(00001 THESIS LIBMRY Michigan State University This is to certify that the thesis entitled SYNTHESIS AND SYNTHETIC APPLICATIONS OF GAMMA BROMINATED BETA DICARBONYLS presented by ERIC JOHN LIND has been accepted towards fulfillment of the requirements for Date SEEM 8 0-7639 MSUi: an Ammnn'u- ‘ ' "1 m" ', Institution IV‘ESI.) RETURNING MATERIALS: Place in book drop to “saunas remove this checkout from ”—- your record. FINES will be charged if book is returned after the date stamped below. SYNTHESIS AND SYNTHETIC APPLICATIONS OF GAMMA BROMINATED BETA DICARBONYLS BY Eric John Lind AN ABSTRACT OF A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Department of Chemistry 1984 ABSTRACT SYNTHESIS AND SYNTHETIC APPLICATIONS OF GAMMA BROMINATED BETA DICARBONYLS BY Eric John Lind The gamma brominations of beta-dicarbonyl compounds were investigated. The initial compound of interest, 7,7’-dibromoacetylacetone . was produced by treating acetylacetone with tetramethylammonium tribromide (TMAT) in ether. In this reaction agfl-dibromoacetylacetone formed first. but the bromine would rearrange to give the more stable 7.71-dibromoacetylacetone isomer in good yield. This alpha-gamma bromine rearrangement was also observed in other beta-dicarbonyl systems when brominated in this manner. The synthetic utility of 7,71dibromoacetylacetone was demonstrated in making its new pyrazole derivative, 3,5-bis(bromomethyl) pyrazole. In conclusion there is a brief discussion of possible reactions of 3.S-bis(bromomethyl)pyrazole with pyrrole derivatives. To my wife Donna. who gives me much happiness. ACKNOWLEGE MENT I would like to thank Professor Eugene LeGoff for making this research enjoyable. His enthusiasm and chemical experience are greatly acknowledged. ii LIST OF FIGURES AND TABLE. INTRODUCTION. Scheme A. Scheme Scheme Scheme Scheme Scheme Scheme Scheme Scheme B. 1. Gamma 2. 3. 4. 5. 6. 7. 8. 9. TABLE OF CONTENTS dicarbonyls. Scheme Scheme Scheme Scheme Scheme 10. 11. 12. 13. 14. EXPERIMENTAL. General Methods. 3-Carbethoxy-2,4-pentanedione (39). . . . . 1.5-Dibromo-3-carbethoxy-2,4-pentanedione (ib). O O O O O O O O O O O O O O O O O O 0 Applications of brominated beta 1.S-Dibromo-Z,4-pentanedione (23). . . . . Copper acetylacetonate (43). . . . . . . . iii PAGE .v . 1 .1 .3 .4 .6 .7 .7 .8 10 14 15 .18 .18 .19 .19 .20 .21 .22 .22 23 23 .24 .25 -B—Bromo-2.4-pentanedione (2b). . . . . . . 1,5-Dibromo-2.4-pentanedion; (25). . . . . 1.1'.5,5lsTetrabromo-z.42pentanedione (29)._ Ethyl-7-bromoacetoacetate (lg). . . . . . . Z-Acetyl-5-bromocyc10pentanone (125). . . . 2-Bromo-5.S-dimethyl-l.3-cyclohexanedione. 2.2-Dibromo-5.5-dimethyl-1,3-cyclohex- anedione. o o o 3,S-Bis(bromomethyl)pyrazole (11b). . . . . Hydrobromide salt of 2,2'-diamino- dithiazolyl-4,4'-methane (12). . . . . . 3,5-Bis(pyrrole methylene)pyrazole (17). APPENDIX. . . . . . LIST OF REFERENCES. iv PAGE .25 .26 ..27 . 28 .29 . 3O .30 .31 .32 .38 LIST OF FIGURES AND TABLE FIGURE PAGE 1 60 MHz 1H NMR spectrum of a mixture with major product being 1,3-dibromo- 2,4-pentanedione as. o o o o o o o o o o 11 2 60 MHz 18 NMR spectrum of a mixture with major product being 1.5-dibromo- 2,4-pentanedione 3;... o o o o o o o o o 12 Al 60 MHz 1H NMR spectrum of 3-carbethoxy- 2.4-pentanedione as. o o o o o o o o o o 32 A2 60 MHz 1H NMR spectrum of 1,5-dibromo- 2,4-pentanedione ago 0 o o o o o o o o o 32 A3 250 MHz 1H NMR spectrum of a mixture of 1,S-dibromo-Z,4-pentanedione g; and 1-bromo-2,4-pentanedione 23. . . . . . . 33 A4 60 MHz 18 NMR spectrum of a mixture of 1,1'.5.5'-tetrabromo-2.4-pentanedione 2g and lower bromination products. . . . 34 55 60 MHz 1H NMR spectrum of ethyl-Y-bromo- .c.t°acetate £2. 0 o o o o o o o o o o o 34 A6 60 MHz la NMR spectrum of Z-acetyl-S- bromocycIOpentanone igg. . . . . . . . . 35 A7 60 MHz 1H NMR spectrum of 2—bromo-5,5- dimethyl-l,3-cyclohexanedione. . . . . . 35 FIGURE A8 A9 A10 TABLE PAGE 60 MHz 1H NMR spectrum of 2,2'- dibromo-5,5-dimethyl-1,1-cyclohex- anedione. . . . . . . . . . . . . . . . 36 60 MHz 1H NMR spectrum of 3,5-bis (bromo-methyl)pyrazole 11b. . . . . . . 36 60 MHz 1H NMR spectrum of hydrobromide salt of 2,2'-diamino-dithiazolyl-4.4'- methane 13. . . . . . . . . . . . . . . 