28092-52-6

Basic information

• Product Name: (3aS-cis)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione
• Synonyms: (3aS-cis)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione;(3aS)-1,3-Dibenzyl-6,6aβ-dihydro-1H-thieno[3,4-d]imidazole-2,4(3H,3aβH)-dione;(3aS,3aβ,6aβ)-1,3-Dibenzylhexahydro-1H-thieno[3,4-d]imidazole-2,4-dione;(3aS,3aβ,6aβ)-Tetrahydro-1,3-bis(phenylmethyl)-1H-thieno[3,4-d]imidazole-2,4-dione;(3aS,6aR)-1,3-Dibenzyl-3a,6a-dihydro-1H-thieno[3,4-d]imidazole-2,4(3H,6H)-dione;(3aβ,6aβ)-1,3-Dibenzylhexahydro-1H-thieno[3,4-d]imidazole-2,4-dione;[3aS,6aβ]-1,3-Dibenzylhexahydro-1H-thieno[3,4-d]imidazole-2,4-dione
• CAS NO: 28092-52-6
• Molecular Formula: C₁₉H₁₈N₂O₂S
• Molecular Weight: 338.42342
• EINECS: 248-833-0
• Mol File: 28092-52-6.mol
• Article Data: 35

Chemical Properties

• Melting Point: 125-126 °C(Solv: ethyl acetate (141-78-6))
• Boiling Point: 578.4°Cat760mmHg
• Flash Point: 303.6°C
• Appearance: /
• Density: 1.331g/cm³
• Vapor Pressure: 2.24E-13mmHg at 25°C
• Refractive Index: 1.67
• PKA: -1.31±0.20(Predicted)
• CAS DataBase Reference: (3aS-cis)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione(CAS DataBase Reference)
• NIST Chemistry Reference: (3aS-cis)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione(28092-52-6)
• EPA Substance Registry System: (3aS-cis)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione(28092-52-6)

Safety Data

• Hazardous Substances Data: 28092-52-6(Hazardous Substances Data)

Usage

InChI:InChI=1/C19H18N2O2S/c22-18-17-16(13-24-18)20(11-14-7-3-1-4-8-14)19(23)21(17)12-15-9-5-2-6-10-15/h1-10,16-17H,11-13H2/t16-,17-/m0/s1

Synthetic route

(3aS,6aR)-1,3-dibenzyltetrahydro-1H-furo[3,4-d]imidazole-2,4-dione (28092-62-8) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
With ammonium xanthate at 120℃; for 9h; Reagent/catalyst; Temperature; Inert atmosphere;	98%
With sodium thioacetate In N,N-dimethyl-formamide at 130℃; for 6h; Temperature; Solvent; Reagent/catalyst; Inert atmosphere;	96.5%
With tiolacetic acid; potassium hydroxide In N,N-dimethyl-formamide; benzene at -10 - 70℃; for 2h; Inert atmosphere;	94%

(4R,5R)-1,3-dibenzyl-5-(mercaptomethyl)imidazolidin-2-one-4-carboxylic acid (112878-95-2) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
With pyridine; dicyclohexyl-carbodiimide; trifluoroacetic acid In chloroform for 5h; Heating;	93%
With pyridine; dicyclohexyl-carbodiimide; trifluoroacetic acid In chloroform at 10℃; for 1h;	80%
With pyridine; toluene-4-sulfonic acid; dicyclohexyl-carbodiimide In toluene at 25 - 62℃; for 20h;	75%

(2S)-2-[(4R)-3-benzyl-2-oxathiazolidin-4-yl]-2-benzylaminoacetamide hydrochloride → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
In N,N-dimethyl-formamide at 120℃; for 5h;	91%
In DMF (N,N-dimethyl-formamide) at 100℃; for 3h;	n/a

cis-1,3-Dibenzyltetrahydro-2H-thieno[3,4-d]imidazole-2,4,6-trione (324012-37-5) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
With (R)-BINAL-H In tetrahydrofuran at -78℃; for 6h; Reduction;	83%

(4R,5R)-1,3-dibenzyl-3,3a,6,6a-tetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (541508-62-7) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
With pyridine In chloroform at 25℃; for 23h;	75%
With pyridine In chloroform at 60℃; for 6h;	88.1 g
In pyridine; chloroform at 20℃; for 23h;

C21H23IN2O3 → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
With HNaS*(x)H2O In N,N-dimethyl-formamide at 20℃; for 17h; Inert atmosphere;	60%

(+)-<3aS-(3α,4α,6aα)>-1,3-dibenzyl-3a,4,6,6a-tetrahydro-4-hydroxy-1H-thieno<3,4-d>imidazol-2(3H)-one (132203-12-4) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
With dimethyl sulfoxide; triethylamine; trifluoroacetic anhydride 1.) dichloromethane, -78 deg C, 1 h, then -60 deg C, 1 h, 2.) -78 deg C, 5 min, then warming to room temperature over 1.5 h; Yield given. Multistep reaction;
With acetic anhydride; dimethyl sulfoxide at 50℃; for 1.5h; Yield given;
With dimethyl sulfoxide; triethylamine; trifluoroacetic anhydride Multistep reaction;

