Highly Regioselective Synthesis of Multisubstituted Pyrroles via Ag-Catalyzed [4+1C]insert Cascade

Article abstract of DOI:10.1021/acscatal.9b05360

An efficient [4+1C]^insert approach to the coupling of enaminones with donor/acceptor or donor/donor carbenes by the AgOTf-catalyzed C-C bond carbenoid formal insertion/cyclization/[1,5]-shift cascade reaction was successfully developed, providi

Full text of DOI:10.1021/acscatal.9b05360

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Letter
Highly Regioselective Synthesis of Multisubstituted
Pyrroles via Ag-Catalyzed [4+1C]insert Cascade
Kaixiu Luo, Shuai Mao, Kun He, Xianglin Yu, Junhong Pan, Jun Lin, ZhiHui Shao, and Yi Jin
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b05360 • Publication Date (Web): 06 Feb 2020
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ACS Catalysis
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Highly Regioselective Synthesis of Multisubstituted Pyrroles via Ag-
Catalyzed [4+1C]insert Cascade
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Kaixiu Luo,†,§ Shuai Mao, ‡,§ Kun He,† Xianglin Yu,† Junhong Pan,† Jun Lin,†,* Zhihui Shao,†,* and Yi
Jin†,*
† State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Key Laboratory of Medicinal for
Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan
University, Kunming 650091, China.
‡ Department of Medicinal Chemistry, School of Pharmacy, Xi’an Jiaotong University, Xi’an 710061, China.
ABSTRACT: An efficient [4+1C]insert approach to the coupling of enaminones with donor/acceptor or donor/donor carbenes by
AgOTf catalyzed C‒C bond carbenoid formal insertion/cyclization/[1,5]-shift cascade reaction was successfully developed,
providing distinct chemo- and regio-selective multisubstituted pyrroles. The plausible reaction mechanism involves two catalytic
cycles: in the first one, silver ions regioselectively catalyze the C–C bond formal insertion reaction; in the second one, silver ions
chemo- and regio-selectively control the cyclization and [1,5]-shift reactions. This method not only provides convenience and
applies atom economy in the synthesis multisubstituted pyrroles but also presents an entry point for further pyrrole diversification
via facile modification of resulting 4-H-pyrrole products, as displayed by a short formal synthesis of the natural product lamellarin
L.
KEYWORDS: C–C insertion, [4+1C], [1,5]-shift, cascade, pyrrole.
Multisubstituted pyrroles, which are valuable five-membered
heterocycles, are found in various biologically active natural
Scheme 1. Synthetic Strategies Used to Prepare Pyrroles
products, pharmaceuticals, and materials.1 Various synthetic
a
. Previous work: [4+1N], [2+2+1] and [3+2]
R3 R3
strategies, including [4+1N], [3+2], and [2+2+1] cycloaddition
or coupling (Scheme 1a), have been developed toward pyrrole
R3
R2
R3
R2
R4
R5
R4
R5
R4
R5
R4
R5
R4
R5
R3
2,3
architecture. However, the direct, region-defined synthesis
R2
R2
R2
of multisubstituted pyrroles remains a significant challenge.2a,
N
R1
N
R1
N
N
R1
N
R1
R1
2c,4
To develop a complementary approach to diversely
[2+2+1]
[3+2]
[4+1N]
substituted pyrroles, we envisage the retrosynthetic possibility
of knocking out a carbon atom on the pyrrole ring to design a
[4+1C]insert cascade reaction (Scheme 1b).5
. This work: [4+1C]insert (C-C insertion/cyclization/[1,5]-shift cascade)
b
R3
R2
X
R3 R4
O
HN
Cat. AgOTf
R4
R1
Remarkable progress in metal-/organo-catalytic cascade
reactions has been reported over the past two decades.6
Exploring new types of cascade transformation attracts
considerable research interest. Transition metal-catalyzed
carbon insertion into C–C bond is recently emerging as a
promising synthetic process;7,8 however, this type of reaction
is rarely used to initiate a cascade transformation.9 To expand
the classes and utilities of cascade transformation, we report
on a type of cascade transfromation involving a previously
unreported AgOTf catalyzed carbenoid C–C bond insertion
into enaminone10 compounds, which chemoselectively and
regioselectively yield multisubstituted pyrroles. The Bi
research group recently disclosed a formal insertion of diazo
compounds into the C–C bond of 1,3-dicarbonyl species to
produce acyclic 1,4-dicarbonyl products.8a,8j No previous
studies the synthesis of pyrrole by C–C insertion cascade have
thus far been reported. Our [4+1C]insert cascade reaction not
only represents a new type of cascade transformation but also
constitutes a complementary process toward multisubstituted
pyrroles with excellent chemo- and regio-selectivities.
