764
`
`J. Org. Chem. 1986, 51, 764-765
`
`Communications
`
`Construction of a Soluble Heptacyclic Terpyridine
`Summary: A new synthesis of the quino[8,7-b][1,10](cid:173)
`phenanthroline nucleus is reported, allowing the intro(cid:173)
`duction of solubilizing substituents and saturated terminal
`rings.
`
`Sir: The useful complexation properties of 2,2'-bipyridine
`and 2,2':6',2"-terpyridine have stimulated interest in higher
`polypyridine homologues. 1 Despite the utility of 1,10-
`phenanthroline as a ligand,2 synthetic difficulties have
`limited access to higher homologues in the pyridine/
`1,10-phenanthroline series. Synthesis of the next member,
`quino[8,7-b][1,10]phenanthroline (1), was reported by
`Case, using the double Skraup condensation of 4,5-di(cid:173)
`aminoacridine.3 Recently, Thummel achieved the syn(cid:173)
`thesis of a tetrahydrodibenzo derivative (2) by Friedlander
`condensation of 2,3, 7 ,8-tetrahydro-4,5(1H,6H)(cid:173)
`acridinedione with o-aminobenzaldehyde.4 We have now
`synthesized the di-n-butyldodecahydro analogue 3, em(cid:173)
`ploying a new method for construction of the quino[8,7-
`b][1,10]phenanthroline nucleus.
`
`1
`N'
`
`2
`
`N'
`
`R
`
`4
`N'
`
`R: !:'-butyl
`
`3
`N'
`
`We are interested both in complexation properties of
`rigidified terpyridines, such as 3, and in synthetic ap(cid:173)
`proaches to hexaazakekulene5 derivatives, such as 4. Since
`flexible side chains are known to enhance the solubilities
`of some rigidly planar molecules,6 our synthetic strategy
`incorporated n-butyl substituents. The 9-n-butylocta-
`
`(1) E.g., quinquepyridine: Constable, E. C.; Lewis, J.; Schroder, M.
`Polyhedron 1982,1,311-312. Sexipyridine: Newkome, G. R.; Lee, H.-W.
`J. Am. Chem. Soc. 1983, 105, 5956-5957. Toner, J. L. Tetrahedron Lett.
`1983,24,2707-2710.
`(2) McBryde, W. A., Ed. "A Critical Review of Equilibrium Data for
`Proton and Metal Complexes of 1,10-Phenanthroline, 2,2'-Bipyridyl and
`Related Compounds"; Pergamon Press: Oxford, 1978. Sliwa, W. Het(cid:173)
`erocycles 1979, 12, 1207-1237.
`(3) Koft, E.; Case, F. H. J. Org. Chem. 1962, 27, 865-868.
`(4) Thummel, R. P.; Jahng, Y. J. Org. Chem. 1985, 50, 2407-2412.
`(5) For studies on the carbocyclic parent system, kekulene, see:
`Diederick, F.; Staab, H. A. Angew Chem., Int. Ed. Engl. 1978, 17,
`372-375.
`(6) E.g.: Piechocki, C.; Simon, J.; Skoulios, A.; Guillen, D.; Weber, P.
`J. Am. Chem. Soc. 1982, 104, 5245-5247.
`
`+
`
`~CHO
`
`-
`
`b -
`
`5
`N
`
`c,d,e -
`
`g,h -
`
`-
`
`+ c¥"''
`i -
`
`3
`N
`
`Synthesis of 5, 11-di-n-butyl-1 ,2,3,4,6,-
`Figure 1.
