`
`Mylan Ex. 1019
`Mylan v. Novartis
`IPR2015-00268
`
`
`
`President
`
`T, Kawasaki
`
`Editor-in-Chief
`
`Vice-President
`K. Tsuda
`
`K. Morita, M. Hirobe,
`
`S. Tejima
`
`A. Tsuji
`U. Sankawa,
`Associate Editors
`K. lnoue,
`A. lchikawa,
`K. Fuji,
`K. Achiwa,
`Editorial Board
`Y. Kawashima, T. Kinoshita,
`H. Kaneto,
`H. Itokawa,
`M. ltoh.
`N. Nanbu,
`H. Ogalaa
`M. Mochizuki. S. Muranishi,
`M. Kurata,
`T. Sato,
`S. Shimomura,
`j_ Okuda,
`'1‘_ Sang,
`Y, Okada,
`T. Tsuruo,
`K. Watanabe. M. Yoshioka
`T. Tsuchiya,
`Y. Takase,
`T. Asami,
`M. Shimada,
`M. Shindo,
`Staff
`N. Anraku,
`Y. Enomoto,
`H. Watanabe,
`E. Sato,
`T. lmai,
`S. Shirnizu
`K. Yokoyama, T. Kato,
`T. Sakamoto,
`R. Harada,
`Ofiice of Secretary Pharmaceutical Society of Japan,
`l2~l5—50l, Shibttya 2—chome. Shibuya-ku, Tokyo
`150, Japan
`
`‘
`H. lrie,
`T. Komortr
`T- Ohmoms
`S. Takano,
`
`Y- Nagaia
`Y. lkegamla
`
`Secretary T. Imai
`Stafl' of Editorial and Publication Department
`T. Kuroiwa
`
`Y_ Maru (Chief), M. Fujita. M. Sato. K. Kubonoya,
`
`The publication of this Journal was supported in part by a Gt'ant—in-Aid for Publication of Scientitic Research Result from the
`Ministry of Education, Science and Culture. which is grtttcfully acknowledge.
`FOREIGN INDIVIDUAL, DOMESTIC MEMBER, AND DOMESTIC BODY SUBSCRIPTIONS FOR I989
`including postage:
`
`[Foreign]
`lndtvidual*
`
`I Yukuguku Z(l.)‘.'i‘III (J. P/zarm. Sat‘. Ju/run) (monthly)
`I C‘/itlmical & P/mrtnuc'et41t'cu/ Bu//Mitt (monthly)
`
`Besides
`membership fee,
`Ordinary
`Student
`’F23.100
`‘$6,300
`‘£54,800
`US$69.00
`’f‘40,000
`’i‘lU.0()0
`’t‘7.900
`US$99.00
`*The foreign individual subscriber is enrolled as it mem-
`ber of the Society.
`_
`Foreign individual, domestic member, and domestic body subscriptions should be addressed to the Plrzirmncetttical Society of
`Jdpan, 12—15 501. Shibuya 2—chome, Shibl.I)"¢l-l(1.1. Tokyo 150, JAPAN.
`DOMESTIC NON-MEMBER RATES FOR 1989 including postage:
`Yakttgaku Zaxr/ii (J. P/mrm. Sana Japan) tmomhty)
`('lwmit'u/ & Pliztrnmcetmcal Bu//elm (monthly)
`FOREIGN NON—MEMBER RATES:
`inquire directly to the unclermentioncd agencies.
`DOMESTIC AND FOREIGN l\'ON-MEMBER SUBSCRIPTIONS of the Journal and Bulletin are handled solely by:
`Japan Publication Trading Co., tU.S.A) lnc., I255 Howard St., San Francisco, Calif. 94l03, U.S.A. and I75 Fifth Avenue. New
`York, NY. 10010, U.S.A.
`
`[Domestic]
`
`30d)’
`
`[ICF COPY
`per copy
`
`’i‘2.300
`¥4.l')O0
`
`Japan Publications Trading Co.. Ltd., Central PO. Box 5030 Tokyo lntcrnationztl. Tokyo, JAPAN.
`Kyowtt Book Co.. Inc, Aktmoto Bldg.. 38. Jimb0~cho l—chome. Kztnda. Chiyoda-ku, Tokyo. JAPAN.
`Maruzen Co., Ltd., P.O. Box 5050. Tokyo lnternzttional
`l()0—3l, JAPAN.
