Medium-sized nitrogen heterocycles are an extremely important class of compounds. The term"medium ring" is usually used to refer to alicyclic compounds with a ring size of from 8 to 11. Theprimary concern of this chapter is eight-membered azaheterocycles, azocines. Azocines are a diverseclass of compounds, that frequently occur as biologically active compounds as well as being widelyused in synthetic chemistry. Although foundations providing pioneering work on azocines had beenstarted in the 1920s and 1930s <26HCA249, 33LA(504)94>, only limited systematic or comparativestudies of azocines as a class have been done. Azocines have received more attention because oftheir increasing usefulness both as synthetic intermediates and as therapeutic agents. Reviews coverthe following topics: a comprehensive account <82CHEC653), a systematic overview <82AHC(31)115>,and syntheses <85YGK603,87MI918-01,89MI918-01,91T9131) of azocines and their derivatives. In orderto avoid repetition as well as to cover all the relevant literature available, some sections such asexperimental, theoretical, and thermodynamics are grouped together in some instances.
9.18.1.1 Scope
This chapter details the nomenclature, thermodynamics, reactions, and synthesis, and summarizesthe experimental structural methods and applications in the following order: (i) unsaturated, par-tially saturated, fully saturated monocyclic azocines, (ii) benzazocines, and (iii) dibenzazocines. Thenitrogen bridged systems and unique compounds are not given detailed treatment owing to spacelimitations.
9.18.1.2 Structure and Nomenclature
Eight-membered rings with one nitrogen atom can be classified broadly into five categories:unsaturated, partially saturated, fully saturated, bridge-head, and fused ring systems (l)-(5). Themost commonly used systematic nomenclature for eight-membered heterocyclic compounds is theHantzsch-Widman system <83MI 918-05). According to this system, the compound (1) with fournoncumulative double bonds is named azocine, with the prefix "aza" indicating the nitrogen atom,followed by the stem "ocine" indicating the ring size and unsaturation. The nitrogen atom takesthe atom number one. Partially saturated systems are expressed by the prefixes dihydro-, tetrahydro-,hexahydro-, and octahydro- with azocine. For example, (2) is named 1,8-dihydroazocine. The fullysaturated system (3) is named "azocane" or "perhydroazocine". The names azacyclooctane andheptamethyleneimine have also been used in the literature. The most prevalent term is 'azocine'with suitable prefix(es).
NN
N
H H H
(1) (2) (3) (4)
N\H
(5)
9.18.2 THEORETICAL METHODS
Since the theoretical aspect of heterocycles is a new addition to this series, it is discussed here ingreater detail. Although eight-membered aza heterocycles have been known since 1906, theoreticalstudies on these systems only occurred from 1960. The conformational property of eight-memberedaza heterocycles is also of utmost importance in understanding their synthesis and reactions.
Eight-membered Rings with One Nitrogen Atom 405
A comparative calculation study was performed for cyclooctanone (6), octahydroazocine (7),and hexahydroazocin-5-one (8) using MM2 and MNDO. For discussion purposes, the proposedgraphical representation of possible conformations by Dunitz and Prelog <60AG896> is used (Figure1). The most symmetrical heterocycle possesses a crown conformation and there are boat-chair(BC), chair-chair (CC), boat-boat (BB) and other forms. In most cases, the position of the individualring atoms is not equivalent; therefore, additional conformations have to be taken into account.Moreover, twisted forms of the above-mentioned conformations might be more stable than the morenoticeable conformations. The calculated heats of formation, Ai/f, are summarized in Table 1.
o\\
(6)
N\R
(3) R = H(7) R = Me
O\\
N
(8)R(9)R
(10) R(11) R
R
MeEtP r i
Bul
Crown (++) BB (OO) BB
(++) BC (-+) BC
Figure 1 Graphic representation of possible conformations.
Table 1 Heats of formation (kJ mol ) by the MM2 method.
The most stable conformer for (6) is (+ + )BC and for (7) is (—h)BC. These calculated resultsfor (6) and (7) are in good agreement with other calculations and stereospecific measurements<72T1173, 74T1629, 75JOC369, 77CC939, 78JCP(69)268, 81T3981>. For (8), three conformations are found tobe rather close in energy: (4- +)BB, ( + +)BC, and (—h)BC. Hence, (8) forms an equilibrium of
406 Eight-membered Rings with One Nitrogen Atom
three conformers; however, this is not in accord with spectroscopic findings. By NMR spectroscopy,the BC form exists in aprotic solvents and the BB form may exist in strong hydrogen bondingsolvents <79CHE699>. Because transannular interactions are an important parameter in determiningthe conformational properties, MNDO calculations have been executed for higher reliability. Theresults (Table 1) show that the most stable conformer is that of the crown (5.5 kJ mol~'), in whichit is more stable than the (+ +)BC form. There is further argument based on dynamic NMR data,estimating an upper limit of 30 kJ mol ' for the transannular interaction between amino andcarbonyl groups in an eight-membered ring <76JCS(P1)913>. Compared with the standard energy ofa N—C single bond, 292 kJ mol"1, this value corresponds to a virtual bond order of 0.10. Thisinteraction is neglected by both theoretical methods. Transannular interactions will be favored,when the two functional groups are in close proximity, allowing significant orbital overlap. Theresults on distance between the two functional groups exclude the crown form, since it has thegreatest value (393 pm), even though it is favored by the MNDO method. But the ( + +)BB and( + +)BC forms have values of 276 pm and 286 pm, respectively, which are rather low. MM2calculations for (9)-(ll) showed that the (+ +)BC conformation was the most stable conformer.The results of x-ray and MM2 calculations revealed that transannular amide resonance in (11) ispossible: if all atoms except hydrogens are fixed at their experimental position, an additional stericenergy of 11.8 kJ mol^1 is calculated, and that has to be compensated by transannular attractions.This energy indicates a N—C bond order of 0.04 <87JOC3362>.
Using a novel NMR shift reagent, for example cobalt(III)meso-tetraphenyl porphyrin (CoTPP),the conformation of (3) is found to be a mixture of many conformations. Theoretical and exper-imental results revealed ring current shift for (3) <90MRC343>. Electronic structure and con-formational properties of the amide linkage were studied in lactams based on MNDO calculationsand photoelectron spectroscopy <85MI 918-01).
Molecular connectivity is a simple and useful method for quantitating the structure of hetero-cycles. Molecular connectivity for 56 JV-bridged compounds was calculated and correlated with theoctanol-water partition coefficient. Steric effects caused deviations from the LFER (Linear FreeEnergy Relationship) <83MI 9l8-0l>.
Reduction of 3,8-dimethyl-2-methoxyazocine (DMMA) in HMPA with sodium metal leads tothe formation of dianion radical and was detected by ESR. The coupling constants are in goodagreement with INDO calculations. It is interesting that the vast majority of the spin density is onpositions 2, 4, 6, and 8 of the ring system. The introduction of the nitrogen in the ring system of cotappears to have the same effect upon the spin density as putting an electron-withdrawing group onthe eight-membered ring <83JA6078>.
9.18.3 EXPERIMENTAL STRUCTURAL METHODS
Various experimental methods have been used to elucidate the structures of eight-membered ringswith one nitrogen atom, to study their conformational properties or to understand their molecularinteraction with biological molecules. A brief account is provided on the available methods.
