Non-biomimetic oxidation of 1,4-dihydropyridines

Article abstract of DOI:10.1039/a606919c

The reaction between N-alkyl-1,4-dihydropyridines and dimethyldioxirane leads to dimeric tetrahydropyridines having oxygen atoms at the 2- and 3-positions in good yields and with good stereocontrol; these compounds are useful iminium ion precursors, and a

Full text of DOI:10.1039/a606919c

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Non-biomimetic oxidation of 1,4-dihydropyridines†
Rodolfo Lavilla,* Francisco Gullo´n, Xavier Baro´n and Joan Bosch*
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
The reaction between N-alkyl-1,4-dihydropyridines and
dimethyldioxirane leads to dimeric tetrahydropyridines
having oxygen atoms at the 2- and 3-positions in good yields
and with good stereocontrol; these compounds are useful
iminium ion precursors, and are satisfactorily transformed
into 2-substituted 3-hydroxy-1,2,3,4-tetrahydropyridines.
oxidation pathway to pyridinium salts. In contrast, the use of
dioxiranes generated in situ from 2-chlorocyclohexanone or
1,1,1-trifluoroacetone in the presence of stochiometric amounts
of Oxone®12 was not satisfactory, showing the incompatibility
of dihydropyridines with strong oxidants like peroxyacids. The
major stereoisomers 2 have a centre of symmetry,13 showing a
cis stereochemistry for the oxygens at C2–C3 and a anti
relationship between the two tetrahydropyridine moieties;
minor amounts of other isomers were isolated, probably having
a syn stereochemistry. The stereochemical assignments were
based on the coupling constants in the 1H NMR spectra and on
1H-1H COSY, HMQC and NOESY experiments. Dioxanes 2
were stable enough to be chromatographed, spectroscopically
characterized and stored indefinitely in the freezer under an
inert atmosphere. An additional interest of dimers 2 lies in the
fact that they are highly functionalized iminium ion pre-
cursors.
1,4-Dihydropyridines are interesting compounds and play an
important role in synthetic, therapeutic and bioorganic chem-
istry.1 New methods for their preparation2 and transformations
have been the subject of research in our laboratory: selective
reductions,3 electrophilic additions4 and total syntheses of
alkaloids5 have been developed.
Here we report an efficient, mild and selective non-
biomimetic oxidation of N-alkyl-1,4-dihydropyridines.‡ Al-
though the conversion of these compounds to the corresponding
pyridinium salts is a well-established process that has relevant
significance in cell metabolism [NAD(P)H is commonly
oxidized to NAD(P)+ in many enzyme-assisted reductions],
very little is known about ‘alternative’ dihydropyridine oxida-
tions (i.e. epoxidations or dihydroxylations).6,7 To our knowl-
edge, no synthetically useful reports dealing with this subject
have been published. After several unsuccessful attempts to
oxidize N-alkyl-1,4-dihydropyridines with MCPBA or OsO4,
we turned our attention to the use of dimethyldioxirane (DMD),
a reagent used in a wide range of functional group transforma-
tions,8 including the oxidation of enamines.9 It should be
mentioned that a chemically related dioxetane was involved in
the ‘normal’ oxidation of a NADH analogue.10
The required N-methyl-1,4-dihydropyridines 1 were pre-
pared by sodium dithionite reduction of the corresponding
pyridinium salts, following published procedures.11 When
dihydropyridines 1 were treated at room temperature with DMD
for 5 min, the tricyclic dioxanes 2 were obtained in good
yields.§¶ This process can be rationalized by considering the
initial epoxidation of the enamine double bond with subsequent
ring opening of the oxirane ring to give an iminium ion that
undergoes dimerization.
A preliminary study of this type of reactivity was undertaken,
including the generation of iminium ions under different
conditions and their subsequent interaction with nucleophiles.
Thus, reduction of 2a with triethylsilane in the presence of
Alk
N
Alk
N
Alk
N
+
Biomimetic
oxidation
Alternative
oxidation
HO
HO
R
R
R
Pyridinium Salt
1,4-DHP
2,3-Dihydroxy-1,2,3,4-THP
R
N
R
O
O
N
O
R′
Me
Me
Acetone, room temp., 5 min
R′
R′
O
N
R
2
1
a R = Me, R′ = CN (72%)
b R = Me, R′ = CO2Me (76%)
c R = Bn, R′ = CN (69%)
d R = Bn, R′ = CO2Me (60%)
This transformation constitutes the first general, non-bio-
mimetic oxidation of 1,4-dihydropyridines, avoiding the natural
Scheme 1
Me
N
Me
N
Me
H
H
H
O
CN
N
CN
OH
v
i
NC
OH
NC
ii
O
N
NC
H
Me
3
2a
7
iii
iv
H
Me
Me
N
Me
M e
N
N
OMe
OH
N
OMe
O
NC
NC
NC
OH
6
4
5
Scheme 2 Reagents and conditions: i, Et3SiH, TiCl4, THF, 260 °C, 5 min (95%); ii, MeOH, TFA, 0 °C, 5 min (72%; cis isomer 24%); iii, 2-methylindole,
TFA, 20 °C, 5 min (60%; cis isomer 24%); iv, 1-methoxyethene, BF3·Et2O, THF–CH2Cl2, 260 °C, 5 min (60%, mixture of isomers at the acetalic carbon);
v, Me3SiCN, TiCl4, CH2Cl2, 0 °C, 5 min (40%; cis isomer 27%)
Chem. Commun., 1997
213

