Intramolecular NC rearrangements involving sulfonamide protecting groups

Article abstract of DOI:10.1016/j.tetlet.2014.10.041

The reaction of amine derivatives orthogonally protected with an aryl sulfonamide and a carbamate, via a base-mediated nitrogen to carbon rearrangement is reported. This noteworthy isomerisation has implications for the use of sulfonamide protecting group

Full text of DOI:10.1016/j.tetlet.2014.10.041

Accepted Manuscript
Intramolecular N-C rearrangements involving sulfonamide protecting groups
Amie Saidykhan, Richard D. Bowen, Richard T. Gallagher, William H.C.
Martin
PII:
S0040-4039(14)01724-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.041
TETL 45270
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
12 August 2014
11 September 2014
8 October 2014
Please cite this article as: Saidykhan, A., Bowen, R.D., Gallagher, R.T., Martin, W.H.C., Intramolecular N-C
rearrangements involving sulfonamide protecting groups, Tetrahedron Letters (2014), doi: http://dx.doi.org/
1
0.1016/j.tetlet.2014.10.041
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Intramolecular N-C rearrangements involving sulfonamide protecting groups
*
Amie Saidykhan, Richard D. Bowen, Richard T. Gallagher , William H. C. Martin

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Intramolecular N-C rearrangements involving sulfonamide protecting groups
a
a
b
a
Amie Saidykhan , Richard D. Bowen , Richard T. Gallagher , William H. C. Martin 
a
Chemical and Forensic Sciences,University of Bradford, Bradford BD7 1DP, UK
Oncology IMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The reaction of amine derivatives orthogonally protected with an aryl sulfonamide and
a carbamate, via a base-mediated nitrogen to carbon rearrangement is reported. This
noteworthy isomerisation has implications for the use of sulfonamide protecting
groups in synthesis.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Protecting groups
Sulfonamides
Rearrangement
Deprotonation
Synthetic strategy
Protection
Protecting groups and protecting group strategies are an
integral part of modern synthetic chemistry. Complex synthesis
conversion into a more polar material was noted by TLC
analysis. The fact that a reaction had occurred before addition of
the alkylating agent meant that it was not possible to form 4
using this synthetic pathway; instead a single and unexpected
new product had formed (Scheme 1).
1
requires that functional groups are masked for certain synthetic
steps, prior to being revealed when reactivity is required at that
particular site in the molecule. The requirements that make a
good protecting group are well accepted: they should be easy to
introduce, inert to subsequent reaction conditions, and then easy
to remove. When a robust protecting group is required for
nitrogen, sulfonamides are quite often the derivatives of choice.
They are straightforward to form from their precursors and are
stable to a number of harsh reaction conditions. The para-
toluenesulfonamide (tosyl) protecting group, for example, is
reported to be stable to strong bases such as lithium
diisopropylamide (LDA) and, as such, is widely and successfully
1
used in synthetic chemistry. On occasion, however, protecting
groups can cease to be bystanders in a reaction, and their
reactivity can lead to unwanted, and to the unprepared,
2
unexplained side-products. This communication reports how
nitrogen-containing molecules orthogonally protected with a
sulfonamide and a carbamate can undergo a base-mediated
intramolecular rearrangement involving the sulfonamide
protecting group.
Scheme 1: Reagents and conditions: i) p-CH
CH Cl , 95% ii) Boc O, DMAP, CH Cl , 78%, iii) LDA, THF,
MeI, -78 C
3 6 5 2 3
C H SO Cl, Et N,
2
2
2
2
2
o
This unexpected product was subjected to spectral analysis to
determine its structure. The FTIR spectrum contained a strong
As part of a research programme focused on investigating the
alkylation of amino acid derivatives, access to an orthogonally
-1
peak at 1718 cm , indicative of the C=O stretch of an aromatic
1
ester. The H NMR spectrum showed the absence of one proton
3
substituted amino acid was required. As such, the t-butyl ester of
ortho to the sulfonamide group of the benzene ring, and an
HMBC experiment gave a correlation between an ester carbon
and the proton in the benzene ring ortho to the methyl in the
valine (1) was treated with para-toluenesulfonyl chloride to give
2
, which was then converted into its tert-butyl carbamate
derivative 3 in good yield. With 3 in hand, its low-temperature
+
benzene ring (Figure 1). High-resolution ESI mass spectrometry
deprotonation and subsequent alkylation were investigated.
+
(
on the prominent MH ion) established that the product had the
o
However, when 3 was treated with LDA at -78 C rapid
—
——

