Synthesis of (+/-)-Pregabalin and its novel lipophilic β-alkyl-substituted analogues from fatty chains

Article abstract of DOI:10.1039/d0nj02263b

In this work, were synthesized for the first time a series of new lipophilic β-alkyl substituted GABA derivatives from fatty alkyl chains. The synthesis of these GABA analogues was investigated by two different bicomponent approaches as a key step. The results showed low yields in the path from aliphatic nitroolefins and Meldrum's acid, whereas the Knoevenagel condensation between aliphatic aldehydes and Meldrum's acid afforded fatty alkylidenes in good yields (75-97%). These compounds were subsequently subjected to a conjugate addition reaction with nitromethane, resulting in the fatty Michael adducts (in 87-97% yields) which were in turn submitted to a one pot domino hydrolysis-decarboxylation, leading to the isolation of β-alkyl-substituted γ-nitro acids in good yields (78-92%). Finally, the reduction of the fatty γ-nitro acids allowed for the access to new lipophilic β-alkyl substituted GABA analogues, which were isolated in high yields (90-98%). The new methodology was also applied to the synthesis of antiepileptic drug (+/-)-Pregabalin, which was obtained after four steps in high overall yield. This journal is

Full text of DOI:10.1039/d0nj02263b

View Article Online
View Journal
NJC
New Journal of Chemistry
Accepted Manuscript
A journal for new directions in chemistry
This article can be cited before page numbers have been issued, to do this please use: C. Doca, E. B.
Mass, R. Ongaratto, A. M. Andrade, M. G. Montes D'Oca and D. Russowsky, New J. Chem., 2020, DOI:
10.1039/D0NJ02263B.
Volume 42
This is an Accepted Manuscript, which has been through the
Number
6
21 March 2018
Pages 3963-4776
Royal Society of Chemistry peer review process and has been
accepted for publication.
NJC
New Journal of Chemistry
rsc.li/njc
A journal for new directions in chemistry
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 1144-2546
PAPER
Chechia Hu, Tzu-Jen Lin et al.
Yellowish and blue luminescent graphene oxide quantum dots
prepared via a microwave-assisted hydrothermal route using
H2O2 and KMnO4 as oxidizing agents
rsc.li/njc

Please do not adjust margins
Page 1 of 11
New Journal of Chemistry
1
2
3
4
5
6
7
View Article Online
DOI: 10.1039/D0NJ02263B
ARTICLE
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Synthesis of (+/-)-Pregabalin and its novel lipophilic -alkyl-
substituted analogues from fatty chains
Caroline Da Ros Montes D'Oca,*a,b Eduardo Bustos Mass,b Renata Fontes Ongaratto,c Arthur
Motta de Andrade,c Marcelo G. Montes D'Ocaa,c and Dennis Russowskyb
In this work, were synthesized for the first time a series of new lipophilic -alkyl substituted GABA derivatives from fatty
alkyl chains. The synthesis of these GABA analogues was investigated by two different bicomponent approaches as a key
step. The results showed low yields in the path from aliphatic nitroolefins and Meldrum’s acid, whereas the Knoevenagel
condensation between aliphatic aldehydes and Meldrum’s acid afforded fatty alkylidenes in good yields (75-97%). These
compounds were subsequently subjected to a conjugate addition reaction with nitromethane, resulting in the fatty Michael
adducts (in 87-97% yields) which were in turn submitted to a one pot domino hydrolysis-decarboxylation, leading to the
isolation of -alkyl-substituted -nitro acids in good yields (78-92%). Finally, the reduction of the fatty nitro acids allowed
for the access to new lipophilic -alkyl substituted GABA analogues, which were isolated in high yields (90-98%). The new
methodology was also applied to the synthesis of antiepileptic drug (+/-)-Pregabalin, which was obtained after four steps in
high overall yield.
seizures, the drug presents little effect in preventing or curing
epilepsy completely.11,12 Although anticonvulsant agents have been
introduced in clinical practices, up to one-third of patients have
developed resistance to recommended doses, emphasizing the need
for the development of improved AEDs drugs.13,14
Introduction
The -aminobutyric acid (GABA, 1) is the most important inhibitory
neurotransmitter of Central Nervous System (CNS).1 The
transmission of electrical signals between nervous cells is mediated
by excitation and inhibition processes, regulated by an equilibrating
level of GABAergic system.2 Concentrations below a threshold level
of GABA in the brain have been directly associated with epilepsy and
also with other important psychiatric disorders such as Alzheimer’s,
Parkinson’s and Huntington’s diseases.3 However, the direct
administration of GABA is not considered an effective therapy due to
the high hydrophilicity of GABA (Figure 1) which results in poor
permeability across lipophilic Blood-Brain Barriers (BBB).
One of the principal methods to raise the GABA level in the CNS
is the use of small molecules, also named GABAergic drugs and
prodrugs, able to diffuse through the BBB and inhibit the activity of
GABA-aminotransferase (GABA-AT). These compounds are mainly -
aryl-4 or -alkyl5,6 substituted, and have been the subject of extensive
investigations to produce GABA analogues, described as lipophilic
GABA derivatives, such as Pregabalin (2a),7Phenibut (3),8 Baclofen
(4),9 and Gabapentin (5)10 (Figure 1).
NH2
NH2
NH2
CO2H
CO2H
CO2H
1
GABA (
)
3
)
Phenibut (
2a
Pregabalin (
)
NH2
NH2
Cl
CO2H
CO2H
4
5
)
Baclofen (
)
Gabapentin (
Fig. 1 GABA, -aryl- and -alkyl-substituted GABA analogues.
Pregabalin (2a) was discovered in 1991 by Silverman et al.,15 and
is used to treat epilepsy and neuropathic pain. Pregabalin, marketed
by Pfizer under the name Lyrica®, due to the wide spectrum of
therapeutic activities, represent profits of about US $ 1 billion
annually for the pharmaceutical market.
The industrial production (first-generation manufacturing
process) of (S)-Pregabalin involves the classical Knoevenagel
condensation between diethyl malonate and iso-valeraldehyde,
resulting in malonyl alkylidene as key intermediate (Scheme 1). In the
next step, the cyanide Michael addition is followed by hydrolysis,
hydrogenation and decarboxylation reactions to yield racemic
Pregabalin (2a). Afterwards, the racemate resolution with (S)-
mandelic acid leads to the biologically active (S)-Pregabalin (2a).
However, in this process toxic CN sources and a large amount of
Raney nickel in the reduction step are required. In addition, in some
cases, the drug is marketed in is racemic form on the basis of overall
In this context, the antiepileptic drug (AED) Pregabalin (2a) has
been the most effective compound in the treating of epilepsy.
However, despite its significant safety and efficacy profile in blocking
a. Departamento de Química, Universidade Federal do Paraná, Centro Politécnico,
Av. Coronel Francisco H. Santos 100, Curitiba-PR, Brazil.
E-mail: carolinedoca@ufpr.br (CRM, D’Oca).
b. Instituto de Química, Universidade Federal do Rio Grande do Sul, Av. Bento
Gonçalves 9500, Porto Alegre-RS, Brazil.
c. Escola de Química e Alimentos, Universidade Federal do Rio Grande, Av. Itália Km
08 s/n, Rio Grande-RS, Brazil.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [NMR 1H and 13C spectra]. See
DOI: 10.1039/x0xx00000x
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 2 of 11
ARTICLE
Journal Name
1
2
3
4
5
6
7
8
9
yield, cost, and high throughput. Alternative methods utilizing These results also suggest that the fatty derivatives with poor water
View Article Online
21
enzymes and sequential-flow method have also been reported.16
solubility and high lipophilicity will likely cross the BBB. In another
example, series of fatty acid–amino acid–1-β-D-
DOI: 10.1039/D0NJ02263B
a
CO2Et
arabinofuranosylcytosine (Ara-C, Cytarabine) analogues were
synthesized in order to improve the lipophilicity and bioavailability of
Ara-C, used for acute nonlymphocytic leukemia (ANLL).24 However,
the bioavailability of Ara-C is relatively low due to its low lipophilicity.
According to the results observed, synthesized Ara-C derivatives
were more lipophilic than Ara-C and the in vitro cytotoxicity and in
vivo anti-tumor activity showed that the fatty derivatives were more
active than Ara-C in Hela cells, but not in HL-60 cells, whereas in vivo
results indicated a higher efficiency for some of the derivatives in
mice bearing S180 tumor, while others showed a decreased activity in
comparison with Ara-C.
In addition, fatty acid analogues and fatty acids hybrids
molecules have been found to be associated with diverse biological
activities such as anti-inflammatory, antioxidant, antimicrobial and
neuroprotective.25,26
In this work, we synthesized, for the first time, a series of new
lipophilic -alkyl substituted g-Aminobutyric acid (GABA) using the
Michael addition reaction as a key step towards fatty alkylidenes
derived from Meldrum’s acid. In addition, this methodology was
applied to synthesis of (+/-)-Pregabalin.
CO2Et
CO2Et
n-Pr2NH
KCN
CHO
CO2Et
AcOH
EtOH
99%
CO2Et
(S)-(+)-
Mandelic acid
1) KOH, MeOH
CO2Et
CO2H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2) H2, Ni
3) AcOH
CN
NH2
2a
(+/-)-
94%
73%
OH
CO2H
1) THF/DIW/IPA
CO2H
NH2
-OOC
2) IPA/DIW
29%
+
NH3
2a
(S)-Pregabalin
Scheme 1. First-generation manufacturing process of the (S)-Pregabalin (2a).
