Pyridines and pyridine derivatives from vinyl allenes and imines

Article abstract of DOI:10.1016/j.tet.2012.09.057

The Lewis acid mediated reaction of acyclic vinyl allenes and imines, yielding tetrahydropyridines has been carried out. Only one cycloadduct was observed in each case, and thus, the reaction progressed in all cases with total regio-, face- and endo/exo s

Full text of DOI:10.1016/j.tet.2012.09.057

Tetrahedron 68 (2012) 9345e9349
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Pyridines and pyridine derivatives from vinyl allenes and imines
*
ꢀ
David Regas, María M. Afonso, J. Antonio Palenzuela
ꢀ
ꢀ
ꢀ
ꢀ
Instituto Universitario de Bio-Organica Antonio Gonzalez, Departamento de Química Organica, Universidad de La Laguna, Avda. Astrofísico Fco. Sanchez 2, 38206 La Laguna, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 August 2012
Received in revised form 4 September 2012
Accepted 11 September 2012
Available online 16 September 2012
The Lewis acid mediated reaction of acyclic vinyl allenes and imines, yielding tetrahydropyridines has
been carried out. Only one cycloadduct was observed in each case, and thus, the reaction progressed in
all cases with total regio-, face- and endo/exo selectivities. The cycloadducts were transformed into
polysubstituted pyridines, including bipyridines, by catalytic transfer hydrogenation using cyclohexene
as hydrogen donor in good yield. The reaction was extended to the aromatization of the bicyclic cy-
cloadducts prepared in previous works from the reaction of semicyclic vinyl allenes and imines, yielding
tetrahydropyridines.
Keywords:
Pyridines
Allenes
Ó 2012 Elsevier Ltd. All rights reserved.
DielseAlder
Dehydrogenation
Tetrahydroquinolines
1. Introduction
reactions, products coming from an ene reaction were also ob-
tained.8 The regio and facial selectivity of the process was complete.
Pyridine derivatives are important compounds due to their
properties. Thus, the pyridine moiety forms part of numerous
natural and synthetic biologically active compounds.1 Many of
them have found pharmaceutical uses, making the pyridine moiety
one of the most studied heterocyclic systems.2
When acyclic vinyl allenes were used with aldehydes as heter-
odienophiles,9 again a mixture of cycloadducts was obtained with
the endo adducts being the major compound isolated. With benz-
aldehyde as heterodienophile, rearranged products were also ob-
tained under forced reaction conditions.
The allene functional group has been used in many different
reactions, especially in the last years, in which the number of
processes involving allenes has grown extraordinarily.3 The pres-
ence of an sp carbon, together with the fact that allenes, due to the
presence of a chiral axis, can be prepared in enantiomerically pure
form by simple procedures, has made the use of allenes common in
many synthetic designs.4 Vinyl allenes have been used in different
reactions, most notably in DielseAlder cycloadditions,5 in which
the substituents on the non-conjugated double bond, which are
orthogonal to the plane of the diene, can exert selectivity on the
approach of the dienophile to the dienic part of the molecule.6
In previous works, we have found that vinyl allenes can act as
dienes in hetero DielseAlder reactions with both, aldehydes7 and
imines8 acting as heterodienophiles, in the presence of a Lewis acid.
The structural requirements for the reaction imply that the allene
must be at least tri-substituted with alkyl or aryl groups. It was
found that, when semicyclic vinyl allenes were used, aldehydes
gave a mixture of endo and exo cycloadducts, whereas with imines,
only the endo isomer was obtained in each case, although in some
We also tried the intramolecular version of the reaction, finding
that both, aldehydes10 and imines,11 reacted to give the expected
cycloadducts.
DFT calculations indicated that the cycloaddition reaction with
aldehydes is a concerted asynchronous process in both, the in-
termolecular7 and the intramolecular10 processes.
In a previous work of our group, about the intramolecular hetero
DielseAlder reaction of vinyl allenes and N-benzyl imines,11 we
tried to deprotect the benzyl group on the cycloadducts by catalytic
transfer hydrogenation, using cyclohexene as the hydrogen source
and 10% Pd on carbon as the catalyst, following literature reports.12
However, our attempts resulted in the unexpected aromatization of
the nitrogen-containing ring, resulting in the synthesis of an
octahydroacridine, a pyridine derivative.
As a continuation of that work, we decided to check whether
that was a general result, which would allow us to prepare a variety
of pyridine derivatives from the cycloadducts obtained in the het-
ero DielseAlder reaction of vinyl allenes and imines.
2. Results and discussion
The preparation of pyridine derivatives (tetrahydroquinolines)
could be achieved using the bicyclic cycloadducts prepared in our
* Corresponding author. Tel.: þ34 922318443; fax: þ34 922318571; e-mail ad-
dress: jpalenz@ull.es (J.A. Palenzuela).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.057

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D. Regas et al. / Tetrahedron 68 (2012) 9345e9349
9346
previous work.8 However, in order to obtain pyridines, we needed
monocyclic nitrogen-containing cycloadducts, the result of the re-
action of acyclic vinyl allenes and imines, a reaction, which have not
been carried out before.
To synthesize those monocyclic cycloadducts, vinyl allenes 1e3,
used in our previous study with aldehydes, were chosen. As het-
erodienophiles we decided to use the benzyl imines of benzalde-
hyde (4), isobutyraldehyde (5) and 2-pyridinecarboxaldehyde (6).
Two Lewis acids, BF3$OEt2 and AlCl3, were used under the same
experimental conditions employed in our previous studies, giving
the results shown in Table 1.
