Synthesis and reactivity of amines containing several cage-like fragments

Russian Journal of Organic Chemistry, Vol. 41, No. 5, 2005, pp. 678-688. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 5, 2005,

pp. 695-705.

Original Russian Text Copyright Ó 2005 by L. Kasyan, Karpenko, A. Kasyan, Isaev.

Synthesis and Reactivity of Amines Containing Several

Cage-like Fragments

L.I. Kasyan¹, D.V. Karpenko¹, A.O. Kasyan ², and A.K. Isaev¹

¹Dnepropetrovsk National University, Dnepropetrovsk, 49050 Ukraine

²Organisch-Chemische Institut bei Rhein-Westfaelische Technische Hochschule, Aachen, BRD

Received March 22, 2004

AbstractBy reaction of bicyclo[2.2.1]hept-5-en-exo- and endo-2-ylmethylamine, exo-5,6-epoxybicyclo[2.2.1]hept-

exo-2-ylmethylamine and benzylamine with 1-adamantanecarbonyl chloride, 1,3-adamantanedicarbonyl dichloride,

and 1,3-adamantanediacetyl dichloride amides were obtained with one, two, and three cage-like fragments that

were reduced to amines by lithium aluminum hydride. The reactivity of the amines was evaluated with the use of

semiempirical quantum-chemical method PM3. Derivatives of the amines were prepared by reactions with arene-

sulfonyl chlorides, p-nitrobenzoyl chloride, succinic and endic anhydrides, p-toluenesulfonyl and m-tolyl

isocyanates, phenyl isothiocyanate, and p-nitrophenyloxirane. The structure of the new compounds was supported

by analysis of their IR and ¹H NMR spectra. The dependence of some reaction conditions was observed on the

number and remoteness of the cage-like fragments from the reaction centers of the amines.

Amines from the norbornene and norbornane series

exhibit versatile pharmacological activity.Antiviral agents

were found among them [1], for example, amine Ia intro-

duced into the medical practice as hydrochloride

(deutiforin) [2]. Mecamilamine Ib is known as ganglio-

blocking preparation [3].Amines exhibit styptic and topical

anesthetic action, they are indicators of psychic and

physical dystrophy, remove fatigue [3].

amines of the Ic group: specific inhibitors have been found

among them for the pathogenic flora, tubercle bacillus,

and other bacteria [5]. Up till now a single amine with

two cage-like fragments was described whose derivatives

(Id, R = COCH₃, CONHAr) possessed anti-arrhythmic,

hypoglycemic, and hypotensive activity [6].

Taking into account the favorable effect of the bicyclic

carbon cage-like structure on the pharmacological char-

acteristics of amines we aimed this research to develop-

ment of synthetic procedures and to study of reactivity

of amines with norbornene and adamantane skeleton, of

the dependence of their chemical behavior on the number

and relative position of the cage-like fragments. The

amines were prepared by reduction with lithium aluminum

hydride of adamantanecarboxamides; a similar procedure

had been previously used in the synthesis of alkyl-

(aralkyl)norbornenylmethylamines [7]. In amides prepara-

tion 1-adamantanecarbonyl chloride (IIa), 1,3-ada-

mantanedicarbonyl dichloride (IIb), and 1,3-adamantane-

diacetyl dichloride (IIc) were used.

Amines of the Ic group are strong analgetics; depend-

ing on the number n and character of the substituents

attached to carbon and nitrogen atoms these compounds

either increase or decrease the blood pressure and show

bactericidal properties [4]. Derivatives of bicyclo[2.2.1]-

hept-5-en-2-ylmethylamine containing piperidine, pyrro-

lidine and other moieties resemble by their activity the

1+&+

&+ 1+

&+

,D

,E

+22&

&22+

5

,,D

,,E

&+ &22+

& 1

5

&+ ꢀꢀ

5

1&+

+22&&+

,G

,F

,,F

1070-4280/05/4105-0678Ó2005 Pleiades Publishing, Inc.

SYNTHESIS AND REACTIVITY OF AMINES

679

As amine components bicyclo[2.2.1]hept-5-en-exo-

and endo-2-ylmethylamines (IIIa and IIIb), and epoxy

derivative IIIc of amine IIIa were chosen. Benzylamine

(IIId) was also used for comparison. Synthesis of amines

IIIa and IIIb was carried out by known procedures [8]

reducing the sterically uniform bicyclo[2.2.1]hept-2-en-

exo- and endo-5-ylcarbonitriles, products obtained by

diene synthesis from cyclopentadiene and acrylonitrile.

Epoxyamine IIIc was preperad by the method we had

developed earlier [9].

stretching vibrations of the carbonyl groups amide I, to

the bending vibrations of the NH bond amide II, and to

the stretching vibrations of the CN bond amide III,

and also an absorption band in the region 3400

1

3330 cm (n_NH) [11].

In the IR spectra of amides with a norbornene

fragment appears a characteristic absorption in the region

1

30603030 (n_=CH) and 725700 cm (d_=CH) [12]. The

position of the latter band is governed by the stereo-

chemical features of amides: in the IR spectrum of exo-

1

isomer IVa this band is close to the lower (712 cm ),

and that of the endo-stereoisomers to the higher limit of

the range. This band lacks in the IR spectrum of

epoxyamide IVc but a band is observed in the region

851 cm characteristic of vibrations of the CO bonds

in the three-membered ring of epoxynorbornanes [13].

&+ 1+

1

&+ 1+

,,,E

,,,D

1

Parameters of the H NMR spectra of amides IVa

2

IVd are presented in Table 1. The exo- and endo-orienta-

tion of substituents in the norbornene skeleton was con-

firmed by criteria previously developed for stereoisomeric

amines IIIa and IIIb and for the corresponding amides

containing aromatic moieties [7]. In keeping with the

known criteria in the spectra of endo-isomers IVb, IVd,

and IVe a significant nonequivalence (up to 0.2 ppm) is

observed in the protons of the olefin fragment (H⁵, H⁶)

and protons attached to atom C³(H^3xand H³ⁿ) (up to

1.3 ppm). Also a slight nonequivalence characterizes the

bridgehead protons (H¹and H⁴) (< 0.1 ppm). On the

contrary, in the spectra of exo-stereoisomers IVa and

IVc the protons at the double bond and in the epoxy ring

&+ 1+

,,,F

,,,G

Crystalline amides IVaIVf were obtained by

reactions of acyl chlorides IIaIIc with amines IIIa

IIId in the presence of triethylamine by procedure [7].

The preparation of amide IVb was formerly described in

[10].

The IR spectra of amides contain absorption bands of

the secondary amide groups in the regions 16351622,

15441526, and 12701243 cm corresponding to the

1

ꢀ

&+ 1+ꢀ2ꢁ&

,9E

,9D

2

&+ 1+ꢀ2ꢁ&

,9F

&+ 1+ꢀ2ꢁ&

&ꢀ2ꢁ1+&+

,9G

&+ 1+ꢀ2ꢁ&

&+ 1+ꢀ2ꢁ&&+

&+ 1+ꢀ2ꢁ&

&+ &ꢀ2ꢁ1+&+

,9H

RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005

,9I

L. KASYAN et al.

680

Table 1. Parameters of ¹H NMR spectra of amides IVaIVe and amines Va, Vb, Vd, and Ve, d, ppm (J, Hz)

