Gabapentin-base synthesis and theoretical studies of biologically active compounds: N-cyclohexyl-3-oxo-2-(3-oxo-2-azaspiro[4.5] decan-2-yl)-3-arylpropanamides and N-(tert-butyl)-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)-2-arylacetamide derivatives

Article abstract of DOI:10.1016/j.molstruc.2017.09.061

An intermolecular Ugi reaction of 2-(1-(aminomethyl)cyclohexyl)acetic acid (gabapentin) with glyoxal and cyclohexyl isocyanide or aromatic aldehyde and tertbutyl isocyanide under mild conditions in ethanol have been developed to produce two novel class of N-cyclohexyl-3-(aryl)-3-oxo-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)propanamideins and N-(tert-butyl)-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)-2-arylacetamide derivatives in good to excellent yields. This presents the first report for the intermolecular Ugi three component reaction of gabapentin, glyoxal, and an isocyanide. Also according to the theoretical studies the electron-donating groups increase the strength of intramolecular hydrogen bond and electron-withdrawing groups decrease the strength of intramolecular hydrogen bond.

Full text of DOI:10.1016/j.molstruc.2017.09.061

Accepted Manuscript
Gabapentin-base synthesis and theoretical studies of biologically active compounds:
N-cyclohexyl-3-oxo-2-(3-oxo-2-azaspiro[4.5] decan-2-yl)-3-arylpropanamides and N-
(tert-butyl)-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)-2-arylacetamide derivatives
Mahboobe Amirani Poor, Ali Darehkordi, Mohammad Anary-Abbasinejad, Marziyeh
Mohammadi
PII:
S0022-2860(17)31248-6
10.1016/j.molstruc.2017.09.061
MOLSTR 24310
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 9 March 2017
Revised Date: 11 September 2017
Accepted Date: 18 September 2017
Please cite this article as: M. Amirani Poor, A. Darehkordi, M. Anary-Abbasinejad, M. Mohammadi,
Gabapentin-base synthesis and theoretical studies of biologically active compounds: N-cyclohexyl-3-
oxo-2-(3-oxo-2-azaspiro[4.5] decan-2-yl)-3-arylpropanamides and N-(tert-butyl)-2-(3-oxo-2-
azaspiro[4.5]decan-2-yl)-2-arylacetamide derivatives, Journal of Molecular Structure (2017), doi:
10.1016/j.molstruc.2017.09.061.
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ACCEPTED MANUSCRIPT
Graphical Abstract

ACCEPTED MANUSCRIPT
Gabapentin-base synthesis and theoretical studies of biologically active
compounds: N-cyclohexyl-3-oxo-2-(3-oxo-2-azaspiro[4.5] decan-2-yl)-3-
arylpropanamides and N-(tert-butyl)-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)-
2-arylacetamide derivatives
Mahboobe Amirani poor, Ali Darehkordi*, Mohammad Anary-Abbasinejad, Marziyeh
Mohammadi
Department of Chemistry, Faculty of Science, Vali-e-Asr University of Rafsanjan, Rafsanjan
77176, Iran
*Corresponding author. Tel.: +98 3431312423; fax: +98 343132429.
E-mail address: adarehkordi@yahoo.com; darehkordi@mail.vru.ac.
Abstract:
An intermolecular Ugi reaction of 2-(1-(aminomethyl)cyclohexyl)acetic acid (gabapentin)
with glyoxal and cyclohexyl isocyanide or aromatic aldehyde and tertbutyl isocyanide under
mild conditions in ethanol have been developed to produce two novel class of N-cyclohexyl-
3-(aryl)-3-oxo-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)propanamideins and N-(tert-butyl)-2-(3-
oxo-2-azaspiro[4.5]decan-2-yl)-2-arylacetamide derivatives in good to excellent yields. This
presents the first report for the intermolecular Ugi three component reaction of gabapentin,
glyoxal, and an isocyanide. Also according to the theoretical studies the electron-donating
groups increase the strength of intramolecular hydrogen bond and electron-withdrawing
groups decrease the strength of intramolecular hydrogen bond.
Keyword:
Gabapentin,
N-Cyclohexyl-3-(aryl)-3-oxo-2-(3-oxo-2-azaspiro[4.5]decan-2-
yl)propanamide, Intermolecular Ugi four-center, Theoretical studies, Hydrogen bond
1. Introduction
Multi-component reactions (MCRs) are potent and useful tools for synthesis combinatorial
libraries for chemical drug finding [1] and hence new MCRs are being designed for the
preparation of new compounds [2]. Multi-component reaction (MCR) contain isocyanide
such as Ugi and Passerini reactions are well known and use in medicinal chemistry [3,4]. In
the recent years, a new version of the three-component four-center reaction contain
isocyanide using an aldehyde and acid has been developed as a bifunctional molecule [5,6].

