Iron-facilitated direct oxidative C-H transformation of allyl arenes to alkenyl aldehydes

Article abstract of DOI:10.1016/j.tetlet.2011.04.041

A direct oxidative approach to alkenyl aldehydes from allyl arenes via allyl sp³ C-H functionalization was disclosed. An inexpensive iron catalyst was employed to facilitate this transformation. The mechanistic studies indicate that the cleavage of the allyl sp³ C-H bond is involved in the rate-determining step.

Full text of DOI:10.1016/j.tetlet.2011.04.041

Tetrahedron Letters 52 (2011) 3208–3211
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Tetrahedron Letters
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Iron-facilitated direct oxidative C–H transformation of allyl arenes to
alkenyl aldehydes
Teng Wang a,b, Shi-Kai Xiang b, Chong Qin b, Jun-An Ma a, Li-He Zhang b, Ning Jiao b,c,
⇑
a Department of Chemistry, Tianjin University, Tianjin 300072, China
b State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Xue Yuan Rd. 38, Beijing 100191, China
c State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
A direct oxidative approach to alkenyl aldehydes from allyl arenes via allyl sp3 C–H functionalization was
disclosed. An inexpensive iron catalyst was employed to facilitate this transformation. The mechanistic
studies indicate that the cleavage of the allyl sp3 C–H bond is involved in the rate-determining step.
Ó 2011 Elsevier Ltd. All rights reserved.
Article history:
Received 3 January 2011
Revised 28 March 2011
Accepted 11 April 2011
Available online 16 April 2011
Alkenyl aldehydes as versatile building blocks have been widely
used in organic synthesis.1 Their importance in chemistry and biol-
ogy has stimulated considerable attention from organic chemists
and encouraged the development of new synthetic strategies to
prepare these compounds.2 Although the selective allylic sp3 C–H
functionalization of simple allyl arenes has received considerable
attention,3,4 the direct approach to alkenyl aldehydes from allyl
arenes via allylic sp3 C–H functionalization has been rarely investi-
gated.5 On the other hand, iron catalyst has been a rising star in
catalysis due to its low price and environmentally benign features.6
Significantly, iron catalyzed sp3 C–H transformations for the for-
mation of C-heteroatom bonds have been recently disclosed but
in limited cases.7 We have recently disclosed an iron catalyzed di-
rect oxidative transformation of 1- or 3-allyl arenes or alkenes to
alkenyl nitriles through the cleavage of three C–H bonds (Eq. 1).8
During the optimization of the reaction conditions, traces of alke-
nyl aldehydes were detected. Inspired by this observation, we envi-
sioned that other nucleophiles such as H2O could attack the
generated allyl cations in situ to achieve versatile sp3 C–H func-
tionalization. Herein, we reported a novel iron facilitated direct
synthesis of alkenyl aldehydes from 1- or 3-allyl arenes through
C–H bonds functionalization (Eq. 2).
aldehyde by-products in our cyanation reaction,8 the FeCl2 cata-
lyzed reaction of 1-allylbenzene 1a with DDQ (2,3-dichloro-5,6-
dicyano-1,4-benzoquinone) as oxidant in the presence of 2.0 equiv.
of water was firstly investigated (Table 1, entry 1). To our delight,
the expected cinnamaldehyde 2a was obtained smoothly in 75%
yield (entry 1). Even with 5 mol % of FeCl2 loading, 2a was produced
in 66% yield (entry 9). Attempts of using other oxidants such as
dioxygen, PIDA, or BQ were not successful (entries 10–12, also see
Supplementary data). Other metal catalysts such as Cu salts, FeCl3,
or FeBr2 exhibited low efficiencies (entries 2–5). Solvents were also
investigated (entries 6–8). Only the reaction in acetonitrile gave 2a
in approximate yield (Table 1, entry 8).
The reaction scope of various allyl arenes was then investigated
with 10 mol % FeCl2 as catalyst (Table 2). Attractively, Z-propenyl-
benzene was highly stereoselectively converted into (E)-cinnamal-
dehyde 2a in 55% yield (Table 2, entry 2). This result indicated that
the (p-allyl) species would be involved in this transformation. Sub-
stitutes at different positions of the arene group (para-, meta-, and
ortho-position) did not affect the efficiencies (entries 5–7). It is
noteworthy that E-2e was obtained in high yield without the
detection of Z isomer (82%, entry 5). In addition, a heteroaryl
substituted propene, such as 1-allyl-2-thiophene (1j) provided 2j
in 58% yield (entry 10). Notably, 3,3-disubstituted propenes (1c)
are tolerated in this transformation leading to the corresponding
b-substituted cinnamaldehyde in moderate yield with two isomers
(entry 3). In comparison, 2,3-disubstituted propenes (1l) only gave
2l in 24% yield (entry 12). This result perhaps can be interpreted as
steric effect. A simple skipped diene (1q) did not work under these
optimized conditions.
On the basis of the observation of trace amount of alkenyl
-
H
C
ref. 8
N3
N
H
H
(1)
(2)
C
R
R
N3
R
R
R
[Fe]
or
R
O
C
H
H
C
DDQ
H2O
OH
R
H
H
This work
To investigate the mechanism, the transformation of 1a was
tested under 18O2 atmosphere. However, 18O labeling product
18O-2a was not detected (Eq. (4)). Further investigation in the pres-
ence of H2O18 (2.0 equiv.) indicates that the oxygen atom of the
cinnamaldehyde 2a originated from water (Eq. (5)), determined
by HRMS, see Supplementary data).
⇑
Corresponding author. Tel./fax: +86 10 8280 5297.
E-mail address: jiaoning@bjmu.edu.cn (N. Jiao).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.041

