Nucleophilic substitution of the acetoxy group in 3- methylbenzoylaminomethyl acetate

Article abstract of DOI:10.1007/s11172-011-0250-4

Replacement of the acetoxy group in 3-methylbenzoylaminomethyl acetate with N- and S-nucleophiles generated from amines and thio compounds using sodium hydride gives the corresponding N-aminomethyl- and N-thiomethylbenzamides.

Full text of DOI:10.1007/s11172-011-0250-4

Russian Chemical Bulletin, International Edition, Vol. 60, No. 8, pp. 1672—1676, August, 2011
1672
Nucleophilic substitution of the acetoxy group
in 3ꢀmethylbenzoylaminomethyl acetate
L. Labanauskas,a R. Mazeikaite,a R. Striela,a O. Gedrimaite,a G. Urbelis,b and A. Zilinskasb
aCenter of Physical and Technological Sciences,
9 ul. A. Goshtauto, LTꢀ01108 Vilnius, Lithuania.
Eꢀmail: labanauskas.linas@gmail.com
bVilnius University,
24 ul. Naugarduko, LTꢀ03225 Vilnius, Lithuania
Replacement of the acetoxy group in 3ꢀmethylbenzoylaminomethyl acetate with Nꢀ and
Sꢀnucleophiles generated from amines and thio compounds using sodium hydride gives the
corresponding Nꢀaminomethylꢀ and Nꢀthiomethylbenzamides.
Key words: nucleophilic substitution of acetoxy group, sodium hydride, Nꢀaminoꢀ
methylbenzamides, Nꢀthiomethylbenzamides, aminals, thioaminals, sulfides.
Scheme 1
Compounds having a benzoylaminomethyl fragment
in their structure are known as selective dopamine D4
receptor agonists1,2 and are practically used in medicine.3—5
We needed to synthesize Nꢀ{[4ꢀ(2ꢀcyanophenyl)piperazinꢀ
1ꢀyl]methyl}ꢀ3ꢀmethylbenzamide known as the PD168077
product (see Ref. 2), which is one of the representatives of
this class of compounds. This compound is commonly
obtained starting from derivatives of benzoylaminomethyl
acetate,1 (benzoylaminomethyl)triethylammonium chlorꢀ
ide,6—9 Nꢀ(benzoylaminomethyl)benzamide, or di(benzoꢀ
ylamino)methane,10—13 as well as by aminomethylation
of benzamide with the imidazole—formaldehyde system.14
In the present work, 3ꢀmethylbenzoylaminomethyl
acetate (1) was chosen as the starting compound, since it is
easily synthesized by acylation of glycine with 3ꢀmethylꢀ
benzoyl chloride with subsequent oxidative decarboxylaꢀ
tion of the intermediate Nꢀ(3ꢀmethylbenzoyl)aminoacetic
acid with lead tetraacetate.
On attempted reproduction of the described proceꢀ
dure1 for the synthesis of PD168077 by the reaction of
acetate 1 with 2ꢀ(1ꢀpiperazinyl)benzonitrile in the presꢀ
ence of triethylamine as a base, 2ꢀ(4ꢀacetylꢀ1ꢀpiperꢀ
azinyl)benzonitrile (the product of aminolysis of the ester
group) was obtained instead of the expected compound,
i.e., the product of nucleophilic substitution for the acetꢀ
oxy group (Scheme 1).
It is possible that other authors also met such a probꢀ
lem. In particular, in the work4 a substrate with more
nucleofuge triethylammonium group was used, in
the work15 sodium hydroxide was applied as a stronger
base, whereas low basic amines were preliminary conꢀ
verted to the lithium derivatives upon treatment with
butyllithium.
In the present work, we showed that for providing such
a deprotonation of an amine, it was reasonable to use
sodium hydride. The yield of the PD168077 product was
80%, its purity was of 98%. To sum up, it was of interest to
determine the scope where such transformations can be
used and synthesize a number of the PD168077 analogs
for further testing of their biological activity.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1646—1650, August, 2011.
1066ꢀ5285/11/6008ꢀ1672 © 2011 Springer Science+Business Media, Inc.

