FeCl2-catalyzed selective C-C bond formation by oxidative activation of a benzylic C-H bond

Article abstract of DOI:10.1002/anie.200701782

(Chemical Equation Presented) Any old iron: Readily available and non-toxic FeCl₂ effectively catalyzes C-C bond formation by oxidative activation of benzylic C-H bonds in the presence of tert-butyl peroxide as a stoichiometric oxidant (see sch

Full text of DOI:10.1002/anie.200701782

Angewandte
Chemie
DOI: 10.1002/anie.200701782
À
C C Bond Formation
À
FeCl2-Catalyzed Selective C C Bond Formation by Oxidative
À
Activation of a Benzylic C H Bond**
Zhiping Li,* Lin Cao, and Chao-Jun Li*
À
The selective and efficient functionalization of C H bonds
has attracted much attention from both academia and
industry in the past decade,[1] and various methods, especially
ones based on transition-metal catalysts, have been developed
and applied in the synthesis of complex molecules.[1,2]
Although great progress has been made in this area, new
as the Gif[6] and Fenton reactions[7] are some of the best
À
known examples of C H functionalization. However, iron-
À
À
catalyzed activation of C H bonds followed by C C bond
formation is virtually unknown.[8] Herein, we report an FeCl2-
À
catalyzed oxidative activation of a benzylic C H bond which
À
is followed by a cross-coupling reaction to form a C C bond
(Scheme 2).[5,9,10]
À
processes for the construction of C C bonds starting from
À
C H bonds are still highly desirable.
The synthesis of benzylic derivatives from starting mate-
À
rials containing a benzylic C H bond is well known
(Scheme 1, paths Aand B), although multistep syntheses
are still commonly used. Alternatively, various catalytic
methods have been developed recently that allow the direct
À
functionalization of benzylic C H bonds (Scheme 1,
À
Scheme 2. Iron-catalyzed functionalization of benzylic C Hbonds.
path C).[3,4]
There are two main challenges in this type of reaction,
namely to avoid homocoupling and to use a catalytic amount
of metal catalyst. As a starting point, we chose diphenyl-
methane (1a) and benzoylacetone (2a) as standard substrates
to investigate suitable reaction conditions for the desired
reaction (Table 1). The desired product (3a) was isolated in
11% yield with CoCl2 as the catalyst and tert-butyl hydrogen
À
Scheme 1. Various methods for the functionalization of benzylic C H
bonds.
Table 1: Optimization of the reaction conditions.[a]
Although transition-metal catalysts are widely used in
organic synthesis, the use of more readily available and
nontoxic catalysts instead of expensive and sensitive catalysts
is highly desirable. The numerous advantages of iron make it
highly attractive as a catalyst or reagent for chemical syn-
thesis.[5] Iron-catalyzed C H bond oxidations in systems such
Entry Catalyst
(mol%)
Oxidant
(equiv)
T [8C] t [h] Yield [%][b]
À
1
2
3
4
5
6
7
8
9
CoCl2 (10)
CuBr/CoCl2 (10/10) TBHP (2)
TBHP (2)
100
100
100
80
80
80
5
5
5
8
8
8
8
8
8
8
8
8
11
30
[*] Prof. Dr. Z. Li, L. Cao
n.d.[c]
46
Department of Chemistry, Renmin University of China
Beijing 100872 (China)
Fax: (+86)10-6251-6444
CuBr (10)
FeCl2 (20)
FeCl2 (20)
FeCl2 (10)
FeCl2 (20)
FeCl2 (20)
FeBr2 (20)
FeCl3 (20)
Fe(OAc)2 (20)
TBHP (2)
TBHP (2)
tBuOOtBu (2)
tBuOOtBu (2)
PhCOOOtBu (2) 80
tBuOOtBu (1)
tBuOOtBu (2)
tBuOOtBu (2)
tBuOOtBu (2)
tBuOOtBu (2)
tBuOOtBu (1)
tBuOOtBu (2)
tBuOOtBu (2)
66
47
E-mail: zpli@chem.ruc.edu.cn
n.d.[c]
64
Prof. Dr. C.-J. Li
80
80
80
80
80
RT
RT
80
Department of Chemistry, McGill University
801 Sherbrooke Street West, Montreal QC H3A 2K6 (Canada)
Fax: (+1)514-398-3739
49
56
10
11
n.d.[c]
46
E-mail: cj.li@mcgill.ca
12[d] FeCl2 (20)
[**] We are grateful to the Scientific Research Starting Foundation of the
Renmin University of China (to Z.L.) and the National Natural
Science Foundation of China (grant no. 20602038). We also thank
the Canada Research Chair (Tier I) foundation (to C.J.L.), and Prof.
