Preparation of biotin derivatives by catalytic oxidative carbonylation of diamines

Abstract

Biotin methyl ester and related heterocyclic ureas were synthesized by W(CO)₆-catalyzed oxidative carbonylation of the corresponding diamines. This procedure provides an alternative to the use of phosgene and phosgene derivatives for formation of the urea moiety.

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Introduction

Biotin (1b), also known as Vitamin H, is a cofactor for biochemical carboxylations. It is manufactured on a large scale as a feed additive for poultry and swine. In addition to its commercial value, biotin has been of great interest as a synthetic target. More than 40 total and formal syntheses have appeared since 1943, when the first racemic synthesis was reported.¹ Many of these approaches involve conversion of a diaminotetrahydrothiophene moiety into the bicyclic urea core. Two general means of achieving this transformation are used repeatedly: 1) reaction of a tetrahydrothiophene diamine with phosgene^2–4 and 2) hydrolysis of a bis(carbamate) derivative of the diamine so that generation of the first free amine triggers ring closure by nucleophilic attack on the remaining carbamate.^5,6

The strategies for biotin preparation reflect the most common approach to the formation of ureas, nucleophilic reaction of amines with phosgene or phosgene derivatives.⁷ Concerns about phosgene⁸ and the value of multiple methodologies for a given chemical transformation have led us to explore catalytic methods for the conversion of amines to ureas. We previously reported the catalytic oxidative carbonylation of primary and secondary amines to ureas using W(CO)₆ as catalyst, I₂ as the oxidant and CO as the carbonyl source.^9–14 Tolerance of functional groups is broad and five- to eight-membered cyclic ureas are accessible from the corresponding diamines.^11,13,14 The first application of this methodology to a functionalized target was formation of the core structure of the HIV protease inhibitors DMP 323 and DMP 450.¹⁵ We now report preparation of biotin methyl ester and related bicyclic systems by catalytic carbonylation of the corresponding diamines.

Results and discussion

Initial attempts to synthesize biotin by oxidative carbonylation of the ammonium salt 1a under the standard conditions were unsuccessful (eqn. (1)). Varying the solvent, temperature, reaction time and the amount of catalyst did not result in the formation of biotin. Since 1a was recovered as a solid at the end of the reaction, we concluded that the low solubility of 1a in CH₂Cl₂ was probably responsible for the failure to obtain the urea.

Based on previously reported functional group compatibility studies,¹³ the carboxylic acid moiety of 1a had been expected to present a problem in the direct synthesis of biotin. Thus, we carried out model studies using 6-aminocaproic acid as the substrate. The results were similar to those for compound 1a. Only trace amounts of the corresponding urea were detected in ¹³C NMR spectra of the reaction mixtures and approximately 90% of the starting material could be recovered. In contrast, when the methyl ester of 6-aminocaproic acid (3a) was carbonylated, 70% yield of the corresponding urea was obtained in 4 h at room temperature (eqn. (2)).

To obtain a biotin precursor that was soluble in organic solvents, carboxylic acid 1a was converted to its methyl ester 2a using SOCl₂ in methanol.¹⁶ Carbonylation of 2a to biotin methyl ester (2b) at room temperature was complete in around 8 h. When the temperature was raised to 50 °C, the reaction time was decreased to 1 h and the yield of 2b was improved to 84%. Longer reaction times resulted in decomposition of the product.

Related diamines such as the tetrahydrofuran derivatives 4a and 5a were also studied based on the promising results obtained from biotin methyl ester (Table 1, eqn. (3)). Unfortunately, carbonylation of 4a afforded “chainless oxybiotin” 4b in trace amounts. Attempts to optimize the reaction conditions by varying the amount of catalyst, or reaction time and temperature did not produce higher yields of 4b. The low solubility of diamine 4a in methylene chloride was clearly problematic and the solubility of urea 4b in water prevented use of the usual workup, which involves extraction. An alternative workup using ion exchange resins did not provide an improvement. Note that reaction of 4a with the phosgene derivative 1,1′-carbonyldiimidazole (CDI) also afforded 4b in low yield.

