SYNTHETIC AND BIOLOGICAL STUDIES ON SELECTED HETEROCYCLIC SYSTEMS
Submitted to Goa university for the Award of the Degree of DOCTOR OF PHILOSOPHY
In CHEMISTRY
By
Mr. MANJUNATH BHIMARAY CHANNAPUR M. Sc.
Under the Guidance of Dr. Ashok. S. Shyadligeri
Syngenta Research and Technology Centre Santa Monica Works,
Corlim-Ilhas-Goa
GOA UNIVERSITY Taleigao Plateau, Goa 403 206
INDIA AUGUST 2019
Goa 403 110 India
CERTIFICATE
This is to certify that thesis entitled, “SYNTHETIC AND BIOLOGICAL STUDIES ON SELECTED HETEROCYCLIC SYSTEMS” submitted by Mr. Manjunath B.
Channapur to the Goa University for the award of the degree of Doctor of Philosophy in Chemistry is a record of research work carried out by the candidate during the period of study under my supervision and that it has not previously formed the basis for the award of any degree or diploma or other similar titles.
I further certify that this thesis or part thereof has not previously formed the basis for the award of any degree, diploma, associateship, fellowship etc. of any other University or Institution.
Goa University Dr. Ashok Shyadligeri
August 2019
Research Guide
DECLARATION
I hereby declare that the work embodied in the thesis entitled “Synthetic and Biological Studies on Selected Heterocyclic Systems” is the result of investigations carried out by me under the guidance of Dr. Ashok S. Shyadligeri at Syngenta Biosciences Pvt. Ltd. Goa.
This research work has not previously formed the basis for the award of any degree or diploma or other similar titles.
In keeping with the general practice of reporting scientific observations, due acknowledgement has been made wherever the work described is based on the findings of other investigators.
Goa University Mr. Manjunath B. Channapur
August, 2019 Ph.D. Student
School of Chemical Sciences Goa University
ACKNOWLEDGEMENT
The process of achieving a doctorate and completing a dissertation (thesis) is long and onerous process and couldn’t be done single handedly.
I am the luckiest person to become the first student of a magnificent and down to earth person my guide Dr. Ashok Shyadligeri for his continuous support and encouragement during my Ph.D. study. I am at loss of words to convey my deep sense of gratitude towards him. His confidence, full of energy and hard work changed me a lot as an efficient person. He has been my constant source of inspiration because of his unique style of teaching. I am thankful for the patience he has shown during difficult times and for the support of entire course of my work. Due to his invariable help and support I could achieve my research career. The association with my guide for my research carrier will remain memorable forever throughout my entire life.
I would like to extent my thanks to Dr. Roger G. Hall Group Leader, Syngenta Crop Protection, Muenchwilen AG, Schaffhauerstrasse, Switzerland for being my mentor. He has been pillar of strength throughout the work and I have been benefitted considerably (profoundly) from his wealth of experience and deep knowledge on numerous occasions and provided me with a great learning experience. My thanks are also due to my research co guide Dr. Sitaram Pal for extending his support.
I am extremely thankful to the Syngenta Biosciences Private Limited, Santa Monica Works, Corlim, Ilhas, Goa, India for the financial support and Goa University, Taleigao Plateau, Goa for giving me this opportunity.
I am grateful to Dr. Bhanu Manjunath (Director of SBPL) and Dr. Robert Haessig (former Head Global P&T Switzerland) for their kind support and providing the necessary infrastructures to carry out my research work
I sincerely acknowledge my subject expert Dr. Surendra Harkal for his reviews and constructive comments during my Ph.D. tenure.
My humble thanks also goes to Dr. Bidhan Shinkre for incentive and valuable suggestions in my work. He has also helped me during the time of thesis correction and research publications.
I thank Dr. Sudhindra Deshpande for analytical support during the Ph.D. programme. The work could not be possible to carry out without the timely help from Mr. Shrikant Shete, Mr. Pankaj Chowdhury, Mr. Manish Parab, Mr. Gopal Khure, and Mr. Laxman Alvae.
I wish to express my gratitude to my PhD lab mate Mr. Subhaskar Panga, Dr. Prashantha Kamath and Dr. Indira Sen supporting me during my thesis preparation.
I would like to extent my thank you to Dr. Girish Rawal, Dr. Mangala Phadte, Dr. Sujit Ghorai, Dr. Vijayagopal, Dr. Sudhindra Deshpande, Dr. Ifat Bilal, Dr. Atul Mahajan, and Dr. Ravi Sonawane for teaching different courses during my course work. I thank Dr.
Rajendra Hosmani and Mr. Ravi Kiran for their suggestions and encouragement and all my departmental (SSG/RSMC) and SBPL colleagues for their support and interest shown by them in the progress of my work.
I wish to thank all Ph.D. lab mates Mrs. Vanitha Acharya, Mr. Sunil Chakve, Mr. Raghu, Mr. Mahesh Kalbagh, Mr. Damodar Karthuri, Mr. Mayukh Dasgupta Dr. Tarak Nath Gowala, Dr. Sanjib Mal and Dr. Swarendu Sasmal for their cooperation, fruitful discussions during group meetings and generous help throughout my research period.
I am profoundly grateful to teachers, Prof. B. R. Srinivasan, Prof. S. G. Tilve, Prof. V. S.
Nadkarni, and Dr. V. M. S Verenkar for their support and guidance during my Ph.D.
tenure. Also I wish to express my earnest gratitude to Dr. Gopakumar (Librarian, Goa University) for his support. I thank Dr. Mahesh Majik, Dr. Sandesh Bugde (present faculty member) for assistance and help in editing thesis. Dr. Durga, Dr. Mayuri and Ms. Rita for their help and support.
I want to express my heartfelt gratitude to my parents Mr. Bhimaray Channapur and Mrs. Sharada Channapur for raising me with love, affection, good moral values and they have always been my inspiration and pillar of support. I will be always grateful to them for all the patience, sacrifice they have made to help me achieve my goals. I am at loss of words to express.
I wish to thank you to all my dearest friends and family who have helped and guided me over the entire course of my education your contributions have played a important role to my success my special thanks goes to my brother Mr. Anandkumar Channapur for always being by my side during my delicate and flexible times. I owe my deepest
acknowledgement to my parent’s in-laws Mr. Ramachandra Bhosale and Mrs. Surekha Bhosale for their encouragement, care and love.
I thank my better half Mrs. Rashmi Channapur and my two angel’s (beloved daughters) Abhina and Aadhya for their prayers and love. I thank all my relatives who have been very supportive in all endeavors.
Finally with silent words I thank the all mighty for granting me good health and strength needed at every stage of my life.
