Effect of copper(II) triflate on intramolecular Diels-Alder reaction of oxazole-olefins

Article abstract of DOI:10.3987/COM-01-9159

Intramolecular Diels - Alder reaction of the oxazole-olefins (8a) and (11a) was effectively promoted by addition of a catalytic amount of copper(II) triflate to afford the cyclopenta[c]pyridines (9a) and (12a), respectively.

Full text of DOI:10.3987/COM-01-9159

HETEROCYCLES, Vol. 55, No. 5, 2001, pp. 823 – 826, Received, 17th January, 2001
EFFECT OF COPPER(II) TRIFLATE ON INTRAMOLECULAR DIELS-ALDER
REACTION OF OXAZOLE-OLEFINS
Masashi Ohba* and Rie Izuta
Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi,
Kanazawa 920-0934, Japan
Abstract - Intramolecular Diels-Alder reaction of theoxazole-olefins (8a) and (11a)
was effectively promoted by addition of a catalytic amount of copper(II) triflate to
afford the cyclopenta[c]pyridines (9a) and (12a), respectively.
Oxazoles have been known to participate as azadiene components in Diels-Alder reactions with olefinic
1
dienophiles to give pyridine derivatives.
Since an intramolecular version of this cycloaddition was
2
reported for the first time by Levin and Weinreb, it has been occasionally used for the synthesis of annu-
3
lated pyridines. Although we have recently achieved the synthesis of two monoterpene alkaloids, (-)-
plectrodorine (3a) and (+)-oxerine (3b), possessing a cyclopenta[c]pyridine ring system, the yields of the
intramolecular Diels-Alder reaction of the oxazole-olefins (1a,b) exploited as a key step of the synthesis
4
were significantly low (2a; 37%, 2b; 23%). This led us to investigate the effect of Lewis acids on the
corresponding cycloaddition of the dimethyl substituted derivatives (8a) and (11a) and the unsubstituted
congeners (8b) and (11b), selected as models for 1a and 1b.
Me
OSiMe Bu
Me
OH
Me
OSiMe Bu
t
O
R
t
2
2
Δ
O
HO
O
N
N
N
R
R
1
a,b
2a,b
3a,b
a: R = CO Me, b: R = H
2
The requisite oxazole-olefins (8a,b) and (11a,b) were prepared from the lactones (4a,b) according to our
4
5
previous procedure for 1a,b. Thus, treatment of α,α-dimethyl-γ-butyrolactone (4a) with 2.5 equiv. of
6
α-lithiated methyl isocyanide in THF at –78°C for 3 h, followed by quenching with AcOH provided the
7
oxazole alcohol (5a) in 85% yield. After Swern oxidation of 5a to the oxazole aldehyde (6a) in 93% yield,
Grignard reaction with vinylmagnesium bromide was performed in THF at –10°C, furnishing the allylic
alcohol (7a) in 90% yield. The desired 8a was then readily obtained from 7a in 85% yield by oxidation
8
with the Dess-Martin periodinane. On the other hand, coupling reaction of 6a with methyl trans-3-
9
iodoacrylate was carried out in DMSO by using CrCl and a catalytic amount of NiCl according to
2
2

1
0
11
to Kishi’s modification of the Nozaki conditions to afford 10a (59% yield),which was also converted into
1a in 86% yield by a similar oxidation. A parallel sequence of reactions sta rting from γ-butyrolactone
4b) and proceeding through the intermediates (5b; 89%), (6b; 67%), (7b; 85%), and (10b; 52%) provided
the unsubstituted substrates (8b; 84%) and (11b; 71%).
1
(
R
R
R
HO
R
R
R
OHC
LiCH NC
(COCl) , DMSO
2
2
O
–78°C
Et N
O
O
3
O
N
N
4
a,b
5a,b
6a,b
R
R
R
HO
O
Dess–Martin
periodinane
R
N
R
R
Δ
O
MgBr
O
O
N
N
7
a,b
8a,b
9a,b
6
a,b
I
CO Me
2
R
R
R
HO
O
Dess–Martin
periodinane
R
N
R
R
CrCl , NiCl
Δ
2
2
O
DMSO
O
O
N
N
MeO C
MeO C
MeO2C
2
2
1
0a,b
11a,b
12a,b
a: R = Me, b: R = H
With four model oxazole-olefins (8a,b) and (11a,b) in hand, we first examined the intramolecular Diels-
Alder reaction of 8a in detail. As listed in Table I, heating a 0.05 M solution of 8a in o-dichlorobenzene
(
o-DCB) at 150°C under argon for 24 h provided the cyclopenta[c]pyridine (9a); the yield, however, was
only 21% (Entry 2). Although Weinreb et al. used DBN successfully in intramolecular oxazole-olefin
2
,3b
Diels-Alder reactions,
no formation of 9a was observed in the presence of the amidine (Entry 3). As
the first example of Lewis acid catalysis in oxazole-olefin cycloadditions, Levin recorded the results of
3
c
investigation on the effect of a europium salt.
In the case of 8a, however, addition of Eu(fod) failed to
3
improve the yield of 9a (Entry 4). Fortunately, several metal triflates, such as Yb(OTf) , Sc(OTf) , and
3
3
Cu(OTf) , proved to be effective to carry out the cycloaddition of 8a (Entries 5-7). The best result was
2
obtained by heating 8a in o-DCB in the presence of 2 mol % of Cu(OTf) at 180°C for 1 h; under these
2
conditions, 9a was produced in 55% yield (Entry 9).
Dramatic rate enhancement was observed for the cycloaddition of 11a possessing an ester group on the
terminal olefin when a catalytic amount of Cu(OTf) was employed (Table II). In the absence of the
2
catalyst, 12a was obtained in only 15% yield together with unaltered 11a (73%) after 24 h at 150°C (Entry
4
), whereas smooth cycloaddition occurred in the presence of 2 mol % of Cu(OTf) , giving 12a in 95%
2
yield after 30 min (Entry 6). Addition of Eu(fod) again failed to effect any improvement (Entry 5). Under
3

