Synthetic Studies in the Preparation of Various

I II I.II l‘I‘ III IIII

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I '4 .mmm SYNTHETIC STUDIES IN THE PREPARATION OF VARIOUS PYRAZOPYRROMETHANES, PYRAZOPYRROMETHENES AND PYRAZOPYRROKETONES AS POSSIBLE ROUTES TO A 4,7:13,16 - DIIMINO - 2,26:18,20 - DIETHYLENE-O, 11 - N,N’ - HYDRAZINE - 22,24 - N,N'OIIMINE- 1,19 - DIAZA(26)ANNULENE

Thesis for the Degree of M. S. MICHIGAN STATE UNIVERSITY JAMES EDWIN MACDONALD 1976

“L m- . u . . .- . - _ _ ,_-__ _"__ -_--_- - -qH—O_ ‘5‘- —--»—-” ' - ._"‘. . n‘ MICHIGAN IIIIIIIIIIIII MIIIIII STATE UNIVERSITYIIIIIIIIIIII B IIIIIIII 01591 3852

ABSTRACT

SYNTHETIC STUDIES IN THE PREPARATION OF VARIOUS PYRAZOPYRROMETHANES. PYRAZOPYRROMETHENES AND PYRAZOPYRROKETONES AS POSSIBLE ROUTES TO A 4,7:13,16-DIIMINO-Z,26:18,20-DIETHYLENE-9,TT-N,N'-HYDRAZINE-22,24- N,N'DIIMINE-T,T9-DIAZA[26]ANNULENE By

James Edwin Macdonald

The 4,7:l3,16-diimino-2,26:l8,20-diethylene-9,ll-N,N'-hydrazine-

22,24-N,N'diimine-l,l9-diaza[26]annulene is proposed as the object of

a synthetic scheme, as it should have interesting physical and chemi-

cal properties. The mode of approach is based on the precedence of

known pyrrole chemistry. The methods employed involve the reaction of

pyrroles that have free a positions with 3,5—disubstituted pyrazoleacid-

chlorides, pyrazoleketones and pyrazolealdehydes or hydroxymethyl-

pyrazoles under a variety of conditions. In no case investigated

could the desired model condensations be achieved, and these methods

do not appear to be a viable route to the proposed system. SYNTHETIC STUDIES IN THE PREPARATION OF VARIOUS PYRAZOPYRROMETHANES,

PYRAZOPYRROMETHENES AND PYRAZOPYRROKETONES AS POSSIBLE ROUTES TO A

4,7:l3,T6-DIIMINO-2,26:lBJK¥DIETHYLENE-9,ll-N,N'-HYDRAZINE-22,24-

N,N'DIIMINE-T,TQ-DIAZA[26]ANNULENE

James Edwin Macdonald

A THESIS

Submitted to Michigan State University in partial fulfillment of the requirements for the degree of

MASTER OF SCIENCE

1976 ACKNOWLEDGEMENTS

The author wishes to express his sincere gratitude to Dr. Eugene

LeGoff for his guidance and aid during the course of this research.

Thanks are also due to my fellow graduate students, especially to Houston Brown, who contributed to making this degree possible and the last two years agreeable.

ii TABLE OF CONTENTS

LIST OF FIGURES ......

INTRODUCTION ......

DISCUSSION OF RESULTS ......

EXPERIMENTAL SECTION ......

3-Diazo-2,4-pentanedione(ll) ...... 4-Methyl-3,5-diacetylpyrazole(l2) ...... Pyrromethenes(l3) from 4—methyT-3,5-diacetylpyrazole(l2) . 3,5-Dimethyl~4-carboethoxypyrromethene(l3a) of (12) . . . . 3,5-Dimethyl-2-pyrromethene(l3b) of (12) ...... 3,5-Dimethyl—4-ethyl-2-pyrromethene(l3c) of (l2) ..... 4-Methyl-3,5-dithioacetylpyrazole(l4) ...... Pyrrolidine fluoroborate(l5) ...... 3,5-Bis(acetylpyrrolidiniminium fluoroborate)-4- methylpyrazole(l6) ...... 3,5-Dicarboxaldehydepyrazole(l7) ...... 3,5-Bis(glyoxate)-4-methylpyrazole(l8) ...... 3,5-Bis(diacetatemethyl)pyrrole(l9) ...... 3,5—Pyrazoledicarboxaldehyde(l7) by an adaption of the method of McFadens and Stevens ...... Pyrazole,3,5—dicarboxaldehyde by the Sonn-Muller Method N-phenylamides from esters ...... B-Anilinoacrolein(22) ...... Diazoacetaldehyde(23) ...... 3-Carboxaldehyde-S-carbethoxyp razole(24)' ...... 2-Pyrro-3-(5-carboethoxypyrazoImethene(25) ...... Reduction of pyrazopyrromethene(25) with zinc ...... Reduction of pyrazopyrromethene(25) with SnCl ...... Reduction of the pyrazopyrromethene with NaBH4 ...... Oxidation of the pyrazopyrromethene(25) with ceric amonium nitrate ...... Pyrazole-3,5-diacid chloride ...... 3,5-Bis(2-pyrrocarbonyl)pyrazole(28) ...... l-Benzylpyrazole—3,5-dicarboxylate(29) ...... Benzylpyrazole-3,5-diacidchloride(30) ...... l-Benzyl-3,5-bis(2-pyrrocarbonyl)pyrazole(3l) ...... Bromination of 3,5-dimethylpyrazole(32) ...... 3,5-Dimethyl-4-carbethoxy-l-pyrazoleamide(33) ...... Bromination of 3,5-dimethyl~4-carbethoxy-l- pyrazoleamide(34) ...... 3,5-Bis(hydroxymethyl)pyrazole(35) ...... 3,5-Bis(methyleneacetate)pyrazole ...... 30 3-Hydroxymethyl-5-carbeth oxypyrazole(37) ...... 30 Pyrazopyrromethanes from pyrazole(37) ...... 30 3-Carbet hyoxy-Z,4-pentanedione(37) ...... 3l l ,5-Dibromo-3-carb etho xy-2 ,4-pentanedione(38) ...... 3l Nucliophilic displacement on (38) with pyrrole ...... 31 Nucleophilic displacement on (38) with hydrazine ..... 32 Nucliophilic displacements on (38) with acetate ...... 32 Nucleophilic displacement on (38) with methanol ...... 32 Tris(3-phenyl-2,4-pentanedionato)chromium III (39) . . . . 33 Tris(l,5-dibromo-3—phenyl-2,4-pentanedionato)- chromiumIII(40) ...... 33

