Ruthenium-catalyzed hydroarylation of methylenecyclopropanes through C-H bond cleavage: Scope and mechanism

Article abstract of DOI:10.1002/chem.201200406

Intermolecular hydroarylation reactions of highly strained methylenecyclopropanes 2-phenylmethylenecyclopropane (1), 2,2- diphenylmethylenecyclopropane (2), methylenespiropentane (3), bicyclopropylidene (4), (dicyclopropylmethylene)cyclopropane (5), and benzhydrylidenecyclopropane (6) through C-H bond functionalization of 2-phenylpyridine (7 a) and other arenes with directing groups were studied. The reaction was very sensitive to the substitution on the methylenecyclopropanes. Although these transformations involved (cyclopropylcarbinyl)-metal intermediates, substrates 1 and 4 furnished anti-Markovnikov hydroarylation products with complete conservation of all cyclopropane rings in 11-93 % yield, whereas starting materials 3 and 5 were inert toward hydroarylation. Methylenecyclopropane 6 formed the products of formal hydroarylation reactions of the longest distal C-C bond in the methylenecyclopropane moiety in high yield, and hydrocarbon 2 afforded mixtures of hydroarylated products in low yields with a predominance of compounds that retained the cyclopropane unit. As byproducts, Diels-Alder cycloadducts and self-reorganization products were obtained in several cases from substrates 1-3 and 5. The structures of the most important new products have been unambiguously determined by X-ray diffraction analyses. On the basis of the results of hydroarylation experiments with isotopically labeled 7 a-[D₅], a plausible mechanistic rationale and a catalytic cycle for these unusual ruthenium-catalyzed hydroarylation reactions have been proposed. Arene-tethered ruthenium-phosphane complex 53, either isolated from the reaction mixture or independently prepared, did not show any catalytic activity. Copyright

Full text of DOI:10.1002/chem.201200406

FULL PAPER
DOI: 10.1002/chem.201200406
Ruthenium-Catalyzed Hydroarylation of Methylenecyclopropanes through
À
C H Bond Cleavage: Scope and Mechanism
Lutz Ackermann,*[a] Sergei I. Kozhushkov,[a] and Dmitry S. Yufit[b]
Abstract: Intermolecular hydroaryla-
tion reactions of highly strained meth-
ylenecyclopropanes 2-phenylmethyle-
necyclopropane (1), 2,2-diphenylme-
thylenecyclopropane (2), methylenes-
piropentane (3), bicyclopropylidene
(4), (dicyclopropylmethylene)cyclopro-
pane (5), and benzhydrylidenecyclo-
complete conservation of all cyclopro-
pane rings in 11–93% yield, whereas
starting materials 3 and 5 were inert
toward hydroarylation. Methylenecy-
clopropane 6 formed the products of
formal hydroarylation reactions of the
byproducts, Diels–Alder cycloadducts
and self-reorganization products were
obtained in several cases from sub-
strates 1–3 and 5. The structures of the
most important new products have
been unambiguously determined by X-
ray diffraction analyses. On the basis of
the results of hydroarylation experi-
ments with isotopically labeled 7a-
[D5], a plausible mechanistic rationale
and a catalytic cycle for these unusual
ruthenium-catalyzed hydroarylation re-
actions have been proposed. Arene-
tethered ruthenium–phosphane com-
plex 53, either isolated from the reac-
tion mixture or independently pre-
pared, did not show any catalytic activ-
ity.
