Palladium-catalyzed intramolecular coupling of vinyl halides and ketone enolates. Synthesis of bridged azabicyclic compounds

Article abstract of DOI:10.1021/ol005973i

(equation presented) The palladium-mediated intramolecular coupling of amino-tethered vinyl halides and ketone enolates is a useful methodology for the synthesis of nitrogen heterocycles and constitutes a new synthetic entry to the 2-azabicyclo[3.3.1]nona

Full text of DOI:10.1021/ol005973i

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2225-2228
Palladium-Catalyzed Intramolecular
Coupling of Vinyl Halides and Ketone
Enolates. Synthesis of Bridged
Azabicyclic Compounds
Daniel Sole´,* Emma Peidro´, and Josep Bonjoch*
Laboratory of Organic Chemistry, Faculty of Pharmacy, UniVersity of Barcelona,
08028-Barcelona, Spain
bonjoch@farmacia.far.ub.es
Received April 20, 2000
ABSTRACT
The palladium-mediated intramolecular coupling of amino-tethered vinyl halides and ketone enolates is a useful methodology for the synthesis
of nitrogen heterocycles and constitutes a new synthetic entry to the 2-azabicyclo[3.3.1]nonane framework. A study about the reaction conditions
and the scope of the process is reported.
As part of our ongoing program in the synthesis of natural
products embodying the 2-azabicyclo[3.3.1]nonane frame-
work,1 we became interested in the synthesis of compounds
with this bridged system bearing a carbonyl at C-6 and
substituted at the 4-position by an alkylidene appendage (e.g.,
1). This framework is an attractive target not only because
systems, such as those of the immunosuppressant FR9014833,4
or the cytotoxic agent madangamine-A.5
We considered that the Pd-catalyzed intramolecular cou-
pling of vinyl halides and ketone enolates (Scheme 1) could
Scheme 1. Pd-Catalyzed Intramolecular Coupling of Vinyl
Halides and Ketone Enolates
it is found in some alkaloids (e.g., strychnopivotine2) but
also because it could be elaborated into more functionalized
be a suitable methodology for the synthesis of the target
system, despite the fact that these types of cyclizations have
been completely ignored for a long time.6 To our knowledge,
(1) (a) Bonjoch, J.; Sole´, D.; Garc´ıa-Rubio, S.; Bosch, J. J. Am. Chem.
Soc. 1997, 119, 7230-7240. (b) Quirante, J.; Escolano, C.; Merino, A.;
Bonjoch, J. J. Org. Chem. 1998, 63, 968-976. (c) Sole´, D.; Bonjoch, J.;
Garc´ıa-Rubio, S.; Peidro´, E.; Bosch, J. Chem. Eur. J. 2000, 6, 655-665.
(2) (a) Isolation: Tits, M.; Tavernier, D.; Angenot, L. Phytochemistry
1980, 19, 1531-1534. (b) Synthetic studies: Teuber, H.-J.; Tsaklakidis,
C.; Bats, J. W. Liebigs Ann. Chem. 1992, 461-466.
(3) (a) Isolation: Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanihi, T.;
Yamashita, M.; Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996,
49, 37-44. (b) Total synthesis: Snider, B. B.; Lin, H. J. Am. Chem. Soc.
1999, 121, 7778-7786.
10.1021/ol005973i CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/21/2000

