THE JOURNAL
OF
Organic Chemistry 0 Copyright 1974 by the American Chemrcal Society
VOLUME39, NUMBER5
MARCH8,1974
Reaction of Pyrimidines with Diarylmethyl Cations Calvert W. Whitehead,* Celia A. Whitesitt, a n d Allen R. Thompson T h e Lilly Research Laboratories, Eli Lilly and C o m p a n y , Indianapolis, Indiana 46206 Received October 12, 1973
Pyrimidine is not alkylated by diarylmethyl cations, but substitutions do occur at an endocyclic nitrogen with 2- and 4-hydroxypyrimidine and at the sulfur of 2-mercaptopyrimidine. Diarylmethylations occur exclusively at the 5-carbon position of 2,4-dihydroxy-, 2,4,6-trihydroxy-,and 6-amino-2,4-dihydroxypyrimidines. The effects of Lewis acid catalysts as well as substituents on the diarylmethyl cations on the alkylation reactions are discussed. Also, alternate synthetic routes to the 5-diarylmethylpyrimidines are given. Pyrimidine and pyrimidine derivatives present several electron-rich nucleophilic centers where a carbonium ion may attack. Only one example of this reaction is reported with a diarylmethyl cation, a n d in this case t h e extranuclear nitrogen of 2-aminopyrimidine is a1kylated.l On t h e other h a n d , alkylations of a carbon atom are reported for 2 - h y d r o ~ y p y r i d i n e ,thiophene,3 ~ 9 - m e t h y l ~ a r b a z o l e ,pyr~ r0le,5 hydroxyquinolines,6 and indole^.^ T h e 2-, 4-,a n d 6-carbon atoms in pyrimidine are electron deficient by virt u e of t h e electron-withdrawing effect of t h e nitrogen atoms a n d are not susceptible t o alkylation.8 Carbonium ion alkylations, therefore, could be expected to take place only at a n electron-rich ring nitrogen or perhaps a t t h e 5carbon atom, although t h e latter is made slightly electron deficient by t h e general inductive effect. This report describes t h e reactions of diarylmethyl carbonium ions with pyrimidine, mercaptopyrimidine, a n d hydroxypyrimidines.
dine t o give a moderately good yield of [(2-diphenylmethy1)thio)pyrimidine (6,T a b l e I). Scheme I Ar
1, R = CCH, 2, R = 2,4-CI2Cl,H,
Ar
Ar-$H-C,H5
3, Ar = ChHj 4, Ar = 2,4. CI,C,H,
C,H,>-CH-C,H,
Results
No C or N alkylation products of pyrimidine were isolated when pyrimidine was treated with benzhydrol (1) in acetic acid either in t h e presence or absence of a Lewis acid catalyst. A very small amount of N-acetyl(dipheny1methy1)amine was isolated a n d t h e remaining 1 was recovered as diphenylmethyl acetate. T h e conversion of 1 t o diphenylmethyl acetate was shown to occur quantitatively within 15 min in hot acetic acid. One electron-releasing substituent on pyrimidine, such as hydroxy or mercapto group in t h e 2 or 4 position, supplied sufficient electron density for electrophilic attack t o take place a t one of the heteroatoms (Scheme I). Partial alkylation of 2-hydroxypyrimidine occurred with 1 and with 2,4-dichlorobenzhydrol (2) in acetic acid t o give low yields of t h e respective 1-diarylmethyl-2(lH)-pyrimidinones (3 a n d 4, Table I). Addition of boron trifluoride had little effect. More complete alkylation of 4-hydroxypyrimidine occurred with 1 t o furnish 3-diphenylmethyl4(3H)-pyrimidinone (5, Table I). T h e diphenylmethyl cation attacked t h e extranuclear sulfur of 2-mercaptopyrimi-
6
Two or three electron-contributing groups a t the 2, 4, and 6 positions of pyrimidine caused t h e diarylmethyl cations to be attracted to the 5 position of pyrimidine (Scheme 11). Reaction of uracil or 2-thiouracil, however, did not occur with 1 after 5 days in refluxing acetic acid. When boron trifluoride or stannic chloride was added, the alkylation was complete in several hours a n d nearly quantitative yields of t h e 5-(diphenylmethyl) derivatives (7 and 8, Table 11) were isolated. Similar reaction conditions with 1 a n d 6-methyluracil gave a good yield of 6-methyl5-(diphenylmethy1)uracil (9, Table 11). Chlorine substituents of 2 had only a slightly inhibitory effect on t h e carbonium ion alkylations of uracil a n d 6-methyluracil. Yields of t h e 5-[(2,4-dichloro)diphenylmethyl]uracils (10 and 11, Table 11) were only a few per cent lower t h a n t h e yields for t h e corresponding 5-(diphenylmethyl)uracils (7 a n d 8 ) . 587
588
J. Org. Chem., Vol. 39, No. 5, 1974
Whitehead, Whitesitt, and Thompson
Table I N-Diarylmethylpyrimidines and [ ( 2 - D i p h e n y l m e t h y l )thio ]pyrimidine
a n d t h e minor product 6-amino-1,3-dimethyl-5-(diphenylmethy1)uracil (23, Scheme 111).
