Azidomethyl 4-Nitrophenyl Carbonate - A Reagent for the One-Step Introduction of the Azidomethyloxycarbonyl (Azoc) Protecting Group

Abstract

Presented here is the three-step synthesis of azidomethyl 4-nitrophenyl carbonate in 58% overall yield. This carbonate allows for the high-yielding (³90%) introduction of the phosphine-labile azidomethyloxycarbonyl (Azoc) protecting group in one step. The reagent protects a range of amines, including amino acids. For nonionic substrates, pure carbamates are obtained after extractive workup.

Key words

Azoc - amine - amino acids - protecting group

References and Notes

• 1 Isidro-Llobet A. Álvarez M. Albericio F. Chem. Rev.  2009,  109:  2455 
• 2 Pothukanuri S. Winssinger N. Org. Lett.  2007,  9:  2223 
• 3 Pothukanuri S. Pianowski Z. Winssinger N. Eur. J. Org. Chem.  2008,  3141 
• 4 Loren JC. Krasinski A. Fokin VV. Sharpless KB. Synlett  2005,  2847 
• 5a Smith PAS. Open-Chain Nitrogen Compounds   Vol. 2:  Benjamin; New York: 1966.  p.211-256  
• 5b Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem. Int. Ed. 2005, 44, 5188
• 5c Bräse S. Bannert K. Organic Azides: Syntheses and Applications   Vol. 1:  Wiley; Chichester: 2010.  p.3-27  
• See, for example:
• 6a Gangwar S. Pauletti GM. Siahaan TJ. Stella VJ. Borchardt RT. J. Org. Chem.  1997,  62:  1356 
• 6b Goebel T, Humbert-Droz E, and Schwarzenbach M. inventors; WO  200029378.  ; Chem. Abstr. 2000, 132, 347496
• 6c Gediya LK. Khandelwal A. Patel J. Belosay A. Sabnis G. Mehta J. Purushottamachar P. Njar VCO. J. Med. Chem.  2008,  51:  3895 
• 6d Gallop MA, Cundy KC, Zhou CX, Yao F, Xiang J.-N, Ollman IR, and Qiu FG. inventors; US 20060229361  A1.  ; Chem. Abstr. 2006, 145, 418708
• 12 Baird E. Dervan PB. J. Am. Chem. Soc.  1996,  118:  6141 
• 15 Bentley DR. et al. Nature (London)  2008,  456:  53 

7

CAUTION: Silver azide is an explosive. Safety equipment such as leather gloves, face shield, protective shield, and ear plugs is recommended. Further safety notes for work with metal and organic azides can be found in ref. 5c.

8

Remaining silver azide may be quenched through oxidation with aq KI₃ solution under sulfide catalysis (iodine-azide reaction): Silver azide containing salts and contaminated filters were added to a stirred aq solution of KI₃ (500 mL, 0.2 M) and Na₂S (50 mg) resulting in immediate development of N₂. This slurry was stirred overnight.

9

Calculated from signals in ^¹H NMR spectrum of crude.

10

Azidomethyl 4-Nitrophenyl Carbonate (1)
AgNO₃ (4.60 g, 27.1 mmol, 1.25 equiv) was dissolved in H₂O (20 mL) and added to a stirred solution of NaN₃ (1.76 g, 27.1 mmol, 1.25 equiv) in H₂O (20 mL). AgN₃ (4.06 g, 27.1 mmol, 1.25 equiv) immediately formed as a white microcrystalline precipitate. The supernatant was aspired with a syringe, and the precipitate was washed with H₂O (3 × 30 mL), acetone (3 × 30 mL), and toluene (3 × 30 mL). The AgN₃ was suspended in toluene (50 mL), MS 4 Å (6.0 g) were added, and the resulting slurry was stirred 15 min under argon. Iodomethyl 4-nitrophenyl carbonate^6b (4, 7.00 g, 21.67 mmol, 1.0 equiv) was added in one portion. Complete conversion was detected by TLC [R _f = 0.52 (CH₂Cl₂-PE = 3:2)] after 3 h of stirring in the dark. Silver salts (compare ref. 8) were filtered off, and the filtrate was diluted with CH₂Cl₂ (200 mL) and washed with H₂O (50 mL), Na₂CO₃ solution (2 × 50 mL, 2 M), H₂O (50 mL), and sat. NaCl solution (50 mL). The organic phase was dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The resulting yellow oil was purified by flash column chromatography, eluting with CH₂Cl₂-PE (3:4) → CH₂Cl₂-PE (1:1). The title compound was obtained as a slight yellowish oil that slowly crystallized (3 d) at -18 ˚C, but rapidly crystallized after addition of a seed crystal (3.72 g, 15.6 mmol, 72%). Yellowish powder, mp 35 ˚C. IR (neat): 3119, 2962, 2559, 2369, 2105, 1967, 1766, 1617, 1594, 1523, 1491, 1347, 1198 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 5.32 (s, 2 H, CH₂N₃), 7.40-7.46 (m, 2 H, ArH), 8.28-8.34 (m, 2 H, ArH). ^¹³C NMR (75 MHz, CDCl₃): δ = 78.96 (CH₂), 121.74 (CH), 125.45 (CH), 145.72, 152.29, 155.04. MS (EI, 70 eV): m/z (%) = 238 (2) [M]⁺, 196 (12), 166 (36), 139 (40), 122 (42), 56 (100), 28 (71). HRMS (EI): m/z calcd for C₈H₆N₄O₅: 238.0338 [M]⁺; found: 238.0319 [M]⁺. Anal. Calcd for C₈H₆N₄O₅: C, 40.35; H, 2.54; N, 23.53. Found: C, 40.25; H, 2.69; N, 23.26.