Once we had the monocyclic cycloadduct in hand, we decided to
check their transformation into pyridines following the same pro-
tocol used for the deprotection of the benzyl group in our work on
the intramolecular reaction, as indicated in the introduction.11
Thus, the tetrahydropyridines obtained as cycloadducts were
dissolved in EtOH and refluxed with cyclohexene and Pd/C (10%).
After 3e6 h, the corresponding pyridine derivatives were obtained
in moderate to good yields as shown in Table 2.
Table 2
Preparation of pyridines from the cycloadducts
As observed in Table 1, only one cycloadduct was obtained in
each reaction in moderated to good yield. No important difference
was observed between the two Lewis acids used. When the sub-
stituent at the inner position of the allene (R2) was a methyl group,
a small amount of the compound resulting from an ene reaction
was obtained together with the expected cycloadduct (entries 1, 5,
and 7, Fig. 1).
Table 1
Hetero DielseAlder reaction of acyclic vinyl allenes and imines
Entry
Cycloadduct
Pyridine (%)a
1
2
3
4
5
7
8
9
10
11
15 (71)
16 (62)
17 (52)
18 (46)
19 (45)
a
Isolated yield.
Entry
Vinyl allene
Imine
Lewis acid
t (h)
Compounds (%)a
7 (42)b
8 (79)
All new compounds were identified by complete spectroscopic
studies, including 2D NMR experiments.
1
2
3
4
5
6
7
1
2
2
2
3
3
3
4
4
4
6
4
5
5
AlCl3
BF3$OEt2
AlCl3
BF3$OEt2
BF3$OEt2
AlCl3
20
14
24
72
48
24
26
All cycloadducts, tetrahydropyridines coming from the reaction
of acyclic vinyl allenes and imines, reacted in moderate to good
yields giving the pyridines as the only isolated compounds.
Once the feasibility of the reaction was confirmed, we decided to
expand its scope by subjecting the bicyclic cycloadducts (20e27),
obtained in previous work from semicyclic vinyl allenes and im-
ines,8 to the same conditions (Table 3).
8 (79)
9 (89)
10 (59)b
11 (36)
11 (32)b
BF3$OEt2
a
Isolated yield.
b
Compounds coming from an ene reaction8 were also isolated (entry 1, 12,
23%),14 (entry 5, 13, 18%),14 and (entry 7, 14, 8%).14
Table 3
Preparation of tetrahydroquinolines from the bicyclic cycloadducts8
Fig. 1. Structure of the minor compounds, coming from ene-reactions, obtained in
entries 1, 5, and 7 of Table 1.
Similar results were obtained in our previous studies with
semicyclic vinyl allenes. In those studies, due to the difficulties
encountered to assign the relative stereochemistry of the centers
adjacent to the nitrogen in the cycloadducts, the stereochemistry
was assigned as cis by an X-ray diffraction analysis of one of the
compounds obtained.8 Based on the comparison of the relevant
signals on the NMR spectra, the relative stereochemistry of the new
cycloadducts was also assigned as cis.
Thus, with acyclic vinyl allenes and imines, the cycloaddition
proceeds with total face selectivity, through the less hindered face
of the vinyl allene. The regioselectivity and endo-selectivity were
also complete yielding only one cycloadduct in each case.
Entry
Cycloadduct
Pyridine (%)a
1
2
3
4
5
6
7
8
20
21
22
23
24
25
26
27
28 (69)
29 (73)
30 (76)
31 (83)
32 (63)
33 (41)
34 (66)
db
a
Isolated yield.
Non aromatic compounds were obtained.
b

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D. Regas et al. / Tetrahedron 68 (2012) 9345e9349
9347
As shown in Table 3, the results are similar to those found for the
monocyclic cycloadducts, yielding the corresponding tetrahy-
droquinolines. The only exception was the reaction of compound
27, which upon the catalytic transfer hydrogenation gave in good
yield only the debenzylated compound (35),14 together with a small
amount of a partially dehydrogenated product. This result can be
due to the difficulties to place the sterically demanding t-butyl
group on the molecular plane of a pyridine ring.
3.82 (d, J¼12.9 Hz, 1H), 3.66 (d, J¼12.9 Hz, 1H), 2.94 (br s, 1H), 2.19
(s, 3H), 2.00 (d, J¼7.3 Hz, 3H), 1.47e1.35 (m, 1H), 1.26e1.18 (m, 2H),
1.13e1.06 (m, 3H), 1.02e0.96 (m, 2H), 0.84 (t, J¼7.3 Hz, 3H),
0.78e0.75 (m, 1H), 0.68e0.65 (m, 1H); 13C NMR (75 MHz, CDCl3):
144.3 (s), 140.6 (s), 131.4 (s), 130.0 (s), 129.8 (d), 129.3 (d), 128.1 (d),
127.2 (d), 126.8 (d), 126.0 (d), 124.8 (d), 66.7 (d), 62.0 (t), 60.9 (d),
34.9 (t), 31.8 (t), 29.0 (t), 27.0 (t), 23.2 (q), 22.6 (t), 15.2 (q), 14.0 (q);
IR (nmax, cmꢁ1): 2900, 1590, 1485, 1440. MS (EI) m/z 373 (Mþ, 0.7),
n
This experiment also indicated that the mechanism of the
transformation is probably the expected debenzylation followed by
the thermal or palladium catalyzed isomerization of the exocyclic
double bond and aromatization of the resulting dihydropyridines.
This procedure allows for the preparation of substituted pyri-
dines and tetrahydroquinolines in an easy way starting from vinyl
allenes and imines. An interesting application is the synthesis of
2,20-bipyridines, compounds of great interest as quelating agents
among other uses.13 Using the procedure described in this work
(Table 2, entry 3), bipyridine 17 was obtained in two steps in a 46%
overall yield, starting from vinyl allene 2 and the imine of 2-
pyridinecarboxaldehyde (6).
