`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 1 of 5
`
`Noven Ex. 1019
`
`

`

`T. Kawasaki
`K. Morita, M. Hirobe, S. Tejima
`
`President
`Vice-President
`K. Tsuda
`A. Tsuji
`U. Sankawa,
`A. Ichikawa,
`K. Fuji,
`K. Achiwa,
`H. Kaneto,
`H. Itokawa,
`Y. Kawashima,
`M. Mochizuki, S. Muranishi, N. Nanbu,
`J. Okuda,
`T. Sano,
`T. Sato,
`T. Tsuruo,
`K. Watanabe, M. Yoshioka
`Y. Takase,
`T. Asami,
`M. Shimada, M. Shindo,
`N. Anraku,
`Y. Enomoto, H. Watanabe, E. Sato,
`S. Shimizu
`T. Kato,
`T. Sakamoto, R. Harada,
`Pharmaceutical Society of Japan, 12-15-501, Shibuya 2-chome, Shibuya-ku, Tokyo
`
`K.Jn_o_u~e~,·~~~B ...... __lri~, --~~---'"'c~----
`T. Kinoshita,
`T. Komori,
`'
`T. Ohmoto,
`H. Ogata,
`S. Shimomura, S. Takano,
`
`Y. Nagai,
`Y. Ikegami,
`
`Editor~in-Chief
`Associate Editors
`Editorial Board
`M. Itoh,
`M. Kurata,
`Y. Okada,
`T. Tsuchiya,
`Staff
`T. Imai,
`K. Yokoyama,
`Office of Secretary
`150, Japan
`
`Secretary T. Imai
`Staff ofEditorial and Publication Department Y. Maru (Chief), M. Fujita, M. Sato, K. Kubonoya,
`T. Kuroiwa
`
`The publication of this Journal was supported in part by a Grant~in~Aid for Publication of Scientific Research Result from the
`Ministry of Education, Science and Culture, which is gratefully acknowledge.
`FOREIGN INDIVIDUAL, DOMESTIC MEMBER, AND DOMESTIC BODY SUBSCRIPTIONS FOR 1989
`including postage:
`
`Yakugaku Zasshi (J. Pharm. Soc. Japan) (monthly)
`{
`Chemical & Pharmaceutical Bulletin (monthly)
`
`Body
`
`per copy
`per copy
`
`¥2,300
`¥4,000
`
`[Foreign]
`[Domestic]
`Besides
`Individual*
`membership fee,
`Ordinary
`Student
`¥23,100
`¥6,300
`¥4,800
`US$69.00
`¥40,000
`¥10,000
`¥7,900
`US$99.00
`*The foreign individual subscriber is ~nrolled as a mem~
`ber of the Society.
`Foreign individual, domestic member, and domestic body subscriptions should be addressed to the Pharmaceutical Society of
`Japan, 12-15-501, Shibuya 2~chome, Shibuya~ku, Tokyo 150, JAPAN.
`DOMESTIC NON-MEMBER RATES FOR 1989 including postage:
`Yakugaku Zasshi (J. Pharm. Soc. Japan) (monthly)
`Chemical & Pharmaceutical Bulletin (monthly)
`FOREIGN NON-MEMBER RATES:
`inquire directly to the undermentioned agencies.
`DOMESTIC AND FOREIGN NON-MEMBER SUBSCRIPTIONS of the Journal and Bullelin are handled solely by:
`Japan Publication Trading Co., (U.S.A) Inc., 1255 Howard St., San Francisco, Calif. 94103, U.S.A. and 175 Fifth Avenue, New
`York, N.Y. 10010, U.S.A.
`Japan Publications Trading Co., Ltd., Central P.O. Box 5030 Tokyo International, Tokyo, JAPAN.
`Kyowa Book Co., Inc., Akimoto Bldg., 38, Jimbo~cho l~chome, Kanda, Chiyoda~ku, Tokyo, JAPAN.
`Maruzen Co., Ltd., P.O. Box 5050, Tokyo International 100-31, JAPAN.
`.t
`NOTICES TO AUTHORS
`Page charges Regular Articles and Notes: ¥4,000/printed page. Communications to the Editor: ¥5, 100/printed page. Language
`correction charge: ¥700/printed page. Photographic Plates and Blocks: ca. ¥1,700/50 cm2
`.
`.
`Reprints 50 reprints: free of charge. Over 50 reprints: ¥60fcopy.
`See CONTRIBUTION RULES, printed in Farumashia, 19 (!), 81 (1983), 21 (8), 797 (1985), 24 (5), 510 (1988), or Chern. Pharm.
