J. Org. Chem. 1983,48, 2337-2346
2337
Anion-Mediated Fragmentation Reactions. Mechanistic and Synthetic Aspects of the Fragmentation and Rearrangement Reactions of Pyrimidinedione-Alkyne P hotoadducts Victor V. Kaminski, Robert N. Comber, Allan J. Wexler, and John S. Swenton* Department of Chemistry, The Ohio State University, Columbus, Ohio 43210 Received November 19, 1982 The acetonesensitized photocycloadditionreactions of uracil, thymine, 5-fluorouracil, and &(trimethylsilyl)uracil It is noteworthy that 5-(trimethylsily1)uracilgives with alkynes afford 2,4-diazabicyclo[4.2.0]oct-7-ene-3,5-diones. very high yields in these reactions. High regioselectivity is exhibited for the reaction of uracil, 5-fluorouracil, and &(trimethylsiiyl)uracilwith 1-alkynes,the 8-alkyl-substitutedproduct being formed nearly exclusively. k c t i o n of the cycloadducta mentioned above with 2 equiv of potassium tert-butoxide gives the appropriate pyridones in good yield. Three of these cycloadducta were rearranged to 1,3-diaza-5,7-octadiene-2,4-diones by silylation followed by treatment of the crude silylation product with silica gel. Thus, a sequence of photocycloaddition and base-mediated fragmentation converts uracil-type systems to pyridones while photocycloaddition followed by rearrangement converts uracil systems to two-carbon ring-expanded heterocycles. The mechanism of the above transformation has been examined by using 13C-and 16N-labeledsystems. This work together with kinetic studies of the fragmentation of these photoadducts in basic media gives a reasonable mechanistic picture of this chemistry.
The photocycloaddition reactions of uracil and a number of its derivatives with alkenes and alkynes afford a one-step route to the 2,4-diazabicyclo[4.2.O]octylring system.'P2 Often these photocycloadditionswith terminal alkenes and alkynes are highly s e l e c t i ~ e ,forming ~ * ~ the 8-substituted ring system regiospecifically. The subsequent chemistry of the 2,4-diazabicyclo[4.2.0]octylring system has not been extensively s t ~ d i e d .Thus, ~ ~ ~we ~ have explored some of the chemistry of these systems with the idea of developing routes to both known and unknown heterocyclic ring systems. One idea was that photocycloaddition of uracils and alkynes followed by dianion formation and ring opening would comprise a two-atom ring expansion of uracils to 1,3-diazacycloocta-5,7-diene-2,4-diones (Scheme I). As we reported in 1979,4" instead of isolating ring-expanded uracils from this reaction, a fragmentation reaction ensued, yielding pyridones. We report here a detailed study of the mechanism of this fragmentation reaction and a successful route from uracil-alkyne-type photoadducts to l,&diazacycloocta-5,7-diene-2,4-diones.
Scheme I. Intended Strategy for Two-Carbon Ring Expansion of Uracils
Table I. Photocycloaddition of wrimidinediones and Alkynes
Photochemical Cycloaddition Studies
The acetone-sensitized photocycloadditions of uracil and its substituted derivatives with alkynes are summarized in Table I. Since full spectroscopic and analytical data for these products are given in the Experimental Section, only the pertinent points concerning the assignment of structure will be noted here. The reactions of uracil with 1-propyne, 1-pentyne, and 1-heptyne all gave one isolable photocycloaddition product in modest yields (Table I, entries, 1-3). The remaining constituents of the reaction (1) (a) Hyatt, J. A.; Swenton, J. S. J. Am. Chem. SOC.1972,94, 7605. (b) Swenton, J. S.; Hyatt, J. A.; Lisy, J. M.; Clardy, J. Zbid. 1974,96,4885. (c) Wexler, A. J.; Hyatt, J. A.; Ftaynolds, P. W.; Cottrell, C.; Swenton, J. S. Zbid. 1978,100, 512. (2) (a) Wexler, A. J.; Balchunis, R. J.; Swenton, J. S. J. Chem. SOC., Chem. Commun. 1975, 601. (b) Wexler, A. J.; Swenton, J. S. J. Am. Chem. SOC.1976,98, 1602. (3) Swenton, J. S.; Grimm, F.; Fritzen, E. L. "Symposium on Photochemistry as a Route to Chemicals" presented before the Division of Petroleum Chemistry, Inc., Joint Meeting of the American Chemical Society and Chemical Society of Japan, Honolulu, April 1-6, 1969, pp 121-129. (4) For preliminary reports of some of this work, see: (a) Comber, R. N.; Swenton, J. S.; Wexler, A. J. J. Am. Chem. SOC.1979,101,5411. (b) Kaminski, V. V.; Swenton, J. S. Tetrahedron Lett. 1982,23,4207-4210.
