Bis-aluminated triflic amide promoted Diels-Alder reactions of α,β-unsaturated lactones

Article abstract of DOI:10.1016/j.tetlet.2004.10.079

The bis-aluminated triflic amides such as TfN[Al(Me)Cl]₂ and TfN[Al(iBu)₂]₂, which are derived from triflic amide (1 mol) and aluminum reagent (2 mol), can efficiently promote the Diels-Alder reaction of α,β-unsaturated la

Full text of DOI:10.1016/j.tetlet.2004.10.079

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9439–9442
Bis-aluminated triflic amide promoted Diels–Alder reactions
of a,b-unsaturated lactones
Akio Saito, Hikaru Yanai and Takeo Taguchi*
Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 14 September 2004; revised 14 October 2004; accepted 15 October 2004
Available online 5 November 2004
Abstract—The bis-aluminated triflic amides such as TfN[Al(Me)Cl]2 and TfN[Al(iBu)2]2, which are derived from triflic amide
(1mol) and aluminum reagent (2mol), can efficiently promote the Diels–Alder reaction of a,b-unsaturated lactone derivatives as
dienophiles. Selection of the ligand on aluminum of these Lewis acids should be important depending on the combination of dieno-
phile and 1,3-diene.
Ó 2004 Elsevier Ltd. All rights reserved.
a,b-Unsaturated aldehydes, ketones, and carboxylic
acid derivatives are widely used as dienophiles in the
Diels–Alder reaction.1–4 However, the reaction of less
reactive a,b-unsaturated lactones such as 5H-furan-2-
one 2a, 5,6-dihydropyran-2-one 2b and their alkyl sub-
stituted derivatives suffer from a limitation of employ-
able dienes even under Lewis acid mediated conditions.4–7
For example, compared to reactions with reactive dienes
such as cyclopentadiene, those with less reactive acyclic
dienes were scarcely achieved. Moreover, no successful
example of the Diels–Alder reaction with a-alkylated
a,b-unsaturated lactones such as 3-methyl-5H-furan-2-
one 2c has been reported under either thermal or Lewis
acid mediated conditions. Although thermal reactions of
5H-furan-2-one derivatives with various dienes have
been studied, there remains problem in stereoselectivities
(endo vs exo e.g.) of the cycloadducts.8 Therefore, in
place of the use of these a,b-unsaturated lactones, maleic
anhydride analogs have been often used, although
reduction of one of the two carbonyl groups of the
cycloadducts would be required to obtain the desired
products.9
tion of such an ester tethered substrate is difficult to
achieve under the thermal or common Lewis acid medi-
ated conditions11 because of the preference of transoid
geometry,12 while bis-aluminated triflic amides such as
TfN[Al(Me)Cl]2 generated in situ by mixing trifluoro-
methanesulfonamide (triflic amide, 1mol) and dimethyl-
aluminum chloride (2mol) were found to strongly
enhance the reactivity of the dienophile, presumably
due to not only large oxophilic Lewis acidity of these
bis-aluminated triflic amides,10 but also a control of
the conformation of ester moiety to be cisoid form A
by the bidentate coordination (Scheme 1). Thus, it was
expected that a,b-unsaturated lactones having cisoid-
like ester structure would be also intensively activated
through effective coordination to bis-aluminated triflic
amide TfN(AlLn)2 (B in Scheme 1). In this paper, we re-
port that bis-aluminated triflic amide TfN(AlLn)2 effects
the Diels–Alder reaction of a,b-unsaturated lactones, in
which selection of ligands on aluminum, for example,
TfN[Al(Me)Cl]2 versus TfN[Al(iBu2)]2, are important
depending on the combination of a,b-unsaturated lac-
tone and 1,3-diene.
