Enantioselective CpRu-catalyzed carroll rearrangement - Ligand and metal source importance

Article abstract of DOI:10.1002/ejoc.200800854

The addition of unstabilized carbonyl nucleophiles to unsymmetrical allyl-metal fragments still represents a challenge to generate stereogenic centers enantio- and regioselectively. In this context, the decarboxylative Carroll rearrangement of allyl β-keto esters is particularly interesting, since chiral γ,δ-unsaturated ketones are obtained. Herein, we show that CpRu half-sandwich complexes can, with selected enantio-pure pyridine-monooxazoline ligands, catalyze this transformation and afford complete conversions along with good levels of regioselectivity and enantioselectivity. Even more challenging (electron-poor) substrates react (up to 86% ee, branched/linear ratio ≥ 97:03). In addition, the use of an air-stable metal precursor, namely [CpRu(η⁶-naphthalene)][PF₆], allows the reaction to be carried out reproducibly even in non-anhydrous THF with a catalyst loading as low as 2 mol-%. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800854

FULL PAPER
DOI: 10.1002/ejoc.200800854
Enantioselective CpRu-Catalyzed Carroll Rearrangement – Ligand and Metal
Source Importance
David Linder,[a] Frédéric Buron,[a] Samuel Constant,[a] and Jérôme Lacour*[a]
Keywords: Allylic compounds / Air-stable precatalyst / C–C coupling / N ligands / Ruthenium / Enantioselective catalysis
The addition of unstabilized carbonyl nucleophiles to unsym-
metrical allyl-metal fragments still represents a challenge to
generate stereogenic centers enantio- and regioselectively.
In this context, the decarboxylative Carroll rearrangement of
allyl β-keto esters is particularly interesting, since chiral γ,δ-
unsaturated ketones are obtained. Herein, we show that
CpRu half-sandwich complexes can, with selected enantio-
pure pyridine-monooxazoline ligands, catalyze this transfor-
mation and afford complete conversions along with good
levels of regioselectivity and enantioselectivity. Even more
challenging (electron-poor) substrates react (up to 86% ee,
branched/linear ratio Ն 97:03). In addition, the use of an air-
stable metal precursor, namely [CpRu(η6-naphthalene)][PF6],
allows the reaction to be carried out reproducibly even
in non-anhydrous THF with a catalyst loading as low as
2 mol-%.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Overall, Cp*Ru derivatives have largely been preferred
over CpRu moieties (Cp* = C5Me5, Cp = C5H5), as the
Introduction
The construction of complex, three-dimensional, mole- more electron-rich Cp* metal fragment is usually catalyti-
cular structures requires straightforward access to enantio- cally more active and leads to higher b/l ratios. With second-
enriched or enantiopure building blocks. Among the wide ary non-racemic allyl carbonates, reactions proceed stereo-
variety of synthetic methodologies available, the attack of specifically with possibly a complete transfer of the stereo-
a nucleophile onto allyl-metal intermediates yielding chiral chemical information.[4] Recently, an “intramolecular” vari-
allylic compounds with high enantiomeric excess is among ant of allylic alkylation was described in the context of re-
the most documented.[1] With unsymmetrical allyl-metal in- gioselective (and stereospecific) Carroll-type rearrange-
termediates, the regioselectivity of the nucleophilic attack is ments. Allyl β-keto esters of type 1 (Scheme 2) reacted
of crucial importance and can be controlled by the nature smoothly with a catalytic amount of [{Cp*RuCl}4] and 2,2Ј-
of the metal.[2] In this context, several Ru complexes have bipyridine (bpy) to form selectively branched γ,δ-unsatu-
proven to be largely effective for the addition of nucleo- rated ketones 2 in high yield. The linear regioisomer 3 was
philes onto the most highly substituted position, thus lead- formed only in trace amounts.[7,8] The particularly mild re-
ing to branched (b) rather than linear (l) products action conditions (CH2Cl2, room temperature), in sharp
(Scheme 1).[3] The most common substrates for Ru-cata- contrast with those of thermal decarboxylative [3,3]-sigma-
lyzed allylic substitutions are allyl carbonates and chlorides tropic Carroll reactions (140–180 °C),[9,10] were particularly
(primary or secondary), for which effective allylic alky- interesting. The involvement of the metal moiety was key to
lation, amination and etherification reactions have been de- the observed enhanced reactivity and augured well for the
veloped.[4–6]
development of an enantioselective version of the reaction.
