The Deuteration of Some N-Methyl-4-pyridones Peter Beak and James Bonham’ Contribution f r o m the Noyes Chemical Laboratory, University of Illinois, Urbana, Illinois. Received March 1, 1965 In contrast to other a,p-unsaturated carbonyl systems N-methyl-4-pyridone (l),3,5-dimethyl- N - methyl-4-pyridone (3)) and 3,5-dibromo-N-methyl-4-pyridone ( 9 ) substitute deuterium f o r protium at the p-(2 and 6)position in basic deuterium oxide at 100”. A mechanistic proposal, supported by kinetic data, is given f o r these substitutions. The base-catalyzed protium-deuterium exchange of the hydrogen located on the a-carbon atom has been reported for a number of a,@-unsaturated carbonyl conipounds.2-5 In marked contrast to this, the basecatalyzed deuterium exchange of N-methyl-4-pyridone (1) leads to substitution at the p-(2 and 6) position of the unsaturated s y ~ t e m . ~The ? ~ present paper details the evidence, provides additional examples, and proposes a mechanism for this reaction.
Results Deuterations. Treatment of N-methyl-Qpyridone (1) with 0.5 N sodium deuteroxide at 100” for 12 hr. yielded a product which was shown by infrared, ultraviolet, n.m.r. (vide infra), and mass spectroscopic criteria to be 92 % N-methyl-4-pyridone-2,6-d~(2) and 8 N-methyl-4-pyridone-2-d in 39 % isolated yield. A preparative experiment yielded 58 % of 2. These yields apparently reflect the difficulty of isolation and purification since ultraviolet, n.m.r., and mass spectral analyses of subsequent kinetic runs indicated that 2 is the major product of the reaction. N-Methyl-4-pyridone-2,6-d2 could be reconverted to the unlabeled compound 1 in 5 6 x isolated yield by heating at 95-98’ with 1.0 N aqueous sodium hydroxide for 9 hr. Similar treatment of 1 at pD 8.5 or with strong acid in deuterium oxide did not lead to measurable (>5 %) deuterium incorporation.*
Structural Assignments. The positional assignment of the deuterium atoms in 2 is based on a comparison of the chemical shifts of the ring protons of 3,5-dimethyl-N-methyl-4-pyridone (3) (H-2 and H-6 at 6 = 8.13 p.p.m.), 2,6-dimethyl-N-methyl-4-pyridone(4) (H-3 and H-5 at 6 = 6.88 p.p.m.), and N-methyl-4-pyridone (1) (H-2 and H-6 at 6 = 8.28 p.p.m., H-3 and H-5 at 6 = 7.01 ~ . p . m .with ) ~ the chemical shift observed for the ring protons in N-methyl-4-pyridone-2,6-dz (2) (H-3 and H-5 at 6 = 7.05 p.p.m.). Confirmation of the critical chemical shift assignments comes from the n.m.r. spectrum of a mixture of N-methyl-4-pyridone-3d (5, 50%) and N-methyl-4-pyridone-3,5-d2 (6, 41 %) prepared by treatment of 4-pyrone with methylamine in deuterium oxide. In the spectrum of the product mixture the resonance at 6 = 7.01 p.p.m. (H-3 and H-5) is ca. one-third of the area of the signal at 6 = 8.28 p.p.m. (H-2 and H-6), in agreement with the mass spectral data used above to determine the relative amounts of monodeuterated and dideuterated com-
x
-
CH3 5
0
I
CH3
L
I CH3 1
HzO, OH-
D
Y
3,R= CH3 9, R= Br
D
CH3 2
(1) Standard Oil of California Fellow, 1964-1965. (2) P. Yates and L. L. Williams, J . Am. Chem. Soc., 80, 5896 (1958). (3) M. F. Zinn, T. M. Harris, D. G. Hill, and C. R. Hauser, ibid., 85, 71 (1963); B. W. Rockett, T. M. Harris, and C. R. Hauser, ibid., 85, 3491 (1963). (4) R. H. Shapiro, J. M . Wilson, and C. Djerassi, Steroids, 1, 1 (1963). ( 5 ) J. Warkentin and L. K. M. Lam, Can. J . Chem.,42, 1676(1964). (6) A cyanide-catalyzed deuterium exchange at the 4-position of the
nicotinamide pyridinium ring of DPN has been reported by A. San Pietro, J . B i d . Chem., 217, 579 (1955). In this case the activation required for proton removal is presumably provided in the usual manner by the cyanide group in the cyanide-DPN adduct. (7) A preliminary report of this reaction has appeared; P. Beak and J. Bonham, Tetrahedron Letters, 3083 (1964). (8) This result is different from the case of 4-pyridone which is reported to substitute deuterium for protium at the 3- and 5-positions in
0
CHs
CH3
6
1
pounds. The formation of 5 and 6 can readily be accounted for by an imineeenamine or keto-enol tautomerism of the ring-opened intermediates usually formulated to rationalize the course of this reaction. lo Additional support for the assigned course of the base-catalyzed deuteration of 1 is found in the fact that 3,5-dimethyl-N-methyl-4-pyridone-2,6-dz (7) and 3,5-
D d 3 ODloo0
0
-
0
R)& D N I
D
CH3 7, R=CH3
8,R = B r
strong acid: P. J. Van Der Haak and Th. J. DeBoer, Rec. t r a y . chim., 83, 186 (1964). (9) The chemical shifts in 6, p.p.m., are extrapolated to infinite dilution relative to external tetramethylsilane for deuterium oxide solutions, (a) These relative chemical shifts are in agreement with those of R. A. Y . Jones, A. R. Katritzky, and J. M. Lagowski, Chem. Ind. (London), 870 (1960). (b) The chemical shifts refer to the centers of each multiplet. Analysis of the n.m.r. spectrum of 1 in deuteriochloroform solution as an AlBl system provides a fit of the calculated and observed spectrum within experimental error with h a = j S 6 = 7.96 C.P.S., h 6 = Jas = 0.01 c.P.s., J S S= J.H = 2.78 c.P.s., and 6vAB = 66.23 C.P.S. We are grateful to Dr. I. JonPB for advice during the course of this analysis and for the use of a computer program; J. JonAi, W. Derbyshire, and H. S . Gutowsky, J . P h y s . Chem., 69, 1 (1965). give a relevant discussion of this type of system. (10) H. Meislich, “Pyridine and Its Derivatives,” Part 111, E. Klingsberg, Ed., John Wiley and Sons, Inc., New York, N. Y., 1962, pp. 552560.
