Palladium-catalyzed hydroalkynylation of alkylidenecyclopropanes

Article abstract of DOI:10.1002/chem.200901821

"Chemical Equation Presented" Halogen-free C-C coupling: Catalytic amounts of [Pd₂(dba)₃] (dba= dibenzylideneacetone) and a sterically encumbered phosphite (L1) promote the addition of C-H bonds of terminal alkynes (2) to alkylidenec

Full text of DOI:10.1002/chem.200901821

DOI: 10.1002/chem.200901821
Palladium-Catalyzed Hydroalkynylation of Alkylidenecyclopropanes
Lara Villarino,[a] Fernando Lꢀpez,*[b] Luis Castedo,[a] and Josꢁ L. MascareÇas*[a]
À
The transition-metal-catalyzed addition of C H bonds
enynes. We also report some mechanistic data, and demon-
strate that the presence of a coordinating heteroatom in the
cyclopropylidene substrate allows complete control of the
regioselectivity of the process.
Alkylidenecyclopropanes (ACPs) are strained but readily
accessible molecules that have proven very useful in the de-
velopment of new synthetic methodologies.[11] In particular,
the presence of a strained ring attached to a coordinating
double bond has allowed the development of a variety of
novel transition-metal-catalyzed rearrangements as well as
[3+n+(m)] cycloaddition processes[12–15] Relevant to the
current work are the Pd-catalyzed hydrofunctionalizations
of ACPs (Scheme 1), mostly developed by Yamamoto and
À
across carbon carbon multiple bonds is a transformation of
high interest due to its potential to increase, in an atom-eco-
nomical manner, the structural complexity of readily avail-
able molecules.[1] While most efforts have been devoted to
À
the addition of C H bonds of arenes to unsaturated
[2]
À
carbon carbon bonds (hydroarylation reactions), the tran-
À
sition-metal-catalyzed addition of other C H bonds, such as
the sp-C H bond of terminal alkynes (hydroalkynylation re-
action), has only received attention in recent years.
À
À
Most processes reported thus far involve a sp-C H bond
activation and its subsequent addition to the same or anoth-
er alkyne molecules (homo- or cross-hydroalkynylations).[3,4]
Catalysts able to promote hydroalkynylations of unsaturated
molecules other than alkynes are still quite rare.[5–10] Usually,
À
in these cases, very reactive C C double bonds such as
those of allenes, enones, or strained cyclic alkenes are re-
quired.[5–7] Indeed, the first examples involving less reactive
alkenes have only been reported very recently, and were
achieved by using Ni catalysts.[8,9]
One of these reports deals with a nickel-catalyzed hydro-
alkynylation of methylenecyclopropanes with trisopropylsi-
lylacetylene,[9] a reaction that provides cyclopropane deriva-
tives. While the transformation is of undoubted synthetic in-
terest, related processes in which the hydroalkynylation re-
action is accompanied by opening of the cyclopropyl ring
might be even more appealing.
Herein, we report the discovery of a palladium-catalyzed
intermolecular hydroalkynylation of alkynylidenecyclopro-
panes, a reaction that provides an entry to a variety of 1,4-
Scheme 1. Previous Pd-catalyzed hydrofunctionalizations of ACPs with
different pronucleophiles.[16]
co-workers.[16] These reactions, which generally lead to allyl-
ic derivatives, have been reported to proceed with several
types of pronucleophiles such as amides, alcohols, heteroaro-
matic rings (i.e. furans), and malonates. In most cases the re-
action requires relatively stringent conditions: high tempera-
tures, long reaction times, and high concentration of reac-
tants.
Our research on this topic began when exploring the fea-
sibility of performing selective Pd-catalyzed [3C+2C] inter-
molecular cycloadditions between the 2-pyridyl derivative
1a and ethynyltrimethylsilane (2a, Scheme 2). We designed
ACP 1a expecting that a hypothetical coordination of the
Pd complex to the nitrogen atom of the pyridine could
direct the oxidative insertion into the cyclopropane ring,
and thereby provide a regioselective [3C+2C] cycloaddition
to the alkyne.[17] Surprisingly, when a mixture of 1a and 2a
was treated under conditions previously shown to be effec-
[a] L. Villarino, Prof. Dr. L. Castedo, Prof. Dr. J. L. MascareÇas
Departamento de Quꢀmica Orgꢁnica
Universidade de Santiago de Compostela
Avda. de las Ciencias, s/n, 15782, Santiago de Compostela (Spain)
E-mail: joseluis.mascarenas@usc.es
[b] Dr. F. Lꢂpez
Instituto de Quꢀmica Orgꢁnica General, CSIC
Juan de la Cierva, 3, 28006, Madrid (Spain)
E-mail: fernando.lopez@iqog.csic.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901821.
