“All new is well-forgotten old”, the proverb goes. The current “fluorine boom” is news only to a novice in the field: the exceptional importance of fluorinated organic compounds in numerous areas has been known for a long time. The sharpest increase in the number of fluorine-containing pharmaceuticals and agrochemicals is dated back to 30 years ago. Also around that time (1979), the first monograph devoted to industrial applications of organofluorine compounds was published, covering not only fluorine-containing biologically active materials but also refrigerants, propellants, surfactants, textile chemicals, polymers, and dyes. The increasingly broad realization of the key role of organofluorine compounds in numerous areas has recently attracted many new scientists to the field. The development of new methods for the selective introduction of fluorine and fluorinecontaining groups into organic molecules for biologically active and other useful materials has become a hot area. Over 100 reviews, book chapters, and highlights on this subject have appeared in the literature in the past few years. As citing all of these publications in this review article is impossible, we provide references to only the most recent, general, and comprehensive ones. Molecules bearing a trifluoromethyl group constitute one of the most important classes of selectively fluorinated compounds. As early as 1928, Lehmann reported his observations of biological activity of some trifluoromethylated organic derivatives and already in 1959 Yale published a detailed review article entitled “The Trifluoromethyl Group in Medicinal Chemistry”. Since then, numerous books and reviews have appeared in the literature covering various aspects of trifluoromethylated organic and organometallic compounds. Within this family, derivatives bearing the CF3 group on aromatic rings are particularly numerous and important. Some examples of such compounds used as active ingredients of pharmaceuticals and agrochemicals are shown in Scheme 1. Trifluoromethylated building blocks and intermediates are clearly needed to make such molecules. The simplest trifluoromethylated aromatic compound, benzotrifluoride, was originally prepared by Swarts at the end of the 19th century. In his work, Swarts treated benzotrichloride with “two thirds of its weight of antimony fluoride” to obtain a mixture of PhCF2Cl and PhCF3, from which the two were separated and isolated pure by distillation. In the early 1930s, two industrial groups, one from Kinetic Chemicals, Inc. and one from I. G. Farbenindustrie AG patented their discoveries on the successful use of HF instead of SbF3 for the Swarts reaction. These inventions were the starting point for the modern large-scale manufacturing of trifluoromethylated aromatics. Other methods have been developed for conversion of various C1 units on the ring to CF3 with a variety of fluorinating agents. While representing an outstanding discovery and a classic of organic and organofluorine chemistry, the Swarts reaction is nonetheless neither atom-economical nor environmentally benign, as it deals with stoichiometric quantities of hazardous chemicals and generates large amounts of chlorine waste. To convert a CH3 group on the ring to CF3, the methyl is first exhaustively chlorinated to produce 3 equiv of HCl as a

Aromatic Trifluoromethylation with Metal Complexes

The demonstration in the 1960's that cis-diamminedichloroplatinum(II), or cisplatin, inhibits cellular division of Escherichia coli1 led to the subsequent discovery that this simple coordination compound is also an effective antitumor agent in mouse models.2 Subsequent studies validated cisplatin as an effective anticancer agent in humans as well,3–7 and FDA approval of cisplatin for the treatment of metastatic ovarian and testicular cancers was granted in 1978.8 Its introduction as a chemotherapeutic agent significantly improved the survival outlook for many cancer patients; the cure rate for testicular cancer before the approval of cisplatin was less than 10%, significantly lower than the 90% cure rate attained with modern platinum chemotherapy.9,10

Cisplatin kills cancer cells primarily by cross-linking DNA and inhibiting transcription.11 The chemical origin of this process begins when cisplatin enters the cell and undergoes aquation involving loss of one or both chloride ligands. The resulting platinum(II) aqua complexes are potent electrophiles that readily react with a number of biological ligands with loss of the bound water molecules. The purine bases of nucleic acids are strongly nucleophilic at the N7 position. Thus, cisplatin binds readily to DNA, forming primarily bifunctional adducts with loss of both chloride ligands. The major cisplatin-DNA adduct is the intrastrand 1,2-d(GpG) cross-link, which accounts for 60–65% of the bound platinum.12 The resulting Pt-DNA adducts, which distort and bend the DNA structure,13–15 impede transcription.16 The downstream effects of transcription inhibition ultimately lead to cell death.

Despite its great curative success in testicular cancer, cisplatin is not universally effective in other cancer types and induces a number of toxic side effects.17–19 Additionally, certain cancers are resistant to cisplatin therapy. This resistance is either intrinsic or developed during prolonged treatment.20,21 To circumvent these problems, new platinum complexes have been pursued and investigated for their antitumor properties. Although well over a thousand complexes have been prepared and tested thus far,22 only two other platinum drugs are approved for clinical use worldwide, and three additional compounds are approved for regional use in Asia.23 These complexes, displayed in Chart 1, operate with a mechanism of action similar to that of cisplatin, which involves DNA binding and transcription inhibition.






