38
`
`the prodrugs to penetrate
`
`the blood-brain barrier before
`
`they are
`
`metabolized to GABA or GABA-like compounds.88-90
`
`Examples
`
`of amino acids which decrease
`
`the GABA
`
`uptake
`
`(i.e., metabolism)
`
`the
`
`related
`
`Pharmacological evaluation of
`
`the
`
`in neuronal cells are nipecotic acid (fila), .
`phenyl esters .lil.t!.. as well as
`the corresponding
`analogues ...fill. - .22. ( Figure 4).
`enantiomers of fila.
`
`individual
`
`revealed
`
`that
`
`( - ) - nipecotic acid
`
`was six
`times more active
`in .llltm in
`
`the
`
`than
`
`the
`
`(+) - stereoisomer when
`
`tested
`
`isolated cerebellar cortex of cats.91
`
`Furthermore,
`
`examination of
`the anticonvulsant properties of
`and fill of lli showed that
`
`the regioisomers fil
`the a - amino acid . analogue fil had
`
`the same
`
`type of action as
`
`fila.92 whereas
`
`the pharmacological
`
`properties
`
`of
`
`the y - amino acid analogue
`
`fill was different.93
`
`Similarly, a - aminoisobutyric acid ~) is believed
`
`to exert
`
`its activ(cid:173)
`
`ity by decreasing the GABA uptake by glial cells.94
`
`Among
`
`the amino acids capable of decreasing
`
`the enzyma(cid:173)
`
`tic metabolism of GABA are
`
`the
`
`two &-unsaturated GABA analogues:
`
`y- acetylenic GABA
`
`(fi.5.) and y- vinyl GABA (fil).17,95-97
`
`Finally, several amino derivatives have been
`
`found
`
`to mimic
`
`GABA action at presynaptic or postsynaptic
`
`receptor sites.
`
`These
`
`include:
`
`isonipecotic acid
`
`(fi.3.).
`
`1) - aminolaevulinic acid {fili) and
`
`~-4-aminocrotonic acid (fil)
`
`(Figure 5).93,98,99
`
`During
`
`the past
`
`two decades there have been several
`
`reports
`
`describing
`
`the antiepileptic activity of select
`
`functionalized
`
`amino acid derivatives. The
`
`first
`
`two articles appeared in the
`
`
`
`the prodrugs to penetrate
`
`the blood-brain barrier before
`
`they are
`
`metabolized to GABA or GABA-like compounds.88-90
`
`Examples
`
`of amino acids which decrease
`
`the GABA
`
`uptake
`
`(i.e., metabolism)
`
`the
`
`related
`
`Pharmacological evaluation of
`
`the
`
`in neuronal cells are nipecotic acid (fila), .
`phenyl esters .lil.t!.. as well as
`the corresponding
`analogues ...fill. - .22. ( Figure 4).
`enantiomers of fila.
`
`individual
`
`revealed
`
`that
`
`( - ) - nipecotic acid
`
`was six
`times more active
`in .llltm in
`
`the
`
`than
`
`the
`
`(+) - stereoisomer when
`
`tested
`
`isolated cerebellar cortex of cats.91
`
`Furthermore,
`
`examination of
`the anticonvulsant properties of
`and fill of lli showed that
`
`the regioisomers fil
`the a - amino acid . analogue fil had
`
`the same
`
`type of action as
`
`fila.92 whereas
`
`the pharmacological
`
`properties
`
`of
`
`the y - amino acid analogue
`
`fill was different.93
`
`Similarly, a - aminoisobutyric acid ~) is believed
`
`to exert
`
`its activ(cid:173)
`
`ity by decreasing the GABA uptake by glial cells.94
`
`Among
`
`the amino acids capable of decreasing
`
`the enzyma(cid:173)
`
`tic metabolism of GABA are
`
`the
`
`two &-unsaturated GABA analogues:
`
`y- acetylenic GABA
`
`(fi.5.) and y- vinyl GABA (fil).17,95-97
`
`Finally, several amino derivatives have been
`
`found
`
`to mimic
`
`GABA action at presynaptic or postsynaptic
`
`receptor sites.
`
`These
`
`include:
`
`isonipecotic acid
`
`(fi.3.).
`
`1) - aminolaevulinic acid {fili) and
`
`~-4-aminocrotonic acid (fil)
`
`(Figure 5).93,98,99
`
`During
`
`the past
`
`two decades there have been several
`
`reports
`
`describing
`
`the antiepileptic activity of select
`
`functionalized
`
`amino acid derivatives. The
`
`first
`
`two articles appeared in the
`
`
`
`39
`
`Figure 3. Amino Acids and Amino Acid Derivatives
`
`Interacting with the
`
`GABAergic ·System: GABA Prodrugs.
`
`0
`CH 'cH,' o~H,
`l\:
`52
`
`~J1s
`
`·
`
`0
`~NH~COOH
`
`53
`
`0
`
`(cHJ,c )~NH~COOH
`
`54
`
`NH~OOH
`
`HOfrOPOH
`I
`'
`N
`
`H,C
`
`/
`
`F op
`
`H2N~NQ I '<
`
`.--c
`
`Cl
`
`56
`
`
`
`40
`
`Interacting with
`Amino Acids and Amino Acid Derivatives
`Figure 4.
`the GABAergic System: Compounds Limiting GABA Uptake.
`
`0
`
`Lf'OH
`N
`H
`~
`
`~: RoH. ~'/ J(
`R:Ro~
`
`59
`
`60
`
`~OOH
`
`~
`
`CX NH 2
`
`COOH
`
`62
`
`COOH
`
`H,C+NH,
`CH,
`
`~
`
`
`
`41
`
`0
`
`~OH
`NH 2
`
`65
`
`figure 5. Amino Acids and Amino Acid Derivatives
`the GABAergic System: GABA Receptor Agonists.
`
`Interacting with
`
`c5"
`
`H
`63
`
`·-- - ·---- - - -
`
`---~~--~~-- -
`
`- ..
`
`
`
`42
`
`patent
`
`literature
`
`and
`
`focused on glycylderivatives 100 and
`
`N-benzoyl
`
`substituted
`
`amino acids 101.
`
`Recently, Kohn and
`
`co-workers68, 102, 1 03
`
`described
`
`the anticonvulsant
`
`properties of
`
`several N-benzyl amino acids. Compounds filL contained many of
`
`the structural elements
`
`(i.e. 4.fill., §.l;;.) present
`
`in phenytoin
`
`(l;ill)
`
`and
`
`the behzodiazepines (24).
