Proline-mediated enantioselective construction of tetrahydropyridines via a cascade Mannich-type/intramolecular cyclization reaction

Article abstract of DOI:10.1002/adsc.200800253

A highly diastereo- and enantioselective synthesis of 2,3-disubstituted tetrahydropyridines was accomplished via a proline-mediated cascade Mannich-type/intramolecular cyclization reaction from preformed N-PMP (p-methoxyphenyl) aldimines and inexpensive aqueous tetrahydro-2H-pyran-2,6- diol.

Full text of DOI:10.1002/adsc.200800253

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DOI: 10.1002/adsc.200800253
Proline-Mediated Enantioselective Construction of Tetrahydro-
pyridines via a Cascade Mannich-Type/Intramolecular Cyclization
Reaction
Rong-Gang Han,a Yao Wang,a Yu-Ye Li,a and Peng-Fei Xua,*
a
State Key Laboratory of Applied OrganicChemistry, College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou 730000, Peopleꢀs Republicof China
Fax : (+86)-931-891-5557; e-mail: xupf@lzu.edu.cn
Received: April 28, 2008; Published online: June 23, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A highly diastereo- and enantioselective
synthesis of 2,3-disubstituted tetrahydropyridines
was accomplished via a proline-mediated cascade
Mannich-type/intramolecular cyclization reaction
from preformed N-PMP (p-methoxyphenyl) aldi-
mines and inexpensive aqueous tetrahydro-2H-
pyran-2,6-diol.
by organic molecules in the presence of water. Ac-
tually, Barbas et al.[7] assessed the impact of the pres-
ence of water on the Mannich-type reaction profile
and found that this reaction could tolerate a signifi-
cant amount of water in the reaction mixture without
compromising the enantiomeric excess obtained for
the Mannich product. Other groups[8] also reported
that some Mannich-type reactions could proceed
enantioselectively in the presence of water or under
aqueous conditions. Thus, it is expected that commer-
cially available, aqueous tetrahydro-2H-pyran-2,6-diol
could be employed directly in this cascade reaction.
Herein, we report the highly diastereo- and enantiose-
lective synthesis of 2,3-disubstituted tetrahydropyri-
Keywords: cascade reactions; imines; Mannich-type
reaction; organocatalysis; tetrahydropyridines
The functionalized tetrahydropyridine and piperidine dines in the presence of water from N-PMP aldimines
ring systems are not only important starting materials and tetrahydro-2H-pyran-2,6-diol.
for numerous biologically active compounds, but are
First, we studied the reaction of N-PMP aldimine
also important structural building blocks of many nat- 1a preformed from p-nitrobenzaldehyde and aqueous
ural products and pharmaceuticals.[1] Therefore, a con- tetrahydro-2H-pyran-2,6-diol 2, using l-proline 4 as
tinuous interest exists in the development of new an organocatalyst (Table 1, entry 1). To our delight,
methodologies for the asymmetricsynthesis of this
the reaction afforded the desired tetrahydropyridine
classes of six-membered nitrogen-containing heterocy- 3a in 74% yield with high diastereoselectivity
cles.[2,3] The development of cascade or tandem reac- (dr>25:1) and enantioselectivity (98% ee). Encour-
tions[4] is a recent new direction in organocatalysis, aged by this result, we performed a catalyst screen
which allows the rapid construction of structurally with various chiral amines 5–8 and found that all the
complex molecules from simple and readily available catalysts except 8 could catalyze the reaction effi-
starting materials in only one operation, thereby de- ciently to furnish the desired product 3a in good
creasing the formation of waste products and increas- yields. Among them, 4-hydroxyproline 6 was as effec-
ing the economy of the process. For example, Hayashi tive as proline (entry 6) and siloxyproline 7, even pro-
et al. successfully used aqueous tetrahydro-2H-pyran- ducing slightly higher enantioselectivity (entry 7). Be-
2,6-diol in a highly enantioselective synthesis of opti- cause proline is inexpensive and both enantiomers are
cally active cyclohexane derivatives[5a] and substituted readily available, we examined several solvents with
tetrahydropyrans[5b] in domino processes.
We anticipated that pentane-1,5-dial, a synthetically optimal for this cascade process. We also tried to de-
useful five-carbon unit generated from aqueous tetra- crease the catalyst loading(entry 11), but this led to a
l-proline as the catalyst and found that DMSO was
AHCTREUNG
hydro-2H-pyran-2,6-diol under equilibrium condi- longer reaction time and a slight reduction in chemi-
tions, might be utilized for the formation of optically cal yield due to the lability of the imine in the pres-
active tetrahydropyridines by a cascade Mannich- ence of water. Thus, we preferred to perform this cas-
type[6]/intramolecular cyclization reaction catalyzed cade reaction with 20 mol% l-proline as the catalyst.
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Adv. Synth. Catal. 2008, 350, 1474 – 1478