11

General Procedure for Azoc Protection with Azidomethyl 4-Nitrophenyl Carbonate (1) and Analytical Data of Compounds 6b,d,g Azidomethyl 4-nitrophenyl carbonate (1, 300 mg, 1.26 mmol, 1.0 equiv) was dissolved in anhyd DMF (3 mL) and cooled to 0 ˚C. Either of compounds 5a-g (1.26 mmol) was dissolved in anhyd DMF (2 mL) in an separate flask and treated with DIPEA (1.39 mmol, 236 µL, 1.1 equiv). The resulting solution was added dropwise, within 2 min, to the solution of 1. The reaction was monitored via TLC (CH₂Cl₂-PE = 3:2). After complete conversion, the reaction mixture was diluted with EtOAc (200 mL) and washed with Na₂CO₃ solution (8 × 50 mL, 2 M). The combined aqueous solutions were re-extracted with EtOAc (30 mL). The extract was washed once with H₂O (10 mL). The combined organic phases were washed with sat. NaCl solution (2 × 50 mL), dried over Na₂SO₄, filtered, concentrated in vacuo and dried at <10^-³ mbar for at least 3 h. Analytical data of compounds 6a and 6f were found to be identical to those in ref. 2.
Azidomethyl 4-Aminobenzylcarbamate (6b) Orange oil which slowly crystallized at -18 ˚C (2 weeks) to give an orange solid with mp 26-28 ˚C. IR (neat): 3423, 3328, 2154, 2098, 1723, 1697, 1617, 1539, 1512 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 3.68 (s, 2 H, NH₂), 4.27 (d, ^³ J = 5.9 Hz, 2 H, CH₂Ar), 5.05-5.20 (m, 3 H, CH₂N₃, NH), 6.62-6.68 (m, 2 H, ArH), 7.08 (d, ^³ J = 8.3 Hz, 2 H, ArH). ^¹³C NMR (75 MHz, CDCl₃): δ = 44.89 (ArCH₂), 75.32 (CH₂N₃), 115.25, 127.59, 128.72, 129.04, 146.08, 155.18. ESI-HRMS: m/z calcd for C₉H₁₁N₅O₂Na: 244.0805 [M + Na]⁺; found: 244.0802 [M + Na]⁺.
Azidomethyl 5-Hydroxypentylcarbamate (6d) Colorless oil. IR (neat): 3329, 2937, 2864, 2140, 2100, 1705, 1532 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.36-1.48 (m, 2 H, H-3), 1.51-1.65 (m, 5 H, H-2, H-4, OH), 3.24 (q, ^³ J = 6.7 Hz, 2 H, CH₂NH), 3.65 (t, ^³ J = 6.4 Hz, 2 H, CH₂OH), 5.02 (s, 1 H, NH), 5.13 (s, 2 H, CH₂N₃). ^¹³C NMR (75 MHz, CDCl₃): δ = 22.87 (C-3), 29.51, 32.13, 41.02 (C-1), 62.55 (C-5), 75.22 (CH₂N₃), 155.36 (C=O). ESI-HRMS: m/z calcd for C₇H₁₄N₄O₃Na: 225.0958 [M + Na]⁺; found: 225.0964 [M + Na]⁺.
Methyl 4-[(Azidomethoxy)carbonylamino]- N -methyl-pyrrole-2-carboxylate (6g) Compound 6g was purified via flash column chromatography using a gradient of CH₂Cl₂ → CH₂Cl₂-MeOH (99:1).
Orange brownish powder; mp 136-138 ˚C. IR (neat): 3509, 3310, 2958, 2163, 2141, 2112, 1967, 1717, 1679, 1586, 1565 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 3.72 (s, 3 H, Me), 3.82 (s, 3 H, Me), 5.27 (s, 2 H, CH₂N₃), 6.69 (d, ⁴ J = 1.9 Hz, 1 H, ArH), 7.14 (d, ⁴ J = 1.9 Hz, 1 H, ArH), 9.80 (s, 1 H, NH). ^¹³C NMR (126 MHz, DMSO-d ₆): δ = 36.09, 50.88, 74.88, 107.56, 118.99, 119.47, 121.92, 152.38, 160.54. ESI-HRMS: m/z calcd for C₉H₁₁N₅O₄Na: 276.0703 [M + Na]⁺; found: 276.0716 [M + Na]⁺.

