An enantioselective CpRu-catalyzed carroll rearrangement

Article abstract of DOI:10.1002/anie.200604573

(Chemical Equation Presented) Simple ligands, catalyst, and conditions: The combination of readily prepared unsymmetrical pyridine-imine ligands and [CpRu(CH₃CN)₃][PF₆] (Cp = C₅H ₅) affords regio- and

Full text of DOI:10.1002/anie.200604573

Communications
DOI: 10.1002/anie.200604573
Synthetic Methods
An Enantioselective CpRu-Catalyzed Carroll Rearrangement**
Samuel Constant, Simone Tortoioli, Jessica Müller, and JØrôme Lacour*
Easy and direct access to enantioenriched molecules is
essential for the construction of complex molecular struc-
tures. Among the wide variety of methods, one of the most
documented is the attack of a nucleophile onto an allyl–metal
intermediate to yield chiral allylic compounds with high
enantiomeric excess. One of the benefits of such substitution
is that the regioselectivity of the reaction with unsymmetrical
allyl substrates can be controlled by the metal catalyst. In this
respect, several ruthenium derivatives have proven to be
largely effective for the introduction of nucleophiles at the
more substituted position, thus leading to branched (b) rather
than linear (l) products [Eq. (1)].[1]
ketoesters of type 4 [Eq. (2)] were shown to react smoothly in
the presence of [{Cp*RuCl}4] (1c) and bpy to form g,d-
unsaturated ketones 5 in high yields and excellent b/l ratios.[7a]
These metal derivatives include, among others, the
tris(acetonitrile) complex [Cp*Ru(CH3CN)3][PF6] (1a;
Cp* = C5Me5) from Trost et al.,[2] diazabutadiene (dab) and
2,2’-bipyridine (bpy) complexes from Bruneau, Demerseman,
Renaud and co-workers (2a and 3a),[3] 1,5-cyclooctadiene
(1,5-cod) complexes from Kondo, Mitsudo, et al,[4] amidinate
derivatives from Nagashima and co-workers,[5] and RuIV
carbonate derivatives from Pregosin and co-workers.[6]
Typical substrates are allyl carbonates and allyl chlorides
(primary or secondary), and effective allylic alkylation,
amination, and etherification reactions have been devel-
oped.[2–6] If nonracemic secondary allyl carbonates are used,
the reactions proceed stereospecifically with possibly com-
plete transfer of chirality.[2] Cp*Ru derivatives are largely
preferred over CpRu moieties (for example, 1a over [CpRu-
(CH3CN)3][PF6] (1b); Cp = C5H5) as the more electron-rich
metal fragment is catalytically more active and leads to higher
b/l ratios. Recently, an intramolecular variant of allylic
alkylation was described in the context of regioselective
(and stereospecific) Carroll-type rearrangements.[7] Allyl b-
The conditions were particularly mild (CH2Cl2, room temper-
ature). This result is in sharp contrast with that of classical
(thermal) decarboxylative [3,3] sigmatropic Carroll reactions
that require elevated temperatures to proceed (typically 140–
1808C);[8] the Carroll rearrangement is nevertheless a highly
useful concerted reaction used for a variety of synthetic
applications.[9,10]
Despite all these advantages, Ru-catalyzed enantioselec-
tive allylic substitutions are rare.[11,12] To our knowledge, the
etherification of allyl chlorides with phenols using, as catalyst,
combinations of Cp*Ru (as in 1a) and bisoxazoline ligands
(for example, 7; Scheme 1) is the single reported example of
enantioselective Ru-catalyzed allylic substitution reaction,
with good enantioselectivity (up to 80% ee) and decent
regioselectivity (d.r. 62:38 to 87:13) being achieved.[13] Herein
we report that the conjunction of simple-to-make unsym-
metrical pyridine–imine ligands and the CpRu derivative 1b
affords highly regio- and enantioselective Carroll rearrange-
ments, this being the first example of Ru-catalyzed asym-
[*] S. Constant, Dr. S. Tortoioli, J. Müller, Prof. J. Lacour
DØpartement de Chimie Organique
UniversitØ de Gen›ve
quai Ernest Ansermet 30, 1211 Gen›ve 4 (Switzerland)
Fax: (+41)22-379-3215
E-mail: jerome.lacour@chiorg.unige.ch
[**] We are grateful for financial support of this work by the Swiss
National Science Foundation and the State Secretariat for Education
and Science. We thank Prof. Dr. Klaus Ditrich (BASF) for generous
gifts of chiral amines and epoxides.
