Increasing global access to the high-volume HIV drug nevirapine through process intensification

New Drug Approvals

Increasing global access to the high-volume HIV drug nevirapine through process intensification

Green Chem., 2017, 19,2986-2991
DOI: 10.1039/C7GC00937B, Paper
Jenson Verghese, Caleb J. Kong, Daniel Rivalti, Eric C. Yu, Rudy Krack, Jesus Alcazar, Julie B. Manley, D. Tyler McQuade, Saeed Ahmad, Katherine Belecki, B. Frank Gupton
Fundamental elements of process intensification were applied to generate efficient batch and continuous syntheses of the high-volume HIV drug nevirapine.

Green Chemistry

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Atom- and step-economical nucleophilic arylation of azaaromatics via electrochemical oxidative cross C-C coupling reactions

Atom- and step-economical nucleophilic arylation of azaaromatics via electrochemical oxidative cross C-C coupling reactions

Green Chem., 2017, 19,2931-2935
DOI: 10.1039/C7GC00789B, Communication
O. N. Chupakhin, A. V. Shchepochkin, V. N. Charushin
A simple and efficient electrochemical method for the synthesis of asymmetrical bi(het)aryls through direct functionalization of the C(sp2)-H bond in azaaromatics with fragments of (hetero)aromatic nucleophiles has been developed

From the journal:

Green Chemistry

Atom- and step-economical nucleophilic arylation of azaaromatics via electrochemical oxidative cross C–C coupling reactions

Abstract

The synthesis of asymmetrical bi(het)aryls through direct functionalization of the C(sp2)–H bond in azaaromatics with fragments of (hetero)aromatic nucleophiles has first been carried out under electrochemical oxidative conditions. This versatile method for C–C bond formation between two aryl fragments can be realized under very mild potential-controlled oxidative conditions, and it does require neither incorporation of any halogen atoms or other leaving groups, nor the use of metal catalysts. The use of the electrochemical SHN methodology for modification of azaaromatic compounds has first been demonstrated.

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C7GC00789B?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

str5

Synthesis of compounds 3a-d

The potassium tert-butoxide (0.55 mmol), corresponding phenols 2a-d (0.55 mmol) and acetonitrile (10mL) were added to electrochemical cell under argon atmosphere. The reaction mixture was stirred at room temperature for 15 min. Then 10-methylacridinium tetrafluoroborate 1 (0.5 mmol, 140 mg) was added to the reaction mixture, and stirred at room temperature for 1 h. The supporting electrolyte (40 mL) was placed in the anode and in the cathode cell compartment (10 mL). Finally, the acetic acid (1 mmol, 57 μL) was placed in the anode cell compartment. Electrolysis was carried out at a controlled potential (reference electrode Ag/AgNO3). Upon passing 2.1F of electricity (for a two-electron process), the electrolysis was stopped, the solvent was distilled off in vacuum from the anolyte, the residue was washed with 30 ml of ether and 10 ml of water. The residue was recrystallized from water and dried on air. 9-(4-Hydroxy-3,5-dimethyl-phenyl)-10-methyl-acridinium tetrafluoroborate (3a) Orange needles. 195 mg (98%). The product was identified as a compound 3a by comparing its 1H NMR spectra with its given in the literature. Satisfactory elemental analysis for C, H and N were obtained for compound 3a; none of the experimentally found percentages deviated from the theoretical values by more than 0.3%.2

1H NMR (500 MHz, [D6]DMSO): δ 9.09 (s, 1H), 8.82 (d, 2H, J=9.2 Hz), 8.45-8.42 (m, 2H), 8.12-8.10 (m, 2H), 7.94-7.91 (m, 2H), 7.16 (s, 2H), 4.90 (s, 3H), 2.33 (s, 6H) ppm. 13C NMR (126 MHz, [D6]DMSO): δ 161.5, 155.2, 141.1, 138.2, 130.3, 130.1, 127.6, 125.7, 124.8, 123.5, 119.0, 38.8, 16.6 ppm.

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Cp2TiCl: An Ideal Reagent for Green Chemistry?

