Rhodium phosphine-phosphite catalysts in the hydrogenation of challenging N-(3,4-dihydronaphthalen-2-yl) amide derivatives

Article abstract of DOI:10.1021/jo400345v

The enantioselective catalytic hydrogenation of N-(3,4-dihydronaphthalen-2- yl) amides (1) with rhodium catalysts bearing phosphine-phosphite ligands 4 has been studied. A wide catalyst screening, facilitated by the modular structure of 4, has found a hig

Full text of DOI:10.1021/jo400345v

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Article
Rhodium Phosphine-Phosphite Catalysts in the Hydrogenation
of Challenging N-(3,4-dihydronaphthalen-2-yl) Amide Derivatives.
Inmaculada Arribas, Miguel Rubio, Patryk Kleman, and Antonio Pizzano
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400345v • Publication Date (Web): 13 Mar 2013
Downloaded from http://pubs.acs.org on March 19, 2013
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The Journal of Organic Chemistry
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Rhodium PhosphineꢀPhosphite Catalysts in the
Hydrogenation of Challenging Nꢀ(3,4ꢀ
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dihydronaphthalenꢀ2ꢀyl) Amide Derivatives
Inmaculada Arribas, Miguel Rubio, Patryk Kleman and Antonio Pizzano*
Instituto de Investigaciones Químicas, CSIC and Universidad de Sevilla, Avda Américo Vespucio 49.
Isla de la Cartuja. 41092 Sevilla, Spain.
*Corresponding author. Eꢀmail: pizzano@iiq.csic.es
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ABSTRACT. The enantioselective catalytic hydrogenation of Nꢀ(3,4ꢀdihydronaphthalenꢀ2ꢀyl) amides
(1) with rhodium catalysts bearing phosphineꢀphosphite ligands 4 has been studied. A wide catalyst
screening, facilitated by the modular structure of 4, has found a highly enantioselective catalyst for this
reaction. This catalyst gives a 93 % ee in the hydrogenation of 1a and also produces high
enantioselectivities, ranging from 83 to 93 % ee, in the hydrogenation of several –OMe and –Br
substituted substrates. On the contrary, structurally related enol esters 2 are very reluctant to the
hydrogenation. A coordination study of representative enamide 1d has shown an unusual η6ꢀarene
coordination mode, over the typical O,C,C chelating mode for enamides, as the preferred one for this
substrate in a Rh(I) complex. Deuteration reactions of 1c and 1d indicate a clean syn addition of
deuterium to the double bond without isotopic effect on enantioselectivity.
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Introduction
Chiral 2ꢀaminotetralines comprise an important class of compounds in medicinal chemistry.1
Comprehensive information covering the biological properties of a large number of examples can be
found in the literature and remarkably, several examples have found application in the pharmaceutical
industry (Figure 1).2 Due to the importance of these chiral derivatives, the development of efficient
procedures for the synthesis of a broad range of these amines is highly desirable. As Nꢀ(3,4ꢀ
dihydronaphthalenꢀ2ꢀyl) amides can readily be prepared in one step from commercially available 2ꢀ
tetralones,3 the hydrogenation of these enamides provides a straightforward procedure for the
preparation of chiral 2ꢀaminotetraline derivatives.
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Diverse catalysts,4ꢀ6 mostly based on ruthenium and rhodium complexes, have been examined in the
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hydrogenation of the aforementioned enamides with very dissimilar performance. Thus, ruthenium
catalysts with diphosphine ligands have provided good activity and enantioselectivity levels, in the
hydrogenation of several examples under relatively high hydrogen pressures (20ꢀ100 atm).1a, 4 In
contrast to that, rhodium catalysts usually show higher activity but they have consistently given low
enantioselectivities in the hydrogenation of the representative substrate Nꢀ(3,4ꢀdihydronaphthalenꢀ2ꢀyl)
acetamide (A, Figure 2).5 This is a rather surprising aspect considering that compound A possess the
auxiliary amide carbonyl group needed for substrate chelation,7 and the vast range of Rh catalysts tested
in the hydrogenation of this substrate.
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N
O
H
N
OH
SMe
N
N
EtO2C
O
Cl
H
N
N
O
SR58611A
LY274600
AR-A2
Cl
S
H
N
S
O O
N
F
N
N
S
NH2
HO2C
F
OH
Terutroban
Rotigotine
Nepicastat
Figure 1. Chiral aminotetralines with pharmaceutical application.
A notable exception among the rhodium catalysts described has been provided by a supramolecular
complex containing phosphine and phosphite ligands, named Supraphos, described by the group of
Reek.8 Following an approach based on the generation of chelating ligands from monodentate
assembling ones, these researchers have achieved a catalyst which provides an outstanding 94 % ee in
the hydrogenation of Nꢀ(3,4ꢀdihydronaphthalenꢀ2ꢀyl) acetamide.
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A comparison between compound A and types of enamides which typically provide highly
enantioselective hydrogenations with Rh catalysts, like dehydroaminoacids (B), enamido phosphonates
(C) or aryl enamides (D),9 reveals some important differences. First of all, compounds B, C, and to a
lesser extent D, possess an electronꢀwithdrawing group bonded to the same carbon (α) as the amido
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group. This arrangement favours the regioselectivity of the olefin insertion step to give an αꢀalkyl
intermediate F. On the contrary, the substitution of the accepting group by an alkyl group and the
presence of a βꢀaryl group may favour the formation of a βꢀalkyl intermediate G in the hydrogenation of
substrates A.10 Moreover, several studies have connected a change in the regioselectivity of the olefin
insertion step with a product enantioreversal.10a, 11 Thus, if a competition between αꢀ and βꢀalkyl
pathways occurs, a severe drop in enantioselectivity may also take place. Moreover, the cyclic nature of
enamides A, which imposes an E olefin configuration, probably impedes achieving high
enantioselectivities. At this regard, it should be mentioned that Zhang and coworkers have recently
demonstrated that the hydrogenation of E isomers of acyclic enamides E occurs with significantly lower
enantioselectivity than that of Z isomers.12 Likewise, Eꢀαꢀacetamidocinnamic acid derivatives usually
give less enantioselective hydrogenations than isomers Z (B).13
NHAc
CO2Me
NHAc
P(O)(OMe)2
NHAc
A
B
C
β
Rh
β
Rh
R1
R2
R1
R2
NHAc
O
O
α
α
N
H
N
H
NHAc
D
E
G
F
Figure 2. Structures AꢀG.
