Copper-catalyzed nitrene transfer as a tool for the synthesis of N-substituted 1,2-dihydro- and 1,2,3,4-tetrahydropyridines

Article abstract of DOI:10.1021/om3008234

The sequential reaction of two different furans and PhI=NTs produces 1,2-dihydropyridines in a quantitative manner in the presence of Tp ^Br3Cu(NCMe) (Tp^Br3 = hydrotris(3,4,5-tribromopyrazolyl) borate) as the catalyst under very mild conditions. The use of a furan and ethyl vinyl ether with PhI=NTs has led to the corresponding 1,2,3,4- tetrahydropyridine.

Full text of DOI:10.1021/om3008234

Article
pubs.acs.org/Organometallics
Copper-Catalyzed Nitrene Transfer as a Tool for the Synthesis of
N‑Substituted 1,2-Dihydro- and 1,2,3,4-Tetrahydropyridines
́
Lourdes Maestre, Manuel R. Fructos, M. Mar Dıaz-Requejo,* and Pedro J. Perez*
́
́
Laboratorio de Catal
́
isis Homogen
́
́
ea, Departamento de Quımica y Ciencias de los Materiales, Unidad Asociada al CSIC, Centro de
Investigacion
́
en Quımica Sostenible (CIQSO), Campus de El Carmen s/n, Universidad de Huelva, 21007 Huelva, Spain
ABSTRACT: The sequential reaction of two different furans and
PhI=NTs produces 1,2-dihydropyridines in a quantitative manner
in the presence of TpBr3Cu(NCMe) (TpBr3 = hydrotris(3,4,5-
tribromopyrazolyl)borate) as the catalyst under very mild
conditions. The use of a furan and ethyl vinyl ether with
PhI=NTs has led to the corresponding 1,2,3,4-tetrahydropyridine.
Scheme 2. Synthesis of 1,2-Dihydropyridines from Furans
and PhINTs Catalyzed by TpxM Complexes (M = Cu, Ag)
INTRODUCTION
■
The metal-mediated catalytic transfer of nitrene (NR) groups
to saturated or unsaturated substrates constitutes a useful tool
in organic synthesis, in both inter- and intramolecular fashions,
the main transformations being the C−H amination or the
C=C aziridination reactions (Scheme 1).1 During the course of
Scheme 1. Metal-Mediated C−H Amination and Olefin
Aziridination Reactions by Nitrene Transfer
our investigations in this area, we found a novel reaction2 in
which alkyl-substituted furans could be selectively converted
into 1,2-dihydropyridines, in a process involving two molecules
of the heterocycle and one molecule of PhI=NTs (Ts = p-
toluenesulfonyl) and with TpxM complexes (Tpx = hydrotris(x-
substituted-pyrazolyl)borate ligand; M = Cu, Ag) as the
catalyst. Mechanistic studies showed that this transformation
takes place along four consecutive catalytic cycles, in which at
least three of them were metal-mediated. The first step
consisted of the aziridination of the furan (2-methylfuran in
Scheme 2) and subsequent spontaneous opening of the
aziridine AZ to give the aldehyde O1. This aldehyde was
converted into the imine O2 throughout a transimination
catalytic step (either metal- or water-induced). The third cycle
involved in this transformation was a metal-induced aza-Diels−
Alder reaction (ADAR) that afforded the bicyclic compound
BC, which finally converted into the 1,2-dihydropyridine upon
a metal-catalyzed H-elimination−migration process.
