Nitrogen heterocycles by palladium-catalyzed cyclization of amino-tethered vinyl halides and ketone enolates

Article abstract of DOI:10.1021/jo034299q

The scope and limitations of Pd(0)-catalyzed intramolecular coupling of amino-tethered vinyl halides and ketone enolates as a methodology for the synthesis of nitrogen heterocycles have been studied. This reaction constitutes a synthetic procedure to obta

Full text of DOI:10.1021/jo034299q

SCHEME 1. P d -Ca ta lyzed In tr a m olecu la r
Cou p lin g of Vin yl Ha lid es a n d Keton e En ola tes
Nitr ogen Heter ocycles by
P a lla d iu m -Ca ta lyzed Cycliza tion of
Am in o-Teth er ed Vin yl Ha lid es a n d Keton e
En ola tes
Daniel Sole´,* Fa¨ıza Diaba, and J osep Bonjoch*
Laboratori de Quı´mica Orga`nica, Facultat de Farma`cia,
Universitat de Barcelona, Av. J oan XXIII s/ n,
08028-Barcelona, Spain
dsole@farmacia.far.ub.es
Received March 7, 2003
In this paper, we present a full discussion of our studies
on the Pd-catalyzed intramolecular coupling of amino-
tethered vinyl halides and ketone enolates (Scheme 1)
in the search for a suitable methodology for the synthesis
of nitrogen heterocycles incorporating an alkylidene side
chain.14 The reaction exploits the electrophilic character
of the palladium atom, and it is presumed to proceed by
sequential oxidative addition and enolization, followed
by conversion to a palladacycle, which undergoes a simple
reductive elimination.
At the beginning of our work, there were only two
examples of this Pd(0)-catalyzed coupling process, devel-
oped by Piers in the carbocyclic series and then success-
fully applied by himself to the synthesis of the diterpe-
noid crinipellin B.15 Contemporaneously with our prelim-
inary studies, Cook reported another example of this Pd-
catalyzed coupling process in the context of the total
synthesis of the alkaloid (+)-vellosimine.16
Abstr a ct: The scope and limitations of Pd(0)-catalyzed
intramolecular coupling of amino-tethered vinyl halides and
ketone enolates as a methodology for the synthesis of
nitrogen heterocycles have been studied. This reaction
constitutes a synthetic procedure to obtain bridged, con-
densed, and monocyclic nitrogen-containing compounds.
The development and implementation of new proce-
dures to assemble nitrogen heterocycles is still a chal-
lenge for organic synthesis.1 Particularly interesting are
cyclization processes in which the formation of a C-C
bond occurs simultaneously with the installation of an
exocyclic double bond, since a significant number of
natural products bear a 3-alkylidenepiperidine motif in
their skeleton (e.g., indole alkaloids of several structural
types: strychnine,2 ervitsine,3 deplancheine,4 and sub-
incanadines;5 as well as pumiliotoxins and related alka-
loids from Dendrobates frogs6). Among the several cy-
clization methodologies leading to alkylidene-bearing
nitrogen heterocycles,7-9 the use of vinyl halides as
starting materials has a wide range of application. Their
cyclization can be performed upon alkenes using different
methodologies, palladium-catalyzed processes (Heck-type
reaction),10 nickel-promoted reactions,11 or radical cycl-
izations,12 and upon aldehydes by means of a chromium-
promoted reaction (Nozaki-Hiyama-Kishi reaction).13
Continuing our studies on the synthesis of compounds
embodying the 2-azabicyclo[3.3.1]nonane framework,17,18
we have focused our efforts on the Pd(0)-catalyzed cycliza-
(10) (a) Rawal, V. H.; Michoud, C. Tetrahedron Lett. 1991, 32, 1695.
(b) Rawal, V. H.; Iwasa, S. J . Org. Chem. 1994, 59, 2685. (c) McAlonan,
H.; Montgomery, D.; Stevenson, P. J . Tetrahedron Lett. 1996, 37, 7151.
