Three-Component [1 + 1 + 1] Cyclopropanation with Ruthenium(II)

Article abstract of DOI:10.1021/acs.organomet.8b00361

We report a one-step, Ru(II)-catalyzed cyclopropanation reaction that is conceptually different from the previously reported protocols that include Corey-Chaykovsky, Simmons-Smith, and metal-catalyzed carbene attack on olefins. Under the current protocol, various alcohols and esters are transformed into sulfone substituted cyclopropanes with excellent isolated yields and diastereoselectivities. This new reaction forms highly congested cyclopropane products with three new C-C bonds, three or two new chiral centers and one new quaternary carbon center. Twenty-two examples of isolated substrates are given. Previously reported synthetic routes for similar substrates are all multistep, linear routes that proceed with overall low yields and poor control of stereochemistry. Commercially available Ru(II) dehydrogenation catalysts, that were recently developed for the dehydrogenative synthesis of esters and amides from alcohol and amine substrates, were used in the reaction, with the best catalyst showing excellent activity at 0.2-1 mol % catalyst loading. Mechanistic investigation showed that in the case of alcohol substrates, the catalyst is only responsible for the first dehydrogenation step, and that the identity of the base and the countercation is crucial in achieving high yields. The catalyst is also required for the cyclopropanation of esters, although no dehydrogenation can proceed in this case, suggesting that substrates sensitive to H₂ may be acylated prior to reaction.

Full text of DOI:10.1021/acs.organomet.8b00361

Article
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Three-Component [1 + 1 + 1] Cyclopropanation with Ruthenium(II)
Tanner C. Jankins,†,§ Robert R. Fayzullin,‡ and Eugene Khaskin*,†
†Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Kunigami-gun, Okinawa 904-0412,
Japan
‡Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov Street,
8, Kazan 420088, Russian Federation
S
* Supporting Information
ABSTRACT: We report a one-step, Ru(II)-catalyzed cyclo-
propanation reaction that is conceptually different from the
previously reported protocols that include Corey−Chaykov-
sky, Simmons−Smith, and metal-catalyzed carbene attack on
olefins. Under the current protocol, various alcohols and
esters are transformed into sulfone substituted cyclopropanes
with excellent isolated yields and diastereoselectivities. This new reaction forms highly congested cyclopropane products with
three new C−C bonds, three or two new chiral centers and one new quaternary carbon center. Twenty-two examples of isolated
substrates are given. Previously reported synthetic routes for similar substrates are all multistep, linear routes that proceed with
overall low yields and poor control of stereochemistry. Commercially available Ru(II) dehydrogenation catalysts, that were
recently developed for the dehydrogenative synthesis of esters and amides from alcohol and amine substrates, were used in the
reaction, with the best catalyst showing excellent activity at 0.2−1 mol % catalyst loading. Mechanistic investigation showed that
in the case of alcohol substrates, the catalyst is only responsible for the first dehydrogenation step, and that the identity of the
base and the countercation is crucial in achieving high yields. The catalyst is also required for the cyclopropanation of esters,
although no dehydrogenation can proceed in this case, suggesting that substrates sensitive to H2 may be acylated prior to
reaction.
Scheme 1. Summary of Cyclopropane Syntheses
INTRODUCTION
■
Cyclopropanes are an important structural motif in many
biosynthetic pathways and are present in a large number of
natural products.1 Compounds bearing it have found use in the
pharmaceutical industry as drugs and antibiotics and as useful
precursors in the synthesis of industrially relevant compounds.2
However, the high ring strain presents many synthetic
challenges. These challenges are further compounded when
forming highly substituted or quaternary center bearing rings.