Table 1 Yields of bicyclic ureas from diamines 4a–5a, 7a–8a

Amine	Urea	W(CO)6/I2 yield^a	CDI yield
a Unless otherwise noted, all reactions were carried out in CH2Cl2 (40 mL) at room temperature under 80 atm of CO. Diamine (1 mmol), W(CO)6 (4 mol%), K2CO3 (3 mmol), I2 (1 mmol). b Yield based on diamine consumed (47%). c Yield based on diamine consumed (70%). d Conditions as above except pyridine (1.0 mL) was used as the base and the reaction was carried out at 50 °C. e Reaction not attempted.
4a	4b	Trace	20%
5a	5b	47%	67%
7a	7b	46%	37%
8a	8b	57%^b	56%^c
9a	9b	4%^d	—^e

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Since an alternative explanation of the low yields from 4a involved reactivity of tetrahydrofuran rings under the reaction conditions, the model compound tetrahydrofurfurylamine (6a) was subjected to catalytic carbonylation to test the stability of the ring (eqn. (4)). The yields of urea 6b were dependent upon the amount of K₂CO₃ in the reaction mixtures and reached a maximum value of 75% when 1.0 equiv. of K₂CO₃ was used. Oxamide 6c was obtained in 2% yield as a byproduct of this reaction.

In order to test a tetrahydrofuran derivative with higher solubility in organic solvents, diamine 5a was prepared from the corresponding diol via the dimesylate and diazide (Scheme 1) and subjected to the carbonylation reaction under 85 atm of CO at room temperature for 30 h. The pure urea 5b was obtained in 47% yield as a white solid. Due to the sensitivity of diamine 5a, attempts to recover remaining starting material from the reaction mixtures failed.

Scheme 1 Synthetic route to 5a.

Nitrogen-containing heterocycles were investigated by carbonylation of N-tert-butoxycarbonyl-2,5-dimethyl-3,4-diaminopyrrolidine 7a at room temperature for 8 h. Urea 7b was isolated in 46% yield after chromatography on silica gel. Longer reaction times and higher temperatures caused the yield of urea to decrease due to the formation of decomposition products. In comparison, conversion of 7a to 7b using the stoichiometric carbonylation reagent CDI afforded the urea in only 37% yield.

The carbocyclic substrates trans-1,2-diaminocyclohexane (8a) and cis-1,2-diaminocyclopentane (9a) were also subjected to the carbonylation conditions. The conversion of 8a to the corresponding urea 8b proceeded in moderate yield. Note that 8a had previously been reported to be a problem substrate for conversion to the urea with phosgene.¹⁷ Although the yield of 8b from catalytic carbonylation is modest, it is comparable to the yield from 8a and CDI. Carbonylation of cyclopentane derivative 9a was unsuccessful due to its instability and the insolubility of its diammonium salt in methylene chloride. Very low yields of 9b were obtained after chromatography and characterization by ¹H NMR and HRMS.

In summary, catalytic oxidative carbonylation has been applied to the preparation of biotin methyl ester and related bicyclic systems as an alternative to phosgene or phosgene derivatives. Yields of the ureas are moderate to good and depend on the solubility of the diamine and urea in methylene chloride. Further applications of this methodology to the synthesis of complex targets are still under investigation.

Experimental

General

Solvents were purged with nitrogen and dried by passing the degassed solvent through a column packed with activated alumina.¹⁸ All other chemicals were purchased in reagent grade and used with no further purification unless stated otherwise. W(CO)₆ was purified by chromatography on silica gel using hexane as eluent.

5-(3,4-Diammoniumtetrahydrothiophen-2-yl)pentanoic acid, sulfate salt (1a)

The hydrolysis product of biotin was prepared in 78% yield as previously described.¹⁹¹H NMR (D₂O): δ 4.23 (m, 2H), 3.86 (m, 1H), 3.36 (m, 1H), 3.01 (m, 1H), 2.39 (t, 2H), 1.86 (m, 1H), 1.62–1.35 (m, 5H); ¹³C NMR (D₂O): δ 179.8, 57.2, 54.9, 47.6, 34.5, 30.4, 28.8, 28.1, 24.8; Anal. Calcd for C₉H₂₀N₂O₆S₂: C 34.17, H 6.37, N 8.85; found: C 34.02, H 6.31, N 8.51.

