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A Novel Intramolecular Defluorinative Cyclization Approach to the Synthesis of Difluoromethylated Quinazolic Acid Derivatives
Abstract
tert-Butyl
2-(difluoromethyl)-3-benzyl-6-methoxy-3,4-dihydro-4-quinazoline-4-carboxyl
ic ester (4) and its related 6-substituted esters, precursors of a new type
of cyclic amino acid, were synthesized via intramolecular
defluorinative cyclization under basic conditions.
A simple palladium-catalyzed selective synthesis of structurally diverse 3,4-dihydroquinazolines from electron-rich arylamines, electron-poor arylamines and glyoxalates has been developed under mild conditions. This reaction is carried out in a tandem...
The chemistry of pyrimidines and their benzo derivatives, including quinazolines, perimidines and benzo[gh]perimidines is reviewed in this chapter, with particular attention paid to work published between 1996 and 2007, which covers the period since the publication of the second edition of Comprehensive Heterocyclic Chemistry. Fully aromatic, and both partially and fully reduced species are included, and oxo derivatives, including nucleosides and nucleotides are also covered. New routes to the synthesis of many of these heterocycles, as well as modern synthetic techniques, including microwave assisted procedures, are described. Both ring synthesis and substituent modification procedures are covered. The relative reactivity of different substituent groups and/or substituent positions is also discussed, including several examples of selective metal catalyzed cross-coupling reactions. Metal catalyzed amination and amidation reactions are also described. The importance of pyrimidine and quinazoline heterocyclic compounds in biological systems is also emphasized, since two of the four DNA bases are pyrimidine derivatives, and many modern pharmaceutical agents contain either pyrimidine or quinazoline fragments. Several examples of biologically important pyrimidine and quinazoline derivatives are identified, and in this context the signal transduction inhibitor imatinib (gleevec) is highlighted as one of the most significant new pyrimidine derivatives to have been identified in the last few years.
A new methodology has been developed to construct C-N and C-P bonds through direct coupling of C-OH and N-H/P-H bonds via dehydrative cross coupling reaction. Furthermore, this protocol offers an efficient and straightforward way to access biologically important nitrogen-heterocycle namely, 3,4-dihydroquinazoline utilizing either an inexpensive iron catalyst or under metal-free conditions.
The novel title method for the synthesis of the compounds (III) is further extended for the unprecedented one-pot construction of biologically important N-heterocycles, namely, 3,4-dihydroquinazoline derivatives like (VI) and (VIII).
A novel and improved method for the synthesis of the title imidazoles (III) (9 examples) based on the van Leusen reaction is given.
A simple and straightforward approach to access C4-substituted-3,4-dihydroquinazolines have been achieved, where copper catalysed activation of α-amino peroxide and hydroxide intermediates to iminium ion precursors has been realized as an important step. Reactions of these intermediates with alkynes, indoles, pyrrole and silylenol ether afforded the structurally diverse C4-substituted-3,4-dihydroquinazoline derivatives in good yields.
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Fluorinated organic compounds, in particular those containing nitrogen atoms, are popular targets in medicinal chemistry. They are obtained through chemical synthesis, usually by employing small, fluorinated molecules as starting building blocks. This account focuses on the reactivity and synthetic applications of different types of fluorinated building blocks. It summarizes recent methodologies developed in our and other laboratories for the synthesis of a variety of nitrogen-containing organofluorine compounds.
1 Introduction
2 Fluorinated Imidoyl Halides
2.1 Reaction of Fluorinated Imidoyl Chlorides with Enolates: Synthesis of Fluorinated β-Amino Acids
2.2 Reaction of Fluorinated Imidoyl Chlorides with Sulfoxides
3 Fluorinated α-Imino Esters and Imines
3.1 Fluorinated α-Imino Esters
3.2 Fluorinated Aldimines and Ketimines
4 Fluorinated Acrylic Acid Derivatives
5 Fluorinated gem-Difluoroalkynes
6 Fluorinated Nitriles
6.1 Synthesis of Fluorinated Uracils
6.2 Synthesis of Fluorinated Pyrimidin-2(1H)-ones
7 Fluorinated β-Dicarbonylic Compounds
8 Miscellaneous
8.1 Tandem Ring-Closing Metathesis-Isomerization
8.2 β-Amino-α-trifluoromethyl Alcohols
9 Conclusion
Recent progress in quinazoline alkaloids and related chemistry was reviewed focusing on developments
of the synthetic methodologies and their synthetic applications. Abrief historical background,
aza–Wittig methodology, microwave-assisted synthesis, solid-phase synthesis, and avariety
of new syntheses of quinazoline compounds by organometallic reagents, metal-catalyzed reactions, heterocyclizations,
pericyclic reactions, etc. are briefly reviewed. Selected topics of total synthesis of various types
of quinazoline alkaloids including substituted type like febrifugine and heterocycle-fused type such
as pyrroloquinazolines, indolopyridoquinazolines, pyrazinoquinazolines, and pyrroloquinazolinoquinolines,
etc. by these methodologies are discussed.
