]+, 1], 221 (M+,
1), 176 (24), 132 (17), 130
(100), 120 (30), 91 (33),
88 (30), 84 27), 74 (11), 57
(27)
1H, *CH), 7.17–7.35 (m, 5H, Harom
)
6cb-d
3300–2000, 1580, 1456,
1398, 1381, 1301, 1085,
1060, 844, 784, 747,
701, 676, 533
0.80 (t, J = 7.1, 3H, CH3), 1.13–1.44
(m, 4H, 2×CH2), 2.27–2.53 (m, 1H,
NCDH), 2.79 and 2.84 (AB of ABX,
JAB = 13.5, JAX = 7.5, JBX = 6.1, 2H,
*CHCH2), 3.22 (dd, J1 = 7.5, J2 = 6.1,
15.8, 22.2, 33.2, 41.4, 48.8
(t, J = 21.2), 67.5, 129.0,
131.0, 131.7, 140.5, 183.9
223 ([M+1]+, 1), 222 (M+,
1), 177 (22), 133 (11),
131 (100), 120 (32), 91
(18), 89 (12), 74 (9), 58
(15)
1H, *CH), 7.17–7.35 (m, 5H, Harom
)
6cc
3280–2000, 1611, 1495,
1482, 1382, 1374, 1342,
1284, 1266, 845, 790,
749, 702, 536, 475
0.73 (s, 9H, 3×CH3), 2.08 and 2.11 (AB, 29.8, 32.3, 41.3, 62.1, 68.8,
236 ([M+1]+, 1), 220 (9),
190 (21), 178 (17), 144
(100), 132 (45), 120 (28),
91 (19), 74 (16), 71 (24)
JAB = 11.0, 2H, NCH2), 2.67 and 2.79
(AB of ABX, JAB = 13.2, JAX = 8.8,
JBX = 5.3, 2H, *CHCH2), 3.07 (dd,
J1 = 8.8, J2 = 5.3, 1H, *CH), 7.04–7.28
129.2, 131.1, 131.9, 140.7,
184.1
(m, 5H, Harom
)
6cd
6ce
6dd
3220–2030, 1618, 1459,
1451, 1437, 1394, 1334,
1205, 1084, 868, 746,
697, 586, 532
2.52 and 2.60 (AB of ABX, JAB = 13.4,
JAX = 7.7, JBX = 6.2, 2H, *CHCH2),
3.00 (dd, J1 = 7.7, J2 = 6.2, 1H, *CH),
3.23 and 3.42 (AB, JAB = 12.6, 2H,
41.5, 53.5, 66.9, 129.1,
129.9, 131.0, 131.1, 131.2,
131.7, 140.5, 141.3, 183.7
256 ([M+1]+, 1), 210 (5),
164 (34), 120 (4), 91
(100), 65 (7)
NCH2), 6.84–7.13 (m, 10H, Harom
)
3230–2000, 1574, 1392,
1374, 1339, 846, 745,
700, 539
0.56 (app t, J = 7.3, 6H, 2×CH3), 2.05–
2.52 (m, 3H, NCH + *CHCH2), 2.91
22.8, 25.0, 41.6, 48.5, 65.0,
128.9, 130.9, 131.6, 140.6,
208 ([M+1]+, 1), 207 (M+,
1), 192 (2), 162 (19), 146
(7), 120 (40), 116 (100),
103 (8), 91 (20), 74 (39),
65 (5), 43 (10)
(app t, J = 7.3, 1H, *CH), 6.50–6.90 (m, 183.9
5H, Harom
)
3330–2020, 1591, 1518,
1464, 1439, 1401, 1334,
1259, 1213, 1178, 1109,
1087, 1061, 968, 864,
832, 753, 702, 642, 571,
540
2.47 (app d, J = 6.2, 2H, *CHCH2),
2.98 (app t, J = 6.6, 1H, *CH), 3.22 and 126.2, 131.2, 131.3, 133.2,
3.38 (AB, JAB = 13.2, 2H, NCH2), 6.32
(app d, J = 8.3, 2H, Harom), 6.67 (app d,
J = 8.3, 2H, Harom), 6.91–7.23 (m, 5H,
40.6, 53.5, 67.2, 121.2,
272 ([M+1]+, 1), 271 (M+,
1), 226 (5), 164 (49), 107
(31), 91 (100), 77 (5), 65
(4)
141.5, 166.9, 184.2
Harom
)
6eb
3410, 3200–2000, 1640,
1450, 1385, 1356, 1300,
1267, 1230, 1098, 1070,
1053, 1010, 995, 861,
813, 760, 755, 653
0.56 (t, J = 7.3, 3H, CH3), 0.84–1.25
(m, 4H, 2×CH2), 2.05–2.36 (m, 2H,
NCH2), 2.83 (app d, J = 6.3, 2H,
*CHCH2), 3.17 (dd, J1 = 13.2, J2 = 6.8,
1H, *CH), 6.82–7.08 (m, 3H, Harom),
7.15–7.28 (m, 1H, Harom), 7.40–7.54 (m,
15.9, 22.4, 31.2, 33.4, 49.4,
66.8, 113.2, 114.3, 121.3,
121.5, 124.2, 126.5, 129.8,
138.6, 184.6
260 (M+, 1), 215 (1), 214
(1), 171 (1), 159 (2), 158
(1), 157 (1), 144 (2), 143
(1), 142 (1), 130 (100),
115 (2), 77 (2)
1H, Harom
)
© 2002 NRC Canada

Verardo et al.
783
Table 3 (Continued).
