alexa An Efficient Synthesis of Some New Azaspirocycloalkane Derivatives fro
ISSN: 2150-3494
Chemical Sciences Journal
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An Efficient Synthesis of Some New Azaspirocycloalkane Derivatives from 1-anilinocycloalkanecarboxamide

Mounir AA Mohamed1, Hassan M Moustafa1 and Mahmoud Abd El Aleem Ali El-Remaily1,2*

1Chemistry Department, Faculty of Science, Sohag University, 82524 Sohag, Egypt

2Department of Organic Chemistry, Faculty of Science, Granada University, Granada, E-18071, Spain

Corresponding Author:
Mahmoud Abd El Aleem Ali El-Remaily
Department of Organic Chemistry, Faculty of Science
Granada University, Granada, E-18071, Spain
Tel: +201008036348
Fax: +209360115982524
E-mail: [email protected]

Received date: May 16, 2014; Accepted date: May 28, 2014; Published date: June 05, 2014

Citation: Mohamed MAA, Moustafa HM, Ali El-Remaily MAEA (2014) An Efficient Synthesis of Some New Azaspirocycloalkane Derivatives from 1-anilinocycloalkanecarboxamide. Chem Sci J 5:083. doi:10.4172/2150-3494.1000083

Copyright: © 2014 Mohamed MAA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

1-anilinocyclohexanecarboxamides 2a-c were found to be a versatile precursors for the synthesis of five-, six- and seven-membered ring spiroheterocycles compounds 3-14. A general high yielding protocol for the synthesis of many functionalized spiro heterocyclic systems was presented.

Keywords

Azaspiroheterocycles; Cycloalkanones; Anilinocyclohexane- 1-carbonitrile; Spiro heterocyclic

Introduction

Spiro-compounds form a group of generally less investigated compounds. However, recently growing efforts have been made to synthesize and characterize these compounds. Many spiro compounds possess very promising biological activities as anticancer agents [1,2], antibacterial agents [3,4], anticonvulsant agents [5-7], antituberculosis agents [8], anti-Alzheimer’s agents [9], pain-relief agents [10,11], anti-dermatitis agents [12] and antimicrobial agents [13,14]. In addition to their medical uses, some spiro-compounds have found other uses in the agricultural and industrial fields. For example, they are used as antifungal agents [15], pesticides [16], laser dyes [17] and electroluminescent devices [18]. Spiro compounds have also been recently used as antioxidants [19,20]. Furthermore, Nitrogen containing heterocyclic compounds constitute the largest portion of chemical entities, which are part of many natural products, fine chemicals, and biologically active pharmaceuticals vital for enhancing the quality of life [21]. Among a large variety of nitrogen containing heterocyclic compounds, heterocycles containing a spiro system are of interest because they constitute an important class of natural and nonnatural products, many of which exhibit useful biological activities and clinical applications [21].

Methods

All melting points were determined on a Koffler melting point apparatus and are uncorrected. 1H-NMR spectra were recorded on a Brukeravance 300 MHz spectrometer using TMS as internal reference (chemical shifts in δ, ppm), and IR spectra were obtained on a Nicolet 710 FT-IR spectrometer (KBr, νmax in cm-1).

Synthesis of 1-anilinocycloalkanecarboxamide (1-phenylaminocycloalkane- 1-carboxylic acid amide 2a-c [22]

The nitrile 1 (0.1 mol) was dissolved in conc. H2SO4 (50 ml) at ~2°C, in a single necked flask with a CaCl2 trap. The reaction mixture was left at room temperature overnight (24 h). Water was added (~150 ml) to the precipitated dihydrogensulphate of amide and then the reaction mixture was neutralized with Na2CO3. The precipitated free amide 2a-c was filtered off, washed with water and air dried. Yield: 17 g (83%).

Synthesis of biazaspiroheterocycles

General procedure: A mixture of compound 2 (0.01 mol) and the proper reagent: ethylchloroacetate; bromomalononitrile; chloroacetonitrile; ethylchloroformate; cyclopentanone and/or cyclohexane (0.01 mol) was dissolved in MeOH (30 ml) then was treated with MeONa (0.01 mol). The reaction mixture was heated under reflux for 8 h, solvent was evaporated invaccuo and the residual mass was triturated with petroleum ether (60-80). The formed solid was collected by filtration and recrystallized from the proper into the corresponding product 3-8.

Synthesis of 6-phenyl-6,9-diazaspiro[4.5]decane-8,10-dione 3a-c

The reaction mixture was refluxed for 3 h; solvent was evaporated under reduced pressure, water was added and the formed solid was collected by filtration and recrystallized from aq. EtOH into white needles (Table 1).

