Enantioselective organocatalytic domino synthesis of tetrahydropyridin-2- ols

Article abstract of DOI:10.1039/c2cc35644a

The asymmetric synthesis of tetrahydropyridin-2-ols from enals and enaminones is described. The organocatalytic domino reaction involves a Michael addition-hemiaminalization sequence using the Jorgensen-Hayashi catalyst. Dehydration or oxidation leads to the corresponding 1,4-dihydro-pyridines or 3,4-dihydropyridin-2-ones in a one-pot fashion. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc35644a

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COMMUNICATION
Enantioselective organocatalytic domino synthesis
of tetrahydropyridin-2-olsw
Jie-Ping Wan,ab Charles C. J. Loh,a Fangfang Panc and Dieter Enders*a
Received 3rd August 2012, Accepted 22nd August 2012
DOI: 10.1039/c2cc35644a
The asymmetric synthesis of tetrahydropyridin-2-ols from enals
and enaminones is described. The organocatalytic domino
reaction involves a Michael addition–hemiaminalization sequence
using the Jørgensen–Hayashi catalyst. Dehydration or oxidation
leads to the corresponding 1,4-dihydro-pyridines or 3,4-dihydro-
pyridin-2-ones in a one-pot fashion.
as diarylprolinol silyl ethers in the reaction of enals with
1,3-dinucleophiles turned out to be particularly practical in the
synthesis of heterocycles. For example, naphthoquinone fused
3,4-dihydropyran-2-ols 3 could be efficiently assembled using
2-hydroxy-1,4-naphthoquinone 2 as a C/O 1,3-dinucleophile in
the domino reaction with enals 1 (eqn (1), Scheme 1).13 On the
other hand, the enamides 4 as analogous C/N-1,3-dinucleophiles
have been successfully employed in similar transformations to
produce the corresponding enantioenriched N-acyl THPs 5
(eqn (2), Scheme 1).11 Recently, Kanger and co-workers
reported their results on the direct enantioselective synthesis
of 1,4-DHPs 7 via the reaction of N-alkyl enamines of type 6
and enals in the presence of a diarylprolinol silyl ether catalyst
(eqn (3), Scheme 1).14
Among the various subareas of the rapidly growing field of
organocatalysis, Lewis base catalysis employing secondary
amines, such as proline, diarylprolinol silyl ethers or imidazo-
lidinones, turned out to be a powerful tool for the asymmetric
synthesis of a great variety of highly enantioenriched organic
compounds.1 In particular, the intermediate iminium salts
formed from a,b-unsaturated aldehydes and enantiopure
secondary amines constitute a prominent activation mode
enabling asymmetric Michael additions.2 As a consequence,
such conjugate additions are often used as the first stereogenic
step in organocatalytic domino reactions leading to more
complex structures.3 Epoxides,4 dihydropyridines (DHPs),5
oxazolidinones,6 cyclohexanes,7 tetrahydropyridines (THPs)8 and
dihydrobenzofurans,9 etc., to name a few, are typical examples
known to be easily accessed via iminium activation-based
enantioselective domino reactions.
To the best of our knowledge, the asymmetric synthesis of
tetrahydropyridin-2-ols 9 bearing N-aryl, 5-aroyl and 2-hydroxyl
substituents and use of enaminones as C/N dinucleophiles in the
reaction with enals have not been reported so far. We now wish to
describe our results on the secondary amine-catalyzed diastereo-
and enantioselective synthesis of tetrahydropyridin-2-ols 9 via
domino reactions of enals 1 and N-aryl enaminones 8. The
products could be used as precursors for the synthesis of related
1,4,5,6-Tetrahydropyridines (THPs) are important heterocyclic
structures and valuable building blocks in organic synthesis, which
can be easily converted to the corresponding piperidines, DHPs and
pyridines via simple reduction or oxidation reactions. More versatile
transformations were possible when conventional functional groups
such as hydroxyl, allyl, etc. are present.10,11 The synthesis of THPs
via direct asymmetric catalysis is of particular significance since it
provides rapid access to enantioenriched THPs as well as to many
other derivatives such as 1,4-DHPs12 and piperidines. In previous
studies, the iminium activation mode via secondary amines such
a Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany.
