From precursor to catalyst: The involvement of [Ru(η5- Cp*)Cl2]2 in highly branch selective allylic etherification of cinnamyl chlorides

Article abstract of DOI:10.1016/j.tetlet.2013.12.074

(RuCp^*Cl₂)₂, a general entry into Cp^*Ru sandwich and half-sandwich chemistry was first used as a precatalyst in allylic etherification of cinnamyl chlorides with up to 98:2 regioselectivity (19 examples). Both the solvent effect and the exsiccant reaction condition are crucial to the reactivity and selectivity. Preliminary mechanism studies and the demonstration of Fluoxetine synthesis were presented in this work as well.

Full text of DOI:10.1016/j.tetlet.2013.12.074

Tetrahedron Letters 55 (2014) 1031–1035
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Tetrahedron Letters
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From precursor to catalyst: the involvement of [Ru(
highly branch selective allylic etherification of cinnamyl chlorides
g
5-Cp⁄)Cl2]2 in
Ravi Kumara Guralamatta Siddappa a,b, Chih-Wei Chang a, Rong-Jie Chein a,
⇑
a Institute of Chemistry, Academia Sinica, 128 Academia Road Sec. 2, Nankang, Taipei 11529, Taiwan
b Molecular Science and Technology Program, Taiwan International Graduate program, Academia Sinica and National Tsing-Hua University, Taiwan
a r t i c l e i n f o
a b s t r a c t
(RuCp⁄Cl2)2, a general entry into Cp⁄Ru sandwich and half-sandwich chemistry was first used as a precat-
alyst in allylic etherification of cinnamyl chlorides with up to 98:2 regioselectivity (19 examples). Both
the solvent effect and the exsiccant reaction condition are crucial to the reactivity and selectivity. Preli-
minary mechanism studies and the demonstration of Fluoxetine synthesis were presented in this work as
well.
Article history:
Received 17 September 2013
Revised 5 December 2013
Accepted 20 December 2013
Available online 27 December 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Ruthenium
Allylic substitution
O-Allylation
Allylic etherification
Pentamethylcyclopentadieneyl
Since the first report of Ru(Cp⁄) precatalyst (Cp⁄ = pentamethyl-
cyclopentadieneyl) in the substitution of cinnamyl carbonate with
piperidine in 1995,1 the studies of the characterization and the
reactions involving Cp⁄g3-allylruthenium(IV) complexes have
undergone huge growth.2 Ruthenium is able to activate allylic sub-
strates through oxidative addition with the assistance of Cp⁄ ligand
which provides both steric protection and electron richness to the
metal center and greatly promotes the regioselectivity of the
reaction, leading the substitution of nucleophiles to the most substi-
tuted terminus of the allylic moieties. Cp⁄RuCl(COD) (2) was
employed in the mono/diallylation of dimethyl malonate3 and the
preparation of allyl thioethers from thiols4 under mild conditions.
Trost et al. used [Cp⁄Ru(CH3CN)3][PF6] (3) for the alkylation of allylic
carbonates by malonate anion with high regioselectivity, whereas
the analogue [CpRu(CH3CN)3][PF6] mainly led to the linear product.5
Other endeavors to apply Cp⁄Ru complexes on allylic etherification6
by Bruneau and co-workers using NHC7 and O-diphenyl-phosphino-
benzenesulfonic acid ligand,8 and later their work on enantioselec-
tive allylation via chiral bisoxazoline9 and chiral pyridine carboxylic
acid10 yielded fruitful results. Comparatively, (RuCp⁄Cl2)2 (1),11 the
general entry into Cp⁄Ru sandwich and, in particular, half-sandwich
chemistry12 (Scheme 1), attracted much less attention from the
chemical society since its introduction in 1984.11a
nol11a or ethanol11b (Scheme 1). The identity of the structure was
determined by the X-ray crystallography analysis as a dimeric
complex bridged by chlorides13 and the two isomeric forms have
been well studied with broken-symmetry density functional the-
ory.14 Surprisingly, to the best of our knowledge, there is only
one report by Hartwig and co-workers directly using this complex
in the borylation of methyl C–H bonds.15 No catalytic activity of
this structurally simple complex in nucleophilic allylic substitu-
tions16 and other fields has been reported. During the course of
our studies on Cp⁄Ru(chiral-SO-ligand17) precatalysts, we were
amazed at the great potential of (RuCp⁄Cl2)2 which catalyzed the
reaction of cinnamyl chlorides and phenols to O-allylated products
in anhydrous condition with very high regioselectivity. Herein, we
report our research results in this regard.
The journey began with the attempt to exploit (RuCp⁄Cl2)2 (1)’s
catalytic viability, particularly in the reaction of nucleophilic allylic
substitution. To our great surprise, the allylic substitution of a cin-
namyl chloride with phenol proceeded smoothly in the presence of
1 mol % precatalyst and 2.5 equiv of potassium carbonate in aceto-
nitrile solvent (8 ppm water impurities). A good selectivity in favor
of the branched phenyl ether (6a) with respect to the linear one
(7a) was observed in a ratio of 93:7 (Table 1, entry 1) based on
1H NMR spectroscopy analysis. Attempts to use other solvents like
dichloromethane, toluene, THF, DMF, or DMSO disclosed a poor
performance in selectivity (entries 2–6). It should be noted that
when acetonitrile from drums, (>1400 ppm H2O content, without
pretreatment) was directly used in the reaction, the branch/linear
ratio (B/L) sharply eroded to 1:3 (entry 7).
(RuCp⁄Cl2)2 (1) can be easily prepared via the direct reaction of
RuCl3ÁH2O with pentamethylcyclopentadiene in refluxing metha-
⇑
Corresponding author.
E-mail address: rjchein@chem.sinica.edu.tw (R.-J. Chein).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.074

