Sulfenyl Ynamides in Gold Catalysis: Synthesis of Oxo-functionalised 4-aminoimidazolyl Fused Compounds by Intermolecular Annulation Reactions

Article abstract of DOI:10.1002/adsc.202000134

Functionalised N-heterocyclic pyridinium N-aminides have been designed and synthesised to evaluate a nitrenoid-based annulation strategy into imidazole-fused oxo-substituted frameworks of importance to medicinal and agrochemical discovery programmes. Sulfenyl substituted ynamides were identified as privileged reactants affording productive gold-catalysed annulation reactions with these and other nitrenoids. This annulation method provides selective and efficient access into geminally amino-sulfenyl substituted nitrogen heterocycles under mild reaction conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.202000134

Title: Sulfenyl ynamides in gold catalysis: Synthesis of oxo-
functionalised 4-aminoimidazolyl fused compounds by
intermolecular annulation reactions
Authors: Elsa Arce, Scott Lamont, and Paul Davies
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Advanced Synthesis & Catalysis
10.1002/adsc.202000134
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Sulfenyl ynamides in gold catalysis: Synthesis of oxo-
functionalised 4-aminoimidazolyl fused compounds by
intermolecular annulation reactions
a
b
a
Elsa M. Arce, Scott G. Lamont and Paul W. Davies *
a
Haworth Building, School of Chemistry, University of Birmingham, Edgbaston. Birmingham B15 2TT, U.K
Tel: +44 (0)1214144408; email: p.w.davies@bham.ac.uk
Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, CB10 1XL, UK
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Functionalised N-heterocyclic pyridinium N-
aminides have been designed and synthesised to evaluate a
nitrenoid-based annulation strategy into imidazole-fused
oxo-substituted frameworks of importance to medicinal and
agrochemical discovery programmes. Sulfenyl substituted
ynamides were identified as privileged reactants affording
productive gold-catalysed annulation reactions with these
and other nitrenoids. This annulation methods provide
selective and efficient access into geminally amino-sulfenyl
substituted nitrogen heterocycles under mild reaction
conditions.
Keywords: Ynamides; Gold catalysis; Heterocycles;
Annulations; Sulfur
Ynamides have become an invaluable tool for
reaction discovery since the advent of broadly
Figure 1. The enabling reactivity profile of ynamides and
their use in annulations with nucleophilic nitrenoids.
[1],[2]
effective methods for their preparation.
They
have been particularly efficacious in the discovery of
π-acid-catalysed[ transformations. The nitrogen
substituent enhances the alkynes ligating π-donor
properties and delivers a keteneiminium species that
3]
that diazine, pyridine and fused 1,3-azole substitution
patterns can be incorporated, we questioned whether
this approach could be used to build imidazole rings
around more functionalised and non-aromatic motifs
provides high reactivity and regiocontrol (Figure
4]
1
a).[ Ynamides have underpinned the discovery of
efficient intermolecular annulations with nucleophilic
nitrenoids, allowing convergent and efficient access
(
Figure 2a). Structures featuring imidazole rings
fused to oxo-substituted heterocycles have shown
potency in medicinal and agrochemical applications
[5]
into nitrogen heterocycles (Figure 1b). Following
[
6],[7]
[18]
initial reports with N-pyridinium aminides,
(
Figure 2b)
and hence were deemed appealing
various nitrenoid types have been developed for
targets for the annulation methodology. However, the
addition of electron-withdrawing carbonyl groups
within the nitrenoids was expected to be a challenge
for the annulation strategy. A further competing
coordination site for the electrophilic gold catalyst is
introduced while the nucleophilic character of the
aminide group is diminished (Figure 2c). Here we
report on the viability of using the gold-catalysed
ynamide-nitrenoid strategy to access imidazo-fused
oxo-substituted heterocycles. We identify sulfenyl
ynamides, a barely-explored subclass of ynamides, as
highly effective for gold-catalysed nitrenoid reactions.
[8],[9]
annulations, including (benzo-fused)isoxazoles,
dioxazoles,[ oxadiazoles,
10]
[11]
azides , azirenes
[12]
[13]
and sulfilimines[ amongst others.