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In recent years, we have studied the application of chiral phosphineꢀphosphites in the hydrogenation of
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several types of olefins by Rh catalysts.11c, 14 From this background and inspired by the results reported
for the Supraphos catalysts, we were interested to investigate the performance of rhodium complexes
based on the conventional phosphineꢀphosphites developed in our laboratory, in the hydrogenation of
the challenging enamide A. Herein, we describe an extensive catalyst screening using a family of
phosphineꢀphosphite ligands in the hydrogenation of several Nꢀ(3,4ꢀdihydronaphthalenꢀ2ꢀyl) amides.
Following a systematic optimization procedure, a highly enantioselective catalyst for this kind of
substrates has been found.
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Results and Discussion
Synthesis of substrates. A series of Nꢀ(3,4ꢀdihydronaphthalenꢀ2ꢀyl) amides 1 has been prepared by
condensation between commercially available 2ꢀtetralones and acetamide or benzamide in the presence
of a catalytic amount of acid in moderate yields (Scheme 1).3 In the set, several methoxy substituted
examples have been considered, as they can provide a convenient access to important hydroxyꢀ2ꢀ
aminotetralines.15 Likewise, structurally similar enol esters 2 were prepared from 2ꢀtetralone using
literature procedures.16 For comparative purposes, enamide 3 derived from αꢀtetralone was also
included.
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O
NHC(O)R
OC(O)R'
RC(O)NH2
Base
1
2
3
TsOH (cat)
R'C(O)Cl
X
X
1
4
2-3
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9
NHBz
NHAc
NHAc
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MeO
1b
1a
1c
OMe
MeO
NHAc
NHAc
NHAc
Br
1d
1f
NHAc
1e
OAc
OPiv
2a
2b
3
Scheme 1. Synthesis and structures of investigated olefin substrates.
Influence of the ligand in the asymmetric hydrogenation. The hydrogenation of the representative
enamide 1a with Rh catalyst precursors based on phosphineꢀphosphite ligands 4 (Scheme 2, Chart 1),
using either isolated catalyst precursors of formulation [Rh(COD)(4)]BF4 (5),14 or generated in situ from
[Rh(COD)2]BF4 and an stoichiometric amount of 4, has been investigated. The library of chiral ligands
contains examples which mainly differ in the nature of the backbone: benzene (4a), ethane (4bꢀ4d) or
substituted ethane (4eꢀ4k). Moreover, the ligands in the set differ in the position of the stereogenic
elements. Thus, ligands 4l and 4m possess a Pꢀstereogenic phosphino fragment. On the other hand,
ligands 4eꢀ4h contain a stereogenic center at the βꢀposition (to the phosphine) of the backbone, while
for ligands 4j and 4k the stereogenic center is at position α. In addition, all of the examples contain an
atropisomeric phosphite fragment.
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NHC(O)R
NHC(O)R
Rh cat
1
2
3
4
X
X
R = Me, Ph
X = H, OMe, Br
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1
5
6
Rh cat: [Rh(COD)(4)]BF4 or [Rh(COD)2]BF4 + 4 (1.1 equiv.)
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Scheme 2. Hydrogenation reaction of enamides 1.
In an initial approach, we examined precatalysts 5a and 5b in the reduction of 1a at 20 bar of
hydrogen and room temperature, as low conversions at 4 bar of hydrogen were observed. Among them,
catalyst based on less rigid 4b offered a superior activity and enantioselectivity (entries 1 and 2, Table
1). An attempt to increase conversion by using alternative phosphine fragments proved to be fruitless
(entries 3,4). After these preliminary results, we performed a set of reactions under different initial
hydrogen pressures (entries 5ꢀ6), without improvement over the value obtained at 20 atm. In addition, an
increase in temperature up to 40 ºC had a deleterious effect on enantioselectivity (entry 7).
On the other hand, considering that the RhꢀSupraphos catalytic system is capable to provide high
enantioselectivities in the presence of a considerable amount of diisopropylethylamine (DIPEA) as an
additive,8, 17 the hydrogenation of 1a with catalyst precursors 5a, 5b and 5d in the presence of 20
equivalents of DIPEA was examined. Most notably, the base has a critical influence on the present
catalytic system. It produces an important, particularly for catalyst based on 4a, increase in conversion,
although racemic products were unexpectedly obtained (entries 8ꢀ10).18ꢀ19 It is noteworthy that catalysts
with different phosphine groups and dynamic properties give null enantioselectivity, pointing to a
general effect of the additive. It looks therefore apparent that the addition of base leads to an alternative
catalyst. In connection with this it should be mentioned that the deprotonation of cationic dihydrides to
give neutral monohydrides, which are highly active olefin hydrogenation catalysts, has been well
documented in the literature.20 Comparing with diphosphine catalysts, the presence of the πꢀacceptor
phosphite group in PꢀOP ligand should increase the acidity of corresponding cationic dihydrides,
favouring deprotonation by the amine. However, the complexity of the system does not confidently
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allow us to assign the lack of enantioselectivity to the purported monohydride Rh(H)(PꢀOP)(S)n (S =
solvent, n = 1ꢀ3) over other alternatives like the formation of metallic clusters upon addition of base,21
the dissociation or the decomposition of the chiral ligand. Therefore, a specific study covering
alternative ligands, additives and substrates is needed to clarify this effect.
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tBu
tBu
PR2
PPh2
O P
O
O
O
O
S
S
O P
4a
tBu
tBu
R = Ph (4b), Xy (4c), iPr (4d)
tBu
tBu
PPh2
O P
PPh2
R
Ph
R
Ph
O
O
O
S
O P
R
O
tBu
4e
4f
tBu
tBu
tBu
tBu
PPh2
PPh2
O P
PPh2
O P
R
S
Me
O
O
O
O
O
S
S
O P
S
Me
O
tBu
tBu
tBu
4i
4h
4g
tBu
tBu
Me
PPh2
O P
PPh2
O P
Me
R
R
O
O
O
O
S
R
tBu
tBu
4j
4k
o-An
o-An
Ph
Ph
tBu
tBu
S
P
S
P
O
O
O
O
O P
S
R
O P
4l
tBu
4m
tBu
Chart 1. Phosphineꢀphosphite ligands 4 used in this study.
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Finally, from a practical point of view, it is interesting to note that similar results were obtained with
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5b and the catalyst generated in situ from [Rh(COD)2]BF4 and 1.1 equivalents of 4b (entry 1, Table 2).
