Convenient synthesis of N-benzyl-1,4-dihydropyridines, cyclohexenones, and bicyclo[3.3.1]nonan-3-one derivatives from 1-aza-1,3-butadienes

Article abstract of DOI:10.1021/jo960942f

Readily available 1-aza-1,3-butadienes (enimines) react with methyl acetoacetate and acetylacetone in the presence of catalytic amounts of lithium iodide to form in high yields unsymmetrically substituted 1,4-dihydropyridines or cyclohexenones. The reacti

Full text of DOI:10.1021/jo960942f

7320
J . Org. Chem. 1996, 61, 7320-7325
Con ven ien t Syn th esis of N-Ben zyl-1,4-d ih yd r op yr id in es,
Cycloh exen on es, a n d Bicyclo[3.3.1]n on a n -3-on e Der iva tives fr om
1-Aza -1,3-bu ta d ien es
J on K. F. Geirsson* and J onina F. J ohannesdottir
Science Institute, University of Iceland, Dunhaga 3, IS-107 Reykjavik, Iceland
Received May 21, 1996X
Readily available 1-aza-1,3-butadienes (enimines) react with methyl acetoacetate and acetylacetone
in the presence of catalytic amounts of lithium iodide to form in high yields unsymmetrically
substituted 1,4-dihydropyridines or cyclohexenones. The reaction pathway depends on the structure
of the enimine used. This divergence was not observed when the enimines were reacted with
dimethyl 1,3-acetonedicarboxylate to provide bicyclo[3.3.1]nonane-3-one derivatives in excellent
yields in a remarkably stereoselective reaction.
Sch em e 1
In tr od u ction
1-Aza-1,3-butadiene derivatives (enimines) are re-
ported to be useful intermediates in various synthetic
procedures1-3 and natural product syntheses.4-7 Their
use as electrophiles in 1,2- and 1,4-additions has been
investigated,8-10 and their utility as dienes in hetero
Diels-Alder reactions continues to be the subject of
considerable interest.11-13 Recently, reports have ap-
peared on the structure14,15 and application16,17 of metal-
coordinated 1-aza-1,3-diene complexes, and an improved
procedure for the preparation of cyclic enimines has been
described.18 Our main interest regarding the 1-aza-1,3-
butadienes has been to investigate whether enimines are
suitable substrates in reactions that involve two consecu-
tive steps, namely a Michael addition to the enimine with
a subsequent ring-closure step.19
In this paper, we disclose results that demonstrate that
the structure of the enimine determines whether it reacts
to afford biologically important 1,4-dihydropyridines20,21
or cyclohexenones, which have been identified as key
intermediates in natural product synthesis.22,23 The
reaction of methyl acetoacetate with N-benzylenimines
like 1 yielded 1,4-dihydropyridines (Scheme 1, path A),
but if the benzyl group in 1 was replaced by a tert-butyl
group, the reaction took a completely different course
affording cyclohexenone derivatives, reportedly difficult
to obtain by other methods24,25 (Scheme 1, path B).
In these reactions the 1,3-dicarbonyl compound con-
tributes either two or three carbon atoms to the produced
six-membered ring. On the basis of this observation the
dicarbonyl compound has been depicted in Scheme 1 as
a C2-building block (path A) or as a C3-building block
(path B), respectively.
* To whom correspondence should be addressed. Phone: + 354 525
4807. Fax: + 354 552 8911. E-mail: jkfg@raunvis.hi.is.
X Abstract published in Advance ACS Abstracts, September 15, 1996.
(1) Ohshiro, Y.; Komatsu, M.; Uesaka, M.; Agawa, T. Heterocycles
1984, 22, 549.
(2) Komatsu, M.; Takamatsu, S.; Uesaka, M.; Yamamoto, S.; Ohs-
hiro, Y.; Agawa, T. J . Org. Chem. 1984, 49, 2691.
(3) Barluenga, J .; J ardo´n, J .; Gotor, V. J . Org. Chem. 1985, 50, 802.
(4) Schumann, D.; Mu¨ller, H.-J .; Naumann, A. Liebigs Ann. Chem.
1982, 1700.
(5) Schumann, D.; Naumann, A. Liebigs Ann. Chem. 1984, 1519.
(6) Coss´ıo F. P.; Odriozola, J . M.; Oiarbide, M.; Palomo, C. J . Chem.
Soc., Chem. Commun. 1989, 74.
(7) Uyehara, T.; Chiba, N,; Suzuki, I.; Yamamoto, Y. Tetrahedron
Lett. 1991, 32, 4371.
(8) Yamasaki, Y.; Maekawa, T.; Ishihara, T.; Ando, T. Chem. Lett.
1985, 1387.
Resu lts a n d Discu ssion
(9) Tomioka, K.; Shindo, M.; Koga, K. J . Am. Chem. Soc. 1989, 111,
8266.
