Multiple oxidative dehydrogenative functionalization of arylacetaldehydes using molecular oxygen as oxidant leading to 2-oxo-acetamidines

Article abstract of DOI:10.1002/adsc.201100892

A novel copper-catalyzed, multiple oxidative dehydrogenative functionalization of arylacetaldehydes leading to 2-oxo-acetamidine compounds has been developed. This transformation is highly efficient with dissociation of six hydrogens including two sp

Full text of DOI:10.1002/adsc.201100892

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DOI: 10.1002/adsc.201100892
Multiple Oxidative Dehydrogenative Functionalization of
Arylacetaldehydes Using Molecular Oxygen as Oxidant Leading
to 2-Oxo-acetamidines
Chun Zhang,a Liangren Zhang,a and Ning Jiaoa,b,*
a
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of Pharmaceutical Sciences, Peking
University, Xue Yuan Rd. 38, Beijing 100191, Peopleꢀs Republic of China
Fax : (+86)-010-8280-5297; e-mail: jiaoning@bjmu.edu.cn
State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, Peopleꢀs Republic
b
of China
Received: November 17, 2011; Revised: January 26, 2012; Published online: April 19, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201100892.
Abstract: A novel copper-catalyzed, multiple oxida-
tive dehydrogenative functionalization of arylacetal-
dehydes leading to 2-oxo-acetamidine compounds
has been developed. This transformation is highly
efficient with dissociation of six hydrogens including
two sp C H and one sp C H bond activations.
This method not only provides an efficient ap-
proach to 2-oxo-acetamidine compounds, but also
offers a valuable mechanistic insight into this novel
copper catalysis.
issues. Herein, we describe a novel copper-catalyzed,
multiple oxidative dehydrogenative functionalization
of aryl acetaldehydes using molecular oxygen as the
oxidant leading to 2-oxo-aceamidines [Eq. (1)]. This
3
2
À
À
Keywords: copper; cross-coupling; dehydrogena-
tion; oxidation; oxygen
chemistry offers not only a novel approach to 2-oxo-
acetamidines via multiple dehydrogenations, but also
In the context of green and sustainable chemistry,[1] valuable mechanistic insights into this novel copper
À
oxidative C H functionalization has presented one of catalysis.
the most attractive and powerful strategies in organic
Compared to Pd-catalysis, the copper-catalyzed de-
synthesis.[2] In the past decade, significant contribu- hydrogenative C H functionalization for C C or
À
À
[3]
[4]
[5]
[6]
À
À
À
À
À
tions on the direct C B, C C, C N, C O,
carbon heteroatom bond formation with loss of two
C P and C Si constructions by dehydrogenative hydrogens is much less well known.[2] Li and co-work-
[7]
[8]
À
À
coupling via dissociation of two hydrogens or dehy- ers have significantly reported some copper-catalyzed
À
À
drogenative oxidation of a C H bond have been C C bond formations by their cross dehydrogenative
made. Despite these elegant advances, there is still coupling (CDC) reactions.[4a,11] The easy occurrence
room for innovation: (i) multiple oxidative dehydro- via a single electron transfer (SET) process in copper-
genative functionalization in one-step leading to com- catalysis would substantially offer some new types of
plicated structures with the formation multiple chemi- transformations and offer new functionalized prod-
cal bonds in one step is rare;[9] (ii) in contrast to stoi- ucts. Recently, some novel copper-catalyzed dehydro-
chiometric oxidants such as DDQ, PhIACTHUNTRGNE(UNG OAc)2, silver genative couplings via an SET process have been de-
or copper metal salts, or peroxide,[2] use of environ- veloped.[12] The azo compound synthesis with dissocia-
mentally friendly molecular oxygen as an ideal oxi- tion of 4 hydrogens has also been realized by copper
dant is still desirable;[10] (iii) mild conditions and high catalysis, in which an aniline radical cation is generat-
efficiency are being sought; (iv) the selectivities of de- ed by a copper-catalyzed SET.[13] We envisioned that
hydrogenative functionalization including chemo-, the aniline radical cations may also be trapped by al-
regio-, and enantioselectivity remain challenging dehydes or imines followed by dioxygen activation.
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Table 1. Copper-catalyzed oxidative dehydrogenative func-
tionalization of phenylacetaldehyde (1a) with 2a.[a]
When this reaction is performed under an atmosphere
of air, 3aa was obtained in 46% yield (entry 13,
Table 1). The reaction under argon did not work
(entry 14, Table 1).
