Rhodium-catalysed hydroacylation or reductive aldol reactions: A ligand dependent switch of reactivity

Article abstract of DOI:10.1039/b810935d

The pathway for the combination of enones and β-S-substituted aldehydes using Rh-catalysis can be switched between a hydroacylation reaction or a reductive aldol reaction by simple choice of the phosphine ligand; this catalyst controlled switch allows access to new ketone hydroacylation products; useful 1,4-diketone intermediates for the synthesis of N-, S- and O-heterocycles. The Royal Society of Chemistry.

Full text of DOI:10.1039/b810935d

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Rhodium-catalysed hydroacylation or reductive aldol reactions: a ligand
dependent switch of reactivityw
James D. Osborne and Michael C. Willis*
Received (in Cambridge, UK) 27th June 2008, Accepted 31st July 2008
First published as an Advance Article on the web 2nd September 2008
DOI: 10.1039/b810935d
The pathway for the combination of enones and b-S-substituted
aldehydes using Rh-catalysis can be switched between a hydro-
acylation reaction or a reductive aldol reaction by simple choice
of the phosphine ligand; this catalyst controlled switch allows
access to new ketone hydroacylation products; useful 1,4-dike-
tone intermediates for the synthesis of N-, S- and O-hetero-
cycles.
b-S-substituted aldehyde 1 acts as the reductant and delivers
the acylated version of the reductive aldol product 7a in good
yield (Scheme 1, reaction C).10,11 Although the reductive aldol
reactions are useful in their own right, we still required an
effective hydroacylation route to 1,4-diketones. In this com-
munication we describe how this substrate controlled switch in
reactivity can be converted to a catalyst controlled system, and
in the process report the first intermolecular rhodium-
catalysed hydroacylation of a,b-unsaturated ketones.
The use of 1,4-diketones in the Paal–Knorr synthesis of
pyrroles, furans and thiophenes is a well established protocol.1
Synthetic routes to the required g-keto-ketone intermediates
centre around the formation of acyl anion equivalents and
their addition to a,b-unsaturated ketones. Umpolung reagents
such as dithianes2 and protected cyanohydrin derivatives3
have proven useful reagents for such 1,4-addition reactions,
however these systems lack step economy.4 The catalytic
Stetter reaction using thiozolium salts, or associated carbenes,
generates acyl anion equivalents directly, however, these
catalysts can suffer from low reactivity or competing benzoin
side reactions.5 Other methods for the synthesis of 1,4-dike-
tones include oxidation of alcohols obtained from enolate
mediated epoxide ring opening,6 and the oxidative dimerisa-
tion of ketones,7 which again lack in step economy and
substrate diversity. To date 1,4-diketones remain a challenging
synthetic moiety. Metal-catalysed hydroacylation has emerged
as a useful method for the synthesis of a variety of ketone-
containing compounds.8 Recently we reported that b-S-
substituted aldehydes, such as 1, are suitable substrates for
chelation assisted intermolecular hydroacylation of alkenes
and alkynes (Scheme 1).9 During our investigations we found
that the combination of aldehyde 1 and methyl acrylate (2a),
using the catalyst [Rh(dppe)ClO4], furnished the desired
g-keto-ester hydroacylation product 3a (Scheme 1, reaction
A). However, reaction of aldehyde 1 with methyl vinyl ketone
(MVK, 4a) using the same catalyst furnished none of the
desired 1,4-diketone, and instead underwent a reductive aldol
coupling, providing ester 5 in a synthetically useful 73% yield
(Scheme 1, reaction B). We further demonstrated that the
reductive aldol system could be used in a three-component
coupling incorporating tert-butyl glyoxylate (6), where the
Our previously reported conditions for chelation assisted
hydroacylation of alkenes and alkynes employed
a
[Rh(nbd)dppe]ClO4 pre-catalyst, using either acetone or
DCE as solvent;9 we found that if DCE was used as solvent,
acrylonitrile, MVK (4a), phenyl vinyl ketone (PVK, 4g) and
phenyl acrylate (2b) all gave good to excellent yields of the
unexpected reductive aldol products. Attempts at using
solvent effects to control the reactivity switch and deliver a
hydroacylation process with ketone 4a were unsuccessful. We
next turned our attention to the use of alternative catalysts to
control the reactivity. Our recently reported second-generation
rhodium catalyst system, [Rh(nbd)DPEphos]ClO4,12 sup-
pressed completely the formation of any reductive aldol
product and gave exclusively the desired hydroacylation
adduct.
