Synthesis of potentially bioactive PABA-related N-(aminoalkyl)lactamic amino acids and esters via selective SNAr reactions

Article abstract of DOI:10.1007/s00726-010-0634-z

Potentially bioactive N-(aminoalkyl)lactamic amino acids and esters were synthesized in satisfactory to good yields by S_NAr reactions of aromatic acids with N-(3-aminopropyl)lactams followed by esterification with tertiary amino alcohols. The addition-elimination S_NAr mechanism was confirmed by NMR and MS measurements. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00726-010-0634-z

Amino Acids (2011) 40:197–204
DOI 10.1007/s00726-010-0634-z
ORIGINAL ARTICLE
Synthesis of potentially bioactive PABA-related
N-(aminoalkyl)lactamic amino acids and esters via selective SNAr
reactions
•
Renato S. Gonc¸alves Patrıcia V. Abdelnur Vanessa G. Santos
•
•
´
•
•
•
´
Rosineide C. Simas Marcos N. Eberlin Alvicler Magalha˜es
´
´
Eduardo R. Perez Gonzalez
Received: 7 March 2010 / Accepted: 15 May 2010 / Published online: 30 May 2010
Ó Springer-Verlag 2010
Abstract Potentially bioactive N-(aminoalkyl)lactamic
amino acids and esters were synthesized in satisfactory to
good yields by SNAr reactions of aromatic acids with N-(3-
aminopropyl)lactams followed by esterification with tertiary
amino alcohols. The addition–elimination SNAr mechanism
was confirmed by NMR and MS measurements.
Furuya et al. 1995; Saavedra et al. 2006). Some of such
derivatives are used as acetylcholinesterase inhibitors in
palliative treatment of the Alzheimer’s disease (Correa-
Basurto et al. 2005). PABA analogs such as procaine and
lidocaine are anesthetics which interact with sodium chan-
nels reducing their sensibility, motion and autonomic func-
¨
¨
tion (Lofstrom 1960; Pateromichelakis 2008; Heath et al.
1984). PABA itself is a water soluble non-poisonous drug
and is easily absorbed by intestinal treatment. It has also
been used against typhus and other rickettsial diseases (Little
2002) and as a common ingredient in sunscreen agents
(Bruze et al. 1990; Gennaro 1991). PABA has also shown
antioxidant properties and is also a component of the vitamin
B-complex (John et al. 1995; Vo-Dinh et al. 2005).
Keywords PABA derivatives ꢀ Lactams ꢀ
Potential bio-activity ꢀ SNAr reaction
Introduction
Derivatives of p-aminobenzoic acid (PABA) have shown
interesting pharmacological properties (Kabbani et al. 2007;
On the other hand, molecules containing N-(3-aminopro-
pyl)-2-azepanone (APA) or N-(3-aminopropyl)-2-pyrroli-
done (APP) moieties have been reported as inhibitors of the
human tryptase, an important mediator in the asthma pathol-
ogy(Zhaoetal. 2004), whereasAPP derivativeswerefoundto
be active against H2N2 and H3N2 strains of the influenza
virus (Stamatiou et al. 2001). APP derivatives have also been
reported as HIV-1 protease inhibitors (Ghosh et al. 2009).
Herein we describe the results of synthesis of several
PABA derivatives 5–6 and analogs 7–8 by a selec-
tive nucleophilic aromatic substitution reaction (SNAr)
(Gierczyk et al. 2003; Terrier 1991; Bunnett and Zahler
1951; Buncel et al. 1995) of 4-chloro-3-nitrobenzoic acid
(1) and 4-chloro-3-nitrobenzenesulfonic acid (2) with
APA (3) and APP (4) amino-lactams.
Electronic supplementary material The online version of this
article (doi:10.1007/s00726-010-0634-z) contains supplementary
material, which is available to authorized users.
