Org. Synth. 2003, 80, 93
DOI: 10.15227/orgsyn.080.0093
THE CATALYTIC INTRAMOLECULAR PAUSON-KHAND REACTION: 2,3,3α,4-TETRAHYDRO-2-[(4-METHYLBENZENE) SULFONYL]CYCLOPENTA[C]PYRROL-5(1H)-ONE
[(Cyclopenta[b]pyrrol-5(1H)-one, 2,3,3a,4-tetrahydro-1-[(4-methylphenyl)sulfonyl]-)]
Submitted by Mittun C. Patel
1, Tom Livinghouse
2, and Brian L. Pagenkopf
1.
Checked by Kyung-Hee Kim and Marvin J. Miller.
1. Procedure
A. N-(2-Propenyl)-4-methylbenzenesulfonamide (2).A 1-L, two-necked, round-bottomed flask equipped with a magnetic stirring bar, internal thermometer and powder funnel is charged with p-toluenesulfonyl chloride (97.2 g, 0.51 mol) (Note 1). The powder funnel is replaced with a rubber septum connected to a positive pressure of argon and an oil bubbler. The apparatus is flushed with argon and charged with tetrahydrofuran (THF) (400 mL, (Note 2)) and pyridine (42.9 mL, 0.53 mol). The flask is placed in an ice bath and, after the reaction mixture has cooled to ca. 10°C, allylamine (37.5 mL, 0.50 mol) (Note 3) is added portion-wise by syringe over ca. 40 min (exothermic) maintaining the internal temperature below 15°C. The ice bath is removed and the resulting solution is allowed to warm to room temperature. After 4 hr the rubber septum is removed and the mixture is treated with 75 mL of a 2M aqueous solution of sodium hydroxide. After another 4 hr, the reaction mixture is transferred to a separatory funnel, the organic phase is separated, and the aqueous phase is extracted with two 100-mL portions of ethyl acetate (EtOAc). The combined organic phases are washed with brine (50 mL) and dried with magnesium sulfate (MgSO4) in the presence of activated carbon (4 g). The solution is filtered through a plug of silica gel (diameter: 5 cm; height: 3 cm) and the cake is washed with EtOAc (300 mL). The combined filtrate and washes are concentrated under reduced pressure. The crude product is recrystallized from 275 mL of 30% EtOAc/hexanes to afford 65 g (62%) of allyl tosylamide as a first crop. A second crop of 27 g (26%, 88% in total) is obtained from the mother liquor (Note 4).
B. N-(2-Propenyl)-N-(2-propynyl)-4-methylbenzenesulfonamide (3). A 500-mL, single-necked, round-bottomed flask equipped with a Teflon-coated stirring bar (Note 1) is charged with allyl tosylamide (31.7 g, 150 mmol), anhydrous potassium carbonate (K2CO3) (24.8 g, 1.2 equiv, 180 mmol) (Note 5), 1-bromo-2-propyne (20.0 mL, 1.2 equiv, 180 mmol), and acetone (300 mL). The flask is equipped with a water-cooled condenser fitted with a rubber septum. The apparatus is flushed with argon introduced through the septum and a positive pressure of argon is maintained with an argon-filled balloon (Note 6). The reaction mixture is heated to reflux with stirring for 24 hr. After complete consumption of starting material, monitored by thin layer chromatography (TLC, (Note 7)), the reaction mixture is allowed to cool and is concentrated under reduced pressure on a rotary evaporator. The residue is diluted with EtOAc (250 mL) and water (125 mL) and the organic phase is separated. The aqueous phase is extracted with 200 mL of EtOAc and the combined organic phases are washed with brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure with a rotary evaporator. The residue is recrystallized from 2.5 mL of ether and 250 mL of 20% EtOAc/hexanes to afford ca. 30 g (80%) of 3 as nearly colorless crystals. A second crop totaling 5.9 g (16%, 96% in total) is also obtained (Note 8).
C. Hexacarbonyl[μ-[(3,4-η:3,4-η)-2-methyl-3-butyn-2-ol]]dicobalt (5). A single-necked, 50-mL, round-bottomed flask (Note 9), equipped with a Teflon-coated stirring bar, is charged with dicobalt octacarbonyl (Co2(CO)8) (1.7 g, 5.0 mmol, 1.0 equiv) (Note 10). After attaching a rubber septum, the flask is flushed with carbon monoxide (CO), then charged with 25 mL of degassed diethyl ether (Note 11). The flask is placed in an ice bath and, after 10 min, a bubbler is connected through the septum, followed immediately by the addition of 2-methyl-3-butyn-2-ol (0.51 mL, 5.3 mmol, 1.05 eq). After removing the ice bath and stirring for 3 hr at ambient temperature, the resultant solution is filtered through a pad of Celite (diameter: 3 cm; height: 1 cm) (Note 12), which is washed with ether until the washes are clear (ca. 75 mL).
