Synthesis, structural and crystallographic study of some carbamates derived from 9-methyl-9-azabicyclo[3.3.1]nonan-3α-ol

Journal of Molecular Structure 708 (2004) 117–125 www.elsevier.com/locate/molstruc

Synthesis, structural and crystallographic study of some carbamates derived from 9-methyl-9-azabicyclo[3.3.1]nonan-3a-ol I. Iriepaa,*, J. Bellanatob, F.J. Villasantea, E. Ga´lveza, A. Martı´nc, P. Go´mez-Salc a

Departamento de Quı´mica Orga´nica, Facultad de Farmacia, Universidad de Alcala´ de Henares, Ctra. Madrid-Barcelona Km. 33.600, 28871 Alcala´ de Henares, Madrid, Spain b Instituto de Estructura de la Materia, C.S.I.C., Serrano 121, 28006 Madrid, Spain c Departamento de Quı´mica Inorga´nica, Universidad de Alcala´ de Henares, Ctra. Madrid-Barcelona Km. 33.600, 28871 Alcala´ de Henares, Madrid, Spain Received 10 February 2004; accepted 2 March 2004 Available online 25 June 2004

Abstract A series of benzimidazole, thiazole and benzothiazole carbamates derived from 9-methyl-9-azabicyclo[3.3.1]nonan-3a-ol was synthesized and studied by 1H, 13C, 2D NMR and IR spectroscopy. To assist in the interpretation of the spectroscopic data, the crystal structure of 3 (9-methyl-9-azabicyclo[3.3.1]nonan-3a-yl 2-amino-1H-benzimidazole-1-carboxilate) was determined by X-ray diffraction. It has been found that 1-carbamates and 2-carbamates can be obtained in the case of the benzimidazole derivatives. The benzimidazole1-carbamates are obtained in higher yields (41, 38%) than the benzimidazole-2-carbamates (3, 9%). The compounds studied displayed in CDCl3 solution a preferred chair– boat conformation with the substituted ring in a distorted boat form and the N– CH3 substituent in an axial position with respect to the chair piperidine ring. This conformation is similar to that determined by X-Ray diffraction for compound 3. q 2004 Elsevier B.V. All rights reserved. Keywords: 9-Methyl-9-azabicyclo[3.3.1]nonan-3a-ol derivatives; Carbamates; Infrared spectroscopy; NMR spectroscopy; Conformational analysis

1. Introduction

2. Experimental

As a part of a continuing effort to develop novel heterocyclic compounds with potential therapeutic activity, we are currently involved in studies in which the 9-methyl-9-azabicyclo[3.3.1]nonane system is being used as a conformationally restricted framework. In the present paper, we report the synthesis, the structural and the conformational studies of a series of benzimidazole, thiazole and benzothiazole carbamates derived from 9-methyl-9-azabicyclo[3.3.1]nonan-3a-ol in order to explore their structure – activity relationships as 5-HT3 receptor antagonists. The structures and preferred conformations of these compounds have been determined with the aid of 1H, 13C, DEPT, double resonance (DR) experiments, IR spectroscopy and also by X-ray data for compound 3. Moreover, the behaviour of the ambident nucleophilic heterocyclic amines towards the acylation has been studied.

2.1. General

* Corresponding author. Tel.: þ 34-91-885-4651; fax: þ34-91-885-4686. E-mail address: [email protected] (I. Iriepa). 0022-2860/$ - see front matter q 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.molstruc.2004.03.066

Trichoromethyl chloroformate was purchased from Fluka and heterocyclic amines were purchased from Aldrich and they were used without further purification. 9-Methyl-9-azabicyclo[3.3.1]nonan-3a-ol was synthesized according to the reported method [1]. Acetonitrile was dried over calcium hydride; pyridine was distilled over sodium hydroxide pellets, and ethyl ether was dried over sodium and benzophenone. Melting points were determined in open capillaries on a Gallenkamp MFB-595-010M apparatus and are uncorrected. The IR spectra of compounds 3– 9 were recorded on a Perkin-Elmer FTIR 1725 £ spectrophotometer, assisted by a computer, in the solid state (KBr) in the 4000 –400 cm21 and in CDCl3 solution (0.05 M) in the 4000 –900 cm21 region using 0.2 mm NaCl cells. Spectra for very dilute CCl4 solutions were taken in the 4000– 2500 cm21 region

