One-Pot, Three-Component Sulfonimidamide Synthesis Exploiting the Sulfinylamine Reagent N-Sulfinyltritylamine, TrNSO

Article abstract of DOI:10.1002/anie.201708590

Sulfonimidamides are increasingly important molecules in medicinal chemistry and agrochemistry, but their preparation requires lengthy synthetic sequences, which has likely limited their use. We describe a one-pot de novo synthesis of sulfonimidamides from widely available organometallic reagents and amines. This convenient and efficient process uses a stable sulfinylamine reagent, N-sulfinyltritylamine (TrNSO), available in one step on 10 gram scale, as a linchpin. In contrast to classical approaches starting from thiols or their derivatives, our TrNSO-based approach facilitates the rapid assembly of the three reaction components into a variety of differentially substituted sulfonimidamides containing medicinally relevant moieties, including pyridines and indoles. Analogues of the sulfonamide-containing COX-2 inhibitor Celecoxib were prepared and evaluated.

Full text of DOI:10.1002/anie.201708590

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Accepted Article
Title: One-pot, Three-Component Sulfonimidamide Synthesis exploiting
the Sulfinylamine Reagent N-Sulfinyltritylamine, TrNSO
Authors: Thomas Q Davies, Adrian Hall, and Michael C. Willis
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708590
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10.1002/anie.201708590
Angewandte Chemie International Edition
COMMUNICATION
One-pot, Three-Component Sulfonimidamide Synthesis exploiting
the Sulfinylamine Reagent N-Sulfinyltritylamine, TrNSO
Thomas Q. Davies,[a] Adrian Hall,[b] and Michael C. Willis*[a]
Abstract: Sulfonimidamides are increasingly important molecules in
medicinal chemistry and agrochemistry, but their preparation
requires lengthy synthetic sequences, which has likely limited their
use. We describe a one-pot de novo synthesis of sulfonimidamides
from widely available organometallic reagents and amines. This
convenient and efficient process uses a stable sulfinylamine reagent,
Sulfonimidamides are typically prepared from the reaction of
amines with sulfonimidoyl chlorides, themselves obtained via
electrophilic chlorination of sulfinamides (Scheme 1a).[7],[8],[9]
Direct N-H transfer to a sulfinamide has also been reported.[10]
However, sulfinamides are not easily accessible and have
limited commercial availability, and are typically prepared from
N-sulfinyltritylamine (TrNSO), available in one step on 10 gram scale, sulfinyl chlorides, accessible via oxidation of thiols or disulfides,
as a linchpin. In contrast to classical approaches starting from thiols
or their derivatives, our TrNSO-based approach facilitates the rapid
or reduction of moisture-sensitive sulfonyl chlorides.[11] In
addition, sulfinyl chlorides are unstable and generally demand
immediate combination with an amine. An additional
disadvantage for discovery chemists is that these lengthy
sequences are not conducive to analogue synthesis, as the R1
group on sulfur is determined by the initial choice of thiol or
sulfonyl chloride at the first step of the sequence. We envisioned
that many of these deficiencies could be addressed by a
synthetic strategy based on the use of a sulfinylamine[12] as a
key N=S=O linchpin (Scheme 1b). The resulting one-pot, three-
component reaction sequence would involve combination of the
assembly of the three reaction components into
a variety of
differentially substituted sulfonimidamides containing medicinally
relevant moieties, including pyridines and indoles. Analogues of the
sulfonamide-containing COX-2 inhibitor Celecoxib were prepared
and evaluated.
