Palladium-catalyzed intramolecular [3C + 2C] cycloaddition of alkylidenecyclopropanes to allenes

Article abstract of DOI:10.1002/adsc.200600347

Allenes are useful and versatile two-carbon partners in palladium catalyzed [3C + 2C] intramolecular cycloadditions with alkylidenecyclopropanes enabling the preparation of dienyl bicyclo[3.3.0]octane adducts with good yields and high diastereoseletivity.

Full text of DOI:10.1002/adsc.200600347

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DOI: 10.1002/adsc.200600347
Palladium-Catalyzed Intramolecular [3C+2C] Cycloaddition of
Alkylidenecyclopropanes to Allenes
Beatriz Trillo,a MoisØs Gulías,a Fernando López,a Luis Castedo,a
and JosØ L. MascareÇasa,*
a
Departamento de Química Orgµnica, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Fax : (+34)-981-595-012; e-mail: qojoselm@usc.es
Received: July 12, 2006; Accepted: September 20, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Allenes are useful and versatile two-
carbon partners in palladium catalyzed [3C+2C]
intramolecular cycloadditions with alkylidenecyclo-
propanes enabling the preparation of dienyl
bicyclo
ACHTREUNG[3.3.0]octane adducts with good yields and
high diastereoseletivity.
Keywords:
alkylidenecyclopropanes;
allenes;
bicyclo[3.3.0]octanes; cycloaddition; palladium
ACHTREUNG
while the cycloaddition seems still to be the major re-
action pathway, there are competitive processes that
result in an important decrease in the efficiency of
the transformation.
Alkylidenecyclopropanes are strained but readily ac-
We envisaged that using allenes instead of alkenes
cessible structures which can participate as three- might provide a good solution to the above problem
carbon components in metal-catalyzed cycloadditions and perhaps lead to more efficient [3+2] cycloaddi-
to afford different types of p-systems.[1] Our group tion processes owing to the presumably higher reac-
has recently shown that alk-5-ynylidenecyclopropanes tivity of the allene unit. Allenes are being increasingly
undergo a mild [3C+2C] intramolecular cycloaddi- used in metal-catalyzed annulation reactions due to
tion upon treatment with appropriate palladium or their unique reactivity and the special manipulation
ruthenium catalysts to provide a variety of fused possibilities that they offer to the resulting products
bicycloACHTREUNG
[3.3.0]octenes.[2] More recently we have also owing to their retaining one double bond of the
demonstrated that it is possible to use alkenes in allene.[5] Despite these potential advantages, we are
place of alkynes as two-carbon components in the cy- not aware of studies on the behaviour of this type of
cloaddition. Although attaining good efficiencies in p-system in transition metal-catalyzed [3C+2C] cy-
these cycloadditions requires a relatively high catalyst cloadditions with methylene- or alkylidenecyclopro-
loading (6% of Pd2dba3, and 20% of the ligand), the panes.[6] Herein, we describe the first examples of pal-
reactions provide a rapid and direct entry to bicyclo- ladium-catalyzed intramolecular cycloadditions be-
pentanoid rings equipped with up to three stereogenic tween allenes and alkylidenecyclopropanes, examples
centers.[3] The cycloadditions can be performed with that confirm the special utility of allenes as two-
either activated (electron-deficient) or non-activated carbon partners in this type of annulation.
alkenes, but it is less efficient when the terminal posi-
Allene 4a, which can be easily assembled from 1-vi-
tion of the alkene is substituted by an alkyl group due nylcyclopropyltosylate and diethyl malonate in two
to competing b-hydride elimination processes on pu- steps,[7] was used as model substrate to investigate the
tative palladacyclic intermediates. Thus, treatment of reaction conditions (Table 1). Heating a solution of 4a
the cyclopropylideneethylamine 1 with Pd2dba3 (6 with 8 mol% of Pd2dba3 and 32 mol% of PACTHER(UNG O-i-Pr)3
mol%) and ligand L1 (20 mol%) in refluxing dioxane in refluxing dioxane gave the expected [3+2] cycload-
provided the cycloadduct 2 in only 57% yield because ducts but in a fairly poor yield and as an equimolecu-
of concomitant formation of the dienyl cycloisomeri- lar mixture of cis- and trans-fused isomers (entry 1).
zation side product 3 [25% yield, Eq.(1)].[4] Thereby, Interestingly, use of the bulky ligand tris(2,4-di-tert-
Adv. Synth. Catal. 2006, 348, 2381 – 2384
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Beatriz Trillo et al.
