The scope and regioselectivity of intramolecular N-C rearrangements of orthogonally protected sulfonamides, including cyclization to saccharin derivatives

Article abstract of DOI:10.1016/j.tetlet.2017.06.053

The scope and regiochemistry of the intramolecular N-C rearrangement involving ortholithiation of orthogonally protected sulfonamides in which an N-acyl or N-carboalkoxy group is transferred from nitrogen to the aromatic ring have been explored. Provided that excess lithium diisopropylamide is used, the process is compatible with the presence of acidic α-protons in a substituent attached to the aromatic ring or if the protons in the migrating acyl group are relatively inaccessible because of steric factors. In certain cases, the isolated product is not the ortho carboalkoxy species, but the derived saccharin; the regiochemistry found for starting materials containing a naphthalene ring is consistent with ortho lithiation at the most electron deficient position.

Full text of DOI:10.1016/j.tetlet.2017.06.053

Accepted Manuscript
The scope and regioselectivity of intramolecular N-C rearrangements of or-
thogonally protected sulfonamides, including cyclization to saccharin deriva-
tives
Amie Saidykhan, Jenessa Ebert, Hashim Ally, Richard T. Gallagher, William
H.C. Martin, Richard D. Bowen
PII:
S0040-4039(17)30784-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.053
TETL 49045
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 March 2017
12 June 2017
16 June 2017
Please cite this article as: Saidykhan, A., Ebert, J., Ally, H., Gallagher, R.T., Martin, W.H.C., Bowen, R.D., The
scope and regioselectivity of intramolecular N-C rearrangements of orthogonally protected sulfonamides, including
cyclization to saccharin derivatives, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.06.053
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The scope and regioselectivity of intramolecular N-C rearrangements of orthogonally protected
sulfonamides, including cyclization to saccharin derivatives
Amie Saidykhan,a Jenessa Ebert,a Hashim Ally,a Richard T. Gallagher,b William H. C. Martina and Richard D. Bowena,*
a
School of Chemistry and Forensic Sciences, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK
b
Oncology IMED, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, UK

1
Tetrahedron Letters
The scope and regioselectivity of intramolecular N-C rearrangements of orthogonally
protected sulfonamides, including cyclization to saccharin derivatives
Amie Saidykhan,a Jenessa Ebert,a Hashim Ally,a Richard T. Gallagher,b William H. C. Martina and Richard D.
Bowena,*
a
School of Chemistry and Forensic Sciences, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK
b
Oncology IMED, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The scope and regiochemistry of the intramolecular N-C rearrangement involving ortholithiation
of orthogonally protected sulfonamides in which an N-acyl or N-carboalkoxy group is
transferred from nitrogen to the aromatic ring have been explored. Provided that excess lithium
diisopropylamide is used, the process is compatible with the presence of acidic -protons in a
