Metal-free, organocatalytic cascade formation of C-N and C-O bonds through dual sp3 C-H activation: Oxidative synthesis of oxazole derivatives

Article abstract of DOI:10.1039/c2cc15813b

An organocatalytic cascade reaction that involves the formation of C-N, C-O and CN bonds in one process via dual sp³ C-H activation has been developed. This protocol affords a facile metal-free methodology for the synthesis of oxazole derivatives in air under mild conditions.

Full text of DOI:10.1039/c2cc15813b

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COMMUNICATION
Metal-free, organocatalytic cascade formation of C–N and C–O bonds
through dual sp3 C–H activation: oxidative synthesis of oxazole derivativesw
Jin Xie,a Honglai Jiang,a Yixiang Chenga and Chengjian Zhu*ab
Received 20th September 2011, Accepted 23rd November 2011
DOI: 10.1039/c2cc15813b
An organocatalytic cascade reaction that involves the formation
Q
activation has been developed. This protocol affords a facile
metal-free methodology for the synthesis of oxazole derivatives
in air under mild conditions.
to forge C–N, C–O and CQN bonds in one process through
dual sp3 C–H functionalization, which affords a facile metal-
free approach for the synthesis of oxazole derivatives.
3
of C–N, C–O and C N bonds in one process via dual sp C–H
In our initial study, the reaction of ethyl acetoacetate 1a
with benzylamine 2a was selected as a model reaction. The
optimized results are summarized in Table 1. Initially, n-Bu4NI
as an organocatalyst and TBHP as an oxidant could initiate
the reaction at room temperature. To our delight, when the
reaction was performed at 40 1C, it resulted in a satisfactory
yield of 67% (entry 1). Upon further increasing the temperature,
a slightly decreased yield was obtained. Among the catalysts
screened, we found n-Bu4NI was the most effective (entries 1–5).
It should be noted that the cascade reaction did not occur in
place of n-Bu4NI with n-Bu4NCl or n-Bu4NBr, which indicated
that the iodide was necessary for the reaction (entries 2 and 3).
The control experiment also demonstrated that 3a could not be
formed in the absence of a catalyst (entry 6). Then, different
C–H bond activations, especially sp3 C–H bond activations,
have attracted considerable attention in recent years.1 Avoiding
prefunctionalization of the substrates, they are more valuable
and straightforward than traditional synthetic strategies.
However, there is one major drawback, that is, most of the
reported sp3 C–H bond activations were restricted to the metal-
mediated approaches.1 Very recently, tetra-alkylammonium
iodide catalysts were found highly effective to replace transition-
metal catalysts.2 Mainly because the low valence iodide com-
pounds could in situ generate the hypervalent iodine intermediate
in the presence of oxidants.3 Although some excellent results
about C–O bond formations have been achieved with tetra-
alkylammonium iodide catalysts,2a–d iodide catalytic C–N
bond formations through sp3 C–H activation have not been
placed a high value.3c,4
Table 1 Optimization of the cascade sp3 C–H activation reaction
conditionsa
Cascade reaction is one of the most powerful, efficient and
atom economical methodologies in contemporary organic
synthesis.5 It usually avoids multiple processes, time-consuming
and the purification of intermediates. Thus, we focused our
attention on the metal-free catalytic cascade sp3 C–H bond
activations. The oxazole moieties are significant structures in
many biologically natural products, such as neooxazolomycin,6a
diazonamide A6b and ulapualide A.6c To the best of our
knowledge, the available reports on catalytic synthesis of
oxazole derivatives were mainly mediated by transition metals.7
The development of an effective organocatalytic protocol for
construction of oxazoles in a cascade C–H activation manner
remains a challenge at the forefront of synthetic chemistry.
Herein, we wish to disclose an organocatalytic cascade reaction
Entry Catalyst
Solvent Oxidantb
Time/h Yieldc (%)
1
2
3
n-Bu4NI EtOAc
n-Bu4NCl EtOAc
n-Bu4NBr EtOAc
TBHP
TBHP
10
24
24
10
10
24
8
67
0
0
TBHP
TBHP
TBHP
TBHP
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
4
NaI
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
DCE
45
36
0
70
32
nd
61
38
o10
27
5
6
I2
—
7
n-Bu4NI
n-Bu4NI
n-Bu4NI
n-Bu4NI
n-BuN4I
n-BuN4I
n-BuN4I
8d
9e
10f
11
12
13
8
6
6
8
8
8
DMF
MeCN
a State Key Laboratory of Coordination Chemistry,
School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, P. R. China. E-mail: cjzhu@nju.edu.cn
b State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, P. R. China
w Electronic supplementary information (ESI) available: The control
experimental details and the characterization data for the products.
