[CONTRIBUTION FROM
THE
LEDERLE LABORATORIES DIVISION,AMERICAK CYANAMID Co.]
AN ANTIMALARIAL ALKALOID FROM HYDRANGEA. V. SOME 3-(@-KETO-sec-AMIh-OALKYL)-4-QUI~AZOLONES B. R. BAKER, MERLE V. QUERRY, ARTHUR F. KADISH, AND JAMES H. WILLIAMS Received September 8Y, 1951
The Hydrangea alkaloid (I) has been observed to form an N-carbamyl derivative (11) with potassium cyanate which cyclized to 111 when heated with acid (1). In order for this cyclization to take place the S H group would have to be
0
> -
0
/ C \ N C H ~I/C - - [ C ~ H ~ ~ O I ITH
I 0
KCNO
>
0
0 / C \ N C H ~I1 C - ~ C ~ H ~ ~ O W J C I1 X H ~
~-H'
--+
I1
0
>
NYCH
N
N
c=o
111 CY or p to the carbonyl. A number of model compounds were synthesized in order to determine which type would duplicate these reactions. Both IV and V are
0
0I!
0 (\.'\7CH2142
~ ' ~ H & C H Z N H -2HC1 ~
IV o'\yCHz \NUCH
H.2HCl
'0 C CH2
H.2HC1
VI
\@H
v 0
0
O c \ T IIC H z & - ( )
\N H.2HC1
\NYCH VI1
52
AN ANTIMBLSRIAL ALKALOID FROM HYDRANGEA. V
53
a-aminoketones, but in V the imine nitrogen is part of a ring. Both VI and VI1 are 8-aminoketones differing in the type of bicyclic ring structure which could form after treatment with potassium cyanate and ring closure. These reactions of the model compounds are described elsewhere (1); in summation only VI duplicated these reactions of the Hydrangea alkaloid. The synthesis of VI demonstrates the general may in which these compounds were prepared. 2-Piperidineacetic acid (VIII) (2) was N-benzoylated (IX) and converted to the acid chloride (X) with phosphorus pentachloride in acetyl chloride (3). The acid chloride was converted to the oily bromomethyl ketone,
A
/’\ -+
‘,\-!CH2COOH
-+
j,N/
LH2coOH COCeHs
a-I
IX
VI11
f\N/ L H 2 co COCsHs
XI
XI11
/I
\N,CH2COCi COCeHs X
-+
4-Quinazolone
---f
c]CH2 C 0 CH2 Br COCgH5
XI1
VI
X [I, by diazomethane and hydrogen bromide. Condensation with sodio 4quinasolone gave XIII, isolated as the hydrochloride. Acid hydrolysis resulted in the desired model compound, VI. The use of the 3,5-dinitrobenzoyl group was also investigated. It had the advantage that the halomethyl ketone mas crystalline, but condensation of the latter with 4-quinazolone under fourteen sets of conditions did not give any of the coupling product related to XIII. Model compound V was synthesized in exactly the same way as VI starting with proline. Again the 3,5-dinitrobenzoyl group was unsuccessful since the step corresponding to XI11 -+ VI failed to take place properly. Model compound VI1 was successfully synthesized from nipecotic acid by use of the 3,S-dinitrobenzoyl blocking group. Model compound IV was very simply made by condensation of 1-bromo-3-phthalimidoacetone(4) with sodio 4-quinazolone followed by acid hydrolysis of the phthalyl group. A t one time a structure of type XVII was considered a likely one to form 3acetonyl-4-quinazolone on pyrolysis (1). It was therefore synthesized from 1benzoyl-3-carbomethoxy-4-piperidinol(5) (XIV) by saponification to XV, pro-
54
BAKER, QUERRY, KADISR, AND WILLIAMS
H XVII tection of the hydroxyl group by acetylation (XVI), followed by build-up in the same way as described for VI. Acknowledgement. The authors are indebted to the late Y. SubbaRow for his many helpful suggestions and to Mr. LouisBrancone and his staff for the microanalysis. EXPERIMENTAL
1-Benzoyl-2-piperidineaceticacid (IX). T o a stirred solution of 12.4 g. of 2-piperidineacetic acid (VIII) (2) in205 cc. of 1N sodium hydroxide waa added 10.4 cc. of benzoyl chloride in one portion. The temperature was kept at 25-35" by occasional cooling. The clear solution obtained after 12 minutes was treated with 205 cc. of 1 N sodium hydroxide and 10.4 cc. of benzoyl chloride, then stirred for 35 minutes. Acidification, extraction with chloroform, and crystallization from benzene-heptane gave 15.9 g. (74%) of product, m.p. 138-143". Recrystallization of a sample from water afforded white crystals, m.p. 144-145'. If the second benzoyl chloride treatment was omitted the yield dropped to 42%. Additional acids made by this method are listed in Table I under method A . 