Thus, the analysis of the influence of the ligand was performed with catalyst precursors generated in
situ.
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After the result shown by the ethane bridged complex 5b, we tried to improve catalyst
enantioselectivity by tuning the backbone structure with substituents in either α or β positions with a
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defined stereochemistry.14d Pairs of ligands with βꢀPh (4e, 4f) and βꢀMe (4g, 4h) substituents, with
different relative backbone configuration to the biphenyl phosphite fragment, as well as βꢀMe2 example
(4i) were then tested (entries 2ꢀ6). No improvement over the result obtained with 4b was obtained,
therefore concluding that the presence of the β substituent is detrimental in these reactions. In contrast,
catalysts with an αꢀMe group to the phosphine group provided relatively good enantioselectivity values
of 75 % ee (4j, entry 7) and 81 % ee (4k, entry 8). The latter catalyst is only slightly more
enantioselective than catalyst based on 4b, and the small improvement does not justify the introduction
of an additional stereogenic center. Overall, the most simple ethane backbone looks more suitable for
this reaction. However, the latter results offered a hint for a further enhancement of the catalyst. The
presence of the αꢀmethyl group in ligands 4j and 4k favours a chiral distribution of aryl phosphine
substituents,22 and prompted us to investigate examples with a Pꢀstereogenic biarylphosphino fragment.
Thus, diastereomeric ligands 4l and 4m bearing a P(oꢀAn)Ph group were examined.14d Most noteworthy,
catalyst based on ligand 4l produced a significant improvement on enantioselectivity up to 93 % ee
(entry 9). On the other hand, the catalyst bearing ligand 4m gave lower enantioselectivity (77 % ee, entry
10). A comparison between these results indicates that the configuration of the product is determined by
the configuration of the phosphite, as observed before in the hydrogenation of methyl Zꢀ(α)ꢀNꢀ
acetamido cinnamate (MAC) and other olefins.14 It should also be mentioned that the enantioselectivity
provided by catalyst based on 4l is very close to the best value obtained with a Rh catalyst in this
reaction (94 % ee).8
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1
2
3
a
Table 1. Hydrogenation of 1a using complexes [Rh(COD)(4)]BF4
4
5
6
7
8
Entry
1
PꢀOP ligand
P (atm H2)
% conv
18
% ee (conf)
68 (S)
81 (S)
46 (S)
38 (S)
63 (S)
77 (S)
53 (S)
rac
20
20
20
20
10
30
30
20
20
20
4a
4b
4c
4d
4b
4b
4b
4a
4b
4d
9
2
63
10
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3b
15
4
67
5
50
6
64
7c
8d
9d
10d
92
100
100
100
rac
rac
aReactions were carried out in CH2Cl2 at room temperature unless otherwise specified. S/C = 100,
1
reaction time 21 h. Conversion was determined by H NMR and enantiomeric excess by Chiral GC.
Configuration was determined by comparing the sign of optical rotation with literature data.5d
bPrecatalyst prepared in situ from [Rh(COD)2]BF4 and 1.1 equivalents of 4c. cReaction performed at 40
ºC. dReactions performed in the presence of 20 equiv of DIPEA.
Scope of the reaction. We further investigated the scope of catalyst bearing 4l in the reduction of
enamides 1 (Table 3). Most noteworthy relatively high enantioselectivities, between 83 and 93 % ee,
were observed in these reactions. Thus, benzamide 1b gave a 93 % ee, although it was less reactive than
1a, and produced a moderate conversion (entry 1). An increase in the temperature to 40 ºC raised
conversion to 70 %, but the enantioselectivity decreased to 82 % ee (entry 2). Alternatively, catalyst
bearing ligand 4k produced lower levels of conversion and enantioselectivity (entry 3). Methoxy
substituted substrates 1c and 1d provided good conversions with enantioselectivities of 88 and 86 % ee
(entries 4ꢀ5), respectively. Most interestingly, substrate 1e, which should apparently be more
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encumbered than the latter enamides, is significantly more reactive. Thus, catalysts bearing ligands 4a,
4m and 4l gave full conversions for this substrate (entries 6ꢀ8). Among the catalysts investigated, that
based on 4l produced again the best enantioselectivity (93 % ee). Moreover, bromide 1f showed a lower
reactivity under our standard conditions, giving a conversion of 67 % and 83 % ee (entry 9). The
reaction at 40 ºC showed a slightly higher conversion (70 %) and a lower enantioselectivity (80 % ee,
entry 10). Alternatively, diastereomeric catalyst based on ligand 4m, showed a better conversion and a
lower enantioselectivity than catalyst of 4l (entry 11). A perusal of the literature indicates that
hydrogenation of substrates 1c, 1e and 1f have not been reported before, while catalyst of 4l provides the
highest enantioselectivity among Rh complexes in the hydrogenation of 1b and 1d. For the latter
substrates, the best enantioselectivities, 96 and 95 % ee respectively, have been provided by Ru
complexes.4c, 4e
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2
3
4
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Table 2. Hydrogenation of 1a with catalysts prepared from [Rh(COD)2]BF4 and 4a
Entry
PꢀOP ligand
% conv
69
% ee (conf)
80 (S)
76 (S)
60 (R)
63 (S)
75 (S)
8 (S)
1
2
3
4
5
6
7
8
9
10
4b
4e
4f
38
80
33
4g
4h
4i
20
82
70
75 (S)
81 (R)
93 (S)
77 (R)
4j
41
4k
4l
90
70
4m
aReactions were carried out at room temperature with an initial hydrogen pressure of 20 bar unless
1
otherwise specified. S/C = 100, reaction time 21 h. Conversion was determined by H NMR and
enantiomeric excess by Chiral GC.
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9
In addition, we were interested in examining the possibility to hydrogenate structurally related enol
esters 2, as an appealing approach to the synthesis of chiral 2ꢀhydroxytetralines. Unexpectedly,
substrates 2 were very unreactive and no conversion was observed in reactions performed with catalyst
precursor 5b under the reaction conditions used for enamides 1 (entries 12, 13).
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12
13
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Table 3. Hydrogenation of substrates 1ꢀ3 with catalysts prepared from [Rh(COD)2]BF4 and 4a
Entry
1
PꢀOP ligand
Substrate
% conv
40
% eeb
93 (S)
82 (S)
50 (R)
88 (S)
86 (S)
83 (S)
81 (R)
93 (S)
83 (S)
81 (S)
68 (R)
n. d.
