Gold-Catalysed Cycloisomerisation of Ynamides to Access 2,2-Disubstituted Tetrahydrothiophene Motifs

Article abstract of DOI:10.1055/a-1434-4273

Ynamides bearing a tethered allyl sulfoxide undergo a gold-catalysed cycloisomerisation to afford tetrahydrothiophene-2-carboxamides and their benzo-fused analogues. The reactions are initiated by a formal 7- endo - dig cyclisation and accommodate a range of different substituents. The use of N -allyl ynamides provided a route into novel spirocyclic ?-lactam structures.

Full text of DOI:10.1055/a-1434-4273

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, A–D
letter
A
en
P. Heer Kaur, P. W. Davies
Letter
Synlett
Gold-Catalysed Cycloisomerisation of Ynamides To Access 2,2-
Disubstituted Tetrahydrothiophene Motifs
R1
ynamide dictated
endo-mode cyclisation
Parmjit Heer Kaur
Paul W. Davies*
R1
N
R2
0
0
0
0
-
0
0
0
2
-
0
3
4
0
-2
4
1
4
R
R2
N
O
Au cat.
S
• 13 examples (31–90%)
• 4 new bonds
School of Chemistry, University of Birmingham, Edgbaston,
Birmingham, B15 2TT, UK
p.w.davies@bham.ac.uk
O
S
R
O2
S
oxidation and
metathesis
spirocyclic
lactams
R
N
R1 = allyl
Ms
O
PSeMcahuaoliCoWl olp.ro.wrDfeCa.sdvhpaieoevmnsiedissi@ntrgbyhA, Uaumtnhi.vaoecr.ruskity of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
Received: 28.01.2021
a) Formation and rearrangement of allyl sulfonium ylides
Accepted after revision: 13.03.2021
Published online: 13.03.2021
sacrificial functionality
N2
[M] cat.
DOI: 10.1055/a-1434-4273; Art ID: st-2021-v0035-l
O
S
S
Abstract Ynamides bearing a tethered allyl sulfoxide undergo a gold-
catalysed cycloisomerisation to afford tetrahydrothiophene-2-carbox-
amides and their benzo-fused analogues. The reactions are initiated by
a formal 7-endo-dig cyclisation and accommodate a range of different
substituents. The use of N-allyl ynamides provided a route into novel
spirocyclic -lactam structures.
S
O
O
[M] cat.
Oxidant
regiocontrol required
b) Cycloisomerisation of alkyne-tethered allyl sulfoxides
R = H, Ph,
CO2Et
Key words gold, ynamides, isomerization, ylides, regioselectivity,
n
n
S
S
thiophenecarboxamides
O
ref. 5
R
O
[M]
R
• 5-exo-dig → 5-membered ring
• 6-exo-dig → 6-membered ring
The -acid-catalysed cycloisomerisation of alkyne-
bearing substrates has delivered a huge diversity of inher-
ently efficient and complexity-building transformations.1
Many such reactions illustrate the capacity of -acid cataly-
sis to access metal carbene-like reactivity patterns.2 Unlike
diazo compounds and other carbene precursors that use a
sacrificial functionality to direct the site of carbene forma-
tion, alkynes offer two sites for metal carbene formation
and, hence, the possibility for divergent reaction outcomes
if effective regiocontrol can be achieved (Scheme 1a).