`NOTICES TO AUTHORS
`
`Page charges Regular Articles and Notes: ¥4.000/printed page. Communications to the Editor: ¥5.l00/‘printed page. Language
`correction charge: ’t‘700/printed page. Photographic Plates and Blocks: cu. ‘H.700/50 (;m2_
`Reprints
`50 reprints: free of charge. Over 50 reprints: ‘F60/copy.
`See CONTRIBUTION RULES, printed in I“urtmtm'/1/‘u, 19 (1), 81 (1983). 21 (8). 797 (I985). 24 (5). 510 (I988), or C/tent. P/turm.
`Bull_, 37 (1), I (1989), before writing :1 paper for C/IEIII. P/mrm. Bull. The RULES collected together into a pamphlet: ‘F950 (including
`postage)/copy.
`
`Page 2 of 5
`
`Page 2 of 5
`
`
`
`308
`
`Chem. Pharm. Bull. 37(2) 303-310 (1989)
`
`Vol. 37, No. 2
`
`Photochemical Iron(III)-Mediated Autoxidation of Dextromethoi-phan
`
`Giovanni BOCCARDI,*‘” Piergiorgio MEZZANZANICA,” Umberto Guzzi,“ Giordano LESM.A,b and Giovanni PALM1sANo*”’
`Certtro Ricerche Midy $,p.A.," SANOFI Recherche, I 20137 Milano, Italy and Dipzzrtimento di C/iimica Organica e Industriale, Facaltti di Scienze,
`Universitd degli Studi,” I 20133 Mz'lano,,Ita!y. Received August I, 1988
`
`~
`
`The photochemical reaction of dextromethorphan 1, a widely used anti-tnssive drug, in hydrochloric acid and in the
`presence of iron(III) salts leads to the 10]}-hydroxyderivative 3 as a major product in a,dfi® EiY9 2-
`The product composition of this reaction is strongly dependent on the experimental conditions and the elfects of solvents
`are presented.
`
`Keywords
`
`pholoclrernjstry; heavy metal catalysis; autoxidation; stability; dextromethorphan
`‘i
`
`Dextromethorphan [3-methoxy-1 7—methyl-(901, l 3a,l4oc)-
`morphinan, 1) is a valuable non-narcotic anti-tussive drug
`in oral pharmaceutical form and its hydrobromide (la) is
`described in several official Pharmacopeias. It has been
`known since 1956' that (la) is moderately stable when
`exposed (3d) in aqueous solution to direct sunlight, fur-
`nishing in a remarkably regioselective reaction the cor-
`responding l0-ketoderivative (2)”; however, in our hands,
`we observed a fast photochemical reaction which was hard
`to reproduce. In accordance with the results of Brossi er
`411.," Proska et al. have also recently reported the isolation
`of the l0—ketocompound from the oxygenated solutions of
`morphine.”
`'
`i
`A
`On the basis of some evidence, in particular the finding of
`traces of iron in glassware, we assumed that the reaction
`required catalysis by suitable inorganic ions. It
`is well
`known that Fe(III) ions and other higher valence metals act
`as efficient one-electron photo-oxidants in hydrochloric
`solutions, whereas‘ photolysis of aqueous s_olutions of
`Fe(III) bromide produces bromine?’ Here an interesting
`example has been reported by Barbier, who found that
`Fe(III)—induced photo-oxidation of benzylic methylenes in
`aqueous acetone occurs to yield the corresponding ketc-
`compounds.“
`In an effort to define the role of trace metals in these
`reactions, we have examined and report here the photo-
`chemical behavior of (la) in the presence of Fe(III) in acidic
`solutions,
`and a
`plausible mechanistic
`sequence
`is
`proposed.
`
`Results and Discussion
`The irradiation of an aqueous or acidic solution of (la) in
`the absence of Fe(III) ions did not induce any decom-
`position, irrespective of the presence or absence of molec-
`ular oxygen. By comparison,
`the irradiation (22h) of a
`2.68 mM solution of (la) in 1M hydrochloric acid in the
`presence of 6.2 mM Fe(IlI) chloride produced (at 85%
`conversion; high performance liquid chromatography
`(HPLC) analysis) a mixture of l0[i-hydroxydextromethor-
`phan (3) (61%) and the_ known 10‘-oxoderivative (2) (26°/,,).
