Stereoselective cis-Vinylcyclopropanation via a Gold(I)-Catalyzed Retro-Buchner Reaction under Mild Conditions

Article abstract of DOI:10.1021/acscatal.7b00737

A highly stereoselective gold(I)-catalyzed cis-vinylcyclopropanation of alkenes has been developed. Allylic gold carbenes, generated via a retro-Buchner reaction of 7-alkenyl-1,3,5-cycloheptatrienes, react with alkenes to form vinylcyclopropanes. The gold(I)-catalyzed retro-Buchner reaction of these substrates proceeds by simple heating at a temperature much lower than that required for the reaction of 7-aryl-1,3,5-cycloheptatrienes (75 °C vs 120 °C). A newly developed Julia-Kocienski reagent enables the synthesis of the required cycloheptatriene derivatives in one step from readily available aldehydes or ketones. On the basis of mechanistic investigations, a stereochemical model for the cis selectivity was proposed. An unprecedented gold-catalyzed isomerization of cis- to trans-cyclopropanes has also been discovered and studied by DFT calculations.

Full text of DOI:10.1021/acscatal.7b00737

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Article
Stereoselective Cis-Vinylcyclopropanation via Gold(I)-
Catalyzed Retro-Buchner Reaction under Mild Conditions
Bart Herlé, Philipp Holstein, and Antonio M. Echavarren
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ACS Catalysis
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Stereoselective
Cis-Vinylcyclopropanation via Gold(I)-
Catalyzed Retro-Buchner Reaction under Mild Conditions
Bart Herlé,† Philipp M. Holstein,† and Antonio M. Echavarren*†,§
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† Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science and Technology, Av. Països
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Catalans 16, 43007 Tarragona, Spain
§ Departament de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, C/Marcel·li Domingo s/n,
43007 Tarragona, Spain.
ABSTRACT: A highly stereoselective gold(I)-catalyzed cis-vinylcyclopropanation of alkenes has been developed. Allylic gold
carbenes, generated via retro-Buchner reaction of 7-alkenyl-1,3,5-cycloheptatrienes, react with alkenes to form vinylcyclopro-
panes. The gold(I)-catalyzed retro-Buchner reaction of these substrates proceeds by simple heating at a temperature much lower
than that required for the reaction of 7-aryl-1,3,5-cycloheptatrienes (75 °C vs 120 °C). A newly developed Julia-Kocienski reagent
enables the synthesis of the required cycloheptatriene derivatives in one step from readily available aldehydes or ketones. Based
on mechanistic investigations, a stereochemical model for the cis-selectivity was proposed. An unprecedented gold-catalyzed
isomerization of cis- to trans-cyclopropanes has also been discovered and studied by DFT calculations.
KEYWORDS: cyclopropanation, vinylcyclopropanes, gold catalysis, retro-Buchner reaction, cycloheptatrienes
INTRODUCTION
stability has been partially circumvented by performing the
cyclopropanation under metal-free conditions with flow-
generated alkenyldiazalkanes.28
Vinylcyclopropanes are common motifs in natural products1
and active pharmaceuticals.2 Moreover, vinylcyclopropanes
are of particular interest as synthetic intermediates,3 because
of their rich downstream chemistry, undergoing rearrange-
ments to cyclopentenes,4 (3+n) and (5+n) cycloadditions,5 or
other transition-metal-catalyzed transformations,6 providing
ready access to molecular complexity.
