Rhodium-catalyzed addition of alcohols to terminal enones

Article abstract of DOI:10.1016/j.tetlet.2004.08.060

[Rh(COD)(OMe)]₂ was found to catalyze the addition of aliphatic and aromatic alcohols with terminal enones to afford β-alkoxyketones in high yields.

Full text of DOI:10.1016/j.tetlet.2004.08.060

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7441–7443
Rhodium-catalyzed addition of alcohols to terminal enones
Marc V. Farnworth, Michael J. Cross and Janis Louie*
University of Utah, Department of Chemistry, 315 South 1400 East, Salt Lake City, UT 84112, USA
Received 5 August 2004; accepted 10 August 2004
Available online 26 August 2004
Abstract—[Rh(COD)(OMe)]2 was found to catalyze the addition of aliphatic and aromatic alcohols with terminal enones to afford
b-alkoxyketones in high yields.
Ó 2004 Elsevier Ltd. All rights reserved.
b-Alkoxyketones serve as valuable building blocks and
structural motifs in a variety of natural products.1 Inter-
molecular oxa Michael additions of alcohols to enones
represent an attractive method for their preparation
but only a few procedures have been reported. They in-
clude UV irradiation of cycloalkenones in methanol,
reactions promoted by strong base (e.g., KH or K-O-t-
bu),2 phosphine catalyzed reactions,3 and acid catalyzed
reactions.4 A few transition metals (e.g., Pd, Cu, V) have
also been found to induce hydroalkoxylation of a,b-
unsaturated ketones.5,6 Herein, we describe a novel
Rh-catalyzed addition of alcohols with terminal enones
to afford b-alkoxyketones.
product arising from transfer dehydrogenation with
MVK (Table 1, entries 1–5). However, [Rh(COD)Cl]2
afforded the alkoxyketone 3 as the predominant product
(entry 7). Addition of a variety of ligands (phosphines,
amines, and imidazolylidenes) to reactions run with
[Rh(COD)Cl]2 led to increased amounts of oxidation
product. Importantly, control reactions confirmed that
Na2CO3 alone did not catalyze the addition reaction
(entry 8).2
Interestingly, [Rh(COD)Cl]2 alone catalyzed the reac-
tion but gave lower yields of 3 (Table 1, entry 9). It is
known that Rh alkoxide complexes are formed from
the reaction of alcohols and [Rh(COD)Cl]2 in the pres-
ence of a weak base such as Na2CO3.7 Thus, it seemed
possible that the addition of base simply served to facili-
tate the generation of a key catalyst such the Rh alkox-
ide complex [Rh-OBn]. Indeed, [Rh(COD)(OMe)]2 (5),7
conveniently prepared from [Rh(COD)Cl]2, MeOH, and
KOH, catalyzed the addition of benzyl alcohol (1) to
MVK in the absence of added base.
The addition of benzyl alcohol (1) to methyl vinyl
ketone (MVK, 2) was chosen as the model reaction
(see Eq. 1) and a series of transition metal complexes
were screened for catalytic activity (see Table 1). MVK
(2equiv) and Na2CO3 (0.6equiv) were added to toluene
solutions (1M) of benzyl alcohol. Reactions were run at
100°C for 4h. Various Ir, Ru, and Rh complexes pre-
dominantly afforded benzaldehyde (4), the oxidation
2 mol% [M]
O
OH
O
O
O
+
+
ð1Þ
0.6 eq Na2CO3
toluene, 100 °C
1
2
3
4
Optimization of the [Rh(COD)(OMe)]2 catalyzed reac-
tion revealed that catalyst loading, reactant ratios, and
substrate concentration did not affect conversion as
much as temperature and solvent. Ultimately, the best
yields were observed for reactions run with 1M BnOH
Keywords: Alcohols; Enones; Rhodium catalyst; Oxa Michael
addition.
*
Corresponding author. Tel.: +1 801 581 7309; fax: +1 801 581
8433; e-mail: louie@chem.utah.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.060

