Gold(I)-catalyzed tandem C-H and C-C activation (Cleavage)

Article abstract of DOI:10.1021/ol902593f

Chemical Equation Presented (Cyclopropylidenecyclohexyl)benzene derivatives, a kind of methylenecyclopropane (MCP) containing a cyclohexyl group, can undergo an interesting tandem intramolecular C-H and C-C bond activation through dehydrogenated rearrangement in the presence of AuPPh ₃Cl/AgOTf by transferring three hydrogen atoms from cyclohexane to cyclopropane, affording the corresponding biaryl derivatives in moderate to good yields. The reaction mechanism has also been carefully investigated by deuterium labeling experiments and DFT calculations

Full text of DOI:10.1021/ol902593f

ORGANIC
LETTERS
2010
Vol. 12, No. 1
116-119
Gold(I)-Catalyzed Tandem C-H and
C-C Activation (Cleavage)
Min Jiang, Le-Ping Liu, Min Shi,* and Yuxue Li*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032 China
mshi@mail.sioc.ac.cn; liyuxue@mail.sioc.ac.cn
Received November 9, 2009
ABSTRACT
(Cyclopropylidenecyclohexyl)benzene derivatives, a kind of methylenecyclopropane (MCP) containing a cyclohexyl group, can undergo an
interesting tandem intramolecular C-H and C-C bond activation through dehydrogenated rearrangement in the presence of AuPPh3Cl/AgOTf
by transferring three hydrogen atoms from cyclohexane to cyclopropane, affording the corresponding biaryl derivatives in moderate to good
yields. The reaction mechanism has also been carefully investigated by deuterium labeling experiments and DFT calculations.
Metal-catalyzed activation of the C-H bond followed by
C-C bond activation is much less frequently observed than
the C-H bond or C-C bond activation.1 A metal-catalyzed
tandem C-H bond and C-C bond activation should be the
most attractive aspect for many organometallic chemists, due
not only to its fundamental scientific interest but also to its
potential utility in organic synthesis. Methylenecyclopropanes
as highly strained but readily accessible molecules can
undergo a variety of ring-opening reactions in the presence
of transition metals or Lewis acids because the relief of ring
strain provides a potent thermodynamic driving force.2,3
Moreover, it should also be noted that release of such strain
energy (27 kcal/mol)4 is not sufficient for high reactivity.
The π character of the ring bonds of a cyclopropane provides
the kinetic opportunity to initiate the unleashing of the strain.5
Thus far, it has been known that the cyclopropane can
undergo the C-C bond cleavage in the presence of various
transition metal catalysts, giving the ring-opening products
in good yields.6 During the past few years, gold(I) has
emerged as the most powerful soft Lewis acid for activation
of alkynes, allenes, and alkenes due to its exceptional
alkenophilicity and alkynophilicity.7 Several C-H bond
activations in alkanes have also been achieved with supported
or homogeneous gold catalysts.8 Therefore, we envisaged
(3) Selected recent contributions from our group. (a) Shi, M.; Liu, L. P.;
Tang, J. J. Am. Chem. Soc. 2006, 128, 7430–7431. (b) Shao, L.-X.; Xu,
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Xu, B.; Huang, J.-W. Org. Lett. 2004, 6, 1175–1178. (d) Tian, G.-Q.; Shi,
M. Org. Lett. 2007, 9, 4917–4920. (e) Shao, L.-X.; Li, Y.-X.; Shi, M.
Chem.sEur. J. 2007, 13, 862–869. Recent examples on the C-C and C-H
activation of MCPs: (f) Fu¨rstner, A.; Aı¨ssa, C. J. Am. Chem. Soc. 2006,
128, 6306–6307. (g) Aı¨ssa, C.; Fu¨rstner, A. J. Am. Chem. Soc. 2007, 129,
14836–14837.
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Milstein, D. Chem. ReV. 2003, 103, 1759–1792, and references therein. (g)
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NATO ASI series; Kluwer Academic Publishers, 1989.
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C. Y. Chem. ReV. 1989, 89, 165–198. (b) Rubin, M.; Rubina, M.;
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.
10.1021/ol902593f  2010 American Chemical Society
Published on Web 12/03/2009

that using (cyclopropylidenecyclohexyl)benzene 1a, a kind
of methylenecyclopropane (MCP) containing cyclohexane,
as the substrate an interesting tandem C-H and C-C
activation might be able to take place by intramolecular or
intermolecular hydrogen transfer from cyclohexane to cy-
clopropane, affording thermodynamically stable biaryl aro-
matic compounds in the presence of a Au(I) catalyst (eq 1).
In this paper, we wish to report such interesting tandem
intramolecular C-H and C-C activation through dehydro-
genated rearrangement of 1 in the presence of AuPPh3Cl/
AgOTf at high temperature in toluene or xylene to give the
corresponding biaryl derivatives in moderate to good yields.
