Index

-acylation 365 ,-unsaturated esters -alkoxymethylenation 364–5 enantioselective synthesis 544 -alkylation formation and reactions of 591–6 of [14C]malonates 359–62 from alkoxycarbonyl[14C]methylenezinc of alkyl [14C]cyanoacetates 422 bromide 335–6 -amino acids, exchange labeling 58, 94–5 from alkyl 2-trimethylsilyl[14C]- -amino acids acetates 329 by enantioselective catalytic from [14C]malonates 265–7, 354, 357 tritiation 530–4 from trialkyl phosphono[14C]acetates 218, by enantioselective tritioreduction of 322–8, 544 oximes 540 ,-unsaturated ketones, exchange from 2-acetamido-2-cyano[2-14C]- labeling 87 acetate 427 ,-unsaturated oximes, exchange from [14C]glycines 316–7 labeling 87 from [2-14C]malonates 371–2 ,-unsaturated ketones 542–4 -arylation absorption see ADME studies of [14C]malonates 362–4 [14C]acarbose, by biotransformation 623 of alkyl [14C]cyanoacetates 422 accelerator mass spectrometry (AMS) 1 [3H]--conotoxin G1 95 [14C]acetaldehyde 290, 445–6 ,-dehydrogenation/tritioreduction of [14C]acetamidines 377–8 carbonyls 483–5 2-acetamido[2-14C]acetate, from [14C]- ,-unsaturated acids, exchange labeling 76 cyanoacetic acid 427 ,-unsaturated acids see also ,-unsaturated acetanilide derivatives, exchange labeling 80 esters [2H,3H]acetic acid (chiral) 617 from [14C]cyanohydrins 406–7 [14C]acetic acids from [14C]malonates by Knoevenagel [14C]acetic anhydride and mixed anhydrides reaction 365–7 from 298–301 ,-unsaturated [14C]aldehydesCOPYRIGHTED 312 [14C]acetoacetates MATERIAL from 346–8 ,-unsaturated amino acids [14C]acetyl halides from 289–90 N-acetyl, enantioselective reduction 532–4 chiral acetate 617 N-acetyl, preparation 530–2 esterification 301–2 reconstitution strategies 530–4 formation of 269, 287–9, 446–7 ,-unsaturated carbonyls 503–5 -halogenation of 308 ,-unsaturated [14C]carboxamides 323, 327 in C-[14C]acetylations 291–6

Preparation of Compounds Labeled with Tritium and Carbon-14 Rolf Voges, J. Richard Heys and Thomas Moenius Ó 2009 John Wiley & Sons, Ltd 640 Index

[14C]acetic acids (Continued ) acetylenic [14C]carboxylic acids 218 in N-[14C]acetylations 297–8 N-acetyl[14C]glycine 316 in O-[14C]acetylations 299 N-[14C]acetylimidazolide 300 in S-[14C]acetylations 300 [14C]acetylpractolol 297 [14C]acetic acid esters 301–7 acid-catalyzed hydrogen isotope Grignard additions to 306–7 exchange 51–6 in ester condensations 302–3 acid-catalyzed hydroxy[14C] in steroid A-ring labeling 306 methylations 246–8 [14C]acetic anhydride 219, 298–301 [14C]acrylic acids/esters 366, 443–4 acetic[3H]formic anhydride 192–3, 235 N-[14C]acyl building blocks 219–21 [14C]acetoacetate esters 291, 346–57 [14C]acrylates acylation reactions 351–3 -acyl derivatives 242–3 aldol reactions 352–3 -[14C]cyanoacrylate, from [14C]cyanoacetic alkylation reactions 348–51 acid 424–5 Knoevenagel-Michael reaction 353–6 3-phenylacrylo[14C]nitrile, from [14C]- preparation 346–8 cyanoacetic acid 424–5 reactions at the functional groups 356–7 acylanilides 85 synthons of 347 [1-14C]acyl azides 219–20 [14C]acetone 337–46 [1-14C]acyl halides 219 carbonyl group reactions 338–43 2-acylamino[14C]malonates 370–1 methyl group reactions 343–6 2-acyl[13C]cyclopropancarboxylic esters 333 preparation 337–8 addition/elimination reactions 276–7 [2-14C]acetonitrile 269–70 [8-14C]adenine 233 [ring-U-14C]acetophenone 459 ADME studies [3H]acetosyringone 185–6 computer-assisted programs 28 2-acetoxy[14C]malonates 374 resource availability 26, 30–1 [14C]acetyl chloride 289–98 quality standards for 6 [14C]acetoacetates 291, 346–8 target preparation 25–31, 44 N-[14C]acetyl compounds 297–8 [14C]adrianomycinone 514 alkyl/aryl [14C]methyl ketones 290–6 [14C]alanines 1-amino[14C]propan-2-ones 291–2 -[3-14C]alanine, from [14C]- preparation 289 cyanoacetate 428 reduction 290, 293–5, 298 (S)-N-Boc-trimethylsilyl[1-14C]alanine, by [14C]acetyl coenzyme A 300–1 diastereoselective synthesis 577–9 [14C]acetyl pivaloyl anhydride 300 [3H]alanines 131–2, 164 acetyl transferases 608 [14C]alaproclate 339 14 14 [ C2]acetylene 441–5 [1- C]alcohols 219, 306–7, 338–40 14 14 [ C2]acetylene tree 441–63 [1- C]aldehydes 14 14 [ C2]acetaldehyde 445–6 by [ C]carbonylation of 14 [ C2]acetic acid 446–7 organoboranes 223 14 14 [ C2]acetylene 441–5 from [ C]nitriles 399–401 14 14 [ C2]alkynols 442–3 via [ C]acylpalladium complexes 224 14 [ Cn]benzene 448–60 aldol reactions 14 14 2-[2,3- C2]butyne-1,4-diol 447 of [ C]acetoacetates 352–3 14 [1,2- C2]dibromoethane 448 in steroid A-ring labeling 506–7 14 14 dimethyl [2,3- C2]- with [ C]acetaldehyde 445–6 acetylenedicarboxylate 447 with [14C]acetones 343, 345–6 14 [ C2]ethylene oxide 448 diastereoselective 331–2, 558–64, 583–90 14 methyl [2,3- C2]propiolate 447 enantioselective 536 14 2-[2,3- C2]propyne-1-ol 447 aldoses 162, 406–7 Index 641 alkali metal [14C]cyanates 415–16 aminobenzoic acids, exchange labeling 91 alkali metal thio[14C]cyanates 416–19 3-amino[3-14C]crotonates 353–4, 379–80 [o-methyl-14C]alkanes 267 aminodecarboxylation 499–501; see also alkoxycarbonylations 271 Curtius degradation alkoxycarbonylmethylenezinc bromide aminoenones, exchange labeling 87 (Reformatsky reagent) 335–7 m-amino[3H]levamisole 52 alkyl [14C]acetoacetates 346–57 aminomethylations 248–53, 401–2 acylation reactions 351–2 1-amino[14C]propan-2-one 292 aldol-type reactions 352–3 amino[3H]quinuclidines 124–5 alkylation reactions 348–51 aminotransferases 612–13 functional group reactions 356–7 ammonia lyases 614 Knoevenagel-Michael reactions 353–6 ammonium thio[14C]cyanates 416 preparation 346–8 [14C]amrinone 430–1 [3H/14C]alkylamines, by alkyl AMS see accelerator mass spectrometry replacement 488–91 analytical procedures alkyl diazoacetates 318–21 chemical identity 6–7 alkyl (dimethylsulfanylideene)[14C]- chemical/enantiomeric purity 7–8 acetates 333 label position 10–11 alkyl methyl [14C]ketones 291 radiochemical/radionuclidic purity 8–9 alkyl [U-14C]phenyl ketones 459 specific activity 9–10 alkyl 2-(phenylsulfonyl)[14C]acrylates 333–5 aniline derivatives, exchange labeling 3 [ Hn]alkylboranes 169 by acid catalysis 52, 54 alkyloxy[14C]carboxylations 232 by heterogeneous catalysis 62 14 [ C2]alkynols 442–3 iridium complex-catalyzed 85, 90–1 14 14 [ C2]alkynylations 442 [ C]anilines 451–3 all-E-[14C]retinoic acid 326 [14C]anisoles 343–4, 455–6 [14C]allethrolones 346 [14C]anthracyclines 432–3 14 14 [2,3- C2]allyl alcohol 447 [1- C]arabinose 273 [14C]alosetron 229–30 [2H]arachidonic acid 512 [3H]alprazolam 64 Arbuzov reaction 531 [carbonyl-14C]amides 226 [guanidino-14C]arginines 465–6, 476 [14C]amidines 409–10 aristolochic acids, exchange labeling 75 [14C]amidoximes 409 aryl[1-14C]carbinols 246 [1-14C]amines aryl/heteroaryl [14C]aldehydes 238–40 from acetophen[14C]one 536, 540 aryl/heteroaryl, diaryl [14C]ketones 224, 227, from [14C]cyanides 402 291–2, 302–3 amino acid dehydrogenases 616 -aminomethyl 292–3 amino acids aryl[14C]acetates 295–6 by biotransformation 616 aryl[1-14C]methyl chlorides 246 by diastereoselective synthesis 567–9, 574, aryl methyl [14C]ketones 227, 291–2 575, 577, 580–2 aryl [14C]methyl ketones 365 by enantioselective synthesis aryloxy[14C]acetates 330 (reduction) 530–4 aryloxy[14C]carboxylations 232 by optical resolution 527–9, 608–12 (S)-[13C]aspartic acids 318, 575–7, 582 from N-acylated 2,3-amino acids 530–1 [14C]astemizole 471–2 from [14C]cyanide by Strecker-Bucherer [14C]atomoxitine 537–8 synthesis, 406 [14C]atorvastatins 305, 562–3 from [14C]cyanide by Strecker synthesis, 406 [3H]avermectin affinity label 151 aminoacetophenones, exchange labeling 91 [13/14C]avermectin B1 626–7 aminobenzoic acids, exchange labeling 76 [14C]avermectin B1a 514–16, 560 642 Index