1032
R. K. G. Siddappa et al. / Tetrahedron Letters 55 (2014) 1031–1035
.
RuCl3 H2O
EtOH
+
Cl
Cl
Cl
-
1,5 - cod
Zn, KPF6
CH3CN
PF6
Ru
Ru
Ru
Ru
NCMe
Cl
Cl
NCMe
NCMe
2
3
1
η2-L*
Ru
Cl
L*
Scheme 1. Synthesis and transformations of (RuCp⁄Cl2)2 (1).
Table 1
Study of (RuCp⁄Cl2)2 (1) as a precatalyst in the allylic substitution of cinnamyl chloride by phenol
OH
O
(RuCp*Cl2)21
+
O
Cl
+
K2CO3 (2.5 equiv),
Solvent, rt, 16 h
4
5a
(1.5 equiv.)
6a
7a
(1.0 equiv.)
Entry
Catalyst loading (mol %)
Solvent
Conv.a (%)
6a/7aa
1b
2b
3b
4b
5b
6b
7c
8b
9d
1
1
1
1
1.5
1.5
1
1.5
1.5
CH3CN
CH2Cl2
Toluene
THF
97
64
44
87
>99
>99
38
>99
>99
14.0/1 (93:7)
1.9/1 (66:34)
2.9/1 (74:26)
2.8/1 (74:26)
1/2 (33:67)
1/5.9 (15:85)
1/3 (25:75)
14.6/1 (93:7)
24.0/1 (96:4)
DMF
DMSO
CH3CN
CH3CN
CH3CN
a
b
c
Data were determined by 1H NMR analysis.
Solvent was freshly dried over a solvent purification system.
CH3CN was directly used without pretreatment.
d
CH3CN freshly from solvent purification system was further dried over CaH2 under a N2 atmosphere.
Table 2
was increased to 1.5 mol % to complete the conversion of the reac-
tion (Table 1, entry 8) and acetonitrile was reprocessed over cal-
cium hydride before usage to reach >99% conversion with 96:4 B/
L ratio for the optimized reaction condition (Table 1, entry 9).
To explore the breadth of the present allylic etherification cata-
lyzed by (RuCp⁄Cl2)2, a variety of aryl alcohols were subjected to
this protocol and the outcomes are highlighted in Table 3. With
the involvement of 1.5 mol % (RuCp⁄Cl2)2, the system efficiently
catalyzed the allylic substitution of cinnamyl chloride by all phe-
nols bearing electron withdrawing (5b–g), neutral (5a, 5p, and
5q), and electron donating (5h–m and 5o) functional groups giving
high selectivity toward the corresponding branched aryl ethers
(6a–m and 6o–q) in good to high yields. 3,4,5-Trifluorophenol
(5f), the most electron poor substrate, showed the highest B/L
selectivity (98:2) with 94% isolated yield of 6f. Furthermore, there
is no significant selectivity difference between ortho- (5g and 5l),
meta- (5e, 5i, 5m, 5k, and 5q), and para-substituted (5b–d, 5h,
5j, 5o, and 5p) phenols. The only lower B/L ratio was observed in
the case of the most steric hindered mesityl alcohol 5n. Fortu-
nately, lower reaction temperature (À20 °C) and higher precatalyst
loading (2 mol %) could improve the B/L ratio from 67:33 to 88:12
and give the branched product 6n in 84% yield. This methodology
is useful for substituted cinnamyl chlorides as well. Both para-
Influence of water content on the B/L selectivity of Ru-catalyzed allylic etherification
of cinnamyl chloride
Entrya
Water contentb (ppm)
6a:7a ratioc
Conv.c (%)
1
2
3
4
5
8
23
227
517
1431
93:7
91:9
87:13
67:13
25:75
>99
>99
>99
60
38
a
Standard reaction condition: cinnamyl chloride (0.65 mmol), K2CO3
(1.63 mmol), (RuCp⁄Cl2)2 (1.5 mol %), phenol (0.98 mmol), CH3CN (1.5 ml), rt, 16 h.
b
Water content was measured by a Karl–Fischer titrator.
c
Data were determined by 1H NMR analysis.
This suggested that the absence of water is crucial for the high
branch selectivity of this ruthenium-catalyzed allylic substitution.
Perhaps the most obvious possibility is that water can compete
with ligands by binding to the metal center, thus destructing the
Cp⁄Ru complex and resulting in the hydrated Ru impurities which
promote the undesirable side reactions to form the linear product.
Thus,
a careful study in the influence of water content
(Karl–Fischer method) on the B/L selectivity was carried out and
the results are shown in Table 2. Finally, the precatalyst loading

