113451-59-5

Basic information

• Product Name: (1S,4S)-2-BOC-2,5-DIAZABICYCLO[2.2.1]HEPTANE
• Synonyms: TERT-BUTYL (1S, 4S)-(-)-2,5-DIAZABICYCLO[2.2.1]HEPTANE-2-CARBOXYLATE;TERT-BUTYL (1S,4S)-2,5-DIAZABICYCLO(2.2.1)HEPTANE-2-CARBOXYLATE;1,1-DIMETHYLETHYL (1S,4S)-2,5-DIAZABICYCLO(2.2.1)HEPTANE-2-CARBOXYLATE;(1S,4S)-N-(TERT-BUTOXYCARBONYL)-2,5-DIAZABICYCLO[2.2.1]HEPTANE;(1S,4S)-(-)-2-BOC-2,5-DIAZABICYCLO[2.2.1]HEPTANE;(1S,4S)-2-BOC-2,5-DIAZABICYCLO[2.2.1]HEPTANE;(1S,4S)-2-T-BOC-2,5-DIAZABICYCLO[2.2.1]HEPTANE;(1S,4S)-2-N-T-BOC-2,5-DIAZABICYCLO[2.2.1]HEPTANE
• CAS NO: 113451-59-5
• Molecular Formula: C₁₀H₁₈N₂O₂
• Molecular Weight: 198.26
• EINECS: -0
• Product Categories: Heterocycle-other series
• Mol File: 113451-59-5.mol
• Article Data: 8

Chemical Properties

• Melting Point: 74-76 °C(lit.)
• Boiling Point: 276.372 °C at 760 mmHg
• Flash Point: 120.946 °C
• Appearance: White to slightly beige/Powder
• Density: 1.105 g/cm³
• Vapor Pressure: 0.005mmHg at 25°C
• Refractive Index: 1.501
• Storage Temp.: Keep in dark place,Sealed in dry,Room Temperature
• PKA: 9.74±0.20(Predicted)
• Water Solubility: Insoluble in water.
• Sensitive: Air Sensitive
• BRN: 6460311
• CAS DataBase Reference: (1S,4S)-2-BOC-2,5-DIAZABICYCLO[2.2.1]HEPTANE(CAS DataBase Reference)
• NIST Chemistry Reference: (1S,4S)-2-BOC-2,5-DIAZABICYCLO[2.2.1]HEPTANE(113451-59-5)
• EPA Substance Registry System: (1S,4S)-2-BOC-2,5-DIAZABICYCLO[2.2.1]HEPTANE(113451-59-5)

Safety Data

• Statements: 34
• Safety Statements: 22-24/25-45-36/37/39-26
• RIDADR: 3263
• WGK Germany: 3
• Hazardous Substances Data: 113451-59-5(Hazardous Substances Data)

Usage

Chemical Properties

White to slightly beige powder

Uses

It is used as an active pharmaceutical intermediate.

InChI:InChI=1/C10H18N2O2/c1-10(2,3)14-9(13)12-6-7-4-8(12)5-11-7/h7-8,11H,4-6H2,1-3H3/t7-,8-/m0/s1

Synthetic route

(2S,4R)-2-(azidomethyl)-1-(tert-butoxycarbonyl)-4-<(methylsulfonyl)oxy>pyrrolidine (113451-54-0) → (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5)

Conditions	Yield
With hydrogen; palladium on activated charcoal In methanol	100%
Stage #1: (2S,4R)-2-(azidomethyl)-1-(tert-butoxycarbonyl)-4-<(methylsulfonyl)oxy>pyrrolidine With triphenylphosphine In tetrahydrofuran at 20℃; for 2h; Staudinger Azide Reduction; Stage #2: With water In tetrahydrofuran for 18h;	71%

(1S,4S)-5-Benzyl-2-tert-butoxycarbonyl-2,5-diazabicyclo<2.2.1>heptane (132666-68-3) → (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5)

Conditions	Yield
With palladium hydroxide 10 wt. % on activated carbon; hydrogen In methanol under 3102.97 Torr;	90%
With palladium 10% on activated carbon; hydrogen In methanol at 50℃; under 22502.3 Torr; for 16h;	85%
With 10% palladium on carbon; hydrogen	76%
With palladium 10% on activated carbon; hydrogen In dichloromethane under 3102.97 Torr;	10.4 g

tert-butyl (2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-carboxylate (922139-40-0) → (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5)

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 22 - 25℃; for 12h; Inert atmosphere;	80.6%

