green and facile reaction of gabapentin with sulfonyl

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Letters in Organic Chemistry, 2018, 15, 000-000 1

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Green and Facile Reaction of Gabapentin with Sulfonyl Chlorides to Syn-thesize Lactams and Sulfonamides Derivatives in Aqueous Medium

Erum Akbar Hussain1, Nosheen Kanwal1, Islam Ullah Khan2,*, Sadaf Mutahir2,3,*, Muhammad Asim Khan3, Maqsood Ahmed4, Arshad Mahmood3, Onur Sahin5, Mehmet Akkurt6, and Muhammad Yar7

1Department of Chemistry, Lahore College for Women University, Lahore –54000, Pakistan; 2Department of Chemistry, Government College University, Lower Mall Lahore – 54000, Pakistan; 3School of Chemical Engineering, Nanjing Uni-versity of Science and Technology, Xiaolingwei 200, Nanjing 210094, China; 4Department of Chemistry, Islamia Uni-versity, Bahawalpur, 63100, Pakistan; 5Scientific and Technological Research Application and Research Center, Sinop University, Sinop– 57000, Turkey; 6Department of Physics, Faculty of Sciences, Erciyes University, 38039 Kayseri, Tur-key; 7Interdisciplinary Research Center in Biomedical Materials, Comsats Institute of Information Technology, Lahore, 54000, Pakistan

A R T I C L E H I S T O R Y

Received: April 30, 2017 Revised: June 14, 2017 Accepted: August 04, 2017 DOI: 10.2174/1570178614666170907143340

Abstract: In the current research, a facile and green one pot synthesis of new gabapentin-lactams (G2-G8) has been achieved by reacting gabapentin (G1) with a variety of sulfonyl chlorides. The new lactamization protocol is furnished under the green solvent i.e., water and reaction was completed in a short period of time by just stirring at room temperature. Whereas in some cases, annulation could not happen and furnished un-cyclized sulfonamide products (G9-G12). The structures of the targeted com-pounds were established by elemental analysis, FT-IR, 1H-NMR and mass spectrometry. The crystals of some new lactams (G2, G3, G4, and G8) were also evaluated by single crystal X-ray diffraction.

Keywords: Crystal structure, gabapentin, green synthesis, lactams, sulfonamides.

1. INTRODUCTION

The gabapentin has been launched as a generic drug since 2004 by Pfizer [1]. This anti-convulsant medication was originally designed for the treatment of cerebral palsy and partial epilepsy [2-7]. This drug has also been used success-fully for treating a range of neuropathic pain conditions in-cluding diabetic neuropathy [8], post herpetic neuralgia [9-13], trigeminal neuralgia, migraine, and pain associated with cancer and multiple sclerosis. It is a GABA analogue which does not bind to GABA receptors or effects GABA metabo-lism in the brain. Its binding site seems to be located on neu-rons in brain areas which are rich in glutaminergic synapses which do not bind to other antiepileptic drugs. It acts as a weak inhibitor of GABA aminotransferase, stimulates glu-tamate dehydrogenase, and is a strong, competitive inhibitor of brain branched chain amino acid aminotransferase - an enzyme involving in the glutamate synthetic pathway [14, 15]. Its therapeutic action on neuropathic pain is considered to involve voltage gated calcium ion channels and Stefani *Address correspondence to these authors at the Department of Chemistry, Government College University, Lower Mall Lahore – 54000, Pakistan; Tel: +92-429-921-0932; E-mails: [email protected]; [email protected]

et al. [16] were the first to demonstrate that gabapentin in-hibited voltage-dependent Ca2+ channel currents at cortical neurons [17]. The above mentioned ability of gabapentin to inhibit Ca2+ channels has been further affirmed by number of other research groups [18-20]. Gabapentin is revealed an achiral amino acid, it is sus-ceptible to intramolecular cyclization to generate the five membered cyclic lactam, aza-spiro[4,5]decan-3-one as shown in Scheme 3 & 4. This lactam has been investigated for its definitive neuroprotective activity and neurotrophic effect [21]. The lactam formation is a spontaneous process which is often observed in the case of reactive amino acids like 3-(2-aminophenyl) propionic acid which usually cy-clizes at room temperature to produce required lactams. This unusual high reactivity has been attributed to the close prox-imity of the amine and the carboxyl groups [22]. However, the above mentioned chemical transformation in gabapentin is very slow at room temperature in an aque-ous solution due to flexible nature of gabapentin which re-sults in a lower effective molarity of its amino group and the formation of a five-membered ring which has more strain than a six-membered ring. We proposed that the sulfonamide formation of gabapentin could alleviate the lactamization

2 Letters in Organic Chemistry, 2018, Vol. 15, No. 0 Hussain et al.

process. Herein, we report an efficient synthesis of gabapen-tin lactams bearing a range of N-substituents and some new sulfonamides (Scheme 1 & 2). Possibly stereo electronic dependent mode of cyclization of gabapentin to lactam is also discussed in detail.