À
metric C C bond-forming allylic substitution.
In view of the previously mentioned results, initial experi-
ments on the enantioselective variant of the Carroll rear-
rangement were conducted by the treatment of allylic ester 4a
[Eq. (2), R = OMe] with catalytic amounts of 1c (2.5 mol% of
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Ru-catalyzed rearrangement of allylic esters 4.[a]
Ester
Ligand
t [h]
Conv. [%]
ee [%]
Conf.[b]
b/l Ratio[c]
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
–
48
20
4
0
100[d]
100
100
97
–
56
–
–
(+)
–
–
9a
bpy
9b
9c
9d
9e
9 f
9g
9h
9h
9h
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
94:6
30
13
92
24
22
20
24
24
120
–
–
50
20
58
66
72
80
74
66
(+)
(+)
(+)
(+)
(+)
(+)
(+), S
(+)
47
100
100
100
100
100
75
95:5
[a] Reaction conditions: 1b (10 mol%), ligand (10 mol%), THF, 608C,
0.5m; the results are the average of at least two runs. [b] Sign of the
optical rotation and absolute configuration when known. [c] Ratios of
branched (5) to linear (6) products were determined at complete
conversion. [d] 95% yield of isolated product.
Scheme 1. Diimine and pyridine–imine ligands.
the tetramer) and bisoxazoline ligand 8 (10 mol%) in CH2Cl2
at room temperature. Unlike the reaction performed in the
presence of bpy (15 min, 100% conversion), poor reactivity
was observed in the presence of this ligand (15% conversion
after 7 days), and no enantioselectivity was achieved (0% ee).
Obviously, ligand 8 did not possess the (stereo)electronic
requirements for the activation of the ruthenium catalyst. To
generate some reactivity, the presence of a pyridine moiety
within the framework of the chiral diimine ligand was deemed
necessary. Ligand 9a, readily synthesized by the condensation
of 2-pyridine-carboxaldehyde and (R)-1-phenyl-propylamine,
was prepared and submitted to the reaction conditions.
Although very modest, the result was better (45% conversion
after 5 days, 13% ee) than that of ligand 8. Intensive screening
of solvent, temperature, concentration, and metal source (1b
and 1c) afforded effective conditions for the “Carroll”
rearrangement. A combination of CpRu complex 1b and
ligand 9a (10 mol% each) in THF at 608C allowed the
reaction to proceed with good yield and a first decent
enantioselectivity (5a: 56% ee, 20 h, 100% conversion, 95%
yield).[14] Significantly, no trace of the linear product 6a was
found using the CpRu catalyst 1b (NMR and GC–MS
monitoring). The occurrence of a perfect b/l ratio under the
optimized conditions was confirmed in reactions performed
with bpy and achiral iminopyridine ligand 9b (Scheme 1). The
results are summarized in Table 1.
At this stage, a rather intensive screening of chiral ligands
was performed; a selection of these ligands is presented in
Scheme 1. To begin, the nature of the pyridine moiety was
varied as substituents were introduced on the aromatic
nucleus (9c: p-NMe2, 9d: o-Me). Whereas the dimethylamino
substituent enhanced the reactivity of the catalyst, the
presence of the methyl group in the proximity of the
coordinating nitrogen atom strongly decreased the reactivity;
both modifications came at the expense of the enantioselec-
tivity. A series of chiral ligands (9e–h) was then prepared by
condensation of 2-pyridine-carboxaldehyde and other chiral
benzylic primary amines.[15] From 9e to 9g, a gradual increase
in the enantioselectivity of the allylic substitution was noticed
(up to 72% ee), which is most probably related to the increase
in size of the benzylic a substituent (from Et (9a) to Pr, Bn,
and then tBu). Finally, a useful level of enantioselectivity was
obtained (80% ee) when the reaction was performed in the
presence of ligand 9h prepared from (R)-1-(2-methoxy-
phenyl)-2,2-dimethylpropan-1-amine.[16,17] Importantly, in all
these examples with the Cp catalyst, the b/l ratio remained
excellent as no trace of compound 6a could be observed.
