Proline-catalyzed asymmetric Diels-Alder reactions of an o-quinodimethane

Article abstract of DOI:10.1016/j.tetlet.2014.05.107

Catalytic asymmetric Diels-Alder reaction of α-amino-o-quinodimethane with α,β-unsaturated aldehydes was achieved with high diastereo- and enantioselectivities in the presence of l-proline, which acts as a promoter to generate the quinodimethane from the corresponding precursor as well as a chiral catalyst for the enantioselective Diels-Alder reaction.

Full text of DOI:10.1016/j.tetlet.2014.05.107

Accepted Manuscript
Proline-Catalyzed Asymmetric Diels-Alder Reactions of an o-Quinodimethane
Hidenori Shirakawa, Hiroshi Sano
PII:
S0040-4039(14)00938-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.107
TETL 44698
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 March 2014
22 May 2014
28 May 2014
Please cite this article as: Shirakawa, H., Sano, H., Proline-Catalyzed Asymmetric Diels-Alder Reactions of an o-
Quinodimethane, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.107
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Proline-Catalyzed Asymmetric Diels-Alder
Reactions of an o-Quinodimehtane
Hidenori Shirakawa, Hiroshi Sano*
Leave this area blank for abstract info.
Ph
N
Ph
NH
COOH
N
H
CHO
CHO
Ar
+
SnBu3
AcOH
MeOH/MeCN
rt, 5 h
Ar
up to 97%ee

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Proline-Catalyzed Asymmetric Diels-Alder Reactions of an o-Quinodimethane
Hidenori Shirakawa, Hiroshi Sano∗
Department of Chemistry, Graduate School of Engineering, Gunma University, Kiryu, Gunma 376-8515 Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Catalytic asymmetric Diels-Alder reaction of α-amino-o-quinodimethane with α,β-unsaturated
aldehydes was achieved with high diastereo- and enantioselectivity in the presence of L-proline,
which acts as a promoter to generate the quinodimethane from the corresponding precursor as
well as a chiral catalyst for the enantioselective Diels-Alder reaction.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
o-Quinodimethane
Proline
Organocatalyst
Enantioselective Diels-Alder
Organotin
The Diels-Alder reaction, which is [4+2] cycloaddition
reaction of 1,3-dienes with dienophiles, is one of the most
powerful synthetic tools for the construction of six-membered
ring systems.1 The asymmetric version of the Diels-Alder
reaction has been of considerable interest in recent years, since
the reaction can be applied to the asymmetric synthesis of
enantioenriched carbocycles and heterocycles.2 Numerous
methods for the reaction have been successfully developed using
many kinds of organocatalysts.3,4 However, in spite of many
attempts to achieve the reaction using proline, which is a simple
and easily available catalyst, few satisfactory results have been
obtained with the exception of a couple of examples.5
Ph
NH
CHO
CHO
Ar
*
*
*
2
Ar
COOH
N
H
6
H2O
H2O
Ph
COOH
NH
N
*
*
*
o-Quinodimethanes (ο-QDMs), or o-xylylenes, are known to
be useful reactive intermediates to synthesize natural products
including tetrahydronaphthalene frameworks such as steroids.6
Very few examples, however, have been reported on
enantioselective Diels-Alder reactions of o-QDMs,7 since (1)
many of the methods that have been developed to generate o-
QDMs in situ require conditions which disturb asymmetric
reactions, (e.g. requiring very high temperature or the use of
anionic promoters, which would hamper the coordination of
chiral catalysts such as chiral Lewis acids to dienophiles);8 (2) o-
QDMs have extremely high reactivity to react easily not only
with dienophiles activated by chiral catalysts but also with free
dienophiles, which would make it difficult to attain high
enantioselectivity in catalytic reactions. Bach accomplished the
first enantioselective cycloaddition of an o-QDM by using an
irradiation-induced method with an excess of a chiral template to
circumvent these problems7a, while successful examples of
catalytic reactions have been limited to the generation of aza-o-
Ar
5
Ph
N
COOH
N
3
Ar
SnBu3
1
H
Ph
N
proline
4
Scheme 1. Asymmetric Diels-Alder Reaction of o-Quinodimethane 4 Catalyzed
by Proline
heterocyles.7c,7d
In our continuous efforts to develop a new precursor of α-
amino-o-QDMs,9 which are important intermediates to synthesize
alkaloids such as chelidonines,9a-c,g we have assumed that
benzylstannanes bearing an imino group at the ortho position are
QDMs and indole, pyrrole, or furan-based o-QDMs leading to
———
∗ Corresponding author. Tel.: +81 277 301282. E-mail address: sano@gunma-u.ac.jp (H. Sano)

2
Tetrahedron
promising compounds which would generate α-amino-o-QDMs
an excess amount of cinnamaldehyde improved the yield (69%)
and diastereoselectivity (92:8) without significant loss of the
enantioselectivity (83% ee) (entry 10). We also evaluated the
effect of co-catalysts on this asymmetric cycloaddition reaction.