COOH

NH2

Fig. (1). Structure of gabapentin (G1).

Na2CO3/H2O

RT, Stirring

SO

O Cl

R'C

N

O

S

O

O

R'

G2-G8

NH2

COOH

G1

+ + H2O

81-85 %

G2, R'= 4-chloroG3, R'= 2,5-dichloroG4, R'= 3-nitroG5, R'= 4-bromoG6, R'= 4-tert-butylG7, R'= 2,3-dichloroG8, R'= Naphthalene

Scheme (1). Synthesis of of lactam analogues of babapentine G2-G8.

2. RESULTS AND DISCUSSION

2.1. Mechanistic Studies of Lactamization Process of Gabapentin

The spontaneous formation of the amide bond in reactive amino acids is a well-known process [22]. For example, due to close proximity of the amine and the carboxyl groups in 3-(2-aminophenyl) propanoic acid this molecule cyclizes at room temperature to produce a lactam. Although gabapentin is an achiral amino acid, this reaction is less favored here and its cyclization process has been only studied after the speed up of the reaction at 80°C [23].

Na2CO3 /H2O

rt, stirring

SO

O Cl

R'NH

SO

O

R'

G9-G12

NH2

COOH

G1

+

84-37 %

G9, R'= 2- NaphthaleneG10, R'= 4-acetamidoG11, R'= 2-nitroG12, R'= 2,4,6-trimethyl

COOH

Scheme (2). Synthesis of sulfonamides of gabapentine G9-G12.

NH2

OHO

NH

O

+ H20

Scheme (3). Lactamization of Gabapentin. The lower reactivity of gabapentin is ascribed to two main reasons: a lower effective molarity of the amino group due to less rigid and pre-organized structure of this substrate

and due to the formation of a five-membered ring in lactam which is more strained as compared to a six-membered ring. Mechanistic investigation of the cyclization process of gabapentin which leads to the formation of its lactam; 2-aza-spiro [4, 5] decan-3-one has been described by Zambon et al [24]. The maximum rate of this reaction is observed at pH 9.80 and the minimum rate has been measured between pH 5.15 - 6.21. They have considered that only the neutral amino group can act as a nucleophile, whereas, the zwitteri-onic form (E) and the cationic form (A) of gabapentin should be unreactive (Scheme 4). The observed reactivity in the pH region above 9.8 is interpreted as the attack of the free amino group on the pro-tonated form (B) or a free carboxyl group form (F) which leads to the formation of a neutral tetrahedral intermediate (D) in both the cases. The slow step of the lactamization of gabapentin would involve the breakdown of (D) to lactam (H). Here, general acid catalysis could take place via the addition of a buffer proton to the leaving hydroxyl group.

Our experimental results are very consistent with the above description (Scheme 1 & 2). Na2CO3 is initially used for sulfonylation of gabapentin which only proceeds after the formation of free amino group as in B and F at pH above 9. As the reaction proceeds, HCl is produced which in turn fa-cilitates the formation of lactam by reducing the pH of the reaction mixture to the desired value of less than 3. Sulfona-mide formation in the first stage also substantially reduces conformational flexibility of the gabapentin which increases the effective molarity of the amino group for intramolecular attack on electrophilic carbon atom and lactam formation in high yield is therefore accomplished in our case at room temperature as seen in the formation of G2, G3, G4, G5, G6, G7, and G8 (Scheme 1). The gem-dialkyl effect has been con-sidered as a reason for an enhanced tendency to undergo cyclization reaction of the compounds such as gabapentin. It has been well established that this effect promotes the cycli-zation reactions and advantageous interactions in the open-chain substrates and an enhanced stability of the correspond-ing cyclic products [25]. In case of the reaction of gabapentin with 2-naphthelene sulfonyl chloride, we get both lactam (G8) and sulfonamide (G9) and separated them by column chromatography (n-hexane: ethyl acetate 50:50). The struc-tures were confirmed by 1HNMR. It was, however, observed that lactamization process did not proceed with some other substituted benzenesulfonyl chlorides and final product is only uncycled sulfonamide. For example, 4-chlorobenzesulfonyl chloride, 2, 5-dichlorobenzenesulfonyl chloride, 3-nitrobenzenesulfonyl chloride and 2-napthalenesulfonyl chlo-ride on reaction with gabapentin did not produce the desired lactams (Scheme 2). This stereoelectronic dependent mode of cyclization of gabapentin is also well supported by single crystal X-Ray diffraction studies. For example gabapentin reacts with o- nitro benzenesulfonyl chloride (Scheme 2) to produce open chain sulfonamide G11. As revealed by X-Ray diffraction studies. In this case, formation of two adjacent six-membered rings through intramolecular hydrogen bonding favored the formation of a linear sulfonamide product [26]. First ring is made as a result of hydrogen bonding between one of the oxygen of o-nitro group and hydrogen of the

