One-pot synthesis of 1,2-dihydropyridines: Expanding the diverse reactivity of propargyl vinyl ethers

Article abstract of DOI:10.1021/jo102545m

The catalyzed synthesis of 1,2-dihydropyridines starting from easily accessible propargyl vinyl ethers was realized. The reaction sequence involving a transition metal-catalyzed propargyl-Claisen rearrangement, a condensation step, and a Bronsted acid-cat

Full text of DOI:10.1021/jo102545m

ARTICLE
pubs.acs.org/joc
One-Pot Synthesis of 1,2-Dihydropyridines: Expanding the Diverse
Reactivity of Propargyl Vinyl Ethers
Tobias Harschneck and Stefan F. Kirsch*
Department Chemie and Catalysis Research Center, Technische Universit€at M€unchen, Lichtenbergstrasse 4, 85747 Garching, Germany
S Supporting Information
b
ABSTRACT: The catalyzed synthesis of 1,2-dihydropyridines starting
from easily accessible propargyl vinyl ethers was realized. The reaction
sequence involving a transition metal-catalyzed propargyl-Claisen re-
arrangement, a condensation step, and a Brønsted acid-catalyzed
heterocyclization furnishes the highly substituted heterocycles in mod-
erate to excellent yields. Additionally, a practical one-pot protocol
toward 1,2-dihydropyridines and 2H-pyrans starting from propargylic
alcohols was developed.
Scheme 1. Synthetic Variability of Propargyl Vinyl Ethers
’ INTRODUCTION
Heterocyclic structures are abundant in natural products as
well as pharmaceutically active substances.1 They can be found as
core structures of a variety of therapeutics against a broad
spectrum of diseases reaching from hypercholesterolemia
(Lipitor)2 to peptic ulcer desease (Zantac)3 and hypertension
(Amlodipine).4 Heterocycles are also important intermediates in
organic synthesis5 and gained importance as building blocks for
the development of new materials.6 Their ubiquity in various
fields of chemical science contributed to an ongoing major
interest in the synthesis of all classes of heterocyclic compounds.
In this context, transition metal-catalyzed approaches have
become a widely used tool7-9 that is nowadays a valuable
alternative to the more classical condensation approaches.10
Over the last five years we demonstrated that propargyl vinyl
ethers are viable substrates for the synthesis of a broad variety of
heterocyclic compounds by use of transition metal catalysts.
Easily accessible, the ethers can3 conveniently be converted into
furans,11 pyrroles,12 and pyrans13 as outlined in Scheme 1. For all
classes of heterocycles, our highly efficient and atom-economic
domino approach14 consists of rearrangement and subsequent
cyclization. In 2005 for example, we reported the first direct
conversion of propargyl vinyl ethers into highly substituted
furans.11 This reaction was believed to proceed through a gold-
catalyzed propargyl-Claisen rearrangement, followed by a 5-exo-
heterocyclization onto the gold-activated allene intermediate
(Scheme 2).15 When an additional condensation step with a
primary amine was implemented into the reaction cascade, the
corresponding pyrroles were obtained via a convenient one-pot
sequence.12,16,17Both the synthesis of furans and pyrroles re-
mained limited to 5-methyl-substituted heterocycles derived from
primary propargylic alcohols. This drawback could be partially
overcome by selective IBX-oxidation in the benzylic position
as shown in Scheme 3.12,18,19 Following our domino approach
to furans and pyrroles, Jiang et al. very recently reported a few
elegant methods for the direct synthesis of furan carbaldehydes
through in situ oxidation in the presence of several transition
metals.20
Further development of the methodology allowed the cata-
lyzed formation of 6-membered heterocycles. Despite extensive
screening, we never succeeded in finding an appropriate transi-
tion metal catalyst for the direct 6-endo-cyclization. To surmount
this problem, the allenyl carbonyl intermediates were isomerized
to 1-oxatrienes, which then underwent 6π-electrocyclization21 to
achieve the product of a formal 6-endo-cyclization.22 We have
also been first to synthesize 1,2-dihydropyridines from propargyl
vinyl ethers23 through a sequence of propargyl-Claisen rearran-
gement, condensation, and heterocyclization in the course of our
studies toward the synthesis of pyrroles (Scheme 4).12 The scope
of the original protocol was quite limited yielding only four
examples of dihydropyridines with low to moderate yields. Since
1,2-dihydropyridines are of great value as core structures in
complex molecules24 and play an important role as synthetic
Received: December 22, 2010
Published: March 07, 2011
r
2011 American Chemical Society
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Scheme 2. Our Synthetic Strategies to 5- and 6-Membered
Heterocycles
Scheme 4. First Results on the Synthesis of 1,2-
Dihydropyridines Starting from Propargyl Vinyl Ethers12
’ RESULTS AND DISCUSSION
Synthesis of the Propargyl Vinyl Ethers. The propargyl vinyl
ethers 2a-k were synthesized in a phosphine-catalyzed 1,4-
addition of propargylic alcohols to ynoic acid esters.28 A broad
variety of substrates are accessible in good to excellent yields
facing very few limitations (Scheme 5). Furthermore, ethyl ester
2j was subjected to reduction and subsequent methylation of the
alcohol to give 2l.
Scheme 3. Oxidative Functionalization of 5-Methyl Furans
and Pyrroles
Transition Metal-Catalyzed Propargyl-Claisen Rearrange-
ment. Earlier work in our group on the transition metal-cata-
lyzed propargyl-Claisen rearrangement showed that but-2-en-
oate derivatives are converted to the corresponding allenes in a
very clean and fast reaction by use of several silver salts. Among
them, AgSbF6 provides the best results.12 Another single example
of a silver-catalyzed propargyl-Claisen rearrangement was re-
ported by Grissom et al. in 1997.29 Toste et al. investigated the
rearrangement of propargyl vinyl ethers with terminal alkenes
and found [(PPh3Au)3O]BF4 to be the most efficient catalyst for
this class of substrates.30,31 Since our own results and the results
reported in the literature32,33 give a somewhat unclear picture of
the efficiency of catalysts, we decided to reinvestigate this
rearrangement step with the focus on subtle changes in the
vinylic moiety. To this end, we started the investigation with
propargyl vinyl ether 2j bearing an electron-withdrawing ester
moiety (R4 = CO2Et) and a methyl donor group (R3 = Me).
Reaction with 0.7 mol % of AgSbF6 proceeded as expected and
provided the product in quantitative yield. Indeed, AuCl and
[(PPh3Au)3O]BF4 containing three atoms gold per molecule
catalyst also turned out to be efficient catalysts for this transfor-
mation (Table 1, entries 1-4). The former, however, stands out
due to its low costs and catalyst loadings as low as 0.1 mol %
which are sufficient to reach full conversion. For example,
conversion of 2j with 0.1 mol % of AgSbF6 provided allene 3j
as a mixture of tautomers in quantitative yield after 24 h in
CH2Cl2 at room temperature (entry 4). Changing the electronic
properties of the double bond by replacing the electron-with-
drawing group with a donating group leads to a markedly
increased reactivity of the substrate. (E)-(3-(4-Methoxybut-2-
en-2-yloxy)pent-1-ynyl)benzene (2l) is converted into the cor-
responding allene by use of both silver and gold catalysts. We feel,
nevertheless, that also in this case AgSbF6 should be the catalyst
of choice due to its excellent efficacy at a low catalyst loading of
0.01 mol % (entry 8). Surprisingly, when acrylate derivate 2a
lacking the additional donor substituent (R3 = H) was used in the
reaction, AgSbF6 only gave poor conversion even after 24 h as did
[(PPh3Au)3O]BF4. However, AuCl smoothly transformed the
propargyl vinyl ether into the allene product. When using a
intermediates on the route to pyridines via oxidation and piper-
idines via reduction,25 we felt it is of importance to continue our
studies in the field with the goal to develop a broadly appli-
cable protocol for the catalyzed transformation of propargyl vinyl
ethers into 1,2-dihydropyridines. In the meantime, Tejedor,
Mꢀendez-Abt, and García-Tellado showed in an independent
study that 1,2-dihydropyridines can be obtained from propargyl
vinyl ethers and primary amines when using microwave irradia-
tion at 120 °C in the absence of transition metal catalysts.26 In
2010, Xu et al. reported a related sequence to 1,2-dihydropyr-
idines catalyzed by gold and silver salts; therein, tosyl amide
and propargyl vinyl ethers with mostly terminal alkynes were
reacted.27
Herein, we now present our full results on the synthesis of
1,2-dihydropyridines from propargyl vinyl ethers. The hetero-
cyclic products are formed in an efficient and easy to perform
reaction cascade, which proceeds via a metal-catalyzed propar-
gyl-Claisen rearrangement and a subsequent condensation step,
and is terminated by an acid-induced 6π-electrocyclization. The
excellent scope of the reaction is defined including its limita-
tions. We also report full details on the transition metal-cata-
lyzed propargyl-Claisen rearrangement that is key for our
heterocycle syntheses. The focus is put on the influence of
the substrate substitution pattern on their behavior in the
catalytic reaction. In addition, an extended one-pot procedure
is introduced, which provides access to 1,2-dihydropyridines
and pyrans starting from propargylic alcohols rather than
propargyl vinyl ethers.
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Scheme 5. Synthesis of Propargyl Vinyl Ethers 2a-l
Table 1. Catalyst Screening for the Conversion of 2 into 3a
Table 2. Substrate Scope of the Propargyl-Claisen
Rearrangementa
entry
3
R1
R2
conversion b,c (%)
conversion
entry 2 R1 R2 R3
R4
catalyst (mol %) time (h) to 3b,c (%)
1
2
3
4
6
i
Et
4-MeO-C4H6
100
100
100
100
100d
d
g
c
e
i-Pr
Ph
1
2
j
Et Ph Me CO2Et
AgSbF6 (0.7)
[(PPh3Au)3O]-
BF4 (0.7)
1.25
1.25
100
100
CH2CH2Ph
n-Pent
Ph
Me
Ph
Ph
3
4
5
6
AuCl (0.7)
1.25
75
100
100
88
a Conditions: 60 μmol of 2, 3 mol % of AuCl, 23 °C, CDCl3 (0.1 M).
b Conversion was determined by 1H NMR. c 3 was detected as the sole
product. d 3e was formed as a 1:1 mixture of diastereoisomers.
AgSbF6 (0.1)
24
l
Et Ph Me CH2OMe AgSbF6 (0.1)
[(PPh3Au)3O]-
3.5
3.5
BF4 (0.1)
played a key role in the reaction outcome. Despite the fact that
reaction of 2j (R3 = Me) using 5 mol % of AgSbF6 provided a
clean allenylcarbonyl compound, subsequent conversion with
1.5 equiv of aniline at 23 °C furnished the 1,2-dihydropyridine
4ja after 16 h in only 27% yield (Scheme 6). As the major side
product the corresponding 2H-pyran 5j was formed due to the
fast base-mediated heterocyclization prior to the condensation
reaction.13 This drawback could not be overcome by any
investigated alteration in the reaction procedure. However, the
scope of the reaction was determined and in all cases the desired
6-methyl-1,2-dihydropyridines 4jb-jf were isolated. Unfortu-
nately, only reactions with aniline derivatives provided the
desired products. The use of aliphatic amines (R5 = i-Pr, Bn)
exclusively led to formation of 2H-pyrans. Reaction of propargyl
vinyl ether 2k (R1 = H) with 3-chloroaniline provided the pyrrole
6kc in a very slow but clean reaction (72% after 24 h).
