A very efficient cerium(IV) ammonium nitrate catalyzed, four-component synthesis of tetrahydropyridines and its application in the concise generation of functionalized homoquinolizine frameworks

Article abstract of DOI:10.1002/chem.200900044

The cerium(IV) ammonium nitrate (CAN) catalyzed, four-component reaction between primary aliphatic amines, β-ketoesters or β-keto-thioesters, α,β-unsaturated aldehydes, and alcohols provided a very efficient and atom-economical access to substituted 6-alk

Full text of DOI:10.1002/chem.200900044

FULL PAPER
DOI: 10.1002/chem.200900044
A Very Efficient Cerium(IV) Ammonium Nitrate Catalyzed, Four-
Component Synthesis of Tetrahydropyridines and Its Application in the
Concise Generation of Functionalized Homoquinolizine Frameworks
Vellaisamy Sridharan, Swarupananda Maiti, and J. Carlos Menꢀndez*[a]
Abstract: The cerium(IV) ammonium
nitrate (CAN) catalyzed, four-compo-
nent reaction between primary aliphat-
ic amines, b-ketoesters or b-keto-
thioesters, a,b-unsaturated aldehydes,
and alcohols provided a very efficient
and atom-economical access to substi-
tuted 6-alkoxy-2-methyl-1,4,5,6-tetrahy-
dropyridines. These materials were
then transformed into homoquinolizine
derivatives in excellent yields by using
a two-step sequence comprised of re-
gioselective g-deprotonation–allylation
and ring-closing metathesis reactions.
The possibility of displacing the alkoxy
group by allylsilane nucleophiles, pre-
sumably through a vinylogous acylimi-
nium intermediate species, was also
demonstrated.
Keywords:
heterocycles
·
iminium compounds · Lewis acids ·
metathesis · molecular diversity
Introduction
pyridoACTHNGUTER[NNUG 2,1-a]azepine system (Scheme 1). This ring system is
a structural fragment of several families of bioactive alka-
loids[6] and can be considered as a ring-expanded analogue
Pyridine and its partially or totally unsaturated derivatives,
namely, the tetrahydropyridines, dihydropyridines, and pi-
peridines, are ubiquitous structural motifs found in natural
products and in compounds of interest for the pharmaceuti-
cal, agrochemical, and other chemical industries. Although
many traditional procedures are available for the synthesis
of these heterocyclic compounds, the development of effi-
cient and versatile methods continues to be a relevant syn-
thetic goal with the pyridines,[1] 1,4-dihydropyridines,[2] and
piperidines[3] having received much attention in this regard.
Most known methods for the synthesis of tetrahydropyri-
dines are focused on the 1,2,3,6-tetrahydro system,[4] where-
as the preparation of compounds containing other hydroge-
nation patterns, especially from acyclic precursors, remains
relatively unexplored.[5]
We herein describe an efficient one-pot synthesis of
highly substituted and functionalized tetrahydropyridine de-
rivatives containing four adjacent hydrogenated atoms, to-
gether with their subsequent application in the generation
of 6:7 fused heterocyclic frameworks derived from the
Scheme 1. Structures of the compounds described in this article.
[a] Dr. V. Sridharan, Dr. S. Maiti, Prof. J. C. Menꢀndez
Departmento de Quꢁmica Orgꢂnica y
Farmacꢀutica Universidad Complutense
Facultad de Farmacia, Plaza de Ramꢃn y Cajal, s.n. (Spain)
Fax : (+34)91-3941822
of quinolizine. Derivatives of the quinolizine system are
widespread in nature and constitute about 25–30% of all
known alkaloids. They exhibit a wide range of pharmacolog-
ical activities, which has led to intensive synthetic efforts in
this field.[7] Although ring homology is one of the classical
criteria for the design of analogues of bioactive compounds,
E-mail: josecm@farm.ucm.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900044.
Chem. Eur. J. 2009, 15, 4565 – 4572
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4565

Table 1. CAN-catalyzed preparation of substituted 6-alkoxy-1,4,5,6-tetra-
hydropyridines.
it has not been applied to quinolizines because of the lack
of suitable synthetic methods.
Entry Compound R1
R3
R4
R5
R6
Yield [%]
1
2
3
4
5
6
7
8
5a
nBu
nBu
allyl
nHex
2-Me-nBu OEt
nBu
Bn
nBu
nBu
allyl
allyl
allyl
allyl
allyl
allyl
OEt
OEt
OMe Me
H
H
H
Et
93
86
90
91
88
87
80
94
5b[a]
5c[b]
5d
5e[c]
5 f
Me Et
Results and Discussion
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
OEt
H
H
H
H
H
H
H
H
H
H
H
H
Et
Et
Et
Et
Me
allyl 90
Et
Et
The sequential four-component reaction,[8,9] catalyzed by
5% cerium(IV) ammonium nitrate (CAN), between the pri-
mary aliphatic amines 1, the b-ketoesters or b-ketothioesters
2, the a,b-unsaturated aldehydes 3, and the alcohols 4 in
acetonitrile at room temperature afforded the tetrahydro-
pyridines 5 in excellent yields (Scheme 2).[10] The reaction
OtBu
OEt
OEt
OEt
OEt
OMe
OEt
OMe
StBu
StBu
5g
5h
5i
5j
5k
5l
5m
5n
5o
9
10
11
12
13
14
15
92
93
95
92
86
95
Me
Me
Et
Me
[a] As a 2:1 diastereomeric mixture. [b] As a 5:1 diastereomeric mixture.
[c] As a 1:1 diastereomeric mixture.
for the synthesis of tetrahydropyridines with a ring-closing
metathesis (RCM) reaction.
A mechanistic rationale of the tetrahydropyridine synthe-
sis is summarized in Scheme 3. The initial CAN-catalyzed
Scheme 2. Four-component reaction between primary amines, b-keto-
ACHTUNGTRENNUNG(thio)esters, a,b-unsaturated aldehydes, and alcohols.
reaction[11] between the amines 1 and the b-keto
ACTHNUGRTENUNG(thio)esters
involves the generation of four bonds in a single operation
À
À
À
(two C N, one C O, and one C C), takes place under mild
reaction conditions, and requires very simple and readily
available starting materials. It also uses an inexpensive, air-
and moisture-stable, nontoxic catalyst. Furthermore, it pro-
ceeds with high atom economy and has water as the only
side product. As shown in Table 1, this reaction allowed the
very efficient synthesis of 1,4,5,6-tetrahydropyridine systems
with up to five substituents, two of which are functional
groups. The ready availability of N-allyl-substituted tetrahy-
dropyridine systems in high yields suggested the possibility
of developing a very concise synthetic method towards bio-
logically relevant bicyclic systems (Table 1, entry 3). These
systems, containing a nitrogen atom at a ring-fusion position,
were prepared by combining our four-component procedure
Scheme 3. Mechanistic rationale proposed for the four-component reac-
tion leading to tetrahydropyridine compounds.
Abstract in Spanish: La reacciꢀn en cuatro componentes
entre aminas alifꢁticas primarias, b-cetoꢂsteres o b-cetotioꢂs-
teres, aldehꢃdos a, b-insaturados y alcoholes, catalizada por
CAN, permite un acceso muy eficiente a 6-alcoxi-2-metil-
1,4,5,6-tetrahidropiridinas sustituidas. Estos compuestos se
transformaron posteriormente en derivados del sistema de
homoquinolizina, de nuevo con rendimientos excelentes, utili-
zando una secuencia de dos pasos consistente en un proceso
de g-desprotonaciꢀn regioselectiva-alilaciꢀn y una reacciꢀn
de metꢁtesis con cierre de anillo. Tambiꢂn se demostrꢀ la po-
sibilidad de llevar a cabo el desplazamiento nucleꢀfilo del
grupo alcoxi por alilsilanos, presumiblemente a travꢂs de una
especie intermedia de tipo aciliminio vinꢃlogo.
2 gives the b-enaminones 6. The Michael addition[12] of
these compounds to the enone system in the aldehydes 3 af-
fords the intermediates 7. The subsequent cyclization of the
latter gives the 2-hydroxytetrahydropyridines 8, which are fi-
nally transformed into the observed products 5 by nucleo-
philic displacement of the hydroxy group by the alcohol 4.
The main experimental observations that support this pro-
posed mechanism can be summarized as follows: 1) reac-
tions starting from the isolated enaminones 6 give identical
products to those obtained when starting from compounds 1
and 2, and 2) intermediates 8, although unstable, can be iso-
lated by carrying out the reaction in the absence of alcohols
4 and can then be transformed into the final products 5 by
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Four-Component Synthesis of Tetrahydropyridines
FULL PAPER
Table 2. Yields for the g-alkylation of the C2-Me substituent in com-
pounds 5.
treatment with 4 under the multicomponent reaction condi-
tions.