5-(3,4-Diammoniumtetrahydrothiophen-2-yl)pentanoic acid methyl ester, sulfate salt (2a)

MeOH (2 mL) was cooled in an ice–salt bath. Thionyl chloride (0.04 mL, 0.6 mmol) was added dropwise with stirring, followed by the diaminocarboxylic acid sulfate 1a (54 mg, 0.17 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 3 days. The clear solution was then concentrated under vacuum to afford an off-white solid in quantitative yield. The product was identified by comparison to literature data.²⁰

Biotin methyl ester (2b)

The crude diamine 2a (82.5 mg, 0.25 mmol) was dissolved in 3 mL of H₂O, neutralized to pH = 5 by adding 1 N KOH solution and diluted to a total of 5 mL. The solution was transferred to a glass-lined 300 mL Parr high pressure vessel, followed by addition of W(CO)₆ (4 mg, 0.01 mmol), K₂CO₃ (138 mg, 1.00 mmol), I₂ (63.5 mg, 0.250 mmol) and 15 mL of CH₂Cl₂. The carbonylation reaction was run at 50 °C for 70 min under 85 atm of CO. After the pressure was released, the aqueous solution was separated from the CH₂Cl₂ layer and extracted with CH₂Cl₂. The organic layers were combined, dried over MgSO₄ and the solvent removed. The crude pale brown solid was rinsed with hexane to afford 54 mg (84% yield) of pure 2b. The product was identified by comparison to literature data.²¹

2-Pentyl-cis-3,4-dihydroxytetrahydrofuran (5d)

2-Pentyl-2,5-dihydrofuran (5c)²² (0.589 g, 4.20 mmol), 4-methylmorpholine N-oxide (2.95 g, 25.2 mmol) and OsO₄ (4 wt% aq. solution, 1.59 mL, 0.252 mmol) were added to 16 mL of 3 ∶ 1 CH₂Cl₂ ∶ THF and stirred at room temperature for 14 h. Then an aqueous solution of Na₂S₂O₅ (20 mL) was added. The mixture was stirred for 1 h and the two layers were then separated. The aqueous layer was extracted with CH₂Cl₂ three times. The combined organic layers were washed with brine and dried over MgSO₄. After removal of solvent, a dark brown residue was obtained. Chromatography on silica gel (1 ∶ 1 hexane ∶ EtOAc) afforded the pure 2-pentyl-cis-3,4-dihydroxytetrahydrofuran (5d) as a mixture of isomers in 59% yield. ¹H NMR (CDCl₃): δ 4.21 (m, 1H), 4.10 (m, 1H), 3.78–3.62 (m, 3H), 3.54 (d, 1H), 3.41 (d, 1H), 1.67–1.30 (m, 8H), 0.89 (t, 3H); ¹³C NMR (CDCl₃): δ 82.8, 76.1, 72.7, 71.2, 33.5, 32.1, 25.7, 22.8, 14.2; Anal. Calcd for C₉H₁₈O₃: C 62.04, H 10.41; found: C 62.10, H 10.61.

2-Pentyl-cis-3,4-di-O-methylsulfonyltetrahydrofuran (5e)

