An aminocatalyzed michael addition/Iron-Mediated decarboxylative cyclization sequence for the preparation of 2,3,4,6-Tetrasubstituted pyridines: Scope and mechanistic insights

Article abstract of DOI:10.1021/acs.joc.7b01789

A novel, scalable strategy for the preparation of 2,3,4,6-tetrasubstituted pyridines is described. This protocol has two steps: an aminocatalyzed addition of ketones to alkylidene isoxazol-5-ones, followed by an iron-mediated decarboxylative cyclization event. Mechanistic insights for both steps are provided based on HRMS-ESI(+) studies.

Full text of DOI:10.1021/acs.joc.7b01789

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Article
An Aminocatalyzed Michael Addition/Iron-mediated Decarboxylative
Cyclization Sequence for the Preparation of 2,3,4,6-
Tetrasubstituted Pyridines: Scope and Mechanistic Insights
Mateus L. Stivanin, Marcelo Duarte, Camila Sartori, Naylil
M. R. Capreti, Celio F. F. Angolini, and Igor D. Jurberg
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01789 • Publication Date (Web): 14 Sep 2017
Downloaded from http://pubs.acs.org on September 14, 2017
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An Aminocatalyzed Michael Addition/Iron-mediated
Decarboxylative Cyclization Sequence for the
Preparation of 2,3,4,6-Tetrasubstituted Pyridines:
Scope and Mechanistic Insights
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Mateus L. Stivanin, Marcelo Duarte, Camila Sartori,† Naylil M. R.
Capreti,† Celio F. F. Angolini, Igor D. Jurberg*
†Equal contributions
Institute of Chemistry, State University of Campinas, 13083ꢀ970, C.P. 6154, SP, Brazil
Abstract. A novel, scalable strategy for the preparation of 2,3,4,6ꢀtetrasubstituted
pyridines is described. This protocol has two steps: an aminocatalyzed addition of
ketones to alkylidene isoxazolꢀ5ꢀones, followed by an ironꢀmediated decarboxylative
cyclization event. Mechanistic insights for both steps are provided based on HRMSꢀ
ESI(+) studies.
Keywords: Pyridines; Isoxazolones; Organocatalysis; Iron; Massꢀspectrometry
Introduction
The pyridine heterocycle is an aromatic motif found in numerous alkaloids,1
pharmaceuticals,2 agrochemicals,3 chiral ligands,4 and materials,5 often present in
R&D programs. Therefore, perhaps not surprisingly, synthetic approaches
leading to this heteroaromatic nucleus are abundant. These approaches generally
rely on condensation reactions of amines with carbonyl compounds,6
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cycloisomerizations7 and cycloadditions,8 among others,9 via the employment of a
variety of substrates and promoters.
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Despite the tremendous advances in the field, the regioselective preparation of
these molecules is still challenging. In this context, numerous solutions have been
described employing Oꢀacetyl oximes as precursors, in the presence of a variety
of partners, so that often a NꢀO bond cleavage event can be mediated by catalytic
amounts of Cu,10 Pd,11 Fe,12 Ru,13 or iodine,14 thus triggering the cyclization step
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toward the corresponding pyridines. Other powerful protocols involving α,β
ꢀ
unsaturated ketoximes and olefins, or alkynes, have also been described
employing Rhꢀ15 and Cuꢀcatalysts.16
Although structurally similar to Oꢀacetyl oximes, isoxazolꢀ5ꢀones have been
much less frequently employed in similar transformations. This is somehow
surprising, because the presence of an active methylene in the cyclic structure of
the isoxazolꢀ5ꢀone ring allows prior
αꢀfunctionalizations, such as alkylation
protocols and condensation reactions (when R2 = H) with aldehydes and ketones,
thus allowing the direct access to the corresponding Michael acceptors,17 that are
not as easily available to Oꢀacetyl oximes (Figure 1).
Figure 1. Identification of structural similarity between isoxazolꢀ5ꢀones and Oꢀacetyl
oximes.
Based on the structural similarity, and following our interest in the chemistry
of isoxazolꢀ5ꢀones,18 we recognized the value of developing a synthetic route
toward pyridines, starting from an appropriate isoxazolꢀ5ꢀone precursor. In this
context, previous works from the groups of Beccalli19 and Chiba20 described the
preparation of quinolines and isoquinolines, via formal [3+3] and [2+4]
approaches, respectively (Scheme 1a and 1b), while Peters21 reported the
preparation of pyridines via a formal [3+3] strategy (Scheme 1c). In this work, a
synthetic route based on a twoꢀstep sequence is described. The first step takes
advantage of an aminocatalyzed conjugate addition of ketones
1 to alkylidene
isoxazolꢀ5ꢀones , thus leading to intermediates , which are then decarboxylated
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and cyclized in the presence of Fe, under air, to produce the corresponding
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5
2,3,4,6ꢀtetrasubstituted pyridines
4 (Scheme 1d).
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Scheme 1. Presentation of previous syntheses of the pyridine core starting
from different isoxazol-5-one precursors and the strategy developed in this
work, which allows the preparation of 2,3,4,6-tetrasubstituted pyridines 4.
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Results and Discussion
The synthetic route showcased in Scheme 1d has been designed based on the
previous observation that Fe can decarboxylate isoxazolꢀ5ꢀones to afford the
corresponding ketones.18a In that context, it was imagined that an iminium ion
intermediate would be involved. If this hypothesis was true, its enamine tautomer
would be equally accessible in acidic media. Therefore, by placing an
appropriately positioned carbonyl group from the enamine nitrogen atom
(considering an intermediate such as 3´, see Scheme 1), one would produce an
intramolecular cyclization event, which could then further undergo an oxidation
step promoted by the presence of air,22 thus generating the corresponding
pyridine
4. After preliminary experiments, the envisioned synthetic plan was
demonstrated feasible and further extensive optimization followed.
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Considering the optimization for the conjugate addition, the model reaction
involved the use of cyclohexanone 1a and alkylidene isoxazolꢀ5ꢀone 2a, thus
leading to adduct 3a. Remarkably, this reaction proceeds with perfect control of
diastereoselectivity. For all aminocatalysts employed, and for all isoxazolꢀ5ꢀone
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intermediates
diastereoisomer. In the context of this work, this is not relevant, because all
stereogenic centers are later destroyed, when pyridines are produced.
3 obtained, they are all produced as a single, allꢀsyn
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4
Nevertheless, this observation is certainly useful for the development of other
chemistry.23
Among the achiral aminocatalysts employed (Table 1, entries 1ꢀ7) in the
presence of benzoic acid (60 mol%), in DCM, at room temperature,
(40 mol%) provided the best yield, 67% (Table 1, entry 7), when compared to the
other amines (Table 1, entries 1ꢀ6). Next, different amounts of ꢀanisidine were
oꢀanisidine
o
evaluated (Table 1, entries 8ꢀ12), but all performed less efficiently than the
previous amount of 40 mol% (Table 1, entry 7).
Then, by varying the nature of the acid employed (Table 1, entries 13ꢀ22), 4ꢀ
fluorobenzoic acid was identified as the best choice, thus providing this time a
70% yield (Table 1, entry 22). Finally, a systematic investigation on the amount
of 4ꢀfluorobenzoic acid needed (Table 1, entries 24ꢀ28) demonstrated that 40
mol% is the optimal choice (Table 1, entry 25). Remarkably, the absence of any
acid coꢀcatalyst also affords a productive reaction, thus delivering a 67% yield
(Table 1, entry 23). A plausible explanation for this observation derives from the
high acidity of the αꢀproton of the carbonyl group at the isoxazolꢀ5ꢀone ring of
3a (pKa ~ 4ꢀ6):24 this proton presumably acts as a promoter of the reaction, thus
enabling tautomerization events needed for the whole process to proceed.
Table 1. Selected entries for the optimization of the aminocatalyzed conjugate
addition of ketone 1a to alkylidene isoxazol-5-one 2a.
entry
amine (x mol%)
BnNH2 (40)
Cyclopropylamine (40)
4ꢀ(OH)C6H4NH2 (40)
acid (y mol%)
PhCO2H (60)
PhCO2H (60)
PhCO2H (60)
y (%)a
44
50
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PhNH2 (40)
CyNH2 (40)
4ꢀ(MeO)C6H4NH2 (40)
2ꢀ(OMe)C6H4NH2 (40)
ꢀ
PhCO2H (60)
PhCO2H (60)
PhCO2H (60)
PhCO2H (60)
PhCO2H (60)
PhCO2H (60)
PhCO2H (60)
PhCO2H (60)
PhCO2H (60)
62
55
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67
0
2ꢀ(OMe)C6H4NH2 (10)
2ꢀ(OMe)C6H4NH2 (20)
2ꢀ(OMe)C6H4NH2 (60)
2ꢀ(OMe)C6H4NH2 (100)
2ꢀ(OMe)C6H4NH2 (40)
2ꢀ(OMe)C6H4NH2 (40)
2ꢀ(OMe)C6H4NH2 (40)
2ꢀ(OMe)C6H4NH2 (40)
2ꢀ(OMe)C6H4NH2 (40)
2ꢀ(OMe)C6H4NH2 (40)
2ꢀ(OMe)C6H4NH2 (40)
2ꢀ(OMe)C6H4NH2 (40)
2ꢀ(OMe)C6H4NH2 (40)
2ꢀ(OMe)C6H4NH2 (40)
2ꢀ(OMe)C6H4NH2 (40)
2ꢀ(OMe)C6H4NH2 (40)
2-(OMe)C6H4NH2 (40)
2ꢀ(OMe)C6H4NH2 (40)
2ꢀ(OMe)C6H4NH2 (40)
2ꢀ(OMe)C6H4NH2 (40)
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66
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<5
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AcOH (60)
4ꢀ(NO2)C6H4CO2H (60)
2ꢀ(NO2)C6H4CO2H (60)
2,4ꢀ(NO2)2C6H3CO2H (60)
4ꢀ(CF3)C6H4CO2H (60)
3ꢀ(CF3)C6H4CO2H (60)
3,5ꢀ(CF3)2C6H3CO2H (60)
C6F5CO2H (60)
2,6ꢀ(F)2C6H3CO2H (60)
4ꢀ(F)C6H4CO2H (60)
ꢀ
4ꢀ(F)C6H4CO2H (20)
4-(F)C6H4CO2H (40)
4ꢀ(F)C6H4CO2H (100)
4ꢀ(F)C6H4CO2H (200)
4ꢀ(F)C6H4CO2H (300)
[a]Yields are estimated based on 1H NMR of crude reaction mixture using 1,3,5ꢀ
trimethoxybenzene as internal standard.
Next, the decarboxylative cyclization event converting
pyridines was optimized. In this context, the acyclic isoxazolꢀ5ꢀone 3k was
chosen as a model substrate.
3 to the desired
4
Only benzoic acid does not promote the reaction (Table 2, entry 1). A number
of iron salts are also ineffective for this transformation (Table 2, entries 2ꢀ4).