(d) Birman, V. B.; Rawal, V. H. J . Org. Chem. 1998, 63, 9146. (e)
Larock, R. C.; Han, X. J . Org. Chem. 1999, 64, 1875. (f) Sole´, D.;
Bonjoch, J .; Garc´ıa-Rubio, S.; Peidro´, E.; Bosch, J . Chem. Eur. J . 2000,
6, 655. (g) Lee, C.-W.; Oh, K. S.; Kim, K. S.; Ahn, K. H. Org. Lett. 2000,
2, 1213. (h) Eichberg, M. J .; Dorta, R. L.; Grotjahn, D. B.; Lamottke,
K.; Schmidt, M.; Vollhardt, P. C. J . Am. Chem. Soc. 2001, 123, 9324.
(11) (a) Sole´, D.; Cancho, Y.; Llebaria, A.; Moreto´ J . M.; Delgado, A.
J . Am. Chem. Soc. 1994, 116, 12133. (b) Bonjoch, J .; Sole´, D.; Bosch,
J . J . Am. Chem. Soc. 1995, 117, 11017. (c) Cancho, Y.; Mart´ın, J . M.;
Mart´ınez, M.; Llebaria, A.; Moreto´, J . M.; Delgado, A.; Tetrahedron
1998, 54, 1221. (d) Yu, S.; Berner, O. M.; Cook, J . M. J . Am. Chem.
Soc. 2000, 122, 7827. (e) Reference 10h.
(12) (a) Kuehne, M. E.; Wang, T.; Seraphin, D. Synlett 1995, 557.
(b) Takayama, H.; Watanabe, F.; Kitajima, M.; Aimi, N. Tetrahedron
Lett. 1997, 38, 5307. (c) Kuehne, M. E.; Bandarage, U. K.; Hammach,
A.; Li, Y.-L.; Wang, T. J . Org. Chem. 1998, 63, 2172. (d) Reference
10h.
(13) Aoyagi, S.; Wang, T.-C.; Kibayashi, C. J . Am. Chem. Soc. 1993,
115, 11393.
(1) (a) Tamaru, Y.; Kimura, M. Synlett 1997, 749. (b) Laschat, S.;
Dickner, T. Synthesis 2000, 1781. (c) Padwa, A.; Danca, M. D.;
Hardcastle, K. I.; McClure, M. S. J . Org. Chem. 2003, 68, 929 and
references therein.
(2) Bonjoch, J .; Sole´, D. Chem. Rev. 2000, 100, 3455.
(3) Bennasar, M.-L.; Vidal, B.; Bosch, J . J . Org. Chem. 1997, 62,
3597.
(4) Itoh, T.; Enomoto, Y.; Ohsawa, A. Heterocycles 2001, 55, 1165
and references therein.
(5) Kobayashi, J .; Sekiguchi, M.; Shimamoto, S.; Shigemori, H.;
Ishiyama, H.; Ohsaki, A. J . Org. Chem. 2002, 67, 6449.
(6) (a) Franklin, A. S.; Overman, L. E. Chem. Rev. 1996, 96, 505.
(b) Kibayashi, C.; Aoyagi, S.; Wang, T.-C.; Saito, K.; Daly, J . W.;
Spande, T. F. J . Nat. Prod. 2000, 63, 1157 and references therein.
(7) For tandem processes involving iminium salts, see: (a) Overman,
L. E.; Bell, K. L.; Ito, F. J . Am. Chem. Soc. 1984, 106, 4192. (b)
Overman, L. E. Acc. Chem. Res. 1992, 25, 352. (c) Lin, N.-H.; Overman,
L. E.; Rabinowitz, M. H.; Robinson, L. A.; Sharp, M. J .; Zablocki, J . J .
Am. Chem. Soc. 1996, 118, 9062.
(8) For nickel-catalyzed cyclizations of ynals or alkynyl enones,
see: (a) Montgomery, J .; Chevliakov, M. V.; Brielmann, H. J . Tetra-
hedron 1997, 53, 16449. (b) Tang, X.-Q.; Montgomery, J . J . Am. Chem.
Soc. 2000, 122, 6950.
