A regio- and diastereoselective platinum-catalyzed tandem [2+1]/[3+2] cycloaddition sequence

Article abstract of DOI:10.1002/anie.201007992

Platinum complexes bearing phosphinous acids have efficiently promoted a tandem intermolecular sequence of [2+1]/[3+2] cycloaddition reactions. This process gave access to novel tricyclic systems and the cascade reactions were regio- and diastereoselective (see scheme; Cy=cyclohexyl). The [3+2] cycloaddition reaction was investigated further and two different alkyne partners were used. Copyright

Full text of DOI:10.1002/anie.201007992

Communications
DOI: 10.1002/anie.201007992
Tandem Reactions
A Regio- and Diastereoselective Platinum-Catalyzed Tandem
2+1]/[3+2] Cycloaddition Sequence**
[
Thierry Achard, Aymeric Lepronier, Yves Gimbert, Hervꢀ Clavier,* Laurent Giordano,*
Alphonse Tenaglia,* and Gꢀrard Buono*
In the context of sustainable chemistry, tandem reactions, so-
called domino or cascade processes, have emerged as power-
ful strategies to assemble nontrivial carbon skeletons, in
reported a platinum-mediated [2+1] cycloaddition between
phenylethyne 1a and norbornene derivatives (Scheme 2).
During the examination of the reaction scope, we observed
that reactions carried out with alkyne 1b in place of 1a led to
the formation of an unexpected tricyclic product 4b.
[9]
[1]
particular for the synthesis of natural products. Interestingly,
the implementation of this strategy implies general CÀC bond
formation and atom economy. Tandem processes involving
[
2]
one cycloaddition step are quite common, however, those
engaging two of more cycloaddition reactions are rare,
[
3,4]
especially when transition metals are involved.
Over the last few years, our research group has been
involved in the synthesis of secondary phosphine oxides
(
SPO) and their applications in coordination chemistry as a
III
[5,6]
preligand in the P form, namely phosphinous acids (PA).
Thus, various complexes of palladium or platinum, such as
those depicted in Scheme 1, have been synthesized and used
in several catalytic reactions. Phosphinous acid ligands were
found to confer a particular activity to the metal and new
catalytic transformations were developed. As an example, we
[
7]
[
8]
Scheme 2. Chemoselectivity difference in platinum-mediated cycloaddi-
tion as a function of the alkyne. Bn=benzyl.
This result prompted us to further examine this reaction to
gain insight into its scope and the mechanism. Herein, we
report an unprecedented intermolecular tandem [2+1]/[3+2]
cycloaddition sequence of norbornadiene with alkynes.
We started with a survey of various reaction parameters
using norbornadiene and propargyl acetate 1c as benchmark
substrates (Table 1). We determined that well-defined plati-
num-based catalyst Cat-1, in the presence of acetic acid in
toluene at 558C after 20 hours, efficiently promoted forma-
tion of the desired tricyclic compound 4c (62% yield; Table 1,
entry 1) along with 10% of methylenecyclopropane (MCP)
Scheme 1. Phosphinous acid–platinum complexes used in this study.
Cy =cyclohexyl.
[*] Dr. T. Achard, A. Lepronier, Dr. H. Clavier, Dr. L. Giordano,
Dr. A. Tenaglia, Prof. Dr. G. Buono
Equipe Chirosciences—UMR CNRS 6263—ISM2
Universitꢀ Aix-Marseille III—Ecole Centrale de Marseille
Av. Escadrille Normandie Niemen
2
c. Increasing the reaction time to 72 hours allowed improve-
ment in the yield of 4c and disappearance of 2c (Table 1,
entry 2). This result suggests that 2c is an intermediate for the
formation of 4c. Changing the substituents on the SPO
preligands or using the catalyst that was generated in situ led
to dramatically lower yields of 4c (Table 1, entries 3–5).
