A practical oxidative conversion of aldehydes into N-chloroaldimines

Article abstract of DOI:10.3184/174751918X15403084696731

A novel method for the preparation of N-chloroaldimines from commonly available aromatic aldehydes has been developed. The reaction proceeded effectively by two steps: aldehydes were initially transformed into imines and then chloro-substitution with NaClO₂ gave the N-chloroaldimines. This simple protocol allows for the preparation of a variety of aromatic N-chloroaldimines in moderate to excellent yields without the isolation of the imine intermediate. We also found that 3-nitrobenzaldehyde and 4-cyanobenzaldehyde were converted into the related benzonitrile directly under the standard conditions.

Full text of DOI:10.3184/174751918X15403084696731

JOURNAL OF CHEMICAL RESEARCH 2018
VOL. 42 NOVEMBER, 547–551
RESEARCH PAPER 547
A practical oxidative conversion of aldehydes into N-chloroaldimines
Can Jina,c*, Feng Wanga, Bin Sunb and Xiaohui Zhuanga
aCollege of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P.R. China
bCollaborative Innovation Centre of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P.R. China
cKey Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou 310014, P.R. China
A novel method for the preparation of N-chloroaldimines from commonly available aromatic aldehydes has been developed. The reaction
proceeded effectively by two steps: aldehydes were initially transformed into imines and then chloro-substitution with NaClO2 gave the
N-chloroaldimines. This simple protocol allows for the preparation of a variety of aromatic N-chloroaldimines in moderate to excellent
yields without the isolation of the imine intermediate. We also found that 3-nitrobenzaldehyde and 4-cyanobenzaldehyde were converted
into the related benzonitrile directly under the standard conditions.
Keywords: aromatic N-chloroaldimines, nitriles, aldehydes, febuxostat
N-chloroaldimines are important compounds not only because
of their interesting chemical and biological properties,1 but
also because they have been widely used as versatile starting
materials for the synthesis of many important compounds. For
example, N-chloroaldimines can be converted into oximes,
amines2 and nitriles3 by hydroxylation, hydrogenation and
dehydrochlorination respectively. In addition, isoxazole, an
important structural feature of nucleozin, which is an effective
anti-influenza drug, can be prepared by the ring formation
between N-chloroaldimines and ethyl acetoacetate.4–6
Due to the extensive applications of N-chloroaldimines, studying
efficient strategies for their synthesis is considered highly desirable.
The traditional method for preparation of N-chloroaldimines
involved chloro-substitution of an aromatic oxime, which
could be prepared by condensation between an aldehyde and
hydroxylamine [Scheme 1, Eqn (1)].5 In the past decades, some
research groups have reported novel methods for the synthesis of
N-chloroaldimines. For example, in 2014, Liu et al. described a
facile two-step method for the synthesis of N-chloroaldimines
by chlorination of phenylmethanamine, followed by
dehydrochlorination with Et3N in dichlomethane to yield the final
products [Scheme 1, Eqn (2)].6 Another facile method for the
synthesis of N-chloroaldimines was developed by Gaspa’s group.2
The chlorination of phenylmethanamine and the consequent
dehydrochlorination proceeded well under ball-milling conditions
[Scheme 1, Eqn (3)].7 It is true that progress has been made in the
preparation of N-chloroaldimines but some drawbacks remain,
such as use of a high boiling point solvent, tedious work-up and low
atom economy. Therefore, developing mild and environmentally
friendly methods for the synthesis of N-chloroaldimines is still
important. We envisaged that the synthesis of N-chloroaldimines
could also be achieved by chlorination of aldimines, which could be
easily prepared by the condensation of aldehydes and amines. We
report here a novel and convenient method for the transformation
of aldehydes to N-chloroaldimines. Firstly, aromatic aldehydes
were reacted with NH4OAc in ethanol at 50 °C for 1 h, forming the
corresponding imine. Then NaClO2 (80%) was added directly to
the mixture and the N-chloroaldimine was obtained after stirring
for a few hours [Scheme 1, Eqn (4)].
Results and discussion
To begin our study, benzaldehyde (1a) was chosen as a model
substrate. The initial reaction of benzaldehyde with NH4OAc
and NaClO2 (added in simultaneously) in ethanol resulted in a
poor yield, which could be attributed to the inevitable oxidation
of benzaldehyde to benzoic acid. This result might indicate
Scheme 1 Formation of N-chloroaldimines from aldehydes.
