A green chemistry method for the regeneration of carbonyl compounds from oximes by using cupric chloride dihydrate as a recoverable promoter for hydrolysis

Article abstract of DOI:10.1055/s-0030-1259730

A mild, efficient, general, and green method for the regeneration of carbonyl compounds from their corresponding oximes is described. Cupric salts promoted hydrolysis of oximes was studied, and the best reaction conditions for the hydrolysis have been found. Carbonyl compounds were obtained in 85-98% yields after the treatment of oximes with 2 molar equivalent of CuCl ₂2H₂O at reflux (around 75 C) in a mixed solvent of acetonitrile and water (4:1). In addition, cupric salt was readily recovered in an almost quantitative yield via the complete precipitation of Cu(OH) ₂2H₂O. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1259730

1028
LETTER
A Green Chemistry Method for the Regeneration of Carbonyl Compounds
from Oximes by Using Cupric Chloride Dihydrate as a Recoverable Promoter
for Hydrolysis
Green Chemistry
M
a
ethod for the
Re
Q
generation of Carb
u
onyl
C
ompo
a
unds n, Xiao-Xin Shi,* Liang-Deng Nie, Jing Dong, Rui-Heng Zhu
Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technology,
130 Mei-Long Road, Shanghai 200237, P. R. of China
Fax +86(21)64252052; E-mail: xxshi@ecust.edu.cn
Received 23 November 2010
Dedicated to Professors Li-Xin Dai and Xi-Yan Lu
tones and aldehydes. Regeneration of carbonyl com-
Abstract: A mild, efficient, general, and green method for the re-
generation of carbonyl compounds from their corresponding
oximes is described. Cupric salts promoted hydrolysis of oximes
was studied, and the best reaction conditions for the hydrolysis have
pounds from oximes via exchange with other carbonyl
compounds (method D) has also been reported. Oxime ex-
change with acetone is sluggish,8b but the exchange with
been found. Carbonyl compounds were obtained in 85–98% yields levulinic acid,8c pyruvic acid,8d or glyoxylic acid8a is rapid
after the treatment of oximes with 2 molar equivalent of
and efficient. However, use of large excess of these
CuCl2·2H2O at reflux (around 75 °C) in a mixed solvent of acetoni-
oxoacids would certainly retard its wide applications.
trile and water (4:1). In addition, cupric salt was readily recovered
Herein we would like to report a mild, efficient, general,
in an almost quantitative yield via the complete precipitation of
and green method for the regeneration of carbonyl com-
Cu(OH)2·2H2O.
pounds from the corresponding oximes, in which
Key words: carbonyl compounds, oxime, hydrolysis, cupric chlo-
CuCl2·2H2O was used as a recoverable promoter for hy-
ride, green chemistry
drolysis.
H
N
Regeneration of carbonyl compounds from the corre-
O
sponding oximes, that is, deoximation, is a very important
reaction,1 because oximes are often used to protect carbo-
nyl compounds2 or as the preferred derivatives for purifi-
cation and characterization of them.3 Furthermore, when
oximes are prepared from noncarbonyl compounds, deox-
imation provides an alternative approach for the syntheses
of aldehydes and ketones.4
R1
R2
R1
R2
H+, H2O
[H]
method B
(reductive
pathway)
H2O
method A
(hydrolytic
pathway)
OH
R2
N
O
R1
R1
R2
OH
R4
[O]
N
R3COR4
H2O
method C
(oxidative
pathway)
So far there are four main pathways (Scheme 1) for the
deoximation, they include hydrolytic5 (method A),
reductive6 (method B), oxidative7 (method C) pathways
and transoximation8 (method D), respectively.9 Due to the
relatively hydrolytic stability of oximes, regeneration of
carbonyl compounds from oximes via direct hydrolysis
(method A) usually needs strong acidic conditions, and
thus leads to the damage of acid-sensitive groups and the
formation of amides as byproducts by Beckmann rear-
rangement.10 Regeneration of carbonyl compounds from
oximes via reductive and oxidative pathways (methods B
and C) only needs weak acidic conditions, because
oximes are reduced or oxidized to form unstable interme-
diates which are much more susceptible to hydrolysis than
oximes themselves. Unfortunately, most of reductive and
oxidative methods involve reagents that are often hazard-
ous or very toxic, expensive or not readily available.
