Exploration of forbidden povarov processes as a source of unexpected reactivity: A multicomponent Mannich-Ritter transformation

Article abstract of DOI:10.1002/anie.201202927

When a door closes, a window opens! The use of geometrically or electronically restricted imines for Povarov-type processes does not afford the anti-Bredt tetrahydroquinolines, but leads instead to highly functionalized structures through novel reaction pathways (see picture; LA=Lewis acid). The exploration of forbidden routes constitutes a valuable approach in the search for new multicomponent reactions. Copyright

Full text of DOI:10.1002/anie.201202927

Angewandte
Chemie
DOI: 10.1002/anie.201202927
Multicomponent Reactions
Exploration of Forbidden Povarov Processes as a Source of
Unexpected Reactivity: A Multicomponent Mannich–Ritter
Transformation**
Sara Preciado, Esther Vicente-Garcꢀa, Salomꢁ Llabrꢁs, F. Javier Luque, and Rodolfo Lavilla*
The ideal synthesis constitutes the ultimate challenge in
organic transformations.[1] In this context, multicomponent
reactions (MCRs) have enormous conceptual and practical
advantages,[2] especially for the exploitation of molecular
diversity based on heterocycles,[3] as these substructures are
widely present in natural products, bioactive compounds, and
drugs. This is exemplified by the Povarov reaction,[4] which
provides highly convenient access to the ubiquitous tetrahy-
droquinoline scaffold. This transformation features the inter-
action of an aniline, a carbonyl compound, and an electron-
rich olefin (under acid catalysis) to generate the MCR adduct
B through the intermediacy of an imine A (Scheme 1).[5,6] In
this process, the olefin should be amenable to bond formation
with the imine carbon and one unsubstituted ortho position of
the aniline ring (Scheme 1). We report here the results of
exploratory chemistry we carried out on systems in which this
pathway is geometrically or electronically infeasible.[7]
The cyclic imine 1a[8] was reacted with 2H-dihydropyran
(2a) under standard conditions with Sc(OTf)3 catalysis[9] in
acetonitrile (3a) at room temperature. The Povarov product
(C, Scheme 1) was not formed as it would feature a highly
Scheme 1. Suitable and unsuitable imines for Povarov MCRs.
L.A.=Lewis acid.
strained anti-Bredt moiety.[10] Instead, the Mannich process
was followed by a sequential Ritter step and completed by
amidine formation through trapping of the nitrilium ion by
the aniline nitrogen,[11] yielding the three-component-reaction
adduct 4a (67%) in a stereoselective manner (Scheme 1). The
structure of 4a was unequivocally determined by X-ray
structure analysis.[12] The stereochemical features of this
product reflect the expected patterns of interaction between
the two p systems to generate a C C bond,[4–6] followed by the
nitrile addition to the cyclic oxocarbenium ion to yield a cis-
fused pyran ring.[13] This finding sparked a series of experi-
ments to determine the usefulness of the new reaction. Its
scope was investigated by systematically scanning all the
components.
À
a-Substituted difluorinated indolenines 1b–d afforded the
corresponding adducts 4b–d (Table 1, entries 1–4). The
carbonyl analogue 1e was also productive (Table 1, entry 5),
whereas the dimethylindolenine 1 f (entry 6) failed to react,
probably because of steric hindrance or lack of activation.
Interestingly, the N- and O-heterocyclic derivatives 1g and 1h
(Table 1, entries 7 and 8) yielded 4g and 4h, respectively, the
latter being isolated after MeOH quenching. However, the
phenyl-substituted derivative 1i gave only traces of the MCR
adduct. In these reactions, N-alkylimines were almost unreac-
tive.[14] Analogous restrictions were found for o,o’-disubsti-
tuted aromatic imines such as 1j (Table 1, entry 9). The latter
substrates did not undergo the Mannich–Ritter process,
except in trace amounts, reflecting the practical limits of the
reaction. In contrast, the highly electrophilic m-dinitroaniline
derivative afforded the trans tetrahydropyran 4k (16%
unoptimized yield; Table 1, entry 10), presumably after
spontaneous epimerization. This is a remarkable example of
[*] S. Preciado, E. Vicente-Garcꢀa, Prof. R. Lavilla
Barcelona Science Park
Baldiri Reixac 10–12, 08028 Barcelona (Spain)
E-mail: rlavilla@pcb.ub.es
S. Llabrꢁs, Prof. F. J. Luque
Department of Physical Chemistry and
Institute of Biomedicine (IBUB), Faculty of Pharmacy
University of Barcelona
Avda Diagonal 643, 08028 Barcelona (Spain)
Prof. R. Lavilla
Laboratory of Organic Chemistry, Faculty of Pharmacy
University of Barcelona
Avda Joan XXIII s/n, 08028 Barcelona (Spain)
[**] This work was supported by DGICYT—Spain (projects
BQUCTQ2009-07758 and SAF2011-27642), Generalitat de Catalu-
nya (projects 2009SGR 1024 and 298), CESCA, and Grupo Ferrer
(Barcelona, Spain).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202927.
