Unusual oxidative bond-forming reactions upon 1,4-dihydropyridines: Manganese(III)-promoted, single- and double-malonate additions

Full text of DOI:10.1021/jo001407p

J . Org. Chem. 2001, 66, 1487-1491
1487
4
Un u su a l Oxid a tive Bon d -F or m in g
Rea ction s u p on 1,4-Dih yd r op yr id in es:
in regio- and stereocontrolled reactions. A rather simple
explanation for this reactivity may involve a kinetic
preference for the chemically productive oxidation path-
way rather than the electron transfer process. Ideally,
in our case, the oxidant would selectively interact with
a malonate (or a related substrate), yielding the radical,
which would undergo â-addition to the dihydropyridine.
The resulting R-amino radical would be in situ oxidized
to an iminium ion. A final nucleophilic trapping by the
aromatic ring (or the solvent) would yield the 2,3-
disubstituted tetrahydropyridine. The main synthetic
novelty with respect to previous approaches resides in
the incorporation of an “electrophilic” malonate residue
Ma n ga n ese(III)-P r om oted , Sin gle- a n d
Dou ble-Ma lon a te Ad d ition s†
Rodolfo Lavilla,* Alessandro Spada, In e´ s Carranco, and
J oan Bosch
Laboratory of Organic Chemistry, Faculty of Pharmacy,
University of Barcelona, 08028 Barcelona, Spain
lavilla@farmacia.far.ub.es
Received September 25, 2000
at the â-position of a pyridine ring system, whereas
nucleophilic” malonates have usually been linked to R-
5
“
2
a,b
The relevance of 1,4-dihydropyridines1 as valuable
intermediates in the total synthesis of natural products
has been highlighted in several reviews.2 In the vast
majority of the successful synthetic approaches, the key
dihydropyridines are formed by reduction or nucleophilic
addition to the corresponding pyridinium salts and are
immediately transformed into “stable” heterocyclic sys-
tems by redox processes or (more commonly) by electro-
philic interaction at the enaminic â-position and subse-
quent cyclization upon an activated aromatic ring
and γ-positions.
2 3
CO
,7 CAN,8
Several oxidants such as Co(OAc)
2
,6 Ag
9
and Mn(OAc)
3
have been employed for the oxidative
generation of electrophilic radicals from â-dicarbonyls,
the latter two being the most widely used. N-Alkyl-1,4-
dihydropyridines 1, bearing representative substituents
at positions 1 and 3, were selected as starting materials
for our studies; their preparation was accomplished by
2 2 4
Na S O reduction of the corresponding pyridinium salts
2, which in turn were prepared by quaternization of the
commercially available pyridines with the appropriate
alkyl halides (methyl iodide, ethyl iodide, benzyl bromide,
and tryptophyl bromide).10
The first experiments were unsuccessful and only
resulted in the biomimetic oxidation of the dihydropy-
(
Wenkert procedure). In connection with studies on the
synthesis of indole alkaloids, we decided to explore the
possibility of promoting radical additions to the enamine
moiety present in the dihydropyridine and, in this way,
to expand the synthetic exploitation of these versatile
compounds (see Scheme 1).
ridines. Thus, on treatment of 1a ,b with Co(OAc)
2
,
Due to the electron-rich nature of the olefin moiety of
the dihydropyridines, we envisaged favorable interactions
with electrophilic radicals, which in turn would be easily
Ag CO /Celite (F e´ tizon reagent) or CAN in the presence
2
3
of an excess of dimethyl malonate in MeOH solution, we
only detected the formation of the corresponding pyri-
3
8b
11
formed in oxidative processes from â-dicarbonyls. This
dinium salts 2a ,b. Although enol ethers and enamines
approach confronts an intrinsic problem, namely the easy
oxidation of dihydropyridines (NADH is naturally con-
do react under the above conditions, in our case the easier
+
verted into NAD in the cellular metabolism). In the last
(4) (a) Lavilla, R.; Coll, O.; Kumar, R.; Bosch, J . J . Org. Chem. 1998,
3, 2728. (b) Lavilla, R.; Bar o´ n, X.; Coll, O.; Gull o´ n, F.; Masdeu, C.;
6
years, however, we have reported the capability of
diversely substituted dihydropyridines to engage in what
we call nonbiomimetic oxidations, avoiding the usual
oxidation pathway leading to pyridinium salts. These
bond-forming processes have allowed the attachment of
oxygen, nitrogen, sulfur, phosphorus, and halogen atoms
Bosch, J . J . Org. Chem. 1998, 63, 10001. (c) Lavilla, R.; Coll, O.;
Nicol a` s, M.; Sufi, B. A.; Torrents, J .; Bosch, J . Eur. J . Org. Chem. 1999,
2997. (d) Lavilla, R.; Kumar, R.; Coll, O.; Masdeu, C.; Spada, A.; Bosch,
J .; Molins, E.; Espinosa, E. Chem. Eur. J . 2000, 6, 1763. (e) Also see:
Lavilla, R.; Spada, A.; Bosch, J . Org. Lett. 2000, 2, 1533.
