514s
SFLSON J. LEOXARD . ~ K DLi-. KEKNEI.H ~LVSKER
Vol. 82
[CONTRIBUTION FROM THE NOYES CHEMICAL LABORATORY, UXIVERSITY OF ILLINOIS, URBANA, ILL.]
Unsaturated Amines. XVI. An Oxidative Cyclization Route to Oxazotidines and Tetrahydro-1,3-0xazines'~~ BY NELSONJ. LEONARD AND W. KENNETH MUSKER~ RECEIVED JANUARY 18, 1960 The mercuric acetate oxidation of many piperidino- and pyrrolidino-alcohols can be controlled t o give fair t o good yields of bicyclic oxazolidines and tetrahydro-1,3-oxazines where the masked aldehyde or ketone carbon atom is a t the bridgehead. Representative bicyclic systems h a r e been obtained for the first time by this method. The main side reaction is over-oxidation t o give amidoalcohols, and the oxidation may also be used as a route to these compounds as major products. The stereochemistry of many of the bicyclic oxazolidines and tetrahydro-1,3-oxazines can be assigned tentatively by observing the infrared bands in the 2700-2800 cm. - l region and by applying conformational analysis.
We provided earlier a single example of oxazolidine ring formation by the mercuric acetate oxidation of a /3-3°-aminoalcohol.4 Further experiments have now shown that the new ring closure method is generally applicable to the synthesis of oxazolidines and tetrahydr0-1,-3-oxazines.~Since the mercuric acetate oxidation had previously been tried only with a bicyclic aminoalcohol, 3hydroxyethyl-3-azabicyclo [3.3.l]nonane (I) (+ 3oxa-6-azatricyclo 16.3.1.023]dodecane6 (11)), in
I
I1
which enamine formation within the ring system was impossible, the use of an aminoalcohol that did not possess a bridgehead /3x-carbon was a possible invitation to enamine alcohol formation followed by dimerization to complex products. It is possible to distinguish between the original tertiary aminoalcohol, the corresponding enamine alcohol and the oxazolidine or tetrahydro-l,3-oxazine by infrared spectroscopy and vapor phase chromat o g r a p h ~ . ~The infrared spectra of the enamine alcohols show absorption maxima in the 1650 and 3400 cm.-' regions, while the spectra of the oxazolidines or tetrahydro-l,3-oxazines are transparent in these regions but should possess a t least three strong bands in the 1000-1200 cm.-l region, characteristic of the N-C-0 g r o ~ p i n g . ~The , ~ bi(1) Presented a t t h e 136th Meeting of t h e American Chemical Society, Atlantic City, N. J., September 13-18, 1959; see Abstracts of Papers, p. 25-P. (2) For article XV in this series, see P;. J. Leonard and W. K . Musker, THISJ O U R N A L , 81, 5631 (1959). (3) US1 (U. S. Industrial Chemicals Co.) Fellow, 1958-1959. (4) hT.J. Leonard, K. Conrow and R. R. Sauers, THISJ O U R N A L , 8 0 , 5185 (19.58). (5) Other reagents which provide isolated examples of N-C-0 ring F. formation, in t h e alkaloid series, are osmium tetroxide in ether (M, Bartlett, J. Edwards, W. I. Taylor and K. Wiesner, Cheiitistry & I n dustry, 323 (1953); S. W. Pelletier a n d W. A. J a c o b , THISJOURNAL, 7 8 , 4144 (19.56)); silver oxide in methanol (K. Wiesner, Z. Valenta, J . F. King, K. IC. Maudgal, L. G. Humber and ShB Ita, Chemisfry f9 I?tdtisluy, 173 (1957)) ; potassium permanganate (F.Sparatore, R. Greenhalgh and I,. Marion, Tsluaheduon, 4 , 157 (1958)); and potassium ferricyanide (S. Sakai, Chent. and Phaum. Bull., 6, 448 (1958)). (6) This compound is now named in t h e 3-oxa-6-aza-sequence rather t h a n t h e 6-aza-3-oxa-sequence t o conform with Chemical A bsfvacls usage. ( 7 ) T h e index of refraction can be employed as a guide t o indicate t h e presence of large amounts of enamine since i t has been found t h a t t h e value for t h e enamine alcohol is usually 0.02 unit higher t h a n t h a t for either t h e oxazolidine or t h e aminoalcohol (R.R. Sauers, Ph.D. Thesis, University of Illinois, 1967).