289 (23), 288 (100), 182 (5), 91 (27); HRMS: calcd for C27H35N:
373.2769; found: 373.2764.
4.2.2. (2R*,3E,6S*)-1-Benzyl-6-(2-benzyloxyethyl)-4-ethyl-3-
ethylidene-2-phenyl-2,6-dihydropyridine
(8). Oil;
1H
NMR
(400 MHz, CDCl3): 7.49e7.11 (m, 15H), 5.44 (br s, 1H), 5.29 (q,
J¼7.3 Hz,1H), 4.41 (d, J¼12.0 Hz, 2H), 4.12 (s, 1H), 3.84 (d, J¼12.9 Hz,
1H), 3.73 (d, J¼12.9 Hz, 1H), 3.70e3.64 (m, 1H), 3.45 (m, 1H), 3.37
(m, 1H), 2.68e2.64 (m, 1H), 2.57e2.53 (m, 1H), 2.03 (d, J¼7.3 Hz,
3H), 1.29e1.26 (m, 1H), 1.23 (t, J¼7.4 Hz, 3H), 1.05e0.99 (m, 1H); 13C
NMR (100 MHz, CDCl3): 144.1 (s), 140.5 (s), 138.7 (s), 136.2 (s), 130.5
(s), 129.3 (d), 128.2 (d), 128.1 (d), 128.1 (d), 127.6 (d), 127.6 (d), 127.3
(d), 127.2 (d), 126.9 (d), 126.1 (d), 124.6 (d), 72.7 (t), 68.1 (t), 66.4 (d),
61.7 (t), 57.5 (d), 34.8 (t), 28.4 (t),15.2 (q), 13.3 (q); IR (nmax, cmꢁ1):
1485, 1440, 1350. MS (EI) m/z 437 (Mþ, 3.5), 408 (5), 346 (4.5), 303
(25), 302 (100); HRMS: calcd for C31H35NO: 437.2718, found:
437.2701.
3. Conclusion
In conclusion, we have carried out the Lewis acid-mediated
hetero DielseAlder reaction of acyclic vinyl allenes and imines.
The reactions proceed with total facial selectivity, regioselectivity
and endo/exo selectivity giving tetrahydropyridines. The
nitrogen-containing cycloadducts can be easily converted into
substituted pyridines by catalytic transfer hydrogenation using
cyclohexene and Pd/C. This reaction was also extended to the
bicyclic cycloadducts (octahydroquinolines) obtained in our
previous studies.
4.2.3. (2S*,3E,6S*)-1-Benzyl-6-(2-benzyloxyethyl)-4-ethyl-3-
ethylidene-2-(2-pyridyl)-2,6-dihydropyridine (9). Oil; 1H NMR
(400 MHz, CDCl3): 8.46e8.45 (m, 1H), 7.52e7.36 (m, 4H), 7.36e7.24
(m, 8H), 7.03e7.00 (m, 1H), 5.40 (s, 1H), 5.26 (q, J¼7.2 Hz, 1H), 4.42
(d, J¼11.9 Hz, 1H), 4.37 (d, J¼11.9 Hz, 1H), 4.23 (s, 1H), 3.81 (d,
J¼13.3 Hz,1H), 3.63 (d, J¼13.3 Hz,1H), 3.62e3.58 (m,1H), 3.51e3.46
(m, 1H), 3.31 (br s, 1H), 2.61e2.56 (m, 1H), 2.48e2.42 (m, 1H), 1.95
(d, J¼7.2 Hz, 3H), 1.39e1.32 (m, 1H), 1.10 (t, J¼7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): 163.4 (s), 148.3 (d), 140.1 (s), 138.6 (s), 138.4 (s),
135.1 (d), 132.1 (s), 129.2 (d), 128.4 (d), 128.2 (d), 127.6 (d), 127.4 (d),
126.8 (d), 126.4 (d), 123.6 (d), 123.1 (d), 121.2 (d), 72.7 (t), 69.6 (d),
68.0 (t), 61.2 (t), 56.9 (d), 35.4 (t), 28.1 (t), 15.1 (q), 13.0 (q); MS (EI)
m/z 438 (Mþ, 8), 360 (15), 347 (7), 303 (100), 91 (53); HRMS: calcd
for C30H34N2O: 438.2671, found: 438.2772.
4. Experimental section
4.1. General procedures
All the reagents were obtained from commercial sources and
used without further purification. Solvents used were purified and
dried as needed following standard procedures. The reactions were
monitored by thin-layer chromatography (TLC) on silica plated
aluminum sheets (Silica gel 60 F254, E. Merck). Flash chromatog-
raphy was performed on silica gel 60 (0.040e0.063 mm). 1H NMR
and 13C NMR spectra were recorded on Bruker spectrometers at
300e400 MHz and 75e100 MHz, respectively. Chemical shifts are
4.2.4. 2-[(2R*,5E,6S*)-1-Benzyl-5-ethylidene-4-methyl-6-phenyl-2,6-
dihydropyridine-2-yl]ethoxy-tert-butyl-diphenyl-silane (10). Oil; 1H
NMR (400 MHz, CDCl3): 7.68e7.63 (m, 4H), 7.47e7.08 (m, 16H),
5.40 (s, 1H), 5.27 (q, J¼7.3 Hz, 1H), 4.09 (s, 1H), 3.90e3.79 (m, 3H),
3.61 (m, 1H), 3.46 (br s, 1H), 2.23 (s, 3H), 2.04 (d, J¼7.3 Hz, 3H),
1.13e1.08 (m, 1H), 1.02 (s, 9H), 0.99e0.95 (m, 1H); 13C NMR
(100 MHz, CDCl3): 144.7 (s), 141.0 (s), 136.0 (d), 134.6 (s), 131.7 (s),
130.7 (s), 130.4 (d), 129.9 (d), 129.8 (d), 128.6 (d), 128.2 (d), 128.0
(d), 127.7 (d), 127.3 (d), 125.6 (d), 66.1 (d), 62.2 (t), 62.1 (t), 57.9
(d), 38.0 (t), 27.3 (q), 23.6 (q), 19.6 (s), 15.7 (q); IR (nmax, cmꢁ1):
1585, 1450: MS (EI) m/z 571 (Mþ, 8), 422 (6), 289 (27), 288 (100),
199 (24); HRMS: calcd for C39H45NOSi: 571.3270; found:
571.3264.