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COMMUNICATION
Table 1. Pd-catalyzed hydroalkynylations of 1a with different terminal
alkynes.
Entry
Alkyne, 2
R
Product, 3
Yield [%][b]
1
2
3
4
2a
2b
2c
2d
TMS
TIPS
nBu
tBu
3aa
3ab
3ac
3ad
55
51
52
41
Scheme 2. Hydroalkynylation of 1a.
5
6
2e
2 f
3ae
3af
44
65
tive for the Pd-catalyzed cycloaddition of alk-5-ynylidenecy-
clopropanes,[13j–l] instead of the [3C+2C] cycloadducts, we
isolated the 1,4-enyne 3aa in 55% yield.
Ph
[a] Reactions carried out with [Pd2ACHTNUGTRENUNG(dba)3] (6 mol%), L1 (20 mol%), 1a
This result led us to analyze the performance of other
metal complexes previously shown to be effective in either
the hydrofunctionalization of ACPs,[9,16] or in Pd-catalyzed
(1 equiv), and 2a–f (2.5 equiv) in refluxing dioxane for 3 h. [b] Yield of
isolated product.
À
hydroalkynylations of different unsaturated C C bonds.
However, the formation of enyne 3aa was not observed
when the reaction was performed with Pd
tion with ethynyltrimethylsilane (2a), in addition to provid-
ing the expected 1,4-enyne 3ba, gave its isomer 4ba and a
small proportion of 5ba (6:3:1). Isomers 3ba and 4ba could
be isolated from the mixture in an excellent combined yield
of 89%.[19] The different outcomes for 1a and 1b must be
attributed to the presence of the nitrogen atom in the 2-po-
sition of the aryl group in 1a, since the reaction of related 3-
and 4-pyridyl derivatives 1c and 1d led to mixtures of
enynes 3–5 in comparable ratios to those obtained from
phenyl derivative 1b (Table 2, entries 2 and 3).
ACHTUNGRTENUN(NG OAc)2/TDMPP
(TDMPP=tri(2,6-dimethoxyphenyl)phosphane),[4b]
Pd-
ACHTUNGTRENNUNG
(OAc)2/dppe (dppe=bis(diphenylphoshanyl)ethane),[4e] or
[6a,16]
Pd
(OAc)2/P
N
Instead, the homo-alkynylated
dimer 6a and/or the 1,3-diene 7a,[18] itself arising from a Pd-
catalyzed rearrangement of 1a (vide infra), were observed
in the crude reaction mixtures, together with unreacted 1a.
