Synthesis of Polysubstituted Fused Pyrroles by Gold-Catalyzed Cycloisomerization/1,2-Sulfonyl Migration of Yndiamides

Article abstract of DOI:10.1021/acs.orglett.1c02360

Yndiamides (bis-N-substituted alkynes) are valuable precursors to azacycles. Here we report a cycloisomerization/1,2-sulfonyl migration of alkynyl-yndiamides to form tetrahydropyrrolopyrroles, unprecedented heterocyclic scaffolds that are relevant to medicinal chemistry. This functional group tolerant transformation can be achieved using Au(I) catalysis that proceeds at ambient temperature, and a thermally promoted process. The utility of the products is demonstrated by a range of reactions to functionalize the fused pyrrole core.

Full text of DOI:10.1021/acs.orglett.1c02360

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Letter
Synthesis of Polysubstituted Fused Pyrroles by Gold-Catalyzed
Cycloisomerization/1,2-Sulfonyl Migration of Yndiamides
Philip J. Smith, Yubo Jiang, Zixuan Tong, Helena D. Pickford, Kirsten E. Christensen, Jeremy Nugent,
and Edward A. Anderson*
Cite This: Org. Lett. 2021, 23, 6547−6552
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ABSTRACT: Yndiamides (bis-N-substituted alkynes) are valuable precursors to
azacycles. Here we report a cycloisomerization/1,2-sulfonyl migration of alkynyl-
yndiamides to form tetrahydropyrrolopyrroles, unprecedented heterocyclic scaffolds
that are relevant to medicinal chemistry. This functional group tolerant transformation
can be achieved using Au(I) catalysis that proceeds at ambient temperature, and a
thermally promoted process. The utility of the products is demonstrated by a range of
reactions to functionalize the fused pyrrole core.
ycloisomerization is a powerful method for the synthesis
of nitrogen heterocycles.1 Pyrroles are no exception, for
Scheme 1. (a) Pyrrole Syntheses Involving 1,2-, 1,3-, or 1,4-
Sulfonyl Migrations and (b) 1,2-Sulfonyl Migration of
Yndiamides 1 in the Synthesis of the Unprecedented
Tetrahydropyrrolopyrrole Scaffold 2
C
example, being accessible from unsaturated sulfonamides via
cyclizations that are accompanied by N-to-C migration of the
sulfonyl group.2 Wan and co-workers described the first
example of this strategy,3 in which alkynyl ene-sulfonamides
underwent cyclization under thermal conditions accompanied
by 1,3- or 1,4-sulfonyl migration (Scheme 1, eq 1); soon after,
a gold-catalyzed dehydrative cyclization of alkynyl sulfona-
mides was reported by the Chan group that also involved a 1,3-
sulfonyl shift (eq 2).4 The use of gold catalysis to promote
cycloisomerizations of ynamides has emerged as a rich source
of medicinally relevant heterocycles,5,6 and accordingly,
pyrroles have been prepared by cycloisomerizations of alkynyl
ynamides (Sahoo et al., eq 3)7 and diynamides (Huang et al.,
eq 4),8 accompanied by 1,3/1,5- and 1,3-sulfonyl migrations,
respectively. Contemporaneously with our studies, Gagosz et
al. developed the first 1,2-sulfonyl rearrangement of ynamides,
which under thermal conditions affords fused pyrroles (eq 5).9
Yndiamides [1 (Scheme 1b)] are a relatively new addition to
the ynamide family that feature a nitrogen substituent at both
alkyne termini.10 Building on our interest in transition metal-
catalyzed ynamide cycloisomerization11 and recent exploration
of gold-catalyzed oxidative functionalizations of yndiamides,12
we were keen to explore their reactivity in gold-catalyzed
processes in which cyclization might be achieved. Alkynyl
yndiamides 1 seemed well-suited for this, given the potential
for activation of either triple bond.6,13 Here we described the
successful realization of this gold-catalyzed cycloisomerization,
which unexpectedly resulted in a rare 1,2-migration of the
sulfonyl group to give fused tetrahydropyrrolopyrroles 2;
unlike most previous sulfonyl migrations, the reaction proceeds
under very mild conditions (ambient temperature) due to the
unique activating properties of the yndiamide. The cyclization
can also be achieved under thermal conditions, where it
displays a complementary substrate scope. While benzannu-
Received: July 15, 2021
Published: August 9, 2021
https://doi.org/10.1021/acs.orglett.1c02360
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6547−6552
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lated analogues of 2 (i.e., pyrrole[3,4-b]indoles) are known,14
2 itself represents a novel heterocyclic scaffold; given the
importance of pyrroles in medicinal chemistry, and the value of
methods that expand heterocycle chemical space,16 access to
this new framework could be of significant utility.