cyclic oxazolidines prepared earlier by Conrow and Sauers4j7formed picrate derivatives which were shown to be in the open, iminium salt form by
+
their infrared spectra (>C=N< absorption a t ca. 1675 cm.-' and 0-H absorption a t 3300 cm.-l) so that such a derivative may not necessarily permit a decision as to whether the basic precursor is an oxazolidine or an enamine alcohol. The tertiary aminoalcohols studied were 3piperidinopropanok (III), 2-piperidinoethanols (Iv), 3-pyrrolidinopropanols (V) and 2-pyrrolidinoethanols (VI). These starting materials are listed in Table I (see Experimental). Since the mercuric acetate attack on substituted 1-methylpiperidines proceeded to give oxidation products in better yields'O than the oxidation of substituted l-methylpyrro1idines,l1 we decided to study the alkylated piperidinoalcohols in greater detail than the pyrrolidinoalcohols. 12-14
R 4 3
R' 111
f3' I V
VI
~ , R = R ' = H b, R = CHI, R' = H C, R = R' = CHj
VI1
R' VI11
X R
(8) E. D. Bergmann, E. Zimkin and S . Pinchas, Rec. fuaz'. c k i m . , 71, 168 (1952), and t h e eight articles following. (9) E . D. Rergmann, D. Lavie arid S. Pinchas, T H E JOURNAL, 73, 5662 (1951). (10) h-.j. Leonard and F. P. Hauck, J r . , ibid., 79, 5279 (1957). (11) N.J. Leonard and A. G. Cook, ibid., 81, 5627 (1959). (12) R. 0. Clinton, U. J. Salvador and S. C. Laskowski, ibid., 71, 3366 (1949). (13) D. E. Adelson, L. G. MacDowell and C. B. Pollard, ibid., 67, 1988 (1935). (14) F. H. Buckwalter and A. P. Granatek, U.S. Patent 2,682,539, June 29, 1954; C. A , , 49, 9042 (1955).
Oct. 5 , 1960
OXIDATIVE CYCLIZATION OF TERT.-.~II\;O.ALCOHOLS
Mercuric Acetate Oxidation of tert.-Aminoalcoho1s.-The mercuric acetate oxidation of many piperidino- and pyrrolidino-alcohols (111-VI) can be controlled to give fair to good yields of bicyclic oxazolidines and tetrahydro- 1,3-oxazines where the masked aldehyde or ketone carbon atom is a t the bridgehead. The bicyclic systems which have been obtained by this method are illustrated by formulas VII-X, and details as to yields and physical properties are provided in Table I1 (see Experimental). The general system which we have used in naming these compounds may be illustrated by two examples: 6,l0-dimethyl-5-oxa-l-azabicyclo [4.4.0]decane for VIIc and 2,6 - dimethyl 7 - oxa - 1azabicyclo [4.3.0]nonane for VIIIc. The oxidation was carried out a t room temperature whenever possible. When the rate of oxidation was very slow, as indicated by the rate of precipitation of mercurous acetate, the reaction was usually warmed so that the theoretical amount of mercurous acetate (calculated for a two-electron oxidation) would be precipitated within a convenient time. The mercurous acetate was removed by filtration, the excess mercuric ion by conversion to the insoluble sulfide and filtration. The sequence of basification with potassium carbonate, ether extraction, solvent removal and fractional distillation of the residue was used for isolation of the products. The mercuric acetate oxidation of piperidinoethanols was generally found to produce bicyclic oxazolidines in conversions of 47 to 75%. The course of the reaction is regarded as an internal nucleophilic attack by the alcohol group on the ternary iminium salt formed in the initial oxidation stage.4 The contaminating enamine alcohols and starting materials were eliminated by distillation. The formation of small amounts of amidoalcohol and amidoester were noted in the high-boiling fractions obtained from the oxidation of 2-piperidinoethanol (IVa) and 2-(3’-methylpiperidino)ethanol under mild conditions. No high-boiling fraction was isolated from the oxidation of 2(2’,6’-dimethyLpiperidino)-ethanol (IVc) . When substituents were present on the 2- or 6-position of the piperidine ring, the yield of bicyclic oxazolidine was increased. We have assigned the structure of the oxazolidine resulting from the oxidation of 2(2’-methylpiperidino)-ethanol (IVb) as 6-methyl7-oxa-1-azabicyclo [4.3.0]nonane (VIIIb) by analogy with the oxidation of 1,2-dimethyIpiperidine by mercuric acetate,IOwhich yielded 1,2-dimethylA2-tetrahydropyridine, corresponding to preponderant oxidation on the tertiary QN-carbon. I n the oxidation product of 2-(2’-methylpiperidinno)ethanol a very weak shoulder was noted on the main oxazolidine peak by vapor phase chromatography, which may be due to a small amount of 2-methyl-7-oxa-1-azabicyclo [4.3.0]nonane. When the oxidation of IVb was carried out a t high temperature for a long period of time, a very small amount (1%) of the mixed amides was obtained. This product indicated that some dehydrogenation had occurred a t the 6-position, since it is unlikely that the oxazolidine formed by cyclization to the 2-position could be oxidized to an amidoalcohol. Consistent with earlier findings, the picrates formed
-
5149
from 6 - methyl - 7 - oxa- 1- azabicyclo [4.3.0] nonane (VIIIb) and 2,6-dimethyl-7-oxa-l-azabicyclo [4.3.0]nonane (VIIIc) were in the open, iminium salt form (XI), as determined by infrared.