[14C]avermectin B1b 560 benzoic acid branch 458–9 8-[2-14C]azaadenine 235 bromobenzene branch 456–7 14 5-[6- C]azacytidines 235–6 by C3-C3 condensations 343–4 14 5-aza[2,4- C2]cytosine 467 iodobenzene branch 457–8 8-[4-14C]azaguanine 427, 430 nitrobenzene branch 451–4 [14C]azapropazone 375–6 pathways for ring-labeled 14 [ C2]aziridinium salts 448–9 aromatics 449–50 azlactones, in exchange labeling of amino phenol branch 454–6 acids 53 preparation 448–9 [14C]azlactones, Erlenmeyer reagents 316 sulfonylbenzene branch 459–60 [14C]azulenes 18–19, 400 [3H]benzene derivatives 54, 63 benzenesulfonamides, exchange labeling 85 -amino acid esters, carbon-14 314–15 [U-14C]benzenesulfonyl chloride 459–60 -blockers 36–7 [3H]benzimidazole derivatives 52, 68 0 14 3 -[15,15 - C2]carotene 442 [ H]benzoate esters 78–79 B-chlorodiisopinocampheylborane [14C]benzodiazepines 235, 276, 318 (DIP-chloride) 535 [1-14C]benzoic acids 368–9 -hydroxy--amino acids 583–5, 590 [ring-U-14C]benzoic acids 458–9 14 3 -[6,7- C2]ionone 443 [ H]benzoic acids 72, 75, 76 -keto esters [14C]benzophenones 408 [14C]acetoacetates, preparation and [3H]benzophenones 79, 81, 145 reactions 346–57 benzotriazol-1-yl groups 394 from [14C]acyl halides 347–8 [3H]benzoyl derivatives 78, 81 from [14C]malonates 357–8, 364 [14C]benzthiophenes 332–3 homologation of [14C]acetoacetate 350–1 [3H]benzthiophenes 59 in Hantzch dihydropyridine synthesis [3H]benzylamine groups 90–1 243, 354 [U-14C]biphenyls 452–3 in steroid A-ring labeling 504–5 biotransformations 607–38 [3H]baccatin III 39–41, 482 cell-containing (fermentative) Barbier reaction 349 systems 618–30 [14C]barbiturates 377–8 cell-free systems (isolated [14C]barbituric acids 375, 469–70 enzymes) 608–11 barium [14C]carbonate conjugation reactions 618 14 [ C2]acetylene tree 441 enantiomerically pure syntheses [14C]cyanide tree 393–4 612–17 preparation and as storage form of [14C]- functional group transformations carbon dioxide 4–5, 211–12 619–21 see also [14C]carbon dioxide tree; multi- multi-enzyme systems 618 carbon building blocks; one-carbon optical resolutions via derivatives building blocks 608–12 Barton reaction 497–9 reconstitution strategies 607, 630–4 base-catalyzed hydrogen isotope [14C]bisaramil 251 exchange 56–60 Bishler–Napieralski reaction 570 2 [ H4]benomyl 52 bishydroxylation 513–14 [ring-U-14C]benzaldehydes 455 [11C]bisoprolol 342 [3H]benzamide derivatives 73, 75, 78, 81 bisphosphine ligands 532–4 14 2 [ C]benzazepines 318–19, 332–3, 507, 509–10 [ H]bleomycin A2 50–1 14 14 [ Cn]benzeneoid aromatics 343–4, 368–9, [ C]bopindolol 37, 339 3 381, 448–60 [ Hn]borane 147, 167–9 alkyl phenyl ketone branch 459 boranes 541 Index 643

Bremsstrahlung radiation 4 carbohydrates, exchange labeling 94–5 bromo[14C]acetic acid/esters 307–8 [14C]carbon dioxide tree aryloxy[14C]acetates from 330–2 [14C]acetic acid 287–9 C-alkylations 315 [14C]acetic acid esters 301–7 chiral glycinates from 318–334 [14C]acetic anhydride 298–301 [14C]glycines from 315 [14C]acetone 337–46 [14C]glyoxylates from 332 [14C]acetyl chloride 289–98 reductions 311–2 alkyl [14C]acetoacetates 346–57 two-carbon P-ylidee olefination reagents [14C]carbon dioxide 211–22, 486–8, from 312, 322–9 492–501 two-carbon S-ylidee olefination reagents [14C]carbon monoxide 222–32 from 333 [14C]formaldehyde 221–2, 240–56 three-carbon olefination reagents from 325, [14C]formic acid 233–40 341–2 halo[14C]acetates 307–37 [14C]glycolic acid/esters from 330 [14C]malonates 357–81 bromo[14C]acetyl halides 308 [14C]methyl iodide 222, 256–70 N-halo[14C]acetylamides/imides multi-carbon building blocks 287–391 (simple) 310–1 [14C]nitromethane 270–7 N-halo[14C]acetylamides/imides (chiral one-carbon building blocks 211–85 auxiliaries) 317, 326–7, 586–90 [14C]carbon dioxide 211–22 14 14 -halo[ C]methyl ketones from 309–10 [ C2]acetylene tree 441 bromo[U-14C]benzenes 452, 456–7 in [14C]carboxylations of bromo[14C]ethanol 311 organometallics 212–18 Buchwald reaction 456–8 in [14C]carboxylation of in situ generated building blocks see multi-carbon building carbanionic species 215–8 blocks; one-carbon building blocks; small in [14C]carbonylation of primary and tritiated building blocks secondary amines 220–1 buspirone 470–1 manipulation of [14C]carboxylation 14 1,3-[1,4- C2]butadiene 403 products 218–19 14 14 1,4-[1,4- C2]butanediol 403 N-[ C]acyl building blocks 219–21 tert-[14C]butanol 339 preparation of important building tert-[14C]butylamine 338 blocks 221–2 14 2-[2,3- C2]butyne-1,4-diol 447 reconstitution strategies 486–8, [14C]butyrolactones 305–7, 362 492–501 [14C]carbon disulfide 268–9 C-[14C]acylation 289, 305–6, 309–10 [14C]carbon monoxide 222–32 C-dealkylation–realkylation 491–3 chlorination 229 cadmium organometallics 262 [14C]carbonylation of [14C]caffeines 233, 472 organoboranes 223–4, 226 [2H]caffeine 79, 88 [14C]carbonylation of aryl/heteroaryl [14C]calanolide 446, 528 halides 224–6 [3H]calcitonin 113 [14C]carbonylative cross couplings 226–7 [3H]camptothecins 86, 94 [14C]carboxaminations 226 [guanidino-14C]canavanine 465–6 homogeneous catalysis 223–5, 226–8 [14C]cannabinoids 265, 369–70 in reconstitution strategies 501 [14C]carbamates 230, 232, 298 [14C]phosgene from 221, 229–32 [14C]carbamoyl chloride 220 preparation of 222, 224–5 carbanion-mediated hydroxymethylation and reduction to [14C]formic acid 222, 233 methylenation 242–5 reduction to [14C]formaldehyde 222, 240 [3H]carbergolines 121 reduction to [14C]methanol 222, 256 644 Index

