Formal γ-alkynylation of ketones via Pd-catalyzed C-C cleavage

Article abstract of DOI:10.1039/c2cc37281a

A formal γ-alkynylation of ketones via Pd-catalyzed C-C bond-cleavage is presented. The method allows for the coupling of tert-cyclobutanols and bromoacetylenes, giving access to versatile alkynes that are beyond reach otherwise.

Full text of DOI:10.1039/c2cc37281a

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Formal c-alkynylation of ketones via Pd-catalyzed C–C
cleavage†‡
Cite this: Chem. Commun., 2013,
49, 4286
Asraa Ziadi, Arkaitz Correa and Ruben Martin*
Received 5th October 2012,
Accepted 29th October 2012
DOI: 10.1039/c2cc37281a
www.rsc.org/chemcomm
A formal c-alkynylation of ketones via Pd-catalyzed C–C bond- optimization, we pleasingly found that the combination of
cleavage is presented. The method allows for the coupling of Pd(OAc)2, SPhos and Cs2CO3 in toluene at 110 1C provided the best
tert-cyclobutanols and bromoacetylenes, giving access to versatile results for the desired coupling reaction, affording the g-alkynylated
alkynes that are beyond reach otherwise.
ketone 3a in 92% isolated yield. Subsequently, we found that the
coupling of the chloro- and iodoethynyl derivatives also afforded 3a,
The high chemical versatility of alkynes and their pivotal role as key but in lower yields.14 Similarly, solvents other than toluene and
synthetic intermediates in chemical biology and material sciences inorganic bases such as K2CO3, NatBuO or K3PO4 had a deleterious
have attracted the attention of organic chemists for decades.1,2 effect on the reactivity, affording 3a in much lower yields.14
Classical methods for preparing alkyne-containing compounds
Encouraged by these findings, we turned our attention to study-
involve the classical dehydrohalogenation of halogen derivatives, ing the generality of this reaction regarding the substitution pattern
alkylation of terminal alkynes, Corey–Fuchs-type reactions or on the tert-cyclobutanol backbone. The results of this investigation
Seyferth–Gilbert homologation, among others.1 Recent catalytic are summarized in Table 1. As shown, the reaction manifests a
strategies have shown their advantages over the classical methods broad substrate scope in which both aromatic and aliphatic groups
in which harsh conditions are avoided with good chemoselectivities.1 at different positions on the tert-cyclobutanol backbone gave access
Unlike the preparation of aromatic alkyne derivatives,3 the metal- to the corresponding g-alkynylated ketones in good yields. The
catalyzed installation of alkynes into functionalized aliphatic back- successful preparation of 3e highlights the greater reactivity of 2a
bones via C(sp3)–C(sp) bond-forming processes is still a remarkable as compared to aryl chlorides. Interestingly, the coupling reaction
challenge.4 Although formidable advances have been made in the was not limited to 3,3-disubstituted tert-cyclobutanols; as shown
a- and b-alkynylation of carbonyl compounds (Scheme 1),5–7 the for 3c–3e and 3j, 3-monosubstituted derivatives yielded the final
development of a general route for the catalytic g-alkynylation of products in comparable yields. Remarkably, 3,3-unsubstituted
carbonyl compounds has not yet been described.8 We wondered tert-cyclobutanols could be applicable as well (3f–3i); no competitive
whether the propensity of tert-cyclobutanols to undergo b-carbon b-hydride elimination from the initially generated C(sp3)–metal
elimination9,10 could step up the stage for a Pd-catalyzed C(sp)– species was observed in the crude reaction mixtures.15 As illustrated
C(sp3) bond-formation as a means to access g-alkynylated ketones for 3f and 3g high levels of regioselectivity were found when using
(Scheme 1, bottom), thus constituting a complementary approach to unsymmetrical tert-cyclobutanols in which the C–C bond cleavage
the well-established g-arylation processes.11 As part of our ongoing
investigations on inert bond-activation,12 we disclose our results that
demonstrate the feasibility of this hypothesis and exploit a previously
unrecognized opportunity for the catalytic coupling of tert-cyclo-
butanols and haloacetylene derivatives.
We began our investigations with 1a, readily prepared in a large
scale from commercially available starting materials,13 as the model
substrate. The effects of palladium precatalyst, ligand, base, solvent
and temperature were systematically examined. After considerable
¨
Institute of Chemical Research of Catalonia (ICIQ), Av. Paısos Catalans 16, 43007,
Tarragona, Spain. E-mail: rmartinromo@iciq.es; Tel: +34 977920248
† This article is part of the ChemComm ‘Emerging Investigators 2013’ themed issue.
