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AUGUST 1961 NOTES 3019
the quinic acid are recorded in Table I. One of the productsgave
the m e , values on paper chromatograms as quinide.The zone with R
, 0.15 on the n-butyl alcoholacetic acid-water developed
chromatograms of the fused quinic acid wascut out, sewn onto
another chromatography paper, anddeveloped in th e benzyl
alcohol-terf-butyl alcohol-isopropylalcohol-water system. Zones
appeared at R f values 0.07,0.24, and 0.53. The middle one, labeled
"FQ-111-B,"proved to be identical with a zone obtained on paper
chroma-tograms of cigarette smoke as described previously.
On heating quinic acid with 6N hydrochloric acid for 1hr. at
loo", Cartwright and Roberts' found that, in addi-tion to quinic
acid itself, three trace spots also make theirappearance on paper
chromatograms. One of these was indi-cated to be quinide.
Preparation of p i n & . Quinide was prepared from
quinicacid by the procedure of Panizzi and co-workers.6
Acknowledgment. This research was supported inpart by the
National Institutes of Health.
CHEMISTRY EPARTMENTUNIVERSITY F OKLAHOMA
NORMAN, KLA.(6) L. Panizzi, M. L. Scarpati, and R. Scarpati,
Gazz.
chim. ital., 84,806 1954); C l r a . Abstr. 50,882 (1956).
Synthesis of Potential Anticancer Agents.
111. Compounds Related to p-pis(2-chloro-
ethyl)aminolbenzylidenemalononitrile',2
FUNK D. POPP
ReceivedDecember .??1,1960
We have recently reported3 the preparation ofp - [bis(2 -
chloroethyl)amino]benzylidenemalono-nitrile (I) and several related
compounds from theKnoevanagel reaction of p
N,N-bis(%chloroethyl)-amino ]benzaldehyde (benzaldehyde nitrogen
mus-tard) (11. R = H). I has been reported4 to exhibitactivity
against the Dunning leukemia in rats over-a wide dosage range and
is currently undergoingfurther extensive pharmacological testing.
Witht,his great interest developing in compound I, ittvas decided
to prepare additional related com-
N(CHzCHzCI)2 SJ(CH&H&1)2 Y(CHZCHZCUZ
/RCH=C (CN) CHO CH=C,=,
I I1 I11 Ab
(1 ) Part II., F. D. Popp, J. Ozg. Chem., 26, 1566(1961).( 2 )
This investigation was supported in part by Re-
search Grant CY 4814 from the National Cancer Institute,U . S.
Public Hea lth Service, and in part by a Resesrch GrantT 177 from
the American Cancer Society. Presented in par tbefore the Division
of Medicinal Chemistry at the 139thMeeting of the American Chemical
Society, St. Louis, Mo.,March 21-30, 1961.
(3 ) F. D. Popp, J . Chem. SOC.,5271(1960).(4 ) Drs. Ralph
Jones, Jr., and Leo Rane, private com-
munication. Complete screening data on the compoundsmentioned
will be published elsewhere a t a later date.
pounds. Of the compounds (111) prepared earlier,3those from
ethyl malonate and cyanoacetamide alsoexhibited some activity4 so
it was decided to in-clude analogues of these in this study. I n
our workwith S c h 8 bases1 it waa found4 th at compoundsprepared
from 4[bis(2-~hloroethyl)amino -o-tolu-aldehyde (11. R = CHa) were
somewhat more activethan those from benzaldehyde nitrogen
mustardand the same amine. This approach was thereforealso tried in
this series.
Malononitrile, cyanoacetamide, a-cyanoacetani-lide, malonic
acid, ethyl malonate, and benxoyl-acetonitrile were condensed with
the appropriatealdehydes in dioxane using piperidine as a
catalystto give the compounds shown in Table I. Reactionof
cyanoacethydrazide (IV) with benzaldehydenitrogen mustard under a
variety of conditionsgave only compound V. V was very insoluble
in
most solvents and apparently this insolubilityprevented further
reaction.
I
T=C(CN),
CNV I
NCHf
\
V
The tricyanoethylene (VI) was prepared bycondensation of
N1N-bis(2-chloroethyl)aniline withtetra~yanoethylene.~ n attempt to
convert V I to4(Zcyano-3-maleimidyl) - N , N -bis (2
chloroethyl)aniline by controlled hydrolysis with
concentratedhydrochloric acid' failed to give an
identifiableproduct. An attempt to prepare the N-phenyl-maleimide
from N1N-bis(2-chloroethy1)aniline,so-dium cyanide and
N-phenyldichloromaleimide6 aveonly recovered s tarting
materials.
Although the screening will be reported later in
more detail,' it can be mentioned than the tricyanocompound VI
was much less active than the dicyanocompound I and the compounds
from a-cyano-acetanilide were leas active than those from
cyano-acetamide. The one arm mustards, prepared fromp - [N - ethyl
- N - (2 - chloroethyl)amino]benzal-dehyde, were inactive.
( 5 ) B. C. McKGck, R. E. Heckert, T. L. Cairns, D. D.Coffman,
and H. F. Mower, J . A m . Chem. Soc., 80 , 2806(1958). We would
like to hank Dr. McKusick fo r a generoussample of
tetracyanoethylene.