R. S. Gonc¸alves
´
ˆ
Programa de Pos-Graduac¸a˜o em Ciencia e Tecnologia
de Materiais (POSMAT), Universidade Estadual Paulista,
Sa˜o Paulo, Brazil
´
´
R. S. Gonc¸alves ꢀ E. R. Perez Gonzalez (&)
´
´
ˆ
´
Laboratorio de Quımica Organica Fina, Departamento de Fısica,
´
ˆ
Quımica e Biologia, Faculdade de Ciencias e Tecnologia,
Universidade Estadual Paulista, Campus de Presidente Prudente,
C.P. 467, Presidente Prudente, SP 19060-900, Brazil
e-mail: eperez@fct.unesp.br
P. V. Abdelnur ꢀ V. G. Santos ꢀ R. C. Simas ꢀ
M. N. Eberlin
We have also note that PABA derivatives (5 and 6) can
be easily transformed via Fischer’s esterification to
potentially bioactive procaine-like compounds (Paramus
and Rutherford 1972; Waukegan 1960). Hence this reac-
tion with the aminoalcohols 3-(dimethylamino)propan-1-ol
(9) and 3-(diethylamino)propan-1-ol (10) afforded the
´
Laboratorio ThoMSon de Espectrometria de Massas,
Instituto de Quımica, Universidade de Campinas UNICAMP,
Campinas, SP, Brazil
´
A. Magalha˜es
Departamento de Quımica Inorganica, Instituto de Quımica,
´
Universidade de Campinas UNICAMP, Campinas, SP, Brazil
ˆ
´
123

198
R. S. Gonc¸alves et al.
corresponding PABA-related N-(3-aminoalkyl)lactamic
aminoesters (11–14) in good yields. This simple and rela-
tively facile and efficient synthesis may lead to a great
variety of such procaine-like compounds with potential
toxicological and pharmacological properties. Biological
activity of amino acids (5–8) and aminoesters (11–14) is
under current investigation and the results will be oppor-
tunely communicated.
following basic operation conditions: capillary and cone
voltages were set to 3,500 and 45 V, respectively, with a
desolvation temperature of 100°C. For the tandem MS
experiments, 15–20 eV collisions with argon were used.
FTIR measurements were conducted in a spectrometer
Bruker, model Vector 22, and the spectra were collected at
room temperature (23°C) with 124 scans, 4 cm-1 spectral
resolution in the form of KBr pellets. All melting points (mp)
were obtained using a Quimis Q-340 M apparatus. Micro-
wave synthesis was realized using a CEM Focused Micro-
wave Synthesis System, model Discover. For normal
pressure operations standard glassware (25 mL two-necked
Pirex round-bottomed flask) with a water-cooled reflux
condenser fitted on top of the cavity was used. The micro-
wave power and reaction temperature were set to 70 W and
120°C.
Materials and methods
Commercial DBU, DBN, 4-chloro-3-nitrobenzoic acid,
4-chloro-3-nitrobenzenesulfonic acid, 3-dimethylamino-1-
propanol and 3-diethylamino-1-propanol were used without
previous purification. Thin layer chromatography (TLC)
was performed on Macherey–Nagel silica gel plates and
visualized using iodine reagent. 1H NMR spectra were
obtained on Varian Inova instrument at 500 MHz. 13C NMR
spectra were obtained on Bruker Avance DPX at 250 MHz.
Chemical shifts for 1H NMR and 13C NMR were referenced
General procedure for the synthesis
of N-(3-aminopropyl)-2-azepanone (3)
and N-(3-aminopropyl)-2-pyrrolidone (4)
1
to residual solvent (CDCl3 d = 7.27 ppm for H NMR,
1,5-Diazabicyclo[4.3.0]non-5-ene (1.86 g, 15 mmol) or
1,8-diazabicyclo[5.4.0]undec-7-ene (2.28 g, 15 mmol) and
water (0.27 g, 15 mmol) were mixed in a round flask
coupled to a reflux condenser and the mixture was heated
for 12 h at 85°C. The corresponding amino-lactams were
obtained as a colorless oil after chromatography (CHCl3–
MeOH–conc. NH3, 9:1:1, then CHCl3–MeOH, 4:1) in
agreement with reported procedure (Kraft 1999). The
reaction was monitored by TLC and GC–MS.