Dihydropyridines (DHPs) are essential intermediates in the
synthetic routes of organic compounds with important
biological activity.3 1,4-Dihydropyridines are starting materials
for a variety of drugs such as Nifedipine4 and AK-2-385 as
Special Issue: Copper Organometallic Chemistry
Received: August 26, 2012
© XXXX American Chemical Society
A
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cardiovascular agents and Nimodipine6 for the treatment of
Alzheimer's disease, all them displaying a 1,4-DHP core in their
structures. 1,2-DHPs also find application in the synthetic
routes of numerous natural products (Scheme 3) with medical
Table 1. Catalyst Screening for the Reaction of 2-
Methylfuran and PhINTs
a
Scheme 3. Some Drugs Produced with the Intermediacy of
1,2-Dihydropyridine Cores
cat.
precursor
yield of
b
yield of
b
entry
BC, %
1,2-DHP, %
1
2
3
4
5
6
7
CuI
25
50
0
75
50
CuCl
CuI + PPh3
CuI + bipy
>99
80
20
50
50
5
CuOTf C6H6
[Cu(NCMe)4]PF6
TpBr3Cu(NCMe)
50
50
95
a
Reaction conditions: 0.025 mmol of catalyst; 0.5 mmol of PhI=NTs;
2.5 mmol of 2-methylfuran; 5 mL of CH2Cl2 as solvent; at room
b
temperature; reaction time 20 h. Based on initial PhI=NTs. TsNH2
was not detected after complete consumption of PhI=NTs.
1,2-DHP were quantitatively converted into the latter by
treatment with alumina.
After the above screening of a series of catalyst precursors,
we turned to the targeted reaction involving two different
furans. In this case, an equimolar mixture of 2,5-dimethylfuran
was reacted with PhI=NTs in the presence of catalytic amounts
of the catalyst source (5 mol % with respect to reactants). After
7 h of stirring the reactants were consumed, providing the
imine intermediate (Scheme 4), and 5 equiv of 2-methylfuran
applications, such as Reserpine7 (hypertension and mental
disorders), the alkaloids Catharanthine8 (precursor of the
anticancer agent vinblastine), and (+)-Lepadin B9 (treatment of
viral infection and cancer metastasis). In spite of the interest in
1,2-DHPs, there have been few described procedures for their
synthesis,10 particularly in a regioselective manner, 1,4-DHPs
being far more developed to date.11
Our previous work2 was performed using a large excess of
furan to be reacted with PhI=NTs in the presence of the
copper- or silver-based catalyst. Therefore, the product
contained two molecules of the starting furan. We wondered
about the possibility of coupling two different furans in the final
1,2-dihydropyridines. Under the appropriate conditions, it has
been possible to obtain novel 1,2-DHPs, demonstrating the
potential of certain copper catalysts to induce their quantitative
synthesis, providing a tool for future, more specific applications.
Scheme 4. Synthesis of 1,2-Dihydropyridines from Two
Different Furans
RESULTS AND DISCUSSION
■
Catalyst Screening. We have first carried out a preliminary
catalyst screening to compare the activity of several simple
copper salts and precatalysts with the well-established catalytic
capabilities of the complex TpBr3Cu(NCMe). As a model
reaction we have reproduced that with 2-methylfuran in our
previous work, using an excess of the heterocycle. Thus, when a
1:20:100 mixture of the catalyst source, PhI=NTs, and 2-
methylfuran were stirred at room temperature for 20 h, all the
catalyst precursors employed provided a mixture of both the
bicyclic compound (BC) and the 1,2-dihydropyridine (1,2-
DHP), in a variable ratio, as shown in Table 1. Simple
copper(I) halides (Table 1, entries 1 and 2) gave 1:1 to 3:1
mixtures of those compounds. However, the addition of a
donor ligand such as PPh3 or bipy led to the enhancement of
the yields in 1,2-DHP (Table 1, entries 3 and 4), the former
providing the desired product in quantitative yield. The
TpBr3Cu(NCMe) complex gave the dihydropyridine in 95%
yield, with a minor amount of the bicyclic precursor (Table 1,
entry 7). It is worth mentioning that the mixtures of BC and
was added to the mixture. Workup (see the Experimental
Section) consisted of elimination of volatiles and filtration
through alumina to drive the reaction mixture to the desired
dihydropyridine 1 (Scheme 4). In this case we have found a
marked difference among the group of catalyst precursors
employed (Table 2). With no doubt, the TpBr3Cu(NCMe)
complex provided the best conversion by far into the 1,2-
dihydropyridine 1. This is explained as the consequence of
furan aziridination as the first step of this transformation (as
shown in Scheme 2). Although most of the catalyst precursors
shown in Table 2 have been described to induce the olefin
aziridination reaction,1 usually such a transformation takes
place with an excess of the olefin with respect to the nitrene
source. The use of equimolar amounts in this system
significantly decreases the yield in the starting aziridine and
subsequent products. Only TpBr3Cu(NCMe) seems to over-
come this drawback, due to its already described capability to
catalyze the olefin aziridination reaction with equimolar
amounts of the reactants.12 Therefore, for the purpose of
B
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fragment and two different furans are assembled to give a more
complex structure with a pyridine skeleton. Interestingly, it is
possible to control the position of the substituents at the end of
the reaction: for instance, 2-methylfuran and 2-ethylfuran led to
two different products, 4 and 6, depending on the order in
which they are employed in the reaction protocol.
