A multicomponent formal [1+2+1+2]-cycloaddition for the synthesis of dihydropyridines

Article abstract of DOI:10.1039/c2cc31495a

Reaction of methoxyvinylmethylketone with different amines and aldehydes under Lewis-acid catalysed conditions results in a novel, formal, step-wise [1+2+1+2]-cycloaddition to give dihydropyridine products.

Full text of DOI:10.1039/c2cc31495a

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COMMUNICATION
A multicomponent formal [1+2+1+2]-cycloaddition for the synthesis of
dihydropyridinesw
P. Ricardo Girling,a Andrei S. Batsanov,a Hong C. Shenb and Andrew Whiting*a
Received 28th February 2012, Accepted 15th March 2012
DOI: 10.1039/c2cc31495a
Reaction of methoxyvinylmethylketone with different amines
and aldehydes under Lewis-acid catalysed conditions results in
a novel, formal, step-wise [1+2+1+2]-cycloaddition to give
dihydropyridine products.
diene precursors, i.e. enones. However, during these investiga-
tions it was found that under certain Lewis acid-catalysed
conditions (where imine hydrolysis was possible), unexpected
dihydropyridines were detected. A closer investigation involving
the reaction of one equivalent of an amine 2 and aldehyde 3,
with two equivalents of 4-methoxy-3-buten-2-one 1 in the
presence of a Lewis acid (see eqn (1)) formed the corre-
sponding diacetyl dihydropyridine. The use of different amine
and aldehyde combinations revealed the reaction to be reason-
ably general using Sc(OTf)3, and after some limited optimi-
sation (Lewis acid and loading, reactant ratios etc) a number
of different examples could be accessed albeit over varying
reaction times depending on the substrate combinations
(see Table 1). Many of the products were also crystalline
and hence, their structures were determined by single crystal
X-ray diffraction (see Fig. 1 for example, and the Supplementary
Informationw).
The ability to perform atom-economic, multi-component reactions
is increasingly important in order to quickly and efficiently
construct target molecules.1 Since the first reported multi-
component Strecker reaction in the 19th century,2 there have
been many challenges, new developments and further examples
reported. The fact that such reactions necessarily require many
different components in the reaction mixture increases the
possibility of unwanted competing side-reactions to occur. Hence,
new multi-component reactions should ideally: (1) minimise
side-product formation; (2) be general processes which work
on a variety of substrates; and (3) be capable of including a
range of functionality for further manipulation. There are
many different examples of this requiring three components,
for example, from the Mannich to the Biginelli reaction.3
However, the use of four or more components is much less
reported, and indeed, the list of known examples is notably
small, including the Ugi, Passerini and Hantzsch pyridine
protocols.4 In this paper, a novel multi-component, formal
[1+2+1+2]-cycloaddition process is reported which efficiently
constructs dihydropyridine derivatives from amine, aldehyde
and enone starting materials.
ð1Þ
At first glance, this reaction looks similar to the Hantzsch
pyridine synthesis,7 however, it almost certainly proceeds
through a novel and different mechanism in order to give rise
to the different dihydropyridines (vide infra). The use of an enone
instead of an a-ketoester to form these types of dihydropyridines
is almost unprecedented; to our knowledge only Inouye et al. in
the late 50s briefly reported the most closely related example,8
whereby 4-chloro-3-buten-2-one was employed instead of
4-methoxy-3-buten-2-one 1.
We have been interested in the synthesis of piperidine
derivatives using a formal aza-Diels–Alder-type process for a
number of years.5 Many of these types of reactions rather than
being a concerted cycloaddition, tend to occur via a stepwise
Mannich-Michael pathway.6 We were interested in developing
new one-pot, rapid assemblies of piperdinones and related
derivatives and were examining reactions of imines and
In terms of the different aldehydes used (see Table 1), higher
yields were generally obtained with aromatic aldehydes, whereas,
for the amines, lower yields were obtained when either the amine
was less nucleophilic (such as aniline, see Table 1, entries 6 and 7)
or more bulky (such as tert-butylamine, Table 1, entries 13 and 14).
In these cases, the reactions tended to stall at the initial
Michael-addition step to form the vinylogous amides, i.e.
resulting in the isolation of compounds 5a–d. This could generally
be overcome to some extent by heating the reaction to 60 1C, as in
the case of Table 1, entry 14, however, this also resulted in the
formation of the double vinylogous amide product 7 being