We recently discovered that highly electrophilic gold(I) com-
plexes are able to cleave two-carbon bonds of norcaradienes,
which are in equilibrium with more stable cyclohepta-
trienes,29 to form in situ gold(I) carbenes.30,31,32 Starting from
readily available 7-aryl substituted cycloheptatrienes, the
retrocyclopropanation (decarbenation) reaction leads to aryl-
substituted gold(I) carbenes, which undergo cyclopropanation
with alkenes,30b intramolecular Friedel-Craft-type reactions,30c
and [4+1] cycloadditions with methylencyclopropanes or
cyclobutenes.30d In contrast to aryl derivatives, 7-alkynyl-
1,3,5-cycloheptatrienes undergo cycloisomerization reactions
at low temperature with gold(I) or gold(III) catalysts to give
indenes via stabilized barbaralyl cations.33,34
Methods for the stereoselective cyclopropanation of alkenes
by formal carbene transfer usually require directing groups
and rely on the use organometallic reagents or diazo-
alkanes,7,8 9 which are hydrolytically unstable, pyrophoric, or
,
potentially explosive. Recent efforts have led to the develop-
ment of safer ways to access metal carbenes from stable pre-
cursors.10 Thus, among others, metal carbenes or carbenoids
have been generated from α,β-unsaturated carbonyl com-
pounds, 11 tosylhydrazones,12 triazols, 13 cyclopropenes, 14 and
propargyl ethers15 or esters, 16 as well as from alkynes by
oxidative processes.17 However, highly stereoselective meth-
ods for the synthesis of vinylcyclopropanes that do not rely on
the use of diazo reagents remain scarce.18 In general, diastere-
opure vinylcyclopropanes are accessed in a stepwise manner
through derivatization of functionalized cyclopropane build-
ing blocks, either by Wittig olefination19 or metal-catalyzed
cross-couplings.20,21
The gold(I)-catalyzed retro-Buchner reaction requires rela-
tively high temperatures (ca. 120 °C) for the efficient cleavage
of the cyclopropane ring of norcaradienes,30bꢀd which results in
low stereoselectivity in the subsequent trapping of the gener-
ated aryl-substituted gold(I) carbenes with alkenes.30b We
envisaged that the retro-Buchner reaction of 7-alkenyl-1,3,5-
cycloheptatrienes (1) would take place with gold(I) under
milder conditions to form more stabilized α,β-unsaturated
gold(I) carbenes I,35 that could react with alkenes 2 to give
rise to vinylcyclopropanes 3 (Scheme 1).
Metal-catalyzed reactions of styryldiazoacetates efficiently
give rise to 1-styrylcyclopropane-1-carboxylates.22,23,24 How-
ever, the synthesis of simple vinylcyclopropanes not bearing
ester groups requires the use of alkenyldiazomethanes, which
are much less stable since they can easily give rise to pyra-
zoles25,26 or undergo dimerization to form trienes.27 This in-
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Scheme 1. Vinyl-Cyclopropanation via Retro-Buchner
Reaction of Alkenylcycloheptatrienes 1.
While the reaction in 1,2-dichloroethane proceeded in slightly
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lower yield, much lower catalytic activity was observed in
toluene or THF (Table 1, entries 2-4). Increasing or decreasing
the steric parameters of the ligand using complexes B and C
(Table 1, entries 5-6) or changing to NHC-gold(I) complexes D
and E had deleterious effects on the reaction outcome (Table
1, entries 7-8). When cycloheptatriene 1a was used in excess,
small quantities of an inseparable bis-cyclopropane were
formed as a result of the cyclopropanation of product 3a. The
transformation proved to be robust as similar yields were
obtained when the reaction was performed in commercial
ethyl acetate containing small amounts of water.
Here, we report the scope of this gold(I)-catalyzed vinylcyclo-
propanation that proceeds at moderate temperatures and for
the first time allows preparing vinylcyclopropanes 3 with very
good cis-stereoselectivities. In contrast to alkenyldiazome-
thanes, the required alkenyl cycloheptatrienes 1 are perfectly
stable compounds that can be obtained from commercially
available tropylium salts or by a new procedure based on the
Julia-Kocienski reaction. We have also found that cis-
configured cyclopropanes can undergo isomerization to form
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trans-cyclopropanes by
cleavage promoted by gold(I).
a reversible carbon-carbon-bond
Table 1. Retro-Buchner/Cyclopropanation to form 3a.
RESULTS AND DISCUSSION
Synthesis of New Alkenylcycloheptatrienes. Alkenyl-
cycloheptatrienes 1 can be obtained by the reaction of alkenyl
lithium or Grignard reagents with tropylium salts.30b,36 In
addition, we have found that alkenyl trifluoroborates can also
be used as softer nucleophiles, which allow performing the
addition reaction at room temperature in DMF.37
Entry Deviation from standard conditionsa
Yield [%]b
1
None
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68
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DCE instead of EtOAc
Toluene instead of EtOAc
THF instead of EtOAc.