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Table 1. Palladium-catalyzed cycloaddition of allenyl derivative 4a.
Entry
mol% Pd2dba3
L (mol%)
(O-i.Pr)3 (32)
5a:6a[a]
Time [h]
Yield [%]
1
2
3
4
8
3
8
8
6
3
1
0.1
PG
1:1.1
3:1
1:1
1.1:1
1:1.1
3:1
6
1.3
6
6
2
0.5
2
2
29
87
24
20
L1 (8)
L2 (32)
L3 (32)
L4 (24)
L1 (8)
L1 (2.6)
L1 (0.26)
5
92
6[b]
7[b,c]
8[b]
99[d]
99[d]
99[d]
3:1
3:1
[a]
1
Determined by H NMR of the crude reaction mixture.
[b]
[c]
[d]
Experiment carried out after a thorough deoxygenation of the reaction mixture.
Reaction carried out at 808C.
Conversion by GC.
(O-i-Pr)3 alk-5-ynylidenecyclopropanes,[2c] also catalyzed the
butylphenyl) phosphite (L1) in place of PACHTREUNG
brought about an important improvement in the process, but led to lower yields and/or selectivities
chemical yield as well as in the stereoselectivity of the (Table 1, entries 3–5). Worth of note is the efficiency
cycloaddition. Thus, the reaction of 4a with 3 mol% of the reaction in the presence of the chiral phosphor-
Pd2dba3 and 8 mol% of L1 afforded, after refluxing amidite ligand L4 (entry 5),[9] a result which warrants
in dioxane for 80 min, a 3:1 mixture of 5a and 6a in the study of enantioselective versions of the cycload-
87% overall yield (entry 2). Together with these two dition using this type of ligand.
cycloadducts we also detected traces of the isomeric
1
Interestingly, a careful analysis by 31P and H NMR
derivative 7a (aprox. 5%), especially when the reac- of the crude reaction mixture resulting from the pro-
tion was allowed to proceed for longer times. This cess described in entry 2 allowed us to detect the
conjugated diene 7a must result from an in situ iso- presence of a considerable amount of tris(2,4-di-tert-
merization of the cis addut 5a since treatment of a butylphenyl) phosphate (8, Figure 1), a side product
mixture of 5a and 6a under the cycloaddition condi- that must arise from oxidation of ligand L1. Further
tions promoted the conversion of 5a into 7a, while the studies (31P NMR) confirmed that such an oxidation
trans-fused isomer 6a remained unaltered.[8]
was occurring prior to and during the cycloaddition
Other phosphorus-based monodentate ligands such reaction, therefore decreasing the amount of the
as L2, L3 or L4 (Figure 1), some of which have been active catalytic species. Consequently, we tested
recently shown to be effective in the cycloaddition of whether a careful deoxygenation of the reaction mix-
ture could improve the cycloaddition outcome.
Indeed, ensuring the removal of oxygen from the re-
action mixture prevented the formation of phosphate
8 and led to a remarkable acceleration of the cycload-
dition process (entry 6). Under these conditions the
reaction could be accomplished at lower temperatures
(808C) reaching full conversion after 2 h (entry 7).
More importantly we could decrease the substrate-to-
catalyst ratio so that the reaction can be efficiently
performed in refluxing dioxane (2 h) even with cata-
lyst loadings as low as 0.1 mol% of Pd2dba3 (0.26
mol% L1) (entry 8), which represents the highest
turnover so far described in a metal-catalyzed [3+2]
cycloaddition process.