Recently we reported that a bidentate Lewis acid effi-
ciently promotes the intramolecular Diels–Alder
(IMDA) reactions of triene systems having ester group
linking diene and dienophile parts.10 The IMDA reac-
Ln
Al
Ln
Al
AlLn
AlLn
O
TfN
O
O
R3
NTf
Al
NTf
Al
O
R2
R1
O
R1
O
O
R1
O
Ln
Ln
R2
R2
R4
B
Keywords: Bis-aluminated triflic amide; Diels–Alder reaction; a,b-
Unsaturated lactone.
cisoid
transoid
A
*
Corresponding author. Tel./fax: +81 426 76 3257; e-mail: taguchi@
ps.toyaku.ac.jp
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.079

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A. Saito et al. / Tetrahedron Letters 45 (2004) 9439–9442
The Diels–Alder reaction of 5H-furan-2-one 2a with iso-
prene was conducted under Lewis acid mediated condi-
tions (Table 1). On using 1.1equiv of TfN[Al(Me)Cl]2
(1a), the reaction of 2a with 10equiv of isoprene pro-
ceeded at 60°C within 6h to give the adduct 3a in 76%
yield with excellent para-selectivity (para/meta > 20:1)
(entry 1). By changing Cl ligand to methyl ligand on
aluminum, thus with TfN(AlMe2)2 (1b), slightly lower
yield (63% yield) and para-selectivity (para/meta = 9.5:1)
of the adduct 3a were observed. Furthermore, with
TfN[Al(iBu2)]2 (1c), which has more bulky two alkyl lig-
ands, higher temperature and longer reaction time were
required for the complete conversion of the dienophile
2a to give the adduct 3a in 52% yield (entry 3). On the
other hand, monodentate Lewis acid Me2AlCl,
Tf2NAl(Me)Cl, or TfN(Ph)[Al(Me)Cl] examined here
did not effectively promote the reaction of 2a with iso-
prene (entries 4–6). That is, contrary to the good result
obtained by the use of the bidentate Lewis acid 1a as
shown in entry 1, when the reaction was conducted with
2.2equiv of these Lewis acids, the Diels–Alder adduct 3a
was obtained in low yield (8–32%) along with the recov-
ery of 2a (23–31%) even after a longer reaction time.
From these results, the bidentate bis-aluminated triflic
amides 1 were found to be effective catalyst for the
Diels–Alder reactions of a,b-unsaturated lactone 2a
with isoprene and the ligands on aluminum strongly
influenced on its efficiency, as shown by the large differ-
ence between 1a and 1c in the reaction of 2a with iso-
prene (entry 1 vs 3). It is also noted that efficiency of
the bis-aluminated triflic amide 1, in particular 1a when
compared with Tf2NAl(Me)Cl or TfN(Ph)[Al(Me)Cl],
cannot be explained simply by the Lewis acidity, rather
the activation of the lactone 2a due to the bidentate
coordination is possibly important.
of ligands on aluminum in each reaction (Table 2). As
in the case with isoprene, the chloro/methyl derivative
1a was found to efficiently accelerate the Diels–Alder
reaction of the butenolide 2a with 2,3-dimethylbutadi-
ene to give the cycloadduct 4a in 94% yield, while the
use of the diisobutyl derivative 1c gave 4a in 43% yield
after 24h at 80°C (entry 7 vs 8). Similarly, in the case
of the six-membered unsaturated lactone 2b, the Lewis
acid 1a rather than 1c worked nicely in the Diels–Alder
reaction with isoprene and 2,3-dimethylbutadiene to
give the adducts 3b and 4b in 77% and 71% yields,
respectively (entries 3 vs 4, 9 vs 10). On the other hand,
in the reaction of less reactive a-methyl substituted
butenolide 2c with these acyclic dienes, the Lewis acid
1c was found to be more effective than 1a with respect
to the yield of the adduct. For example, the adduct 3c
derived from 2c and isoprene was obtained in 58% yield
when the reaction was carried out with 1.1equiv of 1c
for 24h at 80°C, while in 32% yield by using 1a for
9h at 80°C (entries 5 vs 6). Similar tendency was also
observed in the reaction of 2c with 2,3-dimethylbutadi-
ene (entries 11 vs 12). In addition to the results with
cyclopentadiene described below, these results indicated
that when the lactone (dienophile) reacts with diene
slowly due to the steric reason as in the case of a-methyl
substituted butenolide 2c, polymerization of diene cata-
lyzed by the Lewis acid proceeds and the rate of polym-
erization enhances as the Lewis acidity increases.
