Organic Syntheses Procedure

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Org. Synth. 2009, 86, 59

DOI: 10.15227/orgsyn.086.0059

PREPARATION OF 4-SPIROCYCLOHEXYLOXAZOLIDINONE BY C-H BOND NITRENE INSERTION

[3-Oxa-1-azaspiro[4.5]decan-2-one]

Submitted by Kim Huard and Hélène Lebel¹.

Checked by Adam Rosenberg, Darla Seifried, and Kay Brummond.

1. Procedure

A. Rhodium II tetrakis(triphenylacetate) dimer (2). To a 250-mL, one-necked, round-bottomed flask equipped with a magnetic stirring bar, a short-path distillation apparatus and a 100-mL receiving bulb (Note 1) is added rhodium (II) acetate dimer (1.26 g, 2.85 mmol) (Note 2), triphenylacetic acid (1) (6.55 g, 22.7 mmol, 8.0 equiv) (Note 3) and chlorobenzene (120 mL) (Note 3). The mixture is heated with an oil bath that is set to a temperature at which the solvent distills at a rate of 10 mL/hour (approximately 155 °C) (Note 4). The green mixture becomes homogeneous upon heating. After 7 h, the reaction is cooled to 25 °C and the residual solvent is concentrated at 65 °C by rotary evaporation (20-25 mmHg) and then at 0.5 mmHg. The solid residue is dissolved in 200 mL of dichloromethane. The solution is washed with saturated aqueous sodium bicarbonate (3 × 200 mL), saturated aqueous sodium chloride (100 mL), dried over magnesium sulfate (15 g), filtered and concentrated at 40 °C by rotary evaporation (225 mmHg) and then at 0.5 mmHg. To the green solid, methanol (40 mL) is added and the residue is stirred in a 35 °C water bath (Note 5). After 5 minutes, dichloromethane is added portion wise with stirring and heating in a 35 °C water bath until the solid is completely dissolved (approximately 200 mL of DCM). The solution is left to rest at -19 °C for 72 h. The crystals are collected by suction filtration on a fritted glass funnel and dried at 0.5 mmHg to afford 3.01 g (78% yield) of the desired product (Notes 6 and 7).

B. Cyclohexylmethyl N-hydroxycarbamate (4). A 500-mL, one-necked, round-bottomed flask equipped with a magnetic stirring bar and a 50-mL pressure-equalizing addition funnel fitted with a nitrogen inlet is flame-dried and maintained under nitrogen atmosphere. The flask is quickly opened to add 1,1'-carbonyldiimidazole (17.0 g, 105 mmol, 1.05 equiv) (Notes 8 and 9) followed by acetonitrile (200 mL) (Note 10) via cannula. The white suspension is cooled with an ice bath and cyclohexanemethanol (3) (12.3 mL, 100 mmol) (Note 11) is transferred to the addition funnel using a syringe. Cyclohexanemethanol (3) is added dropwise over a 30-minute time period. Addition of the alcohol results in the suspension becoming a homogeneous solution. The addition funnel is rinsed with acetonitrile (10 mL) and the solution is stirred in the ice bath for 1 h. The reaction of cyclohexanemethanol 3 (R_f = 0.63 in 30% EtOAc/DCM) with 1,1'-carbonyldiimidazole to give a carbonylated intermediate (R_f = 0.59 in 30% EtOAc/DCM) can be followed by TLC analysis using a potassium permanganate solution for visualization. Continued stirring does not improve the conversion as the intermediate can be hydrolyzed and the starting alcohol recovered. The solution is then warmed to ambient temperature. To the solution is then added hydroxylamine hydrochloride (20.9 g, 300 mmol, 3.0 equiv) (Note 12) followed by imidazole (13.6 g, 200 mmol, 2.0 equiv) (Note 12) and vigorous stirring is continued for 3.5 h (Note 13). The conversion of the intermediate (R_f = 0.59 in 30% EtOAc/DCM) to cyclohexylmethyl N-hydroxycarbamate 4 (R_f = 0.52 in 30% EtOAc/DCM) can be followed by TLC analysis using a potassium permanganate solution for visualization. The suspension is concentrated at 40 °C by rotary evaporation (130 mmHg) and at 0.5 mmHg. The white residue is dissolved in a 1:1 mixture of ethyl acetate and 10% hydrochloric acid (300 mL) and transferred to a 1-L separatory funnel. After vigorous shaking, the phases are separated and the aqueous phase is extracted with ethyl acetate (2 × 150 mL). The combined organic layers are washed with a saturated sodium chloride solution (100 mL), dried over magnesium sulfate (15 g), filtered and concentrated at 40 °C by rotary evaporation (75 mmHg) and then at 0.5 mmHg to afford 16.57 g of a light amber oil containing the title compound 4 and residual starting alcohol 3 in a ratio of roughly 7:1, as determined by NMR analysis (Note 14). This mixture is used without further purification for the next step. A 200 mg sample of the crude product is purified by silica gel chromatography (Note 15) to afford 167 mg (84% recovery) of the title compound as a white solid (Note 16).

