Synthesis of a Variety of 2-Alkyl-2-Azabicyclo[3.1.1]heptane-1-carbonitriles via a Dynamic Addition-Intramolecular Substitution Sequence

Abstract

An improved two-step synthetic approach towards 3-(2-chloroethyl)cyclobutanone is described and used in the synthesis of a class of 2-alkyl-2-azabicyclo[3.1.1]heptane-1-carbonitriles. The key step consists of a reversible addition of hydrogen cyanide onto the in situ generated imines, followed by an intramolecular nucleophilic substitution, thereby leading to the bicyclic skeleton in moderate to good yields (47-92%). These bicyclic compounds are stable, and the incorporated cyano group can be easily reduced to the corresponding aminomethyl group in high yields (93-99%), ­using lithium aluminum hydride.

Key words

nitriles - heterocycles - bicyclic compounds - ring closure - nucleophilic addition

References and Notes

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• Typical Procedure for the Synthesis of 2-Alkyl-2-Azabicylo[3.1.1]heptane-1-carbonitriles 4
• 12a

  In a dry, pressure resistant vessel (20 mL volume) 3-(2-chloroethyl)cyclobutanone (3, 2.00 g, 15 mmol, 1 equiv), a primary amine (15 mmol, 1 equiv), acetone cyanohydrin (2.57 g, 30 mmol, 2 equiv), and Et₃N (3.05 g, 30 mmol, 2 equiv) were dissolved in dry MeOH (16 mL). The vessel was closed and heated to 110 ˚C for 2-3 d. When using ethyl-(pure) or methylamine (2 M in MeOH), the vessel was heated for 4 d, using 30 mmol of the volatile amine. Isolation of the desired end product could be performed by two means. The first method made use of column chromatography. After washing of the reaction mixture with a sat. NaHCO₃ solution, 3 g of silica were added to the organic phase (CH₂Cl₂), followed by removal of the solvent under vacuum. The end product was then recovered using column chroma-tography. The second purification strategy was more convenient and consisted of an acid-base extraction. After removal of the solvent under reduced pressure, 10 mL of a 2 N HCl solution was added. The solution was extracted with Et₂O (3 × 20 mL) to remove the excess of acetone cyano-hydrin. A concentrated K₂CO₃ solution was added to the H₂O layer until basic, followed by an extraction of the H₂O layer with CH₂Cl₂ (3 × 30 mL). The combined organic layers (CH₂Cl₂) were dried with MgSO₄. After filtration of the solids and removal of the volatiles, the pure 2-R⁰-2-azabicyclo[3.1.1]heptane-1-carbonitrile (4) was obtained in moderate to good yields, depending on the R⁰ group.
  

• 12b

  In a flame-dried flask of 50 mL, 3-(2-chloroethyl)-cyclobutanone (3, 1.00 g, 7.5 mmol) was dissolved in MeCN, together with 14 (8.3 mmol, 1.1 equiv). Hereafter, the reaction mixture was brought to reflux temperature and stirred for 3 d. The pure end product was isolated according to the same procedures as mentioned above in 12a.
  2-(4-Methoxybenzyl)-2-azabicyclo[3.1.1]heptane-1-carbonitrile (4b)
  Yellow crystals (3.09 g, 85%). Anal. Calcd (%) for C₁₅H₁₈N₂O: C, 74.4; H, 7.5; N, 11.6. Found: C, 74.3; H, 7.6; N, 11.3. R _f = 0.35 (PE-EtOAc = 7:3). IR (ATR): 2359 (CN), 1612, 1515, 1495, 1454 (Ar) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.91 (2 H, td, J = 6.6, 3.3 Hz, CH₂), 2.24 (2 H, dd, J = 7.2, 2.2 Hz, 2 × C_qCH_aH_b), 2.41 (2 H, td, J = 7.2, 2.2 Hz, 2 × C_qCH_aH_b), 2.49 (1 H, ca. sept, J = 3.3 Hz, CH), 2.85 (2 H, t, J = 6.6 Hz, NCH₂), 3.79 [5 H, s, NCH₂Ar, OCH₃ (Ar)], 6.86 [2 H, d, J = 8.8 Hz, 2 × CH (Ar)], 7.29 [2 H, d, J = 8.8 Hz, 2 × CH (Ar)]. ^¹³C NMR (75 MHz, CDCl₃): δ = 27.68 (CH₂), 31.25 (CH), 37.21 (2 × C_qCH_aH_b), 42.49 (NCH₂), 55.27 [OCH₃ (Ar)], 56.60 (NCH₂Ar), 58.39 (C_q), 113.72 [2 × CH (Ar)], 120.36 (CN), 130.01 [2 × CH (Ar)], 130.79 [C_q (Ar)], 158.83 [C_q (Ar)]. ESI-MS: m/z (%) = 291 (20), 214 (15), 213 (100) [MH⁺].