1H NMR (D2O–NaOH–DSS)
ꢁ (J in Hz)
13C NMR (D2O–NaOH–DSS)
ꢁ (J in Hz)
Product
IR (KBr) ꢂ (cm–1
)
EI-MS (70eV) m/z (%)
6ec
0.79 (s, 9H, 3×CH3), 2.20 (app s, 2H,
NCH2), 2.99 and 3.05 (AB of ABX,
JAB = 14.3, JAX = 8.1, JBX = 5.7, 2H,
*CHCH2), 3.29 (dd, J1 = 8.1, J2 = 5.7,
1H, *CH), 7.04–7.23 (m, 3H, Harom),
7.39–7.47 (m, 1H, Harom), 7.63–7.72 (m,
29.8, 30.9, 32.8, 62.3, 67.9,
113.3, 114.3, 121.4, 121.6,
124.3, 126.6, 129.8, 138.7,
184.7
274 (M+, 1), 259 (1), 229
(1), 188 (1), 159 (2), 144
(8), 130 (100), 115 (2)
3410, 3290–2000, 1613,
1492, 1444, 1459, 1360,
1341, 1287, 1024, 1007,
854, 739, 582, 533, 514
1H, Harom
)
6ed
6fb
6fd
6ha
3415, 3150–2000, 1602,
1489, 1457, 1449, 1392,
1353, 1348, 1316, 1213,
1082, 893, 802, 744,
2.72 and 2.84 (AB of ABX, JAB = 14.5,
JAX = 7.7, JBX = 6.1, 2H, *CHCH2),
3.06–3.37 (m, 3H, *CH + NCH2), 6.53–
6.90 (m, 3H, Harom), 6.95–7.08 (m, 1H,
31.3, 53.4, 65.4, 113.2,
294 (M+, 2), 248 (1), 164
(1), 130 (100), 91 (19), 77
(3), 65 (2)
114.2, 121.2, 121.5, 124.1,
126.4, 129.5, 129.6, 130.7,
130.9, 138.6, 141.3, 184.1
701, 608, 584, 544, 510
Harom), 7.18–7.28 (m, 1H, Harom)
3300–2100, 1727, 1690,
1580, 1457, 1390, 1125,
1230, 1152, 1080, 1040,
861, 815, 800, 680, 625
0.69 (t, J = 7.2, 3H, CH3), 0.96–1.37
(m, 4H, 2×CH2), 1.40–1.77 (m, 2H,
*CHCH2), 1.82–2.10 (m, 2H, COCH2),
2.13–2.41 (m, 2H, NCH2), 2.81 (dd, J1 =
8.1, J2 = 5.6, 1H, *CH)
15.8, 22.4, 32.3, 33.4, 36.8,
49.5, 66.2, 185.0, 185.2
203 (M+, 1), 185 (9), 158
(37), 142 (12), 140 (100),
114 (19), 98 (23), 84 (92)
3300–2070, 1706, 1632,
1468, 1456, 1370, 1348,
1274, 1089, 1069, 1020,
989, 819, 760, 699, 555,
509
1.71–2.07 (m, 2H, *CHCH2), 2.25 (app
t, J = 8.6, 2H, COCH2), 3.13 (dd,
J1 = 7.7, J2 = 5.7, 1H, *CH), 3.61 and
3.77 (AB, JAB = 12.5, 2H, NCH2), 7.33–
32.4, 36.9, 53.9, 65.6, 130.2,
131.4, 141.6, 184.6, 185.4
238 ([M+1]+, 1), 219 (23),
192 (24), 174 (56), 164
(2), 146 (35), 130 (8), 118
(8), 106 (12), 91 (100), 65
(12)
7.54 (m, 5H, Harom
)
3670–2000, 1578, 1457,
1398, 1138, 1111, 984,
940, 841, 811, 752, 667,
628, 553
0.64 (t, J = 7.5, 3H, CH3), 1.08–1.39
(m, 2H, CH2), 2.11–2.36 (m, 2H,
NCH2), 2.63 (app d, J = 6.6, 2H,
*CHCH2), 3.11 (app t, J = 6.6, 1H,
*CH), 6.65 (s, 1H, Harom), 7.40 (s, 1H,
13.8, 24.6, 33.0, 51.6, 66.4,
121.5, 136.2, 139.8, 184.4
198 ([M+1]+, 2), 197 (M+,
1), 152 (37), 140 (25),
124 (10), 122 (14), 116
(17), 110 (21), 109 (9), 95
(27), 82 (100), 74 (5), 54
(10), 43 (10)
Harom
)
6hb
6hd
3670–2000, 1580, 1448,
1387, 1334, 1260, 1220,
1180, 1110, 1050, 999,
929, 885, 850, 830, 792,
743, 720, 665
0.64 (t, J = 7.3, 3H, CH3), 0.90–1.44
(m, 4H, 2×CH2), 2.10–2.38 (m, 2H,
NCH2), 2.62 (app d, J = 6.8, 2H,
*CHCH2), 3.08 (app t, J = 6.8, 1H,
*CH), 6.60–6.70 (m, 1H, Harom), 7.38–
15.8, 22.3, 32.7, 33.3, 49.4,
66.3, 120.5, 135.6, 138.2,
184.1
211 (M+, 1), 166 (13),
140 (6), 130 (3), 124 (4),
122 (10), 110 (7), 95 (15),
82 (100), 81 (20), 74 (2),
57 (3)
7.44 (m, 1H, Harom
)
3630–2000, 1621, 1500,
1430, 1396, 1330, 1291,
1215, 1191, 1104, 1089,
961, 940, 869, 840, 810,