Though the use of benzoic acid in place of acetic acid gave a
similar result, both the yield and the selectivity were generally
found to decrease with increasing acidity of the co-catalysts
(entries 10-13). It is noteworthy that the reaction proceeded
without co-catalyst in high diastereo- and enantioselectivity,
although a prolonged reaction time was required (entry 14). The
result shows that proline serves as a promoter to facilitate the
reaction as well as a chiral catalyst in this cycloaddition, and
indicates that the co-catalyst also promotes the generation of α-
amino-o-QDM 4. As a result, we chose to use acetic acid as a
suitable co-catalyst for further study.
by protonation of the imino group and subsequent destannylation
of the stannyl group under acidic conditions,10 and envisioned
that L-proline would behave both as a promoter to generate α-
amino-o-QDMs and as
a
chiral catalyst to achieve
enantioselective cycloaddition reactions of the o-QDMs. Thus,
we expected that organotin compound 1 would provide α-amino-
o-QDM 4 in the presence of proline, which has a carboxylic acid
moiety, and then 4 would react selectively with iminium salt 3,
which undergoes LUMO-lowering activation,11,12 formed by the
reaction of proline and α,β-unsaturated aldehydes 2 to generate
cycloadduct 5, which would be hydrolyzed to cycloadduct 6 with
regeneration of proline (Scheme 1). Herein, we describe a highly
diastereo- and enantioselective Diels-Alder reaction of α-amino-
o-QDM 4 catalyzed by L-proline.
Table 2. Proline-Catalyzed Reaction of 1 with Aromatic α,β-Unsaturated
Aldehydesa
Table 1. Effect of Solvent and Co-catalyst in the Reaction of 1 with
Cinnamaldehydea
Ph
Ph
Ph
Ph
N
NH
N
NH
L
-proline
L
-proline
CHO
CHO
Ar
CHO
CHO
Ph
AcOH
+
AcOH
+
SnBu3
SnBu3
MeOH/MeCN (1:3)
rt, 5 h
Ar
solvent, rt
Ph
1
2
6
1
2a
6a
eeh
(%)
(cis)
74
Yieldg
(%)
Ph
Time
(h)
cis:transg
NH
Entry
Solvent
NaBH4
OH
1
MeOH
MeCN
2
3
1
1
1
2
1
1
1
5
5
5
5
15
35
trace
33
33
33
34
27
38
43
69
61
57
51
45
67:33
n.d.
Ar
2
n.d.
74
7
3
MeOH/Hexane (1:1)
MeOH/Et2O(1:1)
72:28
81:19
88:12
82:18
80:20
82:18
91:9
Yieldc of 7
(%)
Entry
Ar
cis:transd
eed (%) (cis)
4
84
5
MeOH/THF (1:1)
MeOH/CH2Cl2 (1:1)
MeOH/CHCl3 (1:1)
MeOH/MeCN(1:1)
MeOH/MeCN(1:3)
MeOH/MeCN(1:3)
MeOH/MeCN(1:3)
MeOH/MeCN(1:3)
MeOH/MeCN(1:3)
MeOH/MeCN(1:3)
84
1
2b
a: Ph
a: Ph
62
76
59
60
60
53
44
92:8
91:9
83
90
89
93
96
97
52
6
82
7
82
3
b: p-MeOC6H4
b: p-MeOC6H4
c: p-ClC6H4
91:9
4b
5
89:11
85:15
90:10
78:22
8
82
9
84
10 b
11 b, c
12 b, d
13 b, e
14 b, f
92:8
83
6
d: p-BrC6H4
91:9
83
7
e: p-NO2C6H4
a
87:13
81:19
93:7
75
Unless otherwise specified, the reactions were conducted using 1 (0.2
mmol), aldehyde 2 (0.8 mmol), L-proline (0.06 mmol) and AcOH (0.06
mmol) at rt followed by NaBH4 reduction.
59
81
a
b Using L-proline (0.24 mmol) and AcOH (0.24 mmol).
c Isolated yield.
d Determined by chiral HPLC analysis of 7.