According to the literature, the BBB is constituted by a vascular
endothelium that interacts directly with astrocytes, neurons and
pericytes. It protects the brain from molecules of systemic circulation
but it has to be overcome for the proper treatment of brain cancer,
psychiatric disorders or neurodegenerative diseases, which are
dramatically increasing as global population ages.17
The capillary endothelial cells present in the BBB are an
additional hurdle and the tight intercellular junctions of which are
believed to present a more significant permeability hurdle than other
membranes such as those of the intestines. Hence, the CNS exposure
of a drug relative to its plasma concentration is function of the
balance between its plasma protein and CNS tissue binding and its
ability to permeate the BBB, all of which are likely to increase with
increasing lipophilicity.18
The drug design based on medicinal chemistry consists of
reversible modifying the physicochemical properties of the drug to
generate prodrugs, that after chemical or enzymatic cleavage exerts
its biological effect.17
The increase in the molecule lipophilicity or reducing the ability
to bind hydrogen may be a strategy to improve its permeability
across the BBB improving its targeting to the CNS.19 These chemical
modifications, such as increasing their lipophilicity, turn the drug
more prone to be internalized in the brain. In addition, others
molecular strategies also are described to bind the drugs such as
liposomes or nanoparticles that will act as drug deliverers in brain.
According Tajes et al., this fusion of the classical pharmacology with
Results and Discussion
In our previous work, we have demonstrated that the synthesis of
(+/-)-Phenibut and (+/-)-Baclofen can be achieved in 63% and 61%
overall yield, respectively, by using a multicomponent/domino
approach which combines reactions between Meldrum’s acid,
aromatic aldehydes and nitromethane in methanol.27 The
multicomponent synthetic strategy was promoted by a mixed
aluminium-magnesium oxide catalyst derived from hydrotalcite (HT).
However, in that same study, the employment of the aliphatic iso-
valeral and hexanoic aldehydes in the multicomponent/domino
reaction afforded the alkyl substituted -nitroesters in low yields,
equal to 15% and 17%, respectively (Scheme 2). This fact was
interpreted as being a consequence of the auto-condensation of
aliphatic aldehydes under basic media.
Previous work
O
O
HT (10mg/mmol)
O
O
OEt
CH3NO2
+
O
+
O
R
H
EtOH, reflux
24 h
nanotechnology has opened
approaches with promising results to hypothesize that BBB will not
be a major problem for the new generation of drugs.17
a wide field to many different
NO2
6a,b
R
Meldrum's
acid
7a,b
NO2
CO2Et
NO2
In this sense, lipophilic compounds, as fatty acid hybrids or fatty
acids derivatives have been described in the literature as a new class
of compounds with a broad range of biological activities and
significance in the field of medicinal chemistry.20
CO2Et
( )4
7b
7a
17%
15%
Fatty acids have been used as starting material to produce
pharmacologically interesting compounds through simple
transformations and their derivatives are promising molecules in the
treatment of cancers, for example, breast (MCF7), lung (NCI-H460),
glioma (C6 rat and U138-MG human) and CNS (SF-268) cell lines.21-23
Scheme 2. Multicomponent synthesis of alkyl substituted -nitroesters.
Based
on
the
poor
results
obtained
in
the
multicomponent/domino approach, in this study, the synthesis of
the -alkyl substituted GABA analogues 2 was investigated based on
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 11
New Journal of Chemistry
Please do not adjust margins
Journal Name
ARTICLE
1
2
3
4
5
6
7
8
9
bicomponent approach by different paths: pathways A or B, from
aliphatic nitroolefin 8 and Meldrum’s acid or aliphatic alkylidenes 9 and Meldrum’s acid (see pathway A, Scheme 3) was investigated
and nitro methane, respectively (Scheme 3).
Next, the Michael addition reaction from long-chain nitroolefins
View Article Online
DOI: 10.1039/D0NJ02263B
(Scheme 5).33,34 In previous works we showed the one pot domino
reaction for the synthesis of -nitroderivatives using hydrotalcite
(HT) as catalyst.33 HTs has shown catalytic applicability as solid
catalysts in several organic reactions, including aldol35 and
Knoevenagel condensations.36 In addition, previously we
demonstrated the ability HTs catalyst to promote the conjugated
addition reaction of 1,3-diketones, 1,3-ketoesters or malonates and
aromatic nitroolefins, leading to the isolation of nitroesters in good
yields. This methodology was extended to a series of reactions
between Meldrum’s acid and several aromatic nitroolefins and -
nitroesters were isolated through a simple filtration process, to give
good yields of the product (85–95%).32
Thus, the reaction from Meldrum’s acid and fatty nitroolefins
8b,f-h was performed in the presence of calcined HT as catalyst at
reflux in ethanol for 24 hours (Scheme 5), under the same
experimental conditions employed for aromatic nitroolefins.
However, the -alkyl substituted nitroesters 7b,f-h were isolated
in poor yields. This result was attributed to a probable instability of
aliphatic nitroolefins under the conditions employed in the reaction.
O
O
NO2
O
R
O
O
O
R
O
O
O
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Meldrum's
acid
A
B
OH
OH
O
O
NH2
NO2
R
R
2
11
R = alkyl chains
R
O
NO2
10
-alkyl GABA
analogues
CH3NO2
Michael
adduct
O
O
9
Scheme 3. Retrosynthetic pathway to synthesis of fatty -alkyl substituted
GABA analogues.
To synthesize the aliphatic nitroolefins 8 or alkylidenes 9, the
several aldehydes were used as starting material and in the all cases
the procedures were based on the literature.28,29 The commercially
available isovaleric (6a), hexanoic (6b), octanoic (6c), decanoic (6d)
and dodecanoic (6e) aldehydes, were used directly as received. The
palmitic (6f), stearic (6g) and oleic (6h) aldehydes were synthesized
from the oxidation of the respective commercially available fatty
alcohols. The linoleic (6i) aldehyde was prepared from the reduction
of commercially available linoleic acid, followed by oxidation of the
respective fatty alcohol. The reduction of linoleic acid was performed
using lithium aluminum hydride under reflux for 24 hours, resulting
in the linoleic alcohol in 90% yield (see 1H and 13C NMR spectra,
Figure S1) in the crude form which was then subjected to further
oxidation without chromatographic purification step. Thus, the
commercially available palmitic, stearic and oleic alcohols, plus
linoleic alcohol obtained by reduction, were submitted to an adapted
Swerns oxidation to give the respective fatty aldehydes 6f-i (Scheme
4) in high yields and purity.30
O
O
O
1)
CH3NO2
O
O
O
OEt
NaOH 10M
EtOH
NO2
Meldrum's acid
NO2
R
R
H
R
2)
trifluoroacetic
anhydride
Et3N, CH2Cl2, Ar
HT (10mg/mmol)
EtOH, reflux, 24 h
8b,f-h
88-93%
7b,f-h
6b,f-h
O
O
O
O
OEt
NO2
OEt
NO2
OEt
OEt
NO2
NO2
(
)
14
(
)
4
(
)
16
(
)
7
( )
7
7b
10%
7f
18%
7h
24%
7g
20%
Scheme 5. Synthesis of fatty nitroolefins and Michael addition reaction in
the presence of Meldrum’s acid and hydrotalcite (HT).
O
O
O
Based on the poor results obtained in the pathway A for the
synthesis of alkyl substituted -nitroesters from long-chain
nitroolefins, the approach based in the Michael addition reaction
from aliphatic alkylidenes and nitro methane (see pathway B,
Scheme 3) was investigated.
(
)
)
7
(
)
7
(
)
(
)
H
H
14
6f
85%
H
16
O
DMSO,
(CO)2Cl2
6h
94%
6g
R
OH
87%
O
R
H
Et3N, CH2Cl2,
-10 ºC
fatty
alcohols
6f-i
(
(
)
7
H
4
6i
92%
Initially, for synthesis of alkylidenes 9a-i the Knoevenagel
condensation reaction was realized in agreement to literature
(Scheme 6).37 The piperidinium acetate catalyst was easily prepared
and isolated by addition of acetic acid to a piperidine solution in dry
toluene. The use of this catalyst and molecular sieves in the reaction
between aliphatic aldehydes 6a-i and Meldrum’s acid afford the
alkylidenes 9a-i in good yields. Afterwards, the compounds 9a-i were
then submitted to conjugate 1,4-addition of nitromethane, in the
presence of DBU, for 8 hours at room temperature. In this way, the
aliphatic Michael adducts 10a-i were isolated in 87-97% yields
(Scheme 6).38 Table 1 show the yields of Knoevenagel condensation
and of Michael adducts 10a-i obtained from aliphatic alkylidenes 9a-i
and nitro methane (see pathway B, Scheme 3).
Scheme 4. Synthesis of fatty aldehydes 6f-i by Swern’s oxidation.
With the aliphatic aldehydes in hand, studies towards the
synthesis of alkyl nitroolefins were performed according to
literature.31 Initially, some representatives saturated and
unsaturated fatty aldehydes were investigated as a model. The Henry
condensation32 reaction with nitromethane under alkaline catalysis,
followed subsequent elimination reaction in the presence of
trifluoroacetic anhydride give nitroolefins 8b,f-h in good yields (88-
93%). The conversion of aldehydes to fatty acid nitroolefins (Scheme
5) was confirmed from the 1H NMR spectrum analysis, where it was
possible to observe the presence of characteristic vinylic hydrogen
signal at 6.9-7.3 ppm.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 4 of 11
ARTICLE
Journal Name
1
2
3
4
5
6
7
8
9
unsuccessful, and for this reason the reduction of unsVaietuwrAarttieclde Onnitlirnoe
O
O2N
O
H
O
N
DOI: 10.1039/D0NJ02263B
acids was suspended.