Mr. Manjunath Channapur
Dedicated To My
Beloved Parents
General Remarks i
Abbreviations ii
Abstract of thesis vi
Publications and conferences xi
CHAPTER 1: SYNTHESIS OF 5-HALO-6-TRIFLUOROMETHYLPYRIDINE-3-
CARBONITRILES AND -CARBOXYLIC ACIDS 1-122
1.1. General introduction 1
1.2. Section I: Fluorine in organic chemistry 3
1.2.1. Introduction 3
1.2.2. Occurrence or discovery 4
1.2.3. Fluorine in nature 5
1.2.4. Fluorinated arenes and their application 6
1.2.5. Fluorine in pharmaceutical chemistry 8
1.2.6. Fluorine in agrochemistry 10
1.2.7. Influence of fluorine on bioactive molecules 13
1.2.8. Fluorinated nitrogen heterocycles 14
1.2.9. Trifluoromethyl significance 16
1.2.10. Application of trifluoromethyl pyridine 18
1.3. Objectives 23
1.4. Literature synthetic methods for preparing CF3-compounds 25
1.4.1. Direct fluorination of heterocycles 40
1.4.2. Synthesis via cyclisation of fluorinated precursors or building block approach 40
1.4.3. Summary 52
1.5. Section II: Result and discussion 54
1.5.1. Route-1: Synthesis of 5-halo-6-trifluoromethylpyridine from 6-
(trifluoromethyl)nicotinonitrile 55
1.5.2. Route-2a: Synthesis of 5-halo-6-trifluoromethylpyridine from halogenated
vinylogus enamine via halogenated vinyl ether. 56
1.5.3. Route-2b: Synthesis of 5-halo-6-trifluoromethylpyridine from halogenated
vinylogus enamine via vinylogus enamine. 59
1.6. Conclusion: 80
1.7. Experimental 81
1.7.1. General procedure for the synthesis of vinylogous enamines (196, 222) 81 1.7.2. Procedure for the synthesis of halogenated vinylogous enamines 81
1.8. Reference 84
1.9. Spectra 99
CHAPTER 2: SYNTHESIS OF 6-CHLORO-5-TRIFLUOROACETYL-NICOTINIC NITRILE AND THEIR APPLICATION IN FUSED HETEROCYCLES
SYNTHESIS 123-277
2.1. Introduction to fused N-heterocycles 123
2.2. Section I: A brief review on N- fused heterocycles towards synthesis of pyrazolo[3,4-b]pyridine, substituted 1,2,4-oxadiazoles, 1,8-naphthyridines and
pyrido[2,3-d]pyrimidines. 124-162
2.2.1. Pyrazolopyridines 124
2.2.2. Application of pyrazolopyridine 125
2.2.3. Fluorine in pyrazolopyridine 125
2.2.4. Objectives 126
2.2.5. Literature synthetic methods for preparing pyrazolo[3,4-b]pyridines
compounds 127
2.2.6. Oxadiazoles 151
2.2.7. Pyrido[2,3-d]pyrimidines 154
2.2.8. 1,8-Naphthyridines 159
2.2.9. Summary 162
2.3. Section II: Result and discussion 163-277
2.3.1. Section-A: A route to synthesis of 3-(trifluoromethyl)-1H-pyrazolo[3,4-
b]pyridine-5-carbonitrile analogues and corresponding carboxylic acids. 171 2.3.2. Section B: Attempted synthesis of 3-(trifluoromethyl)isoxazolo[5,4-b]pyridine-5- carbonitrile and a route to synthesis of 1-[2-chloro-5-[5-(trifluoromethyl)-1,2,4-
oxadiazol-3-yl]-3-pyridyl]-2,2,2-trifluoro-ethane-1,1-diol, 5-(trifluoromethyl)-3-[3- (trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-1,2,4-oxadiazole. 187 2.3.3. Section C: A route to synthesis of 7-amino-5-(trifluoromethyl)-1,8-naphthyridine- 3-carbonitrile and 2-phenyl-4-(trifluoromethyl)pyrido[2,3-d]pyrimidine-6-carbonitrile.
192
2.4. Conclusion: 197
2.5. Experimental 198
2.6. Spectra 242
3.1. General introduction 278
3.2. Objectives 279
3.3.1. Preparation of polysubstituted pyridine compounds 279 3.3.2. Synthetic methods for preparing polysubstituted CF3-pyridines 282
3.3.3. Summary 285
3.4. Section II: Result and discussion 286
3.4.1. Synthesis of 2-chloro-6-(trifluoromethyl)pyridine-3,5-dicarbonitrile (56) 295
3.4.2. Reaction of 56 with nitrogen nucleophiles: 296
3.4.3. Reaction of 56 with oxygen nucleophiles: 299
3.4.4. Reaction of 56 with sulfur nucleophiles: 300
3.4.5. Reaction of 56 with carbon nucleophiles: 300
3.5. Conclusion and perspectives: 301
3.6. Experimental 303
3.7. References 317
3.8. Spectra 320
CHAPTER 4: BIOLOGICAL SCREENING OF NEWLY SYNTHESIZED TRIFLUOROMETHYL HETEROCYCLIC COMPOUNDS IN CROP
PROTECTION 352-376
4.1. General introduction 352
4.2. Objectives 352
4.3. Result and discussion 355
4.3.1 Biological evaluation of synthesized CF3-substituted pyridine derivatives: 355 4.3.2 Biological evaluation of synthesized CF3-substituted pyrazolo[3,4-b]pyridines 360
4.4. Summary and conclusion: 366
4.5. Experimental 368
4.6. References: 375
Appendix A1-A9
Vitae A10
Page i
GENERAL REMARKS
1) The compound numbers, figure numbers, scheme numbers and reference numbers given in each chapter refer to that particular chapter only.
2) Melting points were determined with a MEL-TEMP-Electrothermal digital melting point apparatus and are uncorrected.
3) All the chemical reagents were purchased and used as received, unless otherwise indicated.
4) All reagents were prepared using literature methods.
5) Thin layer chromatography (TLC) was carried out on silica gel 60 F254 aluminium plates purchased from Merck.
6) Column chromatographic purifications were performed on a CombiFlashRf (Teledyne Isco) with silica gel using a mobile phase indicated.
7) 1H NMR spectra were recorded at 400 MHz 13C NMR and 19F NMR spectra were obtained at 101and 377 MHz respectively using a Bruker Avance II-400 spectrometer in CDCl3 or DMSO-d6 solution with tetramethylsilane as the internal standard. Chemical shift values (δ) are given in parts per million.
9) The HRMS analyses were performed on Agilent QTOF 6520 mass spectrometer, LCMS and GCMS analyses on WATER SQ-Detector 2 mass spectrometer and Agilent 5975C with triple axis detector mass spectrometer respectively.
9) Qualitative UV-Vis analysis was performed with a UV-2450 UV-VIS spectrometer from Shimadzu in UV-Vis mode with pedestal in MeOH.
10) IR spectra were recorded on Shimadzu DRS Prestige 21.
11) The X-ray crystal structures were obtained with a Rigaku Oxford Diffraction SuperNova diffractometer at Jealot’s Hill, U.K.
