The Hebrew University of Jerusalem

Faculty of Mathematics & Science

Institute of Chemistry

Synthesis of Fludioxonil Intermediate

Submitted by Reem Rimawi

Student (I.D.) number: 305391559

Supervisor: Prof. Dmitri Gelman

Thesis for the Degree of Master in the Faculty of Science

August 2015

ACKNOWLEDGEMENT

I am very grateful to my supervisor, Prof. Dmitri Gelman, for giving me the opportunity to

conduct my research in his group. In addition, I appreciate his kind guidance, advice, and

suggestions towards the successful completion of this work.

To my group members, I say thank you for the useful discussions we had as well as your support

in various ways and special thanks to Dr. Sanaa Musa.

I would also like to thank all lecturers who have taught me till date for the knowledge they

imparted to me.

Finally to my parents, family and friends I say thank you for your love and support which has

always been a source of urge to succeed.

ABSTRACT

Fludioxonil is a synthetic fungicide compound of the phenylpyrrole group of substances. It can

be used to control fungal disease, making it a useful seed treatment as well as a post-harvest

treatment for fruit. Fludioxonil is a broad-spectrum fungicide which is non-systemic with a long

residual activity. The mode of action of fludioxonil is the inhibition of transport-associated

phosphorylation of glucose as well as preventing glycerol synthesis. This fungicide is allowed for

use in US/Europe (except Austria) and Asia and, so far, was mainly produced by Syngenta

(Novartis) at the 106 tons/year scale.

Starting next year, one of the major generic agrochemical companies Agan Israel (former

Makhteshim-Adama) is planning to initiate manufacturing of this product using local and

international facilities.

The task of our group is to design a novel synthetic strategy toward the synthesis of a key

intermediate toward Fludioxonil using more efficient and catalytic methods. We report now the

de novo designed synthetic approaches to the desired target molecule.

ABBREVIATIONS

AcOH Acetic acid

Ad2PCl Di(1-adamantyl)chlorophosphine

Ad2PBu Di(1-adamantyl)-n-butylphosphine

BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene

BuLi Butyllithium

Dave Phos 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl

DIBAL-H Diisobutylaluminium hydride

DIPEA N,N-Diisopropylethylamine

DMF Dimethylformamide

DMG Directed metallation group

DMSO Dimethyl sulfoxide

DPPF 1,1′-Bis(diphenylphosphino)ferrocene

Et3N Triethylamine

LDA Lithium diisopropylamine

MTBE Methyl tert-butyl ether

NMP N-Methyl-2-pyrrolidone

P(o-tol)3 Tri(o-tolyl)phosphine

TMEDA Tetramethylethylenediamine

TMS-CN Trimethylsilyl cyanide

THF Tetrahydrofuran

Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

X-Phos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

CONTENTS

1. INTRODUCTION …………………………………………………………………………………………………………………….1

1.1 Fungi: definition and diseases ………………………………………………………………………………………1

1.2 Fungicides …………………………………………………………………………………………………………………….2

1.3 The use of fungicides in crop protection ………………………………………………………………………3

1.4 Classification of fungicides ……………………………………………………………………………………….…..4

1.4.1 Chemical structure ………………………………………………………………………………………………..4

1.4.1.1 Triazoles ……………………………………………………………………………………………………..5

1.4.1.2 Aromatics hydrocarbons fungicides ………………………………………………………..…..6

1.4.1.3 Dithiocarbamate fungicides ………………………………………………………………….….…7

1.4.1.4 Benzimidazoles fungicides …………………………………………………………………………..7

1.4.1.5 Piperazines fungicides ………………………………………………………………………………...8

1.4.1.6 Aliphatic aldehydes fungicides ………………………………………………………………….…8

1.4.1.7 Biological fungicides (Biofungicides) …………………………………………………………...8

1.5 Fludioxonil ……………………………………………………………………………………………………………………9

1.5.1 History ………………………………………………………………………………………………………………….9

1.5.2 Toxicity ……………………………………………………………………………………………………………….10

1.5.3 Mode of action ……………………………………………………………………………………………………10

1.5.4 Ways of synthesis ……………………………………………………………………………………………….11

1.5.4.1 Metallation using BuLi followed by decarboxylation ………………………………...11

1.5.4.2 Another metallation approach ……………………………………………………………….…12

1.5.4.3 Palladium-catalyzed cyanation of 4-bromo-2,2-difluorobenzo[d][1,3]dioxole

with subsequent reduction of the corresponding derivative to the target

aldehyde …………………………………………………………………………………………………..13

1.5.4.4 Palladium-catalyzed reductive carbonylation of 4-bromo-2, 2-difluorobenzo

[d][1,3]dioxole in to the target aldehyde …………………………………………………..13

1.5.4.5 Metalation of 2,2-difluorobenzo[d][1,3]dioxole with subsequent nucleophilic

Formylation using metallating reagents other than BuLi …………………………..14

2. RESEARCH OBJECTIVES ………………………………………………………………………………………………………..15

3. METHODOLGY …………………………………………………………………………………………………………………….16

3.1 Instruments ………………………………………………………………………………………………………………..16

3.2 Materials and methods ………………………………………………………………………………………….…..16

4. RESULTS AND DISCUSSION …………………………………………………………………………………………….……17

4.1 Palladium-catalyzed cyanation of 4-bromo-2,2-difluorobenzo[d][1,3]dioxole with

subsequent reduction of the corresponding derivative to the target aldehyde …………..17

4.1.1 Background ………………………………………………………………………………………………………..17

4.1.2 Mechanism …………………………………………………………………………………………………………18

4.1.3 Specific aim ………………………………………………………………………………………………………...19

4.1.4 Results ………………………………………………………………………………………………………………..21

4.1.4.1 Cyanide source ………………………………………………………………………………………….21

4.1.4.2 Ligands’ effect …………………………………………………………………………………………..21

4.1.4.3 Solvents and bases …………………………………………………………………………………...22

4.1.4.4 Optimized protocol …………………………………………………………………………………...23

4.1.4.5 Cyanation of 4-bromo-2,2-difluoro[d][1,3]dioxole …………………………………….25

4.2 Palladium-catalyzed reductive carbonylation of 4-bromo-2, 2-difluorobenzo [d][1,3]

dioxole in to the target aldehyde …………………………………………………………………………….…27

4.2.1 Background ………………………………………………………………………………………………………..27

4.2.2 Mechanism …………………………………………………………………………………………………………28

4.2.3 Specific aim ………………………………………………………………………………………………………...29

4.2.4 Results ……………………………………………………………………………………………………………..…29

4.2.4.1 Ligands’ effect ……………………………………………………………………………………….….29

4.2.4.2 Catalyst effect …………………………………………………………………………………………..31

4.2.4.3 Solvents and bases ……………………………………………………………………………………31

4.2.4.4 Optimized protocol …………………………………………………………………………………...32

4.2.4.5 Reductive carbonylation of 4-bromo-2,2-difluoro[d][1,3]dioxole ……………….34

4.3 Metallation of 2,2-difluorobenzo[d][1,3]dioxole with subsequent nucleophilic

formylation using metalating reagents other than BuLi ………………………………………………34

4.3.1 Background ………………………………………………………………………………………………………..35

4.3.2 Mechanism …………………………………………………………………………………………………………36

4.3.3 Specific aim ………………………………………………………………………………………………………..36

4.3.4 Results ……………………………………………………………………………………………………………….37

4.3.4.1 LDA alternatives ………………………………………………………………………………….……37

4.3.4.2 Temperatures and solvents ………………………………………………………………………37

4.3.4.3 Optimized protocol …………………………………………………………………………………..38

4.4 Conclusions ……………………………………………………………………………………………………………….40

5. EXPERIMENTAL SECTION ……………………………………………………………………………………………….……41

5.1 General consideration ……………………………………………………………………………………………….41

5.2 Preparation of 4-cyanobenzo [1,3]dioxole ……………………………………………………………..….41

5.3 Preparation of 4-cyano-2,2-difluoro[d][1,3]dioxole ……………………………………………………42

5.4 Preparation of 1,3-benzodioxole-4-carboxaldehyde ……………………………………………..…..42

5.5 Preparation of 2,2-difluorobenzo[d][1,3]dioxole-4-carboxaldehyde ………………..………..43

6. REFERENCES …………………………………………………………………………………………………………………….…44

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1. Introduction

One of the major threats facing the yearly production of agricultural crops are Fungi. In

order to minimize their catastrophic effect on the world food production, Fungicides, chemical

compounds that inhibit the growth of fungi or fungal spores, are intensively studied and

developed.