Under these optimized conditions, the scope of sub-
stituted aldehydes was investigated (Table 2). Both
electron-rich and electron-deficient arylacetaldehydes
could be smoothly transformed into the desired prod-
ucts. Furthermore, substituents at different positions
of the arene group (para-, meta-, and ortho-positions)
Entry Catalyst
Solvent Additives
(equiv.)[b]
Yield
[%][c]
Table 2. Copper-catalyzed oxidative dehydrogenative func-
tionalization of different aldehydes (1) with (2a).[a]
1
2
3
4
5
6
7
8
CuBr
CuCl
CuOAc
CuBr2
toluene pyridine (2.0)
toluene pyridine (2.0)
toluene pyridine (2.0)
toluene pyridine (2.0)
83
82
80
37
73
78
56
35
CuACHTUNGTRENNUNG(OAc)2 toluene pyridine (2.0)
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
THF
DMF
pyridine (2.0)
pyridine (2.0)
toluene Na2CO3 (2.0)
toluene triethylamine (2.0) 22
9
10
11
12
13
14
toluene pyridine (3.0)
toluene pyridine (0.2)
toluene none
toluene pyridine (2.0)
toluene pyridine (2.0)
79
37
24
46[d]
0[e]
[a]
Reaction conditions: 1a (0.25 mmol), 2a (1.0 mmol), cata-
lyst (0.0125 mmol), solvent (2.5 mL), O2 (1 atm), 15 h.
Equivalents referred to 1a.
Isolated yields. Azo compounds were obtained as by-
products in these reactions and a trace mount of 2-oxo-2-
phenyl-N-p-tolylacetamide was detected.
[b]
[c]
[d]
[e]
The reaction was carried out under air (1 atm).
The reaction was carried out under argon (1 atm).
Interestingly,
2-oxo-2-phenyl-N,N’-di-p-tolylacet-
ACHTUNGTRENNUNGimidamide (3aa) was produced in the reaction of phe-
nylacetaldehyde (1a) with p-toluidine (2a) catalyzed
by copper salts (Table 1). The best efficiency was
achieved by using CuBr (5 mol%) as the catalyst in
the presence of pyridine (2.0 equiv.) in toluene under
dioxygen (1 atm) (83% yield, entry 1, Table 1). Azo
compounds and trace amounts of a-keto amides were
obtained as by-products in these reactions. Other
copper catalysts including Cu(II) salts gave low effi-
ciencies (entries 1–5, Table 1, and Supporting Infor-
mation).We then surveyed the effect of different sol-
vents. The reactions gave low yields respectively in
DMF, THF or other solvents (entries 1, 6, and 7,
Table 1, and Supporting Information). Further studies
indicated that base can promote this transformation,
and that 2.0 equivalents of pyridine is the optimal
amount. The efficiency decreased when other bases
or ligands, such as sodium carbonate, bipyridine, 1,10-
phenanthroline, TMEDA or triethylamine, were used
(entries 8–12, Table 1, and Supporting Information).
[a]
Standard reaction conditions: 1 (0.25 mmol), 2a (1 mmol),
CuBr (0.0125 mmol), pyridine (0.5 mmol), toluene
(2.5 mL), 608C, O2 (1 atm), 15 h.
Isolated yields.
[b]
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Multiple Oxidative Dehydrogenative Functionalization of Arylacetaldehydes
Table 3. Copper-catalyzed oxidative dehydrogenative func-
tionalization of 1a with dfferent anilines (2).[a]
halo-substituted products, which could be used for
further transformations. In addition, a heteroaryl-sub-
stituted acetaldehyde, 2-(benzofuran-2-yl)acetalde-
hyde (1j) was also tolerated in this transformation
generating 3ja in 60% yield. Unfortunately, alkyl al-
dehydes such as heptanal did not work under these
conditions.
The scope of the copper-catalyzed, multiple oxida-
tive dehydrogenative functionalization was further ex-
panded to a variety of substituted anilines 2 (Table 3).
These results indicated that anilines with both elec-
tron-donating and electron-withdrawing groups also
proceeded well with moderate to excellent yields. No-
tably, halogen-containing anilines, such as 4-choro-
and 4-bromoanilines, can be employed as substrates
in this methodology to provide the expected products
3af and 3ag in 88% and 83% yields, respectively.
Products from a copper-catalyzed Ullmann amination
reaction,[14] which usually requires strong base and
high temperature, resulting in the formation of new
À
C N bonds were not observed in these cases
(Table 3), neither in the case of 3fa nor 3ga (Table 2).
The structure of 3ag was further confirmed by single-
crystal X-ray analysis (see the Supporting Informa-
tion).
Interestingly, the multiple oxidative dehydrogena-
tive functionalization can be carried out employing
two different kinds of anilines producing unsymmetri-
cally substituted 2-oxo-acetamidines (Scheme 1). For
example, the para-, or meta-substituted aniline (2a or
2b) can reacted with phenylacetaldehyde (1a) and an-
[a]
Standard reaction conditions: 1a (0.25 mmol), 2 (1 mmol), other aniline (2h) smoothly with the formation of the
CuBr (0.0125 mmol), pyridine (0.5 mmol), toluene
(2.5 mL), 608C, O2 (1 atm), 15 h.