C. Cyclohexylmethyl N-tosyloxycarbamate (5). A 500-mL, one-necked, round-bottomed flask containing the oily residue obtained from procedure B (15.9 g) is equipped with a magnetic stirring bar and a 50-mL pressure-equalizing addition funnel fitted with a nitrogen inlet. The system is flushed with nitrogen for 30 min and maintained under nitrogen atmosphere. Diethyl ether (200 mL) (Note 17) is added via cannula and the solution is cooled with an ice bath. The system is quickly opened to add p-toluenesulfonyl chloride (20.2 g, 106 mmol) (Note 18). Triethylamine (13.4 mL, 96.4 mmol) (Note 19) is introduced into the addition funnel using a syringe and is added dropwise over a 15-minute time period to the ethereal solution. The addition funnel is rinsed with diethyl ether (10 mL) and the solution is stirred in the ice bath for 1.5 h. Distilled water (75 mL) is added to the white suspension and the resulting clear mixture is transferred to a 500-mL separatory funnel. After vigorous shaking, the organic layer is separated and washed with a saturated sodium chloride solution (75 mL), dried over MgSO₄ (15 g), filtered and concentrated at 40 °C by rotary evaporation (225 mmHg and 20 mmHg) until the residue becomes solid and then at 0.5 mmHg for 12 h to afford a yellowish solid. The solid is dissolved in 50 mL of dichloromethane and is charged on a 6.5 × 11 cm silica gel column (200 g of dry silica) (Note 20). The system is eluted with a mixture of 5% ethyl acetate-dichloromethane. The first 150 mL are discarded and the next 800 mL are collected in a 1-L round-bottomed flask and concentrated at 40 °C by rotary evaporation (225 mmHg, then 20 mmHg) until the residue becomes a solid which is then dried at 0.5 mmHg. The inner surface of the flask is scratched with a spatula in order to loosen the product from the flask. To the 1-L flask is added a 6-cm egg-shaped magnetic stirring bar and 300 mL of hexane (Note 21). The suspension is vigorously stirred for 24 h and filtered on a fritted glass funnel. The white solid is dried at 0.5 mmHg for 8 h to afford 23.75 g (73% yield from 3) of the desired product (Notes 22 and 23). The tosyloxycarbamate must be over 90% purity, as determined by GC/MS, to be used for the next step.