($5
OPic-
R‘ XI
As in the case of the 2-piperidinoethanols, compounds with substituents in the 2’-or 6’-position in the piperidine ring of 3-piperidinopropanols (111) gave better yields of bicyclic tetrahydro1,3-oxazines (VII) than did the unsubstituted aminoalcohol. Yields of the cyclic products from the 3-piperidinopropanols were generally lower than from the corresponding 2-piperidinoethanols. For example, the maximum conversion from 3-piperidinopropanol (IIIa) to 5-oxa-1-azabicyclo [4.4.0]decane (VIIa) was 36%. %Methyl- and 2,6dimethylpiperidinopropanols (IIIb, c) gave bicyclic tetrahydro-1,3-oxazines (VIIb, c) in 65y0 conversions. Over-oxidation generally yielded amidoalcohols. 1-(3’-Hydroxypropyl)-2-piperidone (XIV) was formed in 20% yield using mild oxidation conditions with IIIa; however, when the oxidation was performed for a longer time, the amidoalcohol was isolated in 50% yield. The identity of the amidoalcohol was confirmed by comparing its properties with the known compound prepared by Middleton15 by reducing the corresponding pyridone with Raney nickel. More,-- 0 A c
J
a3 XIV
xv
clod-
over, the compound formed by the addition of perchloric acid to the amidoalcohol was identical with 2,3-tetramethylene-5,6-dihydro-l,3,4-oxazinium perchlorate (XV).15 In order to show that the amidoalcohol could be formed from the tetrahydro1,3-oxazine or its equivalent in the acid-buffered solution, we subjected 5-oxa-l-a7abicyclo [4.4.0]decane (VIIa) to mercuric acetate oxidation and did indeed obtain 1-(3’-hydroxypropyl)-2-piperidone (XIV). The possibility that the tetrahydro1,3-oxazine is one precursor in the mildly acidic (15) W. J. Middleton, University of Illinois, unpublished results, 1952.
5150
NELSON J. LEONARD AND W. KENNETH MUSKER
solution, through the oxidation stage XI1 and the hydrolysis stage X I I I , is attractive since a salt such as the picrate of VIIa, for example, is in the closed form (XVI). However, hydroxy (111, R = O H , R‘=H) and acetoxy (111, li=OAc, R’ = H) forms are also possible precursors. Weak broad enamine absorption in the 1650 cm.-’ region of the infrared spectrum can not easily be distinguished from lactam absorption (ca. 1610-1645 cm.-l However, we observed that both five- and six-membered tertiary lactams give rise to a companion hand at 1490-1505 cm.-l.18 This band is usually strong and sharp in contrast to the broad lactam absorption a t higher frequency. I n addition, the pure amidoalcohol displays an 0-H stretching vibration a t 3400 cm.-’ which is usually sharper than the 0-H absorption in the tertiary aminoalcohol and the enamine alcohol. The oxidation of 3-(2’-methylpiperidino)-propanol (IIIb) with mercuric acetate yielded a mixture of two bicyclic tetrahydro-1,3-oxazines,6methyl-5-oxa-1-azabicyclo [4.4.0]decane (VIIb) and 10-methyl-5-oxa-1-azabicyclo [4.4.0]decane (VII, R = H, R’ = CHJ, with the former predominating by a factor of approximately nine according to vapor phase chromatography. When the reaction was performed using a higher temperature and a longer time, the ratio of isomers was about the same a r d a trace of amidoalcohol was detected. This is approximately the same result experienced with 2-(2’-methylpiperidino)-ethanol (Ivb) except that the yield of the isomeric product is much greater from the piperidinopropanol than from the piperidinoethanol. The oxidation of 3-(2’,6‘-dimethy1piperidino)-propanol (IIIc) gave 6,lO-dimethyl-5-oxa-1-azabicyclo [4.4.0]decane (VIIc) . When the sample was subjected to vapor phase chromatography a shoulder on the main peak was observed. This shoulder may indicate that both stereoisomers (dl-pairs) of 6,l O-dimethyl-5oxa-1-azabicyclo [4.4.0]decane are produced (VIIc’ and VIIc”,representing racemates). 16117).
