A Catalytic Cross-Olefination of Diazo Compounds with Sulfoxonium Ylides

Article abstract of DOI:10.1002/anie.201809934

A ruthenium-catalysed cross-olefination of diazo compounds and sulfoxonium ylides is presented. Our reaction design exploits the intrinsic difference in reactivity of diazo compounds and sulfoxonium ylides as both carbene precursors and nucleophiles, which results in a highly selective reaction.

Full text of DOI:10.1002/anie.201809934

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Accepted Article
Title: A Catalytic Cross-Olefination of Diazocompounds with
Sulfoxonium Ylides
Authors: James Neuhaus, Adriano Bauer, Alexandre Pinto, and Nuno
Maulide
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809934
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A Catalytic Cross-Olefination of Diazocompounds with
Sulfoxonium Ylides
James D. Neuhaus,[a,+] Adriano Bauer,[a,+] Alexandre Pinto[a] and Nuno Maulide*[a]
Abstract:
A
novel ruthenium-catalysed cross-olefination of
electron-donating group adjacent to the diazomethane moiety of
at least one of the reaction partners.[7a,7c-7e] An additional report by
Wang and coworkers relies on the use of cyclopropenes as
diazocompounds and sulfoxonium ylides is presented. Our reaction
design exploits the intrinsic difference in reactivity of diazocompounds
and sulfoxonium ylides as both carbene precursors and nucleophiles,
resulting in a highly selective reaction.
carbene
precursors.
These
are
then
coupled
to
diazocompounds.[6d] The same group published an interesting
coupling of diazocompounds with in situ
difluorocarbene.[6e]
generated
The fascinating properties of alkenes have captured the
imagination of chemists ever since in 1795 a team of Dutch
researchers observed that the reaction between ethylene and
chlorine forms a colourless liquid.[1] This observation led the
authors to name ethene “gaz huileux” (i.e. oil-forming gas). Soon
the term was renamed “gaz oléfiant” and today, over 200 years
later, it is still common practice to use the word “olefin” when
referring to an alkene.
In the last 70 years tremendous developments in the ability to
form C=C double bonds, recognized with Nobel prizes, have
become textbook knowledge such as the Wittig and related
reactions[2,3] or olefin metathesis.[4] A conceptually appealing but
seldom realized retrosynthetic disconnection of alkenes relies on
the union of two carbenes. Indeed, early work showed that the
metal-catalyzed homocoupling of diazocompounds is a valuable
alternative for the generation of symmetrical alkenes.[5] Later
investigations into the intermolecular cross-coupling of
diazocompounds demonstrated that more effective coupling can
be achieved when the nature of the two coupling partners is
sufficiently different.[6,7] An early example by Zotto and coworkers
showed that acceptor-substituted diazocompounds can be
selectively cross-coupled with TMS diazomethane with high
stereoselectivity.[6a] This concept was recently extended by Liu et
al., whereby alkyl-substituted diazocompounds were generated in
situ and selectively cross-coupled to acceptor-substituted
diazocompounds via silver catalysis.[7e] However, poor
stereoselectivity, with 1:1 mixtures of E/Z olefin products, was
observed. Earlier, Davies and coworkers showed that donor-
acceptor diazocompounds can be cross-coupled selectively to
acceptor-substituted diazocompounds via rhodium catalysis.
Stereoselectivity was generally high in favor of the E olefin.[7a]
Although the scope was extended by Sun and coworkers, this
methodology requires both an electron-withdrawing and an
Scheme 1. Previously reported cross-olefinations and this work.
Sulfonium and sulfoxonium ylides have witnessed a renaissance
in contemporary catalysis beyond the well-known Johnson-
Corey-Chaykovsky reactions[8] in C-H functionalization,[9] N-H
insertion[10] and cycloisomerization reactions.[11] Their popularity
is owed to the fact that they are easy to prepare, readily purified
and considerably safer to handle than their diazo counterparts.
Although sulfoxonium ylide dimerization has been observed
indirectly, it has never been used for the effective synthesis of
olefins. This is probably also due to the fact that the generated
products (electron-poor olefins) are also good substrates for
[a]
Dr. J. D. Neuhaus[+], A. Bauer[+],Dr. A. Pinto and Prof. Dr. N.
