RESEARCH
Diketone, isocyanate give 5-acylhydantoin Alkyl phosphites induce amino acid precursor formation and react with ketene to yield diketones Two condensation reactions of alpha dicarbonyl compounds containing pentacovalent phosphorus provide new synthesis routes to amino acids and compounds related to polyoxygenated carbohydrates, according to Dr. Fausto Ramirez and his coworkers of the State University of New York at Stony Brook [/. Am. Chcm. Soc, 89,3026,3030 (1967)]. Dr. Ramirez, Dr. S. B. Bhatia, and Dr. Curtis P. Smith have studied re actions of the phosphorus-containing compounds dioxaphospholenes with arylisocyanates to form 5-acylhydantoins, precursors of β-keto-a-amino acids. And by condensing phospholenes with ketene, they have devel oped an approach to the synthesis of α-hydroxy-^-diketones, y-bromo-ahydroxy-/?-diketones, and their phos phate esters. Hydantoins are one of the synthetic precursors of alpha amino acids. They are heterocyclic compounds; some are associated with powerful anticonvul sant action. For example, 5,5-diphenylhydantoin sodium (Dilantin) is widely used to control epilepsy. Many alkyl and aryl hydantoins have been prepared, but the 5-acylhydantoins haven't received much atten tion from other chemists. Dr. Herman Finkbeiner of General Electric's re search laboratories ( Schenectady, N.Y.) has recently prepared one 5-
acylhydantoin. Acyl hydantoins may hydrolyze to beta-keto-alpha amino acids. However, modifying the carbonyl group of the 5-acylhydantoins before hydrolysis would make a vari ety of beta-substituted alpha amino acids available, Dr. Ramirez says. In the Stony Brook group's approach to 5-acylhydantoins, the alpha dicar bonyl compound is condensed with an isocyanate under the influence of a trialkyl phosphite. For example, they prepare the 2,2,2-trialkoxy-l,3,2-dioxaphospholene from biacetyl and tri methyl phosphite. The phospholene reacts with phenylisocyanate to form l,3-diphenyl-5-acetyl-5-methylhydantoin. A faster reaction is achieved when p-cyanophenylisocyanate combines with the phospholene to give the iY-(p-cyanophenyl)hydantoin. Both hydantoins are isolated in 75(,'( yields. Dr. Ramirez and his coworkers have observed two distinct steps in the re action of the 2,2,2-trialkoxy-l,3,2-dioxaphospholene with phenylisocya nate. In the first step, one of the phospholene's carbon atoms acts as a nucleophile, adding to the carbonyl car bon of the isocyanate. The product is 2,2,2-trimethoxy-4-phenylimino-5acetyl-5-methyl-1,3,2 - dioxaphospholane. In the second step, the phospholane reacts with a second molecule of
PENTACOVALENT. Dr. C. P. Smith, Dr. A. S. Gulati, Dr. F. A. Ramirez, and Dr. S. B. Bhatia (left to right) use compounds containing pentacovalent phosphorus to synthesize 5-acylhydantoins and carbohydrate-related compounds 78 C&EN JUNE 12, 1967
phenyl isocyanate. The products are trimethyl phosphate and 1,3-diphenyl5-acetyl-5-methylhydantoin. The Stony Brook group has detected no in termediate in this reaction. But they assume that the phospholane's nitro gen first performs a nucleophilic addi tion to the isocyanate carbon to form a dipolar intermediate. This interme diate then cyclizes to a five-membered hydantoin ring, ejecting a phosphate ester. The reaction rates of phenylisocya nate with the phospholene and with the phospholane are very similar, the Stony Brook chemists find. There fore, the best procedure to make the