&RPSGꢀꢁ

+ ꢁ + ꢁ

+ ꢁ

+ ꢂꢁ+ ꢁ

ꢋꢀꢍꢊꢁ

+ ꢂꢁ+ ꢁ

6XEVWLWXHQWꢁ

QRꢀꢁ

,9Dꢀ ꢃꢀꢄꢅꢁ ꢆꢀꢇꢈꢁꢆꢀꢄꢈꢁꢉ - ꢁꢆꢆꢀꢃꢂꢁ

ꢆꢀꢆꢋꢁ

ꢃꢀꢅꢈꢁ

ꢆꢀꢃꢄꢂꢁꢆꢀꢈꢇꢁ ꢈꢀꢃꢄꢂꢁꢈꢀꢃꢎꢁ ꢆꢀꢄꢍ±ꢆꢀꢎꢄꢁꢉꢆꢄ+ꢂꢁ$Gꢌꢂꢁ

-

ꢊꢀꢋꢂꢁꢁ

ꢁꢈꢀꢋꢌꢁ

ꢉ - ꢁꢇꢀꢍꢂꢁ

ꢉ - ꢁꢅꢀꢇꢌꢁ ꢄꢀꢄꢋꢁꢉꢆ+ꢂꢁ1+ꢌꢁ

-

ꢁꢃꢀꢋꢌꢁ

ꢍꢀꢄꢃꢁ

,9Eꢀ ꢃꢀꢊꢅꢁ ꢃꢀꢈꢍꢁꢆꢀꢅꢋꢁꢉ - ꢀꢆꢃꢀꢇꢌꢁ

ꢃꢀꢊꢇꢁ ꢋꢀꢆꢆꢂꢁꢋꢀꢍꢋꢁ ꢆꢀꢈꢄꢂꢁꢆꢀꢃꢃꢁ ꢃꢀꢎꢈꢂꢁꢃꢀꢅꢋꢁ ꢆꢀꢄꢄ±ꢆꢀꢎꢍꢁꢉꢆꢄ+ꢂꢁ$Gꢌꢂꢁ

ꢉ - ꢁꢅꢀꢆꢌꢁ ꢉ -

ꢁꢆꢇꢀꢈꢂꢁꢋꢀꢍꢅꢁꢉꢆ+ꢂꢁ1+ꢌꢁ

-

ꢁꢊꢀꢆꢂꢁ

ꢁꢋꢀꢋꢌꢁ

,9Fꢀ ꢃꢀꢃꢎꢁ ꢆꢀꢈꢍꢁꢆꢀꢇꢊꢁꢉ - ꢀꢆꢃꢀꢇꢂꢁ ꢆꢀꢆꢃꢁꢉ -

ꢁ

ꢃꢀꢇꢁ ꢈꢀꢆꢍꢂꢁꢈꢀꢍꢊꢁ ꢆꢀꢃꢆꢂꢁꢍꢀꢅꢅꢁ ꢈꢀꢆꢄꢂꢁꢈꢀꢆꢈꢁ ꢆꢀꢄꢍ±ꢆꢀꢎꢍꢁꢉꢆꢄ+ꢂꢁ$Gꢌꢂꢁ

ꢉ - ꢁꢇꢀꢍꢌꢁ ꢉ - ꢁꢆꢍꢀꢇꢌꢁ ꢄꢀꢋꢋꢁꢉꢆ+ꢂꢁ1+ꢌꢁ

-

ꢁꢅꢀꢇꢂꢁ -

ꢁ

ꢇꢀꢇꢂꢁ

- ꢀꢇꢀꢍꢌꢁ

ꢇꢀꢍꢌꢁ

,9Gꢀ ꢃꢀꢊꢅꢁ ꢃꢀꢇꢆꢁꢆꢀꢈꢅꢁꢉ - ꢀꢆꢆꢀꢅꢌꢁ

ꢍꢀꢄꢆꢁ

ꢃꢀꢋꢅꢁ ꢋꢀꢍꢍꢂꢁꢄꢀꢅꢊꢁ ꢆꢀꢃꢋꢂꢁꢆꢀꢆꢃꢁ ꢃꢀꢅꢍꢂꢁꢈꢀꢍꢍꢁ ꢆꢀꢄꢍ±ꢃꢀꢍꢍꢁꢉꢆꢄ+ꢂꢁ$Gꢌꢂꢁ

ꢉ - ꢁꢅꢀꢋꢌꢁ ꢅꢀꢆꢊꢁꢉꢃ+ꢂꢁ1+ꢌꢁ

ꢃꢀꢅꢆꢁ ꢋꢀꢆꢊꢂꢁꢄꢀꢎꢋꢁ ꢆꢀꢃꢋꢂꢁꢆꢀꢃꢃꢁ ꢃꢀꢎꢊꢂꢁꢃꢀꢎꢇꢁ ꢆꢀꢄꢍ±ꢃꢀꢍꢍꢁꢉꢆꢄ+ꢂꢁ$Gꢌꢂꢁ

ꢁ

,9Hꢀ ꢃꢀꢎꢍꢁ ꢃꢀꢃꢇꢁꢆꢀꢅꢇꢁꢉ - ꢀꢆꢆꢀꢇꢂꢁ

ꢍꢀꢄꢋꢁ

-

ꢁꢎꢀꢆꢂꢁꢁ

ꢁꢈꢀꢎꢌꢁ

ꢉ - ꢁꢈꢀꢎꢂꢁ

ꢀꢃꢀꢆꢌꢁ

ꢉ - ꢁꢁꢄꢀꢇꢂꢁ ꢉ - ꢁꢊꢀꢋꢌꢁ

- ꢁꢃꢀꢇꢂꢁ

ꢄꢀꢄꢋꢁꢉꢃ+ꢂꢁ1+ꢌꢂꢁꢇꢀꢍꢆꢂꢁꢇꢀꢆꢆꢁ

ꢉꢇ+ꢂꢁꢃ&+ $Gꢌꢁ

-

ꢁ

- ꢁꢃꢀꢊꢌꢁ

9Dꢀ ꢃꢀꢋꢃꢁ ꢆꢀꢇꢇꢁꢆꢀꢃꢍꢁꢉ - ꢀꢆꢆꢀꢋꢌꢁ

9Eꢀ ꢃꢀꢊꢋꢁ ꢃꢀꢈꢍꢁꢆꢀꢊꢋꢁꢉ - ꢀꢆꢆꢀꢇꢌꢁ

9Gꢀ ꢃꢀꢋꢄꢁ ꢃꢀꢋꢋꢁꢆꢀꢊꢍꢁꢉ - ꢀꢆꢆꢀꢍꢌꢁ

ꢆꢀꢆꢍꢁ

ꢉ - ꢁꢈꢀꢅꢂꢁ

ꢀꢃꢀꢋꢌꢁ

ꢃꢀꢊꢎꢁ ꢋꢀꢍꢎꢂꢁꢋꢀꢍꢇꢁ ꢆꢀꢃꢇꢂꢁꢆꢀꢈꢍꢁ ꢃꢀꢃꢊꢂꢁꢃꢀꢃꢍꢁ ꢆꢀꢄꢍ±ꢃꢀꢍꢍꢁꢉꢆꢄ+ꢂꢁ$Gꢌꢂꢁ

ꢉ - ꢁꢁꢋꢀꢇꢂꢁ ꢉ - ꢁꢅꢀꢇꢌꢁ

- ꢁꢃꢀꢅꢂꢁ

ꢃꢀꢄꢊ±ꢃꢀꢋꢅꢁꢉꢃ+ꢂꢁ&+ $Gꢌꢂꢁ

ꢃꢀꢊꢎꢁꢉꢆ+ꢂꢁ1+ꢌꢁ

-

- ꢁꢈꢀꢍꢌꢁ

ꢍꢀꢇꢅꢁ

ꢉ - ꢀꢃꢀꢄꢌꢁ

ꢃꢀꢅꢃꢁ ꢋꢀꢆꢃꢂꢁꢄꢀꢅꢅꢁ ꢆꢀꢇꢆꢂꢁꢆꢀꢃꢃꢁ ꢃꢀꢈꢍꢂꢁꢃꢀꢃꢍꢁ ꢆꢀꢄꢍ±ꢃꢀꢍꢍꢁꢉꢆꢄ+ꢂꢁ$Gꢌꢂꢁ

ꢉ - ꢁꢁꢋꢀꢆꢂꢁ ꢉ - ꢁꢅꢀꢅꢌꢁ

- ꢁꢃꢀꢋꢂꢁ

ꢈꢀꢆꢊꢁꢉꢃ+ꢂꢁ&+ $Gꢌꢂꢁꢁ

ꢈꢀꢆꢅꢁꢉꢆ+ꢂꢁ1+ꢌꢁ

- ꢁꢃꢀꢋꢌꢁ

ꢍꢀꢈꢎꢁ

ꢃꢀꢊꢈꢁ ꢋꢀꢍꢈꢂꢁꢄꢀꢊꢅꢁ ꢆꢀꢃꢄꢂꢁꢆꢀꢈꢍꢁ ꢃꢀꢆꢄꢂꢁꢃꢀꢃꢈꢁ ꢆꢀꢄꢍ±ꢃꢀꢍꢍꢁꢉꢆꢇ+ꢂꢁ$Gꢌꢂꢁ

ꢉ - ꢁꢅꢀꢇꢌꢁ

ꢃꢀꢃꢍ±ꢃꢀꢃꢄꢁꢉꢇ+ꢂꢁꢃ&+ $Gꢌꢂꢁ

ꢈꢀꢆꢄꢁꢉꢃ+ꢂꢁꢃ1+ꢌꢁ

9Hꢀ ꢃꢀꢅꢆꢁ ꢃꢀꢃꢄꢁꢆꢀꢅꢇꢁꢉ - ꢀꢆꢆꢀꢇꢌꢁ

ꢍꢀꢄꢋꢁ

ꢉ - ꢀꢈꢀꢋꢂꢁ

ꢃꢀꢅꢎꢁꢋꢀꢆꢋꢂꢁꢄꢀꢎꢋꢁ ꢆꢀꢃꢊꢂꢁꢆꢀꢆꢎꢁꢁ

ꢉ - ꢁꢁꢄꢀꢊꢂꢁꢁ ꢉ - ꢁꢅꢀꢆꢌꢁ

- ꢁꢃꢀꢇꢂꢁꢁ

ꢃꢀꢃꢅꢂꢁꢃꢀꢃꢃꢁ ꢆꢀꢈꢄ±ꢃꢀꢍꢍꢁꢉꢆꢇ+ꢂꢁ$Gꢌꢂꢁ

ꢃꢀꢅꢍꢁꢉꢃ+ꢂꢁꢁꢁꢃ1+ꢌꢂꢁꢃꢀꢎꢋ±

ꢃꢀꢎꢃꢁꢉꢇ+ꢂꢁꢃ&+ $Gꢌꢂꢁ

-

ꢀꢃꢀꢇꢌꢁ

- ꢁꢃꢀꢋꢌꢁ

ꢈꢀꢋꢎꢂꢁꢈꢀꢇꢅꢁꢉꢇ+ꢂꢁꢃ&+ 1+ꢌꢁ

ꢁ

(H⁵and H⁶) and also the protons H^3xH³ⁿare nearly

equivalent, but a significant difference is observed in the

positions of protons H¹and H⁴. For the spectra of

amides containing additionally adamantane fragments

IVaIVd and IVf the most convincing criterium is related

to the resonance of protons at C³atom that is governed

by the contribution of the magnetic anisotropy of the

exocyclic C²C⁸bond. The proton signals from the NH

groups are located in the region 5.58.2 ppm. In the

spectrum of amide IVf the signals at 4.43 (4 H), 5.85 (2

H), and 7.25 ppm (10 H) confirm the presence of two

benzylamine groups in the amide molecule.