+
R1
N
R2
Challenges
Reactivity
X = N2 or NNHTs
Regioselectivity
Chemoselectivity
O
R3 R4
N
C-C
Insertion
R1
R2
Cyclization
& 1,5-Shift
α-Diazocarbonyl compounds are important synthons
exhibiting rich and unexpected chemistry.7a,7c,11 Many research
groups,12 including Wang,12a Feng,9a Beller,12g and our
group,12c have demonstrated that metal carbene originating
from α-diazocarbonyl compounds can engage in cascade
reactions where the metal carbene triggers subsequent inter-
/intramolecular transformation. Enaminones have also recently
attracted particular attention because of the unique push–pull
electronic properties of the C–C double bond.13 On the basis of
achievements in carbene chemistry by silver–catalysis,14 we
investigated whether low-cost silver catalysis could be used to
mediate C–C bond cascade transformation. This process is
highly favorable for the synthesis of multisubstituted pyrroles,
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considering its potential to minimize the degree of trifluoro-methane-sulfonates
Page 2 of 8
failed
to
realize
such
1
2
3
4
5
6
7
8
functionality required for a starting material.
transformation (Table 1, entries 5-15). Solvent screening
revealed that CH2Cl2 was the best solvent; by contrast, THF or
CH3CN as the reaction solvent reduced the yield of the
reaction to varying degrees. Room temperature was also
determined as the best temperature for the reaction. The
optimal catalyst dosage was determined as 5 mol% (Table S2,
SI). The increase (entry 20) or decrease (entry 19) in catalyst
dosage reduced the reaction efficiency. The yield of the
desired product 3a was not increased by extending the reaction
time to 24 h.
Toward this goal, we developed a [4+1C]insert approach to
the coupling of enaminones with donor/acceptor or
donor/donor carbenes by AgOTf-catalyzed C–C bond
carbenoid insertion/cyclization/[1,5]-shift cascade reaction,
providing distinct chemo- and regio-selective multisubstituted
pyrroles.
Table 1. Optimization of Reaction Conditions for [4+1C]insert
Cascadea
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MeOOC
Ph
Ph
Table 2. Reaction Scope of Enaminones 1 with Aryl
Diazoesters 2a
Ph
Ph
COOMe
N
N
Ph
3a
Ph
3a'
Ph
Ar
O
HN
Cat. (x mol%)
Solvent, Temp.
AgOTf (5 mol%)
CH2Cl2, rt, 12 h
N2
R2
N2
+
O
HN
Ph
Ph
COOMe
Ph
COOMe
COOR3
Ph
Ph
COOMe
(1.2 equiv.)
+
R1
Ar
COOR3
N
R1
N
-
2
R2
1a
2a
(1.0 equiv.)
Ph
3b
N
N
1
2
(1.0 equiv.)
(1.2 equiv.)
Ph
3a''
Ph
Ph
Ph
Ph
COOMe
3b
3c
3d
, 77% R = 3-Me
, 75% R = 3-OMe
, 83% R = 4-Br
Ph
3a'''
Ph
COOMe
Yield (%)b
COOMe
N
3e
COOMe , 92% R = 3-F
N
N
N
R
S
3f
,
90% R = 4-NO2
, 72% R = 4-OMe
, 81% R = 3-Br
Ph
Ph
Ph
Ph
3g
3h
Entry
1
Cat. (x mol %)
Pd(OAc)2 (5)
Rh2(OAc)4 (5)
AgOAc (5)
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
T (ºC)
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
40
25
25
3a
2
3a', 3a'', and 3a'''
3i
3j
3k
, 79%
, 63%
, 76%
3b 3h
-
R
ndc
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
3m
, 76% R = 4-Cl
71% R = 4-F
72% R = 3-F
Ph
3n
3o
3p
3q
3r
,
,
,
,
S
2
4
59% R = 2-F
COOMe
Ph
N
89% R = 4-OMe Ph
88% R = 4-Me
86% R = 2-Me
COOMe
N
Ph
COOMe
COOMe
N
3
34
5
Ph
N
,
Ph
3s
,
Ph
Ph
3l
4
PPh3AuNTf2 (5)
CF3CO2Ag (5)
Ag2CO3 (5)
AgNO3 (5)
, 84%
Ph
3m-3s
3t, 84%
R'
3u, 82%
R' = 2-F
R' = 4-OMe
, 78% R = 4-OMe, R' = 4-OMe
, 80% R = 4-Br, R' = 4-Cl
Ph
3aa
, 81% R = 3-F,
, 89% R = 4-F,
3y
, 80% R = 4-Br
3z, 73% R = 3-Me
COOEt
3ab
3ac
3ad
5
52
0
3a
3v
3w
, 89% R = Me
, 79% R = Et
, 68% R = i-Bu
N
R
6
COOR
Ph
N
Ph
3x
, 59% R = isopentyl
S
COOMe
Ph
3a, 3v 3x
N
R
7
3
3y-3z
3aa-3ad
-
Ph
CH3
8
AgOTf (5)
89
21
0
COOMe
N
S
Ph
9
AgF (5)
S
3ah
, 56%
10
11
12
13
14
15
16
17
18
19d
20d
PhCO2Ag (5)
C3F7CO2Ag (5)
Yb(OTf)3 (10)
La(OTf)3 (10)
Sc(OTf)3 (10)
Ca(OTf)3 (10)
AgOTf (5)
Ph
COOMe
COOMe
COOMe
Ph
N
N
N
MeO
S
Ph
Ph
Ph
26
0
COOMe
, 74%
N
3ae