À
longest distal C C bond in the methyl-
enecyclopropane moiety in high yield,
and hydrocarbon 2 afforded mixtures
of hydroarylated products in low yields
with a predominance of compounds
that retained the cyclopropane unit. As
À
propane (6) through C H bond func-
tionalization of 2-phenylpyridine (7a)
and other arenes with directing groups
were studied. The reaction was very
sensitive to the substitution on the
methylenecyclopropanes.
these transformations involved (cyclo-
propylcarbinyl)–metal intermediates,
Although
Keywords: homogeneous catalysis ·
À
C H activation · hydroarylation ·
methylenecyclopropanes
ruthenium
·
substrates 1 and 4 furnished anti-Mar-
kovnikov hydroarylation products with
Introduction
to be probed and enable the development of novel synthetic
methodologies. Thus, metal-mediated or -catalyzed reactions
of methylenecyclopropanes have been studied extensively.[9]
Notably, these transformations proceeded almost exclusively
through the opening of at least one cyclopropane ring,[10]
whereas the formation of cyclopropane-containing com-
pounds was observed as a side reaction only. Recently, we
have developed the first protocol for intermolecular hydro-
arylation reactions of highly strained methylenecyclopro-
Transition-metal-catalyzed reactions are indispensable tools
in modern synthetic chemistry.[1] Particularly, transition-
metal-catalyzed additions of arenes onto C C multiple
bonds, namely, hydroarylation reactions, have received con-
siderable attention as an ecologically and economically
friendly approach to the direct functionalization[2] of aro-
À
À
matic C H bonds. Consequently, a number of valuable pro-
[11,12]
À
tocols for intermolecular hydroarylation reactions of al-
panes through C H bond functionalization
under ruthe-
kenes, alkynes, and allenes have been developed,[3] with
nium catalysis.[13] Surprisingly, these reactions occurred with
complete conservation of all the cyclopropane rings. Such a
formation of functionalized cyclopropane derivatives is
unique and important from the viewpoint of both transition-
metal catalysis and organic synthesis. To elucidate the syn-
thetic versatility of this transformation and probe the influ-
ence of the steric and electronic factors in the arene and
methylenecyclopropane substrates, we performed, and
report herein, detailed synthetic and mechanistic studies on
atom-economical hydroarylation reactions of differently
substituted methylenecyclopropanes 1–6 through ruthenium-
ruthenium-catalyzed[4] directed[5] C H bond functionaliza-
À
tion among the most powerful strategies.[6,7]
The chemistry of highly strained methylenecyclopro-
panes[8] continues to be fascinating because their enhanced
reactivities allow fundamental concepts in organic chemistry
[a] Prof. Dr. L. Ackermann, Dr. S. I. Kozhushkov
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
E-mail: lutz.ackermann@chemie.uni-goettingen.de
À
catalyzed C H bond functionalization of arenes 7–11 with
[b] Dr. D. S. Yufit
various directing groups (Figure 1).
Department of Chemistry
University of Durham
South Road, Durham, DH1 3LE (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200406.
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Scheme 1. Competitive ring-opening reaction of 1 followed by a Diels–
Alder [4+2] cycloaddition. BINAP = 2,2’-bis(diphenylphosphino)-1,1’-bi-
naphthyl, cod=cis-1,4-cyclooctadiene, dppf=1,1’-bis(diphenylphosphi-
no)ferrocene.
lation of 1 with phenylpyridine 7a, thus giving rise to new
product 19a, with phosphane X-Phos (18)[16] being superior.
Detailed NMR spectroscopic studies proved the structure
of the newly formed product to be 2-{[2-(cis-2-phenylcyclo-
propyl)methyl]phenyl}pyridine (19a; Table 1, entries 1–3).
Remarkably, the anti-Markovnikov addition of arene 7a oc-
curred with complete conservation of the three-membered
ring, thus yielding cyclopropane derivate 19a highly selec-
tively. Such reactivity is rather unusual for methylenecyclo-
propanes under transition-metal catalysis.[9,10]
Figure 1. Substituted methylenecyclopropanes 1–6 used in hydroarylation
À
reactions through ruthenium-catalyzed C H functionalization of arenes
7–11.
