Preparation and cycloaddition reactions of enantiopure 2-(N-acylamino)-1,3-dienes for the synthesis of octahydroquinoline derivatives

Article abstract of DOI:10.1021/jo0344687

Stille, Suzuki-Miyaura, and Sonogashira cross-coupling reactions were carried out with a glutarimide-derived vinyl phosphate, bearing a chiral auxiliary on the N atom, to prepare enantiopure 2-(N-acylamino)-1,3-dienes as partners in Diels-Alder reactions.

Full text of DOI:10.1021/jo0344687

P r ep a r a tion a n d Cycloa d d ition Rea ction s of En a n tiop u r e
2-(N-Acyla m in o)-1,3-d ien es for th e Syn th esis of
Octa h yd r oqu in olin e Der iva tives
Fabrizio Lo Galbo,† Ernesto G. Occhiato,*,† Antonio Guarna,† and Cristina Faggi‡
Dipartimento di Chimica Organica “U. Schiff” and ICCOM, Polo Scientifico, Universita` di Firenze,
Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy, and CRIST, Centro Interdipartimentale di
Cristallografia, Universita` di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino (FI), Italy
ernesto.occhiato@unifi.it
Received April 14, 2003
Stille, Suzuki-Miyaura, and Sonogashira cross-coupling reactions were carried out with a
glutarimide-derived vinyl phosphate, bearing a chiral auxiliary on the N atom, to prepare
enantiopure 2-(N-acylamino)-1,3-dienes as partners in Diels-Alder reactions. The cycloadditions
were performed with various dienophiles under thermal conditions, with or without Lewis acids.
With maleimides, the preferential formation of endo cycloadducts was observed, whereas with
acrylamides the exo approach prevailed. Furthermore, in the latter case, 6-substitued octahydro-
quinolinones were obtained in accordance with the predicted regioselectivity. Since diastereopure
compounds were in all cases obtained either by chromatography or by crystallization, and because
of the easy access to a variety of boronic acids, to be used in the coupling step, this methodology is
useful for the short synthesis of differently substituted, enantiopure octahydroquinolinones amenable
to further transformation into decahydroquinolines possessing interesting biological activities.
In tr od u ction
In recent years, the Pd-catalyzed cross-coupling reac-
tions of lactam-derived vinyl triflates1 and phosphates2
1 and 2 (Figure 1) have gained increasing importance in
the synthesis of heterocyclic compounds.3 To this end, an
effective strategy involves reacting 1 with tributyl(vinyl)-
tin in order to obtain coupling products such as 3 (Figure
* To whom correspondence should be addressed. Tel: +39-055-
4573480. Fax: +39-055-4573531.
† Dipartimento di Chimica Organica “U. Schiff” and ICCOM, Polo
Scientifico, Universita` di Firenze.
‡ Centro Interdipartimentale di Cristallografia, Universita` di
Firenze.
F IGURE 1.
(1) (a) Occhiato, E. G.; Trabocchi, A.; Guarna, A. J . Org. Chem. 2001,
66, 2459-2465. (b) Occhiato, E. G.; Trabocchi, A.; Guarna, A. Org. Lett.
2000, 2, 1241-1242; (c) Luker, T.; Hiemstra, H.; Speckamp, W. N. J .
Org. Chem. 1997, 62, 8131-8140. (d) Luker, T.; Hiemstra, H.;
Speckamp, W. N. Tetrahedron Lett. 1996, 37, 8257-8260. (e) Bernabe´,
P.; Rutjes, F. P. J . T.; Hiemstra, H.; Speckamp, W. N. Tetrahedron
Lett. 1996, 37, 3561-3564. (f) Foti, C. J .; Comins, D. L. J . Org. Chem.
1995, 60, 2656-2657. (g) Okita, T.; Isobe, M. Tetrahedron 1995, 51,
3737-3744. (h) Okita, T.; Isobe, M. Synlett 1994, 589-590.
(2) (a) Lepifre, F.; Clavier, S.; Bouyssou, P.; Coudert, G. Tetrahedron
2001, 57, 6969-6975. (b) Lepifre, F.; Buon, C.; Rabot, R.; Bouyssou,
P.; Coudert, G. Tetrahedron Lett. 1999, 40, 6373-6376.
(3) (a) Occhiato, E. G.; Prandi, C.; Ferrali, A.; Guarna, A.; Deagos-
tino, A.; Venturello, P. J . Org. Chem. 2002, 67, 7144-7146. (b) Xu, Z.;
Kozlowski, M. C. J . Org. Chem. 2002, 67, 3072-3078. (c) Buon, C.;
Chacun-Lefe`vre, L.; Rabot, R.; Bouyssou, P.; Coudert, G. Tetrahedron
2000, 56, 605-614. (d) Lindstro¨m, S.; Ripa, L.; Hallberg, A. Org. Lett.
2000, 2, 2291-2293. (e) J iang, J .; De Vita, R. J .; Doss, G. A.; Goulet,
M. T.; Wyvratt, M. J . J . Am. Chem. Soc. 1999, 121, 593-594. (f)
Toyooka, N.; Okumura, M.; Takahata, H.; Nemoto, H. Tetrahedron
1999, 55, 10673-10684. (g) Toyooka, N.; Okumura, M.; Takahata, H.
J . Org. Chem. 1999, 64, 2182-2183. (h) Ha, J . D.; Kang, C. H.;
Belmore, K. A.; Cha, J . K. J . Org. Chem. 1998, 63, 3810-3811. (i)
Luker, T.; Hiemstra, H.; Speckamp, W. N. J . Org. Chem. 1997, 62,
3592-3596. (j) Ha, J . D.; Lee, D.; Cha, J . K. J . Org. Chem. 1997, 62,
4550-4551. (k) Beccalli, E. M.; Marchesini, A. Tetrahedron 1995, 51,
2353-2362.
1) containing a 2-(N-acylamino)-1,3-diene moiety.3h These
are then used for [4 + 2] cycloadditions with various
dienophiles to prepare octahydroquinolines3h,4 as inter-
mediates in the synthesis of decahydroquinolines.5 Our
interest in Pd-catalyzed cross-coupling reactions1a,b,3a has
led us to undertake a research on the use of an imide-
derived vinyl phosphate of type 4 (Figure 1) that bears a
simple and inexpensive chiral auxiliary on the N atom,
for the preparation of enantiopure 2-(N-acylamino)-1,3-
dienes 5 to be used as partners in cycloaddition reactions
for the synthesis of octahydroquinoline derivatives. Fur-
ther interest in this study was stimulated by the fact that
2-(N-acylamino)-1,3-dienes have been very rarely used
(4) A similar approach to the synthesis of enantiopure octahydro-
quinolines is based on Diels-Alder reactions of N-acyl 5-vinyl-2,3-
dihydro-4-pyridones prepared by Stille coupling reaction of the corre-
sponding 5-iodo substituted pyridones with tributyl(vinyl)tin. Kuethe,
J . T.; Brooks, C. A.; Comins, D. L. Org. Lett. 2003, 5, 321-323.
10.1021/jo0344687 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/17/2003
6360
J . Org. Chem. 2003, 68, 6360-6368

Synthesis of Octahydroquinoline Derivatives
in cycloaddition reactions3h,6 and that, therefore, little is
known about their reactivity. For example, a strikingly
anomalous regiochemical preference, in contrast to the
predictions based on HOMO diene-LUMO dienophile
interactions, has been observed in the cycloadditions of
dienes 3 with acrylates and other dienophiles.3h
Imides are good candidates for the generation of type
4 vinyl triflates or phosphates (Figure 1) since the second,
unreacted carbonyl group can stabilize the structure in
the same way as the electron-withdrawing N substituent1c
present in the analogous compounds 1 and 2. That of an
intramolecular Heck reaction leading to racemic cytisine
is the only application example of these imide derivatives
in Pd-catalyzed reactions,7 whereas, to our knowledge,
cross-coupling processes such as Stille, Suzuki-Miyaura,
and Sonogashira reactions involving 4 have never been
described.
SCHEME 1 a
Resu lts a n d Discu ssion
For this study, we chose enantiopure (R)-(+)-glutarim-
ide 6 (Scheme 1) as the starting material for the genera-
tion of the corresponding vinyl phosphate and triflate
derivatives. Imide 6 was prepared starting from com-
mercially available glutaric anhydride and (R)-(+)-1-
phenylethylamine through a modification of a reported
procedure.8 After a series of failed attempts to quanti-
tatively prepare triflate 7, with the concurrent formation
of bis-triflate 8 being in some cases observed, we turned
to the use of cheaper vinyl phosphate 9 for carrying out
the coupling reactions (Scheme 1). Imide 6 was quanti-
tatively converted into vinyl phosphate 9 by treatment
with LHMDS at 0 °C in THF, followed by addition of
(PhO)2P(O)Cl at -78 °C. Attempts at obtaining pure 9
by chromatography on neutral alumina were unfruitful,
since they caused partial degradation to the starting
imide. However, we found that 9 can be conveniently
used in the cross-coupling reactions as a crude material,
although within a few days after its preparation, as it
tends to decompose even when stored at 4 °C. Coupling
carried out with tributyl(vinyl)tin under standard Stille
conditions (Scheme 1) afforded diene 10a in 52% yield.