Page ii
DEFINITION OF ABBREVIATIONS General Abbreviations
g Gram/s Ph Phenyl
mg Milligram/s Me Methyl
µg Microgram/s conc. Concentrated
mol Mole/s aq. Aqueous
mmol Millimole/s SM Starting material
mL Milliliter/s Temp. Temperature
mm Millimeter/s CF3 Trifluoromethyl
nm Nanometre/s MS Molecular sieves
m.p. Melting point psi Pounds per square inch
b.p. Boiling point cat. Catalytic
Å Ångström atm. Atmospheric
lit. Literature et al. Et alia (and others)
d Day/s TLC Thin layer chromatography
h Hour/s sat. Saturated
min Minute/s MW Microwave
sec Second/s anhyd. Anhydrous
µM Micromolar °C Degree Celsius
S Sinister rt Room temperature
ppm Parts per million Z Zussamen (together)
hv Irradiation E Eentegegen (opposite)
% Percentage equiv Equivalent
R Rectus wt./wt. Weight per unit weight
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Compound Abbreviations
Ac Acetyl EtOAc Ethyl acetate
AcOH Acetic acid EtOH Ethanol
Ac2O Acetic anhydride Et2O Diethyl ether AlCl3 Aluminium chloride Et3N Triethylamine BF3.OEt2 Boron trifluoride diethyl
etherate
Et4N+Cl-, Tetraethyl aamonium chloride
Bn Benzyl HCl Hydrochloric acid
Br2 Bromine K2CO3 Potassium Carbonate
Boc t-Butyloxycarbonyl KF Potassium fluoride
n-Bu/Bu normal (primary) Butyl LDA Lithium diisopropylamide n-BuLi n-Butyl lithium MeNHNH2 Methylhydrazine
t-Bu t-Butyl MgSO4 Magnesium sulphate
t-BuOH t-Butyl alcohol Na2CO3 Sodium carbonate t-BuOK /
KTBT
Potassium tertiary butoxide
NaH Sodium hydride
t-BuOH t-Butyl alcohol NaOAc Sodium acetate
CH3CN Acetonitrile NBS N-Bromosuccinimide
m-CPBA m-Chloroperbenzoic acid NCS N-Chlorosuccinimide Cs2CO3 Cesium Carbonate NIS N-Iodosuccinimide Cu(OAc)2 Copper(II) acetate NMP N-Methyl-2-pyrrolidone
CuI Copper iodide PCC Pyridinium chlorochromate
Cy Cyclohexyl Pd/C Palladium on activated charcoal
DBU 1,8-
Diazabicyclo[5.4.0]undec- 7ene
PhCl Chlorobenzene
o-DCB o-Dichlorobenzene NaOH Sodium hydroxide
Page iv
DCC Dicyclohexylcabodiimide PhPOCl2 Phenyl phosphoryl chloride DCE 1,2-Dichloroethane PhNHNH2 Phenyl hydrazine
DCM Dichloromethane POCl3 Phosphorous oxychloride
DDQ 2,3-Dichloro-
5,6dicyanobenzoquinone
PPh3 Triphenylphosphine
DEAD Diethyl azodicarboxylate Py Pyridine DIAD Diisopropyl
azodicarboxylate
SO2Cl2 Sulfuryl chloride
DIH 1,3-Diiodo-
5,5dimethylhydantoin
TBACl Tetrabutylammonium chloride
DMA Dimethylacetamide TBAF Tetra-n-butylammonium fluoride
DME Dimethoxyethane TBHP tert-Butyl hydroperoxide
DMF N,N-Dimethylformamide TEBAC Benzyltriethylammonium chloride DMSO Dimethyl sulfoxide TEMPO 2,2,6,6-Tetramethylpiperidin-1-yl
dppp 1,3-
Bis(diphenylphosphino)pr opane
TFA Trifluoroacetic acid
DTDB Di-tert-butyl peroxide TFAT Trifluoroacetyltriflate NH4OAc Ammonium acetate TFE 2,2,2-Trifluoroethanol
NH2OH Hydroxylamine TfOH Triflic acid
N2H4 Hydrazine THF Tetrahydrofuran
NMP N-Methyl-2-pyrrolidone TMS Tetramethylsilane
PhMe Toluene Tetrakis /
Pd(PPh3)4
Tetrakis(triphenylphosphine)pallad ium(0)
PhNMe2 Dimethyl aniline p-TsOH/p- TSA
p-Toluene sulfonic acid
Page v
Spectroscopic Abbreviations
IR Infrared XRD X-ray diffraction
ʋmax Frequency maximum ppm Parts per million cm-1 Frequency in
wavenumber
ppb Parts per billion
UV Ultra violet δ Delta (Chemical shift in ppm)
NMR Nuclear magnetic resonance
MHz Megahertz
CDCl3 Deuterated chloroform Hz Hertz
DMSO-d6 Deuterated dimethyl sulfoxide
s Singlet
Acetone-d6 Deuterated acetone d Doublet
m Multiplet t Triplet
dd Doublet of doublet q Quartet
td Triplet of a doublet J Coupling constant
dt Doublet of a triplet NOESY Nuclear overhauser spectroscopy
br s Broad singlet HRMS High Resolution Mass
Spectrometry
M+ Molecular ion HPLC High performance liquid
chromatography
m/z Mass to charge ratio HMBC Heteronuclear Multiple Bond Correlation
GCMS Gas chromatography- mass spectrometry
LCMS Liquid chromatography-mass spectrometry
Page vi
ABSTRACTS OF THESIS
SYNTHETIC AND BIOLOGICAL STUDIES ON SELECTED HETEROCYCLIC SYSTEMS
The importance of fluorine in life-sciences oriented research has been outlined, because fluorine dramatically influences the reactivity and bioavailability of active ingredients. The objective of this thesis was to develop synthetic methods for nitrogen containing heterocycles bearing trifluoromethyl functionality. In this document we have detailed the development of different kinds of trifluoromethyl heteroaromatic pyridine derivative, efforts were focused to development of efficient methodologies and screening newly synthesized compounds for agrochemical activity. The thesis is divided into 4 chapters.
The first chapter, describes the importance and versatility of fluorine in organic synthesis followed by importance of trifluromethyl compounds in agro and pharmaceutical chemistry.
The importance of functionalised CF3-pyridine structural motifs is underlined by the continuous appearance in the literature with its useful biological activity, it also presents a review of the various synthetic methodologies employed for the synthesis of trifluoromethylated compounds.
In result and discussion of chapter 1 we described an efficient and concise 3 step synthesis of 5-halo-6-trifluoromethylpyridine-3-carboxyllic acid from a trifluoroacetyl vinylogous enamine starting material.
The key synthetic steps involved are formation of halogenated vinylogous enamines by addition-elimination as well as electrophilic addition of halogens on enamine. During synthesis of halo-vinylogous enamines it was found that chlorination, bromination or iodination was best carried out at low temperatures, −50 °C to 20 °C in dichloromethane, using 1.2–1.4 molar equivalents of sulfuryl chloride, bromine or N-iodosuccinimide, followed by the addition of 1.2 molar equivalents of triethylamine at −50 °C. All halogenated enamines (Cl, Br, I) are later cyclized by using ammonium acetate to synthesize 5-halo 6- trifluoromethyl nicotinic nitriles in high yields (Scheme 1).
Page vii
Step-1 Step-2 & Step-3
Hal = Cl, Br, I R1=R2 = CH3
R1=R2 = (CH2)4
Hal = Cl, Br, I & F
Scheme 1
Reagents and conditions: Step-1. a) SO2Cl2, DCM, -50 °C, 2 h; b) TEA, -50 °C, 1 h (Hal = Cl); c) Br2, DCM, -50 °C, 2 h; d) TEA, -50 °C 1 h (Hal = Br); e) NIS, DCM, 25 °C, 2 h (Hal
= I). Step-2. NH4OAc, DMF, 25 °C, 16 h. Step-3. 10N HCl, 100 °C 3 h.
