[CpRu]-catalyzed carbene insertions into epoxides: 1,4-dioxene synthesis through sn1-like chemistry with retention of configuration

Article abstract of DOI:10.1002/anie.201402994

Rather than lead to the usual deoxygenation pathway, metal carbenes derived from α-diazo-β-ketoesters undergo three-atom insertions into epoxides using a combination of 1,10-phenanthroline and [CpRu(CH ₃CN)₃][BAr_F] as the catalyst. Original 1,4-dioxene motifs are obtained as single regio- and stereoisomers. A perfect syn stereochemistry (retention, e.r. up to 97:3) is observed for the ring opening, which behaves as an S_N1-like transformation.

Full text of DOI:10.1002/anie.201402994

Angewandte
Chemie
DOI: 10.1002/anie.201402994
Synthetic Methods
[CpRu]-Catalyzed Carbene Insertions into Epoxides: 1,4-Dioxene
Synthesis through SN1-Like Chemistry with Retention of
Configuration**
Thierry Achard, Cecilia Tortoreto, Amalia I. Poblador-Bahamonde, Laure Guꢀnꢀe,
Thomas Bꢁrgi, and Jꢀrꢂme Lacour*
Dedicated to Professor Paul Mꢁller on the occasion of his 75th birthday
Abstract: Rather than lead to the usual deoxygenation path-
way, metal carbenes derived from a-diazo-b-ketoesters
undergo three-atom insertions into epoxides using a combina-
tion of 1,10-phenanthroline and [CpRu(CH3CN)3][BArF] as
the catalyst. Original 1,4-dioxene motifs are obtained as single
regio- and stereoisomers. A perfect syn stereochemistry (reten-
tion, e.r. up to 97:3) is observed for the ring opening, which
behaves as an SN1-like transformation.
well-defined stereochemical forms through efficient stereo-
and enantioselective functional-group transformations, or
otherwise available from commercial sources.[1] Owing to
the strain of the three-membered ring, epoxides react with
a wide array of nucleophiles and acids, thus leading to ring-
opening reactions, often with excellent levels of regioselec-
tivity and/or stereoselectivity.[1] Yet, as a rule, epoxides react
differently with (metal) carbenes. Effective deoxygenation
processes occur, thus transforming oxiranes into alkenes.[2]
For instance, treatment of epoxides with acceptor/acceptor
diazo reagents in the presence of a catalytic amount of
[Rh2(OAc)4] leads to a quantitative capture of the oxygen
atom and a stereospecific formation of the corresponding
olefins.[3,4] Herein, in a new development, we report that
metal carbenes derived from the a-diazo-b-ketoester reagents
2 undergo three-atom insertions into a large variety of
epoxides (Scheme 1). The transformation specifically uses
a combination of 1,10-phenanthroline (phen) and the com-
plex [CpRu(CH3CN)3][BArF] as the catalyst (BArF =
E
poxides (1; or oxiranes; Scheme 1) are indispensable
synthetic building blocks, which are readily accessible in
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate).[5]
Original
Scheme 1. Preferred syn-stereoselective 1,4-dioxene formation.
1,4-dioxene motifs of the type 3 are obtained as single
regio- and stereoisomers. A perfect syn stereochemistry
(retention; e.r. up to 97:3) is observed for the ring opening,
which otherwise behaves as an SN1-like transformation.