See DOI: 10.1039/c2cc15813b
a
Reaction conditions: ethyl acetoacetate 1a (0.15 mmol), benzylamine
2a (0.3 mmol), catalyst (20 mol%), oxidant (4.0 equiv.), solvent
b
(1.0 mL), 40 1C. TBHP = 5.5 M tert-butyl hydroperoxide in decane;
H2O2 = 30% hydroperoxide in water; T-HYDRO = 70% tert-butyl
c
d
hydroperoxide in water. Isolated yields. 1.0 equiv. benzylamine
e
was used. Acetic acid (20 mol%) was added as an additive.
f
BF3ÁEt2O (20 mol%) was added as an additive.
c
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Chem. Commun., 2012, 48, 979–981 979

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oxidants were investigated. It was important to find that when
T-HYDRO was used as an oxidant instead of TBHP, the yield
of 3a can be improved to 70% (entry 7). This suggested that a
small amount of water was beneficial to the reaction. Decreasing
the amount of 2a to 1.0 equiv., a lower yield was obtained
(entry 8). It was reported that acidic additives favoured the
C–N bond formation in oxidative condition.2e–f Surprisingly,
when HOAc or BF3ÁEt2O was used as an additive, a less
satisfactory yield was obtained (entries 9 and 10). Finally,
different solvents were examined. It was found that EtOAc
afforded the best result, and DCE, DMF or MeCN led to low
yield (entry 7, entries 11–13). From screening of various
conditions, the optimal reaction should be catalyzed by
20 mol% n-Bu4NI with 4.0 equiv. T-HYDRO as an oxidant
in EtOAc at 40 1C under air.
With the optimized reaction conditions in hand, we investigated
the scope of this protocol between various 1,3-dicarbonyl
compounds and different benzylamines. The experimental
results are listed in Table 2. First, a series of 1,3-dicarbonyl
compounds were examined in the cascade sp3 C–H activation
reaction. When the ethyl acetoacetate was switched to methyl
or t-butyl acetoacetate, a satisfactory yield was obtained
(entries 1–3). Moreover, b-keto esters with different alkyl
substituents can also react with benzylamine 2a smoothly,
furnishing the desired products in 67–76% yield (entries 4–7).
However, when 1,3-diketone was chosen as a substrate with
benzylamine 2a, a decreased yield was obtained (entries 8–10).
For instance, 1,3-diphenylpropane-1,3-dione 1i resulted in
40% yield, since the highly active methylene reactant may
decompose to benzoic acid in the oxidative system.8 It was
worth mentioning that when the asymmetric 1,3-diketone 1j
was employed, excellent regioselectivity was observed (entry 10).
Subsequently, different benzylamines 2a–f were subjected to the
cascade sp3 C–H activation reaction. The results demonstrated
that both electron-rich and electron-deficient benzylamines were
tolerant. They can proceed readily with b-keto esters to afford
the oxazoles 3k–p in 50–73% yield (entries 11–16).
To gain insight into the cascade dual sp3 C–H activation
reaction, several control experiments were run to elucidate the
mechanism. Adding a radical inhibitor BHT (2,6-di-tert-butyl-
4-methylphenol) to the reaction system, it has almost no
significant influence on the reaction of ethyl acetoacetate 1a
with benzylamine 2a. Furthermore, no radical intermediate
was trapped by radical scavenger TEMPO (2,2,6,6-tetra-
methylpiperidine-N-oxyl). These results suggested that a
radical mechanism could be ruled out. Based on the study of
Ishihara and co-workers, we suppose that the active iodine
species ammonium hypoiodite ([n-Bu4N]+[IO]À) or iodite
(n-[Bu4N]+[IO2]À) plays an important role in the cascade sp3
C–H activation reaction. When 3.0 equiv. I2 was added into
the reaction of ethyl acetoacetate 1a with benzylamine 2a, it
hardly afforded the desired product 3a (See ESIw). Notably,
the reaction proceeded smoothly in the presence of 6.0 equiv.