14]
[15]
Aminoimidazole and N-fused imidazole motifs
have been targeted for methodology development
programmes due to their importance as bioactive
molecules.[ Our group introduced a nucleophilic
nitrenoid strategy to prepare heteroaromatic-fused 2-
aminoimidazoles in an expedient and modular
fashion by the use of N-substituted N-pyridinium
16]
[7, 17]
aminides alongside ynamides.
Having established
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202000134
Scheme 1. The development of synthetic sequences for the
preparation of pyridinium N-aminides bearing oxo-
substituted heterocycles. Conditions a) MeI, NaOH,
2
H O:EtOH (2:1), 55 °C; b) MeI, LiHMDS, DMF, 0 °C to
[
24]
2 3
rt; c) N-Amino pyridinium iodide, K CO , MeOH, rt; d)
MeI, DIPEA, DMF, 0 °C to rt; e) Benzaldehyde or 2-
bromobenzaldehyde, AcOH, NaOAc, Reflux; f) PMBCl,
K CO , MeCN, reflux. PMB = p-Methoxybenzyl.
2 3
Figure 2. Representative examples of imidazo-fused
heterocycles and a nitrenoid–based annulation approach
for their preparation.
The putative nitrenoids were then tested in gold-
catalysed annulations against some standard
ynamides. As illustrated with aminide 4, where the
oxo group is vinylogously-conjugated to the nitrenoid
centre, these systems proved significantly less
reactive than previously studied N-heteroaryl
analogues (Scheme 2 and ESI for a broader study of
reaction conditions). No conversion was seen with an
oft-employed ynamide 16a. However, good
conversion was seen with the sulfenyl ynamide 18a.
In order to determine whether a nitrenoid-based
approach to bioactive oxo-substituted heterocyclic
motifs was viable, we investigated whether N-
heterocyclic N-pyridinium aminides could be
prepared from thiouracil 1, rhodanine 5 and
hydantoin 6 (Scheme 1 cf. Figure 2b). An S-
methylation[ and substitution approach
19]
[17, 20]
was
successfully developed for the formation of the oxo-
dihydropyrimidinyl-bearing nitrenoid 4 and the oxo-
dihydrothiazolyl-bearing
8.
The
gram-scale
preparation of 4 and 8 demonstrated the practicality
of these approaches. The use of hydantoin 6 in this
sequence was unsuccessful.
Knoevenagel reaction on 8 afforded 5-benzylidene
and 5-(2-bromobenzylidene) products 9a/b. Inverting
the order of the synthetic sequence was similarly
productive (5→10[ →9a), and this latter approach
was also applicable to hydantoin 6. S-Methylation of
the Knoevenagel product 11[22] was followed by a
regioselective N-alkylation prior to formation of the
aminide 15 (Scheme 1).[
21]
23]
Scheme 2. Surveying the reactivity of N-pyridinium N-(3-
methyl)pyrimidinone aminide 4.
[
a]
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202000134
Table 1. Comparing the reactivity of aryl- and sulfenyl substituted ynamides in annulations by a gold-catalysed formal
[
a]
[
3+2]-dipolar cycloaddition with oxo-functionalised nucleophilic nitrenoids.
Entry
R1
R2
R3
T (h)
Yield
1
2
3
4
4
4
Ts
Ts
Ts
Ph
Ph
Ph
SMe
SPh
3
24
5.5
19a 90%[b]
19b 85%
19c 76%
4
4
Ts
Ph
Ph
22
NR
c]
5
6
7
8
9
1
1
1
1
1
8
8
8
8
9a
9a
9a
9a
9b
9b
Ts
Ts
Ts
Ts
Ts
Ts
Ms
Ms
Ts
Ms
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Bn
Ph
Bn
SMe
SPh
24
24
24
22
1.5
22
5
21a 78%[
21b 50%
[
c]
[
c]
21c 34%
NR
Ph
SPh
Ph
[
d]
22a 98%
22b 67%
[
d]
0
1
2
3
4
[
d]
Ph
22c 74%
22d 75%
[
d]
Thiophen-2-yl 22
SMe
Ph
[
d]
3.5
22
23a 98%
23b 38%
[
d]
1
5
9b
Ms
Me
PMP
22
NR
1
1
1
1
6
7
8
9
15
15
15
15
Ts
Ts
Ts
Ts
Ph
Ph
Ph
Ph
SMe
SPh
18
22
24
22
24a 88%
24b 45%
24c 44%
NR
Ph
[
a]
Isolated yield after purification by column chromatography. Reactions performed in 1,4-dioxane at 90 °C at 0.2 to 3.5
mmol unless otherwise stated. [b] 19a 3.5 mmol (1.39 g).
