A sustainable byproduct catalyzed domino strategy: Facile synthesis of α-formyloxy and acetoxy ketones via iodination/nucleophilic substitution/hydrolyzation/oxidation sequences

Article abstract of DOI:10.1039/c1cc15819h

The sustainable byproduct catalyzed domino strategy has been performed for the facile synthesis of α-formyloxy and acetoxy ketones via iodination/nucleophilic substitution/hydrolyzation/oxidation sequences from simple and readily available aromatic ketone

Full text of DOI:10.1039/c1cc15819h

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 12700–12702
www.rsc.org/chemcomm
COMMUNICATION
A sustainable byproduct catalyzed domino strategy: facile synthesis of
a-formyloxy and acetoxy ketones via iodination/nucleophilic substitution/
hydrolyzation/oxidation sequencesw
Yan-Ping Zhu, Qing-He Gao, Mi Lian, Jing-Jing Yuan, Mei-Cai Liu, Qin Zhao, Yan Yang
and An-Xin Wu*
Received 20th September 2011, Accepted 17th October 2011
DOI: 10.1039/c1cc15819h
The sustainable byproduct catalyzed domino strategy has been
performed for the facile synthesis of a-formyloxy and acetoxy
ketones via iodination/nucleophilic substitution/hydrolyzation/
oxidation sequences from simple and readily available aromatic
ketones/unsaturated methyl ketones.
integration of coupled domino processes to construct multi-
substituted hydantoins. This strategy can efficiently utilize the
excess or partly regenerated I2 in upstream domino reactions
to catalyze the following domino processes.5c
Direct C–H bond acetoxylation and formyloxylation is a
synthetically and mechanistically interesting field. In recent years,
many typical synthetic methods have been established.6 More-
over, a-acetoxy and formyloxy ketones as important intermediates
have attracted much attention.7 Generally a-acetoxy and
formyloxy ketones can be prepared via various methods which
include the reaction of a-bromo ketones with carboxylate ions
or carboxylic acid,8 acetoxylation of aromatic ketones with
Tl(OTf)3 or Pb(OAc)4,9 iodobenzene and m-CMPA catalyzed
acetoxylation10 and PhI(OAc)2 catalyzed acetoxylation.11
However, developing a green and practical methodology is
still needed for the preparation of a-acetoxy and formyloxy
ketones from simple and readily available starting materials
free of highly toxic reagents (Tl3+ or Pb4+) or noble metals.
In our previous studies,5c,12 we have proposed novel self-sorting
and focusing domino strategies for the efficient construction of
CQC bonds from simple and readily available aromatic
ketones in the presence of I2 and CuO, wherein a-iodo ketones
were generated in situ. Meanwhile, CuI was generated as a
byproduct. To demonstrate the power of sustainable byproduct
catalyzed domino strategy, we wonder whether it would be
possible for simple methyl ketones to form a-iodo ketone
intermediates, which were further catalyzed by the byproduct
CuI to afford a-acetoxy and formyloxy ketones in the presence
of DMF or DMA (N,N-dimethylacetamide).
Domino reactions, in which multiple reactions are performed
simultaneously and self-sequentially in a single reaction vessel,
have been widely utilized for the efficient construction of
complex molecules from readily available starting materials.
These reactions, by virtue of their atom-economy, operational
simplicity, saving reagents, energy, time and labor, have been
used in many chemical transformations.1
Maximizing synthetic efficiency and minimizing waste generation
is a very important but challenging task in organic chemistry.2
Nevertheless, stoichiometric byproducts are still unavoidable
in many chemical transformations, such as some PPh3-triggered
reactions,3 and Grignard reactions.4 Therefore, developing new
strategies to improve the utilization efficiency of byproducts is
greatly desirable.