[14C]carbon monoxide (Continued ) [14C]methyl iodide 222, 256–70 14 14 reduction to [ C]carbon monoxide methyl [2,3- C2]propiolate 447 222, 224 multi-carbon building blocks 411–33, carbon-14 441–63, 465–78 14 14 [ C2]acetaldehyde 445–6 N-[ C]acyl building blocks 219–21 14 14 [ C2]acetic acid 446–7 [ C]nitromethane 270–7 [14C]acetic acid 287–9 nucleophilic methylation and [14C]acetic acid esters 301–7 methylenation 262–8 [14C]acetic anhydride 298–301 one-carbon building blocks 211–85 [14C]acetone 337–46 [14C]phosgene 221, 229–32 [14C]acetyl chloride 289–98 photoinitiated carbonylations 228 14 [ C2]acetylene tree 441–63 physical properties 3–5 14 [ C2]acetylene 441–5 polycondensations 255 acid-catalyzed hydroxymethylations 246–8 production 4 14 14 alkyl [ C]acetoacetates 346–57 2-[2,3- C2]propyne-1-ol 447 aminomethylations 248–53 purification of compounds labeled barium [14C]carbonate 4–5, 18, 32–3, with 5–6 211–12, 393–4, 441 reductive methylations 254–5 14 [ Cn]benzene 448–60 replacement strategies 485–8 biotransformations 608–9, 612, 618–21, specialist techniques and equipment 15–20 624–30 stability and storage of compounds labeled 14 2-[2,3- C2]butyne-1,4-diol 447 with 11–15 carbanion-mediated hydroxymethylation and target preparation 25–36, 39–44 methylenation 242–5 thiomethylations 256 [14C]carbon dioxide tree 211–85, 287–391 [14C]thiourea 472–7 [14C]carbon dioxide 211–22 [14C]urea 468–72 [14C]carbon monoxide 222–32 carbon–carbon bond cleavage 514–17 carbonylation with organoboranes 223–4, 1,1-[14C]carbonyldiimidazole 229–31 226 1,1-[14C]carbonyldi-1,2,4-triazole 229–31 carboxylations of organometallics 212–18 carboxylic acids, exchange labeling of 77 [14C]cyanamide tree 465–78 [14C]carboxylic acids [14C]cyanamide 465–7 2-amino-3-hydroxy, chiral 313–4 [14C]cyanide tree 393–439 by -alkylation of esters using alkyl chloro diastereoselective synthesis 549–50, [14C]formates 232 551–81, 584–96 by [14C]carbonylation of aryl or heteroaryl 14 [1,2- C2]dibromoethane 448 halides or triflates 224–6 14 14 dimethyl [2,3- C2] by [ C]carboxylation of organolithium acetylenedicarboxylate 447 or magnesium (Grignard) electrophilic methylations 257–62 compounds 212–5 14 14 [ C2]ethylene oxide 448 by [ C]carboxylation of in situ generated [14C]formaldehyde 221–2, 240–56 carbanionic species 215–9 [14C]formamidine 476–7 by oxidative [14C]carbonylation of [14C]formic acid 233–40 organoboranes 223 [14C]guanidine 467–8 conversion to [14C]acetic anhydride 219 halo[14C]acetates 307–37 conversion to [14C]acyl halides 219 heterogeneous catalysis 213, 223–5, 226–8 esterirication 219 [14C]malonates 357–81 from [14C]acyl halides and diazomethane manipulation of [14C]carboxylation (Arndt-Eister reaction) 433 products 218–19 reduction to [1-14C]alcohols 219 metal [14C]cyanides 393–411 carboxylic esters, exchange labeling of 58 Index 645 carboxypeptidases 608–9 selectivity versus reducible [3H]caroteneic acid 149 functions 142–4 [14C]carotenes 442 [U-14C]catechol 454 [14C]carotenoids 326, 400 [14C]cavicholic acid 497 castanospermine 303–4 CBS see Corey–Bakshi–Shibata catalytic tritiations 109, 110–32 CCKB antagonists 220–1 catalysts, heterogeneous 111–2, 122–3, [14C]cefclidine 311–12 128–30 [14C]cefepime 475 catalysts, homogeneous 126–8 cell-containing (fermentative) diastereoselective 132 systems 618–30 enantioselective 131–2 functional group transformations 619–21 heterogeneous 111–26 hydrolysis of nitriles 620–1 homogeneous 126–32 redox reactions 619–20 isotopic scrambling 111–4, 131 transfer reactions 620 of aldehydes 125–6 cell-free systems 607–18 of alkenes 112–3, 128 amino acid dehydrogenases 616 of alkynes to alkanes 120–1, aminotransferases 612–13 128–31 ammonia lyases 614 of alkynes to alkenes 121–2 conjugation reactions 618 of aromatics 123–4 enantiomerically pure syntheses 612–17 of enamines 118–9 lactate dehydrogenases 615 of heteroaromatics 124–5 multi-enzyme systems 618 of imines, iminium salts 125–6 N-acyl cleavage 608 of ketones 125–6 N-acylation 608 of nitriles 126 O-acyl cleavage 608–10 of unsaturated amino acids and O-acylation 611 peptides 112–3, 120, 131–2 optical resolutions 608–12 of ,-unsaturated carbonyl oxoreductases 616–17 compounds 118 racemases 612 of ,-unsaturated carboxyl redox reactions 611–12 compounds 118 tryptophan synthetase 614–15 selectivity among C,C-multiple [14C]cephalosporins 419, 475 bonds 115–8, 122–3, 128–30 ceramide glucosyltransferase inhibitors 157 selectivity versus reducible chemical decomposition 12 functions 118–20 chemical purity 7–8 stereoselectivity of addition 130–1 chemical resolution 527–8 catalytic tritiolyses 109, 132–46 chemical synthesis 2 catalysts 133–4, 142, 145–6 devolatilization 16–20 of alkyl halides 135–7 fluorodesilylation 181 of aryl halides 133–5, 138–44 planning 29–32 of aryl aldehydes and ketones 144–5 radical translocation 175–6 of benzylic N- and O-functions 144–5 reconstitution strategies 479–522 of heteroaryl halides 133–5, 138–44 Shapiro reaction 180 of heteroaryl aldehydes 144–5 solid-phase synthesis 18–19, 124 of thioacetals, thioketals, disulfides 134, specialist techniques and equipment 15–20 145–6 telescoping reactions 17–18 selectivity among different tritiated building blocks 109, 178–95 halogens 138–40 with tritium 3 selectivity versus C,C-multiple with carbon-14 3 bonds 140–2 see also target preparation 646 Index chiral acetic acid 164 cross-metathesis-effected 12C/14C chiral auxiliaries 547–50 exchange 485–6 14 chiral building blocks 549, 561, 572–3 [3,4- C2]crotonitrile 445–6 chiral [13C]glycolate 332 C-tritiomethylation/ chiral methanol 164 tritiomethylenation 187–90 [14C]chloramphenicol 245, 523 Curtius degradations 219–20, 314–5, 499 chloro[14C]acetic acid/esters 307–8 see also [14C]cyanamides 465–78 bromo[14C]acetic acid/esters [14C]cyanamide, preparation 413–16, chlorodehydroxylation 377–8 465–7 chloro[14C]formates; alkyl, aryl 232 [14C]dicyandiamide 415–6 chloro[14C]methyl benzyl ether 248 [14C]formamidine 476–7 1-chloro-1-nitrosocyclohexane (CNC) 566, [14C]guanidine 401, 467–8 567–71 [14C]thiourea 472–7 [14C]chlorpromazine 254 [14C]urea 468–72 1-chloro[14C]propan-2-one 292 [14C]cyanates 415–16 [14C]cholesterols 322–3 [14C]cyanides 393–439 13 14 [23,24- C2]cholic acid 503 alkali metal [ C]cyanates 415–16 2-[2-14C]chromanone 402 alkali metal thio[14C]cyanates 416–19 chronic myelogenous leukemia 41 -cyanation of pyridines 399 trans-[14C]chrysanthemic acid 342 cyano-deoxygenation 396 chymotrypsin 609–10 [14C]cyanoacetic acid 420–31 [14C]cinafloxin 365 [14C]cyanogen bromide 413–15 [14C]cinnamic acids 300, 366–7 [14C]cyanohydrins 406–7 [14C]cinnolines 373–4 [14C]diazomethane 431–3 2 [ H10]cipemastat 620 hydrolysis 402–7 [3H]ciprofloxacin 64 in displacement reactions 394–7 14 [1,2- C2]citral 443 in Kilani-Fischer synthesis 406–7 -[14C]citronellol 342 in Rosenmund-von Braun reaction 395–6 Claisen condensations introduction into organic substrates 394–9 as side reaction 166 metal [14C]cyanides 393–411 in reconstitution strategies 506 multi-carbon building blocks 411–33 of [14C]acetone 344–5 preparation (M ¼ K, Na, Cu, Zn) 393–4 of alkyl [14C]acetates 302–4 triethyl [14C]orthoformate 419–20 clavulanic acid 628–9 trimethylsilyl[14C]cyanide 395, 412–14 CNC see 1-chloro-1-nitrosocyclohexane cyano-deoxygenation 396 [3H]coenzyme A 94–5 [14C]cyanoacetic acid/esters 420–31 14 14 [ C]coenzyme Q10 348–50 2-acetamido-2-cyano[2- C]acetate 427 competitive tritiolysis 119–20 -alkylations and -arylations 421–3 computer-assisted ADME studies 28 cyclocondensations 428–31 conjugation reactions 618 electrophile reactions 425–7 [13C]coniferyl alcohol 325 ethyl ester 269 construction strategies 29–32, 39–44 Knoevenagel reactions 423–5 convergent synthesis 35–6 methylene group reactions 421–7 copper–zinc couple 181, 190–1 preparation 420–1 Corey–Bakshi–Shibata (CBS) reactions with aldehydes and reagents 535–6, 539 ketones 423–5 Corey–Fuchs reaction 512–13 [14C]cyanogen bromide 413–15 14 cotrimerizations 449 [ C2]cyanoguanidine 467 [14C]coumarins 364–5, 563–4 [14C]cyanohydrins 398–9, 407 covalent attachment methods 525–6 [2-14C]cyanopyridine 399 Index 647

[14C]cyanopyrimidones 426–7 derivatization strategies 34, 38, 52–3 [14C]cyanuric acid, [14C]cyanuric [3H]desipramine 52 chloride 470–1 [14C]desmosterol 503 cyclic ,-unsaturated carbonyls 503–5 Dess–Martin oxidations 506, 540 cyclic ureas 220–1, 415–17 desulfurization 476–7 cycloadditions deuterium 19–20 14 [ C2]acetylene tree 443–4, 447 biotransformations 615, 617 [14C]cyanide tree 411, 413 deuterolysis reactions 141, 143 metathesis reaction 485–6 diastereoselective synthesis 555–6, of chiral , -unsaturated imides and 558, 583 esters 591 isotope exchange reactions 47–8, 56–62, [14C]cycloalkanones 402, 403–4, 408 65, 71, 75–80, 85–6, 89–93 cyclocondensations 428–31 methyllithium 189–90 [1-14C]cyclohexanone 214 devolatilization 16–20, 137 [-14C]cyclohexanones, ,ß-unsaturated 262 dexamethasone 512 cyclopentenyl[2-13C]glycine 610 [14C]dextromethorphan 258–9 14 14 [ C]cyclopropanations 321, 346 trans-1,2-diamino[1,2- C2]cyclohexane 404 [14C]cyclopropancarboxylic acids 320–1, 333 di-tert-butyl azodicarboxylate [14C]cyclopropenations 321 (DBAC) 566–7 cyclopropyl methyl [14C]ketone 306–7 diastereomeric salts 525–6 [14C]cyclosporins 571–2 diastereoselective synthesis 546–96 biological labeling 186 -alkylations of chiral glycinates 571–83 [14C]cyclopeptolide 571–2 -alkylations of chiral imide diastereoselective synthesis 571–2, 589, enolates 551–7 592–3 -aminations of chiral imide [3H]cyclosporin A 64, 114, 131, 140–2, enolates 566–71 481–2 -hydroxylations of chiral imide chemical synthesis 114, 131, 140–2 enolates 571 isotope exchange reactions 71 1,4-additions of chiral imide enolates to reconstitution strategies 481–2 Michael acceptors 564–5, 592–5 [14C]cyphenotrin 320 advantages over enantioselective [14C]cysteines 244, 249, 614–5 synthesis 546–8 5-[6-14C]cytidine 235 aldol reactions of chiral glycinates 583–90 cytochrome P450 28, 135 aldol reactions of chiral [14C]cytosines 474–6 haloacetates 586–90 from [14C]urea 469 aldol reactions of chiral imides and enolates 558–64 Darzens reactions 312–13 chiral auxiliaries 547–50, 582, 584 DBAC see di-tert-butyl azodicarboxylate chiral building blocks 549, 561, 572–3, de-racemization 529 582, 584 dealkylation–realkylation 488–92, 632–4 ester enolates 558–64 [14C]daunorubicin 432 glycinates 571–86 8-deaza[2-14C]adenines 235 glycolates 586 3-deaza[8-14C]adenosine 233 haloacetates 586–90 deaza[14C]guanines 418 imides 558–64, 591–6 deaza[14C]purines 233, 425 quaterny stereogenic centers 556–7, 580 [14C]decaprenol 350 reactions on chiral Michael decomposition, radiation induced 12–15 acceptors 592–5 Delleria’s glycinate 581–3 removal of auxiliaries 551–2, 585 14 deoxy-D-glucose 401 [ C]diazepam 318 648 Index