2-[(4R)-3-benzyl-2-oxathiazolidin-4-yl]-2-benzylaminoacetonitrile (777940-99-5) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: 93 percent / aq. H2O2; K2CO3 / dimethylsulfoxide; CH2Cl2 / 6 h / 20 °C 2: dimethylformamide / 1 h / 90 °C 3: 95.1 g / aq. HCl / dimethylformamide / 3 h / 90 °C 4: 80 percent / pyridine; TFA; DCC / CHCl3 / 1 h / 10 °C View Scheme
Multi-step reaction with 5 steps 1: 93 percent / aq. H2O2; K2CO3 / dimethylsulfoxide; CH2Cl2 / 6 h / 20 °C 2: dimethylformamide / 1 h / 90 °C 3: 95.1 g / aq. HCl / dimethylformamide / 3 h / 90 °C 4: 42 percent / pyridine; TFA; DCC / CHCl3 / 1 h / 25 °C 5: 75 percent / pyridine / CHCl3 / 23 h / 25 °C View Scheme

(2R)-2-[(4R)-3-benzyl-2-oxathiazolidin-4-yl]-2-benzylaminoacetamide (541508-59-2) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: dimethylformamide / 1 h / 90 °C 2: 95.1 g / aq. HCl / dimethylformamide / 3 h / 90 °C 3: 80 percent / pyridine; TFA; DCC / CHCl3 / 1 h / 10 °C View Scheme
Multi-step reaction with 4 steps 1: dimethylformamide / 1 h / 90 °C 2: 95.1 g / aq. HCl / dimethylformamide / 3 h / 90 °C 3: 42 percent / pyridine; TFA; DCC / CHCl3 / 1 h / 25 °C 4: 75 percent / pyridine / CHCl3 / 23 h / 25 °C View Scheme
Multi-step reaction with 2 steps 1.1: dimethylformamide / 1 h / 90 °C 1.2: 95 percent / HCl 2.1: 93 percent / DCC; pyridine; TFA / CHCl3 / 5 h / Heating View Scheme
Multi-step reaction with 4 steps 1: dimethylformamide / 1 h / 90 °C 2: 95.1 g / conc. HCl / dimethylformamide / 3 h / 90 °C 3: DCC; pyridine; TFA / CHCl3 / 1 h / 10 °C 4: 88.1 g / pyridine / CHCl3 / 6 h / 60 °C View Scheme

(4R,5R)-1,3-dibenzyl-2-oxo-5-(mercaptomethyl)imidazolidin-4-carboxamide (541508-64-9) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 95.1 g / aq. HCl / dimethylformamide / 3 h / 90 °C 2: 80 percent / pyridine; TFA; DCC / CHCl3 / 1 h / 10 °C View Scheme
Multi-step reaction with 3 steps 1: 95.1 g / aq. HCl / dimethylformamide / 3 h / 90 °C 2: 42 percent / pyridine; TFA; DCC / CHCl3 / 1 h / 25 °C 3: 75 percent / pyridine / CHCl3 / 23 h / 25 °C View Scheme
Multi-step reaction with 2 steps 1: 0.44 g / aq. HCl / acetic acid / 2 h / 110 °C 2: 75 percent / p-TsOH*H2O; DCC; pyridine / toluene / 20 h / 25 - 62 °C View Scheme
Multi-step reaction with 3 steps 1: 95.1 g / conc. HCl / dimethylformamide / 3 h / 90 °C 2: DCC; pyridine; TFA / CHCl3 / 1 h / 10 °C 3: 88.1 g / pyridine / CHCl3 / 6 h / 60 °C View Scheme

(4S,5R)-1,3-dibenzyl-1H-furo[3,4-d]imidazole-2,4,6-trione (26339-42-4) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 90 percent / toluene / 5 h / Heating 2.1: 82 percent / BF3*Et2O; NaH; chiral polymer-supported oxazaborolidine / tetrahydrofuran / 3 h / Heating 3.1: NaBH4 / ethanol / 4 h / 50 °C 3.2: 90 percent / aq. H2SO4 / ethanol / 1 h / 80 °C 4.1: 82 percent / potassium n-butylthioxanthogenate / N,N-dimethyl-acetamide / 6 h / 125 °C View Scheme
Multi-step reaction with 4 steps 1: 3-(3,5-bis-trifluoromethyl-phenylamino)-4-{[(S)-(6-methoxy-quinolin-4-yl)-((R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl]-amino}-cyclobut-3-ene-1,2-dione / tert-butyl methyl ether / 24 h / 25 °C / Inert atmosphere 2: calcium chloride / ethanol / 0 - 25 °C / Inert atmosphere 3: hydrogenchloride / water / 0.5 h / 55 °C / Inert atmosphere 4: thiobenzoic acid potassium salt / N,N-dimethyl-formamide / 2 h / 150 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: C27H36N4OS / tert-butyl methyl ether / 10 h / 25 °C / Inert atmosphere 2: potassium borohydride; lithium bromide / tetrahydrofuran / 7 h / 40 °C / Inert atmosphere 3: N,N-dimethyl acetamide / 6 h / 125 °C / Inert atmosphere View Scheme

benzylamine (100-46-9) + polymer-supported formate → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 90 percent / toluene / 5 h / Heating 2.1: 82 percent / BF3*Et2O; NaH; chiral polymer-supported oxazaborolidine / tetrahydrofuran / 3 h / Heating 3.1: NaBH4 / ethanol / 4 h / 50 °C 3.2: 90 percent / aq. H2SO4 / ethanol / 1 h / 80 °C 4.1: 82 percent / potassium n-butylthioxanthogenate / N,N-dimethyl-acetamide / 6 h / 125 °C View Scheme

