Introduction Nathan Wilde Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead January 2014

The elements:

Tellurium: Discovered in 1782 as a gold telluride mineral. Named from tellus, the Latin word for "earth." The percent of relative elemental abundance for the universe is far higher than that on Earth, partly because Te forms TeH2, which is volatile so it escapes the Earth. Te has no biological function, but some fungi can incorporate it into peptides in the place of S or Se.

Thallium: Discovered in 1861. It produced a green spectral line by flame spectroscopy, so it is named after thallos, the Greek word for "a green shoot or twig." It is usually at the +1 or +3 oxidation state. Tl+ ions are similar to Ag+ and K+ in size, and in vivo they are pumped into cells through potassium channels, and once inside the cell thallium binds to sulfur in cystein residues and ferrodoxins. Tl3+ ions resemble softer versions of boron and aluminum Lewis acids, and are also a potent oxidants.

Lead: Discovered roughly 9000 years ago in the middle east. In atomic physics, 208Pb is "double magic" because it has 82 protons and 126 neutrons, making it excpetionally stable to radioactive decay. In animals, lead accumulates in the tissues and bones, as well as attacks the nervous system.

Why are they not used?

Tellurium: Not very toxic, but relatively rare and expensive. Humans exposed to as little as 0.01 mg/m3 or less of Te metal in air exude a foul garlic-like odor known as 'tellurium breath'" (Wikipedia: "Tellurium"). Most organisms metabolize tellurium to dimethyl telluride, the source of the smell. Other organo tellurides do not smell bad. Mostly perception is why it's not used.

Thallium: Crazy toxic. "Poisoner's poison": Tl(I) salts are tasteless and odor-free. Also, symptoms of thallium poisoning are similar to other illnesses, so physicians are often confused. Unlike mercury and lead, however, thallium is not a bioaccumulative poison. Tellurium Thallium Lead: Toxic, but not as toxic as public perception leads you to believe. By weight, palladium is more toxic than lead, and some authors in the literature claim palladium is ten times more toxic. Lead is abundant and has many industrial applications, so you're more likely to be Main Sources: affected by it. Pb tends to have high ligand coordination numbers (4-7, even as high as 8 or "Main Group Metals in Organic Synthesis", 2004, edited by H. Yamamoto and K. Oshima. 9), so making as using well-defined organoplumbanes can be difficult. Chapters 9, 13, and 15. Relative abundance in the earth's crust Reviews: Oral LD50 for rat (Sigma Aldrich's MSDS's) Element ppm Te: Synthesis 1991, 793 & 897. Tetrahedron Lead 14 Pb(OAc)2: 4665 mg/kg 2005, 1613. Chem. Rev. 2006, 1032. Tin 2.2 Tl: Synthesis 2010, 1059. Synthesis 1999, Pd(OAc)2: 2100 mg/kg Thallium 0.6 2001. Acc. Chem. Res. 1970, 338. TlCl: 24 mg/kg Iodine 0.14 Pb: Tetrahedron 2001, 5683. TeO2: > 5000 mg/kg Note: Diarrhea Tellurium 0.005 Lead SeO2: 68.1 mg/kg Platinum 0.003 Gold 0.0011 Tellurium Nathan Wilde Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead January 2014

Tellurium reagents and making C-Te bonds See book chapter Homogeneous production of Ti(III) species in inert solvents

Al2Te3 + 3H2O 3H2Te + Al2O3 OH $25/g (Materion) O iBu2Te, TiCl4 Only diasteromer. With aqueous Ph Ph TiCl3 they get a mixture of this Ph H DCM, rt and the meso isomer. Na/NH3 OH Na2Te (or Na2Te2) Chem. Lett. 1986, 1339 99% Te NaBH4/EtOH $1/g (Strem) NaTeH Dehalogenation Bull. Chem. Soc. Jpn. 1986, 3013 R'X TePh RTeR' RM + Te RTeM I (PhTe)2 O NaBH CO Et M = Li, Na, MgX 2 I 4 2 (RTe)2 CO2Et 53%

