mon, it has been shown3 that q5t can be represented as a linear function of the solution composition, or d't = d'b
+
(@a
- d'b>Na = d'a f (d'b - #'a)Nb
(4)
Q"
If dt is a linear function of a or b, then log (Y& would also be expected t o be, such that
I
+
log (?*It = log (?*)a [log ( Y d b - log (Y*)alNb ( 5 ) Substitution of eq. 4 and 5 into eq. 3 yields, after rearrangement
+
P qH2-c00cH3
Q0
N-C H2CH2COOCH3
(AEl/z)obsd = { 2 9 w - Nb) log ( Y d a Nb 1% (Y+)bl 4 . 6 2 ~ [ ( 1- Nb)d'a f Nbd'b]} (6)
+
Now, 1 (AE'/z)obsd
=
Nb
is equal t o Na, and eq. 6 becomes
+
tNaL29.5 log (Yda f 4.62Wa1 NbL29.5 log ( Y + h 4.62@b]]
+
(7)
qy::;fsH5 II
0
m
X
Y
q$'
O0CH3
a n d since [(AEl/z)obsdlb
=
(29.5 log
(Y&)b
+ 4.62 md'b}
(8)
then eq. 7 becomes identical with eq. 1 when one considers that (AE'/l)obsd = (Ei/z)obsd- ( E I / ~ =o.) ~ (3) R. A . Robinson and R. H. Stokes, "Electrolyte Solutions," 2nd Ed., Butterworths, London, 1959, p. 437.
Douglas E. Sellers, Nicholas E. Vanderborgh Parkinson Laboratory, Southern Illinois University Carbondale, Illinois Received May 23, 1964
The Synthesis of Apo-P-erythroidine
XI a, R=n-C4Hg b, R't-CqHg
m
0
xm
Sir : This synthesis was made possible by an interesting, In their work directed toward the elucidation of the partial reversal of the Fischer indole ring closure in structure of P-erythroidine, a physiologically active alkathe 1,2-dihydropyrroIo[3,2,1 -hi]indole series and conloid isolated from several species of Erythrina, Boekelstitutes a practical synthesis of 7-substituted indolines. heide and co-workers obtained a rearranged demethoxy Indolines (I) was nitrosated and then reduced with derivative which they called apo-@-erythroidine. The lithium aluminum hydride to give 1-aminoindoline7 latter compound, to which structure XV was assigned,Ia (11) in 70% yield. Treatment of the substituted hydrawas of interest for its unusual tetracyclic structure, zine I1 with either ethyl benzoylacetate or ethyl acetoits relationship t o the parent alkaloid, and its own acetate gave the hydrazones IIIa,b, which were unstable physiological activity. Several attempts at synthesizing and could not be readily characterized but were conapo-@-erythroidineor its analogs were unsuccessfu12-4 ; verted, by sulfuric acid in absolute ethanol at remost noteworthy with respect to the results reported flux, to 4-phenyl-5-ethoxycarbonyl-1,2-dihydropyrroloin this communication was the observed4 inactivity of [3,2,1-hi]indole (IVa) in 83% yield [m.p. 137-138'; the carbonyl of l-methyl-2,3,4,5-tetrahydro-5-0~0-1-A,,CHpOH 309 (e 9500) and 251 m p (IS,OOO)], and t o the benzazepine toward normal addition reactions (premethyl analog IVb in 54% yield [m.p. 89-90'; "':A: sumably due to nitrogen-carbonyl resonance inter297 (e 14,000), 240 (22,600), and 220 mp (38,OOO)l: action) and the well-known3 difficulty in preparing 7This ring system was previously synthesized for the substituted indolines. first time by a Fischer reaction on the hydrazone of We now wish t o report the synthesis of apo-8I-aminoindoline and ethyl pyruvate t o give the 1,2erythroidine (XV) and isoapo-P-erythroidine (XVI).5 dihydro-4-ethoxycarbonyl derivative.* When IVa was treated with sulfuric acid in aqueous ( I ) (a) See V. Boekelheide, J. Weinstock, M. F. Grundon, G. L. Sauvage, and E. J. Agnello, J . A m . Chem. Soc., 75, 2550 (1953), for a ethanol at reflux, we obtained 7-phenacylindoline, summary of the structural work o n 8-erythroidine. (b) Also see V. which was acetylated t o facilitate isolation and give 1Boekelheide in "The Alkaloids," Vol. VII, R. H. F. Manske, Ed., Academic Press Inc., New York, N. Y . , 1960, pp. 201-227, for a acetyl-7-phenacylindoline (V) in 9 0 % yield (m.p. 136recent summary of the structural work on the Erythrina alkaloids. 137'). This hydrolytic opening is unknown in simpler (c) F. Koniuszy and K. Folkers, J. A m . Chem. Soc., 7 3 , 333 (1951), systems and presumably is the result of considerable isolated a derivative of @-erythroidine. The latter differed in melting point and particularly in optical rotation from the apo-8-erythroidine steric strain in the 6,5,5-fused ring system of IV. isolated by Boekelheide, e f a1.,la and thus was apparently impure or not the same compound. (2) V. Boekelheide and W. G. Gall, J . Org. Chem., 19, 504 (1954). (3) W. G. Gall, B. D. Astill, and V. Boekelheide, ibid., 20, 1538 ( I955 ) . (4) B. D. Astill a n d V. Boekelheide, J . A m . Chem. SOC.77, 4079 (1955).
