A Facile Synthesis of N-Carbamoylamino Acids

Andrey V. Bogolubsky; Sergey V. Ryabukhin; Gennadiy G. Pakhomov; Eugeniy N. Ostapchuk; Alexander N. Shivanyuk; Andrey A. Tolmachev

doi:10.1055/s-2008-1078017

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Synlett 2008(15): 2279-2282
DOI: 10.1055/s-2008-1078017

LETTER

A Facile Synthesis of N-Carbamoylamino Acids

Andrey V. Bogolubsky^a, Sergey V. Ryabukhin*^a,b, Gennadiy G. Pakhomov^a, Eugeniy N. Ostapchuk^a, Alexander N. Shivanyuk^a,b, Andrey A. Tolmachev^b
^a Enamine Ltd., 23 A. Matrosova st., 01103 Kyiv, Ukraine
Fax: +380(44)5373253; e-Mail: Ryabukhin@mail.enamine.net;
^b National Taras Shevchenko University, 62 Volodymyrska st., 01033 Kyiv-33, Ukraine

Further Information

Publication History

Received 17 May 2008
Publication Date:
31 July 2008 (online)

Abstract
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Abstract

N-Carbamoylamino acids were obtained through the alkylation of monosubstituted parabanic acids followed by hydrolysis of the intermediate products. This new methodology furnishes structurally and functionally diverse N-carbamoylamino acids in high preparative yields and excellent purity.

Key words

monosubstituted parabanic acids - N-carbamoylamino acids - ureas - hydrolysis - alkylation

References and Notes

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A diverse set of monosubstituted parabanic acids was obtained by the cyclization of monosubstituted ureas. With oxalyl chloride, see:
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15

The selection of the solvent based only on the solubility of starting compounds.

16

General Procedure
Monosubstituted parabanic acid 1a-g (2 mmol) and alkylating agent 2a-g (2 mmol) were placed in a 15 mL tube and dissolved in 3-4 mL of DMF (or dioxane in the case of 4a,p). Diisopropylethylamine (0.35 mL, 2 mmol) was added to the solution. The tube was thoroughly sealed and allowed to stand at 20 ˚C in ultrasonic bath (BRANSON 2510E-MT) for 16 h. After that, the reaction mixture was diluted by 8-10 mL of 10% aq solution of NaOH and sonicated at 60 ˚C for 8 h. After the neutralization by HCl, the precipitate formed was filtered and washed with i-PrOH (2 mL). Targeted N-carbamoylamino acids 4c-m were obtained as a white powders. In the case of water-soluble compounds 4a,b,n-q the extraction by CH₂Cl₂ was used.

17

Compounds 4a,b,f,g,i were obtained in hundred-gram scale by the general procedure.

