Gold-catalyzed benzylic C-H activation at room temperature

Article abstract of DOI:10.1002/anie.200701521

(Chemical Equation Presented) A tale of the unexpected: Coordinating and potentially chelating groups allow gold-catalyzed benzylic C-H activation at room temperature. Substrates with additional nucleophilic substituents undergo unexpected dimerizations,

Full text of DOI:10.1002/anie.200701521

Communications
DOI: 10.1002/anie.200701521
Gold Catalysis
ꢀ
Gold-Catalyzed Benzylic C H Activation at Room Temperature**
A. Stephen K. Hashmi,* Sascha Schäfer, Michael Wölfle, Cesar Diez Gil, Peter Fischer,
Antonio Laguna,* M. Carmen Blanco, and M. Concepción Gimeno
ꢀ
Catalytic C H activation by metal complexes is a hot topic in
organic chemistry and of growing importance for organic
synthesis.[1] Only in the last few years has gold been
[2]
ꢀ
recognized to be active in C H activation. We reported
gold-catalyzed hydroarylation reactions,[3] He et al. proved
Scheme 1. Gold-catalyzed conversion of 1 into 2. Mes=2,4,6-trimethyl-
phenyl.
that with electron-rich arenes these reactions can proceed by
[4]
ꢀ
ꢀ
initial aryl-C H activation, and Li also suggested a C H
activation step for the additions of b-diketones to reactive
alkenes.[5] The most remarkable gold-catalyzed activation of
an unactivated C(sp ) H bond was achieved by Periana et al.,
who oxidized methane to methanol in concentrated sulfuric
acid with selenic acid as the oxidizing reagent at 1808C with a
turnover number of 30. DFT studies indicated that cationic
Table 1: Conversion of substrates 1 into products 2 (R1 =H).
3
ꢀ
1
Catalyst
Conv.
Yield
to 2 [%][a] of 2 [%]
1a, R2 =nPr
AuCl3
95
27
31
[b]
[(Mes3PAu)2Cl]BF4
n.d.[c]
gold(I) and gold(III) species are able to mediate electrophilic
[6]
ꢀ
ꢀ
C H bond activation. Here we report a gold-catalyzed C H
activation at a benzylic position that takes place in a neutral
solvent at room temperature.
1b, R2 =Ph
1c, R2 =tBu
1d, R2 =TMS
1e, R2 =H
AuCl3
40
36
75
[d]
[e]
[(Mes3PAu)2Cl]BF4
n.d.[c]
The starting point for our studies was the gold-catalyzed
conversion of substrates 1, which were easily available by
Sonogashira coupling of 2-iodobenzyl alcohols. In a highly
selective conversion (monitored by 1H NMR spectroscopy) 1
(R2 = alkyl, phenyl) underwent the expected 6-endo-dig
cyclization to give isochromene derivatives 2 (Scheme 1,
Table 1). Yamamoto et al. reported that related gold-cata-
lyzed ring closures with carbonyl groups instead of hydroxy
groups leads to carbonyl ylides.[7] We observed no reaction
when R2 = trimethylsilyl (TMS), hydrogen, or alkynyl (1d, 1e,
and 1 f, respectively).
AuCl3
[(Mes3PAu)2Cl]BF4
87
24
95
n.d.[c]
AuCl3
[(Mes3PAu)2Cl]BF4
–
–
–
–
AuCl3
[(Mes3PAu)2Cl]BF4
–
–
–
–
1 f, R2 =ethynyl(2-hydroxy- AuCl3
methylphenyl) [(Mes3PAu)2Cl]BF4
–
–
–
–
1
[a] Determined by H NMR spectroscopy. [b] 4.3 mol% catalyst. [c] Not
determined. [d] 7.5 mol% catalyst [e] 5 mol% catalyst.
Since products 2 are very sensitive, the yields were
diminished and 2 could also not be stored for extended
[*] Prof. Dr. A. S. K. Hashmi, Dipl.-Chem. S. Schäfer,
Dipl.-Chem. M. Wölfle, C. Diez Gil, Dr. P. Fischer
Institut für Organische Chemie
periods. Table 2 shows that when AuCl3 served as catalyst, the
initially obtained 2 undergoes significant decomposition (2a
and 2c) or conversion was low (2b, 55% of the substrate was
recovered). In contrast, the AuI catalyst[8] led to good
conversion and good yields when the substituent R was
sterically shielding (2b and 2c but not 2a).
Universität Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
Fax: (+49)711-685-64321
E-mail: hashmi@hashmi.de
Homepage: http://www.hashmi.de
When the substrates bore additional nucleophilic groups
like ester or amide functionalities (1g–1k), not only product 2
but also the unexpected dimer 3 was obtained with both the
gold(I) and the gold(III) catalyst (Table 2). The eight (!) new
bonds formed in this unprecedented dimerization are shown
in bold (Scheme 2).
Prof. Dr. A. Laguna, Dr. M. C. Blanco, Dr. M. C. Gimeno
Departamento de Química Inorgµnica
Instituto de Ciencia de Materiales de Aragón
Universidad de Zaragoza-CSIC
50009 Zaragoza (Spain)
Fax: (+34)976-761185
E-mail: alaguna@unizar.es
The structure eludication of the products 3 was quite
difficult, and efforts to obtain single crystals failed even for
the nitroaryl compound 3k. Mass spectrometry showed 3 to
be a dimer of substrate 1. A combination of 1H NMR,
13C NMR, H,H-COSY, and HMBC spectra finally made an
unambiguous assignment possible.[9] The good solubility,
[**] This work was supported by the Fonds der Chemischen Industrie
and by the European Union (AURICAT EU-RTN, HPRN-CT-2002-
00174). C. Diez Gil is grateful for support by the Socrates/Erasmus
Program of the EU.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
6184
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 6184 –6187

