4116
J. Org. Chem. 1982,47,4116-4120
Fraction C (15.6 g from four batches), which showed the presence of methyl chrysolate ( l b ) as judged from TLC, was subjected to EM Si02-60(500g) column chromatography, eluting the column with CH2Clzfollowed by gradually increasing concentrations of EtOAc. After an initial 400-mL fraction, 20-mL fractions were collected. Fractions 110-130 (CH2C12eluent) containing lb as the major spot as judged from TLC were combined, and after evaporation of the solvent under vacuum the oily residue (1.18 g) was subjected to preparative TLC (Si02-60PF254), using CH2C12/EtOAc(99:l) as the developing solvent system. Repetition of the preparative TLC procedure gave lb as a colorless
oil, homogenous by TLC, [ a ] %-12.3’ ~ (c 2.39, CHC13). The IR (CCh,described in the text), ‘H and 13CNMR (Table I), and mass (Scheme 11) spectra were in accord with structure lb. Anal. Calcd for C21H32O9: mol wt, 332.2351. Found: mol wt, 332.2348 (high-resolution MS).
Acknowledgment. This work was supported by a research agreement with Diamond Shamrock Corp., Dallas, TX. Registry No. la, 82731-92-8; lb, 82731-93-9.
a-Methyl Functionalization of Electron-Poor Heterocycles:’ Chloromethyl Derivatives of B,B’-Bipyridines George R. Newkome,* Wallace E. Puckett, Garry E. Kiefer, Vinod K. GuptaY2Yuanjiao Xia,3 Mark C ~ r e i l and , ~ Melisa A. Hackney4 Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803 Received December 21. 1981
The syntheses of &(chloromethyl)-(3), 6-(chloromethyl)-6’-methyl-(2), and 6,6’-bis(chloromethyl)-2,2’-bipyridme (1) are reported. Complete spectral analyses including ‘H and 13CNMR data are given for each compound. Experimental results and appropriate comparisons justify the reassignments of the 13CNMR spectral data for the bipyridine derivatives. Descriptions of the synthetic techniques with the new, critical modifications utilized to prepare these key starting materials are presented. Bipyridine N-oxides have been shown to undergo intra-ring rearrangements; no N-oxide migration occurs under thermolysis at 200 OC. Over the past few years, the numerous syntheses of macrocycles which possess one or more subheterocyclic unit(s) have been r e p ~ r t e d . ~In view of our interest in site-specific bi- and polynuclear complexes, inclusion of the 2,2‘-bipyridine subunit into macrocycless and organometallics’ has been accomplished from the appropriate a-halomethyl precursors. Although numerous routes to the simple a-(halomethy1)pyridines have been reported,* the literature procedures are either lengthy and/or thwarted with sporatic yields, when applied to the functionalization of polypyridines. We herein report improved
routes to these pivotal bipyridine starting materials: 6(chloromethy1)- (3), 6- (chloromethyl)-6’-methyl-(2),and 6,6’-bis(chloromethyl)-2,2’-bipyridine (1).
Results and Discussion 6,6’-Bis(chloromethyl)-2,2’-bipyridine(1). 6,6’-Difunctionalized bipyridines have been generally derived from 6,6’-dibromo-2,2’-bipyridine (4) via a lithium-bromide
I
(1) Part 80 of “Chemistry of Heterocyclic Compounds” series. For part 79 see: Majestic, V. K.; Newkome, G. R. Top. Curr. Chem., in press. (2) On leave from the University of Delhi, Delhi, India, 1980-1982. (3) On leave from Lanchow Institute of Chemical Physics, Academia Sinica, Lanchow, China, 1981-1982. (4) Undergraduate Researcher. (5) Newkome, G. R.; Sauer, J. D.; Roper, J. M.; Hager, D. C. Chem. Rev. 1977, 77, 513. (6) Newkome, G. R.; Kohli, D. K.; Fronczek, F. J. Chem. SOC.,Chem. Commun. 1980.9. Newkome. G. R.: Kohli. D. K.: Fronczek, F.: Hales, B. J.; Case, E. E.; Chiari, F. J:Am. Chem. Soc. 1980,102, 7608.’ Newk: ome, G. R.; Kohli, D. K. Heterocycles 1981,15,739. Also see: Curtius, N. F. Coord. Chem. Reu. 1968,3,3. Lewis, J.; Wainwright, K. P. J. Chem. SOC.,Chem. Commun. 1974,169; J. Chem. SOC.,Dalton Trans. 1978,440. Haque, Z . P.; Liles,D. C.; McPartlin, M.; Tasker, P. A. Znog. Chim. Acta 1977,23, L21. Buhleier, E.; Wehner, W.; VBgtle, F. Justus Liebigs Ann. Chem. 1978, 35; Chem. Ber. 1978, 111, 200. (7) Newkome, G. R.; Onishi, M.; Puckett, W. E.; Deutsch, W. A. J. Am. Chem. SOC.1980, 102, 4551. Newkome, G. R., unpublished results. (8) N-Oxide rearrangements to a-chloromethyk (a) Kato, T. Yakugaku Zasshi 1955,75,1238. (b) Koenig, T.; Wieczorek, J. S. J. Org. Chem. 1968,33,1530. (c) Vozza, J. F. J. Chem.SOC.1962,3856. (d) Matsumura, E. Nippon Kagaku Kaishi 1953, 74, 363. (e) Ash, M. L.; Pews, R. G. Second Chemical Congress of the North American Continent, San Francisco, CA, Aug 1980; ORGN 168, J. Heterocycl. Chem. 1981,18,939. N-Oxide rearrangement via acetoxymethyl intermediate: (f) Traynelis, 1958,80,6590. (9) Baker, W.; V. J.; Martello, R. F. J. Am. Chem. SOC. Buggle, K. M.; McOmie, J. F. W.; Watkins, D. A. M. J. Chem. Soc. 1958, 3594. Direct chlorination: (h) Mathes, W.; Schuly, H. Angew. Chem.,Int. Ed. Engl. 1963,2,144, German Patent 1204 231,1965; Chem. Abstr. 1966, 64. 2603.