`
`Recent
`
`evidence
`
`has
`
`indicated
`
`that these compounds possess an unique mode of action, suggest(cid:173)
`
`ing
`
`that, they may be a new class of anticonvulsant drugs. 68
`
`Inter-
`
`estingly,
`
`the D-enantiomer of 68a was
`
`thirteen
`
`times more active
`
`than
`
`the L-isomer when
`
`tested orally
`
`in mice
`
`in
`
`the MES seizure
`
`test. A comparable difference
`
`in activity was also noted
`
`for
`
`the
`
`two stereoisomers of
`
`.Q1!Q..
`
`This
`
`information
`
`coupled with
`
`the.
`
`stringent
`
`structure-activity
`
`relationship observed
`
`for
`
`this class of
`
`compounds68
`
`has
`
`led
`
`to
`
`the speculation
`
`that
`
`the anticonvul-
`
`sant properties of these compounds may . be
`
`related
`
`to
`
`interactions
`
`with specific
`
`receptor sites.
`
`~: R:CH,
`!!_:R:Ph
`£_: R:CH,CH,SCH,
`!!_: R:CH(CH,)2
`!_: R: H
`
`
`
`43
`
`In an effort
`
`to
`
`further delineate the structure-activity relation(cid:173)
`
`ship of
`
`pared
`
`this novel class of . antiepileptic compounds, we have pre(cid:173)
`several select analogues of §.a.a and .fill.b. .
`
`tested
`
`and
`
`These substrates were designed
`
`to provide information concerning
`
`the · importance of electronic effects at
`
`the a· carbon site
`
`in modu(cid:173)
`
`In
`lating
`the pharmacological properties of these drug candidates.
`first set of compounds prepared, the phenyl group of filib.. was
`
`the
`
`replaced by various heteroaromatic moieties; while
`
`in the second
`
`series synthesized,
`
`the methyl group of
`
`fi.8a_ was
`
`replaced by
`
`either
`
`polar and/ or unsaturated
`
`substituents.
`
`The synthesis,
`
`spectral properties, and anticonvulsant activity of these
`
`two sets of
`
`compounds are presented
`
`in the Chapters
`
`I and
`
`II, respectively.
`
`
`
`CHAPTER I
`
`SYNTHESIS, SPECTROSCOPIC AND ANTICONVULSANT PROPERTIES
`OF STRUCTURAL ANALOGUES OF 2-ACETAMIDO-N-BENZYLPHENYL(cid:173)
`ACETAMIDE AND 2-ACETAMIDO-N-BENZVL-2-ALKOXY ACETAMIDE.
`
`r.
`
`Introduction.
`The potential
`
`list of heteroaromatic candidates to replace the
`
`phenyl group
`
`in. a-acetamino-N-benzylphenylacetamide
`
`(.2fil2) is large.
`
`In an effort to
`
`limit our initial choice of drug candidates, heterocy(cid:173)
`
`cles containing only a single heteroatom were selected (Tables ~
`
`and
`
`fill.).
`
`The
`
`first series of compounds (Table .:22) chosen consis-
`
`ted of
`
`the simple monocyclic adducts of
`
`furan (filla), pyrrole (fill_Q),
`
`and
`
`thiophene (fill.c., filW).
`
`The second set of compounds (Table
`
`fill) comprised
`
`the corresponding
`
`benzoanalogues ~ - filth.
`
`In
`
`both sets, no effort was made
`
`to control
`
`the site of substitution
`
`on
`
`the heterocycle.
`
`Of
`
`these seven heterocyclic compounds,
`
`two
`
`of
`
`the adducts ~. filW) were
`
`independently prepared
`
`in
`
`this
`
`laboratory.104
`
`We
`
`have also
`
`Included
`
`in both
`
`lists
`
`the
`
`corresponding parent aromatic compounds 2fill.68,103 and ~104.
`
`These compounds serve as suitable
`
`reference substrates
`
`for
`
`the
`
`remaining adducts.
`
`Several
`
`factors contributed to our selection of
`
`these lune-
`
`tionalized amino acid derivatives.
`
`First,
`
`furan CZQ2),
`
`thiophene (11)
`
`and
`
`indole <Z2.) have been previously substituted
`
`for a phenyl
`
`group in both hydantoins U,;i) and succinimides ®) possessing
`
`44
`
`
`
`45
`
`Table 5a. Monocyclic Heteroarornatic Analogues Jill. of 2-Acetarnido(cid:173)
`N-benzylphenylacetamide (filil2).
`
`No
`
`R
`
`0-
`
`O-H
`
`O-s
`0 s
`
`
`
`"16
`
`Table 5b. Benzofused Heteroaromatic Analogues Jill of 2-Acetamido(cid:173)
`N-benzylphenylacetamide .(filll!).
`
`No
`
`R
`
`
`
`47
`
`anticohvulsant properties.
`
`The
`
`resulting
`
`heterocyclic analogues
`
`synthesized also exhibited pronounced biological activity.105-107
`
`Second, many heterocycles possessing side chains
`
`of varying
`
`length and polarities
`
`have been
`
`reported
`
`to
`
`be active
`
`in
`
`anticonvulsant animal screens.5
`
`:n: . . Results and Discussion.
`
`1.
`
`Synthesis.
`Surprisingly, only a
`
`few ex-amino acids having a heterocycle
`
`directly bonded
`
`to
`
`the a-carbon have been reported.
`
`These
`
`in-
`
`clude
`
`the 3-indolyl (ng), the 2-CQJ.2) and 3-~) thienyl,
`
`the 2-furyl
`
`(l;k!) and
`
`Of
`
`these, only
`
`the 2-benzo[b]thienyl (7~ glycine derivatives (Table 6).
`the thienyl compounds l3Q and Tu are commer(cid:173)
`
`cially available.108
`
`In our study, we chose
`
`to prepare
`
`the racemic amino acid
`
`derivatives
`
`rather
`
`than
`
`the
`
`individual
`
`enantiomers so as
`
`to
`
`provide a meaningful comparison with previous
`
`results obtained
`
`in
`
`this
`
`laboratory68, 102.
`
`We anticipated
`
`that
`
`the use of amidoalkyla(cid:173)
`
`tion procedures employing
`
`the parent heterocycle and an appropri(cid:173)
`
`ate amino acid derivative would provide a convenient route
`
`to
`
`the
`
`desired
`
`functionalized amino acid
`
`racemates.
`
`Several
`
`factors
`
`supported
`
`our selection of
`
`this general methodology. First, this
`
`general
`
`technique has been widely utilized
`
`for
`
`the alkylation of
`
`nucleophiles.114-118
`
`Second, substituted amino acids have been
`
`_-"'
`
`:_;
`
`
`
`48
`
`Table 6.
