- Email: [email protected]
Derivatives of alpha Amino Aldehydes*
Derivatives of &&ha Amino Aldehydes* By WILLIAM 0. FOYE and JOHN J. HEFFERRENt A series of nitrogen derivatives of aldehyde analogs of some naturally occurring dl a-amino acids has been re ared. The conversion of the phthaloylamino acids to the corresponding aldehyiesgy means of the Rosenmund method of reduction gave crystalline aldehydes in a majority of cases. The aldehydes were readily converted to semicarbazone, thiosemicarbazone, and dithiobiuret derivatives for testing as possible antiviral agents.
(1) has outlined several possible mechanisms by which antiviral agents may act, among which is that of an antimetabolic effect caused by structures related to essential metabolites of the virus. That this effect may actually be operative has been indicated by the action of sulfonic acid analogs of naturally occurring a-amino acids ( 2 ) , as well as by various aromatic aldehyde thiosemicarbazones (3), which have been shown to be highly active against a variety of viruses. This evidence suggested the possibility that aldehyde analogs of naturally occurring a-amino acids might be inhibitory to the multiplication of viruses, and a series of analogs of this type has accordingly been prepared. These compounds were converted to nitrogen derivatives (I) which provide a similarity to simple dipeptides (11), when i t is considered that the nitrogen side chains are similar to glycine in molecular size and shape, and the aldimine linkage is analogous to a dehydrated arnide linkage.
A
NDREWES
I
R
S
I
IT
I/
-N-CH-CH=N-NH-C-h-
(1)
I
R
I
O
I/
-N-CH-C-NH-CH-C-N(11)
R
O
I
/I
I
Literature on the previous preparation of stable aliphatic a-amino aldehydes is scanty. Fischer and Kanietaka (4), however, obtained L- a-amipopropiona!dehy de, aminoacetaldehyde, and dl-a-amino-a-phenylpropionaldehydeas the diethyl acetals by reduction of the amino acid esters with sodium amalgam. Akabori ( 5 ) and Bullenvell and Lawson (6) used the same pro-
*
Received August 21, 1953, from the School of Pharmacy, University of Wisconsin, Madison. Presented to the Scientific Section. A. PH. A,, Salt Lake City meeting, August, 1953. Abstracted from the dissertation of John J. Hefferren submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, University of Wisconsin, September, 1933. 7 Fellow of the Americau Foundation for Pharmaceutical Bducation 1050-1083.
cedure to obtain a number of amino aldehydes which, however, were not isolated, but converted to imidazoles. Another method was employed by Radde (7) to obtain phthalimidoacetaldehyde and phthalia Rosenmund midopropionaldehyde-namely, reduction of the a-phthaloylamino acid chloride. BalenoviE, et al. (8), have recently utilized this method to prepare optically active amino aldehydes from r.-alanine, 5’-benzyl-L-cysteine, and 0-methyl-L-tyrosine. Other methods attempted in this laboratory for the preparation of a-amino aldehydes include the controlled oxidation of N-benzoylaminoethanol, the reduction of p-phthalimidopropionitrile, and the hydrolysis of phthalimidoacetaldehyde dimethyl acetal. These methods, as well as a Rosenmund reduction of a-benzoylamino acids, failed to give appreciable yields; the latter method failed because of solubility difficulties. Accordingly, the method of Kadde was employed, which involves a Rosenmund reduction of the a-phthaloylarnino acid chloride. This procedure was found to be successful with all a-amino acids tried except methionine, where the sulfur possibly reacts with the acid chloride, since the acid chloride obtained resisted reduction. The general procedure followed is illustrated by Eq. 1. Although Radde claimed that this method was successful only in the case of a-amino acid chlorides,it was found that ~-phthalimidopropionalciehyde could be prepared as successfully as any of the a-amino aldehydes. I t was also found that use of more catalyst for the reduction than that usually required gave much better results. While Mosettig and Mozingo (9) specify one part of catalyst for five to ten parts of acid chloride, the reduction of the a-phthalimido acid chlorides proceeded much faster and gave purer aldehydes with one part of catalyst for two to three parts of acid chloride. The amino aldehydes, in general, were isolated as the phthaloyl derivatives, which crystallized from the reaction mixture on addition of hydrocarbon solvents: The longer cliaiii aldehydes, 134
February, 1954
SCIENTIFIC EDITION
125 0
0
1I
-
0
' c/
A
II
N-CH-C--OH
PC16
II
0
0 0
0
I1
1I
0
H¶
____,
_ I _ ,
Pd/BaSO,
II
I1
0
0
0
Equation 1.-Preparation
S
0 R # = -NH-C-NH~, I1
-NH-C-NH~, 1I
S
II
of a-phthalimido aldehyde derivatives.