37 Gamma brominations of beta-dicarbonyls. 17 vi INTRODUCT ION The brominations of beta-dicarbonyls have been extensively studied. Most of these deal with bromin- ation at the alpha carbon. In an effort to produce M /’ l l a 7 ‘YfYC-dibromoacetylacetone the opportunity to explore gamma brominations of beta-dicarbonyls arose. The . apparent difficulty with this reaction is that the alpha carbon is more reactive then the gamma carbon. The key to gamma brominations lies in the observations made by Hantzsch.1 He noticed that the bromine, in ethyl-a- bromoacetoacetate (lb) he had prepared. would slowly rearrange in the presence of acid to give the gamma brominated compound 13 (Scheme 1). Scheme 1 Br2 UOCZHS Csz Br 1a .. HBr 1b ll OCZHS 1C Br Later Smith established the importance of acid in this rearrangement.2 Ethyl acetoacetate was brominated while sweeping out the hydrogen bromide with a stream of air. He found no bromine rearrangement had occurred. The sole product in the reaction was the alpha-bromo-ester. At about the same time Hirst and Macbeth observed an alpha-gamma bromine shift in the production of ethyl- 7— bromoacetylsuccinate .3 They suggested that, bromine at the alpha position of beta-dicarbonyl compounds is labile and that under acidic conditions it can rearrange to the gamma position. In this thesis the gamma brominations of beta- dicarbonyls is examined further. Two literature prep- arations have been reported for making the desired compound. 7.75- dibromoacetylacetone . Both of these reactions were tried and will be discussed. An im- — proved procedure for making 7.7,- dibromoacetylacetone and other gamma brominated beta-dicarbonyls is described. Subsequent sections deal with synthetic applications of the gamma-bromo-beta-dicarbonyls. A. GAMMA BROMINATIONS OF BETA DICARBONYLS The approach used in the production of gamma brominated beta-dicarbonyls involves the rearrangement of the bromine from the more reactive alpha position to the more stable gamma position. In the literature there have been two methods reported for making the compound of interest. 7{YL dibromoacetylacetone 23. The first method that was tried for making 2; had been put forth by Becker.4aob and is shown in Scheme 2. In the first step the starting material ethyl acetoacetate 13 was acylated using the technique of Spassow5 to give 3-carbethoxy-2.4-pentanedione 3a. Now three carbonyl groups exerted their electron with- drawing affect on the alpha position. This makes a bromine atom in this position highly reactive and it would more readily rearrange to the gamma position. The compound 39 was treated with bromine in ether to give 32. The bromine had rearranged from the alpha to the gamma position. Compound 3b proved to be a potent lachrymator making it difficult to work with. Following decarboxylation of 3b, the crude product was purified by forming its copper complex which was converted to g; by treatment with acid. The pure pro- duct gf was a green oily liquid. The overall yield of only 7% in this five step synthesis was discouraging. Scheme 2 M ”9 "°°' - 0C2Hs _, €sz 13 o Br2 0 0H 0 0 H2504 / -‘ 2f Br Br A Br Br "’ o cszo Cu+2 V Cu/z / * O O H” O OH M 2% Br Br Br Br In retrospect probably the biggest problem with the procedure in Scheme 2 is the decarboxylation step. Compound 32 is heated with sulfuric acid to 90°C for fifteen minutes. After ten minutes the solution would turn from brown to black. This is probably a combination of unwanted polymer and condensation products. As a result there is a substantial loss of compound 2;. which contributed to the poor overall yield. Even though the pure 7.7,- dibromoacetylacetone (if) product was obtained,the poor yields and many steps made it desirable to look for an alternate route. The second method reported in the literature to make 25 involved brominating a metal complex of acetyl- acetone. Before discussing this reaction, an overview of previous brominations of metal acetylacetonates is presented. The alpha brominations of several different metal complexed acetylacetonates including Cu, Ni. Al, Co and Cr to name a few have been reported.5v7o8 These are straight forward brominations and one was tried using copper acetylacetonate (43),(Scheme 3). The copper complex can be formed by adding acetylacetone to a.cupric nitrate solution.9 Any number of bromin- ating agents could have been used. In this case cupric bromide was employed.10 The alpha-brominated product, 22' was obtained in good yields. Scheme 3 OH + M Cuz 4' c"(A°A°)2 ‘1‘? 