[ C O S T R I B U T I O N F R O M THE P H A R l I A C E U T I C A L I S S T I T U T E , h f E D I C A L
FACULTY, U S I V E R S I T Y OF
KYUSFIU]
dl-Phenylserinols : A New Synthesis and its Stereochemical Findings. BY TAXEZO T A G L - C H I , ~ILJSEMITSE T O M O E.4ND D . ~1S:IO 4
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RECEIVED 4%VGUST 9 , 1955 rl new sytlthesis of dl-tiirco-plie~l~lseri~iol from tra ns-cinnamic alcohol is described. Configurations are assigned to t h e iiiterrnedinte products formed in t h e synthesis and evidence is presented for t h e epimerizntion of d l - t ~ ~ i ~ o - l - p h e n y l - 2 - b c 1 ~ ~ ~ y l .iili~iio-1,3-dibroiiiopropaiie by heat t o the e r j ' : / , r o form.
It is interestin? from the standpoints of stereo- carbonate. Boiling YI hydrochloride in water chemistry and of synthetic method that chloram- gave 111; this provides evidence for the imino phenicol may be obtained from cinnaniic alcohol ether structure. Boiling 1-1 tlissol\wl in toluene by steplvise addition and substitution reactions. gave a solid which then went into solution. The Investigation of this problem has been begun with solid product was identified as VI hydrobromide, the synthesis of dl-phenylserinols. which might be formed by preferential combination The cinnamic alcohol (I), 1n.p. 30-33", has been of 1.1 with hydrogen bromide liberated by replaceassigned the traizs form.2 On treatment with ment of the C2-Br atom by the imino group. This bromine in carbon tetrachloride this isomer gave result is analogous to that of Gabriel's in the case of dl-.3-phen!.1--",:3-tlibromopropan-l-o1 ( I I ) , m.p i 3 3-bromoethyl berizimirio ether.4 i 4 3 , in S4% yield, together with a small amount of The toluene solution was evaporated to dryness an oil. Both the dibromide and the oil afforded the under reduced pressure to leave an oily product 0-benzoate 111, m.p. 114-115", with benzoyl chlo- which was transformed to n'l-tizreo-1-phenyl-1ride. -1ssuming that compound (I) does ha\Te the benzoylosy-2-arnino-3-brornopropan.. (IX) hydrotrans configuration and t h a t halogens, as is gener- bromide by hydrolysis with 1Yc aqueous hydrobroally recognized, add preferentially to olefinic double mic acid or aqueous ethanol. Conversion of IX bonds in a trans fashion the dibromide 11 may be hydrobromide to dl-\k-N-benzoylnorepheclrine by catalytic reduction with palladiun-charassigned the erytliro configuration. This assign- (X)5,6 ment is confirmed by the fact t h a t ethyl traizs- coal, followed by treatment with aqueous sodium cinnamate (IV) adds bromine to give ethyl dl- hydroxide, gave definite proof for the structure and erythro-3-phenyl-2,3-dibromopropionate (Y), whose configuration of IX. I n the hydrolysis of the oily configuration has been well established, and t h a t product -k,leaflets of m.p. 103.5-123.5" were isoreduction of V with lithium aluminum hydride re- lated in poor quantity; these n-ere assumed to be dl-erytlzro-1-phenyl- 1,2,3-tribromopropane ( X I ) on sulted in dl-erythro-l-benzoyloxy-2,3-dibromo-3phenylpropane (111), which