Comp. No Mp (°C)* M. F. (M.W.) IR (KBr, n, cm-1) 1H-NMR (DMSO, d ppm)
2a 162-163
(161) [22]
C12H16N2O
(204.26)
3395, 3308, 3248 (NH2, NH), 1674 (CO). 10.21(br, 1H, NH); 7.80-7.44(m, 5H, CH-arom.), 5.35-5.22(br, 2H, NH2), 1.22-0.96(m, 8H, cyclic CH2).
2b 146-150
(148-149) [23]
C13H18N2O
(218.27)
3390, 3302 (NH2), 3245 (NH), 16740 (CO). 10.25(br, 1H, NH); 7.77-7.45(m, 5H, CH-arom.), 5.38-5.24(br, 2H, NH2), 1.24-0.96(m, 10H, cyclic CH2).
2c 173-175
(141-142) [24]
C14H20N2O
(232.32)
3388, 3310, 3242 (NH2, NH), 16748(CO). 10.21(br, 1H, NH); 7.80-7.48(m, 5H, CH-arom.), 5.41-5.30(br, 2H, NH2), 1.28-0.90(m, 12H, cyclic CH2).
3a 172-174 C14H16N2O2
(244.28)
3280(NH), 1691, 1670(2CO) 10.65(br, 1H, NH); 7.70-7.43(m, 5H, CH-arom.), 3.16(s, 2H, CH2), 1.26-0.95(m, 8H, cyclic CH2).
3b 163-165
(160-163) [25]
C15H18N2O2
(258.31)
3277(NH), 1685, 1675(2CO) 10.55(br, 1H, NH); 7.75-7.45(m, 5H, CH-arom.), 3.05(s, 2H, CH2), 1.25-0.92(m, 10H, cyclic CH2).
3c 178-180 C16H20N2O2
(272.34)
3287(NH), 1696, 1678(2CO) 10.52(br, 1H, NH); 7.72-7.45(m, 5H, CH-arom.), 3.12(s, 2H, CH2), 1.30-0.92(m, 12H, cyclic CH2).
4a 212-214 C15H16N4O
(268.31)
3395, 3318, 3283(NH2, NH); 2202(CN); 1682(CO). 10.82(br, 1H, NH); 7.82-7.53(m, 5H, CH-arom.); 5.82-5.68(br, 2H, NH2); 1.21-0.92(m, 8H, cyclic CH2).
4b 202-204 C16H18N4O
(282.28)
3388, 3320, 3290(NH2, NH); 2212(CN); 1675(CO). 10.53(br, 1H, NH); 7.75-7.40(m, 5H, CH-arom.); 5.80-5.68(br, 2H, NH2); 1.20-0.90(m, 10H, cyclic CH2).
4c 196-198 C17H20N4O
(296.32)
3390, 3302, 3284(NH2, NH); 2206(CN); 1681(CO). 10.62(br, 1H, NH); 7.80-7.45(m, 5H, CH-arom.); 5.88-5.72(br, 2H, NH2); 1.35-0.88(m, 12H, cyclic CH2).
5a 192-195 C14H17N3O 3378, 3303, 3268(NH2, NH); 1675(CO). 10.21(br, 1H, NH); 7.72-7.40(m, 5H, CH-arom.); 6.60(d, 1H, =CH); 5.65-5.52(br, 2H, NH2); 1.21-0.95(m, 8H, cyclic CH2).
5b 198-200 C15H19N3O 3388, 3319, 3283(NH2, NH); 1677(CO). 10.52(br, 1H, NH); 7.75-7.45(m, 5H, CH-arom.); 6.55(d, 1H, =CH); 5.60-5.51(br, 2H, NH2); 1.25-0.93(m, 10H, cyclic CH2).
5c 190-193 C16H21N3O 3383, 3309, 3277(NH2, NH); 1678(CO). 10.28(br, 1H, NH); 7.76-7.42(m, 5H, CH-arom.); 6.62(d, 1H, =CH); 5.66-5.55(br, 2H, NH2); 1.28-0.90(m, 12H, cyclic CH2).
6a 202-205 C13H14N2O2
(230.26)
3284(NH), 1668(CO). 10.48(br, 1H, NH); 7.78-7.45(m, 5H, CH-arom.); 1.22-0.95(m, 8H, cyclic CH2).
6b 211-213 C14H16N2O2
(244.27)
3274(NH), 1676(CO). 10.43(br, 1H, NH); 7.81-7.47(m, 5H, CH-arom.); 1.25-0.95(m, 10H, cyclic CH2).
6c 212-214 C15H18N2O2
(258.28)
3278(NH), 1665(CO). 10.40(br, 1H, NH); 7.75-7.45(m, 5H, CH-arom.); 1.28-0.93(m, 12H, cyclic CH2).
7a 241-243 C17H21NO2
(271.35)
1732(CO). 7.79-7.45(m, 5H, CH-arom.); 1.45-0.93(m, 16H, cyclic CH2).
7b 246-248 C18H23NO2
(285.36)
1740(CO). 7.82-7.47(m, 5H, CH-arom.); 1.50-0.90(m, 18H, cyclic CH2).
7c 250-252 C19H25NO2
(299.37)
1738(CO). 7.75-7.43(m, 5H, CH-arom.); 1.55-0.91(m, 18H, cyclic CH2).
8a 305-307 C20H18N2O3
(334.36)
3289(NH), 1733(CO), 1678(CO). 10.21(br, 1H, NH); 7.95-7.40(m, 9H, CH-arom.); 1.21-0.95(m, 8H, cyclic CH2).