Recently, a sustainable synthetic strategy has been proposed
for a domino process, in which the byproduct of an upstream
step could be used to catalyze the downstream reaction.2d,5 In
2008, Alaimo et al. first demonstrated the graceful strategy in a
domino nitroarene reduction–aldimine formation–aza-Diels–Alder
reaction, which utilized the InIII byproducts generated in the
reduction step to catalyze the downstream aza-Diels–Alder
reaction.5a Tian and co-workers reported the utilization of a
catalytic amount of water as a hydrolyzing agent to decompose
the upstream byproduct TMSCl to yield the secondary byproduct
HCl that serves as an active catalyst for the following two
steps.5b In our recent reports, we proposed a sustainable
To initiate our study, we first optimized the procedure for the
preparation of a-formyloxy acetophenone from phenacyl iodine
1a. As DMF is a good formyloxying agent,9a we first conducted
the reaction of phenacyl iodine (1a) in 3 mL DMF and 1 equiv.
of CuI at 90 1C for 2 h. Fortunately, the a-formyloxy
acetophenone 2a was obtained in 85% yield. In the absence
of CuI, a lower yield was obtained (50%). Following these
results, other catalysts, such as CuO, Cu(OAc)2, CuCl, CuBr2,
and PdCl2, were tested for this reaction in the presence of
DMF (Table 1, entries 2–6), but only CuCl and PdCl2 could
afford a trace amount of the desired product. Moreover, CuO,
Cu(OAc)2, and CuBr2 can afford the desired product in 75%,
Key Laboratory of Pesticide and Chemical Biology,
Ministry of Education, College of Chemistry,
Central China Normal University, 152 Luoyu Road, Wuhan 430079,
P. R. China. E-mail: chwuax@mail.ccnu.edu.cn;
Tel: +86 027 6786 7773
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data. CCDC 844753 and
844754. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1cc15819h
c
12700 Chem. Commun., 2011, 47, 12700–12702
This journal is The Royal Society of Chemistry 2011

View Article Online
Table 2 Reaction scope of aromatic ketones 1 and DMFa
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst/equiv.
CuI (1.0)
—
CuO (1.0)
Cu(OAc)2 (1.0)
CuCl (1.0)
CuBr2 (1.0)
PdCl2 (1.0)
CuI (1.0)
CuI (1.0)
CuI (0.5)
CuI (0.3)
CuI (0.1)
Temp/1C
Yieldb (%)
Entry
R
2
Yieldb (%)
1
2
2
3
4
5
6
7
8
9
10
11
90
90
90
90
90
90
90
110
130
110
110
110
85
50
75
66
1
2
3
4
5
6
7
8
4-MeOC6H4 (1a)
Ph (1b)
4-MeC6H4 (1c)
2,4-OMe2C6H3 (1d)
4-NO2C6H4 (1e)
4-BrC6H4 (1f)
3,4-Cl2C6H3 (1g)
4-OHC6H4 (1h)
2-Naphthyl (1i)
2-Furyl (1j)
2-Thienyl (1k)
2-Benzofuryl (1l)
3-Indolyl (1m)
4-PhC6H4 (1n)
(E)-C6H5–CHQCH– (1o)
(E)-4-MeC6H4–CHQCH– (1p)
(E)-4-OMeC6H4–CHQCH– (1q)
(E)-3,4-OMe2C6H4–CHQCH– (1r)
(E)-3-OMe-4-
C6H5OCH2–C6H4–CHQCH– (1s)
(E)-4-NMe2C6H4–CHQCH– (1t)
(E)-4-BrC6H4–CHQCH– (1u)
(E)-4-NO2C6H4–CHQCH– (1v)
(E)-3-NO2C6H4–CHQCH– (1w)
(E)-4-OHC6H4–CHQCH– (1x)
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
92
96
90
89
70
86
82
50
65
80
75
72
82
72
75
72
80
68
80
c
o5
40
o5
95
93
96
94
88
9
10
11
12
13
14
15
16
17
18
19
a
Reaction conditions: 1a (1.0 mmol), in 3 mL DMF in open air.
c
Isolated yields. No catalyst.
b
66% and 40% yields, respectively. It was obvious that CuI was
the most efficient catalyst. The reaction temperature was also
tested. Elevation of the reaction temperature to 110 1C can
increase the reaction yield (up to 95%). Further elevation of
temperature to 130 1C obviously could not enhance the reaction
yield. A slightly lower yield was obtained when the dose of CuI
was decreased to 30% mmol. However, a significant drop of
yield was observed when the dose of CuI was decreased to
10% mmol. Thus, the optimal reaction conditions were obtained;
that is, phenacyl iodine (1a) was heated at 110 1C for 2–4 h with
30 mol% of CuI as catalyst in DMF (Table 1, entry 10). With
these optimal conditions in hand, we wondered whether it would
be possible to prepare the a-formyloxy acetophenone via a
sustainable byproduct catalyzed strategy on the basis of aromatic
ketone, I2 and CuO. After many screening experiments, we found
that the reaction of aromatic ketone 1b (1.0 mmol) with I2
(1.0 mmol), and CuO (1.0 mmol) in DMF (3 mL) at 110 1C
could provide the desired product in 96% yield.
