Phenolic analogues of amino carboxylic acid ligands for 99mTc. V* N-benzyl-2-(2-hydroxyphenyl)glycines (bhpg) N-benzyl-2-(4-hydroxyphenyl)glycines (isobhpg)

Article abstract of DOI:10.1071/CH00054

A series of tridentate ligands, N-benzyl-2-(2-hydroxyphenyl)glycines (bhpg) (4), were prepared by the Mannich reaction of phenol and a number of para-substituted phenols with glyoxylic acid and benzylamine. When the two ortho positions of the phenol were blocked, as in the case of 2,6-dimethyl and 2,6-dichloro phenols, the isomeric compounds N-benzyl-2-(4-hydroxyphenyl)glycines (isobhpg) (5) were formed. When the phenol had one ortho substituent, as in the case of o-cresol and o-chlorophenol, both isomers were isolated. Two examples of the use of the chiral α-phenylethylamine in place of benzylamine are described. CSIRO 2000.

Full text of DOI:10.1071/CH00054

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 53, 2000
© CSIRO 2000
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Aust. J. Chem., 2000, 53, 583–587
Phenolic Analogues of Amino Carboxylic Acid Ligands for 99mTc. V*
N-Benzyl-2-(2-hydroxyphenyl)glycines (bhpg) and
N-Benzyl-2-(4-hydroxyphenyl)glycines (isobhpg)
J. Gerald WilsonA and Andrew G. KatsifisB
A School of Chemistry, F11, University of Sydney, N.S.W. 2006.
Author to whom correspondence should be addressed.
B Bldg 1, Biomedicine and Health Program, ANSTO, Private Bag No. 1,
Menai, N.S.W. 2234.
A series of tridentate ligands, N-benzyl-2-(2-hydroxyphenyl)glycines (bhpg) (4), were prepared by the Mannich
reaction of phenol and a number of para-substituted phenols with glyoxylic acid and benzylamine. When the two
ortho positions of the phenol were blocked, as in the case of 2,6-dimethyl and 2,6-dichloro phenols, the isomeric
compounds N-benzyl-2-(4-hydroxyphenyl)glycines (isobhpg) (5) were formed. When the phenol had one ortho
substituent, as in the case of o-cresol and o-chlorophenol, both isomers were isolated. Two examples of the use of
the chiral ␣-phenylethylamine in place of benzylamine are described.
Keywords. Phenols; benzylamine; glyoxylic acid; glycine; Mannich reaction; hepatobiliary agents.
Introduction
paper we report the synthesis of a series of N-benzyl-2-(2-
hydroxyphenyl)glycines, bhpg (4), derivatives of the triden-
tate subunits, hpg, of the ehpg ligands (1) which were the
subject of Part I of this series,2 and several N-benzyl-2-(4-
hydroxyphenyl)glycines, isobhpg (5) ligands.
Biodistribution and scintigraphic studies1 of the 99mTc
complexes of the hexadentate ligands ehpg2 (1) and ehbg3 (2)
have shown that several members of these two series have
properties that make them suitable hepatobiliary agents. To
gain some insight into the structural requirements for
optimal activity of complexes of ligands of this type, our
investigations were extended to include the smaller structural
units of these ligands. In the previous two papers of this
series, a number of tridentate half-ehbg ligands, the N-(2-
hydroxybenzyl)sarcosines,4 hbs (3a), and the N-(2-hydroxy-
benzyl)glycines,5 hbg (3b), were synthesized. In the present
Results and Discussion
The synthesis of the ehpg ligands (1) described in Part I of
this series was accomplished by means of the Mannich reac-
tion of a phenol, ethylenediamine and glyoxylic acid as the
formaldehyde component. It was decided to apply this strat-
egy to the synthesis of the half-ehpg ligands. Thus a similar
range of phenols to those used in the preparation of the ehpg
ligands was employed and a primary monoamine, benzyl-
amine, replaced ethylenediamine to give N-benzyl-2-(2-
hydroxyphenyl)glycines, bhpg (4) (Scheme 1). Subsequent
removal of the benzyl group would then provide 2-hydroxy-
phenylglycines (hpg).