[14C]diazoacetates 318–21 [14C]carbon monoxide replacement 501 2-diazo[2-14C]malonates 272–3 carbon-14 488–517 3 [ Hn]diazomethane 193–4 carbon–carbon bond cleavage 514–17 [14C]diazomethane 431–3 dealkylation–realkylation 488–92 diazonium salts 373–4, 451–3, 500 1,2-glycols 509–14 14 [1,2- C2]dibromoethane 448 halo-decarboxylation 494–8 1,3-dibromo[14C]propane 380–1 hydroxy-decarboxylation 498–9 N,N-dibutyl[14C]formamide 237 malonate approach 492–4 14 1,o-di[ Cn]carboxylic acids 214 oxidative cleavage of olefins 502–17 [14C]dichloxacillin 351 ozonolysis 502–9 [14C]diclofenac 456–8 target preparation 32–4, 38–9 Dieckmann condensations 404, 423 tritium 488–92 Diels–Alder reactions dispersion of radiolabeled molecules [14C]carbon dioxide tree 242–3 13–14 [14C]cyanide tree 403 distribution see ADME studies 3 diastereoselective synthesis 547–8, 591, 1,3-dithian-2-ylmyrtanyl[ H2]borane 169 595–6 di[14C]methylcadmium 263 [3H]digoxigenins 116 diphenyl[14C]methylsulfonium [3H]dihydrocarbergoline 121 tetrafluoroborate 265 [13C]dihydroisocoumarins 563–4 dithiocarbamates, from thio[14C] [14C]dihydroisoquinolines 570 cyanate 417–8 dihydro[14C]pyridines 239, 243, 291, [14C]methyl 268 353–4, 380 dithiocarboxylates, [14C]methyl 268 3,4-dihydroxy[1-14C]cyclohexane[14C]- [14C]dithiopyr 354 carboxylic acid 626 DNA, exchange labeling 50 1,3-dihydroxy[14C]propane 380–1 DoM see directed ortho-metalation 3 3 [ Hn]diimide 182–3 [ H]DOPA 67 [14C]diiodomethane 346 [14C]dopamine 272–3 3 [ Hn]diiodomethane 190–1 dopamine agonists 229–30 [14C]dilevalol 292 [14C]doxorubicin 432–3 [14C]dimedone 370 dual labeling 27 14 14 dimethyl [2,3- C2] [ C]duloxetine 537–8 acetylenedicarboxylate 447 dimethyl[14C]formamide 237 EADC see ethylaluminium dichloride dimethyl[3H]formamide 192–3 enamines dimethylbenzamides, exchange labeling 88–9 catalytic tritiation 118–9 direct metalation, in tritium labeling 59–60 cyanoborotritide reduction 158 direct replacement see isotope exchange enantiomeric purity 8 reactions enantioselective synthesis 529–46 directed ortho-metalation (DoM) 216–17 ,-unsaturated amino acids 530–4 in tritium labeling 59 hydrogenation/tritiation 530–4 of [ring-U-14C]benzoic acids 458 oxidation of olefins and allylic of [U-14C]phenols 454 alcohols 541–6 [14C]discodermolide 328 reductions of ketones and oximes [3H]discodermolide 159–60 535–41 disconnection–reconnection enol lactones 262 strategies 488–517 enones, exchange labeling 87 amino-decarboxylation 499–501 enterolactones, exchange labeling 55 [14C]carbon dioxide replacement enzymes see cell-containing systems; 492–501 cell-free systems Index 649 epoxidations flavanoids, exchange labeling 55 enantioselective synthesis 542–6 fluoro[U-14C]benzene 451 in metabolism 29 fluorodesilylation 181, 245 [14C]methylsulfoxonium iodide 266 [14C]fluorouracils 427–8 [14C]epoxides 266, 294, 313 [14C]fluoxetine 537–8 Erlenmeyer’s azlactone synthesis 316 [14C]fluvastatin 309, 352–3 14 3 [ C]erucic acid 513 [ Hn]formaldehyde 191–2 [14C]erythromycin 254 [14C]formaldehyde 240–56 [14C]eserine 298 in amino[14C]methylation of C-H acidic ester enolates 58, 558–64 compounds 248–51 [14C]estradiol 492–4 in amino[14C]methylation of reactive [14C]ethanol 290 aromatics/heteroaromatics 250–51 ethylaluminium dichloride (EADC) 55–6 in chloro[14C]methylations 246 ethoxymethylene[14C]malonates 363 in cyclizations 253 14 [ C2]ethylene glycol 448 in cyclizations with 3,4-unsaturated 14 [ C2]ethylene oxide 448 butylamines 251–3 14 14 [ C2]ethynyltestosterone in hydroxy[ C]methylations 243–8 [3H]etorphines 119 in [14C]methylenation of -ketoesters and Evans’ auxiliaries 551–6, 564–5, 586–8, malonates 242–3 591–2 in reductive methylation of carbonyl exchange strategies (direct replacement) 32, compounds 254–5 41 in thio[14C]methylation of C-H acidic 14 CO2/ CO2 487, 492–3 compounds 256 exchangeable pools 49 polycondensations with 255 excretion see ADME studies preparation from [14C]carbon [11C]exaprolol 342 dioxide 221–2, 240–1 [14C]formamides, N,N-disubstituted 237–8 [14C]farnesylacetic acid 350 in [14C]formylation of electron-rich aryl/ fast labeling 25–6 heteroaryl compounds 238–240 [2H]fasudil, hydroxy 619–20 in [14C]formylation of electron-poor FDH see formate dehydrogenase metallated compounds 239–40 fermentative syntheses 621–30 [14C]formamidine 476–7 dilution 621 formate dehydrogenase (FDH) 615 experimental setup 622 [14C]formates 221, 235 incorporation 621 [14C]formic acid 233–40 inhibitors 624–11 acetic [14C]formic anhydride from 236–7 metabolites 618, 619–20 2-amino-[1,3,4][5-14C]thiadiazoles precursor selection 624 from 234 requirements 623–30 N,N-disubstituted [14C]formamides sensitivity to isotopic substitution 630 from 236–7 specific incorporation 621 esterification 235 [2/3H]ferrocenes 53, 59 in -formylation of carbonyl [14C]ferulic acid 626 compounds 236–7 14 14 five-[ Cn]carbon reagents [2- C]indoles from 235 14 [ Cn]furan-2-one, 5 hydroxy-4- preparation 233, 237 methyl 326 [14C]purines and deaza[14C]purines 14 methyl 3-methyl-2-[ Cn]butenoate, from 233–5 achiral 326, 340 formyl[14C]acetate, alkyl 303 FK-506 see tacrolimus formylamino[14C]malonates 371 flash chromatography 6 [1-14C]formyl-5-methylimidazole 235 650 Index fractional crystallization 527 in reconstitution strategies 505 Friedel–Crafts reactions 1-methyl[1-14C]cyclohexanol 306–7 of [U-14C]benzene 459 reaction with [14C]acetone 338–9 [14C]carbon dioxide tree 292, 303, 309–10 [14C]griseofulvin diester 420 of [U-14C]phenols 455 Grubbs’ catalyst 486–7 Fujimoto–Belleau reaction 263, 503–6 [14C]guanidine 377–8, 414–15, 467–8 14 14 [3,4- C2]furan 447 [ C]aminoguanidine 418–19 [14C]furanones 326–7 [14C]guanines 233, 427, 430 14 [ C2]guanylideneurea 467 ,-unsaturated acids and esters 268 -[14C]keto acids 362 halo[14C]acetates 307–37 [14C]galantamines 258, 488–9 carbon nucleophile reactions 314 [3H]galantamines 142, 166 carboxyl group reactions 309–12 ganglioside GM1 631–15 halogen atom reactions 314–37 gastrointestinal stromal tumors (GIST) 41 methylene group reactions 312–14 [3H]geldanamycin 137, 630 nitrogen nucleophile reactions 314–21 [14C]gemifloxacin 365 oxygen nucleophiles 330–2 [3H]genistein 55 phosphorus nucleophile reactions 321–8 [14C]geraniol 264, 339–40 preparation 307–8 [14C]geranylacetone 348–9 silicon functionalities 329–30 [14C]gibberellins 505–6, 509 sulfur nucleophiles 332–5 [3H]gibberellins 151 haloacetates 586–90 [3H]ginkgolide B 152 halodecarbonylation 501 (see also [1-14C]glucose 273 Hunsdiecker, Barton reactions) [3H]-D-glucose 164 halodecarboxylation 494–8 (S)-[13C]glutamic acid 334 halohydrins 294 [14C]glutamic acids 371–2, 485, 612–3 -halo[14C]methyl ketones and -halomethyl [14C]glutaraldehyde 380 [14C]ketones 292–3, 309–310 [14C]glutaric acid 380 Hantzsch dihydropyridine synthesis 14 14 [2,6- C2]glutarimides 405 of dihydro[ C]pyridines 353–4 [14C]glutaronitrile 380 via 2-acyl[14C]acrylates 243 [14C]glycerols 18, 243, 374 via aryl [14C]aldehydes 400 [14C]glycidic esters 313 Hell–Vollhard–Zelinski reaction 308 glycinates, chiral 317–8, 571–86 Helmchen’s auxiliaries 591–2, 594–5 [14C]glycines 315–18, 412, 531–2 heptafluorobutyric anhydride 53–4 [14C]glycolates, chiral 331–2, 586 [3H]herbimycin A 181 [14C]glycolic acid 330 heterogeneous catalysis 1,2-glycols in reconstruction aqueous media 67–8 strategies 509–14 carbonylation with [14C]carbon glycosides 400 monoxide 223–5, 226–8 [4,40-3H]gossypol 53–4 carboxylation with [14C]carbon Grignard reagents dioxide 213 [14C]acetic acid isotopomers 288 catalytic tritiations 109, 110–26 addition to [14C]nitriles 407–8 isotope exchange reactions 60–71 as tritiated building blocks 189–90 metals 61–5, 67–9, 70–1 carboxylation with [14C]carbon organic media 68–9 dioxide 213–15 selectivity of 61–2, 67–9 from [14C]methyl iodide 259–60, 262–4 with tritiated water 60–6 in diastereoselective synthesis 591 with tritium gas 66–71 in preparation of [14C]methyl ketones 290 [14C]hexobarbital 375 Index 651 high-temperature solid-state catalytic isotope via [14C]methylation 259 exchange (HSCIE) 93–6 diastereoselective synthesis 556–7 [3H]homocysteine 186 [14C]ibutilide 536–7 homogeneous catalysis [14C]imatinib 41–4, 465–6 acid-catalyzed exchange 51–6 [3H]imidazoles, C2 labeling by exchange 50 base-catalyzed exchange 56–60 [14C]imidazoles catalytic tritiations 126–32 from [14C]cyanogen bromide 415–6 exchange without added acid/base 49–51 from [14C]formic acid 234–5 isotope exchange reactions 49–60, from [14C]thiocyanate 419, 507–9 71–7 labeling by reconstitution 507–27 metal salts 71–3 [14C]imidazopyridines 318–19 organometallics 73–93 imide enolates ortho-labeling 83, 84–6 -alkylations 551–7 phase transfer catalysis 57–8 -aminations 566–71 selectivity 71, 76–93 -hydroxylations 571 sp2 sites, non ortho 86–8 1,4-additions to Michael acceptors 564–5 sp3 sites 88–90 diastereoselective synthesis 551–7, 564–71 steric effects 81–2 imides 226–7 [14C]homogentisic acids 296 in diastereoselective synthesis 558–64, [2-14C]homoserine 371–2 591–6 Horner–Wadsworth–Emmons reactions imines 53, 401 14 [ C2]acetaldehyde in 445–6 iminium ions 53, 126–7, 152, 158, 253 for extension of methyl [14C]ketones 350 [14C]iminoesters 410 from halo[14C]acetates 307, 321–8 in vitro metabolism studies 30 in diastereoselective synthesis 552, in vivo metabolism studies 30 568–9, 595–6 [14C]indanones 367, 402–3 in enantioselective synthesis 530–1, 545 1H-indazole[14C]carboxylic acid 422–23 in reconstitution strategies 496 indirect replacement 32–4, 42 labeled two-carbon extensions 218 [14C]indole-2-carboxylates 36–7 on [14C]acetone 338–40 [3H]indoles 86 HSCIE see high-temperature solid-state [14C]indoles catalytic isotope exchange 3-amino[14C]methyl, from [14C]- human radiolabeling studies 31 formaldehyde 250 Hundsdiecker degradations 406, 494–7 from [14C]acetoacetates 350 [14C]hydrazones 373–4 from [14C]acetyl chloride 297 -hydroxy acids 615 from [U-14C]aniline 451 hydroxy-decarboxylation 498–9 from [14C]cyanide 401 4-hydroxy[ring-U-14C]benzoic acid 455 from ethyl [14C]formate 235 -hydroxy[14C]carboxylic acids/esters from nitro[14C]methane 272–3 305, 336 in reconstitution strategy 510 4-hydroxy[14C]coumarins 237 in synthetic strategy development 36–7 hydroxymethylations 242–8 indolyl[14C]acetic acid 250 13 hydroxy[ C4]midazolam 619 insect juvenile hormone III 324–5 [8-14C]hypoxanthine 233 interhalogen selectivity 138–44 [14C]HYTRA 305 internal proton return 59 iodo[14C]acetic acid 307–8 [3H]ibogaine 59–60 iodo[U-14C]benzenes 457–8 [3-13C]ibuprofen 503 [14C]iodoform 346 [14C]ibuprofen iodo[14C]pyridines 363–4 14 14 by CO2/CO2 exchange 487 -[ C]ionone 400 652 Index iridium catalysts Jacobsen–Katsuki epoxidation 542, 546–7 in catalytic isotope exchange 69–72, [14C]jasmonic acids 368, 498–9 74–93 [14C]juvenile hormones 324–5 in catalytic tritiations 126 juvenoid derivatives, exchange labeling 68 [3H]isocarbacyclin methyl esters 129 [14C]isocyanates 220, 230 [3H]kainic acid 189–90, 506–7 isolated enzymes see cell-free systems [14C]ketanserin 471–2 [14C]isoleucine 593 -keto[1-14C]aldehydes 237 [14C]isopropanol 341 -keto[4-14C]carboxylic acids/esters 314–5, [14C]isopropyl halides 341–2 350 [14C]isopropylamines 342–3 -[14C]keto esters 302, 345 [methyl-14C]isopropyltriphenylphosphonium ketones, -labeling by exchange 50, 56–7, 66 iodide 265 KIE see kinetic isotope effect [14C]isothiocyanates 417–18 Kiliani–Fischer synthesis 406–7 isotope concentration, in exchange Kim–Corey procedure 481 labeling 48 kinetic isotope effects (KIE) isotope effects see kinetic isotope effects isotope exchange reactions 48 isotope exchange reactions 32–3, 47–107 metabolic switching 28 acid-catalyzed exchange 51–6 reduction-oxidation strategy 483 base-catalyzed exchange 56–60 target preparation 28–9 deuterium 47–8, 56–62, 65, 71, 75–80, tritide reductions 146–8 85–6, 89–93 Knoevenagel reactions direct metalation 59–60 of [14C]cyanoacetates 423–5 exchange without added acid/base 49–51 of [14C]malonates 354–8 exchangeable pools 49 with [14C]formaldehyde 243 heterogeneous catalysis 60–71 with halo[14C]acetates 312, 333 homogeneous catalysis 49–60, 71–93 Knoevenagel–Doebner modification 366 internal proton return 59 Knoevenagel–Michael reactions 353–6 isotope concentration 48 Knorr synthesis 355 kinetic control 58–60 kinetic isotope effects 48 lactams 303–4 oligonucleotides 50–1 lactate dehydrogenases (LDH) 615 phase transfer catalysis 57–8 [14C]lactic acids 357 photoaffinity-labeling 82–3 [25-14C]lanosterol 503 progress towards equilibration 48 Lawesson’s reagent 374 solid-state catalysis 93–6 LDH see lactate dehydrogenases solvent-free catalysis 93–8 lead acetate 509, 512–13 thermal tritium atom bombardment 96–7 Lehnert procedure 365, 368 thermodynamic control 56–8 (S)-[14C]leucine 580–1, 593–5, 616 tritium 47–107 (S)-[3H]leucine 113 isotopic fractionation in chromatography 7 [14C]leucotrienes 312 isotopic labels [3H]leukotrienes 122–3 chemical stability 27 [3H]levamisole 52 dual labeling 27 [14C]levulinic acid 350 metabolic stability 27 [3H]ligands position 10 dihydro FK-506 115 isotopic scrambling 111–14, 130–2, 146 kainic acid 189–90, 506–7 [14C]isovaleric acids 571–2 naloxone 121 [14C]isoxazoles 345–6, 351 nociceptin 113 Itsuno catalysts 535 raclopride 186 Index 653

