One-pot synthesis of fused pyrroles through a key gold-catalysis-triggered cascade

Article abstract of DOI:10.1002/chem.201304204

A two-step, one-pot synthesis of fused pyrroles is realized by firstly condensing an N-alkynylhydroxammonium salt with a readily enolizable ketone under mild basic conditions and then subjecting the reaction mixture to a gold catalyst, which triggers a cascade reaction involving a facile initial [3.3]-sigmatropic rearrangement of the gold-catalysis product, that is, an N,O-dialkenylhydroxamine. The reaction provides a facile access to polycyclic pyrroles in moderate to good yields. A two-step, one-pot synthesis of fused pyrroles is realized by firstly condensing an N-alkynylhydroxammonium salt with a readily enolizable ketone under mild basic conditions and then subjecting the reaction mixture to a gold catalyst, which triggers a cascade reaction involving a facile initial [3.3]-sigmatropic rearrangement of the gold-catalysis product, that is, an N,O-dialkenylhydroxamine. The reaction provides a facile access to polycyclic pyrroles in moderate to good yields (see scheme). Copyright

Full text of DOI:10.1002/chem.201304204

DOI: 10.1002/chem.201304204
Communication
&
Gold Catalysis
One-Pot Synthesis of Fused Pyrroles through a Key Gold-
Catalysis-Triggered Cascade
Zhitong Zheng, Huangfei Tu, and Liming Zhang*[a]
wise.[3] We envisioned that related N,O-dialkenylhydroxamines,
Abstract: A two-step, one-pot synthesis of fused pyrroles
is realized by firstly condensing an N-alkynylhydroxammo-
nium salt with a readily enolizable ketone under mild
basic conditions and then subjecting the reaction mixture
to a gold catalyst, which triggers a cascade reaction in-
volving a facile initial [3.3]-sigmatropic rearrangement of
the gold-catalysis product, that is, an N,O-dialkenylhydrox-
amine. The reaction provides a facile access to polycyclic
pyrroles in moderate to good yields.
again difficult to access in the absence of electronic assistance
and/or excessive heating,[4] could also be made available
through gold catalysis[5] and that their further transformation
would offer valuable opportunities in developing versatile syn-
thetic methods based on an initial gold catalysis. Herein, we
report an implementation of the approach, which led to the
development of a two-step, one-pot expedient synthesis of
fused pyrroles.[6]
In the reaction proposal (Scheme 2) we envisioned that the
condensation between a ketone and an N-monosubstituted
hydroxamine 3 would lead to the more stable N-hydroxy-
enamine 4 instead of the nitrone 4’ if the ketone has an elec-
Recently, we reported an efficient synthesis of 2-alkylindoles
based on the [3.3]-sigmatropic rearrangement of O-vinyl-N-aryl-
hydroxyamines 1, which are generated by gold-catalyzed addi-
tions of N-arylhydroxyamines to terminal alkynes (Scheme 1).[1]
Scheme 2. Proposed reaction.
tron-withdrawing group at its a-position. If the alkyl group of
the original hydroxamine has an ideally positioned CÀC triple
bond, 4 could undergo a gold-catalyzed cyclization to give an
N-alkenyl-O-alkenylhydroxamine 5, which, like the related inter-
mediate 1, should undergo a rapid [3.3]-sigmatropic rearrange-
ment. The thus formed cyclic imino ketone 6 could tautomer-
ize to enamine 7, which might undergo a transannular dehy-
drative cyclization to complete the gold-catalysis-triggered cas-
cade to give product 8 as a 2,3-dihydro-1H-pyrrolizine (n=1)
or as a 5,6,7,8-tetrahydroindolizine (n=2). Such a bicyclic pyr-
role skeleton can be found in bioactive indole alkaloids as part
of the indole ring, such as polysin,[7] flinderoles,[8] antibacterial
indoloquinone 7-methoxymitosene,[9] as well as synthetic com-
pounds studied in medicinal chemistry (Figure 1).[10]
Scheme 1. Indole synthesis triggered by an initial gold-catalyzed generation
of O-alkenyl-N-arylhydroxamines[1] or their N-acyl variants.[2]
The pericyclic reaction occurs readily at ambient temperature,
which is attributed to the weak NÀO bond. Based on the same
type of facile [3.3]-sigmatropic rearrangements, a related trans-
formation by using hydroxamic acids or N-hydroxycarbamates
as substrates was realized through dual Au and Zn catalysis,
which showed a better reaction scope in the synthesis of N-
protected substituted indoles (Scheme 1).[2]
In both cases, gold catalysis was key, since the requisite O-al-
kenyl-N-aryl hydroxamines could not be easily prepared other-
To implement the proposed reaction, we synthesized N-hy-
droxyenamine 4a by condensing N-(pent-4-yn-1-yl)hydroxyl-
amine and 1,3-cyclohexanedione and treated it with various
gold catalysts in dichloromethane (Table 1). To our delight, the
desired reaction occurred readily in the presence of
Ph3PAuNTf2, affording the desired tricyclic pyrrole 8a in a mod-
[a] Z. Zheng, H. Tu, Prof. Dr. L. Zhang
Department of Chemistry and Biochemistry
University of California, Santa Barbara
Santa Barbara, CA 93117 (USA)
E-mail: zhang@chem.ucsb.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304204.