E-mail: enders@rwth-aachen.de; Fax: +49-241-809-2127
b College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang 330022, P.R. China
c Institute of Inorganic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany
w Electronic supplementary information (ESI) available: Full experi-
mental procedure, characterization data of all products, 1H, 13C NMR
spectra, HPLC chromatograms as well as crystal structure of 9a.
CCDC 893719. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2cc35644a
Scheme 1 Amine catalyzed enantioselective syntheses via domino
Michael–hemiacetalization and hemiaminalization reactions.
c
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Chem. Commun., 2012, 48, 10049–10051 10049

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heterocyclic derivatives, such as 1,4-DHPs and 3,4-dihydro-
pyridin-2(1H)-ones (eqn (4), Scheme 1).
target product 9a in terms of yield as well as enantioselectivity.
Either lower values were obtained or no reaction took place in the
entries using I–III and V as catalysts (entries 1–5, Table 1). Other
parameters of the reaction were then investigated by using IV as
catalyst (entries 5–22, Table 1). The best results were obtained
when EtOAc or mixture of EtOAc–Et2O (2/1 mL) was
employed at 0 1C and with 10 mol% benzoic acid as an
additive (entries 16 and 19, Table 1).
As an initial attempt, the reaction of cinnamaldehyde (1a)
and enaminone (8a) was selected as a model to probe the
reaction. Different chiral amine catalysts I–V were first
screened in this model reaction by employing chloroform as
solvent at rt. After stirring at rt for 4 days in the presence of
catalysts I–V with a 20 mol% loading, respectively, it was
found that IV was the best amine catalyst for the formation of the
During the examination on the application scope we firstly
attempted to employ the mixed solvent system (entry 19,
Table 1) considering both the product yield and enantio-
selectivity. When performed in the scale of 0.6 mmol, product
9a could be produced with good results (entry 1, Table 2).
However, lower enantioselectivity was obtained when different
substrates such as methoxyphenyl substituted enaminones or
enals were used. We then employed EtOAc as the sole solvent
in the new entries using different substrates. Typical results are
given in Table 2. Good tolerance on substrates was demon-
strated by variation of the enaminones (R2 and R3) as well as
enals (R1). An electron donating group in the benzoyl frag-
ment (R2) and the p-cyclohexyl group in the aryl amine
fragment (R3) of the enaminones were favorable in this
protocol providing the corresponding products with excellent
enantioselectivity (9b–9f), while an electron withdrawing
group in the benzoyl fragment of 9 was not favorable. It is
notable that a 4-fluoro functionalized enaminone gave a better
er value in mixed EtOAc–Et2O than in pure EtOAc (9k).
Table 1 Optimization on reaction conditionsa
Table 2 Scope of the tetrahydropyridin-2-ol synthesisa
T
Yieldb
Additive (%)
erd
(%)
Entry Catal. (1C) Solvent
drc
1
2
3
4
5
6
7
8
9
10
I
II
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
Toluene
Et2O
—
—
—
—
—
—
—
—
—
—
—
—
26
55
Trace
33
39
56
—
—
—
—
—
III
IV
V
IV
IV
IV
IV
IV
3 : 1 59 : 41
2.3 : 1 85 : 15
—
2.5 : 1 84 : 16
5 : 1 88 : 12
6.5 : 1 86 : 14
—
>
—
Yieldb
(%)
MeOH
THF
—
85 : 15
9
R1
R2
H
R3
Ph
drc
erd
20
10 : 1
3 : 1
>
9ae Ph
9b Ph
9c 4-ClC6H4
9d 4-MeOC6H4
9e Ph
60
57
60
6.0 : 1 >99 : 1
3.4 : 1 96 : 4
4.1 : 1 96 : 4