substituent attached to the aromatic ring or if the protons in the migrating acyl group are
relatively inaccessible because of steric factors. In certain cases, the isolated product is not the
ortho carboalkoxyl species, but the derived saccharin; the regiochemistry found for starting
materials containing a naphthalene ring is consistent with ortho lithiation at the most electron
deficient position.
Available online
Keywords:
Protecting groups
Sulfonamides
Rearrangement
Deprotonation
Synthetic strategy
Protection
2009 Elsevier Ltd. All rights reserved.
Aryl sulfonamides are important moieties that are found in
several biologically active molecules, examples of which are
utilized in the pharmaceutical and agrochemicals industries.1-3
Aryl sulfonamides are also used extensively in organic synthesis,
with the para-toluenesulfonyl (tosyl) group in particular
frequently being employed as a protecting group on nitrogen.4
this rearrangement is intramolecular, rather than intermolecular,
in nature.
Recently we reported a nitrogen to carbon base-catalysed
rearrangement that gives access to aryl sulfonamides substituted
in the 2-position (eg, 1 to 2, Scheme 1).5,6 This novel
rearrangement, which bears some resemblance to the acyl
transfers that occur in imides,7 was initially exploited to prepare a
number of aryl and heteroaryl sulfonamides with acyl and
carboalkoxy substituents in the aromatic ring.5 Subsequently, we
reported that this rearrangement can complicate the reactions of
orthogonally protected amino acids, where migration of a
carboalkoxy substituent from nitrogen to the tosyl protecting
group may lead to unwanted side products when these substrates
are subjected to basic conditions (eg, 3 to 4, Scheme 1).
Scheme 1: Nitrogen to carbon acyl migration in sulfonamide
derivatives. Reagents and conditions: LDA (1-2 equivalents),
-78 °C, 60-80%.
The proposed reaction mechanism invokes Directed Ortho
Metallation (DOM), as aryl sulfonamides are known to be strong
DOM directing groups that promote lithiation at the ortho
position, which in the current case would lead to the lithiated
intermediate 5.8-10 This species then undergoes an intramolecular
rearrangement in which the N-acyl or N-carboalkoxy group is
transferred from nitrogen to carbon to give 6 (Scheme 2). The
driving force for this rearrangement is thought to reflect the
relative stability of the final nitrogen based anion compared to
the previous intermediate in which the formal anionic site is on
carbon.
The rearrangement was done in tetrahydrofuran at low
temperatures (-78 °C) with lithium diisopropylamide (LDA).
When tlc showed complete consumption of the starting material,
the reaction was quenched with saturated aqueous citric acid
solution at -78 °C. Details of a typical procedure are given in the
supplementary information.
Attempts to use BuLi directly failed because the anion
behaved as a nucleophile rather than as a base. Similarly, the
rearrangement could not be performed satisfactorily at higher
temperatures. The absence of crossover products when two
different substrates were treated together with LDA indicated that