4l
1b
1b
1b
1c
1d
1e
1e
1e
1f
1f
1f
2a
2b
3
2 c
70
4l
3
24
4k
4l
4
82
5
80
4l
6
100
100
100
67
4a
4m
4l
7
8
9
4l
10c
11
12
13
14
15
70
4l
75
4m
4b
4b
4l
< 5
< 5
100
100
n. d.
77 (R)
57 (S)
4m
3
aReactions were carried out at room temperature unless otherwise specified. S/C = 100, reaction time 21
h. Conversion was determined by 1H NMR and enantiomeric excess by Chiral HPLC. bConfiguration for
6d has been assigned by comparing optical rotation with literature data,4e while for the rest of
compounds configuration has been assigned by analogy to that observed in hydrogenations of 1a and 1d.
cReaction performed at 40 ºC.
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1
2
3
4
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7
8
9
For comparison, the performance of catalysts based on some ligands 4 in the hydrogenation of the
enamide 3 has also been examined. Then, catalyst based on 4l provided full conversion giving the
hydrogenated compound (R)ꢀ7 with a respectable 77 % ee (entry 14, Table 3). The diastereomeric
catalyst precursor bearing ligand 4m provided the opposite enantiomer (S)ꢀ7 with a 57 % ee (entry 15).
The configuration of the product is therefore determined by the configuration of the phosphite fragment,
as observed in the hydrogenation of substrates 1. Moreover, the configurations of 7 and 6d indicate the
same sense for addition of hydrogen to 3 and 1d, respectively (Figure 3).
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Figure 3. Comparison of product configuration in the hydrogenation of 3 and 1d.
Further mechanistic considerations. The challenging nature of substrates 1 for Rh hydrogenation
along with the lack of mechanistic information about this particular reaction in the literature, prompted
us to investigate several fundamental features of these substrates connected with their hydrogenations.
At this respect, a first aspect of interest regards the coordination mode of enamides 1 towards a [Rh(4)]+
fragment. For this purpose, representative enamide 1d was chosen.
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A compound of composition [Rh(4c)(1d)]BF4 was prepared by hydrogenation of [Rh(COD)(4c)]BF4
1
2
3
in DME, followed by evaporation of the solvent, dissolution in CD2Cl2 and addition of two equivalents
4
5
6
31
of 1d (Figure 4). An analysis of the resulting mixture by P{1H} NMR showed the presence of two
7
8
species in ca. 3:1 ratio characterized by rather similar spectral data. The major species appears as two
9
2
doublet of doublets centered at 125.8 ppm (1JRhP = 322 Hz, JPP = 76 Hz) and 24.8 ppm (1JRhP = 187
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Hz), for the phosphine and phosphite fragments, respectively. The minor species likewise appears as two
2
doublet of doublets centered at 127.5 ppm (1JRhP = 330 Hz, JPP = 76 Hz) and 23.6 ppm (1JRhP = 188
Hz). In addition, an analysis of the major compound by a 2D COSY experiment, allowed us to identify
the signals for Hc and Hd, while the 2D NOESY experiment showed contacts between Hb and Hc with
the OMe group, as well as between Ha and Hb. From this information it can be concluded that Ha, Hb, Hc
3
and Hd appeared at 6.76, 4.97, 5.84 (d, JHH = 7.0 Hz) and 4.12 (d) ppm, respectively, in the major
compound (Table 4, entry 2). For comparison, it should be mentioned that Ha appeared in the free
substrate at 7.09 ppm, while the aromatic protons Hb, Hc and Hd showed signals at 6.59, 6.58 (d, 3JHH
=
7.5 Hz) and 6.96 (d) ppm, respectively (entry 1). Therefore, there is an important high field displacement
of the signals of aromatic protons upon coordination of 1d. These shifts are in good accord with a η6ꢀ
1
arene coordination mode.23 In addition, the relatively high values for JRhP are similar to values found
before for other arene adducts of Rh compounds with phosphineꢀphosphite ligands.11c This coordination
mode can be further confirmed by the chemical shifts of the corresponding CbꢀCd nuclei in the 13C{1H}
NMR experiment, assigned with the help of a HMQC experiment. Therefore, CHb, CHc and CHd signals
appeared for the major isomer at 85.0, 92.2 and 94.8 ppm, respectively (entry 2). For comparison, the
corresponding signals appear in the free substrate at 111.2, 111.7 and 128.0 ppm, respectively (entry 1).
1
Similar high field shifts were observed in the H NMR spectrum for the minor species, and Hb, Hc and
Hd signals are centered at 5.93, 4.64 and 5.81 ppm, respectively (entry 3), also supporting a η6ꢀarene
coordination. From these data, it is reasonable to propose that the two compounds observed in solution
are diastereomers resulting from coordination of 1d by each of its diastereotopic faces. Interestingly, no
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exchange between adducts was observed in the 2D EXSY experiment pointed to a slow decoordination
of the arene adduct in the NMR timeꢀscale.
1
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Figure 4. Synthesis of arene complex [Rh(4c)(η6ꢀ1d)]BF4.
Table 4. 1H and 13C{1H} NMR data of 1d and isomers of complex [Rh(4c)(η6ꢀ1d)]BF4
¶
Entry
Compound
Ha
Hb
Hc
Hd
Ca
Cb
Cc
Cd
1
2
7.09
6.76
6.58
4.97
6.59
5.84
6.96
4.12
110.8
102.9
111.2
85.5
111.7
91.8
128.0
94.9
1d
[Rh(4c)(1d)]+
(maj)
3§
6.39
5.92
5.81
4.65
104.6
91.8
n. a.
n. a.
[Rh(4c)(1d)]+
(min)
13
¶All spectra registered in CD2Cl2 except C{1H} NMR of [Rh(1d)(4l)]BF4, recorded in CDCl3. See
Figure 3 for notation. §Signals for Cc and Cd nuclei of the minor isomer were not detected in the HMQC
experiment due to low concentration.
