Chiral bis-pyridinium salts as novel stereoselective catalysts for the metal-free diels-alder cycloaddition of α,β-unsaturated aldehydes

Article abstract of DOI:10.1055/s-0030-1260462

The synthesis of enantiomerically pure C₂-symmetric bis-pyridinium salts was realized through a simple condensation of 2-pyridyl-carboxyaldehydes with a chiral diamine. The catalytic properties of such novel compounds were preliminarily studied

Full text of DOI:10.1055/s-0030-1260462

1
926
PAPER
Chiral Bis-pyridinium Salts as Novel Stereoselective Catalysts for the
Metal-Free Diels–Alder Cycloaddition of a,b-Unsaturated Aldehydes
M
A
etal-Free Stereos
n
elective
D
ie
d
ls–Alder
C
yc
r
loadditio
e
n
a Genoni, Maurizio Benaglia,* Alessandra Puglisi, Sergio Rossi
Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, via Golgi 19, 20133 Milano, Italy
Fax +39(02)50314159; E-mail: maurizio.benaglia@unimi.it
Received 21 March 2011
1
1
However, of the reactions studied, only a few examples
of hetero-Diels–Alder reactions were reported to be cata-
lyzed by phosphoric acids or Taddol-type derivatives;
Abstract: The synthesis of enantiomerically pure C -symmetric
bis-pyridinium salts was realized through a simple condensation of
2
12
13
2
-pyridyl-carboxyaldehydes with a chiral diamine. The catalytic
properties of such novel compounds were preliminarily studied and furthermore, to the best of our knowledge, no example of
the trifluoracetate salts of chiral bis-imines of 2-picolinaldehydes hydrogen-bond-activation of substrates for Diels–Alder
cycloadditions has been reported.14
derived from 1,1¢-binaphthyl-2,2¢-diamine were shown to catalyze
the Diels–Alder reaction between cyclopentadiene and a,b-unsatur-
We have recently demonstrated that trifluoroacetate salts
ated aldehydes. Modest exo stereoselectivities and enantioselectiv-
of enantiomerically pure bis-amines may be used to cata-
lyze the stereoselective Diels–Alder cycloaddition of cy-
clopentadiene to cinnamaldehyde and crotonaldehyde
with good exo stereoselectivity and enantioselectivities up
to 71%.15
ities of up to 55% were obtained.
Key words: chiral imines, Diels–Alder reaction, pyridinium salt,
enantioselective catalysis, hydrogen bonding activation
The development of novel methodologies for the prepara- Because of our interest in developing novel metal-free
tion of enantiomerically pure compounds is a very active chiral catalysts for hydrogen-bond-promoted reactions,16
topic of great interest for several fields, such as agrochem- we decided to investigate the use of enantiomerically pure
icals, flavor and aroma chemicals, pharmaceuticals, and bis-pyridinium salts derived from picolinic aldehyde as
1
specialty materials. A fundamental reaction that allows catalysts for the Diels–Alder reaction between cyclopen-
C–C bonds to be built stereoselectively is the Diels–Alder tadiene and a,b-unsaturated aldehydes. We wish to report
reaction, which enables the preparation of stereochemi- here the results of our preliminary studies in the field.
2
cally well-defined polyfunctional derivatives.
In our study, we wanted to obtain chiral organocatalysts
In the last few years, great attention has been devoted to by simple reaction of an inexpensive, commercially avail-
the exploration of new catalytic methodologies that in- able, enantiopure material, and to keep the amount of re-
3
volve the use of organocatalysts. In this context, the use quired manipulation to a minimum. Indeed, several
of ‘metal-free’ chiral catalysts that are able to promote derivatives were synthesized in a single-step procedure by
highly stereoselective cycloaddition reactions has offered reaction of a range of enantiomerically pure diamines
a novel, complimentary, powerful approach that has (1,1¢-binaphthyl-2,2¢-diamine, 1,2-diamino cyclohexane,
opened the way to new, valuable, chiral intermediates.4a or 1,2-diphenyl ethylendiamine) with 2-picolinic alde-
Lelais and MacMillan established that both Diels–Alder hyde (compounds 1, 2, 6, and 7) or 2-picolinic acid (com-
reactions and 1,3-dipolar cycloadditions can be catalyzed pounds 3, 4, 8, and 9). For comparison, bis-imine 5,
using chiral amino acid derived imidazolidinones as cata- derived from 3-pyridinecarboxyaldehyde, was also pre-
lysts, and that these catalysts were able to promote the pared (Figure 1).
generation of an iminium ion in situ from a carbonyl com-
pound.
Preliminary studies on the catalytic properties of the syn-
thesized compounds were performed. The trifluoroacetate
4
b
However, the search for alternative modes of activation is salts of compounds 1–9 were prepared and tested as or-
still very active. It has been recently recognized that the ganic catalysts in the enantioselective Diels–Alder reac-
use of hydrogen bonding to activate a suitably functional- tion between cyclopentadiene and cinnamaldehyde
ized substrate may represent a viable alternative to tradi- (Scheme 1).
tional methodology that relies upon Lewis acid catalysis.5
Among the range of chiral compounds capable of donat-
ing one or more hydrogen bonds and, consequently, able
catalyst
Ph
(10 mol%)
CHO
+
Ph
CHO
Ph
+
6
to catalyze stereoselective reactions, phosphoric acids,
7
8
9
CHO
diols, thiourea derivatives, more recently squaramides
1
0
and, less often, carboxylic acids, have been widely used.
Scheme 1 Stereoselective organocatalyzed Diels–Alder reaction
SYNTHESIS 2011, No. 12, pp 1926–1929
x
x.
x
x
.
2
0
1
1
In a typical experimental procedure, the catalysts were
prepared by treating the chiral bis-pyridine derivative in
Advanced online publication: 13.05.2011
DOI: 10.1055/s-0030-1260462; Art ID: C00511SS
Georg Thieme Verlag Stuttgart · New York
©