* Correspondent. E-mail: jincan@zjut.edu.cn

548 JOURNAL OF CHEMICAL RESEARCH 2018
that benzaldehyde should be transformed into the aldimine
first in order to avoid direct oxidation by NaClO2. A range of
solvents for this condensation was originally studied and the
results showed that ethanol was the best choice compared with
the other screened solvents (toluene, methanol, acetonitrile and
acetone). Subsequently, for the complete conversion of aldehyde
1, it was observed that the use of 2.0 equiv. of NH4OAc in
ethanol at 50 °C for 1 h is necessary.
(Table 2, entries 2–13). Furthermore, substituents at different
positions of the benzene ring showed no effect on this reaction.
For example, 2-chloro- or 3-chloro-benzaldehyde gave the
corresponding products in yields of 67 and 72% respectively.
Gratifyingly, a heterocyclic aldehyde, 5-bromo-2-furaldehyde,
also showed excellent tolerance for this transformation and gave
the chloro-product in 62% yield.
Unexpectedly, some of the aromatic aldehydes gave not
only the corresponding N-chloroaldimines, but also the
aromatic nitrile 2′ by dehydrochlorination.8,9 For example,
under the optimised conditions, 3-nitrobenzaldehyde (1o)
yielded the N-chloroaldimine and nitrile with yields of 15
and 54% respectively (Table 2, entry 15). With respect to the
4-formylbenzonitrile, the situation is similar (Table 2, entry 16).
A possible mechanism for formation of N-chloroaldimines
2 and nitriles 2′ is proposed in Scheme 2. Initially, the
aldehyde reacts with ammonium acetate to form the aldimine
3, along with AcOH and H2O. Next, the acidified NaClO2
can immediately release chlorine and the aldimine 3 can be
transformed into the N-chloroaldimine 2 by chloro-substitution.
Further dehydrochlorination can afford the benzonitrile product
2′, in the cases of 2o and 2p, which were both unstable and easy
to transform into the cyano compounds.
Febuxostat, a nonpurine xanthine oxidase inhibitor, is
widely used for the treatment of hyperuricemia. Because
of its inhibition of the formation of uric acid, with relatively
few side effects, it plays an increasingly important role in the
treatment of gout. As the key intermediate for the synthesis of
febuxostat, compound 2q′ can be transformed into febuxostat by
Williamson synthesis and subsequent hydrolysis reactions. The
aldehyde 1q, which was prepared by the Duff reaction using
hexamethylenetetramine as the formylation reagent,10 was used
as the starting material to prepare 2q′. The traditional method
Next,thealdiminewastransformedintotheN-chloroaldimine.
Without any prior isolation of the aldimine, NaClO2 (1.0 equiv.)
was directly added and the mixture was stirred in ethanol for
1.5 h. However, only a 10% yield of product was obtained. Then
the effect of different amounts of NaClO2 on chlorination was
studied. A generally increasing trend was observed when the
amount of NaClO2 was increased from 1.0 equiv. to 1.6 equiv.
The highest yield was obtained when 1.6 equiv. of NaClO2 was
used (Table 1, entry 3) and improvement was not observed
beyond this (Table 1, entry 4). Subsequently, our attention was
focused on searching for a suitable temperature for the chloro-
substitution reaction. It was observed that the highest yield was
obtained when the reaction was carried out at 50 °C (Table
1, entry 7) and increasing or decreasing the temperature all
showed a negative effect (Table 1, entries 5, 6, 8). We also found
that appropriately extending the reaction time could contribute
to a higher yield of desired product (Table 1, entries 9–11) and a
slightly lower yield was obtained when the time was prolonged
over 2 h (Table 1, entry 12). Thus, it can be concluded that the
optimised reaction should be performed at 50 °C in EtOH for 2
h using NaClO2 (1.6 equiv.) as chlorination reagent.
