Alcohol cross-coupling reactions catalyzed by Ru and Ir terpyridine complexes

Article abstract of DOI:10.1039/b815547j

Primary alcohols can be coupled with secondary benzylic alcohols by an air-stable catalytic system involving terpyridine ruthenium or iridium complexes.

Full text of DOI:10.1039/b815547j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Alcohol cross-coupling reactions catalyzed by Ru and Ir terpyridine
complexes†
Dinakar Gnanamgari, Chin Hin Leung, Nathan D. Schley, Sheena T. Hilton and Robert H. Crabtree*
Received 5th September 2008, Accepted 12th September 2008
First published as an Advance Article on the web 17th October 2008
DOI: 10.1039/b815547j
Primary alcohols can be coupled with secondary benzylic alcohols by an air-stable catalytic system
involving terpyridine ruthenium or iridium complexes.
Table 1 A comparison of catalystsa
Organometallic catalysis has typically employed Cp, PR3 or NHC
ligands.1 The NNN pincer, 2,2¢;6¢,2¢¢-terpyridine (terpy), although
Entry Catalyst
Conversionb Yieldc Alcohol/ketone
useful in coordination chemistry2 and molecular recognition,3
has rarely been used in organometallic catalysis.4 Terpy has been
considered as an unusually strong p-acceptor relative to other
N-donors5 and is also both oxidatively and thermally robust.6
Apart from the metal-catalyzed oxidation reaction,7 there are a
few examples of M-terpy complexes as catalysts in asymmetric
cyclopropanation,8 oxidation9 and dehydrogenation10 of alco-
hols, transfer hydrogenation of ketones,11 nitrene transfer,12 co-
oligomerization of alkenes,13 allylic alkylation,14 hydrosilylation,15
Negishi Coupling,16 and rearrangement of oxaziridines.17
In recent years, an alcohol activation strategy for C–C and C–
N coupling reactions has received increasing attention in part
because of the potential to replace toxic alkyl halides with
relatively benign alcohols in alkylation chemistry.18,19 For example,
b-alkylation of secondary alcohols with primary alcohols to give
a coupled alcohol produces water as the sole byproduct and thus
with high atom economy.20
1
2
3
4
5
6
7
1
94%
76%
83%
< 5%
20%
< 5%
< 5%
65%
73%
58%
—
10%
—
100 : 0
90 : 10
100 : 0
—
100 : 0
92 : 8
—
2d
terpyRuCl3
[Ru(p-cymene)Cl2]2
RuCl2(PPh3)3
[Cp*RuCl2]2
[Cp*IrCl2]2
—
a Conditions: 2.5 mmol 1-phenylethanol and benzyl alcohol, 100 mol%
KOH, 1 mol% catalyst in 0.5 mL refluxing toluene under aerobi◦c
conditions. b Conversions were determined by the consumption of the 2
alcohol. c Yields were determined by H NMR spectroscopy using 1,3,5-
1
trimethoxybenzene as an internal standard. d In sealed vial.
catalyst 2 requires a nitrogen atmosphere. Catalyst 2 can operate
effectively under neat conditions.
Table 1 compares 1 and 2 with a number of prior alcohol
activation catalysts and control complexes. The Cp* and p-cymene
complexes were essentially inactive under these conditions, but
RuCl2(PPh3)3 showed weak activity with selectivity analogous
to that of 1. The PPh3 ligand of 1 has a surprisingly small
effect, (terpy)RuCl3 having very comparable activity. We assume
reduction to Ru(II) occurs in the reducing medium. This suggests
that the N-donor ligand has a much more important role than the
PPh3. IrCl3 hydrate, Pd/C, Ir/C and Rh/C showed no significant
activity in our screening.
We now report that [(terpy)Ru(PPh3)Cl2] (1) and [(terpy)IrCl3]
(2) catalyze cross-coupling of alcohols20c as shown in eqn (1), where
Ar can be a variety or aryl groups and R is an aliphatic chain.