Good yields were only obtained when Fe was employed as a single electron
reducing agent. The use of Fe (10 equiv.) in the presence of PhCO2H (10 equiv.)
produced a 70% yield (Table 2, entry 5), while decreasing the amount of benzoic
acid to 1 equiv. significantly decreased the efficiency of the reaction, this time
producing a 46% yield (Table 2, entry 6). Then, we turned our attention to the
optimization of the acid. Among the different acid sources investigated, the use of
NH4Cl, and AcOH seems to be not strong enough to promote this reaction (Table
2, entries 7 and 8, respectively), while the presence of water in the HCl solution
presumably hydrolyzes the intermediates formed, thus affording also low yields
for this transformation (Table 2, entry 9). The use of stronger acids (i.e. compared
to NH4Cl and AcOH) produces higher yields (Table 2, entries 10ꢀ15), with 3,5ꢀ
dimethoxybenzoic acid producing the best result, 76% (Table 2, entry 11).
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Furthermore, reactions using Fe (1 equiv.) or Fe (5 equiv.), both in the
presence of 3,5ꢀdimethoxybenzoic acid (10 equiv.) produced 50% and 60%
yields, respectively (Table 2, entries 16 and 17). On the other hand, the use of Fe
(20 equiv.), in the presence of 3,5ꢀdimethoxybenzoic acid (10 equiv.), does not
improve the reaction performance. In this case, a 76% yield is also obtained
(Table 2, entry 18).
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Table 2. Optimization of the Iron-promoted decarboxylative cyclization of
isoxazol-5-ones 3 toward 2,3,4,6-tetrasubstituted pyridines 4.
entry
Fe source
(x equiv)
ꢀ
acid (y equiv)
yield (%)
1
2
PhCO2H (10)
PhCO2H (10)
<5
<5
<5
<5
70
46
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37
67
76
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76
FeCl3 (1)
Fe(acac)3 (1)
FeSO4.7H2O (10)
Fe (10)
3
PhCO2H (10)
4
PhCO2H (10)
5
PhCO2H (10)
6
Fe (10)
PhCO2H (1)
7
Fe (10)
NH4Cl (10)
8
Fe (10)
AcOH (10)
9
Fe (10)
HCl (10)
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18
Fe (10)
TFA (10)
Fe (10)
Fe (10)
3,5-(OMe)2C6H3CO2H (10)
4ꢀ(NH2)C6H4CO2H
2,4,6ꢀ(OMe)3C6H2CO2H (10)
2,6ꢀ(F)2C6H3CO2H (10)
(CF3SO2)2NH (10)
3,5ꢀ(OMe)2C6H3CO2H (10)
3,5ꢀ(OMe)2C6H3CO2H (10)
3,5ꢀ(OMe)2C6H3CO2H (10)
Fe (10)
Fe (10)
Fe (10)
Fe (1)
Fe (5)
Fe (20)
[a]Yields are estimated based on 1H NMR of crude reaction mixture using 1,3,5ꢀ
trimethoxybenzene as internal standard.
With the optimized conditions in hand, the scope of this twoꢀstep sequence
was evaluated considering different ketones
1 and alkylidene isoxazolꢀ5ꢀones 2
(Scheme 2). Concerning the Michael addition, cyclic and linear ketones produced
good general reactivity, although cyclic ketones typically afforded better results.
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Scheme 2. Pyridines prepared in this work.
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Nevertheless, cyclopentanone (Scheme 2, molecule 4b) and cycloheptanone
(Scheme 2, molecule 4c) afforded somehow lower yields than 6ꢀmembered cyclic
6
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ketones (Scheme 2, molecule 4a, 4dꢀ4j). Acyclic ketones typically produced the
corresponding Michael adducts in slightly lower yields, under more forcing
reaction conditions: a larger excess of ketone (5 equiv) was employed and the
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reactions were stirred for a longer period (7 days) (Scheme 2, molecules 4k
ꢀ4t).
In relation to the alkylidene isoxazolꢀ5ꢀones , either one or two aromatic
2
substitutuents (in R3 and/or R4) allowed good results for this 1,4ꢀaddition step. No
significant conversion was obtained when two aliphatic substituents were present
(Scheme 2, molecule 4u). At this point, it is possible to speculate that
stacking interactions might play an important role for the first aminocatalyzed
addition step.25 Concerning the preparation of pyridines
from adducts , all of
them were produced somehow in similar yields, 48ꢀ76% (Scheme 2, molecules
4a 4t).
πꢀπ
4
3
ꢀ
Furthermore, this twoꢀstep protocol was also evaluated in gramꢀscale
employing cyclohexanone 1a and alkylidene isoxazolꢀ5ꢀone 2a, thus affording
the corresponding pyridine 4a in similar yield as previously established (Scheme
3).
Scheme 3. Synthesis of 4a in a preparative scale.
Finally, the reaction mechanisms involved in both steps were investigated. In
this context, a high resolution massꢀspectrometer (HRMS) operating by positive
electronspray ionization was employed.26 The use of such an equipment is
attractive in this case, because the low concentrations of the reactive species
involved in both steps, as well as the presence of paramagnetic species derived
from a SET reduction mechanism (in the case of the decarboxylative cyclization
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event, promoted by Fe) makes NMR studies challenging. For the examination of
these reactions by HRMSꢀESI(+), aliquots were collected from the reaction
mixture at different periods (see SI for details).
In the study of the aminocatalyzed conjugate addition employing
cyclohexanone 1a and alkylidene isoxazolꢀ5ꢀone 2a, ions of m/z 107.0491,
124.0759, 162.0544, 187.1112, 204.1385, 212.1068, 250.0853, 292.1694,
310.1799, 348.1589, 373.1544, 453.2172 were found and identified. The
observation of these ions support a classical aminocatalyzed conjugate addition
mechanism of an enamine intermediate, derived from the condensation between
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cyclohexanone 1a and oꢀanisidine, on the Michael acceptor 2a, but also reveals
the presence of unanticipated intermediates, which presumably indicates the
involvement of a more complex equilibrium (Scheme 4a).
In order to obtain more information about the formation of these intermediates,
a series of control experiments were performed. For instance, when isolated pure
1
compound 3a is stirred at room temperature under the reaction conditions, H
NMR of the crude reaction mixture indicates that no appreciable amount of
isoxazolꢀ5ꢀone 5, enone 6 or benzaldehyde are formed, while the monitoring of
this same reaction by HRMS reveals the presence of both components. Therefore,
these compounds must be formed in the reaction mixture only in very small
amounts (Scheme 4).
When studying the reaction of isoxazolꢀ5ꢀone
equiv) under the same reaction conditions, the addition product 3a is obtained as
a single diastereoisomer in 35% yield. Furthermore, when cyclohexanone 1a
benzaldehyde and isoxazolꢀ5ꢀone , in a 3:1:1 ratio, respectively, are submitted
5 (3 equiv) with enone 6 (1
,
7
5
to the established aminocatalytic conditions, 3a is produced again as a single
diasteroisomer, this time in 52% yield. In this case, the monitoring of the reaction
by 1H NMR reveals the formation of 2a, thus strongly suggesting that isoxazolꢀ5ꢀ
one
alkylidene isoxazolꢀ5ꢀone 2a as an intermediate, that is subsequently attacked by
the enamine of cyclohexanone 1a
5 undergoes Knoevenagel condensation with benzaldehyde 7 to generate
.
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Scheme 4. a) Proposed equilibrium involved in the formation of 3a, based on
HRMS-ESI(+) experiments. b) Qualitative assessment of relative reaction
rates, based on control experiments.
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Next, the conversions derived of all three possible combinations of reagents that have
been previously identified, all in equimolar amounts to each other, were measured. As a
consequence, a qualitative assessment of relative reaction rates could be established
(Scheme 4b). In more details, after 4 days, the reaction of isoxazolꢀ5ꢀone 5 and enone 6
affords 3a in 22% yield (+ 60% 6), while the reaction between the individual
components cyclohexanone 1a, isoxazolꢀ5ꢀone 5 and benzaldehyde 7 affords 3a in 46%
yield (+ 9% 2a and 0% 7). Finally, the reaction between cyclohexanone 1a and
alkylidene isoxazolꢀ5ꢀone 2a is the fastest, this time affording 3a in 60% yield (+ 5%
2a). This data strongly suggests that the aminocatalyzed Michael addition of ketones 1
to alkylidene isoxazolꢀ5ꢀones 2 is in equilibrium and explains the excellent
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diastereoselectivities for compounds 3 as a result of thermodynamic control (see SI for
more details).
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In the study of the decarboxylative cyclization event promoted by Fe, ions of
m/z 286.1593, 288.1744, 304.1697, 306.1854, 326.1519, 348.1597, 370.1418
were found and identified. The presence of these ions suggests that there is a
bifurcation in the reaction pathway. Accordingly, the adduct 3a is reduced by Fe,
in the presence of 3,5ꢀdimethoxybenzoic acid, thus promoting a decarboxylation
event, that leads to an enamine intermediate. In one pathway, this enamine
intermediate can undergo an oxidation step, followed by a cyclization event. In
the second pathway, this same enamine intermediate can first undergo a
cyclization step, then being followed by an oxidation event. In both cases, the
final outcome is the preparation of the pyridine 4a (Scheme 5).27 At this point, it
is not possible to determine which pathway has a greater contribution for the
formation of the observed pyridines (see SI for more details).
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Scheme 5. Proposed reaction mechanism for the decarboxylative cyclization of
isoxazol-5-one 3a toward pyridine 4a, based on HRMS-ESI(+) experiments.
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Conclusions
In summary, this work describes a twoꢀstep sequence for the preparation of
densely substituted pyridines starting from ketones and alkylidene isoxazolꢀ5ꢀ
ones . This process has been demonstrated to be scalable and both steps have
been studied by HRMSꢀESI(+). In the first step, the results demonstrate that a
more complex equilibrium is involved in the synthesis of adducts , which is
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ultimately responsible for a thermodynamic control, that explains the high
diastereoselectivities observed for this step. In the second step, two reaction
pathways seem to be occurring simultaneously (but not necessarily to the same
extent) in the synthesis of pyridines 4. In one pathway, the cyclization event
occurs first, then being followed by the oxidation step, while in the second
pathway, oxidation occurs first, then being followed by the cyclization event.
Experimental Section
Materials and Methods
All reactions were carried out under air, in oven dried glassware with magnetic
stirring, unless otherwise noted. All reagents employed in this work were purchased
from SigmaꢀAldrich and used without further purification. All solvents employed in the
reactions were distilled from appropriate drying agents prior to use. Organic solutions
were concentrated under reduced pressure on a IKA rotary evaporator RVꢀ10 Control.
Reactions were monitored by thinꢀlayer chromatography (TLC) on Silica gel 60 F254
aluminium plates (Merck). Chromatograms were visualized by fluorescence quenching
with UV light at 254 nm or by staining using paraꢀanisaldehyde solution. Flash column
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chromatography was performed using Merck silica gel 60 (particle size 35ꢀ70µm). H
and 13C NMR spectra were recorded on either Bruker DPXꢀ250, AVꢀ400, AVꢀ500 or
AVꢀ600 MHz spectrometers. Chemical shifts (δ) are given in parts per million,
referenced to the residual peak of CDCl3, δ = 7.26 (1H NMR) and δ = 77.0 (13C NMR)
as internal references. The following abbreviations were used to designate chemical
shift multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, quint. = quintuplet,
sext. = sextuplet, sept. = septuplet, m = multiplet, br s = broad singlet. Highꢀresolution
mass spectra were recorded on Thermo Scientific LTQ FT Ultra and Q Exactive
Orbitrap spectrometers working with an electronspray ionization (ESI).