Entry Reactant Product R1
R2
X
R3
R6 Yield [%]
In most synthetic applications that use the CAN catalyst,
its activity is based on a radical mechanism, as expected
from a powerful one-electron oxidant.[13] In an effort to de-
termine whether the CAN catalyst exerts its role in our di-
hydropyridine synthesis through such an oxidative pathway,
we performed the reaction between ethyl acetoacetate, bu-
tylamine, acrolein and ethanol (entry 1 in Table 1) in the
presence of a large amount of a radical trap (1,1-diphenyl-
ethylene) and found no noticeable loss in yield. This indi-
cates that a radical mechanism is not in operation under our
conditions. In this regard, it has been noted that some litera-
ture precedent shows that the CAN catalyst may behave as
a Lewis acid,[14] although this role has not been systematical-
ly studied. It is also relevant to note the use of catalytic
amounts of the catalyst in our transformation, since most
synthetic applications using CAN require stoichiometric
quantities.[15]
1
2
3
4
5
6
7
8
9
5a
5j
5k
5l
5m
5n
5o
5k
5j
9a
9b
9c
9d
9e
9 f
9g
9h
9i
nBu allyl
allyl allyl
allyl allyl
allyl allyl
allyl allyl
allyl allyl
allyl allyl
I
I
I
I
I
I
I
OEt Et 95
OEt Et 92
OMe Et 95
OEt Me 90
OMe Me 95
StBu Et 95
StBu Me 92
allyl propargyl Br OMe Et 93
allyl propargyl Br OEt Me 94
lizine) system) in excellent yields. (Scheme 4 and Table 3).
As expected, the ring-closing enyne metathesis (RCEYM)
reactions of compounds 9h and 9i to give 11h and 11i, re-
Table 3. Conditions and yields for the RCM reactions leading to homo-
quinolizines 11.
At this stage, we reasoned that the functionalities present
in compounds 5 should allow for their use as starting materi-
als in novel routes to more complex nitrogen heterocycles.
For instance, a RCM reaction between suitable substituents
placed at N-1 and at the C6 methyl group should provide
ready access to bicyclic compounds. To install the latter sub-
stituent, we planned to take advantage of the acidity of the
methyl protons (the acidity is due to their conjugation with
the ester carbonyl) although we found no literature prece-
dent of such a g-deprotonation process in functionalized tet-
rahydropyridine systems.[16] The treatment of compounds 5
with lithium diisopropylamide (LDA) at 08C followed by
the addition of allyl iodide or propargyl bromide at the
same temperature afforded the C6-CH3-substituted deriva-
tives 9 in yields higher than 90% in all cases, without inter-
ference from the alkoxy group at C-2 (Scheme 4 and
Table 2). Exposure of compounds 9 to the Grubbs first-gen-
eration catalyst (10) in dichloromethane at room tempera-
ture afforded the corresponding ring-closed metathesis prod-
Entry
Product[a]
R3
R6
R7
t [h]
Yield [%]
1
2
3
4
5
6
7
8
11b
11c
11d
11e
OEt
OMe
OEt
OMe
StBu
StBu
OMe
OEt
Et
Et
H
H
H
H
H
H
vinyl
vinyl
4
4
3
4
4
2
16
22
95
95
95
92
92
90
90
90
Me
Me
Et
Me
Et
11 f
11g
11h[b]
11i[b]
Me
[a] For greater clarity, the letters used to designate compounds 9 have
been retained here, and hence compound 11a does not exist. [b] The
enyne RCM reactions were carried out in an ethylene atmosphere.
spectively, were quite slow but could be brought to comple-
tion by performing the reaction under an ethylene atmos-
phere.[17] Interestingly, the use of the generally more reactive
Grubbs second-generation catalyst was inefficient in this
case. The three-step sequence starting from the acyclic pre-
cursors led to homoquinolizines in overall yields of approxi-
mately 80%.
ucts 11 (derivatives of the pyridoACTHNUGTRNEUNG[2,1-a]azepine (homoquino-
One very interesting feature of compounds 11 is the pres-
ence of an alkoxy group adjacent to nitrogen, which suggests
the possibility of carrying out additional transformations
based on the generation of a 4,5-dihydropyridinium inter-
mediate 12 that can be viewed as a vinylogous acyliminium
cation.[18,19] Although species related to 12 have been postu-
lated as intermediates in the reduction of 1,4-dihydropyri-
dines in acidic media, to the best of our knowledge they
have not been used for carbon–carbon bond formation reac-
tions, which are relevant because many natural quinolizidine
and pyridoACTHNUTRGENUG[N 2,1-a]azepine alkaloids are substituted at the po-
sition adjacent to nitrogen.[20] To test this possibility, we
briefly examined the Lewis acid catalyzed reaction between
the representative compounds 11 and various nucleophiles,
finding that treatment of compounds 11c, 11e, and 11 f with
allyltrimethylsilane in the presence of boron trifluoride effi-
ciently afforded the corresponding allyl derivatives 13 in
good to excellent yields, presumably through species 12 as
Scheme 4. Synthesis of hexahydropyrido
lation/RCM sequence.
ACHTUNGTRNE[NUNG 2,1-a]azepines through a g-alky-
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4567

J. C. Menꢀndez et al.
intermediates (Scheme 5 and Table 4). It is interesting to
note that in these reactions the ethoxy group was found to
be a better leaving group than methoxy (Table 4, entries 1
and 2) and, in addition, the Grubbs catalyst did not interfere
The method could be easily applied to the generation of
compound libraries.
Experimental Section
General: All reagents (Aldrich, Fluka, SDS, Probus) and solvents (SDS)
were of commercial quality and were used as received. Reactions were
monitored by thin layer chromatography (TLC), on aluminum plates
coated with silica gel with fluorescent indicator (SDS CCM221254). Sepa-
rations by flash chromatography were performed on alumina (Merck
Al2O3 90). Melting points were measured on a Reichert 723 hot stage mi-
croscope, and are uncorrected. Infrared spectra were recorded on a
Perkin–Elmer Paragon 1000 FTIR spectrophotometer with all com-
pounds examined as thin films on NaCl disks. NMR spectra were ob-
tained on a Bruker Avance 250 spectrometer operating at 250 MHz for
1H and 63 MHz for 13C (CAI de Resonancia Magnꢀtica Nuclear, Univer-
sidad Complutense). Elemental analyses were determined by the CAI de
Microanꢂlisis Elemental, Universidad Complutense, by using a Leco 932
CHNS combustion microanalyzer.
General procedure for the four-component tetrahydropyridine synthesis:
Preparation of compounds 5: The CAN catalyst (5 mol%) was added to
a stirred solution of amine 1 (3.9 mmol, 1.3 equiv) and b-keto ester 2
(3 mmol, 1 equiv) in acetonitrile (5 mL) and the stirring continued for
30 min at room temperature. The suitable a,b-unsaturated aldehyde 3
(3.3 mmol, 1.1 equiv) and the alcohol 4 (6 mmol, 2 equiv) were then
added and stirring was continued for further 1 h. After completion of the
reaction, the mixture was diluted with CH2Cl2 (60 mL), washed with
water and then brine, and dried (anhydrous Na2SO4) before the solvent
was evaporated under reduced pressure. Pure compounds 5 were ob-
tained by rapid column chromatography on activated neutral alumina,
eluting with a petroleum ether–ethyl acetate mixture (95:5, v/v).
À
Scheme 5. C C bond forming reactions at the position adjacent to nitro-
gen in compounds 11 through the intermediate vinylogous acyliminium
cation 12.
Table 4. Yields obtained in the nucleophilic allylation of compounds 11
to give 13.
Entry
Reactant
Product
R
R1
t [h]
Yield [%]
1
2
3
11c
11e
11h
13a
13a
13b
Et
Me
Et
OMe
OMe
StBu
2
4
3
95
Ethyl 1-butyl-6-ethoxy-2-methyl-1,4,5,6-tetrahydropyridine-3-carboxylate
(5a): Colorless viscous liquid; yield: 0.751 g, 93%; 1H NMR (CDCl3,
250 MHz): d=0.95 (t, J=7.2 Hz, 3H), 1.21–1.38 (m, 8H), 1.39–1.59 (m,
3H), 1.99–2.08 (m, 1H), 2.30–2.54 (m, 2H), 2.47 (s, 3H), 3.11–3.24 (m,
1H), 3.42–3.58 (m, 3H), 4.12 (q, J=7.2 Hz, 2H), 4.46 ppm (brs, 1H);
13C NMR (CDCl3, 62.9 MHz): d=14.3, 15.0, 15.9, 16.7, 18.5, 20.5, 25.6,
32.5, 50.4, 59.2, 62.5, 86.7, 96.7, 152.3, 169.5 ppm; IR (neat): n˜ =2959.3,
2869.5, 1680.5, 1577.6, 1273.1, 1118.8, 1065.9 cmÀ1; elemental analysis
calcd (%) for C15H27NO3: C 66.88, H 10.10, N 5.20; found: C 66.50, H
10.00, N 5.14.