Results and Discussion
With an active and selective catalyst in hand, we studied
Hydroarylation reactions of 2-phenylmethylenecyclopropane
(1): Although metal-catalyzed reactions of methylenecyclo-
propanes have been studied exhaustibly, their hydroaryla-
its application to the challenging hydroarylation of 1
À
through C H bond functionalization on arenes 7–11
(Table 1). Under the optimized reaction conditions, sub-
strate 7b was converted into the corresponding cis-adducts
19b in even greater yield (78%) with excellent chemo- and
site-selectivity (Table 1, entry 4). Analogous hydroarylation
reactions with arenes 8–11, which possess different directing
groups, appeared to be less efficient (Table 1, entries 5–10).
Interestingly, hydroarylation products were also not formed
in the attempted reaction of substrate 1 with acetophenone
(11a) under recently reported reaction conditions.[7a] Yet, it
is important to note that all of the isolated hydroarylation
products 19a, 19b, 20, and 21b contained a conserved cyclo-
propane moiety. In spite of the fact that no special kinetic
measurements were performed, it should be mentioned that
the attempted hydroarylation of 1 with 7a with 2.5 mol% of
the ruthenium precatalyst or upon heating for 20 hours only
resulted in the formation of 19a in 28 and 25% yield, re-
spectively (Table 1, entry 11). This outcome can be inter-
preted in favor of a first-order reaction with respect to [Ru].
For the pyridine 19b, cis substitution on a cyclopropane
À
tion reactions through the C H bond functionalization of
arenes have never been probed before. Based on previous
reports,[9] one would expect any of the known[14] skeletal re-
organization of a cyclopropane moiety to proceed in these
transformations as well. Indeed, at the outset of our studies,
catalytic amounts of [{RhClACHTNUGTRENUNG(cod)}2] and PPh3 quantitatively
yielded ring opening of 2-phenylmethylenecyclopropane (1)
into a buta-1,3-diene derivative—presumably through initial
hydroruthenation of the C=C bond with subsequent elimina-
tion of the cyclopropane b-carbon atom and final b-hydro-
gen elimination[15]—followed by polymerization, even at
508C. Upon testing hydroarylation reactions of substrate 1
with pyridine 7a and by employing [{RuCl2ACTHNUGTRNE(UNG cod)}n] as the
precatalyst modified with a representative set of commonly
used ligands,[11] application of triarylphosphanes as rac-
BINAP (12) or 1,2-bis(diphenylphosphino)ethane (dppe;
13) as ligands resulted only in the formation of undesired
products 15 and 16 due to Diels–Alder [4+2] cycloaddition
reactions of the intermediate 2-phenylbuta-1,4-diene (14;
Scheme 1). Furthermore, starting material 7a was reisolated
in virtually quantitative yield.
À
ring and the conservation of the ring during C H bond func-
tionalization were unambiguously established by X-ray dif-
fraction analysis of its para-toluenesulfonate 19b·p-TsOH
(Figure 2).
On the contrary, more selective catalysis was achieved
under otherwise identical reaction conditions, when more
the sterically hindered ligands P(o-biphenyl)
Phos; 17) or dicyclohexyl-(2’,4’,6’-triisopropylbiphenyl-2-yl)-
phosphane (X-Phos; 18)[16] were employed in the hydroary-
(tBu)2 (John-
Substitution on the cyclopropane ring: Incorporation of a
second phenyl group into the phenylmethylenecyclopropane
moiety resulted in a drastic decrease of its reactivity toward
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Intermolecular Hydroarylation of Highly Strained Methylenecyclopropanes
Table 1. Ruthenium-catalyzed hydroarylation reactions of methylenecy-
FULL PAPER
and three unidentified minor hydroarylation products, traces
clopropane 1 with arenes 7–11.[a]
of pyridine 24a were also observed. This latter compound
À
corresponds to formal hydroarylation of the distal C C
bond (with respect to the methylene group) of the cyclopro-
pane fragment in 2. Moreover, the product of the rutheni-
um-catalyzed self-reorganization of 2, namely, 2-methylene-
1-phenylindane (25), was formed as a major component of
the reaction mixture.