performed in 1,2-DCB at 125 °C. PMP = p-Methoxyphenyl.
[c]
Using DTBPAu(NCMe)SbF
(5 mol%).
[d]
Reactions
6
Highly electrophilic Au(III) and phosphite Au(I)
species were shown to catalyse this transformation
effectively, while the more electron-rich IPrAu(I)
equivalent did not. Ultimately a high yield of the
sulfenyl-substituted imidazo[1,2-a]pyrimidin-7(8H)-
one 19a was obtained from 18a simply on heating
with 1.5 equivalents of 4 in the presence of bench-
integral as no reaction was seen when the
methyl(phenylethynyl)sulfane was reacted with 4
under those conditions. A gram scale preparation of
19a proceeded in high yield (Entry 1).
The thiophenyl-substituted ynamide 18b was less
reactive than the thiomethyl equivalent 18a, requiring
longer reaction times across the nitrenoids. (Entries 2,
6 and 17 versus entries 1, 5, and 16). A 1,6-
enynamide 18c, which introduces a competing
coordination site as well as a potential intramolecular
cycloisomerisation pathway, proved less reactive than
the other sulfenyl ynamides but still afforded the
intermolecular annulation products (Entries 3, 7 and
18).
Imidazo[2,1-b]thiazolones 21a-c were similarly
produced from aminide 8 bearing an enolisable
carbonyl in direct conjugation (Entries 5-7). The
reactivity trend across 18a-c was more pronounced
than with aminide 4. The Knoevenagel-adducts 9a/b
lacking enolisable sites and with an extended
conjugation to attenuate the carbonyl groups
stable PicAuCl
The role of the sulfonamide group is also integral as
no reaction was seen when the
2
precatalyst in dioxane in 2 hours.
methyl(phenylethynyl)sulfane was reacted with 4
under those conditions.
A similar pattern was seen in the reactions of all
the new nitrenoids (Table 1). Reactions were run with
either PicAuCl
2
or a DBTPAu(I)·CH
3
CN·SbF
6
catalyst in either 1,4-dioxane or 1,2-DCB (see ESI for
a comparison of conditions for particular aminides).
Annulation products were formed in good to
excellent yields from each of the new aminides with
sulfenylated-ynamide 18a (Table 1, entries 1, 5, 13,
1
6). In contrast, much lower or no reactivity was seen
with non-sulfenylated ynamides 16 or 20 (entries 4, 8, influence proved more reactive. Both the S-methyl
10, 15, 19). The role of the sulfonamide group is also
and S-phenyl ynamides 18a/b afforded high yields of
3
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Advanced Synthesis & Catalysis
10.1002/adsc.202000134
heterocycles 22/23 (Entries 9 and 13) and productive
outcomes were even seen with non-sulfenylated
ynamides (Entries 10-12 and 14-15).
level. The structure of 21a contains two crystallographically-
independent molecules of which only one is shown.
When compared with previously employed
nitrenoids, the outcomes fit a model where the
carbonyl or sulfonyl substituent diminishes the
reactivity of the aminide. Both nitrogen atoms of the
putative 1,3-N,N-dipole unit are deactivated which
adversely affects the initial nucleophilic attack and
the cyclisation stages of the annulation (Scheme 1c).