The introduction of the unsubstituted vinyl moiety was
also achieved through a Suzuki-Miyaura coupling with
commercially available vinylboronic acid dibutyl ester
11a (R1 ) R2 ) H, R3 ) n-Bu). Since competing and
a
Key: (a) KHMDS, THF, -78 °C, 1 h; then PhNTf2, - 78 °C to
rt, 1 h; (b) LHMDS, THF, 0 °C to rt, 1 h; then (PhO)2P(O)Cl, -78
°C to rt, 1.5 h; (c) 5% (Ph3P)4Pd, MeONa, THF, 40 °C; (d) 5%
(Ph3P)2PdCl2, THF, 2 M Na2CO3, 40 °C; (e) 4% (Ph3P)4Pd, LiCl
(10 equiv), THF, reflux, 4 h.
sometimes prevailing Heck reactions have been reported
for vinylboronic esters,9 we thought that a quantitative
quaternization of the boron atom prior reacting 11a with
9 under Pd catalysis would decrease the extent of this
unwanted reaction.10 Thus, 11a was treated with 1 equiv
of MeONa in THF and the resulting solution used for
the coupling with 9 in the presence of 5% (Ph3P)4Pd as a
catalyst at 40 °C in THF. The reaction was complete after
2 h and afforded pure 10a in 66% yield after chromatog-
1
raphy. The Heck product was not observed by H NMR
analysis of the crude reaction mixture. Even better
results were obtained by carrying out the reaction under
conditions already experimented for the coupling of
lactam-derived vinyl triflates with boronic acids,1a i.e.,
with 5% (Ph3P)2PdCl2 in THF and aqueous 2 M Na2CO3
as a base, providing 10a in 77% yield.
These conditions were then applied to the coupling of
9 with boronic acids 11b,c (R3 ) H) and 2-[(Z)-1-ethylbut-
1-enyl]benzo-1,3,2-dioxaborole 11d (Scheme 1), affording
the corresponding coupling products 10b-d in 70-85%
yield. All these coupling products proved stable, with the
exception of 10c which tends to decompose and therefore
must be used for the subsequent reactions within a few
days after its preparation.
(5) The importance of these compounds arises from the presence of
the decahydroquinoline ring in several natural alkaloids isolated from,
e.g., the tunicate Clavelina lepadiformis, predatory flatworm Prosth-
eceraeus villatus, Lycopodium club mosses, skin of Dendrobates
amphibians, and myrmicine ants. These and several, related synthetic
molecules exert diverse biological activities which depend on the type
and degree of substitution and ring fusion. See, for example: Spande,
T. F.; J ain, P.; Garraffo, H. M.; Pannell, L. K.; Yeh, H. J . C.; Daly, J .
W.; Fukumoto, S.; Imamura, K.; Tokuyama, T.; Torres, J . A.; Snelling,
R. R.; J ones, T. H. J . Nat. Prod. 1999, 62, 5-21. Daly, J . W.; Garraffo,
H. M.; Spande, T. F. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: New York, 1993; Vol. 43, pp 185-288. Daly, J . W. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1998; Vol.
50, pp 141-169. Ozawa, T.; Aoyagi, S.; Kibayashi, C. J . Org. Chem.
2001, 66, 3338-3347 and referenced therein. Morita, H.; Hirasawa,
Y.; Yoshida, N.; Kobayashi, J . Tetrahedron Lett. 2001, 42, 4199-4201
and references therein.
Coupling of 9 with boronic acid derivatives 11b,c gave
the corresponding dienes 10b,c with the external double
bond having E stereochemistry. The corresponding Z
(9) (a) Hunt, A. R.; Stewart, S. K.; Whiting, A. Tetrahedron Lett.
1993, 34, 3599-3602. (b) Stewart, S. K.; Whiting, A. J . Organomet.
Chem. 1994, 482, 293-300.
(10) This should increase the rate of the transmetalation step.
Molander has recently reported on the use of potassium vinyltrifluo-
(6) (a) Overman, L. E.; Clizbe, L. A. J . Am. Chem. Soc. 1976, 98,
2352-2354. (b) Terada, A.; Murata, K. Bull. Chem. Soc. J pn. 1967,
40, 1644-1649.
roborate as
a useful reagent for introducing a vinyl moiety by
(7) Coe, J . W. Org. Lett. 2000, 2, 4205-4208.
Pd-catalyzed reaction with aryl halides and triflates without competing
Heck reaction. Molander, G. A.; Rivero, M. R. Org. Lett. 2002, 4, 107-
109.
(8) Kiguchi, T.; Nakazono, Y.; Kotera, S.; Ninomiya, I.; Naito, T.
Heterocycles 1990, 31, 1525-1535.
J . Org. Chem, Vol. 68, No. 16, 2003 6361

Galbo et al.
SCHEME 2 a
2.1 M (entry 5). Under these conditions, the cycloaddition
was complete in 3 days, providing the highest endo/exo
product ratio (12:1). The mixture of endo products 14a
and 15a , in which 15a was prevailing (60% de), was
obtained in 90% yield after chromatography. Although
the reaction did not occur with high facial selectivity, the
major diastereomer 15a could be obtained in pure form
and good yield (52%) by crystallization from an EtOAc/
cyclohexane mixture.
X-ray analysis11 of the crystals (see the Supporting
Information) allowed us to assign the absolute configu-
ration of the newly created stereocenters and ascertain
that the dienophile preferentially approached the face of
diene 10a opposite to the phenyl group of the auxiliary,
according to a model in which the smallest substituent
of the auxiliary (the H atom) points toward the external
double bond.8,12
Another reaction of diene 10a with N-phenylmaleimide
was carried out in the presence of 1 equiv of TiCl4 at -78
°C (Scheme 2). The reaction was complete in 15 min, but
provided a mixture of diastereomers 16a and 17a (not
separated by chromatography or crystallization) in a low
ratio (33% de), in which migration of the double bond
had occurred. The structural assignment to the major
diastereomer was possible as treatment of pure 15a
with TiCl4 at - 78 °C for 15 min leads to almost com-
a
Key: (a) see Table 1 for conditions; (b) N-phenylmaleimide,
TiCl4, CH2Cl2, -78 °C, 15 min; (c) TiCl4, CH2Cl2, -78 °C, 15 min.
SCHEME 3 a
1
plete isomerization to 17a (95% conversion by H NMR
analysis).
The reaction of N-phenylmaleimide with a high con-
centration of the dienes 10b and 10c was carried out as
described above at -18 °C (entries 8 and 10), yielding in
both cases separable mixtures of endo/exo products in a
13:1 ratio and major diastereomers 15b and 15c with a
74% de value. Diasteropure 15b and 15c were obtained
in good yields (61-64%) by crystallization from EtOAc/
cyclohexane. X-ray analyses11 of the crystals (see the
Supporting Information) were again consistent with the
model proposed above for the approach of the dienophile.
Finally, diene 10d failed to react with N-phenylmaleim-
ide even in refluxing toluene, presumably because of the
strain between the chiral auxiliary and one of the ethyl
residues, which prevents the diene from assuming the
required s-cis conformation.
In the attempt at increasing the facial selectivity by
double stereodifferentiation, 10a was reacted with both
enantiomers of commercial N-(1-phenylethyl)maleimide
(Scheme 2) under the conditions of entry 3 reported in
Table 1. However, not only did the de values not increase
compared with the cycloaddition with N-phenylmaleim-
ide (Table 1, entry 3), but the sterically more demanding
N substituent of the imide amplified the exo approach.
In fact, the reaction with the R maleimide produced a
mixture of separable endo and exo products in a 2.3:1
ratio, with the predominant isomer 15d (structural
assignment tentative, based on comparison of the 1H
NMR spectra of 15d and 15a ) having a 46% de value.
a
Key: (a) 5% (Ph3P)2PdCl2, 10% CuI, 1-alkyne, TEA-CHCl3
3:1, 1 h, 50 °C; (b) 5% Pd/CaCO3-Pb, H2(g), EtOH, rt; (c)
N-phenylmaleimide, toluene, 100 °C, 24 h; (d) TiCl4, CH2Cl2,
-78 °C.
compounds could be obtained by Sonogashira couplings
of 9 with 1-hexyne and phenylacetylene, followed by
partial hydrogenation of the triple bond (Scheme 3). The
couplings furnished 12a and 12b in 87 and 64% yield,
respectively, but the partial hydrogenation over Lindlar
catalyst proved quite troublesome as dienes 13 could
never be obtained as the only hydrogenation products.
Under the best conditions (5% Pd/CaCO3 + Pb, in EtOH),
compounds 13a and 13b were obtained in 60 and 70%
yield, respectively, as mixtures containing the products
bearing a fully hydrogenated side chain.
In the initial stage of this study, a first series of
cycloadditions was carried out with the symmetrical
dienophile N-phenylmaleimide in order to avoid the
formation of regioisomeric mixtures (Scheme 2). After a
series of experiments (Table 1, entries 1-4), we eventu-
ally found that the reaction of 10a with N-phenylmale-
imide is best carried out at low temperature (-18 °C)
and by increasing the concentration of the diene up to
(11) The X-ray CIF files for all structures have been deposited at
the Cambridge Crystallographic Data Centre and allocated with the
deposition numbers CCDC 200006 for compound 15a , CCDC 200008
for compound 15b, CCDC 200007 for compound 15c, CCDC 201406
for compound 20b, CCDC 208282 for 21d .