(9) For radical-promoted cyclizations, see: (a) Baldwin, J . E.;
Mackenzie Turner, S. C.; Moloney, M. G. Tetrahedron 1994, 50, 9425.
(b) Cossy, J .; Cases, M.; Gomez Pardo, D. Synlett 1996, 909. (c) Alcaide,
B.; Rodr´ıguez-Campos, I. M.; Rodr´ıguez-Lo´pez, J .; Rodr´ıguez-Vicente,
A. J . Org. Chem. 1999, 64, 5377. (d) Hoepping, A.; George, C.; Flippen-
Anderson, J .; Kozikowski, A. P. Tetrahedron Lett. 2000, 41, 7427. (e)
Cossy, J .; Bouzide, A.; Leblanc, C. J . Org. Chem. 2000, 65, 7257. (f)
Pre´vost, N.; Shipman, M. Tetrahedron 2002, 58, 7165.
(14) For a preliminary account of part of these results: Sole´, D.;
Peidro´, E.; Bonjoch, J . Org. Lett. 2000, 2, 2225.
(15) (a) Piers, E.; Marais, P. C. J . Org. Chem. 1990, 55, 3454. (b)
Piers, E.; Renaud, J . J . Org. Chem. 1993, 58, 11.
(16) (a) Wang, T.; Cook, J . M. Org. Lett. 2000, 2, 2057. (b) Liu, X.;
Wang, T.; Xu, Q.; Ma, C.; Cook, J . M. Tetrahedron Lett. 2000, 41, 6299.
(c) For further applications in the indole alkaloid synthesis, see: Yu,
J .; Wearing, X. Z.; Cook, J . M. Tetrahedron Lett. 2003, 44, 543 and
references therein.
(17) (a) Bonjoch, J .; Sole´, D.; Garc´ıa-Rubio, S.; Bosch, J . J . Am.
Chem. Soc. 1997, 119, 7230. (b) Quirante, J .; Escolano, C.; Merino, A.;
Bonjoch, J . J . Org. Chem. 1998, 63, 968. (c) Reference 10f.
(18) For previous synthesis of 2-azabicyclo[3.3.1]nonan-6-ones, see:
(a) Bosch, J .; Bonjoch, J . J . Org. Chem. 1981, 46, 1538. (b) Boger, D.
L.; Patel, M.; Mullican, M. D. Tetrahedron Lett. 1982, 23, 4559. (c)
Teuber, H.-J .; Tsaklakidis, C.; Bats, J . W. Liebigs Ann. Chem. 1990,
781. (d) Quirante, J .; Escolano, C.; Diaba, F.; Bonjoch, J . J . Chem. Soc.,
Perkin Trans 1 1999, 1157.
10.1021/jo034299q CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/07/2003
5746
J . Org. Chem. 2003, 68, 5746-5749

tion of amino-tethered vinyl halides and ketones19,20 that
would afford compounds bearing different alkylidene
substituents on the aforementioned bridged system (Table
1). After optimization studies with vinyl bromide 1a , in
which different bases, Pd sources, and solvents were
examined,14 we found that the combination of KO-t-Bu
(1.5 equiv) and Pd(PPh3)4 (0.2 equiv) in THF at reflux
gave the best results. Under these reaction conditions,
1a afforded 2-azabicyclo[3.3.1]nonan-6-one 6 in 40-50%
yield, together with minor amounts of dimer 7 (entry 1).
The formation of the latter can be explained by the Pd-
catalyzed coupling of 1a with the alkyne 8 formed by
elimination of HBr from the starting vinyl bromide. In
fact, minor amounts of alkyne 8 were obtained in some
runs where the amount of KO-t-Bu was increased.14
As expected, vinyl iodide 1b was more efficient in the
intramolecular coupling than 1a and, under the standard
cyclization conditions (entry 2), gave 6 in 55-60% yield,
the dimer 7 not being obtained. Starting from vinyl
bromide 2, bicycle 9 was obtained in 24% yield as a 1.5:1
mixture of diastereomers (entry 3). The lower yield of the
cyclization could be interpreted on conformational grounds.
