Cyclopropane-alkene metathesis by gold(i)-catalyzed decarbenation of persistent cyclopropanes

Article abstract of DOI:10.1039/c9ob00359b

A gold(i)-catalyzed cyclopropane-alkene metathesis has been demonstrated with two new families of cyclopropane derivatives of naphthalene and phenanthrene (benzo-fused norcaradienes). In this process, metal carbene units are transferred from a persistent

Full text of DOI:10.1039/c9ob00359b

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C9OB00359B
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Cyclopropane-Alkene Metathesis by Gold(I)-Catalyzed
Decarbenation of Persistent Cyclopropanes
Mauro Mato,†a,b Inmaculada Martín-Torres,†a,b Bart Herlé,a and Antonio M. Echavarren*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A gold(I)-catalyzed cyclopropane-alkene metathesis has been cycloisomerization of phenyl-linked 1,6-enynes, can give rise to
demonstrated with two new families of cyclopropane derivatives aryl gold(I) carbenes, releasing naphthalenes.7b,11 Based on
of naphthalene and phenanthrene (benzo-fused norcaradienes). In these precedents, we envisioned that benzo-fused
this process, metal carbene units are transferred from a persistent norcaradienes could act as general precursors for the
cyclopropane to an alkene, upon release of naphthalene or generation of gold(I) carbenes (Scheme 1c). Herein, we present
phenanthrene, allowing the diastereoselective synthesis of a wide the design and synthesis of a range of persistent norcaradienes
range of aryl and vinyl cyclopropanes.
derived from dihydronaphthalenes and dihydrophenanthrenes,
which undergo gold(I)-catalyzed decarbenation reactions. This
allows transferring aryl and vinyl carbene units from a
persistent cyclopropane to an alkene, assembling a new three-
membered carbocycle,12 in a cyclopropane-alkene metathesis
process.13
Gold(I) carbenes1 have often been invoked as intermediates in
a wide array of transformations promoted by gold(I) complexes
and, therefore, are key for the understanding and development
of homogeneous gold(I) catalysis.2 Nevertheless, the controlled
generation of reactive gold(I) carbenes still remains a significant
challenge,3 since the classical methods, such as the
decomposition of diazo compounds (Scheme 1a),4 lack
generality or require the preparation and handling of
potentially unsafe reagents.5 As an alternative method for the
safe generation of gold(I) carbenes, we reported the retro-
Buchner reaction of 7-substituted 1,3,5-cycloheptatrienes
(Scheme 1b),6 which led to the development of different
synthetic methodologies that exploit the use of these
intermediates.7 More recently, we showed that a similar retro-
Buchner process can be carried out under zinc(II)8 or
rhodium(II)9 catalysis, unlocking new reactivity, which was
applied for the synthesis of natural products.
7-Substituted 1,3,5-cycloheptatrienes exist in a tautomeric
equilibrium with its corresponding norcaradienes,10 which can
undergo a metal-catalyzed retro-cyclopropanation generating a
metal carbene upon release of benzene6 or substituted
benzenes.8,9 We have also observed that certain electron-rich
arylcyclopropyl dihydronaphtalene derivatives, obtained by
Scheme 1 a) Classical approach for the generation of metal carbenes. b) Metal-
catalyzed retro-Buchner reaction of cycloheptatrienes. c) This approach: gold(I)-
catalyzed decarbenation of persistent cyclopropanes.
We started our investigation by the synthesis of two types of benzo-
fused norcaradienes derived from dihydronaphtalene. The first one
(4) would allow transferring the phenyl carbene moiety and the
second one (6), could be used as vinyl carbene equivalent. We
prepared 4 by gold(I)-catalyzed intramolecular hydroarylation of
cyclopropyl alkyne 3, which was prepared in gram-scale through a
sequence involving the copper(II)-catalyzed cyclopropanation of E-
stilbene with ethyl diazoacetate, reduction to the aldehyde, and
alkynylation using Bestmann-Ohira reagent (Scheme 2a).14
a. Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science
and Technology. Av. Països Catalans 16, 43007 Tarragona (Spain).
b. Departament de Química Analítica I Química Orgànica, Universitat Rovira i Virgili.
C/ Marcel·li Domingo s/n, 43007 Tarragona (Spain).