(3aS,6R,6aR)-1,3,5-tribenzyl-6-hydroxytetrahydro-4H-pyrrolo[3,4-d]imidazole-2,4(1H)-dione (634188-84-4) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: NaBH4 / ethanol / 4 h / 50 °C 1.2: 90 percent / aq. H2SO4 / ethanol / 1 h / 80 °C 2.1: 82 percent / potassium n-butylthioxanthogenate / N,N-dimethyl-acetamide / 6 h / 125 °C View Scheme
Multi-step reaction with 2 steps 1.1: KBH4; CaCl2 / ethanol / 4 h / 20 °C 1.2: 85 percent / HCl / ethanol; H2O / 0.75 h / 55 - 60 °C 2.1: 88 percent / CH3SC(S)SK / 6 h / 120 °C View Scheme
Multi-step reaction with 2 steps 1.1: KBH4; LiCl / tetrahydrofuran / 2 h / 20 °C 1.2: 90 percent / aq. HCl / tetrahydrofuran / 0.5 h / 55 °C 2.1: 93 percent / potassium ethylthioxanthogenate / dimethylformamide / 3 h / 125 °C View Scheme

1,3,5-tribenzyl-2,4,6-trioxopyrrolo<3,4-d>imidazoline (26511-17-1) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 82 percent / BF3*Et2O; NaH; chiral polymer-supported oxazaborolidine / tetrahydrofuran / 3 h / Heating 2.1: NaBH4 / ethanol / 4 h / 50 °C 2.2: 90 percent / aq. H2SO4 / ethanol / 1 h / 80 °C 3.1: 82 percent / potassium n-butylthioxanthogenate / N,N-dimethyl-acetamide / 6 h / 125 °C View Scheme
Multi-step reaction with 3 steps 1.1: 85 percent / LiH; (1S,2S)-1-(4-NO2C6H4)-2-NH2-3-(triphenylmethoxy)propan-1-ol; BF3*Et2O / tetrahydrofuran / Heating 2.1: KBH4; CaCl2 / ethanol / 4 h / 20 °C 2.2: 85 percent / HCl / ethanol; H2O / 0.75 h / 55 - 60 °C 3.1: 88 percent / CH3SC(S)SK / 6 h / 120 °C View Scheme
Multi-step reaction with 3 steps 1.1: 91 percent / polymer-supported-C6H4-4-SO2-[(S)-2-CPh2OH-pyrrolidin-1-yl]; BH3*SMe2 / tetrahydrofuran / 6 h / Heating 2.1: KBH4; LiCl / tetrahydrofuran / 2 h / 20 °C 2.2: 90 percent / aq. HCl / tetrahydrofuran / 0.5 h / 55 °C 3.1: 93 percent / potassium ethylthioxanthogenate / dimethylformamide / 3 h / 125 °C View Scheme

cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid (51591-75-4, 634188-82-2) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 98 percent / Ac2O / xylene / 13 h / Heating 2.1: 90 percent / toluene / 5 h / Heating 3.1: 82 percent / BF3*Et2O; NaH; chiral polymer-supported oxazaborolidine / tetrahydrofuran / 3 h / Heating 4.1: NaBH4 / ethanol / 4 h / 50 °C 4.2: 90 percent / aq. H2SO4 / ethanol / 1 h / 80 °C 5.1: 82 percent / potassium n-butylthioxanthogenate / N,N-dimethyl-acetamide / 6 h / 125 °C View Scheme
Multi-step reaction with 4 steps 1.1: 95 percent / conc. H2SO4 / benzene / 6 h / Heating 2.1: 80 percent / immobilized PLE on Eupergit C(R); aq. NaOH / aq. phosphate buffer; methanol / 45 h / 30 °C / pH 8 3.1: LiEt3BH / tetrahydrofuran / 0 - 20 °C 3.2: 88 percent / aq. HCl / tetrahydrofuran / 1 h / 45 °C 4.1: 80 percent / EtOC(S)SK / N,N-dimethyl-acetamide / 7 h / 125 °C View Scheme
Multi-step reaction with 4 steps 1.1: 90 percent / pyridine / xylene / 8 h / Heating 2.1: 85 percent / LiH; (1S,2S)-1-(4-NO2C6H4)-2-NH2-3-(triphenylmethoxy)propan-1-ol; BF3*Et2O / tetrahydrofuran / Heating 3.1: KBH4; CaCl2 / ethanol / 4 h / 20 °C 3.2: 85 percent / HCl / ethanol; H2O / 0.75 h / 55 - 60 °C 4.1: 88 percent / CH3SC(S)SK / 6 h / 120 °C View Scheme

(4S,5R)-1,3-bisbenzyl-2-oxo-5-(methoxycarbonyl)imidazolidin-4-carboxylic acid (83889-77-4) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: LiEt3BH / tetrahydrofuran / 0 - 20 °C 1.2: 88 percent / aq. HCl / tetrahydrofuran / 1 h / 45 °C 2.1: 80 percent / EtOC(S)SK / N,N-dimethyl-acetamide / 7 h / 125 °C View Scheme
Multi-step reaction with 3 steps 1: calcium chloride / ethanol / 0 - 25 °C / Inert atmosphere 2: hydrogenchloride / water / 0.5 h / 55 °C / Inert atmosphere 3: thiobenzoic acid potassium salt / N,N-dimethyl-formamide / 2 h / 150 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: potassium borohydride; lithium bromide / tetrahydrofuran / 7 h / 40 °C / Inert atmosphere 2: N,N-dimethyl acetamide / 6 h / 125 °C / Inert atmosphere View Scheme

dimethyl cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylate (56198-73-3) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 80 percent / immobilized PLE on Eupergit C(R); aq. NaOH / aq. phosphate buffer; methanol / 45 h / 30 °C / pH 8 2.1: LiEt3BH / tetrahydrofuran / 0 - 20 °C 2.2: 88 percent / aq. HCl / tetrahydrofuran / 1 h / 45 °C 3.1: 80 percent / EtOC(S)SK / N,N-dimethyl-acetamide / 7 h / 125 °C View Scheme