750, 702, 657, 631, 533
2.44 and 2.53 (AB of ABX, JAB = 14.7,
JAX = 6.8, JBX = 6.8, 2H, *CHCH2),
2.97 (app t, J = 6.8, 1H, *CH), 3.15 and 141.3, 141.4, 184.0
3.32 (AB, JAB = 12.7, 2H, NCH2), 6.41
33.2, 53.5, 65.5, 122.4,
129.8, 131.0, 131.1, 136.5,
246 ([M+1]+, 1), 200 (13),
140 (33), 122 (22), 110
(37), 106 (24), 91 (100),
82 (83), 65 (8)
(app d, J = 1.0, 1H, Harom), 6.81–7.04
(m, 5H, Harom), 7.15 (app d, J = 1.0,
1H, Harom
)
6ib
6jb
3403, 3300–2000, 1641,
1625, 1574, 1458, 1380,
1314, 1037, 858, 810,
775, 684, 639, 587, 559
0.53 (t, J = 7.5, 3H, CH3), 0.83–1.24
(m, 4H, 2×CH2), 1.28–1.68 (m, 2H,
*CHCH2), 1.73–1.90 (m, 2H, COCH2),
1.95–2.23 (m, 2H, NCH2), 2.65 (dd, J1 =
8.1, J2 = 5.5, 1H, *CH)
15.8, 22.3, 31.3, 33.3, 34.3,
49.3, 65.6, 181.3, 184.4
203 ([M+1]+, 1), 185 (6),
184 (6), 169 (10), 157 (24),
142 (26), 140 (100), 130
(13), 128 (8), 114 (16), 98
(16), 84 (55), 72 (8), 70
(8), 57 (11)
3280–2000, 1575, 1460,
1390, 1315, 1232, 1187,
1151, 1065, 980, 955,
858, 796, 760, 740, 700,
675
0.86 (t, J = 6.8, 3H, CH3), 1.14–1.57
(m, 4H, 2×CH2), 1.67–1.94 (m, 2H,
*CHCH2), 2.09 (s, 3H, SCH3), 2.32–
2.60 (m, 4H, SCH2 + NCH2), 3.09 (app
t, J = 7.1, 1H, *CH)
16.0, 16.9, 22.5, 32.4, 33.5,
35.0, 49.6, 65.5, 184.6
205 (M+, 3), 187 (40),
172 (28), 160 (100), 157
(21), 144 (18), 130 (26),
112 (78), 88 (80), 74 (16),
61 (31)
© 2002 NRC Canada

784
Can. J. Chem. Vol. 80, 2002
1
Table 4. Infrared, H and 13C NMR spectra, and EI-MS spectra of N-alkyl amino acid methyl ester hydrochlorides (7).
1H NMR (DMSO-d6/TMS)
ꢁ (J in Hz)
13C NMR (DMSO-d6/TMS)
ꢁ (J in Hz)
Product IR (KBr) ꢂ (cm–1
)
MS (70 eV) m/z (%)
194 ([M+1]+, 2), 192 (2),
178 (1), 134 (100), 106
(36), 92 (30), 91 (95), 65
(21)
1.58 (d, J = 7.2, 3H, CH3), 3.74 (s, 3H,
OCH3), 4.06 (q, J = 7.2, 1H, *CH), 4.16
and 4.21 (AB, JAB = 13.1, 2H, CH2),
7.35–7.50 (m, 3H, Harom), 7.56–7.70 (m,
2H, Harom), 10.20 (br s, 2H, NH)
7ad
3200–2200, 1745, 1548,
1450, 1250, 1208, 1137,
1093, 990, 758, 695, 664
14.4, 48.4, 52.7, 54.1,
128.4, 128.8, 130.2, 131.7,
169.5
7bb
3200–2200, 1749, 1559,
1470, 1392, 1372, 1245,
1211, 1058, 959, 846,
750
0.80–1.15 (m, 9H, 3×CH3), 1.39 (sext, J = 13.3, 19.9, 21.1, 22.8, 24.7, 202 ([M+1]+, 2), 201 (M+,
7.3, 2H, CH3CH2), 1.77 (sept, J = 6.4, 1H, 27.6, 37.9, 46.1, 52.8, 58.2, 1), 158 (3), 144 (9), 142
CH), 1.87–2.12 (m, 4H, 2×CH2), 2.88–
3.17 (m, 2H, NCH2), 3.78–3.97 (m, 4H,
*CH + OCH3), 9.82 (br s, 1H, NH), 10.16
(br s, 1H, NH)
168.6
(100), 130 (4), 102 (13),
88 (7), 86 (8), 84 (7), 57
(9)
7bd
7ca
3200–2100, 1734, 1557,
1463, 1416, 1382, 1360,
1284, 1219, 1182, 1066,
1026, 1001, 944, 742,
702
0.87 (d, J = 6.5, 6H, 2×CH3), 1.59–2.04
(m, 3H, CH + CH2), 3.72 (s, 3H, OCH3),
3.84 (dd, J1 = 9.2, J2 = 4.8, 1H, *CH),
4.12 and 4.22 (AB, JAB = 13.0, 2H,
NCH2), 7.35–7.46 (m, 3H, Harom), 7.60–
7.71 (m, 2H, Harom), 10.42 (br s, 2H, NH)
21.0, 22.8, 24.1, 37.6, 48.7, 236 ([M+1]+, 2), 235 (M+,
52.5, 56.9, 128.3, 128.8,
130.4, 131.4, 169.1
1), 234 (2), 220 (3), 192
(1), 190 (1), 178 (10), 176