n-Bu4NOH (25% in water) and 3.0 equiv. I2, giving the desired
product in 43% yield (See ESIw). It was acceptable that
hypoiodite [IO]À might be generated from I2 under basic
conditions, subsequently disproportioned to the iodite anion
[IO2]À.9 Accordingly, a plausible mechanism is proposed in
Scheme 1. Initially, intermediate 6 is formed in situ from ethyl
Table 2 Organocatalytic cascade sp3 C–H bond activations for the
synthesis of oxazale derivativesa
Entry 1
2
Time/h Product
8
Yieldb (%)
1
2
3
4
5
6
1a ArQC6H5, 2a
1b ArQC6H5, 2a
1c ArQC6H5, 2a
1d ArQC6H5, 2a
1e ArQC6H5, 2a
1f ArQC6H5, 2a
70
10
12
10
10
8
63
72
75
76
69
67
7
8
1g ArQC6H5, 2a
1h ArQC6H5, 2a
8
6
8
8
61
40
56
9
1i ArQC6H5, 2a
1j ArQC6H5, 2a
10
11c 1a ArQ4-ClC6H4, 2b 15
64
73
12
1a ArQ2-ClC6H4, 2c 10
13
14
1a ArQ4-FC6H4, 2d
8
65
62
1a ArQ4-MeC6H4, 2e 8
c
980 Chem. Commun., 2012, 48, 979–981
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Table 2 (continued )
Entry 1
Notes and references
1 For selected reviews on sp3 C–H bond activation, see:
(a) K. R. Campos, Chem. Soc. Rev., 2007, 36, 1069; (b) F. Collet,
R. H. Dodd and P. Dauban, Chem. Commun., 2009, 5061;
(c) C.-J. Li, Acc. Chem. Res., 2009, 42, 335; (d) C. J. Scheuermann,
Chem.–Asian J., 2010, 5, 436; (e) W.-J. Yoo and C.-J. Li, Top. Curr.
Chem., 2010, 292, 281; (f) C. S. Yeung and V. M. Dong, Chem. Rev.,
2011, 111, 1215.
2 For the recent reports on tetra-alkylammonium iodide catalytic
C–H activation reactions, see: (a) M. Uyanik, H. Okamoto,
T. Yasui and K. Ishihara, Science, 2010, 328, 1376; (b) L. Chen,
E. Shi, Z. J. Liu, S. Chen, W. Wei, H. Li, K. Xu and X. B. Wan,
Chem.–Eur. J., 2011, 17, 4085; (c) M. Uyanik, D. Suzuki, T. Yasui
and K. Ishihara, Angew. Chem., Int. Ed., 2011, 50, 5331; (d) W. Wei,
C. Zhang, Y. Xu and X. B. Wan, Chem. Commun., 2011, 47, 10827;
(e) T. Froehr, C. P. Sindlinger, U. Kloeckner, P. Finkbeiner and
B. J. Nachtsheim, Org. Lett., 2011, 13, 3754; (f) L. Ma, X. Wang,
W. Yu and B. Han, Chem. Commun., 2011, 47, 11333.
2
Time/h Product
Yieldb (%)
15
1a ArQFuyl, 2f
1d ArQFuyl, 2f
10
10
50
56
16
a
Reaction conditions:
1
(0.15 mmol),
2
(0.3 mmol), n-Bu4NI
b
(20 mol%), T-HYDRO (4.0 equiv.), EtOAc (1.0 mL), 40 1C. Isolated
yield. The reaction was carried out at room temperature.
c
3 For selected reviews on hypervalent iodine reagents, see:
(a) R. D. Richardson and T. Wirth, Angew. Chem., Int. Ed., 2006,
45, 4402; (b) V. V. Zhdankin and P. J. Stang, Chem. Rev., 2008,
108, 5299; (c) T. Dohi and Y. Kita, Chem. Commun., 2009, 2073.
4 When we started this study, there was no report for C–N bond
formations with the iodide catalytic system. More recently, Yu and
Han reported an oxidative coupling of aminopyridines with b-keto
esters in the catalysis of TBAI with 20 mol% BF3ÁEt2O as an
additive, which forged the C–N bond with a tertiary amine.
However, in this communication, a C–N bond was formed with
a primary amine. See 2f.
5 A book on cascade reactions: L. F. Tietze, G. Brasche and
K. Gericke, Domino Reactions in Organic Synthesis, Wiley-VCH,
Weinheim, 2006.