With this result in hand, we extended the asymmetric
protocol to allylic esters 4b and 4c [Eq. (2); R = H and Cl,
respectively]. The reaction with unsubstituted 4b proceeded
somewhat less selectively in terms of enantio- and regio-
chemistry (74% ee and b/l 94:6). With ligand 9h, (+)-5b was
obtained, for which an S configuration could be determined
by hydrogenation to produce (S)-(2)-4-phenyl-2-hexa-
none.[7b,18] With 4c bearing a chlorine atom, the reaction
was much slower than with 4a and 4b, as five days were
necessary to reach a decent conversion (75%); however, the
regio- and enantioselectivity remained strong (66% ee and b/l
95:5). The effect of the electron-withdrawing atom on the
reactivity is in line with the results of the Bruneau and Tunge
groups.[3,7b]
To gain some insight on the nature of the asymmetric
transformation and achieve possibly higher levels of selectiv-
ity, care was taken to perform the asymmetric Carroll
rearrangement on an enantioenriched secondary allyl ester
to determine 1) whether the reaction still occurred stereo-
specifically under our set of conditions and 2) whether chiral
ligands could positively affect the subsequent selectivity. We
selected compound 10b (Table 2) for our study since the
configurations of both starting material and product are
known. The R and S enantiomers were prepared by olefina-
tion of commercially available enantiopure styrene oxide by
using the protocol developed by Mioskowski and co-workers
and then esterification with acetyl diketene (10b, R and S,
> 99% ee, CSP-GC).[19]
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Communications
Table 2: Ru-catalyzed rearrangement of secondary allylic ester 10b.[a]
understand the intricate details of the unusual aspects of this
transformation and extend the results to other useful pro-
cesses.
Received: November 8, 2006
Published online: February 5, 2007
Ester
Ligand
t [h]
ee [%]
Conf.[b]
b/l Ratio[c]
À
Keywords: C C coupling · enantioselectivity · N ligands ·
rearrangement · ruthenium
(S)-10b
(S)-10b
(S)-10b
(S)-10b
(R)-10b
(R)-10b
(R)-10b
(R)-10b
bpy
9b
9a
9h
bpy
9b
9a
2
6
10
10
2
6
6
6
48
72
84
92
46
72
68
70
(+), S
(+), S
(+), S
(+), S
(À), R
(À), R
(À), R
(À), R
94:6
94:6
92:8
93:7
93:7
94:6
94:6
>99:1
.
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[a] All reactions reached complete conversion by the reported time.
Reaction conditions: 1b (10 mol%), ligand (10 mol%), THF, 608C,
0.5m; the results are the average of at least two runs. [b] Sign of the
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to linear (6b) products were determined at complete conversion.
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(9a, 9h). The results are summarized in Table 2. First, as in
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could be observed in most of these reactions; the ratios, from
93:7 to better than 99:1, remain however in line with the result
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When achiral bpy was used as the ligand, a rather strong
loss of selectivity was observed in our case (46–48% ee), a
result substantially different from that observed by Burger
and Tunge on the same substrate and different reaction
conditions (83–87% ee).[7b] Interestingly, iminopyridine 9b
(Scheme 1) led to a better conservation of chiral information
(72% ee). In the reactions performed with (R)- and (S)-10b in
the presence of chiral ligands, 9a and 9h, a rather distinct
behavior was noticed. In the case of (S)-10b, a “matched”
diastereomeric effect was observed as the reaction was
influenced positively by the chiral ligands, (+)-(S)-5b being
isolated in much better enantiomeric purity (up to 92% ee)
than in the reaction performed with achiral 9b. This result was
not completely unanticipated in view of the tendency of
ligands 9a and 9h to favor the formation of the (+),S
enantiomer starting from 4b. However, more surprising was
the overall lack of (mismatched) influence of the chiral
ligands on the reaction with (R)-10b, as (À)-(R)-5b was
isolated with essentially the same enantiomeric purity as in
the reaction performed with achiral 9b. The origin of this
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(S)-10b remain unclear at this stage.
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[10] For a Pd-catalyzed enantioselective Carroll rearrangement, see:
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In conclusion, we describe the first Ru-catalyzed asym-
metric Carroll rearrangement using simple-to-make unsym-
metrical pyridine–imine ligands and a Cp rather than a Cp*
source of ruthenium. Further studies are being performed to
[11] For a general review on asymmetric allylic alkylation, see: B. M.
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[12] Planar-chiral CpRu complexes with tethered phosphine ligands
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allowing for the formation of a s-allyl Ru intermediate. We
thank a referee for this latter suggestion.
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[14] Ligand 8 did not accelerate the reaction catalyzed by 1b under
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[15] The enantiopure primary amines were commercially available or
readily prepared following literature precedents. (R)-1,2-Di-
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semipreparative CSP-HPLC resolution (Chiralpak IA). For the
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