As cycloisomerizations formally require no external reagents,
we questioned whether the same transformation could also be
effected in the absence of a catalyst under thermal conditions.9a
In the event, heating 1a at 80 and 110 °C resulted in the
formation of 2a in moderate yield but with significant
decomposition (entries 12 and 13, respectively). Pleasingly,
addition of the radical inhibitor butylated hydroxytoluene
(BHT) significantly improved yields (entries 14−16), with 1.0
equiv of BHT proving optimal (76% isolated yield, entry 15).
While a substoichiometric quantity of BHT was equally
effective for the synthesis of 2a (0.1 equiv, 74%, entry 14), this
loading gave inconsistent results for other substrates. We
therefore elected to investigate the reaction scope using 1.0
equiv of BHT.
Investigations began with alkynyl yndiamide 1a (Table 1),
which was readily prepared from the corresponding benzyl 1,1-
a
Table 1. Optimization of Cycloisomerization Conditions
With optimized conditions for both gold-catalyzed (con-
ditions A, Scheme 2) and thermal (conditions B) cyclo-
isomerizations in hand, the scope of the transformation was
evaluated. Both methods successfully afforded a wide range of
pentasubstituted pyrroles, with several displaying contrasting
behavior between the two conditions. We found that both
reactions performed well on a 1 mmol scale with no detriment
to yield 2a [72% (0.43 g) and 76% (0.46 g) for [Au] and
thermal conditions, respectively]. Aryl-substituted alkynes
(2a−2e) were well tolerated under both gold catalysis (27−
71%) and thermal conditions (63−95%), although the
efficiency of the gold-catalyzed process decreased for
electron-rich aromatics. In contrast, subjecting alkyl alkynyl
yndiamide 1f to gold catalysis gave methyl-substituted
pyrrolopyrrole 2f in 67% yield, whereas no reaction was
observed under thermal conditions. Alkenyl groups were
tolerated under gold catalysis (2g and 2h), although the latter
required an extended reaction time. However, whereas 2h
could also be formed via thermal cycloisomerization, 1g
decomposed when heated. Intriguingly, neither 1g nor 1h
underwent (4+2) cycloaddition under heating, as might have
been expected given the reactivity of analogous ynamides,19
highlighting an aspect of divergence between ynamide and
yndiamide chemistry. A terminal alkyne did not react under
gold promotion, possibly as a result of formation of a σ-
complex between the terminal alkyne and the Au(I) catalyst,20
but did undergo the thermal cycloisomerization, albeit
accompanied by extensive decomposition (2i, 22%).
