Journal of the American Chemical Society
3060
(12). Compound 12 was obtained as a glass which resisted crystalli-
zation, although it appeared homogeneous on the basis of LC analysis: (~Y]DE'(" +36.6' ( C 0.45); ' H N M R 6 0.92 (3, s), 1.19 (3. t , J = 7 H z ) , 1.22 (3,s), 1.3-2.6 (18, m), 1.95 (3, s), 3.90 (1, br, exchanges with D20), 4.10 ( I , d of d, J = 9 , 6 Hz), 4.40 ( I , br d, addition of D 2 0 simplifies t o d , J = 12 Hz), 5.12 (1, d of t, J = 12, 3.3 Hz), 5.56 (1, b r d , J = 2 H z ) , 6 . 3 0 ( l , d , J = 10Hz),7.43 ( l , d , J = 2 Hz),7.80(1, d of d, J = IO, 2 Hz); the I3C N M R spectrum of 12 corresponds closely to that of 5, except that the acetate ester absorptions at 6 169.2 and 20.7 are replaced by propionate ester absorptions*' at 172.9 (s, C=O). 29.8 (t, CH2). and 8.7 (q, CH3); E I M S (70 eV) m/e (re1 intensity) 546 (M+, l ) , 528 (M+ - H 2 0 , 2 ) , 394 (3), 376 ( l ) , 221 (IO), 204 (16), 191 (14), 175 (lo), 136 (5), 135 (lo), 123 (14), 57 (71),43 (100). 12-Oxo-2&O-acetyl-3~,1 la-di-O-propionyl-5~-hydroxybufalin (16). Propionyl chloride (100 pL) was added dropwise to a solution of 6 (100 mg, 0.2 mmol) in pyridine (1 mL) and the resulting solution
stirred at room temperature. Portions of the reaction mixture were removed for periodic analysis by LC. The initial reaction product corresponded in Rt to compound 12 and as the reaction progressed a second product of slightly longer retention time was observed. Evaporation of the volatile material in vacuo and purification of the residue by column chromatography gave 16 as a viscous oil (92 mg, 76%): the ' H N M R spectrum of 16 was very similar to that of the triacetate 8, with the resonances of two propionate esters ( 6 1 , I6 (3, t, J = 7 Hz), 1.17 (3, t, J = 7 Hz), 2.35 (4, q,J = 7 Hz)) replacing the acetate resonances of 8; EIMS (70 eV) m/e (re1 intensity) 602 (M+, 0.2).584(M+-H20,0.2),394(5),205(17),204(7), 191 (15), 175 (6), 135 (6), 123 (4), 57 (IOO), 43 (35). Treatment of compound 12 with propionyl chloride under identical conditions also gave 16, while treatment of 7 with propionyl chloride gave a different compound.
Acknowledgments. We are grateful to Professors W. D. McElroy and M. DeLuca for their generous gifts of P. pyralis, to Professors Ch. Tamm and K. Meyer (University of Basel) for providing authentic samples of bufadienolides, and to Mr. Steven Burke (University of Pittsburgh) for his assistance in obtaining the 250-MHz spectrum of 5. Partial support of this work by the National Institutes of Health (Fellowship Award
1 101:l I 1 M a y 23, 1979
CA 05646 (D.F.W.) and Grant No. AI 12020) is acknowledged with pleasure. References and Notes (a) This is report no. 61 of the series "Defense Mechanisms of Arthropods". Report no. 60: D. F. Wiemer, K. Hicks, J. Meinwald, T. Eisner, Experientia, 34, 969 (1978). (b) Department of Chemistry. (c) Section of Neurobiology and Behavior. See, for example, W. Shakespeare, "Hamlet", Act I, Scene V. P. Lincke, "Gluhwurmchen", Apollo Verlag, Germany, 1902; P. Lincke and L. C. Robinson, "Glow-worm", Edward S. Marks Music Co., New York, 1932. For a recent review, see A. D. Carlson and J. Copeland, Am. Sci., 66,340 11978) \ -,.