L-4-hydroxyproline methyl ester hydrochloride (40216-83-9) → (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 17 h / 0 °C 2.1: lithium borohydride / tetrahydrofuran / 26 h / 0 - 20 °C 3.1: pyridine / dichloromethane / 18 h / 40 °C 4.1: trimethylsilylazide; tetrabutyl ammonium fluoride / tetrahydrofuran / 18 h / 70 °C 5.1: triethylamine / dichloromethane / 0.5 h / 0 °C 6.1: triphenylphosphine / tetrahydrofuran / 2 h / 20 °C 6.2: 18 h View Scheme

4R-4-hydroxyproline (51-35-4) → (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: thionyl chloride; hydrogenchloride / water / 18 h / 20 °C / Reflux 2.1: triethylamine / dichloromethane / 17 h / 0 °C 3.1: lithium borohydride / tetrahydrofuran / 26 h / 0 - 20 °C 4.1: pyridine / dichloromethane / 18 h / 40 °C 5.1: trimethylsilylazide; tetrabutyl ammonium fluoride / tetrahydrofuran / 18 h / 70 °C 6.1: triethylamine / dichloromethane / 0.5 h / 0 °C 7.1: triphenylphosphine / tetrahydrofuran / 2 h / 20 °C 7.2: 18 h View Scheme
Multi-step reaction with 6 steps 1.1: sodium carbonate / water 1.3: 20 h 2.1: toluene / Reflux 3.1: hydrogen bromide 4.1: sodium methylate / methanol / 20 °C 5.1: triethylamine / dichloromethane / 0 - 20 °C 6.1: hydrogen; palladium hydroxide 10 wt. % on activated carbon / methanol / 3102.97 Torr View Scheme

1-tert-butyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate (74844-91-0) → (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: lithium borohydride / tetrahydrofuran / 26 h / 0 - 20 °C 2.1: pyridine / dichloromethane / 18 h / 40 °C 3.1: trimethylsilylazide; tetrabutyl ammonium fluoride / tetrahydrofuran / 18 h / 70 °C 4.1: triethylamine / dichloromethane / 0.5 h / 0 °C 5.1: triphenylphosphine / tetrahydrofuran / 2 h / 20 °C 5.2: 18 h View Scheme
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 2 h / 5 - 25 °C 2: sodium azide / N,N-dimethyl-formamide / 3 h / 90 °C 3: potassium borohydride; lithium chloride / tetrahydrofuran / 12 h / 25 °C 4: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 12 h / 22 - 25 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: sodium tetrahydroborate / methanol / 18 h / 20 - 35 °C / Cooling with ice; Large scale 2: triethylamine / dichloromethane / 1 h / 20 - 35 °C / Cooling with liquid nitrogen; Large scale 3: 3 h / 80 °C / Large scale 4: palladium 10% on activated carbon; hydrogen / methanol / 16 h / 50 °C / 22502.3 Torr View Scheme

tert-butyl (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylate (61478-26-0) → (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: pyridine / dichloromethane / 18 h / 40 °C 2.1: trimethylsilylazide; tetrabutyl ammonium fluoride / tetrahydrofuran / 18 h / 70 °C 3.1: triethylamine / dichloromethane / 0.5 h / 0 °C 4.1: triphenylphosphine / tetrahydrofuran / 2 h / 20 °C 4.2: 18 h View Scheme
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 1 h / 20 - 35 °C / Cooling with liquid nitrogen; Large scale 2: 3 h / 80 °C / Large scale 3: palladium 10% on activated carbon; hydrogen / methanol / 16 h / 50 °C / 22502.3 Torr View Scheme

tert-butyl (2S,4R)-4-hydroxy-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-pyrrolidine-1-carboxylate (194089-91-3) → (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: trimethylsilylazide; tetrabutyl ammonium fluoride / tetrahydrofuran / 18 h / 70 °C 2.1: triethylamine / dichloromethane / 0.5 h / 0 °C 3.1: triphenylphosphine / tetrahydrofuran / 2 h / 20 °C 3.2: 18 h View Scheme

(2S,4R)-tert-butyl 2-(azidomethyl)-4-hydroxypyrrolidine-1-carboxylate (114676-96-9) → (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 0.5 h / 0 °C 2.1: triphenylphosphine / tetrahydrofuran / 2 h / 20 °C 2.2: 18 h View Scheme

N-tert-butoxycarbonyl-cis-4-azido-L-proline methyl ester (84520-68-3) → (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium borohydride; lithium chloride / tetrahydrofuran / 12 h / 25 °C 2: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 12 h / 22 - 25 °C / Inert atmosphere View Scheme

(2S,4R)-4-(methylsulfonyloxy)pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester-2-methylester (84520-67-2) → (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium azide / N,N-dimethyl-formamide / 3 h / 90 °C 2: potassium borohydride; lithium chloride / tetrahydrofuran / 12 h / 25 °C 3: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 12 h / 22 - 25 °C / Inert atmosphere View Scheme