Scheme 1. Allylic substitution of unsymmetrical substrates.
[a] Département de Chimie Organique, Université de Genève,
Quai Ernest Ansermet 30, 1211 Genève 4, Switzerland
Fax: +41-22-3793215
E-mail: jerome.lacour@unige.ch
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
Scheme 2. CpRu-catalyzed rearrangement of primary esters with
ligands L.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5778–5785

Enantioselective CpRu-Catalyzed Carroll Rearrangement
Ru-catalyzed enantioselective allylic substitutions remain a complicated “matched/mismatched” situation was also
rare, however. Planar, chiral, CpЈRu complexes with teth- observed (Scheme 3). The “matched” reaction was quite
ered phosphane ligands have been described by Takahashi slower than the “mismatched”, and less effect on the
as effective catalysts for the kinetic resolution of racemic enantioselectivity was seen in the latter case than in the re-
“symmetrical” allyl carbonates.[11] With unsymmetrical action with achiral L4. The conformational lability of pyr-
substrates, Bruneau reported the first example of a Cp*Ru- idine-imine ligands of type L also made rationalizing the
catalyzed enantioselective reaction in the context of the stereochemical outcome difficult. The relatively moderate
etherification of allylic chlorides with phenols;[12] this reac- enantioselectivity obtained was also possibly a consequence
tion was also effectively catalyzed by the above-mentioned of this conformational flexibility.
CpЈRu complexes, as described by Onitsuka.[13]
A new generation of ligands was obviously needed to
In view of this relative lack of asymmetric examples of overcome these limitations associated with the use of pyr-
Ru-catalyzed allylic substitutions in general, and C–C bond idine-imine ligands L1–L4. Herein, we report that simple-
forming reactions in particular, we thought that the devel- to-make pyridine-mono-oxazoline moieties (pymox, 6) are
opment of a Ru-catalyzed enantioselective version of the effective ligands leading to better overall results. We also
Carroll rearrangement would be of particular interest. This demonstrate that, to obtain reproducible results, care must
was achieved recently with a combination of [CpRu- be taken in the choice of the Ru source and detail an air-
(NCMe)3][PF6] (4a)[14] and enantiopure pyridine-imine li- stable alternative to 4a that affords highly regio- and enan-
gands (Scheme 2, L1–L3).[15] The branched isomer 2 was tioselective Carroll rearrangement reactions even under
obtained selectively (b/l up to 99:1) with a decent level of non-inert conditions. In addition, quite a few experiments
enantioselectivity (up to 80% ee with L3); the presence of were performed with more elaborate substrates to shed
pyridine-imine ligands allowed a reversal of the preferential some light on the mechanism at play.
“linear” regioselectivity induced by 4a as the catalyst.[4] Un-
fortunately, these reported conditions require rather large
amounts of metal precursor (10 mol-% of 4a). Long reac-
tion times are also needed (20 h to several days), especially
Results and Discussion
with substrates bearing electron-withdrawing substituents
To circumvent the drawbacks detailed above, the use of
(e.g. a p-Cl).[6f] An acute sensitivity to several reaction pa- a more rigid structural scaffold was considered and that of
rameters, including temperature and solvent, was noticed, the pymox ligands in particular.[16] In the context of arene-
diminishing somewhat the scope of this process. With sec- metal coordination chemistry, this ligand family has been
ondary allylic esters (R)- and (S)-5c and L3 as the ligand, successfully used by Brunner[17] and Davies[18] to control
the configuration of pseudo-tetrahedral Cp and η6-arene-
Ru piano-stool complexes, respectively. Several pymox li-
gands were synthesized following the procedure of Bolm
and co-workers by condensing commercially available
enantiopure 1,2-amino alcohols onto 2-cyanopyridine with
a catalytic amount of ZnCl2.[19]
This series of ligands was subjected to the standard al-
lylation reaction conditions developed for the pyridine-
imine ligands.[15] The results are summarized in Table 1. Li-
gand 6a, bearing the same oxazoline as the most selective
ligand of Bruneau,[12] proved to be quite efficient; the Car-
roll rearrangement of 1a yielded the expected product 2a
with full conversion and a perfect b/l ratio in less than 2 h
with a decent ee value of 53%. A gradual increase of the
bulk of the substituent α to the N atom improved the enan-
tiomeric excess up to 72% with the valinol-derived pymox
6d without any loss of regioselectivity. Surprisingly, ligand
6e, derived from tert-leucinol, displayed no catalytic activity
whatsoever. The completely rigid ligand 6f, derived from
(1R,2S)-cis-1-amino-2-indanol, afforded solely the desired
branched product 2a with an enantioselectivity of 80% at
full conversion. Thus, ligand 6f performed as regio- and
enantioselectively as the most efficient pyridine-imine li-
gand L3 but with a much higher catalytic activity (2 h and
24 h for 6f and L3, respectively). In order to further opti-
mize the structure of the ligand, variations on the substitu-
tion pattern of the pyridine part were undertaken. Electron-
Scheme 3. CpRu-catalyzed rearrangement of secondary esters with
ligands L.
