Compr. Heterocyclic Chem. III Vol.13 Seven-membered Heterocyclic Rings

560 Pages·2008·8.344 MB·English

by  Katritzky A.R., et al. (eds.)

13.01
Azepines and their Fused-ring Derivatives
J.B.Bremner
UniversityofWollongong,Wollongong,NSW,Australia
S.Samosorn
SrinakharinwirotUniversity,Bangkok,Thailand
ª2008ElsevierLtd.Allrightsreserved.
13.01.1 Introduction 1
13.01.2 ExperimentalStructuralMethods 2
13.01.2.1 SpectroscopicData 2
13.01.2.2 X-RayStudies 2
13.01.3 ReactivityofFullyConjugatedRings 2
13.01.4 ReactivityofNonconjugatedRings 5
13.01.5 ReactivityofSubstituentsAttachedtoRingCarbonAtoms 7
13.01.6 RingSynthesisbyRingConstruction 10
13.01.6.1 Typea(N–C–C–C–C–C–C) 10
13.01.6.2 Typeb(C–N–C–C–C–C–C) 14
13.01.6.3 Typec(C–C–N–C–C–C–C) 16
13.01.6.4 Typed(C–C–C–N–C–C–C) 26
13.01.6.5 ReactionInvolvingtheFormationofTwoBonds 30
13.01.7 RingSynthesisbyRingTransformation 30
13.01.8 SyntheticComparisons 36
13.01.9 ImportantCompoundsandApplications 36
13.01.10 FurtherDevelopments 38
References 40
13.01.1 Introduction
The azepine ring system has continued to attract considerable attention since the publication of CHEC-II(1996)
<1996CHEC-II(9)1>.Severalreviewsofthissystemhavealsoappeared<B-1996MI(56)1,2002PAC1317>,andan
account of an efficient ring construction strategy for seven-membered rings, including dihydroazepines, has been
published <2004SL933>. A reference series has also reviewed seven-membered heterocycles including azepines
<2004SOS(17)749>andbenzazepines<2004SOS(17)825>,whileannualsynopsesofthesesystemsarecoveredin
theseriesProgressinHeterocyclicChemistry.Mostofthechemistryhascenteredonreducedoroxidizedformsofthering
system, since the parent 1H-azepine 1 is not stable, although N-substituted derivatives are known. Considerable
chemistryhasbeendescribedforbenz-fusedazepinesandotherfusedderivatives.Chemicalaspectsoftheformer,of
whichtheparentsare1H-1-benzazepine2,1H-2-benzazepine3,and3H-3-benzazepine4,andtheirtautomers,are
alsocoveredinthischapter.
1
2 AzepinesandtheirFused-ringDerivatives
13.01.2 Experimental Structural Methods
13.01.2.1 Spectroscopic Data
The1HNMR,13CNMR(NMR–nuclearmagneticresonance),infrared(IR),ultraviolet(UV),andmassspectro-
metry(MS)datahavebeenreportedforthefirstexample5ofa2H-azepin-2-one(2-azatropone).Thecarbonylgroup
stretchingfrequencyappearedat1682cm(cid:2)1intheIRspectrumoftheneatmaterial<2000JOC6093>.Further1H
and13CNMRspectroscopicdataonazepinederivativeshavebeensummarizedbySmalley<1997HOU(E9d)108>.
Aconformationalstudyofnovelpolyhydroxylatedazepaneshasbeenreportedinwhichthe1HNMRspectroscopy
andmolecularmodeling(molecularmechanics,moleculardynamics,andMonteCarlomethods)affordedinsightsinto
aspectsoftheconformationalanalysis<2004EJO4119>.