`Substituent.
`
`Examples of Amino Acids with an a-Heterocyclic
`
`R
`
`s
`
`No
`
`73a
`
`73b
`
`73c
`
`73d
`
`73e
`
`oQ
`0-
`0
`0-
`00--
`
`{\
`
`s
`
`Ref.
`
`109
`
`110
`
`111
`
`112
`
`113
`
`
`
`49
`
`synthesized by
`
`this procedure. In
`
`these cases,
`
`the amidoalkyla(cid:173)
`
`ting species was usually a glycine derivative bearing a
`
`leaving
`
`group at
`
`the o.-position.
`
`Table 7 lists various examples of
`
`this
`
`reaction. Third, previous examples of amidoalkylation
`
`transforma-
`
`tions
`
`employing heteroaromatic substrates
`
`have been
`
`reported ..
`
`Representative
`
`reactions are
`
`listed
`
`in Tables 8 - 12 for
`
`furan (ZQ.a),
`
`pyrrole CZ4),
`
`indole (l2}, thiophene (Z1) and various other heteroar-
`
`omatic substrates, respectively.
`
`In all
`
`these
`
`reactions, alkylation
`
`on
`
`the heterocycle occurs preferentially at
`
`the most electron
`
`rich
`
`site.
`
`Significantly, only
`
`in
`
`the cases of
`
`furans and
`
`thiophenes
`
`were the parent heterocycles
`
`frequently employed. Amidoalkylation
`
`reactions involving benzofurans (Le. ni.) and benzo[b]thiophenes (i.e.
`
`ZQ_) have not been reported.
`
`The desired compounds 69 a,b.f-h were synthesized by two
`
`general
`
`routes both utilizing an amidoalkylation step.
`
`The yields
`
`were not optimized.
`
`In method A
`
`(Scheme 1 },
`
`the
`
`initial
`
`targets were
`
`the
`
`2-substituted-2-acetamidoacetic acids ~. It was anticipated
`
`that
`
`these compounds would readily undergo condensation with benzyla(cid:173)
`
`mine (.!lli) using
`
`the mixed anhydride coupling method144, 145
`
`to
`
`yield
`
`the desired products fill..
`
`Our projected synthesis of . ~
`
`was patterned after
`
`the procedure described by Chouteeten and
`
`co-workers 12\
`
`These investigators prepared o.-acetamido-2-thio-
`
`
`
`~
`
`.:'.0:·-~~·:~,, ii'.;~~~'.l)T t!;~\~·~\'.~;~i~~~>M
`
`Table 7. Sy·nthesis of Amino Acid Derivatives by
`
`the Amidoalkylation Technique.
`
`Am ldoa!k.yla ting
`Agent
`
`Substre.le
`
`Conditions
`
`Amino Acid
`Derivative
`
`A Rl·coNHCH(OH)COOH
`
`ArH
`
`His.o1.Hc1,
`H2SO~/CH3COOH,
`H3P01
`
`RI CONHCH( Ar)COOH
`
`Rer.
`
`119·
`·121
`
`l>. RlcoNHCH(OH)COOI!
`
`ArCH2R2
`
`CH3S03ll
`
`RI CONHCH(A r.'H 2R2)COOH
`
`122
`
`(.11
`0
`
`£ RI CONHCH(OHlCOOH
`
`R2SH
`
`llzSO;/CH3COOH
`
`R lcoNHCH(SR2JcooH
`
`Jl. RlcoNHCH(OH)COOH
`
`R2cocH2COR3
`
`Hz SO;
`
`RI CONH CH(CH 2COR 2 (JI ICOOH
`
`~ R lcoNHCH(OllJCOOll
`
`R2coCHzCOR)
`
`Cll3S03ll. ll2SO;.
`llzSO;/C113COOJ1
`
`R 'cONHCH(CHzCOR2(3JCOOH
`
`123
`
`124 •
`126
`
`125,
`126
`
`
`
`( RICONHCH(OCH)lCOOCH3
`
`8 RICONHCH(OCH3)COOCH3
`
`l1 RlcoNHCH(QCH3)COOCH3
`
`I R'CONHCH(OCH3)COOCH3
`
`L R 1 CONHCH(OCH3)COOCH3
`
`o A\ CONHCH(OCH3)COOCH3
`
`I CH3COt/HCH(Cl)COOn-C4H9
`
`DFJ , OEt2·
`
`NSAa
`
`OF3.0Et2
`
`HzS04/dioxans
`
`R,_)(_N
`
`OCH,
`
`0 X,Rl
`H R'o 0 fR'
`
`Ri)(~~OCH,
`R'
`0
`R~coocH,
`
`oyN·
`1 PR NHCOR'
`
`R
`
`R'
`
`0
`
`NSAa
`
`R •coNHCH(SR2)COOCH3
`
`0-R!
`
`0
`
`R\__
`RV-
`
`R'"-(cid:173)
`Rv-
`
`R' "-(cid:173)nY-
`
`R2SH
`
`R2COCH2COR3
`
`6F3,0El<?
`
`R \ CONHCH(CH(COR2)(COR3))COOCH3
`
`~~ H
`
`Et3N
`
`0 f)
`_,,.I(~ )_,__COO n-c,H,
`
`U1
`
`127
`
`IU
`
`128
`
`128
`
`1Z3
`
`124,
`126
`
`129
`
`
`
`SnCl4
`
`CH3CONHC(R2)(CH2R 1)CCOC:H2CH3
`
`130
`
`BF3. OE12.
`H2S04
`
`O
`
`R3
`1---1
`HryN-R2
`
`0
`
`120, 131,
`132
`
`Ul
`N
`
`ciCH3CONHC(OCH3)(CH2R1)COOCH2CH3 A2H(ArH, A3SH)
`R10
`
`R4
`
`Rs
`
`0
`
`2
`
`a HY-R
`0
`
`a b·Naphta!ena~u!!onle acid.
`
`R'H(ArH, x ,)
`
`H
`
`R
`
`...
`
`
`
`53.
`
`Table 8. Amidoalkylation Reactions
`furan (ZQQ}.
`
`Involving Furan (lilg) and 2-Methyl
`
`0-R
`
`70
`;!_: R=H
`!!.: R= CH,
`
`amidoalkylating agent
`
`condition
`
`yield
`
`Ref.
`
`127,133
`
`b.