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Alkylidene isoxazolones 2a-i have been prepared in two steps, according to the
literature, using the appropriate βꢀketoester and aldehyde.18,23
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(Z)-4-benzylidene-3-phenylisoxazol-5(4H)-one (2a): Prepared in two steps.23 For the
first step, the crude material obtained is washed with DCM/ hexanes to afford the
intermediate 3ꢀphenylisoxazolꢀ5(4H)ꢀone as a light pink solid (3.49 g, 92%). In the
second step, the title product crashes out of the solution and is isolated by filtration,
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while washing with PrOH, to afford a yellow solid (1.94 g, 78%). H (250 MHz,
CDCl3) δ: 8.31ꢀ8.32 (m, 2H), 7.62ꢀ7.49 (m, 9H).13C (150 MHz, CDCl3) δ: 168.0, 164.0,
152.7, 134.1, 134.0, 132.4, 131.0, 129.3, 129.0, 128.7, 127.4, 118.9. HRMS (ESI+):
Calcd. for [C16H11NO2+H]+: 250.0863, found: 250.0861.
(Z)-4-(4-chlorobenzylidene)-3-phenylisoxazol-5(4H)-one (2b): Prepared in two
steps.23 For the first step, 3ꢀphenylisoxazolꢀ5(4H)ꢀone is synthesized as previously
described for molecule 2a. In the second step, the title product crashes out of the
solution and is isolated by filtration, while washing with iPrOH, to afford a yellow solid
(1.5 g, 70%). 1H (400 MHz, CDCl3) δ: 8.30ꢀ8.28 (m, 2H), 7.63ꢀ7.53 (m, 6H), 7.50ꢀ7.47
(m, 2H). 13C (100 MHz, CDCl3) δ: 168.0, 163.9, 150.9, 140.7, 135.2, 131.2, 130.8,
129.4, 129.4, 128.8, 127.2, 119.3. HRMS (ESI+): Calcd. for [C16H10NO2Cl+H]+:
284.0473, found: 284.0483.
(Z)-3-isopropyl-4-(naphthalen-2-ylmethylene) isoxazol-5(4H)-one (2c): Prepared in
two steps.23 For the first step, the crude material obtained is purified by flash column
chromatography (SiO2, gradient: Hex ꢀ 9:1 Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 7:3
Hex:AcOEt) to afford the intermediate 3ꢀisopropylisoxazolꢀ5(4H)ꢀone as a yellow oil
(2.5 g, 98%). In the second step, the title product crashes out of the solution and is
i
isolated by filtration, while washing with PrOH, to afford a bright yellow solid (762
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mg, 56%). H (400 MHz, CDCl3) δ: 8.82 (s, 1H), 8.45 (dd, J = 8.7Hz, J = 1.7Hz, 1H),
8.97 (d, J = 8.1Hz, 1H), 7.91 (d, J = 8.7Hz, 1H), 7.86 (d, J = 8.1Hz, 1H), 7.65ꢀ7.54 (m,
3H), 3.07 (sept, J = 6.9Hz, 1H), 1.42 (d, J = 6.9Hz, 6H). 13C (100 MHz, CDCl3) δ:
168.5, 168.0, 149.2, 136.5, 135.6, 132.7, 130.0, 129.8, 129.4, 128.6, 128.4, 127.8,
127.0, 118.1, 26.5, 20.2. HRMS (ESI+): Calcd. for [C17H15NO2+H]+: 266.1176, found:
266.1173.
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4-benzylidene-3-ethylisoxazol-5(4H)-one (2d) [10:1 Z:E]: Prepared in two steps.18
For the first step, the crude material obtained is purified by flash column
chromatography (SiO2, gradient: Hex ꢀ 9:1 Hex: Et2O ꢀ 7:3 Hex:Et2O ꢀ 1:1 Hex: Et2O ꢀ
7:3 Et2O:Hex ꢀ Et2O) to afford the intermediate 3ꢀethylisoxazolꢀ5(4H)ꢀone as a yellow
oil (2.25 g, 99%). In the second step, the title product crashes out of the solution and is
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isolated by filtration, while washing with PrOH, to afford a pale yellow solid (10:1 Z:
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E, 2.1 g, 54%). H (500 MHz, CDCl3) (only major isomer Z described) δ: 8.34 (d, J =
7.5Hz, 2H), 7.60ꢀ7.57 (m, 1H), 7.54ꢀ7.50 (m, 2H), 7.45 (s, 1H), 2.69 (q, J = 7.5Hz, 2H),
1.37 (t, J = 7.5Hz, 3H). 13C (125 MHz, CDCl3) (only major isomer Z described) δ:
168.1, 164.8, 149.3, 133.9, 133.7, 132.3, 129.0, 119.1, 19.7, 10.4. HRMS (ESI+): Calcd.
for [C12H11NO2+Na]+: 224.0682, found: 224.0678.
(Z)-4-(furan-2-ylmethylene)-3-isopropylisoxazol-5(4H)-one (2e): Prepared in two
steps.18 For the first step, 3ꢀisopropylisoxazolꢀ5(4H)ꢀone is synthesized as previously
described for molecule 2c. In the second step, the title product is purified by flash
column chromatography (SiO2, gradient: Hexꢀ 9:1 Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 6:4
1
Hex:AcOEt)), to afford a yellow solid (1.38 g, 78%). H (600 MHz, CDCl3) δ: 8.58 (d,
J = 4.0Hz, 1H), 7.78 (d, J = 1.2Hz, 1H), 7.40 (s, 1H), 6.75 (dd, J = 4.0Hz, J =1.2Hz,
1H), 2.98 (sept, J = 6.9Hz, 1H), 1.37 (d, J = 6.9Hz, 6H). 13C (150 MHz, CDCl3) δ:
168.8, 167.5, 150.1, 149.2, 131.4, 125.8, 115.2, 113.0, 26.6, 20.2. HRMS (ESI+): Calcd.
for [C11H11NO3+H]+: 206.0812, found: 206.0810.
(Z)-4-(4-fluorobenzylidene)-3-phenylisoxazol-5(4H)-one (2f): Prepared in two
steps.18 For the first step, 3ꢀphenylisoxazolꢀ5(4H)ꢀone is synthesized as previously
described for molecule 2a. In the second step, the title product crashes out of the
solution and is isolated by filtration, while washing with iPrOH, to afford a yellow solid
(857 mg, 64%). m.p. 173ꢀ175 C. 1H (400 MHz, CDCl3) δ: 8.45 – 8.42 (m, 2H), 7.63 –
o
7.58 (m, 6H), 7.22 (t, J = 8,6Hz, 2H). 13C (100 MHz, CDCl3) δ: 168.2, 166.1 (d, J =
258.2Hz), 164.0, 151.1, 136.9 (d, J = 9.4Hz), 131.1, 129.3, 128.9 (d, J = 3.1Hz), 128.7,
127.3, 118.3, 116.4 (d, J = 21.8Hz). HRMS (ESI+): Calcd. for [C16H10NO2F+H]+:
268.0768, found: 268.0766.
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(Z)-4-benzylidene-3-(4-methoxyphenyl)isoxazol-5(4H)-one (2g): Prepared in two
steps.23 For the first step, the reaction mixture is concentrated to afford the intermediate
3ꢀ(4ꢀmethoxyphenyl)isoxazolꢀ5(4H)ꢀone a reddish solid (1.97 g, 99%). In the second
step, the title product crashes out of the solution and is isolated by filtration, while
washing with iPrOH, to afford a pale yellow solid (1.17 g, 80%). 1H (400 MHz, CDCl3)
δ: 8.33 (d, J = 8.1Hz, 2H), 7.64ꢀ7.51 (m, 6H), 7.09 (d, J = 8.1Hz, 2H), 3.91(s, 3H). 13C
(100 MHz, CDCl3) δ: 168.2, 163.6, 161.8, 152.7, 134.1, 134.0, 132.4, 130.2, 128.0,
119.5, 119.0, 114.8, 55.5. HRMS (ESI+): Calcd. for [C17H13NO3+H]+: 280.0968, found:
280.0967.
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4-(cyclopropylmethylene)-3-phenylisoxazol-5(4H)-one (2h) [9:1 Z:E]: Prepared in
two steps.23 For the first step, 3ꢀphenylisoxazolꢀ5(4H)ꢀone is synthesized as previously
described for molecule 2a. In the second step, the title product is purified by flash
column chromatography (SiO2, gradient: Hexꢀ 95:5 Hex:AcOEt ꢀ 9:1 Hex:AcOEt ꢀ 8:2
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Hex:AcOEt) to afford the title compound as a pink solid (9:1 Z:E, 400 mg, 63%). H
(400 MHz, CDCl3) δ: 7.54ꢀ7.48 (m, 5H), 6.62 (d, J = 12.0Hz, 0.1H), 6.49 (d, J =
11.6Hz, 0.9H), 3.37ꢀ3.27 (m, 0.9H), 1.85ꢀ1.78 (m, 0.1H), 1.47ꢀ1.45 (m, 1.8H), 1.27ꢀ
1.23 (m, 0.2H), 1.02ꢀ0.98 (m, 2H). 13C (100 MHz, CDCl3) (only major isomer Z
described) δ: 170.0, 166.0, 161.1, 130.9, 129.2, 128.1, 127.4, 118.7, 14.7, 13.6. HRMS
(ESI+): Calcd. for [C13H11NO2+H]+: 214.0863, found: 214.0860.
(Z)-4-(cyclopropylmethylene)-3-isopropylisoxazol-5(4H)-one (2i): Prepared in two
steps.23 For the first step, 3ꢀisopropylisoxazolꢀ5(4H)ꢀone is synthesized as previously
described for molecule 2c. In the second step, the title product is purified by flash
column chromatography (SiO2, gradient: Hexꢀ 95:5 Hex:AcOEt ꢀ 9:1 Hex:AcOEt ꢀ 8:2
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Hex:AcOEt) to afford the title compound as a white solid (463 mg, 86%). H (500
MHz, CDCl3) δ: 6.31 (d, J = 11.4Hz, 1H), 3.24ꢀ3.22 (m, 1H), 2.85ꢀ2.81 (m, 1H), 1.42ꢀ
1.40 (m, 2H), 1.28 (d, J = 6.9Hz, 6H), 0.97ꢀ0.96 (m, 2H). 13C (125 MHz, CDCl3) δ:
170.1, 165.8, 162.5, 118.8, 26.6, 20.1, 14.0, 13.0. HRMS (ESI+): Calcd. for
[C10H13NO2+H]+: 180.1019, found: 180.1017.
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General reaction conditions for racemic aminocatalyzed addition of ketones to
alkylidene isoxazol-5-ones (Step 1): ketone (0.6 mmol for cyclic and 1 mmol for
acyclic ones), alkylidene isoxazolꢀ5ꢀone (0.2 mmol), oꢀanisidine (0.08 mmol), 4ꢀ
fluorobenzoic acid (0.08 mmol) and DCM (1 mL) are added under air, at room
temperature to a roundꢀbottom flask and stirred at room temperature for 4ꢀ7 days, being
followed by TLC analysis. Upon completion, the reaction mixture is diluted in DCM,
washed once with an aqueous saturated solution of NaHCO3, dried (MgSO4),
concentrated under reduced pressure and purified by flash column chromatography.