Nꢀ(Aminomethyl)benzamides
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 8, August, 2011
1673
Table 1. Reactions of aminomethyl acetate 1 with amines 2a—e
and allyl thioglycolate 2f
Results and Discussion
We studied a possibility of amino or mercapto groups
to substitute of the acetoxy group in the aminoacetal fragꢀ
ment of compound 1, using sodium hydride for deprotoꢀ
nation of the corresponding amines and thiols (Scheme 2,
Table 1). The structures of the Nꢀ and Sꢀnucleophiles
were selected so that the products that obtained either
could have served as the blocks for further synthesis or
themselves were of interest as potential biologically active
compounds (a probability to display biological activity was
verified using the PASS program16). The data on the preꢀ
dicted and measured activity for the synthesized comꢀ
pounds will be published separately.
YH
Solvent
T/°C
t/h
Product Yield (%)
2a
2b
2c
2d
2e
2f
THF
CH2Cl2
THF
CH2Cl2
CH2Cl2
CH2Cl2
20
20
20
20
Reflux
20
0.5
1
1
2
12
0.5
3a
3b
3c
3d
3e
3f
30
68
42
22
55
89
Note. T is the reaction temperature, t is the reaction time.
under similar conditions did not give the desired product
and the symmetric aminal 4 was only obtained. The same
product 4 was formed in the reaction of compound 1 with
imidazole. In the case of 4ꢀmethylpyrazole, the yield of
the target compound 3d was only 22%. The reaction with
indole led to a complex multicomponent mixture, that is
apparently due to the high reactivity of positions 2 and 3 of
the indole system.
Scheme 2
We supposed to use benzamide 3c for its further transꢀ
formation to monosubstituted piperazine 5, which is
a convenient building block for the synthesis of various
benzamidomethylpiperazines. Unfortunately, even careꢀ
ful attempts of acidic removal of the tertꢀbutoxycarbonyl
group in compound 3c with trifluoroacetic acid or HCl
(cat.) in methanol at room temperature led to its decomꢀ
position and formation of symmetric aminal 4 with trace
impurities of 3ꢀmethylbenzamide. It can be suggested that
this is due to the instability of the aminal fragment of
compound 3c toward acids, which is susceptible to transꢀ
azaacetalization. We also detected slow decomposition of
the starting aminoacetal 1 to aminal 4 and 3ꢀmethylbenzꢀ
amide on standing even at –20 °C.
Aliphatic amines 2a—c reacted with aminomethyl
acetate 1 to give the corresponding products 3a—c in
30—68% yields. When 2ꢀmorpholinoethylamine was used,
the product of disubstitution 3a´ was obtained in 38%
yield together with the target compound 3a.
The synthesis of isomeric anilines 2e,g from methyl
2ꢀmethylꢀ3,5ꢀdinitrobenzoate (6) should be considered
separately (Scheme 3). We succeeded in finding such reꢀ
action conditions, under which anilines 2e or 2g were the
dominating products. For instance, in the case of catalytic
(Pd/C) reduction with formic acid, the ratio of isomers 2e
and 2g was 4 : 1. When metallic iron in acetic acid was
The reaction with less nucleophilic aniline 2e reached
completion only on refluxing the reaction mixture for 12 h.
Its more sterically hindered isomer 2g (see Scheme 3)

1674
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 8, August, 2011
Labanauskas et al.
used as a reducing agent, this ratio was 1 : 4. The synthesis
of isomer 2e has been described earlier,17 however, atꢀ
tempted reproduction of this procedure led to a mixture of
the starting compound 6 and five other difficult to isolate
components.
rivatives. The results obtained can be used in medicinal
chemistry and screening programs.
Experimental
Reaction progress was monitored by thinꢀlayer chromatogꢀ
raphy on Merck Silica gel 60 F254 plates. Preparative chromaꢀ
tography was performed on columns with silica gel Fluka Silica
Gel 60 (0.04—0.063 mm). Melting points were determined on a
Gallenkamp apparatus and were not corrected. 1H and 13C NMR
spectra were recorded on a Varian Unity Inova spectromeꢀ
ter (300 and 75 MHz, respectively) in DMSOꢀd6 or CDCl3.