(100), 106 (19), 91 (81),
65 (11)
3300–2150, 1747, 1599,
1500, 1458, 1442, 1428,
1362, 1348, 1329, 1285,
1251, 1216, 1172, 1043,
951, 750, 704, 607, 524,
501
0.90 (t, J = 7.3, 3H, CH3), 1.62–1.89 (m,
2H, CH3CH2), 2.73–3.02 (m, 2H, NCH2),
3.13 and 3.52 (AB of ABX, JAB = 13.5,
JAX = 9.6, JBX = 4.5, 2H, *CHCH2), 3.58
10.8, 18.8, 34.8, 47.5, 52.3, 222 ([M+1]+, 2), 221 (M+,
60.3, 127.1, 128.4, 129.1,
134.8, 168.4
1), 190 (3), 162 (28), 160
(8), 132 (7), 130 (100),
128 (17), 120 (15), 103
(11), 91 (14), 88 (12), 43
(8)
(s, 3H, OCH3), 4.18 (dd, J1 = 9.6, J2
=
4.5, 1H, *CH), 7.18–7.36 (m, 5H, Harom),
9.68 (br s, 1H, NH), 10.47 (br s, 1H, NH)
7cb
3200–2200, 1750, 1568,
1445, 1350, 1338, 1245,
1215, 1180, 1049, 848,
753, 708, 670
0.89 (t, J = 7.3, 3H, CH3), 1.25–1.46 (m,
2H, CH3CH2), 1.65–1.85 (m, 2H,
CH2CH2), 2.80–3.12 (m, 2H, NCH2), 3.16
13.2, 19.3, 25.0, 27.4, 35.0, 236 ([M+1]+, 4), 235 (M+,
45.8, 52.3, 60.5, 127.1,
1), 192 (6), 176 (91), 144
(100), 132 (18), 120 (33),
103 (18), 102 (57), 91
(29), 88 (30), 57 (21), 41
(20)
128.4, 129.2, 134.8, 168.6
and 3.52 (AB of ABX, JAB = 13.7, JAX
=
9.6, JBX = 4.6, 2H, *CHCH2), 3.60 (s, 3H,
OCH3), 4.19 (dd, J1 = 9.6, J2 = 4.6, 1H,
*CH), 7.20–7.30 (m, 5H, Harom), 10.20
(br s, 2H, NH)
7cc
3290–2200, 1750, 1533,
1472, 1455, 1441, 1377,
1311, 1275, 1235, 1187,
1172, 1080, 1040, 1009,
835, 774, 753, 710, 519
1.05 (s, 9H, 3×CH3), 2.68 and 2.96 (AB,
JAB = 12.2, 2H, NCH2), 3.08 and 3.68
(AB of ABX, JAB = 13.2, JAX = 10.9,
JBX = 4.2, 2H, *CHCH2), 3.55 (s, 3H,
OCH3), 4.09 (dd, J1 = 10.9, J2 = 4.2, 1H,
*CH), 7.18–7.38 (m, 5H, Harom), 10.32
(br s, 2H, NH)
27.1, 30.3, 34.7, 52.1, 56.6, 250 ([M+1]+, 1), 248 (1),
61.4, 126.9, 128.2, 128.9,
135.4, 168.4
234 (19), 192 (30), 190
(50), 174 (10), 164 (19),
158 (100), 132 (81), 120
(51), 103 (11), 91 (22), 88
(52), 71 (25), 43 (30)
7cd
3200–2080, 1753, 1541,
1502, 1496, 1457, 1442,
1266, 1255, 1213, 1180,
1086, 1064, 1041, 1026,
756, 702, 492
3.12 and 3.57 (AB of ABX, JAB = 13.0,
JAX = 10.2, JBX = 4.1, 2H, *CHCH2),
3.53 (s, 3H, OCH3), 4.15 (dd, J1 = 10.2,
J2 = 4.1, 1H, *CH), 4.23 (AB, JAB = 13.0,
2H, NCH2), 7.15–7.36 (m, 5H, Harom),
7.37–7.52 (m, 3H, Harom), 7.55–7.73 (m,
2H, Harom), 10.33 (br s, 2H, NH)
35.1, 49.2, 52.3, 60.0,
127.1, 128.4, 128.9, 129.1,
130.4, 131.4, 134.7, 168.4
270 ([M+1]+, 1), 268 (1),
210 (55), 178 (100), 118
(9), 117 (8), 91 (81), 77
(11), 65 (15)
7cd-d
3220, 2070, 1756, 1566,
1498, 1472, 1453, 1429,
1380, 1262, 1209, 1175,
1079, 1053, 1029, 985,
754, 656, 521, 493
3.11 and 3.59 (AB of ABX, JAB = 13.3,
JAX = 10.2, JBX = 4.1, 2H, *CHCH2),
3.52 (s, 3H, OCH3), 4.13 (dd, J1 = 10.2,
J2 = 4.1, 1H, *CH), 4.24 (s, 1H, NCDH),
7.18–7.36 (m, 5H, Harom), 7.38–7.48 (m,
3H, Harom), 7.58–7.70 (m, 2H, Harom),
10.01 (br s, H, NH), 10.08 (br s, H, NH)
35.1, 48.8 (t, J = 22.3),
52.4, 60.0, 127.2, 128.5,
129.0, 129.2, 130.5, 131.4,
134.9, 168.5
271 ([M+2]+, 1), 270 (M+,
1), 211 (39), 179 (86), 178
(50), 119 (3), 92 (100), 91
(76), 77 (3), 65 (8)
© 2002 NRC Canada

Verardo et al.
