4-hydroxy-2-quinolones. 204.*synthesis, bromination, and analgetic properties of 1-allyl-4-hydroxy- 6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3- carboxylic acid arylalkylamides

Article abstract of DOI:10.1007/s10593-012-1143-7

A simple method has been proposed and used for the preparation of 1-allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-di-hydroquinoline-3-carboxylic acid arylalkylamides. Similar to alkylamides of this acid, the arylalkylamides obtained are halogenated with cyclization by one equivalent of molecular bromine to give the corresponding 2-bromomethyl-7,8-dimethoxy-5-oxo-1,2-dihydro-5H- oxazolo[3,2-a]quinoline-4-carbox-amides. However, the reaction proceeds quite differently when using an excess of bromine. After the usual initial oxazole ring closure, the excess bromine brominates the aromatic ring of the amide fragment. The results of testing for the analgesic activity of these products are presented.

Full text of DOI:10.1007/s10593-012-1143-7

Chemistry of Heterocyclic Compounds, Vol. 48, No. 9, December, 2012 (Russian Original Vol. 48, No. 9, September, 2012)
4-HYDROXY-2-QUINOLONES. 204.* SYNTHESIS,
BROMINATION, AND ANALGETIC PROPERTIES OF
1-ALLYL-4-HYDROXY- 6,7-DIMETHOXY-2-OXO-
1,2-DIHYDROQUINOLINE-3-CARBOXYLIC ACID
ARYLALKYLAMIDES
I. V. Ukrainets1**, E. V. Mospanova2, N. A. Jaradat3,
O. V. Bevz1, and A. V. Turov4
A simple method has been proposed and used for the preparation of 1-allyl-4-hydroxy-6,7-dimethoxy-2-oxo-
1,2-di-hydroquinoline-3-carboxylic acid arylalkylamides. Similar to alkylamides of this acid, the
arylalkylamides obtained are halogenated with cyclization by one equivalent of molecular bromine to give
the corresponding 2-bromomethyl-7,8-dimethoxy-5-oxo-1,2-dihydro-5H-oxazolo[3,2-a]quinoline-4-carbox-
amides. However, the reaction proceeds quite differently when using an excess of bromine. After the usual
initial oxazole ring closure, the excess bromine brominates the aromatic ring of the amide fragment. The
results of testing for the analgesic activity of these products are presented.
Keywords: 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides, amidation, analgesic activity,
bromination, halocyclization.
The synthesis and subsequent study of new compounds similar in structure to compounds, which have
already proven themselves in one way or another remains one of the most effective methods for improving the
useful properties of initially selected lead structures. This method has long been employed in many areas of
science and technology, but has found an especially wide application in medicinal chemistry [2-4]. In the
present communication, we applied this approach in a search for more powerful, non-narcotic analgesics among
4-hydroxy-2-oxoquinoline-3-carboxamides.
_______
*For communication 203, see [1].
**To whom correspondence should be addressed, e-mail: uiv@kharkov.ua.
1National University of Pharmacy, 53 Pushkinska St., Kharkiv 61002, Ukraine.
2Institute of Chemical Technology, Vladimir Dal' Eastern Ukraine National University, 31 Lenina St., Rubizhne
93003, Ukraine; e-mail: elena_mospanova@list.ru.
3Pharmaceutical College, An-Najah National University. Post Office Box 7, Nablus, Palestine; e-mail:
nidaljaradat@yahoo.com.
4Taras Shevchenko Kyiv National University, 62 Volodymirska St., Kyiv 01033, Ukraine; e-mail: nmrlab@univ.kiev.ua.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1445-1455, September, 2012.
Original article submitted June 3, 2011.
