4478
v01. i s
J. C. SHEEHAN, C. IV. BECK,K. R . HENERY-LOGAN ASD J . J . RYAX
Anal. Calcd. for C,H8P\T40S: C , 42.84; H, 4.11. Found: C, 42.87; H, 4.25. 3( 5)-Pyrazolecarboxylic Acid Hydrazide and Carbon Disulfide (a).-A mixture of 3.1 g. (0.025 mole) of 3 ( 5 ) -
Anal. Calcd. for C5H4N40S: C, 35.71; H, 2.40; N, 3 3 . 3 2 . Found: C, 35.86; H,2.60; S , :33.05. A mixture of 2 g . of 2-(3(5)-pyrazolyl)-A*-l,3,4-o~~~diaz(~line-5-thione, 50 ml. of 95% ethyl alcohol and 5 g. of moist pyrazolecarboxylic acid hydrazide,I6 1.3 g. of potassium Raney nickel was heated under reflux for three hours. hydroxide and 5 ml. of carbon disulfide in 50 ml. of ethyl After removal of the nickel by filtration the filtrate was alcohol was stirred together at room temperature for 30 evaporated t o dryness. The residue was recrystallized from minutes. *lbout 50 ml. of dry ether was added and t h e hot water, and o n cooling 200 mg. of 2-(3(5)-pyrazolyl)-1,3,product separated in almost quantitative yield. Potassium 4-oxadiazole ( I X ) was deposited. It melted a t 200-202". 3-(3(5)-pyrazolecarbonyl)-dithiocarbazate( V I I ) melted with A sample wiis obtained by sublimation, m.p. 2U4-205°; decomposition a t about 210°, resolidified and melted again A,, 236 r n p , log e 4.06 (methanol). with dec. a t 255-260'; ,,,A, 303 m p , log E 4.01 (methanol). A n a l . C d c d . for C ~ H I K ~ OC: , 44.12; H, 2.96; S , A n a l . Calcd. for C5HSKK40S2: C , 24.98; H, 2.10; N, 23.31; S, 26.68. Found: C , 25.37; H , 2.34; N, 23.60; 41.17. Found: C , 44.13; H , 3.11; A-, 41.20. S , 26.85. 7-Mercaptopyrazolo [I ,5-d ]as-triazin-4(5H)-one (X).-A X sample of potassium 3-(3(5)-pyrazolccarbonj-l)-clithio- sample of 2-( 3( 5)-pyrazoly1)-A2-1,3,4-oxadiazoline-5-~11i(~ti~ was heated at 200' and 0.5 inm. of mercury pre carbnzate was heated a t 230' for 15 minutes. T h e product The product t h a t was obtaiiied :is t h e sublimate M was dissolved in water and acidified with dilute hydrochloric acid. The solid t h a t formed was collected and recrystal- mercaptopyrazolo [1,5-d]us-triaziri-4-( 5H)-one, m.p. 201202'; Amax 231 mp, log E 3.81; ,,A 262 mp, log E 4.11; A,,, lized from water. I t was shown by infrared d a t a t o be iden297 m p , log e 4.09 (methanol); pK', 4.1 (667,dimethylformtical with compound VI11 (see below). (b).--A mixture of 6.3 g. (0.05 mole) of 3(5)-pprazolecar- amide). boxylic acid hydrazide,lE 2.8 g. (0.05 mole) of potassium A n a l . Calcd. for C5H4N10S: C, 36.71; 11, 2.40; S, hydroxide, 5 ml. of carbon disulfide and 200 ml. of ethyl 19.07. Found: C, 35.37; H, 2.52; S, 18.64. alcohol was heated under reflux for three days. After reA mixture of 1 g. of 7-mercaptopyrazolo [1,5-d]as-trinzinmoval of the alcohol the residue was dissolved in 100 ml. of 4(5H)-one, 50 ml. of 96% ethyl alcohol and 5 g. of moist water and acidified with dilute hydrochloric acid. The Raney nickel was heated under reflux for six hours. After solid t h a t separated was collected, washed well with removal of the nickel by filtration, the filtrate was evaporated water and air-dried, I t melted between 200 ant1 205". t o dryness. T h e residue was dissolved in a small mioutit of T h e product17 was recrystallized from methanol-water mix. sodium hydroxide and then acidified with acetic acid. ture and 5 . 3 g . (63% yield) of 2-(3(5)-pyrazolyl)-Az-l,3,4- 1 V oxadiazoline-5-thione (1.111) was obtained. -1sample was The solid t h a t separated was recrystallized from water :1nd recrystallized from methanol and obtained as a white solid, pyrazolo [1,5-d]as-triazin-4(5H)-one (XI) was obtained as needles, m . p . 