Organocatalysis using protonated 1,2-diamino-1,2-diphenylethane for asymmetric Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2005.07.025

Bisammonium salts of mono-N-alkylated chiral 1,2-diamino-1,2-diphenylethane (DPEN) were employed in the catalytic and asymmetric Diels-Alder reaction between cyclopentadiene and crotonaldehyde. The N-3-pentyl diamine·2HCl catalyst shows high endo/exo selectivity and endo-enantioselectivity for the cycloaddition, and this organocatalysis is the first example of the use of a chiral 1,2-diamine to generate an imine intermediate which is activated by an internal ammonium Br?nsted acid for the cycloaddition in a wet solvent.

Full text of DOI:10.1016/j.tetlet.2005.07.025

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5991–5994
Organocatalysis using protonated 1,2-diamino-
1,2-diphenylethane for asymmetric Diels–Alder reaction
Kyoung Hoon Kim, Seil Lee, Dae-Woong Lee, Dong-Hyun Ko and Deok-Chan Ha*
Department of Chemistry, Korea University, Seoul 136-701, Korea
Received 13 June 2005; revised 29 June 2005; accepted 8 July 2005
Available online 25 July 2005
Abstract—Bisammonium salts of mono-N-alkylated chiral 1,2-diamino-1,2-diphenylethane (DPEN) were employed in the catalytic
and asymmetric Diels–Alder reaction between cyclopentadiene and crotonaldehyde. The N-3-pentyl diamineÆ2HCl catalyst shows
high endo/exo selectivity and endo-enantioselectivity for the cycloaddition, and this organocatalysis is the first example of the use
of a chiral 1,2-diamine to generate an imine intermediate which is activated by an internal ammonium Brønsted acid for the cyclo-
addition in a wet solvent.
Ó 2005 Elsevier Ltd. All rights reserved.
Enantioselective catalysis has made an enormous
advance in synthetic chemistry during the last few
decades.1 Recently, methods based on metal-free organic
catalysts have been attracted great attention, due to the
advantages associated with the use of small organic mol-
ecules as chiral catalysts.2 These organic catalysts are
mostly inexpensive, stable under aerobic wet conditions,
and do not cause metal contamination of the reaction
products.
(DPEN, 1) and its derivatives would be able to directly
catalyze the enantioselective Diels–Alder reaction of
a,b-enals through the formation of imine intermediate
2 in which the imine is activated by an internal hydrogen
bonding with the ammonium proton (Eq. 1). Herein, we
disclose that the bisammonium salts of N-monoalkyl-
ated DPEN are good catalysts for the direct asymmetric
Diels–Alder reaction between crotonaldehyde and
cyclopentadiene.
Ph
Ph
Ph
Ph
As one of the most powerful methods for constructing
enantiomerically enriched molecules, chiral Lewis acid
promoted Diels–Alder reactions have been studied with
great success to achieve, in many cases, almost complete
enantioselection.3 Processes activating the chiral Lewis
acids by Brønsted acids4,5 and activating the dienophiles
with chiral Brønsted acids for Diels–Alder reactions6 are
attracting significant attention. Another notable exam-
ple is the use of chiral imidazolidinones and strong
Brønsted acids for the activation of a,b-enals by revers-
ibly forming iminium ion intermediates as reactive
dienophiles for cycloadditions in wet solvents.7
CHO
H2N
NH2 2 HX
NH2
N
1
CH3
H
CHO
wet solvent
3
2
ð1Þ
In an initial screen of the reaction conditions, we found
that the cycloaddition actually proceeded smoothly for
24 h at room temperature in wet solvents. The reaction
was optimized with the use of 5 mol % of 1 in di-
oxane–water (95:5 by volume) in the presence of hydro-
chloric acid acting as a Brønsted acid (Table 1, entry 4).
Solvents having more than 10% (by volume) of water
showed decreased endo/exo selectivity and endo-enantio-
selectivity. With the use of less than 2 equiv of HCl
for 1 equiv of diamine 1, the endo/exo selectivity and
the enantioselectivity of the endo-3 were also deterio-
rated (Table 1, entry 5). The low conversion yield with
1 equiv of HCl for 1 may be due to the formation of a
tight internal hydrogen bonding of mono-protonated
Based on these advances in organic catalysis, we became
interested in the question as to whether the ammonium
salts of the (R,R)-1,2-diamino-1,2-diphenylethane
Keywords: Organocatalysis; Asymmetric Diels–Alder; Cyclopenta-
diene; Aldehydes; Ammonium salts.
*
Corresponding author. Tel.: +82 02 3290 3131; fax: +82 02 3290
3121; e-mail: dechha@korea.ac.kr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.025

