carboxamide (21).--Propionyl isocyanate ( 2 . 2 g, 0.024 mole) in 5 ml of T H F was added dropwise to a suspension of 4.3 g (0.02 mole) of 1-(5-nitro-2-thiazoIyl)piperazinegin 50 ml of T H F , and the mixture was stirred at room temperature for 45 m i x The solid was collected and recrystallized from I-tOH t o give the product . 1-( Chloroacety1)-4-(5-nitro-2-thiazoly1)piperazine ( 13): Chloroacetyl chloride (1.13 g, 0.01 mole) in 5 ml of T H F was added dropwise to a mixture of I-( S-nitro-2-thiazolyl)piperazineO (2.14 g , 0.01 mole) and Et3X (1.38 ml, 0.01 mole) in 45 ml of THF' :it 0". The misture was stirred for 3 hr at room temperature, wid the solid was rollected, washed with HrO, and recryrtallixed from 1,;tOH. { 0-[(5-Nitro-2-thiazolyl jamino]phenyl} acetic Acid (17):--To n solution of 6.3 g (0.03 mole) of 2-bromo-5-nitrothiazole in 250 nil of RIeOH was added 3.0 g (0.03 mole) of E t 3 S and 80 m l ( 1 equiv) of it I&O rolution of sodium o-aminophenylacetate. The reaction w a s esothermic. The niist,ure \vas allowed to stir for 4 hr. poured into about 3 1. of iced HZO, and acidified with concentrated HCI. The pale green solid which formed was removed by filt,rat,ion :tnd dried. This material (3.6 g ) had a broad melting point and c,ould not 1)e purified. The filtrate upon standing deposited :I yellow solid. This material was dried (1.7 g i anti recrystallized from f-I'rOH to give 1.0 g (12(;) of the product, inp 166--16S0dec. Sodium o-Aminopheny1acetate.- --To 1 1. of H 2 0 vigorously stirred was added 3 S g (0.306 mole) of S:t&Oa.H.O. o-Sitrophenyltrc*et,ic acid (100 g, 0.56 mole),. was added portionmise ( 4 drops of 2-octanol was :tdded t foam). The solution 24' for 16 hr. The war hydrogenated over 1 g of 20 mixl ure w:is filtered through Su )-ello&-solution \vas diluted t o 1475 ml, and aliquots were used as needed. 1-(5-Nitro-2-thiazolyl)-4-(piperidinoacety~~piperazine (28).-Piperidine (1.63 g, 0.0192 mole) was added dropwise to 2.9 g (0.0 I mole 1 of I-((.hloro:Lc:et?-1)-4-(5-riitro-%-thiazo1yl)piperaoine in 4.5 nil o f T H F :it O', arid the misturp W I L $tirreti for 1 hr a i room temperature. The niisture was filtered, and the filtrate was ev:ipimted to dryneps. The residue was recrystallized from I.:tOH. Benzyl ( { [4-(5-Nitro-2-thiazolyl)-l-piperazinyl]carbonyl~ methy1)carbamate (31): -A solution o f 2.1 g (0.01 mole) of dic?-cl(ihesylrarbodiiniide in 5 ml of T H F was added to a solution o f 2.14 g (0.01 mole) of l-(5-nitro-2-thiazolyl)piperazineBand 2.1 g (0.01 mole) of benzylo arhonylglycine i n 30 nil of T H F , and the mixture was stirred for 1 hr at room temperature. The solid was cdlecteti, washed -ivith EtsO, ant1 recrystallized from
-
ICtOH.
1,l'-( Sulfony1diethylene)bis [4-(5-nitro-2- thiazoly1)piperazine I (32).- - A solution of 1.22 g (0.0103 mole) of divinyl sulfone in 12 ml of EtOH was added dropwise to a suspension of 4.4 p (0.0206 mole) of t-(5-nitro-2-thiazolyl)piperazinein 25 ml nf EtOH, a n d the misture was stirred for 4 hr at room temperature. The mixture was allowed t o remain at room temperature overnight and then heated under reflux for 1 hr. The product was removed by filtration and recrystallized from DlIF.