Under the optimised conditions, different sets of experiments
were carried out to investigate the scope and limitations of
this reaction. It was found to be applicable to a wide range
of aromatic aldehydes (1a–n), which were able to undergo
the condensation and chlorination to give the corresponding
N-chloroaldimines12–13 in yields of 54–77% (Table 2). The
results demonstrated that aryl aldehydes with either electron-
donating groups such as tert-butyl or hydroxyl or electron-
withdrawing substituents like fluoro, chloro, bromo, nitro,
cyano or trifluoromethyl all afforded satisfactory yields
Table 2 One-pot transfomation of aldehydes to N-chloroaldiminesa
N
C
NH4OAc
,
NaClO2
N l
C
O
+
,
EtOH 50 o
C
EtOH 50 o
C
R
R
R
'
1st step
2nd step
2
2
1
Yieldb (%)
Table 1 Evaluation of various reaction conditionsa
Entry
Substrate
2
2′
–
–
–
–
–
–
–
–
–
–
–
–
–
NH4OAc
NaClO2
N l
C
1
2
3
4
5
6
7
8
R = H (1a)
75
68
77
66
65
67
72
55
58
55
54
55
57
O
R = 4-tBu (1b)
R = 3-OH (1c)
R = 2-F (1d)
R = 4-F (1e)
R = 2-Cl (1f)
R = 3-Cl (1g)
R = 2-Br (1h)
R = 4-Br (1i)
R = 2-NO2 (1j)
R = 4-NO2 (1k)
R = 2-CN (1l)
R = 4-CF3 (1m)
,
EtOH 50 oC
2
1
1st step
2nd step
Entry
NaClO2 (equiv.) Temperature (°C) Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
1
45
45
45
45
35
40
50
60
50
50
50
50
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.5
1.0
2.0
2.5
10
32
56
53
48
50
62
21
25
60
75
72
1.2
1.6
2
9
10
11
12
13
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
O
r
B
H
C
O
9
14
62
–
(1n)
10
11
12
15
16
R = 3-NO2 (1o)
R = 4-CN (1p)
15
22
54
40
aReaction conditions: 1st step, aldehyde (2 mmol), EtOH (15 mL), NH4OAc (4 mmol),
50 °C, 1 h; 2nd step, NaClO2 (80%, 3.2 mmol), 50 °C, 2 h.
bIsolated yields.
aReaction conditions: 1st step, aldehyde (2 mmol), EtOH (15 mL), NH4OAc (4 mmol),
50 °C, 1 h.
bIsolated yields.

JOURNAL OF CHEMICAL RESEARCH 2018 549
H l
C O2
decomposition
H
H
O
NH
NH4OAc
l
C
l
C
N
l
C
-H2O, HOAc
R
R
R
3
1
2
N
C
R
'
2
Scheme 2 A possible mechanism.
Scheme 3 Synthesis of febuxostat intermediate.
values (ppm) relative to TMS and observed coupling constants (J) are
given in Hertz (Hz). Mass spectra were measured with an HRMS–
EI (Waters GCT Premier) and ESI (Agilent 1200) instrument or a
low-resolution MS instrument using EI (Thermo Fisher ITQ1100)
and ESI (Thermo Fisher LCQTM Deca XP plus). All reagents were
purchased from Aladdin Industrial Corporation and used without prior
purification. Column chromatography was performed on silica gel
(200–300 mesh) and the elution was performed with n-hexane/ethyl
acetate.
for the synthesis of 2q′ was by the condensation between 1q
and NH2OH.HCl, followed by dehydration with HCOOH/
HCOONa.11 However, the excessive amount of HCOOH may
prevent its further application. Employing our procedure it
was possible that the transformation of aldehyde into nitrile
directly could occur directly, such as in the cases of 2o′ and
2p′. Gratifyingly, employing our methods, the compound 1q
was successfully transformed into the desired product 2q′ by
condensation and chlorination on treatment with NH4OAc and
NaClO2 in a total yield of 70%, as shown in Scheme 3. Thus it
may provide a more convenient, environmentally friendly and
high atom economy method for preparation of 2q′.
Synthesis of N-chloro aldimines and nitriles; general procedure
A suspension of an aldehyde 1 (2 mmol) and NH4OAc (0.308 g,
4 mmol) in ethanol (15 mL) was stirred for 1 h at 50 °C. NaClO2 (80%,
0.36 g, 3.2 mmol) was then added and the mixture was stirred strongly
for 2 h. After cooling, the filtrates were rotary-evaporated to dryness
and the residues were purified by column chromatography on silica
gel (ethyl acetate/n-hexane, 1:100) to afford compounds 2a–p and
compounds 2o′–q′.
Conclusion
In conclusion, we have developed a novel efficient two-step
method for the synthesis of N-chloroaldimines. A variety
of aromatic aldehydes were smoothly converted into the
corresponding aromatic N-chloroaldimines by treatment with
NH4OAc in ethanol, followed by chlorination with NaClO2.
Under the same reaction conditions, 3-nitrobenzaldehyde
and 4-cyanobenzaldehyde were converted into the related
benzonitrile directly. In addition, applying this novel strategy,
the key intermediate for febuxostat (2q′) could be obtained
by condensation and chlorination of 1q in 70% yield, which
extended its application in the pharmaceutical industry. To the
best of our knowledge, there are no examples describing the
synthesis of aromatic N-chloroaldimines 2a–p and nitriles 2o′,
2p′ and 2q′ employing the new strategy.
