Palladium-mediated phosphine-dependent chemoselective bisallylic alkylation leading to spirocarbocycles

Article abstract of DOI:10.1002/anie.201204629

Cycles everywhere: The selectivity in the transformations of 1,3-diones to carbocycles by palladium-catalyzed bisallylic alkylations is strongly dependent on the phosphine that is employed (see scheme). Moreover, synthesized vinylcyclopentenes can be easily transformed into cycloheptadiene derivatives through a carboncarbon allylic bond cleavage.

Full text of DOI:10.1002/anie.201204629

Angewandte
Chemie
DOI: 10.1002/anie.201204629
Spiro Compounds
Palladium-Mediated Phosphine-Dependent Chemoselective Bisallylic
Alkylation Leading to Spirocarbocycles**
Hervꢀ Clavier,* Laurent Giordano,* and Alphonse Tenaglia*
À
Allylic substitution is a versatile transformation in organic
synthesis, as highlighted by numerous works, and one of the
furan derivative 5 obtained through sequential C C, then
À
À
C C or C O bond formations (Scheme 1).
À
most powerful tools for the formation of carbon carbon and
We started our investigation by the examination of the
reaction conditions using the benchmark substrates dimedone
1a and dicarbonate 4 (Table 1). We were able to isolate
carbon heteroatom bonds.[1] Transition-metal-promoted
À
allylic substitutions were found to be particularly useful,
because they allow the installation of stereogenic centers in
an enantioselective fashion.[2] The palladium-catalyzed ally-
lation of soft nucleophiles, the so-called Tsuji–Trost reaction,
has been extensively investigated. Surprisingly, despite the
widespread use of this reaction, double allylic substitution
sequences have been little explored and limited exclusively to
bifunctional allylic diacetates and dicarbonates. Either
linear[3] or cyclic products[4] were isolated, depending on the
nucleophile that was employed. Hence, this methodology was
applied to the synthesis of furan or piperazine derivatives. For
instance, Tanimori reported the preparation of vinyldihydro-
furan 3a through a palladium-mediated bisalkylation of
dimedone 1a using the symmetrical allylic diacetate 2
(Scheme 1).[5]
Table 1: Palladium-catalyzed bisallylic substitution with 1,3-dione 1a:
effect of reaction parameters.[a]
Entry
Change from “standard conditions”
Yield [%][b]
5a
6a
1
2
none
no palladium
4
–
26
47
7
64
–
3
4
5
[Pd(dba)2] instead of [{PdCl(allyl)}2]
[Pd2(dba)3]·CHCl3 instead of [{PdCl(allyl)}2]
[Pd(PPh3)4] instead of [{PdCl(allyl)}2] and PPh3
Pd(OAc)2 instead of [{PdCl(allyl)}2]
Pd(OTFA)2 instead of [{PdCl(allyl)}2]
1,4-dioxane instead of THF
toluene instead of THF
CH3CN instead of THF
CH2Cl2 instead of THF
1.5 equiv of 4
2 equiv of 4
608C instead of 258C
39
10
59
58
–
50
46
41
38
14
4
6[c]
7[c]
8
7
–
12
21
15
18
53
61
4
9
10
11
12
13
14
32
[a] Reaction conditions: [Pd] (5 mol%), PPh3 (20 mol%), 1a (0.5 mmol),
4 (0.5 mmol), THF (5 mL, 0.1m), 258C, 8 h. [b] Yields of isolated
products. [c] Palladium and ligand were heated for 15 min at 608C before
substrates were added. dba=dibenzylideneacetone, TFA=trifluoroace-
tyl.
Scheme 1. Palladium-catalyzed bisallylic substitution sequences.
Following our continuous interest in the metal-promoted
formation of carbocycles,[6] we were intrigued by the possi-
bility to use hexadiene dicarbonate 4[7] to form vinylcyclo-
pentene 6 and/or cycloheptadiene 7 in addition to dihydro-
selectively either compound 5a or spiro derivative 6a through
the appropriate choice of conditions. The structure of 6a was
unambiguously confirmed by X-ray chrystallography
(Figure 1, left). The use of [{PdCl(allyl)}2] and PPh3 as
catalytic system allowed the formation of vinylcyclopentene
[*] Dr. H. Clavier, Dr. L. Giordano, Dr. A. Tenaglia
Equipe Chirosciences, UMR CNRS 7313-iSm2, Aix Marseille
Universitꢀ, Ecole Centrale de Marseille
Av. Escadrille Normandie-Niemen, 13397 Marseille Cedex 20
(France)
E-mail: herve.clavier@univ-amu.fr
laurent.giordano@centrale-marseille.fr
alphonse.tenaglia@univ-amu.fr
[**] We acknowledge the CNRS for fundings. We are grateful to
Christophe Chendo and Valꢀrie Monnier for mass spectroscopy
analyses and Michel Giorgi for X-ray determination (Spectropole,
Fꢀdꢀration des Sciences Chimiques de Marseille).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204629.