It is remarkable to note that the η6ꢀarene coordination mode exhibited by 1d is unusual for an Nꢀacyl
enamide, which typically shows a O,C,C chelating mode in Rh(I) complexes.7 On the contrary, arene
complexes formed by the corresponding hydrogenated products, therefore lacking the olefin bond, are
well known in the literature.24
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The participation of complexes of formula [Rh(4)(η6ꢀ1)]+ in the catalytic reaction would however
depend on the mechanism of the hydrogenation of 1. In a detailed study, Gridnev and Imamoto have
compared the energy profile of several mechanistic pathways for the hydrogeanation of MAC with Rh
catalysts bearing strong donor diphosphines,25 pointing to routes involving hydrogen addition prior to
olefin coordination as the most favourable ones. In addition, the hydrogenations described herein are
performed at moderate hydrogen pressures, while compound [Rh(4c)(η6ꢀ1d)]BF4 has been formed in the
absence of hydrogen. However, considering that the stability of Rh(III) dihydrides is favored by electron
rich ligands,26 the low donor ability of PꢀOP ligands may shift the preference for an unsaturated pathway
(i. e. olefin coordination prior to hydrogen addition). At this respect, Maseras and Vidal have proposed
an unsaturated mechanism for the hydrogenation of MAC with Rh catalysts bearing phosphineꢀ
phosphite ligands.27 If an analogous pathway is followed in the present system, dissociation of the arene
ring from the 18ꢀelectron [Rh(4)(η6ꢀ1)]+ and recoordination of 1 in a less stable [Rh(4)(O,C,Cꢀ1]+
(Figure 5) should occur to start the hydrogenation cycle. Moreover it should be recalled that Heller has
nicely demonstrated the detrimental effect that the formation of stable η6ꢀarene complexes produce on
hydrogenation rate, due to the reduced available amount of rhodium complex for catalysis.23c Following
this reasoning, the coordination mode exhibited by 1d would agree with the relatively low rates
exhibited by substrates 1. As an illustrative comparison, it can be mentioned that hydrogenation of MAC
or dimethyl itaconate with complexes 5 at S/C = 100 under 1 bar of hydrogen are typically finished after
1ꢀ2 h, while under these reaction conditions conversion after 72 h for substrates 1a, 1c and 1d were 70,
56 and 53 %, using catalyst bearing ligand 4l. Likewise, the lack of reactivity of enolꢀesters 2 can also be
attributed to the formation of η6ꢀarene species, as the inability of αꢀacyloxyacrylates to displace η6ꢀ
benzene has been reported before.28
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Figure 5. Expected formation of the [Rh(4c)(O,C,Cꢀ1d]+ complex from [Rh(4c)(η6ꢀ1d)]+.
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In addition, we considered of fundamental interest to investigate the deuteration of selected substrates
1c and 1d under our standard conditions (20 bar D2, S/C = 100, room temperature). An analysis of
1
2
product 6d by H, H and 13C{1H} showed a single isotopomer in solution, in which labeling was
observed in positions Ha1 and Hg (Figure 6), in good accord with the characteristic cis addition to the
double bond. No deuterium incorporation was observed either in position 3 or in the aromatic ring.
Likewise, compound 6c showed a similar pattern. An analysis of the enantioselectivity of these reactions
indicated values of 89 and 87 % ee, for 6c and 6d, respectively, identical within the experimental error
to those of the hydrogenation reactions (88 and 86 % ee, respectively). In this context it is pertinent to
recall the enantioreversal observed in the hydrogenation of αꢀ and βꢀacyloxyvinylphosphonates with
complexes 5, which has been rationalized on the formation of αꢀ and βꢀalkyl intermediates,
respectively.11c Thus, a possible factor for erosion of enantioselectivity in the hydrogenation of
substrates 1 could be a competition between αꢀ and βꢀalkyl pathways, considering that they can provide
opposite enantiomers.11 At this regard, a mechanistic study has connected the observation of an isotopic
effect on enantioselectivity in Rh catalyzed enamide hydrogenation with the competition between αꢀ and
βꢀalkyl pathways.29 Based upon that line of reasoning, the absence of isotopic effect observed in the
hydrogenation of 1c and 1d, would agree with an absence of competition between the two pathways.
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(c)
(b)
(a)
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OMe
C(O)Me
Ha1
Ha2
Hg
NHC(O)Me
MeO
f
e
6d
Hg
Ha1
He
Ha2
Hf
Hf
1
1
2
Figure 6. H NMR spectrum of 6d (a); H NMR spectrum (b) and H NMR spectra (c) of product
obtained by deuteration of 1d with [Rh(COD)(4b)]BF4.
Conclusions
The enantioselective catalytic hydrogenation of enamides 1 with rhodium catalysts based on modular
phosphineꢀphosphite ligands 4 has been studied. A broad screening with these catalysts indicates that the
hydrogenation of 1 is very sensitive to subtle changes in ligand backbone, pointing to the need of a
precise optimization of the catalyst structure for substrates 1. Following this approach a highly
enantioselective catalyst based on a ligand with an ethane backbone and a Pꢀstereogenic phosphine
fragment, with matched phosphine and biphenyl configurations, has been found. This catalyst provides
high enantioselectivities, ranging from 83 to 93 % ee, in the hydrogenation of several –OMe and –Br
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substituted substrates 1. In contrast, structurally related enol esters 2 show very little reactivity.
Unexpectedly, the addition of DIPEA to the reaction has a dramatic effect increasing catalyst activity but
leading to racemic products.
1
2
3
4
5
6
7
8
9
Coordination studies of representative enamide 1d have shown a marked preference for a η6ꢀarene
coordination in a Rh(I) complex, which is in accord with the relatively low rates shown by these
substrates. Moreover, deuteration of substrates 1c and 1d under the standard reaction conditions show a
clean 1,2ꢀcis addition to the double bond, without isotopic effect on enantioselectivity. The results
obtained, however, did not show a distinctive feature of the hydrogenation of substrates 1, responsible of
the rather difficult control of enantioselectivity in these reactions.
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Experimental Section
General Procedures. All reactions and manipulations were performed under nitrogen or argon, either
in a glovebox or using standard Schlenkꢀtype techniques. All solvents were distilled under nitrogen with
the following desiccants: sodiumꢀbenzophenoneꢀketyl for diethyl ether (Et2O) and tetrahydrofuran
(THF); sodium for hexanes and toluene; CaH2 for dichloromethane (CH2Cl2); and NaOMe for methanol
(MeOH). Phosphineꢀphosphite ligands 4 were prepared as described previously.14 Enamides 1,3 enol
esters 216 and enamide 330 were synthesized according to literature procedures. All other reagents were
31
purchased from commercial suppliers and used as received. P{1H} NMR shifts were referenced to
13
1
external 85% H3PO4, while C{1H} and H shifts were referenced to the residual signals of deuterated
solvents. All data are reported in ppm downfield from SiMe4. All NMR measurements were carried out
at 25 °C, unless otherwise stated. HRMS data were obtained on a quadrupole analyzer.
