Palladium-catalyzed intermolecular [3 + 2] carbocyclization of alkynols and propiolates: An efficient entry to halo-cyclopentadienes

Article abstract of DOI:10.1039/c3cc47310d

A novel and efficient Pd-catalyzed intermolecular [3 + 2] carbocyclization of alkynols and electron-deficient alkynes for the synthesis of halo-cyclopentadienes (Cps) has been developed. The present protocol employs simple propargyl alcohols as the C3 group to participate in the cyclization reaction, providing a highly convenient and atom-economical entry to the halo-cyclopentadiene framework. The Royal Society of Chemistry.

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DOI: 10.1039/C3CC47310D
A Pd-catalyzed intermolecular [3 + 2] carbocyclization of alkynols and electron-deficient alkynes
for the synthesis of halo-cyclopentadienes has been developed.

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ARTICLE TYPE
Palladium-Catalyzed Intermolecular [3 + 2] Carbocyclization of
Alkynols and Propiolates: An Efficient Entry to Halo-Cyclopentadienes*
Yang Gao, Wanqing Wu*, Huawen Huang, Yubing Huang and Huanfeng Jiang*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A novel and efficient Pd-catalyzed intermolecular [3 + 2]
carbocyclization of alkynols and electron-deficient alkynes for
the synthesis of halo-cyclopentadienes (Cps) has been
developed. The present protocol employs simple propargyl
Scheme 1. Pd-Catalyzed Intermolecular [3 + 2] Carbocyclization of Two
50 Separated Alkynes
10 alcohols as the C3 group to participate in the cyclization
reaction, providing a highly convenient and atom-economical
entry to the halo-cyclopentadiene framework.
connection with our interest in the search for new synthetic
methods involving alkynol reagents,10 we envisioned that
propargylic alcohols might be used as a C3 group to participate in
55 the [3 + 2] carbocyclization reaction. Herein, we disclose the first
example of Pd-catalyzed highly chemo- and regioselective
intermolecular carbocyclization reaction between propargyl
alcohols and electron-deficient alkynes to construct
polysubstituted cyclopentadiene derivatives (Scheme 1). The
60 present protocol directly employs simple propargyl alcohols as
the three-carbon group and successfully introduces the
propargylic carbon atoms to the cyclization reaction, providing
convenient and atom-economical access to the halogenated
cyclopentadiene framework that was difficult to be prepared by
65 traditional methods. Various multi-substituted spiro compounds
which are useful skeletons in many naturally occurring bioactive
compounds11 can be also obtained by this novel transformation.
With the optimal catalytic system in hand (see ESI for details),
we then examined the scope of this novel transformation. A wide
70 variety of tert-propargylic alcohols were found to be successfully
carbocyclized with ethyl propiolate (2a) to afford the
corresponding bromo-cyclopentadiene derivatives (Table 1). For
example, various dialkyl-substituted carbocyclization products
(3aa–3ad) could be obtained with high selectivity in moderate to
75 excellent yields (80%–83%) under the optimal reaction
conditions. The phenyl substituted alkynols also underwent this
Transition metal-catalyzed carbocyclization reactions of
15 unsaturated species have provided useful methods for the
preparation of a wide range of carbo- and heterocycles.1 For
examples, the elegant cycloisomerization reactions of 1,n-
enynes,2a-c 1,n-allenynes, 1,n-allenenes2d,e and 1,n-diynes2f-h
disclosed by Bäckvall and Trost et al. have appeared as
20 conceptually and chemically attractive processes to construct
various cyclization products. However, in the absence of the
constrains imposed by the tethers in intramolecular processes, the
intermolecular carbocyclization involving two or more separated
alkyne entities has been less reported3 for the difficulty in
25 controlling the chemo- and regioselectivity. Further, the
development of complementary sets of catalysts or/and
conditions that provide quick access to five-membered
carbocycle has been intensively pursued by the synthetic
community.4 Among them, cyclopentadienes (Cps) are useful
30 synthetic intermediates in the field of organic and synthetic
chemistry,5 such as valuable building blocks in organic synthesis
and good reaction partners for Diels−Alder reaction. Due to its
importance, several methods have been developed to construct
this useful framework:6 i) nucleophilic addition of 1,4-dilithio-
35 1,3-dienes to aldehydes or ketones; ii) [3 + 2] cycloaddition of
propargyl esters with internal alkynes via Au or Rh carbene
intermediates;
iii)
gold-
or
platinum-catalyzed
cyclization
reaction
to
provide
the
aryl-substituted
cycloisomerizations of vinylallenes or 1,3-dien-5-ynes.
Despite these substantial advances that have been achieved,
40 further development of practical procedures which can enhance
the product diversity, especially for the synthesis of
polysubstituted spiro cyclopentadienes, is still fraught with
challenges.7
On the other hand, propargylic alcohols are one of the most
45 versatile synthetic reagents in organic chemistry.8 Recently,
several metal-catalyzed cross-coupling or/and cycloaddition
reactions have been developed through propargyl carbon-oxygen
bond cleavage or/and carbon-carbon bond formation.9 In
cyclopentadiene 3ae in 51% yield. Notably, the cycloalkane
substituted alkynols (1f, 1j) were found to be the suitable reaction
80 partners for this transformation and gave the spiro
cyclopentadiene compounds 3af–3aj in good yields. These spiro
structures may have potential applications in synthetic and
medicinal chemistry.11 In addition, the structure of 3ah was
further confirmed by X-ray crystallographic analysis (see ESI for
85 details).12
Then, the scope of the reaction with respect to the propiolates
was also studied (Table 1). A range of propiolates with different
substituents could react smoothly with tert-propargylic alcohols