9.18.3.1 X-ray Diffraction
X-ray diffraction studies on (12) revealed that the dimensions of the molecules are as expected.The conformation of the ring showed atoms N(l), C(2), C(5) C(6) planar and C(3), C(4), C(7),C(8) coplanar both within 0.02 A. The two planes are 0.81 A apart and approximately parallel(angle of intersection 2.2(1)°) <85CC85>.
The structure of hydroazocine (13) was confirmed by x-ray diffraction analysis along with 'HNMR results <87CC1296>.
OMe
(12) R1 = CH=CH2, R2 = CN
Eight-membered Rings with One Nitrogen Atom 407
X-ray diffraction data confirmed the structure of the (5)-enantiomer of methyl 5-hydroxy-3,ll-di-2 pyridyl-4,5-dihydro-l//,3//-2,6-methano-6-benz[c]azocine carboxylate of the camphanic ester<88ZN(B)90l>. The relative configuration, in similar such systems, was determined by 'H and 13CNMR <89AP(322)21>.
X-ray diffraction studies on dibenz[6.#]azocine and dibenz[6.#]azocinone have been reported<83AX(C)768, 87JOC2980>.
9.18.3.2 NMR, IR, and UV Spectroscopy
Proton NMR data on fully unsaturated tautomeric azocines (14) and (15) are provided in Table2 (Equation (1)) <90JHC1323>.
Carbon-13 and 'H NMR chemical assignments <87TL2517> for a few hydroazocines are designatedin Structures (16)-(19) (where "a" represents 'H NMR and "b" represents 13C NMR). For otherhydroazocines, 'H NMR data was reported <81JCR(S)306, 82MI 918-01, 82T1579, 83TL5731, 86AJC687,86JOC3652, 87JOC2929, 88JOC2226, 90SL584, 91JCR(S)46, 94JCS(P1)3557>.
Conformational analysis of perhydroazocine (3) was accomplished using a novel cobalt(III)porphyrin shift reagent (see Structures (3a) and (3b)) <90MRC343>. The structure of the N-benzylderivative of perhydroazocine was elucidated by 13C NMR <8iAJC2307>. Natural abundance ofI7O NMR data for 30 lactones and 36 lactams in acetonitrile at 75°C was reported <89H(29)30l,89H(29)307>.
Using 19F NMR data, direct fluorination on heptamethyleneimine was interpreted <90JFC(50)15>.Proton NMR results and discussion have been provided for benzazocine derivatives <83TL413,
NMR results facilitated the structural elucidation of dibenzazocines <73JCS(Pl)205, 84JCS(P1)2O13,85H(23)159, 85H(23)895, 87JOC2980, 88JHC161, 94JOC148).
The NMR technique detected anions of N-methyl-l-benzazocinide and indicated the extensivecharge delocalization in 1-benzazocindiide, and dibenz[6.#]azocindiide <82AG803>.
9.18.3.3 Mass Spectrometry
A series of N-tosylated azacycloalkanes was studied using mass spectrometry. The [M + H]+ ionsof chosen compounds decomposed in the time frame of metastable peak observation, along withthree main competitive unimolecular channels common to all ring sizes: (i) rupture of the S—Nbond to give the MeC6H4SO2
+ ion (m/z 155) and the neutral amine; (ii) ring rupture leading to acommon peak at m/z 184, corresponding to the CH3C6H4SO2NH=CH2 ion; and (iii) formal loss ofthe p-toluenesulfonic acid. Correlations were found between ionic energies and ring size for the firstpathway, and between strain energy and ring size for the second pathway <89OMS(24)29i>.
9.18.3.4 Other Techniques
The absorption and fluorescence properties of iV-substituted azacycloalkanes have been reported<85JCS(P2)1063>.
The liquid crystal method is a sensitive method in studying the stereochemistry of optically active
Eight-membered Rings with One Nitrogen Atom 409
substances, and sometimes complementary to CD spectroscopy. Conversion of nematic liquidcrystals to a cholesteric mesophase may be achieved by adding a small quantity of optically activemolecules. Investigation of the nematic phase of (A) and (B) was accomplished and their absoluteconfigurations were expressed in terms of helicity (i.e., R (A) and R (B) had nematic phase, +58and +19, 8 E7; biaryl helicity, P, and cholesteric helicity, P) <87T1425>.
O
(A) (B)
Separation of nitrosoperhydroazocine as well as its a-substituted derivatives from other nitroso-azaheterocycles was accomplished by HPLC using cyclobond I column and a mobile phase ofmethanol/water <86JLC1783>.
Using cyclic voltametry, the electrochemical properties of the enamines of the cyclic ketones withperhydroazocines as well as with other cyclic amines were studied. The anodic peak potentialsdepend upon the ring size of the amine reacted (5 < 7; 8 < 6 < 1-methyl piperazine < morpholine)<88JCS(P2)369>.
9.18.4 THERMODYNAMIC ASPECTS
9.18.4.1 Azocines
"Aromaticity" and availability of the nitrogen lone-pair electrons are always questions of interestin 7r-excessive heteroannulenes. Addition of two electrons to the completely unsaturated azocine (1)or removal of proton from a dihydroazocine (2) can lead to a dianion or monoanion, respectively,each of which is a 1 Ore-electron system, corresponding to "^-equivalent" and "re-excess" analoguesof cyclooctatetraene. Both of these processes have been demonstrated <82CHE653>. Dianions (18)and (19) were formed, respectively, by reacting (16) and (17) with Schwesinger's strong base,nonionic phosphonimine R 3P=NCH 3 (pKa 27.5 in CH3CN) (Equation (2)). Proton and 13C NMRdata indicated efficient enamine resonance with the butadiene rather than the ethylene section ofthe molecule and thus (16) exists in quasi-half-chair conformation. Contrastingly, the dianions (18)and (19) exhibited planarity or diatropicity <87TL2517>.
:B(2)
(16) R = Bu'(17) R = Tos
(18) R = Bu'(19) R = Tos
The stability of potassium salt of cot dianion is due to solvation and lattice effect. Substitutionof a nitrogen atom for one of the carbon atoms in the eight-membered ring system resulted in anincrease in the energy of the THF solvated dianion, relative to the metal and neutral and organiccompound, due to an increase in the electron-electron repulsion in the dianion <84JPC5417).
9.18.4.2 Hydroazocines
Alkoxyazocines exist in tub conformation without conjugative stabilization, but its dianions,obtained by electrochemical or chemical reduction, exist in aromatic planar conformation <71JA161,71JA168). The existence of 3,8-dimethyl-2-methoxyazocine (DMMA) dianion radical (20) along withits electron distribution and thermodynamic stability were reported for the first time in 1983<83JA6078>. Reduction of DMMA in HMPA with metal sodium or potassium yielded an anion
410 Eight-membered Rings with One Nitrogen Atom
radical, but in THF resulted in only a diamagnetic solution that is devoid of an anion radical. Bothanion and dianions are associated with cations in THF while there is no association with cations inHMPA; this absence of ion association makes it possible to detect DMMA*. Thermodynamicstability of DMMA dianion in comparison with related systems was studied by calorimetry. Ther-modynamic parameters for disproportionation for DMMA' in the absence of ion association isAH°dlsp = +7.0+1.0 kcal mol"1; Kdisp (0°C) (1.3)105 and for coTis AH°disp = +4.6±0.7 kcal mol"1;Kdisp (0°C) (7.5)102. Kdisp for DMMA" is higher than for cot" because of ion association in suchsolvents. The stability of dianion is enhanced by the cation sandwich (20) between nitrogen andoxygen atoms in the solid state. The crystal lattice energy of solid dianion salts appears to play amore dominant role in controlling the heat of formation from the neutral molecules and sodiummetal than do aromaticity considerations and the effect of the nitrogen upon the aromatic characterof the dianion <83JA6078>.