time
(h)
yield
c
b
entry
additive/catalyst
Me2AuCl
IPrAuNTf2
Me2SAuCl and
AgNTf2
solvent
temp
rt
rt
rt
(%)
1
2
3
DCE
DCE
DCE
18
18
18
19
55
50
4
5
6
7
8
9
10
11
12
13
14
15
16
PPh3AuCl and AgNTf2 DCE
rt
rt
rt
rt
rt
rt
rt
rt
3
3
3
3
3
50
75 (72)
67
PPh3AuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
HNTf2
−
−
−
DCE
CHCl3
CH2Cl2
EtOAc
acetone
DCE
DCE
DCE
PhMe
PhMe
PhMe
PhMe
60
12
<5
3
3
6
18
18
18
18
18
18
nr
38
41
74
80 °C
110 °C
110 °C
110 °C
110 °C
0.1 equiv of BHT
1.0 equiv of BHT
3.0 equiv of BHT
78 (76)
76
a
Reactions carried out on a 0.033 mmol scale under Ar using an
anhydrous solvent. The structure of 2a was determined by single-
crystal X-ray diffraction.15 Abbreviations: BHT, butylated hydrox-
ytoluene; DCE, 1,2-dichloroethane; IPr, 1,3-bis(2,6-diisopropylphen-
b
yl)-2-imidazolidinylidene. All additives/catalysts loads are 10 mol %.
c
Yields determined by quantitative 1H NMR spectroscopy using 1,3,5-
trimethoxybenzene as an internal standard. Yields in parentheses are
isolated yields. nr indicates no reaction.
We next investigated variation of the nonmigrating group on
the pyrrole nitrogen atom (R3). Replacing the N-benzyl group
with an n-butyl chain was reasonably well-tolerated under
thermal conditions (2j−2l, 28−71%), but significant decom-
position was observed under gold catalysis (e.g., 2l, 39%).
Varying the electronic character of the N-benzyl group was
similarly well-tolerated under conditions B (2m and 2n, 66−
72%), whereas the PMB protecting group in 1n was
problematic under gold catalysis, leading to a low yield;
bromide-substituted 1m afforded only trace product.
The scope of the yndiamide EWG groups was next probed.
Changing the sulfonyl protecting group on the internal
nitrogen atom to a methanesulfonyl group maintained high
yields under both Au catalysis and heating (both 72%, 2o).
Variation of the migrating sulfonyl group revealed that aryl
sulfonamides underwent cycloisomerization under both
thermal and gold-catalyzed conditions in moderate to good
yields (2p−2r, 45−81%), albeit more electron-deficient
sulfonamides were less efficient under the latter. An alkyl
sulfonamide was successful only using gold catalysis (2s, 25%),
possibly due to competing deprotonation under thermal
dibromoensulfonamide.10,17 Exposure of 1a to various gold(I)
catalysts (10 mol %) at room temperature led to the formation
of fused pyrrole 2a (entries 1−5), with Ph3PAuNTf2 giving an
optimal isolated yield of 72% after reaction for 3 h (entry 5).17
The identity of 2a was readily confirmed by single-crystal X-ray
diffraction studies,15 including the unexpected 1,2-migration of
the sulfonyl group. Notably, the use of preformed
18
Ph3PAuNTf2 offered a significant benefit over its in situ
formation from PPh3AuCl and AgNTf2, which control
experiments revealed is likely due to competing silver-
promoted decomposition of the yndiamide.17 A solvent screen
identified 1,2-dichloroethane (DCE) as optimal, with other
polar aprotic solvents such as chloroform and dichloromethane
generating 2a in lower yields (entries 6 and 7, respectively) and
ethyl acetate and acetone resulting in extensive decomposition
of 1a (entries 8 and 9, respectively). No reaction was observed
using a Brønsted acid catalyst (HNTf2, entry 10) or in the
absence of a catalyst (entry 11).
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Scheme 2. Scope of Gold-Promoted (conditions A, red yields) and Thermal (conditions B, blue yields) Yndiamide
a
Cycloisomerization
a
b
Reactions carried out on a 0.1 mmol scale, under Ar in an anhydrous solvent; yields are isolated yields. n.r. indicates no reaction On a 1.0 mmol
scale. On a 0.05 mmol scale. Reaction time of 42 h. The structures of 2h and 2t were determined by single-crystal X-ray diffraction.15 Yield not
determined (n.d.) due to significant decomposition. With 3.0 equiv of BHT. With 0.1 equiv of BHT. On a 0.06 mmol scale. Reaction time of 24
h. Reaction not conducted.
c
d
e
f
g
h
i
j
k
conditions to form a sulfene, a pathway that is not possible for
arylsulfonamides.4 Attempts to investigate the migration of an
electron-rich sulfonyl group [4-(MeO)C6H4SO2] were un-
successful, as the corresponding yndiamide was unstable.