or
corded in Table I and those of the aldehyde derivatives in Table 11.
S
-C-NH-C-NHz
The physical constants and analytical results of the a-phthalimido aldehydes prepared are re-
II
prepared from leucine and valine, could not be obtained in crystalline form. The oils which resulted in these were readily converted to crystalline aldehyde derivatives, however. The PhthaloYl groups were allowed to remain in the final products for the sake of greater stability.
EXPERIMENTAL
Phthalimido Acids.-The phthalimido acids were prepared by the general procedure of Reese (lo), in which a finely ground mixture of the amino acid and phthalic anhydride is heated with stirring at 130150". The products were obtained by recrystalliza-
TABLE ~.-PHTHALIMIDO ALDEHYDES FROM AMINOACIDS 0
Amino Acid Used
a .
b C
Yield, % (From Phthalimido Acid)
Found
GIycine dl-Alanine dl-8-Alanine
70 51 65
112-114" 109-1 11' 115-117'
d2-Phenvlalanine
50
75-78"
dl-Leucine dl-Valine
Oil Oil
M. P.0
Recorded b
113-114.5' 108.5-1 11
Calcd.
Analysis0
C, 65.01 H, 4.46 C. 73.11 H, 4.69
All melting points are corrected. Radde (7). Analyses for C and H were carried out by the Clark Microanalytical Laboratory, Urbana, Illinois.
Found
C, 65.21 H, 4.79 c. 73.44 H, 4.91
224-22jd
219-220
215-216
200-201
228-229
85
66
88
90
70
All melting points are corrected.
224-226~
85
%
Yield,
19.44
18.53
16.66
%
204-215 190-191 214-215
85 65 74
16.52
18.67
18.28
211-212
Radde (7) lists 233-244'. d Radde (7)lists 225.5-226.5".
C
2lG-208
215-216
70
60
81
Yield,
'
Tbiosemicarbazonc M. P., Nitrogen "C. Calcd.
18.41
17.60
15.90
20.28
20.28
21.36
r----
21.33
...
...
21.53
...
Ana1.b Found
...
-Semicarbazone------M.P.," Nitrogen OC. Calcd.
p
N-CH-CH=N-I\
b Analyses for N were carried out by the Clark Microanalytical Laboratory, Urbana. Illinois.
a
Aldehyde
Phthalirnidoethanal 2-Phthalimidopropanal 3-Phthalimidopropanal 2-Phthalimido3-phenyl propanal 2-Phthalimido4-methyl pentanal 2-Phthalimido3-methy1 butanal
-
0
fi'9
I1
0
17.21
17.27
15.13
19.67
19.99
21.92
Anal. Found
TABLE I ~.-PHTHALIMIDO ALDEHYDE DERIVATIVES
-
%
14
237-239
258-260
256-258
20 18
243-244
251-253
250-251
16.08
15.54
14.13
17.49
17.49
18.37
Dithiobiuret DerivativeM. P., Nitrogen T. Calcd.
