Iron-catalyzed C-C bond formation by direct functionalization of C-H bonds adjacent to heteroatoms

Article abstract of DOI:10.1002/anie.200802215

Iron/oxidant can do: Heteroatom-containing molecules are abundant in natural products, pharmaceuticals, and materials. It is highly desirable to synthesize these molecules and their derivatives by direct C-H functionalization. The novel title reaction provides a simple and efficient method to construct such molecules by using 1,3-dicarbonyl compounds (see scheme). (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200802215

Angewandte
Chemie
DOI: 10.1002/anie.200802215
Synthetic Methods
À
Iron-Catalyzed C C Bond Formation by Direct Functionalization of
C H Bonds Adjacent to Heteroatoms**
À
Zhiping Li,* Rong Yu, and Haijun Li
À
Transition-metal-catalyzed C H functionalization for the
atom- and step-economical synthesis of functional molecules
has attracted tremendous efforts in both academia and
industry. The advantages of this method are the high
efficiency, low cost, and minimal environmental impact.[1,2]
Heteroatom-containing molecules are abundant in natural
products, pharmaceuticals, and materials. It is highly desirable
to synthesize these molecules and their derivatives by direct
Transition-metal catalysts are widely used in organic
synthesis and exhibit high efficiency and selectivity in
chemical bond transformation. The numerous advantages of
iron catalysts make them highly attractive for chemical
synthesis from environmental and economic points of
view.[9] Iron catalysts are well-known catalysts for C H
À
bond oxidation[10] and Friedel–Crafts reactions.[11] Recently,
there have been efforts to develop the redox processes
À
À
À
C H functionalization. Metal carbene insertion into a C H
bond adjacent to an oxygen atom presents an efficient
synthetic approach to ether derivatives (Scheme 1, Meth-
involving iron catalysts for C C bond-forming reactions.
Various iron-catalyzed cross-coupling reactions,[12,13] carbo-
metalations,[14] cycloaddition reactions,[15] and substitution
reactions[16] have been successfully developed. However,
À
utilization of the redox properties of iron catalysts in C H
À
bond functionalization, especially in C C bond formation, is
still a challenge.[17] Herein we report direct functionalization
À
À
of C H bonds adjacent to heteroatoms, featuring C H
activation with an inexpensive and environmentally benign
Fe catalyst (Scheme 2). This method can generate various
functionalized molecules and is expected to have broad
applications in synthesis.
À
Scheme 1. Various methods of functionalization of C H bonds in
ethers.
À
Scheme 2. Iron-catalyzed functionalization of C H bonds.
2
od A).[3] The addition of carbon radicals to C(sp ) X bonds is
=
À
another useful synthetic tool for the formation of C C bonds
We began our explorations with THF (1a) and ethyl
benzoylacetate (2a) as model substrates to identify suitable
reaction conditions (Table 1). Moderate yields of desired
product 3a were obtained when FeCl2 and FeBr2 were used as
catalysts (Table 1, entries 1 and 2). FeCl3 was much less
effective for this transformation (Table 1, entry 3) and the
desired product was not observed when [Fe(acac)2](acac =
acetylacetonate), [Fe(acac)3], or [Fe(dbm)3](dbm = 1,3-
diphenyl-1,3-propanedione) were used (Table 1, entries 4–
6). Comparable yields of 3a were obtained when either
Fe(OAc)2 or [Fe2(CO)9]were used as catalysts (Table 1,
entries 7 and 8). The best result was achieved when 3 equiv-
alents of tert-butyl peroxide and 10 mol% of [Fe2(CO)9]were
employed (Table 1, entry 9). Other metals with CO ligands,
such as W and Cr, were much less effective catalysts (Table 1,
entries 10 and 11). Reagents such as tert-butyl hydroperoxide
and cumyl hydroperoxide were also effective oxidants
(Table 1, entries 12 and 13). However, the desired product
was not obtained when tert-butyl peroxybenzoate or hydro-
gen peroxide were used (Table 1, entries 14 and 15). More-
over, the desired product was not observed at room temper-
ature or in the absence of an iron catalyst (Table 1, entries 16
in organic synthesis (Scheme 1, Method B).[4] The groups of
Li[5] and Sames[6] reported C C bond formation by C H bond
activation adjacent to an oxygen atom (Scheme 1, Method C).
