PPh3-catalyzed [2 + 2 + 2] and [4 + 2] annulations: Synthesis of highly substituted 1,2-dihydropyridines (DHPs)

Article abstract of DOI:10.1039/b915825a

PPh₃-catalyzed [2 + 2 + 2] annulations between two units of an activated terminal alkyne and one unit of an aryl N-tosylimine have been developed to provide a synthetic method for highly substituted dihydropyridines. On the basis of the mechani

Full text of DOI:10.1039/b915825a

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PPh3-catalyzed [2 + 2 + 2] and [4 + 2] annulations: synthesis of highly
substituted 1,2-dihydropyridines (DHPs)w
Huimin Liu, Qiongmei Zhang, Limin Wang and Xiaofeng Tong*
Received (in Cambridge, UK) 3rd August 2009, Accepted 9th November 2009
First published as an Advance Article on the web 24th November 2009
DOI: 10.1039/b915825a
PPh3-catalyzed [2 + 2 + 2] annulations between two units of an
activated terminal alkyne and one unit of an aryl N-tosylimine
have been developed to provide a synthetic method for highly
substituted dihydropyridines. On the basis of the mechanism of
the [2 + 2 + 2] annulation, PPh3-catalyzed [4 + 2] annulations
have also been discovered.
substrate, the compound 4ba was isolated as the major
product (eqn (2), Scheme 1). The structure of 4ba has been
unambiguously established by X-ray crystallography (see the
ESIw). Obviously, this new PPh3-catalyzed [2 + 2 + 2]
annulation of 1-arylpropynones with aryl N-tosylimines provides
facile access (eqn (2)) to highly substituted 1,2-dihydropyridines
(DHPs)7 which have been recognized as pharmaceutically
important small molecules and versatile synthetic intermediates.
In this communication we wish to report the development of
these new [2 + 2 + 2] annulations in detail.
As one of the most powerful intermolecular cycloadditions,
nucleophilic phosphine catalysis has been widely developed as
a reliable platform for synthesizing carbo- and heterocyclics.1
In particular, Lu’s [3 + 2] cycloaddition of allenoates with
alkenes or imines under phosphine catalysis has been deeply
studied2 and has demonstrated great potential utility for the
syntheses of natural products.3 In 2003, Kwon’s group
employed a novel strategy for phosphine-catalyzed reactions
to realize [4 + 2] annulations of 2-substituted allenoates with
imines.4 Very recently, this strategy has been successfully
extended to one novel [3 + 3] cycloaddition.5 Apart from
the above mentioned works, other elegant phosphine-catalyzed
[m + n] annulations have also been realized to construct a
variety of cyclic compounds.6 Despite of all these catalytic
systems reported so far, the chemistry of nucleophilic phosphine
catalysis has not yet been achieved to its full potential,
particularly in the construction of ring systems.
Exploratory studies on the model reaction between aryl-
propynone 1b and phenyl N-tosylimine 2a have been
performed to verify that both 3.0 equiv. of 1b and higher
temperature were needed for a good yield of 4ba. Under the
optimized conditions (see Table S1 in the ESIw), it was
pleasing to discover that the [2 + 2 + 2] annulations
proceeded smoothly with a range of substrates and 1,2-dihydro-
pyridines 4 could be easily obtained in good to excellent yields.
The details are presented in Table 1.
1
It is worth noting that the H NMR spectrum of eqn (2)
clearly showed the existence of compound 3ba when the
[2 + 2 + 2] annulation was conducted at 80 1C (eqn (2)).
Once the temperature was elevated to reflux, 3ba could be
further converted into compound 4ba when one more
equivalent of 1b was added. Thus we envisioned that
compound 3ba might work as a key intermediate for the
[2 + 2 + 2] annulation. However, all our attempts to obtain
a pure sample of 3ba failed. Therefore, we turned our attention
to the compound 3aa which could be viewed as an analog of
3ba. To our delight, 3aa readily reacted with 1b to accomplish
Recently we discovered that alkyl propiolate 1a, in the
presence of 20 mol% of PPh3, reacted with tosylimine 2 to
give the adduct product 3aa (eqn (1), Scheme 1). Surprisingly,
when 1a was replaced by 1-phenylprop-2-yn-1-one 1b as the
Table 1 [2 + 2 + 2] annulations between 1b and 2 in the presence of
20 mol% PPh3
a
Entry
2 (Ar)
4
Yield (%)b
Scheme 1 Different reactivity between 1a and 1b.
1
2
3
4
5
2a (Ph)
4ba
4bb
4bc
4bd
4be
75
90
59
67
85
2b (4-MeO-C6H4)
2c (4-Me-C6H4)
2d (4-Cl-C6H4)
2e (4-Br-C6H4)
Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
Shanghai 200237, China. E-mail: tongxf@ecust.edu.cn;
Tel: 86 21-64253881
w Electronic supplementary information (ESI) available: Experimental
details and spectroscopic and analytical data for all new compounds.
CCDC 739301. For ESI and crystallographic data in CIF or other
electronic format, see DOI: 10.1039/b915825a
a
Reaction conditions: a solution of 1b (1.5 mmol) in toluene (10 mL)