BIBLIOGRAPHY ...... 34

iv LIST OF FIGURES

Figure Page

1 The proposed diaza[26]annulene ...... l

2 Pyrrole and pyrazole ...... 2

3 Dipyrroleketone, dipyrromethene, and dipyrromethene ..... 2

4 Pyrazopyrroketone, pyrazopyrromethane, and pyrazopyrromethene ...... 2

5 The synthetic scheme ...... 3

6 The methene condensation ...... 5

7 Thioketones from ketones ...... S

8 Aldehydes from acetyl groups ...... 6

9 Thiele's method ...... 7

l0 An acid chloride dimer ...... 9

ll The preparation of l-benzylpyrazole-3,5-diacid ...... l0

l2 Methane formation ...... ll

13 Possible reaction of l,5-dibromo-2,4-pentane diones ..... l4

l4 A possible route to substituted pyrazoles ...... l5

15 A possible route to the macrocyclic ring ...... l5

16 A possible multistep route to the desired diaza[26]annulene . l5 INTRODUCTION

Porphyrins are important hetrocyclic aromatic systems that have been intensively studied. An interesting and perhaps useful idea is to expand the porphyrin moiety into an extended ring structure like the diaza[26]annulene in Figure l.

\\ '\\ ‘\\ ‘\\ \\ NH MEN HN \ H H \ N N—N N.» \ I / / / /

Figure l. The proposed diaza[26]annulene

This expanded [26]annulene would be novel in that it may form bimetallic compTexes. In that case mixed metal and mixed metal oxidation states with unusual physicaI properties could be observed. This might lead to the development of novel catalyst systems or to organic conductors.

Annulenes of this size are unusual in that calculations show that they should show little if any aromatic charactor.2 Tests of this prediction could be interesting. The purpose of this work is to apply the methods developed in porphyrin chemistry to the formation of the proposed diaza-

[26]-annulene. This was undertaken using pyrroles and pyrazoles as building blocks (Figure 2). The models for the reactions were [a 4/”) D11 N H H pyrrole pyrazole

Figure 2 derived from the well studied coupling of pyrroles to form a,a' dipyrromethanes, methenes and ketones (Figure 3).

\ \N NJ \ N~ H H H H dipyrroleketone dipyrromethene dipyrromethene Figure 3

Following these models the unknown pyrazopyrromethane, pyrazopyrromethene and pyrazopyrroketone classes of compounds in Figure 4 might be synthesized by the condensation of pyrazoleacidchlorides, pyrazole ketones and aldehydes or hydroxymethylpyrazoles with ant: unsubstituted pyrrole.

/\ // /I / /n \ \ N/N N N,N N/ N/N N\ H H H H H pyrazopyrroketone pyrazopyrromethane pyrazopyrromethene

Figure 4 3

If any of the model systems tested work then the condensation in

Figure 5 would be a reasonable approach to the diaza[26]annulene, (x is any group that is found to react well with pyrrole).

Figure 5. The synthetic sceme

The difficulties found in this approach will be discussed and other potential routes to this system will be considered as future possibilities.

DISCUSSION OF RESULTS

One approach to this proposed diaza[26]annulene system would be to condense two pyrromethanes with two properly functionalized pyrazoles as seen in Figure 5. The pyrromethanes are not difficult to form and are well known intermediates in porphyrin chemistry.5

The objective of this research then is to investegate the unknown condensations of pyrroles with pyrazoles to give methene, methane or ketone linkages as this is the crucial step in the synthesis of the target macrocycle in Figure 5. This investigation can be approached with the least difficulty by first attempting the reactions with small model systems, and if their results are favorable then extend-- ing the reaction to the larger system as in Figure 5.

One approach to the proposed macrocycle is exemplified by the model reaction between 4-methyl-3,5-bis(acetyl)pyrazole(12) and pyrrole which should lead to a 4-methyl-3,5-bis(a-pyrromethene) pyrazole(l3). C? ./ // / +_22 [Z713> ___;> ’/ ‘/’ ,/’ / ‘\‘ \\ HN"N N 6N, HN—N \

(12) (13)

This reaction has many precedents in the reactions of pyrroles with other aIdehydes and ketones, for example, the formation of a pyrromethene salt by the acid catalyzed reaction of pyrrole and 6 3,4,5-trimethylpyrrole carboxaldehyde as in figure 6.

HB H H Figure 6. The methene condensation

The reaction of the pyrazole was carried out in hot ethanol, methanol or hot acetic acid. In all cases the mixture exhibited two peaks in the visible spectra, one at 485nm and one at 605nm. They arose from two different chromophores since the absorption ratio between the two peaks varied over a wide range as the reaction progressed. It was clear from this that the reaction gave a mixture of products. Attempts to separate the two products by crystalization did not succeed. Other pyrroles such as 2,4-dimethyl or 2,4-dimethyl-3-ethyl or 2,4-dimethyl-

3-carbethoxy pyrrole were tried with similar results. Each showed two or more peaks in the visible spectra with variable ratios.

Another approach to pyrazopyrromethenes involves the activation of the ketones in 4-methyl-3,5-bis(acetyl)pyrazole to nucleophilic attack. One method of activating a ketone is to convert it to a thioketone, and this can be achieved by treatment with P255 in benzene, toluene or acetonitrite8 as in Figure 7. ~-——-— P s ,— w -—-> 2 5 W Figure 7. Thioketones from ketones 6

When these methods were used on the 4-methyl-3,5-bis(acetyl) pyrazole the starting diketone was recovered in low yield and intractable, nonidentifiable products were obtained.