265-267'; , , ,X 264 m p , log E 3.86 (methanol). m . p . 220' dec.; Xma, 241 mp, log E 3.89; A,, 286 mp, log e T h e melting point was not depressed when mixed with py4.24 (methanol); p K ' , 5.4 (66% dimethylformamide). razolo [l,5-d]as-triazin-4(5H)-oneio prepared from 3(5)pj-razolecarboxylicacid hydrazide and triethyl orthoformnte. (16) L. Knorr, Bey., 37,3520 (1904). (17) T h e first lot of this material was treated with Raney nickel Anal. Calcd. for C5H4N40: C , 44.12; H , 2 . M ; S , and a small yield of compound XI was isolated, indicating t h a t the 41.17. Found: C, 43.95; H,3.36; N, 41.17. product of this lot was a mixture of compounds VI11 and X. SubISDIATAPOLIS 6 , ISDIASA sequent preparatiiins did not appear t o contain any of compound X .
[CONTRIBUTION FROM
THE
DEPARTMETT O F CHEMISTRY, MASSACHUSETTS INSTITUTE
OF TECHNOLOGY]
The Reaction of Phthaloylglycyl Chloride with 2-Methyl-2-thiazoline' BY
JOHN
c. SHEEHAN, CURT\V.
BECK,KENNETH R. HENERY-LOGAN AND RECEIVEDAPRIL3, 1956
JAMES
J. RYAN?
As part of a program directed toward the synthesis of compounds structurally related t o t h e penicillins, the reaction of phthaloylglycyl chloride ( I ) with 2-methyl-2-thiazoline (11) in t h e presence of triethylamine h a s been studied. Rather t h a n yielding a P-lactam-thiazolidine structure, expected by analogy t o t h e 2-phenyl-2-thiazoline case, t h e reaction leads t o 2-methylene-3-phthaloylglycylthiazolidine(111)a t low temperature and in t h e presence of one equivalent of base, and t o 2-methyl-3-phthaloylglycyl-4-thiazoline(V)a t higher temperatures and in t h e presence of excess base. The structures of compounds I11 and V were established b y hydrogenation t o 2-methyl-3-phthaloylglycylthiazolidine(VI). A mechanism for the reaction is proposed. Analogous products were obtained using phthaloyl-p-alanyl chloride (Ia) as t h e acylating agent
The reaction of diacyl glycyl chlorides with 2 phenyl-2-thiazolines in the presence of triethylamine, yielding fused P-lactam-thiazolidine ring systems, has been a promising approach toward the synthesis of penicillin-type c o m p o ~ n d s . ~I n an investigation of the scope of this synthesis, we have studied the action of phthaloylglycyl chloride (I) and phthaloyl-@-alanyl chloride (Ia) on 2-methyl2-thiazoline (11). I t was found that, depending on reaction conditions, either of two distinct types of products was (1) This work was in part supported b y grants from Swift and Co.. Chicago, Illinois, and Bristol Laboratories, Syracuse, New York. ( 2 ) Abstracted from parts of t h e Ph.D. Dissertations of J. J. R y a n , M.I.T., June 1949, and C. W. Beck, hf I . T . , January 1955. (3) J. C . Sheehan and G. D. Laubach, THISJ O U R N A L , 73, 4376 (1951).
formed. In the presence of one equivalent of triethylamine, I and I1 formed a "low temperature adduct" 111, which precipitated together with triethylammonium chloride. The products were best separated by an aqueous wash, which converted I11 into a crystalline "hydrated adduct" IV with the addition of one equivalent of water. At 60°, and in the presence of excess triethylamine, a "high temperature adduct" V was obtained, which is isomeric with 111, but which did not take up water on washing. Under conditions lying between these two extremes, products were formed which, after washing with water, analyzed for mixtures of compounds IV and V. None of the products obtained possesses infrared absorption indicative of a 0-lactam structure.