Vol. 82
The oxidation of 3-(3’,5’-dimethylpiperidino)propanol (XVII) with mercuric acetate yielded solely the amidoalcohol, 1-(3’-hydroxypropyl)3,5-dimethyl-2-piperidone(XVIII). No trace of bicyclic tetrahydro-1,3-oxazine was found. Moreover, the amido-alcohol XVIII did not undergo cyclization to a dihydrooxazinium perchlorate, in contrast to the compound lacking the methyl groups (XIV XV). Two P-pyrrolidinoalcohols were used in this study. 2-pyrrolidinopropanol (VIb) and 2-pyrrolidinoethanol (VIa). Both gave lower conversions (25% range) to bicyclic oxazolidines (Xb, a) on mercuric acetate oxidation than did the piperidinoethanols. The oxidation of 3-pyrrolidinopropanol (V) to 5-oxa-1-azabicyclo [4.3.0]nonane (IX) proceeded very slowly a t room temperature so that the oxidation was performed a t steam-bath temperature for4 hours. Thestructureof the bicyclic system was checked by reducing the bicyclic tetrahydro-l,3-oxazine with lithium aluminum hydride to the original starting material, which was isolated as the benzoate hydrochloride in 90% yield. Picrates of most of the hicyclic oxazolidines and tetrahydro-1,3-oxazines were obtained. 7-0xa-1azabicyclo [4.3.0]nonane (VIIIa) was exceptional in not forming a stable picrate. It was shown by infrared evidence that the picrates of the bicyclic oxazolidines VIIIb and c. along with that of 6,lOdimethyl-5-oxa-1-azabicyclo [4.4.0]decane (VIIc), existed in the open, iniinium salt form (>C=N+< absorption 1660-1675 cm.-l, 0-H absorption 3340 cm.-l). The other picrates which were --f
+
prepared showed no >C=N
C=N< group in the open form, or, in the extreme, on the relative solubilities of the possible picrate forms. Stereochemical Considerations.-Since the bridgehead nitrogen atom in the free bases is capable of inversion, the trans and cis-ring fusions of unsubstituted quinolizidine and octahydropyrrocoline and of 5-oxa-1-azabicyclo [4.4 .O]decane (VIIa’ and VIIa”) and of 7-oxa-1-azabicyclo[4.3.0]nonane (VIIIa’ and VIIIa”) (all as racemates) are interconvertible. The number or degree of nonbonded interactions for the trans forms, VIIa’ and VIIIa’, is smaller than that for the cis fused rings, in analogy with trans-decalin and trans-hydrindan, 1g--2a and hence the trans forms are regarded as the favored conformations (of VIIa and VIIIa). Infrared absorption in the (19) W. G. Dauben and K. S. Pitzer in “Steric Effects in Orgariic Chemistry,” M. S. Newman, ed., John Wiley and Sons,Inc , New York, N. Y.,1956. (20) N . L. Allinger, 1.Org. Chcm., 21, 016 (1956). (21 D. H. R. Barton and R. C. Cookson, Quart. Revs., 10, 44 (1956). (22) G. Quinkert. Expcrwztio, 18, 381 (1957).
OXIDATIVECYCLIZATION OF TERT.-AMINOALCOHOLS
Oct. 5, 1960
VIIa'
11'
HI
VIIIa'
VIIIa"
5151
XIX
2790 (-) and 2840 cm.-' and thus may be described by the more stable tranb configuration XIX.29 The geometry favored for 5-methyl-7oxa-1-azabicyclo [4.3.0]n~nane,~O which was synthesized by the sodium and butanol reduction of l-hydroxyethyl-3-methyl-2-pyridone, on the basis of the 2700-2800 cm.-l region infrared maxima (liquid film), is illustrated by XX. By contrast, the isomeric 6-methyl -7-oxa-1-azabicyclo [4.3.0]nonane (VIIIb), from IVb, showed no bands in this region (CCL). A preference for the cis conformation (VIIIb') would here be consistent with the lower energy form of 8-methylhydrindan. 2o
2700-2800 cm.-l region (general region, not exact limits) may be used to support the presence of the trans conformations by application of the empirical relations which Bohlmann found t o hold in the quinolizidine series, namely, that when a t least two a-hydrogen atoms are trans coplanar to the electron pair on the bridgehead nitrogen atom, a pair of bands appears in this region.23 Specifically, he found that when a trans fused quinolizidine ring was present, there were two absorption bands in xx VfIIb' the 2700-2800 tin.-' region, but when a cis fused quinolizidine ring was present, the doublet was No bands were found in the 2700-2800 cm.-' not observed. 24-26 Two maxima were observed in the 2700-2800 cm.