Rhodium-catalysed linear-selective alkyne hydroacylation

Article abstract of DOI:10.1039/c2cc32713a

The use of the electron-rich diphosphine ligand, dcpe, allows the efficient and highly linear selective hydroacylative coupling of aldehydes, including aryl examples, with a range of alkynes.

Full text of DOI:10.1039/c2cc32713a

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COMMUNICATION
Rhodium-catalysed linear-selective alkyne hydroacylationw
Sarah-Jane Poingdestre,a Jonathan D. Goodacre,b Andrew S. Wellera and
Michael C. Willis*a
Received 17th April 2012, Accepted 3rd May 2012
DOI: 10.1039/c2cc32713a
The use of the electron-rich diphosphine ligand, dcpe, allows the
efficient and highly linear selective hydroacylative coupling of
aldehydes, including aryl examples, with a range of alkynes.
Table 1 Ligand effects on the regioselectivity of the Rh-catalysed
hydroacylation reaction of aldehyde 1a and alkyne 2aa
The recent advances in transition-metal catalysed alkene and
alkyne hydroacylation have led it to become an attractive
process for the synthesis of ketones and related compounds.1
The continuing development of new catalysts,2 and strategies,3
mean this atom economic methodology can now employ
readily available starting materials, and low catalyst loadings,
to provide access to a broad range of functionalised products.3
The issue of regioselectivity in hydroacylation reactions is one
area which is still relatively unexplored. Linear selectivity represents
the most common pathway for intermolecular hydroacylation, and
although recent years have seen the development of branched-
selective processes, these are typically restricted by the need for a
specific substrate type. For example, Suemune et al.3a,4 and Dong
et al.5 have utilised chelating alkenes to achieve branched-selectivity;
Bolm et al. have achieved branch-selective reactions by the use of
enamide substrates;6 Jun et al. have delivered a branched-selective
process using a Rh/picoline co-catalytic system, provided that aryl
aldehydes and terminal alkyl alkynes are employed;7 and Krische
et al.2d and Ryu et al.2c have both been able to obtain high levels of
branched-selectivity for the hydroacylation of diene substrates.
Examples in which one set of substrates can be converted into
either the linear or branched adduct by the choice of an appropriate
catalyst are very limited.8
Entry
Ligand
Conversionb
3a : 4ab
1
dppe
DPEphos
100%
80%
2 : 1
3.8 : 1
1.1 : 1
1 : >20
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
2c
3d
4
DPEphos
100%
100%
100%
100%
100%
100%
98%
o-iPr-dppe (5a)
dcpm
dcpe
5
6
7
dcpe (5 mol%)
dcpe (2.5 mol%)
dcpe (1 mol%)
8
9e
a
Conditions: aldehyde 1a (0.30 mmol), alkyne (0.45 mmol),
[Rh(nbd)2]BF4 (10 mol%), ligand (10 mol%), acetone, (2 mL,
0.15 M), RT, 2 h. nbd = norbornadiene. Determined by 1H NMR
b
c
analysis of crude reaction mixtures. Reaction performed at 50 1C for
18 h. Reaction performed in 1,2-DCE at 70 1C for 18 h. Reaction
performed at 0.3 M.
d
e
deficient alkynes, particularly in combination with synthetically
useful aryl aldehydes (for example, see Table 1, entry 1). In
this Communication we demonstrate that the use of a catalyst
incorporating the electron-rich diphosphine ligand, dcpe, allows for
efficient linear-selective alkyne hydroacylation reactions between a
wide range of aldehydes and alkynes, including aryl aldehydes and
electron-poor alkynes. The identification of this catalyst system
means that we can now achieve a catalyst dependent regioselectivity
switch across a broad range of substrates (Scheme 1).