This study is focused on the development of environmentally friendly methods for the

synthesis of 2,2-difluorobenzo[d][1,3]dioxole-4-carboxaldehyde, known as Fludioxonil

intermediate. Fludioxonil is synthetic fungicide compounds contain phenylpyrrole groups. It is a

conventional antimicrobial fungicide registered to be applied on various agricultural and

nonagricultural sites, as well as for mold remediation. This fungicide is allowed for use in USA,

Europe and Asia. So far it was mainly produced by Syngenta (Novartis) at the 106 tons/year

scale. In 2016, the production will start in Israel by Makhteshim-Agan (ADAMA group).

This chapter will provide a brief summary about Fungi and their effect on agricultural crops,

Fungicides and their mode of action, Fludioxonil, classical method for its preparation, and the

development of new environmentally friendly methods.

1.1 Fungi: definition and diseases [1]

Fungi are thallophytic plants of widely diverse habits, structures and characteristics, and

comprise large and heterogeneous groups. The two chief features that characterize them are:

(i) a complete lack of chlorophyll, the green coloring matter which enables higher plants to

synthesize carbohydrates from carbon dioxide and water in the presence of sunlight, and (ii)

reproduction typically by spores.

As fungi lack chlorophyll, they cannot synthesize their essential food requirements. They

have therefore to depend on other organisms like plants or animals as food supplier, leading

eventually to deadly diseases. Plant diseases caused by a fungus, are usually restricted to a

particular area, as in the leaf-spot diseases or it may be spread over a considerable area like

wilt. Plants can withstand attack by their tissues, and this way they can endure fungi disease.

2

The more vigorous the plant is, the more rapid and complete the protective reaction.

Sometimes however, successful infection occurs only on healthy and vigorous plants.

By far the simplest treatment method for plant diseases is to use chemicals in dust form.

Disinfectant dusts are made from: (i) organic mercury compounds, (ii) copper compounds, (iii)

non-metallic organic compounds, and (iiii) sulphur based organic compounds. Development of

newer fungicides, thiocarbamates which contain organic sulphur compounds were applied as

sprays or dust form. The dusting technique found to be more useful since the factor of

abundant water supply vanishes, and the difficulties of preparation are reduced.

1.2 Fungicides [2],[3]

Fungicides are either chemicals or biological agents that inhibit the growth of fungi or fungal

spores. Modern fungicides do not kill fungi; they simply inhibit their growth for a period of days

or weeks. Fungi can cause serious damage in agriculture, resulting in critical losses of yield,

quality and profit. Moreover fungicides are applied not only in agriculture but also and to fight

fungal infections in animals. They can be classified according to their mode of action into three

categories; contact, translaminar and systemic. Contact fungicides are not taken up into the

plant tissue, and only protect the plant where the spray is deposited. Translaminar fungicides

spread all over the outer surface of the plant. Systemic fungicides are taken up by the vessels

and spread on the outer face, new leaf growth is protected for a short period.

Although fungicides are very effective, yet several pathogens have developed resistance

against them. Therefore, it has threatened the potential of some highly effective commercial

fungicides and led to poor disease control in many cases. Consequently, extensive studies have

been carried out in recent years on the detection, characterization and mechanism of

resistance in order to build-up different types of “improved” fungicides. The main aim was to

apply resistance strategies to prolong the activity of the fungicides.

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1.3 The use of fungicides in crop protection [2]

For over 200 years, farmers have applied chemicals in order to prevent damage to crops

being caused by fungi. The application of brine (aqueous solution of sodium chloride) to wheat

seed to protect against infection by bunt fungus dates back to the mid-18th century. Later,

copper sulfate solution was found to give better results and hence, copper preparations

became widely used. To overcome diseases of leaves and fruit, sprays based on sulfur,

recommended by Forsyth (1802), were applied increasingly throughout the 19th century,

mainly against powdery mildews. Then, the discovery of Bordeaux mixture led to widespread

use of copper compounds to control grape downy mildew, potato blight and other diseases

that were not controlled by sulfur.

Later on, a range of organic compounds was introduced; the most important one was

dithiocarbamates (e.g. thiram, maneb, mancozeb) which was developed in the 1940s,

phthalimides (e.g. captan, captafol) in the 1950s and chlorothalonil in the 1960s. These contact

fungicides were more effective against many diseases and were less harmful to crop plants.

However, they only acted at the plant surface, forming a protective layer. They penetrated little

into plants and so could not affect established infections. They also had to be applied

frequently to replace losses through weathering and to protect new plant growth. Systemic

fungicides which would penetrate into plants could remove existing infections and resist

weathering and might also move into new areas of growth, were sought for many years in

industrial and academic research centers.

Eventually, in the late 1960s, six different classes of systemic fungicides, all highly effective

against certain diseases, appeared in very rapid sequence: benzimidazoles, oxathiins, amines

(morpholines), 2-aminopyrimidines, organo-phosphorus and antibiotic rice blast fungicides.

Four more highly active fungicide classes with different degrees of systemicity were introduced

in the 1970s: dicarboximides, phenylamides, triazoles and fosetylaluminium. Over the past 20

years, quinone outside inhibitor (Qol) fungicides, anilinopyrimidines, phenylpyrroles,

benzamides, carboxylic acid amides and new succinic dehydrogenase inhibitors have emerged.

4

About 150 different fungicidal compounds are now used in crop protection worldwide,

with a total sales value of the order of US $10 billion/year and accounting for 23% of the total

crop protection chemicals market.

1.4 Classification of fungicides [3]

Different authors have differing classification systems according to chemical structure. In

addition to classification by chemical structural grouping, fungicides can be categorized

agriculturally and horticulturally according to the mode of application (use). According to the

origin of fungicides, they can be classified in two major groups: (i) biologically based fungicides

(biofungicides) which contain living microorganisms (bacteria, fungi) that are antagonistic to the

pathogens that cause turf disease. And (ii) chemically based fungicides which are synthesized

from organic and inorganic chemicals.

1.4.1 Chemical structure [3]

There are 29 generic names that are represented in 16 groups according to their chemical

structures (Table 1). It is important to know which fungicides are chemically related to one

another. All fungicides in the same chemical group generally, control the same diseases. And so

if a pathogen develops resistance to one fungicide in a chemical group, the pathogen is usually

resistant to all fungicides in that particular group.

