Palladium-catalyzed [3 + 3] cycloaddition of trimethylenemethane with azomethine imines

Article abstract of DOI:10.1021/ja061662c

A palladium-catalyzed [3 + 3] cycloaddition of trimethylenemethane (TMM) with azomethine imines has been developed to produce hexahydropyridazine derivatives under simple and mild conditions. The use of substituted TMM precursors highlights the difference

Full text of DOI:10.1021/ja061662c

Published on Web 04/25/2006
Palladium-Catalyzed [3 + 3] Cycloaddition of Trimethylenemethane with
Azomethine Imines
Ryo Shintani and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received March 9, 2006; E-mail: thayashi@kuchem.kyoto-u.ac.jp
Table 1. [3 + 3] Cycloaddition of (2-(Acetoxymethyl)-2-propenyl)-
trimethylsilane (1) with Azomethine Imine 2a
Intermolecular cycloaddition reactions are powerful methods for
the convergent construction of cyclic materials from relatively
simple organic fragments, and achieving such transformations by
the use of transition-metal catalysts is highly desirable in view of
efficiency of the process and mildness of the reaction conditions.
For the construction of six-membered cyclic compounds, [4 + 2]
cycloadditions (e.g., the Diels-Alder reactions) are most widely
used in the literature.1 An alternative approach is the use of [2 +
2 + 2] cycloaddition reactions as often used in the preparation of
aromatic ring systems.2 Although a [3 + 3] cycloaddition strategy
is another legitimate approach toward the formation of six-
membered rings, it has been much less studied3 and only a few
examples of transition-metal-catalyzed [3 + 3] cycloadditions have
been reported to date.4,5 Here we describe the development of a
new palladium-catalyzed [3 + 3] cycloaddition of trimethylene-
methane (TMM) with azomethine imines to produce highly
functionalized hexahydropyridazine derivatives under simple and
mild conditions (eq 1).
entry
Pd catalyst
solvent
yield (%)a
1
2
3
4
5
6
7
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
toluene
MeOH
THF
ClCH2CH2Cl
CH2Cl2
CH2Cl2
CH2Cl2
<2
<2
14
57
Pd(PPh3)4
82 (81)b
82
Pd(OAc)2/4 PPh3
CpPd(η3-C3H5)/4 PPh3
77
a Determined by 1H NMR against an internal standard (MeNO2).
b Isolated yield in parentheses.
Table 2. Palladium-Catalyzed [3 + 3] Cycloaddition: Scope of
Azomethine Imines
In 1979, Trost reported the use of Pd-TMM complexes in the
context of [3 + 2] cycloaddition reactions.6 Since then, he has made
a significant contribution to the development of this attractive
chemistry, showing the high utility of Pd-TMM complexes as a
source of a three-carbon unit in a cyclic framework.7,8 On the other
hand, their use in [3 + 3] cycloadditions is very limited. To the
best of our knowledge, they have only been used in the couplings
with aziridines to furnish piperidine derivatives so far.5
1-Alkylidene-3-oxopyrazolidin-1-ium-2-ides (e.g., 2 in eq 1),
developed by Dorn and Otto in 1968,9 are isolable and stable
azomethine imines and have been used as 1,3-dipoles in the context
of [3 + 2] cycloadditions, giving five-membered nitrogen-contain-
ing heterocycles.10,11 Unfortunately, however, these useful 1,3-
dipoles have never been engaged in a single-step formation of six-
membered rings to date.12
Initially, we examined the reaction of (2-(acetoxymethyl)-2-
propenyl)trimethylsilane (1) with azomethine imine 2a in the
presence of a catalytic amount of Pd(PPh3)4 at 40 °C (Table 1) and
found that the choice of solvent has a significant impact on the
reaction progress. Thus, desired [3 + 3] cycloadduct 3a was
obtained in high yield by the use of dichloromethane (82% yield;
entry 5) in contrast to any other solvents we employed (entries 1-4).
We also found that the use of Pd(OAc)2/PPh3 or CpPd(η3-C3H5)/
PPh3 as a catalyst in dichloromethane produced cycloadduct 3a in