Throughout our work employing b-S-substituted aldehydes in
chelation-controlled intermolecular alkene and alkyne hydroacyla-
tion reactions, we have observed almost exclusive selectivity for the
linear regioisomers.9,10 We recently reported the branched-selective
Rh-catalysed hydroacylation of a range of aldehydes and electron-
poor alkynes using an o-iPr-dppe derived catalyst system.11 We
were, however, surprised to discover that with the use of typically
linear-selective ligands such as dppe and DPEphos, it was in fact
very difficult to obtain linear-selectivity with these electron
a Department of Chemistry, University of Oxford, Chemistry Research
Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
E-mail: michael.willis@chem.ox.ac.uk; Fax: 44 1865 285002;
Tel: 44 1865 285126
b EpiNova DPU, Immuno-Inflammation TAU, GlaxoSmithKline,
Medicines Research Centre, Gunnels Wood Road, Stevenage,
SG1 2NY, UK
w Electronic Supplementary Information (ESI) available: Experi-
mental procedures and data for new compounds. See DOI: 10.1039/
c2cc32713a
Scheme 1 Catalyst-controlled regioselective alkyne hydroacylation
reactions.
c
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To explore the effects of ligand structure on the regioselectivity
of alkyne hydroacylation we chose to study the union of aryl
aldehyde 1a and electron-deficient alkyne 2a. Entry 1 confirms
our earlier findings and demonstrates that use of ‘traditional’
hydroacylation ligands such as the ethylene-bridged dppe,9a–c
results in very little control of regioselectivity, with only a
slight bias for the linear isomer being observed. In order to
achieve good conversion when using the ligand DPEPhos, also
an established hydroacylation ligand,9d,e in place of dppe, it
was necessary to increase the reaction temperature to 50 1C;
this resulted in a 3.8 : 1 linear-selective reaction (entry 2).
Surprisingly, by changing the reaction solvent to 1,2-DCE
(from acetone) and increasing the temperature to 70 1C, a
complete loss in selectivity was observed (entry 3). As we
have previously reported, the introduction of a bulky ortho-
substituent onto the phenyl rings of the diphosphine ligand
(5a), resulted in a dramatic increase in selectivity in favour of
the branched isomer 4a (entry 4).11 Pleasingly, the commercially
available electron-rich cyclohexyl-substituted diphosphine ligands
dcpm and dcpe gave excellent selectivities of >20 : 1 for the linear
isomer (entries 5–8). Additionally, by increasing the concentration
to 0.3 M we were able to significantly reduce the catalyst loading
to only 1 mol% (entry 9). Due to its structural similarity to the
branched-selective ligand 5a, we decided to proceed with dcpe for
further studies.
Table 2 Scope of the intermolecular linear-selective hydroacylation
employing aldehyde 1a with various substituted alkynesa
Entry
1
Alkyne
Product
Regioselectivityb
>20 : 1
Yieldc
93%
3a
2
3
3b
3c
>20 : 1
>20 : 1
83%
91%
4
5
3d
3e
>20 : 1
>20 : 1
93%
91%
Following the establishment of a linear-selective catalyst
system, we next explored the substrate scope of the reaction.
Table 2 documents the generality of the reaction in terms of
the alkyne component. Pleasingly, a range of previously
challenging substrates, electron-deficient aryl alkynes, delivered
the linear adducts with excellent selectivities and isolated yields
(entries 1–7). Entries 3–6 show that it is possible to incorporate
halide-substituents into the alkyne component, which allows for
further functionalisation, such as by SNAr or metal-catalysed
cross coupling processes. Nitro-substituted alkyne (entry 8)
showed a slight decrease in reactivity and a relatively modest
linear: branched selectivity of 7 : 1. However, we were also able
to employ an electron-rich heteroaromatic alkyne and the
simple alkyne, 1-hexyne, with regioselectivities of >20: 1 and
16: 1, respectively (entries 9 and 10).