Conformational behavior of l-alkyl-l,2,3,4-tetrahydroazocin-2-ones was studied by usingdynamic 'H NMR. The Tc (-60 to 40°C) and AGf (10.3-10.9 kcal mor1) values were reasonablyexplained as being due to the ring inversion associated with rotation of the N—C a-bond. Thetemperature-dependent chemical shifts were due to population changes in the chiral azacinone ringsystems, where steric hindrance due to the 3-substituent plays a major role <82JOC1564>.
9.18.4.3 Perhydroazocines
It is well known that conformational effects influence a variety of regiochemical and stereo-chemical reactions. A rational approach has been initiated to control these transformations forsynthetic purposes. Lithiation studies on the iV-benzyl lactam along with other medium-sizedazaheterocycles showed variation to the site of metallation (a to the carbonyl group or a to nitrogen)and is due to their conformations. C-Alkylation had occurred only on the a-carbon to nitrogenunlike in five-, six-, nine-, eleven-, and thirteen-ring azaheterocycles. For the eight-membered ring,the minimum conformational energy may not allow HA or HB to assume the alignment and thusmetallation by benzylic proton is kinetically favored <87JA4405>.
Transannular interaction is a unique feature of medium-sized heterocycles. The chemistry of suchcompounds with two functional groups in appropriate position(s) may be dominated by trans-annular interaction(s). The Hel photoelectron spectral technique was used to study the transannularinteraction and conformation in cycloaminoketone and cycloaminoalkene. In the lower energyregion (10 eV) of the PE spectra, two ionization bands were found for the amino ketones; one forn electrons on the amino group («N) and the other for n electrons on the carbonyl oxygen group(no). It was not possible to identify the bands due to the ionization of the 7rC=O electrons. Theresults (large shift) indicate that no ionization can be considered as an indicator of transannularinteraction(s) for aminoketones. Aminoalkene (22) is isoelectronic with aminoketone (21). Amino-alkenes are much better suited for PE spectroscopy, since both interesting MO's «N and TTC=C areaccessible in the lower energy range of the spectrum. For aminoalkenes, the degree of interaction ismeasured by the shifts of the «N and nC=C orbitals. In total, the results indicate that considerablen/n interactions occur in eight-membered rings. This is consistent with IR results (C=O frequencyis 20-30 cm"1 lower than cyclic ketone) indicating that the partial single bond character of theC=O is due to the transannular amide resonance. In aminoalkene, C=C stretching vibration islocated at 1625 cm"1 indicating a weaker C=C bond due to the transannular interaction with theamino group. This transannular interaction may be due to the preferred conformation (22), whichbrings close contact between the two functional groups. Such a transannular aminoalkene interactionin an eight-membered azaheterocycle was reported for the first time in 1986 <86JOC592>. Trans-annular interaction in medium-sized azaheterocycles was studied by 13C and 17O NMR spectroscopy.In the aminoketone, chemical shifts of 13C and 17O of the carbonyl group changed to 11 ppm (13C)or 81 ppm (17O) relative to the corresponding cycloalkanone. The observed effects AC and AO were
Eight-membered Rings with One Nitrogen Atom 411
linearly correlated <88JCS(P2)2H9>. The ionization potential of the lone-pair electrons of nitrogenwas determined for A^-tolylsulfonyl azacycloalkanes by gas phase ultraviolet spectroscopy. Theionization potentials (IPs) are affected by the strain present in the ring. More precisely, the IPsreflect changes of hybridization of the AMone-pair electrons upon varying the ring size, whereby alower or higher energy is required for the ionization process of the cyclic compounds relative to aseries of open-chain alkylamines <86JCS(P2)667>.
o
-N-i
Me(21) (22)
Ruthenium tetroxide (RuO4) oxidation of JV-alkyllactams proceeded regioselectively dependingon the size of the lactam ring, except for the seven-membered ring. Four- and eight-membered N-methyl and Af-ethyllactams were oxidized at the exocyclic a-carbon adjacent to nitrogen to producethe iV-acyllactam and NH-Xactaxa. Regioselectivity was confirmed in the oxidation of substratehaving a tertiary carbon at the oxidation position <87CPB357>.
Hydrolysis of the enantholactam in 0.5-65% H2SO4 at 59.5-94°C indicated that two mechanismsare operating: (i) via complexation of the lactam with H5O2
+, and/or (ii) via a complex of theprotonated lactam with a water molecule <83IZV777>.
9.18.4.4 Benzazocines
Ketal (23) consists of two stereoisomers. X-ray crystallography and 'H NMR data indicate atwist-boat chair conformation is thermodynamically favored over the twist-boat. The energies ofactivation for the interconversion were estimated to be 26.6 kcal mol"1 (twist-boat chair to twist-boat conformation) and 25.2 kcal mol"1 (twist-boat to twist-boat chair conformation) at 25°C<84JA5378>. Conformational studies on similar such ketals have been reported. These conformationalisomers were easily separated by chromatography and their structures were elucidated by x-rayanalysis. In refluxing benzene, the pseudoaxial conformer isomerized to the thermodynamicallymore stable pseudoequatorial conformer <88JOC5355>.
TosHN
o
9.18.4.5 Dibenzazocines
Conformational studies on dibenzazocines were performed to understand the molecular inter-action between the compounds studied and the biological molecules.
Conformational studies on [c.e] and [c.f] systems are discussed based on ORD and NMR spectraldata, respectively <82AHC(3l)H5>.
Dibenz[£./]azocine derivative exists in three possible conformations, chair, boat, and twist-boatin solution but in solid state, it has been shown to assume only one conformation, the chair form<73JCS(Pl)205>. Proton NMR spectral data supported the half-tub conformation of the tetra-hydroazocine ring and the quasi-equatorial configuration of the 8-hydroxy group of 8-hydroxy-5,6,7,8-tetrahydrodibenz[c.e]azocine <89CPB870>. The conformational behavior of the N-substituteddibenz[Z>./]azacinone (24) in solution by dynamic NMR studies suggested that it exists in an invertedboat-boat form <74CS52>. NMR line shape analysis is a powerful technique for solving the subtleproblems posed by compounds like the dibenzazocinones. The temperature dependence of NMRspectra and the computer simulation of Eu(fod)3 induced resonance shifts (LIS) are useful in
412 Eight-membered Rings with One Nitrogen Atom
determining the preferred configuration and conformation of the systems. The temperature depen-dence studies revealed that the observed kinetic process was due to the inversion of the centraloctaatomic ring which involves a rigid chair and/or mobile boat and twist-boat conformation withall of the series of possible state geometries. In these systems, ring inversion is a slower process thannitrogen inversion. The total line shape method showed that the free energy of activation indicatethat (24) (AG# = 13.9 kcal) has greater ring mobility than (25) (AG# = 21.2 kcal). resonance shiftand LIS simulation data revealed that the greater mobility of (24) is mainly due to AS* and thelower mobility of (25) is due to AH*. Electronic factors can play an important role in determiningthe ring mobility of the central octaatomic ring of dibenzazacinone systems <85H(23)895>. Chemicalproperties of the diketone (26) are significantly influenced by the twist-boat conformation of theeight-membered ring. The methylene protons in the diketone are nonexchangeable because it isenergetically prohibitive to form the endocyclic enol <87JOC2980>.