Synthesis of Tetrasubstituted Dihydropyridines. In con-
trast to but-2-enoate 2j, acrylate 2a (R3 = H) was converted into
the expected allene intermediate by use of 5 mol % of AuCl and
reacted with 1.5 equiv of aniline resulting in a mixture of enamine
7aa (28%) and dihydropyridine 8aa (65%) without giving any
traces of the pyran side product (Scheme 7). Elaboration of the
final cyclization step revealed p-toluenesulfonic acid as an
efficient additive to catalyze the cyclization event. Consequently,
addition of 0.2 equiv of p-TsOH led to completion of the
reaction, and 8aa was provided in 88% yield after 15 h at
40 °C.35 Without the Brønsted acid, the reaction was slowed
markedly and in our hands never did reach full conversion even
after elongated reaction times.
7
8
AuCl (0.1)
3.5
100
100
8
AgSbF6 (0.01)
24
9
a
Et Ph H CO2Et
AgSbF6 (3)
[(PPh3Au)3O]-
BF4 (3)
4
4
10
48
11
12
AuCl (3)
4
100
100
AuCl (0.5)
22
a Conditions: substrate 2, catalyst (mol %), 23 °C, CH2Cl2. b Conver-
sion was determined by 1H NMR. c 3 was detected as the sole product.
minimum of 0.5 mol % of AuCl, allene 3a was still obtained in
quantitative yield after 22 h (Table 1, entry 12).
Subsequently, the substrate scope of the propargyl-Claisen
rearrangement catalyzed by AuCl was investigated for substrates
with R3 = H and R4 = CO2R since these substrates proved best
for the envisaged synthesis of 1,2-dihydropyridines (vide infra)
(Table 2). In all cases, the rearrangement furnished a clean
aldehyde product according to 1H NMR. It should be noted that
only after elongated reaction times the allene products were
obtained as mixtures of tautomers. Isolation of the products was
indeed possible, though problematic, as the allenes partially
reacted to 2H-pyrans (<25%) under various workup and pur-
ification methods.34
Synthesis of 5-Methyl-1,2-dihydropyridines. With these
optimized conditions for the rearrangement of different substrate
classes, we attempted to complete the envisioned cascade by a
condensation step and subsequent heterocyclization. As well as
in the propargyl-Claisen rearrangement the substitution pattern
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Scheme 6. Reactions of But-2-enoates 2j and 2k
Table 3. Substrate Scope of the Conversion of 2 in
1,2-Dihydropyridines 8a
8
entry
R1
R2
R
R5
no. yield (%)b
1
2
3
4
5
6
7
8
9
Et
Et
Et
Et
Et
Et
Et
Et
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et Ph
aa
ag
ah
88
62
75
67c
69
78
85
81
84
77
72
55
55
74
89
Et PMB
Et i-Pr
Et (S)-PhCHMe ai
Me 4-Br-C6H4
bd
Me 3-NO2-C6H4 be
Me 4-MeO-C6H4 bf
Me Bn
Et Ph
Et Ph
Et Ph
Et Ph
Et Ph
bj
ca
da
ea
fa
Scheme 7. Conversion of 2a to Enamine 7aa and
Dihydropyridine 8aa
10 i-Pr
11 Ph
12
H
13 CH2CH2Ph n-C5H9
ga
ha
ia
14 Et
15 Et
4-MeO2C-C6H4 Et Ph
4-MeO-C6H4 Et Ph
a Conditions: (1) 50 mg of 2, 5 mol % of AuCl, 23 °C, CH2Cl2 (0.1 M), 1
h; (2) R5-NH2 (1.5 equiv), 23 °C, 30 min; (3) p-TsOH (20 mol %), 40
c
°C, 15 h. b Yield of pure product after column chromatography. The
product was isolated as a 1:1.3 mixture of diastereoisomers.
the reaction on its own. The sequence was terminated by
condensation with 1.5 equiv of an amine and 0.2 equiv of p-
TsOH at 40 °C for 15 h to give the desired products in good
yields (Scheme 8). It is of particular note that this one-pot
procedure presents the possibility to access 1,2-dihydropyridines
even in cases when the required propargyl vinyl ether is not
accessible due to poor stability. Accordingly, 8ma was ob-
tained in a reasonable yield although the direct propargyl vinyl
ether precursor decomposed upon purification via column
chromatography.
Having demonstrated the efficient generation of 1,2-dihydro-
pyridines directly from propargyl alcohols, the developed se-
quence was also applied to the synthesis of 2H-pyrans. In the case
of internal alkynes, PMe3 proved the better catalyst for the
Michael-type addition reaction. However, this step of the se-
quence remained the crucial one, since complete consumption of
the starting material was never observed. Conversion of pro-
pargylic alcohols 1 with 1 equiv of ethyl but-2-ynoate in the
presence of 0.2 equiv of PMe3, subsequent addition of AuCl
(10 mol %) and AgSbF6 (5 mol %), and finally base-catalyzed
6π-oxaelectrocyclization with 10 mol % of DBU led to the
oxygen-containing 6-membered heterocycles in moderate yields
(Scheme 9).
As a standardized protocol, we performed the dihydropyridine
formation with internal alkynes and used a sequential addition of
reagents and catalysts to obtain reproducibly high yields [(1)
AuCl (5 mol %), 23 °C; (2) R5-NH2; (3) p-TsOH (20 mol %),
40 °C, CH2Cl2]. Under these conditions, and in contrast to the
metal-free protocol developed by Tejedor et al.,26 terminal
alkynes unfortunately did not give the 1,2-dihydropyridines but
reacted to inseparable mixtures of unknown products.36 Never-
theless, a broad variety of previously unknown tetrasubstituted
1,2-dihydropyridines were synthesized in good to excellent yields
by using standard conditions. Reaction with anilines as well as
aliphatic amines furnished the corresponding products (Table 3,
entries 1-8). The formation of 1,2-dihydropyridines also toler-
ated substitution of R1 and R2 with both aryl and alkyl groups
(Table 3, entries 9-15). Compound 8fa bearing no substituent
in the 2-position (R1 = H) was obtained in only moderate yield.
One-Pot Procedures Starting from Propargylic Alcohols.
Next, we expanded this one-pot procedure by an additional step
that is the formation of the propargyl vinyl ethers. When pro-
pargylic alcohols 1 were reacted with 1 equiv of ethyl propiolate
and 5 mol % of P(n-Bu)3, the Michael-addition remained an
efficient process.28 Subsequent addition of both AuCl and
AgSbF6 (5 mol % each) furnished the allenylcarbonyl com-
pounds. Notably, only the use of both catalysts together provided
good and reproducible results; neither one was able to catalyze
Studies on Stereochemical and Mechanistic Details. Me-
chanistically, the cascade reaction to 1,2-dihydropyridine may
proceed via two different pathways delineated in Scheme 10.
After rearrangement and condensation, the imine (or enamine)
moiety could perform a 6-endo-cyclization onto the allene when
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Scheme 8. One-Pot Synthesis of 1,2-Dihydropyridines
8 Starting from Propargylic Alcohols 1
Scheme 11. Stereochemical Course of the
1,2-Dihydropyridine Formation
Scheme 9. One-Pot Synthesis of 2H-Pyrans 5 Starting from
Propargylic Alcohols 1
Scheme 12. Mechanistic Proposal
Scheme 10. Two Possible Pathways of the 1,2-
Dihydropyridine Formation
for the presented domino approach to 1,2-dihydropyridines
outlined in Scheme 12: After Au-catalyzed rearrangement that
most likely proceeds through a cyclization-induced rearrange-
ment mechanism (CIR),39,30 enamine A is formed in a classical
condensation reaction. Protonation of A might lead to achiral
iminium ion B, which is further converted to azatriene C
resulting in a net tautomerization of A into C. Subsequent 6π-
electrocyclization to 1,2-dihydropyridine D then terminates the
reaction sequence.
combined with a proton shift (path a).37 On the other hand,
isomerization to the azatriene system could take place, which
then would undergo a 6π-azaelectrocyclization (path b).38
To conclusively determine mechanistic details, we took a
deeper insight into the stereochemical course of the reaction.
When enantiomerically pure propargyl vinyl ether (S)-2c (98%
ee) was submitted to the standard reaction conditions, the
product 8ca was formed as a racemic mixture with complete loss
of enatiopurity. This observation might point to a mechanism
proceeding through an achiral intermediate (i.e., path b). In
contrast, the reaction of 2a with (S)-1-methylbenzylamine gave
1,2-dihydropyridine 8ai with a slight diastereoselectivity as a
1:1.3 mixture of diastereoisomers (Scheme 11).
’ CONCLUSION
In conclusion, we developed an independently catalyzed
reaction cascade for the convenient synthesis of 1,2-dihydro-
pyridines starting from propargyl vinyl ethers. We also pre-
sented a practical one-pot procedure that includes the in situ
formation of these precursors and provides the nitrogen, as well
as the oxygen, containing 6-membered heterocycles. These
results once again emphasize the value of propargyl vinyl ethers
as easily accessible starting materials for the synthesis of a broad
variety of heterocyclic compounds. Further use of this concept
in the library construction of heterocycles is currently under
investigation.
On the basis of these results and the isolation of the enamine
intermediate 7aa (Scheme 7), we propose a plausible mechanism
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’ EXPERIMENTAL SECTION
NMR (250 MHz, CDCl3) δ 1.09 (t, J = 6.8, 6H), 1.27 (t, J = 7.1, 3H),
2.15 (qd, J = 13.4, 6.7, 1H), 4.17 (q, J = 7.1, 2H), 4.56 (d, J = 5.8, 1H),
5.42 (d, J = 12.5, 1H), 7.29-2.37 (m, 3H), 7.41-7.49 (m, 2H), 7.69 (d,
J = 12.5, 1H); 13C NMR (63 MHz, CDCl3) δ 14.5, 7.8, 18.4, 33.4, 59.9,
77.6, 84.4, 88.5, 98.8, 122.1, 128.5, 128.9, 132.0, 160.9, 167.9 LRMS (EI)
m/z 272.1 (1%), 199.1 (15%) [Mþ - C3H5O2], 157.1 (100%), 142.1
(78%), 129.0 (46%), 115.0 (28%); HRMS (EI) m/z 229.0863 [229.0847
calculated for C14H13O3 (Mþ - C3H7)].
General. All reactions were carried out in sealed reaction vials.
CH2Cl2 was passed through activated alumina columns prior to use. All
other commercial reagents were used as received. (S)-4-Phenylbut-3-yn-
2-ol was synthesized following the procedure of Knochel et al.40 Thin-
layer chromatography (TLC) was conducted with precoated glass-
backed plates (silica gel 60 F254) and visualized by exposure to UV light
(254 nm) or stained with ceric ammonium molybdate. Flash chroma-
tography was performed with silica gel. The eluent used is reported in
parentheses. 1H NMR spectra were recorded on 500, 360, or 250 MHz
spectrometers. 13C NMR spectra were recorded at 126, 90.6, or 63 MHz.
Chemical shifts are reported in ppm relative to solvent signal. Multi-
plicity is indicated as follows: s (singlet); d (doublet); t (triplet);
q (quartet); m (multiplet); dd (doublet of doublets); sep (septet).
J values are given in hertz. Low resolution mass spectra were recorded
applying GC-MS, EI, or ESI technique. High-resolution mass spectra
were obtained by using the EI or ESI ionization method.
General Procedure A for the Formation of Propargyl Vinyl
Ethers 2 Starting from Propargylic Alcohols 1. (E)-Methyl
3-(1-phenylpent-1-yn-3-yloxy)acrylate (2a): To a solution of
800 mg of 1-phenylpent-1-yn-3-ol (4.99 mmol) and 0.51 mL of ethyl
propiolate (498 mg, 4.99 mmol, 1 equiv) in 40 mL of dry CH2Cl2 was
added 0.13 mL of P(n-Bu)3 (101 mg, 0.50 mmol, 10 mol %) dropwise.