Unless otherwise specified, the reactions were conducted using 1 (0.2
mmol), cinnamaldehyde 2a (0.2 mmol), L-proline (0.06 mmol) and AcOH
(0.06 mmol) at rt.
b 4 equiv of cinnamaldehyde (0.8 mmol) was used.
c Benzoic acid was used as a co-catalyst.
d Chloroacetic acid was used as a co-catalyst.
e Trifluoroacetic acid was used as a co-catalyst.
f Without co-catalyst.
Under the optimized reaction conditions, we next investigated
the generality of the reaction using several substituted
cinnamaldehydes (Table 2). The catalytic reaction also proceeded
efficiently in the case of cinnamaldehyde having an electron-
donating group on the benzene ring in high diastereo- and
enantioselectivity (entry 3). When electron-deficient aldehydes
such as p-chloro- and p-bromocinnamaldehyde were employed,
the corresponding cycloadducts were obtained with excellent
g Determined by 1H-NMR analysis.
h
Determined by HPLC analysis after reduction of 6a with NaBH4 to the
corresponding alcohol.
We initially examined the asymmetric cycloaddition reaction
using precursor 1 and an equimolar amount of cinnamaldehyde
2a in the presence of 30 mol% of L-proline as a chiral catalyst
and 30 mol % of acetic acid as a co-catalyst13 in MeOH at room
temperature. The reaction was complete within 2 h and provided
the desired cycloadduct 6a in 35% NMR yield as a mixture of
two isomers (1,2-cis and 1,2-trans). No regioisomer was
discernible in the NMR of the crude mixture. The diastereomer
ratio was found to be 67:33 (1,2-cis:1,2-trans) by NMR analysis
and the enantioselectivity was determined by HPLC analysis of
the corresponding alcohol to be 74% ee (1,2-cis). (Table1, entry
1) On the other hand, almost no reaction occurred in MeCN
(entry 2). The fact that the reaction proceeded successfully in
MeOH prompted us to further investigate the reaction in various
mixed solvents including MeOH. Among the solvents screened,
MeOH/MeCN (1:3) was found to be the best with respect to the
yield and diastereo- and enantioselectivities (entry 9). The use of
enantioselectivity (entries
5
and 6). Unexpectedly, the
introduction of a strong electron-withdrawing group lowered the
yield and selectivity (entry 7). In the case of cinnamaldehyde
and its p-methoxy derivative, the use of a small excess of proline
(120 mol%) enhanced the enantioselectivity (entries 2 and 4).

3
1007; (d) Dias, L. C. J. Braz. Chem. Soc. 1997, 8, 289; (e)
Maruoka, K. In Catalytic Asymmetric Synthesis (2nd Edition);
Ojama, I. Ed.; Wiley-VCH: New York, 2000; pp 467. (f) Corey, E.
J. Angew. Chem., Int. Ed. 2002, 41, 1650; (g) Hayashi, Y. In
Cycloaddition Reaction in Oraganic Synthesis; Kobayashi, S.,
Jørgensen, K. A., Eds; Wiley-VCH: Weinheim, 2002; chap. 1.
3. For selected reviews, see: (a) Notz, W.; Tanaka, F.; Barbas, C. F.
III Acc. Chem. Res. 2004, 37, 580; (b) Hayashi, Y. J. Syn. Org.
Chem. Jpn. 2005, 63, 464; (c) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5413; (d) Akiyama,
T. Chem. Rev. 2007, 107, 5744; (e) MacMillan, D. W. C. Nature
2008, 455, 304; (f) Barbas, C. F., III Angew. Chem., Int. Ed. 2008,
47, 42; (g) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G.
Angew. Chem., Int. Ed. 2008, 47, 6138; (h) Dondoni, A.; Massi, A.
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2010, 1929; (j) Yamashita, Y.; Kobayashi, S. In Handbook of
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1491; (p) Pellissier, H. Tetrahedron 2012, 68, 2197. (q) Ishihara,
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Yamamoto, H., Eds.; Elsevier B.V.: Amsterdam, 2012; Vol. 6, pp
264. (r) Shoji, M.; Hayashi, Y. In Modern Tools for the Synthesis
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John Wiley & Sons: Hoboken, 2012; pp 189. (s) Jiang, X.; Wang,
R. Chem. Rev. 2013, 113, 5515.
Figure 1. ORTEP drawing of 6c. Displacement ellipsoids are drawn at the
50% probability level.