O
o R
(24) R = H(25) R = Me
9.18.5 REACTIVITY AND REACTIONS
9.18.5.1 Azocines
Reference should be made to Section 9.18.4.1.
9.18.5.2 Hydroazocines
Highly functionalized pyrrolizidines are obtained via several sequences from ^-blocked 1,8-dihydroazocines. These sequences allow considerable flexibility in the elaboration of structure andthe regiocontrolled placement of substituents <82T1579>. Tetrahydroazocinones have been convertedinto ethoxytetrahydroazocines with the Meerwein reagent <86AJC687>. Hydroazocine lactams havebeen shown to also undergo acylation <82GEP(O)3l20451). Via modified Tiemann rearrangement,cyclic amidoxime O-methanesulfonate has been transformed into cyclic carbodiimides <83JOC1694>.
9.18.5.3 Perhydroazocines
Perhydroazocines readily undergo nucleophilic substitution to yield JV-substituted derivatives.JV-Substituted compounds are synthesized for their applications in pharmaceutics, agriculture,polymers, etc. TV-Substitution has been achieved by both acylation and alkylation procedures.
iV-Acylation is accomplished by reaction of (3) with (i) acyl chloride <82BRP208i263,82GEP(O)3240908,83GEP(O)3301959, 83JMC1433, 86EUP177361, 86EUP179443, 89JAP(K)01319462>, (ii) 1,1-carbonyldiimidazole<85EUP160436>, and (iii) acid anhydrides <85CCA337>. ^-Alkylation is accomplished by reaction withthe corresponding halides (I, Br, Cl) <82GEP(O)3120451, 88AP(32l)57, 89MIP9009996, 9UMC2624), or byMannich reaction (Equation (3)) <82MI 918-02,85EUP163537).
Eight-membered Rings with One Nitrogen Atom 413
NN'
CHO
(3)
(27) (3) (28)
Electrochemical oxidation of cyclic amines resulted in bicyclic compounds <85CJCll70>. Oxidationof perhydroazocine with aqueous Na2S2O8 in the presence of AgNO3 gave l-formylperhydroazocine<82JCS(Pl)303l>. The tri- and tetranuclear clusters of Ru3(CO)12, [HRu3(CO)n]", and [H3Ru4(CO)12]"~catalyzed the carbonylation of perhydroazocine to give its formamide. The reaction works withonly CO or with a mixture of carbon dioxide and hydrogen <89JOM(368)103>.
Oxidation of TV-substituted and unsubstituted azocines (R = H, Me, Ph) by RuO4 gave thecorresponding lactam, whereas similar oxidation of benzyl cyclic amine gave mixtures of lactamand benzamide <85G325>. TV-Substituted azocine(s) undergo (i) rearrangements assisted by mercuryacetate <90AP(323)47>, and (ii) Beckman rearrangement of oxime sulfonates assisted by organo-aluminum reagent, offering a new route to obtain a-alkylated amines <83JA283l>. Amino groupspresent in the side chain of the TV-substituted azocine underwent protection with phthalimide,deprotection by hydrazinolysis, and acylation with L~ or DL~H-pyroGlu-OC6Cl5 to provide theazocine derivative <82MI 918-03). S-Alkylation of TV-substituted azocine has been reported<83JAP(K)5821674, 83JAP(K)5821675>. Hydrogenation of a-functionalized azocine or nitromethylenederivative with Pd/H gave pyrazine but with Rh-catalyzed reduction gave piperazine <87UC(B)1O7>.
The carbonyl group in the azocinone system (29) reacted with MeNHOH in the presence of KOHto afford the nitrone (30) (Equation (4)) <86Mi 918-01). Azabicyclanone derivative (31) underwentreduction with H2 over Raney nickel or NaBH4 in dioxane affording a mixture of epimeric alcohols(32) <88IZV71>. Under Favorskii conditions, (31) reacted with ethyne to give alcohols (33) (Scheme1) <88IZV76>.
MeNHOH, KOH
(29) Ar = Ph, P-OMe-C6H4
HC = CH, KOH
(4)
R1 = HC=CH2, OHR2 = OH, HC=CH2
(33)
R1 = H, OHR2 = OH, H
(32)
Scheme 1
MeO
The nitrogen atom in enantholactam can also undergo acylation. Subsequent reactions of N-acylated enantholactam yield biologically important compounds <81MI 9l8-0l> or a facile route to
414 Eight-membered Rings with One Nitrogen Atom
large-membered bi- and tricyclic compounds via an aza Wittig reaction (84CB1513, 9UOC1535). Thea-carbon of the lactam (34) was functionalized to obtain the racemic eight-membered lactam (39).The racemic mixtures were resolved via its pyroglutamic salts (Scheme 2) <86JMC25i>.
O
NH2
CF3CO2H
OBu<
(38)
Scheme 2
A novel photochemical transformation of jS-keto vinylogous amide into the unexpected product3-acylpyrrole rather than the expected [2 + 2] product has been reported <93TL7697>. Excitation ofthe vinylogous chromophore (40) leads to homolysis to form the stabilized biradical (41), which caneither regenerate (40) by ring closure or form the ring-expanded ketoimine (42) via cyclization at theterminus of the azaallylic radical. The ketoimine (42) can then undergo a ground-state transannularcyclization, after dehydration, to give the unexpected product (43) (Scheme 3) <93TL7697>.
(43)
Scheme 3
Selective nucleophilic additions of alkyllithium reagents to A^-(trimethylsilyl) lactam (44) providedthe cyclic ketamine (45) in high yield. The only Grignard reagent used, ethylmagnesium bromide,attacked mainly at Si to form the amide anion (Scheme 4) <90JOC3682>. iV-Butoxycarbonyl enan-tholactam was cleaved by reacting with Grignard reagents (RMgBr; R = Bu, Ph) to give y-amino-ketones, which were deprotected with CF3COOH and cyclized with NaOH to give seven-memberedcyclic imines <89JOC228>. Regioselective functionalization of enantholactam was achieved via oc-alkylation using lithium hexamethyldisilazide, followed by alkylhalide. jS-Alkylation was achievedby reaction of a,/?-unsaturated lactam with organocuprates <90SL63>. O-Alkylation of enantho-lactam with Et2SO4 or Et3O+BF4" gave the lactim ether, which on protonation by HC1 or HBF4
afforded the ammonium salts. The salts on hydrolysis yielded y-amino ethyl ester <88SC1625>. Lactimether (46) condensed with heterocyclic enaminonitrile, dihydrofurancarbonitrile (47) to give the
Eight-membered Rings with One Nitrogen Atom 415
heterocondensed pyrimidine (48) or pyrimidophane (49) via a Dimroth rearrangement (Equation(5)) <86CB1070>.
TMS-C1
TEA
(34)
MeLi
TMS
Scheme 4
CN NH
OMe(5)
(47)
Anodic oxidation of enantholactam in the presence of halide ions gave the bicyclic compound<87CJC2770>. Ozonolysis on a-substituted and N-substituted enantholactams has been reported<83SAP8209141>.