poor pyrimidine- and pyrazine-derived ligands (6g and 6h,
Eur. J. Org. Chem. 2008, 5778–5785
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. Linder, F. Buron, S. Constant, J. Lacour
FULL PAPER
respectively) were thus synthesized in a similar manner to Table 1. CpRu-catalyzed rearrangement of allylic ester 1a.[a]
6f. These two ligands afforded solely the branched product
2a with the same ee value of 78%. However, the reactions
with these two electron-poor ligands were noticeably slower
than those with unsubstituted pyridine ligand 6f (Table 1,
Entries 7 and 8). On the other hand, ligand 6i, bearing an
electron-donating methyl group para to the N atom of the
pyridine, afforded a faster reaction with excellent regioselec-
tivity but a lower enantioselectivity (73% ee in 1.5 h for 6i
vs. 80% ee in 2 h for 6f). Electronic factors on the pyridine
side of the ligand seemed to play a crucial role in the kinet-
ics of the reaction (electron-poor ligands affording slower
reactions) but accelerating the reaction seemed detrimental
to the enantioselectivity.[15] In addition, the 5-methyl-substi-
tuted pyridine ligand 6j allowed for full conversion of 1a
into 2a but with a strongly detrimental effect on the kinetics
(76% ee in 4 h for 6j vs. 80% ee in 2 h for 6f). The ad-
ditional methyl group, in the latter case, was probably steri-
cally interacting with the π-allyl fragment and slowing
down the reaction. A “naked” pyridine moiety on the li-
gand thus seemed a good compromise to fulfill the stereoe-
lectronic requirements. Ligand 6f then appeared as the most
suitable candidate for further screening.[20]
Entry Ester Ligand
Time
[h]
Conv.
[%]
ee
Optical
b/l[c]
Using ligand 6f and “classical” conditions (THF, 60 °C,
0.5  of substrate 1, 10 mol-% of 4a and 10 mol-% 6f), the
scope of the reaction was investigated with a variety of sub-
strates (compounds 1a–g, Table 2). The regioisomeric anisyl
derivatives 1a and 1b (o- or p-OMe) and 1f, bearing a 3,4-
methylidene dioxy group, reacted equally well when submit-
ted to the reaction conditions yielding the corresponding
branched products with about 80% ee in all cases. As ob-
served with the pyridine-imine ligands,[15] the reactions were
slower with the more challenging substrates bearing no sub-
stituent or an electron-withdrawing group (1c–e). However,
with 6f as the ligand, reactions occurred within a few days
even with 1e bearing a p-NO2 group. A low b/l ratio of
76:24 was only obtained for this particular substrate, which
was in good agreement with the previously described reac-
tivity of such electron-poor substrates.[6f] Contrary to what
had been previously observed with L3 as ligand, for which
the enantioselectivity was lower when longer reaction times
[%]
rotation[b]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
6a
6b
6c
6d
6e
6f
6g
6h
6i
2
2
2
2
48
2
3.5
3.5
1.5
4
Ͼ97
Ͼ97
Ͼ97
Ͼ97
Ͻ3
Ͼ97
Ͼ97
Ͼ97
Ͼ97
Ͼ97
53
56
63
72
–
80
78
78
73
76
(–)
(–)
(+)
(+)
–
(–)
(–)
(–)
(–)
(–)
Ͼ97:3
Ͼ97:3
Ͼ97:3
Ͼ97:3
–
Ͼ97:3
Ͼ97:3
Ͼ97:3
Ͼ97:3
Ͼ97:3
9
10
6j
[a] Fresh 4a (10 mol-%), ligand 6 (10 mol-%), THF, 60 °C, and 1a
(0.5 ); the results are the average of at least two runs. [b] The sign
of the optical rotation of 2a. [c] Ratios of branched (2) to linear
1
(3) products were determined at complete conversion by H NMR
(400 MHz) spectroscopy.