13

Ammonium 2-[(Azidomethoxy)carbonylamino]ethyl Hydrogenphosphate (6h) Azidomethyl 4-nitrophenyl carbonate (1, 300 mg, 1.26 mmol, 1.0 equiv) and 2-aminoethyl dihydrogen phosphate (177.7 mg, 1.26 mmol, 1.0 equiv) were added to a flask and suspended in DMF (4 mL). DIPEA (4.16 mmol, 707 µL, 3.3 equiv) and H₂O (3 mL) were added. The resulted suspension was sonicated for 2 min and then stirred at 20 ˚C. After 20 min, a clear solution formed. A complete conversion was detected after 30 min via TLC (CH₂Cl₂-PE = 3:2). The reaction mixture was diluted with H₂O (200 mL) and poured on a DEAE-cellulose column [100 g, 20 cm, HCO₃ ^- form, Express-Ion exchanger D, Whatman (Maidstone, UK)]. The column was washed with H₂O (200 mL) and 100 mM NH₄HCO₃ solution (500 mL). The product-containing fractions were combined and the resulting solution concentrated to 20 mL, followed by lyophilization to dryness. The title compound 6h was obtained as a colorless solid (321 mg, 1.25 mmol, 99%). IR (neat): 3210, 2889, 2103, 1705, 1532, 1455 cm^-¹. ^¹H NMR (300 MHz, D₂O): δ = 3.28 (t, ^³ J = 5.3 Hz, 2 H), 3.75-3.83 (m, 2 H), 5.06 (s, 2 H, CH₂N₃). ^¹³C NMR (75 MHz, D₂O): δ = 41.25 (d,
^³ J _P-C2 = 7.8 Hz, C-2), 63.59 (d, ^² J _P-C1 = 5.2 Hz, C-1), 75.71 (CH₂N₃), 157.35 (C=O). ^³¹P NMR (121.5 MHz, D₂O): δ = 1.10. ESI-HRMS: m/z calcd for C₄H₈N₄O₆P: 239.0187 [M]^-; found: 239.0175 [M]^-.

14

Ammonium 3-[(Azidomethoxy)carbonylamino]-propanoate (6i)
A sample of β-alanine (112.2 mg, 1.26 mmol) was treated as described in ref. 13 but in the presence of a smaller amount of DIPEA (471 µL, 2.77 mmol, 2.2 equiv). The column purification used a higher concentration of NH₄HCO₃ (250 mM) for elution from the DEAE-cellulose. The title compound was obtained as colorless oil (236.2 mg, 1.15 mmol, 91%). IR (neat): 3231, 2965, 2103, 1967, 1701, 1524, 1447, 1409, 1219 cm^-¹. ^¹H NMR (300 MHz, D₂O): δ = 2.44 (t, ^³ J = 6.6 Hz, 2 H), 3.31 (t, ^³ J = 6.6 Hz, 2 H), 5.06 (s, 2 H, CH₂N₃). ^¹³C NMR (75 MHz, D₂O): δ = 34.95, 36.79, 75.62 (CH₂N₃), 157.14, 177.60. ESI-HRMS: m/z calcd for C₅H₇N₄O₄: 187.0473 [M]^-; found: 187.0468 [M]^-.