Open in a separate window


Chart 1


Chemical structures of the clinically used platinum-based anticancer drugs. The top three complexes, cisplatin, carboplatin, and oxaliplatin, are approved for use worldwide. The bottom three complexes, nedaplatin, lobaplatin, and heptaplatin, are approved for use in Japan, China, and Korea, respectively.

/pdf/synthetic-methods-for-the-preparation-of-platinum-anticancer-4et0np31b8.pdf

Synthetic Methods for the Preparation of Platinum Anticancer Complexes

Oxidative Addition Reactions of Organoplatinum(II) Complexes with Nitrogen-Donor Ligands.

The protonolysis mechanisms of several alkylplatinum(II) complexes [(tmeda)PtMeCl (2) (tmeda = N,N,N‘,N‘-tetramethylethylenediamine), (tmeda)Pt(CH2Ph)Cl (5), (tmeda)PtMe2 (11), and trans-(PEt3)2Pt(CH3)Cl (15)] in CD2Cl2 and CD3OD have been investigated. These reactions model the microscopic reverse of C−H activation by aqueous Pt(II). Each of the four systems (2 in CD3OD, 5 in CD2Cl2, 11 in CD3OD, and 15 in CD3OD) exhibits different behavior in the protonolysis reaction as observed by low-temperature 1H NMR spectroscopy. Protonolysis of 2 in methanol-d4 proceeds with no observable intermediates. Reversible reaction between 5 and HCl in CD2Cl2 at −78 °C produces (tmeda)Pt(CH2Ph)(H)Cl2 (6), which undergoes reductive elimination of toluene at higher temperatures. Treatment of 11 with HCl in methanol at −78 °C generates (tmeda)PtMe2(H)Cl (12), which incorporates deuterium from solvent (CD3OD) into the methyl groups prior to reductive elimination of methane. Finally, 15 reacts with H+ in methanol to liberate m...

Exploring the Mechanism of Aqueous C−H Activation by Pt(II) through Model Chemistry: Evidence for the Intermediacy of Alkylhydridoplatinum(IV) and Alkane σ-Adducts

Recent studies on organometallic intramolecular-coordination compounds

Displacement of norbornadiene (NBD) from PtMe2(NBD) BY N-donors, dimethylsulfoxide, and cyanide, and reactions of cis-PtMe2L2 iodomethane

Displacement of norbornadiene (NBD) from PtR2(NBD) (R = Me, CF3) by weak ligands

Amino acid complexes of platinum(IV). VI. Ethylenediamine-tetraacetate (EDTA) complexes

Oxidative addition of X (X = Cl, Br, I) to cis-[PtMeL] (L = pyridine, py, or L = N,N,N′,N′-tetramethylethylenediamine (tmen) gave [PtMeXL]. For X = Br, I, treatment with aqueous HClO gave insoluble [{PtMeX}], but for X = Cl, [PtMeCl(HO)] remained in solution, with [{PtMeCl}] depositing only from concentrated solution. [PtMeL] (L = py, 1/2(tmen)) with water gave [PtMe(OH)L], which, on treatment with HClO gave cis-[PtMe(HO)](ClO) in solution. Water also reacted with [PtMe(nbd)] (nbd = norbornadiene) to give [{PtMe](OH)}]·mHO. Alcohols ROH (R = Me, Et) with cis-[PtMepy] gave [PtMe(OR)(OH)py], which reacted with aqueous HClO solution to give fac-[PtMe(OR)(HO)]ClO in solution. Addition of chloride to this solution caused precipitation of [{PtMe(OR)Cl}]. Reaction of [{PtMeXY}] with AgNO in water gave fac-[PtMeX(HO)](NO) in solution (X = Y = Cl, Br, I or Y = Cl, X = OR); for X = I added acid was necessary to prevent precipitation of [{PtMeI(OH)}]. Reaction of a solution of fac-[PtMeBr(HO)](NO) with AgNO gave fac-[PtMe(NO)(HO)](NO ) in solution, but an analogous reaction with AgSCN gave a complex in solution formulated as fac-[PtMe(SCN)(HO)](NO) only in low yield.

Mark A. Williams

Papers

Displacement of norbornadiene (NBD) from PtMe2(NBD) BY N-donors, dimethylsulfoxide, and cyanide, and reactions of cis-PtMe2L2 iodomethane

Displacement of norbornadiene (NBD) from PtR2(NBD) (R = Me, CF3) by weak ligands

Amino acid complexes of platinum(IV). VI. Ethylenediamine-tetraacetate (EDTA) complexes

Synthesis of dimethylplatinum(IV) compounds, [{PtMe2X2}n], [{PtMe2XY}n], and, in solution, fac-[PtMe2X(H2O)3]+, where X and Y are anionic ligands