7442
M. V. Farnworth et al. / Tetrahedron Letters 45 (2004) 7441–7443
Table 1. Catalyst screening for the addition of benzyl alcohol to MVK
(Eq. 1)a
Table 3. Rhodium-catalyzed addition of alcohols to terminal enonesa
Entry
Alcohol
Enone
%Yieldb
Entry
Catalyst
Base
%Conv. of 1
3/4
OH
1a
1b
MVK
PVK
72
61
1
2
3
4
5
6
7
8
9
[Ir(COD)Cl]2
[RuCl2(cymene)]2
Rh(PPh3)3Cl
Rh(PPh3)3Me
Rh(PPh3)2(CO)(Cl)
Rh(CO)2(acac)
[Rh(COD)Cl]2
None
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
None
100
100
73
0:1
0:1
0:1
OH
2a
2b
MVK
PVK
50
92
84
11
1:0.9
1:1
MeO
F3C
53
56
2.2:1
9.6:1
N/A
1:0
OH
3a
3b
MVK
PVK
37
82
<5
25
[Rh(COD)Cl]2
a Reaction conditions: 0.01mmol catalyst, 0.6mmol Na2CO3, 1M
OH
4a
4b
MVK
PVK
69
95
BnOH (1mmol) in toluene, 2mmol MVK (2), 100°C, 12h.
OH
5a
5b
MVK
PVK
82
84
Table 2. Temperature effects for the addition of BnOH (1) to MVK
(2)a
6a
6b
MeOH
EtOH
MVK
PVK
74
99
Entry
Temperature (°C)
%Conv. of 1
1
2
3
4
5
6
rt
40
53
68
72
57
38
40
50
60
70
100
7a
7b
MVK
PVK
88
87
8a
8b
i-PrOH
MVK
PVK
35
64
a Reaction conditions: 0.01mmol [Rh(COD)(OMe)]2 (5), 1M BnOH
(1.1mmol) in toluene, 1mmol MVK (2), 2h.
9a
9b
MVK
PVK
0
34
OH
a Reaction conditions: 0.01mmol [Rh(COD)(OMe)]2 (5), 1M alcohol
(1.1mmol) in benzene-d6, 1mmol enone, 2–10h at 60°C.
b 1H NMR yield (average of two runs).
(1:1.1 BnOH–MVK) in toluene using 1mol%
[Rh(COD)(OMe)]2 at 60°C for 2h (see Table 2). Similar
results were obtained when the reaction was run in tetra-
hydrofuran, benzene, hexanes, and dichloroethylene.
Reactions performed in tert-butyl alcohol displayed
lower conversions and lower yields. No reaction was
observedinpolarsolventssuchasDMSOandacetonitrile.
to note that the reaction of phenol and PVK afforded
the b-alkoxyketone in 34% (entry 9b) whereas no reac-
tion was observed with MVK (entry 9a).
A variety of alcohols were reacted with MVK under the
optimized reaction conditions and are summarized in
Table 3. Both electron withdrawing and donating substi-
tuted benzyl alcohols seemed to moderately attenuate
the reaction (entries 2a and 3a). However, diphenyl-
methanol reacted cleanly with MVK to afford the b-alk-
oxyketone product in good yield (entry 5a). Relatively
small primary alcohols, such as methanol and ethanol,
reacted smoothly with MVK (entries 6a and 7a) whereas
alcohols with increased steric bulk led to decreased
yields. For example, only 35% of the b-alkoxyketone
was obtained from the reaction of iso-propanol with
MVK (entry 8a).
In general, bulky alcohols (e.g., tert-butyl alcohol, tri-
ethylsilanol) did not readily react with either MVK or
PVK and afforded only trace amounts of product. Fur-
thermore, the use of substituted alkenes completely
inhibited the reaction. For example, no product was ob-
served with cyclohexenone or pentenone and catalyst
decomposition was observed. Acrylates also proved to
be unsuccessful coupling partners.
The reaction also displayed moderate product inhibi-
tion. For example, as shown in Scheme 1, addition of
alkoxyketone 3 to the reaction mixtures resulted in
The reaction of phenyl vinyl ketone (PVK) was also
explored (see Table 3). In general, higher yields were
obtained for all alcohols studied. Notably, reactions of
aryl alcohols afforded the corresponding b-alkoxy-
ketones in yields ranging from 61% to 95% (entries
1b–5b). Similarly, reactions with alkyl alcohols also dis-
played increased activities. For example, high yields of
product were observed for MeOH and EtOH (99%
and 87%, respectively; entries 6b and 7b). In addition,
i-PrOH gave the corresponding b-alkoxyketone in 64%
yield (as compared to 35% with MVK). It is interesting
O
0.5 mol%
O
O
O
O
[Rh(COD)(OMe)]2
7
7
2
+
69%
29%
OH
0.5 mol%
[Rh(COD)(OMe)]2
1 eq 3
6
Scheme 1. Product inhibition.

