F. Rombouts et al. / Tetrahedron Letters 51 (2010) 4815–4818
4817
Table 3
material 1. Primary (1g, 1h) and secondary (1b) acyclic amides, and
both cyclic aliphatic (1i) and aromatic amides (1c, 1d, 1j) (Table 2,
entries 1–3 and 6–9) were easily deprotected under our standard
conditions with the only exception of the N-benzylisatin (1k),
which was unstable in the acidic reaction medium and decom-
posed (Table 2, entry 10). Simple aliphatic N-benzylamides such
as 1e and 1f required higher temperatures and prolonged reaction
times to yield the expected compounds: nevertheless the final
amides were obtained in good yields (Table 2, entries 4 and 5).
Interestingly, compound 1g, which presents in its structure both
an N-phenethyl- and N-benzylamide, was successfully deprotected
under standard conditions without altering the N-phenetylcarbox-
amide moiety (Table 2, entry 6). We were pleased to find that tria-
zolones 1l and 1m also underwent the debenzylation process with
TfOH without having to modify the reaction conditions, and the
corresponding deprotected compounds were obtained in good
yield after chromatographic purification.
To further study the scope of this deprotection reaction, a new
set of N-benzylbenzamides (1n–w) carrying different functional
groups were prepared (Fig. 2) and subjected to the TfOH-mediated
debenzylation process in toluene. The results obtained are summa-
rized in Table 3.
As shown in Table 3, both aromatic (1n, 1o) and aliphatic (1r)
amines were compatible with the microwave-assisted N-debenzy-
lation with TfOH, giving moderate to good yields of the corre-
sponding primary benzamides (Table 3, entries 1, 2 and 5).
Furthermore, the debenzylation was found to proceed in moderate
to good yield in the presence of non-benzylic amide (1p), benzyl
chloride (1q), sulfone (1v), and ketone (1w) functional groups (Ta-
ble 3, entries 3, 4, 9, and 10). Two functional groups, the ester (1s),
and the aromatic ether (1t, 1u) were found to be unstable under
Debenzylation reaction of benzamides (1n–w) with TfOH under microwave
irradiation
O
O
TfOH (4 equiv), toluene
µW, 150 ºC, 15 min
N
H
NH2
R
R
1n-w
2n-w
Entry
Amide 1a
Yieldb (%)
1
2
3
4
5
6
7
8
9
1n
1o
1p
1q
1r
1s
1t
1u
1v
1w
86
55
71
57
78
6 (45)c
0 (55)d
0 (62)d
88
10
63
a
b
c
The reactions were carried out on 1 mmol scale.
Isolated yield.
Yield in brackets refers to the isolated 3-carbamoylbenzoic acid, which was
obtained instead of the ester.
d
Yield in brackets refers to the isolated hydroxybenzamide, which was obtained
instead of the ether.
the above-mentioned N-debenzylation conditions. Thus, for the
N-debenzylation of 1s the ester 2s was isolated in 6% yield, while
the major product was the N-debenzylated acid (Table 3, entry
6). The N-debenzylation of amides 1t and 1u occurred with the
cleavage of the ether function affording moderate yields of the cor-
responding 3- and 4-hydroxybenzamides (Table 3, entries 7 and 8).
These results can be easily explained as both alkyl-aryl ethers and
esters are known to cleave under strongly acidic conditions.
In summary, we have developed a new method for the debenzy-
lation of N-benzylamides with TfOH under microwave irradiation.
Initial results point to the use of TfOH as a good alternative to the
known Brönsted acids for this synthetic transformation. The N-
debenzylation method has shown quite a general application and
secondary/tertiary, aliphatic/aromatic, and acyclic/cyclic amides
are suitable substrates for this process. In addition, good functional
group tolerability has been found. Further studies on the scope and
limitations of this methodology are ongoing and will be reported in
due course.
O
O
N
N
H
N
H
N
1n
1o
O
O
N
N
H
H
N
O
Cl
O
1p
1q
O
O
O
N
O
N
References and notes
H
H
N
O
1. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.;
Wiley-Interscience: New York, 2003; (b) Kocienski, P. J. Protecting Groups, 3rd
ed.; Thieme: New York, 2005.
2. For 4-methoxybenzyl (PMB) see: Ford, R. E.; Knowles, P.; Lunt, E.; Marshall, S.
M.; Penrose, A. J.; Ramsden, C. A.; Summers, A. J. H.; Walker, J. L.; Wright, D. E. J.
Med. Chem. 1986, 29, 538–549; For 2,4,6-trimethoxybenzyl see: Weygand, F.;
Steglich, W.; Bajrnason, J. Chem. Ber. 1968, 101, 3642–3648; For 1-phenylethyl
see: Paik, S.; Lee, J. Tetrahedron Lett. 2006, 47, 1813–1815.
1r
1s
O
O
N
N
H
H
O
1t
1u
3. (a) Baker, S. R.; Parson, A. F.; Wilson, M. Tetrahedron Lett. 1998, 39, 331–332; (b)
Kuang, L.; Jing, Z.; Chen, S.; Ding, K. Synthesis 2007, 3129–3133.
4. For recent examples see: (a) Ghosh, S.; Shashidhar, J. Tetrahedron Lett. 2009, 50,
1177–1179; (b) Kündig, E. P.; Seidel, T. M.; Jia, Y.; Bernadinelli, G. Angew. Chem.,
Int. Ed. 2007, 46, 8484–8487; (c) Morales, C. L.; Pagenkopf, B. L. Org. Lett. 2008,
10, 157–159; (d) Almiento, G. M.; Balducci, D.; Bottoni, A.; Calvaresi, M.; Porzi,
G. Tetrahedron: Asymmetry 2007, 18, 2695–2711; (e) Lerchner, A.; Carreira, E.
M. Angew. Chem., Int. Ed. 2006, 12, 8208–8219.
5. (a) Alonso, E.; Ramon, D. J.; Yus, M. Tetrahedron 1997, 53, 14355–14368; (b)
Huang, P. Q.; Zheng, X.; Wang, S. L.; Ye, J. L.; Jin, L. R.; Chen, Z. Tetrahedron:
Asymmetry 1999, 10, 3309–3317.
O
O
N
N
H
O
S
H
O
O
1v
1w
Figure 2. Set of differently substituted N-benzylbenzamides used in the microwave
assisted N-debenzylation reaction.
6. Yanada, R.; Obika, S.; Kobayashi, Y.; Inokuma, T.; Oyama, M.; Yanada, K.;
Takemoto, Y. Adv. Synth. Catal. 2005, 347, 1632–1642.