d = 77.23 ppm for 13C NMR; DMSO-d6 d = 2.50 ppm for
1H NMR, d = 39.5 ppm for 13C NMR; D2O d = 4.8 ppm
1
for H NMR) were reported in ppm, and were observed at
25°C. TSP4 was used as reference for 13C NMR spectra in
D2O solvent. Data are presented as follows: chemical shift,
multiplicity (s = singlet, d = doublet, dd = doublet of
doublet, t = triplet, qua = quadruplet, qu = quintuplet,
m = multiplet, br s = broad singlet), integration, and cou-
pling constants (in Hertz). GC–MS spectra were obtained
using a Shimadzu QP-2010plus. The column inside the GC
was a capillary column coated with 5% diphenyl–95%
dimethyl polysiloxane. The injection port of the GC was set
at 250°C. The GC column was initially set up at 80°C and
held there for 2 min after run was started. A heating rate of
10°C/min was used to heat the column to 280°C, where the
temperature was held for 5 min. The energy used for elec-
tron ionization (EI) was 70 eV. The carrier gas used for the
GC–MS was helium. MS spectra were also obtained by
direct insertion in the mass spectrometer. ESI(?)-MS
spectra were obtained using a Micromass QTof hybrid
quadrupole time-of-flight mass spectrometer operating at
7,000 mass resolution and 5 ppm mass accuracy. The solu-
tions were infused directly into the ESI source by means of
syringe pump at a flow rate of 10 lL/min (Becke 1993). The
gaseous protonated molecules display rather clean tandem
mass spectra with fragment ions formed upon 15–20 eV
collisions with argon that are fully compatible with their
proposed structures. ESI–MS and ESI–MS/MS were
acquired in a QTof Waters Micromass mass spectrometer
using positive ion mode from 1:1 H2O–MeOH solution with
addition of a few microlitres of formic acid, and using the
General procedure for the synthesis of PABA-related
N-(3-aminoalkyl)lactamic amino acids (5–6)
and analogs (7–8)
To a solution of 4-chloro-3-nitrobenzoic acid (1.6 g,
8 mmol) 1 or 4-chloro-3-nitrobenzenosulfonic acid (1.89 g,
8 mmol) 2 in acetonitrile (30 mL) or DMSO (10 mL) was
added slowly N-(3-aminopropyl)-2-azepanone (1.42 g,
10 mmol) 4 or N-(3-aminopropyl)-2-pyrrolidone (1.7 g,
10 mmol) 3 and the mixture was stirred and heated at 85°C
for 8–12 h. The solvent was removed under vacuum and the
product was treated with dilute HCl (5%) for removal excess
of amino-lactam. The crude product was filtered off and
recrystallized from 1:1 H2O–EtOH. The purity of product
was checked by TLC using a toluene–acetone–ethanol
mixture as an eluent.
General procedure for the synthesis of PABA-related
N-(3-aminoalkyl)lactamic esters (11–14)
Compound 5 (2.45 g, 8 mmol) or 6 (2.68 g, 8 mmol) was
dissolved in a toluene (30 mL) and DMF (5 mL) solution.
123

Synthesis of PABA-related N-(aminoalkyl)lactamic amino acids and esters
199
Catalytic amount of H2SO4 or H3PW12O40 (molar relation
carboxylic acid:catalyst was 10 and 1, respectively) was
added and the resulting mixture was stirred with dropwise
addition of 3-(dimethylamino)propan-1-ol (1.03 g,
10 mmol) or 3-(diethylamino)propan-1-ol (1.31, 10 mmol)
followed by heating at 130°C for 10 h under reflux condi-
tions and using a Dean–Stark water separator. Then the
reaction mixture was washed with dilute solution (5%) of
NaHCO3. The organic layer was filtered off and the residual
organic solvent was removed under vacuum given the cor-
responding esters 11–14 as oily products. The purity was
checked by TLC using 45:45:7:3 toluene–acetone–ethanol–
NH4OH (conc.).
3JHH = 8,3 Hz), 7.87 (d, 1H, 3JHH = 8.3 Hz), 3.55 (t, 2H),
3.47 (t, 2H), 3.37 (m, 2H), 3.25 (m, 2H), 1.90 (qu, 2H),
1.60 (m, 6H) ppm; 13C NMR (250 MHz, D2O) d 174.4,
168.6, 149.6, 139.3, 136.5, 134.5, 131.5, 128.8, 50.8, 40.6,
35.4, 31.1, 28.5, 26.0, 21.8, 17,7 ppm; FTIR (KBr) m 3,220,
1,605, 1,680 cm-1; ESI(?)-MS m/z found: 336.201, m/z
calculated for [C16H22N3O5 ? H]?: 336.156, fragment
ions were also observed: [M ? H–H2O]? of m/z 318,
[M ? H–H2O–C2H4]? of m/z 290 and [M ? H–
C7H6N2O4]? of m/z 154 (7-member ring).
Synthesis of 4-[N-(30-aminopropyl)-2-pyrrolidone]-3-
nitrobenzenesulfonic acid (7)
General procedure for study of selectivity
on esterification of aminoalcohols with benzoic acid 1
(compounds 15–17)
The 4-chloro-3-nitrobenzenesulfonic acid (2) and N-(3-
aminopropyl)-2-pyrrolidone (3) were reacted according to
the general procedure yielding a brown solid (1.7 g, 82%):
1
mp [310°C; H NMR (500 MHz, D2O) d 8.25 (d, 1H,
The procedure was the same as used for 11–14. After
washing with dilute NaHCO3 the organic layer is filtered
off and the solvent was removed under vacuum given a
yellow solid from starting aminoalcohols 9 and 10. The
crude products (compounds 15–17) were recrystallized
from 1:1 ethylether–petroleum ether (bp 60–80°C) and
analyzed by GC–MS.