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Communication
through condensation between N-(pent-4-yn-1-yl)hydroxam-
monium trifluoroacetate and 1,3-cyclohexanedione in the pres-
ence of a base at ambient temperature under a nitrogen at-
mosphere. The protonated hydroxamine used as its free form
is prone to oxidation. Mindful of the potential of bases to in-
hibit gold catalysis, we limited the choice of bases to those of
mild nature. As shown in Table 2, while K2CO3 (entry 1) worked
poorly, the other bases, including 8-methylquinoline (entry 2),
sodium tosylate (entry 3), NaOAc (entry 4), and NaHCO3
(entry 5), were all effective, with the last one affording the
highest NMR yield of 4a.
Table 2. Optimizing the conditions of the condensation step.
Figure 1. Natural products and/or bioactive compounds containing a 2,3-di-
hydro-1H-pyrrolizine moiety.
Entry
Base ([equiv])
Time [h]
Yield [%][a]
1
2
3
4
5
K2CO3 (1.5)
8-methylquinoline (1.2)
TsONa (1.0)
NaOAc (1.2)
NaHCO3 (1.2)
4
3
2
2.5
1.5
37
88
80
83
93
Table 1. Reaction discovery and optimization.
[a] NMR yield, determined by using diethyl phthalate as the internal refer-
ence.
Entry
Catalyst
Time [h]
Yield [%][a]
1
2
3
4
5
6
7
Ph3PAuNTf2
IPrAuNTf2
4.5
7
0.5
6
50
72
82
85
57
42[b]
<1[c]
With the mild conditions (Table 2, entry 5) established for
the preparation of 4a, a subsequent gold catalysis by using
the optimized conditions described in Table 1 was performed
in a one-pot manner. To our delight, the reaction proceeded
smoothly, although expectedly slower, and the overall isolated
yield was good (entry 1, Table 3).
BrettPhosAuNTf2
MorDalPhosAuNTf2
(2,4-tBu2PhO)3PAuNTf2
AuCl3
2
overnight
overnight
CF3COOH[c]
[a] NMR yield, determined by using diethyl phthalate as the internal refer-
ence. [b] Reaction not finished when stopped. [c] 10 equivalents used.
With the one-pot, two-step reaction realized, we then inves-
tigated the reaction scope. A series of readily available substi-
tuted 1,3-cyclohexanediones was first examined. Many of them
underwent the reaction smoothly, affording substituted tricy-
clic pyrroles in mostly good yields (Table 3, entries 2–6). Inter-
estingly, when the two carbonyl groups are sterically differenti-
ated, as in the case of 2c or 2 f, the more hindered one re-
mained unchanged while the a-unsubstituted one was incor-
porated into the pyrrole ring of the isolated product (entries 3
and 6), indicating a high level of steric preference. In addition
to cyclohexane-1,3-diones, cyclopentane-1,3-diones also par-
ticipated in the reaction, affording 8g with an exquisite linear
azatriquinane skeleton. While, in most cases, the overall yields
were moderate, these one-pot reactions are valuable given the
enhanced operational efficiency and, moreover, that the aver-
age yield for each step is >70%.
erate yield of 50% (entry 1). Notably, the eight-membered ring
1
intermediate 7 was not detected by H NMR spectroscopy, sug-
gesting that its subsequent transannular condensation is facile.
This encouraging result was readily improved by using other
gold catalysts (entries 2–5). In particular, both BrettPhos-
[11]
[12]
AuNTf2 (entry 3) and MorDalPhosAuNTf2
(entry 4) led to
>80% yield of the desired product, as determined by NMR
spectroscopy. Although the latter catalyst was slightly more ef-
fective, the reaction was much slower and, moreover, the
1
crude H NMR spectrum was less clean than when using the
former catalyst. As a result, BrettPhosAuNTf2 was used for fur-
ther studies. On the other hand, AuCl3 was less effective as
a catalyst (entry 6), and a Brønsted acid such as CF3COOH was
not capable of promoting the reaction, even in the presence
of an excess amount (entry 7).
