Fully diastereoselective synthesis of polysubstituted, functionalized piperidines and decahydroquinolines based on multicomponent reactions catalyzed by cerium(IV) ammonium nitrate

Article abstract of DOI:10.1002/chem.201402607

The cerium(IV) ammonium nitrate (CAN)-catalyzed, three-component reaction between primary amines, β-dicarbonyl compounds, and α,β- unsaturated aldehydes in ethanol heated to reflux, constitutes a general, one-pot synthesis of 1,4-dihydropyridines. Their reduction with sodium triacetoxyborohydride furnished piperidine derivatives bearing up to five substituents with full diastereoselectivity in a hitherto inaccessible stereochemical arrangement. The reaction proceeded with no significant loss of enantiomeric purity under mild reduction conditions that are compatible with several functional groups that are normally sensitive to reduction. Octahydroquinolin-5-one derivatives, which were prepared by a modified version of the initial multicomponent reaction, were not suitable substrates for the sodium triacetoxyborohydride mediated reduction, but they were transformed into the corresponding decahydroquinolines, including a precursor of the amphibian alkaloid pumiliotoxin C, by catalytic hydrogenation under a variety of conditions.

Full text of DOI:10.1002/chem.201402607

DOI: 10.1002/chem.201402607
Full Paper
&
Heterocycles
Fully Diastereoselective Synthesis of Polysubstituted,
Functionalized Piperidines and Decahydroquinolines Based on
Multicomponent Reactions Catalyzed by Cerium(IV) Ammonium
Nitrate
Padmakar A. Suryavanshi,[a] Vellaisamy Sridharan,[a, b] Swarupananda Maiti,[a, c] and
J. Carlos Menꢀndez*[a]
Abstract: The cerium(IV) ammonium nitrate (CAN)-catalyzed,
three-component reaction between primary amines, b-dicar-
bonyl compounds, and a,b-unsaturated aldehydes in etha-
nol heated to reflux, constitutes a general, one-pot synthesis
of 1,4-dihydropyridines. Their reduction with sodium triace-
toxyborohydride furnished piperidine derivatives bearing up
to five substituents with full diastereoselectivity in a hitherto
inaccessible stereochemical arrangement. The reaction pro-
ceeded with no significant loss of enantiomeric purity under
mild reduction conditions that are compatible with several
functional groups that are normally sensitive to reduction.
Octahydroquinolin-5-one derivatives, which were prepared
by a modified version of the initial multicomponent reaction,
were not suitable substrates for the sodium triacetoxyboro-
hydride mediated reduction, but they were transformed into
the corresponding decahydroquinolines, including a precur-
sor of the amphibian alkaloid pumiliotoxin C, by catalytic hy-
drogenation under a variety of conditions.
Introduction
Suitably functionalized piperidine derivatives are one of the
most common building blocks in the biosynthesis of natural
products; indeed, it has been estimated that about 50% of all
known alkaloids contain piperidine substructures.[1] Many bio-
active alkaloids (Figure 1) are derivatives of piperidine itself, in-
cluding pseudoconhydrine, sedamine, solenopsin A, deoxopro-
sopinine a- and b-conhydrine, and methylanabasine. Perhaps
the most famous piperidine alkaloid is coniine, which acts as
a neuromuscular blocker and can be isolated from hemlock
(Conium maculatum), a plant that has been known as a poison
since antiquity and was used in ancient Greece to execute con-
demned prisoners, including the philosopher Socrates in 399
B.C. There are also a large number of bioactive synthetic piper-
Figure 1. Selected natural and unnatural bioactive piperidine derivatives.
idine derivatives, many of which are drugs employed in thera-
peutics. Representative examples include paroxetine,[2]
a member of the selective serotonin reuptake inhibitor (SSRI)
class of antidepressant drugs, and ethylphenidate,[3] a psychos-
timulant drug used for the treatment of attention-deficit hy-
peractivity disorder (ADHD) and postural orthostatic tachycar-
dia syndrome. Pipradrol and desoxypipradrol[4] are employed
as stimulants that act as norepinephrine-dopamine reuptake
inhibitors (NDRI). Other piperidine derivatives with broad ther-
apeutic use include pethidine (meperidine),[5] an opioid analge-
sic drug, and risperidone[6] and haloperidol,[7] two potent anti-
psychotic drugs used for the treatment of schizophrenia that
act as a dopamine inverse agonists.
[a] Dr. P. A. Suryavanshi, Dr. V. Sridharan, Dr. S. Maiti, Prof. J. C. Menꢀndez
Departmento de Quꢁmica Orgꢂnica y Farmacꢀutica
Facultad de Farmacia, Universidad Complutense
Plaza de Ramꢃn y Cajal sn, 28040 Madrid (Spain)
Fax: (+34)91-3941822
E-mail: josecm@farm.ucm.es
[b] Dr. V. Sridharan
Department of Chemistry
School of Chemical and Biotechnology, SASTRA University
Thanjavur 613401, Tamil Nadu (India)
[c] Dr. S. Maiti
Current address: Development Laboratory
Fresenius Kabi Oncology Ltd.
Kalyani, Nadia, West Bengal (India)
Decahydroquinolines are fully saturated nitrogen heterocy-
cles that can be viewed as cyclohexane-fused piperidines; such
compounds often have potent pharmacological activities, par-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402607.
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ticularly as nicotinic receptor antagonists.[8] Furthermore, the
decahydroquinoline system is the key structural fragment of
a large family of bioactive alkaloids[9] present in the skin of
neotropical dendrobatid frogs used by South America aborigi-
nes as a dart poison; such alkaloids apparently arise from alka-
loid-containing formicine ants, which form part of the diet of
the frog.[10] Representative members of this family of bioactive
natural products include pumiliotoxin C, also known as cis-dec-
ahydroquinoline 195a, and lepadin B (Figure 2).