Generic Names Chemical Group

Propiconazole, Triadimefon, Myclobutanil,

Triticonazole, Tetraconazole Triazoles

Fenarimol Pyrimidines

Fluoxastrobin, Trifloxystrobin, Azoxystrobin,

Pyraclostrobin Strobilurins

Polyoxin D Polyoxins

5

Thiophanate-methyl Benzimidazoles

Iprodione, Vinclozolin Dicarboxamides

Mefenoxam Phenylamides

Propamocarb Carbamates

Fosetyl aluminum, Phosphonate Phosphonates

Mancozeb, Thiram Dithiocarbamates

Quintozene, Chloroneb, Ethazole Aromatic hydrocarbons

Hydrogen dioxide Peroxides

Chlorothalonil Nitriles

Fludioxonil Phenylpyrolles

Cyanofamid Cyanoimidazole

Flutolanil, Boscalid Carboxamides

Ecoguard, Sonata, Soilguard Biofungicides

Table 1: Chemical groups of fungicides according the Generic names.

1.4.1.1Triazoles [4]

This chemical family of fungicides, introduced in the 1980s, consists of many members:

difenoconazole, fenbuconazole, myclobutanil, propiconazole, tebuconazole, tetraconazole,

triadimefon, and triticonazole (Figure 1). They are important tools against diseases of

turfgrasses, vegetables, citrus, field crops and ornamental plants. They are applied as foliar

sprays and seed treatments, and may also be applied as protectant or curative treatments, but

they have to be introduced in the early fungal infection process. Once the fungus begins to

produce spores on an infected plant, triazoles become ineffective. Although triazoles do not

have degree of systemic movement of many herbicides, they are xylem-mobile. They are

readily taken up by leaves and move within the leaf. Triazoles are very specific in their mode of

action since they inhibit the biosynthesis of sterol, a critical component for the integrity of

fungal cell membranes. Hence their site of action is very specific, there are resistance concerns.

6

Figure 1: The chemical structure of Difenoconazole (I) and Propiconazole (II) fungicides.

1.4.1.2 Aromatics hydrocarbons fungicides [5]

Major fungicides in this group include chlorothalonil, tecnazine, chloroneb, dichloran,

hexachlorobenzene, quintozene, pentachlorophenol, and sodium pentachlorophenate. They act

as uncouplers of oxidative phosphorylation. This can lead to excessive heat production,

hyperpyrexia, liver damage, and corneal opacities. Chloroneb for example (Figure 2), is a broad

spectrum systemic fungicide taken up by the roots, and used on various fruit and vegetable

crops as a wet or dry application powder or dust. Mechanistic studies showed that fungal

toxicity may inhibit DNA polymerization process.

Figure 2: The chemical structure of Chloroneb fungicide.

7

1.4.1.3 Dithiocarbamate fungicides [6]

The dithiocarbamate fungicides: ferbam, mancozeb, maneb, nabam, thiram, zineb and

ziram were evaluated at the Joint FAO/WHO Meeting in 1967. Thiram is a dimethyl

dithiocarbamate compound used as a contact fungicide to prevent crop damage in the field and

to protect harvested crops from damage in storage or transport (Figure 3). It is available as

dust, flowable, wettable powder, water dispersible granules, water suspension formulations,

and in mixtures with other fungicides.

Figure 3: The chemical structure of Thiram fungicide.

1.4.1.4 Benzimidazoles fungicides [5]

This class contains nitrogen heterocyclic compounds, with parent structures of

thiabendazole and/or benzimidazole. Included in this overall group are benomyl, thiabendazole,

thiophanate, thiophanate–methyl, mebendazole, carbedazim, imazalil, and fuberidazole (Figure

4). Benomyl, carbendazim, thiophanate, and thiophanate–methyl are sometimes referred to

(and classified) as benzimidazoles carbamates. Many of these fungicides inhibit mitochondrial

fumarate reductase, reduce glucose transport, and uncouple oxidative phosphorylation.

Figure 4: The chemical structure of Fuberidazole fungicide.

8

1.4.1.5 Piperazines fungicides [7]

Triforine is a piperazine derivative used as a systemic fungicide with protectant, and

curative characteristics (Figure 5). It is used for control of powdery mildew, rusts, black rot and

scab on cereals, fruit, ornamentals, and vegetables. Triforine is also active against storage

diseases of fruit and suppresses red spider mite activity. Because of its low hazard to beneficial

insects, triforine may be used in Integrated Pest Management (IPM) programs. Triforine comes

in emulsifiable concentrates, liquid seed treatments, and wettable powder formulations.

Figure 5: The chemical structure of Triforine fungicide.

1.4.1.6 Aliphatic aldehydes fungicides [8]

Several aliphatic aldehydes are used as fungicides, amongst them formaldehyde and

formaldehyde releasers. Acrolein reacts with SH groups and is formulated as a liquid (Figure 6).

Figure 6: The chemical structure of Acrolein fungicide.

1.4.1.7 Biological fungicides (Biofungicides) [3]

Biofungicides are microorganisms (microbial pesticides) and naturally occurring substances

that control diseases (biochemical pesticides) and are approved for organic production.

9

Biofungicides are widely used by organic vegetable growers to control selected foliar and

soilborne diseases of vegetable crops. Biofungicides can be applied as an independent

treatment to control a target disease.

1.5 Fludioxonil

Fludioxonil [4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3- carbonitrile] (Saphires,

Maxims, Celests, Wispects) belongs to the phenyl pyrrole family of fungicides. It was originally

developed from the natural product lead pyrrolnitrin (Figure 7), which is an antifungal

secondary metabolite produced by Pseudomonas pyrrocinia. Fludioxonil is used for the control

of a broad spectrum of foliar pathogens in vegetables, grapes, stone fruits, and other crops.

Figure 7: The chemical structure of Fludioxonil fungicide (I) and Pyrrolnitrin (II).

1.5.1 History [9]

Fludioxonil was first marketed in France as a cereal seed treatment in 1993 and

subsequently as a foliar fungicide in 1995. Pyrrolnitrin [3-chloro-4-(3-chloro-2-nitrophenyl)-1H-

pyrrole] served as the lead structure for synthesis optimization in this area. Because of its

interesting antifungal activity, pyrrolnitrin was initially developed as an antimycotic for topical

application in human medicine and also served as a lead structure for pharmaceutical research.

Pyrrolnitrin decomposes upon exposure to environmental conditions especially in light, that’s

10

why pyrrolnitrin more stable analogues were synthesized. In 1969, a Japanese patent showed

that the stability is increased by introducing CN on the pyrrole ring and electron-withdrawing

groups such as dilfuoro-1,3-dioxolane on the phenyl ring. Fenpiclonil was initially selected for

development by Ciba-Geigy (now Syngenta AG), but was superseded by Fludioxonil.

1.5.2 Toxicity [10]

Fludioxonil is not acutely toxic via oral, dermal and inhalation route (LD50>5000 mg/kg/bw,

LD50 >2000 mg/kg bw and LC50 >2.6 mg/L, respectively). It is not a skin and eye irritant.

Fludioxonil does not show any genotoxic, teratogenic and carcinogenic potential. The relevant

NOAEL (no observed adverse effect level) for chronic toxicity is 37 mg/kg bw/day. Fludioxonil is

intended to be used on wine and table grapes and on wheat. The systemic exposure to

fludioxonil formulated as WG (water dispersible granule) was estimated to be below the

established AOEL (admissible operator exposure level), as well as for the FS (flowable

concentrate for seed treatment) formulation.

1.5.3 Mode of action [11],[12]

Biological activity of pyrrolnitrin at low concentrations was demonstrated to be due to the

uncoupling of oxidative phosphorylation in Neurospora crassa and at higher concentrations due

to inhibition of electron transport both in the flavin region and through cytochrome c oxidase.

However, pyrrolnitrin leads to glycerol accumulation and stimulation of triacylglycerol synthesis

resulting in leaky cell membranes and the breakdown of biosynthetic activity followed by the

stopping of cell growth.