0009-3122/12/4809-1347©2012 Springer Science+Business Media New York
1347

This study of 1-allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid arylalkyl-
amides with general formula 1 was suggested by the sufficiently high analgesic activity of alkylamides of this
acid [5] and the lack of marked acidity for these compounds [6]. The lower acidity of these compounds, which
is 800-1000 times less than for known analgesics [7], allows to hope that the use of such compounds would
permit a partial if not complete elimination of the ulcerogenic effect, which is the major cause for a whole series
of contraindications when using non-narcotic analgesics [8].
A good solubility of the starting methyl 1-allyl-6,7-dimethoxy-4-hydroxy-2-oxo-1,2-dihydro-quinoline-
3-carboxylate (2) in alcohols permits the amidation of this ester with arylalkylamines under relatively mild
conditions, completely eliminating the possibility of thermal decomposition, which is characteristic for
quinoline-3-carboxylates substituted in the benzene moiety [9]. Thus, the desired arylalkylamides 1a-u were
synthesized in good yields and purity (Tables 1 and 2).
OH
OH
RNH2, MeOH
COOMe
O
MeO
MeO
CONH-R
O
MeO
MeO
, 3 h
N
N
CH2
1a–u
CH2
2
(from 1g)
1 equiv. Br2, AcOH, room temp.
2 equiv. Br2, AcOH
room temp., 2 h
OMe
O
OMe
O
O
O
O
MeO
MeO
N
H
N
H
N
MeO
N
MeO
O
Br
3
Br
Br
4
1 a R = Bn, b R = 2-FC6H4CH2, c R = 4-FC6H4CH2, d R = 2-ClC6H4CH2, e R = 4-ClC6H4CH2,
f R = 4-MeC6H4CH2, g R = 2-MeOC6H4CH2, h R = 4-MeOC6H4CH2, i R = 3,4-(MeO)2C6H3CH2,
j R = piperonyl, k R = furfuryl, l R = tetrahydrofurfuryl, m R = picolyl-2, n R = picolyl-3,
o R = picolyl-4, p R = PhCH(Me)CH2, q R = PhCH2CH2, r R = 4-ClC6H4CH2CH2,
s R = 4-MeOC6H4CH2CH2, t R = 3,4-(MeO)2C6H3CH2CH2, u R = PhCH2CH2CH2
Similar to the 1-allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid alkyl-
amides described in our previous work [5], their arylalkyl analogs 1a-u also undergo facile halocyclization upon
the addition of an equivalent of molecular bromine in glacial acetic acid, to give the corresponding
2-bromomethyl-7,8-dimethoxy-5-oxo-1,2-dihydro-5H-oxazolo[3,2-a]quinoline-4-carboxamides 3 (the example
of compound 1g is given in this work). However, in the presence of excessive bromine, the reaction takes an
entirely different course due to the aromatic ring in the amide fragment. The introduction of the aromatic ring
leads to an additional reaction site susceptible to halogenation. After closure of the new five-membered ring the
excess of bromine is consumed in ordinary electrophilic aromatic substitution rather than giving oxazolo-
[3,2-a]quinoline tribromides [5].