Sulfonamides have a rich history in medicinal chemistry, and
their stability, hydrogen bonding capabilities, and three-
dimensional shape make them prized functional groups in the
design of bioactive molecules. In contrast, their mono-aza
analogues, sulfonimidamides 1, have only recently started to
attract significant attention.[1] Like their congeners, they are
chemically and metabolically stable,[2] but in addition, the
substitution of an oxygen atom for a nitrogen leads to a
stereogenic sulfur center, presents further opportunities for
directed hydrogen bonding, and provides an additional site for
functionalization. These properties present unique opportunities
for medicinal chemists and agrochemists, and they have been
reported as carboxylic acid[3] and sulfonamide bioisosteres,[4]
and their use as BACE inhibitors[5] and kinase inhibitors[6] has
been disclosed in recent patents. Their use in medicinal- and
agrochemistry has recently been the subject of a review by
Arvidsson and co-authors, where it is noted that “since 2012,
there have been more patents and publications on compounds
with a sulfonimidamide moiety than collectively over history,
demonstrating that this functional group is gaining momentum”.[1]
In order to capitalize on this momentum and the increasing
awareness of sulfonimidamides, more convenient and efficient
methods for their preparation are required; unlike sulfonamides,
there has been little progress in this regard.
sulfinylamine with an organometallic reagent (2
chlorination of the resultant anionic sulfinamide species[13] to
generate sulfonimidoyl chloride (3 and then
4),[7c]
®
3),
a
®
combination with an amine to afford an N-substituted
sulfonimidamide (4 ® 5).[14] The N-R2 substituent would be
cleavable under mild conditions to give medicinally and
synthetically valuable N-H sulfonimidamides (5 ® 1).
a) Typical sulfonimidamide synthesis
R4
HN
R3
R2N
R1
O
O
S
O
S
R2N
R1
O
H2NR2
"Cl+"
R2
R4
S
S
R1
R1
Cl
N
N
Cl
H
R3
[O]
"deprotect"
SH
R1
HN
O
O
S
R4
N
S
R1
R2
N
sulfinylamine
R3
1
sulfonimidamide
b) Our approach
"deprotect"
R4
M(X)
HN
R3
R2N O
S
R2 N O
S
N
O
"Cl+"
S
R1
O
R1M(X)
R2
R4
N
R2
S
R1
R1
Cl
N
R3
2
3
4
5
widely available
organometallics/amines
substituents easily varied
one-pot sequence
[a]
T. Q. Davies, Prof. M. C. Willis
Department of Chemistry, University of Oxford
Chemistry Research Laboratory
Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: michael.willis@chem.ox.ac.uk
Homepage: http://mcwillis.chem.ox.ac.uk
Scheme 1. a)
A typical linear synthesis of sulfonimidamides via the
intermediacy of unstable sulfinyl chlorides. b) This work:
sulfinylamine-based synthesis of sulfonimidamides.
a one-pot
Sulfinylamines have been known since the 19th century and
are prepared by the reaction of primary amines with thionyl
chloride.[15] Several known sulfinylamines, including those
derived from p-toluenesulfonamide[16] and tert-butylcarbamate,[17]
were prepared but exhibited low hydrolytic stability, which is a
[b]
Dr. A. Hall
UCB Biopharma SPRL
Chemin du Foriest, Braine-l’Alleud (Belgium)
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201708590
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Scope with respect to amines.[a]
general property of these highly electrophilic compounds.[12a]
However, we were delighted to find that the reaction of
commercially available tritylamine (100 g, £117, Fluorochem)
with thionyl chloride in the presence of triethylamine gave a
moisture-insensitive white solid, isolated in pure form after
filtration through Celite (Scheme 2). N-Sulfinyltritylamine, TrNSO
(6), showed undiminished reactivity after storage for four months
in the freezer (–20 °C), and could be isolated on 10 gram scale
in excellent yield. The observed stability is attributed to the
considerable steric bulk of the trityl group.[18]
HN
O
HNR1R2, Et3N
then MsOH
TrN
O
4-FC6H4MgBr
then
S
R2
O
N
S
Tr
S
N
Cl
0 °C to rt
R1
t-BuOCl
THF, 0 °C
F
F
6
7
HN
O
HN
O
HN O
S
S
S
N
N
N
N
O
N
F
Me
F
F
F
7a 70%
HN
7b 76%
HN
7c 69%
O
H2N
O
S
O
S
S
N
N
N
SOCl2, NEt3
O
NH2
N
Me
Tr
Tr
S
Cbz
F
F
7d 76%
H2N
7e 66%
7f 70%
Et2O
0 °C, 2 h
10 g
6, 98%
O
H2N O
H2N
O
S
S
S
OMe
N
N
N
Scheme 2. Preparation of the sulfinylamine reagent N-sulfinyltritylamine,
TrNSO. Tr = triphenylmethyl, trityl.
