Catalyst-dependent divergent synthesis of pyrroles from 3-alkynyl imine derivatives: A noncarbonylative and carbonylative approach

Article abstract of DOI:10.1002/anie.201405215

A novel Ru⁰- and Rh^I-catalyzed noncarbonylative and carbonylative cycloisomerization of readily available 3-alkynyl imine derivatives has been developed to provide 3,4-fused or nonfused pyrrole derivatives efficiently in moderate to

Full text of DOI:10.1002/anie.201405215

Angewandte
Chemie
DOI: 10.1002/anie.201405215
Pyrrole Synthesis
Hot Paper
Catalyst-Dependent Divergent Synthesis of Pyrroles from 3-Alkynyl
Imine Derivatives: A Noncarbonylative and Carbonylative
Approach**
Gen-Qiang Chen, Xiao-Nan Zhang, Yin Wei, Xiang-Ying Tang,* and Min Shi*
Abstract: A novel Ru0- and RhI-catalyzed noncarbonylative
and carbonylative cycloisomerization of readily available 3-
alkynyl imine derivatives has been developed to provide 3,4-
fused or nonfused pyrrole derivatives efficiently in moderate to
excellent yields. The key steps involve the formation of
a ruthenium carbenoid intermediate or a rhodacycle inter-
mediate, respectively. In these reactions, CO can serve as
a ligand or a reagent.
O
f all the nitrogen-containing heterocycles, pyrroles are
among the most important motifs in organic chemistry. The
pyrrole nucleus is found prevalently in many bioactive natural
products,[1] pharmaceutically important compounds,[2] and
organic materials[3] including the blockbuster drug Atorvas-
tatin Calcium.[2a] For this reason, the development of a gen-
eral, simple, and efficient synthetic method to generate these
structures has drawn the interest of many organic chemists,
and various synthetic methods have been developed.[1,4] In
addition to the traditional methods, such as the Knorr pyrrole
synthesis, transition-metal-catalyzed approaches have also
been developed.[5] However, new and practically useful
synthetic methods are still highly desirable.
Scheme 1. Three modes for the generation of metal carbenoids from
alkynes.
a lone pair of electrons as the nucleophile, which provides a-
ylide-type metal carbenoids.[9] The first two modes are very
common in the literature, but, the third is relatively rare.
In 2005, Toste and co-workers[5e] reported an interesting
gold-catalyzed synthesis of pyrroles from a homopropargyl
azide (Scheme 2a). The key steps involved the generation of
an a-imino-gold(I) carbenoid through nucleophilic attack on
a gold(I)-activated alkyne and the subsequent gold(I)-assisted
extrusion of N2. The research groups of Zhang[8f] and
Gagosz[8g] later reported similar reactions that led to indole
derivatives. Inspired by the study of Toste and co-workers, we
assumed that if the azide group was replaced by an imino
functionality, an a-(azomethineylide)-metal carbenoid could
be generated through the third mode shown in Scheme 1, and
this would provide an atom-economic and safer route to
multisubstituted pyrroles. The difficulties mainly lie in the
regioselectivity[10] (Scheme 2, this work). On the other hand,
cyclopropylimines[11] are very useful five-atom synthons in
organic chemistry and their reactivities are quite similar to
vinylcyclopropanes (VCPs).[12] In 2000 and 2002, Murai and
co-workers[11a] and Wender et al.[11b] independently reported
the [5+1] and [5+2] cycloaddition of cyclopropylimines
(Scheme 2b). In 2013, we also disclosed an interesting
tandem Pauson–Khand-type reaction of a cyclopropane-teth-
ered 1,4-enyne[13] in the presence of rhodium(I) catalyst
(Scheme 2c).[14] Based on these previous findings, we rea-
soned that carbonylative products could be obtained if the
alkynyl unit was incorporated into the cyclopropylimine
functionality (Scheme 2, this work). Herein, we report the
novel Ru0- and RhI-catalyzed noncarbonylative and carbon-
ylative synthesis of substituted pyrroles from readily available
3-alkynyl imine derivatives.