[Rh(COD)(4c)]BF4 (5c). Ligand 4c (0.100 g, 0.15 mmol) dissolved in CH2Cl2 (5 mL) was added
dropwise to a solution of [Rh(COD)2]BF4 (0.056 g, 0.15 mmol) in CH2Cl2 (5 mL). The resulting orange
solution was stirred for 1 h, concentrated up to oneꢀfourth of its initial volume and filtered. Et2O (20
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mL) was added to the above solution to precipitate the complex. The solid was filtered off, washed with
Et2O (3 × 10 mL) and dried. Yellow solid (0.104 g, 69%). 1H NMR (500 MHz, CDCl3): δ = 7.66 (d, J =
11 Hz, 2H), 7.29 (s, 1H), 7.25 (s, 1H), 7.16 (s, 1H), 7.15 (s, 1H), 6.92 (d, J = 11 Hz, 2H), 5.86 (br s,
1H), 5.17 (br s, 1H), 4.60 (m, 1H), 4.37 (br s, 2H), 3.98 (m, 2H), 3.01 (m, 1H), 2.47 (m, 3H), 2.42 (s,
6H), 2.35 (s, 6H), 2.30 (s, 3H), 2.24 (s, 3H), 2.17 (m, 2H), 2.03 (m, 4H), 1.84 (s, 3H), 1.76 (s, 3H), 1.66
1
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31
(s, 9H), 1.38 (s, 9H); P{1H} NMR (202 MHz, CDCl3): δ = 118.7 (dd, JPRh = 246 Hz, JPP = 60 Hz, Pꢀ
O), 4.05 (dd, JPRh = 140 Hz, PꢀC); 13C{1H} NMR (101 MHz, CDCl3): δ = 144.7 (d, J = 6 Hz), 144.0 (d,
J = 13 Hz), 139.7 (d, J = 11 Hz), 139.5 (d, J = 10 Hz), 137.0, 137.0, 136.3, 135.5, 134.9, 134.0, 133.5,
133.0, 132.9, 129.8, 129.8, 129.3, 129.2, 129.1, 128.7, 128.6, 128.4, 128.2, 128.2, 110.5 (dd, J = 13 Hz,
J = 6 Hz), 107.3 (dd, J = 12 Hz, J = 6 Hz), 106.2 (m), 94.8 (m), 64.9, 35.0, 35.0, 32.4, 31.8, 31.3, 30.7,
30.3, 28.8, 26.0 (dd, J = 31 Hz, J = 13 Hz), 21.7, 21.6, 20.6, 20.5, 16.8, 16.6; elemental analysis calcd
(%) for C50H66BF4O3P2Rh: C, 62.12; H, 6.88; found: C 61.92, H 7.15.
General procedure for the synthesis of enamides 1. Enamides 1 were prepared by an adaptation of a
literature procedure3 as described below. In a 250 mL roundꢀbottom flask equipped with a DeanꢀStark
apparatus were introduced the ketone (10 mmol), the primary amide (25 mmol) and TsOH (1 mmol) in
toluene (60 mL). The mixture was refluxed for 20 h under an inert atmosphere. After cooling down to
room temperature, 150 mL of a saturated solution of sodium hydrogen carbonate were added and the
mixture was warmed to 60 ºC for 30 min. After cooling down to room temperature, the organic layer
was extracted, washed with water (3 x 100 mL), dried over magnesium sulfate and concentrated. The
enamide was purified by chromatography on silica gel or isolated by crystallization.
N-(6-methoxy-3,4-dihydronaphthalen-2-yl)-acetamide (1c). Obtained following the general
procedure as a white powder (0.61 g, 50% yield) after flash column chromatography on silica gel
(AcOEt/hexane, 6/1): mp: 124ꢀ127º; 1H NMR (500 MHz, CDCl3): δ = 7.01 (s, 1H), 6.96 (d, J = 7.8 Hz,
1H), 6.65 (m, 3H), 3.78 (s, 3H), 2.86 (t, J = 7.5 Hz, 2H), 2.43 (t, J = 7.5 Hz, 2H), 2.10 (s, 3H); 13C{1H}
NMR (126 MHz, CDCl3): δ = 168.4, 158.1, 134.5, 132.8, 127.7, 127.1, 113.7, 111.4, 111.3, 55.4, 28.5,
27.5, 24.8; HRMS (EI): m/z 217.1102, [M]+ (exact mass calcd for C13H15NO2: 217.1103).
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N-(8-methoxy-3,4-dihydronaphthalen-2-yl)-acetamide (1e). Obtained as a white powder by
1
2
3
1
crystallization in a CH2Cl2/nꢀhexane (1:1) mixture (0.6 g, 50% yield): mp: 168ꢀ171º; H NMR (500
4
5
6
MHz, CDCl3): δ = 7.17 (s, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.70 (d, J = 7.8 Hz, 2H), 6.65 (br s, 1H), 3.81
13
(s, 3H), 2.86 (t, J = 8.0 Hz, 2H), 2.52 (t, J = 8.0 Hz, 2H), 2.10 (s, 3H); C{1H} NMR (126 MHz,
7
8
9
CDCl3): δ= 168.2, 154.7, 135.0, 134.4, 126.4, 123.4, 119.8, 108.9, 105.7, 55.6, 28.4, 26.9, 24.8; HRMS
(EI): m/z 217.1110, [M]+ (exact mass calcd for C13H15NO2: 217.1103).
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N-(6-Br-3,4-dihydronaphthalen-2-yl)-acetamide (1f). Prepared according to the general procedure
1
and purified by crystallization in toluene. White crystalline solid (0.34 g, 30% yield): mp: 196ꢀ199º; H
RMN (500 MHz, CDCl3): δ = 7.24 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 7.07 (s, 1H), 6.89 (d, J = 8.0 Hz,
1H), 6.58 (br s, 1H), 2.85 (t, J = 8.1 Hz, 2H), 2.41 (t, J = 8.1 Hz, 2H), 2.12 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3): δ = 168.5, 135.3, 134.7, 133.8, 130.0, 129.8, 127.6, , 110.5, 27.8, 27.5, 24.9; HRMS (EI):
m/z 265.0103, [M]+ (exact mass calcd for C12H12NOBr: 265.0102).