The solution was stirred at room temperature until TLC indicated full
conversion. The solvent was removed and the residue was purified by
flash chromatography on silica gel (pentane/EtOAc 98:2). The product
was obtained as a colorless oil (1.24 g, 4.78 mmol, 96%): Rf 0.84
(pentane/EtOAc 95:5) [UV], [CAM]; 1H NMR (250 MHz, CDCl3) δ
1.10 (t, J = 7.4, 3H), 1.28 (t, J = 7.1, 3H), 1.89-2.03 (m, 2H), 4.18 (q,
J = 7.3, 2H), 4.68-4.77 (m, 1H), 5.43 (d, J = 12.5, 1H), 7.28-7.37 (m,
3H), 7.41-7.49 (m, 2H), 7.70 (d, J = 12.5, 1H); 13C NMR (63 MHz,
CDCl3) δ 9.6, 14.5, 28.9, 60.0, 73.4, 85.4, 88.0, 98.9, 122.1, 128.5, 129.0,
132.0, 160.6, 167.9; LRMS (EI) m/z 258 (6%) [Mþ], 228 (5%), 185
(9%), 143 (100%), 128 (74%), 115 (16%), 103 (5%), 43 (8%); HRMS
(EI) m/z 258.1238 [258.1256 calculated for C16H18O3 (Mþ)].
(E)-Ethyl 3-(1,3-diphenylprop-2-ynyloxy)acrylate (2e): Fol-
lowing general procedure A, 2e was obtained as a yellow oil (70%) after
flash chromatography on silica gel (pentane/EtOAc 95:5): Rf 0.52
(pentane/EtOAc 90:10) [UV] [CAM]; 1H NMR (360 MHz, CDCl3)
δ 1.28 (t, J = 7.1, 3H), 4.17 (q, J = 7.1, 2H), 5.51 (d, J = 12.5, 1H), 5.87 (s,
1H), 7.31-7.37 (m, 3H), 7.40-7.45 (m, 3H), 7.48-7.51 (m, 2H),
7.57-7.60 (m, 2H), 7.76 (d, J = 12.5, 1H); 13C NMR (91 MHz, CDCl3)
δ 14.5, 60.0, 73.9, 84.5, 89.9, 99.9, 121.8, 127.7, 128.5, 129.0, 129.2,
129.4, 132.1, 136.6, 160.0, 167.7; LRMS (ESI) m/z 329 (19%) [Mþ þ
Na], 307 (30%) [Mþ þ H], 282 (100%), 261 (14%), 191 (73%); HRMS
(ESI) m/z 307.1329 [307.1334 calculated for C20H19O3 (Mþ þ H)].
(E)-Ethyl 3-(3-phenylprop-2-ynyloxy)acrylate (2f): Follow-
ing general procedure A, 2f was obtained as a light yellow oil (90%) after
flash chromatography on silica gel (pentane/EtOAc 95:5): Rf 0.50
(pentane/EtOAc 90:10) [UV] [CAM]; 1H NMR (250 MHz, CDCl3)
δ 1.28 (t, J = 7.1, 1H), 4.18 (q, J = 7.1, 1H), 4.75 (s, 1H), 5.38 (d, J = 12.6,
1H), 7.30-7.36 (m, 3H), 7.40-7.48 (m, 2H), 7.64 (d, J = 12.6, 1H);
13C NMR (63 MHz, CDCl3) δ 14.5, 59.2, 59.5, 60.1, 82.1, 88.6, 98.5,
121.9, 128.4, 128.5, 129.2, 132.0, 160.9, 167.5; LRMS (EI) m/z 230
(1%) [Mþ], 201 (4%), 157 (9%), 115 (100%), 105 (3%), 89 (5%);
HRMS (EI) m/z 230.0944 [230.0943 calculated for C14H14O3 (Mþ)].
(E)-Ethyl 3-(1-phenyldec-4-yn-3-yloxy)acrylate (2g): Fol-
lowing general procedure A, 2g was obtained as a colorless oil (90%)
after flash chromatography on silica gel (pentane/EtOAc 95:5): Rf 0.35
(pentane/EtOAc 95:5) [UV] [CAM] [KMnO4]; 1H NMR (250 MHz,
CDCl3) δ 0.89 (t, J = 7.1, 3H), 1.27 (t, J = 7.1, 3H), 1.32-1.42 (m, 4H),
1.46 - 1.58 (m, 2H), 2.02-2.17 (m, 2H), 2.23 (td, J = 7.0, 2.0, 2H), 2.78
(t, J = 7.6, 2H), 4.16 (q, J = 7.1, 2H), 4.49 (tt J = 6.5, 1.7, 1H), 5.35 (d, J =
12.5, 1H), 7.16-7.32 (m, 5H), 7.62 (d, J = 12.5, 1H); 13C NMR
(63 MHz, CDCl3) δ 14.1, 14.5, 18.8, 22.3, 28.2, 31.1, 31.3, 37.4, 59.9,
71.2, 89.6, 98.8, 126.3, 128.6, 128.7, 140.8, 160.6, 167.9; LRMS (EI) m/z
328.2 (1%) [Mþ], 143.1 (23%), 117.0 (27%), 91.0 (100%); HRMS (EI)
m/z 328.2041 [328.2038 calculated for C21H28O3 (Mþ)].
(E)-Methyl 4-(3-(3-ethoxy-3-oxoprop-1-enyloxy)pent-1-ynyl)-
benzoate (2h): Following general procedure A, 2h was obtained as a
colorless oil (58%) after flash chromatography on silica gel (pentane/
EtOAc 95:5 f 90:10): Rf 0.36 (pentane/EtOAc 90:10) [UV] [CAM];
1H NMR (250 MHz, CDCl3) δ 1.10 (t, J = 7.4, 3H), 1.27 (t, J = 7.1, 3H),
1.90-2.02 (m, 2H), 3.92 (s, 3H), 4.17 (q, J = 7.1, 2H), 4.72 (t, J = 6.4,
1H), 5.42 (d, J = 12.5, 1H), 7.50 (d, J = 8.6, 2H), 7.67 (d, J = 12.5, 1H),
7.99 (d, J = 8.6, 2H); 13C NMR (63 MHz, CDCl3) δ 9.5, 14.5, 28.8, 52.4,
60.0, 73.1, 87.1, 88.3, 99.1, 126.7, 129.6, 130.3, 131.9, 160.5, 166.5,
167.8; LRMS (EI) m/z 316 (4%) [Mþ], 287 (8%), 243 (14%), 201
(100%), 169 (17%), 142 (62%), 59 (14%); HRMS (EI) m/z 316.1309
[316.1311 calculated for C18H20O5 (Mþ)].
(E)-Ethyl 3-(1-(4-methoxyphenyl)pent-1-yn-3-yloxy)-
acrylate (2i): Following general procedure A, 2i was obtained as a
colorless oil (92%) after flash chromatography on silica gel (pentane/
EtOAc 95:5): Rf 0.48 (pentane/EtOAc 90:10) [UV] [CAM]; 1H NMR
(360 MHz, CDCl3) δ 1.09 (t, J = 7.4, 3H), 1.27 (t, J = 7.1, 3H), 1.90-
1.98 (m, 2H), 3.81 (s, 3H), 4.17 (qd, J = 7.1, 0.7, 2H), 4.71 (t, J = 6.4,
1H), 5.41 (d, J = 12.5, 1H), 6.84 (d, J = 8.9, 2H), 7.38 (d, J = 8.9, 2H),
7.69 (d, J = 12.5, 1H); 13C NMR (91 MHz, CDCl3) δ 9.6, 14.5, 29.0,
55.4, 59.9, 73.6, 84.0, 88.0, 98.8, 114.1, 114.1, 133.5, 160.1, 160.7, 167.9;
LRMS (EI) m/z 288 (3%) [Mþ], 215 (31%), 173 (100%), 158 (34%);
HRMS (EI) m/z 288.1361 [288.1362 calculated for C17H20O4 (Mþ)].
(E)-Methyl 3-(1-phenylpent-1-yn-3-yloxy)acrylate (2b):
Following general procedure A, 2b was obtained as a colorless oil
(85%) after flash chromatography on silica gel (pentane/EtOAc 95:5):
Rf 0.29 (pentane/EtOAc 95:5) [UV] [CAM] [KMnO4]; 1H NMR (360
MHz, CDCl3) δ 1.10 (t, J = 7.4, 1H), 1.96 (quint, J = 6.9, 1H), 3.71 (s,
3H), 4.72 (t, J = 6.4, 1H), 5.44 (d, J = 12.5, 1H), 7.29-7.37 (m, 3H),
7.42-7.47 (m, 2H), 7.70 (d, J = 12.5, 1H); 13C NMR (90.6 MHz,
CDCl3) δ 9.6, 28.9, 51.3, 73.4, 85.3, 88.0, 98.6, 122.0, 128.5, 129.0,
132.0, 160.8, 168.3; LRMS (EI) m/z 244 (1%) [Mþ], 212 (3%), 185
(16%), 143 (100%), 128 (93%), 115 (18%), 103 (17%), 77 (5%);
HRMS (EI) m/z 185.0963 [185.0966 calculated for C13H13O (Mþ
CO2Me)].
-
(E)-Ethyl 3-(4-phenylbut-3-yn-2-yloxy)acrylate (2c): Follow-
ing general procedure A, 2c was obtained as a pale yellow oil (93%) after
flash chromatography on silica gel (pentane/EtOAc 95:5). The enatio-
merically pure (S)-(E)-ethyl 3-(4-phenylbut-3-yn-2-yloxy)acrylate was
synthesized starting from (S)-4-phenylbut-3-yn-2-ol:40 Rf 0.46 (pentane/
EtOAc 90:10) [UV] [CAM]; 1H NMR (250 MHz, CDCl3) δ 1.28 (t, J =
7.1, 3H), 1.65 (d, J = 6.6, 2H), 4.17 (q, J = 7.1, 2H), 4.90 (q, J = 6.6, 1H),
5.42 (d, J= 12.5, 1H), 7.29-7.35 (m, 3H), 7.42-7.45 (m, 2H), 7.68 (d, J =
12.5, 1H); 13C NMR (63 MHz, CDCl3) δ 14.5, 22.0, 60.0, 68.1, 86.3, 87.2,
99.1, 122.0, 128.5, 129.0, 132.0, 160.3, 167.8; LRMS (EI) m/z 244(3%)
[Mþ], 229 (6%), 215 (18%), 171 (63%), 129 (100%); HRMS (EI) m/z
244.1096 [244.1099 calculated for C15H16O3 (Mþ)].
(E)-Ethyl 3-(4-methyl-1-phenylpent-1-yn-3-yloxy)acrylate
(2d): Following general procedure A, 2d was obtained as a pale yellow
oil (71%) after flash chromatography on silica gel (pentane/EtOAc
1
95:5): Rf 0.29 (pentane/EtOAc 95:5) [UV] [CAM] [KMnO4]; H
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(E)-Ethyl 3-(1-phenylpent-1-yn-3-yloxy)but-2-enoate (2j):
Following general procedure A, 2j was obtained as a colorless oil (77%)
after flash chromatography on silica gel (pentane/EtOAc 98:2): Rf 0.73
(pentane/EtOAc 95:5) [UV] [CAM]; 1H NMR (250 MHz, CDCl3) δ
1.04 (t, J = 7.4, 3H), 1.22 (t, J = 7.1, 3H), 1.83-1.97 (m, 2H), 2.27 (s,
3H), 3.98-4.19 (m, 2H), 4.71 (t, J = 6.3, 1H), 5.26 (s, 1H), 7.17-7.30
(m, 3H), 7.33-7.42 (m, 2H); 13C NMR (63 MHz, CDCl3) δ 9.7, 15.0,
19.2, 28.9, 59.5, 69.4, 85.9, 87.1, 93.4, 122.4, 128.4 (2C), 128.8, 132.0
(2C), 168.1, 170.7; LRMS (EI) m/z 272 (3%) [Mþ], 243 (16%), 229
(18%), 199 (36%), 143 (79%), 128 (100%), 115 (24%), 43 (14%);
HRMS (EI) m/z 272.1399 [272.1412 calculated for C17H20O3 (Mþ)].