Scheme 1. Literature precedent for the reduction of Hantzsch dihydropyri-
dines.
In this paper, we describe a new approach to piperidine syn-
thesis that is far more general than previous protocols and in-
volves the two-step synthesis of polysubstituted piperidine de-
rivatives from readily available, simple starting materials via b-
enamino ester intermediates. Interestingly, the relative configu-
ration of the final products is different from those accessible
by previously known routes. We also describe the application
of this protocol to the synthesis of decahydroquinolines relat-
ed to the amphibian alkaloid pumiliotoxin C.
Figure 2. Representative decahydroquinoline alkaloids.
Because of their importance, many methodologies have
been developed for the synthesis of substituted piperidines.[11]
These methods allow access to a variety of substitution pat-
terns, including 2-substituted,[12] 2,3-disubstituted,[13] 2,5-disub-
stituted,[14] 2,6-disubstituted,[15] 3,4-disubstituted,[16] 2,3,6-trisub-
stituted,[17] and 2,4,5-trisubstituted[18] piperidine derivatives.
Polysubstituted piperidines have also been obtained by several
routes,[19] although their preparation cannot be regarded as
a solved problem and many substitution patterns and stereo-
chemical arrangements are not readily accessible by known
methods. In terms of synthetic efficiency, the ideal method
would be one involving the formation of several bonds in
a single operation.[20] Although this may be achieved by ring
expansion, i.e., aziridine- and azetidine-to-piperidine domino
transformations,[21] multicomponent reactions (MCRs) starting
from simple starting materials would be more practical. How-
ever, there is not much precedent for the assembly of piperi-
dines from acyclic starting materials through multicomponent
reactions,[22] and many examples are restricted to the prepara-
tion of piperidones.[22b,c] An alternative MCR-based access to pi-
peridines could be envisioned on the basis of the reduction of
1,4-dihydropyridines prepared by the Hantzsch reaction, one
of the oldest MCRs, although this approach would be limited
by the well-known limitations in the scope of this reaction.[23]
The direct reduction of Hantzsch dihydropyridines to piperi-
dines has received only a limited amount of attention, includ-
ing one example of a catalytic hydrogenation over palladium
hydroxide, which required harsh conditions (608C, 50 psi,
acidic reaction medium) and gave a mixture of the expected
piperidine and a small amount of a decarboalkoxylation prod-
uct.[24] In another approach, the reduction of six examples of
Hantzsch dihydropyridines with triethylsilyl hydride in trifluoro-
acetic acid has been described.[25] The final products were iso-
lated in their thermodynamically more stable all-trans relative
configuration (Scheme 1). Both methods have clear limitations
in terms of reaction scope, which are associated with the use
of a strongly acidic reaction medium at 50–608C.
Results and Discussion
1. Synthesis of dihydropyridines and piperidines
The method described here is based on a multicomponent re-
action developed by our group between primary amines, a,b-
unsaturated aldehydes, b-dicarbonyl compounds, and alcohols
in the presence of cerium(IV) ammonium nitrate (CAN) as
a Lewis acid.[26] This reaction affords 6-alkoxy-1,4,5,6-tetrahy-
dropyridines,[27] which can be transformed into 1,4-dihydropyri-
dine derivatives by heating to reflux in ethanol or acetonitrile
containing suspended neutral alumina.[28] This protocol has the
disadvantage of needing a separate operation to separate the
final products from the alumina by repeated washes with polar
solvents under heating. We have now discovered that the
preparation of dihydropyridines by this strategy can be greatly
improved simply by carrying out the multicomponent reaction
in ethanol at reflux, because, under these conditions, 1,4-dihy-
dropyridines can be isolated in a single step (Scheme 2,
Table 1). The scope of the reaction allowed a wide variety of
aliphatic or aromatic substituents at R1 and R4. The R2 substitu-
ent was normally a small alkyl group owing to the commercial
Scheme 2. One-pot, three-component synthesis of 1,4-dihydropyridines.
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availability of the corresponding starting materials, but the
To complete our synthesis of piperidine derivatives, we
compatibility of the method with the presence of a C=C bond chose to expose the corresponding 1,4-dihydropyridines to
at R2 was proved by employing as the starting material the b- sodium triacetoxyborohydride (STAB), which is a mild reducing
ketoester arising from the alkylation of the ethyl acetoacetate reagent in which the electron-withdrawing effects of the three
dianion with allyl bromide (entry 6). In summary, our method acetoxy groups stabilize the boronÀhydrogen bond.[30]
can be viewed as a variation of the Hantzsch dihydropyridine Although this reagent has been widely employed in reductive
synthesis, and is complementary to the classical method in amination[31] and there is precedent for its use in the reduction
that it is well-suited to the preparation of 5- and 5,6-unsubsti- of endocyclic C=C double bonds that from part of a vinylogous
tuted dihydropyridines. The development of efficient routes to carbamate system,[32] we are not aware of its use in the synthe-
these compounds will allow the systematic study of their bio- sis of piperidines. STAB was generated in situ from sodium
logical activities; it is also important from a synthetic point of borohydride and acetic acid at room temperature, and effected
view because the presence of a C5ÀC6 unsubstituted bond en- the reduction of the dihydropyridine substrates with complete
ables the use of dihydropyridines as enamine-like reagents, al- diastereoselectivity, affording the target piperidines 6 in a one-
lowing the preparation of a variety of complex heterocyclic pot procedure as single diastereoisomers (Scheme 4). With this
frameworks.[29]
Mechanistically, the three-component transformation is pro-
posed to start with the formation of b-enaminone
I
(Scheme 3); indeed, the behavior of the reaction was identical
when starting from an isolated b-enaminone I. Compound I
Scheme 4. Diastereoselective reduction of dihydropyridines 4 to piperidines
6.
method, a broad range of piperidine derivatives bearing up to
five substituents, including a variety of aliphatic or aromatic
substituents at R1 and R4, small alkyl substituents at R2 and R5,
and ester groups at R3 could be synthesized. Furthermore, the
mild reduction conditions were compatible with several func-
tional groups, including ester, nitro, ether, and chloro moieties.