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Ugi multi-component reactions have been used for synthesis of a variety of β-lactam
compounds by using β-amino acids, aldehydes, and isocyanides. For example L-aspartic acid
α-benzyl ester, enantiopure cyclic β-amino acids, and simple β-amino acids have been
extensively used as β-amino acid substrates [7].
In addition to a large number of spiro-compounds have useful biological properties such as
anticonvulsant [8], anticancer [9], antibacterial [10], anti-tuberculosis [11], antioxidants [12],
also there are in some natural products such as sesquiterpenes and alkaloids and find in living
organisms [13] and uses in synthesis of medicinal drugs.
Gabapentin (GBP) is used as an anticonvulsant drug which displays analgesic effects in the
therapy of a variety of chronic pain conditions, such as complex regional pain syndrome,
inflammatory pain, central pain, trigeminal neuralgia, diabetic neuropathy, headaches,
malignant pain, post-herpetic neuralgia, and HIV related neuropathy [14-17]. GBP can also
be utilized as an analgesic drug in precautionary analgesia, acute postoperative pain control
and shows useful effects on post-operative pain scores enabling the reduction of analgesic
consumption after a variety of surgical procedures [18-20]. Also many theoretical studies
have been reported on gabapentin molecule which related to structural and medicinal
properties [21-23].
According to various medicinal applications as anti-pain and epilepsy and considering above
literature reports and in continuing of our studies on the synthesis of bioactive spiro-compounds
[24] and also in other to improve the biologically activity of GBP, we have designed and
synthesized
new
N-cyclohexyl-3-(aryl)-3-oxo-2-(3-oxo-2-azaspiro[4,5]decan-2-
yl)propanamide derivatives by a simple and efficient synthetic method using a Ugi-three-
component reaction involving GBP, various glyoxal and cyclohexyl isocyanide in ethanol
(Table 1).
Also in continuing of this research the possibility of intermolecular hydrogen bonding
formation between N-H and C=O groups (N-H….O=C) has been surveyed by theoretical
calculations for compounds 4a-f. Because in this series of compounds we can investigate
substituent electronical effects on the hydrogen bond strength due to the same position of
these substituent on the aromatic ring.
2. Experimental Section

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General Methods
All of the chemicals and solvents such as ethyl acetate and ethanol, obtained from Merck
Chemical. Co. and were used without further purification. Melting points were determined on
a Melt-Tem II melting point apparatus and are uncorrected. Fourier Transform Infrared (FT-
IR) spectra were obtained on a Matson-1000 FT-IR spectrometer. Peaks are reported in
wavenumbers (cm-1). All Nuclear Magnetic Resonance (NMR) spectra were recorded on a
Bruker model DRX-400 AVANCE (1H: 400 MHz) 13C: 100 MHz) NMR spectrometer.
Chemical shift are reported in parts per million (ppm) from tetramethylsilane (TMS) as an
internal standard in Dimethyl sulfoxide-d6 (DMSO-d6) as a solvent. Element analyses (C, H,
and N) were performed with a Heracus CHN-O-Rapid analyzer. Purity of the compounds was
checked by Thin Layer Chromatography (TLC) on Merck silica gel 60 F254 percolated sheets
in n-Hexane/ethyl acetate mixture and spots were developed using iodine vapors’/ultraviolet
light as visualizing agent.
General Procedure for the Synthesis of 3-(aryl)-N-cyclohexyl-3-oxo-2-(3-oxo-2-
azaspiro[4.5]decan-2-yl)propanamide ( 4a-4f)
A mixture of 2-(1-(aminomethyl)cyclohexyl)acetic acid (1 mmol), glyoxal (1 mmol) and
cyclohexylisocyanide (1 mmol) in methanol or ethanol (4 ml) was stirred at 50 °C for the
appropriate time. The progress of the reaction was monitored by TLC. Upon completion,
solvent was removed under reduced pressure and the crude product was purified by washing
with n-hexane and diethyl ether to afford the pure 3-(aryl)-N-cyclohexyl-3-oxo-2-(3-oxo-2-
azaspiro[4.5]decan-2-yl)propanamide.
General
Procedure
for
the
Synthesis
of
N-(tert-butyl)-2-(aryl)-2-(3-oxo-2-
azaspiro[4.5]decan-2-yl)acetamide ( 4g-4l)
A mixture of 2-(1-(aminomethyl)cyclohexyl)acetic acid (1 mmol), benzaldehyde (1 mmol)
and t-butylisocyanide (1 mmol) in methanol or ethanol (4 mL) was stirred at 50 °C for the
appropriate time. The progress of the reaction was monitored by TLC. Upon completion,
solvent was removed under reduced pressure and the crude product was purified by washing
with n-hexane and diethyl ether to afford the pure N-(tert-butyl)-2-(aryl)-2-(3-oxo-2-
azaspiro[4.5]decan-2-yl)acetamide.
N-cyclohexyl-3-oxo-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)-3-phenylpropanamide (4a)