(E)-Ethyl 3-(3-phenylprop-2-ynyloxy)but-2-enoate (2k):
Following general procedure A, 2k was obtained as a light yellow solid
(71%) after flash chromatography on silica gel (pentane/EtOAc 95:5):
dissolved in 0.4 mL of CD2Cl2 and 14 μL of a 10 mg/mL stock solution
of AgSbF6 in CD2Cl2 (0.14 mg, 0.39 μmol, 0.7 mol %) was added. The
reaction mixture was stirred until TLC indicated complete consumption
of the starting material. Allene 3j was formed in quantitative yield
according to 1H NMR: Rf 0.80 (P/EtOAc 95:5) [UV] [CAM]; 1H NMR
(250 MHz, CDCl3) δ 1.09 (t, J = 7.4, 3H), 1.26 (t, J = 7.1, 3H), 2.12-
2.23 (m, 2H), 2.26 (s, 3H), 4.11-4.27 (m, 2H), 4.57 (d, J = 1.8, 1H),
5.78 (td, J = 6.1, 1.8, 1H), 7.18-7.36 (m, 5H); 13C NMR (63 MHz,
CDCl3) δ 13.2, 14.2, 22.1, 28.5, 61.7, 61.9, 99.2, 101.7, 125.7, 127.3,
128.8, 135.6, 168.6, 202.4, 204.7.
3-(Methoxymethyl)-4-phenylocta-4,5-dien-2-one (3l): To
a solution of 15 mg of 2l (61.4 μmol) in 0.5 mL of CD2Cl2 was added 11
μL of a 2 mg/mL stock solution of AgSbF6 in CD2Cl2 (0.022 mg,
0.06 μmol, 0.1 mol %). The reaction mixture was stirred until TLC
indicated complete conversion. Allene 3l was formed in quantitative
1
Rf 0.43 (pentane/EtOAc 95:5) [UV] [CAM]; H NMR (250 MHz,
1
CDCl3) δ 1.28 (t, J = 7.1, 3H), 2.35 (s, 3H), 4.15 (q, J = 7.1, 2H), 4.71 (s,
2H), 5.18 (s, 1H), 7.29-7.35 (m, 3H), 7.44-7.48 (m, 2H); 13C NMR
(63 MHz, CDCl3) δ 14.6, 19.1, 56.8, 59.7, 82.5, 87.8, 92.7, 122.2, 128.5,
129.0, 132.0, 167.8, 171.1.; LRMS (GC-MS) m/z 244 (32%) [Mþ], 215
(55%), 198 (75%), 171 (45%), 1555 (72%), 128 (100%), 115 (42%);
HRMS (ESI) m/z 245.1173 [245.1172 calculated for C15H17O3
(Mþ þ H)].
yield according to H NMR: Rf 0.52 (P/EtOAc 95:5) [UV] [CAM];
1H NMR (250 MHz, CDCl3) δ 1.07 (t, J = 7.4, 3H), 2.09-2.20 (m, 2H),
2.16 (s, 3H), 3.36 (s, 3H), 3.52-3.64 (m, 1H), 3.81-3.92 (m, 2H), 5.72
(t, J = 6.1, 1H), 7.19-7.26 (m, 1H), 7.30-7.36 (m, 2H), 7.42-7.45
(m, 2H); 13C NMR (63 MHz, CDCl3) δ 13.3, 22.1, 28.1, 53.9, 59.1,
72.6, 98.5, 103.0, 126.2, 127.2, 128.7, 136.1, 203.9, 206.6.
General Procedure B for the Formation of Allenyl Carbo-
nyl Compounds 3a,c,d,e,g,i. Ethyl 2-formyl-3-phenylhepta-
3,4-dienoate (3a): 2a (15.0 mg, 58.1 μmol) was dissolved in 0.4 mL
of CDCl3 and 20 μL of a 20 mg/mL stock solution of AuCl in CDCl3
(0.41 mg, 1.74 μmol, 3 mol %) was added. The reaction was stirred at
room temperature until TLC indicated full conversion. Allene 3a was
formed in quantitative yield according to 1H NMR: Rf 0.42 (P/EtOAc
(E)-(3-(4-Methoxybut-2-en-2-yloxy)pent-1-ynyl)benzene
(2l): 2j (480 mg, 1.76 mmol) was dissolved in 18 mL of dry CH2Cl2 and
4.4 mL of DIBAL-H (1 M in hexane; 4.41 mmol, 2.5 equiv) was added
at -78 °C. The reaction mixture was stirred at the same temperature
for 2 h. The Reaction was quenched by the addition of 20 mL of K-Na-
tartrate solution (20% w/w in water) and 0.88 mL of glycerine (0.2 mL/
mmol DIBAL-H) was added. The mixture was stirred at room tempera-
ture for 1 h. The phases were separated and the aqueous layer was
extracted with 2 ꢀ 20 mL of CH2Cl2. The combined organic phases
were washed with brine and dried over MgSO4. The solvent was
evaporated and the residue was purified by flash chromatography on
silica gel (pentane/EtOAc 80:20). The primary alcohol was obtained as
a colorless oil (368 mg, 1.68 mmol, 95%): Rf 0.46 (pentane/EtOAc
70:30) [UV] [CAM]; 1H NMR (360 MHz, CDCl3) δ 1.09 (t, J = 7.42,
3H), 1.56 (s, 1H), 1.90 (s, 3H), 1.87-1.97 (m, 2H), 4.18 (t, 2H), 4.64
(t, J = 6.4, 1H), 5.06 (t, J = 7.7, 1H), 7.27-7.33 (m, 3H), 7.39-7.46 (m,
2H); 13C NMR (91 MHz, CDCl3) δ 9.6, 31.2, 45.5, 58.0, 64.4, 85.1,
90.2, 122.9, 128.42, 128.5, 128.9, 131.9, 133.6, 137.6; LRMS (EI) m/z
230 (1%) [Mþ], 211 (4%), 199 (12%), 183 (14%), 143 (33%), 131
(100%), 128 (78%), 115 (31%), 103 (30%); HRMS (EI) m/z 199.1114
[199.1123 calculated for C14H15O (Mþ~CH2OH)].
1
93:7) [UV] [CAM]; H NMR (250 MHz, CDCl3) δ 1.10 (t, J = 7.4,
3H), 1.26 (t, J = 7.1, 3H), 2.14-2.25 (m, 1H), 4.22 (qd, J = 7.1, 1.2, 1H),
4.35 (dd, J = 3.0, 1.7, 1H), 5.85 (td, J = 6.2, 1.6, 1H), 7.20-7.40 (m, 5H),
9.67 (d, J = 3.0, 1H); 13C NMR (63 MHz, CDCl3) δ 13.1, 14.2, 22.1,
58.7, 61.9, 99.9, 100.1, 125.9, 127.5, 128.8, 135.2, 168.3, 195.0, 205.3.
Ethyl 2-formyl-3-(4-methoxyphenyl)hepta-3,4-dienoate
(3i:). Following general procedure B, 3i was furnished in quantitative
1
yield according to H NMR: Rf 0.43 (P/EtOAc 95:5) [UV] [CAM];
1H NMR (250 MHz, CDCl3) δ 1.08 (t, J = 7.4, 3H), 1.26 (t, J = 7.1, 3H),
2.12-2.23 (m, 1H), 3.80 (s, 3H), 4.17-4.26 (m, 2H), 4.29-4.32 (m,
1H), 5.81 (td, J = 6.1, 1.4, 1H), 6.87 (d, J = 8.9, 2H), 7.29 (d, J = 8.9, 2H),
9.65 (d, J = 3.2, 1H); 13C NMR (63 MHz, CDCl3) δ 13.1, 13.3, 14.2,
22.2, 55.5, 58.9, 61.8, 99.8, 99.8, 114.3, 127.1, 127.3, 159.2, 168.3,
195.2, 204.6.
Ethyl 2-formyl-6-methyl-3-phenylhepta-3,4-dienoate (3d):
Following general procedure B, 3d was furnished in quantitative yield
according to 1H NMR: Rf 0.58 (P/EtOAc 95:5) [UV] [CAM]; 1H NMR
(250 MHz, CDCl3) δ 1.11 (d, J = 6.8, 3H), 1.11 (d, J = 6.8, 3H), 1.25
(t, J = 7.1, 3H), 2.43-2.56 (m, 1H), 4.22 (qd, J = 7.2, 0.7, 2H), 4.36 (dd,
J = 3.0, 1.8, 1H), 5.80 (dd, J = 5.8, 1.7, 1H), 7.20-7.40 (m, 5H), 9.67 (d,
J = 3.0, 1H); 13C NMR (63 MHz, CDCl3) δ 14.2, 22.4, 22.4, 28.9, 58.7,
61.9, 100.5, 105.5, 125.8, 127.5, 128.8, 135.1, 168.2, 195.0, 204.0.
Ethyl 2-formyl-3-(4-phenylbut-1-enylidene)octanoate (3g):
Following general procedure B, 3g was furnished in quantitative yield
according to 1H NMR: Rf 0.62 (P/EtOAc 95:5) [UV] [CAM]; 1H NMR
(250 MHz, CDCl3) δ 0.88 (t, J = 6.6, 3H), 1.24-1.40 (m, 6H), 1.29 (t,
J = 7.1, 3H), 1.93-2.00 (m, 2H), 2.31-2.40 (m, 2H), 2.70-2.76 (m,
2H), 3.59 (dd, J = 3.6, 1.7, 1H), 4.22 (qd, J = 7.1, 1.6, 2H), 5.36-5.45
(m, 1H), 7.15-7.32 (m, 2H), 9.54 (d, J = 3.6, 1H); 13C NMR (63 MHz,
CDCl3) δ 14.2, 14.3, 22.6, 27.0, 30.6, 31.4, 32.2, 35.3, 60.8, 61.6, 95.1,
98.2, 126.1, 128.5, 128.6, 141.6, 168.3, 195.4, 203.2.
To a stirred suspension of 235 mg of NaH (5.88 mmol, 2 equiv) in
1.5 mL of dry DMF was added a solution of 676 mg of the above alcohol
(2.94 mmol) in 1.5 mL of dry DMF dropwise at 0 °C. The mixture was
stirred for 15 min and 0.46 mL of MeI (1.04 g, 7.35 mmol, 2.5 equiv) was
added. The reaction mixture was warmed to room temperature and
stirred for 2 h. The reaction was quenched by the addition of 10 mL of
saturated NH4Cl solution. The mixture was extracted with 3 ꢀ 10 mL of
Et2O. The combined organic phases were washed with brine and dried
over MgSO4. The solvent was evaporated and the residue was purified by
flash chromatography on silica gel (pentane/EtOAc 95:5). Methyl ether
2l was obtained as a colorless oil (555 mg, 2.27 mmol, 77%): Rf 0.69
(pentane/EtOAc 85:15) [UV] [CAM]; 1H NMR (360 MHz, CDCl3) δ
1.09 (t, J = 7.4, 3H), 1.89 (s, 3H), 1.85-1.97 (m, 2H), 3.32 (s, 3H), 3.98
(dd, J = 2.5, 7.6, 2H), 4.65 (t, 1H), 4.94 (t, J = 7.6, 1H), 7.27-7.34 (m,
3H), 7.39-7.45 (m, 2H); 13C NMR (91 MHz, CDCl3) δ 9.8, 16.7, 29.1,
57.2, 68.2, 68.9, 86.0, 87.7, 96.3, 123.0, 128.3, 128.4, 131.9, 156.2; LRMS
(EI) m/z 230.13 (2%) [M - CH3], 199 (36%), 183 (30%), 141 (65%),
128 (100%), 115 (47%), 105 (26%); HRMS (EI) m/z 245.1554
[245.1536 calculated for C16H21O2 (Mþ þ H)].