Green and Facile Reaction of Gabapentin with Sulfonyl Chlorides Letters in Organic Chemistry, 2018, Vol. 15, No. 0 3

amino group, while the second ring is made by hydrogen bonding between hydrogen of the same amino group and oxygen of the carbonyl group. It is inferred that both these rings give stability to the open rather than cyclized structure leading to lactam ring formation. In case of G10 (Scheme 2) which is again a linear sulfonamide product, the presence of electron withdrawing group at p-position of 4-acetamidobenzenesulfonyl moiety decreased the nucleophilic character of amine, therefore reducing the possibility of in-tramolecular cyclization. Similarly, reaction of 2- mesity-lenesulfonyl chloride (Scheme 2) with G1, furnished a linear product due to steric hindrance of methyl substituents in cy-clization. The overall stereo electronic dependent mode of cyclization of gabapentin is summarized in Scheme 4.

2.2. Crystallographic Studies

2.2.1. Description of Structure G2

The molecular structure of G2 with the atom labeling is shown in Fig. (2). The geometry around the S atom is dis-torted tetrahedral and O–S–O angle is 120.44(10)°. The cy-clohexane ring adopts chair conformation with the puckering parameters [27] QT = 0.554(2) Å, θ = 2.7(2)° and φ = 95(5)°. The pyrrolidine rings have twisted conformations puckering parameters Q(2) = 0.333(2) Å, φ (2) = 94.9(3)°. The phenyl ring plane is approximately planar, with maximum deviation from the least-squares plane being 0.0067(16) Å for atom C5.

Fig. (2). The molecular structure of G2 showing the atom number-ing scheme.

The title compound crystallizes in the space group P21/c, and the molecules are linked into sheets by a combination of three C-H···O hydrogen bonds (Table S3), C-H···π and π···π stacking interactions are, however, absent. Atom C3 in the reference molecule at (x, y, z) acts as a hydrogen-bond donor, via H3, to atom O1 in the molecule at (x, y+1, z), so forming a C(8) [28] chain running parallel to the [010] direction. Atom C8 in the reference molecule at (x, y, z) acts as a hy-drogen-bond donor, via H8A, to atom O1 in the molecule at (−x+1, −y, −z+1), so forming a centrosymmetric R2

2(8) ring centred at (1/2, 0, 1/2). Similarly, atom C10 in the molecule at (x, y, z) acts as a hydrogen-bond donor, via H10A, to atom O2 in the molecule at (−x, −y, −z+1), so forming a centro-symmetric R2

2(10) ring centred at (0, 0, 1/2). The combina-tion of C-H···O hydrogen bonds generates a chain of edge-fused R2

2(8)R44(20) rings running parallel to the ab plane

(Fig. 3).

Fig. (3). Part of the crystal structure of G2 showing the formation of a chain edge-fused R2

2(8)R42(20)rings along ab plane. For the

sake of clarity, the H atoms not involved in the motif shown, have been omitted.


The molecular structure of G3 with the atom labeling is shown in Fig. (4). The geometry around the S atom is dis-torted tetrahedral and O–S–O angle is 119.07(12)°. The pyr-rolidine rings have twisted conformations puckering parame-ters Q(2) = 0.291(3) Å, φ(2) = 109.3(5)° while the cyclohex-ane ring adopts chair conformation with the puckering pa-

NH3OH+

NH2HO OH

+N

OH

OH+H

H N

OH

OH

H

-H2ON

HO

A B C D H

NH3O O+

E

-NH2

O OH

F

N

OH

O

H

G

H + -

Scheme (4). Stereoelectronic dependent mode of cyclization of gabapentin.


rameters QT = 0.552(3) Å, θ = 178.0(3)° and φ = 43(8)°. The phenyl ring plane is approximately planar, with maximum deviation from the least-squares plane being 0.0183 (18) Å for atom C6.


Fig. (5). Part of the crystal structure of G3 showing the formation of a chain edge-fused R2

2(16)R22(18) rings along [111]. For the sake

of clarity, the H atoms not involved in the motif shown have been omitted. The title compound crystallizes in the space group P21/c, and the molecules are linked into sheets by a combination of three C-H···O hydrogen bonds (Table S3), and these sheets are linked into a two-dimensional framework structure by a combination of one C-H···π interaction. In the simplest of the two sub-structures, atom C4 in the reference molecule at (x, y, z) acts as a hydrogen-bond donor, via H4, to atom O1 in the molecule at (−x+1, y+1/2, −z+1/2), so forming a C(9) chain running parallel to the [010] direction. Atom C13 in the reference molecule at (x, y, z) acts as a hydrogen-bond donor, via H13A, to atom O3 in the molecule at (−x, −y+1, −z), so forming a centrosymmetric R2

2(18) ring centered at (0, 1/2, 0). Similarly, atom C14 in the molecule at (x, y, z) acts as a hydrogen-bond donor, via H14B, to atom O2 in the molecule at (−x, −y, −z), so forming a centrosymmetric R2

2(16) ring centred at (0, 0, 0) (Fig. 5). In the final sub-structure, the C11 atom in the molecule at (x, y, z) acts as a hydrogen-bond donor to the phenyl (Cg2) ring in the mole-

cule at (x, -y+1/2, z-1/2), so forming a C(8) chain running parallel to the [001] direction (Fig. 6). Details of this interac-tion are given in Table S3.