Moreover, reductive and oxidative pathways often suffer
from overreduction and overoxidation of liberated ke-
R3
method D
(oxime
exchange)
X
OH
R2
N
+
R1
O
R1
R2
Scheme 1 Main methods for the regeneration of carbonyl com-
pounds from oximes
Although Ragauskas and Jiang have reported a cupric
salts catalyzed, ultrasound-promoted dehydration of al-
doximes to form nitriles in acetonitrile,11 we thought cu-
pric salts would promote hydrolysis of oximes under
aqueous conditions, because the strong coordination abil-
ity of copper ion with hydroxylamine would drive the
equation (Scheme 2) towards the formation of carbonyl
O
OH
R2
N
CuX2
H2O
+
Cu(NH2OH)X2
+
+
R1
R2
SYNLETT 2011, No. 7, pp 1028–1032
x
x.
x
x.
2
0
1
1
R1
Advanced online publication: 10.03.2011
DOI: 10.1055/s-0030-1259730; Art ID: W34110ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

LETTER
Green Chemistry Method for the Regeneration of Carbonyl Compounds
1029
compounds and a hydroxylamine-coordinated copper the study infra. Solvent effect on the hydrolysis has also
complex. With this idea in our mind, and encouraged by been examined. Compared with several other aqueous sol-
Corey’s report12 about the cupric acetate catalyzed facile vents (Table 1, entries 2–7), aqueous acetonitrile (MeCN–
hydrolysis of N,N-dimethylhydrazones, we examined H2O = 4:1) was found to be the best solvent for the hy-
copper salts catalyzed hydrolysis of benzophenone oxime drolysis (Table 1, entry 1).
(1a) under various conditions, the results are summarized
in Table 1.
We then attempted the CuCl2·2H2O-promoted hydrolysis
of various oximes in aqueous acetonitrile. As shown in
Table 2, a total of 22 oximes (1a–v) were tried, either al-
doximes or ketoximes underwent smooth hydrolysis
when they were treated with 2 mol equivalents of
Table 1 Optimization of Reaction Conditions for the Conversion of
Benzophenone Oxime (1a) into Benzophenone (2a)
Entry Reagent (2 equiv) Solvent (4:1)
Temp Time Yield
CuCl2·2H2O in aqueous acetonitrile at reflux (75 °C), cor-
responding carbonyl compounds 2a–v could be obtained
in high yields in all instances.13 Acid-sensitive groups,
such as ester and acetal, kept intact during the hydrolysis
(Table 2, entries 2 and 6–8). An a,b-unsaturated aldehyde
could be obtained in an excellent yield from the conjugate
oxime (Table 2, entry 14). Although hydrolysis of oximes
with a dithiane group gave dicarbonyl compounds in high
yields (Table 2, entries 18 and 19) due to simultaneous re-
moval of the dithiane group by cupric chloride during the
hydrolysis,14 the sulfide moieties survived after the hy-
drolysis under the same conditions (Table 2, entries 20
and 21).
(°C)
75b
80
(h)
(%)a
1
2
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuSO4
MeCN–H2O
DMF–H2O
2
98
12
10
12
12
12
12
12
12
4
80
3
DMSO–H2O
Me2CO–H2O
EtOH–H2O
THF–H2O
80
95
4
54b
72b
64b
78b
75b
75b
75b
75b
75b
75b
75b
75b
75b
75b
75b
30c
90
5
6
25c
80
7
i-PrOH–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
8
86
Table 2 CuCl2·2H2O-Promoted Regeneration of Carbonyl Com-
9
Cu(OAc)2·H2O
CuBr2·2H2O
CuCl
82
pounds from Various Oximesa
10
11
12
13
14
15
16
17
18
93
Entry Oxime 1
Time (h)Product 2
Yield
(%)b
12
12
12
12
12
12
12
12
67c
69c
85
NOH
O
CuBr
1
2
2
98
94
FeCl3·6H2O
NiCl2
40c
45c
60c
2c
1a
2a
CHO
CoCl2·6H2O
ZnCl2
NOH
NOH
2
O
O
O
O
Ni(OAc)2·4H2O
Co(OAc)2·4H2O
1b
2b
10c
MeO
CHO
MeO
a Isolated yield.
b Reflux.