R. K. G. Siddappa et al. / Tetrahedron Letters 55 (2014) 1031–1035
1033
Table 3
Substrate scope of the allylic etherification catalyzed by (RuCp⁄Cl2)2
OH
O
1
(RuCp*Cl2)2 (1.5 mol%)
Cl
+
R'
R
R'
O
K2CO3, CH3CN, rt, 16h
R
5a-q
4, 4a, 4b
6a-s
B/L ratioa, yieldb
O
O
O
F
F3C
Cl
6a
96/4, 93%
6b
96/4, 93%
6c
96/4, 92%
6d
95/5, 91%
I
O
O
F
F
O
O
MeO
Cl
F
6e
6f
6g
6h
96/4, 92%
98/2, 94%
94/6, 87%c
94/6, 86%
O
O
O
O
OMe
6i
6j
6k
6l
91/9, 85%
95/5, 90%
93/7, 89%
92/8, 90%
O
O
O
O
Ph
6o
94/6, 89%
6p
94/6, 91%
6n
6m
94/6, 89%
67/33, 52%
(88/12, 84%)c
O
O
O
Ph
Cl
92/8, 87%
OMe
96/4, 92%
6q
96/4, 92%
6r
6s
a
b
c
B/L ratio was determined by 1H NMR spectroscopy analysis.
Isolated yield of branched product.
Reaction was carried out at À20 °C with 2 mol % of (RuCp⁄Cl2)2.
chlorocinnamyl chloride (4a) and para-methoxycinnamyl chloride
(4b) reacted smoothly with phenol to afford 6r and 6s in high B/L
ratios and yields.
type complex. As expected, the brown powder resumed its cata-
lytic ability upon returning to the reaction of cinnamyl chloride
and phenol (4) in the presence of potassium carbonate, leading
to 90:10 ratio of 6a and 7a.
The resulting branched allyl phenyl ethers are useful intermedi-
ates for accessing to natural products18 and have been demon-
strated as important building blocks in pharmaceutical
chemistry.19 For example, 6c was successfully transformed to Flu-
oxetine 9, an antidepressant of the selective serotonin reuptake
inhibitor class, via a modified simple 3-step procedure in 82% total
yield as illustrated in Scheme 2.20
In order to obtain the mechanistic insight with regard to the ac-
tive Ru–(
g
3-Allyl) intermediate, (RuCp⁄Cl2)2 was treated with ex-
cess amount (7 equiv) of cinnamyl chloride in dry acetonitrile at
room temperature. After the removal of the solvent, the residue
was carefully washed with anhydrous ether under a nitrogen
atmosphere to afford a brown powder. The 1H NMR spectrum of
the brown powder in CD2Cl2 (Fig. 1, lower panel) comprised char-
acteristic peaks of
g
3-Allyl system (A) in monomeric form (B,
methyl on monomeric Cp⁄). Interestingly, no acetonitrile related li-
gand was observed in the spectrum. This observation suggests that
In conclusion, we have developed an efficient catalytic system
for the transformation of cinnamyl chlorides to terminal olefins
using (RuCp⁄Cl2)2 as precatalyst in anhydrous acetonitrile. The
this allylic etherification was not through Cp⁄Ru–(CH3CN)– 3-Allyl
g

1034
R. K. G. Siddappa et al. / Tetrahedron Letters 55 (2014) 1031–1035
Figure 1. 1H NMR spectra (400 MHz, CD2Cl2) of (RuCp⁄Cl2)2 (upper panel) and the brown powder isolated from the mixture of (RuCp⁄Cl2)2 and cinnamyl chloride (lower
panel).
CF3
CF3
CF3
O
O
O
a
b, c
OH
N
H
97%
85%, 2 steps
9
6c
8
Fluoxetine
o
Reagents and conditions: a) disiamylborane (2 equiv), THF, rt to 65 C; 35% H2O2, 3M NaOH.
b) MsCl, Et3N, CH2Cl2. c) MeNH2, EtOH.
Scheme 2. Synthesis of Fluoxetine (9) from 6c.
methodology is useful in a wide range of substrate scope with high
References and notes
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(RuCp⁄Cl2)2/chiral ligands and the related mechanistic pathway
are underway in our laboratory.
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acetonitrile (0.5 mL) in a schlenk tube was added cinnamyl chloride (92
0.65 mmol). The resulting mixture was stirred at room temperature under a
nitrogen atmosphere for 20 min followed by slow addition of the
corresponding phenols (0.98 mmol) (Table 2) in dry acetonitrile (1 mL) over
15 min. The reaction mixture was stirred for another 16 h at room temperature
and then filtered through a celiteÒ plug and washed with dichloromethane
(10 mL). The filtrate was evaporated under reduced pressure and purified by
silica gel column chromatography to afford the branched product.
Characterization data and copies of NMR spectra are available in Supporting
information.
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