Proline-Mediated Enantioselective Construction of Tetrahydropyridines
Table 1. Effect of catalyst and solvent in the reaction of N-PMP aldimine and aqueous tetrahydro-2H-pyran-2,6-diol.[a]
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Entry
Catalyst
Solvent
Time [h]
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
4
5
6
7
8
4
4
4
4
4
4
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
DMF
NMP
dioxane
toluene
DMSO
3.5
5
4
4
12
4
7
6
12
12
8
74
59
72
73
n.r.
72
64
62
40
n.r.
71
>25:1
>25:1
>25:1
>25:1
–
>25:1
>25:1
>25:1
>25:1
–
98
73
98
99
–
96
98
96
96
–
5
6
7[e]
8
9
10
11[f]
>25:1
98
[a]
Unless otherwise specified, all reactions were carried out with 1a (0.5 mmol), 2 (50% in water,1.5 mmol), and organocata-
lyst (20 mol%) in the indicated solvent (5.0 mL) at room temperature.
[b]
[c]
[d]
[e]
[f]
Isolated yield after flash chromatography.
1
Determined by H NMR analysis of crude products.
Determined by chiral-phase HPLC analysis (OD column).
Reaction was performed at 08C.
With 10 mol% of catalyst loading.
Using these optimized reaction conditions, the gen-
erality of the reaction was investigated by employing
several preformed N-PMP aldimines. The results are
summarized in Table 2. The reaction proceeded very
fast with both electron-deficient and electron-rich ary-
limines, while the yield was a little lower with elec-
tron-rich aryl and alkyl derivatives (entries 12, 14 and
15), presumably due to partial hydrolysis of the
imines. In the cases of imines preformed from 2-sub- described in the literature[9] (see Supporting Informa-
stituted benzaldehydes, the reactions were rather slow tion). This absolute configuration is in accordance
and the yields were comparatively poor, perhaps be- with that expected from an l-proline-mediated Man-
cause of the steric hindrance (entries 4, 7 and 16). nich-type reaction.
The diastereoselectivity of the reaction was essentially
Based on the absolute stereochemistry of 9 and
not affected and good to excellent enantioselectivity previous experience with Mannich reactions involving
was obtained regardless of the substituents on the the catalyst l-proline, the following stepwise cascade
imine moiety.
Mannich-type/intramolecular cyclization mechanism
To determine the absolute configuration of the cor- was proposed to account for the stereochemical out-
responding product of this cascade Mannich-type/in- come of the reaction. As shown in Scheme 1, pen-
tramolecular cyclization reaction, the compound 3m tane-1,5-dial, generated from tetrahydro-2H-pyran-
was converted into piperidine 9 by reduction with 2,6-diol under equilibrium conditions, would react
NaBH4 and subsequent hydrogenation under the cat- with l-proline 4 to form enamine 10. Enamine 10
alysis of palladium/carbon without compromising the would react with preformed N-PMP aldimine to give
enantioselectivity [Eq. (1)]. The absolute configura- 11 via a Mannich-type reaction, followed by hemiami-
tion of the compound 9 was determined to be (2S,3S) nal formation to provide intermediate piperidine 13
by comparing its [a]D value and NMR data with those with regeneration of proline 4. Under acidic condi-
Adv. Synth. Catal. 2008, 350, 1474 – 1478
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Rong-Gang Han et al.
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Table 2. Organocatalytic reaction of aqueous tetrahydro-2H-pyran-2,6-diol with preformed N-PMP aldimines for the forma-
tion of optically active tetrahydropyridines.[a]
Entry
R
Product
Time [h]
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
7
8
4-NO2C6H4
3-NO2C6H4
4-CNC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
