NITROGEN ANALOGSOF KETENESWITH CARBOXYLIC ACIDS
Aug. 5 , 1958
Let G = fraction I X formed through path C, then (0.97 c ) is the fraction of I X formed through path E .
0.508 = c
-
97 + 0- c (Table 11); c = 0.046 2
mo = 0.046 X 0.516 = 0.024 me = 0.476 and md = 0.474
Method 2.-The ratio of I X / X from rearrangement of V I = 0.961 (Table I ) . Therefore md X 0.961 = me = 0.455 and m, = 0.500 - 0.455 = 0.045. (b) For erythro-VII; Method 1.-The erythro-glycol has 6870 of its carbon-14 in the 1-position and 32yc in the 2position. From Table 11, x = fraction of rearrangement in X. Therefore 0.32% X 0.68 ( 1 -
= 0.574 x = 0.295 y = fraction of rearrangement in I X , then 0 . 3 2 ~ 0.68 (1 - y ) = 0.66 y = 0.056 0.454 ma "Ld = 0.546; mb m, m, = 0.295 X 0.546 = 0.161; mt, = 0.056 X 0.454 = 0.0251 md = 0.385 m, me = 0.429 m, = md X 1.004 = 0.387; thus m, = 0.012 Method 2 me = llld = 0.961 = 0.370; thU5 ?!I,, = 0.068 (c) For VIII; Method 1 mr -t m'd = 0.600 (Table I ) 0 400 m', = 0.400; m'd = L= 0.397 and mf = 0.203 1.004 Method 2 X )
+
+
+
+
m'd
=
0 .40' = 0.416 and mi 0.961
=
Anal. Calcd. for C23H2102: C, 83.1; H, 7.29. Found: C, 83.27, 83.48; H, 7.31, 7.29. In an analogous experiment 9.5 g. of 4,4'-dimethylbenz ~ i n , 2.6 ~ ? g. magnesium turnings and 16.9 g. of p-bromot~luene-methyl-C~~)-tri-p-tolylethylene glycol, m.p. 161.5"; radioactivity assay, 3.387 =k 0.017 mc./mole. For the preparation of chain-labeled 1,1,2-tri-p-tolylethylene glycol, chain-labeled 4,4'-dimethylbenzoin and nonradioactive p-bromotoluene were employed to yield a product whose m.p. was 161.5', and whose radioactivity assay was 1.871 =k 0.012 mc./mole. Oxidation of this glycol with chromic acid yielded p-toluic acid, 0.1089 =k 0.0002 mc./ mole, and di-p-tolyl ketone, whose 2,4-dinitrophenylhydrazone had a m.p. of 221 O and a radioactivity assay of 1.752 i. 0.003 mc./mole, corresponding to 94.15% carbon-14 in the 1-position and 5.85y0carbon-14 in the 2-position. T h e foregoing isotope position isomers of 1, I ,2-tri-ptolylethylene glycol were subjected to rearrangement in cold concentrated sulfuric acid as described for compounds V I , VI1 and V I I I . T h e products were dissolved in hexane an! passed through alumina to yield 60-S070 of a-p-toly1-4,4 dimethyldesoxybenzoin, a viscous oil which was characterized by alkaline cleavage t o p-toluic acid and di-p-tolylmethane. T h e latter fractions were oxidized with chromic acid in acetic acid t o the di-p-tolyl ketones which were converted t o 2,4-dinitrophenylhydrazones. The degradation products from oxidation of the tolyl-labeled ketone were: toluic acid, m.p. 176", 1.145 & 0.004 mc./mole; di-p-tolyl ketones 2,4-dinitrophenylhydrazone,m.p. 220", 2.188 + 0.016 mc./ mole. The degradation products from oxidation of the chain-labeled ketone were: toluic acid, m.p. 176", 0.1888 i.0.0005 mc./mole, and di-p-tolyl ketone 2,4-dinitrophenylhydrazone, m.p. 221". Calculation of k T o l / k ' B Ratio for the Rearrangement of Tri-p-tolylethylene Glycol.-These calculations are carried out in an analogous fashion t o those previously reported (ref. 3 , Chart I ) for the rearrangement of triphenylethylene glycol. Let x be the fraction of secondary hydroxyl removal (corresponding to path 1 in ref. 3 ) , then (1 - x) represents the fraction proceeding through tertiary hydroxyl re0.0585(1 - x) = 0.1018 and x = moval. Then 0.9415.2 0 ; 0 4 8 i . In order to calculate a minimum value for k T o i / k H we assume t h a t only the unlabeled tolyl group migrates t o the secondary carbonium ion. Thus let y correspond to path 2 (ref. 3) then (0.951 - y ) corresponds t o path 4 and
-
+
0.184
Preparation and Rearrangement of Tri-p-tolylethylene Glycol.-In a typical run, 10 g. of 4,4'-dimethyIbenzoinz7 in 150 cc. of ether was added to the Grignard reagent prepared from 21.4 g. of p-bromotoluene and 3.0 g. of magnesium turnings. -4fter addition was complete the mixture was heated under reflux for 4.5 hours, then poured over ice to which had been added saturated, aqueous ammonium chloride solution. The crude glycol was obtained through ether extraction and weighed 8 g. (6170 of theory). Upon crystallization from ethanol followed by crystallization from hexane there was obtained 5.9 g. of white needles, m.p. 161".
