Pt(II) or Ag(I) salt catalyzed cycloisomerizations and tandem cycloadditions forming functionalized azacyclic arrays

Article abstract of DOI:10.1021/ol047696b

(Chemical Equation Presented) Cyclic ene-N-p-toluenesulfonamides tethered to an electron-deficient alkyne undergo cycloisomerizations readily under the influence of catalytic Pt(II) salts (PtCl₂ or [dppbPtμ-OH] ₂(BF₄)

Full text of DOI:10.1021/ol047696b

ORGANIC
LETTERS
2004
Vol. 6, No. 26
5023-5026
Pt(II) or Ag(I) Salt Catalyzed
Cycloisomerizations and Tandem
Cycloadditions Forming Functionalized
Azacyclic Arrays
Tyler J. Harrison and Gregory R. Dake*
Department of Chemistry, 2036 Main Mall, UniVersity of British Columbia,
VancouVer, B.C., Canada, V6T 1Z1
gdake@chem.ubc.ca
Received November 9, 2004
ABSTRACT
Cyclic ene-N-p-toluenesulfonamides tethered to an electron-deficient alkyne undergo cycloisomerizations readily under the influence of catalytic
Pt(II) salts (PtCl2 or [dppbPt -OH]2(BF4)2) or AgOTf. Yields for this process range from 47% to 99%. The resulting functionalized 2-azahydrindans
can be reacted further using the Diels Alder reaction. Tandem cycloisomerization cycloaddition reactions in one pot generate highly
functionalized 1-azadecalin ring systems in a highly stereocontrolled manner.
µ
−
−
Their combination of structural complexity and biological
potency make alkaloids inspiring targets for the synthetic
organic chemistry community.1 As representative examples,
each of the alkaloids in Figure 1 contains heterocyclic arrays
that have served as the basis of a number of studies.2
enecarbamates (N-carbamoyl enamines), and enesulfon-
amides (N-arylsulfonyl enamines) possess latent nucleophilic
character,3 this property has not been examined extensively,
especially within the context of transition-metal catalyzed
processes.4 The skeletal reorganization of carbon frameworks
catalyzed by the coordination of platinum(II) or other salts
to carbon-carbon π-systems has been a renewed subject of
interest among many researchers.5 We postulated that an
N-carbamoyl or N-sulfonyl enamine may possess sufficient
reactivity to capture a transient electrophilic species generated
(1) (a) Michael, J. P. Nat. Prod. Rep. 2003, 20, 458-475. (b) Michael,
J. P. Nat. Prod. Rep. 2003, 20, 476-493.
(2) Representative synthetic studies. Nakadomarin A: (a) Ono, K.;
Nakagawa, M.; Nishida, A. Angew. Chem., Int. Ed. 2004, 43, 2020-2023.
(b) Magnus, P.; Fielding, M. R.; Wells, C.; Lynch, V. Tetrahedron Lett.
2002, 43, 947-950. (c) Fu¨rstner, A.; Guth, O.; Duffels, A.; Seidel, G.;
Liebl, M.; Gabor, B.; Mynott, R. Chem: A Eur. J. 2001, 7, 4811-4820.
Tabersonine: (d) Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H. J.
Am. Chem. Soc. 2002, 124, 4628-4641. (e) Kobayashi, S.; Peng, G.;
Fukuyama, T. Tetrahedron Lett. 1999, 40, 1519-1522. (f) Kuehne, M. E.;
Bandarage, U. K.; Hammach, A.; Li, Y. L.; Wang, T. S. J. Org. Chem.
1998, 63, 2172-2183. Streptazolin: (g) Trost, B. M.; Chung, C. K.;
Pinkerton, A. B. Angew. Chem., Int. Ed. 2004, 43, 4327-4329. (h) Huang,
S. L.; Comins, D. L. Chem. Commun. 2000, 569-570. (i) Yamada, H.;
Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 1996, 118, 1054-1059. (j)
Kozikowski, A. P.; Park, P. J. Org. Chem. 1990, 55, 4668-4682. (k) Flann,
C. J.; Overman, L. E. J. Am. Chem. Soc. 1987, 109, 6115-6118.
Figure 1. Representative target alkaloids.
In the context of developing new methods for the con-
struction of complex ring systems containing a nitrogen atom
suitable for alkaloid synthesis, we considered the following
transformation (eq 1). Although enamides (N-acyl enamines),
10.1021/ol047696b CCC: $27.50
© 2004 American Chemical Society
Published on Web 12/01/2004