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Table 1: Range of imines 1.
Table 2: Range of nitriles 3.
Entry[a] Imine
1
1
Yield [%][b] Prod.
1a, R1 =Ph
1b, R1 =4-OMe-
67[c]
32[c]
25[c]
4a
4b
4c
Entry[a] Imine Nitrile
3
Yield[%][b]
4
2
3
1
2
1e
1a
3b 69
3c 59
4l, R2 =Pr
4m, R2 =iPr
C6H4
1c, R1 =3,4-
(MeO)2-C6H3
1d, R1 =CO2Et
3
4
1a
1a
3d
–
–
4
5
44
60
4d
4e
3e 40
4n, R2 =Bn
1e
1 f
5
6
1e
1e
3 f 41
3g 53
4o, R2 =(E)-1-propenyl
4p, R2 =vinyl
6
7
–
–
7
8
1e
1e
3h 44
4q, R2 =Ph
4r, R2 =2-hydroxy-2-
methoxyvinyl
1g
63
4g
3i 49[c]
[a] See footnote [a] in Table 1. [b] Yields of isolated products. [c] A
stoichiometric amount of 3i was used and 3d served as the solvent.
1h,R1 =H
1i, R1 =Ph
26[d]
4h
4i
8
9
traces[e]
1j
traces[e]
4j
conjugated amidine 4o. On the other hand, tert-butylcyanide
(3d) was completely unreactive (Table 2, entry 3). Acrylo-
and benzonitrile were suitable substrates for these trans-
formations (Table 2, entries 6 and 7). A functionalized nitrile
such as methyl cyanoacetate (3i) afforded the corresponding
MCR product (4r; Table 2, entry 8) isolated as the enol
tautomer. The main restriction in this process is the require-
ment of a large excess of nitrile 3.[11,15] However, when the
“inert” tert-butylcyanide served as the solvent it was possible
to use only one equivalent of the desired nitrile to achieve
comparable yields (Table 2, entry 8). This is particularly
interesting, since the most useful catalyst, Sc(OTf)3, performs
best in nitrile solvents.[16,17]
10
1k
16
4k
[a] Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3a (excess),
Sc(OTf)3 (0.20 mmol), RT, 24–72 h, Ar. [b] Yields of isolated products.
Isomer ratio >96:4. [c] Traces of the carbonyl analogue of the final
adduct were detected, which formed by hydrolysis of the starting
difluorinated imine. [d] After MeOH quenching. [e] Stereochemistry not
assigned.
Once the range of imines and nitriles was defined,
attention was focused on the activated olefin component.
Distinct types of enol ethers (Table 3, entries 1–4) afforded
the MCR adducts under modified reaction conditions. Thus,
2,3-dihydrofuran (2b) and glucal 2c reacted at higher
temperatures, whereas galactal 2d required microwave irra-
diation. The reaction with vinyl acetate (2e) yielded the
hydrolyzed MCR product (4v) after chromatographic purifi-
cation. In the case of N-activated olefins (Table 3, entries 5–
8), the main product arose from a Mannich interaction, in
sharp contrast with the outcome observed in standard
Povarov reactions.[18] In this way, the unsaturated lactam 2 f
afforded adduct 5a. Analogously, enamide 2g and thiazolone
2h (Table 3, entries 6 and 7) yielded 5b and 5c, respectively,
whereas enamine 2i gave, after the addition process, the
hydrolyzed aldehyde 5d (entry 8). Conjugated olefins such as
styrene 2j (Table 3, entry 9) yielded the expected adduct as
a 4:5 mixture of stereoisomers.
the new MCR, which may formally give rise to standard
Povarov adducts, owing to the free ortho positions on the
aniline precursor.
