Palladium-catalyzed [3C + 2C + 2C] cycloaddition of enynylidenecyclopropanes: Efficient construction of fused 5-7-5 tricyclic systems

Article abstract of DOI:10.1039/b919258a

We report a Pd-catalyzed intramolecular [3C + 2C + 2C] cycloaddition between alkylidenecyclopropanes, alkynes and alkenes. The method provides synthetically relevant 5-7-5 tricyclic structures, with good chemoselectivity and complete diastereoselectivity.

Full text of DOI:10.1039/b919258a

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Palladium-catalyzed [3C + 2C + 2C] cycloaddition
of enynylidenecyclopropanes: efficient construction
of fused 5-7-5 tricyclic systemswz
a
a
a
b
a
´
Gaurav Bhargava, Beatriz Trillo, Marisel Araya, Fernando Lopez,* Luis Castedo and
a
´
Jose L. Mascarenas*
Received (in Cambridge, UK) 16th September 2009, Accepted 12th November 2009
First published as an Advance Article on the web 27th November 2009
DOI: 10.1039/b919258a
We report a Pd-catalyzed intramolecular [3C + 2C + 2C]
cycloaddition between alkylidenecyclopropanes, alkynes and
alkenes. The method provides synthetically relevant 5-7-5
tricyclic structures, with good chemoselectivity and complete
diastereoselectivity.
Modern organic synthesis is eagerly demanding methods that
allow the preparation of target-relevant products from simple
and readily available precursors in a rapid and economical
fashion.1 A particularly relevant strategy to achieve this goal
consists of the development of metal-catalyzed multicomponent
cycloadditions [m + n + o +ꢀ ꢀ ꢀ].2 During the last decades,
Scheme 1 Rationale for the [3 + 2 + 2] cycloaddition.
progress in this area has mainly relied on Rh-, Ir-, Ni-, Co-, or
Ru-catalyzed processes,3 whereas related Pd-catalyzed
methodologies have lagged behind.4 Additionally, while most
metal-catalyzed multicomponent cycloadditions provide
mono- or bi-cyclic structures, processes leading to fused
tricyclic or higher polycyclic systems are very scarce.5
as an additional 2C-p-system. Several ligands previously
found effective in Pd-catalyzed [3 + n] cycloadditions were
tested in combination with different Pd(0) sources (Table 1).9
The best outcome was obtained in the presence of the
catalyst generated from a mixture of Pd2(dba)3 and the bulky
phosphite L1, which produced the tricyclic cycloadduct 3a in
52% yield, after heating in toluene at 90 1C for 30 min.
Phosphoramidite ligands L2 or L3, previously used for inducing
We have recently developed a Pd-catalyzed [3C + 2C]
intramolecular cycloaddition of alkylidenecyclopropanes to
alkynes, reaction that provides an entry to a variety of
bicyclo[3.3.0]octanes.6 Considering that the cycloaddition
may involve the generation of a palladacyclohexane inter-
mediate like 2 (Scheme 1),7 we decided to investigate whether
the presence of an extra 2C-p-system could provide for the
construction of tricycles featuring a seven-membered carbo-
cycle, through a carbometallation and reductive elimination
sequence.8 Herein we demonstrate the viability of the approach
by reporting several examples of Pd-catalyzed intramolecular
[3 + 2 + 2] cycloadditions leading to synthetically relevant
5-7-5 tricyclic structures.
Table 1 Preliminary Pd-catalyzed cycloadditions of 1a–1ca
The study began by investigating the performance of
substrate 1a,9 which exhibits a tethered terminal alkyne unit
Entry
1
Ln
3 : 4 ratiob
Conv (%)c
1
2
3
4
5
1a
1a
1a
1b
1c
L1
L2
L3
L1
L1
1 : 0
1 : 1
—
0 : 1
0 : 0
100 (52)
83 (6)
a
´
´
Departamento de Quımica Organica, Universidade de Santiago de
Compostela, 15782 Santiago de Compostela, Spain.
E-mail: joseluis.mascarenas@usc.es; Fax: +34 981595012;
Tel: +34 981563100
0
27
100 (53% of 5c)d
b
´
´
Instituto de Quımica Organica General (CSIC), 28006, Madrid,
Spain. E-mail: fernando.lopez@iqog.csic.es; Fax: +34 91 5644853;
Tel: +34 915622900
a
Conditions: 10 mol% Pd2(dba)3, Ln 26 mol%, dioxane, 90 1C, 1–2 h.
b
c
Determined by 1H-NMR on crude reaction mixtures. Isolated
d
yield under parenthesis. Yield refers to 5c.
