Platinum dichloride-catalyzed cycloisomerization of ene-ynamides

Article abstract of DOI:10.1021/ol049530g

Various ene-tosylynamides react with platinum(II) chloride and lead to bicyclic nitrogenated heterocycles. This unprecedented and easily operated process can be coupled with a hydrolysis of the intermediate cyclic tosylenamides in a one-pot transformation

Full text of DOI:10.1021/ol049530g

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1509-1511
Platinum Dichloride-Catalyzed
Cycloisomerization of Ene-ynamides
Fre´de´ric Marion, Julien Coulomb, Christine Courillon, Louis Fensterbank,* and
Max Malacria*
Laboratoire de Chimie Organique, Associe´ au CNRS, UniVersite´ Pierre et Marie
Curie, B. 229, 4 Place Jussieu, 75252 Paris Cedex 05, France
fensterb@ccr.jussieu.fr; malacria@ccr.jussieu.fr
Received March 12, 2004
ABSTRACT
Various ene-tosylynamides react with platinum(II) chloride and lead to bicyclic nitrogenated heterocycles. This unprecedented and easily
operated process can be coupled with a hydrolysis of the intermediate cyclic tosylenamides in a one-pot transformation, which provides
cyclobutanones.
The transition metal-catalyzed cycloisomerization of enyne
systems is a powerful synthetic tool that has witnessed
intense development.1 Nevertheless, there is still room for
the implementation of new partners in this process. Among
all potential candidates, ene-tosylynamides are highly ap-
pealing substrates that, to the best of our knowledge, have
never been examined in this context.2,3 Because of the
presence of the nitrogen atom directly attached to the triple
bond, one can anticipate charge-controlled processes.3 This
led us to the use of platinum(II) dichloride as a catalyst, since
this versatile reagent is known to promote charge buildup
on enyne systems.4,5 In addition, the resulting products should
incorporate valuable nitrogen heterocycles.
We have already demonstrated the synthetic potential of
such an approach in the radical cascade field.6 Herein, we
describe our preliminary results of a versatile organometallic
process that transforms different ene-tosylynamides, in the
presence of PtCl2, into bicyclic nitrogenated heterocycles.
Different methods have been reviewed in the literature
describing the preparation of tosylynamides.7 Direct
alkylation of tosylamines with alkynyliodonium salts in the
presence of a base has been notably reported by Witulski.8
In our hands, the alkynyliodonium salts trick has always been
efficient.6 We have also followed Bru¨ckner’s alternative
transformation of formamides.9 This procedure allowed us
to obtain various ene-tosylynamides that are utilized in this
work as precursors of original PtCl2-catalyzed cycloisomer-
izations.
(1) For a review: Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002,
102, 813.
Our first attempt consisted of exposing ene-ynamide 1 to
PtCl2 (5 mol %) in toluene at 80 °C and led to the metathesis
(2) For previous works in RCM, see: (a) Saito, N.; Sato, Y.; Mori, M.
Org. Lett. 2002, 4, 803. (b) Huang, J.; Xiong, H.; Hsung, R. P.;
Rameshkumar, C.; Mulder, J. A.; Grebe, T. P. Org. Lett. 2002, 4, 2417.
(3) For a review on transition metal-mediated cycloadditions of ynamides,
see: Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei,
L.-L. Tetrahedron 2001, 57, 7575. See also: Witulski, B.; Alayrac, C.
Angew. Chem., Int. Ed. 2002, 41, 3281.
(4) (a) Chatani, N.; Kataoka, K.; Murai, S.; Furukawa, N.; Seki, Y. J.
Am. Chem. Soc. 1998, 120, 9104. (b) Me´ndez, M.; Mun˜oz, M. P.; Nevado,
C.; Ca´rdenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2001, 123, 10511.
(c) Fu¨rstner, A.; Szillat, H.; Gabor, B., Mynott, R. J. Am. Chem. Soc. 1998,
120, 8305. (d) Fu¨rstner, A.; Stelzer, F.; Szillat, H. J. Am. Chem. Soc. 2001,
123, 11863. (e) Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. Chem.
Eur. J. 2003, 9, 2677. (f) For reviews, see: Me´ndez, M.; Mamane, V.;
Fu¨rstner, A. Chemtracts 2003, 16(7), 397. (g) Lloyd-Jones, G. C. Org.
Biomol. Chem. 2003, 1, 215.
(5) Mainetti, E.; Mourie`s, V.; Fensterbank, L.; Malacria, M.; Marco-
Contelles, J. Angew. Chem., Int. Ed. 2002, 41, 2132. For the reactivity of
allenyne systems, see: Cadran, N.; Cariou, K.; Herve´, G.; Aubert, C.;
Fensterbank, L.; Malacria, M.; Marco-Contelles, J. J. Am. Chem. Soc. 2004,
126, 3408.
(6) ) Marion, F.; Courillon, C.; Malacria, M. Org. Lett. 2003, 5, 5095.
(7) (a) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.;
Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc.
2003, 125, 236. (b)Wie, L.-L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.;
Douglas, C. J.; Hsung, R. P. Tetrahedron 2001, 57, 459.
(8) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed. 1998, 37, 489.
(9) Bru¨ckner, D. Synlett 2000, 1402.
10.1021/ol049530g CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/31/2004