90
70[a]
[a] Overall yield for the RCM–allylation sequence.
with the allylation procedure, allowing the RCM allylation
process to be carried out in a sequential protocol (Table 4,
entry 3). In a related transformation, the use of propargyltri-
methylsilane as the nucleophile allowed the preparation of
compound 14 in excellent yield, which is of interest in view
of the many synthetic applications of allenes.[21]
Ethyl 1-butyl-6-ethoxy-2,5-dimethyl-1,4,5,6-tetrahydropyridine-3-carboxyl-
ate (5b): Colorless viscous liquid (two diastereoisomers A and B in a 2:1
ratio); yield: 0.730 g, 86%; 1H NMR (CDCl3, 250 MHz): d=0.82 (d, J=
7.0 Hz, 2H; A), 0.92–0.99 (m, 3H; A & B), 1.07 (d, J=6.7 Hz, 1H; B),
1.20–1.40 (m, 8H; A & B), 1.41–1.72 (m, 3H; A & B), 2.03–2.60 (m, 2H;
A & B), 2.44 (s, 3H; A & B), 3.01–3.23 (m, 1H; A & B), 3.40–3.71 (m,
3H;
A & B), 4.04–4.22 ppm (m, 3H; A &
B); 13C NMR (CDCl3,
62.9 MHz): d=14.3, 15.0, 15.1, 15.8, 16.0, 16.4, 16.6, 17.7, 20.4, 20.5, 25.3,
27.3, 27.4, 32.5, 32.6, 33.1, 50.3, 51.4, 59.2, 62.7, 64.7, 91.0, 91.6, 93.6, 97.4,
151.4, 151.6, 169.6, 170.0 ppm; IR (neat): n˜ =2960.4, 2873.4, 1681.5,
1577.7, 1252.1, 1142.4, 1058.3 cmÀ1; elemental analysis calcd (%) for
C16H29NO3: C 67.81, H 10.31, N 4.94; found: C 67.53, H 10.21, N 4.88.
Conclusion
We have developed a new, experimentally convenient, user-
and environmentally friendly procedure for the synthesis of
6-alkoxy-1,4,5,6-tetrahydropyridines in nearly quantitative
yields. The synthetic procedure is based on a CAN-cata-
lyzed, four-component reaction from very simple, acyclic
building blocks. We have also demonstrated the use of the
generated compounds as starting materials in the very effi-
cient, two-step synthesis of homoquinolizine systems using a
hitherto unknown g-deprotonation–alkylation sequence on a
tetrahydronicotinic ester. Finally, we have illustrated the for-
Methyl
1-allyl-6-methoxy-2,4-dimethyl-1,4,5,6-tetrahydro-pyridine-3-car-
boxylate (5c): Colorless viscous liquid (two diastereoisomers A and B in
1
a 5:1 ratio); yield: 0.645 g, 90%; H NMR (250 MHz, CDCl3): d=1.06 (d,
J=8.1 Hz, 3H; B), 1.19 (d, J=7.1 Hz, 3H; A), 1.61–1.68 (m, 1H; A &
B), 1.96–2.02 (m, 1H; B), 2.09–2.20 (m, 1H; A), 2.35 (s, 3H; B), 2.41 (s,
3H; A), 2.87–2.96 (m, 1H; A & B), 3.33 (s, 3H; A & B), 3.69 (s, 3H; A
& B), 3.86–3.98 (m, 1H; A & B), 4.04–4.18 (m, 1H; A & B), 4.37 (brs,
1H; A & B), 5.08–5.27 (m, 2H; A & B), 5.78–5.87 ppm (m, 1H; A & B);
13C NMR (62.9 MHz, CDCl3): d=16.8 (A), 17.0 (B), 21.0 (A), 23.9 (B),
25.6 (B), 26.1 (A), 29.7 (A), 34.0 (B), 49.8 (B), 50.9 (A), 51.7 (A), 53.8
(B), 55.1 (A), 55.7 (B), 85.8 (B), 88.7 (A), 101.9 (A), 104.6 (B), 115.9
(A), 116.8 (B), 134.7 (B), 134.9 (A), 151.1 (B), 151.5 (A), 169.6 (B),
169.9 ppm (A); IR (neat): n˜ =2946.6, 1682.4, 1574.2, 1430.7, 1349.2,
À
mation of C C bonds at the position adjacent to nitrogen of
the homoquinolizine derivatives through the Lewis acid in-
duced generation of a vinylogous acyliminium intermediate.
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Four-Component Synthesis of Tetrahydropyridines
FULL PAPER
1180.9, 1128.3, 1067.5 cmÀ1; elemental analysis calcd (%) for C13H21NO3:
C 65.25, H 8.84, N 5.85; found: C 65.58, H 8.66, N 6.04.
250 MHz): d=1.21–1.30 (m, 6H), 1.42–1.56 (m, 1H), 2.01–2.10 (m, 1H),
2.24–2.37 (m, 1H), 2.42 (s, 3H), 2.51–2.56 (m, 1H), 3.40–3.62 (m, 2H),
3.80–3.93 (m, 1H), 4.05–4.19 (m, 3H), 4.41 (brs, 1H), 5.09–5.21 (m, 2H),
5.76–5.91 ppm (m, 1H); 13C NMR (CDCl3, 62.9 MHz): d=15.0, 15.9,
16.6, 18.3, 25.3, 51.9, 59.3, 62.7, 86.4, 96.9, 116.0, 135.0, 152.4, 169.4 ppm;
Ethyl 6-ethoxy-1-hexyl-2-methyl-1,4,5,6-tetrahydropyridine-3-carboxylate
(5d): Colorless viscous liquid; yield: 0.811 g, 91%; 1H NMR (CDCl3,
250 MHz): d=0.90 (t, J=6.7 Hz, 3H), 1.20–1.40 (m, 12H), 1.42–1.55 (m,
3H), 1.98–2.08 (m, 1H), 2.24–2.53 (m, 2H), 2.43 (s, 3H), 3.10–3.22 (m,
1H), 3.40–3.57 (m, 3H), 4.11 (q, J=7.1 Hz, 2H), 4.46 ppm (brs, 1H);
13C NMR (CDCl3, 62.9 MHz): d=14.4, 15.0, 15.9, 16.6, 18.5, 22.9, 25.6,
26.9, 30.4, 31.9, 50.7, 59.2, 62.5, 86.7, 96.7, 152.2, 169.5 ppm; IR (neat):
n˜ =2957.3, 2858.1, 1681.9, 1574.3, 1272.7, 1119.2, 1067.4 cmÀ1; elemental
analysis calcd (%) for C17H31NO3: C 68.65, H 10.51, N 4.71; found: C
68.41, H 10.43, N 4.65.
IR (neat): n˜ =2976.1, 2900.7, 1681.6, 1578.0, 1273.9, 1121.9, 1066.4 cmÀ1
;
elemental analysis calcd (%) for C14H23NO3: C 66.37, H 9.15, N 5.53;
found: C 66.01, H 8.99, N 5.50.
Methyl 1-allyl-6-ethoxy-2-methyl-1,4,5,6-tetrahydropyridine-3-carboxylate
(5k): Colorless viscous liquid; yield: 0.667 g, 93%; 1H NMR (250 MHz,
CDCl3): d=1.23 (t, J=7.0 Hz, 3H), 1.41–1.56 (m, 1H), 2.00–2.09 (m,
1H), 2.24–2.42 (m, 1H), 2.49 (s, 3H), 2.51–2.58 (m, 1H), 3.43–3.59 (m,
2H), 3.65 (s, 3H), 3.81–3.91 (m, 1H), 4.09–4.19 (m, 1H), 4.41(brs, 1H),
5.07–5.19 (m, 2H), 5.76–5.90 ppm (m, 1H); 13C NMR (62.9 MHz,
CDCl3): d=15.9, 16.5, 18.3, 25.3, 50.8, 52.0, 62.7, 86.3, 96.5, 116.0, 134.9,
152.7, 169.6 ppm; IR (neat): n˜ =2946.7, 1682.3, 1580.1, 1430.6, 1277.4,
1176.4, 1119.9, 1067.9 cmÀ1; elemental analysis calcd (%) for C13H21NO3:
C 65.25, H 8.84, N 5.85; found: C 65.51, H 8.70, N 6.05.