Isolated yields.
corresponding 2-oxo-acetamidines 4 and 5 in 48%
and 55% yields, respectively (Scheme 1). To test the
feasibility of a large-scale reaction, the reaction in-
volving 5 mmol of phenyl acetaldehyde 1a and aniline
2a (20 mmol) was investigated. The reaction produced
[b]
do not affect the efficiency. It is noteworthy that halo- 1.15 g of 3aa in 70% yield [Eq. (2)].
substituted arylacetaldehydes survived well leading to
Scheme 1. Synthesis of unsymmetrically substituted 2-oxo-acetamidines.
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Amidines are important units in biologically acti- action of 2-oxo-2-phenyl-N-p-tolylacetamide 7 and 2a
vate molecules, synthetic drugs or drug candidates.[15] under the standard reaction conditions was investigat-
Furthermore, they serve as useful precursors in a vari- ed. However, the desired product 3aa was not ob-
ety of functional group transformations.[16] For exam- tained with the complete recovery of 7 (100%) [Eq.
ple, a kind of complicated quinazolinone 6 could be (5)]. Moreover, 2-oxo-2-phenylacetaldehyde (8) and
easily constructed form 2-oxo-acetamidines as starting 2-oxo-2-phenylacetic acid (9) were not detected in the
material by the reported method[16a] [Eq. (3)].
reaction of 1a under the standard reaction conditions
The transformation of 1a and 2a in the presence of [Eq. (6)]. These results might exclude 7, 8 or 9 as the
18O2 (1 atm) generated 18O labeling product 18O-3aa key intermediate of this multiple oxidative dehydro-
in 82% yield [18O:16O=6.4:1 due to the oxygen ex- genative transformation.
change in the acidic conditions (see Supporting Infor-
On the basis of the above results, a plausible mech-
mation)]. This result indicates that the oxygen atom anism for the copper-catalyzed oxidative dehydrogen-
of the 2-oxo-acetamidine originated from molecular ative coupling is illustrated in Scheme 2 although the
dioxygen [Eq. (4), as determined by MS and HR-MS, mechanism is not completely clear yet. Aldehydes
see the Supporting Information]. Furthermore, the re- and anilines are initially dehydrated to form an imine
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Multiple Oxidative Dehydrogenative Functionalization of Arylacetaldehydes
Scheme 2. A proposed mechanism for the direct transformation.
(10) which could interconvert to an enamine (11). And the azo product was highly efficiently obtained
The intermediate 10 or 11 can be detected by GC-MS in the absence of the aldehyde patner.[13] These results
(see the Supporting Information). At the same time, maybe support the possibility of the cationic aniline
the Cu(I) salt is initially oxidized by molecular radicals (12). Subsequently, enaminyl radical cations
oxygen to form the more active Cu(II) in this reaction 13 would be generated under these oxidative condi-
system, which could be detected by EPR (see Fig- tions. Then the enaminyl radical cation 13 either
ure S8, Supporting Information). Then, a single-elec- reacts with a neutral aniline or an aniline radical
tron oxidation of anilines mediated by Cu(II) to the cation to form intermediates 14,[17] which can be
corresponding radical cations (12) occurs.[13] The simi- trapped by O2 generating superoxide radicals 15 as
lar reaction by CoACTHNUTRGNE(NUG OAc)2 catalysis gave a moderate the key intermediates. Finally, dismutation of 15 re-
yield (see Table S1, in the Supporting Information).
Figure 1. The electron paramagnetic resonance (EPR) spectra (X band, 9.7 GHz, room temperature) of (trace 1) a reaction
mixture in the presence of the radical trap DMPO (2.5·10À2 M) and (trace 2) a reaction mixture in the presence of the SOD
(2.5·10À3 M) and the radical trap DMPO (1.25·10À2 M).