1
2
3
yield, entrv comDd 1 a 2 b 3 C 4 d 5 e 6 f 7
g
8 9 10 11
h
12
1
i j
k
R' H H H H H CH, CH3 F F F Si(CH,), Si(CH,),
RZ
R3
76
H H H CH3
CH, n-C,H, n-C5H11 CH,
43
'ZH5
'ZH5
CH, CH, H H H H H
H CH, CH, n-C,H, n-C5H11
nGH, nC,H11
25
30 54 31 28 32
29
33 29 95
86
mixture were uracil-type dimers. The regiochemistry of the propyne adduct 3a was established by reduction with deuterium followed by lH NMR analysis of the di-
0022-326318311948-2337$01.50/0 0 1983 American Chemical Society
2338 J. Org. Chem., Vol. 48, No. 14, 1983
Kaminski et al. Table 11. Fragmentation Reactions of Uracil-Alkyne-Type Photoadducts
4
3a
deuterated product [lH NMR (pyridine) 6 1.01 (CH3, s, 3 H), 1.81 (H,, broadened d, J = 6 Hz, 1 H), 3.28 (H6, d of d, J = 8.7, 6 Hz, 1 H), 4.07 (HI, d of d, J = 8.7, -3 HZ which collapses to a d, J = 8.7 Hz, upon shaking with DzO, 1H)].If the alternative regiochemistry had been the case for 3a, the deuteration product analogous to 4 would have shown I-& as a simple doublet, and HI would have appeared as a doublet of doublets. The purity of the photocycloaddition products of uracil with 1-pentyne and 1-heptyne was established by 13C NMR spectroscopy, and the assigned regiochemistry was inferred by analogy with 3a. While the high regioselectivity of the uracil photocycloadditions to 1-alkyne was surprising, the poor mass balance in the reaction does not exclude the possibility of some head-to-head isomer formation. In a similar manner, the orientation of the photocycloaddition products of 5-fluorouracil with propyne, l-pentyne, and 1-hexynewas assigned as the head-to-tail isomers 3h-j, respectively. Thus, hydrogenation of 3h gave the known 5.2b The regiochemistry of 3i and 3j was inferred
H
3
H
3h
5
from the established structure for 3h together with the similarity of the 19Fcoupling constant of the C7 vinylic carbon in the 13C NMR spectrum. The head-to-head regiochemistry of the thymine-propyne photocycloadduct 3f was confirmed by its subsequent chemistry (vide infra). The regioselectivity observed with other uracil reactions is not a general characteristic of thymine reactions. For example, the photocycloaddition of thymine to 1-heptyne gave a 38% yield of a 1.21 mixture of regioisomers as determined by 13C NMR spectroscopy. The photocycloaddition chemistry5 of 5-(trimethylsily1)uracil with alkynes is especially noteworthy. First, not only is the reaction highly regioselective, as noted earlier: but also the yields of isolated photoadduct are very high (entries 11and 12). One reason for the higher yield of cycloadducts with 5-(trimethylsily1)uracilrelative to the other nitrogen bases may be a slower rate of photochemical dimerization of 5-(trimethylsily1)uracil. For examination of this possibility, solutions of 0.01 M uracil and 5-(trimethylsily1)uracil were irradiated at 300 nm under identical conditions. The concentration of uracil as assayed by UV analysis decreased to 65% of its initial concentration in a time period in which no change was detected in the concentration of 5-(trimethylsilyl)uracil. Thus,a major factor in the increased yields of 5-(trimethylsily1)uracil photocycloaddition reactions is its greater photochemical stability. Fragmentation Studies While the pK,'s for the cycloadducts were unknown, the pKl for dihydrouracil in water had been reported as 11.5.6 ( 5 ) Chih, C.; Fritzen, E. L.; Swenton, J. S. J. Org. Chem. 1980,45,4462. (6) Levene, P. A.; Bass,L. W.; Simms, H. S. J. Biol. Chem. 1926, 70, 229.