6
7
3f
>20 : 1
93%
3g
3h
>20 : 1
7 : 1
88%
67%
8
9
3i
3j
>20 : 1
16 : 1
96%
84%
10
a
Conditions: aldehyde 1a (0.30 mmol), alkyne (0.45 mmol),
[Rh(nbd)2]BF4 (5 mol%), dcpe (5 mol%), acetone, (2 mL, 0.15 M),
RT, 1–2.5 h. Determined by 1H NMR analysis of crude reaction
c
mixtures. Yields of isolated products.
b
We next explored the variation in the aldehyde component
using electron-poor alkyne 2a as the common alkyne. A variety
of both electron-rich and electron-poor aromatic aldehydes
delivered the linear enone products with good to excellent
yields and very high selectivities (Table 3, entries 1–5). Electron-
rich aldehydes (entries 1 and 2) are excellent substrates for the
reaction, and the unusual di-methylthio substituted aryl aldehyde
also gave a high yield of the linear adduct (entry 3). Entries 4
and 5 show the tolerance for electron-deficient substituents
on the aromatic ring. Although the 6-chloro substituted
aldehyde required slightly elevated temperatures and a longer
reaction time, the incorporation of a halide at this position
provides the opportunity for further functionalisation (entry 5).
Again, previously the combination of aryl aldehydes and
electron-poor alkynes had proved impossible to achieve with
high linear-regioselectivity. The b-enals employed in entries 6–8
performed equally well, allowing access to synthetically interesting
bis-enones 3p–3r. Notably, it is the first time we have utilised
the 7-membered carbocyclic and dihydropyran-derived aldehydes
in hydroacylation. Finally, entries 9–11 demonstrate the high
reactivity of a range of substituted alkyl aldehydes, whilst
maintaining excellent selectivities. The ability to tolerate
c
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Table 3 Scope of the intermolecular linear-selective hydroacylation
employing alkyne 2a with various b-S-aldehydesa
an a-substituent (entry 10) enables the possibility for the
development of an asymmetric process.12
In conclusion, we have demonstrated a highly linear-selective
alkyne hydroacylation process. Using a dcpe-derived catalyst it is
possible to obtain excellent yields and regioselectivities for a range
of electron-rich and electron-poor aromatic aldehydes, in addition
to alkyl aldehydes and synthetically interesting enal substrates.
Excellent reactivity and selectivity is also observed for a range
of electron-deficient aromatic alkynes, as well as more electron-
rich examples. This methodology, in combination with our
previously reported branch-selective chemistry, allows ligand-
controlled regioselectivity switching across a broad range of
substrate combinations.
Entry
1
Aldehyde
Product
Regioselectivityb
>20 : 1
Yieldc
82%
3k
Notes and references
1 (a) M. C. Willis, Chem. Rev., 2010, 110, 725; (b) C. Jun, E. Jo, C.-H.
Jun, E.-A. Jo and J.-W. Park, Eur. J. Org. Chem., 2007, 1869.
2 Recent examples: (a) A. H. Roy, C. P. Lenges and M. Brookhart, J. Am.
Chem. Soc., 2007, 129, 2082; (b) S. Omura, T. Fukuyama, J. Horiguchi,
Y. Murakami and I. Ryu, J. Am. Chem. Soc., 2008, 130, 14094;
(c) F. Shibahara, J. F. Bower and M. J. Krische, J. Am. Chem. Soc.,
2008, 130, 14120; (d) V. M. Williams, J. C. Leung, R. L. Patman and
M. J. Krische, Tetrahedron, 2009, 65, 5024; (e) A. B. Chaplin, J. F.
Hooper, A. S. Weller, M. C. Willis and M. C. , J. Am. Chem. Soc., 2012,
134, 4885.
3 Recent examples: (a) M. Imai, M. Tanaka, K. Tanaka,
Y. Yamamoto, N. Imai-Ogata, M. Shimowatari, S. Nagumo,
N. Kawahara and H. Suemune, J. Org. Chem., 2004, 69, 1144;
(b) T. Tanaka, M. Tanaka and H. Suemune, Tetrahedron Lett.,
2005, 46, 6053; (c) K. Tanaka, Y. Shibata, T. Suda, Y. Hagiwara
and M. Hirano, Org. Lett., 2007, 9, 1215.
4 Y. Inui, M. Tanaka, M. Imai, K. Tanaka and H. Suemune, Chem.
Pharm. Bull., 2009, 57, 1158.
5 M. C. Coulter, K. G. M. Kou, B. Galligan and V. M. Dong, J. Am.
Chem. Soc., 2010, 132, 16330.