The most common pathways to accessing cyclopropanes
proceed through the generation of a reactive carbene or ylide
species. These reagents often require multistep preparation of
the olefin and carbene precursors. Historical examples include
the Simmons−Smith cyclopropanation, which uses multiple
equivalents of zinc (recently catalytic zinc reagents have been
utilized),3 and the Corey−Chaykovsky cyclopropanation,
where a sulfur ylide adds to an electron-poor olefin (Scheme
1).4,5 Other popular methods for synthesizing cyclopropanes
include olefin additions of carbenes,6 often metal-catalyzed and
formed from the decomposition of diazo reagents.7 More
specialized reactions involving organocatalysis,4g,i,8 ene-yne
catalyzed ring closure,9 and metal-catalyzed additions to
cyclopropenes10 have also been reported. In the vast majority
of cases, these approaches are specific to polarized or electron-
deficient olefins, where a β-carbon substituent often acts as a
directing group.
advantages over previous methods by offering control over
substituents on all three ring carbons, excellent diastereose-
lectivity, and no need for prefunctionalization of complex
olefins or sensitive diazo reagents beforehand. The three-
component assembly of the ring also offers a new
retrosynthetic analysis to cyclopropanes, maximizing the
convergence of a synthetic route. Although quaternary center
In this work, we report a new one-step catalytic cyclo-
propanation of alcohols with sulfones. This new reaction has
Received: May 29, 2018
© XXXX American Chemical Society
A
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sulfone cyclopropanes have been reported in the literature,11
their syntheses are multistep and often involve the preparation
of an advanced thioether intermediate followed by oxidation.
Our new synthetic method eliminates multiple steps and redox
manipulations, while also using benign building blocks that are
all commercially available and cheap. The reaction proceeds
with low catalyst loadings (down to 0.2 mol %) of Ru
dehydrogenation catalyst and gives products with two or three
new stereocenters, one of which is quaternary carbon (Scheme
1).
undetermined products. Pursuant to our recently published
report on the ester metathesis of unsymmetrical esters,22 we
were interested to see if the commercially available Gusev Ru-
SNS catalyst (structure given in Table 2 as catalyst C),23 which
is active in the ester scrambling reaction, could show novel
reactivity in other systems, particularly if it was used together
with esters in the earlier disclosed Milstein procedure.
Reacting unsymmetrical esters, we confirmed that olefins
form as a result of coupling between the benzylic alcohol esters
and alkyl or aryl sulfones (Scheme 3, eqs 1 and 2).
Currently, there is only one previous report by Antonchik,
where all three ring carbons are joined in one step from
different molecules.12 The report mostly shows couplings
between two readily available components to form structurally
unique cyclopropanes. However, the three-component proce-
dure is limited to methyl aryl ketones with the conditions
requiring 10 mol % of catalyst, excess peroxide, and only
forming symmetric products with the same R group on all ring
carbons.
a
Scheme 3. Screening of Various Esters
Although aryl sulfones can be easily reduced in one step to
afford all carbon-substituted cyclopropanes,13 they also have a
unique electron-withdrawing effect conducive to ring-opening
reactions.14 Sulfone-substituted cyclopropanes have been
recently used in an elegant C−N bond coupling technique
by the Baran group.11a,15 Other ring-opening reactions of so-
called “push−pull cyclopropanes” in organic synthesis,
including ring expansion, have been summarized previous-
ly.11a,16
RESULTS AND DISCUSSION
■
Initial Studies and Optimization. In 2014, Milstein and
Srimani reported on a reaction resembling the Julia
olefination17,18 but occurring between alcohols and sulfones
(Scheme 2) in the presence of a Ru dehydrogenative coupling
a
Scheme 2. Julia Olefination and Related Reactions
Conditions: 0.1 mmol sulfone, 0.1 mmol ester, 0.5 mol % of Ru-SNS,
0.11 mmol KOtBu, N2, 16 h, 80 °C closed system, quench with aq
NH4Cl. Qualitative yields were obtained via GC/MS against a
mesitylene internal standard.
Surprisingly, when the alkyl alcohol ester ethyl benzoate and
benzyl phenyl sulfone were coupled, we observed only trace
styrene formation and two new products that at the time could
not be identified based on NMR spectra alone (Scheme 3, eq
4). To avoid the minor product styrene that presumably arose
as a byproduct of ester metathesis, we used the symmetrical
ester, ethyl acetate, on a 1 mmol scale to cleanly form and
isolate the same products. Product 2 conveniently crystallized
after column chromatography. Another symmetrical ester,
hexyl hexanoate, gave related products 3 and 4, with 3
crystallizing. The structures of 2 and 3 were unambiguously
identified by single-crystal X-ray diffraction analysis (Figure 1),
showing agreement with NMR data and allowing us to make
structural assignments and identify related compounds 1 and 4.