(2S,4R)-1-(4-tolylsulfonyl)-4-<(4-tolylsulfonyl)oxy>-2-<<(4-tolylsulfonyl)oxy>methyl>pyrrolidine (5234-75-3) → (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5)

Conditions	Yield
Multi-step reaction with 5 steps 1: toluene / Reflux 2: hydrogen bromide 3: sodium methylate / methanol / 20 °C 4: triethylamine / dichloromethane / 0 - 20 °C 5: hydrogen; palladium hydroxide 10 wt. % on activated carbon / methanol / 3102.97 Torr View Scheme

(1S,4S)-5-Benzyl-2-tosyl-2,5-diazabicyclo<2.2.1>heptane (5234-72-0) → (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogen bromide 2: sodium methylate / methanol / 20 °C 3: triethylamine / dichloromethane / 0 - 20 °C 4: hydrogen; palladium hydroxide 10 wt. % on activated carbon / methanol / 3102.97 Torr View Scheme

(1S,4S)-2-Benzyl-2,5-diazabicyclo<2.2.1>heptane dihydrobromide (100944-15-8, 134003-82-0, 116258-17-4) → (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium methylate / methanol / 20 °C 2: triethylamine / dichloromethane / 0 - 20 °C 3: hydrogen; palladium hydroxide 10 wt. % on activated carbon / methanol / 3102.97 Torr View Scheme
Multi-step reaction with 3 steps 1: sodium methylate / methanol / 20 °C 2: triethylamine / dichloromethane / 0 - 20 °C 3: palladium 10% on activated carbon; hydrogen / dichloromethane / 3102.97 Torr View Scheme

(1S,4S)-N-Benzyl-2,5-diazabicyclo-[2.2.1]heptane (127641-07-0) → (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: hydrogen; palladium hydroxide 10 wt. % on activated carbon / methanol / 3102.97 Torr View Scheme
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: palladium 10% on activated carbon; hydrogen / dichloromethane / 3102.97 Torr View Scheme

2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (1257295-06-9) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → C30H39N9O3 (1257382-14-1)

Conditions	Yield
Stage #1: 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde; (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester In 1,2-dichloro-ethane at 20℃; for 3h; Molecular sieve; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 17h; Molecular sieve;	100%

(1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → (1S,4S)-2,5-Diazabicyclo<2.2.1>heptane dihydrochloride (5260-20-8, 89487-38-7)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane; methanol at 20℃; for 0.5h;	100%

methanesulfonyl chloride (124-63-0) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → (1S,4S)-2-methanesulfonyl-2,5-diazabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester

Conditions	Yield
With triethylamine In tetrahydrofuran at 0 - 20℃; for 20h;	100%
With triethylamine In tetrahydrofuran at 0 - 30℃; for 12h; Inert atmosphere;	100%

isobutyryl chloride (79-30-1) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → tert-butyl (1S,4S)-5-isobutyryl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Conditions	Yield
With triethylamine In dichloromethane at 20℃; Inert atmosphere;	100%

5-bromopyrimidine (4595-59-9) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → tert-butyl (1S,4S)-5-(5-pyrimidinyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Conditions	Yield
	99%
With sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 80 - 85℃; for 5h;	91%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate In toluene at 80 - 85℃; for 5h;	91%

3-Bromopyridine (626-55-1) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → (1S,4S)-tert-butyl 5-(pyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (286946-36-9)

Conditions	Yield
	99%
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 85℃; for 64h; Inert atmosphere;	99%
With sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 80 - 85℃; for 5h;

2,5 dichloropyridine (16110-09-1) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → tert-butyl (1S,4S)-5-(5-chloro-2-pyridinyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Conditions	Yield
	99%

ethyl 6-chloro-5-cyano-2-methylnicotinate (64119-42-2) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → (1S,4S)-tert-butyl 5-(3-cyano-5-(ethoxycarbonyl)-6-methylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (898229-94-2)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h;	99%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h;	99%

4-tert-butylbenzenesulfonyl chloride (15084-51-2) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → C20H30N2O4S (1116571-82-4)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 48h;	99%
With N-ethyl-N,N-diisopropylamine In dichloromethane
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16h; Inert atmosphere;

1-iodo-2-diphenylmethoxy-ethane (153947-34-3) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → (1S,4S)-2-[2-(diphenylmethoxy)ethyl]-5-t-Boc-2,5-diazabicyclo[2.2.1]heptane (321365-86-0)

