Asymmetric synthesis of tetrahydropyridines via an organocatalytic one-pot multicomponent Michael/aza-Henry/cyclization triple domino reaction

Article abstract of DOI:10.1021/ol503024d

A low loading of a quinine-derived squaramide efficiently catalyzes the triple-domino Michael/aza-Henry/cyclization reaction between 1,3-dicarbonyl compounds, β-nitroolefins, and aldimines to provide tetrahydropyridines bearing three contiguous stereogeni

Full text of DOI:10.1021/ol503024d

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of Tetrahydropyridines via an Organocatalytic
One-Pot Multicomponent Michael/Aza-Henry/Cyclization Triple
Domino Reaction
Marcus Blumel, Pankaj Chauhan, Robert Hahn, Gerhard Raabe, and Dieter Enders*
̈
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: A low loading of a quinine-derived squaramide
efficiently catalyzes the triple-domino Michael/aza-Henry/
cyclization reaction between 1,3-dicarbonyl compounds, β-
nitroolefins, and aldimines to provide tetrahydropyridines
bearing three contiguous stereogenic centers in good yields,
excellent enantiomeric excesses, and up to high diastereomeric
ratios.
he tetrahydropyridine ring belongs to a widespread
substructure in naturally occurring compounds and some
ring by sequentially employing two different chiral organo-
T
catalysts (Scheme 1).9 We envisaged that a tetrahydropyridine
synthetic bioactive molecules.1 The tetrahydropyridine I is an
aroma compound generated from the Maillard reaction (Figure
1).2 Arecoline II is a nicotinic acid based alkaloid possessing a
Scheme 1. Organocascade Strategies for the Synthesis of
Tetrahydropyridine Derivatives
Figure 1. Selected bioactive tetrahydropyridine derivatives.
ring could be synthesized via a Michael/aza-Henry/cyclization
domino sequence using merely one organocatalyst at lower
catalyst loading without any other additives.
stimulating effect due its agonistic influence on the muscarinic
acetylcholine receptors.3 Betanin III, a plant pigment, is another
natural product containing a tetrahydropyridine unit used as a
food additive.4 The synthetic tetrahydropyridine derivative IV
has shown proinflammatory protein inhibition activity.5 In
addition, these heterocycles also serve as precursor for the
synthesis of valuable piperidine derivatives.6
In the last 10 years, many interesting organocatalytic cascade
sequences have emerged as powerful tools for the synthesis of
valuable carbo- and heterocycles bearing multiple stereogenic
centers in an highly stereoselective fashion.7 Due to the broad
range of bioactivity, the synthesis of tetrahydropyridine
derivatives in a stereoselective manner is extremly useful.
Hence, the application of organocascade sequences has been
successfully extended for those compounds bearing two
stereogenic centers.8 Recently, Sun, Lin, and co-workers were
able generate three stereogenic centers on a tetrahydropyridine
By following Rawal’s10 and others11 as well as our own
findings12 on the squaramide-catalyzed Michael addition of
dicarbonyl compounds on nitroalkenes, we synthesized the
Michael adduct 5a and carried out domino aza-Henry/half-
aminalization reactions between 5a and various imines in the
presence of squaramide A at the onset. The N-tosylimine,
however, did not provide any products, even in the presence of
an additional base catalyst (Table 1, entry 1−5). The desired
product was obtained in the case of N-(p-methoxybenzyl)
(PMB) and N-(p-methoxypenyl) (PMP) imines, although the
yield was not satisfactory (Table 1, entries 6−13). By switching
Received: October 15, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol503024d | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Screening of Various Imines and Conditions for the
Optimization of the Aza-Henry/Condensation Reaction
Sequence
Table 2. Optimization of the Aza-Henry/Cyclization Reaction
Sequence
a
a
catalyst
b
d
loading
3a
time yield
(%)
ee
c
entry solvent
(mol %)
(equiv) (d)
dr
(%)
1
2
toluene
Et2O
5
5
2
2.5
5
33
58
83
69
82
87
54
78
79
60
1.2:1
2.1:1
1.9:1
1.7:1
1.7:1
1.8:1
2.4:1
1.7:1
2.1:1
6.4:1
94
97
97
98
97
98
98
98
98
99
2
3
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5
2
4
c
e
temp
(°C)
yield
(%)
ee
4
10
1
2
0.5
1.5
1.5
1.5
1.5
1.5
1.5
b
d
entry
R
base
dr
(%)
5
2
1
Ts
−25
−25
25
0
0
6
0.5
0.5
0.5
0.5
0.5
2
2
Ts
DBU (20)
7
1.1
1.5
4
3
Ts
DBU (20)
0
8
4
Ts
K2CO3 (50)
morpholine (20)
−25
−25
−25
−25
25
0
9
5
Ts
0
10
10
6
PMP
14
18
0
n.d.