20
20
15
Yield,
7
Anal. Found
15.75
15.22
13.63
17.12
17.23
18.29
1 3
-
0
February, 1954
SCIENTIFIC EDITION
tion from water or aqueous alcohol, although it was necessary t o extract first with ether in the case of phthaloylvaline. The yields ranged from 85-950/0. Phthalimido Acid Chlorides.-The acid chlorides were all prepared in essentially the same manner by shaking the phthalimido acids (0.02-0.04 mole) with equimolar quantities of phosphorus pentachloride in a 50-cc. Claisen flask for fifteen minutes, followed by heating the mixtures on the steam bath for forty-five minutes. The light yellow liquids obtained were warmed under reduced pressure t o remove phosphorus oxychloride, and the acid chlorides were crystallized from hydrocarbon solvents. In the case of phthaloylleucine and phthaloylvaline, however, the acid chlorides were obtained only a s oils. The use of oxalyl chloride was necessary t o prepare the acid chloride of phthaloylmethionine. Thionyl chloride gave no better results than phosphorus pentachloride, which gave yields of acid chlorides ranging from 8 595% . Preparation of Catalyst.-The catalyst employed for reduction of the acid chlorides was palladium on barium sulfate (palladium content 5%) prepared according to the procedure of Mozingo (11). The quinoline-sulfur poison or regulator was prepared according to the procedure of Hershberg and Cason (12), giving a xylene solution which contained 0.1 Gm. of regulator per cc. Phthalimido Aldehydes.-The reduction of the acid chlorides followed essentially the original method of Rosenmund and Zetsche (13). The acid chloride (0.02-0.04 mole) was dissolved in three t o ten times its weight of purified toluene (refluxed over sodium) in a 250-cc. three-necked flask equipped with a mercury-sealed stirrer, hydrogen trap, and condenser with tubing attached to permit the titration of the evolved gases. The catalyst was added t o give a weight ratio of one part of catalyst t o two or three parts of acid chloride, and the regulator was added in an amount one-tenth that of the catalyst. After the mixture was thoroughly flushed with hydrogen, it was heated to reflux temperature and then stirred until 80-90% of the theoretical amount of hydrogen chloride was evolved, as determined by titration with 1.0 N sodium hydroxide. This generally required four to five hours, at which time the evplution of hydrogen chloride was extremely slow. Heating beyond five hours generally resulted in considerable decomposition. Norite was then added, the catalyst was removed by filtration, and the resulting solution was chilled until crystals appeared. The addition of petroleum ether generally gave a second crop. After recrystallization from mixtures of benzene and petroleum ether, the phthalimido aldehydes were obtained in yields of 60-76y0. The aldehydes prepared from phthaloylleucine and phthaloylvaline were obtained as light yellow oils which could not be crystallized. Preparation of Aldehyde Derivatives.-The semicarbazbnes were prepared in the customary fashion by heating the aldehydes with semicarbazide hydroZhloride and sodium acetate. The thiosemicarbazones were prepared by heating with thiosemicarbazide in aqueous alcohol. The dithiobiuret derivatives were prepared by the procedure of Foye and Hefferren (14) in which dithiobiuret is refluxed with a slight excess of alde-
127
hyde in glacial acetic acid which contains a small amount of anhydrous zinc chloride. After refluxing for thirteen or more hours, the solutions were concentrated slightly and crystalline products were obtained, after at least two days standing at room temperature. After recrystallization from glacial acetic acid, the dithiobiuret condensation products were obtained in yields of 15-20%. Treatment of the phthalimido aldehydes with phenylhydrazine resulted in phenylhydrazones with no cleavage of the phthaloyl group. Phthalimidoethanal phenylhydrazone was prepared from the aldehyde in 60% yield, and melted at 163-165°, which agrees with the value reported by Radde (7). However, treatment of phthalimidoethanal phenylhydrazone with hydrazine hydrate, according to the method of Ing and Manske (15) resulted in apparent decomposition, and a stable product could not be isolated from the reaction.