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1
Light yellow, m.p 123-125 ˚C. IR: ν 3253, 2927, 2853, 1684, 1642 cm-1; H NMR (CDCl3,
400 MHZ): δ 7.95 (d, J = 7.6 , 2 H, arom), 7.60 (t, 1 H, J = 8.0 Hz, arom), 7.49 (m, 2 H,
arom), 6.38 (s, 1 H, NH), 6.1 (s, 1 H, methine), 3.79 (m, 1 H, methine of cyclohexane), 3.44
(d, J = 10.0 Hz, 1 Ha, CH2-NH), 3.38 (d, J = 10.0 Hz, 1 Hb, CH2-NH), 2.31 (d, J = 5.2 Hz, 2
13
H, CH2-C=O), 1.93-1.11 (m, 20 H,); C NMR (CDCl3, 100 MHz): δ 194.0, 175.1, 164.7,
135.3, 133.8, 130.1, 129.0, 127.3, 60.2, 65.5, 48.7, 43.6, 37.1, 36.9, 36.5, 36.2, 32.8, 32.7,
29.7, 25.5, 25,3, 24,7, 22.7, 22.4 ppm. Elemental analysis: Value calculated for C24H32N2O3:
C, 72.70; H, 8.13; N, 7.06 %, Value found: C, 72.59; H, 8.31; N, 6.96 %,
3-(4-chlorophenyl)-N-cyclohexyl-3-oxo-2-(3-oxo-2-azaspiro[4.5]decan-2-yl) propanamide
(4b)
1
Light yellow, m.p 181-185 ˚C. IR: ν 3260, 2927, 2853, 1707, 1686 cm-1; H NMR (CDCl3,
400 MHZ): δ 7.86 (d, 2 H, J = 8.0 Hz), 7.38 (d, 2 H, J = 8.0 Hz), 7.00 (s, 1H, NH), 6.23 (S, 1
H, methine), 3.76 (m, 1 H, methine of cyclohexane) 3.53 (d, J = 12.0 Hz, 1 Ha, CH2-NH),
13
3.33 (d, J = 12.0 Hz, 1 Hb, CH2-NH), 2.23 (s, 2 H, CH2-C=O), 1.87-1.15 (m, 20 H,); C
NMR (CDCl3, 100 MHz): δ 192.4, 175.1, 164.4, 140.2, 133.4, 129.5, 129.0, 60.6, 56.6, 48.6,
43.7, 37.0, 36.5, 36.4, 32.8, 32.6, 29.7, 25.5, 25.4, 24.6, 22.8, 22.7 ppm. Elemental analysis:
Value calculated for C24H31N2O3Cl: C, 66.89; H, 7.25; N, 6.50 %, Value found: C, 67.01; H,
7.08; N, 6.39 %,
3-(4-bromophenyl)-N-cyclohexyl-3-oxo-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)propanamide
(4c)
1
Light yellow, m.p 118-120 ˚C. IR: ν 3259, 2927, 2853, 1686, 1644 cm-1; H NMR (CDCl3,
400 MHZ): δ 7.79 (d, 2 H, J = 8.0 Hz), 7.57 (d, 2 H, J = 8.0 Hz), 6.91 (s, 1H, NH), 6.20 (S, 1
H, methine), 3.76 (m, 1 H, methine of cyclohexane) 3.50 (d, J = 12.0 Hz, 1 Ha, CH2-NH),
13
3.33 (d, J = 12.0 Hz, 1 Hb, CH2-NH), 2.30 (s, 2 H, CH2-C=O), 1.92-1.20 (m, 20 H,); C

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NMR (CDCl3, 100 MHz): δ 192.7, 175.2, 164.3, 133.9, 132.1, 129.7, 129.0, 60.5, 56.6, 48.7,
43.6, 37.0, 36.7, 36.5, 36.4, 32.8, 32.6, 25.5, 25.4, 24.7, 22.8, 22.7 ppm. Elemental analysis:
Value calculated for C24H31N2O3Br: C, 60.63; H, 6.57; N, 5.89 %, Value found: C, 60.45; H,
6.71; N, 5.77 %,
(4d)
N-cyclohexyl-3-oxo-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)-3-(p-tolyl)propanamide
1
Light yellow, m.p 150-152 ˚C. IR: ν 32562, 2927, 2853, 1684, 1645 cm-1; H NMR (CDCl3,
400 MHZ): δ 7.85 (d, 2 H, J = 8.0 Hz), 7.25 (d, 2 H, J = 8.0 Hz), 6.55 (s, 1H, NH), 6.10 (S, 1
H, methine), 3.79 (m, 1 H, methine of cyclohexane) 3.43 (d, J = 12.0 Hz, 1 Ha, CH2-NH),
3.37(d, J = 12.0 Hz, 1 Hb, CH2-NH), 2.41 (s, 3 H, CH3), 2.29 (d, 2 H, J = 4.4 Hz, CH2-C=O),
1.92-1.15 (m, 20 H,); 13C NMR (CDCl3, 100 MHz): δ 193.4, 175.1, 164.7, 144.9, 132.7,
129.5, 128.4, 60.1, 56.5, 48.7, 43.6, 36.9, 36.7, 36.5, 36.3, 32.8, 32.7, 25.5, 25.4, 24.7, 22.7,
22.7, 21.7 ppm. Elemental analysis: Value calculated for C25H34N2O3: C, 73.14; H, 8.35; N,
6.82 %, Value found: C, 73.28; H, 8.21; N, 6.93 %.
N-cyclohexyl-3-(naphthalen-2-yl)-3-oxo-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)propanamide
(4e)
1
Brown powder, m.p 55-58 ˚C. IR: ν 3280, 2927, 2853, 1683, 1645 cm-1; H NMR (CDCl3,
400 MHZ): δ 8.53(s, 1 H, Hα naph), 7.97-7.52 (m, 6H naph) 6.85 (s, 1H, NH), 6.40 (S, 1 H,
methine), 3.70 (m, 1 H, methine of cyclohexane) 3.54 (d, J = 12.0 Hz, 1 Ha, CH2-NH),
3.41(d, J = 12.0 Hz, 1 Hb, CH2-NH), 2.23 (s, 2 H, CH2-C=O), 1.97-1.18 (m, 20 H,); 13C
NMR (CDCl3, 100 MHz): δ 193.6, 175.2, 164.7, 135.8, 132.4, 132.4, 130.3, 129.8, 128.8,
128.6, 127.7, 126.9, 123.6, 60.5, 56.7, 48.7, 43.7, 37.0, 36.7, 36.5, 36.3, 32.8, 32.7, 25.5,
25.4, 24.7, 22.8, 22.7 ppm. Elemental analysis: Value calculated for C28H34N2O3: Elemental
Analysis: C, 75.31; H, 7.67; N, 6.27 %, Value found: C, 75.46; H, 7.52; N, 6.39 %,
(4f)