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with 4 cm quartz cells. The reported wave numbers are estimated to be accurate to within ^ 3 cm21. 1 H NMR spectra were recorded on a Varian UNITY-300 spectrometer (299.949 MHz). Spectral parameters included sweep width of 4000 Hz in 24 K memory and acquisition times of 3 s over 64 transients. Resolution enhancement using lb ¼ 2 0.80; gf ¼ 0.50; gfs ¼ 0.20 was followed by zero filling into 32 K memory prior to Fourier transformations. The DR experiments involved the use of conventional irradiation. The 13C NMR spectra were obtained at 75 MHz on a Varian UNITY-300 spectrometer. The information about the number of C-attached protons was obtained from DEPT experiments. 2.2. Crystal data for compound 3 The crystal data together with the refinement details for compound 3 are included in Table 1. Intensity measurements were performed at room temperature by v scans on an Enraf Nonius CAD4 diffractometer in the range 68 , 2u , 548: Of the 5763 measured reflections for 3, 3508 ½RðintÞ ¼ 0:084 were independent; R1 ¼ 0:048; wR2 ¼ 0:119 (for 1663 reflections with F . 4sðFÞ). The structure was solved, using the WINGX package [2] by direct methods (SHELXS -97) and refined by least-squares against F 2 (SHELXL -97) [3]. All non-hydrogen atoms were Table 1 Crystal data and structure refinement for compound 3 Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions

Volume Z Density (calculated) Absorption coefficient Fð000Þ Crystal size Theta range for data collection Index ranges Reflections collected Independent reflections Completeness to theta ¼ 26.998 Absorption correction Max. and min. transmission Data/restraints/parameters Goodness-of-fit on F 2 Final R indices ½I . 2sðIÞ R indices (all data) Largest diff. peak and hole

C17 H22 N4 O2 314.39 293(2) K ˚ 0.71073 A Monoclinic P2(1)/n ˚, a ¼ 6:9740ð10Þ A ˚, b ¼ 27:8710ð10Þ A ˚ c ¼ 8:4980ð10Þ A a ¼ 908, b ¼ 102:45ð1Þ8, g ¼ 908 ˚3 1612.9(3) A 4 1.295 mg/m3 0.087 mm21 672 0.35 £ 0.25 £ 0.20 mm3 3.08–26.998 28 # h # 0, 235 # k # 35, 210 # l # 10 5763 3508 ½RðintÞ ¼ 0:0841 97.7% Psi scan 0.440 and 0.324 3508/0/296 0.874 R1 ¼ 0:0482; wR2 ¼ 0:1194 R1 ¼ 0:1606; wR2 ¼ 0:1669 ˚ 23 0.173 and 20.230 e A

anisotropically refined, while the hydrogen atoms were located in the difference Fourier map and isotropically refined. CCDC 230172 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/ retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK. Fax: þ 44-1223-336033). 2.3. General procedure for preparing carbamates 3 – 9 About 1.50 g (7.83 mmol) of 9-methyl-9-azabicyclo[3.3.1]nonan-3a-ol hydrochloride (1) was suspended in 15 ml of dry acetonitrile, and 1.94 g (9.79 mmol) of trichloromethyl chloroformate was added dropwise at 0 8C. The reaction mixture was stirred at this temperature for 30 min and then at room temperature for 24 h more, until a clear solution was obtained. The solvent was removed under vacuum and the residue triturated with ethyl ether to afford 2 (91%) pure enough to be used in the following step. The corresponding amine was dissolved in dry pyridine at room temperature and 2 was then added portionwise with stirring. The mixture was stirred for 24 h. After this time the carbamate hydrochloride crystallized; then it was recovered by filtration and washed with ethyl ether. The carbamate hydrochloride obtained was then dissolved in 5N HCl, and 10% aqueous potassium carbonate was added until no further precipitation was observed. This precipitate was filtered, washed with water and then dried under vacuum. Further purification was carried out by recrystallization from the adequate solvent. In this way, carbamates 3, 4, 7–9 were obtained. For carbamates 5 and 6, the filtrate (pyridine) and washings (ether) were combined and concentrated under vacuum. The residue was taken up with 5N HCl, and 10% aqueous potassium carbonate was added until no further precipitation was observed. This precipitate was filtered, washed with water and then dried under vacuum. Finally, it was purified by chromatography column on silica gel with 5:95 MeOH (saturated with ammonia gas) – CHCl3 and then recrystallizated from CHCl3 –hexane to give the corresponding carbamate. 9-Methyl-9-azabicyclo[3.3.1]nonan-3a-yl 2-amino1H-benzimidazole-1-carboxilate (3) and N-(benzimidazol-2yl)-9-methyl-9-azabicyclo[3.3.1]nonan-3a-yl-carbamate (5). Following the general procedure, chloroformate 2 (0.90 g, 3.54 mmol) and 2-aminobenzimidazole (0.48 g, 3.54 mmol) in 5 ml of dry pyridine, after stirring 24 h at room temperature, gave 458 mg (41%) of 3: m.p. 139–141 8C (decomp.). Following the general procedure for carbamates 5 and 6, 34 mg (3%) of carbamate 5 were obtained: m.p. 145 8C (decomp.). 9-Methyl-9-azabicyclo[3.3.1]nonan-3a-yl 2-amino5,6-dimethyl-1H-benzimidazole-1-carboxylate (4) and N-(5,6-dimethylbenzimidazol-2-yl)-9-methyl-9-azabicyclo[3.3.1]nonan-3a-yl-carbamate (6). Following the general procedure, chloroformate 2 (0.3 g, 1.18 mmol)