Au(I)underidenticalconditions.ThecombinationofAuPPh3Cl/
AgBF4 or AuPPh3Cl/AgSbF6 did not have catalytic activity
in this reaction, but using AuCl3/AgOTf as the combined
catalysts afforded 2a in 72% yield. Brønsted acid CF3CO2H
and CH3CO2H (HOAc) did not catalyze the reaction, and
CF3SO3H (HOTf) afforded complex product mixtures under
the standard conditions (Table 1, entries 12, 13, and 15).
The examination of solvent effects revealed that toluene is
the solvent of choice in this reaction (Table 1, entries 16-20).
With the optimized reaction conditions being identified, we
next carried out AuPPh3Cl/AgOTf cocatalyzed rearrangement
reactions of a variety of MCPs 1 to evaluate the scope of this
reaction. The results are summarized in Table 2. As can be seen
Table 2. Gold(I)-Catalyzed Rearrangement of 1 under the
Optimal Conditions
Initial studies using (cyclopropylidenecyclohexyl)benzene
1a as the substrate were aimed at determining the optimal
reaction conditions for the Lewis acid-catalyzed reactions,
and the results of these experiments are summarized in Table
1 (for the detailed description, please see the Supporting
yield (%)b
entrya
1 (R1/R2/R3)
2
1
2
3
4
5
6
7
8
1a (C6H5/H /H)
2a, 85
2b, 77
2c, 79
2d, 76
2e, 82
2f, 79
2g, 74
2h, 82
2i, 57
2j, 63
2k, 71
2l, 55
1b (p-MeC6H4/H /H)
1c (m-MeC6H4/H/H)
1d (o-MeC6H4/H /H)
1e (o,p-Me2C6H3/H/H)
1f (m,m-Me2C6H3/H/H)
1g (m-MeOC6H4/H /H)
1h (p-MeOC6H4/H/H)
1i (p-C6H5C6H4/H/H)
1j (p-ClC6H4/H/H)
1k (C6H5/H/Me)
Table 1. Optimization of the Reaction Conditions for the
Rearrangement of MCP 1a
9
yield (%)b
10
11
12
entrya solvent
catalyst
temp (°C)
2a
1l (C4H9/H/H)
1
toluene AuPPh3Cl/AgOTf
toluene AuPPh3Cl/AgSbF6
toluene AuPPh3Cl/AgBF4
toluene AuPPh3Clc
100
85
a Reaction conditions: 1 (0.2 mmol), AuPPh3Cl (0.01 mmol), AgOTf
(0.02 mmol), toluene (2.0 mL), and the reactions were carried out at 100
°C. b Isolated yield.
2
100
NR
NR
NR
NR
53
3
100
4
100
5
toluene AgOTfc
100
c
6
toluene Sc(OTf)3
100
c
7
toluene Sn(OTf)2
100
45
c
8
toluene Nd(OTf)3
100
60
from Table 2, as for substrates in which R1 ) aryl and R2 )
R3 ) H, the corresponding rearrangement products, 4-propy-
lbiaryls, can be obtained in moderate to good yields within 10 h
as the sole products (Table 2, entries 1-10). Adding electron-
poor substituents on the benzene rings afforded the products in
slightly lower yields (Table 2, entries 2-8 and 9-10). As for
MCP 1k in which R1 ) phenyl, R2 ) H, and R3 ) methyl, the
reaction also proceeded smoothly to give the corresponding
9
toluene BF3·Et2Oc
100
55
c
10
11
12
13
4
toluene Yb(OTf)3
100
NR
NR
NR
NR
72
c
toluene La(OTf)3
100
toluene CF3CO2Hc
100
toluene AcOHc
100
toluene AuCl3/AgOTf
toluene HOTfc
CH3CN AuPPh3Cl/AgOTf
100
15
16
17
18
19
20
100
complex mixtures
NR
68
NR
NR
NR
reflux
reflux
reflux
reflux
reflux
DCE
THF
AuPPh3Cl/AgOTf
AuPPh3Cl/AgOTf
CH2Cl2 AuPPh3Cl/AgOTf
Et2O AuPPh3Cl/AgOTf
a Reaction conditions: 1a (0.2 mmol), Au catalyst (5 mol %), Ag salt
(10 mol %), solvent (2.0 mL), and the reactions were carried out at 100 °C
or under reflux. b Isolated yields. c 10 mol % is used.
(7) (a) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3183–3211. (b)
Jime´mez-Nu´n˜ez, E.; Echavarren, A. M. Chem. Commun. 2007, 333–346.