An interesting feature was observed in the NMR spectra of
the compounds derived from the use of 2,3-dimethylfuran. The
dihydropyridines 3, 5, and 7 contain two stereogenic centers,
and as a result of this, mixtures of two diastereomers have been
detected by NMR spectroscopy. A small diastereomeric excess
of ca. 10% was induced in two cases.
As mentioned above, the formation of the 1,2-DHP by this
procedure takes place through the intermediacy of a bicyclic
compound derived from an aza-Diels−Alder reaction of an
imine and the second molecule of furan (Scheme 2). Although
we were interested in the synthesis of 1,2-DHPs, for the sake of
completeness we focused on the detection of those
intermediates. Therefore, we ran the same protocol with the
exception of the final treatment with alumina. After removal of
volatiles and removal of the metal by quick filtration
throughout a plug of silica gel, we observed by NMR the
nearly quantitative formation of the bicyclic products in the
three representative examples studied (Scheme 6). Compounds
Table 2. Catalyst Screening for the Synthesis of 1,2-
Dihydropyridine 1 (see Scheme 4)
a
b
entry
cat. precursor
CuI
yield of 1, %
1
2
3
4
5
6
7
65
30
50
5
CuCl
CuI + PPh3
CuI + bipy
CuOTf C6H6
[Cu(NCMe)4]PF6
TpBr3Cu(NCMe)
<5
65
94
a
Reaction conditions: 0.025 mmol of catalyst; 0.5 mmol of PhI=NTs;
0.5 mmol of 2,5-dimethylfuran; 2.5 mmol of 2-methylfuran; 5 mL of
CH2Cl2 as solvent; at room temperature; overall reaction time 27 h.
b
The remainder of the initial PhI=NTs up to 100% was converted into
TsNH2.
affording novel DHPs from two different furans, the complex
TpBr3Cu(NCMe) was chosen to develop the reaction scope.
General Procedure for the Synthesis of 1,2-Dihydro-
pyridines from Two Different Furans. After the above
results, we ran a series of seven crossed experiments using four
different furans (Scheme 5), following a similar procedure: a 5
mol % catalyst loading was employed with an equimolar
mixture of an alkyl-substituted furan and PhI=NTs. After 7 h,
the second furan (5 equiv) was added and finally the reaction
mixture was treated with alumina to give the expected
dihydropyridines in very high yield (>95% in all cases).
Overall, this is a very efficient transformation in which a NTs
Scheme 6. Preparation of the Intermediate Bicyclic
Compounds 8−10
Scheme 5. General Synthesis of 1,2-Dihydropyridines from
Two Different Furans
1
8−10 were characterized by means of their H NMR spectra
and comparison with our previous work. However, they
smoothly transform in solution into the corresponding 1,2-
DHPs, precluding the acquisition of 13C{1H} NMR data. In any
case, the interpretation of the available data is unambiguous in
comparison with our previous work2 (see the Experimental
Section), and we propose a bicyclic structure for these three
compounds.
