Assembly of 4-substituted 3-nitro-1,2,3,4-tetrahydropyridines via organocatalytic Michael addition

Article abstract of DOI:10.1002/adsc.201100903

An organocatalytic Michael addition of protected 2-amino-1-nitroethanes to α,β-unsaturated aldehydes followed by treatment with TFA afforded 4-substituted 3-nitro-1,2,3,4-tetrahydropyridines with good diastereoselectivity and excellent enantioselectivity.

Full text of DOI:10.1002/adsc.201100903

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DOI: 10.1002/adsc.201100903
Assembly of 4-Substituted 3-Nitro-1,2,3,4-tetrahydropyridines via
Organocatalytic Michael Addition
Lele Huo,a Anqi Ma,b Yihua Zhang,a,* and Dawei Mab,*
a
Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, Peopleꢀs Republic of China
State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese
b
Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: zyhtgd@sohu.com or madw@mail.sioc.ac.cn
Received: November 21, 2011; Published online: March 27, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100903.
Abstract: An organocatalytic Michael addition of
protected 2-amino-1-nitroethanes to a,b-unsaturat-
ed aldehydes followed by treatment with TFA af-
forded 4-substituted 3-nitro-1,2,3,4-tetrahydropyri-
dines with good diastereoselectivity and excellent
enantioselectivity. Good yields were observed in the
case of b-aryl-substituted a,b-unsaturated aldehydes
as the substrates, while moderate yields were ob-
tained when b-alkyl-substituted a,b-unsaturated al-
dehydes were used.
we would have a short approach for preparing substi-
tuted piperidines 4 through hydrogenation of 5.[7]
As depicted in Table 1, we started our investiga-
tions by treating cinnamaldehyde 6a with N-acetyl-2-
amino-1-nitroethane 7a according to the known pro-
cedure.[6b] It was found that under the catalysis of
10 mol% 9 and 20 mol% PhCO2H the reaction was
complete within 12 h at 08C in methanol to afford
a cyclic hemiaminal, which was directly treated with
TFA to provided 5a with 85% yield, about 9:1 diaste-
reoselectivity and 94% ee (entry 1). Changing the sol-
vent to toluene, DMF, THF and CH3CN gave similar
stereoselectivity but with lower yields (entries 2–5).
When chloroform and dichloromethanee were used,
the enantioselectivity could be slightly improved (en-
tries 6 and 7). Switching the additive to acetic acid
failed to give a better result (entry 8). Further experi-
ments revealed that a similar result could be obtained
Keywords: asymmetric catalysis; Michael addition;
organocatalysis; substituted piperidine; a,b-unsatu-
rated aldehydes
The 4-substituted 3-aminopiperidines 4 and related
heterocycles are valuable building blocks for assem-
bling bioactive molecules. For examples, they have
been employed for synthesizing dipeptidyl peptidase
IV inhibitors 1[1] and 2,[2] and anti-infective agent 3[3]
(Scheme 1). The existing asymmetric methods for pre-
paring these intermediates usually required about 10
steps from commercially available starting materials
and the overall yields were usually not satisfactory.[1–4]
Thus, the development of more efficient approaches
for assembling 4-substituted 3-aminopiperidines 4 and
their synthetic equivalents is highly desirable.
Recently, we reported that protected 2-amino-1-ni-
troethenes 8 are suitable acceptors for organocatalytic
Michael additions.[5] We envisioned that their hydro-
genation products, protected 2-amino-1-nitroethanes
7, might serve as special Michael donors to afford 4-
substituted
3-nitro-1,2,3,4-tetrahydropyridines
5
through addition to a,b-unsaturated aldehydes[6] and
subsequent condensative cyclization. If this were so,