(c) Fu¨rstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410–
3449. (d) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395–403. (e) Marion,
N.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750–2752. (f) Ma, S.;
Yu, S.; Gu, Z. Angew. Chem., Int. Ed. 2006, 45, 200–203. (g) Hoffmann-
Ro¨der, A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387–391. (h) Arcadio,
A.; Di Giuseppe, S. Curr. Org. Chem. 2004, 8, 795–812. (i) Echavarren,
A. M.; Nevado, C. Chem. Soc. ReV. 2004, 33, 431–436.
Information). We found that the reaction proceeded smoothly
in toluene to give 4-propylbiphenyl 2a in 85% yield within
10 h at 100 °C in the presence of AuPPh3Cl/AgOTf (Table
1, entry 1), and other Lewis acids such as Sc(OTf)3,
Sn(OTf)2, Nd(OTf)3, and BF3·Et2O are not as effective as
(8) (a) Hill, C. L.; Weinstock, I. A. Nature 1997, 388, 332–333. (b)
Zhao, R.; Ji, D.; Lv, G.; Qian, G.; Yan, L.; Wang, X.; Suo, J. Chem.
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Org. Lett., Vol. 12, No. 1, 2010
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diaryl derivative 2k in 71% yield (Table 2, entry 11). Using
MCP 1l in which R1 ) C4H9 and R2 ) R3 ) H, the expected
rearrangement product was obtained in 55% yield, indicating
the wide substrate generality in this Au-catalyzed reaction (Table
2, entry 12).
respectively, suggesting that intermolecular hydrogen transferring
also takes place under the standard conditions (Scheme 3).
As for MCP 1m in which R1 ) H, R2 ) C6H5, and R3 ) H,
using gold(I) as a catalyst at 100 °C in toluene afforded the
corresponding product 2m in 38% yield (Scheme 1). Optimiza-
Scheme 3. Crossover Experiments
Scheme 1. Au(I)-Catalyzed Rearrangement of MCPs 1m and 1n
The control experiments shown in Scheme 4 indicate that
a cyclopropane ring and a cyclohexane ring in MCPs 1 are
tion of the reaction conditions revealed that 2m could be
obtained in 53% yield in xylene at 140 °C (Scheme 1). These
reaction conditions also tolerated MCP 1n (R2 ) p-MeC6H4),
providing the corresponding product 2n in 50% yield (Scheme 1).
Deuterium labeling experiments with MCPs 3-d (Ha and
He or He and Ha at CR and CR′ position, D content ) 64%
Scheme 4. Control Experiments
1
and 69%, respectively, on the basis of H NMR and EI-
Mass spectra) and 5-d (Cꢀ and Cγ, D content ) 59% and
60%, respectively) were carried out under the standard
conditions to clarify the reaction mechanism (Scheme 2).
both crucial in this Au(I)-catalyzed transformation since no
reaction occurred using 7 and 8 as the substrates under the
standard conditions (Scheme 4).
Scheme 2. Deuterium Labeling Experiments for the
Rearrangement of MCPs 3-d and 5-d
To reveal the mechanism of this novel Au(I)-catalyzed
tandem C-C and C-H bond cleavage reaction, density
functional theory (DFT) studies have been performed with the
substrate 1a.9 In the calculation, PMe3 is used instead of PPh3.
Previous theoretical works revealed that this simplification is
reasonable.10 On the basis of a series of systematical investiga-
tions, the proposed reaction pathway is shown in Scheme 5.
Under the standard reaction conditions, OTf-Au-PPh3 spe-
cies is generated in situ. The complex of 1a with Au+-PMe3
(A-comp) is 2.0 kcal/mol higher in energy than species A, in
which Au(I) is coordinated with the OTf- anion. Therefore,
the species A is used as the zero reference point of this reaction.
In A-comp, the complexation of Au(I) with the double bond
increases the acidity of the R-H atom in substrate 1a. In the
first step, the OTf- anion abstracts an R-H atom over a barrier
of 19.6 kcal/mol, leading to formation of intermediate B. In
intermediate B, Au forms a covalent bond with C3 (2.096 Å)
stabilizing the carbanion. Then the C1-C3 bond is attacked by
The product 4-d with 37% D content at C1 and 28% D
content at C3 as well as product 6-d with 7% D content at
C1 and 20% D content at C3 were obtained in 75% and 78%
yield within 10 h, respectively, based on the corresponding
1H NMR spectroscopic data (Supporting Information), sug-
gesting that (1) the hydrogen atoms at CR or CR′ transfer to
C1 and C3 and (2) the hydrogen atoms at Cꢀ or Cγ also
transfer to C1 and C3 in the presence of Au(I). In addition,
no influence was observed in the presence or absence of
molecular oxygen under otherwise identical conditions.