Both the linear and the cyclopropane product were unexpected
based on previously known chemistry.
Cyclopropanation of Alcohols. We observed only the
alcohol unit of the ester reacting in the mixed ester
experiments, so we quickly established that it was possible to
replace the ester by a primary, nonbenzylic alcohol, thus
making the reaction more atom economical and offering a
wider range of commercial starting materials. The yield of
linear product 3 could be lowered significantly when 2 equiv
catalyst.19 Similar to the above report, various other products
can be obtained by introducing diverse substrates that can
capture the intermediate aldehyde.20,21 The Milstein procedure
utilized simple sulfones, as in the classical Julia olefination
(Scheme 2), to intercept the aldehyde intermediate, without
the need for an external reductant to form the olefin. The
mechanism of this interesting transformation was not fully
established.
The Milstein procedure was limited to benzylic alcohols,
which under our reaction conditions will also form the olefin
and no cyclopropane. The aliphatic alcohols attempted by
Milstein were reported to give a complex mixture of
B
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Table 2. Optimization of Cyclopropanation Reaction
a
Conditions
Figure 1. ORTEP projections of cyclopropane 2 and linear product 3,
showing anisotropic displacement ellipsoids at the 50% probability
level.
cat.
yield of 4
entry
(mol %)
T (°C) solvent
base
(GC/MS)
b
1
2
3
4
5
6
7
8
9
10
11
12
13
A (2)
B (3)
C (0.5)
D (0.5)
E (2)
C (0.5)
C (0.5)
C (0.5)
C (0.5)
C (0.5)
C (0.2)
C (0.5)
C (0.5)
80
80
80
80
80
80
80
80
80
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
NaOH
LiHMDS
NaHMDS
KOtBu
KHMDS
KHMDS
KHMDS
KOtBu
80%
11%
70%
54%
41%
0%
(with respect to the alcohol) of sulfone was used, increasing
the yield of 4. Thus, no reagents are used in excess equivalents,
making this reaction very efficient and preventing waste of
potentially valuable intermediates. Table 1 showed that the
catalyst is only responsible for dehydrogenation; however, the
controlled rate of aldehyde formation is necessary for allowing
the reaction to proceed with good yield. Using aldehyde as
starting material resulted in side reactions, with ca. 20% of the
desired product obtained (Table 1, entries 1 and 2).
Entries 4, 11, and 12 in Table 1 confirmed that the
potassium cation had to be present in noncatalytic amounts,
with 18-crown-6 acting to shut down the coupling. RuCl3 ×
H2O, which is known to convert to Ru(II) species in situ when
heated in alcohol,24 was found to be a viable homogeneous
precatalyst under the reaction conditions (entry 6) but also
gave many unidentified, relatively low-boiling byproducts.
Interestingly, even NiBr2 was active to some extent, however,
the number of byproducts and unreacted alcohol significantly
exceeded that of even RuCl3.
Catalyst Optimization. Although the above experiments
suggest that perhaps first-row dehydrogenation catalysts may
ultimately be superior on a cost basis, the catalyst identity is
important to minimize formation of byproduct 3 and to enable
an optimal rate of aldehyde formation. Catalyst screening
(Table 2) showed that a number of commercially available Ru
and Os catalysts active in alcohol dehydrogenative couplings
were also competent in the cyclopropanation reaction.
However, the best catalyst was the Ru-SNS (catalyst C)
initially tested.23 The commercially available Milstein catalyst
A25 was also very active, albeit at a higher loading. However, it
0%
0%
70%
b
120
120
80
quantitative
quantitative
35%
80
THF
0%
a
Conditions: 0.2 mmol hexanol scale, 200 mol % of sulfone, 210 mol
% of base, N2 closed vessel. Significant amount of linear product 3
was obtained.
b
also formed byproduct 3 in more significant amounts (20%).
