LETTER
Chemoselective Base-Mediated Protection/Deprotection of Aldehydes
2319
is clearly more robust than the parent compound, but can
be easily deprotected to the aldehyde with TBAF and sub-
sequently trapped in an in situ WHE reaction (Scheme 5).
Acknowledgment
We thank AstraZeneca and the EPSRC for a studentship (MSS), the
National Mass Spectrometry Service at Swansea for HRMS, and
Prof S. V. Ley for continued support.
References
(1) Greene, T. W.; Wuts, P. G. M. 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, V. H.;
Rao, J. A.; Cava, M. P. 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, L. G.; Cha, J. K. Synlett 2001, 1925.
(4) 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: (a) Taggart, M. S.; Richter, G. H. J. Am. Chem.
Soc. 1934, 56, 1385. (b) Later reports indicated their
formation by organometallic additions, including reduction
with H–: Lee, S. D.; Brook, M. A.; Chan, T. H. Tetrahedron
Lett. 1983, 24, 1569. (c) Brandänge, S.; Rodriguez, B. Acta
Chem. Scand. Ser. B 1987, 41, 740. (d) Brandänge, S.;
Holmgren, E.; Leijonmarck, H.; Rodriguez, B. Acta Chem.
Scand. 1995, 49, 922. (e) Evans, D. A.; Borg, G.; Scheidt,
K. A. Angew. Chem. Int. Ed. 2002, 41, 3188.
Scheme 5 a) TBSCl, imidazole, DMF, 35 °C overnight.
b) (EtO)2P(=O)CH2CO2Et, TBAF, THF, –78 °C to r.t. overnight.
When aldehyde protection is a short term strategy, it is
possible to perform in situ protection of the aldehyde via
the O-lithiated pyrrole carbinol.17 The efficiency of this
method is exemplified by the 4-step one-pot sequence out-
lined in Scheme 6.18,19 The stepwise aldehyde protection,
halogen metal exchange, deuterium quench, and tandem
deprotection-WHE occurred smoothly to give the deuter-
ated cinnamate 22 in 80% yield.
(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
(10) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
1984, 25, 2183.
(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.
Scheme 618 a) Pyrrole (1.05 equiv), BuLi (1.0 equiv), –78 °C,
THF, aldehyde. b) BuLi (3 equiv). c) CD3OD (4 equiv).
d) (EtO)2P(=O)CHLiCO2Et (1.25 equiv), THF–EtOH, –78 °C to r.t.
In conclusion, the direct formation of pyrrole carbinols of
aldehydes using lithium pyrrolate in THF offers an effi-
cient chemoselective method of aldehyde protection. The
pyrrole carbinol products are stable to LiBH4 reductions
as well as Grignard addition reactions. Deprotection to the
parent aldehydes is efficient under basic conditions and
can be coupled with an in situ base-mediated trap, such as
the WHE reaction leading to the a,b-unsaturated ester
products.
(13) The reaction was quenched at –78 °C with HOAc instead of
NH4Cl(aq).
Further studies into the utility of these compounds are on-
going and will be reported in due course.
(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.
(16) Maurer, B.; Grieder, A.; Thommen, W. Helv. Chim. Acta
1979, 62, 44.
Synlett 2003, No. 15, 2317–2320 © Thieme Stuttgart · New York