 Abstract Image

The development of Green Chemistry inevitably involves the development of green reagents. In this review, we highlight that Cp2TiCl is a reagent widely used in radical and organometallic chemistry, which shows, if not all, at least some of the 12 principles summarized for Green Chemistry, such as waste minimization, catalysis, safer solvents, toxicity, energy efficiency, and atom economy. Also, this complex has proved to be an ideal reagent for green C–C and C–O bond forming reactions, green reduction, isomerization, and deoxygenation reactions of several functional organic groups as we demonstrate throughout the review.

Cp2TiCl: An Ideal Reagent for Green Chemistry?

 Department of Chemical Engineering, Escuela Politécnica Superior, University of Sevilla, 41011 Sevilla, Spain
 Organic Chemistry, ceiA3, University of Almería, 04120 Almería, Spain
§ Petrochemical Engineering, Universidad de las Fuerzas Armadas-ESPE, 050150 Latacunga, Ecuador
 Department of Organic Chemistry, Faculty of Science, University of Granada, 18071 Granada, Spain
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00098
*E-mail: arosales@us.es.

http://pubs.acs.org/doi/10.1021/acs.oprd.7b00098

Synthesis and Properties of Cp2TiCl

Cp2TiCl is a single-electron-transfer (SET) complex that can be easily prepared from commercial and nontoxic Cp2TiCl2  by using economic and nontoxic reductants such as Mn or Zn. In solution, Cp2TiCl is in an equilibrium between mononuclear and dinuclear species. It has recently been reported that the stoichiometric metal reductant can be replaced by an organic reducing agent.
Figure

Although Cp2TiCl is not a renewable feedstock, it is important to say that this SET is a good alternative to them because it is obtained from nonhazardous materials and also because titanium is one of the most abundant and safe transition metals on Earth

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ChemSpider 2D Image | Titanocene dichloride | C10H10Cl2Ti

Titanocene dichloride

  • Molecular FormulaC10H10Cl2Ti
  • Average mass248.959 Da
1271-19-8 [RN]
Di(2,4-cyclopentadiénide) de dichlorotitane(2+) [French] [ACD/IUPAC Name]
Dichlorotitanium(2+) di(2,4-cyclopentadienide) [ACD/IUPAC Name]
Dichlortitan(2+)di(2,4-cyclopentadienid) [German] [ACD/IUPAC Name]
Titanocene dichloride [Wiki]
Titanocene dichloride
Titanocene dichloride
Ball-and-stick model of titanocene dichloride
Sample of titanocene dichloride
Names
IUPAC name

Dichloridobis(η5-cyclopentadienyl)titanium
Other names

titanocene dichloride, dichlorobis(cyclopentadienyl)titanium(IV)
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.013.669
PubChem CID
RTECS number XR2050000
Properties
C10H10Cl2Ti
Molar mass 248.96 g/mol
Appearance bright red solid
Density 1.60 g/cm3, solid
Melting point 289 °C (552 °F; 562 K)
sl. sol. with hydrolysis
Structure
Triclinic
Dist. tetrahedral
Hazards
R-phrases(outdated) R37R38
S-phrases(outdated) S36
NFPA 704
Flammability (red): no hazard code Health code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g., chloroform Reactivity code 1: Normally stable, but can become unstable at elevated temperatures and pressures. E.g., calcium Special hazards (white): no code

NFPA 704 four-colored diamond

Related compounds
Related compounds
Ferrocene
Zirconocene dichloride
Hafnocene dichloride
Vanadocene dichloride
Niobocene dichloride
Tantalocene dichloride
Molybdocene dichloride
Tungstenocene dichloride
TiCl4
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Titanocene dichloride is the organotitanium compound with the formula (η5-C5H5)2TiCl2, commonly abbreviated as Cp2TiCl2. This metallocene is a common reagent in organometallic and organic synthesis. It exists as a bright red solid that slowly hydrolyzes in air.[1]Cp2TiCl2 does not adopt the typical “sandwich” structure like ferrocene due to the 4 ligands around the metal centre, but rather takes on a distorted tetrahedral shape.[2] It shows antitumour activity and was the first non-platinum complex to undergo clinical trials as a chemotherapy drug.[3]

Preparation

The standard preparations of Cp2TiCl2 start with titanium tetrachloride. The original synthesis by Geoffrey Wilkinson and Birmingham uses sodium cyclopentadienide[4] is still commonly used:

2 NaC5H5 + TiCl4 → (C5H5)2TiCl2 + 2 NaCl

The reaction is conducted in THF. Workup sometimes washing with hydrochloric acid to convert hydrolysis derivatives to the dichloride. Recrystallization from toluene forms acicular crystals.