Conditions	Yield
With potassium carbonate In tetrahydrofuran Heating;	98%

cis-4-(1-(6-iodo-2-methylpyrimidin-4-yl)-5-methyl-1H-indazol-6-yl)-1-methylcyclohexanol + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → cis-(1S,4S)-tert-butyl 5-(6-(6-(4-hydroxy-4-methylcyclohexyl)-5-methyl-1H-indazol-1-yl)-2-methylpyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 50℃;	98%

bromobenzene (108-86-1) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → C16H22N2O2

Conditions	Yield
With sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 80 - 85℃; for 5h;	97%

1-(3-methoxy-4 nitrophenyl)piperidin-4-one (761440-64-6) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → 1,1-dimethylethyl (1S,4S)-5-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1089280-04-5)

Conditions	Yield
Stage #1: 1-(3-methoxy-4 nitrophenyl)piperidin-4-one; (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester With sodium tris(acetoxy)borohydride; acetic acid; triethylamine In dichloromethane for 1h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water	96%

(1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) + Acetoxyacetyl chloride (13831-31-7) → 5-(2-acetoxy-acetyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1146691-54-4)

Conditions	Yield
Stage #1: (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester With triethylamine In dichloromethane at 5℃; for 0.833333h; Stage #2: Acetoxyacetyl chloride In dichloromethane for 16h;	96%

1-(2,4,6-trifluorophenyl)ethan-1-one (51788-77-3) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → tert-butyl (1S,4S)-5-(2-acetyl-3,5-difluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1196958-94-7)

Conditions	Yield
With potassium carbonate In 1,4-dioxane at 100℃; for 24h; Inert atmosphere; regioselective reaction;	96%

(1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-ene-1-carboxylic acid (851916-39-7) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → C25H37N3O3 (1294006-20-4)

Conditions	Yield
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide at 0℃;	95%

4-chloromethylbenzaldehyde (73291-09-5) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → tert-butyl (1S,4S)-5-(4-formylbenzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Conditions	Yield
With potassium carbonate In acetonitrile at 50℃;	93.1%

(1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) + trifluoroacetic anhydride (407-25-0) → (1S,4S)-5-(2,2,2-trifluoroacetyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (878805-66-4)

Conditions	Yield
With triethylamine In tetrahydrofuran at 0℃; for 5h; Inert atmosphere;	93%
With triethylamine In tetrahydrofuran at 20℃; for 1h;

2-[2-(N-benzyloxycarbonyl-2-aminoethoxy)ethoxy]-1-bromoethane + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → (1S,4S)-tert-butyl 5-(3-oxo-1-phenyl-2,7,10-trioxa-4-azadodecan-12-yl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Conditions	Yield
With potassium carbonate In acetonitrile at 80℃; for 24h;	93%
With potassium carbonate In acetonitrile at 80℃; for 24h;	93%

N-(Benzyloxycarbonyl)glycine (1138-80-3) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → 1,1-dimethylethyl(1S,4S)-5-(N-{[benzyloxy]carbonyl}glycyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (774610-01-4)

Conditions	Yield
With 3-methyl-N-(3-methylbutyl)-1-butanamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	92%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane
With 4-methyl-morpholine; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at 20℃; for 24h; Product distribution / selectivity;

2-[4-(2-bromoethoxy)phenoxy]benzothiazole (841200-43-9) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → (S,S)-5-(2-[4-(benzothiazol-2-yloxy)-phenoxy]-ethyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1146691-49-7)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20 - 60℃; for 69h;	92%

(1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → calcium 1-(5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)diazen-1-ium-1,2-diolate

Conditions	Yield
With nitrogen(II) oxide; calcium hydroxide In water at 20℃; under 12929 Torr; for 120h; Green chemistry;	92%

(1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) + 2-[bis(4-fluorophenyl)methoxy]ethyl iodide (321365-84-8) → 3-[2-[bis(4-fluorophenyl)methoxy]ethyl]-8-(1S,4S)-N-t-Boc-2,5-diazabicyclo[2.2.1]heptane (321365-88-2)

Conditions	Yield
With potassium carbonate In tetrahydrofuran Heating;	91%

6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → tert-butyl (1S,4 S)-5-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 90℃;	90%

6-methoxy-3-pyridinecarboxaldehyde (65873-72-5) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → tert-butyl (1S,4S)-5-(6-methoxypyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Conditions	Yield
With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃;	90%

2-fluoro-5-nitrobenzaldehye (27996-87-8) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → (1S,4S)-tert-butyl 5-(2-formyl-4-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 50℃; Inert atmosphere;	89%