Moving to fludioxonil, this systemic fungicide inhibits protein kinase C in Neurospora

crassa which leads to the accumulation of glycerol in the cell and subsequent cell lysis. It also

inhibits a mitogen-activated protein (MAP) kinase in signal transduction of osmo-regulation

(glycerol synthesis). In vitro studies have shown fludioxonil to be active against all development

stages of Botrytis cinerea and Monilinia fructicola. In addition, In vivo studies showed strong

11

activity against germination, penetration and mycelia growth of Botrytis cinerea on grape

leaves at 0.1 gr fludioxonil/100lit. The active ingredient is also stated to be active against a

number of pathogens from Ascomycetes, Deuteromycetes and Basidiomycetes.

1.5.4 Ways of synthesis

The phenyl pyrroles can be prepared in a variety of ways:

1.5.4.1 Metalation using n-BuLi followed by decaboxylation [13],[14]

The lithio-2,2difluoro-1,3-benzodioxole (8), obtained from the reaction of 2,2-difluoro-1,3-

benzodioxole with n-butyl lithium, reacts with ethyl ethoxymethylene cyanoacetic ester to give

ethyl 2-cyano-2-(2,3-difluoro-1,3-benzodioxol-4-yl)-2-propenoic ester (9), which immediately

transforms with p-toluenesulfonylmethyl isocyanide (TosMIC) in the presence of sodium

hydride to produce fludioxonil (10) (Scheme 1).

Scheme 1: Metalation using n-BuLi for the synthesis of fludioxonil (10).

However, this process yields approximately 35-45% of the product due to complicated

purification. Moreover both reagents (sodium hydride and p-toluenesulphonylmethyl

isocyanide) have high susceptibility to hydrolysis associated with a high fire risk due to the

gaseous hydrogen release during hydrolysis. They can be easily decomposed at elevated

temperature and therefore they are not well suited for the technical synthesis. The use of n-

Butyl lithium is industrially disfavored. It is also very susceptible to hydrolysis, pyrophoric and

expensive to prepare. Finally, ethyl 2-cyano-2-(2,3-difluoro-1,3-benzodioxol-4-yl)-2-propenoic

ester is an inconvenient industrial product since it is manufactured through decarboxylation of

12

α-cyanocinnamic acids or their esters under rigorous conditions, while the purification process

and its isolation are complicated. Therefore, this process is not an optimal commercial solution.

1.5.4.2 Another metalation approach [15]

S. Cabiddu et al. described two competitive reactions which occur via treatment of 1,3-

benzodioxole in hexane with n-butyllithium in diethyl ether/hexane. After carbonation of the

reaction mixture, 1,3-benzodioxole-4-carbonic acid (12) is obtained in the yield of 41%. In

addition, pyrocatechol (D) and n-nonane (E) are also obtained in equimolar amounts as a result

of cleavage of the ether bonds (Scheme 2).

Scheme 2: Preparation of 1,3-benzodioxole-4-carbonic acid (12) by metalation.

The obtained carbonic acid can then be converted to aldehyde by reductive oxidation

affoding 1,3-Benzodioxole-4-carboxaldehyde, a pre-key intermediate for the synthesis of

Fludioxonil.[16] However, these two approaches as well as others have lot of disadvantages

making them an unprofitable commercially and environmentally process.

The aim of the present study is to provide alternative approaches for the preparation of

2,2-difluorobenzo[d][1,3]dioxole-4-carboxaldehyde, a fludioxonil intermediate, which are

improved from technical and economic point of view and can be applied generally.

13

1.5.4.3 Palladium-catalyzed cyanation of 4-bromo-2,2-difluorobenzo[d][1,3]dioxole with

subsequent reduction of the corresponding derivative to the target aldehyde

The present approach to 2,2-difluorobenzo[d][1,3]dioxole-4-carboxaldehyde (1) relies on

the robust palladium-catalyzed cyanation of aryl bromides of the readily accessible 4-bromo-

2,2-difluorobenzo[d][1,3]dioxole (3) with an inorganic cyanide followed by the conventional

reduction of the corresponding cyano derivative into the desired aldehyde (1) (Scheme 3).

Scheme 3: General palladium-catalyzed cyanation of 4-bromo-2,2-difluorobenzo[d][1,3]dioxole(3).

1.5.4.4 Palladium-catalyzed reductive carbonylation of 4-bromo-2, 2difluorobenzo[d][1,3]

dioxole

The present approach to 2,2-difluorobenzo[d][1,3]dioxole-4-carboxaldehyde (1) relies on

the robust palladium-catalyzed reductive carbonylation of aryl bromides, in particular, of the

readily accessible 4-bromo-2,2-difluorobenzo[d][1,3]dioxole (3), a one pot reaction yielding the

desired aldehyde (1) as shown in Scheme 4.

Scheme 4: General palladium-catalyzed reductive carbonylation of 4-bromo-2,2-

difluorobenzo[d][1,3]dioxole(3).

14

1.5.4.5 Metalation of 2,2-difluorobenzo[d][1,3]dioxole with subsequent nucleophilic formylation

using metalating reagents other than n-BuLi

The present approach to 2,2-difluorobenzo[d][1,3]dioxole-4-carboxaldehyde (1) relies on

the metalation of 2,2-difluorobenzo[d][1,3]dioxole (7) using lithium diisopropylamine(LDA) as a

safe metalating agent (Scheme 5).

Scheme 5: General palladium-catalyzed cyanation of 2,2-difluorobenzo[d][1,3]dioxole (7).

15

2. Research objectives

The objective of this study is to develop alternative synthetic approaches to the synthesis

of 2,2-difluorobenzo[d][1,3]dioxole-4-carboxaldehyde.

In particular, we will consider the following:

Palladium-catalyzed cyanation of 4-bromo-2,2-difluorobenzo[d][1,3]dioxole with

subsequent reduction of the corresponding derivative to the target aldehyde.

Palladium-catalyzed reductive carbonylation of 4-bromo-2, 2-difluorobenzo

[d][1,3]dioxole in to the target aldehyde.

Metalation of 2,2-difluorobenzo[d][1,3]dioxole with subsequent nucleophilic

formylation using metalating reagents other than n-BuLi.

16

3. Methodology

3.1 Instruments

Characterization of the products and intermediates was carried out by means of NMR and

GC analysis.

NMR spectra were recorded using a Bruker instrument operating at 400 MHz or 500

MHz for protons. Chemical shifts were reported in ppm relative to the residual

deuterated solvent or the internal standard tetramethylsilane.

GC chromatography was recorded using GC Agilent 7820A as 1 mircolitre was injected

to the injector at 250 . The initial temperature of the oven is 80 then it is heated to

250 with a flow of 15 /min.

3.2 Materials and methods

All reagents were purchased from the usual suppliers and used without further

purification. All reagents were weighed and handled in air.

17

4. Results and Discussion

4.1 Palladium-catalyzed cyanation of 4-bromo-2,2-difluorobenzo[d][1,3]dioxole with

subsequent reduction of the corresponding derivative to the target aldehyde

4.1.1 Background

The classical approach for the preparation of benzonitrile derivatives, known as

Rosenmund-von Braun reaction, is a powerful tool for cyanation of simple aryl halides.

However, this strategy usually requires a stoichiometric amount of copper cyanide. It also

requires harsh reaction conditions (e.g. high reaction temperatures) and extra precautions

during the isolation of the final product.[17] Since the discovery of transition metal-catalyzed

cross-coupling reactions, a great deal of interest has been devoted to the development of a

practical catalytic version of this transformation.