Thus, the introduction of a bulkier substituent at the
nitrogen atom hampers the conformational change previ-
ous to the cyclization, allowing degradation processes to
occur. In this context, it is noteworthy that 4-[N-(R-methyl-
benzyl)amino]cyclohexanone was also detected in the
reaction mixtures.21 On the other hand, the low diaster-
oselectivity of the cyclization reaction could be explained
taking into account the scarce control of the chiral
auxiliary in the enolization process.
TABLE 1. Syn th esis of 4-Alk ylid en e-2-a za bicyclo-
[3.3.1]n on a n -6-on es by P d -Ca ta lyzed Cycliza tion of Vin yl
Ha lid es a n d Keton esa
The influence of the substitution pattern on the double
bond was also studied. When starting from the E vinyl
iodide 3, the bridged compound 10 was obtained in good
yield (entry 4). However, this compound, which is the only
one detected in the reaction mixture, could not be
completely characterized because on standing in solution
it isomerizes to the enamine 11. Under the same reaction
conditions, the isomeric Z vinyl iodide 4b gave a mixture
of the cyclization compound 12 and alkyne 13 (entry 5),
due to a decrease in the rate of the oxidative addition
reaction as well as a greater tendency to undergo the E2
elimination of Z vinyl iodides with respect to the E
isomers. When starting from 5b, in which the elimination
process is not possible, azabicyclic compound 14 was
obtained as the only isolable product in good yield (entry
7). The latter is also an unstable compound and isomer-
izes to the enamine 15 in dichloromethane solution as
a
Reactions were carried out with 0.2 equiv of Pd(PPh3)4 and
b
1.5 equiv of KO-t-Bu in THF at reflux. 4-[N-(R-Methylbenz-
yl)amino]cyclohexanone was also detected in the reaction mixture.
cThis was the only compound observed in the reaction mixture
although it was not quantified. KO-t-Bu (1.75 equiv). e After the
d
usual workup, flash chromatography was carried out on Al2O3.
well as during flash chromatography on SiO2. In contrast
with the results obtained with iodides 4b and 5b, vinyl
bromides 4a and 5a were inefficient in the cyclization
process, since, under essentially the standard reaction
conditions, 4a exclusively afforded alkyne 13 (entry 6),
while 5a was recovered unchanged (entry 8).
(19) For the intermolecular vinylation of ketone enolates, see:
Chieffi, A.; Kamikawa, K.; A° hman, J .; Fox, J . M.; Buchwald, S. L. Org.
Lett. 2001, 3, 1897.
(20) For related Pd-catalyzed intramolecular coupling of aryl halides
and ketone enolates, see: (a) Muratake, H.; Natsume, M. Tetrahedron
Lett. 1997, 38, 7581. (b) Muratake, H.; Nakai, H. Tetrahedron Lett.
1999, 40, 2355. (c) Sole´, D.; Vallverdu´, L.; Bonjoch, J . Adv. Synth. Catal.
2001, 343, 439. (d) Sole´, D.; Vallverdu´, L.; Peidro´, E.; Bonjoch, J . Chem.
Commun. 2001, 1888. (e) Sole´, D.; Vallverdu´, L.; Solans, X.; Font-
Bard´ıa, M.; Bonjoch, J . J . Am. Chem. Soc. 2003, 125, 1587. For Pd-
catalyzed intramolecular coupling of aryl halides and amide enolates,
see: (f) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J . F. J . Org.
Chem. 1998, 63, 6546. (g) Lee, S.; Hartwig, J . F. J . Org. Chem. 2001,
66, 3402. (h) Freund, R.; Mederski, W. W. K. R. Helv. Chim. Acta 2000,
83, 1247. (i) Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 193.
(j) Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 1363. (k) Honda,
T.; Namiki, H.; Satoh, F. Org. Lett. 2001, 3, 631. For a Pd-catalyzed
intramolecular coupling of aryl halides and R-amino acid esters, see:
(l) Gaertzen O.; Buchwald, S. L. J . Org. Chem. 2002, 67, 465.