‡ Electronic supplementary information (ESI) available. See DOI: 10.1039/c2cc37281a
Scheme 1 Alkynylation methods of carbonyl compounds.
c
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Table 1 Reaction scopea
or electron-deficient groups (3n). Interestingly, the coupling of ortho-
substituted and heteroaromatic alkynes could also be accomplished
in moderate to good yields under otherwise similar reaction condi-
tions (3o, 3q). However, the coupling of bromoenynes resulted in
partial decomposition, leading to 3r in low yields. Furthermore,
bromoacetylenes substituted with aliphatic backbones possessing
bulky silyl-protected ethers could be tolerated under the reaction
conditions based on Xantphos (3q). As for 3f–3i, 3,3-unsubstituted
tert-cyclobutanols could be utilized for the coupling with (bromo-
ethynyl)benzene, affording 3s in moderate yields.16 Gratifyingly, our
method was not restricted to bromoethynyl derivatives; as shown for
3t, our protocol allowed for the coupling of alkyl halides in high
yields, formally constituting a powerful catalytic manifold for
preparing g-alkylated ketones in a straightforward manner.
Entry Product
Yieldb (%)
1
2
R = Ph, 92 (3a)
R = iPr, 83 (3b)c
3
4
5
R = nHex, 88 (3c)c
R = Ph, 78 (3d)
R = 4-ClC6H4, 53 (3e)
With substantial amounts of 3a in hand, we focused our
attention on demonstrating whether our method could be
6
7
R1 = R2 = Ph, 76 (3f)
R1 = Ph, R2 = H, 69 (3g)
Table 2 Reaction scopea
8
9
R = Ph, 82 (3h)
R = CH2C(Me)2Ph, 86 (3i)
Entry
Product
Yieldb (%)
10
62 (3j)
1
2
3
R = H, 75 (3l)
R = tBu, 58 (3m)
R = CF3, 52 (3n)b
11
41 (3k)d
4
41 (3o)
a
Reaction conditions: 1 (0.35 mmol), 2a (0.52 mmol), Pd(OAc)2
(2 mol%), SPhos (4 mol%), Cs2CO3 (0.40 mmol), toluene (2 mL) at
b
110 1C. Isolated yields, average of at least two independent runs.
c
d
Pd(OAc)2 (4 mol%). Cs2CO3 (2.50 equiv.).
5
6
7
64 (3p)
61 (3q)b
35 (3r)
takes place at the less hindered position. The successful coupling of
amine derivative 1j demonstrates little Lewis acidity of our catalyst,
if any. In line with the same notion, the method allowed for the
coupling of tert-cyclobutanol derivatives possessing unprotected
primary alcohols (1k); in this particular case, 2.5 equivalents of
Cs2CO3 were required, thus yielding 3k, albeit in lower yields.16
Prompted by the precedents shown in Table 1, we hypothesized
whether the method could be extended to bromoacetylene deriva-
tives other than (bromoethynyl)triisopropylsilane. Unfortunately,
neither aromatic nor aliphatic bromoalkyne derivatives could be
coupled with 1a under the optimized reaction conditions in Table 1
based on SPhos. Indeed, not even traces of g-alkynylated ketone
could be detected by GC analysis of the crude reaction mixtures.
These results manifest the remarkable and unique reactivity of 2a
as compared to other coupling partners.6 However, after a careful
re-optimization of the reaction conditions we found that the use of
allylpalladium dimers in combination with Xantphos provided good
yields for the coupling of (bromoethynyl)benzene (Table 2, 3l).17 As
shown in entries 2 and 3, our method could be extended to other
aromatic-substituted acetylenes possessing either electron-rich (3m)
8
46 (3s)
87 (3t)c
9
a
Reaction conditions: 1 (0.50 mmol), 2 (1 mmol), [PdCl(2-Me-allyl)]2
(2.50 mol%), Xantphos (10 mol%), NatBuO (0.60 mmol), toluene (1 mL) at
80 1C; isolated yields, average of two independent runs. b 4 equivalents of
bromoacetylene were used. c Using reaction conditions in Table 1.
c
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Table 3 Synthetic applicability
The authors thank the ICIQ Foundation, the European
Research Council (ERC-277883) and MICINN (CTQ2009-13840
& CTQ2012-34054) for financial support. Johnson Matthey,
Umicore and Nippon Chemical Industrial are acknowledged
for a gift of metal and ligand sources. R.M and A.C thank
MICINN for RyC and JdC fellowships.