F
F
F
F
OMe
7h 79%
7g 69%
H2N
7i 74%
1.5 g TrNSO: 80% (1.27 g product)
Me
O
H2N O
Our efforts then turned to applying this rare example of a
stable sulfinylamine to our planned one-pot synthesis of
sulfonimidamides. The reaction of TrNSO with commercially
available 4-fluorophenylmagnesium bromide in THF was
selected for initial investigation. Despite the steric demands of
the trityl group, complete consumption of the starting material
H2N
O
N
S
S
S
N
N
N
F
F
7j 49%
7k/7l 1:1 dr 31%/31%
7m 78%
Cl
HN
O
R
S
H2N
O
N
S
N
N
was observed within five minutes at
0 °C. Furthermore,
F
O
N
subsequent chlorination of the anionic sulfinamide intermediate
with tert-butyl hypochlorite[19] proceeded with full conversion
within fifteen minutes at the same temperature. The use of N-
chlorosuccinimide[7a] was also explored, but the reaction did not
achieve completion even after five hours using 1.5 equivalents,
while just 1.05 equivalents of tert-butyl hypochlorite proved
sufficient. The in-situ generated sulfonimidoyl chloride was
stirred at room temperature for 16 h with two equivalents of
morpholine, before methanesulfonic acid was added to effect
trityl deprotection. To our delight, the desired N-H
sulfonimidamide was isolated following flash chromatography in
70% yield.
F
R = H:
R = OMe: 7o 41%
7n 54%
7p 67%
[a] Reaction conditions: (i) TrNSO (0.16 mmol), 4-fluorophenylmagnesium
bromide (1.0 equiv), THF [0.16 M], 0 °C, 5 min, (ii) t-BuOCl (1.05 equiv), 0 °C,
15 min, (iii) amine (1.20 equiv), triethylamine (1.0 equiv), 0 °C to rt, 16 h, (iv)
MsOH (5.0 equiv), 15 min, rt. Isolated yields. Cbz = benzyloxycarbonyl.
Having demonstrated a wide scope of amines, we focused
on the tolerance of the reaction towards various
(hetero)aromatic organometallic reagents;
piperazine was chosen as the amine component to produce a
scaffold which could be of interest in medicinal chemistry (Table
a Cbz-protected
Encouraged by this success, we next explored the scope of
amines that could be used in this transformation (Table 1). The
stoichiometry of the amine nucleophile was reduced to 1.2
equivalents relative to TrNSO, and 1 equivalent of triethylamine
was employed. Under these conditions, a range of secondary
amines delivered sulfonimidamides in high yields (7a-e),
including an example with an additional basic nitrogen (7c).
Primary amines were also found to be competent nucleophiles,
in these cases delivering products with a double bond to the
more substituted nitrogen (7f-m).[20] Importantly, the reaction
worked equally well on gram scale; the 80% yield obtained for
compound 7h corresponds to a 95% yield per transformation,
demonstrating the efficiency of the one-pot process.
Propargylamine could be incorporated, albeit in slightly reduced
yield, potentially enabling the convenient application of
sulfonimidamides to click chemistry (7j). When enantiopure (R)-
α-methylbenzylamine was employed, a 1:1 mixture of separable
diastereomers was generated, highlighting the potential for
chemical resolution (7k,l). N’-Aryl sulfonimidamides were
obtained by reaction with anilines, although in the case of 7n
and other more electron-poor anilines (e.g. 4-bromoaniline), acid
sensitivity of the products was observed. The more electron-rich
7o, in contrast, did not show any sign of decomposition on silica.
A sulfonimidamide derived from the complex amine-containing
antidepressant drug Amoxapine could also be obtained in good
yield (7p).