Catalyst B instead of A
Catalyst C instead of A
Catalyst D instead of A
Catalyst E instead of A
To further extend the scope of the cyclopropanation reaction
by increasing the structural diversity on the alkenyl cyclohep-
tatrienes, we also considered applying an olefination reaction
as the ideal method considering the wide availability of alde-
hydes and ketones. Therefore, we prepared the bench-stable
Julia-Kocienski reagents 4a-b (Scheme 2).38 These reagents
allowed accessing a wider variety of alkenyl-cycloheptatrienes
in one step with excellent yields from commercially available
carbonyl compounds. Aromatic aldehydes afforded the de-
sired cycloheptatrienes 1a-e with exclusive E-selectivity from
the lithium salt of 4a at -78 °C. Although poor results were
observed for ketones, due to the competing enolization,
switching to bulkier tetrazole 4b led to cycloheptatrienes 1f-g
in good yields from acetone or cyclohexanone.
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a
Standard conditions: cycloheptatriene 1, styrene 2 (1.5 equiv) with
[JohnPhosAu(MeCN)SbF6] (A) (5 mol%) in EtOAc (0.25 M) at 75 °C for 12
h. b Determined by 1H NMR with diphenylmethane as internal standard.
Reaction Scope. The intermolecular reaction of cyclohepta-
triene 1a with a variety of para-, meta- and ortho-substituted
styrenes gave the corresponding cis-substituted cyclopro-
panes 3a-t in moderate to high yields and with excellent cis-
selectivities (from 15:1 to more than 20:1) (Table 2). In gen-
eral, electron-rich arenes were slightly better substrates for
the reaction and led to higher yields of 3a, 3c, 3g, and 3j,
whereas electron-poor arenes reacted more slowly leading to
lower yields of 3e, 3i, 3n, and 3o. Functional groups such as
aldehydes (3l), esters (3h-i), and nitro groups (3n) were well
tolerated, as were aryl halides (3d, 3f, 3m, 3q, and 3r). How-
ever, traces or low yields of cyclopropanes were observed
with non-aryl substituted alkenes.
Scheme 2. Formation of 7-Alkenyl-1,3,5-cyclohepta-
trienes 1a-g via Julia-Kocienski Reaction
Development of the Vinylcyclopropanation Reaction. We
started by reinvestigating the reaction conditions required to
perform the retro-Bucher/cyclopropanation using trans-
styryl cycloheptatriene 1a (Table 1). In contrast with the
initial conditions (120 °C, 1,2-dichloroethane),30b we found
that the reaction of 1a with styrene 2a proceeds smoothly at
75 °C using ethyl acetate as the solvent in the presence of
[(Johnphos)Au(MeCN)]SbF6 (A) as catalyst (Table 1, entry 1).
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Table 2. Synthesis of cis-Arylcyclopropanes 3a-ac from 1a
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a Relative configuration confirmed by X-ray diffraction.
N-Vinylphthalimide (5) was also cyclopropanated to give
products 6a-h (Table 4). The robustness of the method was
further demonstrated by the synthesis of 6a in a multi-gram
scale with identical high yield and similar diastereoselectivity
(7:1 cis/trans). In general, lower cis-stereoselectivities were
observed using 5 as the alkene, with the exception of 6c, and
in the cases of 6g-h the trans derivatives were obtained as the
major isomers.
Table 4. Synthesis of N-Protected Aminocyclopropanes
6a-h from N-vinylphthalimide (5)
General conditions: cycloheptatriene 1 (0.25 mmol), styrene 2 (0.375
mmol) with (A) (0.0125 mmol, 5 mol%) in EtOAc (1 mL) at 75 °C for 12 to
24 h. a 2 equiv of styrene used. b Relative configuration confirmed by X-ray
diffraction. c 3 equiv of styrene used.
Disubstituted α-styrenes reacted efficiently to give cyclopro-
panes 3u-v, albeit with a lower stereoselectivity in the former
case. Adding one (3w) or two (3x) substituents to the β-
position of the styrene resulted in a decline of the yield. On the
other hand, when cyclic alkenes such as indenes, 1,2-
dihydronaphthalene, and 2H-chromene were used, endo-
tricycles 3y-ac were obtained essentially as single diastere-
omers in 50-85% yields.
Similarly, alkenyl-cycloheptatrienes 1b-i gave rise to vinyl
cyclopropanes 3ad-al with good to excellent cis-selectivities
(from 6:1 to more than 20:1) (Table 3).