Corresponding author. Tel.: +441274233362; e-mail: wmartin@bradford.ac.uk

2
same molecular formula (C H NO S) as 3. These data
2
1
33
6
indicated that a rearrangement had occurred to give the ester, 5.
Figure 1: HMBC confirming the structure of compound 5.
Evidence for the possible mechanism by which the product
was formed was found in the following observations: a single
regioisomer of the product was isolated, in which a new ester
moiety was positioned ortho relative to the existing sulfonamide
linkage, and LDA is not a strong enough base to deprotonate the
aromatic ring directly. These factors point towards a directed
Scheme 3: Reagents and conditions: i) i-PrNH , Et N, CH Cl , ii)
LDA, THF, ROCOCl, -78 C.
2
3
2
2
o
The orthogonally protected isopropylamine derivatives were
o
treated with LDA at -78 C. Sulfonamides with a para-methyl
and
para-methoxy
group,
and
those
based
on
4
ortho metallation (DOM) having occurred. As such,
benzenesulfonamide itself, showed rapid conversion (less than
10 minutes) to give the corresponding aromatic ester derivatives.
Intriguingly, the para-nitrosulfonamide (nosyl) derivatives
showed no reaction and unreacted starting material was
recovered (Scheme 4, Table 1).
deprotonation of 3 could give rise to chelated structure 6, where
the incipient anion is stabilised by the sulfonamide and/or the
carbamate. Rearrangement of this intermediate would then give
the observed product 7 (Scheme 2).
.
o
Scheme 4: Reagents and conditions: i) LDA, THF, -78 C
Scheme 2: Possible mode by which DOM could occur in
compound 3.
Entry
Substrate
Product
R
R
Yield (%)
1
16
20
24
17
21
25
18
22
26
19
23
27
28
29
30
31
32
33
34
35
36
--
Me
Me
Me
H
tBu
Et
85
Although sulfonamides are known to be strong activators for
5
,6
DOM reactions, intramolecular nitrogen to carbon transfer of
an electrophile has not, as far as has been ascertained from the
literature, been reported in systems such as those presented here.
As such, the fact that an intramolecular rearrangement has been
effected by LDA in the present case is noteworthy and will need
to be considered when planning a protecting group strategy in
substrates of this kind.
2
78
3
Me
tBu
Et
83
4
92
5
H
78
6
H
Me
tBu
Et
84
The generality of the rearrangement was then explored by
7
OMe
OMe
OMe
90
synthesising
a
number
of
orthogonally
protected
8
93
isopropylamines. Treatment of isopropylamine with the
corresponding sulfonyl chloride 8-11 gave the sulfonamides 12-
5 in excellent yields. Each of the sulfonamides was then
converted into either their tert-butyl, ethyl or methyl carbamates
to give compounds 16-19, 20-23 and 24-27, respectively, all in
good yield (Scheme 3).
9
Me
tBu
Et
80
1
10
NO
No reaction
No reaction
No reaction
2
1
1
1
2
--
NO2
NO2
--
Me
Table 1
The fact that the para-nitrosulfonamides (entries 10, 11 and
1
2, Table 1) were stable under the reaction conditions, and gave
unreacted starting material was surprising. On first inspection, it
might be supposed that the electron-withdrawing group would
stablise the anion formed by deprotonation of the aromatic ring.
Indeed, a colour change to give a deep-yellow solution was noted
upon addition of LDA to the para-nitrosulfonamide derivatives, a
colour transition that is normally associated with deprotonation

3
of the substrate. The possibility that the nosyl derivatives were
being deprotonated ortho to the nitro group leading to an
unreactive anion that could not undergo intramolecular
rearrangement was investigated. Compound 24 was treated with
o
LDA at -78 C, and was then immediately quenched with D O;
2
no incorporation of deuterium in the recovered sulfonamide was
observed. The fact that the nosyl group is inert to the reaction
conditions, whilst being difficult to explain, presents a solution to
the protecting group incompatability issue identified in this
communication.
In conclusion, it has been shown that orthogonally protected
amines where one of the protecting groups is a sulfonamide and
the other
a carbamate are susceptible to base-induced
rearrangement. However, the para-nitrosulfonamide (nosyl)
protected amines did not undergo this rearrangement. This leads
to the important conclusion that in situations where
rearrangement might be a problem that the nosyl protecting
group should be the protecting group of choice.
Acknowledgments
Messrs. Bilal Majed and Sarmed Bukhari are thanked for their
initial investigations. Dr Kamyar Afarinkia and Dr Helen
Sheldrake are thanked for their useful comments.
References and notes
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1
2
3
4
5
6
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Kocienski, P. J., Protecting Groups 3 edition, Thieme: Stuttgart,
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Supplementary Material
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