Dec. 20, 1052
SYNTIIESIS OF
[CONTRIBUTIONFROM
THE
hf RDIUM RINGSC O N T A I N I N G NITROGEN
CHEMICAL LABORATORIES OF THE UNIVERSITY
OF
6351
ILLINOIS]
The Electrolytic Reduction of Bicyclic a-Aminoketones. A Method for the Synthesis of Medium Rings Containing Nitrogen. I1 BY
NELSONJ. L E O N A R D ,
S H E R L O C K S W A N N , JR., AND
EDWARD I-1. ~ I O T T U S '
RECEIVED AUGUST 4, 1952 The synthesis of eleven- and twelve-membered ring aminoalcohols has been effected by the general method of electrolytic reduction of bicyclic a-aminoketones, using a lead cathode in 30% sulfuric acid a t 60". Specifically, the electrolytic reduction of 6-keto-I-azabicyclo [5.4.0]hendecane led to the monocyclic product, 6-hydroxyazacyclohendecane. The fact that cleavage of the C, -S bond had occurred during the reduction was established by Ii-methylation of the secondary amine product by two independent methods. The similar electrolytic reduction of 7-keto-1-azabicyclo [6.4.0)dodecane produced 7-hydroxyazacyclododecane. The structure of this twelve-membered ring compound was established by N-methylation and by conversion to the symmetrical bicyclic compound, 1-azabicyclo[5.5.0]dodecane.
Our discovery of a new method2 for the production of medium-size3 ring compounds containing a nitrogen atom was applied originally? to the formation of nine- and ten-membered ring aminoalcohols. This method, the electrolytic reduction of bicyclic a-aminoketones in 3Oy0 sulfuric acid a t 60" a t a lead cathode, has now been employed successfully to make eleven- and twelve-membered ring aminoalcohol^.^ Thus, the electrolytic reduction of 6keto-1-azabicyclo[5.4.0]hendecane (I) gave G-hydroxyazacyclohendecane (11), and similar reduction of the higher ring homolog, 7-keto-1-azabicyclo[6.4.O]dodecane (111), gave 7-hydroxyazac~clododecane (IV).
ring closure of the aminodiesters, diethyl piperidine1-6-valerate-2-carboxylate (Va) and diethyl piperidine-1-e-caproate-2-carboxylate (Vb), respectively. Compound Va was obtained by condensation of 6bromovaleronitrile with ethyl 2-piperidinecarboxylate followed by ethanolysis of the ester nitrile. Compound Vb was prepared directly from ethyl 2piperidinecarboxylate and ethyl e-bromocaproate. The closure of the seven-membered ring (Va 3 I) was effected under conditions of high dilution in xylene with potassium t-butoxide.& An over-all yield of 79% of 6-keto-l-azabicyclo[5.4.0]hendecane (1) was realized when the aminodiester (Va) was added over a period of 17 hours. The clo'sure of the eight-membered ring (Vb -+ 111) OH OH was carried out under similar conditions, and 7-keto-l-azabicyclo[6.4.0]dodecane A i 7 (111) was obtained in 24% yield when the S U aminodiester (Vb) was added over a period "vx-I of 54 hours. H The electrolytic reduction of 6-keto-lCH, azabicyclo[5.4.0]hendecane (I) a t a lead VI cathode in a catholyte of 3Oy0 sulfuric acid or-I a t GOo2 gave a product, ClOH21N0, isolated in 71% yield. By analogy with the established formation of nine- and ten-memring amino alcohols v i a electrolytic bNL/ bered reductionI2 this product was regarded as I the eleven-membered ring aminoalcoholI1, CHI I11 VI1 6-hydroxyazacyclohendecane,which would result from I by initial Ca-N cleavage followed by reduction of the carbonyl group to a secondarv alcohol function. The infrared absorptiin spectrum of the CIOH?lNO NCooc2I-I5 compound indicated the absence of a carC!\(CH.).COOC?H: bonyl group and the presence of an hy-sdroxyl (and/or NH) group in the molecule, v together with bonding of the latter. I n HBr VI11 IS order to establish the structure of the prod(a, x = 4; b, x = 5 ) uct as monocyclic, it was necessary only t o The immediate precursors of the bicyclic a- prove the presence of ihe secondary amine func6on. aminoketones I and I11 were the corresponding p- Furthermore, since only Cl(rr)-N1 cleavage (rather ketoesters (not isolated) formed by Dieckmann than Cz-Nl or C11-N' cleavage) in I is consistent with previous observations on the electrolytic reduc(1) Rohm and Haas Company Fellow, 1951-18.52. JOURNAL, (2) N. J. Leonard, S. Swann, Jr., and J. Figueras, Jr., THIS tion of amin~ketones,?*~ a monocyclic product would 74, 4620 (1952). necessarily possess an eleven-membered ring, as in (3) We are using the classification of H. C. Brown and V. Prelog 11. N-Methylation of the reduction product, (see ref. 21 in H. C. Brown, Rosyln S. Fletcher and R. B. Johannesen. i b t d . , 73, 212 (1951)) of medium rings as those containing 8 to 12 ClOHPlNO, with formaldehyde-formic acid6 did members. yield a new compound, CllH23N0, which accord( 4 ) I t has been shown possible to obtain eight-membered ring aminoketones (and thus, certainly, alcohols) via the Dieckmann ring closure (5) N. J. Leonard, s. Swann, Jr., and H. L. Dryden, Jr., i b d , 74,
-L
1 -
pk
I
?--)
Iv$wl -17'7
in dilute solution of the appropriate aminodiester. (See (a) N. J. Leonard and R. C. Sentz, ibid., 74, 1704 (1952), and aloo(b) thisarticle.)