PAPER
Metal-Free Stereoselective Diels–Alder Cycloaddition
1927
N
N
N
R
N
N
N
N
N
N
H
N
N
N
O
O
H
N
N
N
R
N
3
4
R = H
R = Me
1
2
5
N
O
N
N
O
O
H
N
N
N
N
N
N
NH
NH
NH
NH
N
N
H
N
O
6
7
8
9
Figure 1 Novel chiral organocatalysts for stereoselective Diels–Alder cycloaddition
dichloromethane with the required amount of acid and re- From this preliminary investigation, bis-imines emerged
moving the solvent after 15 minutes of stirring at 25 °C; as the catalysts of choice; these were able to promote the
1
7
the salt was used without any further purification. To a cycloaddition with higher chemical yields than the corre-
stirred solution of the catalyst (0.1 equiv) in a suitable sol- sponding bis-amines (Table 1, entries 1 vs. 2 and 6 vs. 7).
vent (see Table 1 and Table 2) under an inert atmosphere, Chiral bis-imines of 2-pyridine carboxyaldehyde 1, de-
aldehyde (1 equiv) was added; after five minutes, cyclo- rived from binaphthyl diamine, performed better than the
pentadiene (5 equiv) was added and the reaction mixture corresponding bis-amines 2, leading to the cycloadduct
was allowed to stir. The reaction mixture was evaporated product in quantitative yield and 55% enantioselectivity
under reduced pressure and analyzed by NMR. The yield for the exo isomer, which is higher than the value obtained
and diastereoisomeric ratio were then confirmed by ana- with catalyst 2. It is noteworthy that the use of chiral bis-
lyzing the isolated product after flash chromatography.
picolinamides, under the present experimental conditions,
was completely ineffective. Bis-imine 5, obtained from 3-
pyridine carboxyaldheyde, catalyzed the reaction in lower
chemical and stereochemical yield. Derivatives of 1,1¢-bi-
naphthyl-2,2¢-diamine were therefore selected for further
optimization studies.
Table 1 Diels–Alder Reaction Catalyzed by Compounds 1–9
Entry
Catalyst
Yield
exo/endob ee exo
ee endo
a
c
(%)c
(
10 mol%) (%)
(%)
55
25
–
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
9
>99
60:40
70:30
–
21
n.d.
–
A selection of enantiomerically pure bis-imines were pre-
pared by reaction of 1,1¢-binaphthyl-2,2¢-diamine with a
range of substituted 2-picolinic aldehydes (compounds
70
n.r.
n.r.
70
1
0–12, Figure 2), and the enantiomerically pure bis-imine
–
–
–
13, derived from 2-quinoline carboxyaldehyde, was also
successfully synthesized. The catalytic activity of the new
chiral organocatalysts was then investigated (Table 2, en-
tries 1–5).
50:50
60:40
65:35
–
41
25
21
–
11
11
n.d.
–
47
From the data collected in Table 2 it is clear that a substit-
uent in the 6-position of the pyridine ring does not signif-
icantly affect the stereoselectivity of the process. Almost
no diastereoselectivity was observed and the enantiose-
lectivities were generally lower than that obtained with
compound 1.
33
n.r.
n.r.
9
–
–
–
a
1
Reaction was run at 25 °C for 72 h; the yield was determined by H
NMR analysis of the crude reaction mixture and confirmed after silica
gel flash column purification (n.r. = no reaction).
With the best performing catalyst 1, attempts were made
b
c
1
Determined by H NMR analysis and confirmed by HPLC analysis. to improve the stereoselectivity by adjusting the experi-
Determined by HPLC analysis with a chiral stationary phase on the
mental conditions and by changing the reaction solvent.
corresponding alcohol (n.d. = not determined).
Synthesis 2011, No. 12, 1926–1929 © Thieme Stuttgart · New York

