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LD3907 1^ 1 .G7 Goldsmith, Edwin Alexander, 192119§° Some derivatives of naphthazoles. New York, 19^9* viii,79 typewritten leaves0 taDie diagrs. 29cm. Thesis (Ph.D.) - New York Univer sity, Graduate School, 19?0. Bibliography: p.77-79* C507H
Xerox University Microfilms,
Ann Arbor, Michigan 48106
T H IS D IS S E R T A T IO N H AS BEEN M IC R O F I L M E D E X A C T L Y AS R E C E IV E D .
library op lit YORK UNIVERSITY wiitirsitt IfEIOHTS
MEW YORK UNIVERSITY
SOME DERIVATIVES OF NAPHTHAZOLES
A DISSERTATION IN THE DEPARTMENT OF CHEMISTRY SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL OF ARTS AND SCIENCE OF NEW YORK UNIVERSITY IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY
V \e/t EDWIN A. GOLDSMITH
The author wishes to express his deepest appre ciation to Professor H. G. Lindwall, who suggested and directed this investigation.
TABLE OF CONTENTS Page
DEDICATION........................................ ill LIST OF ILLUSTRATIONS...........................
LIST OF FLOW SHEETS............................... vii LIST OF TABLES....................................viii INTRODUCTION....................................
REVIEW OF THE LITERATURE.........................
DISCUSSION OF EXPERIMENTAL RESULTS Beta Naphthazoles......................... Beta Beta Naphthazoles ................... Ultraviolet Absorption Spectra ............ Biological Tests .........................
5 11 19 26
EXPERIMENTAL RESULTS Alpha methyl ethylacetoacetate ( I ) ........ 2-carboethoxy beta naphthazole (II)........ 2-carboxy beta naphthazole (III).......... 2-carboethoxy 3-dlmethylamlnomethyl beta naphthazole ( I V ) ......................... 2-carboethoxy 3-dlethylamlnomethyl beta naphthazole (V) ..... 2-carboethoxy 3-morpholylmethyl beta naphthazole ( V I ) ................... 1-beta cyanoethyl 2-carboethoxy beta naphthazole (VII)......................... 1-beta carboxyethyl 2-carboxy beta naph thazole (VIII)........................... 1-beta cyanoethyl 2-carboethoxy 3-dimethylamlnomethyl beta naphthazole (IX).......... 1-beta cyanoethyl 2-carboethoxy 3-diethyl amlnomethyl beta naphthazole ( X ) .......... 1-beta cyanoethyl 2-carboethoxy 3-morpholylmethyl beta naphthazole ( X I ) ........... . . 2-carboxy beta naphthazole 3-acetic acid (XII).................................... 2-carboxy beta naphthazole 3-acetamlde (XIII) 2-carboxy beta naphthazole 3-acetlc acid di amide (XIV).............................
39 40 42 43 45 46 47 48 49 50 51 52 54 55
TABLE OF CONTENTS - Continued
Page Beta benzene azo alpha naphthol (XV). . . . 1-methoxy 2-benzene azo naphthalene (XVI) • 1-methoxy 2-naphthylamlne (XVII).* . . . . . 2-carboethoxy 9-methoxy beta beta naph thazole (XVIII)......................... 2-carboxy 9-methoxy beta beta naph thazole (XIX) ................... 2-carboethoxy 3-dimethylamlnomethvl 9methoxy beta beta naphthazole (XX)........ 1-beta cyanoethyl 2-carboethoxy 3-dimethylamlnomethyl 9-methoxy beta beta naphtha zole (XXI)............................... 1-beta cyanoethyl 2-carboethoxy 9-methoxy beta beta naphthazole (XXII)............. 1-beta carboxyethyl 2-carboxv 9-methoxy beta beta naphthazole (XXIII)............ 2-carboxy 9-methoxy beta beta naphthazole 3-acetic acid (XXIV)..................... 2-carboethoxy 3-morpholylaethyl 9-methoxy beta beta naphthazole (XXV)........... . 1-beta cyanoethyl 2-carboethoxy 3-morpholylmethyl 9-methoxy beta beta naphthazole (XXVI) 2-carboethoxy 3-dlethylamlnomethyl 9-methoxy beta beta naphthazole (XXVII)............ SUMMARY
57 58 59 62 64 66 67 68 69 70 72 74 75
LIST OF ILLUSTRATIONS Figure
1. 2. 3.
5. 6. 7. 8.
Ultraviolet Absorption Spectrum of 2-carboethoxy beta naphthazole (II) in Ethanol.................
Ultraviolet Absorption Spectrum of 2-carboethoxy 9-methoxy beta beta naphthazole(XVIII) in Ethanol •
Ultraviolet Absorption Spectrum of 2-carboethoxy 3-dlmethylamlnomethyl beta naphthazole (IV) in Ethanol..........................................
Ultraviolet Absorption Spectrum of 2-carboethoxy 3-dimethylamlnomethyl 9-methoxy beta beta naph thazole (XX) in Ethanol...........................
Ultraviolet Absorption Spectrum of 2-carboethoxy indole in Ethanol.................................
Ultraviolet Absorption Spectrum of Naphthalene In Ethanol..........................................
Ultraviolet Absorption Spectrum of Phenanthrene in Ethanol..........................................
Ultraviolet Absorption Spectrum of Anthracene In Ethanol..........................................
LIST OF FLOW SHEETS Sheet
Synthesis of 2-carboethoxy beta naphthazole (II)
Synthesis of 2-carboethoxy 9-methoxy beta beta naphthazole (XVIII)...........................
LIST OF TABLES Table
1. Ultraviolet Absorption Data for Pure Compounds
2. Results of Biological Tests with
XII and XIII.
3. Results of Biological Tests with ized by Nicotinic Acid
Introduction Very few compounds of the naphthazole series have been described In the literature.
Only one example of
a "linear” naphthazole (5-6 benzoindole, benz (f) Indole or beta beta naphthazole) was found, but references to several examples of the "angular" series of compounds (4-5 benzoindole, benz (e) Indole or beta naphthazole) were found In a literature search.
ses of compounds of both series were therefore undertak en. Because of the remarkable properties of Indole 3-acetlc acid as a plant hormone, It was deemed Interest ing to prepare the naphthalene analog of this acid. Further, various cyanoethylated derivatives and Mannich compounds were proposed, the latter by taking synthetic advantage of the active 3-position in the heterocyclic ring of the indole nucleus.
Of particular interest were
the 3-dimethylaminomethyl derivatives because of the un usual physiological properties of gramine and of 5methoxy gramine. Determination of the ultra violet absorption spec tra of individual members of both series was proposed for purposes of comparison with each other and with the par ent indole structure. Several of the compounds prepared and characterized
- 2 -
were submitted to the Department of Biology of New York University for microbiological and parisitological test ing. Review of the Literature The Fischer synthesis (1) discovered in 1883, involves the acid catalyzed rearrangement of aryl hydrazones with loss of ammonia to give indoles.
wide choice of catalyst is at the disposal of one em ploying this method, for almost any strong acid of the Lewis type will serve.