References to the use of benzylamine in the Mannich
reaction with phenols are few. It has been used with
formaldehyde and para-substituted phenols to give the cor-
responding ortho-benzylaminomethylphenols when the
components were in equimolecular proportions. With two
equivalents of formaldehyde, a dihydro-benzoxazine was
formed in good yield; this was then converted into the
Mannich base by acid hydrolysis.6 Analogous reactions have
been reported with ␤-naphthol.7 The successful use of ben-
zylamine with ketones and formaldehyde in acid solution
had been earlier reported by Mannich himself 8 to give 1,3-
ketobases in which the nitrogen atom is secondary.
* Part IV, Aust. J. Chem., 1990, 43, 1283.
Manuscript received 26 April 2000
© CSIRO 2000
10.1071/CH00054
0004-9425/00/070583

584
J. G. Wilson and A. G. Katsifis
pH at 9.0–9.5. This method, however, gave rather lower
yields of products and was not pursued.
para-Substituted phenols gave 5-substituted bhpg com-
pounds (4). When this position of the phenol was free, the
bhpg compound was still the main product but it was accom-
panied to a small extent by the isomeric N-benzyl-4-
hydroxyphenylglycine (isobhpg) (5) (Scheme 1). Phenol
itself, however, afforded only the parent bhpg (4a). While the
isobhpg compounds derived from o-cresol and o-chlorophe-
nol were isolated with relative ease, only the bhpg derivatives
were obtained from the meta-isomers of these two phenols.
2,6-Dimethylphenol gave a good yield of the isobhpg com-
pound as did 2,6-dichlorophenol but, in the latter case, the
isobhpg compound separated after a short reaction time as
the relatively insoluble benzylamine salt of 3,5-dichloro
isobhpg (5d). From ␤-naphthol, the corresponding N-ben-
zylglycine derivative (6) was also obtained.
The successful use of benzylamine in the preparation of
bhpg compounds suggested that, by replacing it with ␣-
phenylethylamine, a second chiral centre could be intro-
duced into the bhpg molecule. This was demonstrated by two
examples (7). Thus, the 9-methyl derivatives of 5-bromo
bhpg (7a) and 5-methyl bhpg (7b) were isolated as mixtures
of both racemates as shown by their n.m.r. spectra (see
Experimental section). The use of the commercially avail-
able (+)-␣-phenylethylamine would then provide a route to a
mixture of diastereoisomers separable presumably by
Examples of the use of glyoxylic acid with phenols in the
Mannich reaction are also few. Apart from its application to
the synthesis of the ehpg ligands2 which was first reported in
the patent literature, there appear to be only two references to
its use: with guaiacol, 2,4-dimethylphenol and ␤-naphthol
where morpholine was the amine component,9 and with a
number of phenols where glycine was the amine component.10
The bhpg ligands were prepared in good yields when the
reactants were refluxed in 50% methanol, the initial pH of
the reaction mixture being about 9.5 (Table 1). Alternatively,
dichloracetic acid could be used instead of glyoxylic acid, the
hydrochloric acid generated during the reaction being neu-
tralized by the intermittent addition of base to maintain the
Table 1. N-Benzyl-2-(2-hydroxyphenyl)glycines (bhpg) (4)
All compounds melt with decomposition
Substitution
pattern
Yield
(%)
M.p.