Over the last few decades, transition metals, especially the
alkynophilic ones, have been extensively examined. It is well
known that metal carbenoids[6] can be generated from alkynes
in the following three ways (Scheme 1): 1) nucleophilic attack
of an alkyne activated by metals and subsequent trapping of
the vinyl–metal species by an electrophile;[7] 2) attack of the
activated alkyne by a nucleophile bearing a leaving group
(LG), thereby generating a-oxo-, a-imino-, or a-vinyl-metal
carbenoids;[8] 3) the use of an uncharged element containing
[*] G.-Q. Chen, X.-N. Zhang, Y. Wei, Dr. X.-Y. Tang, Dr. M. Shi
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Linglin Lu, Shanghai 200032 (China)
E-mail: siocxiangying@mail.sioc.ac.cn
mshi@mail.sioc.ac.cn
[**] We are grateful for financial support from the Shanghai Municipal
Committee of Science and Technology (11JC1402600), the National
Basic Research Program of China (973)-010CB833302, and the
National Natural Science Foundation of China (20472096,
21372241, 21361140350, 20672127, 21102166, 21121062,
21302203, and 20732008).
Supporting information for this article (spectroscopic data of the
compounds shown in Tables 1–3 and Scheme 3, the detailed
descriptions of experimental procedures, and the crystal structures
of 2k and 3b) is available on the WWW under http://dx.doi.org/10.
1002/anie.201405215.
We first utilized cyclopropyl-tethered 3-alkynyl imine
1a[15,16] as the substrate and carried out the reaction in the
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Table 1: Optimization of the reaction conditions.
Entry[a] Catalyst
t [h] Solvent
p
T [8C] Yield [%][b]
(1 atm)
2a 3a
1
[{Rh(CO)2Cl}2]
10 p-
xylene
10 p-
xylene
10 p-
xylene
10 p-
xylene
10 p-
xylene
10 p-
xylene
10 toluene CO or 100
Ar
10 p-
xylene
10 p-
xylene
12 DCM
CO
CO
CO
CO
CO
CO
100
100
100
100
100
100
11
46
34
19
18
50
81c
2
[Rh(PPh3)3Cl]
[Rh6(CO)16]
0
3
0
4
[{Rh(cod)Cl}2]
[Rh(dppp)(CO)Cl]
[Rh(PPh3)(CO)Cl]
[Ru3(CO)12]
44
47
44
5[c]
6
7
99[c] n.d.
8[d]
9
[Ru(cod)Cl2]n
[Re2(CO)10]
Ar
Ar
Ar
100
100
RT
31
67
n.d.
n.d.
10[d]
[(S)-PhosAu-
n.d. n.d.
Scheme 2. Previous work and this work. dppm=bis(diphenylphosphi-
no)methane, DCE=1,2-dichloroethane.
(CH3CN)SbF6]
[a] The reaction was performed in a 25 mL flame- and vacuum-dried
Schlenk tube. 1 (0.2 mmol) and the catalyst (2.5 mol%) was added and
then the tube was evacuated and backfilled with CO or Ar five times. Solvent
was then added and the reaction mixture stirred in an oil bath at the
indicated temperature. [b] NMR spectroscopic yield. [c] Yield of isolated
product. [d] 1H NMR spectroscopic analysis of the crude product indicates
that the product contains 1a and 4a. cod=1,5-cyclooctadiene, dppp=1,3-
bis(diphenylphosphino)propane.