Using [PdACHTUNGTRENNUNG(PPh3)4], or a mixture of [PdCAHTUGNTREN(NUGN PPh3)4] (5 mol%)
and P(O)Bu3 (10 mol%), catalysts previously reported for
the hydrofunctionalization of ACPs with amines and hetero-
aromatic pronucleophiles such as furans,[16b,d,f,g,i] we only ob-
served the formation of traces of product 3aa. Low reaction
rates, scarce reproducibility, and the competitive formation
of conjugated diene 7a led us to discard these catalysts for
the current process. On the other hand, Ni catalysts recently
employed in the hydroalkynylation of conjugated dienes[8]
and methylenecyclopropanes,[9] failed to catalyze the ring
opening-coupling process, and mainly led to unreacted 1a
and homodimeric product 6a.[18] Therefore, the choice of the
transition metal (Pd vs. Ni) as well as the nature of the
ligand seems to play an essential role in the current hydroal-
kynylation reaction; the combination leading to the best re-
sults being the bulky triarylphosphite ligand L1 and tris(di-
Table 2. Pd-catalyzed hydroalkynylations of 1b–e.[a]
Entry Ar (1)
R (2)
3:4:5 (ratio)[b] Yield 3+4 [%][c]
1
2
3
4
5
6
7
8
Ph (1b)
TMS (2a) ba (58:32:10) 89
3-pyridyl (1c)
4-pyridyl (1d)
Ph (1b)
Ph (1b)
Ph (1b)
TMS (2a) ca (40:44:16)
TMS (2a) da (62:30:8)
TIPS (2b) bb (47:53:0)
81
33
60
57
42
82
50
tBu (2d)
C6H9 (2e) be (54:46:0)
Ph (2 f) bf (38:46:16)
bd (55:36:9)
Ph (1b)
benzylideneacetone)dipalladium ([Pd
N
p-NO2C6H4 (1e) TMS (2a) ea (88:9:3)
With these conditions in hand, we next analyzed the
scope of the new hydroalkynylation process using 1a as the
alkylidene coupling partner. As can be seen in Table 1, the
reaction can be performed with different terminal alkynes,
affording the corresponding 1,4-enynes (3aa–3af) in moder-
ate to good yields. Interestingly, in contrast to the previous
Ni-promoted alkynylations,[8,9] the presence of a bulky silyl
group at the alkyne terminus (Table 1, entries 1 and 2) is not
strictly required for the success of the process. Thus, both
linear and branched aliphatic groups (Table 1, entries 3–5),
as well as aromatic substituents are tolerated; the corre-
sponding products are obtained in comparable yields.
[a] Reactions carried out with [Pd
(dba)3] (6 mol%), L1 (20 mol%), 1a
(1 equiv), and 2 (2.5 equiv) in refluxing dioxane for 3 h. [b] Based on
1H NMR spectra of the crude reaction mixtures.[c] Isolated combined
yield of 3 and 4.[19]
Other alkynes, such as 2b–f, also participated in the hy-
droalkynylation of 1b, preferentially providing enynes 3 and
4 (Table 2, entries 4–8). The electronic characteristics of the
phenyl group might partially influence the regioselectivity,
as the reaction with the p-nitro derivative 1e afforded a
major proportion of isomer 3 (Table 2, entry 8).
Curiously, use of (cyclopropylidenemethyl)benzene (1b)
instead of the pyridine derivative 1a, in the coupling reac-
A potential mechanism that explains the formation of 1,4-
enynes of type 3, is shown in Scheme 3. The reaction path-
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F. Lꢂpez, J. L. MascareÇas et al.
À
bond. Thus, the insertion of the ACP into the Pd H bond is
most likely irreversible, as well as completely regioselective.
The formation of regioisomeric enynes of type 4 (and the
minor isomers 5), when ACPs other than 1a are employed,
is more difficult to explain. Hypothetically, these enynes
could arise from an in situ isomerization of 3 through a hy-
dropalladation/b-hydride elimination sequence, promoted by
a Pd–hydride species. However, treatment of a mixture of
3bf and 4bf (ratio=62:38) with [Pd2ACTHNUGTRNE(UNG dba)3] (6%), L1
(20%), and 2a (2.5 equiv) in refluxing dioxane did not pro-
mote any modification of the initial isomeric ratios, making
quite unlikely such an isomerization pathway. The formation
of isomer 4 could be explained in terms of a hypothetical
isomerization of the p-allyl–Pd species of type C to C’
(Scheme 5),[21] albeit other alternatives cannot be discarded.
Scheme 3. Plausible mechanism for the formation of product 3. Diene 7a
was observed in the reactions of 1a and 2a with Pd(OAc)2/TDMPP or
AHCTUNGTRENNUNG
with other related catalysts (vide supra and Supporting Information).
way probably involves an initial oxidative addition of the sp-
0
À
C H bond of the terminal alkyne to the Pd catalyst, leading
to the generation of a (hydro)
(alkynyl)palladium(II) inter-
À
mediate A. Insertion of the ACP into the Pd H bond gener-
ates intermediate B, which might undergo a b-carboelimina-
tion with concomitant distal opening of the cyclopropane
ring to afford a p-allyl–Pd species of type C. A final reduc-
tive elimination provides the 1,4-enyne 3, with regeneration
of the Pd0 catalysts. The detection of alkyne homodimeriza-
tion products such as 6a as minor components in the crude
reaction mixtures, is consistent with the participation
Scheme 5. Mechanistic hypotheses.