The range of nitriles was studied next using imines 1a and
1e as probes, and enol ether 2a as the olefin component
(Table 2). In addition to acetonitrile 3a (Table 1, entry 1),
linear, branched alkyl, benzyl, and allyl cyanides worked very
well (Table 2, entries 1, 2, 4, and 5), although the latter adduct
presumably isomerized afterwards under acid catalysis to the
Finally, under standard conditions the sterically hindered
imine 1l afforded the 4-quinolone adduct 6 together with
fluoropyridine 7 (Scheme 2). The former compound was
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Table 3: Range of olefin substrates 2.
Entry[a]
1
Olefin substr.
2
Yield [%][b]
38
Product
2b
4s
2
2c
17
4t[c]
Scheme 2. New pathways for hindered imine 1l.
3
4
5
2d
2e
2 f
47
49
64
4u[d]
4v[e]
5a
À
intermediate generated upon C C bond formation with
indolenine 1e. Calculations were performed for two olefins
that behave in different ways: dihydropyran (2a) (which
yielded 60% MCR adduct) and cyclic enamide 2 f (0%).
Owing to the large size of the intermediate, computations
were performed using a mimic where the bound cyclic imine
was replaced by a methyl group. The energy profiles indicate
that the attack of acetonitrile cis to the methyl group is the
preferred route, as expected from the greater stability of the
chairlike transition state (TS) compared to the boatlike TS
formed by trans addition (Figure 1).[13] The absence of the
MCR adduct for enamide 2 f is explained by the higher
6
7
2g
2h
21
59
5b
5c
8
9
2i
2j
49
25
5d
4w
[a] See footnote [a] in Table 1. [b] Yields of isolated products. [c] 10 min,
808C, MW irradiation. [d] 608C, 12 h. [e] Using 1a as the imine.
unequivocally identified by X-ray structure analysis.[12] The
quinolone derivative[19] may arise from a complex sequence
involving a Grob-type fragmentation,[20] an aza-Michael
process, and a 1,6-hydride shift[21] with concomitant elimina-
tion of a formaldehyde equivalent. The fluoropyridine 7 was
produced in an analogous manner. This represents a very
unusual outcome in a Mannich process involving a cyclic enol
ether, where its a-carbon is lost, leading to a substituted
quinolone.
Since the nature of the olefin plays a major role in
determining the outcome of Povarov MCRs, quantum
mechanical computations (MP2/aug-cc-pVDZ; see the Sup-
porting Information) were carried out to examine the
energetics for the addition of acetonitrile to the carbenium
Figure 1. Energy profile (kcalmolÀ1) for the cis (gray) and trans (black)
addition of acetonitrile to the carbenium intermediate formed from
dihydropyran 2a (a) and cyclic enamide 2 f (b), and representation of
the chair- and boatlike transition states formed in the cis and trans
additions (the length of the forming bond is given in ꢂ).
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barrier of the cis addition (12.7 kcalmolÀ1) compared to that
for 2a (7.5 kcalmolÀ1), which can be attributed to the greater
conformational strain introduced by the planarity of the
amide group in the chairlike TS (Figure S1 in the Supporting
Information).
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processes has led to the discovery of a new MCR providing
cyclic amidines. This finding is complemented by the descrip-
tion of alternative pathways for the formation of these
complex systems, including the production of Mannich and
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different inputs, three bonds are formed in a stereoselective
manner, and complex and diverse products are produced in
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Received: April 17, 2012
Published online: && &&, &&&&
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Keywords: domino reactions · heterocycles ·
multicomponent reactions · Ritter reaction · Schiff bases
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4
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Multicomponent Reactions
S. Preciado, E. Vicente-Garcꢁa, S. Llabrꢂs,
F. J. Luque, R. Lavilla*
&&&& — &&&&
Exploration of Forbidden Povarov
Processes as a Source of Unexpected
Reactivity: A Multicomponent Mannich–
Ritter Transformation
When a door closes, a window opens! The
use of geometrically or electronically
restricted imines for Povarov-type pro-
cesses does not afford the anti-Bredt
tetrahydroquinolines, but leads instead to
highly functionalized structures through
novel reaction pathways (see picture;
LA=Lewis acid). The exploration of “for-
bidden” routes constitutes a valuable
approach in the search for new multi-
component reactions.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!