`7 ,9,10, 12,13,14,15-dodecahydroacridino[ 4,3-b ]benzoU] [1,10](cid:173)
`phenanthroline: (a) KOH, ethanol, 70 °C, 7 h (49% ); (b) NH20-
`H-HCl, Na0Ac-3H20, HOAc, distill, 185 °C, 12 h (32%); (c)
`MCPBA, CH2Cl2, room temperature, 1 h; (d) Ac20, 110 °C, 70
`min; (e) 3M HCl, 100 °C, 1 h (69% from 6); (f) Cr03, HOAc, H20,
`H2S04, room temperature, 2 h (92% ); (g) Me2NNH2, cyclohexane,
`EtOH, TsOH·H20, room temperature, 16 h(C6H6, reflux, 15 min;
`(h) Me30BF4, CH2Cl2, room temperature, 30 min; (i) 210 °C, N2,
`5 min (23% from 8).
`
`hydroacridine 6 was therefore chosen as a key interme(cid:173)
`diate. Our synthesis (Figure 1) commenced with the aldol
`condensation of cyclohexanone with valeraldehyde, using
`conditions previously described for reaction of cyclo(cid:173)
`hexanone with other aldehydes.7 The initial aldol product
`apparently dehydrates, the resulting enone undergoing
`Michael addition to afford a 1,5-diketone, which is isolated
`as crystalline ketol 5.8
`Conversion to 9-n-butyl-
`1,2,3,4,5,6,7,8-octahydroacridine (6) 8 is achieved directly
`by reaction of 5 with hydroxylamine hydrochloride and
`acetic acid. 9 Although the overall yield of 6 from valer(cid:173)
`aldehyde is low (16% ), the preparation of 6 on a 100-g scale
`may be conducted easily and inexpensively.
`The transformation of 6 into 9-n-butyl-2,3,5,6,7,8-
`hexahydro-4(1H)-acridinone (8) involves oxidation at an
`a-CH 2 position, which may be effected by ozonolysis of a
`benzylidene derivative. 10 Unfortunately, condensation of
`6 with benzaldehyde in acetic anhydride results in a
`
`(7) Tilichenko, M. N. Uch. Zap. Sarat. Cos. Univ. 1962, 75, 60-65;
`Chem. Abstr. 1964, 60, 419a.
`(8) Microanalytical data and 1H NMR, IR, and mass spectra were
`consistent with the proposed structure.
`(9) As suggested by a reviewer, this transformation may be conducted
`by using ammonium acetate in refluxing acetic acid (cf. ref 4). This
`method gives 6 in somewhat better yield but involves an additional pu(cid:173)
`rification step.
`(10) Lodde, N.; Reimann, E. Arch. Pharm. 1979, 312, 940-950.
`
`0022-3263/86/1951-0764$01.50/0
`
`© 1986 American Chemical Society
`
`

`
`J. Org. Chem. 1986, 51, 765-767
`
`765
`
`mixture of starting material and monobenzylidine and
`dibenzylidine derivatives. An alternative four-step se(cid:173)
`quence employing Boekelheide rearrangement of an ace(cid:173)
`tylated N-oxide11 proved more convenient (Figure 1).
`Thus, the N-oxide of 6 was treated with hot, deoxygenated
`acetic anhydride, hydrolyzing the resulting acetate in situ
`to afford 7.8 Oxidation of this alcohol with chromic acid
`in aqueous acetic acid12 gave ketone 88 in 63% yield overall
`from 6.
`Conversion of 8 to hepatcyclic terpyridine 3 requires
`symmetrical coupling of a ketone with the introduction of
`a carbon at C-4 of the new pyridine ring. Thummel used
`the reaction of an enamine with formaldehyde, followed
`by aromatization of the resulting diketone, to prepare a
`tetrahydro derivative of 1.4 Newkome and Fishel have
`reported an unusual pyridine synthesis, in which C-4 is
`introduced by methyl migration in the pyrolysis of tri(cid:173)
`methylhydrazonium salts of aromatic ketones.13 We have
`found that this remarkable reaction may be applied to
`hexahydro-4-acridinones (Figure 1). Thus, 8 is converted
`first to the dimethylhydrazone and then to the tri(cid:173)
`methylhydrazonium salt 9 by alkylation with trimethyl(cid:173)
`oxonium tetrafluoroborate. Pyrolysis of the crude salt at
`210 °C under a stream of nitrogen, followed by recrys(cid:173)
`tallization from ethanol, gave the heptacyclic terpyridine
`314 in 23% yield overall from 8. The product was obtained
`as the sesquihydrate in the form of straw-colored needles
`(mp 220-221 °C), which were soluble in many organic
`solvents (e.g., CH2Cl2, CHC13, pyridine, 2-propanol, DMF,
`and acetic acid) and slightly soluble in others (e.g., benzene,
`acetonitrile, ether, THF, and ethanol).
