Sept. 20, 1964
ADDITION OF NITRONES TO OLEFINS
(4) cyclooctane would rearrange to 4-vinylcyclohexene in a single step as a deep-seated rearrangement would be necessary to open the four- and five-membered rings in tricyclooctane and close again to give a six-membered ring. Hence, i t is more reasonable to conclude that the 1,5-cyclooctadiene is a n intermediate in the isomerization of tricyclooctane to 4-vinylcyclohexene. The data in Table I show that in the decornpcsition of tricyclooctane the amount of 1,5-~yclooctadienethat remains is a maximum a t the shortest time a measurement can be made. It can be calculated from the experimental first-order rate constants (at 327.3') that the amount of 1,5-cyclooctadiene would go through a maximum a t only 98/1000 sec. after the reaction had started, and the ratio of 1,5-~yclooctadiene to tricyclooctane would have been 0.034. It is much more difficult to decide whether 1,3butadiene is formed via 1,5-~yclooctadieneor directly in the decomposition of tricyclooctane. Mechanistically it can be seen that the pathway which does not involve 1,5-~yclooctadieneas an intermediate requires the simultaneous cleavage of four bonds as is shown.
-4- 11= - - -
The breaking of these bonds in a stepwise fashion does not seem t o lead to a n energetically favored pathway except in the one instance in which 1,5-cyclooctadiene is formed. Hence, i t is reasonable to conclude that the sequence of reactions is
3759
hexane, the isomerization of tricyclooctane appears to be a homogeneous, unimolecular process which is unaffected by the presence of molecules which act as free-radical traps. The activation energy for the reaction is the same as that for bicyclo [2.1.1]hexane within experimental error. While a t first sight it may appear that the tricyclooctane is a more strained system than bicyclo [2.1.1]hexane, molecular models show that the addition of a second two-carbon bridge diagonally to a cyclobutane ring can be achieved with little or no additional distortion. The fact that the activation energy remains the same is either due to all of the strain energy not being available for the rupture of the cyclobutane system during pyrolysis, or due to the increase in strain energy being no more than the experimental error in the activation energy. I t is surprising that the pre-exponential factor in this instance is larger than for bicyclo [2.1.1]hexane by a factor of 3 which corresponds to a difference of more than 2 e.u. of entropy of activation. Since the isomerization of bicyclo 12.1.1]hexane involves a reaction from a bicyclic to an open-chain system while the isomerization of tricyclooctane involves a reaction from a tricyclic to a monocyclic system, a smaller ratio of pre-exponential factors would have been predicted. In view of the complexity in the decomposition of 1,5cyclooctadiene, very little can be said about the mechanism of this process. The ratio of 4-vinylcyclohexene to 1,3-butadiene is seen to decrease with an increase in temperature. From a plot of the logarithm of this ratio vs. the reciprocal of this temperature, it can be calculated that the difference in the activation energies for the formation of these products ( E , - E z ) equals 6.2 kcal./mole. If the activation energy of the firstorder process from 299.5 to S27.3' is identified with reaction 2, then the activation energy for reaction 1 is probably (49 6) = 55 kcal./mole. This value is of the same order of magnitude as the activation energy of 61.8 kcal./mole for the unimolecular decomposition of 4-vinylcyclohexene to two molecules of 1,3-butadiene.g
+
In common with the decomposition of cyclobutane,2 alkyl substituted cyclobutanes,2 and bicyclo [2.1,1]-
[ C O N T R I B U T I O N FROM THE
DEPARTMENT OF
(9) N. E. Duncan and G. J. Janz, J. Chem. P h y s . . 10, 1644 (1952).
CHEMISTRY, W A Y N E S T A T E U N I V E R S I T Y ,
The Addition of Nitrones to Olefins.
DETROIT 2,
MICH.]
Fused Bicyclic Isoxazolidines'
BY NORMAN A. LEBEL,MARYELLENPOST,A N D
JONC JAI
WHANC
RECEIVED J A N U A R Y 24, 1964 The oxidation of N-methyl-N-5-hexenylhydroxylaminewith mercuric oxide and the condensation between ( 2 ) . Other 5-hexenal and N-methylhydroxylamine afforded cis-S-methyl-3-oxa-2-azabicyclo[3.3.0~octane bicyclic isoxazolidines have been synthesized by the condensation reaction employing unsaturated aldehydes and unsaturated ketones. The structures of these compounds were proved by hydrogenolysis and, in some cases, independent synthesis of the amino alcohols. The mechanism of the cyclization reactions are postulated as intramolecular 1,3-additions of an unsaturated nitrone intermediate. The scope of this preparative route t o fused bicyclic isoxazolidines is discussed in terms of reactivity, orientation, and stereochemistry.
