Enantioselective aza-Diels-Alder reaction of aldimines with "Danishefsky-type diene" catalyzed by chiral scandium(III)-N,N′- dioxide complexes

Article abstract of DOI:10.1021/jo7021263

(Chemical Equation Presented) A new kind of complex prepared from scandium(III) triflate and L-proline-derived N,N′-dioxides has been developed to catalyze the enantioselective aza-Diels-Alder reaction between 1,3-butadiene (diene 1) and aldimines 2, affo

Full text of DOI:10.1021/jo7021263

Enantioselective Aza-Diels-Alder Reaction of Aldimines with
“Danishefsky-Type Diene” Catalyzed by Chiral
Scandium(III)-N,N′-Dioxide Complexes
Deju Shang,† Junguo Xin,† Yanling Liu,† Xin Zhou,† Xiaohua Liu,† and Xiaoming Feng*,†,‡
Key Laboratory of Green Chemistry & Technology (Sichuan UniVersity), Ministry of Education, College of
Chemistry, Sichuan UniVersity, Chengdu 610064, China, and State Key Laboratory of Oral Diseases,
Sichuan UniVersity, Chengdu 610041, China
xmfeng@scu.edu.cn
ReceiVed September 30, 2007
A new kind of complex prepared from scandium(III) triflate and L-proline-derived N,N′-dioxides has
been developed to catalyze the enantioselective aza-Diels-Alder reaction between 1,3-butadiene (diene
1) and aldimines 2, affording the corresponding 2,5-disubstituted dihydropyridinones in moderate to high
yields (up to 92%) with good enantioselectivities (up to 90% ee) at room temperature. A variety of
aldimines including aromatic, heteroaromatic, conjugated, and aliphatic imines were found to be suitable
substrates. Enantiopure samples (up to 99% ee) were obtained for some products by a single
recrystallization. The absolute configuration of the products was determined by X-ray diffraction and
1
CD analysis. On the basis of the investigation of H NMR spectra and the positive nonlinear effect, the
catalyst structure was carefully discussed.
Introduction
intermediates for the synthesis of biologically active natural
products.2-5 Despite its importance for the preparation of six-
As a useful tool for the construction of six-membered
heterocycles, the hetero-Diels-Alder reactions have been
studied very intensively.1 Interest has been focused on the
construction of chiral pyrones and lactones, which are important
(2) For the synthesis of chiral pyrones, see: (a) Schaus, S. E.; Brånalt,
J.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 403-405. (b) Dossetter, A. G.;
Jamison, T. F.; Jacobsen, E. N. Angew. Chem., Int. Ed. 1999, 38, 2398-
2400. (c) Simonsen, K. B.; Svenstrup, N.; Roberson, M.; Jørgensen, K. A.
Chem. Eur. J. 2000, 6, 123-128. (d) Doyle, M. P.; Phillips, I. M.; Hu, W.
H. J. Am. Chem. Soc. 2001, 123, 5366-5367. (e) Aikawa, K.; Irie, R.;
Katsuki, T. Tetrahedron 2001, 57, 845-851. (f) Kii, S.; Hashimoto, T.;
Maruoka, K. Synlett 2002, 931-932. (g) Long, J.; Hu, J. Y.; Shen, X. Q.;
Ji, B. M.; Ding, K. L. J. Am. Chem. Soc. 2002, 124, 10-11. (h) Yamashita,
Y.; Saito, S.; Ishitani, H.; Kobayashi, S. J. Am. Chem. Soc. 2003, 125,
3793-3798. (i) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H.
Nature 2003, 424, 146. (j) Unni, A. K.; Takenaka, N.; Yamamoto, H.;
Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 1336-1337. (k) Rajaram, S.;
Sigman, M. S. Org. Lett. 2005, 7, 5473-5475.
(3) For the synthesis of chiral lactones, see: (a) Fan, Q.; Lin, L. L.; Liu,
J.; Huang, Y. Z.; Feng, X. M.; Zhang, G. L. Org. Lett. 2004, 6, 2185-
2188. (b) Du, H. F.; Zhao, D. B.; Ding, K. L. Chem. Eur. J. 2004, 10,
5964-5970. (c) Fan, Q.; Lin, L. L.; Liu, J.; Huang, Y. Z.; Feng, X. M.
Eur. J. Org. Chem. 2005, 3542-3552. (d) Lin, L. L.; Fan, Q.; Qin, B.;
Feng, X. M. J. Org. Chem. 2006, 71, 4141-4146.
† Key Laboratory of Green Chemistry & Technology.
‡ State Key Laboratory of Oral Diseases.