Spirocyclopropanation of a cyclopropane moiety caused
inertness of methylenespiropentane 3 in hydroarylation re-
actions under the optimized reaction conditions. In this case,
the ruthenium complex only initiated the rearrangement of
substrate 3 into triene 26 by initial hydroruthenation of the
C=C bond followed by elimination of the cyclopropane b-
carbon atom and final b-hydride elimination.[21] A [4+2] cy-
cloaddition reaction of intermediate 26 afforded tetraene 27
in moderate yield (Scheme 2). The relative reactivity of
methylenecyclopropanes 2 and 3 highlights the importance
of steric factors in the hydroarylation reactions. Hence, pre-
sumably, at least one side of the cyclopropane plane should
be available for an approach by the bulky ruthenium com-
plex.
Entry Arene R1
R2
Product Yield of
Yield of prod-
arene [%] ucts 19–22 [%]
1[b]
2
7a
7a
7a
H
H
H
19a
19a
19a
53
39
40
46
53
54
3[c]
4
5
6
7b
8
OMe
H
19b
20
18
75
96
78
19
–
9a
H
21a
7
9b
Me
H
21b
22
–
63
90
95
97
29
<5
–
Substitution at the methylene moiety: Replacement of a
methylene group in methylenecyclopropane with a cyclopro-
pylidene moiety results in an increased efficiency within the
ruthenium-catalyzed hydroarylation reactions, but does not
influence the mode of reactivity. This behavior was demon-
strated in hydroarylation reactions of highly strained bicy-
clopropylidene (4)[22] with arenes 7–11 under identical reac-
tion conditions. As in the case of methylenecyclopropane 1,
no reactions of substrates 9a, 11a, and 11b were observed.
However, compounds 7a, 7b, 8, 9b, and 10 demonstrated
improved results (Table 2). Thus, under the optimized reac-
tion conditions, 7a was quantitatively converted into a mix-
ture of mono- and dialkylated pyridines 28a and 29, which
were isolated in 33 and 60% yield, respectively, whereas
28b was obtained from 7b in an improved yield of the iso-
lated product.
8
10
9
11a
11b
7a
H
10
11
H
–
–
65
64
28[d]
25[e]
H
19a
[a] Reaction conditions:
(cod)}n] (5 mol%), 18 (10 mol%), 1,4-dioxane (3 mL), 1208C, 48 h.
[b] P(o-biphenyl)(tBu)2 (17) as the ligand. [c] N-methylpyrrolidone
1
(3 equiv),[17–20] 7–11 (1–2 mmol), [{RuCl2-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
(3 mL) as the solvent. [d] 2.5 mol% of [{RuCl
20 h.
2ACHTNUGTREN(NNUG cod)}n]. [e] Reaction time
Importantly, X-ray diffraction analyses of these newly
formed products 28a, 28b, 29, and 31b (the latter as its
para-toluenesulfonate species) revealed that all three-mem-
À
bered rings were conserved during the C H bond function-
alization reactions (Figure 3).[23] The bicyclopropyl frag-
ments in molecules 28a, 28b, 29, and 31b do not contain
any abnormal bonds and all the compounds adopted typica-
l[8a] gauche (synclinal) conformations with the torsion angle
f C(Ph)-C(Cp)-C(Cp)-H, which describes the mutual orien-
tation of two adjacent cyclopropane rings, in the range 51.6–
59.38. Short intramolecular C-H···N (C-H···O in 31b) con-
tacts between tertiary hydrogen atoms of bicyclopropyl moi-
eties and nitrogen or oxygen atoms of the heterocycles were
found in all four molecules (H···O: 2.543 in 28a, 2.716 in
28b, 2.447 and 2.704 in 29, and 2.489 ꢃ in 31b). These dis-
tances might be regarded as weak hydrogen bonds. The con-
formations of the molecules in the crystals must result in
each case from energetic compromises between these hydro-
Figure 2. Molecular structure of pyridine para-toluenesulfonate 19b·
p-TsOH in the crystal.
hydroarylation and partially changed the mode of reactivity
(Scheme 2). Thus, along with the formation of products that
retained the cyclopropane moiety (i.e., 23a,b) in low yields
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L. Ackermann et al.
gen bonding, conjugation effects, and intramolecular van der
Waals interactions between hydrogen atoms and crystal-
packing effects.