3
4
5
6
0.5
MeO
2c
91
97
94
92
c 30–95% of compound 1a was recovered.
MeO
1c
NOH
CHO
As can been seen from Table 1, the impact of various met-
al salts on the hydrolysis of oxime 1a in aqueous acetoni-
trile (entries 1 and 8–18) have been investigated. The
metal salts used in our test included cupric chloride dihy-
drate, cupric sulfate, cupric acetate dihydrate, cupric bro-
mide dihydrate, cuprous chloride, cuprous bromide, ferric
chloride hexahydrate, nickel chloride, cobalt chloride
hexahydrate, zinc chloride, nickel acetate tetrahydrate,
and cobalt acetate tetrahydrate. When 2 mol equivalents
of cupric chloride dihydrate or cupric bromide dihydrate
were used, the hydrolysis took place smoothly in aqueous
acetonitrile, affording benzophenone (2a) in excellent
yields (Table 1, entries 1 and 10). Considering cupric
chloride dihydrate is much cheaper than cupric bromide
dihydrate, so we chose to use cupric chloride dihydrate for
0.5
MeO
2d
MeO
1d
NOH
CHO
0.5
HO
2e
HO
1e
NOH
MeO
CHO
MeO
1
BzO
BzO
2f
1f
Synlett 2011, No. 7, 1028–1032 © Thieme Stuttgart · New York

1030
N. Quan et al.
LETTER
Table 2 CuCl2·2H2O-Promoted Regeneration of Carbonyl Com-
Table 2 CuCl2·2H2O-Promoted Regeneration of Carbonyl Com-
pounds from Various Oximesa (continued)
pounds from Various Oximesa (continued)
Entry Oxime 1
Time (h)Product 2
Yield
(%)b
Entry Oxime 1
Time (h)Product 2
Yield
(%)b
NOH
NOH
NOH
CHO
CHO
CHO
CO2Et
CO2Et
7
1.5
92
91
17
3
95
O
F
O
F
2g
2q
1g
1q
NOH
CHO
CHO
CO2Et
CO2Et
S
S
18
19
1
92
89
8
1.5
O
O
OMe
2r
2s
OMe
1r
2h
1h
1i
O
O
NOH
O
2.5
S
S
9
10
11
1.5
3
98
92
90
HON
1s
2i
2j
NOH
O
NOH
O
20
2
85
S
S
1j
2t
1t
NOH
CHO
Cl
2
NOH
O
Cl
Cl
Cl
21
22
2
1
86
88
S
S
2k
1k
NOH
CHO
1u
1v
2u
2v
12
13
2.5
98
93
CHO
O2N
NOH
O2N
2l
1l
N
N
H
H
NOH
HO
CHO
HO
2
a Reaction conditions: CuCl2·2H2O (2 equiv), refluxing (75 °C) in a
mixed solvent of MeCN and H2O (MeCN–H2O = 4:1).
b Isolated yield.
O2N
O2N
2m
1m
NOH
NOH
CHO
Cupric chloride dihydrate might serve as a coordinating
reagent rather than an oxidant in the hydrolysis, because
cuprous chloride could also promote the hydrolysis of
oxime 1a albeit in a moderate yield (Table 1, entry 11),
and no oxidation of the sulfide groups of oximes occurred
through the hydrolysis (Table 2, entries 20 and 21).
14
15
16
1.5
2.5
2.5
92
91
96
2n
1n
1o
O
Two mol equivalents of cupric chloride dihydrate were
necessary for the above-described deoximation, when less
than 2 equivalents of cupric chloride dihydrate were used,
the yields of carbonyl compounds would be diminished.
Cupric chloride was washed into an aqueous solution dur-
ing the workup procedure.13 However, from a green
chemistry point of view,15 cupric salt should be recovered
herein to prevent any possible environmental pollution.