As shown in Table 1, the yields were satisfactory and were typi-
cally in the range of 75–90%.
At this point, we examined the integrity of the stereocenters
during the reduction with sodium triacetoxyborohydride. To
this end, we prepared chiral dihydropyridines by using an or-
ganocatalytic reaction that was reported while this part of our
work was in progress;[33] the approach was based on the reac-
tion between b-enaminones and cinnamaldehyde derivatives
in the presence of the Hayashi–Jørgensen catalyst and benzoic
acid. By using this method, we prepared compounds 4v and
4w, in 89 and 83% enantiomeric excess, respectively. The ap-
plication of our reduction protocol to these materials afforded
the corresponding piperidines 6v and 6w, which were isolated
in 84 and 83% ee, respectively (Scheme 5). We conclude, there-
fore, that the STAB reduction does not significantly erode the
Scheme 3. Mechanistic proposal that explains the three-component dihydro-
pyridine synthesis.
then undergoes Michael addition with compound 1 to give in- integrity of the stereocenters present in the piperidine ring.
termediate II, the 6-exo-trig cyclization of which leads to III, We also examined the reduction of a selection of representa-
which is presumably in equilibrium with IV, and affords 5 tive 6-alkoxy-1,4,5,6-tetrahydropyridines 5 under the same con-
under room temperature conditions[27] or 4 under heating as ditions, and obtained very similar results to those described for
described in this paper. The ease with which the elimination the dihydropyridines (Scheme 6). The starting materials for this
reaction takes place under reflux conditions contrasts with the study (5) are known compounds,[27] and the yields obtained in
thermal stability previously found for 5, and suggests that their reduction are summarized in Figure 3.
under the new conditions the elimination reaction takes place
The stereochemistry of piperidine derivatives was studied
on the 6-hydroxy derivative III or on the corresponding vinylo- with compound 6ac, for which the signals of all key protons
gous acyliminium species IV.
are sufficiently separated to allow meaningful NOE experi-
ments; the results are summarized in Figure 4. These data
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esting to note that this stereo-
chemical arrangement cannot be
reached by previous methods.
Mechanistically, as shown in
Scheme 7, the dihydropyridine
reduction is proposed to start by
the generation of a vinylogous
acyliminium species I through
protonation of the C5=C6
double bond of the starting di-
hydropyridine, which is more nu-
cleophilic because of the ab-
sence of an electron-withdraw-
ing group. This protonation
takes place in such a way that
the R4 and R5 substituents end
up in an equatorial position, and
therefore in a trans arrangement.
In the reactions starting from 6-
alkoxy-1,4,5,6-tetrahydropyri-
Table 1. Scope and yields of the multicomponent synthesis of 1,4-dihydropyridines and their STAB reduction.
Entry
R1
R2
R3
R4
R5
Dihydropyridines
Piperidines
4
Yield
[%]
6
Yield
[%]
1
2
Me
Me
OEt
Ph
Ph
H
H
4a
4b
70
72
6a
6b
88
OtBu
84
78
3
Me
OEt
Ph
H
4c
66
6c
4
5
Me
OEt
OEt
Ph
Ph
H
H
4d
4e
66
60
6d
6e
92
79
nPr
CH2-CH2-
CH=CH2
6
7
8
OEt
OEt
OEt
Ph
H
H
H
4 f
60
62
65
6 f
84
78
71
dines 5, the same intermediate I
is reached by protonation of the
6-ethoxy substituent and loss of
a molecule of ethanol. It is note-
worthy that the STAB reduction
Me
Me
p-MeC6H4
p-MeOC6H4
4g
4h
6g
6h
failed
when
applied
to
9
Me
Me
OEt
p-MeOC6H4
p-NO2C6H4
H
H
4i
4j
68
70
6i
6j
68
82
a Hantzsch dihydropyridine, sug-
gesting that in these cases the
electron density at the dihydro-
pyridine nitrogen is not suffi-
cient to trigger the initial proto-
nation event. Reduction of the
iminium group in I by the hy-
dride donor affords intermediate
II. In subsequent stages, sodium
triacetoxyborohydride reduces
the C=C double bond of the vi-
nylic carbamate group present
in II. This reagent is known to
deliver two hydrogen atoms
from the same face of the
double bond,[32a] according to
the mechanism summarized in
Scheme 7, which involves an ini-
tial coordination of the ester car-
bonyl oxygen with boron (III),
followed by intermolecular hy-
dride transfer onto the resulting
iminium cation to generate in-
termediate IV, with an equatorial
R2 substituent. The final step in-
volves attack of the boron eno-
10
nPr
OtBu
11
12
Me
Me
OEt
OEt
p-NO2C6H4
p-NO2C6H4
H
H
4k
4l
78
72
6k
6l
87
78
13
14
Me
Me
OEt
OEt
p-NO2C6H4
o-NO2C6H4
H
H
4m
4n
86
68
6m
6n
86
79
nBu
15
16
Me
Me
OEt
OEt
p-ClC6H4
H
4o
4p
68
64
6o
6p
90
62
Et
Me
17
18
Me
Me
OEt
OEt
Me
Me
H
H
4q
4r
62
6q
6r
75
77
55[a]
19
20
nPr
nBu
Me
Me
OEt
OEt
Me
Me
H
H
4s
4t
68
65[a]
6s
6t
72
76
[b]
21
Me
OEt
H
Me
4u
–
6u
67
[a] Compounds 4r and 4t are known.[27] [b] This compound was isolated as a mixture with the corresponding
6-ethoxy-1,2,3,4-tetrahydropyridine, a mixture that was reduced without separation to give 6u.
show an all-cis relative configuration for the substituents at C-
2, C-3, and C-4, with the substituent at C-5 being trans with re-
spect to the others. In this structure, all substituents are equa-
torial, except the ester group at C-3, which is axial. It is inter-
late to acetic acid, and affords the final product 6 with loss of
a molecule of boron triacetate.