I.r. (KBr) MHA,B
Molecular
formula
Found (%)
H
Requires (%)
H
(°C) ␯ (CO) (cm–1) m/z
C
N
C
N
None
3-Me
4-Me
5-Me
3,5-Me2
5-But
5-Octi
5-OMe
5-AcNH
5-NO2
3-Cl
4-Cl
5-Cl
3,5-Cl2
5-Br
3,5-Br2
5-I
39
23
53
68
56
57
65
48
50
7
23
52
32
44
40
45
46
200–201
193–195
204–206
199–201
195–197
205–207
206–208
198–200
219–221
212–214
192–194
222–224
211–213
198–200
219–221
198–200
196–198
1658
1662
1632
1610
1631
1630
1640
1622
1624
1620
1638
1667
1618
1648
1618
1630
1618
258
272
272
272
286
314
370
288
315
303
292
292
292
326
336
416
384
C15H15NO3
C16H17NO3
70.0
70.6
70.7
71.0
71.8
73.1
74.8
66.7
64.6
59.6
61.6
61.4
61.8
55.3
53.8
43.5
47.0
5.9
6.3
6.4
6.2
6.8
7.4
8.4
5.9
5.9
4.7
4.9
4.6
5.0
4.1
4.4
3.3
3.8
5.4
5.1
5.5
5.2
4.8
4.5
3.8
5.1
8.9
9.3
4.9
4.9
4.8
4.3
4.0
3.3
4.0
70.0
70.9
5.8
6.3
5.5
5.2
C17H19NO3
C19H23NO3
C23H31NO3
C16H17NO4
C17H18N2O4
C15H14N2O5
C15H14ClNO3
71.6
72.8
74.8
66.9
65.0
59.6
61.8
6.7
8.4
8.4
5.9
5.7
4.6
4.8
4.9
4.9
3.8
4.9
8.9
9.3
4.8
C15H13Cl2NO3
C15H14BrNO3
C15H13Br2NO3
C15H14INO3
55.2
53.5
43.4
47.0
4.0
4.0
3.1
3.7
4.3
4.3
3.4
3.7
A MH refers to the pseudo-molecular ion. For compounds containing halogen, MH is the higher or highest peak in the halogen cluster.
B Relative abundance 100%.

Analogues of Amino Carboxylic Acid Ligands for 99mTc. V
585
fractional crystallization, and, hence, after removal of the
␣-phenylethyl group, to each chiral form of hpg.
Good ␺-molecular ions were obtained in the positive ion
f.a.b. mass spectra of all the bhpg and isobhpg ligands, the
samples being prepared in a glycerol or m-nitrobenzyl
alcohol matrix. The debenzylation of the bhpg and isobhpg
compounds is currently being investigated.
The structures of all compounds were supported by ele-
mental analysis, i.r., n.m.r. and mass spectra (Tables 1–3).
All the compounds exhibited strong infrared bands in the
range 1610–1670 (COO–) cm–1. Their n.m.r. spectra were
uncomplicated. The chemical shifts of the methine protons
(at C 7) were remarkably constant at 4.54–4.77 ppm, while
those of the benzylic protons (at C 9) were observed as AB
quartets at slightly lower field (4.00–4.20 ppm).
Biological Activity of the 99mTc Complexes
Biodistribution and scintigraphic studies of the 99mTc
complexes of the bhpg ligands in rats proved them to be
unsuitable as hepatobiliary imaging agents for diagnostic
Table 2. N-Benzyl-2-(4-hydroxyphenyl)glycines (isobhpg) (5)
All compounds melt with decomposition
Substitution
pattern
Yield
(%)
M.p.
I.r. (KBr) MHA,B
Molecular
formula
Found (%)
H
Requires (%)
H
(°C) ␯ (CO) (cm–1) m/z
C
N
C
N
3-Me
3,5-Me2
3-Cl
5
53
6
209–211
187–189
210–211
188–190
1606
1631
1622
1637
272
286
292
326
C16H17NO3
C17H19NO3·0.4H2O
C15H14ClNO3
70.6
69.9
61.6
54.9
6.1
7.0
4.9
4.3
4.9
4.8
4.9
4.1
70.9
69.8
61.8
55.2
6.3
6.8
4.8
4.0
5.2
4.8
4.8
4.3
3,5-Cl2
21
C15H13Cl2NO3
A MH refers to the pseudo-molecular ion. For compounds containing halogen, MH is the higher or highest peak in the halogen cluster.
B Relative abundance 100%.