`
`0
`
`O)l._NH
`
`'--\OCH 1
`
`PISA a
`
`71
`
`133
`
`(CH~:>--o
`/..._N
`CH,
`I
`COOCH,
`
`H,CO~O H
`
`PISA a
`
`72 - 89
`
`133
`
`PISA a
`
`67
`
`133
`
`
`
`54
`
`Table 8 con't.
`
`amidoalkylating agent
`
`condition
`
`yield
`
`Ref.
`
`o
`Ph'\.
`N-'f
`0~NH
`
`OCH,
`
`BF3 · OEt2
`
`134
`
`..
`
`~~~
`
`. y
`
`CNlOCH
`
`I
`COCH,
`
`,
`
`SnCl4
`
`70
`
`135
`
`!!_
`
`1
`
`g
`
`OH
`
`~N.----CH,
`~o~ PTSAa,b
`
`90 - 94
`
`136
`
`ap-Toluenesulphonic Acid. b PTSA was used as a catalyst and water
`was removed by azeotropic distillation.
`
`
`
`55
`
`Table 9. Amidoalkylation Reactions Involving Pyrrole (74) and Substitu(cid:173)
`ted Pyrroles.
`
`0 H
`
`amidoalkylating agent
`
`conditions
`
`yield(%)
`
`ref.
`
`H
`./'-._/~OH
`n
`Cl-
`0
`
`HCI
`
`31 - 35
`
`137
`
`of)· ol:J
`
`H
`
`H
`
`CH,-N=CH-Ph
`
`62 - 80
`
`138
`
`60 -64
`
`118
`
`
`
`56
`
`Table 10. Amidoakylation Reactions Involving lndole (12) .and Substitu(cid:173)
`ted lridoles.
`
`Amidoalkylating agent
`
`a
`
`0
`~N/"'-...OH
`H
`.
`
`condition
`H2so4
`
`yield(%}
`
`Ref.
`
`35- 90
`
`118, 139
`
`0
`
`h ~N-CH,OH H2so4
`
`0
`
`50- 83
`
`118,139
`
`/CH,
`/N
`
`0
`
`£ Ac1 H~c-N )
`\_N
`'\
`CH3
`
`0
`
`1Ac1 ·
`
`R
`
`Q_
`
`R-N=CH-Ph
`
`a No catalyst was required.
`
`a
`
`52
`
`140
`
`Et3N
`
`30 - 80
`
`118
`
`75 - 83
`
`118,140
`
`
`
`57
`
`Table 11. Arnidoalkylation Reactions Involving Thiophene (71 ).
`
`0 s
`
`71
`
`arnidoalkylating ·agent
`
`conditions
`
`yield(%)
`
`Ref.
`
`.a
`
`OH
`
`H2S04
`
`45- 92
`
`121,127
`
`R)LN,,(_COOH
`H
`
`Q oc /CH,
`
`OH
`
`N
`o,,lo
`
`PTSAa,b
`
`82
`
`136
`
`BF3 · OEt2
`
`46- 68
`
`141
`
`BF3 · OEt2
`
`73
`
`141
`
`(CH,)
`
`(~}-_OCH,
`\
`CHO
`
`((J O N--CHO
`
`a p-Toluenesulphonic Acid. b Only a catalytic amount of PTSA was
`removed by azeotropic distillation.
`required and water was
`
`
`
`58
`
`TablQ j2. Arnidoalkylation Reactions Involving Other Heterocycles.
`
`h~terocycle
`
`amkioarkylating agent
`
`conditjons
`
`yield(%)
`
`Ref.
`
`i!
`
`R'
`
`'N
`H
`
`CH3CooH
`
`15-42
`
`118
`
`NH,CONH>-
`R'
`
`NH,CONH
`
`hR2
`h CCX)
`ro
`co
`
`N
`
`/
`N
`
`e
`
`£
`
`ll
`
`HzS04
`
`0
`R./l-_N~oH
`I 2 R
`PhAN~OH HzS04
`H
`
`0
`
`PhCH,OAN~COOH H2S04/
`
`0
`
`OH
`
`H
`
`CH3COOH
`
`29-59
`
`142
`
`41
`
`118
`
`63
`
`143
`
`75
`
`76
`
`
`
`59
`
`Sch~me 1. Synthesis of 2 -Substituted-2-acetamido-.!:'!-benzylacetam·ides
`(69a b f h). by Method A.
`
`0
`
`~H,
`1]
`
`00
`
`'" HCCOH
`l!
`
`R0.l,H•
`
`w
`RH
`
`"
`
`BF,·0£<, l
`
`RH
`
`.., Me
`a: R
`b_: ff = Et
`
`"
`
`a: R "' 2-Furyl, R" ~ Me
`b:: R == 2-Furyl. A' "' Et
`c: R = 2-pyrryt.R·"" Et
`!1: R ~ 3-pyrryf,R" ~ Et
`
`
`
`60
`
`treatment of 2-acetamido-2-hydroxyacetic
`
`pheneacetic acid Ul.2.f) by the
`acid (Z.9.) with
`thiophene (Zl)
`in the presence of phosphoric acid.
`Compound 19. was readily prepared
`in quantitative. yield
`amide (1Z) and glyoxylic acid (la) 121.
`
`from acet(cid:173)
`
`Replacement of
`
`furan (ZQ.a)
`
`for
`
`thiophene (ll) in this approach
`
`furnished fil?a
`
`in 14 % yield.
`
`The corresponding
`
`reactions using benzofuran (Zfil, pyrrole (Z1) and
`
`indole (Z2.) gave
`
`intractable mixtures of polymeric materials. Substitu(cid:173)
`
`tion of other acids (i.e., sulfuric acid, methanesullonic acid) for
`
`phosphoric ·acid also proved unsuccessful.
`
`Fortunately. use of a
`
`1 :1 mixture of methanesulfonic acid and acetic acid permitted . the
`
`synthesis of the benzofuran derivative a2J;t in modest yield (20%). The
`
`difficulty
`
`encountered
`
`in
`
`these
`
`transformations
`
`prompted our
`
`inspection of
`
`the procedure employed by Ben-lshai, Sataty and
`
`Bernstein 127
`
`for
`
`the synthesis of
`
`the
`
`furan derivative
`
`llA,.
`
`Application of this method required
`the
`initial conversion of 2-acet(cid:173)
`amido-2-hydroxyacetic acid am to the corresponding alkyl 2-acetamido-
`2-alkoxyacetates filLa and 12 (Table 13). This was readily accomplished
`in moderate yields by
`treatment of
`the appropriate alcoholic solution
`containing 19. with sulfuric acid.