`Compound 3 gave a molecular peak at m/: 287 by
`”e'lectr’o'n impact mass spectrum (El-MS) andithis value is in
`agreement with the molecular formula C18H25NOZ, indi-
`cating the presence of an additional oxygen atom. An
`inspection of the MS of 3 in comparison with thatof 1
`showed that the new oxygenated function cannot be -located
`
`in the C— and D-rings since these are encompassed by
`fragment m/z 150 which remains undisplaced in the MS,
`whereas the peak at m/z 230 is displaced by 16 amu as
`compared to m/z 214 for 1.5’ Accordingly, the infrared (IR)
`spectrum was devoid of any carbonyl absorption but had a
`discrete hydroxyl band at 3400cm".
`In the 200-MHz
`proton nuclear magnetic resonance (1H—NMR) spectrum of
`3, the methine proton at C-9 was centered at 2.90ppm
`(sharp doublet, J :2.5 Hz) whereas the. signal of H-10
`appeared as a singlet at 4.72 ppm. The remarkable low-field
`chemical shift position for this proton provided evidence
`for oxygen substitution at this site. The stereochemistry at
`C-10 as depicted in 3 was assigned by application of
`Karplus analysis“ and the lack of any coupling for H—10
`(dihedral angle of approximately 90°) indicated that the
`newly introduced OH group and aminomethylene bridge
`are trans to one another.
`When we carried out the reaction on la under the above
`conditions, no other hydrcxy compound could be detected
`by ‘H—NMR spectroscopy, suggesting that 3 was being
`produced with complete control over
`the regio- and
`stereochemistry.
`Evidence in support of the structure of the minor photo-
`prcduct (2) was secured by comparison with an authentic
`sample prepared according to Brossi et al,“
`Additionally, we confirmed that the presence of exter-
`nally added chloride ions (as hydrochloric acid) affected the
`etficiency of the photo degradation of la induced by Fe(Ill)
`chloride in neutral or acidic solution. In the light of these
`results, the mechanism of the formation of 2 and 3 can b6
`interpreted in terms of an initial benzylic hydrogen abstrac-
`tion by Cl' (Eq. 1) to generate the carbon-centered radical
`(5) (Eq. 2). Although the role of Cl‘ as a radical initiator in
`photo-oxidation of organic compounds has been somewhat
`controversial,” the lack of reactivity in sulfuric acid SO-
`luticns indicated that at least the‘ formation of an Fe(IIl)~-
`chloro complex is necessary for the reaction to take place
`(Eq. 1). Subsequent reaction of 5 with molecular oxygen
`leadsto the secondary hydroperoxide (6) (Eqs. 3, 4) and thi5
`reactive transient species has ‘several options of being
`transformed into final products. Thus, 6 can undergo
`dehydration,
`through 0-0 bond cleavage, to give-the
`oxoderivative (2) (Eq. 5). However, this mechanism ma)’
`only count for a minor part of the observed photodegradatifln
`and the formation of 3 _could be rationalizedzby an alter‘
`native mechanism. The common intermediate (6) can under-
`
`© 1989 Pharmaceutical Society of Japan
`
`—-ev-———-s—-é
`
`g,.
`
`Page 3 of 5
`
`Page 3 of 5
`
`
`
`.M
`
`Februafl 1989
`
`'4 tFex.-.<H.o>,-.P""+x' '
`[FeX,.(H20)s 4.1‘
`1,131: ——»5+HC1
`’5'-1902 ’‘*'G
`1+6 -—5+7
`7-a 2+H,o T
`7+H* ——>8+H202
`s+Hz0 —»3.+H*
`s+MeOH —»4+H+
`
`Chart
`
`1
`
`'
`
`(1)
`(2)
`(3)
`(4)
`(5)
`(6)
`(7)
`(8)
`
`MeO
`
`
`
`"IN-We
`
`3R1, R2, Ra:H
`3Ri:H; R2,R3:0
`IR1, R3‘=H; R2=0H
`IR1, Ra=H? R2=OME
`
`»Awtu»-
`
`6:
`7:
`9‘.
`10:
`
`\
`
`R1, R3=H; R2=00‘
`R1, R3=H; R::=OOH
`R1, Rz=H; R3=OH
`R1=Br; R2, R3=H
`Fig.
`l
`
`*
`. H"’nz,N—Me
`
`5*=-
`8*=+
`
`go ionic decomposition via attack at the B-oxygen atom of
`the hydroperoxide function (C-0 bond fission) with loss of
`a molecule of hydrogen peroxide (Eq. 6). This reaction
`predominates,
`in that the stability of the resulting car-
`benium ion (8) provides the driving force for this reaction,
`and subsequent quenching by a suitable nucleophilic sol-
`vent (é.g., water) leads to 3. Finally, carbocation trapping
`experiments were performed under the above conditions in
`the presence of 0.6 mM Fe(III)'chloride in 1 : 1 methanol—2M
`hydrochloric acid mixture and the corresponding methyl
`ether (4) was isolated in good yield (Eq. 8).