Benzalchloroimine (2a):12 Colourless oil; 1H NMR (600 MHz,
CDCl3): δ 8.83 (s, 1H), 7.71–7.69 (m, 2H), 7.54–7.51 (m, 1H), 7.48–7.45
(m, 2H); 13C NMR (150 MHz, CDCl3): δ 172.6, 133.2, 132.1, 128.9,
128.0; HRMS (EI) calcd for C7H6NCl: [M (35Cl)]+: 139.0189; found:
139.0198 (100%); [M (37Cl)]+: 141.0159; found: 141.0168 (31.5%).
4-tert-Butylbenzalchloroimine (2b): Colourless oil; 1H NMR
(600 MHz, CDCl3): δ 8.80 (s, 1H), 7.64–7.63 (m, 2H), 7.49–7.48 (m,
2H), 1.37 (s, 9H); 13C NMR (150 MHz, CDCl3): δ 172.5, 155.8, 130.5,
127.9, 125.9, 35.1, 31.1; HRMS (EI) calcd for C11H14NCl: [M (35Cl)]+:
195.0815; found: 195.0821 (100.0%); [M (37Cl)]+: 195.0785; found:
197.0816 (31.7%).
3-Hydroxybenzalchloroimine (2c): Colourless oil; 1H NMR
(500 MHz, CDCl3): δ 8.76 (s, 1H), 7.33 (t, J = 9.8 Hz, 1H), 7.23–7.22
(m, 1H), 7.20 (d, J = 9.8 Hz, 1H), 7.03 (dd, J1 = 8.0 Hz, J2 = 3.8 Hz, 1H);
13C NMR (125 MHz, CDCl3): δ 172.6, 156.1, 134.4, 130.4, 121.5, 119.7,
113.7; HRMS (ESI) calcd for C7H7NClO: [M (35Cl) + H]+: 156.0211;
found: 156.0209 (100.0%); [M (37Cl) + H]+: 158.0187; found: 158.0184
(32.0%).
Experimental
Melting points were determined using a digital melting point apparatus
1
(Büchi B-540) and are uncorrected. H and 13C NMR spectra were
recorded on two Varian spectrometers (Bruker Avance III HD Ascend
600 MHz and Bruker Avance III 500MHz) at working frequencies 600
and 150 MHz (or 500 and 125 MHz) respectively in CDCl3 (or DMSO)
using TMS as internal standard. All chemical shifts are reported as δ
2-Fluorobenzalchloroimine (2d): Colourless oil; 1H NMR
(500 MHz, CDCl3): δ 9.09 (s, 1H), 7.92–7.89 (m, 1H), 7.53–7.48 (m,

550 JOURNAL OF CHEMICAL RESEARCH 2018
1H), 7.23 (t, J = 0.8 Hz, 1H), 7.16–7.12 (m, 1H); 13C NMR (125 MHz,
CDCl3): δ 166.4 (d, JC–F = 5.0 Hz), 161.2 (d, JC–F = 253.7 Hz), 133.9
(d, JC–F = 8.8 Hz), 127.4 (d, JC–F = 1.8 Hz), 124.7 (d, JC–F = 3.6 Hz),
121.0 (d, JC–F = 9.9 Hz), 116.2 (d, JC–F = 20.8 Hz); HRMS (EI) calcd
for C7H5NFCl: [M (35Cl)]+: 157.0095; found: 157.0086 (100.0%); [M
(37Cl)]+: 159.0065; found: 157.0067 (31.8%).
136.1, 133.5 (q, JC–F = 32.6 Hz), 128.3, 126.0 (q, JC–F = 3.8 Hz), 123.6
(q, JC–F = 270.9 Hz); HRMS (EI) calcd for C8H4NF3: [M – HCl]+:
171.0296; found: 171.0310.
5-Bromofuran-2-N-chloroaldimine (2n): Pale yellow
1
oil; H NMR
(600 MHz, CDCl3): δ 8.53 (s, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.50 (d,
J = 2.4 Hz, 1H); 13C NMR (150MHz, CDCl3): δ 159.6, 149.6, 128.0,
118.2, 114.2; HRMS (EI) calcd for C5H2NOBr: [M (79Br) – HCl]+:
170.9320; found: 170.9316; [M (81Br) – HCl]+: 172.9299; found:
172.9302.