The pyrolysis of a mixture of the isomeric N-methyla-pipecoline oxides produced, in addition to the predicted unsaturated hydroxylamine, an unexpected bicyclic base. * This product was identified as N( 1 ) A preliminary communication concerning a part of this work has appeared- J A m Chem Sot, 81, 6334 (1959). This work was reported in p a r t : Abstracts, 137th National Meeting of the American Chemical Society. Cleveland, Ohio, April 1960, p. 8.5-0.
methyl-8-oxa-2-azabicyclo[3.3.Oloctane(Z), and was postulated as having arisen from an unsaturated nitrone intermediate ( 1 ) . The nitrone may have been produced from N-inethyl-N-5-hexenylhydroxylan1ine by an oxidation-reduction reaction. However, this unsaturated hydroxylamine was obtained in good ( 2 ) A C Cope and N A LeRel, J A m C h r m S o c , 81, 4656 ( I $ l R O )
N. A. LEBEL, M. E. POST,A N D J . J. WHANG
3760
yield from trans-N-methyl-a-pipecoline oxide and Nmethylhexamethylenimine oxide, without the accompanying formation of 2 . 2 I n order to verify the occurrence of the intermediate nitrone 1, and to investigate the utility of such reactions as preparative routes to bicyclic isoxazolidines, we have studied the intramolecular cyclization of 1 and other related compounds. I t was recognized that, although several routes are available for the synthesis of aliphatic nitrones such as 1, their preparation in pure form would be difficult. Various types of dimeric products are often ~ b t a i n e d . ~ Several -~ monofunctional, nonaromatic nitrones have been reported, but they are alicyclic comRecently, the preparation of relatively stable &hydroxy nitrones 'has been accomplished. We have made no attempt to isolate the reactive nitrone intermediates described in this work. Compound 1 was generated in situ by two different methods, and its monomeric rearrangement products were studied.
OH
CHa=CH(CHz)aC H' 4
Vol. 86 TABLE I
BICYCLICISOXAZOLIDINES R'NHOH,
R'
RCHO, R = CHa=CH(CHi)r-
CHt=CH( C H d C HaCH=C H ( C HI)r-
(!runs) C HsCH=CH( C H d (cis)
-
=
CHa CzHk (CHdrCH C Ha CHI CrH,
Isoxazol- Yield, ----B.p.-idine V0 OC. 41 79-80 llab 42 95-97 llbC 44 93-95 7d,a 48 70-72 11d 55 77-78 lldu 77 88
Mm. 30 28 25 15 33 26
CHI
l l e h . * . k 42
7880
18
(CHahCH
12aj
45
78-80
15
CHI CIH, (CHdrCH CaH,
12b',P 12cm3P
12d"
65 71 74
120'
31
CHaCH=CH(CHdd(Irons)
CH,
H
\ CHI
/
/"\
(CHdr
I
116-118 20 104-105 16 107-108 12 144-145 ( m . p . )
CHaCHCH-
(+I Anal. Calcd. for C7H13NO: C, 66.11; H, 10.31; N, 11.02. * A n a l . Cakd. for C8H15NO: C, 68.04; H, 10.71; N, 9.92. Found: C, 68.32; H, 10.63; N, 10.14. Anal. Calcd. for CgH17X.O: C, 69.63; H, 11.04; N, 9.02. Found: C, 69.89; Consisted of 68y0 cis isomer 7a and 32Y0 H , 11.30; N, 8.93. trans isomer 7 b as determined by g.c. e Anal. Calcd. for CSHI~NO:C, 68.04; H, 10.71; N, 9.92. Found: C, 67.91; H , 11.00; S , 9.52. f Anal. Calcd. for C S H I ~ N O :C, 68.04; H, 10.71; S , 9.92. Found: C, 68.12; H, 10.71; N, 9.87. IAnal. Calcd. for CrH,7SO: C, 69.63; H, 11.04; N, 9.02. Found: C, 69.94; H, 11.39; h ', 8.82. The composition of the aldehyde used in the preparation was 80% cis- and 20% trans5-heptenal. ' A n d . Calcd. for CsH15SO: C, 68.04; H, 10.71; X, 9.92. Found: C, 67.88; H, 10.92; N, 9.67. I Anal. Calcd. for CIIHPINO: C, 72.08; H. 11.55; S, 7.64. Found: C, 72.31; H, 11.46; N, 7.79. I; The isoxazolidine product was shown by g.c. to consist of approximately 80% lle and 20% llc. P u r e lle was separated by preparative g.c. I Anal. Calcd. for C l I H ~ , S O :C. 72.08; H , 11.55; N, 7.64. Found: c, 72.25; I%, 11.67; S , 7.83; [.I]"D -34.2' (4.25, MeOH). Anal. Calcd. for CI2Hz3S0: C, 73.05; H, 11.75; N, 7.10. 