Fig. (6). Part of the crystal structure of G3 showing the formation of a chain along [001] generated by the C-H···π interactions. For the sake of clarity, H atoms not involved in the motif shown, have been omitted.



The title compound G4 contains two crystallographically independent molecules A and B in the asymmetric unit as shown in Fig. (7). In these molecules A and B, the pyr-rolidine rings have twisted conformations puckering parame-ters [27] Q(2) = 0.261(7) Å, φ (2) = 52.9(15)° for molecule A and Q(2) = 0.262(8)Å, φ (2) = 231.6(16)° for molecule B], and the cyclohexane rings adopt chair conformations with the puckering parameters QT = 0.587(8) Å, θ = 0.0(8)° and φ = 261(85)° for molecule A and QT = 0.546(9) Å, θ = 177.6(9)° and φ = 68(17)° for molecule B (Table S2); the bond distances and bond angles in both molecules are all normal [29, 30]. The molecular structure reveals a distorted tetrahedral geometry around the S atom [maximum deviation


from the ideal sp3 hybridized geometry for O–S–O = 120.6(3)° for molecule A and O–S–O = 121.0(3)° for mole-cule B]. In the crystal structure of the title compound, mole-cules are linked by intermolecular C–H···O hydrogen bonds into three-dimensional networks (Table S3 and Fig. 8).

Fig. (8). View of the crystal packing and hydrogen bonding of the G4 along the a-axis. The hydrogen atoms not involved in the hydro-gen bonds have been omitted for clarity.

Fig. (9). The molecular structure of G8 with atomic numbering scheme. The thermal ellipsoids are drawn at the 60 % probability level.


The molecular structure and atom-labeling scheme are shown in Fig. (9). Selected bond distances and angles are described in Table S2. There is one molecule in the asym-metric unit and eight molecules in the unit cell. The cyclo-hexane ring has a chair conformation and the adjacent nitro-gen containing heterocyclic ring also adopts a half chair con-formation. The cyclohexane ring and the heterocyclic ring are almost perpendicular to each other and the torsion angle (N1-C12-C14-C19) is -97.7°(3).

However, the naphthalene rings have planer geometry. As viewed along b-axis, the molecules are stacked over each other in the form of layers and adjacent layers run anti-parallel to each other (Fig. 10). The interplaner distance be-tween the two molecules is 3.429 Å (5) as calculated on the basis of biphenyl rings of each molecule. There is an intra-molecular interaction between O1 and O3 atoms at the dis-tance of 3.017Å with a van der Waals distance less than by a value of -0.023Å. It seems that this particular interaction might be responsible for the specific distorted geometry of the molecule. The molecular assembly is mainly built on the basis of an intermolecular C13-H13A···O3 hydrogen bond with H…O distance of 2.588Å (3) and C-H-O angle of 150.6° (3) Table S3. Besides this, there are a number of weak Van der Waals type interactions between H4-H19B (2.39Å) and H5-H5 (2.397Å) which also contribute in the presence of molecules in crystal.

Fig. (10). Inter- and intra-molecular interactions in G8 along b-axis, showing the molecules stacked over each other in the form of layers and adjacent layers run anti-parallel to each other.

3. EXPERIMENTAL

3.1. Chemicals and Reagents

All chemicals and materials used in this study were of analytical grade. 4-chlorobenzenesulfonyl chloride, 2,5-dichlorobenzenesulfonyl chloride, 3-nitrobenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-tert-butyl ben-zene sulfonyl chloride, 2,3-dichloro benzenesulfonyl chlo-ride and 2-mesitylenesulfonyl chloride were purchased from Alfa Aesar (26 Partridge Rd, Ward Hill, MA, 01835 USA). Sodium hydride was obtained from Sigma Aldrich (Ger-many). Methanol, ethyl acetate and dimethyl-formamide were obtained from Panreac (Spain). Analytical grade HCl was purchased from Merck. Solvents were purified through distillation wherever necessary. Working standard of gabapentin was provided by Lahore Pharmaceuticals, Lahore, Pakistan and characterized for as-say before use. All melting points were obtained on an Elec-tro thermal (Griffin 1090) melting point apparatus and are reported here without correction. The IR spectra of the com-pound were scanned through Perkin Elmer 1600 FT-IR (USA) and MIDAC- M 2000 (USA) by using KBr pellets over the range 4000–400 cm-1. 1H NMR spectra were re-corded at 600 MHz on JEOL-Lambda NMR instrument. Chemical shifts are quoted as δ ppm and the coupling con-