Ru-MACHO, catalyst B, normally is quite active in alcohol
coupling and ester hydrogenation chemistry.26 However, it
reacted very poorly for this transformation and gave no
selectivity for the cyclopropane over linear product. Catalysts
D27 and E28 were not competitive on yield, although their
selectivity was similar to that of C. KHMDS gave outcomes
considerably better than those of KOtBu, whereas LiHMDS
and NaHMDS lead to no product. THF with KHMDS was less
active, and using both THF and KOtBu gave no product.
Increasing the temperature to 120 °C in toluene led to
significant improvements in the yield of 4, while reducing or
completely suppressing linear product formation. Control
a
Table 1. Establishing Viability of Alcohols as Substrates
entry
cat. (mol %)
b or c
additive
none
none
none
10% KBr
none
base
yield of 4 (GC/MS)
1
2
3
4
5
6
7
8
9
C (0.2)
none
C (0.2)
C (0.2)
C (0.2)
RuCl3 (5.0)
C (0.2)
RuCl3 (5.0)
NiBr2 (2.0)
C (0.2)
b
b
c
c
c
c
c
c
c
c
c
c
KHMDS
KHMDS
NaHMDS
NaHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
21%
22%
no reaction
trace
quantitative
85%
quantitative
85%
18%
76%
trace
none
Hg drop
Hg drop
none
1 atm H2
20% NaHMDS
20% 18-crown-6
10
11
12
C (0.2)
C (0.2)
9%
a
Conditions: 0.2 mmol b or c, 200 mol % of sulfone, 210 mol % of base, N2 closed vessel. Qualitative yields were obtained via GC/MS against a
mesitylene internal standard.
C
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Figure 2. Compounds obtained in the course of coupling of alcohols with sulfones. Relative configuration of the major diastereomer is presented.
All substrates with 1 mol % of C except 6, 16, 18, and 20 (0.5 mol % of C). Substrate 7 can be synthesized from 2-butyne-1-ol or 3-butyne-1-ol
under the same conditions but with a 72 h reaction time. 8 and 9 required 72 h of reaction time. Substrate 21 was synthesized from
paraformaldehyde and no catalyst. 1 and 3 are byproducts isolated during synthesis of 2 and 4 from esters. Low isolated yields of products 12 and
19 due to unsuccessful column silica gel passivation.
experiments showed that the reaction did not proceed without
the catalyst C and/or base for the alcohol and ester substrates.
Substrate Scope and Formation of Cross-Coupled
Products. Under optimized conditions (Table 2, entries 10
and 11), we attempted cyclopropanation with a number of
alcohols at the 1 mmol scale, with 0.5−1 mol % of catalyst
loading, using benzyl phenyl sulfone as the model sulfone
because of its low cost and its ability to form crystalline
products, which were important in confirming the stereo-
chemistry of the products. The structures of all isolated
products whose stereochemistry could be determined are given
in Figure 2.
When considering the crude yield that can be determined
from the NMR of the isolated crude, we established that some
linear alcohols react quantitatively under these conditions if
both cyclopropane diastereomers are counted as the product.
The role of sterics for ring closure is illustrated by the low yield
of products 5 and 6. For the latter, the crude yield of ca. 30%
was still reasonable; however, separation from the linear
byproduct that formed in substantial amounts and had a very
similar polarity proved problematic. Due to subtle differences
in sterics, the slightly bulkier isobutyl alcohol was unreactive,
but cyclopropyl alcohol gave product 11 in good yield. In all
cases, we counted the yield as that of the major diastereomer
only after column isolation; however, the similar polarity of the
diastereomers and sometimes the linear byproduct meant that
the isolated yields of one diastereomer could be quite lower
than the crude yield, even if the initial crude selectivity was
quite good. This is especially true of compound 6, where there
was ca. 60% linear byproduct obtained together with 30% of
the cyclopropane (one diastereomer exclusively), and the
polarity is dominated by the adamantyl moiety; after column
chromatography, we only obtain 10% pure product.
Notably, this reaction tolerates many common functional
groups found in natural products and pharmaceutical drugs.