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4-((2-oxocyclohexyl)(phenyl)methyl)-3-phenylisoxazol-5(4H)-one23 (3a): Reaction
time: 96h. Purification by flash column chromatography (SiO2, gradient: Hex ꢀ 9:1
Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 7:3 Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title
compound as a yellow solid (51 mg, 74%). 1H (500 MHz, CDCl3) δ: 7.76ꢀ7.74 (m, 2H),
7.55ꢀ 7.48 (m, 3H), 7.22ꢀ7.13 (m, 3H), 6.73 (br s, 2H), 4.81 (d, J = 4.6Hz, 1H), 3.79 (td,
J = 11.8Hz, J = 4.6Hz, 1H), 3.53 (dd, J = 11.1Hz, J = 4.6Hz, 1H), 2.70ꢀ2.62 (m, 1H),
2.55ꢀ 2.51 (m, 1H), 2.21ꢀ2.18 (m, 1H), 1.76ꢀ1.61 (m, 4H), 1.08ꢀ0.98 (m, 1H). 13C (100
MHz, CDCl3) δ: 214.5, 178.0, 166.6, 135.7, 131.7, 129.2, 128.8, 128.2, 128.1, 127.7,
127.3, 48.7, 47.5, 45.2, 43.2, 34.0, 29.3, 25.5. HRMS (ESI+): Calcd. for
[C22H21NO3+H]+: 348.1594, found: 348.1600.
4-((2-oxocyclopentyl)(phenyl)methyl)-3-phenylisoxazol-5(4H)-one23 (3b): Reaction
time: 96h. Purification by flash column chromatography (SiO2, gradient: Hex ꢀ 9:1
Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title compound as an orange
1
solid (25 mg, 38%). H NMR (400 MHz, CDCl3) δ: 7.65ꢀ7.63 (m, 2H), 7.56ꢀ7.54 (m,
3H), 7.22ꢀ7.14 (m, 3H), 6.77 (d, J = 7.0Hz, 2H), 5.52 (d, J = 4.0Hz, 1H), 3.70ꢀ3.62 (m,
1H), 3.27 (dd, J = 11.3Hz, J = 4.0Hz, 1H), 2.60ꢀ2.52 (m, 1H), 2.33ꢀ2.23 (m, 1H), 1.96ꢀ
1.85 (m, 3H), 1.22ꢀ1.11 (m, 1H). 13C NMR (100 MHz, CDCl3) δ: 177.7, 166.4, 136.3,
131.6, 129.3, 129.3, 129.1, 128.6, 128.2, 128.1, 127.7, 127.3, 47.2, 46.1, 38.5, 29.9,
19.5. HRMS (ESI+): Calcd. for [C21H19NO3+H]+: 334.1438, found: 334.1434.
4-((2-oxocycloheptyl)(phenyl)methyl)-3-phenylisoxazol-5(4H)-one23 (3c): Reaction
time: 96h. Purification by flash column chromatography (SiO2, gradient: Hex ꢀ 9:1
Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title compound as an orange
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solid (29 mg, 40%). H (600 MHz, CDCl3) δ: 7.65ꢀ7.64 (m, 2H), 7.56ꢀ7.53 (m, 1H),
7.52ꢀ7.49 (m, 2H), 7.22ꢀ7.19 (m, 1H), 7.17ꢀ7.14 (m, 2H), 6.75 (br s, 2H), 4.37 (d, J =
5.0Hz, 1H), 4.01 (td, J = 11.3Hz, J = 2.6Hz, 1H), 3.60 (dd, J = 11.3Hz, J = 5.0Hz, 1H),
2.93 (ddt, J = 16.8Hz, J = 4.3Hz, J = 1.3Hz, 1H), 2.56 (quint., J = 8.6Hz, 1H), 2.00ꢀ
1.92 (m, 2H), 1.71ꢀ1.66 (m, 2H), 1.45 (dq, J = 14.2Hz, J = 2.6Hz, 1H), 1.39ꢀ1.32 (m,
1H), 1.24ꢀ1.18 (m, 1H), 1.04ꢀ0.98 (m, 1H). 13C (150 MHz, CDCl3) δ: 216.4, 177.7,
166.4, 136.0, 131.7, 130.2, 129.2, 128.8, 128.2, 127.6, 127.2, 49.5, 47.2, 45.9, 44.3,
30.3, 29.3, 27.9, 22.7. HRMS (ESI+): Calcd. for [C23H23NO3+H]+: 362.1751 Found:
362.1756.
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4-((4-chlorophenyl)(2-oxocyclohexyl)methyl)-3-phenylisoxazol-5(4H)-one23
(3d):
Reaction time: 96h. Purification by flash column chromatography (SiO2, gradient: Hex ꢀ
9:1 Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 7:3 Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title
1
compound as an yellow solid (53 mg, 69%). H (400 MHz, CDCl3) δ: 7.77ꢀ7.75 (m,
2H), 7.56ꢀ7.50 (m, 3H), 7.13 (d, J = 8.4Hz, 2H), 6.67 (br s, 2H), 4.80 (d, J = 4.7Hz,
1H), 3.75 (td, J = 12.0Hz, J = 4.7Hz, 1H), 3.52 (dd, J = 11.1Hz, J = 4.5Hz, 1H), 2.64
(td, J = 12.6Hz J = 6.4Hz, 1H), 2.55ꢀ2.50 (m, 1H), 2.22ꢀ2.17 (m, 1H), 1.76ꢀ1.64 (m,
3H), 1.29ꢀ1.20 (m, 1H), 1.05ꢀ0.97 (m, 1H). 13C (100 MHz, CDCl3) δ: 214.1, 177.8,
166.3, 134.2, 134.0, 131.8, 129.5, 129.3, 129.0, 127.4, 127.3, 48.5, 47.3, 44.6, 43.2,
33.9, 29.2, 25.4. HRMS (ESI+): Calcd. for [C22H20NO3Cl+H]+: 382.1204, found:
382.1199.
3-isopropyl-4-(naphthalen-2-yl(2-oxocyclohexyl)methyl)isoxazol-5(4H)-one23 (3e):
Reaction time: 96h. Purification by flash column chromatography (SiO2, gradient: Hex ꢀ
9:1 Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 7:3 Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title
1
compound as an orange solid (58 mg, 80%). H (500 MHz, CDCl3) δ: 7.85ꢀ7.79 (m,
3H), 7.58 (s, 1H), 7.54ꢀ7.49 (m, 2H), 7.26 (dd, J = 8.5Hz, J = 1.5Hz, 1H), 4.48 (d, J =
5.2Hz, 1H), 3.84 (dt, J = 12.5Hz, J = 4.9Hz, 1H), 3.60 (dd, J = 10.9Hz, J = 5.2Hz,1H),
2.75 (sept., J = 6.9Hz, 1H), 2.69ꢀ2.63 (m, 1H), 2.52 (d, J = 12.5Hz, 1H), 2.23ꢀ2.18 (m,
1H), 1.74ꢀ1.66 (m, 5H), 1.41 (d, J = 6.9Hz, 3H), 1.02 (d, J = 6.9Hz, 3H). 13C (125 MHz,
CDCl3) δ: 213.9, 178.8, 173.3, 134.4, 133.3, 132.9, 129.3, 127.8, 127.7, 127.3, 126.6,
126.3, 125.1, 49.2, 47.5, 44.2, 43.1, 34.2, 29.3, 28.6, 25.5, 20.8, 16.8. HRMS (ESI+):
Calcd. for [C23H25NO3+H]+: 364.1907 Found: 364.1909.
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3-ethyl-4-((2-oxocyclohexyl)(phenyl)methyl) isoxazol-5(4H)-one (3f): Reaction time:
96h. Purification by flash column chromatography (SiO2, gradient: Hex ꢀ 9:1
Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 7:3 Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title
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compound as an yellow oil (47 mg, 78%). H (500 MHz, CDCl3) δ: 7.29ꢀ7.26 (m, 3H),
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7.10ꢀ7.08 (m, 2H), 4.36 (d, J = 5.2Hz, 1H), 3.66 (td, J = 12.5Hz, J = 5.0Hz, 1H), 3.36
(dd, J = 10.9Hz , J = 5.0Hz, 1H), 2.64ꢀ2.56 (m, 1H), 2.48ꢀ2.45 (m, 1H), 2.38 (dq, J =
7.5Hz, J = 3.6Hz, 2H), 2.18ꢀ2.14 (m, 1H), 1.79ꢀ1.70 (m, 1H), 1.69ꢀ1.59 (m, 4H), 1.18
(t, J = 7.5Hz, 3H). 13C (125 MHz, CDCl3) δ: 213.9, 178.4, 170.3, 136.8, 129.2, 128.2,
127.8, 49.2, 47.9, 43.8, 43.0, 34.1, 29.3, 25.5, 21.7, 9.6. HRMS (ESI+): Calcd. for
[C18H21NO3+H]+: 300.1594, found: 300.1596.
4-(furan-2-yl(2-oxocyclohexyl)methyl)-3-isopropylisoxazol-5(4H)-one
(3g):
Reaction time: 96h. Purification by flash column chromatography (SiO2, gradient: Hex ꢀ
9:1 Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ7:3 Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title
1
compound as an orange oil (48 mg, 79%). H (600 MHz, CDCl3) δ: 7.30 (d, J = 1.8Hz,
1H), 6.25 (dd, J = 3.1Hz, J = 1.8Hz, 1H), 6.08 (d, J = 3.1Hz, 1H), 4.14 (d, J = 5.0Hz,
1H), 3.71 (dt, J = 10.7, J = 5.0Hz, 1H), 3.58 (dd, J = 10.7Hz, J = 4.8Hz, 1H), 2.66 (sept,
J = 7.0Hz, 1H), 2.54 (td, J = 12.9Hz, J = 6.1Hz, 1H), 2.46ꢀ2.42 (m, 1H), 2.18ꢀ2.14 (m,
1H), 1.83ꢀ1.79 (m, 1H), 1.74ꢀ1.60 (m, 4H), 1.32 (d, J = 7.0Hz, 3H), 1.14 (d, J = 7.0Hz,
3H). 13C (150 MHz, CDCl3) δ: 213.2, 177.8, 172.8, 150.5, 142.6, 110.2, 108.2, 48.1,
46.1, 42.8, 37.7, 33.5, 29.0, 28.3, 25.3, 20.4, 17.0. HRMS (ESI+): Calcd. for
[C17H21NO4+H]+: 304.1543, found: 304.1537.
4-((4,4-dimethyl-2-oxocyclohexyl)(phenyl) methyl)-3-ethylisoxazol-5(4H)-one (3h):
Reaction time: 96h. Purification by flash column chromatography (SiO2, gradient: Hex ꢀ
9:1 Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 7:3 Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title
1
compound as an yellow oil (48 mg, 49%). H (400 MHz, CDCl3) δ: 7.29ꢀ7.27 (m, 3H),
7.11ꢀ7.08 (m, 2H), 4.35 (d, J = 5.2Hz, 1H), 3.64ꢀ3.56 (m, 1H), 3.36 (dd, J = 11.0Hz, J =
5.2Hz, 1H), 2.55 (d, J = 12Hz, 1H), 2.37 (qd, J = 7.6Hz, J = 2.9Hz, 2H), 2.16 (dd, J =
12.0Hz, J = 2.4Hz, 1H), 1.68ꢀ1.61 (m, 2H), 1.49ꢀ1.42 (m, 2H) 1.19 (t, J = 7.5Hz, 3H),
1.09 (s, 3H), 0.86 (s, 3H). 13C (100 MHz, CDCl3) δ: 213.1, 178.4, 170.3, 136.9, 129.2,
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128.2, 127.8, 55.7, 48.3, 47.9, 43.7, 38.4, 38.3, 31.9, 29.5, 24.8, 21.7, 9.7. HRMS
(ESI+): Calcd. for [C20H25NO3+H]+: 328.1907, found: 328.1905.