The ability to access new S-heterocyclic motifs under
the mild and functional-group-tolerant conditions associat-
ed with gold catalysis is appealing, given the importance of
sulfur heterocycles in medicinal chemistry.3 Cycloisomeri-
sation reactions affording sulfur heterocycles by C–S bond
formation are, however, relatively rare compared with C–O
and C–N bond-forming reactions.4
n
S
• 4 bonds formed
O
• S-substituted quaternary stereocentre
R
This
work
S
S
O
R = NR1R2
O
R
R
[M]
• 7-endo-dig → 5-membered ring
c) Ynamide scaffolds used to test the reactivity hypothesis
gem dialkyl
R
influence
S
S
R
O
O
R1
R1
competing 1,2-
insertion pathways
N
N
R2
R2
2 R = –(CH2)5–
3 R = H
1
Scheme 1 The formation and rearrangement of allyl sulfonium ylides
and access to them by cycloisomerisation of alkyne-tethered allyl sulf-
oxides
Our group previously reported the preparation of dihy-
drothiophen-3(2H)-one and dihydro-2H-thiopyran-3(4H)-
one derivatives from allyl sulfoxide-tethered alkynes under
Pt(II) or Au(III) catalysis.5 This cycloisomerisation creates
four new bonds through the [2,3]-sigmatropic rearrange-
ment of an -oxo allyl sulfonium ylide formed in situ. Ini-
tially, the reactions involve a 5- or 6-exo-dig cyclisation,
leading to an internal redox transfer of an oxygen atom
from sulfur onto the alkyne (Scheme 1b).6 Products from an
endo-dig cyclisation were observed only as minor products
in just two examples, with the exo-pathway dominating.
We questioned whether an initial endo-mode cyclisation
could be enforced to achieve the same type of cycloisomeri-
sation, and here we report our studies using an ynamide
strategy.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
P. Heer Kaur, P. W. Davies
Letter
Synlett
The gold-keteneiminium character generated from
gold-activation of an ynamide has proven to be remarkably
useful for the discovery of efficient new synthetic methods
under gold catalysis.7 Superb regiocontrol has been realised
across numerous intermolecular processes,8 including
those leading to sulfonium ylides.9 Our group has previous-
ly used ynamides to favour 6-endo-dig cyclisation over a 5-
exo-dig pathway.10 In the proposed transformation, howev-
er, a more-challenging 7-endo-dig outcome is required to
produce a five-membered sulfur heterocycle (Scheme 1b).
If achievable, then, because ynamides are accessible directly
from terminal alkynes,11 various types of sulfur heterocycle
might be prepared from the same late-stage precursors
(Scheme 1b).
Table 1 Gold-Catalysed Cycloisomerisation Reactions of Ynamides to
Prepare 2,2-Disubstituted Tetrahydrothiophene Derivativesa
S
S
PicAuCl2 (5 mol%)
R1
R2
O
1,2-DCE (0.2 M)
70 °C
R1
N
N
R2
O
1–3
4–6
Entry Product
R1
R2
4–6
Yieldb (%)
1
2
3
4
Ms
Ms
Ph
Bn
Bu
4a
4b
4c
4d
74
81
88
74
S
R1
R2
N
O
Ms
4a–e
O
Our study centred on three substrate scaffolds 1–3
(Scheme 1c), in which the putative -amido gold carbenoid
is formed adjacent to either an aryl (1) or an alkyl (2 and 3)
substituent. The latter situation introduces a 1,2-CH inser-
tion pathway that competes with sulfonium ylide forma-
tion.8a Scaffolds 2 and 3 are differentiated by gem-dialkyl
substitution, which affects the relative rates of cyclisation
both before and after carbenoid formation. The required
ynamides were prepared by using a modified version of
Stahl’s oxidative coupling approach [see the Supporting In-
formation (SI)].11
N
O
5
4e
85 (dr 1:1)
O
N
O
Bn
6
7
8
9
Ms
Ms
Ms
Ph
Br
5a
5b
5c
5d
69
49
69
47
S
R1
R2
N
Bu
O
5a–d
O
N
On heating in the presence of dichloro(2-pyridinecar-
boxylato)gold (PicAuCl2), ynamides 1–3 underwent rear-
rangement to give the corresponding S-heterocyclic prod-
ucts 4–6 (Table 1).12 Lower conversions and less-clean out-
comes were obtained by using gold(I) complexes. Various
substituted N-sulfonyl and oxazolidinone ynamides 1a–e
underwent cycloisomerisation to give the corresponding
1,3-dihydro-2-benzothiophenes 4a–e in high yields (Table
1, entries 1–5). No transfer of chiral information to the sul-
fur-substituted quaternary centre from the chiral oxazolidi-
none 1e was observed (Entry 5).