H
O
O
O
O
R
O
CH3NO2
(10 mol%)
R
O
O
O
R
H
HO
O
CH2Cl2, 0 ºC
M.S. 4A
O
O
9a-i
DBU, rt,
8 h
OH
H2, Pd/C
OH
O
O
10a-i
6a-i
Meldrum's acid
NO2
NH2
MeOH, 24 h
R
R
11a-g
2a-g
Scheme 6. Knoevenagel condensation and synthesis of Michael adducts
O
O
O
O
from long-chain alkylidenes.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
OH
OH
NH2
OH
NH2
NH2
The formation of the Michael adducts was confirmed by 1H NMR
NH2
(
)
4
(
)
6
( )
8
2b
96%
2c
2d
98%
2a
)
Pregabalin (
O
O
O
analysis, from observation of signals in 4.5-5.0 ppm, as double
doublets attributed to diasterotopic NO2 hydrogens; followed by
doublet at 3.9 ppm, characteristic of carbonyls hydrogen,
confirming the nitromethane addition into the alkylidene structure.
Several attempts of purification by chromatography columns of the
Michael adducts proved to be inefficient, suggesting an instability of
95%
97%
OH
NH2
OH
NH2
OH
NH2
(
)
10
(
)
14
(
)
16
2e
2f
2g
90%
96%
93%
Scheme 8. Synthesis of saturated -alkyl-substituted amino acids 2a-g.
1
compounds. Thus, due to the high purity observed in the H NMR
Our results show that the new lipophilic -alkyl substituted GABA
derivatives 2b-g can be synthesized in high overall yields from fatty
aldehydes. In addition, this new methodology can be applied to the
synthesis of (+/-)-Pregabalin (2a), used to treat epilepsy and
spectrum from crude product, the next transformation was carried
out from crude adducts 10a-i. The domino hydrolysis and
decarboxylation were successfully performed, in accordance to
literature methods, using TsOH.H2O (PTSA, p-toluene sulfonic acid)
as catalyst at reflux in toluene for 24 hours.39 Afterward, the
lipophilic -alkyl substituted -nitro acids 11a-i were isolated in good
yields (Scheme 7).
neuropathic pain, through
a four-step process (Knoevenagel,
Michael addition, hydrolysis, hydrogenation reactions) with a 73%
overall yield from iso-valeraldehyde (Scheme 9).
O2N
O
O
O
O
O2N
O
O
Michael addiction
reaction
TsOH.H2O
O
O
O
O
Meldrum's acid
R
O
OH
PhCH3, reflux
24 h
O
O
H
NO2
97%
CH3NO2
97%
O
O
10a-i
R
6a
Knoevenagel
reaction
O
O
O
10a
11a-i
9a
O
O
( )6
11c
78%
( )10
OH
OH
H2, Pd/C
97%
TsOH.H2O
80%
11e
11a
80%
( )4
11b
86%
( )8
11d
84%
NH2
( )14
11f
83%
NO2
80%
(+/-)-Pregabalin (2a)
11a
( )16
73% overall yield
R=
( )4
( )7
( )7
( )7
11g
80%
11i
87%
11h
92%
Scheme 9. Synthesis of (+/-)-Pregabalin 2a.
Scheme 7. Syntheses of lipophilic -alkyl-substituted -nitro acids 11a-i.
Conclusions
In this study, for the first time, we synthesize a series of new
lipophilic -alkyl GABA’s derivatives from fatty alkyl chains. The
results showed that the Knoevenagel condensation between
aliphatic aldehydes and Meldrum’s acid affords long-chain fatty
alkylidenes in good yields. Furthermore, the conjugate 1,4-addition
of nitromethane resulted in Michael adducts in high yields, which
were submitted to a one pot domino hydrolysis-decarboxylation
process, leading to nitro acids in good yields. Finally, the adducts
were reduced to access the new lipophilic -alkyl substituted GABA’s
derivatives. This methodology led to the new lipophilic GABA
derivatives after four steps with high yields. In addition, this new
methodology afforded the synthesis of the antiepileptic drug (+/-)-
Pregabalin (2a) in a high overall yield (73%) from iso-valeraldehyde.
According to the structures of the new lipophilicity fatty -alkyl
GABA’s derivatives synthesized suggests their likely ability to
permeate through the BBB, representing therefore promising
candidates for the treatment of psychiatric disorders.
Afterwards, the saturated alkyl nitro acids 11a-g, derived from
saturated fatty alkyl chains, were submitted to the same reduction
conditions employed in the synthesis of (+/-)-Pregabalin.40 The
reactions were realized in an appropriate reactor, under hydrogen
atmosphere, in MeOH as solvent for 24 hours. After this period,
removal of the catalyst by filtration on Celite® gave access to the
racemic Pregabalin (2a) and new lipophilic alkyl substituted GABA
derivatives 2b-g, which were isolated in high yields and characterized
by spectroscopic methods (Scheme 8).
Due the incompatibility of the double bond present in alkyl nitro
acids 11h and 11i, attempts to synthesize unsaturated amino acids
were carried out by reduction of alkyl-substituted nitro acid 11h
and 11i in the presence of Indio as catalyst. Initially, the reaction was
investigated using nitro acid 11h. However, even with the
consumption of the starting material after 5 hours of reaction,
observed by Thin Layer Chromatography (TLC), the product 2h was
isolated in poor yields. Attempts to improve the yields have been
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 5 of 11
New Journal of Chemistry
1
2
3
4
5
6
7
View Article Online
DOI: 10.1039/D0NJ02263B
ARTICLE
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Yields of lipophilic alkylidenes and aliphatic Michael adducts after nitro methane addition.
Entry
1
Aldehydes (6a-i)
Alkylidenes (9a-i)
Yielda (%)
Michael adducts (10a-i)
Yieldb (%)
97
O2N
O
O
O
H
O
97
O
O
O
O
O
6a
9a
10a
O2N
(
O
O
H
(
)
4
O
)
2
3
4
95
92
85
4
O
95
90
87
(
(
(
(
(
(
)
)
)
4
O
O
O
O
O
O
O
O
6b
O
O
9b
10b
O2N
(
O
O
H
( )6
O
)
O
6
6
O
O
9c
6c
O
O
10c
O2N
O
O
H
(
)
8
O
( )8
O
8
O
O
6d
O
O
9d
10d
O2N
O
O
H
(
)
10
O
( )10
O
5
6
7
86
80
83
O
O
O
92
90
95
)
)
)
10
O
O
6e
O
9e
10e
O2N
O
O
H
( )14
O
O
( )14
O
14
O
6f
O
9f
10f
O2N
O
O
H
(
)
16
O
( )16
O
16
O
O
6g
O
9g
10g
O2N
(
O
O
H
(
)
(
)
7
O
7
)
(
)
7
O
7
8
9
81
75
92
92
(
)
7
(
)
7
O
O
O
O
O
6h
9h
10h
O2N
O
O
H
(
)
7
O
(
)
4
(
)
7
O
(
)
4
( )7
O
( )4
O
O
6i
O
O
9i
10i
a Yields obtained after chromatographic purification. b Crude yields.
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 6 of 11
1
2
3
4
View Article Online
DOI: 10.1039/D0NJ02263B
5
6
7
8
ARTICLE
9
29.5, 29.6 (3C), 29.7 (2C), 31.9, 43.9, 202.9. IR max, cm-1): 2919,
2848, 2746, 1711, 1474.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental section
Materials and methods
Octadecanaldehyde (6g). Yield 87%. White solid. Melting point 42-
43 °C. 1H NMR (300 MHz, CDCl3):  0.88 (t, 3H, J = 6.0 Hz), 1.25 (m,
26H), 1.63 (m, 4H), 2.42 (dt, 2H, J = 9.0 and 3.0 Hz), 9.77 (t, 1H, J = 3.0
Hz). 13C NMR (75 MHz, CDCl3):  14.1, 22.1, 22.7, 29.1 (2C), 29.3 (3C),
29.4 (2C), 29.6 (2C), 29.7 (3C), 31.9, 43.9, 203.0. IR max, cm-1): 2922,
2852, 2744, 1710, 1470.
