An Abnormal Ring Cleavage of la,2a-Epoxy- 3-keto Steroids by Hydrogen Fluoride

By U. Kerb, G. Schulz, and R. WiechertI*l

2-Chloro- (2a) and 2-bromo-5a-androst-l-en-3-one (2b) have been obtained by treatment of 17P-acetoxy-la,2a- epoxy-5u-androstan-3-one ( I ) [ I ] with hydrogen chloride and hydrogen bromide, respectively [2,3J.

However, hydrogen fluoride causes rearrangement, yielding, from (f), 17~-acetoxy-4~-fluoro-5a-androst-l-en-3-one (31, m.p. 173-174°C (UV: €234 = 10960)[41.

The characteristic signals in the N M R spectrum of this product (3) are the doublets of two olefinic protons (6 = 7.33 and 6.00). the double doublet of the proton on C-4 (S = 4.50), and the signal of the 19-CH3 group (6 = 1.20) which is split to a doublet [5J by 1,3-diaxial interaction with the 4P-fluorine atom.

The la-chloro-4a-fluoro ketone (4 ) (m.p. 173°C with de- camp.) was obtained from (3 ) by means of hydrogen chloride in glacial acetic acid, isomerization at C-4 and addition of HC1 occurring. Hydrogenation o f (3j in presence of Pd,K in methanol and subsequent epimerization by hydrogen chlo- ride in glacial acetic acid led to the 4a-fluoro ketone (5) (m.p. 187.5-188 "C). In the N M R spectra of (4 ) and (5 ) the signal of the 19-CH3 group appears as a singlet, whence i t follows that the fluorine is in the 4a position.

& 0

H f 1) H H

(24, x = c1 f 7) I (2b), X = Br

c1 I

For further proof of the structure of ( 3 ) . 17P-acetoxy-2P- fluoro-5a-androstan-3a-ol (m.p. 205-206 "C) was prepared from the 2a,3u-epoxide (6) and was oxidized to the 2P- fluoro ketone (m.p. 158-160 "C) and converted by acid isom- erization into the known 2a-fluoro compound (7) 141 (m.p. 189-190.5 "C). The double bond was introduced into (7) by bromination and then removal of hydrogen bromide. The 17P-acetoxy-2-fluoro-5a-androst-l-en-3-one (2c) prepared in this way (m.p. 16O.5-161.S0C; UV: €238 = 10100) gavea depression of the melting point on admixture with ( 3 ) . The NMR spectrum of (2c) contains the signal of only one ole- finic proton.

We were unable to rearrange (2c) to (3) by hydrogen fluoride under the conditions of epoxide ring fission, in the way that Djerassi and Scholz "1 observed for the 17.x-benzoyl- oxy-2-bromo-5a-androst-l-en-3-one system which was trans- formed into the 4-bromo isomer. Compound (2c) adds hy- drogen bromide, yielding (8) (m.p. 159.5-160.5 "C).

17~-Aceto .~y -4~-~ i toro -5~- t rndrost - I -en-3-one (3) :

Compound ( l a ) (1 g) is added portionwise to a mixture of a) dimethylformamide (5 ml) and hydrogen fluoride (5 ml) or b) tetrahydrofuran (40 ml) and hydrogen fluoride (10 ml) and the mixture is stirred for 22 h or 48 h, respectively, at room temperature. The reaction mixture is then poured into ice- water and neutralized with K2C03; the precipitate is filtered off and recrystallized from dichloromethane/isopropyl ether (yield 60%).

Received: September 16, 1968 12 875 IEI German version: Angew. Chem. 80, 916 (1968)

~. . .

[*] Dr. U. Kerb, Dr. G. Schulz, and Dr. R. Wiechert Hauptlaboratorium der Schering AG 1 Berlin 65, Miillerstrasse 170-172 (Germany)

[l] W . M . Hoehn, J . org. Chemistry 23, 929 (1958). [2] R. Wiechert, E . Kaspar, and M . Schenck, German Pat. 1076127, (August 30, 1958), Schering AG. [3] R. E. Counsel/ and P . D. Klimstra, J . rned. phannac. Chem. 5, 477 (1962). [4] The fluoro compound prepared by P. D . Klimstra and R. E. Counsefl [J. med. pharmac. Chem. 5, 1216 (1962)l from (2) by means of hydrogen fluoride in glacial acetic acid is probably not (2c), but rather also ( 3 ) . [ 5 ] A. D. Cross and P. W . Landis, J . Amer. chem. SOC. 86, 4005 (1 964). [6] J . Fajkos and F. Sornz, Collect. czechoslov. chem. Commun. 24, 3115 (1959). [7] C. Djerassi and C. R. Scholz, J. Amer. chem. SOC. 69, 2404 (1947).