Another way to activate a ketone is to convert it to its corresponding iminium perchlorate.9 Because perchlorates are danger- ous to work with tetraflouroborate salts were employed. The amine salt precursor and the iminium salt products proved to be very deliquescent and thus difficult to purify. As a result a satisfactory sample of the 4-methyl-3,5-bis(pyrolidine iminium acetyl)pyrazole(l6) could not be prepared.

In light of these results a pyrazole carbonyl compound that is more reactive than the 4-methyl-3,5-bis(acetyl)pyrazole is needed.

Aldehydes are more reactive than ketones so some pyrazole aldehydes were investigated to see if they would form stable methenes with pyrroles. Ideally the 3,5-bis(carboxaldehyde)pyrazole (17) would be the best compound to test as it could be used to construct the desired annulene if its reactions with pyrrole were successful. This aldehyde is unknown so its synthesis was attempted. Collman's reagent is reported to reduce acid chlorides to aldehydes. ]0 Use of the reagent on 3,5-pyrazolediacidchloride may have decarbonylated the pyrazole as well, as the product'slnmeshowed no aldehyde or acid.

A different approach to form aldehydes is to oxidize methyl ketones to glyoxalates and decarboxylate them11 (as in Figure 8).

KMnO

Figure 8. Aldehydes from acetyl groups When 4—methyl-3,5-bis(acetyl)pyrazole was oxidized with permangenate in accordance with this method no product was isolated after extrac-

tion of the aqueous media. 12 In An alternative oxidative procedure is that of Thiele.

this method methyl groups on aromatic systems are oxidized to diace-

tates with chromic anhydride in acetic anhydride (Figure 9).

CFOB’ ACZO -— OAC \ / \ / OAC Figure 9. Thiele's method

Product formed by application of this method to 3,5-dimethypyrazole

could not be isolated from the aquious workup by extraction.

The McFadyen and Stevens method13 and the Sonn and Muller

approach 13 for making aldehydes out of carboxylic acids also ran into

the problem of the solubility of pyrazoles in water. Their applica-

tions did not succeed. Synthesis through functional group manipula-

tion did not seem to be a useful procedure.

The 3,5-dialdehyde would be approached directly by the 1,3-

dipolar addition of diazoacetaldehyde on propyna], The synthesis of

diazoacetaldehyde from B-anilinoacrolein(22) and tosyl azide is

reported. 14 The formation of the B-anilinoacrolein in reasonable yields following the reported procedure was not possible. An alterna-

tive route to the diazoacetaldehyde was attempted. Butylithium in THF will generate the acetaldehyde enolate.15 This enolate could be reacted with toluenesulfonylazide to yield the diazoacetaldehyde(23). An IR

spectrum of the product from the reaction showed no diazo absorptions. O EilLli> (/ L? _T5 N3//\ M2 O Q" //7 (23) H H

This could be due to a C or 0 attack of the enolate on the sulﬁJr of the sulfonylazide with displacement of azide. Since the results of concurrent studies on pyrazole aldehydes showed their reaction products with pyrroles where unstable, the efforts to produce the dialdehyde were halted.

3-Ca rboxaldehyde-S-pyrazolecaboxylate ethyl ester16 was a reasonable model compound with which to test pyrazole aldehyde reactivity as the 3,5-pyrazoledicarboxaldehyde was not available. Its acid catalized condensation with pyrrole in ethanol or acetic acid rapidly gave a deep red solution with a single absorbance peak at

485 nm in ethanol. This product was precipitated and dried at room temperature over night in a vacuum. It then gave a much higher base line and broader peak in its visable spectra. The analogous pyrromethenes slowly decompose, but the process is significantly faster in pyrazopyrromethenes.

If the methene could be reduced to a methane or oxidized to a ketone it would still be of some use in synthesis. A reduction of fresh material was tried with sodium borohydride, zinc metal on tin- dichloride but a methane was not produced. An oxidation of the methene to a ketone was tried with ceric amonium nitrate (which is useful in forming dipyrroketoneslg) without obtaining the desired result. At this point it can be seen that pyrazolealdehydes or ketones will not serve as a route to the formation of a stable pyrazopyrromethene or 9 the formation of a methane or ketone by their oxidation or reduction.

Pyrazopyrroketones could be a useful alternative route to diaza[26]annulene as the analogous pyrroketones3’ 5 are known and used in the synthesis of porphyrins. Pyrroketones are formed by the Friedel-

Crafts catalized reaction of a pyrrole and an acid chloride,3 the reaction of a pyrrole magnesium bromide with an acid chloride or by the reaction of an amide by the Vilsmeier-Haack Procedure.5 These reactions of pyrroles could be extended to the pyrazole acid chlorides to determine if pyrazapyrroketones can be generated in the same manner.

Pyrazopyrroketones formed from the known 3,5-pyrazolediacid- chloride19 would fit the requirements for the synthesis of the diaza-

[26] annulene (Figure 5). In order to determine its reactivity to pyrroles several condensation methods were tested.

First the uncatalyzed reaction between the pyrazolediacidchloride and pyrrole was run in refluxing ether. It gave results that did not warrant further investigation.

In the next approach to ketone formation pyrrole magnesium bromide was added to the acid chloride in ether at -78°, and purified by chromatography. The mass spectra showed fragments up to 73l m.u., this is much higher than the expected 254 m.u. molecular ion of the anticipated product. The reaction appears to have resulted in a polymer. This is most likely due to the acidity of the proton on the l-position and the characteristic property of N-unsubstituted pyrazoleacidchlorides to cyclize4 (Figure lO). 2MC—e \\ N’\ W I N’N \ PI

Figure To. An acid chloride dimer TO

With two acid chlorides on each pyrazole the material formed polymers.

The Lewis acid catalyzed acylation of pyrrole was tried to see

if polymer formation could be avoided in this manner. Silicon tetra-

chloride has been shown to be a mild Lewis acid. 22 When used with

3,5-pyrazoledicacidchloride and pyrrole it gave an impure tarry pro-

duct which could not be purified by recrystalization or chromato-

graphy. It appears that the N-unsubstituted pyrazoles potential for

polymerization is the difficulty in the system.

A suitably protected pyrazole should prevent polymerization.