Therefore, compared to 1c, stronger Lewis acid 1a was
not always effective in the Diels–Alder reaction of 2c
with dienes. Efficiency of the bidentate Lewis acid such
as 1c for the Diels–Alder reaction of 2c with these dienes
should be noted, because there has been no report on a
successful example of the Diels–Alder reaction of a-alk-
ylated a,b-unsaturated lactones under both thermal and
Lewis acid mediated conditions.13
Based on the above result, the Diels–Alder reactions of
a,b-unsaturated lactones 2a–c with isoprene and 2,3-
dimethylbutadiene catalyzed by bidentate bis-alumi-
nated triflic amides 1 were carried out to see the effect
Efficiency of the bulky bidentate Lewis acid 1c was
found remarkable in the reaction of 2c with reactive
cyclopentadiene (Table 3). Thus, in the presence of 1c,
Table 1. Effect of Lewis acid on the Diels–Alder reaction of 2a with isoprene
Lewis acid (1.1 equiv)
O
O
H
H
H
H
O
(10 equiv)
O
O
O
toluene
2a
3a-(para)
3a-(meta)
Entry
Lewis acid
Temp (°C)
Time (h)
Yielda (%)
para/metab
1
TfN[Al(Me)Cl]2 (1a)
TfN(AlMe2)2 (1b)
TfN[Al(iBu)2]2 (1c)
Me2AlCl
60
60
80
60
60
60
6
3
76
63
52
32
28
6
>20:1
9.5:1
7.3:1
5.4:1
2.7:1
NDg
2
3
24
9
4c,d
5c,e
6c,f
Tf2NAl(Me)Cl
TfN(Ph)[Al(Me)Cl]
7
7
a Isolated yield.
b Determined by isolated yield.
c 2.2equiv of Lewis acid was used.
d Recovery of 2a, 30%.
e Recovery of 2a, 23%.
f Recovery of 2a, 31%.
g meta/para ratio was not determined.

A. Saito et al. / Tetrahedron Letters 45 (2004) 9439–9442
Table 2. The Diels–Alder reaction of 2 with acyclic dienes promoted by 1a and 1c
9441
O
O
R
R
1a or 1c (1.1 equiv)
diene (10 equiv)
O
R
O
n
O
n
O
n
toluene
H
3
H
4
2
2a: n = 1, R = H 2b: n = 2, R = H 2c: n = 1, R =Me
Entry
2
Diene
Lewis acid
Temp (°C)
Time (h)
Product
Yielda (%)
para/metab
1
2
3
4
5
6
2a
2a
2b
2b
2c
2c
TfN[Al(Me)Cl]2 (1a)
TfN[Al(iBu)2]2 (1c)
TfN[Al(Me)Cl]2 (1a)
TfN[Al(iBu)2]2 (1c)
TfN[Al(Me)Cl]2 (1a)
TfN[Al(iBu)2]2 (1c)
60
80
60
60
80
80
5
24
6
3a
3a
3b
3b
3c
3c
76
52
77
38
32
58
>20:1
7.3:1
8.4:1c
8.5:1c
5.9:1
4.1:1
24
9
24
7
2a
2a
2b
2b
2c
2c
TfN[Al(Me)Cl]2 (1a)
TfN[Al(iBu)2]2 (1c)
TfN[Al(Me)Cl]2 (1a)
TfN[Al(iBu)2]2 (1c)
TfN[Al(Me)Cl]2 (1a)
TfN[Al(iBu)2]2 (1c)
60
80
60
60
60
80
3
24
24
24
10
24
4a
4a
4b
4b
4c
4c
94
43
71
46
31
42
8
9
10
11
12
a Isolated yield.
b Determined by isolated yield.
c Determined by 1H NMR (300MHz).
Table 3. Effect of Lewis acid on the Diels–Alder reaction of 2 with cyclopentadiene
Lewis acid (1.1 equiv)
O
O
R
O
R
(10 equiv)
R
O
n
O
n
O
n
toluene
H
H
5-exo
2
5-endo
2a: n = 1, R = H 2b: n = 2, R = H 2c: n = 1, R =Me
Entry
2
Lewis acid
Temp (°C)
Time (h)
5
Yielda (%)
endo/exob
1
2c
2c
2c
2c
2c
2c
TfN[Al(iBu)2]2 (1c)
TfN[Al(Me)Cl]2 (1a)
TfN(AlMe2)2 (1b)
(Me2Al)2O60
Rt
Rt
Rt
12
40
Rt
4
12
12
5c
5c
5c
5c
5c
5c
91
10
19
13
12
12
8.2:1
1.4:1
4.8:1
3.1:1
NDc
2.5:1
2
3
4
5
6d
[(Me2Al)2O]2SO2
Me2AlCl
12
5
7
2a
2a
2b
2b
TfN[Al(iBu)2]2 (1c)
TfN[Al(Me)Cl]2 (1a)
TfN[Al(iBu)2]2 (1c)
TfN[Al(Me)Cl]2 (1a)
Rt
Rt
Rt
Rt
13
4
5a
5a
5b
5b
97
92
99
68
5.5:1
1.1:1
7.8:1
4.5:1
8
9
10
4
12
a Isolated yield.