reported on
d scale in parts per million (ppm) with the solvent
indicated as the internal reference. The IR spectra were recorded on
a BRUKER IFS 66 spectrophotometer. High-resolution mass spectra
(HRMS) were recorded on a VG AutoSpec FISONS.
4.2. Typical procedure for the cycloaddition reaction between
acyclic vinyl allenes and imines
A solution of the imine (1.5 equiv) and BF3$Et2O (1.2 equiv) or
AlCl3 (1.2 equiv) in dry CH2Cl2 (0.1 M) at 0 ꢀC under argon, was
stirred for 15 min. Then the vinyl allene (1.0 equiv) was added. The
reaction was allowed to reach room temperature and was followed
by TLC. Once the vinyl allene was consumed, TEA (2.5 equiv) was
added and the reaction was poured over ice-water. The organic
phase was extracted with CH2Cl2, dried over anhydrous MgSO4, and
concentrated. The reaction products were purified by column
chromatography using mixtures of hexanes and EtOAc as eluent.
4.2.5. 2-[(2S*,5E,6R*)-1-Benzyl-5-ethylidene-6-isopropyl-4-methyl-
2,6-dihydropyridin-2-yl]ethoxy-tert-butyl-diphenyl-silane (11). Oil;
1H NMR (400 MHz, CDCl3): 7.71e7.68 (m, 4H), 7.46e7.22 (m, 11H),
5.45 (s, 1H), 5.04 (q, J¼7.2 Hz, 1H), 4.01 (m, 1H), 3.88 (m, 1H), 3.65
(AB system, J¼13.0 Hz, 2H), 3.35 (br s, 1H), 2.21 (d, J¼10.5 Hz, 1H),
2.06 (s, 3H), 1.89 (d, J¼7.2 Hz, 3H), 1.84e1.57 (m, 2H), 1.06 (s, 9H),
1.02e0.90 (m, 1H), 0.80 (d, J¼6.5 Hz, 3H), 0.60 (d, J¼6.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3): 141.2 (s), 136.1 (d), 134.5 (s), 134.1 (s), 130.8
(s), 129.9 (d), 129.8 (d), 129.1 (d), 128.3 (d), 128.0 (d), 127.0 (d), 122.2
(d), 72.0 (d), 62.4 (t), 57.6 (d), 40.4 (t), 29.4 (d), 27.3 (q), 3.1 (q), 21.7
(q), 20.7 (q), 19.6 (s), 15.3 (q); IR (nmax, cmꢁ1): 2900, 1585, 1450; MS
4.2.1. (2R*,3E,6S*)-1-Benzyl-3-ethylidene-6-hexyl-4-methyl-2-
phenyl-2,6-dihydropyridine (7). Oil; 1H NMR (400 MHz, CDCl3):
7.50e7.08 (m, 10H), 5.35 (s, 1H), 5.26 (c, J¼7.3 Hz, 1H), 4.10 (s, 1H),

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D. Regas et al. / Tetrahedron 68 (2012) 9345e9349
9348
(EI) m/z 537 (Mþ, 0.9), 494 (100), 254 (18), 199 (42), 91 (34); HRMS:
calcd for C36H47NOSi: 537.3427; found: 537.3484.
2H), 2.60 (q, J¼7.5 Hz, 2H), 1.30 (t, J¼7.5 Hz, 3H), 1.02 (t, J¼7.5 Hz,
3H); 13C NMR (100 MHz, CDCl3): 159.3 (s), 156.0 (s), 152.1 (s), 142.2
(s), 139.0 (s), 133.1 (s), 129.1 (d), 128.7 (d), 128.5 (d), 28.0 (d), 127.9
(d), 122.7 (d), 73.3 (t), 70.4 (t), 38.8 (t), 25.5 (t), 21.9 (t), 15.1 (q), 3.1
(q); IR (nmax, cmꢁ1): 2900,1585,1445, 1445; MS (EI) m/z 346 (Mþþ1,
93), 307 (25), 254 (15), 154 (100); HRMS: calcd for C24H27NO:
345.2092, found: 345.2146.