3
entry
6
a b c d e
6 7
B
H H H H H CH, CH3
8
h
F
9 10
j
1 2 3
4 5
f
F
Si(CH,),
k
RZ
R1
compd
yield,
R3
7%
H H H CH,
CH, n-C,H, nCsH1r CH,
'ZH5
$H5
CH3 CH, H H H
61
55 70 62 67 69 66 47 70 66
CH, CH3
n-C5%
n-C3H,
Potassium tert-butoxide in tert-butyl alcohol would certainly completely deprotonate the cycloadducts at N3, and it seemed reasonable that the dianion arising from deprotonation at N1 also could be present in a finite concentration at equilibrium. Thus, potassium tert-butoxide in tert-butyl alcohol appeared as a reasonable medium for examining the ring-expansion chemistry outlined in Scheme I. When the adduct 3a was reacted with 2 equiv of potassium tert-butoxide in refluxing tert-butyl alcohol followed by quenching of the reaction mixture with aqueous acid, a new product was isolated in 61% yield by column chromatography. The new compound had the formula C6H7N0by high-resolution mass spectrometry, indicating the loss of HNCO from 3a. This new compound exhibited physical and spectroscopic properties nearly identical with those reported for 5-methylpyrid~ne~ (6a): mp 180-181 "C (lit.' mp 182-183 "C); UV (H,O) 302 nm ( e 5600), 227 (7400) [lit.7UV (CH30H)302 nm ( 6 5700), 227 (SlOO)]; lH NMR, identical with the published spectrum. This reaction then corresponds to the loss of potassium cyanate from the anion of the cycloadduct. When the salt formed in the fragmentation reaction was filtered, the IR (KBr) spectrum of this material showed absorptions at 2185, 1306,1212,652, and 642 cm-'. The reported* absorptions for potassium cyanate are 2170, 1300, 1205,636, and 626 cm-'. Thus, the overall fragmentation reaction is demonstrated to form pyridone and potassium cyanate. Reaction of the other photocycloadducts listed in Table I1 likewise gave the pyridones in good isolated yield. The assigned structures of the pyridones are supported by combustion analysis and/or exact mass, 13C NMR, 'H NMR measurements as detailed in the Experimental Section. For the thymine/propyne cycloadduct, 3f, the H
w
CH y H
3
2 equiv
KO-t-Bu " 3 ' S H 5
a
&N
'O
I
A
3f
H6
1
A 6f
structure of the pyridone was used to establish the structure of the adduct. Thus, the pyridone 6f showed in (7) Abramovitch, R. A,, Ed. "Pyridine and Its Derivatives, Supplement Part 111"; Wiley: New York, 1974; p 8661. (8) Waddington, T. C. J. Chem. SOC.1959, 2499.
J. Org. Chem., Vol. 48, No. 14, 1983 2339
Anion-Mediated Fragmentation Reactions
Scheme 11. Mechanistic Possibilities for Pyridone Formation from Uracil-Alkyne Photoadduct
its 'H NMR spectrum the olefinic hydrogens H5 and HB as a clean AX pattern with signals at 6 6.08 (J= 7 Hz) and 7.18 (J = 7 Hz). This substitution pattern in the pyridone 6f is consistent only with the head-to-head orientation of the photocycloadduct 3f. While no other significant produds were isolated in the fragmentation reaction of uracil, thymine, or 5-(trimethylsilyl)uracil, a highly fluorescent minor product was noted in the fragmentation reactions of 5-fluorouracil cycloadducts 3h and 3j. The new product 7j had the mo-
'5 * H
KO-t-B;
D c S H l l
t-BuOH
I
H
5Hll
3i
/
9
6j
7j, R = n-C5H,,
%,R=H