2-a~ LC“ 8'2 2. H“ OH Br Murakami and Nakamura while studying the electro- phillic brominations of tris(3-phenyl-2,4-pentanediono) cobalt III and chromium III observed that bromination was taking place to a certain extent at the gamma position.11 Pyridinium hydrobromide perbromide (PHP) had been used as a brominating agent (Scheme 4, yields were not reportedlz). The monobrominated chelate was fully characterized by the author. The explanation they gave was that the steric hindrance of the phenyl group at the alpha position prevents the bromine atom from entering there. Scheme 4 o\ 0 Ph / "/3 PHP g Pb / \er \Ph CY/ (D/‘hc, Br — _l 2 53 M = Co ,Cr 5b A second method of forming 25 from the PHP bromin- ation of 42~was reported in a Russian patent abstract.13 While no reaction conditions were reported it was claimed that 42,was brominated at the gamma positions. From previous experimentation done on brominated metal acetylacetonate complexes (Schemes 3 and 4) this Scheme 5 PHP + Cu(AcAc)z "”3 f H 47 M 4a 2f reaction would not appear to be feasible. A metal acetylacetonate complex would be expected to brominate in the alpha position unless there was a bulky group blocking the attack of bromine. This reaction was tried with PHP as the brominating agent using the conditions shown below (Scheme 6), Scheme 6 O OH PHP Ht Br / a! r Cu(A<:Ac)2 CHCI3 + —> 36 hrs + 4.3 r.t . 0 0H / 2.2 Br Surprisingly this procedure worked to Of 7.7,- dibromoacetylacetone if along gamma monobromo compound 23. Similar tained using Al or Ni as the metal in complex. This is an improvement over give 38% (by NMR) with 15% of the results were ob- the acetylacetonate the first method (Scheme 2) as far as the yield and the number of steps in the reaction. The only problem with the second method is that 23, which is formed as the minor product, could not be separated from 2f. The attempts to separate the two compounds using flash chromatography. crystalliza- tion and purification through the copper complex failed. Using an excess of the brominating agent did not lead to increased yields of 25 at the expense of 23. The explanation given by Murakami and Nakamura that the steric hindrance of the phenyl group in the phenyl acetylacetone complex blocks alpha bromination could be questioned now. The gamma bromination occurred in copper acetylacetonate where there is not a bulky group at the alpha position. What appears to be happening in this bromination (Scheme 6) is that the bromine is rearranging from the alpha to gamma position. This will be discussed in the context of the following improved reaction where the same rearrangement was taking place as confirmed by a comparison of their NMR's. An improved method of producing the desired 7;?L dibromoacetylacetone was develOped (Scheme 7). In this reaction acetylacetone was brominated with tetramethyl- ammonium tribromide (TMAT) to give a 79% yield (by NMR) of 22 along with 15% of 23. The bromine at the alpha position in the initially brominated product was shown to rearrange to the gamma position. The NMR of the product, taken after the reaction. (Figure 1) shows 23 to be the major component. The peaks at 4.38 ppm (-CHZBr) and 2.42 ppm (-CH3) are in the ratio of 2:3 and are consistent with the structure 23. Even after only one 10 Scheme 7 \ 1hr. M 2e Br Br “2 g3 24 hrs. 0 OH 2% a! Br Br hour a small amount of 25 has formed as shown by the peaks at 3.9 ppm (-CHZBr) and 6 ppm (vinyl proton) in the ratio 4:1. After twenty four hours at room temperature the peaks attributed to 23 have disappeared. and now 25 can be seen to be the major component (Figure 2). Compounds 23 and 2; are almost completely in their enol form and the enol peak seen at the top of the NMR's has shifted downfield in Figure 2. 