-l region for 5-oxa-1-aza- region of the infrared spectrum of the bicyclic bicyclo [4.4.0]decane in carbon tetrachloride.26 The product resulting from the oxidation of 2-(2',6'trans ring geometry is favorable for explaining the dimethylpiperidin0)-ethanol (IVc), and since the further oxidation of 5-oxa-1-azabicyclo [4.4.0]de- non-bonded interaction will be less in the cis-fused cane with mercuric acetate in aqueous acetic acid ring system with the 2-methyl group in an equa(XII+XIII+XIV) ; trans coplanarity of the torial position, we have tentatively assigned the hydrogen on the a-carbon with the N-Hg bond in the mercurated complex has been shown to be an important steric condition for oxidation in the bicyclic tertiary amine seriesz7 The infrared spectrum (CCL) of 7-oxa-1-azabicyclo [4.3.0]nonane &?/CH3 VIIIC' VIIh' also exhibited bands in the 2700-2800 cm. -l region, consistent with the presence or predominance of stereochemistry represented by VIIIc' (dl pair) the trans conformation VIIIa'. to 2,6-dimethyl-7-oxa-1-azabicyclo 14.3.0Inonane. The trans configuration 11' of the oxazolidine The trans conformation of 6-methyl-5-oxa-1-azamoiety in 3-oxa-6-azatricyclo [6.3.1.02s6] dodecane bicyclo [4.4.0]decane (VIIb') , similar to Irans-9is consistent with the infrared bands in the 2700- methyldecalin, is referred (maxima in the 27002800 cm.-' region (liquid film) and is now favored4 2800 cni.-l region7, but contributions of the conon the basis of probable equilibrium-controlled forniation having cis ring fusion would not be dering closure which should lead to the product having tected by the infrared method. the lower magnitude of non-bonded interactions.20-28 The spectrum of 5-oxa-1-azabicyclo [4.3.0]nonane The ring homolog, 3-oxa-7-azatricyclo ['i.,?. 1.02q- (IX) showed a very weak band of 2710 cm.-' and tridecane, exhibits infrared maxima a t 2740, a strong band a t 2840 cm.-l and in general lower intensity absorption in this region than exhibited (33) F. Bohlmann, Ber., 91, 2157 (1958). The appearance of these bands is actually more general: well-defined bands in the 2700-2800 by the isomeric 7-oxa-1-azabicyclo [4.3.0]nonane cm.-l region are observed for many cyclic and acyclic alkyl tert-amines (VIIIa) under the same conditions. The bicyclo(W. B. Wright, J r . , J . Org. Chem., '24, 1362 (1959); G. F. Smith and [3.3.0]octane systems having cis-fused rings comJ. T. Wr6be1, J. Chem. Soc., 1463 (1860); Prof. C. A. Grab, University parable to pyrrolizidine derivatives. The infrared of Basel, personal communication), However, in the examples presently accumulated the pair o f strong maxima is nof present when spectra of 4-oxa-1-azabicyclo [3.3.0]octane (Xa) and HC-N-CH conformations of the type specified by Bohlmanu 2-methyl-4-oxa-1 -azabicyclo [3.3.0]octane (Xb) I showed no absorption in the 2700-2800 cm.-' cannot exist. region and amide formation by overoxidation was (24) F. Bohlmann and C. Arndt, Ber., 91, 2167 (1958). (25) F. Bohlmann, W. Weise, D. Rahtz and C. Arndt, ibid., 91, 2176 negligible. It is of interest to note that pyrrol(1958). izidine2ais not oxidized under the normal mercuric (26) Complete infrared spectral curves are reproduced in the Ph.D. acetate conditions. thesis of W.K . Musker, University of Illinois, 1959.
dOL //e
(27) N. J. Leonard and D. F. Morrow, THISJOURNAL, 80, 371 (1958). (28) S. P. Findlay, ibid., 7 5 , 4624 (1953).
(29) L. W.Hagnes, University of Illinois, work in progress. (30) Reference 4, see footnote 46 and Experimental for compound and for the name used earlier.
NELSONJ. LEONARD AND W. KENNETH MUSKEK
5152
Vol. 82
TABLE I AMIINOALCOHOLS USEDIN MERCURICACETATE OXIDATIOXS 7 B . p . Compound
'c.
Mm.
ntD
2-Pyrrolidinoethanol 2-Pyrrolidinopropanol 3-Pyrrolidinopropanol 2-Piperidinoethan01 2-(2'-Methy1piperidino)-ethanol 2-(3'-Methy1piperidino)-ethanol 2-( 4'-Phenylpiperidino)-ethanol 2-(2',6'-Dimethy1piperidino)-ethanol 3-Piperidinopropanol 3-(2'-Methy1piperidino)-propanol 3-(2',6'-Dimethylpiperidino)-propanol 3-(3 ',5'-Dimetliylpiperidino)-propanol 2 4 2',6'-Dimethylpiperidino)-l-phenylethanol Benzoate hydrochloride. M.p. 69-72'.
