J . Org. Chem. 1980,45, 161-163
161
g of pyridinium chlorochromate were suspended in CH2C12,and the solution was stirred for 6 h. Ether was added, and the mixture was filtered over florisil. The organic layer was extracted with NaHC03 solution and with H20. After the solution was dried and evaporated, the product was obtained yield 0.3 g; [(Y]578 -19" ( C 1.54, CHZClZ). (S)-(-)-2-Cyclohexenol. To a solution of 2.2 g of (S,S)(-)-2,3-epoxycyclohexanonein 25 mL. of MeOH at 0 "C were added a few drops of acetic acid and 2.5 mL of hydrazine hydrate, and after the solution had been stirred for 0.5 h, it was evaporated. Water was added and extracted with ether. After drying (MgSOJ and evaporating the organic layer, crude product was obtained. Distillation gave 0.93 g of pure (S)-(-)-2-cyclohexenol: yield 48%; [a1578 -15" (C 1.28, CHZC12). Determination of the Enantiomeric Excess of Alcohol 3. Following the procedure described by Mosher,21the ester of the alcohol 3 +219 was prepared, and its 'H and leF NMR were determined: 'H NMR (CDC13)6 7.6-7.4 (m),6.0-5.5 (m), 3.6 (s), 2.1-1.6 (m); l9F NMR (CFC13) 6 72.1 (two signals).
60%; [a]578 -15O (c 0.68, CH2C12);'H NMR (CDC13)6 3.6 (m, 1 H), 3.2 (d, 1 H), 2.3-1.3 (m, 4 H), 1.1 (s, 3 H), 1.0 (s, 3 H). Anal. Calcd: C, 68.54; H, 8.63. Found: C, 67.79; H, 8.65. (R)-(+)-2-Cyclohexenol(3). LiA1H4 (1.69 g, 44 mmol) was suspended in ca. 300 mL of dry ether. Quinine (44 mmol, 14.24 g) was added, and the suspension was refluxed for 15 min. After the mixture was cooled to 0 "C, 3.84 g of cyclohexenone (40 mmol) dissolved in 10 mL of ether was added, and stirring was maintained for 1 h at 0 OC. Water was added (ca. 5 mL) followed by 10% HzSO4 until all of the solid had disappeared. The water layer was extracted with ether (3 x 50 mL). The organic layer was dried (MgSO,) and evaporated, yielding 2.6 g of cyclohexenol (58%), [(Y]578 +21.7" (C 1.95, CH2C12). cis-2,3-Epoxycyclohexanol[ ( )-41. Cyclohexenol (1.5 g) ([a]578 +21.8) and 3.1 g of rn-chloroperbenzoicacid (85% purity) were dissolved in CHzC12at 0 "C. After the mixture was sitrred for 16 h, it was filtered and the organic layer extracted with dilute NaOH solution and HzO. The organic layer was dried (MgS04) and evaporated, yielding 0.85 g of epoxide: +6.4" (c 2.05, CH2C1,); 'H NMR (CDClJ 6 4.0 (m, 1H), 3.3 (s, 2 H), 2.8 (s, OH), 2.0-1.0 (m, 6 H). (S,S)-(-)-2,3-Epoxycyclohexanone. cis-2,3-Epoxycyclohexanol (0.85 g) +6.4), 1.44 g of sodium acetate, and 3.55
+
Registry No. la, 930-68-7; lb, 4694-17-1; IC, 6553-64-6; 2a, 72029-30-2; 2b, 72003-85-1; 2c, 72003-86-2; (R)-3,3413-44-3; (S)-3, 6426-26-2;4, 72029-31-3.
Notes Application of N-Phenyltrifluoromethanesulfonamidesto the Synthesis of Pyrazines
+ 5~~ 'YQ 'I K2C~'(C*312NC*0
~~~~
21+,HCH2U(*NH2
,
31 Ot'CH,OH/CH,o-N.'
R
Br
+
6
+
CF,W2H
Raymond J. Bergeron*
Figure 1. Reaction scheme for the synthesis of the pyrazines
Department of Medicinal Chemistry, J. Hillis Miller Health Center, University 'of Florida, Gainesuille, Florida 32610
Table I
from the corresponding a-imino ketones.
R'
Patrick Hoffman'
0
McCormick and Company, Inc., Hunt Valley, Maryland 21031
N
Received April 18, 1979
Introduction The pyrazines have long been of interest to medicinal chemists. These compounds, many of which are natural products, have proven to be useful as antibiotics,2 tuberorganoleptic^,^ and antitumor c u l o s t a t i c ~ diuretics,* ,~ agents.'j The two most common routes to these heterocycles involve either the self-condensation of a-amino ketones' or the condensation of 1,2-dicarbonyl compounds with 1,2diamines,* followed by oxidation of the resulting di-
I
yield, %
CH,
70
CH, CH,
65 60
hydropyrazines to the corresponding pyrazine~.~ As with most synthetic methods, the utility of the sequence is limited by the accessibility of the starting materials. Unfortunately, none of the above starting materials is easily synthesized in high yield, and at least one group of them, the a-amino ketones, has the added problem of instability.