The course of the reaction examined was experimentally confirmed on the example of 1-allyl-6,7-di-
methoxy-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid 2-methoxybenzylamide (1g). Thus, the
1
characteristic change in the H NMR spectrum indicates that after the reaction with an equivalent amount of
bromine this compound is converted exclusively and in high yield to the 2-bromomethyl-7,8-dimethoxy-5-oxo-
1348

TABLE 1. Characteristics of the Arylalkylamides 1a-u* Synthesized
Found, %
Calculated, %
H
Com-
pound
Empirical
formula
Analgetic
activity*2
Mp, °С
Yield, %
С
N
C22H22N2O5
C22H21FN2O5
C22H21FN2O5
C22H21ClN2O5
C22H21ClN2O5
C23H24N2O5
C23H24N2O6
C23H24N2O6
C24H26N2O7
C23H22N2O7
C20H20N2O6
C20H24N2O6
C21H21N3O5
C21H21N3O5
C21H21N3O5
C23H24N2O5
C23H24N2O5
C23H23ClN2O5
C24H26N2O6
C25H28N2O7
C24H26N2O5
67.08
66.99
64.15
64.07
64.14
64.07
61.53
61.61
61.69
61.61
67.51
67.63
64.96
65.08
65.14
65.08
63.55
63.43
62.90
63.01
62.57
62.49
61.74
61.85
63.68
63.79
63.87
63.79
63.85
63.79
67.50
67.63
5.73
5.62
5.21
5.13
5.08
5.13
5.05
4.94
5.08
4.94
5.80
5.92
5.62
5.70
5.78
5.70
5.86
5.77
4.93
5.06
5.20
5.24
6.11
6.23
5.27
5.35
5.44
5.35
5.42
5.35
5.82
5.92
7.16
7.10
6.87
6.79
6.70
6.79
6.64
6.53
6.61
6.53
6.75
6.86
6.71
6.60
6.69
6.60
6.23
6.16
6.44
6.39
7.21
7.29
7.16
7.21
10.52
10.63
10.70
10.63
10.56
10.63
6.95
6.86
160-162
164-166
173-175
187-189
180-182
146-148
161-163
155-157
182-184
189-191
154-156
166-168
199-201
192-194
181-183
178-180
173-175
185-187
180-182
169-171
162-164
95
90
93
92
96
88
86
90
84
89
93
81
90
92
94
80
88
91
85
87
82
30.9
9.5
1a
1b
1c
1d
1e
1f
15.6
14.4
56.9
24.3
10.8
26.3
39.4
15.4
50.9
20.5
31.9
6.2
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
18.7
9.5
67.71
67.63
62.46
62.37
65.65
65.74
63.97
64.09
5.98
5.92
5.34
5.23
6.07
5.98
5.93
6.02
6.97
6.86
6.20
6.32
6.48
6.39
5.89
5.98
12.7
15.1
17.0
15.6
17.9
1t
68.34
68.23
6.28
6.20
6.75
6.63
1u
_______
*The analgesic activity is 35.2 for diclofenac and 47.1 for ketorolac.
*2Increase of the pain threshold, %.
1
1,2-dihydro-5H-oxazolo[3,2-a]quinoline-4-carboxylic acid 2-methoxybenzylamide (3). The H NMR spectrum of
another compound obtained in a reaction of the same 2-methoxybenzylamide 1g with a twofold excess of
bromine shows that the initial halocyclization in this case is followed by bromination of the aromatic ring of the
benzyl fragment. Both the substituents in the aromatic ring direct bromination to ortho and para positions.
Thus, it would be entirely reasonable to expect competition in the substitution. It is not always possible to give a
precise prediction of the final result of these reactions, but numerous observations show that groups producing
an effect by means of lone electron pairs are more active than groups with an inductive effect [10]. In other
words, the probability of substitution at the ortho or para position relative to the methoxy group in the
bromination of the 2-methoxybenzyl fragment is higher than to such positions relative to the acylaminomethyl
group. However, we should bear in mind that this is only a hypothesis and does not exclude the possibility of a
completely opposite result.
1349

Thus, structural characterization of the product of 1-allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydro-
quinoline-3-carboxylic acid 2-methoxybenzylamide (1g) reaction with a twofold excess of bromine is reduced
largely to determination of the bromine atom position in the benzyl fragment. In principle, such problems are
rather simply solved by NMR spectroscopy using special methods, in particular, the nuclear Overhauser effect
(NOE), although some difficulties may be encountered. For example, investigation of the structure of this
product by the NOE method in the solution of DMSO-d6, which is the most commonly employed solvent, failed
completely for the simple reason that there was an unexpected overlap of the two methoxy group signals. This
coincidence prevented studies involving their selective saturation. The spectrum in a mixed solvent consisting of
DMSO-d6 and deuterated benzene (1:1 mixture) was more suitable for analytical studies. All three methoxy
groups in this spectrum appeared as separate signals, which allowed us to carry out straightforward NOE
experiments. Figure 1 shows the chemical shifts of all the protons in this product; the arrows indicate enhanced
signal intensity under stationary NOE conditions.