Pleasingly, a phosphonate-protected yndiamide also underwent
successful thermal cycloisomerisation in moderate yield (2t,
43%). Whereas reports of sulfonyl migrations (including in
ynamide cycloisomerization) have become more numerous in
recent years,2 equivalent migrations of phosphonate diesters
are, to the best of our knowledge, without precedent.21
Interestingly, equivalent ynamide substrates required extended
reaction times and/or suffered from decomposition under gold
catalysis and proved to be significantly less reactive under
thermal conditions.17
The nature of the sulfonyl migration step was investigated
via a crossover experiment with yndiamides 1d and 1q
(Scheme 3a). No crossover products were observed under
thermal conditions, suggesting that the sulfonyl migration is an
intramolecular process, which is consistent with previously
reported 1,n-sulfonyl/sulfinyl migrations with ynamides as
starting materials.4,7 Equally, no crossover was observed under
gold catalysis.17
intermediate A, followed by an intramolecular 1,2-migration
of the sulfonyl group. A rapid Stevens-type rearrangement may
also be possible involving the transient formation of a sulfonyl
radical B/B′23 that is rapidly captured by the C2-pyrrolyl
radical; both mechanisms would be consistent with the results
of the crossover experiment. There are many proposals of both
radical and polar pathways for sulfonyl migrations in the
literature,2 but as the reaction proceeds efficiently even in the
presence of excess BHT (Table 1, entry 5), the polar migration
process seems more likely.9a The role of the BHT additive
itself is less clear; as it can be used in substoichiometric
amounts, we hypothesize that it sequesters peroxy radicals that
might otherwise initiate diyne degradation pathways.9a,19,24
For the Au-catalyzed reaction (Scheme 3c), we propose
initial coordination of the yndiamide to a π-acidic Au(I)
species, activating the triple bond toward attack by the alkyne
(C).25 For yndiamides, this process would be followed by
formation of a keteniminium ion D, enhancing the electro-
philicity of the π-bond and triggering nucleophilic attack to
give vinyl cation E.26 It is notable that intermediate D cannot
be formed for ynamides (which lack the internal nitrogen
atom), thus explaining their lower reactivity. Vinyl cation E26,27
is then trapped by the external nitrogen atom of the yndiamide,
to form the second ring (F). A 1,2-sulfonyl migration [which
could also be viewed as a (1,5)-sigmatropic rearrangement],
A possible mechanism for the thermal cycloisomerization is
illustrated in Scheme 3b.22 Under these conditions, a
concerted (3+2) cycloaddition could give zwitterionic
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Scheme 3. Crossover Experiment and Mechanistic
Proposals
Scheme 4. Further Transformations of 2a and 2h
a
a
b
On a 0.05 mmol scale. On a 0.025 mmol scale.
form 5 in moderate yield (43%). Treatment of 2a with t-BuOK
in DMSO resulted in a desulfonative Smiles-type rearrange-
ment to form 6. Finally, ozonolysis of the alkene side chain in
2h afforded acyl pyrrole 7 in excellent yield (95%). The ability
to derivatize the core scaffold in this way enhances prospects
for the use of these novel structures in, for example,
pharmaceutical research.
In conclusion, we have developed a novel cycloisomerization
of yndiamides to form fused tetrahydropyrrolopyrroles. The
reaction proceeds under mild conditions using cationic gold
catalysts but can also be performed under thermal conditions
with a complementary substrate scope. The use of gold
catalysts to promote this transformation provides the benefit of
avoiding stoichiometric amounts of the radical inhibitor and
enhances the tolerance of thermally sensitive functional groups.
The highly functionalized nitrogen heterocycles that result
represent an unprecedented bicyclic scaffold, which will be of
interest for medicinal chemistry and biological applications.
The transformation underlines both the utility and the unique
behavior of yndiamides in N-heterocycle synthesis.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02360.
