A new method for the cleavage of nitrobenzyl amides and ethers

Article abstract of DOI:10.1016/j.tetlet.2014.10.006

A mild and efficient o- and p-nitrobenzyl cleavage protocol was developed. o- and p-nitrobenzyl groups were easily removed from a variety of substrates using 20% aqueous NaOH in methanol at 75 °C, presumably via oxidation at the benzylic position by oxygen dissolved in the solution. These easily introducible and removable nitrobenzyl groups can serve as valuable protecting groups for the synthesis of multifunctional, complex molecules.

Full text of DOI:10.1016/j.tetlet.2014.10.006

Tetrahedron Letters 55 (2014) 6467–6469
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Tetrahedron Letters
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A new method for the cleavage of nitrobenzyl amides and ethers
⇑
Seo-Jung Han, Gabriel Fernando de Melo, Brian M. Stoltz
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200
E California Boulevard, MC 101-20, Pasadena, CA 91125, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient o- and p-nitrobenzyl cleavage protocol was developed. o- and p-nitrobenzyl groups
were easily removed from a variety of substrates using 20% aqueous NaOH in methanol at 75 °C, presum-
ably via oxidation at the benzylic position by oxygen dissolved in the solution. These easily introducible
and removable nitrobenzyl groups can serve as valuable protecting groups for the synthesis of multifunc-
tional, complex molecules.
Received 12 September 2014
Revised 30 September 2014
Accepted 1 October 2014
Available online 6 October 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Protecting group
o-Nitrobenzyl group
p-Nitrobenzyl group
Amide protection
Deprotection
The selection of protection groups is critical to the synthesis of
multifunctional complex molecules. Over the past decades, a wide
variety of protecting groups have been developed to mask specific
functional groups selectively.1 However, despite considerable
effort, relatively few protecting groups have been developed for
,2
3
the amide N–H (e.g., PMB, TBS, benzyl, SEM, allyl, etc.). Conse-
quently, limitations associated with the cleavage of amide protect-
ing groups often arise.4 Herein, we report o- and p-nitrobenzyl
groups as easily introducible and removable protecting groups
Scheme 1. o-Nitrobenzyl group cleavage on perophoramidine intermediate (1).
2
for both R N–H (including amides) and RO–H groups.
In the course of our efforts toward the synthesis of the polycy-
clic, complex alkaloid perophoramidine, we serendipitously found
that the o-nitrobenzyl group was easily removed by using 20%
Table 1
Cleavage of nitrobenzyl groups on 3,3-dimethyloxindole
5
aqueous NaOH in methanol at 75 °C (Scheme 1). o-Nitrobenzyl
groups have been used as photocleavable protecting groups for
amides and heterocycles such as indoles, benzimidazole, and
6
,7
6
-chlorouracil as well as the more common hydroxyl group. In
addition, a method for removing p-nitrobenzyl groups on hydroxyl
groups in two steps by reduction to a p-aminobenzyl group
followed by electrochemical oxidation was disclosed by the
Kusumoto and co-workers.8 To the best of our knowledge, ours
was the first example of using simple aqueous NaOH to remove a
nitrobenzyl group from a lactam.
Entry
Substrate
R
Time (h)
Yield (%)
1
2
3
4
3a
3b
3c
3d
3a
3a
3a
-o-Nitrobenzyl
-m-Nitrobenzyl
-p-Nitrobenzyl
-Benzyl
-o-Nitrobenzyl
-o-Nitrobenzyl
-o-Nitrobenzyl
5
69
0
63
0
72
Trace
66
24
1.5
24
6.5
12
6.5
To explore the general reactivity of nitrobenzyl group cleavage
reactions by using simple aqueous NaOH, we initially chose
a
5
6
b
3
,3-dimethyl oxindole as a test substrate (Table 1). We found that
b,c
7
a
b
c
The reaction was performed in the dark.
Degassed water and methanol were used.
Purged with O .
2
⇑
Corresponding author. Tel.: +1 626 395 6064; fax: +1 626 395 8436.
E-mail address: stoltz@caltech.edu (B.M. Stoltz).
http://dx.doi.org/10.1016/j.tetlet.2014.10.006
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0

