[4+2] Cycloaddition of o-xylylenes with imines using palladium catalyst

Article abstract of DOI:10.1021/ja905988e

(Chemical Equation Presented) The cycloaddition of o-(silylmethyl)benzylic carbonates with imines proceeded in the presence of the Pd(η³- C₃H₅)Cp-DPPPent catalyst, affording the tetrahydroisoquinolines in good to high yiel

Full text of DOI:10.1021/ja905988e

Published on Web 08/21/2009
[4+2] Cycloaddition of o-Xylylenes with Imines Using Palladium Catalyst
Satoshi Ueno, Masakazu Ohtsubo, and Ryoichi Kuwano*
Department of Chemistry, Graduate School of Sciences, Kyushu UniVersity, 6-10-1 Hakozaki, Higashi-ku,
Fukuoka 812-8581, Japan
Received July 18, 2009; E-mail: rkuwano@chem.kyushu-univ.jp
Scheme 1. [4+2] Cycloaddition of 1a with 2a
o-Xylylenes, which are 1,3-cyclohexadienes bearing two exo-
methylenes at the 5- and 6-positions, are often used as diene
substrates for the Diels-Alder reaction.1 The [4+2] cycloaddition
of o-xylylenes with alkenes or alkynes has been intensively studied.
As with the carbon dienophiles, imines might be another attractive
dienophile for the o-xylylene cycloaddition. The hetero-Diels-Alder
reaction2 will afford tetrahydroisoquinoline frameworks, which are
found in many useful biologically active compounds. Nevertheless,
only a few reports have been made on the reaction with imines.3
In these works, the o-xylylenes were generated from the thermal
ring-opening reaction of benzocyclobutenes. Herein, we describe
a new approach to the [4+2] cycloaddition of o-xylylene with
imines.
Table 1. [4+2] Cycloaddition of 1a with N-Tosylimines 2a
We previously reported a unique protocol for the o-xylylene
cycloaddition with C-C double bonds using a palladium catalyst.4 In
the palladium catalysis, o-{(trimethylsilyl)methyl}benzyl carbonates
1 were employed as formal o-xylylene precursors. In our initial attempt,
a mixture of 1a and N-tosylimine 2a in DMF was heated at 120 °C
for 24 h in the presence of 3.0% Pd(η3-C3H5)Cp-DPPE catalyst, which
is the most effective for the cycloaddition with methyl acrylate.
However, the desired tetrahydroisoquinoline 3a was obtained in only
11% yield. The catalyst efficiency was significantly affected by the
distance between the phosphorus atoms of bidentate ligand. Use of
DPPPent5,6 in place of DPPE brought about the improved yield of
3a. Gradual decomposition of the catalyst into palladium black was
observed in the course of the cycloaddition. Owing to the catalyst
decomposition, the prolonged reaction was ineffective in enhancing
the yield. The undesirable formation of palladium black was avoided
by increasing the amount of DPPPent. When the ligand was used in
2.2 mol equiv with palladium, the reaction of 1a with 2a successfully
produced 3a in 92% isolated yield, but it required 48 h for the complete
conversion of 1a (Scheme 1).
entry
R (2)
conditionb
time, h
product (3)
yield,c
%
1
2
3
4
5
6
7
8
2-MeC6H4 (2b)
2,6-Me2C6H3 (2c)
4-MeOC6H4 (2d)
4-CF3C6H4 (2e)
4-CF3C6H4 (2e)
3-CF3C6H4 (2f)
1-naphthyl (2g)
2-naphthyl (2h)
A
A
A
A
B
B
B
B
24
24
24
48
3
3
3
3
3b
3c
3d
-
3e
3f
84
78
81
0
67
76
85
81
3g
3h
a Reactions were conducted in DMF (1.0 mL). The ratio of 1a (0.15
mmol):2:Pd(η3-C3H5)Cp:DPPPent:KF was 100:120:3.0:6.6:150. b Condition
A: the reactions were carried out at 120 °C without KF. Condition B:
the reactions were carried out at 100 °C with KF. c Isolated yield.
through the concerted [4+2] cycloaddition of o-xylylene with 2a
but through a reaction pathway involving palladium catalysis.
A range of N-tosylimines underwent the cycloaddition with 1a
under the optimized conditions (Table 1). The DPPPent-palladium
catalyst transformed electron-rich imines 2b-2d into the desired
tetrahydroisoquinolines in good yields (entries 1-3). In these cases,
potassium fluoride brought about a marked enhancement of the
reaction rate but slightly decreased the yields of 3. Substituents at
the ortho-positions of benzimine scarcely disturbed the formations
of 3c and 3d. In contrast, the electron-withdrawing group of 2e
severely hampered the catalytic cycloaddition in the absence of
potassium fluoride (entry 4). However, the use of the fluoride allows
2e and 2f to react with 1a, affording the cycloadducts 3e and 3f