comparably high yield (77-82% yield; entries 6 and 7).
entry
R
product
yield (%)a
1
2
3
4
5
6
7
8
9
Ph (2a)
3a
3b
3c
3d
3e
3f
3g
3h
3i
81
74
92
90
88
70
75
71
20
4-MeC6H4 (2b)
4-CF3C6H4 (2c)
3-ClC6H4 (2d)
2-FC6H4 (2e)
2-MeC6H4 (2f)
3-pyridyl (2g)
1-cyclohexenyl (2h)
t-Bu (2i)
a Isolated yield.
the alkylidene portion, a variety of aryl groups (Table 2, entries
1-6) as well as heteroaryl and alkenyl groups (entries 7 and 8)
can be tolerated, furnishing [3 + 3] cycloadducts in high yield
(70-92% yield). Unfortunately, substrates with an alkyl substituent
are less effective for this [3 + 3] cycloaddition (entry 9).
Azomethine imines bearing substituents on the pyrazolidinone
ring can also be used in the present [3 + 3] cycloaddition reaction
with high efficiency. For example, 4,4-dimethyl-substituted dipole
2j provides corresponding cycloadduct 3j in 94% yield (eq 2). In
addition, 5-methyl-substituted dipole 2k is converted to the six-
membered heterocycle 3k not only in high yield (87%) but also
with high diastereoselectivity (dr ) 96/4; eq 3). The relative
configuration of the major diastereomer was determined by X-ray
crystallographic analysis, as shown in Figure 1.
We have subsequently determined that the scope of the azome-
thine imine is fairly broad. Thus, with respect to the substituent on
We have also examined the reactions using substituted TMM
precursors in combination with azomethine imine 2a. Thus,
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C O M M U N I C A T I O N S
8 with TMM precursor 1 provides corresponding cycloadduct 9 in
91% yield (eq 6).
In summary, we have developed a palladium-catalyzed [3 + 3]
cycloaddition of trimethylenemethane with azomethine imines to
produce hexahydropyridazine derivatives under mild conditions. The
use of substituted TMM precursors highlights the difference of this
system from previously reported [3 + 2] cycloaddition of TMMs
under palladium catalysis. We have also described that the present
[3 + 3] cycloadditions are applicable to couplings with nitrones.
Figure 1. ORTEP illustration of 3k with thermal ellipsoids drawn at the
50% probability level (hydrogen atoms on the methyl and phenyl groups
are omitted for clarity).
Acknowledgment. Support has been provided in part by a
Grant-in-Aid for Scientific Research, the Ministry of Education,
Culture, Sports, Science and Technology, Japan (21 COE on Kyoto
University Alliance for Chemistry).
Supporting Information Available: Experimental procedures and
compound characterization data (PDF) and X-ray data (CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
compound 4 mainly furnished two different products, 3l and 3m,
along with a minute amount of product 3n (3l/3m/3n ) 77/20/3;
eq 4). In contrast, the use of structural isomer 5 generated 3n as
the major product with a small amount of 3l (3l/3m/3n ) 12/1/87;
eq 5). These results show that the substitution pattern of the TMM
precursor is reflected in the product distribution in the present [3
+ 3] cycloaddition with azomethine imine 2a, indicating that the
cycloaddition occurs without significant equilibration between
intermediates 6 and 7 (Scheme 1). This observation strikingly
contrasts to the palladium-catalyzed [3 + 2] cycloadditions of 4 or
5 with electron-deficient olefins described by Trost, which pref-
erentially afford five-membered cyclic compounds derived from
intermediate 7 regardless of the starting TMM precursor (4 or 5)
due to the fast equilibration between 6 and 7 prior to the
cycloaddition.13
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Scheme 1
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These [3 + 3] cycloaddition reactions can be extended to the
couplings with nitrones, as well. For example, a reaction of nitrone
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