Alkene (20), terminal alkyne (14), and sterically demanding
alkyl products (6, 11) arising from common terpene building
blocks were all amenable to the reaction conditions.
Interestingly, aromatic heterocycles (13) that often are
deleterious in other transition-metal-catalyzed reactions were
obtained in moderate yields. Ether (16), thioethers (15, 22,
23), amines (12, 19), and aryl fluorides/trifluoromethyl groups
(8, 9) were also well-tolerated. Some substrates allowed for
their isolation in an impressive ca. 70% yield range; however,
D
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even reaction yields of 10−40% for obtained highly complex
products greatly outperform all other viable approaches for
their synthesis.
Methanol was also amenable to cyclopropanation under the
reaction conditions to give the corresponding C3-unsubsti-
tuted cyclopropane sulfone 7. The reaction was run with
methanol-d4 to give deuterated product 10; to the best of our
knowledge, this is the only example of a one-step method to
produce a deuterated cyclopropane. Interestingly, product 7
was also observed after long reaction times with 2-butyn-1-ol
and 3-butyn-1-ol, hinting at a complicated rearrangement
mechanism accompanied by formal C−C bond cleavage for
substrates where the triple bond is close to the alcohol
functionality. In these cases, however, long reaction times of 72
h are required to achieve similar 40% yields.
We performed a number of “mixed sulfone” reactions in
order to extend the utility of the current method by
introducing substituents from two different sulfones on the
ring carbons of the cyclopropane. Using 1 equiv of each
sulfone often led to selective reactions for cross-coupled
products, with relatively small amounts of the homocoupling
cyclopropane. The selectivity could be predicted based on
sulfone pKa values (see Table S1 in the Supporting
Information), with the more acidic sulfone remaining on the
ring presumably because this sulfone is the first to capture the
in situ produced aldehyde.
Many of the cyclopropanes synthesized by us managed to
crystallize well after column chromatography via slow
evaporation of solvent. Suitable single crystals were studied
by means of X-ray diffraction (Figure 3). Section 7 of the
Supporting Information contains full experimental details
regarding data collection and structure refinement. Figures 1
and 3 illustrate molecular structure and configuration of
compounds analyzed. Interestingly, racemic samples of cyclo-
propanes 2 and 6 crystallize in the Sohncke space group P21 of
the monoclinic crystal system as conglomerates of enantiomer
crystals, which makes direct resolution of their racemates
possible. The other substances studied form racemic compounds
in crystals, containing both enantiomers in the unit cell.
Based on NMR NOESY data and XRD data (Figure 3),
some conclusions can be made on ring substitution trends. The
alcohol unit provides the source of diastereoselectivity, with
the sulfone substituents arranged in a cis configuration.
Interestingly, fluorine-containing cyclopropanes 8 and 9 and
oxygen-containing 16 have a trans configuration of the alcohol
moiety to the remaining sulfone. Because these electronegative
atoms are far away from the cyclopropane core, F/O
coordinating to potassium in the transition state is more likely
the cause of the observed stereochemistry rather than
electronic effects. For products 17, 23, and 24, meso
compounds are formed preferentially, possibly reflecting the
different coordination environment around the potassium
when smaller sulfones are used.
Figure 3. ORTEP projections of cyclopropanes 6−9, 12, 13, 15, and
24, showing anisotropic displacement ellipsoids at the 50% probability
level. The minor components of the disordered trifluoromethyl group
(9) and thiophene moiety (13) are omitted for clarity.
formation reactions disclosed by Krische.30 Alcohol dehydro-
genation and subsequent coupling reactions where the H2 is
subsequently not used20 are more rare. Interestingly, the
reactions with esters showed that dehydrogenation of a free
alcohol is not necessary, although a “Milstein-type” pincer
dehydrogenation catalyst is still required for the reaction to
proceed, and it is mostly the alkoxy part of the ester that reacts.