A preliminary investigation on the scope of the re-
action showed that it can be carried out with sub-
Figure 1.
strates like 4b which contains an amine instead of a
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ACHTREUNG[3C+2C] Cycloaddition of Alkylidenecyclopropanes to Allenes
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malonate unit in the connecting tether.[10] Interesting-
Finally it is worth noting that the cycloaddition re-
ly, in this case the reaction is almost completely dia- action can be coupled to the assembly of the precur-
stereoselective and yields the cis-fused product in sors so that both Pd-catalyzed processes can be car-
68% isolated yield. We also observed the formation ried out in a tandem, one-step process. Thus, treat-
of a small proportion of 7b, a product which can be ment of 1-vinylcyclopropyl tosylate with 1 equivalent
readily obtained from 5b by refluxing under the cyclo- of the sodium carbanion of diethyl 2-(4-methylpenta-
addition conditions for 2 h.[7] The [3 +2] cycloaddition 2,3-dienyl)malonate (9) in the presence of the suitable
reaction turned out to be tolerant to the introduction proportion of dppe, L1 and Pd2dba2 provides, after
of substituents in the non-reactive double bond of the heating, the expected cycloadducts in a 62% isolated
allene. Indeed the dimethylated substrate 4c under- yield (unoptimized) [Eq. (2)].
went an efficient cycloaddition to give products with
better cis/trans selectivity than in the case of the un-
substituted allene (Table 2, entry 2). On the other
hand, the monomethylated derivative 4d was also effi-
ciently converted into the cycloadduct 5d with excel-
lent diastereoselectivity (Table 2, entry 3). These re-
sults indicate that the diastereoselectivity of the pro-
cess can be improved by adjusting the substitution of
the non-reactive double bond of the allene. In the
case of amine 4e the reaction gave the cycloadduct 5e
as a single diasteroisomer (Table 2, entry 4). The high
diastereoselectivity attained from 4d and 4e together
with the clear possibility for obtaining this type of al-
In summary, we have reported the first examples
lenyl precursors in an enantioselective manner,[11] on the use of allenes in palladium-catalyzed [3C+2C]
augurs well for the application of this methodology in intramolecular cycloaddditions with alkylidenecyclo-
the synthesis of enantiomerically enriched bicyclo- propanes. The cycloaddition proceeds with high effi-
ACHTREUNG[3.3.0]octanes. The cycloaddition is also viable with ciency using low catalyst loadings, and its diastereose-
the ether derivative 4f, to give the cis-fused cycload- lectivity can be improved by using allenes with appro-
duct 5f with high distereoselectivity (Table 2, entry 5). priate substituents at the non-reactive double bond.
This result demonstrates that the presence of a substi- Further work on the scope and limitations of the pro-
tuted amine or a geminal diester in the tether is not cess as well as on the development of enantioselective
required for success.
versions is underway.
Table 2. Cycloaddition of allenyl derivatives 4b–4d.
Entry
4
T [8C]
Products
5:6
Time [min]
Yield [%]
1
4b
4c
4d
4e
4f
908C
1018C
1018C
908C
908C
5b
>20:1[a]
6:1[a]
60
15
25
60
90
68
80
90
77
70
2
5c/6c
5d/6d
5e/6e
5f/6f
3[c]
4
>14:1[b]
>20:1[a]
>9:1[b]
5
[a]
1
Determined by H NMR of the crude reaction mixture.
Determined by GC of the crude reaction mixture.
Carried out with Pd2dba3 (3 mol%) and L1 (7.8 mol%).
[b]
[c]
Adv. Synth. Catal. 2006, 348, 2381 – 2384
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Beatriz Trillo et al.
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Rev. 1996, 96, 49–92; d) E. Nakamura, Y. Yamamoto,
Adv. Synth. Catal. 2002, 344, 111–129; e) A. Brandi, S.
Cachi, F. M. Cordero, A. Goti, Chem. Rev. 2003, 103,
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Int. Ed. 2006, 45, 2446–2449; g) B. H. Oh, I. Nakamura,
S. Saito, Y. Yamamoto, Tetrahedron Lett. 2001, 42,
6203–6205.
Experimental Section
General Remarks
Commercially available compounds, including ligands L1
and L3 were used as supplied. L2 and L4 were prepared ac-
cording to published procedures.[2c] Solvents for chromatog-
raphy were technical grade and distilled prior to use. All re-
actions were conducted in dry solvents under an argon at-
mosphere unless otherwise stated. The reactions were fol-
lowed by silica gel TLC and by GC-MS using the Agilent
Technologies 6890N, Network GC System, equipped with
the Agilent 190915–433 column and the Agilent 5973 Inert
Mass Selective Detector in electron impact or chemical ioni-
[2] a) A. Delgado, J. R. Rodríguez, L. Castedo, J. L. Mas-
careÇas, J. Am. Chem. Soc. 2003, 125, 9282–9283; b) F.