11 .MM ocOwUmccucanv.mlosounapu . made uonooua Momma an“: oucuxwe o no Esnuoonn mxz MHHNm2.0W .H oucmwm 12 \ .mm-seafloocmucmalo.mloeounwplm.H ocaon uosooun MOncE nu“: ousuxfie o no Edwuooan «:2 ma um: co .N ousoam .1». 4. o. a . .2 on o. 2. it on so 3 i. H— . d‘ ‘ ‘ h 1‘ l‘ 11 11 (— N d 1“ l- l. N d N ‘ ‘ N l. 1 T l N l1 ‘ N J «l l‘ 1 1 . 1 4 4 . 1 1 . 4 m - 1 - m A 1 4 4 “r N 1 4 m ‘1 - m 4 M d Ll m'mz‘ f.‘ m Q 1 1 d “M’ 1 N 1 N N“ N N 4 d "—y' d N J “P ‘ ‘ 1 E‘IV‘N’Pl 1" i 1t ’ 13 A mechanism that accounts for this bromine rearrange- ment is seen in Scheme 8. A similar explanation is given by House14 for the rearrangement of bromine in monoketones. Initially bromination can take place at the more reactive alpha position to give 22. In the presence of hydrogen bromide the alpha bromination is reversible. An alpha bromine can be abstracted with a bromide ion which leads to molecular bromine and 23. Compound 23 can slowly isomerize to its B-V’enol 23'. Then bromination of 23' produces the more stable Vbbromoacetylacetone 22. Once bromination occurs at the gamma position it does not appear to be reversible to any extent. The fornation of 23 has been previously observed when brominating in acidic media.15'16 If another equivalent of brominating agent is used the process can be repeated to give the gamma dibromo product 2;. Various brominating agents were tried while exper- imenting with this reaction (Scheme 7). Among these’ were TMAT17. PHP, pyrrolidone hydrotribromide (PHT)18. NBS19 and Brz. The TMAT was the reagent of choice since there was the least amount of the gamma mono bromo product 23 formed and it, with the exception of Br2, brominated the fastest. The other perbromides released bromine slower which was apparent by the rate of hydrogen bromide evolution. The NBS brominated more completely at the alpha position of acetylacetone and took the longest for the bromine to rearrange from the alpha to the gamma position since there was less hydrogen bromide present. 14 Scheme 8 ll )fi/A HBf f -Br Et’O 15 In this bromination there is also the possibility that any of the bromoacetylacetone compounds with bromine at the alpha position could themselves be brominating agents. Other alpha-bromo-beta-dicarbonyls have been used in this regard (Scheme 9). The alpha-bromo meldrums acid derivative 9 has been used to brominate 3,3-di- methylthietan-1,1-dioxide 23.20 Diethyl dibromomalonate, ‘g was also used as a brominating agent in the production of 2-bromo-cis-8,cis-ll.cis-14-eicosatrienoic acid 2b.21 Scheme 9 Br ‘0 O rt + s o 3‘ so >< >95“ “5% ’ Li Br .9. 72-. 19 % gm 3 't + R- = = - - CH c-o+ 27% R C|H-C 0—}— Br Br Br 9a 8 "“ 9b w R: CH3(CH2)4- c:=ccn2 (cm). 3 . 16 The bromination of acetylacetone to give 77Y¢dibromo- acetylacetone using the different methods is summarized in Table 1. Some gamma brominations of other beta- dicarbonyls that were done are shown. Further bromina- tion of 25 with 2 equivalents of TMAT produced 737(7273 tetrabromoacetylacetone as the major product. Mono-- bromination of ethyl acetoacetate and 2-acyl-cyclopent- anone with TMAT gave the gamma-bromo products 23 and 199 respectively. The products as and 199 were both obtained in high yields with little evidence of other compounds present (TLC & NMR). This alpha-gamma bromine rearrangement appears to be fairly general in beta-dicarbonyls. but some beta- dicarbonyls tried did not rearrange. One compound that failed to show this rearrangement was dimedone. The bromination of dimedone was previously studied by V’oitila22 and later by Iris and Arakawa.23 They did not report the direct production of the gamma bromo compound 4- bromo-5.5-dimethyl-1.3-cyclohexanedione which was what we attempted to do. When the bromination of dimedone was tried with one equivalent of TMAT,bromination took place at the alpha or 2 position and no rearrangement to the gamma or 4 position was detected. Even when two equivalents of TMAT were used no rearrangement occurred and the only product isolated was 2.2-dibromo-5.5-dimethyl- 1,3-cyclohexanedione. 17 Table 1. Gamma brominations of beta-dicarbonyls. Method Substrate Product used %Yielda Time Scheme# (hrs) OH O OH 0 23-. 