Synthesis of 1,2-dihydropyridines using vinyloxiranes as masked dienolates in imino-aldol reactions

Article abstract of DOI:10.1021/ol061086p

The application of vinyloxiranes, substituted with an electron-withdrawing group, as masked dienolates in vinylogous imino-aldol reactions was achieved. Under the reaction conditions highly substituted 1,2-dihydropyridines were obtained in moderate to good yields. Mechanistic studies indicate that the reaction proceeds via the formation of an (E)-amino-α,β-unsaturated aldehyde, followed by isomerization to the (Z)-isomer, cyclization, and elimination of a water molecule, leading to the formation of the 1,2-dihydropyridine.

Full text of DOI:10.1021/ol061086p

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3473-3476
Synthesis of 1,2-Dihydropyridines Using
Vinyloxiranes as Masked Dienolates in
Imino-Aldol Reactions
Bernhard Brunner, Nicole Stogaitis, and Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
Toronto, Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
Received May 3, 2006
ABSTRACT
The application of vinyloxiranes, substituted with an electron-withdrawing group, as masked dienolates in vinylogous imino-aldol reactions
was achieved. Under the reaction conditions highly substituted 1,2-dihydropyridines were obtained in moderate to good yields. Mechanistic
studies indicate that the reaction proceeds via the formation of an (E)-amino-r,â-unsaturated aldehyde, followed by isomerization to the
(Z)-isomer, cyclization, and elimination of a water molecule, leading to the formation of the 1,2-dihydropyridine.
Vinyloxiranes are valuable building blocks for a variety of
synthetic transformations and have found wide applications
Scheme 1. Vinylogous Imino-Aldol Reactions with
in organic synthesis.1 In particular, transition metal and Lewis
acid catalyzed ring opening of the epoxides, with subsequent
rearrangement, gives access to useful products for the
synthesis of biologically active compounds.2,3 Recently, our
group reported the amphoteric character of 2-vinyloxiranes
in the presence of a Lewis acid.4a The 2-vinyloxiranes are
either used as synthetic equivalents for â,γ-unsaturated
aldehydes (electrophiles) or dienols (nucleophiles). Thus, the
reaction of 2-vinyloxiranes with aldehydes4a and subsequently
with aldimines4b,4c (Scheme 1) was demonstrated, and the
preparation of silyl-dienolates was avoided.5 We now apply
this methodology to a new synthesis of 1,2-dihydropyridines,
which are not easily accessible by other methods. Usually,
Substituted 2-Vinyloxiranes and Their Proposed Transformation
to 1,2-Dihydropyridines 4
1,2-dihydropyridines are synthesized through a nucleophilic
addition onto N-acyl- or N-alkylpyridinium salts.6 However,
(4) (a) Lautens, M.; Quellet, S. G.; Raeppel, S. Angew. Chem., Int. Ed.
2000, 39, 4079-4082. (b) Lautens, M.; Tayama, E.; Nguyen, D. Org. Lett.
2004, 6, 345-347. (c) Lautens, M.; Tayama, E.; Nguyen, D. Tetrahedron
Lett. 2004, 45, 5131-5133.
(5) For a review of vinylogous aldol reactions, see: (a) Denmark, S. E.;
Heemstra, J. R., Jr.; Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682-
4698. For a review on vinylogous Mannich reactions, see: (b) Bur, S. K.;
Martin, S. F. Tetrahedron 2001, 57, 3221-3242.
(6) For reviews of dihydropyridines, see: (a). Lavilla, R. J. Chem. Soc.,
Perkin Trans. 1 2002, 1141-1156. (b) Stout, D. M.; Meyers, A. I. Chem.
ReV. 1982, 82, 223-243. For representative procedures for the preparation
of 1,2-dihydropyridines, see: (c) Charette, A. B.; Grenon, M.; Lemire, A.;
Pourashraf, M.; Martel, J. J. Am. Chem. Soc. 2001, 123, 11829-11830.
(d) Comins, D. L.; Hong, H.; Salvador, J. M. J. Org. Chem. 1991, 56, 7197-
7199.
(1) For a review, see: (a) Marshall, J. A. Chem. ReV. 1989, 89, 1503-
1511. For recent examples, see: (b) Trost, B. M.; Brown, B. S.; McEachern,
E. J. Chem. Eur. J. 2003, 9, 4442-4451. (b) Restorp, P.; Somafai, P. Chem.
Commun. 2004, 2086-2087, (c) Pineschi, M.; Bertolini, F.; Haak, R. M.;
Crotti, P.; Macchia, F. Chem. Commun. 2005, 1426-1428.
(2) For recent examples with transition metals, see: (a) Marion, F.;
Calvet, S.; Marie, J.-C.; Courillon, C.; Malacria, M. Eur. J. Org. Chem.
2006, 453-462. (b) Courillon, C.; Fol, R. F.; Vandendris, E.; Malacria, M.
Tetrahedron Lett. 1997, 38, 5493-5496
(3) For recent examples with Lewis acids, see: (a) Deng, X.-M.; Sun,
X.-L.; Tang, Y. J. Org. Chem. 2005, 70, 6537-6540. (b) Jung, M. E.;
Anderson, K. L. Tetrahedron Lett. 1997, 38, 2605-2608. (c) Wipf, P.; Xu,
W. J. Org. Chem. 1993, 58, 825-826.
10.1021/ol061086p CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/12/2006