Because of the medicinal chemical significance of 1-benzoyl-1H-1-benzazepines, as highly potent and selective
nonpeptidic agonists for the arginine vasopressin (AVP) V receptor, some fundamental structural studies of the
2
N-substituted 1-benzazepine derivatives 6–9 have been assessed. Dynamic 1H NMR spectroscopy was used to
investigatesolutionstateconformationalstructuresinassociationwithmolecularmechanicsstudies.Inthecaseof8,
an axial conformer (with the 5-methyl group axial) was shown to be preferred over the equatorial conformer; the
energy difference between the two was calculated to be 1.2kcalmol(cid:2)1 by molecular mechanics calculations and
0.9kcalmol(cid:2)1 experimentally from the equilibrium constant at 298K <2005JOC1545>. Also, as the amide bond
distortionbecomesmoremarked,agreaterreluctancetoundergoconformationalchangeswasobserved.
13.01.2.2 X-Ray Studies
ThesinglecrystalX-raystructureofthefirstreported2-azatroponehasbeendescribedbyKimuraetal.,inwhichthe
ringwasshowntohaveatwist-boat-likeconformation<2000JOC6093>.SinglecrystalX-raydatawerealsousedto
confirmthestructureofanumberof3H-azepines<1996LA887>,3H-1-benzazepine<1997HOU(E9d)336>,anda
series of 1H-1-benzazepine derivatives 6–9, where the exocyclic double bond, present in 6, showed the expected
flatteningoftheseven-memberedringtofavorahalf-chairconformation.Thecarbonylgroupwasorientedantitothe
fusedbenzeneringineachofthesolid-statestructuresof6–8<2005JOC1545>.
13.01.3 Reactivity of Fully Conjugated Rings
Satake et al. have described the mechanistic aspects of the formation of 2-methoxy-2H-azepine derivatives 11a–d
from3H-azepines10a–duponreactionwithbromine<2003H(60)2211>(Scheme1).Unlikethesituationobserved
with cycloheptatrienes, delocalized azatropylium salts were not formed from the reaction of 3H-azepines with
bromine in the absence of an alcoholic solvent. Reaction of 12 with bromine gave 13 plus the bis-ether 14 and
bromomethane. The product 14 was also observed in the reaction of 12 with NBS (0.5equiv); with 1equiv of
N-bromosuccinimide(NBS)12affordedthesuccinimido-substitutedderivative15,whichuponeliminationofHBrin
thepresenceofbasegavethe2H-azepine16(Scheme2)<2003H(60)2211>.
AzepinesandtheirFused-ringDerivatives 3
Scheme1
Scheme2
Inan extension ofthe above workon reactions of3H-azepines, 17 with NBSat very low temperature((cid:2)98(cid:3)C)
followedbytreatmentwithbasegavemainlythesubstitutedazepine16.At25(cid:3)C,bisazepinyletherswereobtained,
including18(43%),plussome16(10%)(Scheme3)<2005JOC3425>.
Scheme3
Anelectrochemicalreactionontheazepinecarbamates19resultedinaringcontractiontogivetheN-substituted
anilines 20 in moderate yield (Equation 1). Mechanistically, initial oxidation of the carbamate to give the radical
cation 21, followed by electrocyclic rearrangement to 22, C–N cleavage, and then reduction was proposed
<1998H(48)1151>.
4 AzepinesandtheirFused-ringDerivatives
ð1Þ
Reactionofthe3H-azepines23(R¼R2¼But,R1¼R3¼H)and23(R¼R2¼H,R1¼R3¼But)withbromineand
quenching with MeOH afforded the respective 2-methoxy-2H-azepine derivatives, which formed the more stable
3H-tautomers at 25(cid:3)C. In the latter, tautomerization proceeded further to produce the stable 2-azabicyclo[4.1.0]-
heptadiene analogue 24 <1997J(P1)2015>. The 3H-azepines 25 with a 2-methoxy, 2-amino, or 2-dimethylamino
substituentunderwentvalencetautomerizationunderUVlightirradiationtogive3-substituted2-azabicyclo[3.2.0]-
hepta-2,6-dienes26(Equation2)<1997JCM276>;no5-substitutedderivativeswereobserved.
ð2Þ
Aphoto-induced[6þ2]cycloadditionofthechiralacrylate28withthechromiumcarbonylcomplex27affordedthe
endo-adduct29inhighdiastereomericexcess(Equation3)<1995JOC7392>.