I. Iriepa et al. / Journal of Molecular Structure 708 (2004) 117–125

and 2-amino-5,6-dimetilbenzimidazole (0.19 g, 1.18 mmol) in 2 ml of dry pyridine, after stirring 24 h at room temperature, gave 155 mg of 4 (38%): m.p. 181 –183 8C (decomp.) Following the described procedure, 37 mg (9%) of carbamate 6 were obtained: m.p. 149 –151 8C (decomp.). N-(Benzothiazol-2-yl)-9-methyl-9-azabicyclo[3.3.1]nonan-3a-yl-carbamate (7). Using the general procedure, chloroformate 2 (0.2 g, 0.79 mmol) and 2-aminobenzothiazole (118 mg, 0.79 mmol) in 0.8 ml of anhydrous pyridine gave 186 mg of 7 (71%): m.p. 200 8C (decomp.). N-(Thiazol-2-yl)-9-methyl-9-azabicyclo[3.3.1]nonan3a-yl-carbamate (8). Following the general procedure, chloroformate 2 (0.2 g, 0.79 mmol) and 2-aminothiazole (79 mg, 0.79 mmol) in 0.6 ml of anhydrous pyridine gave 158 mg of 8 (72%): m.p. 171 8C (decomp.). N-(6-Methoxybenzothiazol-2-yl)-9-methyl-9-azabicyclo-[3.3.1]nonan-3a-yl-carbamate (9). Using the general procedure, chloroformate 2 (0.2 g, 0.79 mmol) and 2-amino6-methoxybenzimidazole (0.142 g, 0.79 mmol) in 0.5 ml of dry pyridine gave 176 mg of 9 (62%): m.p. 182 8C (decomp.).

3. Results and discussion 3.1. Chemistry Scheme 1 shows the synthesis of carbamates 3 – 9. Two different benzimidazole derivatives can be expected,

119

the benzimidazole-1-carbamate and the benzimidazole2-carbamate. In our reaction conditions the 1-carbamates (3, 4) are obtained in higher yields (41 and 38%, respectively) than the 2-carbamates (5, 6) (3 and 9%, respectively). In the case of 2-aminobenzothiazole, 2-aminothiazole and 2-amino-6-methoxybenzothiazole the reaction takes places in the exocyclic nitrogen atom resulting only one carbamate derivative. We have previously synthesized and studied the corresponding b-derivatives [4] obtaining similar results to these published in this paper. The low yield obtained after isolation of carbamates 5 and 6 can be explained by their partial decompositions. In fact, we isolated the corresponding methyl carbonate as one of the decomposition products resulting by reaction with the methanol used as eluent during the purification process (chromatography column). 3.2. Description of the structure of compound 3 Table 2 shows bond lengths and bond and torsion angles. Fig. 1 displays the structural formula with the numbering used in the crystallographic study. Fig. 2 shows a view of the packing of the molecules in the unit cell. The molecules are linked by two N – H· · ·N hydrogen bonds and in each molecule exists an intramolecular hydrogen bond between O1· · ·H11 (Figs. 1 and 2, Table 3). The molecules in the crystal present a chair – boat conformation with the N-methyl group in axial disposition

Scheme 1. Synthesis of carbamates 3– 9.