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data of previously unknown reaction
products. CCDC 748242. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/b919258a
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Table 2 Pd-catalyzed [3C + 2C + 2C] cycloadditions of 1d–la
hand, substitution with an electron withdrawing group
(1c, R = CO2Et) triggered an alternative [2C + 2C + 2C]
cycloaddition (entry 5), which occurs with preservation of the
cyclopropane ring. Thus, the exclusive formation of 5c from 1c
suggests that the Pd complex preferentially coordinates the
dyine prior to the oxidative addition at the cyclopropanic
unit.4c
3 : 4
ratiob Cycloadduct 3
3
Entry Substrate 1
(% Yield)c
1
2.3 : 1
68
84
In order to avoid the competing [2 + 2 + 2] cycloaddition,
and to further explore the possibilities of the process, we
studied the performance of related precursors incorporating
an alkene instead of an alkyne as second 2C-p-component.
Gratifyingly, the cycloaddition of 1d proceeded smoothly,
providing the desired 5-7-5 tricyclic system 3d, along with
the corresponding [3C + 2C] cycloaddutct 4d in a 2.3 : 1 ratio.
The major cycloadduct 3d could be easily separated from the
mixture and was isolated in a reasonable 68% yield (entry 1).
Importantly, the reaction was completely diastereoselective,
exclusively providing the isomer with the fused-hydrogens
in a cis configuration.10 The influence of the structural
characteristics of the tethers was next investigated. As shown
in the table, the cycloaddition proceeded efficiently with
precursors 1e–1h providing different ratios of the [3 + 2 + 2]
and [3 + 2] adducts. Complete chemoselectivities were
achieved with substrates 1e and 1f which feature ether and
amine units in the connecting tethers (entries 2 and 3).
Confirmation of the structure and stereochemical assignment
was unambiguously obtained by X-ray crystallographic
analysis on the [3 + 2 + 2] cycloadduct 3f (Fig. 1).8
2
1 : 0
3
4
1 : 0
2 : 1
58
51
5
6
1.5 : 1
1 : 1.9
49d
16e
Other related systems, such as 1g or 1h provided lower
chemoselectivities (entries
4 and 5), albeit the desired
[3 + 2 + 2] cycloadducts 3g and 3h could be still isolated in
respectable yields after a simple flash chromatography (51 and
49% yield, respectively). Furthermore, it is worth to remark
that, regardless of the tether moiety employed, the formation
of the [3 + 2 + 2] adducts was completely diastereoselective.
The use of a saturated hydrocarbon linkage between the
alkene and the alkyne units (1i) was prejudicial for the
cycloaddition, as 3i was now obtained as a minor component
and in only 16% yield (entry 6). The access to a fully carbon-
based 5-7-5 tricyclic structure could however be achieved
with substrate 1j, which includes two malonate linking units
(entry 7).
7
8
1.4 : 1
48f
9 : 1
75
60
We next reasoned that the introduction of an electron
withdrawing group at the alkene unit might increase its metal
coordination ability and favour the second carbometallation
step, thereby improving the [3 + 2 + 2]/[3 + 2] ratio.
9
1 : 0
a
Conditions: 10 mol% Pd2(dba)3, L1 26 mol%, dioxane, 90 1C, 1–2 h.
3 : 4 ratios determined by NMR on crude mixtures. Isolated yield
b
c
d
of pure 3. [3 + 2] cycloaddut 4h was isolated in 23% yield.
e
f
[3 + 2] cycloaddut 4i was isolated in 44% yield. [3 + 2] cycloaddut
4j was isolated in 36% yield. E = CO2Et.
[3C + 4C] cycloadditions of alkylidenecyclopropanes,6e were
ineffective (entries 2 and 3). Once the feasibility of the
cycloaddition was demonstrated, the impact of the alkyne
substitution was studied. Unfortunately, use of a disubstituted
alkyne such as in 1b, hampered the required second carbo-
metalation, and the [3 + 2] adduct 4b was the only product
that could be isolated, yet in low yield (entry 4). On the other
Fig. 1 X-Ray crystal structure of 3f.
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3 For selected recent examples, see: [5
+ 1 + 2 + 1]:
(a) P. A. Wender, G. G. Gamber, R. D. Hubbard, S. M.