[CONTRIBUTIONFROM
4065
THE
y = 0.0645; (0.951 - y) = 0.88i and
OAKRIDGE, TENNESSEE
CHEMISTRY DEPARTMENT OF
WAYNE STATE ~ h 7 V E R S I T Y I
Nitrogen Analogs of Ketenes. 1V.l Reactions with Carboxylic Acids BY
CALVIN
L.
S T E V E N S AND M O R T O N
E.
MUNK2r3
RECEIVED MARCH7, 1958 The nitrogen analogs of ketenes react readily with carboxplic acids to form imides in good yield. The dicarboxylic acids, phthalic and succinic, form the acid anhydride when treated with a ketenimine. The structure of one of the unsymmetrical imides was proved by independent synthesis and infrared anal\&. Evidence was obtained that the reaction of ketenimines with carboxylic acids proceeded via an intermediate t h a t was a more active acylating agent than the imide. This intermediate is considered t o be the isuimide. The imides tvere shown t o be acylating agents for alcohols, aliphatic amines and aromatic amines. The attack of a nucleophilic agent upon a n unsymmetrical imide was shown t o be subject to steric control.
Staudinger published the first study of nitrogen analogs of ketenes in 19204and 1921.5 The keten-
imines were prepared by reaction of a ketene with a phosphinimine or an isocyanate with a phosphine-
(1) Part I11 is in THIS JOURNAL, 7 9 , 6057 (1957). (2) Abstracted from the dissertation submitted by M. E. .Munk in Partial fulfillment of the requirement for the degree of Doctor of Philosophy, Wayne State University, 1957.
(3) National Science Foundation Fellow, 1954-1955; Ethyl Corporation Fellow, 1955-1956. (4) H. Stsudinger and J. Meyer, Ber., 638,72 (1920). (5) H. Staudinger and E. Hauser, Hclw. Chim. A d a , 4, 887 (1921).