One potential protecting group would be benzyl, which can be added

to pyrazoles and removed from them with relative ease. 2] It should

prevent polymer formation due to the nucleophilicity of the pyrazole

nitrogens.

The l-benzylpyrazole-3,5-diacarboxylate can be made from the 3,5-diester (Figure ll). The acid chloride of this diacid can be

formed with SOCl 2.

1.IVCIC)P¢H3 MeO 2 C / CO 2 Me 2 . Q CH Br HO CWO H W / m. 2 ——> 2 H 2 H CH2¢

Figure ll. The preparation of l-benzylpyrazole-3,5-diacid

Its reaction with pyrrole magnesium bromide however is not as expected.

The product after chromatography is a yellow oil which did not Chrystal-

iae out of ethanol at 20° and turned black over 24 hours.

It would seem that the conditions necessary to form a pyrazo-

pyrroketone are not the same as the conditions that have proven to

work well in the formation of pyrroketones. Because of this ll pyrazopyrroketones do not seem to offer a viable approach to the proposed hetrocyCTic system.

Another possible route to the diaza[26]annulene exists in the pyrazopyrromethanes based on the precedence of the analogous 20 dipyrromethanes. The route to the pyrromethanes involves the reaction of a hydroxymethylpyrrole or a halomethylpyrrole with a pyrrole (Figure 12).22 va X OH,E3r Q‘im / H H H Figure l2. Methane formation

This might be adapted to a 3,5-bis(bromomethyl) or (hydroxymethyl)- pyrazole to form mixed methanes and ultimately diaza[26]annulene.

The desired a-bromomethylpyrazoles are unknown, so it was necessary to synthesize the desired 3,5-bis(bromomethyl)pyrazole in order to test its reactivity. N—bromosuccinimide (NBS) in carbon tetrachloride reacts with benzylic methyl groups. Its reaction with 3,5-dimethylpyrazole should yield 3,5-bis(bromomethyl)pyrazole with a potential side product being a 4—bromopyrazole. The reaction gave three pyrazole products. With bromine as the reagent the number of products was the same. Evaporation of the reactions did not yield crystals and the material formed a hard glass over the period of a week. The tendency to form polymers in these systems also has been observed in the case of 4-chloromethylpyrazole,2] so the decomposition of this bromopyrazole is unfortunately an analogous reaction. It would appear that the l2

nucleophilicity of the pyrazole is again a drawback.

In order to block the brominations of the pyrazole at the

4-position and block the nucliophilic nitrogen, pyrazole(27) was

made. CéEt N1 /// Me

CONH Q” 2

It should brominate only on the methyl groups and give only one

dibromo product, however, in reality it gave several products. Due to

the multiplicity of products the reaction was not investigated farther.

Based on these results it would seem that bromomethylpyrazoles are

difficult to generate by direct bromination of pyrazoles. This has

made it difficult to investigate their reactivity to pyrroles.

Hydroxymethylpyrazoles could reasonably be expected to yield

pyrazopyrromethanes in a manner similar to the hydroxymethylpyrroles

forming dipyrrolemethanes. 20 In order to approach the target

diaza[26]annulene in the most direct manner 3,5-bis(hydroxymethyl)-

pyrazole(35) was made by reducing the diester.

MeOQCWCOZMe LAHI I 4 XHOH2C . // CHZOH

7 H H mm

This dialcohol was a wax that would not crystalize in methanol,

ethanol or water. The diacetate was made in an attempt to purify the T3 diol but it was extremely deliquescent. The diol turned out to be unstable, a sample allowed to sit for two months became insoluble in ethanol or water. Due to the difficulties in handling the diol and purifying it, a more reasonable model system was investigated.

The easily accessible 3-hydroxymethyl-5-carbethoxypyrazole(37) can be obtained by reducing 3-carboxaldehyde-5—carboethoxypyrazole with sodium borohydride.

802ch H O NOB H 4 % EtO2CﬂC H 20 H HN— lN—N H (37)

The reaction of this hydroxymethylpyrazole with three different pyrroles was carried out by a modification of the method of MacDonald.20

In the case of kryptopyrrole the hydroxymethylpyrazole remained unreacted over several hours while all the kryptopyrrole reacted and a red color developed. It appears that the solvent acetic acid was more reactive than the pyrazole to the pyrrole and the red color due to the methene formation. When the hydroxymethylpyrazole was reacted

With pyrrole 0P 2a4-d1'methyl-3-carbethoxypyrrole the pyrazole reacted over a twenty-four hours but not with the pyrroles, which remained unreacted. This was unfortunate as it made the simple routes to pyrazopyrromethanes unatainable.

These last results combined with those for attempted methene and ketone formations means that standard methods of porphyrin chemistry do not appear to be applicable to the formation of analogous systems of pyrazoles and pyrazoles such as the diaza[26]annulene. T4

Alternatives nay exist to the use of pyrazopyrromethenes, methanes or ketones, a possible approach to the synthesis of diaza-

[26]annulene could be through the use of l,5-dibromo-2,4-pentanediones. A nucleophile should displace the bromide and then the beta dione could be converted with hydrazine to form a 3,5-difunctional pyrazole (Figure 13).

Mi. Nuc 2. N H A Nuc / Nuc EBF' E3F‘ P¢—- H/ Figure l3. Possible reaction of l,5-dibromo-2,4-pentaned iones

Displacements on l,5-dibromo-3-carboethoxy-2,4-pentanodione with pyrrole, hydrazine, acetate or methanol did not yield l,5-difunctional-

2,4-pentanediones which could be isolated as copper complexes. A

Favorski reaction could have occurred in the presence of base and resulted in the destruction of the dione.

Some way of protecting the system from the Favorski reaction seemed to be needed, and a nonlabile metal complex might do it. The III III chromium and cobalt complexes of l,5-dibromo-3-phenyl-2,4-pen- 25 Itanedione have been made but their yields were not reported. In- vestigating the reaction showed the yields to be very low. No nucle- ophic displacements were attempted on the brominated compexes. Other possible routes to the diaza[26]annulene exist that were not investigated in the lab. One way is through substituted diazo- compounds reacting with substituted acetylenes to form pyrazoles, if the materials used are like those in Figure 14 then pyrazopyrromethanes should be formed. 15

\ NaH

2 W+ QCH-CE—C-H—ﬁ Fgi-N N// 2 / H H Figure l4. A possible route to substituted pyrazoles

For Figure 14 the diazo is not known and the best reported yield of z-

-(propyne)pyrrole is l5%, 26 this product after reaction with formalde- hyde might yield the desired macrocycle with oxidation. In Figure l5 the problem of precursor synthesis can be seen to be doubly more difficult.