7.78 (s)
4.57
3.77
O
O
H
OMe
HH
MeO
H 6.88 (d)
H 7.41 (d)
N
3.81
H
3.95 MeO
H
7.51 (s)
O 10.85
H 5.58
Br
N
H
Br
6.98 (s)
H
H
4.64
4.34
H
H
4.00
Fig. 1. NOE determination of the bromine atom position in the benzyl fragment of amide 4.
We immediately notice the multiplicity of the signals in the aromatic part of the spectrum. Three
singlets (7.78, 7.51, and 6.98 ppm) and two doublets (7.41 and 6.88 ppm) are observed. After subtracting out
the two singlets due to quinolone protons, one singlet and two doublets remain for the benzyl fragment, which
considerably simplifies the problem since such a combination of signals completely excludes the theoretically
Fig. 2. Molecular structure of 5-bromo-2-methoxybenzylamide 4.
1350

1351

1352

possible ortho substitution. Whether the bromine atom is in the para position to the methoxy group or to the
acylaminomethyl group, was determined by NOE. Although the absolute value of the NOE did not exceed 3%,
this proved entirely sufficient for making reliable conclusions concerning the spatial proximity of the methoxy
groups and the corresponding aromatic protons. The existence of NOE between the methoxy group signal at
3.77 ppm and the doublet at 6.88 ppm proved to be most useful for elucidating the structure of this compound.
This finding clearly proves that the indicated methoxy group and aromatic proton are adjacent to each other.
Thus, the bromine atom is in para position to the methoxy group. Otherwise, the multiplicity of the signal at
6.88 ppm would be completely different. Furthermore, we concurrently solved an additional problem for this
structure, which might not be as important for structural characterization, but is nevertheless quite interesting,
namely, the specific assignment of the signals of the methoxy groups in the quinolone system.
Thus, there is every reason to believe that the product of the 2-methoxybenzylamide 1g reaction with a
twofold excess of bromine is 2-bromomethyl-7,8-dimethoxy-5-oxo-1,2-dihydro-5H-oxazolo[3,2-a]quinoline-
4-carboxylic acid 5-bromo-2-methoxybenzylamide (4). This conclusion is supported by the results of our X-ray
structural analysis (Fig. 2), which revealed several important features of the three-dimensional structure of the
5-bromo-2-methoxybenzylamide 4 obtained. In particular, it is shown that the quinolone fragment and atoms
C(11), O(1), O(2), C(13), O(5), and O(6) in this compound lie in a single plane to within 0.02 Å. The bond
length values in the pyridone and oxazole rings are close to those in the previously studied compounds with a
similar structure [11-13].
The five-membered heterocycle is disordered between two "envelope" conformations (A and B); the
A:B occupancy ratio is 7:3. The carbon C(10) deviates from the mean-square plane of the other ring atoms by
0.45 Å in conformer A and -0.40 Å in conformer B. In both conformers, the atom C(12) has a pseudo-equatorial
orientation (the C(9)O(1)C(10)C(12) dihedral angle is -142.6(7)° in the conformer A and 142.8(8)° in the
conformer B). The bromine atom is not disordered and is found in -sc and +sc conformations in both conformers
relative to the O(1)C(10) bond (the O(1)C(10)C(12)−Br(1) dihedral angle is 59(1)° in the conformer A and
79(2)° in the conformer B). A shortened H(2)···C(11) intramolecular contact (2.74 Å) is found in the tricyclic
fragment (the sum of the van der Waals radii is 2.87 Å [14]).
