Regioselective and Enantiospecific Synthesis of Dioxepines by (Cyclopentadienyl)ruthenium-Catalyzed Condensations of Diazocarbonyls and Oxetanes

Article abstract of DOI:10.1002/adsc.201700638

1,4-Dioxepines result from the decomposition of α-diazo-β-keto esters in the presence of oxetanes using the catalytic combination of the (cyclopentadienyl)ruthenium complex [CpRu(CH₃CN)₃][BAr_F] and 1,10-phenanthroline. The regioselective [4+3] insertions follow an S_N1-like mechanism and occur yet enantiospecifically (es 74%). The retention of configuration was ascertained by vibrational circular dichroism (VCD) and solid state analyses. Furans, products of [4+1] insertions, are only observed as traces in the above protocol. To promote their formation under CpRu catalysis, it is necessary to use a two-step process with γ-halogenated alcohols as substrates. (Figure presented.).

Full text of DOI:10.1002/adsc.201700638

Title: Regioselective and Enantiospecific Synthesis of Dioxepines by
CpRu-Catalyzed Condensations of Diazocarbonyls and Oxetanes
Authors: Leo Egger, Laure Guenee, Thomas Buergi, and Jérôme
Lacour
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10.1002/adsc.201700638
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Regioselective and Enantiospecific Synthesis of Dioxepines by
CpRu-Catalyzed Condensations of Diazocarbonyls and
Oxetanes
Léo Egger,a Laure Guénée,b Thomas Bürgi c and Jérôme Lacoura*
a
Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet 30, 1211 Geneva 4, Switzerland
Phone: +41 22 379 60 62; Fax: +41 22 379 32 15; E-mail:jerome.lacour@unige.ch
Laboratory of Crystallography, University of Geneva, Quai Ernest Ansermet 24, 1211 Geneva 4, Switzerland
Department of Physical Chemistry, University of Geneva, Quai Ernest Ansermet 30, 1211 Geneva 4, Switzerland
b
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
1b). Recently, it has been shown that combinations of
α-diazo-β-ketoesters in the presence of oxetanes using the 1,10-phenanthroline (phen) and [CpRu(CH3CN)3][X]
Abstract. 1,4-Dioxepines result from the decomposition of
catalytic combination of [CpRu(CH3CN)3][BArF] and 1,10-
phenanthroline. The regioselective [4+3] insertions follow
a SN1-like mechanism and occur yet enantiospecifically (es
74%). The retention of configuration was ascertained by
vibrational circular dichroism (VCD) and solid state
analyses. Furans, products of [4+1] insertions, are only
observed as traces in the above protocol. To promote their
formation under CpRu catalysis, it is necessary to use a
two-step process with -halogenated alcohols as substrates.
(X
=
PF6 1a or
X
=
BArF, tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate 1b) efficiently
catalyze the decomposition of α-diazo-β-ketoesters
and promote selective 1,3-C-H insertions into THF
[12]
and condensation reactions with ketones, lactones
and cyclic carbonates.[13] With oxiranes (epoxides),
[3+3] insertions lead to the formation of a large
variety of 1,4-dioxene moieties.[14] Herein, in a new
development, condensations of oxetanes 2 and α-
diazo-β-ketoesters
3
under CpRu-catalysis are
Keywords: diazo compounds; oxetanes; insertions; metal
carbenes; oxonium ylides; retention of configuration.
reported affording 1,4-dioxepines 4 (Scheme 1c). To
our knowledge, it is the first report of 7-membered
heterocycle formation in this type of reaction. Of
interest, the 1,4-dioxepines are obtained as single
regioisomers via SN1-like mechanisms that proceed
nevertheless with a certain level of enantiospecificity
(es 74%); the retention of configuration being
ascertained by vibrational circular dichroism (VCD)
analysis.
