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Results and discussion
In our effort to generate an acylchloride from the C-terminus of
a N-Boc protected peptidomimetic using oxalyl chloride, we
observed the concomitant formation of the deprotected N-Boc
to form the peptidomimetic with a free amine. We therefore set
out to investigate if oxalyl chloride can mildly promote the
deprotection of N-Boc substrates. Using 1-napthylamine as
a model compound, we screened oxalyl chloride with a host of
organic solvents at varying temperature conditions and equiv-
alence. We found that the deprotection reaction proceeds
poorly in neat oxalyl chloride. In addition, the reaction proceeds
to access deprotected amino substrates in CHCl3 in moderate
yields at room temperature over 24–48 h. However, under
reuxing conditions in CHCl3, N-chloroalkyl products formed,
which were detected by GC-MS even aer aqueous work-up.
Further optimization led to the identication of a reaction
condition that involved the use of ve (5) equivalents of oxalyl
chloride in methanol, which rapidly deprotects N-Boc
substrates with respectable yields (Table 1). Ultimately, the use
of three (3) equivalents of oxalyl chloride in MeOH achieved
good-to-excellent yields of deprotected tert-butyl carbamates.
Here, we report a mild, and selective deprotection of tert-butyl
carbamates using oxalyl chloride in methanol. The approach is
tolerant to several functional groups.
The general deprotection scheme is shown in Scheme 1. We
then applied this deprotection strategy to a variety of aromatic,
aliphatic, and heterocyclic substrates.
Table 2 illustrates the wide substrate scope of the oxalyl
chloride–methanol deprotection strategy. It was effective
against structurally diverse N-Boc amines; from aromatics,
heterocyclic, aliphatics to alicyclic systems.
Generally, the deprotection of N-Boc directly linked to
aromatic moieties (entries 1–9) were reasonably fast, occurring
within 3 h and with high yields, >70%. Especially, compounds
with electron withdrawing groups (EWG) including nitro, u-
oro, chloro, iodo, or bromo display a faster response to the
oxalyl chloride deprotection reagent with reactions in an hour.
Conceivably, electronic destabilization of the aryl carbamate
induced by EWG promotes its cleavage by oxalyl chloride. We
further observed that steric hindrance of methyl or isopropyl
units attached to the aromatic ring and adjacent to the N-Boc
group slows the reaction as seen for entries 2, 5, and 6. More-
over, the deprotection reaction of heteroaromatics in entry 11
Scheme 1 General deprotection reaction scheme.
deprotection of aromatics by this deprotection strategy can be
attributed to favorable electronic effects of these selected
aromatic systems. The enhanced reactivity of the aromatic
systems in contrast to their non-aromatic counterparts can be
rationalized on the basis of the weakly nucleophilic oxygen
atom of the carbonyl N-Boc atom. This oxygen is oen stabilized
or destabilized by the side group/chain directly connected to the
N-Boc group. For entries possessing aromatics and electron-
withdrawing groups, the pronounced ground-state destabiliza-
tion of the carbonyl group caused by resonance or inductive
effects, informs the increased O-atom reactivity to the electro-
philic oxalyl chloride. This phenomenon could explain why the
rate of reaction for alicyclic or heterocyclic systems were rela-
tively slower.
Hybrid drugs possess multiple pharmacological activity.36
These agents oen have sensitive functional groups and their
synthesis require protection and deprotection steps that are
mild and of broad tolerance. One such molecule of interest in
our laboratory is 5, which is a dual inhibitor of indoleamine-2,3-
dioxygenase 1 (IDO1) and DNA polymerase gamma.
Hybrid drugs possess multiple pharmacological activity.
These agents oen have sensitive functional groups and their
synthesis require protection and deprotection steps that are
mild and of broad tolerance. One such molecule of interest in
our laboratory is 5, which is a dual inhibitor of indoleamine-2,3-
dioxygenase
1 (IDO1) and DNA polymerase gamma. To
demonstrate the versatility of this deprotection strategy, we
used the N-Boc protected small-molecule precursor of 5, which
possess acid-labile functionality. The synthesis of 4 was
accomplished through, rst, N-Boc protection of D-tryptophan,
1 and the subsequent N-methylation of the indole nitrogen to
yield compound 2. Second, hydroxymenadione, 3 was synthe-
sized from a derivatized quinone and a Danishefsky diene.
Third, amide coupling of D-methyl tryptophan and hydrox-
ymenadione afforded 4 in 10% yield. Initial attempts to convert
4 to 5 using traditional acid-mediated protocols were unsuc-
cessful. For example, experiments with (1–60%) TFA in DCM,
and HCl in dioxane/methanol did not yield FC1. However,
products corresponding to the cleavage of the ester bond in EC1
were observed. We envisaged that the facile functional group
tolerance of the described oxalyl chloride/MeOH methodology
may work for our compound, 4. We therefore applied our
deprotection methodology to 5. We observed a clean trans-
formation of 4 to 5 (Scheme 2). Overall, oxalyl chloride is
a worthy N-Boc deprotection reagent for compounds with
multiple functional groups and acid-labile groups.
proceeded modestly in
4 h. Taken together, favorable
Table
1 Optimization of deprotection using N-Boc-1-naphthyl-
amine-aminea
Entry
Reaction conditions
Time (h)
Yield (%)a
1
2
3
4
5
Oxalyl chloride, neat, RT
Oxalyl chloride, CHCl3
72
24
24
24
0.5
0
23b
12
0
Oxalyl chloride, CHCl3, 50 ꢀC
Oxalyl chloride, CHCl3, 62 ꢀC
Oxalyl chloride, MeOH, RT
80b
a
Conditions: (a) (COCl)2 (1–3 equiv.), (b) (COCl)2 (3 equiv.).
24018 | RSC Adv., 2020, 10, 24017–24026
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