were needed (80, 74 and 66% ee for 1a, 1c and 1d, respec- matched/mismatched situation was observed as ee values of
tively),[15] only the b/l ratio was significantly influenced by 45 and 87% were obtained with (S)-5c and (R)-5c, respec-
the electronic properties of the cinnamyl fragment (Table 2, tively (Table 3). In addition, in the mismatched series, the
Entries 1, 4 and 5). No important effect on the enantio- reaction was slower, and the b/l ratio was noticeably lower.
selectivity was observed in this series. This observation indi- When racemic 5c was submitted to the reaction conditions,
cates that the enantio- and the regiodetermining steps of a slightly enantio-enriched product was obtained at 86%
this reaction are probably distinct and independent. The conversion [15% ee in favor of the (–)-(R) enantiomer] in
configuration of the substrate was also important. For in- good accordance with the results obtained in both enantio-
stance, compound 1g, the Z isomer of 1a, reacted to form pure series and the fact that the reaction is globally stereo-
2a as the major product. However, the reaction was signifi- specific with branched secondary allylic substrates.[4,7b]
cantly slower (7 h vs. 2 h) and much less selective (15 vs.
80% ee) than that with 1a; the same levorotatory enantio- rived from ligand 6f, we then investigated lowering the cata-
mer of 2a was predominant in both cases.[21,22]
lyst loading towards a more practical level. Interestingly,
Due to the higher reactivity of the catalytic system de-
With this catalytic system in hand, we decided to revisit only 2 mol-% of 4a and 2.4 mol-% of 6f were necessary to
the rearrangement of the secondary acetoacetates 5, for maintain the level of conversion and stereochemical out-
which no obvious matched/mismatched effect could be ob- come if the concentration of the substrates was increased to
served with L3 as the ligand.[15] In the case of 6f, a clear 2.0 . Details are given in the Supporting Information.
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Enantioselective CpRu-Catalyzed Carroll Rearrangement
Table 2. CpRu-catalyzed rearrangement of allylic esters 1.[a]
by the condition of 4a.[20] Needless to say, all the previously
described experiments were carried out with freshly pre-
pared precatalyst 4a (less than one week old).
To circumvent this problem, we envisaged a different
source of metal precursor, the [CpRu(η6-naphthalene)][PF6]
complex 4b in particular (Table 4).[14] As reported recently
by Hintermann and Bolm,[23] this air-stable complex can be
used as a precatalyst for the hydration of terminal alkynes.
Initial experiments validated this choice, as salt 4b was in-
deed able, with ligand 6f, to provide the desired product
2a with excellent regioselectivity. However, in experiments
performed under standard conditions, a quite lower
enantioselectivity value was obtained (71% ee with 4b,
Table 4, Entry 2 vs. 80% ee with 4a, Table 2, Entry 1). We
reasoned that the presence of the substrate during the dis-
placement of the η6-naphthalene by the pymox ligand was
perturbing the outcome of the reaction. This problem was
then overcome by treating complex 4b with the ligand prior
to the addition of the substrate. To determine the optimal
induction period, reactions were performed with an initia-
tion time of 30, 60 or 90 min before introducing the allylic
ester. In the latter two cases, the enantioselectivity was es-
sentially restored (79% ee, Table 4, Entries 3 and 4).