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4-((4-fluorophenyl)(8-oxo-1,4-dioxaspiro[4.5]decan-7-yl)methyl)-3-phenylisoxazol-
5(4H)-one (3i): Reaction time: 96h. Purification by flash column chromatography
(SiO2, gradient: Hex ꢀ 9:1 Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 7:3 Hex:AcOEt ꢀ 1:1
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o
Hex:AcOEt) affords the title compound as a white solid (64 mg, 76%). m.p. 95ꢀ97 C.
1H (500 MHz, CDCl3) δ: 7.75ꢀ7.74 (m, 2H), 7.56ꢀ7.50 (m, 3H), 6.85 (t, J = 8.4Hz, 2H),
6.70 (s, 2H), 4.82 (d, J = 4.5Hz, 1H), 4.16 (ddd, J = 16.8Hz, J = 11.6Hz, J = 5.4Hz,
1H), 4.04ꢀ3.99 (m, 1H), 3.93ꢀ3.88 (m, 2H), 3.82.3.78 (m, 1H), 3.50 (dd, J = 11.3Hz, J =
4.5Hz, 1H), 2.98 (td, J = 13.8Hz, J = 6.6Hz, 1H), 2.48 (ddd, J = 13.3Hz, J = 5.1Hz, J =
2.7Hz, 1H), 2.16ꢀ2.11 (m, 1H), 1.98 (td, J = 13.8Hz, J = 5.1Hz, 1H), 1.65 (ddd, J =
13
13.3Hz, J = 5.1Hz, J = 3.8Hz, 1H), 1.35 (t, J = 13.6Hz, 1H). C (125 MHz, CDCl3) δ:
212.8, 177.5, 166.3, 162.4 (d, J = 246.2Hz), 131.8, 131.0, (d, J = 3.4Hz), 129.8, 129.4,
127.5, 127.3, 115.9 (d, J = 21.3Hz), 106.9, 64.8, 64.6, 47.5, 44.3, 44.1, 40.2, 39.0, 35.6.
HRMS (ESI+): Calcd. for [C24H22FNO5+H]+: 424.1555, found: 424.1550.
4-((4-fluorophenyl)(4-oxotetrahydro-2H-thiopyran-3-yl)methyl)-3 phenyl isoxazol-
5(4H)-one (3j): Reaction time: 96h. Purification by flash column chromatography
(SiO2, gradient: Hex ꢀ 9:1 Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 7:3 Hex:AcOEt ꢀ 1:1
1
Hex:AcOEt) affords the title compound as an orange oil (31 mg, 41%). H (500 MHz,
CDCl3) δ: 7.70 (d, J = 7.1Hz, 2H), 7.58ꢀ7.51 (m, 3H), 6.88 (t, J = 8.3Hz, 2H), 6.73 (br
s, 2H), 4.66 (d, J = 4.7Hz, 1H), 4.14 (td, J = 11.4Hz, J = 4.4Hz, 1H), 3.58 (dd, J =
11.4Hz, J = 4.7Hz, 1H), 3.05 (s, 2H), 2.90ꢀ2.88 (m, 2H), 2.51 (dd, J = 13.5Hz, J =
2.8Hz, 1H), 2.36 (t, J = 13.5Hz, 1H). 13C (125 MHz, CDCl3) δ: 211.7, 177.5, 166.1,
162.5 (d, J = 246.8Hz), 131.9, 131.4, (d, J = 3.1Hz), 129.8, 129.4, 127.4, 127.2, 116.2
(d, J = 21.1Hz), 51.9, 47.1, 45.8, 43.9, 36.1, 32.6. HRMS (ESI+): Calcd. for
[C21H18NO3SF+H]+: 384.1064, found: 384.1057.
4-(3-oxo-1-phenyl-3-(p-tolyl)propyl)-3-phenylisoxazol-5(4H)-one23 (3k): Reaction
time: 168h. Purification by flash column chromatography (SiO2, gradient: Hex ꢀ 9:1
Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ7:3 Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title
1
compound as an brownish solid (31 mg, 40%). H (500 MHz, CDCl3) δ: 8.02 (d, J =
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8.0Hz, 2H), 7.96ꢀ7.94 (m, 2H), 7.62ꢀ7.61 (m, 3H), 7.34 (d, J = 8.0Hz, 2H), 7.25ꢀ7.22
(m, 3H), 6.94 (d, J = 8.0Hz, 2H), 4.62 (dd, J = 18.7Hz, J = 11.6Hz, 1H), 4.52ꢀ5.51 (m,
1H), 4.18 (dt, J = 11.6Hz, J = 3.1Hz, 1H), 3.30 (dd, J = 18.7Hz, J = 3.1Hz, 1H), 2.47 (s,
3H). 13C (125 MHz, CDCl3) δ: 198.5, 177.4, 166.1, 144.6, 137.3, 134.0, 131.8, 129.4,
129.3, 128.7, 128.2, 128.1, 127.8, 127.5, 127.3, 47.9, 39.9, 38.2, 21.6. HRMS (ESI+):
Calcd. for [C25H21NO3+H]+: 384.1594, found: 384.1606.
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4-(5-methyl-3-oxo-1-phenylhexyl)-3-phenylisoxazol-5(4H)-one23 (3l): Reaction time:
168h. Purification by flash column chromatography (SiO2, gradient: Hex ꢀ 9:1
Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title compound as an orange
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solid (37 mg, 53%). H (600 MHz, CDCl3) δ: 7.82ꢀ7.80 (m, 2H), 7.57ꢀ7.54 (m, 3H),
7.21ꢀ7.20 (m, 1H), 7.18ꢀ7.15 (m, 2H), 6.79 (d, J = 7.2Hz, 2H), 4.36 (d, J = 4.2Hz, 1H),
4.03ꢀ3.97 (m, 1H), 3.94ꢀ3.90 (m, 1H), 2.76 (dd, J = 18.4Hz, J = 2.4Hz, 1H), 2.49 (dd, J
= 15.8Hz, J = 6.9Hz, 1H), 2.40 (dd, J = 15.8Hz, J = 7.2Hz, 1H), 2.25 (hept, J = 6.8Hz,
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1H), 0.99 (d, J = 6.8Hz, 3H), 0.97 (d, J = 6.8Hz, 3H). C (150 MHz, CDCl3) δ: 210.1,
177.3, 166.1, 137.1, 131.8, 129.4, 128.7, 128.2, 127.7, 127.5, 127.3, 52.2, 47.7, 42.9,
39.6, 24.8, 22.6, 22.5. HRMS (ESI+): Calcd. for [C22H23NO3+H]+: 350.1751, found:
350.1758.
4-(3-cyclopropyl-3-oxo-1-phenylpropyl)-3-phenylisoxazol-5(4H)-one (3m): Reaction
time: 168h. Reaction performed using aniline (0.08 mmol, 40 mol %) as aminocatalyst
and benzoic acid (0.12 mmol, 60 mol %) as acid coꢀcatalyst. Purification by flash
column chromatography (SiO2, gradient: Hex ꢀ 9:1 Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 7:3
Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title compound as an orange solid (33 mg,
50%). m.p. 126ꢀ128 oC. 1H (600 MHz, CDCl3) δ: 7.82 (d, J = 8.1Hz, 2H), 7.56ꢀ7.53 (m,
3H), 7.22ꢀ7.16 (m, 3H), 6.82 (d, J = 7.Hz, 2H), 4.37 (d, J = 4.1Hz, 1H), 4.18 (dd, J =
18.8Hz, J = 11.5Hz, 1H), 3.93 (dt, J = 11.5Hz, J = 3.2 Hz, 1H), 2.96 (dd, J = 18.8Hz, J
= 2.8Hz, 1H), 2.11ꢀ2.07 (m, 1H), 1.19ꢀ1.13 (m, 2H), 1.05ꢀ0.96 (m, 2H). 13C (150 MHz,
CDCl3) δ: 209.9, 177.4, 166.1, 137.1, 131.8, 129.3, 128.7, 128.2, 127.7, 127.5, 127.3,
47.8, 42.8, 39.7, 21.2, 11.4, 11.3. HRMS (ESI+): Calcd. for [C21H19NO3+H]+:
334.1438, found: 334.1447.
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4-(3-oxo-1-phenylbutyl)-3-phenylisoxazol-5(4H)-one23 (3n): Reaction time: 168h.
Purification by flash column chromatography (SiO2, gradient: Hex ꢀ 9:1 Hex:AcOEt ꢀ
8:2 Hex:AcOEt ꢀ 7:3 Hex:AcOEt ꢀ 1:1 Hex:AcOEt). affords the title compound as
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brown oil (27 mg, 44%). H (500 MHz, CDCl3) δ: 7.81ꢀ7.79 (m, 2H), 7.57ꢀ7.52 (m,
3H), 7.23ꢀ7.15 (m, 3H), 6.80ꢀ6.78 (m, 2H), 4.39 (d, J = 4.3Hz, 1H), 4.01 (dd, J =
18.8Hz, J = 11.3Hz, 1H), 3.91ꢀ3.89 (m, 1H), 2.82 (dd, J = 18.8Hz, J = 2.8Hz, 1H), 2.31
(s, 3H). 13C (125 MHz, CDCl3) δ: 207.8, 177.4, 166.1, 136.1, 136.9, 131.8, 129.3,
128.7, 128.2, 127.6, 127.3, 47.7, 43.2, 39.6, 30.4. HRMS (ESI+): Calcd. for
[C19H17NO3+H]+: 308.1281, found: 308.1279.
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4-(3-oxo-1-phenylhept-6-en-1-yl)-3-phenylisoxazol-5(4H)-one23 (3o): Reaction time:
168h. Purification by flash column chromatography (SiO2, gradient: Hex ꢀ 9:1
Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 7:3 Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title
1
compound as an orange solid (21 mg, 30%). H (500 MHz, CDCl3) δ: 7.81ꢀ7.89 (m,
2H), 7.57ꢀ7.53 (m, 3H), 7.21ꢀ7.15 (m, 3H), 6.80ꢀ6.79 (m, 2H), 5.89ꢀ5.81 (m, 1H), 5.08
(dq, J = 17.2Hz, J = 1.5Hz, 1H), 5.02 (dq, J = 10.2Hz, J = 1.5Hz, 1H), 4.36 (d, J =
4.3Hz, 1H), 4.02 (dd, J = 18.5Hz, J = 11.4Hz, 1H), 3.95ꢀ3.91 (m, 1H), 2.79 (dd. J =
18.5Hz, J = 2.7Hz, 1H), 2.76ꢀ2.71 (m, 1H), 2.67ꢀ2.60 (m, 1H), 2.46ꢀ2.41 (m, 2H). 13C
(125 MHz, CDCl3) δ: 209.4, 177.3, 166.0, 137.0, 136.6, 131.8, 129.4, 128.7, 128.2,
127.6, 127.5, 127.3, 115.6, 47.7, 42.5, 42.1, 39.6, 27.6. HRMS (ESI+): Calcd. for
[C22H21NO3+H]+: 348.1594, found: 348.1590.