IR spectra were recorded on a Perkin—Elmer BX FTꢀIR specꢀ
trometer in KBr pellets. Mass spectra were recorded on a Microꢀ
mass UK Quattro Ultima Pt instrument.
Scheme 3
Synthesis of compounds 3a—f (general procedure). 3ꢀMethylꢀ
benzoylaminomethyl acetate (1) (1 g, 4.8 mmol) and the correꢀ
sponding reactant 2 (4.8 mmol) were dissolved in dichloroꢀ
methane or THF (10 mL) (see Table 1), followed by addition of
sodium hydride (9.6 mmol, 0.23 g of 60% dispersion in mineral
oil), the mixture was stirred for 0.5—12 h at a given temperature,
monitoring the reaction course by TLC. After the full conversion
of the starting compound 1 was reached, the reaction mixture was
poured into water (200 mL) and extracted with dichloromethane
(100 mL). The organic layer was dried with anhydrous sodium
sulfate, concentrated in vacuo, and treated as indicated further.
Nꢀ{[4ꢀ(2ꢀCyanophenyl)piperazinꢀ1ꢀyl]methyl}ꢀ3ꢀmethylbenzꢀ
amide (PD168077). The oil that obtained was dissolved in hot
propanꢀ2ꢀol (4 mL) and mixed with a solution of maleic acid
(1 g) in hot propanꢀ2ꢀol (6 mL), then cooled, and filtered to
obtain white crystalline compound (3.64 g, 80%) 98% in purity.
1H NMR is identical to that described earlier.1
4ꢀ{2ꢀ[(3ꢀMethylbenzoylaminomethyl)amino]ethyl}morphoꢀ
line (3a) and 4ꢀ{2ꢀ[N,Nꢀbis(3ꢀmethylbenzoylaminomethyl)amino]ꢀ
ethyl}morpholine (3a´) were separated by chromatography (eluent
dichloromethane—methanol (3 : 2)), Rf 0.35 and 0.50, respecꢀ
tively. Compound 3a. The yield was 0.20 g (30%), oil. 1H NMR
(CDCl3), δ: 2.24 (m, 7 H, ArCH3, N(CH2)2); 2.33 (t, 2 H,
CH2N(CH2)2, J = 6.0 Hz); 2.67 (t, 2 H, CH2CH2N(CH2)2,
J = 6.0 Hz); 3.54 (m, 4 H, O(CH2)2); 4.25 (d, 2 H, CONHCH2,
J = 6.0 Hz); 7.17 (m, 2 H, HAr); 7.50 (m, 3 H, NH, HAr).
13C NMR (CDCl3), δ: 21.6, 42.8, 53.8, 55.6, 58.7, 67.0, 124.2,
128.0, 128.6, 132.5, 134.5, 138.5, 168.6. IR, ν/cm–1: 1643 (CO);
The mercapto group in allyl thioglycolate has proved
reactive enough under such conditions, and the yield of
sulfide 3f was 89% (see Scheme 2). In the case of thio
compounds 2h,i of more complicated structure and disꢀ
posed to thioamideꢀiminothiol tautomerism, both reacꢀ
tion centers of the ambident nucleophile reacted with acetꢀ
oxymethylbenzamide 1 (Scheme 4). In the case of 2,4ꢀdiꢀ
hydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (2h), a disubstituted
product 3h was isolated in 19% yield. The reaction with
1,3ꢀdihydroꢀ2Hꢀbenzimidazoleꢀ2ꢀthione (2i) led to a mixꢀ
ture, from which 3ꢀmethylbenzamide, aminal 4, and
unreacted acetoxymethylbenzamide 1 were only isolated
by preparative chromatography. Analysis of other prodꢀ
ucts were performed by LCꢀMS, which indicated the presꢀ
ence of ions with m/z 445 [M + H]+ and 298 [M –
– CH3C6H4CONHCH2 + H]+. The latter can be assigned
to the target product with the structure suggested as 3i. In
all the cases studied, substitution for the acetoxy group did
not occur without addition of NaH.