The reduction of amides IVaIVf with lithium

aluminum hydride in a boiling anhydrous ether (TLC

monitoring) afforded oily amines containing several

carbon cage-like structures VaVf that were additionally

characterized by preparation of the corresponding

crystalline hydrochlorides VIbVIf.

The IR spectra of amines lack bands amide I but

1

possess absorption bands in the region 34003350 cm

(n_NH) [11]. In the spectra of compounds containing

norbornene moieties appear absorption bands in the region

1

30653030 and 730710 cm (n_=CH, d_=CH). The R_f

values (ether) of amines are fairly high (0.830.96), for

RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005

SYNTHESIS AND REACTIVITY OF AMINES

681

&+ 1+&+

9D

9E

2

&+ 1+&+

9F

9G

&+ 1+&+ &+

&+ &+ 1+&+

&+ 1+&+

9H

9I

diamines VdVf they equal to 0.200.30. In the IR spectra

of amines hydrochlorides VIbVIf the absorption bands

828.45, and 847.28 kJ mol^-1respectively). In the

molecules of the secondary amines the HOMO is

localized on the nitrogen atoms, and OMO II on the

carbons of the ethylene fragments of the norbornene

carbon skeleton. The thorough study of reactivity was

carried out by an example of amine Vb which was

converted into sulfonamides (VIIaVIIc , X = NO₂, Cl,

CH₃), carboxamide VIId, amido acids VIIe and VIIf,

ureas VIIg and VIIh, and thiourea VIIi.

1

are observed in the region 27252700 cm (n_as⁺NH₂)

and also bands corresponding to the unsaturated parts of

the salt molecules [12].

1

The parameters of H NMR spectra of amines are

compiled in Table 1. They differ from the spectra of initial

amides by an upfield shift of proton signals from H^8Aand

H^8Band by appearance of proton signals from the

methylene group CH₂Ad located in the region 2.60

3.20 ppm; in the same region are also situated the proton

signals from both amino groups. In the spectrum of amine

Vd, like in the spectra of the other substituted norbornenes,

signals are present from the protons H⁵and H⁶(doublets

of doublets in the region 6.02 and 5.79 ppm), and also

a resonance of proton H³ⁿtaking a special place in the

spectra of this and other endo-stereoisomers (0.39 ppm).

In the spectrum of amine Vf the protons of benzyl groups

give rise to signals in the region 3.71 and 7.25 ppm.

The amine was brought into a reaction with an available

epoxide, p-nitrophenyloxirane, an intermediate compound

in manufacturing the antibiotic chloramphenicol [15].

Compounds VIIa, VIIb, VIIdVIIg were obtained

in a crystalline state, and the other compounds were oily

substances purified by chromatography on columns

packed with silica gel.

Sulfonamides VIIaVIIc were prepared by two

procedures: in a two-phase system (etherwater) at

equimolar ratio of the reagents (amine, sulfonyl chloride,

and sodium hydroxide) and in a one-phase system (in

chloroform with pyridine as base). Although the aryl-

sulfonylation of the initial primary amines IIIaIIId had

been previously performed along both pathways at room

temperature [16], we succeeded in carrying out the

reactions with amine Vb only in the one-phase mode at

60°C. The heating was also required in preparation of

amide VIId by the reaction of amine with p-nitrobenzoyl

chloride in chloroform in the presence of a base; the

reactions with succinic and endic anhydrides were

In the molecules of amines VaVf one or several

amino groups are surrounded by cage-like fragments

located at various distance. The electron density distribu-

tion in the molecules of the amines we studied by quantum-

chemical calculations carried out by semiempirical method

PM3 [14]. The proton affinity found as the difference

between the heat of formation of the protonated and free

amines VaVc was estimated at 857.61, 861.97, and

846.93 kJ mol^-1respectively. These values are greater

that the proton affinity of the initial primary amines IIIa

IIIc and of the 1-adamantylmethylamine (840.08, 845.03,

RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005

L. KASYAN et al.

682

&+ 1&+

62

&+ 1&+

&2ꢀ&+ ꢁ &22+

9,,H

;

&2

12

9,,G

9,,D F

2

&22+

&

&+ 1&+

&21+5

&61+& +

9,,JꢀꢁK

9,,L

9,,I

VII, X = NO₂(a), Cl (b), CH₃(c); R = SO₂C₆H₄CH₃-p (g), C₆H₄CH₃-m (h).

2+

&+

12

+ &

&+ &+

12

2

9E

Lꢀ3U2+ꢁꢂꢃꢄ &

&+ 1&+

9,,M

performed by short heating in ethyl acetate and benzene

respectively. The other processes (with p-toluenesulfonyl

and m-tolyl isocyanates, and with phenyl isothiocyanate)

were performed in benzene at room temperature.

VIIj the observed absorption bands correspond to hydroxy

1

(3395 cm ) and nitro (1534 and 1350 cm ) groups. The

absorption band of the strained double bond in the most

spectra is overlapped by the bands originating from

vibrations of the bonds in the aromatic fragments.

In the IR spectra of sulfonamides VIIaVIIc and of

sulfonylurea VIIg absorption bands are observed

originating from bond vibrations in the sulfonyl group

Under similar conditions the related amines Va and

Vb reacted with p-nitrophenylsulfonyl chloride and

p-toluenesulfonyl isocyanate affording compounds VIIIa

VIIIc.

1

(13521340 and 11901180 cm ). In the spectra of com-

pounds VIIdVIIh absorption bands of the amide moiety

1

are present: amide I in the region 16501605 cm

(n_C=O) and amide III in the region 12801270 cm

The chemoselective transformation of epoxyamine Vc

occurring with the retention of the epoxy ring is due to

the spatial hindrances for the attack from the rear (endo)

side of the carbon skeleton in the absence of acid catalysts

[17].

1

(n_CN), but the absorption from the NH bonds is lacking

in the spectra except for those of ureas VIIg and VIIh

[11]. In the IR spectrum of the thiourea lacks the

absorption band of the carbonyl group, and a band is

The reactions of compound Vd possessing two amino

groups and three cage-like fragments with five versatile

electrophilic reagents ( p-nitrobenzenesulfonyl and p-nitro-

benzoyl chlorides, succinic anhydride, p-toluenesulfonyl

and m-tolyl isocyanates) afforded compounds IXaIXe.

1

observed in the region 1310 cm (n_C=S). The spectra of

amido acids VIIe and VIIf contain the bands in the region

1

1712 and 1710 cm belonging to the carbonyls in the

carboxy groups [11]. In the spectrum of aminoalcohol

RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005

SYNTHESIS AND REACTIVITY OF AMINES

683

2

&+ 1&+

62

&+ 1&+

62

&+ 1&+

12

&ꢀ2ꢁ1+62

9,,,F

&+

9,,,D

9,,,E

In reactions of diamine Vd a necessity was again

observed previously found for amines VaVb to carry

out arenesulfonylation and benzoylation under rigorous

conditions confirming the importance of the steric factor

in reactions where in the immediate vicinity of the reaction

site (removed by a single methylene group) were located

the cage-like fragments of norbornene, norbornane, and

adamantane.

atives contain the absorption bands corresponding to the

fragments present in the molecule: sulfonamide, carbox-

amide, nitro groups. The parameters of ¹H NMR spectra

of sulfonamides VIIa, VIIb, VIIIa, VIIIb, and Xa and

sulfonylureas VIIg and IXd are presented in Table 2.

The spectra of stereoisomers VIIa and VIIIa have

considerably different positions of the signals from

protons H²(1.48 and 2.55 ppm), H^3X(1.14 and 1.62 ppm),

H³ⁿ(0.92 and 0.47 ppm); this difference is informative

and is well consistent with the differences discussed above

concerning the structure of carboxamides and the initial

amines with two cage-like fragments. In the spectrum of

the epoxy compound VIIIb the characteristic signals from

the protons of the epoxy ring H⁵and H⁶were observed

(3.31 and 3.29 ppm), and a doublet of the proton H^7a

shifted upfield by 0.86 ppm due to the effect of the

magnetic anisotropy of the three-membered ring [18].