A powerful tool in the prepara
tion of indoles is the Japp-Klingemann reaction (2). By diazotlzlng the properly chosen aromatic amine and coupling with an active methylene compound, aryl hydrazones which otherwise would be difficult to prepare are synthesized conveniently. Hughes and Lions (3), by availing themselves of both the Japp-Klingemann reaction and the Fischer syn thesis prepared several beta naphthazole derivatives containing a carboxy or carboethoxy group in the 2position.
Earlier, Schlieper (4) prepared the free
beta naphthazole, beta naphthazole 2-carboxylic acid and 3-methyl beta naphthazole from the beta naphthylhydrazones of acetaldehyde, pyruvic acid and acetone respec tively.
- 3 -
In a series of papers, Hinsberg and co-workers (5) discussed the preparation of a series of beta naph thazole derivatives by condensation of the glyoxalbisulfite adduct with beta naphthylamlne.
compounds prepared were beta naphthoxindole, beta naphthisatin and the free beta naphthazole.
It is inter
esting to note that the last named compound differed markedly from that prepared by Schlieper (4)» and that the 2-carboxy beta naphthazole of Schlieper differs tre mendously from that of Hughes and Lions, (3). In the beta beta naphthazole series, the only re corded reference located was in a paper by Llebermann (6), wherein a series of alpha naphthoquinone deriva tives was reported.
DISCUSSION OF EXPERIMENTAL RESULTS
- 5 -
Beta Naphthazoles The procedures of Hughes and Lions (loc. cit.) were followed for the preparation of the angular series of compounds, the parent compound being 2-carboethoxy beta naphthazole.
The Intermediate beta naphthylhydra-
zone of ethyl pyruvate was conveniently prepared follow ing the directions of these authors, but this compound was not characterized.
The physical characteristics
of the indole ester and the corresponding a d d prepared in this fashion differ markedly from those obtained by Hughes and Lions.
For example, they report the melting
point of the acid as 160°, and that of the ester as 161°, the latter as a white compound recrystallisable from petroleum ether.
It was found that the ester
melted at 164-16?°, and the acid from 224-226°, the latter value in agreement with that of Schlieper (loc. cit.).
The ester is obtained as an orange compound
which is very slightly soluble in high boiling petro leum ether fractions.
Repeated crystallizations failed
to produce a completely colorless product. It is interesting to note that although the Ehrlich Reagent is a test for a free 3-posltion of in dole, none of the 2-carboxy or 2-carboethoxy compounds reported herein gave even a faint test.
- 6 -
observation has been made with other Indoles substi tuted with these groups, although prolonged boiling Is reported to give a red color (7).
A convenient method
used for ester compounds of this type as a means of testing for ring closure is to heat a few milligrams of the substance with about 1 cc. of dilute potassium hy droxide for several minutes.
After acidification with
hydrochloric acid, the water Is evapor&ted, leaving the dry organic and Inorganic matter which is heated over an open flame until charring or decarboxylation Is not ed.
After cooling, alcohol is added to dissolve the
organic matter, followed by a drop or two of hydro chloric acid and Ehrllch's solution (5% solution of jg-dlmethylaminobenzaldehyde In water containing a few drops of hydrochloric acid)•
if the original material
were a 2-carboethoxy indole, a red color would result, while an aryl hydrazone gives no color under these conditions. The Instability of the Indole ring system in strongly acid solutions Is particularly marked In the naphthazole series.
Blue compounds of undetermined
compositions are formed even In the cold In the pres ence of dilute strong acids.
This militates against
substitution in the naphthalene ring of the naphtha zole nucleus by ordinary substitution reactions. For
- 7 -
this reason, and because properly substituted naph thalene compounds are not available, all the compounds in the "angular series" are unsubstituted in the homocyclic portion of the molecule. Through failure to prepare pure beta naphthylhydrazine, the alternative procedure of Warner and Moe (8) was unsuccessful.
The procedure of Fisbher (9),
reduction of the dlazonlum salt of beta naphthylamlne with either stannous chloride and acid or with sulfite and acid is very poor, and attempts at recrystalliza tion of the hydrazine hydrochloride seems to result in rearrangement to an amino compound of unknown structure. The free hydrazine is so unstable that exposure to air for only a few seconds results in the development of pink-red oxidation products.
It decomposes more slow
ly in an inert atmosphere, such as nitrogen or carbon dioxide.
The compound is listed as a side shelf re
agent in the text by Shriner and Fuson (10), but let ters of inquiry to these authors
as to commercial
availability elicited the response that "Organic Syn theses" would be very happy to accept a good synthet ic method, should the author be able to devise one. An alternative procedure for preparation was at tempted, that of a Hofmann degradation on N-beta naphthyl urea, for Schestakov (11) had reported a 66#
- 8 -
yield of hydrazine from urea Itself via the Hofmann re action, and Elliott (12) reported poor yields of j)-chloro phenylhydrazlne and of 2,4,6, trlchlorophenylhydrazlne from N chloro N f phenyl ureas.
The requisite naphthyl
urea was prepared from beta naphthyl amine &n acid solu tion and an aqueous solution of potassium isocyanate according to the procedure of Young and Clark (13). The alpha isomer was very conveniently prepared from alpha naphthyllsocyanate and aqueous ammonia, but preliminary experiments using sodium hypochlorite were unsuccess ful, and the work was abandoned.
Mannlch Reactions The first observation of a condensation of the type now referred to as the Mannlch reaction was made by Tollens (14, 15) who Isolated the tertiary amine from ammonium chloride, formaldehyde and acetophenone. Later, Petrenko-Krltschenko (16) and co-workers studied condensations of this kind, but failed to recognize the reaction as a general one.
The detailed study by
Mannlch was initiated by the observation that antipyrine salicylate, formaldehyde and ammonium chloride re acted to form a tertiary amine. (17).
rlne (4-dimethylaminoantipyrine) failed to react, it
- 9 -
vas evident that the reaction Involved the hydrogen at carbon 4 of antlpyrlne. As a result of Mannlch* s work, the reaction has been shown to be general, and consists In the condensa tion of ammonia or a primary or secondary amine with formaldehyde and a compound containing an active hydro gen.
In this research, this reaction was successfully
carried out on 2-carboethoxy beta naphthazole with dimethylamlne, dlethylamlne and morphollne. were of the order of 45-55#•
Alkaline hydrolysis of
the resulting amino esters was unsuccessful, no amino acids being isolated.
The destructive effects of al
kali on compounds of this type has been reported by Lindwall and Bell (18) •
Contrary to the experience of
Mantell (19) who successfully hydrolyzed 2,5-dlcarboethoxy 3-dlmethylamlno-methylindole to the corresponding dl-acld with concentrated hydrochloric acid, the pres ent author was unable to carry out the same procedure In the naphthazole series.
Extensive decomposition oc
curred in acid solution, resulting In a deep blue col ored material which proved to be Insoluble In both acids and bases. Cyanoe thylatl ons Because of the marked reactivity of Indoles
- 10 -
towards acrylonitrile in the presence of "Tryton B" (trlmethylbenzylammonium hydroxide), the reaction was carried out by using 2-carboethoxy beta naphthazole (II) as well as the various Mannlch products prepared, to produce 1-beta cyanoethyl 2-carboethoxy beta naphtha zole (VII), 1-beta cyanoethyl 2-carboethoxy 3-dimethylaminomethyl beta naphthazole (IX), 1-beta cyanoethyl 2-carboethoxy 3-d1ethylaminomethyl beta naphthazole (X). Of these, 1-beta cyanoethyl 2-carboethoxy beta naphtha zole was hydrolyzed to the corresponding di-acid (VIII) in almost quantitative yield.
