Base-promoted ring-closing carbonyl-allene metathesis for the synthesis of 2,4-disubstituted pyrroles

Article abstract of DOI:10.1039/c8gc01675e

A base-promoted ring-closing carbonyl-allene metathesis reaction of N-allenyl β-enaminones (generated in situ from N-propargyl β-enaminones) gives 2,4-disubstituted pyrroles with cleavage of the C(sp)-C(sp³) bond. This transition metal-free procedure generates 1 equiv. of acetic acid as the sole byproduct. A preliminary mechanistic study supports a stepwise [2 + 2] cycloaddition/retro [2 + 2] reaction pathway.

Full text of DOI:10.1039/c8gc01675e

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Base-promoted ring-closing carbonyl–allene metathesis for the
synthesis of 2,4-disubstituted pyrroles
Received 00th January 20xx,
Accepted 00th January 20xx
Guolin Cheng,* Weiwei Lv and Lulu Xue
DOI: 10.1039/x0xx00000x
www.rsc.org/
A base-promoted ring-closing carbonyl–allene metathesis reaction
of N-allenyl -enaminones (generated in situ from N-propargyl
a) Organocatalysed ring-opening carbonyl-olefin metathesis
2HCl
β
β
-enaminones) gives 2,4-disubstituted pyrroles with cleavage of the
C(sp)–C(sp3) bond. This transition metal-free procedure generates
1 equiv of acetic acid as the sole byproduct. A preliminary
mechanistic study supports a stepwise [2+2] cycloaddition/retro
[2+2] reaction pathway.
R1 R2
NH
R2
O
N
N
N
(cat.)
R3
H
+
O
R1
R2 R1
retro [3+3]
[3+3]
R3
R3
b) FeCl3-catalysed ring-closing carbonyl-olefin metathesis
FeCl3 (cat.)
Metathesis reactions for the construction of C−C double bonds
are of high synthetic value due to the broad applications of
olefins both as synthetic targets, including natural products
and pharmaceuticals, and as feedstock for further chemical
transformations. The classic Wittig reaction1 and olefin
metathesis reaction2 have both been adopted widely for the
construction of C−C double bonds. However, the former
reaction produces stoichiometric amounts of phosphine oxide
wastes, and the latter one requires sophisticated transition
metal alkylidenes as catalysts. Thus, organic chemists have
been fascinated to develop carbonyl–olefin metathesis
reaction for the synthesis of olefinic products.3 The reported
procedures for carbonyl–olefin metathesis are, however, far
from ideal in terms of their generality and practicality.
Typically, stoichiometric amounts of reagents (transition
metal,4 Lewis acid,5 or Brønsted acid6) or photochemical
promotion,7 were needed in these reactions. In 2012, Lambert
disclosed an organocatalytic ring-opening carbonyl–olefin
R1
R1
Fe
O
+
retro [2+2]
[2+2]
O
R2
O
R1
R2
R2
This work
c)
: base-promoted ring-closing carbonyl-allene metathesis
R1
O
R1
R1
O
O
base
[2+2]
+
R2
R2 retro [2+2]
N
H
R2
N
H
N
H
IV
I
Scheme 1 Carbonyl–olefin/allene metathesis.
aforementioned reactions, the development of novel
metathesis reactions is still one of the major research
endeavors in synthetic chemistry. Especially, development of
new carbonyl–olefin metathesis approaches toward aromatic
heterocycles, in an atom-economical and environmentally
friendly fashion from readily available starting materials and
under mild reaction conditions, is in highly demand. Although
metathesis reaction between aldehydes and highly strained the synthesis of fused aromatic hydrocarbons relying on the
iron-catalyzed carbonyl–olefin metathesis reaction was
realized very recently, 9d the direct construction of monocyclic
cyclopropenes, representing a breakthrough in this area
(Scheme 1a).8 Recently, Schindler9 and, subsequently, Li10
reported a revolutionary FeCl3-catalyzed ring-closing carbonyl–
olefin metathesis reaction, which enables the synthesis of
functionalized carbocycles under mild reaction conditions
(Scheme 1b). Despite these significant advances offered by the
aromatic heterocycles via metathesis reaction is still
a
challenge due to the difficulties in achieving the desired
starting materials.11
Our previous works have documented that N-allenyl
β
-
-
enaminones
enaminones
I
could be generated from N-propargyl
β
1
via propargyl-allenyl isomerisation reaction
under basic conditions.12,13 We questioned whether the
oxetane intermediate IV could be formed from intramolecular
[2+2] cycloaddition of I. Then, opening of the highly strained
oxetane ring and giving an aromatic product would be the
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thermodynamic driving forces for the subsequent [2+2] (Table 1, entries 9, 10). When performed in the presence of
cycloreversion process (Scheme 1c). As our ongoing interest in KOtBu (Table 1, entry 11), only trace of product was observed,
heterocyclic chemistry,14 we report herein an unprecedented and 1a was completely consumed. Alternative bases were also
base-promoted ring-closing carbonyl–allene metathesis examined, and K2CO3 was found to give the best result (80%
reaction, which could provide a straightforward access to yield) (Table 1, entries 12−15). Further investigation showed
pyrrole derivatives.