To further expand the reaction scope, we turned to acyclic
1,3-diketone compounds. Instead of the anticipated product,
that is, acyl-substituted 1,2-fused pyrrole 9 (Scheme 3), the iso-
xazonium intermediate 10 was detected. This heteroarene is
likely formed during the first condensation step in the absence
of the gold catalyst and, notably, NaHCO3 might not be in-
To improve the overall operational efficiency, we probed
whether the synthesis of the N-hydroxyenamine precursor 4
and the subsequent gold catalysis could be performed in
a one-pot process. First, we examined the synthesis of 4a
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Table 3. One-pot synthesis of tricyclic pyrroles from different 1,3-cyclodi-
Table 4. Expanded reaction scope.[a]
ketones.
Entry Hydroxylamine
Ketone
Product
Yield
[%][b]
Entry
Substrate
Product
Yield Time
[%][a] [h][b]
1
42[c]
1
2
3
4
5
6
7
75
4
2
37
55
4
62[c]
52
4.5
4
3
4
61
56
57
3.5
8
[a] Reactions were run under the same conditions as described in Table 3.
[b] Isolated yield. [c] Structure determined by nOe experiments.
63[c]
50
charged isoxazole ring. Indeed, when 1,1,1-trifluoropentane-
2,4-dione was employed, the expected bicyclic pyrrole was ob-
tained in 42% yield (Table 4, entry 1). Though with a low effi-
ciency, the reaction was highly selective toward the less elec-
trophilic carbonyl group. An alternative approach to avoid the
formation of isoxazonium intermediates is the replacement of
one of the carbonyl groups with a different electron-withdraw-
ing group. For example, when a 4-nitrophenyl group was em-
ployed, a serviceable yield of the substituted bicyclic pyrrole
8i was realized (entry 2). We also varied the N-alkynylhydrox-
amine; a benzene-fused variant 11 reacted readily to afford
the tetracyclic pyrrole 8j in a good overall yield for the two-
step sequence (entry 3). A homologue with a one-carbon-
longer linker also reacted smoothly, leading to the formation
of piperidine-fused tricyclic pyrrole 8k in a good overall yield
(entry 4).
7.5
[a] One-pot overall isolated yield. [b] Reaction time referring to both
steps. [c] Regiochemistry established by nOe experiments.
In summary, we have developed a facile two-step, one-pot
method for the synthesis of a range of fused pyrroles from N-
alkynylhydroxamines and readily enolizable ketones. By varying
the substrates, fused pyrroles of different bicyclic, tricyclic, and
tetracyclic skeletons can be readily accessed in moderate to
good yields. This reaction employs a key gold-catalysis step to
trigger a cascade process featuring an initial facile [3.3]-sigma-
tropic rearrangement of the gold-catalysis product, that is, an
N,O-dialkenylhydroxamine. Further work on combining gold
catalysis with facile downstream transformations will be report-
ed in due course.
Scheme 3. Applying acyclic 1,3-diketone compounds to the reaction condi-
tions.
volved in the reaction, as shown in the proposed mechanism
(Scheme 3). Indeed, when the substrates were mixed in 1,2-di-
chloroethane (DCE), 10 was formed in 60% NMR yield within
the same time frame.
To circumvent the formation of 10 or its congeners, we rea-
soned that an electron-withdrawing R1 or R2 group in 10 might
retard its formation due to the destabilization of the positively
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Experimental Section
One-pot synthesis of fused pyrroles (8a–k) though gold-cat-
alysis-triggered cascade
N-Alkylhydroxylammonium trifluoroacetate (0.1 mmol), ketone 2a–
i (1.2 equiv), NaHCO3 (1.2 equiv), and 1,2-dichloroethane (2 mL)
were added to a vial with a magnetic stirring bar. The system was
degassed with N2 and the mixture was stirred at room tempera-
ture. When the reaction was finished (monitored by TLC), the cap
was opened and BrettPhosAuNTf2 (5 mol%) was added. The reac-
tion was allowed to stir at room temperature until completion
(monitored by TLC) and thenconcentrated under reduced pressure.
The residue was purified by flash column chromatography to
afford the corresponding product 8a–k.
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Acknowledgements
The authors thank NIGMS (R01 GM084254) for generous finan-
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Keywords: catalysis
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Received: October 28, 2013
Published online on January 30, 2014
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