M. V. Farnworth et al. / Tetrahedron Letters 45 (2004) 7441–7443
7443
depressed yields of 7 (29% vs 69%), which is believed to
be due to chelation effects.
Acknowledgements
We thank the University of Utah for support of this
research. M.V.F. gratefully acknowledges the University
of Utah for an Undergraduate Research Opportunity
Fellowship (UROP).
The reversibility of the reaction was also explored. 4-
Methyl benzyl alcohol (6) readily underwent exchange
with 3 in the presence of Rh to afford a 1:1 mixture of
3 and 7, suggesting that the reaction is reversible
(Scheme 2). No exchange was observed in the absence
of catalyst.
References and notes
1. (a) Misra, M.; Luthra, R.; Singh, K. L.; Sushil, K. In
Comprehensive Natural Products Chemistry; Barton, D. H.
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Tetrahedron Lett. 1993, 34, 1259; (c) Dumez, E.; Rodriguez,
O
O
no catalyst
no exchange
3
+
OH
O
O
0.5 mol%
[Rh(COD)(OMe)]2
6
7
`
J.; Dulcere, J.-P. J. Chem. Soc., Chem. Commun. 1997,
1831.
Scheme 2. Reversibility of the Rh-catalyzed oxa Michael reaction.
3. (a) Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am.
Chem. Soc. 2004, 125, 8696; (b) Kisanga, P. B.; Ilankuma-
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Biomol. Chem. 2003, 1, 1953.
Labelling experiments were also performed to provide
insight into the mechanism of the reaction. Deuterated
benzhydrol (8), prepared from NaBD4 reduction of benzo-
phenone, was added to MVK under our optimized reac-
tion conditions (Eq. 2). Deuterium scrambling was not
observed in the b-alkoxyketone product (9), which indi-
cated that b-hydride elimination does not lie on the cat-
alytic pathway.
O
Ph Ph
2
0.5 mol% 5
+
D
O
O
ð2Þ
OH
D
6. For aza-Michael addition catalysts, see: (a) Srivastava, N.;
Banik, B. K. J. Org. Chem. 2003, 68, 2109; (b) Zhuang, W.;
Hazell, R. G.; Jørgensen, K. A. Chem. Commun. 2001,
1240; (c) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org.
Lett. 2002, 4, 1319; (d) Sibi, M. P.; Gorikunti, U.; Liu, M.
Tetrahedron 2002, 58, 8357.
Ph
Ph
8
9
In summary, [Rh(COD)(OMe)]2 serves as a catalyst for
the addition of alcohols to terminal enones under mild
conditions. The catalyst may be generated in situ
through the addition of Na2CO3 to an alcoholic solution
of [Rh(COD)Cl]2.
7. Uson, R.; Oro, L. A.; Cabeza, J. A. Inorg. Synth. 1985, 23,
126.