20
21
22
23
24
2t
50
55
65
60
58
2u
2v
2w
2x
a
Reaction conditions: 1 (1.0 mmol), I2 (1.0 mmol), CuO (1.0 mmol) in
b
DMF (3 mL) at 110 1C for 1–6 h. Isolated yields.
2k, 2l, and 2m were obtained in 80%, 75%, 72% and 82%
yields, respectively. To further expand the scope of the ketones,
unsaturated methyl ketones such as 1o–1x were also investigated.13
To our delight, unsaturated methyl ketones could also react with I2
and CuO in DMF to give the corresponding product in 50–80%
yields.
When the same reaction protocol used in a-formyloxylation of
ketones was conducted in DMA instead of DMF, the a-acetoxy
ketones were obtained in moderate to good yields (52–80%)
(Table 3). Significantly, heterocycles containing aromatic ketones,
including furan (1f) and thiophene (1g), were tolerated in the
transformation. What’s more, unsaturated methyl ketones
could also undergo a-acetoxylation with satisfying yields
(57–70%) using the same reaction protocol.
The efficient formation of the desired product prompted us
to study the reaction scope further. A series of aromatic
ketones 1b–x were examined under the optimal conditions.
While the benzene rings bore electron-donating groups (e.g.,
4-Me, 4-OMe, 2,4-OMe2), the corresponding products 2a,
2c–d were obtained in good yields (89–92%, entries 1, 3 and
4, Table 2). And when the benzene rings were substituted with
electron-withdrawing groups (e.g., 4-Cl, 4-Br, 3-NO2, 4-Ph),
the corresponding products 2e–g were obtained in moderate to
good yields (70–86%, entries 5–7, Table 2). It should be noted
that an electron-donating substituent on the benzene ring caused
a considerable increase in the yield. To our great satisfaction,
the sensitive hydroxy group (OH) was not affected under these
reaction conditions, and the expected product 2h was obtained
in 50% yield. Moreover, 2-naphthyl methyl ketone (1i) also
gave a satisfying result. Encouraged by the results obtained
with aryl methyl ketones, we turned our attention to the
heteroaryl ketones. The heterocycles, including furan (1j),
thiophene (1k), benzofuryl (1l), and 3-indolyl (1m), did not
affect the overall efficiency, and the corresponding products 2j,
All these target molecules were characterized by the NMR,
HRMS and IR spectra. Furthermore, the target compounds 2e
and 3d were further determined by X-ray single diffraction
analysis (see ESIw).
To gain insight into the mechanism, the isotope labeling experi-
ment and control experiment were performed (Scheme 1). In
eqn (1) and (2), air and moisture had shown little effect on the
reaction efficiency. However, lower yields were obtained in
either an O2 or Ar atmosphere with anhydrous DMF, which
indicated that the water was necessary for this transformation
(eqn (3) and (4)). Further investigation in the presence of
H2O18 (0.15 mL) indicates that water participated in the
reaction (eqn (5), determined by MS (ESI), see ESIw).
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12700–12702 12701

View Article Online
Table 3 Reaction scope of aromatic ketones 1 and DMAa
ketones and unsaturated methyl ketones. This transformation
contains three noteworthy characteristics: (1) both I2 and
DMF play dual roles in the whole transformation, (2) byproduct
CuI generated in the upstream reaction was utilized as the
secondary catalyst, (3) a broad scope of substrates were tolerated.
We thank the National Natural Science Foundation of China
(Grant 20872042, and 201032001) and PCSIRT (No. IRT0953).