(10) Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K. Tetrahedron Lett.
1990, 31, 6681.
(11) Hwang, Y. C.; Fowler, F. W. J . Org. Chem. 1985, 50, 2719.
(12) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology
in Organic Synthesis; Academic Press, Inc.; San Diego, 1987; Vol. 47.
(13) Boger, D. L.; Corbett, W. L.; Wiggins, J . M. J . Org. Chem. 1990,
55, 2999.
The 1-aza-1,3-butadienes 1 and 2 were conveniently
prepared by stirring the dichloromethane solution of an
R,â-unsaturated aldehyde and an amine over molecular
sieves at ambient temperature for 24 h under nitrogen.
(20) Goldmann, S.; Stoltefuss, J . Angew. Chem., Int. Ed. Engl. 1991,
30, 1559.
(14) Wolf, G.; Wu¨rthwein, E.-U. Chem. Ber. 1991, 124, 889.
(15) Davis, J . M.; Whitby, R. J .; J axa-Chamiec, A. J . Chem. Soc.,
Chem. Commun. 1991, 1743.
(16) Duetsch, M.; Stein, F.; Funke, F.; Pohl, E.; Herbst-Irmer, R.;
de Meijere, A. Chem. Ber. 1993, 126, 2535.
(21) Yasui, S.; Nakamura, K.; Fujii, M.; Ohno, A. J . Org. Chem.
1985, 50, 3283.
(22) Hauser, F. M.; Pogany, S. A. Synthesis 1980, 814.
(23) Pietrusiewicz, K. M.; Salamon˜czyk, I. J . Org. Chem. 1988, 53,
2837.
(17) Kno¨lker, H.-J .; Gonser, P.; J ones, P. G. Synlett 1994, 405.
(18) Schuster, E.; Hesse, C.; Schumann, D. Synlett 1991, 916.
(19) Geirsson, J . K. F.; Gudmundsdottir, A. D. Acta Chem. Scand.
1989, 43, 618.
(24) Thomas, H. G. Houben-Weyl, 4th ed.; Georg Thieme Verlag:
Stuttgart, 1976; Vol. VII/2b, p 1530.
(25) Pietrusiewicz, K. M.; Monkiewicz, J .; Bodalski, R. J . Org. Chem.
1983, 48, 788.
S0022-3263(96)00942-5 CCC: $12.00 © 1996 American Chemical Society

Synthesis of N-Benzyl-1,4-dihydropyridines
J . Org. Chem., Vol. 61, No. 21, 1996 7321
Ta ble 1. P r ep a r a tion of Com p ou n d s 3, 4, 5, 8 a n d 10
Sch em e 2
yielda
(%)
compd
R1
R2
R3
bp (°C)/Torr [mp (°C)]
3a
3b
3c
3d
3e
3f
3g
4a
4b
4c
4d
5a
5b
5c
5e
Me
Et
Ph
Me
Me
H
H
H
Me
H
H
H
H
61
44
55
44
72
63
27
66
60
50
20
50
20
40
45
38
56
25
30
44
80
34
62
120-130/0.008
130-140/0.03
180-200/0.03
180-200/0.05
140-150/0.008
[173-174]
H
Me
R ) H
R ) Ph
[117-118]
Me
Et
Ph
Me
Me
Et
Ph
Me
Me
Et
Ph
Me
Me
Et
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
Me
H
H
95-100/0.04
70-80/0.008
[90-92]
30-40/0.05
110-120/0.005
110-120/0.008
190-200/0.008
130-140/0.06
55-65/0.04
This procedure afforded the air- and moisture-sensitive
products as colorless or pale yellow oils in 50-80% yield
after distillation. The molecular sieves could be replaced
by potassium carbonate.26 The protocol was in all cases
advantageous compared with conventional condensation
using a Dean-Stark trap. The N-tert-butylenimines
were less sensitive toward air and moisture than their
N-benzyl analogues and could be stored for months
refrigerated under an inert atmosphere, as judged from
their NMR spectra. It is noteworthy that neither acrolein
nor R,â-unsaturated ketones produced the desired en-
imines.
8a
8b
8c
80-90/0.008
210-220/0.07
80-90/0.008
50-60/0.008
40-50/0.008
170-180/0.008
70-80/0.06
8e
10a
10b
10c
10e
Ph
Me
H
Me
a
Satisfactory spectroscopic data were obtained for all com-
pounds in the table.