The reagents were purchased from Aldrich Chemical Co. and
used without further purification. All organic solvents used for
the synthesis were of analytical grade. Hydrotalcite (HT, Mg/Al
ratio 3:1) was synthesized according to previous works.27,32,41
The piperidinium acetate catalyst was prepared in situ and
isolated from the addition of acetic acid to a piperidine solution
in dry toluene according to literature.36 Column
chromatography was performed using a Silica Gel 60 A (ACROS
Organics, 0.035–0.070 mesh). Infrared (IR) spectra were
(Z)-Octadec-9-enaldehyde (6h). Yield 94%. Yellow liquid. 1H NMR
(300 MHz, CDCl3):  0.90 (t, 3H, J = 6.0 Hz), 1.29-1.33 (m, 20H), 1.65
(m, 2H), 2.03 (m, 4H), 2.44 (dt, 2H, J = 6.0 and 3.0 Hz), 5.37 (m, 2H),
9.78 (t, 1H, J = 3.0 Hz).13C NMR (75 MHz, CDCl3):  13.4, 21.4, 22.0,
26.5, 26.6 (2C), 28.4, 28.5, 28.6, 28.7, 28.9, 29.0, 29.1, 31.3, 43.2,
129.0, 129.3, 201.7. IR max, cm-1): 3009, 2928, 2855, 2717, 1722,
1462, 1123, 710.
measured
on
a
Schimadzu
PRESTIGIE-21
FT-IR
spectrophotometer. The NMR spectra were recorded using a
Varian VNMRS 300 spectrometer (1H at 300 MHz and 13C at 75.5
MHz) in CDCl3, MeOH-d4, DMSO-d6 or D2O as solvents. The
chemical shift data are reported in units of δ (ppm) downfield
from tetramethylsilane (TMS), which was used as an internal
standard. The coupling constants (3J) are reported in Hz and
refer to apparent peak multiplicities. The melting points were
obtained on a Fisatom 430D apparatus and are uncorrected.
High resolution mass spectra (HRMS) were recorded on Waters
XEGO G2 Q-TOF Mass Spectrometer.
(9Z,12Z)-Octadeca-9,12-dienaldehyde (6i). Yield 92%. Yellow liquid.
1H NMR (300 MHz, CDCl3):  0.84 (t, 3H, J = 6.0 Hz), 1.31 (m, 14H),
1.63 (m, 2H), 2.05 (q, 4H, J = 6.0 Hz), 2.41 (dt, 2H, J = 6.0 and 3.0 Hz),
2.77 (t, 2H, J = 6.0 Hz), 5.35 (m, 4H), 9.76 (t, 1H, J = 3.0 Hz). 13C NMR
(75 MHz, CDCl3):  13.9, 21.9, 22.4, 25.5, 27.0, 27.1, 28.9, 29.0, 29.1,
29.2, 29.4, 31.4, 43.7, 127.7, 127.9, 129.8, 130.0, 202.6. IR max, cm-
1): 3009, 2920, 2855, 2717, 1722, 1462, 718.
Synthesis
Synthesis of long-chain alkylidenes 9a-i.
General procedure for the synthesis of fatty aldehydes 6f-i.
To a round-bottom flask equipped with a magnetic stirring bar were
added Meldrum's acid (1.1 mmol) in CH2Cl2 (3 mL) and piperidinium
acetate (10 mol%). The mixture was kept under stirring for 5 minutes
at room temperature and then cooled to 0 °C. In the next step, the
aliphatic aldehyde (6a-i, 1 mmol) was added slowly, maintaining
stirring for 45 minutes at 0 °C in an ice bath. Finally, activated 4 Å
molecular sieves were added to the system, maintaining the stirring
for 15 minutes at room temperature. The mixture was extracted with
CH2Cl2 (3×10 mL) and washed with distilled water (3×10 mL) until a
neutral pH. The organic solution was washed with saturated NaHCO3
and NaCl solutions, dried over MgSO4 and solvent evaporated under
reduced pressure, giving long-chain alkylidenes 9a-i.
To a round-bottom flask equipped with an addition funnel and
magnetic stirring bar under N2 atmosphere at -10 °C were added dry
CH2Cl2 (5 mL) and oxalyl chloride (C2O2Cl2, 11 mmol). Then, with an
addition funnel, DMSO (24 mmol) in 5 mL CH2Cl2 was slowly added
for 2 minutes at the same temperature. After, 5 mmol of respective
fatty alcohol in 5 mL of CH2Cl2 were added slowly, maintaining
vigorous stirring for 5 minutes at -10 °C. In the next step, Et3N (25
mmol) was added, with stirring maintained at -10 °C for 15 minutes.
Afterwards, the reaction was warmed to room temperature before
the addition of 10 mL of H2O. The mixture was extracted with CH2Cl2
(3×10 mL) and washed with the same quantities of brine, 1% HCl, H2O
and 5% Na2CO3, respectively. The combined organic phases were
dried over MgSO4, filtered and evaporated under reduced pressure
to provide fatty aldehydes 6f-i.
2,2-dimethyl-5-(3-methylbutylidene)-1,3-dioxane-4,6-dione (9a).7
Yield 97%. Yellow viscous liquid. 1H NMR (300 MHz, CDCl3):  1.01 (d,
6H, J = 6.0 Hz), 1.75 (s, 6H), 1.96 (sept., 1H, J = 7.5 Hz), 2.86 (t, 2H, J =
7.5 Hz), 7.96 (t, 1H, J = 7.5 Hz). 13C NMR (75 MHz, CDCl3):  22.5 (2C),
Hexadecanaldehyde (6f). Yield 85%. White solid. Melting point 33-
35 °C. 1H NMR (300 MHz, CDCl3):  .88 (t, 3H, J = 6.0 Hz), 1.26 (m,
22H), 1.63 (m, 4H), 2.40 (dt, 2H, J = 9.0 and 3.0 Hz), 9.77 (t, 1H, J = 3.0 27.6 (2C), 28.6, 39.7, 104.8, 118.6, 159.8, 161.8, 167.9. IR max, cm-
Hz). 13C NMR (75 MHz, CDCl3):  14.0, 22.0, 22.6, 29.1, 29.3, 29.4 (2C),
Please do not adjust margins

Page 7 of 11
New Journal of Chemistry
Please do not adjust margins
Journal Name
ARTICLE
1
2
3
4
5
6
7
8
9
1): 3479, 3004, 2956, 2860, 1789, 1733, 1637, 1476, 1286, 1202, 2,2-Dimethyl-5-(Z)-(octadec-9-enylidene)-1,3-dioxane-4,6-dione
View Article Online
1
DOI: 10.1039/D0NJ02263B
1001, 912, 799.
(9h). Yield 81%. Yellow liquid. H NMR (300 MHz, CDCl3):  0.89 (t,
3H, J = 6.0 Hz), 1.28 (m, 20H), 1.60 (m, 2H), 1.74 (s, 6H), 2.01 (m, 4H),
2.95 (m, 2H), 5.36 (m, 2H), 7.94 (t, 1H, J = 6.0 Hz). 13C NMR (75 MHz,
CDCl3):  14.1, 22.6, 27.1(2C), 27.5, 27.6, 28.0, 28.1, 29.1(2C), 29.3,
29.4(2C), 29.6(2C), 29.7, 31.8, 104.8, 105.7, 129.7, 130.0, 159.8,
165.4, 169.0. IR max, cm-1): 3004, 2924, 2844, 1741, 1620, 1467,
1274, 1202, 1017, 792, 719.
2,2-Dimethyl-5-(hexylidene)-1,3-dioxane-4,6-dione (9b). Yield 95%.
Yellow liquid. 1H NMR (300 MHz, CDCl3):  0.92 (t, 3H, J = 6.0 Hz), 1.38
(m, 4H), 1.62 (m, 2H), 1.76 (s, 6H), 2.96 (q, 2H, J = 7.5 Hz), 7.95 (t, 1H,
J = 7.5 Hz). 13C NMR (75 MHz, CDCl3):  14.7, 23.2, 28.3, 29.5, 31.7,
32.3, 105.4, 118.6, 160.4, 162.5, 165.6, 169.6. IR max, cm-1): 3479,
3004, 2956, 2860, 1789, 1733, 1637, 1476, 1286, 1202, 1001, 912,
799.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,2-Dimethyl-5-(9Z,12Z)-(octadeca-9,12-dienylidene)-1,3-dioxane-
4,6-dione (9i). Yield 76%. Yellow liquid. H NMR (300 MHz, CDCl3):
1
2,2-Dimethyl-5-(octylidene)-1,3-dioxane-4,6-dione (9c). Yield 92%.
Yellow liquid. 1H NMR (300 MHz, CDCl3):  0.90 (t, 3H, J = 6.0 Hz), 1.30
(m, 10H), 1.61 (quint, 2H, J = 6.0 Hz), 1.76 (s, 6H), 2.96 (q, 2H, J = 6.0
Hz), 7.95 (t, 1H, J = 6.0 Hz). 13C NMR (75 MHz, CDCl3):  14.7, 23.2,
28.3, 28.8, 29.6, 30.0, 31.8, 32.3, 105.4, 118.7, 160.5, 162.5, 165.6,
169.7. IR max, cm-1): 3446, 3009, 2936, 2855, 1795, 1746, 1624,
1560, 1357, 1301, 1195, 1017, 928, 799.
 0.90 (t, 3H, J = 6.0 Hz), 1.32 (m, 14H), 1.76 (s, 6H), 2.06 (m, 4H), 2.79
(m, 2H), 2.95 (m, 2H), 5.36 (m, 4H), 7.94 (t, 1H, J = 6.0 Hz). 13C NMR
(75 MHz, CDCl3):  14.1, 22.7, 25.6, 26.3, 27.2 (2C), 27.9 (2C), 29.7
(2C), 29.8(2C), 29.9(2C), 31.9, 104.6, 125.7, 127.3, 127.7, 130.0,
130.3, 155.7, 162.4, 165.0. IR max, cm-1): 3478, 3017, 2936, 2839,
1730, 1629, 1454, 1381, 1284, 1195, 1025, 912, 710.
Synthesis of Michael adducts 10a-i.
2,2-Dimethyl-5-(decylidene)-1,3-dioxane-4,6-dione (9d). Yield 85%.