Beak, Bonham
Deuteration of Some N-Methyl-4-pyridones
3365
conditions N-methyl-4-pyridone substituted 85 deuterium for protium at the ring atoms adjacent to nitrogen. Kinetics. The rate of the over-all conversion of 1 to 2 as followed by n.m.r. was found to be first order in base and first order in N-methyl-4-pyridone over a concentration range of 0.5 to 1.5 N for both species. As summarized in Table I the kinetic data gave a second-
14
Table I. Rates of Formation of N-Methyl-4-pyridone-2,6-d2 (2) in Deuterium Oxide at 100" 1600
3200
4800
Sec.
Figure 1. The amounts of N-methyl-4-pyridone (A), N-methyl4-pyridone-2-d (O), and N-methyl-4-pyridone-2,6-d2 (a)as a function of time in 0.471 M NaOD in deuterium oxide at 100'. The lines were drawn with the aid of an analog computer programmed for two consecutive first-order reactions.
NaOD, M
1, M
0.471 0.471 0.471 0.471 0.471 0.471 0.945 0.945 1.530 1.530
0.499 0.521 0.980 1.04 1.38 1.48 0.535 0.45 0.5 0.5
k,, X lo4, X lo4, 1. mole-' sec.-la sec.-lb kaD,Bv X lo4
kobsd
1.91 i 0.09 1.94 i 0.06 2.05 i 0.06 1.81 & 0.04 2.09 i 0.07 2.05 i 0.04 3.97 i 0.14 3.81 i 0.06 7.15 i 0.17 6.89 i 0.19
4.05 4.12 4.35 3.84 4.44 4.35 4.20 4.03 4.67 4.50
4.26 i 0.21
dibromo-N-methyl-4-pyridone-2,6-d2 (8) can be prepared in 77 and 91 % yields, respectively, by heating the corresponding unlabeled pyridones, 3 and 9, in basic deuterium oxide. 3,5-Dibromo-N-methyl-4-pyr- The first-order rates were calculated using a weighted, leastidone (9) was regenerated from 8 in 64% yield by heatsquares program. The base concentration used in calculating ing in strong aqueous base. k,, was not corrected for a small carbonate error. In contrast to the deuteration of 3 treatment of 2,6dimethyl-N-methyl-4-pyridone (4) with 0.5 N base at order rate constant of 4.26 i 0.21 X IO-* 1. mole-' 96" overnight led to deuterium incorporation at the Cset.-' as an average of ten runs. Titrations throughout methyl groups to produce 10. the run established that base was constant to 95 f 5 % of the initial base concentration during the reaction, and ultraviolet analysis showed that the chromophore of DzO, ODN-methyl-4-pyridone was essentially invariant throughCD3 out the reaction. The rate of the formation of 2 in CH3 D3C I deuteriuni oxide with deuteroxide catalysis at 100" (kH) CH3 CH3 10 4 was compared with the rate of formation of 1 from 2 in water with hydroxide catalysis at 100" ( k , ) (Table In a comparison of the base-catalyzed deuterations of 11) and a kH/kDratio of 1.23 + 0.16 obtained. molecules formally similar to 1 it was found that treatment of 4-methoxy-N-methylpyridinium fluoborate (11) with 0.85 N sodium methoxide in deuteriomethanol Table 11. Rates of Formation of N-Methyl-4-pyridone in Water at 100" led to essentially complete selective substitution of deuterium at the ring carbon atoms adjacent to nitrogen k,, X IO4, within 15 min. at room temperature. On the other NaOH, k o b s d X lo4, 1. mole-' M 2, M sec.-la sec.-'b k,, x lo4 hand, N-methylpyrrole (12), pyridine, and 4-methoxy-
LCH3NaOCHa DOCHa
BFI-
N
7.50
I CH3
D
6 I
D
1.00 1.00 1.00
0.56 0.56 0.56
3.07 i 0.09 3.81 i 0 . 0 6 3.53 i 0.12
3.07 3.81 3.53
3.47 i 0 . 2 7
The first-order rates were calculated using a weighted, leastsquares program. * The base concentration used in calculating k,, was not corrected for a small carbonate error.
BF;
CHa 11
I N! I
NaOCHS DOCHs ~
62'
less than 2% deuterium incorporation
CH3 12
pyridine gave less than 5 % exchange on heating at 62" for 66 hr. in the same medium." Under the latter ( 1 1) (a) N-Methylpyrrole is reported to metallate at the 2-position: I