3,5-Dinitrobenzoyl acids were prepared by the method of Saunders (6) and are recorded in Table I under method B. 1 -Benzoyl-~-hydroxypiperidine-3-carboxylic acid (XV). A mixture of 8.8 g. of 1-benzoyl3-carbomethoxy-4-piperidinol(XIV), [m.p. 136-138", prepared according to method described for the ethyl ester (5)], and 26 cc. of 10% sodium hydroxide was heated on the steam-bath until homogeneous (four minutes). The clear solution was acidified, saturated with salt, and extracted with ethyl acetate. The combined extracts were quickly dried with magnesium sulfate. On standing the solution deposited crystals of the product, m.p. 162164". Additional data is summarized in Table I. 1-Benzoyl-4-aceloxypiperidine-3-carboxylic acid (XVI). A solution of 4.2 g. of l-benzoyl4-hydroxypiperidine-3-carboxylic acid (XV) in 21 cc. of acetic anhydride was heated on the steam-bath for one hour, then cautiously treated with 21 cc. of water and heated ten minutes more. The clear solution was evaporated t o dryness in vacuo and the residue crystallized from benzene t o give 4.9 g. (99%) of product, m.p. 190-192". Additional data may be found in Table I. l-Benzoyl-2-(-y-bromoacelonyl)piperidine(XII). To a suspension of 5.0 g. of l-benzoylpiperidyl-2-acetic acid (IX) in 25 cc. of pure acetyl chloride was added 4.5 g. of phosphorus pentachloride. Solution rapidly took place on swirling. After 20 minutes volatile matter was removed in vacuo (bath 45-50') and the evaporation repeated with 50 cc. of toluene. The crude acid chloride, dissolved in 25 cc. of benzene, was added dropwise with swirling
55
AN ANTIMALARIAL ALKALOID FROM HYDRANGEA. V
TABLE I SUBSTITUTED ACIDS,RCOOH ANALYSIS
YIELD,
R
-
%
__ --1-1-
74 32 66 94 88 68 56 55 99 64
68.0 49.8 58.2
__
1-Bz-piperidine-2-CH21-DKB-piperidine-2-CH~Anilide l-Bz-Z-pyrrolidine-2l-DKB-l-pyrrolidine-2Anilide l-llNB-piperidine-31-13z-4-OH-piperidine-31-13z-4-AcO-piperidine-3Anilide -
A B C A B Cd B f f
Ch
144-145a 204-207* 189-191* 154-156c 153-155a 151-1538 215-217" 162-164a 193-195 122-1240
__
6.93 5.67 67.7'7.28 6.01 4.45 12.4 49.64.9012.2 4.85 '13.6 58.1 5.08 13.9 ~
-
Bz = benzoyl ; DNB = 3,5-dinitrobenzoyl 0 Recrystallized from HzO. *Recrystallized from MeOH-H20. CLit. ( i ) , m.p. 156". dNo crystalline anilide by method D . cRecrystallized from Methyl Cellosolve-H20. lSee experimental. URecrystallized from benzene-petroleum ether. M e t h o d D gave a poor product difficult to purify. TABLE I1
SUBSTITUTED HALOMETHYL KETOXESXCHzCR ANALYSIS
Calc'd
R
X
M.P., "C.
YIELD,'
Br
oil 107-1 1la 90-934 oil 130-132* 110-112c 110-112 d.d 125-12P oil
80 60 42 72 21 27 66 951 71
I
Found
%
-.
1-132 -piperidine-2-CH~l-I>?u'B-piperidine-2-CH~1-1)NB -piperidine -2-CH2l-Bz-pyrrolidine-2l-IlNB-pyrrolidine-21-1)NB-p yrrolidine -21-1lNB-piperidine-31-1lN B-piperidine -3l-Bz-4-.4cO-piperidine-3-
c1 Br Br c1 Br
KZ c1 Br
Bz = benzoyl; DNB = 3,5-dinitrobenzoyl Contains one-half molecule of benzene of crystallization when crystallized from benzene. bRecrystallized from EtOAc. cRecrystallized from MeOH. dRecrystallized from abs. EtOH. e.411 yields based on starting acid except /based on diazoketone. a
t o an ice-cooled solution of ethereal diazomethane [prepared from 10.5 g. of nitrosomethylurea (8) and dried with potassium hydroxide] over a period of three minutes. After ten minutes in the ice-bath and one hour without cooling, the solution was treated with 5 cc.
56
BAKER, QUERRY, KADISH, AND WILLIAMS
of acetic acid to destroy excess diazomethane, then 21 cc. of 30% hydrogen bromide in acetic acid was added with cooling. Five minutes later the mixture was washed with water, excess aqueous sodium bicarbonate, and water. Evaporation in vacuo gave 5.2 g. (80%) of product as an orange oil. Additional halomethyl ketones prepared in the same manner except that absolute alcoholic hydrogen chloride was employed for the chloro ketones, are listed in Table 11.All of the solids were yellow colored. Since some difficulty was encountered in the early Fork TABLE 111 0
0
@-SUBSTITUTED-@-KETOETHYL-4-QUI!iAZOLONES
ANALYSIS
I R
Phthalimidomethyl Aminomethyl 1-Bz-piperidyl-2-CHzl-Piperidy1-2-CHr1-Bz -pyrrolidyl-2l-DNB-pyrrolidyl-2Pyrrolidyl-2l-DNB-piperidyl-3Pi per idyl -3-
METHOD
Aa Bc A B A AQ B Aa i B
Y.P.,
Calc'd
-
"c.