The proton signals from the adamantane skeleton

appeared in the region 1.552.05 ppm, and those from

CH₂Ad in the region 2.903.17 ppm

To confirm the contribution of the contiguous carbon

cage-like structures we studied reactions of amine Ve

where the cage-like fragments are further from the

nitrogen (by two methylene groups), and also reactions

of amine Vf, analog of compound Vd with benzyl groups

instead of norbornenyl ones. The products of amines Ve

and Vf were obtained in reactions with p-nitrobenzene-

sulfonyl chloride and p-toluenesulfonyl isocyanate

(compounds Xa, Xb and XIa, XIb respectively).

In contrast to the compounds obtained before sulfon-

amides Xa and XIa were prepared under mild conditions

(20°C) in chloroform at the common reagents ratio with

the use of the same base.

The comparison of ¹H NMR spectra of sulfonylureas

VIIg and IXd, derivatives of endo-amine IIIb, and of

adamantanecarboxylic acids IIa and IIb revealed the

different ratio of signals belonging to nuclei of norbornene

and adamantine skeletons.

Among the derivatives of amines Va, VcVe alongside

crystalline compounds a number of oily substances was

obtained, in particular, amides of adamantanedicarboxylic

acids IIIb and IIIc. The IR spectra of the amines deriv-

&+ 1&+

5

&+ &+ 1&+

5

&+ 1&+

5

&+ 1&+ &+

5

,;D ,;H

;Dꢀꢁ;E

&+ 1&+

5

&+ 1&+

5

;,Dꢀꢁ;,E

R = SO₂C₆H₄NO₂-p (IXaXIa), C(O)C₆H₄NO₂-p (IXb), C(O)CH₂CH₂COOH (IXc), C(O)NHSO₂C₆H₄CH₃-p(IXd, Xb, XIb),

C(O)NHC₆H₄CH₃-m (IXe).

RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005

L. KASYAN et al.

684

Table 2. ¹H NMR spectra of derivatives VIIaVIIg, VIIIa, VIIIb, IXd, Xa obtained from amines VaVe, d, ppm (J, Hz)