Cp2TiCl2 can also be prepared by using freshly distilled cyclopentadiene rather than its sodium derivative:

2 C5H6 + TiCl4 → (C5H5)2TiCl2 + 2 HCl

This reaction is conducted under a nitrogen atmosphere and by using THF as solvent. The product is purified by soxhlet extractionusing toluene as solvent.[5]

The complex is pseudotetrahedral. Each of the two Cp rings are attached as η5 ligands.

Applications in organic synthesis

Cp2TiCl2 is a generally useful reagent that effectively behaves as a source of Cp2Ti2+. A large range of nucleophiles will displace chloride. Examples:

Application in preparing sulfur allotropes[edit]

Titanocene dichloride is used to prepare titanocene pentasulfide, a precursor to unusual alloptropes of sulfur:

Li2S5 + (C5H5)2TiCl2 → (C5H5)2TiS5 + LiCl

Structure of pentasulfur-The resulting pentasulfur-titanocene complex is allowed to react with polysulfur dichloride to give the desired cyclosulfur of in the series:[10]

Reactions

Cp2TiCl2 undergoes anion exchange reactions, e.g. to give the pseudohalides. With NaSH and with polysulfide salts, one obtains the sulfido derivatives Cp2Ti(SH)2 and Cp2TiS5.

One Cp ligand can be removed from Cp2TiCl2 to give tetrahedral CpTiCl3. This conversion can be effected with TiCl4 or by reaction with SOCl2.[11]

Reduction with zinc gives the dimer of bis(cyclopentadienyl)titanium(III) chloride in a solvent-mediated chemical equilibrium:[12][13]

N-RB equilibrium.jpg

Ti(II) derivatives

Cp2TiCl2 is a precursor to many TiII derivatives, though titanoce itself, TiCp2, is so highly reactive that it rearranges into a TiIII hydride dimer and has been the subject of much investigation.[14][15] This dimer can be trapped by conducting the reduction of titanocene dichloride in the presence of ligands; in the presence of benzene, a fulvalene complex, μ(η55-fulvalene)-di-(μ-hydrido)-bis(η5-cyclopentadienyltitanium), can be prepared and the resulting solvate structurally characterised by X-ray crystallography.[16] The same compound had been reported earlier by a lithium aluminium hydride reduction[17] and sodium amalgam reduction[18] of titanocene dichloride, and studied by 1H NMR[19] prior to its definitive characterisation.[14][15]

“Titanocene” is not Ti(C5H5)2, but rather this isomer with a fulvalene dihydride structure.[15][16]

Reductions have been investigated using Grignard reagent and alkyl lithium compounds. More conveniently handled reductants include Mg, Al, or Zn. The following syntheses demonstrate some of the compounds that can be generated by reduction of titanocene dichloride in the presence of π acceptor ligands:[20]

Cp2TiCl2 + 2 CO + Mg → Cp2Ti(CO)2 + MgCl2
Cp2TiCl2 + 2 PR3 + Mg → Cp2Ti(PR3)2 + MgCl2
Cp2TiCl2 + 2 Me3SiCCSiMe3 + Mg → Cp2TiMe3SiCCSiMe3 + MgCl2

With only one equivalent of reducing agent, TiIII species such as Cp2TiCl result.