4-(1-(4-fluorophenyl)-5-methyl-3-oxohexyl)-3-phenylisoxazol-5(4H)-one
(3p):
Reaction time: 168h. Purification by flash column chromatography (SiO2, gradient: Hex
ꢀ 9:1 Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 7:3 Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title
1
compound as an orange oil (54 mg, 74%). H (400 MHz, CDCl3) δ: 7.83ꢀ7.80 (m, 2H),
7.58ꢀ7.52 (m, 3H), 6.85 (t, J = 8.6Hz, 2H), 6.78ꢀ6.75 (m, 2H), 4.34 (d, J = 3.9Hz, 1H),
3.99ꢀ3.89 (m, 2H), 2.73 (d, J = 15.8Hz, 1H), 2.48 (dd, J = 15.8Hz, J = 7.0Hz, 1H), 2.40
(dd, J = 15.8Hz, J = 7.0Hz, 1H), 2.24 (sept, J = 6.7Hz, 1H), 0.98 (d, J = 6.7Hz, 3H),
0.96 (d, J = 6.7Hz, 3H). 13C (100 MHz, CDCl3) δ: 209.8, 177.2, 165.9, 162.3 (d, J =
242.8Hz), 132.8 (d, J = 3.3Hz), 131.9, 129.4, 129.3 (d, J = 8.1Hz), 127.3, 127.2, 115.6
(d, J = 21.3Hz), 52.1, 47.7, 42.9, 38.8, 24.8, 22.6, 22.5. HRMS (ESI+): Calcd. for
[C22H22NO3F+H]+: 368.1656, found: 368.1652.
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3-(4-methoxyphenyl)-4-(5-methyl-3-oxo-1-phenylhexyl)isoxazol-5(4H)-one
(3q):
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Reaction time: 168h. Purification by flash column chromatography (SiO2, gradient: Hex
ꢀ 9:1 Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 7:3 Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title
compound as an orange solid (49 mg, 64%). m.p. 127ꢀ129 oC. 1H (400 MHz, CDCl3) δ:
7.80ꢀ7.77 (m, 2H), 7.21ꢀ7.14 (m, 3H), 7.07ꢀ7.03 (m, 2H), 6.83ꢀ6.81 (m, 2H), 4.29 (d, J
= 4.1Hz, 1H), 4.00 (dd, J = 18.4Hz, J = 11.4Hz, 1H), 3.93ꢀ3.90 (m, 1H), 3.90 (s, 3H),
2.75 (dd, J = 18.4Hz, J = 2.3Hz, 1H), 2.49 (dd, J = 15.7Hz, J = 6.9Hz, 1H), 2.41 (dd, J
= 15.7Hz, J = 6.9Hz, 1H), 2.24 (sept, J = 6.7Hz, 1H), 0.99 (d, J = 6.7Hz, 3H), 0.96 (d, J
= 6.7Hz, 3H). 13C (100 MHz, CDCl3) δ: 210.1, 177.5, 165.5, 162.3, 137.1, 129.0, 128.7,
128.1, 127.7, 119.9, 114.8, 55.4, 52.2, 47.8, 42.9, 39.7, 24.8, 22.6, 22.5. HRMS (ESI+):
Calcd. for [C23H25NO4+H]+: 380.1856, found: 380.1854.
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3-(4-methoxyphenyl)-4-(3-oxo-1-phenylbutyl)isoxazol-5(4H)-one (3r): Reaction
time: 168h. Purification by flash column chromatography (SiO2, gradient: Hex ꢀ 9:1
Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 7:3 Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title
1
compound as an orange oil (34 mg, 50%). H (400 MHz, CDCl3) δ: 7.79ꢀ7.75 (m, 2H),
7.21ꢀ7.15 (m, 3H), 7.06ꢀ7.03 (m, 2H), 6.83ꢀ6.80 (m, 2H), 4.32 (d, J = 4.2Hz, 1H), 4.03
(dd, J = 18.8Hz, J = 11.4Hz, 1H), 3.90 (s, 3H), 3.89ꢀ3.86 (m, 1H), 2.82 (dd, J = 18.8Hz,
J = 2.7Hz, 1H), 2.31 (s, 3H). 13C (100 MHz, CDCl3) δ: 207.9, 177.5, 165.5, 162.3,
137.0, 129.0, 128.7, 128.2, 127.7, 119.9, 114.8, 55.4, 47.8, 43.3, 39.8, 30.4. HRMS
(ESI+): Calcd. for [C20H19NO4+H]+: 338.1387, found: 338.1382.
4-(1-cyclopropyl-5-methyl-3-oxohexyl)-3-phenylisoxazol-5(4H)-one (3s): Reaction
time: 168h. Purification by flash column chromatography (SiO2, gradient: Hex ꢀ 9:1
Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 7:3 Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title
o
1
compound as an yellow solid (35 mg, 56%). m.p. 93ꢀ95 C. H (600 MHz, CDCl3) δ:
7.92ꢀ7.90 (m, 2H), 7.53ꢀ7.51 (m, 3H), 4.16 (d, J = 3.2Hz, 1H), 3.55 (dd, J = 19.1Hz, J
= 11.3Hz, 1H), 2.60 (dd, J = 19.1Hz, J = 2.8Hz, 1H), 2.43 (dd, J = 15.7Hz, J = 7.0Hz,
1H), 2.37 (dd, J = 15.7Hz, J = 7.0Hz, 1H), 2.21 (sept., J = 6.8Hz, 1H), 1.89 (tt, J =
11.0Hz, J = 2.8Hz, 1H), 0.98 (d, J = 6.7Hz, 3H), 0.96 (d, J = 6.7Hz, 3H), 0.67ꢀ0.61 (m,
1H), 0.42ꢀ0.34 (m, 2H), ꢀ0.18 (sext., J = 4.9Hz, 1H), ꢀ0.27 (sext., J = 4.9Hz, 1H). 13C
(150 MHz, CDCl3) δ: 210.9, 177.7, 166.8, 131.7, 129.3, 127.6, 127.1, 52.2, 47.0, 43.7,
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39.4, 24.8, 22.6, 22.5, 11.8, 4.8, 2.5. HRMS (ESI+): Calcd. for [C19H23NO3+H]+:
314.1751, found: 314.1745.
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4-(1-cyclopropyl-3-oxobutyl)-3-phenylisoxazol-5(4H)-one (3t): Reaction time: 168h.
Purification by flash column chromatography (SiO2, gradient: Hex ꢀ 9:1 Hex:AcOEt ꢀ
8:2 Hex:AcOEt ꢀ 7:3 Hex:AcOEt ꢀ 1:1 Hex:AcOEt) affords the title compound as an
orange solid (34 mg, 63%). m.p.: decomposition. 1H (500 MHz, CDCl3) δ: 7.92ꢀ7.90
(m, 2H), 7.52ꢀ7.50 (m, 3H), 4.19 (d, J = 3.2Hz, 1H), 3.58 (dd, J = 19.3Hz, J = 11.3Hz,
1H), 2.68 (dd, J = 19.3Hz, J = 2.7Hz, 1H), 2.26 (s, 3H), 1.87 (tt, J = 11.0Hz, J =
2.8Hz, 1H), 0.68ꢀ0.61 (m, 1H), 0.43ꢀ0.34 (m, 2H), ꢀ0.18 (sext., J = 4.9Hz, 1H), ꢀ0.27
(sext., J = 4.9Hz, 1H). 13C (100 MHz, CDCl3) δ: 208.5, 177.8, 166.8, 131.7, 129.3,
127.6, 127.2, 47.0, 44.1, 39.5, 30.3, 11.7, 4.8, 2.5. HRMS (ESI+): Calcd. for
[C16H17NO3+H]+: 272.1281, found: 272.1278.
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General reaction conditions for the iron-promoted decarboxylative cyclization of
isoxazol-5-ones toward pyridines (Step 2): isoxazolꢀ5ꢀone (0.1 mmol), Fe (1 mmol),
3,5ꢀdimethoxybenzoic acid (1 mmol), and MeOH (1 mL) are added to a round bottom
flask, under air, at room temperature. The reaction mixture is capped with a rubber
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septum and stirred at 65 C overnight. Then, the reaction mixture is diluted in AcOEt,
washed with an aqueous saturated solution of NaHCO3, dried (MgSO4), concentrated
under reduced pressure and purified by flash column chromatography.
2,4-diphenyl-5,6,7,8-tetrahydroquinoline (4a): Purification by flash column
chromatography (SiO2, gradient: Hex ꢀ 95:5 Hex:AcOEt ꢀ 9:1 Hex:AcOEt ꢀ 8:2
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Hex:AcOEt) affords the title compound as a white solid (17 mg, 60%). H (600 MHz,
CDCl3) δ: 7.98ꢀ7.97 (m, 2H), 7.47ꢀ7.34 (m, 9H), 3.1 (t, J = 6.4Hz, 2H), 2.66 (t, J =
6.4Hz, 2H), 1.97ꢀ1.93 (m, 2H), 1.78ꢀ1.74 (m, 2H). 13C (150 MHz, CDCl3) δ: 157.6,
154.3, 150.3, 139.8 (2x), 128.6 (2x), 128.5, 128.4, 128.3, 127.7, 126.9, 119.1, 33.4,
27.3, 23.1, 23.0. HRMS (ESI+): Calcd. for [C21H19N+H]+: 286.1590, found: 286.1591.
2,4-diphenyl-6,7-dihydro-5H-cyclopenta [b]pyridine (4b): Purification by flash
column chromatography (SiO2, gradient: Hex ꢀ 98:2 Hex:AcOEt ꢀ 95:5 Hex:AcOEt ꢀ
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9:1 Hex:AcOEt) affords the title compound as an yellow solid (13 mg, 48%). H (500
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MHz, CDCl3) δ: 7.99 (d, J = 7.3Hz, 2H), 7.55ꢀ7.53 (m, 3H), 7.50ꢀ7.39 (m, 6H), 3.17 (t,
J = 7.5Hz, 2H), 3.07 (t, J = 7.5Hz, 2H), 2.16 (quint., J = 7.5Hz, 2H). 13C (125 MHz,
CDCl3) δ: 166.7, 156.5, 145.9, 139.9, 139.0, 133.1, 128.6 (2x), 128.4, 128.2 (2x), 127.0,
118.1, 34.8, 30.6, 23.5. HRMS (ESI+): Calcd. for [C20H17N+H]+: 272.1434, found:
272.1427.
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2,4-diphenyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (4c): Purification by flash
column chromatography (SiO2, gradient: Hex ꢀ 98:2 Hex:AcOEt ꢀ 95:5 Hex:AcOEt ꢀ
9:1 Hex:AcOEt) affords the title compound as an yellow solid: 20 mg, 67%. m.p. 87ꢀ88
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oC. H (500 MHz, CDCl3) δ: 8.00 (d, J = 7.4Hz, 2H), 7.48ꢀ7.32 (m, 9H), 3.24ꢀ3.22 (m,
2H), 2.78ꢀ2.76 (m, 2H), 1.91ꢀ1.89 (m, 2H), 1.84ꢀ1.81 (m, 2H), 1.68ꢀ1.66 (m, 2H). 13C
(125 MHz, CDCl3) δ: 164.1, 153.3, 149.5, 140.4, 139.7, 134.0, 128.8, 128.6, 128.3 (2x),
127.5, 126.8, 119.4, 39.7, 32.4, 29.5, 28.0, 26.7. HRMS (ESI+): Calcd. for
[C22H21N+H]+: 300.1747, found: 300.1744.
