Divergent Construction of Fully Substituted Pyrroles and Cyclopentadiene Derivatives by Ynamide Annulations: 1,2-Cyclopropyl Migration versus Proton Transfer

Article abstract of DOI:10.1021/acs.orglett.0c01819

A switchable cyclopropyl ynamide cyclization to construct fully substituted pyrroles and cyclopentadiene derivatives in the presence of a gold catalyst was developed. In this version of pyrrole generation, a novel method to furnish gold vinylidenes through [1,2]-cyclopropyl migration was described. On the contrary, the production of cyclopentadienes proceeded through a proton-transfer step. These intriguing mechanisms were proposed based on the structure identification of the alkynyl enamine intermediate and a crossover experiment. The feasibility of cyclobutyl ynamides to specifically construct cyclopentadienes through ring expansion was also investigated.

Full text of DOI:10.1021/acs.orglett.0c01819

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Letter
Divergent Construction of Fully Substituted Pyrroles and
Cyclopentadiene Derivatives by Ynamide Annulations: 1,2-
Cyclopropyl Migration versus Proton Transfer
Wenqing Zang, Yin Wei, and Min Shi*
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ABSTRACT: A switchable cyclopropyl ynamide cyclization to construct fully substituted pyrroles and cyclopentadiene derivatives
in the presence of a gold catalyst was developed. In this version of pyrrole generation, a novel method to furnish gold vinylidenes
through [1,2]-cyclopropyl migration was described. On the contrary, the production of cyclopentadienes proceeded through a
proton-transfer step. These intriguing mechanisms were proposed based on the structure identification of the alkynyl enamine
intermediate and a crossover experiment. The feasibility of cyclobutyl ynamides to specifically construct cyclopentadienes through
ring expansion was also investigated.
(Scheme 1a).8 In 2019, Sahoo’s group reported a gold-
wing to their easy availability and high reactivity,
Oynamide derivatives have been extensively used for the catalyzed intramolecular cycloisomerization of yne-tethered
ynamide to furnish multisubstituted pyrroles based on an
umpolung strategy (Scheme 1b).9 Pioneered by these excellent
works as well as upon the consideration of a few investigations
of the transformation of cycloalkyl ynamides,10 we envisioned
that the installment of strained small cycloalkyl groups on the
alkyne moiety may exhibit diversified reaction pathways upon
gold catalysis.11 In this scenario, we wish to depict the
feasibility of cyclopropyl or cyclobutyl ynamide cyclizations to
realize the divergent synthesis of fully substituted pyrrole and
cyclopentadiene derivatives under gold catalysis. Notably, a
possible pattern to generate gold vinylidene species12 through
an unconventional [1,2]-cyclopropyl migration was discovered
in this version of pyrrole generation, whereas the cyclo-
pentadienes were produced by proton transfer. In addition,
synthesis of versatile N-heterocyclic molecules such as pyrroles
and quinolines. Ynamides can be regioselectively activated by
an electrophile to initiate various intra- or intermolecular
cyclizations with either nucleophiles or dipoles in these
reactions.1 During the last several decades, the use of gold
catalysis in organic synthesis has been thoroughly investigated
due to its unique performance as a Lewis acid catalyst, π-
activator, or carbenoid intermediate.2 In particular, electro-
philic gold catalysts have become a powerful and useful
synthetic tool for catalyzing a wide variety of cyclization
reactions initiated by nucleophilic attack on activated
unsaturated bonds such as alkyne,3 allene,4 or olefin5 moieties.
Among them, the annulation of ynamides in gold catalysis has
attracted considerable attention.6
Employing anthranils, 1,2-benzisoxazoles, alkenes, or azide
analogues as nucleophiles, the regulation of selectivity has
deserved priority in ynamide cyclizations.7 However, alkynes
are rarely treated as counterparts in these transformations.
