hai guys :3 this was taken from the vespiary, original synth can b found here. i tried 2 fix any typos i saw but if there r some remaining pls lmk ^_^
First, one starts with α-bromopropiophenone. If one does not have this precursor then it will have to be made from readily available and cheap as shit propiophenone. There are many ways to effect the transformation of propiophenone to α-bromopropiophenone but the best of the lot is as follows:
Selective Bromination with Copper(II) Bromide
L.C. King & G.K. Ostrum
J. Org. Chem.29, 3459-3461 (1964)
Abstract
A heterogeneous system consisting of copper(II) bromide in chloroform-ethyl acetate will effect selective bromination of ketones. This system is the cleanest and the most direct for selective bromination reported to date. In the present paper the selective bromination of hydroxyacetophenones is reported.
Here is a general review of the process for brominated ketones (particularly acetophenones) with CuBr2 in refluxing 1:1 ethylacetate/chloroform solvent.
General Proceedure for the Heterogeneous Bromination Using Copper(II) Bromide
The copper(II) bromide was finely ground, without drying, in a mortar and pestle to ca. 80 mesh to ensure a large surface area for reaction. Copper(II) bromide (0.050 mol) was placed in an erlenmeyer flask fitted with a reflux condenser, and ethyl acetate (25 mL) was added and brought to reflux on a magnetic stirrer-hot plate. The compound to be brominated (0.030 mole; it is advisable to use a slight excess to avoid the possibility of dibromination) was dissolved in or diluted with hot chloroform (25 mL) (or an additional 25 mL of ethyl acetate if the compound was not soluble in chloroform) and added to the flask. The resulting reaction mixture was refluxed with vigorous stirring to ensure complete exposure of the copper(II) bromide to the reaction medium until the reaction was complete as judged by a color change of the solution from green to amber, disappearance of all black solid, and cessation of hydrogen bromide evolution. With numerous compounds the bromination was estimated, form the composition of the mixed copper bromides recovered, to be 90-95% complete in 30-60 min even though the deep green color persisted much longer. The color could be removed by decoloration with Norit A after removal of the copper(I) bromide by filtration. An induction period which varied with the starting material was observed in each case. The copper(I) bromide was collected by filtration and washed well with ethyl acetate. Recovery of copper(I) bromide was 96-100% in every case. The solvents were removed form the filtrate under reduced pressure, except when the product had a low boiling point, a property which required fractional distillation.
Anyway, once you have your α-bromopropiophenone you can go one of two ways. The inconvenient way is where you must isolate your α-bromopropiophenone first to then use in the following reaction (tedious and smelly unless, of course, you have α-bromopropiophenone already made):
Keep in mind that α-pyrrolidino-propiophenone is one of their experimental models but for the experimental reaction example, they use diethylamine to make α-diethylamino-propiophenone. Substituting pyrrolidine for diethylamine in this reaction will yield the desired α-pyrrolidino-propiophenone.
Taken from Chem. Abs. Vol. 56, 2384g and/or US Pat. 3,001,910 (1961):
"1145g of α-bromopropiophenone and 850g of diethylamine are combined under stirring and heated on a water bath to boiling. The precipitate is filtered off under suction and washed with benzene. The filtrate is shaken up with aqueous hydrogen chloride, the aqueous solution made alkaline and etherfied. The solution freed of the ether is fractionated. The boiling point (6 mm) is 140°C and the yield 800g. The base is dissolved in ethyl acetate and precipitated with isopropanolic hydrogen chloride. After suction filtration and washing with ether the yield is found to be 750g (80%) and the melting point 168°C."
A much better and convenient way to go is to start right where the synthesis of α-bromopropiophenone in refluxing ethyl acetate/chloroform left off: substituting pyrrolidine for pyridine will yield the desired α-pyrrolidino-propiophenone.
Preparation of the Substituted 1-Benzoylpyridinium Salts
"The pyridinium bromides could be prepared directly form the filtrate containing the crude α-bromo ketone by addition of a slight excess (0.03 mol) or pyridine followed by heating on the steam bath. An alternate procedure was to remove the chloroform-ethyl acetate under reduced pressure and dissolve the crude α-bromo ketone (lachrymatory!) in acetone before addition of the pyridine. The latter method sometimes gave crude products which were less discolored and had higher melting points. Both methods gave good yields."