(1) Reviews: (a) Kagan, H. B. ComprehensiVe Organic Chemistry;
Pergamon Press: Oxford, 1992; Vol. 8. (b) Noyori, R. Asymmetric Catalysis
in Organic Synthesis; Wiley: New York, 1994. (c) Boger, D. L.; Weinreb,
S. M. Hetero Diels-Alder Methodology in Organic Synthesis; Academic
Press: San Diego, CA, 1987; Chapter 2. (d) Danishefsky, S. J.; De Ninno,
M. P. Angew. Chem., Int. Ed. Engl. 1987, 26, 15-23. (e) Lin, L. L.; Liu,
X. H.; Feng, X. M. Synlett 2007, 14, 2147-2157. (f) Carmona, D.; Lamata,
M. P.; Oro, L. A. Coord. Chem. ReV. 2000, 200-202, 717-772. (g) Corey,
E. J. Angew. Chem., Int. Ed. 2002, 41, 1650-1667. (h) Jørgensen, K. A.
Eur. J. Org. Chem. 2004, 2093-2102. (i) Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2000, 39, 3558-3588. (j) Nicolaou, K. C.; Snyder, S. A.;
Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41,
1668-1698 and references therein.
10.1021/jo7021263 CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/19/2007
630
J. Org. Chem. 2008, 73, 630-637

EnantioselectiVe Aza-Diels-Alder Reaction of Aldimines
SCHEME 1. Aza-Diels-Alder Reaction; TMS ) Trimethylsilyl
membered optically active nitrogen-containing compounds, the
hetero-Diels-Alder reaction of imines (aza-Diels-Alder reac-
tion) has made progress only in recent years since the pioneering
work of Danishefsky and co-workers.6,7 Different kinds of chiral
Lewis acids, such as boron, zirconium, silver, copper, and zinc
complexes, have been employed to catalyze this type of
reaction.8-14 Although rare earth metals have shown excellent
catalytic efficiency for the achiral aza-Diels-Alder reaction,
chiral complexes especially for scandium have not been fully
studied for this reaction.15,16 Ishitani and Kobayashi developed
a ytterbium-binaphthol complex to catalyze the enantioselective
synthesis of tetrahydroquinoline derivatives using imine 2 as
an azadiene in 1996.17
Furthermore, the products obtained in the previous works
were mainly monosubstituted dihydropyridinones (Scheme 1).
As for multisubstituted ones,18 to the best of our knowledge,
only three examples including zirconium-binaphthol,9a boron-
binaphthol,8a and chiral copper ferrocene complexes11c were
reported hitherto. As part of our ongoing program aimed at
developing metal and amide N-oxide complexes as efficient
catalysts,19 we described here our efforts on the catalytic
asymmetric aza-Diels-Alder reaction of Danishefsky-type diene
1 and aldimines 2, using a novel scandium(III) complex of N,N′-
dioxide as the catalyst. Various 2,5-disubstituted dihydropyri-
dinones have been obtained with up to 92% yield and 90% ee.
(4) For other reports, see: (a) Liu, P.; Jacobsen, E. N. J. Am. Chem.
Soc. 2001, 123, 10772-10773. (b) Evans, D. A.; Johnson, J. S.; Olhava,
E. J. J. Am. Chem. Soc. 2000, 122, 1635-1649. (c) Thompson, C. F.;
Jamison, T. F.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 9974-9983.
(d) Yao, S.; Johannsen, M.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem.
1998, 63, 118-121.
Results and Discussion
(5) For our own work in this field, see: (a) Wang, B.; Feng, X. M.; Cui,
X.; Liu, H.; Jiang, Y. Z. Chem. Commun. 2000, 1605-1606. (b) Wang,
B.; Feng, X. M.; Huang, Y. Z.; Liu, H.; Cui, X.; Jiang, Y. Z. J. Org. Chem.
2002, 67, 2175-2182. (c) Gao, B.; Fu, Z. Y.; Yu, Z. P.; Yu, L.; Huang, Y.
Z.; Feng, X. M. Tetrahedron 2005, 61, 5822-5830. (d) Yang, W. Q.; Shang,
D. J.; Liu, Y. L.; Du, Y.; Feng, X. M. J. Org. Chem. 2005, 70, 8533-
8537.
(6) For reviews, see: (a) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999,
99, 1069-1094. (b) Buonora, P.; Olsen, J. C.; Oh, T. Tetrahedron 2001,
57, 6099-6138. (c) Waldmann, H. Synthesis 1994, 535-551.
(7) (a) Kerwin, J. F.; Danishefsky, S. Tetrahedron Lett. 1982, 23, 3739-
3742. (b) Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807-
7808.
(8) (a) Hattori, K.; Yamamoto, H. J. Org. Chem. 1992, 57, 3264-3265.
(b) Hattori, K.; Yamamoto, H. Tetrahedron 1993, 49, 1749-1760. (c)
Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H. J. Am. Chem.
Soc. 1994, 116, 10520-10524. For another report, see: (d) Newman, C.
A.; Antilla, J. C.; Chen, P.; Predeus, A. V.; Fielding, L.; Wulff, W. D. J.
Am. Chem. Soc. 2007, 129, 7216-7217.
(9) (a) Kobayashi, S.; Komiyama, S.; Ishitani, H. Angew. Chem., Int.
Ed. 1998, 37, 979-981. (b) Kobayashi, S.; Kusakabe, K.-i.; Komiyama,
S.; Ishitani, H. J. Org. Chem. 1999, 64, 4220-4221. (c) Kobayashi, S.;
Kusakabe, K.-i.; Ishitani, H. Org. Lett. 2000, 2, 1225-1227. (d) Yamashita,
Y.; Mizuki, Y.; Kobayashi, S. Tetrahedron Lett. 2005, 46, 1803-1806.