by metal catalysis. If feasible, this process would produce
azabicyclic systems that possess functional group arrays suit-
able for further manipulation. We have uncovered just such
a reactivity profile using either platinum(II) or silver(I) salts.
This report documents the results of our initial investigations.
proved to be more stable, but the reaction of 1d was
complicated by the formation of isomeric dienes 2d and 3d
(entry 4) in 52% combined yield. Gratifyingly, the reaction
of alkynoate 1e generated one isomeric diene, 3e, in 69%
yield. Not only did the ester functionality make the alkyne
more reactive, the reaction product 3e was substantially more
stable.
With the feasibility of this proposed process established,
alkynoate 1e was subjected to a wide variety of conditions
in order to improve this process in terms of yield, rate and
catalyst loading. Importantly, no reaction products were ob-
served in the absence of metal catalysts or using BF3‚OEt2
(1 equiv) as a Lewis acid. After a number of metal precatalyst
systems were examined, two alternative methods stood out
(eq 3).7
Our preliminary experiments were somewhat promising
(eq 2 and Table 1). Alkynes 1a-e6 were subjected to a
Table 1. Test Reactions of 1a-e with PtCl2
entry
substrate
T (°C)
time (h)
% yielda
ratio 2/3b
8
The complex [(dppb)Pt(µ-OH)]2(BF4)2 (4) proved to be
effective in the conversion of 1e to 3e. In addition, as silver
salts are used in the literature preparation of 4, we decided
to examine the capability of silver(I) salts in promoting this
reaction. Happily, in our first attempt, the cycloisomerization
of 1e using 1 mol % of silver trifluoromethanesulfonate in
CH2Cl2 efficiently produced 3e in 75% yield. The yield of
the silver(I)-catalyzed process could be improved to 99%
through minor modification of the experimental conditions
(see Figure 2).
1
2
3
4
5
1a
1b
1c
1d
1e
80
50
80
80
80
15
3
2
4.5
0.75
NR
20
58
52
69
n/a
1:0
1:0
1:1
0:1
a Isolated yields; NR ) no reaction. b Ratios established by 1H NMR
spectroscopy of the product mixture; n/a ) not applicable.
standard set of conditions (10 mol % of platinum(II) chloride)
in toluene at 80 °C for the designated time. The trimethyl-
silyl-substituted alkene 1a failed to react (entry 1), and the
terminal alkyne 1b (or its corresponding products) decom-
posed under the reaction conditions. Only a 20% yield of
2b could be recovered from its reaction mixture (entry 2).
Despite these drawbacks, we were excited to observe the
formation of 2c in 58% isolated yield when the internal
alkyne 1c was subjected to these reaction conditions. The
isolation, purification, and characterization of 2b and 2c was
difficult as these materials readily decomposed. Alkynes that
contain conjugating substituents such as in 1d and 1e were
tested in an effort to alleviate this problem. The products
With these lead results, a series of substrates were sub-
jected to these precatalyst systems (Figure 2). A number of
(5) For examples, see: (a) Chatani, N.; Furukawa, N.; Sakurai, H.; Murai,
S. Organometallics 1996, 15, 901-903. (b) Chatani, N.; Inoue, H.; Ikeda,
T.; Murai, S. J. Org. Chem. 2000, 65, 4913-4918. (c) Me´ndez, M.; Mun˜oz,
M. P.; Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc.
2001, 123, 10511-10520. (d) Fu¨rstner, A.; Stelzer, F., Szillat, H. J. Am.
Chem. Soc. 2001, 123, 11863-11869. (e) Oi, S.; Tsukamoto, I.; Miyano,
S.; Inoue, Y. Organometallics 2001, 20, 3704-3709. (f) Madine, J. W.;
Wang, X.; Widenhoefer, R. A. Org. Lett. 2001, 3, 385-388. (g) Kisanga,
P.; Goj, L. A.; Widenhoefer, R. A. J. Org. Chem. 2001, 66, 635-637. (h)
Ferna´ndez-Rivas, C.; Me´ndez, M.; Nieto-Oberhuber, C.; Echavarren, A.
M. J. Org. Chem. 2002, 62, 5197-5201. (i) Mart´ın-Matute, B.; Nevado,
C.; Ca´rdenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2003, 125, 5757-
5766. (j) Liu, C.; Han, X.; Wang, X.; Widenhoefer, R. A. J. Am. Chem.
Soc. 2004, 126, 3700-3701. (k) Cadran, N.; Cariou, K.; Herve´, G.; Aubert,
C.; Fensterbank, L.; Malacria, M.; Marco-Contelles, J. J. Am. Chem. Soc.
2004, 126, 3408-3409. (l) Mamane, V.; Gress, T.; Krause, H. Fu¨rstner, A.
J. Am. Chem. Soc. 2004, 126, 8654-8655. For reviews, see: (m) Me´ndez,
M.; Mamane, V.; Fu¨rstner, A. Chemtracts-Org. Chem. 2003, 16, 397-
425. (n) Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. Chem.sEur. J.
2003, 9, 2627-2635.
(6) The substrates used in this study are readily available in five to seven
steps from N-p-toluenesulfonyl-2-piperidone, as adapted from the method
of Shono: Shono, T.; Terauchi, J.; Ohki, Y.; Matsumura, Y. Tetrahedron
Lett. 1990, 31, 6385-6286.
(7) Other precatalysts that were investigated include HBF4, PdCl2,
Pd2(dba)3, (COD)PtCl2, (dppb)PtCl2, K2PtCl4, K2PtCl6, (phen)PtCl2, [(phen)-
Ptµ-OH]2(BF4)2, and RuCl3.
(8) (a) Li, J. J.; Li, W.; Sharp, P. R. Inorg. Chem. 1996, 35, 604-613.
(b) Gavagnin, R.; Cataldo, M.; Pinna, F.; Strukul, G. Organometallics 1998,
17, 661-667.
(3) (a) Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, S.; Yamane,
T.; Kanazawa, T.; Aoki, T. J. Am. Chem. Soc. 1982, 104, 6697-6703. (b)
Eberson, L.; Malmberg, M.; Nyberg, K. Acta Chem. Scand. 1984, 38, 391-
396. (c) Angle, S. R.; Frutos, R. P. J. Chem. Soc., Chem. Commun. 1993,
171-173. (d) de Faria, A. R.; Salvador, E. L.; Correia, C. R. D. J. Org.
Chem. 2002, 67, 3651-3661. (e) Adam, W.; Bosio, S. G.; Turro, N. J.;
Wolff, B. T. J. Org. Chem. 2004, 69, 1704-1715. (f) Cossey, K. N.; Funk,
R. L. J. Am. Chem. Soc. 2004, 126, 12216-12217.
(4) (a) Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew. Chem., Int.
Ed. 2004, 43, 1679-1681. (b) Matsubara, R.; Nakamura, Y.; Kobayashi,
S. Angew. Chem, Int. Ed. 2004, 43, 3258-3260. (c) Matsubara, R.; Vital,
P.; Nakamura, Y.; Kiyohara, H.; Kobayashi, S. Tetrahedron 2004, 60,
9769-9784. (d) For a palladium-catalyzed cycloisomerization of an alkynyl
N-acyl enamine that does not act as a latent nucleophile, see: Trost, B. M.;
Pedregal, C. J. Am. Chem. Soc. 1992, 114, 7292-7294.
5024
Org. Lett., Vol. 6, No. 26, 2004