The scope of the new hydroacylation systemz was explored
on a range of carbonyl containing compounds; 2a,b and 4a–i
(Table 1). The [Rh(nbd)DPEphos]ClO4 system tolerated the
coupling of primary and secondary alkyl vinyl ketones in good
Department of Chemistry, University of Oxford, Chemical Research
Laboratory, Mansfield Road, Oxford, UK OX1 3TA.
E-mail: michael.willis@chem.ox.ac.uk; Fax: 44 1225 285002;
Tel: 44 1225 285126
w Electronic supplementary information (ESI) available: Experimental
procedures and analytical data for all new compounds. See
DOI: 10.1039/b810935d
Scheme 1 Rh-catalysed hydroacylation and reductive aldol reactions:
A substrate controlled reactivity switch.
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Table 1 Rh-catalysed hydroacylation reactions between a,b-unsatu-
rated carbonyls and aldehydes 1 and 8a
Table 2 Rh-catalysed reductive aldol reactions between a,b-unsatu-
rated carbonyls and aldehydes 1 and 8a
Entry Aldehyde Ketone Product
drb
Yieldc (%)
92
Alde-
Entry hyde Ketone
Yieldb
(%)
Product
1
2
3
4
5
1
1
1
1
1
4a
4b
4c
4d
4e
7a, R = Me
7b, R = Et
7c, R = Pent
3 : 1
2.2 : 1 94
2.1 : 1 77
2 : 1
—
1
1
1
1
1
1
1
9a, R = Me
84
79
68
82
53
69
(4a)
(4b)
i
7d, R = Pr
96
86
2
9b, R = Et
(4c)
3
9c, R = Pent
6d
7d
8d
9d
10d
11
12d
a
1
1
1
1
1
1
8
4f
7f, R = CHCHPh
7g, R = Ph
2.3 : 1 92
2.1 : 1 83
2.7 : 1 91
2.7 : 1 83
2.3 : 1 54e
4g
4h
4i
2b
2a
4g
(4d)
(4e)
(4f)
i
9d, R = Pr
7h, R = 2-thienyl
7i, R = 2-furyl
11b, R = OPh
3a (hydroacylation)
7i, R = Ph
4
—
2 : 1
76
82
t
9e, R = Bu
5
t
Reaction conditions: aldehyde (1.0 equiv.), ketone (3.0 equiv.), Bu-
b
glyoxylate (1.0 equiv.), [Rh(DPEphos)]ClO4 (10 mol%). Measured
6c
9f,
R = CHCHPh
by 1H NMR spectroscopy. Isolated yield. Ketone (1.5 equiv.).
c
d
e
Compound 11b isolated together with 42% of ester 10.
(4g)
7c
1
1
1
1
1
8
9g, R = Ph
74
75
68
76
57
95
[Rh(nbd)dppe]ClO4 promoted reactions, we found that the
addition of two equivalents of MeCN, a known hydroacyla-
tion additive,13 to the reaction, increased the yield of the
reductive aldol product from 73 to 92% and suppressed
formation of any hydroacylation adduct. In general, all the
ketones explored using these modified conditions gave the
three-component coupled products in high yields with moder-
ate diastereoselectivities (2:1 to 3:1). Primary and secondary
(4h)
(4i)
8c
9h, R = 2-thienyl
9i, R = 2-furyl
3a, R = OMe
3b, R = OPh
9j, R = Ph
9c
(2a)
(2b)
10c
11
aliphatic,
aromatic
and
heteroaromatic
vinyl
ketones reacted to give the corresponding reductive aldol
products in 77–96% yields (entries 1–4, 6–9). In the aliphatic
systems a limiting factor appears to be the steric bulk of
the ketone, with the hindered tert-butyl vinyl ketone
(4e) furnishing only the Tischenko type product 10 and
no hydroacylation product (entry 5). Again, cinnamyl vinyl
ketone (4f) reacted to leave the internal double bond intact
for possible further elaboration, in an excellent 92%
yield (entry 6). Aromatic ester 2b gave conversion to the
reductive aldol compound 11b in 54% yield in the absence
of any hydroacylation product 3b, however 42% of the
Tischenko reduction product 10 was also produced (entry
10). In contrast, methyl acrylate 2a gave exclusively the
hydroacylation product 3a in 76% yield (entry 11). The
catalyst controlled switch was also demonstrated with 2-
(methylthio)benzaldehyde (8) and PVK, where 82% of the
reductive aldol product 7j was isolated (entry 12).