Pale yellow paste. 1H NMR (300 MHz, CDCl3):  0.88 (t, 3H, J = 6.0 Hz),
1.26 (m, 10H), 1.59 (m, 2H), 1.74 (s, 6H), 2.94 (q, 2H, J = 9.0 Hz), 7.93
(t, 1H, J = 7.5 Hz). 13C NMR (75 MHz, CDCl3):  14.7, 23.3, 28.3 (2C),
28.8, 28.9, 29.9, 30.0, 30.1, 31.8, 32.5, 105.5, 118.7, 160.5, 162.6,
169.7. IR max, cm-1): 3009, 2928, 2847, 1792, 1752, 1738, 1639,
1467, 1381, 1296, 1201, 1002, 925, 799.
To a round-bottom flask equipped with a magnetic stirring bar, the
long-chain alkylidene (9a-i, 1 mmol) was added. In the next step,
CH3NO2 (5 mmol) and DBU (1 mmol) were added. The mixture was
kept under stirring at room temperature for 8 hours. Afterwards, the
excess of nitromethane was evaporated under reduced pressure and
the crude was dissolved in 20 mL of CH2Cl2 and washed with 1% HCl
(3 x 10 mL). The organic solution was dried over MgSO4 and solvent
evaporated under reduced pressure, giving long-chain nitro adducts
10a-i.
2,2-Dimethyl-5-(dodecylidene)-1,3-dioxane-4,6-dione (9e). Yield
1
86%. Pale yellow solid. Melting point 67-69 °C. H NMR (300 MHz,
CDCl3):  0.91 (t, 3H, J = 7.5 Hz), 1.28 (m, 16H), 1.62 (m, 2H), 1.76 (s,
6H), 2.96 (q, 2H, J = 6.0 Hz), 7.96 (dt, 1H, J = 9.0 e 6.0 Hz). 13C NMR
(75 MHz, CDCl3):  14.7, 23.3, 28.3, 28.8, 29.9(2C), 30.1(2C), 30.2(2C),
31.6, 31.8, 32.5, 105.4, 118.7, 160.5, 162.6, 169.7. IR max, cm-1):
3398, 3009, 2920, 2847, 1802, 1748, 1738, 1641, 1568, 1462, 1381,
1309, 1203, 1009, 912, 807, 718.
2,2-dimethyl-5-(4-methyl-1-nitropentan-2-yl)-1,3-dioxane-4,6-
dione (10a).32 Yield 95%. Pale yellow solid. Melting point 73-75 °C. 1H
NMR (300 MHz, CDCl3):  0.94 (d, 3H, J = 6.0 Hz), 0.98 (d, 3H, J = 6.0
Hz), 1.20 (m, 1H), 1.55 (m, 2H), 1.79 (s, 3H), 1.81 (s, 3H), 3.36 (m, 1H),
3.89 (d, 1H, J = 3.0 Hz), 4.53 (dd, 1H, J = 12.0 e 6.0 Hz), 4.98 (dd, 1H,
J = 12.0 e 9.0 Hz). 13C NMR (75 MHz, CDCl3):  21.4, 23.1, 25.6, 26.8,
28.2, 34.3, 38.1, 47.1, 75.7, 105.4, 163.9, 164.1. IR max, cm-1): 2958,
2873, 1782, 1754, 1549, 1549, 1307, 1195, 980, 631.
2,2-Dimethyl-5-(hexadecylidene)-1,3-dioxane-4,6-dione (9f). Yield
80%. White solid. Melting point 81-83 °C. 1H NMR (300 MHz, CDCl3):
 0.88 (t, 3H, J = 6.0 Hz), 1.28 (m, 24H), 1.60 (m, 2H), 1.74 (s, 6H), 2.94
(q, 2H, J = 6.0 Hz), 7.93 (t, 1H, J = 7.5 Hz). 13C NMR (75 MHz, CDCl3):
 14.0, 27.6(2C), 28.1, 29.2, 29.3(2C), 29.4(2C), 29.5(2C), 29.6(4C),
31.1, 31.9, 104.7, 118.0, 159.8, 161.9, 169.0. IR max, cm-1): 3001,
2920, 2855, 1795, 1746, 1730, 1641, 1462, 1381, 1301, 1195, 1001,
799, 718.
2,2-Dimethyl-5-(1-nitroheptan-2-yl)-1,3-dioxane-4,6-dione (10b).
Yield 95%. Yellow viscous liquid. 1H NMR (300 MHz, CDCl3):  0.87 (t,
3H, J = 7.5 Hz), 1.28-1.58 (m, 8H), 1.77 (s, 3H), 1.79 (s, 3H), 3.25 (m,
1H), 3.89 (d, 1H, J = 3 Hz), 4.55 (dd, 1H, J = 12.0 e 6.0 Hz), 4.93 (dd,
1H, J = 15.0 e 9.0 Hz). 13C NMR (75 MHz, CDCl3):  14.1, 22.8, 23.9,
25.7, 26.8, 26.9, 29.6, 33.2, 49.0, 76.2, 105.4, 164.1, 164.9. IR max
,
cm-1): 2906, 2863, 1778, 1730, 1560, 1397, 1317, 1203, 1047, 841,
685.
2,2-dimethyl-5-(octadecylidene)-1,3-dioxane-4,6-dione (9g). Yield
83%. White solid. Melting point 78-79 °C. 1H NMR (300 MHz, CDCl3):
 0.90 (t, 3H, J = 7.5 Hz), 1.27 (m, 28H), 1.61 (m, 2H), 1.76 (s, 6H), 2.95
(q, 2H, J = 6.0 Hz), 7.95 (t, 1H, J = 7.5 Hz). 13C NMR (75 MHz, CDCl3):
 13.6, 22.4, 27.2(2C), 27.7, 28.8(2C), 28.9(2C), 29.0(2C), 29.1(2C),
29.2(4C), 30.7, 31.4, 104.3, 117.5, 159.3, 161.4, 168.5. IR max, cm-1):
3001, 2920, 2847, 1786, 1738, 1624, 1471, 1390, 1293, 1195, 1009,
799, 718.
2,2-Dimethyl-5-(1-nitrononan-2-yl)-1,3-dioxane-4,6-dione
(10c).
Yield 90%. Yellow viscous liquid. 1H NMR (300 MHz, CDCl3):  0.90 (t,
3H, J = 7.5 Hz), 1.28-1.42 (m, 12H), 1.81 (s, 3H), 1.83 (s, 3H), 3.30 (m,
1H), 3.92 (m, 1H), 4.58 (dd, 1H, J = 15.0 e 6.0 Hz), 5,00 (dd, 1H, J =
12.0 e 9.0 Hz). 13C NMR (75 MHz, CDCl3):  14.1, 22.8, 23.7, 25.9, 26.9,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 8 of 11
ARTICLE
Journal Name
1
2
3
4
5
6
7
8
9
27.1, 29.2, 29.4, 29.6, 32.1, 51.0, 77.9, 104.9, 164.2, 164.8. IR max
,
(75 MHz, CDCl3):  14.0, 22.5 (2C), 25.5, 26.8, 27.1(2VCie),w2A7rt.ic3le, O2n8l.in2e,
29.0(2C), 29.1, 29.3(2C), 29.5, 31.4, 36.4, 4D6O.9I:, 1705.1.083, 91/0D50.N4J,0122276.38B,
128.0, 129.9, 130.2, 164.0. IR max, cm-1): 3009, 2920, 2847, 1778,
1722, 1560, 1454, 1211.
cm-1): 2964, 2932, 2851, 1781, 1749, 1550, 1306, 1210, 1073.
2,2-Dimethyl-5-(1-nitroundecan-2-yl)-1,3-dioxane-4,6-dione (10d).
Yield 87%. Yellow viscous liquid. 1H NMR (300 MHz, CDCl3):  0.88 (t,
3H, J = 6.0 Hz), 1.25 (m, 16H), 1.79 (s, 3H), 1.81 (s, 3H), 3.26 (m, 1H),
3.90 (d, 1H, J = 3.0 Hz), 4.57 (dd, 1H, J = 9.0 e 3.0 Hz), 4.97 (m, 1H).
Synthesis of lipophilic -alkyl-substituted nitro acids 11a-i.
13C NMR (75 MHz, CDCl3):  14.1, 22.6, 26.8, 27.4, 28.2, 29.2(2C), To a round bottom flask, the long-chain nitro adduct (10a-i,1 mmol)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
29.3(2C), 29.4(2C), 31.8, 36.4, 46.9, 77.0, 105.4, 164.1. IR max, cm-
1): 2930, 2850, 1775, 1735, 1550, 1470, 1390, 1190, 1069, 1013, 973,
884, 845.
and 5 ml of toluene were added. After complete dissolution of the
starting material p-toluenesulfonic acid (0.5 mmol) and 2.5 mmol of
H2O were added to the solution at room temperature. The reaction
mixture was kept under reflux with continuous magnetic stirring for
2,2-Dimethyl-5-(1-nitrotridecan-2-yl)-1,3-dioxane-4,6-dione (10e). 24 hours. Afterwards, the solvents were evaporated under reduced
Yield 92%. Yellow viscous liquid. 1H NMR (300 MHz, CDCl3):  0.88 (t,
3H, J = 6.0 Hz), 1.25 (m, 20H), 1.79 (s, 3H), 1.81 (s, 3H), 3.27 (m, 1H),
3.89 (d, 1H, J = 3.0 Hz), 4.56 (dd, 1H, J = 12.0 e 6.0 Hz), 4.96 (dd, 1H,
J = 12.0 e 9.0 Hz). 13C NMR (75 MHz, CDCl3):  14.0, 22.6, 26.8, 27.3,
28.2, 29.2(2C), 29.3(2C), 29.4(2C), 29.5(2C), 31.8, 36.4, 46.9, 75.8,
105.4, 164.0. IR max, cm-1): 2906, 2858, 1783, 1735, 1550, 1390,
1310, 1205, 981, 877, 716.
pressure and the residue obtained was purified by flash column
chromatography on silica gel using hexane:ethyl acetate (90:10)
mixture as eluent, giving long-chain nitro acids 11a-i.