The absolute configuration of the cycloadduct 6c obtained
from the reaction of 1 with p-chlorocinnamaldehyde was
determined as (1S, 2S, 3R) by X-ray crystallography (Figure 1).14
In a control experiment, the use of methyl ester of proline in
place of proline resulted in a remarkable decrease of the
enantioselectivity from 83% ee to 8% ee under the conditions of
entry 1 in Table 2, showing that the carboxylic acid moiety of
proline plays an important role in determining the
enantioselectivity. Based on these results, we propose the
reaction transition state for the cycloaddition of α-amino-o-QDM
4 with iminium salt 3 (Scheme 2). Thus, the reaction should
proceed through a transition state assembly being organized by
hydrogen-bonding such as 8, thereby facilitating the approach of
o-QDM 4 to the re-face of the iminium salt 3 with an endo
orientation to give the cycloadduct 6, which is consistent with the
experimental result.
In summary, we have developed a new precursor of α-amino-
o-QDM 4 and achieved a catalytic enantioselective Diels-Alder
reaction of the o-QDM with α,β-unsaturated aldehydes.
Organotin compound 1, which can be prepared in short steps, is a
good precursor for the generation of 4 in the presence of L-
proline, which catalyzes the asymmetric Diels-Alder reaction
with dienophiles to give tetrahydronaphthalene derivatives 6 in
good yields with high to excellent diastereo- and
enantioselectivities in most cases. It has been suggested that the
stereoselectivity of the cycloaddition is dictated by the formation
of a hydrogen bond between o-QDM 4 and iminium salt 3.
4. For recent reports, see: (a) Enders, D.; Joie, C.; Deckers, K. Chem.
Eur. J. 2013, 19, 10818. (b) Wang, Z.-Y.; Wong, W.-T.; Yang, D.
Org. Lett. 2013, 15, 4980. (c) Ma, C.; Gu, J.; Teng, B.; Zhou, Q.-
Q.; Li, R.; Chen, Y.-C. Org. Lett. 2013, 15, 6206. (d) Abbasov, M.
E.; Hudson, B. M.; Tantillo, D. J.; Romo, D. J. Am. Chem. Soc.
2014, 136, 4492. (e) Weise, C. F.; Lauridsen, V. H.; Rambo, R. S.;
Iversen, E. H.; Olsen, M.-L.; Jørgensen, K. A. J. Org. Chem. 2014,
79, 3537.
5. For attempts of proline-catalyzed enantioselective Diels-Alder
reactions of 1,3-dienes, see: (a) Thayumanavan, R.: Dhevalapally,
B.; Sakthivel, K.; Tanaka, F.; Barbas, C. F., III Tetrahedron Lett.
2002, 43, 3817; (b) Ramachary, D. B.; Chowdari, N. S.; Barbas, C.
F., III Tetrahedron Lett. 2002, 43, 6743; (c) Ramachary, D. B.;
Chowdari, N. S.; Barbas, C. F., III Angew. Chem., Int. Ed. 2003,
42, 4233; (d) Sundén, H.; Ibrahem, I.; Rios, R.; Xu, Y.; Ericksson,
L.; Córdova, A. Angew. Chem., Int. Ed. 2005, 44, 4877; (e)
Sundén, H.; Ibrahem, I.; Adolfsson, H.; Córdova, A. Tetrahedron
Lett. 2005, 46, 3385; (f) Sundén, H.; Ibrahem, I.; Ericksson, L.;
Córdova, A. Adv. Synth. Catal. 2007, 349, 2549; (g) Hong, B.-C.;
Wu, M.-F.; Tseng, H.-C.; Huang, G.-F.; Su, C.-F.; Liao, J.-H. J.
Org. Chem. 2007, 72, 8459; (h) Hong, B.-C.; Tseng, H.-C.; Chen,
S.-H. Tetrahedron 2007, 63, 2840; (i) de Figueiredo, R. M.;
Frӧhlich, R.; Christmann, M. Angew. Chem., Int. Ed. 2008, 47,
1450; (j) Stowe, G. N.; Janda, K. D. Tetrahedron Lett. 2011, 52,
2085; (k) Hong, B.-C.; Dange, N. S.; Ding, C.-F.; Liao, J.-H. Org.
Lett. 2012, 14, 448; (l) Sinha, D.; Perera, S.; Zhao, C.-G. Chem.
Eur. J. 2013, 19, 6976.
Ph
H
Ph
N
NH
H
O
O
CHO
Ar
1
2
3
+
4
3
N
(1S, 2S, 3R)
Ar
8
6
Scheme 2. Proposed Reaction Transition State for the Cycloaddition.