Seven to eleven-membered cycles, also called
medium sized rings, are important building blocks,
being present in a large variety of biologically
relevant natural and medicinal products.[1] Due to
strain and entropy factors,[2] their synthesis is often
challenging but it can be approached with confidence
through cycloaddition, ring-closing metathesis,
coupling or ring expansion reactions among others.[3]
In the particular context of ring-expansions,[4] the use
of reactive substrates such as readily-accessible
[5]
oxetanes can be advantageous.[6] In fact, the high
[7]
nucleophilicity of oxygen lone pairs
and the
[8]
important ring strain (~25 kcal.mol-1)
permit the
facile formation of reactive oxonium ylide
intermediates that decompose spontaneously into
higher ring systems, regio and stereoselectively.[9] For
[9a,9b,9g,9h,9l]
instance,
under
Cu-catalysis
or
photochemical conditions,[10] diazo reagents react
with oxetanes in [4+1] processes to form substituted
furans (Scheme 1a, [1,2]-shift mechanism). On the
[11]
[9i]
contrary, under Rh(II)
or Pd(II)
catalysis,
decompositions of α-diazo-carbonyls in the presence
of oxetanes (solvent) afford 15-membered
macrocycles by [3+4+4+4] condensation (Scheme
1
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10.1002/adsc.201700638
Advanced Synthesis & Catalysis
Scheme 1. Oxonium ylide formation by decomposition of
diazo reagents in the presence of oxetanes and subsequent
reactivity (a, b or c).
35% yield using an aldehyde containing diazoester
reagent (entry 9).
After this first screen of diazo reactivity, the reaction
was performed with various oxetanes (Table 2).[17] 1-
Naphthalenyl 2b afforded the corresponding 7-
membered ring 4bB with a lower yield than 4aB, due
probably to the increased steric hindrance (Table 2,
entry 1). A higher yield of 4cB was however obtained
with 1-phenyl oxetane (entry 2, yield 54%, Table
2).[18]
As just mentioned, efficient decomposition of
diazocarbonyls can be provided by the catalytic
combination of [CpRu(CH3CN)3] salts 1 and diimine
ligands. In many instances, in the presence of
carbonyl groups and cyclic ethers, rather unexpected
reactivities were reported.[12-14] These results led us to
consider the reactivity of other Lewis bases with the
catalytic combination, and oxetanes in particular. The
first experiments were achieved by dissolving 2-
naphthalenyl oxetane 2a (1.0 equiv) in a CH2Cl2
solution of complex 1b and phen (2.5 mol% each). In
practice, diazoacetoacetate 3A (2.0 equiv) was added
in one portion and the mixture was warmed up to
60 °C. From the beginning, dinitrogen release could
be observed and the reaction was stirred until full
conversion of oxetane 2a (16 hours, TLC monitoring).
1H-NMR spectroscopic analysis of the crude reaction
mixture led to the identification of ring-expanded 7-
membered ring 4aA in low yield (18% NMR).[15] In
view of the importance of 7-membered heterocycles
in synthesis and medical chemistry, it was decided to
study the reaction further and improve the reactivity.
However, despite many attempts (see supporting
information), the optimization of the reaction was
rather difficult and only a moderate increase in yield
was achieved. Eventually with a milder procedure,
decreasing the temperature down to 30 °C and using
5 mol% of catalyst led to full conversion of starting
2a in 16 hours and 4aA was obtained with a yield of
35% (Table 1, entry 1). The structure of 4aA was
confirmed by X-ray diffraction analysis (Table 1,
supporting information).[16] With these conditions in
hand, various diazocarbonyls were reacted. Using
diazo reagents with longer alkyl ester chains, such as
ethyl 3B and benzyl 3C, slightly higher yields were
obtained in the presence of oxetane 2a (entries 2 and
3). Not surprisingly, the sterically hindered
adamantyl group was found to have a negative effect
on the formation of 4aD as an oxetane conversion of
only 50% was observed after extended reaction time
(3 days, entry 4). p-Chlorophenyl 3E was tolerated as
product 4aE was obtained with a similar yield to the
methyl derivative 4aA (entry 5). With tosyl or mesyl
groups instead of ester moieties, formation of 1,4-
dioxepines 4aF and 4aG was achieved in 39% and
38% respectively (entries 6 and 7). Furthermore,
introduction of an α-ketoester group in place of the
acetyl moiety led to diester dioxepine 4aH in 19%
yield only (entry 8). The reason for the lower
reactivity could be the lesser nucleophilicity of the
enolate intermediate (vide infra, Scheme 2, species D
with R2 = CO2Et). Alternatively, 4aH was found to
be particularly sensitive to acidic conditions and the
lower yield could be the result of a degradation
during purification (silica gel chromatography).
Finally, trisubstituted enol ether 4aI was obtained in
Table 1. Diazocarbonyl reactivity.[a]
[a]
Reaction conditions: 1b (5 mol%), phen (5 mol%),
CH2Cl2, 30 °C, 16 h unless otherwise noted, c = 0.5 M;
1
conversions (conv.) determined by H-NMR spectroscopy.