2).
A range of electron-rich and electron-poor benzene
derivatives provided high yielding reactions (7q-t), and
substitution was tolerated even in the ortho- position with only a
minor reduction in yield (7u); a remarkable result considering the
steric crowding around sulfur atom in the intermediate N-trityl
sulfonimidoyl chloride. Heterocyclic organometallics were also
suitable substrates for the reaction (7v-z). The organolithium
reagent derived from 5-bromo-2-methoxypyridine could be
employed in an excellent 80% yield (7v), and a challenging 2-
pyridyl organomagnesium reagent (7w), generated using
Knochel’s turbo Grignard,[21] proceeded in moderate yield.
Indole- and 2-thienyl-substituted sulfonimidamides were also
obtained (7y,z). Pleasingly, the reaction was not limited to
aromatic nucleophiles; alkyl Grignard reagents, notably including
cyclopropylmagnesium bromide (7ac), were also amenable. An
S-alkenyl sulfonimidamide (7ae) was obtained in low yield, likely
due to decomposition related to its strong Michael acceptor
ability.
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10.1002/anie.201708590
Angewandte Chemie International Edition
COMMUNICATION
Table 2. Scope with respect to organometallic reagents.[a]
parent sulfonimidamide (17) could be prepared in high yield by
oxidative cleavage of the DMB-protected sulfonimidamide 14.
HN
R
O
1-Cbz-piperazine
NEt3
RM(X)
then
S
TrN
R
O
N
O
N
CF3
S
Tr
S
Cl
N
OBn
t-BuOCl
CF3
CF3
N
then MsOH
0 °C to rt
ii. TrNSO
iii. t-BuOCl
iv. HNR1R2
THF, 0 °C
N
6
7
N
O
N
Ar
Me
N
nBuLi
N
HN
O
HN
O
HN
O
Me
THF
-78 °C
v. MsOH
-78 °C to rt
S
S
S
N
N
N
NH
R1
N
N
N
S
Cbz
Cbz
Me
Me
MeO
Cbz
Cl
Cbz
Cbz
N
R2
O
Br
Li
11
7q 67%
HN
7r 77%
7s 74%
HN
10
12, R1=R2 = -CH2CH2OCH2CH2-
13, R1=H, R2 = cyclobutyl
54%
34%
O
O
HN O
S
S
S
N
14, R1=H, R2 = 3,4-dimethoxybenzyl 43%
N
N
N
N
N
N
MeO
N
CF3
Me
7u 54%
HN
Cbz
CF3
CF3
N
7v 80%
HN
7t 61%
HN
N
N
Pd2(dba)3
RuPhos
NaOtBu, PhBr
Ar
N
S
N
S
N
O
O
O
i. NaH
ii. MeI
Me
Me
S
S
Br
S
N
N
N
THF
0 °C to rt
THF
100 °C
N
N
N
N
Cbz
Cbz
N
Cbz
NPh
NMe
NH
Me
S
Br
N
N
N
O
7w 42%
7x 44%
7y 58%
O
O
O
O
O
HN
S
O
HN O
HN
O
15, 99%
12
16, 77%
S
S
Me
S
N
Me
N
N
CF3
CF3
11
CF3
N
N
N
Cbz
Cbz
Cbz
N
N
N
N
N
7z 45%
7aa 60%
7ab 57%
HN
N
CAN
Me
Me
Me
HN
O
N
HN
O
O
Me
Me
MeCN/H2O
0 °C
S
Me
S
S
N
N
NH
NH2
S
N
Me
N
N
S
N
MeO
MeO
O
S
H2N
Cbz
Cbz
Cbz
O
O
H2N
Celecoxib
O
7ac 45%
7ad 43%
7ae 38%
14
17, 85%
[a] Reaction conditions: (i) TrNSO (0.16 mmol), organometallic reagent (1.0
equiv), THF [0.16 M], 0 °C, 5 min, (ii) t-BuOCl (1.05 equiv), 0 °C, 15 min, (iii) 1-
Cbz-piperazine (1.0 equiv), triethylamine (1.0 equiv), 0 °C to rt, 16 h, (iv)
MsOH (5.0 equiv), 15 min, rt. Isolated yields. Cbz = benzyloxycarbonyl.