`Heptacyclic terpyridine 3 differs from 2 in the presence
`of flexible substituents and saturated terminal rings.
`These features make 3 particularly suitable as a precursor
`to hexaazakekulene derivatives, such as 4. Oxidative
`functionalization of 3 and methods for pyridine synthesis
`by unsymmetrical coupling of two ketones are currently
`under investigation.
`Acknowledgment. This research was supported by the
`National Institutes of Health (PHS Grant GM32937), and
`the National Science Foundation is acknowledged for
`providing funds toward the purchase of a Nicolet NT-300
`NMR spectrometer (Grant 8114412).
`Registry No. 3, 99922-89-1; 5, 24133-22-0; 6, 99922-90-4; 7,
`99922-91-5; 8, 99922-92-6; 9, 99922-94-8; NH20H·HC1, 5470-11-1;
`Me 2NNH2, 57-14-7; cyclohexanone, 108-94-1; valeraldehyde,
`110-62-3.
`
`(11) Review: Traynelis, V. J. In "Mechanisms of Molecular
`Migrations"; Thyagarajan, B.S., Ed.; Interscience: New York, 1969; Vol.
`2, pp 1-42. See also: Cohen, T.; Deets, G. L. J. Am. Chem. Soc. 1972,
`94, 932-938.
`(12) Yanagida, A. J.; Gansser, C. J. Heterocycl. Chem. 1978, 15,
`249-251.
`(13) Newkome, G. R.; Fishel, D. L. J. Org. Chem. 1972,37, 1329-1336.
`(14) 1H NMR (80 MHz, CDC13, o relative to Me4Si) 7.36 (s, 1 H, Ar
`H), 3.8 (br s, 3 H, H 20), 3.o-3.2 (m, 4 H, a-PyCH2), 2.92 (s, 8 H,
`ArCH 2CH2Ar), 2.5-2.9 (m, 8 H, Ar CH2), 1.7-1.9 (m, 8 H,
`CH2CH2CH2CH2), 1.25-1.5 (m, 8 H, CH2CH2CH2CH3), 0.97 (t, 6 H, CHa);
`IR (KBr) 3350 (br), 2940 (s), 2850 (ms), 1650 (sh), 1550 (m), 1430 (m),
`1390 (m), 1240 (m), cm-1; UV (95% EtOH) Xmax (E) 245 (22000), 297
`(10000), 306 (14000), 346 (24000), nm; MS (70 eV), mje (relative in(cid:173)
`tensity) 505 (M+, 100). Anal. Calcd for C35H4EN30~,5: C, 78.90; H. 8.70;
`N, 7.89. Found: C, 78.73; H, 8.68; N, 7.65.
`(15) Note added in proof: An alternate approach to unsubstituted
`hexaazakekulene derivatives has appeared recently: Ransohoff, J. E. B.;
`Staab, H. A. Tetrahedron Lett. 1985, 26, 6179-6182.
`Thom~s W. Bell,* Albert Firestone
`Department of Chemistry
`State University of New York at Stony Brook
`Stony Brook, New York 11794-3400
`Received October 17, 1985
`
`Synthesis of a Lophotoxin Intermediate
`
`Summary: The carbometalation of an optically active
`homopropargyl alcohol is the key step in preparing the
`C-7,C-12 fragment of the marine neuromuscular agent
`( + )-lophotoxin.