Mechanistic Discussion. Previous methods for the
diastereoselective synthesis of cyclopropanes, which are
summarized in Scheme 1, often required low temperatures to
enable selectivity. We were thus interested in obtaining insight
into the unusual mechanism of the current reaction. In 1991,
Julia showed that addition of sulfone carbon anions could be
catalyzed by nickel complexes to add across double bonds and
give cyclopropanes in various degrees of diastereoselectivity.31
Other examples in the literature showed that carbanions can
add to vinyl sulfones to give cyclopropanes where the sulfone
functionality is maintained32 or eliminated. In the case of
elimination, the SO2Ph moiety leaves as a phenyl sulfi-
nate.31−33
A number of other structurally interesting alcohols and
sulfones could be cyclopropanated, but resulted in mixtures
that could not be separated. A table of these substrates, that
includes a tetrazole sulfone from the recent report on complex
sulfone synthesis13 along with an explanation of why isolation
was not further pursued, is given in the Supporting
Information (Figure S85).
Catalytic dehydrogenation of alcohols and their subsequent
use in a reaction has been used in “hydrogen borrowing”
chemistry developed by Williams,29 as well as in CC bond
E
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Cyclopropanation of methanol-d4 (Figure 2, compound 10)
showed that the carbon atom from the alcohol was still fully
deuterated, with the other sulfone-based CH being partially
deuterated due to exchange with the D atom of methanol’s
OD. The retention of deuterium in the product shows that
exchange does not occur after the formation of the initial
aldehyde.
Based on Table 2, it is also clear that the noncoordinating
HMDS anion improves the reactivity when compared to that
of other potassium bases. THF, which can compete for binding
with potassium, inhibits the reaction. It is presently not clear
whether coordination of a ligand to potassium is strictly
required.
The dehydrogenation catalyst is active at lower temper-
atures, as shown in earlier reports,22,23 and does not necessarily
require high temperature to form the aldehyde intermediate.
Consequently, we believe it is the (likely potassium-promoted)
cyclization that requires high temperatures. Linear product was
not observed in Table 1, entry 2, where hexanal and no catalyst
was used, suggesting that formation of linear species 1 and 3 is
catalyst-mediated. Large amounts of byproducts 1 and 3 were
isolated in the initial prescreening experiments that could be
used in interrogating the mechanism. We treated isolated 3
with 1 equiv of base and sulfone under the catalytic reaction
conditions with and without catalyst and in the presence or
absence of 1 equiv of water because water is a likely product of
the cyclopropanation reaction (Scheme 1). In all cases, the
intermediate was completely unreactive. As 3 fails to give the
final product 4, its formation was minimized by using high
reaction temperatures and catalysts that do not lead to its
formation as easily (i.e., C but not A). Addition of 1 equiv of
water to the reaction did not lead to an effect, but 3 equiv was
deleterious, likely due to immediate quenching of the base or
by altering the coordination environment around potassium
(Scheme 4). This could also be due to the catalyst being shut
down in the presence of excess water or hydroxide, which is a
known degradation pathway of similar catalysts.20a However,
addition of molecular sieves to the reactions did not affect the
yields.
The lack of reactivity with stoichiometric vinyl sulfone,
which is modeling the intermediate that would be produced in
the synthesis of product 17 (Scheme 4, reaction 3), suggests
that olefin species are not intermediates formed in large
amounts, in contrast with the earlier results obtained by Julia.31
A catalytic reaction with hexanol set up with an open system
under a flow of argon gas that would allow generated H2 to
escape did not alter the yields or selectivity of the reaction.
However, it is possible that vinyl sulfone polymerizes under
our reaction conditions, which offers an explanation for why no
cyclopropane was detected when vinyl sulfone was used
stoichiometrically. On the other hand, adding 1 equiv of vinyl
sulfone with 2 equiv of benzyl phenyl sulfone and 1 equiv of
alcohol under the normal reaction conditions lowered the yield
of 4 and increased the amount of 3, while also forming more
byproducts, thus suggesting a retarding effect for the olefinic
vinyl sulfone species. A reaction set up with vinyl sulfone and 1
equiv of water and benzyl phenyl sulfone (Scheme 4, reaction
5) did give a trace peak of a cyclopropane that would be
expected if addtion of water to the double bond did occur and
formed an intermediate similar to ii, suggesting that the
reaction proceeds from an alkoxy-type species and not an
olefin. This product was completely absent when no water was
present (Scheme 4, reaction 3).