The methoxy groups at the atoms C(3) and C(4) are coplanar to the aromatic ring plane (dihedral angle
C(22)O(5)C(3)C(4) is -177.6(7)° and dihedral angle C(23)O(6)C(4)C(3) is -179.5(6)°) despite the
significant repulsion between these groups and the benzene fragment atoms. The following shortened
intramolecular contacts are seen: H(2)···C(22), 2.41 Å (sum of the van der Waals radii 2.87 Å); H(2)···H(22b),
2.25 Å (2.34 Å); H(2)···H(22c), 2.19 Å (2.34 Å); H(22b)···C(2), 2.75 Å (2.87 Å); H(22c)···C(2), 2.71 Å (2.87 Å);
H(5)···C(23), 2.52 Å (2.87 Å); H(5)···H(23c), 2.25 Å (2.34 Å); H(23c)···C(5), 2.71 Å (2.87 Å); H(23b)···C(5),
2.80 Å (2.87 Å).
The carbamide group of the substituent at the atom C(8) is virtually coplanar to the plane of the bicyclic
system (the C(9)C(8)C(13)N(2) dihedral angle is 172.5(6)°), which is apparently a result of formation of the
N(2)H(2N)···O(2) intramolecular hydrogen bond (H···O, 1.94 Å; N−H···O, 136°). The carbon C(14) is in the
ap conformation relative to the C(13)C(8) bond (the C(14)N(2)C(13)C(8) dihedral angle is 177.7(6)°),
while the bromomethoxyphenyl substituent is oriented virtually perpendicular to the C(13)N(2) bond and
coplanar to the N(2)C(14) bond (the C(13)N(2)C(14)C(15) dihedral angle is 78.4(8)° and the
N(2)C(14)C(15)C(20) dihedral angle is -3(1)°). This conformation of the indicated substitutent apparently is
facilitated by the following shortened intramolecular contacts: H(20)···N(2), 2.54 Å (the sum of the van der
Waals radii is 2.67 Å) and H(20)···C(13), 2.54 Å (2.87 Å). The methoxy group at the C(16) atom is somewhat
non-coplanar to the aromatic ring plane (the C(21)O(4)C(16)C(17) dihedral angle is 11(1)°), probably due
to the marked repulsion between the methyl group and benzene ring atoms. The following shortened contacts
are seen: H(17)···C(21), 2.52 Å (2.87 Å); H(17)···H(21c), 2.17 Å (2.34 Å); H(21c)···C(17), 2.69 Å (2.87 Å).
Shortened intermolecular contacts between molecules of 5-bromo-2-methoxybenzylamide 4 were found
in the crystal: H(22a)···H(12c)' (-1-x, 0.5+y, -0.5-z), 2.17 Å (2.34 Å); H(14a)····H(11c)' (x, 0.5-y, 0.5+z), 2.25 Å
(2.34 Å); H(21c)···C(8)' (x, 0.5-y, 0.5+z), 2.71 Å (2.87 Å); H(21a)···Br(1)' (-1-x, 0.5+y, 0.5-z), 3.16 Å (3.23 Å);
1353

H(21b)···Br(1)' (1+x, 0.5-y, 5+z), 3.00 Å (3.23 Å); H(22b)···Br(1)' (x, 0.5-y, -0.5+z), 3.04 Å (3.23 Å);
H(11a)···Br(2)' (-1+x, 0.5-y, -0.5+z), 3.17 Å (3.23 Å); H(14b)···Br(2)' (-x, 0.5+y, 0.5-z), 3.15 Å (3.23 Å).
The analgesic activity of all the synthesized 1-allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydro-
quinoline-3-carboxylic acid arylalkylamides 1a-u was studied in white non-pedigreed male rats. The standard
method involving the irritation of rectal mucosa with electric current was employed [15]. The compounds
studied were introduced orally in a fine aqueous suspension stabilized with Tween-80. The dose was 20 mg/kg.