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Table 2 ˚ ), and bond and torsion angles (8) for compound 3 Bond lengths (A Bond lengths N(1) –C(21) N(2) –C(21) N(3) –C(21) N(4) –C(13) N(4) –C(41) O(2) –C(1) C(11)– C(12) C(12)– C(13) C(14)– C(18) C(16)– C(17) C(22)– C(23) C(23)– C(24) C(25)– C(26) Bond angles C(1)–N(2) –C(21) C(21)– N(2)–C(22) C(13)– N(4)–C(14) C(14)– N(4)–C(41) O(1) –C(1)–O(2) O(2) –C(1)–N(2) O(2) –C(11)–C(15) C(11)– C(12)–C(13) N(4) –C(13)–C(12) N(4) –C(14)–C(18) C(18)– C(14)–C(15) C(17)– C(16)–C(13) C(17)– C(18)–C(14) N(3) –C(21)–N(2) C(23)– C(22)–C(27) C(27)– C(22)–N(2) C(23)– C(24)–C(25) C(27)– C(26)–C(25) C(26)– C(27)–N(3) Some torsion angles C14–N4–C13–C12 C11–C12–C13–N4 C15–C11–C12–C13 C12–C11–C15–C14 C14–N4–C13–C16 N4–C14–C15–C11 C13–N4–C14–C15 C13–N4–C14–C18 H122–C12–C13–H131

1.332(3) 1.418(3) 1.299(3) 1.460(4) 1.462(4) 1.330(3) 1.506(4) 1.546(4) 1.530(4) 1.522(6) 1.386(3) 1.377(4) 1.392(4) 124.9(2) 105.6(2) 110.0(2) 112.4(3) 126.3(2) 109.5(2) 104.5(2) 112.3(2) 108.2(2) 112.7(3) 111.8(3) 110.9(3) 111.0(3) 112.7(2) 121.9(2) 104.7(2) 122.3(3) 118.0(3) 128.2(2) 66.6(1) 29.1(1) 245.1(1) 45.6(1) 257.9(1) 8.3(1) 266.3(1) 58.1(1) 1.2 (1)

N(2)– C(1) N(2)– C(22) N(3)– C(27) N(4)– C(14) O(1)– C(1) O(2)– C(11) C(11)–C(15) C(13)–C(16) C(14)–C(15) C(17)–C(18) C(22)–C(27) C(24)–C(25) C(26)–C(27) C(1)–N(2) –C(22) C(21)–N(3) –C(27) C(13)–N(4) –C(41) C(1)–O(2) –C(11) O(1)– C(1)–N(2) O(2)– C(11)–C(12) C(12)–C(11)– C(15) N(4)– C(13)–C(16) C(16)–C(13)– C(12) N(4)– C(14)–C(15) C(11)–C(15)– C(14) C(18)–C(17)– C(16) N(3)– C(21)–N(1) N(1)– C(21)–N(2) C(23)–C(22)– N(2) C(22)–C(23)– C(24) C(24)–C(25)– C(26) C(26)–C(27)– C(22) C(22)–C(27)– N(3) C11–C12–C13– C16 N4–C13–C16–C17 C12–C13–C16– C17 C18–C14–C15– C11 N4–C14–C18–C17 C15–C14–C18– C17 C13–C16–C17– C18 C16–C17–C18– C14 H141–C14–C15–H152

1.382(3) 1.418(3) 1.399(3) 1.463(4) 1.202(3) 1.461(3) 1.517(4) 1.529(4) 1.531(4) 1.512(6) 1.395(3) 1.383(4) 1.374(4) 129.6(2) 105.8(2) 113.3(3) 117.9(2) 124.2(2) 109.7(2) 113.1(2) 113.0(3) 112.0(3) 108.7(2) 112.3(3) 111.7(3) 125.8(2) 121.5(2) 133.4(2) 116.6(3) 120.5(3) 120.6(2) 111.2(2) 116.1(1) 54.5(1) 268.0(1) 2116.7(1) 255.1(1) 67.6(1) 250.2(1) 50.6(1) 21.0(1)

3.3. NMR spectra

In the case of 13C NMR assignment, substituent steric and electronic effects on 13C chemical shifts and signal multiplicity obtained from DEPT experiment were taken into consideration. The 13C NMR chemical shifts are tabulated with the signal assignments in Table 6.

The assignment of proton and carbon resonances for compounds 3– 9 was made on the basis of DR experiments, our previous study of the corresponding b-derivatives [4], and the literature data of a-and b-granatanols [5,6] and related compounds [7,8]. The values of the proton magnetic parameters were deduced by analysis of the respective spin systems and are listed in Tables 4 and 5.

3.3.1. Spectral analysis The 1H NMR spectra of compounds 3 –9 in CDCl3 exhibit high complexity due to the large number of couplings between the bicyclic system protons, but in general the signals appear well differentiated. The signals corresponding to H6(8)a and H7b protons appear as a doublet and as a low resolution multiplet, respectively.

with respect to the chair piperidine ring and the carbamate group in an endo disposition with respect to the disubstituted ring.

I. Iriepa et al. / Journal of Molecular Structure 708 (2004) 117–125

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Fig. 1. ORTEP view of compound 3 showing the intermolecular and intramolecular hydrogen bonding interactions with the numbering used in the crystallographic study.

