Gold-catalyzed intermolecular synthesis of alkylidenecyclopropanes through catalytic allene activation

Article abstract of DOI:10.1002/chem.201402935

A stereoselective gold(I)-catalyzed intermolecular cyclopropanation of allenamides with stabilized sulfonium ylides is reported. This transformation enables the direct synthesis of diacceptor alkylidenecyclopropanes and proceeds under very mild conditions through allene activation. Three is my lucky number: A mild stereoselective gold(I)-catalyzed intermolecular cyclopropanation of allenamides with stabilized sulfonium ylides is reported. This transformation delivers diacceptor alkylidenecyclopropanes and unusually proceeds through allene activation rather than by metallocarbene formation (see scheme, EWG=electron-withdrawing group).

Full text of DOI:10.1002/chem.201402935

DOI: 10.1002/chem.201402935
Communication
&
Sulfonium Ylide Chemistry
Gold-Catalyzed Intermolecular Synthesis of
Alkylidenecyclopropanes through Catalytic Allene Activation
Juliette Sabbatani,[a] Xueliang Huang,[b] Luꢀs F. Veiros,[c] and Nuno Maulide*[a]
Abstract: A stereoselective gold(I)-catalyzed intermolecu-
lar cyclopropanation of allenamides with stabilized sulfoni-
um ylides is reported. This transformation enables the
direct synthesis of diacceptor alkylidenecyclopropanes
and proceeds under very mild conditions through allene
activation.
Scheme 1. Alternative methods for the preparation of alkylidenecyclopro-
panes.
Methylenecyclopropanes or alkylidenecyclopropanes (MCPs or
ACPs) are stable compounds that display a high level of ring-
strain, endowing them with remarkable chemical reactivity.[1] In
particular, ACPs bearing electron-withdrawing groups are
prime candidates for engaging in various ionic ring-opening
processes, as their electron density distribution favors the for-
mation of negatively charged open intermediates. The versatili-
ty of this type of substrate has been exploited in several reac-
tions such as cycloisomerizations,[2] ring-opening rearrange-
ments,[3] cycloadditions,[4] and iodolactonizations.[2] Hence, the
development of alternative approaches to their synthesis has
been investigated over the last decade. The predominant strat-
egy in this field relies on the cyclopropanation of allenes by in
situ generated carbenes; these are most typically formed by
decomposition of diazo compounds, either by the action of
rhodium catalysts or through photochemical irradiation
(Scheme 1a).[3,4] Although this is an efficient synthetic strategy,
the known hazards associated with the use of diazo com-
pounds somewhat mitigate its synthetic usefulness, particularly
when large-scale applications are considered.
tivity and electronic features, lending themselves to interesting
applications featuring gold catalysis,[6,7] including an unusual
intramolecular olefin cyclopropanation through catalytic olefin
activation.[8] Herein, we describe an intermolecular gold-cata-
lyzed synthesis of alkylidenecyclopropanes employing sulfoni-
um ylides and activated allenes,[9] as well as mechanistic stud-
ies on this transformation (Scheme 1b).
Since stabilized sulfonium ylides are competent nucleophiles
towards gold-activated alkenes[7] and alkynes,[6] we became in-
terested in exploring their behavior regarding allenes. Initial
experiments involved reacting ylide 1 with allenamide 2[10,11] in
the presence of 5 mol% of chloro(triphenylphosphine)gold(I)
and silver(I) hexafluoroantimonate in chloroform (0.4m) at
238C. The desired product was obtained in an encouraging
51% yield (Table 1, entry 1). Several different co-catalysts were
screened, ranging from diverse silver salts to copper(II) triflate
(entries 2 to 5).[13] Silver(I) tosylate proved to be the most effec-
tive salt from those tested (entry 5), affording the cyclopropa-
nation product in 75% yield. Different phosphine and phos-
phite ligands were then examined, with triphenylphosphine
proving to be superior (entries 6 to 8). A solvent screening
confirmed that dichloromethane is the most effective medium
for this transformation. Indeed, the reaction becomes signifi-
cantly slower in solvents such as THF or toluene (entries 10
and 11). Control experiments also revealed that the conjunc-
tion of silver(I) and gold(I) species is indispensable for success
(entries 12 and 13). This reaction could also be performed in
a 1 mmol scale (entry 14), and interestingly did not require
strictly anhydrous conditions, affording similar yields even
when the reaction vessel was open to air (entry 15).