Fortunately, the cupric salt could be readily recovered in
an almost quantitative yield just by adding 2.2 mol equiv-
alents of NaOH into the above aqueous extract to allow
2o
O
NOH
1p
2p
Synlett 2011, No. 7, 1028–1032 © Thieme Stuttgart · New York

LETTER
Green Chemistry Method for the Regeneration of Carbonyl Compounds
1031
1984, 337. (h) Olah, G. A.; Arvanaghi, M.; Prakash, G. K. S.
Synthesis 1980, 220. (i) Pojer, P. M. Aust. J. Chem. 1979,
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Soc. 1970, 92, 5276. (l) Pines, S. H.; Chemerda, J. M.;
Kozlowski, M. A. J. Org. Chem. 1966, 31, 3446.
(7) Numerous methods for the oxidative deoximation have been
reported, recent examples are as follows: (a) Zhou, X.-T.;
Yuan, Q.-L.; Ji, H.-B. Tetrahedron Lett. 2010, 51, 613.
(b) Shaabani, A.; Farhangi, E. Appl. Catal., A 2009, 371,
148. (c) Ganguly, N. C.; Barik, S. K. Synthesis 2008, 425.
(d) Gupta, P. K.; Manral, L.; Ganesan, K. Synthesis 2007,
1930. (e) Gogoi, P.; Hazarika, P.; Konwar, D. J. Org. Chem.
2005, 70, 1934. (f) Shaabani, A.; Naderi, S.; Rahmati, A.;
Badri, Z.; Darvishi, M.; Lee, D. G. Synthesis 2005, 3023.
(g) Khazaei, A.; Manesh, A. A. Synthesis 2005, 1929.
(h) Jain, N.; Kumar, A.; Chauhan, S. M. S. Tetrahedron Lett.
2005, 46, 2599. (i) Li, Z.; Ding, R.-B.; Xing, Y.-L.; Shi,
S.-Y. Synth. Commun. 2005, 35, 2515. (j) Khazaei, A.;
Manesh, A. A. Synthesis 2004, 1739. (k) Yang, Y.; Zhang,
D.; Wu, L.-Z.; Chen, B.; Zhang, L.-P.; Tung, C.-H. J. Org.
Chem. 2004, 69, 4788. (l) Arnold, J. N.; Hayes, P. D.;
Kohaus, R. L.; Mohan, R. S. Tetrahedron Lett. 2003, 44,
9173. (m) Krishnaveni, N. S.; Surendra, K.; Nageswar, Y. V.
D.; Rao, K. R. Synthesis 2003, 1968. (n) Narsaiah, A. V.;
Nagaiah, K. Synthesis 2003, 1881. (o) Bose, D. S.; Reddy,
A. V. N.; Das, A. P. R. Synthesis 2003, 1883.
Cu(OH)2·2H2O completely precipitated as a bluish sol-
id.16 Moreover, when the above Cu(OH)2·2H2O was con-
verted into CuCl2·2H2O, it could be reused for the
hydrolysis of oximes without any observable difference
from the commercial one.17
In conclusion, a mild, efficient, and general method for
the regeneration of carbonyl compounds from their corre-
sponding oximes has been developed. Some merits such
as simple manipulation, mild reaction conditions, high
yields, wild scope of application, cheapness of cupric
chloride dihydrate, as well as the complete recovery of the
cupric salt might allow this green method to be very useful
for the regeneration of ketones and aldehydes from vari-
ous ketoximes and aldoximes.
Acknowledgment
We thank the National Natural Science Foundation of China (No.
20972048) and the Shanghai Educational Development Foundation
(The Dawn Program: No. 03SG27) for the financial support of this
work.
References and Notes
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Synthesis 2000, 403.
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Synthesis, 3rd ed.; John Wiley: New York, 1999.
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Systematic Identification of Organic Compounds, 6th ed.;
John Wiley: New York, 1980.
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(9) Carbonyl compounds can also be regenerated from oximes
via photochemical and electrochemical methods, but only a
few examples have been reported: (a) de Lijser, H. J. P.;
Fardoun, F. H.; Sawyer, J. R.; Quant, M. Org. Lett. 2002, 4,
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(12) Corey, E. J.; Knapp, S. Tetrahedron Lett. 1976, 41, 3667.