The crossover experiments of 3-d and 1h under the standard
conditions afforded product 4-d with 27% D content and 29%
D content at C1 and C3 as well as product 2h-d with 18% D
content and 9% D content at C1 and C3 in 75% and 75% yield,
(9) See Supporting Information for the details. As for the dehydration
and dehydrogenation to give aromatic compound, see: (a) Arumugam, N.;
Kumaraswamy, A. Synthesis 1981, 367–368. (b) Woods, G. F.; Oppelt,
J. C.; Isaacson, R. B. J. Am. Chem. Soc. 1960, 82, 5232–5235.
(10) Shi, F.-Q.; Li, X.; Xia, Y.; Zhang, L.; Yu, Z.-X. J. Am. Chem.
Soc. 2007, 129, 15503–15512.
118
Org. Lett., Vol. 12, No. 1, 2010

Scheme 5. Proposed Mechanism of the Au(I)-Catalyzed Tandem Reactiona
a The geometries have been fully optimized at the B3LYP/6-31+G**/Lanl2DZ level. The relative free energies in gas phase ∆Ggas(298 K) and the
relative free energies including solvent effect ∆Gsol(298 K) are in kcal/mol.
the proton of the HOTf molecule. The cyclopropane is opened,
and the R-H is transferred to C1, leading to the gold carbenoid
intermediate C. This is the rate-determining step. Therefore,
the whole reaction should be facilitated by the release of the
strain energy in the cyclopropane ring. Considering the experi-
mental conditions, the barrier (26.9 kcal/mol) is reasonable. In
the next step, the OTf- anion abstracts a ꢀ-H atom over a small
barrier of TS-CD yielding the alkenylgold intermediate D. The
protonation of intermediate D by HOTf leads to formation of
intermediate E1-Comp and regenerates the [Au+] catalyst.
E1-Comp may transform to its more stable conformational
isomer E2-Comp via the dissociation/association process of the
Au(I) catalyst and the CdC double bonds. The OTf- anion
abstracts the γ-H atom in E2-Comp, affording intermediate F,
which is converted to the cyclohexa-1,2-diene intermediate G
by protonation on C3. Our calculation results indicate that Au(I)
cannot facilitate the deprotonation of G any longer.9,10 Further
control experiments also confirmed that G can be easily
transformed to the phenyl derivative by deprotonation under
the reaction conditions without the assistance of the Au(I)
catalyst (Supporting Information).9
three hydrogen atoms from the cyclohexyl ring to the cyclo-
propane ring intra/intermolecularly in the presence of Au(I). It
should be also noted that intermolecular hydrogen transfer with
OTf- is a very minor process on the basis of the deuterium
labeling experiment. Since biaryls constitute core structural units
for a wide range of functional molecules13 and are synthesized
primarily using transition-metal-catalyzed aryl-aryl cross-
coupling reactions,14 this new Au(I)-catalyzed process provides
an alternative way to attain such compounds. The mechanistic
study by DFT calculation shows that OTf-/HOTf can act as
proton carrier to finish up the hydrogen transfer intra/intermo-
lecularly. If using BF3 as the catalyst, the active species
HBF3OH derived from the reaction of BF3 with trace amounts
of water might be able to trigger a similar hydrogen transfer
with BF3OH- to afford the corresponding biaryl product.15
Efforts are in progress to further understand the scope and
limitations of this reaction.
Acknowledgment. We thank the Shanghai Municipal
Committee of Science and Technology (06XD14005,
08dj1400100-2), National Basic Research Program of China
(973)-2009CB825300, and the National Natural Science
Foundation of China for financial support (20472096,
20872162, 20672127, 20821002, and 20732008).
Supporting Information Available: Detailed description
of experimental procedures, full characterization of new com-
pounds shown in Tables 1 and 2 and Schemes 1-3. This
material is available free of charge via the Internet at
http://pubs.acs.org.
On the basis of this mechanism, the OTf-/HOTf pair can
act as a proton carrier to finish up the hydrogen transfer intra/
intermolecularly, which is consistent with the deuterium-labeling
experimental results. Previous DFT studies on the Au(PR3)+-
catalyzed reactions also showed that the counterion OTf- can assist
the 1,2-H shift effectively.11 In the optimized structures, the OTf-
anion is relatively free and often resides far away from the gold
site. This result is also in line with the recent studies.12
In conclusion, we have developed an effective AuPPh3Cl/
AgOTf-cocatalyzed tandem intramolecular C-H and C-C
activation through dehydrogenated rearrangement of methyl-
enecyclopropanes 1 to produce biaryl derivatives in good yields
at high temperature. The reaction proceeds through transferring
OL902593F
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Reactions, 2nd ed.; Wiley-VCH: New York, 2004. (b) Miyaura, N., Ed.
Cross-Coupling Reactions: A Practical Guide; Springer: Berlin, 2002.
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H. A.; Weinberger, M. A. Nature 1946, 157, 102–102. (b) Evans, A. G.;
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