Figure l5. A possible route to the macrocyclic ring

A different route can be visualized which avoids non stabilized diazo compounds and is shown if Figure 16. OHC ” ‘ <%L—”4§U2 H H * VN__ PCDBBF‘ *' —__—_> H I QDEF3F' (;H:LJS)F+1 H” 7

II FTCDEEBrr

H Figure 16. A possible multistep route to the desired diaza[26]annulene 16 Figu re 16 con.

Figure l6 circumvents the problem of the formation of the diazo- pyrrole which would be a most difficult compound to make.

These methods were not used due to their complexity and the amount of time available for the project. They are, however, potential routes to the proposed diaza[26]annulene. EXPERIMENTAL SECTION

3-Diazo-2,4-pentanedione(ll): made by the method of M. Regitz.28

4-Methyl-3,5-diacetylpyrazole(12) made by the method of Wolf.29

Eyrromethenes(l3) from 4-methyl-3,5-diacetylpyrazole(12)

3,5-Dimethyl-4-carbethoxypyrromethene(l3a) of (l2)_4-methyl-3,5- diacetylpyrazole, (0.368 grams, 2 m mole) was disolved in 2 ml of methanol. Then 0.668 g of 2,4-dimethyl-3-carbethoxypyrrole was. added and followed by 1 ml of concentrated HBr. After stirring two hours at room temperature there was no change of color. It was then heated to 60° for ten hours. The reaction mixture became a deep green. The visable spectrum showed the development of two peaks, one at 485 nm and the other at 605 nm in ethanol. They showed a varia- tion in their absorption ratio as the reaction progressed. The reaction products were precipitated by the addition of 40 ml of water and collected by filtration. Attempts to seperate the two products by crystalization with ethanol, methanol or acetic acid were not successful.

18 l9

3,5-Dimethyl-2-pyrromethene(l3b) of4(12)_

To 10 m mole

3,5-Dimethy1-4-ethyl-2-pyrromethene(13c) of (12)

To a mixture of 1 ml of methanol and 1 ml of concentrated hydroiodic acid was added 1 nmole of 4-methyl-3,5—diacetylpyrazole and then 2 111110181“ of 2,4-dimethy1-3-carbethoxypyrrole. The mixture was then refluxed forEShours. The spectrum showed three peaks in the visible region at 480, 600 and 720 nm. Dilution with water gave a green oil also with 3 peaks when disolved in ethanol.

4-Methyl-3,5-dithioacetylpyrazole(]4) ‘

a) In toluene

To 15 m1 of toluene was added 0.332 g of 4-methyl-3,5-diacety1- pyrazole, after it disolved 0.289 g of P235 was added. This mixture was refluxed for six hours and then cooled. The yellow solid produced was filtered out and washed with toluene. It was insoluble in toluene, acetonitrile, ethanol, or water. The toluene contained only a small amount of disolved solid. b) In acetonitrile8

To 5 ml of acetonitrile was added 1.72 g of 4-methyl-3,5- diacetylpyrazole. P255, 6.29, was disolved in 15 m1 of acetonitrile.

The two were mixed and 4.98 g of sodium bicarbonate was added and the 20 mixture was stirred at 60° for six hours. Two workups could be used.

The first was to dilute with 300 ml of water and collect the precipitate . It did not form so 3N HCl was added until one did. The fine predipitate passed through filter paper and could not be centrifuged out. Extraction with ether led to an emulsion. An alternative workup is to add 200 ml of ether and filter out the phosphate salts.

The filtrate is evaporated and chromatographed on alumina eluting with acetone. The starting diketone was recovered to the extent of

10% and no other material was obtained from the column.

Pyrrolidine fluoroborate(l§)

Acetic anhydride, 5 ml, was added to 2 g of stirred 48%‘f1uoro- boric. acid while chilling the mixture in ice. This was followed by dilution with 20 ml of ether and then 0.90 ml of pyrrolidine in

20 ml of ether was added. The mixture was cooled and the large plate-

1ike crystals collected and dried in a vacuum over P205. The crystals were very deliquescent and dissolved readily in water. Pyrrolidine could be recovered from the basified aquous solution by extraction.

3,5-Bis(acetylpyrrolidiniminium fluoroborate)-4-methy1pyrazole(l6)

Pyrrolidine fluoroborate, 0128 g, was added to 0.14 g of 4-methyl-

3,5-diacety1pyrazole in 30 ml of benzene. After refluxing three hours a tar formed which proved to be insoluble in benzene or acetonitrile.

3,5-Oicarboxa1dehydepyrazole(l7)

8 Collman's reagent, 1.373 g (4.0 m mole) was placed in a 50 m1 three neck flask under nitrogen and then 10 ml of dry oxygen free THF 21 was added. Pyrazole-3,5-dicarbony1chloride],9 01338 g,(2.0 m mole) was disolved in 10 m1 of THF and added dropwise to the Collman's reagent at room temperature. It was allowed to stir for 1.5 hours followed by the addition of 0.65 ml of acetic acid which was allowed to react for five minutes. The reaction mixture was poured into 50 ml of water, extracted once with 20 ml of pentane and twice with 50 ml of ether.

The concentrated extracts showed no acid or aldehyde protons.

3’5‘3I5blyoxalatelﬁzmetbxlmzoleﬂj) 3.5-Diacetyl-4-methylpyrazole, 0.368 g, was disolved in 50 ml of water containing .25 g of potasium hydroxide. It was cooled to

0° and 0.995 g of potasium permangenate was added. Keeping the temperature under 15° it was allowed to stir for 3.5 hours. It was filtered and the filtrate clarified with sodium bisulfite. 0n acidi- fication or basification no filterable precipitate was formed. Ex- traction with ether of the acidified or neutral solutions gave no products.