(12) A Monte Carlo conformational search did not rule out, however,
other possible conformations stabilized by π-stacking between the
phenyl group of the auxiliary and the external double bond, which
further complicate the interpretation of the stereochemical outcome.
6362 J . Org. Chem., Vol. 68, No. 16, 2003

Synthesis of Octahydroquinoline Derivatives
TABLE 1. Cycloa d d ition s of 10a -c w ith N-P h en ylm a leim id e
endo/exo
14 + 15
de of 15 after
entry
R
conditions
time (h)
product ratioa
(% yield)b
de (%)c
crystallizationc (%) (% yield)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
n-Bu
n-Bu
n-Bu
Ph
benzene, refluxd
DCM,d 20 °C
DCMe
2
168
4:1
5.5:1
6:1
5.5:1
12:1
3.5:1
6:1
13:1
5:1
13:1
53
85
34
46
47
43
60
49
61
74
64
74
>99 (39)
>99 (52)
DCM,f 20 °C
DCM,f -18 °C
benzene,d reflux
DCMe
0.75
72
2
90
58
85
92
68
88
>99 (44)
>99 (64)
>99 (36)
>99 (61)
DCM,f -18 °C
DCMe
72
10
Ph
DCM,f -18 °C
72
a
b
d
By 1H NMR of the crude reaction mixture. After chromatography. c By 1H NMR. Concentration of diene 0.12 M, 1.5 equiv of
N-phenylmaleimide. e A 0.08 M solution of diene was concentrated under vacuum by a rotary evaporator, heating with an external bath
at 40 °C, 1.5 equiv of N-phenylmaleimide. f Concentration of diene 2.1 M, 1.5 equiv of N-phenylmaleimide.
SCHEME 4 a
With (S)-N-(1-phenylethyl)maleimide we observed the
same endo/exo product ratio as above, but we incurred
in a mismatched case, since the two endo products 14e
and 15e were obtained in a 1:1 ratio.
The cycloaddition of dienes 13 (Scheme 3) with N-
phenylmaleimide should in principle yield epimers of
compounds 14 and 15. However, phenyl-substituted diene
13a did not react under any conditions, while n-butyl-
substituted diene 13b gave a low conversion to cycload-
ducts 18 and 19 (25% yield after chromatography, 72%
de) after heating at 100 °C in toluene for 24 h. The steric
clash between the distal n-butyl chain and the proton
on C-5, which would destabilize the s-cis conformation,
may be attributed to these results. The harsh reaction
conditions caused also migration of the double bond. An
NOE study on major isomer 19 allowed us to assign a
cis relative stereochemistry of protons 4-H and 9b-H.
This is consistent with an exo approach of the dienophile
favored by the high reaction temperature. Moreover, pure
compound 19 was obtained by TiCl4-induced isomeriza-
a
Key: (a) ethyl acrylate, toluene, 90 °C, 24 h; (b) CH2Cl2, rt, 4
tion of 15b. Thus its formation must have occurred by a
days; (c) N-substituted acrylamide, CH2Cl2, rt or 50 °C; (d)
N-benzylacrylamide, TiCl4, CH2Cl2, 0-20 °C, 24 h.
prevailing attack of the dienophile on the “upper face” of
the diene 13b (the high de value of 19 excludes double
bond isomerization followed by the cycloaddition reac-
tion).
reacting N-benzylacrylamide as the dienophile with
10c: in this case, at a 2.8 M concentration of the diene
(and 1.5 equiv of the acrylamide), the reaction proceeded,
albeit slowly, at room temperature, to yield a roughly
equimolar mixture of compounds 20a and 21a (not
separated), in 46% yield after chromatography.14 The low
yield was attributed to the decomposition of starting
material 10c during the long reaction time (4 days). The
regiochemistry of the two compounds, assigned by com-
plete NMR analysis of the mixture, was in accordance
with the theoretical predictions: apart from a weak
coupling (3.3 Hz) with 8-H, in both 20a and 21a the
proton on C-7 (which resonates at 3.72 and 3.49 ppm),
couples with one proton only (i.e., with 6-H), thus
excluding the 5-substituted regioisomer. The correspond-
ing coupling constant (7.0 Hz) is indicative of an exo
approach of the dienophile, since it is very close to that
observed between the same protons in compound 20b,
whose trans relative stereochemistry was unambiguously
assigned by X-ray analysis (see later).
The cycloaddition of 10a -c with N-phenylmaleimide
provided, after crystallization, diastero- and enantiopure,
di- and trisubstituted octahydroquinolinones 15a -c in
good overall yield. The reactions occurred through a
preferential endo approach of the dienophile, comparable
to that previously reported for lactam-derived dienes.1b,c,3h
The next step was to study the Diels-Alder reactions
with monosubstituted dienophiles, such as acrylates and
acrylamides, for which the prevailing regiochemical
outcome had to be determined besides the facial and
endo/exo selectivities. The reaction of 10a -c with ethyl
acrylate (Scheme 4) occurred by heating in toluene at 90
°C (24 h) or also at room temperature (4 d) when the
concentration of the dienes was increased up to 2.8 M.
In both cases, four major diastereomers (by 1H NMR and
HPLC analysis) were obtained but their separation was
difficult and we could not assign the regiochemistry.13
Two major diastereomers were instead obtained by
Lewis acids could be used to enhance the regio- and
stereoselectivity of these cycloadditions. With AlCl3 and
(13) STO 3-21G* ab initio calculations allowed us to predict, for the
reaction of dienes 10a -c with ethyl acrylate, the formation of the
6-substituted products according to HOMO diene-LUMO dienophile
interactions. In the case of 10b, the exact ratio between the four major
diastereomers was 2.3:2:1.2:1.
(14) Other unidentified cycloaddition products constituted less than
10% (by 1H NMR) of the crude reaction mixture.
J . Org. Chem, Vol. 68, No. 16, 2003 6363

Galbo et al.
TiCl4 at low temperature, complete decomposition of the
dienes was observed when a preformed complex of the
Lewis acid with ethyl acrylate was added to a cooled
CH2Cl2 solution of 10a -c, while with Et2AlCl neither
reaction nor decomposition occurred after 18 h at room
temperature. It is possible that the Lewis acid exchanges
with the amide group of 10 once the reagents are mixed,
causing degradation of the dienes. Mixing 1 equiv of AlCl3
and 10b at -78 °C in CH2Cl2 affords a mixture of
products deriving from ring opening, thus demonstrating
that strong Lewis acids may cause the decomposition of
these 2-(N-acylamino)-1,3-dienes.
analysis.11 Quite surprisingly, while the analysis con-
firmed the consistent 6-regiochemistry and relative trans
stereochemistry of the two substituents, this major
diastereomer resulted to be compound 21d (see the
Supporting Information) which derives from an “upper
face” approach of the dienophile.16
The regioselectivity observed in the cycloadditions of
imide-derived dienes 10 matches only in part what has
been reported in the literature so far for the correspond-
ing lactam-derived dienes. For example, the addition of
ethyl acrylate in one case occurred according to theoreti-
cal predictions;3e however, in other cases an unexpected
opposite regioselectivity has been observed.3h Interest-
ingly, the same authors found that with chiral acryla-
mides as dienophiles, lactam-derived dienes gave pre-
dominantly the expected regioisomer (one exception
only),3h thus in accordance with the results report herein.
Interestingly, the same process did not occur in the
TiCl4-catalyzed reaction of N-phenylmaleimide with 10a
(Scheme 2) or when a preformed complex of N-benzyl-
acrylamide with TiCl4 in CH2Cl2 was added to a solution
of 10c (Scheme 4). In the latter case, cycloaddition was
complete after 24 h at 20 °C, yielding again only two
diastereomers in a 2.3:1 ratio (regiochemistry not deter-
mined) with the usual isomerization of the double bond.
Con clu sion s
In conclusion, we have for the first time carried out
Stille, Suzuki-Miyaura, and Sonogashira cross-coupling
reactions with an imide-derived vinyl phosphate to give
in good to excellent yields enantiopure 2-(N-acylamino)-
1,3-dienes that are potentially useful in Diels-Alder
reactions for the construction of octahydroquinolinone
rings. This has been demonstrated by reacting dienes
10a -c with various dienophiles such as maleimides and
acrylamides. One feature of dienes 10a -c was their
reactivity at low temperature, although with acrylamides
a slight heating proved necessary to achieve cycloaddi-
tion. With maleimides, a preferential endo approach was
observed and, regarding the facial selectivity, de values
up to 74% were achieved. Diasteropure compounds were
always obtained in good yield by crystallization. As for
the regio preference, with acrylamides the reactions
occurred according to theoretical predictions and showed
proclivity toward the formation of the exo products. In
the cycloadditions of (R)- and (S)-N-(1-phenylethyl)-
acrylamide with 10b and 10c, the low facial diastereo-
selection (up to 33% de), compared to the reactions with
N-phenylmaleimide, could be a consequence of a less
congested transition state deriving from the exo approach
of the dienophile. Despite this, the methodology main-
tains a synthetic usefulness, since the cycloaddition of
chiral N-(1-phenylethyl)acrylamides consistently provides
a major 6,7-disubstituted octahydroquinoline derivative
which can be isolated in pure form by chromatography.