(5) W. D. McElroy and B. Glass, "Light and Life", The Johns Hopkins Press, Baltimore, Md., 1961. (6) For a leading reference, see E. H. White, N. Suzuki, and J. D. Miano, J. Org. Chem., 43, 2366 (1978). (7) T. Eisner, D. F. Wiemer, L. W. Haynes, and J. Meinwald, Proc. Natl. Acad. Sci. U.S.A., 75, 905 (1978). (8) We thank Dr. James E. Lloyd for identifying the fireflies. (9) T. J. Batterham. NMR Spectra of Simple Heterocycles", Wiley-lnterscience, New York, 1973, pp 391-392. (10) K. Nakanishi, "infrared Absorption Spectroscopy", Holden-Day, San Francisco, Calif. 1962, p 52. (1 1) A. I. Scott, "Ultraviolet Spectra of Natural Products", Pergamon, Oxford, 1964, p 141. (12) W. V. Turner and W. H. Pirkle, J. Org. Chem., 39, 1935 (1974). (13) K. Nakanishi, T. Goto, S. Ito, S.Natori, and S. Nozoe, "Natural Products Chemistry", Academic Press, New York, 1974. (14) P. Brown, Y. Kamano, and G. R . Pettit. Org. Mass Spectrom., 6, 47 (197 1). 'L. &ell and C. Tamm, Helv. Chim. Acta, 52, 551 (1969). W. Karrer, "Konstitution und Vorkommen der Organischen Pflanzenstoffe", Birkhauser Verlag, Basel, 1958, p 833. In making this calculation, no correction for the presence of a 2fl-acetoxy group was included. Models suggest that the expected influence of this substituent on the angular methyl resonances would be minimal. H. Fuhrer, R. F. Zurcher, and T. Reichstein, Helv. Chim. Acta, 52, 616 11969). K,-To-i, H. Ishii, 2. W. Wolkowski, C. Chachaty, M. Sangare, F. Piriou, and G. Lukacs. Tetrahedron Lett.. 1077 (1973). J. Krepinsky, J. A. Findley, B. Danieii, G.'Palmisano, P. Beynon, and S. Murakami, Org. Magn. Reson., 10, 255 (1977). A small number of P. pyralis were captured live and extracted individually with 10% EtOH-CHC13, and the extracts were examined by LC. Compounds A-E were detected in each animal, accounting for 85-91 % of the total absorbance at 313 nm in the males and 78% in the female. Sex-related differences in steroid corstent and relative ratios is presently under investigation. J. E. Stothers, "Carbon-13 NMR Spectroscopy", Academic Press, New York. 1972.
Identity of the Chain-Carrying Species in Halogenations with Bromo- and Chloroarylalkoxyiodinanes: Selectivities of Iodinanyl Radicals Ronald L. Amey and J. C. Martin* Contribution f r o m Roger Adams Laboratory. School of Chemical Sciences, Unicersity of Illinois, Urbana, Illinois 61801, Received October I I , 1978
Abstract: The free-radical halogenation of substituted toluenes by haloiodinanes 2a-b and 3a-b in benzene solvent is highly selective for benzylic hydrogens. The process involves cyclic iodinanyl radicals. except in the case of 3b, which appears to react via a bromine atom chain. The essentiall) identical values of p+ for 2a (-I .46) and 2b (-1.48) are consistent with there being a common chain-carrying species for both bromination and chlorination. Identical p+ values were not observed for 3a (- 1.3 I ) and 3b ( - I .55 vs. Br, - 1.58). Such iodinanyl radicals, unlike those derived from phenyliodine dichloride, are constrained to a C-1-0 angle far smaller than l SOo, allowing an opportunity to stud) the effects of bending on radical selectivities. The intermediacy of iodinanyl radicals in free-radicals chlorinations is further supported by evidence from photoinitiated reactions of 2a and 3a with 2,3-dimethylbutane. Comparisons of selectivities with those determined in other studies show that chlorine atoms are not involved. The allylic chlorinations of cis- and rrans-2-butenes by 2a and 3a were studied and found to be selective, high-yield reactions which give little or no addition to the carbon-carbon double bond.
Introduction Organic compounds of tricoordinate iodine(ll1) ma) be generally designated as hypervalent' iodine species and more 0002-7863/79/ I501-3060$0l .OO/O
specifically as iodinanes.2 The formation of iodine-centered radical intermediates from such iodinanes, since it involves breaking weak bonds to iodine, is expected to be an energetically favorable process.
0 1979 American Chemical Society
/
Amey, Martin
Selectivities of Iodinanyl Radicals
306 1
Table I. Slopes ( p + ) for Halogenations of Substituted Toluenes (50 “C. Bcnzene Solvent)“ ~
~
~
~~~~~~
slope, p+
reagent Chlorination Cl*h I-CdHgOCI (40 “C)‘ Ih
-1.01 -0.75 (p) -1.51 1.46 -1.31
-
2ah
3a
d
4:
- I .58
7hh
-I
- I .48
0.
55
Slopes of log k,,, vs. u+ plot. This work. R. D. Gilliom and F. Ward, Jr., ref 13, found a correlation with u rather than a+.
B.