nicotine 186 methylene group reactions with nitrogen urocortin 113 electrophiles 370–4 lignanolactones, exchange labeling 55 methylene group reactions with nitrogen Lindlar’s catalyst 121–3, 142, 442 nucleophiles 374–8 linear synthesis 35–6 Michael additions 368–70 lipases 610–11 oxidation of methylene group 374 liquid scintillation counting (LSC) 8, 9–10 preparation 357–8 [3H]lisuride 142 selective saponification 360 3 14 lithium [ H2]boratabicyclo[3.3.1]nonane 166–7 [ C]malondinitriles 429 14 14 lithium [ C2]acetylidee 442–3 [ C]malonyl dichloride 381 lithium aluminum hydride Mannich reactions 192, 248–52 diastereoselective synthesis 552 Mannich–Overman reactions 252–3 enantioselective synthesis 536–7, 539–40 [1-14C]mannose 273 preparation of [14C]formaldehyde 240–1 MAP-kinase inhibitors 229–30 preparation of [14C]methyl iodide 256 mass spectrometry (MS) 31 14 reduction of [ C]acetyl chloride 290 MDBT2 169 reduction of alkyl [14C]phenyl mechanical separation of enantiomers 527 ketones 459–60 [14C]medroxyprogesterone 512 reduction of [14C]malonate Meldrum’s acid 291, 346–8, 365, 379–80 derivatives 374, 380–1 [14C]menaquinone 350 reduction of [14C]nitriles 399–400 [3-14C]mepindolol 37 lithium aluminum tritide 147, 170–2 [14C]mepindolol 297, 342 lithium borotritide 147, 161–3 mercury(II) catalysis 444 lithium [14C]methylborinates 264 [14C]mesoporphyrin, cobalt(II) 265 lithium Super-Tritide 163–5 [3H]mesulergine 114 lithium T-Selectride 165–6 metabolic switching 5, 28–9 lithium tri-sec-butylborotritide 165–6 metabolism see also ADME studies lithium triethylborotritide 163–5 metabolic stability 26–29 lithium tritide 160–1 metabolic switching 28–9 liver homogenates 619 primary metabolites 622 [14C]loprinone 431 secondary metabolites 623 LSC see liquid scintillation counting metal [14C]cyanides 393–411 lysergic acid [14C]diethylamides 298 carbon nucleophiles 407–8 (S)-[3H]lysine 113 cycloadditions 411, 413 13 (S)-[2,6- C2]lysine 574–5 displacement reactions 394–7 hydrolysis 402–7 McKillop rearrangements 295–6 in preparation of [14C]nitriles 409–10 Madelung synthesis 236–7 nitrogen nucleophiles 409–10 [14C]malonates 232, 267, 357–81, 492–4 nucleophilic additions 397–9 -acylation 346–8, 365 oxygen nucleophiles 402–7 -alkoxymethylenation 364–5 reduction 399–402 -alkylation 359–62 synthetic transformations 399–411 -arylation 362–4 metal–halogen exchange 215–16 ,-dialkylation with ,!-dihalides metathesis-effected 12C/14C exchange 485–6 carboxyl function reactions 374–81 methanesulfonyl azide 372–3 decarbalkoxylation 361 [14C]methanol 241 hydride reduction of ester functions 380–1 methionines Knoevenagel reactions 365–8 application in biosynthesis 625 [14C]malonyl dichloride 381 [methyl-14C] 259 3 Meldrum’s acid 365, 379–80 [methyl- Hn] 186 654 Index

[3H]methoprenes 116–17 [14C]methyllithium 263–4 methoxy[14C]methyltriphenylphosphonium in cross coupling of [14C]methyl borinates chloride 247 and stannanes 264–5 [3H]methyl arylsulfonates 186–7 [14C]methylmagnesium halides 262–3 [14C]methyl azastannanes 264 8-[2H]methylquinoline 79 methyl [1-14C]carbinols (sec, tert) [14C]methylphosphonate, diethyl 218 263–4 [14C]methyltriphenylphosponium 2-(N-methyl-N-[14C]formyl)- halides 264–5 aminopyridine 237 -[14C]methyltryptophan 259, 609 methyl groups, exchange labeling 89 [14C]methylzinc reagent 265 3 14 [ Hn]methyl iodide 136–7, 183–90, 556 [ C]methysergide 488–9 14 14 [ C]methyl iodide 222, 256–70 [4,5- C2]mevalonolactone 443 [2-14C]acetic acid from 288 [14C]mevalonolactone 303–4, 345 [2-14C]acetonitrile from 269–70 Meyers’ bislactam approach 556–7 as electrophilic methyl group Michael additions 271–2, 274–5, 368–70 synthon 257–62 Michael–Claisen reactions 368–70 [14C]carbon disulfide from 268–9 Michaelis–Arbusov reactions 323–4 diastereoselective [14C]midazolam 276 C-tritiomethylations 552, 556 [14C]mitomycins 230, 491–3 in C-[14C]methylations 259–62, 263–4, [3H]mitomycins 151 265–6 Mitsunobu reactions 294, 537, 539, 615 in N-[14C]methylations 257–8 moenomycins 543 in O-[14C]methylations 258–9 [14C]morphines 488–9 in S-[14C]methylations 259, 267–8 [14C]moxifloxacin 365 in P-[14C]methylations (for Wittig and [14C]moxonidine 378, 410–11 Horner-Emmons olefinations) 265–6 MS see mass spectrometry in nucleophilic methylation and multi-carbon building blocks 14 methylenation 262–8 [ C2]acetaldehyde 445–6 14 in preparation of important building [ C2]acetic acid 446–7 blocks 268–70, 288 [14C]acetic acid 287–9 [14C]methyl phenyl sulfone from 267–8 [14C]acetic acid esters 301–7 preparation from [14C]carbon dioxide [14C]acetic anhydride 298–301 222, 256 [14C]acetone 337–46 [14C]methyl phenyl sulfone 267–8 [14C]acetyl chloride 289–98 14 14 methyl [ C]isocyanate 298 [ C2]acetylene tree 441–63 14 14 [ C]methyl ketones 262–3, 267–8 [ C2]acetylene 441–5 N-[14C]methyl-N-nitroso-p- alkali metal [14C]cyanates 415–16 toluenesulfonamide 431 alkali metal thio[14C]cyanates 416–19 methyl [14C]olivetolate 369–70 alkyl [14C]acetoacetates 346–57 14 14 [ C]methyl phenyl sulfone 267–8 [ Cn]benzene 448–60 14 14 N-methyl-N-phenyl[ C]formamide 237 2-[2,3- C2]butyne-1,4-diol 447 14 14 methyl [2,3- C2]propiolate 447 [ C]carbon dioxide tree 287–391 14 methyl [1,6,- C3]salicylate 447 carbon-14 411–33 [14C]methyl--tocotrienol 249–50 [14C]cyanamide tree 465–78 N-methyl-N-p-tolyl[14C]formamide 237 [14C]cyanamide 465–7 N-[14C]methylamines 232 [14C]cyanide tree 411–33 3 14 methyl[ H2]borane 169 [ C]cyanoacetic acid 420–31 [14C]methylcuprates 260, 263 [14C]cyanogen bromide 413–15 methylenations 242–5, 262–8 [14C]diazomethane 431–3 14 methylene groups, exchange labeling 89 [1,2- C2]dibromoethane 448 Index 655

