exo-selective asymmetric Diels-Alder reaction catalyzed by diamine salts as organocatalysts

Article abstract of DOI:10.1021/ol060621i

A novel binaphthyl-based diamine (R)-2 was designed and synthesized. A protonic acid-(R)-2 salt catalyst has the advantage of exhibiting unprecedented high exo selectivity in the asymmetric Diels-Alder reaction of α,/β-unsaturaled aldehydes. For instance, the reaction between cinnamaldehyde and cyclopentadiene in the presence of 12 mol % of binaphthyl-based diamine (R)-2 and 10 mol % of P-TsOH·H₂O in α,α,α-trifluorotoluene at -20 °C gave the corresponding exo cycloadduct with 92% ee as a major diastereomer (exolendo = 13/1).

Full text of DOI:10.1021/ol060621i

ORGANIC
LETTERS
2
006
Vol. 8, No. 13
687-2689
exo-Selective Asymmetric Diels−Alder
Reaction Catalyzed by Diamine Salts as
Organocatalysts
2
Taichi Kano, Youhei Tanaka, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo,
Kyoto 606-8502, Japan
maruoka@kuchem.kyoto-u.ac.jp
Received March 14, 2006
ABSTRACT
A novel binaphthyl-based diamine (R)-2 was designed and synthesized. A protonic acid
unprecedented high exo selectivity in the asymmetric Diels Alder reaction of -unsaturated aldehydes. For instance, the reaction between
cinnamaldehyde and cyclopentadiene in the presence of 12 mol % of binaphthyl-based diamine (R)-2 and 10 mol % of p-TsOH O in
trifluorotoluene at 20 C gave the corresponding exo cycloadduct with 92% ee as a major diastereomer (exo/endo 13/1).
−(R)-2 salt catalyst has the advantage of exhibiting
−
r,â
‚H
2
r,r,r-
−
°
)
The Diels-Alder reaction remains one of the most powerful
tools in synthetic organic chemistry as exemplified by its
broad application to the regio- and stereochemically defined
synthesis of a wide variety of natural products, and hence, a
number of enantioselective as well as diastereoselective
the Diels-Alder family of reactions. In contrast, the opposite
exo selectivity, particularly the catalyst-controlled exo-
selective Diels-Alder reaction, is not readily attainable by
deliberate modification of existing methodologies especially
with simple R,â-unsaturated aldehydes and ketones.2 In
consideration of the current importance and the rapid
development of organocatalytic reactions in practical organic
,3
1
Diels-Alder reactions have been developed to date. Among
such stereoselective processes, the enantioselection is con-
trolled by chiral reagents or catalysts, while the degree of
diastereoselectivity depends mainly on the structure of
substrates. For instance, the Diels-Alder reaction of cyclo-
pentadiene with R,â-unsaturated carbonyl compounds such
as acrolein, methyl vinyl ketone, and methyl acrylate is
known to give the endo cycloadducts predominantly. This
endo selectivity is considered to be a general attribute of
4
synthesis, we have been interested in the possibility of
(
2) (a) Maruoka, K.; Imoto, H.; Yamamoto, H. J. Am. Chem. Soc. 1994,
1
16, 12115. (b) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 4243. (c) K u¨ ndig, E. P.; Saudan, C. M.; Alezra, V.;
Viton, F.; Bernardinelli, G. Angew. Chem., Int. Ed. 2001, 40, 4481. (d)
Cavill, J. L.; Peters, J.-U.; Tomkinson, N. C. O. Chem. Commun. 2003,
728.
(
3) exo-Selective Diels-Alder reactions of acrylic esters and amides:
i) Chiral substrates: (a) Lamy-Schelkens, H.; Ghosez, L. Tetrahedron Lett.
989, 30, 5891. (b) Avenoza, A.; Bueno, M. P.; Cativiela, C.; Mayoral, J.
(
1
(
1) For recent reviews of enantioselective Diels-Alder reactions: (a)
A. Tetrahedron: Asymmetry 1992, 3, 343. (c) Fraile, J. M.; Garc ´ı a, J. I.;
Gracia, D.; Mayoral, J. A.; Pires, E. J. Org. Chem. 1996, 61, 9479. (d)
Kawamura, M.; Kudo, K. Chirality 2002, 14, 727. (ii) Chiral Lewis acids:
(e) Sagasser, I.; Helmchen, G. Tetrahedron Lett. 1998, 39, 261. (f) Desimoni,
G.; Faita, G.; Guala, M.; Pratelli, C. Tetrahedron 2002, 58, 2929. (iii)
Catalytic antibody: (g) Gouverneur, V. E.; Houk, K. N.; de Pascual-Teresa,
B.; Beno, B.; Janda, K. D.; Lerner, R. A. Science 1993, 262, 204. See,
also: (h) Powers, T. S.; Jiang, W.; Su, J.; Wulff, W. D.; Waltermire, B. E.;
Rheingold, A. L. J. Am. Chem. Soc. 1997, 119, 6438.
Evans, D. A.; Johnson, J. S. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
1
999; Vol. 3, p 1177. (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, 1007. (d) Diaz, L. C. J. Braz. Chem.
Soc. 1997, 8, 289. (e) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650.
(
f) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G.
Angew. Chem., Int. Ed. 2002, 41, 1668.
1
0.1021/ol060621i CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/24/2006

