Ligand effects in the rhodium-catalyzed addition of alkynes to aldehydes and diketones. Modification of the β-diketonate ligand

Article abstract of DOI:10.1016/j.tetlet.2007.10.010

A catalytic amount of dicarbonylacetonato rhodium(I) and a phosphine ligand bearing bulky electron-donating alkyl groups has been shown to generate an effective catalyst for the addition of alkynes to aldehydes and activated ketones under mild, neutral conditions. While previous studies have shown that modification of the phosphine has significant effects on the activity of the catalyst, the role of the β-diketonate ligand has not been probed. Six different β-diketonate rhodium complexes were synthesized and their ability to catalyze the alkyne addition reaction was evaluated. Changing the structure of the β-diketonate ligand can have a noticeable effect on the reaction rate. Acetylacetonate derivatives with strong electron withdrawing groups have a detrimental effect on the catalytic activity, while bulky and electron rich β-diketonate derivatives provide more efficient catalysts.

Full text of DOI:10.1016/j.tetlet.2007.10.010

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Tetrahedron Letters 48 (2007) 8743–8746
Ligand effects in the rhodium-catalyzed addition of alkynes to
aldehydes and diketones. Modification of the b-diketonate ligand
Pawan K. Dhondi, Patrick Carberry and John D. Chisholm*
Department of Chemistry, Syracuse University, Syracuse, NY 13244, United States
Received 7 August 2007; revised 1 October 2007; accepted 2 October 2007
Available online 6 October 2007
Abstract—A catalytic amount of dicarbonylacetonato rhodium(I) and a phosphine ligand bearing bulky electron-donating alkyl
groups has been shown to generate an effective catalyst for the addition of alkynes to aldehydes and activated ketones under mild,
neutral conditions. While previous studies have shown that modification of the phosphine has significant effects on the activity of the
catalyst, the role of the b-diketonate ligand has not been probed. Six different b-diketonate rhodium complexes were synthesized and
their ability to catalyze the alkyne addition reaction was evaluated. Changing the structure of the b-diketonate ligand can have a
noticeable effect on the reaction rate. Acetylacetonate derivatives with strong electron withdrawing groups have a detrimental effect
on the catalytic activity, while bulky and electron rich b-diketonate derivatives provide more efficient catalysts.
Ó 2007 Elsevier Ltd. All rights reserved.
The transition-metal catalyzed addition of alkynes to
aldehydes and ketones has become an intensely investi-
gated area.1–4 These reactions have been applied to
the synthesis of natural products and other compounds
of medicinal interest.5–9 Recently our group disclosed
a rhodium-catalyzed alkyne addition method using
Rh(acac)(CO)2 (3) as the metal precatalyst in the pre-
sence of bulky, electron-rich phosphine ligands such as
2-(di-t-butylphosphino)biphenyl (4) (Scheme 1).10 The
advantages of this method include mild conditions,
improved functional group tolerance, and good reacti-
vity with enolizable 1,2-diketones and 1,2-ketoesters,
which are problematic substrates for the more common
zinc-catalyzed transformations.11
One significant advantage that zinc-catalyzed reactions
hold over the rhodium-catalyzed reaction is the control
of the absolute stereochemistry of the propargyl alcohol
products.1–4 Zinc mediated reactions take advantage of
chiral alcohol and phenol based ligands to control asym-
metry, which provide enantioenriched products with
high selectivity.12,13 Given that the rhodium-catalyzed
reaction uses a phosphine ligand, use of a chiral phos-
phine ligand is an obvious choice to induce asymmetry
in the propargyl alcohol products. In our previous work
we examined the effect changing the structure of the
phosphine ligand had on the alkyne addition reaction
and found that only phosphines with at least two bulky
alkane substituents provided acceptable yields in the
rhodium-catalyzed addition reaction.10 As these phos-
phines are relatively new,14,15 there are few readily avail-
able chiral phosphine ligands that possess the requisite
bulky alkyl groups required to facilitate the rhodium-
catalyzed alkyne addition reaction. Attempts to examine
available chiral phosphine ligands for a platform to
modify into a dialkyl chiral phosphine have met with
difficulties, as conversions tend to be quite low. This
casts doubt on the results of the ligand screen.16
3 mol %
Rh(acac)(CO)2 (3)
9 mol % ligand 4
HO
HO
1
O
+
HO
5
O
THF, 40˚C
2
O
ligand (4) =
P(t-Bu)2
Faced with difficulties in using chiral phosphines, a
second approach was considered. The precatalyst has a
b-diketonate ligand, and therefore the use of a chiral
b-diketonate may induce asymmetry in the reaction
products. Unlike the phosphine, the structure of the
Scheme 1.
*
Corresponding author. Tel.: +1 315 443 6894; fax: +1 315 443
4070; e-mail: jdchisho@syr.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.010