(10) Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2003, 125, 4018-4019.
Initially, N,N′-dioxide L1 (Figure 1) was complexed with
various metal salts to catalyze the aza-Diels-Alder reaction of
diene 1 and aldimine 2a (Table 1). Racemic products were
obtained with Zn(OTf)2, Cu(OTf)2, and In(OTf)3 as Lewis acids
(Table 1, entries 4-6). Zr(OiPr)4, which had proved to be
effective for this kind of reaction, gave only poor results (Table
1, entry 7).9a However, Yb(OTf)3, Sc(OTf)3, and Sm(OTf)3
showed good inductive potential in this reaction (Table 1, entries
1-3). Especially for Sc(OTf)3, 91% yield and 25% ee could
be afforded (Table 1, entry 2).
The molar ratio of central metal to ligand significantly
affected the enantioselectivity. Because of the strong background
reaction of Sc(OTf)3, excess amount of metal in the catalytic
system increased the yield dramatically, while the enantiose-
lectivity decreased (Table 2, entries 1-3). In contrast, lowering
the amount of metal turned out to be favorable for the reaction
(16) (a) Kobayashi, S.; Ishitani, H.; Nagayama, S. Synthesis 1995, 1195-
1202. (b) Kobayashi, S.; Araki, M.; Ishitani, H.; Nagayama, S.; Hachiya, I.
Synlett 1995, 233-234. (c) Wang, Y. H.; Wilson, S. R. Tetrahedron Lett.
1997, 38, 4021-4024. (d) Ali, T.; Chauhan, K. K.; Frost, C. G. Tetrahedron
Lett. 1999, 40, 5621-5624. (e) Collin, J.; Jaber, N.; Lannou, M. I.
Tetrahedron Lett. 2001, 42, 7405-7407. (f) Loncaric, C.; Manabe, K.;
Kobayashi, S. Chem. Commun. 2003, 574-575. (g) Cheng, K.; Zeng, B.
Q.; Yu, Z. P.; Gao, B.; Feng, X. M. Synlett 2005, 1018-1020.
(17) Ishitani, H.; Kobayashi, S. Tetrahedron Lett. 1996, 37, 7357-7360.
(18) For the application of dihydropyridinone, see: Clive, D. L. J.;
Bergstra, R. J. J. Org. Chem. 1991, 56, 4976-4977.
(11) (a) Yao, S.; Johannsen, M.; Hazell, R. G.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 1998, 37, 3121-3124. (b) Yao, S.; Saaby, S.; Hazell, R.
G.; Jørgensen, K. A. Chem. Eur. J. 2000, 6, 2435-2448. (c) Mancheno,
O. G.; Arrayas, R. G.; Carretero, J. C. J. Am. Chem. Soc. 2004, 126, 456-
457.
(12) Guillarme, S.; Whiting, A. Synlett 2004, 711-713.
(13) For another example, see: Bromidge, S.; Wilson, P. C.; Whiting,
A. Tetrahedron Lett. 1998, 39, 8905-8908.
(14) For the enantioselective aza-Diels-Alder reaction catalyzed by
organocatalysts, see: (a) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem.,
Int. Ed. 2006, 45, 4796-4798. (b) Akiyama, T.; Tamura, Y.; Itoh, J.; Morita,
H.; Fuchibe, K. Synlett 2006, 141-143. (c) Sunden, H.; Ibrahem, I.;
Eriksson, L.; Cordova, A. Angew. Chem., Int. Ed. 2005, 44, 4877-4880.
(d) Rueping, M.; Azap, C. Angew. Chem., Int. Ed. 2006, 45, 7832-7835.
(e) Liu, H.; Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z. Org. Lett.
2006, 8, 6023-6026.
(19) (a) Li, Q. H.; Liu, X. H.; Wang, J.; Shen, K.; Feng, X. M.
Tetrahedron Lett. 2006, 47, 4011-4014. (b) Shen, Y. C.; Feng, X. M.; Li,
Y.; Zhang, G. L.; Jiang, Y. Z. Eur. J. Org. Chem. 2004, 129-137. (c)
Zhang, X.; Chen, D. H.; Liu, X. H.; Feng, X. M. J. Org. Chem. 2007, 72,
5227-5233. (d) Zeng, B. Q.; Zhou, X.; Liu, X. H.; Feng, X. M. Tetrahedron
2007, 63, 5129-5136. (e) Zheng, K.; Qin, B.; Liu, X. H.; Feng, X. M. J.
Org. Chem. 2007, 72, 8478-8483. (f) Qin, B.; Xiao, X.; Liu, X. H.; Huang,
J. L.; Wen, Y. H.; Feng, X. M. J. Org. Chem. 2007, 72, 9323-9328. For
another example using scandium and N-oxide complex as catalyst, see: (g)
Nakajima, M.; Yamaguchi, Y.; Hashimoto, S. Chem. Commun. 2001, 1596-
1597.