Scheme I11
5
3. 4
*"
6
Compd no.
AI
Mu, OC
% yield
3
C6HS 2,4-C12CsHa C6HS CeH5
204 185-187 158-159 104
13 18 51 63
4 5 6
CH, I
I
OH
NH2 However, t h e chloro substituents had a pronounced inhib22 23 itory effect upon t h e reactions with 4,6-dihydroxypyrimiXanthen-9-01 is completely oxidized to xanthen-9-one dine a n d 4,6-dihydroxy-2-(methylthio)pyrimidine. A 40% within 15 min in hot acetic acid. Successful competitive yield of 5 - [ (2,4-dichloro)diphenylmethyl]uracil(12, Table 11) was obtained from 2 a n d 4,6-dihydroxypyrimidine, alkylations of pyrimidines by xanthen-9-01 occurred rapidly or otherwise not a t all. Barbituric acid and 4,6-dihycompared with a 78% yield of 4,6-dihydroxy-5-(diphenyldroxypyrimidine gave excellent yields of t h e corresponding methy1)pyrimidine (13, Table 11) obtained from 1 and 5-(9-~anthenyl)pyrimidines(24 a n d 25, Table 111). At4,6-dihydroxypyrimidine.A very low yield of 5 - [ (2,4-ditempted reactions with uracil a n d thiouracil, on t h e other c hloro)diphenylmethyl]-4,6-dihydroxy-2-( methy1thio)pyrihand, failed because of their low solubility in acetic acid. midine (14, Table 11) resulted from 4,6-dihydroxy-2Cytosine gave a 55% yield of 5-(9-xanthenyl)cytosine (26, (methy1thio)pyrimidine a n d 2 while t h e similar 4,6-dihyTable 111), b u t only a very low yield of 4-amino-5-(diphendroxy-2-methylpyrimidinereacted quantitatively with 1 t o 4,6-dihydroxy-5-(diphenylmethyl)-2-methylpyrimi-ylmethyl)-2-hydroxypyrimidine (27, Table 11) was obgive tained from cytosine and 1. dine (15,Table 11).
Scheme 11
Scheme IV
37R' +
Barbituric acid was alkylated by diarylmethyl cations without t h e aid of strong acid catalysts, but t h e yields were low (Table 11), even with longer t h a n usual reaction times. When either stannic chloride or boron trifluoride was present, alkylation with 1, 4-chlorobenzhydrol, or 2 gave good t o excellent yields of the respective 5-diarylmethylbarbituric acids (16, 17, a n d 18). T h e alkoxy groups of 3,4-diethoxybenzhydrol retarded t h e alkylation reaction of barbituric acid (19, Table 11), but this effect was less t h a n t h a t observed with t h e 2,4-dichloro- a n d 4chlorobenzhydrols. Tritylation of barbituric acid was accomplished, but because of a n unusual and interesting behavior of t h e product t h e results will be reported in a n other paper. A Lewis acid catalyst did not enhance t h e diphenylmethylation of 6-aminouracil. T h e yield of 6-amino-5(diphenylmethy1)uracil (20, Table 11) obtained without t h e catalyst was twice t h a t with t h e catalyst. Alkylations of hydroxypyrimidines by diphenylmethyl cation were a t tempted in concentrated sulfuric acid and in polyphosphoric acid; both were unsuccessful because of low yields. Sulfuric acid, added t o t h e acetic acid solution, may have catalyzed the reaction of 1 with 4-amino-6-hydroxy-2-pyrimidinethiol t o give a 52% yield of 4-amino-6-hydroxy-5(diphenylmethyl)-2-pyrimidinethiol(21, Table 11). A Lewis acid catalyst was not required for t h e reaction between 1 and 6-amino-1,3-dimethyluracil. Alkylation a t t h e 5-carbon position was a t least 80% complete in hot acetic acid. Partial hydrolysis of t h e 6-amino group occurred a n d t h e reaction mixture yielded t h e major product 1,3-dimethyl-5-(diphenylmethyl)barbituricacid (22)
26
Since fluoren-9-01 was oxidized in acetic acid, reactions of this tricyclic carbinol with hydroxypyrimidines were not attempted. T h e reaction of 10,11-dihydro-5H-dibenzo(a,d]cyclohepten-5-ol with uracil gave a moderately good yield of 5-(lO,ll-dihydr0-5H-dibenzo[a, d ] cyclohepten-5-y1)uracil (28, Table 111) and with barbituric acid kave a n excellent yield of 5-(lO,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)barbituric acid (29, Table 111). T h e large dibenzo[a, dlcycloheptene group of 29 is restricted from freely rotating about t h e bond to t h e pyrimidine ring. T h e n m r doublet signal, centered a t 3.85 ppm from t h e pyrimidyl-5 proton, and t h e doublet, centered a t 4.50
J . Org. Chern., Vol. 39,No. 5, 1974 589
Pyrimidines with Diarylmethyl Cations
Table I1 5-Diarylmethylhydroxypyrimidines and 5-Diarylmethyl Mercaptopyrimidines
No.