`Bull., 37 (!), 1 (:989), before writing a paper for Chern. Pharm. Bull. The RULES collected together into a pamphlet: ¥950 (including
`postage)fcopy.
`
`L__ __
`
`Page 2 of 5
`
`Noven Ex. 1019
`
`

`

`l
`r
`,,
`'I
`I
`
`308
`
`Chern. Pharm. Bull. 37(2) 308-310 (1989)
`
`Vol. 37, No. 2
`
`Photochemical Iron(Ili)-Mediated Autoxidation of Dextromethorphan
`
`Giovanni BoccARDI,*'a Piergiorgio MEZZANZANICA,a Umberto Guzzi, a Giordano LESMA,b and Giovanni PALMISANo*·b
`
`Centro Ricerche Midy S.p.A.," SANOFI Recherche, I 20137 Milano, Italy and Dipartimento di Chimica Organica e Industriale, Facolta di Scienze,
`Universita degli Studi,b I 20133 Milano, Italy. Received August I, 1988
`
`The photochemical reaction of dextromethorphan 1, a widely used anti-tussive drug, in hydrochloric acid and in the
`presence of iron(III) salts leads to the 10/J-hydroxyderivative 3 as a major product in addition to the 10-ketoderivative 2=·~~­
`The product composition of this reaction is strongly dependent on the experimental conditions and the effects of solvents
`are presented.
`
`Keywords photochemistry; heavy metal catalysis; autoxidation; stability; dextromethorphan
`
`Dextromethorphan [3-methoxy-1 7-methyl-(9a, 13a, 14a)(cid:173)
`morphinan, 1) is a valuable non-narcotic anti-tussive drug
`in oral pharmaceutical form and its hydrobromide (la) is
`described in several officiai Pharmacopeias. It has been
`known since 1956 that (1a) is moderately stable when
`exposed (3d) in aqueous solution to direct sunlight, fur(cid:173)
`nishing in a remarkably regioselective reaction the cor(cid:173)
`responding 10-ketoderivative (2) 1l; however, in our hands,
`we observed a fast photochemical reaction which was hard
`to reproduce. In accordance with the results of Brossi et
`al., 1
`l Proska et al. have also recently reported the isolation
`of the 10-ketocompound from the oxygenated solutions of
`morphine.2 l
`·
`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 solutions of
`Fe(III) bromide produces bromine. 3l 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 keto(cid:173)
`compounds.4l
`In an effort to define the role of trace metals in these
`reactions, we have examined and report here the photo(cid:173)
`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 (1a) in
`the absence of Fe(III) ions did not induce any decom(cid:173)
`position, irrespective of the presence or absence of molec(cid:173)
`ular oxygen. By comparison, the irradiation (22 h) of a
`2.68 mM solution of (la) in 1 M hydrochloric acid in the
`presence of 6.2 mM Fe(III) chloride produced (at 85%
`liquid chromatography
`conversion; high performance
`(HPLC) analysis) a mixture of 10,8-hydroxydextromethor(cid:173)
`phan (3) (61 %) and thekriown 10~.oxoderivative (2) (26%).
`Compound 3 gave a molecular peak at m/~ 287 by
`electron impact mass spectrum (El-MS) and this value is in
`agreement with the molecular formula C 18H 25N02 , indi(cid:173)
`cating the presence of an additional oxygen atom. An
`inspection of the MS of 3 in comparison with that of 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 mjz 230 is displaced by 16 amu as
`compared to m/z 214 for 1.5l Accordingly, the infrared (IR)
`spectrum was devoid of any carbonyl absorption but had a
`discrete hydroxyl band at 3400 em -I. In the 200-MHz
`proton nuclear magnetic resonance CH-NMR) spectrum of
`3, the methine proton at C-9 was centered at 2.90ppm
`(sharp doublet, 1=2.5Hz) 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-1 0 as depicted in 3 was assigned by application of
`Karplus analysis6l 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 1a under the above
`conditions, no other hydroxy compound could be detected
`by 1H-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(cid:173)
`product (2) was secured by comparison with an authentic
`sample prepared according to Brossi eta!. I)
`Additionally, we confirmed that the presence of exter(cid:173)
`nally added chloride ions (as hydrochloric acid) affected the
`efficiency of the photo degradation of 1a induced by Fe(III)
`chloride in neutral or acidic solution. In the light of these
`results, the mechanism of the formation of 2 and 3 can be
`interpreted in terms of an initial benzylic hydrogen abstrac(cid:173)
`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,7l the lack of reactivity in sulfuric acid so(cid:173)
`lutions indicated that at least the· formation of an Fe(III)(cid:173)
`chloro complex i.s necessary for the reaction. to take place
`(Eq. 1). Subsequent reaction of 5 with molecular oxygen
`leads to the secondary hydroperoxide (6) (Eqs. 3, 4) and this
`reactive transient species. has several opt'ions 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 maY
`only count for a minor part of the observed photodegradation
`and the formation of 3 could be rationalized. by an alter(cid:173)
`native mechanism. The common intermediate (6) can under-
`
`© 1989 Pharmaceutical Society of Japan
`
`Page 3 of 5
`
`Noven Ex. 1019
`
`

`

`February 1989
`
`[FeX.(Hz0)6-np-n ~[FeX.-J(H20)6-np-n+X.