29 Ma NOR 7 94° 30 r e $2 Off R o 0 Br <>2K 7 95C 24 22a 12c a isolated yield: b not separated from minor products, yield based on NMR integration: c crude yield. TLC showed one spot. 18 B. APPLICATIONS OF GAMMA BROMINATED BETA DICARBONYLS The most general and widely applicable method for the preparation of pyrazoles consist of the addition of hydrazine to beta-dicarbonyl compounds. Symmetrical heterocyclic compounds can be produced efficiently in this manner (Scheme 10).24 Scheme 10 M ”“2 "“2 — "N—I / 15°C 7 \ 11? 73-75% This method was chosen for making 3,5-bis(bromomethyl) pyrazole 11b. The beta-dicarbonyl used. VTyLdibromo- acetylacetone 25 is now readily available (Scheme 7). In Scheme 11 hydrazine hydrate was added to a solution of 23 in 90% ethanol at ice bath temperatures. The reaction was tried in absolute ethanol but the product was too soluble and did not crystallize out of solution. On cooling,the new compound 11b crystallized out of solution as white needles in 66% yield. There was the question before trying this reaction of whether the hydrazine would add at the carbonyl 19 Scheme 11 OH 0 NH NH r/4§§v/JL\3 2 2 1;. Br r 90% EtOH o°c 2f 11b carbons or undergo a substitution reaction at the gamma carbons to displace the bromines. Under these conditions (Scheme 11) the carbonyl carbons were found to be more reactive. The compound 2; also showed utility in the synthesis of the thiazole derivative 12 (Scheme 12).25 In this reaction both addition at the carbonyl carbons and nucleo- phillic substitution occurred. When this reaction was tried the hydrobromide salt was obtained in good yield. Subsequent formation of the free amine was not accom- plished here, but was previously formed and characterized elsewhere.25 Scheme 12 OH thiourea A NaHCO; \ ooc ' 20 A future consideration is to explore reactions of 3,5-bis(bromomethyl)pyrazole with pyrrole derivatives. ' This could lead to the formation of the potentially interesting macrocycle octaaza-(26)-annulene a}. The strategy that would be used in the formation of this expanded porphine is based on known pyrrole chem- istry. One possibility can be seen in Scheme 13 where the two halves 2i and 2S could couple to form the macro- cycle.25 Scheme 13 H+ 21 In an effort to form a compound similar to 22 the 3,S-bis(bromomethyl)PYrazole 11b was added to Knorr pyrrole in a preliminary study (Scheme 14). The purpose of this reaction was to test the reactivity of the benzyllic-like bromines in the pyrazole derivative. In this reaction a dark tar-like material was formed after heating which contained no identifiable products. Further work is planned in this area. Scheme 14 czusozc CH3 I—NH + / \ / CH3 N COZCZHS Br Br '4 11b 16 w H3PO4 EXPERIMENTAL General Methods All melting points were determined using a Thomas-Hoover capillary melting point apparatus and are uncorrected. Unless otherwise noted, all NMR spectra were obtained in chloroform-d1 solution with the chemical shifts reported in parts per million downfield from the tetramethylsilane standard. Proton NMR spectra were obtained on Varian T-60 and Bruker WM-ZSO spectrometers at 60 MHz and 250 MHz, respectively. Infrared spectra were obtained on a Perkin-Elmer 237 grating spectrometer and were cali- brated using the polystyrene 1601 cm'1 peak. Mass spectra were obtained on a Finnigan 4000 instrument at 70 eV or using ionized methane. Galbraith Labor- atories. Inc. provided elemental analysis data. Flash column chromatography refers to the method of Still, Kahn and Mitra.27 All reactions were done under N2 atmosphere unless otherwise noted. 22 23 3-Carbethoxy-2.4:pentanedione (3a). According to the procedure of Spassow5 0.2 moles of ethyl-acetoacetate is diluted with 50 ML of benzene and then 0.1 moles of Mg shavings are added. Then 0.3 moles of acetyl chloride is added. During the addition of acetyl chloride there is a slow evolution of gas. Then warm to 80-85 °C for 1 h. Cool the reaction mix- ture to 25 0C, decant from unreacted Mg. Wash the unreacted Mg with ether. Combine the ether layers and wash several times with water. Then separate the ether layer and dry it over anhydrous Na2804. The remaining liquid was vacuum distilled bp 93-94/11mm Hg to pro- duce 68% yield of 23. This appeared pure (by NMR) and was used directly in the preparation of 22. 