Scheme 4. Synthesis of sulfonimidamide drug analogues.
With several drug analogues in hand, we investigated their
properties in comparison to Celecoxib. The biological inhibition
of COX-2 was investigated for three analogues,[23] namely the
parent sulfonimidamide (17), the closest analogue, and the
morpholino (12) and cyclobutyl (13) derivatives. The data show
that replacement of the sulfonamide by the sulfonimidamide
decreases COX-2 inhibition by almost 100-fold, whereas
additional substitution of the sulfonimidamide is not well
tolerated and results in a further decrease in activity (Table 3). A
head-to-head comparison between Celecoxib and the parent
sulfonimidamide analogue (17) reveals some beneficial
parameters, including lower lipophilicity and increased metabolic
stability, particularly in human liver microsomes, which also
results in a lower calculated hepatic extraction ratio. Although it
is unclear whether the improvement in metabolic stability for the
sulfonimidamide is simply due to the lower lipophilicity or as a
result in weakened interactions with the metabolic enzyme, it
supports the further investigation and use of the sulfonimidamide
in medicinal chemistry.
Significant reduction of the intermediate sulfonimidoyl
chloride was observed when ammonia was used as the amine
component, complicating the preparation of the parent
sulfonimidamide (Scheme 3). After extensive experimentation, it
was found that 3,4-dimethoxybenzyl-protected sulfonimidamide
8 was a suitable precursor to the desired product. Oxidative
cleavage with ceric ammonium nitrate proceeded quickly and
cleanly at 0 °C, affording sulfonimidamide 9 in excellent yield.
i. 4-FC6H4MgBr
ii. t-BuOCl
HN
O
S
O
N
NH2
Tr
S
iii. NH3 (0.5 M in THF), Et3N
iv. MsOH, THF
F
H2N
O
HN O
CAN (2.5 equiv)
S
OMe
OMe
S
N
NH2
MeCN/H2O 2:1
0 °C, 40 min
Ph
Ph
8
9, 89%
Scheme 3. a) Ammonia fails to give desired unsubstituted sulfonimidamide. b)
Ready oxidative cleavage of DMB-protected sulfonimidamide. CAN = ceric
ammonium nitrate.
Table 3. Summary of data for Celecoxib versus compounds 17, 12 and 13.
Compound
COX-2
pIC50
7.33
HT
logD[a]
HLM
HLM
RLM
RLM
Eh
[b]
[c]
[b]
CLint
16.1
4.84
404
Eh
CLint
11.2
8.21
114
Having developed
a
convenient method to prepare
sulfonimidamides, we wished to investigate its suitability for
preparing complex, drug-like molecules. We therefore elected to
investigate the preparation of sulfonimidamide analogues of the
sulfonamide-containing non-steroidal anti-inflammatory drug
(NSAID) Celecoxib (Scheme 4). Organolithium reagent 11 was
obtained from the corresponding bromide and employed in the
synthesis of three sulfonimidamides (12-14). Possibilities for
further functionalization on these complex structures were
explored; N-alkylation of 12 with methyl iodide proceeded
quantitatively (15), while N-arylation via a palladium-catalyzed
cross-coupling was also successful (16).[22] Pleasingly, the
Celecoxib
3.6
0.439
0.19
0.223
0.174
0.745
17
5.46
3.0
12
< 5 (42%@10 uM)
3.7
0.951
13
<5 (39% @ 10 uM)
4.3
95
0.822
50
0.561
[a] High Throughput (HT) logD. [b] Intrinsic clearance (CLint) measured in
human or rat liver microsomes (HLM or RLM respectively), in μL/min/mg
protein. [c] Calculated hepatic extraction ratio, based on the assumption Fu
(fraction unbound) = 1 for all compounds. See Supplementary Information
for assay details.