O
10
Ms
Ms
Ts
Bn
6a
6a
6b
31c
63
40
S
R1
11d
12d
Bn
N
(CH2)2OTBS
R2
O
3a–b
a Reactions were carried out at 0.2 M in DCE using PicAuCl2 (5 mol%) at 70
°C.
b Isolated yields after flash column chromatography.
c The ynamide hydration product was also obtained in 16% isolated yield.
d Reaction in freshly distilled DCE.
Effective cycloisomerisation occurred with scaffolds 2
and 3, affording heterocycles 5a–d and 6a–b, respectively,
under the same reaction conditions, despite the presence of
C(sp3)–H bonds adjacent to the gold carbenoid.13 Products
from competing ynamide hydration were observed when
an undried solvent was used with substrate 3a, which lacks
a gem-dialkyl substitution pattern between the reacting
centres (entry 10); however, the yield of 6a doubled on us-
ing freshly distilled solvent (entry 11). A silyl ether was also
tolerated (6b; entry 12).
The observed products are consistent with the broad
mechanism previously proposed for terminal and internal
alkynes (Scheme 2).5 In this case, however, the gold-ketene-
iminium character resulting from the coordination of the
active gold catalyst to the ynamide A forces an overall endo-
dig addition. Sulfoxide attack generates the vinyl gold car-
benoid B, which then evolves to ylide D and, subsequently,
to the observed products through the release of the gold
catalyst and a [2,3]-sigmatropic rearrangement. The ab-
sence of products from potentially available and fast path-
ways such as 1,2-CH insertion8a indicates ready C–S bond
formation. Within the constraints of a cyclic system, the
stereoelectronic requirement for S–O bond cleavage align
that bond with the alkene -system in B, positioning the
sulfur to interact with the electrophilic carbon in C.
Representative examples of the sulfur-heterocycle mo-
tifs were oxidised to assess the potential of the cycloisom-
erisation method to access novel cyclic sulfones. Oxidation
of 4b and 6b by using ammonium heptamolybdate and hy-
drogen peroxide gave high yields of 7a and 7b, respectively
(Figure 1).
We envisaged that the formation of -allyl amide motifs
in this cycloisomerisation could be harnessed in a prepara-
tion of new and usefully functionalized structures contain-
ing reactive groups that might be introduced through the
ynamide nitrogen. Spirocyclic compounds are desirable
motifs for drug discovery due to their conformationally
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–D

C
P. Heer Kaur, P. W. Davies
Letter
Synlett
well-defined and three-dimensional character.14 Ynamides
with N-allyl substituents were therefore prepared to test
whether spirocyclic lactams might be obtainable by using a
post-cycloisomerisation ring-closing metathesis. Ynamides
8 and 11 underwent gold-catalysed reactions to give the
sulfur heterocycles 9 and 12, respectively (Scheme 3). No
products from cyclopropanation were observed. Diene 9
was oxidised to the sulfone and subjected to metathesis
conditions using either the first- or second-generation
Grubbs catalyst, with the latter giving an excellent yield of
the dispirocycle 10.15 The same sequence was then applied
to ynamide 11, affording the benzo-fused spirocycle 14 in
excellent yield.16
In summary, ynamides with tethered allyl sulfoxide
moieties undergo gold-catalysed cycloisomerisation to