4.2.6. (ꢂ)-(E,2Z)-N-Benzyl-2-ethylidene-3-methylene-1-phenyl-un-
dec-4-en-1-amine (12). Oil; 1H NMR (400 MHz, CDCl3): 7.39e7.24
(m, 10H), 5.99 (d, J¼15.5 Hz, 1H), 5.79 (q, J¼6.7 Hz, 1H), 5.47 (dt,
J¼7.7, 15.5 Hz, 1H), 5.07 (s, 1H), 4.57 (s, 1H), 4.28 (s, 1H), 3.76 (AB
system, J¼13.4 Hz, 2H), 2.02e1.99 (m, 3H), 1.59 (d, J¼6.7 Hz, 3H),
1.36e1.29 (m, 8H), 0.95 (t, J¼6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3):
145.4 (s), 142.4 (s), 141.7 (s), 140.7 (s), 133.1 (d), 130.5 (d), 128.3 (d),
128.1 (d), 128.0 (d), 126.8 (d), 126.8 (d), 122.5 (d), 115.5 (t), 67.2 (d),
51.9 (t), 32.6 (t), 31.7 (t), 29.3 (t), 28.9 (t), 22.6 (t),14.5 (q),14.1 (q); IR
4.3.3. 6-(2-Benzyloxyethyl)-3,4-diethyl-2-(2-pyridyl)pyridine
(17). Oil; 1H NMR (400 MHz, CDCl3): 8.66 (br s, 1H), 7.80e7.76 (m,
1H), 7.57e7.55 (m, 1H), 7.32e7.25 (m, 6H), 7.13 (s, 1H), 4.53 (s, 2H),
3.87 (t, J¼6.7 Hz, 2H), 3.14 (t, J¼6.7 Hz, 2H), 2.77e2.69 (m, 4H), 1.27
(t, J¼7.5 Hz, 3H), 1.01 (t, J¼7.5 Hz, 3H), 13C NMR (75 MHz, CDCl3):
159.2 (s), 156.1 (s), 155.4 (s), 152.9 (s), 148.5 (d), 138.5 (s), 136.5 (d),
133.9 (s), 128.3 (d), 127.6 (d), 127.5 (d), 124.4 (d), 123.4 (d), 122.6 (d),
72.9 (t), 69.9 (t), 38.0 (t), 25.1 (t), 20.9 (t), 15.0 (q), 14.6 (q); MS (EI)
m/z 346 (Mþ, 82), 331 (56), 303 (59), 255 (49), 91 (100); HRMS:
calcd for C23H26N2O: 346.2045, found: 346.2053.
(
nmax, cmꢁ1): 2900, 1585, 1485, 1445.
4.2.7. (ꢂ)-(E,2Z)-N-Benzyl-7-[tert-butyl(diphenyl)silyl]oxy-2-
ethylidene-3-methylene-1-phenyl-hept-4-en-1-amine (13). Oil; 1H
NMR (400 MHz, CDCl3): 7.74e7.15 (m, 20H), 6.03 (d, J¼15.5 Hz, 1H),
5.81 (q, J¼6.7 Hz, 1H), 5.46 (dt, J¼7.8 Hz, J¼15.5 Hz, 1H), 5.10 (s, 1H),
4.61 (s, 1H), 4.27 (s, 1H), 3.75 (AB system, J¼13.2 Hz, 2H), 3.60 (t,
J¼6.8 Hz, 2H), 2.29 (q, J¼6.8 Hz, 2H),1,82 (br s,1H),1.59 (d, J¼6.7 Hz,
3H), 1.11 (s, 9H); 13C NMR (100 MHz, CDCl3): 145.7 (s), 142.7 (s),
142.0 (s), 141.1 (s), 136.0 (d), 134.5 (s), 132.9 (d), 130.0 (d), 129.2 (d),
128.7 (d), 128.5 (d), 128.4 (d), 128.1 (d), 127.3 (d), 127.2 (d), 123.1 (d),
116.7 (t), 67.5 (d), 64.0 (t), 52.2 (t), 36.4 (t), 27.3 (q), 19.7 (s), 14.9 (q);
IR (nmax, cmꢁ1): 2900, 1585, 1450. MS (EI) m/z 571 (Mþ, 68), 494
(34), 302 (21), 199 (71), 196 (77), 91 (100); HRMS: calcd for
C39H45NOSi: 571.3270, found: 571.3264.
4.3.4. tert-Butyl-[2-(5-ethyl-4-methyl-6-phenyl-2-pyridyl)ethoxy]-
diphenyl-silane (18). Oil; 1H NMR (400 MHz, CDCl3): 7.62e7.59 (m,
4H), 7.43e7.32 (m, 11H), 7.05 (s, 1H), 4.05 (t, J¼6.3 Hz, 2H), 3.04 (t,
J¼6.3 Hz, 2H), 2.60 (q, J¼7.5 Hz, 2H), 2.36 (s, 3H), 1.05 (t, J¼7.4 Hz,
3H),1.02 (s, 9H); 13C NMR (75 MHz, CDCl3): 158.6 (s),155.7 (s),145.7
(s), 141.7 (s), 135.6 (d), 133.9 (s), 133.3 (s), 129.5 (d), 128.8 (d), 128.0
(d), 127.5 (d), 127.4 (d), 125.1 (d), 63.8 (t), 41.0 (t), 26.8 (q), 22.1 (t),
19.2 (q), 19.2 (s), 14.3 (q); IR (nmax, cmꢁ1): 2900, 1590, 1450, 1460,
MS (EI) m/z 480 (Mþþ1, 97), 460 (18), 422 (43), 307 (100), 289 (36);
HRMS: calcd for C32H37NOSi: 479.2644, found: 479.2711.