( 5 ) Isoapo-@-erythroidine is an isomer of apo-@-erythroidine obtained when the latter is chromatographed on alumina; see ref. l a . ( 6 ) H. Rapoport and J. R . Tretter, J . Org. Chem., 23, 248 (1958). (7) Satisfactory elemental analyses were obtained for all compounds reported herein. (8) H. Rapoport and J. R . Tretter, J . A m . Chem. Soc., 80, 5574 (1958).
Communications to the Editor
1397
Reaction of the phenacylindoline V with hydrazoic violet spectra, and thin layer chromatography; apo-(3acid in chloroform followed by alkaline hydrolysis of erythroidine, m.p. 128-129' (lit.Ifi 132-132.5'); v:?'~ the resulting mixture of amides gave a 52% yield of 71737 cni.-'; 345 (e 3500) and 240 mp (24,500); isoapo-P-erythroidine, m.p. 146-148" (lit.lfi 146indolinacetic acid (VI, m.p. 157-158") plus 7-aminomethylindoline (VII), as a colorless oil, in 10 to 15% 147"); v:7?'3 1705 cm.-'; A ~ a ~ " 379 H ( E 6500), 288 yield. Esterification of VI and alkylation with methyl (lO,SOO), and 253 mp (16,800). P-bromopropionate gave VIII, which on cyclization (16) G. L.Sauvage and V. Boekelheide, J . Am. Chem. SOC.,72, 2062 with potassium t-butoxide in benzene resulted in a 55 % (1950). (17) National Institutes of Health Predoctoral Fellow. yield of 6-oxo-7-methoxycarbonyl- 1,2,4,5,6,7-hexahydroazepino[3,2,l-hi]indoleg[IX, m.p. 91-92' ; AEzoH James Blake," James R. Tretter, Henry Rapoport 253 (e 10,800) and 218 m p (16,000); A ~ a ~ a 0 H - C z H 5 0 H Department of Chemisrry, University of California 285 ( E 11,700) and 245 mp (16,000)]. Acid decarboxylBerkeley, California Received Jutiuary 21, 1965 ation of IX gave the ketone X in 60% yield [m.p. 8283"; ,,A, CHIOH 257 ( E 6400) and 300 (sh) mp (1500); 1713 cm.-'1. When the ketone X was treated with the readily Mass Spectrometry in Structural and Stereochemical available n-butyl glyoxylateI0, l 1 in methanol, using a Problems. LXIX.' Methyl Migration in an piperidine-acetic acid catalyst, we obtained not the Electron Impact Induced Fragmentation' desired ester Xla but instead the lactol ether XI1 [m.p. Sir : 176'; 402 ( E 5500), 290 (9000), and 255 mp (16,300); v:,": 1750 cm.-l], presumably arising via Hydrogen rearrangements in mass spectrometric methanol attack on the ketone carbonyl of XIa followed fragmentation reactions are frequently of great mechby butoxide displacement. Substitution of t-butyl anistic significance3 and much attention has been paid glyoxylate12 as reagent and t-butyl alcohol as solvent recently to this subject in our l a b ~ r a t o r y . ~However, gave 6- ox 0-7 - t -but oxy car b on ylmethylene- 1,2,4,5,6,7rearrangements of alkyl groups (initially encountered hexahydroazepino[3,2,1-hi]indole13(XIb) in 59 % yield in hydrocarbonsb) have not been studied extensivelyfi 378 (e 5200) and 251 mp (15,200); vg','1720 and have largely escaped mechanistic scrutiny. We and 1710 cm.-']. now wish to record an interesting example of methyl Reaction of XIb with dimethyloxosulfonium methylmigration for which a plausible rationale can be ideI4 in dimethyl sulfoxide gave 6-hydroxymethyl-7proposed. carboxymethylene- 1,2,4,7 - tetrahydroazepino[3,2,1 - hi]The second most intense peak in the mass spectrum' indole &lactone (XIV), presumably arising from reof trans-A3-10-methyl-2-octalone (Ia) and its 6,7-dearrangement of the expected intermediate epoxide XIII. hydro analog I b occurs at m/e 69 and has been shown by The assignment of structure XIV is supported by the high-resolution mass measurements to correspond to the following data: (1) extended conjugation as seen in C 4 H 6 0 +rather than the C5H9+ion. In the spectrum the electronic spectrum 428 (e 5000), 300 of the 4-dl-labeled derivative IIbs the peak is moved to (11,000), and 260 mp (lO,OOO)]; (2) infrared spectrum mje 70 and, since migration of a deuterium (respectively (single carbonyl band at 1723 cm.