Carrying out experiments at 408C slowed down the reaction,
whereas at 808C some degradation occurred (Table 1,
entries 6 and 7). Neither tetrahydrofuran (THF) nor 1,2-
dichloroethane (DCE) solvents were as effective as toluene
1
3397 Marseille Cedex 20 (France)
Fax: (+33)4-9128-2742
E-mail: herve.clavier@univ-cezanne.fr
laurent.giordano@ec-marseille.fr
alphonse.tenaglia@univ-cezanne.fr
gerard.buono@ec-marseille.fr
Homepage: http://cab.ism2.univ-cezanne.fr
Dr. Y. Gimbert
Dꢀpartement de Chimie Molꢀculaire—UMR CNRS 5250—ICMG
FR-2607, Universitꢀ Joseph Fourier de Grenoble
BP 53, 38041 Grenoble Cedex 9 (France)
(Table 1, entries 8 and 9). Furthermore, it was observed that
acetic acid was a key component of the reaction (Table 1,
entry 10). Notably, during the optimization step 4c was
isolated as a single regio- and stereoisomer. This outcome
was confirmed by 2D NMR spectroscopy experiments.
Next, the scope of this catalytic transformation was
examined with respect to the alkyne partner (Table 2).
[
**] We are grateful to the CNRS and the ANR (program BLAN07-
1_190839) for funding. A.L. acknowledges the Ministꢁre de la
Recherche et de la Technologie for a PhD grant. We thank Dr. Michel
Giorgi for his kind assistance with X-ray crystallographic analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007992.
3
552
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 3552 –3556

Table 1: Optimization of reaction parameters for the platinum-mediated
tandem [2+1]/[3+2] cycloaddition sequence.
was isolated (Table 2, entries 3 and 7–10). Single-crystal X-ray
analysis of 4i unambiguous confirmed its structure as a single
regio- and stereoisomer with a trans configuration within the
[
a]
[
11]
fused five-membered ring (Figure 1). Alkyne 1k bearing a
[
b]
Entry Change from the “standard reaction conditions”
Yield [%]
2
c
4c
1
2
3
4
5
6
7
8
9
1
none
10
–
4
8
–
8
–
7
11
5
62
71
6
10
30
49
55
4
72 h instead of 20 h
Cat-2 instead of Cat-1
Cat-3 instead of Cat-1
[
c]
Cat-4, AgOAc, Et N instead of Cat-1
3
408C instead of 558C
808C instead of 558C
THF instead of toluene
DCE instead of toluene
no AcOH
35
20
0
Figure 1. Ball-and-stick representation of tricyclic product 4i.
[
a] Reaction conditions: norbornadiene (0.5 mmol), 1c (1 mmol), cata-
lyst (5 mol%), AcOH (1 mmol), toluene (10 mL, 0.05m), 558C, 20 h.
b] Yield of isolated product. [c] AgOAc (10 mol%), Et N (10 mol%).
[
3
carbonate group was also effective for the tandem cyclo-
addition reactions (Table 2, entry 11). In the case of trime-
thylsilyl ether 1l, the yield of the reaction dropped dramat-
ically down to 21%, owing to some degradation that occurred
during the purification step (Table 2, entry 12). Propargylic
thioether 1m was moderately tolerated and gave adduct 2m
Table 2: Investigation of the scope for the tandem [2+1]/[3+2] cycload-
dition sequence.
[
a]
(26%) and a trace amount of 4m (Table 2, entry 13). Overall,
the oxygen atom in homopropargylic position appears to be
crucial in the tandem cycloaddition process. Importantly, all
cycloadducts 4 were isolated as single regio- and diastereo-
mers.
[
b]
Entry
Alkyne
R
Yield [%]
2
4
Because MCP 2 was supposed to be the intermediate for
1
2
3
4
5
6
7
8
9
1a
1d
1b
1c
1e
1 f
1g
1h
1i
Ph
nBu
CH OBn
CH OAc
CH OBz
CH OPiv
CH O(2-MeC H )
CH O(4-OMeC H )
CH O(3-NO C H )
CH O(2,4-(NO ) C H )
CH OCO Bn
CH OTMS
2a, 17
2d, 46
–
2c, 10
–
–
–
–
–
–
–
–
–
[
12]
the [3+2] cycloaddition, treatment of MCP 2c with prop-
argyl acetate 1c in the presence of Cat-1 under the usual
reaction conditions led to tricycle 4c as a single stereoisomer
with a moderate yield (Scheme 3). Notably, the remaining
mass balance accounted for the starting material MCP 2c.