The others were character
ized as to melting points, crystalline form and color. Several of these have been submitted for microbiologi cal testing as noted above.
In all cases, the yields
were quite high. Alkylatlons The procedure of Snyder and co-workers (20) for the alkylation of sodium cyanide was carried out suc cessfully.
Two products were isolated from the reac
tion mixture, and were shown by analysis to be 2-carboxy beta naphthazole 3-acetic acid (XII), and 2-carboxy beta naphthazole 3-acetamlde (XIII). The expected 2-car. boethoxy beta naphthazole 3-acetamlde was not isolated. The di-acid (XII) was converted to the di-amide (XIV) in good yield through the dl-acld chloride.
- 11 -
Beta Beta Naphthazoles Approach to the "linear series" (or 5-6-benzlndoles) was far more entailed, for an appropriately 1-substltuted 2-naphthylamlne was necessary, the group In the 1-posltlon to act as a blocking group and pre vent ring closure to that position,
ho such compound
was available commercially, and a synthetic approach was needed.
The compound finally selected was 1-methoxy
2-naphthylamlne, and when this reacted In the JappKlinggmann reaction using alpha methyl acetoacetlc ester, the alpha methoxy, beta naphthylhydrazone of ethyl pyruvate was produced.
The latter was success
fully cyclized to form 2-carboethoxy 9-methoxy beta beta naphthazole In 27# yields. The preparation of the methoxy amine was accom plished via a rather involved synthesis.
was coupled with the dlazonlum salt of sulfanllle acid to form Orange II, according to Organic Syntheses (21). This was reduced to 1-amlno 2-naphthol hydrochloride, and the latter oxidized to beta naphthoquinone (21).
procedure of Zlncke (22) was used to convert the qulnone to beta naphthoquinone hydrazone, tautomeric with beta benzene-azo-alpha naphthol.
was encountered In methylating this, for the procedures
- 12 -
of McPherson (23) and of Noelting et al (24) gave yields of less than 1#.
Dimethylsulfate and sodium
hydroxide were used at ordinary temperatures with no success, for the naphthol Is almost Insoluble In aqua* ous alkali.
At temperatures as high as 85°, 10-15#
conversions to the methoxy azo compound were obtained, but then the difficulty of separating the unreacted naphthol from the methylated compound was encountered. Repeated extractions with hot alkali were performed, but the resulting compound was still highly impure. Repeated crystallizations (and accompanying loss of ma terial) was then necessary to yield an approximately pure product.
However, It was found that methylation
with dimethylsulfate at higher temperatures, I.e., 95-100°, yielded the desired methoxy compound in yields approximating 70-80#.
One or two crystalliza
tions from ethanol were then sufficient to purify the compound. Several explanations for the non-reactivity of the azo naphthol towards methylating agents at ordinary temperatures are possible.
The idea of steric hindrance
was the first that came to mind, and a Fisher Hirschfelder - Taylor model of the molecule was con structed.
On the basis of this model, it was evident
- 13 -
that if the molecule existed in the cis configuration (as it probably does, for hydrogen bonding between the nitrogen and oxygen atoms could then occur, which phenom enon would add to the stability of the compound; how ever, see below) that steric interference would be very marked.
The attacking reagent would be constrained to
approach from only one direction, from either the back or the front of the molecule, and in a rather steep path.
Such interference could certainly account for
some or all of the difficulties encountered.
Wheland (25) on the other hand, states that thetautomerlsm in the molecule is analagous to that between nitroso phenols and quinone monoxlmes.
Since the ortho compound
under discussion is not appreciably soluble in aqueous alkali as hydroxy azo compounds would be expected to be, Wheland is of the opinion that it should be considered as the quinone mono phenylhydrazone.
He states that a hy
drogen bond undoubtedly exists between the nitrogen and oxygen atoms.
On this basis, the hydroxyazo and quinone
monoxlme structures should be written as depicted below. 0— H
Inasmuch as the position of the proton Is not the same in both structures shown, resonance between them probably does not occur.
Since, however, only a very slight
change in the position of the proton is sufficient to transform either structure into the other, the tautomerism may be expected to be exceptionally mobile. The method of Noeltlng (24) for preparation of the methoxy amine is very Involved, utilizing reduction with stannous chloride and acid, extractions, precipitation of the tin with hydrogen sulfide, extraction, and final ly steam distillation of the desired amine. number of side reactions cut the yield down.
Further, a Rather than
this, the much more elegant procedure of Whitmore and Revukas (26) involving catalytic reduction with Raney Nickel in absolute ethanol was used, and resulted in al most quantitative yields of the amine in a pure enough state to obviate the necessity for recrystalllzatlon. As noted above, the amine was used in the Japp-Klingemann reaction, the hydrazone being obtained as a deep red oil, necessitating its extraction with ether from the re action mixture.
The Fischer synthesis followed in about
27J6 yields. Earlier it was hoped that the chosen naphthylamlne could be synthesized from alpha naphthol through the 2-nitro compound, followed by methylation and
- 15 -
reduction of the nltro group with metal and acid.
ever, direct nitration even at temperatures below zero degrees resulted in a mixture of 4-nitro 1-naphthol and 2,4*di-nitro 1-naphthol.
The procedures of Deninger
(27) and of Grandmougin and Michel (28) gave extremely poor yields of the desired 2-nitro naphthol.
cedure was finally developed involving hydrogen perox ide oxidation (both in acid and in basic solutions) of 2-nitroso 1-naphthol, prepared from 1-naphthol accord ing to the procedure of Illinski and Henriques (29). However, it proved impossible to methylate this under all conditions employed.
The sodium salt of the nltro
naphthol is extremely insoluble in all solvents tested, whether prepared with sodium or sodium hydroxide.
suspension of this salt in methanol or in water precip itates the original naphthol upon treatment with di methylsulfate.
Refluxing the salt with methyl iodide
for several weeks gave negative results.
After a great
deal of effort, this approach was regretfully abandoned. A possible explanation for the entirely negative results obtained in methylation of the nitro naphthol lies in the possibility of formation of addition com pounds.
it has been known for some time that alcoholic
alkali gives intense colorations with dl and trl nltro
- 16 -
These are due to addition compounds.
1,3,5 trlnitro benzene In methanol produces a red crys talline compound of formula (C^H^CNC^^CH^OK^ * H2°‘ when treated with potassium hydroxide (30).
pound, and others of a similar type formed from other trl-nitro compounds are formulated by Meisenheimer (31) as ii O G H
Further, It is of Interest to note that while nitro ben zene and alpha nitro naphthalene give no such compounds, beta nitro naphthalene (31) and 9 - nitro anthracene (32) yield
- 17 -
It Is entirely conceivable that the orange insoluble salt formed upon addition of alkali and methanol to the nitro naphthol is Identical with formula nan above. Al ternatively, it may be tentatively formulated as depict ed belov. ONa
Methylation of alpha naphthol with either di methyl sulfate or methyl iodide followed by nitration failed of realization, for the 4-nitro compound or a mixture of this and the 2,4 di-nitro compound was ob tained. Mannlch Derivatives Mannich derivatives entirely analagous to those prepared in the angular series were prepared.
dimethyl amine, diethyl amine and morpholine were used, to yield 2-carboethoxy 3-dimethylaminomethyl 9-methoxy beta beta naphthazole (XX), 2-carboethoxy 3-diethylaminomethyl 9-methoxy beta beta naphthazole (XXVII) and 2,-citrboethoxy 3-morpholylmethyl 9-methoxy beta beta
- 18 -
naphthazole (XXV) respectively.