4JHH = 2.1 Hz), 7.76 (dd, 1H, 4JHH = 2.1, 3JHH = 8.3 Hz),
6.92 (d, 1H, 3JHH = 8.3 Hz), 3.55 (t, 2H), 3.31 (m, 2H), 2.87
(t, 2H), 2.72 (t, 2H), 2.30 (m, 2H), 1.91 (m, 2H) ppm; 13C
NMR (250 MHz, DMSO-d6) d 178.6, 146.5, 142.6, 132.9,
130.5, 124.5, 123.2, 53.3, 47.9, 42.0, 39.3, 29.8, 18.1 ppm;
FTIR (KBr) m 3,570, 1,653, 1,269 cm-1; ESI(?)-MS m/z
found: 344.099, m/z calculated for [C13H17N3O6S ? H]?:
344.092, fragment ions were also observed: [M ? H–H2O]?
of m/z 326, [M ? H–C2H4]? of m/z 298 and [M ? H–
C6H6N2O5S]? of m/z 126 (5-member ring).
Synthesis of 4-[N-(30-aminopropyl)-2-pyrrolidone]-3-
nitrobenzoic acid (5)
The 4-chloro-3-nitrobenzoic acid (1) and N-(3-aminopro-
pyl)-2-pyrrolidone (3) were reacted according to the general
procedure yielding a yellow solid (2.18 g, 89%): mp = 219–
224°C; 1H NMR (500 MHz, CDCl3) d 8.53 (d, 1H,
4JHH = 1.9 Hz), 8.22 (dd, 1H, 4JHH = 1.9, 3JHH = 8.2 Hz),
7.53 (d, 1H, 3JHH = 8.2 Hz), 5.28 (s, 1H), 3.62 (t, 2H), 3.51
(t, 2H), 3.40 (t, 2H), 3.13 (t, 2H), 2.16 (qu, 2H), 2.04 (qu, 2H)
ppm; 13C NMR (250 MHz, D2O) d 170.6, 164.5, 146.5,
136.6, 133.7, 131.6, 128.3, 125.8, 41.9, 37.7, 31.1,
Synthesis of 4-[N-(30-aminopropyl)-2-azepanone]-3-
nitrobenzenesulfonic acid (8)
The 4-chloro-3-nitrobenzenesulfonic acid (2) and N-(3-
aminopropyl)-2-azepanone (4) were reacted according to
the general procedure yielding a brown solid (2.55 g,
86%): mp[310°C; 1H NMR (500 MHz, DMSO-d6) d 8.41
4
4
(d, 1H, JHH = 1.9 Hz), 8.12 (dd, 1H, JHH = 1.9,
3JHH = 8,3 Hz), 7.79 (d, 1H, 3JHH = 8,3 Hz), 3.54 (t, 2H),
3.47 (t, 2H), 3.26 (t, 2H), 2.68 (m, 2H), 1.91 (qu, 2H), 1.63
(m, 6H) ppm; 13C NMR (250 MHz, CDCl3) d 170.7, 152.5,
142.1, 139.4, 136.9, 132.5, 131.3, 58.8, 53.3, 43.1, 36.9,
33.7, 31.4, 28.8, 24.4 ppm; FTIR (KBr) m 3,600, 1,703,
1,270 cm-1; ESI(?)-MS m/z found: 372.110, m/z calcu-
lated for [C15H22N3O6S ? H]?: 372.123, fragment ions
were also observed: [M ? H–H2O]? of m/z 354, [M ? H–
C2H4]? of m/z 326 and [M ? H–C6H6N2O5S]? of m/z 154
(7-member ring).
29.7, 17.9 ppm; FTIR (KBr) m 3,214, 1,608, 1,683 cm-1
;
ESI(?)-MS m/z found: 308.141, m/z calculated for
[C14H17N3O5 ? H]?: 308.125, Fragment ions were also
observed: [M ? H–H2O]? of m/z 290, [M ? H–H2O–
C2H4]? of m/z 262 and [M ? H–C7H6N2O4]? of m/z 126
(5-member ring).