Thus, the angles between the planes of the pyridine and
benzene moieties in the more sterically congested com-
pounds 28b (79.4) and 29 (71.78) are higher than those
angles in 28a, with one bicyclopropyl fragment (55.18). This
finding holds true for the angles between the planes of the
benzene ring and the adjacent three-membered ring of the
bicyclopropyl core in 28b (122.68), 29 (123.8 and 120.38),
and 28a (118.48). Broadening of signals of the methylene
carbon atoms in the 13C NMR spectrum of 29 (see below)
indicates an increased rotation barrier for the bicyclopropyl
moieties in solution as well. In all four structures, the mole-
cules are linked by C-H···p interactions, and the shortest C-
H···C distances are 2.764, 2.941, 2.779, and 2.615 ꢃ in 28a,
28b, 29, and 31b, respectively. Interestingly, no stacking
p···p interactions were observed in structures 28a, 28b, and
29, and such contacts between the benzene rings of the adja-
cent molecules are present only in 31b, probably due to re-
placement of the pyridine ring by the less-bulky dihydrooxa-
zole ring.
Surprisingly, replacement of a methylene group in methyl-
enecyclopropane with a dicyclopropylmethylene fragment
completely inhibited hydroarylation under ruthenium cataly-
sis in methylenecyclopropane 5.[24] In contrast, diphenylation
of a methylene moiety, as in benzhydrylidenecyclopropane
(6), increased the reactivity of the methylenecyclopropane
moiety, but drastically changed the mode of reaction.
Hence, in each case the major products 33 and 35 corre-
spond to formal hydroarylation reactions of the longest[22a]
Scheme 2. Ruthenium-catalyzed hydroarylation reactions of substrates 2
Table 2. Ruthenium-catalyzed hydroarylation reactions of bicyclopropyli-
dene 4 with arenes 7–11.[a]
À
distal C C bond in cyclopropane in 6 (Scheme 3). This out-
come indicates that the mechanisms of hydroarylation reac-
tions of alkenes 1 and 4 and of benzhydrylidenecyclopro-
pane (6) are different at the rate-limiting step, likely be-
cause of the delocalizing effects of the bulky phenyl sub-
stituents in the latter case.
Entry Arene R1
R2
Products Yield of
Yield of
arene [%] products [%]
28a
29
33
60
X-ray crystal analysis of these newly formed pyridines
33a, 33b, and 35 (the latter as its para-toluenesulfonate)
confirmed their structures as products with an unusual type
of ring opening[12] from starting material 6 (Figure 4).
As side products of the transformation of substrate 6, sig-
nificant amounts of 4-phenyl-1,2-dihydronaphthalene (36)
and traces of 4-chloro-1,1-diphenyl-but-1-ene (37) were iso-
lated (Scheme 3). Presumably, intermediate 34, initially
formed by hydroruthenation of the C=C bond in 6, is prone
to elimination of the cyclopropane b-carbon atom to give in-
termediate 38. The latter can either undergo intramolecular
1
7a
7a
H
H
0
28a
29
65
28
2[b]
9
3
4
5
7b
8
OMe
H
28b
30
–
0
65
95
85
21
0
9a
H
6
7
8
9
9b
Me
H
31b
32
–
54
82
97
96
40
11
–
[15b,g]
À
C H insertion
with the neighboring phenyl ring fol-
10
lowed by elimination or direct elimination of the ruthenium
atom to afford product 37.