2871 (1952). (6) Orp. Syntheses, 25, 89 (1945).
G252
N12I.SOX
J, LEONARD, SHERLOCK
SWANN, JR., AND
ingly coulcl be assigned structure 1'1, 1-methyl-(iicyclohrndec,me, since the iriir,ired al, wrptioii spectrum iritlicdtrtl the presence of :I methyl group mtl the retention ot the hydroxyl group. LIrthylation of C1~HzlNO(11) with an t-rluiiiiolar amount of methyl iodide in the presence o f potdssiurri bicarbonate gave the same product (VI), as evidenced by absorption spectra and the identity of the picrates of the coinpounds obtained by the two iiiethylation procedures. Direct evidence for the position of the hydroxyl group in I1 and VI was not obtained, but in view of the previou5 work in these laboratories,a there was no reason to expect that the original carbonyl group and the final hydroxyl group would occupy different relative positions. The electrolytic reduction of ;-keto- l-azabicyclo[6.4.0ldodecane (111)gave a single isolable product, CIIH&O, in -427; yield of the purified material. 011 the basis of analogy with the reduction products of the ring homologs of 111, elemental analysis of the \ u s e arid its picrdte, arid infrared spectral data, which indicated the absence of the carbonyl group a11d the presence of OH and/or NH, together with :t definite bonded structure, the reduction product was regarded as the twelve-membered ring arninoalcohol 1Ir, i-hydroxyazacyclododecane. It is of interest to nvte that 11' is the only member of the series of azacycloalkdiiols thus far obtained24 b which is a solid (tii.p. 1 2 i 125'1. Scale molecular ruodels show the strong possibility- o f ititratnolecu1,ir N - &O boiiding, which would result in brautifully syiliiiictric;d c.cinfortii.itiori. Proof that I Y IS thc itrurturc of tlic rc,tluctioii product was not tull! .ittained b y t1ie incthvlatioii sequence. Thc wtioii of fornialdcliy~lcforuiic acid o n the reduction product C11H23N0gCtwL' base which did not have the exact coniposition reyuired for l-methyl-7hydroxyazacyclododecane i 1711) , C12H2&0, although a picrate was obtained which had the correct analysis for this derivative of VII. The infrared spectrum of the base showed the retention of the hydroxyl group arid the introduction of a methyl group; however, the spectrum also indicated the presence of a carbonyl-containing impurity. .in alternative structure proof for IV was followed which indicated both the presence of the secundary amine function and the location of the hydroxyl at C-7. Compound IV was converted by treatment with 4gC,; hydrobromic acid to the bromoamine hytlrobrornide 17111, which was not isolated but was treated directlv with sodium hydroxide to effect iriternal alkylation. The base thus obtained was characterized as I -azabicyclo [5.5.O]dodecane (IX) h p melting point and infrared comparison of the picrate with an authentic sample of l-azabicyclo.?. .i.O]dodecane picrate. Experimental8 Ethyl Piperidine-I-6-valeronitrile-2-carboxylate. -Alkylation? of ethyl 2-piperidinec'irboxylate with b-bromovaleroi 7 j S. J . I.ronard and I V , E. Goode, Tms JOrJRN.4L, 73, 5404 IUTd),. 8 1 All melting points are corrected. We are indebted to Miss Helen Xliklas f o r t h e determination o l t h e infrared spectra and for her a-qistancr in tlirir interpretatirrn, and t o SIrs. Jean Fortney, Mrs. t i a t h e r i n e 1'111 ?iIrii lisrhrr f:rtl R l r Jc,seph N r m e t h and hfiss Emily 11 iilr t h r 111r r . = , i ~ a ' b , . < t i l .
EDWARD H.
LfOTTUS
1'01. 74
nitrile in the mesetice of nnhvdrous notassium mrhonatc .1nal.
Calcd. for C).13H?2X?02:C, 65.51; 11, 9 . 3 1 ~ ;S , I~ouricl: C, G.40; I I , 9.41); S , 12. Ifi:
1 1 .Ti;; ,URD, ti,rj.41).
.11/