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N-cyclohexyl-3-(4-nitrophenyl)-3-oxo-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)propanamide
Yellow, m.p 194 ˚C. IR: ν 3259, 2927, 2853, 1686, 1644 cm-1; 1H NMR (CDCl3, 400 MHZ):
δ 8.45 (d, 2 H, J = 8.0 Hz), 8.34 (d, 2 H, J = 8.0 Hz), 6.91 (s, 1H, NH), 6.20 (S, 1 H,
methine), 3.76 (m, 1 H, methine of cyclohexane) 3.50 (d, J = 12.0 Hz, 1 Ha, CH2-NH), 3.33
13
(d, J = 12.0 Hz, 1 Hb, CH2-NH), 2.30 (s, 2H, CH2-C=O), 1.92-1.20 (m, 20 H,); C NMR
(CDCl3, 100 MHz): δ 192.0, 175.1, 164.7, 133.3, 132.0, 129.7, 129.0, 60.5, 56.6, 48.7, 43.7,
37.0, 36.7, 36.5, 36.4, 33.0, 32.4, 25.5, 25.4, 24.7, 22.8, 22.7 ppm. Elemental analysis: Value
calculated for C24H31N3O5: C, 65.29; H, 7.08; N, 9.52 %, Value found: C, 65.08; H, 7.23; N,
9.41 %,
(4g)
N-(tert-butyl)-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)-2-phenylacetamide
1
Light yellow, m.p 144-145 ˚C. IR: ν 3303, 1686, 1667 cm-1; H NMR (CDCl3, 400 MHZ): δ
7.42-7.34 (m, 5 H, arom), ), 5.76 (S, 1 H, methine), 5.65 (s, 1H, NH) 3.53 (d, J = 12.0 Hz, 1
Ha, CH2-NH), 2.77 (d, J = 12.0 Hz, 1 Hb, CH2-NH), 2.20-2.38 (m, 2 H, CH2-C=O), 1.56-
13
1.21 (m, 19 H) ; C NMR (CDCl3, 100 MHz): δ 174.5, 168.3, 135.1, 129.0, 128.8, 128.3,
58.6, 55.8, 51.7, 43.9, 36.7, 36.5, 36.1, 28.5, 25.6, 22.8, 22.5 ppm. Elemental analysis: Value
calculated for C21H30N2O2: C, 73.65; H, 8.83; N, 8.18 %, Value found: C, 73.51; H, 8.96; N,
8.09 %,
(4h)
N-(tert-butyl)-2-(4-fluorophenyl)-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)acetamide
Light
1
brown, m.p 142-144 ˚C. IR: ν 3300, 1668, 1659 cm-1; H NMR (CDCl3, 400 MHZ): δ 7.36-
7.33 (m, 2 H), 7.10-7.05 (d, 2 H, J = 8.0 Hz), 5.83 (s, 1H, NH), 5.76 (S, 1 H, methine), 3.50
(d, J = 12.0 Hz, 1 Ha, CH2-NH), 2.78 (d, J = 12.0 Hz, 1 Hb, CH2-NH), 2.29 (m, 2 H, CH2-
C=O), 1.55-1.21 (m, 19 H,); 13C NMR (CDCl3, 100 MHz): δ 174.5, 168.16, 163.7, 161.6,