I would guess 24 hours would be good enough to effect the desired transformation. Probably less would be needed. One could easily gauge the progress of the reaction by observing the slow deposition of pyridine salt. Also, there is no fear of significant side product formation as the nature of the α-pyrrolidino-propiophenone structure obviates any formation of pyrazine contaminant. If effect, α-pyrrolidino-propriophenone should be the only material recovered. Most definitely this synthesis is ideal as one goes directly from commercial propiophenone to final product α-pyrrolidino-propiophenone without the use of vacuum distillation in what is basically a "one-pot" process.
As for the dosage, I don't know. The tablets that were to be manufactured, according to the patent, ideally would contain 25 mg each of product. These were to be taken at each meal each day, making the daily dose 75 mg on average. Side effects were a temporary lowering of blood pressure, with the desirable lack of any observed hypertensive response (Good for me!)
(fidelis note: this was to the right side of the "US Pat. 3,001,910" section but in its own little box so i was unsure where exactly 2 place it) Possible one-pot bromination/amination?
Ref: J. Org. Chem. 29, 3459-3461 (1964)
Concerning the direct amination of α-bromoketones with heterocycles, Table II (p. 3460) in this paper presents yields of 66-99% for various α-pyridino-acetophenones. This strongly suggests that proceeding from the CHCl3-EtOAc reaction phase immediately to substition with pyrrolidine is the best and safest way to go. As noone likes to handle lachrymatory α-bromopropiophenone, this modification makes for a welcome streamlining of the process from start to finish. I wonder if a salt of the desired product precipitates, or simply a salt of pyrrolidine itself? Or even if there is any precipitated salt?
Well, I'd begin with concentration of the of the CHCl3/EtOAc mixture (bp 77/82°C), wash the concentrate with dilute NaOH and then water. Next; the organic phase is extracted with 10% HCl, the acid extracts pooled and carefully basified, the product extracted into a suitable solvent and the amine precipitated with dry HCl gas. Who knows though? Maybe the solvent can just be evaporated to yield a crystalline base.
Simple α-Bromination of Propiophenone in 95% Yield
I quote:
"Of the many ways to α-brominate ketones, we've had uniformly excellent results with CuBr2 in refluxing CHCl3-EtOAc"
Taken from:
Iodide Catalysis of Oxidations with Dimethyl Sulfoxide.
A Convenient Two-Step Synthesis of α-Diketones from α-Methylene Ketones
D.P. Bauer R.S. Macomber
J. Org. Chem. 40, 1990-1992 (1975)
General Procedure:
2-Bromocylcododecanone
Cyclododecanone (9.1 g 0.050 mol) chloroform (50 mL), and ethyl acetate (50 mL) were placed in a 250 mL three-necked flask equipped with magnetic stirrer, nitrogen inlet tube, and reflux condenser. Powdered cupric bromide (22.3 g, 0.10 mol) was added in small portions over a 2 hr period, with the reaction mixture maintained at 75-80°C while a constant stream of nitrogen gas was bubbled through the reaction solution. The green color from each portion was allowed to disappear before the next portion was added. After the addition was completed, the solution was heated for 1.5 hrs until the green color and dark cupric bromide disappeared, cooled, and filtered, and the colorless solid cuprous bromide was washed with 25 mL of chloroform. The combined filtrate and washings were rotary evaporated and the oily residue was redissolved in 200 mL of diethyl ehter, washed with water (50 mL), 5% sodium bicarbonate (2×50 mL), and brine (50 mL), then dried over sodium sulfate. After filtration, rotary evaporation of solvent, and cooling (-10°C), the resulting oil solidified to give cream-colored crystals (11.8g, 90%) of 2-bromocyclododecanone.
α-Bromopropiophenone was prepared on a 100 mmol scale (addition 1.5 h, stirring 1.5 h) as an oil. Yield 95%, bp 64-66°C (1 mmHg) [lit. bp 110-111°C (3 mmHg)].