Synthesis of 4-[N-(30-aminopropyl)-2-azepanone]-3-
nitrobenzoic acid (6)
The 4-chloro-3-nitrobenzoic acid (1) and N-(3-aminopro-
pyl)-2-azepanone (4) were reacted according to the general
Synthesis of N,N-dimethylaminopropyl-4-[N-(30-
aminopropyl)-2-pyrrolidone]-3-nitrobenzoate (11)
procedure yielding
1
a
yellow solid (1,74 g, 86%):
mp = 157–159°C; HNMR (500 MHz, DMSO-d6) d 8.47
(d, 1H, JHH = 1.9 Hz), 8.16 (dd, 1H, JHH = 1.9,
The 4-[N-(30-aminopropyl)-2-pyrrolidone]-3-nitrobenzoic
4
4
acid (5) and 3-(dimethylamino)propan-1-ol were reacted
123

200
R. S. Gonc¸alves et al.
Synthesis of N,N-diethylaminopropyl-4-[N-(30-
aminopropyl)-2-azepanone]-3-nitrobenzoate (14)
according to the general procedure yielding a yellow oily
(2.03 g, 65%): 1H NMR (500 MHz, CDCl3) d 9.14 (d, 1H,
4JHH = 2.9 Hz), 8.50 (br s, 1H), 8.26 (dd, 1H, 4JHH = 2.9,
3JHH = 9.2 Hz), 6.91 (d, 1H, 3JHH = 9.2 Hz), 4.43 (t, 2H),
3.47-3.38 (m, 8H), 2.84 (t, 6H), 3.16 (m, 2H), 2.43 (m, 2H)
ppm; 13C NMR (250 MHz, CDCl3) d 176.1, 165.0, 148.3,
136.6, 130.5, 129.9, 116.6, 113.8, 61.7, 55.7, 47.7, 43.3,
41.3, 40.6, 31.1, 26.9, 24.6, 18.2 ppm; ESI(?)-MS m/z
found: 393.224, m/z calculated for [C19H28N4O5 ? H]?:
393.213, fragment ions were also observed: [M ? H–
C2H7N]? of m/z 348, [M ? H–C5H13NO]? of m/z 290 and
[M ? H–C12H17N3O4]? of m/z 126 (5-member ring).
The 4-[N-(30-aminopropyl)-2-azepanone]-3-nitrobenzoic
acid (7) and 3-(diethylamino)propan-1-ol were reacted
according to the general procedure yielding a yellow oily
(2.47 g, 69%): 1H NMR (500 MHz, DMSO-d6) d 8.64
4
(t, 1H), 8.58 (d, 1H, JHH = 1.8 Hz), 7.93 (dd, 1H,
3
3
4JHH = 1.8, JHH = 9.1 Hz), 7.1 (d, 1H, JHH = 9.1 Hz),
3.79 (t, 2H, JHH = 5.6 Hz), 3.47–3.29 (m, 10H), 2.99 (m,
4H), 1.46–1.89 (m, 10H), 1.05–1.17 (m, 6H) ppm; 13C
NMR (250 MHz, DMSO-d6) d 175.4, 166.4, 136.4, 130.8,
128.9, 117.7, 114.8, 100, 63.5, 58.6, 48.9, 46.8, 45.1, 36.9,
29.7, 28.7, 27.2, 24.5, 23.4, 9.4 ppm; ESI(?)-MS m/z
found: 449.272, m/z calculated for [C23H36N4O5 ? H]?:
449.276, fragment ions were also observed: [M ? H–
C2H7N]? of m/z 376, [M ? H–C5H11NO]? of m/z 318 and
[M ? H–C7H6 N2O4]? of m/z 154 (7-member ring).
Characterization of intermediate 4-N,N-dimethylamino-
3-nitrobenzoic acid (15) Yellow solid: 1H NMR
(500 MHz, CDCl3) d 8.51 (d, 1H); 8.04 (dd, 1H), 7.0 (d,
1H), 3.01 (s, 6H); DEPT 13C NMR (250 MHz, CDCl3) d
169.7, 49.0, 136.7, 134.1, 130.1, 116.9, 116.5, 42.1 ppm;
ESI(?)-MS m/z found: 211.068, m/z calculated for
[C14H21N3O4 ? H]?: 211.071, fragment ions were also
observed: [M ? H–H2O]? of m/z 193, [M ? H–H2O–
CH3]? of m/z 177, [M ? H–H2O–C2H6]? of m/z 163 and
[M ? H–H2O–C2H6–CO]? of m/z 135.
