402
A. A. Haddach et al. / Tetrahedron Letters 43 (2002) 399–402
The proposed mechanism for this N-debenzylation
reaction is shown in Scheme 3. This mechanism is very
similar to the one that has previously been proposed by
Gigg and Conant for the N-debenzylation of amides.
The base in this reaction may be either potassium
tert-butoxide itself or the methylsulfinylmethyl anion,
which could be formed in small amounts under the
reaction conditions.10 The newly formed benzylic anion,
19, reacts with oxygen as it is being bubbled into the
reaction mixture.11 The intermediate peroxy anion, 20,
is easily reduced in the presence of DMSO to afford the
sulfone and an anion, 21, which breaks down to afford
benzaldehyde and the deprotected heterocycle.
flask. While stirring the solution at room temperature,
benzimidazole (2 mmol) was added dropwise. The reac-
tion was allowed to stir for 30 min. Benzyl bromide (2.2
mmol) was then added. Upon completion, the reaction
was quenched with satd NH4Cl and extracted with
EtOAc. The organics were combined and dried over
MgSO4 and concentrated. Column chromatography
afforded pure product in 87% yield.
7. A typical procedure for N-debenzylation: 1-Benzyl-benz-
imidazole (2.4 mmol) was dissolved in DMSO (24 mmol)
and added to a flame-dried flask. While stirring the
solution at room temperature, KOtBu (16.8 mmol, 1 M
soln in THF) was added (total reaction volume of ꢀ19
ml). Oxygen was then bubbled into the solution, via a gas
dispersion tube, for 10 min. Upon completion (deter-
mined by TLC) the reaction was quenched with saturated
ammonium chloride. The product was extracted three
times with EtOAc. The organics were combined, dried
over Na2SO4 and concentrated. Column chromatography
using 8% MeOH/CH2Cl2 gave benzimidazole in 92%
yield (entry 3, Table 1).
In conclusion, the N-debenzylation of heterocycles can
be carried out rapidly and efficiently via the use of
KOtBu/DMSO and O2. This procedure works well on a
wide variety of nitrogen-containing heterocycles and is
also well tolerated by a variety of functional groups.
Being a base-promoted process, it is a complementary
addition to the methods for N-debenzylation.
8. Physical data on compound 12b: 1H NMR (300 MHz,
CDCl3) l 7.74 (dt, J1=8.2 Hz, J2=1.0 Hz, 1H), 7.47–
7.21 (m, 8H), 5.61 (s, 2H). 13C NMR (300 MHz, CDCl3)
l 53.8, 110.1, 120.3, 121.7, 121.9, 127.7, 128.0, 128.4,
129.2, 133.6, 136.7, 141.3. IR w (cm−1) 702, 753, 1177,
1339, 2900–3100. HRMS: calcd for C14H12ClN2 [(M+1)+]:
243.0689. Found: 243.0701.
Supplementary material. All compounds (other than
Compound 12b8) that are described in this article are
either commercially available materials or they have
been previously cited in the scientific literature. The
reaction products were compared via standard analyti-
cal techniques (NMR, HPLC, MS) to the analytical
data that is available for these materials.
9. Kawakami, T.; Suzuki, H. Tetrahedron Lett. 2000, 41,
7093–7096.
10. The pKa of potassium tert-butoxide in DMSO is 32.2.
The pKa of the methylsulfinylmethyl anion in DMSO is
35.1. pKa values obtained from: Olmstead, W. N.; Mar-
golin, Z.; Bordwell, F. G. J. Org. Chem. 1980, 45, 3295–
3299. Matthews, W. S.; Bares, J. E.; Bartmess, J. E.;
Bordwell, F. G.; Cornforth, F. J.; Druker, G. E.; Mar-
golin, Z.; McCallum, R. J.; McCollum, G. J.; Vanier, N.
R. J. Am. Chem. Soc. 1975, 97, 7006–7014.
References
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11. This reaction is successful if just left open to the air,
however, it is much more rapid if the oxygen is added to
the system intentionally. Also, because the reaction is
slower in that case, decomposition of the starting materi-
als can be a major side reaction. If the reaction is run
under an inert atmosphere, no N-debenzylation occurs
and, after an extended period of time, decomposition
products are predominant.
4. Watanabe, T.; Kobayashi, A.; Nishiura, M.; Takahashi,
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1983, 465–466.
6. Typical procedure for N-benzylation: NaH (2.4 mmol) was
dissolved in anhydrous THF and added to a flame-dried