4 n a l . Calcd. for Found: C, 73.36; H , 11.51; S , 7.29. C , : I H ~ ~ X OC,: 73.88; H , 11.93; N, 6.63 Found: C. 73.96; €-I, 11.85; S ,6.72. Anal. Calcd. for CIIHZPNO:C, 78.32; H , 9.45; N, 5.71. F o u n d : C , 78.23; H, 10.02; N, 5.75. p G.c. analysis showed that 12c consisted of 73-80y0 of a major isorrier (trans,trans), 13-147, of a cis isomer (as indicated by n.1n.r analysis), and 4-15% of an unidentified component. Cornpound 12b was %'yopure when prepared at room temperature, h u t contained 12y0 of an isomer with refluxing toluene as solvent. Z ,
Oxidation of an ether or alcoholic solution of Nmethyl-N-5hexenylhydroxylamine (3) with excess mercuric oxide afforded 2 in 18-24y0 yield. The isoxazolidine was identified as 2 by its infrared spectrum, by gas chromatography, and by preparation of derivatives. In addition, 5-hexenal (4) was isolated and characterized as its 2,l-dinitrophenylhydrazone. Alternatively, 2 was prepared by the condensation of 5-hexenal (4) and freshly prepared N-methylhydroxylamine (Table I ) . Further proof for the structure of 2 was furnished by product was identified as N-methyl-cis-2-hydroxyzinc anti acetic acid hydrogenolysis. The amino alcohol methylcyclopentylamine ( 5 ) by comparison with an authentic The reactian was extended to include the homolog 7. The mercuric oxide oxidation of N-methyl-N6-heptenylhydroxylamine (6) afforded cis-N-methylcH3 8-oxa-7-azabicyclo[4.3.O]nonane(l-methyloctahydro5 anthranil, 7) in 18Y0 yield. From the neutral fraction of this oxidation it was possible to isolate tiheptenal (8) as its 2,4-dinitrophenylhydrazone. An authentic sample o f 8 was prepared from the 1' k known 5-hexen-l-ol.Io The condensation of 8 and R N-methylhydroxylamine proceeded smoothly to produce an isoxazolidine mixture which was shown to be identical with 7 by infrared and gas chromatographic analyses, and by comparison of derivatives. The isolation of the unsaturated aldehydes 5hexenal (4) anti 6-heptenal (8) in the oxidation reactions in over 6Oy0 vield as their derivatives lends a.dditional support to the preferential formation of the most highly substituted nitrorie groups.6 '!Oi
l i I
; 1.1 I s (:lH). C - C f j , for 48, L W V doublets ( J i = 0 , J L = R 5 ) . 0~ CFi; 4ti : J = , N ('fia. 1.0fia. C - C H I , minor iwmer: 4.+Zd h i o a d , O - C H * ; 2.45. S C H I . 1.14, C - C ' I I z . Chemical shift values arr 1:- p . p m ro,lpliny rimstants in c I) s.
3763
pressure; hydrogen and Raney nickel a t ca. 30 p.s.i.g.; lithium aluminum hydride in tetrahydrofuran solvent; and zinc and acetic acid. These reactions are summarized in Table 111. Reductions of the methiodides have also been carried out efficiently under catalytic conditions and with lithium aluminum hydride (Table 111). Several other modes of cleavage of isoxazolidines-which when coupled with the intramolecular addition reaction represent synthetic routes of wide utility-have been observed and will be discussed in a later manuscript. The infrared spectra of the pure isoxazolidines are O-H, devoid of absorption bands in the N-H; C=O, and C=C regions, but are rather complex in the fingerprint region. However, relatively consistent bands occur a t about 950 cm.-', a region that has been single bond generally assigned to the normal N-0 frequency.22 Another absorption band that has occurred repeatedly is found in the vicinity of 1070 cm.-'.