4b, 65
4c, 62
4e, 44
4 f, 44
4g, 74
4h, 43
4I, 50
4j, 90
4k, 52
4l, 21
traces
2
2
2
2
2
6
4
2
6
4
2
2
6
4
10
11
12
13
1j
1k
1l
2
2
2
6
4
2
2
–
2
1m
CH S(2-MeC H )
2m, 26
2
6
4
[
(
[
a] Reaction conditions: norbornadiene (0.5 mmol), 1 (1 mmol), Cat-1
5 mol%), AcOH (1 mmol), toluene (10 mL, 0.05m), 558C, 20 h.
b] Yield of isolated product. Bz=benzoyl, Piv=pivaloyl, TMS=tri-
Scheme 3. Synthesis of tricyclic product 4c with MCP 2c as the
intermediate.
methylsilyl.
[12]
Having established that MCP 2c was the intermediate
involved in the [3+2] cycloaddition, other alkyne partners for
this transformation were examined (Scheme 4). First, 1-
hexyne 1d was chosen because it did not contain any
oxygen atoms. Pleasingly, we isolated the desired product
5d in good yield. On the other hand, an unexpected by-
product identified as 6d was isolated in a significant 25%
Aryl- or alkyl-substituted alkynes such as phenylethyne 1a or
1
2
-hexyne 1d, led only to [2+1] adducts (Table 2, entries 1 and
). Also, dicyclopropanation adducts 3 were isolated in 52%
yield for 3a (Table 2, entry 1) and a small amount for 3d
[
10]
(
Table 2, entry 2). On the other hand, with ester-containing
[13]
alkynes 1c, 1e, and 1 f the tandem [2+1]/[3+2] cycloaddition
sequence took place almost exclusively to provide of tricyclic
compounds 4 in fair to good yields (Table 2, entries 4–6).
Propargylic ethers 1b and 1g–1j, were found to be equally
good candidates for the tandem process and up to 90% of 4
yield. This unusual reactivity of alkylidenecyclopropane
may be related to the palladium-mediated tandem
[2+1] cycloaddition/ring expansion reported with tertiary
[
8b]
propargylic acetates.
When we evaluated benzylidenecy-
clopropane 2a for [3+2] cycloaddition with propargyl acetate,
Angew. Chem. Int. Ed. 2011, 50, 3552 –3556
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3553

Communications
Notably, for all compounds 5 a single stereo- and
regioisomer was observed by NMR analysis of the crude
reaction mixtures. X-ray crystallographic analysis of sulfone-
containing adduct 5r confirmed both atoms connectivity and
[11]
configuration (Figure 2).
Scheme 4. Cross-over experiments using MCPs as intermediates.
the MCP moiety was left unchanged. However, the tandem
2+1]/[3+2] cycloaddition process took place on the norbor-
[
nene CÀC double bond to form 7 as a 1:1 mixture of
diastereomers (Scheme 4). This finding clearly shows that an
allylic oxygen substituent plays
3+2] cycloaddition.
Examples of [3+2] cycloaddition reactions that illustrate
a major role in the
[
Figure 2. Ball-and-stick representation of tricyclic product 5r.
the scope of this new platinum-mediated method are pro-
vided in Table 3. Among the various alkynes tested, only
Although the mechanism of this unusual [3+2] cyclo-
addition remains unclear at that time, we believe the cationic
platinum species A coordinates to the exocyclic CÀC double
[
a]
Table 3: Examination of the scope for the [3+2] cycloaddition reaction.