Table 3. Synthesis of cis-Arylcyclopropanes with Cyclo-
heptatrienes 1b-i
a Isolated yield for reaction on 10 mmol scale, 2.1 g isolated with 7:1 d.r.
See supporting information for details. b Relative configuration (both cis
and trans) confirmed by X-ray diffraction. c Major isomer depicted.
Application to the Synthesis of Diverse Cyclopropanes.
The phthalimido protecting group of 6a could be readily re-
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moved by treatment with NaBH4 followed by addition of dry
metathesis on terminal vinylcyclopropanes,46 only a single
HCl to form the amine hydrochloride 7,39 which could be con-
veniently re-protected to form carbamate 8 (Scheme 3). Con-
sidering the importance of sterically constrained β-amino
example of a comparable reaction has been reported.47 It is
also important to note that cis-trans isomerization of cyclo-
propanes has been observed under the conditions of ring-
closing metathesis in the presence of Grubbs-carbenes via
expansion of the intermediate cyclopropyl ruthenium(II)
carbenes to form ruthenacyclopentenes.45d However, using the
second generation Grubbs’ catalyst,48 cross metathesis of 3g
with methyl crotonate proceeded smoothly to form cis-14
without erosion of the diastereoselectivity (Scheme 5).
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acids,40 41 we developed a simple access to such building
,
blocks containing a cyclopropane ring. Thus, ozonolysis of 6a
followed by reductive workup yielded cis-aldehyde 9a. Subse-
quent formation of the ester proved challenging, as this push-
pull substituted cyclopropane was prone to undergo opening
under basic conditions, leading to the corresponding dihydro-
furan. Acidic conditions, on the other hand, led to complete
epimerization of the aldehyde affording trans-cyclopropane
9b. Finally, methyl ester 10 could be obtained by oxidation
with hydrogen peroxide and vanadium oxide in methanol
under mild acidic conditions.42
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Scheme 5. Cross Metathesis of Vinylcyclopropane 3g.
Mechanistic investigations. The usually high cis-
stereoselectivities observed in this study are in contrast with
the seemingly erratic stereoselectivities observed before in
the cyclopropanation from aryl cycloheptatrienes that had to
be performed at higher temperatures (120 °C, 1,2-
dichloroethane).30b At the same time, we were interested by
the lower selectivity observed in the cyclopropanation of N-
vinylphthalimide (5) (Table 4). Intriguingly, lower diastere-
oselectivities were observed when those reactions were per-
formed for longer reaction times. The progress of the reaction
between 1a and 5 followed by 1H NMR revealed a fast con-
sumption of the cycloheptatriene 1a along with the formation
of cis-6a, which was then followed by a slow isomerization of
cis-6a to from trans-6a, until an equilibrium was reached
(Scheme 6). Performing the reaction at 120 °C in iPrOAc al-
lowed for the isolation of the trans-6a in a synthetically rele-
vant yield of 55%. When pure cis-6a was heated with catalyst
A in EtOAc at 75 °C for 132 h, a 1.6:1 mixture of trans-6a and
cis-6a was obtained. No isomerization was observed in the
absence of the gold(I) catalyst, which excludes a radical back-
ground reaction.49,50,51
Scheme 3. Deprotection of the Phthalimide and Oxidative
Cleavage.
Gold(I)-catalyzed enyne cycloisomerizations are able to rapid-
ly build up chemical complexity.43 We wondered whether it
would be possible to selectively cyclopropanate a 1,5-enyne to
generate a new 1,7-enyne, which would then be cycloisomer-
ized with the same gold(I) catalyst. To demonstrate this con-
cept, 1,5-enyne 11 was first converted with remarkable
chemo- and diastereoselectivity into cis-cyclopropane 12a by
reaction with cycloheptatriene 1a in the presence of catalyst A
(Scheme 4). After desilylation, 1,7-enyne 12b was cleanly
transformed by catalyst A at room temperature to furnish
cyclopropyl-diene 13 by a single cleavage rearrangement
cascade.44
a Yields determined by 1H NMR (diphenylmethane as internal standard).
