Gold(I)-catalyzed intra- and intermolecular alkenylations of β-yne-pyrroles: Facile formation of fused cycloheptapyrroles and functionalized pyrroles

Article abstract of DOI:10.1021/ol500744k

An efficient gold(I)-catalyzed alkenylation of β-alkyne-substituted pyrroles is reported. The intramolecular reaction gives straightforward access to different types of seven-membered-ring-fused pyrroles with endo-selectivity, and the intermolecular react

Full text of DOI:10.1021/ol500744k

Letter
pubs.acs.org/OrgLett
Gold(I)-Catalyzed Intra- and Intermolecular Alkenylations of β‑Yne-
pyrroles: Facile Formation of Fused Cycloheptapyrroles and
Functionalized Pyrroles
Bin Pan, Xiaodong Lu, Chunxiang Wang, Yancheng Hu, Fan Wu, and Boshun Wan*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
S
* Supporting Information
ABSTRACT: An efficient gold(I)-catalyzed alkenylation of β-
alkyne-substituted pyrroles is reported. The intramolecular
reaction gives straightforward access to different types of
seven-membered-ring-fused pyrroles with endo-selectivity, and
the intermolecular reaction with alkynes provides function-
alized pyrrole derivatives.
seven-membered-ring fused pyrrole skeleton is a
component of many interesting natural products, such as
ambiguine K isonitrile, densanins A, and hymenialdisine
(Figure 1). From a pharmaceutical point of view, these fused
product, whereas the substrates cyclized readily with a cationic
gold(I) complex but only gave six-membered-ring products by
a 6-exo-dig pathway (Scheme 1, a). Such rearrangement or 1,2-
A
Scheme 1. Gold-Catalyzed Intramolecular Alkenylation of α-
Yne-pyrroles and β-Yne-pyrroles
Figure 1. Natural products with seven-membered-ring fused pyrrole.
cycloheptapyrroles and their derivatives selectively inhibited a
considerable number of different kinases and cytokines.1
Therefore, this class of compounds has been considered as a
potential lead for the development of promising therapeutic
molecules, as well as attractive targets for organic synthesis.
Although various methods for the preparation of seven-
membered ring systems have been reported,2 new strategies
for the efficient synthesis of seven-membered-ring fused
pyrroles are still extremely desirable.
The alkenylation of arenes catalyzed by electrophilic
transition-metal complexes has received much attention in the
past decade.3 In particular, gold-catalyzed cyclizations of
aromatic and heteroaromatic compounds with alkynes offer a
new way for the construction of a polycyclic system,4−8
including seven-membered-ring fused pyrroles. As the first
attempt, Beller and co-workers reported the cyclization of
pyrroles tethered to alkynes.9a,c Later, Broggini and Van der
Eycken developed this strategy to synthesize pyrrolopyridi-
nones and pyrroloazepinones, respectively.9c−f
migration via spiro intermediate seemed unavoidable because
the α position of pyrrole is normally more nucleophilic than the
β position. Considering the uncontrollability of regioselectivity
when α-yne-pyrrole substrates were used, a promising solution
might be using β-yne-pyrroles. Thus, the annulated inter-
mediate D would be formed directly without isomerization
(Scheme 1, b). Unfortunately, to the best of our knowledge,
amide-tethered α-yne-pyrroles9 were the only option in the
intramolecular alkenylation, and a straightforward synthesis of
β-yne-pyrroles was proved irrealizable. Very recently, we
developed a Ni-catalyzed [3 + 2] cycloaddition of methyl-
eneaziridines and diynes to give pyrroles with the alkyne chain
attached at the β position.10a This work provided us an
However, it is very difficult to control the chemoselectivity of
gold-catalyzed reactions at not fully substituted pyrroles,8e
including alkyne-substituted pyrroles. Au(III)-catalyzed cycliza-
tion involved the cationic spiro intermediate A, which might
form cation B by rearrangement and generated isomerized side
Received: March 11, 2014
Published: March 31, 2014
© 2014 American Chemical Society
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Letter
opportunity to study the gold-catalyzed alkenylations of β-yne-
pyrroles.
Scheme 2. Gold(I)-Catalyzed Intramolecular Alkenylation of
β-Yne-pyrroles
a,b
To validate our hypothesis, β-yne-pyrrole 1a was prepared as
a model substrate for the investigation of alkenylation (Table
1). Disappointingly, AuCl3 and AuCl were completely futile to
a
Table 1. Optimization of Reaction Conditions
a
Reaction conditions: 1a (0.25 mmol), 5 mol % of catalyst, 5 mL of
a
Reaction conditions: β-yne-pyrroles 1 (0.3 mmol), JohnPhos-[Au] (5
b
c
d
e
solvent. Isolated yield. No reaction. Under 80 °C. IPr = 1,3-
b
mol %) in toluene or CH2Cl2 (3 mL). Isolated yield.
bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
under 90 °C for 24 h. The low reactivity of substrate 1o should
be attributed to electronic reasons rather than steric hindrance.
In particular, a totally different regioselectivity was observed
when terminal-alkyne substrate 1p was introduced, and six-
membered-ring fused pyrrole 2p was isolated as the sole
product, corresponding to previous reports of β-yne-furans.7g
This result suggested that the regioselectivity of cyclization
could be tuned by electronic effects of suitable substituents on
the alkyne moieties.
catalyze the reaction. PtCl2, which has been successfully applied
in other alkenylations,7b,8c,9f only gave the desired fused
cycloheptapyrrole 2a in 21% yield. To our delight, Au(I)
complexes bearing N-heterocyclic carbene ligands or bulky
phosphanes could catalyze the intramolecular reaction of β-yne-
pyrroles. The best catalyst for the formation of fused
cycloheptapyrrole 2a is JohnPhos-[Au] (Table 1, entry 6),
which allows the cyclizations to be achieved in the absence of
Ag(I) salts. Screening of the solvents showed that the reaction
proceeded well in toluene, giving the desired product in 80%
yield. The identity of 2 was unambiguously secured by X-ray
crystallographic analysis of 2n (Supporting Information).
With the optimal conditions established, we set out to
explore the substrate scope of various β-yne-pyrroles in this
transformation (Scheme 2). First, substituents on the nitrogen
atom did not remarkably influence the final chemical output,
providing the corresponding fused cycloheptapyrrole products
(2a,b,d−g) in good yields. However, the steric effect may be
the primary reason for the low yield of 2c, irrespective of the
electronic nature. Subsequently, the tethering unit of pyrroles
and alkynes was investigated. To our delight, the link X is not
limited to malonate-, substrates containing CH2- (2j),
tosylamide- (2k), O- (2l), and dimedone- (2m) tethers could
all undergo this cyclization and be transformed into different
types of seven-membered-ring fused pyrroles in moderate to
good yields. It should be noted that the substituents in the R2
position played significant roles in this alkenylations. The
phenyl group (2n) was tolerated, and good yield was obtained.
Nevertheless, the less hindered trimethylsilyl (TMS) moiety
inhibited this cyclization process, and no identifiable product
(2o) was detected even when the reaction was performed
Although gold(I)-catalyzed intermolecular alkenylation of
alkynes with furans and indoles has been reported,6b,7g the
intermolecular reaction with pyrroles was less investigated. We
were curious whether such reaction could occur on β-yne-
pyrroles, which inherently had alkyne moieties after all. To our
delight, the intermolecular addition reaction with terminal
alkynes proceeded satisfactorily in the presence of 5 mol % of
JohnPhos-[Au] and was not affected by the internal alkyne
moieties, giving functionalized pyrrole products in moderate to
excellent yields (Scheme 3). It should be mentioned that
intermolecular reactions of furans7g or indoles6b with alkynes
were not possible to achieve such selective reactions. The
substituents in the R position of the terminal alkyne were
crucial to the reactivity and regioselectivity. Phenyl group (3a)
and electron-donating p-methoxyphenyl group (3b) were
tolerated, and high yields were obtained. Notably, the tolerance
of the propargyl alcohol with a free hydroxyl group (3d) offered
the opportunity for further functionalization. It is noteworthy
that the electron-withdrawing −CO2Me group showed different
regioselectivity and generated 3e as a single isomer with E
configuration. In contrast, the alkyl groups such as cyclohexyl
and tertiary butyl were futile in this intermolecular alkenylation,
and the intramolecular reaction was dominant, giving seven-
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Scheme 3. Gold(I)-Catalyzed Intermolecular Alkenylation of
β-Yne-pyrroles with Alkynes
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* Supporting Information
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General experimental procedures, characterization data, 1H and
13C NMR spectra, and X-ray crystallographic analysis of
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bswan@dicp.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science
Foundation of China (21372219).
■
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NOTE ADDED AFTER ASAP PUBLICATION
■
The author names were incorrect in reference 7g in the version
published ASAP on March 31, 2014; the correct version
reposted April 18, 2014.
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