3,5-Bis(diacetylemethy1)pyrrole(19)

3,5-Dimethy1pyrazole, 1.92 g (20 m mole) was disolved in 20 ml of acetic anhydride and 4 ml of concentrated sulfuric acid, and then cooled to 0°. Chromic anhydride, 12 g, was added with stirring to

50 ml of acetic anhydride.r The chromic anhydride was then added dropwise at 0° to the solution of pyrazole over 4 hours, and stirred for two hours at 0°. Following that it was poured into 500 ml of water and extracted five times with 50 ml of ether. The extracts were dried and evaporated and they gave no residue. 22

3,5-Pyrazoledicarboxaldehyde(l7) by an adaption of the method of

McFadens and Stevens13

a) Acid hydrazone from an ester

3,5-pyrazoledicarboxylate dimethyl ester, 1.26 g, was refluxed

in 10 ml of hydrazine hydrate for 15 hours in a nitrogen atmosphere.

Then 30 ml of ethanol was added and the mixture cooled and filtered.

The precipitate was washed with water and dried at 110°. The infrared spectrum showed no ester carbonyl band. The yield was 0.540 g.

b) B-toluenesulfonylacidhydrazone from acidhydrazone

The above acid hydrazone, 0.54 g, was disolved in 10 m1 of dry pyridine, 1.24 g of toluenesulfonylchloride disolved in 10 ml of dry pyridine was added dropwise to the solution and the mixture was allowed to stand for two hours. It was then added to 50 ml of concentrated hydrochloric acid and cooled with ice and filtered. The solid was disolved in hot ethanol, cooled and filtered. The filtrate was warmed, saturated with water, cooled and filtered. Yield 0.350 g. c) Aldehyde from B-toluenesufonylhydr azone The product from step b was disolved in 10 ml of ethylene glycol and warmed to 150° 0. Then 3.5 m mole of sodium bicarbonate was added to the stirred solution, and after the foaming stopped it was poured into 20 m1 of water. Phenylhydrazine, 0.15 g, and three drops of acetic acid were added and a precipitate formed. Its NMR showed methyl groups and so could not be the 3, 5-dia1dehyde.

Eyrazolei-S,5-dicarboxaldehyde by the Sonn-Muller Method N-phenylamidg§_

from esters

3,5-dicarbomethoxypyrazole, 1.84 g, was refluxed in 5 ml of 23

aniline for 15 hours. After cooling it was disolved in hot ethanol,

cooled and filtered. The infrared spectrum showed a mixture of ester

and amide, no attempt to circumvent this difficulty was made.

B-Anilinoacrolein(22)30

2-Propyn—l-ol, 2.95 ml, and 5.6 m1 of aniline were mixed in

40 m1 of dry benzene and treated in portions with active manganese

dioxide, and then allowed to stir for 12 hours. It was then filtered

and vacuum evaporated to dryness and stored at -20°. Nmr showed no

2-propynol and no vinyl protons as reported for the B-anilinoacrolein.

Distillation of the residue as reported did not yield any product.

Diazoacetaldehyde(23),

The acetaldehyde enolate was generated by the method of R.

Bates.15 Then 15 mmoles of toluene sulfonylazide in 10 ml of THF

was added to 15 mmoles of the enolate in 20 ml of THF. The solution

was allowed to stir for 1 hour. It was then filtered and the solid 14 washed with 8 m1 of THF. The workup was as reported by J. Kucera.

An infrared spectrum of the residue obtained showed no diazoaldehyde.

_3-Carboxaldehyde-5-carbethoxypyrazole(24),

Produced by the method of R. Huttel.16

2-Pyrro-3-(5-carbethoxypyrazo)methene(25)g

3-Carboxaldehyde-5-carbethoxypyrazole(24), 33.6 mgs was dissolved in 0.5 m1 of methanol and 13.4 mgs offpyrrole was added.

The solution was stirred at 40° for 5 minutes, in which no color change 24 occurred. With addition of one drop of concentrated hydrochloric acid a deep red color developed rapidly. After 5 minutes the solution was diluted with one ml of hydrobromic acid, one ml of methanol and then two ml of water, and the product was obtained by filtration. The filtrate slowly turns black on exposure to air. Before decomposition its visible spectrum showed a peak at 485 nm and no other peaks.

Ethanol and acetic acid gave the same results, a single absorption peak which decomposed.

Reduction of pyrazopyrromethene(25) with zinc

The methene (0.2 m mole) generated in acetic acid as above was treated with 2.0 m mole of zinc powder, after stirring 30 minutes the zinc powder was coated with an insoluble black tar. Dilution with

10 m1 of water and extraction with 10 m1 of ether gave no ether soluble product.

Reduction ofpyrazopyrromethene(25) with SnCl2

The methene generated in acetic acid as in (25) was treated with

2 g of SnCl2 disolved in 2 ml of concentrated hydrochloric acid. It was allowed to stir and a tar precipitated over 45 minutes. Dilution with 10 m1 of water and extraction with 10 m1 of ether gave no ether soluble product.

Reduction of the pyrazopyrromethene with NaBH4

The methene (0.2 m mole) generated in ethanol as in (25) was treated with sodium borohydride (10 m mole) disolved in 5 ml of ethanol. The reaction mixture was allowed to stir for 10 minutes during 25 which time no color change was observed. Dilution with 25 m1 of water and extraction with 10 m1 of ether gave no ether soluble product.

Oxidation of the pyrazopyrromethene(25) with ceric amonium nitrate

The methene (0.2 m mole) generated in acetic acid was treated with 0.4 m mole of ceric amonium nitrate in 8 ml of acetic acid.

The mixture was stirred for 30 minutes and then diluted with 50 ml of water. Extraction with 20 ml of ether gave no ether soluble products.