Whether the liberated naphthalene moiety was involved in
the reaction after its displacement is debatable; it was al-
most quantitatively recovered at the end of the reaction,
and thus, provided an internal reference for approximate
GC-yield calculations.
Entry Ester
Time
[h]
Conv.
[%]
ee
[%]
Optical
b/l[c]
rotation[b]
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
2
3
7
24
120
1.5
7
Ͼ97
Ͼ97
Ͼ97
Ͼ97
Ͼ97
Ͼ97
Ͼ97
80
78
77
77
75
77
15
(–)
(–)
(–)-(R)
(–)
(–)
(–)
Ͼ97:3
Ͼ97:3
95:5
93:7
76:24
Ͼ97:3
95:5
1g
(–)
[a] Fresh 4a (10 mol-%), ligand 6f (10 mol-%), THF, 60 °C, and 1
(0.5 ); the results are the average of at least two runs. [b] The sign
of the optical rotation of 2 and the absolute configuration, when
known. [c] Ratios of branched (2) to linear (3) products were deter-
mined at complete conversion by 1H NMR (400 MHz) spec-
troscopy.
Table 3. Rearrangement of secondary substrates.[a]
Table 4. Initiation-time effect with 4b.[a]
Entry
Ester
Time
[h]
Conv.
[%]
ee
[%]
Optical
b/l[c]
rotation[b]
Entry Ligand Initiat. time Time
Conv.
[%]
ee
[%]
Optical
b/l[c]
rotation[b]
1
2
3
(R)-5c
(S)-5c
rac-5c
2.5
3
3
Ͼ97
85
86
87
45
23
(–)-R
(+)-S
(–)-R
95:5
90:10
88:12
[min]
[h]
1
2
3
4
5
–
0
0
30
60
90
48
6
6
6
6
Ͻ3
–
–
–
6f
6f
6f
6f
Ͼ97
Ͼ97
Ͼ97
Ͼ97
71
74
79
79
(–)
(–)
(–)
(–)
Ͼ97:3
Ͼ97:3
Ͼ97:3
Ͼ97:3
[a] Fresh 4a (10 mol-%), ligand 6f (10 mol-%), THF, 60 °C, and 5c
(0.5 ); the results are the average of at least two runs. [b] The sign
of the optical rotation of 2. [c] Ratios of branched (2) to linear
(3) products were determined at complete conversion by H NMR
(400 MHz) spectroscopy.
1
[a] 4b (2.5 mol-%), ligand 6f (3 mol-%), THF, 60 °C, and 1a (2 );
the results are the average of at least two runs. [b] The sign of the
optical rotation of 2. [c] Ratios of branched (2) to linear (3) prod-
ucts were determined at complete conversion by 1H NMR
(400 MHz) spectroscopy.
Importantly, we observed during the initial screening
process that the enantioselectivity with 1a varied from one
reaction to the next under the same conditions. After exten-
sive investigation of reaction parameters, this phenomenon
The generality of this catalytic combination was then
was correlated to a change of aspect of the [CpRu(NCMe)3]- tested with some of the substrates described previously. The
[PF6] salt and to the shelving time of 4a in the freezer, in results are detailed in Table 5. For all tested substrates, the
particular. Indeed, the color of this precatalyst, although catalyst generated in situ from 4b performed as selectively
kept under an argon atmosphere at –20 °C, gradually as the one derived from 4a. In the particular case of the
changed from bright yellow (when fresh) to brown-orange less active substrates (Table 5, Entries 3 and 4), regio- and
after a few weeks. A gradual decrease of the enantio- enantioselectivities were even slightly better. Importantly,
selectivity was observed from 80% ee with freshly prepared complex [CpRu(η6-naphthalene)][PF6] could be stored at
4a to 69% ee with a five-week-old sample. Interestingly, nei- ambient temperature under ambient atmosphere in a screw-
ther the b/l ratio nor the conversion after 2 h was affected cap vial for over 6 months without any noticeable erosion
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D. Linder, F. Buron, S. Constant, J. Lacour
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of reactivity or selectivity. However, due to the photosensi- enolate subsequently adds to the π-allyl complex to regener-
tivity of [CpRu(η6-naphthalene)][PF6],[24] 4b must be stored ate the catalytically active Ru complex and furnishes the
in the dark.