(13) Typical Procedure for the CuCl2·2H2O-Promoted
Regeneration of Carbonyl Compounds from Various
Oximes
(5) (a) De S, K. Tetrahedron Lett. 2003, 44, 9055. (b) Shirini,
F.; Zolfigol, M. A.; Safari, A.; Mohammadpoor-Baltork, I.;
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Oxime 1a (1.01 g, 5.12 mmol) was dissolved in MeCN (20
mL), CuCl2·2H2O (1.73 g, 10.15 mmol) and H2O (5 mL)
were added. When the suspension was heated to reflux, the
mixture became a bluish clear solution. The resulting
reaction solution was then stirred at reflux (75 °C) for
around 2 h and monitored by TLC (EtOAc–hexane, 1:6).
After the reaction was complete, the solvents were removed
by vacuum distillation. The residue was partitioned between
EtOAc (50 mL) and H2O (30 mL), the organic and aqueous
phases were separated. Organic phase was washed with
brine (5 mL) and dried over anhyd MgSO4. Concentration of
the organic solution gave crude product, which was purified
by flash chromatography to afford benzophenone (2a, 0.914
g, 5.02 mmol) in 98% yield. To the above-mentioned
(6) (a) Majireck, M. M.; Witek, J. A.; Weinreb, S. M.
Tetrahedron Lett. 2010, 51, 3555. (b) Martin, M.; Martinez,
G.; Urpi, F.; Vilarrasa, J. Tetrahedron Lett. 2004, 45, 5559.
(c) Lukin, K. A.; Narayanan, B. A. Tetrahedron 2002, 58,
215. (d) Watanabe, Y.; Morimoto, S.; Adachi, T.;
Kashimura, M.; Asaka, T. J. Antibiot. 1993, 46, 647.
(e) Akazome, M.; Tsuji, Y.; Watanabe, Y. Chem. Lett. 1990,
635. (f) Curran, D. P.; Brill, J. F.; Rakiewicz, D. M. J. Org.
Chem. 1984, 49, 1654. (g) Barton, D. H. R.; Motherwell, W.
B.; Simon, E. S.; Zard, S. Z. J. Chem. Soc., Chem. Commun.
Synlett 2011, No. 7, 1028–1032 © Thieme Stuttgart · New York

1032
N. Quan et al.
LETTER
aqueous phase was added an aq solution of NaOH (11.0 mL,
2 M, 22.00 mmol). After vigorous stirring for 1 h, the bluish
solid was collected on a Buchner funnel by suction. After
being dried in a warm air at around 50 °C for 12 h until the
weight of the solid kept constant, Cu(OH)2·2H2O (1.34 g,
10.03 mmol) was recovered in 99% yield.
Spectral analysis showed that compounds 2a–e,i–l,n–s,v
obtained from the above hydrolysis are identical with the
commercially available authentic samples. Characterization
data of compounds 2f–h,m,t,u are as follows:
(d, J = 8.6 Hz, 1 H), 10.07 (s, 1 H), 10.58 (s, 1 H). IR (KBr):
n = 3255, 3085, 2870, 1700, 1620, 1585, 1530, 1480, 1450,
1315, 1255, 1165, 1140, 1080, 985, 850, 760, 705, 540 cm–1.
MS (EI): m/z (%) = 167 (100) [M+], 166 (44), 151 (1), 136
(3), 119 (7), 109 (4), 92 (3), 81 (3), 63 (6).
Compound 2t: 1H NMR (400 MHz, CDCl3): d = 2.28 (s, 3
H), 3.50–3.69 (m, 2 H), 4.88 (dd, J1 = 6.1 Hz, J2 = 8.1 Hz, 1
H), 7.03 (d, J = 7.9 Hz, 2 H), 7.13–7.26 (m, 5 H), 7.28–7.35
(m, 2 H), 7.37–7.44 (m, 2 H) 7.48–7.55 (m, 1 H), 7.82–7.89
(m, 2 H). MS (EI): m/z (%) = 332(4) [M+], 209 (5), 179 (2),
123 (13), 105 (100), 91 (6), 77 (59). IR (KBr): n = 3035,
2920, 1685, 1595, 1490, 1450, 1420, 1335, 1220, 980, 810,
745, 700, 685, 550 cm–1.