formed as the major product. The best yield was obtained when
a Centre for Sustainable Chemical Processes,
Department of Chemistry, Durham University, South Road,
Durham, DH1 3LE, UK. E-mail: andy.whiting@durham.ac.uk;
Fax: +44 191 384 4737; Tel: +44 191 334 2081
b Merck & Co., RY800-C114, 126 East Lincoln Avenue,
P.O. Box 2000, Rahway, NJ 07065-0900, USA
w Electronic supplementary information (ESI) available: full experimental
details, characterisations, 1H and 13C NMR spectra for new compounds,
and full crystallographic data (excluding structure factors) in CIF
format for 4a (two polymorphs), 4d, 4e, 4f, 4g, 4h, 4i, 4k and 6. CCDC
869480–869489. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2cc31495a
c
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Table 1 [1+2+1+2]-Cycloadditions to form dihydropyridines
of type 4 (see eqn (1)a)
Table
2
Mechanistic studies for the [1+2+1+2]-
cycloaddition reaction
Time Cycloadduct Other products
(days) isolated
Entry Reaction
Entry R1
R2
isolated
1
2a (R1 = 3a (R2 =
11
4a (86%)b
—
Bn)
2a
2a
p-NO2Ph)
3b (R2 = Ph) 10
1
2
2
3
4b (59%)
4c (59%)
—
—
3c (R2 =
p-MeOPh)
13
4
5
2a
2a
3d (R2 = Et) 19
4d (13%)b
4e (42%)b
5a (28%)
—
3e (R2 =
CH(OMe)2)
4
2b (R1 =
Ph)
6
3a
11
4f (31%)b
3
4
7
8
2b
3f (R2 =
14
8
—
5b (45%)
t-Bu)
2c (R1 = 3a
allyl)
4g (62%)b
—
9
2c
2c
2c
3b
3c
3e
2
8
4
20
4h (58%)b
4i (34%)b
4j (20%)
—
—
—
—
10
11
12
2d (R1 = 3d
Me)
4k (28%)b
13
2e (R1 = 3d
t-Bu)
17
—
5c (99%)
a
Conversions estimated with respect to the amount of MeOH
1
produced in the reaction, by H NMR integration.
4l (30%
at 60 1C
in toluene)
It is possible to be reasonably certain that the initial inter-
mediate formed in these formal [1+2+1+2]-cycloaddition
reactions is the vinylogous amide species, i.e. 5 (eqn (1)), for
several reasons and from NMR studies reported in Table 2,
since: (1) this intermediate has been isolated several times in
these reactions, i.e. see Table 1, entries 4, 7, 13 and 15;
(2) reaction of enone 1 (2 equiv.) with amine 2 (1 equiv.) in the
absence of aldehyde gives the vinylogous amide and unreacted
enone 1 (Table 2, entry 1) and subsequent addition of aldehyde
gives rapid conversion to the cycloadduct (ca. 60%); (3) if the
enone (2 equiv.) was reacted with the amine (2 equiv.), only the
intermediate vinylogous amide was formed and addition of
the aldehyde (1 equiv.) results in a less efficient formation of
the dihydropyridine (Table 2, entry 2); (4) the vinylogous
amide was formed even in the absence of a Lewis acid, as in
Table 2, entry 3, and subsequent addition of aldehyde and
Lewis acid provided the cycloadduct, though similarly less
efficiently to entry 2 (Table 2); (5) the dihydropyridine ring
was formed most efficiently and cleanly by reaction of enone
(1 equiv.), amine (1 equiv.) and aldehyde (1 equiv.), followed
by the addition of another equivalent of enone (See Table 2,
entry 4).
14
2e
3a
7
2
c
—
15
2f (R1 = 3b
p-MeOPh)
5d (25%)
a
b
All reactions were carried out using Sc(OTf)3 as catalyst. Denotes
c
that single crystal X-ray structures obtained (see ESIw). An insepa-
rable mixture of cycloadduct and its MeOH adduct was obtained in ca.
1
a 3 : 1 ratio in an estimated yield (by H NMR) of 39%.
using benzylamine and p-nitrobenzaldehyde (Table 1, entry 1).
Interestingly, when the role of the solvent was examined by
running the reaction in different solvents and monitoring by
TLC analysis after 48 h, and observing the complexity of
product distribution, DCM appeared to provide the cleanest
reactions compared with other solvents (DCM 4 THF 4
EtOAc 4 MeOH 4 toluene), as reported in Table 1.
These results strongly suggest that the order of events is as
outlined in Scheme 1, rather than the related process examined
by Inouye which is claimed to proceed through 2 equivalents
of a vinylogous amide reacting with 1 equivalent of aldehyde.9
We propose that intermediate A (i.e. 5) forms quickly and
reacts with an aldehyde to give the key species B assisted by
the Lewis acid. From this intermediate, it is likely that two
possible pathways may then operate. Either a Diels–Alder
cycloaddition pathway can occur via scandium-assisted
oxide elimination to derive electron deficient aza-diene C,
Fig. 1 X-ray-derived molecular structure of 4h (Olex2 graphics).10
4894 Chem. Commun., 2012, 48, 4893–4895
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[1+2+1+2]-cycloaddition pathway. After optimisation, the
dihydropyridine ring can be formed with high conversion
within a week.
We thank Merck & Co. (formerly Schering-Plough, Newhouse,
UK) for funding and the EPSRC National Mass Spectrometry
Service at Swansea.
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c
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Chem. Commun., 2012, 48, 4893–4895 4895