Furthermore, our group[7] and others[8] reported direct
À
À
À
functionalization of C H bonds adjacent to either a sulfur
or nitrogen atom. Although these methods are efficient for
C H functionalization, a practical and efficient method
toward such a transformation is still a challenge in synthetic
chemistry.
À
[*] Prof. Dr. Z. Li, R. Yu, H. Li
Department of Chemistry, Renmin University of China
Beijing 100872 (P.R. China)
Fax: (+86)10-6251-6444
E-mail: zhipingli@ruc.edu.cn
[**] We are grateful to the program for New Century Excellent Talents in
University, the Scientific Research Starting Foundation of RUC (to
Z.L.), and the NSFC (No. 20602038). We also thank Prof. Zhenfeng
Xi, Peking University, for helpful discussions and the supply of
chemicals and instruments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802215.
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Communications
Table 1: Optimization of reaction conditions.[a]
Table 2: Representative results.[a]
Entry
1
1
2
Cat. [mol%]
3
Yield [%][b]
Entry
Catalyst
Oxidant (equiv)
Yield [%][b]
1
2
3
4
5
6
7
8
FeCl2
FeBr2
FeCl3
tBuOOtBu (2)
tBuOOtBu (2)
tBuOOtBu (2)
tBuOOtBu (2)
tBuOOtBu (2)
tBuOOtBu (2)
tBuOOtBu (2)
tBuOOtBu (2)
tBuOOtBu (3)
tBuOOtBu (3)
tBuOOtBu (3)
tBuOOH (3)
PhMe2COOH (3)
PhCOOOtBu (3)
H2O2 (3)
tBuOOtBu (3)
tBuOOtBu (3)
tBuOOtBu (3)
52
64
5
1a
1a
1a
1a
1a
1a
2b: R3 =Ph,
R4 =Ph
10
10
10
10
10
20
3b 78
[Fe(acac)2]
[Fe(acac)3]
[Fe(dbm)3]
Fe(OAc)2
[Fe2(CO)9]
[Fe2(CO)9]
[W(CO)6]
[Cr(CO)6]
[Fe2(CO)9]
[Fe2(CO)9]
[Fe2(CO)9]
[Fe2(CO)9]
[Fe2(CO)9]
–
n.d.[c]
n.d.
n.d.
70
2
3
4
5
6
2c: R3 =Ph,
R4 =Me
3c 81(1:1)
3d 77(1:1)
3e 56(2:1)
3 f 53(2:1)
3g 72(1:1)
2d: R3 =Ph,
R4 =NHPh
2e: R3 =Me,
R4 =OEt
69
82
trace
trace
72
9
10
11
12
13
14
15
16[d]
17
18[e]
2 f: R3 =Me,
R4 =OtBu
2g: R3 =Me,
R4 =Oallyl
75
n.d.
n.d.
n.d.
trace
68
7
1b
1b
1b
2a
2b
2e
5
5
10
3h 83(1:1)
3i 54
3j 56(2:1)
[Fe2(CO)9]
8
9
[a] 1a (1 mL), 2a (0.25 mmol), catalyst (0.025 mmol, 10 mol%), reflux,
1 h, unless otherwise noted. [b] Yield of isolated product. [c] Not
detected by 1H NMR methods. [d] Room temperature for 24 h. [e] 1a
(10 mL), 2a (10 mmol), catalyst (0.5 mmol, 5 mol%). n.d.=not deter-
mined.
10[c]
1c
1d
2a
2a
2a
20
10
10
3k 83(1:1)
3l 90(1:1)
3m 88(1:1)
11[d]
and 17). Notably, 3a was still isolated in 68% yield when
10 mmol of 2a was used in 10 mL THF in the presence of
5 mol% of an iron catalyst (Table 1, entry 18).