Table 1. Scope of the Reaction Using Vinylepoxide 1a and
Benzhydryl-Protected Aldimines 2a-g
entrya
R1
R2
2; 4
conv 2 [%]b
yield 4 [%]c
1
2
3
4
5
6
7
F
H
a
b
c
d
e
f
70
70
75
65
75
70
47d
61
60
62
37
43
53
19
Cl
H
Br
H
H
H
NO2
Cl
H
Cl
H
Bpin
g
a All reactions were performed by using 0.75 mmol of 1 and 0.5 mmol
of 2 in 1.0 mL of dry THF. b Determined via 1H NMR spectroscopy from
the crude product. c Isolated yields. d 15% of the aldimine is hydrolyzed
into the corresponding aldehyde.
Figure 1. Crystal structure of 1,2-dihydropyridine 4a.
equiv of water during the reaction. Other Lewis acids such
as BF3‚OEt2 were far less effective.14 In general the conver-
sions of the aldimines were high (>70%)15 using para-
halogen-substituted aldimines 2a-c, and so 1,2-dihydropy-
ridines 4a-c were obtained in good yields.
Nitro- and boronic ester substituted aldimines 2e and 2g
were also reactive and stable under the reaction conditions.
The decreased conversion of aldimine 2g is probably due to
the bulky ortho-substituent. We next turned our attention to
the reaction of vinyloxiranes with aryl-protected aldimines
(Table 2). The aryl-protected aldimines showed higher
unsymmetrically substituted pyridinium salts often result in
inseparable mixtures because the nucleophile attacks at the
2, 4, or 6 position.6,7 Herein, we report a novel method that
overcomes these selectivity problems and allows the syn-
thesis of 2-, 3-, and 5-substituted 1,2-dihydropyridines
(Scheme 1).
We focused our studies on the investigation of 2-vinyl-
oxirane 1 bearing an electron-withdrawing group on the vinyl
moiety (e.g., R1 ) EtO2C-, Scheme 1), on the basis of the
following considerations: the vinyloxiranes are (1) easily
accessible8 and (2) relatively stable during purification and
storage, and most importantly (3) cyclization of 3 to the
corresponding 1,2-dihydropyridine 4 was possible. We
assumed that the presence of an electron-withdrawing group
R1 would facilitate the E/Z-isomerization that is required for
the cyclization. We initiated our investigations with the
reaction of vinylepoxide 1a with a benzhydryl-protected
aldimine 2a in the presence of a catalytic amount of Sc-
(OTf)3.9 Under the optimized reaction conditions (15 mol
% Sc(OTf)3, 1.5 equiv of vinylepoxide 1a, 1.0 equiv of
aldimine 2a, 0-50 °C in THF),10 the desired 1,2-dihydro-
pyridine 4a was obtained in 61% isolated yield as a stable
crystalline compound.11 The structure was confirmed by
X-ray analysis (Figure 1).12 The crystal structure shows that
the p-fluorophenyl group is almost orthogonal to the dihy-
dropyridine ring.13 It is important to note that a water-stable
Lewis acid must be employed because of the release of 1
Table 2. Scope of the Reaction Using Vinylepoxide 1a and
Aryl-Protected Aldimines 2h-j
entrya
R1
R2
2; 4
conv 2 (%)b
yield 4 (%)c
1
2
3
I
Br
Br
H
H
OCH3
h
i
j
100d
100d
88e
51
37
41
a All reactions were performed by using 0.75 mmol of 1 and 0.5 mmol
of 2 in 1.0 mL of dry THF. b Determined via 1H NMR spectroscopy from
the crude product. c Isolated yields. d 20-30% of the aldimine is hydrolyzed
into the corresponding aldehyde. e 10% of the aldimine is hydrolyzed into
the aldehyde
(7) Bennasar, M. L.; Roca, R.; Monerris, M.; Juan, C.; Bosch, J.
Tetrahedron 2002, 58, 8099-8106.
reactivity but less stability in the presence of the Lewis acid,
resulting in partial hydrolysis of the aldimine to give the
corresponding amine and aldehyde moiety. Fortunately,
ortho-substituted aldimines (R1 ) I, Br) are sufficiently stable
(8) For the preperation of the vinyloxiranes 1a and 1b, see Supporting
Information.
(9) Other N-alkyl aldimines (e.g., N-phenyl, N-allyl) showed no or poor
reactivity, and no or just minor product formation was observed.
(10) For a solvent screening, see Supporting Information.
(11) It is highly recommended to perform the reactions at a scale of at
least 0.5 mmol; otherwise reduced yields are obtained as a result of
decomposition of the product on silica gel.
(12) Product 4f gave also crystals suitable for X-ray analysis. See
Supporting Information.
(13) For a previously reported crystal structure, see: Krow, G. R.;
Raghavachari, R. J. Org. Chem. 1986, 51, 1916-1918.
(14) Results with BF3‚OEt2 as a Lewis acid in the reaction of 1a with
2a to 4a: 30 mol % BF3, messy reaction; 1.5 equiv of BF3, 18% isolated
yield of 4a.
(15) We assume that the nonquantitative conversions are due to the
coordination of the product 4 to Sc(OTf)3, which results in an inhibition of
the catalytic cycle and therefore product inhibition.
3474
Org. Lett., Vol. 8, No. 16, 2006