Ethyl 2-formyl-3-phenylhexa-3,4-dienoate (3c): Following
general procedure B, 3c was furnished in quantitative yield according to
1H NMR: Rf 0.39 (P/EtOAc 95:5) [UV] [CAM]; 1H NMR (250 MHz,
CDCl3) δ 1.28 (t, J = 7.1, 3H), 1.83 (d, J = 7.2, 3H), 4.24 (q, J = 7.1, 2H),
4.33 (dd, J = 3.1, 1.6, 1H), 5.75 (qd, J = 7.3, 1.6, 1H), 7.20-7.38 (m,
Synthesis of Allenyl Carbonyl Compounds 3. Ethyl 2-acet-
yl-3-phenylhepta-3,4-dienoate (3j): 2j (15 mg, 55.1 μmol) was
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ARTICLE
5H), 9.70-9.70 (m, 1H); 13C NMR (63 MHz, CDCl3) δ 13.9, 14.2,
58.8, 61.9, 92.8, 98.9, 126.1, 127.5, 128.8, 135.1, 168.3, 194.9, 206.6.
Ethyl 2-formyl-3,5-diphenylpenta-3,4-dienoate (3e): Fol-
lowing general procedure B, 3e was furnished in quantitative yield
according to 1H NMR: Rf 0.30 (P/EtOAc 95:5) [UV] [CAM]; 1H NMR
(250 MHz, CDCl3) δ 1.16-1.27 (m, 6H), 4.09-4.29 (m, 4H), 4.50-
4.53 (m, 2H), 6.77 (d, J = 1.3, 1H), 6.79 (d, J = 1.4, 1H), 7.25-7.47
(m, 20H), 9.75 (d, J = 2.5, 1H), 9.76 (d, J = 2.4, 1H); 13C NMR
(63 MHz, CDCl3) δ 14.1, 14.2, 59.0, 59.6, 62.2, 62.2, 100.8, 101.1, 103.5,
103.5, 126.2, 126.2, 127.4, 127.6, 128.1, 128.2, 128.2, 129.0, 129.0, 129.1,
132.5, 132.7, 133.9, 133.9, 167.9, 168.0, 194.5, 194.6, 207.8, 208.1.
General Procedure C for the Synthesis of Dihydropyri-
dines 4. Ethyl 6-ethyl-2-methyl-1,4-diphenyl-1,6-dihydro-
pyridine-3-carboxylate (4ja): Propargyl vinyl ether 2j (50.0 mg,
184 μmol) was dissolved in 1.8 mL of CH2Cl2 and 3 mg of AgSbF6
(9.2 μmol, 5 mol %) was added. The solution was stirred at room
temperature until TLC indicated the completion of the rearrangement.
Aniline (25.2 μL, 25.7 mg, 276 μmol, 1.5 equiv) was added and the
reaction mixture was stirred 16 h at room temperature. The solvent was
evaporated and the residue was purified by flash chromatography
(pentane/EtOAc 98:2). The product was obtained as a dark yellow
solid (17.0 mg, 48.7 μmol, 27%): Rf 0.43 (pentane/EtOAc 95:5) [UV]
[CAM]; 1H NMR (250 MHz, CDCl3) δ 0.68 (t, J = 7.1, 3H), 1.04 (t, J =
7.4, 3H), 1.59-175 (m, 1H), 1.83-1.97 (m, 1H), 2.29 (s, 3H), 3.69-
3.93 (m, 2H), 4.13-4.22 (m, 1H), 5.33 (d, J = 6.6, 1H), 7.14-7.38 (m,
10H); 13C NMR (63 MHz, CDCl3) δ 9.7, 13.6, 20.2, 26.4, 59.4, 62.7,
108.3, 114.0, 125.5, 125.6, 126.6, 127.0, 127.9, 129.2, 137.3, 142.7, 145.4,
150.2, 168.3; LRMS (EI) m/z 347 (4%) [Mþ], 318 (11%), 243 (100%),
215 (26%), 43 (45%); HRMS (EI) m/z 318.1491 [318.1494 calculated
for C21H20NO2 (Mþ - C2H5)]
= 8.7, 1H); 13C NMR (63 MHz, CDCl3) δ 9.8, 13.6, 20.1, 26.4, 59.6,
62.6, 110.0, 114.6, 118.4, 126.7, 126.8, 127.0, 128.0, 132.2, 137.1, 142.2,
144.5, 148.7, 168.2; LRMS (EI) m/z 426 (4%) [Mþ], 398 (100%), 368
(30%), 121 (38%), 43 (27%); HRMS (EI) m/z 396.0594 [396.0599
calculated for C21H19BrNO2 (Mþ)].
Ethyl 6-ethyl-2-methyl-1-(3-nitrophenyl)-4-phenyl-1,6-
dihydropyridine-3-carboxylate (4je): Following general proce-
dure C, 4je was obtained as an orange solid (31%) after flash chroma-
tography on silica gel (pentane/EtOAc 95:5): Rf 0.26 (pentane/EtOAc
1
95:5) [UV] [CAM]; H NMR (360 MHz, CDCl3) δ 0.69 (t, J = 7.1,
3H), 1.08 (t, J = 7.5, 3H), 1.67-1.79 (m, 1H), 1.81-1.95 (m, 1H), 2.29
(s, 1H), 3.74-3.82 (m, 1H), 3.85-3.94 (m, 1H), 4.29-4.25 (m, 1H),
5.49 (d, J = 6.6, 1H), 7.19-7.30 (m, 5H), 7.38 (ddd, J = 8.1, 2.2, 1.0,
1H), 7.44-7.49 (m, 1H), 7.92-7.97 (m, 2H); 13C NMR (91 MHz,
CDCl3) δ 9.6, 9.9, 13.6, 20.0, 26.3, 59.9, 62.3, 113.9, 116.2, 118.2, 118.8,
127.0, 127.0, 128.1, 129.7, 129.7, 136.9, 141.5, 146.2, 146.7, 149.0, 167.9;
LRMS (EI) m/z 392 (4%) [Mþ], 363 (100%) [Mþ], 131 (27%); HRMS
(EI) m/z 363.1346 [363.1345 calculated for C21H19N2O4 (Mþ
-
C2H5)].
Ethyl 6-ethyl-1-(4-methoxyphenyl)-2-methyl-4-phenyl-
1,6-dihydropyridine-3-carboxylate (4jf): Following general pro-
cedure C, 4jf was obtained as a yellow solid (13%) after flash chroma-
tography on silica gel (pentane/EtOAc 95:5): Rf 0.20 (pentane/EtOAc
1
95:5) [UV] [CAM]; H NMR (360 MHz, CDCl3) δ 0.65 (t, J = 7.1,
3H), 1.00 (t, J = 7.4, 3H), 1.56-1.67 (m, 1H), 1.82-1.94 (m, 1H), 2.23
(s, 1H), 3.69-3.77 (m, 1H), 3.80 (s, 3H), 3.80-3.87 (m, 1H), 4.03-
4.12 (m, 1H), 5.23 (d, J = 6.5, 1H), 6.86 (d, J = 9.0, 2H), 7.09 (d, J = 9.0,
2H), 7.22-7.28 (m, 5H); 13C NMR (91 MHz, CDCl3) δ 9.5, 13.6, 19.8,
26.6, 30.5, 55.7, 59.2, 63.3, 76.8, 77.2, 77.5, 105.9, 113.0, 114.5, 126.5,
127.1, 127.9, 137.8, 138.6, 143.1, 151.6, 158.0, 168.5; LRMS (EI) m/z
377 (8%) [Mþ], 348 (100%), 320 (26%); HRMS (EI) m/z 377.1991
[377.1991 calculated for C24H27NO3 (Mþ)].
Ethyl 1-(3-chlorophenyl)-2,5-dimethyl-4-phenyl-1H-pyr-
role-3-carboxylate (6kc): Following general procedure C, 6kc was
obtained as a white solid (72%) after flash chromatography on silica gel
(pentane/EtOAc 95:5): Rf 0.22 (pentane/EtOAc 95:5) [UV] [CAM];
1H NMR (250 MHz, CDCl3) δ 1.02 (t, J = 7.1, 3H), 1.90 (s, 3H), 2.33
(s, 3H), 4.08 (q, J = 7.1, 2H), 7.15-7.19 (m, 1H), 7.23-7.38 (m, 6H),
7.45-7.47 (m, 2H); 13C NMR (63 MHz, CDCl3) δ 11.3, 12.7, 14.1,
59.4, 111.7, 122.9, 126.2, 126.7, 126.8, 127.6, 128.8, 129.1, 130.5, 135.2,
135.7, 136.4, 139.2, 165.9; LRMS (EI) m/z 353 (5%) [Mþ], 244 (61%),
215 (26%), 198 (68%), 171 (41%), 139 (46%), 128 (43%), 115 (41%),
105 (33%), 84 (100%); HRMS (EI) m/z 353.1173 [353.1183 calculated
for C21H20ClNO2 (Mþ)].
General Procedure D for the Synthesis of Dihydropyri-
dines 8. Ethyl 6-ethyl-1,4-diphenyl-1,6-dihydropyridine-3-
carboxylate (8aa): Propargyl vinyl ether 2a (50.0 mg, 194 μmol) was
dissolved in 1.9 mL of CH2Cl2 and 2.2 mg of AuCl (9.7 μmol, 5 mol %)
was added. The mixture was stirred at room temperature until TLC
showed completion of the rearrangement. Aniline (26.5 μL, 27.0 mg,
290 μmol, 1.5 equiv) was added and the mixture was stirred for another
30 min at room temperature. After addition of 7.4 mg of p-TsOH (38.7
μmol, 20 mol %) the reaction mixture was heated to 40 °C and stirred for
15 h. The solvent was evaporated and the residue was purified by flash
chromatography on silica gel (pentane/EtOAc 95:5). The product was
obtained as a yellow solid (56.7 mg, 170 μmol, 88%): Rf 0.19 (pentane/
EtOAc 95:5) [UV] [CAM]; 1H NMR (250 MHz, CDCl3) δ 0.99 (t, J =
7.1, 3H), 1.04 (t, J = 7.5, 3H), 1.59-1.75 (m, 1H), 1.88-2.05 (m, 1H),
3.89-4.13 (m, 2H), 4.55-4.64 (m, 1H), 5.30 (d, J = 6.4, 1H), 7.13-
7.31 (m, 8H), 7.34-7.43 (m, 2H), 7.90 (d, J = 1.6, 1H); 13C NMR (63
MHz, CDCl3) δ 8.9, 14.1, 26.1, 58.8, 59.5, 106.3, 114.9, 118.7, 124.2,
126.9, 127.6, 127.7, 129.7, 136.6, 141.3, 141.5, 144.2, 166.5; LRMS (EI)
m/z 333 (6%) [Mþ], 304 (100%), 276 (40%), 230 (12%), 77 (15%);
HRMS (EI m/z 333.1723 [333.1729 calculated for C22H23NO2 (Mþ)].