D. 4-Spirocyclohexyloxazolidinone (6). Using a 250-mL one-necked, round-bottomed flask equipped with a magnetic stirring bar, a solution of cyclohexylmethyl N-tosyloxycarbamate (5) (16.4 g, 50.0 mmol) in dichloromethane (50 mL) (Note 24) is prepared. A 1-L three-necked, round-bottomed flask equipped with a 6-cm egg-shaped magnetic stirring bar is charged with dichloromethane (75 mL) and distilled water (10 mL). Potassium carbonate (7.60 g, 55 mmol, 1.1 equiv) (Note 25) is added to the flask, which is fitted with a rubber septum, an internal thermometer, glass stopper and a short needle (through the septum) opened to the atmosphere, and the mixture is stirred until the white solid is dissolved. The dichloromethane solution containing 5 (Note 26) is taken up in a 60-mL glass syringe, which is installed on a syringe pump system set for an addition time of 60 minutes. Tetrakis(triphenylacetate) rhodium dimer (2) (0.678 g, 0.5 mmol, 0.01 equiv) is added to the biphasic solution and the dropwise addition is begun. Upon the addition of the tosyloxycarbamate 5 solution, the green reaction mixture becomes thicker, a white solid forms, and the internal temperature slowly rises to reach 30 °C when approximately half of the starting material is added. Then the mixture slowly cools down to room temperature. The starting material is added dropwise to avoid any significant rise of internal temperature. When the complete volume is added, the 250-mL flask and the syringe are rinsed with 10 mL of dichloromethane and this volume is added to the mixture which is stirred for a further 3 h to ensure complete consumption of the starting material. The dichloromethane is evaporated at 40 °C by rotary evaporation (225 mmHg) until only the residue and the water are left in the flask. The aqueous residue is dissolved in a 1:1 mixture of ethyl acetate and water (400 mL) and transferred to a 1-L separatory funnel. The phases are separated and the aqueous layer is extracted with ethyl acetate (2 × 100 mL). The combined organic extracts are washed with a saturated sodium chloride solution (100 mL), dried over MgSO₄ (15 g), filtered and concentrated at 40 °C by rotary evaporation (75 mmHg) and then at 0.5 mmHg to afford a yellowish solid. The solid is dissolved in 20 mL of dichloromethane and charged on a 6.5 × 22 cm column of silica gel (350 g of dry silica) (Note 20). The system is eluted with a mixture of 30% ethyl acetate-dichloromethane. Because the product is difficult to visualize by TLC, the first 900 mL are discarded and the next 1400 mL are collected and concentrated at 40 °C by rotary evaporation (225 mmHg then 20 mmHg) until the residue solidifies. It is then dried at 0.5 mmHg to afford 6.1 g (79% yield) of the title compound as a yellowish solid of purity higher than 98% as determined by NMR and GC/MS analysis (Note 27).

2. Notes

1. All glassware was flame-dried under vacuum and allowed to cool under an atmosphere of nitrogen.

2. Rhodium (II) acetate dimer was purchased from Strem Chemicals. It was stored and weighed in a glove box and was used without further purification.

3. Triphenylacetic acid (99%) and chlorobenzene (99%) were purchased from Aldrich Chemical Company, Inc. and used as received.

4. Slow distillation of the solvent (bp 132 °C) removes the acetic acid (bp 117 °C) formed from the ligand exchange. If the distillation rate is higher than 10 mL/hour, chlorobenzene is added in order to keep the total volume of the reaction mixture over 40 mL.

5. The solid is insoluble in methanol and the color changes from green to purple-blue.

6. A half-scale run provided 1.75 g (89%) of the rhodium II tetrakis(triphenylacetate) dimer.

7. Analytical data for Rhodium II tetrakis(triphenylacetate) dimer (2): R_f = 0.19 (10% ethyl acetate/hexane); ¹H NMR pdf (300 MHz, CDCl₃) δ: 3.51 (residual MeOH), 6.63 (d, J = 7.5 Hz, 24 H), 6.86 (t, J = 8.1 Hz, 24 H), 7.07 (t, J = 7.5 Hz, 12 H); ¹³C NMR pdf (75 MHz, CDCl₃) δ: 69.2 (residual MeOH), 126.8, 127.4, 130.7, 143.4, 192.9; IR (film) 3055, 1590, 1580, 1365 cm^-1; Analysis calc. for C₈₀H₆₀O₈Rh₂: C 70.90, H 4.46; found: C 67.96, H 4.73 %. The low value obtained for the carbon analysis is due to residual coordinated methanol from the recrystallization. Up to 2 equiv of MeOH per molecule of dimer (determined by ¹H NMR, δ = 3.51 and ¹³C NMR, δ = 69.2) can be present and do not affect the reactivity of the catalyst.