(
5) Although less common than γ-addition processes, several reports
deal with the addition of malonates to the R-position of pyridinium
salts: (a) Wanner, J . M.; Koomen, G. J .; Pandit, U. K. Tetrahedron
1
983, 39, 3673. (b) Wenkert, E.; Michelotti, E. L.; Pyrek, J . St. J . Org.
*
To whom correspondence should be addressed. Phone: (34)-
Chem. 1984, 49, 1832. (c) Wenkert, E.; Angell, C.; Drexler, J .; Moeller,
P. D. R.; Pyrek, J . St.; Shi, Y.-J .; Sultana, M.; Vankar, Y. J . Org. Chem.
1986, 51, 2995.
9
34024537. FAX: (34)934021896.
†
This paper is dedicated to Professor Ernest Wenkert on the
occasion of his 75th birthday.
1) For reviews on the chemistry of dihydropyridines, see: (a) Eisner,
U.; Kuthan, J . Chem. Rev. 1972, 72, 1. (b) Stout, D. M.; Meyers, A. I.
Chem. Rev. 1982, 82, 223. (c) Sausins, A.; Duburs, G. Khim. Geterotsikl.
Soedin. 1993, 579. (d) Sausins, A.; Duburs, G. Heterocycles 1988, 27,
(6) Tarakeshwar, P.; Iqbal, J .; Manogaran, S. Tetrahedron 1991, 47,
297.
(7) Lee, Y. R.; Kim, B. S.; Wang, H. C. Tetrahedron 1998, 54, 12215.
(8) (a) Baciocchi, E.; Giese, B.; Farshchi, H.; Ruzziconi, R. J . Org.
Chem. 1990, 55, 5688. (b) Linker, T.; Sommermann, T.; Kahlenberg,
F. J . Am. Chem. Soc. 1997, 119, 9377.
(
2
91. (e) Kutney, J . P. Heterocycles 1977, 7, 593. (f) Comins, D. L.;
O’Connor, S. Adv. Heterocycl. Chem. 1988, 44, 199. (f) Fowler, F. W.
In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees, C.
W., Eds.; Pergamon: Oxford, 1984; Vol. 2, pp 365-394. (g) Lounasmaa,
M.; Tolvanen, A. In Comprehensive Heterocyclic Chemistry II, Katritz-
ky, A. R.; Rees, C. W.; Scriven, E. F. V. Eds.; Pergamon: Oxford, 1996;
Vol. 5, pp 135-165.
(9) For reviews, see: (a) Snider, B. B. Chem. Rev. 1996, 96, 339. (b)
Melikyan, G. C. Organic Reactions 1997, 49, 427. (c) Snider, B. B. In
Transition Metals for Organic Synthesis. Building Blocks and Fine
Chemicals; Beller, M.; Bolm, C., Eds.; Wiley - VCH: Weinheim, 1998;
Vol. 1, pp 439-446. (d) Iqbal, J .; Bhatia, B.; Nayyar, N. K. Chem. Rev.
1994, 94, 519. For recent work, see: (e) Yoshinaga, T.; Nishino, H.;
Kurosawa, K. Tetrahedron Lett. 1998, 39, 9197. (f) D’Annibale, A.;
Nanni, D.; Trogolo, C.; Umani, F. Org. Lett. 2000, 2, 401. (g) Yang, D.;
Ye, X.-Y.; Xu, M.; Pang, K.-W.; Cheung, K.-K. J . Am. Chem. Soc. 2000,
122, 1658.
(
2) (a) Wenkert, E. Pure Appl. Chem. 1981, 53, 1271. (b) Wenkert,
E. Heterocycles 1984, 21, 325. (c) Bennasar, M.-L.; Lavilla, R.; Alvarez,
M.; Bosch, J . Heterocycles 1988, 27, 789. (d) Bennasar, M.-L.; Bosch,
J . Synlett 1995, 587.
(
3) (a) Giese, B. Radicals in Organic Synthesis: Formation of
Carbon-Carbon Bonds; Pergamon: Oxford, 1986; Chapters 2, 3, and
. (b) Curran, D. P. In Comprehensive Organic Synthesis, Trost, B.