6
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S.-J. Han et al. / Tetrahedron Letters 55 (2014) 6467–6469
both ortho- and para-nitrobenzyl groups on oxindoles 3a and 3c
were smoothly cleaved under our standard conditions (entries 1
and 3). However, a meta-nitrobenzyl group as well as a simple ben-
zyl group on the oxindole nitrogen (3b and 3d) were both unreac-
tive (entries 2 and 4). Notably, the o-nitrobenzyl group was also
successfully removed even in the absence of light (entry 5). Interest-
ingly, only trace amounts of product were observed when degassed
water and methanol were used (entry 6). Furthermore, we discov-
ered that cleavage of the o-nitrobenzyl group was successful when
the degassed water and methanol were purged with oxygen gas
substrates (Table 2). o- and p-nitrobenzyl protected substrates
were easily prepared by a variety of methods, including reductive
amination, simple alkylation, EDCI coupling, and acylation. The
o-nitrobenzyl group on a highly functionalized communesin F
intermediate 5 was smoothly cleaved under our standard condi-
5
tions in good yield (entry 1). p-Nitrobenzyl groups on amide 7
and lactam 9 were also cleaved in moderate yields (entries 2 and
3). The p-nitrobenzyl group on urea 11 was also successfully
cleaved and methyl 4-nitrobenzoate was isolated as a by-product
(entry 4). An attempt to remove the p-nitrobenzyl group on sec-
ondary carbamate 13 proved unsuccessful (entry 5). Additionally,
removal of the p-nitrobenzyl group on amine 15 was facile, fur-
nishing aniline 16 in 65% yield (entry 6). Interestingly, 4-nitrobenz-
aldehyde was isolated as a by-product in this reaction, presumably
(
entry 7). We therefore concluded that oxygen was necessary for
the reaction, but light was not.
With the standard conditions in hand, we explored the scope of
the o- and p-nitrobenzyl group cleavage reactions with various
Table 2
Scope of the o- and p-nitrobenzyl deprotection reactions
Entry
Substrate
R
Time (h)
Yield (%)
1
4
70
2
3
4
12
42
1
55
10.5
94a,b
5
6
7
6
2
0
65c
32
59b (74)d
8
48
48
a
b
c
Methyl 4-nitrobenzoate was isolated as a by-product.
See Ref. 9 for details.
4
-Nitrobenzaldehyde was isolated as a by-product.
d
Yield based on recovered starting material.

