O -substituted alkyl aldehydes for rhodium-catalyzed intermolecular alkyne hydroacylation: The utility of methylthiomethyl ethers

Article abstract of DOI:10.1021/ol1030662

Combining α-methylthiomethyl (MTM) ether substituted aldehydes and 1-alkynes in the presence of [Rh(dppe)]ClO₄ results in efficient intermolecular alkyne hydroacylation to deliver α-O-MTM-substituted enone products. The product MTM ethers can be converted to the free hydroxyl group either in situ, by the addition of water to the completed reaction, or in a separate operation, by the action of silver nitrate.(Figure Presented)

Full text of DOI:10.1021/ol1030662

ORGANIC
LETTERS
2011
Vol. 13, No. 5
998–1000
O-Substituted Alkyl Aldehydes for
Rhodium-Catalyzed Intermolecular Alkyne
Hydroacylation: The Utility of
Methylthiomethyl Ethers
Scott R. Parsons, Joel F. Hooper, and Michael C. Willis*
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, OX1 3TA, U.K.
michael.willis@chem.ox.ac.uk
Received December 18, 2010
ABSTRACT
Combining R-methylthiomethyl (MTM) ether substituted aldehydes and 1-alkynes in the presence of [Rh(dppe)]ClO4 results in efficient
intermolecular alkyne hydroacylation to deliver R-O-MTM-substituted enone products. The product MTM ethers can be converted to the free
hydroxyl group either in situ, by the addition of water to the completed reaction, or in a separate operation, by the action of silver nitrate.
The transition-metal-catalyzed addition of aldehydes
across alkenes or alkynes; alkene and alkyne hydroacy-
lation, respectively; are effective processes for the atom
economic preparation of ketone containing molecules.1
Intermolecular versions of these reactions are often pla-
gued by competing decarbonylation processes. Despite
significant recent advances, in particular from the groups
of Brookhart2 and Krische,3 a general intermolecular reac-
tion has yet to be described.4 One approach to achieve
efficient intermolecular reactions has been to stabilize the
key acyl-metal intermediates through chelation control.
For example, the temporary formation of picolylimines5
and the use of salicylaldehydes6 or acrylamides7 have all
delivered effective reactions.8 Our laboratory has investi-
gated the use of alkyl aldehydes in intermolecular hydro-
acylation chemistry, and we have found that β-S-sub-
stituted aldehydes work well in rhodium-catalyzed alkene
and alkyne hydroacylation reactions.9 Although chelation
control has provided a number of very useful solutions for
hydroacylation chemistry, the strategy has an inherent
limitation in that the chelating group present in the starting
materials will also be present in the products. The β-S-
substituted ketone products, generated from the corre-
sponding β-S-substituted aldehyde substrates, offer a num-
ber of opportunities for derivatization of the S-based
functional group.10 However, if the focus is to employ a
chelating group more likely to be required in the final
product, then O-based functionality becomes appealing
(1) (a) Willis, M. C. Chem. Rev. 2010, 110, 725. (b) Jun, C.-H.; Jo,
E.-A.; Park, J.-W. Eur. J. Org. Chem. 2007, 1869.
(2) (a) Lenges, C. P.; White, P. S.; Brookhart, M. J. Am. Chem. Soc.
1998, 120, 6965. (b) Roy, A. H.; Lenges, C. P.; Brookhart, M. J. Am.
Chem. Soc. 2007, 129, 2082.
(3) (a) Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc.
2008, 130, 14120. (b) Williams, V. M.; Leung, J. C.; Patman, R. L.;
Krische, M. J. Tetrahedron 2009, 65, 5024.
(4) Other nonchelating examples: (a) Schwartz, J.; Cannon, J. B.
J. Am. Chem. Soc. 1974, 96, 4721. (b) Vora, K. P.; Lochow, C. F.; Miller,
R. G. J. Organomet. Chem. 1980, 192, 257. (c) Marder, T. B.; Roe, D. C.;
Milstein, D. Organometallics 1988, 7, 1451. (d) Kondo, T.; Tsuji, Y.;
Watanabe, Y. TetrahedronLett. 1987, 28, 6229. (e)Omura, S.;Fukuyama,
T.; Horiguchi, J.; Murakami, Y.; Ryu, I. J. Am. Chem. Soc. 2008, 130,
14094.
(6) (a) Kokubo, K.; Matsumasa, K.; Nishinaka, Y.; Miura, M.;
Nomura, M. Bull. Chem. Soc. Jpn. 1999, 72, 303. (b) Imai, M.; Tanaka,
M.; Tanaka, K.; Yamamoto, Y.; Imai-Ogata, N.; Shimowatari, M.;
Nagumo, S.; Kawahara, N.; Suemune, H. J. Org. Chem. 2004, 69, 1144.
(c) Tanaka, T.; Tanaka, M.; Suemune, H. Tetrahedron Lett. 2005, 46,
6053. (d) Stemmler, R. T.; Bolm, C. Adv. Synth. Catal. 2007, 349, 1185.
(f) Coulter, M. M.; Kou, K. G. M.; Galligan, B.; Dong, V. M. J. Am.
Chem. Soc. 2010, 132, 16330. (g) Phan, D. H. T.; Kou, K. G. M.; Dong,
V. M. J. Am. Chem. Soc. 2010, 132, 16354.
(7) (a) Tanaka, K.; Shibata, Y.; Suda, T.; Hagiwara, Y.; Hirano, M.
Org. Lett. 2007, 9, 1215. (b) Shibata, Y.; Tanaka, K. J. Am. Chem. Soc.
2009, 131, 12552.
(5) (a) Jun, C.-H.; Lee, D.-Y.; Lee, H.; Hong, J.-B. Angew. Chem.,
Int. Ed. 2000, 39, 3070. (b) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc.
Chem. Res. 2008, 41, 222.
(8) (a) Suggs, J. W. J. Am. Chem. Soc. 1978, 100, 640.
r
10.1021/ol1030662
Published on Web 02/10/2011
2011 American Chemical Society