Acknowledgments.---The authors express their appreciation to Dr. Paul E. Thompson and coworkers of thrsc laboratories for the antiparasitic evaluation of these compounds. Wc also thank Dr. ,J. M. Tandenbelt anti coworkers for t'he spectral studies, arid Mr. Charles E. Childs arid associates for t'he microanalyses. Antimalarials. Some Q u i n u c l i d i n e Derivatives of 7-Chloro-4-aminoquinoline a n d 6-3Zethoxy-8-aminoquinoline '1'41tL SIiVGH, l b 1 i I It1 ( j . S I E l N , I T I R L I N H. KOLLLING, JOHXF. HOOP^, ~ K JOHN D H. B i n
Krseuiih /,ahoratories qf .i/drzch Chemical Con,pany, Znc., Jfzlwaukee, Tl'nsconszn 53,910
Experimental Section
.I11 melting points were determined in open c a p i h r y tulles in Thomas-Hoover Unimelt :tnd are uncorrected. Reference. should be made t o Tahle I for relevant information. 7-Chloro-4-( 3-ketoquinuclidinyl-2-methyleneamino)quinoline (1).----.1 mixture of 7-c.tiloro-4-aminoquinoline3 (2.0 g, 0.01 1 inol:l and 2-methylene-3-quinuclidinc,ne' (3.0 g, 0.022 mol) was heated at 80" with stirring for I hr. The reaction was cooled anti diluted with 200 nil of l I e O H when it white solid (1.0 g ) prerip-
:t
ititted. 7-Chloro-4-( 3-hydroxyquinuclidinyl-2-methyleneamino)quinoline (2): -The quinuclidinone derivative 1 (2.0 g, 0.006 mol) w i s dissolved in 60 nil of l I e O H iit 0 " and 11) this was added S:tHII.i (5.0 g ) in small portions. Tlie inisturc~was allowed to st:intl : I I room temperature for :L few hour inti then worked up :is usu:il to give 1.3 g of the product. 7-Chloro-4-( 3-quinuclidinylamino)quinoline ( 3j.- --A mist ure of 4,7-dichloroquinoline (25.0 g, 0.1 25 mol 3-amino (tihydrochloride (25.0 g, 0.125 mol), S:rOJIe (12.0 g j and 100 ml of phenol \vas 1ie:tted :it 140" for 3 hr. Ihloro--l-(I-niethg-l-4-niet hylnminohutylaniii~oj~~uinoline" ( 1 2.5 g , 0.045 mol) and ?-met hylerie-:)-quiii~Ic.lidinonein 300 nd o f l l e O H was stirred at room temperature for 14 hr. The re:tction was rooled in an ice bath, 1re:tleti with SaBHa (15.0 g ) in sInall portions over a period of 1 hr, :ind :illowed t o stand at room temperature for 2 hr. 1IeOH w:is r:v:iporateil off i j i ~ ~ ( L C I I Oand , the residuc w a s treated with 300 mi of HzO :inti r>str:ir(edwith CsH,. Thc CsH6 estract was dried (IGCO,) :tnd evaporated t o give :I gl which was passed through a 1):tsicalumina column (30 g of alumina to 1.0 g of material) in CsHs solutiori. After eluting with 31 1. of C6H6t o wash off impurities, thc product (12.5 g ) was e h t e d \villi like m:iterial :ind nielt vi1 lIeO€I-C6Hs ( 1 : 19). It \v:i. Ijver a wide range. 7-Chloro-4- [ l-methyl-l-N-ethyl-( 3-hydroxyquinuclidinyl-2methylene)aminobutylamino]quinoline(5) was prepared froin the corresponding S-ethyl c ~ ) m p o u n d:rnd ~ purified in the sanit' 7-Chloro-4-[N'-(3-quinuclidinyl)hydrazino]quinoline (6): -1 solution of T-chloro-.L-li~drazinoquinoline6 (3.86 g, 0.02 mol), :;-quinuclidinone ( 2 . 5 g, 0.02 mol), and 0.1 g of p-toluenesulfoiiic* acid hydrate in 100 ml of 1IeOH \vas refluxed for 12 hr. The ~
IZeceived October 11, 1868
Quiiiuclittiiie is ai1 iinportaiit moiety of cinchoiia alkaloitls. T h v recent availability of' ciuiiiuclicliiioiit, (Altlricli) i ~ i i dtho f'acilc preparation of 2-metli?-lmic-:2-
~
) A.
K. Hansen and H ,
ler. J . Ifelerocycl. Chem., 3 , 109 i l U t i 0 ) .