S.-J. Han et al. / Tetrahedron Letters 55 (2014) 6467–6469
6469
resulting from the oxidation reaction at the benzylic position by
References and notes
oxygen dissolved in the solution. Furthermore, we successfully
removed the p-nitrobenzyl groups from ethers 17 and 19 in mod-
erate yields (entries 7 and 8). This work offers a one-step alterna-
1
.
(a) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis,
th ed.; John Wiley & Sons: New York, 2007; (b) Kocienski, P. J. Protecting
Groups; George Thieme: Stuttgart and New York, 1994.
4
8
tive to previous work by Kusumoto and co-workers. In the cases of
2. Recent examples: (a) Evans, V.; Mahon, M. F.; Webster, R. L. Tetrahedron 2014.
http://dx.doi.org/10.1016/j.tet.2014.07.080; (b) Yang, Q.; Njardarson, J. T.
Tetrahedron Lett. 2013, 54, 7080–7082; (c) Sugiura, R.; Kozaki, R.; Kitani, S.;
Gosho, Y.; Tanimoto, H.; Nishiyama, Y.; Morimoto, T.; Kakiuchi, K. Tetrahedron
2013, 69, 3984–3990.
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3477–3493; (d) Overman, L. E.; Rosen, M. D. Angew. Chem., Int. Ed. 2000, 39,
deprotection reactions from urea 11 and ether 17, the correspond-
ing hemiaminal ether and acetal intermediates were observed (see
Ref. 9). It is important to note that these deprotection conditions
are compatible with free hydroxyl groups, aminals, aryl bromides,
methyl carbamates, silyl ethers, and Boc groups present on the
substrates.
A representative procedure is as follows: To a 20 mL scintilla-
tion vial with a magnetic stir bar were added p-nitrobenzyl pro-
tected oxindole 3c (30 mg, 0.10 mmol, 1.0 equiv), MeOH (1.0 mL),
and 20% aq NaOH (1.0 mL). The reaction mixture was stirred for
4
1
596–4599; (e) Würdemann, M.; Christoffers, J. Org. Biomol. Chem. 2010, 8,
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1
02, 2122–2123.
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46–352; (b) Hennessy, E. J.; Buchwald, S. L. J. Org. Chem. 2005, 70, 7371–7375;
c) Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am.
3
(
1
.5 h at 75 °C. The reaction mixture was then cooled to 23 °C,
and extracted with EtOAc (3 Â 2 mL). The organic layer was
washed with brine, dried over MgSO , and concentrated in vacuo.
The residue was purified by column chromatography to afford
Chem. Soc. 2005, 127, 18054–18065; (d) Fetter, J.; Giang, L. T.; Czuppon, T.;
Lempert, K.; Kajtár-Peredy, M.; Czira, G. Tetrahedron 1994, 50, 4185–4200; (e)
Smith, A. B., III; Haseltine, J. N.; Visnick, M. Tetrahedron 1989, 45, 2431–2449.
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4
5.
3
,3-dimethyloxindole 4 (10.3 mg, 63% yield).
In summary, a mild and efficient deprotection protocol was dis-
6. (a) Piloto, A. M.; Costa, S. P. G.; Goncalves, M. S. T. Tetrahedron 2014, 70, 650–
6
3
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59–362; (c) Snider, B. B.; Busuyek, M. V. Tetrahedron 2001, 57, 3301–3307; (d)
covered for the cleavage of o- and p-nitrobenzyl ethers, amides,
ureas, and anilines. Since relatively few options for protection of
the amide N–H functionality exist, easily introducible and remov-
able o- and p-nitrobenzyl groups could prove useful in the synthe-
sis of alkaloids and biologically active molecules, which possess
amide functionalities. In our laboratory, this has already proven
to be the case in our formal syntheses of communesin F and per-
ophoramidine. In addition, p-nitrobenzyl protected anilines, ureas,
and alcohols were also competent substrates for this transforma-
tion, which may further its utility as a mild deprotection method
in cases where other conditions fail.
Miknis, G. F.; Williams, R. M. J. Am. Chem. Soc. 1993, 115, 536–547.
7. (a) Stutz, A.; Pitsch, S. Synthesis 1999, 930–934; (b) Pitsch, S. Helv. Chim. Acta
1997, 80, 2286–2314.
8.
Fukase, K.; Tanaka, H.; Torii, S.; Kusumoto, S. Tetrahedron Lett. 1990, 31, 389–
92.
3
9.
From the deprotection reaction of urea 11, hemiaminal ether intermediate 21
was observed in 1 h under the standard reaction conditions and intermediate 21
was converted to propyl urea 12 after 10.5 h. In addition, acetal 22 was observed
in 2 h during the deprotection reaction of ether 17, and the desired phenylethyl
alcohol 18 was isolated after 32 h.
O
O
OMe
O
2
0% aq NaOH
MeOH, 75 °C
94% yield)
N
N
N
N
N
NH
Acknowledgments
NO2
NO2
(
1
1
21
12
The authors wish to thank NIH-NIGMS (R01GM080269-01),
Amgen, and Caltech for financial support. S.-J.H. thanks Fulbright
OMe
2
0% aq NaOH
(
Foreign Student Program, No. 15111120) and the Ilju Foundation
O
O
MeOH, 75 °C
of Education & Culture (Pre-doctoral Research Fellowship) for
financial support.
OH
NO2 (59% yield;
NO2
74% yield
based on
1
7
22
18
recovered 17)
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.10.
0
06.