γ,δ-unsaturated ketone.
Table 5. CpRu-catalyzed rearrangement of allylic esters 1 with 4b.[a]
Entry Ester
Time[b]
[h]
Conv.
[%]
ee
[%]
Optical
b/l[d]
rotation[c]
1
2
3
4
1a
1c
1d
1e
6
25
120
400
Ͼ97
Ͼ97
Ͼ97
Ͼ97
79
77
81
79
(–)
(–)
(–)
(–)
Ͼ97:3
95:5
93:7
79:21
[a] 4b (2.5 mol-%), ligand 6f (3 mol-%), THF, 60 °C, and 1 (2 );
the results are the average of at least two runs. [b] Reaction time
without 1 h of initiation time. [c] The sign of the optical rotation
of 2. [d] Ratios of branched (2) to linear (3) products were deter-
mined at complete conversion by 1H NMR (400 MHz) spec-
troscopy.
The robustness of this catalytic system was further as-
sessed by performing the rearrangement of allylic ester 1a
in non-anhydrous conditions. The results of the reactions
performed with various amounts of water are reported in
Table 6. We observed no effect on the regioselectivity
(Ͼ97:3) and only a very small effect on the enantio-
selectivity (78 vs. 79% ee) of the process with 10, 300 and
2100 ppm of water in THF (Table 6, Entries 1–3). When the
amount of water was raised to approximately 0.3% (v/v),
the branched product was still exclusively obtained but with
a slightly lower enantioselectivity (Table 6, 75 vs. 79% ee,
Entry 4). Thus, this reaction can also be performed under
non-anhydrous conditions with standard bottled solvent
(typically less than 50 ppm of water for commercially avail-
able, analytical-grade THF) with virtually no effect on the
stereochemical outcome of the reaction.
Scheme 4. Postulated mechanistic rational.
To confirm the nature of the nucleophilic intermediate,
we attempted to intercept the transient species. When the
reaction of 1c was conducted with 1 equiv. of dimethylma-
lonate,[7a] no incorporation of the malonate fragment onto
the allyl fragment was observed (GC-MS). This suggests
that the addition of the alleged “unstabilized” enolate onto
the allyl fragment is much faster than the deprotonation
of the acidic malonic ester. Moreover, in contrast to the
observation of Tunge with a Cp*Ru-based catalyst,[7c] the
enolate could not be trapped by a Michael acceptor (typi-
cally substituted methylenemalononitriles) under the stan-
dard reaction conditions. In view of the lack of interception
of the nucleophilic species, it was then debatable whether
the reaction proceeded intramolecularly rather than inter-
molecularly.
Table 6. CpRu-catalyzed rearrangement of allylic ester 1a with 4b
in non-anhydrous THF.[a]
Entry Water[b]
[ppm]
Time[c]
[h]
Conv.
[%]
ee
[%]
Optical
b/l[e]
rotation[d]
To solve this issue, a double-crossover experiment was
performed with a ca. 1:1 mixture of 1a and 1n (Scheme 5).
After 6 h, GC and MS analysis of the resulting crude reac-
tion mixture showed the formation of all possible branched
and linear products compatible with intermolecular pro-
cesses (2a, 3a, 2n and 3n and crossover products 7a, 8a, 7n
and 8n, Scheme 5). This result indicated that the alkylation
reaction clearly proceeded through the fragmentation of
substrates into nucleophilic and electrophilic species, which
resulted in crossover.[25]
1
2
3
4
10
300
2100
11600
8
8
8
8
Ͼ97
Ͼ97
Ͼ97
Ͼ97
79
78
78
75
(–)
(–)
(–)
(–)
99:1
98:2
98:2
97:3
[a] 4b (2 mol-%), ligand 6f (2.4 mol-%), THF, 60 °C, and 1a (2 );
the results are the average of at least two runs. [b] Measured with
a Karl Fischer apparatus. [c] Reaction time without a 1 h initiation
time. [d] The sign of the optical rotation of 2. [e] Ratios of branched
(2) to linear (3) products were determined at complete conversion
by GC-MS.