(4g)
12c
a
Reaction conditions: aldehyde (1.0 equiv.), ketone (3.0 equiv.),
b
[Rh(DPEphos)]ClO4 (10 mol%). Isolated yield. Ketone (1.5 equiv.).
c
yields (up to 84%, entries 1–4). tert-Butyl-vinyl ketone also
furnished the hydroacylation product but in a reduced yield of
53% (entry 5). The system tolerates both simple (entry 7) and
heteroaromatic substrates (entries 8 and 9). The hydro-
acylation of cinnamyl vinyl ketone 4f occurred exclusively at
the terminal double bond in 69% yield (entry 6). Acrylates
again gave the expected hydroacylation products (entries 10
and 11). Finally, the combination of PVK and the more
conformationally constrained 2-(methylthio)benzaldehyde (8)
proceeded in an excellent 95% yield (entry 12).
Tables 1 and 2 demonstrate ten examples where we were
able to successfully switch between the reductive aldol and
hydroacylation pathways by tuning of the rhodium catalyst,
based primarily on a change in the ligand. The origin of this
catalyst control is not yet fully understood. However, in
To demonstrate the generality of the reactivity switch we
evaluated the same range of ketones in three-component
reductive aldol reactions employing tert-butyl glyoxylate and
the dppe-derived catalyst. The results are shown in Table 2.
Whilst investigating the effect of solvents in the
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collaboration with Weller and co-workers we have reported
crystallographic and experimental data that demonstrates the
DPEphos ligand functioning in a hemilabile manner, switch-
ing between bidentate and tridentate chelation, in a related
hydroacylation reaction.12,14 The dppe ligand is restricted to
bidentate chelation. We believe the ability to adopt varied
coordination modes plays an integral role in the catalytic
cycle, as the tethered but structurally similar ligand Xantphos,
and the carbon- and sulfur-linked analogues of DPEphos do
not display activity in the studied rhodium-catalysed hydro-
acylation process.12
2 (a) M. Yus, C. Najera and F. Foubelo, Tetrahedron, 2003, 59,
6147; (b) P. C. B. Page, M. B. van Niel and J. C. Prodger,
Tetrahedron, 1989, 45, 7643; (c) B.-T. Grobel and D. Seebach,
¨
Synthesis, 1977, 357; (d) E. J. Corey and D. Seebach, Angew.
Chem., Int. Ed. Engl., 1965, 4, 1077.
3 For a review, see: J. D. Albright, Tetrahedron, 1983, 20, 3207.
4 J. S. Johnson, Angew. Chem., Int. Ed., 2004, 43, 1326.
5 For a review, see: D. Enders, O. Niemeier and A. Henseler, Chem.
Rev., 2007, 107, 5606.
6 S. Nimgirawath, E. Ritchie and W. C. Taylor, Aust. J. Chem.,
1976, 29, 339.
7 (a) D. Ivanoff and A. Spassoff, Bull. Soc. Chim. Fr., 1935, 2, 76;
(b) Y. Ito, T. Konoike, T. Harada and T. Saegusa, J. Am. Chem.
Soc., 1977, 99, 1487; (c) R. H. Frazier and R. L. Harlow, J. Org.
Chem., 1980, 45, 5408; (d) L. A. Paquette, E. I. Bzowej, B. M.
Branan and K. J. Stanton, J. Org. Chem., 1995, 60, 7277; (e) P. S.
Baran and M. P. DeMartino, Angew. Chem., Int. Ed., 2006, 45,
7083.
8 For a review, see: (a) C.-H. Jun, E.-A. Jo and J.-W. Park, Eur. J.
Org. Chem., 2007, 1869; for recent examples of rhodium-catalysed
hydroacylation, see: (b) Z. Shen, H. A. Khan and V. M. Dong, J.
Am. Chem. Soc., 2008, 130, 2916; (c) R. T. Stemmler and C. Bolm,
Adv. Synth. Catal., 2007, 349, 1185; (d) K. Tanaka, Y. Shibata, T.
Suda, Y. Hagiwara and M. Hirano, Org. Lett., 2007, 9, 1215; (e) A.
M. Roy, C. P. Lenges and M. Brookhart, J. Am. Chem. Soc., 2007,
129, 2082; (f) Y.-T. Hong, A. Brachuk and M. J. Krische, Angew.
Chem., Int. Ed., 2006, 45, 6885; (g) D.-Y. Lee, I.-J. Kim and C.-H.
Jun, Angew. Chem., Int. Ed., 2002, 41, 3031; (h) B. Bosnich, Acc.
Chem. Res., 1998, 31, 667.