40G6
CALVIPJ L. STEVEISAND MORTOX E. NUNK
methylene. Backer6 reported the preparation of ketenimines by reaction of diazomethane with negatively substituted acetonitriles. Recently two new methods for the rapid and convenient preparation of a variety of ketenimines were reported from this Laboratory' and the present paper reports a study of the reaction of the ketenimines with carboxylic acids. Diphenylketene-N-p-tolylirnine(1) reacted readily with acetic acid, benzoic acid and diphenylacetic acid in benzene solution to give 76, 57 and SOY;, respectively, of the corresponding imide 111. In an early study of unsymmetrical imides, MummS showed that reactions designed to produce the isoimide or imino anhydride structure I1 gave only compounds of structure 111. I n the structural determination work of this investigation. one example of 111 (R = CH3)was synthesized by acylation of two different amides. Dipheiiylacetic acid p-toluide was acetylated aia the sodium salt to give I11 (R = CH,) and the sodium salt of acetic acid p-toluide was diphenylacetylated to give the same product. The fact that these two reactions produced the same material indicated that the structure of the product is I11 since if 0-acylation had occurred in either case a t least one other isomer should have been formed. AIuinm4 assigned the imide structure from the fact that a pair of imino chlorides reacted with the appropriate pair of carboxylic acid sodium salts to give the same product. Compound I11 was also prepared by the reaction of iLIumin8 from IV and is the fourth reaction for the formation of I11 (K = CHa).g Further evidence for the imide structure for I11 appeared in the infrared spectra. The adduct from acetic acid I11 (R = CH3) had a characteristic doublet in the carbonyl region a t 3.80 and 5.85 /.L) the benzoic acid adduct I11 (R = C6Hj) had a doublet a t 5.53 and 5.85 p , and the diphenylacetic acid had a doublet at 5 3 2 and 5.SB p . The bands correspond well with those reported by Witkop'O (530 and 5.84 p ) and Sheehan" (5.80 and 5.S5 p ) for diacyl amides. IVitkop'" also reported other examples which varied little and all of these examples had the doublet bands approximately the same distance apart: AO.0.7 p , A 1 5 cm.-'. The two carbonyl bands of anhydrides vary in position depending upon whether the carbonyl groups are conjugated or unconjugated, part of a strained five-membered ring or part of an open chain system, but the bands are always approximately the same distance apartI2: A60 cni.-', A0.20 p . As model compounds for the imino anhydride structure IIa, the known azlactone V and the f6) R. Dijkstra and H. J. Backer, Rec. fruu. chirn., 73, 575, 695 (1954). ( 7 ) C . I-. Stevens and J . C. French, THISJOURNAL, 7 6 , 657 (1953); 76, 4398 (1954). ( 8 ) 0. hfumm, H . Hesse and IT. Volquartz, Ber., 4 8 , 388 (191.5). (9) However these reactions do n u l rigorously prove the structure of I I I ( K = CHa) siuce in the unlikely event t h a t one uf the two 0acyl arnides was the most stable of the three isomers, the other 0acyl amide isomer and the imide coulil conceivably rearrange tu it by 0 t o S an(i/or I\: to 0 acyl migrations. no matter which is t h e initial product of reaction. (10) U.1Titkop and I. B. Patrick, T I i r s JOURNAL, 74, 3561 (1952). (11) J. C Sheehan and E. J . Corey, ibid., 74, 360 (1952). (12) L. J . Bellamy, "The Infra-red Spectra of Complex Molecules," T"hn W i l e ? a n d Soos, Jnc., Piew York, N. Y.,1954, p. 110.
Yol.
so
phthalic imino anhydride VI were prepared and the infrared spectrum compared with those of 111. Emh spectrum had two bands in the carbonyl region; V absorbed a t 5.48 and 5.92 p and VI absorbed at 5.56 and 5.83 p. The position of the bands is not meaningful since the imino anhydride structure is incorporated into a strained five-membered ring in both examples, but the fact that the distance betveen the bands is A136 cm.-', 10.44 p in one example and A87 ern.-', 10.25 p in the other supports the imide structure for 111. In the reaction of the ketenimine I with carboxylic acids to give 111, the existence of an intermediate was demonstrated in the following way. The ketenirnine I was dissolved in glacial acetic acid a t room temperature. Within 15 minutes 77% of amide VI1 was formed and the presence of acetic anhydride in the acetic acid was apparent from spectroscopic data. Imide I11 was formed in the amount of 1.3%. The crystalline acetic acid adduct I11 (R = CH3) was dissolved in glacial acetic acid I
+ CH3COOH +I1 + CHiCOOH * CH-COOCOCH, + (CeHs)zCHCOSHCsHdCHs ( V J I )
and after nine hours 96% of the starting material could be recovered by diiution of the reaction mixture with water. From these data compound I was considered to react with acetic acid to give TI, which in the presence of a high concentration of the polar acetic acid was able to acylate the acetic acid (7770) by a bimolecular reaction before an appreciable amount (13%) of intramolecular rearrangement product was formed. The formation of good yields of I11 with one equivalent of acetic acid in dilute nonpolar solution is consistent with this view. The intermediate is clearly a more active acylating agent than 111. The imino anhydride intermediate I1 could not be isolated from the reaction of the hindered mesitoic acid and the ketenimine I ; only the imide 111 (R = mesityl) was the product. Highly hindered carbonyl groups have been shown to undergo intramolecular reactions, the intermolecular analogs of which could not be realized.13 LVith phthalic and succinic acid the product of reaction with I was the anhydride in S i and 47% yield, respectively. On the basis of the previous experiments, the anhydride formation undoubtedly proceeded by initial reaction of one carboxylic acid group with the ketenimine to give the imino anhydride VIII, followed by intramoleczdar acylation to give the amide and the anhydride. However, an attempt to disprove the alternate mechanism involving rearrangement to IX prior to acylation failed; IX was prepared independently by hydrogenolysis of the benzyl ester. From the hydrogenation mixture only anhydride could be obtained, which showed that intramolecular acylation of an acid by an imide proceeded readily while the corresponding bimolecular acylation of acetic acid by I11 did not take place, even in pure acetic acid. Although the imides I11 were not able to acylate acetic acid a t room temperature, they were rela(13) R. C. Fuson and K C Hammann THISJ O U R N A L , 74, 1626 A Wohl observed In 1910 ( B P Y 48, , 3476 (1910)) t h a t Intra(lY52). molecular rearranrements are not significantly Influenced by s t e w effects.