ð3Þ
Anewoxidativeringcleavageofthedialkyl-3H-azepine30ontreatmentwithseleniumdioxideafforded4-oxo-
octa-2,5-dienal 31 together with minor amounts of the pyrrolone 32 and pyridine 33 plus the first report of the
2-azatropone34(Equation4).Theisomericdi-t-butylazepine35affordedmainlythepyridinederivative36,plusthe
isomeric azepine 37, although in very low yield (Equation 5) <2000JOC6093>. In contrast, selenium dioxide
oxidation of the methyl groups in the 1H-azepine derivative 38 afforded dialdehyde 39 in moderate yield
(Equation6)<1999JOC1849>.
AzepinesandtheirFused-ringDerivatives 5
ð4Þ
ð5Þ
ð6Þ
13.01.4 Reactivity of Nonconjugated Rings
An alternative route to racemic 2-substituted azepanes 41, R¼Bu (65%), Ph (59%), involved addition of the
appropriate Grignard reagent to the N-acyliminium ion species generated in situ from 40 upon elimination of the
benzotriazolylmoiety(Equation7)<2005JOC3066>.
ð7Þ
Isomerization of the enantiopure hydroxylated azepane 42, after hydroxyl group activation, afforded either the
ring-contractedpiperidinederivative45(onO-mesylationto43followedbyinternaldisplacementtotheaziridinium
ionintermediate44andsubsequentchlorideioninducedringopening)orthechiralethylene-bridgedmorpholines
48via47andanintramolecularMitsunobureactionof46(Scheme4)<1996TL1613>.
AdifferentapproachtoazepinederivativesinvolvedaPd-catalyzedcross-couplingreactionofthevinyltriflate49
with the (cid:2)-alkoxyboronate 50 (R¼H) to give 51 in 45% yield; acid-catalyzed hydrolysis then gave the azepine
derivative52andthefusedazepine53,althoughyieldsweremodest(Scheme5)<2002JOC7144>.
6 AzepinesandtheirFused-ringDerivatives
Scheme4
Scheme5
AzepinesandtheirFused-ringDerivatives 7
13.01.5 Reactivity of Substituents Attached to Ring Carbon Atoms
ParallelliquidsynthesishasbeenappliedtothepreparationofavarietyofN,N9-disubstituted3-aminoazepin-2-ones
54(e.g.,R1¼m-BrC H )startingfrom1-substituted3-aminoazepin-2-ones<2003BMC3193>.
6 4
Substituted3-aminoazepanonesalsoformedthecoreofanumberofcyclolysine-basedbioactivenaturalproducts.
A facile approach to these derivatives was based on electrooxidation of 55 to give the methoxy derivatives 56 in
moderateyields<2004SL1029>.Theselatterderivativesinturncouldthenbeconvertedvia57totheenamides58
(Scheme6).OxidationoftheseenamideswithOsO /NMOthengave,aftertwofurtherfunctionalgroupmodifica-
4
tionsteps,the6-acetoxyazepanones61,via59and60(Scheme7).
Scheme6
Scheme7
The tetrahydroazepine diphenylphosphates 62 (R¼OPO(OPh) , R1¼CO Ph) underwent a Stille coupling and
2 2
carbonylation to form 62 (R¼CHTCH , R1¼CO Ph) and 62 (R¼CO Me, R1¼CO Ph), respectively
2 2 2 2
<1998CC1757>.
8 AzepinesandtheirFused-ringDerivatives
The synthesis of the reduced 2H-azepin-2-imine 64 (as its hydrochloride salt) via 63 with ammonia in EtOH
followedbytreatmentwithhydrochloricacidindioxanehasalsobeendescribed<2003BMC689>;64isnotablyan
inhibitorofinduciblenitricoxidesynthase.