Scheme 6. Cis-trans Isomerization of Vinylcyclopropanes.a
Scheme 4. Gold(I)-Catalyzed Cyclopropanation and 1,7-
Enyne Cyclization.
We examined theoretically the complete reaction pathways
for the formation of 3b, 6a, and 6g by DFT calculations at the
M06/6-31G(d) / M06/6-311+G(2d,p) (C, H, N, O, P) and SDD
(Au) levels, taking into account the solvent effect (SMD =
dichloromethane) and employing JohnPhos as the phosphine
ligand.52
Finally, in order to access substrates bearing electron-
withdrawing functional groups at the alkene that would oth-
erwise be beyond the scope of our method, the feasibility of
using cross-metathesis on styryl cyclopropanes was investi-
45
gated. Apart from ring-closing metathesis
or cross-
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ACS Catalysis
The reaction to form 3b starts with the retro-Buchner reac-
PBE
1.3
3.2
1.7
6.0
0.7
3.7
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tion of 1a, which involves the stepwise cleavage of two C-C
bonds in complex II (Figure 1a). The cleavage of the second
bond determines the activation barrier for the generation of
PBE-D3(BJ)
gold(I)-carbene V, which was calculated to be 25.1 kcal·mol-
aValues given in kcal·mol-1
.
1
,
53 corresponding to the experimentally estimated value of 27
kcal·mol-1.54 55 The cyclopropanation of styrene by V proceeds
through an asynchronous concerted mechanism, with an
energy difference of 3.1 kcal·mol-1 between the cis- and trans-
pathways (Figure 1b)
,
The calculated mechanisms reveal a unified stereomodel for
all three reactions explaining the diastereoselectivity in the
cyclopropanation step, which we consider relevant for other
gold-catalyzed cyclopropanation reactions.14a,16b,30b Our model
distinguishes itself from a previous proposal16b by considering
non-covalent interactions to explain the high diastereoselec-
tivity of the reaction and also takes into account the steric
bulk of the phosphine ligand, which forces the substrates to
adopt a particularly rigid geometry.
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The cyclopropanations of alkene 5 also favor the cis-product,52
through closely similar transition states (Figure 1c-d). Elec-
tronic non-covalent interactions, namely π-π interactions in
the cis-TS and the lack thereof in the trans-TS, provide an
explanation for the preferred formation of cis products56 since
the interplanar distances and stabilization energies for the cis-
TS are within the typical range for such stabilizing interac-
tions (3.6 Å, 5 kcal·mol-1).57 Additionally, calculations corrobo-
rate that dispersion interactions are responsible for a signifi-
cant stabilization of the cis-transition states (Table 5, compare
rows 2 and 3 for PBE and PBE-D3(BJ) functionals, respective-
ly). Lastly, the color-filled reduced density gradient (RDG)
isosurface identified the weak van der Waals interactions (in
green) between the π-systems (Figure 1b).52,58 Remarkably,
even in the case of TSc-(VIc-VIIc) (Figure 1d) lacking the phenyl
substituent at the carbene, π-π-interactions between the
alkene and the phthalimide result in the stabilization of the
cis-TS.
For the subsequent isomerization of the cis-cyclopropanes to
the corresponding trans-isomers, we identified two transition
states with a linear carbocationic structure resulting from the
cleavage of the C1-C2 bond (Figure 2).59 As expected, the sta-
bility of the transition states depends on the stabilization of
the carbocation. For the most favorable pathway, natural bond
orbital analysis showed that the positive charge is stabilized
as an allylic carbocation in TSc-Xb-t-Xb, resulting in an activation
barrier of 29.4 kcal·mol-1, which agrees well with the experi-
mentally determined value of 29 kcal·mol-1.54 The alternative
regioisomeric cleavage of the cyclopropane requires a much
higher activation energy (38.4 kcal·mol-1) through TSc-VIIIb-t-
where the positive charge is stabilized through participa-
VIIIb
tion of the nitrogen lone pair leading to an iminium-like struc-
ture, as demonstrated by natural population analysis.