18

^¹ H NMR Data
^¹H NMR (400 MHz and 500 MHz) were recorded on a Varian Mercury-400 and Bruker Avance DRX 500 spectrometers with TMS as an internal standard in DMSO-d ₆ as a solvent.
Compound 4a (500 MHz): δ = 2.79 (s, 3 H), 3.86 (s, 2 H), 8.02 (s, 1 H), 11.82 (br s, 2 H).
Compound 4b (500 MHz): δ = 2.55 (d, ^³ J _HH = 4.4 Hz, 3 H), 4.24 (d, ^³ J _HH = 6.0 Hz, 2 H), 5.85 (q, ^³ J _HH = 4.4 Hz, 1 H), 6.46 (t, ^³ J _HH = 6.0 Hz, 1 H), 7.32 (d, ^³ J _HH = 7.8 Hz, 2 H), 7.86 (d, ^³ J _HH = 7.8 Hz, 2 H), 12.75 (br s, 1 H).
Compound 4c (500 MHz): δ = 3.69 (d, ^³ J _HH = 5.9 Hz, 2 H), 4.19 (d, ^³ J _HH = 5.9 Hz, 2 H), 6.16 (t, ^³ J _HH = 5.9 Hz, 1 H), 6.62 (t, ^³ J _HH = 5.9 Hz, 1 H), 7.27 (m, 5 H).
Compound 4d (400 MHz): δ = 4.26 (d, ^³ J _HH = 6.0 Hz, 2 H), 4.32 (d, ^³ J _HH = 6.0 Hz, 2 H), 5.55 (m, 2 H), 7.35 (m, 1 H), 7.51 (m, 4 H), 7.61 (m, 2 H), 7.85 (m, 2 H).
Compound 4e (400 MHz): δ = 4.22 (d, ^³ J _HH = 6.0 Hz, 2 H), 4.28 (d, ^³ J _HH = 6.0 Hz, 2 H), 6.69 (t, ^³ J _HH = 6.0 Hz, 1 H), 6.74 (t, ^³ J _HH = 6.0 Hz, 1 H), 7.18-7.31 (m, 5 H), 7.40 (t, ^³ J _HH = 7.5 Hz, 1 H), 7.46 (d, ^³ J _HH = 7.5 Hz, 1 H), 7.78 (d, ^³ J _HH = 7.5 Hz, 1 H), 7.86 (s, 1 H).
Compound 4f (500 MHz): δ = 1.22 (d, ^³ J _HH = 7.4 Hz, 3 H), 4.09 (quin, ^³ J _HH = 7.4 Hz, 1 H), 4.18 (d, ^³ J _HH = 5.6 Hz, 2 H), 6.28 (d, ^³ J _HH = 7.4 Hz, 1 H), 6.54 (t, ^³ J _HH = 5.6 Hz, 1 H), 7.28 (m, 5 H).
Compound 4g (400 MHz): δ = 0.85 (t, ^³ J _HH = 7.3 Hz, 3 H), 1.55-1.59 (m, 1 H), 1.65-1.70 (m, 1 H), 4.06 (q, ^³ J _HH = 5.6 Hz, 1 H), 4.19 (m, 2 H), 6.23 (d, ^³ J _HH = 8.2 Hz, 1 H), 6.50 (t, ^³ J _HH = 5.6 Hz, 1 H), 7.22 (m, 3 H), 7.25 (m, 2 H).
Compound 4h (500 MHz): δ = 4.20 (m, 2 H), 5.18 (d, ^³ J _HH = 7.3 Hz, 1 H), 6.67 (t, ^³ J _HH = 5.6 Hz, 1 H), 6.82 (d, ^³ J _HH = 7.7 Hz, 1 H), 7.23 (m, 3 H), 7.28 (m, 4 H), 7.35 (m, 3 H).
Compound 4i (500 MHz): δ = 4.21 (d, ^³ J _HH = 5.3 Hz, 2 H), 4.26 (d, ^³ J _HH = 4.6 Hz, 2 H), 6.33 (br t, 1 H), 6.50 (br q, 2 H), 7.11 (t, ^³ J _HH = 1.9 Hz, 1 H), 7.23 (m, 3 H), 7.29 (m, 2 H).
Compound 4j (500 MHz): δ = 3.47 (d, ^³ J _HH = 5.9 Hz, 2 H), 6.51 (t, ^³ J _HH = 5.9 Hz, 1 H), 6.82 (t, ^³ J _HH = 6.5 Hz, 1 H), 7.17 (t, ^³ J _HH = 7.8 Hz, 2 H), 7.41 (d, ^³ J _HH = 7.8 Hz, 2 H), 9.28 (s, 1 H).
Compound 4k (400 MHz): δ = 4.38 (m, 2 H), 6.51 (m, 1 H), 6.84 (m, 1 H), 7.38 (m, 4 H), 7.91 (m, 2 H), 7.91 (m, 2 H), 8.33 (m, 1 H).
Compound 4l (500 MHz): δ = 0.88 (t, ^³ J _HH = 7.3 Hz, 3 H), 1.53 (m, 1 H), 1.55 (m, 1 H), 4.13 (m, 1 H), 6.47 (d, ^³ J _HH = 7.9 Hz, 1 H), 6.90 (t, ^³ J _HH = 6.5 Hz, 1 H), 7.22 (t, ^³ J _HH = 7.8 Hz, 2 H), 7.36 (d, ^³ J _HH = 7.8 Hz, 2 H), 8.70 (s, 1 H).
Compound 4m (500 MHz): δ = 4.31 (br d, 2 H), 6.23 (s, 1 H), 6.65 (s, 1 H), 6.82 (t, ^³ J _HH = 6.5 Hz, 1 H), 7.18 (t, ^³ J _HH = 7.8 Hz, 2 H), 7.54 (d, ^³ J _HH = 7.8 Hz, 2 H), 8.68 (s, 1 H), 10.01 (s, 1 H).
Compound 4n (500 MHz): δ = 0.98 (t, ^³ J _HH = 7.1 Hz, 3 H), 3.01 (m, 2 H), 4.23 (d, ^³ J _HH = 6.0 Hz, 2 H), 5.93 (t, ^³ J _HH = 5.2 Hz, 1 H), 6.38 (t, ^³ J _HH = 6.0 Hz, 1 H), 7.33 (d, ^³ J _HH = 7.8 Hz, 2 H), 7.86 (d, ^³ J _HH = 7.8 Hz, 2 H), 12.75 (br s, 1 H).
Compound 4o (500 MHz): δ = 0.81 (d, ^³ J _HH = 6.6 Hz, 6 H), 1.59 (m, 1 H), 2.50 (t, ^³ J _HH = 6.1 Hz, 2 H), 4.25 (d, ^³ J _HH = 5.9 Hz, 2 H), 6.01 (t, ^³ J _HH = 6.1 Hz, 1 H), 6.35 (t, ^³ J _HH = 5.9 Hz, 1 H), 7.32 (d, ^³ J _HH = 7.8 Hz, 2 H), 7.87 (d, ^³ J _HH = 7.8 Hz, 2 H), 12.75 (br s, 1 H).
Compound 4p (500 MHz): δ = 0.32 (m, 2 H), 0.54 (m, 2 H), 2.38 (s, 1 H), 3.66 (d, ^³ J _HH = 7.5 Hz, 2 H), 6.12 (s, 1 H), 6.41 (s, 1 H), 12.50 (br s, 1 H).
Compound 4q (500 MHz): δ = 3.14 (q, ^³ J _HH = 5.5 Hz, 2 H), 3.18 (s, 3 H), 3.30 (t, ^³ J _HH = 5.5 Hz, 2 H), 4.24 (d, ^³ J _HH = 5.9 Hz, 2 H), 6.02 (t, ^³ J _HH = 5.5 Hz, 1 H), 6.46 (t, ^³ J _HH = 5.9 Hz, 1 H), 7.31 (d, ^³ J _HH = 7.8 Hz, 2 H), 7.86 (d, ^³ J _HH = 7.8 Hz, 2 H), 12.75 (br s, 1 H).