Na2Te R Te 2 Other reactions with similar mechanisms: Reformatsky-type, epoxides ArX + Na Te Ar Te RX 2 2 with an -LG give allylic alcohols, dealkylation of quaternary ammonium R = alkyl Na2Te2 X = I, or N2BF4 (requires heat) (RTe)2 salts, removal of nitro groups, removal of sulfones, and more. See the

TeCl3 above review. TeCl + (RTe)2 + X2 RTeX3 4 $5/g (Aldrich) Cl JOC 1992, 6598 Telluronium Ylides ... do the same things as sulfonium ylides Reduction O ACIE 1980, 1009 LiTMP O OH Te(iBu)2 Ar H H2Te Te(iBu)2 Works on aliphatic aldehydes and THF, -78°C TMS (from Al2Te3 + H2O) ketones too, but with lower yields. TMS Ph H Ph O 100% , -unsaturated esters and ketones can also TMS O OD undergo cyclopropanation. Ar H D2Te D2O is a cheap way to reductively (from Al2Te3 + D2O) deauterate things. Ph H Ph D 100% Tet. Lett. 1983, 2599 O O If your HWE isn't working, telluronium ylides can do that too. H2Te t R CO Et (from Al2Te3 + H2O) KO Bu 2 Ph H Ph H Br CO2Et then RR'CO 89% Te(nBu)2 Te(nBu) CO Et 2 2 R' Other reductions possible with Te reagents (such as NaTeH, PhTeSiMe3): Note: stabilized sulfonium ylides such as these are inert to carbonyl groups. aryl alkenes, enemines and imines, nitrones, thio carbonyls, nitro groups, N-oxides, azides. See the reviews, especially Synthesis 1991, 793. Tellurium Nathan Wilde Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead January 2014

Or even a Julia-olefination-type dimerization JOC 1984, 3559 Halotelluration of alkynes Ar R Br TeLi Li ArTeBr3 ArTeBr3 nBuLi R Ar SO Ph then cat. Te Te Li 2 Ar SO2Ph Br TeBr Ar benzene MeOH R TeBr Ar Ar SO Ph 2 2 2 syn-addition anti-addition -LiO2SPh Ar SO2Ph ArBr2 ‡ -LiO SPh Te 2 R ‡ Ar TeCl4 R -Te Te Ar Ar Br TeBr2Ar Br Ar CHCl3, reflux Ar Ar

Hydrotelluration of alkynes see Chem. Rev. 2006, 1032 Br Br NaBH4 R H M H (R'Te)2, NaBH4 R TeBr2Ar R TeAr R H M M = Al, B, Zr EtOH R TeR' syn-addition anti-addition So what do you do with all these fancy tellurides you can make? Metal-tellurium exchange and direct cross-coupling! ‡ R ‡ EtO H R R Li R CuCNLi2 H M TeR'

BuLi Me CuCNLi (nBuTe)2, NaBH4 2 2 Ph Ph TenBu 88% EtOH Pd(0), Ph AlEt3 R3 n R Ph Ph Te Bu 75% R TeR' R AlEt2 R3

Ph OH Pd(0), HO ZnEt R2M 2 TenBu 77%

OTBS OTBS R R2 R ZnEt Ph TenBu 72% Ph M = SnR3, ZnR, Cu, B(OH)2 This method also works great for Michael-addition on alkynes bearing an EWG. You can even trap with an electrophile stereospecifically, opening possibilities for stereodefined tetrasubstituted olefins. Tellurium Nathan Wilde Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead January 2014

Syntheses using telluride chemistry Me Marino's macrolactin A synthesis. JACS 2002, 1664 H Romo's gymnodimine synthesis OPMB Me OH OTBS M SnBu3 Me O H N Me OTIPS I H O O O Me + CO2H O O HO Me O OTBS H H H O HN OH Me Me O OTBS HO O Me Me ( )-gymnodimine Me Me ( )-macrolactin A PhO2S