&RPSGꢀꢁ

QRꢀꢁ

+ ꢁ

+ ꢂꢁ+ ꢁ

+ ꢂꢁ+ ꢁ + ꢂꢁ+ ꢁ

6XEVWLWXHQWꢁ

9,,Dꢀ ꢃꢀꢅꢄꢁ ꢃꢀꢄꢄꢁ

ꢆꢀꢋꢃꢁ

ꢍꢀꢇꢊꢁ

ꢃꢀꢋꢄꢁ ꢋꢀꢍꢅꢂꢁꢄꢀꢎꢍꢁ ꢆꢀꢃꢅꢂꢁꢆꢀꢃꢃꢁ ꢃꢀꢅꢍ±ꢃꢀꢎꢍꢁꢆꢀꢄꢍ±ꢃꢀꢍꢍꢁꢉꢆꢄ+ꢂꢁ$Gꢌꢂꢁ

ꢁꢃꢀꢎꢍ±ꢈꢀꢆꢍꢁ ꢉꢃ+ꢂꢁ &+ $Gꢌꢂꢁ

ꢅꢀꢍꢈꢂꢁꢅꢀꢃꢄꢁꢉꢇ+ꢂꢁ+ ꢌꢁ

9,,Eꢀ ꢃꢀꢊꢍꢁ ꢃꢀꢃꢋꢁ

ꢆꢀꢄꢃꢁꢁ

ꢍꢀꢇꢍꢁꢉ - ꢁꢁ ꢃꢀꢋꢄꢁ ꢋꢀꢆꢃꢂꢁꢄꢀꢊꢅꢁ ꢆꢀꢈꢊꢂꢁꢆꢀꢃꢅꢁꢁ ꢃꢀꢅꢍ±ꢃꢀꢎꢍꢁꢆꢀꢄꢍ±ꢃꢀꢍꢍꢁꢉꢆꢄ+ꢂꢁ$Gꢌꢂꢁ

ꢉ - ꢀꢆꢃꢀꢄꢌꢁ ꢃꢀꢄꢂꢁ - ꢀꢀ

ꢉ - ꢁꢁꢁꢁꢋꢀꢃꢌꢁ ꢉ - ꢁꢅꢀꢋꢌꢁ

ꢁꢈꢀꢍꢍ±ꢈꢀꢆꢍꢁ ꢉꢃ+ꢂꢁ &+ $Gꢌꢂꢁ

ꢊꢀꢅꢄꢂꢁꢊꢀꢊꢄꢁꢉꢇ+ꢂꢁꢁ+ ꢌꢁ

ꢃꢀꢇꢌꢁ

9,,Fꢀ ꢃꢀꢎꢃꢁ ꢃꢀꢈꢄꢁ ꢆꢀꢄꢍ±ꢆꢀꢅꢍꢁ

ꢍꢀꢄꢅꢁ

ꢃꢀꢅꢍꢁ ꢋꢀꢃꢍꢂꢁꢄꢀꢎꢄꢁ ꢆꢀꢃꢅꢂꢁꢆꢀꢃꢃꢁ ꢃꢀꢅꢄ±ꢈꢀꢍꢍꢁꢆꢀꢄꢍ±ꢃꢀꢍꢍꢁꢉꢆꢄ+ꢂꢁ$Gꢌꢂꢁꢁ

ꢈꢀꢆꢍ±ꢈꢀꢃꢍꢁꢉꢃ+ꢂꢁ&+ $Gꢌꢂꢁꢁ

ꢊꢀꢆꢄꢂꢁꢊꢀꢋꢄꢁꢉꢇ+ꢂꢁ+ ꢌꢁ

9,,Hꢀ ꢃꢀꢅꢎꢁ ꢃꢀꢈꢍ±

ꢆꢀꢅꢄꢁ

ꢍꢀꢄꢇꢁꢁ

ꢃꢀꢊꢊꢁ ꢋꢀꢆꢊꢂꢁꢄꢀꢎꢊꢁ ꢆꢀꢈꢈꢂꢁꢆꢀꢃꢃꢁꢁ ꢃꢀꢇꢍ±ꢃꢀꢄꢍꢁꢆꢀꢄꢍ±ꢃꢀꢍꢍꢁꢉꢆꢄ+ꢂꢁ$Gꢌꢂꢁꢃꢀꢇꢍ±ꢁ

ꢃꢀꢇꢍꢁ ꢁꢉ - ꢁꢆꢆꢀꢇꢂꢁ ꢉ - ꢁꢈꢀꢅꢌꢁ

ꢉ - ꢁꢁꢁꢄꢀꢆꢂꢁ ꢉ - ꢁꢊꢀꢅꢌꢁ

- ꢁꢃꢀꢊꢂꢁ

- ꢁꢈꢀꢍꢌꢁ

ꢃꢀꢈꢅꢁꢉꢃ+ꢂꢁ&+ $Gꢌꢂꢁꢃꢀꢈꢃꢁꢁ

ꢉꢇ+ꢂꢁ&+ &+ ꢌꢁ

-

ꢁꢅꢀꢇꢂꢁꢁ

ꢁꢈꢀꢎꢌꢁ

9,,Iꢀ ꢃꢀꢎꢄꢁ ꢃꢀꢃꢍ± ꢆꢀꢊꢍ±ꢆꢀꢅꢍꢁꢁ

ꢍꢀꢋꢇꢁꢁ

ꢃꢀꢅꢆꢁ ꢋꢀꢃꢃꢂꢁꢋꢀꢍꢇꢁ ꢆꢀꢈꢄꢂꢁꢆꢀꢃꢊꢁꢁ ꢃꢀꢄꢄ±ꢃꢀꢋꢄꢁꢆꢀꢇꢄ±ꢃꢀꢍꢍꢁꢉꢆꢄ+ꢂꢁ$Gꢌꢂꢁꢃꢀꢄꢍ±ꢁ

ꢃꢀꢈꢍꢁ ꢉ - ꢆꢆꢀꢇꢌꢁ ꢉ - ꢁꢈꢀꢃꢌꢁ

ꢉ - ꢁꢁꢁꢄꢀꢇꢂꢁ ꢉ - ꢁꢊꢀꢅꢌꢁ

- ꢁꢃꢀꢅꢂꢁꢁ

ꢃꢀꢋꢊꢁꢉꢃ+ꢂꢁ&+ $Gꢌꢂꢁꢅꢀꢃꢍ±ꢁ

ꢅꢀꢈꢃꢁꢉꢃ+ꢂꢁ1+ꢂꢁ2+ꢌꢁ

- ꢁꢈꢀꢍꢌꢁ

9,,Jꢀ ꢃꢀꢎꢍꢁ ꢃꢀꢇꢍꢁ

ꢆꢀꢅꢋꢁꢁ

ꢆꢆꢀꢋꢌꢁ

ꢍꢀꢄꢅꢁ

ꢃꢀꢅꢍꢁ ꢋꢀꢃꢃꢂꢁꢋꢀꢍꢍꢁ ꢆꢀꢈꢄꢂꢁꢆꢀꢃꢈꢁꢁ ꢃꢀꢅꢍ±ꢃꢀꢎꢍꢁꢆꢀꢄꢍ±ꢃꢀꢍꢍꢁꢉꢆꢄ+ꢂꢁ$Gꢌꢂꢁꢈꢀꢈꢄꢂꢁꢁ

ꢉ -

ꢉ - ꢁꢅꢀꢆꢌꢁ

ꢈꢀꢃꢅꢁꢉꢃ+ꢂꢁ&+ $Gꢌꢂꢁꢊꢀꢎꢍꢁꢁ

ꢉꢆ+ꢂꢁ1+ꢌꢂꢁꢊꢀꢃꢄꢂꢁꢊꢀꢊꢍꢁꢉꢇ+ꢂꢁꢁ

+

ꢌꢁ

9,,,Dꢀ ꢃꢀꢊꢇꢁ ꢆꢀꢇꢅꢁ

ꢆꢀꢆꢇꢁꢁ

ꢍꢀꢎꢃꢁꢁ

ꢃꢀꢅꢃꢁ ꢋꢀꢍꢍꢂꢁꢄꢀꢅꢋꢁ ꢆꢀꢈꢄꢂꢁꢆꢀꢃꢊꢁꢁ ꢃꢀꢎꢍ±ꢈꢀꢆꢄꢁꢆꢀꢄꢍ±ꢃꢀꢍꢍꢁ ꢉꢆꢄ+ꢂꢁ $Gꢌꢂꢁ ꢈꢀꢈꢄ

ꢉ - ꢁꢆꢃꢀꢍꢌꢁ ꢉ - ꢁꢇꢀꢍꢂꢁ

ꢀꢃꢀꢋꢌꢁ

ꢉ - ꢁꢁꢁꢋꢀꢇꢂꢁ ꢉ - ꢁꢅꢀꢇꢌꢁ

- ꢁꢃꢀꢋꢂꢁ

ꢈꢀꢃꢅꢁ ꢉꢃ+ꢂꢁ &+ $Gꢌꢂꢁ ꢅꢀꢍꢍ

ꢅꢀꢈꢇꢁꢉꢇ+ꢂꢁ+ ꢌꢁ

-

- ꢁꢃꢀꢅꢌꢁ

9,,,Eꢀ ꢃꢀꢊꢆꢁ ꢆꢀꢄꢍ±

ꢃꢀꢃꢆꢁ

ꢍꢀꢎꢊꢁ

ꢃꢀꢅꢄꢁ ꢈꢀꢈꢆꢂꢁꢈꢀꢃꢎꢁ ꢆꢀꢃꢇꢂꢁꢍꢀꢅꢋꢁ ꢃꢀꢅꢍ±ꢈꢀꢍꢍꢁꢆꢀꢄꢍ±ꢃꢀꢍꢍꢁ ꢉꢆꢄ+ꢂꢁ $Gꢌꢂꢁ ꢃꢀꢅꢍ±

ꢈꢀꢍꢍꢁ ꢉꢃ+ꢂꢁ &+ $Gꢌꢂꢁ ꢊꢀꢎꢊ

ꢆꢀꢋꢍꢁ

ꢅꢀꢈꢄꢁꢉꢇ+ꢂꢁ+ ꢌꢁ

,;Gꢀ ꢃꢀꢅꢆꢁ ꢃꢀꢆꢆꢁ

ꢆꢀꢊꢄꢁ

ꢍꢀꢇꢇꢁꢁ

ꢃꢀꢅꢄꢁ ꢋꢀꢍꢎꢂꢁꢄꢀꢅꢋꢁ ꢆꢀꢈꢋꢂꢁꢆꢀꢆꢅꢁꢁ ꢃꢀꢊꢍ±ꢈꢀꢍꢍꢁꢆꢀꢄꢍ±ꢃꢀꢍꢍꢁ ꢉꢆꢄ+ꢂꢁ $Gꢌꢂꢁ ꢃꢀꢊꢍ±

ꢉ - ꢁꢆꢃꢀꢍꢂꢁ ꢉ - ꢁꢈꢀꢋꢂꢁ

ꢉ - ꢁꢄꢀꢅꢂꢁꢁ ꢉ - ꢁꢅꢀꢍꢌꢁ

- ꢁꢃꢀꢎꢂꢁ

- ꢁꢃꢀꢅꢌꢁ

ꢈꢀꢍꢍꢁꢉꢃ+ꢂꢁ&+ $Gꢌꢂꢁꢋꢀꢃꢆꢁꢉꢆ+

1+ꢌꢂꢁꢊꢀꢈꢈꢂꢁꢊꢀꢊꢊꢁꢉꢇ+ꢂꢁ+ ꢌꢁ

-

ꢁꢎꢀꢃꢂꢁꢁ

ꢁꢈꢀꢅꢌꢁ

-

ꢀꢃꢀꢇꢌꢁ

;Dꢀ

ꢃꢀꢅꢈꢁ ꢃꢀꢈꢆꢁ

ꢆꢀꢅꢃꢁꢁ

ꢉ - ꢁꢆꢆꢀꢇꢂꢁ

ꢁꢅꢀꢊꢌꢁ

ꢍꢀꢄꢇꢁ

ꢁ

ꢃꢀꢎꢃꢁ ꢋꢀꢃꢍꢂꢁꢄꢀꢎꢅꢁ ꢆꢀꢇꢇꢂꢁꢆꢀꢃꢊꢁꢁ ꢃꢀꢅꢍ±ꢈꢀꢍꢍꢁꢆꢀꢇꢍ±ꢃꢀꢍꢍꢁ ꢉꢆꢄ+ꢂꢁ $Gꢌꢂꢁ ꢈꢀꢍꢍ±

ꢉ - ꢁꢄꢀꢊꢂꢁꢁ ꢉ - ꢁꢅꢀꢊꢌꢁ

- ꢁꢃꢀꢊꢂꢁ

ꢈꢀꢃꢄꢁꢉꢃ+ꢂꢁ&+ 1ꢌꢂꢁꢊꢀꢎꢋꢂꢁꢅꢀꢈꢋ

ꢉꢇ+ꢂꢁ+ ꢌꢁ

-

- ꢁꢈꢀꢍꢌꢁ

ꢁ

In the ¹H NMR spectrum of compound VIIj signals

product is present in the reaction mixture whose respec-

tive signals in the H NMR are observed at 4.64 and

3.62 ppm. The area ratio of signals (2:1) and their position

suggest that the side product arises from the epoxy ring

opening anti-Krasusky.

1

appeared in the regions 4.94 and 2.54, 2.42 ppm belonging

to the proton of the methine group (H^x) neighboring to

a hydroxy group, and to the protons of the methylene

group (H^A, H^B) contiguous with the nitrogen. The area

ratio of signals corresponding to the mentioned groups

evidences that the epoxy group of the p-nitrophenyl-

oxirane opens in keeping with Krasusky rule [19];

however alongside the main aminolysis product a side

EXPERIMENTAL

IR spectra were measured on a spectrophotometer

Specord 75-IR in the region 4000400 cm from thin

1

RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005

SYNTHESIS AND REACTIVITY OF AMINES

685

1

films or KBr pellets. H NMR spectra were registered

Found, %: N 6.51. C₂₈H₃₈N₂O₂. Calculated, %: N 6.45.

on spectrometers Varian VXR (operating frequencies

200 and 300 MHz) from solutions of compounds in

deutero-chloriform or deuterodimethyl sulfoxide using

TMS for internal reference. The spectra of compounds

IVaIVe, Va, Vb, Vd, Ve, VIIaVIIc, VIIeVIIg,

VIIIa, VIIIb, IXd, and Xa are listed in Tables 1 and 2.

The reaction progress was monitored and the purity of

compounds obtained was checked by TLC on Silufol-

60F₂₅₄plates, eluent ether, development in iodine vapor.

Elemental analysis was carried out on a Karlo Erba

analyzer.

N,N'-Bis(bicyclo[2.2.1]hept-5-en-endo-2-

ylmethyl)adamantane-1,3-diacetamide (IVe) was

prepared similarly from amine IIIb and 1,3-adamantane-

diacetic acid. Yield 72%, oily substance, R_f0.35. IR

spectrum, cm : 3345, 3050, 1635, 1530, 1270, 1192, 851.

Found, %: N 6.14. C₃₀H₄₂N₂O₂. Calculated, %: N 6.06.

1

N,N'-Dibenzyl-1,3-adamantanedicarboxamide

(IVf) was prepared analogously. Yield 70%, mp 151

1

152°C, R_f0.33. H NMR spectrum, d, ppm: 1.84 m,

2.11 m, 2.25 m, 4.43 d, 7.29 m. Found, %: N 6.90.