Recently, using combinations of [CpRu(CH3CN)3][PF6]
([4][PF6])[6] and diimine ligands as catalysts,[7] the reagents 2
[*] Dr. T. Achard, C. Tortoreto, Dr. A. I. Poblador-Bahamonde,
Prof. J. Lacour
Department of Organic Chemistry, University of Geneva
Quai Ernest Ansermet 30, 1211 Geneva 4 (Switzerland)
E-mail: jerome.lacour@unige.ch
ꢀ
provided selective 1,3-C H insertions into
THF[8] and O H insertion and condensation
Homepage: http://www.unige.ch/sciences/chiorg/lacour/
ꢀ
Dr. L. Guꢀnꢀe
reactions with alcohols, nitriles, ketones and
Laboratory of Crystallography, University of Geneva
Quai Ernest Ansermet 24, 1211 Geneva 4 (Switzerland)
aldehydes.[9] These results led us to examine
the reactivity of other Lewis basic moieties
with the catalytic combination, and epoxides
Prof. T. Bꢁrgi
Department of Physical Chemistry, University of Geneva
Quai Ernest Ansermet 30, 1211 Geneva 4 (Switzerland)
in particular. In practice, the first experiments were per-
formed by treatment of a CH2Cl2 solution of the cyclooctene
oxide 1a (1.0 equiv), the complex [4][PF6] (2.5 mol%), and
phen (2.5 mol%) with the methyl diazoacetoacetate 2A
(R3 = R4 = Me, 0.5m; Scheme 1). At 608C, gas evolution was
observed and complete consumption of 2A was achieved in
4 hours. Analysis of the reaction mixture indicated the
formation of one major product (3aA, 60%)[10] together
with some unreacted epoxide. Cyclooctene was only a minor
component of the crude reaction mixture. Based on detailed
1H and 13C NMR spectroscopy, and IR analyses, only the
original bicyclic structure with a 1,4-dioxene core and
a cis junction between the two rings (3J = 9.5 Hz) was
[**] We thank the University of Geneva, the Swiss National Science
Foundation, and the NCCR Chemical Biology for financial support.
We are also grateful to Dr. Klaus Ditrich (BASF) for a generous gift of
enantiopure epoxides. We also acknowledge the contributions of
the Sciences Mass Spectrometry (SMS) platform at the Faculty of
Sciences, University of Geneva.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402994. CCDC 988756,
988757, 988758 and 988759, products 3aA, 3hA, (+)-(S)-3pA, and
3jA, contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
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Table 2: Diazo reagent scope.[a]
consistent with the data. The motif was confirmed by X-ray
diffraction studies (Figure 1).[11,12]
First, total conversion of 1a was obtained using an excess
of the 2A (2 equiv). This 1:2 ratio between epoxide and diazo
reagent was maintained for the rest of the study. A search for
the best catalytic combination was performed. The results are
summarized in Table 1 for ruthenium complexes. The phen-
anthroline is clearly important, because in its absence the
reaction leads to larger amounts of the undesired cyclooctene
5a (entries 2 and 3; up to 30% of 5a). Most probably, phen
acts as a donor chelate ligand which stays on the metal
throughout the reaction and the catalytic cycle. Changing the
nature of the counterion additionally improved the conver-
sions (entries 4–6). The reactions were faster with lipophilic
anions like TRISPHAT [tris(tetrachlorobenzenediolato)
phosphate],[13] BArF, and SbF6, when compared to that with
PF6. Not surprisingly, conversions were lower with an anion
which is able to coordinate to the metal center (TRISPHAT-
N).[14] The complex [Cp*Ru(CH3CN)3][7b] (Cp* = pentameth-
ylcyclopentadienyl) and its mono-CF3 analogue did not
improve the transformation (entries 8–10). Other metal
sources were briefly tested. While copper salts did not
induce the formation of the dioxene product, only a small
amount (10%) of 3aA was observed in the reaction catalyzed
by [Rh2(OAc)4]. The 1:1 combination of phen and the salt
[4][BArF] (entry 6) was thus selected and used in further
experiments.
[a] Reaction conditions: diazo compound 2B–I (0.64 mmol), 1a
(0.32 mmol), [4][BArF], and phen (2.5 mol % each) in CH2Cl2 (0.6 mL) at
608C. Reaction times and ratios between dioxene and corresponding
alkenes are indicated. Yield of isolated compound 3 is an average of at
least two reactions. [b] Conv.=80%. [c] Conv.=81%.