M.; Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 715-778.
(10) See, for instance: Brewster, M. E.; Simay, A.; Czako, K.;
Winwood, D.; Farag, H.; Bodor, N. J . Org. Chem. 1989, 54, 3721.
(11) Herten, B. W.; Poulton, G. A. J . Chem. Soc., Chem. Commun.
1975, 456.
6
1
0.1021/jo001407p CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/25/2001

1
488 J . Org. Chem., Vol. 66, No. 4, 2001
Notes
Sch em e 1
1
electron-transfer pathway led exclusively to the observed
oxidation. In fact, this well-documented process has found
some synthetic applications in the oxidation of Hantzsch
bonyl groups give rise to only one set of signals in the H
and 13C NMR spectra, probably because of a fast inter-
conversion on the NMR time scale. With respect to
tetrahydropyridine 3a , the chemical connectivity was
secured through the HMBC spectrum, which allowed the
unequivocal assignment of the most significant signals.
The only isomer detected shows a trans-trans stereo-
chemistry, displaying the three contiguous substituents
axially in the main conformation (vicinal coupling con-
-H around 1.2 Hz). It
4
should be noted that in a flattened six-membered ring
(with three sp atoms) this arrangement does not suffer
from serious 1,3-diaxial repulsions, and, on the other
hand, it may test the benefits of an anomeric-type effect.
1
a,12
dihydropyridines.
Despite a similar report dealing
1
3
with Mn(OAc) , we tried an analogous experiment with
3
this reagent and were pleased to isolate (albeit in low
yield, ≈10%) tetrahydropyridine 3a , together with minor
amounts of anhydro base 4a . The structural assignment
of these new compounds was performed with the aid of
1
13
spectroscopical techniques (IR, UV, MS, H and C NMR,
as well as bidimensional NMR experiments, including
COSY, NOESY, HETCOR, and HMBC) and elemental
analysis (Figure 1).
stants between H
2
-H
3
and H
3
2
F igu r e 1. Structural assignment [Diagnostic data. Rounded
1
13
boxes ( H NMR chemical shifts), squared boxes ( C NMR
chemical shifts), plain curves (NOESY correlations), dashed
curves (HMBC correlations)] for compounds 3a and 4a .
Anhydro base14 4a shows an unusually high chemical
1
shift for H-5 in the H NMR spectrum (around 2 ppm
Several questions were raised at this moment. The
mechanistic rationale behind this reaction was the first
to be looked at. This rare process may be tentatively
explained by considering again a kinetic competition
between the biomimetic and nonbiomimetic oxidation
pathways. In this case (see Scheme 2) the dihydropyri-
dine 1a would be oxidized to the corresponding salt 2a
higher than expected for this kind of enaminic hydro-
gens). This fact may reflect the anisotropic deshielding
of one carbonyl group nearby. In an optimized structure
(calculation performed with MMF94 and AM-1 Hamil-
tonian, using SPARTAN on SGI) the distance between
this hydrogen and the oxygen atom of the syn (coplanar)
carbonyl group is 1.9 Å, thus justifying the observed
effect. Interestingly, the two diastereotopic methoxycar-
(this step would bias the initially planned radical addi-
tion) to subsequently suffer the nucleophilic attack of the
malonate [in an almost neutral medium, probably through
the Mn(III) enolate]. The resulting 1,4-dihydropyridine
(
(
12) Pfister, J . R. Synthesis 1990, 689.
13) For the Mn(OAc) -promoted oxidation of Hantzsch dihydropy-
3
ridines, see: Varma, R. S.; Kumar, D. Tetrahedron Lett. 1999, 40, 21.
14) (a) Rodig, O. R. In Pyridine and its Derivatives (The Chemistry
5
a would then undergo a further oxidation by Mn(OAc)
3
(
to give anhydro base 4a and would interact competitively
with the electrophilic malonyl radical [generated from the
of Heterocyclic Compounds Vol. 14); Abramovitch, R. A., Ed.; Wiley:
New York, 1974; Part 1, pp 351-353.

Notes
J . Org. Chem., Vol. 66, No. 4, 2001 1489
Sch em e 2
5a was isolated simply by removing the volatiles (includ-
ing the excess of dimethyl malonate) from the organic
phase after an extraction (EtOAc) from an aqueous
2
mixture (MeOH-H O), and the yield was higher (25%
from 1a , 68% from 2a ). This may lead to a practical
improvement of the original procedure.