developing a hitherto difficult exo-selective asymmetric
5
,6
Diels-Alder reaction using a certain chiral organocatalyst.
Table 1. exo-Selective Diels-Alder Reaction of
Here, we wish to report the realization of such a cycload-
dition reaction catalyzed by chiral binaphthyl-modified
diamine salts (Figure 1).
Cyclopentadiene with R,â-Unsaturated Aldehydes Catalyzed by
Amine-TfOH Saltsa
Figure 1. Binaphthyl-based diamines.
To find an appropriate amine salt catalyst for the exo-
selective Diels-Alder reaction, we first examined the
chemical behavior of N-methylaniline derivatives as second-
ary amines due to their ease of preparation and further
structural modification. In addition, introduction of both
electron-donating (methyl) and electron-withdrawing (phen-
yl) substituents on nitrogen atom is expected to accelerate
the formation and hydrolysis of an iminium salt as a reactive
intermediate, respectively.2 Thus, the Diels-Alder reaction
of cyclopentadiene with cinnamaldehyde was carried out in
the presence of catalytic secondary amine (12 mol %) and
catalytic trifluoromethanesulfonic acid (10 mol %) in dichlo-
romethane at room temperature, and the results are sum-
marized in Table 1. With N-methylaniline catalyst, the
desired exo adduct was obtained as a major product (exo/
endo ) 2.2:1) in 75% yield (entry 1). In contrast, the parent
aniline showed none of the reactivity (entry 2), and use of
N-methylbenzylamine as an aliphatic secondary amine
produced the cycloadducts in only 20% yield with slightly
higher exo selectivity (entry 3). These findings prompted us
to investigate the substituent effect of other secondary amines
with an N-alkylaniline core. Although neither the introduction
of ortho substituents on the aromatic ring of N-methylaniline
nor the use of N,N′-diphenylethylenediamine affected the
diastereoselectivity (entries 4-7), the improved selectivity
was achievable with biphenyldiamine 3 (entry 8). Further-
more, axially chiral diamines 4 and 5 exhibited better exo
selectivity than 3 (entries 9 and 10). Similar high exo
d,5
a
The reaction of cyclopentadiene (3 equiv) with the R,â-unsaturated
aldehyde in CH2Cl2 was carried out in the presence of 12 mol % of amine
and 10 mol % of TfOH. b Isolated yield. c Determined by H NMR.
1
selectivity is also observed in the Diels-Alder reaction
between cyclopentadiene and other R,â-unsaturated alde-
hydes with binaphthyldiamine catalyst 5 (entries 11-13).
With this information, we set out to design enantiopure
binaphthyldiamine catalysts for the exo-selective asymmetric
Diels-Alder reaction. Attempted use of enantiopure (R)-5,
however, resulted in formation of the cycloadduct with low
enantioselectivity in the Diels-Alder reaction of cyclopen-
tadiene with cinnamaldehyde (Table 2, entry 1). We then
screened octahydrobinaphthyldiamine catalysts as novel
binaphthyl-modified chiral diamines, which were readily
prepared as follows (Scheme 1): Axially chiral diamine (R)-
7
6 was converted to diamine (R)-8 in two steps by ethoxy-
carbonylation and subsequent reduction. Careful bromination
of (R)-8 with NBS in THF yielded (R)-9, which was treated
by Suzuki-Miyaura coupling with phenylboronic acid and
(
4) For reviews, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2001, 40, 3726. (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
004, 43, 5138.
5) Chiral amine salt catalyzed enantioselective Diels-Alder reactions:
a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
458. (b) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127, 10504.
c) Kim, K. H.; Lee, S.; Lee, D.-W.; Ko, D.-H.; Ha, D.-C. Tetrahedron
Lett. 2005, 46, 5991. (d) Lemay, M.; Ogilvie, W. W. Org. Lett. 2005, 7,
141, and ref 2b.
2
4
-tert-butylphenylboronic acid to furnish (R)-1 and (R)-2,
(
(
2
(
respectively.
Selected results are summarized in Table 2. Although
octahydrobinaphthyl diamine (R)-8 exhibited lower reactivity
and enantioselectivity (entry 2), the introduction of phenyl
groups at 3,3′-positions of octahydrobinaphthyl moiety
4
(
6) Other organocatalytic Diels-Alder reactions: (a) Riant, O.; Kagan,
H. B. Tetrahedron Lett. 1989, 30, 7403. (b) Thayumanavan, R.; Dhevala-
pally, B.; Sakthivel, K.; Tanaka, F.; Barbas, C. F., III. Terahedron Lett.
2
2
002, 43, 3817. (c) Braddock, D. C.; MacGilp, I. D.; Perry, B. G. Synlett
003, 1121, and ref 2d.
(7) Shi, M.; Wang, C.-J. Chirality 2002, 14, 412.
Org. Lett., Vol. 8, No. 13, 2006
2688