Zhenfeng Xi (Peking University) for helpful discussions and the
supply of chemicals and instruments.
13
14
15
FeCl2 (20)
FeCl2 (20)
–
36 65
36 80
8
n.d.[c]
[a] 1-Benzoylacetone (0.5 mmol), diphenylmethane (6.0 mmol), and
TBHP (5–6m in decane) under nitrogen, unless otherwise noted.
[b] Yield of isolated product. [c] Not detected by NMR spectroscopy.
[d] Only 1.0 mmol of diphenylmethane was used.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 6505 –6507
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6505

Communications
peroxide (TBHP) as the oxidant (Table 1, entry 1). The yield
Various compounds were tested as substrates for the
benzylic alkylation reaction under the optimized conditions.
of 3a increased to 30% when CuBr and CoCl2 were used as
co-catalysts, while CuBr alone was not effective under the
same reaction conditions (Table 1, entries 2 and 3, respec-
tively). Further investigations showed that FeCl2 is a more
effective catalyst (Table 1, entry 4). The use of tert-butyl
peroxide instead of TBHP as an oxidant increased the
product yield to 66% (Table 1, entry 5). Other iron salts
were either less effective than FeCl2 or inactive (Table 1,
entries 9–11).[11]
The reaction was also found to proceed efficiently at room
temperature, and 3a was isolated in up to 80% yield on
extending the reaction time (Table 1, entries 13 and 14).[12] All
the above coupling reactions are clean: only 1a, 2a, and the
product (3a) are observed when the reactions are stopped,
although a trace amount of benzophenone was also found on
occasions.
À
The benzylic C H bonds of both more activated diaryl
methanes (Table 2, 1a–1e) and less activated cyclic substrates
(Table 3, 1 f and 1j) were found to react smoothly with 1,3-
dicarbonyl compounds under these conditions. b-Ketone
esters and a b-ketone amide were also found to react with
diphenylmethane to give the desired products in good yields
(Table 2, entries 1–4). Alow yield was obtained when a tert-
butyl-substituted 1,3-diketone was used (Table 2, entry 5),
probably because of the steric effects of the tert-butyl
substituent. Whereas no obvious electronic effect was
observed with 1b, which bears an electron-withdrawing
para-fluoro group, or 1c, which bears an electron-donating
para-methoxy group, a very low yield was obtained with the
ortho-substituted substrate 1e (entries 6–8, respectively, in
Table 2). 10,11-Dihydro-5H-dibenzo[a,d]cycloheptene (1e)
was selectively transformed into 3j (Table 2, entry 9).
[a]
À
Table 2: Alkylation of diaryl C Hbonds.
The cyclic benzylic compounds 1 f and 1j gave the
expected oxidative coupling products in good yields
(Table 3), although the desired products were obtained as
an approximately 1:1 mixture of diastereomers from the
Entry
Diaryl
Product
Yield [%][b]
substrate
1
68
[a]
À
Table 3: Alkylation of cyclic benzylic C Hbonds.