that higher temperatures favored this transformation (Table 1,
On the other hand, pyrroles represent one of the most entries 16, 17). Remarkably, a respectable 86% yield of 2a was
important classes of heterocycles in natural products,15 achieved using 0.5 equiv of K2CO3 (Table 1, entry 18). A slight
modern pharmaceuticals,16 and materials science.17 As a lower yield was obtained when 1 equiv of H2O was added to
result, chemists are interested in developing many new the reaction system (Table 1, entry 19). A similar result was
synthetic methods to obtain a wide spectrum of pyrrole obtained when the reaction was carried out under nitrogen
derivatives.18
atmosphere (Table 1, entry 20). Finally, no product was
We began our study to examine the model reaction of 1,3- observed in the absence of base (Table 1, entry 21). Then, the
diphenyl-3-(propargylamino)-2-propen-1-one 1a in the optimized reaction conditions were identified as follows: 1a
o
presence of 1 equiv of K3PO4 as the base in DMSO at 80 oC (0.1 mmol), K2CO3 (1 equiv), NMP (1 mL), at 90 C, and under
(Table 1). Gratifyingly, we observed the desired metathesis air atmosphere.
product 2a, albeit in a low yield (entry 1). The use of a proper
O
solvent was crucial for this reaction. No reaction took place
R1
K2CO3 (1 equiv), NMP (1 mL)
R1
air, 90 oC, 12 h
with nonpolar solvents and protic solvents (Table 1, entries
2−5). Investigations on other polar aprotic solvents indicated
that NMP performed better than others, affording the desired
product 2a in 67% yield (Table 1, entries 6−8). The choice of a
suitable base was also crucial to this metathesis reaction.
Under similar conditions, no reactivity was observed with
K2HPO4 and Et3N, and 1a could be recovered
R2
N
R2
N
H
H
1a-v (0.1mmol)
2a-v
Me
tBu
F
Table 1. Screening of the reaction conditionsa
Ph
Ph
2c, 64%
Ph
Ph
2a, 93%
N
N
N
N
H
H
H
H
2d, 94%
2b, 90%
F3C
Cl
Br
Me
Ph
Ph
Ph
Ph
N
H
N
H
N
H
N
H
Entry
1
Solvent
DMSO
Toluene
DCE
Base
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2HPO4
Et3N
Yield (%)b
2e, 83%
2f, 78%
2h, 77%
2g, 70%
27
0
OMe
2
F
OMe
Cl
3
0
4
MeOH
H2O
0
Ph
Ph
Ph
Ph
5
0
N
H
N
H
N
H
N
H
6
DMF
48
57
67
0
2i, 71%
2l, 80%
2j, 75%
2k, 60%
7
DMA
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
Cl
8
Cl
9
S
10
11
12
13
14
15
16c
17d
18e
19f
20g
21
0
Ph
KOtBu
Na2CO3
K2CO3
Cs2CO3
DBU
trace
69
80
55
45
93
85
86
90
94
0
Ph
Ph
N
H
N
H
N
H
2m, 70%
2n, 82%
2o, 68%
Me
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
-
Ph
Ph
Ph
N
N
H
N
H
H
Me
OMe
Me
2p, 86%
2r, 72%
2q, 63%
Ph
Ph
Ph
Me
Me
a Reaction conditions: 1a (0.1 mmol), base (0.1 mmol), and solvent (1 mL) at 80 o
under air for 12 h. b Isolated yields based on 1a. c at 90 oC. d at 100 oC. e 0.5 equiv
C
N
H
2t
N
N
N
H
Cl
H
F
H
f
g
2s, 78%
, 68%
2v, 82%
2u, 65%
of K2CO3 were used. 1 equiv of H2O was added. Under nitrogen atmosphere.