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to give the bromo-cyclopentadiene products (3ba–3jg) in good
yields (64%–82%). Functional groups such as (SMe, Me, F, Cl,
Br, CF3, NO2) were well tolerated for this novel transformation. It 30 compounds 6a and 6b in excellent yields. When treated with n-
Suzuki−Miyaura cross-coupling reactions of 3 with different
arylboronic acids respectively delivered arylated cyclopentadiene
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DOI: 10.1039/C3CC47310D
should be noted that these functional groups could be used for
further modifications to achieve more complex structures. To our
delight, amide substituted cyclopentadiene products (3ka, 3la)
could be obtained in moderate yields by switching one of the
butyl lithium reagent, 3aa was converted to the hydroxy product
7 in 86% yields. Furthermore, 3aa could readily undergo the
hydrolysis process to provide the free carboxylic acid 8 in
excellent yield.
5
reaction partners from propiolate to propiolamide. However, our 35 Scheme 2. Transformations of Brominated Cyclopentadienes (Cps)
O
attempts to employ internal alkyne as the substrate turned out to
10 be unfruitful, which might be caused by the steric hindrance
induced by the substitution on the alkyne moiety.
PdCl2
5a, Ar = Ph, 89%
5b, Ar = 4-Br-Ph, 80%
O
+
3
Ar
DMF, 80 o
C
Br
Ar
Br
O
O
( )3
Table 1. Substrate Scopea, b
HO
R
O
O
( )3
HO
O
Ar
Br
Br
5c, 86%
Ph
6a, Ar = Ph, R = t-Bu, 88%
6b, Ar = Naphthyl, R = Et, 90%
7, 86%
8, 92%
To gain insight into the mechanism of the intermolecular
carbocyclization process, several control experiments were
conducted (Scheme 3). First, two deuterated experiments were
40 carried out to distinguish whether the proton transfer process
existed in this carbocyclization reaction. As depicted in [eqn. (a)],
deuterium product 3aa' was obtained exclusively in 80% isolated
yield and the deuterium atom (98% examined by 1H NMR
spectroscopy) was still present. However, when deuterated acetic
45 acid was used as the solvent [eqn. (b)], there was no deuterium in
the product. Furthermore, the possibility of 2a' detected in the
reaction system as an intermediate was excluded for 2a' could not
be transformed to the desire product 3aa when treated with 1a
under the standard conditions [eqn. (c)]. Additionally, allenic
50 bromide 1a' could not transfer to the desired product in this
reaction system, thus excluding the pathway that involved the
intermolecular carbocyclization of allenic bromide and the
Michael acceptor.13
Scheme 3. Control Experiments
a
Reaction conditions: unless otherwise noted, all reactions were
performed with 1a (0.5 mmol), 2 (0.5 mmol), Pd(OAc)2 (5 mol %), LiBr
(1 mmol) in CH3CN/HOAc (2 mL, v/v = 1:1) as solvent at 60 °C for 8 h. b
Isolated yield.
To further highlight the versatility of this strategy, we applied
this method to the synthesis of chlorinated cyclopentadiene
products and the result showed that the addition of 1 equiv of
.
15 CuCl2 2H2O instead of LiBr gave the expected chlorinated
cyclopentadiene products 4a and 4b in 56% and 68% yields.
55
Although the detailed mechanism of this intermolecular
carbocyclization reaction is still under investigation, a plausible
catalytic cycle is proposed (Scheme 4). The reaction might be
initiated by cyclopalladation of alkyne14 to form the
60 palladacyclopentadiene species I, which would undergo the β-OH
elimination to give the enallene intermediate II with the aid of
HOAc.10 Then, the nucleophilic attack of halide ion to the allene
moiety formed the cyclopalladium species III,15 followed by
reductive elimination of the C(sp2)-C(sp3) bond to afford the
65 halo-cyclopentadiene products and regenerate the active Pd0
species.
To demonstrate the synthetic utility of this protocol, the newly
formed cyclopentadienes derivatives were employed for further
20 transformations to prepare a series of functionalized products
(Scheme 2). It is worth mentioning that the resulting ester-
substituted cyclopentadiene derivatives could undergo Diels-
Alder cycloaddition with styrene to obtain poly-substituted endo-
norbornenes 5a-c in 89%, 80% and 86% yields, respectively. In
25 addition, the vinyl halide and the ester functionalities in the
products enable them to be attractive and versatile synthetic
building blocks in a variety of chemical transformations. The
2
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Scheme 4. Plausible Mechanism
6
In summary, we have developed a novel and efficient Pd-
catalyzed method for the synthesis of halo-cyclopentadiene
derivatives from intermolecular [3 + 2] carbocyclization of
alkynols and propiolates. Through Pd-catalyzed propargyl
carbon-oxygen bond cleavage and carbon-carbon bond formation,
we successfully introduce the propargylic carbon atoms of
alkynol to the cyclization reaction. This direct carbocyclization
5
70
75
10 reaction of two separated alkyne entities is a conceptually and
chemically attractive process that may broaden the scope of
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cyclopentadiene products can be applied to the construction of
different poly-substituted norbornenes via Diels-Alder
15 cycloaddition, thus illustrating the potential applications of this
methodology in synthetic and medicinal chemistry. The detailed
reaction mechanism and further synthetic applications are under
investigation in our laboratory, and the results will be reported in
due course.
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20 We are grateful to the financial support from the National Basic
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School of Chemistry and Chemical Engineering, South China University
of Technology, Guangzhou 510640, China. Fax: +86 20-87112906; Tel:
+86 20-87112906; E-mail: jianghf@scut.edu.cn; cewuwq@scut.edu.cn
30 † Electronic Supplementary Information (ESI) available: Experimental
section, characterization of all compounds, copies of 1H and 13C NMR
spectra for selected compounds. See DOI: 10.1039/b000000x/
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