Amine-catalyzed (3+n) annulations of 2-(acetoxymethyl)buta-2,3-dienoates with 1,n-bisnucleophiles (n = 3-5)

Article abstract of DOI:10.1039/c0cc01966f

A tertiary amine-catalyzed formal (3+n) annulation of 2-(acetoxymethyl) buta-2,3-dienoate with 1,n-binucleophiles has been developed, which provides a facile entry to heterocyclic compounds. The mechanism, involving tandem S _N2′-S_N2′ substitution and Michael addition, has also been established. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0cc01966f

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Amine-catalyzed (3+n) annulations of 2-(acetoxymethyl)buta-
2,3-dienoates with 1,n-bisnucleophiles (n = 3–5)w
Chaolong Li, Qiongmei Zhang and Xiaofeng Tong*
Received 19th June 2010, Accepted 24th August 2010
DOI: 10.1039/c0cc01966f
A
tertiary amine-catalyzed formal (3+n) annulation of
2-(acetoxymethyl)buta-2,3-dienoate 1a with 3-oxo-3-phenyl-
propanenitrile 2a (Scheme 1).6 For this transformation, both
the formation of electrophilic intermediate B0 and double
nucleophilic addition of 2a to g- and b0-positions of B0 have
been established as crucial steps. Furthermore, we envision
that a similar ammonium-containing intermediate B would be
formed with the use of tertiary amine catalyst via the same
addition–elimination mechanism as that for intermediate B0
(Scheme 1). In contrast to facile nucleophilic addition of 2a to
the g-position of intermediate B0, intermediate B would be
unlikely to enable this process at the corresponding g-position
due to the poorer ability7 of the ammonium ion to stabilize the
ylide. Fortunately, the b0-position of B could serve as an
electrophilic center available for the nucleophile. Therefore,
it is likely that different reactivity of 1a might be induced by
different nucleophilic catalysts (Scheme 1). Herein, the amine-
catalyzed formal (3+3) annulations of 1a and 1,3-binucleophiles
are reported (eqn (1)).
2-(acetoxymethyl)buta-2,3-dienoate with 1,n-binucleophiles has
been developed, which provides a facile entry to heterocyclic
compounds. The mechanism, involving tandem SN20–SN20
substitution and Michael addition, has also been established.
Over the last 40 years, a diverse range of Lewis bases have
been tremendously explored as nucleophilic catalysts to
provide numerous novel reaction protocols.1 In this context,
nucleophilic catalysis via conjugate addition of N- and
P-nucleophiles to activated p-systems represents an important
subset of Lewis base activation modes, which would generally
result in the formation of highly reactive zwitterionic inter-
mediates.2 For example, zwitterions A could be formed by the
reaction of 2,3-dienoate with phosphine catalyst (Scheme 1).2d
We envision that intermediate A0 will result from the
introduction of an acetate group to the a-position of anion
of A. Hence, 1,2-elimination of this leaving group is anticipated to
subsequently occur to quench the negative charge of A0 and to
afford electrophilic intermediate B0, which might provide
a
mechanistic alternative for the development of new
bond-forming processes. This strategy has been proved to be
an efficient one for Lewis base catalysis, such as the N- or
P-nucleophile-catalyzed regioretentive allylic substitution3 of
Morita–Baylis–Hillman (MBH) acetates, nucleophilic carbene-
catalyzed internal redox reaction4 of a-haloaldehydes, as well
as phosphine-catalyzed cycloaddition5 of allylic compounds.
Recently, we have also successfully employed this strategy
to realize the phosphine-catalyzed (4+1) annulation of
ð1Þ
To test the validity of the postulation outlined in Scheme 1, 1a
was exposed to 20 mol% DABCO under otherwise our
previous identical standard conditions6 (eqn (1)). To our
delight, a new product, which was assigned to be compound
3aa, could be isolated in the yield of 34%. Thus, a novel
amine-catalyzed (3+3) annulation between 1a and 2a was
disclosed, in which 1a served as a three-atom unit and 2a as
1,3-C,O-bisnucleophile. Optimization of the reaction conditions
was then undertaken at room temperature to improve the
yield. Various reaction parameters were studied, including
solvent, base and catalyst loading (Table 1). Ultimately, the
optimized conditions were identified as follows: 20% DABCO
as catalyst, 1.3 equiv. K2CO3 as a base with DMF as solvent
(entry 8, Table 1).