78-79 93-96 100-101 95-96 96-98 98-100 104- 108 114 114 119-120 136 114 116b
18 16 15 20 12 16 0.1 12 19 17 18 13 0.3
1.4703 1.4755 1.4704 1.4775 1.4779 1.4698 1.5442 1.4819 1.4731 1 4771 1.4819 1.4659
I n conclusion, this general oxidative cyclization of aminoalcohols represents one of a series of possible ring closures wherein a nucleophilic group (hydroxyl, amino, enolic, aromatic or heteroaromatic type, etc.) combines with an iminium salt
+
grouping (>C=NC==N+< or 0-H region, indicating that the salt exists in the closed form XVI. The iiew bicyclic c u m pounds and their picrates are listed in Table 11. (35) R . B. Iloffett, J . O r g . Che?n., 14, 862 (1949), R . B. Moffett, Org. Synlheses, 33, 82 (1953). (36) H. G. Kolloff, J. H. Hunter, E. H. Woodruff and R . R . I l o f f r t t , THIS JOURNAL, 7 0 , 3862 (1948). (37) L. H. Andrems and S. M . McElvain, ibid., 5 1 , 887 (1929). '38) C. Vassiliadhs, Bd1. SOL. chim., 4 , 1131 (1937). (39) R. 0 . Clinton, U. J , Salvador, S C Laskomski and .I S Buck, THISJOURNU, 72, 1331 (1950). (4Oj S. M ,1IcKlvain and T . P. C a m e , , ibid., 6 8 , 2R02 ( l R l 6 l
5153
OXIDATIVECYCLIZATION OF TERT. -AMINOALCOHOLS
Oct. 5 , 1960
TABLE 11 FL-SED OXAZOLIDISES A?YD TETRAHI DRO-1,3 OXAZINES Conyerslon,
Product
---B.p.? O C .
Mm.
n f ~
1,
"C.
Derivative
bI.p.,
"C.
A. By mercuric acetate oxidation of aminoalcohols Picrate 79-80 27 15 1 4682 25 4-Oxa-1-azabicyclo[3.3.0]octane(Xa) 32 Picrate 95-96.5 2-Methyl-4-oxa-1-azabicyclo [3.3.0]octane (Xb) 22 11 1.4555 25 53 Picrate 104.5-105 5-Oxa-1-azabicyclo[4.3.0]nonane ( I X ) 37 60-61 14 1.4673 25 0 5 4 7 12 1 4705 24 5 Sone 7-Oxa-1-azabicyclo [43.01nonane (VIlIa) 4; -Picrate 76.5-78 66 IJ 18 1.4675 24 6-Methyl-~-oxa-l-azabicyclo[4.3.0]nonane ( VIlIb) Picrate 150-154 18 1 4670 24 2,6-Dimethyl-7-oxa-l-azabicyclo [4.3.0]nonane (T'IIIc) IJ 84 Picrate 106-108 87 18 1.4750 25 5-Oxa-1-azabicyclo[4.4.0]decane (VIIa) 36 6(lO)-Methy1-5-oxa-l-azabicyclo14.4 Oldecane (VIIb Picrate 81.5-83.5 mainly) 91 15 1.4782 24 63 Picrate 93-94 12 1.4709 25 6,10-Dimethyl-5-oxa-1-azabicyclo[4.4.0]decane (VIIc) 65 105
..-
B.