An iodinanyl radical intermediate was first suggested by Russell3 to explain the chlorination reactions of molecular chlorine i n the presence of iodobenzene solvent. The same iodinanyl radical was postulated as an intermediate in the photoinitiated chlorination reactions of phenyldichloroiodinane ( l).4.5The intermediacy of iodinanyl radicals has also been
I
-a
1 proposed in the iodination reactions of tert-butyl hypoiodite,6 in several intramolecular hypoiodite reactions,’ in the decompositions of iodinated peroxidesxa-cand peresters,8d and in the chlorination reactions of the iodinane derived from the oxidation of iodobenzene by rert-butyl h y p o ~ h l o r i t e . ~ Breslow l o has cbncluded that iodinanyl radicals are involved in the chlorination of steroids which are mediated by covalently bound aryl iodide “templates”. These provide a synthetically useful method for the selective functionalization of unactivated sites in the attached steroid. The chloroiodinanyl radicals postulated to be important herc, like those which are intermediates in radical chlorinations with dichloroiodinane 1, have few constraints imposed on the geometry about iodine by other structural features of this molecule. The cyclic structures of the iodinanyl radicals derived from 2a,b and 3a,b, on the other
CH,
2a, x = ci 26, x = Br 2C, X = F
-
s
Bromination N-bromosuccinimideh 2bh
c1-I
0.4
bo
3a, x = CI 3b, X = Br
hand, require C-1-0 angles much less than 180’. The “bent” iodinanyl radicals could perhaps show changes in selectivity which could be correlated with angle strain. The implications of Breslow’s template approach to synthesis provides added interest to the study of iodinanyl radical selectivities. Our approach to this question has led us to study the highly selective free-radical halogenations effected by a series of bromo- and chloroarylalkoxyiodinanes,2a,b and 3a,b.
-0.4
-0.4
0
0.4
U+
Figure 1. Halogenation of substituted toluenes with iodinanes Za and Zb: 0 . Za, r = 0.9867; 0,Zb, r = 0.9965; 2a and 2b, p+ = -1.47. r = 0.9998.
Results Halogenation of Substituted Toluenes. A comparison of the selectivities of several chlorinating agents is shown in Table I . An excellent fit of the points to the Hammett correlation is obtained when Brown’s’ (T+ values are used. The p+ values for chloroiodinanes 1 (-1,5l), 2a (-1.46), and 3a (-1.31) differ substantially from those of chlorine atom (-1.01) and tert-butyl hypochlorite (-0.75). The following substituted toluenes gave the relative rate constants shown in parentheses for benzylic chlorinations: 2a,p-OCH3 (13.7), p-CH3 (2.88), p-(CH3)3C (2.50), H ( I .OO), m-OCH3 (0.85), p-CI (0.68), p-Br (0.60), and m - F (0.31); 3a, p-CH3 (2.6), p-(CH3)3C (2.2), H (1.00), m - F (0.35),and m-Br (0.29). The analogous p+ values for brominations by 2b (- 1.48), 3b (-1.55), and N-bromosuccinimide (NBS) (-1.58) are shown in Table I (phenyldibromoiodinane is not known). Brominations of methoxytoluenes by 2b or 3b show significant amounts of nuclear bromination. These data are therefore omitted from the statistical calculations. The following relative rates for benzylic bromination (in parentheses) were observed for substituted toluenes: 2b, p-CH, (2.9 1 ), p-(CH3)3C (2.35), H ( I .OO), p-CI (0.68), p-Br (0.59), and m-F (0.30); 3b, p OCH3 (15.4), H ( 1 .OO), m - F (0.27), and m-Br (0.23). When bromination data for 2b and chlorination data for 2a are considered together, in correlations with (T+, the correlation coefficient, r (0.9998), is greater than that for either of the individual sets of data (2a, r = 0.9862; 2b, r = 0.9965). For the correlation of relative rate constants with o+ values, see Figure I . Application of the Student t test12 to these data show that the benzylic chlorination with 2a and bromination with 2b proceed with the same selectivity within 98% confidence levels. The selectivities shown in halogenations by 3a and 3b are different within 98% confidence levels. Chlorination of 2,3-Dirnethylbutane. A comparison of the selectivities shown by 2a and 3a in the photochlorination of 2,3-dimethylbutane with those shown by other chlorinating agents, expressed in terms of the ratio of tertiary to primary abstraction (per hydrogen atom), is shown in Table I I . Allylic Halogenations. The irradiation of cis- or trans-2butene in the presence of chloroiodinane 2a or 3a at 40 * C results in, respectively, either the cis- or trans- I -chloro-2butene and 3-chloro- I-butene. The amount of other products,
Journal of the American Chemical Society f 101:11 f May 23, 1979
3062
Table 111. Selectivities (Primury/Secondar)j Product Ratios, Percent) in Allylic Chlorinations of cis- and traris-2-Butcnc with V IIr i ou s C h lor i na t i ne A yen t s
1.2
olefin
2a
3a'
63:37 73:27
79:2 I 80:20
84: 16 88: I2
ci 5 - 2- but e ne (/ rrtins-2-butene"
0.8
-2
tert-CaHqOCI tJ
('40 O C , butene as solvent. Reference 22. This work. Ratios ol' I -chloro-2-butene (cis or trans) to 3-chloro-l-butene; addition products were < I 0% of total. N o iso11icri7ationobserved (