ORTEP view of the crystal structure of 4aA. Thermal
ellipsoids are drawn at 50% probability. Ad = 1-adamantyl;
Ts = p-toluenesulfonyl and Ms = methanesulfonyl.
Globally, this increased reactivity was confirmed
with phenyl substituents carrying electron-
withdrawing (F, Cl) or donating (Me) groups at the
para position of the aromatic ring (4dB-4fB, entries 3
to 5, 55-61%); the reactivity being lower only in the
presence of a bulkier mesityl group (4gB, entry 6,
41%). Finally, p-tolyl oxetane 2f was reacted with
three other α-diazo-β-ketoesters. While similar results
were obtained with isobutyl and 2-methoxyethyl
chains (4fJ-4fK, entries 7 and 8, 52% and 53%
respectively), a slightly lower yield was observed
2
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10.1002/adsc.201700638
Advanced Synthesis & Catalysis
with the trichloroethylcarboxylate (Troc) ester (4fL,
entry 9, 40%).
3
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10.1002/adsc.201700638
Advanced Synthesis & Catalysis
Table 2. Oxetane reactivity.[a]
and theoretical spectra of (+) and (R)-configurated
4cB. This finding is in agreement with what was
observed by X-ray crystallographic study of (+)-4cB
(see supporting information). Due to the lack of
heavy atoms in the structure, the Flack parameter
could not be determined with good precision but its
value was found to be around zero (x = -0.13(16)).
These results clearly indicate that the formation of
4cB occurs with a global retention of configuration.
[a]
Reaction conditions: 1b (5 mol%), phen (5 mol%),
Figure 1. Experimental VCD spectra (CD2Cl2, 298 K) of
(+)-4cB (black) and (–)-4cB (red). Calculated spectrum of
(R)-4cB (green).
CH2Cl2, 30 °C, c = 0.5 M.
Additionally and of importance for the mechanistic
discussion, the enantiospecificity of the reaction was
examined. Enantioenriched oxetane (R)-2c (ee >99%)
was synthesized under reported conditions.[9l]
Treatment under the optimized conditions led to 1,4-
dioxepine (+)-4cB with exactly the same yield (eq 1).
Chiral stationary phase HPLC analysis indicated an
enantiomeric ratio of 87:13 for 4cB and hence a
chirality transfer (enantiospecificity) of 74%.
At this stage, a mechanistic rationale can be proposed
(Scheme 2). First, ruthenium salt 1b reacts with phen
to generate complex [CpRu(phen)(CH3CN)][BArF].
Then, upon dissociation of the acetonitrile ligand,
catalytically active 16-electron species A is formed.
After nucleophilic attack of diazo reagents 3 onto A
and dinitrogen extrusion, metal-carbenes of type B
are generated. Intermediates B behave as electrophilic
Fischer carbenes and nucleophilic attacks of Lewis
basic oxetanes yield metal-bound oxonium ylide
intermediates C. Due to ring strain and the
electrophilic activation of the aromatic rings,
regioselective C-O bond cleavage occurs to form
stabilized carbocationic intermediates D. The
neighboring carbonyl groups then trap the
carbocations leading to fast intramolecular 7-
membered
ring
formation
(D→E).
After
decomplexation, catalyst A and the 1,4-dioxepines
are released. Importantly, this mechanistic rationale
explains not only the global SN1-like regioselectivity
but also the observed (partial) retention of
configuration with substrate (R)-4cB. In fact, the
proximity between the carbonyl groups and the
secondary carbocationic center in D ensures rapid 7-
endo-trig cyclization.[19] This avoids, to a large extent,
the scrambling of the stereotopic faces of carbenium
ions D (through internal C-C rotations) and the
racemization.