(21) The formation of deallylated products has also been reported
by Cook.16b
The tendency of the 4-alkylidene-2-azabicyclo[3.3.1]-
nonan-6-ones 10 and 14 to undergo isomerization to the
corresponding enamines can be accounted for considering
the A(1,3) strain between the methyl group of the (Z)-
ethylidene or isopropylidene side chain and the hydro-
gens at C-3 of the bicyclic ring. Although the 2-azabicyclo-
[3.3.1]nonane framework is a conformationally mobile
system, compounds 10 and 14 in either of their CC
J . Org. Chem, Vol. 68, No. 14, 2003 5747

TABLE 2. Syn th esis of Nitr ogen Heter ocycles by
P d -Ca ta lyzed Cycliza tion of Vin yl Ha lid es a n d Keton es
F IGURE 1. Conformational analysis of 14.
F IGUR E 2. Conformational analysis and selected NOESY
correlations of 2-azabicyclo[3.3.1]nonan-6-one 12.
(chair-chair) or CB (chair-boat) conformations cannot
relieve the aforementioned allylic strain (Figure 1) and,
since they cannot gain a greater stability through a
conformational equilibrium, follow an isomerization path-
way to furnish enamines 11 and 15. In contrast, (E)-
ethylidene-bearing azabicycle 12 in its CB conformation
can avoid the A(1,3) strain, and consequently is a consti-
tutionally stable compound.22 The conformational equi-
librium in 12 between the CC and CB conformations is
supported by NMR studies (NOESY data, Figure 2),
which also showed that methylene derivative 6 prefers
the CC conformation, as occurs in the 2-azabicyclo[3.3.1]-
nonanes lacking steric interactions.23
After studying the 2-azabicyclo[3.3.1]nonane series, we
decided to extend the Pd-catalyzed intramolecular cou-
pling of vinyl halides and ketone enolates to the synthesis
of other nitrogen heterocycles bearing alkylidene sub-
stituents. On treatment with 0.2 equiv of Pd(PPh3)4 and
1.5 equiv of KO-t-Bu in refluxing THF (method A in Table
2), vinyl iodide 16 gave the 2-azabicyclo[4.3.1]decanone
22, although in low yield (entry 1).24
a
Method A: KO-t-Bu (1.5 equiv), Pd(PPh3)4 (0.2 equiv), THF
reflux, 30 min. Method B: Cs2CO3 (3 equiv), Et3N (3 equiv),
PdCl2(PPh3)2 (0.2 equiv), toluene 110 °C, sealed tube, 24h. b Alkyne
8 was also detected in the reaction mixture along with several
unidentified products. c N-Benzyl-2-cyclohexenylamine (29%) was
d
also isolated. 4 h.
3,4-Disubstituted piperidine derivatives could also be
obtained by this annulation process. Starting from vinyl
bromide 17, a 1:7 mixture of piperidine 23 and tetrahy-
dropyridine 24 was obtained (entry 2), the latter arising
from the initially formed annulation product 23 when this
undergoes an isomerization to the more stable conjugated
ketone under strongly basic reaction conditions.25 It
should be noted that in some runs minor amounts of
alkyne 25 and dimer 26 were obtained together with the
cyclization compounds. On the contrary, the Pd-catalyzed
cyclization of vinyl iodide 18 exclusively afforded piperi-
dine 27 (entry 3), and no isomerization compound was
detected.
The synthesis of five-membered nitrogen heterocycles
was also examined. In this series, the Pd-catalyzed
cyclization could be accomplished by using either KO-t-
26
Bu or Cs2CO3 as the base. When KO-t-Bu was used,
vinyl bromide 19 afforded a reaction mixture in which
the only product detected was pyrroline 28, although a
1:1 mixture of 28 and pyrrole 29 was obtained after
column chromatography (entry 4). Meanwhile, the use
of Cs2CO3 resulted in the direct formation of pyrrole
29 (entry 5). Similar results were obtained from
vinyl bromide 20, which underwent cyclization to afford
mixtures of hydroindoles 30 and 31, although in lower
yields (entries 6 and 7). It should be noted that pyrro-
lidines 28 and 30 could not be completely characterized
because on standing in solution they easily suffer air
oxidation to pyrroles 29 and 31, respectively.27
(22) In fact, all indole alkaloids bearing a 20-ethylidene side chain
in the piperidine ring shows an E configuration: Bosch, J .; Bennasar,
M. L. Heterocycles 1983, 20, 2471.
(23) Casamitjana, N.; Bonjoch, J .; Gra`cia, J .; Bosch, J . Magn. Reson.