Enzymaticreactionsnowhaveasoundplaceincontemporarysyntheticmethodology.Illustrativeofthis,lipase-
catalyzedtransesterificationoftheracemicalcohol65hasbeenusedeffectivelytoproduce(S)-(þ)-66(LipaseQL,
0–5(cid:3)C,4h;47%yield;>99%ee),plusthe(R)-((cid:2))-acetoxyderivative67(Equation8).The1-benzazepinederivative
66 was then converted to a chiral precursor required for the synthesis of the nonpeptide vasopressin V receptor
2
agonist, OPC-51803 <2002H(58)635>. The synthesis of a 1-benzazepine-based antagonist (OPC-41061) at this
receptorhasalsobeenreported<2002H(56)123>.
ð8Þ
TheasymmetricsynthesisofthespiroazepinoneskeletonpresentincertainmarinetoxinswasreportedbyMurai
etal.ADiels–Alderreactionwaskeytothesyntheticapproach.Forexample,70wasaccessedin82%yield(96%ee;
99:1exo/endoratio)from68andthediene69withX¼AsF inthechiralcoppercomplex(Equation9)<2002SL403>.
6
ð9Þ
In connection with studies on structure–property relationships with dermal penetration enhancers, substituted
azepinonederivatives(e.g.,74,R¼Meand75,R¼Me)weremadebyKimetal.fromthe3-aminoazepanone71via
72and73usingstandardfunctionalgroupmanipulations(Scheme8)<2001MI183>.
Reactions of a 2-benzazepin-1-one derivative involving a spiroannelation procedure from 76 to afford the spiro-
cyclic3-benzazepinederivative83via77–82havebeenreported(Scheme9)<2005H(65)1359>,whileotherchiral
substituted 2-benzazepines have been prepared from D-glucose via furo[3,2-c][2]benzazepine derivatives
<2005S2307>.
Lactim ether formation from 2,3,4,5-tetrahydro-1H-1-benzazepin-2-one on reaction with dimethyl sulfate and
triethyloxonium tetrafluoroborate has been described, and reactions of the lactim ether with a number of primary
amineswerereported<2003CHE344>.
AzepinesandtheirFused-ringDerivatives 9
Scheme8
Scheme9
10 AzepinesandtheirFused-ringDerivatives
13.01.6 Ring Synthesis by Ring Construction
13.01.6.1 Type a (N–C–C–C–C–C–C)
In a very significant development, the parent 2H-azepine 85 was prepared for the first time (Scheme 10)
<1995AGE1469>. A ring construction was adopted involving N-BOC deprotection of 84 followed by treatment with
strongbasetoafford85afterintramolecularimineformationandbase-inducedeliminationofacetate.Whiletheyieldwas
only1%,theazepinewassufficientlystableat25(cid:3)Cfor48htoallowfor1Hand13CNMRspectroscopiccharacterization.
Scheme10
An extension of the above work to N-BOC deprotection of the amino ketones 86 gave the optically active
2H-azepines87(e.g.,87,R1¼Me,R2¼Me;56%).Readyisomerizationof87bya[1,5]-Hshifttothecorresponding
3H-azepineswasobservedwhentheformerwereleftinsolutioninorganicsolventsat25(cid:3)CoronwarminginCHCl
3
solution(Equation10)<1996T10883>.
ð10Þ
Anovelroutetotheazepinonesystemin93and94,basedonanintramolecularnitrone–eneallenecycloaddition
(in 91 and92, whichwere accessed inturnfrom 88 via 89 and 90) andsubsequent rearrangement via N–Obond
homolysisandanelectrocyclicrecyclizationstep)hasbeendescribed(Scheme11)<2005EJO2715>.Onheating93
intoluene,equilibriumwiththeisomericazepinone95wasestablished,althoughcomprisinglessthan3%of95.The
generalsyntheticapproachwasappliedtothesynthesisofananalogueofthealkaloidastrocasine.
Scheme11
Azepinones,forexample,97,canalsobeaccessedinhighyieldfromanalleneprecursor(e.g.,96)byBOC-group
removalandthenintramolecularamineadditiontotheallene(Scheme12)<2005T6309>.
AstereoselectivesynthesisoftheazepanecoreoftheproteinkinaseCinhibitorandfungalmetabolite,((cid:2))-balanol,
andinvolvingC–Nbondformationintheringformingstep,hasbeendescribed(Scheme13)<2006TL1585>.The