Experimental procedures and characterization data for
novel compounds (PDF)
Accession Codes
a
(a) Reaction carried out on a 0.033 mmol scale, yields determined
CCDC 2090822−2090824 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
by quantitative 1H NMR spectroscopy using 1,3,5-trimethoxybenzene
as the internal standard. (b) Proposed mechanism for thermal
cycloisomerization. (c) Proposed mechanism for Au-catalyzed
cycloisomerization.
followed by aromatizing deauration of G, leads to the product
and re-forms the cationic Au(I) species to complete the
catalytic cycle.
AUTHOR INFORMATION
Corresponding Author
■
The novel bicyclic structures formed in this cycloisomeriza-
tion are appealing from the perspective of expanding
heterocycle chemical space,16 as the sulfonamide protecting
groups present in the products (N-Ts and C-Ts) have the
potential for removal under orthogonal conditions, allowing for
selective postcycloisomerization diversification. For example
(Scheme 4), treatment of 2a with AlCl3 resulted in efficient
substitution of the C-Ts group with chlorine (3, 83%), while
selective removal of the N-Ts protecting group could be
achieved with magnesium to form 4 in good yield (82%).
Hydrogenation of 2a selectively removed the C-Ts group to
Edward A. Anderson − Chemistry Research Laboratory,
Oxford OX1 3TA, U.K.; orcid.org/0000-0002-4149-
0494; Email: edward.anderson@chem.ox.ac.uk
Authors
Philip J. Smith − Chemistry Research Laboratory, Oxford
OX1 3TA, U.K.
Yubo Jiang − Faculty of Science, Kunming University of
Science and Technology, Kunming 650500, China;
orcid.org/0000-0002-6066-4613
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Containing Pyrrolo[2,1-a]isoquinolines from Diynamides: Evidence
for Consecutive Sulfonyl Migration. ACS Catal. 2019, 9, 2610−2617.
(9) (a) Campeau, D.; Pommainville, A.; Gagosz, F. Ynamides as
Three-Atom Components in Cycloadditions: An Unexplored
Chemical Reaction Space. J. Am. Chem. Soc. 2021, 143, 9601−9611.
For examples of gold-catalyzed pyrrole synthesis from ynamides
without sulfonyl migration, see: (b) Tokimizu, Y.; Wieteck, M.;
Rudolph, M.; Oishi, S.; Fujii, N.; Hashmi, A. S. K.; Ohno, H. Dual
Gold Catalysis: A Novel Synthesis of Bicyclic and Tricyclic Pyrroles
from N-Propargyl Ynamides. Org. Lett. 2015, 17, 604−607. (c) Shen,
W.-B.; Zhou, B.; Zhang, Z.-X.; Yuan, H.; Fang, W.; Ye, L.-W. Gold-
catalyzed cascade cyclization of N-propargyl ynamides: rapid access to
functionalized indeno[1,2-c]pyrroles. Org. Chem. Front. 2018, 5,
2468−2472.
Zixuan Tong − Chemistry Research Laboratory, Oxford OX1
3TA, U.K.
Helena D. Pickford − Chemistry Research Laboratory, Oxford
OX1 3TA, U.K.
Kirsten E. Christensen − Chemistry Research Laboratory,
Oxford OX1 3TA, U.K.
Jeremy Nugent − Chemistry Research Laboratory, Oxford
OX1 3TA, U.K.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02360
Notes
(10) Mansfield, S. J.; Christensen, K. E.; Thompson, A. L.; Ma, K.;
Jones, M. W.; Mekareeya, A.; Anderson, E. A. Copper-Catalyzed
Synthesis and Applications of Yndiamides. Angew. Chem., Int. Ed.
2017, 56, 14428−14432.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(11) (a) Mekareeya, A.; Walker, P. R.; Couce-Rios, A.; Campbell, C.