4.1 : 1 98 : 2
4.0 : 1 97 : 3
10 : 1 >99 : 1
11
12
IV
IV
rt
rt
MeCN
EtOAc
—
—
28
22
67 : 33
91 : 9
4-MeO Ph
4-MeO 4-ClC6H4
H
4-MeO 4-MeC6H4
4-MeO 2-Chloro-
pyridin-5-yl
10 : 1
f
13e
14
15f
16
17
18
IV
IV
IV
IV
IV
IV
rt
rt
rt
0
0
0
EtOAc
EtOAc
EtOAc
EtOAc
Et2O
PhCO2H 32
PhCO2H 59
PhCO2H 61
PhCO2H 38
PhCO2H 59
10 : 1 89 : 11
5 : 1 90 : 10
5.5 : 1 77 : 23
3 : 1
5 : 1
5.8 : 1 96 : 4
5.7 : 1 97 : 3
3.6 : 1 89 : 11
4-c-HexylC6H4 20
72
44
9f Ph
99 : 1
937
9g Ph
9h Ph
9i Ph
9j 4-ClC6H4
9ke Ph
9l Ph
9m 2-MeOC6H4
9n 4-MeOC6H4
9o 2-MeOC6H4 4-Me
H
4-c-HexylC6H4 44
4-MeO 4-ClC6H4 42
4-MeO 4-c-HexylC6H4 57
3.4 : 1 92 : 8
7.8 : 1 91 : 9
5.9 : 1 90 : 10
2.5 : 1 89 : 11
3.5 : 1 89 : 11
5.4 : 1 87 : 13
2.7 : 1 86 : 14
6.0 : 1 85 : 15
2.4 : 1 85 : 15
Et2O–EtOAc PhCO2H 64
(4 : 1)
Et2O–EtOAc PhCO2H 75
(2 : 1)
Et2O–EtOAc PhCO2H 43
(1 : 4)
Et2O–EtOAc PhCO2H 38
(2 : 1)
4-MeO Ph
4-F
H
H
H
63
30
48
52
22
33
19
IV
IV
IV
IV
0
0
0
0
Ph
4-MeC6H4
Ph
Ph
20
21g
22h
7 : 1
89 : 11
4-ClC6H4
a
Et2O–EtOAc PhCO2H 52
(2 : 1)
5.2 : 1 97 : 3
General reaction conditions: enaminone 8 (0.6 mmol) and cinna-
maldehyde 1 (0.9 mmol), catalyst IV (0.12 mmol) and PhCO2H
b
a
(0.06 mmol) in EtOAc (6 mL), stirred at 0 1C for 4 days. Yield of
two isolated diastereoisomeric products. The dr was calculated based
on isolated masses of the major (trans) and the minor (cis) diaster-
General reactions conditions: 1a (0.45 mmol), 8a (0.3 mmol), and
chiral amine catalyst (0.06 mmol) in 3 mL solvent, stirred at rt for
c
b
days. Yield of isolated product. Diastereomeric ratios (dr)
c
4
was calculated based on the masses of the isolated diastereomers.
d
eomers. er of the major product measured by HPLC on a chiral
e
stationary phase. The syntheses of 9a and 9k were performed in a
d
e
Measured by HPLC on a chiral stationary phase. 5 mol% PhCO2H.
f
mixture of EtOAc–Et2O (4/2 mL). c-Hexyl = cyclohexyl.
f
g
15 mol% PhCO2H. 10 mol% catalyst IV. 15 mol% catalyst IV.
h
c
10050 Chem. Commun., 2012, 48, 10049–10051
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Notes and references
1 (a) B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc.,
2000, 122, 2395; (b) B. List, J. Am. Chem. Soc., 2000, 122, 9336;
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H. Gotoh, T. Hayashi and M. Shoji, Angew. Chem., 2005, 117, 4284
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G. Dickmeiss, H. Jiang, Ł. Albrecht and K. A. Jørgensen, Acc.
Chem. Res., 2012, 45, 248.
2 For reviews on iminium activation using chiral amine catalysts,
see: (a) A. Erkkila, I. Majander and P. M. Pihko, Chem. Rev.,
2007, 107, 5416; (b) G. Lelais and D. W. C. MacMillan,
Aldrichimica Acta, 2006, 39, 79.
3 For selected reviews on organocatalyzed enantioselective domino
reactions, see: (a) D. Enders, C. Grondal and M. R. M. Huttl,
Angew. Chem., 2007, 119, 1590 (Angew. Chem., Int. Ed., 2007,
46, 1570); (b) Ł. Albrecht, H. Jiang and K. A. Jørgensen, Angew.
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(c) D. Bonne, Y. Coquerel, T. Constantieux and J. Rodriguez,
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Synth. Catal., 2012, 354, 237; (e) C. de Graaff, E. Ruijter and
R. V. A. Orru, Chem. Soc. Rev., 2012, 41, 3969.
Scheme 2 One-pot enantioselective synthesis of 1,4-dihydropyridines
and 3,4-dihydropyridin-2(1H)-ones.
No evident impact of the substituent on the enal was observed,
but aliphatic enals such as (E)-but-2-enal were not proper
reaction partners as sensitive mixed diastereoisomeric products
were obtained.