presence of [{Rh(CO)2Cl}2] in a CO atmosphere. Compounds
2a and 3a were obtained in 11% and 81% yields, respectively
(Table 1, entry 1; for details see Scheme S7 in the Supporting
Information). Next, we turned our attention to find the
optimized reaction conditions for the current reaction by
screening various rhodium catalysts such as the Wilkinson
catalyst, [Rh6(CO)16], [{Rh(cod)Cl}2], [Rh(dppp)(CO)Cl] and
[Rh(PPh3)2(CO)Cl] (Table 1, entries 1–6). [{Rh(CO)2Cl}2]
was found to be the best catalyst for the carbonylative
synthesis of pyrroles. To our delight, when [Ru3(CO)12][16a,17,18]
was used as the catalyst, the noncarbonylative product 2a was
obtained in almost quantitative yield without formation of 3a
(Table 1, entry 7). [Ru(cod)Cl2]n produced 2a in 31% yield
(Table 1, entry 8), and [Re2(CO)10] gave 2a in 67% yield
(Table 1, entry 9). The cationic gold catalyst [(S)-PhosAu-
(CH3CN)SbF6] did not afford the desired product (Table 1,
entry 10).
The substrate scope of the ruthenium(0)-catalyzed reac-
tion was next evaluated. Changing the R2 substituent from
a simple alkyl group to a benzyl, PMB, or 2-phenylethyl group
afforded the desired products in excellent yields (Table 2,
entries 1–7). The substituent on the alkyne functionality could
be the substituted phenyl groups thienyl or Bn, which gave the
desired products in moderate to excellent yields (Table 2,
entries 7–16). The ketimine 1r also afforded the desired
product in excellent yield (Table 2, entry 17). However, the
oxime ether[19] 1s did not produce the desired product under
the optimized conditions, probably because of the low
nucleophilicity of the nitrogen atom in the oxime ether
(Table 2, entry 18). The structure of 2 was further confirmed
by X-ray diffraction analysis of product 2k (see the Support-
ing Information for the ORTEP drawing and the CIF data).[20]
The substrate generality of the carbonylative pyrrole
synthesis was also examined. The reactions proceeded
smoothly when the R2 substituent was changed from
a simple alkyl group to a benzyl, PMB, or 2-phenylethyl
group to afford the desired products in moderate to good
yields (Table 3, entries 1–5). The substituent on the alkyne
functionality could also tolerate a substituted phenyl group or
thienyl, which provided the desired products in yields ranging
from moderate to good (Table 3, entries 6–11). In this
reaction, irrespective of whether an electron-donating group
or electron-withdrawing group was introduced on the phenyl
ring, the corresponding product was obtained in a relatively
low yield. Ketimine 1r could also afford the desired product
3r in good yield (Table 3, entry 12). The oxime ether 1s
afforded the desired product 3s in 31% yield under the
optimized conditions (Table 3, entry 13). The structure of 3
was further determined by X-ray diffraction analysis of
product 3b (see the Supporting Information for the ORTEP
drawing and the CIF data).[21]
Imines other than the cyclopropane-tethered ones (1t and
1u) were also synthesized and subjected to the standard
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Table 2: Substrate generality of the ruthenium(0)-catalyzed noncarbo-
nylative reaction.
Entry
R1, R2, R3
Yield [%][a]
1
2
3
4
5
6
7
8
1b, R1 =Ph, R2 =nPr, R3 =H
2b, 97
2c, 83
2d, 95
2e, 91
2 f, 94
2g, 89
2h, 94
2i, 97
2j, 96
2k, 93
2l, 85
2m, 67
2n, 93
2o, 98
2p, 80
2q, 84
2r, 93[b]
2s, –
1c, R1 =Ph, R2 =iPr, R3 =H
1d, R1 =Ph, R2 =iBu, R3 =H
1e, R1 =Ph, R2 =Bn, R3 =H
1 f, R1 =Ph, R2 =PMB, R3 =H
1g, R1 =Ph, R2 =2-Ph-Et, R3 =H
1h, R1 =p-Ph-Ph, R2 =PMB, R3 =H
1i, R1 =p-Me-Ph, R2 =nBu, R3 =H
1j, R1 =3,5-di-Me-Ph, R2 =nBu, R3 =H
1k, R1 =p-Cl-Ph, R2 =nPr, R3 =H
1l, R1 =p-F-Ph, R2 =nPr, R3 =H
1m, R1 =p-NO2-Ph, R2 =nPr, R3 =H
1n, R1 =p-MeO-Ph, R2 =nPr, R3 =H
1o, R1 =1-naphthyl, R2 =nPr, R3 =H
1p, R1 =2-thienyl, R2 =nPr, R3 =H
1q, R1 =Bn, R2 =nPr, R3 =H
9
10
11
12
13
14
15
16
17
18[c]
1r, R1 =Ph, R2 =nPr, R3 =Me
Scheme 3. Reactions of imines other than the cyclopropane-tethered
ones.