785
Table 4 (continued).
1H NMR (DMSO-d6/TMS)
ꢁ (J in Hz)
13C NMR (DMSO-d6/TMS)
ꢁ (J in Hz)
Product IR (KBr) ꢂ (cm–1
)
MS (70 eV) m/z (%)
7ce
3220–2150, 1748, 1568,
1498, 1459, 1389, 1322,
1294, 1233, 1180, 1152,
1135, 1063, 961, 851,
773, 751, 705, 516
1.34 (d, J = 6.7, 6H, 2×CH3), 3.15 and
222 ([M+1]+, 1), 220 (1),
206 (3), 162 (69), 146
(18), 130 (100), 120 (49),
103 (10), 91 (14), 88 (45),
43 (9)
18.0, 19.0, 35.3, 49.1, 52.3,
58.0, 127.0, 128.3, 129.0,
134.7, 168.3
3.59 (AB of ABX, JAB = 13.7, JAX
=
10.2, JBX = 4.5, 2H, *CHCH2), 3.35 (sept,
J = 6.7, 1H, NCH), 3.58 (s, 3H, OCH3),
4.17 (dd, J1 = 10.2, J2 = 4.5, 1H, *CH),
7.20–7.46 (m, 5H, Harom), 9.70 (br s, 1H,
NH), 10.53 (br s, 1H, NH)
7db
3280, 3200–2300, 1737,
1617, 1594, 1521, 1445,
1352, 1326, 1271, 1246,
1212, 1182, 1108, 1062,
960, 854, 827, 780, 656,
563, 526
0.83 (t, J = 6.9, 3H, CH3), 1.05–1.45 (m,
4H, 2×CH2), 1.90 (br s, 1H, NH), 2.25–
2.55 (m, 2H, NCH2), 2.68 and 2.74 (AB
13.6, 19.6, 31.6, 38.7, 46.6, 252 ([M+1]+, 2), 208 (3),
50.8, 62.8, 114.8, 127.6,
129.7, 155.7, 174.5a
192 (56), 144 (100), 107
(28), 102 (51), 91 (10), 88
(21), 57 (16), 41 (11)
of ABX, JAB = 13.4, JAX = 7.5, JBX
=
5.9, 2H, *CHCH2), 3.21 (dd, J1 = 7.5, J2
= 5.9, 1H, *CH), 3.54 (s, 3H, OCH3),
6.49–6.59 (m, 2H, Harom), 6.92–7.03 (m,
2H, Harom), 9.02 (br s, 1H, OH)a
7dd
3280, 3200–2400, 1734,
1614, 1596, 1521, 1450,
1437, 1370, 1324, 1309,
1284, 1260, 1230, 1214,
1184, 1109, 1033, 980,
843, 830, 754, 702, 653
3.02 and 3.40 (AB of ABX, JAB = 13.8, 34.4, 49.2, 52.5, 60.3,
286 ([M+1]+, 2), 285 (M+,
1), 226 (12), 178 (100),
118 (5), 107 (10), 91 (83),
77 (5), 65 (7)
JAX = 9.7, JBX = 4.6, 2H, *CHCH2), 3.40
(br s, 1H, NH), 3.55 (s, 3H, OCH3), 4.05
(dd, J1 = 9.7, J2 = 4.6, 1H, *CH), 4.14
and 4.24 (AB, JAB = 13.1, 2H, NCH2),
6.70–6.80 (m, 2H, Harom), 6.95–7.07 (m,
2H, Harom), 7.36–7.46 (m, 3H, Harom),
7.54–7.65 (m, 2H, Harom), 9.02 (br s, 1H,
OH)a
115.4, 124.4, 128.6, 129.1,
130.2, 130.5, 131.4, 156.7,
168.6a
7ea
3415, 3300–2300, 1745,
1619, 1566, 1461, 1438,
1360, 1341, 1261, 1224,
1100, 1071, 748
0.89 (t, J = 7.6, 3H, CH3), 1.62–1.86 (m,
2H, CH2), 2.75–3.05 (m, 1H, NCH2),
3.29–3.43 (m, 1H, *CHCHH), 3.47–3.61
(m, 4H, OCH3 + *CHCHH), 4.14 (dd,
J1 = 9.2, J2 = 4.3, 1H, *CH), 6.96–7.13
(m, 2H, Harom), 7.26 (d, J = 2.2, 1H,
Harom), 7.33–7.42 (m, 1H, Harom), 7.53–
7.62 (m, 1H, Harom), 9.49 (br s, 1H, NH),
10.42 (br s, 1H, NH), 11.16 (s, 1H,
10.9, 18.8, 25.2, 47.5, 52.4, 260 (M+, 2), 201 (9), 144
59.8, 106.4, 111.4, 118.0,
118.4, 120.9, 124.5, 126.7,
136.1, 168.8
(8), 130 (100), 115 (8),
102 (13), 88 (17), 77 (15),
70 (18), 43 (32), 41 (13)
NHarom
)
7ec
3380, 3300–2400, 1747,
1476, 1457, 1433, 1368,
1355, 1284, 1202, 1178,
1124, 1098, 1068, 1024,
975, 828, 802, 780, 741,
624
0.84 (s, 9H, 3×CH3), 2.15 and 2.33 (AB, 27.3, 28.7, 31.2, 51.0, 55.9, 288 (M+, 5), 273 (3), 229
JAB = 11.1, 2H, NCH2), 3.05 (app d, J =
63.1, 119.8, 111.3, 118.1,
(25), 202 (8), 160 (11),
158 (100), 144 (56), 143
(11), 132 (25), 131 (89),
130 (99), 102 (11), 88
(62), 71 (25), 43 (29)
6.4, 2H, *CHCH2), 3.47 (app t, J = 6.4, 118.2, 120.7, 123.3, 122.7,
1H, *CH), 3.54 (s, 3H, OCH3), 6.33 (s,
1H, NH), 6.48 (s, 1H, NH), 6.92–7.09 (m,
2H, Harom), 7.11 (d, J = 2.2, 1H, Harom),
7.36 (app d, J = 7.6, 1H, Harom), 7.51
(app d, J = 7.3, 1H, Harom), 10.87 (s, 1H,
127.2, 136.0, 174.7
NHarom
)
7ed
3420, 3300–2300, 1746,
1622, 1566, 1457, 1434,
1344, 1259, 1212, 1184,