in the presence of strong Lewis acids to afford dihydropy-
ridines 4h-4j in moderate yields (37-51%).
During our studies on the reactions of vinylepoxide 1a
with benzhydryl- and aryl-protected aldimines, we observed
that aryl-protected aldimines are more reactive than the
benzhydryl-protected aldimines in the vinylogous imino-aldol
reaction (Table 3) as a result of their increased electrophilic
was also perfomed. We found, that the phenyl-substituted
vinyloxirane 1b is still reactive in the vinylogous imino-
aldol reaction, giving 1,2-dihydropyridine 4m in 46% isolated
yield.
When we used aldimines 2i/n substituted with electron-
withdrawing groups (2i R ) Br, 2n R ) CF3) and performed
the reaction at 0 °C, the corresponding (E)-amino-R,â-
unsaturated aldehydes 3i and 3n were obtained in moderate
to good isolated yields (Table 3).16,17 This discovery con-
firmed our assumption that an (E)-amino-R,â-unsaturated
aldehyde is a likely reaction intermediate (Scheme 1).
When a mixed solvent (toluene/THF 1:1) was used,
satisfactory yields were achieved with 74% and 81% for the
formation of the addition-only products, 3i and 3n (Table 3,
entries 2 and 3).18 When â-aminoester 3i was subjected to
the reaction conditions without Sc(OTf)3, no desired product
4i was observed. Only after the addition of 15 mol % Sc-
(OTf)3 to the reaction mixture at 50 °C was the corresponding
1,2-dihydropyridine 4i formed. The crude 1H NMR spectrum
showed a complete conversion of the (E)-amino-R,â-unsatur-
ated aldehyde 3i to the dihydropyridine 4i. However, after
column chromatography the 1,2-dihydropyridine was isolated
in poor yield (28%), which again demonstrates the low
stability of this type of 1,2-dihydropyridines.11
Table 3. Synthesis of â-Aminoesters 3 through a Direct
Vinylogous Imino-Aldol Reaction Using Vinyloxirane 1a as
Masked Dienolate
entry
R
conditiona
2; 3
yield (%)b
1
2
3
Br
A
B
B
i
i
n
48c
74
81
Br
CF3
a Condition A: reaction was performed by using 0.75 mmol of 1a and
0.5 mmol of 2 in 1.0 mL dry THF. Condition B: reactions were performed
by using 0.75 mmol of 1a and 0.5 mmol of 2 in a solvent mixutre of 1.0
mL of THF and 1.0 mL of toluene. b Isolated yields. c 35% of the aldimine
is hydrolyzed into the corresponding aldehyde and amine.
Based on the experimental data, we propose the mecha-
nism described in Scheme 3 for the formation of the 1,2-
character. However, the cyclization to the 1,2-dihydropyri-
dine occurs faster using the benzhydryl-protected aldimine
as a result of the higher nucleophilicity of the nitrogen.
Therefore, we decided to explore R-iminoester 2k (Scheme
2 (I)), which should combine the two advantages. A clean
Scheme 3. Proposed Catalytic Cycle for the Formation of
1,2-Dihydropyridines
Scheme 2. Variation of the Substituents on the Aldimine
Building Block (I, II) and the Vinyloxirane Building Block (III)
dihydropyridines. Following a coordination of Sc(OTf)3 to
(16) The E-configuration of the double bond was confirmed by ROESY
NMR spectroscopy.
(17) The diastereomeric ratios of the products are 1.3:1 for 3n and 1.9:1
for 3i.
(18) (a) This is not just an effect of the lower concentration of the reaction
mixture (0.25 M). When the reaction was performed solely in THF (0.25
M) or toluene (0.25 M), messy reactions were observed in both cases. (b)
Application of this solvent system for the synthesis of the 1,2-dihydropy-
ridines in Tables 1 and 2 gave no improvement in the yields.
reaction was observed, and the desired 1,2-dihydropyridine
4k was obtained in 63% yield after column chromatography.
The heteroaryl-aldimine 2l was also stable and reactive under
the standard reaction conditions, and the corresponding 1,2-
dihydropyridine was isolated in 37% yield. The variation of
substituent R2 (R2 ) Ph, Scheme 2 (III)) at the vinyloxirane
Org. Lett., Vol. 8, No. 16, 2006
3475