stants J in Hz. Signals are described as s (singlet), d (dou-blet), m (multiplet), br (broad). Elemental analysis (CHNS) was performed by using Vario Micro Cube, Elementar, Ger-many. Mass spectra were recorded on a JEOL MS Route with Ionization mode: EI+.1H-NMR spectra were recorded on Bruker AVANCE AV 600 and DPXQ 400 spectrometers. The single-crystals data were collected using a Bruker Kappa APEX II CCD diffractometer (graphite monochromated Mo-Kα radiation, λ = 0.71073 Å) at room temperature and data reductions were performed using SAINT [31]. The structures were solved by direct methods with SHELXS and the result-ing atomic models were developed and refined against |F|2 using SHELXL [32]. The “observed data” threshold for cal-culating the R(F) residuals was set as I> 2σ(I). The C and N bound H atoms were placed in idealised locations (C–H = 0.96–0.97 Å, N–H = 0.86 Å) and refined as the riding atoms. The O-bound H atoms were located in the difference Fourier maps and refined as riding on their relative atoms. All non-hydrogen atoms were refined with anisotropic parameters. The structural models were analysed and validated with PLATON [33, 34] and full refinement details are given in the CIF (Crystal Information File). Program used for molecular graphics was Mercury [33]; software used to prepare mate-rial for publication was WinGX [35]. Supramolecular analy-ses were performed and the diagrams were prepared with the aid of PLATON [33] and CrystalMaker® [36].

3.2. Synthesis

3.2.1. General Method for the Synthesis of Lactams (G2-G8)

To gabapentin (1eq, 1.2 mmol) in distilled water (10 ml) sulfonyl chloride, G2-G8 (1eq, 1.2 mmol) was added while maintaining the pH of the reaction mixture at 8 by using 3 % aqueous sodium carbonate solution. The consumption of the reactants was confirmed by TLC. Once the reaction was completed, the pH of the reaction mixture was adjusted to 3 by using 3N HCl. The precipitates formed were washed with plenty of water, dried and crystallized from methanol: ethyl acetate (50:50 % v/v).

3.2.2. 2-[(4-Chlorophenyl) sulfonyl] -2-azaspiro [4.5] de-can-3-one (G2)

Colorless solid, Yield 61 %, m.p. 128-130oC. Anal.Calcd. For C15H18ClNO3S (327.826): C, 54.96; H, 5.53; N, 4.27, S, 9.78. Found: C, 54.73; H, 5.60; N, 3.97, S, 9.458. IR νmax (KBr, cm-1) 3258 cm-1 (sec sulfonamide ), 3105, 2904, 2925 cm-1 (CH str), 2852, 1710 cm-1 (C-O str cyclic), 1585, 1429, 1396 cm-1 (C-C aromatic ring str), 1477, 1453, 1357, 1279 cm−1 (CN stretching), 1338 cm-1 {asymm (S=O)2 str}, 1166 cm-1{symm (S=O)2 stretch}, 1082 cm-1 (aromatic CCl), 820 cm-1 (out-of-plane aromatic CH bend), 679 cm-1 (out-of-plane aromatic ring C-C bend). 1H NMR (600 MHz, CD3OD, δ, ppm, J/Hz): 7.81 (d, J = 8.4, 2H, H-2', H-6'), 7.57 (d, J = 8.4, 2H, H-3', H-5'), 2.91 (s, 2H, H-9), 2.28 (s, 2H, H-2), 1.44-1.38 (m, 10H, H-3-H-7). MS m/z (%): 327 (66, M +), 291 (18), 274 (10), 263 (37), 241 (11), 186 (4), 154 (100).

3.2.3. 2-[(2, 5-Dichlorophenyl) sulfonyl]-2-azaspiro [4.5] decan-3-one (G3)

Colorless plates, yield 59 %, m.p. 142-144°C. Anal. Calcd. For C15H17Cl2NO3S (362.271): C, 49.73; H, 4.73; N,

3.87, S, 8.85. Found: C, 49.95; H, 4.71; N, 3.63; S, 8.62. IR νmax (KBr, cm-1) 3300 cm-1 (sec sulfonamide ), 3105, 2928, 2870 cm-1 (CH str), 2859, 1708 cm-1 (C-O str cyclic), 1686 cm-1, (C-C aromatic str), 1449, 1408, 1375 and 1283 cm-1 (CN str), 1341 cm-1{asymm (S=O)2 stretch} and 1166 cm-

1{symm (S=O)2 str}, 1085, 1098 cm-1 (aromatic CCl), 826 cm-1 (out-of-plane aromatic CH bending), 676 cm-1 (out-of-plane aromatic ring C-C bend). 1H NMR (600 MHz, CD3OD, δ, ppm, J/Hz): 8.00 (d, J = 1.8, 1H, H-6'), 7.59 (m, 2H, H-3'-H-4'), 3.00 (s, 2H, H-9), 2.29 (s, 2H, H-2), 1.43- 1.36 (m, 10H, H-3-H-7). MS m/z (%): 362 (M +), 154 (54), 91 (4).