Because of the number of available boronic acids (which
are in any case easily prepared) and the possibility of
controlling the absolute configuration of up to four
stereocenters on the octahydroquinoline ring by changing
the configuration of the chiral auxiliaries, the methodol-
ogy is useful for a short synthesis of several, differently
substituted octahydroquinoline derivatives in enan-
tiopure form, further amenable to transformation into
decahydroquinolines which could possess interesting
biological activities.
Because of the loss of a stereocenter in the Lewis acid-
catalyzed reactions, we decided to avoid their use and
exploit instead double-stereodifferentiated reactions with
the aim of increasing the facial selectivity. This was done
by preparing both enantiomers of the cheap, enantiopure
N-(1-phenylethyl)acrylamide from acryloyl chloride and
(S)- and (R)-1-phenylethylamine and reacting them with
10c (Scheme 4). The expected reactions did not take place
at room temperature and at high concentration (3 M) of
the diene. The cycloadditions were complete after heating
for 48 h at 50 °C a 2.8 M solution of 10c in toluene in
the presence of 1.5 equiv of the acrylamide. 1H NMR
analysis of the crude mixture revealed, in the case of the
cycloaddition with (S)-N-(1-phenylethyl)acrylamide, the
presence of two products in a 2:1 ratio. We were pleased
to find out that the major product 20b could easily be
isolated by chromatography (28% yield; degradation of
diene 10c in the course of the reaction lowered the yield).
As in the case of the reaction with N-benzylacrylamide,
the cycloaddition with the chiral acrylamide S preferen-
tially occurred according to anticipation on the basis of
HOMO diene-LUMO dienophile interactions, affording
the 6-substituted regioisomer. The trans stereochemical
relationship of the two protons, arising from the exo
approach, was assigned by X-ray analysis of 20b (see the
Supporting Information). This confirms the proclivity of
diene 10c to give exo cycloadducts with acrylamides.
Again, the absolute stereochemistry of 20b indicates that
the dienophile preferentially approached the bottom face
of the diene. The cycloaddition with the R acrylamide
yielded instead two major products 20c and 21c in a ca.
1:1 ratio, one of which was obtained in pure form by
chromatography. Analogously to the case above, NMR-
based analysis15 allowed us to assign the 6-regio- and
relative trans stereochemistry of this diastereomer. We
also carried out the cycloaddition of (S)-N-(1-phenyleth-
yl)acrylamide with 10b. The reaction takes place at 50
°C affording two major products in an approximately 2:1
ratio. The major diastereomer was isolated by chroma-
tography (39%) and its structure determined by X-ray
(16) The reasons behind this stereochemical result have to be sought
in the interaction between the two chiral residues and the n-butyl chain
in the transition state of the process, although it is difficult at the
present to suggest a model. It is interesting to observe that a similar
“upper face” approach was prevailing in the formation of the exo
product 19 in the reaction of N-phenylmaleimide with n-butyl substi-
tuted diene 13b.
(15) H-7 couples with only one proton on C-6 (which excludes the
5-regioisomer), with a J ) 6.8 Hz very close to that between the same
protons in 20b (6.3 Hz).
6364 J . Org. Chem., Vol. 68, No. 16, 2003

Synthesis of Octahydroquinoline Derivatives
Meth od B (Su zu k i-Miya u r a Cou p lin g). To a stirred
solution of crude 9 (632 mg, ∼1.06 mmol) in THF (14 mL),
maintained under nitrogen atmosphere, were added 2 M
Na2CO3 (aq) (7 mL), (Ph3P)2PdCl2 (37 mg, 53 µmol), and 11a
(0.35 mL, 1.59 mmol). The mixture was stirred for 1.5 h at 40
°C, and then it was diluted with water (20 mL) and extracted
with Et2O (3 × 15 mL). The combined organic layers were dried
over K2CO3 for 30 min and concentrated under vacuum to give
an orange oil. Chromatography as above afforded pure 10a
(185 mg, 77%) as a colorless oil.
Meth od C (Stille Cou p lin g). To a stirred solution of crude
9 (1.372 g, ∼2.30 mmol) in THF (12 mL) were added, under
nitrogen atmosphere, tributyl(vinyl)tin (1.00 mL, 3.45 mmol),
(Ph3P)4Pd (106 mg, 92 µmol), and LiCl (975 mg, 23.0 mmol),
and the mixture was refluxed for 4 h. After cooling to room
temperature, the reaction mixture was diluted with water (20
mL) and extracted with Et2O (3 × 25 mL), and the organic
phase was dried for 30 min over K2CO3. Evaporation of the
solvent furnished an orange oil which was chromatographed
as above to give pure 10a (272 mg, 52%) as a colorless oil:
[R]26D -30.6 (c 0.79, CHCl3); 1H NMR (CDCl3) δ 7.33-7.16 (m,
5 H), 5.92 (dd, J ) 16.9, 10.6 Hz, 1 H), 5.70 (q, J ) 7.3 Hz, 1
H), 5.46 (t, J ) 5.0 Hz, 1 H), 5.35 (dd, J ) 16.9, 1.5 Hz, 1 H),
4.89 (dd, J ) 10.6, 1.5 Hz, 1 H), 2.58-2.47 (m, 2 H), 2.28-
2.19 (m, 2 H), 1.70 (d, J ) 7.3 Hz, 3 H); 13C NMR (CDCl3) δ
171.2 (s), 142.1 (s), 141.7 (s), 132.6 (d), 128.2 (d, 2 C), 126.6
(d), 126.2 (d, 2 C), 116.2 (t), 108.2 (d), 51.6 (d), 32.7 (t), 19.3
(t), 17.7 (q); MS m/z 227 (M+, 14), 105 (100). Anal. Calcd for
C15H17NO: C, 79.26; H, 7.54; N, 6.16. Found: C, 78.98; H, 7.54;
N, 6.50.
Exp er im en ta l Section
All solvents were degassed before use. Chromatographic
separations were performed under pressure on silica gel using
flash-column techniques; Rf values refer to TLC carried out
on 25-mm silica gel plates (Merck F254), with the same eluant
indicated for the column chromatography. 1H NMR, COSY,
and NOESY spectra were recorded at 200 and 400 MHz; 13C
NMR spectra at 50.33 MHz. Molecular modeling was carried
out by using the MM2* force field implemented in MacroModel
v6.5 using the default values of the software for all calcula-
tions. Ab initio calculations were carried out through Spartan
SGI 5.1.1, Wavefunction, Inc. using the default values of the
software.
(R)-(+)-1-(1-P h en yleth yl)p ip er id in e-2,6-d ion e (6). To a
solution of glutaric anhydride (9.730 g, 0.085 mol) in toluene
(200 mL), kept under nitrogen atmosphere, was added drop-
wise a solution of (R)-(+)-1-phenylethylamine (11.0 mL, 0.085
mol) in toluene (40 mL). The solution was heated and allowed
to reflux for 8 h. After the solution was cooled to room
temperature, evaporation of the solvent gave an oil which was
dissolved in CHCl3 (350 mL). The organic solution was washed
with 1 M HCl (2 × 100 mL) and then dried over Na2SO4. After
filtration and evaporation of the solvent, the yellow oil was
transferred into a flask equipped with
a condenser and
dissolved in acetyl chloride (30 mL). The solution was refluxed
for 8 h, and then the excess of acetyl chloride was removed by
distillation. The crude was dissolved in CHCl3 (150 mL) and
washed with saturated NaHCO3(aq) (100 mL). The aqueous
phase was extracted with CHCl3 (2 × 50 mL), and the
combined
organic
layers
were
dried
over
(R)-(-)-6-[(E)-Hex-1-en yl]-1-(1-ph en yleth yl)-3,4-dih ydr o-
1H-p yr id in -2-on e (10b). To a stirred solution of crude 9
(1.492 g, ∼2.50 mmol) in THF (30 mL) were added, under
nitrogen atmosphere, 2 M Na2CO3 (aq) (15 mL), (Ph3P)2PdCl2
(88 mg, 125 µmol), and hex-1-enylboronic acid 11b (480 mg,
3.75 mmol). The mixture was heated to 40 °C, left under
stirring 1 h, and after cooling, diluted with water (30 mL) and
extracted with Et2O (3 × 30 mL). The organic phase was dried
for 30 min over K2CO3 and concentrated in vacuo. The crude
brown oil was chromatographed (EtOAc-petroleum ether 1:4,
1% TEA, Rf 0.39) to give 10b (582 mg, 82%) as a yellowish oil:
[R]24D -22.4 (c 0.21, CHCl3); 1H NMR (CDCl3) δ 7.32-7.17 (m,
5 H), 5.84-5.66 (m, 2 H), 5.52 (d, J ) 15.4 Hz, 1 H), 5.32 (t, J
) 5.0 Hz, 1 H), 2.54-2.46 (m, 2 H), 2.26-2.16 (m, 2 H), 1.91-
1.82 (m, 2 H), 1.70 (d, J ) 7.3 Hz, 3 H), 1.22-1.14 (m, 4 H),
0.87-0.80 (m, 3 H); 13C NMR (CDCl3) δ 171.2 (s), 142.3 (s),
141.5 (s), 133.6 (d), 128.1 (d, 2 C), 126.4 (d), 126.2 (d, 2 C),
125.3 (d), 106.9 (d), 51.4 (d), 32.8 (t), 32.0 (t), 30.9 (t), 22.1 (t),
19.3 (t), 17.6 (q), 13.8 (q); MS m/z 283 (M+, 8), 103 (100). Anal.