Pyrazole-3,5-diacid chloride(zz)

by the method of E. Eidebenz.19

3,5-Bis(2-pyrrocarbonyl)pyrazole(28)

a) 3,543yrazolediacidchloride, 0.338 g,(2.0 m mole), was disolved in 25 m1 of ether and 0.269 g of pyrrole added. The mixture was refluxed for 4 days in which the reaction slowly formed a precipitate which was insoluble in ether, acetone or water. The pale yellow solid turned black from 180° to 230° and did not melt.

b) 3,5-Pyrazolidiacidchloride, 0.338 g (2.0 m mole) was disolved in 20 ml of ether and chilled to -78° and 4 m mole of pyrrole magnesium bromide in 10 m1 of ether was added dropwise to the rapidly stirred solution at -78°. After the addition was complete the reaction was allowed to stir at -78° for one hour and then warm slowly to room temperature. The solids were centrifuged out, the solvent vacuum evaporated, and the residue chromatographed on silica with acetonitrile. There was obtained 18.5 mg of solid having a melting 26 point of 239-243°. The mass spectrum showed a polymer of weights up to 730 m.u. c) 3,5-Pyrazolediacidchloride (0.338 g, 2.0 mmoles) and pyrrole

(4 nmoles) were mixed in 20 m1 of dry methylenechloride. The mixture was treated with 4 "moles of silicon tetrachloride in 20 m1 of methylene chloride over 45 minutes at -10° C, and then stirred at -10° for one hour. After stirring for an additional sixteen hours at room temperature the solids were filtered out and dried inra vacum, yielding

0.2098 9. An attempt to purify the solids by chromatography failed as the product would not come off the absorbent.

l-Benzy1pyrazole-3,5-dicarboxy1ate(29)

3,5-Dicarbomethoxypyrazole, 9.2 g, was disolved in 25 ml of hot methanol and added to 50 m mole of sodium methoxide in 20 ml of methanol. This mixture was evaporated to about one half its volume, cooled and filtered. The yield was 9.0 g of the sodium salt. This was placed in 40 m1 of mesitylene with 7.4 g of benzyl bromide with

0.9 grams of dicyclohexyl-lB-crown-6 and refluxed for 36 hours.

Following that the solvent was stripped off at 0.2 mm and 100° C.

The product was hydrolyzed with 10 g of sodium hydroxide in 200 ml of ethanol/water (1:1) by refluxing for 14 hours. Following that it was vacuum evaporated to about 75 ml. Then it was acidified with hydrochloric acid and the solid collected by filtration. It was recrystalized from ethanol/water and then from ethanol/benzene. The yield was 5.34 g and its melting point was 234-234°. The mass spectrum showed the expected molecular ion and benzyl fragment.

Alternatively the product of the alkylation was purified by 27

chromatography on alumina with benzene/hexane 1:1 as elutant. The

dimethyl ester obtained was recrystalized from ethanol/water and then

benzene/hexane. It had a mp of 84-85°. Its nmr showed a benzyl

group (67.1, 5.7) and two almost coincidental methyl peaks for the

two esters (63.8). Its mass spectrum showed the expected parent ion

and the benzyl fragment. Hydrolysis gave the diacid.

Benzylpyrazole-3,5-diacidchloride(30)

The diacid(29), 2.5 g, was dissolved in 5 ml of thionyl chloride

and refluxed for 48 hours, then 100 ml of dry toluene was added and

the mixture was evaporated to dryness. The oil was disolved in 80 ml

of dry pentane and cooled to 0° and then -20°, the acid chloride

crystalizes as large needles with a mp of 42-43°. The infrared

spectrum showed acidchloride carbonyl (1775 cm']) and no acid or

anhydride, yield was 2.4 9. When disolved in 10 ml of methanol with

2 m1 of triethylamine 1.3 g of the acidchloride gave 0.95 g of the

diester, a yield of 75% with a mp of 86-87°.

l-Benzyl-3,5—bis(2-pyrrocarbonyl)pyrazole(31)

l—Benzyl-3,5-pyrazolediacidchloride(30), 1.04 g, was disolved

in 5 ml of dry THF and cooled to -78° under nitrogen. Then 7.34 mmoles of pyrrole magnesium bromide in 20 ml of THF was added dropwise

to the cold solution. After addition was completed it was allowed

to come to room temperature over two hours. It was then poured into

70 m1 of water and extracted twice with 20 m1 of ether. The extract was dried and vacuum evaporated down to an oil. Chromatography on

alumina with acetone gave a light yellow oil after removal of the 28 solvent. The oil was disolved in warm ethanol which was then cooled to -20° for twenty-four hours. The oil had separated out and turned black. It did not crystalize and was not worked with further.

Bromination of 3,5-dimethy1pyrazole(32)

a) In a 250 m1 flask was placed 4.8 g of 3,5-dimethylpyrazole

(50 m mole) and N-bromosuccinimide (17.8 g, 100 m mole). 80 m1 of carbon tetrachloride was added and refluxed until the succinimide floated, which took about 40 minutes. The mixture was cooled and then filtered to remove the succinimide. Concentration gave an oil which did not crystalize. TIC of the oil showed three major products with almost the same migratory aptitude. The oil turned into an insoluble glass over a week.

b) 3,5-dimethylpyrrole, 2.4 g (25 m mole) was disolved in

20 m1 of acetic acid and then 12.0 g of bromine was added and it was refluxed until the red color was gone. Removal of the solvent under vacuum gave an oil. TIC of the oil showed a product mix similar to the N.B.S. reaction.

3,5-Dimeth1—4-carbethoxy-1-pyrazoleamide(33)4A

3-Carbethoxy22,4-pentanedione, 1.15 g, was mixed with 3 m1 of ethanol. Semicarbazide hydrochloride, 0.74 g, and 0.542 g of sodium acetate were disolved in 2 m1 of water. The two solutions were mixed and allowed to stand at room temperature for two hours, then they were diluted with 20 m1 of water and filtered to collect the solid. The yield was 0.9505 g. The proton nmr spectrum was consis- tant with the expected structure. 29

Bromination of 3,5-dimethyl-4-carboethoxyel-pyrazoleamide(34)

3,5-Dimethyl-4-carboethoxy-1-pyrazoleamide, 0.2112 g was dis-

olved in 60 m1 of carbon tetrachloride with 0.356 g of NBS plus a

small quantity of benzoly peroxide and refluxed for eight hours. It was allowed to cool to room temperature, filtered and the solvent

vacuum evaporated. The residue was disolved in pentane and filtered.