there are only two examples of this reaction, which was
developed by Piers in the carbocyclic series and successfully
applied to the synthesis of the diterpenoid crinipellin B.7 The
reaction exploits the electrophilic character of the palladium
atom and it is presumed to proceed by sequential oxidative
addition and deprotonation, followed by conversion to a
palladacycle, which undergoes a simple reductive elimina-
tion.
by the Pd-catalyzed coupling of 2a with the alkyne 4 formed
by elimination of HBr from the starting vinyl bromide.11 The
In this paper we report the implementation of the above
methodology to the synthesis of nitrogen heterocycles.8 Our
efforts were initially focused on the cyclization of vinyl
halides 2a and 2b (Table 1), which were readily available
amount of the catalyst could be reduced to 0.1 equiv without
any significant effect on the yield of the cyclization (entry
2), although smaller amounts of Pd(PPh3)4 resulted in worse
yields. The use of Pd[P(o-tolyl)3]2Cl2 (entry 3) and Pd(OAc)2/
PPh3 (entry 4) as the catalyst afforded similar yields of
cyclized product. Bases other than KOt-Bu were examined,12
and among them only NaH (entry 5) and TBAF (entry 6)
afforded the desired azabicyclic compound 1, although in
low yields.
Table 1. Pd-Catalyzed Cyclization of 2a and 2b
Other bases studied (HMDS, NaOH, TMG, KF, and CsF)
did not give any reaction, even after long reaction times at
reflux. The solvent was also important; thus, although the
cyclized product 1 was also observed in CH3CN (entry 7),
DMF (entry 8) failed to promote the cyclization, with
considerable amounts of alkyne 4 being isolated. The use of
Cs2CO3 as the base in toluene at reflux6a mainly resulted in
dealkylation of the starting material to give 4-(benzylamino)-
cyclohexanone. It is noteworthy that dealkylation of the
2-haloallylamine seems to be a common competing reaction
since the secondary amine was detected, although not
quantified, in nearly all the cyclization mixtures. Finally,
addition of n-Bu4NCl to the otherwise standard cyclization
of 2a increased the amount of dimer 3, while the addition
of AgNO3 resulted in recovery of the starting vinyl bromide.
On the other hand, as expected, vinyl iodide 2b was more
efficient in the intramolecular coupling than 2a. Thus,
treatment of 2b with 0.2 equiv of Pd(PPh3)4 and 1.5 equiv
base
solvent products
entry
1
X
catalyst (equiv)
(equiv) (temp)
(%)a
Br Pd(PPh3)4 (0.2)
Br Pd(PPh3)4 (0.1)
KOt-Bu THF
1 (40-50)
3 (5)
(1.5)
KOt-Bu THF
(1.5)
(rfx)c
Br Pd[P(o-tol)3]2Cl2 (0.2) KOt-Bu THF
(1.5)
(rfx)c
KOt-Bu THF
(rfx)c
2
3
4
5
6
7
1 (43)
3 (10)
1 (50)
Br Pd(OAc)2 (0.2)
PPh3 (0.4)
Br Pd(PPh3)4 (0.2)
1 (40)
3 (5)
1 (22)
(1.5)
NaH
(1.5)
TBAF
(2)b
(rfx)d
THF
(rfx)e
THF
(rfx)e
Br Pd(PPh3)4 (0.2)
Br Pd(PPh3)4 (0.2)
1 (15)
3 (8)
KOt-Bu CH3CN 1 (7)
(1.5)
(rfx)d
3 (7)
4 (10)
3 (5)