n.d.
n.d.
n.d.
a
Reactions were carried out on a 0.25 mmol scale with the indicated
7
PMP DBU (20)
PMP DBU (20)
PMP K2CO3 (50)
PMB
amount of imine and squaramide catalyst A in 0.2 mL of solvent (c =
1.25 M) for the stated time at −25 °C. Yield of the isolated product
after flash chromatography. Diastereomeric ratio of (4R,5R,6S) to
8
b
9
−25
−25
25
0
c
d
10
11
12
13
14
15
16
17
13
11
41
5
n.d.
n.d.
n.d.
n.d.
n.d.
98
(4R,5R,6R). Determined by HPLC with a chiral stationary phase.
PMB
n.d.
PMB DBU (20)
PMB DBU (25)
Me
−25
25
1.4:1
n.d.
the best conditions were found with 0.5 mol % of A and 2 equiv of
an N-methylimine in CH2Cl2 at −25 °C.
−25
25
79
67
21
0
1.9:1
1:1.1
1:1.3
Me
n.d.
n.d.
With the optimized reaction conditions in hand, we started to
examine the scope of this organocatalytic asymmetric Michael/
aza-Henry/cyclization cascade starting from the Michael
addition of the dicarbonyl compound to the nitroalkene. β-
Nitroolefins bearing various substituents on the aryl ring
provided the corresponding tetrahydropyridines 4a−d in 69−
88% yield and high enantioselectivities. Furthermore, the
nitroalkene substituted with a heteroaromatic ring was also
tolerated under the standard reaction conditions, hence yielding
4e in an excellent yield of 91% with high enantiomeric excess. To
our delight, even an aliphatic nitroalkene provided 4f in 32%
yield with excellent dr of >20:1 and 93% ee. Interestingly, the
thienyl- as well as the cyclohexyl-substituted nitroolefins gave a
higher dr. For the next set of reactions, we varied the substituents
of the 1,3-dicarbonyl compound. Both β-ketoesters tested gave
high yields and enantiomeric excesses of the corresponding
products 4g and 4h. Moreover, 4i was obtained in 89% yield and
high enantiomeric excess by using a phenyl-substituted diketone.
Although β-ketoamides and various cyclic dicarbonyl com-
pounds could be transformed to the corresponding Michael
adducts, they did not react in the second step. Finally, we
employed aldimines with different substituents. As expected, the
nature with regard to steric hindrance of the imine carbon and
the bulkiness of the R4 moiety is crucial for the outcome of the
reaction. Whereas several ortho- and meta-substituted imines did
not react, the para-substituted imines led to the desired
tetrahydropyridines 4j and 4k. Furthermore, different hetero-
cyclic substituted imines, e.g., 2-furanyl and 3-Boc-indolyl, have
proven to be suitable substrates for this transformation (Table 3,
4l,m). Imines bearing an alkyne group also worked well to
provide synthetically interesting 6-ethynyl-substituted N-hetero-
cycle 4n in 62% yield, 1.5:1 dr and 99% ee. The alkyne-
substituted N-(p-methoxybenzyl)imine gave 22% yield of 4o in
excellent dr and enantiomeric excess.
