Stereoselective Ir(iii)-catalyzed dimerization reaction of enynes: An entry to functionalized polyunsaturated and cyclic systems

Article abstract of DOI:10.1039/c0cc00721h

The Ir(iii) complex [Ir₂H₂I₃((rac)-Binap) ₂]⁺I^- efficiently promotes the selective dimerization of 1,6-, 1,7-enynes and functionalized alkynes. This catalytic process results in the formati

Full text of DOI:10.1039/c0cc00721h

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Stereoselective Ir(III)-catalyzed dimerization reaction of enynes: an entry
to functionalized polyunsaturated and cyclic systemsw
Mehdi Ez-Zoubir,a Florent Le Boucher d’Herouville,a Jack A. Brown,b
a
a
´
Virginie Ratovelomanana-Vidal* and Veronique Michelet*
Received 1st April 2010, Accepted 5th July 2010
DOI: 10.1039/c0cc00721h
The Ir(III) complex [Ir2H2I3((rac)-Binap)2]+IÀ efficiently promotes
the selective dimerization of 1,6-, 1,7-enynes and functionalized
alkynes. This catalytic process results in the formation of
head-to-head isomers with (E)-stereoselectivity. Subsequent
Rh-catalyzed cycloisomerization under reductive conditions led
to the corresponding 1,2-dialkylidenecyclopentane derivatives.
Table 1 [Ir]-catalyzed dimerization of 1,6-enyne 1a
Transition-metal-catalyzed C–C bond coupling reactions of
alkynes have attracted considerable attention within the chemical
literature.1 Amongst this class of reactions, the dimerization of
alkynes2 has been a field of constant research, given the synthetic
utility of the resulting enynes.3 The main challenge presented by
this chemistry is in the control of the observed regioselectivity of
the reaction, that is, the head-to-head and head-to-tail ratio as
well as the stereoselectivity of the reaction (Scheme 1). Examples
of this reaction catalyzed by iridium complexes are rather rare4,5
and to the best of our knowledge only a recent report has detailed
the use of a well-defined Ir(III) catalyst for the dimerization
reaction of three model substrates.5 We have previously
described the synthesis of cationic dinuclear triply halogen-
bridged Ir(III)–atropisomeric ligand complexes and their use in
hydrogenation reactions.6 The potential of such complexes in
carbon–carbon bond formations being still unknown, we
embarked upon a study of their reactivity towards alkynes.
Considering the broad applications of 1,n-enynes,7 we envisaged
exploring the Ir-catalyzed dimerization reaction of functionalized
1,6-enynes. In this communication, we describe an efficient
iridium-catalyzed dimerization of 1,6-enynes and further cyclo-
isomerization of the intermediate trienyne.
Conv.a
T/1C (%)
Entry Catalyst
2ab 3a 4a 5aa 6aa
1
2
3
4
[Ir2H2I3((rac)-Binap)2]+ À
[Ir2H2I3((rac)-Binap)2]+ À
[Ir2H2I3((rac)-Binap)2]+ À
In situ [Ir(cod)Cl]2/rac-
Binap/HI
I
I
I
RT
60
80
80
0
/
n.i. /
/
/
/
/
/
/
/
43
99
99
72
35
/
/
/
/
8
/
4
9b
5
6
7
8
9
In situ [Ir(cod)Cl]2/PPh3/HI 80
In situ [Ir(cod)Cl]2/dppf/HI 80
99
99
99
99
74
99
/
25
/
20a 20a
8
3
3
/
/
/
/
/
/
/
/
11b
/
7
[Ir(cod)Cl]2/HI
[Ir(cod)Cl]2/HOAc
[Ir(cod)Cl]2/PPh3/NEt3
80
80
50
80
20b
/
30b
/
/
/
/
51d
52
c
10e,f [Ir2H2I3((rac)-Binap)2]+ À
I
41
7
n.i. not isolated. Determined by 1H NMR of the isolated products.
a
b
c
Isolated yield. 1.5 mol% catalyst, 20 h. (E)/(Z) 65/35 mixture.
d
e
f
1 mol%, 40 h. Determined by H NMR of the crude mixture.
1
material was observed at 60 1C and room temperature using
our previously reported Ir(III) complex6 (entries 1 and 2).