phospholane involves a slow addition of isocyanate to excess phospholene. Dr. Ramirez and his group have used infrared spectra and Ή and 3 1 P nuclear magnetic resonance spectros copy to establish the structure of the phospholane. The 3 1 P NMR data show that five oxygen atoms are bound to the phosphorus. The 1 H NMR results show the presence of the acetyl group, the methyl group, and the three methoxy groups. The IR spectrum indicates the presence of the C=^ group and the C = 0 group. IR studies show that the hydantoin contains carbonyl groups at C-2 and C-4, and an acetyl carbonyl group. The *H NMR spectrum of the hydan toin shows that it contains 10 aromatic hydrogens, an acetyl group, and a methyl group. The Stony Brook group's work on the 5-acylhydantoin synthesis points to a new general method of making car bon-carbon single bonds using triplyand quintuply-bonded phosphorus compounds. The method seems adaptable to synthesizing alpha amino acids and carbohydrates, Dr. Ramirez says. Studies of these syntheses are now under way at Stony Brook. The Stony Brook group's approach to the synthesis of o:-hydroxy-/?-diketones, y-bromo-o:-hydiOxy-/?-diketones, and their phosphate esters starts with the condensation of a phospholene with ketene. For example, they react ketene with 2,2,2-trimethoxy-4,5-dimethyl-l,3,2-dioxaphospholene at 0° C. in methylene chloride solution to give 2,2,2-trimethoxy-4-methylene-5acetyl - 5 - methyl -1,3,2 - dioxaphospholane in 90% yield. They have estab-
Stony Brook group's syntheses give precursors of 0-keto-a-aniino acids and /3-diketones and their phosphate esters
Hs c xH
Η .Η
•I
R.
r->
R
I?
Κ
O
c
c-c-u. ο ο ο
c
ο c R' R Ν Ι Η
11
ι
c-c-c
Λ 2,2,2,-trimethoxy, 3,2-dioxaphospholene
ο ο ο
χ
y CWTP
ΌΟΗ-
OCM-. R-N=C=o
R
R. ο
ι ι « c-c-c
&r~
n
/
ο ο+ ο
>J^CH 3
CH30
OCK}
A phospholane HCI gas
\ R CH
R R CH3 ι 1 c~c-c
Excess /-/ 2 θ\ Benzene
ι ι c-c-c
Il
cr
a 1 H 0 0 0 I 0 = P~OCHa
I
II
ο ο ο j P-oi-c*t 3 /N crt3o ocH^
I
I
I
Ό
I Ο
R
R
I
l
j[ Ο
°
II
I
CH,
+ (cH3o)3Po
Excess H20
c—c—c II
+ CH, Br
ÛioP
1
OCH3
1
p.
CH^o-P W-jC
11
OCria
OCH*
I
c-c-c
ecu
ocH3
CH 3 0
ocHo
owe
ι
I
* *
_ c + p(ocH^) II II
c
R Ι
R R ÇHxBr
Κ C
===*
Benzene
»
ο ori ο Λ 3-ol-2,4-dione
Postulated intermediate Osp-ocH3 I
R.
R Ο
CH30
r.-CL-C
ο P.
+ CH3CI M-R-f (CH30\PO
M
c II
σ
β-Keto-oc-amino acids
A 5-acyl hydantoin precursor
lished the structure of the phospholane using 3 1 P NMR, Ή NMR, and IR. The phospholane reacts with hy drogen chloride to give a quantitative yield of the dimethyl phosphate ester of 3 - methylpentan - 3 - ol - 2,4dione. Dr. Ramirez views this reac tion as an alkylation of hydrogen chloride by the unsaturated phos pholane. The phospholane reacts with
bromine at 0° C. in carbon tetra chloride to give a quantitative yield of a γ-bromo-a-hydroxy-^-diketone. Hydrolysis of the a-hydroxy-/?-diketone phosphotriester in aqueous ben zene at 80° C. gives the 3-methyl-pentan - 3 - ol - 2,4 - dione ( diacetylmethylcarbinol ). This is a remarkably fast hydrolysis, Dr. Ramirez points out. The phospholane is converted easily
into diacetylmethylcarbinol by an ex cess of water in benzene at 80° C. Condensing alpha dicarbonyl com pounds with ketenes using trialkyl phosphites opens a new route to a variety of polyoxygenated functions re lated to the carbohydrates, Dr. Rami rez says. The phosphate esters of these sugarlike materials can also be obtained this way, he adds. JUNE 12, 1967 C&EN 79