Sept. 5 , 1956
PHTHALOYLGLYCYL
CHLORIDE WITH 2-~fETHYL-2-THIAZOLINE
447 9
Qualitative tests showed that free carboxyl groups respective reaction conditions can be rationalized were absent (insolubility in aqueous sodium hy- convincingly. Figure 1 illustrates a possible mechadroxide), and left the presence of basic centers in nism leading to the established structures, as well doubt (solubility in 3 N hydrochloric acid only with as the reactions used in their identification. 2decomposition and concurrent liberation of sulfhy- Methyl-2-thiazoline (11) may be considered to be dryl groups). The relative instability of com- in prototropic equilibrium with the isomeric 2pounds I11 and IV is further underlined by decom- methyl-3-thiazoline (imine) and 2-methyl-4-thiazoposition on storage a t room temperature for as short line (enamine) forms a t least under the reaction a period of time as one week. The decomposition conditions. Similar 1,3-proton shifts are known to products, as well as the hydrolysis products, be favored by excess base and elevated temperawere amorphous and resisted efforts a t identifica- tures.’ Thus either the 3- or the 4-thiazoline taution. tomer will be the reacting species a t 60” and in the This evidence may be reconciled either with an presence of excess triethylamine. Either of these intact thiazoline ring structure, or with ring scis- lead to the 2-methyl-3-phthaloylglycyl-4-thiazoline sion leading to N,S-diacylthioethanolamines.The structure established for the “high temperature adinfrared spectra of all three “adducts” were similar, duct” V. Reaction a t low temperatures and withand were strikingly reminiscent of the spectra of out excess base, on the other hand, leads to 2substituted thiazolines. A Kuhn-Roth C-methyl methylene-3-phthaloylglycylthiazolidine,i.e., the determination4 on the “high temperature adduct” “low temperature adduct” 111. An analogy for V yielded 0.83 equivalent of acetic acid, very close this type of prototropy is afforded by the Bergmann to the value of 0.80 equivalent obtained from 2 - rearrangement* of oxazolones, where the imine methyl-2-thiazoline under identical conditions. enamine + isomeric imine shift is catalyzed by pyIf both the high and low temperature “adducts” ridine. This reaction has been investigated previindeed are substituted N-phthaloylglycylthiazo- ously in this L a b ~ r a t o r y . ~ lines, hydrogenation should lead, in either case, to The remaining problem concerns the nature of 2-methyl-3-phthaloylglycylthiazolidine(VI). The the water molecule in the “hydrated adduct” IV. latter compound was prepared, for comparison, by As mentioned previously, the addition of water prodirect acylation of 2-methylthiazolidine (VII) with duces no major changes in the infrared spectrum. phthaloylglycyl chloride (I) in the presence of tri- The characteristic band a t 11.43 p (875 cm.