11. und L. R m e , J. .Wed. Chem., 10, 431 (19tiii. ) T. S. Osdene, 1'. 13. I1 iiskr. 0. Biistein, F. J. Kreyaa, J. T . Maj.nni.d, ) R.C. Elderfield. TV. J. ,11ii1 J. Galbriiith, J . . l i / i e r . ( . ' h m i . Snc.. 68. 3250 (1946). 84) 11, (':wmack, 0 . Fr. H u l i t t . Jr.. C;, K . H w d r i c l i , I,, I V . iii>>inger, : m i 1. \.c)n. tbid., 6 8 , 1220 f l94ti) .ii \, 13, SurrtL: iind I : . ,\, C ' U I I C , t M . , 6 8 , 2,;iil (1!146).
YOTES
525
TABLEI R
Crystn solvent
Formula
.Inalyses
Ci6HroClJ3.0.5H20
C, H, N, Cl(total),
R
I
c1
O D
NHCH,
NHCH, “ O
I
225-227
38.0
240.5-242
12.0
330-335 dec
m
“HQ
CHJ
29.0
EtOH
C1-, HzO
wD
60.0
65-110
Cz3Ha3CIN40
C, H, N
85.0
66-75
CzaH3bClN40
H, N ; Cb
55.0
263.5-265 dec
CiiHziCla1\14
H, N ; Cc
NHCH(CH ) YCH, 31~
CH3
NHNH 2HC1
hIeOH-Eta0
7
120-122
CisHziN30z
C, H, N
8
196-197
Ci8HzaN3Oz
C, H, ?;
9
196-198
CHzC1-petr ether
CISHBN~OL
H, N ;
98-102
EtsO-petr ether
CISH~S~SO
C, H; N6
Cd
NHCH, HoNQ
HzNsD
10
NHCHP
11 N HIC H ( C H J 3 N v CH,
12
17.7
150 (0.001)
C17HziX-30
C, H ,
77.0
210-222 (0,005)
CiiHaoN40
C, H , S
80.0
210-220 (0.002)
CzzH3zNaO
C, H, N
?;
NHCH(CHJ3HX
13
“C 65.78.
*
c: calcd, 66.88; found, 66.43. calcd, 64.66; found, 64.21. N : calcd, 21.52; found, 21.01.
C: calcd, 51.15; found, 51.65.
C: calcd, 66.23; found,
e
solvent was evaporated off zn vacuo and the hydrazone was dissolved in 100 ml of THF and added slowly to a mixture of LA4H (5.7 g, 0.15 mol) in 250 ml of THF. After refluxing for 12 hr, the reaction miyture was cooled in an ice bath and carefully decomposed with 5.4 ml of H2O followed by 5.4 ml of a 15.007, S a O H solution and 16.2 ml of Hz0. After stirring for 3 hr, the inorganic salts were removed by filtration and washed with THF and the filtrate was concentrated to a green oil. I t was converted to the dihydrochlonde and crystallized to give 2.3 g of the salt. 6-Methoxy-d-(3-ketoquinuclidinyl-2-met1iyleneamino)quinoline (7).--A solution of 6-methoxy-8-aminoquinoline (34.8 g, 0.20 mol) and 2-methylene-3-quinuclidinone in 50 ml of RleOH was stirred and refluxed for 0.5 hr. On cooling the mixture t o
room temperature, 46.5 g of the product crystallized; it was filtered off and washed with LIeOH. 6-Methoxy-8-( 3-hydroxyquinuclidinyl-2-methy1eneamino)quinoline (8).-The ketone derivative 7 (10.0 g, 0.033 mol) was dissolved in EtOAc and hydrogenated a t room temperature and atmospheric pressure using a PtOy catalyst. After the absorption of a little over 1 equiv of Hzj the catalyst was removed by filtration, and the filtrate was concentrated and allowed t o crystallize to give 5.5 g of 8. 6-Methoxy-8-( 3-quinuc1idineamino)quinoline( 11).-.k mixture of 6-methoxy-8-aminoquinoline ( 1 7 . 4 g, 0.01 mol), 3-quinuclidinone (12.50 g, 0.01 mol), p-toluenesulfonic acid (0.40 g), and 400 ml of C6H5 was refluxed for 18 hr using a Dean-Stark HzO
sep:trat or. The reaction mixture was cooled to room temperature, stirred with anhydrous K&O3 (15.0 g ) for 0.5 hr, arid filtered a n d the filtrate was evaporated to dryness. The crude Schiff base was reduced with SaBH4 and distilled t o give 5.0 g of 11.