Me TBSO O O TBSO O O ZnCl2, O Cl S Cl S DIBAL Me TeBu nBuLi, OEt pTol pTol (BuTe) Me 2 O Me Me Me NaBH4 MeN Me TBSO OH O OH O Me OMe CsF O >19:1 Z:E Cl S S Me pTol pTol epoxide OTBS O Et2AlCl, NaHMDS Me TsN O OTBS TBSO TBSOTf TsN (BuTe) Me 2 OTBS BuCuCN(2-Th)Li2 OTBS They got the same Me diastereomer using either NaBH4 TeBu [Cu] olefin geometry, Me suggesting a stepwise DA.

Barbier-type OTBS macrocyclization OTBS

R 1. Me C(OMe) Me Vinylogous 2 2 H N O 2. TFAA M Mukaiyama O Me epoxide 3. Ph3PCHCHO aldol coupling O O HO O O Me O S Me O H NHK HO pTol O coupling Me Me O M Me ACIE 2009, 7402. Org. Lett. 2005, 5127. Org. Lett. 2000, 763 Tellurium Nathan Wilde Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead January 2014

Miscellaneous telluride applications from Li-Te exchange Not covered Acyl anions JACS 1990, 455 O Many more ways to make C-Te bonds! O O O Allylic oxidations nBuLi tBu tBu Me R Telluroxide eliminations R TeBu R Li HO Me Tellurolactonization R = Ph, 85% Not much on tellurium heterocycles Acyl stannanes or selenoesters don't do this. Thallium Butenolide synthesis Tetrahedron 2012, 10601 O Standard electrode potentials R TeBu nBuLi, O R 1. BuTeLi R R Hg(II) Hg(0) = +0.91 V then CO2, Me + OH then H3O O O Pd(II) Pd(0) = +0.915 V 2. NaBH4 Tl(III) Tl(I) = +1.25 V O HO Me Me 2- Me Cr2O7 2Cr(III)= +1.33 V Tellurophene synthesis Tetrahedron 1997, 4199 Pb(IV) Pb(II) = +1.69 V - MnO4 Mn(II) = +1.70 V BuTe nBuLi BuTe TeBu Li Te Li Synthesis 1999, 2001 nBuLi E+

Bases in Suzuki coupling TBSO OTBS Li I Li OTBS Te E TBSO OTBS OAc Pd(PPh ) TBSO Radical-polar crossover reaction Org. Lett. 2013, 5122 OTBS OTBS 3 4 Me (0.25 eq) Me OTBS base O Ph OH TBSO O O Et3B, O2 O O H O O THF/H2O OAc O OAc Ph H OAc OTBS TePh OTBS DCM O (HO) B 2 OTBS O 87% OMe single isomer No reaction with the selenium acetal. Base Time Yield O ‡ OTBS OH Et KOH 2 hr 86% Me Me Ph O O Kishi's palytoxin B TlOH <<30 s 92% OMe H HO TlOEt 30 min 74% substrates Me Me O O O Ag2O 5 min 92% O O Et Ph JACS 1987, 4756. See also Org. Lett. 2000, 2691. AcO OAc H These Tl(I) salts also seems to be very capable of alkylating and acylating 1,3-dicarbonyls and AcO OBz HO Me trigohownin A phenols. See Acc. Chem. Res. 1970, 338. Thallium Nathan Wilde Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead January 2014

Tl(III) Oxidative Rearrangements An example in synthesis of ( )-bakkenolide A JOC 2010, 2877 OH O OH Tl(NO3)3 R Me Me R R Ar Tl(NO ) Iodine(III) reagents Ar Ar -NO3 Me 3 3 Me (O N) Tl gave a 1:1 mixture 3 2 HC(OMe) / 3 MeO C of diastereomers MeOH (7:3) 2 MeOH O and 40% overall 59% yield O OH single diastereomer -[O] of ketones is also MeO possible by this R R Ar mechanism, but I won't MeO -TlNO3 Me Me show any examples. Ar -NO3 Tl(NO ) Me Me 3 2 1. H2, Pd/C Me 1. HMDS, TMSI MeO C 2. KOH, MeOH 2. MeLi, then 2 3. MeLi NCCO Me -aryl esters from aryl ketones Synth. Commun. 1995, 3931 2 Me O OMe O O OMe O Me H O H Tl(NO3)3 Et Me CO2Me O Me Me HC(OMe) O Me 3 1. PhI(OAc)2, MeOH KOH O O Ph P=CH 76% 2. HO2CCF3 3 2