Fig. 2. Packing diagram of 3.

H1(5) protons appear as an unresolved broad doublet or singlet, and could not be analyzed. The multiplets corresponding to H2(4)a, H2(4)b and H3 have been considered as patterns of the four spin systems ABCX formed by H1, H2a, H2b and H3 (or H5, H4a, H4b and H3) protons whose first order analysis allowed the establishment of their respective proton magnetic parameters (chemical shifts and geminal and vicinal coupling constants). The multiplets corresponding to H6(8)b and H7a appear simplified as a triplet of triplets and a quartet of triplets,

Table 3 ˚ , deg) in compound 3 with ESD values in Hydrogen bonding interactions (A parentheses Atoms D–H· · ·A

D· · ·A

H· · ·A

kD–H· · ·A

Intramolecular N1–H11· · ·O1

2.717(3)

2.094(1)

127.0(2)

Intermolecular N1–H12· · ·N3

2.974(2)

2.100(1)

171.0(2)

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I. Iriepa et al. / Journal of Molecular Structure 708 (2004) 117–125

Table 4 1 H RMN chemical shifts (d, ppm) for compounds 3 –9 in CDCl3

H1(5) H2(4)b H2(4)a H6(8)b H6(8)a H7b H7a N–CH3 H3 H40 H50 H60 H70 NH carbamate NH2 OCH3 CH3

3

4

5

3.10 (d) 2.67 (ddd) 1.74 (ddd) 1.99 (tt) 1.19 (d) 1.53 (m) 2.09 (m) 2.47 (s) 5.43 (q) 7.33 (d) 7.20 (t) 7.05 (t) 7.64 (d) – 6.27 (brs) – –

3.12 (m) 2.73 (ddd) 1.80 (ddd) 2.05 (m) 1.31 (d) 1.54 (m) 2.21 (m) 2.53 (s) 5.41 (q) 7.11 (s) – – 7.42 (s) – 6.23 (brs) – 2.30 (s)

6

3.08 (d) 2.58 (ddd) 1.67 (ddd) 1.96 (tt) 1.15 (d) 1.47 (m) 2.08 (m) 2.49 (s) 5.30 (q) 7.54 (m) 7.17 (dd) 7.17 (dd) 7.54 (m) 10.68 (brs) – – –

7

3.12 (d) 2.65 (ddd) 1.72 (ddd) 1.96 (tt) 1.16 (d) 1.43 (m) 2.11 (m) 2.51 (s) 5.31 (q) 7.29 (m) – – 7.29 (m) 10.60 (brs) – – 2.33 (s)

8

3.04 (m) 2.60 (ddd) 1.63 (m) 1.96 (m) 1.12 (d) 1.38 (m) 1.96 (m) 2.49 (s) 5.32 (q) 7.90 (d) 7.40 (t) 7.30 (d) 7.80 (d) 10.40 (brs) – – –

9

3.00 (m) 2.53 (ddd) 1.56 (ddd) 1.96 (tt) 1.24 (m) 1.45 (m) 2.13 (tt) 2.46 (s) 5.20 (tt) 7.37 (d) 6.90 (d) – – 11.62 (brs) – – –

3.09 (d) 2.65 (ddd) 1.67 (ddd) 2.00 (m) 1.18 (d) 1.40 (m) 2.00 (m) 2.53 (s) 5.30 (tt) 7.75 (d) 6.99 (dd) – 7.28 (d) 10.60 (brs) – 3.87 (s) –

Abbreviations: brs, broad singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublet of doublets; dt, doublet of triplets; m, multiplet; q, quintuplet; s, singlet; t, triplet; tt, triplet of triplets.

respectively, and have been considered as patterns of the five spin system ABCDE formed by H1, H8b, H8a, H7b and H7a (or H5, H6b, H6a, H7b and H7a). Their first order analysis led to the determination of the corresponding magnetic parameters included in Tables 4 and 5. It was observed that l2 JH6ð8Þb 2 H6ð8Þa l < l3 JH6ð8Þb 2 H7a l < l2 JH7b 2 H7a l < 13 Hz

H6(8)a protons appear as an apparent doublet of broad signals due to the geminal coupling with H6(8)b. The vicinal coupling constants 3J H6(8)a 2 H7b and 3J H6(8)a 2 H1(5) could not be determined. Therefore, a limit value of ca. 2 Hz has been estimated, taking into account the value of 3 J H6(8)a 2 H7a (Table 5) deduced from the analysis of the H7a signal and the W1/2 of each signal of the apparent doublet due to H6(8)a. 3.3.2. Conformational study The bicyclo[3.3.1]nonane system can adopt three groups of conformations: chair –chair, chair – boat, and boat – boat

and 3 JH6ð8Þb 2 H7b <3 JH6ð8b Þ 2 H1ð5Þ < 5 Hz:

Table 5 Coupling constantsa (J, Hz) deduced from the analysis of the 1H NMR spectra of compounds 3– 9

H2(4)a–H2(4)b H2(4)a–H1(5) H2(4)a–H3 H2(4)b–H1(5) H2(4)b–H3 H6(8)a–H6(8)b H6(8)b–H7a H6(8)b–H7b H6(8)b–H1(5) H6(8)a–H7a H6(8)a–H1(5) H7a–H7b H40 – H5 H50 – H6 H50 – H7 H60 – H7 a b c

3

4

5

6

7

8

9

214.1 2.4 8.1 9.7 7.2 212.5 –c –c –c –c –c 212.5 8.1 7.7 – 8.1

213.3 ,2b 6.6 9.1 6.6 212.7 –c –c –c –c –c 212.7 – – – –

214.5 2.6 7.5 9.3 7.4 213.2 13.2 4.1 4.1 –c –c 214 –c –c –c –c

214.2 2.3 8.2 9.5 7.3 213.3 13.3 4.3 4.3 –c –c 213.1 – – – –

214.1 ,2b 6.8 7.4 6.7 210.5 –c 4.8 4.8 –c –c 210.5 7.6 7.0 –c 7.6

214.9 2 5.5 7.6 7.4 213.3 13.3 5.2 5.2 5.0 –c 213.1 3.6 – – –

214.4 2.2 7.0 9.2 6.9 212.5 213 4.0 4.0 3.9 3.9 213.0 8.9

Values deduced from the first order analysis of the corresponding system protons. J H2(4)a –H1(5) are very small and only an estimated value could be deduced. This coupling constant could not be established owing to low resolution.

2.8

I. Iriepa et al. / Journal of Molecular Structure 708 (2004) 117–125 Table 6 13 C RMN chemical shifts (d, ppm) for compounds 3 –9 in CDCl3 3

4

5

6

7

8

9

C1(5) C3 C2(4) C6(8) C7 N–CH3 CyO O–CH3 CH3

51.44 72.67 31.34 24.34 14.58 40.23 153.76 – –

51.62 69.40 31.42 24.70 14.30 40.31 155.12 – –

51.70 69.18 31.60 24.41 14.28 40.21 155.59 – 20.08

51.29 69.07 31.00 25.55 14.73 40.68 161.79 – –

51.04 69.82 30.81 24.32 14.13 40.22 160.08 – –

51.63 68.93 31.13 24.60 14.00 40.21 158.71 55.84 –

C20 C3a0 C40 C50 C60 C70 C7a0

151.57 130.12 113.86 120.73 124.52 116.45 142.29

51.46 71.84 31.14 24.64 14.58 40.26 153.14 – 20.38 20.02 151.59 129.08 114.67 128.25 132.91 117.31 140.37

148.73 121.64 113.03 121.64 121.64 113.03 121.64

148.58 130.34 114.02 130.34 130.34 114.02 130.34

153.54 – 136.80 112.39 – – –

152.61 148.57 120.46 125.52 123.22 120.85 131.83

152.99 142.88 121.29 104.24 156.59 121.29 133.00

[1,4 – 10]. It is known that the 9-azabicylo[3.3.1]nonane ring system adopts a double chair conformation [11] which is slighty flattened to relieve the transanular steric interactions of the endo hydrogens on carbons 3 and 7. Substitution at the 3-endo or both 3-endo and 7-endo positions of the bicyclic system introduces severe transanular 3,7-interactions and 1,3-diaxial interactions in the chair – chair form and forces the substituted ring to adopt a boat conformation. Therefore, substituents at these positions determine the conformation of this system and chair–boat forms must have a predominant contribution to the conformational equilibrium [1,4 – 10]. Chemical shifts of C7 are the more significant carbon parameters for the conformational analysis of compounds (3 – 9). The observed chemical shifts (14.0 – 14.7 ppm) are similar to the reported value for a-granatanol (14.5 ppm) [6] and related compounds [1,8], implying that our bicyclic systems exist predominantly in a chair – boat conformation in order to relieve the steric interactions present in the chair–chair conformation between endo carbamate group and H7 hydrogens. Moreover, in the 1H NMR spectra the W1/2 for the H1(5) signal (ca. 17 Hz) [1,8] corresponds to a piperidine substituted ring in a boat conformation. In fact, the deduced coupling constants between H2(4)a, H2(4)b and H1(5) (Table 5) support a preferred boat conformation for the ring with the carbamate group in an endo disposition. The preferred conformation found in solution for compounds 3– 9 is in good agreement with that observed in the solid state for compound 3. The chemical shifts of carbon and protons of the N – CH3 substituent (Tables 4 and 6) are in agreement with an axial disposition with respect to the piperidine ring [1,8]. In the case of compounds 3 and 4 the 1H-NMR data revealed that they exist in the tautomeric amino form and not in the imino form. The broad singlet at 6.20 ppm