Aug. 5, 1 9 3
NITROGEN ,$NALOGS OF
KETEXES WITH CARBOXYLIC ACIDS
tively active acylating agents. Base-catalyzed alcoholysis of I11 proceeded to give 61y0of the ptoluide VI1 of diphenylacetic acid. More important was the ability of the imides to acylate amines. Treatment of I11 (R = CH3) with one equivalent of N-butylamine in hexane gave 92% of the amide VI1 and GOY0 of N-butylacetamide, p-Toluidine was acetylated by the symmetrical adduct I11 (R = (C6Ha)2CH)to give 61% of N-ptolyldiphenylacetamide (1711). With the unsymmetrical imide I11 (R = CH3) the nucleophilic agents attacked the acetyl carbonyl in preference to the diphenylacetyl carbonyl. The reactions of unsymmetrical imides have been studied recently by Wieland14 who lists the order of reactivity as acetyl > propionyl > butyryl > benzoyl. I n 1914, Titherley16 found that Nbenzoyl-o-toluoamide (X) was hydrolyzed by hot or cold basic solution to give complete attack on the benzoyl carbonyl with the formation of benzoic acid and o-toluic amide. Hydrolysis of the p-isomer XI cold gave mostly benzoic acid, hot gave about half benzoic acid and half p-toluic acid. These data indicate electronic and steric effects can be used to direct the attack of nucleophilic agent to a particular carbonyl group. To test the steric influence ethylbutylketene N-butylimine was allowed t o react with diphenyl(14) T. Wieland and H. Mohr, A n n . , 699, 222 (1956). (15) A. W. Titherley and L. Stubbs, J . Chem. S O L . ,106, 299 (1914).
4067
acetic acid and the resulting imide XI1 used to acylate p-toluidine. The isolation of VI1 in 27% yield showed the ethyl and butyl groups to effectively hinder attack on the caproyl carbonyl.16 The rearrangement of I1 to I11 must involve an intramolecular 0 to N acyl migration ain a fourmembered ring transition state. Although the number of such rearrangements recorded in the literature is not large, one closely related example occurs in the reaction of a carbodiimine with a carboxylic acid to give an acylurea.” The reaction of an isocyanate with a carboxylic acid to give an amide and carbon dioxidela and the reaction of an isothiocyanate with a thiol acid to give an amide and carbon disulfidetg involve two other very similar 0 to N acyl migrations.