Chem. 1992, 30, 183.
(24) Quirante, J .; Escolano, C.; Bonjoch, J . Synlett 1997, 179.
(25) The isomerization of the initially formed annulation products
to the conjugated enones under the reaction condition was also
observed by Piers.15a
(26) It should be noted that no cyclization product was obtained in
none of the series leading to six-membered rings when Cs2CO3 was
used as the base.
5748 J . Org. Chem., Vol. 68, No. 14, 2003

1H, H-9R), 2.24 (dm, J ) 13 Hz, 1H, H-9â), 2.25-2.33 (m, 1H,
H-8eq), 2.45 (dd, J ) 17.5, 8.5 Hz, 1H, H-7eq), 2.59 (ddd, J )
17.5, 10.5, 8.5 Hz, 1H, H-7ax), 3.08 (br s, 1H, H-1), 3.24 (br s,
1H, H-5), 3.34 (s, 2H, H-3), 3.70 (d, J ) 13.5 Hz, 1H, NCH2Ar),
3.77 (d, J ) 13.5 Hz, 1H, NCH2Ar), 4.84 (s, 1H, dCH), 4.91 (s,
1H, dCH), 7.22-7.36 (m, 5H, ArH); 13C NMR (CDCl3, 75.5 MHz)
δ 25.4 (C-8), 32.7 (C-9), 37.9 (C-7), 49.9 (C-1), 53.5 (C-5), 53.7
(C-3), 59.8 (NCH2Ar), 112.6 (dCH2), 127.1 (p-C), 128.5 and 128.7
(o-C and m-C), 139.0 (ipso-C), 141.0 (C-4), 210.5 (C-6). Anal.
Calcd for C16H19NO (241.3): C, 79.63; H, 7.94; N, 5.80. Found:
C, 79.34; H, 7.79; N, 5.45.
Finally, Pd-catalyzed cyclization of vinyl iodide 21
exclusively afforded pyrrolidine 32 with either KO-t-Bu
or Cs2CO3 (entries 8 and 9), and no isomerization comp-
ound was detected. However, it should be noted once
again that on standing in solution 32 slowly oxidizes to
pyrrole 33. Interestingly, in contrast to what happens in
the bridged azabicyclic compounds, in the monocyclic
series the isopropylidene derivatives are more stable than
the methylene analogues, which easily isomerize to the
conjugated enones.
In summary, we have developed a methodology for the
synthesis of nitrogen heterocycles based on the pal-
ladium-catalyzed intramolecular coupling of vinyl halides
and ketone enolates. These processes have shown to work
better when using vinyl iodides, rather than bromides,
except in the methylene series where the halogen influ-
ence is weak. When planning to use this synthetic
methodology it should be borne in mind that in some
substrates side reactions can occur, such as the elimina-
tion of HX from the starting material to give an alkyne
and the isomerization of the initially formed annulation
product to the conjugated ketone or enamine. Neverthe-
less, looking at the full picture, the Pd(0)-catalyzed
reaction here described constitutes a promising method-
ology for the synthesis of heterocycles. Further studies
directed to the synthesis of natural products embodying
the 2-azabicyclo[3.3.1]nonane framework using this meth-
odology are in progress and will be reported in due course.