Calcd for C19H25NO: C, 80.52; H, 8.89; N, 4.94. Found: C,
80.36; H, 8.66; N, 4.83.
Na2SO4. After filtration and evaporation of the solvent, the
solid was chromatographed (CH2Cl2-MeOH, 40:1, Rf 0.65) to
give pure 6 (4.14 g, 78%) as a white solid. As an alternative,
pure 6 can be obtained by crystallization from EtOH: mp
1
123-124 °C (lit.8 mp 124-127 °C); H NMR (CDCl3) δ 7.35-
7.17 (m, 5 H), 6.04 (q, J ) 7.3 Hz, 1 H), 2.62 (t, J ) 6.6 Hz, 4
H), 1.90 (quintet, J ) 6.6 Hz, 2 H), 1.74 (d, J ) 7.3 Hz, 3 H).
(R)-P h osp h or ic Acid 6-Oxo-1-(1-p h en yleth yl)-1,4,5,6-
tetr a h yd r op yr id in -2-yl Ester Dip h en yl Ester (9). To a
solution prepared by diluting with 6 mL of THF a 1 M solution
of LHMDS in THF (3.31 mL, 3.31 mmol), cooled at 0 °C and
under nitrogen atmosphere, was added dropwise and under
stirring a solution of (R)-(+)-1-(1-phenylethyl)piperidine-2,6-
dione 6 (0.720 g, 3.31 mmol) in THF (7 mL). The cooling bath
was removed, and after 1 h at room temperature, the resulting
suspension was cooled to -78 °C. A solution of diphenyl
chlorophosphate (0.69 mL, 3.31 mmol) in THF (3 mL) was
added, and after 10 min, the reaction mixture was allowed to
warm to room temperature and left stirring for 1.5 h. After
the addition of 10% NaOH (25 mL), the mixture was extracted
with Et2O (3 × 25 mL), and the combined organic layers were
dried for 30 min over K2CO3. Evaporation of the solvent under
vacuum yielded 9 (1.975 g) as an orange oil which was directly
used for the next coupling steps: 1H NMR (CDCl3) δ 7.34-
6.90 (m, 15 H), 5.89 (q, J ) 7.0 Hz, 1 H), 5.28 (m, 1 H), 2.58-
2.51 (m, 2 H), 2.30-2.20 (m, 2 H), 1.64 (d, J ) 7.0 Hz, 3 H).
(R)-(-)-1-(1-P h en yleth yl)-6-vin yl-3,4-d ih yd r o-1H-p yr i-
d in -2-on e (10a ). Meth od A (Su zu k i-Miya u r a Cou p lin g).
MeONa (75 mg, 1.38 mmol) was added to a solution of
vinylboronic acid dibutyl ester 11a (0.30 mL, 1.38 mmol) in
anhydrous THF (7 mL), cooled with an ice bath, under stirring
and nitrogen atmosphere. The cooling bath was removed, and
stirring was continued for 15 min. The resulting solution was
added by syringe to a mixture of crude 9 (549 mg, ∼0.92 mmol)
and (Ph3P)4Pd (53 mg, 46 µmol) in THF (9 mL), and the
reaction mixture was stirred for 2 h at 40 °C under a nitrogen
atmosphere. Water (25 mL) was added and the reaction
mixture extracted with Et2O (3 × 20 mL). The combined
organic layers were dried 30 min over K2CO3 and concentrated
under vacuum to give a yellow-orange oil. Pure 10a (139 mg,
66%) was obtained by chromatography (EtOAc-petroleum
ether 1:5, 1% TEA, Rf 0.32) as a colorless oil.
(R)-(-)-1-(1-P h en yleth yl)-6-[(E)-styr yl]-3,4-d ih yd r o-1H-
p yr id in -2-on e (10c). To a stirred solution of crude 9 (794
mg, ∼1.33 mmol) in THF (18 mL), were added, under nitro-
gen atmosphere, 2 M Na2CO3 (aq) (9 mL), (Ph3P)2PdCl2 (47
mg, 67 µmol), and trans-2-phenylvinylboronic acid 11c
(296 mg, 2.00 mmol). The mixture was stirred for 3 h at 40
°C, diluted with water (20 mL), and extracted with Et2O
(3 × 20 mL). The organic phase was dried for 30 min over
K2CO3 and concentrated in vacuo. Chromatography of the
crude (EtOAc-petroleum ether 1:5, 1% TEA, Rf 0.33) gave
10c (343 mg, 85%) as a yellowish oil: [R]22 -104.9 (c 0.41,
D
CHCl3); 1H NMR (CDCl3) δ 7.31-7.16 (m, 8 H), 7.10-7.06 (m,
2 H), 6.61 (d, J ) 15.8 Hz, 1 H), 6.16 (d, J ) 15.8 Hz, 1 H),
5.94 (q, J ) 7.0 Hz, 1 H), 5.57 (t, J ) 5.5 Hz, 1 H), 2.61-2.53
(m, 2 H), 2.33-2.28 (m, 2 H), 1.69 (d, J ) 7.0 Hz, 3 H); 13C
NMR (CDCl3) δ 171.4 (s), 142.2 (s), 141.0 (s), 136.2 (s),
130.2 (d), 128.4 (d, 2 C), 128.2 (d, 2 C), 127.2 (d), 126.6 (d),
126.3 (d), 126.2 (d), 123.7 (d), 108.3 (d), 50.9 (d), 32.5 (t), 19.3
(t), 17.6 (q); MS m/z 303 (M+, 20), 104 (100). Anal. Calcd for
C21H21NO: C, 83.13; H, 6.98; N, 4.62. Found: C, 83.29; H, 6.62;
N, 4.79.
J . Org. Chem, Vol. 68, No. 16, 2003 6365

Galbo et al.
(R)-(-)-6-[(Z)-(1-Eth ylbu t-1-en yl)-1-(1-p h en yleth yl)-3,4-
d ih yd r o-1H-p yr id in -2-on e (10d ). To a stirred solution of
crude 9 (883 mg, ∼1.48 mmol) in THF (20 mL) were added,
under nitrogen atmosphere, 2 M Na2CO3 (aq) (10 mL), (Ph3P)2-
PdCl2 (52 mg, 74 µmol), and 2-[(Z)-1-ethylbut-1-enyl]benzo-
1,3,2-dioxaborole 11d (448 mg, 2.22 mmol). The mixture was
stirred 1 h at 40 °C, diluted with water (30 mL), and extracted
with Et2O (3 × 40 mL). The organic phase was dried for 30
min over K2CO3 and concentrated in vacuo. Chromatography
(EtOAc - petroleum ether 1:5, 1% TEA, Rf 0.47) yielded 10d
(292 mg, 70%) as a colorless oil: [R]25D -101.1 (c 0.53, CHCl3);
1H NMR (CDCl3) δ 7.33-7.13 (m, 5 H), 5.51 (t, J ) 7.3 Hz, 1
H), 5.19 (t, J ) 4.8 Hz, 1 H), 4.86 (q, J ) 7.0 Hz, 1 H), 2.55-
2.25 (m, 2 H), 2.22-1.87 (m, 6 H), 1.82 (d, J ) 7.0 Hz, 3 H),
0.97 (t, J ) 7.7 Hz, 3 H), 0.96 (t, J ) 7.7 Hz, 3 H); 13C NMR
(CDCl3) δ 171.4 (s), 145.8 (s), 142.4 (s), 138.2 (s), 133.1 (d),
127.9 (d, 2 C), 126.3 (d, 2 C), 108.8 (d), 54.5 (d), 33.4 (t), 21.9
(t), 20.9 (t), 19.3 (t), 17.6 (q), 13.9 (q), 12.8 (q); MS m/z 283
(M+, 14), 105 (100). Anal. Calcd for C19H25NO: C, 80.52; H,
8.89; N, 4.94. Found: C, 80.19; H, 8.97; N, 4.58.
mixture was suspended in cyclohexane (4.5 mL) and heated
to reflux. The minimum amount of EtOAc was added dropwise
to completely dissolve the products and then the solution was
slowly cooled to room temperature. After 24 h, the solvent was
removed and the crystals were washed with cyclohexane (2 ×
0.5 mL).