• 13 Grygorenko OO. Artamonov OS. Palamarchuk GV. Zubatyuk RI. Shishkin OV. Komarov IV. Tetrahedron: Asymmetry  2006,  17:  252 

9

3-(2-Chloroethyl)-2,2-dichlorocyclobutanone (9b) In an oven-dried two-necked flask of 500 mL, a solution of homoallyl chloride (15 g, 166 mmol) and a zinc-copper couple (43.32 g, 663 mmol) in dry Et₂O (250 mL) was cooled to 0 ˚C under a nitrogen atmosphere. A solution of trichloroacetyl chloride (60.24 g, 331 mmol) and 1,2-dimethoxyethane (29.86 g, 331 mmol) in dry Et₂O (150 mL) was added dropwise, after which the reaction mixture was stirred overnight at r.t. The solution was filtered over Celite^® and washed with Et₂O. This filtrate was extracted with H₂O (2 × 100 mL), NaHCO₃ (4 × 100 mL), brine (2 × 100 mL). The organic layer was dried over MgSO₄ and the solvent removed under reduced pressure, leading to the desired 3-(2-chloroethyl)-2,2-dichlorocyclobutanone (26.24 g, 78%) as a clear orange oil. IR (NaCl): 1811 (C=O) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 2.05-2.17 (1 H, m, CHCH₂), 2.38-2.50 (1 H, m, CHCH₂), 3.10 (1 H, dd, J = 16.2, 9.4 Hz, CH₂CO), 3.11-3.24 (1 H, m, CH), 3.44 (1 H, dd, J = 16.2, 9.4 Hz, CH₂CO), 3.66-3.72 (2 H, m, CH₂Cl). ^¹³C NMR (75 MHz, CDCl₃): δ = 33.94 (CHCH₂), 42.12 (CH₂Cl), 43.50 (CH), 47.64 (CH₂CO), 88.51 (C_q), 191.87 (C=O). ESI-MS: m/z (%) = 205 (35), 203 (85), 201 (100).

10

3-(2-Chloroethyl)cyclobutanone (3)
A solution of 3-(2-chloroethyl)-2,2-dichlorocyclobutanone (9b, 28.23 g, 140 mmol) in AcOH (100 mL) was vigorously stirred, while slowly adding 2 equiv of zinc (18.32 g, 280 mmol). Two extra equiv of zinc (18.32 g, 280 mmol) were added to the reaction mixture, after which it was refluxed overnight. After cooling, the mixture was filtered over Celite^® and washed with CH₂Cl₂. The filtrate was neutra-lized with a sat. NaHCO₃ solution. The organic phase was dried with MgSO₄, filtered, and the solvent was removed in vacuo. 3-(2-Chloroethyl)cyclobutanone (3) was obtained as a bright yellow oil in 86% yield (15.90 g).
IR (NaCl): 1778 (C=O) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 2.08 (2 H, dd, J = 13.8, 6.6 Hz, CHCH₂), 2.54-2.69 (1 H, m, CH), 2.72-2.82 (2 H, m, 2 × CH₂CO), 3.15-3.27 (2 H, m, 2 × CH₂CO), 3.59 (2 H, t, J = 6.6 Hz, CH₂Cl). ^¹³C NMR (75 MHz, CDCl₃): δ = 21.71 (CH), 38.57 (CHCH₂), 43.41 (CH₂Cl), 52.34 (2 × CH₂CO), 207.01 (C=O). ESI-MS: m/z (%) = 135 (45), 133 (100).