DMSO dimethylsulfoxide, DMF N,N-dimethylformamide, DMA N,N-
=
=
=
dimethylacetamide, NMP = N-methyl-2-pyrrolidone.
Scheme 2 Scope of N-propargyl
β-enaminones
2 | J. Name., 2012, 00, 1-3
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With the optimized reaction conditions established, we then
examined the scope of substituted N-propargyl -enaminone
substrates (Scheme 2). A wide range of substituents were
well tolerated under the metathesis reaction conditions
affording the corresponding pyrroles (2a ) in 60−94% yields.
First, the substituents on the aroyl moiety of were examined,
and the substrates with electro-donating groups (2b 2c 2h 2i
β
1
−
v
1
,
,
, ,
and 2l) as well as electro-withdrawing group (2g) were all
suitable for this reaction system, affording the corresponding
products in good to excellent yields. Substrates with halogen
substituents (F, Cl, and Br) were well tolerated, giving the
corresponding products in good yields (2d
The significant influence of the steric hindrance on this
reaction was observed 2h ). For instance, the orth-
substituted substrates led to lower yields than the para-
substituted substrates (2h vs. 2b 2j vs. 2d, and 2k vs. 2e).
Other representative aromatic substrates, such as naphthyl
−f, 2j, 2k, and 2m).
Scheme 3 Possible reaction mechanism
(
−k
thus affording the intermediate
I
.
Subsequently, the
deprotonation of
atom, following a Baldwin-preferred 5-exo-trig cyclization onto
the carbonyl carbon would deliver the cyclic alcoholate III
I at the allene group adjacent to nitrogen
,
.
and thienyl groups, were also tolerated (2n, 2o). In addition,
the aromatic rings of R2 with methyl, methoxyl, chloro, or
fluoro groups were also tested and gave the desired products
Then the fused oxetane intermediate IV is formed from III via
4-exo-dig cyclization. Finally, the stepwise retro [2+2] reaction
of the highly strained oxetane
the metathesis product and ketene fragment
be further trapped by H2O to generate acetic acid derivative
On the other hand, oxetane can undergo ring cleavage at the
C−O bond, thus generaꢀng the byproduct 3 20
B
resulting in the formation of
in 63−86% yields (2p−v).
2
C
, which could
The gram-scale experiment of this metathesis reaction was
demonstrated by employing 1a as a model substrate in the
presence of 1 equiv of K2CO3, the metathesis product 2a was
4.
B
.
obtained in 87% yield, along with a byproduct
3, which
probably was derived from the direct ring-opening reaction of
the tentative oxetane intermediate (eq. 1).
Conclusions
In summary, we have developed an unprecedented ring-
closing carbonyl–allene metathesis reaction of N-propargyl
β-
enaminones providing a general and practical method for the
straightforward construction of synthetically useful 2,4-
disubstituted pyrroles. For the first time, the base-mediated
ring-closing metathesis reaction of a carbonyl group with an
allenyl group (generated in situ) has been realized. In view of
the readily available starting materials, broad scope of
substrates, and high reaction efficiencies, the base-mediated
ring-closing metathesis reaction can be expected to find wide
synthetic applications.
To gain more insight into the reaction mechanism, control
experiments were carried out. Firstly, our reaction conditions
failed to generate 2a from
3
(eq. 2), which suggested that it is
to serve as an intermediate in
unlikely for an acetyl pyrrole
3
the reaction. Moreover, internal alkyne-containing substrate
This work was supported by the NSF of China (21672075)
and the Program for New Century Excellent Talents in Fujian
Province University.
1w could also give the metathesis product 2a in 31% yield,
along with 4-methoxyphenylacetic acid
4 in 24% yield. In this
case, pyrrole 5 formed via 5-exo-dig cyclization was isolated as
major product (50% yield).19
Conflicts of interest
There are no conflicts to declare.
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4 | J. Name., 2012, 00, 1-3
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The synthesis of 2,4-disubstituted pyrroles from N-propargyl
via ring-closing carbonyl–allene metathesis reaction is reported.
β-enaminones