However, upon increasing the reaction temperature to 80 1C,
we were delighted to note the formation of the desired trienyne
2a. Indeed, the head-to-head isomer was exclusively formed and
the desired product 2a was isolated in 72% yield as a single
(E)-isomer (entry 3). The use of alternative solvents such as
dioxane or acetonitrile did not lead to conversion of the starting
material to product. This unprecedented reactivity was parti-
cularly interesting considering the high reactivity of 1,6-enynes in
the presence of transition metal complexes7,8 as the group of
Trost published few examples of dimerization of 1,6-enynes in
the presence of Pd catalysts, leading to head-to-tail isomers.9
As a model reaction, we prepared 1,6-enyne 1a and attempted
its dimerization in the presence of various iridium systems
(Table 1). Low conversion or no reactivity of the starting
Scheme 1 [M]-catalyzed dimerization of alkynes.
a
´
Laboratoire Charles Friedel, Ecole Nationale Superieure de Chimie
de Paris Chimie ParisTech UMR 7223, 11 rue P. et M. Curie,
F-75231 Paris Cedex 05, France.
E-mail: virginie-vidal@chimie-paristech.fr,
When an Ir–hydride complex was generated in situ,1,8a
a
lower isolated yield was observed (entry 4). Moreover,
by-products, whose structures were identified by NMR and
mass spectroscopy, were isolated including the cyclo-
isomerized products 3a–4a, the vinyliodide 5a (resulting from
hydroiodination) and the diene 6a (resulting from partial
veronique-michelet@chimie-paristech.fr
b Epinova DPU, II CEDD, GlaxoSmithKline, Medicines Research
Centre, Gunnels Wood Road, Stevenage, UK SG1 2NY
w Electronic supplementary information (ESI) available: Experimental
procedure, full analyses of 2a–2q, 5a and 7–9. See DOI: 10.1039/
c0cc00721h
c
6332 Chem. Commun., 2010, 46, 6332–6334
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Table 2 [Ir]-catalyzed dimerization of enynes 1b–k
hydrogenation of the alkyne moiety). Several additional
products were detected but could not be identified. The reaction
conditions and products distribution were highly ligand
dependent as no trace of the desired trienyne 2a was found in
the presence of PPh3 (entry 5). The use of an in situ [Ir(cod)Cl]2/
dppf/HI system allowed the formation of the desired product,
accompanied with other identified by-products (entry 6). The
use of hydroiodic acid or acetic acid8a,10 without additional
phosphorous ligand led, respectively, to the vinyliodide
derivative 5a and the known cycloisomerized8a product 4a
(entries 7 and 8). To further evaluate the selectivity of our
new system compared to other iridium catalysts, the enyne 1a
was subjected to Miyaura’s conditions4 (entry 9). The dimeriza-
tion reaction indeed afforded the expected enyne, but in lower
conversion and yield. A relatively poor stereoselectivity was
observed as the (E)/(Z) ratio dropped to 65/35. Lowering the
catalyst loading to 1 mol% was tempted and led to the
competitive formation of 4a and 6a (entry 10). The compat-
ibility and efficiency of our [Ir2H2I3((rac)-Binap)2]+IÀ complex
with various 1,6 and 1,7-enyne substrates was then examined
(Table 2). The dimerization reactions of carbon-tethered enynes
1b, 1c and 1d afforded the corresponding trienynes 2b, 2c and 2d
in good to excellent yields (82–93% yield, entries 1–3). It is
noteworthy that the outcome of the reaction did not depend on
the alkenyl side chain, as 3-methylbutenyl, 2-methylpropenyl
and allyl did not react during the process. The dimerization of
disulfone-linked enynes 1e and 1f led to the formation of several
products resulting from the degradation of starting material at
80 1C. When lowering the reaction temperature at 60 1C, the
corresponding derivatives 2e and 2f could be efficiently isolated
in 93% and 70% yields (entries 4 and 5). Amino-tethered
enynes were also subjected to the optimized reaction conditions
(entries 6–8). The use of N-tosyl protected enynes 1g–i led to the
desired derivatives 2g–i in 50% and 70% yields. The reaction
conditions were also tested on 1,7-enynes 1j and 1k (entries 9
and 10). The corresponding trienynes 2j and 2k were isolated in
70% and 85% yields.
Entry Enyne
Product
Yielda (%)
1
1b
2b 85
2
3
1c
1d
2c 82
2d 93
4
1e
2e 93b
5
6
7
1f
2f 70b
2g 50b
2h 50b
1g
1h
To evaluate the implication of the alkenyl moiety in the
mechanism and to further study the efficiency of the catalytic
system, we tested the reactivity of simpler alkynes (Scheme 2).11
The reaction of propargylic mono- or disubstituted malonates
afforded the desired dimers 2l–2o in moderate to good yields
(56–84%). It’s noteworthy that the reaction conditions were
compatible with a chlorine atom. The bissulfone and N-tosyl
protected alkynes were also dimerized and gave rise to the
formation of 1p and 1q in, respectively, 75% and 54%.