In 2011, a gold-catalyzed ynamide dimerization to construct
a cyclopentadiene structure through a keteniminium inter-
mediate was described by Gagosz, Skrydstrup, and coworkers
Received: June 1, 2020
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© XXXX American Chemical Society
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A

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the additives was examined in the reaction, and we found that
adding AgOTf could afford 2a in a higher yield of 61% (Table
1, entries 4−7).13 Next, the solvent effect was thoroughly
investigated by using toluene, DCM, CH3CN, dioxane, PhF,
and chlorobenzene (PhCl) as the solvents, revealing that PhCl
was the best one to deliver 2a in 70% yield (62% isolated
yield) (Table 1, entries 8−13), which was eventually
considered to be the optimized conditions (Table 1, entry
13). The yield of 2a sharply dropped to 52% when the gold
catalyst loading was increased to 10 mol %, perhaps due to the
fact that the higher catalyst loading accelerated the
precipitation of gold(0) in the presence of reducing substrates
(Table 1, entry 14).14 Using prepared IPrAuOTf as the catalyst
provided no target product, suggesting that the catalytic
process may exhibit a “silver effect” (Table 1, entry 15).15 The
control experiment indicated that no 2a was generated in the
absence of a gold catalyst (Table 1, entry 16). It should also be
mentioned that cyclopentadiene derivative 3a was detected as
a byproduct during these screening processes. The structure of
2a has been unequivocally confirmed by X-ray diffraction. (See
the Supporting Information.)
Having established the optimal reaction conditions, we
decided to investigate the substrate scope, and the results are
summarized in Scheme 2. First, when R1 was a Me group,
employing phenylsulfonyl ynamide 1b as the substrate, the
corresponding fully substituted pyrrole 2b could be delivered
in 73% yield. Then, we examined the reaction outcomes by
using 1 with different electron-donating-group (EDG)-
substituted phenyls as substrates. As can be seen from Scheme
2, for substrates 1c−i, the reactions proceeded smoothly in
PhCl, furnishing the corresponding products 2c−i in 48−84%
yields. In particular, substrate 1i bearing a Ph group afforded
the desired product 2i in 84% yield. When an electron-
withdrawing group (EWG) was substituted on the phenyl
Scheme 1. Gold(I)-Catalyzed Annulation of Ynamides to
Construct Cyclic Compounds
cyclobutyl ynamides could specifically yield a fused cyclo-
pentadiene backbone through the ring expansion process
(Scheme 1, this study).
The examination of the optimal reaction conditions was
conducted by applying 1a as a model substrate, and the results
are summarized in Table 1. First, using NaBArF as the
counterion, we examined the gold catalysts with different
phosphine ligands such as PPh3AuCl (5 mol %) and
JohnPhosAuCl (5 mol %) in 1,2-DCE, but we found that
the reaction did not afford the desired product (Table 1,
entries 1 and 2). However, when IPrAuCl (5 mol %), an
NHC-ligated (N-heterocyclic-carbene-type ligand) gold com-
plex, was used as the catalyst, the desired pyrrole product 2a
was given in 60% yield within 6 h (Table 1, entry 3). The use
of silver salts such as AgBF4, AgNTf2, AgOTf, and AgSbF6 as
Table 1. Optimization of the Reaction Conditions for Gold(I)-Catalyzed Transformation of 1a to 2a and 3a
a
yield (%)
b
entry
Au cat (5 mol %)
[Ag] or additive (5 mol %)
solvent
2a
3a
1
2
3
4
5
6
7
8
PPh3AuCl
JohnPhosAuCl
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
NaBArF
NaBArF
NaBArF
AgBF4
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
toluene
DCM
CH3CN
dioxane
PhF
PhCl
PhCl
N.D.
N.D.
60
48
50
61
54
60
16
trace
trace
57
70 (62)
52
17
14
16
18
16
16
6
AgNTf2
AgOTf
AgSbF6
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
9
10
11
12
13
14
15
16
24
24 (20)
c
c
IPrAuCl
IPrAuOTf
AgOTf
23
PhCl
PhCl
N.D.
N.D.
AgOTf
a
b
Yield was determined by 1H NMR yield using 1-bromo-4-methoxybenzene as an internal standard. Reaction scale is 0.1 mmol of 1a in anhydrous
c
solvent (0.1 M) at rt for 6 h. 10 mol %, 1 h.
B
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in Scheme 3. When R1 is an ethyl group and R2 is an aromatic
sulfonyl moiety having no substitution or bearing an EDG or
Scheme 2. Substrate Scope of Ynamides 1 to Produce
Pyrroles 2 with Cyclopentadienes 3 as Byproducts
a
Scheme 3. Substrate Scope of Ynamides 1 to Specifically
a
Deliver Cyclopentadienes 3
a
General conditions: 1 (0.2 mmol), IPrAuCI (5 mol %) and AgNTf2
(5 mol %) in 1,2-DCE (0.1 M) with 3 Å MS at 80 °C, 24 h. All yields
are the isolated yields.
EWG substituent, the reactions could afford the corresponding
products 3t−w in moderate yields ranging from 35 to 47%.