In the case of XXV, the
reaction was run with the anhydrous amine and with an approximately 33# solution of the amine in water.
comparable reaction times (6 hours on the steam bath) the former gave a crude yield of 85#, and the latter 60#. On the other hand, addition of water seemed to Increase the yield In the case of the di-ethyl derivative (30# in anhydrous medium and 39# with an approximately 33# solution of the amine in water).
In any event, the
observations of Blicke (33) as to lower reactivity of diethyl amine in the Mannich reaction as compared to dimethyl amine were corroborated in this research. Cyanoethylatlons Again, reactions similar to those in the "angu lar" series were carried out to accomplish N-cyanoethylation, and to produce 1-beta cyanoethyl 2-carbo ethoxy 9-mettooxy beta beta naphthazole (XXII), 1-beta cyanoethyl 2-carboethoxy 3-dimethylaminomethyl 9-meth oxy beta beta naphthazole (XXI) and 1-beta cyanoethyl 2-carboethoxy 3-morpholylmethyl 9-methoxy beta beta naphthazole (XXVI). Compound XXII was hydrolyzed to corresponding di-acid (XXIII) in good yield.
- 19 -
AlkylatIons The procedure of Snyder (20) was again used to alkylate sodium cyanide, but in this Instance the mix ture of products was not isolated.
Instead, the re
action mixture was acidified to precipitate the acid components, and these were taken up in alkali and re fluxed for several hours to form the 2-carboxy 9-meth oxy beta beta naphthazole 3-acetic acid (XXIV). Absorption Spectra The ultraviolet absorption spectra of several of the compounds prepared were determined in the region of 220 - 360 mu.
The solvent was ethanol in all cases,
and this was prepared following the directions of Leighton, Crary and Schipp (34)• figures 1 - 4 *
The results appear In
P o p purposes of comparison, measurements
were made with 2-carboethoxy indole (figure 5) prepared according to the procedure of Brehm (35)•
It may be
seen that there is no resemblance at all between the naphthazoles and the parent Indole structure in this re spect.
The latter exhibits one broad band with a maxi
mum of 294 mu.
Several amldlc derivatives of indole
2-carboxylic acid (curves not shown) exhibit exactly the same shaped curve and a maximum in the same region.
- 20 -
the other hand, the naphthazoles used exhibit 5 or 6 nar rower bands In the spectral region examined.
1 for a summary of absorption data). Further, the curves for both the "angular” and the "linear" series of com pounds are markedly similar, several of the maxima being shifted to slightly longer wave lengths in the "linear" series. The differences described above are undoubtedly due to the conjugation brought about by the additional 6 membered aromatic ring In the naphthazoles.
since resonance is practically the same In both types of naphthazole compounds, it is hardly surprising that their respective absorption curves should be so similar. it was deemed of Interest to determine the effect of the pyrrole ring In the naphthazole nucleus.
structural similarities with anthracene and phenanthrene are evident, the absorption spectra of these compounds and of naphthalene Itself In the same region were sought.
Data for naphthalene was found In the work of
Laazlo (36), (see figure 6) and that for phenanthrene and anthracene In papers by Mayneord and Roe (37), Capper and Marsh (38) and Jones (39).
(Figures 7, 8).
Phenanthrene exhibits a broad band at about 230 mu, 6 narrow bands around 330 mu, and 3 more between 270
- 21 -
and 300 mu.
Naphthalene Itself shows 8 narrow bands
from 294 - 310 mu and 7 others scattered between 255 and 290 mu.
Marked similarities exist In the spectra of
these two molecules.
In the case of phenanthrene a shift
of absorption to longer wave lengths is evident.
case of anthracene, a series of narrow bands exists from about 310 - 380 mu, and these seem comparable to the long wave length bands of naphthalene and phenanthrene. However, the absorption maxima at shorter wave lengths appear absent here. Upon examination of the absorption curves, It be comes evident that the substitution of a pyrrole ring for a benzene ring cuts down the absorption in the ultra vi olet.
Although 5 bands are found In the spectra of the
naphthazoles, they are broader, more diffuse and more widely spread than those In the aromatic hydrocarbons. In general, however, the experimental curves are more closely akin to those of the aromatic hydrocarbons than they are to Indole itself.
In particular, comparison
with the 5 bands of naphthalene (figure 6) in the region of 270 - 290 mu reveals striking similarities.
gion In Laszlofs curve Is practically equivalent to the entire experimental region In this work, 5 succeeding
- 22 -
maxima followed by a sudden, steep drop.
Since the pres
ent work and that of Laszlo cover approximately the same spectral region, It may be easily seen that the curve structure for naphthalene Is much more detailed than that of the naphthazoles, and that It Is far more com pressed.
The possibility exists that further details of
structure corresponding to the 8 bands of naphthalene at 294 - 310 mu may be found spread out further towards the red end of the spectrum.
However, this was not pursued
further. A more rigorous and profitable comparison might well be made among the spectra of the corresponding naphthofuranes, naphthothiophenes and the compounds prepared in this research.
Unfortunately, however, a search of
the literature provided no data for such compounds. Determination of the absorption curves was profit able as added proof of the structure of the linear com pounds, In that several possible events In the course of their preparation were ruled out.
First, there was the
possibility that ring closure of the methoxy hydrazone Intermediate might proceed to the 1-posltion, either with cleavage of the ether bond or with complete elimination of the methoxy group.
As a broad analogy for this there
Is the example of ring closure In a quinoline synthesis
- 23 -
using either 1-bromo 2-naphthylamine or 1-nitro 2-naphthylamine (40).
This resulted In formation of the
"angular" quinoline derivative, ring closure proceeding exclusively to the 1-position with elimination of the bromo or nitro group.
(For this reason a chloro or oth
er halo amine was not used as a starting material In the Japp-Kllngemann synthesis.)
Secondly, It Is known that
naphthols and naphthylamlnes suffer easy reduction In the unsubstituted ring to yield tetrahydro derivatives (41), and it was conceivable that such might have taken place during the catalytic reduction of the methoxy azo compound (XVI).
If such were the case, one could not
tell from the ensuing reactions, for the amine group would still retain Its aromatic character and would undergo dlazotlzatlon and the Japp-Kllngemann reaction. The similarity In the experimental curves of both series of compounds clearly Indicates that neither of these supposed events occurred.
In the former case,
the 6 membered ring adjacent to the pyrrole ring would be non-aromatic In character; In the latter, the other ring would lack aromatlcity, and the absorption curves could hardly be so much alike.