3af
3ag
, 61%
, 68%
R
, 74%
3ai
Ph
COOMe
Ph
MeO
R1
COOMe
0
Ph
N
0
R2
=
N
COOMe
Ph
COOMe
Ph
3aj
N
Ph
N
0
nBu
OMe
, 81%
3al
, 65% R = 4-Cl
3am
1=R2=4-F-Ph
, 66%
3ak
3an
R
, 69% R = H
68
59
80
79
86
aReaction conditions: In a 10 mL reaction tube, enaminone 1 (1
mmol), diazoester 2 (1.2 mmol), AgOTf (0.05 mmol), and CH2Cl2
AgOTf (5)
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
AgOTf (5)
b
(5 mL), under air, stirred for 12 h at room temperature. Isolated
AgOTf (1)
yield of 3 based on 1.
AgOTf (10)
Under optimized reaction conditions, the scope of
enaminone starting materials (1) was investigated with a
variety of aryl diazoesters (2) (Table 2). A range of
enaminones was first examined. The cascade reaction
generally tolerated a broad range of substituted enaminones
(3b–3h: R1= m-Me, m-OMe, m-F, m-Br, p-OMe, p-NO2, or p-
Br phenyl) to afford high to excellent yields of the
corresponding multisubstituted 1H-pyrroles. A study on the
electronic influence of the phenyl group (R1) indicated that
although both electron-donating (e.g., 3g) and electron-
withdrawing (e.g., 3e and 3f) groups worked well and resulted
in good yields, electron-deficient enaminones achieved a
higher yield (92% yield). Moreover, the cascade reaction
produced equally satisfactory results by using thiophenyl 3i
and naphthalenyl 3l. Notably, both aliphatic styrene 3k and
isobutene 3j can be introduced as substrates in this cascade
reaction. Similarly, a range of donor/acceptor diazoesters,
including substituted aryl, 2-thienyl, and 2-naphthyl, obtained
high to excellent yields of desired products under the standard
conditions (3m–3u), whereas the acceptor-only (e.g., ethyl
aReaction conditions: In a 10 mL reaction tube, enaminone 1a (1
mmol), diazoester 2a (1.2 mmol), metal catalyst (0.05 mmol),
solvent 5 mL, under air (1 atm), stirred for 12 h at room
temperature. bIsolated yield of 3a based on 1a. cnd means not
detected. dDetailed survey of catalyst dosage was listed in SI file.
Our initial attempt involved the cascade reaction of N-
phenyl-enaminone 1a and phenyl diazoester 2a by using
various metal catalysts (5 mol%) in dichloromethane. When
the reaction was performed using AgOAc as catalyst at room
temperature for 12 h (Table 1), the envisioned pyrrole 3a was
obtained in 34% isolated yield. The C–C bond
insertion/cyclization/[1,5]-shift cascade reaction showed
exclusive chemoselectivity and regioselectivity, considering
that 1,3,5-triphenyl pyrrole-2-carboxylate 3a was the only
product formed in the reaction; the products 3aʹ, 3aʹʹ, or 3aʹʹʹ
were not detected. With these results, we continued to
optimize the reaction conditions. Catalyst screening displayed
that AgOTf produced a higher yield (89%) of corresponding
1H-pyrrole than that of Ag2CO3, and PhCO2Ag and other
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diazoacetate) diazo compounds failed to accomplish this
desired products in good yield (5a–5aa). The substituents of
the enaminone continued to exert electronic effects: electron-
deficient enaminones performed more efficiently than
electron-rich enaminones (78% yield). Notably, donor-only
diazo compounds (e.g., N-tosylhydrazone derived from
benzaldehyde) obtained the desired product (5y) in high yield
under the standard conditions. Meanwhile, by using cyclic
cascade reaction with the same reaction sequence. Different R3
groups of aryl diazoesters exerted evident steric effects, with
Methyl, Ethyl, and i-Bu (in this particular order) exhibiting the
highest efficiency, followed by isopentyl (3a, 3v–3x). Finally,
functional N-substituents (R2), such as benzyl, p-OMe phenyl,
n-Bu, and cyclopropyl were compatible under the standard
reaction conditions, thus leading to products 3ai, 3aj, 3ak, and
3al in 74%, 66%, 81%, and 65% yield, respectively (Table 2).