Scheme 1. Structures of bioactive 4-subtsituted 3-aminopi-
peridines and our retrosynthetic analysis.
Adv. Synth. Catal. 2012, 354, 991 – 994
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Table 1. Screening of reaction conditions for the formation
of 5a from cinnamaldehyde 6a and nitroalkane 7a.[a]
Table 2. Synthesis of 4-substituted 3-nitro-1,2,3,4-tetrahydro-
pyridines 5 from a,b-unsaturated aldehydes 6 and N-pro-
tected 2-amino-1-nitroethanes 7.[a]
Entry Product
Yield [%][b] dr[c]
ee [%][d]
1
80
91:9
96
Entry Additive Solvent
t
Yield
dr[c] ee
[%][d]
[h] [%][b]
2
3
4
5
6
7
8
5c: R=4-MeOC6H4 72
5d: R=2-O2NC6H4 72
5e: R=4-O2NC6H4 64
86:14 93
93:7 94
89:11 99
1
2
3
4
5
6
7
8
9e
PhCO2H MeOH 12 85
PhCO2H toluene 15 77
89:11 94
88:12 95
88:12 94
89:11 95
85:15 95
88:12 96
89:11 96
88:12 94
87:13 95
PhCO2H DMF
PhCO2H THF
28 73
17 77
5f: R=2-BrC6H4
5g: R=4-BrC6H4
5h: R=4-FC6H4
5i: R=2-Furyl
71
78
75
83
>99:1 96
87:13
87:13
96:4
95
94
99
PhCO2H CH3CN 10 69
PhCO2H CHCl3
PhCO2H CH2Cl2
5
6
7
73
77
73
AcOH
CH2Cl2
PhCO2H CH2Cl2 11 77
9
79
88:12 95
[a]
Reaction conditions: 6a (0.2 mmol), 7a (0.3 mmol), 9
(0.02 mmol), 20 mol% additive, solvent (0.3 mL), 08C;
then TFA.
Isolated yield for 2 steps.
Determined by HPLC.
Determined by chiral-phase HPLC analysis of 5a.
5 mol% 9 and 10 mol% PhCO2H were used.
[b]
[c]
[d]
[e]
10[e]
77
91:9
95
11
43
60
87:13
87:13
94
87
12[f]
if the catalytic loading was reduced to 5 mol%, al-
though a prolonged reaction time was required.
Based on these observations, we decided to use
PhCO2H as the additive and dichloromethane as the
solvent in further studies.
13
64
73
89:11 92
88:12 86
14f
The established optimized conditions were found to
be applicable for a number of a,b-unsaturated alde-
hydes and protected 2-amino-1-nitroethanes, as sum-
marized in Table 2. For b-aryl-substituted a,b-unsatu-
rated aldehydes, their electronic nature seemed to
have little influence on the reaction process because
the substrates with both electron-donating and elec-
tron-withdrawing groups worked well, providing tetra-
hydropyridines 5b–5i with good yields and stereose-
lectivities (entries 1–8). The functional groups in the
aromatic ring would allow further transformations to
generate increasingly diverse 4-substituted 3-nitro-
1,2,3,4-tetrahydropyridines or their derivatives.
Changing the N-protecting group from acetyl to Boc
was possible, as evident from the fact that tetrahydro-
pyridine 5j was obtained in 79% yield from the corre-
sponding a,b-unsaturated aldehyde (entry 9). To our
delight, using the enantiomer of 9 as the catalyst, the
2,4,5-trifluorophenyl-substituted product 5k was iso-
lated in 77% yield, 91:9 dr and 95% ee (entry 10),
which could serve as a promising intermediate to syn-
thesize dipeptidyl peptidase IV inhibitor 2.[2] When b-
15
43
96:4
98
16
50
88:12 93
[a]
Reaction conditions:
6
(0.2 mmol), 7 (0.3 mmol), 9
(0.02 mmol for entries 1–10; 0.04 mmol for entries 11–
16), 20 mol% additive (for entries 1–10 only), CH2Cl2
(0.3 mL), 08C; then TFA.
[b]
[c]
[d]
[e]
[f]
Isolated yield for 2 steps.
Determined by HPLC.
Determined by chiral phase HPLC analysis.
The enantiomer of 9 was used as the catalyst.
Reaction was carried out in methanol.
alkyl substituted a,b-unsaturated aldehydes were uti- 16). In this case introducing an additive was found to
lized, the Michael addition became sluggish and only be useless. Switching the solvent from dichlorome-
moderate yields were observed (entries 11, 13, 15 and thane to methanol provided improved yields, but with
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Adv. Synth. Catal. 2012, 354, 991 – 994