8b 308-310 C21H20N2O3
(348.37)
3279(NH), 1730(CO), 1668(CO). 10.25(br, 1H, NH); 7.90-7.42(m, 9H, CH-arom.); 1.25-0.93(m, 10H, cyclic CH2).
8c 310-312 C22H22N2O3
(362.37)
3295(NH), 1741(CO), 1672(CO). 10.18(br, 1H, NH); 7.88-7.41(m, 9H, CH-arom.); 1.28-0.90(m, 12H, cyclic CH2).
9a 182-184 C15H14N2O2
(254.28)
2203(CN), 1682(CO). 7.77-7.45(m, 5H, CH-arom.); 6.15(s, 1H, CH); 1.22-0.94(m, 8H, cyclic CH2).
9b 180-183 C16H16N2O2
(268.29)
2210(CN), 1677(CO). 7.75-7.45(m, 5H, CH-arom.); 5.98(s, 1H, CH); 1.25-0.94(m, 10H, cyclic CH2).
9c 188-190 C17H18N2O2
(282.30)
2205(CN), 1676(CO). 7.80-7.47(m, 5H, CH-arom.); 6.06(s, 1H, CH); 1.30-0.95(m, 12H, cyclic CH2).
10a 220-222 C15H17N3O2
(271.31)
3380, 3312, 3282(NH2, NH); 1675(CO). 9.98(br, 1H, NH), 7.77-7.45(m, 5H, CH-arom.); 6.18-6.12(br, 2H, NH2); 5.56(s, 1H, =CH); 1.20-0.92(m, 8H, cyclic CH2).
10b 225-228 C16H19N3O2
(285.32)
3395, 3310, 3285(NH2, NH); 1677(CO). 9.95(br, 1H, NH), 7.774-7.45(m, 5H, CH-arom.); 6.16-6.12(br, 2H, NH2); 5.41(s, 1H, =CH); 1.25-0.92(m, 10H, cyclic CH2).
10c 228-230 C17H21N3O2
(299.33)
3383, 3313, 3277(NH2, NH); 1667(CO). 10.05(br, 1H, NH), 7.78-7.44(m, 5H, CH-arom.); 6.12-6.08(br, 2H, NH2); 5.45(s, 1H, =CH); 1.32-0.95(m, 12H, cyclic CH2).
11a 233-235 C21H18N2O
(314.38)
2222(CN); 1668(CO) 7.88-7.38(m, 10H, CH-arom.); 1.22-0.96(m, 8H, cyclic CH2).
11b 230-232 C22H20N2O
(228.40)
2220(CN); 1666(CO) 7.82-7.40(m, 10H, CH-arom.); 1.26-0.95(m, 10H, cyclic CH2).
11c 241-243 C23H22N2O
(342.42)
2214(CN); 1671(CO) 7.85-7.42(m, 10H, CH-arom.); 1.32-0.90(m, 12H, cyclic CH2).
12a 251-253 C23H23N3O
(357.44)
3385, 3320, 3265(NH2, NH); 2205(CN); 1669(CO). 10.35(br, 1H, NH), 7.83-7.38(m, 10H, CH-arom.); 6.22-6.16(br, 2H, NH2); 4.86(s, 1H, CH); 1.22-0.95(m, 8H, cyclic CH2).
12b 250-253 C24H25N3O
(371.47)
3380, 3315, 3270(NH2, NH); 2211(CN); 1675(CO). 10.28(br, 1H, NH), 7.80-7.36(m, 10H, CH-arom.); 6.20-6.16(br, 2H, NH2); 4.75(s, 1H, CH); 1.25-0.95(m, 10H, cyclic CH2).
12c 258-260 C24H27N3O
(385.50)
3387, 3316, 3275(NH2, NH); 2218(CN); 1672(CO). 10.40(br, 1H, NH), 7.86-7.36(m, 10H, CH-arom.); 6.24-6.18(br, 2H, NH2); 4.83(s, 1H, CH); 1.35-0.95(m, 12H, cyclic CH2).
13a 244-246 C27H23NO2
(393.47)
1778(CO). 8.15-7.30(m, 15H, CH-arom.); 1.20-0.95(m, 8H, cyclic CH2).
13b 248-250 C28H25NO2
(407.50)
1776(CO). 8.07-7.33(m, 15H, CH-arom.); 1.25-0.95(m, 10H, cyclic CH2).
13c 255-257 C27H23NO2
(421.53)
1773(CO). 8.12-7.32(m, 15H, CH-arom.); 1.32-0.91(m, 12H, cyclic CH2).
14a 302-305 C27H26N2O
(394.50)
3250(NH); 1770(CO). 10.25(s, 1H, NH); 8.05-7.38(m, 15H, CH-arom.); 6.42-6.40(s, 1H, =CH); 1.20-0.96(m, 8H, cyclic CH2).
14b 303-305 C28H28N2O
(408.53)
3243(NH); 1768(CO). 10.12(s, 1H, NH); 8.01-7.35(m, 15H, CH-arom.); 6.40-6.37(s, 1H, =CH); 1.25-0.95(m, 10H, cyclic CH2).
14c 310-312 C29H30N2O
(422.56)
3256(NH); 1775(CO). 10.38(s, 1H, NH); 8.12-7.40(m, 15H, CH-arom.); 6.55-6.52(s, 1H, =CH); 1.35-0.91(m, 12H, cyclic CH2).

