Sequential catalysis: A metathesis/dihydroxylation sequence

Article abstract of DOI:10.1002/anie.200503552

(Chemical Equation Presented) A real step-saver: A single ruthenium-carbene complex catalyzes a sequence of two reactions, namely, a metathesis reaction (ring-closing or cross metathesis) and subsequent dihydroxylation of the newly formed double bond. A v

Full text of DOI:10.1002/anie.200503552

Communications
Synthetic Methods
A common goal in the development of new reactions is
not only high catalyst efficiency, but also the use of a single
catalyst for more than one chemical transformation in a single
synthetic operation. Ultimately this can lead to the use of a
single catalyst to mediate two or more reactions that are
fundamentally different in nature, so-called sequential catal-
DOI: 10.1002/anie.200503552
Sequential Catalysis: A Metathesis/
Dihydroxylation Sequence**
[
9]
ysis. Such sequential reactions have been demonstrated
combining an olefin metathesis step with the processes
described above. One of the most striking examples is the
one-pot synthesis of (R)-(À)-muscone reported by the
Grubbs group, in which three steps—ring-closing metathesis
(RCM), transfer dehydrogenation, and hydrogenation—are
Samuel Beligny, Stefan Eibauer, Simon Maechling, and
Siegfried Blechert*
During the last years olefin metathesis has become a powerful
[
1]
[4]
tool in synthetic organic chemistry. The advent of well-
defined catalysts such as the commercially available ruthe-
nium complexes 1–5 has allowed chemists to develop a wide
catalyzed by a single ruthenium source. Snapper and co-
workers as well as Schmidt have also reported the synthesis of
cyclic enols by a tandem RCM/olefin isomerization catalyzed
[
2]
[10,11]
range of useful applications (Scheme 1). The utility of some
by the Grubbs I catalyst.
We report herein a sequential
metathesis/dihydroxylation sequence involving RCM or
cross-metathesis (CM) followed by cis-dihydroxylation of
the resulting CÀC double bond utilizing the same ruthenium
source, resulting in the facile synthesis of dihydroxylated
products in modest to excellent yields under mild conditions.
[
12]
[13]
A variety of ruthenium sources, such as RuCl3, RuO2,
RuCl (dppp) ] (dppp = 1,3-bis(diphenylphosphanyl)pro-
[
2
2
[
14]
[15]
pane), [RuCl (PPh ) ], [Ru(acac) ] (acac = acetylaceto-
2
3
3
3
[
15]
[15]
nate) TPAP (tetrapropylammonium perruthenate), and
Ru/C, have been used for the formation of the oxidative
species RuO in different oxidation reactions. The method
[
15]
[
16]
4
of choice for dihydroxylation of olefins is in situ formation
from a catalytic amount of RuCl ·3H O using NaIO as the
3
2
4
[
17]
stoichiometric oxidant.
To the best of our knowledge,
ruthenium–carbenes have not been used for this purpose. The
choice of solvent was found to be critical, and when a 3:3:1
mixture of MeCN/EtOAc/H O was employed, a very fast cis-
2
Scheme 1. Commercially available ruthenium metathesis complexes.
[
18]
dihydroxylation of olefins was observed. Brønsted acids,
and especially Lewis acids, have been shown to further
accelerate the rate of hydrolysis and minimize side reactions
[
19]
ruthenium–carbene complexes in catalytic processes has been
extended beyond olefin metathesis to other synthetic trans-
formations. For example, carbene 1 has been used in the
such as over-oxidation.
We envisaged that it would be
possible to utilize a ruthenium–carbene to perform a meta-
thesis reaction and then oxidize this ruthenium source to
conduct a cis-dihydroxylation of the newly formed disubsti-
tuted olefin in a single reaction vessel.
In our initial studies we examined the utility of ruthe-
nium–carbenes 1–5 as precatalysts for the dihydroxylation of
tetrahydropyridine 6. The best results were found when the
olefinic substrate was dissolved in a 3:3:1 mixture of MeCN/
[
3]
Kharasch addition, and carbenes 1 and 4 were reported to
catalyze a variety of hydrogenation processes such as
regiospecific ketone and olefin reductions, transfer dehydro-
genation of ketones, and dehydrogenative oxidation of
[
4]
alcohols. Complexes 1 and 4 were, in addition, shown to
be efficient catalysts for the isomerization of double bonds
[
5–8]
and also for the deprotection of allylic amines.