Vinyl Ethyl Ether As Substrate: Synthesis of a
Tetrahydropyridine. Since the generation of the imine
from the copper-catalyzed reaction of a furan and PhI=NTs
seems to be a clean process, we wondered about the addition of
a dienophile distinct to furan in the second step of this
transformation. On the basis of the initial use of 2-methylfuran,
we first tried styrene and 3-hexyne as representative examples
C
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(CH3). ESI-MS analysis: calcd for C18H21NO4S, 347.43; found,
348.12.
of alkenes and alkynes, respectively. Unfortunately, we observed
no reaction at all with these substrates. However, when we
employed ethyl vinyl ether, we observed the formation of
compound 11, a tetrahydropyridine derived from the aza-
Diels−Alder reaction of the imine and the unsaturated ether
shown in Scheme 7. The synthesis of chiral tetrahydropyridines
1-(4-Acetyl-6-methyl-1-tosyl-1,2-dihydropyridin-2-yl)butan-2-
one (2). 1H NMR (CDCl3, 400 MHz): δ 7.51 (d, 2H, J = 8 Hz), 7.12
(d, 2H, J = 8 Hz), 6.09 (s, 1H), 6.15, 5.22, 2.68, 2.58 (ABMX spin
system, δA 2.58, δB 2.68, δM 5.22, δX 6.15, JAB = 18 Hz, JAM = 4 Hz, JBM
= 8 Hz, JMX = 6 Hz), 2.37 (2H, J = 7.5 Hz), 2.28 (s, 3H), 2.18 (s, 3H),
1.85 (s, 3H), 0.97 (s, 3H, J = 7.5 Hz). 13C{1H} NMR (CDCl3, 100
MHz): δ 207.9 (CO), 195.3 (CO), 144.0 (Cq), 135.9 (Cq), 135.6
(Cq), 132.3 (Cq), 132.0 (olefinic CH), 129.6 (aromatic CH), 127.2
(aromatic CH), 112.4 (olefinic CH), 51.3 (CH), 45.7 (CH2), 36.0
(CH2), 24.8 (CH3), 23.2 (COCH3), 21.4 (CH3), 7.5 (CH3). ESI-MS
analysis: calcd for C19H23NO4S, 361.45; found, 362.14.
Scheme 7. Synthesis of the Tetrahydropyridine 11
3-(4-Acetyl-6-methyl-1-tosyl-1,2-dihydropyridin-2-yl)butan-2-
one (3). Two diastereomers, 1:1 mixture. Data for diastereomer A are
1
as follows. H NMR (CDCl3, 400 MHz): δ 7.51 (d, 2H, J = 8 Hz),
7.10 (d, 2H, J = 8 Hz), 6.11 (s, 1H), 6.10 (d, 1H, J = 6 Hz), 4.93 (dd,
1H, J = 6, 10 Hz), 2.62 (dq, 1H, J = 7.5, 10 Hz), 2.29 (s, 3H), 2.15 (s,
3H), 2.05 (s, 3H), 1.82 (s, 3H), 1.04 (d, 3H, J = 7.5 Hz). 13C{1H}
NMR (CDCl3, 100 MHz): δ 208.9 (CO), 194.8 (CO), 143.9 (Cq),
135.0 (Cq), 132.8 (Cq), 131.1 (Cq), 129.9 (olefinic CH), 129.6
(aromatic CH), 126.6 (aromatic CH), 105.6 (olefinic CH), 54.1
(CH), 49.4 (CH), 29.7 (COCH3), 24.7 (CH3), 23.0 (COCH3), 21.3
is an area of interest. A recent work by Carretero and co-
workers13 with chiral nickel-based catalysts has proven the
validity of the aza-Diels−Alder reaction to generate those
molecules.
1
(CH3), 14.1 (CH3). Data for diastereomer B are as follows. H NMR
(CDCl3, 400 MHz): δ 7.51 (d, 2H, J = 8 Hz), 7.10 (d, 2H, J = 8 Hz),
6.10 (s, 1H), 6.02 (d, 1H, J = 6 Hz), 5.0 (dd, 1H, J = 6, 10 Hz), 2.62
(dq, 1H, J = 7.5, 10 Hz), 2.29 (s, 3H), 2.21 (s, 3H), 2.18 (s, 3H), 1.85
(s, 1H), 1.22 (d, 3H, J = 7.5 Hz). 13C{1H} NMR (CDCl3, 100 MHz):
δ 209.6 (CO), 195.4 (CO), 144.1 (Cq), 133.6 (Cq), 130.6 (olefinic
CH), 129.8 (aromatic CH), 126.7 (aromatic CH), 135.6 (Cq), 131.6
(Cq), 109.3 (olefinic CH), 54.3 (CH), 49.7 (CH), 28.6 (COCH3),
24.6 (CH3), 24.1 (COCH3), 21.5 (CH3), 13.4 (CH3).