Sch em e 3
Rea ction of N-Ben zyl-1-a za -1,3-bu ta d ien es w ith
Acetoa ceta te a n d Acetyla ceton e. We have previously
noted that basic reaction conditions in reactions between
enimines and 1,3-dicarbonyl compounds did not yield any
isolable products,19 and this result was ascribed to the
diminished reactivity of the enimine toward nucleophiles
as compared to the corresponding unsaturated carbonyl
compounds. In order to enhance the reactivity of the
enimines the reaction was carried out with catalytic
amounts of p-toluenesulfonic acid (TsOH) and produced
in good yields 3a from 1a (Scheme 2) and 4a from 2a
(Scheme 4). Unfortunately, the employment of TsOH as
a catalyst was not extendable to the other enimines, and
further efforts to promote the reaction by conventional
Lewis acids (AlCl3, FeCl3, TiCl4, BF3‚OEt2) did not furnish
the products 3/4 in satisfactory yields. Recently, Scettri
et al. reported on the use of lithium iodide as a preferable
catalyst in the Michael reaction when performed under
neutral reaction conditions.27 A minor modification of
their procedure was successful with our compounds.
Stirring a dimethoxyethane (DME) solution of the reac-
tants in the presence of 10 mol % of lithium iodide at
ambient temperature for 24 h afforded the products 3 in
good to excellent yields after chromatographic purifica-
tion (Table 1).
The reaction of 1a -e with acetylacetone yielded the
1,4-DHP 5, but only 5a ,c,e were obtained in satisfactory
yields (see Table 1). The concomitant formation of the
enamino ketone 7 was observed in 20-50% yields, and
in the case of 1d it was formed in 50% yield as the sole
isolable product. An analogous product, the enamino
ester 6, was isolated in small amounts in the reaction of
methyl acetoacetate with enimines 1c and 1d only. The
formation 6 and 7 can be rationalized as an iminolysis
of the dicarbonyl compound,28,29 initiated by the attack
of the imine nitrogen on the carbonyl group. The
synthetic potential of this reaction sequence is exempli-
fied by the transformation of 1e into 1,4-dihydronicoti-
namide derivatives 3f,g as depicted in Scheme 3.
Reaction of N-ter t-Bu tyl-1-aza-1,3-bu tadien es with
Acetoa ceta te a n d Acetyla ceton e. The reaction of
enimines 2 with methyl acetoacetate furnished the cy-
clohexenones 4 in relatively high yields, as seen in Table
1. We did not succeed in isolating 4e in pure form, yet
the phenol 10e was obtained in 62% yield in a one-pot
procedure starting with the enimine 2e.
A competitive reaction channel leading to products
analogous to 6 and 7 was not detected in the case of
enimines 2, but the formation of different reaction
products 9c,d from 2c,d was observed (Scheme 4). These
highly conjugated reaction prodcuts are probably formed
by an initial 1,2-addition of the dicarbonyl compound to
the enimine with subsequent elimination of the amino
functionality. It is noteworthy that the use of catalytic
amounts of Hg(OAc)2 seemed to generally facilitate such
an 1,2-addition. Nevertheless, the isolated yields of 9
remained low (<25%).
The prepared cyclohexenones were easily converted to
the aromatic compounds 10 by treatment with bromine
in acetic acid.22 Similar phenol derivatives have been
used in natural product synthesis,22,23,30 and related
trifluoromethyl derivatives are reported to exhibit bio-
logical activity.31 Attempts to develop this procedure into
a one-pot protocol for the synthesis of phenols were
(26) Afarinkia, K.; Cadogan, J . I. G.; Rees, C. W. Synlett 1992, 123.
(27) Antonioletti, R.; Bonadies, F.; Monteagudo, E. S.; Scettri, A.
Tetrahedron Lett. 1991, 32, 5373.
(28) Sain, B.; Baruah, J . N.; Sandhu, J . S. J . Chem. Soc., Perkin
Trans. 1 1985, 773.
(29) Georgieva, A.; Stanoeva, E.; Spassov, S.; Haimova, M.; De
Kimpe, N.; Boelens, M.; Keppens, M.; Kemme, A.; Mishnev, A.
Tetrahedraon 1995, 51, 6099.
(30) Hauser, F. M.; Ellenberger, S. E. Synthesis 1987, 723.
(31) Hegde, S. G.; Bryant, R. D. Synth. Commun. 1993, 23, 2753.

7322 J . Org. Chem., Vol. 61, No. 21, 1996
Geirsson and J ohannesdottir
Sch em e 4
Sch em e 5
unfruitful with regard to yields, apart from the previously
mentioned 10e.
Analogously, enimines 2 and acetylacetone afforded
cyclohexenones 8 in reasonable yields (see Table 1),
except for enimine 2d , which did not furnish detectable
amounts of 8d . All reactions produced to some extent
the R,â-unsaturated aldehyde from which the enimine
was originally prepared.
Sp ectr oscop ic Id en tifica tion of th e P r od u cts. The
structures of all products were determined from their
NMR spectral data by comparison with previously pub-
lished data of known or similar compounds.