`
`These ethers were
`
`then
`
`reacted
`
`with either furan (1.Qg) or pyrrole (Z1)
`
`in
`
`the presence of boron tri(cid:173)
`
`fluoride etherate
`
`in ether to give
`
`the corresponding 2-substituted-
`
`2-acetamidoacetates (81 a-d) (Table 14). Hydrolysis of
`
`these esters
`
`81 a-d with aqueous alcoholic potassium hydroxide gave the required
`
`
`
`61
`
`13. Selected Physical and Spectral Data
`Table
`2-Acetamido·2~alkoxyacetates (!ill).
`
`for
`
`Alkyl
`
`OR'
`
`)l~oR'
`
`80
`
`No.
`
`R
`
`yielda
`
`44-46
`
`1735.1090
`
`162 (1)e
`
`35-36
`
`1735, 1085(br)
`
`190 (5)e
`
`aPurified yield (%) from 2-acetamido-2-hydroxyacetic acid 0l.). bMelting
`points (°C) are uncorrected. c Infrared peak positions are
`recorded in
`the 1601 cm-1 band
`in polystyrene
`reciprocal centimeters (cm·1) vs.
`and were
`taken
`in KBr disks. d The molecular
`ion peak in
`the
`mass spectrum was obtained at an ionizing voltage of 70 eV. The
`number
`in parentheses
`indicates
`the intensity of this ion
`relative
`to
`the base peak in
`the spectrum. e Protonated .!l.Q..
`
`.
`0 0
`Ph ,.r-.,..0.)l.,_f.i~ocH,
`
`H
`
`0
`
`84
`
`
`
`62
`
`Table 14. Selected Physical and Spectral Data for a-Substituted Alkyl
`2-Acetamidoacetates (.fil).
`
`81
`
`No.
`
`R
`
`R'
`
`Yielda mpb
`
`I~
`
`M+;ed
`
`Jl.1.a
`
`2-Furyl
`
`CH3
`
`62
`
`80 - 81
`
`1740,1530(br),890
`
`197 (14)e
`
`filll.
`
`2-Furyl
`
`CHzCH3
`
`2-Pyrryl
`
`CHzCH3
`
`51
`
`41
`
`69-70
`
`1750, 1530,900
`
`211 (8)e
`
`104 -106 1715,1515 (br)
`
`210 (22)e
`
`lll£
`
`.8.1.d
`
`3-Pyrryl
`
`CH2CH3
`
`12
`
`92 -93
`
`1720,1640 (br)
`
`210 (12)e
`
`the alkyl 2-acetamido-2-alkoxyacetates (.6.Q).
`aPurified yields (%) from
`bMelting points (°C) are uncorrected. c Infrared peak positions are re(cid:173)
`corded
`in reciprocal centimeters (cm-1) vs.
`the 1601 cm-1 band in
`polystyrene and were taken in KBr disks. d The molecular ion peak in
`ionizing voltage of 70 eV.
`the mass spectrum was obtained at an
`The number
`in parentheses
`indicates
`the
`intensity of
`this
`ion
`relative to the base peak
`in
`the spectrum. e The M+ 1 ion peak was
`also observed.
`
`
`
`63
`
`acids ~ (Table 15)
`
`needed
`
`for
`
`the mixed anhydride coupling
`
`reaction.
`
`Several important observations were made
`
`for
`
`these amido(cid:173)
`
`alkylation
`
`tained
`
`for
`
`reactions. First, although slightly higher yields were ob(cid:173)
`the methyl ester fillli
`
`than
`
`for
`
`the corresponding ethyl
`
`ester
`
`fil!Q
`
`(Table 14),
`
`the ease of purification of fil!Q made
`
`this
`
`derivative
`
`the
`
`reagent of
`
`choice
`
`in this
`
`transformation.
`
`Second,
`
`the site of amidoalkylation on
`
`the heterocycle was similar
`
`to
`
`that
`
`previously observed
`
`in other electrophilic aromatic substitution
`
`reac(cid:173)
`
`tions.
`
`Accordingly, a 1 :3.4
`
`ratio was observed
`
`for
`
`the alkylation
`
`of pyrrole (Z.1) at
`
`the 3- and 2-positions,
`
`respectively; while
`
`furan
`
`(ZQ.gJ was alkylated only at
`
`the 2-position.
`
`Third,
`
`the
`
`reactivity of
`
`the furan
`
`(?Oa) and pyrrole
`
`(74) were comparable.
`
`Similar
`
`observations have been previously noted_ 146
`
`The benzo[b)thiophene acetic acid derivative 82e listed in
`
`Table 15 was
`
`independently prepared
`
`from
`
`the corresponding amino
`
`acid 73e by acetylation with acetic anhydride (85) in basic medium
`
`73e by acetylation with acetic anhydride
`
`ill.§.)
`
`in basic medium
`
`(Scheme 2). A sample of compound ~ was generously provided
`
`by
`
`the Eli Lilly Research Laboratories.
`
`The
`final step
`in Method A required
`the coupling of the
`unnatural amino acids .a2. with benzylamine (ill!).
`
`In our hands, use
`
`of
`
`the mixec:l anhydride method144, 145 proved unsatisfactory,
`
`· · - - - · - - - -
`
`
`
`64
`
`Table 15. Selected Physical and Spectral Data for a-Substituted
`2-Acetamidoacetic Acids (a2_).
`
`R
`
`)lN~OH
`H
`0
`
`82
`
`No.
`
`R
`
`.62a
`
`ll.2.b.
`
`2-Furyl
`
`2-Pyrryl
`
`Ji2l;_
`
`3-Pyrryl
`
`ll2Q
`
`2-Benzofuryl
`
`yield a
`
`mpb
`
`JRC
`
`M+;ed
`
`51 (14)e
`
`171 - 172
`
`1705, 1580 (br),900
`
`183 (2)
`
`29
`
`38
`
`201
`
`112-114
`
`1720, 1530 (br)
`
`135-138
`
`1700, 1530 (br)
`
`182 (1)
`
`182 (4)
`
`203 -204
`
`1720,1535 (br)
`
`233 (12)9
`
`E-2.e.
`
`2-Benzo[b]thienyl
`
`a3h
`
`224 -226
`
`1710, 1520 (br)
`
`249 (22)9
`
`aPurified yields (%) from the corresponding o: - substituted alkyl 2-aceta(cid:173)
`midoacetates (fil) by saponification (KOH, EtOH;H20) unless otherwise
`c
`Infrared peak
`indicated. b Melting points (°C) are uncorrected.
`positions are
`recorded in reciprocal centimeters (cm-1) vs. the 1601
`cm-1 band
`in polystyrene and were
`taken
`in KBr disks. d The
`molecular
`ion peak in the mass
`spectrometer was obtained at a
`ionizing voltage of 70 eV.