The possibility of using metal salts to promote this type
of conjugate addition was explored, but FeCl failed to
3
catalyze the dimethyl malonate (or other â-dicarbonyl
compounds) addition to pyridinium salt 2a under several
experimental conditions.18 With respect to the optimiza-
tion of the process, carrying out the reaction in MeOH
at reflux temperature from salt 2a resulted in the almost
exclusive formation of the anhydro base 4a in an in-
creased yield (52%), whereas careful control of the
conditions [usual reaction time 8h (TLC control), reflux
3
temperature, 5 equiv of Mn(OAc) , and 10 equiv of
dimethyl malonate] allowed the preparation of 3a in 42%
yield starting from 1a ; the use of an excess of dimethyl
malonate (25 equiv) did not increase the yield. AcOH,
which is the usual solvent for Mn(III)-promoted reactions,
was avoided because of the unstability of dihydropy-
ridines in acids, and MeOH was used instead. The
1
9
addition of Cu(OAc)
2
or the use of ultrasound activa-
tion20 did not improve the yield.21
The scope of the reaction was studied next, and we
examined the effect of different alkyl substituents on the
heterocyclic nitrogen. Dihydropyridines 1b, 1c, and 1d
(
with ethyl, benzyl, and tryptophyl groups, respectively)
corresponding Mn(III) enolate] to afford an R-amino
radical. Oxidation followed by nucleophilic trapping by
the solvent (MeOH) would account for the formation of
the final bis(malonyl)tetrahydropyridine 3a . The stereo-
chemical outcome of the whole sequence is in agreement
with the favored trans stereochemistry of radical addi-
were used. Following the previously developed method,
the corresponding tetrahydropyridines 3b (33%) and 3c
(25%) were obtained, whereas 3d was isolated only in
22
minute amounts, the main products being the corre-
sponding anhydro base 4d (12%) and indoloquinolizidine
6
cyclization of the intermediate dihydropyridine 5d . When
the reaction was carried out at a lower temperature with
reduced amounts of oxidant, and the crude 5d exposed
to a dry HCl saturated Et
improved to 30% (Scheme 3).
d (10%), the latter coming from the acid-promoted
1
5
tions on substituted cyclohexenes and the stereocon-
trolled trapping of iminium ions.16
Some features of this mechanistic proposal deserve
comment. The initial oxidation of dihydropyridine 1a ,
although documented, was demonstrated by running the
process starting from the corresponding salt 2a . In this
way, tetrahydropyridine 3a and anhydro base 4a were
positively identified from the resulting reaction mixture.
Also 1,4-dihydropyridine 5a was produced at a lower
2
O solution, the yield of 6d
We have also modified the electron-withdrawing group
at the â-position of dihydropyridines 1. No bis-malonate
products were obtained from substrates 1e and 1f, the
corresponding anhydro bases being obtained instead. In
3
temperature (40 °C) with reduced amounts of Mn(OAc) ,
both from 1a and 2a . It is noteworthy that this compound
could be isolated and characterized by spectroscopic
methods, which is unusual for this type of labile 1,4-
dihydropyridine intermediates. Further treatment of this
(
18) For recent examples, see: (a) Christoffers, J .; Oertling, H.;
Leitner, M. Synlett 2000, 349. (b) Christoffers, J .; Oertling, H.
Tetrahedron 2000, 56, 1339.
(19) For recent examples, see: (a) Cossy, J .; Bouzide, A. Tetrahedron
999, 55, 6483. (b) Ishibashi, H.; Toyao, A.; Takeda, Y. Synlett 1999,
468. Also see ref 9.
1
1
dihydropyridine 5a with Mn(OAc)
mixture of 3a and 4a , although under similar conditions
a is not converted into tetrahydropyridine 3a , in agree-
ment with the mechanistic sequence depicted in Scheme
. It should be remarked that in the Wenkert procedure,
3
in MeOH afforded a
(
20) (a) Peters, D. In Transition Metals for Organic Synthesis.
Building Blocks and Fine Chemicals, Beller, M.; Bolm, C., Eds. Wiley
VCH: Weinheim, 1998; Vol 2, pp 428-430. (b) For a recent result,
see: Linker, T.; Linker, U. Angew. Chem., Int. Ed. 2000, 39, 902.