TV-Chloroacetyl enantholactam underwent cycloaddition reaction with MeO2CC=CCO2Me andjV-phenylmaleimide via isomunchnone to give a pyridone derivative <87JOC1599>.
Photolysis of enantholactam (34) produced the amidyl radical intermediate in the presence of thehypervalent organoiodine reagent, (diacetoxyiodo)benzene (DIB), and iodine. The radical under-went transannular hydrogen abstraction to afford intramolecularly functionalized 5-oxoindolizidine(51). It is noteworthy that the #em-diiodide (50) is formed through an unexpected double hydrogenabstraction. This result indicated that the first hydrogen abstraction from C-5 resulting in mono-iodide is not a propitious step, even though it adopts a conformation which favors cyclization, butthe second abstraction of the geminal iodide hydrogen step occurs instead (Scheme 5) <89CC1168>.
(51)
Scheme 5
Modifications of the side chain substituted on nitrogen atom and/or oe-C functionalization ofthe enantholactams have been accomplished to obtain antihypertensive compounds <82EUP49842,82EUP46289, 84CB1513, 84USP4470988, 85SAP8308227>.
9.18.5.4 Benzazocines
Benzazocines can be easily alkylated by alkyl halides <88MI 9l8-0l>, and acylated by acid chlorides<86Mi 918-02, 87MI 918-02). Benzazocines also underwent oxidation with NaWO4
#2H2O<87JAP(K)62212363>. Benzazonium ylide (52) with sodamide in liquid ammonia solely underwent theStevens rearrangement (1-2 migration) rather than the Sommelet-Hauser reaction (2-3 migration)to afford one carbon ring enlargement product (53) (Equation (6)) <89S327>. When the nitrogenatom bears one methyl group and another methyl or ethyl group, (55) afforded the ring-openedproduct, enamine (56) (Scheme 6) <87S727>. Thermolysis of 2-methyl hexahydrobenzazocine N-oxide (57) afforded the ring-enlarged product, methylhexahydrooxabenzazonines (58) (Equation
416 Eight-membered Rings with One Nitrogen Atom
(7)) <89CCC2767>. Modified Tiemann rearrangement of cyclic amidoxime Omethanesulfonateafforded the carbodiimide on treatment with NaOH and Aliquat 336 in CH2C12 <83JOC1694>.
Ring C-alkylation was achieved by exploiting the chiral formamidine leaving group allylic protonpKa. Subsequent reduction of unsaturation using Rh/C furnished the benzomorphan( + )-met-azocine <85JA7974>. The a-carbon was functionalized into an amino group via bromination, phthal-imidation, alkylation, or amination to obtain (60) from (59). The introduced amino group wasfurther reductively alkylated and saponified to give (61). Various related derivatives were preparedwith a number of "R" groups on the aromatic ring (Scheme 7) <84USP4470988>. A similar strategywas used to prepare benzazacinone and its derivatives <85USP4537885>. OAcylation on the aromaticring of benzazocine was achieved by Schotten-Baumann Oacylation using the corresponding acidchloride <87Mi 918-03). The aromatic ring in benzazocine was functionalized into thiol and wasfurther alkylated <85JAP(K)60l69465>. Regioselective O-methylation, ketalization, and N-tosylationof benzazocine derivatives were achieved in the synthesis of potential intermediates of mitomycin<88JOC5355>.
AcOi,Pd/C
ii, PBr3
iii, Kphthal
o
i, PhCH2CH2CO2Et
ii, NaBHCN
Ph
Eight-membered Rings with One Nitrogen Atom All
The hydroxyl group on the azocinyl ring was oxidized and subsequently cyanated<85JAP(K)6048990>. The amidocarbonyl group on the azocinyl ring was reduced by (MeO-CH2CH2O)2HAlNa <84CZP2l0993> and was reacted with 1-methylpiperazine <88CPB2386>. The car-bonyl group at the 6-position underwent (i) reduction with Grignard and dialkyllithium reagents<90AP(323)l77>, sodium borohydride <88ZN(B)90l, 89AP(322)2i>, LAH <89AP(322)2l>; and (ii) ketal-ization with 1,2-diol <88JOC5355> and hydrazine in methanol <90USP4973693>. The first example ofamide dianion regioselective alkylation by sequential addition of two electrophiles has been reported.Thioethers (63) were oxidized to sulfoxides (64), which on thermolysis afforded the cc,/?-unsaturatedlactams (65). Addition of thiolactic acid and removal of the protecting groups completed thesynthesis of l-(carboxymethyl)-3-(thiomethyl)-2,3,4,5-tetrahydro-l/f-l-benzazocin-2-one (67) from(62) (Scheme 8) <84JMC816>.
Tetrahydrobenzazacinone underwent acid-catalyzed cyclization with polyphosphoric acid toafford the novel 1,3-bridged hexahydromethanobenzazocinones <83H(20)l979>.
Ph
COMe
(67)
9.18.5.5 Dibenzazocines
Treatment of tetrahydromethanodibenzazocine ,/V-oxide under basic conditions yielded tetra-hydroisoquinolines <84CC1644>. iV-Alkylation on dibenz[c.e]azocine <91CCC2986> as well as nucleo-philic addition of alkyl and cyclic amine on the iV-epoxypropyl substituted dibenz[c.e]azocine werereported <91CCC1725>.
9.18.6 SYNTHESIS
Synthesis of azocines embraces that of azepines and azonines in the use of general methods:Beckmann rearrangement, Schmidt reaction, and intramolecular cyclization. In general, cyclizationdepends upon the probability of end-to-end encounters. It is determined by the activation energyof the process. In an eight-membered azacycle, energy of activation depends upon (i) Pitzer strain(torsional effect in a single bond), (ii) Baeyer strain (deformation of ring bond angles from theirpreferred angles), and (iii) transannular (nonbonded through space) interaction which occurs whenatoms across the ring are forced into close proximity. These strains will be reflected in the enthalpyof activation for the cyclization. There is a negative AS1 contribution during the cyclization and thiswill tend to lower the cyclization rate; thus, accomplishing an eight-membered ring via a cyclizationprocedure is rather challenging.
Since azocines are a diverse class of compounds, their preparative methods remain specific andoften inefficient. The order of discussion is as outlined in the introduction.
418 Eight-membered Rings with One Nitrogen Atom
9.18.6.1 Azocines
In the literature, synthesis of azocine/azacyclotetraene was achieved by the only route, photo-cycloaddition <85CC85, 88T1449, 89JCR(S)lio, 90JHC1323). Cycloaddition of a nitrile group into anaromatic ring is uncommon. It may be due to an assumption that arenes involve intramolecularelectron transfer via the S! n n* state. However, formation of (70) along with two or^o-photoadductsrepresents the first example of photocycloaddition of a nitrile group (69) into an aromatic ring (68)(Equation (8)) <85CC85>. This methodology is successful only if the benzenes have both electron-donor and electron-acceptor substituents in the para relationship to give azocines. Acrylonitrile,cinnamonitrile or 4-hydroxybenzonitrile did not react with phenol. But /wa-substituted methoxybenzonitrile (72) reacted with phenol (71) to yield lactam (75) by initial 1,2-photocycloaddition,followed by ring opening and tautomerization (Scheme 9) <89JCR(S)ll0>. Studies on the substituenteffect of the photocycloaddition of phenol to substituted benzonitriles revealed that, in general, allsubstituted benzonitriles are less productive than benzonitrile itself. The para substitution seems tobe better than the others. The photolabilities of these arenes in the presence of phenol varyappreciably. Solvent polarity enhanced the reaction, suggesting the photo-induced electron transferfrom the phenol to the cyano compound and that the radical-ion species thus formed either undergoaddition or react with oxygen <9OJHC1323>.
