Novel nitrogen to carbon rearrangement forming nicotinic acid sulfonamides

Article abstract of DOI:10.1016/j.tetlet.2013.06.105

The synthesis of nicotinic acid derivatives via the base-mediated nitrogen to carbon rearrangement of N-substituted pyridine 2-sulfonamides is reported. This noteworthy isomerisation of the pyridine sulfonamide protecting group has implications for the use of this protecting group in synthesis.

Full text of DOI:10.1016/j.tetlet.2013.06.105

Accepted Manuscript
Novel nitrogen to carbon rearrangement forming nicotinic acid sulfonamides
Evelynne Rushingwa, Hadijatou K. Touray, Richard D. Bowen, Richard T.
Gallagher, William H.C. Martin
PII:
S0040-4039(13)01081-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.06.105
TETL 43158
Reference:
To appear in:
Tetrahedron Letters
Please cite this article as: Rushingwa, E., Touray, H.K., Bowen, R.D., Gallagher, R.T., Martin, W.H.C., Novel
nitrogen to carbon rearrangement forming nicotinic acid sulfonamides, Tetrahedron Letters (2013), doi: http://
dx.doi.org/10.1016/j.tetlet.2013.06.105
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Novel nitrogen to carbon rearrangement forming nicotinic acid sulfonamides
Evelynne Rushingwa, Hadijatou K. Touray, Richard D. Bowen, Richard T. Gallagher, William H. C.
Martin*
O
O
R
LDA, -78 oC
R
H
N
N
Ph
N
S
Ph
N
S
O O
O O

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Novel nitrogen to carbon rearrangement forming nicotinic acid sulfonamides
Evelynne Rushingwaa , Hadijatou K. Touraya, Richard D. Bowena, Richard T. Gallagherb, William H. C.
Martina
a Chemical and Forensic Sciences, School of Applied 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 synthesis of nicotinic acid derivatives via the base-mediated nitrogen to carbon
rearrangement of N-substituted pyridine 2-sulfonamides is reported. This noteworthy
isomerisation of the pyridine sulfonamide protecting group has implications for the use of this
protecting group in synthesis.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Nicotinic acids
Sulfonamides
Protecting groups
Rearrangement
The pyridine sulfonamide
1
and nicotinic acid
2
The work presented in this communication establishes that the
pyridine sulfonamide protecting group can participate in a base-
mediated nitrogen to carbon rearrangement to yield potentially
useful nicotinic acid sulfonamide derivatives.
functionalities are two important structural subunits whose
properties have been exploited in a number of biologically
important molecules. Derivatives of nicotinic acids are a very
common structural motif in natural product and medicinal
chemistry, with nicotinic acid itself being classified as one of the
80 essential nutrients required for human health. Commercially
important nicotinic acids include the vasodilatory drug,
Nicorandil and the respiratory stimulant, Nikethamide. As such,
the development of novel approaches to nicotinic acids continues
to engage the interest of synthetic chemists and numerous
approaches to this important system have been reported.1
Pyridine sulfonamides have been shown to act as chelators of
metal ions2 and heteroaromatic sulfonamides have been found to
be effective inhibitors of carbonic anhydrase.3 A reliable route to
derivatives of nicotinic acid sulfonamides would therefore seem
to offer the opportunity to explore further the properties of these
biologically important subunits.
As part of a study being undertaken in our laboratory into the
alkylation of amino acid derivatives that could potentially exploit
the property of axial chirality,5 we required access to
orthogonally protected amino acid derivatives. The pyridine-2-
sulfonamide entity has found increasing use as a protecting group
in synthetic chemistry.6 It is resistant to a number of chemical
conditions; moreover, the products from sulfonamide protection
tend to be crystalline solids. We hypothesised that the use of the
pyridine sulfonamide group in conjunction with a carbamate
protecting group would give rise to the conditions whereby axial
chirality along the carbon nitrogen bond could be established.
To this end, treatment of 2-mercaptopyridine 3 with sodium
hypochlorite
and
hydrochloric
acid
gave
2-
pyridinesulfonylchloride 4.7 It was found advantageous not to
isolate this compound as it was unstable to air, and instead
immediate treatment of the crude solution of 4 with the tert-butyl
ester of valine gave the corresponding sulfonamide . Protection
of the sulfonamide as its tert-butyl carbamate delivered 5 as a
crystalline solid in excellent overall yield. With orthogonally
protected valine in hand, we next investigated its treatment with
base to form the ester enolate, and subsequent trapping of the
enolate with methyl iodide to give 6. However, upon treatment of
O
NRR'
OR
N
S
O O
N
1
2
Figure 1: The pyridine sulfonamide and nicotinic acid cores
The chemistry arising from the interaction of protecting
groups with substrates and reagents can frequently lead to
unexpected difficulties in synthetic manipulations. Sometimes,
however, the resultant chemistry can give rise to useful
transformations in their own right.4
o
5 with LDA at -78 C, we were surprised to note that within two
minutes a new lower-running spot was observed by TLC.
Complete conversion to this new compound was achieved within
5 minutes, with no methyl iodide having been added.
*Corresponding author. Tel.: +44 1274233362
E-mail address: w.martin@bradford.ac.uk