Takagi and coworkers reported the first palladium-catalyzed cyanation reaction.[18]

Moderate to high yields of benzonitrile derivatives were isolated when aryl iodides were

introduced. Aryl chlorides and bromides were found to be essentially inactive. Moreover, the

reaction proceeded under high temperatures (i.e. >150 oC) and can be considered energetically

disfavored. Beller and Weissman showed that K4[Fe(CN)6], a non-toxic food additive, could

serve as a cyanide source for palladium-catalyzed coupling reactions.[19] Aqueous system using

K4[Fe(CN)6]•3H2O with a phase transfer catalyst have been reported, yet it still require

temperatures higher than 140 °C.[20] Significant advances were reported by Huang and

Kwongwho applied the biphasic system concept to enable cyanide transfer from

K4[Fe(CN)6]•3H2O under milder conditions.[21] Despite the variety of handful methods that

mainly targeted simple aryl halides, heteroaryl halides however, have been rarely investigated.

We thus felt the need to develop a powerful tool that can solve the problems related to these

challenging motifs by developing the palladium-catalyzed cyanation system which proved to be

applicable to a variety of aryl halides with low catalyst loading and under mild conditions.

18

4.1.2 Mechanism [22]

Similarly to most of the known cross-coupling reactions, the plausible mechanism of the

reaction includes several common steps: i) Initially, a low-valent palladium complex Pd(0) reacts

with the aryl halide by oxidative addition generating an aryl-palladium (II) halide species. [23] The

rate of this step is rationalized to the reactivity of carbon-halogen bond (i.e. I>Br>>Cl). ii) Ligand

exchange step results the halogen-cyanide exchange leading to the formation of new aryl

cyano-palladium species. iii) Finally, this complex undergoes reductive elimination to form the

coupling product that contains a new carbon-carbon bond while regenerating the Pd(0)

catalyst.

The main problem associated with this particular transformation is inhibition of the

catalytic cycle. Exposure of palladium species to high concentrations of cyanide ions can

generate inactive palladium cyanide species which cannot be easily reduced to catalytically

active Pd(0) compounds. This problem, namely the problem of slow cyanide delivery, can be

successfully solved by a careful choice of reaction solvents and cyanide sources. Thus,

introduction of KCN, CuCN, or Zn(CN)2 in nonpolar solvents such as toluene or xylene was found

to be beneficial in palladium-catalyzed transformations. The recently suggested employment of

the masked cyanides such as TMS-CN or acetone cyanohydrin to control the dosage of the

inhibiting species appears as an even more elegant overcoming of this drawback.

19

Our group reported the employment of nontoxic cyanide sources such as potassium

hexacyanoferrate K4Fe(CN)6 that makes the palladium-catalyzed cyanation of aryl halides an

attractive laboratory method.[24] The method is based on the use of a catalyst derived from

Pd(OAc)2 and 1,8-bis-diisopropylphosphinotriptycene (1) as a ligand (Scheme 6). Other wide

chelating ligands such as 1,5-bis-diphenylphosphinopentane, 1,6-bis-diphenylphosphinohexane

and 1,7-bis-diphenylphosphinoheptane (all three are commercially available) showed

comparable reactivity in some cases.

Scheme 6: Palladium-catalyzed cyanation of aryl halides using (K4Fe(CN)6) as a cyanide source.

4.1.3 Specific aim

Synthesis of the key 2,2-difluorobenzo[d][1,3]dioxole-4-carboxaldehyde (1) intermediate is

suggested in two steps: i) Regio- and chemoselective conversion of 4-bromo-2,2-

difluorobenzo[d][1,3]dioxole (3) into 4-cyano-2,2-difluorobenzo[d][1,3]dioxole (2) with ii)

reduction of the cyano derivative as shown in Scheme 7.

Scheme 7: General palladium-catalyzed cyanation of 4-bromo-2,2-difluorobenzo[d][1,3]dioxole(3).

20

The synthetic approach toward 4-bromo-2,2-difluorobenzo[d][1,3]dioxole (3) has already

been adapted by Makhteshim-Agan. Therefore, the palladium-catalyzed cyanation of toward 4-

bromobenzo [1,3]dioxole (4) is a natural starting point.

Reduction of cyano moiety directly to aldehyde is a well-established transformation and

can be performed in high yield by the reduction with DIBAL-H (requires -20 to 0 oC cooling and

inert atmosphere, but in principle, can be performed even under flow reactor conditions, see

for example, Tetrahedron Lett, 2011, 6058-6060) or, alternatively, via sodium

hypophosphite/AcOH reduction in the presence of Raney Ni catalyst (see for example, J. Chem.

Soc. 1962, 3961-3964).[25],[26]

We optimized the reaction condition simultaneously for (3) and (4) (Figure 8) because, in

principle, fluorination of the methylene bridge may be performed post-cyanation as shown in

Scheme 8 below:

Scheme 8: General palladium-catalyzed cyanation of 4-bromobenzo[d][1,3]dioxole(4) with subsequent

reduction of the corresponding derivative to the target aldehyde (1).

This could be a more profitable approach as fluorinated products are usually more costly.

Therefore, fluorination at the later stage will reduce the fluorinated product cost, and

consequently, the overall process expenses. Fortunately, (5) is supposed to be stable under

radical chlorination/HF conditions.

21

4.1.4 Results

Figure 8: The chemical structure of 4-bromo-2,2-difluorobenzo[d][1,3]dioxole (3) and 4-

bromobenzo [1,3]dioxole (4).

4.1.4.1 Cyanide source

Our initial investigation was based on previous study developed in our group which showed

that K4Fe(CN)6 is an efficient source for cyanide ions (Scheme 6).[24] We decided to stick to this

cyanide source because unlike other metal cyanides, this compound is nontoxic and even used

as a food additive.

4.1.4.2 Ligands’ effect

Ligands can affect the reaction as they play an important role in oxidative addition and

reductive elimination steps of the catalytic cycle. Ligands with higher electron density can

accelerate the oxidative addition On the other hand; however, steric properties of the ligands

can also affect the catalyst stability. Since ligands protect the Pd center from bonding CN ions.

Therefore, different electron rich ligands were tested as shown in Table 2. The highest

conversion was achieved using Xantphos ligand.

22

Ligand Conversion

DPPF

Low conversion*

Dave Phos

Low conversion*

BINAP

Low conversion*

Xantphos

100%

Table 2: ligand optimization for the cyanation of 4-bromobenzo [1,3]dioxole(4).

*Both reactant and product were obtained.

4.1.4.3 Solvents and bases

Bases also play a role in the reaction as they affect the rate of the anion exchange in the

catalytic cycle. Table 3 shows the effect of different types of bases on the catalytic reaction.

Potassium phosphate tribasic afforded a full conversion compared to Cesium and potassium

carbonate.

23

Base Conversion

Cs₂CO₃ Low conversion

K₂CO₃ Low conversion

K₃PO₄ 100%

Table 3: bases optimization for the cyanation of 4-bromobenzo [1,3]dioxole(4).

Finally, different solvents were tested: dry DMF, dry NMP, DMSO and xylene. The highest

conversion was achieved using dry DMF.

4.1.4.4 Optimized protocol

Based on the above mentioned results, the optimized procedure for 4-cyanobenzo

[1,3]dioxole (5) is developed (Scheme 9):

Scheme 9: Optimized protocol for palladium-catalyzed cyanation of 4-bromobenzo [1,3]dioxole (4).