Further, If reduction
had taken place In the ring further away from the pyr role ring, It would be expected that similarities to
the spectrum of the parent Indole structure would he found*
In view of these facts, and since anglytlcal
data for 2-carboethoxy 9-methoxy beta beta naphthazole (XVIII) and other compounds In the "linear” series agreed so well with calculated values, it may be as sumed that the structure postulated is definitely es tablished.
Ultraviolet Absorption Data for Pure Compounds 294
Indole 2Carboxylic Ester
Max* Log £ 4*31 __________________ mu 232 Min. Log £ 3.29
4.59 4.14 4.34 4.22 4.16 4.15
4.13 4.10 4 . H 4.05 3.97
4.51 4.35 4.19 4.16 4.13
4.11 3.98 4.10 3.98
4.54 4.10 4.23 4.19 4.23 4-23 4.23
4.09 4.09 4.19 3.98 4.12 4.03
4.52 4.47 4.23 4.25 4.22
4.29 4.06 4*15 4.02
_ 26 _
Biological Tests Through the courtesy of Professor R. P. Hall of the Department of Biology of Nev York University, stud ies are in progress to determine the effects of several compounds prepared in this research upon the growth rates of a protozoan and of a series of bacterial cul tures.
In all, nine compounds were submitted for such
tests, but at the time of writing, partial data for only two compounds are available.
These are 2-carboxy beta
naphthazole 3-acetic acid (XII) and 2-carboxy beta naph thazole 3-acetamide (XIII). The complete experimental data for these preparations, and for the others await ing test (Compounds IV, VI, VII, VIII, IX, X and XXV) will appear elsewhere when completed. The organism used in these studies was Chllomonas parameclum, an algal flagellate, an organism widely used in nutritional studies.
Measurements of growth were made
using a Coleman spectrophotometer, the percent transmis sion of each culture being measured at the start of an experiment, and then again after a four day incubation period.
If growth occurs, the culture becomes less trans
parent, and percent transmission decreases.
if growth is stifled or stopped completely, the initially recorded transmission remains practically constant.
In the tables below, "A" refers to 2-carboxy beta naphthazole 3-acetamide and "B" to 2-carboxy beta naphthazole 3-acetic acid.
It vill be seen that WBW
completely Inhibits growth in concentrations as low as 1 microgram per milliliter, and "B" in concentrations of 2 micrograms per milliliter. Table II Additions ug./ml.
Control - 0.0 A*•• 1.0 A*•• 2.0 A..• 5*0 A..•10 *0 B.*• 1.0 B.•. 2.0 B... 5.0 B...10.0
98.7 99.6 99.4 99-4 99.4 99.8 99.7 98.9 97.8
Final 75.8 89.5 99.1 99.8 100.0 98.6 99.3 99.8 100.0
Since the test organism synthesizes nicotinic acid among other compounds in the course of its life cycle, and since nicotinic acid seems to stimulate its growth, it was deemed of interest to determine whether the effects of the compounds tested could be reversed by addition of this acid to the cultures.
available only for compound "B" (XII) at this time, and this appears in Table III below.
It will be noted that
the attempt at reversal was unsuccessful In the concen tration range of nicotinic acid employed.
there is some slight indication that Increased amounts of the added acid might Indeed reverse the complete in hibition of growth, and further work along these lines is in progress. Table III Compound B and Nicotinic Acid (N.A.)
B Added, ug./ml.
0.0 2.0 0.0 2.0 0.0 2.0 0.0 2.0 0.0 2.0
0.0 0.0 1.0 1.0 0.1 0.1 0.01 0.01 0.001 0.001
97.6 98.2 98.3 98.7 97.5 98.4 97.8 98.7 98.4 99.2
78.6 98.3 78.9 97.1 79.9 98.6 79.9 97.7 78.3 97.7
In the above data, a control was run in each experiment, and it is obvious that growth of the culture did occur in the absence of "B", but was completely inhibited once this material was added.
_ 29 _
26 0 WAV E
Fig. 1 - Ultraviolet
30 0 L E N G T H ( MU )
Spectrum of II in Ethanol.
(1.79 x 10“5 K.)
Fig. 2 - Ultraviolet Absorption Spectrum of AVTII in Ethanol (4.2 x 10“5 M.)
_ 31 _
jfig. 3 - Ultraviolet Absorption Spectrum of IV in Ethanol ( 2.56 x 10"5
Pig. 4 - Ultraviolet Absorption Spectrum or H (1,86 x 10“5 M.)
- 33 -
Fig. 5 - Ultraviolet Absorption Spectrum of 2-oarboethoxy indole in Ethanol. (5.5 10 10"5 M . )
- 3* _
Fig. 6 - Ultraviolet Absorption Spectrum of Naphthalene in Ethanol,
(of. Laszlo, Ref. 36)
2 40 0
28 0 0 WAVE
30 O 0 ( ANSTR OM S)
Fig. 7 - Ultraviolet Absorption Spectrum of Phenanthrene in Ethanol,
(of. Mayneoard and Roe, Ref. 37)
_ 36 _
Fig. 8 - Ultraviolet Absorption Spectrum of Anthracene in Ethanol, (of. Jones, Ref. 39)
‘< ^ IN Nn|/1 OOOC2H5
Flow Sheet I Synthesis of 2-oarboethoxy beta naphthazole
S ' S
N rN -C 6 H 5
//\ s \ . m i
,x A ® 3 y
^ JmH N - CCJOOCgHg
, ^ A f ' J / iuOOC2H5 CHgO
PLOW SHEET 2
Synthesis of 2-oarboethoxy 9-methoxy beta beta naphthazole
_ 39 _
alpha methyl ethylacetoacetate. I
CH3GO OH (GH3 )GOO C3H5
To 2 liters of absolute ethanol in a three necked flask equipped with an efficient reflux condensor and sealed stirrer, there was added 57 g. sodium over a peri od of three hours.
The solution was allowed to cool, and
325 g. of ethylacetoacetate was then added.
al was heated to boiling on a steam bath and 375 g. of methyl iodide was added dropwise with vigorous stirring. The addition took almost two hours.
Refluxlng was con
tinued for three hours after addition was complete, or until the mixture was neutral to moist litmus paper. After arranging for downward distillation, alcohol was distilled off until the precipitated sodium iodide caused bumping.
The material was cooled, taken up in benzene,
and washed with water in a separatory funnel to remove the inorganic salt.
Water and benzene were removed as an aze-
otrope, the remaining benzene removed at reduced pressure, and the residue fractionated in vacuo, the pressure vary ing between 40.5 mm - 44 aim*
The product distilled be
tween 92 and 95° at this pressure, the yield being 241 g* > or 62% based on ethylacetoacetate.
- 40 2-carboethoxy beta naphthazole. II
OOOCgHg To a cold (-10°) solution of 50 cc. of 95# etha nol, 7.2 grains (0.05 mol.) alpha methyl ethylacetoacetate, 17 cc. of 50# potassium hydroxide and 100 grams of Ice, there was added with vigorous stirring, a cold (-10°) solution of diazotized beta naphthylamine (7.15 grams, 0.05 mol., In 20 cc. of concentrated hydrochloric acid, 3.5 grams of sodium nitrite and 30 cc. of water). The mixture turned yellow and then red. ated out whieh soon solidified.
An oil separ
This was filtered off,
washed well with water and dried in a vacuum desiccator. The hydrazone so obtained weighed 12 grams, 94-# of the ory.