General Procedure for Catalytic Hydrogenation Reactions. In a glovebox, the appropriate olefin
(0.036 mmol), phosphineꢀphosphite ligand (0.46 ꢀmol) and [Rh(COD)2]BF4 (0.42 ꢀmol) from freshly
prepared stock solutions in CH2Cl2 (total volume = 0.5 mL), were added to a 2 mL glass vial. Vials were
placed in a steel reaction vessel model HEL CAT18 that holds up to eighteen reactions. The reactor was
purged three times with H2 and finally pressurized to the required pressure. In the case of deuteration
reactions the reactor was purged with Ar, partially evacuated under vacuum and filled with D2 at 20 atm.
After the desired reaction time, the reactor was slowly depressurized, solutions were evaporated and
conversions were determined by 1H NMR. The resulting mixtures were dissolved in EtOAc, and filtered
through a short pad of silica to remove the catalyst. Enantiomeric excess was analyzed by chiral GC or
HPLC, as follows: N-(1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (6a): GC, Supelco βꢀDEX 110;
100 °C (2 min), then 2 °C/min up to 190 °C; 28.0 psi He; t1 = 46.41 min, t2 = 46.59 min; N-(1,2,3,4-
tetrahydronaphthalen-2-yl)-benzamide (6b): HPLC, Daicel Chiralcel OJꢀH 90:10/ nꢀhexane:iꢀPrOH,
t1 = 18.5 min., t2= 22.3 min; N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (6c):
HPLC, Daicel Chiralcel OJꢀH 90:10/ nꢀhexane:iꢀPrOH, t1 = 20.82 min., t2= 30.70 min.; N-(7-methoxy-
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1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (6d): HPLC, Daicel Chiralcel OJꢀH 90:10/ nꢀhexane:iꢀ
PrOH, t1 = 20.6 min., t2= 32.9 min; N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide
(6e): HPLC, Daicel Chiralcel OJꢀH 90:10/ nꢀhexane:iꢀPrOH, t1 = 12.12 min., t2= 13.54 min.; N-(6-Br-
1,2,3,4-dihydronaphthalen-2-yl)-acetamide (6f): HPLC, Daicel Chiralcel OJꢀH 90:10/ nꢀhexane:iꢀ
PrOH, t1 = 11.09 min., t2= 13.18 min.; N-(1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide (7): HPLC,
Daicel Chiralcel OJꢀH 99.5:0.5/ nꢀhexane:iꢀPrOH, t1 = 14.6 min., t2= 15.6 min.
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N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (6c). Obtained with a 82 %
conversion following the general procedure, further purified by preparative TLC (CH2Cl2/nꢀhexane: 9:1)
giving 6c as a yellow solid (26 % yield): mp: 109ꢀ112º; [α]D 20 = ꢀ25.1 (c 0.1, CHCl3, S enantiomer 88 %
1
ee); H NMR (500 MHz, CDCl3) δ = 6.97 (d, J = 8.4 Hz, 1H), 6.70 (dd, J = 2.4 Hz, J = 8.4 Hz, 1H),
6.64 (d, J = 2.5 Hz, 1H), 5.51 (br s, 1H), 4.28 (m, 1H), 3.78 (s, 3H), 3.05 (dd, J = 4.9 Hz, J = 15.9 Hz,
1H), 2.85 (m, 2H; CH2), 2.57 (dd, J = 7.7 Hz, J = 16.0 Hz, 1H), 2.03 (m, 1H), 1.98 (s, 3H), 1.79 (m,
13
1H); C{1H} NMR (100.6 MHz, CDCl3): δ = 169.9, 158.1, 136.7), 130.5, 126.0, 113.5, 112.5, 55.4,
45.5, 35.0, 28.5, 27.3, 23.7; HRMS (EI): m/z 219.1256, [M]+ (exact mass calcd for C13H17NO2:
219.1259).
N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (6e). According to the general
procedure, obtained with a 95 % yield. Yellow powder: mp: 119ꢀ122º; [α]D 20 = ꢀ27.0 (c 0.1,CHCl3, S
1
enantiomer 93 % ee); H NMR (400 MHz, CDCl3): δ = 7.12 (t, J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz,
1H), 6.67 (d, J = 8.0 Hz, 1H), 5.65 (br s, 1H), 4.27 (m, 1H), 3.80 (s, 3H), 3.06 (dd, J = 6.0 Hz, J = 17.3
Hz, 1H), 2.85 (m, 2H), 2.45 (dd, J = 8.0 Hz, J = 17.3 Hz 1H), 2.04 (m, 1H), 2.10 (s, 3H), 1.76 (m, 1H);
13C{1H} NMR (126 MHz, CDCl3): δ = 170.0, 157.6, 137.0, 126.6, 123.1, 121.1, 107.2, 55.4, 45.3, 29.8,
28.3, 27.3, 23.6; HRMS (EI): m/z 219.1258, [M]+ (exact mass calcd for C13H17NO2: 219.1259).
N-(6-Br-1,2,3,4-dihydronaphthalen-2-yl)-acetamide (6f). According to the general procedure
compound 6f was obtained with a 70 % conversion. Attempts to separate it from remaining 3f were
1
unsuccessful, therefore 6f is assessed by NMR and HRMS: H NMR (500 MHz, CDCl3): δ = 7.23 (m,
2H), 6.93 (d, J = 8.0 Hz, 1H), 5.48 (br s, 1H), 4.27 (m, 1H), 3.07 (dd, J = 4.8 Hz, J = 16.5 Hz, 1H), 2.85
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(m, 2H; CH2), 2.57 (dd, J = 8.1 Hz, J = 16.5 Hz, 1H), 2.04 (m, 1H), 1.99 (s, 3H), 1.73 (m, 1H); 13C{1H}
NMR (126 MHz, CDCl3): δ = 169.7, 162.6, 137.9, 133.1, 131.7, 131.2, 129.2, 45.0, 35.4, 29.9, 28.4,
27.0, 23.7; HRMS (CI): m/z 268.0347, [M+H]+ (exact mass calcd for C12H15BrNO: 268.0337).