To verify the structure of the multisubstituted pyrrole, 3an15
was selected as the representative compound and was
characterized by X-ray crystallography (Table 2, 3an).
1
2
3
4
5
6
7
8
tosylhydrazones as
a
reaction substrate, indole, and
cyclohepta[b]pyrrole derivatives were finally produced (5p
and 5q). In addition, donor–donor diazo compounds derived
from unsymmetrical aryl ketones or other EWGs apart from
the esters group (e.g., 5z and 5aa) can be used in this cascade
reaction. The results showed that the products remain highly
chemo- and regio-selective. Lastly, the NOE spectra of 5a
confirmed that the Ar group was shifted to the C2-position of
the pyrrole ring (Figure S1, SI).
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10
11
12
13
14
15
16
17
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19
20
21
22
23
24
25
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27
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60
Table 3. Reaction Scope of Enaminones 1 with N-
tosylhydrazones 4a
AgOTf (5 mol%),
R3
R2
Li2CO3 (1.0 equiv.),
NNHTs
To gain insights into the reaction mechanism, we first
conducted isotopic labeling experiments under the standard
conditions (Scheme 2). Deuterium hydrogen-labeling
experiments were conducted, and the pyrrole product of
deuterium hydrogenation at the C4-position was detected
(Scheme 2, Eq. 1). 15N was also retained in the 1H-pyrrole
product when 15N-labeled enaminones were used as starting
materials in the cascade reaction (Scheme 2, Eq. 2). These
results showed that an exchange of active hydrogen atoms
occurred in the catalytic cycle, and that nitrogen atoms in the
pyrrole ring were introduced by the enaminones. To obtain
evidence for C–C bond insertion and Ag-catalyzed selective
control, we separated the intermediate 1,4-iminone (3a-q)
O
HN
toluene, 110 oC, 36 h
R1
Ar
R3 Ar
N
+
R1
R2
(1.0 equiv.)
5b
1
4
(1.2 equiv.)
5a
, 70% R = H
5b
5c
5d
5e
, 62% R = 3-OMe
, 75% R = 4-Br
, 78% R = 3-F
, 77% R = 4-NO2
58% R = 4-CH3
, 63% R = 3-CH3
Ph
Ph
Ph
N
Ph
N
N
Ph
, 61%
N
R
O
S
Ph
Ph
5h
Ph
5f
5g
,
5j
5i
, 55%
, 72%
5a 5g
-
R
R
Ph
Ph
N
5k
5l
N
, 77% R = 4-Cl
81% R = 4-F
Ph
N
Ph
,
N
Ph
Ph
Ph
5m 67% R = 4-CH3
5n
, 65% R = Ethyl
Ph
5p
5o
, 58% R = Isopropyl
5q
5k 5m
, 42%
-
, 51%
containing
a quaternary carbon center under standard
Ph
N
N
N
Cl
conditions (Scheme 2, Eq. 3). A single crystal structure
(Scheme 2, 3a-q-Crystal)14 confirmed that this compound was
the product of the C–C bond formal insertion reaction of the
enaminone and diazoester. In addition, 1,4-iminone (3a-q)
could be converted into 1H-pyrrole products 3a under standard
conditions; however under TfOH catalysis, no reaction
occurred at room temperature, and two selective products (3a
and 3a′) appeared in the reflux, indicating that the silver ion
controlled several reaction steps, including the C–C bond
insertion reaction, as well as the condensation and migration
reactions.
Ph
5t
Ph
5r
Ph
, 62%
, 68%
5s
, 73%
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
N
S
S
Cl
Ph
Ph
5u
, 69%
5v
5w
5x
, 52%
, 68%
, 56%
Ph
Ph
CF3
Ph
N
N
N
Ph
5z
F
Ph
Ph
5aa
, 76%
5y
, 69%
, 73%
aReaction conditions: In a 10 mL reaction tube, enaminone 1 (1
mmol), N-tosylhydrazones 4 (1.2 mmol), Li2CO3 (1.0 mmol),
AgOTf (0.05 mmol), and toluene (5 mL), under air, stirred for 36
h at 110 oC. bIsolated yield of 5 based on 1.