`The number in parentheses indicates
`the
`intensity of
`this
`ion relative to
`the base peak
`in
`the spectrum. e
`From 2-acetamido-2-hydroxyacetic acid 02) in the presence of H3P04.
`f From 2-acetamido-2-hydroxyacetic acid
`in
`the presence of
`(ZQ)
`methanesulfonic acid. g The M + 1 ion peak was observed. h From
`acetylation of o:-aminobenzo[b]thiopheneacetic acid @!z).
`
`
`
`65
`
`Scheme 2. Preparation of a-Acetarnido-2-benzo{b]thiopheneacetic Acid
`
`(~.
`
`~.NH,
`V--?'cooH
`
`73e
`
`NaOH
`(cH,co),o s5
`
`~ ;NHCOCH,
`~s/"\cooH
`82e
`
`
`
`66
`
`furnishing low amounts ( 6 - 16%) of
`
`the desired products (Table 16).
`
`All efforts
`
`to improve
`
`the yield of
`
`the
`
`reaction by varying
`
`the
`
`temperature,
`
`the alkylchloroformate and
`
`the concentration of
`
`the
`
`reagent were not successful.
`Other coupling
`reactions were also
`the direct condensation of esters .!lib. and i;;.
`
`tried. These
`
`included
`
`the use of dicyclohexylcarbodiimide 147
`with benzylamine «la), and
`!}.2a and .123.. No significant
`
`·in conjunction with acid
`
`improvement in
`
`product yields were noted
`
`for these modifications.
`
`In an effort
`
`to circumvent
`
`this problem, we examined
`
`the
`
`synthetic pathway outlined
`
`in Scheme 3 (Method B).
`
`In
`
`this
`
`procedure, the · coupling
`
`reaction was conducted prior to the amido(cid:173)
`
`alkylation
`
`etates
`
`transformation.
`.b. with
`
`.film and
`
`Treatment of alkyl 2-acetamido-2-alkoxyac(cid:173)
`
`benzylamine (.!l_;i)
`
`in alcoholic
`
`solution
`
`produced
`
`,!lQa and
`
`the corresponding 2-acetamido-H-benzyl-2-alkoxyacetamides
`.b..
`
`respectively (Table 17). Higher yields and cleaner
`
`product mixtures were noted
`
`for the synthesis of ethoxy adduct ~
`
`versus
`
`the methoxy derivative !l.Qa. Compound ~ was
`
`then con(cid:173)
`
`verted
`
`to
`
`the · final desired products §9. using
`
`the amidoalkyJation
`
`procedure previously described
`
`in Method A. This synthetic
`
`route
`
`permitted
`
`the preparation of compounds 69a,b.f-b.
`
`Moderate yields
`
`for furan (1.Qa), pyrrole (M), indole (Z2)
`this step were observed
`for
`and benzofuran fill (28 - 58 %), while only a four percent yield was
`obtained for benzo[b}thiophene am (Table 16).
`In
`this
`last case,
`
`
`
`67
`
`Selected Physical and Spectral Data
`Table 16.
`2-Acetamido-J:!-benzylacetamides (2a).
`
`for a-Substituted
`
`No.
`
`R
`
`lia.a_
`
`2-Furyl
`
`58 (13}e 178-179
`
`1625,1525
`
`273 (1)f
`
`fill_b_
`
`2-Pyrryl
`
`69cg 2-Thienyl
`
`35
`
`37
`
`174 -1 75
`
`1570 (br}
`
`167 - 169
`
`271 (12)1
`
`289 (2)
`
`filli
`
`2-Benzofuryl
`
`33 (13)e 195 - 196
`
`1625 - 1520
`
`322 (5)f
`
`.6.8.Q.
`
`3-lndolyl
`
`28
`
`213 - 214
`
`1610 - 1515
`
`69h
`
`2-Benzo[b]thienyl 4 (16)e
`
`226 - 227
`
`161 O - 151 O
`
`321 (5)1
`
`338 (8)1
`
`apurified yields (%) from the 2-acetamido-J:!-benzyl-2-ethoxyacetamide
`otherwise
`indicated. b Melting
`are
`(°C) points
`(M.12.) unless
`uncorrected. Clnfrared peak positions are
`recorded
`in
`reciprocal
`the 1601 cm-1 band in polystyrene and were
`centimeters (cm-1) vs.
`taken
`in KBr disks. d The molecular
`ion peak
`in
`the mass spectrum
`was obtained at an ionizing voltage of 70 eV.
`The number
`in
`parentheses
`indicates
`the relative
`intensity of
`this
`ion
`relative
`to
`the
`corresponding
`the base peak
`in the spectrum.
`e From
`o:-substituted-2-acetamidoacetic · acid l:!2. (mixed anhydride route, Method
`A).
`f The M + 1 ion peak was observed.
`g Ref. 104.
`
`r ......... .
`
`.. -·--
`
`l:>
`l
`
`
`
`68
`
`Scheme 3. Synthesis of· 2-Substituted-2-acetamido-N-benzylacetamides
`(69a,b 1-h) by Method B.
`
`.· ..
`
`
`
`69
`
`Selected Physical and Spectral Data for 2-Acetamido-N-
`Table 17.
`benzyl-2-alkoxyacetamides Wfil.
`
`OR'
`O JyH
`,.)l-_N
`N......_.,.Ph
`o
`H
`
`86
`
`No.
`
`R'
`
`yielda
`
`mpb
`
`IRc
`
`M+;ed
`
`~ CH3
`
`§.Q_.Q.
`
`CH2CH3
`
`32
`
`70
`
`145 - 146
`
`1550, 1060
`
`237 (1)
`
`153 - 155
`
`1550 (sh),1060
`
`251 (4)
`
`the corresponding alkyl 2-acetamido-2-alkoxy(cid:173)
`apurified yield (%) from
`acetates (00). b Melting points (°C) are uncorrected. Clnfrared peak
`positions are
`recorded
`in
`reciprocal centimeters (cm-1) vs.
`the 1601
`cm-1 band . in polystyrene and
`.were
`taken
`in KBr disks. · d The
`molecular
`ion peak in the mass spectrum was not observed at an
`ionizing potential of 70 eV, · instead
`the M + 1 ion peak was
`detected. The number in parentheses
`indicates the
`relative
`intensity
`of this ion relative to the base peak
`in
`the spectrum.
`
`
`
`70
`
`a large amount of unreacted starling material was recovered.