Fmoc-Leu-OH (35661-60-0) + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → 1,1-dimethylethyl (1S,4S)-5-(N-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-L-leucyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1186643-72-0)

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	88.3%

5-(3-(4-(2-bromoethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile + (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (113451-59-5) → (1S,4S)-tert-butyl 5-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Conditions	Yield
With potassium carbonate In acetonitrile at 80℃; for 12h;	87.7%

Upstream product

• 113451-54-0 (2S,4R)-2-(azidomethyl)-1-(tert-butoxycarbonyl)-4-<(methylsulfonyl)oxy>pyrrolidine 
• 132666-68-3 (1S,4S)-5-Benzyl-2-tert-butoxycarbonyl-2,5-diazabicyclo<2.2.1>heptane 
• 40216-83-9 L-4-hydroxyproline methyl ester hydrochloride 
• 51-35-4 4R-4-hydroxyproline 
• 74844-91-0 1-tert-butyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate 
• 61478-26-0 tert-butyl (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylate 
• 194089-91-3 tert-butyl (2S,4R)-4-hydroxy-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-pyrrolidine-1-carboxylate 
• 114676-96-9 (2S,4R)-tert-butyl 2-(azidomethyl)-4-hydroxypyrrolidine-1-carboxylate 
• 84520-68-3 N-tert-butoxycarbonyl-cis-4-azido-L-proline methyl ester 
• 922139-40-0 tert-butyl (2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-carboxylate 
• 84520-67-2 (2S,4R)-4-(methylsulfonyloxy)pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester-2-methylester 
• 5234-75-3 (2S,4R)-1-(4-tolylsulfonyl)-4-<(4-tolylsulfonyl)oxy>-2-<<(4-tolylsulfonyl)oxy>methyl>pyrrolidine 
• 5234-72-0 (1S,4S)-5-Benzyl-2-tosyl-2,5-diazabicyclo<2.2.1>heptane 
• 100944-15-8 (1S,4S)-2-Benzyl-2,5-diazabicyclo<2.2.1>heptane dihydrobromide 

Downstream Products

• 286946-44-9 tert-butyl (1S,4S)-5-[5-(benzyloxy)-3-pyridinyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate 
• 924643-28-7 C₁₇H₂₁IN₂O₃ 
• 927679-46-7 1,1-dimethylethyl (1S,4S)-5-[[4-(methoxycarbonyl)phenyl]methyl]-2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylate 
• 635308-46-2 7-((1S,4S)-2,5-diazabicyclo(2.2.1)hept-2-yl)-1-(4-(dimethylamino)benzyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 

Relevant articles and documents

Method for preparing (1S, 4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane

The invention discloses a method for preparing (1S, 4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane. The method comprises the following steps: (1) preparing an intermediate I by using N-Boc-trans-4-hydroxy-L-proline methyl ester as a raw material; (2) preparing an intermediate II by reacting the intermediate I with an organic base and a sulfonylating reagent; (3) preparing an intermediate III from the intermediate II and benzylamine; and (4) finally preparing (1S, 4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane by debenzylating the intermediate III. The method provided by the invention simplifies reaction steps, reduces raw material cost and time cost, has high product yield, tends to purify and amplify production, and can reduce waste discharge.

Multicomponent synthesis of some new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro anti-proliferative activity against CaSki, MDA-MB-231 and SK-Lu-1 tumour cells as apoptosis inducing agents without necrosis

Identification of a new class of antitumor agent capable to induce apoptosis without triggering necrotic cell death event is challenging. The present communication describes the multicomponent synthesis of seven new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro antiproliferative activity on cervical cancer cell line (CaSki), breast cancer cell line (MDA-MB231), lung cancer cell line (SK-Lu-1) and human lymphocytes. Among the synthesized dithiocarbamates, compound 9e displayed significant antiproliferative activity without inducing any necrotic cell death (both on tumour cells and lymphocytes) and induced apoptosis in tumor cells by the caspase dependent apoptotic pathway. The compound 9e also exhibited greater tumor selectivity than human lymphocytes. In silico ADME predictions revealed that compound 9e has the potential to be developed as a drug candidate. Rapid chemical modifications of this lead are thus highly necessary for further investigation as a drug like safer antitumor candidate and also to achieve compounds with better activity profile.

A practical synthesis of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane

The rigid piperazine homologue 2,5-diazabicyclo[2.2.1]heptane (DBH) finds extensive application in medicinal chemistry and pharmaceutical research, but access to this scaffold is non-trivial. This letter details a concise synthetic sequence that gives ready access to DBH on gram scale. The route features a Staudinger reduction of an azide to facilitate a transannular cyclisation.