Table 3. 1H n.m.r. data for bhpg compounds (4)
Substitution
Aromatic
7.24–6.79, m, 9H
H 7
H 9
Substituents
None
3-Me
4.56, s
4.55, s
7.40, m, 5H; 7.04, d, J 7.5 Hz, 2H;
6.74, t, J 7.6 Hz, 1H
4.13, 4.07, q, J 13.1 Hz
4.02, 3.96, q, J 13.1 Hz
4.05, 3.97, q, J 13.1 Hz
4.13, 4.05, q, J 13.1 Hz
4.03, 4.09, q, J 13.1 Hz
2.14, s, 3-Me
2.20, s, 4-Me
2.18, s, 5-Me
4-Me
7.40, m, 5H; 7.09, d, J 7.6 Hz, 1H;
6.63, m, 2H
4.50, s
4.50, s
4.50, s
4.56, s
5-Me
7.40, m, 5H; 7.04, d, J 1.8 Hz, 1H;
6.93, m, 1H; 6.71, d, J 8.1 Hz, 1H
3,5-Me2
5-But
7.40, m, 5H; 6.85, s, 2H
2.17, s, 5-Me;
2.10, s, 3-Me
7.40, m, 5H; 7.26, d, J 2.4 Hz, 1H;
7.15, dd, J 2.4 and 8.4 Hz, 1H;
6.74, d, J 8.6 Hz, 1H
1.23, s, 9H
5-Octi
7.40, m, 5H; 7.25, s, 1H; 7.14, d,
J 8.5 Hz, 1H; 6.73, d, J 8.4 Hz, 1H
4.54, s
4.55, s
3.99, 3.95, q, J 13.1 Hz
4.07, 4.00, q, J 13.1 Hz
1.65, s, 2H; 1.29,
s, 6H; 0.69, s, 9H
5-MeO
7.40, m, 5H; 6.89, d, J 2.45 Hz, 1H;
3.66, s, MeO
6.74, m, 2H
5-AcNH
5-NO2
7.36, m, 7H; 6.72, d, J 8.7 Hz, 1H
4.54, s
4.74, s
3.92, 3.97, q, J 13.2 Hz
4.08, 3.99, q, J 13.1 Hz
1.98, s, Ac
8.27, d, J 2.9 Hz, 1H; 8.05, dd,
J 9.0 and 2.8 Hz, 1H; 7.40, m, 5H;
6.93, d, J 9.0 Hz, 1H
3-Cl
7.40, m, 5H; 7.30, dd, J 7.9 and
1.4 Hz, 1H; 7.18, d, J 7.9 Hz, 1H;
6.84, d, J 9.1 Hz, 1H
4.66, s
4.15, 4.08, q, J 13.1 Hz
4-Cl
5-Cl
7.38, m, 5H; 7.23, d, J 8.2 Hz, 1H;
6.85, m, 2H;
4.56, s
4.58, s
4.15, 3.95, q, J 13.1 Hz
4.05, 3.97, q, J 13.1 Hz
7.39, m, 5H; 7.31, d, J 2.8 Hz, 1H;
7.16, dd, J 8.6 and 2.8 Hz, 1H;
6.82, d, J 8.6 Hz, 1H
3,5-Cl2
5-Br
7.40, m, 6H; 7.26, d, J 2.6 Hz, 1H
4.77, s
4.58, s
4.19, 4.10, q, J 12.9 Hz
4.05, 3.97, q, J 13.1 Hz
7.40, m, 6H; 7.28, dd, J 8.7 and
2.6 Hz, 1H; 6.78, d, J 8.6 Hz, 1H
3,5-Br2
5-I
7.67, d, J 2.3 Hz, 1H; 7.42, m, 6H
4.77, s
4.58, s
4.21, 4.10, q, J 13.0 Hz
4.06, 3.98, q, J 13.1 Hz
7.44, dd, J 8.5 and 2.3 Hz, 1H;
7.42, m, 6H; 6.67, d, J 8.5 Hz, 1H

586
J. G. Wilson and A. G. Katsifis
tion. A second fraction separated overnight (7.9 g, m.p. 199–201°). This
fraction was dissolved in ethanol (30 ml), water (20 ml) and conc.
hydrochloric acid (2.5 ml). When the pH was raised to 3.5, the isomeric
N-benzyl-3-chloro-4-hydroxyphenylglycine (5b) crystallized from the
hot solution (3.6 g, 6%), m.p. 210–211°. It gave a brown Fe3+ reaction.
1H n.m.r. ␦ (400 MHz, (CD3)2SO) 3.84, 3.79, ABq, J 13.3 Hz, H9; 4.16,
s, H7; 6.93, d, J5,6 8.4 Hz, H5; 7.12, dd, J5,6 8.4 Hz, J2,6 2.1 Hz,
H 6; 7.35, m, aromatic.
nuclear medicine. They were rapidly excreted mainly
through the urinary route and revealed no specificity for the
target organ.