the vinyloxirane 1 to give complex A, intermediate B is
generated by ring opening of the epoxide followed by a 1,2-
hydride shift and a subsequent enolization.4 Intermediate B
reacts with aldimine 2 in a vinylogous imino-aldol reaction
to give the (E)-amino-R,â-unsaturated aldehyde C. The (E)-
isomer C isomerizes under the influence of Sc(OTf)3 to the
(Z)-isomer E. The E/Z-isomerization probably occurs via the
dienolate intermediate D, whose formation is accelerated by
the ester group. The (Z)-amino-R,â-unsaturated aldehyde E
can cyclize to the hemiaminal F, and in the last step the
elimination of water occurs to give the corresponding 1,2-
dihydropyridine 4.
access to 1,2-dihydropyridines that are selectively substituted
at the 1, 2, 3, and 5 position.
Acknowledgment. We gratefully acknowledge the fi-
nancial support of the Natural Sciences and Engineering
Research Council (NSERC) of Canada, the Merck Frosst
Centre for Therapeutic Research for an Industrial Research
Chair, and the University of Toronto. B.B. would like to
thank the Degussa-Foundation (Germany) for a postdoctoral
fellowship. We also thank Dr. Alan J. Lough (University of
Toronto, Department of Chemistry) for acquisition of X-ray
crystallographic data.
Supporting Information Available: Experimental pro-
cedures and characterization of all new compounds, including
CIF files. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, we have developed a new one-pot procedure
for the synthesis of substituted 1,2-dihydropyridines by a Sc-
(OTf)3-catalyzed reaction of 2-vinyloxiranes with aldimines.
The process is very flexible with regard to the substituents
on the aldimine as well as the vinyloxirane moiety and gives
OL061086P
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Org. Lett., Vol. 8, No. 16, 2006