The reactivity-enhancing effect of a sulfenyl
substituent could be explained by sulfur-gold
Use of hydantoin-derived nitrenoid 15 granted
direct access to (Z)-2-ylideneimidazo[2,1-b]thiazol-
3
(2H)-one products 24a-c on reaction with sulfenyl
ynamides despite the steric crowding around the
iminoyl group (Entries 16-18). Again, no reaction
was seen with a non-sulfenylated ynamide (Entry 19).
A saccharin-derived nitrenoid 25 was then
prepared to test the effect of an alternative electron-
withdrawing group at the aminide (Scheme 3). No
reaction was seen with ynamide 20, but again
annulation occurred with sulfenyl ynamide 18a to
deliver the benzo[d]imidazo[1,2-b]isothiazolyl 26.
interactions
stabilising
the
polarised
gold
keteneiminium contribution B’ to generate a more
effective electrophile (Scheme 4). Sulfur-gold
interactions could also conceivably help to favour
productive
unproductive
Invoking
gold-ynamide
interaction
coordination
with nitrenoid.
over
[
26,27]
[28]
a
stabilising
dative
or
[29]
hyperconjugative interaction between the gold and
sulfur can explain the lower reactivity observed with
S-phenyl ynamide 18b over S-methyl ynamide 18a.
Both interactions would limit conformational
flexibility and position the sulfur substituent toward
the incoming nitrenoid whereby increasing steric bulk
would hinder the initial nucleophilic attack and the
Scheme 3. A saccharin-derived nitrenoid and its use to
access the benzo[d]imidazo[1,2-b]isothiazolyl structure.
[30]
subsequent cyclisation steps (Scheme 4 inset).
Crystal structures were obtained for the
heterocycles derived from rhodanine, thiouracil,
hydantoin and saccharin and confirm the
[25]
regioselectivity of the annulation (Figure 3).
Scheme 4. Proposed mechanistic rationale for the gold-sulfur
interaction responsible of the enhancement in reactivity.
There are only a few isolated examples of sulfenyl
[31],[32]
ynamides being used in catalysis.
Their success
alongside the new nitrenoids led us to explore the
wider potential of sulfenyl ynamides in nitrenoid-
based annulations in order to access heterocycles with
vicinal amino-sulfenyl substitution patterns. C2-
amino-C3-sulfenyl imidazo-[1,2-a]-pyridines have
Figure 3. Crystal structures of, from top-left clockwise, 21a,
4a, 19a and 26 with ellipsoids drawn at the 50% probability
[33]
2
been identified as inhibitors of human rhinovirus
[34]
and as anthelmintics,
while sulfenylated-
4
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Advanced Synthesis & Catalysis
10.1002/adsc.202000134
heterocycles and their S-oxide derivatives are of
[35]
general interest due to their biological activity and
synthetic utility.[ Thus, it seemed appealing to see
whether annulations of sulfenyl ynamides allowed
access to these substitution patterns on diverse
heterocyclic motifs in a regioselective and convergent
fashion.
36]
Broad tolerance and applicability was seen when
we examined the combination of sulfenyl ynamides
[
7,
with various aminide-based nitrenoids (Scheme 5).
1
7]
Imidazole-fused heterocycles 27-38 were obtained
in generally high to quantitative yields through
reactions that were more effective and/or faster than
with non-sulfenyl ynamides. Of particular note were
the formation of the caffeine-derived heterocycle 36
and the pyridine-fused system 38 as the required
nitrenoids had both reacted sluggishly in previous
studies with ynamides.[
17]
The ability of this annulation approach to access
highly heterosubstituted heterocycles is demonstrated
with the formation of 29 and its subsequent
elaboration by cross-coupling reaction to deliver 30.
Oxidation of these sulfenyl heterocycles proceeded
smoothly affording the desirable heteroarylsulfoxide
(
27→28) and heteroarylsulfone (34→35).
Scheme 5. The use of sulfenyl ynamides with other
nucleophilic nitrenoids. [O] = mCPBA (2.2 eq.), DCM,
0
°C to rt; [Pd] = Pd(PPh
3
)
4
(5 mol%), K
2 3
CO , 1,4-
[
a]
dioxane:H
2
O, 85 °C; Using 1,4-dioxane at 90 °C.