Based on the above mechanistic studies and previous
literature examples, we considered two main pathways leading
to 4 that are outlined in Scheme 5. Initial formation of an
Scheme 5. Proposed Mechanism
a
Scheme 4. Mechanistic Investigation Reactions
intermediate aldehyde34 is followed by attack of a sulfone
anion to create intermediate i. The initial dehydrogenation
step is likely irreversible judging by the deuterated methanol
experiment (Figure 2, entry 10). Formation of iii is catalyst-
mediated, but using a higher temperature either allows the
cyclopropanation to proceed more readily or decomposes the
catalyst before too much iii is made; thus relatively less 3 is
formed at 120 °C. No olefins (species like iv) were ever
a
120 °C/N2/0.5 mol % catalyst C/toluene. 1.05 eq. of KHMDS for
every 1 eq. of benzyl phenyl sulfone. Qualitative yields via GC/MS
against mesitylene internal standard. *Yield determined by GC/MS.
F
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isolated, detected by GC/MS, or observed by in situ NMR, so
it is proposed that this intermediate is highly reactive and
formation of either 3 or 4 will happen instantaneously upon
formation of iv. Unfortunately, the reaction produces a
heterogeneous slurry which prevented effective detection of
trace intermediates by in situ NMR techniques.
Scheme 6. Flow Chart for Nonhindered Olefin Substrates
It is important to note that the catalyst must maintain the
right kinetic balance of aldehyde (and thus intermediate i),
without over-reacting to lead to Tishchenko or aldol pathways.
The catalyst must also not enable the formation of 3, which
can be considered an interesting product in its own right.
Catalyst C contains the ideal properties to control the right
balance of reagents and not react to give side product 3.
Whereas A and B also form i at an appropriate rate, they also
readily form iii, which leads to greater amounts of side product
3.
we could not solve the issue of isomerization, so the synthesis
and isolation of this substrate was not attempted on a larger
scale. However, it may be possible to use prior esterification as
a general strategy for substrates that are sensitive to H2 or that
tend to produce too much linear product. In general, we only
see a trace contribution to cyclopropane formation from the
acyl moiety, and that is probably due to partial ester
metathesis.22 Because the ester is probably rapidly converted
back to aldehydes in an outer sphere process, as shown by
Gusev recently,35 and in currently unpublished work on the
Shvo catalyst, the selectivity and the high yield for the alkoxy
part of the ester (>50%) are puzzling. This strategy will be
explored as a pathway for poorly performing substrates in the
future.
In the non-olefin pathway, pathway 1, intermediate i is first
protonated, then ii is attacked in an “interrupted E1cb”
fashion. The other equivalent of sulfone carbanion attacks the
hydroxonium carbon as it is forming, followed by immediate
intramolecular ring closure by the back-attack of the newly
formed carbanion sulfone on the α-carbon of the other sulfone.
We propose the interaction of K+ to set the stereochemistry by
chelation to the sulfone oxygen and alcohol oxygen. In the
olefin pathway, pathway 2, the olefin is first formed in a
traditional E1cb fashion. The sulfone is then templated by
potassium to give the cyclized product 4. We currently do not
possess enough data to rule out either pathway. Pathway 2 is
only possible when the concentration of olefin is low,
preventing its polymerization or other side reactions. There
is also previous literature precedent for addition of anions to
olefins to give cyclopropanes, but this process is metal-
catalyzed, whereas we established that metal is not necessary in
the aldehyde experiments.31−33 The non-olefin pathway 1 is
preferred by us because the proposed olefin intermediate was
never isolated or detected in any of the reactions by GC/MS
or NMR. The reaction using stoichiometric vinyl sulfone also
failed to give any product, and when vinyl sulfone was added to
a catalytic reaction, it partially inhibited the transformation.
Furthermore, the yield remains largely unchanged when the
reaction is run in an open system, or under 1 atm of H2,
although if the rate of ring closure were much faster than
hydrogenation of the double bond, this would not rule out
pathway 2. The olefin intermediate for cyclopropanation was
shown to be necessary for Julia olefination, and it is the
substrate in metal-catalyzed carbene synthesis. However, these
examples appear to be fundamentally different mechanistically
and also based on substrate and product nature.