T. Wang et al. / Tetrahedron Letters 52 (2011) 3208–3211
3209
Table 1
Direct transformation of allylbenzene 1a to cinnamaldehyde 2aa
catalyst (10 mol %)
CHO
H2O (2.0 equiv)
Oxidant (2.3 equiv)
Solvent, 60 °C, 2 h
1a
2a
Entry
Catalyst (mol%)
Solvent
Oxidant
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
FeCl2 (10)
FeBr2 (10)
FeCl3 (10)
CuCl (10)
CuBr (10)
FeCl2 (10)
FeCl2 (10)
FeCl2 (10)
FeCl2 (5)
FeCl2 (10)
FeCl2 (10)
FeCl2 (10)
None
DCE
DCE
DCE
DCE
DCE
THF
DMF
CH3CN
DCE
DCE
DCE
DCE
DCE
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
BQ
75
71
73
45
49
21
0
74
66
0
PIDA
O2
DDQ
0
0
42
a
Reaction conditions: 1a (0.5 mmol) and H2O (1.0 mmol), catalyst and oxidant (1.2 mmol) were added in dry DCE (3 mL)
with stirring at 60 °C under air for 2 h.
b
Isolated yield.
Table 2
Iron-facilitated oxidative transformation of 1- or 3-allyl arenes 1 to alkenyl aldehydes 2a
FeCl2 (10 mol %)
H2O (2.0 equiv)
CHO
R
DDQ (2.3 equiv)
DCE, 60 °C, 2 h
R
1
2
Entry
1
2
Yieldb (%)
1a
1b
2a
CHO
CHO
1
2
75
55
Ph
Ph
Ph
3
51c
2c
1c
Ph
MeO
Ph
R
2d
1d
4
50d
CHO
R
5
6
7
8
9
R = o-Me
R = m-Me
R = p-Me
R = p-Cl
1e
1f
1g
1h
1i
2e
2f
2g
2h
2i
82
55
56e
76
R = p-OMe
61f
1j
10
11
58
2j
CHO
S
S
CHO
61g
1k
2k
CHO
12
13
24
0
Bn
2l
CHO
1l
CH2
3
1m
2m
a
b
c
d
e
f
Standard conditions: 1 (0.5 mmol), H2O (1.0 mmol), FeCl2 (0.05 mmol) and DDQ (1.2 mmol) was added in dry DCE (3 mL) with stirring at 60 °C under air for 2 h.
Isolated yield.
E/Z = 3:1, as determined by 1H NMR analysis.
E/Z = 6:1, as determined by 1H NMR analysis.
E/Z = 3:1, as determined by 1H NMR analysis.
E/Z = 5:1, as determined by 1H NMR analysis.
E/Z = 3:1, as determined by 1H NMR analysis.
g