-l), asethylamine. signed to the exocyclic double bond in 111, does not Hydrogenation of the “low temperature adduct” disappear. This position should be the preferred I11 over 30y0 palladium-on-carbon catalyst5 was point of attack in any reaction leading to ring cleavcomplete in four hours, yielding, after recrystalliza- age. It therefore appears that the water is only tion, 60% of a product which was shown to be iden- physically bound to the adduct, ;.e., that compound tical with VI by melting point, mixed melting point, IV is a simple hydrate, In corroboration of this infrared spectra and double analyses. The “high view, it was found that the “hydrated adduct” IV temperature adduct” V proved much more resist- could be dehydrated by drying over phosphorus ant to hydrogenation, but after several days, and pentoxide a t room temperature and low pressure. with a threefold excess of catalyst (on a weight-to- The dehydrated material, which melted lower than weight basis), i t absorbed 0.96 equivalent of hydro- the hyd‘rate, was not crystalline. gen and yielded, after recrystallization, 46% of The reaction of phthaloyl-&alanyl chloride (Ia) VI. with 2-methyl-2-thiazoline (11) was also studied. Thus both “adducts” differ from VI only by con- At 60”)in the presence of excess triethylamine, taining one double bond each. Positions available there was obtained a “high temperature adduct” for double bond formation are limited to either (a) (Va), which was found to be a homolog of V. The C4-C5, or (b) C2-methylcarbon. Spectrographic basic skeleton was established by hydrogenation, in evidence based on olefinic double bond absorption which Va took up one mole of hydrogen and gave an in the infrared cannot distinguish between these 80% yield of 2-methyl-3-phthaloyl-~-alanylthiazolitwo cases; furthermore, in the compounds under dine (VIa). The latter was synthesized independconsideration, the respective region (6.0-6.3 p ; ently by direct acylation of 2-methylthiazolidine 1670-1590 cm.-’) is obscured by the absorption of (VII) with phthaloyl-fl-alanyl chloride (Ia). Oxidathe benzene ring of the phthaloyl group. How- tion of VIa with potassium permanganate in 80% ever, exocyclic methylene groups show a very char- acetic acid gave 2-methyl-3-phthaloyl-~-alanylthiaacteristic band a t 11.43 p (875 cm.-l), due to C-H zolidine sulfone (VIIIa) , a reaction characteristic of rocking.6 A band in this region is present in both N-acylthiazolidines. lo The double bond in Va is the “low temperature adduct” I11 and the “hy- assigned to the position C&26, rather than Cz-methdrated adduct” IV, but is missing in the “high ylcarbon, by analogy with the structure of V, and temperature adduct” V, thus favoring the assign- by a Kuhn-Roth C-methyl determination4 which ment of the 2-methylene-3-phthaloylglycylthiazoli- gave 0.92 equivalent of acetic acid. dine structure for 111,and of the 2-methyl-3-phthal(7) W. Htickel, “Theoretische Grundlagen der Organischen Chemie,” 1. Band, Akademische Verlagsgesellschaft, Leipzig, 1949. oylglycyl-4-thiazoline structure for V. The formation of the two “adducts” under their pp. 259 ff,,244, 526 ff.
-
( 4 ) R . Kuhn and H. Roth, Ber.. 66, 1274 (1933).
( 5 ) N. D. Zelinsky and hl. B. ( 1925).
Turowa-Pollak, ibid., 68, 1295
(6) L. J. Bellamy, “The Infrared Spectra of Complex Molecules,” John Wiley and Sons Jnc., N e w York, N. Y . , 1054. p. 44.
( 8 ) M. Bergmann and F. Stern, A n n . , 448, 20 (1926). (9) J. C. Sheehan and W. E. Duggins, THISJ O U R N A L , 72, 2475 (1950). ’ (10) H. T. Clarke, J. R. Johnson and R. Robinson, editors, “The Chemistry of Penicillin,” Princeton University Press, Princeton, N. J . 1949. p. 929.
44so
J. C.S F I E E I I . ~ ,C.W.
BECK,
IC.
ri.