In optimizing conditions for catalyst 1, a 100% loading of
KOH relative to PhCHOHMe with 1% catalyst in toluene proved
best (94% conversion, 1 h). The reaction could also be run in
the absence of solvent with lower conversion (80% conv.; 55%
yield; alcohol/ketone 100 : 0). K2CO3 was inactive and KOtBu
gave results only slightly inferior to KOH (90% conv.; 60%
yield). Although a strong base, Ca(OH)2 was inactive, probably
because of its very low solubility in the medium. Catalyst 2
showed similar behavior to 1 with the various bases, except that
a substoichiometric amount (20% relative to alcohol) of KOH
proved adequate. Solventless conditions gave better yields than
with toluene as solvent. In a sealed vial, ketone production is kept
at around 10% of the product. On the other hand, opening the
reaction mixture to the atmosphere enhances ketone production
up to ca. 70% of the products in 3 h, possibly due to oxidation by
oxygen.
(1)
Complexes
1 and 2 were synthesized from terpy and
RuCl2(PPh3)3 or IrCl3.21 Among the novel points that come out
of the present work, 1 and 2 have higher activity relative to prior
systems,20 achieving full conversion of the substrates in as little
as 1 h.22 For 1, the catalytic reactions can be run under air but
Yale Chemistry Department, 225 Prospect St., New Haven, CT 06511, USA.
E-mail: robert.crabtree@yale.edu; Fax: +1 203 432 6144; Tel: 1 203 432
3915
† Electronic supplementary information (ESI) available: Optimization of
reaction conditions and NMR spectra. See DOI: 10.1039/b815547j
The scope of the reaction is shown in Table 2. The reaction
was tolerant of a number of functional groups. Catalyst 1 showed
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Table 2 b-Alkylation of secondary alcohols with primary alcohols catalyzed by 1 and 2a
Entry
Ar
R
Catalyst
t (h)
Conversionb
Yieldc
Alcohol : ketone
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-ClC6H4
4-MeC6H4
Ph
Ph
Ph
Ph
Ph
Ph
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
1
2
2
2
1
4
4
7
2
2
0.5
3
2
2
2
94%
90%
82%
95%
83%
83%
95%
82%
87%
95%
99%
74%
95%
99%
94%
65%
60%d
56%
62%
61%d
72%
84%
70%
61%
66%
95%
65%
95%
88%d
77%d
100 : 0
100 : 0
100 : 0
100 : 0
100 : 0
89 : 11
90 : 10
90 : 10
100 : 0
100 : 0
93 : 7
4-nBuOC6H4
4-ClC6H4
4-MeC6H4
4-tBuC6H4
PhCH2
nPr
iPr
Ph
Ph
Ph
nPr
93 : 7
96 : 4
92 : 8
88 : 12
4-ClC6H4
4-nBuOC6H4
4-tBuC6H4
a Conditions: Catalyst 1: 2.5 mmol of 1◦ and 2◦ alcohols, 100 mol% KOH, 1 mol% catalyst in 0.5 mL refluxing toluene under aerobic conditions. Catalyst
2: 2.5 mmol of 1◦ and 2◦ alcohols, 20 mol% KOH, 1 mol% catalyst, neat at 120 ◦C under N2. b Conversions were determined by the consumption of the
2◦ alcohol. c Yields were determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. d Isolated yield.
excellent selectivity for producing the coupled alcohol product.
Moving to aliphatic primary alcohols still gave the desired
products, except that a small amount of ketone was sometimes
seen and the reaction required longer times for completion. The
yield of products detectable in the solution phase and subsequently
isolated did not correspond to the conversion. Some of the material
(5–30%) seems to be converted to an insoluble polymer. Catalyst
2 gives a somewhat higher yield for most substrates but is less
(3)
selective, giving up to 12% ketone.
