1914 J . Org. Chem., Vol. &,,No. 13, 1975
Weinstock, Gaitanopoulos, and Sutton
ratories) for the 100-MHz NMR and field ionization mass spectral studies, respectively. Registry No.-la, 1793-07-3; 2a, 55043-76-0; 2a S c h i f f base, 55043-77-1; 2b, 55043-78-2; 3, 55043-79-3; 4, 55043-80-6; 5b, 474317-3; 6a, 5100-23-2; 6b, 18928-48-8; 7a, 55043-81-7; 7b, 55043-82-8; 8a, 23829-79-0; 8b, 23829-80-3; 10, 1904-58-1; 12,)30386-01-7; 13, 55043-83-9; 18, 7143-42-2; 19, 85-91-6; 20, 33923-02-3; 21, 5504384-0; 23,55043-85-1; 24,55043-86-2; 25,55043-87-3; methylhydrazine, 60-34-4; p-nitrobenzaldehyde, 555-16-8; potassium t e r t - b u toxide, 3999-70-0; methanol, 67-56-1; urea, 57-13-6; e t h y l chloroformate, 541-41-3.
References and Notes (a) G. A. Archer and L. H. Sternbach, Chem. Rev., 68, 747 (1968); (b) L. H. Sternbach in "The Benzodiazepines", Raven Press, New York, N.Y., 1973, pp 1-27. Class here refers to position of the nitrogen atoms in the triazepine ring and not to positions of unsaturation. The six classes, thus, refer to nitrogen atoms in the following positions: 1,3.4; 1.2,5; 1,3,5; 1,2,4; 1,2,3: and 2.3,4. For example, see H. Kohl, P. D. Desai, A. N. Dohadwalla, and N. J. de Souza, J. fharm. Scl., 63, 838 (1974). (a) For example, see S. Rossi, British Patent 1,219,847; Chem. Abstr., 74, 141901j (1971): S. Rossi, German Patent 2,064,207; Chem. Abstr., 7 5 , 76854a (1971). (b) We have developed a new entry into this class of compound in our laboratories which will be the subject of a later report. For example, see G. Doleschall, G. Hornyak, B. Agai, G. Simig, J. Fetter, and K. Lempert, Tetrahedron Lett., 5069 (1973), and references cited therein. The structure of 2a follows from spectral and chemical evidence. The NCH3 and NHz signals in the NMR spectrum of 2a appear as singlets at 6 3.19 and 3.97, respectively. Compound 2a formed a Schiff base with p-nitrobenzaldehyde (see Experimental Section). Based on the known relative nucleophilicities of the nitrogen atoms in methylhydrazine, 2e is the expected isomer from the reaction of l a with methylhydrazine. Other authors7 have reported reactions of methylhydrazine with phenyl isocyanates to yield products analogous to 2, but offer no evidence to distinguish their products from the other possible isomers. (a) M. Wiicox, J. Med. Chem., 11, 171 (1968); (b) French Patent 1,521,959; Chem. Abstr., 71, 3166k (1969). Y. Iwakura, K. Uno, and S. Kang, J. Org. Chem., 31, 142 (1966).
(9) 0. Hromatka. F. Krenmuller, and M. Knollmuller, Monatsh. Chem., 100, 934 (1969). (IO) (a) E. Thielepape, Chem. Ber., 68, 751 (1935): (b) W. S. Fones, J. Org. Chem., 14, 1099 (1949); (c) see also the preparation of 21 from 12 in the Experimental Section. (11) A. K. Butler in "Organic Reaction Mechanisms", B. Capon and C. W. Rees, Ed., Wiley, New York. N.Y., 1972, p 189. (12) A. L. Langis and M. P. Charest, Chim. Ther., 349 (1967). (13) R. L. Jacobs, J. Heterocycl. Chem., 7 , 1337 (1970). We tharik Dr. Jacobs, of Sherwin-Williams Chemicals, for an authentic sample of this compound. Compound 12 was also identical with a commercial sample of 3-amino-2,4(1H,3h)-quinazolinedione obtained from Carbolabs Inc., New Haven, Conn. (14) Two of the benzotriazepinediones reported by Langis and Charest were prepared from the N-(2-aminobenzoy1)semicarbazides i and ii by thermal cyclization in decalin. Since the reported melting points for the products thus obtained from i and ii do not closely jibe, respectively, with those of compounds obtained from their treatment of iii and iv with urea in decalin (compounds which we suspect are quinazolinediones), the products derived from i and ii may be authentic benzotriazepinediones.