OMeOMe
(8)
(69) (70)
OH
254 nm
OH
X
X = H, Me, OMe; R = H, OMe
Scheme 9
9.18.6.2 Hydroazocines
Generally hydroazocines are prepared via cycloaddition; but depending upon the degree ofunsaturation, the preparation can also be achieved by other routes.
9.18.6.2.1 Hexahydroazocines
Intramolecular cyclization of (76) in the presence of NaH gave exo (77) and endo (78) products(Equation (9)) <90SL584>. Allene-based electrophile-mediated cyclization afforded Af-tosyl iodohexa-hydroazocines <94JCS(Pi)3549>. Photochemical intramolecular cycloaddition of phthalimide in acet-one afforded the ring-opened product <82TL498l>. An unstable enaminone azocine derivative (81)was formed after the desulfurization of the bicyclic aminal (80), which in turn was synthesized from
Eight-membered Rings with One Nitrogen Atom 419
the Diels-Alder adduct, dihydrothiopyranone (79). Azocine (81) rearranged to (formylmethylene)piperidone derivative (Scheme 10) <88JOC2226>. Lactam (82) underwent a two-carbon insertion withPh3SiC=CLi to give (84) (Equation (10)) <87JOC2929>. Otonecine (87) was synthesized in its racemicform from the pyrrolizinecarboxylate (85) via lactone (86) in six steps (Scheme 11) <83TL573l>.Biosynthesis of otonecine (87) has been reported <9UCR(S)46>.
NaH
(77)
(9)
Bu'O O
(79) (80)
Scheme 10
N .+ Li- -SiPh3
Me
(82) (83)
(10)
CO2Me
(85)
OSePh
(87)
Scheme 11
9.18.6.2.2 Tetrahydroazocines
The [2 + 2] cycloaddition of tetrahydropyridine (88) with HC==CCO2Me gave tetrahydroazocine(90) (Equation (11)) <8UCR(S)306, 82MI 9l8-0l>. Cycloaddition of fulvene (91) with cyclic imine (92)gave the azocine (93) (Equation (12)) <86S908>. N-Alkyl substituted 2-pyridones (94) underwentphotocycloaddition with methyl acrylate (95) to afford the eight-membered unsaturated chiralazacinones (97) (Scheme 12) <82JOC1564>. On heating, 1,2-divinylazetidines (98) underwent a Coperearrangement to yield tautomeric mixtures of azocines (99) and (100) (Equation (13)) <86JOC3652>.
420 Eight-membered Rings with One Nitrogen Atom
The reaction of acetyl-substituted aminopyran (101) with arylidenemalonitrile (102) afforded anovel bridge-head azocine (103) (Equation (14)). The controversy over its structure was resolved byx-ray crystallography <92T1581>. A one-pot, decarboxylative three-carbon ring expansion of a cyclicsecondary amino acid afforded a tetrahydroazocine derivative (87CC1296).
N
R1
(88)
= — CO2Me
(89)
R1 = Bn, R2 = CO2Me
CO2Me
CO2Me(11)
(91) (92)
OEtOEt
NC CN
(93)
(12)
(94)
NaOH, heat
(98)
(13)
Ph
NC
H2N
COMe
(101)
Ph
N C ' "CN
(102)
(14)
9.18.6.2.3 Dihydroazocin.es
Unsymmetrically substituted ethynes (104) bearing at least one electron-withdrawing groupunderwent efficient cycloaddition with l-/?-styryl-l,2-dihydropyridine (105) to provide 3,4-sub-stituted 1,8-dihydroazocines (106) regioselectively (Equation (15)) <82T1579>.
Eight-membered Rings with One Nitrogen Atom 421
Bu l0
R1 R2 N
Ph
(15)
(104) (105) (106)
9.18.6.3 Perhydroazocines
Intramolecular cyclization of suitable starting materials with appropriate reagents afforded per-hydroazocines <82G3l, 82SC733). Reaction of in situ generated immonium ions with allylsilanes ledto intramolecular condensation and desilylation resulting in an azocine derivative; however, thereaction time was five days <86TL5067>. The secondary y-styryl (TV-methylamino)alkane (107) under-went intramolecular photochemical addition to yield regioisomeric adducts in which C—N bondformation had occurred either at the a-carbon to give TV-substituted azocine (109) or at the /?-carbonto give TV-substituted azepine (108) (Equation (16)) <9UA3498>. Lactamization of simple a,y-aminocarboxylic acid had been reported in the literature via catecholborane <78JOC4393) andAl2O3/SiO2 <80TL2443>. More recent successful methods used since the early 1980s, are via dibutyltinoxide <83JA7l30>, titanium tetraisopropoxide <88TL3049>, and a high dilution method for activateda,y-amino acid <83JOC2680, 84CPB3789). An efficient synthesis of eight-membered lactam from a,y-aminoacids using Et3Ga has been reported <89CL797>.
NI
H
Me h\
(107)
N(16)
Ph Me
(109)
Ring expansion is another route to obtain perhydroazocine derivatives. Insertion of TV-substitutedfragments into azapinone (110) afforded enantholactam (111) (Scheme 13) <85OS(63)188, 89TL4207,91TL2429). This is a less well-known methodology. In general, functionalization at the C-5 positionwas achieved via ring-opening of pyrrolizinium perchlorate (112) to yield (113) and (115) (Scheme14) <85JCS(Pl)26ll, 86H(24)2l2l>. Synthesis of diketone (117) was accomplished by controlled criss-cross annulation. This is a versatile method overcoming difficulties such as high dilution, low overallyield, and a lack of regiospecificity at the cyclization stage (Scheme 15) <83TL4253>. The saturatedbicyclic eight-membered lactam, carbocepham, was synthesized by palladium-catalyzed car-bonylation of vinyl halide <89H(29)853>.
4-NO2-C6H4-SO2ONHMe
i, (EtO)3CHii, MeNH-OSO2-C6H4-NO2-p
iii, Nal
O
NMe
(110) (111)
i, H2N-OSO3Hii, HCO2H, reflux
Scheme 13
422 Eight-membered Rings with One Nitrogen Atom
Cia
(112)
aq. alkali
H
(113)
i, R2C6H4CH2MgI
ii, Mel
R2 = H, 2-C1, 3-C1,4-C1,4-Me
Scheme 14
(114)
HO
(115)
I-
R
(116)= Me81%
R = Bn 65%
Scheme 15
O
(117)
Rearrangement by thermolysis of unsymmetrically substituted tricyclic derivatives of 2,6-epi-dioxypiperidine (118) afforded the ketamide (119) (Equation (17)) <9OKGS1O9>. Synthesis of N-substituted 5-azalactanone (121) was accomplished by CO insertion. Thexylborane-cyanidationhydroboration protocol proved to be the most useful method with moderate to high yield (Equation(18)) <82JOC1494>.