Meth od B. N-Phenylmaleimide (29 mg, 0.16 mmoli) was
added to a solution of 10a (25 mg, 0.11 mmol) in CH2Cl2 (52
µL) cooled at -18 °C, and the resulting mixture was stirred
for 3 days. After evaporation of the solvent, chromatography
(EtOAc-petroleum ether, 1:1) gave the mixture of exo products
(Rf 0.38, 3 mg, 7%) and the mixture of endo products 14a and
15a (Rf 0.15, 40 mg, 90%). Crystallization as above gave pure
15a (23 mg) in 52% yield: mp 198-199 °C; [R]25D +7.3 (c 0.23,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.50-7.40 (m, 3 H),
7.16-7.08 (m, 7 H), 5.75 (q, J ) 7.0 Hz, 1H), 5.07 (dt, J ) 7.8,
2.7 Hz, 1 H), 3.32 (dd, J ) 9.0, 5.5 Hz, 1 H), 3.24 (ddd, J )
9.0, 7.4, 1.2 Hz, 1 H), 2.92-2.75 (m, 4 H), 2.44-2.35 (m, 1 H),
2.25 (ddd, J ) 7.4, 3.5, 2.0 Hz, 1 H), 2.17-2.10 (m, 1 H), 1.74
(d, J ) 7.0 Hz, 3 H); 13C NMR (CDCl3) δ 178.1 (s), 176.3 (s),
170.3 (s), 140.3 (s), 138.6 (s), 131.5 (s), 128.9 (d, 2 C), 128.5 (d,
2 C), 126.6 (d), 126.3 (d, 2 C), 125.8 (d, 2 C), 103.7 (d), 53.1
(d), 43.8 (d), 40.3 (d), 35.6 (d), 33.3 (t), 24.3 (t), 20.8 (t), 16.6
(q); MS m/z 400 (M+, 7), 105 (100). Anal. Calcd for
(R)-(+)-1-(1-P h en yleth yl)-6-p h en yleth yn yl-3,4-dih ydr o-
1H-p yr id in -2-on e (12a ). To a solution of crude 9 (1.295 g,
∼2.17 mmol) in TEA (11 mL) and CHCl3 (3.5 mL) were added
under nitrogen atmosphere phenylacetylene (0.24 mL, 2.17
mmol), CuI (41 mg, 0.22 mmol), and (Ph3P)2PdCl2 (76 mg, 0.11
mmol), and the mixture was stirred for 1 h at 50 °C. Then
water (20 mL) was added and the mixture extracted with Et2O
(5 × 20 mL). The combined organic layers were dried for 30
min over K2CO3 and concentrated. Chromatography of the
brown-black oil (EtOAc-petroleum ether 1:4, 1% TEA, Rf 0.39)
C
25H24N2O3: C, 74.98; H 6.04; N 7.00. Found: C, 75.52; H 6.02;
N 7.10.
(+)-(3a R,4R,9a R,9b S)-4-Bu t yl-2-p h en yl-6-[(R)-1-p h e-
n yleth yl]-4,6,8,9,9a,9b-h exah ydr o-3aH-pyr r olo[3,4-f]qu in -
olin e-1,3,7-tr ion e (15b). Meth od A. A solution of 10b (82
mg, 0.29 mmol) and N-phenylmaleimide (75 mg, 0.43 mmol)
in CH2Cl2 (3.5 mL) was concentrated under vacuum as
described above. Chromatography (EtOAc-petroleum ether,
2:3) gave a mixture of exo products (Rf 0.38, 19 mg, 14%) and
the mixture of endo products 14b and 15b (Rf 0.17, 113 mg,
85%). Crystallization from cyclohexane/EtOAc provided pure
15b (58 mg, 44%, colorless crystals).
provided 12a (571 mg, 87%) as an orange oil: [R]22 +14.1 (c
D
1
0.29, CHCl3); H NMR (CDCl3) δ 7.34-7.19 (m, 8 H), 7.18-
7.10 (m, 2 H), 6.05 (q, J ) 7.3 Hz, 1 H), 5.82 (t, J ) 5.1 Hz, 1
H), 2.63-2.55 (m, 2 H), 2.42-2.33 (m, 2 H), 1.84 (d, J ) 7.3
Hz, 3 H); 13C NMR (CDCl3) δ 169.8 (s), 141.6 (s), 131.2 (d, 2
C), 128.5 (d), 128.1 (d, 2 C), 128.0 (d, 2 C), 126.4 (d, 2 C), 124.3
(s), 122.0 (s), 118.1 (d), 91.2 (s), 83.9 (s), 51.3 (d), 31.8 (t), 20.3
(t), 17.2 (q); MS m/z 301 (M+, 6), 102 (100). Anal. Calcd for
C21H19NO: C, 83.69; H, 6.35; N, 4.65. Found: C, 84.87; H, 5.96;
N, 4.50.
Meth od B. N-Phenylmaleimide (28 mg, 0.16 mmol) was
added to a solution of 10b (31 mg, 0.11 mmol) in CH2Cl2 (52
µL) cooled at -18 °C, and the mixture was stirred for 3 days.
After evaporation of the solvent, chromatography gave a
mixture of exo products (3 mg, 5%) and the mixture of endo
products 14b and 15b (45 mg, 92%). Crystallization as above
yielded pure 15b (32 mg, colorless crystals) in 64% yield: mp
(R)-(+)-6-Hex-1-yn yl-1-(1-p h en yleth yl)-3,4-d ih yd r o-1H-
p yr id in -2-on e (12b). To a solution of crude 9 (871 mg, ∼1.46
mmol) in TEA (8 mL) and CHCl3 (2.5 mL) were added, under
nitrogen atmosphere, 1-hexyne (0.17 mL, 1.46 mmol), CuI (28
mg, 0.15 mmol), and (Ph3P)2PdCl2 (51 mg, 73 µmol), and the
mixture was stirred for 1 h at 50 °C. Water (15 mL) was added
and the mixture extracted with Et2O (5 × 15 mL). The organic
phase was dried over K2CO3 and concentrated in vacuo. The
brown-black crude oil was chromatographed (EtOAc-petro-
leum ether 1:5, 1% TEA, Rf 0.30) to yield 12b (261 mg, 64%)
162-164 °C; [R]25 +40.7 (c 0.17, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 7.49-7.38 (m, 3 H), 7.19-7.08 (m, 7 H), 5.63 (q, J )
7.0 Hz, 1H), 4.94 (t, J ) 2.7 Hz, 1 H), 3.31 (dd, J ) 8.6, 5.1
Hz, 1 H), 3.23 (dd, J ) 8.6, 6.7 Hz, 1 H), 2.93-2.71 (m, 3 H),
2.42-2.27 (m, 2 H), 2.17-2.10 (m, 1 H), 1.94-1.85 (m, 1 H),
1.75 (d, J ) 7.0 Hz, 3 H), 1.62-1.54 (m, 1 H), 1.51-1.43 (m, 1
H), 1.40-1.32 (m, 3 H), 0.93 (t, J ) 7.0 Hz, 3 H); 13C NMR
(CDCl3) δ 176.0 (s), 175.5 (s), 170.2 (s), 140.4 (s), 138.4 (s), 131.6
(s), 128.8 (d, 2 C), 128.4 (d, 2 C), 126.6 (d), 126.3 (d, 2 C), 125.9
(d, 2 C), 109.5 (d), 53.6 (d), 44.6 (d), 43.9 (d), 36.8 (d), 36.0 (d),
33.3 (t), 31.2 (t), 30.4 (t), 22.5 (t), 20.7 (t) 16.7 (q), 14.0 (q); MS
as a yellowish oil: [R]22 +86.0 (c 1.19, CHCl3); 1H NMR
D
(CDCl3) δ 7.33-7.15 (m, 5 H), 5.90 (q, J ) 7.1 Hz, 1 H), 5.60
(t, J ) 4.8 Hz, 1 H), 2.58-2.37 (m, 2 H), 2.32-2.22 (m, 2 H),
2.13-2.06 (m, 2 H), 1.79 (d, J ) 7.1 Hz, 3 H), 1.56-1.19 (m, 4
H), 0.96-0.80 (m, 3 H); 13C NMR (CDCl3) δ 169.9 (s), 141.8
(s), 127.9 (d, 2 C), 126.4 (d, 2 C), 126.3 (d), 124.9 (s), 116.0 (d),
92.9 (s), 75.2 (s), 51.8 (d), 32.0 (t), 30.0 (t), 21.9 (t), 20.1 (t),
18.8 (t), 17.0 (q), 13.5 (q); MS m/z 281 (M+, 5), 102 (100). Anal.
Calcd for C19H23NO: C, 81.10; H, 8.24; N, 4.98. Found: C,
80.98; H, 8.54; N, 4.57.
m/z 351 (M+
29H32N2O3: C, 76.29; H 7.06; N 6.14. Found: C, 76.68; H 7.06;
N 6.28.
- 105, 47), 103 (100). Anal. Calcd for
C
(+)-(3a R,4R,9a R,9bS)-2,4-Dip h en yl-6-[(R)-1-p h en yleth -
yl]-4,6,8,9,9a ,9b-h exa h yd r o-3a H-p yr r olo[3,4-f]qu in olin e-
1,3,7-t r ion e (15c). Met h od A. A solution of 10c (268 mg,
0.88 mmol) and N-phenylmaleimide (229 mg, 1.32 mmol) in
CH2Cl2 (10 mL) was concentrated under vacuum as described
above. Chromatography (EtOAc-petroleum ether, 3:2) gave
a mixture of exo products (Rf 0.60, 88 mg, 21%) and the mixture
of endo products 14c and 15c (Rf 0.23, 284 mg, 68%).
Crystallization as above furnished pure 15c (152 mg, 36%,
colorless crystals).