4 M. Marigo, J. Franzen, T. B. Poulsen, W. Zhuang and
K. A. Jørgensen, J. Am. Chem. Soc., 2005, 127, 6964.
5 P. T. Franke, R. L. Johansen, S. Bertelsen and K. A. Jørgensen,
Chem.–Asian J., 2008, 3, 216.
6 M. Marigo, T. Schulte, J. Franzen and K. A. Jørgensen, J. Am.
Chem. Soc., 2005, 127, 15710.
7 (a) Y. Wang, L.-G. Han, Y.-L. Zhao, S. Yang, P.-F. Xu and
D. J. Dixon, Angew. Chem., 2009, 121, 10018 (Angew. Chem., Int.
Ed., 2009, 48, 9834); (b) J. L. G. Ruano, V. Marcos, J. A. Suanzes,
L. Marzo and J. Aleman, Chem.–Eur. J., 2009, 15, 6576.
8 (a) S. Tong, D.-X. Wang, L. Zhao, J.-P. Zhu and M.-X. Wang,
Angew. Chem., 2012, 124, 4493 (Angew. Chem., Int. Ed., 2012,
51, 4417); (b) L. Hu, A. Ma, Y. Zhou and D. Ma, Adv. Synth.
Catal., 2012, 354, 991.
9 Ł. Albrecht, L. K. Ransborg, V. Lauridsen, M. Overgaard,
T. Zweifel and K. A. Jørgensen, Angew. Chem., 2011, 123, 12704
(Angew. Chem., Int. Ed., 2011, 50, 12496).
10 V. Sridharan, S. Maiti and J. C. Menendez, Chem.–Eur. J., 2009,
15, 4565.
11 L. Zhu, H. Xie, H. Li, J. Wang, X. Yu and W. Wang, Chem.–Eur.
J., 2008, 14, 6333.
12 For an early auxiliary controlled asymmetric synthesis of enan-
tioenriched 1,4-DHPs, see: D. Enders, S. Muller and A. S. Demir,
Tetrahedron Lett., 1988, 29, 6437.
The relative and absolute configuration of the products was
assigned by X-ray diffraction on a single crystal of 9a (see ESIw
for the ORTEP structure)15 and by comparing the optical
rotation data of the 1,4-DHP product 10a with analogous
compounds reported in the literature (see Scheme 2).14,16
Taking advantage of the unique reactivity of products 9, we
further explored the possibility of establishing a one-pot
enantioselective synthesis of other related heterocycles. In-
deed, after the prior formation of 9a with our protocol,
Na2SO4–TMSCl and PCC were employed to effect a dehydration
and oxidation, respectively. Under these conditions we were
glad to find that the corresponding 1,4-DHP 10a and the
3,4-dihydropyridinone 11a could be obtained both in good
enantiomeric excesses (Scheme 2). These results demonstrate
the tunable and versatile utility of our one-pot protocol in the
asymmetric synthesis of related optically active heterocycles.
In conclusion, we have developed an enantioselective organo-
catalytic domino reaction for the synthesis of 1,4,5,6-tetrahydro-
pyridin-2-ols from enals and enaminones employing a Michael–
hemiaminalization sequence. In addition, our protocol opens a one-
pot entry to the corresponding 1,4-dihydropyridines via dehydra-
tion and 3,4-dihydropyridin-2-ones after oxidation, respectively.
We thank BASF SE and the former Degussa AG for the
donation of chemicals. J.-P. Wan is grateful for a supported
postdoctoral fellowship from the Chinesisch-Deutsches Zentrum
fur Wissenschaftsforderung.
13 M. Rueping, E. Sugiono and E. Merino, Angew. Chem., 2008,
120, 3089 (Angew. Chem., Int. Ed., 2008, 47, 3046).
14 A. Noole, M. Borissova, M. Lopp and T. Kanger, J. Org. Chem.,
2011, 76, 1538.
15 CCDC 893719w.
16 (a) K. Yoshida, T. Inokuma, K. Takasu and Y. Takemoto, Synlett,
2010, 2865; (b) J. Jiang, J. Yu, X.-X. Sun, Q.-Q. Rao and
L.-Z. Gong, Angew. Chem., 2008, 120, 2492 (Angew. Chem., Int.
Ed., 2008, 47, 2458).
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 10049–10051 10051