† These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: For detailed experimental
procedures, characterization data, and copies of NMR spectra of all new
compounds, see DOI: 10.1039/x0xx00000x
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cyclopropane in moderate to good yields, with cis/trans ratios
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of up to 12:1. Alkenes with differentDeOlIe: c10tr.1o0n3i9c/Ca9nOdB0s0t3e5r9iBc
properties were tolerated, and aryl halides (8c, 8f–g) were
found to be compatible with the reactions conditions (Scheme
3). Cyclopropanation of E-stilbene gives exo-1,2,3-
tripheynlcyclopropane (8h) also in good yield. Remarkably, this
cyclopropane-alkene metathesis, in which an aryl gold(I)
carbene is transferred, takes place efficiently at 80 °C,
comparing favorably to the 120 °C required with the use of 7-
aryl 1,3,5-cycloheptatrienes.6
Furthermore, considering that the gold(I)-based catalytic
system that is used in the hydroarylation of 3 to give 4 is the
same than the one used in the decarbenation–
cyclopropanation sequence, we designed a one-pot strategy
which uses directly alkyne 3 as a synthetic equivalent of a
phenyl carbene (Scheme 4). This led to the optimization of a
more practical procedure in which 1 equiv of 3 was mixed with
Scheme 2 Synthesis of phenyl (a) and vinyl (b) dihydronaphthalene carbene
precursors 4 and 6a–d. EDA = ethyl diazoacetate. [Rh] = [Rh(TFA)2]2. PCC =
Pyridinium chlorochromate. a [Au] = [(JohnPhos)Au(MeCN)]SbF6.
In a different route, cyclopropanation of naphthalene with ethyl
diazoacetate in the presence of only 0.25 mol% of [Rh(TFA)2]2
affords the corresponding cyclopropyl ester,15 which can
subsequently be reduced to give aldehyde 5 in 39% yield over
6
equiv of
a
styrene
7
in the presence of
[(JohnPhos)Au(MeCN)]SbF6 at 80 °C, giving directly the
corresponding cyclopropane, in comparable yields and
diastereoselectivities to those achieved in the two-step method
(Schemes 3 and 4).
three steps. Wittig reaction of
5
with different
triphenylphosphonium halides gave vinyl carbene precursors
6a–d.14
Scheme 4 One-pot sequential gold(I)-catalyzed hydroarylation–decarbenation–
cyclopropanation of styrenes with alkyne 3. Yields are for isolated products. The
a
cis cyclopropane is obtained as major diastereoisomer.
[Au]
=
b
[(JohnPhos)Au(MeCN)]SbF6. Isolated as a mixture with the product of phenyl
cyclopropanation of 4.
Under the same reaction conditions, we found that vinyl
derivatives 6 also undergo a gold(I) catalyzed decarbenation,
and the resulting carbenes can be trapped by styrenes, allowing
the assembly of vinyl cyclopropanes (Scheme 5).
Scheme 3 Scope of the phenyl cyclopropanation of styrenes. Yields are for isolated
a
products. The cis cyclopropane is obtained as major diastereoisomer. [Au] =
[(JohnPhos)Au(MeCN)]SbF6. b Stirred at 100 C for 20 h. c Isolated as a mixture with
the product of phenyl cyclopropanation of 4. d 3 equiv of alkene employed.
First, we explored the phenyl cyclopropanation of a range of
styrenes via gold(I)-catalyzed decarbenation of 4 (Scheme 3).
The main side-reaction on this process is the phenyl
cyclopropanation of 4 giving a biscyclopropane which is
unreactive towards retro-cyclopropanation.14 Fortunately, this
pathway can be minimized statistically by the use of an excess
of commercially available styrenes 7. Accordingly, the reaction
of 1 equiv of 4 with 6 equiv of 3-methylstyrene (7a) in the
presence of 5 mol% of [(JohnPhos)Au(MeCN)]SbF6 at 80 °C gave
Scheme 5 Scope of the vinyl cyclopropanation of styrenes. Yields are for isolated
products. The cis cyclopropane is obtained as major diastereoisomer. [Au] =
[(JohnPhos)Au(MeCN)]SbF6.
a
Symmetrical vinyl cyclopropanes with alkyl substituents can be
easily prepared by this method, although the
diastereoselectivity in the cyclopropanation reaction is lower
cis-cyclopropane 8a in 68% yield and
diastereoisomers. Different styrenes were tested under the
same conditions, obtaining in all cases the corresponding
a 5:1 ratio of
2 | J. Name., 2012, 00, 1-3
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than for the transfer of carbene units bearing aromatic with the use of microwave heating. The reaction of 12a with
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moieties, presumably due to the reduced steric discrimination only 2 equiv of 3-bromostyrene in the pDreOsIe: 1n0c.e10o39f/1C09OmB0o0l%359oBf
and the lack of π−π stabilizing interactions (9a–d).7d The same [(JohnPhos)Au(MeCN)]SbF6 upon 60 min of microwave
strategy allowed carrying out
a styryl cyclopropanation irradiation in 1,2-dichloroethane at 160 °C led to the clean
reaction, transferring either E or Z styryl carbenes, with good formation of cyclopropane 8c in 60% yield, upon release of
diastereoselectivity (9e–f).
phenanthrene. Different cis-cyclopropanes could be obtained
by this method, bearing different substituents in both aromatic
rings (Scheme 7). Interestingly, as expected, increasing the
electron density on the aromatic ring of the carbene unit,
drastically speeds up the reaction, allowing to reach full
conversion and excellent yields at a lower temperature (8l–n).