Figure 1. Ball-and-stick representation of compounds 6a (left) and 7a
(right). Some hydrogen atoms have been omitted for clarity.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
6a in 64% yield in eight hours at 258C with traces of 5a
(Table 1, entry 1). The selectivity toward the products was not
affected when [Pd(PPh3)4] or Pd(OAc)2 were used (Table 1,
entries 5 and 6). In contrast, we were able to reverse the
selectivity by using [Pd2(dba)3]·CHCl3 (Table 1, entry 4),
whereas Pd(OTFA)2 was found to be ineffective (entry 7).
The solvent appeared to play a minor role in the reaction
outcome (Table 1, entries 8–11). Because noticeable amounts
of unreacted dimedone 1a were detected at the end of the
reaction, the degradation of dicarbonate 4 through a reductive
elimination to form 1,3,5-hexatriene was assumed.[8] There-
fore, an excess of 4 was used to improve the formation of
product 5a (Table 1, entries 12 and 13). Increasing the
temperature led to reduced yields of isolated products as
a consequence of degradation processes (Table 1, entry 14).
Next, we carefully investigated the effect of ligands on the
reaction outcome (Table 2). The use of electron-rich PCy3
afforded only traces of 5a (Table 2, entry 3). Electron-poor
phosphines, such as trifurylphosphine, P(OPh)3, or P(C6F5)3,
gave either 6a or 5a in low yields (Table 2, entries 4–6). The
bulky P(o-Tol)3 led to the formation of spiro product 6a
(Table 2, entry 7). Interestingly, when P(o-C6H4OMe)3 was
employed, a new product, cycloheptadiene 7a, was isolated as
the major product (66%) along with 6a in 11% yield. The
structure of 7a was unambiguously determined by X-ray
crystallography (Figure 1, right). In order to understand the
factors that govern the formation of 7a, meta- and para-
substituted tris(methoxyphenyl)phosphines were tested.
These ligands afforded product mixtures, in which 6a
appeared to be the major component (Table 2, entries 8–
10). Meanwhile, only traces of 5a were isolated when P(2,6-
C6H3(OMe)2)3 was used. These results suggest that both
electron-rich properties and appropriate steric congestion of
the ligands favor the formation of 7a. Examination of
bidentate ligands showed that Xantphos gave preferentially
cycloheptadiene 7a (Table 2, entries 12–14). This ligand is
well-known to have different coordination modes with
participation of its oxygen atom.[9] Thus, secondary interac-
tions of ligand oxygen atoms, such as P(o-C6H4OMe)3 or
Xantphos with the palladium center should be considered to
rationalize the formation of 7a.
Examples of palladium-catalyzed 1,3-oxygen-to-carbon
alkyl migrations have been reported in the literature,[10] and
dihydrofuran 5a was supposed to be a key intermediate for
the formation of spirocarbocycles. Treatment of 5a under the
usual reaction conditions and PPh3 led to vinylcyclopentene
6a (Scheme 2). When P(o-C6H4OMe)3 was employed, the
yield and ratio of 6a to 7a were found to match those
obtained from dimedone 1a and 4.
Scheme 2. Conversion of dihydrofuran derivative 5a into carbocycles
6a and 7a.
Following our efforts to study rearrangement processes,
the conversion of 6a into cycloheptadiene 7a was attempted
(Scheme 3). Unexpectedly, when the catalytic system that
includes P(o-C6H4OMe)3 was used, the transformation of 6a
Table 2: Palladium-catalyzed bisallylic substitution with 1,3-dione 1a:
ligand effect.[a]
Entry
Ligand
Yield [%][b]
5a
6a
7a
1
2
3
None
PPh3
PCy3
–
4
6
–
64
–
–
–
–
Scheme 3. Transformation of vinylcyclopentene 6a into cyclohepta-
diene 7a.