Entry
R
3
Yieldb (%)
Notes and references
1
2
3
4
5
6
7
8
Ph (1a)
4-MeC6H4 (1b)
4-MeOC6H4 (1c)
4-NO2C6H4 (1d)
4-BrC6H4 (1e)
2-Furyl (1f)
2-Thienyl (1g)
2-Naphthyl (1h)
(E)-C6H5–CHQCH– (1o)
(E)-3,4-OMe2C6H4–CHQCH– (1r)
(E)-3-OMe-4-
C6H5OCH2–C6H4–CHQCH– (1s)
(E)-4-NO2C6H4–CHQCH– (1v)
(E)-3-NO2C6H4–CHQCH– (1w)
3a
3b
3c
3d
3e
3f
3g
3h
3o
3r
3s
80
74
78
52
68
80
75
58
70
62
65
1 For some reviews of domino reactions, see: (a) L. F. Tietze,
G. Brasche and K. Gericke, Domino Reactions in
Organic Synthesis, Wiley-VCH, Weinheim, Germany, 2006;
(b) L. F. Tietze, Chem. Rev., 1996, 96, 115; (c) K. C. Nicolaou,
T. Montagnon and S. A. Snyder, Chem. Commun., 2003, 551;
(d) R. J. K. Talor, M. Reid, J. Foot and S. A. Raw, Acc. Chem.
Res., 2005, 38, 851; (e) J. C. Wasilke, S. J. Obrey, R. T. Brker and
G. C. Bazan, Chem. Rev., 2005, 105, 1001.
2 (a) B. M. Trost, Science, 1991, 254, 1471; (b) R. A. Sheldon, Pure
Appl. Chem., 2000, 72, 1233; (c) P. Anastas and N. Eghbali, Chem.
Soc. Rev., 2010, 39, 301; (d) J.-J. Cao, F. Zhou and J. Zhou,
Angew. Chem., Int. Ed., 2010, 49, 4976.
9
10
11
12
13
3v
3w
65
57
3 For reviews, see: (a) X. Lu, C. Zhang and Z. Xu, Acc. Chem. Res.,
2001, 34, 535; (b) L.-W. Ye, J. Zhou and Y. Tang, Chem. Soc. Rev.,
2008, 37, 1140; (c) V. Nair, A. T. Biju, S. C. Mathew and
B. P. Babu, Chem.–Asian J., 2008, 3, 810.
a
Reaction conditions: 1 (1.0 mmol), I2 (1.0 mmol), CuO (1.0 mmol) in
b
DMA (3 mL) at 110 1C for 1–6 h. Isolated yields.
4 (a) M. B. Smith and J. March, March’s Advanced Organic Chem-
istry Reactions: Mechanisms and Structure, John Wiley & Sons
Inc., New York, 5th edn, 2001, pp. 1205–1209; (b) P. Anastas and
E. Nicolas, Chem. Soc. Rev., 2010, 39, 301.
5 (a) P. J. Alaimo, R. O’Brien, A. W. Johnson, S. R. Slauson,
J. M. O’Brien, E. L. Tyson, A.-L. Marshall, C. E. Ottinger,
J. G. Chacon, L. Wallace, C. Y. Paulino and S. Connell, Org.
Lett., 2008, 10, 5111; (b) B.-L. Yang, Z.-T. Weng, S.-J. Yang and
S.-K. Tian, Chem.–Eur. J., 2010, 16, 718; (c) M. Gao, Y. Yang,
Y.-D. Wu, C. Deng, W.-M. Shu, D.-X. Zhag, L.-P. Cao, N.-F. She
and A.-X. Wu, Org. Lett., 2010, 12, 4026.
6 For selected examples, see: (a) M. S. Chen and M. C. White, J. Am.
Chem. Soc., 2004, 126, 1346; (b) X. Chen, X.-S. Hao,
C. E. Goodhue and J.-Q. Yu, J. Am. Chem. Soc., 2006,
128, 6790; (c) H.-F. Jiang, H.-J. Chen, A.-Z. Wang and
X.-H. Liu, Chem. Commun., 2010, 46, 7259; (d) Y.-T. Leng,
F. Yang, W.-G. Zhu, Y.-J. Wu and X. Li, Org. Biomol. Chem.,
2011, 9, 5288.