Experimental
General Details
1H n.m.r. spectra were run in (CD3)2SO and recorded on a JEOL
JNM-GX400 FT spectrometer and on a Bruker AC 200 and a Bruker
AM 400. Mass spectra were recorded on a JEOL JMS-DX 300 spec-
trometer in the f.a.b. mode by using argon gas, or, where indicated, on
an AEI MS902 double-focusing magnetic sector mass spectrometer
operating with an ionization potential of 70 eV. Infrared spectra were
recorded on a Perkin–Elmer 237 instrument as KBr disks and on a Bio-
Rad FTS-7 infrared spectrometer. Elemental analyses were carried out
by the Australian Microanalytical Service, Melbourne. Melting points
are uncorrected.
4-Chloro bhpg (4l) (From m-Chlorophenol)
On acidification, the reaction mixture deposited fine creamy crys-
tals of the crude product (30.5 g, 52%), m.p. 209–211°. This material
(25.4 g) was taken up in ethanol (100 ml) and conc. hydrochloric acid
(8 ml) on warming. On dilution of the hot, filtered solution with water
(125 ml), the product separated and was collected when ambient tem-
perature was reached (15.4 g, m.p. 222–224°) (Table 1). It gave a
purple-violet Fe3+ reaction. A second fraction obtained on raising the
pH to 4.0 consisted of a mixture of the two isomers.
General Procedure—Illustrated by the Preparation of
5-Bromo bhpg (4o)
N-Benzyl-3,5-dimethyl-4-hydroxyphenylglycine (5c)
Glyoxylic acid (18.4 g, 0.2 mol) in water (50 ml) was neutralized
with sodium carbonate (10.6 g, 0.1 mol). 4-Bromophenol (34.6 g, 0.2
mol) in methanol (75 ml) was added followed by benzylamine (21.5 ml,
0.2 mol), also in methanol (25 ml). The reaction mixture (the pH was c.
9.6 and it was not further adjusted) was refluxed for 6 h. The volume
was reduced to about half, diluted with water to give approx. the origi-
nal volume and extracted with ether (×3). The aqueous layer to which
ethanol (50 ml) had been added was heated to c. 70° and acidified with
conc. hydrochloric acid to pH 7.0. The solid which separated immedi-
ately was collected after being allowed to stand for several hours at
room temperature, washed with 50% ethanol, then ethanol to give the
product (28.0 g). The compound was taken up in ethanol (140 ml) by
adding conc. hydrochloric acid (11 ml). The hot, filtered solution was
diluted with an equal volume of water and brought to pH 4.0 with
ammonia. The finely crystalline 5-bromo bhpg which separated imme-
diately was collected after 3 h and washed as above (26.9 g, 40%, m.p.
219–221°) (Tables 1 and 3).
When 2,6-dimethylphenol was used in the general procedure, 3,5-
dimethyl isobhpg was obtained in 53% yield, m.p. 187–189° (dec.). 1H
n.m.r. ␦ (400 MHz, (CD3)2SO) 3.81, 3.77, ABq, J 13.4 Hz, H9; 3.97, s,
H 7; 6.90, s, H2, H 6; 7.35, m, aromatic H; 2.13, s, 3-Me and 5-Me.
N-Benzyl-3,5-dichloro-4-hydroxyphenylglycine (5d) and Its
Benzylamine Salt
The reaction mixture (half the scale of the general procedure) was
heated under reflux to give a clear solution which began to deposit crys-
tals after 30 min. The solution was stirred and heated for a further 4 h
with the amount of solid increasing and gas (CO2) evolving. The silky
crystals were collected from the cooled reaction mixture, and then
washed with water/ethanol (1:1) to give the benzylamine salt of 3,5-
dichloro isobhpg (5d) (11.32 g, 26%), m.p. 194–196° (dec). An aliquot
of this product (2.0 g) was dissolved in ethanol (400 ml); the solution
was filtered and boiled to incipient crystallization (c. 200 ml). After 1
day at ambient temperature, the crystals were collected, washed with
cold ethanol and dried in air (1.64 g), m.p. 193–195° (Found: C, 60.9;
H, 5.2; N, 6.3; Cl, 16.4%. C15H13Cl2N2O3.C7H7NH2 requiresC, 61.0; H,
5.1; N, 6.5; Cl, 16.4%). ␯max (KBr) 1570, 1449 cm–1. 1H n.m.r. ␦ (200
MHz, (CD3)2SO) 3.67, s, H9; 3.87, s, H7; 3.91, s, CH2 of benzylamine;
7.23, s, H2, H 6; 7.24–7.38, m, aromatic H. Mass spectrum (f.a.b.) m/z
326 (52%), 328, 330 (2×Cl).