4
5
6
7
8
9
10
11
12
13
14
P(2-Fu)3
P(OPh)3
P(C6F5)3
P(o-Tol)3
P(o-OMeC6H4)3
P(m-OMeC6H4)3
P(p-OMeC6H4)3
P(2,6-(OMe)2C6H3)3
dppf
–
38
–
–
26
11
61
28
–
–
–
–
–
66
5
23
–
–
31
2
12
14
–
–
6
14
5
16
13
7
to 7a at 258C which proceeded with a low yield (20%) was
significantly improved by increasing the temperature to 608C
(87% yield after 3 h). This result represents one of the rare
À
examples of palladium-promoted C C allylic bond cleavage,
especially at room temperature.[11]
When PPh3 was used under the same reaction conditions,
no trace of 7a was detected and 80% of the starting material
was recovered. This result confirms that the formation of the
seven-membered ring occurs only in the presence of
P(o-C6H4OMe)3 in the catalytic system.[12]
Having established the optimal reaction conditions, we
next investigated the scope of the formation of vinylcyclo-
pentenes with a range of 1,3-diones or derivatives (Table 3).
6
10
67
Xantphos
Dpephos
[a] Reaction conditions: [{PdCl(allyl)}2] (2.5 mol%), Ligand (20 mol%
for monodentate, 10 mol% for bidentate), 1a (0.5 mmol), 4 (0.5 mmol),
THF (5 mL, 0.1m), 258C, 8 h. [b] Yields of isolated products. Dpe-
phos=bis[(2-diphenylphosphino)phenyl] ether, dppf=diphenylphos-
phinoferrocene.
2
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Table 3: Investigation of the substrate scope for the formation of
vinylcyclopentene products 6.[a]
bulk of the crude reaction mixture consisted of unreacted
compounds 1l and 4.
Next, the direct access to cycloheptadienes from various
1,3-diones was attempted. Unfortunately, indanedione 1e or
pyrazolidinedione 1j were converted to vinylcyclopentenes
6e (72%) and 6j (55%) only in the presence of [{PdCl-
(allyl)}2]/P(o-C6H4OMe)3 as the catalytic system after two
hours at 608C. On the other hand, isomerization of a number
of vinylcyclopentenes 6 to the corresponding cyclohepta-
dienes 7 was achieved under the above-mentioned conditions
in moderate to good yields (Table 4).
Entry
Substrate
Product
t
[h]
Yield
[%][b]
1
2
3
4
8
16
16
2
72
72
83
85
Table 4: Examination of the substrate scope for the ring expansion.[a]
Entry
1
Substrate
Product
Yield [%][b]
41
5
5
4
53
2
3
4
5
72
75
79
65
70
(d.r.=
1:1.3)
6
7
5
79
71
78
8
2
9
2
[a] Reaction conditions: [{PdCl(allyl)}2] (2.5 mol%), P(o-OMeC6H4)3
(20 mol%), 6 (0.5 mmol), THF (5 mL, 0.1m), 608C, 3 h. [b] Yields of
isolated products.
67
(d.r.=
1:1)
10
11
4
To illustrate the synthetic potential of vinylcyclopentene
substrates 6, Meldrumꢀs acid derivative 6h treated with N-
bromosuccinimide underwent a bromolactonization to give
bicyclic lactone 8 as a mixture of diastereomers in a ratio of
2.5:1 in a good yield. (Scheme 4).[14]
A plausible mechanism to explain the formation of
spirocarbocycles is shown in Scheme 5. At first, an allylic
substitution takes place via intermediate A to afford mono-
carbonate B. Then, the oxidative addition process gives rise to
the syn,syn h3-allyl palladium complex C, which can release
kinetic product 5 through O-alkylation or evolve into the
anti,syn h3-allyl intermediate D through a p-s-p isomer-
ization. Intermediate D leads to vinylcyclopentene 6 by C-
alkylation. Dynamic equilibration of D into syn h3-allyl
24
trace
[a] Reaction conditions: [{PdCl(allyl)}2] (2.5 mol%), PPh3 (20 mol%), 4
(0.5 mmol), 1 (0.5 mmol), THF (5 mL, 0.1m), 258C. [b] Yields of isolated
products.
Cyclopentane-1,3-dione-based substrates 1b–1e were good
candidates, which afforded the expected vinylcyclopentenes
6b–6e in satisfactory yields (Table 3, entries 1–4). With
cyclohexane-1,3-dione 1 f, product 6 f was obtained in a mod-
erate yield (Table 3, entry 5).[13] The use of substrate 1g
allowed to determine that the reaction was not diastereose-
lective (Table 3, entry 6). More acidic dicarbonyl compounds,
such as Meldrumꢀs acid 1h, 1,3-dimethylbarbituric acid 1i, or
1,2-diphenyl-3,5-pyrazolidinedione 1j, were well-tolerated
(Table 3, entries 7–9). These results led us to examine 5-
pyrazolinone 1k as a substrate, which gave the expected
product without any diastereoselectivity but in a satisfactory
yield (Table 3, entry 10). In deep contrast, acyclic 1,3-dione 1l
gave rise to only trace amounts of 6l (Table 3, entry 11). The
Scheme 4. Bromolactonization of compound 6h. NBS=N-bromo-
succinimide.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
24, 2745 – 2748; b) T. Tsuda, M. Okada, S.-i. Nishi, T. Saegusa, J.