Alkyne and benzyne derivatives of titanocene are well known.[21] One family of derivatives are the titanocyclopentadienes.[22]

Titanocene equivalents react with alkenyl alkynes followed by carbonylation and hydrolysis to form bicyclic cyclopentadienones, related to the Pauson–Khand reaction).[23] A similar reaction is the reductive cyclization of enones to form the corresponding alcohol in a stereoselective manner.[24]

Reduction of titanocene dichloride in the presence of conjugated dienes such as 1,3-butadiene gives η3-allyltitanium complexes.[25] Related reactions occur with diynes. Furthermore, titanocene can catalyze C-C bond metathesis to form asymmetric diynes.[22]

Derivatives of (C5Me5)2TiCl2

Many analogues of Cp2TiCl2 are known. Prominent examples are the ring-methylated derivatives (C5H4Me)2TiCl2 and (C5Me5)2TiCl2. The ethylene complex (C5Me5)2Ti(C2H4) can be synthesised by Na reduction of (C5Me5)2TiCl2 in the presence of ethylene. The Cp compound has not been prepared. This pentamethylcyclopentadienyl (Cp*) species undergoes many reactions such as cycloadditions of alkynes.[21]

Medicinal research

Titanocene dichloride was investigated as an anticancer drug.[26] In fact, it was both the first non-platinum coordination complex and the first metallocene to undergo a clinical trial.[3]The mechanism by which it acts is not fully understood; however, it has been conjectured that its activity might be attributable to the compound’s interactions with the protein transferrin.[3][27]