Experimental Addition of Carboxylic Acids to Diphenylketene-p-tolylimine.--h solution of 2.0 g. (7.05 millimoles) of diphenylketene-p-tolylimine (I) and 4.0 g. (66 millimoles) of glacial acetic acid in 100 rnl. of dry benzene was refluxed until t h e yellow color of t h e ketenimine was conipletrly discharged. (10) Cf.M. S. Newman, T H I SJOWRXAI.. 7 2 , 4783 (1950). (17) F. Zetzsche, e1 a / . , Der., 71, 1089 (1U38), and subsequent papers: J. C. Sheehan and G. P. Hess, TPIIS J O U R N A L , 77, 1007 (1955); H. G. Rhorana, Chemistry & I n d i c s f r y , 1087 (1955). (18) C. Naegeli and A. Tyabji, Hdu. Chim. A d a , 17, 931 (1934); 18, 142 (1935); S . Goldschmidt and M Wick, Ani?.,676, 217 (1952). (19) H. L. Wheeler and H. F. Merriam, THISJOWRNAL, 23, 283 (1901); J. yon Braun, &I., 63,3520 (1903); J. E. Hodgkins and Id.G. Ettlinger, J . Ore. Ckcm., 21, 404 (1956).
40(jS
CALVIN L. STEVENS A N D MORTON E. MUNK
'
lCO f tllc amide L7117was not depressed, m . p . 172-173". Reaction -Of I11 ( R = CR,) with n-Butylamine.- To :I solution of , .O g. (20.4 millimoles'l of the imide I11 (I< = CH3.1 in 60 nil. of tetrahydrofuran v a s adtletl 1.6 g. (22.0 millimoles') of n-butylamine. The srilution became n.arin on admixture and t h e reaction was heated at reflus for 12 hours. The tetrahydrofuran was evaporated and the resulting solid filtered and washed with petroleuni ether. Tlic solid amounted t o 5.6 g. (92Yc) of amide V I I , m.p. 167-169". The petroleum ether was evaporated from the filtrate, wliich consisted of two layers, and the residual S-butylacetartiitle'3 ~ purified b y distillation t o give 1.4 g. (60%,1: n 2 41.1395. cjf
(22) H. Walbaum, J . brokl. Chem., 121 68, 212 (1903). (23) R . H. Wiley. 0. H. Borum and L. I,. Bennett J O U R N A L , 71, 2899 (1949).
J r , THIS
ilug. 5, 195s
X PEPTIDE BONDBY NITROGEN ANALOGS OF KETENES
Reaction of N-p-Tolyldiphenylacetimide(111, R = (C6H6)tCH) with p-Toluidine.--A solution of 0.4 g. (0.8 millimoles) of the imide I11 (R = (CeH&CH) and 0.8 millimole of p-toluidine in 15 ml. of toluene was refluxed for 80 hours and then evaporated t o dryness in vacuo. T h e resulting white solid, m.p. 169-172', was recrystallized from 957, ethanol to yield 0.3 g. (610/,) of N-(p-tolyl)-diphenylacetamide (VII), m.p. 179-180'. Reaction of Adduct XI1 with p-Toluidine.-A solution of 3.6 g. (20 millimoles) of ethyl-n-butylketene n-butylimine' and 8.5 g. (40 millimoles) of diphenylacetic acid in 60 ml. of dioxane was refluxed for 12 hours and then evaporated t o dryness in vacuo. The residue was dissolved in 100 ml. of ethyl acetate and washed three times with a saturated sodium bicarbonate solution, two times with water and finally two times with saturated sodium chloride solution. The ethyl acetate solution was dried over anhydrous magnesium sulfate, filtered and evaporated t o dryness in vacuo to yield 6.57 g. (847,) of the oily diphenylacetic acid adduct of the ketenimine X I I . The adduct was dissolved in 50 ml. of dioxane and refluxed for 50 hours with 10.0 g. (0.1 mole) of p-toluidine. The clear solution was evaporated t o dryness in wacuo to yield an oily residue which was dissolved in 150 ml. of ethyl acetate and washed three times with 3 N hydrochloric
[CONTRIBUTION FROM THE CHEMISTRY
4069
acid, two times with water and finally two times with a saturated solution of sodium chloride. T h e ethyl acetate solution was dried over anhydrous magnesium sulfate, filtered and evaporated t o dryness in vacuo. Petroleum ether (3060") was added to theooily residue and the contents were cooled overnight a t 4 . The resulting crystalline solid was collected by filtration and washed with cool petroleum ether t o yield 1.35 g. (2770 based on theoadduct) of N-(ptolyl)-diphenylacetamide, m.p. 167-169 . Recrystallization from hexane-acetone raised the melting point to 172173' and a mixture melting point with authentic amide was not depressed.