product 2 in 98% yield, whose structure was secured by
comparison to Mori’s data (Scheme 1). Mori has indeed
more stable compounds through a second reaction in a one-
pot process.
First, we performed ozonolysis, which provided easily
isolable keto-lactams 8-10, which could be useful building
blocks in total synthesis of more complex alkaloid natural
products.12 Nevertheless, the moderate yields (Table 1), yet
Scheme 1. Transformation of Ene-tosylynamides with PtCl2
Table 1. Ozonolysis
investigated the ring-closing metathesis transformation of 1
and found out that this reaction was accelerated in the
presence of the second-generation Grubb’s catalyst.2 More-
over, she performed efficient ring-closing metathesis with
several precursors bearing a different carbon tether between
the amide function and the carbon-carbon double bond like
precursors 3 and 5. We show here a completely distinct and
original reactivity of these substrates in the presence of
platinum dichloride. Thus, in the case of ene-tosylynamide
3, cyclization occurred and yielded the bicyclic[4.2.0]
compound 4.10 This fragile structure, partially degrading
during the purification process, was obtained in 44% yield,
which we had some difficulty in reproducing since these
reactions proved to be sensitive to moisture. The bicyclic
derivative 6 was similarly obtained by reacting the â-di-
methyl-substituted ene-ynamide 5 with 5-10 mol % equiv
of PtCl2 in 71% yield. The structural assignment for 4 and
6 was based on the following data: 1H NMR spectra show
no stereogenic center and 13C NMR spectra display no CH
signal, indicating that the double bond is shared by the two
cycles. Quaternary carbon signals around 122 and 135 ppm
confirm the structure of the bicyclic product. These platinum-
(II)-catalyzed cyclizations could not easily be monitored by
TLC because of the close Rf values for the product and the
starting material that, in addition, appear as faint spots.
Therefore, we followed the consumption of the ene-ynamide
by IR spectroscopy and checked the vanishing of the triple-
bond band.
consistent with the literature,13 drove us to switch to a
hydrolysis reaction as the second step. Thus, after cyclo-
isomerization reaction in the presence of 10 mol % PtCl2,
addition of a 1 M HCl solution to the crude cycloisomerized
product gave cyclobutanones formed by hydrolysis of the
intermediate enamines. The results of this cyclization-
hydrolysis sequence are summarized in Table 2.
Table 2. Cyclization-Hydrolysis-Sequence
Because of the general lability of the final products,11 we
decided to transform the crude bicyclic products directly into
(10) Isolation of cyclobutenes from metal-catalyzed [2 + 2] of enynes
has been described, see: (a) Pd(II): Trost, B. M.; Yanai, M.; Hoogsten, K.
J. Am. Chem. Soc. 1993, 115, 5294. (b) Trost, B. M.; Tanoury, G. J. J. Am.
Chem. Soc. 1988, 110, 1636. In the latter case, the double bond is shifted
to give a more stable cyclobutene product. (c) Pt(II): see ref 4d. (d) Pt-
(IV): Blum, J.; Beer-Kraft, H.; Badrieh, Y. J. Org. Chem. 1985, 60, 5567.
In this particular case, the cyclobutene adduct reacts with O2. (e) Ga(III):
Chatani, N.; Inoue, H.; Kotsuma, T.; Murai, S. J. Am. Chem. Soc. 2002,
124, 10294.
The four-atom-tethered substrates 3 and 5 are transformed
in good yields into the corresponding cyclobutanones 11 and
(12) Martin, S. F.; Chen, H.-J.; Courtney, A. K.; Liao, Y.; Pa¨tzel, M.;
Ramser, M. N.; Wagman, A. S. Tetrahedron 1996, 52, 7251.
(13) (a) Strobel, M. P.; Morin, L.; Paquer, D. New. J. Chem. 1980, 4,
603. (b) Mahajan, J. R.; Ferreira, A. L.; Arau´jo, H. C.; Nunes, B. J. Synthesis
1976, 112.
(11) For a related report of instability, see: Smith, A. B., III; Cui, H.
Org. Lett. 2003, 5, 587. See also ref 10d.
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Org. Lett., Vol. 6, No. 9, 2004

