4. K. ROSE, B. N. GIIOSH-MAZUMDAR AND B.
2382
formyl fluoride (61yoof the theoretical over-all yicld). Only minor amount r?f acetyl fluoric!e was detected. Aromatic Aldehydes.-(a) Formyl fluoride (24 g., 0.5 mole) was dissolved in 1.O mole of the corresponding alkylbenzene (toluene, xylene, mesitylene, isodurene) a t -3070" (depending on the freezing point of the hydrocarbon). Into this cold solution boron trifluoride was introduced to saturation (0.5 mole). Generally a deeply colored complex lower layer is formed. The mixture was then allowed slowly t o warm up t o room temperature. The complex decomposed with strong boron trifluoride evolution. The reaction mixture was washed acid-free with water, dried over calcium chloride and fractionated. ( b ) One-half mole of the corresponding aromatic hydrocarbon was dissolved in 150 ml. of C&. IVhile the temperature of the reaction mixture was maintained at 0 t o 10" a slow stream of formyl fluoride and boron trifluoride (in the ratio of 1 : l ) was passed through with stirring. After 3 hours when a weight increase corresponding t o the reaction of 0.5 mole of formyl fluoride was observed (in the form of the boron fluoride complex) the interaction was stopped, the reaction mixture was stirred for another half-hour, then washed acid-free with cold water, dried over calcium chloride and fractionated. The following aldehydes were prepared: benzaldehyde (56% yield), tolualdehyde (po-isomer mixture, 76y0), dimethylbenzaldehyde (mixture, 7870). 2,4,6trimethylbenzaldehyde (70%), 2,3,4,6-tetramethylbenzaldehyde (72%), naphthaldehyde (a-with about 20% P, 67%). Alkyl (Aryl) Formates.-One-half mole of the corresponding alcohol (phenol) and 0.5 mole of tri-ethylamine were dissolved in 150 ml. of dry ether. Into the stirred solution was introduced 24 g . (0.5 mole) of formyl fluoride. The temperature of the reaction mixture was kept around 0". After the addition of the formyl fluoride was completed the stirring was continued for a n additional half-hour. The precipitated amine hydrofluoride was filtered off. The ethereal solution was fractionated. The following formates were prepared: methyl (89% yield), ethyl (92%), n-propyl (81%), n-butyl :I
[COSTRIBUTION FROX THE
G.CII.\TTERJEE
Yol.
ss
( 8 0 % ) , sec-butyl (84%), n-amyl (78%), isoamyl (YO%), noctyl ( 7 3 % ) , benzyl (69%) and phenyl (75%). Alkyl (Aryl) Thiolformates-One-half mole of the corresponding mercaptans (thiophenol) and 0.5 mole of triethylamine was dissolved in 200 ml. of dry ether. Formyl fluoride (24 g., 0.5 mole) was introduced into the stirred solution rhile maintaining the temperature with ice cooling at 0 to 5 " . After the addition of the formyl fluoride was completed the stirring was continued for a n hour. The precipitated triethylamine hydrofluoride was filtered off and the ethereal solution was fractionated. Date on the thiolformates obtained are summarized in Table I. Formamides. (a) Excess Amine as Acid-binding Agent.One mole of the corresponding primary or secondary amine was dissolved in 200 ml. of dry ether and treated with 24 g. (0.5 mole) of formyl fluoride while maintaining the temperature about 0". After the addition of the formyl fluoride was completed the stirring was continued for a n additional half-hour. The precipitated amine hydrofluoride was filtered off and the ethereal solution fractionated. (In the case of X-benzyl formamide the ether was distilled off and the solid residue recrystallized from alcohol.) The following Nalkyl formamides were obtained: N-methyl (89% yield), N, N-dimethyl (92 yo), N-isopropyl (87yo), N, N-diprop yl (go%), N-isobutyl (S5Y0), N,N-di-isobutyl (93y0),h',N-din-butyl (86%), X-octyl (88%), N-allyl (79y0), N-morpholine (go%), N-benzyl (87%), N-cyclohexyl (83%), N-Pphenylethyl (85%). (b) Triethylamine a s Acid-binding Agent.-One-half mole of the corresponding primary or secondary amine and 50.5 g. (0.5 mole) of triethylamine were dissolved in 200 ml. of dry ether and treated with stirring with 24 g. (0.5 mole) ;f formyl fluoride while maintaining the temperature about 0 . After the addition of the formyl fluoride was completed the stirring was continued for a half-hour. The precipitated amine hydrofluoride was filtered off and the ethereal solution fractionated.