1s, R1 =Ph, R2 =MeO, R3 =Me
[a] Yield of isolated product. [b] This product was not stable enough for
column chromatography, and the yield was determined by 1H NMR
spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.
[c] 1s was recovered quantitatively. Bn=benzyl, PMB=p-methoxyben-
zyl.
the cyclohexane-tethered imine 1v, the desired product 2v
was obtained in 41% yield (Scheme 3). In the cases of
noncyclic symmetrical imines 1w and 1x, the corresponding
pyrroles 2w and 2x could be also formed in moderate yields.
Furthermore, the unsymmetrical substrates 1y, 1z, and 1a,
afforded the corresponding pyrroles 2y, 2z, and 2a in almost
quantitative yields as single regioisomers.[22] No enyne
cyclization product was observed, thus indicating that
[Ru3(CO)12] is a very mild p acid. In the presence of
[{Rh(CO)2Cl}2] as the catalyst under CO, 1t afforded 2t in
90% yield rather than the carbonylative product, which
suggests that CO insertion is only suitable for the cyclo-
propane-tethered substrate under RhI catalysis (Scheme 3).
An NMR monitoring experiment was conducted using 1a
as a model substrate to gain further insight into the reaction.
2a was formed quantitatively in less than 5 min in the
presence of [Ru3(CO)12] in an ambient atmosphere. The use
of [{Rh(CO)2Cl}2] as the catalyst in an ambient atmosphere
led to product 3a in less than 10% yield after a few minutes,
and product 2a formed only slowly. It is quite clear that
[Ru3(CO)12] and [{Rh(CO)2Cl}2] show completely different
catalytic abilities (see Figure S1 in the Supporting Informa-
tion).
On the basis of the NMR monitoring experiment and
a control experiment (see Scheme S7 in the Supporting
Information), a plausible reaction mechanism was proposed
with 1a used as a model substrate. For the formation of
product 3a:[23] oxidative addition of RhI to 1a forms
a rhodacyclobutane intermediate A, which is in equilibrium
with A’ through 1,3-migration.[11] Intramolecular nucleophilic
attack of the imine on the activated alkyne and the
subsequent rearrangement forms rhodium-containing pyrrole
intermediate B.[24] Carbonylation of intermediate B gives C,
Table 3: Substrate generality of the rhodium(I)-catalyzed carbonylative
reaction.
Entry[a]
R1, R2, R3
Yield [%][b]
1
2
3
4
5
6
7
8
1b, R1 =Ph, R2 =nPr, R3 =H
2b, 83
2c, 58
2e, 61
2 f, 51
2g, 61
2i, 77
2j, 75
2k, 42
2l, 54
2n, 50
2p, 49
2r, 84
2s, 31
1c, R1 =Ph, R2 =iPr, R3 =H
1e, R1 =Ph, R2 =Bn, R3 =H
1 f, R1 =Ph, R2 =PMB, R3 =H
1g, R1 =Ph, R2 =2-Ph-Et, R3 =H
1i, R1 =p-Me-Ph, R2 =nBu, R3 =H
1j, R1 =3,5-di-Me-Ph, R2 =nBu, R3 =H
1k, R1 =p-Cl-Ph, R2 =nPr, R3 =H
1l, R1 =p-F-Ph, R2 =nPr, R3 =H
1n, R1 =p-MeO-Ph, R2 =nPr, R3 =H
1p, R1 =2-thienyl, R2 =nPr, R3 =H
1r, R1 =Ph, R2 =nPr, R3 =Me
1s, R1 =Ph, R2 =MeO, R3 =Me
9
10
11
12
13
[a] The reaction was conducted on a 0.2 mmol scale. 2 was formed as
minor product in all cases. [b] Yield of isolated product.