1H NMR: 51.37(3H,t), 2.40(6H,s), 4.27(2H.q). 15.9(1H,s). 1,5-Dibromo-3-carbethoxy-2,4-pentanedione (3b). According to Becker4a in a 500 mL round bottom flask 50 g of 23 in 150 mL of absolute ether and 93 g of dry bromine is stirred at ~15 °C for 1% h. After this the reaction mixture is allowed to warm to 25 0C. After approximately 17 h the reaction is complete. One pours it into 250 mL of ice water. Thencthe mix- ture is extracted with ether. dried with anhydrous 24 Na2804 and the ether is distilled off. Upon cooling to -15 °C one obtains.24 g of crystals and 21 g oil. Recrystallization from 30 mL alcohol produces 17 g of pure white product. Cooling the oil to -15 °C produces an additional 3-4 g of crystals. The yield is 21% of 23: mp 52-53 °C (lit. mp 54-55 oC).4a This appeared pure by the melting point and was used directly in the preparation of 2f. 1,5-Dibromo-2,4-pentanedione (2f). The decarboxylation4b involves taking 10 g of 2b and dissolving it in 35 mL of cone. H2804. Heat this solution to 90 °C. At about 65 0C 002 begins to evolve. After about 15 min at 85-90 °C the solution is cooled to 25 °C. then poured slowly over 200 g of ice. The dark oil ppt. is extracted with two 75 mL portions of ether. Then the volume of ether is reduced to about 30 mL. This can be purified by shaking with a cupric diacetate solution to obtain the copper salt: mp 149-152 °C with decomposition. To decompose the copper salt. first take 5 g of 29 and suspend it in 30 mL of ether. This mixture is shaken for 10 min with 30 mL of 20% H2804. The.ether layer is separated and dried over anhydrous Na2804. The ether is distilled off and a dark green oil (25) is recovered in 47% yield from 22: mp 6-7 °C. 25 This appeared pure (by NMR) and was used directly in the production of 13?. 1H NMR: 63.9(4H,s). 4.02(2H.t). 6.04(1H,s). Mh§.: m/e=258 (parent)triplet isotope cluster. 163 (base peak). IR (neat): 3445. 1720. 1600 cm'l. Copper acetylacetonate (4a) Using the method of Jones9 cupric nitrate trihy- drate (10 g) was dissolved in distilled water (100 mL) and cone. aqueous ammonia (15 mL) was added. To the resulting solution of Cu(NH3)§? acetylacetone (11 mL) was added dropwise while stirring. A light blue pre- cipitate was obtained. Jones obtained a 98% yield of 43. l 3-Bromo-2,4-pentanedione (2b) The purpose of this reaction was to verify bromin- ation at the alpha position. An excess of cupric bromide was added to 1 g of 23 in 30 mL of a 1:1 EtOAc/CHC13 solution at 25 °C. The solution turned to a blue color upon addition. After approximately 1 h the white CuBr began to ppt. out of solution. After 2 h the reaction is done. The CuBr is filtered from the solution. The solution is washed with water and the organic layer is dried and put in the refrigerator. Within a period of a few hours green needles crystallize out of the solution 26 and are collected and dried. After decomposition of the complex with acid an NMR was taken. The NMR indicated bromination had taken place at the alpha position. 1H NMR: 62.4(6H,d). 4.77(1H.m). 1,5-Dibromo-2,4-pentanedione (2f). The second method of producing 25 involves taking 1.0 g of copper acetylacetonate and dissolving in 30 mL of CHC13. Then 4.9 g of PHP is added.: The solution is stirred for 36 h at 25 °C. Then the solution is treated with 20% 82804 to decompose what copper complex is re- maining. After this the solution is washed several times with water and then dried over anhydrous Na2804. Then the CHC13 is distilled off. The yield is 38% of the green oil 25 (by NMR) with 15% of 23. These compounds could not be separated. .Datalof compound 25: 13 NMR: 63.9(4H,s), 4.02(2H.t), 6.04(1H,s). M;§.: m/e=258 (parent) triplet isotope cluster, 163 (base peak). IR: 3445. 1720. 1600 cm-1. 