Acknowledgments
We are grateful to Prof Hideki Amii (Gunma University) for
his useful suggestion. We also thank to Prof Ken-ichiro Kanno
(Gunma University) for supporting X-ray analysis.
6. Reviews: (a) Oppolzer, W. Synthesis 1978, 793; (b) Charlton, J.
L.; Alauddin, M. M. Tetrahedron 1987, 43, 2873; (c) Segura, J.
L.; Martin, N. Chem. Rev. 1999, 99, 3199; (d) Sano, H.;
Nishimura, J. In Science of Synthesis, Houben-Weyl Methods of
Molecular Transformations; Siegel, J. S., Tobe, Y., Eds.; Georg,
Thieme Verlag: Stuttgart, 2009: Vol. 45a, pp 483.
Supplementary data
Supplementary data associated with this article can be found,
in the online version
7. (a) Grosch, B.; Orlebar, C. N.; Herdtweck, E.; Massa, W.; Bach, T.
Angew. Chem., Int. Ed. 2003, 42, 3693; Grosch, B.; Orlebar, C.
N.; Herdtweck, E.; Kaneda, M.; Wada, T.; Inoue, Y.; Bach, T.
Chem. Eur. J. 2004, 10, 2179; (b) Takinami, M.; Ukaji, Y.;
Inomata, K. Tetrahedron: Asymmetry 2006, 17, 1554; (c) Wang,
C.; Tunge, J. A. J. Am. Chem. Soc. 2008, 130, 8118; (d) Liu. Y.;
Nappi, M.; Arceo, E.; Vera, S.; Melchiorre, P. J. Am. Chem. Soc.
2011, 133, 15212.
References and notes
1. (a) Diels, O.; Alder, K. Justus Liebigs Ann. Chem. 1928, 460, 98;
(b) Norton, J. A. Chem. Rev. 1942, 42, 319; (c) Huisgen, R.;
Grashey, R.; Sauer, J. In The Chemistry of the Alkenes; Patai, S.,
Ed.; Wiley: London, 1964; pp 739.
8. Thermolysis (benzocyclobutene: 200 °C) and anion-induced 1,4-
elimination reactions are widely used for the generation of o-
QDMs.6
2. For selected reviews, see: (a) Evans, D. A.; Johnson, J. S. In
Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: New York, 1999; Vol. 3, pp 1177
and references therein; (b) Oppolzer, W. In Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: New York,
1991; Vol. 5; (c) Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92,
9. (a) Oppolzer, W.; Kelier, K. J. Am. Chem. Soc. 1971, 93, 3836; (b)
Oppolzer, W. Heterocycles 1980, 14, 1615; (c) Oppolzer, W.;
Robbiani, C. Helv. Chim. Acta 1983, 66, 1119; (d) Klemm, L. H.;
Hwang, Y. N.; Louris, J. N. J. Org. Chem. 1983, 48, 1451; (e)
Kessar, S. V.; Singh, T.; Mankotia, A. K. S. J. Chem. Soc., Chem.

4
Tetrahedron
Commun. 1989, 1692; (f) Kessar, S. V.; Mankotia, A. K. S.;
Agnihotri, K. R. J. Chem. Soc., Chem. Commun. 1993, 598; (g)
Ma, Z.-X.; Feltenberger, J. B.; Hsung, R. P. Org. Lett. 2012, 14,
2742.
10. For generations of o-QDMs via elimination of stannyl groups, see:
(a) Sano, H.; Ohtsuka, H.; Migita, T. J. Am. Chem. Soc. 1988, 110,
2014; (b) Sano, H.; Kawata, K.; Migita, T. Synlett 1993, 831; (c)
Woo, S. H. Tetrahedron Lett. 1993, 34, 7587; (d) Woo, S. H.
Tetrahedron Lett. 1994, 35, 3975; (e) Sano, H.; Mashio, H.;
Nakayama, T.; Migita, T. Tetrahedron Lett. 1996, 37, 8891.
11. Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243.
12. In most of the proline-catalyzed enantioselective Diels-Alder
reactions which have been reported so far, proline is used for the
activation of 1,3-dienes (HOMO-raising activation).5
13. The co-catalyst is usually used to promote the formation of the
iminium intermediate from an α,β-unsaturated aldehyde and a
secondary amine; see ref. 11.
14. Crystallographic data for compound 6c have been deposited with
the Cambridge Crystallographic Data Centre (CCDC 972989).