Formation of Adenosine Triphosphate (ATP) from Adenosine Diphosphate (ADP) and

Phosphate during Oxidation of Mercaptoacetate by Bromine 11 1

By Th. Wieland and E. Bauerlein[*l

We have converted oxidation energy into the energy of the "energy-rich" diphosphate bond, e.g., that in ATP, by oxida- tion of S-alkylmonothiohydroquinones (21, N-acetylhomo- cysteine thiolactone [ 3 1 , thiazolidones 141, monoacetylduro- hydroquinone [51, a-tocopherol 161, and S-p-tolyl thioacetate (61 by bromine in pyridine in the presence of ADP and phos- phate (P). We have now found that under these conditions mercaptoacetate also gives ATP from the tetrabutylammoni- um (TBA) salts of ADP and P, and that yields exceed 30%.

In several batches, 13.33 ml of 0.1 N (TBA).OH solution in 2-propanol/methanol (Merck, Darmstadt) was treated with 0.67 ml of 1 N solution of cu. 90% phosphoric acid in di- oxane; 0.107 g of ADPH3.3 H20 (C. F. Boehringer und Soehne, Tutzing) was dissolved therein, and then 0.016 ml of freshly distilled mercaptoacetic acid was added. The solu- tion was evaporated under vacuum, and the residue was dried over P4O10 for 20 min at 0.1 torr and then dissolved with stirring in 9 m l of anhydrous pyridine, whereupon a deep yellow color developed. (A solution of the TBA salt of mercaptoacetic acid in anhydrous pyridine is colorless.) The solution was then treated, by dropwise addition within a few minutes, with 519 mmole (0.028 ml), 219 mmole (0.011 ml), or 0.133 mmole (= 1 . 2 ~ 1 1 9 mmole) (0.007 ml) of bromine, each amount in 1 ml of anhydrous pyridine.

This caused a color change from deep yellow through deep red to pale yellow; a precipitate was formed after a few minutes. After 1 h each batch (several repeats) was worked up for determination of ATP (results in Table 1).

No more than conjectures can be made at present about the mechanism of this coupled reaction. It may be that a sulfenyl bromide is first formed by bromination of the thiol and then combines with the phosphate ion to give a mixed sulfenic phosphoric anhydride R-S-O-P03H-, which is the actual phosphorylating agent.

Angew. Chem. internat. Edit. / Vol. 7 (1968) No. I I 893

Table I . Yields of ATP (calc. on the 84 % ADP used on simultaneous oxidation of equivalent amounts of (TBA)zHPO,,, (TBA)3ADP, and TBA niercaptoacetate by 1.2, 2.0, and 5.0 equivalents of bromine.

Aldehyde [a] Dimethyl

acetal Aldehyde

Oxime Aldehyde

Dimethyl acetal

Br2 (equiv) 1 1.2 1 I 2.0 1 I 5.0 1 1: _ _ ~ _ _ ~ _ _ _ _

out

Yield (%) of ATP

____- - ~ -

____- Net yield (%) 5.8 of ATP I

I-Adamantyl I-Adamantyl

3-Methyl-I-adamantyl

3-Methyl- 1 -adamantyl 3,5,7-Trimethyi-

I-adamantyl 3,5,7-TrimethyI-

1-adamantyl

with- out

0

Received: September 18, 1968 [Z 876 1El German version: Angew. Chem. 80, 915 (1968)

-~___ [*I Prof. Dr. Th. Wieland and Dr. E. Bauerlein

Institut fur Organische Chemie der Universitat 6 Frankfurt/Main, Robert-Mayer-Strasse 7-9 (Germany) Present address: Institut fur Chemie im Max-Planck-Institut fur medizinische Forschung 69 Heidelberg, Jahnstrasse 29 (Germany)

[l ] Model Experiments on Oxidative Phosphorylation, Part. 10.- Part 9: [4]. [2] Th. Wieland and E. Bauerlein, Mh. Chem. 98, 1381 (1967). [3] Th. Wieland and E. Bauerlein, Chem. Ber. 100, 3869 (1967). 141 Th. Wieland and H. Aquila, Chem. Ber. 101, 3031 (1968). [ 5 ] Th. Wieland and H . Aquila, Angew. Chem. 80, 190 (1968); Angew. Chem. internat. Edit. 7, 213 (1968). [6] E. Buuerlein and Th. Wieland, Chem. Ber., in press