C₂₆H₃₀N₂O₂. Calculated, %: N 6.97.

Stereoisomeric bicyclo[2.2.1]hept-5-en-2-yl-

methylamines (IIIa and IIIb) and exo-5,6-epoxybi-

cyclo-[2.2.1]hept-exo-2-ylmethylamine (IIIc) were

prepared as described in [8, 9], and their properties were

consitent with the published data.

N-(1-Adamantylmethyl)bicyclo[2.2.1]hept-5-en-

exo-2-ylmethylamine (Va). To a stirred dispersion of

0.40 g (10.5 mmol) of lithium aluminum hydride in 10 ml

of anhydrous ethyl ether was added dropwise a solution

of 1.40 g (5.0 mmol) of amide IVa in 10 ml of anhydrous

ether. The mixture was stirred for 8 h at reflux (TLC

monitoring). The excess lithium aluminum hydride was

decomposed with aqueous ether and then with ice water.

The organic layer was separated, dried over anhydrous

magnesium sulfate, the solvent was removed. Yield 95%,

N-(Bicyclo[2.2.1]hept-5-en-exo-2-ylmethyl)-1-

adamantanecarboxamide (IVa). To a stirred mixture

of 2.20 g (17.8 mmol) of amine IIIa and 1.76 g (2.4 ml,

17.8 mmol) of triethylamine in 15 ml of chloroform was

added dropwise a solution of 3.50 g (17.8 mmol) of

1-adamantanecarbonyl chloride in chloroform. The stirring

at room temperature was continued till the completion of

reaction (TLC monitoring). The reaction mixture was

treated in succession with water, 5% hydrochloric acid

solution, once more with water, then the organic layer

was dried over anhydrous magnesium sulfate, the solvent

was removed, and the reaction product was purified by

recrystallization from an aqueous 2-propanol. Yield 70%,

1

oily substance, R_f0.92. IR spectrum, cm : 3391, 3065,

1571, 712. Found, %: N 5.24. C₁₉H₂₉N. Calculated, %:

N 5.17. Hydrochloride VIa of amine Va was prepared

by passing a flow of dry hydrogen chloride through an

ether solution of the amine. Yield 70%, mp 230°C

1

(decomp.). IR spectrum, cm : 3071, 2722, 1440, 730.

N-(1-Adamantylmethyl)bicyclo[2.2.1]hept-5-en-

endo-2-ylmethylamine (Vb) was prepared by the above

procedure from amide IVb. Yield 94%, oily substance,

1

mp 180181°C, R_f0.31. IR spectrum, cm : 3334, 3056,

1

R_f0.88. IR spectrum, cm : 3348, 3040, 1568, 718. Found,

1631, 1535, 1270, 712. Found, %: N 4.85. C₁₉H₂₇NO.

Calculated, %: N 4.91.

%: N 5.25. C₁₉H₂₉N. Calculated, %: N 5.17. Hydro-

chloride VIb was obtained in 74% yield, mp 230°C

N-(Bicyclo[2.2.1]hept-5-en-endo-2-ylmethyl)-1-

adamantanecarboxamide (IVb) was prepared from

amine IIIb by the above procedure. Yield 69%, mp 179

1

(decomp.). IR spectrum, cm : 3061, 2725, 1440, 720.

N-(1-Adamantylmethyl)-exo-5,6-epoxybicyclo-

[2.2.1]hept-exo-2-ylmethylamine (Vc) was obtained

analogously from amide IVc. Yield 87%, oily substance,

1

181°C [10], R_f0.34. IR spectrum, cm : 3430, 3026, 1622,

1526, 1243, 725.

1

R_f0.96. IR spectrum, cm : 3368, 3030, 1551, 856. Found,

N-(exo-5,6-Epoxybicyclo[2.2.1]hept-5-en-exo-2-

ylmethyl)-1-adamantanecarboxamide (IVc) was

prepared by the above procedure from epoxyamine IIIc.

%: N 4.93. C₁₉H₂₉NO. Calculated, %: N 4.87. Hydro-

chloride (VIb) was obtained in 71% yield, mp 191193°C.

1

IR spectrum, cm : 3028, 2703, 1440, 855.

1

Yield 55%, mp 9698°C, R_f0.75. IR spectrum, cm :

N,N'-Bis(bicyclo[2.2.1]hept-5-en-endo-2-yl-

methyl)-1,3-adamantanedimethylamine (Vd) was

obtained analogously by reduction of amide IVd. Yield

3361, 3028, 1635, 1530, 1270, 1192, 851. Found, %:

N 4.60. C₁₉H₂₇NO₂. Calculated, %: N 4.65.

1

N,N'-Bis(bicyclo[2.2.1]hept-5-en-endo-2-yl-

methyl)adamantane-1,3-dicarboxamide (IVd) was

prepared similarly from amine IIIb and 1,3-adamantane-

dicarbonyl chloride. Yield 64%, mp 200202°C, R_f0.37.

97%, oily substance, R_f0.28. IR spectrum, cm : 3410,

3041, 1573, 720. Found, %: N 6.80. C₂₈H₄₂N₂. Calculated,

%: N 6.89. Hydrochloride VId was obtained in 80%

1

yield, mp 185187°C. IR spectrum, cm : 3030, 2700,

1

IR spectrum, cm : 3345, 3050, 1623, 1544, 1250, 730.

1440, 720.

RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005

L. KASYAN et al.

686

N,N'-Bis(bicyclo[2.2.1]hept-5-en-endo-2-yl-

was likewise prepared from amine Vb and p-toluene-

sulfonyl chloride. Yield 61%, oily substance, R_f0.79.

Found, %: N 3.37. C₂₆H₃₅NO₂S. Calculated, %: N 3.29.

methyl)-1,3-adamantanediethylamine (Ve). To a stir-

red dispersion of 0.39 g (10.3 mmol) of lithium aluminum

hydride in 10 ml of anhydrous ethyl ether was added

dropwise a solution of 1.20 g (2.6 mmol) of amide IVe in

10 ml of anhydrous ether, and the mixture was stirred for

10 h at room temperature (TLC monitoring). The excess

lithium aluminum hydride was decomposed with aqueous

ether and then with ice water. The organic layer was

separated, dried over anhydrous magnesium sulfate, the

solvent was removed. Yield 94%, oily substance, R_f0.24.

N-(1-Adamantylmethyl)-N-(bicyclo[2.2.1]hept-5-

en-endo-2-ylmethyl)-p-nitrobenzamide (VIId). To a

stirred mixture of 0.20 g (0.7 mmol) of amine Vb and

0.006 g (0.06 ml, 0.74 mmol) of pyridine in 8 ml of

anhydrous chloroform was added dropwise at room

temperature a solution of 0.15 g (0.7 mmol) of p-nitro-

benzoyl chloride in 6 ml of chloroform, the mixture was

heated to 60°C and stirred at this temperature for 4 h.

The completion of the process was fixed by TLC, then

the reaction mixture was treated in succession with water,

5% solution of hydrochloric acid, again with water. Then

the organic layer was separated, dried over anhydrous

magnesium sulfate, the solvent was removed, and the

reaction product was recrystallized from a mixture of

2-propanol and water.Yield of VIId 78%, mp 135136°C,

1

IR spectrum, cm : 3315, 3062, 1561, 730. Found, %:

N 6.52. C₃₀H₄₆N₂. Calculated, %: N 6.45. Hydrochloride

VIe was obtained in 78% yield, mp 196198°C. IR

1

spectrum, cm : 3064, 2720, 1452, 731.

N,N'-Dibenzyl-1,3-adamantanedimethylamine

(Vf) was similarly prepared from amide IVf. Yield 98%,

1

oily substance, R_f0.23. IR spectrum, cm : 3400, 3028,

1573, 703. ¹H NMR spectrum, d, ppm: 1.42 m, 1.64 m,

2.00 m, 2.25 s, 3.71 s, 7.26 m. Found, %: N 7.42.

C₂₆H₃₄N₂. Calculated, %: N 7.49. Hydrochloride VIf was

obtained in 83% yield, mp 202204°C. IR spectrum,

1

R_f0.81. IR spectrum, cm : 3057, 1635, 1527, 1350, 1280,

720. Found, %: N 6.60. C₂₆H₃₂N₂O₃. Calculated, %:

N 6.67.

1

3-[N-(1-Adamantylmethyl)-N-bicyclo[2.2.1]-

hept-5-en-endo-2-ylmethyl]carbamoylpropionic acid

(VIIe). To a solution of 0.15 g (0.5 mmol) of amine Vb

in 5 ml of ethyl acetate was added a solution of 0.05 g

(0.5 mmol) of succinic anhydride, and the mixture was

heated for a short time (15 min) at 4050°C. On cooling

the separated precipitate was filtered off, washed with

ethyl acetate, the reaction product was recrystallized from

hot ethyl acetate. Yield of amidoacid 69%, mp 139140°C,

cm : 2700, 1440, 705.