After removal of the pentane the nmr spectrum showed a complex mix

of methyl groups, more than just methyl and monobromomethyl.

3,5-Bis(hydroxymethyl)pyrazole(35)

3,S-Dicarbomethoxypyrazole, 4.8 g, was disolved in 40 m1 of

dry THF and 1.5 g of LAH was added with stirring and the mixture was refluxed under nitrogen for 40 hours. Ten m1 of water was then

added and the mixture evaporated to dryness. The solid was sus-

pended in 120 m1 of water and heated on a steam bath for three hours.

Following that it was filtered and the solid washed again with 250

ml of hot water. The two extracts were combined and vacuum evapor-

ated to dryness, the residue disolved in methanol and filtered.

After removal of the methanol a wax was obtained which did not crys-

talize from methanol,ethanol or a mixture of these alcohols with water.

The material was insoluble in less polar solvents like acetone or acetonitrile. Mass spectrum showed the expected molecular ion at 128 m.u.

The proton nmr spectrum showed the hydroxymethyl protons (6 54.4) and a weak pyrazole proton (6 86.6). The C ‘3 nmr spectrum showed three chem- ically different carbon absorptions (103.43, 100.55 and a multiplit at 54.10 to 52.8). The first two are ring carbons and the multiplit is the hydroxymethyl carbon. It is split by the duterium on the hydroxyl 30

as the solvent was 020.

3,5-Bis(methyleneacetate)pyrazole(3§)

3,5-Dicarbomethoxypyrazole, 4.8 g, was reduced with 1.5 g of

LiAlH4 in 40 m1 of THF at reflux for 40 hours under nitrogen. Acetic

anhydride (18ml) was added and the mixture refluxed for 2 hours and

then vacuum evaporated to dryness. The solid was extracted with

absolute ethanol, and the extract precipitated by the addition of

, petrolium ether. 0n filtration the solid melted on exposure to air

and was not obtained in the solid state.

3-Hydroxymethyl-5-carboethoxypyrazole(37)

4.2 grams of aldehyde(24) was disolved in 200 ml of ethanol

and cooled to 17 degrees. Following that 0.28 g of sodium borohydride

disolved in 50 m1 of ethanol was added and the mixture allowed to

stir for 14 hours. The ethanol was vacuum evaporated and the resi-

due taken up in 75 ml of hot acetonitrile, cooled and filtered. The

solution was concentrated and chromatographed on alumina with ethanol

and yielded 2.32 g of product. The nmr spectrum showed the hydroxy-

methylprotons (65.4) and the ethyl group of the ester and no

aldehyde. The infrared spectrum showed the ester, the hydroxyl group

and does not show the boropyrazole. The mass spectrum also gave the

expected molecular ion at 170 a.u.

Pyrazopyrromethanes from pyrazole(37)

a) 2,4-Dimethyl—3-carboethoxypyrrole and pyrazole(36) Pyrazole(36), 0.2 grams, and 0.2 grams of 2,4-dimethyl-3- 31 carDEthOXYPYPPOIe were placed in 5 ml of acetic acid and refluxed under nitrogen for 21 hours. TLC showed that the pyrazole reacted but the pyrrole remained unchanged.

b) Kryptopyrrole and pyrazole(36) Pyrazole(36), 0.170 grams, and 0.134 grams of 2,4-dimethyl-3- ethylpyrrole were refluxed in 5 ml of acetic acid under nitrogen.

Thin layer chromatography showed the kryptopyrrole to have all reacted over four hours without the pyrazole reacting.

c) Pyrrole with pyrazole(36)

Pyrazole(36),0.l70 grams, were mixed with 0.067 grams of pyrrole in 5 ml of acetic acid and refluxed under nitrogen. TLC showed that the pyrazole reacted over night and the pyrrole remained unchanged.

3—Carbethyoxy-2,4-pentanedione(37)

Org. Syn. Coll. Vol. 3, p. 390.

1,5-Dibromo-3-carbethoxy:2,4:pentanedione(38)s

A. Becker.23

Nucleophilic displacement on (38) with pyrrole

In a 50 ml flask was placed 0.66 g (2 m mole) of the dibromide(38) and 10 m mole of pyrrole. It was flushed with nitrogen and then 25 ml of dry THF was added. The mixture was refluxed for 4 hours. During the reflux the dibromide was consumed and an intractable tar formed which did not form a copper complex. 32

Nucleophilic displacement on (38) with hydrazine

In a 50 ml flask with a condenser was placed 0.66 grams of the dibromide (38) and .15 grams of hydrazine hydrate in 1 m1 of acetic acid. An oil precipitated out when the mixture was diluted with ether.

The red oil did not give a copper complex and would not crystalize

from ethanol/water mixtures.

Nucleophilic displacements on (38)_with acetate

Potassium acetate, 3 g, was disolved in 7 ml of glacial acetic acid followed by 4.0 m mole of the dibromide(38) at 45°. It was stirred for two hours and potasium bromide was filtered out. Treat- ment with 25 m1 of copper sulfate solution and 50 ml of water gave a copper complex. It was isolated by filtration and the diketone was freed by shaking with 20% H2504 and ether. The ether was washed with water, dried, and evaporated. The nmr spectrum of the residue

showed predominately the starting dibromide.

Nucleophilic displacement on (38) with methanol

In a 25 m1 flask was placed 0.66 g of the dibromide (38) and

10 ml of methanol. The solution was stirred for two days, then added

to 25 ml of saturated copper sulfate and 50 ml of water. The complex was filtered out and 0.19 grams was obtained. The dione was freed by

shaking with 20% sulfuric acid and ether. The extract was washed, dried, and concentrated. The nmr spectrum of the residue showed

primarily compound (38) and what may have been a trace of methyl

ether. 33

Tris(3-pheny1-2,4-pentanedionato)chromium 111(39)

by the method of Katsayuki Nakamura and Y. Murakumi

Tris(1,5-dibromo-3-phenyl-2,4-pentanedionato)chromiumI11(40)

by the method of K. Nakamura25 BIBLIOGRAPHY

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