CONCLUSIONS
■
In summary, we have employed the complex TpBr3Cu(NCMe)
as a catalyst for a transformation in which two different furans
and PhI=NTs react to produce 1,2-dihydropyridines. The
procedure also applies to a furan and ethyl vinyl ether to give a
1,2,3,4-tetrahydropyridine. All the reactions took place in
quantitative yields and under very mild conditions. The
generation of stereocenters opens a window for the future
development of the asymmetric catalytic version of this
transformation.
1-(4-Acetyl-1-tosyl-1,2-dihydropyridin-2-yl)butan-2-one (4). 1H
NMR (CDCl3, 400 MHz): δ 7.59 (d, 2H, J = 8 Hz), 7.20 (d, 2H, J
= 8 Hz), 6.66 (d, 1H, J = 7.5 Hz), 5.91 (d, 1H, J = 7.5 Hz), 6.30, 5.04,
3.01, 2.72 (ABMX spin system, δA 2.72, δB 3.01, δM 5.04, δX 6.30, JAB
=
18 Hz, JAM = 4 Hz, JBM = 8 Hz, JMX = 6 Hz), 2.37 (q, 2H, J = 7.5 Hz),
2.38 (s, 3H), 2.08 (s, 3H), 0.98 (t, 3H, J = 7.5 Hz). 13C{1H} NMR
(CDCl3, 100 MHz): δ 208.3 (CO), 195.4 (CO), 144.3 (Cq), 136.2
(Cq), 133.1 (Cq), 129.9 (aromatic CH), 129.7 (olefinic CH), 126.7
(aromatic CH), 126.1 (olefinic CH), 104.8 (olefinic CH), 49.8 (CH),
48.2 (CH2), 36.3 (CH2), 25.2 (COCH3), 21.6 (CH3), 7.5 (CH3). ESI-
MS analysis: calcd for C18H21NO4S, 347.43; found, 346.11.
EXPERIMENTAL SECTION
■
General Methods. All preparations and manipulations were
carried out under an oxygen-free nitrogen atmosphere using
conventional Schlenk techniques or inside a drybox. The copper
salts, substituted furans, and other reagents were purchased from
Aldrich and were rigorously dried previously to their use. Solvents
were dried and degassed before use with a MBRAUN SPS system. The
TpBr3Cu(NCMe) complex14 and PhI=NTs15 were prepared according
to literature methods. NMR experiments were run in a Varian Mercury
400 MHz spectrometer. ESI-MS analyses were carried out at CITIUS
(Universidad de Sevilla, Spain).
General Catalytic Experiment for the Synthesis of Dihy-
dropyridines 1−7. The catalyst precursor (0.025 mmol) was
dissolved in 5 mL of CH2Cl2, and 0.5 mmol of the first alkylfuran
(see Scheme 5) was added. To the resulting colorless solution was
added PhI=NTs (0.5 mmol, 186 mg) as yellow crystals. The mixture
turned greenish within a few seconds, and the color slowly changed to
orange with time. After 7 h of stirring, 5 equiv (2.5 mmol) of the
second alkylfuran was added, and the mixture was stirred for an
additional 20 h. Volatiles were then removed under vacuum, 2 mL of
methylene chloride was added, and the solution was passed
throughout a plug of neutral alumina. The solution was evaporated,
and the resulting reddish solids corresponded to pure dihydropyridines
1−7. Isolated yields: >95%.