Pd(OAc)2 (2 mol%) and Xantphos (3 mol%) were added to a dry flask under nitrogen followed by

the addition of DMF (3 mL). The mixture was allowed to stir for 5-10 minutes. Then, potassium

ferrocyanide (0.3 equivalents) and potassium phosphate (2 equivalents) were added to the flask

and the mixture was stirred for 10 minutes. The reactant (2 mmol) was injected to the mixture

and the flask was sealed and heated at 100 for 24 hours resulting in full conversion of the

starting material into the product (over 98% yield according to GC). The reaction mixture was

diluted with ethyl acetate and washed several times with water to remove DMF from the

organic phase. After drying over anhydrous MgSO4, solvents were evaporated on vacuum and

the product was separated in 78% isolated yield using column chromatography (10% ethyl

24

acetate in hexane). The desired product (5) was obtained as an off-white solid and was

characterized by 1H-NMR, 13C-NMR analysis and GC chromatography. 13C-NMR shows a peak at

δ = 114.60 ppm due to the presence of the cyanide.

25

4.1.4.5 Cyanation of 4-bromo-2,2-difluorobenzo[d][1,3]dioxole

Unfortunately, the application of these optimized conditions to substrate (3) led to the

formation of the desired cyanid in low yield due to the formation of by-produced amide as

shown in Scheme 11.

Scheme 11: Palladium-catalyzed cyanation of of 4-bromo-2,2-difluorobenzo[d][1,3]dioxole (3)

according to the optimized protocol.

The amide (A), apparently, originates from the desired product (2) by hydrolysis in

presence of water. The only source of water in this reaction is potassium phosphate tribasic, so

we scanned different amounts of the base. The highest yields of the reaction were achieved

using 0.5 equivalents of potassium phosphate tribasic instead of 2 equivalents as was found

during the optimization studies. Increasing the reaction temperature to 140 also helped to

achieve better yields.

Thus the final protocol for the Pd-catalyzed cyanation of the 4-cyano-2,2-difluorobenzo

[d][1,3]dioxole (2)(Scheme 12):

Scheme 12: Final protocol for palladium-catalyzed cyanation of of 4-bromo-2,2-

difluorobenzo[d][1,3]dioxole (3).

26

Pd(OAc)2 (2 mol%) and Xantphos (3 mol%) were added to a dry flask under nitrogen followed by

the addition of DMF (3 mL). The mixture was allowed to stir for 5-10 minutes. Then, potassium

ferrocyanide (0.3 equivalents) and potassium phosphate (0.5 equivalents) were added to the

flask and the mixture was stirred for 10 minutes. The reactant (2 mmol) was injected to the

mixture and the flask was sealed and heated at 140 for 24 hours resulting in full conversion

of the starting material into the product (over 98% yield according to GC). The reaction mixture

was diluted with ethyl acetate and washed several times with water to remove DMF from the

organic phase. After drying over anhydrous MgSO4, solvents were evaporated on vacuum and

the product was separated in 91% isolated yield using column chromatography (10% ethyl

acetate in hexane).The desired product (2) was obtained as an off-white solid and was

characterized by 1H-NMR, 13C-HMR analysis and GC chromatography. 13C-NMR shows a peak at

δ = 112.82 ppm due to the presence of the cyanide.

27

4.2 Palladium-catalyzed reductive carbonylation of 4-bromo-2, 2difluorobenzo[d][1,3]

dioxole.

4.2.1 Background [23],[29]

The palladium-catalyzed reductive carbonylation of aryl and vinyl halides to aromatic or

α,β-unsaturated aldehydes was first described more than 30 years ago by Richard Heck

(Scheme 13).[27]

Scheme 13: General palladium-catalysed reductive carbonylation reaction by Heck.

However, the conditions established by Heck were not readily applicable to the industrial

operation, since they involved high pressure (greater than 80 bar of 1:1 CO:H2). The other set of

conditions included PdX2(PPh3)2 (X: Cl, Br, I) as catalyst at ca. 1% loading, with aromatic

hydrocarbons as a solvent and tertiary amine as base under 80-150 °C, was better suited for

large-scale implementation. Therefore this reaction has attracted interest with the aim of

overcoming the pressure limitation.

Since palladium reacts readily with carbon monoxide at low pressure, it was evident that a

key change was required to provide more effective hydride donor. This was demonstrated by

the work of Stille using Bu3SnH.[28] He reported the conversion of aryl iodides, bromides, and

triflates to aldehydes under mild conditions: 1-3 bar of CO and 50 °C with Pd(PPh3)4 as catalyst.

However, direct reduction of the aryl halide to the corresponding arene often proved to be a

side reaction, requiring control by slow addition of the tin reagent and an increase in the CO

pressure. He noted that electron-donating or -withdrawing substituents on the aryl halide had

no effect on the reaction, while steric effects were more significant. Product contamination

with tin residues is often an issue for applications in pharmaceutical synthesis; therefore, other

investigators continued to seek alternative hydride sources.

28

In 2007, Beller and colleagues reported the use of palladium/di(1-adamantyl)-n-

butylphosphine (cataCXium A) as an excellent catalyst for the synthesis of aromatic and

heteroaromatic aldehydes, as well as α,β-unsaturated aldehydes (Scheme 14).[29] The ligand

di-1- adamantyl-n-butylphosphine formed highly active catalyst species, yet insensitive to air

and moisture. Due to its superior performance compared with other palladium catalysts, the

system can be employed for industrial production large scale.

Scheme 14: General palladium-catalysed reductive carbonylation reaction by Beller.

4.2.2 Mechanism [23]

As in cyanation, the plausible mechanism of this reaction includes several common

steps: i) Initially, a low-valent palladium complex Pd(0) reacts with the aryl halide by oxidative

addition generating an aryl-palladium (II) halide species. [23] The rate of this step is rationalized

to the reactivity of carbon-halogen bond (i.e. I>Br>>Cl). ii) CO insertion step which introduces

the carbonyl ligand into the coordination sphere forming a carbamate or carboxylate group.

29

This occurs very rapidly for simple phenyl complexes, but it is the interaction with carbon

monoxide that accounts for the high sensitivity of these reactions to steric features of the

substrate. iii) Finally, the complex undergoes reductive elimination to form the coupling

product that contains a new carbon-carbon bond while regenerating the Pd(0) catalyst. It

should be mentioned that carbonylation reaction is usually very sensitive to the concentration

of CO. As low concentration of CO hardly forms active species, high concentration could

dramatically slow the reaction rate since all the active sites are saturated with CO ligands.

4.2.3 Specific aim

Synthesis of the key 2,2-difluorobenzo[d][1,3]dioxole-4-carboxaldehyde (1) intermediate is

suggested in a one pot reaction: reductive carbonylation (Scheme15).

Scheme 15: General palladium-catalysed reductive carbonylation of 4-bromo-2,2-

difluorobenzo[d][1,3]dioxole (3).

Same as in cyanation reaction we optimized the reaction condition simultaneously for (3)

and (4).

4.2.4 Results

4.2.4.1 Ligands’ effect

Ligands can affect the reaction as they play an important role in oxidative addition and

reductive elimination steps of the catalytic cycle. Different ligands were tested as shown in

Table 4. The highest conversion was achieved using Ad₂PBu ligand.

30

Along with the desired aldehyde, 1,3 benzodioxole (11) was obtained as a by-product in a

small yield resulting from reductive dehalogenation.

Ligand Conversion

Xantphos

Low conversion*

Ad2PCl

Low conversion*

BINAP

Low conversion*

X-Phos

Low conversion*

P(o-tol)3

Low conversion*

31

Ad2PBu

100%

Table 4: Ligand optimization for the reductive carbonylation of 4-bromobenzo [1,3]dioxole(4).

* Both reactant and product were obtained.

4.2.4.2 Catalyst effect

As different sources of transition metals can behave differently, different catalysts were

tested. The best result was obtained using 5mol% Pd(OAc)2 as shown in Table 5.