14 14 dimethyl [2,3- C2]- [ C]nicarpidine 353 acetylenedicarboxylate 447 [14C]nimopidine 291, 353 14 14 [ C2]ethylene oxide 448 [ C]nisopidine 353 [14C]formamidine 476–7 [14C]nifedipine 354 [14C]guanidine 467–8 [14C]niridazole 475 halo[14C]acetates 307–37 [14C]nitrepidine 353 [14C]malonates 357–81 nitrile hydratases 620–1 14 14 methyl [2,3- C2]propiolate 447 [ C]nitriles 14 2-[2,3- C2]propyne-1-ol 447 addition of carbon nucleophiles 407–8 [14C]thiourea 472–7 addition of nitrogen nucleophiles 409–10 triethyl [14C]orthoformate 419–20 addition of oxygen nucleophiles 402–7 trimethylsilyl[14C]cyanide 412–13, 414 -amino[14C]nitriles 398–99 [14C]urea 468–72 benzo[14C]nitriles 395–7, 408–9 multi-enzyme systems 618 cycloadditions with 411, 413 [14C]myristic acids 562, 589 -hydroxy[14C]nitriles 398–99 hydrolysis with enzymes 620 N-[14C]acyl building blocks 219–21 nucleophilic additions to 397–9 N-acyl cleavage 608 reductions of 399–402 N-[14C]acylation 289, 301, 310–1 synthetic transformations of 399–411 of chiral auxiliaries 555, 559–60, 564–5, -[14C]nitroalcohols 272 569, 573, 577–8, 589, 592 nitroaldol reactions 272–4 N-[3H]acylation 181, 194 nitro[14C]arenes 275, 343–4 N-alkylamines 488–9 [14C]nitroalkanes 271 N-dealkylation–realkylation 488–9 [14C]nitrobenzenes and derivatives 451–4 N-methylations 257–9 [3H]nitrobenzene derivatives 70, 85 N-succinimidyl [2,3-3H]propionate 195 -nitro[14C]carboxylates 274 N-tritioacetoxyphthalimide 194–5 nitro[2-14C]malonates 370 N-tritiomethylations 184–6 [14C]nitromethane 270–7 NAD see nicotinamide adenine dinucleotide addition/elimination reactions of 276–7 NADPH-dependent cleavage 27 alkoxycarbonylations of 271 Nafion 65–6 C-alkylations of 270–1 [3H]naloxone 121–2 condensation reactions 271–5 [14C]naphthalenes 448, 459 dimerizations of 271–2, 277 [14C]naphthyridines 364–5 electrocyclization to [14C]nitroaryls 275–6 13 2 [ C, H3]naratriptan 489–90 homologation of sugars (Sowden-Fischer [3H]nedocromil sodium 73 synthesis) 272–3 nemadectin 628 in Michael additions 274 nickel catalysts nitroaldol reaction of 272 in catalytic tritiations 125–6 preparation 270 in catalytic tritiolyses 134, 139, [14C]nitroolefins 272, 274 145–6 NMR see nuclear magnetic resonance in isotope exchange reactions 61, [3H]nortriptylin 171 64–5 nuclear magnetic resonance (NMR) [14C]methyl iodide 264–5 chemical identity 6–7 nickel salts 154 isotope exchange reactions 61, 63, 70 [3H]nicotinamide adenine dinucleotide label position 10–11 (NAD) 94–5 nucleophilic desulfurization 476–7 nicotinamide adenine dinucleotide nucleophilic methylation and (NAD) 616–17 methylenation 262–8 nicotinic acids 356 nucleosides, exchange labeling 67 656 Index

O-acyl cleavage 608–10 organoborons 558–60 O-[14C]acylation 289, 299 organocadmiums 262 O-dealkylation–realkylation 489–90 organoiridiums 70, 74–93, 126 O-[14C]methylations 258–9 organolithiums O-tritiomethylations 186 carboxylation with [14C]carbon [14C]octreotride 580 dioxide 215–17 olefinations formylation reactions 239–40 Horner–Wadsworth–Emmons 323–8 [14C]methyl iodide 264 Peterson 329–30 reaction with [14C]acetone 338–9 Still–Gennari 328 organometallics Wittig–Horner 322–3, 340–2 carboxylation with [14C]carbon olefinic compounds, exchange labeling 71 dioxide 212–18 [14C]oleic acid 509 deprotonation of C–H acidic substrates 218 oligonucleotides, exchange labeling 50–1 directed ortho-metalation 216–17 one-carbon building blocks 211–85 in preparation of [14C]acetic acids 288 acid-catalyzed hydroxymethylations 246–8 metal–halogen exchange 215–16 aminomethylations 248–53 reaction with [14C]acetyl chloride 290 barium [14C]carbonate 211–12 transmetalation 217, 263 carbanion-mediated hydroxymethylation and see also Grignard reagents methylenation 242–5 organorhodiums 126–32 [14C]carbon dioxide 211–22 organorutheniums 73–4, 126 [14C]carbon monoxide 222–32 organotins 290 carbonylation with organoboranes 223–4, organozirconiums 176–7 226 (S,S)-[5-3H]ornithine 567–8 carboxylations of organometallics 212–18 ortho labeling 84–6 electrophilic methylations 257–62 osmium catalysts 509–11 [14C]formaldehyde 221–2, 240–56 O-tritiomethylations 185–6 [14C]formic acid 233–40 [14C]oxadiazoles 409, 420 heterogeneous catalysis 213, 223–5, 226–8 [14C]oxaloacetates, dialkyl 302 manipulation of [14C]carboxylation oxazaborolidines (CBS) catalysts 539 products 218–19 1,4-[3-13C]oxazin-2-one, N-Boc-5-phenyl [14C]methyl iodide 222, 256–70 (Dellaria’s reagent) 318, 334 N-[14C]acyl building blocks 219–21 1,3-oxazolidin-2-ones 551–8, 561, 564–7, [14C]nitromethane 270–7 583–4, 586 nucleophilic methylation and 4-benzyl-3-[2-(4-methoxybenzyl)[13C]- methylenation 262–8 acetyl] 332 [14C]phosgene 221, 229–32 [14C]oxazolidinones 332 photoinitiated carbonylations 228 [14C]oxazolones 316 polycondensations 255 oxidation–reduction preparation of important building biotransformations 631–2 blocks 221–2, 268–70 hydroxyls 480–3 reductive methylations 254–5 oxidative cleavage 502–17 selectivity 216–17 oximes 87 thiomethylations 256 oxiranes Oppolzer’s auxiliaries/buidling blocks 551–6, [14C], chiral 294 564–5, 586–8, 591–5 diastereoselective synthesis 590 optical resolution enantioselective synthesis 537, 543–4 by biotransformations 608–12 [3H]oxoguanosines 94 by chemical processes 524–9 oxoreductases 616–17 organoboranes 223–4, 226 ozonolysis 502–9 Index 657

[3H]paclitaxels 36–41, 82–3, 168 phenyl[1-14C]acetic acid, 4-nitro 422–3 derivatives 38, 41, 82–3 9-phenyl[9-2H]fluorene 60 [14C]paclitaxels 313–4 phenyl groups, exchange labeling 90, 92 7-O-[14C]acetyl 299 [U-14C]phenyl ketones 459 13 14 [ C6]BMS-275183 41–2 [ C]phenylalanines 567–8, 576–7, 581 palladium catalysts [3H]phenylalanines 131–2, 580, 614 14 14 [ C2]acetylene tree 456–9 [U- C]phenylboronic acids 452–3, 456–7 in carbonylations with [14C]carbon phenyl[1-14C]glycine 529 monoxide 223–5, 226–8 [U-14C]phenylhydrazine 451 in carboxylations with [14C]carbon phenylpyridines 87–8, 91 dioxide 221 [3H]PHIP 55 in catalytic tritiations 109–28 [14C]phosgene in catalytic tritiolyses 133–45 preparation from [14C]carbon dioxide 221 in cross-coupling reactions 226–8 preparation from [14C]carbon [14C]cyanide tree 396–7, 407 monoxide 229 in diastereoselective synthesis 591 synthetic uses 229–32 in isotope exchange reactions 61–4, 67–9, [14C]phosgene surrogates 229–231 71, 93–6 phosphono[14C]acetates, alkyl bis(2,2, in methylations with [14C]methyl 2-trifluoroethyl) 328 iodide 260–2, 264, 267–8 phosphono[2-14C]acetates, trialkyl 265, in preparation of [14C]formaldehyde 241 323–8 with tritiated silanes 177–8 phosphono[2-14C]acetonitrile, diethyl 269 with tritide reagents 154–6 phosphono[14C]propionates, trialkyl 325, [3H]papaverine 133–4 341–2 [14C]paraherquamide A 515–17 [14C]phosphorus ylidees 213, 264–6, 321–3 paroxetine 247, 525 [3H]phosphorus ylides 189–90 [3H/14C]paspalic acid 628 photoaffinity-labeling 82–3 Pearlman’s catalyst 143 photoinitiated carbonylations 228 [14C]peptides 525–6, 632 [14C]phthalic acids 449, 459 [3H]peptides [3H]phthalic acid 62 N-[3H]acetyl 194–5 phytosphingosines 545–6 N-[3H]formyl 165, 193 Pictet–Spengler reactions 253 by exchange labeling 95 [14C]pilocarpine 507, 509 Leu labeled: urocortin, nociceptin, [14C]pindolol 37, 342, 447 neurotensin, salmon calcitonin 113 [3H]pinoline 126–7 14 Lys labeled: antamanide 120 [ C2]pipecolic acid 575, 595, 626–7 Met labeled 186 [2H]piperazines 42 N-[2,3-3H]propionyl 195 [3H]piperazines 74, 89 14 peptides 525–6, 632 [ C2]piperazine 448 Perkin reactions 299–300 [3H]piperidines 74 [14C]permethrin 509, 511 [14C]piperidines 374–5, 402, 448–9 Peterson-olefination 329 [14C]piperidones 251–2, 374–5 2 13 Pfitzer–Moffat variant 481 [ H3, C]pivalic acid 556–7 pharmacokinetics 27 platinum catalysts phase transfer catalysis 57–8 in catalytic tritiations 114, 116–18, [14C]phenanthrolines 303 123–6, 134 [ring-U-14C]phenethylamine 459 in isotope exchange reactions 61–3, 71, 93 [14C]phenobarbital 375 [3H]pleuromutilin 71, 114 [U-14C]phenols 454–6 polycondensations 255 [3H]phenols 51, 62, 63 polyhalides 135 658 Index polymer resins 65–6 from [14C]acetoacetates 354–5, 356 [13C]porphobilinogen 296 from [14C]formaldehyde 243 14 porphyrins 505, 507 from [2,6- C2]glutarimides 405 positron emission tomography 3 [14C]pyridopyrimidines 468, 476–7 14 14 potassium [ C2]acetylidee 442 [ C]pyrimidinediones 375–7, 428 practolol, N-[14C]acetyl 297 [14C]pyrimidines [14C]pravastatin 552–3, 619 from [14C]amidines 409–11 [14C]pregnenolone 407–8 from [14C]bromocyanogen 415–16 primary external decomposition 12 from triethyl [14C]orthoformate primary internal decomposition 12 419–20 prochiral carbonyls 535–9, 541 from cyano[14C]acetate 427–8 prochiral oximes 539–41 from [14C]guanidine 467–8 [3H]progesterone 484–5 from [14C]malonates 375–8 (S)-[3H]proline 113 from [14C]thiourea 472–4 13 14 (S)-[2,6- C2]proline 574–5 from [ C]urea 468–72 14 14 [2,3- C2]propargyl alcohol 447 [2- C]pyrimidine-6-ones 467–8 14 14 2-[2,3- C2]propyne-1-ol 447 [ C]pyrimidones 426–7 [14C]prostacyclin 492 [14C]pyronaridine 250–1 [14C]prostaglandins 213, 265, 330–1 pyrroles, exchange labeling 70 [3H]prostaglandins 115, 122, 129 [14C]pyrroles 355 proteins pyrrolidines, exchange labeling 70, 89 N-[14C]acylated 297 [14C]pyrrolidinone 275 [N-methyl-14C] 254 [14C]pyrrolopyrimidines 469–70 proteins, exchange labeling of 96 [11C]pyruvic acid 611 [14C]protoporphyrin IX dimethyl ether 505, 507 [3H]quinazolines 124–5 [14C]pseudoephedrins 576–8 [2-14C]quinazoline-2,4-dione 416 [14C]pseudomonic acid 325 [14C]quinolines Pummerer rearrangements 491, 492 [14C]carbon dioxide tree 276, purification of labeled compounds 5–6 364–5, 380 [14C]purines [14C]cyanide tree 399 9-deaza 425 [3H]quinolines by isotope exchange 78–9, from cyano[14C]acetate 427–30 84–5, 88 from [14C]formic acid 233 [14C]quinolones 364–5, 380 from [14C]guanidine 467–8 [3-14C]quinuclidine, 4-cyano 312 from triethyl[14C]orthoformate 419–20 QWBA 30 [3H]purines, C8 labeling by exchange 50 [14C]pyranones 381 racemates pyranouronic acids 618 chiral HPLC separation of 524–5 [14C]pyrazoles 345 crystallization of diasteromeric salts 525 [14C]pyrazolin-5-ones 356–7 racemase enzymes 612 [14C]pyrethrin I 320 resolution 524–9 [3H]pyridaben, photoaffinity probe 162 resolution by enzymes 608–12 pyridine[14C]acetic acid esters 363 resolution, dynamic kinetic 529, 612 [3H]pyridines reracemization 529 by heterogeneous catalytic exchange 65, 69 radical scavengers 14, 123 by iridium complex-catalyzed radical translocation 175–6 exchange 75, 78, 81, 88 radiochemical purity 8–9 [14C]pyridines radiolytic decomposition 11–15 cyano[2-14C]pyridine 399 radionuclidic purity 9 Index 659