(6) For the Pd-catalyzed intramolecular coupling of aryl halides and
enolates, see: (a) Muratake, H.; Natsume, M. Tetrahedron Lett. 1997, 38,
7581-7582. (b) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org.
Chem. 1998, 63, 6546-6553. (c) Muratake, H.; Nakai, H. Tetrahedron Lett.
1999, 40, 2355-2358. For the Pd-catalyzed intermolecular coupling of aryl
halides and enolates, see: (d) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2000, 122, 1360-1370 and references therein.
(7) (a) Piers, E.; Marais, P. C. J. Org. Chem. 1990, 55, 3454-3455. (b)
Piers, E.; Renaud, J. J. Org. Chem. 1993, 58, 11-13.
8
9
Br Pd(PPh3)4 (0.2)
KOt-Bu DMF
(1.5)
KOt-Bu THF
(1.5)
(rfx)c
KOt-Bu THF
(1.3)
(rt)f
(70 °C)d 4 (22)
I
I
Pd(PPh3)4 (0.2)
Pd(PPh3)4 (0.2)
1 (55-60)
10
1 (42)
a Yields refer to pure isolated products. b HMPA (6 equiv). c 30 min.
d 1 h. e 3.5 h. f 24 h.
(8) For the elaboration of 3-alkylidene piperidine rings by Heck reactions
in the synthesis of alkaloids, see: (a) Rawal, V. H.; Michoud, C.; Monestel,
R. F.J. Am. Chem. Soc. 1993, 115, 3030-3031. Rawal, V. H.; Iwasa, S. J.
Org. Chem. 1994, 59, 2685-2686. (b) Birman, V. B.; Rawal, V. H.
Tetrahedron Lett. 1998, 39, 7219-7222. Birman, V. B.; Rawal, V. H. J.
Org. Chem. 1998, 63, 9146-9147. (c) See ref 1c.
by alkylation of 4-(benzylamino)cyclohexanone.9 In the
presence of 0.2 equiv of Pd(PPh3)4 and 1.5 equiv of KOt-
Bu in refluxing THF (entry 1), vinyl bromide 2a underwent
the desired cyclization reaction to give 2-azabicyclo[3.3.1]-
nonan-6-one 1 in 40-50% yield,10 together with minor
amounts of dimer 3. The formation of 3 can be explained
(9) Quirante, J.; Escolano, C.; Massot, M.; Bonjoch, J. Tetrahedron 1997,
53, 1391-1402.
(10) For other recent synthetic methods to build up this azabicyclic
system, see: (a) Molander, G. A.; Harris, C. R. J. Org. Chem. 1997, 62,
7418-7429. (b) Yamazaki, N.; Suzuki, H.; Kibayashi, C. J. Org. Chem.
1997, 62, 8280-8281. (c) Quirante, J.; Escolano, C.; Diaba, F.; Bonjoch,
J. J. Chem. Soc., Perkin Trans. 1 1999, 1157-1162.
(11) The detection of alkynes was also reported by Piers, who minimized
the formation of such byproducts by slowly adding the base at room
temperature.7a
(4) For our studies in this field, see: Bonjoch, J.; Diaba, F.; Puigbo´, G.;
Sole´, D.; Segarra, V.; Santamar´ıa, L.; Beleta, J.; Ryder, H.; Palacios, J.-M.
Bioorg. Med. Chem. 1999, 7, 2891-2897.
(5) (a) Isolation: Kong, F.; Andersen, R. J.; Allen, T. M. J. Am. Chem.
Soc. 1994, 116, 6007-6008. (b) Synthetic studies: Matzanke, N.; Gregg,
R. J.; Weinreb, S. M. J. Org. Chem. 1997, 62, 1920-1921.
(12) Following the suggestion of a reviewer, sodium tert-butoxide6b,d
has also been tried as a base for this process. Using the reaction conditions
of entry 1 (Table 1) and the aforementioned base, there was no significant
change in the yield of compound 1.
2226
Org. Lett., Vol. 2, No. 15, 2000

