A survey of suitable protecting groups for the synthesis of hydroxylamines by Mitsunobu reactions

Article abstract of DOI:10.1016/S0040-4039(01)00234-9

A variety of protecting groups, commonly associated with peptide synthesis, are suitable for the N,O-protection of hydroxylamine; the resulting reagents are all suitable for N-alkylhydroxylamine synthesis using the Mitsunobu method.

Full text of DOI:10.1016/S0040-4039(01)00234-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2593–2595
A survey of suitable protecting groups for the synthesis of
hydroxylamines by Mitsunobu reactions
David W. Knight* and Mathew P. Leese
Department of Chemistry, Cardiff University, PO Box 912, Cardiff CF10 3TB, UK
Received 23 October 2000; accepted 7 February 2001
Abstract—A variety of protecting groups, commonly associated with peptide synthesis, are suitable for the N,O-protection of
hydroxylamine; the resulting reagents are all suitable for N-alkylhydroxylamine synthesis using the Mitsunobu method. © 2001
Elsevier Science Ltd. All rights reserved.
In connection with our studies of the reverse-Cope
reaction,1,2 we required access to various N-alkylhy-
droxylamines 2 containing a suitably positioned alkene
group, using an approach which was capable of deliver-
ing chiral, non-racemic material. While there are rela-
tively limited but, in many cases viable approaches to
such hydroxylamine derivatives,3 the most suitable for
the elaboration of single enantiomers appeared to be by
Mitsunobu inversion4,5 of the corresponding alcohols 1
using N,O-doubly protected hydroxylamines as the
nucleophiles. Such species have been used before in
related hydroxylamine synthesis: the bis-Boc reagent 3
can be N-allylated under PTC conditions6 by allylic
bromides and also by related allylic electrophiles using
a Pd(0) catalyst,7 and additions, both Pd-catalysed and
uncatalysed, of its sodium salt to 1-chlorocyclohex-2-
enes.8 The Mitsunobu method itself has been used to
N-alkylate the bis-phenoxycarbonyl reagent 4 by alco-
hols,9 based on much earlier work by Miller et al.,10
who first introduced this idea, using the O-benzyl
reagent 5. However, these derivatives contained pro-
tecting groups which were too stable for our purposes.
For example, removal of the Boc functions from
derivatives of reagent 3 also caused hydrolysis of other
protecting groups and gave poor yields of the required
hydroxylamines, phenylcarbamates derived from
reagent 4 were too stable and hydrogenolysis of the
O-benzyl group in derivatives of reagent 5 was incom-
patible with the presence of an alkene group in the
projected reverse-Cope substrates, despite the fact that
this can be done without NꢀO bond cleavage.11
In general bis-protected species related to reagent 3
should be good Mitsunobu nucleophiles, as the pres-
ence of two electron withdrawing groups should lower
the pKa of the NꢀH bond to be broken, a crucial
enabling feature in such chemistry.12 Herein, we report
our study of a range of alternative hydroxylamine
protecting groups which suggests that this should be a
very widely applicable method.
As representative examples, offering a range of depro-
tection possibilities, we chose the symmetrically pro-
tected mixed carbamate–carbonates 6–9, featuring Z,13
Alloc,14 Troc15 and Teoc15 functions, respectively.
These were all readily prepared by a Schotten–Bauman
procedure consisting of treating an ice-cold solution of
hydroxylamine hydrochloride in aqueous tetra-
hydrofuran containing 3.3 equivalents of sodium car-
bonate with two equivalents of the respective
O
O
O
OH
NHOH
HN
O
O
O
HN
O
OPh
OPh
HN
O
O
R2
R2
R1
R1
1
2
O
O
Ph
3
4
5
Keywords: hydroxylamines; carbamates; carbonates; protection; Mitsunobu.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00234-9