Under the optimized conditions, the DABCO-catalyzed
(3+3) annulations of 1a with a wide range of readily available
1,3-C,O-bisnucleophiles 2 smoothly proceeded to construct
diverse 4H-pyran derivatives 3 in good to excellent yields
(Table 2). In general, a variety of functional groups, such as
nitrile, sulfonyl, acyl as well as ester, can be easily incorporated
into C3 of 4H-pyrans 3. By varying substituent R, both aryl
and alkyl groups can be introduced into C2 of 4H-pyrans 3. It
is noteworthy that fused multi-cycle 4H-pyrans 3ag and 3ah
are also readily accessible from the substrates 2g and 2h,
respectively.
Scheme 1 Design plan.
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: Preparative
methods and analytical data for all new compounds. See DOI:
10.1039/c0cc01966f
c
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Table 1 Optimization for DABCO-catalyzed (3+3) annulationa
Entry
Base
Solvent
t/h
Yield (%)b
1
2
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
K2CO3
Benzene
Toluene
CH2Cl2
Acetone
THF
MeCN
DMF
DMF
18
18
24
12
8
34
96
68
96
84
97
94
99
95
91
4
0.5
0.5
1
Scheme 2 Reactivity of b0-substituted 2,3-dienoates 1b and 1c.
9
DMF
DMF
10c
0.5
37% enantiomeric excess (entry 3, Scheme 2). Under the same
conditions, 3ca was also isolated in 82% yield and with 19%
enantiomeric excess (entry 4, Scheme 2). These results strongly
indicated that this amine-catalyzed (3+3) annulation probably
proceeded through a mechanism involving the destruction
and subsequent reconstruction of the stereogenic center of
b0-carbon (vide infra).2a
a
Reaction conditions: to the solution of 2a (26.1 mg, 0.18 mmol,
1.2 equiv.), base (1.3 equiv.), DABCO (20 mol%) in DMF (2 mL) was
slowly added the solution of 1a (36.9 mg, 0.15 mmol) in DMF (2 mL)
b
c
over 20 min. Isolated yield. 10% catalyst was used.
Table 2 The scope of DABCO-catalyzed (3+3) annulationsa,b,c
Upon the success of 1,3-C,O-binucleophiles, we extended
our research to 1,n-N,N-binucleophiles (Scheme 3). Sulfuric
diamide 4a, working as a 1,3-N,N-binucleophile, could easily
react with 1a to give (3+3) annulation product 5aa in 76%
yield (eqn (2)). Diamine derivatives 4b and 4c were also found
to be suitable reaction partners for (3+4) and (3+5) annulations
with 1a. Thus, the corresponding 1,4-diazepine 5ab and
1,5-diazocine 5ac could be readily produced in the yield of
94% and 74%, respectively (eqn (3)–(4)).
Our proposed mechanism is shown in Scheme 4. Addition9
of DABCO to the b-carbon of allenoate 1b initiates the
addition–elimination process to yield intermediate B. Apparently,
this process can destroy the stereogenic center of the b0-carbon
and enhance its electrophilicity. Consequently, Michael-type
addition of 2a to the b0-position of B occurs with the help
of a base to generate intermediate C, which is followed by
1,2-elimination of DABCO catalyst to deliver intermediate D.