1098, 1075, 746, 701
3.36 and 3.64 (AB of ABX, JAB
14.5, JAX = 9.2, JBX = 4.3, 2H, *CHCH2), 106.5, 111.5, 118.0, 118.4,
=
25.4, 49.1, 52.4, 59.3,
308 (M+, 5), 249 (12), 206
(5), 178 (66), 131 (89),
130 (100), 103 (13), 91
(99), 77 (11), 65 (8)
3.50 (s, 3H, OCH3), 4.11 (dd, J1 = 9.1,
J2 = 4.3, 1H, *CH), 4.18 and 4.27 (AB,
JAB = 13.0, 2H, NCH2), 6.94–7.14 (m,
2H, Harom), 7.25 (d, J = 2.4, 1H, Harom),
7.35–7.46 (m, 4H, Harom), 7.49–7.56 (m,
1H, Harom), 7.59–7.67 (m, 2H, Harom),
10.00 (br s, 1H, NH), 10.71 (br s, 1H,
121.0, 124.5, 126.7, 128.4,
128.9, 130.4, 131.3, 136.1,
168.7
NH), 11.11 (s, 1H, NHarom
)
© 2002 NRC Canada

786
Can. J. Chem. Vol. 80, 2002
Table 4 (concluded).
1H NMR (DMSO-d6/TMS)
ꢁ (J in Hz)
13C NMR (DMSO-d6/TMS)
ꢁ (J in Hz)
Product IR (KBr) ꢂ (cm–1
)
MS (70 eV) m/z (%)
7ee
1.32 (d, J = 6.2, 6H, 2×CH3), 3.25–3.48
(m, 2H, NCH + *CHCHH), 3.48–3.72 (m,
17.9, 19.0, 25.7, 49.2, 52.4, 260 (M+, 8), 201 (17), 159
3394, 3300–2150, 1745,
1622, 1578, 1453, 1397,
1384, 1353, 1330, 1236,
1184, 1105, 1065, 1046,
1013, 950, 835, 746,
625, 564
57.4, 106.5, 111.4, 117.9,
118.5, 121.0, 124.4, 126.7,
136.1, 168.9
(6), 131 (81), 130 (100),
115 (8), 103 (8), 88 (57),
77 (7), 43 (8)
4H, *CHCHH + OCH3), 4.14 (dd, J1
=
9.7, J2 = 4.1, 1H, *CH), 6.93–7.18 (m,
2H, Harom), 7.28 (d, J = 1.6, 1H, Harom),
7.34–7.43 (m, 1H, Harom), 7.52–7.63 (m,
1H, Harom), 9.36 (br s, 1H, NH), 10.43
(br s, 1H, NH), 11.12 (s, 1H, NHarom
)
7fa
7fc
7fd
7fe
3150–2300, 1742, 1565,
1442, 1388, 1301, 1281,
1254, 1217, 1180, 1078,
1003, 981, 784, 722
0.90 (t, J = 7.3, 3H, CH3), 1.71 (sext, J =
7.6, 2H, CH2), 2.02–2.36 (m, 2H,
*CHCH2), 2.42–2.68 (m, 2H, COCH2),
2.71–2.97 (m, 2H, NCH2), 3.61 (s, 3H,
10.8, 18.9, 23.9, 29.0, 47.4, 218 ([M+1]+, 2), 217 (M+,
51.3, 52.6, 57.9, 168.8,
171.9
1), 202 (1), 188 (5), 186
(13), 158 (100), 130 (9),
128 (11), 126 (31), 98
(11), 84 (16)
OCH3), 3.74 (s, 3H, OCH3), 3.98 (dd, J1
7.6, J2 = 5.3, 1H, *CH), 9.60 (br s, 2H,
NH)
=
3250–2300, 1755, 1743,
1544, 1476, 1434, 1382,
1336, 1274, 1259, 1236,
1205, 1092, 1040, 992,
963, 887, 827, 746
1.03 (s, 9H, 3×CH3), 2.10–2.28 (m, 2H,
*CHCH2), 2.49–2.60 (m, 2H, COCH2),
2.67 and 2.86 (AB, JAB = 10.5, 2H,
NCH2), 3.61 (s, 3H, OCH3) 3.74 (s, 3H,
OCH3), 3.98 (dd, J1 = 7.7, J2 = 4.6, 1H,
*CH), 9.13 (br s, 1H, NH), 9.75 (br s, 1H,
NH)
23.5, 27.1, 29.5, 30.3, 51.3, 246 ([M+1]+, 3), 245 (M+,
52.6, 56.8, 59.0, 168.4,
172.0
1), 230 (8), 214 (9), 198
(5), 188 (100), 186 (75),
156 (15), 144 (8), 128
(46), 84 (28), 68 (14)
3200–2200, 1740, 1544,
1470, 1438, 1370, 1315,
1289, 1276, 1260, 1222,
1194, 1100, 1015, 950,
858, 765, 712
2.05–2.40 (m, 2H, CH2), 2.45–2.62 (m,
2H, COCH2), 3.60 (s, 3H, OCH3), 3.72 (s, 57.6, 128.5, 128.9, 130.3,
24.0, 29.0, 49.1, 51.4, 52.8, 266 ([M+1]+, 1), 233 (15),
206 (82), 174 (100), 146
(21), 106 (20), 92 (29), 91
(91), 65 (20)
3H, OCH3), 4.01 (dd, J1 = 7.9, J2 = 4.9,
1H, *CH), 4.14 and 4.21 (AB, JAB = 12.9,
2H, NCH2), 7.36–7.49 (m, 3H, Harom),
7.53–7.66 (m, 2H, Harom), 10.28 (br s, 2H,
NH)
131.4, 168.5, 171.9
3200–2300, 1744, 1561,
1474, 1438, 1388, 1360,
1314, 1230, 1189, 1156,
1139, 1072, 977, 959,
834, 750
1.29 (d, J = 6.4, 3H, CH3), 1.31 (d, J =
6.4, 3H, CH3), 2.02–2.39 (m, 2H,
*CHCH2), 2.42–2.68 (m, 2H, COCH2),
3.32 (sept, J = 6.4, 1H, NCH), 3.62 (s,
3H, OCH3), 3.75 (s, 3H, OCH3), 4.07 (dd,
J1 = 8.2, J2 = 4.9, 1H, *CH), 9.51 (br s,
2H, NH)
18.0, 18.9, 24.1, 28.9, 48.9, 218 ([M+1]+, 2), 217 (M+,