3210
T. Wang et al. / Tetrahedron Letters 52 (2011) 3208–3211
O
O
Cl
Cl
CN
CN
1a, or 1b
Fe(II)
OH
+
CHO
Ph
2a
SET
Cl
Cl
CN
DDQ
or
H2O
CN
OH
O
OH
OH
Cl
CN
OH
and/or
+
Ph
OH
Ph
Ph
3a
A
Cl
CN
Fe(III)
4
Cl
Cl
CN
CN
O
SET
H2O
Fe(II)
+
Ph
B
Scheme 1. A proposed mechanism for the oxidative transformation.
FeCl2 (10%)
H2O (2.0 eq)
ly, the desired product 2a is subsequently formed through the fol-
lowed oxidation of 3a and 4a by the iron assisted DDQ oxidative
system.10
CHO
ð3Þ
DDQ (2.3 eq)
18O2 , DCE
1a
2a
H
D
standard conditions
H/D
Ph
CHO
H
FeCl2 (10%)
CH18O
ð7Þ
ð8Þ
72 %
kH/kD = 2.3:1
H218O (2.0 eq)
ð4Þ
ð5Þ
ð6Þ
DDQ (2.3 eq)
N2 , DCE
18O-2a
FeCl2 (10 mol%)
H2O (2.0 eq)
1a
CHO
OH
DDQ (1.3 eq)
FeCl2 (10 mol%)
DDQ (1.1 eq)
CHO
OH
DCE
31 % of 1a recovered
2a, 45 %
3a, 0 %
1a
DCE
3a
OH
2a, 94 %
In conclusion, we have demonstrated a novel iron catalyzed di-
rect oxidative transformation of allyl arenes to the corresponding
alkenyl aldehydes at mild conditions. The mechanistic studies indi-
cate that the cleavage of the allyl sp3 C–H bond is involved in the
rate-determining step. This observation provides a new synthetic
tool for constructing synthetically and medicinally important alke-
nyl aldehydes. Further studies on the synthetic applications and
the allyl sp3 C–H functionalization with other nucleophiles are
ongoing in our group.
O
FeCl2 (10 mol%)
DDQ (1.1 eq)
CHO
DCE
4a
2a, 68%
5a, 12%
Moreover, the conversion from (E)-3-phenylprop-2-en-1-ol 3a
into the desired product 2a with 1.1 equiv. of DDQ produced has
been proved (94%, Eq. (5)). The reaction of 1-phenylprop-2-en-1-
ol (4a) under the same conditions produced 2a in 68% yield with
the detection of 12% 1-phenylprop-2-en-1-one (5a) (cf. Eq. (5)
and (6)).
Acknowledgments
Furthermore, the intra-molecular kinetic isotopic effect was
established for the methylene C–H bond of allybenzene with kH/
kD = 2.3 (Eq. (7)). In addition, the reaction of 1a was carried out
employing 1.3 equiv of DDQ as oxidant. Interestingly, 2a instead
of (E)-3-phenylprop-2-en-1-ol 3a was obtained with 1a (31%)
recovered (Eq. (8)). It suggests dehydrogenation of 3a with DDQ
is rapid and thermodynamically favorable. All of these results indi-
cate that the cleavage of the allyl sp3 C–H bond is involved in the
rate-determining step.
On the basis of the above results, the hypothesized mechanism
of this transformation was shown in Scheme 1. Initially, allyl–
arene 1a, or 1b undergoes the iron-assisted single-electron-trans-
fer (SET) oxidation with DDQ9 to produce the corresponding allyl
radical A, which could be further oxidized to the allyl cation B.
Then stereoselective substitution reaction of allyl cation B by water
generates (E)-3-phenylprop-2-en-1-ol (3a) and/or 1-phenylprop-
2-en-1-ol (4a). In some cases, trace of corresponding ketones 5
were detected, which is concordant with the result of Eq. (6). Final-
Financial support from Peking University, National Science
Foundation of China (Nos. 20702002, 20872003) and National
Basic Research Program of China (973 Program 2009CB825300) is
greatly appreciated.
Supplementary data
Supplementary data (Experimental details and NMR spectra.
This material is available.) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2011.04.041.
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