This reaction pathway can be described as
a tandem
SN20–SN20 substitution process, which is very similar to that
of regiospecific allylic substitution of MBH acetates catalyzed
a
Reaction conditions: to the solution of 2 (0.18 mmol, 1.2 equiv.),
base (0.195 mmol, 1.3 equiv.), DABCO (0.03 mmol, 20 mol%) in
DMF (2 mL) was slowly added the solution of 1a (36.9 mg, 0.15 mmol)
b
in DMF (2 mL) over 20 min. Isolated yield. E = CO2Bn.
c
In order to get a further demonstration of the reaction
scope, the (3+3) annulations of b0-substituted 2,3-dienoates
1b and 1c with 2a were attempted. Under the optimized
conditions, the corresponding 4-substituted 4H-pyrans 3ba
and 3ca were obtained in the yields of 53% and 69%,
respectively (entries 1 and 2, Scheme 2). For these trans-
formations, a new stereogenic center is formed at C4 of 4H-
pyran, which would allow for the development of the asymmetric
version of this (3+3) annulation with the use of chiral amine
catalyst.8 Delightfully, enantioenriched 3ba could be obtained
in 52% isolated yield by the treatment of 1b and 2a with 20%
mol quinine (QN) as catalyst in benzene, although with only
Scheme 3 (3+n) Annulations of 1a with 1,n-N,N-binucleophiles.
Chem. Commun., 2010, 46, 7828–7830 7829
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attempted with quinine as the chiral catalyst and up to 37%
enantioselectivity is obtained. Further studies on other types
of binucleophiles and asymmetric catalysis are ongoing in our
laboratories and will be reported in due course.
Shanghai Municipal Committee of Science and Technology
is greatly appreciated for funding support (09ZR1408500).
This work is also supported by the Fundamental Research
Funds for the Central Universities. Special gratitude goes to
Professors Xingyi Wang and Dao Li and Ms. Shuzhen Jiang
for their long-term support.
Notes and references
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Scheme 4 Proposed mechanism (E = CO2Bn).
2 For reviews, see: (a) D. Basavaiah, A. J. Rao and
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by tertiary amine or phosphine Lewis bases.3 In the case of QN
catalyst, asymmetric Michael-type addition of 2a induced by
chiral catalyst would allow for the reconstruction of the
stereogenic center of the b0-carbon. Once again, the b-carbon
of allenoate D works as an electrophilic center for 6-endo-trig
type oxo-Michael addition to form intermediate F. In the end,
compound 3ba can be obtained via continuous isomerization
and protonation, furnishing a formal (3+3) annulation.10 In
fact, compound 6, an analogue to intermediate D, can be
isolated when the reaction of 1a and 2a is conducted in
benzene solvent for a short period of time. Conversion of 6
to 3aa is observed with longer reaction time (eqn (5)), providing
strong evidence for the proposed mechanism. At present, we
do not have a precise explanation for the moderate ee value
of 3ba, but we believe that the stereochemistry of the
newly-formed double bond in intermediate B would play an
important role in the asymmetric induction and the epimerisation
of the newly-formed chiral center, if possible, would also lead
to erosion of the ee value.11
ð5Þ
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C. Johansson, Chem. Rev., 2007, 107, 5596.
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10 C. A. Evans, B. J. Cowen and S. J. Miller, Tetrahedron, 2005, 61,
6309.
In summary, we have realized the tertiary amine-catalyzed
(3+3) annulations of 2-(acetoxymethyl)buta-2,3-dienoate
with 1,3-binucleophiles, which provide a facile method for
synthesis of six-membered heterocyclic compounds. Under the
optimized conditions, 1,4-diazepine and 1,5-diazocine deriva-
tives can also be obtained via the corresponding (3+4) and
(3+5) annulations of 1a. The reaction mechanism, consisting
of the tandem SN20–SN20 substitution and intramolecular
Michael addition, has been established on the basis of
the isolable compound 6. The dynamic kinetic resolution
of racemic b0-substituted 2,3-dienoates 1b and 1c has been
11 We thank referees for their suggestion related to asymmetric
induction.
c
7830 Chem. Commun., 2010, 46, 7828–7830
This journal is The Royal Society of Chemistry 2010