D.; Steven, A.; Paton, R. S.; Anderson, E. A. Mechanistic Insight into
Palladium-Catalyzed Cycloisomerization: A Combined Experimental
and Theoretical Study. J. Am. Chem. Soc. 2017, 139, 10104−10114.
(b) Straker, R. N.; Peng, Q.; Mekareeya, A.; Paton, R. S.; Anderson, E.
A. Computational ligand design in enantio- and diastereoselective
ynamide [5 + 2] cycloisomerization. Nat. Commun. 2016, 7, 10109.
(c) Walker, P. R.; Campbell, C. D.; Suleman, A.; Carr, G.; Anderson,
E. A. Palladium- and ruthenium-catalyzed cycloisomerization of
enynamides and enynhydrazides: A rapid approach to diverse
azacyclic frameworks. Angew. Chem., Int. Ed. 2013, 52, 9139−9143.
(12) Tong, Z.; Garry, O. L.; Smith, P. J.; Jiang, Y.; Mansfield, S. J.;
Anderson, E. A. Au(I)-Catalyzed Oxidative Functionalization of
Yndiamides. Org. Lett. 2021, 23, 4888−4892.
(13) (a) Campeau, D.; León Rayo, D. F.; Mansour, A.; Muratov, K.;
Gagosz, F. Gold-Catalyzed Reactions of Specially Activated Alkynes,
Allenes, and Alkenes. Chem. Rev. 2021, 121, 8756−8867. (b) Asiri, A.
M.; Hashmi, A. S. K. Gold-catalysed reactions of diynes. Chem. Soc.
Rev. 2016, 45, 4471−4503. (c) Harris, R. J.; Widenhoefer, R. A. Gold
carbenes, gold-stabilized carbocations, and cationic intermediates
relevant to gold-catalysed enyne cycloaddition. Chem. Soc. Rev. 2016,
45, 4533−4551.
P.J.S. and H.D.P. thank the EPSRC Centre for Doctoral
Training in Synthesis for Biology and Medicine for student-
ships (EP/L015838/1), generously supported by AstraZeneca,
Diamond Light Source, Defence Science and Technology
Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer,
Syngenta, Takeda, UCB, and Vertex. Y.J. thanks the China
Scholarship Council (201908535023) for financial support.
J.N. thanks the Marie Skłodowska-Curie actions for an
Individual Fellowship (GA No 786683). E.A.A. and J.N.
thank the EPSRC for support (EP/S013172/1).
REFERENCES
■
(1) (a) Marin-Luna, M.; Nieto Faza, O.; Silva Lopez, C. Gold-
catalyzed homogeneous (Cyclo)Isomerization Reactions. Front. Chem.
2019, 7, 296. (b) Lee, Y.-C.; Kumar, K. Gold(I) Catalyzed Enyne
Cycloisomerization − A Roadmap to Privileged Heterocyclic
Scaffolds. Isr. J. Chem. 2018, 58, 531−556. (c) Michelet, V.;
Toullec, P. Y.; Genet, J. P. Cycloisomerization of 1,n-enynes:
Challenging metal-catalyzed rearrangements and mechanistic insights.
Angew. Chem., Int. Ed. 2008, 47, 4268−4315.
(2) Flynn, A. J.; Ford, A.; Maguire, A. R. Synthetic and mechanistic
aspects of sulfonyl migrations. Org. Biomol. Chem. 2020, 18, 2549−
2610.
(14) (a) Welch, W. M. Synthesis of 2-Benzyl-4-phenyl-2,4-
dihydropyrrolo[3,4-b]indole. J. Org. Chem. 1976, 41, 2031−2032.
(b) Gribble, G. W.; Pelkey, E. T.; Simon, W. M.; Trujillo, H. A.
Regioselective 1,3-Dipolar Cycloaddition Reactions of Unsymmetrical
(3) Xin, X.; Wang, D.; Li, X.; Wan, B. Highly Regioselective
Migration of the Sulfonyl Group: Easy Access to Functionalized
Pyrroles. Angew. Chem., Int. Ed. 2012, 51, 1693−1697.