[Rh(4c)(1d)]BF4. Compound 5c (18 mg, 0.02 mmol) was dissolved in DME (0.5 mL) and the solution
pressurized with 4 bars of hydrogen. The reaction was monitored until dissapearance of the starting
material and the resulting solution evaporated to dryness. The resulting residue was dissolved in CD2Cl2
and 1d (9 mg, 0.04 mmol) was added. The resulting solution showed the enamide adduct as a mixture of
two isomers (maj and min) in a ca. 3:1 ratio. Assignment of aromatic protons of coordinated 1d (see
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1
next figure) have been made with the help of NOESY, COSY and HMQC experiments: H NMR (500
MHz, CD2Cl2): δ = 7.82 (s, 1H), 7.38 (s, 1H), 7.27 (d, J = 10.5 Hz, 2H), 7.26 (s, 1H), 7.17 (s, 2H), 7.02
(d, J = 12.0 Hz, 2H), 6.76 (s, 1H, Ha), 5.85 (dd, J = 7.0 Hz, J = 2.0 Hz, 1H, Hc), 4.97 (s, 1H, Hb), 4.34
(m, 2H), 4.10 ((d, J = 7.0 Hz, 1H, Hd), 4.03 (m, 2H), 3.09 (s, 3H), 2.60 (m, 2H), 2.41 (s, 3H), 2.36 (s,
6H), 2.33 (s, 6H), 2.26 (m, 2H), 2.25 (s, 3H), 2.12 (s, 3H), 2.07 (s, 3H), 2.01 (s, 3H), 1.52 (s, 9H), 1.45
31
(s, 9H); P{1H} NMR (CD2Cl2, 162 MHz): δ = 136.4 (dd, JRhP = 345 Hz, JPP = 69 Hz, PO), 26.4 (dd,
13
JRhP = 191 Hz, JPP = 69 Hz, PC); C{1H} NMR (125.8 MHz, CDCl3): δ = 170.2, 145.9, 142.3, 139.3,
139.1, 139.0, 137.2, 136.3, 136.2, 135.6, 134.1, 134.0, 133.8, 133.1, 132.8, 132.2, 131.9, 131.8, 130.1,
130.0, 129.6, 129.5, 128.7, 127.9, 110.6, 102.5 (CHa), 94.4 (CHd), 91.0 (CHc), 84.5 (CHb), 63.9, 55.8,
33.0, 32.9, 32.1, 31.8, 26.8, 25.1, 24.6, 21.5, 21.4, 21.3, 20.5, 20.2, 16.7, 16.3. Characteristic signals for
the min isomer: 1H NMR (500 MHz, CD2Cl2): δ = 6.25 (s, 1H, H arom, Hb), 5.84 (d, J = 7.0 Hz, 1H, H
31
arom, Hc), 4.43 (s, 1H, H arom, Hd), 3.58 (s, 3H, C(O)Me); P{1H} NMR (CD2Cl2, 162 MHz): δ =
13
139.3 (dd, JRhP = 354 Hz, JPP = 74 Hz, PO), 27.7 (dd, JRhP = 191 Hz, JPP = 74 Hz, PC); C{1H} NMR
(126 MHz, CDCl3): δ = 90.6 (CHc), 91.0 (CHb), 56.3 (OMe). Due to low intensity CHc and CHd signals
for the min isomer could not be located. MS (ESI): m/z 988.4, [M]+ (mass calcd for C55H69NO5P2Rh:
988.4).
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H
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ACKNOWLEDGMENT. We thank Prof. Ilya Gridnev (Tohoku University) for helpful comments.
MICINN (CTQ2009ꢀ11867 and CONSOLIDERꢀINGENIO, CSD2007ꢀ00006, FEDER support) and
Junta de Andalucía (2008/ FQMꢀ3830 and 2009/FQMꢀ4832) are also acknowledged for financial
support. P. K. acknowledges EU for an early stage researcher contract (PITN 2008ꢀ215193). We also
thank CITIUS for technical support on NMR and HRMS experiments.
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Supporting Information Available.
NMR spectra for compounds 1, 6, [Rh(COD)(4c)]BF4 and [Rh(4c)(1d)]BF4. This material is available
free of charge via the Internet at http://pubs.acs.org.
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References
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4. (a) Devocelle, M.; Mortreux, A.; Agbossou, F.; Dormoy, J.ꢀR. Tetrahedron Lett. 1999, 40, 4551. (b)
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Imanishi, M.; Nakajima, Y.; Tomishima, Y.; Hamashima, H.; Washizuka, K.; Sakurai, M.; Matsui, S.;
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8. Jiang, X.ꢀB.; Lefort, L.; Goudriaan, P. E.; de Vries, A. H. M.; van Leeuwen, P. W. N. M.; de Vries, J.
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16. Li, B.ꢀJ.; Xu, L.; Wu, Z.ꢀH.; Guan, B.ꢀT.; Sun, C.ꢀL.; Wang, B.ꢀQ.; Shi, Z.ꢀJ. J. Am. Chem. Soc.
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2009, 131, 14656.
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17. However, at the optimal Rh/P of ca. 3, this catalyst also gives a high enantioselectivity (91 % ee) in
the absence of amine.
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18. The different response to the addition of DIPEA between the Supraphos catalyst and those based on
phosphineꢀphosphites 4 may look surprising. However, either the size or the expected flexibility of the
backbone in the Supraphos catalyst, which may even allow a trans coordination of the bidentate ligand,19
or even the third equivalent of phosphorus ligand, are remarkable differences between the two catalytic
systems which can be responsible for the different influence of base on them.
19. For a highly enantioselective system based on a trans ligand that operates in the presence of base,
see: Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem. Soc. 2000, 122, 7614.
20. (a) Schrock, R. R.; Osborn, J. A. J. Am. Chem. Soc. 1976, 98, 2134. (b) Schrock, R. R.; Osborn, J.
A. J. Am. Chem. Soc. 1976, 98, 4450. (c) Raebiger, J. W.; DuBois, D. L. Organometallics 2004, 24,
110.
21. Preetz, A.; Baumann, W.; Drexler, H.ꢀJ.; Fischer, C.; Sun, J.; Spannenberg, A.; Zimmer, O.; Hell,
W.; Heller, D. Chem. As. J. 2008, 3, 1979.
22. (a) MacNeil, P. A.; Roberts, N. K.; Bosnich, B. J. Am. Chem. Soc. 1981, 103, 2273. (b) Bakos, J.;
Tóth, I.; Heil, B.; Szalontai, G.; Párkányi, L.; Fülöp, V. J. Organomet. Chem. 1989, 370, 263.
23. (a) Singewald, E. T.; Slone, C. S.; Stern, C. L.; Mirkin, C. A.; Yap, G. P. A.; LiableꢀSands, L. M.;
Rheingold, A. L. J. Am. Chem. Soc. 1997, 119, 3048. (b) Heller, D.; Drexler, H.ꢀJ.; Spannenberg, A.;
Heller, B.; You, J.; Baumann, W. Angew. Chem. Int. Ed. 2002, 41, 777. (c) Fischer, C.; Thede, R.;
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