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column (eluent: petroleum ether/ethyl acetate=20:1) to
afford 3aa as a yellow solid; yield: 67.9 mg (83%); mp 135–
1368C. 1H NMR (DMSO-d6, 400 MHz): d=7.79 (d, J=
7.2 Hz, 2H), 7.72 (brs, 2H), 7.60 (t, J=7.6 Hz, 1H), 7.47 (t,
J=7.6 Hz, 2H), 7.13 (brs, 2H), 6.83 (brs, 2H), 6.60 (brs,
2H), 3.34 (s, 1H), 2.26 (brs, 3H), 2.08 (brs, 3H); 13C NMR
(DMSO-d6, 100 MHz): d=192.3, 151.8, 145.8, 137.6, 134.5,
133.7, 131.4, 131.0, 129.2, 129.0, 128.97, 121.7, 119.4, 20.4,
20.2; IR (neat): n=3343.6, 2917.3, 1661.4, 1631.2,
sults in the desired 2-oxo-acetamidine 3 with the for-
mation of the hydroxyl radicals 16.[18]
To probe the mechanism of this transformation, we
tried to observe possible intermediates by EPR. Inter-
estingly, in the EPR spectra monitored with the addi-
tion of the radical trap 5,5-dimethyl-1-pyrroline N-
oxide (DMPO), the signals corresponding to DMPO-
OO(H) [see the ꢂaꢀ peaks in trace 1, Figure 1, which
are classical 12 peaks; the calculated hyperfine split-
tings are g0 (2.007), aN (15.4 G), ab (13.5 G), ag (2.6
818.4 cmÀ1
;
HR-MS (ESI): m/z=329.1645. calcd. for
C22H21N2O (M+H)+: 329.1648; 331.1692, calcd for
C22H21N218O (M+H)+: 331.1690.
H
H
G)], and to DMPO-O(H) [see the ꢂbꢀ peaks in trace
1, Figure 1, which are classical 4 peaks; the calculated
hyperfine splittings are g0 (2.007), aH (14.9 G)] have
been identified.[19] Furthermore, the above signals dis-
appeared with the addition of the superoxide dismu-
tase (SOD) (trace 2 in Figure 1). The EPR results
(for more details, see the Supporting Information) in-
dicate that the superoxide radicals 15 and the hydrox-
yl radical 16 (Scheme 2) as the key intermediates may
N’-(4-Methoxyphenyl)-2-oxo-2-phenyl-N-p-tolyl-
acetimidamide or N-(4-Methoxyphenyl)-2-oxo-2-
phenyl-N’-p-tolylacetimidamide; Typical Procedure
CuBr (2.9 mg, 0.02 mmol), 2-phenylacetaldehyde 1a (72 mg,
0.6 mmol), p-toluidine 2a (21.4 mg, 0.2 mmol), 4-methoxy-
AHCTUNGTRENNUNG
be involved in this kind of transformation. In addi- atm). The reaction mixture was vigorously stirred at 608C
for 15 h. After cooling down to room temperature and con-
centration under vacuum, the residue was purified by flash
chromatography on a short silica gel column (eluent: petro-
leum ether/ethyl acetate=25:1) to afford 4 as a yellow
liquid; yield: 33 mg (48%). H NMR (DMSO-d6, 400 MHz):
d=7.82–7.65 (m, 4H), 7.61 (t, J=7.4 Hz, 1H), 7.48 (t, J=
tion, the EPR results demonstrate that the hydroxyl
radical (16) is derived from the superoxide radicals
15, because the hydroxyl radical comes into existence
at the same time as the disappearance of 15 ruined by
SOD. These facts could prove that superoxide radical
intermediate (15) transforms to 3 through a dismuta-
tion process.
1
7.6 Hz, 2H), 7.17–7.11 (m, 1H), 6.90–6.82 (m, 2H), 6.61
(brs, 3H), 3.72–3.57ACTHNUGRTENUNG(m, 3H), 3.33 (s, 1H), 2.26–2.08 (m,
3H); 13C NMR (DMSO-d6, 100 MHz): d=192.6, 154.8,
In conclusion, we have demonstrated a novel
copper-catalyzed, multiple oxidative dehydrogenative
151.9, 145.9, 141.5, 134.5, 133.7, 131.4, 129.6, 129.2, 129.0,
functionalization of arylacetaldehydes under mild 128.6, 128.3, 127.8, 127.5, 122.6, 121.7, 120.9, 119.4, 114.5,
113.8, 55.2, 20.4, 20.2; IR (neat): n=2985.0, 1739.0, 1505.8,
1373.5, 1243.4 cmÀ1; HR-MS (ESI): m/z=345.1594, calcd.
for C22H21N2O2 (M+H)+: 345.1598.
conditions leading to 2-oxo-acetamidines. This trans-
formation is highly efficient with dissociation of six
3
2
À
À
hydrogens including two sp C H and one sp C H
bond activations. Furthermore, the usage of molecular
oxygen (1 atm) as oxidant with H2O as the by-product
under mild conditions makes this transformation very
green and practical. This method not only provides an
efficient approach to 2-oxo-acetamidine compounds,
which are useful precursors in a variety of functional
group transformations, but also offers a valuable
mechanistic insight into this novel copper catalysis.
Further studies to clearly understand the reaction
mechanism and the synthetic applications are ongoing
in our laboratory.
Acknowledgements
Financial support from Peking University, National Science
Foundation of China (No. 20872003) and National Basic Re-
search Program of China (973 Program 2009CB825300) is
greatly appreciated. We thank Prof. Jingfen Lu for helpful
discussion. We thank Zejun Xu in this group for reproducing
the results of 3ba, 3af and 5.
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