SUMMARY
1. A series of aldehyde analogs of a-amino acids was prepared t o test for the possibility of antiviral action. Stable derivatives were obtained by preparing the a-phthalimido aldehydes which were converted to semicarbazone, thiosemicarbazone, and dithiobiuret derivatives. 2. A general method of preparation was found in the Rosenmund method of reduction of the a-phthalimido acid chlorides, except where sulfur was present in the molecule. A j3-phthalimido aldehyde was also prepared by this method. 3. The following new compounds were characterized : 3-phthalimidopropanal, 2-phthalimido-3-phenylpropanal, the semicarbazone, thiosemicarbazone, and dithiobiuret derivatives of 3-phthalimidopropanal, 2-phthalimido-3-phenylpropanal, 2-phthalimido-4-methylpentana1,and 2-phthalimido-3-methylbutana1,a n d the thiosemicarbazone and dithiobiuret derivatives of phthalimidoethanal a n d 2-phthalimidopropanal. REFERENCES (1) Andrewes, C. H., and King, H.. Brit. Med. Bull., 4, 272( 1946). (2) Brown, G . C., J . Immunol., 69, 441(1952); Spizizen, J.. J . Znfecfious Diseascs, 73, 212(1943). 13) Hamre. D.. Bmwnlee. K. A.. and Donovick. R.. J .
(6) Bullerwell, R . A. F., and Lawson, A,, J . Chem. Sc 1951, 3030. (7) Radde, E., Ber., 55, 3174(1922). (8) Balenovir, K., Bregant. N., Cerar, D.. Ples, D., and JambresiE., I.. $. Ow. Chem., 18, 297(1953). (9) Mosettig, P., and Mozingo R. “Organic Reactions,” Vol. IV John Wiley & Sons, New’Yo;k, 1948, p. 362. (10) Reese. L., Ann., 242, !(1887). (11) Mozingo, R., “Organic Syntheses,” Vol. 26, John Wiley & Sons New York 1946, p. 77. (12) HenhLerg, E. B., k d Cason, J., ibid., Vol. 21, 1941, p. 84. (13) Rosenmund, K. W., and Zetsche. F., Ber., 54. 425 (1921). (14) Foye, W. 0.. and Hefferren, J. J., THIS JOURNAL, 42, 3 1(1953). (15) Ing, H. R., and Manske. R. H. F., J . Chem. Soc., 1926, 2348.
(1) has outlined several possible mechanisms by which antiviral agents may act, among which is that of an antimetabolic effect caused by structures related to essential metabolites of the virus. That this effect may actually be operative has been indicated by the action of sulfonic acid analogs of naturally occurring a-amino acids ( 2 ) , as well as by various aromatic aldehyde thiosemicarbazones (3), which have been shown to be highly active against a variety of viruses. This evidence suggested the possibility that aldehyde analogs of naturally occurring a-amino acids might be inhibitory to the multiplication of viruses, and a series of analogs of this type has accordingly been prepared. These compounds were converted to nitrogen derivatives (I) which provide a similarity to simple dipeptides (11), when i t is considered that the nitrogen side chains are similar to glycine in molecular size and shape, and the aldimine linkage is analogous to a dehydrated arnide linkage.
A
NDREWES
I
R
S
I
IT
I/
-N-CH-CH=N-NH-C-h-
(1)
I
R
I
O
I/
-N-CH-C-NH-CH-C-N(11)
R
O
I
/I
I
Literature on the previous preparation of stable aliphatic a-amino aldehydes is scanty. Fischer and Kanietaka (4), however, obtained L- a-amipopropiona!dehy de, aminoacetaldehyde, and dl-a-amino-a-phenylpropionaldehydeas the diethyl acetals by reduction of the amino acid esters with sodium amalgam. Akabori ( 5 ) and Bullenvell and Lawson (6) used the same pro-
*
Received August 21, 1953, from the School of Pharmacy, University of Wisconsin, Madison. Presented to the Scientific Section. A. PH. A,, Salt Lake City meeting, August, 1953. Abstracted from the dissertation of John J. Hefferren submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, University of Wisconsin, September, 1933. 7 Fellow of the Americau Foundation for Pharmaceutical Bducation 1050-1083.