Moreover, the benzyl group was also tolerated, giving the
desired product 3x in 24% yield. The reaction also occurred
when the R2 group was switched to a nPr or a nBu group, giving
the corresponding products 3y and 3z in 35% yields,
respectively.
a
General conditions: 1 (0.2 mmol), IPrAuCI (5 mol %), and AgOTf
b
(5 mol %) in PhCI (0.1 M) at rt, 12 h. All yields are the isolated
yields. (The yields of side product 3 are presented in parentheses.)
c
80 °C.
To clarify the reaction mechanism, several control experi-
ments were carried out, as shown in Scheme 4. First, we
quenched the reaction after 30 min under the standard
conditions, and an alkynyl enamine intermediate F was isolated
in 42% yield, indicating that a [1,2]-cyclopropyl migration
moiety in substrates 1j to 1o, even upon introducing CN and
CO2Me substituents, the desired products 2j−o were still
given in moderate to good yields ranging from 50 to 71% after
increasing the reaction temperature to 80 °C. The reaction also
performed well when a vinyl group was installed on the phenyl
moiety, giving the corresponding product 2p in a yield of 58%.
Changing the phenyl group to a 2-naphthyl group, the desired
product 2q was obtained in 60% yield. A heteroaromatic group
was also tolerated, furnishing the desired product 2r in 89%
yield. Moreover, the substrate 1s bearing an aliphatic sulfonyl
group was also compatible, giving the desired product 2s in
58% yield after increasing the reaction temperature to 80 °C.
However, when R1 was a phenyl group, the reaction afforded
no desired pyrrole products. It should also be noted that the
isolated yields of the corresponding byproduct cyclopenta-
dienes 3 are summarized in parentheses in Scheme 2.
Scheme 4. Control Experiments
Interestingly, when an alkyl group other than a methyl group
was substituted at the R1 position, the substrates could
undergo a specific reaction pathway to produce cyclo-
pentadiene backbones 3 without the formation of correspond-
ing pyrroles. This may be due to the stronger hyperconjugation
of the C−C σ bond than that of the C−H σ bond on the alkyl
group (donor orbital) with an N-cationic unit (vacant p
orbital) (see Scheme 5 for the description), which can provide
a more stable keteniminium intermediate for intermolecular
dimerization instead of intramolecular rearrangement.16 After
the reaction conditions were screened by using 1t as a model
substrate (see Table S1 in the Supporting Information), we
decided to conduct the reaction in 1,2-DCE and apply
IPrAuCl/AgNTf2 (5 mol %) as the optimal catalyst to
investigate the substrate scope, and the results are summarized
C
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indeed took place in the catalytic cycle, and the reaction may
proceed through the corresponding gold vinylidene complexes.
The structure of species F has been unequivocally confirmed
by X-ray diffraction. In addition, the isolated intermediate F
could be further transformed to the desired product 2b in 86%
yield under the standard conditions, and no 2b was detected in
the absence of gold catalyst (Scheme 4a). A crossover
experiment was also conducted upon treating 1c with 1h
under the standard conditions. We found that the products
were afforded with no selectivity, and a mixture of homodimers
and crossover heterodimers was produced (Scheme 4b). This
result further indicated a dimerization process of ynamides.
Moreover, by employing gem-dimethyl or phenyl ynamides
instead of cyclopropyl ynamides, none of the desired pyrroles
were detected as products (Scheme 4c). This result indicated
the unique character of the cyclopropane moiety in the
reaction.
Scheme 6. Plausible Reaction Mechanism for Substrates 1b
Dimerization to Give Cyclopentadienes 3b
On the basis of these mechanistic studies and previous
works, a plausible mechanism17 for the transformation of 1 to
2 is outlined in Scheme 5. As for substrate 1b, the coordination
Scheme 5. Plausible Reaction Mechanism for the
Transformation of Ynamides 1 to Pyrroles 2
migration, the intermediate A′ would undergo an intermo-
lecular nucleophilic attack of 1b, giving rise to keteniminium
species G. A subsequent [1,5]-H shift followed by a metalla-
Nazarov cyclization would lead to a gold carbenoid
intermediate I through intermediate H. Then, a proton
transfer could furnish intermediate J, and the cyclopentadiene
3b would be finally produced through the protodeauration of
the gold catalyst.