N-(1-Adamantylmethyl)-N-(bicyclo[2.2.1]hept-5-

en-endo-2-ylmethyl)-p-nitrophenylsulfonamide

(VIIa). To a stirred mixture of 0.20 g (0.74 mmol) of

amine Vb and 0.006 g (0.06 ml, 0.74 mmol) of pyridine in

8 ml of anhydrous chloroform was added dropwise at

room temperature a solution of 0.17 g (0.74 mmol) of

p-nitrobenzenesulfonyl chloride in 6 ml of chloroform, the

mixture was heated to 60°C and stirred at this temperature

for 4 h. The completion of the process was fixed by TLC,

then the reaction mixture was treated in succession with

water, 5% solution of hydrochloric acid, again with water.

Then the organic layer was separated, dried over

anhydrous magnesium sulfate, the solvent was removed,

and the reaction product was purified by recrystallization

from an aqueous 2-propanol. Yield 84%, mp 145146°C,

1

R_f0.18. IR spectrum, cm : 3412, 3071, 1712, 1645, 1552,

721. Found, %: N 3.71. C₂₃H₃₃NO₃. Calculated, %:

N 3.77.

endo-3-[N-(1-Adamantylmethyl)-N-(bicyclo-

[2.2.1]hept-5-en-endo-2-ylmethyl)carbamoyl]-

bicyclo[2.2.1]hept-5-en-endo-2-carboxylic acid

(VIIf). To a solution of 0.15 g (0.5 mmol) of amine Vb in

5 ml of anhydrous benzene was added a solution of

0.90 g (0.5 mmol) of endic anhydride in the same solvent,

and the mixture was heated for a short time (15 min) at

4050°C. On cooling the separated precipitate was filtered

off, washed with cool benzene, the reaction product was

recrystallized from hot benzene. Yield 63%, mp 132

1

R_f0.82. IR spectrum, cm : 3051, 1530, 1370, 1352, 1250,

1190, 730. Found, %: N 6.05. C₂₅H₃₂N₂O₄S. Calculated,

%: N 6.14.

N-(1-Adamantylmethyl)-N-(bicyclo[2.2.1]hept-5-

en-endo-2-ylmethyl)-p-chlorophenylsulfonamide

(VIIb) was likewise prepared from amine Vb and p-

chlorobenzenesulfonyl chloride. Yield 45%, mp 105

1

133°C, R_f0.25. IR spectrum, cm : 3060, 1740, 1700,

1

1651, 1550, 1270, 740. Found, %: N 3.29. C₂₈H₃₇NO₃.

Calculated, %: N 3.22.

106°C, R_f0.76. IR spectrum, cm : 3050, 1583, 1341,

1180, 732. Found, %: N 3.07. C₂₅H₃₂ClNO₂S.

Calculated, %: N 3.14.

N-(1-Adamantylmethyl)-N-(bicyclo[2.2.1]hept-5-

en-endo-2-ylmethyl)-N'-p-toluenesulfonylcarbamide

(VIIg). To a solution of 0.15 g (0.5 mmol) of amine Vb

N-(1-Adamantylmethyl)-N-(bicyclo[2.2.1]hept-5-

en-endo-2-ylmethyl)-p-toluenesulfonamide (VIIc)

RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005

SYNTHESIS AND REACTIVITY OF AMINES

687

in 3 ml of benzene was added at room temperature

0.10 g (0.5 mmol, 0.1 ml) of p-tosyl isocyanate; the end

of reaction was checked by TLC. The separated pre-

cipitate was filtered off, washed on the filter with benzene,

and dried. The reaction product was recrystal-lized from

the benzene-hexane mixture. Yield 76%, mp 9395°C,

nitrophenylsulfonamide (VIIIb) was prepared from

amine Vc and p-nitrobenzenesulfonyl chloride along the

procedure described for compound VIIIa. Yield 50%,

1

mp 156158°C, R_f0.94. IR spectrum, cm : 3025, 1527,

1

1340, 1168, 1115, 858. Parameters of H NMR spectrum

are given in Table 2. Found, %: N 5.99. C₂₅H₃₂N₂O₅S.

Calculated, %: N 5.93.

1

R_f0.42. IR spectrum, cm : 3412, 3068, 1645, 1570, 1351,

1270, 730. Found, %: N 6.07. C₂₇H₃₆N₂O₃S. Calculated,

%: N 5.98.

N-(1-Adamantylmethyl)-N-(exo-5,6-epoxybi-

cyclo[2.2.1]hept-5-en-endo-2-ylmethyl)-N'-p-tolu-

enesulfonylcarbamide (VIIIc) was prepared from

amine Vc and p-tosyl isocyanate along the procedure

described for compound VIIg. Yield 80%, mp 9293°C,

R_f0.68. IR spectrum, cm : 3361, 1653, 1530, 1310, 1165,

859. Found, %: N 5.70. C₂₇H₃₆N₂O₄S. Calculated, %:

N 5.79.

N-(1-Adamantylmethyl)-N-(bicyclo[2.2.1]hept-5-

en-endo-2-ylmethyl)-N'-m-tolylcarbamide (VIIh)

was prepared in the same fashion from amine Vb and

m-tolyl isocyanate. Yield 61%, oily substance, R_f0.81.

1

IR spectrum, cm : 3345, 3065, 1640, 1551, 1240, 730.

Found, %: N 7.03. C₂₇H₃₆N₂O. Calculated, %: N 6.93.

N-(1-Adamantylmethyl)-N-(bicyclo[2.2.1]hept-5-

en-endo-2-ylmethyl)-N'-phenylthiocarbamide (VIIi)

was prepared in the same fashion from amine Vb and

phenyl isothiocyanate. Yield 72%, oily substance, R_f0.88.

IR spectrum, cm : 3310, 3067, 1540, 1310, 1110, 732.

Found, %: N 6.98. C₂₆H₃₃N₂S. Calculated, %: N 6.91.

1,3-Bis[N-(p-nitrophenylsulfonyl)-N-(bicyclo-

[2.2.1]hept-5-en-endo-2-ylmethyl)amino-methyl]-

adamantane (IXa) was prepared along the procedure

described for compound VIIa from amine Vd and p-nitro-

benzenesulfonyl chloride. Yield 63%, oily substance, R_f

1

0.91. IR spectrum, cm : 3056, 1537, 1370, 1349, 1190,

731. Found, %: N 7.08. C₄₀H₅₀N₄O₈S₂. Calculated, %:

N 7.20.

2-[N-(1-Adamantylmethyl)-N-(bicyclo[2.2.1]-

hept-5-en-endo-2-ylmethyl)aminO]-1-(p-nitro-

phenyl)-1-ethanol (VIIj). To a solution of 0.15 g

(0.5 mmol) of amine Vb in 3 ml of 2-propanol was added

at room temperature a solution of 0.10 g (0.5 mmol) of

p-nitrophenyloxirane in the same solvent; the end of

reaction was checked by TLC. The solvent was removed,

the mixture of products was subjected to column

chromatography on silica gel (eluent ether). Yield 63%,

1,3-Bis[N-(p-nitrobenzoyl)-N-(bicyclo[2.2.1]-

hept-5-en-endo-2-ylmethyl)aminomethyl]-

adamantane (IXb) was obtained similarly to amide VIId

from amine Vd and p-nitrobenzoyl chloride. Yield 69%,

1

oily substance, R_f0.92. IR spectrum, cm : 3070, 1613,

1531, 1375, 731. Found, %: N 7.82. C₄₂H₅₀N₄O₆. Cal-

culated, %: N 7.93.

1

oily substance, R_f0.93. IR spectrum, cm : 3395, 3070,

1610, 1534, 1351, 1160, 730. Found, %: N 6.70.

C₂₇H₃₆N₂O₃. Calculated, %: N 6.61.

1,3-Bis[N-(3-carboxypropionyl)-N-(bicyclo-

[2.2.1]hept-5-en-endo-2-ylmethyl)aminomethyl]-

adamantane (IXc) was prepared from 0.20 g (0.5 mmol)

of amine Vd in 5 ml of ethyl acetate and 0.10 g

(1.0 mmol) of succinic anhydride by the procedure

described for amidOacid VIIIe. The reaction product

was purified by column chromatography on silica gel

(eluent ether).. Yield 58%, oily substance, R_f0.65. IR

N-(1-Adamantylmethyl)-N-(bicyclo[2.2.1]hept-5-

exo-2-methyl)-ï-nitrophenylsulfonamide (VIIIa). To

a stirred mixture of 0.20 g (0.74mmol) of amine Va and

0.006 g (0.06 ml, 0.74 mmol) of pyridine in 8 ml of

anhydrous chloroform was added dropwise at room

temperature a solution of 0.17 g (0.74 mmol) of p-nitro-

benzenesulfonyl chloride in 6 ml of chloroform, the

mixture was heated to 60°C and stirred at this

temperature for 4 h. The completion of the process was

fixed by TLC, then the reaction mixture was subjected

to commom workup. The reaction product was purified

by column chromatography on silica gel (eluent ether).