Me
DBU (30)
25
t-Bu
−25
a
Reactions were carried out on a 0.25 mmol scale with 0.5 mmol (2.0
equiv) of imine and 5 mol % of squaramide catalyst A in 0.2 mL of
CH2Cl2 (c = 1.25 M) for 1.5−4 days. Amount of additive given in
mol % in parentheses. Yield of the isolated product after flash
b
c
d
chromatography. Diastereomeric ratio of (4R,5R,6S) to (4R,5R,6R).
e
Determined by HPLC with a chiral stationary phase.
to an N-methylimine, the desired tetrahydropyridine was
obtained in 79% yield, 1.9:1 dr, and 98% ee (Table 1, entry
14). In order to distinguish between beneficial steric or electronic
effects, we also tried the tert-butylimine as substrate (Table 1,
entry 17). The fact that no reaction was observed in this case
suggests that the steric hindrance is the limiting factor for this
reaction step.
With the best imine found, we went on to optimize the general
reaction conditions by first screening different solvents. In
contrast to the enantiomeric excess, which remained constant,
the yield turned out to be strongly dependent on the nature of
the solvent. Among the tested mediums, toluene, diethyl ether,
acetonitrile, and CH2Cl2, the latter turned out to be the best one
(Table 1, entry 14, and Table 2, entries 1−3). Second, we varied
the catalyst loading. Interestingly, the catalyst promotes the
reaction more efficiently at lower loadings. Thus, merely 0.5 mol
% of catalyst A was found to be sufficient to obtain 4a in high
yield of 87% in a slightly prolonged reaction time without any
loss of enantioselectivity (Table 2, entry 6). Lastly, we expanded
the optimization on the amount of imine to determine its impact
on the yield and the selectivity. We found that the diastereomeric
ratio slightly increased by varying the amount, whereas the
overall yield decreased (Table 2, entries 7−10). Consequently,
B
dx.doi.org/10.1021/ol503024d | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Scope of the One-Pot Reaction to Tetrahydropyridines
b
c
d
e
4
R1
R2
R3
R4
R5
time (d)
yield (%)
dr
ee (%)
a
Me
Me
Me
Me
Me
Me
OMe
OEt
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
PMB
1 + 2
1 + 2
1 + 2
1 + 2
1 + 0.5
1 + 3
1 + 2
1 + 2
1 + 2
1 + 2
1 + 2
1 + 2
1 + 2
1 + 4
1 + 4
81
80
69
88
91
32
80
88
89
37
77
78
45
62
22
1.7:1
2.1:1
2.1:1
2.3:1
13.3:1
>20:1
1.5:1
1.5:1
1.1:1
1.5:1
1.7:1
1.2:1
98 (99)
97 (99)
99
b
c
d
e
f
p-MeC6H4
p-FC6H4
o-ClC6H4
2-thienyl
Cy
98
98 (96)
93
g
h
Ph
98
Ph
99
f
g
i
Ph
99
j
Me
Me
Me
Me
Me
Me
Ph
p-BrC6H4
99
99
k
l
Ph
p-MeC6H4
2-furanyl
g
Ph
96
m
Ph
2-(N-Boc-indolyl)
PhCC
1:1.4
99
99
95
h
n
o
Ph
1.5:1
h
Ph
PhCC
>20:1
a
Reactions were carried out with 0.25 mmol of 1 and 2 combined with 0.5 mol % of A in 0.2 mL (c = 1.25 M) of CH2Cl2. After 1 day, 0.5 mmol (2.0
equiv) of 4 was added and the reaction was continued at −25 °C for the indicated time. Reaction time of first + second step. Yield of the isolated
product after flash chromatography. Diastereomeric ratio of (4R,5R,6S) to (4R,5R,6R). Enantiomeric excess of the main diastereomer determined
by HPLC with a chiral stationary phase. Values for the recrystallized samples are given in parentheses. A small amount of the (4R,5S,6S) isomer was
also obtained. Enantiomeric excess of the (4R,5R,6R) diastereomer. Reactions were carried out with 0.5 mmol of 1 and 2 combined with 0.5 mol
b
c
d
e
f
g
h
% A in 0.4 mL of CH2Cl2 (c = 1.25 M) and 1.0 mmol of 3 after 1 day.