According to Table I, the reaction using propiophenone was 5 hrs in total with a 95% yield.
First, one starts with α-bromopropiophenone. If one does not have this precursor then it will have to be made from readily available and cheap as shit propiophenone. There are many ways to effect the transformation of propiophenone to α-bromopropiophenone but the best of the lot is as follows:
Selective Bromination with Copper(II) Bromide
L.C. King & G.K. Ostrum
J. Org. Chem.29, 3459-3461 (1964)
Abstract
A heterogeneous system consisting of copper(II) bromide in chloroform-ethyl acetate will effect selective bromination of ketones. This system is the cleanest and the most direct for selective bromination reported to date. In the present paper the selective bromination of hydroxyacetophenones is reported.
Here is a general review of the process for brominated ketones (particularly acetophenones) with CuBr2 in refluxing 1:1 ethylacetate/chloroform solvent.
General Proceedure for the Heterogeneous Bromination Using Copper(II) Bromide
The copper(II) bromide was finely ground, without drying, in a mortar and pestle to ca. 80 mesh to ensure a large surface area for reaction. Copper(II) bromide (0.050 mol) was placed in an erlenmeyer flask fitted with a reflux condenser, and ethyl acetate (25 mL) was added and brought to reflux on a magnetic stirrer-hot plate. The compound to be brominated (0.030 mole; it is advisable to use a slight excess to avoid the possibility of dibromination) was dissolved in or diluted with hot chloroform (25 mL) (or an additional 25 mL of ethyl acetate if the compound was not soluble in chloroform) and added to the flask. The resulting reaction mixture was refluxed with vigorous stirring to ensure complete exposure of the copper(II) bromide to the reaction medium until the reaction was complete as judged by a color change of the solution from green to amber, disappearance of all black solid, and cessation of hydrogen bromide evolution. With numerous compounds the bromination was estimated, form the composition of the mixed copper bromides recovered, to be 90-95% complete in 30-60 min even though the deep green color persisted much longer. The color could be removed by decoloration with Norit A after removal of the copper(I) bromide by filtration. An induction period which varied with the starting material was observed in each case. The copper(I) bromide was collected by filtration and washed well with ethyl acetate. Recovery of copper(I) bromide was 96-100% in every case. The solvents were removed form the filtrate under reduced pressure, except when the product had a low boiling point, a property which required fractional distillation.
Anyway, once you have your α-bromopropiophenone you can go one of two ways. The inconvenient way is where you must isolate your α-bromopropiophenone first to then use in the following reaction (tedious and smelly unless, of course, you have α-bromopropiophenone already made):
Keep in mind that α-pyrrolidino-propiophenone is one of their experimental models but for the experimental reaction example, they use diethylamine to make α-diethylamino-propiophenone. Substituting pyrrolidine for diethylamine in this reaction will yield the desired α-pyrrolidino-propiophenone.
Taken from Chem. Abs. Vol. 56, 2384g and/or US Pat. 3,001,910 (1961):
"1145g of α-bromopropiophenone and 850g of diethylamine are combined under stirring and heated on a water bath to boiling. The precipitate is filtered off under suction and washed with benzene. The filtrate is shaken up with aqueous hydrogen chloride, the aqueous solution made alkaline and etherfied. The solution freed of the ether is fractionated. The boiling point (6 mm) is 140°C and the yield 800g. The base is dissolved in ethyl acetate and precipitated with isopropanolic hydrogen chloride. After suction filtration and washing with ether the yield is found to be 750g (80%) and the melting point 168°C."
A much better and convenient way to go is to start right where the synthesis of α-bromopropiophenone in refluxing ethyl acetate/chloroform left off: substituting pyrrolidine for pyridine will yield the desired α-pyrrolidino-propiophenone.
Preparation of the Substituted 1-Benzoylpyridinium Salts
"The pyridinium bromides could be prepared directly form the filtrate containing the crude α-bromo ketone by addition of a slight excess (0.03 mol) or pyridine followed by heating on the steam bath. An alternate procedure was to remove the chloroform-ethyl acetate under reduced pressure and dissolve the crude α-bromo ketone (lachrymatory!) in acetone before addition of the pyridine. The latter method sometimes gave crude products which were less discolored and had higher melting points. Both methods gave good yields."