Experimental23 N-Alkylhydroxy1amines.-The zinc dust-ammonium chloride procedure of Beckman*' for the reduction of nitro compounds to hydroxylamines was employed. N-Methylhyroxylamine hydrochloride was obtained in yields of 33-40y0, m.p. 87" (lit.*' m.p. 83-83.5'). after two recrystallizations from ethanol. Prior t o use, pure 5-methylhydroxylamine, b.p. 60-63" (20 mm.), n z s ~ 1.4151 (lit.24b.p. 62" a t 15 mm., n% 1.4164), was obtained by treating a methanol solution of the hydrochloride with an equivalent amount of sodium methoxide, followed by distilkatiori. m.p. 59"), was simiN-Ethylhydroxylarnine, m.p. 58-59" larly obtained, as was N-isopropylhydroxylamine, n1.p. 85-86" (lit." m.p. 89'). The N-ethyl and N-isopropyl compounds were stored as ether solutions, and were sublimed just prior to use. N-Phenylhydroxylamine was prepared according to the prncedure given in ref. 25. Aldehydes.-Four of the olefinic aldehydes employed a5 starting materials for the ring-closure reaction were synthesized oiu reaction of a Grignard reagent, prepared from the homologous bromide, with ethyl orthoformate. Steam distillation o f the diethyl acetal from IOf,;,; aqueous sulfuric acid gave the desired aldehyde. Alternatively, reduction of the nitrile with diisobutylaluminum hydride has also been employed .% trans-S-Heptenal.-trans-?-Hexen-l-ol (98"; pure by gas chromatography' was prepared in 83r; yield by cleavage. o f 2bromo-3-methylletrahydropyran with sodium27; b.p. 102" ( 7 8 mm.), n% 1.4396 (lit.% b.p. 158-159", l t 2 0 ~1.4102). T h e reaction of 100 g. (1.0 mole) of this alcohol with phosphorus tribromide and pyridine in ethere9gave 89 g. (55r;) of trans-Ibromo-3-hexene, b.p. 98-100" (95 mm.j, n% l.l(i58 (lit.?' b.p. 63+5" a t 35 mm., n% 1.1652). The Grignard reagent was prcpared from 32.6 g. (0.2 mole) of the bromide, and was allowed to react with freshly distilled ethyl orthoformate." The rcwction mixture was hydrolyzed with dilute sulfurir acid, the upper oily layer was taken up in ether, and the ether w i s reinoved b y distillation. Steam distillation from IOf,; sulfuric acid ailti subsequent work-up gave 8.5 g. (38keri irp i n peritanr. .-\ftcr back-washiiig with water, thc ; w ~ t a n rsaiutioii was tlrieci and concentrated. I>istillation af'cj-drc! 0.98 g. ( 3 F i j of the isoxazolidine 2 , b.p. 62-f;4' (20 nirn.),
51.93 45.40 46.87 53.86 45.40 46.87 45.40 51.93 49.51 49.51 4428 50.70 51.81 55.69 48.24 45.40 46.87
%---Found
51.77 45.66 47.15 53.67 45.58 46.79 45.70 51.77 49.66 49.37 44.35 50.74 51.99 55.54 48.47 45.62 47.13
-
-Hydrogen, Calcd.
7.42 4.90 5.25 7.81 4.90 5.25 4.90 7.42 5.87 5.87 7.44 6.15 6.41 5.53 5.57 4.90 5.25
YoFound
7.16 4.85 5.37 7.68 5.04 5.20 5.00 7.16 5.79 6.13 7.65 6.17 6.45 5.58 5.81 5.07 5.48
-
Y N i t r o g e n , %CalCd. Found
6.06 15.13 14.58 5.71 15.13 14.58 15.13 6.06 13.59 13.59 4.31 13.14 12.72 11.81 14.07 15.13 14.58
6.04 15.00 14.27 5.71 14.94 14.41 14.65 6.04 13.67 13.64 4.53 13.15 12.84 11.72 13.94 14.83 14.36
identical with that obtained previously. The product was found to be homogeneous by gas chromatography on column A at 138". Method B. Toluene. trans, frans-l,3,3,6-Tetramethyl-3a,4,5,6,7,7a-hexahydro-2, 1-benzisoxazoline ( 12b ) .-A mix turc of 10.0 g. (0.06 mole) of citronellal and 200 ml. of toluene was heated to reflux in a flask to which was attached a Stark water separator. A solution of 5 . 0 g . (0.11 mole) of N-rnethylhydroxylamine in 50 ml. of toluene and 10 ml. of absolute methanol was added dropwise over a period of 2 hr. The theoretical amount of water was collected (1.2 ml.) and the mixture was heated under reflux for an additional 16 hr. The cooled solution was extracted with six 35ml. portions of lo?& hydrochloric acid. The acid extract was washed with ether and then was basified with 20'); sodium hydroxide solution. The liberated organic product was extracted with ether. The combined ether extract was washed with water, dried (MgSO,), and concentrated. Distillation of the residue through a spinning-band column afforded 8.2 g. (707;) of the isoxazolidine 12b, b.p. 102-104" (16 mm.). The product was found by g.c. (column C at 162") to consist of a major isomer (12b, 86%)contaminated with 12% of a second isomer. Benzene was also employed as a solvent in these condensations. The yields were usually lower than those obtained with toluene under comparable conditions. Ethanol at reflux temperature for 24 hr. also gave good yields. Method C. Ethanol a t Room Temperature. Preparation of 12b.-A solution of 3.05 g. (0.065 mole) of X-methylhydroxylamine in 50 ml. of absolute ethanol was added dropwise with stirring t o a solution of 12.81 g. (0.07 mole) of citronellal in 200 ml. of ethanol. After 24 hr., the mixture was acidified to pH 2 and was concentrated at reduced pressure. The acidic solution was washed thoroughly with ether t o remove citrotlellal. Basification and extraction with ether, followed by drying and concentmtion. gave the crude product 12b; g.c. analysis indicated 97% punty; contamination by 3YGo f an isomer was noted. Distillation afforded a 25yp yield of 12b, b.p. 102-103" (16 mm. j , n"D 1.4607. Similar results were obtained with toluene as a solvent. The products from these condensation reactions are summarized iu Table I.