Pham and L. Zhang, J. Am. Chem. Soc., 2005, 127, 2836–2837;
[5 + 2 + 1]: (b) P. A. Wender, G. G. Gamber, R. D. Hubbard and
L. Zhang, J. Am. Chem. Soc., 2002, 124, 2876–2877 and references
cited therein; [4 + 2 + 2]: (c) M. H. Baik, E. W. Baum,
M. C. Burland and P. A. Evans, J. Am. Chem. Soc., 2005, 127,
1602–1603 and references therein; (d) P. A. Evans and E. W. Baum,
J. Am. Chem. Soc., 2004, 126, 11150–11151; (e) P. A. Evans,
J. E. Robinson, E. W. Baum and A. N. Fazal, J. Am. Chem.
Soc., 2002, 124, 8782–8783; (f) S. R. Gilbertson and B. DeBoef,
J. Am. Chem. Soc., 2002, 124, 8784–8785; [4 + 2 + 1]: (g) Y. Ni
and J. Montgomery, J. Am. Chem. Soc., 2006, 128, 2609–2614;
[3 + 2 + 2]: (h) P. A. Evans and P. A. Inglesby, J. Am. Chem. Soc.,
2008, 130, 12838–12839; (i) S. Saito, S. Komagawa, I. Azumaya
and M. Masuda, J. Org. Chem., 2007, 72, 9114–9120 and references
therein; (j) K. Maeda and S. Saito, Tetrahedron Lett., 2007, 48,
3173–3176; (k) S. Komagawa and S. Saito, Angew. Chem., Int. Ed.,
2006, 45, 2446–2449; (l) L. G. Zhao and A. de Meijere, Adv. Synth.
Catal., 2006, 348, 2484–2492; (m) J. Barluenga, R. Vicente,
P. Barrio, L. A. Lopez, M. Tomas and J. Borge, J. Am. Chem.
Soc., 2004, 126, 14354–14355; [3 + 3 + 1]: (n) S. Y. Kim, S. I. Lee,
S. Y. Choi and Y. K. Chung, Angew. Chem., Int. Ed., 2008, 47,
4914–4917; [3 +1 + 1]: (o) K. Kamikawa, Y. Shimizu, S. Takemoto
and H. Matsuzaka, Org. Lett., 2006, 8, 4011–4014; [2 + 2 + 2 + 1]:
(p) J. J. Kaloko, Y. H. Gary and T. I. Ojima, Chem. Commun., 2009,
4569–4571; (q) B. Bennacer, M. Fujiwara, S. Y. Lee and I. Ojima,
J. Am. Chem. Soc., 2005, 127, 17756–17767; [2 + 2 + 1 + 1]:
(r) Q. F. Huang and R. Hua, Chem.–Eur. J., 2007, 13, 8333–8337; [2
+ 2 + 2]: (s) See reviews on ref. 2f–h. See also: (t) T. Iwayama and
Y. Sato, Chem. Commun., 2009, 5245–5247; (u) N. Saito,
K. Shiotani, A. Kinbara and Y. Sato, Chem. Commun., 2009,
4284–4286; [2 + 2 + 1]: (v) T. Kondo, M. Nomura, Y. Ura,
K. Wada and T. A. Mitsudo, J. Am. Chem. Soc., 2006, 128,
14816–14817; (w) P. A. Wender, M. P. Croatt and
N. M. Deschamps, Angew. Chem., Int. Ed., 2006, 45, 2459–2462.
4 For a Pd-catalyzed [3 + 2 + 2] cocyclization process, see:
(a) N. Tsukada, Y. Sakaihara and Y. Inoue, Tetrahedron Lett.,
Scheme 2 Tandem Pd-catalyzed allylic alkylation and [3 + 2 + 2]
cycloaddition reaction.
Gratifyingly, the cycloaddition of 1k, which features an ester
group at the alkene terminus, took place with significantly
higher chemoselectivity than that obtained from the parent
precursor 1j, providing the desired [3 + 2 + 2] cycloadduct 3k
in a good 75% yield (entry 8). Importantly, the reaction
was completely diastereoselective, thus allowing the direct
construction of a functionalized and stereochemically rich
5-7-5 tricarbocycle.11 Similarly, the cycloaddition result of 1l
was clearly superior to that of the alkene-unsubstituted
homologue 1g, providing 3l with complete selectivity, in a
60% isolated yield (entry 9).
Finally, we also analyzed the possibility of carrying out the
assembly of the precursors and the [3 + 2 + 2] cycloaddition
reaction in a tandem, one-step protocol, since both reactions
are Pd-catalyzed processes. Gratifyingly, heating of 1-vinyl-
cyclopropyl tosylate 7 with one equivalent of the sodium salt
of 6 in the presence of the suitable proportion of dppe,12 L1
and Pd2dba3, provided the expected cycloadduct 3d in 62%
isolated yield (Scheme 2).
In conclusion, we have developed a new Pd-catalyzed multi-
component intramolecular cycloaddition reaction between
alkylidenecyclopropanes (3C), alkynes (2C) and alkenes (or a
terminal alkyne, 2C). The transformation takes place with
moderate to excellent chemoselectivities and complete diastereo-
selectivities, providing straightforward access to a variety of
synthetically relevant 5-7-5 tricyclic systems.
2007, 48, 4019–4021; For [2
+ 2 + 1] annulations, see:
(b) R. Grigg, L. X. Zhang, S. Collard and A. Keep, Chem.