`1+Cl" ----->5+HCI
`-5 +-302 ------>6
`
`1+6->5+7
`7-2+H20
`7+H+ ----->8+Hz02
`S+H20----->3+H+
`S+MeOH--.4+H+
`
`Chart I
`
`309
`
`(I)
`
`(2)
`
`(3)
`
`(4)
`
`(5)
`
`(6)
`
`(7)
`
`(8)
`
`that substitution had occurred at the 2-position.
`The difference in reactions between Cl" and Br · rna y be
`explained on the basis of frontier orbital theory; in the·
`hydrogen-abstraction reactions, generally SOMO (singly
`occupied molecular orbital)/HOMO interaction-control(cid:173)
`led, the SOMO energy of X·- lies between that of the
`HOMO (rr orbital of C-H bond) and the radical with the
`higher-energy SOMO will be less reactive than the one with
`the lower-energy SOM0. 10
`l This explains why the elec(cid:173)
`trophilic Cl" radical (SOMO energy: -13 eV) 11 l reacts
`faster in hydrogen abstraction of the benzylic methylene
`than the Br" radical (SOMO energy:- 11.8eV). In the light
`of these arguments, two bfQmine radicals would recombine
`to yield bromine and the expected electrophilic substitution
`at the A-ring of dextromethorphan would be cleanly ob(cid:173)
`served as the exclusive reaction channel.
`
`6 : R~, R3=H; Rz=OO'
`1 : R~, Rz, R3=H
`7 : R~, R3=H; Rz=OOH
`2 : Rt =H; Rz, R3=0
`9 : R~, R2 =H; R3=0H
`3 : R1, R3=H; Rz=OH
`4: R1, R3=H; Rz=OMe 10 : R1 =Br; Rz, R3=H
`Fig. I
`
`5*=·
`8*=+
`
`go ionic decomposition via attack at the /3-oxygen atom of
`the hydroperoxide function (C-O bond fission) with loss of
`a molecule of hydrogen peroxide (Eq. 6). This reaction
`predominates, in that the stability of the resulting car(cid:173)
`benium ion (8) proviqes the driving force for this reaction,
`and subsequent quenching by a suitable nucleophilic sol(cid:173)
`vent (e.g., water) leads to 3. Finally, carbocation trapping
`experiments were performed under the above conditions in
`the presence of0.6 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 ~op face and a similar stereochemical outcome
`recently been reported on morphinandienones.8l
`has
`Bettomside oxygen entry would be rather restricted es(cid:173)
`pecially because of the aminomethylene bridge. An un(cid:173)
`ambiguous stereochemical assignment for 3 was accom(cid:173)
`plished by reduction of 2 with LiAlH4 in refluxing tetrahy(cid:173)
`drofuran (THF). The sole isomer formed in this process is
`assigned the a-hydroxyl stereochemistry depicted in 9 since
`this is the expected result of hydride delivery from the least
`encumbered face of tlie carbonyl function in 2.1) Ac(cid:173)
`cordingly,_ the methine hydrogen at C-10 in 9 appears at
`4.88ppm [ vs. 4.72ppm in 3] as a doublet (J==;6.0Hz) (i.e.,
`H-9 and-.I:l~W a-re-cis~Gn:iented~-and this assignment agrees
`with the generalization that an equatorial proton resonates
`at lower field than its axial epimer.9l
`By exposure of. 1a to sunlight in 1 M aqueous hy(cid:173)
`drobr,omic acid in the presence of Fe(III) ions we observ(cid:173)
`ed a rapid and clean transformation to 2-bromo-dextro(cid:173)
`methorphan (10) in 62% yield as the sole product. Com(cid:173)
`pound 10 [M + • 351/349(81 BrF9Br)] was identified by spec(cid:173)
`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 1H-NMR, thus confirming
`
`Experimental
`Melting points were determined on a Buechi 510 apparatus and are
`uncorrected. The 1H-NMR spectra were recorded on a Bruker WP-80 CW
`or on a Varian XL-200 spectrometer in CDCI3 solutions with tetramethyl(cid:173)
`silane as an internal standard. Chemical shifts are reported in ppm (b) and
`signal described as s (singlet), d (doublet), m (multiplet) or br (broad).