czs,frans-l,3,3,7-Tetramethyl-Z-oxa-l-azabicyclo[3.3.0]octane (24).-Condensation between 2,6dimethyl-5-heptenal( melanal,3i 3 9.) and 2.5 g. of N-niethylhydroxylamine i n toluene gave 1.91 g. (5If,%) of isoxazolidine 24, b.p. 101" (45 rnm.), R = D 1.1539. The picrate Is given in Table 11. cis-1 .&Dimethyl-2-oxa- I-azabicyclo [3.3.O] octane 126).--Coridensation uf 5.52 g. (0.05 mole) of 6-hepten-2-one ( 2 5 ) and 6 g . (0.1 inole) N-methylhydro~ylaniinr by t h e toluene method afforded 5.58 g. (80";)of isoxilzolidine 26, b.p. 87-88" 140 nim.j, n2% 1.462i; g.c. un column C a t 1 5 0 " showed only onr coniponext. . - i d . Calcd. for CXiJ>&O: C , 68.04, H, 1 0 . 7 1 ; h, 9 92. Found: C ,68.16; !I, 10 3:; S , :0.20. The picrate is given in Table J I . -. . ... _ _ _ _ _ _ ~~
(35) C:enervesly srlppiied by Professor L. Friedman, Caw Ins?ltii!? of rcchaoirigv.
N. A. LEBEL,M. E. POST,AND J. J. WHANC
3766
Vol. 86
TABLE I11 AMINOALCOHOLS FROM REDUCTION OF ISOXAZOLIDINES Amino alcohol
5
Procedure'
A Ab A
45-46d 104-104.5d
67.08 71.30
66.93 71.38
11.96 12.51
11.73 12.58
9.78 7.56
9.79 7.43
77-81 ( 1)" 75-78 (0.5)" 88-90 (2)" 12+13Od
72.30 72.30 73.18 78.86
72.59 72.18 73.00 79.04
12.64 12.64 12.75 10.19
12.63 12.47 12.58 10.44
7.03 7.03 6.57 5.66
6.94 7.04 6.62 5.75
73.87
73.59
11.92
11.83
6.63
6.92
33
F
Poor
88-90 (2)"
34
C
80
&71(1.3)"
35
C
88
70 (1.5)"
B C D
E B E
I
k,
X
--Hydrogen. yoCalcd. Found
C
H , Rz = CH,
-Nitrogen. YoCalcd. Found
Found
Properties
32 85 56 45 82 41 81 78 72 97
9 31, RI
" HNIO
%
7%-
-Carbon, Calcd.