`It is quite reasonable that the introduction of OH or
`OMe groups proceeded by entry from the sterically more
`accessible top face and a similar stereochemical outcome
`has
`recently been reported on morphinandienones.”
`Bottomside oxygen entry would be rather restricted es-
`pecially because of the aminomethylene bridge. An un-
`ambiguous stereochernical assignment for 3 was ‘accom-
`plished by reduction of 2 with LiAlH4 in refluxing tetrahy-
`drofuran (THF). The sole isomer formed in this process is‘
`assigned the ac-hydroxyl stereochemistry depicted in 9 since
`this is the expected resul_t of hydride delivery from the least
`encumbered face of the carbonyl function in 2.1’ Ac-
`cordingly, the methine hydrogen at C-10 in 9 appears at
`4.88 ppm [ vs. 4.72 ppm in 3] as a doublet (J; 6.0 Hz) (i.e.,.
`H-9 and-=I:I.:—l—0.are—cis=orien.ted)-and this assignment agrees
`with the generalization that an equatorial proton resonates
`at lower field than its axial epimer.”
`.
`By exposure of . 1a to sunlight
`in 1 M aqueous hy-
`drobromic acid in the presence of Fe(III) ions we observ-
`ed a rapid and clean transformation to 2-bromo-dextro-
`Inethorphan (10) in 62% yield as the sole product. Com-
`Pound 10 [M + ' 351 /349(31Br/79Br)] was identified by spec-
`tral methods and unambiguous synthesis. In particular,
`the two aromatic protons appeared as singlets at 7.28 ppm
`(H-1) and 6.85 ppm (H-4) in the ‘H-NMR, thus confirming
`
`
`
` r?""”‘"‘"""'.“'"——'”—T“i2
`
`309
`
`that substitution had occurred at the 2-position.
`The difference in reactions between‘ Cl' and Br’ may be
`explained on the basis of frontier orbital theory; in the‘
`hydrogen-abstraction reactions, generally S'OMO"(sin’gly '
`occupied molecular orbital)/HOMO interaction—control-
`led,
`the SOMO energy of ‘X" lies between that of the
`HOMO (0 orbital of C_—H bond) and the radical with the
`higher-energy SOMO will be less reactive than the one with
`the lower-energy SOMO.1°‘ This explains why the elec-
`trophilic Cl'
`radical
`(SOMO energy: —13eV)‘“ reacts
`faster in hydrogen abstraction of the benzylic methylene
`than the Br ' radical (SOMO energy: — 11.8 eV). In the light
`of these arguments, two bromine radicals would recombine
`to yield bromine and the expected electrophilic substitution
`at the A-ring of dextromethorphan would be cleanly ob-
`served as the exclusive reaction channel.
`
`Experimental
`Melting points were determined on a Ruechi 510 apparatus and are
`uncorrected. The ‘H-NMR spectra were recorded on a Bruker WP-80 CW
`or on a Varian XL-200 spectrometer in CDC], solutions with tetramethy1-
`silane as an internal standard. Chemical shifts are reported in ppm (6) and
`signal described as s (singlet), d (doublet),
`in, (multiplet) or br (broad).