Angewandte
Chemie
Table 2: Conversion of substrate 1 into 2 and dimer 3.
1
Catalyst
Yield
Yield
of 2 [%]
of 3 [%]
1g
AuCl3
[(Mes3PAu)2Cl]BF4
20
3635
78
R1 =H,
R2 =CH2CH(CO2Me)2
Scheme 3. Intramolecular migration of the oxygen atom of the benzylic
alcohol.
1h
AuCl3
[(Mes3PAu)2Cl]BF4
32
37
29
33
R1 =H,
R2 =CH2C(Me)(CO2Me)2
1i
AuCl3
[(Mes3PAu)2Cl]BF4
37
48
56
37
R1 =H,
R2 =CH2CH2CO2Me
1j
AuCl3
[(Mes3PAu)2Cl]BF4
1673
39
R1 =H,
–
R2 =CH2CH2CONMe2
1k
AuCl3
[(Mes3PAu)2Cl]BF4
21
34
26
–
R1 =NO2,
R2 =CH2CH2CONMe2
Scheme 4. Proposed mechanism for the formation of the ether bridge
between the two substrate units and the intramolecular oxygen trans-
fer.
Scheme 2. An unprecedented dimerization was observed with 1g–1k.
ent. The nucleophilic attack of the carbonyl group and a
subsequent protodemetalation would lead to the olefin
complex B, which then could deliver C by an intramolecular
addition of the hydroxy group. Intermediate C represents an
activated derivative of the benzyl alcohol. Attack of a second
molecule of 1 would then form the dibenzyl ether bond and
explain the intramolecular oxygen transfer from the benzylic
position to the ketone.
which prevented crystallization of 3, was finally utilized and
an INADEQUATE spectrum of a concentrated solution of 3g
confirmed the structural assignment. Most striking are the
conversion of one arylalkynyl group into an aryl ketone and
ꢀ
the formation of two new C C bonds at a benzylic position;
ꢀ
the latter can be explained only by activation the benzylic C
H bonds by the gold catalyst. The dimers are not of the type
Echavarren and Nevado obtained in AgI-catalyzed reac-
tions,[10] and radical reactions like those in related work of Li
and Li[11] can be excluded—our reaction readily proceeded in
the presence of the radical inhibitor di(tert-butyl)hydroxyto-
luene (BHT).
Intermediate D could again coordinate a gold species at
the alkyne (Scheme 5), and the resulting carbenoid E[10,13,14]
could insert[15] into the benzylic C H bond to form F.
ꢀ
Migration of the benzylic hydrogen would lead to olefin G,
An isotopic-labeling experiment with 18O-1g proved an
intramolecular oxygen shift. In the mass spectrum the
molecular-ion peak of (18O)2-3g appeared as the base peak,
indicating that the 18O atoms of both substrate molecules
were incorporated in the dimer (Scheme 3).
A mechanistic proposal for the formation of 3 must
consider that the dimer 3 is formed only in the presence of the
additional nucleophilic groups. After coordination of the
alkyne to the gold catalyst (Scheme 4, intermediate A),[12]
either the hydroxy group can attack as a nucleophile (path a),
or the second nucleophilic group can attack (path b). The
latter competing reaction is more effective, when the group is
more nucleophilic (better for amide 1j than for ester 1i) or
when two of these groups are present (less effective for 1i
with one ester group than for 1g with two ester groups). The
regioselectivity of these competing pathways would be differ-
Scheme 5. Conceivable transformation of D to 3g.
Angew. Chem. Int. Ed. 2007, 46, 6184 –6187
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6185