In conclusion, the [Rh(nbd)DPEphos]ClO4 catalysed hydro-
acylation proved
a versatile system; aliphatic, alkenyl,
aromatic and heteroaromatic substrates were all successfully
employed to form a variety of useful 1,4-diketone heterocycle
precursors. In contrast, the use of the [Rh(nbd)dppe]ClO4
catalyst, with MeCN as an additive, provided a parallel range
of three-component reductive aldol products. Further investi-
gation into the role of the phosphine ligands in these two
important reactions is currently underway, along with the
development of a one-pot synthesis of heterocycles via
rhodium-catalysed hydroacylation/Paal–Knorr cyclisation
cascade.
9 (a) M. C. Willis and S. Sapmaz, Chem. Commun., 2001, 2558;
(b) M. C. Willis, S. J. McNally and P. J. Beswick, Angew. Chem.,
Int. Ed., 2004, 43, 340; (c) M. C. Willis, H. E. Randell-Sly, R. L.
Woodward and G. S. Currie, Org. Lett., 2005, 7, 2249; (d) M. C.
Willis, H. E. Randall-Sly, R. L. Woodward, S. J. McNally and G.
S. Currie, J. Org. Chem., 2006, 71, 5291.
Notes and references
z General procedure for the hydroacylation of a,b-unsaturated
ketones: DCE (2.0 mL) was added to pre-catalyst [Rh(DPE-
phos)(nbd)]ClO4 (13 mg, 0.015 mmol) under argon. The catalyst was
activated in situ by bubbling H2 gas though the solution for 2 min or
until a colour change from orange to red was observed. After this time
the hydrogen atmosphere was purged by passing argon through the
solution for 0.5 min. The aldehyde 1 or 8 (0.15 mmol) followed by the
appropriate ketone (0.3 mmol) were then added to the reaction
solution. The resulting mixture was stirred and heated at 70 1C for
1–2 h. After this time the solution was cooled to room temperature,
filtered through a silica plug, reduced in vacuo and purified by flash
chromatography.
10 M. C. Willis and R. L. Woodward, J. Am. Chem. Soc., 2005, 127,
18012.
11 For recent examples of Rh-catalysed reductive aldol reactions, see:
(a) H.-Y. Jang, R. R. Huddleston and M. J. Krische, J. Am. Chem.
Soc., 2002, 124, 15156; (b) G. A. Marriner, S. A. Garner, H.-Y. Jang
and M. J. Krische, J. Org. Chem., 2004, 69, 1380; (c) T. Muraoka,
S.-I. Kamiya, I. Matsuda and K. Itoh, Chem. Commun., 2002, 1284;
(d) M. Freirıa, A. J. Whitehead, D. A. Tocher and W. B. Motherwell,
´
Tetrahedron, 2004, 60, 2673; (e) C.-H. Jung and M. J. Krische, J. Am.
Chem. Soc., 2006, 128, 17051; (f) T. Shiomi and H. Nishiyama, Org.
Lett., 2007, 9, 1651; (g) C. Bee, S. B. Han, A. Hassan, H. Lida and
M. J. Krische, J. Am. Chem. Soc., 2008, 130, 2746.
1 For recent examples of Paal-Knorr synthesis, see: (a) B. M. Trost
and G. A. Doherty, J. Am. Chem. Soc., 2000, 122, 3801; (b) R. U.
Braun, K. Zeitler and T. J. Muller, J. Org. Lett., 2001, 3, 3297;
(c) A. A. Kiryanov, P. Sampson and A. J. Seed, J. Org. Chem.,
2001, 66, 7925; (d) B. Quiclet-Sire, L. Quintero, G. Sanchez-
Jimenez and S. Z. Zard, Synlett, 2003, 75; (e) G. Minetto, L. F.
Raveglia and M. Taddei, Org. Lett., 2004, 6, 389; (f) B. K. Banik,
S. Samajdar and I. Banik, J. Org. Chem., 2004, 69, 213; (g) B. K.
Banik, I. Banik, M. Renteria and S. K. Dasgupta, Tetrahedron
Lett., 2005, 46, 2643; (h) Y. Guodong, W. Zihua, C. Aihua, G.
Meng, W. Anxin and P. Yuanjiang, J. Org. Chem., 2008, 73, 3377.
12 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.
13 M. Imai, M. Tanaka, S. Nagumo, N. Kawahara and H. Suemune,
J. Org. Chem., 2007, 72, 2543.
14 For additional examples of DPEphos acting in a tridentate man-
ner, see: (a) P. W. N. M. van Leeuwen, M. A. Zuideveld, B. H. G.
Swennenhuis, Z. Freixa, P. C. J. Kamer, K. Goubitz, J. Fraanje,
M. Lutz and A. L. Spek, J. Am. Chem. Soc., 2003, 125, 5523; (b) R.
Venkateswaran, J. T. Mague and M. S. Balakrishna, Inorg. Chem.,
2007, 46, 809.
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