(R)-3-benzyl-2-oxothiazolidine-4-carbaldehyde (541508-56-9) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 99 percent / NaHSO3 / ethyl acetate; H2O / 18 h / 20 °C 2.1: dimethylformamide / 1 h / 90 °C 2.2: 95 percent / HCl 3.1: 93 percent / DCC; pyridine; TFA / CHCl3 / 5 h / Heating View Scheme
Multi-step reaction with 3 steps 1: 99 percent / NaHSO3 / ethyl acetate; H2O / 18 h / 20 °C 2: 91 percent / dimethylformamide / 5 h / 120 °C View Scheme
Multi-step reaction with 6 steps 1: 96 percent / toluene 2: 93 percent / H2O2; K2CO3 / dimethylsulfoxide 3: dimethylformamide / 1 h / 90 °C 4: 95.1 g / conc. HCl / dimethylformamide / 3 h / 90 °C 5: DCC; pyridine; TFA / CHCl3 / 1 h / 10 °C 6: 88.1 g / pyridine / CHCl3 / 6 h / 60 °C View Scheme

(R)-3-benzyl-4-hydroxymethyl-2-oxothiazolidine (541508-55-8) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 90 percent / DCC; pyridine; TFA / dimethylsulfoxide; ethyl acetate / 3 h / 50 °C 2.1: 99 percent / NaHSO3 / ethyl acetate; H2O / 18 h / 20 °C 3.1: dimethylformamide / 1 h / 90 °C 3.2: 95 percent / HCl 4.1: 93 percent / DCC; pyridine; TFA / CHCl3 / 5 h / Heating View Scheme
Multi-step reaction with 4 steps 1: 90 percent / DCC; pyridine; TFA / dimethylsulfoxide; ethyl acetate / 3 h / 50 °C 2: 99 percent / NaHSO3 / ethyl acetate; H2O / 18 h / 20 °C 3: 91 percent / dimethylformamide / 5 h / 120 °C View Scheme
Multi-step reaction with 7 steps 1: 89 percent / DCC; pyridine; TFA / dimethylsulfoxide / 25 - 45 °C 2: 96 percent / toluene 3: 93 percent / H2O2; K2CO3 / dimethylsulfoxide 4: dimethylformamide / 1 h / 90 °C 5: 95.1 g / conc. HCl / dimethylformamide / 3 h / 90 °C 6: DCC; pyridine; TFA / CHCl3 / 1 h / 10 °C 7: 88.1 g / pyridine / CHCl3 / 6 h / 60 °C View Scheme

Sodium; (R)-((S)-3-benzyl-2-oxo-thiazolidin-4-yl)-hydroxy-methanesulfonate → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dimethylformamide / 1 h / 90 °C 1.2: 95 percent / HCl 2.1: 93 percent / DCC; pyridine; TFA / CHCl3 / 5 h / Heating View Scheme
Multi-step reaction with 2 steps 1: 91 percent / dimethylformamide / 5 h / 120 °C View Scheme

benzylamine (100-46-9) + N-acetyl-N'-(3,4-dichlorophenylhaloacetyl)-hydrazide → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 90 percent / pyridine / xylene / 8 h / Heating 2.1: 85 percent / LiH; (1S,2S)-1-(4-NO2C6H4)-2-NH2-3-(triphenylmethoxy)propan-1-ol; BF3*Et2O / tetrahydrofuran / Heating 3.1: KBH4; CaCl2 / ethanol / 4 h / 20 °C 3.2: 85 percent / HCl / ethanol; H2O / 0.75 h / 55 - 60 °C 4.1: 88 percent / CH3SC(S)SK / 6 h / 120 °C View Scheme
Multi-step reaction with 4 steps 1.1: 95 percent / 4 Angstroem molecular sieves / xylene / 12 h / Heating 2.1: 91 percent / polymer-supported-C6H4-4-SO2-[(S)-2-CPh2OH-pyrrolidin-1-yl]; BH3*SMe2 / tetrahydrofuran / 6 h / Heating 3.1: KBH4; LiCl / tetrahydrofuran / 2 h / 20 °C 3.2: 90 percent / aq. HCl / tetrahydrofuran / 0.5 h / 55 °C 4.1: 93 percent / potassium ethylthioxanthogenate / dimethylformamide / 3 h / 125 °C View Scheme

(1R,2S,4R)-3-benzyl-4-carbamoyl-2-oxo-2-phenylimidazo[1,5-c]thiazolidine (646512-43-8) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: Zn; AcOH / 2 h / 100 °C 2: 0.44 g / aq. HCl / acetic acid / 2 h / 110 °C 3: 75 percent / p-TsOH*H2O; DCC; pyridine / toluene / 20 h / 25 - 62 °C View Scheme

benzylamino-2-[(2R,4R)-3-phenoxycarbonyl-2-phenylthiazolidin-4-yl]acetonitrile → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: 60 percent / K2CO3; aq. H2O2 / dimethylsulfoxide / 17 h / 25 °C 2: 60 percent / dimethylformamide / 2 h / 100 °C 3: Zn; AcOH / 2 h / 100 °C 4: 0.44 g / aq. HCl / acetic acid / 2 h / 110 °C 5: 75 percent / p-TsOH*H2O; DCC; pyridine / toluene / 20 h / 25 - 62 °C View Scheme