0022-326318211947-4116$01.25/0
R
1, R = R = CH,C1 2, R = CH,Cl; R = CH, 3, R = CH,Cl; R’ = H 4, R = R = Br 5, R = R = CHO 6 , R = R = CH,OH 7, R = R = CH, 8 , 2 N+O; R = R = CH, 9, R = R = CH,OAc 10,R = R‘= CHCl,
11,N+O; R = R’ = CH, 12,R = CH,OAc; R’ = CH, 13,R = CH,OH; R’ = CH, 14,R = R’ = H 15, R = CH,; R’ = H 16, R = CHC1,; R’ = H 17,N+O; R = CH,; R’ = H 18,”’0; R = CH,; R’ = H 19, R = CH,OAc; R‘ = H 20, R = CH,; R‘ = OAc 21, R = CH,OH; R = H
exchange, followed by addition of suitable electrophiles, e.g., N,N-dimethylformamide, to give dialdehyde 5.9 Quantitative reduction (NaEiH4)of 5 gave the bis carbinol 6, which upon treatment with purified’O SOClz afforded (73%) the bis(chloromethy1) derivative 1. Care must be
exercised in handling all of these halomethyl derivatives (9) (a) Parks, J. E.; Wagner, B. E.; Holm, R. H. J.Organomet. Chem. 1973,56,53. (b) Parks, J. E. Ph.D. Dissertation, University of Wisconsin, 1972. (c) Wagner, B. E. Ph.D. Dissertation, Massachusetts Institute of Technology, 1972. (d) Sauer, J. D. Ph.D. Dissertation, Louisiana State University, 1976. (IO) Vogel, A. I. “Practical Organic Chemistry”; Longmans: London, 1973; p 189.
1982 American Chemical Society
Functionalization of Electron-Poor Heterocycles since they are extremely initating to the skin and mucous membranes." The disadvantages of known sequences are as follows: (1)unavailability and/or cost of 2,6-dibromopyridine; (2) immense net molecular weight loss (-2 Br); (3) arduous large-scale lithiations; (4) potentially hazardous coupling procedure. Direct coupling of 6-amino-2-picoline to give 7 via either the Gomberg-Bachmann or Gatterman reactions failed (65%) the desired sym-dichloride 1. Unchanged starting material and sym-tetrachloride 10 were also isolated; the latter was characterized ('H NMR) especially by the singlet at 6 6.80 for the methine hydrogen. No hexachlorinated products were observed, contrary to the halogenation of related a-methyl heterocycles.l8 The use of N-bromosuccinimide (NBS) under diverse conditionslg gave in our hands only complex brominated products, all in low yields. The procedures delineated by Ash and Pews" to directly convert 2-picoline N-oxide into 2-(chloromethy1)pyridine were conducted; in all cases, complex mixtures resulted (11)Note: 3-(Chloromethyl)pyridine is a carcinogen in rata, whereas, the 2-isomer is not (NCI; personnel communication of Dr. T. D. Bailey, Reily Tar and Chemical Corp.). Thus extreme care must be taken in view of the potential alkylating properties common with all of these a-halomethvl comoounds. -. .~~ ---r(12) DeTar, D. R. Org. React. 1957,9,409. (13) Fabian, R. H.; Klassen, D. M.; Sonntag,R. W. Znorg. Chem. 1980, -19. -, 1977. - - . .. (14) Bamfield, P.; Quam, P. M. Synthesis 1978, 537. (15) Haginiwa, J.; Higuchi, Y. Yakugaku Zasshi 1973,93, 144. (16) Murase, I. Nippon Kagaku Zasshi 1956, 77, 682. Kanno, H.; Kashiwabara, K.; Fujita, J. Bull. Chem. SOC.Jpn. 1979, 52, 1908. (17) Ford, P. W.; Swan, J. M. A u t . J. Chem. 1965, 18, 867. Cohen, T.; Deeta, G. L. J . Am. Chem. SOC.1967,89, 3939. (18) Newkome, G. R.; Maiestic, V. K.; Kiefer, G. E., to be submitted for publication. (19) See: Offermann, W.; Vogtle, F. J. Org. Chem. 1979, 44, 710. I-
~
~~
J. Org. Chem., Vol. 47, No. 21, 1982 4117 from which 1 could only be isolated (