Yield,
CH,
I Procedure A = Zn-HOAc; B = LiAlH. in T H F ; C = Hs, Pd-C; C = HI-Pt; E = Hz-Pt reduction of the methiodide; F = LiAlH, reduction of the niethiodide in T H F suspension. Properties are those of the alcohol from reduction of N-cis-2-carboxycyclohexylforinanride (IO). B.p.. "C (nim.). M.p., "C.. 1 ,'la-Dimethyl-Ja ,4,5,6,7,7a-hexahydro-2, 1-benzisoxazoline (28).-Frorn 8.3 g. (0.066 rnole) of 7-octen-2-one (27)and an excess of N-nietliylhydrosylainitie there was obtained 7.08 g. (69',';) of 28, b.p. 105-10Go (37 mtn.), n f m1.4768; ~ g.c. on column C a t 150" indicated that 28 was homogeneous, but the n.m.r. spectrum (ref. 21) suggested two isomers. Anal. Caled. for C9H17NO: C, 69.63; H , 11.04; N, 9.02. Found: C, 69.64; H. 11.16; N, 8.89. The picrate is given in Table 11. Isoxazolidine Derivatives.-Several derivatives were appropriate for thc characterization of the isoxazolidines, and those eniployed arc summarized in Table 11. Picrates were usually recrystallized from 95'& ethanol, methiodides from acetone or alcohol-ether tnisturcs, hydrogen oxalates from ethyl acetate or rnetli;inol -ethyl acetate mixtures. The Condensation of Citral and N-Ethylhydroxylamine .-Employing the usual apparatus for the cyclization reaction,' 11.1 g. ( 0 . 0 7 3 rnolc) of citral in benzene was treated with 4.45 g. (0.073 mole) of N-etliylhydroxylamine. The theoretical amount of water was collected and the reaction mixture was worked up as described previously. There was obtained 4.58 g. of product, b.p. 82- 90' (13 mm.), n m 1.4721. ~ A viscous residue (2.78 g.) reniained. The distillate was a clear liquid which became dark 011 stailding. I t gave positive triphenyltetrazolium chloride and 2,44initroplienyIhydrafone tests. For purification, the crude prtxluct was dissolved in 25 nil. of 12c/b hydrochloric acid and the solution was hcatcd a t 100' for 2 hr. After cooling, the solution was extracted with ether and basified; the product was extracted with pentane. Distillation gave 2.2 g. (15%) of l-ethyl, 3,3,fi-trirtiethyI-cis-3a,4,5,7a-tetrahydr~~, 1-benzisoxazoline (29), 1.4752. The liquid material b.p. 10%-110" (15 mm.), n% was sllown to be homogeneous by gas chromatography on column A a t 182'; infrared bands a t 1670 (m), 1380 (s), 1365 ( s ) , 1230 (m). 1235 (m). 1200 ( m ) , 1165 (s), 1075 ( m ) , 985 (w), 965 (w), 935 (s), 906 (s), 875 (s), 850 (m), 785 (m), 720 (m) cm.-'. Other preparations. avoiding the acid purification procedure, afforded 4 : 1 mixtures of c i s (29) and trans isomers, respectively, in yields up to 27y0. :lnal. Calcd. for Cj2H2lNO: C, 73.79; H, 10.64; N, 7.17. Found: C , 73.50; H, 10.94; N, 7.29. The picrate was recrystallized twice from ethanol; m.p. 136137". .4na/. Calcd. for C18H2rSrOs:C, 50.91; H, 5.70; N, 13.20. Found: C, 50.99; H, 5.77; N , 13.24.
The methiodide formed readily and was recrystallized from acetone; m.p. 158.5-159". Anal. Calcd. for C1aH2,NOI: C, 46.29; H, 7.17; N, 4.17; I,37.63. Found: C, 46.16; H, 7.41; N, 4.33; I, 37.50. A solid remained from the distillation of 29 and weighed 0.18 g. It was recrystallized twice from ether-pentane mixtures, m.p. 180-181' and was formulated as N-ethyl-4,9,9-trimethyl-&oxa-7azabicyclo 14.3.O] nonan-4-01. Anal. Calcd. for ClrH~3NOz:C, 67.56; H, 10.86; N, 6.59. Found: C,67.21; H , 10.82; N,6.94. The Condensation of Citronellal with N-Phenylhydroxylamine. Twenty-five grams (0.162 mole) of citronellal was condensed with 17.7 g. (0.162 mole) of N-phenylhydroxylamine. The pentane extract was dried and concentrated and a crystalline solid (9.1 g., 23o/c) was obtained. After two recrystallizations from aqueous ethanol followed by sublimation, the product, N-phenyl-trans,~rans-4,9,9-trimethyl-8-oxa-7-azabicyclo(4.3 .O] nonane ( 12e), had 248 ma ( e 7850). m.p. 147-148', N-czs-2-Carboxycyclohexylformamide( lO).-cis-Hexahydroanthranilic acid was prepared by hydrogenation of anthranilic acid over 5% rhodium-on-alumina or 10% rhodium-oncharcoal catalyst.% It was recrystallized from aqueous acetone; m.p. 232-233' dec. (1it.a'm.p. 234-234.5' with dec.). A mixture of 3.0 g. (0.021 mole) of cis-hexahydroanthranilic acid and 1.28 g. (0.025 mole) of 90% formic acid was heated for 4 hr. The resulting solution was kept at room temperature for 2 hr. and crystals were deposited. The product was recrystallized twice from water to furnish 1.93 g. (54%) of product, m.p. 2W201". An analytical sample was obtained by sublimation, m.p. 201". Anal. Calcd. for CsHlaNOz: C, 56.12; H , 7.65; N, 8.18. Found: C,56.25; H , 7.93; N, 8.21. Hydrogenolysis of the Isoxazolidines .-Several different procedures were found suitable for the reductive cleavage of the isoxazolidines or their methiodides. These procedures are summarized below. Zinc and Acetic Acid Reduction. N-Methyl-trans,trans-2-(2'hydroxy-2 '-propyl)-5-methylcyclohexylamine -(3 1).-A solution of ,500 mg. of isoxazolidine 12b in 0.5 ml. of glacial acetic acid was added to a stirred suspension of 420 mg. of zinc dust in 4 ml. of 1 : l acetic acid-water. After 5 hr. a t 50450". the mixture w a s (36) We wish to thank Professor A. C . Cope for informing us of a procedure for the preparation of this acid. (37) S . Hunig and H . Kahanek, Bcr., 86, 518 (1953).