2-Pentyl-cis-3,4-dihydroxytetrahydrofuran (5d) (0.174 g, 1.00 mmol), Et₃N (0.313 g, 3.09 mmol) and methylsulfonyl chloride (0.252 g, 2.20 mmol) were added to 10 mL of dry CH₂Cl₂ and stirred in an ice–acetone cold bath (−10 °C) for 1 h. Then the reaction mixture was diluted with CH₂Cl₂ and washed with 0.12 N HCl, saturated NaHCO₃, and H₂O. The solution was dried over MgSO₄ and the crude product was obtained by evaporation of the solvent. Flash chromatography on silica gel (2 ∶ 1 hexane ∶ EtOAc) afforded a white solid as a mixture of isomers in 97% yield. ¹H NMR (CDCl₃): δ 5.16 (m, 1H), 4.68 (m, 1H), 4.25 (m, 1H), 4.00 (m, 2H), 3.13 (d, 6H), 1.75–1.30 (m, 8H), 0.89 (t, 3H); ¹³C NMR (CDCl₃): δ 79.9, 78.9, 76.4, 70.6, 38.8, 32.6, 31.8, 25.2, 22.7, 14.2; Anal. Calcd for C₁₁H₂₂O₇S₂: C 39.98, H 6.71; found: C 40.25, H 6.74.

2-Pentyl-cis-3,4-diazidotetrahydrofuran (5f)

To 25 mL of dry DMF, 2-pentyl-cis-3,4-di-O-methylsulfonyltetrahydrofuran (5e) (0.783 g, 2.37 mmol) and NaN₃ (2.16 g, 33.2 mmol) were added and heated at 150 °C for 24 h. After the mixture was cooled to room temperature, water was added to dissolve the pale brown solid. This solution was then extracted three times with 1 ∶ 1 Et₂O ∶ hexane. The combined organic layers were dried over MgSO₄ and the solvent was removed under vacuum. The pure diazide (5f) was obtained as a single diastereomer by chromatography on silica gel (8 ∶ 1 hexane ∶ EtOAc) in 46% yield as a colorless oil. Further elution with 4 ∶ 1 hexane ∶ EtOAc afforded the monosubstituted azide product 5g (0.138 g, 21%). Compound 5g was dissolved in DMF (15 mL), and NaN₃ (0.259 g, 4.0 mmol) was added to the solution. The mixture was stirred at 145 °C for 21 h. After the workup as described above and chromatography on silica gel, an additional amount of pure 5f (0.031 g) was obtained. The total yield of 5f was 52%. ¹H NMR (CDCl₃): δ 4.24 (m, 1H), 4.01 (m, 2H), 3.88 (m, 1H), 3.80 (m, 1H), 1.73–1.30 (m, 8H), 0.90 (t, 3H); ¹³C NMR (CDCl₃): δ 81.5, 68.7, 65.6, 63.2, 38.8, 31.9, 30.2, 25.9, 22.7, 14.2; Anal. Calcd for C₉H₁₆N₆O: C 48.20, H 7.19, N 37.47; found: C 48.40, H 7.39, N 37.73.

2-Pentyl-cis-3,4-diaminotetrahydrofuran (5a)

2-Pentyl-cis-3,4-diazidotetrahydrofuran (5f) (0.244 g, 1.09 mmol) and 40 mg of 10% Pd/C were added to 6 mL of MeOH. The reaction mixture was degassed and refilled with H₂ at 1 atm and then stirred at room temperature for 18 h until no starting material was evident by TLC. The mixture was filtered through Celite and solvent was removed to yield the crude product. Pure 5a was obtained as a single diastereomer by chromatography on silica gel (10% MeOH in CH₂Cl₂ with 1% Et₃N) as a colorless oil in 82% yield. ¹H NMR (CDCl₃): δ 3.97 (t, 1H), 3.84 (m, 1H), 3.61 (m, 1H), 3.40 (t, 1H), 3.11 (m, 1H), 1.59–1.31 (m, 8H), 0.89 (t, 3H); ¹³C NMR (CDCl₃): δ 82.4, 72.2, 55.9, 55.3, 32.2, 30.2, 26.1, 22.8, 14.2; Anal. Calcd for C₉H₂₀N₂O: C 62.75, H 11.70, N 16.26; found: C 62.39, H 12.05, N 15.59.