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P. K. Dhondi et al. / Tetrahedron Letters 48 (2007) 8743–8746
R
b-diketonate ligand was not varied in our initial catalyst
screens, as these complexes must be synthesized and iso-
lated. Use of a chiral b-diketonate ligand also attracted
our attention as an underutilized approach for control-
ling the enantioselectivity in an organic transformation.
While numerous variants of chiral b-diketonates have
been described,17–22 only a few have been used effectively
in asymmetric transformations.17,22
O
i) LiHMDS
toluene, 0˚C
O
ii)
O
R
MeO
R = Cl
9
R = Cl 13 87%
R = OMe 14 89%
R = OMe 10
R
11
12
R = Cl
R = OMe
R
Ba(OH)2
pet. ether
reflux
Modification of the b-diketonate ligand will only have a
chance to impart enantioselectivity on the products if
the ligand stays bound to the rhodium catalyst during
1
the catalytic cycle. To probe this point H NMR, 31P
R
NMR, and IR were used to monitor any intermediates
in the reaction. A typical alkyne addition was prepared
in an NMR tube using phenylacetylene, 2,3-butane-
dione, the rhodium precatalyst, and phosphine 4 in
O
O
CO
CO
O
O
[ClRh(CO)2]2
Ba
Rh
1
pet. ether
reflux
benzene-d6. Use of H NMR to monitor ligand changes
on the catalyst proved difficult, as the methyl groups of
the b-diketonate ligand were obscured by signals from
2,3-butanedione. No change in chemical shift was
observed on the signal for the C–H present on C3 of
the b-diketonate, which appeared as a singlet at
5.14 ppm throughout the catalytic reaction. Three peaks
were observed in the 31P NMR spectra during the exper-
iment, a doublet at 79.9 ppm, a singlet at 57.2 ppm, and
a singlet at 19.4 ppm. The singlet at 19.4 ppm was attrib-
uted to phosphine 4, while the signal at 57.2 ppm repre-
sented small amounts of phosphine oxide formed from
adventitious oxidation of the phosphine.23 Consistent
with this analysis, the signal at 57.2 ppm was slowly
growing larger during the course of the reaction, while
the peak at 19.4 ppm was slowly decreasing in size.
The doublet observed at 79.9 ppm had a coupling con-
stant of 182 Hz, which was consistent with rhodium
phosphine coupling constants in complexes with the
general formula Rh(acac)(CO)(PR3).24,25
17 85%
18 71%
(yields over 2 steps)
R = Cl
R = OMe
R
R
2
R = Cl 15
R = OMe 16
Scheme 2.
have been replaced with trifluoromethyl (6), t-butyl
(7), and phenyl (8) groups were prepared.26 In addition,
b-diketonate ligands with modified phenyl rings were
prepared by Claisen condensation of the corresponding
esters and ketones (Scheme 2). Deprotonation of the
1,3-diketones with barium hydroxide followed by salt
metathesis with rhodium using [ClRh(CO)2]2 provided
the desired rhodium complexes.27
With the modified precatalysts in hand, their effect on
the alkyne addition reaction of 4-pentyn-1-ol (1) with
2,3-butanedione (2) was examined (Table 1). The yields
of the reactions using complexes 7 and 18 were better
than with the parent precatalyst 3. Conversely, the yield
decreased when electron-withdrawing groups were
incorporated on the b-diketonate ligand. Furthermore,
the stronger the electron-withdrawing character of the
ligand, the worse the yield became (Table 1, entries 2
and 5).
The same signal at 79.9 ppm was observed in the 31P
NMR of the product of the reaction between Rh(acac)-
(CO)2 and phosphine 4 in benzene-d6 with no added
alkyne or 1,2-diketone. Further confirmation on the
structure of the persistent intermediate Rh(acac)-
(CO)(PR3) came from IR studies on the reaction of rho-
dium complex 3 and ligand 4. The loss of a CO ligand
and the continued presence of the b-diketonate was
detected in the IR spectra, which showed the disappear-
ance of the carbonyl peaks for complex 3 (two absorben-
cies at 2082 cmÀ1 and 2011 cmÀ1) and the appearance of
a new signal at 1957 cmÀ1, consistent with Rh(acac)-
(CO)(PR3).24,25 Infrared absorbencies at 1590 cmÀ1
and 1523 cmÀ1 showed the b-diketonate ligand was still
bound to the rhodium. Given the persistent nature of
the signal at 79.9 ppm in the 31P NMR during the alkyne
addition reaction, the b-diketonate ligands presence on
the active catalyst seemed secure.
Table 1. Effect of catalyst structure on the yield of the addition
reaction
CO
OC
Rh
O
O
HO
3 mol %
1
HO
O
+
R
R
9 mol % ligand 4
5
HO
2
O
THF, 40˚C
O
Entry
Rh Catalyst
Yield (%)
Before synthesizing any chiral b-diketonate rhodium
complexes, it would be prudent to determine the effect
modifying the b-diketonate has on the catalytic reaction.
To facilitate this study, the synthesis of several rhodium
complexes was undertaken. Derivatives of Rh(acac)-
(CO)2 in which the methyl groups of the b-diketonate
1
2
3
4
5
6
R = Me (3)
R = CF3 (6)
R = t-Bu (7)
R = Ph (8)
R = 4-Cl–Ph (17)
R = 4-OMe–Ph (18)
86
6
99
91
72
98