Ethyl
6-ethoxy-2-methyl-1-(2-methylbutyl)-1,4,5,6-tetrahydropyridine-3-
carboxylate (5e): Colorless viscous liquid (two diastereoisomers A and B
in a 1:1 ratio); yield: 0.747 g, 88%; 1H NMR (CDCl3, 250 MHz): d=
0.85–0.95 (m, 6H; A & B), 0.99–1.17 (m, 1H; A & B), 1.20–1.29 (m, 6H;
A & B), 1.34–1.70 (m, 3H; A & B), 2.00–2.08 (m, 1H; A & B), 2.29–2.53
(m, 2H; A & B), 2.42 (s, 3H; A & B), 2.85 (dd, J=14.9, 8.9 Hz, 1H; A),
3.02 (dd, J=14.9, 7.6 Hz, 1H; B), 3.36–3.61 (m, 3H; A & B), 4.05–4.16
(m, 2H; A & B), 4.45–4.47 ppm (m, 1H; A & B); 13C NMR (CDCl3,
62.9 MHz): d=11.8, 11.9, 15.0, 15.9, 17.0, 17.1, 17.7, 18.7, 25.2, 25.3, 27.3,
27.6, 36.1, 36.6, 56.2, 56.9, 59.2, 62.6, 86.4, 87.3, 96.7, 152.6, 152.7,
169.6 ppm; IR (neat): n˜ =2964.1, 2878.8, 1681.8, 1574.2, 1381.2, 1270.3,
1116.4, 1067.5 cmÀ1; elemental analysis calcd (%) for C16H29NO3: C
67.81, H 10.31, N 4.94; found: C 67.45, H 10.11, N 4.82.
Ethyl 1-allyl-6-methoxy-2-methyl-1,4,5,6-tetrahydropyridine-3-carboxylate
(5l): Colorless viscous liquid; yield: 0.681 g, 95%; 1H NMR (250 MHz,
CDCl3): d=1.27 (t, J=7.1 Hz, 3H), 1.42–1.57 (m, 1H), 2.04–2.14 (m,
1H), 2.21–2.36 (m, 1H), 2.43 (s, 3H), 2.51–2.53 (m, 1H), 3.35 (s, 3H),
3.81–3.91 (m, 1H), 4.04–4.19 (m, 3H), 4.32–4.35 (m, 1H), 5.09–5.21 (m,
2H), 5.76–5.91 ppm (m, 1H); 13C NMR (62.9 MHz, CDCl3): d=14.6,
16.1, 18.1, 24.5, 52.3, 54.3, 58.7, 87.6, 96.8, 115.6, 135.6, 151.8, 168.6 ppm;
IR (neat): n˜ =2932.1, 1682.7, 1574.0, 1430.2, 1347.2, 1273.7, 1115.8,
768.2 cmÀ1; elemental analysis calcd (%) for C13H21NO3: C 65.25, H 8.84,
N 5.85; found: C 65.07, H 8.54, N 6.05.
tert-Butyl 1-butyl-6-ethoxy-2-methyl-1,4,5,6-tetrahydropyridine-3-carboxyl-
ate (5 f): Colorless viscous liquid; yield: 0.775 g, 87%; 1H NMR (CDCl3,
250 MHz): d=0.94 (t, J=7.2 Hz, 3H), 1.24 (t, J=7.0 Hz, 3H), 1.26–1.40
(m, 2H), 1.41–1.61 (m, 3H), 1.47 (s, 9H), 1.96–2.06 (m, 1H), 2.20–2.49
(m, 2H), 2.39 (s, 3H), 3.09–3.22 (m, 1H), 3.39–3.60 (m, 3H), 4.45 ppm (t,
J=2.0 Hz, 1H); 13C NMR (CDCl3, 62.9 MHz): d=14.3, 15.9, 16.7, 19.0,
20.5, 25.6, 28.9, 32.6, 50.4, 62.4, 78.4, 86.7, 98.6, 150.9, 169.3 ppm; IR
(neat): n˜ =2961.7, 2870.5, 1681.1, 1579.9, 1364.2, 1281.7, 1119.6,
1068.0 cmÀ1; elemental analysis calcd (%) for C17H31NO3: C 68.65, H
10.51, N 4.71; found: C 68.27, H 10.38, N 4.50.
Methyl 1-allyl-6-methoxy-2-methyl-1,4,5,6-tetrahydropyridine-3-carboxyl-
ate (5m): Colorless viscous liquid; yield: 0.621 g, 92%; 1H NMR
(250 MHz, CDCl3): d=1.42–1.56 (m, 1H), 2.04–2.13 (m, 1H), 2.21–2.33
(m, 1H), 2.42 (s, 3H), 2.49–2.56 (m, 1H), 3.33 (s, 3H), 3.66 (s, 3H), 3.81–
3.91 (m, 1H), 4.12–4.22 (m, 1H), 4.33 (brs, 1H), 5.08–5.19 (m, 2H), 5.76–
5.88 ppm (m, 1H); 13C NMR (62.9 MHz, CDCl3): d=16.3, 18.1, 24.6,
50.6, 52.4, 54.6, 87.7, 96.7, 115.9, 134.9, 152.4, 169.3 ppm; IR (neat): n˜ =
2946.0, 1682.7, 1579.8, 1430.0, 1347.4, 1277.4, 1170.2, 1117.9, 1067.5 cmÀ1
;
Ethyl 1-benzyl-6-ethoxy-2-methyl-1,4,5,6-tetrahydropyridine-3-carboxylate
(5g): Colorless viscous liquid; yield: 0.727 g, 80%; 1H NMR (CDCl3,
250 MHz): d=1.21–1.31 (m, 6H), 1.52–1.66 (m, 1H), 2.03–2.12 (m, 1H),
2.33–2.47 (m, 1H), 2.42 (s, 3H), 2.57–2.66 (m, 1H), 3.38–3.62 (m, 2H),
4.14 (q, J=7.1 Hz, 2H), 4.40–4.53 (m, 2H), 4.83 (d, J=17.6 Hz, 1H),
7.18–7.41 ppm (m, 5H); 13C NMR (CDCl3, 62.9 MHz): d=15.0, 15.9,
16.9, 18.4, 25.3, 52.9, 59.4, 62.8, 86.6, 97.3, 126.5, 127.5, 129.2, 139.1, 152.5,
169.4 ppm; IR (neat): n˜ =2975.4, 2903.7, 1681.7, 1576.2, 1381.3, 1273.6,
1121.0, 1066.4 cmÀ1; elemental analysis calcd (%) for C18H25NO3: C
71.26, H 8.31, N 4.62; found: C 70.89, H 8.11, N 4.51.
elemental analysis calcd (%) for C12H19NO3: C 63.98, H 8.50, N 6.22;
found: C 64.04, H 8.37, N 6.50.
S-tert-Butyl 1-allyl-6-ethoxy-2-methyl-1,4,5,6-tetrahydropyridine-3-carbo-
thioate (5n): Pale yellow viscous liquid; yield: 0.766 g, 86%; 1H NMR
(CDCl3, 250 MHz): d=1.23 (t, J=7.0 Hz, 3H), 1.47–1.60 (m, 1H), 1.50
(s, 9H), 2.04–2.13 (m, 1H), 2.38 (s, 3H), 2.40–2.47 (m, 1H), 2.55–2.63 (m,
1H), 3.39–3.62 (m, 2H), 3.81–3.92 (m, 1H), 4.08–4.19 (m, 1H), 4.38 (brs,
1H), 5.07–5.21 (m, 2H), 5.75–5.90 ppm (m, 1H); 13C NMR (CDCl3,
62.9 MHz): d=15.9, 17.2, 18.9, 25.4, 30.7, 46.8, 51.9, 62.8, 85.9, 105.8,
116.3, 134.6, 150.8, 191.3 ppm; IR (neat): n˜ =2961.5, 2928.6, 1628.9,
Ethyl 1-butyl-6-methoxy-2-methyl-1,4,5,6-tetrahydropyridine-3-carboxylate
(5h): Colorless viscous liquid; yield: 0.719 g, 94%; 1H NMR (CDCl3,
250 MHz): d=0.95 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.1 Hz, 3H), 1.26–1.38
(m, 2H), 1.39–1.58 (m, 3H), 2.01–2.10 (m, 1H), 2.19–2.36 (m, 1H), 2.48
(s, 3H), 2.48–2.58 (m, 1H), 3.10–3.22 (m, 1H), 3.34 (s, 3H), 3.47–3.59 (m,
1H), 4.12 (q, J=7.1 Hz, 2H), 4.39 ppm (t, J=2.2 Hz, 1H); 13C NMR
(CDCl3, 62.9 MHz): d=14.3, 15.0, 16.7, 18.5, 20.5, 25.1, 32.6, 50.9, 54.7,
59.3, 88.1, 97.2, 152.0, 169.5 ppm; IR (neat): n˜ =2958.3, 2874.7, 1681.9,
1574.7, 1348.2, 1273.4, 1064.2 cmÀ1; elemental analysis calcd (%) for
C14H25NO3: C 65.85, H 9.87, N 5.49; found: C 65.50, H 9.80, N, 5.32.