Acknowledgment.-The authors wish to thank Dr. J. M . Vandenbelt, R. B. Scott and their associates a t Parke, Davis and Co. for the infrared specral determinations. They are particularly indebted to Professor c h . Prevost, in whose laboratories a t the Sorbonne much of this work was done, for his kindness and hospitality. The aid of the John Simon Guggenheim Memorial Foundation also is gratefully acknowledged. DETROIT 2, MICHIGAN
DEPARTMENT O F LVAYNE
STATE USIVERSITY]
Nitrogen Analogs of Ketenes. V.l Formation of the Peptide Bond BY CALVIN L.
STEVENS AND
MORTONE.
MUNK2*3
RECEIVED MARCH 7, 1958 Xitrogen analogs of ketenes have been used as reagents for the formation of the peptide bond. The N-protected amino acids glycine, alanine and methionine were converted in high yield t o stable, crystalline adducts with the ketenimine I. T h e adducts were formed in non-polar, aqueous or alcoholic solutions. Reaction of an amino acid ester with an adduct afforded the peptides; alternately, the three starting materials could be placed in the reaction mixture a t the same time. py.lminobenzoic acid ethyl ester was acylated in good yield. Dipeptide derivatives of L-cysteinyl-L-tyrosine and L-asparaginyl-L-cysteine were prepared in about 30 and 4570 yield, respectively, indicating t h a t the phenol of tyrosine need not be protected and that dipeptides of good optical purity could be obtained by this method.
In the previous paper' in this series, the nitrogen analogs of ketenes were found to react with carboxylic acids with the formation of imides and these imides were found to be active acylating agents. In view of the striking success of carbodiimines* as reagents for the formation of peptides, the purpose of this investigation was to determine the use of the ketenimines for the same purpose. The reaction of phthaloylglycine (11) with the ketenimine I gave the adduct I11 in 92% yield. The adduct was purified by recrystallization and was stable. Similar adducts from N-carbobenzoxyglycine, phthaloyl-@-alanine, and phthaloylDL-methionine were prepared in 89, 76 and 60% yields, respectively. An inert solvent was satisfactory for the adduct formation, although ethanolwater and dioxane-water reaction mixtures could be used. Acylation of glycine ethyl ester with the adduct I1 produced the dipeptide derivative, phthaloylglycylglycine ethyl ester, in 70% yield. I n the presence of an appropriate base, amino acid or (1) P a r t I V describes t h e reaction of ketenimines with carboxylic acids and is in THISJ O U R N A L , 80, 4065 (1958). (2) Supported by a Parke-Davis Research Fellowship. (3) Abstracted from t h e dissertation submitted by 31. E M u n k in partial fulfillment of the requirement for t h e degree of Doctor of Philosophy, Wayne State Unlversity, 1957. (4) J. C Sheehan and G. P. Hess. THISJOURNAL, 7 7 , 1067 (1955), and later papers; L Velluz, G. Amiard, J. Rartos, B. Goffinet and R Heymes, Biril. SOC. chim. France, 1164 (1956).
peptide ester hydrochlorides could be used as the starting materials. The tripeptide derivative, phthaloylglycylglycylglycine ethyl ester, was prepared in 50'% yield from the adduct I11 and glycylglycine ethyl ester hydrochloride in the presence of triethylamine. Ethyl p-aminobenzoate was used to test the ability of the adduct I11 to acylate an aromatic amine. After reaction in benzene solution the product, ethyl phthaloylglycyl-9-aminobenzoate, was isolated in 73% yield. A similar reaction was performed in methylene chloride in which the three starting materials ketenimine I, phthaloylglycine and ethyl p-aminobenzoate were placed in the reaction mixture a t the same time. The yield of product was 77%. I n view of the mechanism of the reaction of ketenimines with carboxylic acids as described in the previous paper, the acylation of the amino acid ester in this latter reaction probably proceeded in part via the isoimide adduct. I n each of the reactions described so far, the byproduct amide V was separated easily from the peptide derivative by taking advantage of solubility differences in various solvents. In other examples the separation problem was not as easily solved. In these examples the peptide ester was selectively saponified and removed as a carboxylic acid. In the preparation of phthaloylglycyl-Lleucine, the reaction mixture was subjected to acid