8. 1,1'-Carbonyldiimidazole, reagent grade, was purchased from Aldrich Chemical Company, Inc. It was stored and weighed in a glove box to avoid hydrolysis and was used without further purification.

9. Short exposure to 1,1'-carbonyldiimidazole could cause serious temporary or residual injury. This reagent should be handled with careful attention to avoid contact with skin.

10. Acetonitrile was distilled over calcium hydride. If wet acetonitrile is used, hydrolysis of a reaction intermediate reduces the yield.

11. Cyclohexanemethanol (3), 99+%, was purchased from Aldrich Chemical Company, Inc. and was used as received.

12. Hydroxylamine hydrochloride (99%) and imidazole (99%) were purchased from Alfa Aesar and used as received.

13. An excess of hydroxylamine and imidazole is used in order to accelerate the reaction and minimize the hydrolysis of the intermediate.

14. The ¹H NMR pdf methylene resonances of the N-hydroxycarbamate (doublet at 3.96 ppm) and the starting alcohol (doublet at 3.44 ppm) are used to determine the product ratio.

15. Flash chromatography is performed on a 3 × 10 cm silica gel column (33 g of dry silica). The product is charged on the column and the system is eluted with 50 mL of 20% ethyl acetate-dichloromethane. At that point, fraction collection (8-mL fractions) is begun and elution is continued with 450 mL of a 20% ethyl acetate-dichloromethane mixture. Collected fractions were analyzed by TLC, eluting with 30% ethyl acetate-dichloromethane (R_f = 0.52 for 4 and 0.63 for 3). Visualization was accomplished by spraying with a potassium permanganate solution followed by heating. All the fractions (10-30) containing the desired product were combined and concentrated at 45 °C by rotary evaporation (40-50 mmHg) and then at 0.5 mmHg.

16. Analytical data for cyclohexylmethyl N-hydroxycarbamate (4): mp 33-34 °C; ¹H NMR pdf (300 MHz, CDCl₃) δ: 0.85-1.04 (m, 2 H), 1.06-1.37 (m, 3 H), 1.40-1.90 (m, 6 H), 3.99 (dd, J = 6.3, 5.1 Hz, 2 H), 7.03 (br s, 1 H), 7.28 (br s, 1 H); ¹³C NMR pdf (75 MHz, CDCl₃) δ: 25.7, 26.4, 29.6, 37.4, 71.5, 159.9; IR (film) 3291, 2922, 2851, 1712, 1449, 1267, 1121 cm^-1; HRMS (TOF⁺) calc. for C₈H₁₅NO₃Na [M+Na]⁺: 196.0950; found: 196.0940; Analysis calc. for C₈H₁₅NO₃: C 55.47, H 8.73, N 8.09; found: C 55.49, H 8.81, N 7.93 %.

17. Anhydrous diethyl ether was obtained by filtration through a drying column on a Sol-Tec solvent purification system.

18. p-Toluenesulfonyl chloride, 99+%, was purchased from Aldrich Chemical Company, Inc. and was used as received.

19. Triethylamine was purchased from Fisher Scientific and was freshly distilled from CaH₂ (88-90 °C) under argon atmosphere prior to use.