`
`Several
`
`amidoalkylation
`
`interesting observations were noted concerning these
`reaction of pyrrole ®
`
`In
`
`· the
`
`transformations.
`
`with Jlfill. only a minute amount of
`
`the 3-substituted product was
`
`detected (TLC analysis).
`
`A much
`
`larger percentage of
`
`the
`
`corresponding adduct
`
`was observed
`
`ester
`
`when
`
`.llil.D. was
`the case of indole (12).
`the
`
`In
`
`employed as the starting material.
`3-substituted derivative film was
`
`the only product detected. This re(cid:173)
`
`sult
`
`hand,
`
`trifluoride
`
`the other
`typical for electrophilic substitution of 72.146 On
`is
`treatment of .!illQ_ with benzofuran fill in the presence of boron
`furnished only the 2-substituted derivative fillf. despite
`
`the
`
`known
`
`tendency of
`
`this heterocycle
`
`to undergo alkylation at both
`
`the 2- and 3-positions.148
`
`In
`
`the benzo[b]thiophene (lfil reaction,
`
`only
`
`the 2-substituted product fillli. was observed. This
`
`result was
`
`surprising since
`
`this heterocycle
`
`is
`
`reported
`
`to
`
`react at
`
`the
`
`3-position with most
`
`electrophiles.148
`
`The
`
`low yield of
`
`this
`
`transformation, however,
`
`did not permit us
`
`to conjecture on the
`
`factors
`responsible
`for
`this
`inversion
`reactivity of Juran (ZQa), pyrrole ®
`
`in site selectivity.
`
`The
`
`and
`
`thiophene Cl.1)104 were
`
`comparable
`
`in this amidoalkylation
`
`transformation and
`
`the yields
`
`The
`ranged between 35 - 38 %.
`observed for Z1. versus ZQ..a and R
`
`relatively high conversion
`
`rate
`
`is surprising, since
`
`thiophene
`
`(l1)
`
`is usually
`
`less
`
`reactive
`
`than
`
`furan CZQ.a) . and pyrrole (M).146
`
`I
`
`'l
`
`
`
`71
`
`In
`
`the case of
`
`the annelated
`
`and lJi higher yields were noted
`
`heteroaromatic substrates lJ.., ~
`for ll and ~-
`
`Previous results
`
`concerning
`
`the ease of substitution of
`
`these
`
`substrates have
`
`produced widely varying resutts.148
`
`Finally, during
`
`the purification
`
`of
`
`the
`
`product mixture
`
`obtained
`
`from
`
`the
`
`synthesis
`
`of
`
`a-acetamido-N-benzyl-3-indoleacetamide ~. a . compound possessing
`
`a molecular weight of 351 (electron
`
`isolated and
`
`identified as
`
`the
`
`indole
`
`impact mass spectrometry) was
`trimer fil.
`
`lndole fil) is
`
`known
`
`to undergo
`
`trimerization
`
`in
`
`the presence of both mineral
`
`and Lewis
`
`acids.149-151
`
`A mechanism
`
`for
`
`this polymerization
`
`has been previously proposed1 49 · and
`
`is depicted in Scheme 4.
`
`Table 18 summarizes our
`
`initial
`
`results
`
`for
`
`the various
`
`amidoalkylation
`
`transformations conducted using
`
`the
`
`heterocycles
`
`ZQ.a, 1.1. 12. and 74 - 76.
`conceivable but have
`not
`
`Many atternate
`
`procedures are
`
`been examined.
`
`In
`
`general, we
`
`observed higher yields and cleaner product mixtures when boron
`
`trifluoride
`
`etherate was employed as
`
`the
`
`acid source with both
`
`alkyl 2-acetamido-2-alkoxyacetates filIBJl and 2-acetamido-N-benzyl-
`.!lli..Q.. Correspondingly.
`
`the use of mineral acids
`
`2-ethoxyacetamide
`
`in
`
`the amidoalkylation transformations gave unpredictable
`
`results and
`
`always gave rise
`
`to polymeric-type materials.
`
`<--
`
`~:
`
`
`
`72
`
`Scheme 4. Acid Catalyzed Trimerization of lndole
`
`4
`(IQ). 1
`
`9
`
`co
`
`"
`
`-a
`
`...
`
`H
`
`oj"
`
`/.
`
`!"
`
`It
`
`1
`t~
`~ ~ ""'
`
`~
`
`12
`
`:;_~
`
`\.\
`!J
`
`0).
`i
`"
`~ . -
`t
`OQ-6>
`"
`
`~
`
`iw
`
`~
`
`
`
`73
`
`Involving
`Table 18. Comparison of Several Amidoalkylation Reactions
`lndole (Z2), Benzofuran fill
`Furan (ZQQ), Pyrrole (74), Thiophene (l1),
`and Be.nzo[b]thiophene (1fil Beginning with Either fill.. ll2.a and l:2 or
`.!lli.l:L a
`-
`
`R·-H
`
`R'•H
`
`R'· Me
`
`. ff-Et
`
`R' ·Et
`
`fr-OH
`
`R"-OH
`
`R"-OMe R"-OEt
`
`R"·NHCH2Ph
`
`CH3S03H/ BF3 · OEt2c BF3 • OEtzc
`H3P04'
`CH3COOHb CH3COOH
`
`BF3 ·OEt2C
`
`15[2]
`Furan Q'Q_)
`Pyrrole (74)
`0
`d
`Thiophene(IJ}
`Benzofuran (Zfil
`0
`lndole (72)
`0
`Benzo[b]thiophene(Zfil d
`
`d
`d
`d
`39[2]
`0
`d
`
`62[2]
`d
`d
`d
`d
`d
`
`51 (2]
`41[2],12(3]
`d
`d
`d
`d
`
`58[2]
`35[2]e
`37[2]
`33[2]
`28[3]
`4[2]
`
`the purified yield (%). The number in
`a The number in each entry is
`brackets indicates the position of alkylation on
`the heterocyc\e. b Ref.
`121.
`c Ref. 127. d The
`reaction was not performed. e A
`trace
`. amount of the 3-substituted derivative was observed by
`thin-layer
`chromatography.
`f Ref. 104.
`
`.,_,.,
`
`~,; .
`
`r
`
`r
`
`- ----~- - · - - - -
`
`
`
`74
`
`2. Spectral Evaluation.
`
`a.
`
`Infrared Spectra.
`
`Characteristic absorption bands were observed in the infrared
`"
`the alkyl 2-acetamido-2-alkoxyacetates llil.
`spectra
`for
`the alkyl
`2-substituted-2-acetamidoacetates fil, the corresponding acids .a2. and
`the functionalized amino acid derivatives .29. and 1IB. and are
`
`listed in
`
`Tables 19 - 22, respectively.