Results and Discussion This investigation is directed at improving the diamine sequence described above. Our scheme emphasizes the synthesis of a reactive imino ketone intermediate which can be condensed with the appropriate diamine and the resulting dihydropyrazine oxidized to the corresponding pyrazine. The sequence proceeds in good yield and does not require the isolation of intermediates. In an earlier investigation we determined that Nphenyltrifluoromethanesulfonamides could be alkylated
(1) This work was done in partial fulfillment of the requirements for a Doctorate in Chemistry at the University of Maryland. (2) J. Briggs, J. Chern. Soc., 2995 (1965). (3) I. M. Weiner and J. P. Tinker, J. Pharrnacol. Exp. ?'her., 180, 411 (1972). (4) Kenneth L. Shepard, Wasyl Halczenko, and Edward J. Cragoe, Jr., J. Heterocycl. Chern., 13, 1219 (1976). (5) J. A. Maga and C. E. Sizer, "Pyrazines in Food", T. E. Furia and N. Bellanca, Eds., CRC Press, Inc., Cleveland, OH, 1975, p 47. (6) Andre Rosowsky, Katherine K. N. Chem, and Nickolas Papathanasopoulos, J . Heterocycl. Chem., 13, 727 (1976). (7) H. Iida, K. Hayashida, M. Yamada, K. Takahashi, and K. Yamada, Synth. Comrnun., 3, 225 (1973). (8) N. Sato, J . Heterocycl. Chem., 15, 665 (1978).
0022-3263!/80/1945-0161$01.00/0 ,
RZ
~
~~
(9) T. Akiyama, Y. Enomoto, and T. Shibamoto, J. Agric. Food Chem., 26, 1176 (1978).
0 1980 American Chemical Societv -
162
J. Org. C'hem., Vol. 45, No. 1, 1980
in high yield with a variety of alkyl halides a n d a-halo ketones under mild conditions.1° When the alkylating agents were a-halo ketones or aldehydes, we observed that even under the mildest reaction conditions, i.e., in K2C03/ acetone, the elements of CFBS02Hwere eliminated from the product. We have now shown that these a-imino ketones when reacted with diamines followed by oxidation with molecular oxygen under basic conditions produce pyrazines. Furthermore, the starting a-halo ketones or aldehydes for the sequence are accessible in high yield through a variety of different techniques. The scheme is summarized in Figure 1. The yields of a number of pyrazines prepared by t h i s method are summarized in Table I. In general, the procedure involves alkylation of N phenyltriflamide with a n a-bromo ketone in DMF at 80 "C with K2C03as the base. The elimination to the imino ketone can be effected concurrently with the alkylation by using an excess of K2C03,or, alternatively, the alkylation product can be isolated. However, owing to their instability, neither the imino ketones nor t h e dihydropyrazines were isolated. The condensation of the imino ketone with t h e diamine was carried out on the crude imino ketone by using a slight excess of the diamine. Although the dihydropyrazines were not isolated, the reactions were followed by GC/MS which indicated the major products to be aniline and the dihydropyrazine. At this point, t h e reaction mixture was added to a n oxidizing media consisting of 02/NaOH/CH30H. The resulting pyrazines were easily isolated by standard procedures.
Experimental Section Materials. Trifluoromethanesulfonic anhydride (triflic anhydride) and N-phenyltrifluoromethanesulfonamide(phenyltriflamide) were prepared as previously described by Hendrickson et al." The infrared (IR) spectra were recorded on a Perkin-Elmer 257 grating spectrophotometer. The 'H NMR spectra were recorded on a Varian EM 360 spectrometer; the chemical shifts are given in parts per million relative to internal Me4&. Mass spectra were taken on a Du Pont 21-490 mass spectrometer. Elemental analyses were done by Galbraith Laboratories, Inc., Knoxville, TN. Melting points were taken on a Thomas-Hoover apparatus and are uncorrected. VPC analyses were done on a Hewlett-Packard 5710A equipped with a thermal conductivity detector and using a glass column packed with 5% SF96 on Chromosorb WAW, DMCS, or on a Varian Aerographi 1400 equipped with a flame ionization detector and using a glass column packed with 10% SE30 on Chromosorb WAW, DMCS. Preparative thin-layer plates (silica gel GF) were supplied by Analtech, Inc. 5-Methyl-3-bromo-2-hexanone. This compound was prepared from 5-methyl-2-hexanone in 96% yield by using the method described by Bauer and Macornber.l2 The product was distilled, bp 41-44 "C (30 mmHg), and an analytical sample collected by gas chromatography: IR (neat) 2956, 1714, 1460, 1351 cm-'; 'H NMR (CDClJ 6 4.32 (t, 1,J = 7.2 Hz), 2.38 (s, 3), 1.80 (m, 3, CH and CH2),0.98 (m, 6, CH,'s); mass spectrum, m / e (re1 intensity) 195, 194, 193, 192 (>l),138 (12), 136 (13), 43 (100); m / e 195 and 193 are due to inn-molecule interactions (p + 1). Anal. Calcd for C7H13BrO: C, 43.54; H, 6.79. Found: C, 43.85; H, 6.71. 3-Bromo-2-undecanone. Bromination of 2-undecanone was effected by using the method of Davies and Sumrner~.'~The yield of 3-bromo-2-undecanone was quantitative; bp 141-143 "C (17 mmHg). An analytical sample was collected by gas chromatography: IR (neat) 2930, 2957, 1724,1458,1354, 1222, 1147 cm-'; 'H NMR (CDC13)6 4.23 (t, 1, J = 6.8 Hz), 2.33 (s, 3), 1.98 (m, 2), 1.29 (m, 12, CH2's),0.89 (t, 3, J = 5 Hz); mass spectrum, (10) R. J. Bergeron and P. G. Hoffman, J.Org. Chem., 44, 1835 (1979). (11)J. B. Hendrickson, D. D. Sternbach, and K. W. Bais, Acc. Chem. Res., 10, 306 (1977). (12) D. P. Bauer and R. S. Macomber, J. Org. Chem., 40,1990 (1975). (13) A. R. Davies and G. H. P. Summers, J. Chem. Sot. C, 1227 (1967).
Notes
m / e (re1 intensity) 251, 250, 249, 248 (