1544.5, 1333.2, 1061.0 cmÀ1
;
elemental analysis calcd (%) for
C16H27NO2S: C 64.60, H 9.15, N 4.71; found: C 64.42, H 9.00, N 4.60.
S-tert-Butyl 1-allyl-6-methoxy-2-methyl-1,4,5,6-tetrahydropyridine-3-car-
bothioate (5o): Pale yellow viscous liquid; yield: 0.807 g, 95%; 1H NMR
(250 MHz, CDCl3): d=1.49 (m, 9H), 1.56–1.60 (m, 1H), 2.07–2.16 (m,
1H), 2.26–2.33 (m, 1H), 2.38 (s, 3H), 2.55–2.63 (m, 1H), 3.33 (s, 3H),
3.82–3.92 (m, 1H), 4.04–4.42 (m, 1H), 4.31 (brs, 1H), 5.08–5.20 (m, 2H),
5.75–5.89 ppm (m, 1H); 13C NMR (62.9 MHz, CDCl3): d=17.1, 18.7,
24.7, 30.6, 46.6, 52.3, 54.8, 87.3, 105.9, 116.3, 134.5, 150.4, 191.3 ppm; IR
(neat): n˜ =2957.5, 1628.8, 1538.4, 1345.9, 1254.8, 1068.5, 922.2, 767.2 cmÀ1
;
Ethyl 6-allyloxy-1-butyl-2-methyl-1,4,5,6-tetrahydropyridine-3-carboxylate
(5i): Colorless viscous liquid; yield: 0.759 g, 90%; 1H NMR (CDCl3,
250 MHz): d=0.94 (t, J=7.2 Hz, 3H), 1.27 (t, J=7.1 Hz, 3H), 1.27–1.35
(m, 2H), 1.40–1.55 (m, 3H), 2.01–2.08 (m, 1H), 2.32–2.49 (m, 2H), 2.44
(s, 3H), 3.08–3.21 (m, 1H), 3.44–3.57 (m, 1H), 4.02 (dd, J=5.7, 1.2 Hz,
2H), 4.12 (q, J=7.1 Hz, 2H), 4.52 (t, J=2.2 Hz, 1H), 5.18–5.34 (m, 2H),
5.87–6.00 ppm (m, 1H); 13C NMR (CDCl3, 62.9 MHz): d=14.3, 15.0,
16.7, 18.6, 20.5, 25.7, 32.6, 50.5, 59.3, 68.1, 86.1, 97.3, 117.4, 135.3, 152.1,
169.5 ppm; IR (neat): n˜ =2958.8, 2873.5, 1682.0, 1576.0, 1380.8, 1273.4,
1119.3, 1037.5 cmÀ1; elemental analysis calcd (%) for C16H27NO3: C
68.29, H 9.67, N 4.98; found: C 68.00, H 9.52, N 4.90.
elemental analysis calcd (%) for C15H25NO2S: C 63.56, H 8.89, N 4.94, S
11.31; found: C 63.67, H 8.88, N 5.11, S 11.31.
General procedure for the g-alkylation of compounds 5: Preparation of
compounds 9: LDA (prepared from diisopropylamine (2 equiv) and
nBuLi (1.6m hexane solution, 2.05 equiv), 30 min, 08C) was added to a
solution of the suitable 1,4,5,6-tetrahydropyridine derivative 5 (1 mmol)
in dry THF (10 mL). The reaction mixture was stirred at À5 to 08C for
30 min before the addition of allyl iodide or propargyl bromide
(1.1 equiv). The resulting solution was stirred at 08C for 2 h, and, after
verifying the completion of the reaction by TLC, a few drops of cold
water were added and the organic layer was concentrated to dryness. The
residue was dissolved in CH2Cl2 and washed with brine. The organic
Ethyl
1-allyl-6-ethoxy-2-methyl-1,4,5,6-tetrahydropyridine-3-carboxylate
(5j): Colorless viscous liquid; yield: 0.698 g, 92%; 1H NMR (CDCl3,
Chem. Eur. J. 2009, 15, 4565 – 4572
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4569

J. C. Menꢀndez et al.
layer was dried over Na2SO4 and concentrated to dryness. The crude resi-
due was subject to chromatography on neutral Al2O3 (activity II-III),
eluting with a 98:2 petroleum ether–ethyl acetate mixture containing
0.25% Et3N.
3.32 (s, 3H), 3.79–3.89 (m, 1H), 4.08–4.17 (m, 1H), 4.31–4.32 (m, 1H),
4.98–5.20 (m, 4H), 5.74–6.01 ppm (m, 2H); 13C NMR (62.9 MHz,
CDCl3): d=19.0, 25.1, 28.7, 30.6, 33.5, 46.8, 52.2, 54.8, 87.3, 106.2, 115.1,
116.8, 134.9, 138.3, 152.9, 190.7 ppm; IR (neat): n˜ =2959.2, 2923.9, 1630.7,
1538.1, 1453.1, 1348.7, 1068.6, 921.4 cmÀ1; elemental analysis calcd (%)
for C18H29NO3S: C 66.83, H 9.04, N 4.33, S 9.91; found: C 66.54, H 9.00,
N 4.35, S 9.78.
Ethyl 1-butyl-2-(but-3-en-1-yl)-6-ethoxy-1,4,5,6-tetrahydropyridine-3-car-
boxylate (9a): Colorless viscous liquid; yield: 0.294 g, 95%; 1H NMR
(250 MHz, CDCl3): d=0.96 (t, J=7.2 Hz, 3H), 1.14–1.37 (m, 6H), 1.41–
1.59 (m, 4H), 1.99–2.08 (m, 1H), 2.16–2.65 (m, 6H), 3.08–3.33 (m, 2H),
3.37–3.58 (m, 3H), 4.08–4.19 (m, 2H), 4.49 (brs, 1H), 4.99–5.14 (m, 2H),
5.87–6.04 ppm (m, 1H); 13C NMR (62.9 MHz, CDCl3): d=14.3, 15.0,
15.8, 18.8, 20.5, 26.1, 28.6, 32.8, 33.8, 50.7, 59.3, 62.4, 86.7, 97.5, 114.9,
138.5, 155.2, 168.9 ppm; IR (neat): n˜ =2959.0, 2930.4, 1681.8, 1573.4,
1273.5, 1144.9, 1121.2, 1052.1 cmÀ1; elemental analysis calcd (%) for
C18H31NO3: C 69.86, H 10.10, N 4.53; found: C 69.65, H 9.89, N 4.32.
Methyl 1-allyl-2-(but-3-yn-1-yl)-6-ethoxy-1,4,5,6-tetrahydropyridine-3-car-
boxylate (9h): Colorless viscous liquid; yield: 0.258 g, 93%; 1H NMR
(250 MHz, CDCl3): d=1.23 (t, J=7.0 Hz, 3H), 1.43–1.56 (m, 1H), 2.02–
2.07 (m, 2H), 2.25–2.64 (m, 4H), 2.70–2.81 (m, 1H), 3.33–3.45 (m, 1H),
3.52 (q, J=7.0 Hz, 2H), 3.69 (s, 3H), 3.77–3.95 (m, 1H), 4.19–4.27 (m,
1H), 4.44 (brs, 1H), 5.12–5.22 (m, 2H), 5.79–5.93 ppm (m, 1H);
13C NMR (62.9 MHz, CDCl3): d=15.8, 18.4, 18.6, 25.6, 28.5, 51.1, 52.5,
62.7, 69.2, 84.2, 86.5, 97.5, 116.6, 135.1, 154.4, 168.8 ppm; IR (neat): n˜ =
Ethyl
1-allyl-2-(but-3-en-1-yl)-6-ethoxy-1,4,5,6-tetrahydropyridine-3-car-
3294.8, 2947.6, 1682.6, 1573.9, 1432.6, 1278.2, 1163.7, 1115.2, 1067.2 cmÀ1
;
boxylate (9b): Colorless viscous liquid; yield: 0.270 g, 92%; 1H NMR
(250 MHz, CDCl3): d=1.24–1.33 (m, 6H), 1.42–1.57 (m, 1H), 1.99–2.09
(m, 1H), 2.16–2.61 (m, 5H), 3.19–3.42 (m, 1H), 3.47–3.58 (m, 2H), 3.70–
3.90 (m, 1H), 4.08–4.19 (m, 3H), 4.44 (brs, 1H), 4.98–5.32 (m, 4H), 5.77–
5.98 ppm (m, 2H); 13C NMR (62.9 MHz, CDCl3): d=14.9, 15.9, 18.6,
25.7, 28.6, 33.6, 52.1, 59.3, 62.6, 86.3, 97.2, 114.9, 116.5, 135.3, 138.3, 155.4,
168.7 ppm; IR (neat): n˜ =2977.2, 1681.9, 1574.0, 1446.7, 1272.1, 1168.3,
elemental analysis calcd (%) for C16H23NO3: C 69.29, H 8.36, N 5.05;
found: C 69.57, H 8.09, N 5.14.