To further extend the reaction scope, the examination of
cyclobutyl ynamides 4 was performed as the last part of this
scenario (Scheme 7). Substituted by a methyl group at the R4
position, either an EWG or an EDG on the phenylsulfonyl
moiety, the reactions efficiently proceeded, affording the
corresponding cyclopentadiene products 5a−h through ring
Scheme 7. Substrate Scope of Ynamides 4 to
a
Cyclopentadienes 5 and 5′
with the employed gold catalyst gives intermediate A, which
undergoes a [1,2]-cyclopropyl migration, affording vinyl gold
carbenoid intermediate B, followed by the nucleophilic
addition of another molecule of substrate 1b to this gold
vinylidene complex, leading to the formation of the
keteniminium species C. Next, an intramolecular C−N bond
formation and 1,2-sulfonyl shift process occur in concert to
render an intermediate D.18 Subsequently, 1,2-migration of the
sulfonyl group takes place again to form pyrrolyl intermediate
E. Finally, species E undergoes a gold elimination to afford the
desired product 2b along with the regeneration of the gold
catalyst. During this catalytic cycle, the existence of
intermediate F, which is derived from an N-nucleophilic attack
on the keteniminium unit from intermediate C followed by
another C−N bond cleavage, also contributes to the
generation of intermediate D under gold catalysis. (See the
Supporting Information for more details.)
a
General conditions: 4 (0.2 mmol), PPh3AuNTf2 (5 mol %) in 1,2-
b
In terms of the dimerization of cyclopentadiene compounds
3 from ynamides 1, an alternative mechanism is demonstrated
in Scheme 6.8 Instead of the intramolecular cyclopropyl
DCE (0.1 M) at rt, 12 h. All yields are the isolated yields. (The total
yields of isomers 5 and 5′ are presented in parentheses.) 60 °C. 80
°C.
c
d
D
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expansion in moderate to good yields ranging from 52 to 68%.
(The detailed mechanism is depicted in Scheme S1.) A
heteroaromatic group was also tolerated, furnishing the desired
product 5i in 60% yield. Moreover, the ratios of products 5′,
which are the regioisomers of 5, are also listed in Scheme 7.
The reaction also proceeded smoothly when R4 was switched
to other alkyl groups, giving 5j′−m′ in 62−73% yields as single
regioisomers after increasing the reaction temperature to 60
°C. The reaction also proceeded smoothly when R5 was a Ms
group, producing 5n′ in 45% yield. The structures of 5a′, 5i,
and 5l′ have been unequivocally confirmed by X-ray
diffraction. (See the Supporting Information.) It should also
be mentioned that the cyclopentyl ynamide only gave rise to a
complex mixture.
In summary, we have discovered gold-catalyzed cyclopropyl
ynamide cyclizations to selectively synthesize fully substituted
pyrroles and cyclopentadiene derivatives. In this version of
pyrrole construction, an unconventional pattern to generate
gold vinylidene species through [1,2]-cyclopropyl migration
was proposed. On the contrary, the cyclopentadienes were
produced through proton transfer. Moreover, the dimerization
of cyclobutyl ynamides could specifically produce cyclo-
pentadienes through ring expansion. Further investigations of
the mechanistic details and exploration of new methodologies
based on this new gold carbene generation process are
currently underway in our laboratory.
Chemistry, Chinese Academy of Sciences, Shanghai 200032,
China; orcid.org/0000-0003-0484-9231
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01819
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the Strategic Priority
Research Program of the Chinese Academy of Sciences (grant
no. XDB20000000) and sioczz201808 and the National
Natural Science Foundation of China (nos. 21372250,
21121062, 21302203, 20732008, 21772037, 21772226,
21861132014, and 91956115) and the Shenzhen Nobel Prize
Scientists Laboratory Project. Dedicated to the 70th
anniversary of the Shanghai Institute of Organic Chemistry
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01819.
1
Experimental procedures, characterization data, and H
and 13C NMR spectra for new compounds (PDF)
Accession Codes
CCDC 1907300, 1919649, 1948342, 1952765, and 1995246
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.ca-
m.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.
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AUTHOR INFORMATION
■
Corresponding Author
Min Shi − State Key Laboratory of Organometallic Chemistry,
Center for Excellence in Molecular Synthesis, University of
Chinese Academy of Science, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032,
China; orcid.org/0000-0003-0016-5211; Email: mshi@
mail.sioc.ac.cn; Fax: 86-21-64166128
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Wenqing Zang − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
University of Chinese Academy of Science, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai
200032, China
Yin Wei − State Key Laboratory of Organometallic Chemistry,
Center for Excellence in Molecular Synthesis, University of
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(a) Allegue, D.; Gonzalez, J.; Fernandez, S.; Santamaría, J.;
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