Catalyst Conversion

Pd(dba)₂ Low conversion*

PdCl₂(CH₃CN)₂ Low conversion*

Pd(OAc)2 100%

Table 5: catalyst optimization for the reductive carbonylation of 4-bromobenzo [1,3]dioxole(4).

*Both reactant and product were obtained.

4.2.4.3 Solvents and bases

Different bases were tested as well. Table 6 shows the effect of bases on the reaction rate.

TMEDA found to have a huge impact on the reaction compared to DIPEA and triethylamine as it

was the only base that yielded in a full conversion.

32

Base Conversion

DIPEA Low conversion

Et3N Low conversion

TMEDA 100%

Table 6: bases optimization for the reductive carbonylation of 4-bromobenzo [1,3]dioxole(4).

Finally, different solvents were tested: toluene, benzene, dimethoxy ethane (DME) and

acetonitrile. The highest conversion was achieved using toluene.

4.2.4.4 Optimized protocol

Based on these results, the optimized procedure for 1,3-Benzodioxole-4-carboxaldehyde

(6) is developed (Scheme 16):

Scheme 16: Optimized protocol for palladium-catalyzed reductive carbonylation of 4-bromobenzo

[1,3]dioxole(4).

Palladium acetate (5 mol%) and di(1-adamantyl)-n-butylphosphine (10 mol%) were added to

dry toluene (3mL) and stirred for 5-10 minutes in the Parr hydrogenation bomb under nitrogen.

The base (0.75 eq.) and the reactant (2 gr) were injected to the mixture and the flask was

33

pressurized with 1:1 syngas (100 psi), and heated at 100 for 24 hours resulting in full

conversion of the starting material into the product. After the reaction mixture was cooled to

room temperature, the solvent was evaporated on vacuum and the product was separated in

91% isolated yield using column chromatography (10% ethyl acetate in hexane).The desired

product (6) was obtained as a brown-orange solid and was characterized by 1H-NMR, 13C-NMR

analysis and GC chromatography. 1H-NMR shows a peak at δ= 9.98 ppm due to the presence of

the aldehyde. 13C-NMR also shows a peak at δ= 187.719 ppm referred also to the aldehyde.

34

4.2.4.5 Reductive carbonylation of 4-bromo-2,2-difluorobenzo[d][1,3]dioxole

Unfortunately, application of the reaction conditions with or without alternation to 4-

bromo-2,2-difluorobenzo[d][1,3]dioxole (4) led to low yield of the desired product due to

decomposition of the starting material, apparently via cleavage of the fluorinated dioxole

moiety as shown in Scheme 17.

Scheme 17: Palladium-catalyzed reductive carbonylation of 4-bromo-2,2-

difluorobenzo[d][1,3]dioxole(3).

4.3 Metalation of 2,2-difluorobenzo[d][1,3]dioxole with subsequent nucleophilic formylation

using metalating reagents other than n-BuLi

4.3.1 Background [30]

2,2-difluorobenzo[d][1,3]dioxole-4-carbaldehyde (1) was synthesized using traditional

lithiation strategy (Scheme 18). The directed ortho metalation (DoM) reaction comprises the

deprotonation of an ortho-position to a heteroatom containing directed metalation group

(DMG) by a strong base, normally an alkyllithium reagent, leading to an ortho-lithiated species.

These species, upon treatment with electrophilic reagents like DMF can afford the desired

aldehyde. Despite the simplicity of this strategy, large-scale reactions are inapplicable, and

successful adaption of this protocol to the industrial-scale Fludoxonil synthesis by Makhteshim-

Agan requires replacement of these unsafe, synthetically unreliable and uneconomical reagents

(alkyl lithium).

35

Scheme 18: The traditional lithiation strategy for the synthesis of 2,2-difluorobenzo[d][1,3]dioxole-

4-carbaldehyde(1).

Alternative solution is replacing n-BuLi in the original metalation of 2,2-difluorobenzo

[d][1,3] dioxole by the commercially available and cheap LDA. 2,2-difluorobenzo[d][1,3] dioxole

is lithiated at the position 4 via proton abstraction by lithium diisopropylamine (LDA is a non-

nucleophilic base), then DMF is added forming the desired aldehyde in a one pot reaction

(Scheme 19).

Scheme 19: General metalation of 2,2-difluorobenzo[d][1,3]dioxole (7).

36

4.3.2 Mechanism [30]

Scheme 20: Mechanism of metalation of 2,2-difluorobenzo[d][1,3]dioxole (7).

Although undoubtedly simple, the DoM process may be viewed as a four-step sequence.

The first step is deprotonation of the ortho hydrogen to give the coordinated ortho-lithiated

species (8). This hydrogen is highly acidic due to the spatial proximity to the electron-

withdrawing oxygen and fluoro groups which indicates the selectivity of this step. Then, the

othro-lithiated specie attacks the electrophilic dimethyl formamide (DMF) resulting in an

intermediate product (B). In addition of water aminal (C) is obtained which collapses to the

desired aldehyde (1) by releasing dimethylammonium (Scheme 20).

4.3.3 Specific aim

Replacing n-BuLi in the original metalation of 2,2-difluorobenzo[d][1,3]dioxole by the

commercially available and cheap LDA followed by the nucleophilic formylation of the

metalated intermediate with DMF (Scheme 21).

Scheme 21: General metalation of 2,2-difluorobenzo[d][1,3]dioxole (7).

37

4.3.4 Results

4.3.4.1 LDA alternatives

LDA can be prepared by a simple reaction of diisopropylamine with 1.1 eq. of n-BuLi in dry

THF at -78 oC as shown in Scheme 22 below.[31]

Scheme 22: Preparation of LDA using n-BuLi.

We tried replacing n-BuLi by LiH but the reaction didn’t work at -78 oC. Moving to

commercial LDA (CAS# 4111-54-0), the aldehyde was obtained at -78 oC but not in a full

conversion. We also tried to replace LDA by LiH or KOtBu as shown in Scheme 23. The mixture

was allowed to stir for 3 hrs under nitrogen at -78 oC. Then 0.15 ml dry DMF was added and left

to stir overnight. The best result was obtained using LDA.

Scheme 23: Replacing LDA by LiH or KOtBu.

4.3.4.2 Temperatures and solvents

Different temperatures were tested: -78 oC (using acetone/dry ice bath), -40 oC (using

acetonitrile/dry ice bath), -20 oC (using CCl4/dry ice bath) and -15 oC (using ethylene glycol/dry

ice bath). All of the above mentioned temperatures gave the desired product in high yield.

38

Finally, different solvents were tested at -15 oC: THF, MeTHF, MTBE and cyclopentylmethyl

ether. High conversions and yields of the desired aldehyde were obtained.

4.3.4.3 Optimized protocol

Based on the above mentioned results, the optimized procedure for 2,2-

difluorobenzo[d][1,3]dioxole-4-carboxaldehyde (1) is developed (Scheme 24):

Scheme 24: Optimized protocol for metalation of 2,2-difluorobenzo[d][1,3]dioxole (7).

0.375ml diisopropylamine (2.68mmol) and 2 ml n-BuLi (1.1 eq.) were stirred under nitrogen in

10 ml dry THF* for 30 min at -15 oC. The reactant (0.2 ml) was injected to the mixture and was

allowed to stir for 3 hrs under nitrogen at -15 oC. Finally dry DMF (0.15 ml) was added and the

mixture was allowed to stir overnight resulting in full conversion of the starting material into

the product (over 94% yield according to GC). The reaction mixture was diluted with DCM and

washed several times with water to remove DMF from the organic phase. After drying over

anhydrous MgSO4, solvents were evaporated on vacuum and the product was separated in 90%

yield.