6 H.-J. Zhang and C. Bolm, Org. Lett., 2011, 13, 3900.
7 C.-H. Jun, H. Lee, J.-B. Hong and B.-I. Kwon, Angew. Chem., Int. Ed.,
2002, 41, 2146.
8 Dong has described a ligand-controlled branched to linear switch
for a single substrate employed in an intramolecular Rh-catalysed
alkene hydroacylation: M. M. Coulter, P. K. Dornan and
V. M. Dong, J. Am. Chem. Soc., 2009, 131, 6932.
2
3l
>20 : 1
73%
3
3m
3n
3o
3p
3q
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
70%
94%
78%
85%
63%
4
5d
6
7
9 (a) M. C. Willis, S. J. McNally and P. J. Beswick, Angew. Chem., Int.
Ed., 2004, 43, 340; (b) M. C. Willis, H. E. Randell-Sly, R. L. Woodward
and G. S. Currie, Org. Lett., 2005, 7, 2249; (c) M. C. Willis,
H. E. Randell-Sly, R. L. Woodward, S. J. McNally and G. S. Currie,
J. Org. Chem., 2006, 71, 5291; (d) G. L. Moxham, H. E. Randell-Sly,
S. K. Brayshaw, R. L. Woodward, A. S. Weller and M. C. Willis,
Angew. Chem., Int. Ed., 2006, 45, 7618; (e) G. L. Moxham,
H. E. Randell-Sly, S. K. Brayshaw, A. S. Weller and M. C. Willis,
Chem.–Eur. J., 2008, 14, 8383; (f) J. D. Osborne and M. C. Willis, Chem.
Commun., 2008, 5025; (g) H. E. Randell-Sly, J. D. Osborne,
R. L. Woodward, G. S. Currie and M. C. Willis, Tetrahedron, 2009,
65, 5110; (h) R. J. Pawley, G. L. Moxham, R. Dallanegra,
A. B. Chaplin, S. K. Brayshaw, A. S. Weller and M. C. Willis,
Organometallics, 2010, 29, 1717; (i) P. Lenden, D. A. Entwistle and
M. C. Willis, Angew. Chem., Int. Ed., 2011, 50, 10657; (j) S. R. Parsons,
J. F. Hooper and M. C. Willis, Org. Lett., 2011, 13, 998; (k) P. Lenden,
8
3r
3s
>20 : 1
>20 : 1
84%
9e
80%f
10
3t
>20 : 1
>20 : 1
54%
74%
11
3u
P. M. Ylioja, C. Gonzalez-Rodrıguez, D. A. Entwistle and M. C. Willis,
´ ´
Green Chem., 2011, 13, 1980.
10 Specific substrate combinations lead to branched products: vinyl-
sulfone,9a diene,9a nitrile-substituted alkyne9c.
11 C. Gonzalez-Rodriguez, R. J. Pawley, A. B. Chaplin, A. L. Thompson,
A. S. Weller and M. C. Willis, Angew. Chem., Int. Ed., 2011, 50, 5134.
a
Conditions: aldehyde 1a (0.30 mmol), alkyne (0.45 mmol),
[Rh(nbd)2]BF4 (5 mol%), dcpe (5 mol%), acetone, (2 mL, 0.15 M),
RT, 1–2.5 h. Determined by 1H NMR analysis of crude reaction
b
c
d
mixtures. Yields of isolated products. Reaction carried out at 50 1C
for 18 h. Aldehyde used as a 9 : 1 mixture of anti:syn diastereomers.
e
12 (a) C. Gonza
M. C. Willis, Chem.–Eur. J., 2010, 16, 10950; (b) C. Gonza
Rodrıguez and M. C. Willis, Pure Appl. Chem., 2011, 83, 577.
´
lez-Rodrı
´
guez, S. R. Parsons, A. L. Thompson and
f
´
lez-
Obtained as a 9 : 1 mixture of anti:syn diastereomers.
´
c
This journal is The Royal Society of Chemistry 2012
6356 Chem. Commun., 2012, 48, 6354–6356