19

^¹³ C NMR Data
^¹³C NMR (125 MHz) were recorded on a Bruker Avance DRX 500 spectrometer with TMS as an internal standard in DMSO-d ₆ as a solvent.
Compound 4a: δ = 24.4, 46.5, 161.8, 172.6.
Compound 4b: δ = 26.9, 43.2, 127.4, 129.5, 129.8, 146.8, 159.1, 167.7.
Compound 4c: δ = 42.1, 43.4, 127.0, 127.5, 128.7, 141.2, 158.5, 172.9.
Compound 4d: δ = 42.2, 42.5, 128.1, 128.2, 128.3, 128.9, 129.8, 135.9, 141.3, 154.8, 157.9, 166.4.
Compound 4e: δ = 43.1, 43.4, 126.9, 127.4, 127.9, 128.2, 128.7, 127.8, 131.7, 131.9, 141.4, 142.0, 158.8, 168.0.
Compound 4f: δ = 18.8, 43.2, 48.7, 127.01, 127.5, 128.7, 141.2, 158.1, 175.6.
Compound 4g: δ = 10.3, 25.7, 43.3, 54.1, 127.1, 127.5, 128.7, 141.2, 158.2, 174.9.
Compound 4h: δ = 43.3, 57.6, 127.03, 127.4, 127.5, 127.9, 128.7, 128.8, 139.5, 141.1, 157.8, 173.2.
Compound 4i: δ = 37.2, 43.5, 108.9, 119.1, 127.1, 127.5, 128.7, 141.2, 144.2, 158.2, 158.8, 159.8.
Compound 4j: δ = 44.6, 117.9, 120.9, 128.9, 141.7, 155.7, 173.1.
Compound 4k: δ = 42.5, 127.1, 128.4, 129.5, 131.1, 141.2, 153.8, 156.9, 157.7, 166.6.
Compound 4l: δ = 10.3, 25.5, 53.8, 117.9, 121.5, 129.1, 140.9, 155.5, 174.6.
Compound 4m: δ = 36.3, 108.2, 112.9, 118.2, 120.9, 128.8, 141.9, 151.7, 153.9, 155.9, 163.7.
Compound 4n: δ = 16.2, 34.7, 43.2, 127.4, 129.6, 129.8, 146.9, 158.5, 167.7.
Compound 4o: δ = 20.5, 29.1, 43.2, 47.4, 127.4, 129.6, 129.8, 146.9, 158.6, 167.6.
Compound 4p: δ = 6.9, 22.8, 42.04, 159.2, 172.9.
Compound 4q: δ = 43.2, 58.3, 58.4, 72.1, 127.4, 129.6, 129.8, 146.8, 158.8, 167.7.