Analysis of the crystal structure of Celecoxib bound to
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10.1002/anie.201708590
Angewandte Chemie International Edition
COMMUNICATION
mouse COX-2 reveals a potential explanation for the reduced
activity of the sulfonimidamide analogue (17). Celecoxib is a
lipophilic compound which largely makes hydrophobic
interactions with COX-2 (Scheme 5), apart from the
sulfonamide moiety which makes polar interactions, namely
the NH2 group donates a hydrogen bond to the backbone
carbonyl moiety of Leu338, whilst each of the O-atoms accept
a hydrogen bond (Arg499 & Phe504, see Schemes 5 and 6).
Thus, replacement of one of the O-atoms by NH would be
predicted to be detrimental due to the loss of a HBD interaction
(resulting in ~10-fold decrease in activity), in addition to a
potential unfavourable interaction with Arg499 or Phe504.
Furthermore, there may be an additional cost due to an
increased desolvation penalty for the more polar
sulfonimidamide-containing ligand. The weaker activity of the
substituted sulfonimidamide analogues (12 & 13) can be
rationalised by the increased steric requirements of the
ligands.
the process, while primary and secondary amines and anilines
all proved competent nucleophiles, allowing access to a truly
broad range of medicinally relevant sulfonimidamides and in so
doing opening up previously difficult-to-access chemical space.
Furthermore, several analogues of the COX-2 inhibitor
Celecoxib were prepared using the methodology and their
biological activity and physicochemical properties were
evaluated. Although COX-2 inhibition decreased for the tested
compounds,
sulfonimidamide (17) was improved relative to Celecoxib,
demonstrating potential benefit of sulfonimidamides in
the
metabolic
stability
of
the
parent
a
medicinal chemistry. We anticipate that this method will quickly
find use in medicinal chemistry and agrochemistry programmes,
and should encourage further investigation into this increasingly
important class of molecules.
Acknowledgements
This work was supported by the EPSRC (EP/K024205/1). TQD
is grateful to the EPSRC Centre for Doctoral Training in
Synthesis for Biology and Medicine (EP/L015838/1) for
a
studentship. We would also like to thank Katerina Puncochova
for logD measurements, Anne-Gaëlle Letombe for COX-2 data
and Anna-Lena Ungell for DMPK and discussions (all UCB).
Keywords: sulfur functional groups • medicinal chemistry •
sulfonimidamides • sulfinylamines • one-pot synthesis
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[2]
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Scheme 5. Depiction of the interactions formed between Celecoxib and
mouse COX-2 (PDB: 3LN1). Generated using Maestro Elements 2.5
(Schrödinger), Release 2016-1.
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Scheme 6. Depiction of Celecoxib bound to mouse COX-2 (PDB: 3LN1),
hydrogen bonds denoted by dashed lines. Generated using Maestro
Elements 2.5 (Schrödinger), Release 2016-1.
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In conclusion, we have developed a convenient and high-
yielding one-pot synthesis of sulfonimidamides, exploiting the
sulfinylamine TrNSO as a linchpin reagent. (Hetero)aryl and
alkyl organometallic reagents were found to be compatible with
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(http://www.cerep.fr/cerep/users/pages/catalog/Affiche_CondExp_Test.
asp?test=4186) in 10-point dose-response assay; 10, 3, 1, 0.3, 0.1,
0.03, 0.01, 0.003, 0.001 & 0.0001 uM.
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COMMUNICATION
R3
M
HN
R2
"Cl+"
one-pot process
R1
HN
O
O
N
32 examples
up to 80% yield
R3
T. Q. Davies, A Hall and M. C. Willis*
__________ Page – Page
S
Tr
S
TrNSO
R1
N
R2
One-pot, Three-Component,
Sulfonimidamide Synthesis exploiting
the Sulfinylamine Reagent N-
Sulfinyltritylamine, TrNSO
The stable, readily prepared sulfinylamine reagent TrNSO is exploited as a linchpin to
join organometallic reagents and amines to provide sulfonimidamides in a high yielding
one-pot process. Good variation of both reaction components is possible.
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