However, 5-fluoro-6-trifluoromethyl nicotinic nitrile was synthesised by applying Halex reaction on 5-chloro-6-trifluromethyl-nicotinic nitrile in 58% yield after purification, (Scheme 3) to complete all halogenated nicotinic nitriles synthesis (Scheme 2).
58%
Sulfolane 4 h, 180 °C
KF
Scheme 2
Further, all 5-halogenated 6-trifluoromethyl nicotinic nitriles under best hydrolysis condition yielded the corresponding nicotinic acids in good yields, isolated by column chromatography. Thus we accomplished all 5-halo-6-trifluoromethyl nicotinic nitriles and corresponding carboxylic acids synthesis in good yield from trifluoroacetyl vinylogous enamine starting material.
The second chapter deals with the introduction and literature review on synthesis, reactions, applications and biological activities of compounds containing pyrazolo[3,4-b]pyridines, naphthyridines, pyridopyrimidines, oxadiazoles substituted trifluoromethylpyridines and azaindazoles in its first section of literature survey.
Page viii
Section II, describes the usefulness of 6-chloro-5-trifluoroacetyl-nicotinic nitrile in constructing N-fused heterocycles. Reactivity of 6-chloro-5-trifluoroacetyl-nicotinic nitrile with 1,2- and 1,3-bisnucleophiles was investigated and summarized. Section II is subdivided in to 3 subsections namely A, B and C.
Section-A: Reaction of 6-chloro-5-(trifluoroacetyl)nicotinonitrile with hydrazine (N,N- bisnucleophile) methodology was successfully applied for the direct synthesis of 3- (trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and corresponding carboxylic acids analogues (Scheme 3).
60-80%
16 examples R= alkyl,aryl,heteroaryl
R1=CN, CO2H
1,2-N,N-bis-nucleophiles R-NHNH2
OR
Scheme 3
Section B: This section is dealt with the investigation on reaction of 6-chloro-5- (trifluoroacetyl)nicotinonitrile with hydroxylamine (N,O-bisnucleophile) and our efforts towards synthesis of 3-(trifluoromethyl)isoxazolo[5,4-b]pyridine and [3,4-b]pyridine -5- carbonitrile.
Finally scope of this investigation was extended to hydroxylamine (N,O-bisnucleophile) by synthesizing 1-[2-chloro-5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]-2,2,2- trifluoro-ethane-1,1-diol and 5-(trifluoromethyl)-3-[3-(trifluoromethyl)-1H-pyrazolo[3,4- b]pyridin-5-yl]-1,2,4-oxadiazole in moderate yield (Scheme 4).
Step-2a
52%
1,2-N,O-bis-nucleophile 58%
i.
ii.
iii.
NH2OH Step-1
Step-2
Step-2b & 2c 78%
Scheme 4
Page ix
Reagent and conditions: Step-1 i. aq. NH2OH, ACN, 25 °C, 12 h; Step-2 i. TFAA, ACN, 25
°C, 16 h; ii. NH2NH2.H2O, 80 °C, 2 h; iii. TFAA, ACN, 25 °C, 16 h.
Section C: This section discusses the investigation on reaction of 6-chloro-5- (trifluoroacetyl)nicotinonitrile with aminocrotonate and amidines (1,3(N-C-N)- binucleophiles) and our efforts towards synthesis of 7-amino-5-(trifluoromethyl)-1,8- naphthyridine-3-carbonitrile and 2-phenyl-4-(trifluoromethyl)pyrido[2,3-d]pyrimidine-6- carbonitrile (Scheme 5).
60%
1,3-N-C-N-bis-nucleophiles
70%
i
R = Me R = Ph
Scheme 5
Reagent and condition: i. K2CO3, Mol. Sieves 4A, CH3CN, 80 oC, 2-8 h
We have prepared a novel, highly functionalized trifluoroacetyl pyridine, 6-chloro-5- (trifluoroacetyl)-pyridine-3-carbonitrile from readily available starting materials. The value of this intermediate has been demonstrated by the elaboration to novel, trifluoromethyl azaindazole derivatives, substituted at the N-1 or N-2 position. Hydrolysis of the nitrile substituent leads to corresponding carboxylic acids, which can be further elaborated if desired. We have also demonstrated that reaction with hydroxylamine follows a different reaction pathway to that of hydrazine. Reaction of 1,3-bisnucleophiles leads to novel bicyclic trifluoromethyl-substituted heterocycles with excellent scope for further derivatization.
The third chapter describes a methodology for the construction of tetrasubstituted trifluoromethylated pyridines from vinylogus enamine as starting material. Tetra-substituted pyridines were accessed by reaction of vinylogous enamine with hydroxylamine in acetonitrile at refluxing temperature. The probable mechanism involved in the internal cyclisation of the enamine to tetrasubstituted pyridine synthesis is proposed based on the
Page x
literature. The hydroxypyridine derivatives were converted to corresponding chloroderivative by reaction with POCl3 in toluene at 110 °C temperature (Scheme 6). It was envisioned that the chloropyridine derivative can be easily functionalised with different carbon, sulfur, nitrogen and oxygen nucleophiles.
N-Nucleophiles 72-90% yield
C-Nucleophile 60% yield O-Nucleophile
76% yield
R1 = Ph
R1 = H, Me, Ph 56% yield
70% yield 76% yield
RNH+
S-Nucleophiles 80-86% yield
POCl3,Toluene 110 oC, 3h Aq.NH2OH,
ACN 80 oC, 3h
R4 = Et, Me, Bn, (H, R4' = OMe), NHBoc
R4N = piperdin-1-yl, morpholin-4-yl, Bn R5 = Ph R = Me, (CH2)4
R3 = Me, Bn R2 = Me, CH2CF3, Et
Scheme 6
The fourth chapter describes the biological screening and fungicidal, insecticidal, herbicidal activities of newly synthesized CF3-heterocycles viz trifluoromethylpyridines, pyrazolo[3,4- b]pyridine derivatives, pyridopyrmidine, and napthyridnes.
Some of the 6-CF3 substituted pyridines showed insecticidal activity against plutella xylostella (diamondback moth) and few 3-CF3-substituted pyrazolo[3,4-b] compounds showed fungicidal activity control against the species uromyces viciae-fabae (bean preventive).
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LIST OF PUBLICATIONS
1. An Efficient synthesis of 5-Halo-6-Trifluoromethyl Nicotinic Nitriles and Acids.
Channapur, M. B.; Hall, R. G.; Lal, M.; Pal, S.; Shyadligeri, A. S. Heterocycl.
Commun. 2017, 23, 415 (Refer Appendix Section).
2. Synthesis of 6-chloro-5-(trifluoroacetyl)-pyridine-3-carbonitrile; a novel, versatile intermediate for the synthesis of trifluoromethyl-azaindazole derivatives Channapur, M. B.; Hall, R. G.; Kessabi, J.; Montgomery, M.; Shyadligeri, A. S.