EtOAc/H O at 08C in the presence of 10 mol% of
2
YbCl ·6H O before 1.5 equivalents of NaIO and 1.5 mol%
3
2
4
of the ruthenium–carbene were added. Because the reaction
mixture was heterogeneous, vigorous stirring was of prime
importance for reproducible results. The reaction was
quenched with saturated aqueous Na S O when TLC anal-
ysis showed complete consumption of the starting material.
All five ruthenium catalysts promoted formation of the
vicinal cis-diol 7; however, the Grubbs I catalyst 1, the Ciba
catalyst 2, and the Hoveyda–Grubbs I catalyst 3 gave the best
results (Table 1, entries 1–3) providing the diol in excellent
yield and short reaction time. The lower yields and longer
reaction times observed for catalysts 4 and 5 are probably a
consequence of the strong binding between the N-hetero-
[
*] Dr. S. Beligny, S. Eibauer, Dr. S. Maechling, Prof. Dr. S. Blechert
Technische Universität Berlin
Strasse des 17. Juni 135, 10623 Berlin (Germany)
Fax: (+49)30-314-23619
E-mail: blechert@chem.tu-berlin.de
2
2
3
[
**] We are grateful to the Fonds der Chemischen Industrie, the
Friedrich-Naumann-Stiftung, and the Graduiertenkolleg “Syntheti-
sche, mechanistische und reaktionstechnische Aspekte von
Metallkatalysatoren” for financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
1
900
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Angewandte
Chemie
Table 1: Comparison of precatalysts for dihydroxylation.
Table 2: RCM/dihydroxylation sequence using ruthenium–carbene 1 as
precatalyst.
[
a]
Entry
Cat.
t [min]
Yield [%]
Entry Starting
cmpd.
Equiv Product
NaIO4
t [min] Yield
1
2
3
4
5
1
2
3
4
5
10
10
10
30
40
81
81
88
63
63
[%]
1
1.2
60/10
88
[a] Yields of isolated products.
2
3
4
1.4
1.3
1.2
60/20
60/40
60/10
88
70
71
cyclic carbene (NHC) ligand and the ruthenium in these
complexes which slows down the formation of the oxidative
species.
[
15]
Following these observations, we attempted a one-pot
RCM/dihydroxylation using catalyst 1. A variety of dienes
were treated with 1 mol% of 1 in dichloromethane under
reflux conditions. Early studies showed that the presence of
small quantities of dichloromethane resulted in low yields in
the dihydroxylation step. Therefore, the solvent was removed
in vacuo after completion of the RCM step. The crude ring-
closed product was dissolved in a 3:3:1 mixture of MeCN/
EtOAC/H O, cooled to 08C, and treated with 10 mol% of
2
5
6
1.6
1.4
60/40
60/20
21
74
YbCl ·6H O and 1.2–1.6 equivalents of NaIO . The reaction
3
2
4
was generally rapid and gave the desired vicinal diol in
modest to excellent yields and was performed in the presence
of a variety of functional groups.
1
H NMR coupling constants and NOE experiments as
well as comparison with analytical data of known compounds
showed that the products obtained were, as expected, cis-1,2-
diols. The overall yield was generally linked to the reaction
time of the second step; shorter reaction times gave in most
cases better yields. For entries 1 and 4 in Table 2, 1.2 equiv-
[a]
7
8
9
1.6
1.4
1.6
12h/40 46
alents of NaIO were used, whereas for some cases such as
4
entries 2 and 5, up to 1.6 equivalents were required in order to
drive the reaction to completion. In the case of entries 10 and
60/25
49
1
1, the electron density of the double bond appears to
influence dihydroxylation, with electron-poor double bonds
leading to higher yields. When a stereocenter was already in
place after the RCM step, the dihydroxylation occurred with
excellent stereoselectivity (24:1 in favor of the trans product
for entry 8 and 28:1 in favor of the trans product for entry 9).
These high diastereoselectivities are in line with prior
[a]
120/20 49
[
20]
observations.