The sulfenyl ynamide 18a also proved productive
in reactions with other types of nitrenoids. Smooth
and relatively rapid reactions were observed with the
N,O-heterocycles 39 and 40 introduced by the groups
[8]
[9]
of Ye
and Hashmi,
delivering 2-amino-3-
thiopyrrole and 2-amino-3-thio-indole frameworks 41
and 42 respectively in the presence of Au(I) catalysts.
In summary, new types of pyridinium N-aminides
have been prepared that bear non-aromatic and oxo-
substituted heterocycles as putative nitrenoids for
gold catalysed annulation reactions with ynamides.
These species proved generally less reactive than the
previously explored N-heteroaryl pyridinium N-
aminides, likely because of reduced nucleophilicity.
While several of the new aminides did not react with
commonly employed ynamides, each aminide did
react smoothly when combined with a sulfenyl
ynamide. Imidazo-fused heterocycles were prepared
from each nitrenoid under gold catalysis, providing a
5
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Advanced Synthesis & Catalysis
10.1002/adsc.202000134
convergent new route into systems of interest in
Heimburger, N. Henry, K. Jouvin, G. Karthikeyan, A.
Laouiti, M. Lecomte, A. Martin-Mingot, B. Métayer, B.
Michelet, A. Nitelet, C. Theunissen, S. Thibaudeau, J.
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medicinal chemistry such as imidazo[2,1-b]thiazol-
3
(2H)-one,
imidazo[1,2-a]imidazolone
and
imidazo[1,2-a]pyrimidinone. The reactions are
practically straightforward and applicable on a gram
scale. Sulfenyl ynamides are effective substrates
across a range of different nitrenoids providing access
to various nitrogen-heterocycles with geminal amino-
sulfenyl substitution patterns in a mild and
regioselective fashion.
[
3] A. Fürstner, P. W. Davies, Angew. Chem. Int. Ed. 2007,
4
6, 3410-3449.
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This study highlights the reactivity-enhancing
influence of sulfur substitution in gold catalysis with
N,S-substituted alkynes behaving as privileged
substrates in these annulation reactions. We conclude
that the ability to ‘switch-on’ otherwise unproductive
processes offers significant potential for reaction
discovery based on π-acid activation and that the
wider use of sulfenyl ynamides in such programmes
may prove beneficial.
[
5] For reviews, see a) P. W. Davies, M. Garzón, Asian J.
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Experimental Section
A heat-gun dried Schlenk tube under argon was charged
[
[
[
6] P. W. Davies, A. Cremonesi, L. Dumitrescu, Angew.
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with ynamide 18a (1.11 g, 3.50 mmol), aminide 4 (1.06 g,
5
.25
mmol
1.5
eq.)
and
dichloro(2-
pyridinecarboxylate)gold (68.2 mg, 5 mol%) in dry 1,4-
dioxane (35 mL) and the mixture was stirred at 90 °C for 3
h. The reaction mixture was allowed to cool down to room
temperature and the solvent was removed under reduced
pressure. The residue obtained was purified by flash
column chromatography [Hexane:EtOAc (3:2)] affording
imidazole 19a as a beige solid (1.39 g, 90%).
7] M. Garzón, P. W. Davies, Org. Lett. 2014, 16, 4850-
4
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Acknowledgements
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7
97.
We thank the University of Birmingham and AstraZeneca plc for
funding (studentship to EMA). The authors gratefully
acknowledge support from the Centre for Chemical and
Materials Analysis in the School of Chemistry at UoB and its staff.
Matthew Wakeling and Dr Miguel Garzón (UoB) are thanked for
the donation of some ynamides.
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Advanced Synthesis & Catalysis
10.1002/adsc.202000134
UPDATE
Sulfenyl ynamides in gold catalysis: Synthesis of
oxo-functionalised 4-aminoimidazolyl fused
compounds by intermolecular annulation reactions
Adv. Synth. Catal. Year, Volume, Page – Page
Elsa M. Arce, Scott G. Lamont and Paul W.
Davies*
8
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