conditions. In the presence of [Ru3(CO)12], the cyclobutane-
or cyclopentane-tethered imine 1t or 1u could undergo the
reaction smoothly to give the expected ring-expansion
product 2t or 2u in good yield (Scheme 3). In the case of
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which undergoes reductive elimination to afford product 3a
and regenerates the RhI species. For the formation of product
2a: the coordination of ruthenium(0) to the alkyne moiety of
1a generates intermediate D, which undergoes intramolecular
nucleophilic attack by the imine to form the vinyl-metal
intermediate E and its resonance structure F. Ring expansion
of the cyclopropane ring to cyclobutane and release of the
metal catalyst produces 2a and regenerates the catalytic
species (Scheme 4). The reaction takes place by a completely
different pathway when [{Rh(CO)2Cl}2] or [Ru3(CO)12] is
used as the catalyst, probably because of the following
reasons: 1) oxidative addition of [{Rh(CO)2Cl}2] (608C) to
the cyclopropylimine is easier than with [Ru3(CO)12] (1608C)
(Scheme 2b);[11] 2) as for [{Rh(CO)2Cl}2], the oxidative
addition to cyclopropane takes place faster than its p-
activation process.
In conclusion, an interesting noncarbonylative and car-
bonylative approach to substituted pyrrole derivatives cata-
lyzed by Ru0 and RhI in a highly chemoselective and safe
manner have been developed. With this method, 3-
azabicyclo[3.2.0]hepta-1,4-diene and 5,6-dihydrocyclopen-
ta[c]pyrrol-4(2H)-one derivatives can be synthesized diver-
gently from readily available cyclopropane tethered 3-alkynyl
imine derivatives. This reaction can also be extended to other
cyclic or acyclic 3-alkynyl imines. A plausible mechanism has
also been proposed. Further efforts are in progress to develop
the application of this method in the synthesis of biologically
active molecules.
Received: May 13, 2014
Published online: && &&, &&&&
À
Keywords: C C bond activation · pyrrole synthesis · rhodium ·
ring expansion · ruthenium
.
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[21] CCDC 973556 (3b) contains the supplementary crystallographic
data for this paper.
[22] Our preliminary calculation indicated that the high regioselec-
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Figure S2 in the Supporting Information).
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Angewandte
Communications
[23] In the absence of CO, product 2a can be formed by reductive
elimination from intermediate B; see M. Murakami, H. Amii, Y.
Ito, Nature 1994, 370, 540 – 541.
[24] Carbonylation of intermediate A’ to form a lactam was quite
difficult, instead dehydrogenation may occur preferentially (see
Ref. [11a]). Alternatively, another mechanism can also explain
the formation of product 3a, however, this mechanism involves
the formation of a very strained intermediate, which makes this
mechanism seem less possible (Scheme S9 in the Supporting
Information).
6
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Angewandte
Chemie
Communications
Pyrrole Synthesis
G.-Q. Chen, X.-N. Zhang, Y. Wei,
X.-Y. Tang,* M. Shi*
&&&& — &&&&
Catalyst-Dependent Divergent Synthesis
of Pyrroles from 3-Alkynyl Imine
Derivatives: A Noncarbonylative and
Carbonylative Approach
Carbonylation or not: A novel Ru0- and
RhI-catalyzed noncarbonylative and car-
bonylative synthesis of multisubstituted
pyrroles from readily available 3-alkynyl
imine derivatives has been developed.
The key steps involve an oxidative addi-
tion and a 1,2-alkyl shift, respectively.
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
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These are not the final page numbers!