b Determined by isolated yield.
c endo/exo ratio was not determined.
d 2.2equiv of Lewis acid was used.
a-methylated butenolide 2c reacted with cyclopentadi-
ene (10equiv) at room temperature within 4h to give
the corresponding adduct 5c in excellent yield and with
high endo selectivity (91%, endo/exo = 8.2:1) (entry 1). In
contrast, the use of relatively strong Lewis acids 1a or
1b, remarkable decrease in the chemical yield of the
cycloadduct 5c (10% and 19%, respectively), was ob-
served, possibly due to polymerization of cyclopentadi-
ene and decomposition of 2c by these Lewis acids
prior to the Diels–Alder reaction (entries 2 and 3).
were not effective for the Diels–Alder reaction of 2c with
cyclopentadiene giving rise to the adduct 5c in low yield
(entries 4–6). The bulky bidentate Lewis acid 1c was also
found to be more effective than the stronger Lewis acid
1a in the reactions of the unsaturated lactone 2a, 2b with
cyclopentadiene with respect to both chemical yield and
endo selectivity of the adduct 5a, 5b (entries 7–10).15
Next, the Diels–Alder reactions of c-substituted sub-
strates 2d, 2e with cyclopentadiene were examined
(Scheme 2). As shown in Scheme 2, it was reported that
the thermal reaction of c-methylated compound 2d with
Bidentate Lewis acid (Me2Al)2O14a and (Me2AlO)2-
14b
SO2
or monodentate Lewis acid such as Me2AlCl

9442
A. Saito et al. / Tetrahedron Letters 45 (2004) 9439–9442
8226; (c) Kawamura, M.; Kudo, K. Chirality 2002, 14,
(1.1 equiv)
(10 equiv)
1c
O
O
O
727–730.
H
H
H
4. Chiral cationic oxazaborolidine catalyzed Diels–Alder
reactions including an example of 5H-furan-2-one with
cyclopentadiene was reported, see: Ryu, D. H.; Lee, T. W.;
Corey, E. J. J. Am. Chem. Soc. 2002, 124, 9992–9993.
5. (a) Ikeda, T.; Yue, S.; Hutchinson, C. R. J. Org. Chem.
1985, 50, 5193–5199; (b) Drew, M. G. B.; Mann, J.;
Thomas, A. J. Chem. Soc., Perkin Trans. 1 1986, 2279–
2285; (c) Chen, Z.; Ortun˜o, R. M. Tetrahedron: Asymme-
try 1994, 5, 371–376; (d) Carretero, J. C.; Garcia Ruano, J.
L.; Martin Cabrejas, L. M. Tetrahedron 1997, 53, 14115–
14126.
O
O
O
toluene
H
5-exo
R
R
R
2
5-endo
Thermal reaction (ref. 8b)
2d: R = Me
Lewis acid mediated reaction
2d: R = Me
2e: R = CH2OTBS
80 °C
5d: 85%, endo/exo = 3.0:1
rt, 5 h
5d: 74%, endo/exo = 7.3:1
5e: 74%, endo/exo = 8.0:1
rt, 12 h
6. Total synthesis of natural product using Lewis acid
mediated Diels–Alder reaction, see: (a) Takadoi, M.;
Katoh, T.; Yamaguchi, K.; Terashima, S. Tetrahedron
Lett. 1999, 40, 3399–3402; (b) Shoji, M.; Kobayashi, E.;
Inomata, K.; Numazawa, M. J. Tohoku Pharm. Univ.
2000, 47, 47–53.
7. Branchadell, V.; Sodupe, M.; Ortun˜o, R. M.; Oliva, A.;
Gomez-Pardo, D.; Guingant, A.; DÕAngelo, J. J. Org.
Chem. 1991, 56, 4135–4141.