4.2.8. (ꢂ)-(E,4Z)-N-Benzyl-9-[tert-butyl(diphenyl)silyl]oxy-4-
ethylidene-2-methyl-5-methylene-non-6-en-3-amine (14). Oil; 1H
NMR (400 MHz, CDCl3): 7.68e7.66 (m, 4H), 7.44e7.22 (m,11H), 6.09
(d, J¼15.6 Hz, 1H), 5.71 (dt, J¼7.8 Hz, J¼15.6 Hz, 1H), 5.60 (q,
J¼6.7 Hz, 1H), 5.16 (s, 1H), 4.75 (s, 1H), 3.80e3.58 (AB system,
J¼13.2 Hz, 2H), 3.69 (t, J¼6.5 Hz, 2H), 2.86 (d, J¼4.5 Hz, 1H), 2.34 (q,
J¼6.6 Hz, 2H),1.79 (m,1H), 1.62 (d, J¼6.7 Hz, 3H),1.60 (br s,1H), 1.05
(s, 9H), 0.93 (d, J¼6.7 Hz, 3H), 0.84 (d, J¼6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): 146.0 (s), 141.2 (s), 138.8 (s), 135.5 (d), 133.9 (s),
133.0 (d), 129.4 (d), 128.6 (d), 128.1 (d), 127.5 (d), 126.5 (d), 122.2
(d),115.5 (t), 68.6 (d), 63.4 (t), 51.5 (t), 35.9 (t), 29.7 (d), 26.7 (q), 21.0
(q), 19.1 (s), 16.7 (q), 14.5 (q); IR (nmax, cmꢁ1): 2900, 1715, 1585,
4.3.5. tert-Butyl-[2-(5-ethyl-6-isopropyl-4-methyl-2-pyridyl)eth-
oxy]-diphenyl-silane (19). Oil; 1H NMR (400 MHz, CDCl3): 7.62e7.60
(m, 4H), 7.42e7.33 (m, 6H), 6.79 (br s, 1H), 4.03 (t, J¼6.6 Hz, 2H),
3.28 (m, 1H), 2.97 (br s, 2H), 2.66 (q, J¼7.5 Hz, 2H), 2.26 (s, 3H),
1.29e1.23 (m, 6H), 1.13 (t, J¼7.5 Hz, 3H), 1.02 (s, 9H); 13C NMR
(100 MHz, CDCl3): 163.9 (s), 158.8 (s), 144.8 (s), 136.0 (d), 134.5 (s),
132.0 (s), 129.8 (d), 127.9 (d), 123.5 (s), 64.4 (t), 41.6 (t), 31.0 (d), 27.2
(q), 23.1 (q), 21.3 (t), 19.6 (s), 15.0 (q); IR (nmax, cmꢁ1): 2900, 1590,
1450, 1460. MS (EI) m/z 446 (Mþþ1, 100), 388 (74), 368 (40); HRMS:
calcd for C29H39NOSi: 445.2801, found 445.2706.
t
1450; MS (EI) m/z 537 (Mþ, 41), 495 (64), 494 (87), 480 (Mþꢁ Bu,
12), 199 (100); HRMS: calcd for C36H47NOSi: 537.3427, found:
537.3456.
4.3.6. 3,4-Diethyl-2-phenyl-5,6,7,8-tetrahydroquinoline (28). Oil; 1H
NMR (300 MHz, CDCl3): 7.43e7.31 (m, 5H), 2.93 (br s, 2H), 2.79 (br
s, 2H), 2.70 (q, J¼7.5 Hz, 2H), 2.58 (q, J¼7.5 Hz, 2H), 1.88 (m, 4H), 1.18
(t, J¼7.5 Hz, 3H), 1.00 (t, J¼7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3):
156.7 (s), 153.8 (s), 149.7 (s), 142.1 (s), 132.1 (s), 129.1 (s), 128.7 (d),
128.0 (d), 127.2 (d), 33.2 (t), 25.7 (t), 23.1 (t), 22.9 (t), 21.8 (t), 21.4 (t),
15.6 (q), 13.8 (q); IR (nmax, cmꢁ1): 2900, 1700, 1550, 1440, 1400. MS
(FAB) m/z 266 (Mþþ1, 100), 154 (11); HRMS: calcd for C19H23N:
265.1830, found: 265.1907.
4.3. Typical procedure for the dehydrogenation reaction
To a solution of the cycloadduct in methanol (0.045 M) and
cyclohexene (0.25 M), was added 10% Pd/C (50% in weight). The
mixture was refluxed for 3e6 h. After cooling, the reaction was
filtered, washed with methanol and concentrated. The crude mix-
ture was purified by column chromatography using mixtures of
hexanes and EtOAc as eluent.
4.3.7. 3,4-Diethyl-2-isopropyl-5,6,7,8-tetrahydroquinoline (29). Oil;
1H NMR (400 MHz, CDCl3): 3.25 (m, 1H), 2.88 (br s, 2H), 2.71e2.57
(m, 6H), 1.82 (br s, 4H), 1.27 (d, J¼6.7 Hz, 6H), 1.16 (t, J¼7.5 Hz, 3H),
1.13 (t, J¼7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): 161.8 (s), 154.2 (s),
149.1 (s), 131.1 (s), 128.9 (s), 33.6 (t), 30.9 (d), 26.0 (t), 23.7 (t), 23.4
(t), 23.2 (q), 21.9 (t), 21.2 (t), 16.2 (q), 14.2 (q); IR (nmax, cmꢁ1): 2900,
1555, 1450, 1400; MS (FAB) m/z 232 (Mþþ1, 72), 231 (12), 154 (100),
136 (55); HRMS: calcd for C16H25N: 231.1987, found: 231.2079.
