A New Chemoselective Base-Mediated Protection/Deprotection Method for Aldehydes

Abstract

A wide range of aldehydes was efficiently protected as pyrrole carbinol derivatives by direct addition of lithium pyrrolate in THF at -78 °C. The protection is chemoselective towards aldehydes over ketones and the O-lithiated, O-protonated or O-silylated carbinols may be used to block the aldehyde from nucleophilic and basic reagents at low temperatures. Mild, basic deprotection using DBU, NaOMe or TBAF allows for in situ trapping-reactions (such as Wadsworth-Horner-Emmons olefination) of the released aldehyde.

Key words

aldehydes - protecting-group - pyrrole carbinol - tandem reactions - chemoselective

References

• 1 Greene TW. Wuts PGM. Protective Groups in Organic Synthesis   3rd ed:  Wiley; New York: 1999. 
• 2 Although cyanohydrins are formed under basic conditions, they are not always compatible with organometallic reagents and are normally used in their silyl ether form. Problems in their formation from conjugated aldehydes and ketone containing compounds can also occur see: Rawal VH. Rao JA. Cava MP. Tetrahedron Lett.  1985,  26:  4275 ; and references cited therein
• 3 An imidazole/TBSCl protection of aldehydes was recently reported where the adducts were deblocked using HF. See: Quan LG. Cha JK. Synlett  2001,  1925 
• The pyrrole carbinol moiety was first reported in 1934 by Taggart and, to the best of our knowledge, represents the only formation by nucleophilic addition of pyrrole to aldehydes:
• 4a Taggart MS. Richter GH. J. Am. Chem. Soc.  1934,  56:  1385 
• 4b Later reports indicated their formation by organometallic additions, including reduction with H^-: Lee SD. Brook MA. Chan TH. Tetrahedron Lett.  1983,  24:  1569 
• 4c Brandänge S. Rodriguez B. Acta Chem. Scand. Ser. B  1987,  41:  740 
• 4d Brandänge S. Holmgren E. Leijonmarck H. Rodriguez B. Acta Chem. Scand.  1995,  49:  922 
• 4e Evans DA. Borg G. Scheidt KA. Angew. Chem. Int. Ed.  2002,  41:  3188 
• 10 Blanchette MA. Choy W. Davis JT. Essenfeld AP. Masamune S. Roush WR. Sakai T. Tetrahedron Lett.  1984,  25:  2183 
• 16 Maurer B. Grieder A. Thommen W. Helv. Chim. Acta  1979,  62:  44 
• The in situ protection of aldehydes as amino alkoxides using lithium morpholide and lithium 2-[N-methyl-N-(2-pyridyl)]-amide nucleophiles was first studied by Comins et al. See as examples:
• 17a Comins DL. Brown JD. Tetrahedron Lett.  1981,  22:  4213 
• 17b Comins DL. Brown JD. Mantlo NB. Tetrahedron Lett.  1982,  23:  3979 
• 17c Comins DL. Brown JD. J. Org. Chem.  1984,  49:  1078 

5

Note: Freshly distilled pyrrole was used. Distilled pyrrole will stay fresh for long periods if stored under Ar at -30 °C.

6

The THF was rigorously degassed before use.

7

The reactions were carried out on a 10 mmol scale.

8

Representative method: To a stirred solution of pyrrole (0.792 mL, 10.5 mmol) in THF (40 mL) at -78 °C was added n-BuLi (4 mL, 10 mmol, 2.5 M in hexanes) via syringe. The reaction mixture was allowed to stir at this temperature for 15 min before 3-bromobenzaldehyde (10 mmol) was added dropwise. Stirring was maintained for a further 30 min before quenching with NH₄Cl (4 mL) at -78 °C. The resultant mixture was warmed to r.t. and water (5 mL) was added before extraction with Et₂O (1 × 40 mL, 1 × 5 mL). The combined organics were washed with brine (5 mL), dried (MgSO₄) and concentrated in vacuo to yield an oil which was purified by chromatography on silica gel.

9

For a detailed study of the stability of pyrrole carbinols towards bases see ref. [4e]

11

Triethylphosphonoacetate (1.5 equiv) was deprotonated at 0 °C in THF with n-BuLi (1.2 equiv), and the solution was then added to the pyrrole carbinol (1 equiv) at -78 °C.

12

Synthesised in one step from 1-methyl-pent-1-ene, via ozonolysis in 70% yield. The aldehyde can be stored for short periods at -30 °C under Ar.

13

The reaction was quenched at -78 °C with HOAc instead of NH₄Cl(aq).

14

Determined by ¹H NMR (500 MHz).

15

The recovery of starting material is attributed to in situ protection of the keto group by intramolecular attack of the deprotonated pyrrole carbinol into the ketone.

18

To a stirred solution of pyrrole, (729 µL, 10.5 mmol) in THF (40 mL) at -78 °C was added n-BuLi (4 mL, 10 mmol, 2.5 M in hexanes) dropwise via syringe. After 15 min, 3-bromobenzaldehyde, (1.16 mL, 10 mmol) was added dropwise, and after 30 min n-BuLi (12 mL, 30 mmol, 2.5 M in hexanes) was added rapidly. The reaction was stirred for 1 h before AcOD (2.29 mL, 40 mmol) was added. After stirring for a further 30 min, a solution of the lithium triethylphosphonoacetate [formed by the addition of n-BuLi (5 mL, 12.5 mmol, 2.5 M in hexanes) to triethyl phosphonoacetate (2.97 mL, 15 mmol) in THF (10 mL)-EtOH (10 mL) at 0 °C] was added and the reaction was allowed to warm to r.t. overnight. The reaction mixture was diluted with Et₂O, washed with water, then brine, dried (MgSO₄) and concentrated in vacuo. Purification by flash column chromatography eluting with 40-60 petroleum ether-Et₂O (25:1-1:1) yielded the title compound, 22 (1.42 g, 80%). ¹H NMR (400 MHz, CDCl₃): δ = 7.71 (d, J = 16.0 Hz, 1 H, CHCHCO₂Et), 7.53 (m, 2 H, Ph), 7.39 (m, 2 H, Ph), 6.46 (d, J = 16.0 Hz, 1 H, CHCHCO₂Et), 4.30 (q, J = 7.2 Hz, 2 H, CH ₂CH₃), 1.36 (t, J = 7.2 Hz, 3 H, CH₂CH ₃). ¹³C NMR (100 MHz, CDCl₃): δ = 167.0 (CO₂), 144.5 (C=CHCO₂), 134.5 (CCH=C), 130.0 (CH), 128.8 (CH), 128.6 (CD, J = 24.4 Hz) 128.0 (2 × CH), 118.2 (CHCO₂), 60.4 (CH₃ CH₂O), 14.2 (CH₃). IR (film): 1706, 1636, 1308, 1246, 1175, 1164, 1034, 982 cm^-1. MS (EI): m/z [M] calcd for C₁₁H₁₁O₂D: 177.0899; found: 177.0894.

19

All new compounds were characterized by ¹H NMR, ¹³C NMR, HRMS, and IR.