X
r) F8.H; II /
WwCNNHC0"-
w
SH,
i, X = H ii, X
=
C1
P X
II
wcyHNH w SH,
~ hX , lV,
=
H
x = ci
(15) (a) D. M. Bailey, U.S. Patent 3,607,866 (1971); Chem. Abstr., 75, 1 4 0 9 1 0 ~(1971); (b) Dr. Bailey has examined a preprint of this manuscript and concurs with these findings. (16) N. P. Peet and S. Sunder, J. Org. Chem., 39, 1931 (1974). (17) The structure of this material has been identified and will be disclosed in a future report. (18) The reactant concentration in this preparation was 0.094 M. When run at a reactant concentration of 0.25 M,the yield of 7a was 10.7%. (19) E. Kuhle and R. Wegler, JustusLlebigs Ann. Chem., 616, 183 (1958). (20) An aliquot of the reaction mixture withdrawn at this point showed the precipitate to be 12. (21) G. B. Barlin, J. Appl. Chem., 12, 148 (1962). (22) We have also prepared 10 by heating isotoic anhydride and hydrazine hydrate neat or in DMF at 50". (23) J. R. A. Pollack and R . Stevens, Ed., "Dictionary of Organic Compounds", Vol. . 4, Oxford University Press, London, 1965, p 21 19. (24) A. I. Vogel, "Practical Organic Chemistry", Longmans. Green and Co.. New York, N.Y., 1956, p 1000.
Synthesis of Fused Phenothiazines. 2,3-Dihydro- 1H-pyrimido[ 5,6,1-kl]phenothiazine- 1,3-dione and 6H,16H-[ 1,5]Diazocino[3,2,1-kl:7,6,5-k'l']diphenothiazine-6,16-dione Joseph Weinstock,* Dimitri E. Gaitanopoulos, and Blaine M. Sutton Smith K l i n e a n d F r e n c h Laboratories, Philadelphia, Pennsylvania 19101 Received F e b r u a r y 25,1975
10-Trifluoromethyl-2,3-dihydro-l~-pyrimido[5,6,l-kl]phenothiazine-3-one-l-thione (6) was prepared starting f r o m 8-trifluoromethylphenothiazine-1-carboxylic acid (3) by t h e r m a l cyclization o f t h e acid isothiocyanate. T h i s was converted t o tee 1,3-dione by acid hydrolysis o f t h e 1 - m e t h y l mercaptan derivative. A l k y l a t i o n a n d oxidation t o sulfoxide a n d sulfone derivatives are described. Pyrolysis o f t h e anhydride of 3 gave 3,13-bis(trifluoromethyl)6 H , 16H-[1,5]diazocino[3,2,1-k~:7,6,5-k'l']dipher~othiazine-6,16-dione.
Quinazoline-2,4-diones ( l ) ,derived from flufenamic acid, were recently described as anti-inflammatory agents1 0
Since we previously observed anti-inflammatory properties with 8-trifluoromethylphenothiazine-1-carboxylic acid (3),2 an analog of flufenamic acid, we undertook preparation of some pyrimidinediones (2) derived from 3. Typical syntheses of quinazolinediones such as 1 involve fusing the N-arylanthranilic acid, ester, or amide with urea, thiourea, or ethyl carbamate a t 200°.3 However, these reaction conditions using 3 returned unreacted starting material. Also treatment of the ethyl ester of 3 with sodium cyanate in trifluoroacetic acid, another quinazoline-1,3dione synthesis: also failed. A possible cause for these failures was a low reactivity of the diary1 nitrogen owing to it
Synthesis of Fused Phenothiazines
J . Org. Chern., Vol. 40, No. 13, 1975 1915
C=O
COR
l
3, R = O H
4, R = CI 5. R = K C S
15
7
8
0,)
I
9. R = CH,CH, 10, R = CH,CH,OH 11, R = CH?CHOHCH,OH 12. R = CH,CHOAcCH,OAc
13, n = 1 14, n = 2
Table I 2-Alkyl- lO-trifluoromethy1-2,3-dihydro1Hpyrimido[5,6,1-kl]phenothiazine- 1,3-dione Sulfoxides (13) a n d Sulfones (14) ' R
n
Yi