Assembly of 4-Substituted 3-Nitro-1,2,3,4-tetrahydropyridines via Organocatalytic Michael Addition
terms of overall yield and synthetic steps is eviden-
t.[4a,d]
In summary, we have developed a new method for
preparing 4-substituted 3-nitro-1,2,3,4-tetrahydropyri-
dines, which relies on an organocatalytic Michael ad-
dition of protected 2-amino-1-nitroethanes into a,b-
unsaturated aldehydes and subsequent transforma-
tions. The products could be converted into substitut-
ed piperidinones and piperidines via simple opera-
tions, as demonstrated by the quick assembly of di-
peptidyl peptidase IV inhibitor 1 and 4-ethyl 3-amino-
piperidine 4l. This result not only extends the scope
of organocatalytic Michael additions of nitroalkanes
to a,b-unsaturated aldehydes, but also gives addition-
al examples for illustrating the usage of organocata-
lytic reactions in preparing pharmaceutically impor-
tant compounds.
Scheme 2. Formal synthesis of dipeptidyl peptidase IV inhib-
itor 1.
slightly decreased enantioselectivity (compare en- Experimental Section
tries 11–14). When 2-substituted aryl or b-isopropyl-
substituted a,b-unsaturated aldehydes were em- General Procedure for Synthesis of 4-Substituted 3-
ployed, the diastereoselectivity could be enhanced Nitro-1,2,3,4-tetrahydropyridines
upto 93:7 to 99:1 (entries 3, 5 and 15), indicating the
To a suspension of catalyst (10 mol%), 2-nitroethylaceta-
influence of steric hindrance for the stereochemical
mide (0.3 mmol) and benzoic acid (20 mol%) in dichlorome-
thane (0.3 mL) was added a, b-unsaturated aldehyde
(0.2 mmol) at 08C. The reaction mixture was stirred for 1 h
outcome. The absolute configuration of these prod-
ucts was assigned based on previous studies.[6]
In order to further demonstrate the utilities of the
present method, we conducted the Michael addition
of a,b-unsaturated aldehyde 6k with Boc-protected 2-
amino-1-nitroethane 7b to give the corresponding
cyclic hemiaminal, which was oxidized with PDC to
provide lactam 10 in 63% yield (Scheme 2). After
separation by column chromatography, the pure trans-
isomer was treated with TFA to remove the Boc-pro-
tecting group, which delivered lactam 11 with 95%
yield and 99.8% ee. This product has been utilized for
the large-scale preparation of dipeptidyl peptidase IV
inhibitor 1 that has been selected as a drug candidate
for treatment of type 2 diabetes mellitus.[1] Notewor-
thy is that in previous syntheses this intermediate was
assembled through a 6-step sequence from an asym-
metric Michael adduct and this protocol is clearly
comparable with Merckꢀs procedure.[1]
at 08C and then allowed to warm to room temperature. The
stirring was continued until a, b-unsaturated aldehyde was
consumed (monitored by TLC). The solution was diluted to
2 mL volume with dichloromethane and trifluoroacetic acid
(0.4 mmol) was added, then the reaction mixture was stirred
for another 3 h. The reaction was quenched by the addition
of saturated NaHCO3 solution. The water phase was extract-
ed two times with dichloromethane, and the combined or-
ganic layers were dried over Na2SO4 and concentrated. Pu-
rification by flash column chromatography (silica gel,
hexane/isopropanol) afforded the product. The trans/cis
ratio (dr) was determined by HPLC of the crude mixture,
the enantiomeric excess (ee) of each pure isomer was deter-
mined by HPLC on a chiral phase.
Acknowledgements
Additionally, 4-ethyl 3-aminopiperidine 4l, which
has been employed for preparing anti-infective agent
3,[3] was obtained from product 5l via hydrogenation
and subsequent deprotection (Scheme 3). The superi-
ority of this procedure over the previous studies in
The authors are grateful to the Ministry of Science and Tech-
nology (grant 2009ZX09501-00), the Chinese Academy of
Sciences and the National Natural Science Foundation of
China (grants 20632050 and 20921091) for financial support.
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