Commun., 2003, 1902–1903; For [2 + 2 + 2] cycloadditions, see
reviews on ref. 2f–h. See also: (c) Y. Sato, T. Tamura, A. Kinbara
and M. Mori, Adv. Synth. Catal., 2007, 349, 647–661;
´
(d) C. Romero, D. Pena, D. Perez and E. Guitian, J. Org. Chem.,
2008, 73, 7996–8000 and references cited threin.
5 For some examples, see ref. 3p–q, and those cited therein.
This work was supported by the Spanish MICINN
[SAF2007-61015, Consolider-Ingenio 2010 (CSD2007-00006)],
Xunta de Galicia (PGIDIT06PXIB209126PR and GRC2006/
132), CSIC and Comunidad de Madrid (CCG08-CSIC/
PPQ3548). BT thanks the Spanish MICINN for a predoctoral
fellowship. We thank Johnson-Matthey for the gift of metals.
6 (a) A. Delgado, J. R. Rodrı
J. Am. Chem. Soc., 2003, 125, 9282–9283; (b) J. Dura
L. Castedo and J. L. Mascarenas, Org. Lett., 2005, 7, 5693–5696;
For [3+2] cycloadditions to alkenes, see: (c) M. Gulıas, R. Garcıa,
´
guez, L. Castedo and J. L. Mascarenas,
´
n, M. Gulıas,
´
´
´
A. Delgado, L. Castedo and J. L. Mascarenas, J. Am. Chem. Soc.,
2006, 128, 384–385; For [3+2] cycloadditions to allenes, see:
(d) B. Trillo, M. Gulı
J. L. Mascarenas, Adv. Synth. Catal., 2006, 348, 2381–2384; For
related [3 + 4] cycloadditions, see: (e) M. Gulıas, J. Duran,
F. Lopez, L. Castedo and J. L. Mascarenas, J. Am. Chem. Soc.,
2007, 129, 11026–11027.
7 For a theoretical study on the Pd-catalyzed cycloadditions of
alkylidenecyclopropanes, see: (a) R. Garcıa-Fandino, M. Gulıas,
L. Castedo, J. R. Granja, J. L. Mascarenas and D. J. Cardenas,
as, F. Lopez, L. Castedo and
´ ´
Notes and references
´
´
1 (a) P. A. Wender, S. T. Handy and D. L. Wright, Chemistry
& Industry, 1997, 765–769; (b) T. Hudlicky and M. G. Natchus, in
Organic Synthesis: Theory and Applications, ed. T. Hudlicky,
JAI Press, Greenwich, 1993, vol. 2, pp. 1–26; (c) P. A. Wender,
Chem. Rev., 1996, 96, 1–2; (d) P. A. Wender and B. L. Miller,
Nature, 2009, 460, 197–201.
´
´
´
´
Chem.–Eur. J., 2008, 14, 272–281; (b) T. Suzuki and H. Fujimoto,
Inorg. Chem., 2000, 39, 1113–1119.
8 For Rh- and Ni-catalyzed intermolecular [3 + 2 + 2] cyclo-
additions of alkylidenecyclopropanes see ref. 3h–l.
9 See Electronic Supplementary Information for synthetic details.
10 DFT calculations to confirm the mechanistic hypothesis and
explain the sterochemical results are ongoing.
2 For selected reviews discussing multicomponent metal-catalyzed
cycloadditions, see: (a) G. Balme, G. Bouyssi and N. Monteiro, in
Multicomponent Reactions, ed. J. Zhu and H. Bienayme,
´
Wiley-VCH, Weinheim, 2005, pp. 224–276; (b) R. V. A. Orru
and M. de Greef, Synthesis, 2003, 1471–1499; (c) J. Montgomery,
Acc. Chem. Res., 2000, 33, 467–473; (d) B. Heller and M. Hapke,
Chem. Soc. Rev., 2007, 36, 1085–1094; (e) E. Guitian, D. Perez and
´ ´
11 In contrast to the cycloaddition of dyine 1c (Table 1), in the
cycloaddition of 1k we did not observe the formation of [2 + 2 + 2]
cycloadducts of type 5.
12 The presence of dppe ensures a small proportion of a bidentate Pd
complex which facilitates the coupling reaction.
D. Pena, in Topics in Organometallic Chemistry, ed. J. Tsuji, Springer
Verlag, Weinheim, 2005, vol. 14, pp. 109–146; (f) P. R. Chopade and
J. Louie, Adv. Synth. Catal., 2006, 348, 2307–2327; (g) S. Saito and
Y. Yamamoto, Chem. Rev., 2000, 100, 2901–2915; (h) T. Shibata,
Adv. Synth. Catal., 2006, 348, 2328–2336.
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This journal is The Royal Society of Chemistry 2010
272 | Chem. Commun., 2010, 46, 270–272