The filtrate and washings from the reaction were reduced to about
half volume, water was added to give the original volume and the solu-
tion was extracted with ether (×2). The aqueous solution was warmed to
evaporate the dissolved ether and, after being left overnight, deposited
a second fraction of the above compound which was collected as above
(3.05 g) (33% in all). The filtrate from the above fraction was worked
up in the usual way and gave the product (5d) (10.00 g, 31%), m.p.
192–194° dec. This was purified by warming in ethanol (35 ml) and the
addition of just enough conc. hydrochloric acid to give a clear solution
which was then filtered, treated with water (60 ml) and brought to pH 4
with ammonia. Crystals of 3,5-dichloro isobhpg (5d) (6.98 g), m.p.
187–189°, were obtained. 1H n.m.r. ␦ (400 MHz, (CD3)2SO) 3.73, 3.82,
ABq, J 13.4 Hz, H9; 4.17, s, H7; 7.33–7.38, m, aromatic H.
Procedures for the Isolation of Isomeric Products
3-Methyl bhpg (4b) (From o-Cresol)
Acidification of the hot reaction mixture gave crystals of fraction 1
which was collected after 1 h (26.2 g), m.p. 190°. This was dissolved in
ethanol (130 ml) and water (130 ml) by adding conc. hydrochloric acid
(7.5 ml) to the hot suspension, which was then filtered and brought to
pH 3.5. Powdery crystals of 3-methyl bhpg (4b) separated immediately
(12.56 g, 23%), m.p. 193–195° (Table 1). The filtrate from fraction 1
deposited a second fraction (4.4 g, 8%), m.p. 203–206°, which was col-
lected after 16 h at room temperature. Recrystallization as above
[ethanol (25 ml), water (20 ml) and conc. hydrochloric acid (c. 2 ml)
followed by adjustment of the pH to 4.0] afforded N-benzyl-3-methyl-
4-hydroxyphenylglycine (3-methyl isobhpg) (5a) (2.55 g, 5%), m.p.
209–211°, which separated from the hot solution. It gave a pale brown
Fe3+ reaction. 1H n.m.r. ␦ (400 MHz, (CD3)2SO) 3.82, 3.79, ABq, J 13.6
Hz, H9; 4.06, s, H7; 6.74, d, J5,6 8.3 Hz, H5; 6.98, dd, J5,6 8.3 Hz, J2,6
2.1 Hz, H6; 7.07, d, J2,6 1.9 Hz, H2; 7.36, m; 2.09, s, 3-Me.
4-Methyl bhpg (4c) (From m-Cresol)
5-Bromo-9-methyl bhpg (7a)
On acidification of the reaction mixture to pH 3.5 the product (29.0
g, 53%), m.p. 205°, was obtained unaccompanied by the other isomer.
An analytical sample was prepared by dissolving the compound (5 g) in
50% ethanol and adding conc. hydrochloric acid and then warming. On
adjusting the pH of the filtered solution to 3.5, crystalline 4-methyl
bhpg (3.7 g) separated, m.p. 204–206° (Table 1). It gave a blue Fe3+
reaction. Later fractions from the reaction mixture consisted of insepa-
rable mixtures of the two isomers.
By using ( )-␣-phenylethylamine with p-bromophenol according to
the general procedure on a 0.05 M scale, the product (7a) was obtained
in 45% yield (7.95 g, m.p. 219–221° dec.). Purification in the usual way
did not raise the melting point. The product consisted of approx. 45%
of one racemate (A) and 55% of the other racemate (B) as estimated by
the 400 MHz n.m.r. spectrum (Found: C, 54.6; H, 4.8; N, 3.7%.
C16H16BrNO3 requires C, 54.9; H, 4.6; N, 4.0%). ␯ 1614 cm–1. 1H
max
n.m.r. ␦ (400 MHz, (CD3)2SO) (A) 1.48, d, JMe,9 6.8 Hz, Me-9; 4.21, q,
J9,Me 6.8 Hz, H9; 4.19, s, H7; 6.70, d, J3,4 8.8 Hz, H3; 7.25–7.42, m,
aromatic H. (B) 1.38, d, JMe,9 6.4 Hz, Me9; 3.82, q, J9,Me 6.6 Hz, H9;
4.27, s, H7; 6.38, d, J3,4 8.8 Hz, H 3; 7.25–7.42, m, aromatic H.