5992
K. H. Kim et al. / Tetrahedron Letters 46 (2005) 5991–5994
Table 1. Enantioselective Diels–Alder cycloaddition between cyclopentadiene and (E)-crotonaldehyde catalyzed by bisammonium salts of (R,R)-1,2-
diamino-1,2-diphenylethane
Ph
Ph
5 mol %
CHO
H2N
NH2 2 HX
CH3
CHO
CH3
exo-3 (2R)
1
+
+
CHO
solvent, rt, 24 h
endo-3 (2R)
Entry
HX
Solvent
Yield (%)a,b
endo:exoc
% ee, endo (exo)c
1
2
3
4
5
6
7
8
HCl
HCl
HCl
MeOH–H2O (95:5)
THF–H2O (95:5)
DME–H2O (95:5)
Dioxane–H2O (95:5)
Dioxane–H2O (95:5)
Dioxane–H2O (95:5)
Dioxane–H2O (95:5)
Dioxane–H2O (95:5)
Dioxane–H2O (95:5)
Dioxane–H2O (95:5)
H2O
97
92
98
96
96
46
98
96
61
76
98
2.4:1
3.8:1
2.4:1
4.8:1
2.3:1
2.2:1
4.3:1
3.4:1
1.2:1
1.1:1
3.3:1
56 (46)
72 (26)
62 (25)
79 (31)
75 (23)
65 (15)
77 (30)
54 (22)
47 (30)
31 (28)
77 (34)
HCl
HCld
HCle
HBr
HClO4
p-TsOH
CF3CO2H
9
10
11
CH3(CH2)11C6H4SO3H
a GC conversion yields.
b 0.5 M aldehyde concentration.
c Determined by chiral GC (Chiraldex C-TA column).
d 7.5 mol % HCl used.
e 5 mol % HCl used.
diamine 1 as a result of which the catalytic cycle of the
formation and hydrolysis of the imine intermediate is
slowed down (entry 6).8 Several other strong Brønsted
acids were also tested and a gradual decrease in stereo-
selectivity was observed as the size of the acid increased
(entries 7–9). Closely interacting ion pairs of the ammo-
nium salts, which are not completely dissociated in this
wet solvent, are supposed to affect the stereocontrol in
this cycloaddition. We also tested the capacity of
p-dodecylbenzenesulfonic acid (DBSA) to act both as
a Brønsted acid and a surfactant for this asymmetric
Diels–Alder reaction.9 This 1 (DBSA)2 salt, poorly solu-
ble in wet dioxane, was found to be a good catalyst for
the cycloaddition in water, although the resultant
stereocontrol was less effective than that observed in
the case where HCl was used as a Brønsted acid in wet
dioxane (entry 11).
stable conformation of 5 would provide the enantio-
meric endo-3 (2S) product.
Ph
H
H
H
N
Ph
R
N
H
N
H
H
Ph
RH2N
H
Ph
4
5
The experiments on the steric contribution of the N-
alkyl group of the diamine to the diastereomeric and
enantiomeric control in the Diels–Alder reaction are
summarized in Table 2.10 Increasing the size of the N-
substituted secondary alkyl group from isopropyl (6a)
to 3-pentyl (6c)11 gradually improved the regio- and
enantioselectivity, and maximum stereoselectivity
(endo/exo, 7.8:1; endo 91% ee) was observed with 6c
(Table 2, entries 1–3).12 With longer and more branched
N-alkyl groups, a slight loss of stereocontrol was observed
(entries 4 and 5). Much lower stereoselectivity and yield
resulted from the use of a primary alkyl (6f and 6g) or
phenyl (6h) N-substituent. The N,N-dialkylated di-
amine, 6i having a pyrrolidine ring, showed a level of
stereocontrol almost comparable to that of diamines
having only one secondary alkyl substituent. One meth-
ylene group bonded to the nitrogen in the pyrrolidine
ring of 6i seems to assume a pseudo-equatorial position
with respect to the hydrogen bonded five-membered ring
4, thereby causing the si-face to be subjected to less ste-
ric constraint than expected. The N,N0-dialkylated
derivatives 6j and 6k showed poor reactivity and stereo-
selectivity. These results, together with that observed
for 6f, obviously indicate that this cycloaddition takes
place through imine intermediates, rather than through
With these results in hand, we tried structural modifica-
tions of 1, by attaching an alkyl substituent to one of the
two amino nitrogens. We expected that imine 4, which is
generated in situ from the mono-N-alkylated diamine
and crotonaldehyde, would adapt its (E)-geometry to
avoid the non-bonding interaction between the substrate
olefin and the geminal phenyl group. We also antici-
pated that the neighboring phenyl group would force
the alkyl group, which is attached to the ammonium
nitrogen of 4, to occupy the opposite face of the hydro-
gen bonded five-membered ring to which it is attached.
With this steric arrangement, improved stereocontrol
was expected, since the re-face of dienophile 4 would
be effectively shielded by both the phenyl and N-alkyl
groups, leaving the si-face more favorable for the cyclo-
addition to give endo-3 (2R) as a major product. Cyclo-
addition through another possible intermediate,
diprotonated amino-imine 5, is unlikely since the most