14

General Procedure for the Synthesis of 2-Methyl-2-Alkyl/Aryl Aminopropionitriles (14)
A primary amine (30 mmol) was mixed with acetone cyanohydrin 13 (2.55 g, 30 mmol) in dry MeOH (25 mL). The solution was stirred at r.t. for 24 h, while N₂ gas was bubbled through. The solvent was removed in vacuo, and the propionitriles 14 were obtained in moderate to excellent yields (64-99%). Analytical samples were obtained after filtration over silica or recrystallization in MeOH.
2-(4-Methoxybenzylamino)-2-methylpropionitrile (14b) Yellow crystals (6.07 g, 99%). Anal. Calcd (%) C₁₂H₁₆N₂O: C, 70.6; H, 7.9; N, 13.7. Found: C, 70.3; H, 8.0; N, 13.5. IR (ATR): 3275 (NH), 2359 (CN), 1611, 1515 (Ar) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.51 (7 H, s, 2 × CH₃, NH), 3.80 [3 H, s, OCH₃ (Ar)], 3.83 (2 H, s, NCH₂), 6.87 [2 H, d, J = 8.3 Hz, 2 × CH (Ar)], 7.28 [2 H, d, J = 8.3 Hz, 2 × CH (Ar)]. ^¹³C NMR (75 MHz, CDCl₃): δ = 27.44 (2 × CH₃), 49.00 (NCH₂), 51.68 (C_q), 55.29 [OCH₃ (Ar)], 113.98 [2 × CH (Ar)], 122.85 (CN), 129.60 [2 × CH (Ar)], 131.11 [C_q (Ar)], 158.97 [C_q (Ar)]. ESI-MS: m/z (%) = 178 (100)
[M - CN]⁺).

15

General Protocol for the Synthesis of (2-Alkyl-2-azabicyclo[3.1.1]hept-1-yl)methylamine 15 A solution of LiAlH₄ (0.19 g, 5 mmol,2 equiv) in dry THF (15 mL) was stirred at -78 ˚C under a nitrogen atmosphere. A flame-dried syringe was used to slowly add a solution of 2-alkyl-2-azabicyclo[3.1.1]heptane-1-carbonitrile 4 in dry THF (2.5 mmol). Upon completion of the addition, the reaction was stirred overnight at r.t., followed by a careful addition of H₂O to neutralize the excess of LiAlH₄. The solution was dried with MgSO₄, followed by filtration of the solids and evaporation of the solvent to give the pure {2-alkyl-2-azabicyclo[3.1.1]hept-1-yl}methylamine (15, 93-99%). When necessary, the compounds could be further purified using filtration over a short silica column (CH₂Cl₂-MeOH = 9:1).
C -{2-(4-Methoxybenzyl)-2-azabicyclo[3.1.1]hept-1-yl}methylamine (15b)
Bright yellow oil (0.60 g, 97%). IR (ATR): 3365 (NH₂), 1684 (Ar) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.37 (2 H, br s, NH₂), 1.65 (2 H, td, J = 6.6, J = 2.8 Hz, 2 × C_qCH_aH_b), 1.90 (2 H, td, J = 6.6, J = 3.3 Hz, CH₂), 1.96 (2 H, dd, J = 6.6, J = 2.8 Hz, 2 × C_qCH_aH_b), 2.43 (1 H, sept, J = 3.3 Hz, CH), 2.66 (2 H, s, C_qCH₂NH₂), 2.92 (2 H, t, J = 6.6 Hz, NCH₂), 3.53 (2 H, s, NCH₂Ar), 3.80 [3 H, s, OCH₃ (Ar)], 6.86 [2 H, d, J = 8.8 Hz, 2 × CH (Ar)], 7.26 [2 H, d, J = 8.8 Hz, 2 × CH (Ar)]. ^¹³C NMR (75 MHz, CDCl₃): δ = 28.42 (CH₂), 30.13 (CH), 33.84 (2 × C_qCH_aH_b), 43.77 (NCH₂), 48.33 (C_qCH₂NH₂), 52.64 (NCH₂Ar), 55.42 [OCH₃ (Ar)], 68.29 (C_q), 113.82 [2 × CH (Ar)], 129.54 [2 × CH (Ar)], 133.53 [C_q (Ar)], 158.51 [C_q (Ar)]. ESI-MS: m/z (%) = 247 (100) [MH⁺]. ESI-HRMS: m/z calcd C₁₅H₂₃ON₂: 247.18049 [MH⁺]; found: 247.17857.