(R)-2-benzylamino-2-[(2R,4R)-3-phenoxycarbonyl-2-phenylthiazolidin-4-yl]acetamide (646512-51-8) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: 60 percent / dimethylformamide / 2 h / 100 °C 2: Zn; AcOH / 2 h / 100 °C 3: 0.44 g / aq. HCl / acetic acid / 2 h / 110 °C 4: 75 percent / p-TsOH*H2O; DCC; pyridine / toluene / 20 h / 25 - 62 °C View Scheme

(R)-3-benzyl-2-oxothiazolidine-4-carboxylic acid (98155-23-8) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 8 steps 1: 89 percent / Me2S*BH3 2: 89 percent / DCC; pyridine; TFA / dimethylsulfoxide / 25 - 45 °C 3: 96 percent / toluene 4: 93 percent / H2O2; K2CO3 / dimethylsulfoxide 5: dimethylformamide / 1 h / 90 °C 6: 95.1 g / conc. HCl / dimethylformamide / 3 h / 90 °C 7: DCC; pyridine; TFA / CHCl3 / 1 h / 10 °C 8: 88.1 g / pyridine / CHCl3 / 6 h / 60 °C View Scheme

(2R)-2-[(4R)-3-benzyl-2-oxathiazolidin-4-yl]-2-benzylaminoacetonitrile (541508-57-0) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: 93 percent / H2O2; K2CO3 / dimethylsulfoxide 2: dimethylformamide / 1 h / 90 °C 3: 95.1 g / conc. HCl / dimethylformamide / 3 h / 90 °C 4: DCC; pyridine; TFA / CHCl3 / 1 h / 10 °C 5: 88.1 g / pyridine / CHCl3 / 6 h / 60 °C View Scheme

benzyl bromide (100-39-0) + polymer-bound NMe3(1+)*SCN(1-) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 84 percent / NaH / dimethylformamide / 17 h / 20 °C 2: 92 percent / AcSK / dimethylformamide View Scheme

(3aS,6aR)-tetrahydro-1H-furo[3,4-d]imidazole-2,4-dione (159912-63-7) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 84 percent / NaH / dimethylformamide / 17 h / 20 °C 2: 92 percent / AcSK / dimethylformamide View Scheme

(4R,5S)-1-benzyloxycarbonylamino-4-benzyloxymethoxy-methylimidazolidin-2-one-5-carboxylic acid (429691-52-1) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 80 percent / H2 / 10 percent Pd(OH)2/C / aq. methanol / 17 h / 20 °C / 2574.28 Torr 2: 84 percent / NaH / dimethylformamide / 17 h / 20 °C 3: 92 percent / AcSK / dimethylformamide View Scheme

ethyl 5-bromovalerate (14660-52-7) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → ethyl (3aS,4Z,6aR)-5-(1,3-dibenzyl-2,3,3a,4,6,6a-hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-5-ylidene)pentanoate (292151-18-9)

Conditions	Yield
Stage #1: ethyl 5-bromovalerate With chloro-trimethyl-silane; tetra-(n-butyl)ammonium iodide; sodium iodide; zinc In tetrahydrofuran; ethylene dibromide at 25 - 65℃; for 8.3h; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione With palladium 10% on activated carbon In tetrahydrofuran; ethylene dibromide; N,N-dimethyl-formamide; toluene at 25℃; for 15h;	100%

(3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) + potassium thioacetate (10387-40-3) → biotin (58-85-5)

Conditions	Yield
In water at 0 - 60℃; Temperature;	97%

ethyl 5-iodopentanoate (41302-32-3) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → ethyl (3aS,4Z,6aR)-5-(1,3-dibenzyl-2,3,3a,4,6,6a-hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-5-ylidene)pentanoate (292151-18-9)

Conditions	Yield
Stage #1: ethyl 5-iodopentanoate With chloro-trimethyl-silane; bromine; zinc In tetrahydrofuran; toluene at 50 - 60℃; for 1h; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione With N,N-dimethyl-formamide; palladium on activated charcoal In tetrahydrofuran; toluene at 25 - 30℃; for 18h; Fukuyama coupling reaction; Further stages.;	95%
Stage #1: ethyl 5-iodopentanoate With bromine; zinc In tetrahydrofuran; toluene at 50 - 60℃; for 1h; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione; palladium on activated charcoal In tetrahydrofuran; N,N-dimethyl-formamide; toluene at 28 - 40℃; for 5h; Stage #3: With hydrogenchloride In tetrahydrofuran; N,N-dimethyl-formamide; toluene at 20℃; for 1h;	94%
Stage #1: ethyl 5-iodopentanoate With chloro-trimethyl-silane; ethylene dibromide; zinc In tetrahydrofuran at 30 - 60℃; for 1h; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione; palladium hydroxide - carbon In N,N-dimethyl-formamide; toluene at 25 - 35℃; for 2h; Fukuyama coupling reaction; Stage #3: With toluene-4-sulfonic acid In toluene at 20℃; for 1.5h;	87%
Stage #1: ethyl 5-iodopentanoate With chloro-trimethyl-silane; zinc In tetrahydrofuran; toluene at 50℃; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione; palladium on activated charcoal In tetrahydrofuran; N,N-dimethyl-formamide; toluene at 30℃; Fukuyama coupling; Stage #3: With hydrogenchloride In tetrahydrofuran; N,N-dimethyl-formamide; toluene at 20℃; Further stages.;	95 % Chromat.