It was dissolved in 75 cc. of absolute ethanol,
and gaseous hydrochloric acid was bubbled through the solution until a precipitate of ammonium chloride was noted.
At this point the mixture was heated to boiling
under reflux, and then allowed to cool to room tempera ture.
The gas flow was stopped and the material allowed
to stand undisturbed for several hours.
At the end of
this time, It was poured on to Ice with stirring, the precipitated solid filtered off, washed well with water and dried.
The crude ester was golden yellow in color,
and weighed 7.5 grams, 63# of theory.
(If the heating
noted above is eliminated, a sticky, difficultly filter able product Is obtained in lower yields.)
zation from ethanol and acetone afforded the desired In dole ester in 4-3# yield. Although Hughes and Lions (3) report this prepar ation to melt at 161°, and to be colorless crystals, It was found almost Impossible to get the material color less by recrystallizatlon.
After bone-blacking in eth
anol five or six times, the solution was still deep orange, and the crystals obtained were the same color. Repeated crystallizations from ligroin resulted in pale yellow fluffymaterial melting from 164-165°.
possible to get a colorless product by saponification, purification of the resulting acid and re-esterlflcation. However, the material was used in further syntheses as orange crystals, of melting point as noted above. Calcd. forc15\ ^ ° 2 Found:
C, 75.29# 75.29# 75.34#
_ 42 _
2-earboxv beta naphthazole. Ill
2.4- grams (0.01 mol.) of 2-carboethoxy beta naphthazole was suspended In 15 cc. of water containing 2 grams of sodium hydroxide, and the mixture refluxed until solution was obtained.
After cooling and filtra
tion, the filtrate was treated with Norlte twice and acidified with cold dilute hydrochloric acid.
precipitated as a white material which turned pale blue in contact with the acid mother liquor.
tact caused formation of dark blue-green decomposition products.
The yield was almost quantitative.
filtration and washing with water, the crude material was recrystallized from aqueous alochol as lustrous silvery plates, melting point 224-226°, in 85% yield. Calcd. for C13H9M02 Found:
N, 6.64J* 8,57%
_ +3 _
2-carboethoxy 3-dlmethylamlnomethyl beta naphthazole. IV________________
CHg -1OH2N s CHg I000C2H5
M / ‘
1.3 grams (7.5 mmol.) of 2-carboethoxy beta naph thazole (II) was added to a cold mixture of 3.5 cc. of gla cial acetic acid and 2.1 cc. of 33$ solution of dl-methyl amine.
1.2 cc. of 37$ formaldehyde was added, and the
mixture heated on the steam bath for 2 hours.
ing for two hours further, 15 cc. of water were added, aid the precipitated difficultly filterable sticky solid fil tered off.
The filtrate was made alkaline with cold am
monium hydroxide and the free amine precipitated as a cream-orange colored solid.
This was filtered off, washed
well with water, dissolved In acetic acid and the result ing solution treated with Norlte until colorless.
ammonium hydroxide was again added to precipitate the base as a white curdy mass.
The crude yield was 53$ of theory.
Recrystalllzatlon from ethanol afforded 0.8 grams of white needles of melting point 168-169° (36$).
It Is of
interest to note that while extension of reaction time
to six hours did not appreciably affect the yield, one run made for eight hours increased the yield of crude ma terial to 75$> and the yield of purified material to 59$.
Calcd. for C H M 0 18 20 2 2 Found:
N , 9.4-6$
_ +5 _
2-carboethoxy 3-d 1ethy3amlnorogthy1 beta naphthazole. V
OOOCgHg 6.0 grams (25 mmol.) of 2-carboethoxy beta naph thazole (11) was added to a solution of 50 cc. of gla cial acetic acid, 6 cc. of diethylamine, 12 cc. of water and 6 cc. of 37# aqueous formaldehyde.
ture was warmed on the steam bath for 4-1/2 hours and then allowed to stand at room temperature over night. 30 cc. of water and about 1 gram of Norite were added, and the mixture shaken and then filtered.
trate was poured into ice cold excess ammonium hydrox ide with stirring, and the precipitated free base fil tered and washed free of ammonia with water. yield was 4.1 grams, or 46#.
95# ethanol afforded 2.4 grams (29#) of white crystals, melting point 175-176°. Calcd. for C„
20 24 2 2
N, 8.63# 8.52#
2-carboethoxy 3-morpholylmethyl beta naphthazole. VI
1.15 g* (4*3 nmol.) of 2 carboethoxy beta naphtha zole was added to a cold solution of 0.6 g. morphollne in 5 cc. of acetic acid.
0.65 cc. of 3758 formalin was then
added, and the mixture heated on the steam bath for two hours.
After standing at room temperature for two hours
further, 10 cc. of water was added, and the mixture fil tered.
Cold ammonia was added to precipitate the amine,
and the precipitate filtered and washed thoroughly with w§ter.
The amine was dissolved in acetic acid, and the
solution treated with Norlte until colorless.
cold ammonia was again added, and the amine filtered, washed with water and recrystallized from 9558 ethanol as white fine needles. Yield:
0.67 g., 41J8, melting point 174.5-175.5°.
Calcd. for C20H22N2°3
_ 47 _
1-beta cyanoethyl 2-carboethoxy beta naphthazole. VII
n / Ioooo2h5
CHgCHgCN 1.11 g. (4 .7 mmol.) of 2-carboethoxy beta naphtha zole was added to 5 cc. of dioxane.
0.2 cc. of "Tryton
B" (trlmethylbenzylammonlumhydroxlde) and 0.5 cc of acrylonltrlle were added, and the mixture warmed to 75° on a steam bath.
It was kept at this temperature for 30 min
utes and then allowed to stand overnight at room temper ature.
Complete solidification occurred.
ic acid was added to neutralize the base, and the mixture filtered.
The resulting crude material was washed well
with water and dried.
Recrystallization from 95* ethanol
resulted in 1.2 g. (88%) of white fluffy crystals, melt ing point 176-177.5°. Calcd. for
1-beta earboxyethyl 2 carboxy beta naphthazole. VIII
,U00H !\K '■'V-'-NK
0.5 g. of 1-beta cyanoethyl 2-carboethoxy beta naphthazole (VIII) was suspended in 9 cc. of water con taining 2 cc. of 50# potassium hydroxide. was refluxed.
Solution took place in fifteen minutes,
but the odor of ammonia was noticeable even after two hours.
Evidently, the ester linkage was hydrolyzed first.
Refluxing was continued for three and one-half hours, and the solution cooled and filtered.
Acidification of the
filtrate with cold acetic acid precipitated a white sol id.
This was washed with water and dried.
tion from ethanol produced white fine crystals in 91# yield, melting point 228-229°. Calcd. for Found
_ 49 _
1-beta cyanoethyl 2-carboethoxy 3-dimethylaminomethyl ________________ beta naphthazole. IX_______________
/CH3 iOHgNN 0H3 .J0OOC3H5 -Ni'
OH2CH2GN To a suspension of 1.33 g. of 2-carboethoxy 3dimethylamlnomethyl beta naphthazole (4 .7mmol.) In 5 cc. of dloxane, there was added 0.2 cc. "Tryton Bn and 0.5 cc. of aerylonitrile.