Compound 2f: 1H NMR (400 MHz, CDCl3): d = 3.89 (s, 3
H), 7.35 (d, J = 7.9 Hz, 1 H), 7.48–7.57 (m, 4 H), 7.62–7.69
(m, 1 H), 8.18–8.24 (m, 2 H), 9.98 (s, 1 H). MS (EI): m/z (%)
= 256 (4) [M+], 217 (18), 182 (2), 155 (2), 105 (100), 77 (17).
IR (KBr): n = 3005, 2885, 1735, 1680, 1600, 1505, 1450,
1400, 1255, 1190, 1140, 1120, 1060, 1025, 850, 805, 730,
700 cm–1.
Compound 2u: 1H NMR (400 MHz, CDCl3): d = 2.05 (s, 3
H), 2.29 (s, 3 H), 2.92–3.08 (m, 2 H), 4.63 (dd, J1 = 6.8 Hz,
J2 = 7.8 Hz, 1 H), 7.03 (d, J = 8.0 Hz, 2 H), 7.18 (d, J = 8.0
Hz, 2 H), 7.19–7.26 (m, 5 H). MS (EI): m/z (%) = 270 (32)
[M+], 213 (2), 147 (43), 124 (100), 103 (5), 91 (12), 77 (7),
43 (43). IR (neat): n = 3030, 2940, 1720, 1490, 1455, 1410,
1360, 1150, 1020, 810, 700, 535, 500 cm–1.
Compound 2g: 1H NMR (400 MHz, CDCl3): d = 1.30 (t,
J = 7.1 Hz, 3 H), 4.30 (q, J = 7.1 Hz, 2 H), 4.71 (s, 2 H), 7.02
(d, J = 6.9 Hz, 2 H), 7.85 (d, J = 6.9 Hz, 2 H), 9.90 (s, 1 H).
IR (neat): n = 2980, 2835, 2770, 1755, 1690, 1600, 1510,
1440, 1380, 1310, 1280, 1205, 1160, 1080, 1025, 835, 715,
610 cm–1. HRMS (EI): m/z calcd for C11H12O4 [M+]:
208.0736; found: 208.0730.
(14) Stutz, P.; Stadler, P. A. Org. Synth., Coll. Vol. VI 1988, 109.
(15) (a) Horvath, I. T.; Anastas, P. T. Chem. Rev. 2007, 107,
2167. (b) Horvath, I. T. Acc. Chem. Res. 2002, 35, 685.
(16) When the pH value was kept higher than 9.5, the
precipitation of Cu(OH)2·2H2O was complete, which was
determined by adding 2 drops of an aq solution of Na2S into
the filtrate. No black CuS appeared.
(17) Conversion of Cu(OH)2·2H2O into CuCl2·2H2O
The above Cu(OH)2·2H2O was first heated at 150 °C for
around 6 h, and the resulting brown anhyd CuO was then
treated with 2.2 molar equivalent of aq HCl at reflux for 2 h.
Removal of H2O under vacuum at 45 °C gave blue
Compound 2h: 1H NMR (400 MHz, CDCl3): d = 1.30 (t,
J = 7.1 Hz, 3 H), 3.96 (s, 1 H), 4.28 (q, J = 7.1 Hz, 2 H), 4.79
(s, 2 H), 6.84 (d, J = 8.1 Hz, 1 H), 7.41–7.46 (m, 2 H), 9.87
(s, 1 H). IR (KBr): n = 2980, 2940, 2910, 1750, 1680, 1590,
1510, 1470, 1430, 1395, 1270, 1200, 1140, 1070, 1030, 870,
810, 780, 735, 640 cm–1. HRMS (EI): m/z calcd for C12H14O5
[M+]: 238.0841; found: 238.0839.
Compound 2m: 1H NMR (400 MHz, CDCl3): d = 7.52 (dd,
J1 = 1.6 Hz, J2 = 8.6 Hz, 1 H), 7.67 (d, J = 1.6 Hz, 1 H), 8.29
crystalline CuCl2·2H2O in a nearly quantitative yield.
Synlett 2011, No. 7, 1028–1032 © Thieme Stuttgart · New York

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