In conclusion, the studies performed showed that the
acetoxy group in the aminoacetyl fragment of 3ꢀmethylꢀ
benzoylaminomethyl acetate can be substituted for by the
SN2 mechanism when strong enough Nꢀ and Sꢀnucleoꢀ
philes are used, namely, the amine and thiol sodium deꢀ
Scheme 4

Nꢀ(Aminomethyl)benzamides
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 8, August, 2011
1675
3313 (NH). Found (%): C, 65.11; H, 8.21; N, 15.39. C15H23N3O2.
Calculated (%): C, 64.95; H, 8.36; N, 15.15. Compound 3a´.
The yield was 0.31 g (38%), oil. 1H NMR (CDCl3), δ: 2.34 (s, 6 H,
2 ArCH3); 2.50 (t, 4 H, N(CH2)2, J = 4.2 Hz); 2.61 (t, 2 H,
(CH2NH)2NCH2, J = 5.1 Hz); 2.92 (t, 2 H, (CH2NH)2NCH2CH2,
J = 5.4 Hz); 3.70 (t, 4 H, O(CH2)2, J = 4.5 Hz); 4.50 (d, 4 H,
2 CONHCH2, J = 6.6 Hz); 7.28—7.34 (m, 4 H, HAr); 7.58—7.61
(m, 4 H, HAr); 7.93 (t, 2 H, 2 NHCH2, J = 6.3 Hz). 13C NMR
(CDCl3), δ: 21.5, 45.9, 54.2, 57.4, 57.5, 67.0, 124.5, 128.1, 128.7,
132.8, 134.2, 138.6, 169.1. IR, ν/cm–1: 1644; 1645 (CO); 3334
(NH). Found (%): C, 68.18; H, 7.84; N, 12.97. C24H32N4O3.
Calculated (%): C, 67.90; H, 7.60; N, 13.20.
3ꢀMethylꢀNꢀ(morpholinꢀ4ꢀylmethyl)benzamide (3b) was isoꢀ
lated by chromatography (eluent dichloromethane—ethyl aceꢀ
tate (1 : 1)), Rf 0.1. The yield was 0.76 g (68%), oil. 1H NMR
(CDCl3), δ: 2.41 (s, 3 H, ArCH3); 2.65 (t, 4 H, N(CH2)2,
J = 4.5 Hz); 3.73 (t, 4 H, O(CH2)2, J = 4.5 Hz); 4.30 (d, 2 H,
NHCH2, J = 6.3 Hz); 6.70 (m, 1 H, NHCH2); 7.33—7.35
(m, 2 H, HAr); 7.57—7.63 (m, 2 H, HAr). 13C NMR (CDCl3), δ:
21.6, 50.7, 62.1, 67.0, 124.2, 128.0, 128.8, 132.8, 134.3, 138.8,
168.5. IR, ν/cm–1: 1667 (CO); 3386 (NH). Found (%): C, 66.74;
H, 7.63; N, 12.22. C13H18N2O2. Calculated (%): C, 66.64;
H, 7.74; N, 11.96.
(CDCl3), δ: 2.39 (s, 3 H, ArCH3); 3.45 (s, 2 H, SCH2CO);
4.59—4.61 (m, 2 H, COOCH2); 4.70 (d, 2 H, NHCH2, J = 6.3 Hz);
5.19—5.34 (m, 2 H, OCH2CHCH2); 5.80—5.93 (m, 1 H,
OCH2CH); 7.28—7.64 (m, 5 H, HAr, NH). 13C NMR (CDCl3),
δ: 20.9, 33.8, 42.9, 65.9, 118.6, 123.5, 127.4, 128.0, 128.1, 130.9,
132.1, 138.0, 166.8, 170.8. IR, ν/cm–1: 1646, 1733 (CO); 3322
(NH). Found (%): C, 60.56; H, 6.44; N, 4.83. C14H17NO3S.
Calculated (%): C, 60.19; H, 6.13; N, 5.01.