6-Methoxy-8- [l-methyl-4-(3-quinuclidineimino)butylamino]quinoline (12):-.4 mist'ure of primaquine6 (7.77 g, 0.03 mol!, 3-quinuclidinone (3.75 g, 0.03 mol), p-toluenesulfonic acid 10.1 g), and 200 ml of P h l I e was refluxed for 12 hr when 0.6 mi11 of' HrO collected in the Dean-Stark separtttor. The rlenr w l u t i i n i wis concentrated t o a viscous oil arid distilled i o give 7.4 g i d ;I yellow glasslike inaterial. 6-Methoxy-8- [1-methyl-4-(3-quinuclidineamino)butylamino]quinoline (13).----The Schiff base 12 (7.X g, 0.021 mol) was dissolved in i-PrOH, rcioled in an ice-H.0 h t h , and treated with X.0 g of SaBH4. The mixture n-orketl up as usual t o give
\
and aliphatic ketoiics with 11. The yield, rneltiiig poiiit. :uid forinula for euc+ of thc i i m ~coiiipouiids of t h c s types III--\- :ire listctl in TaLlcs 1-111.
Acknowledgment.-- this work was supported by the
I-.S . -Army Il1e:lical Research
aiid Development Conirnancl through Research Contract 50.DA1-49-193-;\1D2869 ant1 is (:oiitrilnition S o . 488 from the Arniy 1iesc:~rchPrograiii o i l Alnlariu. ( 6 ) It. (*. Elderfield, H. b'. I l e r t e l , I t . C'. M i t c h , I. 11. \Tempen, m d I. \Vrsrtiel, ibid., 77, 4816 (I!l>Zj.
Some Xew Thiosemicarbazides, Thioureas, and Thiosemicarbazones from
4-Isothiocyanatobenzenesulfonpiperidide '
Several types of compounds containing the thiocttrboiij 1 group have been slio~vii to possess fungistatic properties. For example, thioseinicarbazoiies2 and c~ithiose~nicarbazoiies~ have lieen sho~v-11to lie effectivr against the cellulolytic microorganism Clzaetomiuiti globosuni. In addition, it has heen found4that 4-isothiocyaiiatobenzeiiesulfoiipi~eri(1itle (I) has considerable value as a fungicide. SC +S ,O
-
S J-(
1
111 thc present work, thrcc series of iiew compouncls I i c w i synthesized from I, their structures have 1)ec.i~tleduced from elemental analysis and ir absorptioii rritasurc~ments,and the antifungal effectiveuess of them h:is I m i i ( valuated against tivo microorganisms, ('huetoiniu~tiylobosuni and Asperyzllus niger. I reacts rcatlily with hydrazirie hydratr, substituted hyclraziiies, mi(1 amines to forin thr ciesircd substituted thiosemic:trt):izitlcs (11, 111) and suhstitutetl thioureas (IT.'), Iiavc
I
_--
+
___
YXH.
-
Y h H ( Y S H ~ S O N 3 11 Y=H.K 111 Y = R,R-N I\'. Y = R
-
( I ) Issued as NRCC KO. 10TL6. ( 2 ) R. G. Benny, B 1 Gingras, and C'. H H a s l e l , A p p l . M\lzcrobiol., 8 , 353 (1960). ( 3 j D. 11. Ttllr., I3
(Jiily 6, 1960).
.\. ( J ~ ~ ~ arid g ~ ~'r.b buprurichub, , Can J. Cheni , 45.
rldeh? r t r lb
-\i-etone
l i
?-~utdnUlll
r 1 ) I
lbc)
(iiH~
dined frtiiii lIe?CO-H30. Ilecli>italliLed from dlo\an finm I,tO€l-€LO.
It 15 ireccssar? to obtain some direct evitlciice, 111 :uLclition to thr anst12 tical c1ata.j in support of t h r btrurtures proposed for the new compounds reported 11cw In each case. the observatioii of particular ir absorptioii bands, cliaracteristic of particular structural eiitities, verifies the structures shown in the tables. The substituted thioseinicarbazides, the thioseinicarbazones. and the substituted thioureas were screelied as potential fungicides by the tube dilution niethoc1.l The results of the effectiveness against C'haetomui// ylobosurn inn! 1~ summarized as follows : (a) ~0111I I) I3 here annl\sc, are iiidic.ited o d r br s ) rnhols of the elemrrlrs. m a l r t i i 11 rebultz ohtamed for those elenlcnts u e r e u i t h i n * O 4% of the theoretlLa1 rrliit