However, with the allylglycine derivative
10
1.6
1.6
60/30
60/35
63
33
(
entry 2) only a 0.8:1 mixture of diastereoisomers was
obtained. The low diastereoselectivity observed in this
particular case seems to be the result of a low degree of
substrate induction rather than of epimerization at the carbon
bearing the ester moiety during the course of the dihydrox-
ylation. The diastereoisomeric excess was studied at different
reaction times. Regardless of whether the reaction was
quenched after 5, 10, 20, or 120 minutes, the same ratio of
diastereoisomers was observed. The reaction was also suc-
cessful with trisubstituted olefins (entry 3 and 7), which
widens the scope of the method.
11
[
a] Reaction was conducted with 2.0 mol% Grubbs I catalyst. [b] Reac-
tion time RCM/dihydroxylation.
We next embarked on the studies of the tandem CM/
dihydroxylation. We chose CM partners likely to give both
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1901

Communications
[
21]
good selectivity and good yield in the CM step. For this
reaction the protocol was slightly changed. The Hoveyda–
Grubbs II catalyst 5 (2.5–3.0 mol%) was used as it has been
shown to be very efficient for CM with electron-deficient
olefins.
1
2.1 mL of the solvent mixture MeCN/EtOAc/H
reaction mixture had been cooled to 08C, solid NaIO4 (128 mg,
.6 mmol, 1.2 equiv) was added and the mixture stirred vigorously
until the olefin was completely consumed (TLC). The mixture was
quenched with 2 mL of saturated aqueous Na S O solution, and the
2
O (3:3:1). After the
0
[
22]
2
2
3
The amount of YbCl ·6H O was increased to
3 2
5 mol%. A 1:1 mixture of coupling partners was used for
reactions (1) and (3) depicted in Scheme 2. Three equivalents
resulting slurry was extracted with methyl tert-butyl ether (MTBE;
” 5 mL). The combined organic layers were washed with brine
(10 mL) and dried (Na SO ). Filtration and concentration in vacuo
3
2
4
afforded the crude product. Flash column chromatography on silica
eluting with 1% MeOH in CH Cl gave product 7 as a white solid in
2
2
1
8
8% yield (120 mg, 0.44 mmol). m.p. 138–1408C; H NMR
(
500 MHz, CDCl ): d = 7.64 (d, 2H, J = 8.0 Hz, H-Ar), 7.32 (d, 2H,
3
J = 8.0 Hz, H-Ar), 3.86 (m, 1H, H-3), 3.77 (m, 1H, H-4), 3.17 (dd, 1H,
J = 3.0, 11.5 H-2), 3.09–2.97 (m, 3H, H-2, H-6), 2.47–2.37 (m, 4H,
CH -Ts, OH), 2.23 (brs, 1H, OH), 1.93–1.79 ppm (m, 2H, H-5);
3
1
3
C NMR (125 MHz, CDCl ): d = 143.9 (C-Ar quart.), 133.1 (C-Ar
3
quart.), 129.9 (CH-Ar), 127.7 (CH-Ar), 67.9 (CH-OH, C-3), 67.5
(
2
(
CH-OH, C-4), 47.9 (CH , C-2), 42.0 (CH , C-6), 29.5 (CH , C-5),
2
2
2
À1
1.6 ppm (CH -Ts); IR (ATR): n˜ = 3446, 2928, 1338, 1163 cm ; MS
3
+
+
EI, 70 eV): m/z (%) 271 (8) [M ], 184 (26), 155 (30) [Ts ], 116 (100)
+
+
[
[
MÀTs ], 91 (66) [TsÀSO ]; HRMS(EI): calcd for C 12H NO S
2
17
4
+
M ] 271.0878, found 271.0876.
Typical procedure for CM/dihydroxylation (Scheme 2, reac-
tion (1)): Acetate 29 (30 mL, 0.2 mmol, 1.0 equiv) and ester 30
20.5 mL, 0.2 mmol, 1.0 equiv) were dissolved in CH Cl (200 mL).
(
2
2
Scheme 2. CM/dihydroxylation sequence using ruthenium–carbene 5
as precatalyst. a) 1. 5 (2.5–3.0 mol%), CH Cl , reflux; 2. NaIO ,
The Hoveyda–Grubbs II catalyst 5 (3.1 mg, 0.005 mmol, 2.5 mol%)
was added. The resulting solution was refluxed until the starting
material was completely consumed (TLC). CH Cl was removed by
2
2
4
YbCl ·6H O, MeCN/EtOAc/H O, 08C.