1ꢀ(3ꢀMethylbenzoylaminomethyl)ꢀ5ꢀ[(3ꢀmethylbenzoylaminoꢀ
methyl)sulfanyl]ꢀ1Hꢀ1,2,4ꢀtriazole (3h). The reaction was carꢀ
ried out by reflux in dichloromethane for 7 h. The product was
isolated by chromatography (eluent dichloromethane—ethyl
acetate (1 : 2)), Rf 0.2. The yield was 0.18 g (19%), oil. 1H NMR
(CDCl3), δ: 2.30, 2.31 (both s, 6 H, 2 ArCH3); 5.01 (d, 2 H,
NHCH2S, J = 6.6 Hz); 5.65 (d, 2 H, NHCH2N, J = 6.6 Hz);
7.19—7.30 (m, 4 H, HAr); 7.48—7.61 (m, 4 H, HAr); 7.92 (t, 1 H,
NHCH2S, J = 6.6 Hz); 8.25 (t, 1 H, NHCH2N, J = 6.6 Hz);
8.42 (s, 1 H, CH triazole). IR, ν/cm–1: 1654 (CO); 3346, 3407
(NH). Found (%): C, 61.02; H, 5.61; N, 17.52. C20H21N5O2S.
Calculated (%): C, 60.74; H, 5.35; N, 17.71.
Methyl 5ꢀaminoꢀ2ꢀmethylꢀ3ꢀnitrobenzoate (2e). A solution
of 85% aqueous formic acid (36 mL, 1.12 mol) in acetonitrile
(80 mL) was slowly added to a cooled with ice solution of triethylꢀ
amine (80 mL, 0.57 mol) in acetonitrile (80 mL). The solution
that formed was cooled to 0—5 °C, followed by addition of
methyl 2ꢀmethylꢀ3,5ꢀdinitrobenzoate (6) (40 g, 0.17 mol) and 10%
Pd/C (1.2 g). The reaction mixture was stirred for 12 h with
cooling in an ice bath and additionally for 3 days at room temꢀ
perature, then it was filtered and concentrated in vacuo. The
residue was dissolved in dichloromethane, washed with water
and saturated aq. sodium carbonate, dried with anhydrous sodiꢀ
um sulfate, and concentrated in vacuo. The residue was twice
recrystallized from toluene. The yield was 14.3 g (41%), m.p.
135—137 °C (agrees with the data in Ref. 17), Rf 0.3 (dichloroꢀ
methane—ethyl acetate (10 : 1)).
Methyl 3ꢀaminoꢀ2ꢀmethylꢀ5ꢀnitrobenzoate (2g). Methyl
2ꢀmethylꢀ3,5ꢀdinitrobenzoate (6) (0.5 g, 2.1 mol) and iron powꢀ
der (0.5 g, 8.9 mol) were added to the boiling acetic acid. After
the exothermic reaction began, the heating was removed. After
dinitro compound 6 was completely consumed, the reaction mixꢀ
ture was poured on ice and filtered. A precipitate was dissolved
in dichloromethane, washed with water and saturated aq. sodiꢀ
um carbonate, dried with anhydrous sodium sulfate, and conꢀ
centrated in vacuo. The residue was recrystallized from methaꢀ
nol. The yield was 0.22 g (50%), m.p. 145—147 °C, Rf 0.65
(dichloromethane—ethyl acetate (19 : 1)). 1H NMR (CDCl3), δ:
2.41 (s, 3 H, ArCH3); 3.91 (s, 3 H, OCH3); 4.11 (s, 2 H, NH2);
7.61 (m, 1 H, HAr); 8.04 (m, 1 H, HAr). 13C NMR (CDCl3), δ:
14.6, 52.8, 111.3, 115.0, 130.4, 132.36, 146.4, 147.0, 167.4. IR,
ν/cm–1: 1717 (CO); 3391, 3476 (NH2). Found (%): C, 51.58;
H, 4.92; N, 13.18. C9H10N2O4. Calculated (%): C, 51.43;
H, 4.80; N, 13.33.