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Figure 3. Additional piperidines obtained by the reduction of representative
compounds 5.
Scheme 5. Synthesis of chiral piperidines.
Figure 4. Stereochemical study of compound 6ac.
b-enaminone from 7 and 8, then cooling to 08C before addi-
tion of the remaining reagents (acrolein and ethanol) and final-
ly allowing the reaction to warm to room temperature. Under
these modified conditions, we were able to prepare the target
compound 9 in excellent yields in a reproducible and scalable
manner. By using a similar sequential protocol, we were finally
able to employ the stable and inexpensive CAN catalyst, al-
though in this case the use of lower temperatures was neces-
sary (entries 13–16).
Scheme 6. Direct synthesis of piperidines from open-chain precursors, via
compounds 5.
2. Synthesis of decahydroquinolines
The extension of our multicomponent strategy to the synthesis
of decahydroquinolines required the use of a derivative of 1,3-
cyclohexanedione (7) as the b-dicarbonyl. Due to our interest
in the synthesis of the Dendobatridae alkaloids, most of which
lack substitution at nitrogen, we performed our studies with
benzylamine 8, because we expected to be able to remove the
benzyl substituent by hydrogenolysis. The optimization of our
multicomponent reaction for the synthesis of quinoline deriva-
tives (Table 2) turned out to be more troublesome than antici-
pated because the standard conditions (CAN, CH3CN, RT) led
only to decomposition products. We resorted to the use of
other Lewis acids and found that, in the case of scandium tri-
flate (entries 1–5), indium triflate (entries 6–9), and indium tri-
chloride (entries 10–12), it was preferable to carry out the reac-
tion in a sequential fashion, by first preparing the intermediate
Once compound 9 was available in suitable amounts, we
transformed it into 2-allyl derivative 10, which is useful as a po-
tential precursor to pumiliotoxin C, by means of a Hosomi–Sa-
kurai reaction with allyltrimethylsilane in the presence of
boron trifluoride (Scheme 8).
Because of the failure of all attempts at the reduction of 10
to the decahydroquinoline state with sodium triacetoxyboro-
hydride, we examined its catalytic hydrogenation under a varie-
ty of conditions; the results are summarized in Scheme 9. The
reduction of 10 under standard conditions (H2 at atmospheric
pressure, Pd-C as catalyst, room temperature) afforded only
compound 11, from reduction of the allyl side chain. Harsher
conditions [60 psi (4 atm) H2, acetic acid as solvent] brought
about an additional N-debenzylation, furnishing compound 12.
When this material was submitted to further hydrogenation,
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Scheme 8. Multicomponent synthesis of octahydroquinoline derivative 9
and its Hosomi–Sakurai reaction with allyltrimethylsilane.
Scheme 7. Mechanistic proposal for the reduction of 4 and 5 to piperidines
6 in the presence of sodium triacetoxyborohydride and an explanation of
the observed diastereoselectivity.
Table 2. Optimization of the sequential four-component synthesis of 1-
benzyl-2-ethoxy-1,2,3,4,7,8-hexahydroquinolin-5(6H)-one (9).
Entry Catalyst[a]
Conditions[b]
Yield
[%]
1
2
3
4
Sc(OTf)3 (10%)
95
93
92
91[c]
Sc(OTf)3 (5%) CH3CN, RT, 1 h (7+8), then acrolein and
Sc(OTf)3 (2%) ethanol, 08C (30 min), then RT, 6 h
Sc(OTf)3 (2%)
Scheme 9. Transformation of 10 into decahydroquinoline derivatives under
several hydrogenation conditions and formal synthesis of the alkaloid (Æ)-
pumiliotoxin C by preparation of its precursor 12; n.r.=no reaction.
5
Sc(OTf)3 (2%) CH2Cl2, RT, 1 h (7+8), then acrolein and
ethanol, 08C (30 min), then RT, 6 h
92
this time under 90 atm hydrogen and in the presence of Pt-C,
the reduction of the endocyclic conjugate double bond was
achieved, affording compound 13. Finally, the hydrogenation
of 10 under conditions similar to those used for the prepara-
tion of 12, but employing a higher load of Pd-C, afforded com-
pound 14, a propyl derivative of the parent decahydroquino-
line system. We have previously demonstrated the transforma-
tion of 12 into the alkaloid pumiliotoxin C.[34]
6
7
8
9
In(OTf)3 (5%)
95
92
93
91[c]
CH2Cl2, RT, 1 h (7+8), then acrolein and
In(OTf)3 (2%)
ethanol, 08C (30 min), then RT, 6 h (entry 6),
In(OTf)3 (1%)
8 h (entry 7) or 12 h (entries 8 and 9)
In(OTf)3 (1%)
10
11
12
InCl3 (10%)
InCl3 (10%)
InCl3 (1%)
CH2Cl2, RT, 1 h (7+8), then acrolein and
ethanol, 08C (30 min), then RT, 6 h
(entries 10 and 11) or 12 h (entry 12)
94
92[c]
35
13
CAN (10%)
CH2Cl2, RT, 1 h (7+8), then acrolein and
ethanol, 08C (30 min), then RT, 6 h
0[d]
Conclusion
14
15
16
CAN (10%)
CAN (5%)
CAN (5%)
92
91
90[c]
CH2Cl2, RT, 1 h (7+8), then acrolein and
ethanol, À158C (2 h), then RT, 6 h
The CAN-catalyzed, three-component reaction between pri-
mary amines, b-dicarbonyl compounds, and a,b-unsaturated
aldehydes in ethanol at reflux constitutes a general, one-pot
synthesis of 1,4-dihydropyridines. Their reduction with sodium
triacetoxyborohydride furnished piperidine derivatives bearing
[a] All catalyst loadings are given as mol%. [b] Reactions carried out on
a 1 mmol scale, unless noted otherwise. [c] Reactions carried out on
a 20 mmol scale. [d] Decomposition was observed.