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(NCH3), 60.6 (C-2), 66.4 (C-3), 69.2 (C-5), 108.0 (C-3 indole), 110.6 (C-7
indole), 117.8 (C-4 indole), 119.8 (C-6 indole), 120.0 (CN), 121.6 (C-5
indole), 122.2 (C-3a indole), 134.5 (C-2 indole), 136.1 (C-7a indole), 148.5
(C-6). HRMS (e.i.) m/z: calc. 267.1372, found 267.1381. For 6 (major
stereoisomer): 1H NMR (300 MHz, CDCl3): 1.97 (ddd, 1 H, J 13.7, 7.5 and
2.9 Hz, H-3), 2.40 (m, 1 H, H-3), 2.47 (m, 2 H, H-7), 2.92 (s, 3 H, NCH3),
3.35 (s, 3 H, OCH3), 3.55 (m, 1 H, H-3a), 4.25 (m, 1 H, H-7a), 5.02 (dd, 1
H, J 5.9 and 2.9 Hz, H-2), 6.72 (s, 1 H, H-5); 13C NMR (75.4 MHz, CDCl3)
25.5 (C-7), 36.6 (C-3), 40.8 (NCH3), 55.4 (OCH3), 57.1 (C-3a), 73.5 (C-7a),
79.9 (C-6), 104.0 (C-2), 123.1 (CN), 147.1 (C-5). HRMS (e.i.) m/z: calc.
194.1055, found 194.1060. For 7 (major stereoisomer, trans): 1H NMR (300
MHz, CDCl3) 2.30 (ddd, 1 H, J 16.8, 2.6 and 2.3 Hz, H-4), 2.75 (ddd, 1 H,
J 16.8, 3.6 and 2.0 Hz, H-4), 3.08 (s, 3 H, NCH3), 3.98 (dd, 1 H, J 2.6 and
2.3 Hz, H-2), 4.39 (m, 1 H, H-3), 6.77 (d, 1 H, J 2.0 Hz, H-6); 13C NMR
(75.4 MHz, CDCl3) 27.2 (C-4), 41.3 (NCH3), 52.7 (C-2), 63.2 (C-3), 76.3
(C-5), 115.4 (CN), 120.7 (CN), 145.9 (C-6). HRMS (e.i.) m/z: calc.
163.0746, found 163.0746.
titanium tetrachloride afforded tetrahydropyridinol 3, whereas
TFA-induced addition of methanol gave the ‘protected’ a-
alcoxy tetrahydropyridine 4. On the other hand, addition of
2-methylindole was achieved under acid catalysis, affording
adduct 5 with moderate stereoselectivity. In the latter two
reactions, minor amounts of the cis isomers were isolated.
Addition of methoxyethylene was achieved in the presence of
boron trifluoride. In this case, the intramolecular trapping of the
resulting carbonium ion by the hydroxy group allowed the
formation of the partially reduced furopyridine 6 (ring fusion
cis) in a one-pot transformation. Finally, Me3SiCN was added to
give a-amino nitrile 7 (epimeric mixture at C-2) in good
yield.∑
In conclusion, a useful, mild and selective method for the
formal epoxidation of 1,4-dihydropyridines has been devel-
oped, and some relevant reactions of the resulting compounds,
which act as iminium ion precursors, are reported. These results
present interesting possibilities in the study of the chemical
reactivity of dihydropyridines, a class of compounds with a
significant role in biochemistry and in natural product synthesis
(e.g. alkaloids and azasugars).
References
1 For reviews on the chemistry of dihydropyridines, see: U. Eisner and
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This work was supported by the Direccio´n General de
Investigacio´n Cient´ıfica y Te´cnica, Spain, (PB94-0214) and by
the Comissionat per Universitats i Recerca (Generalitat de
Catalunya, Grant SGR95-00428).
2 R. Lavilla, T. Gotsens, M. Guerrero and J. Bosch, Synthesis, 1995, 382
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Footnotes
† Presented in part at the Eigth FECHEM Conference on Heterocycles in
Bio-Organic Chemistry, September 1–4, 1996, Villa Olmo, Italy.