Synlett 2019, 30, 1057 (Refer Appendix Section).
3. Synthesis of 2-chloro-6-(trifluoromethyl)pyridine-3,5-dicarbonitrile and its reactivity with C-, N-, O- and S nucleophiles (Manuscript under preparation).
List of National/ International conferences attended:
1. Presented poster entitled “An efficient synthesis of 5-Halo-6-Trifluoromethyl Nicotinic Nitriles and Acids” at Emerging Trends in AgroScience- Chemistry &
Technology SBPL Site, Santa Monica, Old Goa, Hotel Cidade De Goa, 403110, Goa, INDIA (21st -23rd November 2016).
2. Participated in National Conference on New Frontiers in Chemistry from Fundamentals to Applications (NFCFA 2015) Department of Chemistry BITS PILANI KK Birla Goa Campus, Goa, 403726 (18th -19th December 2015).
3. Participated in INDIAN COUNCIL OF CHEMISTS 32nd Annual National Conference (ICC) Department of Studies in Chemistry Karnatak University, Dharwad, Karnataka, 580001 (28th -30th November 2013).
CHAPTER 1
Synthesis of 5-halo-6- trifluoromethylpyridine-3-
carbonitriles and -carboxylic acids
Manjunath B. Channapur, Ph. D. Thesis, Goa University Page 1
1.1. General introduction
Heterocycles form by far the largest of classical divisions of organic chemistry and are of immense importance both, biologically and industrially. Heterocyclic compounds are most widely distributed in nature, both in animal and plant kingdom. These represent more than half of all known organic compounds. These are cyclic compounds in which one or more ring carbon atoms have been replaced by the hetero atoms like S, O, N, B, P, and Si in majority of cases. Heterocyclic chemistry is one of the most demanding applied branch of organic chemistry which has contributed to the development of society from a biological and industrial point of view as a result of which a great endeavor of scientific research is devoted to this field. It has contributed to improve our quality of life by understanding living organisms at the molecular level.1 For more than a century, heterocycles constituted one of the largest areas of research in organic chemistry. Heterocycles are chemically more flexible and able to respond to the many demands of biochemical systems. These are widely spread across natural products and involved in a wide range of reaction types. Due to the presence of the heteroatom, they can behave as acids or bases, depending on the medium. In addition, some of them can be the target of electrophilic reagents, whereas others are able to undergo nucleophilic attack. Some heterocycles will be readily oxidized and able to resist reduction, and it will be the contrary with others. Finally, all of these properties, depending on the electronics of the heterocyclic rings, influences the biological activity of heterocyclic molecules. Compounds such as vitamins, antibiotics, haemoglobin, essential amino acids, enzymes, nucleic bases, neurotransmitters and a large number of synthetic drugs and dyes contain heterocyclic rings.2
The design of bioisosteres requires detailed insight into the physicochemical properties of an element, heterocycle, or functional group, if effective emulation is to be achieved and ideally, complemented by a similar level of understanding of the binding site of a molecule3,4.
A number of marketed drugs and lead structures currently in clinical development contain usually one or more heterocyclic rings. Many natural products and most of the molecules involved in natural processes contain heterocyclic structures. Their importance is not only due to their abundance, but also to their significance in the chemical and the biological fields.5 It is impossible to cover every aspect of these over few pages, in short, we can say heterocycles are widespread among biologically active molecules and agrochemical and pharmaceutical research could not do without this class of compounds. Approximately 70%
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of all agrochemicals that have been introduced to the market within the last 20 years have at least one heterocyclic ring.6 Heterocyclic scaffolds have taken a major share in the field of both medicinal7 and crop protection chemistry8 by exhibiting relevant biological activities.
Their structural diversity is impressive, as is the wide range of different modes of actions involved. Typically, the synthetic accessibility and physicochemical properties of heterocyclic active ingredients are much more advantageous than those of carbocyclic counterparts.
Among the all heterocyclic compounds, nitrogen-containing heterocycles constitute the major part and increasingly gaining popularity in terms of its use in many fields.9
2 1
5
3
6
Paraquat
Azoxystrobin Serotonin
4
8 7
Adenine Vitamin B1
(thiamin)
Uric acid Nicotine
Morphine
Figure 1. N-heterocycles in biological process
Nitrogen containing organic compounds are widely studied because of their application in diverse fields like pharmaceutical drugs, agrochemicals, cosmetics and nutrients. Numerous heterocyclic natural products have been used as drugs for centuries, mainly alkaloids isolated from plants for example morphine, codeine, atropine, quinine etc. Similarly, natural products have also been used in agriculture for example nicotine has been used (Figure 1). It is also evident from current literature a vast number of drugs in the market contain one or more heterocyclic rings of which nitrogen heterocycle constitute a major part. Overall, compounds with heteroaromatic structures which comprises N-heterocycles are numerous and present interesting properties (Figure 2).10
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Figure 2. N-Heterocyclic structural classes relative distribution
Constantly, accelerating rate of research and development in heterocyclic chemistry suggested that enormous number of heterocyclic systems are well known and this number is increasing very rapidly. Heterocyclic compounds have also been synthesized in laboratory, synthetic organic chemistry plays a vital role in meeting the quantities required for their study and also allows derivative synthesis giving library of compounds for screening, as quantities of chemical entities isolated from natural sources are often very less, making it difficult to study. More precisely, heteroaromatic structures such as pyridines, pyrazoles and pyrimidines are numerous and present interesting properties.
1.2. Section I: Fluorine in organic chemistry 1.2.1. Introduction
Organofluorine chemistry emerged in the mid 1950’s, with the discovery of antitumor properties of fluoro-uracil and the drastic improvement of the biological activity of corticoids by introduction of a fluorine atom.
First of all, fluorine is the most electronegative of all the elements (3.98, Pauling scale).
which is closer to that of oxygen, which is reflected in the dipole moment of the C−F bond being larger and in the opposite direction of a C−H but less than that of C=O, S=O, C−OH, and C-C−CN moieties. Fluorine is modestly more lipophilic than a hydrogen atom and significantly more lipophilic than OH, C=O, CN, or sulfoxide and sulfone substituents. This has a great influence on the electron distribution in a molecule. Hence, its electronic effects are numerous; it stabilises α-carbocations and destabilises β-carbocations, it can have +M
0 50 100 150 200 250 300 350 400
Thee &
Four
Five Six Seven &
Eight
Fused Bicyclic Macrocyclic 74
250
379
33
88
35 22
N-Heterocyclic structural classes relative distribution
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and +I effects in aromatic rings.11 But the high electronegativity of fluorine is more importantly demonstrated by its effect on the acidity of vicinal functional groups.12 In addition, fluorine has a small Van der Waals radius (1.47 Å), situated between that of hydrogen (1.20 Å) and oxygen (1.52 Å); it is the second smallest element after hydrogen.
Fluorine is approximately 20% larger than hydrogen based on comparison of the van der Waals radii, while the length and size of a C−F bond is more closely aligned with a C=O bond than either the shorter C−H or longer C−OH, C-C−CN or S=O bonds. Hence, it can replace a hydrogen atom or a hydroxy group, as its volume is not much different. These two physical properties of the fluorine atom involve several consequences onto the physicochemical properties of molecules that are useful in the design of bioactive molecules.