1-bromo-4-ethoxybutane (3448-29-1) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → C25H30N2O2S

Conditions	Yield
Stage #1: 1-bromo-4-ethoxybutane With iodine; magnesium In tetrahydrofuran for 1h; Inert atmosphere; Reflux; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione In tetrahydrofuran for 2h; Reflux; Inert atmosphere; Stage #3: With sulfuric acid In tetrahydrofuran; water for 3h; Reflux;	95%

(3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) + 5-ethoxy-5-oxopentylzinc iodide → 5-[(3aR,6aS)-1,3-Dibenzyl-2-oxo-hexahydro-thieno[3,4-d]imidazol-(6E)-ylidene]-pentanoic acid ethyl ester (333355-49-0)

Conditions	Yield
Stage #1: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione; 5-ethoxy-5-oxopentylzinc iodide; palladium dihydroxide In tetrahydrofuran; N,N-dimethyl-formamide; toluene at 30℃; Fukuyama coupling reaction; Stage #2: With hydrogenchloride In tetrahydrofuran; N,N-dimethyl-formamide; toluene	92%

(5-ethoxy-5-oxopentyl)zinc(II) iodide (109976-46-7) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → 5-[(3aR,6aS)-1,3-Dibenzyl-2-oxo-hexahydro-thieno[3,4-d]imidazol-(6E)-ylidene]-pentanoic acid ethyl ester (333355-49-0)

Conditions	Yield
Stage #1: (5-ethoxy-5-oxopentyl)zinc(II) iodide; (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione With N,N-dimethyl-formamide In tetrahydrofuran; toluene at 25 - 35℃; for 2h; Fukuyama Coupling; Stage #2: With hydrogenchloride In toluene	92%

ethyl 5-bromovalerate (14660-52-7) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → ethyl 5-{(3aS,6aR)-1,3-dibenzyl-4-hydroxy-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl}-pentanoate (1041862-06-9)

Conditions	Yield
Stage #1: ethyl 5-bromovalerate With iodine; zinc In tetrahydrofuran; toluene at 40 - 50℃; for 3.5 - 4.5h; Fukuyama coupling reaction; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione; anion exchange resin D296 dispersed nano-palladium In tetrahydrofuran; N,N-dimethyl-formamide; toluene at 30 - 35℃; for 12h; Stage #3: With water In tetrahydrofuran; N,N-dimethyl-formamide; toluene at 20℃; for 0.5h; Product distribution / selectivity;	87%
Stage #1: ethyl 5-bromovalerate With iodine; zinc In tetrahydrofuran; toluene at 50℃; for 4.5 - 5.5h; Fukuyama coupling reaction; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione; anion exchange resin D290 dispersed nano-palladium In tetrahydrofuran; N,N-dimethyl-formamide; toluene at 30 - 40℃; for 24h; Stage #3: With water In tetrahydrofuran; N,N-dimethyl-formamide; toluene Product distribution / selectivity;	85.7%

Vinyl bromide (593-60-2) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → (3aR,8aS)-tetrahydro-1,3-bis(phenylmethyl)-1H-thiepino-[3,4-d]imidazole-2,8(3H,4H)-dione (1187740-53-9)

Conditions	Yield
Stage #1: Vinyl bromide With magnesium In tetrahydrofuran at 20℃; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione In tetrahydrofuran at 0 - 20℃;	86%

1,4-dibromo-butane (110-52-1) + carbon dioxide (124-38-9) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → 5-((3aS,4S,6aR)-1,3-dibenzyl-4-hydroxy-2-oxo-1H-thieno[3,4-d]imidazole-4-yl)pentanoic acid

Conditions	Yield
Stage #1: 1,4-dibromo-butane With iodine; magnesium In tetrahydrofuran for 3.5h; Grignard Reaction; Inert atmosphere; Reflux; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione In tetrahydrofuran at -30 - -20℃; for 1h; Inert atmosphere; Stage #3: carbon dioxide With acetic acid at -30 - 50℃; for 3.5h; Inert atmosphere;	86%

5-bromopentanoic acid (2067-33-6) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → ethyl 5-{(3aS,6aR)-1,3-dibenzyl-4-hydroxy-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl}-pentanoate (1041862-06-9)

Conditions	Yield
Stage #1: 5-bromopentanoic acid With iodine; zinc In tetrahydrofuran; toluene at 50℃; for 2.5h; Fukuyama cross-coupling reaction; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione In tetrahydrofuran; tyoluene; N,N-dimethyl-formamide at 35℃; for 10h; Fukuyama cross-coupling reaction;	85%

ethyl 5-iodopentanoate (41302-32-3) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → biotin (58-85-5)

Conditions	Yield
Stage #1: ethyl 5-iodopentanoate With bromine; zinc In tetrahydrofuran; toluene at 40℃; for 1h; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione With palladium 10% on activated carbon In tetrahydrofuran; N,N-dimethyl-formamide; toluene at 28 - 40℃; for 5h; Further stages;	85%

C5H10ClMgO(1-)*Cl(1-)*Mg(2+) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → C24H30N2O3S

Conditions	Yield
In tetrahydrofuran at 20℃; for 5h; Temperature; Inert atmosphere; Cooling with ice;	83%

(5-ethoxy-5-oxopentyl)zinc(II) iodide (109976-46-7) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → ethyl (3aS,4Z,6aR)-5-(1,3-dibenzyl-2,3,3a,4,6,6a-hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-5-ylidene)pentanoate (292151-18-9)