of KOt-Bu in refluxing THF (entry 9) gave 1 in 55-60%
yield. Moreover, starting from vinyl iodide 2b the cyclization
was achieved at room temperature (entry 10) to afford 1 in
acceptable yield and without the formation of appreciable
amounts of byproducts. In contrast, under the same reaction
conditions vinyl bromide 2a was recovered unchanged.
The Pd-catalyzed intramolecular coupling could also be
accomplished by generating the enolate starting from the
corresponding silyl enol ether.13 Thus, treatment of 5 with
0.2 equiv of Pd(PPh3)4 and 2 equiv of TBAF in refluxing
THF afforded azabicyclic ketone 1 in 49% yield together
with a small amount of dimer 3 (Scheme 2). An alternative
Table 2. Synthesis of Nitrogen Heterocycles by Pd-Catalyzed
Cyclization of Vinyl Halides and Ketone Enolates
Scheme 2
explanation for the formation of 1 involving a Heck reaction
upon the silyl enol ether double bond, followed by
F--mediated desilylation of the cyclized product, was
rejected, because in the absence of TBAF and under the same
reaction conditions the starting silyl enol ether 5 was
recovered.
The Pd-catalyzed intramolecular coupling of vinyl halides
and ketone enolates was extended to other substrates (Table
2). Under the standard cyclization conditions, vinyl bromide
6 afforded bicycle 7 in 24% yield (entry 1). 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
previous to the cyclization step.
Starting from vinyl iodide 8 the bridged compound 9 was
obtained in good yield (entry 2). It is interesting to note that
on standing this compound, which is the only one detected
in the reaction mixture, isomerized to the enamine 10.
a Method A: KOt-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, 24 h. b 1.5 h. c 4-[N-(R-Methylben-
zyl)amino]cyclohexanone was also detected in the reaction mixture. d 1.5:
1 mixture of diastereomers. e Alkyne 4 was also detected in the reaction
mixture along with several unidentified products. f N-Benzyl-2-cyclohex-
enylamine (29%) was also isolated.
Pd-catalyzed annulation of â-aminoketones 13 and 16, which
led to the formation of five-membered nitrogen heterocycles.
Treatment of 13 under the standard cyclization conditions
(entry 4) afforded a reaction mixture in which the only
product detected was pyrroline 14, which arises when the
initially formed annulation product undergoes an isomeriza-
tion to the more stable conjugated ketone under strongly basic
reaction conditions.15 Nevertheless, after column chroma-
tography a 1:1 mixture of 14 and pyrrole 15 was obtained.16
Interestingly, the Pd-catalyzed cyclization of 13 can also be
accomplished by using Cs2CO3 as the base (entry 5). Under
these conditions and after column chromatography, pyrrole
On the other hand, the 2-azabicyclo[4.3.1]decane system14
(e.g., 12) can be obtained, although in low yield, starting
from vinyl iodide 11 (entry 3). Finally, we examined the
(13) (a) For Pd-catalyzed intermolecular arylation of tin enolates, prepared
in situ from silyl enol ethers and Bu3SnF, see: Kuwajima, I.; Urabe, H. J.
Am. Chem. Soc. 1982, 104, 6831-6833. (b) For Pd-catalyzed intermolecular
alkenylation of tin enolates, prepared in situ from enol acetates and Bu3-
SnOMe, see: Kosugi, M.; Hagiwara, I.; Sumiya, T.; Migita, T. Bull. Chem.
Soc. Jpn. 1984, 57, 242-246.
(15) The isomerization of the initially formed annulation products to the
conjugated enones under the reaction conditions was also observed by
Piers.7a
(16) For the easy air oxidation of 3-acylpyrrolines to 3-acylpyrroles,
see: Chou, S.-S. P.; Yuan, T.-M. Synthesis 1991, 171-172.
(14) Quirante, J.; Escolano, C.; Bonjoch, J. Synlett 1997, 179-180.
Org. Lett., Vol. 2, No. 15, 2000
2227

15 was obtained in acceptable yield. Similar results were
obtained starting from 16, which underwent cyclization to
afford mixtures of hydroindoles 17 and 18, after column
chromatography, although in lower yields (entries 6 and 7).
In summary, the utility of the Pd-catalyzed intramolecular
coupling of vinyl halides and ketone enolates to the synthesis
of nitrogen heterocycles has been reported. Further studies
directed toward the application of this methodology to the
synthesisofnaturalproductsembodyingthe2-azabicyclo[3.3.1]-
nonane framework are in progress and will be reported on
in due course.
Acknowledgment. This work was supported by the
DGICYT, Spain (Project PB97-0877). Financial support for
DGEU, Catalonia (1999SGR00067) is also acknowledged.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 1, 3, 4, 7, 9,
10, 12, 14, 15, 17, and 18. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL005973I
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Org. Lett., Vol. 2, No. 15, 2000