2
3
4
5
1a
1a
1a
1a
65
65
84
25
Entry
Cyclic
substrate
Product
Yield [%][b]
71 (1.2:1)
1
2
3
4
5
6
1 f
1 f
1 f
87 (1:1)
78 (1:1)
61
6
7
8
9
66
64
40
67
85 (1.2:1)
1j
1j
60
7
80 (1:1)
[a] Conditions:
1 (6.0 mmol), 2 (0.5 mmol), tert-butyl peroxide
[a] Conditions:
1
(6.0 mmol),
2
(0.5 mmol), tert-butyl peroxide
(1.0 mmol), FeCl2 (0.1 mmol), 808C, 8 h. [b] Yield of isolated product.
(1.0 mmol), FeCl2 (0.1 mmol), 808C, 8 h. [b] Yield of isolated product.
The ratio of the two diastereomers is given in parentheses.
6506 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 6505 –6507

Angewandte
Chemie
À
reaction with unsymmetrical dicarbonyl compounds (Table 3,
entries 1–3, 5, and 7).
Keywords: C Hactivation · cross-coupling · iron · peroxides ·
redox chemistry
.
À
Atentative mechanism for the iron-catalyzed C C bond
À
formation of benzylic C H bonds is shown in Scheme 3.
[1] K. Godula, D. Sames, Science 2006, 312, 67 – 72.
[2] Handbook of C-H Transformations (Ed.: D. Dyker), Wiley-
VCH, Weinheim, 2005.
[3] Intramolecular reactions: a) H. Ren, P. Knochel, Angew. Chem.
2006, 118, 3541 – 3544; Angew. Chem. Int. Ed. 2006, 45, 3462 –
3465; b) G. B. Bajracharya, N. K. Pahadi, I. D. Gridnev, Y.
Yamamoto, J. Org. Chem. 2006, 71, 6204 – 6210; carbenoid-
induced insertion: c) H. M. L. Davies, S. J. Hedley, B. R. Bohall,
J. Org. Chem. 2005, 70, 10737 – 10742; d) H. M. L. Davies, Q.
Jin, P. Ren, A. Y. Kovalevsky, J. Org. Chem. 2002, 67, 4165 –
4169; Ir-catalyzed reactions: e) Y. Matsuo, A. Iwashita, E.
Nakamura, Chem. Lett. 2006, 858 – 859.
[4] For the “cation pool” method of electrochemistry, see: M.
Okajima, K. Soga, T. Nokami, S. Suga, J. Yoshida, Org. Lett.
2006, 8, 5005 – 5007.
[5] Reviews: a) C. Bolm, J. Legros, J. Le Paih, L. Zani, Chem. Rev.
2004, 104, 6217 – 6254; b) A. Furstner, R. Martin, Chem. Lett.
2005, 34, 624 – 629.
[6] Reviews: a) P. Stavropoulos, R. Celenligil-Cetin, A. E. Tapper,
Acc. Chem. Res. 2001, 34, 745 – 752; b) D. H. R. Barton, D.
Doller, Acc. Chem. Res. 1992, 25, 504 – 512.
[7] Reviews: a) C. Walling, Acc. Chem. Res. 1998, 31, 155 – 157;
b) P. A. MacFaul, D. D. M. Wayner, K. U. Ingold, Acc. Chem.
Res. 1998, 31, 159 – 162.
Scheme 3. A tentative mechanism for the FeCl2-catalyzed benzylic
alkylation.
[8] There is only one report involving photolytic conditions: W. D.
Jones, G. P. Foster, J. M. Putinas, J. Am. Chem. Soc. 1987, 109,
5047 – 5048.
In summary, we have developed an efficient method for
À
the construction of a C C bond by an FeCl2-catalyzed
À
functionalization of benzylic C H bonds. The reaction has
[9] Iron-catalyzed cross-coupling reactions: a) T. Nagano, T. Hay-
ashi, Org. Lett. 2004, 6, 1297 – 1299; b) A. Fürstner, A. Leitner,
M. Mendez, H. Krause, J. Am. Chem. Soc. 2002, 124, 13856 –
13863; c) M. Nakamura, K. Matsuo, S. Ito, E. Nakamura, J. Am.