2-Ben zyl-4-[(Z)-eth ylid en e]-2-a za bicyclo[3.3.1]n on a n -6-
on e (10): flash chromatography (SiO2, from CH2Cl2 to 98:2 CH2-
1
Cl2/MeOH); IR (film) 1712 cm-1; H NMR (CDCl3, 200 MHz) δ
1.52 (dd, J ) 7, 1.2 Hz, 3H), 1.60-1.80 (m, 1H), 1.94 (dt, J )
12.8, 3 Hz, 1H), 2.23 (dq, J ) 12.8, 3.4 Hz, 1H), 2.26-2.44 (m,
1H), 2.43 (dd, J ) 17.2, 8.2 Hz, 1H), 2.58 (ddd, J ) 17.2, 10.6, 8
Hz, 1H), 3.08 (br s, 1H), 3.13 (br s, 1H), 3.23 (d, J ) 14.6 Hz,
1H), 3.61 (d, J ) 14.6 Hz, 1H), 3.79 (s, 2H), 5.43 (qm, J ) 7 Hz,
1H), 7.20-7.45 (m, 5H); 13C NMR (CDCl3, 75.5 MHz, DEPT) δ
13.0 (CH3), 25.5 (CH2), 32.8 (CH2), 38.0 (CH2), 48.4 (CH2), 50.2
(CH), 54.4 (CH), 59.9 (CH2), 122.3 (CH), 127.5 (CH), 128.3 (CH),
128.6 (CH), 131.5 (C), 139.0 (C), 211.2 (C); HRMS calcd for
C17H21NO 255.1623, found 255.1627.
2-Ben zyl-4-[(E)-eth ylid en e]-2-a za bicyclo[3.3.1]n on a n -6-
on e (12):28 flash chromatography (SiO2, from CH2Cl2 to 98:2
CH2Cl2/MeOH); IR (film) 1709 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 1.62 (d, J ) 7 Hz, 3H, CH3), 1.67 (dddd, J ) 14, 11.5, 7.5, 4
Hz, 1H, H-8ax), 1.91 (dt, J ) 13.5, 3 Hz, 1H, H-9R), 2.14 (ddm,
J ) 14, 8 Hz, 1H, H-8eq), 2.26 (dq, J ) 13.5, 3.5 Hz, 1H, H-9â),
2.35 (dd, J ) 16.5, 7.5 Hz, 1H, H-7eq), 2.75 (ddd, J ) 16.5, 11.5,
8 Hz, 1H, H-7ax), 3.08 (br s, 1H, H-1), 3.25 (d, J ) 13.5 Hz, 1H,
H-3ax), 3.31 (d, J ) 13.5 Hz, 1H, H-3eq), 3.51 (br s, 1H, H-5),
3.71 (d, J ) 13.5 Hz, 1H, NCH2Ar), 3.76 (d, J ) 13.5 Hz, 1H,
NCH2Ar), 5.42 (q, J ) 7 Hz, 1H, dCH), 7.22-7.36 (m, 5H); 13C
NMR (CDCl3, 75.5 MHz) δ 12.9 (CH3), 27.9 (C-8), 31.6 (C-9), 37.4
(C-7), 47.5 (C-5), 51.1 (C-1), 54.7 (C-3), 60.5 (NCH2Ar), 122.5
(dCH), 127.0 (p-C), 128.2 and 128.7 (o-C and m-C), 132.1 (C-4),
138.9 (ipso-C), 210.6 (C-6); HRMS calcd for C17H21NO 255.1623,
found 255.1615. Anal. Calcd for C17H21NO‚H2O: C, 74.69; H,
8.48; N, 5.12. Found: C, 74.29; H, 8.06; N, 4.79.
Exp er im en ta l Section
2-Ben zyl-4-isop r op ylid en e-2-a za b icyclo[3.3.1]n on a -6-
on e (14):28 flash chromatography (Al2O3, from hexane to 8:2
hexane/AcOEt); IR (film) 1704 cm-1; 1H NMR (C6D6, 300 MHz)
δ 1.15 (dddd, J ) 13.5, 12, 6.3, 3.3 Hz, 1H, H-8ax), 1.27 (s, 3H,
CH3), 1.42 (dt, J ) 13.2, 3 Hz, 1H, H-9R), 1.66 (s, 3H, CH3), 1.67
(ddm, J ) 13.5, 8 Hz, 1H, H-8eq), 1.92 (dq, J ) 13.2, 3.5 Hz,
1H, H-9â), 2.15 (br dd, J ) 15.3, 6.3 Hz, 1H, H-7eq), 2.58 (br t,
J ) 3 Hz, 1H, H-1), 2.67 (ddd, J ) 15.3, 12, 8 Hz, 1H, H-7ax),
3.20 (s, 2H, H-3), 3.44 (s, 2H, NCH2Ar), 3.45 (br s, 1H, H-5),
7.04-7.28 (m, 5H); 13C NMR (C6D6, 75.5 MHz) δ 20.2 (CH3), 20.6
(CH3), 29.4 (C-8), 31.1 (C-9), 37.0 (C-7), 48.7 (C-1), 49.5 (C-3),
51.2 (C-5), 61.1 (NCH2Ar), 125.9 (C), 127.3 (p-C), 128.6 and 128.8
(o-C and m-C), 128.7 (C), 139.9 (ipso-C), 208.2 (C-6); HRMS calcd
for C18H23NO 269.1780, found 269.1771.