21) In an attempt to carry out this transformation without the need
of an oxidant, we tested the atom transfer additions of bromomalonates
see: Curran, D. P.; Chang, C.-T. J . Org. Chem. 1989, 54, 3140] to
dihydropyridines 1 (toluene, AIBN, or Me Sn ). No productive processes
4
-
2
(
the key dihydropyridines are produced in a highly basic
nonpolar medium, and some degradation and/or the
reversibility of the process causes the yield to be usually
low (typically around 15%).17 In our case, dihydropyridine
[
6
2
were observed, and the dihydropyridines remained unreacted, even
after long reaction times or decomposition took place and the corre-
sponding pyridinium salts were detected. A plausible explanation may
be the abstraction of an allylic hydrogen atom from the dihydropyridine
by the malonate radical. For a similar situation, see: Truksa, S. V.;
Nibler, A.; Schatz, B. S.; Krosley, K. W.; Gleicher, G. J . J . Org. Chem.
1992, 57, 2967.
(
15) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions; VCH: Weinheim, 1996; pp 139-143.
16) See for instance: Overman, L. E.; Ricca, D. J . In Comprehensive
Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford,
991; Vol. 2, pp 1007-1046.
17) (a) Wenkert, E.; Halls, T. D. J .; Kunesch, G.; Orito, K.; Stephens,
R. L.; Temple, W. A.; Yadav, J . S. J . Am. Chem. Soc. 1979, 101, 5370.
b) Also see ref 2. (c) For a higher yield, see: J okela, R.; Taipale, T.;
Ala-Kaila, K.; Lounasmaa, M. Heterocycles 1986, 24, 2265.
(
(22) Tryptophyltetrahydropyridine 3d : 1H NMR δ 8.15 (br s, 1H),
7.56 (d, J ) 8.0 Hz, 1H), 7.40 (d, J ) 7.5 Hz, 1H), 7.23-7.10 (m, 2H),
7.03 (d, J ) 1.5 Hz, 1H), 6.45 (s, 1H), 4.36 (br s, 1H), 4.23 (d, J ) 12.0
Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.80-3.70 (m, 2H),
3.66 (s, 3H), 3.36 (s, 3H), 3.18 (d, J ) 10.2 Hz, 1H), 3.00 (m, 3H), 2.85
(d, J ) 12.0 Hz, 1H).
1
(
(

1
490 J . Org. Chem., Vol. 66, No. 4, 2001
Notes
Sch em e 3
In conclusion, a very unusual chemically productive
oxidation of N-alkyl-1,4-dihydropyridines is described.
Although the scope of the reaction seems to be limited
(
only cyano groups are tolerated at the â-position of the
dihydropyridine ring), the process deserves interest as
it involves a triple action mode for the Mn(OAc) (oxidant,
3
enhancer for the nucleophilicity of the dimethyl malonate
and promoter of the formation of the electrophilic mal-
onate radical) in a stereoselective cascade reaction.
Exp er im en ta l Section
Gen er a l. All solvents were purified and dried by standard
methods. All reagents were of commercial quality from freshly
opened containers. Organic extracts were dried with anhydrous
Na SO . Melting points were determined in a capillary tube and
2 4
are uncorrected. Microanalyses and HRMS were performed by
Centro de Investigaci o´ n y Desarrollo (CSIC), Barcelona. Unless
otherwise quoted, NMR spectra were recorded in CDCl
3
solution
1
with TMS as an internal reference at 200, 300, or 500 MHz ( H)
1
3
and 50.3 or 75 MHz ( C). Only noteworthy IR absortions are
-
1
listed (cm ). UV spectra were obtained in MeOH solution.
Tetr a h yd r op yr id in e 3a . A solution of dihydropyridine 1a
(120 mg, 1 mmol), dimethyl malonate (1.32 g, 1.14 mL, 10 mmol),
these cases, the corresponding pyridinium salts 2 under-
went the malonate addition to yield dihydropyridines 5
to a comparable extent. Also, similar additions with
and Mn(OAc)
stirred at reflux temperature under N
dihydropyridine was detected by TLC (8 h). EtOAc (50 mL) was
added, and the mixture was successively washed with aqueous
2 3 2 2 3
Na CO (10%, 100 mL) and Na S O (0.5 M, 100 mL) solutions
and brine (100 mL). The organic phase was dried and evapo-
rated, and the residue was chromatographed (silica gel pre-
treated with Et
3
dihydrate (1.34 g, 5 mmol) in MeOH (10 mL) was
atmosphere until no
2
3
-formyl- or 3-acetyl-1,4-dihydropyridines resulted in
failure. The apparent exclusivity of the cyano group in
allowing the transformation may be related with the
lower rate of (biomimetic) oxidation measured in 3-cyano-
1
,4-dihydropyridines as compared with dihydropyridines
3 2 2
N, elution with hexanes/CH Cl ) to yield 3a (173
1
1
0
mg, 42%) as a waxy solid. H NMR δ 6.72 (s, 1H), 4.25 (m, J )
bearing other substituents at the â-position. This would
allow the intermediate dihydropyridines 5a -c to undergo
a kinetically competitive radical addition at a rate
comparable with the rate of oxidation to the anhydro
base, whereas in the remaining cases the latter process
would overshadow the former.