Ethyl 1-allyl-2-(but-3-yn-1-yl)-6-methoxy-1,4,5,6-tetrahydropyridine-3-car-
boxylate (9i): Colorless viscous liquid; yield: 0.260 g, 94%; 1H NMR
(250 MHz, CDCl3): d=1.28 (t, J=7.1 Hz, 3H), 1.40–1.55 (m, 1H), 1.99–
2.10 (m, 2H), 2.19–2.44 (m, 2H), 2.50–2.74 (m, 3H), 3.34 (s, 3H), 3.38–
3.47 (m, 1H), 3.82–3.92 (m, 1H), 4.11 (q, J=7.1 Hz, 2H), 4.21–4.29 (m,
1H), 4.35 (brs, 1H), 5.10–5.21 (m, 2H), 5.76–5.91 ppm (m, 1H);
13C NMR (62.9 MHz, CDCl3): d=13.5, 17.0, 17.3, 23.7, 27.1, 51.5, 53.4,
58.1, 67.9, 82.7, 86.6, 96.9, 115.2, 133.6, 152.2, 167.0 ppm; IR (neat): n˜ =
3294.5, 2980.0, 2932.8, 1681.2, 1574.0, 1452.5, 1275.2, 1163.6, 1067.5,
770.9 cmÀ1; elemental analysis calcd (%) for C16H23NO3: C 69.29, H 8.36,
N 5.05; found: C 69.29, H 8.42, N 5.05.
1122.5, 1067.4, 956.4, 913.9 cmÀ1
; elemental analysis calcd (%) for
C17H27NO3: C 69.59, H 9.28, N 4.77; found: C 69.64, H 9.04, N 4.95.
Methyl 1-allyl-2-(but-3-en-1-yl)-6-ethoxy-1,4,5,6-tetrahydropyridine-3-car-
boxylate (9c): Colorless viscous liquid; yield: 0.265 g, 95%; 1H NMR
(250 MHz, CDCl3): d=1.23 (t, J=7.0 Hz, 3H), 1.41–1.56 (m, 1H), 1.93–
2.58 (m, 6H), 3.20–3.32 (m, 1H), 3.47–3.57 (m, 2H), 3.67 (s. 3H), 3.79–
3.95 (m, 1H), 4.07–4.17 (m, 1H), 4.43 (brs, 1H), 4.97–5.23 (m, 4H), 5.76–
6.01 ppm (m, 2H); 13C NMR (62.9 MHz, CDCl3): d=15.8, 18.5, 25.7,
28.7, 33.6, 50.9, 52.2, 62.6, 86.3, 96.9, 114.9, 116.5, 135.2, 138.3, 155.9,
169.0 ppm; IR (neat): n˜ =2976.9, 2946.2, 1687.0, 1573.8, 1275.4, 1174.3,
1132.1, 1067.8 cmÀ1; elemental analysis calcd (%) for C16H25NO3: C
68.79, H 9.02, N 5.01; found: C 68.54, H 8.81, N 4.87.
General procedure for the RCM reaction of compounds 9: Preparation
of pyridoazepines 11: The Grubbs first-generation catalyst 10 (10 mol%)
was added to a solution of the suitable 1,4,5,6-tetrahydropyridine deriva-
tive 9 (1 mmol) in dry CH2Cl2 (10 mL) and the reaction mixture was
stirred at room temperature for the times indicated in Table 3. After veri-
fying completion of the reaction by TLC, the organic layer was concen-
trated to dryness and the crude residue was purified by chromatography
on a neutral Al2O3 (activity II-III) column, eluting with a 96:4 petroleum
ether–ethyl acetate mixture containing 0.25% Et3N. For the preparation
of compounds 11h and 11i, the enyne RCM reactions were carried out
under an ethylene atmosphere.
Ethyl 1-allyl-2-(but-3-en-1-yl)-6-methoxy-1,4,5,6-tetrahydropyridine-3-car-
boxylate (9d): Colorless viscous liquid; yield: 0.251 g, 90%; 1H NMR
(250 MHz, CDCl3): d=1.21 (t, J=7.1 Hz, 3H), 1.47–1.55 (m, 1H), 1.95–
2.67 (m, 7H), 3.33 (s, 3H), 3.78–3.87 (m, 1H), 4.07–4.22 (m, 3H), 4.34
(brs, 1H), 4.97–5.19 (m, 4H), 5.73–6.03 ppm (m, 2H); 13C NMR
(62.9 MHz, CDCl3): d=14.9, 18.6, 25.1, 28.7, 33.7, 52.5, 54.8, 59.4, 87.9,
97.6, 114.9, 116.6, 135.2, 138.3, 155.1, 168.7 ppm; IR (neat): n˜ =2978.3,
Ethyl 4-ethoxy-2,3,4,6,9,10-hexahydropyridoACTHNUTRGNE[NUG 1,2-a]azepine-1-carboxylate
2946.9, 1682.4, 1574.0, 1453.6, 1273.0, 1167.6, 1121.2, 1067.7, 914.6 cmÀ1
;
(11b): Colorless viscous liquid; yield: 0.252 g, 95%; 1H NMR (250 MHz,
CDCl3): d=1.24 (t, J=7.0 Hz, 3H), 1.27 (t, J=7.1 Hz, 3H), 1.44–1.58 (m,
1H), 1.96–2.05 (m, 1H), 2.24–2.56 (m, 4H), 3.29–3.45 (m, 2H), 3.53 (q,
J=7 Hz, 2H), 4.01 (brs, 2H), 4.14 (q, J=7.1 Hz, 2H), 4.46 (brs, 1H),
5.73–5.75 ppm (m, 2H); 13C NMR (62.9 MHz, CDCl3): d=15.0, 16.1,
18.4, 26.2, 26.4, 29.3, 49.5, 59.5, 62.8, 88.8, 95.9, 125.6, 133.2, 157.7,
169.8 ppm; IR (neat): n˜ =2974.3, 2898.1, 1677.4, 1577.3, 1267.2, 1158.3,
1105.5, 1066.0 cmÀ1; elemental analysis calcd (%) for C15H23NO3: C
67.90, H 8.74, N 5.28; found: C 68.17, H 8.78, N 5.28.
elemental analysis calcd (%) for C16H25NO3: C 68.79, H 9.02, N 5.01;
found: C 68.75, H 8.77, N 4.85.
Methyl
1-allyl-2-(but-3-en-1-yl)-6-methoxy-1,4,5,6-tetrahydropyridine-3-
carboxylate (9e): Colorless viscous liquid; yield: 0.252 g, 95%; 1H NMR
(250 MHz, CDCl3): d=1.45–1.57 (m, 1H), 2.03–2.60 (m, 7H), 3.35 (s,
3H), 3.68 (s, 3H), 3.80–3.89 (m, 1H), 4.12–4.21 (m, 1H), 4.36 (brs, 1H),
4.99–5.21 (m, 4H), 5.78–5.99 ppm (m, 2H); 13C NMR (62.9 MHz,
CDCl3): d=18.5, 25.1, 28.7, 33.6, 51.0, 52.5, 54.8, 87.8, 97.2, 115.0, 116.6,
135.1, 138.3, 155.7, 169.1 ppm; IR (neat): n˜ =2946.3, 1684.2, 1573.9,
1432.5, 1274.5, 1167.9, 1120.5, 1067.9 cmÀ1; elemental analysis calcd (%)
for C15H23NO3: C 67.90, H 8.74, N 5.28; found: C 68.15, H 9.07, N 5.52.