bond on the exo face of MCP 2, thus triggering an oxidative
coupling with the alkyne to form the platinacyclopentene
[
b]
Entry
Alkyne
R
Yield [%]
5
6
1
2
3
4
5
6
7
8
9
1a
1d
1n
1l
1o
1g
1p
1q
1r
Ph
nBu
TMS
CH OTMS
CH OH
CH O(2-MeC H )
CH NHTs
CH Pht
CH SO Ph
a complex mixture
5d, 70
6d, 25
<5
<5
[
c]
5n, 61
[
c]
5l, 67
2
5o, 39
5g, 65
5p, 38
5q, 61
5r, 63
6o, 7
<5
6p, 10
6q, 12
6r, 26
2
2
6
4
2
2
2
2
[a] Reaction conditions: methylenecyclopropane 2c (0.5 mmol), 1
(
5
1 mmol), Cat-1 (5 mol%), AcOH (1 mmol), toluene (10 mL, 0.05m),
58C, 20 h. [b] Yield of isolated product. [c] Conversion determined by
1
H NMR spectroscopy. Pht=phthalimide, Ts=4-toluenesulfonyl.
phenylethyne 1a led to a complex mixture of products
Scheme 5. Postulated mechanism for [3+2] cycloaddition.
(
Table 3, entry 1). Trimethylsilylethyne 1n and trimethyl silyl
ether 1l were well tolerated, nevertheless some degradation
of adducts 5l and 5n occurred upon purification on silica gel
[
14]
(
Table 3, entries 3 and 4). Therefore, unprotected propargyl
intermediate C (Scheme 5). Importantly, the regioselectiv-
ity accommodates steric interactions between substituents. At
this stage, the oxygen atom could have a directing influence
by assisting the cyclopropane fragmentation and therefore the
1,2 shift of the platinum moiety (intermediate D, only one
enantiomer depicted), therefore giving rising to the platina-
cyclohexene E. Finally, a reductive elimination gives product
5 and regenerates active species A. This proposed mechanism
alcohol 1o was quite compatible and provided 5o in moderate
yield along with a small amount of by-product 6o (Table 3,
entry 5). Propargyl aryl ether 1g gave 5g in good yield
(
Table 3, entry 6). In spite of substantial amounts of by-
products 6, the platinum-based catalytic system was found to
be tolerant of other heteroatom groups such as sulfonamide,
phtalamide, or sulfone (Table 3, entries 7–9).
3
554
www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 3552 –3556

takes into account the structural features of the cycloadducts
and stereochemical considerations.
The formation of by-products 6 occurred only with allylic
acetate 2c. We assume the formation of the platinum p-allyl
Keywords: cycloaddition · methylenecyclopropanes · platinum ·
secondary phosphine oxides · tandem reactions
.
species
F through the release of the acetoxy group
(
Scheme 6). At this point, cyclopropane ring opening gen-
[
1] a) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem.
2006, 118, 7292 – 7344; Angew. Chem. Int. Ed. 2006, 45, 7134 –
7186; b) S. Arns, L. Barriault, Chem. Commun. 2007, 2211 –
2221; c) B. B. Tourꢀ, D. G. Hall, Chem. Rev. 2009, 109, 4439 –
4486; d) K. C. Nicolaou, J. S. Chen, Chem. Soc. Rev. 2009, 38,
2993 – 3009; e) Domino Reactions in Organic Synthesis (Eds:
L. F. Tietze, G. Brasche, K. M. Gericke), Wiley-VCH, Wein-
heim, 2006.
[
2] a) L. F. Tietze, Chem. Rev. 1996, 96, 115 – 136; b) J.-C. Wasilke,
S. J. Obrey, R. T. Baker, G. C. Bazan, Chem. Rev. 2005, 105,
1
1
001 – 1020; c) D. J. Ramꢁn, M. Yus, Angew. Chem. 2005, 117,
628 – 1661; Angew. Chem. Int. Ed. 2005, 44, 1602 – 1634; d) V.
Dragutan, I. Dragutan, J. Organomet. Chem. 2006, 691, 5129 –
147; e) C. J. Chapman, C. G. Frost, Synthesis 2007, 1 – 21; f) D.
5
Tejedor, F. Garcꢂa-Tellado, Chem. Soc. Rev. 2007, 36, 484 – 491.
3] For a review, see S. E. Denmark, A. Thorarensen, Chem. Rev.
[
[
1996, 96, 137 – 166.