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130.5, 115.7, 57.7, 55.7, 51.7, 43.9, 36.7, 36.5, 36.2, 28.6, 25.5, 22.7, 22.6 ppm. Elemental
analysis: Value calculated for C21H29FN2O2: C, 69.97; H, 8.11; N, 7.77 %, Value found: C,
67.09; H, 7.95; N, 7.89 %,
(4i)
N-(tert-butyl)-2-(4-chlorophenyl)-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)acetamide
1
Light yellow, m.p 164-166 ˚C. IR: ν 3309, 1691, 1662 cm-1; H NMR (CDCl3, 400 MHZ): δ
7.36-7.29 (m, 4 H), 5.87 (s, 1H, NH), 5.76 (S, 1 H, methine), 3.51 (d, J = 12.0 Hz, 1 Ha, CH2-
NH), 2.78 (d, J = 12.0 Hz, 1 Hb, CH2-NH), 2.35-2.21 (m, 2 H, CH2-C=O), 1.54-1.21 (m, 19
H,); 13C NMR (CDCl3, 100 MHz): δ 174.5, 167.9, 134.3, 133.6, 130.2, 129.0, 57.8, 55.8,
51.8, 43.8, 36.7, 36.5, 36.2, 28.6, 25.5, 22.7, 22.6 ppm. Elemental analysis: Value calculated
for C21H29ClN2O2: C, 66.92; H, 7.76; N, 7.43 %, Value found: C, 67.08; H, 7.55; N, 7.59 %,
(4j)
2-(4-bromophenyl)-N-(tert-butyl)-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)acetamide
1
Light yellow, m.p 164-166 ˚C. IR: ν 3308, 1690, 1663cm-1; H NMR (CDCl3, 400 MHZ): δ
7.59-7.49 (m, 2 H), 7.29-7.23 (m, 2H), 5.83 (s, 1H, NH), 5.73 (S, 1 H, methine), 3.50 (d, J =
12.0 Hz, 1 Ha, CH2-NH), 2.78 (d, J = 12.0 Hz, 1 Hb, CH2-NH), 2.35-2.19 (m, 2 H, CH2-
C=O), 1.56-1.21 (m, 19 H,); 13C NMR (CDCl3, 100 MHz): δ 174.5, 167.9, 134.3, 133.6,
130.2, 129.0, 57.8, 55.8, 51.8, 43.8, 36.7, 36.5, 36.2, 28.6, 25.5, 22.7, 22.6 ppm. Elemental
analysis: Value calculated for C21H29BrN2O2: C, 59.86; H, 6.94; N, 6.65 %, Value found: C,
59.97; H, 6.81; N, 6.78 %,
(4k)
N-(tert-butyl)-2-(2-chlorophenyl)-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)acetamide
1
Light yellow, m.p 181-184 ˚C. IR: ν 3309, 1671cm-1; H NMR (CDCl3, 400 MHZ): δ 7.53-
7.43 (m, 2 H), 7.35-7.31 (m, 2H), 5.96 (S, 1 H, methine), 5.75 (s, 1H, NH), 3.41(d, J = 12.0

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Hz, 1 Ha, CH2-NH), 2.60 (d, J = 12.0 Hz, 1 Hb, CH2-NH), 2.38-2.19 (m, 2 H, CH2-C=O),
1.58-1.21 (m, 19 H,); 13C NMR (CDCl3, 100 MHz): δ 174.0, 168.3, 134.9, 133.0, 130.1,
130.0, 129.7, 126.9, 56.4, 51.6, 43.6, 36.6, 36.4, 36.3, 28.5, 25.6, 22.7, 22.6 ppm. Elemental
analysis: Value calculated for C21H29ClN2O2: C, 66.92; H, 7.76; N, 7.43 %, Value found: C,
66.81; H, 7.88; N, 7.30 %,
(4l)
N-(tert-butyl)-2-(3-nitrophenyl)-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)acetamide
1
Light yellow, m.p 231-233 ˚C. IR: ν 3449, 1684, 1630 cm-1; H NMR (CDCl3, 400 MHZ): δ
7.53-7.43 (m, 2 H), 7.33-7.31 (m, 2H), 5.95 (S, 1 H, methine), 5.75 (s, 1H, NH), 3.41(d, J =
12.0 Hz, 1 Ha, CH2-NH), 2.59 (d, J = 12.0 Hz, 1 Hb, CH2-NH), 2.38-2.19 (m, 2 H, CH2-
C=O), 1.57-1.23 (m, 19 H,); 13C NMR (CDCl3, 100 MHz): δ 174.4, 167.3, 133.9, 133.2,
130.1, 130.0, 128.2, 127.9, 56.1, 51.6, 44.1, 36.6, 36.4, 36.3, 28.5, 25.6, 22.8, 22.5 ppm.
Elemental analysis: Value calculated for C21H29N3O4: C, 65.10; H, 7.54; N, 10.84 %, Value
found: C, 65.23; H, 7.40; N, 10.97 %,
Computational methods
The electronic ground state equilibrium geometries of complexes 4a-4f were fully optimized
using the M05-2X method with the 6-311++G(d,p) basis set by the Gaussian 09 program
package [25]. Frequency calculations were carried out at the same level to ensure that these
structures are minima on the potential energy surfaces.
2
Analysis of the electronic charge density (ρ) and its Laplacian ( ρ) were done by using the
theory of molecular structure suggested by Bader [26]. The calculated electron density, ρ, and
its second derivative, 2ρ were used for describing the nature of the intramolecular N−H···O

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hydrogen bond. The atoms in molecules (AIM) [26] analysis was performed using AIM 2000
software [27] at the M05-2X /6-311++G(d,p) level.
The population analysis was carried out by the natural bond orbital (NBO) method [28] at the
M05-2X /6-311++G(d,p) level on the optimized structures using NBO program [29] for a
better understanding of intramolecular interactions.
3. Results and Discussion
Synthesis
Although recently growing efforts have been made to synthesize and characterize spiro-
compounds, but synthesis of these compounds generally less was investigated. In the present
work we designed and synthesized a new series of spiro-compounds with
potential
biological activities by reaction of arylglyoxals or aldehydes and GBP drug with isocyanides.
The glyoxal derivative used in this investigation were prepared in an excellent yield by
reaction of aryl methyl ketone derivatives bearing electron-donating, electron-withdrawing,
and neutral substituents with selenium dioxide according the literature reported [30] (Scheme
1).
Scheme 1: Synthesis of arylglyoxal derivative
Firstly, we examined the mode coupling of GBP (1) with phenylglyoxal (2), and isocyanide
(3) in MeOH as solvent. The reaction carried out smoothly in MeOH at 50 °C to affording the
corresponding N-cyclohexyl-3-(aryl)-3-oxo-2-(3-oxo-2-azaspiro[4,5]decan-2-yl)propanamide
derivative 4a in 88% yield after 30 h. The synthetic pathway adopted to obtain the target
compounds are presented in Schemes 2.
The effect of the other different solvents such as H2O, 96% ethanol, absolute ethanol, and
ethanol-H2O, DMF, CH3CN and THF on the reaction was also examined. We found in