Table 1: Analytical and spectral data for the obtained compounds.

Synthesis of 8-amino-10-oxo-6-phenyl-6,9-diazaspiro[4.5] dec-7-ene-7-carbonitrile 4a-c

The reaction mixture was refluxed for 4 h; solvent was evaporated under reduced pressure, the formed solid was collected and recrystallized from aq.EtOH into pale yellow crystals (Table 1).

Synthesis of 8-amino-6-phenyl-6,9-diazaspiro[4.5]dec-7-en- 10-one 5a-c

The reaction mixture was refluxed for 3 h; solvent was evaporated under reduced pressure, water was added, the formed solid was filtered off and recrystallized from aq. EtOH into white crystals (Table 1).

Synthesis of 1-phenyl-1,3-diazaspiro[4.4]nonane-2,4-dione 6a-c

The reaction mixture was refluxed for 3 h; solvent was evaporated under reduced pressure, the formed solid was collected and recrystallized from MeOH into brownish crystals (Table 1).

Synthesis of 6-phenyl-6,12-diazadispiro[4.1.4.2]tridecan-13- one 7a-c

The reaction mixture was refluxed for 5 h; solvent was evaporated under reduced pressure, the formed solid was collected and recrystallized from aq. EtOH into white needles (Table 1).

Synthesis of 6-phenyl-6,13-diazadispiro[4.1.5.2]tetradecan- 14-one 8a-c

The reaction mixture was refluxed for 5 h; solvent was evaporated under reduced pressure, the formed solid was collected and recrystallized from aq. EtOH into white powder (Table 1).

Synthesis of biazaspiroheterocycles 9-14

General procedure: A mixture of compound 1 (0.01 mol) and the proper reagent: ethylcyanoacetate; benzylidinemalononitrile and/or chalcone (0.01 mol) was dissolved in dioxan (60 ml) and was treated with solid K2CO3 (~7 g) and TBAB [tetrabutylammonium bromide] (~25 mg). The reaction mixture was stirred at 60°C for 5 h, then cooled and the solid pot. Carbonate was filtered off, washed with dioxane (~10 ml). Dioxane layer was evaporated under reduced pressure and the formed slurry was triturated with petroleum ether (60-80) where compounds 9, 11 and 13 respectively were formed in low yields (40- 45%). Carbonate layer was dissolved in water, acidified with AcOH and left overnight and the formed solids were collected by filtration and were identified as compounds 10, 12 and 14 respectively (yields: 20-25%).

