A convenient synthetic route to sulfonimidamides from sulfonamides

Article abstract of DOI:10.1039/c4ra14056g

Sulfonimidamides were prepared in a one-pot transformation from sulfonamides, through nucleophilic substitution of sulfonimidoyl chlorides formed in situ with different amines. This methodology represents a convenient, safe, and easily accessible synthetic route to sulfonimidamides.

Full text of DOI:10.1039/c4ra14056g

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A convenient synthetic route to sulfonimidamides
from sulfonamides†
Cite this: RSC Adv., 2015, 5, 4171
*
Yantao Chen and James Gibson
Received 7th November 2014
Accepted 8th December 2014
DOI: 10.1039/c4ra14056g
www.rsc.org/advances
Sulfonimidamides were prepared in a one-pot transformation from chlorides or sulnamides, is usually poor compared to the
sulfonamides, through nucleophilic substitution of sulfonimidoyl corresponding sulfur(VI) compounds. Oxidative chlorinating
chlorides formed in situ with different amines. This methodology reagents, such as tert-butyl hypochlorite, are high-energy or
represents a convenient, safe, and easily accessible synthetic route to unstable compounds that require special care.14
sulfonimidamides.
Levchenko also used phosphorus pentachloride (PCl5) as
direct chlorinating reagent.15 In 1993, Roy synthesised sulfoni-
midates from SICs, which were directly synthesised from tri-
Sulfonamides (SAs) are a popular motif in drug discovery and
development.1 Sulfonimidamides (SIAs) as the isosteric
replacements for SAs have received less attention from the
scientic community than SAs, presumably due to the lack of
commercial availability and synthetic accessibility. Chemistry
of SIAs has focussed on three perspectives: (1) chemistry on the
sp2 N atom;2 (2) chemistry on the sp3 N atom;3 (3) utilisation of
the chirality in asymmetric hydrogenation,4 metal-catalyzed
C–H amination and aziridination,5 and serving as chiral
ligands in aldol reactions6 and Henry reactions.7
Recently SIAs have been proposed as bioisosteres of SAs and
carboxylic acids.8 The replacement of SAs with SIAs can be a
useful approach for the optimisation of lead compounds in
drug discovery. However this replacement has been little-used,
presumably due to the limitation of the synthesis of sulfoni-
midoyl chlorides (SICs) – the key intermediates to SIAs.
The rst reported approaches to SICs were from Levchenko
(Scheme 1).9
methylsilyl
(TMS)
group
substituted
SAs
and
triphenyldichlorophosphorane (Ph3PCl2) – a replacement of
PCl5.14b
To our knowledge, a one-pot methodology for the synthesis
of SIAs from SAs has not been reported. We herein describe a
one-pot procedure for the synthesis of SIAs: (1) synthesis of
fresh Ph3PCl2; (2) in situ synthesis of SICs from SAs; (3) nucle-
ophilic substitution with amines or anilines to afford SIAs; and
(4) acidic workup on the tert-butyl dimethylsilyl group (TBS)
protected intermediates to afford the products in moderate to
excellent yields (Scheme 2).
Because primary SAs will react with in situ formed SICs,
sulfonamide-N protection is necessary. In this work we changed
TMS, which was used by Roy, into the TBS group as it proved to
be more stable (relevant experiments available in the ESI†).
Additionally, the TBS protected SIAs can be isolated by column
chromatography. Fig. 1 shows the structure of substrates 1–3
that were used in this work and the relevant intermediates –
SICs 1a–3a, and 2b, which was only used for the stability study.
Reaction conditions were screened using 0.1 mmol of
substrate 3 (Table 1). The relevant SIC 3a was reported by Tillett
through the reaction of 4-methylbenzene-1-sulfonyl chloride
and N,4-dichlorobenzamide – an intermediate that was syn-
thesised from 4-chlorobenzamide.16 In our work, it was directly
The oxidative route (approach 1) is based on the reaction of
sulnyl chlorides with N-halogen compounds.10 Contemporary
routes employ oxidative chlorinating reagents such as chlorine,
N-chlorobenzotriazole,11 tert-butyl hypochlorite,12 anhydrous
chloramine-T,13 and N-chlorosuccinimide2,8b,14a to synthesise
SIAs from sulnamide substrates. However, this approach has
limitations as the accessibility and ease of handling of sulnyl
AstraZeneca Innovative Medicines Cardiovascular and Metabolic Diseases, S-431 83
¨
Molndal, Sweden. E-mail: yantao.chen@astrazeneca.com; yantaochen.se@gmail.
com; Fax: +46-31-776-3710; Tel: +46-31-706-5577; +46-72-589-9827
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data for compounds 1, 2, 4a–k, 5a–f, and 6a–i. See DOI:
10.1039/c4ra14056g
Scheme 1 Literature precedent to make SICs.