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absolute ethanol, the desired product was obtained in 88% yield, while in 96% ethanol, 4a
was isolated in 86% yield (Scheme 2). When the water content in the reaction mixture, was
increased, the yield of the product decreased, and using water as the solvent gave very low
yields. The reaction GBP (1) with phenylglyoxal (2a), and cyclohexyl isocyanide (3), was
also carried out in DMF, THF and CH3CN solvents under the same conditions. In these
solvents desired product was not formed. Although absolute ethanol or methanol produced 4a
in higher yields than with 96% ethanol, but the latter was chosen for this transformation due
to the safety, cost, and environmental concerns.
Scheme 2: The mode reaction of GBP (1) with phenylglyoxal (2a), and isocyanide (3a) in
various solvents.
To extend the reaction to the other arylglyoxal derivatives and investigation of the
substitution effect on the time and yield of reaction, we carried out reaction of GBP and
isocyanide with different arylglyoxals. We did not observe any significant change in time and
yield of the reaction with
changing electron-withdrawing or electron-donating groups
substituted on the arylglyoxals.
Interestingly, substituted arylglyoxal with electron-withdrawing groups such as, p-fluoro, p-
bromo, p-chloro, p-nitro derivatives and substituted arylglyoxal with electron-donating
groups such as p-methyl each participated effectively in this reaction. In all the cases, the
reactions were clean and provided the desired, N-cyclohexyl-3-(aryl)-3-oxo-2-(3-oxo-2-
azaspiro[4.5]decan-2-yl)propanamide derivatives in good to excellent yields. The scope and
generality of this process are illustrated with different arylglyoxal (Table 1). All products
were fully characterized and confirmed by NMR, IR and elemental analysis.
The IR spectrum of N-cyclohexyl-3-oxo-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)-3-phenylpropanamide
(4a) showed absorption band at 3253 cm-1 corresponding to -NH stretching, C-H aromatic
and C-H aliphatic stretching appeared at 2927 and 2853 cm-1. Also absorption bands of C=O
1
groups appeared at 1686, 1644 cm-1. The H-NMR spectrum of 4a showed a signal at δ 6.38
ppm corresponding to the NH group, a signal at δ 6.1 ppm, and a multiplet at δ 3.79 ppm

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corresponding to the methanes groups. Also the 1H-NMR spectrum of 4a showed two dublets
at δ 3.44 (d, J = 10.0 Hz, 1 H), 3.38 (d, J = 10.0 Hz, 1 H), corresponding to the –CH2 (two
diastereotopic CH), a multiplet at δ 1.93-1.11 ppm corresponding to cyclohexyl rings CH2
protons and one dublet at δ 7.95 (J = 7.6 Hz), a triplet at δ 7.60 (J = 8 Hz), and one multiplets at
13
δ 7.49 ppm due to the aromatic protons. The C-NMR spectrum of 4a displayed downfield
signals at δ 194.0, 175.1 and 164.7 ppm for three carbonyls groups and at δ 135.3, 133.8,
130.1, 129.0, 127.3 ppm for aromatic carbons and 60.2, 65.5, 48.7, 43.6, 37.1, 36.9, 36.6,
36.5, 36.2, 36.1, 32.8, 32.7, 29.7, 25.5, 25.4, 25,3, 24,7, 22.7, 22.4 ppm, for the CH and CH2
carbons. The IR, 1H-NMR and 13C NMR data for all of the synthesized compounds have been
provided in the experimental section.
In continuing of this work we investigated the scope of this reaction with several substituted
aldehydes and tert-butyl isocyanide. In this case we select coupling reaction of GBA with
benzaldehyde and tert-butyl isocyanide in various solvents as model (Scheme 3) . Reaction
of GBP and substituted aldehydes with tert-butyl isocyanide in 96% ethanol as a solvent at 50
OC were successfully produced corresponding product (N-(tert-butyl)-2-(4-aryl)-2-(3-oxo-2-
azaspiro[4.5]decan-2-yl)acetamide) in good to excellent yield after 20 h (Table 2).
Scheme 3: The mode reaction of GBP (1) with benzaldehyde (2g), and isocyanide (3b) in
various solvents
Also all of these products were fully characterized and confirmed by NMR, IR and elemental
analysis.
The IR spectrum of N-(tert-butyl)-2-(4-chlorophenyl)-2-(3-oxo-2-azaspiro[4.5]decan-2-
yl)acetamide (4i) indicated absorption band at 3309 cm-1 corresponding to -NH stretching,
2923 and 2848 cm-1 , C-H aromatic and C-H aliphatic stretching respectively. Also absorption
1
bands of C=O groups appeared at 1691, 1662 cm-1. The H-NMR spectrum of 4i showed a
signal at δ 5.87 ppm corresponding to the NH group, a signal at δ 5.76 ppm corresponding to
the methanes groups. Also the 1H-NMR spectrum of 4i showed two dublets at δ 3.51 (d, J =
10.0 Hz, 1 H), 2.78 (d, J = 10.0 Hz, 1 H), corresponding to the –CH2 (two diastereotopic