3
2
2
2
2
evaporation in vacuo, and YbCl ·6H O (0.03 mmol, 11.6 mg,
3
2
15 mol%) was added followed by 840 mL of the solvent mixture
of acrylonitrile were used in reaction (2), and the excess was
removed in vacuo together with the dichloromethane prior to
the dihydroxylation step. The dihydroxylated products were
successfully obtained, though the overall yields were lower
than those for the RCM/dihydroxylation. This is presumably
because catalyst 5 promotes the dihydroxylation less effec-
tively (see above). Accordingly, formation of the diol required
more time, with up to two hours for reaction (2). Pleasingly,
the dihydroxylation [reaction (3)] was finished after
MeCN/EtOAc/H O (3:3:1). After the reaction mixture had been
cooled to 08C, NaIO (64.2 mg, 0.3 mmol, 1.5 equiv) was added and
4
2
the mixture was stirred vigorously until the olefin was completely
consumed (TLC). The mixture was quenched with 1 mL of saturated
aqueous Na S O solution, and the resulting slurry was extracted with
2
2
3
MTBE (3 ” 3 mL). The combined organic layers were washed with
brine (5 mL) and dried (Na SO ). Filtration and concentration in
2
4
vacuo afforded the crude product. Flash column chromatography on
silica eluting with 1% MeOH in CH Cl gave product 31 in 56% yield
28 mg, 0.11 mmol). H NMR (500 MHz, CDCl ): d = 4.30 (q, 2H, J =
2
2
1
(
3
7
.0 Hz, CO CH CH ), 4.14–4.06 (m, 3H, H-2, H-7), 3.91–3.86 (m, 1H,
2 2 3
1
3
0 minutes. The product of reaction (2) was obtained as a
:1 mixture of diastereoisomers, which is consistent with
H-3), 3.06 (d, 1H, J = 5.0 Hz, OH), 2.05 (s, 3H, OCOCH ), 1.94 (d,
3
1
1
H, J = 9.5 Hz, OH), 1.72–1.51 (m, 5H, H-4, H-5, H-6), 1.50–1.40 (m,
literatures precedent showing that the CM of acrylonitrile
with similar substrates gives mixtures of geometric isomers in
13
H, H-5), 1.32 ppm (t, 3H, J = 7.0 Hz, CO CH CH ); C NMR
2
2
3
(125 MHz, CDCl ): d = 173.6 (C O), 171.3 (C O), 73.1 (CH-OH, C-
= =
3
[
22a]
favor of the Z isomer.
2), 72.3 (CH-OH, C-3), 64.3 (CH , C-7), 62.3 (CO CH CH ), 33.5
2
2
2
3
In summary, a new process combining a metathesis step
and a dihydroxylation step has been developed. Owing to the
high tolerance of functional groups, this process has an
interesting potential, notably in natural product synthesis.
This process also presents an alternative to the pinacol
coupling. The combination of two catalytic processes relying
on a single ruthenium source, in addition to low catalyst
loading make this reaction particularly interesting. Further
studies to extend this process with emphasis on the synthesis
of natural products are in progress.
(CH
2
, C-4), 28.5 (CH
2
, C-6), 22.3 (CH , C-5), 21.1 (OCOCH ),
2
3
1
1
4.2 ppm (CO CH CH ); IR (ATR): n˜ = 3454, 2942, 1735, 1367,
240 cm ; MS(EI, 70 eV): m/z (%) 115 (18), 104 (100), 85 (78), 76
2 2 3
À1
+
(76); HRMS(EI): calcd. for C H O [MH ] 249.1338, found
11 21 6
249.1343.
Received: October 6, 2005
Published online: February 10, 2006
Keywords: dihydroxylation · metathesis · ruthenium–carbenes ·
.
sequential catalysis
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Grubbs I catalyst (0.005 mmol, 4.1 mg, 1 mol%) was added to a
solution of diene 8 (132 mg, 0.5 mmol, 1.0 equiv) in CH Cl (1 mL).
2
2
The resulting solution was refluxed at 508C until the starting diene
was completely consumed. CH Cl was removed by evaporation, and
2
2
YbCl ·6H O (0.05 mmol, 19.4 mg, 10 mol%) was added followed by
3
2
1
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Angewandte
Chemie
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1903