8
9
1i
2i 70
Mechanistically, a first pathway would classically be based on
an initial Z2 coordination of an iridium(I) complex fragment to
the alkyne function, which would then undergo oxidative
addition (Scheme 3).2,4,12 The active catalyst specie A would
presumably arise from the dinuclear complex [Ir2H2I3((rac)-
Binap)2]+IÀ.6 Hydrometallation step leading to C intermediate
would be followed by reductive elimination (D intermediate)
releasing the (E)-head-to-head 1,3-enyne. An alternative
pathway would involve intermediate E as proposed by
1j
2j 70
10
1k
2k 85
Passarelli, Perez-Prieto and co-workers.5,13
A stabilizing
involvement of the alkene moiety or the functional carbonyl,
sulfonyl or nitrogen groups might be advocated for the selective
reactivity of the enynes or functionalized alkynes.
a
b
Isolated yields. 60 1C.
c
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l’Education et de la Recherche for financial support. M.E.-Z.
is grateful to the Centre National de la Recherche Scientifique
and GlaxoSmithkline for a grant (2007–2010).
Notes and references
1 For representative examples, see: (a) R. Chinchilla and C. Najera,
Chem. Rev., 2007, 107, 874; (b) S. Derien, F. Monnier and
P. H. Dixneuf, Top. Organomet. Chem., 2004, 11, 1; (c) C. Bruneau
and P. H. Dixneuf, Acc. Chem. Res., 1999, 32, 311; (d) D. B.
Grotjahn, in Comprehensive Organometallic Chemistry II, ed. E. W.
Abel, F. G. A. Stone and G. Wilkinson, Pergamon Press, New York,
1995, vol. 12; (e) P. Siemesen, R. C. Livingston and F. Diederich,
Angew. Chem., Int. Ed., 2000, 39, 2632; (f) B. M. Trost, F. D. Toste
and A. B. Pinkerton, Chem. Rev., 2001, 101, 2067; (g) T. Naota,
H. Takaya and S. I. Murahashi, Chem. Rev., 1998, 98, 2599.
2 For a seminal review, see: E. Bustelo and P. H. Dixneuf, in
Handbook of C–H transformations, ed. G. Dyker, Wiley-VCH,
Weinheim, 2005, p. 62.
Scheme 2 [Ir]-catalyzed dimerization of alkynes 1l–q.
3 (a) K. C. Nicolau, W. M. Dai, S. C. Tsay, V. A. Estevez and
W. Wrasidlo, Science, 1992, 256, 1172; (b) D. H. Camacho,
I. Nakamura and Y. Yamamoto, J. Org. Chem., 2006, 71, 1152;
(c) Y. Liu, M. Nishiura, Y. Wang and Z. Hou, J. Am. Chem. Soc.,
2006, 128, 5592.
4 (a) T. Ohmura, S. I. Yorozuya, Y. Yamamoto and N. Miyaura,
Organometallics, 2000, 19, 365; (b) M. V. Jimenez, E. Sola, F. J. Lahoz
´
and L. A. Oro, Organometallics, 2005, 24, 2722; (c) J. P. Qu, D. Masui,
¨
Y. Ishii and M. Hidai, Chem. Lett., 1998, 1003; (d) R. Ghosh,
X. Zhang, P. Achord, T. J. Emge, K. Krogh-Jespersen and
A. S. Goldman, J. Am. Chem. Soc., 2007, 129, 853; (e) C. H. Jun,
Z. Lu and R. H. Crabtree, Tetrahedron Lett., 1992, 33, 7119.
5 M. Ciclosi, F. Esteban, P. Lahuerta, V. Passarelli, J. Perez-Prieto
and M. Sanau, Adv. Synth. Catal., 2008, 350, 234.
Scheme 3 Proposed mechanisms.
6 (a) T. Yamagata, H. Tadaoka, M. Nagata, V. Ratovelomanana-
Vidal, J. P. Genet and K. Mashima, Organometallics, 2006, 25,
2505; (b) C. Deport, M. Buchotte, K. Abecassis, H. Tadaoka,
T. Ayad, T. Ohshima, J. P. Genet, K. Mashima and
V. Ratovelomanana-Vidal, Synlett, 2007, 2743; (c) H. Tadaoka,
D. Cartigny, T. Nagano, T. Gosavi, T. Ayad, J. P. Genet,
T. Ohshima, V. Ratovelomanana-Vidal and K. Mashima,
Chem.–Eur. J., 2009, 15, 9990.