Finally, a series of experiments (and the synthesis of new
To further characterize the nucleophilic species and
substrates) were performed to gain some insight into the probe the generality of the reaction, several more elaborate
reaction mechanism. Generally, Cp*Ru- and CpRu-cata- cinnamyl keto esters were synthesized (1h–m). Their reac-
lyzed allylation reactions are believed to proceed through tions are summarized in Table 7.[26] Substrates 1h–j, bearing
the formation of Ru-π-allyl complexes with leaving group an α substituent between the carbonyl moieties, reacted
release,[5,6] and the decarboxylative addition of enolates is with similar kinetics and enantioselectivities to those of un-
no exception.[7] In this latter case (Scheme 4), the oxidative substituted 1c (Table 2, Entry 3 vs. Table 7, Entries 1–3).
addition of the metal complex to the substrate leads to the However, the regiochemistry favored the branched adducts
release of a keto acetate moiety, which upon decarboxyl- noticeably less (down to 81:19). Clearly, the bulkier the nu-
ation, generates an “unstabilized” enolate. This nucleophilic cleophile, the more of the linear product was provided.
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Enantioselective CpRu-Catalyzed Carroll Rearrangement
Substrates 1h, 1k and 1l, designed to probe the existence
of enolate intermediates and their regioisomeric stability,
reacted smoothly under the reaction conditions. In the par-
ticular case of 1k, as there are no α hydrogen atoms between
the two carbonyl groups, the selective formation of 2k indi-
cated that the decarboxylation of the corresponding keto
acetate occurred necessarily prior to the attack onto the π-
allyl complex. In addition, the fact that the new C–C bonds
in 2h to 2l and 3h to 3l (Scheme 6) resulted solely from
the attack of the carbon previously bearing the carboxylate
moiety is compatible with the formation of enolates whose
regiochemistry is preserved throughout the catalytic cycle.[7]
Scheme 5. Double-crossover experiment (linear products 3 and lin-
ear crossover products 8 are omitted for clarity; ratios were mea-
sured by GC-MS).
Furthermore, the presence of an α substituent led to the
introduction of a stereogenic centre and, as a result, four
stereoisomers of compounds 2 and two enantiomeric linear
adducts 3 were obtained.
For branched derivative 2h, GC analysis indicated that
the diastereoselectivity linked to the presence of the new
stereocenter was low (ca. 2:1).[27] As a similarly low selectiv-
ity was also observed for (cyclic) 2i and 2j, it was probably
not due to a lack of control of the E/Z geometry of the
postulated enolate intermediate. Interestingly, and in slight
contrast to these results, the chiral linear products 3h and
Scheme 6. Conservation of the enolate regiochemistry for 1k.
Finally, the benzoyl-substituted substrate 1m reacted
3i were obtained with a decent enantioselectivity (67% and smoothly with faster kinetics but the same selectivity as
79% ee, respectively). This shows that the facial approach those of 1c under the same conditions.[8a] The faster reac-
of the alleged enolate was better controlled when the attack tion for this substrate allowed the temperature to be low-
onto the electrophilic fragment occurred at the unsubsti- ered to 25 °C, and 2m was obtained in 86% ee and a b/l
tuted, allylic, terminal position rather than α to the aro- ratio of 95:5 within 64 h. These results confirmed that bet-
matic moiety.[2,28]
ter ee values were obtained at a lower temperature.[29]
Table 7. CpRu-catalyzed rearrangement of allylic esters 1.[a]
Entry
Ester
Time[b]
[h]
Conv.[c]
[h]
b/l[d]
dr[d]
ee (b1, b2, l)[e,f]
Optical
[%]
rotation[g]
1
2
3
4
5
6
7
8
1h
1i
9
9
9
9
9
5
24
64
Ͼ97
Ͼ97
Ͼ97
Ͼ97
Ͼ97
Ͼ97
Ͼ97
Ͼ97
81:19
87:13
86:14
83:17
85:15
92:8
68:32
64:36
64:36
–
–
–
–
–
72, n.d., 67
n.d., 81, 79
77, 77, n.d.