`
`In particular,
`
`the absorption bands
`
`for
`
`the secondary amide groups were
`
`readily distinguished
`
`in all these
`
`compounds.
`
`This group
`
`typically shows
`
`three absorption bands
`
`corresponding
`
`to
`
`the NH
`
`stretching mode (3320 - 3270 cm·1 ), a
`
`carbonyl stretching mode
`
`(amide I band, 1680 - 1630 cm·1). and a
`
`NH bending mode
`
`( amide I I band, 1570 - 1515 cm-1)_152 These
`
`and 1500 - 1535 cm·1-,
`
`respectively,
`
`absorption bands were observed between 3200 - 3290, 1610 - 1655,
`in N-benzylamides .29. and JIB.
`In acids .az. the NH and .
`and esters .fill. and fil (Tables 19, 20, 22).
`from
`these values and
`
`CO stretching modes were slightly shifted
`
`were detected between 3305- 3340 and 1585 - 1590 cm·1 , respec(cid:173)
`
`tively (Table 21 ).
`
`A consistent set of absorption bands
`
`in
`
`the
`
`infrared
`
`spectra for
`
`the phenyl group of
`
`the 2-substituted-2-acetamido-N-ben(cid:173)
`
`zylacetamides fill. and JIB. were observed. The CC stretching mode
`
`of
`
`the phenyl group appeared
`
`between 1610 - 1630 cm-1 and
`
`always overlapped
`
`the carbonyl stretching absorption.
`
`The
`
`in-plane
`
`bending mode
`
`for
`
`the phenyl group was observed between 1095 -
`
`1090 cm-1, while
`
`the most characteristic out-of-plane bending modes
`
`
`
`75
`
`Infrared Spectral Data
`. Table 19. Selected
`2-alkoxyacetates (fill)a.
`
`for Alkyl 2-Acetamido-
`
`No. R'
`
`NH
`stretching
`
`CO(COOR') CO(NHCO) NH
`stretching
`stretching
`bending
`
`OR'
`
`COOR'
`
`3270
`
`1735
`
`1650
`
`1505
`
`1ogob 12os.101oc
`
`1735
`
`1655
`
`1510
`
`1085b 1200,1010c
`
`recorded
`Infrared peak positions are
`a
`band
`in
`(cm-1)
`vs.
`the 1601 cm·1
`antisymmetric stretch.
`c CO stretches.
`
`reciprocal
`in
`polystyrene.
`
`centimeters
`b COG
`
`
`
`76
`
`Infrared Spectral Data
`Table 20. Selected
`2-acetamidoacetates {fil)a.
`
`for Alkyl 2-Substituted-
`
`81
`
`No. R
`
`R'
`
`CO( COOR') CC(NHCO) NH
`NH
`bending
`stretching
`stretching stretching
`
`R'b
`
`Rb
`
`2-Furyl %
`
`3200
`
`1740
`
`Jl.1i!
`
`fil.!;>_
`
`2-Furyl C~CH3 3200
`
`.Ilk
`
`2·Pyrryl CH2CH3 3200
`
`1750
`
`1715
`
`1620
`
`1635
`
`1635
`
`1530
`
`1530
`
`1205,102oc
`
`a sod
`
`12os, 102oc
`
`a sod
`
`1515
`
`1220.101oc
`
`3310•
`
`fild.
`3-Pyrryl %CH3 3240
`Infrared peak 'positions are recorded in reciprocal centimeters {cm· 1)
`a
`vs.
`the 1601 cm-1 band
`in polystrene.
`b Characteristic bands for
`R ·and R'. c co stretches. d Furan ring deformation. eNH stretch.
`
`1510
`
`121 o,1010c
`
`3320°
`
`1720
`
`1640
`
`
`
`77
`
`·Selected
`Table 21.
`2-acetamidoacetic Acids
`
`Infrared
`(fil!)a.
`
`Spectral Data
`
`for 2-Substituted-
`
`No.
`
`R
`
`ll2a 2-Furyl
`
`a2ll 2-Pyrryl
`
`ll2l;_ 3-Pyrryl
`
`ll2Q 2-Benzoluryl
`
`NH
`stretching
`
`CO(COOHJ
`stretching
`
`CO(CONH]
`stretching
`
`NH
`OH
`bending bending
`
`R
`
`3320
`
`3300
`
`3300
`
`3340
`
`1705
`
`1710
`
`1700
`
`1720
`
`1580
`
`1590
`
`1585
`
`1590
`
`1530
`
`1210
`
`sgob
`
`1530
`
`1220
`
`3340C
`
`1525
`
`1240
`
`334oc
`
`1535
`
`1200
`
`sgod
`
`3305
`
`1710
`
`I@. 2-Benzo[b]lhienyl
`a
`Infrared peak positions are
`recorded
`centimeters
`in reciprocal
`(cm-1) vs.
`the 1601 cm-1
`band of polystyrene. b Furan
`ring
`deformation. c NH stretch. d Benzofuran ring deformation.
`
`1580
`
`1520
`
`1200
`
`
`
`78
`
`Iable 22.
`Infrared Spectral Data
`Selected
`!.6.9.. .fili) a.
`2-acetamido-N-benzyfacetamides
`
`for 2-Substituted-
`
`R ov
`
`. A~ "-../Ph
`
`0
`
`. fill.. fili
`
`No.
`
`R
`
`CO,CC(Ph) NH
`NH
`stretching stretching .
`bending
`
`Ph
`ip,oop bendingb
`
`R
`
`fill.a
`
`2-Furyl
`
`fill2
`
`2-Pyrryl
`
`lill1
`
`2-Benzofuryl
`
`l&ll
`
`3-lndolyl
`
`3230
`
`3230
`
`3230
`
`3260
`
`.!ill!l
`
`ll.ll.a
`
`2-Benzo[b]thienyl
`
`3240
`
`OCH3
`
`3260
`
`1625
`
`1610
`
`1625
`
`1610
`
`1610
`
`1625
`
`1525
`
`1090,740,690
`
`s9od
`
`1500
`
`1070,740,685
`
`e
`
`1520
`
`1090,735,690
`
`s9of
`
`1515
`
`1095,735,695
`
`34009
`
`1510
`
`1505
`
`1085,730,685
`
`1065,740,690
`
`112oh
`
`.fifill OCH2CH3
`
`3260
`
`1630
`
`1505
`
`1060,740,690
`
`1115h
`
`in reciprocal centimeters (cm-1)
`a Infrared peak positions are
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