A small amount of undissolved matter also appeared in the
course of the reaction of catalyst 2, but it does not appear to be
involved in catalysis. In an experiment conducted with 2, filtering a
spent reaction mixture (1 h of heating, +99% complete conversion
of starting materials) through Celite 545 and then recharging with
1 equivalent of substrates and 20% KOH, led to almost complete
conversion to the coupled products after an extra hour of heating.
Similarly, recharging a spent reaction of 1 with new substrates
and KOH resulted in complete conversion to the corresponding
alcohol [eqn (2)].
Two probable aldol products should be formed when both
components can enolize. In fact, only the products shown (3
and 4) are formed, implying that the enolate nucleophile arises
exclusively from the secondary alcohol. This could be a result
of the presence of the Ar nucleus, because the enol is then a
conjugated, unhindered styryl system. Mechanistic studies are
under way to determine the selectivity patterns observed.
Conclusions
We report efficient terpy Ru and Ir catalysts for b-alkylation of
secondary alcohols with primary alcohols that are superior to
prior systems. This green reaction is highly atom economical as it
only produces H2O as a byproduct. The present system does not
need any hydrogen donors or acceptors.
(2)
Experimental
b-Alkylation of alcohols is normally ascribed to a hydrogen bor-
rowing process19b [eqn (3)] involving a) alcohol dehydrogenation;
b) aldol condensation with loss of water from the resulting alcohol;
and c) reduction to furnish the saturated product. Essentially all
the hydrogen removed in the first step is used to hydrogenate the
aldol enone in the final step. A similar mechanism was proposed
by Fujita and coworkers.20c
TerpyRuPPh3Cl21b (1), terpyRuCl3,21b terpyIrCl3,21a (2), [Ru(p-
26
cymene)Cl2]2,23 RuCl2(PPh3)3,24 [Cp*RuCl2]2,25 [Cp*IrCl2]2 were
all prepared according to known procedures. All the solvents were
used as received. All the reagents were received from Aldrich
and used as is without any further purification. All the catalytic
runs for catalyst 1 were conducted under air without any special
precautions. Catalyst 2 required a N2 atmosphere. NMR spectra
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were recorded at room temperature using CDCl3 on 400 and
500 MHz Bruker spectrometers and referenced to the internal
standard peak (d in ppm and J in Hz). Column chromatography
was performed using 230–400 mesh silica gel from EMD chemicals
Inc. HRMS was performed using 9.4T Bruker Qe FT-ICR MS at
the Keck Biotechnology Resource Laboratory (New Haven, CT).
3-(4-Butoxyphenyl)-1-phenylpropan-1-one
1H NMR (400 MHz, CDCl3) d 7.87 (2H, d, J 7.6 Hz), 7.47 (1H,
t, J 7.6 Hz), 7.36 (2H, t, J 7.6 Hz), 7.07 (2H, d, J 8.8 Hz), 6.75
(2H, 2d, J 8.8 Hz), 3.85 (2H, t, J 6.4), 3.18 (2H, t, J 7.5 Hz),
2.92 (2H, t, J 7.5 Hz), 1.71–1.64 (2H, m), 1.43–1.37 (2H, m), 0.89
(3H, t, 7.4 Hz). 13C NMR (101 MHz, CDCl3) d 199.63, 157.73,
137.05, 133.22, 129.49, 128.77, 128.22, 114.71, 77.55, 77.23, 76.91,
67.87, 40.93, 31.54, 29.47, 19.44, 14.06. HRMS calcd (found) for
C19H22O2 M+: 283.1695 (283.1692)
General procedure for catalytic b-alkylation of secondary alcohols
with primary alcohols
Catalyst 1. 2.5 mmol of both secondary and primary alcohol,
1,3,5-trimethoxybenzene, KOH (100 mol%), and the catalyst (1
mol%) were combined in a Schlenk tube with toluene (0.5 mL)
as solvent and refluxed for the appropriate amount of time. The
mixture was then cooled to room temperature and was diluted with
CH2Cl2 (2.0 mL). The mixture was then filtered through a Celite
filter to remove the insoluble inorganic material. An aliquot was
then taken from the reaction mixture and diluted with CDCl3.