(4) Teo, W. T.; Rao, W.; Koh, M. J.; Chan, P. W. H. Gold-Catalyzed
Domino Aminocyclization/1,3-Sulfonyl Migration of N-Substituted
N-Sulfonyl-aminobut-3-yn-2-ols to 1-Substituted 3-Sulfonyl-1H-pyr-
roles. J. Org. Chem. 2013, 78, 7508−7517.
Munchnones (1,3-Oxazolium-5-olates) with 2- and 3-Nitroindoles. A
̈
New Synthesis of Pyrrolo[3,4-b]indoles. Tetrahedron 2000, 56,
10133−10140. (c) Pindur, U.; Erfanian-Abdoust, H. Indolo-2,3-
quinodimethanes and stable cyclic analogs for regio- and stereo-
controlled syntheses of [b]-annelated indoles. Chem. Rev. 1989, 89,
1681−1689.
(5) (a) Hong, F. L.; Ye, L. W. Transition metal-catalyzed tandem
reactions of ynamides for divergent N-heterocycle synthesis. Acc.
Chem. Res. 2020, 53, 2003−2019. (b) Pan, F.; Shu, C.; Ye, L.-W.
Recent progress towards gold-catalyzed synthesis of N-containing
tricyclic compounds based on ynamides. Org. Biomol. Chem. 2016, 14,
9456−9465. (c) Wang, X.-N.; Yeom, H.-S.; Fang, L.-C.; He, S.; Ma,
Z.-X.; Kedrowski, B. L.; Hsung, R. P. Ynamides in Ring Forming
Transformations. Acc. Chem. Res. 2014, 47, 560−578.
(6) For a recent review of unsaturated ynamide cycloisomerizations,
see: Prabagar, B.; Ghosh, N.; Sahoo, A. K. Cyclization and
Cycloisomerization of π-Tethered Ynamides: An Expedient Synthetic
Method to Construct Carbo- and Heterocycles. Synlett 2017, 28,
2539−2555.
(7) Prabagar, B.; Mallick, R. K.; Prasad, R.; Gandon, V.; Sahoo, A. K.
Umpolung Reactivity of Ynamides: An Unconventional [1,3]-Sulfonyl
and [1,5]-Sulfinyl Migration Cascade. Angew. Chem., Int. Ed. 2019, 58,
2365−2370.
(8) Liu, J.; Chakraborty, P.; Zhang, H.; Zhong, L.; Wang, Z. X.;
Huang, X. Gold-Catalyzed Atom-Economic Synthesis of Sulfone-
(15) Low-temperature single-crystal X-ray diffraction data for 2a, 2h,
and 2t were collected using a Rigaku Oxford SuperNova
diffractometer at 150 K. Raw frame data were reduced using
CrysAlisPro, and the structures were determined using ‘Superflip’ (
Palatinus, L.; Chapuis, G. J. Appl. Crystallogr. 2007, 40, 786−790. )
before refinement with CRYSTALS [ (a) Parois, P.; Cooper, R. I.;
Thompson, A. L. Crystal structures of increasingly large molecules:
meeting the challenges with CRYSTALS software. Chem. Cent. J.
2015, 9, 30. (b) Cooper, R. I.; Thompson, A. L.; Watkin, D. J. J. Appl.
Crystallogr. 2010, 43, 1100−1107. ]. Further details about the
refinements, including disorder modeling and restraints, are
documented in the CIF. Crystallographic data have been deposited
with the Cambridge Crystallographic Data Centre (CCDC 2090822−
2090824) and can be obtained via www.ccdc.cam.ac.uk/data_
request/cif.
(16) (a) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the
structural diversity, substitution patterns, and frequency of nitrogen
heterocycles among U.S. FDA approved pharmaceuticals. J. Med.
Chem. 2014, 57, 10257−10274. (b) Taylor, R. D.; MacCoss, M.;
6551
https://doi.org/10.1021/acs.orglett.1c02360
Org. Lett. 2021, 23, 6547−6552

Organic Letters
pubs.acs.org/OrgLett
Letter
Lawson, A. D. G. Rings in Drugs. J. Med. Chem. 2014, 57, 5845−5859.