Figure 2. Cycloisomerization experiments.
points deserve comment. Unless specifically indicated, the
reactions were quite clean and the designated time was
required to consume the starting material. Cyclizations of
1c and 1d catalyzed by AgOTf were unsuccessful, even when
heated to 120 °C (entries 1c and 2c). Electron-withdrawing
groups such as ketones, esters, amides, and nitriles were
sufficient to both activate the alkyne and stabilize the reaction
products. With ynoates or ynones, reactions catalyzed by
AgOTf typically proceed with much lower catalyst loading
and can result in substantially higher yields compared to the
reactions catalyzed by platinum(II) salts (entries 3-5).
Reactions were found to be faster, but not as clean, in
chlorinated solvents (CH2Cl2, CHCl3, ClCH2CH2Cl). A
mixture of THF and a chlorinated solvent proved to be
optimal in terms of rate and efficiency. Although dimethyl
amide 1i cyclized smoothly with PtCl2 or 4, catalysis using
AgOTf proved to be quite sluggish. Even after 69 h, the
process using AgOTf gave only a 31% yield of 3i with 44%
of 1i remaining (entry 7). The cycloisomerization of nitrile
1j using PtCl2 or AgOTf proceeded in high yield, but in those
cases produced 3j as a mixture of alkene isomers (entries
8a and 8c).
As the robust p-toluenesulfonyl protecting group can some-
times be difficult to remove, enecarbamate 5 was subjected
to cycloisomerization conditions (eq 4). These reactions
proved to be quite efficient, providing diene 6 in 80% and
91% yield using PtCl2 or AgOTf catalysis, respectively.
The products of these cycloisomerization processes are
obvious candidates for further manipulation using the Diels-
Alder reaction. Diene 3e undergoes smooth low-temperature
Org. Lett., Vol. 6, No. 26, 2004
5025