1
The H NMR spectra of compounds 4 revealed for H-6,
located R to both carbonyl groups, a doublet with a
coupling constant between 11.4 and 12 Hz. The observa-
3
tion of this large J (H-6,H-5) led to the assignment of
pseudoaxial dispositions for both pertinent nuclei, thereby
reserving the pseudoequatorial positions for the larger
groups (alkyl/phenyl at C-5 and carbomethoxy at C-6).32
The high stereoselectivity achieved in these cases is
concordant with the findings of other authors.25
Th e Rea ction of 1-Aza -1,3-bu ta d ien es w ith Dim -
eth yl 1,3-Aceton ed ica r boxyla te. In continuing our
studies on the synthetic utility of enimines derived from
relatively simple open-chain R,â-unsaturated aldehydes,
we wished to diversify the products and at the same time
obtain compounds that could serve as intermediates for
further transformations. For that purpose, enimines 1
and 2 were reacted with dimethyl 1,3-acetonedicarboxy-
late (dimethyl 3-oxopentanedioate) 12, in the hope of
realizing similar control of the reaction pathway as
outlined in Scheme 1. When the keto diester 12 was
treated with either 1a or 2a , the only isolable product
was a crystalline compound, whose 1H and 13C NMR
spectra revealed four methoxycarbonyl groups. This
result suggested the participation of two molecules of the
keto diester in the reaction, and so the reaction was
repeated with a diester/enimine ratio of 2:1, affording the
same crystalline product 13a in 80% yield after recrys-
tallization. Similarly, enimines 1c/2c and 1e/2e pro-
duced the bicyclo derivatives 13c and 13e as the sole
products in 82% and 73% yields, respectively. A probable
pathway for the formation of the bicyclo[3.3.1]nonan-3-
one derivatives 13a ,c,e is outlined in Scheme 5, proposing
the intermediate formation of a cyclohexenone derivative
Sch em e 6
that undergoes a second Michael addition with 12 with
an ensuing ring closure. All attempts to isolate or to
identify the cyclohexenone intermediate were to no avail,
and in Scheme 5 the stereochemistry of this intermediate
has been tentatively drawn with reference to 4. Unex-
pectedly, enimines 1b/2b did not afford any isolable
products. The reaction of 12 with enimines 1d /2d
provided the cyclohexanone derivative 14d in 96% yield,
after recrystallization (Scheme 6). The formation of 14d
can easily be explained as an initial 1,2-addition of the
(32) Geirsson, J . K. F.; Gudmundsdottir, A. D. Synthesis 1990, 993.

Synthesis of N-Benzyl-1,4-dihydropyridines
J . Org. Chem., Vol. 61, No. 21, 1996 7323
keto diester to the enimine to afford a product analogous
to 9. A second molecule of the keto diester then under-
goes a Michael addition (1,4-addition) to this intermedi-
ate with a subsequent cyclization. With this in mind,
we returned to the reaction of methyl acetoacetate with
enimines 1c,d /2c,d , which produced 9c,d . A closer look
at these reactions revealed that only the reaction for 1c/
2c, when performed in the presence of catalytic amounts
of Hg(OAc)2, rendered small amounts of a compound 11
comparable to 14d (Scheme 4). The yields of 11 were
increased to 33% if the ratio of acetoacetate/enimine was
raised from 1:1 to 2:1. An analogous cyclohexanone
derivative has been reported as a side product in a
Hantzsch-related synthesis of N-substituted dihydropy-
ridines.33 The stereochemistry proposed for 11 and
displayed in Scheme 4 is based on the observation that
the signals assigned to H-2 and H-4 appeared as doublets
with J ) 11.9 Hz. A third signal at δ 3.87 was assigned
to H-3 and exhibited a dt with J ) 9.7 and 11.9 Hz. This
led to the assignment of axial dispositions for all three
protons. The proposed relative configuration at C-5 is
supported by the observation of a long-range coupling
between the hydroxyl proton of the C-5 hydroxyl and a
proton at C-6, indicating that both the hydroxyl group
and the H-6 are in axial dispositions. The hydroxyl group
is probably hydrogen bonded to the ester carbonyl at C-4,
which might provide the conformational homogeneity to
allow detectable long-range coupling. An analogous
argument was used to define the stereochemistry of
14b,d . A long range coupling between the hydroxyl
proton of the C-3 hydroxyl and H-4 was observed in both
cases.