(c) Pitt, W. R.; Parry, D. M.; Perry, B. G.; Groom, C. R.
Heteroaromatic Rings of the Future. J. Med. Chem. 2009, 52,
2952−2963.
(17) See the Supporting Information for details.
(18) Mézailles, N.; Ricard, L.; Gagosz, F. Phosphine Gold(I) Bis-
(trifluoromethanesulfonyl)imidate Complexes as New Highly Effi-
cient and Air-Stable Catalysts for the Cycloisomerization of Enynes.
Org. Lett. 2005, 7, 4133−4136.
(19) Dunetz, J. R.; Danheiser, R. L. Synthesis of highly substituted
indolines and indoles via intramolecular [4 + 2] cycloaddition of
ynamides and conjugated enynes. J. Am. Chem. Soc. 2005, 127, 5776−
5777.
(20) (a) Fabian León Rayo, D.; Hong, Y. J.; Campeau, D.; Tantillo,
D. J.; Gagosz, F. On the Mechanism of Au-Catalyzed Enynamide-yne
Dehydro-Diels-Alder Reactions: An Experimental and Computational
Study. Chem. - Eur. J. 2021, 27, 10637−10648. (b) Long, N. J.;
Williams, C. K. Metal alkynyl σ complexes: Synthesis and materials.
Angew. Chem., Int. Ed. 2003, 42, 2586−2617.
(21) For examples in which a phosphonate diester is resistant to
migration in ynamide chemistry, see: (a) Dekorver, K. A.; Walton, M.
C.; North, T. D.; Hsung, R. P. Introducing a new class of N-
phosphoryl ynamides via Cu(I)-catalyzed amidations of alkynyl
bromides. Org. Lett. 2011, 13, 4862−4865. (b) Dekorver, K. A.;
Wang, X. N.; Walton, M. C.; Hsung, R. P. Carbocyclization cascades
of allyl ketenimines via aza-Claisen rearrangements of N-phosphoryl-
N-allyl-ynamides. Org. Lett. 2012, 14, 1768−1771.
(22) The mechanism proposed here is consistent with that
elucidated compuationally for ynamide cyclizations in ref 9, reported
immediately prior to the submission of our manuscript.
(23) Pan, X.-Q.; Zou, J.-P.; Yi, W.-B.; Zhang, W. Recent advances in
sulfur- and phosphorous-centered radical reactions for the formation
of S−C and P−C bonds. Tetrahedron 2015, 71, 7481−7529.
(24) Ingold, K. U.; Pratt, D. A. Advances in Radical-Trapping
Antioxidant Chemistry in the 21st Century: A Kinetics and
Mechanisms Perspective. Chem. Rev. 2014, 114, 9022−9046.
(25) Hashmi, A. S. K. Homogeneous Gold Catalysis Beyond
Assumptions and ProposalsCharacterized Intermediates. Angew.
Chem., Int. Ed. 2010, 49, 5232−5241.
(26) Wurm, T.; Bucher, J.; Duckworth, S. B.; Rudolph, M.;
Rominger, F.; Hashmi, A. S. K. On the Gold-Catalyzed Generation of
Vinyl Cations from 1,5-Diynes. Angew. Chem., Int. Ed. 2017, 56,
3364−3368.
(27) (a) Odabachian, Y.; Le Goff, X. F.; Gagosz, F. An Unusual
Access to Medium Sized Cycloalkynes by a New Gold(I)-Catalysed
Cycloisomerisation of Diynes. Chem. - Eur. J. 2009, 15, 8966−8970.
(b) Lin, Y.; Zhou, T.; Guo, W.; Teng, Z.; Xia, Y. The mechanism of
the gold-catalyzed intramolecular [3 + 2]-cycloaddition of 1,6-diynes:
a DFT study. Dalton Trans 2019, 48, 5698−5704.
6552
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Org. Lett. 2021, 23, 6547−6552