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5.79 (d, J=7.5 Hz, 1H), 6.69–6.84 ppm (m 3H); 13C NMR (CDCl3,
63 MHz): d=14.8, 16.0, 25.3, 28.6, 36.6, 52.1, 56.2, 59.5, 101.5,
109.4, 111.7, 112.4, 121.1, 129.2, 131.1, 148.1, 148.7, 149.3,
169.6 ppm; IR (neat, NaCl): n˜ =2954, 1681, 1591, 1556, 1516, 1464,
1454, 1416, 1395, 1359, 1335, 1263, 1237, 1169, 1141, 1099,
1029 cmÀ1; elemental analysis calcd (%) for C20H27NO4 (345.19): C
69.54, H 7.88, N 4.05; found: C 68.12, H 7.59, N 4.15.
up to five substituents with full diastereoselectivity, in a hither-
to inaccessible stereochemical arrangement. The reaction pro-
ceeded under mild reduction conditions that were compatible
with several functional groups and did not lead to a significant
loss of enantiomeric purity. Modified conditions allowed the
preparation of octahydroquinolin-5-one derivatives that were
hydrogenated to the corresponding decahydroquinolines, in-
cluding a precursor of the amphibian alkaloid pumiliotoxin C.
Synthesis of polysubstituted piperidine derivatives through
the reduction of dihydropyridines with sodium triacetoxy-
borohydride: General procedure
Experimental Section
Sodium borohydride (6 equiv) was added in three portions to
stirred glacial acetic acid (3 mL per mmol), keeping the tempera-
ture between 15 and 208C, to prepare sodium triacetoxyborohy-
dride [NaBH(OAc)3]. After hydrogen evolution had ceased (10 min),
the requisite substituted dihydropyridine was added in one portion
and the reaction mixture was stirred for 2 h. After completion of
the reaction, as monitored by TLC, the reaction mixture was dilut-
ed with water (10 mL), neutralized with saturated sodium hydro-
gen carbonate solution, and extracted with dichloromethane (2ꢂ
20 mL). The combined organic layers were dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The crude prod-
ucts were purified by flash column chromatography on neutral alu-
mina (petroleum ether/ethyl acetate, 70:30 to 80:20, v/v). Charac-
terization data for representative piperidine derivatives are given
below. For full characterization data, see the Supporting Informa-
tion.
Multicomponent synthesis of dihydropyridine derivatives:
General procedure
A solution of the primary amine (1 mmol), b-ketoester (1 mmol),
and CAN (5 mol%) in ethanol (3 mL) was heated to reflux for
30 min. A suitable unsaturated aldehyde (1 mmol) was added and
reflux was continued for a further 30 min. Upon completion of the
reaction, as monitored by TLC, the reaction mixture was diluted
with water (5 mL) and extracted with dichloromethane (10 mL).
The organic layer was separated and dried over sodium sulfate.
Solvents were evaporated under reduced pressure and the crude
residue was purified by chromatography on silica gel (petroleum
ether/ethyl acetate, 80:20–90:10, v/v). Characterization data of rep-
resentative compounds are given below. For the full characteriza-
tion data, see the Supporting Information.
(Æ)-Ethyl 1-(3,4-dimethoxyphenethyl)-2-methyl-4-phenyl-1,4-di-
hydro-pyridine-3-carboxylate (4a): Prepared from ethyl acetoace-
tate (130 mg, 1 mmol), 3,4-dimethoxyphenethylamine (181 mg,
1 mmol), and cinnamaldehyde (132 mg, 1 mmol). Yield: 284 mg
(Æ)-(2S*,3S*,4R*)-Ethyl 1-(3,4-dimethoxyphenethyl)-2-methyl-4-
phenyl-piperidine-3-carboxylate (6a): Prepared from 4a (122 mg,
1
0.3 mmol). Yield: 108 mg (88%); pale-brown viscous liquid; H NMR
1
(70%); brown viscous liquid; H NMR (CDCl3, 250 MHz): d=1.11 (t,
(CDCl3, 250 MHz): d=0.93 (t, J=7.1 Hz, 3H), 1.26 (d, J=6.8 Hz, 3H),
1.74 (d, J=9.0 Hz, 1H), 2.50–2.58 (m, 1H), 2.71–2.88 (m, 7H), 2.94–
3.01 (m, 1H), 3.30 (d, J=11.1 Hz, 1H), 3.80–3.93 (m, 8H), 6.75–6.85
(m, 3H), 7.19–7.34 ppm (m, 5H); 13C NMR (CDCl3, 63 MHz): d=14.1,
18.6, 25.7, 29.9, 44.6, 53.1, 53.6, 55.6, 55.9, 56.0, 57.3, 59.4, 111.3,
112.1, 120.5, 126.5, 127.4, 128.2, 133.6, 142.8, 147.3, 148.8,
171.3 ppm; IR (neat, NaCl): n˜ =2940, 1730, 1590, 1510, 1460, 1270,
1030 cmÀ1; elemental analysis calcd (%) for C25H33NO4 (411.24): C
72.96, H 8.08, N 3.40; found: C 72.62, H 7.82, N 3.49.