HENERY-LOGAN A N D J. J. RYI\N
Vol. 7s
'J CH=CH I
/S
HN\ CH
I
0
/I
111, V, TI:R-C
0 =
phthaloylglycyl
I1
Ya,V I a : R-C-
=
plitlialoyl-p-alanyl
CH3
Experimental" The Reaction between Phthaloylglycyl Chloride a n d 2Methyl-2-thiazoline. A. "Low Temperature Adduct" 111.-A solution of 5.60 g. (0.0250 mole) of phthaloylglycyl chloride in anhydrous benzene was added dropwise t o a stirred solution of 3.79 g . (0.0375 mole) of 2-methyl-2thiazolinel*and 2.53 g. (3.47 ml., 0.0250 mole) of triethylamine in anhydrous benzene a t room temperature. The addition required 30 minutes. After stirring for an additional 30 minutes, the thick white precipitate was removed by filtration, washed with pentane, and dried at room temperature. T h e crude product weighed 9.4 g. or 88% of the combined theoretical weight of triethylammonium chloride and adduct. Stirring the crude product with 200 ml. of water a t 35' for 15 minutes, removing the insoluble material by filtration and drying under reduced pressure yielded 6.3 g. (82%). of "low temperature adduct ." After one recrystallization from boiling acetone, the compound melted a t 183.5-185' with partial decomposition, slight discoloration beginning at about 170". Further recrystallizations from boiling acetone lowered the melting point of the material, which then no longer appeared crystalline. Recrystallizing a fresh portion by pouring boiling acetone over i t , filtering rapidly, and cooling the filtrate in ice raised the melting point t o 186188Odec. Anal. Calcd. for C14H12S?OaS.Hp0: C, 54.89; H, 4.61; R', 9.15. Found: C , 54.63; H , 5.40; N, 9.21. T h e same product was obtained by carrying out the addition a t 0'. B. "High Temperature Adduct" V.-To a solution of 2.02 g. (0.02 mole) of 2-methyl-2-thiazoline and l U . l g. (0.10 mole) of triethylamine in 30 ml. of anhydrous benzene, a solution of 4.48 g. (0.02 mole) of phthaloylglycyl chloride in 50 ml. of anhydrous benzene was added dropwise while stirring rapidly- and maintaining the temperature of the reaction mixture a t 60". The addition required 20 minutes. .Wer stirring a t room temperature for a n additional 3 hours, the solid was removed b y filtration, washed with dry benzene, and dried in a vacuum desiccator, yielding 6 . 3 g . (74%) of a light yellow material. a f t e r stirring this crude product in water a t room temperature for 15 minutes, there remained 3.5 g. (61y0) of a cream-colored solid, which melted a t 197-199' dec. after three recrystallizations from boiling acetone.
Anal. Calcd. for ClcH12Na03S: C , 58.34; H , 4.20; N, 9.72. Found: C, 58.57; H , 4.34; S,9.82. Repetition of the run a t 60", b u t using only- one equivalent of triethylamine, yielded, after washing with water and recrystallization from ethanol, 54Yo of a solid melting a t 196198' dec., which gave a n analysis (found: C, 57.45; €1, 4.36; N, 9.00) indicating a mixture of "low temperature adduct" I11 and "high temperature adduct" T'. 2-Aminoethanethiol Hydrochloride .-To 75 ml. of 6 lV hydrochloric acid was added 14.35 g. of freshly distilled 2methyl-2-thiazoline12 and the solution was refluxed for 21 hours under nitrogen. The colorless scilution was concentrated a t 70" (15 m m . ) then flushed with SO-ml. portions of absolute ethanol, absolute ethanol-benzene and benzene. The resulting crystals were dried a t 0.1 m m . t o 1-ield 15.79 g. (98%), m.p. 68-69". Recrystallization from absolute etlianol-ether raised the melting t o 69.;i-70.5° (reported13 _ point _ m .p ., 70 .2-70.7" ) . 2-Methvlthiazolidine IVII).'d-To a si~luticin of 19.3 R. (0.142 m d e ) of sodium aketate trihydrate in 75 ml. of watef, swept with a nitrogen stream, was added 15.8 g. (0.139 mole) of thioethanolamine hydrochloride. T o this solution a t 05" was added an ice-cold solution of 6.3 g. (0.142 mole) of acetaldehyde in 25 ml. of water with stirring over a period of 15 minutes. The solution was stored under uitrogen ovcrnight at 5'; then 15 g. of sodium carbonate was addctl, a n d t h e mixture extracted with three 100-ml. portions of ether. T h e combined ethereal extracts were dried over calcium sulfate and concentrated a t 35 m m . pressure. distil la ti ox^