The desired product (1) was obtained as yellow liquid and was characterized by 1H-NMR,

13C-NMR analysis and GC chromatography. 1H-NMR shows a peak at δ= 10.075 ppm due to the

presence of the aldehyde. 13C-NMR also shows a peak at δ= 186.0633 ppm also referred to the

aldehyde.

*Different solvents were tested: dry THF, dry MeTHF, MTBE and cyclo pentylmethyl ether.

39

40

4.4 Conclusions

We targeted three alternative catalytic approaches to the synthesis of 2,2-difluorobenzo

[d][1,3]dioxole-4-carboxaldehyde (1): i) Palladium-catalyzed cyanation of 4-bromo-2,2-

difluorobenzo[d][1,3]dioxole with subsequent reduction of the corresponding derivative to the

target aldehyde, ii) Palladium-catalyzed reductive carbonylation of 4-bromo-2,2-

difluorobenzo[d][1,3]dioxole and iii) Metalation of 2,2-difluorobenzo[d][1,3]dioxole with

subsequent nucleophilic formylation using metalating reagents other than n-BuLi.

The optimization of the reaction conditions of the palladium-catalyzed cyanation approach

led to the development of the efficient two step synthesis of the target aldehyde in overall 69%

isolated yield (after two steps). The reliable and reproducible cyanation step and the use of

non-toxic reagents make this approach more preferred than the classical cyanation reaction.

However, it’s still a two-step protocol.

An alternative one-step approach is the palladium-catalyzed reductive carbonylation.

Optimization of the reaction conditions led to the successful one-step synthesis of the aldehyde

from non-fluorinated precursor, nevertheless, reductive carbonylation of 4-bromo-2,2-

difluorobenzo[d][1,3]dioxole (3) led to low yield of the desired product due to decomposition of

the starting material, apparently via cleavage of the fluorinated dioxole moiety.

The last non-catalytic approach is metalation using LDA. Optimization of the reaction

conditions led to the desired aldehyde in a one pot reaction in overall 90% isolated yield. The

commercially available and cheap LDA makes this approach industrially desired.

41

5. Experimental section

5.1 General Considerations

All reagents were purchased from the usual suppliers and used without further

purification. All reagents were weighted and handled in air. Yields refer to isolated compounds

greater than 95% purity as determined proton Nuclear Magnetic Resonance spectroscopy (1H-

NMR) analysis. 1H-, 13C-NMR spectra were recorded on a Bruker 400 or 500 MHz instruments

with chemical shifts reported in ppm relative to the residual deuterated solvent or the internal

standard tetramethylsilane.

5.2 Preparation of 4-cyanobenzo [1,3]dioxole (5)

Pd(OAc)2 (2 mol%) and Xantphos (3 mol%) were added to a dry flask under nitrogen followed by

the addition of DMF (3 ml). The mixture was allowed to stir for 5-10 minutes. Then, potassium

ferrocyanide (0.3 equivalents) and potassium phosphate (2 equivalents) were added to the flask

and the mixture was stirred for 10 minutes. The reactant (2 mmol) was injected to the mixture

and the flask was sealed and heated at 100 for 24 hours resulting in full conversion of the

starting material into the product (over 98% yield according to GC). The reaction mixture was

diluted with ethyl acetate and washed several times with water to remove DMF from the

organic phase. After drying over anhydrous MgSO4, solvents were evaporated on vacuum and

the product was separated in 78% isolated yield using column chromatography (10% ethyl

acetate in hexane). The desired product (5) was obtained as an off-white solid.

1H-NMR (CDCl3), δ: 6.1379 (s, 2H), 6.9 (t, 1H, J=8Hz), 7.03 (dd, 2H, J=8Hz, J=8Hz). 13C-NMR

(CDCl3), δ: 93.623, 102.495, 112.576, 114.559, 122.354, 123.869, 148.35, 150.437.

42

5.3 Preparation of the 4-cyano-2,2-difluorobenzo [d][1,3]dioxole (2)

Pd(OAc)2 (2 mol%) and Xantphos (3 mol%) were added to a dry flask under nitrogen followed by

the addition of DMF (3 ml). The mixture was allowed to stir for 5-10 minutes. Then, potassium

ferrocyanide (0.3 equivalents) and potassium phosphate (0.5 equivalents) were added to the

flask and the mixture was stirred for 10 minutes. The reactant (2 mmol) was injected to the

mixture and the flask was sealed and heated at 140 for 24 hours resulting in full conversion

of the starting material into the product (over 98% yield according to GC). The reaction mixture

was diluted with ethyl acetate and washed several times with water to remove DMF from the

organic phase. After drying over anhydrous MgSO4, solvents were evaporated on vacuum and

the product was separated in 91% isolated yield using column chromatography (10% ethyl

acetate in hexane).The desired product (2) was obtained as an off-white solid.

1H-NMR (CDCl3), δ: 7.22 (t, 1H, J=8Hz), 7.3479 (dd, 2H, J=8Hz, J=8Hz). 13C-NMR (CDCl3), δ:

95.3498, 112.8279, 114.0269, 124.376, 126.5319, 131.5546, 144.195, 145.2874.

5.4 Preparation of 1,3-Benzodioxole-4-carboxaldehyde (6)

Palladium acetate (5 mol%) and di(1-adamantyl)-n-butylphosphine (10 mol%) were added to

dry toluene (3 ml) and stirred for 5-10 minutes in the Parr hydrogenation bomb under nitrogen.

The base (0.75 eq.) and the reactant (2 gr) were injected to the mixture and the flask was

pressurized with 1:1 syngas (100 psi), and heated at 100 for 24 hours resulting in full

conversion of the starting material into the product. After the reaction mixture was cooled to

43

room temperature, the solvent was evaporated on vacuum and the product was separated in

91% isolated yield using column chromatography (10% ethyl acetate in hexane).The desired

product (6) was obtained as a brown-orange solid.

1H-NMR (CDCl3), δ: 5.999 (s, 2H), 6.7951 (t, 1H, J=8Hz), 6.8871 (d, 1H, J=7Hz), 7.143 (d, 1H,

J=8Hz). 13C-NMR (CDCl3), δ: 102.56, 113.256, 119.261, 120.748, 121.624, 148.805, 149.216,

187.719.

5.5 Preparation of 2,2-difluorobenzo[d][1,3]dioxole-4-carboxaldehyde (1)

0.375ml diisopropylamine (2.68mmol) and 2 ml n-BuLi (1.1 eq.) were stirred under nitrogen

in 10 ml dry THF* for 30mins at -15 oC. The reactant (0.2 ml) was injected to the mixture and

was allowed to stir for 3 hrs under nitrogen at -15 oC. Finally dry DMF (0.15 ml) was added and

the mixture was allowed to stir overnight resulting in full conversion of the starting material

into the product (over 94% yield according to GC). The reaction mixture was diluted with DCM

and washed several times with water to remove DMF from the organic phase. After drying over

anhydrous MgSO4, solvents were evaporated on vacuum and the product was separated in 90%

yield.

The desired product (1) was obtained as yellow liquid.

*Different solvents are also possible: dry THF, dry MeTHF, MTBE and cyclo pentylmethyl ether.

1H-NMR (CDCl3), δ: 7.1653 (t, 1H, J=8Hz), 7.2505 (d, 1H, J=8Hz), 7.484 (d, 1H, J=8Hz), 10.075 (s,

1H). 13C-NMR (CDCl3), δ: 114.5989, 119.7987, 123.276, 123.9171, 132.0132 (t, J=257Hz),

143.8121, 144.4726, 186.0633.

44

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