was identical with t h a t the basis of the empirical formula C9H9Br3and by analogy to the fact t h a t dibromoethylene' was obtained from the cinnamic alcohol (I). obtained by pyrolysis of B-bromoethyl benzimino H H ether hydrobromide. -4 similar partial hydrolysis Brz I I p,,>C=C(H + Ph-C-C-CH20H of VI-hydrobromide may have occurred here. FI CH?OH I I The pH of an aqueous solution of IX hydrobroI hr Br 11 rnide, upon boiling, rapidly decreased from 5,4 to 1.6, suggesting the liberation of hydrobromic acid BzCl by hydrolysis of the C3-Br atom. The solution was v concentrated under reduced pressure and made alj. H H kaline to yield an oily product, which slowly crysI I tallized and was identical with dl-threo-l-phenyl-2Ph-C-C-CH?OBz benzoylamirio-1,3-propanediol( X I I I ) (7370). The I 1 oily product (A) was boiled in water for three hours Br Br 111 and made alkaline to afford XI11 directly in 21yo 1-ield. 1, LiAIH4; 2 , BzCl By further analogy to Gabriel's results with 9I brornoethyl benzimino ether i t may be concluded H H that the oily product (-\) consists inainly of Ph E1 Br2 I 1 d/-1- phenyl - 2 - benzoylarnino - 1,3- dibromopropane, >c=c( + Ph--C--C--CO2C?Ha formed from VI via dl-2-phenyl-4-phenylbrornoH ~CO?CzHs I 1 11Br Br V methyl A2-oxazoline. On the basis of the fact t h a t substitution a t the A dry ether solution of dl-erythro-3-phenyl-2,3dibromopropan-1-01 (11) and benzonitrile upon C2-Br by the imino group may take place via S s 2 saturation with hydrogen chloride and standing in reaction with inversion, the oily product (*k)may be assigned the threo form (VIIIa). However, A the cold gave dl-e~ytizro-3-phenyl-2,3-dibromopropyl benzimino ether (VI) hydrochloride, which was con- was found to give IX hydrobromide by presurn~ hydrolysis; this suggests the erpthro verted to the free base by treatment with sodium ably S Nacidic
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(1) Studies in Stereochemistry, VIII. (2) L. F. H a t c h and H . E. Alexander, THMJOURNAL, 72, 5643 (1950). (3) E. Grovenstein, Jr., and D. E . Lee, i b i d . , 76, 2639 (1953).
( 4 ) S. Gabriel and A . Neumann, Bcr., 26, 2383 (1892). ( 5 ) W. N. Nagai and S. Kanao, Ann., 470, 157 (1920). (6) M. Honjo, J . Pkorm. SOL.Jopon, 7 3 , 368 (1953). (7) A. Pinner and F. Klein, Ber., 10, 1892 ( 1 S i i ) .
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April 5 , 1‘356
dl-PIJENYLSERINOLS:
SYNTIIESIS AND ITS
1469
STEREOCIJE3IICAL FINDINGS
Ph
I I O I
HCI,HN=C H
H
I
/
I
/
H P h C S , dry HC1
Ph--C-C-C€I~OH
I
,
/\
I
Br H HBr
it:ry
toluciie w i t h niihytl. S a 2 C 0 3 , 1 lir.
f- licat i i i
i l 1’11-C-C-CHz
I
1
(
I
Br Br vI
+
SI
I
aq. EtOH-HBr
Pli-C-C-CH?Br
1 cold
Br H \-IIIa
I
I
Pli-C-C-CII?Br ;HBz YIIIb
]
H
NH?.HBrfHCIl
I
1
\
H
,
I
L
1_____f
(10% HC1)
I
OH H
Br H
H
I
Pli-C-C-CH,
s
S I 1,HBr(HC1)
1% IIBr
SHBz
I
> Ph-C-C-CHzOBz 1 1
I
heat in toluene, 6 lir.
[
l
I1 II 1 1 > \.IIIb I’li-C-C-CII2~3r (major) Br I Br I (Iiiilior)
1
~~
1
0
a q . HBr( HC1)
SHBz
1
I
heat in toluciic
\‘I I .H Br
H
Br Br
I
I1 H
\
P~-C-C-CII~OBZ
______f
I
HS=C
II s 0 I ’ PIi-c-C-CII,!