The orange solution was warmed to
75°> kept at this temperature for two hours and then allowed to stand at room temperature over night.
of water and several drops of 50J6 aqueous potassium hy droxide solution were added, the solution cooled in an ice bath and the precipitated tan solid filtered and washed with water.
The crude material weighed 1.17 g.
(71J6). Crystallization from 9556 ethanol resulted in 0.7 g. (4350 of a white crystalline materia], melting point 119-120°. Calcd. for C H N O 21 23 3 2 Found
_ 50 _
1-beta cyanoethyl 2-carboethoxy 3-diethylamino__________methyl beta naphthazole* X
GHgN' ° 2 H5
To a solution of 1.40 grams (4.32 mmol.) of 2carboethoxy 3-diethylaminomethyl beta naphthazole (y) in 10 cc. of dloxane, there were added 0.2 cc. of "Tryton B" and 0.5 cc. of acrylonitrile.
was warmed to 75-80° on a water bath and kept at this temperature for one hour.
It was then cooled to room
temperature and allowed to stand over night.
of 15 cc. of water and several drops of 50# potassium hydroxide caused the formation of a milky solution, and this, upon cooling in the refrigerator for several hours, deposited 1.335 grams of pale yellow crystals. Recrystalllzatlon of these from ethanol afforded the de sired product as white crystals, melting point 105-106°. The yield was .98 g., 60# of theory. Calcd. for C ^ H g ^ O g Found:
N, 11.11# 10.98,
1-beta cyanoethyl 2-carboethoxy 3-morpholylmethyl beta naphthazole, XI______________
00OC3K5 ‘0H2CH2CN To a solution of 0.425 g. (1.08mol.) of 2-car boethoxy 3-morpholylmethyl beta naphthazole (VI) in 3 cc. of dioxane there was added 0.1 cc. of "Tryton Bn and 0.2 cc. of aerylonitrile.
The solution was warmed to 75°>
kept at this temperature for an hour and then allowed to stand at room temperature over night.
10 cc. of water
were added, followed by several drops of 50% potassium hydroxide, the mixture shaken, cooled and filtered. The grey crude material was crystallized from 95% ethan ol, resulting In 360 mg. (84$) of fine white crystals, melting point 149.5-150.5°. Calcd. for C H N O 23 25 3 3 Found
2-carboxy beta naphthazole 3-acetlc acid, XII
1 gram of 2-carboethoxy 3-dimethylaminomethyl beta naphthazole (IV) was added to a mixture of 70 cc. of 95# ethandl, 10 cc. of water and 3 grams of sodium cyanide, and the mixture refluxed for eighty hours.
85 cc. of water was added, and the ethanol removed using an aspirator.
The resulting suspension was cooled and the
precipitated tan material filtered and washed with water. The filtrate was set aside for the isolation of 2-carboxy beta naphthazole 3-acetamide, (XIII). The solid material proved to be Insoluble In all organic solvents tested, and melted with severe decomposition between 320 and 345°. It was suspended in 20# aqueous potassium hydroxide and refluxed, solution being complete after 10 minutes.
monia was evolved, and the refluxing was continued for flve-slx hours longer until the odor of ammonia was no longer detectable.
The solution was cooled, filtered, and
the filtrate acidified with cold dilute hydrochloric acid.
- 53 -
A white precipitate formed which turned pale blue, and then darker blue in contact with acid.
It was filtered
off, washed with water, taken up in aqueous sodium hy droxide, and the solution treated with Norite until it was colorless.
Careful acidification with cold acetic
acid reprecipitated the dl-acid as a white powdery mate rial.
After washing with water and drying in a vacuum
oven it was melted.
The material darkened at 240°, and
slow decomposition occurred which was complete at 280°. No liquefaction or evolution of gas was noted.
sample was Inserted in the melting point block at 285°, and a small portion of this sublimed to the cooler por tions of the capillary tube. at 295°.
The yield was 0.42 grams, or 4856 of theory.
Calcd. for C__H..N0. 15 11 4 Founds
Decomposition was complete
N, 5.20# 5.42#
- 54 -
2-carboxy beta naphthazole 3-acetamlde. XIII
The first filtrate from the isolation of 2-carboxy beta naphthazole 3-acetic acid (XII) was cautiously acidified (hoodl) with cold acetic acid, cooled and the pale blue precipitate filtered off and washed thoroughly with water.
It was dissolved in di
lute sodium hydroxide, treated with Norlte until the solution was colorless, and repreclpltated with dilute cold acetic acid.
Filtration, followed by thorough
washing with water produced 0.21 gram of a white amor phous powder, melting point 246-24-7° with severe de composition.
H H 0 15 3.2 2 3
N, 10.45# ' * 10.20, 10.26
2-carboxy beta naphthazole 3-acetlc acid diamlde. XIV
^ N ^ 0®2 1 gram (4«1 mmol.) of 2-carboxy beta naphthazole 3-acetic acid (XII) was suspended in 50 cc of absolute ether in a three-necked flask equipped with a sealed stirrer, a reflux condensor equipped with a drying tube and a ground glass stopper.
The suspension was stirred
vigorously, and 5 grams of thionyl chloride was quickly added.
Stirring was continued for thirty minutes, and
then the ether and excess thionyl chloride were distilled in vacuo.
20 cc. of absolute ether containing 5 grams of
thionyl chloride was added and the process of stirring and distillation repeated.
50 cc. of a saturated solu
tion of ammonia In ether was added, and the mixture stirred for twenty minutes.
Approximately two-thirds of
the ether ammonia mixture was removed In vacuo, and 25 cc. more of the amaonlacal ether solution added.
ring was continued for twenty minutes, and then the flask was stoppered and allowed to stand in the refrigerator
_ 56 _
The mixture was taken just to dryness in
vacuo and the residual solid suspended in water and fil tered.
The tan solid was washed with water until the
washings gave a negative chloride test. weighed 0.71 grams (65%)•
After drying it
Recrystallization from gla
cial acetic acid after treatment with Norlte in that sol vent produced white crystals, melting point 298-301° with severe decomposition.
The yield was 0.36grams or
33% of theory. Calcd. for
- 57 2-benzene-azo 1-naphthol (beta naphthoquinone hydrazone). XV
To a suspension of 100 grams (0.633 mol.) of beta naphthoquinone in 1000 cc. of glacial acetic acid there was added with vigorous shaking, an aqueous solution of 94 grams (0.65 mol.) of phenylhydrazine hydrochloride. The mixture turned red immediately.
After shaking for
10 minutes to break up lumps of unreacted qulnone, the mixture was allowed to stand undisturbed over night. The bright red precipitate was filtered off, washed with dilute hydrochloric acid and then thoroughly with water. theory.
The crude material weighed 108 grams, 69# of Recrystallization from acetone produced 87
grams (55#) of red plates, melting point 137-138°. (Literature reported melting point 138°, ref. 22 b).
1-methoxy 2-benzene-azo-naphthalene. XVI
To a solution of 25 grams of sodium hydroxide in 250 cc. of hot (85°) water, there was added with vigor ous stirring, 22 grams (0.089 mol.) of 2-benzene-azo 1-naphthol.
40 cc. of technical dimethyl sulfate was
added all at once (hoodl).