Scheme 2. Control Experiments
H/D
Ph
Ph
Ph
H
Aryl diazoesters act as donor/acceptor carbene precursors
that can efficiently perform cascade reaction; thus we
subsequently studied the reactivity of N-tosylhydrazones16 (4)
as donor/donor-carbene sources with different substituents in
the cascade reaction (Table 3). The release of carbene from N-
tosylhydrazones 4 requires base catalysis. Thus, we first
screened for the effects of varying bases and temperatures
under the standard conditions (Table S1, SI). By adding 1
equivalent of Li2CO3 to the standard reaction conditions and
increasing the temperature to 110 °C for 36 h, the cascade
reaction was performed efficiently. The regioselectivity and
chemoselectivity of the reaction were as-expected, with the
electron-deficient aryl group migrating to the C2-position of
the pyrrole ring; meanwhile, the alkyl insertion site remains in
the C3-position of the pyrrole ring. Under the newly optimized
reaction conditions, various substituted enaminones (R1 = aryl,
heteroaryl, and alkyl; R2 = phenyl, ethyl, and cyclopropyl)
reacted well with different tosylhydrazones (Ar = substituted
phenyl, and thiophenyl; R3 = methyl, and ethyl) affording the
standard
conditions
O
HN
N2
Eq. 1
Eq. 2
COOMe
H:D=3:2
Ph
+
+
N
Ph
COOMe
COOMe
CD3OD
H
Ph
3a
-d
1a
2a
N2
Ph
standard
conditions
15
Ph
Ph
O
HN
1N5
Ph
Ph
COOMe
Ph
Ph
Ph
Ph
3a
1a
-
15N
Ph
2a
N2
O
HN
+
Eq. 3
Ph
COOMe
O
COOMe
N
2a
1a
Ph
3a
, 94%
AgOTf (5 mol%)
CH2Cl2, rt, 3 h
AgOTf (5 mol%)
CH2Cl2, rt, 12 h
COOMe
N
Ph
Ph
Ph
3a-q
MeOOC
, 17%
TfOH (0.1 equiv)
Ph
CH2Cl2, reflux. 12 h
3a
Ph
+
N
TfOH (0.1 equiv)
CH2Cl2, rt. 12 h
Ph
3a'
3a : 3a' = 2 : 1
3a-q
-Crystal
No reaction
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Scheme 3. Plausible Reaction Mechanism for AgOTf Catalyzed [4+1C]insert Synthesis of Multisubstituted Pyrroles
1
2
3
4
5
6
7
Ag
R2
N
R4
R3
OAg
R4
T8
R3
R1
NR2
3/5-q
[1, 5]
R1
Ag
R2
R2
R4
3/5
Ag
O
N
T4
OTf
H+
H+
N
R1
R1
T3
R4
T7
R3
R3
8
9
AgOTf
Cyclization/1,5- shift cycle
C-C formal insertion cycle
H2O
H+
Ag
R2
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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R4
R3
Ag
O
Ag
O
R1
H+
R2
3/5-q
1'
R2
R1
R2
R4
O
N
Ag
N
N2
2 4
R3
T6
OTf
O
N
R1
T2
R1
/
R3 R4
T5
Start from here
T1
On the basis of these results and control experiments, we
propose a plausible catalytic cycle for AgOTf-catalyzed
[4+1C]insert cascade synthesis of multisubstituted pyrroles with
enaminone 1 and diazoester 2/4 (Scheme 3). In the silver
catalyzed C-C bond insertion cycle, cis/trans-enaminone were
in thermodynamic equilibrium, in which cis-enaminone 1′ was
first converted by AgOTf into silver enaminone T1, which
reacted with diazoester 2/4 to give electrophilic silver
carbenoid T2 following the loss of N2. Cyclopropanation of
T2 resulted in the intermediate T3. Owing to the assistance of
the nitrogen lone pairs and ring strain, the C–C bond is
regioselectively cleaved at the α,β-position of the carbonyl
group to yield silver enolate T4. Upon protonation by HOTf,
T4 released 1,4-iminone 3/5-q with an all-carbon quaternary
center following regeneration of the silver catalyst (Scheme 3,
left cycle). In contrast to the existing catalytic methods used
for the insertion of diazoesters into 1,3-dicarbonyl
compounds,8a,8c-e the cyclopropanation in the current study
selectively occurred at the double bond of the predominant
enamine form rather than the enol imine form or the
previously reported pathway that relied on the ability of the
migrating groups, in which migration of the C2 carbon atom
would likely be disfavored. The regioselective
cyclopropanation represents a novel mode of carbenoid
reactivity. Subsequently, in the Ag-catalyzed cyclization/[1,5]-
shift steps, 3H-pyrrole T7 was formed via the dehydration of
the hydroxyl-pyrroline T6, formed by the intramolecular
condensation of 1,4-iminone T5 driven by the coordination of
silver with N and O atoms. Then, Ag+ induced chemo- and
regio-selective thermal [1,5]-shift of the 3H-pyrrole T7
yielded the 2H-pyrrole T8, which was dehydroaromatized to
produce multisubstituted 1H-pyrroles 3/5 (Scheme 3, right
cycle). Numerous studies have been conducted on the thermal
[1,5]-sigmatropic rearrangements of 2H-pyrroles to ultimately
give 1H-pyrroles,17 but similar rearrangements with 3H-
pyrroles as the starting materials are rarely reported.8a,18 In
contrast to the reported thermolysis of 3H-pyrroles used to
prepare 1H-pyrroles as the dominant product,18 the AgOTf-
catalyzed cascade synthesis of multisubstituted pyrroles
regioselectively and chemoselectively produced 1H-pyrroles,
representing a novel thermal rearrangement of 3H-pyrroles.