Interestingly, the base-catalyzed Michael reaction
between the keto diester 12 and the corresponding R,â-
unsaturated aldehyde furnished in excellent yield com-
pounds 13a ,c,e and 14b,d . As previously noted, en-
imines 1b/2b did not afford any identifiable products in
the reaction with the keto diester, but the corresponding
aldehyde, 2-pentenal, reacted to produce a cyclohexanone
derivative 14b in 68% yield (Scheme 6). Acrolein, which
defied transformation to an enimine, reacted to form a
bicyclo[3.3.1]nonan-3-one derivative 13f in 67% yield. The
transformation of the R,â-unsaturated aldehyde to the
less reactive 1-aza-1,3-butadiene derivative obviously
offers no advantages in these cases. Compounds 13 are
thus accessible by a remarkably simple procedure from
readily available starting materials.
the cyclohexane ring defined by C-9, C-5, C-6, C-7, C-8,
and C-1, due to a repulsive interaction with hydrogen or
a substituent on C-9. The stereochemical assignments
at C-7, C-8, and C-9 of 13a were determined for the
1
following data. In the H NMR spectrum, a doublet at δ
2.70 ppm was assigned to the proton at C-8. The large
coupling constant, 3J ) 12.05 Hz, was interpreted as
being due to axial-axial interaction, positioning both the
proton at C-7 and the proton at C-8 in the axial
configurations. A signal observed at δ 1.59 ppm (dtd)
was assigned to the equatorial proton at C-6. This signal
4
displayed a long-range coupling constant, J ) 1.0 Hz,
suggesting that the proton at C-9 possessed an equatorial
orientation. A broad singlet at δ 11.96 ppm was indica-
tive of the fully enolized structure; treatment of 13a with
acetic anhydride in the presence of 4-(dimethylamino)-
pyridine led to the acetylation of the enolic hydroxy
group.
In light of previous results illustrated in Scheme 1, it
is noteworthy that dimethyl 1,3-acetonedicarboxylate
reacted with 1 and 2 merely as a C3-building block,
irrespective of which group, benzyl or tert-butyl, was
attached to the nitrogen atom.
In spite of the absence of rigorous data, the formation
of the products 3, 4, 5, 8, and 13 can be rationalized as
a two-step reaction, the second step being the cyclization
of the Michael adduct 15, depicted in Scheme 7 for
enimines 1a /2a . Examination of models with R′ ) H
suggests that when R ) tert-butyl, steric crowding in the
intermediate 16 is responsible for the alternate reaction
along pathway B. By presuming that the intermediate
15 cyclizes to form 4 through its enol tautomer 17, it can
be tentatively inferred that the low concentration of 17
makes this reaction channel only feasible when pathway
A is hindered. With R′ ) methoxycarbonyl, the situation
is arguably different, i.e., the keto-enol tautomerism
favors tautomer 18 as compared to 17, and cyclohexenone
formation is apparently faster than a competitive reaction
along pathway A, irrespective of which group is attached
to the enimine nitrogen.
In summary, we have disclosed how 1-aza-1,3-buta-
dienes, derived from simple open-chain R,â-unsaturated
aldehydes, give access to unsymmetrically substituted
1,4-DHP or cyclohexenones, depending on the structure
of the 1-aza-1,3-butadiene. For the formation of the
cyclohexenone derivatives 4 and 8 it is clearly advanta-
geous to convert the R,â-unsaturated aldehydes to the
less reactive enimines before conducting the Michael
reaction. Contrary to this result, for the formation of the
bicyclo[3.3.1]nonan-3-one derivatives 13 it is more expe-
dient to apply to enals directly. We did not succeed in
preparing enimines from R,â-unsaturated ketones, and
that limits the scope of the reaction.
It is worthy of note that the prepared compounds 13
exhibited considerable antitumor activity.34 Moreover,
these compounds deserve attention in view of the fact
that bicyclo[3.3.1]nonan-3-one derivatives have been used
as key precursors in a synthetic strategy toward the
taxane skeleton.35-37
The structures of 13 were elucidated on the basis of
their spectral data, representatively illustrated for com-
pound 13a (see Scheme 5, R ) Me, R′ ) H). It has been
argued38,39 for bicyclo[3.3.1]nonane derivatives that an
equatorial substituent on C-7 excludes the boat form for
Exp er im en ta l Section
The H and 13C NMR spectra were recorded on a 250 MHz
1
spectrometer. Chemical shifts are reported in ppm with
respect to residual CHCl3 at 7.26 downfield from Me4Si.
Multiplicities in the 13C NMR spectra were determined using
DEPT pulse sequences. 2D COSY (H/H and C/H) experiments
were performed with compounds 13a ,e and 14b. IR spectra
were recorded as thin films or KBr pellets. Elemental analyses
were carried out at the University of Iceland. Melting points
were determined in open capillaries and are uncorrected.
(33) Chupp, J . P. J . Heterocycl. Chem. 1990, 27, 1697.
(34) Tested for us by Dr. V. L. Narayanan and his team at the
National Cancer Institute, Bethesda, MD.
(35) Neh, H.; Blechert, S.; Schnick, W.; J ansen, M. Angew Chem.
1984, 96, 903.
(36) Blechert, S.; Kleine-Klausing, A. Angew. Chem., Int. Ed. Engl.
1991, 30, 412.
(37) Blechert, S.; J ansen, R.; Velder, J . Tetrahedron 1994, 50, 9649.