2
Tetrahedron
OtBu
O
OtBu
O
O
S
O
S
i
ii, iii
iv
X
OtBu
N
Cl
OtBu
N
N
N
SH
N
S
N
O O
O O
O O
3
6
5
4
Scheme 1. Reagents and conditions: (i) HCl, NaOCl, CH2Cl2, 0 oC - rt. (ii) t-butylvaline ester, Et3N, CH2Cl2,
rt. (iii) Boc2O, Et3N, CH2Cl2, rt. (iv) LDA, -78 oC, CH3I, THF
Irrespective of the precise mechanism, subsequent
rearrangement of either species would then generate the nicotinic
acid derivative 12. It can be suggested that the driving force for
the amino-Chan rearrangement is the lower pKa of the resultant
carbamate anion compared to that of the ester enolate.
Presumably the analogous difference in the pKa of the conjugate
acids of the initial anion and the rearranged product anion is also
a driving force in the present case.
The compound isolated was subjected to spectral analysis to
determine its structure. The FTIR spectrum contained diagnostic
peaks at max 3200 cm-1 (medium intensity, N-H stretch of
sulfonamide), 1727 cm-1 (strong, C=O stretch of aromatic ester),
1307 and 1138 cm-1 (strong, asymmetric and symmetric S=O
stretches, respectively, of conjugated sulfonamide). 1H NMR
showed the loss of H-3 in the pyridine ring and an HMBC
experiment gave a correlation between an ester carbon and H-4
of the pyridine ring. High resolution ESI+ mass spectrometry (on
the prominent MH+ ion) established that the product had the same
molecular formula (C19H30N2O6S) as 5. The nicotinic acid
derivative 7 was consistent with all the spectroscopic data
Intrigued to determine the scope of this reaction, a number of
N-substituted pyridine sulfonamides were synthesised. Pyridine
sulfonyl chloride 4 was prepared as described above, and then
addition of benzylamine gave sulfonamide 13 as a crystalline
solid.10 Treatment of 13 with sodium hydride and the appropriate
acyl chloride, or in the case of entry 6, with the anhydride, gave a
range of N-substituted pyridine sulfonamide products 14 in
moderate to good overall yield. In certain cases where the acid
chloride bears an acidic proton the reaction mixture had to be
treated with a second equivalent of base and acid chloride to
bring the reaction to completion.
obtained.
HMBC interaction
H
N
O
OtBu
O
H
N
S
O O
OtBu
7
Figure 2: Spectral indication of structure
O
S
O O
14
R
i
ii
H
The transformation represented by 5 to 7 can be thought of as
a base-mediated nitrogen to carbon rearrangement. Several
examples of this type of reaction have been reported in the
literature, most notably in the amino-Chan reaction8 where, upon
treatment with a strong base, an acyl group is transposed from the
nitrogen to the carbon of 8 to give the β-ketoester anion 9. In the
current case, the initial anion on pyridine has been formed
exclusively at the 3-position. This, coupled with the fact that the
protons on pyridine cannot normally be removed with LDA,
would seem to suggest that either the sulfone or the carbamate
was involved in the deprotonation step, via formation of a chelate
species involving either a 5 or 7-membered ring, 10 and 11,
respectively (Figure 3).9
N
N
Cl
N
S
CH2Ph
N
CH2Ph
N
S
O O
O O
5
13
Scheme 2. Reagents and conditions: (i) PhCH2NH2, Et3N,
CH2Cl2, 98% (ii) NaH, THF, RCOCl, 0 oC - rt or RCO2COR,
DMAP, py.
Table 1 – Formation of N-acyl derivatives
Entry
R
Yielda
O
O
O
1
2
3
4
5
6
7
8
C6H5
OCH3
OC(CH3)3
C(CH3)3
CHClCH3
CH3
80%
75%
95%
75%
78%
95%
82%
77%
75%
92%
OR
N
OR
Boc OLi
NBoc
8
9
Li
O
OtBu
O
O
O
S
N
C5H11
O
N
OtBu
CH(C6H5)CH2CH3
CH2CH2CHCH2
N-CH2CHCH2
OtBu
9
O
10
10b
N
N
S
O O
OtBu
O
OtBu
Li
a
12
Isolated yield after purification by flash column
O
N
chromatography
b Formed by treatment of 13 with NaH, and CH2CHCH2Br
S
OtBu
N
O
O
11
Figure 3: The amino-Chan rearrangement - comparison with the
present case