3.2.4. 2-[(3-Nitrophenyl) sulfonyl]-2-azaspiro [4.5] decan-3-one (G4)

Colorless crystals. Yield 74 %, m.p. 157-158°C. Anal. Calcd. For C15H18N2O5S (338.379) C, 53.24; H, 5.36; N, 8.28, S, 9.48. Found: C, 53.46; H, 5.38; N, 8.06; S, 9.64. IR νmax (KBr, cm-1) 3329 cm-1 (sec sulfonamide), 3098, 2928, 2925 cm-1 (CH str), 2852, 1706 cm-1 (C-O str), 1585, 1429, 1396 cm-1 (C-C aromatic ring str), 1347, 1279 cm-1 (CN str), 1347 cm-1 {asymm (S=O)2 str} and 1163 cm-1{symm (S=O)2 str}. 1H NMR (600 MHz, CD3OD, δ, ppm, J/Hz): 8.66 (brs, 1H, H-2'), 8.45 (brd, J = 7.8, 1H, H-4'), 8.21 (d, J = 7.8, 1H, H-6'), 7.83 (t, J = 7.8, 1H, H-5'), 2.96 (s, 2H, H-9), 2.29 (s, 2H, H-2), 1.45-1.38 (m, 10H, H-3-H-7). MS m/z (%):(338 M+), 275 (19), 274 (100), 257 (24), 231 (42), 218 (45), 152 (5.4), 123 (27), 96 (40), 95 (38), 81 (80), 76 (14), 67 (35), 55 (14.3), 54 (12), 41 (12).

3.2.4. 2-[(4-Bromophenyl) sulfonyl]-2-azaspiro [4.5] decan-3-one (G5)

White crystals, Yield 81 %, m.p. 83°C. Anal. Calcd. For C15H20NO4SBr (372.293) C, 46.16; H, 5.17; N, 3.59, S, 8.22. Found: C, 45.97; H, 5.31; N, 3.48; S, 8.35. IR νmax (KBr, cm-

1) 821 (out-of-plane aromatic C-H bending), 1167 cm-1 {symm (S=O)2 str}, 1246, 1336, 1393, 1416 (C N str), 1455, 1416 (C-C aromatic ring str), 2857, 1708 (C=O str, cyclic), 1540 cm-1 (C-C aromatic ring str), 3067, 3028, 2925 cm-1 (C-H str), 3380 (sec sulfonamide). 1H NMR (600 MHz, CD3OD, δ, ppm, J/Hz): 7.75 (d, J = 8.4, 2H, H-2', H-6'), 7.73 (d, J = 8.4, 2H, H-3', H-5'), 2.92 (s, 2H, H-9), 2.29 (s, 2H, H-2), 1.44-1.37 (m, 10H, H-3-H-7). MS m/z (%): 308 (M+−SO2) (100), 249(27), 247 (22), 218 (24), 185 (56), 184 (27), 156(32), 154 (34), 123 (45), 95(30), 81(77), 66 (36), 40 (21).

3.2.5. 2-[(4-Tert-butyl phenyl) sulfonyl]-2-azaspiro [4.5] decan-3-one (G6)

White crystals. Yield 84 %, m.p. 71°C. Analytical calcd. for C19H27NO3S (349.489): C, 65.29; H, 7.78; N, 4.01; S, 9.17. Found: C, 65.11; H, 7.69; N, 4.11; S, 9.03 %. IR νmax (KBr, cm-1) 836 (out-of-plane aromatic C-H bending), 1173 {symm (S=O)2 str}, 1266, 1325, 1373, 1465 (C N str), 1465 (C-C aromatic ring str), 2870, 1704 (C=O str, cyclic), 1589 (C-C aromatic ring str), 2936 (C-H str). 1H NMR (600 MHz, CD3OD, δ, ppm, J/Hz): 7.99 (d, J = 8.4, 2H, H-2', H-6'), 7.76 (d, J = 8.4, 2H, H-3',H-5'), 2.89 (s, 2H, H-9), 2.29(s, 2H, H-2), 1.31-1.48 (m, 10H, H-3-H-7), 1.38 (s, 9H, H-1"). MS m/z (%): 285 (M+− SO2) (21), 270 (100), 234 (42), 220 (52), 218


(81), 216 (91), 197 (77), 191 (37), 189 (76), 183 (43), 166 (32), 105 (31), 103 (35), 91 (76), 77 (50), 69 (29), 65 (14).