Finally, we demonstrated that a domino reaction proceeds
smoothly without any loss of efficiency when all the substrates as
well as the catalyst A were added together at the beginning
(Scheme 2). Furthermore, a gram-scale reaction was successfully
configuration was assigned by the X-ray crystal structure (Figure
2).13,14
Scheme 2. Synthesis of Tetrahydropyridines under Domino
Conditions
Figure 2. X-ray crystal structure of 4a.14
performed without much alternation of the product yield and
stereoselectivity, which shows the practical and preparative utility
of this domino process (Scheme 3).
The relative configuration was determined by NOE contacts
between the concerning hydrogen atoms, whereas the absolute
In conclusion, we have developed a squaramide-catalyzed
asymmetric multicomponent Michael/aza-Henry/cyclization
triple domino reaction of 1,3-dicarbonyl compounds, β-nitro-
olefins, and imines to provide potentially bioactive 1,4,5,6-
tetrahydropyridines in very good yields and up to high diastereo-
and excellent enantioselectivities. Additionally, this protocol
required only one catalyst at an extremely low catalyst loading of
0.5 mol %. The new procedure can be successfully scaled up to
gram amounts without losing the reaction efficiency. Further
applications of squaramide-catalyzed organocascade sequences
for the synthesis of valuable chiral heterocycles are under
investigation, and the results will be reported in due course.
Scheme 3. Gram-Scale Synthesis of Tetrahydropyridines
C
dx.doi.org/10.1021/ol503024d | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Oh, J. S.; Lee, Y. S.; Song, C. E. Chem. Commun. 2011, 47, 9621−9623.
(b) Bae, H. Y.; Some, S.; Lee, J. H.; Kim, J.-Y.; Song, M. J.; Lee, S.;
Zhang, Y. J.; Song, C. E. Adv. Synth. Catal. 2011, 353, 3196−3202.
(c) Wang, Y. F.; Chen, R.-X.; Wang, K.; Zhang, B.-B.; Lib, Z.-B.; Xu, D.-
Q. Green Chem. 2012, 14, 893−895. (d) Chen, D.-F.; Wu, P.-Y.; Gong,
L.-J. Org. Lett. 2013, 15, 3958−3961.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data including
copies of the NMR and HPLC spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
(12) (a) Hahn, R.; Raabe, G.; Enders, D. Org. Lett. 2014, 16, 3636−
3639. (b) Chauhan, P.; Urbanietz, G.; Raabe, G.; Enders, D.
Chem.Commun. 2014, 50, 6853−6855. (c) Urbanietz, G.; Atodiresei,
I.; Enders, D. Synthesis 2014, 46, 1261−1269. (d) Chauhan, P.; Mahajan,
S.; Loh, C. C. J.; Raabe, G.; Enders, D. Org. Lett. 2014, 16, 2954−2957.
(e) Loh, C. C. J.; Chauhan, P.; Hack, D.; Lehmann, C.; Enders, D. Adv.
Synth. Catal. 2014, 356, 3181−3186.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: enders@rwth-aachen.de. Fax: (+49)-241-809-2127.
Notes
The authors declare no competing financial interest.
(13) The complete determination of the relative configuration can be
found in the Supporting Information.
ACKNOWLEDGMENTS
(14) CCDC 1021665. The crystallographic data of compound 4a are
available free of charge at http://www.ccdc.cam.ac.
■
We gratefully thank the European Research Council for funding
this project with an ERC Advanced Grant 320493 “DOMI-
NOCAT” and BASF SE for the donation of chemicals.
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