16

Typical Procedure for the Synthesis of 2-Aryl-2-azabicyclo[3.1.1]heptane-1-carboxylic Acid Hydrochlorides 16
An amount of the 2-aryl-2-azabicyclo[3.1.1]heptane-1-carbonitrile 4 (0.5 mmol) was dissolved in 6 N HCl (4 mL). The reaction mixture was refluxed overnight. After cooling to r.t., the mixture was kept in the freezer to crystallize the acid from the aqueous solution.
2-(4-Methoxybenzyl)-2-azabicyclo[3.1.1]heptane-1-carboxylic Acid Hydrochloride (16b) White needles (133.7 mg, 90%). Anal. Calcd (%) for C₁₅H₁₉NO₃: C, 68.9; H, 7.3; N, 5.4. Found: C, 68.9; H, 7.4; N, 5.35. IR (ATR): 3358 (br, OH), 1739 (CO), 1637, 1548 (Ar) cm^-¹. ^¹H NMR (300 MHz, D₂O, MeCN): δ = 2.20 (2 H, td, J = 6.6, J = 3.3 Hz, CH₂), 2.47 (2 H, dd, J = 9.4, J = 2.8 Hz, 2 × C_qCH_aH_b), 2.75 (1 H, sept, J = 3.3 Hz, CH), 2.94 (2 H, dd, J = 11.8, J = 6.6 Hz, 2 × C_qCH_aH_b), 3.51 (2 H, t, J = 6.6 Hz, NCH₂), 3.86 [3 H, s, OCH₃ (Ar)], 4.60 (2 H, s, NCH₂Ar), 7.08 [2 H, d, J = 8.8 Hz, 2 × CH (Ar)], 7.52 [2 H, d, J = 8.8 Hz, 2 × CH (Ar)]. ^¹³C NMR (75 MHz, D₂O, MeCN): δ = 24.72 (CH₂), 30.30 (CH), 35.84 (2 × C_qCH_aH_b), 46.50 (NCH₂), 50.07 [OCH₃ (Ar)], 58.27 (NCH₂Ar), 59.63 (C_q), 115.39 [2 × CH (Ar)], 121.02 [C_q (Ar)], 133.43 [2 × CH (Ar)], 161.17 [C_q (Ar), COOH]. ESI-MS: m/z (%) = 263 (20), 262 (100) [MH⁺].

17

Synthesis of 2,4-Methanepipecolic Acid (17)
A suspension of 2-benzyl-2-azabicyclo[3.1.1]heptane-1-carboxylic acid hydrochloride (16a, 251 mg, 0.94 mmol) and Pd/C (10 wt%, 125 mg) in dry MeOH (2 mL) was placed in a Parr apparatus which was degassed and filled with H₂. The mixture was stirred overnight applying a constant pressure of 5 bar of H₂. Filtration of the heterogeneous suspension over Celite^®, followed by evaporation of the solvent in vacuo delivered the crude 2,4-methanepipecolic acid (17), which was purified by recrystallization from MeOH; colorless crystals (124.7 mg, 94%). Anal. Calcd (%) for C₇H₁₁NO₂: C, 59.6; H, 7.85; N, 9.9. Found: C, 59.6; H, 7.9; N, 9.8. IR (ATR): 3358 (br, OH), 3187 (NH), 1742 (CO) cm^-¹. ^¹H NMR (300 MHz, D₂O, MeCN): δ = 1.87 (2 H, dd, J = 8.3, J = 2.8 Hz, 2 × C_qCH_aH_b), 2.09-2.23 (4 H, m, 2 × C_qCH_aH_b, CH₂), 2.60 (1 H, sept, J = 3.3 Hz, CH), 2.81 (2 H, br s, OH, NH), 3.53 (2 H, t, J = 7.2 Hz, NCH₂). ^¹³C NMR (75 MHz, D₂O, MeCN): δ = 25.75 (CH₂), 29.01 (CH), 33.38 (2 × C_qCH_aH_b), 37.66 (NCH₂), 65.21 (C_q), 171.65 (COOH). ESI-MS: m/z (%) = 143 (20), 142 (100) [MH⁺].