In the case of the 2-pyridyl derivative 1a, such an isomeriza-
tion process is probably prevented by the coordination of
the pyridine nitrogen atom to the Pd center, which facili-
tates the accumulation of a s-complex like E, which upon
reductive elimination would provide 3, the only isomer ob-
served.
(hydro)
As discussed above, in presence of Pd reagents other than
[Pd2A(dba)3]/L1, we observed, the formation of minor
ACHTUNGTRENNUNG
(alkynyl)metal intermediate A.[20]
CHTUNGTRENNUNG
amounts of diene 7a, in the hydroalkynylation of 1a with
2a. This product might arise from the regioisomeric hydro-
metallation intermediate B’, which could evolve through a
b-carboelimination followed by b-hydride elimination.
Consistent with the mechanistic proposal, when deuterat-
ed phenylacetylene ([D]-2 f) was allowed to react with 1a,
the monodeuterated product [D]-3af, in which the deuteri-
um isotope is only incorporated at the C-5 position (deute-
rium content> 95%), was obtained (Scheme 4). Moreover,
when the same reaction was not allowed to reach full con-
version (reaction time of 1 h), the recovered ACP (1a) did
not show any incorporation of deuterium into the double
The obvious relevance of the 2-pyridyl nitrogen in con-
trolling the regioselectivity of the hydroalkynylation process
suggested that other cyclopropane substrates containing
topologically comparable heteroatoms might provide similar
outcomes. In particular, we considered assessing the perfor-
mance of easily accessible ACP 1 f, which features a carbox-
ylate substituent as a potential directing group.[1–2] In the
event of a successful reaction the synthetic scope of the
methodology would be considerably expanded owing to the
versatility of the ester functional group.
Gratifyingly, the reaction of 1 f with ethynyltrimethylsi-
lane (2a), in the presence of catalytic amounts of ligand L1
and [Pd2ACTHNUGTRNE(UNG dba)3], proceeded very efficiently, exclusively pro-
viding the desired enyne 3 fa in 63% yield (Scheme 6). The
reaction can be extended to other alkynes so that a variety
of enynes (3 fa–3 ff) could be obtained in good yields. Nota-
bly, a,b-unsaturated regioisomers of type 4, or enynes of
type 5, were never detected in the crude mixtures (or after
flash chromatography on silica gel), confirming the directing
effect of the carboxylate of 1 f.
In summary, we have shown that a Pd0 catalyst generated
from [Pd2ACHTNUGRTENUNG(dba)3] and a sterically encumbered phosphite
Scheme 4. Hydroalkynylation of 1a with deutarated phenylacetilene [D]-
2 f.
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Hydroalkynylation of Alkylidenecyclopropanes
COMMUNICATION
À
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Scheme 6. Hydroalkynylation of 1 f with several terminal alkynes.
ligand (L1) is capable of promoting a tandem ring-opening
coupling process involving terminal alkynes and alkylidene-
cyclopropanes. Importantly, we have demonstrated that the
presence of an appropriate directing group, such as a 2-pyr-
idyl unit or a carboxylate moiety, leads to a regioselective
hydroalkynylation, most probably due to a direct coordina-
tion of the sp2-heteroatom to the palladium catalyst. Cres-
À
cent interest in C H activation chemistry of alkynes and in
À
atom-economical C C coupling reactions between partners
lacking heteroatom groups at the coupling positions, war-
rants further studies to increase the efficiency and potential
of the described chemistry.
Experimental Section
Procedure for the Pd-catalyzed hydroalkynylations of 1a with 2a–f (ex-
emplified for 1a and 2a): [Pd2ACTHNUTRGNE(NUG dba)3] (21.0 mg, 6%) and phosphite L1
(50.0 mg, 20%) were mixed in a dried Schlenk tube under argon. Diox-
ane (3 mL) was added and the solution was deoxygenated (three
vacuum–argon cycles) and stirred for 5 min at room temperature. A solu-
tion of 1a (50 mg, 0.382 mmol) in dioxane (1 mL) was then added and
the resulting mixture was further deoxygenated (one vacuum–argon
cycle). Alkyne 2a (0.13 mL, 0.954 mmol) was added and the reaction
mixture was heated under reflux for 2.5 h, allowed to cool to room tem-
perature, diluted with Et2O (8 mL), and filtered through a short pad of
Fluorisil (elution with Et2O). The filtrate was concentrated and purified
by flash chromatography on silica gel [deactivated with 2% NEt3/hexanes
(20–30% Et2O/hexanes)] to afford 3aa as a colorless oil (47.7 mg, 55%).