5-Methyl-3-(nitromethyl)-hexanoic acid (11a).37 Yield 80%. Yellow
1
viscous liquid. H NMR (300 MHz, CDCl3):  0.93 (t, 6H, J = 6.0 Hz),
1.29 (m, 2H), 1.67 (non, 1H, J = 6.0 Hz), 2.51 (d, 2H, J = 3.0 Hz), 2.69
(hept, 1H, J = 6.0 Hz), 4.44 (dd, 1H, J = 9.0 e 3.0 Hz), 4.48 (dd, 1H, J =
9.0 e 3.0 Hz), 10.4 (sl, 1H). 13C NMR (75 MHz, CDCl3):  22.1, 22.3,
24.9, 31.7, 35.6, 40.3, 78.4, 177.7. IR max, cm-1): 3179, 2952, 2863,
1714, 1551, 1381, 1211, 944.
2,2-Dimethyl-5-(1-nitrohepdecan-2-yl)-1,3-dioxane-4,6-dione (10f).
Yield 90%. Palle yellow paste. 1H NMR (300 MHz, CDCl3):  0.88 (t, 3H,
J = 7.5 Hz), 1.25 (m, 28H), 1.79 (s, 3H), 1.81 (s, 3H), 3.26 (m, 1H), 3.90
(d, 1H, J = 3.0 Hz), 4.56 (dd, 1H, J = 15.0 e 3.0 Hz), 4.95 (dd, 1H, J =
15.0 e 9.0). 13C NMR (75 MHz, CDCl3):  14.1, 22.6, 26.8, 27.3,
28.2(2C), 29.2, 29.3(2C), 29.4(2C), 29.5, 29.6(4C), 30.9 (2C), 31.9,
46.9, 75.8, 105.4, 164.0. IR max, cm-1): 2911, 2855, 1786, 1738,
1551, 1462, 1374, 1309, 1203, 880, 710.
3-(Nitromethyl)-octanoic acid (11b). Yield 86%. Yellow liquid. 1H
NMR (300 MHz, CDCl3):  0.90 (t, 3H, J = 7.5 Hz), 1.31-1.44 (m, 8H),
2.53 (d, 2H, J = 9.0 Hz), 2.64 (hept, 1H, J = 6.0 Hz), 4.50 (m, 2H), 9.62
(sl, 1H). 13C NMR (75 MHz, CDCl3):  13.8, 22.3, 25.9, 31.1, 31.4, 33.8,
35.5, 78.2, 177.9. IR max, cm-1): 3163, 2928, 2855, 1705, 1551, 1381,
1220, 928.
2,2-Dimethyl-5-(1-nitrononadecan-2-yl)-1,3-dioxane-4,6-dione
(10g). Yield 95%. Yellow paste. 1H NMR (300 MHz, CDCl3):  0.81 (t,
3H, J = 6.0 Hz), 1.18 (m, 32H), 1.71 (s, 3H), 1.74 (s, 3H), 3.19 (m, 1H),
3.84 (d, 1H, J = 3.0 Hz), 4.48 (dd, 1H, J = 15.0 e 6.0 Hz), 4.7 (dd, 1H, J
= 15.0 e 9.0 Hz). 13C NMR (75 MHz, CDCl3):  14.8, 23.3, 27.5, 28.0,
28.9(2C), 29.9(2C), 30.0(2C), 30.1(2C), 30.2(3C), 30.3(4C), 32.5, 37.1,
47.6, 76.5, 106.1, 164.7. IR max, cm-1): 3492, 2920, 2850, 1791,
1735, 1542, 1470, 1310, 1213, 1061, 877.
3-(Nitromethyl)-decanoic acid (11c). Yield 78%. Yellow liquid. 1H
NMR (300 MHz, CDCl3):  0.90 (t, 3H, J = 6.0 Hz), 1.29 (m, 10H), 1.45
(m, 2H), 2.54 (d, 2H, J = 6.0 Hz), 2.64 (hept, 1H, J = 6.0 Hz), 4.51 (m,
2H), 8.52 (sl, 1H). 13C NMR (75 MHz, CDCl3):  14.4, 22.9, 26.7, 29.4,
29.6, 31.6, 32.0, 34.2, 35.9, 78.6, 178.2. IR max, cm-1): 3155, 2928,
2855, 1714, 1551, 1374, 1288, 936, 718.
1
3-(Nitromethyl)-dodecanoic acid (11d). Yield 84%. Yellow liquid. H
2,2-dimethyl-5-(Z)-(1-nitrononadec-10-en-2-yl)-1,3-dioxane-4,6-
1
NMR (300 MHz, CDCl3):  0.88 (t, 3H, J = 6.0 Hz), 1.26 (m, 14H), 1.43
(m, 2H), 2.52 (d, 2H, J = 6.0 Hz), 2.63 (hept, 1H, J = 7.5 Hz), 4.49 (m,
2H), 8.66 (sl, 1H). 13C NMR (75 MHz, CDCl3):  14.0, 22.5 (2C), 26.3,
29.2, 29.3, 29.4, 31.2, 31.7, 33.8, 35.5, 78.2, 177.7. IR max, cm-1):
3203, 2920, 2847, 1714, 1551, 1381, 1211, 936, 718.
dione (10h). Yield 92%. Yellow liquid. H NMR (300 MHz, CDCl3): 
0.89 (t, 3H, J = 6.0 Hz), 1.28 (m, 24H), 1.79 (s, 3H), 1.82 (s, 3H), 2.01
(m, 4H), 3.28 (m, 1H), 3.90 (d, 1H, J = 3.0 Hz), 4.57 (dd, 1H, J = 9.0 e
3.0 Hz), 4.96 (m, 1H), 5.36 (m, 2H). 13C NMR (75 MHz, CDCl3):  14.0,
22.6 (2C), 26.7, 27.0, 27.1, 27.3, 28.1, 29.0, 29.1(2C), 29.2, 29.4(2C),
29.6, 29.7, 30.8, 31.8, 36.3, 46.9, 75.8, 105.4, 129.6, 129.9, 164.0. IR
max, cm-1): 3004, 2924, 2844, 1741, 1620, 1467, 1274, 1202, 1017,
792, 719.
3-(Nitromethyl)-tetradecanoic acid (11e). Yield 80%. Pale yellow
1
paste. H NMR (300 MHz, CDCl3):  0.81 (t, 3H, J = 6.0 Hz), 1.19 (m,
16H), 1.36 (m, 2H), 2.44 (d, 2H, J = 6.0 Hz), 2.55 (hept, 1H, J = 6.0 Hz),
4.42 (m, 2H), 8.46 (sl, 1H). 13C NMR (75 MHz, CDCl3):  14.1, 22.6,
2,2-dimethyl-5-(10Z,13Z)-(1-nitrononadeca-10,13-dien-2-yl)-1,3-
dioxane-4,6-dione (10i). Yield 92%. Yellow liquid. 1H NMR (300 MHz, 26.3, 29.3(2C), 29.4(2C), 29.5(2C), 31.2, 31.8, 33.9, 35.4, 78.2, 177.6.
CDCl3):  0.91 (t, 3H, J = 7.5 Hz), 1.31 (m, 20H), 1.80 (s, 3H), 1.83 (s, IR max, cm-1): 3195, 2920, 2847, 1705, 1551, 1228.
3H), 2.06 (m, 4H), 2.79 (m, 2H), 3.29 (m, 1H), 3.91 (d, 1H, J = 3.0 Hz),
4.58 (m, 1H), 4.97 (dd, 1H, J = 15.0 e 9.0 Hz), 5.37 (m, 4H). 13C NMR
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 11
New Journal of Chemistry
Please do not adjust margins
Journal Name
ARTICLE
1
2
3
4
5
3-(Nitromethyl)-octadecanoic acid (11f). Yield 83%. Yellow paste. 1H
NMR (300 MHz, CDCl3):  0.92 (t, 3H, J = 7.5 Hz), 1.29 (m, 26H), 1.47
(m, 2H), 2.56 (d, 2H, J = 6.0 Hz), 2.66 (hept, 1H, J = 6.0 Hz), 4.53 (m,
1H, J = 12.0 e 3.0 Hz). 13C NMR (75 MHz, MeOH-d4): 14.5, 23.7, 27.6,
View Article Online
-1
DOI: 10.1039/D0NJ02263B
33.2, 33.9, 35.7, 42.8, 45.5, 180.5. IR max, cm ): 2972, 2915, 2851,
2152, 1572, 1403, 993, 703. Elemental Analysis: calcd. for C9H19NO2,
2H), 8.58 (sl, 1H). 13C NMR (75 MHz, CDCl3):  14.1, 22.6, 26.4, C, 62.39; H, 11.05; N, 8.08; O, 18.47; found: C, 62.30; H, 10.94; N,
6
7
8
29.3(3C), 29.5(2C), 29.6(4C), 31.3(2C), 31.9, 33.9, 35.5, 78.3, 177.6. 8.06; O, 18.38.