11a
11b
H
Mechanistic rationale for ruthenium-catalyzed hydroaryla-
tion reactions of methylenecyclopropanes: Because the high
H
–
–
À
selectivity of our novel ruthenium catalyst enabled C H
bond functionalization to occur with either an unprecedent-
ed retention of the cyclopropane moiety or, in rare cases,
[a] Reaction conditions: 4 (3 equiv), 7–11 (1–2 mmol), [{RuCl2ACTHNUTRGNEN(UG cod)}n]
(5 mol%), 18 (10 mol%), 1,4-dioxane (3 mL), 1208C, 48 h. [b] Com-
pound 17 (10 mol%) as the ligand.
and 3.
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Intermolecular Hydroarylation of Highly Strained Methylenecyclopropanes
FULL PAPER
Scheme 3. Ruthenium-catalyzed hydroarylation reactions of substrates 6
with arenes 7a and 7b. [a] Yields based on [{RuCl2A(cod)}n].
Figure 3. Molecular structures of pyridines 28a, 28b, 29, and oxazoline
para-toluenesulfonate 31b·p-TsOH according to X-ray crystal studies.[23]
CTHUNGTRENNUNG
with complete opening of the cyclopropane ring, we became
interested in testing its working mode. Indeed, the efficiency
of these reactions did correlate neither with the basicity of
the directing group (pKa =5.37, 1.28, and 14.18 for pyridine,
pyrimidine, and 1H-pyrazole, respectively)[25] nor with the
known first ionization energies of the alkenes (9.10, 8.93,
and 8.25 eV for 3–5, respectively).[26] To shed light on the
mechanism of these hydroarylation reactions, we subjected
deuterium-labeled pyridine 7a-[D5] to the optimized reac-
tion conditions for the hydroarylation of alkenes 1, 4, and 6
(Schemes 4 and 5). Ratios of [D3]/[D5] isotopomers for the
1
adducts were obtained by H NMR spectroscopic and mass-
spectrometric (ESI) analysis (see the Supporting Informa-
tion).
Interestingly, deuterium incorporation into the cyclopro-
pane moiety of products 19-[Dn], 28-[Dn], 29-[Dn], 24-[Dn],
and 35-[Dn] was only 50, 63, 50, 65, and 61%, respectively.
Moreover, the recovered starting material revealed a regio-
selective deuterium/proton exchange in the ortho position of
pyridine 7a-[D5],[27] and the content of incorporated hydro-
gen (23–90%) into [D3]/[D5] isotopomers depended mainly
on the reaction time (see the Supporting Information).
Notably, hydroarylation of alkenes 1, 4, and 6 with pyri-
dine 7a-[D5] highlighted a regioselective deuterium/proton
À
exchange as well, thus indicating that C H bond metalation
is not rate limiting (Schemes 4 and 5). When using DMF-
Scheme 4. Ruthenium-catalyzed hydroarylation of alkenes 1 and 4 with
pyridine 7a-[D5] (Dinc =2H incorporation).
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L. Ackermann et al.
Scheme 5. Ruthenium-catalyzed hydroarylation of alkene 6 with pyridine
7a-[D5].
In our first attempt to prove this hypothesis, the reaction
of substrates 1 and 7a-[D5] with dppf (13) as the ligand re-
sulted in isolation of Diels–Alder adducts 15 and 16
(Scheme 1), which did not contain any deuterium, and re-
covery of 7a-[D5] demonstrated a deuterium/proton ex-
change of less than 5%.
From the reaction mixture obtained from substrate 7a-
[D5] and methylenespiropentane 3 (Scheme 2), 1,4,4-trivinyl-
cyclohexene (27-D) was isolated, which did contain deuteri-
um at the methyne positions of the double bonds according
Figure 4. Molecular structures of pyridine 33a, 33b, and pyridine para-
toluenesulfonate 35·p-TsOH according to X-ray crystal studies.[23]
1
to the H NMR and mass spectra (see Supporting Informa-
tion). Fortunately, formation of the deuterium-labeled 4-
phenyl-1,2-dihydronaphthalene (36-Dn) and of 4-chloro-1,1-
diphenyl-but-1-ene (37-Dn) (Scheme 5) undoubtedly demon-
strated the alkenes to be the proton donors in deuterium/
proton exchange reactions.