3.2.6. 2-[(2, 3-Dichlorophenyl) sulfonyl]-2-azaspiro [4.5] decan-3-one (G7)

White solid, Yield 65 %, 160°C. Analytical calcd. for C15H17Cl2NO3S (362.271): C, 49.73; H, 4.73; N, 3.87; S, 8.85. Found: C, 49.56; H, 4.88; N, 3.66; S, 8.94. IR νmax (KBr, cm-1) 3370 cm-1 (sec sulfonamide), 3104 cm-1 (C-H str), 2928, 2865, 1710 cm-1 (C=O str cyclic), 1449 cm-1 (C-C aromatic ring str), 1449, 1241 cm-1 (C N str), 1344 cm-1 {asymm (S=O)2 str} and 1171 cm-1{symm (S=O)2 str},1099, 1069 cm-1 (aromatic CCl), 687, 616 cm-1 (out-of-plane aromatic ring C-C bend). 1H NMR (600 MHz, CD3OD, δ, ppm, J/Hz): 8.01 (dd, J = 1.2, 8.4, 1H, H-6'), 7.79 (dd, J = 0.6, 7.8, H-4'), 7.46 (t, 1H, J = 7.8, H-5'), 2.98 (s, 2H, H-9), 2.29 (s, 2H, H-2), 1.41-1.28 (m, 10H, H-3-H-7). MS m/z (%): 362 (M+), 328 (31), 326 (71), 264 (91), 263 (40), 261 (100), 239 (21), 237 (23), 170(15), 144 (26), 95 (39), 81 (38), 67 (18), 55 (11), 41 (10).

3.2.7. 2-[(2-Naphthalene) sulfonyl]-2-azaspiro [4.5] decan-3-one (G8)

Needle shaped crystals: yield 35%, mp 106oC. Analytical calcd. for G8 (C19H21NO3S) (343.434): C, 66.44; H, 6.16; N, 4.08; S, 9.34. Found: C, 66.15; H, 6.25; N, 3.92; S, 9.21. IR νmax (KBr, cm-1) 3361 cm−1 (sec sulfonamide), 3207 (N H str), 3079 cm-1 (C-H str), 2924, 2854 (C=O str cyclic), 1504 cm-1 (C=C aromatic ring str), 1363 cm-1 {asymm (S=O)2 str} and 1171 cm-1{symm (S=O)2 str}, 767 cm-1 (in-phase –CH– out-of-plane bending vibration or in-phase –CH– wagging). MS m/z (%):(343.43 M+), 279.2 (55), 191 (41), 156 (52), 127.1 (100), 81 (33), 67 (35).

3.3. General Method for the Synthesis of Sulfonamides (G9-G12)

Following this, the general procedure has been adopted for the synthesis of sulfonamides: gabapentin (1 eq, 1.169 mmol) was suspended in dist. water (15 ml) and Na2CO3 solution, to adjust the pH at 8–9, followed by the addition of sulfonyl chloride (1 eq, 1.169 mmol), was suspended in the drug solution. The evolution of reaction was scrutinized by TLC. The reaction was completed when the suspension turned into a clear solution. The reaction mixture was acidi-fied to obtain white precipitate. The products were separated, rinsed with dist. water and recrystallized in MeOH.

3.3.1. 2-(1-((naphthalene-2-sulfonamido)methyl) cyclohexyl)acetic acid (G9)

Yield 37%, m.p.137oC, C19H21NO3S (361.46): N, 66.45%, C, 66.45%, H, 6.16%. IR νmax (KBr, cm-1) 3361 (sec sulfonamide), 3207 (N H stretching), 3079 (C-H stretching), 2924, 2854 (C=O stretching cyclic), 1504 (C=C aromatic ring stretch), 1363 {asymm (S=O)2 stretch} and 1171{symm (S=O)2 stretch}, 767 (in-phase – CH– out-of-plane bending vibration or in-phase –CH– wagging). MS m/z: 361.13 (100.0%), 362.14 (21.0%), 363.13 (4.5%), 363.14 (3.2%), 362.13 (1.2%).

3.3.2. 2-(1-((4-acetamidophenylsulfonamido)methyl) cyclohexyl)acetic acid (G10)

White crystals. Yield 64 %, m.p. 182°C. 1H NMR (600 MHz, CD3OD, δ, ppm, J/Hz): 7.76 (d, J=8.4, 2H, H-2′, H-6′), 7.74 (d, J=8.4, 2H, H-3′, H-5′), 2.88 (s, 2H, H-9), 2.29 (s, 2H, H-2), 2.14 (s, 3H, H-1′′), 1.43-1.39 (m, 10H, H-7-H-3). IR νmax (KBr, cm−1) 1155 {symm (S=O)2 stretch}, 1322, 1403 (C-N stretching), 1690, (C=O), 1594 (C-C aromatic ring stretch), 3250 (amide NH), 3338 (sec sulfonamide). Anal. Calcd. For C17H24N2O5S (368.447): C, 55.42; H, 6.57; N, 7.60, S, 8.70. Found: C, 55.05; H, 6.96; N, 7.52; S, 8.978%. %. MS m/z (%): 304 (M+ −SO2), 286 (100), 244 (91), 227 (20), 197 (43), 120 (32), 107 (17), 92 (22), 81 (37), 65 (17), 43 (20).