R
Rl
Rz
7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 27
HO HS HO HO HO H H CHaS CHz HO HO HO HO HO HS HO
HO HO HO HO HO HO HO HO HO HO HO HO HO HO NHz NHz
H H CHI H CHa HO HO HO HO HO HO HO HO NHz OH H
"/o yield
MP, 'C
AI
CsHs C6H5 CsH5 2,4-ClzCeH3 2,4-C1zCsH3 2,4-C1zCaHa C6H5 2,4-ClzCsH3 C6H5 C6H5 4-ClCsHa 2,4-Cl&sH3 3,4- ( C 2 H 5 02C6Ha ) CsHs C6H5 C6H5
298-300 264 285-287 294 247-249 305 329-330 255 >300 220 l l O d
234 180-182 330-342 170-180d 236
96" 99 80 81," 95" 71° 40 78 14 98 98'9' 7 3e 67,atJ83* 42 670 52 4h
SnCh was used as catalyst (5 g/O.1 mol). * W i t h BFa catalyst (5 g/O.1 mol). c T h e yield was 56% without BFa catalyst. Solvated. 8 T h e yield was 37.5% without BF3. T h e yield was 22% without catalyst. 0 T h e yield was 38.5% with SnCh catalyst. T h e same reaction conditions were used for compound 21.
Table I11 5- (9-Xanthenyl) and 5- (10,ll-Dihydro5H-dibenzo [a,d Icyclohepten-5-yl )pyrimidines
Table IV Aralkyl Malononitriles and Malondiamides
-
K-CH
Compd no.
24 25 26 28 29
X
0 0 0 (CH?)? (CHI)?
R
Hi
RZ
Mp, "C
%yield
HO H HO HO HO
HO HO HzN HO HO
HO HO H H HO
290 285 320 dec 295 244-246
81 95 55 68 85
Scheme V
N /
+
:($$
\ 7 O % x 29
p p m from t h e 9,10-dihydrobenzo[a,dlcycloheptenyl-5 proton, have J values of 9 Hz indicating t h a t the molecule
/x \
x
Compd no.
R
X
Mp, OC
30 31 32 33 34 35
(CeHs)zCH 2,4-C12CsHaCHCsHs (CaH5)yCH 2,4-ClzC6HaCHCsHs CISH~O' (CsHi)&
CONH? CONHz C-N C=N C=N C=N
285 270-274 62-64 108-114 184 155
(%yield
91.2 55 6" 87 85 75 45.5
T h e yield was reduced to 47.4% when glacial acetic acid was used as the reaction solvent. * Xanthen-9-yl. exists approximately two-thirds of the time in the trans configuration. Rotation of the xanthen-9-01 group bonded t o the 5 position of barbituric acid, as in 25, is not restricted a n d t h e signals from the vicinal protons a t the bond are split by only 3 Hz. An alternate synthesis of 5-diarylmethylpyrimidines was investigated wherein malonic acid derivatives were alkylated by arylmethyl cations, and t h e products were cyclized. Malononitrile failed to react with either 1 or 2 in hot acetic acid a n d , when boron trifluoride was added, exothermic reactions occurred t o give intractable mixtures of products. However, the two carbinols did react with malondiamide in acetic acid a n d boron trifluoride (Scheme VI) but gave low yields of the diarylmethylmalondiamides (30 a n d 31, Table IV). Yields improved when t h e solvent was formic acid a n d a nearly quantitative yield of diphenylmethylmalondiamide (30) was obtained. The halogen substituents of 2, here again, retarded the carbonium ion reaction a n d a lower yield of 2,4dichloro(diphenylmethy1)malondiamide (31) resulted. The malondiamides (30 and 31) were dehydrated with phosphorus oxychloride in acetamide to give good yields of the corresponding diarylmethylmalononitriles (32 a n d 33, Table IV). T h e reactions of xanthen-9-01 and triphenyl-
590
J. Org. Chem., Vol. 39, No. 5, 1974
Whitehead, Whitesitt, a n d Thompson
Table V Cyclizations of 2-Diarylmethylmalondiamides (Compounds 12 and 13) HCONH?, ml
Base
K O C ICH3)J N a 0 C?H5 KOCI C H J ) ~ NaOCHj NaOCHJ NaOCHP NaOCH3 NaOH
(CHs):SO, ml
Temp, " C
Time, hr
0
Reflux Reflux 100 100 135 125 125 125
3 10 15 15 16 15 15 7
150 50 50 50
d
50 50
40
60
50 50 50
50 50 50
% yield of pyrimidine