Sept. 20, 1964
PHENONIUM
3767
IONS I N WAGNER-MEERWEIN REARRANGEMENTS TABLE IV DERIVATIVES OF AMINOALCOHOLS
Compound
M . P . , OC.
5 oxalate 9 hydrogen oxalate 9 bisbenzoate 30 picrate 14 picrate 31 hydroiodide 34 bisbenzoate 35 bisbenzoate
181-181.5 104-105 118119 154-155 196-197 203-204 94.595 117-1 1 7 . 5
-Carbon. Calcd.
%-
THE
-Hydrogen, Calcd.
%-
-Nitrogen.
$4-
Found
Calcd.
Pound
8 ..04 6.00
8.13 5.77
55.15 51.49
54.98 51,72
9.26 8.21
9.20 8.13
51.57 55.45 4.36 75.18 75.58
51.86 55.74 43.91 75.11 75.23
6.83 5.93 8.01 7.17 7.45
6.59 6.05 8.02 7.39 7.64
filtered and the excess zinc was washed with 5YG hydrochloric acid. Basification, followed by continuous extraction with methylene chloride, gave 354 mg. of crude product. Chromatography over a small quantity of alumina and elution with ether gave 277 mg. (56Y0) of the amino alcohol 31, m.p. 104-104.5". Catalytic Hydrogenation. A. Palladium-on-Carbon. Reduction of 12b to 31.-A solution of 500 mg. of 12b in 15 ml. of ethanol was added t o 200 mg. of prereduced 1OyGpalladiumcarbon catalyst in 10 ml. of ethanol; 90% of the theoretical amount of hydrogen was taken up in 45 min. 'After filtration and evaporation of the solvent, 140 mg. of crude product was obtained. Chromatography on alumina gave 415 mg. (81.5y0) of 31, m.p. 104-104.5". N-Phenyl-t runs ,trans-2-( 2 '-hydroxy-2 '-propy1)J-methylcyclohexylamine (14).-Hydrogenation of 1.4 g. (0.00s mole) of 12f in the presence of 0.33 g. of lOyopalladium-carbon catalyst gave 1.37 g. (97yG)of a solid amino alcohol 14, m.p. 121-123'. Recrystallization from hexane raised the melting point t o 129-130'. Catalytic Reduction. B. Platinum Oxide. Reduction of 12b to 31.-A solution of 500 mg. of isoxazolidine in 25 ml. of ethanol was hydrogenated in the presence of 250 mg. of prereduced platinum oxide. After 18 hr., an additional 195 mg. of catalyst was added. The total uptake of hydrogen amounted to 66Cr,. The crude product was chromatographed to give a 59v0 yield of amino alcohol 31, m.p. 104-104.5". N-Ethyl,N-methyl-trans,trans-2-( 2 '-hydroxy-2 '-propyl)-5methylcyclohexy1amine.-The methiodide of 12c (6.13 g., 0.19 mole) was hydrogenated in 200 ml. of ethanol with prereduced platinum oxide as the catalyst. Evaporation of the solvent gave a crystalline hydroiodide of the amino alcohol, m.p. 203-204'. The salt was dissolved in water, basified, and extracted with methylene chloride. Distillation gave a liquid amino alcohol 32, b.p. 88-90" ( 2 mm.), n 2 * D 1.4669. Lithium Aluminum Hydride Reduction of 12b.--,4 mixture of 1 g. of 12b, 0.2 g. of lithium aluminum hydride, and 50 ml. of tetrahydrofuran was heated a t reflux for 20 hr. Work up was effected by the addition of 0.2 g. water, 0.6 g. of 157, potassium hydroxide solution, and 0.2 g. of water. After removal of the salts by filtration, the filtrate and washings were dried and concentrated to give 0.86 g. of crude material. Chromatography on alumina gave 0.56 g. of recovered starting material (54.5%) and 0.46 g. (45.5%) of amiiioalcohol31, m.p. 104-104.5° The amino alcohol products and derivatives are given in Tables 111 and IV. N ,N-Dimethyl-trans ,trans-2-( 2 '-propenyl)-5-methylcyclohexylamine (17).-A mixture of 5.97 g. (0.025 mole) of amino alcohol
[CONTRIBUTION N O . 1619 FROM
Found
12.67 11.76 4.26 3.99 3.83
12.63 11.80 4.43 3.88 3.66