4.3.1. 3-Ethyl-6-hexyl-4-methyl-2-phenyl-pyridine (15). Oil; 1H
NMR (300 MHz, CDCl3): 7.42e7.26 (m, 5H), 6.95 (s, 1H), 2.75 (t,
J¼7.8 Hz, 2H), 2.57 (q, J¼7.5 Hz, 2H), 2.37 (s, 3H), 1.77e1.67 (m, 2H),
1.41e1.32 (m, 6H), 1.03 (t, J¼7.5 Hz, 3H), 0.91e0.87 (t, J¼6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3): 158.8 (s), 158.5 (s), 145.9 (s), 141.8 (s),
132.8 (s), 128.7 (d), 128.0 (d), 127.3 (d), 123.3 (d), 38.1 (t), 31.8 (t),
30.2 (t), 29.2 (t), 22.6 (t), 22.1 (t), 19.2 (q), 14.3 (q), 14.1 (q); IR (nmax
,
cmꢁ1): 2900, 1585, 1540, 1450; MS (EI) m/z 282 (Mþþ1, 100), 211
4.3.8. 3-Ethyl-4-methyl-2-phenyl-5,6,7,8-tetrahydroquinoline
(30). Oil; 1H NMR (400 MHz, CDCl3): 7.40e7.37 (m, 5H), 2.93 (br s,
2H), 2.69 (br s, 2H), 2.57 (q, J¼7.5 Hz, 2H), 2.23 (s, 3H), 1.88e1.85 (m,
4H), 1.03 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): 156.5 (s),
153.8 (s), 144.8 (s), 142.5 (s), 133.1 (s), 130.3 (s), 129.1 (d), 128.4 (d),
127.7 (d), 36.6 (t), 27.1 (t), 23.5 (t), 23.3 (t), 23.0 (t), 15.1 (q), 15.0 (q);
(4), 154 (16); HRMS: calcd for C20H27N: 281.2143, found: 281.2049.
4.3.2. 6-(2-Benzyloxyethyl)-3,4-diethyl-2-phenyl-pyridine (16). Oil;
1H NMR (400 MHz, CDCl3): 7.42e7.26 (m, 10H), 7.08 (s, 1H), 4.55 (s,
2H), 3.89 (t, J¼6.7 Hz, 2H), 3.12 (t, J¼6.7 Hz, 2H), 2.71 (q, J¼7.5 Hz,

ꢀ
D. Regas et al. / Tetrahedron 68 (2012) 9345e9349
9349
IR (nmax, cmꢁ1): 2900, 2500, 1560, 1440, 1410; MS (FAB) m/z 252
(Mþþ1, 100), 154 (6); HRMS: calcd for C18H21N: 251.1674, found:
251.1660.
(30), 267 (51), 236 (88), HRMS: calcd for C21H27N: 293.2143, found:
293.2113.
Supplementary data
4.3.9. 3-Ethyl-2-isopropyl-4-methyl-5,6,7,8-tetrahydroquinoline
(31). Oil; 1H NMR (300 MHz, CDCl3): 3.26 (m, 1H), 2.88 (br s, 2H),
2.72e2.61 (m, 4H), 2.16 (s, 3H), 1.85e1.80 (m, 4H), 1.28 (d, J¼6.7 Hz,
6H), 1.13 (t, J¼7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): 160.6 (s), 153.3
(s), 131.3 (s),127.9 (s), 33.1 (t), 30.6 (d), 26.6 (t), 23.2 (t), 22.9 (t), 22.7
(q), 21.3 (t), 14.7 (q), 14.3 (q); IR (nmax, cmꢁ1): 2900, 1550, 1440,
1400. MS (FAB) m/z 218 (Mþþ1, 100), 217 (Mþ, 22), 154 (49), 137
(37); HRMS: calcd for C15H23N: 217.1830, found: 217.1928.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.09.057.
References and notes
1. (a) Jones, G. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., McKillop, A., Eds.; Pergamon: Oxford, 1996; Vol. 5,
pp 167e243; (b) Henry, G. D. Tetrahedron 2004, 60, 6043; (c) Joule, J. A.;
Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell Science: Cambridge, 2000;
pp 63e120; (d) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627; (e) Hill, M. D.
Chem.dEur. J. 2010, 16, 12052; (f) Bagley, M. C.; Dale, J. W.; Merritt, E. A.;
Xiong, X. Chem. Rev. 2005, 105, 685.
2. (a) Jayasinghe, L.; Jayasooriya, C. P.; Hara, N.; Fujimoto, Y. Tetrahedron Lett. 2003,
44, 8769; (b) Nishi, T.; Kubota, T.; Fukushi, E.; Kawabata, J.; Fromont, J.; Ko-
bayashi, J. Tetrahedron Lett. 2007, 48, 4983; (c) Swainston Harrison, T.; Scott, L. J.
Drugs 2005, 65, 2309.
4.3.10. 3-Benzyl-4-methyl-2-phenyl-5,6,7,8-tetrahydroquinoline
(32). White solid; mp: 150e152 ꢀC; 1H NMR (400 MHz, CDCl3):
7.38e6.99 (m, 10H), 4.0 (s, 2H), 3.01 (br s, 2H), 2.70 (br s, 2H), 2.06
(s, 3H), 1.91e1.89 (br s, 4H); 13C NMR (100 MHz, CDCl3): 156.8 (s),
154.6 (s), 145.9 (s), 141.5 (s), 140.6 (s), 130.0 (s), 128.7 (d), 128.4 (d),
128.0 (d),127.9 (d),127.4 (d),125.7 (d), 35.6 (t), 33.3 (t), 26.6 (t), 23.0
(t), 22.8 (t), 15.3 (q).
3. (a) Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH:
ꢀ
Weinheim, Germany, 2004; (b) Ma, S. Chem. Rev. 2005, 105, 2829; (c) Lopez, F.;
~
Mascarenas, J. L. Chem.dEur. J. 2011, 17, 418; (d) Pinho e Melo, T. M. V. D.
Monatsh. Chem. 2011, 142, 681.