cedure to obtain a number of amino aldehydes which, however, were not isolated, but converted to imidazoles. Another method was employed by Radde (7) to obtain phthalimidoacetaldehyde and phthalia Rosenmund midopropionaldehyde-namely, reduction of the a-phthaloylamino acid chloride. BalenoviE, et al. (8), have recently utilized this method to prepare optically active amino aldehydes from r.-alanine, 5’-benzyl-L-cysteine, and 0-methyl-L-tyrosine. Other methods attempted in this laboratory for the preparation of a-amino aldehydes include the controlled oxidation of N-benzoylaminoethanol, the reduction of p-phthalimidopropionitrile, and the hydrolysis of phthalimidoacetaldehyde dimethyl acetal. These methods, as well as a Rosenmund reduction of a-benzoylamino acids, failed to give appreciable yields; the latter method failed because of solubility difficulties. Accordingly, the method of Kadde was employed, which involves a Rosenmund reduction of the a-phthaloylarnino acid chloride. This procedure was found to be successful with all a-amino acids tried except methionine, where the sulfur possibly reacts with the acid chloride, since the acid chloride obtained resisted reduction. The general procedure followed is illustrated by Eq. 1. Although Radde claimed that this method was successful only in the case of a-amino acid chlorides,it was found that ~-phthalimidopropionalciehyde could be prepared as successfully as any of the a-amino aldehydes. I t was also found that use of more catalyst for the reduction than that usually required gave much better results. While Mosettig and Mozingo (9) specify one part of catalyst for five to ten parts of acid chloride, the reduction of the a-phthalimido acid chlorides proceeded much faster and gave purer aldehydes with one part of catalyst for two to three parts of acid chloride. The amino aldehydes, in general, were isolated as the phthaloyl derivatives, which crystallized from the reaction mixture on addition of hydrocarbon solvents: The longer cliaiii aldehydes, 134
February, 1954
SCIENTIFIC EDITION
125 0
0
1I
-
0
' c/
A
II
N-CH-C--OH
PC16
II
0
0 0
0
I1
1I
0
H¶
____,
_ I _ ,
Pd/BaSO,
II
I1
0
0
0
Equation 1.-Preparation
S
0 R # = -NH-C-NH~, I1
-NH-C-NH~, 1I
S
II
of a-phthalimido aldehyde derivatives.
or
corded in Table I and those of the aldehyde derivatives in Table 11.
S
-C-NH-C-NHz
The physical constants and analytical results of the a-phthalimido aldehydes prepared are re-
II
prepared from leucine and valine, could not be obtained in crystalline form. The oils which resulted in these were readily converted to crystalline aldehyde derivatives, however. The PhthaloYl groups were allowed to remain in the final products for the sake of greater stability.
EXPERIMENTAL
Phthalimido Acids.-The phthalimido acids were prepared by the general procedure of Reese (lo), in which a finely ground mixture of the amino acid and phthalic anhydride is heated with stirring at 130150". The products were obtained by recrystalliza-
TABLE ~.-PHTHALIMIDO ALDEHYDES FROM AMINOACIDS 0
Amino Acid Used
a .
b C
Yield, % (From Phthalimido Acid)
Found
GIycine dl-Alanine dl-8-Alanine
70 51 65
112-114" 109-1 11' 115-117'
d2-Phenvlalanine
50
75-78"
dl-Leucine dl-Valine
Oil Oil
M. P.0
Recorded b
113-114.5' 108.5-1 11
Calcd.
Analysis0
C, 65.01 H, 4.46 C. 73.11 H, 4.69
All melting points are corrected. Radde (7). Analyses for C and H were carried out by the Clark Microanalytical Laboratory, Urbana, Illinois.