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CH), a multiplet at δ 1.54-1.21 ppm corresponding to tert-butyl protons and cyclohexyl rings
CH2 protons and one multiplets at δ 7.36-7.29 ppm due to the aromatic protons. The 13C-
NMR spectrum of 4i displayed downfield signals at δ 174.5 and 167.9 ppm for carbonyls
groups and at δ 134.3, 133.6, 130.2, 129.0 ppm for aromatic carbons and 57.8, 55.8, 51.8,
1
43.8, 36.7, 36.5, 36.2, 28.6, 25.5, 22.7, 22.6 ppm for the CH2 and CH3 carbons. The IR, H-
NMR and 13C NMR data for all of the synthesized compounds have been provided in the
experimental section
A plausible mechanism for reaction of gabapentin with glyoxal and cyclohexyl isocyanide are
shown in scheme 4. We assume that the reaction proceeds via the initial formation of imine
(A) which is formed in situ from reaction of arylglyoxal and GBP. Then the oxo-imine
intermediate is attacked by the nucleophilic isocyanide, followed by abstraction of a proton
from the carboxylic acid and leading to formation of nitrilium carboxylate (B). Subsequent
attack of the carboxylate anion on the nitrilium ion generates the cyclic intermediate (C),
which undergoes a Mumm rearrangement to give the desired lactam 4 (Scheme 4).
Scheme 4. A plausible reaction pathway.

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Table 1: Synthesis of N-cyclohexyl-3-oxo-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)-3-
arylpropanamides
Entry
Glyoxal
Product
Yield (%)a
1
88
2
3
91
94
4
5
90
89

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6
78
Table 2: Ugi three-component, four-center reaction of a gabapentin with benzaldehydes and
t-butylisocyanide
Entry
Aldehyde
Product
Yield (%)a
1
93
O
2
3
85
90
H
2h
F
93
88
4
5

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91
6
aIsolated yield
2.2. Theoretical Calculations
Geometrical Parameters:
Most important geometrical parameters, which were optimized at M05-2X /6-311++G(d,p)
level of theory are summarized in Table 3.
Table 3. The most important optimized parameters (in Å and degrees) and estimated H-bond
energy (kJ mol-1)
rO···H
rN-H
θN-H···O
EHB
2.2417
2.2470
2.2503
2.2451
2.2684
2.2472
1.0126
1.0127
1.0127
1.0126
1.0126
1.0128
139.194
138.987
138.876
138.997
136.879
139.101
4a
4b
4c
4d
4e
4f
-12.409
-12.252
-12.163
-12.324
-11.853
-12.225
As can be seen, The O···H bond length lies in the range of 2.2417–2.2684 Å. Furthermore, the
hydrogen bond formation in all complexes is accompanied with elongation of N-H bond and
diminishing of O···H intramolecular distance. The minimum and maximum values of O···H
bond length correspond to 4a and 4e, respectively. The relationship between electron charge
density ρ calculated at hydrogen bond critical points (HBCPs) by using AIM and hydrogen
bond energy have been reported in the many studies: Stronger H-bond has higher ρHBCP [26].
The topological analysis of electron densities established by Bader et al. [31-33] can be used
to study the nature of hydrogen bond in these complexes. H-bonding can be specified by the
change of electron density for the bonded moiety. With formation of an H-bond, the electron
density decreases around the proton and proton acceptor, while it increases between the

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proton and its acceptor. Bader et al. mentioned that the shared interactions (as covalent and
polar bonds) have negative ∇2ρ(r) at the BCP commonly corresponds to a local accumulation
of electron density into the line of interaction linking the nuclei. In contrast, the closed shell
interactions (as ionic bonds or any other interaction between molecules such as van der
Waals, medium-weak hydrogen bonding and etc.) have a positive Laplacian and the electron
density decreases in the interatomic surface [34].
The total energy density is the sum of potential electronic and the local kinetic energies, V(r)
and G(r), respectively, at the BCP [35]
H (rBCP) = V (rBCP) + G (rBCP
)
Where the potential energy is correspond to the Laplacian of the electron density by the local
form of the virial theorem [36]
V (rBCP) = 1/4 2ρ (rBCP) - 2G (rBCP
)
and the kinetic energy is obtained by partitioning of the electron density [37]
G (rBCP) = 3/10 (3π2)2/3ρ (rBCP 5/3 + 1/6 2ρ (rBCP
)
)
Cremer and Kraka found that the local kinetic energy density G(rBCP) in closed-shell
interactions is more than local potential energy density V(rBCP). Because the G(rBCP) and
V(rBCP) are everywhere positive and negative respectively, thus H(rBCP) > 0. Moreover, the
greater of ∣V(rBCP)∣ caused the greater of the shared character of the interaction and the
stability of the structure. It is also viewed that the value of kinetic energy per electron is large
(G(rBCP)/ρ(rBCP) > 1 in atomic units) in closed-shell interactions [38]. A typical molecular
graph is shown in Fig. 1.