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Acknowledgements
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This work was supported by the Spanish MEC [SAF2007–61015, and
Consolider-Ingenio 2010 (CSD2007–00006)], Xunta de Galicia
(GRC2006/132, PGIDIT06PXIB209126PR), CSIC and Comunidad de
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À
C C
Keywords: alkylidenecyclopropanes
·
alkynes
·
À
coupling · C H activation · palladium
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H. Takaya, J. Am. Chem. Soc. 1970, 92, 5780–5781; b) P. Binger, U.
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Nakamura, B. Ho Oh, S. Saito, Y. Yamamoto, Angew. Chem. 2001,
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Delgado, J. R. Rodrꢀguez, L. Castedo, J. L. MascareÇas, J. Am.
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Rodrꢀguez, L. Castedo, J. L. MascareÇas, J. Am. Chem. Soc. 2004,
126, 10262–10263; i) A. I. Siriwardana, I. Nakamura, Y. Yamamoto,
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[14] For examples on [3+4] cycloadditions, see: a) M. Gulꢀas, J. Durꢁn,
F. Lꢂpez, L. Castedo, J. L. MascareÇas, J. Am. Chem. Soc. 2007, 129,
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595- 598.
[17] The [3C+2C] intermolecular cycloadditon of ACPs with alkynes
has only been reported under Ni catalysis.[13c,d] However, intramolec-
ular versions, are very efficient with Pd catalysts.[13g,h,j]
[18] See Supporting Information for a list of results with other catalysts
employed.
[19] Regioisomers 3 and 4 were isolated together after standard chroma-
tography. The minor isomer of type 5 could be separated from the
mixture of 3 and 4 but it turned out to be slightly contaminated by
L1 and other very minor reaction components. Therefore, yields
refer to the mixture of the major components, 3 and 4.
[20] The reaction of 2a with [Pd2ACHTNUTRGENNUG(dba)3] (6%) and L1 (20%), in the ab-
sence of 1b, exclusively provided 1,2-enyne homodimerizations
adduct 6a [Eq. (1)]. On the other hand, treatment of 1b with [Pd2-
AHCTUNGRTEG(NUNN dba)3] (6%) and L1 (20%), in the absence of 2a, led to the recov-
ery of 1b [Eq. (2)].
[15] For examples on [3+2+2] cycloadditions, see: a) P. Binger, U.
Schuchardt, Chem. Ber. 1980, 113, 1063–1071; b) S. Saito, M.
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c) L. Zhao, A. de Meijere, Adv. Synth. Catal. 2006, 348, 2484–2492;
d) S. Komagawa, S. Saito, Angew. Chem. 2006, 118, 2506–2509;
Angew. Chem. Int. Ed. 2006, 45, 2446–2449; e) S. Saito, S. Komaga-
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f) K. Maeda, S. Saito, Tetrahedron Lett. 2007, 48, 3173–3176;
g) P. A. Inglesby, P. A. Evans, J. Am. Chem. Soc. 2008, 130, 12838–
12839; h) R. Yamasaki, I. Sotome, S. Komagawa, I. Azumaya, H.
Masu, S. Saito, Tetrahedron Lett. 2009, 50, 1143–1145.
[21] This type of isomerization process has been previously proposed in
a related hyfrofunctionalization os ACPs, see reference [16e].
[16] a) Y. Yamamoto, U. Radhakrishnan, Chem. Soc. Rev. 1999, 28, 199–
207; b) N. Tsukada, A. Shibuya, I. Nakamura, Y. Yamamoto, J. Am.
Chem. Soc. 1997, 119, 8123–8124; c) D. H. Camacho, I. Nakamura,
Received: July 1, 2009
Published online: November 10, 2009
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