7 (a) T. W. Green and P. G. M. Wuts, Protective Groups in Organic
Synthesis, Wiley, New York, 1991, pp. 87–104; (b) Z.-Q. Liu,
Z.-P. Cao and H.-F. Du, Org. Biomol. Chem., 2011, 9, 5369;
(c) S. R. Neufeldt and M. S. Sanford, Org. Lett., 2010, 12, 532;
(d) D.-W. Wang, X.-H. Ye and X.-D. Shi, Org. Lett., 2010, 12, 2088.
8 (a) F. Wang, H. Liu, L.-F. Cun, J. Zhu, J.-G. Deng and
Y.-Z. Jiang, J. Org. Chem., 2005, 70, 9424.
9 (a) J. C. Lee, Y. S. Jinn and J.-H. Choi, Chem. Commun., 2001,
957; (b) H. Urata, Y. Nishioka, T. Tobashi, Y. Matsumura,
N. Tomimori, Y. Ono, Y. Kiso and S. I. Wada, Chem. Pharm.
Bull., 2008, 56, 1611.
10 M. Ochiai, Y. Takeuchi, T. Katayama, T. Sueda and
K. Miyamoto, J. Am. Chem. Soc., 2005, 127, 12244.
Scheme 1 The isotope labeling experiment and control experiment.
Unless otherwise noted, reactions conditions were I2 (1.0 mmol), CuO
(1.0 mmol), DMF (3 mL), 110 1C for 2 h.
On the basis of the above results, a plausible mechanism of
the present reaction could be described as follows using
acetophenone (1b) as an example (Scheme 2). Initially, the
acetophenone 1b is converted to B in the media of I2 and CuO.
Subsequently, DMF as a nucleophilic agent reacts with inter-
mediate B in the presence of CuI, which forms as a byproduct
from the upstream iodination process, to afford intermediate
C. Finally, intermediate C undergoes hydrolyzation/oxidation
reaction to furnish the desired product in the presence of a
catalytic amount of water.9a,14 More importantly, both I2 and
DMF play dual roles in this process. Molecule I2 could not
only react with acetophenone (1a) to afford intermediate B,
but also promotes the transformation of CuO into the secondary
catalyst CuI. DMF acts as both the solvent and nucleophilic
reagent.
11 (a) Y. Sun and R.-H. Fan, Org. Lett., 2009, 11, 5174; (b) Y. Sun
and R.-H. Fan, Chem. Commun., 2010, 46, 6834.
12 (a) G.-D. Yin, B.-H. Zhou, X.-G. Meng, A.-X. Wu and Y.-J. Pan,
Org. Lett., 2006, 8, 2245; (b) M. Gao, Y. Yang, Y.-D. Wu,
C. Deng, L.-P. Cao, X.-G. Meng and A.-X. Wu, Org. Lett.,
2010, 12, 1856; (c) M. Gao, G.-D. Yin, Z.-H. Wang, Y.-D. Wu,
C. Guo, Y.-J. Pan and A.-X. Wu, Tetrahedron, 2009, 65, 6047.
13 Compounds 1o–1x were synthesized via condensation of aromatic
aldehyde and acetone in the presence of NaOH. See: N. L. Drake
and P. Allen, Jr., Org. Synth. Coll. Vol. 1, John Wiley & Sons,
London, 1941, pp. 77–78.
In summary, we have developed a sustainable byproduct
catalyzed domino method for the facile synthesis of a-formyloxy
and acetoxy ketones from simple and readily available aromatic
14 For water catalyzed hydrolyzation/oxidation reactions, see:
(a) A. Takemiya and J. F. Hartwig, J. Am. Chem. Soc., 2006,
128, 14800; (b) G. D. Vo and J. F. Hartwig, Angew. Chem., Int.
Ed., 2008, 47, 2127; (c) Y. Liu, C.-L. Deng, R.-Y. Tang,
X.-G. Zhang and J.-H. Li, Org. Lett., 2011, 13, 2184.
Scheme 2 The plausible mechanism of the present reaction.
12702 Chem. Commun., 2011, 47, 12700–12702
c
This journal is The Royal Society of Chemistry 2011