References

  1. Jump up^ Budaver, S., ed. (1989). The Merck Index (11th ed.). Merck & Co., Inc.
  2. Jump up^ Clearfield, Abraham; Warner, David Keith; Saldarriaga Molina, Carlos Hermán; Ropal, Ramanathan; Bernal, Ivan; et al. (1975). “Structural Studies of (π-C5H5)2 MX2 Complexes and their Derivatives. The Structure of Bis(π-cyclopentadienyl)titanium Dichloride”. Can. J. Chem53 (11): 1621–1629. doi:10.1139/v75-228.
  3. Jump up to:a b c Roat-Malone, R. M. (2007). Bioinorganic Chemistry: A Short Course (2nd ed.). John Wiley & Sons. pp. 19–20. ISBN 978-0-471-76113-6.
  4. Jump up^ Wilkinson, G.; Birmingham, J.G. (1954). “Bis-cyclopentadienyl Compounds of Ti, Zr, V, Nb and Ta”. J. Am. Chem. Soc. 76 (17): 4281–4284. doi:10.1021/ja01646a008.
  5. Jump up^ Birmingham, J. M. (1965). “Synthesis of Cyclopentadienyl Metal Compounds”. Adv. Organometal. Chem. 2: 365–413. doi:10.1016/S0065-3055(08)60082-9.
  6. Jump up^ Payack, J. F.; Hughes, D. L.; Cai, D.; Cottrell, I. F.; Verhoeven, T. R. (2002). “Dimethyltitanocene”Org. Synth. 79: 19.
  7. Jump up^ Claus, K.; Bestian, H. (1962). “Über die Einwirkung von Wasserstoff auf einige metallorganische Verbindungen und Komplexe”. Justus Liebigs Ann. Chem. 654: 8. doi:10.1002/jlac.19626540103.
  8. Jump up^ Herrmann, W.A. (1982). “The Methylene Bridge”. Adv. Organomet. Chem20: 159–263. doi:10.1016/s0065-3055(08)60522-5.
  9. Jump up^ Straus, D. A. (2000). “μ-Chlorobis(cyclopentadienyl)(dimethylaluminium)-μ-methylenetitanium”. Encyclopedia of Reagents for Organic Synthesis. London: John Wiley.
  10. Jump up^ Housecroft, Catherine E.; Sharpe, Alan G. (2008). “Chapter 16: The group 16 elements”. Inorganic Chemistry (3rd ed.). Pearson. p. 498. ISBN 978-0-13-175553-6.
  11. Jump up^ Chandra, K.; Sharma, R. K.; Kumar, N.; Garg, B. S. (1980). “Preparation of η5-Cyclopentadienyltitanium Trichloride and η5-Methylcyclopentadienyltitanium Trichloride”. Chem. Ind. – London44: 288–289.
  12. Jump up^ Manzer, L. E.; Mintz, E. A.; Marks, T. J. (1982). “Cyclopentadienyl Complexes of Titanium(III) and Vanadium(III)”. Inorg. Synth. 21: 84–86. doi:10.1002/9780470132524.ch18.
  13. Jump up^ Nugent, William A.; RajanBabu, T. V. “Transition-metal-centered radicals in organic synthesis. Titanium(III)-induced cyclization of epoxy olefins”. J. Am. Chem. Soc. 110 (25): 8561–8562. doi:10.1021/ja00233a051.
  14. Jump up to:a b Wailes, P. C.; Coutts, R. S. P.; Weigold, H. (1974). “Titanocene”. Organometallic Chemistry of Titanium, Zirconium, and Hafnium. Organometallic Chemistry. Academic Press. pp. 229–237. ISBN 9780323156479.
  15. Jump up to:a b c Mehrotra, R. C.; Singh, A. (2000). “4.3.6 η5-Cyclopentadienyl d-Block Metal Complexes”. Organometallic Chemistry: A Unified Approach (2nd ed.). New Delhi: New Age International Publishers. pp. 243–268. ISBN 9788122412581.
  16. Jump up to:a b Troyanov, Sergei I.; Antropiusová, Helena; Mach, Karel (1992). “Direct proof of the molecular structure of dimeric titanocene; The X-ray structure of μ(η55-fulvalene)-di-(μ-hydrido)-bis(η5-cyclopentadienyltitanium)·1.5 benzene”. J. Organomet. Chem. 427 (1): 49–55. doi:10.1016/0022-328X(92)83204-U.
  17. Jump up^  Antropiusová, Helena;  Dosedlová, Alena;  Hanuš, Vladimir; Karel,  Mach (1981). “Preparation of μ-(η55-Fulvalene)-di-μ-hydrido-bis(η5-cyclopentadienyltitanium) by the reduction of Cp2TiCl2 with LiAlH4 in aromatic solvents”. Transition Met. Chem. 6 (2): 90–93. doi:10.1007/BF00626113.
  18. Jump up^ Cuenca, Tomas; Herrmann, Wolfgang A.; Ashworth, Terence V. (1986). “Chemistry of oxophilic transition metals. 2. Novel derivatives of titanocene and zirconocene”. Organometallics5 (12): 2514–2517. doi:10.1021/om00143a019.
  19. Jump up^ Lemenovskii, D. A.; Urazowski, I. F.; Grishin, Yu K.; Roznyatovsky, V. A. (1985). “1H NMR Spectra and electronic structure of binuclear niobocene and titanocene containing fulvalene ligands”. J. Organomet. Chem. 290 (3): 301–305. doi:10.1016/0022-328X(85)87293-4.
  20. Jump up^ Kuester, Erik (2002). “Bis(5-2,4-cyclopentadienyl)bis(trimethylphosphine)titanium”. Encyclopedia of Reagents for Organic Synthesis. John Wiley. doi:10.1002/047084289X.rn00022.
  21. Jump up to:a b Buchwald, S.L.; Nielsen, R.B. (1988). “Group 4 Metal Complexes of Benzynes, Cycloalkynes, Acyclic Alkynes, and Alkenes”. Chem. Rev. 88 (7): 1047–1058. doi:10.1021/cr00089a004.
  22. Jump up to:a b Rosenthal, U.; et al. (2000). “What Do Titano- and Zirconocenes Do with Diynes and Polyynes?”. Chem. Rev. 33 (2): 119–129. doi:10.1021/ar9900109.
  23. Jump up^ Hicks, F. A.; et al. (1999). “Scope of the Intramolecular Titanocene-Catalyzed Pauson-Khand Type Reaction”. J. Am. Chem. Soc. 121 (25): 5881–5898. doi:10.1021/ja990682u.
  24. Jump up^ Kablaoui, N. M.; Buchwald, S. L. (1998). “Development of a Method for the Reductive Cyclization of Enones by a Titanium Catalyst”. J. Am. Chem. Soc. 118 (13): 3182–3191. doi:10.1021/ja954192n.
  25. Jump up^ Sato, F.; Urabe, Hirokazu; Okamoto, Sentaro (2000). “Synthesis of Organotitanium Complexes from Alkenes and Alkynes and Their Synthetic Applications”. Chem. Rev. 100(8): 2835–2886. PMID 11749307doi:10.1021/cr990277l.
  26. Jump up^ WO 2004005305, Knox, R. J. & P. C. McGowan, “Metallocenes as Anti-Tumour Reagents”, issued 2004
  27. Jump up^ Waern, J. B.; Harris, H. H.; Lai, B.; Cai, Z.; Harding, M. M.; Dillon, C. T. (2005). “Intracellular Mapping of the Distribution of Metals Derived from the Antitumor Metallocenes”. J. Biol. Inorg. Chem. 10 (5): 443–452. doi:10.1007/s00775-005-0649-1.