(38) Aranda, G.; Bernassau, J .-M.; Fetizon, M.; Hanna, I. J . Org.
Chem. 1985, 50, 1156.
(39) Camps. P.; Castan˜e, J .; Feliz, M.; J aime, C.; Minguillo´n, C.
Chem. Ber. 1989, 122, 1313.

7324 J . Org. Chem., Vol. 61, No. 21, 1996
Geirsson and J ohannesdottir
Sch em e 7
Distillation of small amounts was effected with a bulb-to-bulb
distillation in a Kugelrohr oven. Analytical TLC was per-
formed by using 0.25 mm coated silica gel plates with F-254
indicator. Visualization was accomplished by UV light.
for C18H24O10: C, 54.00; H, 6.04; O, 39.96. Found: C, 54.34;
H, 5.96.
1-H y d r o x y -2,4,8,9-t e t r a k i s (m e t h o x y c a r b o n y l)-7-
ph en ylbicyclo[3.3.1]n on an -3-on e (13c): yield 82%; mp 176-
1
177 °C (methanol); IR (KBr) 1730, 1755, 3500 cm-1; H NMR
Gen er a l P r oced u r e. The reactions were carried out under
nitrogen in thoroughly dried glassware, and the procedure was
essentially the same in all cases. A solution of the dicarbonyl
compound (0.01 mol) and lithium iodide (0.001 mol) in 2-3
mL of dry DME was added dropwise to a stirred solution of
the enimine (0.01 mol) in 5-10 mL of dry DME. The resulting
mixture was stirred at ambient temperature for 24 h (for the
preparation of 3f,g, molecular sieves (4A) were added and the
mixture was stirred at 0 °C for 48 h). After removal of the
solvent under reduced pressure, oily residues were purified
by short column chromatography (silica gel, eluted with
dichloromethane/ethyl acetate) and Kugelrohr distillation.
Crystals were recrystallized from dichloromethane (3f), 1-bu-
tanol (3g), hexane (4c, 11), and methanol (13, 14).
(CDCl3) δ 1.64 (1 H, ddd, J ) 3.1, 12.3, 14.0 Hz), 1.69 (1 H,
ddd, J ) 3.1, 5.6, 14.0 Hz), 2.98 (1 H, dt, J ) 5.6, 12.3 Hz),
3.42 (1 H, d, J ) 12.3 Hz), 3.42 (3 H, s), 3.60 (1 H, q, J ) 3.1
Hz), 3.65 (1 H, d, J ) 3.1 Hz), 3.74 (3 H, s), 3.78 (3 H, s), 3.85
(3 H, s), 4.49 (1 H, s), 4.50 (1 H, s), 7.11-7.28 (5 H, m), 12.07
(1 H, s); 13C NMR (CDCl3) δ 32.0 (d), 33.7 (t), 39.6 (d), 46.4
(d), 51.7 (q), 51.9 (q), 52.2 (d), 52.4 (q), 52.5 (q), 56.3 (d), 72.0
(s), 101.8 (s), 127.0 (d), 127.5 (d, 2 C), 128.4 (d, 2 C), 141.2 (s),
167,7 (s), 170.0 (s), 170.8 (s), 172.1 (s), 173.4 (s). Anal. Calcd
for C23H26O10: C, 59.74; H, 5.67; O, 34.58. Found: C, 59.85,
H, 5.53.
1-H y d r o x y -2,4,8,9-t e t r a k is (m e t h o x y c a r b o n y l)-6,7-
d im eth ylbicyclo[3.3.1]n on a n -3-on e (13e): yield 73%; mp
1
127-128 °C (methanol); IR (KBr) 1735, 1750, 3500 cm-1; H
Compounds 3, 4, 5, 8, and 10 are either known or similar
to known compounds. The analytical and spectra data for 11,
13, and 14 are as follows.
NMR (CDCl3) δ 0.78 (3 H, d, J ) 5.4 Hz), 0.81 (3 H, d, J ) 5.8
Hz), 1.24 (1 H, ddq, J ) 3.0, 12.0, 5.8 Hz), 1.48 (1 H, tq, J )
12.0, 5.4 Hz), 2.78 (1 H, d, J ) 12.0 Hz), 3.47 (1 H, t, J ) 3.0
Hz), 3.53 (1 H, d, J ) 3.0 Hz), 3.70 (3 H, s), 3.73 (3 H, s), 3.77
(3 H, s), 3.78 (3 H, s), 4.50 (2 H, s), 12.24 (1 H, s); 13C NMR
(CDCl3) δ 16.4 (q), 16.9 (q), 33.2 (d), 37.1 (d), 38.7 (d), 47.8 (d),
51.6 (q), 51.8 (d), 51.9 (q), 52.3 (q), 52.4 (q), 57.8 (d), 71.8 (s),
99.6 (s), 168.4 (s), 170.2 (s), 171.6 (s), 173.2 (s), 173.6 (s); LD-
FTMS m/z 437 (M + Na+), 405, 365. Anal. Calcd for
C19H26O10: C, 55.07, H, 6.32; O, 38.61. Found: C, 54.96; H,
6.18.