`Ultraviolet (UV) absorption spectra were recorded on a Beckman DU 6
`spectrophotometer. EI-MS were measured on a Varian MAT 112 spectro-
`meter. Silica gel chromatography (thin layer chromatography, TLC) was
`carried out on Merck .pre-coated 60F25,, plates. Preparative silica gel
`chromatography was performed on Merck pre-coated 60F254 (thickness:
`1 mm, 20 x 20). HPLC analysis was performed on a Varian M 6000 pump,
`M 440 UV detector and 840 integrator system with l0,11m micro
`Bondapack C-18 column (i.d. 3.9x 300 mm, Waters). The mobile phase
`was prepared by dissolving 5.8 g of dioctyl sulfosuccinate in water, MeOH,
`THF and concentrated I-ISPO4 330:630:37:l and adjusting the pH to
`3.30 with concentrated ammonia?“
`Irradiation of la in HCl in the Presence of FeCl3 Dextromethorphan
`hydrobromide (1a) (1.0 g, 2.68 mmol) was dissolved in l M HCl (1000 ml)
`containing FeCl3 (1.0 g, 6.2mmol) in ten different borosilicate vessels and
`irradiated with tungsten light (500 W, Philips PF 308 E/21) at 50 cm from
`the reaction vessels after saturation with oxygen. After 22 h, disodium
`ethylenediaminetetraacetic acid (EDTA) was added and the mixture was
`made alkaline with 10% ammonia and extracted with EtOAc (500 ml). The
`organic layer was washed with water (200 ml), dried and concentrated in
`vacuo; Preparative TLC (benzene-EtOH—l0°/L, ammonia, 89: 10: 1, one
`development, recovery with acetone) afforded the known 10-ketoderiv-
`ativc (2)1) (Rf 0.45; 212mg, 26%),
`the starting material (1) (Rf 0.29;
`125 mg) and the amorphous 105-hydroxydextromethorphan (3) (Rf 0.16;
`500 mg, 61%). 10-Keto-3-methoxy-17-methyl-(9oc,13a,14a)-morphinan (2):
`mp 188-189 ‘C (MeOH). UV »',§j’,‘,‘§“°Lnm (loge): 287" (4.18), 231.(4.05).
`[zx],23° -139 ° (c=3, CHC13). IR (KBr): 2930, 2850, 1665 cm“. ll-I-NMR:
`1.0—2.s (131-1, m), 2.34 (3H, s, CH,—N), 2.97 (1H, d, ./'=3.0 Hz, H-9), 3.88
`(3H, s, CH3—O), 6.90 (2H, in), 8.00 (1H, m). Anal. Calcd. for C,3H23NO2:
`C, 75.76; H, 8.12: N, 4.91. Found: C, 75.54; H, 8.19; N, 4.85.
`10/3-Hydroxy-3-methoxy—l7—methyl—(9oc,l3o:,l4a)—morphinan (3): UV
`Af,j;‘:"°1 rim (loge): 284 (3.20), 277 (3.22), 234 (3.92). IR (KBr): 3400, 2929,
`2830cm". 1H-NMR: l.l—-2.5 (13H, m), 2.49 (3H, s, N-Cl-I3), 2.90 (1H,
`d, J=2.5 Hz, H-9), 3.81 (3H, s, CI-I3—O), 4.72 (1H, s_. l-I-10), 6.80 (2H, m,
`H-2 and H-4),
`7.42 (1H, m, H-1). MS m/z 287
`(M+'),
`230
`(M*" —CzN4NCH3), 150, 143.5 (M“).
`.
`1609,
`(-9)»- Hydrochloride: mp 184 °C (MeOH-).—-IR (KBr): 3200,
`1023 cm”. ‘H-NMR: 0.8-2.9 (14H, m), 2.96 (3H, s, CH3—N), 3.5 (1H, m,
`H-9), 3.72 (3H, s, 0—CH3), 4.88 (1H, br d, J:6.0 Hz, H-10), 6.54 (1H, d,
`J=2.0 Hz, H-4), 6.88 (1 H, dd, J=8.0, 2.0 Hz, H-2), 7.49 (1 H, d, J: 8.0 Hz,
`H-1). Anal. Calcd’ for C,5HZ5NO-I-ICl-1/2H,0: C, 65.02; H, 8.19;N, 4.21.
`Found: C, 65.10; H, 8.22; N, 4.16.
`1a (1.5 g,
`Irradiation of la in HCl and MeOH in the Presence of FeCl3
`4rnmol) in a 1 : 1 mixture of MeOH and 2M HCl (30 ml) containing FeCl:,
`(3.2 mg, 0.02 mmol)
`in a borosilicate vessel
`.was set aside at
`room
`temperature under direct sunlight for 24 h. After evaporation of half of the
`solvent, water (100 ml) was added and the mixture was made alkaline with
`10% ammonia at 0°C and extracted with dichloromethane (50 ml). The
`extract was washed with aqueous sodium potassium tartrate solution
`
`Page 4 of 5
`
`Page 4 of 5
`
`
`
`
`
`310
`
`Vol. 37, Ng_ 2
`
`(50 ml) and water (50 ml) and dried. Filtration and‘ evaporation afforded ‘a
`syrup (1.08 g), which \vas shown by TLC (benzene—EtOH—lO°/0 amrr1onia,.
