An Au(i)-catalyzed rearrangement/cyclization cascade toward the synthesis of 2-substituted-1,4,5,6-tetrahydrocyclopenta[b]pyrrole

Article abstract of DOI:10.1039/c5cc03979g

An Au(i)-catalyzed tandem reaction for the synthesis of 2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole derivatives from 1-(1-hydroxy-3-phenylprop-2-yn-1-yl)cyclobutanol and primary amines or NH₄OAc has been developed to afford a series of poly

Full text of DOI:10.1039/c5cc03979g

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DOI: 10.1039/C5CC03979G
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Au(I)-Catalyzed Rearrangement/Cyclization Cascade Toward the
Synthesis of 2-Substituted-1,4,5,6-
tetrahydrocyclopenta[b]pyrrole†‡
Received 00th January 20xx,
Accepted 00th January 20xx
Xue-Qing Mou,a Zheng-Liang Xu,a Shao-Hua Wang,*ab Dao-Yong Zhu,a Jie Wang,a Wen
DOI: 10.1039/x0xx00000x
Bao,a Shi-Jiang Zhou,a Chao Yanga and Di Zhanga
www.rsc.org/
An Au(I)-catalyzed tandem reaction for the synthesis of 2- Following this consideration and in connection with our
phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole derivatives interest in the transition metal catalyzed cyclization reactions
from 1-(1-hydroxy-3-phenylprop-2-yn-1-yl)cyclobutanol and and the development of synthetic methodologies toward the
primary amine or NH4OAc has been developed to afford a synthesis of heterocycles,17,18 we envisioned that a facile and
series of polysubstituted pyrroles in moderate to good yields.
efficient tandem reaction procedure to pyrrole structures from
1-(1-hydroxy-3-phenylprop-2-yn-1-yl)-cyclobutanol and
Since its first detection by F. F. Runge in 1834 and structure
elucidation by von Bayer in 1870’s, pyrrole has been
considered as one of the most important heterocycles due to
its broad utilities.1-4 Up to now, pyrroles and its derivatives not
only present in lot of biological contexts, but also represent as
the key structure components of many bioactive molecules5-6
and some organic conducting materials,7-8 e.g., vitamin B12,
atorvastatin and polypyrroles. Therefore, developing synthetic
methodologies toward the construction of pyrrole skeleton is
always of considerable interest to synthetic chemists and has
led to several classical strategies like Hantzsch pyrrole
synthesis,9 Knorr pyrrole synthesis,10 Paal-Knorr pyrrole
synthesis,11 Van Leusen reaction,12 Barton-Zard reaction13 and
Piloty-Robinson pyrrole synthesis.14 Especially, in recent years,
under the promotion of transition metal catalyzed annulation
reactions,15 a number of efficient methodologies toward the
construction of pyrrole compounds have also been
developed.16 Despite of the results achieved, it is still highly
desirable to further explore alternative approaches toward the
synthesis of such an important heterocycle.
primary amine could be achieved through a Meyer-Schuster
Rearrangement19 / 1,2-migration20 / Paal-Knorr cyclization
cascade in the presence of proper catalyst, and would afford
the products with a cyclopenta[b]pyrrole moiety, which is a
common structural motif of many bioactive molecules, such as
(+)-roseophilin,21
D-amino
oxidase
inhibitor22
and
cyclooxygenase 2 inhibitors23 (Scheme 1). To our knowledge,
there is no report about such a reaction to give 1,4,5,6-
tetrahydrocyclopenta[b]pyrrole via a tandem process, which is
highly desirable in terms of reaction efficiency and atom
economy. Herein, we present a new and unique strategy to
construct 1,4,5,6-tetrahydrocyclopenta[b]pyrrole via an Au(I)-
catalyzed tandem reaction (Scheme 1).
As we all known, the Paal–Knorr pyrrole synthesis utilizing
1,4-diketones and amines as starting materials is one of the
most commonly used method to construct multi-substituted
pyrroles. Therefore, it is likely that a similar type of reaction
Scheme 1 Proposed synthetic strategy and related bioactive
molecules.
could take place between
a 1,4-diketone intermediate
generated in situ and an amine within a tandem process.
In order to realize such a tandem reaction, we first
investigated systematically a variety of reaction conditions
such as Lewis acid catalysts, solvents, reaction temperature
and
time
with
1-(1-hydroxy-3-phenylprop-2-yn-1-
yl)cyclobutanol (1a) and NH4OAc (2a) as the model substrates.
As summarized in Table 1, the desired reaction was attempted
initially in the presence of Ph3PAuCl (0.1 equiv) and AgOTf (0.1
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equiv) in DCM at room temperature, as similar type of
catalysts has been used in the Meyer-Schuster
Rearrangement.24 To our delight, the desired product 2-
phenyloctahydrocyclopenta[b]pyrrole (3a) was isolated in 26%
yield (Table 1, entry 1). Inspired by this result, we next
screened different solvents and reaction temperature. And it
was found that nonpolar solvents usually gave better yields
than polar ones. For example, when toluene, cyclohexane, n-
hexane, or n-heptane were employed, the reaction could
afford the expected product in higher yields than other
solvents, like THF, DCE, 1,4-dioxane and DCM (Table 1, entries
1-9). Among the nonpolar solvents screened, the use of n-
heptane could give the highest yield of 74% at 80 °C (Table 1,
entry 9). And it was also observed that either decreasing or
increasing temperature would cause a diminished yield of
desired product (Table 1, entries 8-10). Next, different Lewis