12[d]
À
Subsequently, the scope of this C H transformation was
investigated, and some representative results are listed in
Table 2. Both cyclic ether derivatives 1a–1e and linear ether
derivatives 1 f–1h reacted smoothly with various dicarbonyl
substrates (2) to give the corresponding products (3) (Table 2,
entries 1–16). The results show that not only b-ketone esters,
but also 1,3-diketones and b-ketone amides reacted with ether
derivatives to give the desired products in good yields under
the standard reaction conditions. Although the reaction of
diethyl ether (1 f) and 2a gave desired product 3n in 73%
yield, 30 mol% of the iron catalyst was needed to completely
consume substrate 2a (Table 2, entry 13). We postulated that
the low reaction temperature was the main reason for the
required higher iron catalyst loading. Notably, sulfide and
amine groups could also be used in this novel iron-catalyzed
1e
1 f
13[c]
2a
2b
30
20
3n 73(2:1)
3o 52
14[c] 1 f
15[d]
1g
2a
2a
10
10
3p 75(2:1)
3q 82(1:1)
16[e]
1h
17
À
C H transformation under the standard reaction conditions.
The reaction of tetrahydothiophene (1i) or N,N-dimethylani-
line (1j) with 2 gave the desired products in good to excellent
yields (Table 2, entries 17–21). The various types of substrates
that can be used make the present transformation attractive
for future applications.
1i
2a
2b
2c
2e
10
10
10
10
3r 98(1:1)
3s 71
3t 68(1:1)
3u 74(1:1)
18
19
20
1i
1i
1i
21[e]
In addition, deuterated product [D]-3a was isolated in
80% yield when [D8]THF was used instead of THF [Eq. (1)].
The scrambling of deuterium into the other possible products
was not observed. Therefore, the formation of an iron–
carbene species was ruled out from this result.[18] Subsequent
kinetic isotopic effect (KIE) experiments were carried out by
1j
2a
10
3v 53
[a] 1 (1 mL), 2 (0.25 mmol), tBuOOtBu (0.75 mmol), reflux, 1 h, unless
otherwise noted. [b] Yield of isolated product reported; the ratios of two
diasteromers are reported in the parentheses. [c] Reaction time is 10 h.
[d] 1008C. [e] 808C.
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Chemie
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À
effective catalyst for the selective activation of C H bonds
À
adjacent to heteroatoms for subsequent C C bond formation.
Additional investigations (experimental and theorhetical)
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reaction are in progress.
Experimental Section
General procedure for 3: Ethyl benzoylacetate (2a; 0.25 mmol) was
added to a mixture of THF (1a; 1 mL) and [Fe2(CO)9](9.2 mg,
0.025 mmol) under a nitrogen atmosphere at room temperature, and
then tert-butyl peroxide (0.139 mL, 0.75 mmol) was added dropwise
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petroleum ether= 1:20). The fraction having an Rf = 0.3 (ethyl
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3a. The ratio of the two diasteromers was 1:1. 1H NMR: d = 8.05–8.01
(m, 4H), 7.62–7.55 (m, 2H), 7.50–7.44 (m, 4H), 4.74–4.64 (m, 2H),
4.46 (d, J = 9.0 Hz, 1H), 4.41 (d, J = 9.0 Hz, 1H), 4.17 (q, J = 7.2 Hz,
2 ” 2H), 3.92–3.69 (m, 4H), 2.28–2.15 (m, 2H), 1.99–1.84 (m, 4H),
1.57–1.45 (m, 2H), 1.18 (t, J = 6.9 Hz, 3H), 1.17 ppm (t, J = 6.9 Hz,
3H); 13C NMR: d = 193.5, 193.2, 167.8, 167.4, 136.7, 136.2, 133.7,
133.3, 128.7, 128.6, 128.5, 78.0, 77.6, 68.1, 68.0, 61.5, 61.3, 60.1, 59.2,
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Received: May 12, 2008
Revised: July 10, 2008
Published online: August 13, 2008
À
Keywords: C H activation · cross-coupling · heterocycles · iron ·
peroxides
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