3
The N-substituted pyridine sulfonamides were then subjected
to the rearrangement conditions of treatment with 1.5 equivalents
of LDA at -78 C, to give, in most cases, the corresponding
nicotinic acid compounds 15 (Scheme 3). Reaction times were
generally short, with complete consumption of the starting
material being observed within 5 minutes by TLC. Two cases did
not deliver the desired product, however. The acetyl derivative,
Table 1 entry 6, gave an intractable mixture of products, possibly
due to competing deprotonation on the acetyl group. The N-allyl
In conclusion, a new method is presented for the synthesis of
potentially biologically interesting nicotinic acid sulfonamide
derivatives, with the possibility of quickly forming a library of
related compounds. The latent reactivity of the 2-
pyridinesulfonamide protecting group is also highlighted, with
the observation that the pyridine can participate in base-mediated
rearrangement chemistry.
o
References and notes
substituted compound, Table
1
entry 10, returned the
sulfonamide 13, presumably due to competing nucleophilic
displacement of the allyl group to give the nitrogen anion.
1. Hill, M, Chem. Eur. J. 2010, 16, 12052-12062.
2. Beloso, L.; Castro, J.; Garcia-Vazquez, J. A.; Perez-Lourido, P.;
Romero, J.; Sousa, A. Inorg. Chem. 2004, 44, 336-341.
3. Nishmori, I.; Vullo, D.; Innocenti, A.; Scozzafra, A.; Supuran, C.
T. Bioorg. Med. Chem. Lett. 2005, 15, 3828-3833.
4. Kocienski, P. J., Protecting Groups 3rd edition, Thieme: Stuttgart,
2000.
5. Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K. Angew. Int. Ed.
Engl., 2000, 39, 2155-2157.
6. Goulaouic-Dubois, C.; Guggisberg, A.; Hesse, M. J. Org. Chem.
1995, 60, 5969-5972.
7. Diltz, S.; Aguirre, G.; Ortega, F.; Walsh, P. J. Tetrahedron:
Asymmetry, 1997, 8, 3559-3562.
8. Nemoto, T.; Harada, T.; Matsumoto, T., Hamada, Y. Tetrahedron.
Lett. 2007, 48, 6304-6307.
9. Marsais, F.; Cronnier, A.; Trecourt, F.; Queguiner, G. J. Org.
Chem. 1987, 52, 1133-1136
However,
a number of nicotinic acid derivatives were
successfully synthesized, with both esters and ketones formed
cleanly and in good yield (Figure 4).
O
O
S
R
i
R
H
N
N
N
S
CH2Ph
N
CH2Ph
O O
O O
15
14
Scheme 3. Reagents and conditions: (i) LDA, -78 oC, THF
10. Wright, S.W.; Hallstrom, K. N., J. Org. Chem. 2006, 71, 1080-
1084.
O
O
OMe
Ph
O
O
N
N
S
S
CH2Ph
CH2Ph
O
N
O
N
H
H
78 %
Supplementary Material
82%
O
O
General experimental procedures and NMR data for all new
compounds are provided.
OtBu
tBu
O
O
N
N
S
S
CH2Ph
CH2Ph
O
N
H
O
N
H
86 %
88 %
O
O
C5H11
Cl
O
O
N
N
S
S
CH2Ph
CH2Ph
O
N
H
O
N
H
96%
76%
O
O
Ph
O
O
N
N
S
S
CH2Ph
CH2Ph
O
N
H
O
N
H
85 %
90 %
Figure 4. Structures of the synthesized nicotinic acid
sulfonamides