5-H yd r oxy-2,4-Bis(m et h oxyca r b on yl)-5-m et h yl-3-(2-
p h en yleth en yl)cycloh exa n on e (11): mp 182-183 °C (hex-
ane); IR (KBr) 1710, 1725, 1740, 3410 cm-1; 1H NMR (C6D6) δ
0.93 (3 H, s), 1.67 (1 H, dd, J ) 2.7, 14.3 Hz), 2.26 (1 H, d, J
) 11.9 Hz), 2.53 (1 H, d, J ) 14.3 Hz), 3.06 (3 H, s), 3.07 (1 H,
d, J ) 11.9 Hz), 3.37 (3 H, s), 3.59 (1 H, d, J ) 2.7 Hz (D2O-
exchangeable)), 3.87 (1 H, dt, J ) 9.7, 11.9 Hz), 5.83 (1 H, dd,
J ) 9.7, 15.6 Hz), 6.50 (1 H, d, J ) 15.6 Hz), 7.05-7.19 (5 H,
m); 13C NMR (CDCl3) δ 28.7 (q), 43.6 (d), 52.2 (d), 52.3 (q),
52.4 (t), 55.6 (d), 61.5 (d), 72.9 (s), 126.5 (d, 3 C), 128.0 (d),
128.6 (d, 2 C), 133.8 (d), 136.3 (s), 168.3 (s), 174.4 (s), 200.8
(s). A resolution of the signal at 126.5 ppm was achieved in
acetone-d6; LD-FTMS m/z 385 (M + K+), 329. Anal. Calcd
for C19H22O6: C, 65.88; H, 6.40; O, 27.71. Found: C, 65.54;
H, 6.47.
1-Hyd r oxy-2,4,8,9-tetr a k is(m eth oxyca r bon yl)bicyclo-
[3.3.1]n on a n -3-on e (13f): yield 67%; mp 116-117 °C (metha-
nol); IR (KBr) 1725, 1760, 3510 cm-1; 1H NMR (CDCl3) δ 1.57
(3 H, m), 1.81 (1 H, m), 3.33 (1 H, dd, J ) 4.5, 12.6 Hz), 3.45
(1 H, q, J ) 2.9 Hz), 3.50 (1 H, d, J ) 2.9 Hz), 3.74 (3 H, s),
3.75 (3 H, s), 3.76 (3 H, s), 3.78 (3 H, s), 4.18 (1 H, s), 4.67 (1
H, s), 12.00 (1 H, s); 1H NMR (C6D6) δ 1.22-1.30 (1 H, m),
1.38-1.70 (3 H, m), 3.14 (3 H, s), 3.16 (3 H, s), 3.25 (3 H, s),
3.40 (3 H, s), 3.42 (1 H, q, J ) 3.2 Hz), 3.49 (1 H, dd, J ) 4.8,
12.5 Hz), 3.95 (1 H, dd, J ) 0.8, 3.2 Hz), 4.72 (1 H, s), 5.10 (1
H, s), 12.66 (1 H, s); 13C NMR (CDCl3) δ 21.4 (t), 24.7 (t), 32.0
(d), 46.6 (d), 48.7 (d), 51.9 (q), 52.11 (q), 52.14 (q), 52.6 (q),
53.0 (d), 71.3 (s), 101.4 (s), 167.4 (s), 169.8 (s), 170.9 (s), 173.1
(s), 173.9 (s); LD-FTMS m/z 409 (M + Na+), 355, 337. Anal.
Calcd for C17H22O10: C, 52.85; H, 5.74; O, 41.41. Found: C,
53.00; H, 5.74.