Based on our mechanistic studies, we propose the follow-
ing mechanistic rationalization depicted in Schemes 6 and 7.
Coordination of the catalytically competent ruthenium com-
[D7] as the solvent, the proton/deuterium exchange was not
observed for pyridines 7a and 19 under otherwise identical
reaction conditions. Most likely, in the deuterium/proton ex-
change reactions, starting materials 1, 4, and 6, respectively,
served as proton donors. Thus, ruthenium-catalyzed reorgan-
ization (Schemes 3 and 5) through initial hydroruthenation
of the C=C bond in 1 and 6 followed by elimination of the
cyclopropane b-carbon atom and final b-hydride elimination
from intermediates 38 and 40[15] replaced [RuD] with the
[RuH] species.
À
plex 41 initiates the rapid and reversible C H bond metala-
tion, thus providing ruthenacycle 43. Subsequently, cyclome-
talated complex 43 adds to a double bond or, alternatively,
to a distal bond of methylenecyclopropane 44 to yield inter-
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Intermolecular Hydroarylation of Highly Strained Methylenecyclopropanes
FULL PAPER
least of the order as the rate observed for the well-known,
very fast rearrangement of (cyclopropylmethyl)–metal to
homoallyl–metal.[9e,15,28] The latter reorganization, along
with a subsequent b-hydride elimination, results in the for-
mation of buta-1,3-dienes as byproducts according to mech-
anism discussed above (Scheme 5i), which accounts for the
observed deuterium/proton exchange reactions with 7a-[D5]
as the substrate. The detailed mechanism of the hydroruthe-
nation of a distal bond in methylenecyclopropanes can only
be speculated on. However, by taking into account the un-
usual type of ring opening and distribution of the deuterium
label, it is most likely that this transformation proceeds in
several steps with the participation of cyclopropyl cationic
intermediates (Scheme 7). These latter species undergo ring-
opening reactions to form allylic cations almost without en-
ergetic barriers and are typical reactions for methylenecyclo-
propanes,[26b,29] for example, chloropalladation reactions.[30]
According to this process, two phenyl groups in 6 promote a
stepwise addition of [RuH] species onto a double bond of 6
with an initial formation of the half-opened or closed[29a] car-
bocation 49, which rearranges to intermediate 50 and then
to the more-stable carbocation 51. Hydride transfer in this
latter compound followed by reductive elimination of 52
furnishes products of the type 33 or 35. Hydride transfer to
the benzhydrilic position in 52 and reductive elimination can
afford compounds of the type 24. However, by taking into
consideration the low deuterium content in 24-[Dn], forma-
tion of the latter can better be explained through isomeriza-
tion of 33 through addition/elimination of [RuH] ([RuD])
intermediates.
Scheme 6. Proposed catalytic cycle for Ruthenium-catalyzed hydroaryla-
tion reactions of methylenecyclopropanes 44 with the conservation of the
three-membered ring.
The exact structure of the catalytically competent rutheni-
um complex 41 demands further elucidation. The high selec-
tivity obtained with monophosphane biphenyl ligands 17
and 18 could probably be explained by the formation of
arene-tethered ruthenium–phosphane complexes. A number
of such complexes has previously been synthesized.[31]
Indeed, in several hydroarylation reactions, traces of air-
and moisture-stable ruthenium complexes have been isolat-
ed (see the Experimental Section), and X-ray diffraction
analysis revealed the structure of dichloro[h6:h1-dicyclohex-
yl-(2’,4’,6’-triisopropylbiphenyl-2-yl)phosphane]ruthenium(II)
(53; Figure 5).