1,5-Dibromo-2.4:pentanedione (25). The third method of producing 25 proceeds as follows: 2 g of acetylacetone was added to 13.2 g of TMAT26 in 50 mL of anhydrous ether. Then the solution is stirred 27 at 25 °C. Hydrogen bromide is given off immediately. The solution goes from the orange color of TMAT to the white color of tetramethylmmlonium bromide (TMAB) within 1 h. The TMAB is filtered off from the solution. Then the solution is washed several times with water. The ether layer is separated and dried over anhydrous NaZSO4. The ether is distilled off at 0.5 mm Hg. The solution is put in the refrigerator for approximately 24 h to allow the bromine torrearrange. The yield is 79% of the green oil 25. (by NMR) along with 15% of 23. These compounds could not be separated. Data of com- pound g: 1H mm: 63.9(4H,s). 4.02(2H,t). 6.04(1H,s). 12.82(1H,bs). M‘§.: m/e=258, 163 (base peak). 15: 3445, 1720, 1600 cm-1. 3,1'.5.5'-Te§£3bromo-2.4:pentanedione (29). To a mixture of 3.83 g TMAT in 40 mL of ether was added 1.5 g of 23. The solution was stirred at 25 °C for 48 h. Then the white TMAB is filtered off from the solution. The dark bronze filtrate is washed several times with water. The ether layer is dried over anhy- drous Na2804. The ether is distilled off to give a dark brown oil. The yield is 75% (by NMR) of 29 along with approximately 17% of lower brominated products. These compounds could not be separated. Data of compound 2g: 1H NMR: 55.87(2H,d), 6.32(1H,d), 12.5(1H.bs). 28 M.S.: m/e=416 (parent) quintuplet isotope cluster, 243 (base peak). 23: 3410, 1735. 1585 cm‘l. Ethyl-V-bromoacetoacetate-(lc).. In a 250 mL flask 3.29 g of TMAT is added to 30 mL of anhydrous ether. Then 1.24 g of ethylvacetoacetate is added. The reaction is stirred for 1 h at 25 °C. Then the TMAB is filtered off. The solution is washed several times with water. The ether layer is dried over anhydrous Na2804 and then the ether is distilled off. The solution is allowed to stand in the refrigerator for approximately 30 h. The oily liquid appeared fairly pure (by TLC). The crude yield was 94%. 1H NMR: 51.31(3H,t), 3.70(ZH.s). 4.07(2H.s). 5.27(1H.s), 8.33 (1H.s). fl;§.: m/e=209 doublet isotope cluster, 43 (base peak). IR: 3410. 1720 cm‘l. 2-Acetyl-5-bromocyclogentanone (10c). In a 250 mL round bottom flask was added 2.3 g of TMAT in 30 mL ether. Added to this was 1 g of 2-acety1- cyclopentanone. This solution was stirred at 25 °C for 1 h. Then the TMAB was filtered from the reaction mix- ture. The filtrate was washed several times with water. The ether layer is dried over anhydrous Na2804, The solution is allowed to stand in the refrigerator for 29 approximately 24 h. The oily liquid appeared fairly pure (by TLC). The crude yield was 95%. 1H NMR: 162.1 (3H,s), 2.37(2H,t). 2.6(2H.m), 4.6(1H.t). 12.66(1H.s). ‘M&§.: m/e=205 (parent) doublet isotope cluster, 43 (base peak). 33: 3405, 1710, 1610 cm-1. 2-Bromo-5.5-dimethyl-1,3-cyclohexanedione In a 250 mL round bottom flask 2.67 g of NBS was added to 25 mL of CCl4. Then 2 g of dimedone was added. The Solution was stirred at 25 °C for 3% h. At that time all of the succinimide had floated to the top of the CCl4. The reaction mixture was washed several times with water. The white solid that ppt. was collected. The yield was 85%: mp 174-175 0c (11:. mp 175-176 °C).22 la NMR: 61.10(6H,s). 2.47(4H.s). M;§.: m/e=220 (parent) doublet isotope cluster, 162 (base peak). 2,2-Dibromo-5,5-dimethyl-1.3-cyc;ohexanedione In a 250 mL round bottom flask 2.67 g of NBS was added to 25 mL of CCl4. Then 1 g of dimedone was added. This was stirred at 25 °C for 4 h. At that time all of the succinimide had floated to the top of the CC14. The reaction mixture was washed several times with water. The white solid that ppt. was collected. The yield was 75%: mp 146-148 00 (lit. mp 148-149 °c).22 1H NMR: 30 61.03(6H.s), 3.0(4H.s). M.S.: m/e=298 (parent) triplet isotope cluster, 83 (base peak). 3 S-Bis bromometh l razole (11b). In a 25 mL flaSk was added 1.45 g of 1.5-dibromo- 2,4-pentanedione to 5 mL of 90% ethanol. This solution was cooled to ice bath temperature. Then 0.281 g of hydrazine hydrate was added dropwise while stirring the mixture. The reaction was not run under nitrogen. After addition was complete the solution was allowed to stir an additional 10 min. Then the solution is put in the freezer. White crystals are collected in 66% yield: mp 78-79 °C. 1H NMR: 64.43(4H,s). 