`Ultra,violet (UV) absorption spyctra were recorded on a Beckman DU 6
`spectrophotometer. El-MS were measured on a Varian MAT 112 spectro(cid:173)
`meter. Silica gel chromatography (thin layer chromatography, TLC) was
`carried out ort Merck pre-coated 60F254 plates. Preparative silica gel
`chromatography was performed on Merck pre-coated 60F254 (thickness:
`I mm, 20 x 20). HPLC analysis was performed on a Varian M 6000 pump,
`M 440 UV detector and 840 integrator system with 10 11m micro
`Bondapack C-18 column (i.d. 3.9 x 300 mm, Waters). The mobile phase
`was prepared by dissolving 5.8 g of dioctyl sulfosuccinate in water, MeOH,
`THF and concentrated H 3P04 330: 630: 37: I and adjusting the pH to
`3.30 with concentrated ammoniaY>
`_
`Irradiation of 1a in iiCI irt the Presence of FeCI3 Dextromethorphan
`hydro bromide (1a) (1.0 g, 2.68 mmol) was dissolved in I M HCI (1000 ml)
`containing FeCI3 (1.0 g, 6.2mmol) in ten different borosilicate vessels and
`irradiated with tungsten light (500W, Philips PF 308 E/21) at 50cm from
`the reaction ve.ssels 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 (200m!), dried and concentrated in
`vacuo; Preparative TLC (benzene-EtOH-10% ammonia, 89: 10: I, one
`development, recovery with acetone) afforded the known 10-ketoderiv(cid:173)
`ative (2)1> (Rf 0.45; 212 mg, 26%), the starting material (1) (R/ 0.29;
`l25mg) and the amorphous 10,8-hydroxydextromethorphan (3) (R/0.16;
`500 mg, 61 %). I O-Keto-3-methoxy-l7-methyl-(9o:, 13o:, !4o:)-morphinan (2):
`mp 188-189 °C (MeOH). UV ,\~~:" 01-um (loge): 287 (4.18), 231 .(4.05).
`1H-NMR:
`[o:Jb0 -139° (c=3, CHCI3 ). IR (KBr): 2930,2850, 1665cm- 1
`.
`1.0-2.8 (l3H, m), 2.34 (3H, s, CH3-N), 2.97 (I H, d, 1 =3.0 Hz, H-9), 3.88
`(3H, s, CH3-0), 6.90 (2H, m), 8.00 (IH, m). Anal. Calcd. for C18H23N02 :
`C, 75.76; H, 8.12; N, 4.91. Found: C, 75.54; H, 8.19; N, 4.85.
`IO,B-Hydroxy-3-methoxy-17-methyl-(9o:, 13o:, I4o:)-morphinan (3): UV
`,\~~:not nm (loge): 284 (3.20), 277 (3.22), 234 (3.92). IR (KBr): 3400, 2929,
`2830cm- 1 . 1H-NMR: Ll-2.5 (l3H, m), 2.49 (3H, s, N-CH 3), 2.90 (IH,
`d, 1 =2.5 Hz, H-9), 3.8I (3H, s, CH3-0), 4.72 (IH, s, H-IO), 6.80 (2H, m,
`(M+·), 230
`H-2 and H-4), 7.42 (IH, m, H-1). MS mjz 287
`(M+. -C2N4NCH3 ), !50, 143.5 (M2+).
`(9)- Hydrochloride: mp 184 oc (MeOH)~IR (KBr): 3200, 1609,
`I023cm- 1 • 1H-NMR: 0.8-2.9 (14H, m), 2.96 (3H, s, CH3-N), 3.5 (IH, m,
`H-9), 3.72 (3H, s, O-CH3), 4.88 (IH, brd, 1=6.0Hz, H-10), 6.54 (IH, d,
`1=2.0 Hz, H-4), 6.88 (IH, dd, 1=8.0, 2.0Hz, H-2), 7.49 (IH, d, 1=8.0Hz,
`H-1). Anal. Calcdfor C18H25 NO· HCI·Ij2H20: C, 65.02; H, 8.I9; N, 4.21.
`Found: C, 65.IO; H, 8.22; N, 4.16.