(15) For reviews, see: (a) Shibasaki, M.; Yoshikawa, N. Chem. ReV.
2002, 102, 2187-2209. (b) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam,
W. W. L. Chem. ReV. 2002, 102, 2227-2302.
J. Org. Chem, Vol. 73, No. 2, 2008 631

Shang et al.
FIGURE 1. Ligands employed for the aza-Diels-Alder reaction.
TABLE 1. Survey of Central Metals on Aza-Diels-Alder Reaction
To clarify the influence of each unit of the ligand on the
reaction, L-proline-derived N,N′-dioxides with different amide
groups and with varying chain length of the spacer as well as
other amino acid derivatives were examined. The steric effect
of R groups of amide moiety played an important role on the
enantioselectivity, and bulkier groups provided better results
(Table 3, entries 1-6). Ligand bearing electron-withdrawing
groups gave only racemic product (Table 3, entry 8). When R
was aliphatic cyclic group, low yield and ee value were obtained
(Table 3, entry 7). L-Proline-derived N,N′-dioxide L1 exhibited
its superiority toward this reaction compared with other amino
acid derivatives (Table 3, entry 1 vs 12 and 13). Further
decreasing or increasing the length of the carbon chain did not
give better results (Table 3, entry 1 vs 9, 10, and 11). On the
other hand, when the complex of amide ligand L14 and
scandium(III) triflate was applied to this reaction, only racemic
product was obtained, which confirmed the importance of
N-oxide moiety (Table 3, entry 14). Accordingly, L1 was chosen
as the ligand for the next investigation.20
of Aldimine 2a with Diene 1a
entry
metal
yield (%)b
ee (%)c
1
2
3
4
5
6
7
Yb(OTf)3
Sc(OTf)3
Sm(OTf)3
Zn(OTf)2
Cu(OTf)2
In(OTf)3
Zr(OiPr)4
>99
91
41
25
45
17
25
23
0
0
0
63
trace
N.D.d
a All reactions were carried out on a 0.2 mmol scale in 2.0 mL of THF
with 5 mol % catalyst loading (metal-ligand ) 1:1) at room temperature
for 24 h. b Isolated yield. c Determined by HPLC on a Chiralcel OD-H
column. d Not determined.
Further solvent examination exhibited their important effect
in terms of both enantioselectivity and yield. The reaction carried
out in toluene, CH2Cl2, or Et2O only delivered the product with
up to 29% ee (Table 4, entries 2-4). Although 1,4-dioxane
provided similar enantioselectivity, the yield was somewhat low
(Table 4, entry 5). Use of MeOH as solvent improved the yield
of corresponding 2,5-disubstituted dihydropyridinone 3a to 99%,
but the enantioselectivity was deteriorated (Table 4, entry 6).
Therefore, THF was still the best solvent for this reaction (Table
4, entry 1).
TABLE 2. Effect of Molar Ratio between Metal and Ligand on
Aza-Diels-Alder Reactiona
We next turned our attention to investigate the influence of
other protecting groups of imine on this reaction (Table 5).
When electron-withdrawing tosyl group was used instead, no
ee value was obtained, although the yield was satisfying (Table
5, entry 4).11c The aza-Diels-Alder reaction of phenyl and
4-methoxyphenyl imines also proceeded without stereoselec-
tivity (Table 5, entries 2 and 5). It should be noticed that when
the hydroxy group of imine was methylated, no reaction
occurred, which established the importance of the phenolic group
(Table 5, entry 6 vs 1). Accordingly, it was speculated that both
the hydroxy group and nitrogen atom on imine coordinated with
the central metal. The steric hindrance of the bulky 2-methox-
metal loading
(mol %)
ratio
(L1-metal)
entry
yield (%)b
ee (%)c
1
2
3
4
5
6
7
5.0
7.5
6.0
5.0
3.3
2.5
2.0
0:1
>99
>99
>99
91
88
59
1:1.5
1:1.2
1:1
1.5:1
2:1
7
25
25
37
57
54
2.5:1
53
a All reactions were carried out on a 0.2 mmol scale in 2.0 mL of THF
at room temperature for 24 h. b Isolated yield. c Determined by HPLC on
a Chiralcel OD-H column.
enantioselectivity (Table 2, entries 4-7). The best result was
obtained when 1:2 molar ratio of Sc(OTf)3-L1 was used (Table
2, entry 6).
(20) Although L9 provided similar results as L1, L1 was still chosen as
the standard ligand because of its easier preparation compared with L9.
632 J. Org. Chem., Vol. 73, No. 2, 2008

EnantioselectiVe Aza-Diels-Alder Reaction of Aldimines
TABLE 3. Ligand Screening on Aza-Diels-Alder Reaction of Diene 1a
entry
ligand
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
L1
L2
L3
L4
L5
L6
L7
L8
59
30
61
57
50
70
38
36
58
35
44
47
52
52
57
7d
30
17
43
25
14
0
57
40
33
50
40
0
L9
L10
L11
L12
L13
L14
a All reactions were carried out on a 0.2 mmol scale in 2.0 mL of THF with 2.5 mol % catalyst loading (metal-ligand ) 1:2) at room temperature for
24 h. b Isolated yield. c Determined by HPLC on a Chiralcel OD-H column. d The product was obtained with R configuration, and the others were S.