Complex 53 has also been prepared independently from
[{RuCl2ACTHNUGTRNE(UNG cod)}n] and X-Phos in virtually quantitative yield by
adapting a modified reported procedure,[32] and X-ray dif-
fraction analysis confirmed the structure of 53a. Unfortu-
nately, complex 53 did not demonstrate catalytic activity in
our hydroarylation reactions. Heating a solution of 4 in
CDCl3 in the presence of 53a (5 mol%, 708C, 96 h) also
caused no reorganization of 4.[33]
Scheme 7. Proposed mechanistic rationalization for Ruthenium-catalyzed
hydroarylation reactions of methylenecyclopropanes 44 with cyclopro-
pane ring opening.
mediates 45 (Scheme 6) or 46 (Scheme 7), respectively. Re-
ductive elimination of the latter compound affords products
47 or 48, respectively, thereby regenerating the catalytically
active species 41. In the case of intermediate 45, the rate of
the final reductive elimination in the catalytic cycle is at
Conclusions
We have developed the first protocol for intermolecular hy-
droarylation reactions of highly strained methylenecyclopro-
panes through C H bond functionalization. Notably, this re-
À
Chem. Eur. J. 2012, 00, 0 – 0
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www.chemeurj.org
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L. Ackermann et al.
Chen, K. M. Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. 2009, 121,
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À
[3] Selected reviews: a) Handbook of C H Transformations (Ed.: G.
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Figure 5. Molecular structure of 53 according to X-ray crystal studies.[23]
ORTEP (left) and ball-and-stick (right) presentations.
action is very sensitive to the substitution pattern on methyl-
enecyclopropane. Although these transformations involved
(cyclopropylcarbinyl)–metal intermediates, in most cases
these hydroarylation reactions resulted in complete reten-
tion of the cyclopropane moieties in the products. Even
minor steric hindrance on the cyclopropane fragment, how-
ever, drastically decreased the yields of the hydroarylation
products. This unique reactivity pattern is a strong testament
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À
to the mild reaction conditions of ruthenium-catalyzed C H
bond functionalization. In several rare cases, however, an
unusual mode of ring opening of the cyclopropane moiety,
which corresponds to formal hydroarylation reactions of the
À
longest distal C C bond in cyclopropane fragment, was ob-
served.
Acknowledgements
Support by the DFG, the Fonds der Chemischen Industrie and EPSRC
(UK) is gratefully acknowledged.
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Intermolecular Hydroarylation of Highly Strained Methylenecyclopropanes
FULL PAPER
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ACTHNUTRGNEUNG
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(35·p-TsOH), 884971 (53), and 884973 (53a) contain the supplemen-
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[24] This result is unexpected in view of an attempted reaction in the
presence of H2O (1 equiv) under otherwise identical reaction condi-
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Supporting Information) through the ruthenium-catalyzed hydrata-
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À
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L. Ackermann et al.
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sors [RuCl
cymene)}2], and cis-[RuCl CTHGNUTRENNUNG
with 7a under the same reaction conditions revealed no improve-
ment of the yield, whereas selectivity depends predominantly on the
ligand (see also ref. [11]).
G
2ACHTUNGTRNENUG(benzene)}2], [{RuCl2ACHTUNGTRENNUNG(p-
[29] a) G. Boche, H. M. Walborsky, Cyclopropane Derived Reactive Inter-
mediates (Eds.: S. Patai, Z. Rappoport), Wiley, Chichester, 1990,
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Intermolecular Hydroarylation of Highly Strained Methylenecyclopropanes
FULL PAPER
A highly chemo- and site-selective
ruthenium catalyst has achieved inter-
molecular hydroarylation reactions of
methylenecyclopropanes (see scheme)
Catalytic Hydroarylation
L. Ackermann,* S. I. Kozhushkov,
D. S. Yufit ...................... &&&& — &&&&
À
through chelation assistance. The C H
Ruthenium-Catalyzed Hydroarylation
of Methylenecyclopropanes through
bond functionalization of 2-phenylpyri-
dine and other arenes with directing
groups has been studied. Furthermore,
a plausible mechanistic rationale and a
catalytic cycle for these unusual ruthe-
nium-catalyzed hydroarylation reac-
tions are proposed.
À
C H Bond Cleavage: Scope and
Mechanism
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!