Table 5. Calculation of difference in activation energies
(ΔΔE) between cis- and trans-cyclopropanation.a
In analogy to the isomerization pathway of cis-6a, a linear,
carbocationic transition state with a relatively low activation
energy of 25.9 kcal·mol-1 was also identified for the isomeriza-
tion of cyclopropane cis-6g.52
Functional
M06
TSt-(VIa-VIIa)
TSc-(VIa-VIIa)
-
TSt-(VIb-VIIIb)
TSc-(VIb-VIIb)
-
TSt-(VIc-VIIc)-
TSc-(VIc-VIIc)
3.1
5.8
3.9
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Figure 1. (a) Calculated energies for the gold(I)-catalyzed retro-Buchner reaction and cyclopropanation reaction
using SMD(CH2Cl2)-M06/6-311+G(2d,p), SDD(Au, ζf=1.05)//SMD(CH2Cl2)-M06/6-31G(d), SDD(Au) at the standard
state; [Au] = Au-JohnPhos. For the full PES see the SI. Energies in kcal·mol-1. (b-d) Newman projections of the cyclo-
propanation transition states (most hydrogen atoms are omitted for clarity) and color-filled RDG isosurface for TS(VIa-
(isovalue set to 0.5). Blue color: areas of attraction (covalent bonding), green color: vdW interaction, red color:
VIIa)
areas of repulsion (steric and ring effects).
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Figure 2. Calculated energies for the gold-catalyzed cis-trans isomerization and NPA charges of TScXb-t-Xb (hydrogen
atoms are omitted for clarity). Computational details identical as in Figure 1. Energies in kcal·mol-1. For the full PES
see the SI.
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48
49
50
51
52
53
54
55
56
57
58
59
60
The isomerization reaction of phthalimide-substituted cyclo-
propane such as 6a was found to be more general (Scheme
7).60 Thus, for example, p-methoxy-substituted substrate cis-
3g could be isomerized to form trans-3g by heating in the
presence of gold(I) complex A.
other cycloheptatrienes. Our method allows for the prepara-
tion of diversely functionalized cis-cyclopropanes in diastere-
omerically pure form. Combined experimental and computa-
tional investigations of the reaction mechanism led to a re-
fined stereochemical model for the cyclopropanation, in
which stabilizing π-π-interactions account for the excellent
cis-selectivity. In addition, the mechanism of an unprecedent-
ed gold(I)-catalyzed cis-trans isomerization of cyclopropanes
has been elucidated, which also allows for the preparation of
trans-cyclopropanes. With a more clear understanding of the
selectivity-determining elements, we are currently pursuing
the development of enantioselective cyclopropanation reac-
tions based on the retro-Buchner reaction.
AUTHOR INFORMATION
Corresponding Author
aechavarren@iciq.es
ORCID
Scheme 7. Experimental and Theoretical Determination
of the cis-trans Equilibration of Cyclopropanes 3g and
6a.37
Antonio M. Echavarren: 0000-0001-6808-3007
Notes
CONCLUSIONS
No competing financial interests have been declared.
We have developed a highly cis-selective gold-catalyzed cy-
clopropanation for the formation of vinylcyclopropanes and
vinyl-aminocyclopropanes using stable and readily available
7-alkenyl-1,3,5-cycloheptatrienes as the source of the reactive
metal carbenes. Remarkably, the decarbenation takes place at
75 °C, under much milder conditions than those required for
ASSOCIATED CONTENT
Supporting Information All procedures and characteri-
zation data for new compounds and full details on the theo-
retical calculations. The Supporting Information is available
free of charge on the ACS Publications website.
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ACKNOWLEDGMENTS
1
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3
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7
8
We thank the European Research Council (Advanced
Grant No. 321066), MINECO/FEDER, UE (CTQ2016-75960-
P), MINECO-Severo Ochoa Excellence Acreditation 2014-
2018, SEV-2013-0319), the AGAUR (2014 SGR 818), and
CERCA Program / Generalitat de Catalunya for financial
support. We also thank Yahui Wang for additional work on
the synthesis of cycloheptatrienes from trifluoroborate salts,
Imma Escofet for work on the isomerization of 1,2-
diarylcyclopropanes, Dr. Andrey I. Konovalov for his assis-
tance with the DFT calculations and helpful discussions and
the ICIQ X-ray diffraction unit.
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(55) The activation barrier for the retro-Bucher reaction of 1g
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(60) 1,2-Diaryl-cyclopropanes also undergo gold(I)-catalyzed
cis-trans isomerization. See Supporting Information for details.
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ACS Paragon Plus Environment