`Irradiation of 1a in HCI and MeOH in the Presence of FeCl3 1a ( 1.5 g,
`4 mmol) in a I: I mixture of MeOH and 2M HCI (30 ml) containing FeCI3
`(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 (lOOm!) was added and the mixture was made alkaline with
`!0% ammonia at 0°Cand extracted with dichloromethane (50ml). The
`extract was washed with aqueous sodium potassium tartrate solution
`
`I
`I
`i
`i
`~'
`
`Page 4 of 5
`
`Noven Ex. 1019
`
`

`

`310
`
`(50 ml) and water (50 ml) and dried. Filtration and evaporation afforded a
`syrup (1.08 g), which was shown by TLC (benzene-EtOH-10% ammonia,.
`89: 10: I) to contain the starting material, the 10-ketoderivative (2) and 3,
`together with a new compound (R/0.38). Separation of this was achieved
`by careful preparative TLC using the same eluant and 250 mg (20%; 42%
`based on the recovered startinK material) of pure 10,8-methoxydextro(cid:173)
`methorphan (4) was isolated as an amorphous glass. UV A~~:"01 nm (log~:):
`284 (3.23), 277 (3.25). 1H-NMR: 1.8-2.8 (13H, m), 2.49 (3H, s, CH3-N),
`3.51 (3H, s, O-CH3 ), 3.78 (3H, s, O-CH3), 4.12 (IH, s, H-10), 6.8 (2H, m),
`7.3 (IH, m). MS mjz 301 (M+'), 271 (M+· -OCH2), 150.5 (M2+), 150
`(M+. -151).
`Photochemical Synthesis of 2-Bromo-3-methoxy-17-methyl-(9<X,l3<x,14<X)(cid:173)
`morphinan (10)
`la (!50 mg, 0.4 mmol) in I M HBr (I 00 ml) containing
`FeCI3 (65 mg, 0.4 mmol) in a borosilicate vessel was exposed to direct
`sunlight for 4h. The mixture was made alkaline with 10% ammonia and
`extracted with dichloromethane (50ml). The extract was washed with 2%
`aqueous sodium EDTA solution (50 ml) and water (50 ml), dried and
`evaporated. The solid obtained was subjected to ·preparative TLC
`(CH 2CI2-MeOH-IO% ammonia, 85: 15:0.1) to give 93mg (62%) of pure
`title compound (10). mp 130 oc (MeOH-H20). IR (KBr): 2906, 2855,
`1595, 727, 712cm- 1
`1H-NMR: 1.0-3.0 (14H, m), 2.48 (3H, s, CH3-N),
`.
`3.90 (3H, s, O-CH3), 6.85 (IH, s, H-4), 7.26 (IH,s, H-1). Anal. Calcd for
`C18H24BrNO: 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 according to the
`following procedure: la (2.1 g, 5.6 mmol) was dissolved in I 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
`
`Vol. 37, No.2
`
`until the color disappeared. The solution was extracted with ethyl acetate
`(2 x 300 ml), dried and evaporated. The solid was dissolved in MeOH:
`(40ml) and precipitated with water (40ml) giving 750mg of a colorless
`crystalline solid (38%). This compound was identical with that obtained by
`the photochemical procedure.
`
`References and Notes
`I) Q. Haefiger, A. Brossi, L. H. Chopard-dit-Jean, M. Walter and Q.
`Schnider, Helv. Chim. Acta, 39, 2053 (1956).
`2) B. Proska, Z. Voticky,L. Molanar, J. Putek and ~t_S_t~(ek, Chern
`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).
`5) C. Koeppel, J. Tenczer and K. Ibe, Arzneim. Forsch., 37, 1304 (1987).
`6) M. Karplus, J. Chern. Phys., 30, II (1959); M. Karplus, J. Am. Chern.
`Soc., 85, 2870 (1963); S. Sternhell, Quart. Rev. (London), 23, 236
`(1969).
`7) A. Cox and T. J. Kemp, J. Chern. Soc., Faraday Trans. 1, 71, 2490
`(1975).
`.
`8) T. W. Bentley and S. J. Morris, J. Org. Chern., 51, 5005 (1987).
`9) L. M. Jackman, "Applicati9n of Nuclear Magnetic Resonance
`Spectroscopy in Organic Chemistry," Pergamon Press, Inc., New
`York, 1959.
`.
`I. Fleming, "Frontier Orbitals and Organic Chemical Reactions"
`Wiley, New York, 1976.
`'
`'
`II) R. W. Henderson, J. Am. Chern. Soc., 97, 213 (1975).
`12) G. W. Halstead, J. Pharm. Sci., 71, I 108 (1982).
`
`10)
`
`l
`I
`
`I
`
`Page 5 of 5
`
`Noven Ex. 1019
`
`