Diazo reagents with different alkyl ester substituents, 2B–
I, were then tested and reactions with 1a were allowed to run
until full conversion (Table 2). Good yields of the isolated
products 3 were afforded with bulkier alkyl esters, sometimes
after prolonged reaction times (3aB–aD). With the reagents
2B–D, dioxene formation was clearly favored over the alkene
formation. In all cases, cis isomers were obtained as deter-
mined by NMR spectroscopy. The preference for the syn-
stereoselective epoxide opening was confirmed with reagents
2E–I, which bear substituents other than methyl in the a-
position of the keto group. In the presence of a propyl chain
(2E, R4 = Pr), a similar reactivity was observed (3aE). With
aryl and benzyl residues, reactions were slower and lower
yields were obtained (3aF–H). In the case of the CF3-
substituted diazo 2I, a longer reaction time was also necessary
(80% conversion after 48 h) to afford 3aI as a single
stereoisomer (63% yield upon isolation). Such a trifluorome-
thylated heterocycle is related to known agrochemicals, the
preparation of which requires six steps.[15]
The reaction was then tested with a variety of cis-
configurated epoxides (1b–l), using 2A as the diazo reagent
(Table 3). Satisfactorily, the 1,4-dioxene products 3bA–lA
were obtained in all cases as single cis isomers irrespective of
the cyclic or acyclic nature of the oxiranes.[16,17] Even the
sterically crowded epoxide 1e reacted well under the standard
conditions. By using the nonsymmetrical disubstituted oxir-
anes 1i–l, reactions proceeded equally well. Importantly, in
addition to being syn stereoselective, ring openings were fully
regioselective as single dioxene products 3iA–lA were again
obtained.[18] Clearly, the substitution reactions occur at the
more activated carbon centers bearing aryl or vinyl substitu-
Figure 1. ORTEP view of the crystal structure of the cis-configurated
3aA. Thermal ellipsoids are drawn at 50% probability.
Table 1: Ruthenium complex selection.[a]
Entry
[Ru]
Anion
Conv.[b]
3/5[c]
1
[CpRu(CH3CN)3]
[CpRu(naphthalene)]
[CpRu(CH3CN)3]
[CpRu(CH3CN)3]
[CpRu(CH3CN)3]
[CpRu(CH3CN)3]
[CpRu(CH3CN)3]
[Cp*Ru(CH3CN)3]
[Cp*Ru(CH3CN)3]
[(C10H12F3)Ru(CH3CN)3]
PF6
PF6
PF6
SbF6
TRISPHAT
BArF
TRISPHAT-N
PF6
SbF6
PF6
86
4.5:1
2.5:1
2.5:1
4.4:1
3.7:1
4.4:1
2:1
2:1
2.4:1
2.4:1
2[d]
3[d]
4
69[d]
85[d]
94
5
6
7
8
9
10
95
100
45
63
42
44
[a] Reaction conditions: diazo compound 2 A (0.64 mmol), [Ru] and
phen (2.5 mol % each), and 1a (0.32 mmol) in CH2Cl2 (0.6 mL) for 3 h at
608C. [b] Conversions of 1a monitored by 1H NMR spectroscopy using
1,3,5-trimethoxybenzene as an internal reference. [c] Ratio was deter-
mined by 1H NMR analysis of the crude reaction mixture. [d] Without
phen ligand.
2
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Table 3: Substrate scope.[a]
Table 4: Chirality transfer.[a]
Entry
X[b]
Substrate
e.r.[c]
Product
e.r.[c]
1
2
3
4
H
H
OMe
F
(+)-(R)-1p
(ꢀ)-(S)-1p
(+)-(R)-1q
(+)-(R)-1r
99.5:0.5
99.5:0.5
99.0:1.0
98.5:1.5
(ꢀ)-(R)-3pA
(+)-(S)-3pA
(ꢀ)-3qA
97:3
97:3
77:23
94:6
(ꢀ)-3rA
[a] Reaction conditions: see Table 3, entries 15–17. [b] The para sub-
stituent on substrates 1p, 1q, and 1r. [c] Determined by CSP-HPLC.