State
Closed Closed Closed Open Open Closed Closed Open
By sodium and butanol reduction of amidoalcoliol Pield
Product
5-Methyl-7-oxa-1-azabicyclo [4.3.0Inonane (XX)'
%
66
An attempt was made to form trinitrobenzene arid tetrnnitrofluorenone adducts of the bicyclic tetrahydro-l,3-oxazine in glacial acetic acid, ethanol, methanol and benzene. A deep red color developed when the reactants were mixed and heated, but on cooling only amorphous, non-crj-stallizable material could be obtained. The presence of recovered 3-piperidinopropanol in the distillate was confirmed by the formation of a benzoate hydrochloride in 9170 yield which showed no depression of its melting point on admixture with authentic 3-piperidinopropyl benzoate hydrochloride. The high-boiling fraction was shown to be 1-(3'-hydroxypropyl)-2-piperidone by analysis and by comparison with an authentic sample prepared by middlet ton,'^ b.p. 138-139" (1.25 mm.), ?225.3D 1.4949 (reportedL5b.p. 155" (1.5 mm.), n Z 01.4983); ~ 1620 and 1500 cm.-l (lactam), 3400 cm.-l(O-H). Anal. Calcd. for CsH15N02: C, 61.12; H, 9.62; X, 8.91. Found: C, 61.57; H, 9.68; S,8.68. The 2,3-tetramethylene-5,6-dihydro-l,3,4-oxazinium perchlorate (XV) was formed by adding a solution of 50% perchloric acid-50% ethanol to an ethereal solution of the amidoalcohol. The product which separated was recrystallized as colorless needles from ethanol, after one recrystallization, m.p. 178-179" (reported15 m.p. 1 8 5 O ) , Y ~ : : " ~ 1672 ctn.-' (>C=N +C= colorless plates, m.p. 185-186", ~2:'
81-84
21 1 4667 24.5
Picrate
94-98
Open
X-apor phase chromatography of the product showed three peaks: one was shown to be 3-(2'-methy1piperidino)-propanol while the other two can be assumed to be 6-methyl-5oxa-l-azabicyclo[4.4.0] decane (VIIb) and lO-methyl-5-oxa-lazabicyclo[4.4.0]decane (VII, R = H , R'=CHs), with the former presumably predominating by a factor of nine. Distillation of the crude tetrahydro-l,3-oxazine gave the same mixtures of isomers, as indicated by vapor phase chro2700matography, b.p. 91' (15 mm.), TLZ4D 1.4782, ':EY 2800 cm.-l and 1000-1200 cm.-l regions. Anal. Calcd. for C9H1?NO: C, 69.63; H, 11.04; N, 9.02. Found: C, 69.94; H, 11.01; S , 8.97. The picrate was formed in ether and was recrystallized from absolute ethanol as yellow needles, m.p. 81.5-83.5' dec. The infrared spectrum (Sujol) showed no absorption in the 3 and 6p regions. Anal. Calcd. for C25H20S40,:C, 46.87; H, 5.25; N, 14.58. Found: C, 47.14; H, 5.06; S , 14.43. Higher Temperature (95') Mercuric Acetate Oxidation of 3-(2 '-Methy1piperidino)-propanol.-The oxidation of 14.95 g. (0.95 mole) of 3-(2'-meth>1piperidino)-propanol with mercuric acetate was performed a t 95-98' for 2 hours. The total amount of mercurous acetate formed in this time was 42.7 g. (8670). The oxidation was continued for another 5 hours a t 95" and although no additional mercurous acetate was formed, a small amount of mercur) (1.04 9.) was found in the flask. The solution developed a deep yellow color during the course of the reaction. The reaction was worked up in the usual way yielding 8.34 g. (57Yc) of the crude mixture of 6-methyl- and l0-methyl-5-oxa-l-azabicyclo[4.4.0] decanes (in about the same ratio as in the milder oxidation) and 0.76 g. of d mixture of amidoalcohol and amidoester,' b.p. 126" (0.1 mm.), T L ~ 1.4910. ~ D The infrared spectrum of the mixture showed absorption at 3380 cm.-l (0-H), 1738 cm.-' (acetate C=O) and 1620 and 1475 cm.-l (6may membered lactam). X wide shoulder a t ca. 1675 indicate the presence of a small amount of enamine. Mercuric Acetate Oxidation of 3-(2',6'-DimethylpiperiiY+C=N+C=N+< regions, indicating that the picrate exists in the closed form. Anal. Calcd. for C13H16X407: C, 43.82; H , 4.53; N, 15.73. Found: C, 43.90; H, 4.39; N, 15.70. Mercuric Acetate Oxidation of 3-Pyrrolidinopropano1.The oxidation of 12.91 g. (0.1 mole) of 3-pyrrolidinopropanol with mercuric acetate was performed a t 95" for 5 hours. The total amount of mercurous acetate formed in this time was 50.95 g. (98%). The reaction was worked up in the usual way to give 4.31 g. (34%) of crude S-oxa-l-azabicyclo[4.3.0]nonane (377, conversion), and 0.47 g. of high-boiling material. Vapor phase chromatography of the metoxazine showed only a trace of aminoalcohol. The crude product was redistilled to give the chromatographically pure 5-oxa-1-azabicyclo[4.3.O] nonane (IX), b.p. 60-60.5" (14 mm.), ZZ'D 1.4673. The infrared spectrum (10% in carbon tetrachloride) showed no absorption in the enamine or hydroxyl regions. X o multiplet of bands appeared in the 2700-2800 em.-' region, but the characteristic bands appeared in the 1000-1200 em.-' region.