Ethyl 6-ethyl-2-methyl-1-(naphthalen-1-yl)-4-phenyl-1,6-
dihydropyridine-3-carboxylate (4jb): Following general proce-
dure C, 4jb was obtained as a white solid (44%) after flash chromatog-
raphy on silica gel (pentane/EtOAc 99:1): Rf 0.28 (pentane/EtOAc
95:5): [UV] [CAM]; 1H NMR (250 MHz, CDCl3) δ 0.68 (t, J = 7.1,
3H), 1.01 (t, J = 7.4, 3H), 1.64-1.74 (m, 1H), 2.01-2.10 (m, 1H), 2.14
(s, 3H), 3.70-3.88 (m, 2H), 4.99-4.11 (m, 1H), 5.32 (d, J = 6.6, 1H),
7.25-7.44 (m, 5H), 7.45-7.56 (m, 4H), 7.76-7.91 (m, 3H); 13C NMR
(63 MHz, CDCl3) δ 9.2, 13.6, 18.8, 26.7, 59.1, 63.1, 76.7, 77.2, 77.7,
102.9, 112.1, 123.1, 125.4, 126.5, 126.8, 127.1, 127.5, 127.7, 127.9, 128.2,
128.4, 131.1, 134.9, 138.6, 141.5, 143.6, 154.1, 168.5; LRMS (EI) m/z
397 (3%) [Mþ], 368 (53%), 84 (34%), 43 (100%); HRMS (EI) m/z
368.1657 [368.1650 calculated for C25H22NO2 (Mþ - C2H5)].
Ethyl 1-(3-chlorophenyl)-6-ethyl-2-methyl-4-phenyl-1,6-
dihydropyridine-3-carboxylate (4jc): Following general proce-
dure C, 4jc was obtained as a dark yellow solid (39%) after flash
chromatography on silica gel (pentane/EtOAc 99:1): Rf 0.45 (pentane/
EtOAc 95:5) [UV] [CAM]; 1H NMR (360 MHz, CDCl3) δ 0.68 (t, J =
7.1, 3H), 1.05 (t, J = 7.5, 3H), 1.60-1.72 (m, 1H), 1.82-1.94 (m, 1H),
2.28 (s, 3H), 3.72-3.81 (m, 1H), 3.83-3.92 (m, 1H), 4.12-4.18 (m,
1H), 5.39 (d, J = 6.6, 1H), 7.00 (ddd, J = 8.0, 2.1, 1.0, 1H), 7.10-7.15
(m, 2H), 7.20-7.28 (m, 7H); 13C NMR (63 MHz, CDCl3) δ 9.8, 13.5,
20.1, 26.3, 59.6, 62.4, 110.9, 115.1, 123.0, 124.9, 125.0, 126.8, 126.9,
128.0, 130.0, 134.7, 137.0, 142.0, 146.7, 148.2, 168.1; LRMS (EI) m/z
382 (1%) [Mþ], 352 (48%), 243 (100%), 43 (34%); HRMS (EI) m/z
352.1100 [352.1104 calculated for C21H19ClNO2 (Mþ - C2H5)].
Ethyl 1-(4-bromophenyl)-6-ethyl-2-methyl-4-phenyl-1,6-
dihydropyridine-3-carboxylate (4jd): Following general proce-
dure C, 4jd was obtained as a white solid (10%) after flash chromatog-
raphy on silica gel (pentane/EtOAc 99:1): Rf 0.38 (pentane/EtOAc
1
95:5) [UV] [CAM]; H NMR (250 MHz, CDCl3) δ 0.68 (t, J = 7.1,
3H), 1.04 (t, J = 7.4, 3H), 1.60-1.69 (m, 1H), 1.82-1.93 (m, 1H), 2.27
(s, 3H), 2.72-3.80 (m, 1H), 3.82-3.91 (m, 1H), 4.09-4.15 (m, 1H),
5.36 (d, J = 6.6, 1H), 7.00 (d, J = 8.7, 1H), 7.20-7.30 (m, 2H), 7.44 (d, J
2152
dx.doi.org/10.1021/jo102545m |J. Org. Chem. 2011, 76, 2145–2156

The Journal of Organic Chemistry
ARTICLE
Ethyl 6-ethyl-1-(4-methoxybenzyl)-4-phenyl-1,6-dihy-
dropyridine-3-carboxylate (8ag): Following general procedure
D, 8ag was obtained as a brown oil (62%) after flash chromatography
on silica gel (pentane/EtOAc 90:10): Rf 0.13 (pentane/EtOAc 90:10)
[UV] [CAM]; 1H NMR (250 MHz, CDCl3) δ 0.98 (vq, J = 7.3, 6H),
1.42-1.57 (m, 1H), 1.74-1.92 (m, 1H), 3.83 (s, 3H), 3.89-4.08 (m,
3H), 4.44 (s, 2H), 4.86 (d, J = 5.7, 1H), 6.92 (d, J = 8.7, 2H), 7.20-7.30
(m, 7H), 7.68 (d, J = 1.0, 1H); 13C NMR (63 MHz, CDCl3) δ 8.4, 14.2,
26.1, 55.5, 57.3, 57.8, 58.9, 98.7, 113.0, 114.5, 126.6, 127.4, 127.8, 128.2,
128.6, 129.1, 137.3, 142.1, 148.9, 159.6, 166.8, 195.4; LRMS (ESI) m/z
378 (26%) [Mþ þ H], 348 (1%), 256 (3%), 121 (100%); HRMS (ESI)
m/z 378.2054 [378.2069 calculated for C24H28NO3 (Mþ þ H)].
Ethyl 6-ethyl-1-isopropyl-4-phenyl-1,6-dihydropyridine-
3-carboxylate (8ah): Following general procedure D, 8ah was
obtained as a brown oil (75%) after flash chromatography on silica gel
(pentane/EtOAc 95:5): Rf 0.18 (pentane/EtOAc 90:10) [UV] [CAM];
1H NMR (250 MHz, CDCl3) δ 0.92 (t, J = 7.1, 3H), 0.96 (t, J = 7.4, 3H),
1.29 (d, J = 6.6, 3H), 1.38 (d, J = 6.7, 3H), 1.69-187 (m, 1H), 3.42-3.54
(m, 1H), 3.82-4.01 (m, 2H), 4.03-4.11 (m, 1H), 4.87 (d, J = 6.0, 1H),
7.17-7.31 (m, 5H), 7.68 (d, J = 1.5, 1H); 13C NMR (63 MHz, CDCl3)
δ 8.4, 14.2, 22.1, 23.6, 27.7, 46.2, 54.3, 58.8, 59.3, 98.6, 112.0, 126.5,
127.4, 127.8, 137.6, 142.3, 144.6, 166.9; LRMS (EI) m/z 299 (9%)
[Mþ], 270 (100%), 228 (23%), 205 (40%), 57 (39%), 43 (31%); HRMS
57 (29%); HRMS (ESI) m/z 364.1424 [364.1423 calculated for
C21H20N2O4 (Mþ)].
Methyl 6-ethyl-1-(4-methoxyphenyl)-4-phenyl-1,6-dihy-
dropyridine-3-carboxylate (8bf): Following general procedure
D, 8bf was obtained after flash chromatography on silica gel
(pentane/EtOAc 90:10) as an orange solid (85%): Rf 0.51 (pentane/
EtOAc 85:15) [UV] [CAM]; 1H NMR (360 MHz, CDCl3) δ 1.02 (t, J =
7.5, 3H), 1.56-1.67 (m, 1H), 1.85-1.99 (m, 1H), 3.54 (s, 3H), 3.82 (s,
3H), 4.52-4.58 (m, 1H), 5.20 (d, J = 6.1, 1H), 6.92 (d, J = 9.0, 2H), 7.16
(d, J = 9.0, 2H), 7.23-7.33 (m, 2H), 7.81 (d, J = 1.6, 1H); 13C NMR (91
MHz, CDCl3) δ 8.8, 26.4, 50.7, 55.7, 59.7, 103.8, 114.2, 114.8, 121.2,
126.9, 127.6, 127.7, 136.6, 138.0, 141.2, 143.1, 157.0, 166.8; LRMS (EI)
m/z 349 (8%) [Mþ], 320 (100%), 207 (15%), 175 (22%), 84 (46%);
HRMS (EI) m/z 349.1684 [349.1678 calculated for C22H23NO3
(Mþ)].
Methyl 1-benzyl-6-ethyl-4-phenyl-1,6-dihydropyridine-
3-carboxylate (8bj): Following general procedure D, 8bj was ob-
tained as a yellow oil (81%) after flash chromatography on silica gel
(pentane/EtOAc 85:15): Rf 0.36 (pentane/EtOAc 85:15) [UV]
1
[CAM]; H NMR (250 MHz, CDCl3) δ 0.98 (t, J = 7.4, 3H), 1.44-
1.58 (m, 1H), 1.73-1.90 (m, 1H), 3.49 (s, 3H), 4.00-4.07 (m, 1H),
4.48 (s, 2H), 4.88 (d, J = 5.7, 1H), 7.42-7.42 (m, 10H), 7.66 (d, J = 1.1,
1H); 13C NMR (91 MHz, CDCl3) δ 8.4, 26.1, 50.4, 57.8, 58.0, 98.5,
113.3, 126.7, 127.4, 127.6, 127.7, 128.2, 129.1, 136.3, 137.1, 141.7, 149.2,
166.7; LRMS (EI) m/z 333 5%) [Mþ], 304 (68%), 91 (100%); HRMS
(EI) m/z 333.1729 [333.1729 calculated for C22H23NO2 (Mþ)].
Ethyl 6-methyl-1,4-diphenyl-1,6-dihydropyridine-3-car-
boxylate (8ca): Following general procedure D, 8ca was obtained
as a yellow solid (84%) after flash chromatography on silica gel
(EI) m/z 270.1499 [270.1494 calculated for C17H20NO2 (Mþ
-
C2H5)].
Ethyl 6-ethyl-4-phenyl-1-((S)-1-phenylethyl)-1,6-dihydro-
pyridine-3-carboxylate (8ai): Following general procedure D, 8ai
was obtained as an orange oil (67%, dr 1:1.3) after flash chromatography
on silica gel (pentane/EtOAc 95:5): Rf 0.33 (pentane/EtOAc 95:5)
[UV] [CAM]; 1H NMR (250 MHz, CDCl3) δ 0.87-0.98 (m, 13.8H),
1.25-1.47 (m, 2.3H), 1.69 (d, J = 2.7, 1.3H), 1.72 (d, J = 2.8, 1H), 1.77-
1.87 (m, 2.6H), 3.83-4.12 (m, 6.9H), 4.49-4.64 (m, 2.3H), 4.82 (d, J =
6.1, 1.3H), 4.92 (d, J = 6.1, 1H), 7.20-7.38 (m, 23H), 7.65 (d, J = 1.5,
1H), 7.94 (d, J = 1.4, 1.3H); 13C NMR (63 MHz, CDCl3) δ 8.4, 8.6,
14.1, 14.1, 21.1, 21.6, 26.3, 27.8, 58.7, 58.9, 58.9, 59.3, 60.9, 62.5, 99.3,
99.8, 112.2, 112.4, 126.1, 126.5, 126.5, 127.1, 127.4, 127.8, 127.8, 127.9,
128.1, 128.9, 129.0, 131.8, 137.4, 137.4, 141.1, 142.1, 142.2, 142.9, 144.0,
146.2, 166.8, 167.1; LRMS (GC-MS) m/z 361 (5%) [Mþ], 332 (46%),
255 (13%), 228 (65%), 105 (100%); HRMS (ESI) m/z 362.2110
[362.2120 calculated for C24H28NO2 (Mþ þ H)].