‡ The term non-biomimetic is used in a broad sense, meaning that the
process involves an oxygen transfer rather than the usual two-electron
oxidation observed in nature.
§ All new compounds were characterized by 1H and 13C NMR, IR, UV, MS
and HRMS.
¶ Typical procedure: A 1.1 fold excess of DMD (0.07 m) in acetone14 was
added to a solution of the dihydropyridine 1a (1 mmol) in acetone (20 ml)
at 0 °C. The progress of the reaction was monitored by TLC. When all the
starting material had been consumed (ca. 5 min), the solvent was removed
under reduced pressure and the residue was chromatographed through
neutral alumina (CH2Cl2–MeOH) to give the corresponding dioxane 2a
(72%). 1H NMR (300 MHz, CD3OD) 2.16 (ddd, 1 H, J 16.3, 2.7 and 1.5 Hz,
H-4), 2.53 (ddd, 1 H, J 16.3, 3.7 and 1.9 Hz, H-4), 3.15 (s, 3 H, CH3), 3.83
(m, 1 H, H-3), 4.41 (dd, 1 H, J 2.6 and 1.5 Hz, H-2), 6.74 (d, 1 H, J 1.9 Hz,
H-6); 13C NMR (75.4 MHz, CD3OD) 24.4 (C-4), 39.3 (CH3), 63.9 (C-3),
70.3 (C-5), 80.4 (C-2), 122.7 (CN), 146.0 (C-6). HRMS (e.i.) m/z: calc.
272.1273, found 272.1272.
∑ Selected spectral data for 3: 1H NMR (300 MHz, CDCl3) 2.20 (br s, 2 H,
H-4 and OH), 2.49 (br d, 1 H, J 15.8 Hz, H-4), 2.95 (s, 3 H, CH3), 3.01 (m,
1 H, J 12.6, 5.6, 2.5 and 0.9 Hz, H-2), 3.17 (ddd, 1 H, J 12.6, 2.6 and 1.1 Hz,
H-2), 4.19 (br s, 1 H, H-3), 6.79 (d, 1 H, J 0.9 Hz, H-6); 13C NMR (75.4
MHz, CDCl3): 30.0 (C-4), 42.9 (CH3), 52.9 (C-2), 61.9 (C-3), 69.5 (C-5),
123.0 (CN), 147.5 (C-6). For 4 (major stereoisomer, trans): 1H NMR (300
MHz, CDCl3) 2.12 (ddd, 1 H, J 16.6, 2.2 and 1.3 Hz, H-4), 2.40 (ddd, 1 H,
J 16.6, 3.8 and 1.9 Hz, H-4), 3.09 (s, 3 H, NCH3), 3.38 (s, 3 H, OCH3), 3.93
(m, 1 H, H-3), 4.07 (dd, 1 H, J 3.2 and 1.2 Hz, H-2), 6.77 (dd, 1 H, J 2.0 and
1.0 Hz, H-6); 13C NMR (75.4 MHz, CDCl3): 25.6 (C-4), 42.6 (NCH3), 56.4
(OCH3), 61.8 (C-3), 73.1 (C-5), 89.4 (C-2), 122.1 (CN), 145.2 (C-6). HRMS
(e.i.) m/z: calc. 168.0899, found 168.0902. For 5 (major stereoisomer,
trans): 1H NMR (300 MHz, CDCl3) 2.33 (dd, 1 H, J 15.6 and 6.7 Hz, H-4),
2.43 (s, 3 H, CH3), 2.50 (dd, 1 H, J 15.6 and 4.0 Hz, H-4), 2.81 (s, 3 H,
NCH3), 4.20 (ddd, 1 H, J 6.7, 5.4 and 4.0 Hz, H-3), 4.30 (d, 1 H, J 5.4 Hz,
H-2), 7.02 (s, 1 H, H-6), 7.07–7.20 (m, 2 H, H-5 and H-6 indole), 7.33 (d,
1 H, J 8.0 Hz, H-7 indole), 7.47 (d, 1 H, J 7.7 Hz, H-4 indole), 8.10 (br s,
1 H, NH); 13C NMR (75.4 MHz, CDCl3) 11.8 (CH3), 28.3 (C-4), 40.9
10 W. Adam, M. Heil and R. Hutterer, J. Org. Chem., 1992, 57, 4491.
11 M. E. Brewster, A. Simay, K. Czako, D. Winwood, H. Farag and
N. Bodor, J. Org. Chem., 1989, 54, 3721.
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Liebigs Ann. Chem., 1983, 1986; W. Adam, K. Peters and M. Sauter,
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14 DMD solutions were prepared according to W. Adam, J. Bialas and
L. Hadjiarapoglou, Chem. Ber., 1991, 124, 2377, and the dioxirane
content (ca. 0.07 m) was determined by iodometric titration.
Received, 9th October 1996; Com. 6/06919C
214
Chem. Commun., 1997