Preparation of 4,4-difluoro-L-arginine 1 as an L-arginine surrogate is described starting with tBoc-D-serine. pKa of guanidine moiety of 1 was found to be 11.2 compared to 13.2 of arginine guanidine group.
Data on the methods for synthesis of fluorine-substituted analogues of the natural aliphatic amino acids are systematised in the review. The increased interest in these amino acids is explained by the wide spectrum of their biological action and also by the possibility of using them to solve theoretical and practical problems in medicine, biochemistry, enzymology, biotechnology and other related scientific areas. Particular attention is paid in the review to preparative methods of synthesis of the fluorine-containing aliphatic amino acids and to the means of obtaining these compounds in an optically pure state. The bibliography contains 120 references.
Incubation of δ-(L-α-aminoadipoyl)-L-(3,3-difluorohomocysteinyl)-D-valine with isopenicillin N synthase gave a thiocarboxylic acid, consistent with the formation of a monocyclic lactam intermediate.
2,2-Difluoroketene silyl acetal, generated in situ by treating methyl difluoroiodoacetate with Zn followed by chlorosilane, readily reacted with α,β-unsaturated carbonyl compounds or acetals to give the 1,4-addition products, preferentially. The difluoro analogs of glutamic acid and lysine were prepared through the present reaction.
Reaction of aldehydes, ketones, imines and isothiocyanates with N-(2-bromophenyl) ethylimidates 1a in presence of lithium, is considered as an original route to 4H-3,1-benzoxazines, 3,4-dihydroquinazolines and 4(3H)-quinazolinethiones.
A Lewis acid is needed in order to allow the [2,3]-sigmatropic rearrangement of N-alkyl N-allyl α-amino esters to give rise to N-alkyl C-allyl glycine esters. Addition of iodomethane, rather than a Lewis acid, promotes quaternary ammonium salt formation, in situ ylide formation and [2,3]-sigmatropic rearrangement to N,N-dialkyl C-allyl glycine esters.
The methodology for the construction of β-trifluoromethyl-substituted isoserine is reported. The fluorinated α-hydroxy-β-imino esters which are the precursors to amino acid derived isoserine were formed firstly via a base catalyzed intramolecular rearrangement of imino ethers, and the subsequent conversions of these compounds resultedin the formation of the designedisoerines and the related fluorinated compounds.
2,2-Difluoro enol silyl ethers were readily prepared by Mg-0 promoted selective defluorination of trifluoromethyl ketones in the presence of TMSCl, which involves C-F bond cleavage.
Ring opening of lithio derivatives of N-(alpha-alkoxyalkyl)benzotriazoles 9 and 22 and subsequent extrusion of nitrogen at -78 degrees C gave novel o-iminophenyl anions which enable synthetically useful preparations of ortho-substituted anilines (19 and 25) and of benzoheterocycles (14, 20, 21, 24, and 26).
Trifluoroacetimidoyl chlorides 1 were obtained in 80-90 % yields when a mixture of trifluoroacetic acid and a primary amine was heated in carbon tetrachloride in the presence of triphenylphosphine and triethylamine. The corresponding bromides 2 were obtained when carbon tetrabromide was used instead of carbon tetrachloride. Imidoyl iodides 3 were prepared by substitution of the chloro group of 1 by iodide ion in acetone.
DL-3,3-Difluoroglutamic acid was synthesized from a masked 3-hydroxyprolinol, 6-hydroxy-1-aza-3-oxabicyclo[3.3.0]octan-2-one, in eight steps. The described synthetic route expands the utility of fluoroproline derivatives as precursors of fluoroglutamic acids. Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/30676/1/0000320.pdf
ALTHOUGH the enzymatic decarboxylation of amino acids is of substantial importance to biochemistry1, there are few inhibitors of the decarboxylase enzymes which combine activity with selectivity. Several of the amines formed by in vivo decarboxylation of amino acids (biogenic amines) have key roles in physiology. The neurotransmitters dopamine, 5-hydroxytryptamine, histamine and gamma-aminobutyric acid result from such enzymatic decarboxylation; dopamine in turn serves as the precursor of noradrenaline2. The involvement of catecholamines in peripheral and central control of blood pressure has been the subject of many investigations; for example, elevated catecholamine levels were found in some of the 27 brain regions investigated in spontaneously hypertensive rats. Specifically, elevated noradrenaline and dopamine levels were found in regions implicated in the control of arterial blood pressure3. A widely reported biochemical theory of schizophrenia suggests disturbance of the dopaminergic system as the causative factor.4 Elevated histamine levels are believed to be involved in such diseases as allergy, hypersensitivity, gastric ulcer and inflammation5. Ornithine decarboxylase is also an important target for inhibition, as it is the initial enzyme in the biosynthesis of polyamines and increased levels of the latter have been associated with rapid cell division, including tumour growth6. Thus, selective inhibitors of these key enzymes could be of help in elucidating the complexities of neurophysiology and neurochemistry, as well as of service in medicine by correcting pathological levels of these agonists. We report here examples of the transformation of amino acids (C) into the corresponding substituted 3-fluoro-alanines (B), resulting in potent time-dependent decarboxylase inactivators (Table 1). In addition, we have prepared the fluoromethyl derivatives (D) corresponding to some of the amine products of these decarboxylases and find them also to be inactivators (Table 1).