acid catalysts were further applied into the reaction, but none
of them gave higher yields than the combination of Ph3PAuCl
and AgOTf (Table 1, entries 11 −21). Moreover, when Ph3PAuCl
or AgOTf alone was used as the catalyst, no desired product 3a
was detected except the decomposition of the substrate 1a
(Table 1, entries 18-19). Based on the information above, the
loading of the catalyst, the reaction time were evaluated as
well, and we were pleased to find that a lower amounts of
catalyst (5 mol%) could catalyze the reaction well to give a
yield of 75% by slightly prolonging the reaction time (Table 1,
entry 22). Without catalyst, no conversion was observed (Table
1, entry 23), which indicated that the catalyst played a pivotal
role in the reaction.
21
22e
23e
AlCl3 (10)
Ph3PAuCl+AgOTf(5)
no catalyst
n-heptane Vi8ew0ArticlenO.ndli.nde
n-heDpOtaI:n1e0.1039/C5CC03979G
80 75
n-heptane 80
n.d.d
a Reaction condition: without other notification, all of the reactions
were
performed
with
1-(1-hydroxy-3-phenylprop-2-yn-1-
yl)cyclobutanol (0.5 mmol), ammonium acetate (5 equiv.), catalyst
c
in solvent (1 mL) at 80 °C under Ar for 4 h. b Isolated yield. c-
d
e
Hexane = cyclohexane. n.d. = not detected. The reaction time
was 6 h.
With the optimized reaction conditions in hand (Table 1,
entry 22), we subsequently investigated the substrate scope of
such a transformation. Firstly, a series of amines were
subjected to the tandem reaction with compound 1a. As
shown in Table 2, in most cases, the amines tested could
proceed smoothly to transform into the polysubstituted
pyrrole products in moderate yields (Table 2, 3a–3p). Among
them ammonium acetate as the amine source usually gave
higher yield than aliphatic and aromatic amines. Among the
aromatic amine investigated, the electronic effect of the
substituents on phenyl ring was not clearly observed. The
presence of electronic neutral or deficient substituent group
like bromo, chloro and nitro could give the expected products
in moderate yield leading to additional possibilities for further
derivatization (Table 2, 3h-3k). Besides, benzylamine and (4-
methoxyphenyl)methanamine also could go through the
reaction to give the desired products in moderate yield, which
might simplify the synthesis process in case the pyrrole
nitrogen needs pre-protection (Table 2, 3l
when cyclic alkyl amine (2f 2n), alkoxy substituted alkyl amine
(2o) and propargyl amine (2s) were subjected to the tandem
-3m). Additionally,
,
Table 1 Optimization of reaction conditions.a
reaction with compound 1a, they all afforded the desired
products. Encouraged by these results, we next applied the
tandem reaction process to examine the scope of propargylic
alcohols. It was found that introducing an additional electron
donating group like methyl and methoxy group on the
aromatic ring of substrate 1a were well-tolerated, although
they gave slightly lower yield than that of 1a ( for example,
Ent
ry
1
2
3
4
5
6
7
T
(°C)
30
60
60
60
60
110
80
60
80
100
80
80
80
80
80
80
80
80
80
80
Yieldb
(%)
26
30
25
35
32
54
48
65
74
69
trace
trace
n.d.d
42
54
46
Catalyst (mol%)
Solvent
Ph3PAuCl+AgOTf(10)
Ph3PAuCl+AgOTf(10)
Ph3PAuCl+AgOTf(10)
Ph3PAuCl+AgOTf(10)
Ph3PAuCl+AgOTf(10)
Ph3PAuCl+AgOTf(10)
Ph3PAuCl+AgOTf(10)
Ph3PAuCl+AgOTf(10)
Ph3PAuCl+AgOTf(10)
Ph3PAuCl+AgOTf(10)
Ph3PAuCl+CF3CO2Ag(10)
AuCl+AgOTf(10)
AuCl+ CF3CO2Ag(10)
Ph3PAuCl+AgSbF6 (10)
IPrAuCl+AgOTf(10)
IPrAuCl+AgSbF6(10)
SPhosAuCl+AgOTf(10)
Ph3PAuCl(10)
CH2Cl2
DCE
THF
product 3g and 3r, 3p and 3s). Also, replacing the phenyl group
of compound 1a with a steric hindered tert-butyl group proved
to be efficient under standard conditions, and therefore it
revealed that the aromatic ring of propargylic alcohol
dioxane
c-hexanec
toluene
substrate
1
is not a prerequisite in this reaction. With respect
, phenyl
to R2 component in propargylic alcohols substrate
1
n-hexane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
8
9
was also compatible to give corresponding product, albeit in
low yield. It should be noted that when the substrates with a
cyclopentanol moiety instead of cyclobutanol was applied to
this tandem reaction, no desired products were obtained,
which might be attributed to the low reactivity of such a five-
membered unit during the 1,2-migration step.
10
11
12
13
14
15
16
17
18
19
20
Table
2 Gold-catalyzed tandem synthesis of polysubstituted
pyrrole.a
23
n.d.d
n.d.d
n.d.d
AgOTf(10)
Cu(OTf)2(10)
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In summary, an Au(I)-catalyzed tandem reaction, involving a
View Article Online
DOI: 10.1039/C5CC03979G
/ 1,2-migration / Paal-
Meyer-Schuster rearrangement
Knorr cyclization cascade has been successfully developed.
Through the use of this methodology, series of
a
polysubstituted pyrroles were obtained in moderate to good
yields, which might provide a simple and versatile procedure
for the synthesis of 1,4,5,6-tetrahydrocyclopenta[b]pyrrole
derivatives as well as related bioactivity screening.
Acknowledgements
This work was supported by the NSFC (No. 21202073 and
21472077), the fundamental research funds for the central
universities (lzujbky-2014-k20, lzujbky-2015-k12), and the Opening
Project of Key Laboratory of Drug Targeting and Drug Delivery
System, Ministry of Education (Sichuan University).
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