The alkyne cobalt complex is purified by silica gel chromatography. To the red solution is added 2 g of silica gel and the mixture is concentrated on a rotary evaporator (Note 13). The silica gel is then placed under vacuum (1 mm) until effervescence ceases (about 10 min). The dried silica gel is placed at the top of a column of silica gel (diameter: 3 cm; height: 9 cm), eluting first with hexane to remove non-polar by-products and subsequently with 15% ether/hexane. The desired product elutes as a red band. Concentration of the appropriate fractions on a rotary evaporator (Note 13) and under high vacuum (0.7 mm for 10 min) affords 1.4 g (79%) of 5 as a fine red powder (Note 14).
D. 2,3,3α,4-Tetrahydro-2-[(4-methylbenzene)sulfonyl]cyclopenta[c]pyrrol-5(1H)-one (6). A 250-mL, two-necked, round-bottomed Schlenk flask, equipped with a thermometer and Teflon-coated stirring bar, is charged with 6.0 g (24.1 mmol) of enyne 3 prepared in Step B (Note 1). A 12-cm, air-cooled condenser is attached to the flask. The top of the condenser is fitted with a rubber septum, which is connected to a CO supply and the apparatus is flushed with CO through the Schlenk valve (Note 15) for several min. After the CO purge is completed, the flask is charged with 120 mL of 1,2-dimethoxyethane (1,2-DME) (Note 16). Meanwhile, another 50-mL, round-bottomed Schlenk flask is charged with the Co2(CO)6-alkyne complex 5 (445 mg, 1.20 mmol, 5 mol%) (Note 9) and flushed with CO with a CO-filled balloon as described above. To the flask containing the Co2(CO)6-alkyne complex 5 are added sequentially 22.5 mL of 1,2-DME, cyclohexylamine (0.413 mL, 3.61 mmol, 15 mol%), 3 eq of amine/cobalt dimer) and triethylsilane (Et3SiH) (2.40 mL of a 0.5M solution in xylenes, 1.20 mmol, 5 mol%). The assembly is heated in an oil bath at 67°C for 15 min (Note 17), then transferred via cannula under an atmosphere of CO to the Schlenk flask containing enyne 3 (Note 18). The resulting mixture is heated at 67°C for 24 hr, when the reaction is usually complete as determined by TLC analysis (Note 19). After complete carbocyclization, the reaction mixture is transferred (in air) to a single-necked flask and concentrated on a rotary evaporator. The dark residue is dissolved in 150 mL of dichloromethane (CH2Cl2), washed with 10% aqueous sulfuric acid (2 × 15 mL), water (15 mL), and brine (45 mL) and treated with ca. 4 g of activated carbon and anhydrous sodium sulfate (Na2SO4). After 4 hr the solution is filtered through a pad of Celite (diameter: 5 cm; height: 2 cm) (Note 12) and concentrated on a rotary evaporator to afford a brown solid. Purification by flash chromatography with silica gel (Note 20) affords 5.8-6.2 g (86-93% yield) of 6 as a slightly yellow solid. Colorless microcrystalline material may be obtained by recrystallization from a cold (−20°C) solution of 1:1 2-propanol:CH2Cl2 (4.6-5.1 g, 69-77%) (Notes 21, 22).
2. Notes
1.
All glassware is dried in a 200°C oven overnight prior to use, assembled while hot, and allowed to cool to room temperature under dry
argon.
2.
Mallinckrodt ChromAR® HLPC grade THF was used as received.
3.
Allylamine was purchased from Acros Organics and distilled from calcium sulfate before use.
4.
The checkers obtained
80 g (
76%). Properties of
23:
mp 58.0-59.0°C (EtOAc/hexanes);
1H NMR (CDCl
3) δ: 2.34 (s, 3H), 3.49 (app t, J = 5.95, 2H), 4.96-5.12 (m, 2H), 5.23 (s, 1H), 5.57-5.68 (m, 1H), 7.21 (d, J = 8.2, 2H), 7.69 (d, J = 8.2, 2H);
13C NMR (CDCl
3) δ: 21.2, 45.5, 117.2, 126.9, 129.5, 132.9, 136.9, 143.2.
5.
Unless otherwise noted,
all solvents and reagents were purchased from VWR Scientific or Aldrich Chemical Co., Inc. and used as received.