4-(4-chlorophenyl)-2-phenyl-5,6,7,8-tetrahydroquinoline (4d): Purification by flash
column chromatography (SiO2, gradient: Hex ꢀ 98:2 Hex:AcOEt ꢀ 95:5 Hex:AcOEt ꢀ
9:1 Hex:AcOEt ꢀ 8:2 Hex:AcOEt) affords the title compound as an yellow solid (20 mg,
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63%). H (400 MHz, CDCl3) δ: 7.98ꢀ7.95 (m, 2H), 7.46ꢀ7.36 (m, 6H), 7.29ꢀ7.27 (m,
2H), 3.09 (t, J = 6.4Hz, 2H), 2.63 (t, J = 6.4Hz, 2H), 1.97ꢀ1.91 (m, 2H), 1.80ꢀ1.74 (m,
2H). 13C (100 MHz, CDCl3) δ: 157.9, 154.4, 149.1, 139.6, 138.1, 133.9, 129.9, 128.7,
128.6 (x2), 128.3, 126.9, 118.9, 33.3, 27.3, 23.1, 23.0. HRMS (ESI+): Calcd. for
[C21H18ClN+H]+: 320.1201, found:320.1201.
2-isopropyl-4-(naphthalen-2-yl)-5,6,7,8-tetrahydroquinoline (4e): Purification by
flash column chromatography (SiO2, gradient: Hex ꢀ 98:2 Hex:AcOEt ꢀ 95:5
Hex:AcOEt ꢀ 9:1 Hex:AcOEt ꢀ 8:2 Hex:AcOEt ꢀ 7:3 Hex:AcOEt) affords the title
o
compound as an orange solid (20 mg, 67%). m.p. 68ꢀ70 C. 1H (600 MHz, CDCl3) δ:
7.90ꢀ7.86 (m, 3H), 7.75 (d, J = 1.0Hz, 1H), 7.54ꢀ7.51 (m, 2H), 7.42 (dd, J = 8.3Hz, J =
1.7Hz, 1H), 6.96 (s, 1H), 3.09 (quint., J = 7.0Hz, 1H), 3.02 (t, J = 6.4Hz, 2H), 2.63 (t, J
= 6.4Hz, 2H), 1.94ꢀ1.90 (m, 2H), 1.74ꢀ1.70 (m, 2H), 1.32 (d, J = 7.0Hz, 6H). 13C (100
MHz, CDCl3) δ: 164.1, 156.5, 150.1, 137.5, 133.1, 132.6, 128.0, 127.8, 127.7, 127.4,
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127.3, 126.7, 126.4, 126.3, 118.3, 36.1, 33.0, 27.3, 23.1, 23.0, 22.8. HRMS (ESI+):
Calcd. for [C22H23N+H]+: 302.1903, found: 302.1903.
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2-ethyl-4-phenyl-5,6,7,8-tetrahydroquinoline (4f): Purification by flash column
chromatography (SiO2, gradient: Hex ꢀ 95:5 Hex:AcOEt ꢀ 9:1 Hex:AcOEt ꢀ 8:2
Hex:AcOEt ꢀ 7:3 Hex:AcOEt) affords the title compound as an yellow solid (15 mg,
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63%). m.p. 56ꢀ58 C. H (500 MHz, CDCl3) δ: 7.44ꢀ7.36 (m, 3H), 7.30ꢀ726 (m, 2H),
6.85 (s, 1H), 2.98 (t, J = 6.5Hz, 2H), 2.79 (q, J = 7.6Hz, 2H), 2.59 (t, J = 6.5Hz, 2H),
1.92ꢀ1.87 (m, 2H), 1.73ꢀ1.69 (m, 2H), 1.30 (t, J = 7.6Hz, 3H). 13C (125 MHz, CDCl3) δ:
160.1, 156.7, 150.0, 139.8, 128.5, 128.2, 127.6, 126.9, 120.1, 33.0, 31.1, 27.1, 23.1,
23.0, 14.3. HRMS (ESI+): Calcd. for [C17H19N+H]+: 238.1590, found: 238.1587.
4-(furan-2-yl)-2-isopropyl-5,6,7,8-tetrahydroquinoline (4g): Purification by flash
column chromatography (SiO2, gradient: Hex ꢀ 95:5 Hex:AcOEt ꢀ 9:1 Hex:AcOEt ꢀ 8:2
Hex:AcOEt ꢀ 7:3 Hex:AcOEt) affords the title compound as an yellow oil (17 mg,
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71%). H (500 MHz, CDCl3) δ: 7.55 (d, J = 1.3Hz, 1H), 7.35 (s, 1H), 6.69 (d, J =
3.4Hz, 1H), 6.53 (dd, J = 3.4Hz, J = 1.8Hz, 1H), 3.04 (sept., J = 7.0Hz, 1H), 2.97 (t, J =
6.4Hz, 2H), 2.83 (t, J = 6.4Hz, 2H), 1.93ꢀ1.88 (m, 2H), 1.85ꢀ1.81 (m, 2H), 1.32 (d, J =
7.0Hz, 6H). 13C (125 MHz, CDCl3) δ: 164.1, 157.1, 151.5, 142.7, 137.3, 125.1, 114.4,
111.6 (2x), 36.2, 33.5, 27.8, 23.1, 22.8 (x2). HRMS (ESI+): Calcd. for [C16H19NO+H]+:
242.1539, found: 242.1535.
2-ethyl-7,7-dimethyl-4-phenyl-5,6,7,8-tetrahydroquinoline (4h): Purification by
flash column chromatography (SiO2, gradient: Hex ꢀ 95:5 Hex:AcOEt ꢀ 9:1 Hex:AcOEt
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ꢀ 8:2 Hex:AcOEt) affords the title compound as an yellow oil (13 mg, 50%). H (500
MHz, CDCl3) δ: 7.45ꢀ7.41 (m, 2H), 7.39ꢀ7.36 (m, 1H), 7.30ꢀ7.28 (m, 2H), 6.86 (s, 1H),
2.79 (q, J = 7.6Hz, 2H), 2.76 (s, 2H), 2.60 (t, J = 6.6Hz, 2H), 1.50 (t, J = 6.6Hz, 2H),
1.30 (t, J = 7.6Hz, 3H), 1.04 (s, 6H). 13C (125 MHz, CDCl3) δ: 160.4, 156.3, 149.9,
139.9, 128.5, 128.2, 127.6, 125.4, 120.1, 46.9, 35.7, 31.1, 29.7, 28.2, 24.1, 14.2. HRMS
(ESI+): Calcd. for [C19H23N+H]+: 266.1903, found: 266.1900.
4-(4-fluorophenyl)-2-phenyl-7,8-dihydro-5H-spiro[quinoline-6,2'-[1,3]dioxolane]
(4i): Purification by flash column chromatography (SiO2, gradient: Hex ꢀ 98:2
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Hex:AcOEt ꢀ 95:5 Hex:AcOEt ꢀ 9:1 Hex:AcOEt) affords the title compound as a white
solid (27 mg, 75%). m.p. 155ꢀ157 oC. 1H (500 MHz, CDCl3) δ: 7.96 (d, J = 7.3Hz, 2H),
7.45 (t, J = 7.4Hz, 2H), 7.40ꢀ7.37 (m, 2H), 7.32ꢀ7.29 (m, 2H), 7.15 (t, J = 8.6Hz, 2H),
4.02ꢀ3.93 (m, 4H), 3.30 (t, J = 6.8Hz, 2H), 2.87 (s, 2H), 2.11 (t, J = 6.8Hz, 2H). 13C
(125 MHz, CDCl3) δ: 162.5 (d, J = 246.3Hz), 156.2, 155.1, 149.6, 139.5, 135.0 (d, J =
3.4Hz), 130.3, 130.2, 128.7, 126.9, 125.5, 119.3, 115.5 (d, J = 21.5Hz), 107.9, 64.6
(x2), 37.1, 31.6, 31.5. HRMS (ESI+): Calcd. for [C23H20FNO2+H]+: 362.1551, found:
362.1551.
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4-(4-fluorophenyl)-2-phenyl-7,8-dihydro-5H-thiopyrano[4,3-b]pyridine
(4j):
Purification by flash column chromatography (SiO2, gradient: Hex ꢀ 98:2 Hex:AcOEt ꢀ
95:5 Hex:AcOEt ꢀ 9:1 Hex:AcOEt) affords the title compound as a yellow solid (16 mg,
50%). m.p. 116ꢀ117 oC. 1H (400 MHz, CDCl3) δ: 8.00ꢀ7.98 (m, 2H), 7.48ꢀ7.32 (m, 6H),
7.18 (t, J = 8.6Hz, 2H), 3.70 (s, 2H), 3.37 (t, J = 6.4Hz, 2H), 3.06 (t, J = 6.4Hz, 2H). 13C
(100 MHz, CDCl3) δ: 162.7 (d, J = 246.6Hz), 157.4, 155.0, 147.7, 139.1, 134.5 (d, J =
3.4Hz), 130.5 (d, J = 8.1Hz), 128.9, 128.7, 127.2, 126.9, 119.5, 115.7 (d, J = 21.5Hz),
34.3, 26.6, 26.4. HRMS (ESI+): Calcd. for [C20H16NFS+H]+: 322.1060, found:
322.1057.
2,4-diphenyl-6-(p-tolyl)pyridine (4k): Purification by flash column chromatography
(SiO2, gradient: Hex ꢀ 95:5 Hex:AcOEt ꢀ 9:1 Hex:AcOEt ꢀ 8:2 Hex:AcOEt) affords the
title compound as a yellow solid (24 mg, 76%).1H (400 MHz, CDCl3) δ: 8.23ꢀ8.21 (m,
2H), 8.12 (d, J = 8.0Hz, 2H), 7.88 (s, 2H), 7.77ꢀ7.74 (m, 2H), 7.57ꢀ7.44 (m, 6H), 7.33
(d, J = 8.0Hz, 2H), 2.45 (s, 3H). 13C (100 MHz, CDCl3) δ: 157.5, 157.4, 150.1, 139.7,
139.2, 139.0, 136.8, 129.4, 129.1, 129.0, 128.9, 128.7, 127.2, 127.1, 127.0, 116.8 (2x),
21.3. HRMS (ESI+): Calcd. for [C24H19N+H]+: 322.1590, found: 322.1588.
2-isobutyl-4,6-diphenylpyridine (4l): Purification by flash column chromatography
(SiO2, gradient: Hex ꢀ 98:2 Hex:AcOEt ꢀ 95:5 Hex:AcOEt ꢀ 9:1 Hex:AcOEt) affords the
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title compound as an orange oil (20 mg, 70%). H (500 MHz, CDCl3) δ: 8.07ꢀ8.05 (m,
2H), 7.74 (d, J = 1.3Hz, 1H), 7.71ꢀ7.69 (m, 2H), 7.52ꢀ7.40 (m, 6H), 7.27 (d, J = 1.3Hz,
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1H), 2.80 (d, J = 7.2Hz, 2H), 2.28 (sept., J = 6.8Hz, 1H), 1.01 (d, J = 6.8Hz, 6H). C
(125 MHz, CDCl3) δ: 162.0, 157.5, 149.2, 140.0, 139.1, 129.0, 128.8, 127.7 (2x), 127.1
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(x2), 120.0, 116.2, 47.8, 29.1, 22.6. HRMS (ESI+): Calcd. for [C21H21N+H]+: 288.1747,
found: 288.1743.