12. Alkyl substitution is tolerated both on the alkyne partner
(precursor 13) and on the alkene partner (precursors 15 and
17). In the case of 17, the nonopened bicyclic aminal 18
was obtained in 76% yield. As anticipated, introduction of
a gem-dimethyl group in the tether resulted in improved
yields (substrates 3 and 15 vs 5 and 17).14
When the tether was lengthened to up to five atoms,
corresponding to intermediate 7, the 4-bicyclic adduct still
gave a satisfactory yield of cyclobutanone 19. In this case,
some aminal could also be observed in the crude product
but was not isolated after separation on silica gel.
The original results summarized in Scheme 1 and in both
Tables 1 and 2 are consistent with the formation of bicyclic
intermediates C and D, with the double bond either exo or
endo at the ring junction. Following Fu¨rstner’s cationic
manifold proposal,4c,d,f initial π-complexation of the alkyne
partner would generate the nonclassical “homoallyl-cyclo-
propylmethyl-cyclobutyl” cation, best represented under the
canonical form B.15
C:D ratio would be controlled by the ring strain associated
with the bicyclic edifice. For n ) 1, the double bond remains
exo and cyclobutene D undergoes an electrocyclic ring
opening leading to the metathesis adduct 2. For n ) 2 or 3,
an intermediate of type C would be favored as demonstrated
by the isolation of 4 and 6. However, in the case of precursors
15 and 17, intermediate C is not attainable. Instead, an
intermediate of type D16 could also lead to the hydrolysis
products 14 and 16.
In conclusion, we herein report the first use of ene-
ynamides as versatile partners for PtCl2-catalyzed cyclo-
isomerization reactions. A formal [2 + 2] cycloaddition gives
birth to versatile cyclobutenyl bicyclic substrates that we
could ozonolyze to provide medium-sized nitrogen hetero-
cycles and hydrolyze to give various cyclobutanone deriva-
tives. In the latter case, the reaction corresponds to an
intramolecular addition of a ketene on the alkene partner via
a nitrogen tether. These preliminary elements of reactivity
confirm the high synthetic potential of the introduction of
ene-ynamides in organometallic chemistry and pave the way
for important applications we will disclose in due course.
Scheme 2. PtCl2-Catalyzed Cyclization Mechanism
Acknowledgment. The authors thank Pierre Fabre Labo-
ratories for F.M.’s Ph.D. grant. M.M. is a member of the
Institut Universitaire de France, and the authors thank IUF
for generous financial support of this work.
Supporting Information Available: Experimental pro-
cedures and description of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL049530G
(14) Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224.
(15) Intermediacy of cyclopropylcarbene species is also conceivable; see
ref 4e and references therein.
(16) Analysis of the crude cycloisomerization product from precursor
15 is consistent with the formation of an exo-cyclobutene intermediate.
Metal elimination from B then would produce D, which
could isomerize to form C by proton-catalyzed process. The
Org. Lett., Vol. 6, No. 9, 2004
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