5155
Anal. Calcd. for C7HIINO: C, 66.10; H , 10.30; N, 11.01. Found: C, 66.06; H, 10.42; N, 10.75. The picrate was formed in ether and was recrystallized from absolute ethanol as yellow needles, m.p. 104.5-105'. The infrared spectrum (Nujol) showed no absorption between 1650 and 2600 em.-' or above 3000 em.-', indicating that the picrate exists in the closed form. Anal. Calcd. for C15H163&: C, 43.82; 13, 4.53; N, 15.73. Found: (2,43236; H,4.47; N, 15.85. The infrared spectrum of the high-boiling fraction exhibited strong maxima a t 1495 and 1665 cm.-I (5-membered lactam), 1737 em.-' (ester C s O stretching) and 3410 em.-' (0-H stretching) indicating a mixture of amidoalcohol and amidoester. Mercuric Acetate Oxidation of 5-Oxa-l-azabicyclo[4.3.0] nonane (IX).-The mercuric acetate oxidation of 5-oxa-lazabicyclo[4.3.0]nonane 5-ieldeda small amount of a mixture of amidoester and amidoalcohol. The infrared spectrum was almost identical t o the infrared spectrum of the highboiling material described above. Lithium Aluminum Hydride Reduction of 5-Oxa-1-azabicyclo [4.3.O]nonane.-The reduction of 5-oxa-1-azabicyclo[4.3.0]nonane was performed in the same way as described earlier for the reduction of 7-oxa-l-azabicyclo[4.3 .O]nonane. The aminoalcohol was isolated as the benzoate hydrochloride, yield 90%. No depression of the melting point was observed on admixture with authentic 3-pyrrolidinopropyl benzoate hydrochloride. 2-(4'-Pheny1piperidino)-ethanol.-Ethylene oxide was slowly bubbled into a boiling solution of 28.90 g. (0.18 mole) of 4-phenylpiperidine42 in 100 ml. of methanol until the theoretical amount (0.18 mole) of oxide had been absorbed. The methanol was removed under reduced pressure and the product was distilled in a small Vigreux column. The yield of 2-(4'-fhenylpiperidino)-ethanol was 32.22 g. (87%), b.p. 104-108 (0.1 mm.), n Z 4 D 1.5442; ukk? 700, 1495, 1600 (0-H). cm.-I (monosubstituted benzene) and 3400 Anal. Calcd. for ClaHlpNO: C, 76.05; H, 9.33; N, 6.82. Found: C,75.95; H,9.30; N,6.94. The benzoate hydrochloride was prepared in the usual way and was recrystallized from isopropyl alcohol as colorless plates, m.p. 183-186' dec. Anal. Calcd. for C2oH&lNOg: C, 69.45; H , 6.99; N, 4.05. Found: C,69.51; H,6.90; E,4.11. Mercuric Acetate Oxidation of 2-(4'-Phenylpiperidino)ethanol.-The oxidation of 10.1 g. (0.049 mole) of 2-(4'pheny1piperidino)-ethanol was performed a t ca. 60" for 88 hours. The total amount of mercurous acetate formed in this time was 22.9 g. (90%). The reaction was worked up in the usual way to give 5.31 g. (51%) of crude 4-phenyl-7-oxal-azabicyclo[4.3.0]nonane. The product solidified on distillation. The infrared spectrum of the crude product showed a trace of absorption in the enamine and hydroxyl regions. The crude product could not be recrystallized due to its extreme solubility in all the solvents which were tried (pentane, cyclohexane, ethyl acetate, ether, chloroform and methanol). 2-(2 '6'-Dimethylpiperidino)-l-phenylethanol.-The alkylation of 22.6 g. (0.2 mole) of 2,6-dimethylpiperidine with 24 g. (0.2 mole) of styrene oxide was carried out by an adaptation of the method of Buchwalter and Granatic.14 The mixture of reagents was SkJWly heated to a temperature of 190' over a period of 5 hours and was held a t this temperature for 2 hours longer. The solution was distilled, using a heat lamp to prevent solidification in the apparatus, to give 40.12 g. (86%) of 2-( 2 ',6'-dimethylpiperidino)- l-phenylethanol, b.p. 116' (0.3 mm.). The aminoalcohol was purified by sublimation a t 60" (1 mm.) forming colorless needles, m.p. 69-i2". Anal. Calcd. for ClsHzJVO: C, 77.20; H , 9.94; N, 6.00. Found: C, 77.11; H, 10.21; N,6.13. The hydrochloride was prepared by bubbling anhydrous hydrogen chloride into a n ethereal solution of the aminoalcohol. The precipitate which separated was filtered and was recrystallized from isopropyl alcohol as colorless plates, m.p. 239-240.5' dec. Anal. Calcd. for ClsH&lNO: C, 66.76; H , 8.96; X, 5.20. Found: C,66.81; H,8.77;N, 5.11. (42) C . H. Schmidle and R . C. Mansfield, THISJOURNAL, 77, 4636 (1955).