Scheme 4. Formal Synthesis of Lamellarin L
i-PrO
OMe
N2
i-PrO
H2N
Oi-Pr
COOMe
2g
EtOOC
O
O
7
HN
MeO
OMe
O
OMe
Oi-Pr
O
EtO
EtO
COOMe
a
b
N
O
3ap
1k
6
Oi-Pr
OMe
NBS, DMF,
0 oC to rt, 6 h
c
i-PrO
OMe
OMe
OMe
Oi-Pr
i-PrO
MeO
OMOM
B(OH)2
i-PrO
OMe
OMe
HO
Br
Ref. 18
9
OH
O
d
COOMe
COOMe
EtOOC
N
N
O
OMe
OH
O
N
10
8
O
Lamellarin L
Oi-Pr
i-PrO
OMe
OMe
Reaction conditions: aStirred in THF for 12 h at 20–60 oC, 87%. bCat. AgOTf (5 mol%), CH2Cl2, stirred for 12 h at rt, 68%. cNBS,
DMF, 0 oC to rt, 6 h, 99%. d1) 9 (2.0 equiv.), Pd(PPh3)4 (10 mol%), THF, reflux, 18 h, 2) concd HCl, MeOH, reflux 1 h (two-step,
94%).
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To show the utility of this method to pyrroles, we applied
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3
4
5
6
7
8
the C–C bond insertion/cyclization/[1,5]-shift cascade strategy
for the synthesis of the pyrrole moiety of lamellarin L. Scheme
4 presents our synthesis of this compound. The desired
cascade transformation occurred (3ap) under the usual
reaction conditions with a yield of 68%. Bromination of the
remaining vacant pyrrole position proceeded in quantitative
yield to give bromopyrrole 8 (99% yield). Subsequently,
chromeno[3,4-b]pyrrol-4(3H)-one 10 (75% yield) was
obtained over two-steps, via Suzuki coupling of bromopyrrole
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8
with phenylboronic acid
9
and intramolecular
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transesterification reaction. Decarboxylation coupling
cyclization and deprotection of pyrrole can provide lamellarin
L and various related compounds.1b,19 Compared with that of
the industrial (Paal–Knorr) synthesis of pyrrole, the value of
the method described in the present study lies not only in its
use of readily available starting materials and the number of
reaction steps but also its modularity, allowing access to
various substituents on the pyrrole ring.
In summary, we demonstrated a distinct chemo- and
regioselective cascade catalytic [4+1C]insert cascade reaction
for the preparation of pyrroles from enaminones and carbene
precursors by using AgOTf. This technique was used to
formally synthesize lamellarin L. Control experiments
provided a plausible reaction mechanism in which silver ions
first catalyzed C–C bond carbene insertion and then controlled
cyclization and [1,5]-shift. Further development of this
AgOTf-catalyzed pyrrole synthesis is ongoing in our
laboratory.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org. Experimental procedures,
characterization data including 1H and 13C NMR spectra, IR
spectra and HR-MS, and copies of NMR spectra (PDF)
X-ray data for 3an (CIF)
X-ray data for 3a-q (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: jinyi@ynu.edu.cn
*E-mail: zhihui_shao@hotmail.com
*E-mail: linjun@ynu.edu.cn
Author Contributions
§ These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors gratefully acknowledge for financial support of the
Program for Changjiang Scholars and Innovative Research Team
in University (No. IRT17R94), the NSFC (Nos. 21662044,
81760621, 21672184, 21861042, and 21602169), the Program for
Innovative Research Team (in Science and Technology) in
University of Yunnan Province, the Training Program for Young
and Middle-aged Academic and Technical Leaders in Yunnan
Province (2015HB004), the the Foundation of “Yunling Scholar”
Program of Yunnan Province (YNWR-YLXZ-2014009) and the
Program for Excellent Young Talents，Yunnan University.