`
`Sir: During the course of our synthetic study of the related
`marine furanocembranoids (+)-lophotoxin1 and (+)-pu(cid:173)
`kalide,2 we wished to prepare lactone 1. The vinyl iodide
`
`CHO
`
`(-!-) - Lophotoxin
`
`{+) - Pukal ide
`
`provides the functionality that is needed to form the C-
`6,C-7 bond of the natural products either through palla(cid:173)
`dium(0)3 or rhodium(I)-catalyzed4 coupling to a furyl nu(cid:173)
`cleophile. Control of the geometry of the trisubstituted
`alkene is crucial to the success of this approach. The
`zirconocene dichloride mediated addition of trimethyl(cid:173)
`aluminum to an alkyne5 appeared to offer a convenient
`solution to this problem. This reaction has been reported
`to be successful with unprotected homopropargyl alcohols;5
`therefore the reaction with racemic alcohol 2 was examined
`(Scheme I). The preparation of 2 from 1,4-butanediol was
`straightforward; however, the yield of the following syn(cid:173)
`thetic step, carbometalation5 followed by quenching with
`iodine, was disappointing (35% isolated yield of 3a). Silyl
`ether 4 was prepared and was subjected to the same re(cid:173)
`action conditions. The yield was again unacceptably low
`(20% isolated yield of 3b). In neither reaction was there
`any evidence of unreacted starting material.
`The conceptual simplicity of the carbometalation-iod(cid:173)
`ination5 sequence suggested that this approach to the
`C-7,C-12 fragment be pursued. Since homopropargyl al(cid:173)
`cohols have been shown to be good substrates for this
`reaction it was reasonable to assume that the remote ox(cid:173)
`ygen was responsible for the poor yields of 3a and 3b.
`Accordingly 7-(phenylthio)hept-1-yn-4-ol (5) and 7-
`chlorohept-1-yn-4-ol (6) were prepared (Scheme II).
`Carbometalation5 of 5 and 6 followed by iodination pro(cid:173)
`duced vinyl iodides 7 (7o-80% yield) and 8 (76-82% yield),
`respectively. The vastly improved yields for the reactions
`of 5 and 6 suggested that the earlier results with 2 and 4
`were a consequence of bidentate chelation of aluminum
`by both oxygen atoms.
`The introduction· of the second oxygen atom could be
`accomplished either through a Pummerer10 reaction of 7
`
`(1) Fenical, W.; Okuda, R. K.; Bandurraga, M. M.; Culver, P.; Jacobs,
`R. S. Science (Washington, D.C.) 1981, 212, 1512-1514.
`(2) Missakian, M. G.; Burreson, B. J.; Scheuer, P. J. Tetrahedron 1975,
`31' 2513-2515.
`(3) Negishi, E.-i.; Luo, F.-T.; Frisbee, R.; Matsushita, H. Heterocycles
`1982, 18, 117-122.
`(4) Larock, R. C.; Narayanan, K.; Hershberger, S. S. J. Org. Chem.
`1983,48,4377-4380.
`(5) (a) Rand, C. L.; Horn, D. E. V.; Moore, M. W.; Negishi, E. J. Org.
`Chem. 1981,46,4093-4096. (b) For a review, see: Negishi, E. Pure Appl.
`Chem. 1981, 53, 2333-2356.
`(6) Lombardo, L. Tetrahedron Lett. 1984, 227-228.
`(7) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647-2650.
`(8) Propargylmagnesium bromide was prepared from propargyl brom-
`ide and magnesium in the presence of catalytic mercuric chloride: Son(cid:173)
`dheimer, F.; Arnie!, Y.; Gaoni, Y. J. Am. Chem. Soc. 1962,84, 27Q-274.
`(9) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94,
`619Q-6191.
`
`0022-3263/86/1951-0765$01.50/0 © 1986 American Chemical Society