Maulide
Institute of Organic Chemistry, University of Vienna
Währinger Straße 38, 1090 Vienna (Austria)
E-Mail: nuno.maulide@univie.ac.at
Homepage: http://maulide.univie.ac.at
[+]
These authors contributed equally
Supporting information for this article is given via a link at the end of
the document.
Johnson-Corey-Chaykovsky cyclopropanation under the reaction
[12]
conditions.
Indeed, sulfoxonium ylides are generally better
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10.1002/anie.201809934
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nucleophiles than their diazo analogues, but tend to undergo
decomposition to the metal carbene at much slower rates than
their diazo counterparts, rendering a catalytic, hypothetical
sulfoxonium ylide (cross)-coupling a difficult prospect.[13]
This led us to speculate that the catalytic cross-coupling of a
diazocompound with a sulfoxonium ylide should be possible. We
proposed that formation of a metal carbene should take place
faster from the diazocompound precursor, and that the resulting
electrophilic carbene would be attacked preferentially by the more
nucleophilic sulfoxonium ylide. However, we were uncertain
whether the coupling product (a Michael acceptor) would be prone
to undergoing conjugate addition by the sulfoxonium ylide.
In our first trials, a range of iridium(II) and rhodium(II) catalysts
were investigated for the cross olefination of diazoester 1a and
sulfoxonium ylide 2a, due to their well-documented proficiency in
metallocarbene formation.[7a],[14] Those preliminary experiments
(Table1, entries 1-2; see the Supporting Information for further
experiments) led to low but promising yields of the desired product
accompanied by diethylmaleate/diethyl fumarate resulting from
homodimerization of diazoester 1a as the main side product.
Importantly, homodimerization of the sulfoxonium ylide 2a was
virtually absent, corroborating our initial hypothesis. Unreacted
sulfoxonium ylide could be removed completely along with the
catalyst during workup, resulting in a clean and easy to analyze
crude 1H NMR spectrum. Cyclopropanation by-products were
never observed.[15] In the course of catalyst screening, we found
that the cheap ruthenium complex [Ru(p-cymene)Cl2]2 [16] displays
the highest efficiency for this cross-olefination. Further
optimization of the conditions led to good isolated yields above
70% with a Z/E ratio of 9:1 (Table 1, entry 5).
Table 1. Optimization of the cross olefination.
Entry
Catalyst
Temperature
NMR
Yield 3aa
Z : E
1
2
3
[Ir(COD)Cl]2
Rh2(OAc)4
r.t.
r.t.
r.t.
13%
20%
32%
1.0 : 1
1.9 : 1
1.9 : 1
[Ru(p-cymene)Cl2]2
4
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
Rh2(Esp)2
-78 °C to r.t.
-78 °C to r.t.
-78 °C to r.t.
-78 °C to r.t.
53%
71%[*]
10%
7.8 : 1
9.0 : 1
1 : 9.0
1 : 7.5
5[a]
6[a]
7[a]
Rh2(OPiv)2
17%
[a] 2.0 eq. of Sulfoxonium ylide used [*] Isolated yield, All reactions were
performed on a 0.2 mmol scale (diazo compound) under air.
With optimized conditions in hand, we examined the scope of
ylides (Scheme 2).[17] Pleasingly, electron-poor (2b-d, 2h)
sulfoxonium ylides afforded similar yields as well as Z/E
selectivities. Para-substituted substrates (2b/h) gave particularly
selective olefination with Z/E ratios up to 13:1. Electron-rich
substrates (2e/i) show lower selectivity. Noteworthy, the aryl
iodide 2f reacted smoothly without competing oxidative addition.
The product 3ai, which has shown antimicrobial activity (M.
tuberculosis), could be prepared in a single step.[18]
The ketone moiety on the ylide was not a prerequisite for
successful cross-olefination, as sulfone (3ak) afforded
comparable yields and high selectivities.