Methyl 4-ethoxy-2,3,4,6,9,10-hexahydropyridoACTHNUTRGNE[NUG 1,2-a]azepine-1-carboxylate
(11c): Colorless viscous liquid; yield: 0.238 g, 95%; 1H NMR (250 MHz,
CDCl3): d=1.23 (t, J=6.8 Hz, 3H), 1.50–1.55 (m, 1H), 1.99–2.04 (m,
1H), 2.29–2.52 (m, 4H), 3.36–3.46 (m, 2H), 3.53 (q, J=6.7 Hz, 2H), 3.65
(s, 3H), 4.01 (brs, 2H), 4.46 (brs, 1H), 5.74 ppm (brs, 2H); 13C NMR
(62.9 MHz, CDCl3): d=15.9, 18.3, 26.2, 26.3, 29.1, 49.6, 50.9, 62.8, 88.9,
95.3, 125.4, 132.9, 157.9, 169.6 ppm; IR (neat): n˜ =2927.8, 1679.1, 1574.3,
1269.0, 1158.0, 1108.2, 1066.5 cmÀ1; elemental analysis calcd (%) for
C14H21NO3: C 66.91, H 8.42, N 5.57; found: C 67.17, H 8.31, N 5.73.
S-tert-Butyl 1-allyl-2-(but-3-en-1-yl)-6-ethoxy-1,4,5,6-tetrahydropyridine-3-
carbothioate (9 f): Pale yellow viscous liquid; yield: 0.320 g, 95%;
1H NMR (250 MHz, CDCl3): d=1.24 (t, J=7.0 Hz, 3H), 1.44–1.63 (m,
1H), 1.51 (s, 9H), 2.02–2.62 (m, 6H), 3.16–3.27 (m, 1H), 3.45–3.57 (m,
2H), 3.81–3.90 (m, 1H), 4.06–4.14 (m, 1H), 4.39 (brs, 1H), 4.98–5.20 (m,
4H), 5.76–5.95 ppm (m, 2H); 13C NMR (62.9 MHz, CDCl3): d=15.9,
18.9, 25.7, 28.7, 30.6, 33.4, 46.6, 51.9, 62.7, 85.9, 105.8, 115.0. 116.6, 134.9,
138.3, 153.2, 190.3 ppm; IR (neat): n˜ =2961.9, 2923.3, 1605.2, 1533.0,
1452.4, 1360.4, 1162.2, 1068.0, 918.2 cmÀ1; elemental analysis calcd for
C19H31NO3S: C 67.61, H 9.26, N 4.15, S 9.50; found: C 67.90, H 9.32, N
4.38, S 9.42.
Ethyl 4-methoxy-2,3,4,6,9,10-hexahydropyridoACTHNUTRGNE[NUG 1,2-a]azepine-1-carboxylate
(11d): Colorless viscous liquid; yield: 0.238 g, 95%; 1H NMR (250 MHz,
CDCl3): d=1.26 (t, J=7.1 Hz, 3H), 1.43–1.57 (m, 1H), 1.96–2.55 (m,
6H), 3.36 (s, 3H), 3.41–3.57 (m, 1H), 3.86–3.99 (m, 1H), 4.06–4.19 (m,
3H), 4.37 (brs, 1H), 5.69–5.80 ppm (m, 2H); 13C NMR (62.9 MHz,
CDCl3): d=14.9, 18.2, 25.6, 26.4, 29.1, 49.9, 55.0, 59.3, 90.5, 95.9, 125.5,
132.9, 157.3, 169.2 ppm; IR (neat): n˜ =2976.0, 2929.3, 1678.3, 1578.1,
1267.8, 1158.8, 1106.9, 1064.4 cmÀ1; elemental analysis calcd (%) for
C14H21NO3: C 66.91, H 8.42, N 5.57; found: C 67.10, H 8.30, N 5.59.
S-tert-Butyl 1-allyl-2-(but-3-en-1-yl)-6-methoxy-1,4,5,6-tetrahydropyridine-
3-carbothioate (9g): Pale yellow viscous liquid; yield: 0.297 g, 92%;
1H NMR (250 MHz, CDCl3): d=1.49 (s. 9H), 1.54–1.58 (m, 1H), 2.04–
2.23 (m, 2H), 2.30–2.50 (m, 3H), 2.54–2.62 (m, 1H), 3.22–3.29 (m, 1H),
4570
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Chem. Eur. J. 2009, 15, 4565 – 4572

Four-Component Synthesis of Tetrahydropyridines
FULL PAPER
Methyl 4-methoxy-2,3,4,6,9,10-hexahydropyrido
[1,2-a]azepine-1-carboxyl-
S-tert-Butyl-4-allyl-2,3,4,6,9,10-hexahydropyridoACTHGNUTERNNU[G 1,2-a]azepine-1-carbo-
ate (11e): Colorless viscous liquid; yield: 0.218 g, 92%; 1H NMR
(250 MHz, CDCl3): d=1.44–1.68 (m, 1H), 1.91–2.68 (m, 6H), 3.35–3.53
(m, 1H), 3.37 (s, 3H), 3.66 (s, 3H), 3.91–3.99 (m, 1H), 4.09–4.16 (m, 1H),
4.39 (brs, 1H), 5.75–5.81 ppm (m, 2H); 13C NMR (62.9 MHz, CDCl3):
d=18.2, 25.6, 26.4, 29.1, 50.0, 50.9, 55.1, 90.5, 95.6, 125.4, 133.0, 157.7,
169.6 ppm; IR (neat): n˜ =2944.6, 1681.6, 1574.4, 1433.1, 1270.9, 1159.8,
1109.4, 1063.9 cmÀ1; elemental analysis calcd (%) for C13H19NO3: C
65.80, H 8.07, N 5.90; found: C 66.06, H 8.32, N 5.77.
thioate (13b): Colorless viscous liquid; yield: 0.214 g, 70%; 1H NMR
(250 MHz, CDCl3): d=1.52 (brs, 10H), 1.86–1.93 (m, 1H), 2.16–2.65 (m,
7H), 3.19–3.29 (m, 1H), 3.64–3.89 (m, 2H), 4.14–4.27 (m, 1H), 5.08–5.22
(m, 2H), 5.65–5.82 ppm (m, 3H); 13C NMR (62.9 MHz, CDCl3): d=18.1,
23.1, 25.9, 27.1, 29.5, 35.9, 45.2, 48.5, 59.4, 99.6, 117.2, 124.1, 131.7, 133.4,
156.2, 188.6 ppm; IR (neat): n˜ =2925.0, 1616.0, 1532.2, 1455.6, 1360.8,
1144.2, 1023.8 cmÀ1; elemental analysis calcd (%) for C18H27NOS: C
70.77, H 8.91, N 4.59, S 10.50; found: C 70.39, H 8.54, N 4.39, S 10.31.
Methyl 4-(prop-1,2-dienyl)-2,3,4,6,9,10-hexahydropyridoACTHNUTRGNE[NUG 1,2-a]azepine-1-
S-tert-Butyl 4-ethoxy-2,3,4,6,9,10-hexahydropyridoACTHNUGTRNEUNG[1,2-a]azepine-1-carbo-
carboxylate (14): Colorless viscous liquid; yield: 0.225 g, 92%; 1H NMR
(250 MHz, CDCl3): d=1.26–1.35 (m, 1H), 1.83–1.89 (m, 2H), 2.27–2.59
(m, 4H), 3.38–3.46 (m, 1H), 3.67 (s, 3H), 3.71–3.88 (m, 2H), 4.05–4.16
(m, 1H), 4.79–4.92 (m, 2H), 5.12 (q, J=6.6 Hz, 1H), 5.72–5.73 ppm (m,
2H); 13C NMR (62.9 MHz, CDCl3): d=18.1, 25.0, 25.9, 27.6, 47.9, 49.4,
58.8, 75.8, 90.3, 90.8, 123.9, 131.5, 158.3, 168.3, 206.86 ppm; IR (neat): n˜ =
2947.8, 1955.0, 1683.7, 1558.4, 1435.8, 1266.3, 1156.0, 1097.2 cmÀ1; elemen-
tal analysis calcd (%) for C15H19NO2: C 73.44, H 7.81, N 5.71; found: C
73.15, H 7.64, N 5.47.
thioate (11 f): Colorless viscous liquid; yield: 0.284 g, 92%; 1H NMR
(250 MHz, CDCl3): d=1.08 (t, J=6.5 Hz, 3H), 1.26 (s, 9H), 1.58–2.33
(m, 7H), 3.15 (brs, 1H), 3.37 (q, J=6.6 Hz, 2H), 3.85 (brs, 2H), 4.28
(brs, 1H), 5.57 ppm (s, 2H); 13C NMR (62.9 MHz, CDCl3): d=15.9, 18.8,
26.2, 26.6, 28.7, 30.6, 46.5, 49.4, 62.8, 88.2, 104.7, 125.2, 132.8, 155.3,
190.8 ppm; IR (neat): n˜ =2925.8, 2855.5, 1681.1, 1362.9, 1172.8, 1026.0,
909.9, 847.6, 732.3 cmÀ1; elemental analysis calcd (%) for C17H27NO2S: C
65.98, H 8.79, N 4.53, S 10.36; found: C 65.72, H 8.43, N 4.31, S 10.12.