2594
D. W. Knight, M. P. Leese / Tetrahedron Letters 42 (2001) 2593–2595
chloroformate. All four products were thus secured in
80–90% isolated yield after a simple extractive work-up.
The only difficulty encountered was the ability of the
Troc derivative 8 to retain water tenanciously.15
The key Mitsunobu displacements were carried out by
the addition of diisopropyl azodicarboxylate to an ice-
cold solution of triphenylphosphine, a hydroxylamine
reagent 6–10 and an alcohol in tetrahydrofuran, fol-
lowed by stirring without external cooling for a further
2 h. During this work, it was observed that older
samples of the azodicarboxylate often delivered inferior
yields, in which cases, substitution by a recently pur-
chased sample usually restored good yields. The results
obtained are presented in Table 1; yields refer to pure,
isolated products which have been fully characterised.
The yields obtained are mostly highly viable with pri-
mary alcohols, but were slightly lower with the two
aliphatic secondary alcohols examined. In the case of
the propargylic alcohol, the displacements appeared to
proceed entirely by the expected SN2 mechanism; in no
Mixed derivatives were also readily obtainable, due to
the greater nucleophilicity of the amino group in
hydroxylamine. Thus, using the same Schotten–Bau-
man protocol but with less than an equivalent of the
chloroformate, reasonable 50–60% yields of the mono-
N-protected derivatives were isolated; subsequent repe-
tition, but with a different chloroformate, then gave
representative mixed derivatives (e.g. 10 and 11).
Returning to the original procedure, the bis-9-fluorenyl-
oxycarbonyl (Fmoc) species 12, mp 129°C, was
obtained in 79% isolated yield.
O
O
O
O
SiMe3
SiMe3
HN
O
O
O
Ph
Ph
HN
O
O
O
HN
O
O
O
CCl3
CCl3
HN
O
O
O
O
O
O
O
6
7
8
9
O
O
Fmoc
Fmoc
Fmoc
HN
O
O
O
HN
O
O
O
HN
Ph
N
Ph
O
O
Fmoc
O
O
10
11
12
13
Table 1. Isolated yields from Mitsunobu reactions of protected hydroxylamines 3, 6–10
O
OH
OH
OH
HN
O
OR1
OR2
Ph
OH
Ph
OH
O
R1 = R2 = PhCH2
87
96
83
90
78
79
73
91
75
76
82
69
69
80
69
68
55
61
--
22
38
38
17
[6]
R1 = R2 = CH2CH:CH2
[7]
R1 = R2 = CH2CCl3
[8]
R1 = R2 = (CH2)2SiMe3
--
[9]
R1 = R2 = But
[3]
R1 = CH2CH:CH2;
62
58
33
R2 = PhCH2
[10]

D. W. Knight, M. P. Leese / Tetrahedron Letters 42 (2001) 2593–2595
2595
instances were any allenic products isolated, arising
References
from SN2% reactions. Most yields were comparable or
slightly better than those obtained using the known
bis-Boc derivative 3 and were not improved by either
initial complexation of the phosphine and the azodicar-
boxylate or by using the reportedly more reactive tetra-
methyl azodiamide (TMAD) analogue.16 In contrast,
reactions involving cyclohexanol uniformly gave poorer
yields. This is a phenomenon which has been observed
previously16,17 and it would seem, at this stage, that
Mitsunobu reactions in general with cyclic secondary
alcohols should be viewed as potentially inefficient. In
no case was any decomposition of the various protect-
ing groups observed. However, perhaps not surpris-
ingly, the bis-Fmoc hydroxylamine 12 delivered a
relatively lower 58% yield of the N-benzyl derivative 13
when coupled with benzyl alcohol, presumably due to
the sensitivity of this functionality to various basic
species present in the Mitsunobu mixture.
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2. For recent leading work on the reverse-Cope reaction,
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Deprotection was accomplished using standard
methodology in the cases of derivatives of the reagents
7–10. Firstly, in all examples, the carbonate could be
cleaved regiospecifically by exposure to methanolic
potassium carbonate to give singly protected carba-
mates in 90–95% isolated yields. This could offer a
benefit in cases where the chloroformate is particularly
valuable, as much cheaper analogues, such as ethyl
chloroformate, can be used to elaborate in the carbon-
ate function in the two-step protection method. Com-
plete deprotection of derivatives of the hydroxylamines
7–10 was achieved, at least in the examples shown in
Table 1, by using Pd(Ph3P)4 in the presence of dime-
done, zinc metal or fluoride, respectively. Some exam-
ples of this are included in the following paper;18 in
general, the expected hydroxylamines were isolated in
>70% yields, but the sensitive nature of these meant
that the samples were not purified completely. The Troc
deprotections gave lower yields (40–50%), presumably
due to some NꢀO bond cleavage. In practise, such
deprotections would usually be followed by the next
synthetic step in a particular sequence, such as nitrone
formation or, as outlined in the following paper, a
reverse-Cope cyclisation.
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In summary, we have demonstrated that a range of
typical amine protecting groups are suitable for the
protection of hydroxylamines and also compatible with
the Mitsunobu reaction, suggesting that this could be a
very general method, and that the exact protecting
groups used could be tailored to the requirements of
the subsequent chemistry. Of particular significance is
that this method should allow ready access to enantio-
pure hydroxylamines from the corresponding secondary
alcohols.
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16. Tsunoda, T.; Yamamiya, Y.; Itoˆ, S. Tetrahedron Lett.
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Acknowledgements
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We thank the EPSRC Mass Spectrometry Service, UC
Swansea for the provision of high resolution Mass
Spectral data and the EPSRC for financial support.
.