Comparison of the experimental data (Table 1) with the results of the previous studies [5] showed that going
from the already investigated alkylamide derivatives to the arylalkylamide derivatives examined in this work
had no significant effect on biological properties. As previously found, all the compounds without exception
have the analgesic activity, the most of which reveal a moderate antinociceptive effect. Two compounds,
namely, 4-chlorobenzylamide 1e and furfurylamide 1k were found with the specific activity superior to that of
the commonly used non-narcotic analgesics, diclofenac and ketorolac [8], and should be subjected to detailed
testing. Attention should be also paid to the trend that might be useful in our targeted search for new analgesics,
which is clearly seen in all groups of compounds with the same aromatic system in the arylalkylamide fragment,
such as going from benzyl derivative 1a to 2-phenylethyl derivative 1q to 3-phenylpropyl derivative 1u and
from 4-chlorobenzyl derivative 1e to 2-(4-chlorophenyl)ethyl derivative 1r, etc. Removal of the aromatic
substituent from the amide nitrogen atom leads to a marked drop in the analgesic activity of the corresponding
1-allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid arylalkylamides.
Thus, in this work, we have proposed a simple method for the preparation of 1-allyl-4-hydroxy-6,7-di-
methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid arylalkylamides and studied the halocyclization of the
resultant amides upon the reaction with bromine. The results of testing the compounds for the analgesic activity
suggest that the further search for new analgesics among 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbox-
amides should be concentrated on benzylamides and their heterocyclic analogs.
EXPERIMENTAL
1
The H NMR spectra of arylalkylamides 1a-u and oxazoloquinoline 3 were recorded on a Varian
Mercury VX-200 spectrometer (200 MHz) in DMSO-d6. The NOE experiments on 5-bromo-2-methoxybenzyl-
amide 4 were carried out on a Varian Mercury VX-400 spectrometer (400 MHz) in 1:1 DMSO-d6−C6D6. TMS
served as internal standard in all cases. The starting 1-allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydro-
quinoline-3-carboxylic acid methyl ester (2) was prepared according to our previous procedure [16].
1-Allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic Acid Amides 1a-u
(General Method). The corresponding amine (0.011 mol) was added to a solution of 1-allyl-4-hydroxy-
6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (2) (3.19 g, 0.010 mol) in methanol (30
ml) and heated at reflux for 3 h. The reaction mixture was cooled, diluted by adding cold water, and brought to
pH ~4 by adding dilute hydrochloric acid (acetic acid was used in the isolation of picolylamides 1m-o). The
precipitate formed was filtered off, washed with cold water, dried, and recrystallized from ethanol.
2-Bromomethyl-7,8-dimethoxy-5-oxo-1,2-dihydro-5H-oxazolo[3,2-a]quinoline-4-carboxylic Acid
2-Methoxybenzylamide (3). A solution of Br2 (0.52 ml, 0.01 mol) in acetic acid (5 ml) was added with vigorous
stirring to a solution of 1-allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid
2-methoxybenzylamide (1g) (4.24 g, 0.01 mol) in glacial acetic acid (30 ml). The red-brown color of bromine
disappeared immediately. The reaction mixture was diluted by adding cold water, the precipitate was filtered
off, rinsed with cold water, and dried to give methoxybenzylamide 3. Yield 4.32 g (86%); mp 135-137°С
1
(DMF). Н NMR spectrum, δ, ppm (J, Hz): 10.54 (1Н, t, J = 5.8, NН); 7.57 (1H, s, H-6); 7.39 (1Н, dd, J = 8.5,
J = 2.3, Н-6'); 7.24 (1Н, t, J = 7.5, H-4'); 7.03-6.95 (2Н, m, Н-9,3'); 6.88 (1Н, t, J = 8.1, Н-5'); 5.63-5.49 (1Н, m,
NCH2СНО); 4.65 (1Н, t, J = 9.7, NCH); 4.41 (2Н, d, J = 4.7, NHCH2); 4.28 (1Н, dd, J = 9.7, J = 6.7, NCH);
1354

4.01-3.96 (2Н, m, CH2Br); 3.92 (3H, s, OCH3); 3.82 (6H, s, 2OCH3). Found, %: C 54.75; H 4.52; N 5.46.