20. UltraPure silica gel (32-63 μm) was purchased from EcoChrom.

21. Omnisolv grade hexane was purchased from EMD and was used as received.

22. A second run on approximately half-scale provided a 79% yield.

23. The physical properties of 5 are as follows: R_f 0.68 (5% ethyl acetate/dichloromethane); mp 88-90 °C; ¹H NMR pdf (500 MHz, CDCl₃) δ: 0.82-0.85 (m, 2 H), 1.0-1.3 (m, 3 H), 1.46-1.57 (m, 3 H), 1.63-1.67 (m, 3 H), 2.46 (s, 3 H), 3.83 (d, J = 6.3 Hz, 2 H), 7.35 (d, J = 8.1 Hz, 2 H), 7.87 (d, J = 8.1 Hz, 2 H); ¹³C NMR pdf (125 MHz, CDCl₃) δ: 21.9, 25.7, 26.3, 29.3, 37.1, 72.2, 129.7, 129.9, 130.5, 146.2, 155.9; IR (film) 3230, 2927, 2853, 1740, 1597, 1380, 1191, 1179 cm^-1; HRMS (TOF⁺) calc. for C₁₅H₂₁NO₅SNa [M+Na]⁺: 350.1038; found: 350.1006; Analysis calc. for C₁₅H₂₁NO₅S: C 55.03, H 6.47, N 4.28, S 9.79; found: C 54.85, H 6.30, N 4.11, S 10.07 %.

24. Dichloromethane was purchased from Fisher Scientific and was used as received.

25. Granular potassium carbonate was purchased from J.T. Baker and was used as received.

26. The total volume added is approximately 60 mL.

27. Analytical data for 3-oxa-1-azaspiro[4.5]decan-2-one (6): R_f 0.53 (30% ethyl acetate/dichloromethane); mp 81-82 °C; ¹H NMR pdf (300 MHz, CDCl₃) δ: 1.20-1.72 (m, 10 H), 4.08 (s, 2H), 6.82 (br s, 1H); ¹³C NMR pdf (75 MHz, CDCl₃) δ: 22.7, 24.9, 37.2, 57.9, 75.8, 159.7; IR (film) 3230, 2932, 2858, 1745, 1397, 1251, 1031 cm^-1; HRMS (TOF⁺) calc. for C₈H₁₃NO₂Na [M+Na]⁺: 178.0844; found: 178.0843; Analysis calc. for C₈H₁₃NO₂: C 61.91, H 8.44, N 9.03; found: C 61.99, H 8.61, N 8.94 %.

Working with 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

This procedure describes an attractive method for the preparation of oxazolidinones using a rhodium-catalyzed nitrene C-H bond insertion reaction. It is well known that nitrene species are accessible by photolysis or thermolysis of acyl azides. However, their employment in the formation of oxazolidinones is limited to some specific cases,² because of their lack of stability and selectivity.³ Alternatively, metal nitrenes are prepared via the oxidation of carbamates using hypervalent iodine reagents which generate a stoichiometric amount of iodobenzene as byproduct.⁴ In the described procedure, a tosyloxycarbamate is decomposed with a base to form a metal nitrene in the presence of a rhodium catalyst. The insertion reaction proceeds then smoothly, with total conversion. The only stoichiometric byproduct is potassium tosylate, which is simply removed by an aqueous work up. The starting material is a stable white solid easily prepared from the corresponding commercially available alcohol. The metal nitrene insertion is effective at ethereal, benzylic, tertiary, secondary, and even primary positions, providing an interesting route to various substituted oxazolidinones (Table 1).⁵

Table 1. Oxazolidinone formation^a,b

Chiral oxazolidinones can also be prepared by this method using an enantioenriched N-tosyloxycarbamate as starting material, as the C-H insertion occurs with total retention of configuration (Entry 5). The method has been initially developed on a 0.5 mmol scale, using 6 mol% of rhodium dimer and 3 equivalents of potassium carbonate in dichloromethane at room temperature. Under the optimized reaction conditions on a 50 mmol scale, the catalyst loading is lowered to 1 mol% and 1.1 equivalent of base is used for complete conversion. The intermolecular version of the reaction has also been reported using 2,2,2-trichloroethyl N-tosyloxycarbamate as the source of nitrene and Troc-protected amines derived from various unfunctionalized substrates were isolated in good yields.⁶