Org. Chem. 1986, 51, 421 – 426; c) K. Tsurugi, N. Nomura, K.
Aoi, Tetrahedron Lett. 2002, 43, 469 – 472.
[4] For selected examples of cyclic products, see: a) I. Shimizu, Y.
Ohashi, J. Tsuji, Tetrahedron Lett. 1985, 26, 3825 – 3828; b) B. M.
Trost, G. B. Tometzki, M.-H. Hung, J. Am. Chem. Soc. 1987, 109,
2176 – 2177; c) T. Tsuda, M. Okada, S.-i. Nishi, T. Saegusa, J. Org.
Chem. 1990, 55, 3388 – 3390; d) Y. Uozumi, A. Tanahashi, T.
Hayashi, J. Org. Chem. 1993, 58, 6826 – 6832; e) M. Massacret, P.
Lhoste, R. Lakhmiri, T. Parella, D. Sinou, Eur. J. Org. Chem.
1999, 2665 – 2673; f) S. Tanimori, M. Kirihata, Tetrahedron Lett.
2000, 41, 6785 – 6788; g) H. Nakano, J.-i. Yokoyama, R. Fujita, H.
Hongo, Tetrahedron Lett. 2002, 43, 7761 – 7764; h) K. Ito, Y.
Imahayashi, T. Kuroda, S. Eno, B. Saito, T. Katsuki, Tetrahedron
Lett. 2004, 43, 7761 – 7764; i) X. Liao, S. Huang, H. Zhou, D.
Parrish, J. M. Cook, Org. Lett. 2007, 9, 1469 – 1471; j) X.-T. Sun,
A. Chen, Tetrahedron Lett. 2007, 48, 3459 – 3461; k) C. S. Chavez,
H. Rudler, A. Parlier, P. Herson, Tetrahedron Lett. 2008, 49,
5843 – 5846; l) S. Lalibertꢂ, P. K. Dornan, A. Chen, Tetrahedron
Lett. 2010, 51, 363 – 366.
[5] S. Tanimori, Y. Kato, M. Kirihata, Synthesis 2006, 865 – 869.
[6] a) H. Clavier, K. Le Jeune, I. De Riggi, A. Tenaglia, G. Buono,
Org. Lett. 2011, 13, 308 – 311; b) T. Achard, A. Lepronier, Y.
Gimbert, H. Clavier, L. Giordano, A. Tenaglia, G. Buono,
Angew. Chem. 2011, 123, 3614 – 3618; Angew. Chem. Int. Ed.
2011, 50, 3552 – 3556; c) A. Tenaglia, S. Marc, L. Giordano, I.
De Riggi, Angew. Chem. 2011, 123, 9228 – 9231; Angew. Chem.
Int. Ed. 2011, 50, 9062 – 9065.
Scheme 5. Mechanistic proposal.
[7] a) N. Nomura, K. Tsurugi, T. V. RajanBabu, T. Kondo, J. Am.
Chem. Soc. 2004, 126, 5354 – 5355; b) B. M. Trost, A. Aponick, J.
Am. Chem. Soc. 2006, 128, 3931 – 3933.
[8] For a reductive elimination of enedicarbonates, see: B. M. Trost,
G. B. Tometzki, J. Org. Chem. 1988, 53, 915 – 917.
[9] For the dynamic coordination environment of Xantphos, see:
a) P. W. N. M. van Leeuwen, P. C. J. Kamer, J. N. H. Reek, P.
Dierkes, Chem. Rev. 2000, 100, 2741 – 2770; b) J. R. Martinelli,
D. A. Watson, W. M. M. Freckmann, T. E. Barder, S. L. Buch-
wald, J. Org. Chem. 2008, 73, 7102 – 7107; c) G. L. Williams,
C. M. Parks, C. R. Smith, H. Adams, A. Haynes, A. J. H. M.
Meijer, G. J. Sunley, S. Gaemers, Organometallics 2011, 30,
6166 – 6179.
[10] a) B. M. Trost, T. A. Runge, L. N. Jungheim, J. Am. Chem. Soc.