4. (a) Krause, N.; Hoffmann-Roder, A. Tetrahedron 2004, 60, 11671; (b) Brum-
4.3.11. 3-Benzyl-2-isopropyl-4-methyl-5,6,7,8-tetrahydroquinoline
(33). Oil; 1H NMR (400 MHz, CDCl3): 7.28e7.18 (m, 3H), 7.04e7.02
(m, 2H), 4.10 (s, 2H), 3.19 (m,1H), 2.94 (br s, 2H), 2.64 (br s, 2H), 2.06
(s, 3H), 1.86 (br s, 4H), 1.21 (d, J¼6.7 Hz, 6H), 13C NMR (100 MHz,
CDCl3): 162.0 (s), 154.7 (s), 145.3 (s), 140.5 (s), 128.8 (d), 128.6 (s),
128.3 (d), 127.7 (s), 126.3 (d), 34.1 (t), 33.7 (t), 31.6 (d), 27.0 (t), 26.3
(t), 23.3 (t), 22.8 (q), 15.5 (q).
€
mond, K. M.; DeForrest, J. E. Synthesis 2007, 795; (c) Yu, S.; Ma, S. Chem.
Commun. 2011, 5384; (d) Alcaide, B.; Almendros, P.; Campo, T. M. D. Chem.
dEur. J. 2010, 16, 5836; (e) Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria, M.;
Simonneau, A. Chem. Rev. 2011, 111, 1954; (f) Krause, N.; Aksin-Artok, O.;
Asikainen, M.; Breker, V.; Deutsch, C.; Erdsack, J.; Fan, H.-T.; Gockel, B.; Min-
kler, S.; Poonoth, M.; Sawama, Y.; Sawama, Y.; Sun, T.; Volz, F.; Winter, C. J.
Organomet. Chem. 2012, 704, 1.
5. (a) Bertrand, M.; Grimaldi, J.; Waegell, B. Bull. Soc. Chim. Fr. 1971, 962; (b) Koop,
U.; Handke, G.; Krause, N. Liebigs Ann. Chem. 1996, 1478; (c) Katoh, T.; Noguchi,
C.; Kimura, H.; Fujiwara, T.; Ichihashi, S.; Nishide, K.; Kajimoto, T.; Node, M.
Tetrahedron: Asymmetry 2006, 17, 2943; (d) Choi, S.; Hwang, H.; Lee, P. H. Eur. J.
Org. Chem. 2011, 1351; (e) Cao, J.; Yang, X.; Hua, X.; Deng, Y.; Lai, G. Org. Lett.
2011, 3, 478.
4.3.12. 3-Isopropyl-4-methyl-2-phenyl-5,6,7,8-tetrahydroquinoline
(34). White solid; mp: 90e93 ꢀC; 1H NMR (300 MHz, CDCl3):
7.43e7.31 (m, 5H), 3.26 (m, 1H); 2.96 (br s, 2H), 2.68 (br s, 2H), 2.34
(s, 3H), 1.87 (br s, 4H), 1.26 (d, J¼7.3 Hz, 6H); 13C NMR (75 MHz,
CDCl3): 156.4 (s), 153.1 (s), 145.0 (s), 143.0 (s), 136.1 (s), 130.8 (s),
128.6 (d), 128.2 (d), 127.1 (d), 33.1 (t), 29.8 (d), 26.5 (t), 23.1 (t), 22.8
(t), 21.6 (q), 16.3 (q); IR (nmax, cmꢁ1): 2950, 1550, 1435; MS (EI) m/z
265 (Mþ, 46), 264 (100), 250 (24), 235 (8); HRMS: calcd for
C19H23N: 265.1830, found: 265.1769.
6. Reich, H. ,J.; Eisenhart, E. K.; Whipple, W. L.; Kelly, M. J. J. Am. Chem. Soc. 1988,
110, 6432.
ꢀ
7. Regas, D.; Ruiz, J. M.; Afonso, M. M.; Palenzuela, J. A. J. Org. Chem. 2006, 71, 9153.
ꢀ
8. Regas, D.; Afonso, M. M.; Rodríguez, M. L.; Palenzuela, J. A. J. Org. Chem. 2003,
68, 7845.
ꢀ
9. Ruiz, J. M.; Regas, D.; Afonso, M. M.; Palenzuela, J. A. J. Org. Chem. 2008,
73, 7246.
ꢀ
10. Regas, D.; Ruiz, J. M.; Afonso, M. M.; Galindo, A.; Palenzuela, J. A. Tetrahedron
Lett. 2003, 44, 8471.
11. Regas, D.; Afonso, M. M.; Palenzuela, J. A. Synthesis 2004, 5, 757.
12. Midland, M. M.; Afonso, M. M. J. Am. Chem. Soc. 1989, 111, 4368.
13. (a) Hapke, M.; Brandt, L.; Lutzen, A. Chem. Soc. Rev. 2008, 37, 2782; (b) Bobrov,
D. N.; Tyvorskii, V. I. Tetrahedron 2010, 66, 5432.
14. See Experimental section for analytical data and Supplementary data for copies
of spectra.
4.3.13. (2S*,8aR*,E)-4-tert-Butyl-3-ethylidene-2-phenyl-
1,2,3,5,6,7,8,8a-octahydroquinoline (35). Oil; 1H NMR (300 MHz,
CDCl3): 7.90e7.88 (m, 2H), 7.41e7.30 (m, 3H), 5.46 (br s, 1H),
2.96e2.86 (m, 1H), 2.32 (m, 2H), 2.03e1.48 (m, 6H), 1.80 (d,
J¼7.0 Hz, 3H), 1.36 (s, 9H); MS (EI) m/z 293 (Mþ, 60), 292 (100), 278
ꢀ
€