7 For selected recent reviews on metal-catalyzed cycloisomerizations:
(a) V. Michelet, P. Y. Toullec and J. P. Genet, Angew. Chem., Int.
Ed., 2008, 47, 4268; (b) E. Gimenez-Nunez and A. M. Echavarren,
Chem. Rev., 2008, 108, 3326; (c) P. Belmont and E. Parker, Eur. J.
Org. Chem., 2009, 6075.
8 (a) N. Chatani, H. Inoue, T. Morimoto, S. Muto and S. Murai,
J. Org. Chem., 2001, 66, 4433; (b) T. Shibata, M. Yamasaki,
S. Kadowaki and K. Takagi, Synlett, 2004, 2812; (c) S. Kezuka,
T. Okado, E. Niou and R. Takeuchi, Org. Lett., 2005, 7, 1711;
(d) T. Shibata, Y. Kobayashi, S. Maekawa, N. Toshida and
K. Takagi, Tetrahedron, 2005, 61, 9018.
9 (a) B. M. Trost, C. Chan and G. Ruther, J. Am. Chem. Soc., 1987,
109, 3486; (b) B. M. Trost, M. T. Sorum, C. Chan, A. E. Harns and
G. Ruther, J. Am. Chem. Soc., 1997, 119, 698.
10 For the use of acetic acid to generate Ru- or Pd–hydride complexes,
see: (a) B. M. Trost, Chem.–Eur. J., 1998, 4, 2405; (b) J. L. Pailh,
´
D. C. Rodriguez, S. Derien and P. H. Dixneuf, Synlett, 2000, 95.
11 When various aryl-substituted alkynes such as phenylacetylene and
4-methoxy or 4-N-dimethylaminophenylacetylene were subjected
to the standard conditions, several by-products were detected,
including trimeric adducts. The desired dimers were observed as
very minor products. The dimerization of other simple alkynes
such as hexyne did not lead to a clean reaction.
We then envisaged taking advantage of the remaining
1,6-enyne fragment in trienyne derivatives 2c, 2f, 2h and
turned our attention to catalytic reductive methods for
carbon–carbon bond formation.14 The reactivity of 1,6-enynes
was particularly impressive where the use of a cationic
rhodium catalyst in the presence of (rac)-Binap afforded
1,2-dialkylidene-cyclopentane derivatives in a highly selective
manner.15 As such reductive coupling reactions had never
been conducted with polyunsaturated derivatives, we were
pleased to observe a clean and selective cycloisomerization
reaction. The use of cationic Rh(cod)2OTf, rac-Binap, under
1 atm of hydrogen in dichloromethane at room temperature
afforded the desired 1,2-dialkylidenecyclopentane 7–9 in good
yields (60–70% yield) (Scheme 4).
In summary, we have shown that the Ir(III) catalyst
[Ir2H2I3((rac)-Binap)2]+IÀ efficiently promotes the selective
dimerization reaction of 1,6-, 1,7-enynes and functionalized
alkyl-substituted alkynes. The catalytic process afforded the
formation of the head-to-head isomers with complete (E)
stereoselectivity. The carbon- and nitrogen-tethered trienynes
were isolated in moderate to excellent yields.
This work was supported by the Centre National de
la Recherche Scientifique (CNRS) and the Ministere de
12 (a) X. Li, T. Vogel, C. D. Incarvito and R. H. Crabtree,
Organometallics, 2005, 24, 62; (b) M. V. Jimenez, E. Sola,
´
F. J. Lahoz and L. A. Oro, Organometallics, 2005, 24, 2722.
13 For an Z3-butenynyl Ru-complex, see: J. M. Lynam, T. D. Nixon
and A. C. Whitwood, J. Organomet. Chem., 2008, 693, 3103 and
references cited therein.
14 (a) H. Y. Jang and M. J. Krische, Acc. Chem. Res., 2004, 37, 653;
(b) R. L. Patman, J. F. Bower, I. S. Kim and M. J. Krische,
Aldrichimica Acta, 2008, 41, 95.
15 H. Y. Jang and M. J. Krische, J. Am. Chem. Soc., 2004, 126, 7875.
Scheme 4 Rh-catalyzed reductive C–C bond formations.
6334 Chem. Commun., 2010, 46, 6332–6334
c
This journal is The Royal Society of Chemistry 2010