(entries 5, 6). The fluoride additive was effective for the reactions
of polycyclic aromatic aldimines 2g and 2h (entries 7, 8).
o-(Silylmethyl)benzyl carbonates 1b-1f, which have substituents
on the aromatic ring, also worked as formal o-xylylene precursors
in the catalytic cycloaddition with imine 2a as shown in Table 2.
The substituents at the ortho-positions of both reaction sites have
no effect on the reactivity of the substrates 1. The substrate 1b,
which has a phenyl group at the 6-position, was converted into a
regioisomeric mixture of 4b and 5b in the molar ratio 89:11, when
the reaction was carried out with potassium fluoride (entry 1). In
the absence of the additive, a mixture of 4b and 5b was obtained
The reaction rate of the catalytic cycloaddition was dramatically
enhanced by stoichiometric potassium fluoride, which activated the
C-Si bond.7 The reaction of 1a with 2a finished within 3 h,
affording the cycloaddition product 3a in 85% isolated yield. The
choice of the fluoride source was crucial for the catalytic reaction.
Use of cesium or tetrabutylammonium fluoride led to immediate
disappearance of 1a but failed to produce 3a. The reactive fluoride
sources induced the rapid generation of free o-xylylene from 1a
without the involvement of palladium catalysis.8 The o-xylylene
decomposed before it reacted with 2a. In contrast, potassium
fluoride was less reactive to 1a because of its low solubility in
organic solvent. The low reactivity caused a selective acceleration
of forming an organopalladium species equivalent to o-xylylene in
the catalytic cycle. Although potassium fluoride is known to be
effective for the generation of o-xylylene from 1a,9,10 little
formation of 3a was observed when a mixture of 1a and 2a was
treated with potassium fluoride in the absence of Pd(η3-C3H5)Cp.11
The observation suggests that the formation of 3a proceeds not
9
12904 J. AM. CHEM. SOC. 2009, 131, 12904–12905
10.1021/ja905988e CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. [4+2] Cycloaddition of o-(Silylmethyl)benzyl Esters 1 with
be observed in the reactions of 1b-1f. Consequently, the latter
pathway is ruled out by the results of Table 2.
2aa
The good regioselectivity in the reaction of 1b or 1c with 2a is
illustrated as shown in Figure 1b. As described above, both
substrates react with 6 to yield the identical palladacycle 8′. The
1,2 insertion of 2 into the upper C-Pd bond in 8′ leads to the
formation of 5b. However, the approach of 2 to 8′ following arrow
A is hampered by the steric bulkiness of the phenyl group. In
contrast, the 1,2 insertion into the lower C-Pd bond occurs without
serious steric repulsion between the imine and 8′. Therefore,
preferential formation of 4b was observed in the reactions of entries
1-4 in Table 2. The size of the methyl group in 1d or 1e was
insufficient for controlling the regiochemistry.
In conclusion, we developed a new method for the [4+2]
cycloaddition of o-xylylenes with imines.14 The cycloaddition
proceeded in the presence of a DPPPent-ligated palladium complex,
providing a range of tetrahydroisoquinolines in good yield. The
palladium catalyst allowed the aza-Diels-Alder reaction of the
parent o-xylylene.
entry
R (1)
time, h
product
4:5b
yield,c
%
1
6-Ph (1b)
6-Ph (1b)
3-Ph (1c)
3-Ph (1c)
6-Me (1d)
3-Me (1e)
4,6-Me2 (1f)
4
72
4
24
4
4b, 5b
4b, 5b
89:11
89:11
81
72
76
72
73
78
76
2d
3
4c () 5b), 5c () 4b) 10:90
4c () 5b), 5c () 4b) 11:89
4d, 5d
4e () 5d), 5e () 4d) 43:57
4f, 5f 88:12
4d
5
56:44
6d
7
48
3
a Reactions were conducted under condition B in Table 1 unless
otherwise noted. b Determined by the 1H NMR spectra of the crude
products. c Isolated yields of the mixtures of 4 and 5. d The reactions
were conducted under condition A in Table 1.
Acknowledgment. This work was supported by KAKENHI
(No. 19685008) and a Grant-in-Aid for the Global COE Program,
“Science for Future Molecular Systems” from MEXT.
Supporting Information Available: Experimental procedures and
characterization data for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
Figure 1. (a) A plausible mechanism of the catalytic cycloaddition of 1a
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JA905988E
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J. AM. CHEM. SOC. VOL. 131, NO. 36, 2009 12905