1
(pentane/EtOAc 95:5): Rf 0.18 (P/EtOAc 95:5) [UV] [CAM]; H
NMR (250 MHz, CDCl3) δ 1.00 (t, J = 7.1, 3H), 1.39 (d, J = 6.4, 3H),
3.91-4.14 (m, 2H), 4.73-4.84 (m, 1H), 5.28 (d, J = 6.4, 1H), 7.13-
7.31 (m, 8H), 7.35-7.43 (m, 2H), 7.86 (d, J = 1.6, 1H); 13C NMR (63
MHz, CDCl3) δ 14.1, 18.8, 53.3, 59.5, 106.2, 116.7, 118.4, 124.1, 126.8,
127.6, 127.7, 129.7, 135.8, 140.7, 141.1, 144.1, 166.6; LRMS (EI) m/z
319 (8%) [Mþ], 304 (100%), 276 (57%), 242 (14%), 230 (12%), 77
(20%); HRMS (EI) m/z 320.1652 [320.1645 calculated for C21H22NO2
(Mþ - C2H5)].
Ethyl 6-isopropyl-1,4-diphenyl-1,6-dihydropyridine-3-
carboxylate (8da): Following general procedure D, 8da was obtained
as an orange oil (77%) after flash chromatography on silica gel
(pentane/EtOAc 95:5): Rf 0.77 (pentane/EtOAc 90:10) [UV]
[CAM]; 1H NMR (360 MHz, CDCl3) δ 0.95-0.99 (m, 6H), 1.08 (d,
J = 6.7, 3H), 2.08-2.17 (m, 1H), 3.91-4.07 (m, 2H), 4.68 (td, J = 5.9,
1.5, 1H), 5.18 (d, J = 6.0, 1H), 7.13-7.18 (m, 1H), 7.23-7.26 (m, 3H),
7.27-7.32 (m, 4H), 7.36-7.41 (m, 2H), 7.94 (d, J = 1.4, 1H); 13C NMR
(91 MHz, CDCl3) δ 14.1, 17.0, 18.6, 32.9, 59.4, 63.4, 105.7, 113.3, 119.7,
124.4, 126.8, 127.6, 127.7, 129.7, 137.5, 141.6, 142.6, 145.0, 166.5;
LRMS (EI) m/z 347 (13%) [Mþ], 333 (33%), 318 (38%), 304 (28%),
205 (61%), 131 (80%), 93 (91%), 83 (100%); HRMS (EI) m/z
347.1886 [347.1885 calculated for C23H25NO2 (Mþ)].
Methyl 1-(4-bromophenyl)-6-ethyl-4-phenyl-1,6-dihy-
dropyridine-3-carboxylate (8bd): Following general procedure
D, 8bd was obtained as a yellow oil (69%) after flash chromatography on
silica gel (pentane/EtOAc 92:8): Rf 0.17 (pentane/EtOAc 90:10) [UV]
[CAM]; 1H NMR (500 MHz, CDCl3) δ 1.03 (t, J = 7.5, 3H), 1.60-1.68
(m, 1H), 1.89-1.98 (m, 1H), 3.56 (s, 3H), 4.52-4.56 (m, 1H), 5.34 (d,
J = 6.4, 1H), 7.06 (d, J = 9.0, 2H), 7.22-7.22 (m, 5H), 7.49 (d, J = 9.0,
2H), 7.81 (d, J = 1.7, 1H); 13C NMR (126 MHz, CDCl3) δ 8.9, 25.9,
51.0, 58.6, 106.8, 115.4, 117.0, 120.0, 127.1, 127.6, 127.7, 132.6, 136.4,
140.7, 140.8, 143.2, 166.6; LRMS (EI) m/z 397 (7%) [Mþ], 370
(100%), 105 (28%), 83 (98%); HRMS (EI) m/z 397.0690 [397.0678
calculated for C21H20NO2Br (Mþ)].
Methyl 6-ethyl-1-(3-nitrophenyl)-4-phenyl-1,6-dihydro-
pyridine-3-carboxylate (8be): Following general procedure D,
8be was obtained as a yellow solid (78%) after flash chromatography
on silica gel (pentane/EtOAc 90:10 f 80:20): Rf 0.21 (pentane/EtOAc
80:20) [UV] [CAM]; 1H NMR (500 MHz, CDCl3) δ 1.08 (t, J = 7.4,
3H), 1.67-1.75 (m, 1H), 1.94-2.03 (m, 1H), 3.59 (s, 3H), 4.60-4.64
(m, 1H), 5.46 (d, J = 6.3, 1H), 7.23-7.26 (m, 2H), 7.29-7.34 (m, 3H),
7.48-7.49 (m, 1H), 7.29-7.34 (m, 1H), 7.85 (s, 1H), 7.98 (d, J = 8.1,
1H), 8.01 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 9.0, 25.7, 51.2, 58.3,
76.9, 77.2, 77.4, 109.2, 112.3, 116.5, 118.0, 123.3, 127.3, 127.5, 127.8,
127.8, 130.5, 136.3, 139.2, 140.3, 145.0, 149.4, 166.3; LRMS (GC-MS)
m/z 364 (7%) [Mþ], 335 (100%), 289 (36%), 216 (29%), 184 (63%),
Ethyl 1,4,6-triphenyl-1,6-dihydropyridine-3-carboxylate
(8ea): Following general procedure D, 8da was obtained as a yellow
solid (72%) after flash chromatography on silica gel (pentane/EtOAc
1
93:7): Rf 0.38 (P/EtOAc 90:10) [UV] [CAM]; H NMR (360 MHz,
CDCl3) δ 0.98 (t, J = 7.1, 3H), 5.48 (dd, J = 6.5, 0.4 1H), 3.92-4.10,
5.70 (dd, J = 6.5, 1.5, 1H), 7.12-7.16 (m, 3H), 7.19-7.22 (m, 2H),
7.24-7.41 (m, 10H), 8.15 (dd, J = 1.5, 0.4, 1H); 13C NMR (91 MHz,
CDCl3) δ 14.1, 59.6, 62.1, 105.8, 116.5, 119.4, 124.6, 125.4, 126.9, 127.6,
127.7, 127.9, 129.1, 129.5, 134.9, 141.0, 142.2, 142.3, 122.7, 166.4;
LRMS (EI) m/z 381 (17%) [Mþ], 304 (95%), 292 (100%), 219 (87%),
191 (48%), 149 (47%), 105 (74%), 57 (63%), 44 (53%); HRMS (EI) m/
z 381.1721 [381.1729 calculated for C26H23NO2 (Mþ)].
2153
dx.doi.org/10.1021/jo102545m |J. Org. Chem. 2011, 76, 2145–2156

The Journal of Organic Chemistry
ARTICLE
Ethyl 1,4-diphenyl-1,6-dihydropyridine-3-carboxylate(8fa):
Following general procedure D, 8fa was obtained as a red oil (55%) after
flash chromatography on silica gel (pentane/EtOAc 95:5 f 90:10):
μL, 87.2 mg, 963 μmol, 1.5 equiv) was added and the solution was stirred
for 30 min before adding 23.1 mg of p-TsOH (125 μmol, 20 mol %). The
reaction mixture was heated to 40 °C and was kept at this temperature
for 16 h. The solvent was evaporated and the residue was purified by
flash chromatography on silica gel (pentane/EtOAc 95:5). The product
was obtained as a yellow solid (66%). The analytical data were in good
accordance to those reported above.
Ethyl 6-isopropyl-1,4-diphenyl-1,6-dihydropyridine-3-car-
boxylate (8da): Following general procedure E, 8da was obtained
after flash chromatography on silica gel (pentane/EtOAc 95:5) as an
orange solid (63%). The analytical data were in good accordance to
those reported above.
Methyl 6-ethyl-1-(4-methoxyphenyl)-4-phenyl-1,6-dihy-
dropyridine-3-carboxylate (8bf): Following general procedure E,
8bf was obtained after flash chromatography on silica gel (pentane/
EtOAc 90:10) as an orange solid (75%). The analytical data were in good
accordance to those reported above.
1
Rf 0.19 (pentane/EtOAc 95:5) [UV] [CAM]; H NMR (250 MHz,
CDCl3) δ 0.97 (t, J = 7.1, 3H), 4.00 (q, J = 7.1, 2H), 4.51 (d, J = 4.4, 2H),
5.26 (t, J = 4.4, 1H), 7.13-7.17 (m, 2H), 7.21-7.31 (m, 5H), 7.37-7.45
(m, 3H), 7.89 (d, J = 0.5, 1H).; 13C NMR (63 MHz, CDCl3) δ 14.1,
47.7, 59.5, 105.9, 111.9, 117.8, 124.1, 126.9, 127.4, 127.7, 129.5, 137.4,
141.1, 143.8, 144.4, 166.5; LRMS (ESI) m/z 306 (100%) [Mþ þ H],
290 (63%), 276 (7%), 226 (10%), 182 (3%); HRMS (ESI) m/z
306.1497 [306.1494 calculated for C20H20NO2 (Mþ þ H)].
Ethyl 4-pentyl-6-phenethyl-1-phenyl-1,6-dihydropyridine-
3-carboxylate (8ga): Following general procedure D, 8ga was
obtained as a light yellow oil (55%) after flash chromatography on silica
gel (pentane/EtOAc 95:5): Rf 0.75 (pentane/EtOAc 90:10) [UV]
1
[CAM]; H NMR (250 MHz, CDCl3) δ 0.93 (t, J = 7.1, 3H), 1.32
(t, J = 7.1, 3H), 1.40-1.53 (m, 4H), 1.76-2.05 (m, 2H), 2.21-2.31 (m,
3H), 2.49-2.61 (m, 1H), 2.66-2.78 (m, 1H), 3.00 (dd, J = 14.5, 2.3,
1H), 3.99-4.07 (m, 1H), 4.16-4.29 (m, 2H), 6.50-6.50 (m, 1H),
6.99-7.03 (m, 2H), 7.06-7.09 (m, 1H), 7.13-7.17 (m, 2H), 7.19-
7.23 (m, 1H), 7.26-7.34 (m, 4H), 7.81 (s, 1H); 13C NMR (91 MHz,
CDCl3) δ 14.2, 14.7, 22.8, 27.0, 27.9, 32.3, 32.4, 32.6, 55.3, 59.6, 103.2,
118.4, 123.4, 123.5, 126.3, 126.9, 128.5, 128.6, 129.6, 138.9, 141.2, 144.8,
167.3; LRMS (ESI) m/z 807 (3%) [2Mþ þ H], 426 (4%) [Mþ þ Na],
404 (100%) [Mþ þ H], 358 (4%), 242 (6%), 167 (3%); HRMS (ESI)
m/z 404.2585 [404.2584 calculated for C27H34NO2 (Mþ þ H)].