31 and 10 ml. of acetic anhydride was heated a t reflux for 10 hr. The solution was chilled and was basified with 20y0 potassium hydroxide solution. After extraction with ether, the extract was dried and concentrated. Distillation gave 4.23 g. (75y0) of 17, b.p. 69-7Oo(3.5mm.),n % ~1.4658, [ a ] " D +9.15". Anal. Calcd. for ClrHpaN: C, 79.48; H , 12.76; N, 7.73. Found: C, 79.52;. H , 13.01; N, 7.29. The n.m.r. spectrum and infrared spectrum of 17 confirmed the presence of the terminal methylene group. The picrate was prepared and was recrystallized from 95Yo ethanol; m.p. 153.5-154'. Anal. Calcd. for C18H2&101: C, 52.68; H, 6.39; N, 13.65. Found: C,52.77; H,6.33; N, 13.94. N,N-Dimethyl-1-methylamine ( 18).-The amine 17 was hydrogenated in methanol solution in the presence of 107, prereduced Pd-C catalyst. Upon distillation, there was obtained 0.69 g. (69%) Of 18, b.p. 75-76" (4.9 mm.), 7l"D 1.4565, [ a ] " D -49.6" (lit."b.p.85"at7mm.,n"D1.4552, [ a ] " D -51.20'). Trimethyl-1-methylammonium Iodide.-The methiodide of 18 was prepared and was recrystallized from acetone; m.p. 192.5-193.5, [ a ] % D ( H 2 01.55) , -18.7' (lit."m.p. 192.3-192.5'. 193-194', [ a ] " D -40.5", -37.6'), m.m.p. 193-194'. N,N-Dimethyl-1-menthylammonium Picrate.-The picrate of 18 was prepared; m.p. 128.5129'. The picrate of synthetic N,N-dimethyl-l-menthylamine" ( [a] a~ -47.6') melted a t 127.5128', m.m.p. 127.5-128'. Relative Configurations of Isoxazolidines 1IC and 1le.-Samples of 131 mg. each of isomeric isoxazolidines l l c and l l e were hydrogenated with 1OyoPd-C in absolute ethanol to the corresponding amino alcohols (infrared spectra different). Each amino alcohol was acetylated to the diacetyl derivative (infrared spectra different). The diacetates were saponified with 1 N sodium hydroxide a t room temperature and the N-acetylamino alcohols were isolated (infrared spectra different). Oxidation with potassium dichromate and sulfuric acid in a two-phase system with ether gave h'-methyl-S-acetyl-czs-2-acetylcyclopentylamine (15) (infrared spectra nearly identical). The 2,4-dinitrophenylhydrazones were prepared and were recrystallized from benzene; m.p. 189-190' (from l l c ) , 189-190' (from l l e ) , m.m.p. 190'.
Acknowledgment.-This work has been supported by a generous grant from the National Science Foundation, and, in part, by the Research Corporation. (38) N. L . McNiven and J Reed, J . Chrm SOC, 153 (1952); A C. Cope and E. M. Acton. J . A m . Chcm. S O L ,80, 3.57 (1958).
DEPARTMENT OF CHEMISTRY O F THE UNIVERSITY LOS ANGELES, CALIF.]
OF
CALIFORNIA A T
LOS
ANGELES,
Phenonium Ions as Discrete Intermediates in Certain Wagner-Meerwein Rearrangements BY DONALD J. CRAM RECEIVED FEBRUARY 12, 1964 The case is stated for the existence of phenonium ions in certain Wagner-Meerwein rearrangements.
Thirteen years after the original evidence for the existence of ethylene phenonium ions was published,' H. c. Brown has in print2 questioned the validity of the ( I ) (a) D. J. Cram, J . A m . Chrm. Sor.. T I . 3863 (1949); (1949).
(b) 71, 3875
original interpretation^.^ This event requires a summation of the case for the existence of ethylene pheno( 2 ) H . C . Brown, "The Transition State." Special Puhlication S o . 16. The Chemical Society. Imndon. 1W2. p. 140. (3) In numerous seminars. colloquia. and symposia since 1!#58. H . C Brown has enthusiastically attacked bridged phennnium ion interpretations