TABLE 4. Solvent Effect on the Aza-Diels-Alder Reaction of
significance of the suitable acidity of the additives for the
reaction (Table 6, entry 8 vs 7). The addition of sodium
toluenesulfonate gave almost the same results as that in the
absence of additive (Table 6, entry 3 vs 1). Therefore, the
possibility that toluenesulfonic anion functioned as a ligand to
coordinate with the central metal was excluded. Further attempts
to decrease the substrate concentration and increase the catalyst
loading (10 mol %) improved the ee value to 81% (Table 6,
entries 9-13).
Imine 2aa
entry
solvent
THF
toluene
CH2Cl2
Et2O
yield (%)b
ee (%)c
1
2
3
4
5
6
59
46
70
87
43
99
57
29
29
16
55
5
When the substrate scope of this reaction was probed, 15
mol % of sulfanilic acid seemed to be more suitable for other
substrates to obtain better results (Table 7, entries 3-5).
Accordingly, the optimized catalytic system was 10 mol %
scandium(III)-N,N′-dioxide L1 (1:2), 0.2 mmol aldimine, and
2.0 equiv of diene in 3.0 mL of THF in the presence of 15 mol
% p-sulfanilic acid at room temperature. Under these conditions,
aromatic, heteroaromatic, conjugated, and aliphatic aldimines
were converted into the corresponding 2,5-disubstituted dihy-
dropyridinones with moderate to good yield and up to 90% ee.
For aromatic imines bearing electron-donating substituents, up
to 77% yield and 86% ee could be obtained (Table 7, entries 6,
10, 13, 16, 17, and 23). Notably, this method was rather efficient
for imines bearing electron-withdrawing groups at the para
position, a class of substrates that, to our knowledge, had never
been mentioned previously (Table 7, entries 5, 11, 15, 20, and
21). For example, the aza-Diels-Alder reaction of p-cyanoben-
zaldehyde-derived imine 2b proceeded well to give 1-(2-
hydroxyphenyl)-2-(4-cyanophenyl)-5-methyl-2,3-dihydropyridin-
4-one in 84% yield with 90% ee (Table 7, entry 5). Even R,â-
unsaturated imine 2i and heteroaromatic imine 2u were tolerated
in the catalytic reaction (Table 7, entries 12 and 24). For
aliphatic imines, which were hard to prepare, a new in situ imine
generation strategy was employed. Fortunately, 74% ee could
also be obtained for substrate 2v (Table 7, entries 25 and 26).
Additionally, for products 3f, 3j-3l, and 3q, enantiopure
samples (up to 99% ee) were obtained upon a single recrystal-
1,4-dioxane
CH3OH
a All reactions were carried out on a 0.2 mmol scale in 2.0 mL of solvent
with 2.5 mol % catalyst loading (metal-ligand ) 1:2) at room temperature
for 24 h. b Isolated yield. c Determined by HPLC on a Chiralcel OD-H
column.
yphenyl and benzhydryl groups could shield the coordination
of central metal with imines and hence prevent the reaction
(Table 5, entries 3 and 6).
To further improve the reactivity and enantioselectivity of
the reaction, some acids acting as additives were employed.21
In the presence of toluenesulfonic acid or sulfanilic acid, product
3a was obtained with 75% ee (Table 6, entries 2 and 7).
Comparably, sulfanilic acid showed higher reactivity, which
might attribute to the buffer action of the amino group on the
sulfanilic acid. In contrast, use of weaker or stronger acids
deteriorated the enantioselectivity deeply (Table 6, entries 4-6).
The reaction carried out with 5 mol % toluenesulfonic acid and
5 mol % aniline together as additives provided results similar
to that with sulfanilic acid, which further established the
(21) Review: Vogl, E. M.; Groger, H.; Shibasaki, M. Angew. Chem.,
Int. Ed. 1999, 38, 1570-1577. For a representative example using acid as
additive, see ref 14b.
J. Org. Chem, Vol. 73, No. 2, 2008 633

Shang et al.
TABLE 5. Investigation of the Protecting Group of Imine 2 on the Aza-Diels-Alder Reactiona
entry
R
yield (%)b
ee (%)c
1
2
3
4
5
6
2-hydroxyphenyl
phenyl
benzhydryl
tosyl
4-methoxyphenyl
2-methoxyphenyl
59
50
57
0
N.R.d
75
0
0
39
N.R.d
a All reactions were carried out on a 0.2 mmol scale in 2.0 mL of THF with 2.5 mol % catalyst loading (metal-ligand ) 1:2) at room temperature for
24 h. b Isolated yield. c Determined by HPLC on a Chiralcel OD-H column. d No reaction.