highly diastereoselective manner in 74% and 75% yields,
respectively. The structural constitution of 7 was confirmed
by single-crystal X-ray crystallography. This one-pot, two-
step process can also be carried out using silver(I) catalysis
in the cycloisomerization step [(a) 1 mol % AgOTf in
CH2Cl2, (b) R-methylacrolein; 93% of 8].
Scheme 1. Tandem Cycloisomerization-Cycloaddition
Reactions
In summary, the ability of enesulfonamides to cyclize
onto electron-deficient alkynes under the influence of plati-
num(II) or silver(I) salt precatalysts has been demonstrated.
The functionalized azahydrindan ring systems in the reaction
products are well suited for further reactions, especially
within a tandem cyclization-cycloaddition manifold. Further
studies, including detailed investigations into the mechanism
of these metal-catalyzed processes, an evaluation of the scope
of this process, and applications in total synthesis, are
currently underway in our laboratories.
Acknowledgment. We thank the University of British
Columbia, the Natural Science and Engineering Research
Council (NSERC) of Canada, the Canada Foundation for
Innovation (CFI), Merck-Frosst, and Glaxo SmithKline for
the financial support of our programs. T.J.H. thanks NSERC
for PGS A and PGS B graduate fellowships.
(-78 °C) Diels-Alder reactions with acrolein and R-meth-
ylacrolein.9 In fact, because of the relative mildness of both
the catalyzed cycloisomerization reaction and the cycload-
dition process, these reactions may be sequentially carried
out in one reaction vessel (Scheme 1).10 As examples, the
consecutive reactions of 1e with 4 at 40 °C, followed by
cooling of the reaction mixture to -78 °C, and addition of
the dienophile (acrolein or R-methylacrolein) with catalytic
amounts of BF3‚Et2O produce cycloadducts 7 and 8 in a
Supporting Information Available: Experimental pro-
cedures and characterization data for previously unreported
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) These experiments are presented in the Supporting Information.
(10) For some reviews of “tandem” or “domino” reactions, see: (a)
Neushutz, K.; Velker, J.; Neier, R. Synthesis 1998, 227-255. (b) Tietze,
L. F. Chem. ReV. 1996, 96, 115-136.
OL047696B
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Org. Lett., Vol. 6, No. 26, 2004