254-256 198-202 d.d 195-196e 228-230 d.' 200-202 d.e 215-217 d. 170 d.d 231-233 d . 235-237 d.d 190-192 d.* 240-242 d.d
Found
H
28b 42 78 74 45 14 65* 57 97 31 76
65.7 45.5 64.9 51.1 63.5 55.9
3.75 4.49 5.68 6.17 5.09 3.80 50.9 5.19 56.8 4.12 52.3 5.57 61.8 5.22 50.0 5.32
= Denzoyi; U ~ F D = 6,o-ainiLroaenzoyi The haloketone was dissolved in Methyl Cellosolve and added t o a methanolic solution of sodio 4-quinazolone. bFrom crude bromoketone (IV). cRefluxed 20 hours with 10 parts HOAc and 20 parts 9 N HCI. Qihydrochloride. SMonohydrochloride. fDihydrochloride monohydrate. QReactionrun at -3" for 42 hours in Methyl Cellosolve. No product under the usual conditions of A . hBy hydrolysis of N-benzoyl derivative. No product isolatable from D N B derivative. "ifteen hours reaction time. DZ
a
in preparing these ketones, attributed t o poor acid chloride formation, a study of the latter was made by conversion t o the anilide. The above described phosphorus pentachlorideacetyl chloride method (3) is listed in Table I as method C. The thionyl chloride-etherpyridine method, D, is described in the following experiment. N -(3,5-Dinitrobenzoyl)-$-diazoacet ylpiperidine. A mixture of 5.4 g. of N-(3,5-dinitrobenzoyl)piperidyl-3-carboxylicacid, 16 cc. of reagent ether (containing 0.5% pyridine), and 32 cc. of thionyl chloride was shaken for 35 minutes when solution was essentially complete. The filtered solution was evaporated to dryness in vacuo (bath 50") and the evaporation repeated twice after adding benzene. The acid chloride was converted t o the diazoketone as in the preceding experiment. The diazoketone crystallized from the ethereal solution; yield, 3.8 g. (660/0), m.p. 102-105" dec. -4dditional data are listed in Table 11. $-@-Keto-y-(l-beneoyZ-2-piperidyl)propyl]-~-p2iinazolone (XIII) hydrochloride.To a solu-
AN ANTIMALARIAL ALKALOID FROM HYDRdNGEA. V
57
tion of 1.8 g. of 4-quinazolone in 13 cc. of 1 W methanolic sodium methoxide was added a (XII) in 46 cc. of methanol. solution of 4.6 g. of l-benzoyl-2-(-y-bromoacetonyl)piperidine After one hour the reaction mixture was diluted with 200 cc. of iced-water and 80 cc. of 10% sodium hydroxide. The mixture was extracted twice with chloroform. Evaporation of the combined extracts gave a gum which was crystallized as the hydrochloride by treatment with saturated absolute alcoholic hydrogen chloride; yield, 4.1 g. (78%), m.p. 195196". Compounds prepared in a similar manner are listed in Table I11 under method A. The hydrochlorides were purified by recrystallization from absolute alcohol-ether. The compounds isolated as the free base crystallized from the reaction mixture and were recrystallized from Methyl Cellosolve. S-[t¶-Keto-y(S-piperidy~)propy~]-4-quinazolone (VI) dihydrochloride. A mixture of 4.0 g. of XI11 hydrochloride and 40 cc. of 6 N hydrochloric acid was refluxed seven hours, cooled, filtered from benzoic acid, and the filtrate evaporated t o dryness in vacuo. Trituration with hot absolute alcoholic hydrogen chloride, then cooling, gave 2.5 g. (74%) of product, m.p. 228-230" dec. Similar hydrolyses are listed in Table 111 under method B. SUMMARY
The syntheses of four model compounds employed to determine the position of the imine with respect to the ketone in the side chain of the Hydrangea alkaloid have been described. PEARL RIVER,K.Y. REFERENCES (1) HUTCHINGS, GORDON, ABLONDI, WOLF,AND WILLIAMS,Paper I11 of this series (2) KOENIGSAND HAPPE,Ber., 36, 1343 (1902). Ber., 39, 2893 (1906). (3) FISCHER, (4) GABRIEL,Ber., 44, 1905 (1911). (5) &ELVAINAND STORK,J. A m . Chem. SOC.,68, 1049 (1946). ( 6 ) SAUNDERS, J . Chem. SOC.,1397 (1938). ( 7 ) ABDERHALDEN AND HEYNS,Ber., 67, 530 (1934). (8) ARNAT,Org. Syntheses, Coll. Vol. 11, 164 (1943), note 3.