Conditions	Yield
With bis(acetylacetonate)nickel(II) In monoethylene glycol diethyl ether; toluene at 20℃; for 15h; Product distribution; Further Variations:; Reagents; Solvents; Temperatures;	81%

(4-carboxybutyl)triphenylphosphonium bromide (17814-85-6) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → (3aS,4Z,6aR)-5-{hexahydro-1,3-dibenzyl-2-oxo-4H-thieno[3,4-d]imidazol-4-ylidene}pentanoic acid (452100-87-7)

Conditions	Yield
Stage #1: (4-carboxybutyl)triphenylphosphonium bromide With potassium tert-butylate In toluene at 25℃; for 0.75h; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione In toluene at 135℃; for 7h; Wittig reaction;	81%

5-iodovaleronitrile (6727-75-9) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-one-4-ylidenepentane nitrile (634188-85-5)

Conditions	Yield
Stage #1: 5-iodovaleronitrile With chloro-trimethyl-silane; ethylene dibromide; zinc In tetrahydrofuran at 30℃; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione; nickel on carbon In tetrahydrofuran; N,N-dimethyl-formamide; toluene at 20℃; for 30h; Fukuyama coupling reaction;	80%

2-(4-bromobutyl)-4,5-dihydrooxazole + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → 5-[(3aS,6aR)-1,3-dibenzyl-2-oxo-tetrahydro-1H-thieno[3,4-d]imidazol-4-ylidene]pentanoic acid

Conditions	Yield
With magnesium In tetrahydrofuran; ethylene dibromide Inert atmosphere; Reflux;	78.2%

C5H10BrMgO(1-)*Cl(1-)*Mg(2+) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → C24H30N2O3S

Conditions	Yield
In tetrahydrofuran at 20℃; for 5h; Inert atmosphere; Cooling with ice;	77%

diethylzinc (557-20-0) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → (3aS,4Z,6aR)-2-[1,3-dibenzyl-2,3,3a,4,6,6a-hexahydro-2-oxo-1H-thieno[3,4-d]imidazol-4-ylidene]-ethane (1041865-17-1)

Conditions	Yield
With bromine; N,N-dimethyl-formamide; zinc; palladium diacetate In tetrahydrofuran; toluene at 45℃; for 2h; Fukuyama coupling reaction;	76%

(3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) + benzyl 5-iodopentanoate (118058-70-1) → benzyl (3aS,6aR)-5-(1,3-dibenzyl-2,3,3a,4,6,6a-hexahydro-2-oxo-4-hydroxyl-1H-thieno[3,4-d]imidazol-4-yl)pentanoate (1042432-14-3)

Conditions	Yield
Stage #1: benzyl 5-iodopentanoate With bromine; zinc In tetrahydrofuran; toluene at 50 - 60℃; for 1h; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione; nanopalladium catalyst In tetrahydrofuran; N,N-dimethyl-formamide; toluene at 30℃; for 24h; Fukuyama coupling; Further stages.;	75%
Stage #1: benzyl 5-iodopentanoate With bromine; zinc In tetrahydrofuran; toluene at 10 - 60℃; for 1h; Fukuyama coupling reaction; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione; anion exchange resin D290 dispersed nano-palladium In tetrahydrofuran; N,N-dimethyl-formamide; toluene at 30℃; for 24h; Stage #3: With water; ammonium chloride In tetrahydrofuran; N,N-dimethyl-formamide; toluene at 20℃; for 0.5h; Product distribution / selectivity;	75%
Stage #1: benzyl 5-iodopentanoate With iodine; zinc In N,N-dimethyl-formamide at 80℃; for 3h; Fukuyama coupling reaction; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione; anion exchange resin D296 dispersed nano-palladium In tetrahydrofuran; N,N-dimethyl-formamide; toluene at 30℃; for 24h; Stage #3: With water; ammonium chloride In tetrahydrofuran; N,N-dimethyl-formamide; toluene at 20℃; for 0.5h; Product distribution / selectivity;	75%

ethyl 5-bromovalerate (14660-52-7) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → ethyl (3aS,4RS,6aR)-5-(1,3-dibenzyl-2,3,3a,4,6,6a-hexahydro-4-hydroxy-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)pentanoate (1236230-80-0)

Conditions

Yield

Stage #1: ethyl 5-bromovalerate With iodine; zinc In N,N-dimethyl-formamide at 80℃; for 4.5h; Fukuyama coupling; Inert atmosphere; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione With palladium 10% on activated carbon In tetrahydrofuran; N,N-dimethyl-formamide; toluene at 30℃; for 30h; Fukuyama coupling; Inert atmosphere; Stage #3: With water; ammonium chloride In tetrahydrofuran; N,N-dimethyl-formamide; toluene

75%

5-iodovaleronitrile (6727-75-9) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → C24H25N3OS

Conditions	Yield
Stage #1: 5-iodovaleronitrile With chloro-trimethyl-silane; zinc; ethylene dibromide In tetrahydrofuran at 20 - 30℃; for 0.75h; Fukuyama coupling reaction; Heating / reflux; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 35h;	73%

Iodomethyl methyl ether (13057-19-7) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → (3aS,4S,6aR)-1,3-dibenzyl-2-oxohexahydro-1H-thieno[3,4-d]imidazole-4-carbaldehyde (154097-01-5)

Conditions	Yield
Stage #1: Iodomethyl methyl ether With magnesium In dibutyl ether; toluene at 45℃; for 1h; Grignard reaction; Stage #2: (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione In dichloromethane; dibutyl ether at 15℃; for 3h; Stage #3: With hydrogenchloride In dibutyl ether; toluene for 3h; Heating;	70%