Ring contraction JOC 1998, 1716 O H H Me Me ( )-bakkenolide A

Tl(NO3)3•3H2O CO2H O DCM, rt, 24 hr To shift or to eliminate? J. Chem. Soc., Perkin Trans. 1 1992, 2565 H H Me Me H 90% O Ph O Ph (III) Me Me Me Tl Tl(OAc)3 Tl(III) Tl(OAc) O Ph AcOH, reflux 2 O O OH Me O Me Me OH H O Tl(OTs)3 O Ph H2O O TsOH, reflux Me Me Me Tl(III) Tl(OTs)2 Ph O O OH OH Aryl shift doesn't work with Me Me Me electron-poor arenes. CO2H O -Tl(I) OH Thallium Nathan Wilde Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead January 2014

Ring expansion Tet. Lett. 1996, 3865 Olefins and alkynes react with Tl(III) with and without rearrangement, much like other pi-acids. Here is a one-pot synthesis of coumarins. O TMSO HO OH HO O O Tl(O2CCF3)3 82% Ph CO2H MeCN Tl(OAc)3 Ph Ph polyphosphoric acid Ph

TMSO O O Tl(O2CCF3)3 HO OH (AcO)2Tl O P R 74% Ph CO H CO2H MeCN 2 OH

Tl(OAc)2 Tl(OAc)2 O TMSO Ph O Tl(O CCF ) 2 3 3 cis:trans = 9:1 H OP R J. Chem. Res. 1998, 392 Ph MeCN 70% OH Phenol oxidation. JOC 1995, 6499 Estrone semisynthesis JOC 1994, 5439 OH Me O O Ar O Tl(NO3)3 Me MeO Me H HOBr Pb(OAc)4 MeOH MeO O H H OMe AcO Ar AcO Br OH PhI(O2CCF3) does not activate the olefin, but it does do the other oxidation. HO Evans: JACS 1997, 3419 and refs. Vancomycin syntheses Completed Vancomycin w/o Tl(III): ACIE 1998, 2700 Zn OH O O Tl(NO ) O 3 3 O R I R OAr Tl(NO ) R I AcO AcO AcO 3 3 HOAr CrCl2 Br Tl(NO3)2 MeOH one-pot H2O OH R R OMe R OMe

-CH2O OH -TlNO3 AcO 3 steps Me O R OAr -NO AcO 3 80% H

H H R Yamamura: Tetrahedron Lett. 1996, HO estrone 8791 and refs. Thallium Nathan Wilde Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead January 2014