was slowly added to a mixture of 2 (0.5 mmol) and PPh3 (0.1 mmol) in
b
toluene (10 mL) at 120 1C over 1.5 h. Isolated yield.
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Table 2 PPh3-catalyzed [4 + 2] annulations between 1b–d and 3a
further evidence to support our hypothesis that 3 might work
as an intermediate for the [2 + 2 + 2] annulation.
(4)
(5)
Entry 1 (Ar)
3 (R, Ar1)
5 Yield (%)b
5ba (59)
1
2
3
4
5
6
7
1b
1b
1b
3aa (Me, Ph)
3ab (Me, 4-MeO-C6H4) 5bb (96)
3ae (Me, 4-Br-C6H4) 5bc (86)
1c (4-MeO-C6H4) 3ab (Me, 4-MeO-C6H4) 5cb (59)
1d (4-Me-C6H4)
1c
1b
3ae (Me, 4-Br-C6H4)
3ae (Me, 4-Br-C6H4)
3eb (Bn, 4-MeO-C6H4)
5dc (60)
5cc (50)
5bd (63)
a
Reaction conditions: a solution of 1 (0.6 mmol) in toluene (6 mL)
was slowly added to a mixture of 3 (0.3 mmol) and PPh3 (0.06 mmol)
On the basis of the above observations, our suggested
reaction mechanism is outlined as shown in Scheme 3.
Addition of PPh3 to propiolate 1a forms the zwitterion A1.8
The corresponding A2 can also be obtained from phenyl-
propynone 1b. The zwitterions A (A1, A2) undergo a
Mannich-type reaction with N-tosylimine 2 to give the inter-
mediate B. With two consecutive proton transfers, B is
converted to D via intermediate C. Then [1,5]-elimination
of PPh3 yields compound 3. It is worth noting that propiolate
1a does not react with either 3aa or 3ba at all under the [4 + 2]
annulation conditions. Thus we assume that the nucleo-
philicity of the zwitterions A (A1, A2) is strongly reliant upon
on the nature of the activating group (e.g. ester or ketone).
Due to its stronger nucleophilicity, A2 undergoes a Michael-
type addition with 3 to form intermediate E. Subsequent
conjugate addition and [1,2]-elimination of PPh3 generates
intermediate G. Finally, a [1,3]-proton transfer occurs to give
the product 4 or 5.
b
in toluene (6 mL) at 120 1C over 1.0 h. Isolated yield.
the [4 + 2] annulation under reflux conditions and meanwhile
the corresponding 1,2-dihydropyridine 5 could be obtained
(eqn (3)). The [4 + 2] annulations also presented a similar
performance under the same conditions as those of the
[2 + 2 + 2] annulations and the results are outlined in Table 2.
Apparently, eqn (1) (Scheme 1) and eqn (3) (Table 2) share
almost common reaction conditions except for the reaction
temperature. This observation inspired us to explore the
possibility of preparing compound 3 in situ for the [4 + 2]
annulation (Scheme 2). Fortunately, this one-pot strategy
could be smoothly achieved through direct addition of
compound 1b to the reaction systems in which compound 3
was firstly formed with 2b and the propiolate as starting
materials at 80 1C (see the ESIw). The products 5bb and 5bd
could also be obtained in yields of 58% and 53%, respectively.
Obviously, these numbers were somewhat lower compared
to the yield of the corresponding products in Table 2.
Furthermore, for better performance of the one-pot strategy,
both an additional 20 mol% amount of PPh3 and elevated
temperature (reflux) were needed for the second step (Scheme 2).
In order to get more details about the reaction mechanism,
we conducted two control experiments with deuterium-labeled
substrates. Firstly, when compound 2b-D was subjected to the
[2 + 2 + 2] annulation with 1b (eqn (4)), the deuterium atom
was found to be fully incorporated into the product 4bb-D
with 20% D at the C1 atom and 80% D at the C3 atom.
Secondly, with deuterium-labeled 3ab-D as the substrate
(eqn (5)), 30% D and 70% D were incorporated into the C1
and C3 atoms of 5bb-D, respectively. These results disclosed
the entire picture of the H-transfer process and provided
In summary, we have realized, for the first time, PPh3-
catalyzed [2 + 2 + 2] annulations of two units of 1-aryl-
propynone 1 and one unit of aryl N-tosylimine 2. This new
chemistry provides a straightforward synthetic protocol for
Scheme
3
The proposed mechanism for the PPh3-catalyzed
Scheme 2 Synthesis of 5bb and 5bd in one-pot way.
[2 + 2 + 2] and [4 + 2] annulations.
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the construction of highly substituted 1,2-dihydropyridines in
good to excellent yields. The mechanism of the [2 + 2 + 2]
annulation has been proposed with 3 as an important inter-
mediate, which has led us to discover the PPh3-catalyzed
[4 + 2] annulation. Efforts are underway to provide more
mechanistic details and extend this study to new PPh3-
catalyzed reactions.
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Shanghai Municipal Committee of Science and Technology
are greatly appreciated for funding support (09ZR1408500).
Special gratitude also goes to Prof. Xingyi Wang and Dao Li
for their long-term support.
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ꢀc
This journal is The Royal Society of Chemistry 2010
314 | Chem. Commun., 2010, 46, 312–314