C5H10IMgO(1-)*Cl(1-)*Mg(2+) + (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (28092-52-6) → C24H30N2O3S

Conditions	Yield
In tetrahydrofuran at 20℃; for 5h; Inert atmosphere; Cooling with ice;	65%

Upstream product

• 129301-68-4 (+/-)-1,3-dibenzyl-5c-formyl-2-oxo-imidazolidine-4r-carboxylic acid 
• 28092-55-9 6ξ-acetoxy-1,3-dibenzyl-(3ar,6ac)-tetrahydro-furo[3,4-d]imidazole-2,4-dione 
• 132203-12-4 (+)-<3aS-(3α,4α,6aα)>-1,3-dibenzyl-3a,4,6,6a-tetrahydro-4-hydroxy-1H-thieno<3,4-d>imidazol-2(3H)-one 
• 28092-62-8 (3aS,6aR)-1,3-dibenzyltetrahydro-1H-furo[3,4-d]imidazole-2,4-dione 
• 100-46-9 benzylamine 
• 98155-23-8 (R)-3-benzyl-2-oxothiazolidine-4-carboxylic acid 
• 100-44-7 benzyl chloride 
• 56198-34-6 (3aα,6aα)-1,3-dibenzylhexahydro-1H-thieno<3,4-d>imidazol-2(3H)-one 
• 157378-76-2 C₁₉H₂₀N₂O₄ 
• 21035-72-3 (+)-cis-1,3-dibenzyl-hexahydro-1H-thieno[3,4-d]imidazole-2,4-dione 
• 132150-93-7 4-<(3β,5α)-Cholestan-3-yloxy>-<3aS-(3aα,4α,6aα)>-tetrahydro-1,3-bis(phenylmethyl)-1H-thieno<3,4-d>imidazol-2(3H)-one 
• 132203-10-2 Methyl (S)-α-<<3aS-(3aα,4α,6aα)>-2-hexahydro-2-oxo-1,3-bis(phenylmethyl)-1H-thieno<3,4-d>imidazol-4-yloxy>benzeneacetate 
• 132203-11-3 (S)-α-<<3aS-(3aα,4α,6aα)>-2-Hexahydro-2-oxo-1,3-bis(phenylmethyl)-1H-thieno<3,4-d>imidazol-4-yloxy>benzeneacetic acid 
• 132203-08-8 4-<(S)-1-Phenylethoxy>-<3aS-(3aα,4α,6aα)>-tetrahydro-1,3-bis(phenylmethyl)-1H-thieno<3,4-d>imidazol-2(3H)-one 

Downstream Products

• 634188-85-5 (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-one-4-ylidenepentane nitrile 
• 333355-49-0 5-[(3aR,6aS)-1,3-Dibenzyl-2-oxo-hexahydro-thieno[3,4-d]imidazol-(6E)-ylidene]-pentanoic acid ethyl ester 
• 31099-31-7 (3aS,4S,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2(3H)-one-4-ylpentane nitrile 
• 1041862-06-9 ethyl 5-{(3aS,6aR)-1,3-dibenzyl-4-hydroxy-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl}-pentanoate 
• 1187740-57-3 C₂₁H₂₄N₂O₂S 
• 1187740-53-9 (3aR,8aS)-tetrahydro-1,3-bis(phenylmethyl)-1H-thiepino-[3,4-d]imidazole-2,8(3H,4H)-dione 
• 1236230-80-0 ethyl (3aS,4RS,6aR)-5-(1,3-dibenzyl-2,3,3a,4,6,6a-hexahydro-4-hydroxy-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)pentanoate 
• 58-85-5 biotin 
• 33719-11-8 (3aR)-1,3-dibenzyl-2-oxo-(3ar,8ac,8bc)-decahydro-thieno[1',2':1,2]thieno[3,4-d]imidazolium; bromide 
• 1042432-14-3 benzyl (3aS,6aR)-5-(1,3-dibenzyl-2,3,3a,4,6,6a-hexahydro-2-oxo-4-hydroxyl-1H-thieno[3,4-d]imidazol-4-yl)pentanoate 
• 1041865-17-1 (3aS,4Z,6aR)-2-[1,3-dibenzyl-2,3,3a,4,6,6a-hexahydro-2-oxo-1H-thieno[3,4-d]imidazol-4-ylidene]-ethane 
• 115495-39-1 (3aS,6aR)-1,3-dibenzyl-4-pentylidene-1H-hexahydrothieno<3,4-d>imidazole-2-one 
• 115587-50-3 (3aS,4S,6aR)-1,3-dibenzyl-4-n-pentyl-1H-tetrahydrothieno<3,4-d>imidazole-2(3H)-one 
• 292151-18-9 ethyl (3aS,4Z,6aR)-5-[1,3-dibenzyl-2,3,3a,4,6,6a-hexahydro-2-oxo-1H-thieno[3,4-d]imidazol-5-ylidene]-pentanoate 

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Practical Synthesis of (+)-Biotin Key Intermediate by Calcium Borohydride Reduction and Temperature-Dependent Purity Upgrade during Crystallization

An expedient synthesis of a key intermediate for (+)-biotin has been accomplished through high-yielding reduction of chiral imide with calcium borohydride and efficient isolation of the desired isomer by crystallization at a specific temperature where only undesired isomer was converted to soluble anhydrate while the desired isomer kept unchanged as a less soluble monohydrate.

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