Chem. Soc. 2004, 126, 3686 – 3687; d) I. Sapountzis, W. Lin, C. C.
Kofink, C. Despotopoulou, P. Knochel, Angew. Chem. 2005, 117,
1682 – 1685; Angew. Chem. Int. Ed. 2005, 44, 1654 – 1657; e) K.
Itami, S. Higashi, M. Mineno, J. Yoshida, Org. Lett. 2005, 7,
1219 – 1222; f) L. K. Ottesen, F. Ek, R. Olsson, Org. Lett. 2006, 8,
1771 – 1773; g) K. Bica, P. Gaertner, Org. Lett. 2006, 8, 733 – 735;
h) J. Kischel, K. Mertins, D. Michalik, A. Zapf, M. Beller, Adv.
Synth. Catal. 2007, 349, 865 – 870.
À
the following advantages: 1) C C bonds can be formed
directly from C H bonds; 2) it proceeds under mild reaction
conditions; and 3) it uses inexpensive iron as a catalyst.
Further studies on the scope, mechanism, and synthetic
applications of this reaction are in progress.
À
Experimental Section
General procedure for the synthesis of products 3: Diphenylmethane
(1 mL, 6.0 mmol) was added to a mixture of 1-benzoylacetone (81 mg,
0.5 mmol) and FeCl2 (12.6 mg, 0.1 mmol) under nitrogen at room
temperature and tert-butyl peroxide (0.188 mL, 1.0 mmol) was then
added dropwise. The resulting mixture was stirred at room temper-
ature for 36 h or at 808C for 8 h. The resulting solid was diluted with
dichloromethane and purified by flash column chromatography on
silica gel with dichloromethane/petroleum ether (2:1) as eluent. The
band that eluted with Rf = 0.5 was collected to give the desired
[10] Baran and co-workers have recently reported oxidative enolate
coupling reactions in the presence of a stoichiometric amount of
FeIII or CuII (2 equiv) as the oxidant: a) P. S. Baran, M. P.
DeMartino, Angew. Chem. 2006, 118, 7241 – 7244; Angew. Chem.
Int. Ed. 2006, 45, 7083 – 7086; b) P. S. Baran, N. B. Ambhaikar,
C. A. Guerrero, B. D. Hafensteiner, D. W. Lin, J. M. Richter,
ARKIVOC 2006, 310 – 325.
[11] Other iron salts, such as FeI2, FeS, Fe(OEt)3, Fe2O3, Fe-
(TMHD)3, and Fe(DBM)3 (TMHD = 2,2,6,6-tetramethyl-3,5-
heptanedionato, DBM = dibenzoylmethanato) were found to
be inactive under the same conditions.
[12] Various solvents (CH3CN, dmso, thf, CH2Cl2, CHCl3, dmf, Et2O,
toluene, etc.) were also tested in the reaction of 2 equiv of 1a
with dibenzoylmethane under the same reaction conditions at
room temperature. The desired product (3b) was isolated in only
about 15% yield in CHCl3 or Et2O. No product was isolated with
the other solvents.
1
product 3a. M.p. 149.8–150.78C; H NMR (300 MHz, CDCl3, TMS):
d = 7.95 (d, J = 7.8 Hz; 2H), 7.53–7.03(m; 13H), 5.62 (d, J = 12.0 Hz;
1H), 5.10 (d, J = 12.0 Hz; 1H), 2.04 ppm (s; 3H); 13C NMR
(75.4 MHz, CDCl3, TMS): d = 203.0, 194.2, 141.7, 141.2, 136.9, 133.6,
129.0, 128.7, 128.6, 128.1, 127.7, 127.1, 126.7, 68.9, 51.5, 27.8 ppm.
Received: April 23, 2007
Published online: July 25, 2007
Angew. Chem. Int. Ed. 2007, 46, 6505 –6507
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 6507