SARNIA, OSTARIO,CANADA
APPLIED CHEMISTRY DEPARTMENT OF THE INDIAN
INSTITUTE O F TECHNOLOGY]
Ease of Cyclization to the P-Lactam Ring1 BY
AJAY K.
B. N. GHOSH-MAZUMDAR AND B. G. CIIATTERJEE
BOSE,2
RECEIVED JUNE 24, 1959 The cyclization of w-haloacylaminomalonicesters in presence of bases has been studied. Four- and five-membered lactams are formed with ease when triethylamine a t room temperature is used, but six- and seven-membered lactams are not obtained under these conditions. Attempts to cyclize the N-chloroacetyl derivatives from benzylaniline, phenylglycine ester and a-anilinophenylacetic ester were unsuccessful. Several 3-substituted azetidin-2-ones were prepared by the cyclization of appropriate malonic ester derivatives. Substituents included chloro, bromo and phthalimidomethyl groups.
The method of Sheehan and Bose3s4for the synthesis of ,&lactams involving the cyclization of an 0-haloacetamidomalonic ester I in the presence of such a weak base as triethylamine a t room temperaRiN-CH( C02Ra)r
I
I
X
RIX-C( NEts -+
OC-CHRr I
I
C02Rs)z
1
OC-CHR2
I1
the cyclization of diethyl w-bromopropylmalonate (111) takes place in presence of such a strong base as sodium alkoxide. When trimethylamine is used as the base, only the quaternary salt from I11 is formed. The yield of the cyclization product IV, even in the presence of a strong base, is far from quantitative. CH2--CH( C0zEt)z
I
ture, is reminiscent of Perkin's6 synthesis of a cyclobutane derivative IV from trimethylene bromide and diethyl malonate. Walborsky6has shown that
CHz-CHtBr
(1) Presented a t the 135th Meeting of the American Chemical Society, Boston, Mass., April, 1959. Abstracted from the Ph.D. dissertation of B. N. Ghosh-hlazumdar submitted to the Indian Institute of Technology in 1957. (2) Chemistry Department, Stevens Institute of Technology, Hoboken, N. J. (3) J. C. Sbeehan and A. K. Bose, Tms JOWRNAL, 74, 5158 (19.50). (4) J. C. Sheehan and A. K. Bose, i b i d . , 73, 1261 (1951). (5) W. H. Perkin, B e y . , 16, 1793 (1883). ( 6 ) H N. Watborsky, TEIISJOIIRNAI., 71, 2041 (3949).
CHz-CH(
I
I11
NaOEt
- I
CHz-C( C0z)Et)z
I
CHz-CHZ
IV
C02Et)z
+
CH2-CH2-hTMe3
Br-
The cyclization of I involves the intramolecular alkylation of an amidomalonic ester instead of an alkylmalonic ester as in Perkin's synthesis. Extensive work has been done on the intermolecular alkylation of acetamidomalonic ester and similar
amidomalonic esters. Such alkylations have invariably been carried out in the presence of a strong base, such as sodium alkoxide. The intramolecular alkylation of I is remarkable in that i t can be carried out in the presence of a weak base and a t room temperature in a high yield. We have tried to alkylate diethyl N-phenylacetamidomalonate (V) with such an active alkylating agent as ethyl bromide in presence of triethylamine but without success. One difference between I and TI is that the halogen in the former is adjacent to a carbonyl group (although an amide carbonyl) and is therefore likely to be more reactive than the alkyl halide type halogen in 111. We have, however, found that when V is treated with ethyl bromoacetate and triethylamine, only the quaternary salt from the halo-ester is formed. PhN-CIS(
I
COCH,
2383
EASEOF CYCLIZATION TO THE B-LACTAM RING
May 5, 1960
C02Et)z
V
RihT-CH( C O P R P ) ~
i”
‘
OC-CH=CHz
VI1
tained. The crystalline material, which was a quaternary salt, was assigned the structure X because its infrared spectrum showed a peak a t 5.99 p characteristic of an amide carbonyl. Under the influence of triethylamine the compounds X I and XI1 also failed to cyclize to the corresponding 6and elactams. h>t - -> r