Average of at least two reactions.
(R)- and (S)-1p were tested and the product 3pA was
obtained with a 97:3 e.r. in favor of the levo- and dextro-
rotatory enantiomers respectively. With (R)-1q and (R)-1r,
strong and slight decreases in the enantiospecificity of the
reaction were noticed (3qA: e.r. 77:23 and 3rA: e.r. 94:6).
The origin of this variation is discussed in the mechanism
section.
Care was taken to determine the absolute configuration of
the ring-opened products. It was established by vibrational
circular dichroism (VCD).[21,22] IR absorption and VCD
spectra were measured for solutions (CD2Cl2) of both (ꢀ)-
and (+)-3pA and compared to the most stable conformer of
(S)-3pA (Figure 2), thus accounting for about 95% according
[a] Reaction conditions: diazo compound 2 A (0.64 mmol), 1b–s
(0.32 mmol), [4][BArF], and phen (2.5 mol % each) in CH2Cl2 (0.6 mL) at
608C. Ratios between dioxene and the corresponding alkenes are
indicated. Yield of the isolated compound 3 is an average of at least two
reactions. Reaction time 3 h, unless otherwise stated.
Figure 2. Experimental VCD spectra (CD2Cl2, 298 K) of (ꢀ)-3pA (red)
and (+)-3pA (blue). Calculated spectrum of (S)-3pA (green).
ents. Encouraged by these results, reactions were attempted
with the monosubstituted substrates 1m–s. To our satisfac-
tion, full control over the regioselectivity was again obtained,
with the ring opening occurring only at the more substituted
carbon atom. These important observations will be discussed
in the mechanistic discussion (see below). Interestingly, with
vinyl epoxides 1l–o, only the 1,4-dioxenes 3lA and 3oA were
isolated. These results contrast with literature precedents for
which products of [1,2]-insertion or [2,3]-sigmatropic rear-
rangements were observed, however such compounds are
absent from the current transformation.[2d,j,k] Also, with
epoxides carrying aryl substituents, slower reactions and
lower yields were globally observed. Possibly, 4 reacts with the
aromatic rings, thus leading to a decrease in the effective
concentration of the catalyst.[19,20]
to its Boltzmann weight. Overall, a good agreement between
the experimental and theoretical spectra was observed, thus
allowing the assignment of S and R configurations for the
dioxenes (+)- and (ꢀ)-3pA, respectively. This finding was
confirmed by an X-ray crystallographic study of (+)-3pA.[23]
These results clearly indicate that the formation of 3pA
occurs with retention of configuration.
A mechanistic rationale, consistent with all the exper-
imental information collected, is proposed in Scheme 2. The
catalyst precursor [4][BArF] reacts with phen to generate
a [Cp(phen)(CH3CN)Ru][BArF] species which, upon dissoci-
ation of the monodentate ligand, forms the catalytically active
16-eꢀ complex A. The diazo reagents 2 then react with this
electron-deficient species to afford the metal carbene inter-
mediate B. At this stage, a nucleophilic attack of the epoxide
To shed light on the process, the styrene oxides 1p–r were
then used in highly enantioenriched forms (Table 4). Both
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_
Scheme 2. Mechanistic rationale. NN represents the ligand phen.
R2 >R1 in terms of electron-donating ability.
occurs and the metal oxonium ylide intermediate C is formed.