`89: 10: 1) to contain the starting material, the 10-lcetoderivative (2) and 3,
`together with a new compound (Rf 0.38). Separation of this was achieved
`by careful preparative TLC using the same eluant and 250mg (20 %; 42%
`based on the recovered starting_ material) of pure 10B-methoxydextro-
`methorphan (4) was isolated as an amorphous glass. UV /l,°,§‘,‘,f"°‘nm (loge):
`284 (3.23), 277 (3.25). ‘H—N.\/IR: l.8#2.8 (131-I, m), 2.49 (3H, s, Cl-I3AN),
`3.51 (3H, s, O—CH3), 3.78 (3H, s, O—CH3), 4.12 (1H, s, H-10), 6.8 (21-Lm),
`7.3 (1H, in). MS m,z 301 (M*'), 271 (M*‘—0cH,), 150.5 (M“), 150
`(M*‘—151).
`..
`.
`Photochemical Synthesis of 2-Bmmo-3-methoxy-17-methyl-(9a,1391,1441)-
`morphinan (10)
`1a (150 mg, 0.4mmo1) in 1M HBr (100 ml) containing
`FeC13 (65 mg, 0.4 mmol) in a borosilicate vessel was exposed to direc:
`sunlight for 4h. The mixture was made alkaline with 10% ammonia and
`extracted with dichloromethane (50 ml). The extract was washed with 2%
`aqueous sodium EDTA solution (50m1) and water (50 ml), dried and
`evaporated. The solid obtained was subjected to ‘preparative TLC
`(C1-1ZCl2—Me0H—l0% ammonia, 85: 15:01) to give 93 mg (62%) of pure
`title compound (10). mp 130 “C (MeOH—H2 :1. IR (KBr): 2906, 2855,
`1595, 727, 712cm". ‘H—NMR: 1,043.0 (14H, m), 2.48 (3H, s, CH3—N),
`3.90 (3H, S, O—CH3), 6.85 (1H, 5, H14), 7.26 (lH,_s, H-1). Amzl. Calcd for
`C,sHz4BrNO: C, 61.72; H, 6.90: N, 4.00. Found: C, 61.56; H, 6.88; N,
`3.92.
`.
`The same compound was obtained in 38‘‘/, yield aocording to the
`following procedure: 1a (2.1 g, 5.6 mmol) was dissolved in 1 M HBr (50 ml)
`and water (200 ml) and bromine (2 g, 12 mmol) were added dropwise under
`stirring. After 4 h the solution was filtered and sodium bisulfite was added
`
`until the color disappeared. The solution was extracted with ethyl acetate
`(2 x 300 ml), dried and evaporated. The solid was dissolved in MeOH
`(40 ml) and precipitated with water (40 ml) giving 750 mg of a colorless
`crystalline solid (38 °/;). This compound was identical with that obtained by
`the photochemical procedure.
`
`References and Notes
`
`1) Q. Haefiger, A. Brossi, L. H. Chopard—dit-Jean, M. Walter and Q_
`Schnider, Helv. Chim. Acta, 39, 2053 (1956).
`
`2)
`13- Proskaa 2. V0t.ic.ky,_L. Mo1anarfl11tiaadrM._S_t_e.f_e1,c, Chem.
`Zvestii, 32, 710 (1978).
`3) S.,N. Chen, N. N. Lichtinand and G. Stein, Science, 190, 879 (1975)_
`4) M. Barbier, Helv. Chim. Acta. 67, 866 (1984).
`S) C. Koeppel, J. Tenczer and K. Ibe, Arzneim. Forsclz, 37, 1304 (1987).
`6) M. Karplus, J. Chem. Phys., 30, 11 (1959); M. Karpltis, J. Am. Chem,
`Soc., 85, 2870 (1963); S. Stemhell, Quart. Rev. (London), 23, 236
`(1969).
`,
`7) A. Cox and T. J. Kemp, J. Chem. Soc, Faraday Trans. 1, 71, 2490
`(1975).
`'
`3) T. W. Bentley and S. J. Morris, J. Org. Chem., 51, 5005 (1987).
`9) L. M. Jaclcman, “Application of Nuclear Magnetic Resonance
`Spectroscopy in Organic Chemistry,” Pergamon Press, rI11c., New
`York, 1959.
`V
`j
`’
`I. Fleming, “Frontier Orbitals and Organic Chemical Reactions,”
`10)
`Wiley, New York, 1976.
`~'
`11) R. W. Henderson, J. Am. Chem. Soc., 97, 213 (1975).
`12) G. W. Halstead, J. Pharm. Sci., 71, 1108 (1982).
`
`11;.
`1.
`k‘A
`
`Page 5 of 5
`
`Page 5 of 5