Raney nickel replacement strategies 32–4, 479–88 [14C]carbon dioxide tree 374 [14C]resorcinols 355–6, 368–70 in catalytic reduction of carbonyls 125–6 [14C]retinoic acids 325–7, 340, 443 [14C]cyanamide tree 476 [3H]retinoic acids 189 [14C]cyanide tree 399–401 [14C]retinoids 265, 400 in selective tritiodehalogenations 139 [3H]retinoids 149, 171, 189 in tritiodeoxygenations 134 retrosynthesis 29–32, 42 in tritiodesulfurizations 145–6 rhodium catalysts isotope exchange reactions 64–5 in catalytic tritiations 119–20, 123–32, 134 [14C]rapamycins in enantioselective synthesis 532–4 by biotransformation 575, 627–8 in isotope exchange reactions 69, 72–3, 77, 14 from [ C2]cyclohexenecarboxylic 93, 95 acid 327–8 in [3H]silane additions 177–8 [3H]rapamycin 175–6 [14C]riboflavin 377, 629 40-(2-hydroxyethyl) 164–5, 175–6 [3H]riboflavin 631 receptor binding assays 30 [1-14C]ribose 273 3 reconstitution strategies 3, 479–521 D-[ H]ribose 125–6 amino-decarboxylation 499–501 rivastigmine 294, 536, 540 biotransformations 607, 630–4 Rosenmund–von Braun reaction 395–6 [14C]carbon dioxide replacement 486–8, ruthenium catalysts 492–501 in catalytic tritiations 119–20, 123–5, 126 [14C]carbon monoxide replacement 501 in diastereoselective synthesis 591 carbon-14 485–517 in isotope exchange reactions 69, 72, 73–4 carbon-carbon bond cleavage 514–17 in reconstitution strategies 480–1, 486–7 cross-metathesis-effected 12C/14C exchange 485–6 S-[14C]acylation 289 dealkylation–realkylation 488–92, 632–4 S-dealkylation–realkylation 490–1 disconnection–reconnection S-ylides 333 strategies 488–517 Sandmeyer reactions 453–4 1,2-glycols 509–14 [14C]sagopilone 486–7 halo-decarboxylation 494–8 [14C]safrole 512 hydroxy-decarboxylation 498–9 [14C]salinomycin 623 malonate approach 492–4 [3H]sanglifehrin 166 oxidation–reduction 631–2 Schmidt reactions 316–17 oxidative cleavage of olefins 502–17 Schollkopf’s€ bislactam ether 581–2, 586 3 ozonolysis 502–9 [ Hn]Schwartz’s reagent 176–7 replacement strategies 479–88 second order asymmetric transformation 529 target preparation 32–4, 38–42 secondary decomposition 12–13 tritium 479–85, 488–92 secondary isotope effect 5 two-step ,-dehydrogenation/ Seebach’s reagent 584–5 tritioreduction of carbonyls 483–5 Sekiya–Ishikawa reaction 396–7 two-step oxidation–reduction of [14C]semicarbazides 231 hydroxyls 480–3 [14C]serines 244, 585, 589, 624 recrystallization 6 SFC see supercritical fluid chromatography redox biotransformation reactions 611–12, Shapiro reaction 180 619–20 Sharpless bishydroxylation 542–4, 546 reductive alkylations 157–8 Sharpless epoxidation 542, 544–6 14 reductive methylations 254–5 [1,2- C2]shikimic acid 444 Reformatsky rearrangements 305, 335–7, 340–1 Simmons–Smith reactions 190–1, 346 Reissert–Henze reaction 399 [14C]sinapic acid 626 660 Index