The alanine racemase from Escherichia coli B has been shown to process DL isomers of beta -fluoroalanine as suicide substrates with an identical partitioning ratio for each enantiomer of 820 catalytic eliminations of HF per enzymatic inactivation event [Wang, E., & Walsh, C. T. (1978) Biochemistry 17, 1313], suggesting the aminoacrylate--PLP complex as a common, symmetrical partitioning species. In an attempt to vary the partition ratio, an index of killing efficiency, systematically the beta, beta-difluoroalanine and beta, beta, beta-trifluoroalanine isomers have now been evaluated for substrate processing, suicidal inactivation kinetics and partitioning ratio, and stability of inactive, derivatized enzyme forms. Both difluoroalanine isomers show high Km values (116 mM for D, 102 mM for L) in catalytic HF loss to form fluoropyruvate. The Vmax for the D isomer is about 14-fold higher than that for the L isomer. Limiting inactivation rate constants, calculated from kcat and observed partition ratios of 5000 and 2600, respectively, are 2.2 min-1 for D-difluoroalanine and 0.33 min-1 for L-difluoroalanine. For comparison, DL-trifluoroalanine turns over less than 10 times per enzyme molecule inactivated and so is a very efficient suicide substrate. The estimated inactivation rate constant is less than or equal to 1.0 min-1. These data are analyzed in terms of partitioning behavior of the monofluoro- and difluoroaminoacrylate--PLP complexes as partitioning intermediates for turnover or for racemase inactivation. While mono- and trifluoroalanines yield stable inactive species, the difluoroalanine isomers produce labile enzyme derivatives, and regain of catalytic activity is analyzed in terms of the anticipated oxidation state at the beta carbon of the substrate fragment adducted to the enzyme.
DL-4,4-Difluoroglutamic acid (DL-4,4-F2Glu) and its methotrexate analogue, DL-gamma,gamma-difluoromethotrexate (DL-gamma,gamma-F2MTX), were synthesized and evaluated as alternate substrates or inhibitors of folate-dependent enzymes. Synthesis of DL-4,4-F2Glu involved the nitroaldol reaction of ethyl nitroacetate with a difluorinated aldehyde ethyl hemiacetal as a key step. Attempted ligation of DL-4,4-F2Glu to methotrexate (MTX), catalyzed by human folylpoly-gamma-glutamate synthetase (FPGS), revealed that DL-4,4-F2Glu is a poor alternate substrate. DL-gamma,gamma-F2MTX was synthesized by a route proceeding through N-[4-(methylamino)benzoyl]-4,4-difluoroglutamic acid di-tert-butyl ester followed by alkylation with 6-(bromomethyl)-2,4-pteridinediamine hydrobromide. DL-gamma,gamma-F2MTX was found to be neither a substrate nor an inhibitor of human FPGS. The fluorinated analogue of MTX, however, inhibits DHFR and cell growth with the same potency as MTX.
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K. L. Kirk and R. Filler, Recent Advances in the Biomedicinal Chemistry of Fluorine-containing Compounds, in Biochemical Fron-tiers of Fluorine Chemistry, ed. I. Ojima, J. R. McCarthy and J. T. Welch, ACS Symposium series, Washington, D.C., 1996; (b) J. Kollonitsch, in Biomedicinal Aspects of Fluorine Chemistry, ed. R. Filler and Y. Kobayashi, Kodansha & Elsevier, 1982, pp. 93–122;
4-dihydroquinazoline skeleton has been mostly constructed by intramolecular condensation of iminoesters of o-aminobenzylamines
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3,4-dihydroquinazoline skeleton has been mostly constructed by
intramolecular condensation of iminoesters of o-aminobenzylamines;
(a) A. R. Katritzky, G. Zhang and J. Jiang, J. Org. Chem., 1995, 60,
7625; (b) M. L. El Efrit, B. Hajjem, H. Zantour and B. Baccar, Synth.
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for 19 F NMR analysis and VBL for X-ray analy- sis. Notes and references 1
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No 12450356) and the SC-NMR Laboratory of Okayama
University for 19 F NMR analysis and VBL for X-ray analy-
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Notes and references
1 K. Uneyama, J. Hao and H. Amii, Tetrahedron Lett., 1998, 39, 4079.
2 (a) K. L. Kirk and R. Filler, Recent Advances in the Biomedicinal
Chemistry of Fluorine-containing Compounds, in Biochemical Frontiers of Fluorine Chemistry, ed. I. Ojima, J. R. McCarthy and J. T.