K. H. Kim et al. / Tetrahedron Letters 46 (2005) 5991–5994
5993
Table 2. Enantioselective Diels–Alder cycloaddition catalyzed by bis-ammonium salts of N-alkylated (R,R)-1,2-diamino-1,2-diphenylethane
Ph
Ph
5 mol %
RHN
N R' 2 HCl
R"
CHO
CH3
CHO
CHO
CH3
+
6
+
dioxane-H2O (95:5), rt, 24 h
endo-3 (2R)
exo-3 (2R)
Entry
R
R0,R00
Yield (%)a,b
endo:exoc
% ee, endo (exo)c
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
i-Pr, H (6a)
97
96
97
94
98
65
75
68
98
77
70
94
6.3:1
6.5:1
7.8:1
7.1:1
6.5:1
3.0:1
2.2:1
1.3:1
7.0:1
2.0:1
2.1:1
4.3:1
86 (43)
85 (39)
91 (38)
87 (49)
81 (32)
26 (37)
50 (18)
30 (15)
84 (22)
19 (9)
Cyclohexyl, H (6b)
3-Pentyl, H (6c)
5-Nonyl, H (6d)
2,4-Dimethyl-3-pentyl, H (6e)
1-Decyl, H (6f)
CH2Ph, H (6g)
Ph, H (6h)
–(CH2)4– (6i)
i-Pr, H (6j)
Cyclohexyl, H (6k)
3-Pentyl, H (6c)
9
H
i-Pr
Cyclohexyl
H
10
11
12d
22 (10)
78 (37)
a Isolated yield.
b 0.5 M aldehyde concentration.
c Determined by chiral GC (Chiraldex C-TA column).
d CH3(CH2)11C6H4SO3H (10 mol %) was used in pure water.
the iminium ions formed with the participation of the
secondary amines. This primary amine catalyzed asym-
metric cycloaddition was also tested with 6cÆ(DBSA)2
in pure water. However, in this case, the stereocontrol
was found to be less effective than that observed with
the use of 6cÆ(HCl)2 in wet dioxane (entry 12).
ene-1-carboxaldehyde was not reactive under the reac-
tion conditions used in this study (entries 4 and 5).
In summary, we showed that the bisammonium salt of
mono-N-alkylated chiral 1,2-diamino-1,2-diphenyl-
ethane is an efficient organocatalyst for the asymmetric
Diels–Alder reaction between cyclopentadiene and cro-
tonaldehyde with high endo/exo selectivity and endo-
enantioselectivity. Although the successful application
of this reaction is restricted to the use of b-substituted
a,b-enals as the dienophile, this organocatalysis is the
first example of the use of a chiral 1,2-diamine to gener-
ate an imine intermediate which is activated for the
cycloaddition by an internal ammonium Brønsted acid
in wet solvent.
The scope of the unsaturated aldehyde as the dienophile
for this cycloaddition was briefly probed and the results
are summarized in Table 3. Slight losses of stereocontrol
and reaction yield were observed as the increased size and
the electron-donating ability of the b-substituent of the
dienophile were increased (Table 3, entries 1–3). Meth-
acrolein, an a-substituted a,b-enal, showed exo-selective
cycloaddition with low enantioselectivity, and cyclohex-
Table 3. Diels–Alder cycloaddition catalyzed by bisammonium chloride of 6c
Ph
Ph
R1
R2
CHO
R1
R2
CHO
NH(3-pentyl)
H2N
2 HCl
CHO
+
+
6c (5 mol %)
R2
R1
exo
dioxane-H2O (95:5), rt, 36 h
endo
7
Entry
R1
R2
Yield (%)a
endo:exob
% eeb
endo
exo
1
2
3
4
5
H
H
H
CH3
n-Pr (7a)
Ph (7b)
2-Furyl (7c)
H (7d)
90
75
67
65
4.7:1
9.0:1
8.0:1
1:4.3
—
85 (2R)
78 (2S)
85 (2S)
34 (2R)c
—
18 (2R)
17 (2S)
29 (2S)
30 (2R)
–(CH2CH2CH2CH2)– (7f)
Trace
a Isolated yields.
b Determined by chiral GC (Chiraldex C-TA column).
c Absolute configuration and enantiomeric excess determined by comparison with the known optical rotation after separation of the endo/exo mixture
by silica gel chromatography.13

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K. H. Kim et al. / Tetrahedron Letters 46 (2005) 5991–5994
Natl. Acad. Sci. U.S.A. 2004, 101, 5846; (d) Unni, A. K.;
Acknowledgements
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This work was financially supported by the Center for
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Supplementary data
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Supplementary data associated with this article can be
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˚
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