The temperature rose rapidly
to 100° with the evolution of clouds of foul smelling vapor.
The mixture was stirred for 1/2 hour further,
and then cooled to room temperature In an ice bath. The dark red precipitate was filtered off, washed thor oughly with water and dried.
The dry crude product
weighed 22.3 grams, 96# of theory.
from 95# ethanol,after bone-blacking twice in that sol vent, produced 17.6 grams of beautiful orange platelets, melting point 100-101°, 76# of theory.
of the mother liquor afforded 4 grams of less pure ma terial, and this, on further purification produced 1.7 grams of the pure product. fore 84# of theory.
The total yield was there
The procedures of McPherson (23)
and of Jfoelting et al (24) gave yields of less than 1# after tedious purification.
The former author reported
the compound to melt at 95°, the latter authors report ing 102-103°.
_ 59 _
1-methoxy 2-naphthyianiine. XVII
26.2 grams, (0.1 mol.) of 1-methoxy 2-benzene azonaphthalene (XVI) was suspended in 250 cc. of absolute ethanol in a heavy walled hydrogenation bottle.
imately 5-6 grams of Raney nickel catalyst (see below for preparation) were added, and the bottle placed on a Parr Instrument Co. hydrogenation apparatus.
was evacuated, and then hydrogen at about 50 p.s.i. was admitted.
The process of evacuation and admission of
hydrogen was repeated three times more to Insure complete removal of air, and finally, shaking was started at 50 p.s.i.
The orange azo compound rapidly went into solu
tion as reduction proceeded, the color fading at the same time.
After about one-half hour absorption of hydrogen
was complete, shaking was stopped, and the bottle re moved.
The pale yellow ethanollc solution was rapidly
filtered from the catalyst, and possessed a beautiful deep blue fluorescence.
Addition of hydrochloric acid
to form the amine salt caused a change in color to deep wine red.
Most of the solvent ethanol was removed in
vacuo, the last traces by admission of steam until vapor temperature reached 100°.
The suspension of the pink
amine salt was then cooled with ice, and excess ice cold 20# sodium hydroxide added.
Steam was rapidly passed in
to the mixture, and distillation was carried out until the distillate was perfectly clear.
Cooling the distil
late in the refrigerator over night caused solidifica tion of the methoxy amine as beautiful white platelets. These were filtered off and dried in a vacuum desiccator The yield was 15.6 grams of pale pink crystals, melting point 43-49°, or 92# of theory.
melting point 49-50°, ref. 24)•
The remaining 8# of
material may be recovered from the aqueous filtrate by saturation with sodium chloride and extraction with ether.
After drying the ether solution with magnesium
sulfate, the amine may be Isolated as the hydrochloride by saturation with dry hydrogen chloride gas.
since the by- product aniline will also be extracted, the material Isolated will be contaminated by aniline hydrochloride, and the separation of the two salts is not practicable.
The methoxy amine is slowly oxidized
by air to form pink, and finally red oxidation products, so it is desirable to use it as soon as it is thorough ly dried.
The Raney nickel catalyst is prepared hy slowly adding 100 grams of the ni eke1-aluminum alloy to a so lution of 100 grams of sodium hydroxide in 500 cc. of water, with stirring.
When the alloy has all been add
ed, the suspension is heated on a steam bath for two hours, and the nickel washed free of alkali by decantation.
A solution of 50 grams of sodium hydroxide in
500 cc. of water is added, and the process of heating and washing with distilled water repeated, the latter until all traces of alkali have been removed.
terial is then washed with 95# ethanol three times, and finally twice with absolute ethanol.
It is stored in
a glass stoppered bottle under absolute ethanol.
is intensely pyrophoric, and while it retains this prop erty after use in reduction it was used only once, and then discarded.
If necessary, the catalyst may be used
a second time, although reduction time for similar runs is increased.
2-carboethoxy 9-methoxy beta beta naphthazole. XVIII
M x 000 ° 2 H5
To a cold (-10°) mixture of 14.4 grams (0.1 mole) of alpha methyl ethylacetoacetate, 75 cc. of 95# ethanol, 34 cc. of 50# potassium hydroxide and 100 grams of ice there was added a cold (-10°) solution of
1-methoxy 2-naphthylamine (XVII), (17.3 grams, 0.1 mole, 40 cc. of concentrated hydrochloric acid and 6.9 grams of sodium nitrite) with vigorous stirring.
The stirring was
continued for five minutes, as the reaction mixture turned yellow, orange and finally deep red.
The deep red oily
1-methoxy 2-naphtbyl hydrazone of ethyl pyruvate was ex tracted with ether, the ether solution washed three times with successive 200 cc. portions of cold 5# potas sium hydroxide, and finally with ice water until free of alkali.
The red solution was dried over magnesium sul
fate over night, the solid filtered off, and the ether distilled on a steam bath.
Last traces of the solvent
were removed using an aspirator.
100 cc. of absolute
ethanol were added, and a rapid stream of hydrogen
_ 63 _
chloride gas passed Into the solution.
The heat gen
erated here necessitates the use of a reflux condensor, equipped with a drying tube to exclude moisture.
gas flow was continued for 90-120 minutes, or until a precipitate of ammonium chloride was noted.
point, the flow was stopped, and the mixture allowed to stand undisturbed for two hours.
It was then poured on
to 600 grams of ice with stirring, and the precipitated brown sticky solid filtered off and washed free of acid with water.
The crude material was dissolved in chloro
form, and the purple solution treated hot with norlte three or four times.
It was then concentrated until a
thick dark solution resulted.
This was cooled and fil
tered and the solid recrystallized from ethanol until it was a pale pink.
A colorless material may be obtained
by continued crystallization, but the accompanying loss of material is quite significant, and more than over shadows gain in purity.
The yield is 7.3 grams of pink-
white material melting at 229-230°, or 27# of theory. Calcd. for C Found
,0 N 16 15 3
H, 5.62# it, 5.41#
C, 71.26# 71.31#
H, 5.69# 5.65#
- 64 2-carboxy 9-methoxy beta beta naphthazole. XIX
V V ^ N / cHgO
500 milligrams (1.86 mmol.) of 2-carboethoxy 9-methoxy beta beta naphthazole (XVIII) was suspended In 10 cc. of water containing 0.5 grams of sodium hy droxide. effected.
The mixture was refluxed until solution was The solution was then cooled in an ice bath
and acidified with ice cold dilute hydrochloric acid. A white gelatinous precipitate formed, and this was fil tered off rapidly, washed well with water and dried at 90°•
The yield was almost quantitative.
It Is not ad
visable to allow the compound to remain In prolonged contact with hydrochloric acid, for blue decomposition products are formed even at Ice bath temperatures. Crystallization from aqueous ethanol afforded 370 milligrams of tiny white crystals, 82# of theory, melting point 243-245° with decomposition.
- 65 -
of the material occurs at about 230°. gives a negative test "with Ehrllchts
The acid Itself reagent, but If
the capillary used for the melting point determination Is crushed, and the material therein taken up in etha nol, boiled, and then treated with Ehrlich*s reagent and a few drops of hydrochloric acid, a pink-red positive test color is produced.
Calcd. for C l J O
H 11 3
C, 69.70# H,