1-H y d r o x y -2,4,8,9-t e t r a k i s (m e t h o x y c a r b o n y l)-7-
m eth ylbicyclo[3.3.1]n on a n -3-on e (13a ): yield 80%; mp
163-165 °C (methanol); IR (KBr) 1710, 1735, 1760, 3490 cm-1
;
1H NMR (CDCl3) δ 0.83 (3 H, d, J ) 6.4 Hz), 1.15 (1 H, ddd, J
) 3.2, 11.8, 14.1 Hz), 1.59 (1 H, dtd, J ) 1.0, 3.2, 14.1 Hz),
1.87 (1 H, m), 2.70 (1 H, d, J ) 12.0 Hz), 3.50 (1 H, q, J ) 3.2
Hz), 3.53 (1 H, dd, J ) 1.0, 3.2 Hz), 3.71 (3 H, s), 3.73 (3 H, s),
3.78 (3 H, s), 3.79 (3 H, s), 4.45 (1 H, s) 4.52 (1 H, s), 11.96 (1
H, s); 13C NMR (CDCl3) δ 19.3 (q), 28.0 (d), 31.8 (d), 34.1 (t),
46.4 (d), 51.8 (q), 51.88 (d), 51.92 (q), 52.3 (q), 52.4 (q), 57.9
(d), 71.9 (s), 101.9 (s), 167.6 (s), 170.2 (s), 170.8 (s), 173.0 (s),
173.5 (s); LD-FTMS m/z 439 (M + K+), 351, 319. Anal. Calcd
5-(1-Bu ten yl)-3-h yd r oxy-2,4,6-tr is(m eth oxyca r bon yl)-
3-[(m eth oxyca r bon yl)m eth yl]cycloh exa n on e (14b): yield
68%; mp 140-141 °C (methanol); IR (KBr) 1730, 1750, 3530

Synthesis of N-Benzyl-1,4-dihydropyridines
J . Org. Chem., Vol. 61, No. 21, 1996 7325
1
cm-1; H NMR (CDCl3) δ 0.88 (3 H, t, J ) 7.5 Hz), 1.92 (2 H,
10.3, 11.8, 11.9 Hz), 4.36 (1 H, d, J ) 0.6 Hz), 4.53 (1 H, d, J
) 1.8 Hz (D2O-exchangeable)), 4.82 (1 H, dm, J ) 10.3 Hz);
13C NMR (CDCl3) δ 18.1 (q), 25.8 (q), 37.5 (d), 42.4 (t), 51.8
(q), 51.9 (q), 52.1 (q), 52.7 (q), 53.1 (d), 61.6 (d), 61.8 (d), 74.8
(s) 122.0 (d), 138.1 (s), 167.7 (s), 170.0 (s), 170.5 (s), 170.6 (s),
197.9 (s); LD-FTMS m/z 453 (M + K+), 405, 365. Anal. Calcd
for C19H26O10: C, 55.07; H, 6.32; O, 38.61. Found: C, 54.92;
H, 6.18.
ddq, J ) 1.2, 6.5, 7.5 Hz), 2.71 (AB system 2 H, νA ) 2.64 ppm,
νB ) 2.79 ppm, J AB ) 17.6 Hz), 3.17 (1 H, dd, J ) 1.8, 12.0
Hz), 3.34 (1 H, dd, J ) 0.6, 12.0 Hz), 3.59 (1 H, dt, J ) 8.7,
12.0 Hz), 3.67 (3 H, s), 3.699 (3 H, s), 3.701 (3 H, s), 3.78 (3 H,
s), 4.33 (1 H, d, J ) 0.6 Hz), 4.47 (1 H, d, J ) 1.8 Hz (D2O-
exchangeable)), 5.16 (1 H, ddt, J ) 15.3, 8.7, 1.2 Hz), 5.67 (1
H, dt, J ) 15.3, 6.5 Hz); 13C NMR (CDCl3) δ 13.6 (q), 25.4 (t),
41.2 (d), 42.4 (t), 51.8 (q), 51.9 (q), 52.1 (q), 52.6 (q), 52.9 (d),
61.5 (d), 61.8 (d), 74.7 (s), 126.1 (d), 137.6 (d), 167.6 (s), 169.8
(s), 170.5 (s), 170.5 (s, 2 C), 197.7 (s). Anal. Calcd for
C19H26O10: C, 55.07; H, 6.32; O, 38.61. Found: C, 55.10; H,
6.35.
Ack n ow led gm en t. Support of this work from the
Icelandic Science Foundation is gratefully acknowl-
edged. We are indepted to Dr. B. O¨ . Gudmundsson for
discussion of the NMR spectra and to Dr. A. Bjarnason
for discussion of the mass spectra. J .K.F.G. thanks
Professor D. L. Comins at the North Carolina State
University, Raleigh, for use of his facilities during a stay
in North Carolina.
3-H yd r oxy-2,4,6-t r is(m et h oxyca r b on yl)-3-[(m et h oxy-
c a r b o n y l)m e t h y l]-5-(2-m e t h y l-1-p r o p e n y l)c y c lo h e x -
a n on e (14d ): yield 96%; mp 148-149 °C (methanol); IR (KBr)
1730, 1750, 3490 cm-1; H NMR (CDCl3) δ 1.63 (3 H, d, J )
1
1.3 Hz), 1.66 (3 H, d, J ) 1.3 Hz), 2.70 (AB system 2H, νA
)
2.63 ppm, νB ) 2.78 ppm, J AB ) 17.6 Hz), 3.11 (1 H, dd, J )
1.8, 11.8 Hz), 3.28 (1 H, dd, J ) 0.6, 11.9 Hz), 3.65 (3 H, s),
3.69 (3 H, s), 3.70 (3 H, s), 3.78 (3 H, s), 3.94 (1 H, ddd, J )
J O960942F