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Fig. 1. A typical molecular graph. Small red spheres, small yellow spheres, and lines
represent bond critical points (BCP), ring critical points (RCP), and bond paths, respectively.
The values of ρHB, ∇2ρHB, and HHB at the ΗBCP were determined by the AIM method at the
M05-2X/6-311++G(d,p) level of theory (Table 4).
Table 4.Topological electron density properties at O···H bond critical point in atomic unit
ρ×102
2ρ×102
H×102
1.428
1.412
1.403
1.419
1.369
1.410
4.993
4.933
4.896
4.957
4.741
4.925
0.1515
0.1499
0.1488
0.1503
0.1412
0.1500
4a
4b
4c
4d
4e
4f
Rozas et al. [39] suggested that weak H-bonds have ∇2ρ(rBCP) > 0 and HBCP > 0, medium H-
bonds are characterized by ∇2ρ(rBCP) > 0 and HBCP < 0 and strong H-bonds reveal ∇2ρ(rBCP) <
0 and HBCP < 0. According to the results, the O···H hydrogen bond in all complexes is
classified as weak H- bond. The values of ρHB lie in the range of 1.369-1.428 e/au3. The trend
in ρHB is in agreement with geometrical data.

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Espinosa et al. in 1998 [40] suggested that the hydrogen-bond energy, EHB, could be
extracted from the potential energy density
EHB = 0.5 V (rBCP)
The values of EHB are reported in Table 1. As can be seen in this table, the values calculated
-1
|
|
at mentioned level range from -11.853 to -12.409 kj mol . Also, the trend in Eꢀꢁ is 4a>
4d> 4b> 4f> 4c> 4e. The hydrogen bond interaction energy increased by decreasing rO···H
hydrogen bond length. Also, these results are consistent with AIM data.
The EHB values versus r(O···H) are shown in Fig. 2.
-11.8
-11.9
R² = 0.97
-12.0
-12.1
-12.2
-12.3
-12.4
-12.5
2.270
2.265
2.260
2.255
2.250
2.245
2.240
rO...H (Å)
1.44
1.43
1.42
1.41
1.40
1.39
1.38
1.37
1.36
R² = 0.98
2.270
2.265
2.260
2.255
2.250
2.245
2.240
rO...H (Å)
Fig. 2. The linear correlation between a) EHB b) ρHB and OꢀꢀꢀH bond length.

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As can be seen, there is a good linear relationship between EHB and r. The correlation
coefficient is approximately equal to 0.97. Such a linear relationship is observed between ρHB
and r(O···H) (R2 = 0.98).
The NBO analysis has been performed on the studied complexes at M05-2X /6-311++G(d,p)
level. The NBO analysis is a useful tool for describing charge transfer in the interacting
orbitals, i.e., changes of charge density in antibonding and lone pair orbitals and also the
factors that are responsible for the changes in the internal geometry of the molecule. The
NBO calculations show that the most important donor–acceptor interaction is Lp(O) →
σ*(N–H). Also, it is observed that the values of both Lp1O → σ*(N–H) and Lp2O → σ*(N–H)
interactions were above threshold limit of 0.5 kcal mol-1. The energy values of these
interactions (E(2)) are gathered in Table 5.
Table 5. Second order perturbation energies E(2) (kcal mol-1) for LPO→σ*NH related to
hydrogen bond formation obtained using NBO calculations at M05-2X/6-311++G** level of
theory.
LP (1) O→BD*N-H
LP (2) O→BD*N-H
Σ
0.8
1.3
2.1
4a
4b
4c
4d
4e
4f
0.78
0.77
0.79
0.74
0.77
1.25
1.23
1.28
1.19
1.24
2.03
2
2.07
1.93
2.01
The values of total E(2) (Σ) lie in the range of 1.93-2.03 kcal mol-1. The trend in the values of
total E(2) is similar to EHB. It is worthwhile to note that there is a correlation between bond
length and stabilization energy E(2), i.e., smaller bond lengths (strong hydrogen bonds) have
larger stabilization energy.
4. Conclusion

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In summary, we have illustrated a new approach for the synthesis of N-cyclohexyl-3-(aryl)-3-
oxo-2-(3-oxo-2-azaspiro[4.5]decan-2-yl)propanamides
and
N-(tert-butyl)-2-(3-oxo-2-
azaspiro[4.5]decan-2-yl)-2-arylacetamide derivatives via an Ugi four-center three-component
coupling reaction. This method is simple and convenient to produce the N-alkyl-3-(aryl)-3-
oxo-2-(3-oxo-2-azaspiro[4.5]decan-2-yl compounds in good to excellent yields from readily
available precursors under mild conditions. It is a very useful strategy to produce 2-
azaspiro[4.5]decan-4-one derivatives in a single-step process.
Also the results of theoretical studies indicated that the electron-donating groups (CH3 and
Phenyl groups) increase the strength of intramolecular hydrogen bond and electron-
withdrawing groups (Cl, Br, NO2 groups) decrease the strength of intramolecular hydrogen
bond. Therefore the electron- donating groups result to conformers’ stability and electron-
withdrawing groups result to instability of conformers.
Studies on the biologically activities of these compounds are in progress in our laboratory.
Acknowledgements
We gratefully acknowledge, the Vail-e-Asr University of Rafsanjan Faculty Research Grant
for financial support.
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Research Highlights
● Novel class of azaspiro-compounds were prepared.
● Simple procedure
● High yielding
● Bioactive azaspiro-compounds.