4] For selected examples, see: a) G. J. Kuster, F. Kalmoua, R.
de Gelder, H. W. Scheeren, Chem. Commun. 1999, 855 – 856;
b) L. W. A. van Berkom, G. J. T. Kuster, F. Kalmoua, R.
de Gelder, H. W. Scheeren, Tetrahedron Lett. 2003, 44, 5091 –
5093; c) J. B. Feltenberger, R. Hayashi, Y. Tang, E. S. C. Babiash,
R. P. Hsung, Org. Lett. 2009, 11, 3666 – 3669; d) Y. Sasaki, D.
Kato, D. L. Boger, J. Am. Chem. Soc. 2010, 132, 13533 – 13544.
5] For reviews on secondary phosphine oxides, see: a) N. V.
Dubrovina, A. Bꢃrner, Angew. Chem. 2004, 116, 6007 – 6010;
Angew. Chem. Int. Ed. 2004, 43, 5883 – 5886; b) L. Ackermann,
Synthesis 2006, 1557 – 1571; c) L. Ackermann, R. Born, J. H.
Spatz, A. Althammer, C. J. Gschrei, Pure Appl. Chem. 2006, 78,
209 – 214; d) L. Ackermann, Synlett 2007, 507 – 526; e) L.
Ackermann in Phosphorus Ligands in Asymmetric Catalysis,
Vol. 2 (Ed: A. Bꢃrner), Wiley-VCH, Weinheim, 2008, pp. 831 –
Scheme 6. Proposed mechanism for the formation of by-products 6.
[
erates the symmetrical vinyl p-allylplatinum species G, with
the platinum center located on the exo face to minimize steric
[
15]
hindrance. A ligand exchange with the alkyne unit releases
acetic acid and forms the dialkylplatinum species H. Finally, a
reductive elimination releases by-product 6 and restores
active species A.
847.
[
6] a) A. Leyris, D. Nuel, L. Giordano, M. Achard, G. Buono,
Tetrahedron Lett. 2005, 46, 8677 – 8680; b) A. Leyris, J. Bigeault,
D. Nuel, L. Giordano, G. Buono, Tetrahedron Lett. 2007, 48,
In summary, we have shown that secondary phosphine-
oxide-based platinum complexes can catalyze an unprece-
dented intermolecular [2+1]/[3+2] cycloaddition sequence of
norbornadiene with several alkynes. The tandem [2+1]/[3+2]
process was found to be limited to alkynes bearing an oxygen
substituent on the propargylic carbon atom, however in view
of the pervasiveness of oxygen-containing functional groups
in organic molecules, the reaction scope spanned various
functionalities. We have also demonstrated that methylene-
cyclopropanes 2 are the intermediates for the [3+2] cyclo-
addition and we explored this transformation with various
alkynes. To the best of our knowledge, most of the cyclo-
addition reactions involving MCPs and alkynes have been
5247 – 5250; c) D. Moraleda, D. Gatineau, D. Martin, L. Gior-
dano, G. Buono, Chem. Commun. 2008, 3031 – 3033.
[7] T. Achard, L. Giordano, A. Tenaglia, Y. Gimbert, G. Buono,
Organometallics 2010, 29, 3936 – 3950.
[
8] a) J. Bigeault, L. Giordano, G. Buono, Angew. Chem. 2005, 117,
831 – 4835; Angew. Chem. Int. Ed. 2005, 44, 4753 – 4757; b) J.
Bigeault, I. de Riggi, Y. Gimbert, L. Giordano, G. Buono, Synlett
008, 1071 – 1075; c) R. Thota, D. Lesage, Y. Gimbert, L.
4
2
Giordano, S. Humbel, A. Millet, G. Buono, J.-C. Tabet, Organo-
metallics 2009, 28, 2735 – 2743; d) D. Gatineau, D. Moraleda, J.-
V. Naubron, T. Bꢄrgi, L. Giordano, G. Buono, Tetrahedron:
Asymmetry 2009, 20, 1912 – 1917.
[16]
[9] J. Bigeault, L. Giordano, I. de Riggi, Y. Gimbert, G. Buono, Org.