H I1 H20
Br Br
C
I
/
> Ph-C-C-CHI
in ether
Br Br
H
/
1, H r , Pd-C 2, 10% NaOH
f
SH2 HBr(HC1)
I I Pli-C-C-CH2Br I 1
1, HzO t
2, 10% NaOH
OBz H IX.HBr(HC1)
form (lrIIIb). To resolve these conflicting conclusions about the configuration of (-4) further experiments were undertaken. The imino ether VI was boiled in toluene with sodium carbonate for an hour t o give dl-threo-2phenyl-4-phenylbromomethyl-A2-oxazoline (VII). This compound (VII) added one mole of water on treatment with hydrochloric or hydrobromic acids to give the corresponding salts of dl-threo-l-benzoyloxy-2-arnino-3-bromo-3-phenylpropane (XII). The oxazoline VI1 hydrobromide was boiled in toluene for an hour to yield a neutral solid, m.p. 182-134’, .accompanied by an oily product (B). The solid is characterized as dl-tlzreo-l-phenyl-2benzoylamino-1,3-dibromopropane(VIIIa) by microanalytical data, infrared spectra and the knowledge4 that oxazoline hydrohalide is converted to pacylaminoethyl halide by heating. Both VIIIa and X I 1 are assigned to be threo for the further reason t h a t their formation reactions do not involve the breaking of any bonds to asymmetric carbon atoms. h further proof for t h e configuration of V I I I a is its hydrolysis in cold aqueous alcoholic hydrobromic acid to give X I 1 hydrobromide. This result also indicates that acyl participation a t Cs
H
SHBz
I
1
1
1
Ph-c-c-cII?OII 013 S I 1H1
is preferred over participation a t C1 in the t h e 0 isomer (VIIIa). However, when VIIIa was boiled in toluene for several hours, it changed to an oily product (C) which was hydrolyzed in 1% warm aqueous hydrobromic acid to give I X hydrobromide. Also, the oily product (B) gave I X hydrobromide upon similar hydrolysis. Thus, the oily products (A, B and C) are commonly formed whenever VIIIa, as starting material or possible intermediate, is exposed to heat with exclusion of moisture, and give I X hydrobromide upon partial hydrolysis. Therefore, they are assumed to be identical and t o be dl-erythro- 1-phenyl -2-benzoylamino - 1,3-dibromopropane(VIIIb). I n each case the erythro isomer VIIIb was formed by epimerization of the threo form VIIIa. Furthermore, a heated acidic hydrolysis of VIIIa, in contrast to that in the cold, gave I X and XI1 hydrobromides in the ratio of 1 :4,IX hydrobromide presumably resulting from epimerization of V I I I a t o VIIIb, followed by hydrolysis. Thus, there are no contradictions in the assignments of configuration to VIIIa and VIIIb, and in the epimerization of VIIIa to VIIIb.
1470
TANEZO TAGIUCHI, MUNEMITSU TOMOEDA AND ISAOARATANI
Vol. 78
Experimental8
chloric acid and 9 cc. of ethanol was added and the solution was kept a t room temperature for several days. The predl-cryti~ro-3-Phenyl-2,3-dibromopropan-l-ol (II).-To a cipitate was collected, washed with acetone and weighed, solution of 100 g. of dl-lrans-cinnamic alcohol in 1000 cc. of 4.5 g. (96%). Rcrrystallization from methanol gave colorcarbon tetrachloride, 131 g. of bromine in 100 cc. of carbon less needles, m.p. 176-179" dec., $'A:: a t 3.74, 3.85, 3.94, tetrachloride was added with stirring a t -5'. The carbon 5.81 and 6.57 p. Anal. Calcd. for CI6Hl7O2NBrC1: C, tetrachloride solution was washed with dilute sodium bi51.84; H, 4.62; N, 3.78. Found: C, 51.61; H, 4.29; N, sulfite, saturated sodium bicarbonate and finally with water. The carbon tetrachloride solution was dried over anhydrous 3 3 6 . ( b ) Hydrobromide.-Two grams of VI1 in 15 cc. of acesodium sulfate and concentrated in ztacuo till a solid appeared tone was treated with 0.92 g. of 46% hydrobromic acid as after cliilliiig. Filtration and recrystallization from petroleum beiizine gave large colorless needles, m . p . 