Found
C, 65.21 H, 4.79 c. 73.44 H, 4.91
224-22jd
219-220
215-216
200-201
228-229
85
66
88
90
70
All melting points are corrected.
224-226~
85
%
Yield,
19.44
18.53
16.66
%
204-215 190-191 214-215
85 65 74
16.52
18.67
18.28
211-212
Radde (7) lists 233-244'. d Radde (7)lists 225.5-226.5".
C
2lG-208
215-216
70
60
81
Yield,
'
Tbiosemicarbazonc M. P., Nitrogen "C. Calcd.
18.41
17.60
15.90
20.28
20.28
21.36
r----
21.33
...
...
21.53
...
Ana1.b Found
...
-Semicarbazone------M.P.," Nitrogen OC. Calcd.
p
N-CH-CH=N-I\
b Analyses for N were carried out by the Clark Microanalytical Laboratory, Urbana. Illinois.
a
Aldehyde
Phthalirnidoethanal 2-Phthalimidopropanal 3-Phthalimidopropanal 2-Phthalimido3-phenyl propanal 2-Phthalimido4-methyl pentanal 2-Phthalimido3-methy1 butanal
-
0
fi'9
I1
0
17.21
17.27
15.13
19.67
19.99
21.92
Anal. Found
TABLE I ~.-PHTHALIMIDO ALDEHYDE DERIVATIVES
-
%
14
237-239
258-260
256-258
20 18
243-244
251-253
250-251
16.08
15.54
14.13
17.49
17.49
18.37
Dithiobiuret DerivativeM. P., Nitrogen T. Calcd.
20
20
15
Yield,
7
Anal. Found
15.75
15.22
13.63
17.12
17.23
18.29
1 3
-
0
February, 1954
SCIENTIFIC EDITION
tion from water or aqueous alcohol, although it was necessary t o extract first with ether in the case of phthaloylvaline. The yields ranged from 85-950/0. Phthalimido Acid Chlorides.-The acid chlorides were all prepared in essentially the same manner by shaking the phthalimido acids (0.02-0.04 mole) with equimolar quantities of phosphorus pentachloride in a 50-cc. Claisen flask for fifteen minutes, followed by heating the mixtures on the steam bath for forty-five minutes. The light yellow liquids obtained were warmed under reduced pressure t o remove phosphorus oxychloride, and the acid chlorides were crystallized from hydrocarbon solvents. In the case of phthaloylleucine and phthaloylvaline, however, the acid chlorides were obtained only a s oils. The use of oxalyl chloride was necessary t o prepare the acid chloride of phthaloylmethionine. Thionyl chloride gave no better results than phosphorus pentachloride, which gave yields of acid chlorides ranging from 8 595% . Preparation of Catalyst.-The catalyst employed for reduction of the acid chlorides was palladium on barium sulfate (palladium content 5%) prepared according to the procedure of Mozingo (11). The quinoline-sulfur poison or regulator was prepared according to the procedure of Hershberg and Cason (12), giving a xylene solution which contained 0.1 Gm. of regulator per cc. Phthalimido Aldehydes.-The reduction of the acid chlorides followed essentially the original method of Rosenmund and Zetsche (13). The acid chloride (0.02-0.04 mole) was dissolved in three t o ten times its weight of purified toluene (refluxed over sodium) in a 250-cc. three-necked flask equipped with a mercury-sealed stirrer, hydrogen trap, and condenser with tubing attached to permit the titration of the evolved gases. The catalyst was added t o give a weight ratio of one part of catalyst t o two or three parts of acid chloride, and the regulator was added in an amount one-tenth that of the catalyst. After the mixture was thoroughly flushed with hydrogen, it was heated to reflux temperature and then stirred until 80-90% of the theoretical amount of hydrogen chloride was evolved, as determined by titration with 1.0 N sodium hydroxide. This generally required four to five hours, at which time the evplution of hydrogen chloride was extremely slow. Heating beyond five hours generally resulted in considerable decomposition. Norite was then added, the catalyst was removed by filtration, and the resulting solution was chilled until crystals appeared. The addition of petroleum ether generally gave a second crop. After recrystallization from mixtures of benzene and petroleum ether, the phthalimido aldehydes were obtained in yields of 60-76y0. The aldehydes prepared from phthaloylleucine and phthaloylvaline were obtained as light yellow oils which could not be crystallized. Preparation of Aldehyde Derivatives.