Interestingly,
in
terms
of
stereospecific
transformations, only SN2 ring expansion of oxetanes
have been reported.[9d,9e] Care was thus taken to
determine the absolute configuration of product (+)-
4cB. It was established by vibrational circular
dichroism (VCD). A comparison between measured
VCD spectra for both (+)-4cB and (–)-4cB, obtained
enantiomerically pure by semi-preparative CSP
HPLC separation of (±)-4cB with the theoretical
spectrum of the most stable conformers (Boltzmann
distribution) of (R)-4cB was performed (Figure 1). A
good agreement was achieved between experimental
4
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10.1002/adsc.201700638
Advanced Synthesis & Catalysis
intermediates are observed leading to a large variety
of dioxenes. In view of the efficiency of the method,
care was taken to apply it for the synthesis of 1,4-
dioxepines. Reactions under CpRu catalysis of
alcohols 6c and 6h with 3B afforded halogenated
ketoesters 7c and 7h in good yields, 90% and 79%
respectively (Scheme 4). These compounds were then
treated with NaH (1.2 equiv) in DMF. However,
instead of forming 1,4-dioxepine products, reactions
afforded oxolanes 5c and 5h exclusively (62% and
70% yields). Clearly, the ketoenolate intermediates
undergo C-alkylation preferentially to form the
corresponding furans. According to Baldwin’s rules,
both 5-exo and 7-exo-tet cyclizations are favored; the
reactivity under Bull’s conditions indicates a clear
bias toward the 5-membered ring formation.[19]
Scheme 2. Mechanistic proposal.
Also of mechanistic importance, acid-sensitive furan
5c could be isolated from the reaction of oxetane 2c
with 3B (Scheme 3). In fact, careful analysis revealed
a proportion of 5-10% of 5c in crude mixtures (GC-
FID estimation).[20] The formation of 5c can be
Scheme 4. 5 vs. 7-membered ring cyclizations.
explained by
a
second route starting from
intermediates C or D (Scheme 3). At that stage, direct
C-alkylation gives rise to furan 5c, of structure
similar to that described by Nozaki and Noyori.[9a,9b]
Moreover, 5c is isolated as a single diastereomer, an
In
conclusion,
the
combination
of
[CpRu(CH3CN)3][BArF] and 1,10-phenanthroline
leads to a new reactivity between -aryl oxetanes and
carbenes derived from α-diazo-β-ketoesters. 1,4-
Dioxepines are obtained in moderated yields but with
a good enantiospecificity in an original SN1-like
transformation, as determined by VCD and X-ray
diffraction analyses. Baldwin’s rules for the ring
closure can be applied to explain the preferential
formation of dioxepines 4 vs. furan 5.
observation that tends to indicate
a
highly
stereoselective process as described in the literature.
[9a,9b,9l][21]
The preferred formation of 4cB over 5c can
be explained by Baldwin’s rules since 7-endo-trig
cyclizations are favored over 5-endo pathways.[19]
Experimental Section
In a 2 mL screw-cap vial equipped with a magnetic stirring
bar, 1,10-phenanthroline (3 mg, 16 mol, 5 mol%) and
[CpRu(CH3CN)3][BArF] (18 mg, 16 mol, 5 mol%) are
dissolved in 0.60 mL of dry dichloromethane. The vial is
flushed with nitrogen and capped. The resulting deep red
solution is stirred for 10 minutes at 25 °C before the
addition of oxetane 2 (0.32 mmol, 1 equiv) and the desired
diazo derivative 3 (0.64 mmol, 2 equiv). The solution is
stirred at 30 °C until full conversion (1H-NMR monitoring).
The crude mixture is purified by column chromatography
(pentane/Et2O, SiO2) to afford 1,4-dioxepine 4.
Scheme 3. Formation of furan 5c
Acknowledgements
Finally, Bull and co-workers have described recently
the formation of 1,4-dioxenes in two steps using -
halogenoalcohols as substrates.[22] In a first step,
CpRu-catalyzed O−H insertions of α-diazo-β-
ketoesters occur, followed by intramolecular
cyclizations under basic conditions. Using this
protocol, only O-alkylations of ketoenolate
We thank the University of Geneva and the Swiss National
Science Foundation for financial support. We acknowledge the
contributions of the Sciences Mass Spectrometry (SMS) platform
at the Faculty of Sciences, University of Geneva.
5
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10.1002/adsc.201700638
Advanced Synthesis & Catalysis
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[20] Overlapping H-NMR signals of 1,4-dioxepine 4 and
furan 5 rendered the spectroscopic analysis difficult for
a quantitative study.
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6
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Advanced Synthesis & Catalysis
COMMUNICATION
Regioselective and Enantiospecific Synthesis of
Dioxepines by CpRu-Catalyzed Condensations of
Diazocarbonyls and Oxetanes
Adv. Synth. Catal. Year, Volume, Page – Page
Léo Egger, Laure Guénée, Thomas Bürgi and
Jérôme Lacour*
7
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