4-BrC6H4
2-FC6H4
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3.5
3.5
3.5
24
5
5
24
5
5
5
5
6
74
65
63
51
61
61
39
55
61
60
54
43
56
21
<10
<10
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
19:1
98
98
98
94
94
92
95
94
>99
96
91
85
92
69
n.d.
n.d.
9
10
11
12
13
14
15
16
3-FC6H4
2-naphthyl
4-MeC6H4
Ph
(E)-PhCH2CH
n-C3H7
5
5
6
24
n.d.
n.d.
2-NO2C6H4
[a]
The reactions were carried out with 1 (0.5 mmol), 2 (50% in water,1.5 mmol), and l-proline (20 mol%) in DMSO
(5.0 mL) at room temperature.
[b]
[c]
[d]
Isolated yield after flash chromatography.
1
Determined by H NMR analysis of crude products.
Determined by chiral-phase HPLC analysis (OD column).
Scheme 1. Proposed mechanism for the cascade reaction.
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Proline-Mediated Enantioselective Construction of Tetrahydropyridines
COMMUNICATIONS
[2] For recent reviews on the stereoselective synthesis of pi-
peridine derivatives, see: a) M. P. G. Buffat, Tetrahedron
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e) P. D. Bailey, P. A. Millwood, P. D. Smith, Chem.
Commun. 1998, 633.
tions, the unstable intermediate 13 undergoes a dehy-
dration reaction to afford the final optically active tet-
rahydropyridine 3.
In summary, we have developed an enantioselective
syntheticmethod for substituted tetrahydropyridines
via a proline-mediated cascade Mannich-type/intra-
molecular cyclization, in which easily prepared N-
PMP aldimines and inexpensive aqueous tetrahydro-
2H-pyran-2,6-diol are employed as the starting mate-
rials. It is a noteworthy advantage of the organocata-
lyst that the Mannich-type reaction proceeds efficient-
ly with excellent diastereo- and enantioselectivity in
the presence of water. This strategy will easily provide
access to structurally diverse N-PMP piperidines. We
are currently applying this methodology to the syn-
thesis of small natural alkaloids.
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Experimental Section
General Experimental Procedure
Glutaraldehyde solution
2
(50% in water, 0.26 mL,
1.5 mmol) was added to a mixture of preformed N-PMP al-
dimine 1 (0.5 mmol) and l-proline (11.5 mg, 0.1 mmol) in
DMSO (5.0 mL) under an argon atmosphere at room tem-
perature. The reaction mixture was stirred at room tempera-
ture until the imine was consumed as monitored by TLC.
The reaction was worked up by addition of saturated NH4Cl
solution and extracted with EtOAc. The combined organic
fractions were washed with water and brine, dried over an-
hydrous Na2SO4, and concentrated under reduced pressure.
The residue was purified by flash column chromatography
on silica gel (PE/EtOAc) to afford the corresponding tetra-
hydropyridine 3.
Supporting Information
Detailed experimental procedures, NMR spectra data for
new compounds, and HPLC analyses are available in the
Supporting Information.
Acknowledgements
We are grateful for the financial support of the National Nat-
ural Science Foundation of China (NSFC, 20772051,
20572039), the Program for NCET-05–0880 and the Doctoral
Funds from Chinese Ministry of Education of P. R. China.
[5] a) Y. Hayashi, T. Okano, S. Aratake, D. Hazelard,
Angew. Chem. 2007, 119, 5010; Angew. Chem. Int. Ed.
2007, 46, 4922; b) D. Hazelard, H. Ishikawa, D. Hashi-
zume, H. Koshino, Y. Hayashi, Org. Lett. 2008, 10, 1445.
[6] For the reviews of enantioselective organocatalyzed
Mannich reaction, see: a) A. Córdova, Acc. Chem. Res.
2004, 37, 102; b) M. M. B. Marques, Angew. Chem. 2006,
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e) M. Shibasaki, N. Yoshikawa, Chem. Rev. 2002, 102,
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