Synthesis of N,N-diethylaminopropyl-4-[N-(30-
aminopropyl)-2-pyrrolidone]-3-nitrobenzoate (12)
The 4-[N-(30-aminopropyl)-2-pyrrolidone]-3-nitrobenzoic
acid (5) and 3-(diethylamino)propan-1-ol were reacted
according to the general procedure yielding an orange
oily (2.41 g, 72%): 1H NMR (500 MHz, CDCl3) d
4
8.83 (d, 1H, JHH = 2.4 Hz), 8.20 (t, 1H), 8.03 (dd,
=
4
1H, JHH = 2.4, JHH = 8.7 Hz), 6.86 (d, 1H, JHH
3
3
8.7 Hz), 4.37 (t, 2H), 3.47-3.37 (m, 8H), 2.89 (m, 4H),
2.41 (t, 2H), 2.16 (qu, 2H), 2.06 (qu, 2H), 1,94 (qu, 2H),
1.25 (t, 6H) ppm; 13C NMR (250 MHz, CDCl3) d 175.8,
165.1, 147.8, 136.5, 131.6, 129.8, 117.1, 113.7, 62.8,
49.1, 47.6, 46.8, 41.0, 40.5, 31.0, 26.9, 18.1, 10.1 ppm;
ESI(?)-MS m/z found: 421.239, m/z calculated for
[C21H33N4O5 ? H]?: 421.245, fragment ions were also
observed: [M ? H–C4H11N]? of m/z 348, [M ? H–
C7H17NO]? of m/z 290 and [M ? H–C14H21N3O4]? of
m/z 126 (5-member ring).
Synthesis of N,N-dimethylaminopropyl-40-(N,N-
dimethylamino)-30-nitrobenzoate (16)
The 4-chloro-3-nitrobenzoic acid (1) and 3-(dimethyl-
amino)propan-1-ol were reacted according to the general
procedure yielding an orange oily (1.69 g, 60%): 1H NMR
(500 MHz, CDCl3) d 8.42 (d, 1H), 8.0 (dd, 1H), 6.97 (d,
1H), 4,34 (t, 2H), 2.98 (s, 6H), 2.45 (t, 2H), 2.27 (s, 6H),
1.94 (qu, 2H) ppm; DEPT 13C NMR (250 MHz, CDCl3) d
162.5, 145.8, 134.6, 131.1, 126.5, 115.8, 114.0, 60.7, 53.5,
42.6, 39.5, 24.3 ppm; ESI(?)-FTMS m/z found: 296.160,
m/z calculated for [C14H21N3O4 ? H]?: 296.161, fragment
ions were also observed: [M ? H–C2H6N]? of m/z 251 and
[M ? H–C5H12NO]? of m/z 193.
Synthesis of N,N-dimethylaminopropyl-4-[N-(30-
aminopropyl)-2-azepanone]-3-nitrobenzoate (13)
The 4-[N-(30-aminopropyl)-2-azepanone]-3-nitrobenzoic
acid (6) and 3-(dimethylamino)propan-1-ol were reacted
according to the general procedure yielding an orange oily
(2.01 g, 60%): 1H NMR (500 MHz, DMSO-d6) d 8.64
4
(t, 1H), 8.6 (d, 1H, JHH = 1.9 Hz), 7.95 (dd, 1H,
3
3
4JHH = 1.9, JHH = 9.2 Hz), 7.1 (d, 1H, JHH = 9.2 Hz),
3.44 (t, 2H, JHH = 5.8) Hz 3.35–3.40 (m, 10H), 2.45 (m,
6H), 2.41 (t, 2H), 1.74 (t, 2H), 1.65–1.62 (m, 2H), 1.55–
1.52 (m, 6H) ppm; 13C NMR (250 MHz, DMSO-d6) d
175.7, 166.7, 147.8, 136.7, 131.1, 129.1, 118, 115, 59.2, 56,
49.2, 45.4, 44.1, 41.1, 40.6, 37.1, 29.9, 29, 27.4, 23,7 ppm;
ESI(?)-MS m/z found: 421.278, m/z calculated for
[C21H33N4O5 ? H]?: 421.245, fragment ions were also
observed: [M ? H–C2H7N]? of m/z 376, [M ? H–
C5H11NO]? of m/z 318 and [M ? H–C7H6 N2O4]? of m/z
154 (7-member ring).