IR max, cm-1): 2920, 2845, 1726, 1548, 1465, 1251, 924, 728.
9
3-(Aminomethyl) decanoic acid (2c). Yield 95%. White solid. Melting
3-(Nitromethyl)-icosanoic acid (11g). Yield 80%. Pale yellow solid. point 140-144 °C. 1H NMR (300 MHz, MeOH-d4):  0.92 (t, 3H, J = 6.0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Hz), 1.33 (m, 12H), 2.04 (m, 1H), 2.29-2.49 (m, 2H), 2.87-3.03 (m, 2H).
Melting point 58-60 °C. H NMR (300 MHz, CDCl3):  0.90 (t, 3H, J =
7.5 Hz), 1.28 (m, 30H), 1.45 (m, 2H), 2.54 (d, 2H, J = 6.0 Hz), 2.65 13C NMR (75 MHz, MeOH-d4): 14.6, 23.8, 27.9, 30.5, 30.9, 33.1, 33.8,
(hept, 1H, J = 7.5 Hz), 4.52 (m, 2H). 13C NMR (75 MHz, CDCl3):  14.1, 35.5, 41.9, 45.3, 179.9. IR max, cm-1): 3292, 2928, 2847, 2596, 2175,
22.7, 26.4, 29.3(2C), 29.4(3C), 29.5, 29.6(3C), 29.7(2C), 31.3(2C), 1705, 1544, 1398, 645. Elemental Analysis: calcd. for C11H23NO2, C,
31.9, 33.9, 35.5, 78.3, 177.4. IR max, cm-1): 3452, 2922, 2850, 1783,
1711, 1550, 1470, 1222, 1077, 716.
65.63; H, 11.52; N, 6.96; O, 15.89; found: C, 65.59; H, 11.34; N, 6.72;
O, 15.71.
3-(Aminomethyl) dodecanoic acid (2d). Yield 98%. White solid.
Melting point 167-170 °C. H NMR (300 MHz, MeOH-d4):  0.90 (t,
(Z)-3-(Nitromethyl)-icos-11-enoic acid (11h). Yield 92%. Pale yellow
liquid. H NMR (300 MHz, CDCl3):  0.81 (t, 3H, J = 7,5 Hz), 1.19 (m,
1
1
3H, J = 6.0 Hz), 1.30 (m, 16H), 1.98 (m, 1H), 2.26 (dd, 1H, J = 15.0 e
9.0 Hz), 2.43 (dd, 1H, J = 15.0 e 6.0 Hz), 2.84 (dd, 1H, J = 12.0 e 6.0
Hz), 2.96 (dd, 1H, J = 12.0 e 6.0 Hz). 13C NMR (75 MHz, MeOH-d4):
 14.6, 23.9, 28.0, 30.6, 30.8, 30.9, 33.2 (2C), 34.0, 35.7, 43.2, 45.6,
180.7. IR max, cm-1): 3302, 2915, 2851, 2610, 2173, 1668, 1540,
1403, 647. Elemental Analysis: calcd. for C13H27NO2, C, 68.08; H,
22H), 1.56 (m, 2H), 1.89 (m, 4H), 2.37 (d, 2H, J = 6.0 Hz), 2.55 (m, 1H),
4.41 (m, 2H), 5.32 (m, 2H). 13C NMR (75 MHz, CDCl3):  14.0, 22.6,
25.8, 26.4, 27.1, 28.5, 29.1(2C), 29.3, 29.4, 29.5(2C), 29.7, 31.3, 31.8,
34.2, 35.8, 78.5, 130.0, 130.4, 171.6. IR max, cm-1): 3452, 2922,
2850, 1783, 1711, 1550, 1470, 1222, 1077, 716.
(11Z,14Z)-3-(Nitromethyl)-icosa-11,14-dienoic acid (11i). Yield 87%. 11.87; N, 6.11; O, 13.95; found: C, 67.26; H, 10.96; N, 5.93; O, 13.90.
1
Palle yellow liquid. H NMR (300 MHz, CDCl3):  0.91 (t, 3H, J = 6.0
3-(Aminomethyl) tetradecanoic acid (2e). Yield 96%. White solid.
Melting point 145-149 °C. H NMR (300 MHz, MeOH-d4):  0.90 (t,
Hz), 1.32 (m, 16H), 2.03 (q, 4H, J = 6.0 Hz), 2.80 (t, 3H, J = 6.0 Hz), 4.52
(dd, 1H, J = 9.0 e 3.0 Hz), 4.61 (dd, 1H, J = 9.0 e 6.0 Hz), 5.38 (m, 4H).
13C NMR (75 MHz, CDCl3):  14.0, 22.5, 25.6, 26.2, 27.1, 28.9, 29.1,
29.2, 29.3, 29.6, 31.5, 33.6, 35.9, 38.5, 41.4, 75.9, 127.8, 128.1, 129.9,
130.2, 181.4.
1
3H, J = 6.0 Hz), 1.29 (m, 20H), 2.00 (m, 1H), 2.26-2.48 (m, 2H), 2.81-
3.00 (m, 2H). 13C NMR (75 MHz, MeOH-d4):  13.0, 22.3, 26.4, 29.1,
29.2, 29.3(3C), 29.4(2C), 31.7, 32.3, 34.0, 43.9, 178.5. IR max, cm-1):
3422, 2920, 2855, 2173, 1632, 1527, 1454, 1381, 701. Elemental
Analysis: calcd. for C15H31NO2, C, 69.99; H, 12.14; N, 5.44; O, 12.43;
found: C, 69.94; H, 12.09; N, 5.38; O, 12.35.
Synthesis of saturated -alkyl-substituted -aminobutyric acids 2a-g.
In an appropriate flask, after two nitrogen cycles to replace air inside
the reaction flask, were added the long-chain nitro acid (11a-g, 0.5
mmol) and 10 mL of methanol. Then, 20 mg of 10% Pd/C was added
to the system. The reaction mixture was vigorously stirred at 25 ºC
under 1 atm of hydrogen for 24 hours. After the reaction, the mixture
was filtered under Celite® using methanol as the solvent. The solvent
was evaporated under reduced pressure, giving long-chain -
aminobutyric acids 2a-g.
3-(Aminomethyl) octadecanoic acid (2f). Yield 90%. White paste. 1H
NMR (300 MHz, DMSO-d6):  0.88 (t, 3H, J = 6.0 Hz), 1.26-1.32 (m,
28H), 2.05 (m, 1H), 2.10-2.30 (m, 2H), 2.50-2.70 (m, 2H). 13C NMR (75
MHz, DMSO-d6):  14.0, 22.7, 26.8, 29.2, 29.5 (2C), 29.6(6C), 29.4,
31.6, 32.0, 34.0, 39.0, 45.0, 178.8. IR max, cm-1): 3438, 2911, 2847,
1641, 1527, 1454, 1390, 855. Elemental Analysis: calcd. for
C19H39NO2, C, 72.79; H, 12.54; N, 4.47; O, 10.21; found: C, 72.47; H,
12.28; N, 4.43; O, 10.19.
3-(Aminomethyl) icosanoic acid (2g). Yield 93%. Pale yellow solid.
Melting point 59-62 °C. 1H NMR (300 MHz, DMSO-d6):  0.85 (t, 3H, J
= 6.0 Hz), 1.23 (m, 32H), 1.68 (m, 1H), 2.23-2.38 (m, 2H), 2.73-2.74
(m, 2H). 13C NMR (75 MHz, DMSO-d6):  13.9, 22.1, 25.8, 28.7(3C),
28.8(2C), 28.9(3C), 29.0(3C), 30.3, 30.7(2C), 31.34(2C), 36.4, 175.3. IR
max, cm-1): 3446, 2911, 2847, 1714, 1471, 1220, 726. Elemental
Analysis: calcd. for C21H43NO2, C, 73.84; H, 12.69; N, 4.10; O, 9.37;
found: C, 73.57; H, 12.65; N, 4.12; O, 9.35.
3-(Aminomethyl)-5-methyl hexanoic acid, (+/-)-Pregabalin (2a).42
Yield 97%. White solid. Melting point 169-171 °C. 1H NMR (300 MHz,
D2O):  0.73 (d, 3H, J = 3.0 Hz), 0.75 (d, 3H, J = 3.0 Hz), 1.08 (t, 2H, J =
7.5 Hz), 1.51 (hept, 1H, J = 7.5 Hz), 2.02 (m, 1H), 2.15 (m, 2H), 2.81
(dd, 1H, J = 12.0 e 6.0 Hz), 2.88 (dd, 1H, J = 12.0 e 6.0 Hz). 13C NMR
(75 MHz, D2O):  21.6, 22.0, 24.4, 31.7, 40.6, 40.7, 43.7, 181.0. IR
max, cm-1): 3389, 2952, 2602, 1641, 1551, 1398, 1333, 1276.