R ep r esen t a t ive P r oced u r e for t h e P d (0)-Ca t a lyzed
In tr a m olecu la r Cou p lin g Usin g KO-t-Bu a s th e Ba se
(Ta ble 1, En tr y 2). To a solution of Pd(PPh3)4 (60 mg, 0.05
mmol) in dry THF (5 mL) were added under argon a solution of
vinyl bromide 1b (100 mg, 0.27 mmol) in dry THF (2 mL) and
KO-t-Bu (0.4 mmol, 0.4 mL of 1 M solution in tert-butyl alcohol).
The solution was heated at reflux for 30 min. After being cooled
to room temperature, the mixture was diluted with ether and
washed with saturated aqueous NH4Cl. The aqueous layer was
extracted with ether, and the combined organic extracts were
washed with brine, dried, and concentrated. The residue was
purified by flash chromatography (SiO2, from CH2Cl2 to 98:2
CH2Cl2/MeOH) to give azabicyclic compound 6 (39 mg, 60%).
R ep r esen t a t ive P r oced u r e for t h e P d (0)-Ca t a lyzed
In tr a m olecu la r Cou p lin g Usin g Cs2CO3 a s th e Ba se in
Tolu en e (Ta ble 2, Meth od B: En tr y 5). A solution of vinyl
bromide 19 (100 mg, 0.34 mmol), Cs2CO3 (332 mg, 1.02 mmol),
Et3N (0.14 mL, 1.02 mmol), and PdCl2(PPh3)2 (49 mg, 0.07 mmol)
in dry toluene (10 mL) was stirred at 110 °C in a sealed tube
for 24 h. After being cooled to room temperature, the mixture
was diluted with CH2Cl2 and washed with saturated aqueous
NaHCO3. The aqueous layer was extracted with CH2Cl2, and
the combined organic extracts were dried and concentrated. The
residue was purified by flash chromatography (Al2O3, from
hexane to 8:2 hexane/AcOEt) to give pyrrole 29 (33 mg, 45%).
2-Ben zyl-4-m eth ylen e-2-azabicyclo[3.3.1]n on an -6-on e (6):
28 IR (film) 1710 cm-1; 1H NMR (CDCl3, 500 MHz) δ 1.72 (dddd,
J ) 14.5, 10.5, 8, 4.5 Hz, 1H, H-8ax), 1.97 (dt, J ) 13, 2.7 Hz,
Ack n ow led gm en t. This work was supported by
MCYT, Spain (Project BQU2001-3551). Thanks are also
given to the DURSI (Catalonia, 2001SGR-00083).
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for all new compounds and experimental procedures for
preparation of starting materials. Conformational analysis and
NOESY correlations for compounds 6 and 14. 1H and 13C NMR
spectra for compounds 1b, 4a ,b, 6-12, 14, 15, 18, 20-22, and
29. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O034299Q
(28) The signals in the 1H and 13C NMR spectra of this compound
were unambiguously assigned with the aid of 2D-NMR experiments
(COSY and HSQC) and NOESY.
(27) For easy air oxidation of 3-acylpirrolines to 3-acylpyrroles,
see: Chou, S.-S. P.; Yuan, T.-M. Synthesis 1991, 171.
J . Org. Chem, Vol. 68, No. 14, 2003 5749