TABLE 6. Investigation of Additive, Substrate Concentration, and Catalyst Loading on Aza-Diels-Alder Reaction of Aldimine 2a with Diene
1a
entry
x (mol %)
additive (mol %)
solvent (mL)
yield (%)b
ee (%)c
1
2
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
5.0
10.0
15.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
3.0
4.0
3.0
3.0
3.0
59
55
54
30
46
66
73
57
65
49
65
74
77
57
75
61
28
42
26
75
76
78
77
76
81
74
p-CH3C6H4SO3H (5%)
p-CH3C6H4SO3Na (5%)
CH3CO2H (5%)
3
4
5
C6H5CO2H (5%)
6
CF3SO3H (5%)
7
p-NH2C6H4SO3H (5%)
p-CH3C6H4SO3H (5%)d
p-NH2C6H4SO3H (5%)
p-NH2C6H4SO3H (5%)
p-NH2C6H4SO3H (5%)
p-NH2C6H4SO3H (5%)
p-NH2C6H4SO3H (5%)
8
9
10
11
12
13
a All reactions were carried out on a 0.2 mmol scale in THF (metal-ligand ) 1:2) at room temperature for 24 h. b Isolated yield. c Determined by HPLC
on a Chiralcel OD-H column. d 5 mol % aniline was used together as additive.
lization (Table 7, entries 9, 13, 14, 15, and 20).22 Undoubtedly,
this good substrate generality combined with the simplicity of
the experimental procedure for this reaction made it very
attractive from a synthetic point of view.
Through the Bijvoet method, the absolute configuration of
product 3r was determined unambiguously to be S with an
absolute structure parameter of -0.002(15) on the basis of
anomalous dispersion of bromine heavy atom. Compared with
the Cotton effect in the CD spectra of 3r, the products of 3a-
3h, 3j-3q, 3s, and 3t possessed the same S configuration (for
details, see the Supporting Information).
resonance of NH protons shifting from 9.16 to 9.61 ppm
confirmed the coordination between L14 and scandium (Figure
2a,b). Considering the four magnetically equivalent NH protons
and the steric effect of the bulky 2,6-diisopropylphenyl groups,
we assumed that the carbonyl oxygens, rather than the amide
nitrogens, participated in the coordination with the scandium
(complex A).
The NH proton of N,N′-dioxide L1 showed a strong deshield-
ing effect at 13.58 ppm due to the strong hydrogen bond between
1
N-oxide and the NH proton (Figure 2c).23 When the H NMR
spectra of scandium(III)-N,N′-dioxide L1 (1:2) complex was
studied, the signal at 13.58 ppm of L1 completely disappeared
and two new signals at 9.64 and 11.69 ppm were observed
(Figure 2d). Compared with the chemical shift of NH proton at
9.61 ppm in complex A, the new peak at 9.64 ppm suggested
the coordination of carbonyl oxygen with scandium. In addition,
according to the appearance of the signal at 11.69 ppm, we
speculated that, for all the amide hydrogens of complex B in
Catalyst Structure Consideration. For this reaction, the best
result was obtained when the molar ratio of ligand to metal
1
was 2:1 with acid as additive. Therefore, a series of H NMR
spectra of ligand-scandium (2:1) complex were examined to
gain preliminary insight into the structure of the catalyst (Figure
2). In the 1H NMR spectra of ligand L14 (the precursor of N,N′-
dioxide L1) and scandium(III) triflate (2:1) complex, the
(22) The catalytic products were recrystallized in CH2Cl2-CH3OH-n-
hexane to provide the enantiomerically pure compounds with 50-70% yield.
(23) Qin, B.; Liu, X. H.; Shi, J.; Zheng, K.; Zhao, H. T.; Feng, X. M. J.
Org. Chem. 2007, 72, 2374-2378.
634 J. Org. Chem., Vol. 73, No. 2, 2008

EnantioselectiVe Aza-Diels-Alder Reaction of Aldimines
TABLE 7. Scope of the Enantioselective Aza-Diels-Alder Reaction between Diene 1 and Aldimines 2a
Entry
R
Additive (mol%)
Product
yield (%)b
ee (%)c
81(S)
71(S)
84(S)
88(S)
90(S)
86(S)
84(S)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Ph (2a)
Ph (2a)
5
10
5
3a
3a
3b
3b
3b
3c
3d
3e
3f
74
63
66
80
84
66
54
80
85
65
66
92
77
69
69
72
46
89
69
64
73
72
p-CNC6H4 (2b)
p-CNC6H4 (2b)
p-CNC6H4 (2b)
p-CH3OC6H4 (2c)
o-NO2C6H4 (2d)
R-Naphthyl (2e)
â-Naphthyl (2f)
o-CH3C6H4 (2g)
p-FC6H4 (2h)
(E)-PhCH=CH (2i)
p-CH3C6H4 (2j)
m-NO2C6H4 (2k)
p-NO2C6H4 (21)
p-PhC6H4 (2m)
m-PhOC6H4 (2n)
o-ClC6H4 (2o)
10
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
87(S)
84(S)(99)d
80(S)
3g
3h
3i
85(S)
84
3j
85(S)(>99)d
80(S)(>99)d
89(S)(>99)d
84(S)
3k
31
3m
3n
3o
3p
3q
3r
3s
84(S)
83(S)
m-ClC6H4 (2p)
p-CIC6H4 (2q)
p-BrC6H4 (2r)
80(S)
85(S)(>99)d
87(S)e
82(S)
23
15
3t
57
81(S)
24
25
26
2-thienyl (2u)
2-propyl (2v)
2-propyl (2v)
15
15
15
3u
3v
3v
46
67
41
82f
71g
74h
a Without otherwise noticing, all reactions were carried out on a 0.2 mmol scale in 3.0 mL of THF with 10 mol % scandium(III) triflate and 20 mol %
L1 at room temperature for 72 h, using sulfanilic acid as additive. b Isolated yield. c Determined by HPLC on chiral columns. The absolute configurations
were assigned by comparing the Cotton effect of the CD spectra with that of 3r. d After a single recrystallization. e The absolute configuration was determined
by X-ray crystal structural analysis of 3r on the basis of the anomalous dispersion of the heavy bromine atom. f Reaction time was 120 h. g Catalyst was
added to the imine generated in situ. h Imine generated in situ was added to the catalyst.