Synthesis of 3-diethylaminopropyl-40-(N,N-
dimethylamino)-30-nitrobenzoate (17)
The 4-chloro-3-nitrobenzoic acid (1) and 3-(diethyl-
amino)propan-1-ol were reacted according to the general
1
procedure yielding an orange oily (1.42 g, 55): H NMR
(500 MHz, CDCl3) d 8.43 (d, 1H), 7.99 (dd, 1H), 6.98 (d,
1H), 4.35 (t, 2H), 2.99 (s, 5H), 2.6 (m, 6H), 1,93 (t, 2H);
1.05 (qua, 6H); DEPT 13C NMR (250 MHz, CDCl3)
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Synthesis of PABA-related N-(aminoalkyl)lactamic amino acids and esters
201
d 165.0, 148.4, 137.2, 133.7, 129.1, 118.5, 116.7, 63.5,
49.2, 46.8, 42.1, 26.3, 11.5 ppm; ESI(?)-FTMS m/z found:
324.191, m/z calculated for [C16H25N3O4 ? H]?: 324.192,
fragment ions were also observed: [M ? H–C4H10N]? of
m/z 251 and [M ? H–C7H16NO]? of m/z 193.
we have carried out the synthesis of analogs 7 and 8
(Table 2, entries 5 and 6) using DMSO as solvent.
The synthesis of procaine-like PABA-related aminoest-
ers (11–14) was performed according to Scheme 2 below.
DMF was used as a co-solvent for improvement of
interfacial reaction and for a more efficient bulk heating of
the reaction mixture. Esterification was also performed
using H3PW12O40 (HPW) as catalyst with similar yields of
the esters. Yield (%) of product 12 was 72 and 75% using
H2SO4 and H3PW12O40 as catalysts, respectively. Thus,
sulfuric acid can be replaced by a more eco-friendly HPW
catalyst.
Results and discussion
Synthesis
Hydrolysis of amidines DBU and DBN were performed by
reported methods (Kraft 1999; Shi and Shen 2002). We
have also investigated DBU and DBN hydrolysis under
microwave irradiation with a dramatic improvement of
reaction times (Table 1).
NMR and MS characterization
1
The H NMR spectra of amino acids 5–8 and aminoesters
Some works have reported in situ preparation of the
APA and APP lactams in the presence of chloropentaflu-
orbenzene for one-pot SNAr reaction (Gierczyk et al.
2003). However, we did not have good results using this
procedure for N-arylation of APA and APP with benzoic
and benzenesulfonic acids 1 and 2. Therefore, we have
carried out the SNAr reactions by a two-step procedure with
improved yields (Scheme 1).
11–14 showed the methylenic protons signals bonded to
heteroatoms in the aliphatic chain in the range of 3.13–
4.43 ppm. The chemical shifts of aromatic protons were
1
observed in the range of 7.50–8.53 ppm. The H NMR
coupling constants of aromatic protons 3JHH = 8.2–9.1 Hz
and 4JHH = 1.9–2.1 Hz have been measured supporting the
formation of addition–elimination SNAr products.
The 13C NMR spectra of compounds 5–8 and 11–14 have
shown the signals corresponding to aromatic carbon atoms in
the range of 123.2–152.5 ppm. The chemical shifts for car-
bon atom bonded to chlorine in the starting compounds 1 and
2 are usually observed at about 132.8–134.1 ppm. However,
13C NMR spectra of 5–8 and 11–14 showed chemical shifts
The solvent effect on the SNAr reaction was studied for
synthesis of intermediates 5 and 6 in acetonitrile and
DMSO (Table 2).
Both the higher solvating strength and dielectric con-
stant of DMSO (Jorgensen and Acevedo 2004) seems to
favor reaction by stabilizing the ionic intermediate of an
addition–elimination SNAr reaction (Table 2). Therefore,
Table 2 Solvent effect in the SNAr – formation of PABA derivatives
5–6
Entry
Solvent
Compound
Time (h)
Yielda (%)
1
2
3
4
5
6
a
Acetonitrile
DMSO
5
5
6
6
7
8
12
8
59
89
60
86
82
87
Table 1 Microwave-assisted and classical hydrolysis results for
DBN and DBU
Acetonitrile
DMSO
12
8
Amidine
Microwave-assisted
Classical heating
DBN
DBU
80–89% and 15 min
70–80% and 15 min
85–94% and 12 h
75–82% and 12 h
DMSO
8
DMSO
8
Out put power 70 W, reaction temperature 120°C for both methods
Isolated product
Scheme 1 Synthesis of
PABA-related
N-(3-aminopropyl)lactamic
amino acids
R
R
Acetonitrile or DMSO
85° C, 8-12h
N
NH2
NO2
NH
NO2
n
O
N
O
Cl
n
1. R = COOH
2. R = SO3H
3. n = 1
4. n = 3
5. n = 1, R = COOH
6. n = 3, R = COOH
7. n = 1, R = SO3H
8. n = 3, R = SO3H
123