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tautomerism of SIAs by Arvidsson was based on theoretical
1
calculations.2 In our work H NMR (DMSO-d6 as solvent for all
compounds) was used to determine the stable forms of tauto-
mers. Compounds 4a, 5a, and 5b are TBS-protected products.
Therefore, protons on N can only sit on the sp3 N atoms. The
chemical shis of these protons (S–NH2) are >6.10 ppm. Inter-
estingly, the chemical shis of the protons on the sp2 N atoms
(S]NH) in compounds 4d, 4e are generally below 4.5 ppm. This
chemical shi difference of protons on sp3 N and sp2 N atoms
was applied to facilitate the structure determination. For
instance, two different NH peaks were found in compounds 4c,
4h, 4i, and 5e. This means that there is no tautomerism (in NMR
solvent) aer TBS deprotection. On the other hand, only one
relevant peak is found in compounds 4f, 4g, 4j, 4k, and 5d. One
can conclude that tautomerism happens on those compounds
to give the more stable forms (in NMR solvent). The similarity of
4-Br-phenyl and 4-Cl-phenyl groups in 6f makes a clear structure
determination difficult. The observed NH chemical shis in
compounds 6e, 6f are very similar, and they are different from
the NH chemical shi in 6g. We speculate that a rapid proton
exchange exists in 6e and 6f, but not in 6g. From an electro-
negativity perspective, the structure of 6f is empirically
proposed as shown in Table 4. In general, all compounds in
Table 4 keep the S]N double bonds connecting to the 4-Cl-
phenyl groups without tautomerism.
Scheme 2 One-pot preparation of SIAs starting from Ph3P (this work).
Fig. 1 SAs (1–3) and key intermediates SICs (1a–3a).
synthesised from 3. In practice, few drops of the reaction
mixture of SIC 3a were mixed with an excess of ethylamine to
convert 3a into N-ethyl sulfonimidamide 3b, which could be
detected by LCMS.
For substrate 3, entry 4 showed the best results. For
substrates 1 and 2, we kept the same conditions as in entry 4,
but optimised temperature and reaction time. The optimal
conditions for these three substrates were shown in the tables
below. When TBS protecting group was applied, some of the
products were deprotected to give nal products (Tables 2–4).
Migration of a proton from one nitrogen atom to another in a
SIA structure leads to tautomerisation. A recent report on
Enantiomerically pure SIA (S)-4j and its analogues were used
in the intermolecular nitrene C–H insertion.5f The
Table 2 Substrate scope of 1a
Table 1 Screening of reaction conditions
Entrya
Solvent
Time (h)
Temp (ꢀC)
Conversionb to 3b%
1
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
THF
24
24
4
6
6
4
4
4
4
rt
rt
57
15
90
95
61
16
10
25
21
45
10
2c
3
35
35
45
35
35
35
35
35
35
4
5
6d
7e
8c
9f
10g
11
4
4
a
Reactions were usually conducted on a 1.0 mmol scale unless
specically stated. Conditions: (i) 1 (1.0 mmol), Ph3PCl2 (1.1 mmol),
triethylamine (TEA, 1.5 mmol), CHCl3 (3.0 mL), 0 ꢀC, 20 min; (ii)
amines/anilines (3.0 mmol), 0 ꢀC for 30 min, and then rt for 30 min
to 2 days; (iii) aqueous acid (HCl, HCOOH, or HOAc) or HCl/dioxane,
20–90 min.
a
b
1.02 eq. Ph3PCl2, 1.5 eq. base (DIPEA or TEA) were used. As
c
d
determined by LCMS. Pyridine was used as base. 4-Methylpyridine
was used as base. 2-Methoxypyridine was used as base. Acetonitrile
(30% vol) was used as co-solvent. THF (30% vol) was used as co-
solvent.
e
f
g
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Table 3 Substrate scope of 2a
that were made from tosyl chloride in 6 steps.17 In our work,
compound 4e, the key intermediate in Arvidsson's paper was
obtained in 87% yield from 1, and 6c was obtained in 25% yield
in one-pot procedure from 3.
In conclusion, we have disclosed a multi-step, one-pot
procedure to synthesise sulfonimidamides from the corre-
sponding and readily available sulfonamides. The trans-
1
formation can be performed under mild conditions. H NMR
was successfully applied in the tautomerism elucidation.
Through the replacement of S]O in sulfonamides with S]NR,
this remarkable functional group transformation affords a new
modication opportunity for sulfonamides, an important
functional group in drug discovery and development.
a
Reactions were usually conducted on a 1.0 mmol scale unless
Acknowledgements
specically stated. Conditions: same as in Table 2, but 2 was used as
starting material.
J.G. thanks AstraZeneca for nancial support. The authors
¨
thank SSL, SAM, and CM, AstraZeneca R&D Molndal for assis-
tance. The authors also thank Matthew Perry for useful
comments on this manuscript.
Table 4 Substrate scope of 3a
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