lecular formula CllH14N202by combustion analysis and exact mass measurement, corresponding to loss of hydrogen fluoride from 3j. The 'H NMR spectrum (Me2SO-ds) [6 0.09 (distorted t, J N 6 Hz, 3 H), 1.35 (m, 6 H), 2.49 (obscured by Me2SO), 6.7 ( 8 , 1 H), 7.24 (s, 2 H), 11.3 (br s, 1 H)] showed in addition to the absorptions of the aliphatic side chains two vinyl hydrogens and one N-H resonance. The reporteds 'H NMR spectrum (Me2SO-de) for pyrrole-l,2-dicarboximide(8) gave vinyl absorptions at 6 6.6,6.9, and 7.5 and an N-H absorption at 6 11.2. The 13CNMR spectrum showed 11 lines. The absorptions at 158.9 and 148.2 ppm are assigned as carbonyl carbons; the 134.9- and 126.1-ppm signals are assigned as quaternary sp2 carbons with the two remaining hydrogen-bearing sp2 carbons at 116.3 and 114.6 ppm. Finally, the IR (CHCl,) absorptions reporteds for 8 were a t 3440,1795, and 1745 cm-l, while 7j exhibited IR (CHC13) absorptions at 3425, 1797, and 1748 an-'. Thus,the spectroscopic data strongly support the structural assignment of 7j. S t r u c t u r a l Aspects of the Rearrangement Although the ring-expansion pathway outlined in Scheme I did not occur under the basic fragmentation conditions, a diazacycloodatetraene-typestructure was still a plausible intermediate in the formation of the pyridone. However, attempts to detect intermediate products in the 3 6 fragmentation by quenching the reaction at incomplete conversion of 3 led only to isolation of a mixture of 3 and 6. Since the direct observation of an intermediate in this fragmentation was unsuccessful, a method which would demonstrate the intervention of a diazacyclooctatetraene-type species was developed. If such an intermediate were present in the reaction, the known chemistry of cyclooctatetraene suggested that under the reaction conditions an equilibrium could exist between different bicyclic dianions and the bond-shift isomer 12 (Scheme 11).l0 Three of these bicyclic isomers, 11,13, and 14, could undergo [2 + 21 cycloreversion to give the observed pyridone. In addition, the sequence 9 15 16 17 could afford pyridone without involving an eight-membered-ring intermediate. Appropriate 13C-and l5N-labeling experiments as outlined in Scheme I1 would furnish evidence on the course of the 3 6 fragmentation. If ring-expanded intermediates 10 or 12 are involved in the reaction, then the 13C and I5N labeling shown in Scheme I1 would establish whether fragmentation occurs exclusively from 11, 13, or
-
---
-
(9) Papadopouloe, E. P. J . Org. Chem. 1972, 37, 351. (10)For a review, see: Paquette, L. A. Tetrahedron 1975,31, 2855.
po -0 NQ
R 17
Scheme 111. Synthesis of Uracil-''CC, 0 "ZN
CH2LC02W2 H
ANH NaOEt, ~
A*
h
O I
H
0
1)POCI 3HA$ 2)NaOH
I
3)H2, PdlC
H
14 since a differently labeled pyridone would result. Likewise, if pyridone formation is occurring from 11, 13, and 14, some ratio of 17-15N,17-13C,15N,and 17 would result. Unfortunately, the above labeling does not distinguish between the pathways 9 15 16 17-15Nand 9 ---* 10 11 17-"N. Rather than employ a doubly labeled uracil, two singly labeled systems were prepared. The 13C-labeled uracil was prepared from ureaJ3C (90 atom % 13C) as outlined in Scheme 111. For the photocycloaddition to 1-heptyne, it was diluted with uracil to afford 3c (10 atom % 13C). Fragmentation of 3cJ3C3gave pyridone 6c which showed
-
3c- 1 3.c3
---
.
6c
no enhancement of any peak in its 13C NMR spectrum relative to a standard pyridone sample. This complete loss of the 13Clabel rigorously excludes 13 in the pathway for pyridone formation. The 15N-labeleduracil was prepared as shown in Scheme IV by employing ammonium chloride (95 atom % 15N). The u r a ~ i l - ' ~ so N ~obtained was diluted with uracil to give uracil-I5N1(28 atom 5% 15N)which was used in the photocycloaddition. Fragmentation of 3c-15N2gave pyridone-15Nwhich had retained >95% of the original 15N.
Kaminski et al.