It has been well documented that the installation of fluorine atoms into molecules remarkably change their physical and pharmacological properties.13 Unlike chlorine, bromine, and iodine, fluorine does not engage in halogen bonding and is nonpolarizable, a property that underlies strong electrostatic interactions which can be attractive or repulsive.
These properties confer fluorine with considerable versatility such that it has been explored as a potential bioisostere of the hydrogen atom, carbonyl and sulfonyl functionalities, the carbinol moiety, and the nitrile with effective functional mimicry very much dependent upon the biochemical context.
1.2.2. Occurrence or discovery
Fluorine is the most common halogen in the earth’s crust contributing to 0.065% of the overall make up, this is significantly more than other halogens such as chlorine and bromine, which have abundances of 0.017% and 0.0003% respectively.14 It is, therefore, surprising that there are upwards of 4,500 natural products containing these less common halogens compared to the 30 natural products containing fluorine.15 In nature, compounds bearing fluorine are rare, compared to the chlorinated, brominated and iodinated ones which can be found.16 In order to give comparison, only 13 have been reported to contain fluorine in 3000 natural products to contain other halogens. Even if fluorine is the 13th most abundant element in the earth’s crust (much more than chlorine and bromine), it is mostly found as minerals which are insoluble in water. This induces that fluorine is not available to living organisms, hence it cannot be found in numerous natural products.17 Fluorine may be relatively abundant as an element, however the uptake of fluorine into biological systems is compromised by a number of factors. The naturally forming fluorine-containing minerals, such as fluorite, have
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poor solubility in aqueous media due to strong ionic bonds between the fluorine and the metal. Once a fluorine atom is present in water, a very tight solvation shell means the anion has poor nucleophilicity. Oxidation of halogens from X- to X+ is an important process in their incorporation into natural compounds. However, as the oxidation potential of fluoride (-2.87 eV) is higher than hydrogen peroxide (-1.87 eV), this process cannot take place.18 1.2.3. Fluorine in nature
Even with above said obstacles, nature has managed to incorporate fluorine into a limited number of natural products. This is exemplified in nature, with little more than 30 naturally occurring organofluorine compounds and only one isolated enzyme, adenosyl-fluoride synthase, known to catalyse the production of C-F bonds (Figure 3).14
9a 9b 9c 9d
3-Carboxy-2-fluoro
-3-hydroxy-pentanedioic acid ω-Fluoroleic acid Nucleocidin 1-Fluoro-propan-2-one
Figure 3. Naturally occurring fluorinated compounds 18
Adenosyl-fluoride synthase, an enzyme identified from the bacteria Streptomyces cattleya was found to convert S-adenosylmethionine (SAM) 10 to 5’-fluoro-5’deoxyfluoroadenosine (5’-FDA) 11 (Scheme 1).
Fluorinase
12b 12a
10 11
Scheme 1. Nucleophilic fluorination reaction catalyzed by enzyme, adenosyl-fluoride synthase
This transformation involves the nucleophilic attack of the fluoride ion onto the 5’ carbon on the ribose ring eliminating the amino acid, methionine. 5’-FDA 11 can then be readily
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transformed into the fluorinated building blocks fluoroacetate 12a and 4-fluorothreonine 12b (fluorinated natural product).
However, the installation of fluorine atoms is not a trivial matter for organic chemists.
Fluorine has played a prominent role in drug design since the approval of the first fluorinated drug, the synthetic 9α-fluoro-substituted corticosteroid fludrocortisone, on August 18, 1955.19 The development of fluorinated compounds is known over a century, but medicinal application is not older than two decades. Remarkable historical events have occurred in the field of development of fluorinated compounds. The replacement of a hydrogen atom by fluorine in a drug candidate can impart subtle or drastic effects on a variety of physical and biological properties.20 The lone pair of electrons on the fluorine atom is too strongly attracted to the electronegative centre to form any noteworthy hydrogen bonding interactions with proton donating functionalities. This lack of polarizability of the fluorine atom leads to the general increase in the lipophilicity of molecules upon fluorination. As a consequence of the inclusion of fluorine atoms, organic molecules display an increase in metabolic stability.
When administered to the body a lipophilic drug molecule will be modified by enzymes involved in the metabolic processes, changing the molecular structure. This often involves oxidation, which not only decreases the biological activity but can also lead to an increase in the hydrophilic nature of the compound causing an increased rate of expulsion from the body through urination. The inclusion of fluorine atoms can be used to block such degradation by deactivating the labile sites prone to oxidation, by reducing the availability of electrons in the molecule which can interact with the metabolic enzymes.
1.2.4. Fluorinated arenes and their application
Fluorinated drugs like Flufenisal 13 Diflunisal 14 (Dolobid®) Flurbiprofen 15 (Froben®) became promising candidate for replacement of nonsteroidal or analgesic drugs like Paracetamol, Asprin and Ibuprofen. The discovery of 5-fluorouracil 16 and its anti-tumor activity led to the contributions to chemotherapy,21,22 its toxic side effects was overcome by the synthetic analogue ftorafur 17 (futraful®) (Figure 4).
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13 14
18 15
16 17
Flufenisal Diflunisal Fluribiprofen
Aprepitant Ftorafur
5-Fluorouracil
Figure 4. Fluorinated arene and heteroarenes as drugs
In the development of Emend (aprepitant) 18, a drug used to treat nausea, the two trifluoromethyl groups provided a significant increase in CNS permeability, and the incorporation of a fluorine atom on the other arene led to a further 2-fold increase in potency.23 Taken together, introducing fluorine atoms and or fluorine containing groups in to bioactive heterocyclic molecules could lead to have a range of overall positive effects such as rendering them more selective, potent, increasing efficacy.24 Another crucial function of the C-F bond is to increase the ability of drug-like molecules to cross the lipid bilayer surrounding cells. Many biologically active molecules have modes of action that are carried out inside cells, targeting enzymes, DNA etc.25 If a molecule is too lipophobic, it will not be able to diffuse through the internal lipid layer of the cell membrane and will have to enter the cell by other means, or be rendered ineffective. The increase in lipophilicity caused by the fluorination of drug-like molecules facilitates their transport into cells, therefore increasing the intracellular drug concentration. Fluorination can also be used to make a drug viable for oral administration instead of less practical approaches. The increase in lipophilicity can be enough to facilitate transport across the gut and stomach linings and also make compounds more chemically stable towards the highly acidic environment of the stomach.26
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1.2.5. Fluorine in pharmaceutical chemistry
In life science industry, fluorine containing products have to do with their superior potency and therapeutic value.27 Greater importance emphasized on fluorine containing drugs in pharmaceutical chemistry due to its pronounced success.28 Fluorine being the one of heavy hitters in terms of their number and frequency of drugs in top 10 in the study of analyzing 12 human disease focused pharmaceutical posters for the elemental composition of drugs (Figure 5).29
Figure 5. Number of approved drugs containing halogens as per disease category An important example is the oxidation of phenyl groups by enzyme cytochrome P450.