form 2,2-disubstituted tetrahydrothiophenes. The reaction
works well when the ynamide is connected to the allyl sulf-
oxide through either an aromatic or an aliphatic linking
group. As the ynamides are prepared directly from terminal
alkynes, two distinct sulfur heterocycles are accessible
S
PicAuCl2 (5 mol%)
1,2-DCE, 70 °C
S
Ms
O
N
N
O
Ms
8
9 60%
i) Mo7O24(NH4)64H2O, H2O2
EtOH/H2O2, 0 °C to rt
O
SO2
MsN
ii) Catalyst (5 mol%)
1,2-DCE, 70 °C
10
Catalyst
(PCy3)2RuCl2CHPh
(SIMes)(PCy3)RuCl2CHPh
50%
81%
S
S
PicAuCl2 (5 mol%)
O
1,2-DCE, 70 °C
O
N
MsN
12 90%
Ms
11
EtOH/H2O2
0 °C to rt
Mo7O24(NH4)64H2O
H2O2
(SIMes)(PCy3)RuCl2CHPh
SO2
SO2
(5 mol%)
S
S
S
O
O
1,2-DCE, 70 °C
O
O
MsN
R1
MsN
81%
O
R2
N
R2
R1
N
R1
N
R2
14
13 97%
E
[Au]
Scheme 3 Use of the ynamide-based cycloisomerisation to access nov-
el functionalised -spirocyclic lactam structures. SIMes = 1,3-bis(2,4,6-
trimethylphenyl)imidazolin-2-ylidene.
S
R
S
O
R1
[Au]
R2
O
N
N
R2
[Au]
R1
D
A
from a common alkyne intermediate by -acid-catalysed
cycloisomerisation. This study highlights the potential of
ynamides in controlling -acid-catalysed reaction path-
ways, in this case imposing an initial 7-endo-dig cyclisation
outcome. In addition to providing a regiocontrol element,
the ynamide unit can also be used to introduce useful func-
tionality that can be combined with that assembled during
the cycloisomerisation reaction, as demonstrated by the
ready formation of sp3-rich spirocyclic lactams.
R1
N
R1
N
[Au]
[Au]
R2
R2
S
S
O
O
B
C
Scheme 2 Mechanistic outline for the observed transformation
Conflict of Interest
O
SO2
NTs
The authors declare no conflict of interest.
SO2
O
NMs
Bn
TBSO
7b 82%
Funding Information
7a 92%
We thank the EPSRC for funding (EP/F031254/1).
E
n
gineeri
n
g
an
d
P
h
ysical
S
ciences
R
esearch
C
o
u
n
cil(EP/F
0
3
1
2
5
4
/1)
Figure 1 Cyclic sulfones formed by ammonium heptamolybdate-cata-
lysed oxidation of the analogous sulfides with hydrogen peroxide in eth-
anol (see SI for the conditions). Isolated yields following flash column
chromatography are reported. Yields in parenthesis were determined
by analysis of the crude reaction mixture by 1H NMR spectroscopy with
an internal standard.
Acknowledgment
The authors gratefully acknowledge support from the Centre for
Chemical and Materials Analysis in the School of Chemistry.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–D

D
P. Heer Kaur, P. W. Davies
Letter
Synlett
Supporting Information
Gade, C. A.; Hashmi, A. S. K. Angew. Chem. Int. Ed. 2013, 52, 5880.
(h) Li, L.; Shu, C.; Zhou, B.; Yu, Y.-F.; Xiao, X.-Y.; Ye, L.-W. Chem.
Sci. 2014, 5, 4057; For reviews, see ref. 7.
Supporting information for this article is available online at
https://doi.org/10.1055/a-1434-4273. Su
p
p
ortingInformatio
n
Su
p
p
ortingInformatio
n
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(b) Baker, T.; Davies, P. W. Eur. J. Org. Chem. 2019, 2019, 5201.
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7262.
References and Notes
(11) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833.
(12) Cycloisomerisation of Ynamides: General Procedure
AuPicCl2 (5.0 mol%, 5 mol) was added to a 0.2 M solution of
the appropriate ynamide in DCE (0.1 mmol) in a flame-dried
Schlenk tube under argon, and the mixture was heated at 70 °C.