-I); (3) elemental hydrogen) atom attached t o a double bond is an analysis; (4) mass spectrum (mass peak at 239); ( 5 ) unlikely process, this result implies that carbon atom 4 nuclear magnetic resonance absorption (deuterioaceis retained in the ion of mass 69 in Ia and Ib. Furthertone) which showed six protons in the region 6 2.5-3.5 more, since the high-resolution mass measurements (TMS, external standard), a two-proton singlet at 6 demonstrated the presence of the oxygen atom, carbon 4.4 corresponding to the methylene on the lactone atoms 2 and 3 must also be included in the ion. Only oxygen, two vinyl protons at 6 6 corresponding to a a one mass unit shift to mje 70 was observed in the singlet superimposed on a triplet, and three aromatic mass spectra of the l,l,3-ds-labeled analogs IIIa and protons. ( I ) Paper LXVIII: H . Budzikiewicz, R . T. Aplin, D . A. Lightner, Hydrogenation of the diene lactone XIV with 5 % C. Djerassi, R . Mechoulam, and Y . Gaoni, Tetrahedron, in press. Pd-BaS04 in ethyl acetate gave apo-P-erythroidine (XV) (2) Financial support provided by the National Institutes of Health o f the U. S. Public Health Service (Grants N o . CA-07195 and A M and isoapo-P-erythroidine (XVI) in 14 and 20% yields, 04257) is gratefully acknowledged. respectively, which were shown to be identical with (3) See, for instance, H. Budzikiewicz, C . Djerassi, and D. H . Williams, "Interpretation of Mass Spectra of Organic Compounds," authentic samples15 by melting point, infrared and ultra-
Az,foH
(9) Nomenclature is based on the parent aromatic compound, azepino[3,2,1-hi]indole,as used in Chemical Abstracfs. (IO) See M . S . Newman, W. C. Sagar, a n d C. C. Cochran, J . Org. Chem., 23, 1832 (1958), for the use of glyoxylate condensations to add a two-carbon acid side chain to ketones. ( 1 1) F. J. Wolff a n d J. Weijlard, Org. Syn., 35, 18 (1955). ( 1 2) This previously unknown compound was synthesized from di-1-butyl fumarate (m.p. 69-70", prepared from fumaric acid and isobutylene) which was oxidized with permanganate to the tartrate (m.p. 84-85"), and the latter was converted to t-butyl glyoxylate by the action of lead tetraacetate. Recently, L. A . Carpino [ J . Org. Chem., 29, 2820 (1964)] has isolated t-butyl glyoxylate as the hydrate from hydrolysis of the a-bromo-a-alkoxyacetate. (13) The stereochemistry of XIb is presumed to be cis-r-butoxycarbony1 with respect to the ketone group on the basis o f the observed cyclization of XIa and the subsequent cyclization of the epoxide XIII. (14) E.J. Corey and M . Chaykovsky, J . Am. Chem. Soc., 84,867( I 962). (I 5) Prepared16 from a sample of @-erythroidine hydrochloride, kindly supplied by D r . Karl Folkers.
1398
Journal of t h e American Chemical Society 1 87:6
Holden-Day, Inc., San Francisco, Calif., 1964. (4) C. Djerassi, Pure Appl. Chem., 9, 159 (1964), and references cited therein. (5) F. H. Field and J. L. Franklin, "Electron Impact Phenomena," Academic Press Inc., New York, N. Y.,1957,pp. 185-194; N . D i n h Nguyen, R . Ryhage, S. Stallberg-Stenhagen, and E. Stenhagen, Arkiv Kemi, 18, 393 (1961). (6) Some examples are the ion (ionized methyl ethyl ketone ?) resulting from loss o f carbon monoxide (confirmed in o u r laboratory by highresolution measurements) from isopropenyl acetate (A. S. Ne-ton and P. 0. Strom, J . Phys. Chem., 62, 24 (1958)), the elimination of a propyl radical from positions 2, 3, and 4 of long-chain methyl esters (see E. Stenhagen, 2.anal. Chem., 205, 109 (1964)), the expulsion o f ethylene from the straight-chain portion of isohexyl cyanide ( R . Beugelmans, D. H . Williams, H . Budzikiewicz, and C. Djerassi, J . Am. Chem. Soc., 86, 1386 (1964)),and reactions associated with the loss of carbon dioxide in ethyl carbamates (C. P. Lewis, Anal. Chem., 36, 176 (1964)). (7) See Figures 8 and 9 in ref. 3, p. 157. (8) J. Karliner, H . Budzikiewicz, and C. Djerassi, J . Am. Chem. Soc.,
87, 580 (1965).
March 20, 1965