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(12) For recent reports related diazo reaction, see: (a) Xu, S.; Chen,
R.; Fu, Z.; Zhou, Q.; Zhang, Y.; Wang, J. Palladium-Catalyzed
Formal [4+1] Annulation via Metal Carbene Migratory Insertion and
C(sp2)–H Bond Functionalization. ACS Catal. 2017, 7, 1993−1997. (b)
Ye, F.; Qu, S.; Zhou, L.; Peng, C.; Wang, C.; Cheng, J.; Hossain, M.
L.; Liu, Y.; Zhang, Y.; Wang, Z. X. Palladium-Catalyzed C–H
Functionalization of Acyldiazomethane and Tandem Cross-Coupling
Reactions. J. Am. Chem. Soc. 2015, 137, 4435−4444. (c) Luo, K. X.;
Zhao, Y. Q.; Zhang, J. W.; He, J.; Huang, R.; Yan, S. J.; Lin, J.; Jin,
Y. Enantioselective Epoxypyrrolidines via a Tandem Cycloaddition/
Autoxidation in Air and Mechanistic Studies. Org. Lett. 2019, 21,
423−427. (d) Xiao, Q.; Wang, B.; Tian, L.; Yang, Y.; Ma, J.; Zhang,
Y.; Chen, S.; Wang, J. Palladium-Catalyzed Three-Component
Reaction of Allenes, Aryl Iodides, and Diazo Compounds: Approach
to 1, 3-Dienes. Angew. Chem., Int. Ed. 2013, 52, 9305−9308. (e)
Gutierrez-Bonet, A.; Julia-Hernandez, F.; De Luis, B.; Martin, R. Pd-
Catalyzed C(sp3)–H Functionalization/Carbenoid Insertion: All-
Carbon Quaternary Centers via Multiple C–C Bond Formation. J. Am.
Chem. Soc. 2016, 138, 6384−6387. (f) Della Ca, N.; Fontana, M.;
Motti, E.; Catellani, M. Pd/Norbornene: a Winning Combination for
Selective Aromatic Functionalization via C–H Bond Activation. Acc.
Chem. Res. 2016, 49, 1389−1400. (g) Pena-Lopez, M.; Beller, M.
Functionalization of Unactivated C(sp3)−H Bonds Using Metal-
Carbene Insertion Reactions. Angew. Chem., Int. Ed. 2017, 56, 46−48;
(h) Meng X.; Yang B.; Zhang L.; Shao, Z.-H. Rh(II)/Brønsted Acid
Catalyzed General and Highly Diastereo- and Enantioselective
Propargylation of in Situ Generated Oxonium Ylides and C-Alkynyl
N-Boc N, O-Acetals: Synthesis of Polyfunctional Propargylamines.
Org. Lett. 2019, 21, 1292−1296; (i) Harada, S.; Tanikawa, K.;
Homma, H.; Sakai, C.; Ito, T.; Nemoto, T. Silver-Catalyzed
Asymmetric Insertion into Phenolic O–H Bonds Using Aryl
Diazoacetates and Theoretical Mechanistic Studies. Chem. - Eur. J.
2019, 25, 12058−12062.
(13) Representative works featuring enaminones: (a) Zhou, S.; Wang,
J.; Wang, L.; Song, C.; Chen, K.; Zhu, J. Enaminones as Synthons for
a Directed C−H Functionalization: Rh(III)-Catalyzed Synthesis of
Naphthalenes. Angew. Chem., Int. Ed. 2016, 55, 9384−9388. (b) Chen,
J.; Guo, P.; Zhang, J.; Rong, J.; Sun, W.; Jiang, Y.; Loh, T. P.
Synthesis of Functionalized α-Vinyl Aldehydes from Enaminones.
Angew. Chem., Int. Ed. 2019, 58, 12674−12809. (c) Yang, L.; Wei, L.;
Wan, J. P. TPAOH Assisted Size-Tunable Gd2O3@mSi Core–Shell
Nanostructures for Multifunctional Biomedical Applications. Chem.
Commun. 2018, 54, 7475−750. (d) Weng, Y.; Lv, W.; Yu, J.; Ge, B.;
Cheng, G. Preparation of 2, 4, 5-Trisubstituted Oxazoles through
Iodine-Mediated Aerobic Oxidative Cyclization of Enaminones. Org.
Lett. 2018, 20, 1853−1856. (e) Toh, K. K.; Biswas, A.; Wang, Y. F.;
Tan, Y. Y.; Chiba, S. Copper-Mediated Oxidative Transformation of
N-Allyl Enamine Carboxylates toward Synthesis of Azaheterocycles.
J. Am. Chem. Soc. 2014, 136, 6011−6020. (f) Toh, K. K.; Wang, Y. F.;
Ng, E. P.; Chiba, S. Copper-Mediated Aerobic Synthesis of 3-
Azabicyclo[3.1.0]hex-2-enes and 4-Carbonylpyrroles from N-
Allyl/Propargyl Enamine Carboxylates. J. Am. Chem. Soc. 2011, 133,
13942−13945. (g) Lourdusamy, E.; Yao, L.; Park, C. M.