3-(4-Acetyl-1-tosyl-1,2-dihydropyridin-2-yl)butan-2-one (5). Data
1
for the major diastereomer (55%) are as follows. H NMR (CDCl3,
400 MHz): δ 7.55 (d, 2H, J = 8 Hz), 7.15 (d, 2H, J = 8 Hz), 6.57 (d,
1H, J = 7.5 Hz), 6.17 (d, 1H, J = 6 Hz), 6.10 (d, 1H, J = 7.5 Hz) 4.88
(dd, 1H, J = 6, 10 Hz), 2.81 (dq, 1H J = 7.5, 10 Hz), 2.31 (s, 3H), 2.10
(s, 3H), 1.99 (s, 3H), 1.22 (d, 3H, J = 7.5 Hz).13C{1H} NMR (CDCl3,
100 MHz): δ 209.4 (CO), 195.1 (CO), 144.1 (Cq), 135.5 (Cq), 133.2
(Cq), 129.6 (aromatic CH), 127.9 (olefinic CH), 126.8 (aromatic
CH), 126.2 (olefinic CH), 104.7 (olefinic CH), 54.9 (CH), 54.6
(CH), 28.5 (COCH3), 25.0 (COCH3), 21.5 (CH3), 10.9 (CH3). Data
1
for the minor diastereomer (45%) are as follows. H NMR (CDCl3,
400 MHz): δ 7.58 (d, 2H, J = 8 Hz), 7.21 (d, 2H, J = 8 Hz), 6.68 (d,
1H, J = 7.5 Hz), 6.10 (d, 1H, J = 6 Hz), 5.82 (d, 1H, J = 7.5 Hz), 5.04
(dd, 1H, J = 6, 10 Hz), 2.98 (dq, 1H, J = 7.5, 10 Hz), 2.34 (s, 3H),
2.14 (s, 3H), 2.09 (s, 3H), 1.22 (d, 3H, J = 7.5 Hz). 13C{1H} NMR
(CDCl3, 100 MHz): δ 209.9 (CO), 195.4 (CO), 144.4 (Cq), 137.4
(Cq), 134.4 (Cq), 129.9 (olefinic CH), 129.9 (aromatic CH), 127.3
(olefinic CH), 126.8 (aromatic CH), 109.1 (olefinic CH), 55.0 (CH),
49.8 (CH), 29.8 (COCH3), 25.1 (COCH3), 21.6 (CH3), 14.1 (CH3).
ESI-MS analysis (mixture of diastereomers): calcd for C18H21NO4S,
347.43; found, 346.11.
1-(4-Acetyl-6-methyl-1-tosyl-1,2-dihydropyridin-2-yl)propan-2-
one (1). 1H NMR (CDCl3, 400 MHz): δ 7.52 (d, 2H, J = 8 Hz), 7.12
(d, 2H, J = 8 Hz), 6.09 (s, 1H), 6.17, 5.21, 2.73, 2.61 (ABMX spin
system, δA 2.61, δB 3.09, δM 5.21, δX 6.17, JAB = 18 Hz, JAM = 4 Hz, JBM
= 8 Hz, JMX = 6 Hz), 2.29 (s, 3H), 2.19 (s, 3H), 2.08 (s, 3H), 1.85 (s,
3H). 13 C{1H} NMR (CDCl3, 100 MHz): δ 204.2 (CO), 194.2 (CO),
143.0 (Cq), 134.9 (Cq), 134.7 (Cq), 132.4 (Cq), 130.8 (olefinic CH),
128.3 (aromatic CH), 126.2 (aromatic CH), 111.5 (olefinic CH), 50.3
(CH), 46.0 (CH2), 29.0 (COCH3), 23.8 (COCH3), 22.1 (CH3), 20.4
1-(2-(2-Oxopropyl)-1-tosyl-1,2-dihydropyridin-4-yl)propan-1-one
1
(6). H NMR (CDCl3, 400 MHz): δ 7.67 (d, 2H, J = 8 Hz), 7.28 (d,
2H, J = 8 Hz), 6.65 (d, 1H, J = 7.5 Hz), 5.92 (d, 1H, J = 7.5 Hz), 6.29,
5.00, 3.04, 2.72 (ABMX spin system, δA 2.72, δB 3.04, δM 5.00, δX 6.29,
JAB = 18 Hz, JAM = 4 Hz, JBM = 8 Hz, JMX = 6 Hz), 2.40 (q, 2H, J = 7.5
Hz), 2.35 (s, 3H), 2.07 (s, 3H), 0.91 (t, 3H, J = 7.5 Hz). 13C{1H}
D
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NMR (CDCl3, 100 MHz): 205.7 (CO), 198.4 (CO), 144.3 (Cq),
136.2 (Cq), 132.5 (Cq), 129.8 (aromatic CH), 128.5 (olefinic CH),
126.7 (aromatic CH), 126.1 (olefinic CH), 105.4 (olefinic CH), 49.5
(CH), 30.4 (CH2), 30.3 (COCH3), 21.6 (CH3), 8.0 (CH3). ESI-MS
analysis: calcd for C18H21NO4S, 347.43; found, 346.11.