4-Pentyltetrahydrofuro[3,4-d]imidazol-2-one (5b)

To a glass lined 300 mL Parr high pressure vessel were added 2-pentyl-cis-3,4-diaminotetrahydrofuran (5a) (220 mg, 1.28 mmol), W(CO)₆ (18 mg, 0.051 mmol), K₂CO₃ (530 mg, 3.84 mmol), I₂ (325 mg, 1.28 mmol) and 45 mL of CH₂Cl₂. The reaction was run under 85 atm of CO at room temperature for 30 h. After the pressure was released, the solid was collected by filtration and washed with chloroform. The combined organic solutions were evaporated to dryness to afford a brown solid. The pure product (118 mg) was obtained as a single diastereomer by chromatography on silica gel (20 ∶ 1 EtOAc ∶ MeOH) as a white solid in 47% yield. mp: 105–107 °C; IR (CH₂Cl₂): ν_CO 1716 cm⁻¹; ¹H NMR (CDCl₃): δ 5.55 (s, br, 1H), 5.33 (s, br, 1H), 4.37 (m, 1H), 4.20 (m, 1H), 3.90 (m, 2H), 3.54 (m, 1H), 3.45 (m, 1H), 1.72–1.30 (m, 8H), 0.89 (t, 3H); ¹³C NMR (CDCl₃): δ 163.3, 83.1, 74.6, 59.3, 57.9, 32.0, 29.0, 26.2, 22.8, 14.2; Anal. Calcd for C₁₀H₁₈N₂O₂: C 60.58, H 9.15, N 14.13; found: C 60.85, H 9.30, N 13.74.

4-Pentyltetrahydrofuro[3,4-d]imidazol-2-one (5b) by reaction with CDI

2-Pentyl-cis-3,4-diaminotetrahydrofuran (5a) (0.183 g, 1.06 mmol) and 0.170 g (1.05 mmol) of 1,1′-carbonyldiimidazole (CDI) were added to 40 mL of dry THF and stirred at room temperature for 21 h. After the solvent was evaporated, the white residue was dissolved in CHCl₃ and washed with 0.12 N HCl, followed by brine. The solution was then dried over MgSO₄. The crude product was purified by chromatography on silica gel (20 ∶ 1 EtOAc ∶ MeOH). The pure urea was obtained in 67% yield as a white solid and identified by comparison to an authentic sample prepared as above.

N-tert-Butoxycarbonyl-2,5-dimethylpyrroline (7d)

To 5 mL MeOH were added 2,5-dimethylpyrroline (0.118 mL, 0.996 mmol), di-tert-butyl dicarbonate (0.24 g, 1.1 mmol) and NaHCO₃ (250 mg). This mixture was subjected to ultrasonic irradiation for 4 h.²³ Excess NaHCO₃ was removed by filtration and the MeOH was evaporated under vacuum. The residue was redissolved in Et₂O and a second filtration was carried out. Evaporation of Et₂O afforded the pure product in 96% yield. The crude product was used for the next step without further purification. ¹H NMR (CDCl₃): δ 5.59 (m, 2H), 4.58–4.48 (m, 2H), 1.48 (s, 9H), 1.33 (d, 3H), 1.27 (d, 3H); ¹³C NMR (CDCl₃): δ 153.9, 130.6, 130.3, 79.2, 60.3, 60.0, 28.8, 21.1, 19.7.

N-tert-Butoxycarbonyl-2,5-dimethyl-3,4-dihydroxypyrrolidine (7e)

The oxidation product of N-tert-butoxycarbonyl-2,5-dimethylpyrroline (7d) was prepared as described in the literature.²⁴ The pure product was obtained by chromatography (1 ∶ 1 hexane ∶ EtOAc) in 86% yield as a colorless oil. ¹H NMR (CDCl₃): δ 4.32 (m, 1H), 3.90 (m, 3H), 3.05 (m, 3H), 1.47 (s, 9H), 1.29 (m, 3H), 1.17 (d, 3H); ¹³C NMR (CDCl₃): δ 154.6, 79.8, 70.9, 59.0, 55.3, 28.7, 18.5, 14.5; Anal. Calcd for C₁₁H₂₁NO₄: C 57.12, H 9.15, N 6.06; found: C 57.45, H 9.40, N 6.01.