We recently developed a new methodology to directly
access stabilized sulfonium ylides in a single step, by a process
termed ylide transfer.[5] Those compounds display unique reac-
[a] J. Sabbatani, Prof. Dr. N. Maulide
Faculty of Chemistry, Institute of Organic Chemistry
University of Vienna
Wꢀhringer Strasse 38, 1090 Vienna (Austria)
E-mail: nuno.maulide@univie.ac.at
[b] Prof. Dr. X. Huang
State Key Laboratory of Structural Chemistry
Fujian Institute of Research on the Structure of Matter
Chinese Academy of Sciences
Yangqiao West Road 155#, Fuzhou, Fujian 350002 (P. R. China)
[c] Prof. Dr. L. F. Veiros
Using the conditions newly found, a variety of sulfonium
ylides were evaluated as possible substrates in the intermolec-
ular cyclopropanation of activated allenes. As shown in
Scheme 2, various functional groups are tolerated, and the re-
actions typically reach full conversion in less than 2 h at room
Centro de Quꢁmica Estrutural
Instituto Superior Tꢂcnico, Universidade de Lisboa
Av. Rovisco Pais 1, 1049-001 Lisbon (Portugal)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402935.
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Table 1. Optimization of experimental conditions using the reaction be-
tween 1 and 2 as a model system.[a]
Entry
Solvent
Catalyst/Additive
Time [h]
Yield [%]
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
[PPh3AuCl]/AgSbF6
[PPh3AuCl]/AgNTf2
[PPh3AuCl]/AgOTf
[PPh3AuCl]/Cu(OTf)2
[PPh3AuCl]/AgOTs
[(4-CF3C6H4)PAuCl]/AgOTs
[(2,6-tBuC6H3O)PAuCl]/AgOTs
[Cy3PAuCl]/AgOTs
[PPh3AuCl]/AgOTs
[PPh3AuCl]/AgOTs
[PPh3AuCl]/AgOTs
[PPh3AuCl]
0.5
0.5
0.5
24
0.5
1
51
45
62
-
75
64
43
46
55
12
22
–
Scheme 3. Allenamide scope of the intermolecular gold-catalyzed cyclopro-
panation.
2
16
16
16
16
24
24
0.5
0.5
Furthermore, the allenamide substituents could also be
varied to some extent as shown in Scheme 3. Therefore, alkyl
and aryl moieties could be tolerated on nitrogen.
9
10
11
12
13
14[b]
15[c]
THF
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
The exclusive E-geometry of the exocyclic double bond of
1
AgOTs
[PPh3AuCl]/AgOTs
[PPh3AuCl]/AgOTs
–
75
75
the products was assigned by H NMR analysis. Indeed, a NOE
effect was observed between the methylene hydrogens of the
three-membered ring and the aromatic protons of the tosyl
group. Unambiguous structural determination was obtained
upon single-crystal X-ray analysis of the product 3d, as depict-
ed in Figure 1.
[a] Reactions were carried out under argon in
a Schlenk tube, in
a 0.10 mmol scale of 1 and 2 using 5 mol% of catalyst in 0.25 mL of sol-
vent at 238C, the yield was determined by 1H NMR spectroscopy of the
crude reaction mixture. [b] The reaction was carried out in a 1 mmol
scale. [c] The reaction was carried out open to air.
Figure 1. X-ray structure of alkylidenecyclopropane 3c.
An additional experiment was carried out to qualitatively
study the influence of electronic factors on the reaction rate
(Scheme 4). When an allenamide carrying an electron-with-
drawing group on nitrogen was employed, the reaction rate
was markedly accelerated: complete conversion was virtually
instantaneous upon mixing the reagents at 238C and required
only 3 h at 08C (4e). In sharp contrast, an allene bearing an
electron-rich arene on nitrogen slowed down the reaction (4 f).
Scheme 2. Scope of the intermolecular gold-catalyzed cyclopropanation.
temperature. The ylide derived from a-bromoacetophenone af-
forded the halogenated product 3b in 93% yield. Symmetrical
ylides were viable substrates, including those derived from ma-
lononitrile (1e), dimethylmalonate (1c), or acetylacetone (1h).
Additionally, ylides bearing diverse electron-withdrawing moi-
eties were also tolerated such as cyanoesters (1d), ketonitriles
(1 f), or nitroesters (1g).
Scheme 4. Qualitative influence of electronic properties of the reactants on
the reaction rate.