CDCl3 was filtered through basic alumina (Aldrich Chemical Co., Inc.) prior to use.
6.
The checkers used a double needle in the septum, one for
argon supply and the other attached to an argon-filled balloon.
7.
The R
f of the starting material and product is 0.30 and 0.52, respectively (1:1 EtOAc:hexanes).
8.
The checkers obtained
33.2 g (
89%). Properties of
3:
mp 60.8-61.5°C (EtOAc/hexanes);
1H NMR (CDCl
3) δ: 1.96 (t, J = 2.4, 1 H), 2.35 (s, 3H), 3.76 (d, J = 6.5, 2H), 4.02 (d, J = 2.4, 2H), 5.25-5.14 (m, 2H), 5.72-5.59 (m, 1 H), 7.23 (d, J = 8.1, 2H), 7.66 (dd, J = 8.3, 1.5, 2H);
13C NMR (CDCl
3) δ: 21.3 (CH
3), 35.7 (CH
2), 48.9 (CH
2), 73.6 (CH
2), 119.7 (CH
2), 127.6 (CH), 129.3 (CH), 131.8 (CH), 136.0 (C), 143.4 (C); IR (thin film) cm
−1: 3257, 3049, 2987, 2885, 2117, 1646, 1601, 1425, 1330, 1165.
9.
The glassware must be cooled to room temperature before use.
10.
Caution. Dry Co2(CO)8 can be pyrophoric. Co
2(CO)
8 is toxic and should be handled in a glove box or well-ventilated hood.
Co2(CO)8 was purchased from Strem Chemical Co., Inc. High purity Co
2(CO)
8 is critical for successful catalytic reactions. A freshly opened sample of Co
2(CO)
8 stored in a dry box is often sufficiently pure to be used directly in this reaction provided three eq of
cyclohexylamine per Co
2(CO)
8 are added to the reaction mixture. However, a more reliable approach is to generate the active
cobalt catalyst in situ as described herein.
11.
Ether was distilled from a purple solution of
sodium/
benzophenone ketyl and degassed by bubbling with
argon.
12.
Celite 545 was purchased from Fluka.
13.
The bath temperature of the rotary evaporator must be kept below 35°C.
14.
The checkers obtained
1.35 g (
75%) Properties of
54:
1H NMR (CDCl
3) δ: 1.55 (s, 6H), 1.70 (s, 1 H), 6.01 (s, 1 H);
13C NMR (CDCl
3) δ: 33.4, 71.7, 72.9, 76.8, 107.3, 200.0 (m).
15.
Carbon monoxide is highly toxic and should be handled in a well-ventilated hood.
16.
All solvents must be rigorously degassed for the Pauson-Khand step. 1,2-DME obtained from VWR Scientific was freshly distilled from a deep blue solution of
sodium/
benzophenone ketyl and degassed with
argon prior to use.
17.
The internal temperature of the mixture is 64°C. Temperatures above 70°C lead to catalyst decomposition.
18.
To facilitate transfer of the catalyst, the CO source connected to the large reaction vessel is removed and replaced with a line leading to a
mineral oil bubbler. When the transfer is complete, the bubbler is disconnected and a CO-filled double-walled balloon is connected to the top of the condenser and used to maintain a CO atmosphere throughout the reaction. Strict exclusion of air during these transfers is critical.
19.
The course of the reaction may be monitored by TLC: R
f of
3 and
6 is 0.82 and 0.36, respectively (1:1 EtOAc:hexanes). The color of the reaction mixture typically turns from burgundy to dark brown at the end of the reaction.
20.
The solid residue is dissolved in a minimum of
dichloromethane and purified by flash chromatography on silica gel (8 cm diameter by 15 cm long column), eluting with 1.5 % EtOH in CH
2Cl
2.
21.
The crystals are collected by filtration on a
fritted glass filter funnel, rinsed with
ether and dried under reduced pressure.
22.
The checkers obtained
4.3 g (
65%). Properties of
6:
mp 147.0-148.0°C (2-PrOH/CH
2Cl
2);
1H NMR (CDCl
3) δ: 1.96-2.03 (dd, J = 17.9, 3.7, 1H), 2.37 (s, 3H), 2.48-2.60 (m, 2H), 3.04-3.10 (m, 1H), 3.93-4.00 (dd, J = 14.3, 5.1, 2H), 4.27 (d, J = 16.5, 1H), 5.92 (s, 1H), 7.29 (d, J = 8.1, 2H), 7.66 (d, J = 8.2, 2H);
13C NMR (CDCl
3) δ: 21.0 (CH
3), 39.3 (CH
2), 43.4 (CH), 47.1 (CH
2), 51.9 (CH
2), 125.6 (CH), 126.9(CH), 129.5 (CH), 133.0 (C), 143.6 (C), 178.2 (C), 206.8 (C); IR (KBr) cm
−1: 3067, 1711, 1648, 1343, 1162, 1090.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
The Pauson-Khand reaction is one of the most convenient methods for the synthesis of cyclopentenones, and both inter- and intramolecular variations exist.