1
3
3
1
.2 Hz, 1H), 4.16 (d, J ) 11.1 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H),
.78 (s, 3H), 3.75 (s, 3H), 3.38 (s, 3H), 3.26 (d, J ) 9.0 Hz, 1H),
.03 (s, 3H), 3.01 (m, 1H), 2.90 (m, J ) 11.1, 1.2, and 1.2 Hz,
13
H); C NMR δ 168.2, 167.9, 167.6, 167.5, 146.4, 120.6, 88.2,
74.1, 56.5, 54.3, 53.0, 52.8, 52.6, 52.5, 52.4, 42.7, 35.1, 34.3; IR
(KBr) 2195, 1726, 1635; UV (MeOH) 266 (4.10); EI MS (m/z, %)
+
2
49 (100); CI MS (NH
3
, m/z, %) 430 (M + NH
H , 1). Anal. Calcd for C18
Found: C, 52.59; H, 5.89; N, 6.83. Further elution with
CH Cl /MeOH afforded anhydro base 4a (20 mg, 8%).
4
, 100), 413 (M +
To test the reactivity of dihydropyridines less prone
to undergo the biomimetic oxidation, we prepared the
N-benzoyldihydropyridine 723 but, after the interaction
with Mn(OAc) and dimethyl malonate under the usual
3
conditions, only complex mixtures were produced, and
the expected products were not detected.
+
24 2 9
H N O : C, 52.43; H, 5.83; N, 6.80.
2
2
Tetr a h yd r op yr id in e (3b). Operating as above, from dihy-
dropyridine 1b, the ethyl derivative 3b (33%) was obtained as
1
a foam. H NMR δ 6.78 (s, 1H), 4.27 (br s, 1H), 4.19 (d, J ) 11.5
Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.75 (s, 3H), 3.35
(
2
s, 3H), 3.22 (m, 1H), 3.17 (m, 1H), 3.08 (d, J ) 9.4 Hz, 1H),
.97 (br d, J ) 9.4 Hz, 1H), 2.85 (br d, J ) 11.5 Hz,1H), 1.11 (t,
1
3
J ) 7.2 Hz, 3H); C NMR δ 168.2, 167.9, 167.7, 167.4, 145.1,
1
3
20.8, 86.9, 74.2, 56.0, 54.3, 53.1, 52.8 (2C), 52.5, 52.3, 48.8, 34.7,
4.3, 14.6; IR (KBr) 2195, 1735, 1635; UV (MeOH) 264 (4.31);
+
EI MS (m/z, %) 426 (M , 15), 295 (15), 263 (100). CI MS (NH
3
,
+
4
, 100); HRMS (EI) mass calcd for
m/z, %) 444 (M + NH
426.1638, found 426.1639.
Tetr a h yd r op yr id in e (3c). Operating as above, from dihy-
19 26 2 9
C H N O
dropyridine 1c, the benzyl derivative 3c (25%) was obtained as
a foam. H NMR δ 7.35 (m, 3H), 7.19 (m, 2H), 6.88 (br s, 1H),
Finally, we examined the influence of the substitution
at the γ-position of the dihydropyridine ring.24 As it was
clear that the unsubstituted substrates 1 are first
oxidized and converted to γ-malonyldihydropyridines 5,
which then suffer the radical addition, it is tempting to
suggest that a γ-substituent may slow the rate of the
oxidation step and consequently favor the addition
process. However, unfortunately, reactions from 4-me-
thyldihydropyridine 825 were not productive, and the
expected product was only detected in trace amounts
1
4
.35 (d, J ) 14.3 Hz, 1H), 4.29 (d, J ) 14.3 Hz, 1H), 4.23 (d, J
) 11.1 Hz, 1H), 4.16 (br s, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.73
(s, 3H), 3.47 (s, 3H), 3.28 (s, 3H), 3.06 (d, J ) 10.5 Hz, 1H), 2.96
1
3
(br d, J ) 10.5 Hz, 1H), 2.87 (br d, J ) 11.1 Hz, 1H); C NMR
δ 167.8, 167.7, 167.6, 167.3, 145.7, 135.1, 129.0 (2C), 128.4, 120.6,
5.7, 74.8, 57.3, 56.2, 54.3, 53.1, 52.8, 52.7, 52.6, 51.9, 34.5, 34.2;
IR (NaCl) 2196, 1732, 1630; UV (MeOH) 266 (4.18); EI MS (m/
8
+
z, %) 488 (M , 5), 357 (6), 325 (100). HRMS (EI) mass calcd for
488.1794, found 488.1786.