(6) E. L. Martin, C. L. Dickinson, and J. R. Roland,Absirads,
138th Meeting of the American Chemical Society,New York, Sept.,
1960, page 94P. We would like t o thankDr. Martin for experimental
details and samples.
(7 ) R. . E ldde l d , I. S. Covey, J. R. Geiduschek, W.
L.Meyer, A. B. Ross, and J. H. Fkm, J . Org. Chem., 2 3 ,
1749(1958).
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TABLE IANALOGUES B p BIs( - C H L O R O E T H Y L ) A M I N O ]
BENZYLZDENEMALONONITRILE
R
CHzCHiCl
CHzCHzClCHzCHzC1CIHSCHzCHzCl
CHzCHzC1CHzCHzC1CHzCH?CICHzCHzCl
CzHs
R"
HHHHHH
CNHHH
Rtt /
CNCNCNCNCNCN
CNCOaCzHsCNH
R / / / I
CONHaCONHICONHCiEISCONHC&CONHCB,CN
CNCOIC*&COCeH6COeH
Yield, Calcd. FoundbM.P.' '% Carbon Hydrogen Carbon Hydrogen
20.1-204.5c178-178. 5'215-216'182-182.5'
165-16Gd180-18lC
128-131d92-93d88-8gd
1Y3-194c~e
59 55.22 5.25 55.00 5.2949 60.54 5.81 60.85' 5.8297 61.86 4.93
61.77 4.7151 62.69 5.26 62.46 5.4566 67.88 5.70 68.02 5.9265 58.45
4.91 58.63 4.98
90 56.44 3.79 56.38 3.7893 56.72 6 .26 56.45 6.1677 64.35 4.86
64.46 4.9272 54.18 5.25 54.37 5.40
All melting points are uncorrected. Analyses by Spang
Microanalytical Labora tory, Ann Arbor, Mich., and Drs. Weilerand
Strauss, Oxford, England. Recrystallized from anhydrous chloroform.
Recrystallized from absolute ethanol. Frommalonic acid.
EXPERIMENTAL
Reagents. Benzaldehyde nitrogen mustard,'
4-[bis(2-chloroethyl)amino]-~-tolualdehyde,~ nd
p[N-ethyl-N-(2-chloroethyl) amino] benzaldehyde' were prepared by
litera-ture methods. The authors thank Kay-Fries Chemicals,Inc.,
for several of the chemicals used in this work.
Typica2 condensation. A mixture of 0.01 mole of aldehydeand 0.01
mole of th e active hydrogen compound in 15 to25 ml. of dry dioxane
at 0' was treated with about 0.2 ml.of piperidine. After s tanding
from 2-12 hr. at room tem-perature, the crystals were filtered or
the solution waa slowlyconcentrated until c rystals were obtained.
The productewere recrystallized from an appropria te solvent as
shown inTable I.
Condensation with cyanoacethydrazide. Equimolar quanti-ties of
cyanoacethydrazide and benzaldehyde nitrogen mus-tard were heated
in abaolute ethanol for 10 min. After cool-ing, a quanti tat ive
yield of solid, m.p. 212-214', was ob-tained. Washing with ho t
ethanol and h ot chloroform didnot change th e melting point.
Anal. Calcd. for CI,&&T,OCI~: C, 51.39; H, 4.93;
N,17.12. Found: C, 51.13; H, 4.95; N, 16.80.The same p,roduct was
obtained when 0.01 mole of cyano-acethydrazide and 0.02 mole of
benzaldehyde nitrogen mus-tar d in dioxane was treat ed wi th
piperidine.
TO7.4 g . (0.034 mole) of N,N-bis(Zchloroethyl)aniline in 18ml.
of dimethylformamide at 25-30 was added slowly 3.84g. (0.03 mole)
of tet racyanoethylene . After stirring for 10min. at 50-55', the
mixture was cooled and diluted withwater to give 8.61 g. of red
solid. T he properties of this solidare included in Table I.
p - [Bis( kchloroethyl)amino] phenylethaetriearbonitrile.
Acknowledgment. We acknowledge the aasist-ance of J. Pattee and
W. Kirsch in the preparationof some of the aldehydes used in this
work.
DEPARTMENT F CHEMISTBYUNIVERSITYF M u mCOWL GABLES, LA.
Syntheaie of Potential Anticancer Agents. IV .
Phenylpyruvate Mustard'I2
FRANK . POPP
R w * v e dJanuary 6, 1961
Baker and co-workersg have recently reported asynthesis of p b i
s ( Z - c h l o r o e t h y l ) ~ ~ ] henyl-pyruvic acid
(phenylpyruvate mustard) from p -nitrobenzaldehyde via the key
intermediate, methyla-benzamido - p - [bis(2 -
chloroethyl)amino]cinna-mate (I). We have also been working on a
synthesisof phenylpyruvate mustard and had prepared I ,before the
appearance of Baker's report,' by a some-what more convenient
route.
NHCOCsHsI
CH=C-CO~CH~ C H OI
1 ICH=C -C=O
6N(CH,CH?CI)?
I11
(1) Part 111, F. D. Popp, J . 01.8. C h . , 6,3021 (1961).(2)
This investigation was supported in part by a Re-
search Grant T 177 from the American Cancer Society.