-[3-14C]sitosterol 504 oxidation-reduction 480 Skraup synthesis 374 oxidative cleavage 502–17 small-scale equipment 15–16 reconstitution 32, 38–41, 479–521 sodium borotritide 147, 148–57 replacement see reconstitution sodium [3H]cromoglycate 73 Strecker modifications 406 sodium cyanoborotritide 147, 157–9 S-tritiomethylations 186–7 14 sodium/tetramethylammonium [ C2]suberic acid 406 triacetoxyborotritide 159–60 [14C]succinic acids 403, 448 [14C]solanesylacetone 350 [14C]succinic acid, -alkyl, chiral 314–5 14 solid-phase synthesis 18–19, 124 [2,3- C2]succinic anhydride 448 solid-state catalysis 93–6 [14C]succinimides 405 solvent isotope exchange 109–10 N-succinimidyl [2,3-3H]propionate 195 14 solvent-free catalysis 93–8 [2,3- C2]succinonitrile 448 Sowden–Fischer reactions 272–3 [14C]sugars 272–3, 401, 406–7 specialist techniques and equipment 15–20 [3H]sugars 94–5 specific activity 9–10 sulfonyl[U-14C]benzenes 459–60 [14C]spermines 375–6 sulfonyl[14C]ureas 229 spillover hydrogen phenomenon 93–4 sultams 554–5, 564–8, 571, 573, 577, 590–3 [3H]spirooxindolamine 115–16 [14C]sumatriptan 507, 509–11 [14C]squalenes 265, 271–2, 341–2, 348–50 supercritical fluid chromatography (SFC) 6 [3H]squalenes 513–4 Suzuki couplings 264, 452–3 [14C]squaric acid 331 Suzuki cross-couplings 512–13, 533 stability of radiolabeled compounds 11–15, 36 stabilizing solvents 14 TA see thermal tritium atom bombardment [14C]stanozolol 237 tacrolimus [14C]sterculic acid 320–1 by biotransformation 623–5 [14C]steroids by diastereoselective synthesis 586–7 A-ring labeling 305–6 dihydro 115 14 [ C2]acetylidee addition to 442 carbon-13 labeled 331–2 [14C]cyanide tree 399 tritium labeled 64 hydroxy[14C]methylenation 237 target preparation 2, 25–45 nucleophilic [14C]methylation 262 ADME studies 25–31, 44 reconstitution strategies 484–6, 497, 503–4 case studies 36–44 side chain labeling 322–3 construction strategies 29–32, 39–44 [3H]steroids convergent synthesis 35–6 by catalytic tritiation 115–6, 129–30, 153 derivatization strategies 34, 38 by isotope exchange labeling 55–6, 67, 79 dual labeling 27 by tritiodehalogenation 173–4 exchange strategies 41 via C-methylations 187–8 fast labeling 25–6 via Shapiro reaction 180 intermediates 35–6, 44 Still–Gennari reactions 308, 328 linear synthesis 35–6 Stille reactions 264–5 metabolic switching 28–9 storage of radiolabeled compounds 11–15, 36 number of radiolabeled steps 35 strategies planning strategies 29–44 carbonyl replacement 501 reconstitution strategies 32–4, 38–42 carboxyl replacement 492–9 resource availability 25–6, 30–2, 35–6 construction 29, 41–44 retrosynthesis 29–32, 42 dealkylation–realkylation 42, 488–92, specifications for 25–9 632–4 stability and storage 36 derivatization 34 strategy selection 34–6 Index 661 tartaric acid 529 [3H]tiazofurin 94 [3H]taxadienes 190 Tiffeneau–Demjanov rearrangements 402 telescoping reactions 17–18 titanium catalysts 555–6, 558–9, 564–5 [14C]temocillin 367–8 TLC see thin layer chromatography [14C]terbinafine 339 -[12-13C]tocopherol 503 [3H]terodiline 54–5 -tocotrienol, 5-[14C]methyl 250 [14C]terpenoids 325, 339–40 [14C]toluene 306 [14C]testosterone 306, 442 o-[3,4,5,6-14C]toluic acid 449 3 2 [ H]testosterone 485–6 [ H3]tradamol 28–9 tetrahydro[14C]cannabinol (THC) 369–70 [3H]-trans-zeatin 96 [14C]tetrahydrofurans 383 transesterification 552, 555 [14C]tetralone 362, 459 transfer reactions 620 tetramethylammonium transmetalation 217, 263 triacetoxyborotritide 159–60 ,-[14C]trehalose 624 [14C]tetrazoles 411, 413 triacetoxyborotritide 159–60 thalidomide 523 trialkyl phosphonoacetates see THC see tetrahydrocannabinol phosphonoacetates; Horner–Wadsworth– [14C]theobromine 471–2 Emmons reactions 14 3 [ C]theophylline 233, 472 [ Hn]trialkylsilanes 177–8 thermal transcarboxylation 487–8 [14C]triamcinolone 512 thermal tritium atom (TA) [14C]triazenes 414–15 bombardment 96–7 [14C]triazolines 401 [14C]thiadiazoles 234–5, 418 [14C]triazolones 410 [14C]thiazoles 410, 475 tri-n-butyltin tritide 172–6 [14C]thiazolines 475–6 tricyclic [14C]lactams 332 thin layer chromatography (TLC) 6, 8–9 triethyl [14C]orthoformate 419–20 [14C]thioamides 410–1, 413 triflate displacement 152 thio[14C]cyanates 416–19 trifluoroacetic acid, in exchange labeling 51, thio[14C]carbamates 220–1 53–4, 58 thio[14C]methylations 256 trifluoro[14C]methyl derivatives 269 [14C]thionin 254 [14C]trifusal 457 [14C]thiopental 361, 375–6 [14C]triglycerides 374 [14C]thiophenes 367–8 [14C]trilazad 469–70 [14C]thiosemicarbazides 418–19 trimethylsilyl[14C]acetate, benzyl 329 [14C]thiosemicarbazones 417–18 trimethylsilyl[14C]cyanide 412–13, 414 [14C]thiouracils 474 [14C]trimethylsulfonium iodide 266 [14C]thiourea 417–8, 467, 472–7 1,2,2-triphenyl-1,2-ethandiol-2-[14C] Thorpe–Ziegler condensations 408 acetate 301 14 14 three-[ Cn]carbon reagents triptyline, nor-[N-methyl- C] 232 Horner–Wadsworth–Emmons trisyl azide 566–8 propionate 329 tritiated alkylboranes 169 [14C]isopropylphosphonium and –sulfonium tritiated borane 147, 167–9 reagents 341–2 tritiated building blocks 109, 178–95 2-(phenylsulfonyl)[13C]acrylic acid acetic [3H]formic anhydride 192–3 esters 334 N-[3H]acetoxyphthalimide 194–5 [14C]threonines 351–2, 585 [3H]diazomethane 193–4 [14C]thymines and [14C]thymidines [3H]diamide 182–3 from [14C]urea 468–9 [3H]diiodomethane 190–1 from 2-[14C]cyanopropionic acid 422 dimethyl[3H]formamide 192–3 [3H]thymine 145 [3H]formaldehyde 191–2 662 Index tritiated building blocks (Continued ) of alcohols to alkanes via tosylates, [3H]methyl iodide 183–90 triflates 152, 163–4 [3H]methyllithium 189 of allylic alcohols to alkanes 158–9 [3H]methylmagnesium halides 188–9 of aldehydes 148–9, 158 [3H]methyl p-nitrobenzenesulfonate 19–20 of alkenes to alkanes 154–5 [3H]methyltriphenylphosphonium of alkenes to alkylboranes halides 189–90 (enantioselective) 169 N-succinimidyl [2,3-3H]propionate 195 of alkyl halides 154, 156, 176 tritiated water 179–81 of alkynes to alkanes 154–5, 176 tritiated diazomethane 193–4 of alkynes to alkenes 168, 178 tritiated diimide 182–3 of amides to amines 163, 169, 170 tritiated diiodomethane 190–1 of tert-amides to alcohols 163 tritiated formaldehyde 191–2 of anhydrides 162–3 tritiated methyl iodide 183–90 of aryl halides 155–6 tritiated Schwartz’s reagent 176–7 of carbamates 171 tritiated trialkylsilanes 177–8 of carbon dioxide 165, 172 tritiated water 179–81 of carboxylic esters 150, 153, 165, 167, tritiations see catalytic tritiations 170–1 tritide reagents of -hydroxyketones to cis diols [3H]boratabicyclo[3.3.1]nonane 166–7 (stereoselective) 159–60 3 [ Hn]borane 167–9 of enamines 158 3 1,3-dithian-2-yl[ Hn] of epoxides 164 myrtanylborane 166–7 of imines, iminium salts, peptides, lithium aluminum tritide 170–2 proteins 152, 157, 158 lithium borotritide 161–3 of ketones 148–9, 153, 162; lithium tri-sec-butylborotritide (stereoselective) 166–7 (L-Selectride) 165–6 of -keto esters to ,-unsaturated lithium triethylborotritide (L-Super- esters 176 Tritide) 163–5 of lactones to aldoses 162, 164 lithium tritide 160–1 of nitriles 154 Schwartz’s reagent 176–7 of nitroalkanes to alkanes 175 sodium borotritide 148–57 of nitroolefins to nitroalkanes 151 sodium borotritide-metal salt of propargylic esters to allylic alcohols 171 reagents 153–5 of ,-unsaturated carbonyl compounds to sodium borotritide-palladium(0) allylic alcohols 149, 151, 153, 166, reagents 156 168, 171 sodium cyanoborotritide 157–9 of ,-unsaturated carbonyl compounds to sodium cyanoborotritide-zinc iodide 158–9 saturated ketones 151, 173 sodium triacetoxyborotritide 159–60 of ,-unsaturated esters to saturated tetramethylammonium esters 154, 166 triacetoxyborotritide 159–60 of ,-unsaturated sulfones to saturated [3H]triethylsilane 177–8 sulfones 151 [3H]trihexylsilane 177–8 of ,-unsaturated nitriles to saturated tritide reductions 109, 146–78 amines 154 isotopic scrambling in 146 protic media 147 kinetic isotope effects in 146–8 radical translocation 175–6 of acyl halides 149–50 reductive alkylations 157–8 of alcohols to alkanes via N-tritioacetoxyphthalimide 194–5 aryloxythiocarbonates, tritiodehalogenations 133–44, 156, 163, 173 alkyldithiocarbonates 173–4 tritiodenitration 174–5 Index 663 tritiodeoxygenation 158–9, 173–4 Horner–Wadsworth–Emmons 323–6 tritiodesulfurizations 134, 145–6 glycolate (chiral) 332–3 tritiolyses see catalytic tritiolyses HYTRA (chiral) 305 tritiomethylations see C-, N-, O-or malonates 359–70 S-tritiomethylations Meldrum’s acid 379–80 tritium PABS (chiral) 326–7, 586–90 analysis of compounds labeled with 6–11 Peterson reagent 329 applications 1–2 Schmidt reagent 317 biotransformations 614, 617–18, 626, 629, Still–Gennari reagent 328 631–4 Wittig–Horner reagents 322–3 catalytic tritiations 109, 110–32 two-step ,-dehydrogenation/tritioreduction catalytic tritiolyses 109, 132–46 of carbonyls 483–5 chemical synthesis 3 two-step oxidation–reduction of devolatized building blocks 137 hydroxyls 480–3 disconnection–reconnection [14C]tyrosines 456, 581–2, 611 strategies 488–92 [3H]tyrosine derivatives 68–9 enantioselective synthesis 530–41 heterogeneous catalysis 60–71 Ullman synthesis 453 homogeneous catalysis 49–60, 71–93 ,-unsaturated carbonyls 118, 148, 173, 214 homogeneous catalytic tritiations 126–32 [14C]uracils isotope exchange reactions 47–107 6-amino[6-13C]uracil 429 physical properties 3–5 E-5-(2-bromo[2-14C]vinyluracil 366 production 4 from [14C]cyano acetate 427–8 purification of compounds labeled 5-fluoro[14C]uracil 427 with 5–6 from ethyl formyl[1-14C]acetate 303 replacement strategies 479–85 from [14C]malonates 377–8 solvent-free catalysis 93–8 from [14C]urea 468–9 specialist techniques and equipment 15–20 from [14C]thiourea 473–4 stability and storage 11–15 uranium tritide 16 target preparation 25–41 [14C]urapidil 377–8 tritiated building blocks 109, 178–95 [14C]urea 468–72 tritide reductions 109, 146–78 ureas tritiodehalogenations 133–44, 156, 173 from [14C]acetyl chloride 298 tritiodenitration 174–5 from [14C]carbon dioxide 220–1 tritiodeoxygenation 158–9, 173–4 from [14C]cyanamide 467 tritiodesulfurizations 134, 145–6 from [14C]cyanate 415–17 Zn–Cu couple/tritiated water 181 from [14C]phosgene 229, 231–2 tritium atom bombardment (TA) 96–7 [14C]uric acid 472 tritium NMR 11 tRNAs, exchange labeling 50 vacuum line systems 16–7 tryptophan synthetase 614–15 [11C]valines 611 tryptophans [13C]valine 613 [alanine-2-14C], from [14C]malonate 370–1 [14C]valines 317, 574, 580, 594 [alanine-3-14C], from [14C] [2H,13C]valine 545 formaldehyde 250 [14C]valproic acid 361 applications in biotransformations 614–15 1-O-valproyl--D-glucopyranoic acid 618 enantiomeric purity 528–9 [14C]valsartan 574 preparation by biotransformation 628 [14C]vardenafil 409–10 14 14 two-[ Cn]carbon reagents [ C]veronal 375 BABS (chiral) 326–7, 586–90 verruculogen 625 664 Index

Vilsmeyer–Haack reactions 238–40 Wittig–Horner labeled reagents and vinyloxycarbonyls (VOC) 259 reactions 307, 322–3, 329–32 [14C]vitamin A 259 [14C]vitamin B2 377, 629 xanthates, [14C]methyl 269 [3H]vitamin B2 631 [14C]xanthines [3H]vitamin D analog 56 from [14C]cyanate 471–2 [14C]vitamin D analog 329 from [14C]cyanoacetate 427–30 VOC see vinyloxycarbonyls from imino[14C]ester 410–2 volatilization 16–20 o-[3,4,5,6-14C]xylene 448–9 [14C]vorinostat 322–3 [14C]ylidees P-ylidees 213, 265–5, 265–6, 321–3, Wilkinson’s catalyst 117, 128–31, 484–5 333–4 Willgerodt–Kindler reactions 295–6 S-ylidees 333–4 Williamson reactions 489–90 [3H]ylidees 189–90 Wittig reactions 14 14 3 alkoxyl[ Cn]carbonyl[ Cn] [ H]zaleplon 64 methylenations 322 [3H]-trans-zeatin 96 14 14 13 amino[ Cn]carbonyl[ Cn] [ C]zeaxanthin 325–6 methylenations 322 zeolites 66, 96 [14C]cyanoalkenylations 395 [3H]zervamicin IIB 95 14 14 [ Cn]formyl[ Cn]methylenations 312 Zimmerman–Traxler type transition states 558 [14C]methylenations 265 zinc–copper couple 181, 190–1 in diastereoselective synthesis 560 zinc nitrile 397 on [14C]acetone 338 [3H/14C]ziracin 625–6 reconstitution strategies 506–7, 513, 515 zirconium catalysts 176–7