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corresponding to two protons suggests the presence of the NH2 group. For an imino structure two different signals corresponding to the NH groups should be expected. This conclusion is also supported by IR data (see below) and X-Ray diffraction for compound 3. Compounds 5 and 6 can also be described as the amido tautomer (Scheme 1) and not as the imido tautomer. This conclusion has been made by comparison of the NMR and IR data of these compounds with those of the corresponding b-derivatives and by X-Ray diffraction of (N-(benzimidazol-2-yl)-9-methyl-9-azabicyclo[3.3.1]nonan-3b-yl-carbamate) [4]. For these compounds 13C NMR data also suggest intramolecular hydrogen bonding in our working conditions: The D[ dCyO (7 – 9) 2 dCyO(5)] , 5 ppm is explained by the fact that in compound 5 the CyO group is hydrogen bonded (Scheme 1). The D[dCyO(7 – 9) 2 dCyO(6)] , 5 ppm can also be explained in the same way. 3.4. Infrared spectra Data for the infrared spectra of compounds 3– 9 in the N –H and double bond stretching regions are given in Table 7. 3.4.1. Aminobenzimidazole derivatives The infrared spectra of compounds 3, 4 in the solid state (KBr) showed a sharp-medium band at 3440 –3441 cm21 and a non-well defined absorption at about 3040 – 3032 cm 21 which upon dilution in CCl4 (, 0.0005 M) were replaced by two medium bands at 3515 – 3514 and 3392– 3391 cm21, respectively. In CDCl3 solution (, 0.05 M) the corresponding bands appeared at 3509 – 3508 and 3389– 3390 cm21. These results are similar to those obtained for the related b-derivatives, which were confirmed by partial deuteration [4,12,13] and reveal that compounds 3, 4 exist in the tautomeric amino-form and not in the imino-form. X-ray data for 3 (see above) confirm infrared conclusions. Moreover, taking into account results in the solid state at the liquid air temperature, and also X-ray data for compound 3 the higher frequency band is assigned to the stretching vibration of an intramolecularly bonded N –H (N – H· · ·OyC) of the primary amino group (Scheme 1). The lower frequency band is assigned to an intermolecularly bonded NH (N – H· · ·N) of the primary amino group in a cyclic dimer. In solution the two observed bands correspond to the asymmetric and symmetric modes of the NH2 group, respectively. It should be remarked that in CDCl3 solution and even in a very dilute CCl4 solution a part of molecules (mainly in 4 in CDCl3) remains bonded in equilibrium with free species indicating the high strength of the intermolecular hydrogen bond in the solid (Table 7). In the double bond region a strong band appeared at 1734 – 1730 cm21 in 3 and at 1731 – 1728 cm21 in 4 which is assigned to the n(CyO) of the carbamate system.

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I. Iriepa et al. / Journal of Molecular Structure 708 (2004) 117–125

Table 7 Infrared frequencies (cm21) of compounds 3–9 Compound

Medium

b

3

4

5

6

7

n(N –H)a,b

n(NH2) d

KBr

3440 mf

CDCl3

3509 m

3389 m

CCl4 KBr

3515 m 3441 w-m

3392 m

CDCl3

3508 m

3390 m

CCl4 KBr

3514 m

3391 m

n(N– H)c

,3040 w,brg

e

3413 m

,2690 br

CDCl3

3410 m

,2680 bre

CCl4

3405 m

KBr

3408 m

3435 shj ,2680 bre ,2750bre

CDCl3

3411 m

–i

CCl4 KBr

3407 m

3440 shj ,2530 bre

8

3423 mj 2083k

9

CDCl3 CCl4 KBr

c

e f g h i j k

1666 m 1646 sh 1658 sh 1640 vs –i 1663 m 1648 sh 1656 sh 1642 s –i 1642 vs

1728 vs

CCl4 KBr

d

1734 vs

–i 1731 vs

,3032 wg

3410 wj

a

Heterocyclic ring

1730 vs

CDCl3

b

n(CyO)

e

–i 1709 sh 1694 s 1715 s

1640 vs

1607 mh 1593 w 1604 mh 1590 vs –i 1619 w 1587 vw 1612 sh 1585 w –i 1598 vsh 1588 vs 1598 vsh 1588 vs –i