(–)
(–)
(–)
(–)
(–)
(–)
(–)
(–)
1j
1k
1l
1m
1m[h]
1m[i]
57
67
78
83
86
95:5
95:5
[a] 4b (10 mol-%), ligand 6f (12 mol-%), THF, 60 °C, and 1 (2 ); the results are the average of at least two runs. [b] Reaction time without
1
1 h of initiation time. [c] Determined by H NMR (400 MHz) spectroscopy. [d] Ratios of branched (2) to linear (3) products and dia-
stereomeric ratios among compounds 2 (dr) were determined at complete conversion by GC-MS. [e] The ee value of the first and second
eluted branched stereoisomers of 2 and of the linear 3, respectively. [f] n.d.: nothing detected. [g] The sign of the optical rotation of 2.
[h] Reaction was performed at 40 °C. [i] Reaction was performed at 25 °C.
Eur. J. Org. Chem. 2008, 5778–5785
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5783

D. Linder, F. Buron, S. Constant, J. Lacour
FULL PAPER
Minnaard, B. L. Feringa, Chem. Rev. 2008, 108, 2824–2852; l)
A. Alexakis, J. E. Bäckvall, N. Krause, O. Pàmies, M. Diéguez,
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12, 5178–5187.
Conclusions
Herein, we reported that the conjunction of simple-to-
make and readily available, enantiopure, pymox ligands (in
one step from commercially available sources) and a CpRu
precatalyst provided an efficient catalytic system for Car-
roll-type rearrangements of allyl-β-keto esters of type 1 with
good to perfect regioselectivity and good enantiomeric con-
trol. Even challenging substrates bearing strongly electron-
withdrawing groups reacted with catalyst loadings as low as
2 mol-%. In addition, to avoid the phenomenon of catalyst
aging, which is detrimental to selectivity, an alternative
catalytic combination was developed composed of air-stable
[CpRu(η6-naphthalene)][PF6] 4b and indanyl-pymox ligand
6f, which provided reproducibly high selectivities even in
non-anhydrous media.
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For recent examples of Ir-catalyzed syntheses of enantio-en-
riched γ,δ-unsaturated ketones, see: a) H. He, X. J. Zheng, U.
Yi, L. X. Dai, S. L. You, Org. Lett. 2007, 9, 4339–4341; b) D. J.
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Despite these harsh conditions, the Carroll rearrangement has
found many applications in synthesis: a) M. Defosseux, N.
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Experimental Section
CpRu-Catalyzed Carroll Rearrangement. Improved Procedure (Typi-
cal Procedure): In a 2 mL screw-cap vial equipped with a magnetic
stirring bar, [CpRu(η6-naphthalene)][PF6] (6.6 mg, 0.015 mmol,
2.5 mol-%) and 6f (4.3 mg, 0.018 mmol, 3 mol-%) were dissolved
in dry THF (0.3 mL). The vial was flushed with argon and capped.
After 1 h of heating at 60 °C, allyl β-keto ester 1a (150 mg,
0.6 mmol) was added in one portion, and heating was continued
for another 6 h. The cooled reaction mixture was diluted with di-
ethyl ether/pentane (60:40, 1.5 mL). After precipitation, the metal
salts were filtered through a short SiO2 column (0.5 cmϫ4 cm, elu-
tion diethyl ether/pentane, 60:40). The solvents were then evapo-
rated under reduced pressure to afford the crude reaction mixture
as a pale yellow oil.
[6]
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures, spectroscopic and analytical
data (1H, 13C, and HRMS) for new compounds, and Chiral Sta-
tionary-Phase-GC or HPLC separation methods for all chiral prod-
ucts.
[7]
[8]
Acknowledgments
We are grateful for financial support of this work by the Swiss
National Science Foundation and the State Secretariat for Educa-
tion and Research. We are also very thankful to Prof E. P. Kündig
for fruitful scientific discussions.
[9]
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Eur. J. Org. Chem. 2008, 5778–5785

Enantioselective CpRu-Catalyzed Carroll Rearrangement
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[23]
[24]
[25]
The bimolecular addition of a Ru enolate to a Ru allyl remains
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[20] For further conditions used in the screening of reaction condi-
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Received: September 4, 2008
[21] Isomeric substrates (E)-1a and (Z)-1g lead, upon reaction with
Published Online: October 20, 2008
the metal fragment, to diastereomeric Ru complexes and, as
Eur. J. Org. Chem. 2008, 5778–5785
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5785