Cytochrome P450 oxidises phenyl rings at the para position which leads to an increase in the hydrophilic nature of the drug candidate. However, the inclusion of a fluorine atom at the para position deactivates the phenyl ring towards oxidation, hence slowing metabolism without changing the sterics of the drug molecule significantly. This strategy was utilised in the production of the cholesterol-absorption inhibitor 20.
19 20
38 60
22 77
54
34 26
14 92
81
50 45
19 19 12 53 30 12 19 9 57 43 22 16
ALM AIN BBO CAR DER END GUS MSK NER ONC RES SEN Halogens F
Disease category
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Figure 6. Cholesterol-absorption inhibitor: SCH 48461
Compound 19 was identified as a lead compound for the inhibition of cholesterol-absorption mechanisms, however in vivo metabolism at certain labile sites hindered the activity of the compound. Fluorination at the para position of two of the phenyl rings was used to block the action of metabolic enzymes and drastically improve the activity in vivo using a hamster model. This resulted in lowering the ED50 value from 2.20 mg per Kg for 19 to 0.04 mg per Kg for 20 (Figure 6),30 19 undergoes oxidation of the phenyl ring during metabolism which reduces the drug activity in vivo. Addition of fluorine as in 20 increases activity 400 fold by blocking this oxidation.31
While early applications of fluorine as a bioisostere focused on the relatively simple replacement of hydrogen atoms in drug molecules, often as a means of influencing metabolism, the last 20 years have seen broader deployment of fluorine and fluorinated motifs in the construction of more sophisticated structural arrangements that are able to emulate and influence a number of more traditional functionalities.
Indeed, fluorinated molecules find applications in the treatment of cardiovascular diseases, in antipsychotic drugs, as well as in the treatment of diabetes and hypercholesteremia.32 Cholesterol lowering drugs atorvastatin 21 (the world’s best-selling pharmaceutical between 1996 and 2012)43 fluvastatin 22 and antibiotic ciprofloxacin 23 produced by Bayer all have C-F bonds in their structures which is paramount to their efficiency (Figure 7).33
21 22 23
Figure 7. Cholesterol lowering and antibiotic drugs
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The alteration of the pKa of a molecule is another way the introduction of fluorine atoms can be used to tune potential drug candidates. If one of the forms, protonated or non-protonated, is the active form, then the change in pKa can be used to shift the equilibrium to favour one isoform. Installation of fluorine can lower the pKa of surrounding protons, so addition of a number of fluorine atoms can be used to tune the pKa to favour the active form of a compound.34 The change of basicity of nearby sites upon fluorination was demonstrated eloquently by van Niel and coworkers. They found that fluorination of human 5-HT1D receptor 24 reduced the pKa, favouring the un-ionised species, and so significantly increased the compounds bioavailability and viability for oral administration. 25 a fluorinated analogue of 24 (acting on human 5-HT1D receptor) having lower pKa (9.7 for 24 and 8.7 for 25) and improved bioavailability to a medium value (F = 14%) (Figure 8).35
24 25
Figure 8. Fluorinated analogue 25 of human 5-HT1D receptor 24 1.2.6. Fluorine in agrochemistry
Since 1940, there has been a rise in the number of launched agrochemicals containing halogens. In past 30 years, agrochemical research and development have witnessed a period of significant expansion in the use of halogenated compounds or mixed halogens, e.g. one or more fluorine, chlorine, bromine or iodine atoms in addition to one or further halogen atoms. 36,37 Significant rise in the number of commercial pesticides containing fluorine atoms has been there in recent years. More than half of commercial pesticides (2010–2016) are fluorinated (Figure 9).
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Figure 9. Distribution of halogenated products vs fluorinated products
Because of its properties, fluorine is often used in agrochemical research. Several insecticides present fluorinated substituents: Fludioxonil 26 (Syngenta) a benzodioxole moiety bearing a gem-difluoride and Tefluthrin 27 (Syngenta) contains a trifluoromethyl and a perfluorobenzyl substituent. The pro-insecticide Chlorfenapyr 28 (BASF) contains a pyrrole core bearing a trifluoromethyl substituent. The fungicide Bixafen 29 (Bayer CropScience) contains a pyrazole pattern bearing a difluoromethyl group (Figure 10).
28 29
26
Bixafen Bayer 27
Chlorfenapyr BASF Teflutrin
Syngenta Fluodinoxil
Syngenta
Figure 10. Some agrochemicals bearing fluorinated substituent
The applications of fluorine in the design of drugs and agricultural chemicals continues to grow as our knowledge and understanding of how to take full advantage of the unique properties of this element matures.38-43
To illustrate how fluorine substitution is used successfully in contemporary to enhance binding affinity to the target protein in crop protection research, for example, as a chemical isostere of the essential tertiary hydroxy group (–OH versus – F, isoelectronic; bioisosterism)
Halogenated products
48%
Fluorinated products 52%
Halogenated vs Fluorinated products
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into the DMI triazole fungicide flutriafol 30 (1984, Impact; ICI/Zeneca, now Syngenta) Figure 11.
Trifluorinated analog Flutriafol (fungicide)
30 31
Figure 11. The fungicide flutriafol and its trifluorinated analog
The trifluorinated analogue 31 retains some biological activity, despite an overall reduction in spectrum. Unlike the hydroxy group organic fluorine is exceptionally poor H-bond acceptor and is not an H-bond donor in 30.66
Metabolic stability is one of the key factors in determining the bioavailability of agrochemicals. Rapid oxidative metabolism, e.g. by the P450 cytochrome enzymes, can often lead to limited bioavailability. Therefore, a frequently employed strategy to overcome this problem is to block the reactive site by the introduction of halogen atoms. The replacement of hydrogen atoms at an oxidisable site by fluorine atoms protects against hydroxylation processes mediated by P450 cytochrome enzymes.
Cotton Wheat, maize
35
33 34
Diclosulam 32 Soyabeans
Scheme 2. Pathways of Diclosulam 32 metabolism in various crop species
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The different metabolic pathways of the triazolopyrimidine herbicide diclosulam 32 (Dow AgroSciences) are guided by the fluorine substituent at the 7-position on the triazolopyrimidine ring system.38
1.2.7. Influence of fluorine on bioactive molecules
The incorporation of an electron-withdrawing fluorine or fluorinated group will result in a decrease in basicity, or an increase in acidity of neighboring functionality. The impact on pKa can impact hydrogen-bonding and other binding interactions between a compound and target. The attachment of fluorine or a fluoroalkyl group to an arene most often leads to an increase in lipophilicity, which can lead to enhanced membrane permeability, absorption, and bioavailability. Since fluorine is the most electronegative element, its incorporation in a molecule tends to decrease the susceptibility of a compound to oxidation, a common enzymatic degradation method that leads to removal of a drug from the system. By impeding this metabolic process, fluorine incorporation often leads to an increased half-life of a drug candidate and can prevent the formation of toxic byproducts that result from such oxidation processes. The C-F bond presents a high energy (116 kcal/mol), and this can be exploited in order to enhance the metabolic stability of a molecule. Therefore, substitution of a metabolically labile position with a fluorine atom can increase bioavailability. These all effects of fluorine in a bioactive small molecule can improve the biological activity and efficacy. Henceintroduction of fluorine can lead to resistance toward oxidative metabolism, fluorination has developed into a popular approach to addressing the poor pharmacokinetic performance of compounds in vitro and in vivo.39
The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp (P- glycoprotein) recognition of a molecule and temper inhibition of the hERG channel by basic amines. Applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule.40 These properties of fluorine makes organofluorine compounds are of paramount importance in medicinal chemistry where the properties of the C-F bond are often used to turn highly active compounds into potential drug candidates that can survive in a biological environment. This has been fostered by the
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development of innovative synthetic methodology which is providing access to new fluorinated motifs with interesting topographies and physicochemical attributes.41,42
To conclude, fluorinated molecules is a very important class of compounds, representing 20% of all marketed pharmaceuticals, and 30% of all marketed active ingredients in the agrochemicals.43 The applications of fluorinated compounds extend far beyond pharmaceutical compounds, as fluorine is common place in several other areas of chemistry, including polymer chemistry (Teflon, Nafion), materials, electronics, refrigerants, and dyes.44
1.2.8. Fluorinated nitrogen heterocycles
The nitrogen atom in aromatic and heteroaromatic ring systems can have many significant effects on molecular and physicochemical properties and intra- and intermolecular interactions that can translate to improved pharmacological profiles.45
As previously discussed, Nitrogen containing heterocycles are abundant in nature and increasingly, in synthetically produced molecules. Pyridine is the second most commonly used nitrogen heterocycle among all other N-heterocycles.