Upon completion of the reaction (TLC), the crude mixture was
passed through a small plug of silica to remove gold residues.
The solvent was then evaporated, and the residue was purified
by column chromatography (hexanes–EtOAc).
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T.; Muñoz, M. P. Top. Heterocycl. Chem. 2016, 46, 117.
(2) (a) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395. (b) Fürstner,
A.; Davies, P. W. Angew. Chem. Int. Ed. 2007, 46, 3410.
(c) Adcock, H. V.; Davies, P. W. Synthesis 2012, 44, 3401.
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S. Acc. Chem. Res. 2014, 47, 966. (f) Wang, Y.; Muratore, M. E.;
Echavarren, A. M. Chem. Eur. J. 2015, 21, 7332. (g) Harris, R. J.;
Widenhoefer, R. A. Chem. Soc. Rev. 2016, 45, 4533. (h) Ye, L.-W.;
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Hashmi, A. S. K. Chem. Rev. 2021, in press DOI:
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2019, 180, 486. (b) Feng, M.; Tang, B.; Liang, S. H.; Jiang, X. Curr.
Top. Med. Chem. 2016, 16, 1200.
(4) For early examples, see: (a) Morita, N.; Krause, N. Angew. Chem.
Int. Ed. 2006, 45, 1897. (b) Nakamura, I.; Sato, T.; Yamamoto, Y.
Angew. Chem. Int. Ed. 2006, 45, 4473. For a review, see:
(c) Debrouwer, W.; Heugebaert, T. S. A.; Roman, B. I.; Stevens, C.
V. Adv. Synth. Catal. 2015, 357, 2975.
1-Allyl-N-benzyl-N-(methylsulfonyl)-1,3-dihydro-2-ben-
zothiophene-1-carboxamide (4b)
Purified by column chromatography [silica gel, hexanes–EtOAc
(7:3)] as a yellow viscous oil; yield: 31 mg (81%). IR (neat): 2925
(w), 1679 (s), 1351 (s), 1162 (s) cm–1 1H NMR (300 MHz,
.
CDCl3):  = 2.92 (s, 3 H) overlaps with 3.01–2.95 (m, 1 H), 3.10
(dd, J = 14.2, 7.4 Hz, 1 H), 4.19 (d, J = 14.2 Hz, 1 H), 4.33 (d, J =
16.0 Hz, 1 H), 4.41 (d, J = 14.2 Hz, 1 H), 4.83 (d, J = 16.0 Hz, 1 H),
4.92–5.05 (m, 2 H), 5.46–5.64 (m, 1 H), 7.14–7.31 (m, 9 H). 13C
NMR (101 MHz, CDCl3):  = 238.0, 43.3, 47.2, 50.6, 69.0, 120.1,
125.2, 125.3, 127.8, 127.9, 128.4, 128.5, 128.6, 132.2, 135.6,
140.2, 141.0, 175.1. MS (TOF ES+): m/z = 410 (100%) [M + Na]+.
HRMS (TOF ES+): m/z calcd for C20H21NNaO3S2: 410.0861; found:
410.0859.
(5) Davies, P. W.; Albrecht, S. J.-C. Angew. Chem. Int. Ed. 2009, 48,
8372.
(6) (a) Lu, B.; Li, Y.; Wang, Y.; Aue, D. H.; Luo, Y.; Zhang, L. J. Am.
Chem. Soc. 2013, 135, 8512. (b) Shapiro, N. D.; Toste, F. D. J. Am.
Chem. Soc. 2007, 129, 4160. (c) Li, G.; Zhang, L. Angew. Chem. Int.
Ed. 2007, 46, 5156.