202
R. S. Gonc¸alves et al.
Scheme 2 Synthesis of
procaine-like derivatives 11–14
R
O
OH
O
O
N R
C
C
Toluene/DMF/H
Dean-Stark
R
N
+
HO
R
130 °C, 10-12h
NO2
NO2
n
N
NH
HN
N
9. R = Me
10. R = Et
n
O
O
5. n = 1
6. n = 3
Yield 60-72%
11. n = 1, R = Me
12. n = 3, R = Me
13. n = 1, R = Et
14. n = 3, R = Et
for this carbon nucleus in the range of 146.5–152.5 ppm
indicating the substitution of chlorine atom for nitrogen
atom of the amino terminal group of the amino-lactams 3 and
4. The observation of typical lactamic carbonyl resonances
(Terrier 1991; Bunnett and Zahler 1951) at 170.0–
174.4 ppm has proved the presence of (aminoalkyl)lactamic
moieties in the structures of 5–8 and 11–14. For 5 and 6,
chemical shifts of carboxylic carbon have been observed at
163.8 and 168.7 ppm, respectively. Finally, 13C NMR
spectra of carboxylic esters 11–14 showed signals in the
range of 164.8–166.8 ppm which were attributed to ester
carbonyl groups.
and 14 the fragment ions of m/z 376 and 318 are formed by
respective loss of C3H9N and C7H15NO.
Reaction selectivity
We have also investigated the direct esterification of 9 and
10 with the benzoic acid 1 and we have been observed that
amination with DMF (Scheme 3) has also occurred leading
to the formation of ester-SNAr adducts 16–17 and the
possible intermediate 15.
Full-scan FTMS spectra of the reaction mixture have
shown [M ? H]? ions of m/z 296 for compound 16 and m/z
324 for compound 17. High-resolution MS data have
shown that the elemental composition of these ions is
C14H22O4N3 and C16H26O4N3, respectively. ESI(?)-
FTMS/MS spectra were also acquired showing the most
abundant ions of m/z 251 and 193 for 16 and 17 corre-
Compounds 5–8 and 11–14 were also characterized by
tandem mass spectrometry using electrospray ionization in
the positive ion mode (ESI(?)-MS/MS). The most favored
structurally diagnostic dissociation channel involves the
neutral loss of the respective aniline R–Ph–NH2 to form the
major fragment ion corresponding to protonated form of
N-allyl(five-member)lactamic ring of m/z 126 for 5, 7, 11
and 13 and seven-member ring of m/z 154 for 6, 8, 12 and
14, respectively. Loss of water (m/z 290, 318, 326 and 354)
followed by C2H2 (m/z 262, 290, 298 and 326) now
involving most likely the lactamic ring is also an important
dissociation channel for the gaseous protonated molecules
of 5–8. In the ESI–MS/MS of procaine-like derivatives 11
and 12, the fragment ions of m/z 348 and 290 are formed by
loss of C5H13N and C5H11NO respectively, whereas for 13
sponding to the neutral loss of the (CH3)2NH (45 g mol-1
)
or (C2H5)2NH (73 g mol-1) leading to the fragment ion of
m/z 251 and neutral loss of the aminoalcohols (CH3)2N-
(CH2)3-OH (103 g mol-1
)
and (C2H5)2N-(CH2)3-OH
(131 g mol-1) leading to the fragment ion of m/z 193.
Reactions illustrated in Scheme 3 above, have been
monitored by GC–MS. The total ion chromatograms show
sharp peaks for 16 and 17 at retention time of 21.0 and
22.0 min, respectively. Moreover, both chromatograms
show the broad peaks corresponding to the same
Scheme 3 Formation ester –
SNAr adducts 16 and 17
R
O
OH
O
OH
O
O
N R
C
C
C
N
Toluene/DMF/H+
Dean-Stark
R
N
HO
R
after 2-4 h
130 °C, overnight
NO2
NO2
CH3
NO2
CH3
9. R = Me
10. R = Et
Cl
N
H3C
H3C
1
16. R = Me
17. R = Et
15
123

Synthesis of PABA-related N-(aminoalkyl)lactamic amino acids and esters
203
Spectrometry Laboratory for FTMS studies and to NMR Laboratory
of the Institute of Chemistry, University of Campinas—UNICAMP
for the NMR measurements.
intermediate product (m/z 210), the 4-(N,N-dimethyl-
amino)-3-nitrobenzoic acid 15. This is in agreement with
amination of benzoic acid 1 with DMF used as co-solvent.
Similar reaction has been reported in a recent work (Tsai
et al. 2008).
The 1H NMR spectra of compounds 15–17 showed
signals of aromatic protons (C2, C6 and C5) in the range of
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