the influence of 10 mol % of Cu(OTf) , the above reaction proceeded even at a lower temperature (Entries 1
2
and 3).
TABLE I. Intramolecular Diels-Alder Reactions of 8a
Entry
Solvent
Additive (mol %)
Temp., °C Time, h
Yield (%) of 9a
1
2
3
4
5
6
7
8
9
Toluene
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
Cu(OTf) (10)
Reflux
150
150
150
150
150
150
180
180
180
24
24
2
26
21
0
2
—
DBN (75)
Eu(fod) (10)
8
8
3
Yb(OTf) (10)
2
37
40
48
20
55
52
3
Sc(OTf) (10)
3
3
Cu(OTf) (10)
3
2
—
24
1
Cu(OTf) (2)
2
1
0
Cu(OTf) (10)
0.5
2
TABLE II. Intramolecular Diels-Alder Reactions of 11a
Entry Solvent
Additive (mol %)
Temp., °C
Time, h Recovery (%) Yield (%)
of 11a
of 12a
1
2
3
4
5
6
Benzene
Toluene
Toluene
o-DCB
o-DCB
o-DCB
Cu(OTf) (10)
Reflux
Reflux
Reflux
150
16
24
3
27
88
0
58
3
2
—
Cu(OTf) (10)
93
15
6
2
—
24
8
73
47
0
Eu(fod) (10)
150
3
Cu(OTf) (2)
150
0.5
95
2
Finally, we focused our attention on the intramolecular Diels-Alder reaction of the unsubstituted substrates
8b) and (11b). As compared with the dimethyl substituted compounds (8a) and (11a), the cycloaddition
(
of 8b and 11b turned out to be apparently slow and less effective (Table III). Thus, heating a 0.05 M
solution of 8b in o-DCB at 180°C for 24 h produced 9b in a poor yield along with unaltered 8b (30%)
(
Entry 1). Even in the presence of Cu(OTf) (10 mol %), the yield of 9b remained low after 8 h (Entry 3).
2
Although this cycloaddition was somewhat promoted by introduction of the ester group on the terminal
olefin of 8b, the yield of 12b was moderate (Entry 5).
In conclusion, it has been clarified that the intramolecular Diels-Alder reactions of 8a and 11a are consider-
ably accelerated in the presence of Cu(OTf) to provide 9a and 12a, respectively, possessing the cyclo-
2
penta[c]pyridine skeleton, in moderate to excellent yield. The large rate enhancement, namely, the “ gem-

dimethyl effect,” observed for the dimethyl substituted substrates (8a) and (11a) may be explained in terms
1
2
of the “reactive rotamer effect” described by Jung.
TABLE III. Intramolecular Diels-Alder Reactions of 8b and 11b in o-DCB
Entry
Substrate Additive (mol %)
Temp., °C
Time, h
Product
Yield, %
1
2
3
4
5
6
8b
8b
—
180
180
180
150
180
180
24
8
9b
9b
6
15
24
19
42
28
Sc(OTf) (10)
3
8b
Cu(OTf) (10)
8
9b
2
11b
11b
11b
Cu(OTf) (10)
4
12b
12b
12b
2
Cu(OTf) (2)
2
2
Cu(OTf) (10)
1
2
REFERENCES AND NOTES
1
2
3
.
.
.
For reviews on the Diels-Alder reaction of oxazoles, see A. Hassner and B. Fischer, Heterocycles,
993, 35, 1441 and references cited therein.
(a) J. I. Levin and S. M. Weinreb, J. Am. Chem. Soc., 1983, 105, 1397; (b) Idem, J. Org. Chem.,
984, 49, 4325.
1
1
(a) S. Shimada and T. Tojo, Chem. Pharm. Bull., 1983, 31, 4247; (b) C. Subramanyam, M.
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1
989, 30, 2355; (d) M. E. Jung and S. M. K. Dansereau, Heterocycles, 1994, 39, 767; (e) A.
Padwa, M. A. Brodney, B. Liu, K. Satake, and T. Wu, J. Org. Chem., 1999, 64, 3595; (f) M. Ohba,
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(
g) M. Ohba, H. Kubo, and H. Ishibashi, Tetrahedron, 2000, 56, 7751.
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5
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.
M. Ohba, R. Izuta, and E. Shimizu, Tetrahedron Lett., 2000, 41, 10251.
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8
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.
H. Oda, T. Kobayashi, M. Kosugi, and T. Migita, Tetrahedron, 1995, 51, 695.
1
1
0. H. Jin, J. Uenishi, W. J. Christ, and Y. Kishi, J. Am. Chem. Soc., 1986, 108, 5644.
1. (a) K. Takai, K. Kimura, T. Kuroda, T. Hiyama, and H. Nozaki, Tetrahedron Lett., 1983, 24, 5281;
(
b) K. Takai, M. Tagashira, T. Kuroda, K. Oshima, K. Utimoto, and H. Nozaki, J. Am. Chem. Soc.,
986, 108, 6048.
2. M. E. Jung, Synlett, 1999, 843.
1
1