N-tert-Butoxycarbonyl-2,5-dimethyl-3,4-di-O-methylsulfonylpyrrolidine (7f)

To a solution of N-tert-butoxycarbonyl-2,5-dimethyl-3,4-dihydroxypyrrolidine (7e) (0.466 g, 2.02 mmol) in 10 mL anhydrous pyridine cooled in an ice–salt bath, was added dropwise methylsulfonyl chloride (0.694 g, 6.06 mmol). After addition, the solution was slowly warmed to room temperature and allowed to stir for 4 h. After the solvent was removed, the brown residue was dissolved in CH₂Cl₂–H₂O and extracted with CH₂Cl₂. The combined organic solutions were then washed with 0.1 N HCl until the pH of the aqueous layer was acidic. After the organic solution was washed by brine and dried over MgSO₄, the solvent was removed under vacuum to afford 7f as a yellow oil in quantitative yield. The compound was not purified before the next step. ¹H NMR (CDCl₃): δ 5.15 (m, 1H), 4.91 (m, 1H), 4.19 (m, 2H), 3.14 (m, 3H), 1.48 (s, 9H), 1.33 (m, 6H); ¹³C NMR (CDCl₃): δ 154.6, 79.8, 70.9, 59.0, 55.3, 28.7, 18.5, 14.5.

N-tert-Butoxycarbonyl-2,5-dimethyl-3,4-diazidopyrrolidine (7g)

To 20 mL of dry DMF were added N-tert-butoxycarbonyl-2,5-dimethyl-3,4-di-O-methylsulfonylpyrrolidine (7f) (1.161 g, 3.0 mmol) and NaN₃ (2.73 g, 42.0 mmol). The mixture was heated to 120 °C for 21 h. After cooling to room temperature, deionized H₂O and mixed solvent (3 ∶ 2 Et₂O ∶ hexane) were added and the layers were separated. The organic phase was dried over MgSO₄ and concentrated under vacuum to afford the crude product. The pure compound was obtained in 31% yield by chromatography on silica gel (5 ∶ 1 hexane ∶ EtOAc). ¹H NMR (CDCl₃): δ 4.29 (m, 1H), 4.08 (m, 1H), 3.87 (m, 2H), 1.47 (s, 9H), 1.35–1.27 (m, 6H); ¹³C NMR (CDCl₃): δ 153.5, 80.3, 67.8, 62.8, 57.6, 54.9, 28.6, 19.6, 15.6; Anal. Calcd for C₁₁H₁₉N₇O₂: C 46.96, H 6.81, N 34.85; found: C 47.37, H 6.94, N 34.84.

N-tert-Butoxycarbonyl-2,5-dimethyl-3,4-diaminopyrrolidine (7a)

To a 7 mL MeOH solution of N-tert-butoxycarbonyl-2,5-dimethyl-3,4-diazidopyrrolidine (7g) (0.355 g, 1.26 mmol) was added 200 mg of 10% Pd/C. The slurry was degassed and refilled three times with H₂ at 1 atm. The reaction mixture was stirred at room temperature until no starting material was evident by TLC. The catalyst was filtered through Celite and the solvent was removed to afford a pale yellow oil. Further purification by chromatography on silica gel (5% MeOH in CH₂Cl₂ with 1% TEA) afforded pure diamine 7a in 76% yield. IR (Nujol): 3373, 3318, 1694 cm⁻¹; ¹H NMR (DMSO-d₆, 90 °C): δ 3.71 (dq, J = 8 Hz, J = 7 Hz, 1H), 3.55 (dq, J = 2 Hz, J = 7 Hz, 1H), 3.42 (dd, J = 8 Hz, J = 5 Hz, 1H), 2.95 (dd, J = 5 Hz, J = 2 Hz, 1H), 2.85 (s, br, 2H), 1.41 (s, 9H), 1.22 (d, J = 6 Hz, 3H), 1.14 (d, J = 6 Hz, 3H); ¹³C NMR (DMSO-d₆, 90 °C): δ 153.0, 77.6, 59.2 (2 × C), 54.7, 52.6, 27.8, 18.4, 14.5; HRMS (LSIMS): Calcd for C₁₁H₂₄N₃O₂ (M+H)⁺ 230.1868, found 230.1880.