Regarding the diastereoselectivity, cyclopropanes bearing only
electron-withdrawing groups were obtained preferentially as
the cis isomer. On the other hand, electron-rich cyclopropanes
bearing p-methoxy substituents were obtained almost
exclusively as the trans isomers (8l–n). This trend was already
observed in the context of cyclopropanation by retro-Buchner
reaction of 7-aryl 1,3,5-cycloheptatrienes,6 and can be
rationalized by a cis to trans isomerization catalyzed by gold(I).7d
Since there are reports of the generation of free carbenes from
certain dihydrophenanthrene derivatives without the need of
transition metals,17 the reaction was tested without catalyst,
giving no conversion, which confirms the need of the gold(I)
complex for the decarbenation reaction to proceed. Besides, it
is worth highlighting the cleanness of this transformation, since
no byproducts other than phenanthrene were detected in the
reaction mixtures.
In our search for a new family of more robust carbene
precursors, we designed
a route for the synthesis of
phenanthrene derivatives 12 (Scheme 6). Initial screening on
the use of known exo-bromocyclopropane 1016 as electrophile
is cross-coupling reactions with aryl organometallic reagents
only gave yields below 20% for the desired aryl cyclopropane
products 12. Alternatively, lithium-halogen exchange of 10 and
trapping with isopropoxypinacolborane gives access to boronic
ester 11 in gram-scale. Suzuki-Miyaura coupling of 11 with
different aryl iodides allowed the assembly of carbene
precursors 12a–c in good yields.14 The structure of exo-12a was
confirmed by X-ray diffraction.
Ar-I, t-BuOK
Pd(dba)2, SPhos
1) n-BuLi, THF
H
H
DME, t-BuOH, 80 ºC
H
OB(pin)
16– 18h
2)
H
H
H
B(pin)
Br
Ar
10
11 (79%, 4 g)
12a Ar = Ph (63%)
12b Ar = 3,5-Me2C6H3 (52%)
12c Ar = p-MeOC6H4 (62%)
12a
In conclusion, we have demonstrated the possibility of carrying
out a cyclopropane-alkene metathesis through the gold(I)-
catalyzed decarbenation of persistent cyclopropanes. We
designed the synthesis of cyclopropyl dihydronaphthalene and
dihydrophenanthrene derivatives, which display a benzo-fused
norcaradiene structure, and allowed the transfer of aryl and
vinyl carbenes to a wide range of styrenes. This represents
another alternative to the use of potentially dangerous non-
stabilized diazo compounds, and a step forward towards the
development of an ideal cyclopropane metathesis process.
Scheme 6 Synthesis of aryl dihydrophenanthrene carbene precursors 12a–c by
palladium-catalyzed Suzuki coupling of 11 with aryl iodides and X-ray structure of
12a.
Acknowledgments
We thank the Agencia Estatal de Investigación (AEI)/FEDER, UE
(CTQ2016-75960-P and FPI predoctoral fellowship to M.M. and
I.M.-T.), the AGAUR (2017 SGR 1257), and CERCA
Program/Generalitat de Catalunya for financial support. We
thank Xiang Yin for preliminary experiments on the synthesis of
4. We also thank the ICIQ X-ray diffraction unit.
Scheme 7 Scope of the gold(I)-catalyzed aryl cyclopropanation of styrenes. Yields
are for isolated products. The major diastereoisomer obtained is the one depicted
for each example. a [Au] = [(JohnPhos)Au(MeCN)]SbF6. b Isolated as a mixture with
1 equiv of phenanthrene.
Author information
Corresponding Author
*E-mail: aechavarren@iciq.es
Analogous reaction conditions than those for the decarbenation
of cyclopropanes 4 or 6 only afforded conversions of 12a lower
than 20% in temperature ranges from 50 to 120 °C. A solution
to the lower reactivity of the phenanthrene derivatives came
ORCID
Mauro Mato: 0000-0002-2931-5060
Inmaculada Martín-Torres: 0000-0002-8882-4199
Antonio M. Echavarren: 0000-0001-6808-3007
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Conflicts of interest
The authors declare no conflicts of interest.
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DOI: 10.1039/C9OB00359B
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Benzo-fused norcaradienes derived from naphthalene and phenanthreneDOuIn: 1d0.e10r3g9o/C9OB00359B
gold(I)-catalyzed cyclopropane-alkene metathesis via decarbenation