N,3-Diallyl-N-(methylsulfonyl)-2-thiaspiro[4.5]decane-3-
carboxamide (9)
Colourless viscous oil; yield: 21.3 mg (60%); IR (neat): 2924 (s),
1
2852 (m), 1681 (s), 1352 (s), 1165 (s) cm–1. H NMR (300 MHz,
CDCl3):  = 1.21–1.63 (m, 10 H), overlaps with 1.53 (d, J = 13.6
Hz, 1 H), 2.55 (dd, J = 14.4, 7.2 Hz, 1 H), 2.70 (dd, J = 14.4, 5.8 Hz,
1 H), 2.69 (d, J = 10.7 Hz, 1 H), 2.77 (d, J = 10.7 Hz, 1 H), 2.96 (d,
J = 13.6 Hz, 1 H), 3.28 (s, 3 H), 4.39–4.56 (m, 2 H), 5.05–5.20 (m,
2 H), 5.25–5.42 (m, 2 H), 5.63–5.81 (m, 1 H), 5.86–6.03 (m, 1 H).
13C NMR (101 MHz, CDCl3):  = 23.0, 24.0, 26.1, 34.6, 37.8, 43.3,
44.5, 45.8, 46.5, 47.7, 62.3, 119.5, 132.5, 132.8, 174.6. MS (TOF ES+):
m/z = 380 (100%). HRMS (TOF ES+): m/z calcd for C17H27NNaO3S2:
380.1330; found: 380.1338.
(7) (a) Hong, F.-L.; Ye, L.-W. Acc. Chem. Res. 2020, 53, 2003.
(b) Campeau, D.; León Rayo, D. F.; Mansour, A.; Muratov, K.;
Gagosz, F. Chem. Rev. 2021, in press DOI: 10.1021/acs.chem-
rev.0c00788. (c) Evano, G.; Lecomte, M.; Thilmany, P.;
Theunissen, C. Synthesis 2017, 49, 3183. (d) Wang, X.-N.; Yeom,
H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.; Kedrowski, B. L.; Hsung, R. P.
Acc. Chem. Res. 2014, 47, 560. (e) DeKorver, K. A.; Li, H.; Lohse, A.
G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010,
110, 5064.
(8) For early examples see: (a) Davies, P. W.; Cremonesi, A.; Martin,
N. Chem. Commun. 2011, 47, 379. (b) Li, C.; Zhang, L. Org. Lett.
2011, 13, 1738. (c) Davies, P. W.; Cremonesi, A.; Dumitrescu, L.
Angew. Chem. Int. Ed. 2011, 50, 8931. (d) Kramer, S.;
Odabachian, Y.; Overgaard, J.; Rottländer, M.; Gagosz, F.;
Skrydstrup, T. Angew. Chem. Int. Ed. 2011, 50, 5090.
(e) Mukherjee, A.; Dateer, R. B.; Chaudhuri, R.; Bhunia, S.; Karad,
S. N.; Liu, R.-S. J. Am. Chem. Soc. 2011, 133, 15372. (f) Dateer, R.
B.; Shaibu, B. S.; Liu, R.-S. Angew. Chem. Int. Ed. 2012, 51, 113.
(g) Rettenmeier, E.; Schuster, A. M.; Rudolph, M.; Rominger, F.;
(13) To complement the 2-thiaspiro[4.5]decane motif 5 accessed
from ynamides 2, their alkyne precursor was tested under the
conditions previously developed for the reaction of terminal
alkynes (see ref. 5), providing access to a 2-thiaspiro[5.5]unde-
can-4-one motif (see SI).
(14) (a) Zheng, Y.; Tice, C. M.; Singh, S. B. Bioorg. Med. Chem. Lett.
2014, 24, 3673. (b) Zheng, Y.-J.; Tice, C. M. Expert Opin. Drug Dis-
covery 2016, 11, 831.
(15) Spagnol, G.; Heck, M.-P.; Nolan, S. P.; Mioskowski, C. Org. Lett.
2002, 4, 1767.
(16) Attempts to extrude sulfur dioxide from 13 were unsuccessful
with no conversion even in diphenyl ether at 280 °C.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–D