S-tert-Butyl 4-methoxy-2,3,4,6,9,10-hexahydropyridoACHTNUTRGNEUNG[1,2-a]azepine-1-car-
bothioate (11g): Colorless viscous liquid; yield: 0.266 g, 90%; 1H NMR
(250 MHz, CDCl3): d=1.49 (s, 9H), 1.56–1.59 (m, 1H), 2.03–2.10 (m,
1H), 2.29–2.58 (m, 4H), 3.20–3.31 (m, 2H), 3.35 (s, 3H), 3.92–4.11 (m,
2H), 4.34 (brs, 1H), 5.74–5.75 ppm (m, 2H); 13C NMR (62.9 MHz,
CDCl3): d=18.9, 25.6, 26.8, 28.9, 30.6, 46.9, 49.8, 55.1, 89.9, 105.2, 125.1,
133.2, 155.2, 191.4 ppm; IR (neat): n˜ =2957.4, 2923.9, 1626.5, 1545.7,
1452.2, 1143.9, 1065.8, 1025.2, 789.7 cmÀ1; elemental analysis calcd (%)
for C16H25NO2S: C 65.05, H 8.53, N 4.74, S 10.85; found: C 64.88, H 8.25,
N 4.50, S 10.48.
Acknowledgements
Financial support from MEC (grant CTQ2006-10930/BQU) and CAM-
UCM (Grupos de Investigaciꢃn UCM, grant 920234) is gratefully ac-
knowledged.
Methyl 4-ethoxy-8-vinyl-2,3,4,6,9,10-hexahydropyridoACHTNUTRGNEUNG[1,2-a]azepine-1-car-
boxylate (11h): Colorless viscous liquid; yield: 0.249 g, 90%; 1H NMR
(250 MHz, CDCl3): d=1.22 (t, J=7 Hz, 3H), 1.42–1.54 (m, 1H), 1.88–
2.64 (m, 6H), 3.30–3.37 (m, 1H), 3.47–3.62 (m, 2H), 3.66 (s, 3H), 3.91–
4.16 (m, 2H), 4.44 (brs, 1H), 4.98–5.18 (m, 2H), 5.70–5.86 (m, 1H), 6.25–
6.35 ppm (m, 1H); 13C NMR (62.9 MHz, CDCl3): d=15.9, 18.2, 25.6,
26.2, 27.7, 49.2, 50.9, 62.8, 88.6, 95.2, 113.0, 127.1, 140.5, 141.1, 157.6,
169.6 ppm; IR (neat): n˜ =2932.4, 2853.5, 1681.2, 1574.1, 1432.6, 1274.0,
1154.5, 1111.6, 1067.7 cmÀ1; elemental analysis calcd (%) for C16H23NO3:
C 69.29, H 8.36, N 5.05; found: C 69.03, H 8.12, N 4.87.
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Ethyl 4-methoxy-8-vinyl-2,3,4,6,9,10-hexahydropyridoACHTNUTRGNEUNG[1,2-a]azepine-1-car-
boxylate (11i): Colorless viscous liquid; yield: 0.241 g, 90%; 1H NMR
(250 MHz, CDCl3): d=1.28 (t, J=7.1 Hz, 3H), 1.44–1.57 (m, 1H), 2.00–
2.57 (m, 6H), 3.35 (s, 3H), 3.38–3.54 (m, 1H), 4.09–4.19 (m, 4H), 4.34–
4.46 (m, 1H), 5.00–5.21 (m, 2H), 5.73–5.85 (m, 1H), 6.27–6.38 ppm (m,
1H); 13C NMR (62.9 MHz, CDCl3): d=15.0, 18.2, 25.7 (2 signals), 27.7,
49.7, 55.0, 59.4, 90.3, 95.8, 113.1, 127.2, 140.5, 141.1, 157.0, 169.2 ppm; IR
(neat): n˜ =2978.0, 2933.4, 1681.5, 1580.8, 1271.4, 1156.0, 1112.6, 1070.0,
769.9 cmÀ1; elemental analysis calcd (%) for C16H23NO3: C 69.29, H 8.36,
N 5.05; found: C 69.13, H 8.17, N 4.91.
General procedure for the cross-coupling reaction of compounds 11:
Preparation of pyridoazepines 13 and 14: BF3·Et2O (2 equiv) was added
to a solution of the suitable pyridoazepine derivative 11 (1 mmol) in dry
dichloromethane (10 mL), followed by allyltrimethylsilane for com-
pounds 13 (1 equiv) or propargyltrimethylsilane for compounds 14. The
reaction mixture was stirred at À58C for 10 min and then at room tem-
perature for 2–4 h. After verifying completion of the reaction by TLC,
the reaction mixture was washed with water, dried over Na2SO4, and con-
centrated to dryness. The crude residue was purified on neutral Al2O3
column, eluting with a 97:3 petroleum ether–ethyl acetate mixture con-
taining 0.25% Et3N.
Methyl
4-allyl-2,3,4,6,9,10-hexahydropyridoACHTGUNTRENNU[G 1,2-a]azepine-1-carboxylate
(13a): Colorless viscous liquid; yield: 0.235 g, 95%; 1H NMR (250 MHz,
CDCl3): d=1.54–1.72 (m, 1H), 1.81–1.90 (m, 1H); 2.10–2.56 (m, 7H),
3.16–3.27 (m, 1H), 3.52–3.74 (m, 2H), 3.66 (s, 3H), 4.14–4.27 (m, 1H),
5.01–5.15 (m, 2H), 5.66–5.79 (m, 3H). 13C NMR (62.9 MHz, CDCl3): d=
19.8, 24.9, 27.1, 29.4, 37.5, 50.7, 51.3, 61.6, 91.7, 118.5, 126.1, 133.5, 135.6,
160.0, 170.4; IR (neat): n˜ =2926.2, 1728.6, 1674.1, 1564.6, 1433.7, 1262.9,
1156.1, 1099.5 cmÀ1; elemental analysis calcd (%) for C15H21NO2: C
72.84, H 8.56, N 5.66; found: C 72.53, H 8.60, N 5.34.
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Chem. Eur. J. 2009, 15, 4565 – 4572
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J. C. Menꢀndez et al.
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ACHTUNGTRENNUNG[3,2b]pyridine derivatives, although only in an average of 47% yield,
see: R. Noꢆl, M.-C. Fargeau-Bellassoued, C. Vanucci-Bacquꢀ, G.
Lhommet, Synthesis 2008, 1948–1954. A two-component version of
this reaction can be found in reference [12].
[19] For a theoretical study that shows that 4,5-dihydropyridinium spe-
cies are stabilized by an electron-withdrawing group at C-3, see: E.
Pop, M. E. Brewster, M.-J. Huang, N. Bodor, J. Mol. Struct. 1995,
344–373, 49–55.
[20] See, for instance: J. P. Michael, C. Accone, C. B. de Koning, C. W.
van der Westhuyzen, Beilstein J. Org. Chem. 2008, 4, 5.
[11] For the precedent of the fast generation of enaminones from amines
and b-ketoesters under CAN catalysis, see: V. Sridharan, C. Aven-
daÇo, J. C. Menꢀndez, Synlett 2007, 881–884.
[12] For the precedent for the Michael additions of b-enaminones, see,
for instance: a) P. M. T. De Kok, L. A. M. Bastiaansen, P. M. Van Li-
er, J. A. J. M. Vekemans, H. M. Buck, J. Org. Chem. 1989, 54, 1313–
1320; b) E. Caballero, P. Puebla, M. Medarde, A. San Feliciano, Tet-
rahedron 1993, 49, 10079–10088.
[21] For a recent monograph on the synthesis and applications of allenes,
see: Modern Allene Chemistry (Eds.: N. Krause, A. S. K. Hashmi),
Wiley-VCH, 2004.
Received: January 7, 2009
Published online: March 13, 2009
4572
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