Results and Discussion

Considering the above reports, we wish to report here a simple, convenient, and high-yielding method for the synthesis of some new spiro nitrogen containing hetyerocyclic compounds starting with 1-anilinocycloalkanecarboxamide 2a-c [22-27] which were obtained from the acid hydrolysis of 1-anilinocycloalkane-1- carbonitrile 1a-c (Scheme 1).

chemical-sciences-journal-Synthesis

Scheme 1

We have concentrated most of our work for the preparation of bioactive nitrogen-containing heterocycles, and we have already found that the reaction of 1-anilinocyclohexanecarboxamide2b with ethyl chloroacetate in refluxing MeOH in the presence of a catalytic amount of MeONa afforded 1-phenyl-1,4-diazaspiro[5.5]undecane-3,5-dione 3b (Scheme 2).

chemical-sciences-journal

Scheme 2

The reaction pathway was assumed to follow a preliminary nucleophilic attack of the secondary amine into the α-halo ester with subsequent elimination of HCl molecule followed by another nucleophilic attack of the amino group onto the ester carbonyl group with subsequent elimination of EtOH molecule, (Scheme 2). The anticipated structure of compound 3b was in agreement with the spectral data, where the IR spectra of compound 3b showed bands at 3277 cm-1 corresponding to the NH group and two sharp peaks at 1691 and 1670 cm-1 corresponding to two carbonyl groups, where the 1H-NMR spectrum of compound 3b showed a broad band at δ 10.65 ppm for NH proton, muliplet at 7.70-7.43 ppm for the aromatic protons, singlet at 3.16 ppm for CH2 group and another muliplet at 1.26-0.95 ppm for cyclic CH2.

Encouraged by this success, we extended the reaction of compound 2b with α–halo compounds as bromomalononitrile, chloroacetonitrile and ethyl chloroformate under the same experimental conditions (MeONa/MeOH), where the corresponding biazaspiroheterocycles namely 3-amino-5-oxo-1-phenyl-1,4-diazaspiro[5.5]undec-2-ene-2- carbonitrile 4b, 3-amino-1-phenyl-1,4-diazaspiro[5.5]undec-2-en- 5-one 5b and 1-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione 6b were obtained respectively (Scheme 3).

chemical-sciences-journal

Scheme 3

In continuation of our study, compound 2b was reacted with some cyclic ketones as cyclopentanone and cyclohexanoneunder the same experimental conditions (MeONa/MeOH) where the corresponding spiroheterocycles 6-phenyl-14-oxa-6-azadispiro[4.1.5.2] tetradecan-13-one 7b and 7-phenyl-7,14-diazadispiro[5.1.5.2]-pentadecan-15-one 8b were obtained, respectively (Scheme 3).

On the other hand, the reaction of 1-anilinocyclohexanecarboxamide 2b with ethyl cyanoacetate under phase transfer conditions (dioxan/K2CO3/TBAB) afforded a mixture of two compounds one was obtained from dioxan layer and identified as 2,4-dioxo-1-phenyl- 1-azaspiro[4.5]decane-3-carbonitrile 9b where the other was isolated from carbonate layer after acidification with AcOH and was identified as 10-amino-7-phenyl-7,11-diazaspiro[5.6]dodec-9-ene-8,12-dione 10b cf (Scheme 4).

chemical-sciences-journal

Scheme 4

The mechanism of this reaction was assumed to follow a preliminary nucleophilic attack of the secondary amino group onto the ester carbonyl of ethylcyanoacetate and subsequent elimination of EtOH molecule to the nonisolable intermediate II which then undergoes cyclization in two different ways: compound 9b was isolated from dioxan layer and may be formed initially via Michael type addition followed by elimination of NH3 molecule, where compound 10b was isolated from carbonate layer after acidification with AcOH and was formed via a nucleophilic addition of the amino group into the cyano group (Scheme 5).

chemical-sciences-journal

Scheme 5

Similarly, compound 1b was allowed to react with benzylidenemalononitrile and 1,3-diphenylprop-2en-1-one (chalcone) where two products were obtained from each reaction one from dioxan and the other from carbonate layer after acidification, Scheme 4. Likewise, the reaction of 1-anilinocyclopentanecarboxamide2a and 1-anilino-cycloheptanecarboxamide2c were subjected to this procedure to produce the corresponding azaspiroheterocycles 3-14 (Table 1).

In conclusion, we have described a direct, simple and highly efficient method for the synthesis of biazaspiroheterocycles under traditional basic conditions as well as under phase transfer conditions (PTC).

Conclusion

The synthesis of five, six and seven-membered ring spiroheterocycles from 1-anilinocyclohexanecarboxamides 2a-c. A general high yielding protocol for the synthesis of many functionalized spiro heterocyclic systems was presented.

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