J=7.1 Hz, 3H), 2.45 (s, 3H), 2.85 (t, J=7.6 Hz, 2H), 3.51 (quint., J=
7.7 Hz, 1H), 3.71 (quint., J=7.6 Hz, 1H), 3.07–3.09 (m, 6H), 4.00 (q,
J=7.1 Hz, 2H), 4.61 (d, J=5.4 Hz, 1H), 4.96 (dd, J=7.6, 5.4 Hz, 1H),
5.90 (d, J=7.6 Hz, 1H), 6.71–6.85 (m, 3H), 7.17–7.32 ppm (m, 5H);
13C NMR (CDCl3, 63 MHz): d=13.1, 14.6, 35.2, 39.2, 50.9, 54.8, 58.2,
98.9, 107.0, 110.3, 110.9, 119.7, 124.9, 126.3, 127.1. 127.4, 129.5,
146.8, 147.3, 147.8, 147.9, 168.0 ppm; IR (neat, NaCl): n˜ =2935,
1681, 1621, 1516, 1453, 1418, 1368, 1263, 1238, 1157, 1097,
1028 cmÀ1; elemental analysis calcd (%) for C25H29NO4 (407.21): C
73.68, H 7.17, N 3.44; found: C 73.49, H 7.03, N 3.29.
(Æ)-(2S*,3S*,4R*)-Ethyl 1-(3,4-dimethoxyphenethyl)-2-methyl-4-
(p-tolyl)-piperidine-3-carboxylate (6g): Prepared from compound
4g (126 mg, 0.3 mmol). Yield: 99 mg (78%); brown solid; m.p. 82–
(Æ)-Ethyl 1-(furan-2-ylmethyl)-2-methyl-4-phenyl-1,4-dihydropyr-
idine-3-carboxylate (4d): Prepared from ethyl acetoacetate
(130 mg, 1 mmol), 2-furfurylamine (97 mg, 1 mmol), and trans-cin-
namaldehyde (132 mg, 1 mmol). Yield: 213 mg (66%); pale-brown
1
838C; H NMR (CDCl3, 250 MHz): d=0.93 (t, J=7.0 Hz, 3H), 1.21 (d,
J=6.4 Hz, 3H), 1.69 (d, J=7.7 Hz, 1H), 1.85–2.06 (m, 2H), 2.30 (s,
3H), 2.44–2.54 (m, 1H), 2.69–2.82 (m, 6H), 3.23–3.28 (m, 1H), 3.82–
3.88 (m, 8H), 6.72–6.81 (m, 3H), 7.05–7.14 ppm (m, 4H); 13C NMR
(CDCl3, 63 MHz): d=14.2, 18.7, 26.0, 29.8, 44.3, 53.3, 53.7, 55.7,
55.9, 56.0, 57.4, 59.4, 111.3, 112.1, 120.6, 127.3, 128.9, 133.7, 135.9,
139.9, 147.2, 148.9, 171.4 ppm; IR (neat, NaCl): n˜ =2920, 1710,
1500, 1260, 1140, 1020 cmÀ1; elemental analysis calcd (%) for
C26H35NO4 (425.26): C 73.38, H 8.29, N 3.29; found: C 73.10, H 7.95,
N 3.15.
1
viscous liquid; H NMR (CDCl3, 250 MHz) d=1.12 (t, J=7.1 Hz, 3H),
2.55 (s, 3H), 4.1 (q, J=7.1 Hz, 2H), 4.45–4.55 (m, 3H), 5.00 (dd, J=
7.6, 5.5 Hz, 1H), 6.03 (d, J=7.6 Hz, 1H), 6.26 (d, J=3.2 Hz, 1H), 6.38
(dd, J=3.1, 2.0 Hz, 1H), 7.13–7.28 (m, 5H), 7.42–7.43 ppm (m, 1H);
13C NMR (CDCl3, 63 MHz) d=14.2, 15.8, 40.3, 47.0, 59.4, 101.3,
107.8, 108.5, 110.5, 126.0, 127.6, 128.2, 128.7, 142.6, 148.3, 148.8,
151.2, 169.0 ppm; IR (neat, NaCl): n˜ =2980, 1680, 1570, 1370,
1100 cmÀ1; elemental analysis calcd (%) for C20H21NO3 (323.15): C
74.28, H 6.55, N 4.44; found: C 73.91, H 6.24, N 4.21.