Table 2. exo-Selective Asymmetric Diels-Alder Reaction of
Cyclopentadiene with R,â-Unsaturated Aldehydes Catalyzed by
Chiral Diamine Saltsa
Scheme 1
chiral
entry diamine
conditions % yieldb % eed (config)e
(°C, h) endo
(exo/endo)c exo
R
1
2
3
4
5
6
7
8
9
1
(R)-5 Ph
(R)-8 Ph
rt, 20 99 (9.2/1) 9 (R) 15 (R)
rt, 23
rt, 36
rt, 20
rt, 9
0, 50
0, 55
61 (8.2/1) 38 (S) 27 (R)
90 (5.6/1) 53 (R) 39 (R)
87 (6.5/1) 72 (R) 68 (R)
89 (8.6/1) 79 (R) 71 (R)
80 (9.5/1) 86 (R) 79 (R)
(R)-1 Ph
(R)-2 Ph
(R)-2 Ph
(R)-2 Ph
(R)-2 Ph
(R)-2 Ph
(R)-2 Me
f
f
f,g
f,g,h
f,g,h
93 (11/1)
87 (R) 86 (R)
92 (R) 91 (R)
-20, 160 80 (13/1)
-20, 160 72 (>20/1) 88 (S)
EtO2C -60, 144 90 (5.5/1) 83
0f,g
(R)-2
56
a
Unless otherwise noted, the reaction of cyclopentadiene (3 equiv) with
the R,â-unsaturated aldehyde in CH2Cl2 was carried out in the presence of
with excellent exo- and enantioselectivity (entry 8). This
reaction system was also applicable to other R,â-unsaturated
aldehydes (entries 9 and 10). Unfortunately, however, this
reaction system was only suitable for a combination of R,â-
unsaturated aldehydes and cyclopentadiene. For example, the
reactions of R,â-unsaturated aldehydes with other dienes such
as 1,3-cyclohexadiene and 1,3-pentadiene gave only traces
of cycloadducts.
b
1
2 mol % of chiral diamine and 10 mol % of TfOH. Isolated yield.
c
1
d
Determined by H NMR. Determined by GC analysis using a chiral
capillary column or HPLC analysis using a chiral column. Details are given
e
in the Supporting Information. The absolute configuration at the 2-position
was determined by comparison of the sign of optical rotation with reported
f
g
values. See ref 2b. R,R,R-Trifluorotoluene was used as a solvent. p-
h
TsOH‚H2O was used as an acid. Additional cyclopentadiene (2 equiv)
was added twice after 48 and 96 h.
In summary, we have developed the highly exo-selective
Diels-Alder reaction of cyclopentadiene with R,â-unsatur-
ated aldehydes catalyzed by the binaphthyl-modified diamine
salt. With the novel axially chiral diamine, an asymmetric
variant of this process has also been realized. Further work
aimed at the elucidation of the mechanism and broadening
the scope of this reaction is currently in progress.
enhanced the enantioselectivity (entry 3). In particular,
sterically more congested diamine (R)-2 showedgood levels
of exo- and enantioselectivity (entry 4). We then optimized
the reaction conditions using diamine (R)-2. The use of
R,R,R-trifluorotoluene8 as solvent in place of dichlo-
romethane resulted in faster reaction rate and higher stereo-
selectivities (entry 5). Lowering the reaction temperature also
increased both the exo- and enantioselectivity at the expense
of the reaction rate (entry 6). Among several Brønsted acids,
p-toluenesulfonic acid was found to be more effective for
the reaction than trifluoromethanesulfonic acid (entry 7).
Finally, the reaction could be performed at -20 °C under
the optimized conditions to give the desired exo cycloadduct
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Experimental details
and characterization data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(
8) R,R,R-Trifluorotoluene is known as a useful alternative to dichlo-
romethane; see: Ogawa, A.; Curran, D. P. J. Org. Chem. 1997, 62, 450.
OL060621I
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