73-74",@ described under ( a ) t o yield 2 g. (76%) of X I 1 hydrobromide. Recrystallization from metlianol gave colorless needles, wt. 180 g. (84%). Concentratioii of the filtrate left a n oily m.p. 190-192O dec. Anal. Calcd. for C16H1702NBr2:C , residue. dl-erythro-l-Benzoyloxy-2,3-dibromo-3-phenylpropane 46.29; H , 4.13; S , 3.37. Found: C, 46.28; H, 3.92; N, 3.31. (111). (a).-A mixture of 500 mg. of I1 and 500 mg. of (c) Picrate.--A niethaiiol solution of X I 1 hydrochloride benzoyl chloride was lieatcd at 13-140' for 1.5 hours. or hydrobromide was added t o saturated sodium picrate to After cooling, thc reaction mixture was mixed with saturated sodium bicarbonate and crystallized gradually in the give a yellow precipitate. Recrystallization from methanol gave ycllow plates which melted at 117-120" after softening cold. After filtration, recrystallization from methanol at 10F0, but melted a t 134-136" after drying over phosphorus gave colorless nccdlcs, m.p. 114-115', wt. 500 mg. (74%). pentoxide in oucuo at 50". Anal. Calcd. for C22H1909N1Br: .lnal. Calcd. for C I G I ~ I I ~ O ZC, B ~48.27; Z: 11, 3.54. Found: C, 46.90; H , 3.40; N, 9.95. Found: C, 47.10; H, 3.37; C , 48.33; H, 3.47. The oily residue described above was IT, 9.64. similarly treated with benzoyl chloride to give colorless dl-threo-l-Phenyl-2-benzoylamino-l,3-dibromopropane needles, n1.p. 113-114" alone and mixed with 111. (VIIIa). ( a ) From VII, with Oily By-product (B).-A solu(b).-To ;L solution of 230 mg. of lithium aluminum hytion of 500 mg. of VI1 in 5 cc. of dry benzene was saturated dride in 5 cc. of dry ether, a solution of 2 g. of ethyl dlwith dry hydrogen bromide and concentrated in vacuo t o ery/iiio-3-plie1i~-l-3,3-dibromopropionate~~ ( V ) in 10 cc. of give a n oily residue. The oil was boiled with 5 cc. of dry dry ether was added dropwise a t O " , and the reaction mixture toluene for a n hour. The solution was evaporated to drykept n t room teniperxture for 30 minutes and then boiled for ness i n vacuo to leave a n oily residue which crystallized upon :in hour. The wiiole treatment was carried out with vigoraddition of a small voluhe of ethyl acetate. After filtration, ous stirring. After cooling, ether and 10% sulfuric acid were it melted at 129-132" and weighed 200 mg. (32%). Readded to the reaction mixture. The ether layer was washed crystallization from benzene gave colorless needles, m.p. with satur,ited sodium bicarbonate and then water, dried over :inhydrous sodium sulfate and concentrated to leave a n 132-134", A?': at 3.11, 6.11 and 6.58 p. Anal. Calcd. oily product. The oil was heated with 2 g. of benzoyl for C ~ ~ H I S O N B : C,~ ~ 48.39; H, 3.81; N, 3.53. Found: chloride a t 130-140' for two hours, and, after cooling, satuC, 48.05; H, 3.65; N, 3.50. rated sodium bicarbonate was added and the mixture allowed T h e ethyl acetate solution was concentrated t o dryness to to stand for two days at room temperature. The mixture give a n oily product (B) which gave IX hydrobromide, was extracted with ethyl acetate and the extract washed with m.p. 206-208' dec., 440 mg. (67%), by hydrolysis with 1% water, dried over anhydrous sodium sulfate and evaporated hydrobromic acid worked up exactly as in the case of oily to dryness. T h e residue crystallized by addition of methproduct ( A ) , below. -4nal. Calcd. for C16H170~NBr2: anol and recrystallized from ethanol, giving colorless needles, C , 46.20; H, 4.13; N, 3.37. Found: C, 46.70; H , 4.39; m.p. 113-115" alone and on admixture with I11 derived I3.48. ,Picrate: Recrystallization from methanol gave from 11. Anal. Calcd. for ClbH1402Br2: C , 48.27; H, yellow prisms, m.p. 171-174' which did not depress the m.p. 3.54. Found: C, 48.03; H, 3.55. on admixture with a n authentic sample of IX picrate obdl-erythro-3-Phenyl-2,3-dibromopropylBenzimino Ether tained by the procedure described below. Anal. Calcd. (VI) Hydrochloride.