3-Chloro bhpg (4k) and 3-Chloro isobhpg (5b) (From o-Chlorophenol)
The product (4k) separated from the hot solution over several hours
(13.3 g, 23%), m.p. 192–194° (Table 1); it gave a dark purple Fe3+ reac-

Analogues of Amino Carboxylic Acid Ligands for 99mTc. V
587
Assignments were confirmed by decoupling experiments. Mass spec-
(8.55 g) in 56% yield (m.p. 189–190° dec.). It gave an emerald green
Fe3+ reaction (Found: C, 74.6; H, 5.4; N, 4.5%. C19H17NO3 requires C,
74.3; H, 5.5; N, 4.6%). ␯max 1622, 1600, 1545, 1519, 1447, 1259 cm–1.
1H n.m.r. (400 Hz, (CD3)2SO) ␦ 3.80, s, H11; 5.20, s, H9; 7.08, d, J 8.4
Hz, H 3; 7.25–7.31, m, aromatic H; 7.73–7.86, m, aromatic H. Mass
spectrum (f.a.b.) 308 (100%) MH+.
trum (e.i.) m/z 349 (6.5%), M+.
5,9-Dimethyl bhpg (7b)
This compound was obtained as above from p-cresol in 58% yield
(8.31 g, m.p. 196–197° dec.). It consisted of approx. 42% of one race-
mate (A) and 58% of the other racemate (B), as estimated by the 400
MHz n.m.r. spectrum (Found: C, 70.1; H, 6.6; N, 5.2%.
References
C17H19NO3·0.25H2O requires C, 70.5; H, 6.7; N, 4.8%).
␯
max
1606 cm–1. 1H n.m.r. ␦ (400 MHz, (CD3)2SO) (A) 1.50, d, JMe,9 6.8 Hz,
Me-9; 2.17, s, Me-6; 4.27, q, J9,Me 6.7 Hz, Me-9; 4.18, s, H 7; 6.64, m,
7.00, m, 7.33, m, aromatic H. (B) 1.40, d, JMe,9 6.9 Hz, Me-9; 2.17, s,
Me-6; 3.86, q, J9,Me 6.8 Hz, H 9; 4.18, s, H 7; aromatic H same as for A.
Mass spectrum (e.i.) m/z 285 (27.5%) M+.
1
Hunt, F. C., Maddalena, D. J., Wilson, J. G., and Bautovich, G. J., Int.
J. Radiat. Appl. Instrum., Part B, Nucl. Med. Biol., 1986, 13, 289.
Wilson, J. G., Aust. J. Chem., 1987, 40, 1695.
Wilson, J. G., Aust. J. Chem., 1988, 41, 173.
Wilson, J. G., Aust. J. Chem., 1990, 43, 783.
Wilson, J. G., Aust. J. Chem., 1990, 43 , 1283.
Burke, W. J., Kolbezen, M. J., and Stephens, C. W., J. Am. Chem.
2
3
4
5
N-Benzyl-(2-hydroxy-1-naphthyl)glycine (6)
6
When ␤-naphthol was used in the general procedure on a 0.05 M
scale, the reaction mixture was left at room temperature for 1 h before
being refluxed for 5 h. The crude product (10.95 g, 69%, m.p. 185° dec.)
was taken up in hot 50% ethanol (100 ml) and conc. hydrochloric acid
(c. 5 ml). The pH of the filtered solution was adjusted to c. pH 4 with
ammonia to obtain the product (6) as a fine, granular, greyish solid
Soc., 1952, 74, 3601.
Mannich, C., and Hieronymus, O., Chem. Ber., 1942, 75, 46.
Biekert, E., and Funck, T., Chem. Ber., 1964, 97, 363.
Burke, W. J., J. Am. Chem. Soc., 1949, 71 , 609.
McCrary, A. L., and Wilson, D. A., U.S. Patent 3825592, 1974; C.A.
1975, 81 , 77684.
7
8
9
10