1548 w 1530 sh 1533 vw –i 1545 vw 1547 vw 1528 w –i 1519 m 1521 m

–i

–i

1738 sh 1712 s 1735 sh 1715 s –i 1730 sh 1712 vs 1728 s

1646 s 1628 sh 1647 s

1597 vsh 1599 vsh

1548 w 1520 m 1520 m

–i

–i 1604 m

–i 1560 vs

1602 m

1562 sh 1546 vs –i 1550 sh

–i 1581 s

3416 wj 3429 mj ,2510 vwe

–i 1718 m 1700 vs 1716 s –i 1720 s

CDCl3

3411 wj

1724 s

1608 s

CCl4

3425 mj

–i

–i

1568 s –i 1609 s

–i

1542 s –i 1576 s 1559 s 1570 sh 1553 s –i

Heterocycle. Intermolecularly bonded NH. Carbamate group. Symmetric mode of the NH2 group. Intermolecularly bonded NH. Abbreviations: br, broad; m, medium; s, strong; sh, shoulder; v, very; w, weak. Tentative assignment. Probable contribution of phenyl ring band. Not measured. Free N-H group. Transmission maximum of the double band system.

Bands characteristic of the heterocyclic ring appeared in the 1670 – 1500 cm 21 region. The differences observed between solid and solution in this region are attributed to the breaking of the intermolecular hydrogen bonds, which implies changes in the coupling of deformation amino vibrations with heterocyclic n(CyN). In the case of compound 5, the infrared spectrum in the solid state presented a medium band at 3413 cm21 which was shifted to 3405 cm21 in CCl4 (3410 cm21 in CDCl3). These results suggest the existence of intramolecular

bonding, in this case between the CyO carbamate and the benzimidazole NH group as it was revealed by X-ray data for the related b-derivative [4]. A broad absorption below 2750 cm21 is assigned to strong NH· · ·N bonding in a cyclic dimer. This assignment is also in accordance with X-ray data for the related b-derivative. Upon dilution in CCl4 (, 0.0005 M) this absorption greatly decreased giving place to a new absorption at 3435 cm21 corresponding to free species. It must be remarked that in CDCl3 solution (0.05 M) most of the molecules remained bonded

I. Iriepa et al. / Journal of Molecular Structure 708 (2004) 117–125

and the presence of free NH groups could not be detected in the corresponding spectrum. Infrared results for compound 6 are similar to those obtained for 5 in CDCl3 and in CCl4 solution although small differences could be detected in the solid state. 3.4.2. Thiazole and benzothiazole derivatives The infrared spectra of compounds 7 – 9 showed in the solid state broad absorptions below 3000 cm 21 and upon dilution in CCl4 (, 0.0005 M) one band at 3423 – 3429 cm 21 (3410 – 3416 cm21 in CDCl3 ). In CDCl3 (0.05 M) bonded molecules exist in equilibrium with free molecules. The infrared results indicate the presence of a strong intermolecular hydrogen bond which is probably formed between the carbamate NH group and the heterocyclic nitrogen. In the double bond region a strong band appeared at 1700 – 1728 cm21 which is assigned to the carbamate n(CyO). Characteristic bands of the benzothiazol or thiazole ring appeared in the 1610 –1540 cm21 region. Differences between solid and solution can be explained by coupling between d(N – H) and n(CyN) modes.

4. Conclusions Although several methods have been reported for preparing carbamates, we found that condensation of 9-methyl-9-azabicyclo[3.3.1]nonan-3a-ol-chloroformate with 2-aminobenzimidazole, 2-aminothiazole and 2-aminobenzothiazole and substituted derivatives was a efficient method to synthesize these compounds. Acylation of 2-aminobenzimidazole and derivatives took place in the exocyclic and in the endocyclic nitrogens with production of the 2-carbamate and the 1-carbamate, respectively. Both carbamates are obtained

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in an approximately 4:1 ratio (for compounds 4 and 6) and in a 13:1 ratio (for compounds 3 and 5) in favour of the 1-carbamate. In CDCl3 solution the carbamates 3– 9 adopt a preferred chair–boat conformation with the N –CH3 substituent in an axial position with respect to the chair piperidine ring. The preferred conformation in solution is in agreement with the crystal structure determined by X-ray diffraction for compound 3. These compounds were expected to be biologically active as 5-HT3 antagonists; however, the results of the pharmacological evaluation showed that the reference compounds were more active than the tested substances.

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