2
Entry
R1
R
14
13
i
CH3
CH3
0
78
83
0
ii
CH3
CH2CH2CH3
CH(CH3)2
CH2CH(CH3)2
CH2C(CH3)3
CH3
0
iii
iv
v
CH3
98
46
55
0
CH3
0
CH3
0
vi
vii
viii
ix
x
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH3
90
92
0
Scheme 2: DOM and incompatibility with acidic protons
CH2CH2CH3
CH(CH3)2
CH2CH(CH3)2
CH2C(CH3)3
C(CH3)3
0
The initial study5 indicated that simple transfer of an acetyl
group was not possible: attempted rearrangement of the
sulfonamide 7 did not give the desired product 8 (Scheme 2).
This finding suggested that the presence of groups containing an
additional (more) acidic proton might prevent the rearrangement,
because deprotonation of the migrating group would convert the
carbonyl group into an enolate and reduce its electrophilicity.
68
65
50
46
0
0
xi
0
Table 1: The effect of varying the structure of R
In order to investigate the influence of acidic protons remote
from the migrating group, the 4-acylsulfonamide, 10, was
prepared. When treated with excess LDA at -78 °C, clean
conversion to the rearranged product 11 occurred (Scheme 2).
Therefore, the presence of acidic protons in groups attached to
the aromatic ring does not necessarily prevent rearrangement,
provided that excess LDA is employed.
The data of Table 1 reveal that the nature of the group that
may migrate has a profound effect on the competition between
rearrangement and decomposition of the starting material. The
rearrangement may be successfully induced in certain cases
despite the presence of additional acidic protons. When the acyl
group contains an unbranched alkyl group (such as n-propyl),
decomposition of the starting material occurred, as was
previously observed for the archetypal homologue with an acetyl
group.5 In contrast, branching at the - or - carbon atom (where
the acyl substituent contains an isopropyl, isobutyl or neopentyl
group, respectively, that would be expected to offer a significant
steric obstacle to deprotonation by a large base), favours transfer
of the acyl group to the ortho position. In these more hindered
systems, clean transfer of the iC3H7CO, iC4H9CO or neoC5H11CO
substituent occurred, without decomposition of the starting
material. As was initially reported,5 transfer of acyl substituents,
such as tC4H9CO, which do not contain acidic -protons, is
easily achieved. The discovery that acyl groups in which the acyl
substituent has one or two relatively inaccessible acidic -
protons may be transferred from nitrogen to the aromatic ring
further expands the scope of this rearrangement, which may
involve reversible metallation and/or interconversion of isomeric
anions or dianions, as has been observed for N,N-
diethylbenzamides.8
Scheme 3: Reagents and conditions: i) i-PrNH2, Et3N, CH2Cl2 -5
°C, 99% ; ii) BOC2O, DMAP, py, rt, 60%; iii) LDA (3
equivalents), -78 °C, 99%.
The scope of the rearrangement was further extended by
investigating higher homologues of 7 that contain protons on the
-carbon atom of the acyl group which might either migrate or
be deprotonated. A series of compounds in which the level of
steric hindrance to deprotonation of the -carbon atom was
progressively increased was prepared. Treatment of the acyl
derivative 13 under the standard conditions for rearrangement
then either gave the rearranged product 14 or decomposed the
starting material (Scheme 4 and Table 1).
The possibility of conducting a second rearrangement to give
a sulfonamide product substituted in both ortho positions of the
aromatic ring was also explored. To this end, the product after
one rearrangement, 15, was elaborated with methyl
chloroformate and sodium hydride to give 16, which was then
1
subjected to another rearrangement in the usual way. The H
NMR spectrum of the product, 17, showed that ring closure to
form a saccharin derivative had taken place (Scheme 5).
Scheme 4: Reagents and conditions: i) NaH, THF, R’OCOCl, 0
°C – rt; iii) LDA, (3 equivalents), -78 °C. See Table 1 for yields.
Scheme 5: Reagents and conditions: i) BOC2O, DMAP, py, 92%;
ii) LDA, 1.5 equivalents -78 °C, 64%.
Saccharin derivatives had not previously been identified as
products of this rearrangement. However, in sterically hindered