Ph
O
(118)
R
R = H, Me
Ph
Ph
(119)
(17)
RI
N
(120)
CO/H2
O
R
N\
(121)
(18)
R = CO2Me, CO2C7H7, SO2Ph
Eight-membered Rings with One Nitrogen Atom 423
9.18.6.4 Benzazocines
The benzo-fused azocine derivatives are diverse, hence grouping them together and presentingstrategic synthetic routes becomes rather intricate. Benzazocine derivatives are mostly formed asunexpected cyclized products, as intermediates, or as one of the "other" products in a reaction. Buta desirable benzazocine can be easily separated from other products by flash chromatography.
Isolation and structural elucidation of is-clausenamide, a benzo-fused lactam, were accomplishedfrom the leaves of Clausena lansium <87GEP(O)3700706,91MI918-01).
Intramolecular cyclization is one of the common methods used to obtain benzazocines<86JCS(Pl)1533, 86JCS(P1)1977, 88MI 918-02). Base-catalyzed cyclization of l,2-6iy(2-isocyano-2-tosyl-ethyl) benzene with KOH in ROH (R = Me, Et, i-Pr) afforded benzazocines <84JHC611>, but inr-BuOH it gave benzazocinone <87CPB3475>. Again, base catalyzation of TY-phthalimido substituted/Mcetoester provided benzazocine trione <94H(38)751>. Cyclization of hydroxylamine derivative (122)in MeOH with NaBH3CN gave (123) (Equation (19)) <91JAP(K)03l 15287). Thermal rearrangementand cyclization of spirooxoazolidines (126) provided a straightforward synthesis of benzazocinone(128) (Scheme 16) <89T5917>. A novel approach to obtain FR-900482 (131) via a ring-formingmetathesis reaction has been reported <95TL1169>. Electrochemical removal of the iV-tosyl groupfrom phenylenediamine derivative (132) in the presence of cooperative systems of anthracene andascorbic acid afforded the benzazocine (133) via a criss-cross annulation (Equation (20)) <84JOC953>.A review is dedicated to the synthesis of 1-benzazocinone deivatives by controlled criss-crossannulation <88MI 918-03). Tetrahydro-l-benzazocin-5-ones are achieved by a Dieckman con-densation <83H(20)2051>.
OMe OMe MeOOMe
(19)
(123)
Ph O-
(124)
Ph
Ph-
PhvJ>Ph -N
(125) (126)
O
(127) 20%
Ph
(128) 14%
O
(129) 14%
Scheme 16
OH
OHC
(131)
424 Eight-membered Rings with One Nitrogen Atom
(20)
(132) (133)
Numerous investigators have used ring-expansion strategies. Ring expansion was achieved (i) byBeckmann rearrangement of TV-oxime (134) leading to benzazocine (135) (Equation (21)) (82JHC941,83JCS(Pl)2053, 83TL413, 9OJCS(Pl)lO83, 90JCS(Pi)l09l>; (ii) from ^-ketoesters (136) (Equation (22))<84JCR(S)246, 86AP(319)1079), both reactive as well as unreactive jS-ketoesters have been discussed<84JCR(S)246>; (iii) by photolytic <85CL727> and thermal <82AP(315)749, 90H(3l)l769, 9lH(32)2089>rearrangement of tricyclic compounds such as (138), resulting in ring expansion to give benzazocine(139) (Equation (23)); (iv) from suitable starting heterocycle(s), for example (140), with the aid of avariety of reagents, such as cerium sulfate (Equation (24)) <87AP(320)48l>, ammonium carbonate<84H(22)i77l>, and lead tetraacetate (Equation (25)) <89JCS(Pl)i93i, 92OS(70)i39>; and (v) by oxidativecleavage <84H(22)355>, fluoride-ion induced desilylation <91CPB36>, intramolecular condensation<9UHC1625>, criss-cross annulation <90CC468>, cycloaddition <82CPB3959, 89T5917), ring opening ofoxaaziridine with an increase in three atoms <84AJC599>, intramolecular Grew cyclization <85JA7974>,ring contraction <92CPB617>, and ring-closing metathesis of dienes <95JA2108>.
NOH
(21)
(134) (135)
CO2Me
HO CO2Me
,CO 2 Me
i, NaH, PhMe, 25 °C, 3 hii, MeO2C : = CO2Me, 0 °C, 6 h
iii, 25 °C, 24 h(22)
(136) (137)
(138)
toluene, 100 °C
R = Me, Et
(23)
(139)
(140)
Ce(SO4)2
2 (NH4)2SO4
(24)
(141)
MeO
MeO
Eight-membered Rings with One Nitrogen Atom
MeOPb(OAc)4
CH2C12, AcOH MeO
425
(25)
(142) (143)
9.18.6.5 Dibenzazocines
Unlike other azocines, dibenzazocines are easily synthesized by the most exploited route, intra-molecular cyclization. It is achieved by two approaches: (i) connecting the two phenyl rings alwaysaffords the dibenz[c.e]azocine, and (ii) connecting the two functional groups (e.g. amine and ester)of two side chains of two participating aromatic rings provides [c.e], [b.g], and [b.f] dibenzazocinesystems.
Synthesis of 5,6,7,8-tetrahydrodibenz[c.e]azocine derivative(s) (145) was achieved by using KIand a stoichiometric amount of zero valent nickel, generated in situ (Equation (26)) <88JCR(S)8,88JHC161, 89CPB870, 89CPB1744). Photochemical cyclization of the amine <85CPB126O, 85H(23)159> andintramolecular cyclization of Ph(CH2)2NRCH2C6H4NO2-3 in the presence of Fe(CO)5 also affordeddibenzazocine derivatives <85TL5815>. An intramolecular Friedel-Craft reaction of isoquinolinol(146) afforded dibenz[c./]azocine (147) (Equation (27)) <92H(34)747>. Intramolecular cyclization wasalso achieved by connecting the two functional groups such as amine and ester in the side chains ofthe two phenyl rings (148) at elevated temperature to give (149) (Equation (28)) (83CZP209400,84JCS(P1)2O13,86CB3165,91MI918-02). A similar approach was successful in synthesizing functionalizeddibenzazocine derivatives <88KGS1OOO>. Intramolecular cyclization involving two ester groups (150)with reagents like alkyllithium or alkylmagnesium yielded dibenz[fr.#]azocines (26) (Equation (29))<85ZNB858, 86CB3165, 87JOC2980). a,a'-Disilylated benzamide (151) constitutes an ortho- and a'-carbanion synthon, which provides dibenzazocines (154) by Peterson alkenation (Scheme 17)<89TL5841>. Synthesis of dibenzazocine derivatives was also achieved by electrochemical oxidationof aromatic ethers <83JCS(Pi)2053>, by intramolecular cycloaddition <90JOC2103, 90UKZ749), and byring enlargement via Sommelet-Hauser rearrangement of ammonium ylides <94JOC148>. The last isan attractive method for the reason that the rearrangement occurs regioselectively at milderconditions. Photocycloaddition of 6-substituted phenanthridines and electron-rich alkenes, such asfra«5-anethole and PhOCH=CH2 gave azocine or azetidine derivatives <82BCJ219O>. Synthesis andproperties of dibenz[6./]azocine functional derivatives have been reported <91KGS1O9>.