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chromatography (SiO2, gradient: Hex ꢀ 98:2 Hex:AcOEt ꢀ 95:5 Hex:AcOEt ꢀ 9:1
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Hex:AcOEt) affords the title compound as a yellow oil (16 mg, 60%). H (600 MHz,
CDCl3) δ: 8.08ꢀ8.06 (m, 2H), 7.70ꢀ7.68 (m, 3H), 7.51ꢀ7.40 (m, 6H), 7.29 (d, J = 1.4Hz,
1H), 2.17 (quint., J = 4.8Hz, 1H), 1.23ꢀ1.20 (m, 2H), 1.05ꢀ1.02 (m, 2H). 13C (150 MHz,
CDCl3) δ: 163.0, 157.0, 149.1, 139.8, 139.2, 129.0, 128.7 (2x), 128.6, 127.1, 126.9,
117.9, 115.5, 17.4, 9.9. HRMS (ESI+): Calcd. for [C20H17N+H]+: 272.1434, found:
272.1432.
2-methyl-4,6-diphenylpyridine (4n): Purification by flash column chromatography
(SiO2, gradient: Hex ꢀ 98:2 Hex:AcOEt ꢀ 95:5 Hex:AcOEt ꢀ 9:1 Hex:AcOEt) affords the
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title compound as a yellow solid (16 mg, 64%). H (500 MHz, CDCl3) δ: 8.08ꢀ8.03 (m,
2H), 7.73 (d, J = 1.0Hz, 1H), 7.70ꢀ7.68 (m, 2H), 7.52ꢀ7.42 (m, 6H), 7.33 (d, J = 1.0Hz,
1H), 2.71 (s, 3H). 13C (125 MHz, CDCl3) δ: 158.8, 157.6, 149.6, 139.7, 138.8, 129.0,
128.9, 128.8, 128.7, 127.2, 127.1, 119.8, 116.2, 24.7. HRMS (ESI+): Calcd. for
[C18H15N+H]+: 246.1277, found: 246.1276.
2-(but-3-en-1-yl)-4,6-diphenylpyridine (4o): Purification by flash column
chromatography (SiO2, gradient: Hex ꢀ 98:2 Hex:AcOEt ꢀ 95:5 Hex:AcOEt) affords the
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title compound as a brown oil (17 mg, 61%). H (500 MHz, CDCl3) δ: 8.07ꢀ8.06 (m,
2H), 7.75 (d, J = 1.5Hz, 1H), 7.70ꢀ7.68 (m, 2H), 7.52ꢀ7.40 (m, 6H), 7.31 (d, J = 1.5Hz,
1H), 6.00ꢀ5.93 (m, 1H), 5.12 (dq, J = 17.2Hz, J = 1.4Hz, 1H), 5.02 (dq, J = 10.2Hz, J =
1.4Hz, 1H), 3.03 (t, J = 7.5Hz, 2H), 2.67ꢀ2.62 (m, 2H). 13C (125 MHz, CDCl3) δ: 161.8,
157.5, 149.5, 139.9, 139.0, 138.1, 129.0, 128.8 (2x), 128.7, 127.1 (x2), 119.4, 116.3,
115.0, 37.9, 33.7. HRMS (ESI+): Calcd. for [C21H19N+H]+: 286.1590, found: 286.1586.
4-(4-fluorophenyl)-2-isobutyl-6-phenylpyridine (4p): Purification by flash column
chromatography (SiO2, gradient: Hex ꢀ 98:2 Hex:AcOEt ꢀ 95:5 Hex:AcOEt ꢀ 9:1
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Hex:AcOEt) affords the title compound as a yellow oil (19 mg, 62%). H (600 MHz,
CDCl3) δ: 8.06ꢀ8.04 (m, 2H), 7.69 (d, J = 1.5Hz, 1H), 7.68ꢀ7.65 (m, 2H), 7.50ꢀ7.47 (m,
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2H), 7.43ꢀ7.41 (m, 1H), 7.22 (d, J = 1.5Hz, 1H), 7.43ꢀ7.17 (m, 2H), 2.79 (d, J = 7.2Hz,
2H), 2.28 (sept., J = 6.7Hz, 1H), 1.02 (d, J = 6.7Hz, 6H). 13C (150 MHz, CDCl3) δ:
163.3 (d, J = 247.2Hz), 162.1, 157.6, 148.1, 139.9, 135.1 (d, J = 3.3Hz), 128.9 (d, J =
8.5Hz), 128.8, 128.7, 127.1, 119.8, 116.1, 115.9 (d, J = 4.0 Hz), 47.7, 29.1, 25.5. HRMS
(ESI+): Calcd. for [C21H20NF+H]+: 306.1653, found: 306.1649.
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2-isobutyl-6-(4-methoxyphenyl)-4-phenylpyridine (4q): Purification by flash column
chromatography (SiO2, gradient: Hex ꢀ 98:2 Hex:AcOEt ꢀ 95:5 Hex:AcOEt ꢀ 9:1
Hex:AcOEt) affords the title compound as an orange oil (18 mg, 57%). 1H (500 MHz,
CDCl3) δ: 8.02 (d, J = 8.7Hz, 2H), 7.69ꢀ7.68 (m, 3H), 7.51ꢀ7.42 (m, 3H), 7.22 (s, 1H),
7.01 (d, J = 8.7Hz, 2H), 3.87 (s, 3H), 2.78 (d, J = 7.2Hz, 2H), 2.28 (sept., J = 6.7Hz,
1H), 1.02 (d, J = 6.7Hz, 6H). 13C (125 MHz, CDCl3) δ: 161.8, 160.3, 157.1, 149.1,
139.2, 132.7, 129.0, 128.7, 128.4, 127.1, 119.3, 115.4, 114.0, 55.3, 47.8, 29.0, 22.6.
HRMS (ESI+): Calcd. for [C22H23NO+H]+: 318.1852, found: 318.1849.
2-(4-methoxyphenyl)-6-methyl-4-phenylpyridine (4r): Purification by flash column
chromatography (SiO2, gradient: Hex ꢀ 98:2 Hex:AcOEt ꢀ 95:5 Hex:AcOEt ꢀ 9:1
Hex:AcOEt) affords the title compound as an orange solid (15 mg, 55%). m.p. 93ꢀ95
oC. 1H (600 MHz, CDCl3) δ: 7.99 (d, J = 8.8Hz, 2H), 7.68ꢀ7.67 (m, 3H), 7.51ꢀ7.43 (m,
3H), 7.26 (d, J = 1.0Hz, 1H), 7.00 (d, J = 8.8Hz, 2H), 3.87 (s, 3H), 2.67 (s, 3H). 13C
(150 MHz, CDCl3) δ: 160.3, 158.7, 157.3, 149.4, 139.0, 132.5, 129.0, 128.8, 129.4,
127.1, 119.2, 115.4, 114.1, 55.4, 24.8. HRMS (ESI+): Calcd. for [C19H17NO+H]+:
276.1383, found: 276.1382.
4-cyclopropyl-2-isobutyl-6-phenylpyridine (4s): Purification by flash column
chromatography (SiO2, gradient: Hex ꢀ 98:2 Hex:AcOEt ꢀ 95:5 Hex:AcOEt ꢀ 9:1
Hex:AcOEt) affords the title compound as an orange oil (13 mg, 52 %). 1H (500 MHz,
CDCl3) δ: 7.97ꢀ7.95 (m, 2H), 7.44 (t, J = 7.2Hz, 2H), 7.39ꢀ7.36 (m, 1H), 7.18 (d, J =
1.2Hz, 1H), 6.72 (d, J = 1.2Hz, 1H), 2.67 (d, J = 7.2Hz, 2H), 2.20 (sept., J = 6.7Hz,
1H), 1.87ꢀ1.82 (m, 1H), 1.10ꢀ1.06 (m, 2H), 0.97 (d, J = 6.7Hz, 6H), 0.86ꢀ0.82 (m, 2H).
13C (125 MHz, CDCl3) δ: 161.1, 156.7, 154.2, 140.2, 128.6, 128.5, 127.1, 118.9, 115.1,
47.5, 29.0, 22.5, 15.1, 10.2. HRMS (ESI+): Calcd. for [C18H21N+H]+: 252.1747, found:
252.1745.
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Page 29 of 32
The Journal of Organic Chemistry
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4-cyclopropyl-2-methyl-6-phenylpyridine (4t): Purification by flash column
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chromatography (SiO2, gradient: Hex ꢀ 98:2 Hex:AcOEt ꢀ 95:5 Hex:AcOEt ꢀ 9:1
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Hex:AcOEt) affords the title compound as a yellow oil (12 mg, 57%). H (400 MHz,
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CDCl3) δ: 7.94ꢀ7.92 (m, 2H), 7.47ꢀ7.36 (m, 3H), 7.18 (d, J = 1.0Hz, 1H), 6.76 (d, J =
1.0Hz, 1H), 2.57 (s, 3H), 1.92ꢀ1.86 (m, 1H), 1.10ꢀ1.05 (m, 2H), 0.86ꢀ0.81 (m, 2H). 13C
(100 MHz, CDCl3) δ: 158.1, 157.0, 154.4, 140.1, 128.6, 128.5, 127.1, 118.6, 115.2,
24.6, 15.1, 10.1. HRMS (ESI+): Calcd. for [C15H15N+H]+: 210.1277, found: 210.1275.
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(E)-2-benzylidenecyclohexan-1-one (6): Prepared according to the literature.28
Purification by flash column chromatography (SiO2, gradient: Hex ꢀ 98:2 Hex:AcOEt ꢀ
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95:5 Hex:AcOEt) affords the title compound as a yellow solid (110 mg, 87%). H (400
MHz, CDCl3) δ: 7.49 (t, J = 2.1Hz, 1H), 7.41ꢀ7.30 (m, 5H), 2.84 (td, J = 6.4Hz, J =
2.1Hz, 2H), 2.54 (t, J = 6.7Hz, 2H), 1.96ꢀ1.90 (m, 2H), 1.80ꢀ1.74 (m, 2H). 13C (100
MHz, CDCl3) δ: 201.8, 136.7, 135.6 (2x), 130.3 (2x), 128.5, 128.3 (2x), 40.3, 28.9,
23.9, 23.4. HRMS (ESI+): Calcd. for [C13H14O + H]+: 187.1117, found: 187.1115.
Acknowledgements
M.L.S. acknowledges FaepexꢀUnicamp for a M. Sc. fellowship (127/16). The authors
are grateful to Fapesp for a research grant to I.D.J. (2015/20809ꢀ4) and B. Sc.
fellowships to M.D. (2016/12749ꢀ4), C.S. (2015/01331ꢀ6) and N.M.R.C. (2014/15718ꢀ
7). CNPq is acknowledged for a research grant to I.D.J. (458416/2014ꢀ2) and a postꢀ
doctoral fellowship to C.F.F.A. (162191/2015ꢀ4). The authors are in debt to Prof.
Marcos N. Eberlin (Unicamp, Brazil) for granting access to his MS facility and Dr.
Déborah Simoni (Unicamp, Brazil) for Xꢀray crystal structure analysis of 4k.
Associated Content
Supporting Information.
1H and 13C NMR spectra and HRMS of all compounds, melting points of new
crystalline solids and Xꢀray crystallographic data of 4k.
Author information
Corresponding author
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