2340 J. Org. Chem., Vol. 48, No. 14, 1983
H,NkN -
Scheme VI. Kinetic Scheme for Fragmentation of 3c
Scheme IV. Synthesis of UracilJSN
0
CN
2)(Et0)3CH,)
AEt
Et
0-
NH4CI NaOH
A
A
H
22
k
23
0-
Scheme V. Preparation of 21c
24
19
QOCH3 CH3 21c
20
Thus, intermediate 14 is rigorously excluded as an intermediate leading to pyridone. 0
5H1 1
3c-
15 N2
KO-t-BU 15 6 ~ - N2
The labeling results noted above afford no evidence for a diazacycloodatetraene-typeintermediate since a pathway of 9 15 16 17 would also accommodate the labeling studies. What was required was an alternative strategy for preparation of the diazacyclooctatetrane-typeintermediate. Surmising that anionic repulsion might constitute some of the driving force for the [2 + 21 cycloreversion in a species such as 11, we examined silylation of 3c. For the disilylated compound 19, such a driving force would be absent, and perhaps the ring-expanded system could be detected. Reaction of 3c with trimethylsilyl chloride, hexamethyldisilazane, and trimethylamine (Scheme V) gave a new compound with an R, on TLC slightly greater than that of 3c. Workup of the reaction mixture followed by chromatography on silica gel gave a new product assigned as 21c in 71% yield. The 'H NMR spectrum [200MHz; two N-H absorptions at 6 7.63 ( 8 , 1H) and 6.80 ( 8 , 1H), an AB pattern at 6.15 (ABq, JAB= 12 Hz, Avm = 31.4 Hz), a singlet at 5.91 (1H), and the pentyl side chain at high field], the 13C NMR spectrum, and exact mass analysis strongly supported 21c as the structure of this new product. C o d i n g evidence was obtained by the quantitative conversion of 21c to 3c upon irradiation. This ring-expansion reaction of photoadducts 3 to the two-carbon ring-expanded compound 21 was also performed with 3i and 3k to give 21i and 21k, respectively. Attempts were made to isolate and study the dynamics of valence isomerizations of the disilylation product of 3c; however, this compound was extremely labile, decomposing to 3c and 21c with any trace of moisture. The crude 13C
---
NMR spectrum of the disilylation product was very similar to 21c with the exception of two additional signals due to the two trimethylsilyl groups. The IR spectrum (CHClJ showed strong absorptions at 1685,1660, and 1258 cm-' l1 and the absence of any N-H stretch. The azocine 20 has reported IR (film) absorptions at 1685, 1640, and 1280 cm-'. The 'H NMR spectrum of the disilylation product was nearly identical with that of the vinyl region [6 6.17 (ABq, JAB= 12 Hz, Av = 31 Hz, 2 H) and 5.92 (br s, 1H)] of 21c. While recognizing that these spectroscopic data were obtained on the crude silylation product, it appears to us that the major component obtained from silylation of 3c is the 0-silylated compound 19 or its bond-shift isomer. With the eight-membered-ring system available, its chemical reactivity under the conditions of the fragmentation reaction could be examined. When 21c was treated with 2 equiv of potassium tert-butoxide in tert-butyl alcohol, it was converted to the pyridone 6c in 84% yield. Interestingly, the 21c 6c conversion required 5 min, while the conversion 3c 6c under the same reaction conditions took 4 h. For completeness,the l5N-1abeled 21c
--
2 equiv
h
5
d
H
15 2 1 ~ - N1
,
KO-t-Bu -'
0QC5"l HI
6c- 15N1
was fragmented, yielding pyridone with >95% retention of the 15Nlabel. Evidence has now been presented for the plausible intermediacy of the dianion of 21 in the 3 6 fragmentation reaction.
-
-
Kinetic Studies Kinetic measurements were made on the 3c 6c conversion to obtain more detailed information on the steps in the fragmentation reaction. First, the relative acidity of the N-H protons in 3c was determined by potentiometric titration of 3c in tert-butyl alcohol with potassium tert-butoxide in tert-butyl alcohol. One end point in the titration was observed at an apparent pKal2J3of 14.3. Thus, the monoanion 22 would be nearly completely formed under the reaction conditions. Since a second end
-
(11)Paquette, L.A.;Hansen, J. F.; Phillips, J. C. J.Am. Chem. SOC. 1971,93,152. (12)No thermodynamic significance should be attached to the pK, values obtained in tert-butyl alcohol; however, they are valid as measures of relative acidity. (13)The potentiometric measurements were made as described by: Simms, H. S. J. Am. Chem. SOC.1926,48, 1239.
J. Org. Chem., Vol. 48, No. 14, 1983 2341
Anion-Mediated Fragmentation Reactions
I
40 r
36 32
A
0 not shown
0.01 0.01 0.01
0,011 0.011 0.021
0.38 0.37 0.38
1
4 t 1.1
0
2.2
3.3
4.4
5.5
6.6
8.8
7.7
9.9
0
11
0
5000
10000
time (minl
Figure 1. Plot of kinetic expression for 3c fragmentation: a. = initial concentration of 3c; bo = effective base concentration ([KO-t-Bu] - ao);r = concentration of pyridone 6c.
k2[22] [KO-t-Bu] k3 k_,[t-BuOH]
+
)
In the presence of excess potassium tert-butoxide, the initial concentration of 22 is equal to the initial concentration of 3c, [3cI0. One equivalent of base is now needed to convert 3c to 22; thus, the effective base concentration is equal to the initial base concentration less [3cI0. On the assumption that k3