Ni/KI
R2
(26)
R5
R2
R2
(145)
R1 = H, OMe; R2 = H, OMe; R5 = H, Me, Ac
R3
(27)
N-
(146) (147)
R1 = H, OMe, F, Cl, Et; R2-R4 = H, OMe
426 Eight-membered Rings with One Nitrogen Atom
O
(150)
(28)
(29)
O TMS
/K. Bu'Li/TMEDAN TMSMe THF,-78°C
(151)R = H, 3-OMe, 4-OMe
O TMS
0sO TMS
TMS
Me
TfO-C6H4-CHO-o
Pd, LiCl, DMF, 100 °C
(152)
N TMS CsF, DMFMe
OHC
(153)
Scheme 17
Although several methods are reported in the literature for the synthesis of azocines, the need fora general, versatile, and stereoselective method still remains a challenge.
9.18.7 APPLICATIONS
Eight-membered azaheterocycles have found a wide spectrum of applications as summarized inthe following sections.
9.18.7.1 Azocines
The fully saturated azocine (1), has not been exploited for application purposes up to 1995. Allstudies have been done for academic reasons. Applications of partially saturated azocines are notwell known and the only system which has found its application is otonecine (87). Otonecine is thebase portion of the alkaloid emiline which was originally extracted from the plant, Emilia flammea.Emiline has hepatotoxic and carcinogenic effects <83CL125,83TL5731,89JCR(S)358,91JCR(S)46>.
Completely saturated azocines possess numerous applications. JV-Acylated derivatives ofperhydroazocines are used as herbicides <83JAP(K)5821674, 83JAP(K)5821675, 84GEP3238007,89JAP(K)O1319462>, as antiarrhythmic agents (85EUP160436, 86EUP177361), and they also possess anti-con vulsant activity <88JMC2218>.
iV-Alkyl or aryl substituted heptamethyleneimines are used as magenta dye image stabilizers
Eight-membered Rings with One Nitrogen Atom All
<87JAP(K)62278549>, in treatment of hypertension <85JAP(K)60239458>, central nervous systemdisorders, diabetes, sexual impotence, and to control appetite <90MiP90i5047>.
effect on neuromuscular junctions <87EUP235942>, antiarrhythmic activity <85JAP(K)60239458,91MIP9101299), cognitive performance enhancing activity <86GEP(O)35l5093>, and antinociceptiveactivity <9UMC2624>. JV-(Alkyldialkoxysilyl) cyclicamine is used as an electron donor for oe-alkenepolymerization <91EUP41O443>. Metallic [Cu(II), Ni(II), Fe(III), Mn(II)] complexes of 2-acetyl-pyridine thiosemicarbazone showed reduced antimalarial activity but enhanced antileukemic prop-erty relative to the free ligands <82JMC1261>. N-Nitroso heptamethyleneimine (NHMI) was foundto be a carcinogen/mutagen <82MI 918-04, 86MI 918-03, 90MI 918-01 >. It is unusual to find so manyapplications for just two compounds, A^-substituted derivatives (155) and (156): antihypertensive,antidiabetic, gastric secretion inhibition, anticholesteremic, central nervous system depressant, andantidepressant activity <82MI 918-02). Quaternary salts of perhydroazocine are useful as softeners,conditioners, and/or bactericides in cosmetics, mouthwashes, and textile treating agents<88MIP8802985>, and hair and skin treating formulations with bactericidal properties <89USP4883655>.Azacyclooctanones are effective in stabilizing diazo compounds and materials against precoupling,loss of shelf-life, and image fading <83USP4419432>. Unsubstituted enantholactam is used as anadditive for heat resistant ABS resin <86JAP(K)6193158>, in biologically active seed coating com-position <85MIP34313>, as an angiotensin converting enzyme inhibitor <83MI 918-02), a hydrophobicphotographic additive (85EGP229514), a drying inhibitor for aqueous inks <91GEP4001644), and adiscoloration preventing reagent in the photochlorination reaction of /?ara-xylenes <82JAP(K)98225>.JV-Acyl enantholactams have found wider application in polymer synthesis (85JA5817, 86MM1530,86PP118, 87USP4644050), to provide improved mechanical properties, heat resistance and decreasedflammability <8iMiP2iooo>, reinforced thickness for glass fibers <82CZP193697>, and coating com-position on electrically insulating wire <86JAP(K)6100270), as well as being used as antihypoxic andantiamnesic agents in pharmacological studies <83KFZ1439>. Bicyclic perhydroazocine derivative isused as a capacitor <88JAP(K)63305507>, as well as in treating heart disease <88GEP(O)370466l>.
(155)X = N, CH, CCH2OHR = H, 5-C1, N-NH2, 5,6-Cl2
Numerous studies have been done on guanethidine (157). Reviews which focus on guanethidineare <8OMI 918-01,81MI918-02,82MI918-05,84MI918-01,86MI918-04). A complete discussion is beyond thescope of this chapter, hence, only the available references are indicated. Since (157) is proven to bean antihypertensive agent <83MI 918-03), studies on hypertension have been done on all systems ofmammals: nervous system, ophthalmic system, cutaneous system, digestive system, excretory system,cardiovascular system, pulmonary system, reproductive system, neonatal studies, biochemical stud-ies, and physicochemical studies. Guanethidine sulfates are antidiabetic <8iSAP8002i6l> and used inointment composition <89JAP(K)O1216928>. Platinum(II) and (IV) complexes of guanethidine exhibitantitumor activity <82MI 918-06).
(157)
9.18.7.2 Benzazocines
Benzazocines are a biologically important group of compounds because of their diverse func-tions. Interestingly, some benzazocines are analgesics <84JAP(K)59i3760, 91MI 918-03) and some are
428 Eight-membered Rings with One Nitrogen Atom
antagonists of analgesics <82CPi 128934). Benzazocine 1,3-diones possess antiarrhythmic activity<88USP4755505>. Benz-fused lactams have been shown to be (i) antagonists of the peptide hormone,cholecystokinin (CCK) <86EUP166353, 87USP4644050, 89JMC1681), (ii) antagonists of angiotensin con-verting enzyme <83BBR1O8,83BBR161,84EUP107095,84JMC816,85USP4537885), and (iii) antihypertensives<84SAP8303903, 84USP4474778, 85SAP8309532, 85SAP8503670, 85SAP8503670, 88EUP292840). Various benza-zocines with diverse structures exhibit effects on the central nervous system <82DIS(B)185O, 83MI918-04,84MIP54268,87JAP(K)62212372,88CPB2386,90JCS(Pl)l09i>. A well-known class of antitumor antibiotics,mitomycins (158) are benzazocine derivatives <90CC468>. FR-900482 is another antibiotic (131),isolated from the bacterial culture, Streptomyces sandaensis, which has structural resemblance withmitomycin C (158), and FR-900482 is active against mitomycin C and vincristine-resistant P388cells <89TL6491,95TL1169>.
OCONH2
OMe
9.18.7.3 Dibenzazocines
Dibenzazocines have found major applications in the area of pharmacology. Dibenz[c.e]azocineand apogalanthamine analogs have been proven to be adrenergic blocking agents <85CJCH70,85CPB1260, 85H(23)159, 85MI918-02, 88JCR(S)8, 88JHC161,89CPB870, 89CPB1744). Yet other pharmacologicaluses such as antihistaminic, antiinflammatory, antiarrhythmic, and anticholinestrase have beenmentioned <82AHC(3l)H5>.