Further reading

IR of Titanocene dichloride

MS of Titanocene dichloride

HNMR of Titanocene dichloride

ESR of Titanocene dichloride

ESR

MORE……………

Introduction

Natural product synthesis is an exigent test for newly developed methodologies. Within this context, Rajanbabu and Nugent reported a series of seminal papers about the potential role of Cp2TiCl as a new tool in organic synthesis.1 Soon afterwards, Gansäuer’s group published a collection of relevant papers where a substoichiometric version of this protocol was developed.2Those results were especially important in the development of the corresponding asymmetric reactions using chiral titanocene(III) complexes.3 After these inspiring works, titanocene(III) complexes, essentially titanocene(III) chloride (Cp2TiCl), have recently emerged as a powerful tool in organic synthesis. They are soft single-electron-transfer (SET) reagents capable of promoting different kinds of reactions, such as homolytic epoxide4 and oxetane5 openings, Barbier-type reactions,6 Wurtz-type reactions,7 Reformatsky-type reactions,8 reduction reactions,9 and pinacol coupling reactions (Scheme 1).10

image file: c3qo00024a-s1.tif
Scheme 1 General reactivity of Cp2TiCl.

Image result for Titanocene chloride

From a practical point of view, titanocene(III) complexes can be prepared and stored. Nevertheless, they are usually highly oxygen-sensitive compounds. Interestingly, they can be easily prepared in situ by simply stirring the corresponding titanocene(IV) precursor and manganese or zinc dust. Another key characteristic of the titanocene(III) chemistry is that whatever the reaction in which it is involved, a catalytic cycle can be closed. In that case, a titanocene(IV) regenerating agent and an electron source, such as manganese or zinc dust, are required. Although some of them have been described in the literature, only two are commonly used: the simple combination of trimethylsilyl chloride and 2,4,6-collidine for aprotic reaction conditions11 and 2,4,6-collidinium hydrochloride for aqueous conditions (see Scheme 2).2

image file: c3qo00024a-s2.tif
Scheme 2 Catalytic cycles in titanocene(III) chemistry.

http://pubs.rsc.org/en/Content/ArticleHtml/2014/QO/c3qo00024a

Conclusions

Titanocene(III)-mediated radical processes have been applied to the synthesis of natural products of diverse nature. Beyond simple functional group interconversions, radical cyclizations, mainly from epoxides, have demonstrated their utility to yield (poly)cyclic natural skeletons, which are valuable synthons in organic synthesis. This radical approach has in many cases resulted in better yields and stereoselectivities than the cationic equivalents. In particular, the synthesis at room temperature of stereodefined terpenic skeletons without enzymatic assistance is remarkable. In this context, the main limitation of this bioinspired approach is, in fact, its extraordinary stereoselectivity, which avoids obtaining cis-fused decalins and/or substituents in axial positions. Such stereochemistry is present in many interesting natural terpenes. On the other hand, as can be seen in the first part of the review, the diverse reactivity of titanocene(III) complexes derives in some functional group incompatibilities. It is expected that in near future judicious designs of new titanocene(III) complexes can resolve this drawback. In any case, the evolution of the applications of titanocene(III) in natural product synthesis suggests that these reagents can be a matter of choice in the arsenal of a synthetic organic chemist.

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