5,6 In the classical procedure, the enyne is mixed with one equivalent of Co
2(CO)
8 and the mixture is heated (either at reflux or in a sealed tube) for several hours to days. The synthetic ease of the Pauson-Khand reaction was enhanced when it was discovered that silica gel, tertiary amine N-oxides and DMSO all markedly accelerated the reaction.
6 The Pauson-Khand reaction is compatible with enynes containing esters, ethers, amines, sulfides, 1,2-disubstituted olefins and substituted or terminal alkynes. A major drawback to large scale, classical Pauson-Khand reactions is the requirement for stoichiometric quantities of Co
2(CO)
8. We recently reported the first catalytic Pauson-Khand reaction conveniently operative at 1 atmosphere of CO.
7,8 The key factors of successful catalytic cyclizations are the use of highly purified Co
2(CO)
8, strictly anaerobic conditions, and temperature control. To circumvent the requirement for very pure Co
2(CO)
8 we developed a chemically robust, air-stable Co
2(CO)
6-alkyne complex as a source of pure Co
2(CO)
8 when released by silylative decomplexation.
9 This procedure employs
cyclohexylamine, which has been shown to accelerate stoichiometric Pauson-Khand reactions
10 and minimizes the sensitivity of the catalyst to
oxygen. The scope of the catalytic Pauson-Khand has been further enhanced by the discovery that
2,2,2-trifluoroethanol as a co-solvent minimizes some non-carbonylative isomerization processes.
11 The utility of the method is demonstrated by the diverse range of substrates shown in the Table.
Table
Thermally Promoted Catalytic Pauson-Khand Cyclizations
|
|
Entry
|
Enyne
|
Product
|
Yield (diastereomer ratio)
|
|
|
1
|
|
|
95a
|
|
2
|
|
|
90b (>30:1)
|
|
3
|
|
|
96a,c(30:1)
|
|
4
|
|
|
74a,d(2.5:1)
|
|
5
|
|
|
84b
|
|
|
|
|
|
cReaction solvent was 2,2,2-trifluoroethanol; see ref. 11
|
dReaction solvent was 2:1 2,2,2-trifluoroethanol:1,2-DME; see ref. 11.
|
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
N-(2-Propenyl)-4-methylbenzenesulfonamide:
Benzenesulfonamide, 4-methyl-N-2-propenyl- (9); (50487-71-3)
p-Toluenesulfonyl chloride:
Benzenesulfonyl chloride, 4-methyl- (9); (98-59-9)
Allylamine:
2-Propen-1-amine (9); (107-11-9)
Pyridine (8, 9); (110-86-1)
N-(2-Propenyl)-N-(2-propynyl)-4-methylbenzenesulfonamide:
Benzenesulfonamide, 4-methyl-N-2-propenyl-N-2-propynyl- (9); (133886-40-5)
1-Bromo-2-propyne:
1-Propyne, 3-bromo- (9); (106-96-7)
Hexacarbonyl[μ[(3,4-η:3,4-η)-2-methyl-3-butyn-2-ol]]dicobalt:
Cobalt, hexacarbonyl [μ-[(3,4-η:3,4-η)-2-methyl-3-butyn-2-ol]]di-, (Co-Co) (9); (40754-33-4)
Dicobalt octacarbonyl:
Cobalt, di-(-carbonylhexacarbonyl di-, (Co-Co) (8, 9); (10210-68-1)
2-Methyl-3-butyn-2-ol:
3-Butyn-2-ol, 2-methyl- (8, 9); (115-19-5)
2,3,3α,4-Tetrahydro-2-[(4-methylbenzene)sulfonyl]cyclopenta[c]pyrrol-5(1H)-one:
Cyclopenta[b]pyrrol-5(1H)-one, 2,3,3a,4-tetrahydro-1-[(4-methylphenyl)sulfonyl]- (9); (205885-50-3)
Carbon monoxide (8, 9); (630-08-0)
1,2-Dimethoxyethane:
Ethane, 1,2-dimethoxy- (8, 9); (110-71-4)
Cyclohexylamine:
Cyclohexanamine (9); (108-91-8)
Triethylsilane:
Silane, triethyl- (8, 9); (617-86-7)
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