3-(Aminomethyl) octanoic acid (2b). Yield 96%. White solid. Melting
point 153-155 °C. 1H NMR (300 MHz, MeOH-d4):  0.92 (t, 3H, J = 7.5
Hz), 1.33 (m, 8H), 2.00 (m, 1H), 2.27 (dd, 1H, J = 15.0 e 9.0 Hz), 2.43
(dd, 1H, J = 15.0 e 3.0 Hz), 2.85 (dd, 1H, J = 12.0 e 6.0 Hz), 2.97 (dd,
Conflicts of interest
The authors declare no conflict of interest.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 10 of 11
ARTICLE
Journal Name
1
2
3
4
5
6
7
8
9
18. H. Wolburg and A. Lippoldt, Vasc. Pharmacol., 200V2ie,w38Ar,ti3cl2e3O.nline
DOI: 10.1039/D0NJ02263B
19. M. M. Patel, B. R. Goyal, S.V. Bhadada, J.S. Bhatt and A.F. Amin.
Acknowledgements
The authors are thankful for financial support from Conselho
Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and
Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul
(FAPERGS/PRONEM 11/2069-0). Fellowships from CNPq and
Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior
(CAPES) are also acknowledged.
CNS Drugs, 2009, 23, 35.
20. V. Venepally and R. C. R. Jala, Eur. J. Med. Chem., 2017, 141, 113.
21. T. G. M. Treptow, F. Figueiro, E. H. F. Jandrey, A. M. O. Battastini,
C. G. Salbego, J. B. Hoppe, P. S. Taborda, S. B. Rosa, L. A. Piovesan,
C. R. Montes D'Oca, D. Russowsky and M. G. M. D'Oca, Eur. J.
Med. Chem., 2015, 95, 552.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
22. V. P. Mujeebur-Rahman, S. Mukhtar, W.H. Ansari and G. Lemiere,
Eur. J. Med. Chem., 2005, 40, 173.
23. D. C. Cabrera, S. B. Rosa, F. S. de Oliveira, M. A. G. Marinho, C. R.
M. D'Oca, D. Russowsky, A. P. Horn, M. G. M. D'Oca, Med. Chem.
Comm., 2016, 7, 2167.
24. B. Liu, C. Cui, W. Duan, M. Zhao, S. Peng, L. Wang, H. Liu and G.
Cui. Eur. J. Med. Chem., 2009, 44, 3596.
25. H. Takahashi, M. Kosaka, Y. Watanabe, K. Nakade and Y.
Fukuyama. Bioorg. Med. Chem., 2003, 11, 1781.
26. R. C. Brinkerhoff, E. Santa-Helena, P. C. do Amaral, D. C. Cabrera,
R. F. Ongaratto, P. M. de Oliveira, C. R. Montes D'Oca, C. A. N.
Gonçalves, L.E.M. Nery and M. G. M. D'Oca, RSC Adv., 2019, 9,
24688.
27. C. R. M. D’Oca, F. F. Naciuk, J. C. Silva, E. P. Guedes, C. C. Moro,
M. G. M. D’Oca, L. S. Santos, F. M. Natchigalle and D. Russowsky,
J. Braz. Chem. Soc., 2017, 28, 285.
28. R. C. M. Alves Sobrinho, P. M. de Oliveira, C. R. Montes D'Oca, D.
Russowsky and M. G. M. D'Oca, RSC Adv., 2017, 7, 3214.
29. T. V. K. Reddy, B. L. A. P. Devi, R. B. N. Prasad, P. Sujitha and C. G.
Kumar, Eur. J. Med. Chem., 2013, 67, 384.
30. A. Mancuso, S. L. Huang and D. Swern, J. Org. Chem., 1978, 43,
2480.
31. J-M. Receveur, J. S. Bryans, M. J. Field, L. Singh and D. C. Horwell,
Bioorg. Med. Chem. Lett., 1999, 9, 2329.
32. Bulbule, V. J.; Deshpande, V. H.; Velu, S.; Sudalai, A.; Sivasankar,
S.; Sathe, V. T. Tetrahedron 1999, 55, 9325.
33. F. F. Naciuk, D. Z. Vargas, C. R. M. D’Oca, C. C. Moro and D.
Russowsky, New J. Chem., 2015, 39, 1643.
34. A. O. Kataja and A. M. P. Koskinen, ARKIVOC, 2010, (ii), 205.
35. J. Cerveny, J. Splıchalova, P. Kacer, F. Kovanda, M. Kuzma and L.
Cerveny, J. Mol. Catal. A: Chem., 2008, 285, 150.
36. K. Motokura, N. Fujita, K. Mori, T. Mizugaki, K. Ebitani and K.
Kaneda, Tetrahedron Lett., 2005, 46, 5507.
37. C. Milite, S. Castellano, R. Benedetti, A. Tosco, C. Ciliberti, C.
Vicidomini, L. Boully, G. Franci, L. Altucci, A. Mai, G. Sbardella,
Bioorg. Med. Chem. 2011, 19, 3690.
38. F. Felluga, G. Pitacco, E. Valentin and D. V. Venneri, Tetrahedron-
Asymm., 2008, 19, 945.
39. K. L. Kimmel, J. D. Weaver and J. A. Ellman, Chem. Sci., 2012, 3,
121.
References
1. (a) A. L. Peek, T. Rebbeck, N. AJ. Puts, J. Watson, M-E. R. Aguila
and A. M. Leaver, NeuroImage, 2020, 210, 116532. (b). Goodman
and Gilman’s The Pharmacological Basis of Therapeutics, 10th
ed.; J. G. Hardman, L. E. Limbird and G. A. Goodman, Eds.;
McGraw Hill: New York, 2001.
2. D. Sutoo, K. Akiyama and K. Yabe, Hum. Brain Mapp., 2000, 11,
93.
3. (a)P. Krogsgaard-Larsen, J. Scheel-Krueger and H. Kofod, Eds.
GABA-Neurotransmitters. Pharmacochemical, Biochemical and
Pharmacological Aspects; Munksgaard: Copenhagen, 1979. (b) K.
Anderssen, C. Braestrup, F. C. Groenwald, A. S. Jørgensen, E. B.
Nielsen, U. Sonnewald, P. O. Sørensen, P. D. Suzdak and L. J. S.
Knutsen, J. Med. Chem., 1993, 36, 1716.
4. G. Costantino, A. Macchiarulo, A. E. Guadix and R. Pellicciari, J.
Med. Chem., 2001, 44, 1827.
5. J. S. Bryans and D. Wustrow, Med. Res. Rev., 1999, 19, 149.
6. T. R. Belliotti, T. Capiris, V. Ekhato, J. J. Kinsora, M. J. Field, T. G.
Heffner, L. T. Melzer, J. B. Schwarz, C. P. Taylor, A. J. Thorpe, M.
G. Vartanian, L. D. Wise, T. Zhi-Su, M. L. Weber and D. J. Wustrow,
J. Med. Chem. 2005, 48, 2294.
7. O. Bassas, J. Huuskonen, K. Rissanen and A. M. P. Koskinen, Eur.
J. Org. Chem., 2009, 9, 1340.
8. I. Lapin, CNS Drug Rev., 2001, 7, 471.
9. O. V. Maltsev, A. S. Kucherenko, I. P. Beletskaya, V. A. Tartakovsky
and S. G. Zlotin, Eur. J. Org. Chem. 2010, 15, 2927.
10. J-M. Receveur, J. S. Bryans, M. J. Field, L. Singh and D. C. Horwell,
Bioorg. Med. Chem. Lett., 1999, 9, 2329.
11. T. Yang, B. Kong, J. W. Gu, Y. Q. Kuang, L. Cheng, W. T. Yang, J. M.
Cheng, Y. Ma and X. K. Yang, Pharmacol. Biochem. Behav., 2013,
111, 97.
12. T. H. C. Marques, M. L. B. Marques, J. V. Medeiros, T. C. Lima, D.
P. Sousa and R. M. Freitas, Pharmacol. Biochem. Behav., 2013,
124, 421.
13. R. Ali and N. Siddiqui, Sci. World J., 2014, 1.
14. M. Bialer, S. I. Johannessen, H. J. Kupferberg, R. H. Levy, E.
Perucca and T. Tomson, Epilepsy Res., 2004, 61, 1.
15. R. B. Silverman, Angew. Chem. Int. Ed. 2008, 47, 3500.
16. (a) S. Debarge, P. McDaid, P. O’Neill, J. Frahill, J. W. Wong, D. Carr,
A. Burrell, S. Davies, M. Karmilowicz and J. Steflik, Org. Process
Res. Dev., 2014, 18, 109. (b) H. Ishitani, K. Kanai, Y. Saito, T.
Tsubogo and S. Kobayashi, Eur. J. Org. Chem. 2017, 6491.
17. M. Tajes, E. Ramos-Fernández, X. Weng-Jiang, M. Bosch-Morató,
B. Guivernau, A. Eraso-Pichot, B. Salvador, X. Fernàndez-
Busquets, J. Roquer, and F. J. Munõz, Mol. Membr. Biol., 2014,
31, 152.
40. H. Gotoh, H. Ishikawa and Y. Hayashi, Org. Lett., 2007, 9, 5307.
41. J. C. Rodrigues, T. M. H. Costa, M. R. Gallas and C. C. Moro, Phys.
Chem. Miner., 2009, 36, 439.
42. M. S. Hoekstra, D. M. Sobieray, M. A. Schwindt, T. A. Mulhern, T.
M. Grote, B. K. Huckabee, V. S. Hendrickson, L. C. Franklin, E. J.
Granger and G. L. Karrick, Org. Process. Res. Dev., 1997, 1, 26.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 11 of 11
New Journal of Chemistry
View Article Online
DOI: 10.1039/D0NJ02263B
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Graphical Abstract
296x188mm (96 x 96 DPI)