A New Method for the Cleavage of Nitrobenzyl Amides and Ethers

Abstract

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.

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.^1,2 However, despite considerable effort, relatively few protecting groups have been developed for the amide N-H (e.g., PMB, TBS, Benzyl, SEM, allyl, etc.).³ Consequently, limitations associated with cleavage of amide protecting groups often arise.⁴ Herein, we report o- and p-nitrobenzyl groups as easily introducible and removable protecting groups for both R₂N-H (including amides) and RO-H groups.

In the course of our efforts toward the synthesis of the polycyclic, complex alkaloid perophoramidine, we serendipitously found that the o-nitrobenzyl group was easily removed by using 20% aqueous NaOH in methanol at 75 °C (Scheme 1).⁵ o-Nitrobenzyl groups have been used as photocleavable protecting groups for amides and heterocycles such as indoles, benzimidazole, and 6-chlorouracil as well as the more common hydroxyl group.^6,7 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 group.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.

Scheme 1.

o-Nitrobenzyl group cleavage on perophoramidine intermediate (1).

To explore the general reactivity of nitrobenzyl group cleavage reactions by using simple aqueous NaOH, we initially chose 3,3-dimethyl oxindole as a test substrate (Table 1). We found that 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 benzyl group on the oxindole nitrogen (3b and 3d) were both unreactive (entries 2 and 4). Notably, the o-nitrobenzyl group was also successfully removed even in the absence of light (entry 5). Interestingly, only trace amounts of product were observed when degassed water and methanol were used (entry 6). Furthermore, we discovered that cleavage of the o-nitrobenzyl group was successful when the degassed water and methanol were purged with oxygen gas (entry 7). We therefore concluded that oxygen was necessary for the reaction, but light was not.

Table 1.

Cleavage of nitrobenzyl groups on 3,3-dimethyloxindole.

Entry	Substrate	R	Time (h)	Yleld (%)
1	3a	-o-nitrobenzyl	5	69
2	3b	-m-nitrobenzyl	24	0
3	3c	-p-nitrobenzyl	1.5	63
4	3d	-benzyl	24	0
5a	3a	-o-nitrobenzyl	6.5	72
6b	3a	-o-nitrobenzyl	12	trace
7b,c	3a	-o-nitrobenzyl	6.5	66

^aThe reaction was performed in the dark.

^bDegassed water and methanol were used.

^cPurged wlth O₂.

With the standard conditions in hand, we explored the scope of the o- and p-nitrobenzyl group cleavage reactions with various 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 conditions in good yield (entry 1).⁵ 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 secondary carbamate 13 proved unsuccessful (entry 5). Additionally, removal of the p-nitrobenzyl group on amine 15 was facile, furnishing aniline 16 in 65% yield (entry 6). Interestingly, 4-nitrobenzaldehyde was isolated as a by-product in this reaction, presumably resulting from the oxidation reaction at the benzylic position by oxygen dissolved in the solution. Furthermore, we successfully removed the p-nitrobenzyl groups from ethers 17 and 19 in moderate yields (entries 7 and 8). This work offers a one-step alternative to previous work by the Kusumoto group.⁸ In the cases of deprotection reactions from urea 11 and ether 17, the corresponding 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.

Table 2.

Scope of the o- and p-nitrobenzyl deprotecion reactions.

Entry	Substrate	Product	Time (h)	Yield (%)
1			4	70
2			12	42
3			1	55
4			10.5	94a,b
5			6	0
6			2	65c
7			32	59b (74)d
8			48	48

^aMethyl 4-nitrobenzoate was isolated as a by-product.

^bSee Ref. 9 for detail.

^c4-Nitrobenzaldehyde was isolated as a by-product.

^dYield based on recovered starting material.

A representative procedure is as follows: To a 20 mL scintillation vial with a magnetic stir bar were added p-nitrobenzyl protected 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 1.5 h at 75 °C. The reaction mixture was then cooled to 23 °C, and extracted with EtOAc (3×2 mL). The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. The residue was purified by column chromatography to afford 3,3-dimethyloxindole 4 (10.3 mg, 63% yield).

In summary, a mild and efficient deprotection protocol was discovered 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 removable o- and p-nitrobenzyl groups could prove useful in the synthesis 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 perophoramidine. In addition, p-nitrobenzyl protected anilines, ureas, and alcohols were also competent substrates for this transformation, which may further its utility as a mild deprotection method in cases where other conditions fail.