I would guess 24 hours would be good enough to effect the desired transformation. Probably less would be needed. One could easily gauge the progress of the reaction by observing the slow deposition of pyridine salt. Also, there is no fear of significant side product formation as the nature of the α-pyrrolidino-propiophenone structure obviates any formation of pyrazine contaminant. If effect, α-pyrrolidino-propriophenone should be the only material recovered. Most definitely this synthesis is ideal as one goes directly from commercial propiophenone to final product α-pyrrolidino-propiophenone without the use of vacuum distillation in what is basically a "one-pot" process.
As for the dosage, I don't know. The tablets that were to be manufactured, according to the patent, ideally would contain 25 mg each of product. These were to be taken at each meal each day, making the daily dose 75 mg on average. Side effects were a temporary lowering of blood pressure, with the desirable lack of any observed hypertensive response (Good for me!)
(fidelis note: this was to the right side of the "US Pat. 3,001,910" section but in its own little box so i was unsure where exactly 2 place it) Possible one-pot bromination/amination?
Ref: J. Org. Chem. 29, 3459-3461 (1964)
Concerning the direct amination of α-bromoketones with heterocycles, Table II (p. 3460) in this paper presents yields of 66-99% for various α-pyridino-acetophenones. This strongly suggests that proceeding from the CHCl3-EtOAc reaction phase immediately to substition with pyrrolidine is the best and safest way to go. As noone likes to handle lachrymatory α-bromopropiophenone, this modification makes for a welcome streamlining of the process from start to finish. I wonder if a salt of the desired product precipitates, or simply a salt of pyrrolidine itself? Or even if there is any precipitated salt?
Well, I'd begin with concentration of the of the CHCl3/EtOAc mixture (bp 77/82°C), wash the concentrate with dilute NaOH and then water. Next; the organic phase is extracted with 10% HCl, the acid extracts pooled and carefully basified, the product extracted into a suitable solvent and the amine precipitated with dry HCl gas. Who knows though? Maybe the solvent can just be evaporated to yield a crystalline base.
Simple α-Bromination of Propiophenone in 95% Yield
I quote:
"Of the many ways to α-brominate ketones, we've had uniformly excellent results with CuBr2 in refluxing CHCl3-EtOAc"
Taken from:
Iodide Catalysis of Oxidations with Dimethyl Sulfoxide.
A Convenient Two-Step Synthesis of α-Diketones from α-Methylene Ketones
D.P. Bauer R.S. Macomber
J. Org. Chem. 40, 1990-1992 (1975)
General Procedure:
2-Bromocylcododecanone
Cyclododecanone (9.1 g 0.050 mol) chloroform (50 mL), and ethyl acetate (50 mL) were placed in a 250 mL three-necked flask equipped with magnetic stirrer, nitrogen inlet tube, and reflux condenser. Powdered cupric bromide (22.3 g, 0.10 mol) was added in small portions over a 2 hr period, with the reaction mixture maintained at 75-80°C while a constant stream of nitrogen gas was bubbled through the reaction solution. The green color from each portion was allowed to disappear before the next portion was added. After the addition was completed, the solution was heated for 1.5 hrs until the green color and dark cupric bromide disappeared, cooled, and filtered, and the colorless solid cuprous bromide was washed with 25 mL of chloroform. The combined filtrate and washings were rotary evaporated and the oily residue was redissolved in 200 mL of diethyl ehter, washed with water (50 mL), 5% sodium bicarbonate (2×50 mL), and brine (50 mL), then dried over sodium sulfate. After filtration, rotary evaporation of solvent, and cooling (-10°C), the resulting oil solidified to give cream-colored crystals (11.8g, 90%) of 2-bromocyclododecanone.
α-Bromopropiophenone was prepared on a 100 mmol scale (addition 1.5 h, stirring 1.5 h) as an oil. Yield 95%, bp 64-66°C (1 mmHg) [lit. bp 110-111°C (3 mmHg)].
According to Table I, the reaction using propiophenone was 5 hrs in total with a 95% yield.