3
systems such as 17, preference for the saccharin product comes
into effect. Saccharin derivatives have previously been prepared
by metallation of sulfonamides,9-12 however, the current route is
potentially useful because ring closure of the parent ester (which
would be formed by migration of the carboalkoxy group to the
aromatic ring) normally requires elevated temperatures.13
In order to probe the regiochemical preferences of the
rearrangement in more complex aromatic systems, the
naphthalene analogues 20-23 were prepared and investigated.
The migration terminus for rearrangement of the 2-substituted
naphthalenes, 18 and 19, could be either the 1 or the 3 position.
The 1H NMR spectra of 18 and 19 contained a distinctive singlet
at lowest chemical shift ( 8.45 and 8.42 ppm, respectively),
assigned to the proton in the 1 position. No such signal was
present in the 1H NMR spectra of the rearrangement products, 20
and 21. Consequently, 20 and 21 must be 1,2-derivatives, formed
by migration of the CO2R group to the 1-position (Scheme 6).
As would be expected intuitively, studies of naphthalene
derivatives have established that metallation usually occurs in the
position and ring in which the electron density is lowest.10,14,15
Therefore, the metallation of 18 and 19 at the 1-position, leading
to 20 and 21, respectively, is consistent with earlier results.16,17
Scheme 7: Reagents and conditions: i) LDA (2 equivalents), -78
°C, 60-75%.
The formation of a saccharin analogue from 22, but not 18,
may be explained in terms of the general influence of steric
factors in the reactions of naphthalene derivatives. Unfavourable
interaction between the SO2NiC3H7 entity, which has
a
considerable steric requirement, with the “peri” hydrogen atom
will tend to favour elimination of methoxide to form the
saccharin analogue, in which steric crowding will be less
pronounced than in the product with SO2NHiPr and CO2CH3
substituents in the 1 and
2 positions. In contrast, the
corresponding steric effects in 18 arising from interaction of the
“peri” hydrogen atom with the much smaller CO2CH3
substituent, are far less pronounced. Consequently, there is no
longer a thermodynamic driving force for cyclisation. The fact
that 23 does not undergo cyclisation, despite possessing a larger
CO2tBu substituent, is explicable because expulsion of tbutoxide
is unfavourable.
Scheme 6: Reagents and conditions: i) LDA (2 equivalents), -78
°C, 70%.
Parallel results were obtained for the 1-substituted species, 22
and 23, for which rearrangement to either the 2 or 8 (“peri”)
position could occur. Treatment of 22 with excess LDA (2
equivalents) under standard conditions gave the 1,2-disubstituted
1
product, 24: the H NMR spectrum of this product showed a
In conclusion, four further useful discoveries have been made
about the scope and regioselectivity of the nitrogen to carbon
rearrangement of orthogonally protected sulfonamides. Firstly,
the rearrangement may be induced even when a substituent that
could be deprotonated under the reaction conditions required for
the acyl or carboalkoxy transfer is attached to the aromatic ring,
provided that excess lithium diisopropylamide is employed, so as
to deprotonate the other group and facilitate ortho metallation.
Secondly, acyl substituents containing acidic -protons may be
caused to migrate, provided that these protons are flanked by
branched alkyl groups. Thirdly, sequential migration of two
substituents can be effected; moreover, spontaneous cyclisation
of the intermediate species sometimes occurs to form a saccharin
derivative, which would otherwise be accessible only under more
forcing conditions. Fourthly, essentially regiospecific migration
of a carboalkoxy group in naphthalene systems is possible to the
electron deficient ring to which the sulfonamide substituent is
attached. These discoveries substantially enhance the synthetic
utility of this novel rearrangement.
singlet at 1.70 ppm and a doublet at 4.92 ppm, which were
assigned to the t-butyl and NH group, respectively (Scheme 7).
Similar behaviour was observed for 23, but the isolated
compound was not the 1,2-disubstituted product, but the derived
saccharin analogue, 26. The regiochemistry of this rearrangement
is generally consistent with literature precedent: metallation
would be expected to occur at the 2-position because this ring has
the sulfonamide substituent (and is, therefore, less electron rich
than the unsubstituted ring) and is “ortho” to the sulfonamide
group. 11,14-16
A plausible mechanism by which a saccharin analogue could
be formed from 22 is direct elimination of a methoxide anion
from the tetrahedral intermediate, 25 (Scheme 7). The formation
of a saccharin analogue from the intermediate tetrahedral anion
formed from 23 would entail elimination of a tbutoxy anion,
which is a distinctly poorer leaving group than a methoxy anion.
References and notes
1.
2.
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4.
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H.; Arvidsson, P. L., Angew. Int. Ed. Engl., 2017, 56, 4100-4109.
Kocienski, P. J., Protecting Groups 3rd edition, Thieme: Stuttgart,
2000.

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Tetrahedron Lett., 2015, 56, 66-68.
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Masmali, A. H., ARKIVOC, 2015, 19-47
12. Ould Aliyenne, A.; Khiari, J. E.; Kraıem, J.; Kacem, Y.; Hassine,
B. B., Tetrahedron Lett., 2006, 47, 6405-6408.
13. Wrobel, J.; Dietrich, A.; Woolson, S. A.; Millen, J.; McCaleb, M.;
Harrison, M. C.; Hohman, T. C.; Sredy, J.; Sullivan, D., J. Med.
Chem., 1992, 35, 4613-4627.
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105-108.
Supplementary Material
Illustrative experimental procedures and full experimental
data for new compounds are provided.

5
Highlights

The rearrangement can tolerate acidic protons.

In sterically demanding substrates the
saccharine is formed directly.

The rearrangement of naphthalene derivatives
is regioselective.