Synthesis of 1-Adamantanecarbaldehydes

By K . Bo?t[*l

According to a process described in the patent literature [ I ]

free I-adamantanecarbaldehydes can be prepared by reduc- tion of 1-[1-(adamantanecarbonyl)]aziridines using LiAIH4. We have now found that I-adamantanecarbaldehydes (4) can be obtained in essentially higher yields (92-96%) by de- composition of the aziridinones ( I ) with aqueous mineral acids (Table 1). Compounds (2) and ( 3 ) are assumed to be intermediates because the aldimonium salts (3) can be iso- lated quantitatively on working in anhydrous ether [21.

Table I . Characterization of the aldehydes (4)

139-141 [bl 40-41

Colorless oil 76-11 74-75

54-55

1722 [cl

1710

- 1710 [cl

[a] First characterized as 2,4-dinitrophenylhydrazone [31. [ b ] Described in ref. [ I ] as an oil; according to ref. [Sl, m. p. 195 to 197.3OC. [cl KBr disc.

Although 1 -adamantanecarbaldehydes lose CO on heating under nitrogen, they are converted in to stable dimethyl acetals when dissolved in methanol containing hydrogen chloride.

3,5,7-Trimethyl-I-adumantunecarbaldehyde:

1 -?err- Butyl-2-(3,5,7-trimethy~-l-adamantyl)aziridinone~~~ (1.50 g) is heated to 100°C under nitrogen for a period of 15 min with a mixture of water (75 ml) and methane-sulfonic acid (7.0 9). The aldehyde formed is steam-distilled into an ice-cooled receiver, filtered off, and dried over PzO5 in a vacuum; yield 1.03 g (96%); m.p. 74-75 "C.

Received: August 27, 1968; revised: September 19, 1968 [ Z 878 IEI German version: Angew. Chem. 80, 970 (1968)

[*I Dr. K. Bott Forschungslaboratorien der Chemische Werke Huls A.G. 437 Marl (Germany)

111 V . L. Narayanan, US-Pat. 3300480 (1967), Squibb and Sons. [2] K. Bott, Tetrahedron Letters 1968, 3323. [3] H. Stetfer and E. Rauscher, Chern. Ber. 93, 1161 (1960). [4] K. Boft , Angew. Chem. 79, 943 (1967); Angew. Chem. inter- nat. Edit. 6 , 946 (1967). [ S ] D. E. Applequist and L. Kaplan, J. Amer. chem. SOC. 87, 2194 (1965)

New Possibilities of Direct Substitution of Adamantane

By H. Sfe f t e r , M. Krause, and W.-D. Last[*]

An ionic mechanism has been proposed for halogenation of adamantane "1; correspondingly. Friedel-Crafts catalysts catalyze this reaction. Adamantane can be halogenated also by halogenated hydrocarbons in the presence of such cata- lysts [21. Thus treating adamantane with aluminum chloride in carbon tetrachloride at room temperature gives a mixture of 1-chloroadamantane ( I ) [ I ] and 1,3-dichloroadarnantane (2) [31 in 84 % yield.

c1 q1 ,- I "

13) 72%

Using thionyl chloride instead of halogenated hydrocarbons also affords chlorinated adamantanes. However, surprisingly, at -15 "C I-adamantanesulfinyl chloride (3) is formed in 72% yield. On increase in the temperature the proportion of (3) formed decreases, and 1,3,5-trichloroadamantane [31 is the main product at the boiling point. I-Chloroadamantane ( I ) always gives a smaller proportion of the sulfinyl chloride (3) under comparable conditions. We assume that a chain reaction occurs in which the I-adamantylium ion RQ participates.

RQ + SOClz + RSOCl + CIS

C l @ + RH + R @ + HCl

The chloride (3) can be converted into methyl l-adamantane- sulfinate (4 ) (colorless crystals, m.p. 44-46 "C) in 83 % yield by means of boiling anhydrous methanol (6 h). and this ester is converted into I-adamantanethiol (5) [41 in 90% yield by LiAIH4 in anhydrous ether (17 h, 36'C). Further, the acid

894 Angew. Chem. internat. Edit, Vol. 7 (1968) NO. I1