At this juncture, the substrate scope for the diazocompound was
investigated (Scheme 3). As depicted, the reaction is general for
a range of diazoesters. Notably, several alkenes (1c/i), a silane
(1e) and even an alkyne (1b) were well tolerated with Z/E ratios
of up to 11:1. No trace of competing cyclopropanation of the
unsaturated moieties was observed. Furthermore, esters of
functionalized terpene alcohols such as cholesterol (1f),
citronellol (1l) or a β-pinene derivative (1j) were smoothly
converted to the desired olefin. [19]
Scheme 2. Substrate scope for sulfoxonium ylides. Z/E ratios determined by
crude 1H NMR analysis. All yields are for pure, isolated material unless indicated
otherwise. [a] 1H NMR yield with Mesitylene as internal standard. [b] DMF was
used as a cosolvent.
Under these conditions, donor-acceptor diazoesters, (popularised
by the elegant work of Davies[20]), such as ethyl (E)-2-diazo-4-
phenylbut-3-enoate 4, were typically recovered suggesting that
conversion to the metal carbene did not take place.
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Ylide
Diazo
0%
20%
40%
3al
60%
3ma 3aa
80%
100%
Scheme 3. Substrate scope of diazocompounds. Z/E ratios determined by
crude 1H NMR analysis. All yields refer to pure, isolated material unless
indicated otherwise. [a] 1H-NMR yield with mesitylene as internal standard.
Scheme 5. Direct comparison of the cross-olefination procedure with the cross-
coupling of two different diazocompounds. Conditions: EDA 1.0 eq.,
Acetophenone derivative 2.0 eq., Z/E ratio determined by crude 1H NMR
analysis, 1H NMR yields with mesitylene as internal standard
Scheme 4. Unexpected reaction of a donor-acceptor diazo compound. 1H NMR
yields with mesitylene as internal standard.
Changing to rhodium(II) catalysis instead of ruthenium(II) (cf.
Scheme 4), the corresponding -ketoester 5 was observed (21%
and 49% starting material, NMR yield).
This suggests that our procedure is orthogonal to the work of
Davies. [7a]
Scheme 6. Isomerization to (E)-olefins.
In conclusion, a novel ruthenium-catalysed cross-olefination
of diazocompounds and sulfoxonium ylides is presented. Our
reaction design exploits the intrinsic difference in reactivity of
diazocompounds and sulfoxonium ylides as both carbene
precursors and nucleophiles, resulting in a highly selective
reaction that nicely complements known, often less selective
diazo-diazo coupling reactions. This results in olefin products with
high Z-selectivity.
A direct comparison of the cross-olefination protocol reported
herein with the cross olefination of two diazocompounds reveals
that yield and selectivity are considerably higher when
sulfoxonium ylides are employed (Scheme 5). Moreover, while
the cross-olefination of sulfoxonium ylides and diazoesters
delivers the homo-dimerization of the ester moiety (product 3ma,
cf. Scheme 5) as the only undesired byproduct in small amounts,
cross-olefination of two diazocompounds results in a mixture of all
the three possible coupling products with virtually no selectivity (in
the event, the desired cross-couple product 3aa is not even the
major product).
Acknowledgements
During optimization studies, several quenching agents were
investigated. While pyridine, pyrimidine and dimethylsulfide shut
down the reaction, triphenylphosphine had an additional effect:
Z/E diastereomeric mixtures were converted completely to the E
isomer when substoichiometric amounts of PPh3 were added to
the reaction mixture. Further studies showed that this
isomerization[21] takes place not only under the reaction conditions
but also in solutions of isolated products (Scheme 6).
Financial support of this research by the DFG (MA 4861/4-2), the
ERC (CoG VINCAT) and Covestro AG is acknowledged. Ms. C.
Bold (U. Köln) is acknowledged for the preparation of selected
starting materials and products. We thank the University of Vienna
for its continued and generous support of our research programs.
Keywords: Cross olefination • Homogenous catalysis • sulfur
ylide • diazocompound • ruthenium
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Entry for the Table of Contents (Please choose one layout)
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James D. Neuhaus, Adriano Bauer,
Alexandre Pinto and Nuno Maulide*
Page No. – Page No.
A Catalytic Cross-Olefination of
Diazocompounds with Sulfoxonium
Ylides
Similar, yet so different: A novel ruthenium-catalysed cross-olefination of
diazocompounds and sulfoxonium ylides is presented. Our reaction design exploits
the intrinsic difference in reactivity of diazocompounds and sulfoxonium ylides as
both carbene precursors and nucleophiles, resulting in a highly selective
transformation.
This article is protected by copyright. All rights reserved.