Communications
and migration of the double bond would form an extended
conjugated system (3g).[16]
A second conceivable mechanism for the conversion of
ꢀ
intermediate D into 3g could proceed by electrophilic C H
activation (Scheme 6),[6] possibly assisted by the carbonyl
Figure 1. Solid-state structure of [(Mes3P)AuCH2COCH3].
Scheme 6. Conceivable alternative route from D to G.
group as an additional ligand (H). Insertion of the alkyne to
give I and protodemetalation would deliver G. From this
point the mechanism would be the same as above. Recently,
Li et al. suggested a similar (chelate-like) assistance of a
ketone and the ester or amide as chelating ligands, no
additional base is needed.
The importance of these chelating groups is further
underlined by the substrates 6a and 6b, which contain keto
groups as less nucleophilic carbonyl groups (in comparison to
esters and amides in 1g–k). Reaction of the b-diketone 6a led
to the spiroketal 7;[21] With 6b only the isochromene
derivative 2l was obtained (Scheme 7). No dimers related to
3 were observed in either case.
ꢀ
neighboring phenolic hydroxy group for the C H activation
of a formyl group.[17]
Control experiments with substrates 4 and 5, which both
represent substructures of D, gave no conversion even in the
presence of 1g. Since 1g reacted as usual, the catalytic activity
of an intermediate gold species differing from the precatalyst
can be excluded for 4 and 5 as well. This proves the
importance of the additional coordinating groups: they
seem to be involved not only in the first step as the
nucleophile (A!B) but also as additional chelating ligands.
Crucial information regarding the mechanism then came
from attempts to recrystallize a [(Mes3P)AuX] catalyst from
acetone. In this situation the carbonyl compound was present
Scheme 7. Products obtained when there are keto groups in the side
chain.
in high concentration, and
a direct a-auration was
observed.[18] Single crystals of [(Mes3P)AuCH2COCH3] for a
crystal structure analysis were obtained (Figure 1).[19] In the
X-ray crystal structure the distinction between an acetate and
an acetone enolate was not possible, but the ESI mass
spectrum of the crystals in the positive-ion mode clearly
shows the protonated molecular ion at m/z 643 (acetate would
lead to m/z 645) and its fragmentation by loss of C3H6O (58)
to m/z 585 (with acetic acid 60 rather than 58 would be lost).
Since in D a vinylogous a position of a ketone is present, the
observation of the direct auration of acetone (which in fact is
the microscopic reverse of the proto-deauration, the last step
in many gold-catalyzed reactions)[2b] links the reactivity of 1 to
the Ito–Sawamura–Hayashi aldol reaction.[20] But in D,
because of the assistance of the carbonyl group of the
Overall, we have described the unexpected and unprece-
ꢀ
dented reaction of 1 to give 3, which must involve C H
activation, and we have presented experimental proof of the
direct auration of acetone. In the light of previous reports on
ꢀ
C H activation assisted by coordinating groups at higher
temperatures,[17] this indicates that gold-catalyzed C H
ꢀ
activation, when directed by proper coordination/chelation,
should generally proceed under very mild conditions. Future
work will address the further exploitation of this principle in
highly functionalized substrates.
Received: April 6, 2007
Published online: July 10, 2007
6186
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 6184 –6187