the catalytic system, some of them (δ ) 11.69 ppm) were still
affected by the intramolecular hydrogen bond interaction, while
others (δ ) 9.64 ppm) were not. The molar ratio of these two
kinds of hydrogens was determined to be 3:7 on the basis of
the integral level of the 1H NMR spectra (Supporting Informa-
tion). After the addition of toluenesulfonic acid, the intramo-
lecular hydrogen bond in complex B totally broke down.
Therefore, the signal at 11.69 ppm disappeared (Figure 2, part
e vs d). Moreover, only two NH hydrogens (totally four
hydrogens) were observed in Figure 2 (parts d and e), which
delivered two amide nitrogen anions complexed with scandium
(as shown in Figure 2, complex B). On the basis of these
observations and the discussion here, it was plausible that the
N,N′-dioxide L1 coordinated with scandium in a 2:1 manner,
and L1 provided a carbonyl oxygen and an amide nitrogen for
coordination (as shown in Figure 2). In the presence of
p-toluenesulfonic acid, a C2 symmetric scandium-N,N′-dioxide
L1 (1:2) complex with good chiral environment might be
generated.
Meanwhile, the relationship between the enantiomeric excess
of the product 3a and the chiral ligand L1 was studied (Figure
3). In both cases, strong positive nonlinear effect was observed,
which further validated the existence of L1-Sc(OTf)3 (2:1)
complex such as complex B (Figure 2). It was logical to suggest
that homochiral and heterochiral complexes such as (-)(-)-
complex B and (+)(-)-complex B coexisted in the reaction
system. As could be found in Girard and Kagan’s excellent
review of nonlinear effects, the homochiral one seemed to be
more active than the heterochiral one, which resulted in the
positive nonlinear effect.24
Conclusion
The asymmetric aza-Diels-Alder reaction of a variety of
aldimines with Danishefsky-type diene 1 has been achieved by
(24) Reviews: (a) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. 1998,
37, 2922-2959. (b) Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.;
Palacios, J. C. Tetrahedron: Asymmetry 1997, 8, 2997-3017. For an
example, see: (c) de Vries, A. H. M.; Jansen, J. F. G. A.; Feringa, B. L.
Tetrahedron 1994, 50, 4479-4491.
J. Org. Chem, Vol. 73, No. 2, 2008 635

Shang et al.
FIGURE 2. 1H NMR spectra investigation of amide protons: (a) L14; (b) ligand L14-scandium(III) triflate complex (ratio 2:1); (c) L1; (d) ligand
L1-scandium(III) triflate complex (ratio 2:1); (e) ligand L1-scandium(III) triflate complex with toluenesulfonic acid as additive (ratio 2:1:2).
layer was extracted with CH2Cl2 (3 × 5 mL), and the combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The crude product was purified by flash
chromatography (petroleum ether-ethyl acetate, 3:2) to afford a
yellow solid (42 mg, 74% yield, 81% ee). The ee was determined
by HPLC analysis using a chiral OD-H column (hexane-2-
propanol, 90:10, 1.0 mL/min, tr (major) ) 9.787 min, tr (minor) )
11.572 min). Mp 148-149 °C; [R]25D +101.4° (c 0.214, CH2Cl2);
1H NMR (300 MHz, CDCl3): δ 7.21-6.74 (m, 11H), 5.10 (dd, J
) 9.0, 6.2 Hz, 1H), 3.07 (dd, J ) 16.5, 6.2 Hz, 1H), 2.92 (dd, J )
16.6, 9.2 Hz, 1H), 1.78 (s, 3H) ppm. 13C NMR (100 MHz,
CDCl3): δ 191.6, 154.1, 151.8, 138.8, 131.9, 128.5, 128.0, 127.9,
127.1, 126.4, 119.8, 117.1, 106.3, 62.7, 43.1, 12.8 ppm; ES-HRMS
calcd for C18H16NO2 [M-], 278.1187; found, 278.1181.
FIGURE 3. Amplification observed in the aza-Diels-Alder reaction
of 1 and 2a using scandium(III) triflate complex of N,N′-dioxide L1
as the catalyst.