1980, 102, 2840 – 2841; b) B. M. Trost, T. A. Runge, J. Am. Chem.
Soc. 1981, 103, 7559 – 7572.
[11] a) Y. I. M. Nilsson, P. G. Andersson, J.-E. Bꢁckvall, J. Am. Chem.
Soc. 1993, 115, 6609 – 6613; b) H. Bricout, J.-F. Carpentier, A.
Mortreux, Tetrahedron Lett. 1997, 38, 1053 – 1056; c) N. Vicart, J.
Gorꢂ, B. Cazes, Tetrahedron 1998, 54, 11063 – 11078; d) H.
Nakamura, H. Iwama, M. Ito, Y. Yamamoto, J. Am. Chem. Soc.
complex E may give either 6 or the less disfavored anti h3-allyl
palladium complex F, thus triggering the formation of cyclo-
heptadiene product 7.
In summary, we have developed a palladium-mediated
bisallylic substitution leading to five- and seven-membered
carbocycles. The chemoselectivity of the reaction depends on
the phosphorous ligand that is used. More importantly, we
À
observed a cleavage of carbon carbon allylic bonds through
activation under mild conditions, thus allowing the isomer-
ization of vinylcyclopentenes into cycloheptadienes. To the
best of our knowledge, this metal-catalyzed ring expansion
process is unprecedented. Further investigations are under-
way in our laboratories to better apprehend the mechanism
and develop an asymmetric version of this bisallylic substi-
tution sequence.
Received: June 13, 2012
Published online: && &&, &&&&
ˇ
1999, 121, 10850 – 10851; e) D. Necas, M. Tursky, M. Kotora, J.
À
Keywords: allylic substitution · C C activation · palladium ·
phosphines · spiro compounds
Am. Chem. Soc. 2004, 126, 10222 – 10223; f) E. L. Fisher, T. H.
Lambert, Org. Lett. 2009, 11, 4108 – 4110; g) Y. Sumida, H.
Yorimitsu, K. Oshima, Org. Lett. 2010, 12, 2254 – 2257.
.
[12] Various experiments to obtain 6a from 7a were unsuccessful.
[13] Small amounts of 5 f were also isolated (< 10%).
[1] a) B. M. Trost, Acc. Chem. Res. 1996, 29, 355 – 364; b) M.
Johannsen, K. A. Jørgensen, Chem. Rev. 1998, 98, 1689 – 1708;
c) S. Norsikian, C.-W. Chang, Curr. Org. Synth. 2009, 6, 264 – 289.
[2] a) Z. Lu, S. Ma, Angew. Chem. 2008, 120, 264 – 303; Angew.
Chem. Int. Ed. 2008, 47, 258 – 297; b) B. M. Trost, T. Zhang, J. D.
Sieber, Chem. Sci. 2010, 1, 427 – 440; c) I. G. Rios, A. Rosas-
Hernandez, E. Martin, Molecules 2011, 16, 970 – 1010; d) Tran-
sition Metal Catalyzed Enantioselective Allylic Substitution in
Organic Synthesis (Ed.: U. Kazmaier), Springer, Heidelberg,
2012.
[14] Lactone 8 is an advanced intermediate in the synthesis of the
cyclic core of Bacillariolides, see: a) H. Miyaoka, M. Tamura, Y.
Yamada, Tetrahedron 2000, 56, 8083 – 8094; b) S.-Y. Seo, J.-K.
Jung, S.-M. Paek, Y.-S. Lee, S.-H. Kim, K.-O. Lee, Y.-G. Suh,
Org. Lett. 2004, 6, 429 – 432; c) S. Ghosh, S. Sinha, M. G. B.
Drew, Org. Lett. 2006, 8, 3781 – 3784.
[3] For selected examples of linear products, see: a) J. P. Genet, M.
Balabane, J.-E. Bꢁckvall, J. E. Nystrçm, Tetrahedron Lett. 1983,
4
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Spiro Compounds
H. Clavier,* L. Giordano,*
A. Tenaglia*
&&&& — &&&&
Cycles everywhere: The selectivity in the
transformations of 1,3-diones to carbo-
cycles by palladium-catalyzed bisallylic
alkylations is strongly dependent of the
phosphine that is employed (see
scheme). Moreover, synthesized vinyl-
cyclopentenes can be easily transformed
into cycloheptadiene derivatives through
Palladium-Mediated Phosphine-
Dependent Chemoselective Bisallylic
Alkylation Leading to Spirocarbocycles
À
a carbon carbon allylic bond cleavage.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!