E. J. Snider, S. W. Wright / Tetrahedron Letters 52 (2011) 3171–3174
3173
NaBr mixture served to generate small amounts of hypobromous
acid (HOBr) in situ, and that the partial deprotection reaction that
was observed was mediated by this reagent.
addition, the Cbz protected amines 8a and 8b were likewise unaf-
fected by the conditions used to remove the MPoc group. The FMOC
protected amines 9a and 9b underwent bromination under these
conditions but were unaffected upon exposure to MPoc deprotec-
tion mediated by mercuric acetate (Table 2, entries 16 and 18) or
catalytic hydrogenation (vide infra). Not surprisingly, the Alloc pro-
tected amines 7a and 7b underwent addition of HOBr to the allyl
group.
The MPoc protected amines 4 and 5 were also subjected to cat-
alytic hydrogenation over the platinum group metals, since it is
known that cyclopropanes can be cleaved under these conditions13
and the Cbz group is most commonly cleaved by hydrogenation
over palladium. Hydrogenolysis of the cyclopropane of 4 could be
expected to afford 10 and/or the sec-butyl carbamate 11, depend-
ing upon the regioselectivity of the hydrogenolysis.
We were pleased to find that exposure of the MPoc group to
hypobromous acid (generated in situ from N-bromosuccinimide
and TFA) resulted in the rapid and complete deprotection of the
MPoc group. Again, the by-product 6 was isolated when the reac-
tion mixture was made alkaline. We therefore adjusted the workup
conditions in the following manner: the deprotection mixture was
treated with a small amount of sodium bisulfite to destroy electro-
philic bromine species,10 after which hydroxylamine hydrochloride
(15 equiv) was added. The mixture was then made alkaline with
sodium carbonate and extracted as usual.11 Under these condi-
tions, the by-product 4-bromo-2-butanone was consumed by reac-
tion with hydroxylamine and remained in the aqueous phase; the
deprotected amine was isolated in high yield.12
In order to establish that the MPoc group is orthogonal to other
common protecting groups (BOC, CbZ, Alloc, FMOC), we prepared
the model compounds 7a–10a from the amine 3 (Scheme 5). The
model compounds 7b–10b were prepared similarly from 1-N-
BOC-4-aminopiperidine.
These compounds were exposed to the hypobromous acid MPoc
deprotection protocol described above. Results are summarized in
Table 3.
H
O
N
O
N
O
11
We were surprised to observe that the BOC group was unaf-
fected by these conditions (entries 6 and 10). No amine was de-
tected when the BOC protected amines 10a and 10b were
subjected to the hypobromous acid deprotection reaction; nor were
any products of decomposition or other side reactions observed. In
Exposure of the MPoc protected amines 4 and 5 to hydrogena-
tion over palladium on carbon at 25 °C resulted in no reaction. Un-
der these conditions, the Cbz protected amines 8a and 8b were
completely deprotected.
However, hydrogenation of 4 and 5 at 100 °C resulted in com-
plete cleavage of the MPoc group to afford the amines. Neither
the BOC nor the sec-butyl carbamate could be detected. Exposure
of the BOC protected amines 10a and 10b to these conditions re-
sulted in quantitative recovery of the BOC starting materials, elim-
inating a mechanism involving hydrogenolysis of the MPoc to a
BOC group followed by thermolytic cleavage of the BOC group.
Hydrogenolysis of the MPoc group was also effected by transfer
hydrogenation using ammonium formate in ethanol at reflux.14
Remarkably, exposure of the MPoc protected amines 4 and 5 to
hydrogenation over RaneyÒ nickel or platinum on carbon at 25 or
100 °C returned only unchanged starting material.
R2
N
O
O
R1
R1
O
N
R2
O
O
7a,b
8a,b
R2
N
R1
O
N
O
R1
R2
O
In conclusion, the (1-methyl)cyclopropyl carbamate (MPoc)
group represents a new and potentially useful semi-permanent
protecting group for amines. It adds relatively little molecular
weight and has a simple 1H NMR spectrum, with no resonances be-
low 1.6 ppm. It is resistant to extremes of pH, amines, halogens and
other oxidizing agents, and to hydrogenation at ambient tempera-
ture. It is cleaved upon exposure to hypobromous acid, followed by
a hydroxylamine quench prior to workup. It is also cleaved by
hydrogenolysis over palladium at 80 °C or higher. It is orthogonal
to the commonly used BOC, Cbz, and FMOC groups, in that (a)
the conditions for MPoc cleavage do not affect BOC, Cbz, and FMOC
groups, and (b) the conditions for BOC, Cbz, FMOC (and Alloc)
cleavage do not affect the MPoc group.
9a,b
10a,b
Scheme 5. Model Alloc, Cbz, FMOC, and BOC substrates: (a) R1 = (4-piperidin-1-yl)-
p-toluamide; R2 = H; (b) R1 = R2 = 4-(p-toluamido)-piperidine.
Table 3
Evaluation of stability of Alloc, Cbz, FMOC, and BOC protecting group models towards
hypobromous acid conditions used to cleave the MPoc groupa
Entry
Substrate
Protecting group
Conv’nb (%)
1
2
3
4
5
6
7
8
9
10
4
5
MPoc
MPoc
Alloc
CBZ
FMOC
BOC
Alloc
CBZ
FMOC
BOC
100
100
Rc
NR
R
NR
R
NR
R
7a
8a
9a
10a
7b
8b
9b
10b
Acknowledgments
The authors thank the Pfizer Summer Intern Program for a sum-
mer internship (EJS) and their support of this work. The authors
also thank Professor E. J. Corey for helpful discussions.
NR
a
Experiments were performed using 0.1 mmol of substrate, 0.2 mmol of NBS,
and 0.3 mmol of TFA in 0.5 mL of 3/1 dioxane–water (v/v) at 50 °C for 2 h and
References and notes
monitored by LCMS and tlc.
b
NR indicates that no amine product was observed by LCMS or tlc of the reaction
1. (a) See, for example, Epple, R; Lelais, G.; Nikulin, V.; Westscott-Baker, L.
WO2010/6191 A1, 2010; Chem. Abstr. 152:144488.; (b) Neelamkavil, S. F.;
Boyle, C. D.; Chackalamannil, S.; Greenlee, W. J. WO2010/9195 A1, 2010; Chem.
Abstr. 152:192139.
mixture at the end of the experiment; starting material was subsequently recovered
in >90% yield.
c
Indicates that the protecting group underwent reaction with HOBr without
production of the amine.
2. Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A. Synthesis 1991, 234.
Snider, Erik J.