Figure 12. Six membered N-heterocycles distribution
The pyridine unit is a motif of high biological relevance and features in many naturally- occurring compounds, with examples including the human enzyme cofactor pyridoxyl phosphate (active form of vitamin B6),46 the NAD and NADP precursor niacin (vitamin B3),47 and the plant alkaloid nicotine.48 Pyridines are also extensively used in medicinal
Other 23%
Pyridine 16%
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chemistry as both key functional groups and scaffold structures.They are also used in the pharmaceutical and material industries as solvents, bases, ligands and even components in molecular devices.49 Thus, it is not surprising that the pyridine moiety features in several high selling pharmaceutical drugs such as the proton pump inhibitor Nexium® 36, the anti- tuberculosis drug Isoniazid® 37 and the diabetes treatment Actos® 38 (Figure 13).50,51,52
36 37 38
Figure 13. Heartburn relief drugs
Pyridine-based compounds have been playing a crucial role as agrochemicals or pesticides including fungicides, insecticides/acaricides and herbicides, etc. Most remarkable is that three pyridine-based products chlorantraniliprole, imidacloprid and paraquat ranked No.2, No.5 and No.7 with sales of $1240, $1070 and $905 million US, respectively.53
Significance of fluorinated nitrogen heterocycles
Introduction of fluoroalkyl groups into organic molecules in a selective and efficient way has been highly desirable, which have diverse applications and are used as pharmaceutical drugs, potential agrochemical ingredients54 and in the materials industry. Therefore, there is a high demand for cost-effective methodology for the construction of fluorinated nitrogen heterocycles. Although much progress has been made in this area there is still scope for improvement to make these compounds readily available and economically viable targets.
In the market there are already significant examples with both key agrochemicals and pharmaceuticals comprising such functionality. The herbicide fluroxypyr 39 is a prime example possessing a fluorine atom in the 2 position of a fully substituted pyridine unit.55 Lansoprazole 40 is a proton pump inhibitor used in the treatment of stomach ulcers and gastric reflux disease.56 Another important example discussed previously is atorvastatin 21 which has a p-fluorobenzene substituent on a pyrrole ring system (Figure 7, 21) and Roche’s anti-malarial treatment mefloquine 41 (Figure 14).57,58
Manjunath B. Channapur, Ph. D. Thesis, Goa University Page 16 Mefloquinine
Fluroxypyr Lansoprazole (proton pump inhibitor)
39 40 41
Figure 14. Some fluorinated heterocycles
It can also be noticed that in fluorinated hetroarenes, the introduction of a single fluorine atom or a trifluoromethyl substituent have been widely studied. The most common perfluoroalkyl derivatives are those in which the fluorinated substituent is a trifluoromethyl group which are also active.
1.2.9. Trifluoromethyl significance
The trifluoromethyl substituent is particularly valuable due to its exceptional physical and chemical properties.59 The presence of a trifluoromethyl moiety in to organic molecules often confers significant and useful changes in the physical and chemical properties of a compound making it a privileged motif in medicinal,60 agrochemical61 and materials chemistry.62,63The size of the CF3-moiety has also been somewhat challenging to definitively assess and this moiety has often been considered to be isosteric with an iso-propyl substituent, although it is clearly of a different shape.43
The replacement of a substituent, or addition of a trifluoromethyl group to a lead compound can alter “the shape and size of a compound”64 “the acidity”65 “dipole moments”66 and
“lipophilicity”.67 The CF3-group possesses high electronegativity of 3.44 (Pauling scale),68 low polarizability and high inertness [E(C–F) = 116 kcal/mol)]. These properties of fluorinated molecules, are highly sought after in industry, especially by medicinal and materials chemists hoping to fine tune the properties of their target molecules. The CF3- moiety has been found to sterically dominate a phenyl or tert-butyl substituent in defining the stereochemical outcome of an aldol reaction in few circumstances.69 Moreover, the trifluoromethyl group activates fluoro and nitro groups for nucleophilic aromatic substitution thus facilitating the formation of poly(arylene)ethers.
Manjunath B. Channapur, Ph. D. Thesis, Goa University Page 17 Trifluridine
(antiviral)
Trifloxystrobin Bistrifluron
Fluoxetine (antidepressant)
Efavirenz (antiviral)
Celebrex (anti-inflammatory)
42 43 44
45 46 47
Figure 15. Application of CF3-arenes in medicinal, agrochemical and material chemistry Fluoxetine 42 the active component of the drug Prozac, is a well-known antidepressant.70 This compound selectively inhibits the uptake of serotonin with a six-fold increase of activity over its non-fluorinated parent compound. Besides trifluoromethylated pharmaceuticals, other biologically relevant compounds containing the trifluoromethyl group are extensively used in crop protection. Efavirenz 43 is non-nucleoside reverse transcriptase inhibitor drug that shows potent inhibitory activity against HIV-1.71 Celebrax 44 is a COX-2 inhibitor and nonsteroidal anti-inflammatory manufactured by Pfizer.72 Trifluridine 45 (trifluorothymidine) is an antiviral agent for topical use in the eye, it acts against herpes viruses, and inhibit some of the enzymes involved in DNA synthesis.73 The introduction of electron-withdrawing groups often extend the pesticidal spectrum of inhibitors of chitin formation based on N-benzoyl-N’-phenylureas (e.g. Bistrifluoron) 46.74 The 3- trifluoromethylphenyl moiety is also an essential building block for inhibitors of carotenoid synthesis fungicides like Trifloxystrobin 47 (tradename Flint) 75 which has an outstanding activity (Figure 15). Trifluoromethylated compounds have also found wide applications in material science. The introduction of a -CF3 group usually increases solubility, thermal stability, optical transparency, flame resistance, and decreases the dielectric constant along with the ability of the polymers to crystalize.44