Ethyl 6-ethyl-4-(4-(methoxycarbonyl)phenyl)-1-phenyl-
1,6-dihydropyridine-3-carboxylate (8ha): Following general
procedure D, 8ha was obtained as a dark yellow solid (74%) after flash
chromatography on silica gel (pentane/EtOAc 90:10): Rf 0.31 (pentane/
EtOAc 85:15) [UV] [CAM]; 1H NMR (500 MHz, CDCl3) δ 0.99 (t, J =
7.1, 3H), 1.04 (t, J = 7.5, 3H), 1.64-1.73 (m, 1H), 1.92-2.01 (m, 1H),
3.91 (s, 3H), 3.95-4.07 (m, 2H), 4.60-4.63 (m, 1H), 5.33 (d, J = 6.3,
1H), 7.16-7.21 (m, 2H), 7.31 (d, J = 8.1, 1H), 7.39-7.42 (m, 2H), 7.91
(d, J = 1.5, 1H), 7.98 (d, J = 8.5, 1H); 13C NMR (126 MHz, CDCl3) δ
8.9, 14.2, 26.1, 52.1, 58.8, 59.6, 105.7, 115.9, 118.9, 124.5, 127.8, 128.6,
129.1, 129.7, 136.0, 141.9, 144.1, 146.3, 166.3, 167.3; LRMS (EI) m/z
391 (7%) [Mþ], 362 (83%), 334 (26%), 84 (100%); HRMS (EI) m/z
391.1782 [391.1783 calculated for C24H25NO4 (Mþ)].
Ethyl 6-ethyl-4-(4-methoxyphenyl)-1-phenyl-1,6-dihy-
dropyridine-3-carboxylate (8ia): Following general procedure D,
8ia was obtained as a yellow oil (89%) after flash chromatography on
silica gel (pentane/EtOAc 95:5): Rf 0.22 (pentane/EtOAc 90:10) [UV]
[CAM]; 1H NMR (250 MHz, CDCl3) δ 1.04 (q, J = 7.3, 6H), 1.62-
1.72 (m, 1H), 1.86-2.04 (m, 1H), 3.81 (s, 3H), 3.93-4.16 (m, 2H),
4.53-4.61 (m, 1H), 5.27 (d, J = 6.4, 1H), 6.84 (d, J = 8.8, 2H), 7.12-
7.21 (m, 5H), 7.35-7.42 (m, 2H), 7.88 (d, J = 1.5, 1H); 13C NMR (63
MHz, CDCl3) δ 8.9, 14.3, 26.0, 55.4, 58.7, 59.5, 106.3, 113.1, 114.2,
118.7, 124.1, 128.8, 129.6, 133.7, 136.1, 141.4, 144.2, 158.8, 166.5;
LRMS (GC-MS) m/z 363 (9%) [Mþ], 334 (100%), 306 (38%), 256
(13%), 207 (10%), 77 (11%); HRMS (ESI) m/z 364.1913 [364.1907
calculated for C23H26NO3 (Mþ þ H].
Ethyl 4-pentyl-1,6-diphenyl-1,6-dihydropyridine-3-carbo-
xylate (8ma): Following general procedure E, 8ma was obtained as
a yellow oil (41%) after flash chromatography on silica gel (pentane/
EtOAc 98:2 f 95:5): Rf 0.19 (pentane/EtOAc 93:7) [UV] [CAM];
1H NMR (250 MHz, CDCl3) δ 0.71 (t, J = 6.9, 3H), 0.78-0.90 (m, 1H),
0.94-1.10 (m, 3H), 1.34 (t, J = 7.1, 1H), 1.74-1.98 (m, 2H), 2.61 (dd,
J = 13.9, 4.7, 1H), 3.00 (dd, J = 13.9, 2.2, 1H), 4.17-4.30 (m, 2H), 5.08-
5.11 (m, 1H), 6.23 (t, J = 7.6, 1H), 7.00-7.07 (m, 3H), 7.17-7.33
(m, 7H), 8.11 (s, 1H); 13C NMR (63 MHz, CDCl3) δ 14.1, 14.7, 22.3,
27.4, 32.0, 59.7, 61.0, 104.5, 118.3, 122.5, 123.5, 125.9, 127.4, 127.7,
128.7, 129.5, 139.3, 141.0, 145.4, 167.2; LRMS (GC-MS) m/z 375
(64%) [Mþ], 346 (20%), 332 (100%), 298 (96%), 207 (22%), 141
(21%), 77 (33%); HRMS (ESI) m/z 376.2269 [376.2271 calculated for
C25H30NO2 (Mþ þ H)].
General Procedure F for the Formation of 2H-Pyrans 5
Starting from Propargylic Alcohols 1. Ethyl 2-ethyl-6-meth-
yl-4-phenyl-2H-pyran-5-carboxylate (5j): 1-Phenylpent-1-yn-3-
ol (50 mg, 312 μmol) was dissolved in 3.1 mL of dry CH2Cl2. Ethyl
butynoate (36.2 μL, 35.0 mg, 312 μmol, 1 equiv) and 62.4 μL of PMe3 1
M in toluene (62.4 μmol, 20 mol %) were added. The reaction was
stirred at room temperature until TLC indicated full consumption of the
propargylic alcohol. AuCl (3.6 mg, 15.6 μmol, 5 mol %) and 11.3 mg of
AgSbF6 (31.2 μmol, 10 mol %) were added and the mixture was stirred
for another hour at room temperature. DBU (4.7 μL, 4.8 mg, 31.2 μmol,
10 mol %) was added to the solution. After 1 h of stirring the solvent was
evaporated and the residue was purified by flash chromatography in silica
gel (pentane/EtOAc 95:5). The product was isolated as a colorless oil
(40.1 mg, 147 μmol, 47%). 1H and 13C NMR spectra were in accordance
with those reported before:13 Rf 0.65 (pentane/EtOAc 80:20) [UV]
[CAM]; 1H NMR (360 MHz, CDCl3) δ 0.72 (t, J = 7.1, 3 H), 1.04 (t, J =
7.4, 3 H), 1.74-1.96 (m, 2 H), 2.35 (s, 3 H), 3.81-3.87 (m, 2 H), 4.63
(dt, J = 3.8, 6.4, 1 H), 5.29 (d, J = 3.8, 1 H), 7.31-7.34 (m, 3 H), 7.44-
7.48 (m, 2 H); 13C NMR (91 MHz, CDCl3) δ 9.4, 13.6, 18.8, 27.1, 59.8,
77.7, 108.3, 116.1, 126.6, 127.1, 128.1, 137.2, 140.9, 165.8, 167.4.
Ethyl 4-(4-tert-butylphenyl)-2-ethyl-6-methyl-2H-pyran-
5-carboxylate (5n): Following general procedure F, 5n was isolated
after flash chromatography on silica (pentane/EtOAc 95:5) as a color-
less oil (42%). 1H and 13C NMR spectra were in accordance with those
One-Pot Procedures for the Synthesis of 6-Membered
Heterocycles Starting from Propargylic Alcohols 1. General
Procedure E for the Formation of 1,6-dihydropyridine-3-
carboxylates 8 Starting from Propargylic Alcohols 1. Ethyl
6-ethyl-1,4-diphenyl-1,6-dihydropyridine-3-carboxylate (8aa):
To a solution of 100 mg of 1-phenylpent-1-yn-3-ol (624 μmol) and 63.3
μL of ethyl propiolate (61.2 mg, 624 μmol, 1 equiv) in 6.2 mL of CH2Cl2
was added 7.8 μL of P(n-Bu)3 (6.3 mg, 31.2 μmol, 5 mol %). The
mixture was stirred at room temperature until TLC indicated full
consumption of the propargylic alcohol. AgSbF6 (9.08 mg, 25.0 μmol,
4 mol %) and 5.80 mg of AuCl (25.0 μmol, 4 mol %) were added and the
solution was stirred for another hour at room temperature. Aniline (85.5
1
reported before:13 Rf 0.78 (pentane/EtOAc 80:20) [UV] [CAM]; H
NMR (360 MHz, CDCl3) δ 1.02 (t, J = 7.4, 3 H), 1.30 (s, 9 H), 1.73-
1.94 (m, 2 H), 2.33 (s, 3 H), 3.76-3.90 (m, 2 H), 4.61 (dt, J = 3.8, 6.4, 1
H), 5.28 (d, J = 3.8, 1 H), 7.11 (d, J = 8.5, 2 H), 7.29 (d, J = 8.5, 2 H); 13
C
NMR (91 MHz, CDCl3) δ 9.4, 13.4, 18.8, 27.1, 31.5, 34.6, 59.8, 77.7,
108.4, 115.5, 124.7, 125.0, 126.3, 129.8, 136.9, 137.9, 150.2, 165.6, 167.5.
Ethyl 2-ethyl-6-methyl-4-(thiophen-3-yl)-2H-pyran-5-car-
boxylate (5o): Following general procedure F, 5o was isolated after
flash chromatography on silica (pentane/EtOAc 95:5) as a colorless oil
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The Journal of Organic Chemistry
ARTICLE
(42%). 1H and 13C NMR spectra were in accordance with those
reported before:13 Rf 0.54 (pentane/EtOAc 80:20) [UV] [CAM];
1H NMR (360 MHz, CDCl3) δ 0.88 (t, J = 7.1, 3 H), 1.02 (t, J = 7.4,
3 H), 1.73-1.91 (m, 2 H), 2.30 (s, 3 H), 3.93 (dq, J = 1.9, 7.1, 2 H), 4.58
(dt, J = 3.7, 6.8, 1 H), 5.35 (d, J = 3.6, 1 H), 6.93 (dd, J = 1.4, 5.0, 1 H),
7.07 (dd, J = 1.4, 3.0, 1 H), 7.21 (dd, J = 3.0, 5.0, 1 H); 13C NMR
(91 MHz, CDCl3) δ 9.4, 13.8, 18.8, 27.0, 60.0, 77.5, 108.4, 115.5, 120.5,
125.0, 127.0, 131.9, 141.2, 165.2, 167.5.
Poonoth, M.; Sawama, Y.; Sun, T.; Winter, C. Pure Appl. Chem. 2010,
82, 1529.
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Ethyl 2-ethyl-6-methyl-4-(4-phenoxyphenyl)-2H-pyran-5-
carboxylate (5p): Following general procedure F, 5p was isolated
after flash chromatography on silica (pentane/EtOAc 95:5) as a color-
less oil (39%). 1H and 13C NMR spectra were in accordance with those
1
reported before:13 Rf 0.59 (pentane/EtOAc 95:5) [UV] [CAM]; H
NMR (360 MHz, CDCl3) δ 0.85 (t, J = 7.2, 3 H), 1.04 (t, J = 7.4, 3 H),
1.74-1.96 (m, 2 H), 2.34 (s, 3 H), 3.87-3.94 (m, 2 H), 4.61 (dt, J = 3.6,
6.6, 1 H), 5.28 (d, J = 3.6, 1 H), 6.93 (d, J = 8.6, 2 H), 6.99 (d, J = 7.5, 2
H), 7.09 (t. J = 7.5, 1 H), 7.17 (d, J = 8.6, 2 H), 7.32 (t, J = 7.5, 2 H); 13C
NMR (91 MHz, CDCl3) δ 9.4, 13.8, 18.9, 27.0, 59.9, 77.7, 108.3, 115.8,
118.7, 118.8, 123.3, 128.0, 129.8, 136.1, 136.5, 156.5, 157.5, 165.8, 167.3.
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H and 13C NMR
S
b
spectra of 2, 3, 4, 5, 6, and 8. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
stefan.kirsch@ch.tum.de
’ ACKNOWLEDGMENT
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We gratefully acknowledge the work of Johannes Lehmann
and Joka Pipercevic. The research was supported by Deutsche
Forschungsgemeinschaft (DFG), Fonds der Chemischen Indus-
trie (FCI), and TUM Graduate School.
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(34) Toste and co-workers directly reduced their rearrangement
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(35) Isolated enamine 7aa reacted smoothly to 1,2-dihydropyridine
8aa in the presence of p-TsOH in CH2Cl2 at 23 °C.
(36) Xu and co-workers reported that they obtained exclusively 1,2-
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