Lett. 2007, 9, 3567 – 3570.
reported for intramolecular processes. The present work
describes a rare example of such cycloadditions in a inter-
molecular fashion. The regio- and stereoselective outcomes
suggest a specific mechanism and imply to us that a promising
enantioselective variant could be achieved using chiral SPO
preligands.
[
[
10] Dicyclopropanation adduct 3d was
1
only detected by H NMR analysis of
the crude reaction mixture, but could
not be isolated.
11] CCDC 803469 (4i), 803470 (5r), and
659994 (5) contain the supplemen-
tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received: December 17, 2010
[12] MCP 2c was synthesized by palladium-mediated [2+1] cyclo-
Published online: March 10, 2011
addition, see reference [8a].
Angew. Chem. Int. Ed. 2011, 50, 3552 –3556
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3555

Communications
[
13] For reviews on alkylidenecyclopropane reactivity, see: a) M.
Rubin, M. Rubina, V. Gevorgyan, Chem. Rev. 2007, 107, 3117 –
179; b) H. Pellissier, Tetrahedron 2010, 66, 8341 – 8375.
[16] For selected examples with Pd, see: a) A. Delgado, R. Rodrꢂ-
guez, L. Castedo, J. L. Mascareꢅas, J. Am. Chem. Soc. 2003, 125,
9282 – 9283; b) J. Durꢇn, M. Gulꢂas, L. Castedo, J. L. Mascareꢅas,
Org. Lett. 2005, 7, 5693 – 5696; c) G. Bhargava, B. Trillo, M.
Araya, F. Lꢁpez, L. Castedo, J. L. Mascareꢅas, Chem. Commun.
2010, 46, 270 – 272; with Ru, see: d) F. Lꢁpez, A. Delgado, R.
Rodrꢂguez, L. Castedo, J. L. Mascareꢅas, J. Am. Chem. Soc.
2004, 126, 10262 – 10263; with Ni, see: e) S. Saito, M. Masuda, S.
Komagawa, J. Am. Chem. Soc. 2004, 126, 10540 – 10541; f) S.
Komagawa, S. Saito, Angew. Chem. 2006, 118, 2506 – 2509;
Angew. Chem. Int. Ed. 2006, 45, 2446 – 2449; g) S. Saito, K.
Maeda, R. Yamasaki, T. Kitamura, M. Nakagawa, K. Kato, I.
Azumaya, H. Masu, Angew. Chem. 2010, 122, 1874 – 1877;
Angew. Chem. Int. Ed. 2010, 49, 1830 – 1833; with Co, see:
h) M. Schelper, O. Buisine, S. Kozhushkov, C. Aubert, A.
de Meijere, M. Malacria, Eur. J. Org. Chem. 2005, 3000 – 3007.
3
[
14] For references suggesting platinacyclopentene intermediates,
see: a) M. Mꢀndez, M. P. Muꢅoz, C. Nevado, D. J. Caꢆrdenas,
A. M. Echavarren, J. Am. Chem. Soc. 2001, 123, 10511 – 10520;
b) N. Cadran, K. Cariou, G. Hervꢀ, C. Aubert, L. Fensterbank,
M. Malacria, J. Marco-Contelles, J. Am. Chem. Soc. 2004, 126,
3408 – 3409; c) E. Soriano, J. Marco-Contelles, Chem. Eur. J.
2005, 11, 521 – 533; for other selected metallacyclopentene
intermediates, see: d) B. M. Trost, A. B. Pinkerton, F. D. Toste,
M. Sperrle, J. Am. Chem. Soc. 2001, 123, 12504 – 12509; e) M.
Jeganmohan, C.-H. Cheng, Chem. Eur. J. 2008, 14, 10876 – 10886.
15] The high exo selectivity seen with bicyclo[2.2.1]heptene sub-
strates has been well-established: R. D. Mazzola, Jr., T. D.
White, H. R. Vollmer-Snarr, F. G. West, Org. Lett. 2005, 7,
[
2799 – 2801, and references therein.
3
556
www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 3552 –3556