References and Notes

Département de Chimie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, Canada, H3C 3J7.
(a) Berndt, D. F.; Norris, P. Tetrahedron Lett. 2002, 43, 3961-3962; (b) Kan, C.; Long, C. M.; Paul, M.; Ring, C. M.; Tully, S. E. Rojas, C. M. Org. Lett. 2001, 3, 381-384; (c) Yuan, P.; Plourde, R.; Shoemaker, M. R.; Moore, C. L.; Hansen, D. E. J. Org. Chem. 1995, 60, 5360-5364; (d) Schneider, G.; Hackler, L.; Szanyl, J.; Sohar, P. J. Chem. Soc. Perkin Trans. 1 1991, 37-42; (e) Banks, M. R.; Cadogan, J. I. G.; Gosney, I.; Gaur, S.; Hodgson, P. K. G. Tetrahedron Asymm. 1994, 5, 2447-2458.
Meth-Cohn, O. Acc. Chem. Res. 1987, 20, 18-27.
(a) Espino, C. G.; Du Bois, J. Angew. Chem. Int. Ed. 2001, 40, 598-600; (b) Cui, Y.; He, C. Angew. Chem. Int. Ed. 2004, 43, 4210-4212.
(a) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127, 14198-14199; (b) Lebel, H.; Leogane, O.; Huard, K.; Lectard, S. Pure Appl. Chem. 2006, 78, 363-375.
Lebel, H.; Huard, K. Org. Lett. 2007, 9, 639-642.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

Rhodium II acetate: (15956-28-2)

Triphenylacetic acid: Benzeneacetic acid, α,α-diphenyl-; (595-91-5)

Rhodium (II) tetrakis(triphenylacetate); (142214-04-8)

Cyclohexylmethyl N-hydroxycarbamate: Carbamic acid, hydroxy-, cyclohexylmethyl ester; (869111-30-8)

1,1'-Carbonyldiimidazole: Methanone, di-1H-imidazol-1-yl-; (530-62-1)

Cyclohexanemethanol; (100-49-2)

Hydroxylamine hydrochloride; (5470-11-1)

Imidazole; (288-32-4)

p-Toluenesulfonyl chloride: Benzenesulfonyl chloride, 4-methyl-; (98-59-9)

Triethylamine; (121-44-8)

Cyclohexylmethyl N-tosyloxycarbamate: Benzenesulfonic acid, 4-methyl-, [(cyclohexylmethoxy)carbonyl]azanyl ester; (869111-41-1)

4-Spirocyclohexyloxazolidinone: 3-Oxa-1-azaspiro[4.5]decan-2-one: (81467-34-7)

Potassium carbonate; (584-08- 7)

	Hélène Lebel received her B.Sc. degree in biochemistry from the Université Laval in 1993. She conducted her Ph.D. studies in organic chemistry at the chemistry department of the Université de Montréal under the supervision of professor André B. Charette as a 1967 Science and Engineering NSERC Fellow. In 1998, she joined the research group of professor Eric Jacobsen at Harvard University as a NSERC Postdoctoral Fellow. She started her independent career in 1999 at the Université de Montréal, where her research program focuses on the development of novel synthetic methods.
	Kim Huard was born in Granby, Québec, Canada in 1979. She received a B.Sc. degree in chemistry in 2004 from Université de Montréal. She then received her Ph.D. in Hélène Lebel's research group at Université de Montréal where she studied rhodium-catalyzed C-H bonds amination. She has been recipient of NSERC Postgraduate Scholarships. She is currently a postdoctoral fellow at University of California at Irvine under the guidance of Professor Larry Overman.
	Adam Rosenberg obtained his B.S. in chemistry from the University of Rochester while performing undergraduate research in Dr. Boeckman's research group. He is currently pursuing graduate studies in the laboratory of Professor Kay Brummond at the University of Pittsburgh. His graduate work has included investigations into the total synthesis of 3a-hydroxy-15-rippertene as well as novel multi-component cycloaddition reactions.
	Darla Seifried is a graduate of the University of Pittsburgh with a Bachelor of Science in biology. She is currently earning her B.S. in chemistry from the University of Pittsburgh. Darla plans to attend graduate school beginning in the fall of 2009.

Notes