6.32(1H,s). Md m/e8254 (parent peak) triplet isotope cluster, 173 (base peak). Anal. Calcd. for CSHGNzBrZ: C, 23.62: H. 2.36: N, 11.02 Br, 62.99. Found: C, 23.84: H, 2.52: N. 11.38 Br. 62.27. Hydrobromide salt of 2.2'-diamino-dithiazolyl-4,4(-e methane (22). In a flask 0.93 g of thiourea was dissolved in 30 mL of Eton/ether (2:1). This was cooled to 0 °C. Then 1.5 g of 1,5-dibromo-2,4-pentanedione was added drOpwise. After addition the solution was stirred for 15 more min. 31 Then this was put in the freezer. Within 2 h a tan solid was collected. The crude yield was 91%: decomp. mp 269- 271 °C. 1H NMR:' 64~05(2H,s), 4.8(6H.s), 6.76(ZH,s). 3.5-Bis(pyrrole methylene)pyrazole (17). In a three necked flask fitted with a condenser, 0.75 g of Knorrs pyrrole was added to phosphoric acid.18 This was heated to 120-130 0C for 15 min . Then the reaction mixture was cooled to 40 °C. Then 0.9 g of 12b was added to the solution. The solution turned from yellow to brown. After stirring the mixture for 5 h it was washed several times with water. The solu- tion was extracted with ether. The ether layer was dried over anhydrous Na2804. Then the ether was dis- tilled off. There were no identifiable products (by NMR) from this reaction. APPENDIX 32 16 15 _r— :giit 11£ .;‘.. .i;fi}i . ‘;i ‘“:j:‘., 1i: .1 Figure Al. 60 MHz 1H NMR spectrum of 3-carbethoxy- 2,4-pentanedione 23. 60 MHz 1H NMR spectrum of 1.5-dibromo- Figure A2. 2,4-pentanedione 2f. 33 _. L Isl Jim 3 M V— 4g [LLLLLLLLLLILLLLLLLLLLIILLLLLLILLDLLLLITL_ 7 5 5 4 3 2 1 0 Figure A3. 250 MHz 1H NMR spectrum of a mixture of 1.5-dibromo-2,4-pentanedione 2E and 1- bromo-2,4-pentanedione 2E. 34 A A A A A A A A A A A I l A A I A A A A l l A A as In. ‘9’ u as Figure A4. 60 MHz 1H NMR spectrum of a mixture of 1,1' H5 5' -tetrabromo-2 4-pentanedione 2g. and lower bromination products. — “* A A A A A A A A A A A l A A A A A A A A l A A A A I A a A A l A A A A I A 4 A A I A A A J I J14 4 A l A A J A ] A 4 A A I g N. In Figure A5. 60 MHz in NMR spectrum of ethyl-7-bromo- acetoacetate 2g. 35 . - .A A 1/_A I . vi WW V V V v V v v v Vfi I , 3-1-- - J -236 14 >13 12 11 A: AA _ i . ' I l . . l l A 1 AAA 1 A A l A A A I A A as n u u v... V :- Figure A6. 60 MHz 1H NMR spectrum of 2-acetyl-5- bromocyclopentanone 10c. A l A A l A A A l A A l_‘ A l A A A J A A A A l A A A l ’1 l A A A A A A A __ L A A A l A A A A A 1 A As I A A A A J A A A A1] A A A A 1‘ A as to so as ea- ‘9' ce‘ )e n 1m "I Figure A7. 60 MHz 1H NMR spectrum of 2-bromo-5,5- dimethyl-l,3-cyclohexanedione. 36 I A 1 - AAl A A 1 A 1 A 1 . . l - l A A l A A A A _l A A A A I A A A A l A A A A l A A A A I A A A A A A A AL A A AA A l A u n u u n- ‘9‘ u - n n 10 Figure A8. 60 MHz 1H NMR spectrum of 2.2'-dibromo- 5,5-dimethyl-1,3-cyclohexanedione. AA A A '- —vv fi— r W v v—v ‘— l A AA 1 A A A A J A AA A l A A I A A A l A A A I A A A l A A A A l A A I A AA A A A A A A A A I A A A A l A A A A J l A A A A A l A A AA I u n u u w- . u u M u- Figure A9. 60 MHz 1H NMR spectrum of 3,5-bis(bromo- methy1)pyrazole 11b. 37 15‘ .. H 'l u . I a j v V WW “— fi ‘—A A “A! _ AA h— ‘ _ vv v—vw 'VTw' v v v—v - _._1 A A 1 A. A A . _A A A l A A A l I A A A l A A A A ‘ A_A A l A A A A I A A A l A ‘ A A l A A A A I gL 4 4 I 4 4 A A l J A A A A j A J l I A A A I A A A A l A A A A l J u. I» .0 >0 m u} .o )0 no oo c Figure A10. 60 MHz 1H NMR spectrum of hydrobromide salt of 2.2'-diamino-dithiazoly1-4,4'- methane 12. 1. 2. 3. 4. 5. 6. 7. 9. 10. 11. 12. 13. 14. 15. 16. LIST OF REFERENCES Hantzsch. A. Chem. Ber. (1894) 21, 3168. Smith, L.I. J. Am. Chem. Soc. (1922) fig, 216. Hirst. E.L.: Macbeth, A.K. J. Chem. Soc. (1922) 121, 2169. (a) Becker, A. gglv. Chim. Acta. (1949) 33. 1114. (b) Becker, A. Helv. Chim. Acta. (1949) 32. 1584. Spassow, A. Chem. Ber. (1937) 19. 2381. Kluiber, R.A. J. Am. Chem. Soc. (1960) 83, 4839. Collman, J.: Blair. R.: Marshall, R.: Slade, L. Inorg. Chem. (1963) g. 576. Kulkarni, 8.3. J. gnorg. Nuc. Chem. (1977) 32, 1238. Jones, M. J. Am. Chem. Soc. (1959) 81, 3188. LeGoff, E.: Kowar. T.R. J. Org. Chem. (1976) 4;. 3760. Murakami. Y.: Nakamura, K. Chem. Soc. Bull. Japan (1968) 21, 1859. 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