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A. Genoni et al.
PAPER
Protic acids other than trifluoroacetic acid were em-
ployed, but no improvement in either the chemical or ste-
reochemical yield was observed (Table 2, entry 6).18
Changing the solvent also did not lead to any significant
improvement. As expected, best results were obtained in
non-polar and non-coordinating solvents, such as hexane
or toluene, where the activation of the substrate by the cat-
alyst through hydrogen bonding should work better; how-
ever, modest stereoselectivities were obtained even in
these cases.19
R
N
N
N
N
N
N
N
N
R
1
1
1
R = H
R = Me
R = Br
12
0
1
In summary, enantiomerically pure metal-free catalysts
for the Diels–Alder reaction have been easily prepared by
mixing commercially available chiral diamines and pyri-
dine carboxyaldehyde. The trifluoroacetate salt of chiral
bis-imine of 2-picolinaldehyde, derived from 1,1¢-binaph-
thyl-2,2¢-diamine, was able to catalyze the Diels–Alder
reaction between cyclopentadiene and cinnamaldehyde;
modest diastereoselectivities and enantioselectivity of up
to 55% were observed. While the stereoselection of the
process is still unsatisfactory and several issues still need
to be addressed, we believe the present work may open
new perspectives towards the development of organocat-
alyzed Diels–Alder cycloaddition through hydrogen-
bond-activation of reaction substrates.
N
N
N
N
1
3
Figure 2 Binaphthyl diamine-derived organocatalysts for the
Diels–Alder reaction
Table 2 Diels–Alder Reaction Catalyzed by Compounds 1 and 10–
13
Synthesis of Catalyst; General Procedure
To a solution of chiral diamine (10 mmol) in anhydrous toluene (20
mL), aromatic aldehyde (20.2 mmol) was added. The mixture was
stirred in the presence of 4 Å molecular sieves for 40–72 h at
Entry Catalyst Solvent
Yield
exo/endob ee exo ee endo
a
c
(%)c
21
23
35
15
19
11
21
14
15
16
12
(
%)
(%)
55
45
21
33
21
45
41
40
43
37
39
1
10 °C. The reaction mixture was cooled to r.t., filtered and the sol-
1
2
3
4
1
10
11
12
13
1
CHCl3
CHCl3
CHCl3
>99
53
71
39
91
87
73
95
93
71
51
60:40
52:48
55:45
55:45
58:42
61:39
62:38
51:49
48:52
47:53
55:45
vent was evaporated under vacuum to give the corresponding
imines in yields >90%. The bis-imine may be crystallized from eth-
anol.
Catalyst 1
1
CHCl3
H NMR (200 MHz, CDCl ): d = 8.53 (m, 2 H), 8.43 (s, 2 H), 8.07
3
(
d, J = 8.7 Hz, 2 H), 7.99 (d, J = 8.2 Hz, 2 H), 7.63 (t, J = 6.0 Hz,
5
CHCl3
2
H), 7.47–7.50 (m, 4 H), 7.44 (t, J = 6.0 Hz, 2 H), 7.29–7.32 (m,
6d
4 H), 7.17 (d, J = 8.7 Hz, 2 H).
CHCl3
1
3
C NMR (50 MHz, CDCl ): d = 162.5, 155.4, 150.6, 148.8, 137.6,
3
7e
8
1
CH Cl
2
2
132.9, 130.3, 129.1, 127.8, 127.6, 127.1, 126.3, 126.2, 121.6, 119.9,
18.2.
1
1
hexane
toluene
THF
Diels–Alder Reaction; General Procedure
9
1
The catalysts were prepared by treating the diamine in anhydrous
CH Cl (0.5 mL) with the required amount of acid and removing the
1
0
1
2
2
solvent after 15 min stirring at 25 °C; the salt was used without any
further purification. To a stirring solution of catalyst (0.03 mmol) in
11
1
MeCN
CHCl (0.3 mL) under an inert atmosphere, aldehyde (0.3 mmol)
a
1
3
Reaction was run at 25 °C for 72 h; the yield was determined by H
was added. After 5 min, cyclopentadiene (1.5 mmol) was added and
the reaction mixture was allowed to stir for 72 h at 25 °C. The reac-
tion mixture was evaporated under reduced pressure and analyzed
by NMR. The yield and diastereoisomeric ratio were then con-
firmed with the pure isolated product after flash chromatography on
a short silica gel column (EtOAc–hexanes). The enantiomeric ex-
cess was determined by HPLC on the alcohol obtained by NaBH4-
mediated reduction of the cycloadducts (for exo isomer: Chiralpak
OJ-H column; hexane–isopropanol, 7:3; flow rate 0.8 mL/min; l =
NMR analysis of the crude reaction mixture and confirmed after silica
gel flash column purification.
Determined by H NMR analysis and confirmed by HPLC analysis.
b
c
1
Determined by HPLC analysis on a chiral stationary phase on the
corresponding alcohol.
d
AcOH was used.
Reaction performed in 1,2-dichloroethane afforded similar results.
e
2
25 nm; t
= 38.7 min, t
= 51.8 min).
minor
major
Synthesis 2011, No. 12, 1926–1929 © Thieme Stuttgart · New York

PAPER
Metal-Free Stereoselective Diels–Alder Cycloaddition
1929
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Synthesis 2011, No. 12, 1926–1929 © Thieme Stuttgart · New York