Meth od B. N-Phenylmaleimide (33 mg, 0.19 mmol) was
added to a solution of 10c (39 mg, 0.13 mmol) in CH2Cl2 (61
µL) cooled at -18 °C, and the mixture was allowed to stir for
3 days. Chromatography gave the exo product mixture (4 mg,
7%) and the mixture of endo products 14c and 15c (54 mg,
(+)-(3a R ,9a R ,9b S )-2-P h e n yl-6-[(R )-1-p h e n yl-e t h yl]-
4,6,8,9,9a,9b-h exah ydr o-3aH-pyr r olo[3,4-f]qu in olin e-1,3,7-
tr ion e (15a ). Meth od A. A solution of 10a (90 mg, 0.40 mmol)
and N-phenylmaleimide (103 mg, 0.59 mmol) in CH2Cl2 (5 mL)
was concentrated under vacuum by a rotary evaporator,
heating with an external bath at 40 °C. The crude mixture
obtained just after complete evaporation of the solvent was
chromatographed (EtOAc-petroleum ether, 1:1) to give a
mixture of exo products (Rf 0.38, 19 mg, 12%) and the mixture
of endo products 14a and 15a (Rf 0.15, 135 mg, 85%). Pure
15a (62 mg, 39%, colorless crystals) was obtained by crystal-
lization from cyclohexane/EtOAc as follows: the diastereomeric
6366 J . Org. Chem., Vol. 68, No. 16, 2003

Synthesis of Octahydroquinoline Derivatives
88%). Crystallization as above furnished pure 15c (37 mg) in
ethyl)acrylamide (302 mg, 1.73 mmol), and the mixture was
allowed to react under stirring for 48 h at 50 °C, with
monitoring by TLC. After evaporation of the solvent, the crude
was chromatographed (EtOAc-petroleum ether 3:2, Rf 0.33)
to give 20b (152 mg, 28%) as a colorless solid. Colorless crystals
for X-ray analysis were obtained from ethyl acetate-cyclo-
61% yield: mp 216-218 °C; [R]25 +108.5 (c 0.19, CHCl3); 1H
D
NMR (400 MHz, CDCl3) δ 7.46-7.35 (m, 3 H), 7.33-7.26 (m,
3 H), 7.21-7.19 (m, 2 H), 7.13-7.03 (m, 5 H), 6.84-6.81 (m, 2
H), 6.12 (q, J ) 7.0 Hz, 1 H), 5.20-5.19 (m, 1 H), 3.73-3.70
(m, 1 H), 3.40-3.34 (m, 2 H), 3.17-3.07 (m, 1 H), 2.91-2.85
(m, 2 H), 2.50-2.42 (m, 1 H), 2.21-2.14 (m, 1 H), 1.71 (d, J )
7.0 Hz, 3 H); 13C NMR (CDCl3) δ 175.5 (s), 174.1 (s), 170.4 (s),
149.9 (s), 139.7 (s), 137.2 (s), 131.5 (s), 128.6 (d, 4 C), 128.5 (d,
2 C), 128.3 (d, 2 C), 128.2 (d), 127.2 (d), 126.7 (d), 126.4 (d, 2
C), 126.1 (d, 2 C), 108.4 (d), 51.6 (d), 47.1 (d), 44.7 (d), 42.0
(d), 35.6 (d), 33.3 (t), 21.0 (t), 15.5 (q); MS m/z 476 (M+, 9),
104 (100). Anal. Calcd for C31H28N2O3: C, 78.13; H 5.92; N
5.88. Found: C, 78.03; H 5.91; N 6.07.
(3a R,9bR)-2-P h en yl-6-[(R)-1-p h en yleth yl]-4,5,6,8,9,9b-
h exa h yd r o-3a H-p yr r olo[3,4-f]qu in olin -1,3,7-tr ion e (17a ).
To a solution of 15a (9 mg, 0.022 mmol) in anhydrous CH2Cl2
(5 mL), cooled at -78 °C and under nitrogen atmosphere, was
slowly added a solution of 1 M TiCl4 in CH2Cl2 (0.03 mL, 0.03
mmol). After 15 min of stirring, 1 mL of water was added and
the mixture allowed to warm to room temperature. When the
ice completely melted, another 5 mL of water was added, and
the mixture was extracted with CH2Cl2 (3 × 5 mL) and dried
over Na2SO4. After evaporation of the solvent, 17a (9 mg) was
obtained (95% conversion by 1H NMR): 1H NMR (CDCl3) δ
7.47-7.36 (m, 3 H), 7.30-7.09 (m, 7 H), 6.00 (q, J ) 7.3 Hz, 1
H), 3.59 (d, J ) 8.4 Hz, 1 H), 3.26-3.12 (m, 1 H), 2.88-2.66
(m, 1 H), 2.61-2.54 (m, 2 H), 2.41-2.27 (m, 1 H), 2.10-2.02
(m, 2 H), 1.69 (d, J ) 7.3 Hz, 3 H), 1.62-1.19 (m, 2 H).
hexane as reported above: mp 184-185 °C; [R]23 -68.3 (c
D
1
0.43, CHCl3); H NMR (CDCl3) δ 7.35-7.12 (m, 13 H), 6.88-
6.81 (m, 2 H), 6.28 (q, J ) 7.3 Hz, 1 H), 5.29 (d, J ) 7.3 Hz, 1
H), 4.99 (quintet, J ) 7.3 Hz, 1 H), 4.95-4.90 (m, 1 H), 3.70-
3.67 (m, 1 H), 2.88-2.55 (m, 2 H), 2.45-2.34 (m, 1 H), 2.30-
2.04 (m, 2 H), 1.90-1.59 (m, 3 H), 1.66 (d, J ) 7.3 Hz, 3 H),
1.19 (d, J ) 7.3 Hz, 3 H); 13C NMR (CDCl3) δ 172.6 (s), 169.3
(s), 143.6 (s), 143.0 (s), 141.6 (s), 137.1 (s), 128.5 (d), 128.3 (d),
128.2 (d), 127.6 (d), 127.2 (d), 126.5 (d), 126.3 (d), 126.0 (d),
125.5 (d), 111.7 (d), 50.4 (d), 48.4 (d), 47.2 (d), 43.2 (d), 32.8
(d), 32.7 (t), 30.3 (t), 27.0 (t), 21.3 (q), 15.3 (q); MS m/z 478
(M+, 25), 105 (100). Anal. Calcd for C32H34N2O2: C, 80.30; H
7.16; N 5.85. Found: C, 80.54; H 7.17; N 5.79.
(-)-(4a S,6S,7S)-7-Bu t yl-2-oxo-1-(R)-(1-p h en ylet h yl)-
1,2,3,4,4a ,5,6,7-octa h yd r oqu in olin e-6-ca r boxylic Acid (S)-
(1-P h en yleth yl)a m id e (21d ). To a solution of 10b (371 mg,
1.31 mmol) in toluene (0.47 mL) was added (S)-N-(1-phenyl-
ethyl)acrylamide (344 mg, 1.97 mmol), and the mixture was
allowed to react under stirring for 3 days at 50 °C. After
evaporation of the solvent and chromatography (EtOAc-
petroleum ether, 3:2), the major diastereomer 21d (Rf 0.17,
234 mg, 39%) was obtained as a white solid. Colorless crystals
were obtained from n-hexane/EtOAc: mp 136-137 °C; [R]25
D
+82.8 (c 0.24, CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.38-
7.14 (m, 10 H), 6.04 (q, J ) 7.3 Hz, 1H), 5.66 (d, J ) 7.3 Hz,
1H), 5.11 (quintet, J ) 7.3 Hz, 1 H), 4.93 (br s, 1 H), 2.68-
2.36 (m, 2 H), 2.15-1.96 (m, 4 H), 1.78-1.44 (m, 3 H), 1.72 (d,
J ) 7.3 Hz, 3 H), 1.38 (d, J ) 7.3 Hz, 3 H), 1.29-1.10 (m, 6
H), 0.90-0.80 (m, 3 H); 13C NMR (CDCl3) δ 173.7 (s), 169.5
(s), 143.3 (s), 140.8 (s), 137.0 (s), 128.4 (d, 2 C), 128.2 (d, 2 C),
127.2 (d), 126.4 (d), 126.0 (d, 2 C), 110.9 (d), 52.1 (d), 48.2 (d),
43.6 (d), 36.1 (d), 35.0 (t), 33.0 (t), 32.8 (d), 30.7 (t), 29.0 (t),
26.8 (t), 22.6 (t), 21.4 (q), 17.2 (q), 13.9 (q); MS m/z 458 (M+,-
10), 103 (100). Anal. Calcd for C30H38N2O2: C, 78.56; H 8.35;
N 6.11. Found: C, 78.44; H 8.36; N 6.07.
(3a R,4R,9b R)-4-Bu t yl-2-p h en yl-6-[(R)-1-p h en ylet h yl]-
4,5,6,8,9,9b-h exa h yd r o-3a H-p yr r olo[3,4-f]qu in olin -1,3,7-
tr ion e (19). To a solution of 15b (3 mg, 0.007 mmol) in
anhydrous CH2Cl2 (0.25 mL), cooled at -78 °C and under
nitrogen atmosphere, was slowly added a solution of 1 M TiCl4
in CH2Cl2 (0.01 mL, 0.01 mmol). Workup as reported above
for 17a furnished 19 (3 mg, 100%) as a white solid: 1H NMR
(CDCl3) δ 7.48-7.36 (m, 3 H), 7.29-7.10 (m, 7 H), 5.97 (q, J )
7.0 Hz, 1H), 3.59 (d, J ) 8.1 Hz, 1 H), 3.18 (dd, J ) 8.1, 4.4
Hz, 1 H), 2.76-2.64 (m, 1 H), 2.60-2.53 (m, 2 H), 2.38-2.28
(m, 1 H), 2.17-2.10 (m, 1 H), 1.93-1.83 (m, 1 H), 1.78-1.09
(m, 7 H), 1.71 (d, J ) 7.0 Hz, 3 H), 0.90-0.73 (m, 3 H).