An h yd r o Ba se (4a ). A solution of pyridinium salt 2a (246
mg, 1 mmol), dimethyl malonate (1.32 g, 1.14 mL, 10 mmol),
and Mn(OAc) dihydrate (1.34 g, 5 mmol) in MeOH (10 mL) was
24 28 2 9
C H N O
(NMR and MS evidence).
3
(
23) For the method, see: Obika, S.; Nishiyama, T.; Tatematsu, S.;
Nishimoto, M.; Miyashita, K.; Imanishi, T. Heterocycles 1997, 44, 537.
24) For an intramolecular reductive radical addition to γ-substituted-
,4-dihydropyridines, see: Mangeney, P.; Hamon, L.; Raussou, S.;
Urbain, N.; Alexakis, A. Tetrahedron 1998, 54, 10349.
(25) (a) Dihydropyridine
8
was prepared from 3-cyano-4-
2
5b,c
(
methylpyridine
by methylation followed by dithionite reduction. (b)
1
Lounasmaa, M.; J ohansson, C.-J . Tetrahedron 1977, 33, 113. (c)
Bobbitt, J . M.; Scola, D. A. J . Org. Chem. 1960, 25, 560.

Notes
J . Org. Chem., Vol. 66, No. 4, 2001 1491
stirred at reflux temperature under N
2
atmosphere for 8 h.
1H), 3.97 (dd, J ) 6.4 and 5.0 Hz, 1H), 3.76 (s, 6H), 3.52 (d, J )
6.4 Hz, 1H), 3.01 (s, 3H); 13C NMR δ 167.2, 144.6, 130.3, 120.1,
101.7, 77.6, 58.3, 52.5, 40.9, 34.1; IR (NaCl) 2194, 1730, 1678;
EI MS (m/z, %) 250 (M , 16), 249 (16), 191 (28), 159 (50), 119
(60), 83 (100).
EtOAc (50 mL) was added, and the mixture was successively
washed with aqueous Na CO (10%, 100 mL) and Na (0.5
2
3
2 2 3
S O
+
M, 100 mL) solutions and brine (100 mL). The organic phase
was dried and evaporated, and the residue was chromatographed
(
silica gel pretreated with Et
Cl , tetrahydropyridine 3a (39 mg, 10%) was obtained. Further
elution with CH Cl /MeOH yielded anhydro base 4a (129 mg,
2%) as a yellow solid. Further purification may be achieved by
3 2
N). On elution with hexanes/CH -
In d oloqu in olizid in e 6d . Operating as above, from dihydro-
pyridine 1d (250 mg, 1 mmol), crude dihydropyridine 5d was
obtained and then dissolved in anhydrous THF (50 mL). The
resulting solution was kept at 0 °C, and enough of a HCl-
2
2
2
5
1
recrystallization from acetone-Et
2
O, mp 181-183 °C. H NMR
saturated Et
solution was stirred at room temperature for 2 h and then poured
into aqueous saturated Na CO solution (125 mL) and extracted
with EtOAc. The organic phase was dried and evaporated, and
the residue was chromatographed (silica gel, elution with CH
Cl /MeOH) to yield indoloquinolizidine 6d (115 mg, 30%) as a
foam. H NMR δ 8.27 (br s, 1H), 7.47 (d, J ) 7.5 Hz, 1H), 7.33
d, J ) 7.8 Hz, 1H), 7.21-7.08 (m, 2H), 7.00 (s, 1H), 4.48 (br d,
J ) 11.4 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.70 (m, 1H), 3.58
d, J ) 9.6 Hz, 1H), 3.54 (m, 1H), 3.3 (m, J ) 9.6, 5.1, and 2.1
Hz, 1H), 2.90 (m, 1H), 2.78 (m, 1H), 2.46 (m, J ) 16.2, 2.1, and
2
O solution was added to reach pH 2-3. The
δ 7.95 (d, J ) 8.1 Hz, 1H), 7.46 (d, J ) 1.8 Hz, 1H), 6.83 (dd, J
1
3
)
1
8.1 and 1.8 Hz, 1H), 3.66 (br s, 6H), 3.51 (s, 3H); C NMR δ
2
3
67.9, 146.8, 143.9, 135.7, 115.8, 115.4, 98.2, 94.3, 50.8, 43.0;
IR (KBr) 2220, 1722, 1705, 1680, 1640; UV (MeOH) 353 (4.41);
EI MS (m/z, %) 248 (M , 100), 217 (100), 159 (48), 148 (54), 132
(
Found: C, 57.92; H, 4.73; N, 11.23.