4,6-Dimethyl-2-oxo-hexahydropyrrolo[3,4-d]imidazole-5-carboxylic acid tert-butyl ester (7b)

To a 300 mL glass lined Parr high pressure vessel were added W(CO)₆ (16 mg, 0.045 mmol), 40 mL of CH₂Cl₂, N-tert-butoxycarbonyl-2,5-dimethyl-3,4-diaminopyrrolidine (7a) (0.26 g, 1.1 mmol), K₂CO₃ (0.47 g, 3.4 mmol), and I₂ (0.288 g, 1.13 mmol). The vessel was then charged with 85 atm of CO and left to stir at room temperature for 8 h. The pressure was released and the pale yellow solution was filtered. The CH₂Cl₂ solution was washed with 0.1 N HCl and aqueous Na₂S₂O₃ solution. After drying over MgSO₄ and filtration, the resulting solution was then concentrated to afford a pale brown solid. The white solid urea was obtained in 46% yield after chromatography on silica gel (15 ∶ 1 EtOAc ∶ MeOH). mp: 232–234 °C; IR (CH₂Cl₂): ν_CO 1720, 1690 cm⁻¹; ¹H NMR (CDCl₃): δ 5.42 (s, br, 1H), 5.23 (s, br, 1H), 4.28 (m, 1H), 3.86–4.00 (m, 3H), 1.47 (s, 9H), 1.35 (d, 3H), 1.19 (d, 3H); ¹³C NMR (CDCl₃): δ 163.2, 154.8, 80.1, 62.8, 56.1, 28.7, 18.5, 15.9; Anal. Calcd for C₁₂H₂₁N₃O₃: C 56.45, H 8.29, N 16.46; found: C 56.40, H 8.56, N 16.34.

Octahydrobenzoimidazol-2-one (8b)

To a glass lined 300 mL Parr high pressure vessel were added W(CO)₆ (28 mg, 0.08 mmol), 80 mL of CH₂Cl₂, trans-cyclohexane-1,2-diamine (8a) (0.23 g, 2.0 mmol), K₂CO₃ (0.828 g, 5.99 mmol), and I₂ (0.508 g, 2.00 mmol). The vessel was then charged with 75 atm of CO and left to stir at 120 °C for 52 h. The pressure was released after cooling to room temperature and the brown solution was filtered. The CH₂Cl₂ solution was washed with 0.1 N HCl, dried over MgSO₄ and filtered. The resulting solution was then concentrated to afford a pale brown solid. The white solid urea was obtained after chromatography on silica gel (EtOAc) in 58% yield based on conversion. Unreacted starting material was recovered as the diammonium salt in 53% yield. The urea was identified by comparison to literature data.¹⁷

Hexahydrocyclopentaimidazol-2-one (9b)

To a glass lined 300 mL Parr high pressure vessel were added W(CO)₆ (28 mg, 0.08 mmol), 80 mL of CH₂Cl₂, cis-cyclopentane-1,2-diammonium chloride (the hydrochloride salt of 9a) (0.454 g of the trihydrate, 2.00 mmol), pyridine (1.0 mL), and I₂ (0.508 g, 2.00 mmol). The vessel was then charged with 87 atm of CO and left to stir at 50 °C for 14 h. The pressure was released after cooling to room temperature and the brown solution was filtered. The CH₂Cl₂ solution was washed with aqueous Na₂S₂O₃ solution and the solvent was removed to afford a pale brown solid. The white solid urea was obtained after chromatography on silica gel (5% MeOH in EtOAc) in 4% yield. ¹H NMR (CDCl₃): δ 1.70 (m, 6H), 4.24 (m, 2H), 4.67 (s, 2H). HRMS (EI): Calcd for C₆H₁₀N₂O (M⁺) 126.0793, found 126.0792.

Acknowledgements

Funding was provided by the donors of the Petroleum Research Fund. K.F. and C.R.P. were supported by the US-France NSF-REU program at the University of Florida.

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