Aromatic thallation OMe OMe Lead

CHO Tl(O2CCF3)2 Making lead reagents and making C-Pb bonds CHO Tl(O2CCF3)3 For R = vinyl or alkynyl, M = Hg, Sn. Cl SnBu 3 CHO For R = aryl, M = Si, Zn, B(OH)2 are HO CCF Pb(OAc) + RM RPb(OAc) N 2 3 Cl Pd(PPh3)4 4 3 also used. Note: transfer with B(OH) H 2 N requires Hg(OAc) as catalyst. H Cl 2 N Synlett 1996, 609 H ArH + PbX4 ArPbX3 +HX X=OAc,O2CCF3 Ar must be electron-rich Thallation then halogenation Tet. Lett. 1969, 2427 Arylation and vinylation of enolates Synlett 1996, 609. Tetrahedron 2001, 5683. Tl(O2CCF3)3 KI Ar Tl(O CCF ) CO Bn Ar H 2 3 2 Ar I CO2Bn NHTr 2 HO2CCF3 H2O O (or MeCN) BocHN BocHN Na OBn Substrate Product Yield OH DCM, rt benzene iodobenzene 96% + O O NHTr fluorobenzene o:p = 11:89 70% O OBn o-xylene 4-iodo-o-xylene 98% O anisole o:p = 17:83 75% Tl(O CCF ) MeO Pb(OAc) Br MeO benzoic acid ortho only 96% 2 3 3 3 O 2-methylthiophene 2-methyl-5-iodothiophene 98% 40% O Towards diazonamide. unoptimized single diastereomer Br Thallation then Pd-coupling JACS 1984, 5274 Enantioselective arylation of phenols Yamamoto: JACS 1999, 8943 O styrene O OLi PdCl OH OH 2 O Or you can do it with brucine Ru, Cu, and alkynes: + MeCN Org. Lett. 2012, 930. R toluene Tl(O2CCF3)2 Ph 80% R R Me Me Pb(OAc)3 -20°C Me Me

Not covered N R = iPr 99%, >99% de, 61% ee R = Ph 68%, >99% de, 83% ee MeO H One-electron aryl-aryl coupling H Me Me Ph Triorganothallium and tetraorganothallate MeO N H O 0 H Reductions with Tl O brucine O Pb L L N* Attempts to make the same C-C bonds, much less enantioselectively, gave lower yields for Pd-catalysis and no triaryl for Ni-catalysis. Lead Nathan Wilde Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead January 2014

Enolate vinylation towards CP-263,114 Shair: JACS 1998, 10784 Oxidative cleavage of C-C bonds Tet. Lett. 2000, 9655

O 1) LiSnMe3 HO nHex O nHex 2) H O H Pb(OAc) , O O O HO 4 O R Bu3Sn CaCO3 Pb(OAc) BF3•OEt2 H OMe 4 BrMg H CO Me SnMe3 51% 2 SnMe3 64% O O H H R Me O (AcO)3Pb O O O O nHex O H O 2 O O O Me H R = CH CH OTBDPS OAc H O 5 2 2 Shair did finish the molecule. Although they didn't use SnMe3 CO2H the organolead vinylation, they did use the same oxy- Cope strategy. JACS 2000, 7424. (+)-CP-263,114 Bioorg. Med. Chem. 2001, 347 OMe Me OMe Me More functionalization through radical intermediates Carbonylation of saturated alcohols JACS 1998, 8692 Me Me O Me Pb(OAc)4, Me Cu(OAc)2, H Pb(OAc)4, O quinoline R OH CO R O R CO H benzene H 2 H 63% 9% Me Me Me Me [O] O O Tet. Lett. 1966, 1017 H R O R OH CO R OH [O] R OH

O O O O h Na2CO3 O O -oxidation of carbonyls Tet. Lett. 1998, 5693 O O O O O (OAc)2 Pb AcO O Pb(OAc)4 Me O H2, via: O Pb(OAc) N toluene, reflux N 4 Pd/C + CO H CO2Bn CO2Bn 2 Me Me N CO2H basketene! CO2Bn Me Lead Nathan Wilde Unused Elements in Organic Synthesis: Thallium, Tellurium, Lead January 2014

It should be pointed out that more effective structural design of lead species would be possible if one could control the number of coordination sites and complex ligand exchange. Carboxylate ligands are labile and rapidly undergo intermolecular exchange. In connection with this undesirable equilibrium, concomitant formation of oligomeric or polymeric structures as a result of complex intermolecular interactions imposes significant limitations on further development in this area of research. -Taichi Kano and Susumu Saito, 2004

Not covered

Pb(II) as a Lewis acid. N-arylation (lead version of a Buchwald reaction) Olefin aziridination Carbon radicals from organolead species Alkylation of aldehydes with tetraorganolead species Allylic and benzylic acetoxylation Pb(0) reductions