Notes and references
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Reaction conditions: (a) TBAF (1.1 equiv.), THF, rt, 99%; (b) (Chex)2BH,
NaBO3, THF, 58%; (c) AuCl3 (5 mol%), AgOTf (15 mol%), DCM, 99%; (d)
BnN3, Cu(OAc)2 (5 mol%), sodium ascorbate (25 mol%), tBuOH-H2O, rt,
96%; (e) BnN3, Cp*RuClCOD (2 mol%), toluene, rt, 85%.
3 For a recent review on the classical Sonogashira–Hagihara reaction,
´
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´
5 For a recent catalytic a-alkynylation event, see: D. F. Gonzalez,
Scheme 2 Enantioselective g-alkynylation of ketones.
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Table 3, this was indeed the case; the significant increase in
molecular complexity achieved by otherwise simple and reliable
transformations is quite appealing, thus giving access to struc-
tures that are difficult to obtain by other means. Notably, a
formal anti-Markovnikov hydration of alkyne 4a via a hydro-
boration–oxidation sequence18 gave synthetically-attractive
aldehyde 5a in 58% overall yield. Interestingly, cyclohexenone
8 For an isolated example, see ref. 6.
9 For selected reviews, see: T. Seiser, T. Saget, D. N. Tran and
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could easily be prepared as single regioisomers via Cu-20 or
Ru-catalyzed21 [3+2]-type cycloadditions with benzyl azide.
Despite remarkable advances in the field of C–C bond-cleavage
in recent years, particularly via b-carbon elimination pathways,9 the
development of enantioselective C–C bond cleavage approaches
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still remains a formidable challenge.22 Although a thorough inves- 12 N. Barbero and R. Martin, Org. Lett., 2012, 14, 796; P. Novak,
´
A. Correa, J. Gallardo-Donaire and R. Martin, Angew. Chem., Int.
Ed., 2011, 50, 12236; P. Alvarez-Bercedo and R. Martin, J. Am. Chem.
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tigation awaits further studies, we have preliminarily found that a
certain level of asymmetric induction can be obtained when using
DTBM-SegPhos for the coupling of 3aa and 2a (Scheme 2). While
modest, this result represents the first asymmetric route for pre-
paring g-alkynylated ketones and holds great promise for future
developments in this area.
In summary, we have developed the first route to g-alkynylated
ketones via Pd-catalyzed C–C bond-cleavage. The chosen approach is
A. Correa and R. Martin, J. Am. Chem. Soc., 2010, 132, 466;
A. Correa and R. Martin, J. Am. Chem. Soc., 2009, 131, 15974.
13 B. D. Johnson, E. Czyzewska and A. C. Oehlschlager, J. Org. Chem.,
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14 See ESI‡ for details.
15 J. F. Hartwig, Inorg. Chem., 2007, 46, 1936.
16 No byproducts other than the recovered starting material and
homocoupling of the haloacetylene derivatives were observed.
highly convergent and involves a minimum number of manipula- 17 For an example of using bidentate phosphines with bromo-
acetylenes, see: S. Nicolai and J. Waser, Org. Lett., 2011, 13, 6324.
18 G. W. Kabalka, S. Yu and N.-S. Li, Can. J. Chem., 1998, 76, 800.
19 T. Jin and Y. Yamamoto, Org. Lett., 2007, 9, 5259.
tions due to the ready availability of the starting materials. Such a
route provides a direct access to scaffolds that are beyond reach
otherwise and allows the conversion of g-alkynyl ketones into a 20 V. Rostovtsev, L. Green, V. Fokin and K. B. Sharpless, Angew. Chem.,
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21 B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang, H. Zhao, Z. Lin,
diverse array of advanced synthetic intermediates. Further investiga-
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G. Jia and V. V. Fokin, J. Am. Chem. Soc., 2008, 130, 8923.
route to g-alkynyl ketones are currently ongoing in our laboratories. 22 T. Seiser and N. Cramer, Org. Biomol. Chem., 2009, 7, 2835.
c
4288 Chem. Commun., 2013, 49, 4286--4288
This journal is The Royal Society of Chemistry 2013