An h yd r o Ba se (4d ). Obtained as a yellow solid foam in 12%
yield by oxidation of dihydropyridine 1d under the above
conditions. Further purification may be achieved by recrystal-
lization from acetone-Et
(
2
-
+
2
70). Anal. Calcd for C12
H
12
N
2
O
4
: C, 58.06; H, 4.84; N, 11.29.
1
(
(
1
2
O, mp 112-114 °C. H NMR δ 8.40
13
1
.8 Hz, 1H), 1.88 (m, J ) 16.2, 11.4, and 5.1 Hz, 1H); C NMR
br s, 1H), 8.02 (d, J ) 8.0 Hz, 1H), 7.55 (d, J ) 7.5 Hz, 1H),
δ 168.1, 167.8, 148.9, 136.2, 131.1, 126.5, 122.2, 121.9, 119.7,
17.9, 111.1, 107.9, 72.7, 56.9, 53.0, 52.8, 50.9, 47.8, 32.1, 30.7,
1.7; IR (NaCl) 3300, 2187, 1750, 1730, 1627; UV (MeOH) 275
4.64); EI MS (m/z, %) 379 (M , 25), 246 (100). HRMS (EI) mass
7
1
3
.39 (d, J ) 8.0 Hz, 1H), 7.22-7.15 (m, 2H), 7.00 (d, J ) 1.8 Hz,
H), 6.81 (d, J ) 1.3 Hz, 1H), 6.59 (dd, J ) 8.0 and 1.3 Hz, 1H),
.96 (t, J ) 7.2 Hz, 2H), 3.75 (br s, 6H), 3.10 (t, J ) 7.2 Hz, 2H);
C NMR δ 167.0, 145.4, 142.2, 136.3, 134.0, 125.9, 123.3, 122.5,
19.9, 117.6, 115.9, 115.0, 111.8, 108.9, 99.5, 93.6, 56.9, 51.3,
6.7; IR (NaCl) 3400, 2220, 1705, 1680, 1636; UV (MeOH) 356
1
2
(
+
1
3
calcd for C21
21 3 4
H N O 379.1532, found 379.1533.
1
2
(
+
Ack n ow led gm en t. This work was supported by the
DGICYT, Spain (project PB94-0214). Thanks are also
due to the Comissionat per Universitats i Recerca
4.12), 271 (3.72); EI MS (m/z, %) 377 (M , 20), 345 (15), 216
25), 144 (100). Anal. Calcd for C21 : C, 66.84; H, 5.04;
(
19 3 4
H N O
N, 11.14. Found: C, 66.62; H, 5.38; N, 10.87.
Dih yd r op yr id in e (5a ). A solution of dihydropyridine 1a (246
mg, 1 mmol), dimethyl malonate (660 mg, 0.57 mL, 5 mmol),
and Mn(OAc)
was stirred at 40 °C under N
mL) was added, and the mixture was successively washed with
aqueous Na CO (10%, 100 mL) and Na (0.5 M, 100 mL)
(Generalitat de Catalunya) for Grant SGR99-00079. A.
S thanks Universit a` “La Sapienza” (Roma) for a fellow-
ship. Professors A. Vallribera and R. Pleixats (Univer-
sitat Autonoma de Barcelona) are thanked for helpful
discussions.
3
dihydrate (536 mg, 2 mmol) in MeOH (10 mL)
2
atmosphere for 1 h. EtOAc (50
2
3
2 2 3
S O
solutions and brine (100 mL). The organic phase was dried and
evaporated, and the excess malonate was removed by heating
under high vacuum (0.01 Torr, 60 °C) to yield labile dihydro-
pyridine 5a (63 mg, 25%) slightly impurified. Starting from
pyridinium salt 2a and operating as above, dihydropyridine 5a
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
13
cedures for compounds 7 and 8. H and C NMR spectra of
compounds 3b, 3c, 5a , and 6d . This material is available free
of charge via the Internet at http://pubs.acs.org.
1
was obtained in 68% yield. H NMR δ 6.61 (d, J ) 1.2 Hz, 1H),
5
.84 (dd, J ) 7.9 and 1.2 Hz, 1H), 4.84 (dd, J ) 7.9 and 5.0 Hz,
J O001407P