Experimental Procedure for the Enantioselective Aza-Diels-
Alder Reaction in a New in Situ Imine Generation Strategy.
2-Aminophenol (21.8 mg, 0.2 mmol), isobutyraldehyde (36 µL, 0.4
mmol), and Na2SO4 (85.2 mg, 0.6 mmol) were dissolved in 2.0
mL of THF and stirred in a test tube at room temperature under Ar
atmosphere. After 2 h, the solution was added to another test tube
containing ligand L1 (24.8 mg, 0.04 mmol) and Sc(OTf)3 (10.0
mg, 0.02 mmol) in 0.5 mL of THF under Ar atmosphere. After the
addition of sulfanilic acid (5.2 mg, 0.03 mmol), this test tube was
washed with another 0.5 mL of THF. The mixture was stirred at
room temperature for 15 min, and diene (100 µL, 0.4 mmol) was
added and stirred at room temperature for 96 h. Then, the mixture
was cooled to 0 °C, 1 N HCl (1 mL) was added, and this solution
was stirred for another 1 h. Saturated NaHCO3 (5 mL) was added,
and the solution was stirred for an additional 5 min. It was diluted
with 5 mL of CH2Cl2. The aqueous layer was extracted with CH2-
Cl2 (3 × 5 mL), and the combined organic layers were washed
with brine, dried over Na2SO4, and concentrated in vacuo. The crude
product was purified by flash chromatography (petroleum ether-
ethyl acetate, 2:1) to afford a yellow oil (20 mg, 41% yield). The
product was treated with 3 mL of 20% MeI-acetone and 100 mg
of K2CO3.9c The mixture was stirred at room temperature for 6 h,
and saturated aqueous NH4Cl was added to quench the reaction.
After extraction of the aqueous layer with CH2Cl2, the crude product
was chromatographed on silica gel (petroleum ether-ethyl acetate,
2:1) to afford the corresponding methylated product with 74% ee
as a yellow oil. The ee was determined by HPLC analysis using a
chiral OD-H column (hexane-2-propanol, 99:1, 1.0 mL/min, tr
the catalysis of chiral scandium complex of N,N′-dioxides, which
has added a new catalyst for this class of reactions. Various
2,5-disubstituted dihydropyridinones have been produced in high
enantioselectivities (up to 90% ee; single recrystallization, up
to 99% ee) and moderate to high yields (up to 92%). On the
basis of 1H NMR spectra investigation and the positive nonlinear
effect, the catalyst structure is carefully discussed. Further efforts
will be devoted to the investigation of the details of the reaction
mechanism, the aza-Diels-Alder reaction with other kinds of
dienes, and synthetic application of the products.
Experimental Section
General Procedure for the Enantioselective Aza-Diels-Alder
Reaction. Ligand L1 (24.8 mg, 0.04 mmol), Sc(OTf)3 (10.0 mg,
0.02 mmol), sulfanilic acid (1.7 mg, 0.01 mmol), and imine 2a
(39.4 mg, 0.2 mmol) were dissolved in 3.0 mL of THF and stirred
in a test tube under Ar atmosphere. After 15 min, diene (100 µL,
0.4 mmol) was added to the mixture and stirred at room temperature
for 24 h. Then, the mixture was cooled to 0 °C, 1 N HCl (1 mL)
was added, and this solution was stirred for another 1 h. Saturated
NaHCO3 (5 mL) was added, and the solution was stirred for an
additional 5 min. It was diluted with 5 mL of CH2Cl2. The aqueous
636 J. Org. Chem., Vol. 73, No. 2, 2008

EnantioselectiVe Aza-Diels-Alder Reaction of Aldimines
(major) ) 20.508 min, tr (minor) ) 23.758 min). [R]25D +60.7° (c
20732003 and 20472056). We also thank Sichuan University
Analytical & Testing Center for NMR spectra, X-ray diffraction,
and CD spectrum analysis.
1
0.270, CHCl3); H NMR (400 MHz, CDCl3): δ 7.27-6.96 (m,
5H), 3.96 (dd, J ) 12.0, 6.8 Hz, 1H), 3.88 (s, 3H), 2.79 (dd, J )
16.4, 6.4 Hz, 1H), 2.58 (dd, J ) 16.4, 7.6 Hz, 1H), 1.96 (m, 1H),
1.72 (s, 3H), 0.85 (dd, J ) 8.4, 7.6 Hz, 6H) ppm. 13C NMR (100
MHz, CDCl3): δ 192.0, 154.6, 152.0, 133.9, 127.9, 127.7, 121.0,
112.0, 105.4, 63.6, 55.7, 55.6, 36.3, 29.3, 19.6, 17.2, 12.6 ppm;
ES-HRMS Calcd for C16H22NO2 [M + H+], 260.1645; found,
260.1649.
Supporting Information Available: Experimental procedures,
structural proofs for catalysts, spectral and analytical data for the
products, and crystallographic data (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was financially supported by
the National Nature Science Foundation of China (Nos.
JO7021263
J. Org. Chem, Vol. 73, No. 2, 2008 637