AUTHOR INFORMATION
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
We thank MINECO (CTQ2011-28942-CO2-01) and Junta de
3-(4-Propionyl-1-tosyl-1,2-dihydropyridin-2-yl)butan-2-one (7).
Data for the major diastereomer (55%) are as follows. 1H NMR
(CDCl3, 400 MHz): δ 7.66 (d, 2H, J = 8 Hz), 7.27 (d, 2H, J = 8 Hz),
6.57 (d, 1H, J = 8 Hz), 6.15 (d, 1H, J = 6 Hz), 6.09 (d, 1H, J = 8 Hz)
4.84 (dd, 1H, J = 6, 10 Hz), 2.81 (dq, 1H, J = 7.5, 10 Hz), 2.39 (q, 2H,
J = 7.5 Hz), 2.07 (s, 3H), 1.18 (d, 1H, J = 7 Hz), 0.85 (t, 3H, J = 7.5
Hz). 13C{1H} NMR (CDCl3, 100 MHz): δ 209.4 (CO), 197.9 (CO),
144.1 (Cq), 135.6 (Cq), 132.5 (Cq), 129.6 (aromatic CH), 126.6
(aromatic CH), 126.5 (olefinic CH), 126.1 (olefinic CH), 109.6
(olefinic CH), 54.7 (CH), 49.7 (CH), 30.4 (CH2), 29.8 (COCH3),
21.5 (CH3), 10.9 (CH3), 8.1 (CH3). Data for the minor diastereomer
(45%) are as follows. 1H NMR (CDCl3, 400 MHz): δ 7.67 (d, 2H, J =
8 Hz), 7.28 (d, 2H, J = 8 Hz), 6.67 (d, 1H, J = 7 Hz), 6.09 (d, 1H, J =
6 Hz), 5.83 (d, 1H, J = 8 Hz), 5.02 (dd, 1H, J = 6, 10 Hz), 2.97 (dq,
1H, J = 7.5, 10 Hz), 2.40 (q, 2H, J = 7.5 Hz), 2.15 (s, 3H), 1.20 (d,
1H, 7 Hz), 0.92 (t, 3H, J = 7 Hz). C{1H} NMR (CDCl3, 100 MHz): δ
209.9 (CO), 198.3 (CO), 144.3 (Cq), 136.5 (Cq), 133.8 (Cq), 129.9
(aromatic CH), 128.8 (olefinic CH), 127.2 (olefinic CH), 126.8
(aromatic CH), 105.3 (olefinic CH), 54.9 (CH), 54.6 (CH), 30.4
(CH2), 28.5 (COCH3), 21.5 (CH3), 14.1 (CH3), 8.1 (CH3). ESI-MS
analysis: calcd for C19H23NO4S, 361.45; found, 360.12.
General Catalytic Experiment for the Synthesis of the
Bicyclic Compounds 8−10. Following a procedure identical with
that detailed above, the final reaction mixture, using the furans shown
in Scheme 6, was filtered through a plug of silica gel to retain the
catalyst. Solvent removal led to the isolation of reddish orange oils that
were identified by NMR as the bicyclic compounds 8−10 (vide infra).