-A solution of 20 g. of I1 and 7 g. of for C22HL909N4Br: N, 9.95. Found: N, 9.75. benzonitrile in 10 cc. of dry ether was saturated with dry ( b ) From VI, with Oily By-product (A).-A solution of hydrogen chloride a t 0". A solid precipitated after stand1.6 g. of VI in 16 cc. of toluene was boiled for 1.5 hours and ing in the cold for several days. The solid was collected, then worked up exactly as described under ( a ) t o give VIIIa, washed with dry ether and dried over sodium hydroxide i n m.p. 131-133", wt. 200 nip. (13%) and a small amount of nacuo, t o give 23.3 g. (79%) melting at 148-150'. Anal. a n oily product (A) which was converted to IX hydrochloCalcd. for C & I G O ~ - B ~ Z CN, I : 3.23. Found: N, 3.18. ride, m.p. 196-198" dec., 320 mg. (22%). by hydrolysis An aqueous solution of \'I hydrochloride was boiled for with 10% hydrochloric acid. Anal. Calcd. for VIIIa, a n hour t o result in precipitation of colorless needles melting CISHISONBr?:C, 48.39; H , 3.81; N, 3.53. Found: C, a t 114-115' and identicnl with I11 by a mixed m.p. deter48.40; H, 3.35; N, 3.38. mination. Salts of dl-thrco-~-Phenyl-l-benzoyloxy-Z-amho-3-bromodl-erylhro-3-Phenyl-2,3-dibromopropylBenzimino Ether propane (IX). ( a ) From VI via the Oily Product ( A ) AS(VI).-Twenty-six grCinis of 1'1 hydrochloride was ground sumed to be dl-erythro-l-Phenyl-Z-benzoylamio-1,3-dibrowith 130 cc. of 10% sodium carbonate solution in a mortar mopropane (VIIIb).-Hydrobromide: (i) A solution of for ten minutes and the solid was collected, washed with 8.1 g. of VI in 40 cc. of toluene was boiled for nine hours. water and dried. Recrystallization from acetone gave At the beginning colorless needles" appeared and disapcolorless prisms, m.p. 133.u5-1350, wt. 22 g. (92%). Anal. penrcd soon afterward. T h e toluene solution was evapoCalcd. for CL~H150SBr2:C, 48.39; H , 3.81; N. 3.53. rated to dryness in V U C Z L Oto give a n oily product ( A ) . This Found: C,48.54; H,3.77; N,3.48. was heated in 16 cc. of 1% hydrobromic acid on a stearndl-tizreo-Z-Phenyl-4-phenylbromomethyl-A*-oxazoline (VII) . bath for a n hour with occasional shaking and crystals prc-A mixture of 15 g. of \rI and 30 g. of anhydrous sodium cipitated gradually while heating. The crystals were filcarbonate in 300 cc. of toluene was boiled with occasional tered, washed with,acetone and dried, 4.5 g. (53%). Reshaking for a n hour. After filtration, the pale yellow filtrate crystallization from watcr gave colorless needles, m.p. 206was concentrated zn vacuo and with addition of small amounts 208" dec. Anal. Calcd. for CIGH~IOZSB~?: C, 46.29; of ether gave prisms, 10.3 g. (87%). After rccrb H, 4.13; S , 3.37. Found: C, 46.55; H , 3.80; 9, 3.24. tion from ether, it melted a t 103-105", a t fi.O(i p . The acetone solution was concentrated t o lc~rvc:L solid. Recrystallization from niethaliol gave colorlcss leaflets of dl. l n o l . Calcd. for C16ITtaONBr: C , G0.77; H, 4.46; PI', erytk~o-i-:~hc11yl-~,2,3-tribron~opropane ( X I ) , g 111.p. 123.5 4.43. Found: C, 60.97; IT, 4.20; Ii, 4.62. Salts of dl-tbveo-l-Benzoyloxy-2-amino-3-bromo-3-phenyl-125.5', 1 g. Anal. Calcd. for CoHsBr3: C, 3U.2X; 11, propane (XII). ( a ) Hydrochloride.-To a solution of 4 g. of 2.54. Found: C, 30.43; H , 2.57. (ii) \Vhen 95y0 ctllmol was used in place of 1% liyclroVI1 in 200 cc. of ether, a mixture of 5.5 cc. of 10% hydro(8) All melting points are uncorrected. (0) E. Grimaux, Ruli. .TO