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planation for the rate decrease observed in the for-
mation of 4g (with the electron-richer ylide). That
result suggests that ylide nucleophilicity is not a de-
termining factor for the reaction rate.
In summary, we have developed a gold-catalyzed
intermolecular methylenecyclopropanation of allenes
with sulfonium ylides. This process allows a direct
access to functionalized methylenecyclopropanes
and employs stable, readily available and easily han-
dled sulfur ylide substrates, thus providing an inter-
esting and safe alternative to diazo derivatives. The
methylenecyclopropane products are formed in good
yields and with remarkable E-double bond selectivity.
Mechanistic studies supported by DFT calculations
support a methylenecyclopropanation proceeding by
allene activation, in contrast to the usual in situ gen-
erated metallocarbene pathways.
Experimental Section
General procedure for the methylenecylopropana-
tion
A dry Schlenk tube was charged with chloro(triphenyl-
phosphine)gold(I) (0.005 mmol) and silver(I) p-toluenesul-
fonate (0.005 mmol). The resulting mixture was dissolved
in dry CH2Cl2 (0.25 mL) and stirred at 238C. Then ylide
(0.100 mmol) and allene (0.100 mmol) were added and
Figure 2. Mechanism and free energy profile (kcalmolÀ1) calculated by DFT for the gold-
catalyzed intermolecular cyclopropanation of sulfonium ylides and allenes.
the reaction mixture was stirred at 238C until complete conversion
(as monitored by TLC). The solvent was removed under reduced
pressure and the residue was purified by chromatography on silica
gel with Hexane/EtOAc as eluent.
For comparison, full conversion to 4 f required 2 h, whereas
the analogous allenamide with an unsubstituted aryl ring (3a)
only needed 30 min. The use of a sulfur ylide containing a p-
methoxyphenyl ketone (4g) also markedly slowed down the
cyclopropanation process.
The mechanism of this intermolecular alkylidenecyclopropa-
nation was studied by exploratory DFT calculations,[12] using
the reaction of the dimethylmalonate ylide (1c) as a case study
(Figure 2). The reaction starts with activation of the allene C=C
bond through p-coordination to the gold catalyst, as shown in
intermediate A. From A, intermolecular attack of the ylidic
carbon atom on the terminal allene C atom results in the
gold–vinyl complex B. In the subsequent step, loss of SPh2 and
nucleophilic attack of the metallic C-sp2 back onto the original
ylidic carbon leads to the formation of complex C. Finally, from
C, ligand exchange with release of the product and addition of
a new molecule of allene regenerates the p-complex A, thus
closing the catalytic cycle in a practically thermoneutral step
(DG=0.9 kcalmolÀ1). Stereochemical constraints force the two
consecutive CÀC bond formation steps to occur as far away as
possible from the N atom and from its bulky substituents, lead-
ing to exclusive formation of the E isomer of the product. All
steps of the mechanism are thermodynamically favorable
(Figure 2) and the rate-limiting step is the first one, that is, nu-
cleophilic attack from the ylide to coordinated allene. This
mechanism is also consistent with the observed rate enhance-
ment of electron-poor allenamides depicted in Scheme 4, as
a more electrophilic complex A should lead to a faster nucleo-
philic attack from the sulfur ylide. However, it provides no ex-
Acknowledgements
This work was funded by the University of Vienna, the DFG
(Grants MA 4861/4–1 and MA 4861/4–2) and the Fundażo
para a CiÞncia e Tecnologia (PEst-OE/QUI/UI0100/2011 and
PTDC/QUI-QUI/099389/2008 to L.V.). We also gratefully ac-
knowledge the Max-Planck-Institut fꢂr Kohlenforschung, where
parts of this research were carried out.
Keywords: alkylidenecyclopropanes · allenes · catalysis · gold ·
sulfonium ylides
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Published online on && &&, 0000
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Communication
COMMUNICATION
Three is my lucky number: A mild ste-
reoselective gold(I)-catalyzed intermo-
lecular cyclopropanation of allenamides
with stabilized sulfonium ylides is re-
ported. This transformation delivers di-
acceptor alkylidenecyclopropanes and
unusually proceeds through allene acti-
vation rather than by metallocarbene
formation.
&
Sulfonium Ylide Chemistry
J. Sabbatani, X. Huang, L. F. Veiros,
N. Maulide*
&& – &&
Gold-Catalyzed Intermolecular
Synthesis of Alkylidenecyclopropanes
through Catalytic Allene Activation
Chem. Eur. J. 2014, 20, 1 – 5
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