and should allow ready access to hydroxyl- and carbonyl-
based functional groups. Although salicylaldehydes (and
derivatives) have been employed successfully as hydroacy-
lation substrates,6,11 there are no examples of O-substituted
alkyl aldehydes being used in these reactions.
Table 1. Scope of Alkyne Variation using Aldehyde 3aa
Scheme 1. O,O- and O,S-Acetals in Alkyne Hydroacylation
As we had previously shown that a simple β-methyl ether
substituted aldehyde was a poor substrate in Rh-catalyzed
intermolecular hydroacylation reactions,9a we were inter-
ested in evaluating alternativeO-substituents. In particular,
we speculated that the extra oxygen atom of an acetal or
ketal group might be beneficial for reactivity. Accordingly,
R- and β-O-THP-substituted aldehydes 1a and 1b were
evaluated in intermolecular hydroacylation reactions with
hexyne using a dppe-derived Rh-catalyst (Scheme 1).12
Although β-substituted aldehyde 1b provided a modest
amount of the hydroacylation adduct we were unable to
further optimize the reaction. Given our previous success
with S-chelating aldehydes we reasoned that O-methylthio-
methyl (MTM) ethers 3a and 3b, featuring O,S-acetal
groups, would offer advantages over the simple O,O-
acetals. Pleasingly, the reaction between R-O-MTM alde-
hyde 3a and hexyne delivered the hydroacylation adduct in
good yield after a 2 h reaction.
a Reaction conditions: aldehyde 3a (1.0 equiv), alkyne (2.0 equiv),
[Rh(dppe)]ClO4 (10 mol %), ClCH2CH2Cl, 70 °C. Catalyst generated in
situ from [Rh(dppe)(nbd)]ClO4 and H2. b Isolated yields.
R-O-MTM aldehyde 3a could be combined with a broad
range of terminal alkynes (Table 1): simple and branched
alkyl (entries 1-4), as well as electronically varied aryl
alkynes (entries 5-8), all provided the expected enone
products in high yields. A variety of functional groups
were also tolerated, including trimethylsilyl, chloro, ester,
and free- and protected-hydroxyl groups (entries 9-14).
Although 10 mol % of catalyst was routinely employed in
these reactions, lower loadings were also possible; for
example, repetition of entry 5 employing 5 mol % catalyst
resulted in a 90% yield after a 2 h reaction. However,
performing the same transformation with 2.5 mol % of
catalyst delivered only 53% product after 24 h. In all cases,
single regio- and geometrical isomers were isolated. Un-
fortunately, internal alkynes were unreactive under these
conditions.
Variation of the aldehyde to include either a methyl or
phenyl R-substituent was also possible. Table 2 documents
the reactions of aldehydes 3c and 3d with a number of
representative alkynes. In all cases good yields of the
hydroacylation products were returned.
One of the motivations for exploring the use of alkyl O-
substituted chelating aldehydes was the desire to access the
corresponding alcohols. Although a number of MTM
ether cleavage conditions have been described,13 we estab-
lished that treatment of MTM ether 7 with AgNO3, while
excluding light,14 effected smooth deprotection (Scheme 2).
Alternatively, we found that simply introducing a small
amount of water (0.1 mL to a 2.0 mL reaction) into the
reaction flask when the hydroacylation reaction had
(9) (a) Willis, M. C.; McNally, J. S.; Beswick, P. J. Angew. Chem., Int.
Ed. 2004, 43, 340. (b) Willis, M. C.; Randell-Sly, H. E.; Woodward,
R. L.; Currie, G. S. Org. Lett. 2005, 7, 2249. (c) Willis, M. C.; Wood-
ward, R. L. J. Am. Chem. Soc. 2005, 127, 18012. (d) Willis, M. C.;
Randell-Sly, H. E.; Woodward, R. L.; McNally, S. J.; Currie, G. S.
J. Org. Chem. 2006, 71, 5291. (e) Moxham, G. L.; Randell-Sly, H. E.;
Brayshaw, S. K.; Woodward, R. L.; Weller, A. S.; Willis, M. C. Angew.
Chem., Int. Ed. 2006, 45, 7618. (f) Moxham, G. L.; Randell-Sly, H. E.;
Brayshaw, S. K.; Weller, A. S.; Willis, M. C. Chem.;Eur. J. 2008, 14,
8383. (g) Osborne, J. D.; Willis, M. C. Chem. Commun. 2008, 5025. (h)
Osborne, J. D.; Randell-Sly, H. E.; Currie, G. S.; Cowley, A. R.; Willis,
M. C. J. Am. Chem. Soc. 2008, 130, 17232. (i) Randell-Sly, H. E.;
Osborne, J. D.; Woodward, R. L.; Currie, G. S.; Willis, M. C. Tetra-
hedron 2009, 65, 5110. (j) Pawley, R. J.; Moxham, G. L.; Dallanegra, R.;
Chaplin, A. B.; Brayshaw, S. K.; Weller, A. S.; Willis, M. C. Organo-
ꢀ
metallics 2010, 29, 1717. (k) Gonzalez-Rodrıguez, C.; Parsons, S. R.;
Thompson, A. L.; Willis, M. C. Chem.;Eur. J. 2010, 16, 10950. For an
example of S-chelation used in an intramolecular reaction, see: (e)
Bendorf, H. D.; Colella, C. M.; Dixon, E. C.; Marchetti, M.; Matukonis,
A. N.; Musselman, J. D.; Tiley, T. A. Tetrahedron Lett. 2002, 43, 7031.
(10) For example, β-thioethers can be eliminated to generate enones,
while thioacetals can either be hydrolysed to the corresponding carbo-
nyl, or reduced to deliver a methylene unit (see ref 9d).
(11) For examples of salicylaldehydes used in intramolecular hydro-
acylation reactions, see: Coulter, M. M.; Dornan, P. K.; Dong, V. M.
J. Am. Chem. Soc. 2009, 131, 6932.
(13) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in
Organic Synthesis, 4th ed.; Wiley: NJ, 2007.
(14) Corey, E. J.; Bock, M. G. Tetrahedron Lett. 1975, 16, 3269.
(12) A dppe-derived catalyst was selected as being the most general
from our own β-S-aldehyde examples (see refs 9).
Org. Lett., Vol. 13, No. 5, 2011
999