Angewandte
Chemie
ꢀ
[11] Z. Li, C.-J. Li, J. Am. Chem. Soc. 2005, 127, 3672 – 3673.
[12] A. S. K. Hashmi, Gold Bull. 2003, 36, 3 – 9.
[13] S. Ma, S. Yu, Z. Gu, Angew. Chem. 2006, 118, 206 – 209; Angew.
Chem. Int. Ed. 2006, 45, 200 – 203.
[14] C. Bruneau, Angew. Chem. 2005, 117, 2380 – 2386; Angew.
Chem. Int. Ed. 2005, 44, 2328 – 2334.
[15] M. R. Fructos, T. R. Belderrain, P. de FrØmont, N. M. Scott, S. P.
Nolan, M. M. Díaz-Requejo, P. J. PØrez, Angew. Chem. 2005,
117, 5418 – 5422; Angew. Chem. Int. Ed. 2005, 44, 5284 – 5288.
[16] For related isomerizations, see: A. S. K. Hashmi, M. C. Blanco,
E. Kurpejovic, W. Frey, J. W. Bats, Adv. Synth. Catal. 2006, 348,
709 – 713.
Keywords: alkynes · C H activation · gold · heterocycles ·
homogeneous catalysis
.
[1] a) G. Dyker, Angew. Chem. 2000, 112, 4407 – 4409; Angew.
Chem. Int. Ed. 1999, 38, 1698 – 1712; b) G. Dyker, Handbook of
C–H activation, 1st ed., Wiley-VCH, Weinheim, 2005.
[2] a) A. S. K. Hashmi, R. SalathØ, T. M. Frost, L. Schwarz, J.-H.
Choi, Appl. Catal. A 2005, 291, 238 – 246; For general reviews on
gold catalysis, see b) A. S. K. Hashmi, G. J. Hutchings, Angew.
Chem. 2006, 118, 8064 – 8105; Angew. Chem. Int. Ed. 2006, 45,
7896 – 7936; c) N. Krause, A. Hoffmann-Röder, Org. Biomol.
Chem. 2005, 3, 387 – 391.
[3] a) A. S. K. Hashmi, L. Schwarz, J.-H. Choi, T. M. Frost, Angew.
Chem. 2000, 112, 2382 – 2385; Angew. Chem. Int. Ed. 2000, 39,
2285 – 2288; b) G. Dyker, E. Muth, A. S. K. Hashmi, L. Ding,
Adv. Synth. Catal. 2003, 345, 1247 – 1252; c) A. S. K. Hashmi, L.
Grundl, Tetrahedron 2005, 61, 6231 – 6236.
[4] Z. Shi, C. He, J. Am. Chem. Soc. 2004, 126, 13596 – 13597.
[5] R.-V. Nguyen, X.-Q. Yao, D. S. Bohle, C.-J. Li, Org. Lett. 2005, 7,
673 – 675.
[6] R. Periana, C. J. Jones, D. Taube, V. Ziatdinov, R. Nielsen, J.
Oxgaard, W. Goddard III, Angew. Chem. 2004, 116, 4726 – 4729;
Angew. Chem. Int. Ed. 2004, 43, 4626 – 4629.
[7] a) N. Asao, K. Takahashi, S. Lee, T. Kasahara, Y. Yamamoto, J.
Am. Chem. Soc. 2002, 124, 12650 – 12651; b) G. Dyker, D.
Hildebrandt, J. Liu, K. Merz, Angew. Chem. 2003, 115, 4536 –
4538; Angew. Chem. Int. Ed. 2003, 42, 4399 – 4402.
[8] A. S. K. Hashmi, M. C. Blanco, E. Kurpejovic, W. Frey, J. W.
Bats, Adv. Synth. Catal. 2006, 348, 709 – 713.
[9] For a detailed discussion, see the Supporting Information.
[10] C. Nevado, A. M. Echavarren, Chem. Eur. J. 2005, 11, 3155 –
3164.
[17] R. Skouta, C.-J. Li, Angew. Chem. 2007, 119, 1135 – 1137; Angew.
Chem. Int. Ed. 2007, 46, 1117 – 1119.
[18] For an earlier example of the direct auration of acetone in the
presence of Ag2O as a base, see: A. N. Nesmeyanov, K. I.
Grandberg, V. P. Dyadchenko, D. A. Lemenovskii, E. G. Pere-
valova, Izv. Akad. Nauk SSSR Ser. Khim. 1974, 1206 – 1212;
CAN 81:49772.
[19] CCDC-638472 contains the supplementary crystallographic data
fort his paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[20] Y. Ito, M. Sawamura, T. Hayashi, J. Am. Chem. Soc. 1986, 108,
6405 – 6406.
[21] Comparable to: a) X. Li, A. R. Chianese, T. Vogel, R. H.
Crabtree, Org. Lett. 2005, 7, 5437 – 5440; b) A. Arcadi, S.
Di Giuseppe, F. Marinelli, E. Rossi, Adv. Synth. Catal. 2001,
343, 443 – 446; for related cyclizations of b-dicarbonyl com-
pounds and alkynes, see: c) S. T. Staben, J. J. Kennedy-Smith,
F. D. Toste, Angew. Chem. 2004, 116, 5464 – 5466; Angew. Chem.
Int. Ed. 2004, 43, 5350 – 5352.
Angew. Chem. Int. Ed. 2007, 46, 6184 –6187
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6187