-The semicarbazbnes were prepared in the customary fashion by heating the aldehydes with semicarbazide hydroZhloride and sodium acetate. The thiosemicarbazones were prepared by heating with thiosemicarbazide in aqueous alcohol. The dithiobiuret derivatives were prepared by the procedure of Foye and Hefferren (14) in which dithiobiuret is refluxed with a slight excess of alde-
127
hyde in glacial acetic acid which contains a small amount of anhydrous zinc chloride. After refluxing for thirteen or more hours, the solutions were concentrated slightly and crystalline products were obtained, after at least two days standing at room temperature. After recrystallization from glacial acetic acid, the dithiobiuret condensation products were obtained in yields of 15-20%. Treatment of the phthalimido aldehydes with phenylhydrazine resulted in phenylhydrazones with no cleavage of the phthaloyl group. Phthalimidoethanal phenylhydrazone was prepared from the aldehyde in 60% yield, and melted at 163-165°, which agrees with the value reported by Radde (7). However, treatment of phthalimidoethanal phenylhydrazone with hydrazine hydrate, according to the method of Ing and Manske (15) resulted in apparent decomposition, and a stable product could not be isolated from the reaction.
SUMMARY
1. A series of aldehyde analogs of a-amino acids was prepared t o test for the possibility of antiviral action. Stable derivatives were obtained by preparing the a-phthalimido aldehydes which were converted to semicarbazone, thiosemicarbazone, and dithiobiuret derivatives. 2. A general method of preparation was found in the Rosenmund method of reduction of the a-phthalimido acid chlorides, except where sulfur was present in the molecule. A j3-phthalimido aldehyde was also prepared by this method. 3. The following new compounds were characterized : 3-phthalimidopropanal, 2-phthalimido-3-phenylpropanal, the semicarbazone, thiosemicarbazone, and dithiobiuret derivatives of 3-phthalimidopropanal, 2-phthalimido-3-phenylpropanal, 2-phthalimido-4-methylpentana1,and 2-phthalimido-3-methylbutana1,a n d the thiosemicarbazone and dithiobiuret derivatives of phthalimidoethanal a n d 2-phthalimidopropanal. REFERENCES (1) Andrewes, C. H., and King, H.. Brit. Med. Bull., 4, 272( 1946). (2) Brown, G . C., J . Immunol., 69, 441(1952); Spizizen, J.. J . Znfecfious Diseascs, 73, 212(1943). 13) Hamre. D.. Bmwnlee. K. A.. and Donovick. R.. J .
(6) Bullerwell, R . A. F., and Lawson, A,, J . Chem. Sc 1951, 3030. (7) Radde, E., Ber., 55, 3174(1922). (8) Balenovir, K., Bregant. N., Cerar, D.. Ples, D., and JambresiE., I.. $. Ow. Chem., 18, 297(1953). (9) Mosettig, P., and Mozingo R. “Organic Reactions,” Vol. IV John Wiley & Sons, New’Yo;k, 1948, p. 362. (10) Reese. L., Ann., 242, !(1887). (11) Mozingo, R., “Organic Syntheses,” Vol. 26, John Wiley & Sons New York 1946, p. 77. (12) HenhLerg, E. B., k d Cason, J., ibid., Vol. 21, 1941, p. 84. (13) Rosenmund, K. W., and Zetsche. F., Ber., 54. 425 (1921). (14) Foye, W. 0.. and Hefferren, J. J., THIS JOURNAL, 42, 3 1(1953). (15) Ing, H. R., and Manske. R. H. F., J . Chem. Soc., 1926, 2348.