(Æ)-(2S*,3S*,4R*)-Ethyl 1-butyl-2-methyl-4-(2-nitrophenyl)piperi-
dine-3-carboxylate (6n): Prepared from compound 4o (103 mg,
1
(Æ)-Ethyl 1-(3,4-dimethoxyphenethyl)-2,4-dimethyl-1,4-dihydro-
0.3 mmol). Yield: 82 mg (79%); pale-brown viscous liquid; H NMR
pyridine-3-carboxylate (4q): Prepared from ethyl acetoacetate
(CDCl3, 250 MHz): d=0.88–0.96 (m, 6H), 1.14 (d, J=6.5 Hz, 3H),
1.21–1.33 (m, 2H), 1.35–1.56 (m, 3H), 2.36 (td, J=11.6, 2.5 Hz, 1H),
2.45–2.91 (m, 4H), 2.95–2.98 (m, 1H), 3.14 (dt, J=11.2, 3.1 Hz, 1H),
3.37 (dt, J=12.9, 3.8 Hz, 1H), 3.84 (q, J=7.1 Hz, 2H), 7.30–7.36 (m,
1H), 7.50 (d, J=3.9 Hz, 2H), 7.80 ppm (d, J=7.9 Hz, 1H); 13C NMR
(CDCl3, 63 MHz): d=14.2, 18.5, 20.9, 25.3, 26.6, 40.0, 51.7, 52.8,
53.2, 57.3, 59.5, 124.5, 127.4, 129.6, 132.7, 137.2, 149.9, 171.3 ppm
(130 mg,
1 mmol),
3,4-dimethoxyphenethylamine
(181 mg,
1 mmol), and crotonaldehyde (70 mg, 1 mmol). Yield: 213 mg
1
(62%); brown solid; m.p. 79–808C; H NMR (CDCl3, 250 MHz): d=
1.00 (d, J=6.4 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H), 2.33 (s, 3H), 2.78 (t,
J=7.4 Hz, 2H), 3.34–3.48 (m, 2H), 3.67 (quint, J=7.3 Hz, 1H), 3.88–
3.89 (m, 6H), 4.15 (q, J=7.1 Hz, 2H), 4.87 (dd, J=7.5, 5.8 Hz, 1H),
Chem. Eur. J. 2014, 20, 1 – 10
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(two aliphatic carbon atoms are merged with others). IR (neat,
NaCl): n˜ =2940, 1620, 1520, 1350, 1160, 1030 cmÀ1; elemental anal-
ysis calcd (%) for C20H28N2O4 (348.20): C 65.49, H 8.10, N 8.04;
found: C 65.43, H 7.86, N 8.12.
(2 mmol) were then added and the mixture was stirred for a further
30 min. Upon completion of the reaction, as monitored by TLC, the
mixture was diluted with ethyl acetate (20 mL) and washed with
water (5 mL). The organic phase was dried (anhydrous Na2SO4) and
the solvent was removed by rotavapor below 258C. The residue
(compounds 5) was reduced with sodium triacetoxyborohydride
by using the protocol described above. Characterization data for
representative piperidine derivatives obtained by this method are
given below. For the full characterization data, see the Supporting
Information.
Enantioselective synthesis of dihydropyridines and their re-
duction to piperidines: General procedure
4-Nitrocinnamaldehyde (1 mmol, 2 equiv) and benzoic acid
(0.1 mmol, 12 mg, 20 mol%) were added to a solution of the Haya-
shi–Jørgensen catalyst (0.1 mmol, 60 mg, 20 mol%) in toluene
(1.5 mL) under an Ar atmosphere. After 10 min stirring, the requi-
site b-enaminone[35] (0.5 mmol, 1 equiv) was added as a solution in
toluene (0.5 mL) and the reaction mixture was stirred at RT for 3 h.
Upon completion of the reaction, as monitored by TLC, the reac-
tion was quenched with NaHCO3 (2 mL) and extracted with di-
chloromethane (2ꢂ10 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude dihydropyridine products were purified by
column chromatography on silica gel, using a mixture of petrole-
um ether and ethyl acetate as eluent. The reduction of compounds
4v and 4w thus obtained with sodium triacetoxyborohydride gave
6v and 6w, as described in the general procedure. The enantio-
meric purity of all these compounds was calculated by HPLC analy-
sis by using a Chiralcel OD-H column, eluting with 10% iPrOH in
hexane and is expressed as enantiomeric excess. Characterization
data for representative piperidine derivatives are given below. For
the full characterization data, see the Supporting Information.
(Æ)-(2S*,3S*)-Ethyl
1-butyl-2-methylpiperidine-3-carboxylate
(6x): Prepared from the corresponding 6-alkoxy-1,2,3,4-tetrahydro-
pyridine derivative[26] (66 mg, 0.3 mmol). Yield: 54 mg (80%); pale-
brown sticky paste; 1H NMR (CDCl3, 250 MHz): d=0.81–0.93 (m,
6H), 1.21–1.47 (m, 9H), 1.54–1.66 (m, 2H), 1.69–1.74 (m, 1H), 2.31–
2.43 (m, 3H), 2.69–2.77 (m, 1H), 3.36–3.45 (m, 1H), 4.12 ppm (q, J=
7.1 Hz, 2H); 13C NMR (CDCl3, 63 MHz): d=5.5, 14.3, 14.5, 20.7, 21.0,
24.5, 30.1, 45.4, 46.1, 53.4, 54.7, 60.3, 174.3 ppm; IR (neat, NaCl):
n˜ =3380, 1720, 1560, 1150, 1040 cmÀ1; elemental analysis calcd (%)
for C13H25NO2 (227.19): C 68.08, H 11.08, N 6.16; found: C 68.09, H
10.98, N 5.97.
(Æ)-(2S*,3S*,4R*,5R*)-Ethyl 1-(furan-2-ylmethyl)-2,5-dimethylpi-
peridine-3-carboxylate (6ac): Prepared from the corresponding 6-
alkoxy-1,2,3,4-tetrahydropyridine derivative[26] (86 mg, 0.3 mmol).