Stereoselective Synthesis of α-Diazo Oxime Ethers and Their
Application in the Synthesis of Highly Substituted Pyrroles through a
[3+2] Cycloaddition. Angew. Chem., Int. Ed. 2010, 49, 7963−7967. (h)
Bernini, R.; Fabrizi, G.; Sferrazza, A.; Cacchi, S. Copper-Catalyzed
C–C Bond Formation through C–H Functionalization: Synthesis of
Multisubstituted Indoles from N-Aryl Enaminones. Angew. Chem., Int.
Ed. 2009, 48, 8078−8081.
Decomposable Diazo Surrogates. Chem.
4756−4760.
(15) CCDC 1960340 (3an), and 1960342 (3a-q) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
- Eur. J. 2017, 23,
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(16) Selected examples of N-tosylhydrazones as carbene reagents: (a)
Wang, Y.; Wen, X.; Cui, X.; Wojtas, L.; Zhang, X. P. Asymmetric
Radical Cyclopropanation of Alkenes with in Situ-Generated Donor-
Substituted Diazo Reagents via Co(II)-Based Metalloradical Catalysis.
J. Am. Chem. Soc. 2017, 139, 1049−1052. (b) Xiao, Q.; Xia, Y.; Li,
H.; Zhang, Y.; Wang, J. Coupling of N-Tosylhydrazones with
Terminal Alkynes Catalyzed by Copper(I): Synthesis of Trisubstituted
Allenes. Angew. Chem., Int. Ed. 2011, 50, 1114−1117. (c) Xia, Y.;
Wang, J. N-Tosylhydrazones: Versatile Synthons in the Construction
of Cyclic Compounds. Chem. Soc. Rev. 2017, 46, 2306−2362; (d)
Shao, Z.-H.; Zhang, H.-B. N-Tosylhydrazones: Versatile Reagents for
Metal-Catalyzed and Metal-Free Cross-Coupling Reactions. Chem.
Soc. Rev. 2012, 41, 560−572.
(17) (a) Sammes, M. P.; Katritzky, A. R. The 2H-and 3H-Pyrroles.
Adv. Heterocycl Chem. 1982, 32, 233−284. (b) Kotzner, L.; Leutzsch,
M.; Sievers, S.; Patil, S.; Waldmann, H.; Zheng, Y. Y.; Thiel, W.; List,
B. The Organocatalytic Approach to Enantiopure 2H- and 3H-
Pyrroles: Inhibitors of the Hedgehog Signaling Pathway. Angew.
Chem., Int. Ed. 2016, 55, 7693−7967. (c) Laurent, A.; Mison, P.;
Nafti, A.; Pellissier, N. Thermolyse de Trans-crotyl-2 2H-Pyrroles:
Competition entre Rearrangements de Cope et D'aza-2 Claisen.
Tetrahedron Lett. 1982, 23, 655−658.
(18) Chiu, P. K.; Sammes, M. P. Thermal Rearrangement of 3H-
Pyrroles by Competitive [1, 5]-Sigmatropic Shifts, and the
Reversibility of the 3H- to 2H-Pyrrole Interconversion. Tetrahedron
Lett. 1987, 28, 2775−2778.
(19) Fujikawa, N.; Ohta, T.; Yamaguchi, T.; Fukuda, T.; Ishibashi,
F.; Iwao, M. Total Synthesis of Lamellarins D, L, and N. Tetrahedron
2006, 62, 594−604.
(14) (a) Thompson, J. L.; Davies, H. M. Enhancement of
Cyclopropanation Chemistry in the Silver-Catalyzed Reactions of
Aryldiazoacetates. J. Am.Chem. Soc. 2007, 129, 6090−6091. (b) Luo,
H.; Wu, G.; Zhang, Y.; Wang, J. Silver(I)-Catalyzed N-
Trifluoroethylation of Anilines and O-Trifluoroethylation of Amides
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Insert Table of Contents artwork here
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R3
R4
Ag+
C-C insertion
Ag+
[1,5]-shift
Ag+
Cyclization
R2
X
O
HN
R1
R3 R4
N
R2
R1
+
No LG & Safer
Practical & Atom Economic
X = N2 or NNHTs
R3 and R4 = Ester, Aryl, or Alkyl
Chemoselectivity
& Regioselectivity
Broad scope
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Pyrrole: Ag-catalyzed [4+1C]insert cascade to coupling of enaminones with donor/donor or donor/acceptor carbenes, which provides
distinct chemo- and region-selective multisubstituted pyrroles. This atom-economical, environmentally friendly methodology offers
easy access to a range of substituted pyrroles in moderate to good yields.
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