1ꢀtertꢀButoxycarbonylꢀ4ꢀ[(3ꢀmethylbenzoylamino)methyl]ꢀ
piperazine (3c) was isolated by chromatography (eluent dichloroꢀ
methane—ethyl acetate (1 : 1)), Rf 0.15. The yield was 0.66 g
(42%), crystalline compound, m.p. 123—125 °C. 1H NMR
(CDCl3), δ: 1.48 (s, 9 H, C(CH3)3); 2.44 (s, 3 H, ArCH3); 2.61
(t, 4 H, N(CH2)2, J = 10.2 Hz); 3.48 (t, 4 H, CON(CH2)2,
J = 9.9 Hz); 4.36 (d, 2 H, NHCH2, J = 6.3 Hz); 6.54 (m, 1 H,
NHCH2); 7.35—7.37 (m, 2 H, HAr); 7.59—7.64 (m, 2 H, HAr).
13C NMR (CDCl3), δ: 21.6, 28.6, 43.3, 51.1, 61.8, 80.0, 124.3,
128.1, 128.7, 132.7, 134.3, 138.6, 154.9, 168.7. IR, ν/cm–1: 1673
(CO); 3386 (NH). Found (%): C, 65.08; H, 8.52; N, 12.31.
C18H27N3O3. Calculated (%): C, 64.84; H, 8.16; N, 12.60.
3ꢀMethylꢀNꢀ[(4ꢀmethylꢀ1Hꢀpyrazolꢀ1ꢀyl)methyl]benzamide
(3d) was isolated by crystallization from hexane. The yield was
0.25 g (22%), m.p. 121—123 °C, Rf 0.5 (dichloromethane—ethyl
1
acetate (1 : 1)). H NMR (CDCl3), δ: 2.07 (s, 3 H, CH3); 2.33
(s, 3 H, ArCH3); 5.67 (d, 2 H, NHCH2, J = 6.3 Hz); 7.27—7.64
(m, 6 H, CH); 8.71 (m, 1 H, NH). 13C NMR (CDCl3), δ: 9.1,
21.5, 55.2, 117.0, 124.6, 128.3, 128.6, 130.2, 133.0, 133.4, 138.4,
140.6, 168.4. IR, ν/cm–1: 1662 (CO); 3256 (NH). Found (%):
C, 68.21; H, 6.82; N, 18.34. C13H15N3O. Calculated (%):
C, 68.10; H, 6.59; N, 18.33.
Methyl 2ꢀmethylꢀ5ꢀ[(3ꢀmethylbenzoylaminomethyl)amino]ꢀ
3ꢀnitrobenzoate (3e). The reaction was carried out by reflux in
dichloromethane for 12 h. The product was isolated by chromaꢀ
tography (eluent dichloromethane—ethyl acetate (19 : 1)),
Rf 0.25. The yield was 0.48 g (55%), crystalline compound, m.p.
1
105—107 °C. H NMR (CDCl3), δ: 2.36 (s, 3 H, ArCH3); 2.45
(s, 3 H, ArCH3); 3.91 (s, 3 H, OCH3); 4.90—4.94 (m, 2 H,
NHCH2); 5.26 (m, 1 H, ArNH); 7.26—7.35 (m, 5 H, HAr);
7.52—7.58 (m, 2 H, CONH, HAr). 13C NMR (CDCl3), δ: 15.6,
21.5, 49.8, 52.8, 110.8, 119.4, 121.8, 124.3, 128.0, 128.8, 133.0,
133.7, 134.3, 138.8, 144.5, 152.8, 167.5, 169.1. IR, ν/cm–1: 1642,
1726 (CO); 3365 (NH). Found (%): C, 60.31; H, 5.57; N, 12.02.
C18H19N3O5. Calculated (%): C, 60.56; H, 5.36; N, 11.76.
Allyl 2ꢀ[(3ꢀmethylbenzoylaminomethyl)sulfanyl]acetate (3f)
was isolated by chromatography (eluent dichloromethane—ethyl
acetate (1 : 1)), Rf 0.88. The yield was 1.34 g (89%), oil. 1H NMR
This work was financially supported by the State Fund
for Science and Studies of Lithuania (Grant Tꢀ82/09).
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Received July 21, 2010;
in revised form July 7, 2011