Yield: 62 mg (71%); pale-brown viscous liquid; 1H NMR (CDCl3,
250 MHz): d=0.79 (d, J=6.5 Hz, 3H), 0.86 (t, J=7.1 Hz, 3H), 0.92–
1.13 (m, 2H), 1.22–1.30 (m, 6H), 1.58–1.69 (m, 1H), 1.91 (t, J=
11.2 Hz, 1H), 2.21–2.33 (m, 1H), 2.34–2.45 (m, 1H), 2.66 (t, J=
4.0 Hz, 1H), 2.84 (dd, J=11.3, 3.9 Hz, 1H), 3.71 (d, J=15.6 Hz, 1H),
3.97 (d, J=15.6 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 6.14 (d, J=3.1 Hz,
1H), 6.31 (dd, J=3.1, 1.9 Hz, 1H), 7.35 ppm (dd, J=1.8, 0.8 Hz, 1H);
13C NMR (CDCl3, 63 MHz): d=11.8, 14.5, 17.3, 18.3, 22.7, 31.2, 47.2,
49.3, 49.4, 56.5, 59.6, 61.2, 109.1, 109.9, 141.8, 151.7, 172.4 ppm; IR
(neat, NaCl): n˜ =3360, 2940, 1720, 1570, 1460, 1380, 1140,
1010 cmÀ1; elemental analysis calcd (%) for C17H27NO3 (293.20): C
69.59, H 9.28, N 4.77; found: C 69.20, H 8.96, N 4.92.
(R)-Ethyl
1-benzyl-2-methyl-4-(4-nitrophenyl)-1,4-dihydropyri-
dine-3-carboxylate (4v): Prepared from 4-nitrocinnamaldehyde
(194 mg, 0.55 mmol, 1.1 equiv) and the appropriate b-enamino
ester (109 mg, 0.5 mmol, 1 equiv). Yield: 132 mg (70%); yellow vis-
cous liquid; 89% ee (Chiralcel OD-H column; 1 mLminÀ1; 10%
iPrOH in hexane; 254 nm); [a]2D5 = +328 (c 2.5 mg in 2 mL CHCl3);
1H NMR (CDCl3, 250 MHz): d=1.22 (t, J=7.1 Hz, 3H), 2.59 (s, 3H),
4.12 (q, J=7.1 Hz, 2H), 4.73 (d, J=16.9 Hz, 1H), 4.83 (d, J=16.9 Hz,
1H), 4.92 (d, J=5.4 Hz, 1H), 5.07 (dd, J=7.5, 5.5 Hz, 1H), 6.6 (d, J=
7.6 Hz, 1H), 7.33–7.40 (m, 2H), 7.45–7.54 (m, 5H), 8.27 ppm (d, J=
8.7 Hz, 2H); 13C NMR (CDCl3, 63 MHz): d=14.3, 16.1, 40.6, 53.9, Acknowledgements
59.6, 99.3, 106.7, 123.8, 126.3, 127.8, 128.3, 129.1, 130.4, 137.7,
146.3, 150.0, 156.0, 168.4 ppm; IR (neat, NaCl): n˜ =2940, 1660,
We thank the Ministerio de Economꢃa y Competitividad,
MINECO, for support of this research through grant CTQ-2012–
33272-BQU. One of us (P.A.S.) also gratefully acknowledges
a doctoral fellowship from Agencia EspaÇola de Cooperaciꢄn
Internacional y Desarrollo (AECID).
1500, 1340, 1100 cmÀ1
.
(2S*,3S*,4R*)-Ethyl
1-benzyl-2-methyl-4-(4-nitrophenyl)piperi-
dine-3-carboxylate (6v): Prepared from 4v (80 mg, 0.2 mmol,
1 equiv). Yield: 68 mg (85%); yellow viscous liquid; 84% ee (Chiral-
cel OD-H column; 1 mLminÀ1; 20% iPrOH in hexane; 254 nm);
[a]2D5 = +59 (c 2.8 mg in 2 mL CHCl3); 1H NMR (CDCl3, 250 MHz):
d=1.15 (t, J=7.1 Hz, 3H), 1.43 (d, J=6.5 Hz, 3H), 1.76 (dd, J=12.0,
1.8 Hz, 1H), 2.26 (td, J=11.7, 2.6 Hz, 1H), 2.84–2.89 (m, 1H), 2.94
(dd, J=12.2, 4.0 Hz, 1H), 3.03 (m, 1H), 3.13 (dt, J=12.8, 4.3 Hz,
1H), 3.24 (dt, J=11.5, 3.1 Hz, 1H), 3.36 (d, J=13.9 Hz, 1H), 4.06 (q,
J=7.1 Hz, 2H), 4.26 (d, J=13.9 Hz, 1H), 7.35–7.58 (m, 7H),
8.28 ppm (dd, J=8.8 Hz, 2H); 13C NMR (CDCl3, 63 MHz): d=14.3,
19.1, 25.4, 44.5, 53.1, 53.6, 57.0, 58.8, 59.8, 123.5, 126.8, 128.3,
128.4, 128.7, 139.7, 146.6, 150.7, 170.8 ppm; IR (neat, NaCl): n˜ =
Keywords: alkaloids · diastereoselectivity · multicomponent
reactions · nitrogen heterocycles · piperidines
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Received: March 14, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 10
www.chemeurj.org
9
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
&
Heterocycles
P. A. Suryavanshi, V. Sridharan, S. Maiti,
J. C. Menꢀndez*
&& – &&
CAN can! The combination of a ceriu-
m(IV) ammonium nitrate (CAN)-cata-
lyzed, three-component dihydropyridine
synthesis with a sodium triacetoxyboro-
hydride reduction afforded polysubsti-
tuted piperidines with complete diaste-
reoselectivity (see scheme). The reduc-
tion step could be applied to chiral di-
hydropyridines without loss of stereo-
chemical integrity. A similar strategy af-
forded decahydroquinolines, including
a precursor to the amphibian alkaloid
pumiliotoxin C.
Fully Diastereoselective Synthesis of
Polysubstituted, Functionalized
Piperidines and Decahydroquinolines
Based on Multicomponent Reactions
Catalyzed by Cerium(IV) Ammonium
Nitrate
&
&
Chem. Eur. J. 2014, 20, 1 – 10
www.chemeurj.org
10
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!