3.3.3. 2-{1-[(2-Nitrobenzenesulfonamido)-methyl] cyclo-hexyl} acetic acid (G11)

Yield 53%, m.p. 141oC. 1H NMR (600 MHz, CD3OD, δ, ppm, J/Hz): 8.07 (dd, J=2.6, 8.0, 1H, H-3'), 7.86 (dd, J=2.6, 8.0, 1H, H-6'), 7.80 (dd, J=2.6, 6.0, 2H, H-4', H-5'), 3.07 (s, 2H, H-9), 2.31 (s, 2H, H-2), 1.47-1.41 (m, 10H, H-3-H-7). IR νmax (KBr, cm−1) 1167 {symm (S=O)2 stretch}, 1358 (N O aromatic ring), 1415 (C-N stretching), 1694 (C=O), 1540 (C-C aromatic ring stretch), 2930 (C-H Stretching) 3100 (amide NH), 3346 (sec sulfonamide). Anal. Calcd. For C15H20N2O6S (356.394) C, 50.55; H, 5.66; N, 7.86, S, 9.00. Found: C, 50.56; H, 5.39; N, 8.06; S, 8.64 %. MS m/z (%): 292 (M+−SO2), 228(100), 186(32), 182 (13), 152 (20), 95 (34), 81 (35), 67 (18), 55(10), 44(8.8), 41(9).

3.3.4. 2-[(2, 4, 6-Trimethylphenyl) sulfonyl] amino} methyl) cyclohexyl] acetic acid (G12)

Colourless solid: Yield 75%, m.p. 138-140°C. 1H-NMR (600 MHz, CD3OD, δ, ppm, J/Hz):, δ 6.93(s, 2H, H-3′, H-5′), 2.79 (s, 2H, H-9), 2.62 (s, 6H, H-1′′), 2.33 (s, 3H, H-2′′), 2.27 (s, 2H, H-2), 1.38-1.36 (m, 10H, H-3-H-7). IR νmax (KBr, cm-1) 3280 (sec sulfonamide), 2975, 2936 (CH stretch-ing), 1652 (C H bending), 1542 (C-C aromatic ring stretch), 1384 (asymm (S=O)2 stretch), 1169 {symm (S=O)2 stretch}, 1130 (aromatic C-Cl), 549 (out-of-plane aromatic ring C-C bend). Analytical calcd. For C18H27NO4S (353.476): C, 61.16; H, 7.70; N, 3.96 %. Found C, 60.86, H, 7.69, N, 4.07, S, 7.99 %. MS m/z (%): (353.2 M+), 289 (3) 271 (13), 183 (55), 119 (100), 95 (21), 91 (60), 77 (75), 67 (34), 55 (36).

CONCLUSION

Novel gabapentin-lactam derivatives have been prepared in a single step reaction using water as a solvent by just stir-ring at room temperature in good yields. Sulfonamides hav-ing electron withdrawing or sterically hindered moieties af-forded un-cyclized products and the remaining sulfonamides delivered lactams. These derivatives open new doors for the researchers in this field to evaluate their biological potential.

ASSOCIATED CONTENT

CCDC reference numbers 843820 for G2, 843821 for G3, 1405438 for G4 and 929135 for G8 contain supplementary crystallographic data. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html,


or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223 336 033; or e-mail: [email protected].

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

We acknowledge Higher Education Commission for fi-nancial support. Authors would like to thank Prof. Khalid M. Khan, HEJ Institute of Chemistry, University of Karachi, Dr. Saif Ullah Salik, University of Oxford, UK for their kind assistance in 1H NMR and mass spectral measurements and Dr. Shahzad Sharif, Department of Chemistry, GCU, Lahore for his kind assistance in X-ray diffraction studies.

SUPPLEMENTARY MATERIAL

Parameters for data collection and structure refinement of G-2, G-3, G-4, and G-8. Selected Bond Lengths (Å) and Bond Angles (°) For Compound G-2, G-3, G-4, and G-8. Hydrogen-bond parameters (Ǻ) of Compound G-2, G-3, G-4, and G-8 are present in SM. Supplementary material is avail-able on the publisher’s website along with the published arti-cle.

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o2171. DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Edito-rial Department reserves the right to make minor modifications for further improvement of the manuscript.

green and facile reaction of gabapentin with sulfonyl

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