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DOI: 10.1055/s-2006-941571
The [2+2] Photocycloaddition of Uracil Derivatives with Ethylene as a General Route to cis-Cyclobutane β-Amino Acids
Publication History
Publication Date:
22 May 2006 (online)
Abstract
A three-step procedure, based on the [2+2]-photochemical reaction of uracils with ethylene followed by controlled degradation of the heterocyclic ring, has been developed for the synthesis of a range of C1- and C2-substituted cis-cyclobutane β-amino acids, in good overall yield.
Key words
β-amino acids - cyclobutane - uracils - [2+2]-photocycloaddition - substituent effects
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References and Notes
Compound 1c was obtained from 5-iodouracil by Suzuki reaction with phenylboronic acid.
21Compound 1r was obtained by esterification of orotic acid in excess n-hexanol (as solvent) in the presence of anhydrous HCl.
27
Representative Procedure for Photocycloaddition.
Compound 1j (0.250 g, 1.76 mmol) was introduced into a cylindrical water-cooled reactor containing
a 1:1 mixture of acetone-H2O (160 mL), which was vented under a fume hood. The mixture was stirred at r.t. and
degassed with argon for 30 min, then sat. with ethylene for 30 min. Then, whilst ethylene
bubbling continued, the mixture was irradiated with a 400 W medium-pressure mercury
lamp fitted with a Pyrex filter for 4 h. The solution was evaporated and the solid
residue was washed with cyclohexane then acetone. The cyclobutane adduct 2j was obtained as a white solid in 86% yield (0.257 g, 1.51 mmol). Mp 146-148 °C. 1H NMR (400 MHz, DMSO-d
6): δ = 1.78-1.88 (m, 3 H), 2.06-2.13 (m, 1 H), 3.43 (dd, J = 10.8, 5.3 Hz, 1 H), 3.60 (dd, J = 10.8, 6.0 Hz, 1 H), 3.79 (td, J = 7.1, 4.2 Hz, 1 H), 5.08 (br t, J = 5.4 Hz, 1 H), 7.69 (br s, 1 H), 10.03 (br s, 1 H) ppm. 13C NMR (100 MHz, DMSO-d
6): δ = 22.8, 27.5, 46.9, 48.8, 63.9, 152.4, 174.7 ppm. MS (ES+): m/z = 193 [MNa]+. HRMS (ES+): m/z calcd for C7H10N2O3Na: 193.0589; found: 193.0597.
Representative Procedure for Heterocyclic Ring-Opening.
Compound 2j (0.245 g, 1.44 mmol) was dissolved in 0.5 M NaOH solution (17.6 mL) and stirred overnight
at r.t. Cation exchange resin (Bio-Rad AG 50W-X8, H+, 20-50 mesh) was then added until pH was about 4. Filtration and then evaporation
of H2O left the desired compound 3j as a white paste in 87% yield (0.236 g, 1.25 mmol). 1H NMR (400 MHz, DMSO-d
6): δ = 1.62-1.74 (m, 1 H), 1.85-1.98 (m, 2 H), 2.04-2.15 (m, 1 H), 3.49 (d, J = 10.8 Hz, 1 H), 3.61 (d, J = 10.8 Hz, 1 H), 4.13 (q, J = 8.9 Hz, 1 H), 4.80 (br s, 1 H), 5.56 (s, 2 H), 6.16 (d, J = 8.9 Hz, 1 H), 12.25 (br s, 1 H) ppm. 13C NMR (100 MHz, DMSO-d
6): δ = 20.5, 25.6, 47.5, 57.6, 64.6, 157.8, 174.7 ppm. MS (ES+): m/z = 189 [MH]+, 211 [MNa]+. HRMS (ES+): m/z calcd for C7H12N2O4Na: 211.0695; found: 211.0691.
Representative Procedure for Diazotization.
Compound 3j (0.180 g, 0.96 mmol) was dissolved in 3.5 M HCl solution (22 mL). Then, 1 equiv of
NaNO2 (0.066 g; 0.96 mmol) was added and the mixture was stirred overnight at r.t. The
solution was deposited on a cation-exchange column (Dowex 5 × 8 W, H+, 50-100 mesh). The column was washed with H2O until the eluent was neutral, then the amino acid was eluted with 1 M NH4OH. Pure product 4j was recovered after evaporation of appropriate fractions as a white solid in 70%
yield (0.097 g, 0.67 mmol). Mp 91-94 °C. 1H NMR (400 MHz, D2O): δ = 1.77-1.89 (m, 1 H), 1.92-2.18 (m, 2 H), 2.13-2.25 (m, 1 H), 3.55 (d, J = 11.4 Hz, 1 H), 3.72 (d, J = 11.4 Hz, 1 H), 3.68-3.72 (m, 1 H) ppm. 13C NMR (100 MHz, D2O): δ = 22.5, 23.3, 47.9, 52.7, 65.9, 180.7 ppm. MS (ES+): m/z = 146 [MH]+, 168 [MNa]+. HRMS (ES+): m/z calcd for C6H12NO3: 146.0817; found: 146.0822.