Yield 72%, oily substance, R_f0.90. Found, %: N 6.08.

C₂₅H₃₂N₂O₄S. Calculated, %: N 6.14.

1

spectrum, cm : 3390, 1712, 1631, 1555, 1290, 730. Found,

%: N 4.72. C₃₆H₅₂N₂O₆. Calculated, %: N 4.61.

1,3-Bis[N-(p-toluenesulfonylcarbamoyl)-N-

(bicyclo[2.2.1]hept-5-en-endo-2-ylmethyl)amino-

methyl]adamantane (IXd) was obtained from amine

Vd and and p-tosyl isocyanate along the procedure

described for compound VIIg. Yield 63%, mp 104

106°C, R_f0.56. Found, %: N 7.13. C₄₄H₅₆N₄O₆S₂.

Calculated, %: N 7.00.

N-(1-Adamantylmethyl)-N-(exo-5,6-epoxybi-

cyclo[2.2.1]hept-5-en-endo-2-ylmethyl)-p-

1,3-Bis[N-(m-toluenecarbamoyl)-N-(bicyclo-

[2.2.1]hept-5-en-endo-2-ylmethyl)aminomethyl]-

RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005

L. KASYAN et al.

688

adamantane (IXe) was obtained from amine Vd and

m-tosyl isocyanate along the procedure described for

compound VIIg. The product was purified by passing

through a column packed with silica gel (eluent ether).

Yield 51%, oily substance, R_f0.61. IR spectrum, cm :

3351, 3070, 1642, 1556, 1290, 731. Found, %: N 8.21.

C₄₄H₅₆N₄O₂. Calculated, %: N 8.33.

Boreko, E.I., Vladyko, G.V., and Korobchenko, L.V., Khim.

Farm. Zh., 1987, vol. 4, p. 454.

2. Mashkovskii, M. D., Lekarstvennye sredstva (Medicines),

Kharkov: Torsing, 1997.

3. Krieger, H., Arzn.-Forsch., 1968, vol. 18, p. 487.

4. Yale, H.L. and Shechan, J.T., J. Org. Chem., 1961, vol. 26,

p. 4325.

5. Tschesche, R., Bruegmann, Y., Marquardt, H.W., and

Mashleidt, H., Lieb. Ann., 1961, p. 648, p. 185.

1

1,3-Bis[N-(p-nitrophenylsulfonyl)-N-(bicyclo-

[2.2.1]hept-5-en-endo-2-ylmethyl)-(2-aminoethyl)]-

adamantane (Xa). To a stirred mixture of 0.25 g

(0.6 mmol) of amine Ve and 0.11 g (0.16 ml, 1.1 mmol)

of triethylamine in 8 ml of dry chloroform was added

dropwise a solution of 0.26 g (1.1 mmol) of p-nitro-

benzenesulfonyl chloride in 6 ml of chloroform. The

mixture was stirred at room temperature for 7 h. The

end of the process was checked by TLC. After the

common workup the reaction product was purified by

passing through a column packed with silica gel (eluent

ether). Yield 57%, oily substance, R_f0.76. IR spectrum,

6. Ranise, A., Bondavalli, F., Schenone, P., Angrisani, M.,

Lisa, M., Marrazzo, R., and Marmo, E., Formaco Ed. Sci.,

1988, vol. 43, p. 79.

7. Kasyan,A.O., Tarabara, I.N., Zlenko, E.T., Mamchur, V.I.,

and Kasyan, L.I., Zh. Org. Khim., 1999, vol. 35, p. 1042.

8. Alder, K., Krieger, H., and Weib, H., Chem. Ber., 1955,

vol. 88, p. 144; Alder, K., Heimbach, K., and Reubke, R.,

Chem. Ber., 1958, vol. 91, p. 1516; Wilder, P. and

Knight, D.B., J. Org. Chem., 1965, vol. 30, p. 3078.

9. Kasyan, L.I., Okovity, S.I., and Kasyan, A.O., Heteroatom

Chem., 1997, vol. 8, p. 185; Kasyan, L.I., Krasnov-

skaya, O.Yu., Okovityi, S.I., and Kasyan, A.O., Zh. Org.

Khim., 1995, vol. 31, p. 347.

10. Kasyan, L.I., Tarabara, I.N., Saveleva, O.A., and Kas-

yan, A.O., Heteroatom Chem., 2001, vol. 12, p. 119.

11. Nakanisi, K., Infrakrasnye spektry organicheskikh

soedinenii (IR Spectra of Organic Compounds), Moscow:

Mir, 1965, 210 p.; Bellamy, L.J., The Infra-Red Spectra of

Complex Molecules, London: Methuen, 1958.

1

cm : 3061, 1542, 1370, 1344, 1186, 730. Found, %: N

6.78. C₄₂H₅₄N₄O₈S₂. Calculated, %: N 6.91.

1,3-Bis[N-(p-toluenesulfonylcarbamoyl)-N-

(bicyclo[2.2.1]hept-5-en-endo-2-ylmethyl)-(2-

aminoethyl)]adamantane (Xb) was obtained from

amine Ve and and p-tosyl isocyanate along the procedure

described for compound VIIg. Yield 71%, mp 8788°C,

12. Zefirov, N.S. and Sokolov, V.I., Usp. Khim., 1967, vol. 36,

p. 243.

1

R_f0.69. IR spectrum, cm : 3392, 3236, 3065, 1641, 1556,

1335, 1270, 1161, 730. Found, %: N 6.85. C₄₆H₆₀N₄O₆S₂.

Calculated, %: N 6.73.

13. Kasyan, L.I., Seferova, M.F., and Okovityi, S.I., Alitsikli-

cheskie epoksidnye soedineniya. Metody sinteza (Ali-

cyclic Epoxicompounds. Synthesis Methods), Dnepro-

petrovsk: Izd. Dnepropetrovsk. Gos. Univ., 1996, 192 p.

14. Dewar, M.J.S., Zoebisch, E.G., Healy, E.F., and Stewart, J.J.P.,

J. Am. Chem. Soc., 1985, p. 107, p. 3902.

15. Shemyakin, N.N., Khokhlov,A.S., Kolosov, M.N., Berel-

son, L.D., and Antonov, V.K., Khimiya antibiotikov

(Chemistry ofAntibiotics), Moscow: Izd.Akad. Nauk SSSR,

1961, pp. 2, 15, 27, 337, 1442.

16. Kasyan, A.O., Isaev, A.K., and Kasyan, L.I., Zh. Org.

Khim., 2002, vol. 38, p. 579; Kasyan,A.O., Maletina, I.I.,

Yagupolskii, L.M., Markov, V.I., and Kasyan, L.I., Zh.

Org. Khim., 1995, vol. 31, p. 357.

17. Kasyan, L.I., Zh. Org. Khim., 1999, vol. 35, p. 661.

18. Tori, K., Kitahonoki, K., Tanida, H., and Tsuyi, T.,

Tetrahedron Lett., 1964, vol. 11, p. 559; Zefirov, N.S.,

Kasyan, L.I., Gnedenkov, L.Yu., Shashkov, A.S., and

Cherepanova, E.G., Tetrahedron Lett., 1979, vol. 11, p. 949.

19. Kirk, D.N., Chem. Ind., 1973, p. 109; Krasuskii, K.A., Zh.

Obshch. Khim., 1936, 6, p. 460.

1,3-Bis[N-(p-nitrobenzenesulfonyl)-N-(benzyl)-

aminomethyl]adamantane (XIa) was obtained at room

temperature from amine Vf and ï-nitrobenzenesulfonyl

chloride along the procedure described for compound Xa.

1

Yield 87%, mp 160162°C, R_f0.56. IR spectrum, cm :

3043 1534, 1360, 1180, 1138. Found, %: N 7.40.

C₃₈H₄₂N₄O₈S₂. Calculated, %: N 7.51.

1,3-Bis[N-(p-toluenesulfonylcarbamoyl)-N-

(benzyl)aminomethyl]adamantane (XIb) was obtained

in the same way as compound Vg from amine Vf and

p-tosyl isocyanate. Yield 75%, mp 112114°C, R_f0.52.

1

IR spectrum, cm : 3381, 1647, 1605, 1570, 1356, 1276.

Found, %: N 7.32. C₄₂H₅₀N₄O₆S₂. Calculated, %: N 7.27.

REFERENCES

1. US Patent 3444302, 1969; Ref. Zh. Khim., 1970, 14N, p. 392;

Novakov, I.A., Kulev, I.A., Rodchenko, S.S., Birznieks, K.A.,

RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005

Article Doi

Synthesis and reactivity of amines containing several cage-like fragments

DOI: 10.1007/s11178-005-0226-7

Source and publish data:

Authors:

Article abstract of DOI:10.1007/s11178-005-0226-7

Full text of DOI:10.1007/s11178-005-0226-7

Products guided by the article

R&D Labs maybe for 864977-64-0

Relevant to this article

Hot Product