Isolated yields: >95%. Samples converted into dihydropyridines on
standing for several hours in solution, precluding the acquisition of
13C{1H} NMR spectra.
■
́
Andalucia (Proyecto P10-FQM-06292). L.M. thanks the Plan
Propio de Investigacion
fellowship.
́
(Universidad de Huelva) for a research
REFERENCES
■
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2H, J = 8 Hz), 7.20 (d, 2H, J = 8 Hz), 5.41 (d, 1H, J = 8 Hz), 5.40 (m,
1H), 5.30 (m, 1H), 4.48 (br s, 1H), 3.23 (dd, 1H, J = 8, 1.2 Hz), 2.34
(s, 3H), 1.98 (m, 2H), 1.93 (s, 3H), 1.84 (s, 3H), 0.93 (t, 3H, J = 7.5
Hz).
(12) Mairena, M. A.; Díaz-Requejo, M. M.; Belderrain, T. R.; Nicasio,
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1
pyridine-7-yl)ethanone (9). H NMR (CDCl3, 400 MHz): δ 7.58 (d,
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2H, J = 8 Hz), 7.25 (d, 2H, J = 8 Hz), 5.45 (d, 1H, J = 8.5 Hz), 5.32
(d, 1H, J = 9 Hz), 5.21 (dd, 1H, J = 1.5, 8.5 Hz), 3.17 (dd, 1H, J = 1.5,
8.5 Hz), 2.34 (s, 3H), 2.05 (s, 3H), 1.62 (s, 3H), 1.61 (s, 3H), 1.48 (s,
3H).
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8 Hz), 7.23 (d, 2H, J = 8 Hz), 6.54 (d, 1H, J = 7.5 Hz), 5.39 (dd, 1H, J
= 7.5 Hz), 5.00 (dd, 1H, J = 9, 1.5 Hz), 4.88 (d, 1H, J = 9 Hz), 3.18
(dd, 1H, J = 1.5, 7.5 Hz), 2.4 (s, 3H), 1.73 (s, 3H), 1.70 (s, 3H), 1.64
(s, 3H).
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(15) Yamada, Y.; Yamamoto, T.; Okawara, M. Chem. Lett. 1975,
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General Catalytic Experiment for the Synthesis of 1-(2-
Ethoxy-6-methyl-1-tosyl-1,2,3,4-tetrahydropyridin-4-yl)-
ethanone (11). This compound was prepared following a procedure
identical with that detailed above, using 2-methylfuran as the starting
material. After the initial 7 h of stirring, 5 equiv of ethyl vinyl ether (2.5
mmol) was added, and the final reaction mixture was treated with silica
to yield, after removal of volatiles, 90% isolated yield of compound 11
as a brown-orange oil.
1H NMR (CDCl3, 400 MHz): δ 7.58 (d, 2H, J = 8 Hz), 7.23 (d, 2H,
J = 8 Hz), 6.60 (d, 1H, J = 8 Hz), 5.25 (dd, 1H, J = 8, 1.5 Hz), 5.14 (br
s, 1H), 3.58 (dt, 1H, J = 7, 1.5 Hz), 3.40 (dt, 1H, J = 7, 1.5 Hz), 2.57
(m, 1H), 2.49 (m, 1H), 2.37 (s, 3H), 2.07 (s, 3H), 1.26 (m, 1H), 0.96
(t, 3H, J = 7 Hz). 13C{1H} NMR (CDCl3, 100 MHz): δ 209 (CO),
143.9 (Cq), 137.4 (Cq), 129.8 (aromatic CH), 126.7 (aromatic CH),
123.3 (olefinic CH), 107.7 (olefinic CH), 80.0 (CH), 63.1 (CH2),
41.6 (CH), 28.7 (CH2), 28.5 (COCH3), 21.6 (CH3), 14.6 (CH3). ESI-
MS analysis: calcd for C16H19NO4S, 321.39; found, 320.09.
E
dx.doi.org/10.1021/om3008234 | Organometallics XXXX, XXX, XXX−XXX