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P. K. Dhondi et al. / Tetrahedron Letters 48 (2007) 8743–8746
Table 2. Relative rates of the formation of product 20
8745
While comparing the yield of the reactions is one way of
determining the reactivity differences of the b-diketonate
ligands, another measure is the rate of the reactions.
Toward this end, the rates of the reactions were com-
pared by monitoring the reactions using 1H NMR
(Fig. 1). The reaction between phenylacetylene and
2,3-butanedione was used as it occurs rapidly even at
room temperature and can be easily monitored by the
disappearance of the alkyne C–H in the 1H NMR.
Deuterated benzene was used as a solvent for these
reactions, as the reaction performs nearly as well in
benzene as in THF. In all cases the reactions were very
clean with only signals for the starting material, addition
product, and excess 2,3-butanedione appearing in the
spectra (as well as trace amounts of the phosphine
ligand). As the hexafluoro derivative 6 was shown to
provide poor conversion in the addition reaction, it
was omitted from the rate study.
Entry
Rh Catalyst
krel
1
2
4
5
6
R = Me (3)
R = t-Bu (7)
R = Ph (8)
R = 4-Cl–Ph (17)
R = 4-OMe–Ph (18)
1
1.51
0.81
0.45
1.13
to steric effects increasing the facility of ligand substitu-
tion or electronic effects increasing the electron density
on the rhodium center. Comparison of the three cata-
lysts bearing aromatic rings allowed for a more relevant
comparison of electronic factors on the reaction, since
the catalysts generated from complexes 8, 17, and 18
all possess similar steric properties. From these results
we can conclude the incorporation of electron-with-
drawing groups on the b-diketonate is detrimental to
the rate of the reaction. Also supporting this trend is
the comparison between catalysts 3 (R = Me) and 8
(R = Ph), with the greater electronegativity of the
phenyl ring decreasing the reaction rate. These results
support the necessity of an electron-rich rhodium cata-
lyst similar to the results observed in the phosphine
screen preformed earlier.10
In all cases, the reactions showed excellent agreement
with a first-order relationship in regard to the starting
alkyne. With the data from the rate studies in hand,
the relative rates of the reactions were calculated (Table
2). While the rate of the addition reaction was changed
by the modification of the group on the b-diketonate
ligand, these changes were quite subtle. Substitution of
the methyl group with a bulky t-butyl group appeared
to slightly increase the reaction rate. This could be due
Variation of the b-diketonate ligand on the rhodium has
small but significant effects on the addition reaction of
1
CO
OC
Rh
O
O
0.9
3 mol %
O
R
R
HO
20
9 mol % ligand 4
+
Ph
19
2
benzene-d6
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Ph
O
O
R = Me (3)
R = t-Bu (7)
R = Ph (8)
R = 4-Cl-Ph (17)
R = 4-OMe-Ph (18)
0
3600
7200
10800
14400
18000
21600
25200
28800
32400
36000
39600
Time (s)
Figure 1. Rate comparison on the disappearance of alkyne 19.

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P. K. Dhondi et al. / Tetrahedron Letters 48 (2007) 8743–8746
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withdrawing substituents on the b-diketonate ligand
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The reaction tolerates the incorporation of bulky
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