Scheme 2.
cyclopentadiene proceeded at 80°C with complete p-
facial selectivity to minimize steric influence of c-methyl
group, while the cycloadduct 5d was obtained as an
endo/exo mixture in a ratio of 3.0:1.8b The present biden-
tate Lewis acid 1c was also an effective catalyst for the
same reaction; that is, in the presence of 1c the reaction
of 2d with cyclopentadiene proceeded at room tempera-
ture within 5h to give the adduct 5d in 74% yield with
complete p-facial selectivity and a higher endo selectivity
(endo/exo = 7.3:1). Similar result was observed in the
reaction of c-silyloxymethyl derivative 2e with cyclo-
pentadiene catalyzed by 1c to give the adduct 5e (74%
yield, endo/exo = 8.0:1).
8. (a) Ortun˜o, R. M.; Corbera, J.; Font, J. Tetrahedron Lett.
1986, 27, 1081–1084; (b) Ortun˜o, R. M.; Batllori, R.;
´
Ballesteros, M.; Monsalvatje, M.; Corbera, J.; Sanchez-
Ferrando, F.; Font, J. Tetrahedron Lett. 1987, 28, 3405–
3408; (c) Ortun˜o, R. M.; Ballesteros, M.; Corbera, J.;
Sanchez-Ferrando, F.; Font, J. Tetrahedron 1988, 44,
1711–1719; (d) De Jong, J. C.; Van Bolhuis, F.; Feringa,
B. L. Tetrahedron: Asymmetry 1991, 2, 1247–1262.
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In conclusion, we have shown that the Diels–Alder reac-
tions of a,b-unsaturated lactone derivatives including
their a-methylated substrate with acyclic dienes and
cyclopentadiene can be efficiently promoted by the bis-
aluminated triflic amide, TfN[Al(Me)Cl]2 and TfN[Al-
(iBu)2]2. Selection of these Lewis acids based on the ligand
on the aluminum should be crucial to obtain high yield
and high selectivity of the cycloadduct depending on the
combination of a,b-unsaturated lactone and 1,3-diene.
13. We conducted the reaction of 2c with isoprene in the
presence of 2.2equiv of monodentate Lewis acid Me2 AlCl
in toluene at 80°C, but the recovery of 2c was the result.
14. (a) Hanawa, H.; Maruoka, K. Tetrahedron Lett. 1999, 40,
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References and notes
1. For reviews on the Diels–Alder reactions: (a) Oppolzer,
W. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5,
Chapter 4.1, pp 315–399; (b) Kagan, H. B.; Riant, O.
Chem. Rev. 1992, 92, 1007–1019; (c) Dias, L. C. J. Braz.
Chem. Soc. 1997, 8, 289–322; (d) Evans, D. A.; Johnson, J.
S. In Comprehensive Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
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Chem., Int. Ed. 2002, 41, 1650–1667.
15. Regarding the retro Diels–Alder reaction,16,17 we carried
out the reactions of 3b-endo under the similar conditions
(in toluene, rt, 4h) using the bidentate Lewis acid,
TfN[Al(Me)Cl]2, and TfN[Al(i-Bu)2]2, respectively. With
TfN[Al(Me)Cl]2,
a mixture of 3b-endo and 1b was
obtained in a ratio of 1.7:1, while with TfN[Al(i-Bu)2]2
the reaction proceeded more slowly (3b-endo:1b = 4.7:1).
In contrast, the exo adduct 3b-exo did not change at all by
mixing with TfN[Al(Me)Cl]2.
2. For a reference on synthetic applications of the Diels–
Alder reactions, see: Nicolaou, K. C.; Snyder, S. A.;
Montagnon, T.; Vassilikogiannakis, G. Angew. Chem.,
Int. Ed. 2002, 41, 1668–1698.
16. For a review on the retro Diels–Alder reaction, see:
Rickborn, B. Org. React. 1998, 52, 1–393.
3. For recent reports on the Diels–Alder reactions of acrylate
derivatives as dienophiles, see: (a) Ishihara, K.; Kobaya-
shi, J.; Inanaga, K.; Yamamoto, H. Synlett 2001, 394–396;
(b) Mathieu, B.; Ghosez, L. Tetrahedron 2002, 58, 8219–
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54, 6008–6010; (c) Grieco, P. A.; Abood, N. J. Chem. Soc.,
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