Conversions and yields were determined by comparing to the
internal standard.
Synthesis of 3-(4-tert-butylphenyl)-1-phenylpropan-1-ol from 1
The same procedure as above and the mixture was separated
using silica gel using a gradient column (ethyl acetate/hexanes).
The desired compound was isolated as a yellow liquid (409 mg,
1
61% yield). The compound was dried under vacuum. H NMR:
d (500 MHz, CDCl3) 7.37–7.06 (9H, m), 4.67 (1H, dd, J 5.4,
7.7), 2.80–2.53 (2H, m), 2.20–1.87 (2H, m), 1.29 (9H, s). 13C { H}
1
NMR: d (126 MHz) 148.77, 144.74, 138.78, 128.61, 128.19, 127.72,
126.07, 125.40, 74.24, 40.79, 34.48, 31.62, 29.84. HRMS calcd
(found) for C19H24O M+: 268.1827 (268.1820).
Catalyst 2. A 5 mL Schlenk tube equipped with a stir bar was
charged with 1.0 mmol of each of the substrates, KOH (20 mol%),
and catalyst 2 (1 mol%). It then went under three freeze-pump-
thaw cycles and was heated under an atmosphere of N2 in a 120 ◦C
oil bath for the specified amount of time. CDCl3 and ca. 10 mg of
1,3,5-trimethoxybenzene as an internal standard was added at the
end of the reaction time for determination of yield.
Synthesis of 3-(4-tert-butylphenyl)-1-phenylpropan-1-ol and
3-(4-tert-butylphenyl)-1-phenylpropan-1-one from 2
Analogous to method described above for 2. 2.04 mmol of
substrates used, product mixture eluted from column of silica
gel (1 : 9 ethyl acetate/hexanes). Yields 1.39 mmol of 3-(4-tert-
butylphenyl)-1-phenylpropan-1-ol (68% yield) and 0.19 mmol
3-(4-tert-butylphenyl)-1-phenylpropan-1-one (9.3%) as colorless
1
oils. H NMR (400 MHz, CDCl3) d 7.95 (2H, d, J 7.6 Hz), 7.54
Synthesis of 3-(4-butoxyphenyl)-1-phenylpropan-1-ol from 1
(1H, t, J 7.6 Hz), 7.45–7.42 (2H, m), 7.31 (2H, d, J 8.7 Hz), 7.18
(2H, d, J 8.7 Hz), 3.29 (2H, t, J 7.6 Hz), 3.02 (2H, t, J 7.6 Hz), 1.29
(3 H, s). 13C NMR (101 MHz, CDCl3) d 199.32, 148.85, 138.07,
136.74, 132.94, 128.48, 127.94, 125.31, 40.38, 34.27, 31.27, 29.44.
HRMS calcd (found) for C19H22O M+: 267.1743 (267.1742).
2.5 mmol of 1-phenylethanol and of 4-butoxybenzyl alcohol were
combined with KOH (100 mol%), and the catalyst 1 (1 mol%) in
a Schlenk tube with toluene (0.5 mL) as solvent and refluxed for
2 h. The mixture was then cooled to room temperature and diluted
with CH2Cl2 (2.0 mL). The mixture was then filtered through a
Celite filter and the resultant mixture was separated using silica
gel (2% acetone/toluene). The desired compound was isolated as
a colorless liquid (427 mg, 60% yield). The compound was dried
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1
under vacuum. H NMR: d (500 MHz, CDCl3) 7.54–6.58 (9H,
m), 4.63 (1H, ddd, J 3.0, 5.3, 8.0), 3.91 (2H, t, J 6.5), 2.78–2.42
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