51.3, 51.7, 52.7, 55.3,
168.7, 171.9
1), 202 (7), 174 (21), 158
(100), 144 (14), 142 (14),
88 (10), 84 (68), 56 (16)
aSpectrum obtained after neutralization.
When sterically hindered 2,2,2-trimethylacetaldehyde (3c)
or benzaldehyde (3d) were used in connection with 2, the
addition of acetic acid (1 mol equiv) and the less reactive
pelletized NaBH4 were found to be beneficial to the reaction
(Method C). In fact, under these experimental conditions,
carbonyl compounds (3c) and (3d) and imine 5 are more re-
active towards 2 and NaBH4, respectively, because they are
partially protonated.
tion to completion. The results of the reactions involving 2
are listed in Table 2.
When NaBD4 was used instead of NaBH4, a deuterium
atom was introduced in the ꢀ position of the entering N-
substituent. This procedure was successfully employed in
the synthesis of N-(1-deuterio)butyl phenylalanine (6cb-d)
and N-(ꢀ-deuterio)benzyl phenylalanine methyl ester hydro-
chloride (7cd-d).
The reaction of 2 with acetone (3e), the least reactive car-
bonyl compound considered, required more acetic acid (2
mol equiv) than Method C. In addition, THF was added to
reduce the reactivity of pelletized NaBH4 towards 3e (Method D).
With the sterically hindered and (or) less electrophilic
2,2,2-trimethylacetaldehyde (3c), benzaldehyde (3d), and ac-
etone (3e), GC–MS analysis sometimes showed the presence
of unreacted 2 or 5. A further addition of 3 and NaBH4 or
NaBH4 alone (see Experimental) was used to bring the reac-
The mass spectra (EI positive ion at 70 eV) of some of N-
alkyl derivatives of 6 and 7 showed the presence of the [M + 1]+
peak (Tables 3 and 4) and the almost complete absence of
the parent ion. This species might be produced by an ion–
molecule reaction, as invoked to explain the behaviour of
substituted malonic acids (22).
Data pertinent to the synthesized N-alkyl amino acids (6)
and amino methyl esters hydrochlorides (7) are collected in
Tables 3 and 4, respectively.
© 2002 NRC Canada

Verardo et al.
787
The GC–MS analyses of 7ad, 7cb, 7ec, and 7fa per-
formed using a chiral column showed that the enantiomeric
purity of the original ꢀ-amino acid methyl ester was re-
tained.
Melting points were determined with an automatic Mettler
(Mod. FP61) melting point apparatus and are not corrected.
Method A
N-Alkyl amino acids (6)
The aldehyde (3a–d, 14.0 mmol) was added to a stirred
solution of the amino acid (1, 10.0 mmol) in MeOH (25 mL)
neutralized with finely powdered NaOH (0.42 g,
10.5 mmol). After 10 min at room temperature, the solution
was cooled with an ice bath and NaBH4 pellets (0.49 g,
13.0 mmol) were added. The reaction mixture was stirred for
120 min at 0°C, then acidified with 37% HCl up to the
isoelectric point of starting amino acid 1. The solvents were
distilled off and the residue was triturated in acetone and fil-
tered. The solid was washed with H2O to remove NaCl and
pure N-alkyl amino acid 6 was obtained.
Conclusions
In conclusion, the method described here is very simple,
fast, and inexpensive, with respect to both the handling of
chemicals and the equipment required. It is also applicable
both to amino acids and amino methyl esters with various
carbonyl compounds, and the preformation and isolation of
the imine is not required. It appears essential, however, to
find the most suitable conditions for successful
experimentations.