6 For selected examples, see: (a) A. S. Kende, K. Kawamura and
R. J. DeVita, J. Am. Chem. Soc., 1990, 112, 4070;
(b) K. C. Nicolaou, M. Bella, D. Y.-K. Chen, X. Huang, T. Ling
and S. A. Snyder, Angew. Chem., Int. Ed., 2002, 41, 3495;
(c) G. Pattenden, N. J. Ashweek, C. A. G. Baker-Glenn,
G. M. Walker and J. G. K. Yee, Angew. Chem., Int. Ed., 2007,
46, 4359.
7 For the recent examples on catalytic synthesis of oxazole derivatives by
metal: (a) E. F. Flegeau, M. E. Popkin and M. F. Greaney, Org. Lett.,
2006, 8, 2495; (b) C. Verrier, T. Martin, C. Hoarau and F. Marsais,
J. Org. Chem., 2008, 73, 7383; (c) F. Besselievre, S. Piguel,
F. Mahuteau-Betzer and D. S. Grierson, Org. Lett., 2008, 10, 4029;
(d) F. Besselievre, F. Mahuteau-Betzer, D. S. Grierson and S. Piguel,
J. Org. Chem., 2008, 73, 3278; (e) E. F. Flegeau, M. E. Popkin and
M. F. Greaney, Org. Lett., 2008, 10, 2717; (f) B. Shi, A. J. Blake,
I. B. Campbell, B. D. Judkins and C. J. Moody, Chem. Commun.,
2009, 3291; (g) K. Lee, C. M. Counceller and J. P. Stambuli,
Org. Lett., 2009, 11, 1457; (h) C. Verrier, C. Hoarau and
F. Marsais, Org. Biomol. Chem., 2009, 7, 647; (i) F. Besselievre and
S. Piguel, Angew. Chem., Int. Ed., 2009, 48, 9553; (j) C. Wan, J. Zhang,
S. Wang, J. Fan and Z. Wang, Org. Lett., 2010, 12, 2338; (k) B. Shi,
A. J. Blake, W. Lewis, I. B. Campbell, B. D. Judkins and C. J. Moody,
J. Org. Chem., 2010, 75, 152; (l) M. Austeri, D. Rix, W. Zeghida and
J. Lacour, Org. Lett., 2011, 13, 1394; (m) W. He, C. Li and L. Zhang,
J. Am. Chem. Soc., 2011, 133, 8482; (n) D. J. Ritson, C. Spiteri and
J. E. Moses, J. Org. Chem., 2011, 76, 3519.
8 Y. Yuan, X. Ji and D. Zhao, Eur. J. Org. Chem., 2010, 5274.
9 S. Yamada, D. Morizono and K. Yamamoto, Tetrahedron Lett.,
1992, 33, 4629.
10 Intermediate 6 was isolated during the reaction of ethyl acetoacetate
1a with benzylamine 2a, and it was identified by 1H NMR,
13C NMR and MS. On the other hand, Ishihara et al. found that
the addition of a catalytic amount of piperidine was effective for
giving a-benzyloxy aldehyde, see 2c. The reason for it may be
that piperidine could react with aldehyde to form the enamine
intermediate.
Scheme 1 Plausible mechanism.
acetoacetate 1a and benzylamine 2a,10 then it reacts with
[n-Bu4N]+[IO2]À 5 to form intermediate 7. Subsequent nucleo-
philic attack of 7 by benzylamine 2a gives 8. Further oxidation
of 8 to 9, then hydrolysis of 9 generates 10, which could
undergo an intra-molecular nucleophilic addition to afford
intermediate 11. Finally, 11 may be oxidized by 4 or 5 to
produce 3a easily.
In summary, we have developed an organocatalytic cascade
reaction to forge C–N, C–O and CQN bonds in one process
via dual sp3 C–H bond activations, which affords a facile
metal-free approach for synthesis of oxazole derivatives. The
presence of water and air does not have any effect to this
protocol. We also proposed the possible mechanistic pathway
on the basis of control experiments. Further studies for the
detailed mechanism and exploration of novel oxidative
coupling reactions with iodide catalytic system are under
way in our laboratory.
We gratefully acknowledge the National Natural Science
Foundation of China (20832001, 20972065, 21074054,
21172106) and the National Basic Research Program of China
(2010CB923303) for their financial support.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 979–981 981