C23H23BrN2O6. Calculated, %: C 54.88; H 4.61; N 5.57.
2-Bromomethyl-7,8-dimethoxy-5-oxo-1,2-dihydro-5H-oxazolo[3,2-a]quinoline-4-carboxylic Acid
5-Bromo-2-methoxybenzylamide (4). A solution of Br2 (1.04 ml, 0.02 mol) in acetic acid (5 ml) was added with
vigorous stirring to a solution of 1-allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic
acid 2-methoxybenzylamide (1g) (4.24 g, 0.01 mol) in glacial acetic acid (30 ml) and left for 2 h at room
temperature. The reaction mixture was diluted by adding cold water. The yellowish white precipitate was
filtered off, washed with cold water, and dried. Yield 4.71 g (81%). Recrystallization from DMF gave the
bromomethoxybenzylamide 4 as colorless monoclinic crystals with mp 263-265°C. 1Н NMR spectrum, δ, ppm
(J, Hz): 10.85 (1Н, br. s, NH); 7.78 (1H, s, H-6); 7.51 (1Н, s, Н-6'); 7.41 (1Н, dd, J = 8.8, J = 2.0, Н-4'); 6.98
(1Н, s, Н-9); 6.88 (1Н, d, J = 8.8, Н-3'); 5.61–5.55 (1Н, m, NCH2СНО); 4.64 (1Н, t, J = 9.8, NCH); 4.57 (2Н, t
with poor resolution, J = 4.9, NHCH2); 4.34 (1Н, dd, J = 9.8, J = 6.6, NCH); 4.03-3.97 (2Н, m, CH2Br); 3.95
(3H, s, 8-OCH3); 3.81 (3H, s, 7-OCH3); 3.77 (3H, s, 2'-OCH3). Found, %: C 47.53; H 3.77; N 4.87.
C23H22Br2N2O6. Calculated, %: C 47.45; H 3.81; N 4.81.
X-ray Structural Analysis of Bromomethoxybenzylamide 4. The unit cell parameters of monoclinic
crystals of 5-bromo-2-methoxybenzylamide 4 (DMF) at -173°C are as follows: a 8.990(3), b 14.848(5),
c 17.068(4) Å, β 105.12(2)°, V 2199(1) Å3, M 582.25, Z 4, space group P21/c, dcalc 1.758 g/cm3, μMoKα 3.730
mm-1, F(000) = 1168. The unit cell parameters and intensities of 8049 reflections (3777 independent reflections,
Rint = 0.080) were measured on an Xcalibur-3 diffractometer using MoKα radiation, CCD detector, graphite
monochromator, ω-scanning, 2θmax 50°. Absorption was taken into account using a semiempirical method for
the ψ-scanning results (Tmin = 0.194, Tmax = 0.664).
The structure was solved by a direct method using the SHELXTL software package [17]. In the
structure refinement, limits were placed on the bond lengths in the disordered fragment O−Csp 1.46 Å,
3
C −C 1.54 Å. The positions of the hydrogen atoms were calculated geometrically and refined using the
3
3
sp
sp
"rider" model with Uiso = nUeq for the non-hydrogen atom attached to a given hydrogen atom (n = 1.5 for methyl
groups and n = 1.2 for the other hydrogen atoms). The structure was refined relative to F2 by the full-matrix
least-squares method in anisotropic approximation for the non-hydrogen atoms to wR2 = 0.145 for 3755
reflections (R1 = 0.060 for 2320 reflections with F > 4σ(F), S = 1.018). The complete crystallographic data were
deposited at the Cambridge Crystallographic Data Center (deposit CCDC 2155347).
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