With tyrosine (1d) and glutamic acid (1f), twice the amount
of NaOH (0.84 g, 20.1 mmol) was used to neutralize all the
acid centers.
When acetone 3e was used as the carbonyl compound, the
procedure was the same, but 30.0 mmol (2.20 mL) of 3e was
used.
Experimental
General
All the L-amino acids (1a–j), the L-amino acid methyl es-
ter hydrochlorides (2a–f), the carbonyl compounds (3a–e),
and NaBD4 powder (96 atom% D, pelletized with an IR die)
were purchased from Aldrich, Italy; NaBH4 (Venpure®)
caplets and granular was kindly donated by Morton Interna-
tional S.p.A. (now Rohm and Haas; Mozzate, Como, Italy).
Thin layer chromatography was performed on silica gel
(Kieselgel 60 F254 Merck, Darmstadt, Germany) and EtOAc–
hexane (50:50) was used as the eluent. Solvents were used
as received. GC–MS analyses were performed with a Fisons
TRIO 2000 gas chromatograph–mass spectrometer, working
in the positive-ion 70 eV electron-impact mode. Spectra
were recorded in the range 35–450 u. Injector temperature
was kept at 250°C and the column (Supelco SPBTM-5, 30 m
long, 0.25 mm i.d.) temperature was programmed from 60 to
300°C with a gradient of 10°C min–1. Direct-inlet mass
spectra (DI-MS) were obtained on the same instrument: tem-
peratures between 150 and 250°C were found suitable to
volatilize all the compounds into the ion source. The
enantiomeric purity of 7ad, 7cb, 7ec, and 7fa was deter-
mined using chiral-GC analysis, upon comparison with the
racemic mixtures obtained from the reaction of the corre-
sponding D,L-amino acid methyl esters under the same con-
ditions (using a Chrompack 7495 WCOT column, liquid
phase Chirasil-val-L, 26 m long, 0.22 mm i.d.). IR spectra
Method B
N-Propyl and N-butyl amino acid methyl ester
hydrochlorides (7)
Propanal or butanal (3a or 3b, respectively, 14.0 mmol)
was added to a stirred solution of the amino acid methyl es-
ter hydrochloride (2, 10.0 mmol) in MeOH (50 mL) neutral-
ized with finely powdered NaOH (0.42 g, 10.5 mmol). After
10 min at room temperature, the solution was cooled with an
ice bath and granular NaBH4 (0.30 g, 8.0 mmol) was added.
The reaction mixture was stirred for 60 min at 0°C, then
MeOH was distilled off, the residue re-dissolved in EtOAc,
and NaCl filtered off. The organic phase was washed with
brine and dried over Na2SO4. EtOAc was removed in vacuo
and the residue, dissolved in Et2O, was treated with ethereal
HCl (2 M, 5 mL, 10 mmol); N-alkyl amino acid methyl ester
hydrochloride 7 was filtered and washed with Et2O. If the
residue was insoluble in Et2O, it was dissolved in EtOAc,
treated with ethereal HCl and, after elimination of solvents
under reduced pressure, 7 was crystallized from Et2O.
Method C
were obtained with
a
Nicolet FT-IR Magna 550
spectrophotometer using the KBr technique for solids and
recorded in the range 4000–400 cm–1. 1H and 13C NMR
spectra were recorded at room temperature on a Bruker AC-
F 200 spectrometer at 200 and 50 MHz, respectively, using
D2O–NaOH for the N-alkyl amino acids (6) and DMSO-d6
for the N-alkyl amino acids methyl ester hydrochlorides (7)
as solvents. NMR peak locations are reported as ꢁ values
from DSS (2,2-dimethyl-2-silapentane-5-sulfonate) and
N-Benzyl and N-neopentyl amino acid methyl ester
hydrochlorides (7)
2,2,2-Trimethylacetaldehyde or benzaldehyde (3c or 3d,
respectively, 15.0 mmol) and acetic acid (0.57 mL,
10.0 mmol) were added to a stirred solution of the amino
acid methyl ester hydrochloride (2, 10.0 mmol) in MeOH
(50 mL) neutralized with finely powdered NaOH (0.42 g,
10.5 mmol). After 10 min at room temperature, the solution
was cooled with an ice bath and NaBH4 pellets (0.38 g,
10.0 mmol) were added. The reaction mixture was stirred for
60 min at 0°C and if the GC–MS analysis of the reaction
mixture showed the presence of unreacted imine 5, granular
NaBH4 (0.19 g, 5.0 mmol) was added. The reaction mixture
was stirred for an additional 30 min, then MeOH was dis-
tilled off, the residue dissolved in EtOAc, and NaCl filtered
1
TMS, respectively. Some H NMR multiplets are character-
ized by the term app (apparent): this refers only to their ap-
pearance and may be an oversimplification. Optical rotations
were determined at 21°C using a POLAX-D polarimeter
purchased from ATAGO (Japan). Elemental analyses were
performed with a Carlo Erba Mod. 1106 elemental analyser
and were in satisfactory agreement with calculated values.
© 2002 NRC Canada

788
Can. J. Chem. Vol. 80, 2002
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Acknowledgments
Financial support was obtained from the Italian Ministry
of University, Sciences and Technology (MURST 40% 2000
and 2001 to GV). PG is the recipient of a three-year scholar-
ship from the Ministry of Agriculture. The authors are grate-
ful to Dr. P. Martinuzzi for recording 1H and 13C NMR
spectra and Mr P. Padovani for expert instrumental mainte-
nance.
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© 2002 NRC Canada