Table 2. Me- and Ph-Substituted Aldehydes 3c and 3d in Inter-
molecular Alkyne Hydroacylation Reactionsa
Table 3. Probing the Reactivity of O- and S-Substituted Alde-
hydes in Alkyne Hydroacylation Reactionsa
a Reaction conditions: aldehyde (1.0 equiv), alkyne (2.0 equiv),
[Rh(dppe)]ClO4 (10 mol %), ClCH2CH2Cl, 70 °C. Catalyst generated
in situ from [Rh(dppe)(nbd)]ClO4 and H2. Isolated yields.
to probe the importance of each heteroatom of the O-
MTM functional group (Table 3). Reactions with alde-
hyde 3e, corresponding to deletion of the MTM S-atom,
did not deliver any hydroacylation products. The corre-
sponding O-deleted aldehyde, 3f, provided the enone in
14% yield. Finally, and as expected from the earlier
experiments using the O-THP aldehydes, the O-MOM
aldehyde, 3g, was also ineffective. These data indicate that
both the S- and O-atoms of the O-MTM group are needed
for reactivity. The requirement for a free coordination site
on the Rh-center to allow for alkyne binding suggests that
O,S-bidentate coordination does not take place; one pos-
sible explanation is that the presence of the O-atom acts to
make 6-membered S-chelation more favorable via an
electronic bias for a gauche conformation.15
In conclusion, we have shown for the first time that O-
substituted alkyl aldehydes can be employed in rhodium-
catalyzed intermolecular alkyne hydroacylation reactions.
R-O-MTM-substituted aldehydes are effective substrates
in combination with a broad range of functionalized
alkynes, delivering linear enone products with good selec-
tivities and in high yields.
a Reaction conditions: aldehyde (1.0 equiv), alkyne (2.0 equiv),
[Rh(dppe)]ClO4 (10 mol %), ClCH2CH2Cl, 70 °C. Catalyst generated
in situ from [Rh(dppe)(nbd)]ClO4 and H2. Isolated yields.
reached completion allowed the hydroxy-enone product
(8) to be isolated directly, albeit in a reduced yield.
Having established R-O-MTM aldehydes as viable sub-
strates for intermolecular alkyne hydroacylation reactions
we wanted to explore the origin of their favorable reactiv-
ity. With the β-S-aldehyde series we had been able to use
X-ray diffraction studies to establish the formation of
5-membered S-chelated intermediates.9e,f Unfortunately,
with the O-MTM aldehydes we were unable to isolate
suitable crystalline material. We therefore resorted to
studying the reactivity of a series of of aldehydes designed
Acknowledgment. We thank the EPSRC and Merck,
Sharp & Dohme for their support of this study.
Scheme 2. Deprotection of O-MTM-Hydroacylation Adducts
Supporting Information Available. Experimental pro-
cedures and full characterization for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) The Anomeric Effect and Associated Stereoelectronic Effects;
Thatcher, G. R. J., Ed.; ACS Symposium Series; American Chemical Society:
Washington, DC, 1993.
1000
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