Promoted by strain and by the electrophilic activation, a C O
ꢀ
bond cleavage occurs in the direction of the carbon atom
which better stabilizes the developing positive charge. This
step (C!D) involving an SN1-like pathway explains the
observed regioselectivity.[24] The carbocationic intermediate
D is then trapped by the keto group to form the cyclic 1,4-
dioxene skeleton. To retain the original configuration of the
reacting carbon center, this step (D!E) must be fast,
otherwise a racemization/epimerization occurs by a scram-
bling of the stereotopic faces through an internal rotation
ꢀ
around the C1 C2 bond. It is fortunately happening only with
1q for which the intermediate D is strongly stabilized by the
para-methoxy group. The products 3 are then released and the
catalytic cycle continues.[25]
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In conclusion, a new reactivity is reported for metal
carbene reactions with epoxides owing to the combination of
1,10-phenanthroline and [CpRu(CH3CN)3][BArF] as the
catalyst. Novel 1,4-dioxene motifs of the type 3 are obtained
as single regio- and stereoisomers. A syn stereochemistry
(retention, e.r. up to 97:3) is observed for the ring opening,
which behaves as an SN1-like transformation. Further appli-
cations of this approach are looked for.
Received: March 4, 2014
Revised: March 24, 2014
Published online: && &&, &&&&
Keywords: carbenes · diazo compounds · ruthenium ·
.
stereoselectivity · ylides
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Frequencies were scaled by 0.98. VCD spectra were constructed
from calculated rotational strengths assuming Loretzian band
shape with a half-width at half maximum of 5 cmꢀ1. All
calculations were performed using Gaussian09, RevisionC.01.
[23] The product (+)-3pA was purified up to a 99.5:0.5 e.r. by
semipreparative CSP-HPLC and crystallized in a dichlorome-
thane/pentane mixture. Using a single crystal, the Flack param-
eter was affined to 0.0(2) value indicative of a S configuration as
well. The ORTEP diagram of (+)-3pA is detailed in the
Figure S3.
ꢀ
[24] With disubstituted unsymmetrical epoxides, the C O bond
[16] Corresponding alkenes were usually observed in most cases as
minor products with percentages around 5–15%.
cleavage occurs to preferentially form benzylic carbenium ions.
With monosubstituted epoxides, secondary rather than primary
carbocations are formed.
[17] The cis configuration was ascertained by X-ray analysis. The
ORTEP diagram of 3hA is detailed in the Figure S1.
[18] Regio- and stereoselectivity were ascertained by X-ray analysis.
The ORTEP diagram of 3jA is detailed in the Figure S2.
[19] R. Hermatschweiler, I. Fernꢂndez, P. S. Pregosin, F. Breher,
Organometallics 2006, 25, 1440 – 1447.
[20] Alternatively, as a result of the the presence of the benzo groups,
ansa-ligated RuII h6-arene complexes made by ligand exchange
between the aryl and cyclopentadienyl moieties could also be
formed: a) Y. Miyaki, T. Onishi, H. Kurosawa, Inorg. Chim. Acta
[25] Preliminary computational studies starting from the intermedi-
ate B (R1 = H, R2 = Ph) confirm the proposed mechanism. The
rate-limiting step of the reaction is the coordination of the
epoxide (+ 9.8 kcalmolꢀ1
) en route to the oxonium ylide
intermediate C. From this species, the formation of intermediate
D requires only 1.7 kcalmolꢀ1. The final C O bond formation is
ꢀ
a barrier less process (+ 0.4 kcalmolꢀ1), which explains why the
retention of configuration is so kinetically favored. Further
calculations are in progress.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Synthetic Methods
T. Achard, C. Tortoreto,
A. I. Poblador-Bahamonde, L. Guꢁnꢁe,
T. Bꢂrgi, J. Lacour*
&&&& — &&&&
[CpRu]-Catalyzed Carbene Insertions into
Epoxides: 1,4-Dioxene Synthesis through
SN1-Like Chemistry with Retention of
Configuration
Oxygen sticks around: Rather than lead
to the usual deoxygenation pathway,
metal carbenes derived from a-diazo-b-
ketoesters undergo three-atom insertions
into epoxides using a combination of
1,10-phenanthroline and [CpRu-
(CH3CN)3][BArF]. 1,4-Dioxene motifs are
obtained as single regio- and stereoiso-
mers with perfect syn stereochemistry.
BArF =tetrakis[3,5-bis(trifluoromethyl)-
phenyl]borate, Cp=cyclopentadienyl.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!