López, A. Delgado, J. R. Rodríguez, L. Castedo, J. L.
MascareÇas, J. Am. Chem. Soc. 2004, 126, 10262–
10263; c) J. Durµn, M. Gulías, L. Castedo, J. L. Mascar-
eÇas, Org. Lett. 2005, 7, 5693–5696.
[3] M. Gulías, R. García, A. Delgado, L. Castedo, J. L.
MascareÇas J. Am. Chem. Soc. 2006, 128, 384–385.
[4] When the reaction is carried out with a substrate con-
taining an (EtO2C)2C unit in the tether, instead of the
NBn group, we obtained a complex mixture containing
cycloadducts and cycloisomerization products, which
could not be separated by chromatography.
1
zation mode (with methane). H and 13C NMR spectra were
recorded in CDCl3, on Bruker 250 MHz, Varian 300 and
Bruker 500 MHz spectrometers. 31P NMR spectra were re-
corded in CDCl3 at 121 MHz using an internal phosphoric
acid standard. Data of known compounds were in agree-
ment with literature data, while the new compounds were
characterized.
[5] For selected recent examples of metal-catalyzed reac-
tions with allenes, see: a) B. Alcaide, P. Almendros,
Eur. J. Org. Chem. 2004, 3377–3383; b) K. M. Brum-
mond, H. Chen, B. Mitasev, A. D. Casarez, Org. Lett.
2004, 6, 2161–2163; c) T. Shibata, S. Kadowaki, K.
Takagi, Organometallics 2004, 23, 4116–4120; d) K. M.
Brummond, B. Mitasev, Org. Lett. 2004, 6, 2245–2248;
e) P. A. Wender, M. Fuji, C. O. Husfeld, J. A. Love,
Org. Lett. 1999, 1, 137–139; f) H. A. Wegner, A. de
Meijere, P. A. Wender, J. Am. Chem. Soc. 2005, 127,
6530–6531; g) J. Barluenga, R. Vicente, P. Barrio, L. A.
López, M. Tomµs, J. Am. Chem. Soc. 2004, 126, 5974–
5975.
General Procedure for the Cycloaddition
To
a Schlenk tube containing deoxygenated dioxane
(3.6 mL) – obtained by three short vacuum-argon cycles –
Pd2dba3 (3.3 mg, 3.6 mmol), L1 (6.0 mg, 9.4 mmol) and the
substrate 4a (100 mg, 0.36 mmol) were added, deoxygenat-
ing the mixture after the addition of every component. The
reaction mixture was heated under reflux, cooled to room
temperature and filtered through a short pad of silica gel,
eluting with EtOAc/hexanes (10%). The filtrate was con-
centrated and purified by flash chromatography (1%
EtOAc/hexanes) to afford 5a (yield: 65 mg, 65%) and 6a
(yield: 22 mg, 22%).[7]
[6] On page 132 of the review in ref.[1a] there is a comment
suggesting that the intermolecular reaction between
methylenecyclopropane and allene gives the [3+2] cy-
cloadduct, but in very poor yields. In any case we are
not aware of the publication of these results.
Acknowledgements
[7] See Supporting Information for details.
This work was supported by the Spanish Ministry of Educa-
tion and Science (SAF2004–01044). F.L and B.T. thank the
Spanish M.E.C. for a Ramón y Cajal contract and a FPU
predoctoral fellowship, respectively. M.G. thanks the Xunta
de Galicia for a predoctoral grant. We thank Jonhson Mat-
they for the generous gift of Pd2dba3.
[8] Compound 7a could not be obtained from 5a or 6a by
simple heating or by treatment with acids (i.e., p-
TsOH, toluene, reflux).
[9] B. L. Feringa, Acc. Chem. Res. 2000, 33, 346–353.
[10] Reactions were carried out with 2 mol% Pd2dba3 for
practical reasons and to induce faster cycloaddition
process so that the isomerization of the products to 7b
can be minimized.
[11] There are numerous and powerful catalytic methods to
obtain enantiomerically rich allenyl precursors. For an
excellent recent example, see: B. M. Trost, D. R. Fan-
drick, D. C. Dinh, J. Am. Chem. Soc. 2005, 127, 14186–
14187.
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2381 – 2384