P r ep a r a tion of N-Ben zyla cr yla m id e. Acryloyl chloride
(0.50 mL, 6.20 mmol) and then, dropwise, a solution of
benzylamine (0.74 mL, 6.82 mmol) in TEA (1.03 mL, 7.44
mmol) were added to cold (0-5 °C) CH2Cl2 (10 mL) under
nitrogen atmosphere. The resulting white suspension was
allowed to stir for 16 h at room temperature, diluted with
CH2Cl2 (5 mL), washed with water (10 mL), 1 M H2SO4 (10
mL), 1 M NaHCO3 (10 mL), and brine (10 mL), and finally
dried over Na2SO4. After evaporation of the solvent, the
acrylamide was obtained as a white solid (989 mg, 99%): 1H
NMR (CDCl3) δ 7.35-7.21 (m, 5 H), 6.30 (dd, J ) 17.2, 1.8
Hz, 1 H), 6.08 (dd, J ) 17.2, 9.9 Hz, 1 H), 5.95 (br s, 1 H), 5.63
(dd, J ) 9.9, 1.8 Hz, 1 H), 4.48 (d, J ) 5.5 Hz, 2 H).
(S)-N-(1-P h en yleth yl)a cr yla m id e. Prepared as reported
above for N-benzylacrylamide. Starting from acryloyl chloride
(1.62 mL, 20 mmol) and (S)-(-)-1-phenylethylamine (2.84 mL,
22 mmol), the pure title compound (3.403 g, 97%) was obtained
after chromatography (EtOAc-petroleum ether, 2:3, Rf 0.31)
as a white solid: 1H NMR (CDCl3) δ 7.32-7.23 (m, 5 H), 6.27
(dd, J ) 16.8, 1.5 Hz, 1 H), 6.05 (dd, J ) 16.8, 10.3 Hz, 1 H),
5.79 (br-s, 1 H), 5.61 (dd, J ) 10.3, 1.5 Hz, 1 H), 5.19 (quintet,
J ) 7.0 Hz, 1 H), 1.50 (d, J ) 7.0 Hz, 3 H).
(R)-N-(1-P h en yleth yl)a cr yla m id e. Prepared as reported
above for N-benzylacrylamide, starting from acryloyl chloride
(1.62 mL, 20 mmol) and (R)-(-)-1-phenylethylamine (2.84 mL,
22 mmol), the pure title compound (3.302 g, 95%) was obtained
as a white solid after chromatography.
X-r a y Cr ysta llogr a p h ic Deter m in a tion of Com p ou n d s
15a -c, 20b, a n d 21d . Compound 15a :
C25H24N2O3, M )
400.46, orthorhombic, space group P212121 a ) 8.524(1) Å, b
) 10.040(3) Å, c ) 24.132(5) Å, V ) 2065.2(8) Å3, Z ) 4, F(000)
) 848, µ ) 0.682 mm-1, Dc ) 1.288 g/cm-3. The reflections
collected were 2530, of which 2343 unique (2θmax ) 130°). In
determining and refining the structure, 2222 reflections and
277 parameters were used; the final agreement factor was R
) 0.0472 for reflections having I > 2σ(I) and 0.0489 for all
data.
Compound 15b: C29H32N2O3, M ) 456.57, orthorhombic,
space group P212121, a ) 9.079(1) Å, b ) 9.920(1) Å, c ) 27.771-
(2) Å, V ) 2501.2(4) Å3, Z ) 4, F(000) ) 976, µ ) 0.621 mm-1
,
Dc ) 1.212 g/cm-3. The reflections collected were 2632, of which
2443 unique (2θmax ) 120°). In determining and refining the
structure, 2117 reflections and 317 parameters were used; the
final agreement factor was R ) 0.0673 for reflections having
I > 2σ(I) and 0.0737 for all data.
Compound 15c: C31H28N2O3, M ) 476.55, monoclinic, space
group P21, a ) 8.986(1) Å, b ) 9.522(1) Å, c ) 14.420(1) Å, â
) 90.139(2)°, V ) 1233.8(2) Å3, Z ) 2, F(000) ) 504, µ ) 0.659
mm-1, Dc ) 1.283 g/cm3. The reflections collected were 3684,
of which 2239 unique (2θmax ) 108°). In determining and
refining the structure, 1791 reflections and 331 parameters
were used; the final agreement factor was R ) 0.0460 for
reflections having I > 2σ(I) and 0.0638 for all data.
Compound 20b: C32H34N2O2, M ) 478.61, monoclinic, space
group P21, a ) 10.191(1) Å, b ) 13.857(2) Å, c ) 10.568(1) Å,
â ) 114.60(2)°, V ) 1356.9(3) Å3, Z ) 2, F(000) ) 512, µ )
0.568 mm-1, Dc ) 1.171 g/cm3. The reflections collected were
2686, of which 2289 unique (2θmax ) 120°). In determining and
(-)-(4a R,6R,7R)-2-Oxo-7-p h en yl-1-(R)-(1-p h en yleth yl)-
1,2,3,4,4a ,5,6,7-octa h yd r oqu in olin e-6-ca r boxylic Acid (S)-
(1-P h en yleth yl)a m id e (20b). To a solution of 10c (349 mg,
1.15 mmol) in toluene (0.41 mL) was added (S)-N-(1-phenyl-
J . Org. Chem, Vol. 68, No. 16, 2003 6367

Galbo et al.
refining the structure, 2153 reflections and 355 parameters
were used; the final agreement factor was R ) 0.055 for
reflections having I > 2σ(I) and 0.057 for all data.
were found in the Fourier difference synthesis; all of them were
refined as isotropic. Anisotropic thermal parameters were used
for all the non hydrogen atoms. The structures were solved
by direct methods of SIR9719 and refined using the full-matrix
least squares on F2 provided by SHELXL97.20
Compound 21d : C30H38N2O2, M ) 458.62, orthorhombic,
space group P212121, a ) 9.415(1) Å, b ) 9.884(1) Å, c )
30.493(2) Å, V ) 2837.6(5) Å3, Z ) 4, F(000) ) 992, µ ) 0. 518
mm-1, Dc ) 1.074 g/cm3. The reflections collected were 6277,
of which 2931 unique (2θmax ) 112°). In determining and
refining the structure, 2931 reflections and 309 parameters
were used; the final agreement factor was R ) 0.0915for
reflections having I > 2σ(I) and 0.1498 for all data.
Data sets for 15a , 15b, and 20b were collected on a Bruker
P4 X-ray diffractometer using the (Cu KR) radiation (λ )
1.5418 Å) for the cell parameter determinations and data
collections. The intensities of two standard reflections were
monitored during data collections to check the stability of the
crystals; no loss of intensity was recognized. In case of 15c
and 21d , the analysis was carried out with a Bruker CCD
X-ray diffractometer and Crossed Gobel mirrors monochro-
mated Cu KR radiation was used for cell parameter determi-
nation and data collection. The intensities of some equivalents
were monitored during data collection to check the stability
of the crystal. The data acquisition, integration, and data
reduction were performed using SMART and SAINT pro-
grams.17 In all cases, the integrated intensities, measured at
room temperature (293 K), were corrected for Lorentz and
polarization effects.18 Hydrogen atom positions were calculated
(C-H ) 0.96 Å), except for H6 in 15a , H6 in 15b, H3, H4, H5,
H6, H8 in 15c, and HN, H1, H3, H8, H9, H17 and H25 in 20b which
Ack n ow led gm en t. We thank MIUR and University
of Florence (COFIN 2000-2002) for financial support.
Prof. Paolo Dapporto is acknowledged for his assistance
in the X-ray analyses, Mrs. Brunella Innocenti, and Mr.
Maurizio Passaponti are acknowledged for their techni-
cal assistance.
Su p p or tin g In for m a tion Ava ila ble: ORTEP plots for
15a -c, 20b, and 21d . X-ray crystallographic information files
for 15a -c, 20b, and 21d . 1H NMR spectra of 15a -c, 20b, and
21d . This material is available free of charge via the Internet
at http://pubs.acs.org.
J O0344687
(17) Bruker Molecular Analysis Research Tool V 5.625, 1997-2000,
Bruker AXS.
(18) Walker, N.; Stuart, D. D. Acta Crystallogr. Sect. A 1983, 39,
158-166.
(19) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna,
R. J . Appl. Crystallogr. 1999, 32, 115-119.
(20) Sheldrick, G, M. SHELXL97: Program for Crystal Structure
Refinement; Institut fu¨r Anorganische Chemie de Universitat Go¨ttin-
gen, Go¨ttingen, Germany.
6368 J . Org. Chem., Vol. 68, No. 16, 2003