CONCLUSIONS
■
In conclusion, we have outlined a new cyclopropanation
reaction that utilizes homogeneous Ru dehydrogenation
catalysts. This reaction uses alcohols and sulfones as diverse
and cheap substrates that lead to complex products with three
new carbon−carbon bonds, two or three new chiral centers,
and one new quaternary carbon center formed in a single
reaction. Esters, which cannot be dehydrogenated, are also
catalytically transformed to cyclopropanes but require the
catalyst for reactivity. This reaction is a rare example of all
three ring substituents coming from separate synthetic units,
opening up new possibilities for a more convergent,
retrosynthetic analysis of cyclopropanes. Importantly, the
catalyst is also commercially available and reasonably priced,
which should help expedite the use of this new method in
current research.
We are currently trying to enable reactivity of other
substrates that were not active at high temperatures by
screening suitable ligands for potassium or other cations that
can produce a similar templating effect. We are also attempting
to establish the correct mechanism of the reaction by
experimental and DFT studies.
Lastly, it should be mentioned that the first part of the
mechanism would be different without a source of hydrogen
from the alcohol and may have implications as to whether
pathway 1 or 2 is active. We presented compound 20 as an
example of a successful olefinic alcohol that can be cyclo-
propanated, but it has a protected, trisubstituted double bond
that is not prone to hydrogenation or isomerization by the Ru
catalyst. Although olefin substrates are amenable to the
reaction, we find that partial hydrogenation or isomerization
and subsequent isolation of only one product is a significant
problem. Because catalysis is also possible with non-H2-
producing esters, we investigated a terminal olefin substrate on
a small scale both as an ester and as an alcohol (Scheme 6).
It is possible to avoid hydrogenation of the olefin moiety by
using the ester as the starting material; however, at this point,
EXPERIMENTAL SECTION
■
General Procedure for Closed System: To an oven-dried 100
mL Schlenk flask in an N2 glovebox were added benzyl phenyl sulfone
(464 mg, 2 mmol), KHMDS (410 mg, 2.05 mmol), and Ru-SNS (6.3
mg, 0.01 mmol) before the addition of ∼10 mL of toluene. The
alcohol or ester (1 mmol) was added to the reaction mixture; the
vessel was sealed and stirred at 120 °C for 12 h. The reaction was
allowed to cool to room temperature and then quenched with 5 mL of
saturated NH4Cl solution. The mixture was extracted with 20 mL of
ethyl acetate (×3), and the organic layers were collected and dried
over MgSO4. The solution was concentrated under vacuum and
purified by flash silica chromatography with a typical gradient of
100:0−88:12 (hexane/ethyl acetate). A picture of the experimental
apparatus is presented in the Supporting Information.
G
DOI: 10.1021/acs.organomet.8b00361
Organometallics XXXX, XXX, XXX−XXX

Organometallics
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00361.
■
S
Experimental details, NMR spectra of all products,
discussion about assigning the structure, a listing of
substrates that were attempted but did not work or were
not pursued for isolation including the relevant
discussion, and crystal structure details (PDF)
Accession Codes
CCDC 1562834−1562836, 1562838−1562844, 1562864, and
1562865 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: eugenekhaskin@oist.jp.
ORCID
Robert R. Fayzullin: 0000-0002-3740-9833
Eugene Khaskin: 0000-0003-1790-704X
■
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Present Address
§Department of Chemistry and Chemical Biology, The Scripps
Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA
92037, USA.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Michael Chandro Roy, Research Support
Division, Okinawa Institute of Science and Technology
Graduate University for mass analyses and separating
enantiomers of compound 2. Prof. Dmitry Gusev is also
gratefully acknowledged for a 1 g sample of osmium catalyst E
and for a preprint copy of a manuscript relevant to the
mechanistic discussion. The Baran group at TSRI is acknowl-
edged for a donation of two complex sulfone substrates (see
SI). T.C.J. would like to acknowledge Prof. Keary Engle for
helpful discussion.
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