4-Fluorobenzalchloroimine (2e): Colourless oil; 1H NMR
(600 MHz, CDCl3): δ 8.80 (s, 1H), 7.73–7.70 (m, 2H), 7.17–7.14 (m,
2H); 13C NMR (150 MHz, CDCl3): δ 171.2, 165.0 (d, JC–F = 252.2 Hz),
130.2 (d, JC–F = 8.9 Hz), 129.5 (d, JC–F = 3.3 Hz), 116.3 (d, JC–F = 22.1
Hz); HRMS (EI) calcd for C7H5NFCl: [M (35Cl)]+: 157.0095; found:
157.0100 (100.0%); [M (37Cl)]+: 159.0065; found: 159.0081 (31.9%).
2-Chlorobenzalchloroimine (2f):13 Colourless oil; 1H NMR
(600 MHz, CDCl3): δ 9.27 (s, 1H), 7.98–7.97 (m, 1H), 7.59–7.54(m,
1H), 7.45–7.44 (m, 1H), 7.36–7.33 (m, 1H); 13C NMR (150 MHz,
CDCl3): δ 169.6, 134.7, 133.0, 130.7, 130.1, 128.0, 127.3; MS (EI) m/z
(%) = 173.0 ([M (35Cl)]+, 100.0%), 175.0 ([M (37Cl)]+, 32.0%); HRMS
(EI) calcd for C7H5NCl2: [M (35Cl)]+: 172.9799; found: 172.9810
(100.0%); [M (35Cl + 37Cl)]+: 174.9770; found: 174.9783 (63.9%).
3-Chlorobenzalchloroimine (2g): Colourless oil; 1H NMR
(600 MHz, CDCl3): δ 8.78 (s, 1H), 7.72 (t, J = 0.3 Hz, 1H), 7.57–7.55
(m, 1H), 7.50–7.48 (m, 1H), 7.41 (t, J = 6.0 Hz, 1H); 13C NMR (150
MHz, CDCl3): δ 171.3, 135.2, 134.7, 132.1, 130.3 127.7, 126.3; MS
(EI) m/z (%) = 173.0 ([M (35Cl)]+, 100.0%), 175.0 ([M (37Cl)]+, 31.9
%); HRMS (EI) calcd for C7H5NCl2: [M (35Cl) – HCl]+: 137.0032;
found: 137.0037 (100.0%); [M(37Cl) – HCl]+: 139.0005; found:
139.0003 (31.9%).
2-Bromobenzalchloroimine (2h): Pale yellow oil; 1H NMR
(600 MHz, CDCl3): δ 9.23 (s, 1H), 7.97–7.96 (m, 1H), 7.64–7.63
(m, 1H), 7.41–7.36 (m, 2H); 13C NMR (150 MHz, CDCl3): δ 171.9,
133.4, 133.2, 132.3, 128.5, 127.9, 124.5; MS (EI) m/z (%) = 218.9 ([M
(35Cl) (81Br)]+ & [M (37Cl) (79Br)]+, 100.0 %), 216.9 ([M (35Cl) (79Br)]+,
77.6 %), 220.9 ([M (37Cl) (81Br)]+, 24.0 %); HRMS (EI) calcd for
C7H5NClBr: [M (35Cl) (81Br)]+ & [M(37Cl) (79Br)]+: 218.9271; found:
218.9285 (100.0%); [M(35Cl) (79Br)]+: 216.9294; found: 216.9306
(77.3%); [M (37Cl) (81Br)]+: 220.9244; found: 220.9267 (24.2%).
4-Bromobenzalchloroimine (2i): Pale yellow oil; 1H NMR
(500 MHz, CDCl3): δ 8.77 (s, 1H), 7.61–7.58 (m, 2H), 7.56–7.54
(m, 2H); 13C NMR (125 MHz, CDCl3): δ 171.5, 132.6, 132.3, 129.3,
126.9; MS (EI) m/z (%) = 218.9 ([M (35Cl) (81Br)]+ & [M (37Cl)
(79Br)]+, 100.0%), 216.9 ([M (35Cl) (79Br)]+, 76.6%), 220.9 ([M(37Cl)
(81Br)]+, 24.4%); HRMS (EI) calcd for C7H5NClBr: [M (35Cl) (81Br)]+
& [M(37Cl) (79Br)]+: 218.9271; found: 218.9298 (95.0%); [M (35Cl)
(79Br)]+: 216.9294; found: 216.9309 (100%); [M (37Cl) (81Br)]+:
220.9245; found: 216.9267 (20.1%).
3-Nitrobenzalchloroimine (2o):13 Pale yellow oil; 1H NMR
(600 MHz, CDCl3): δ 8.93 (s, 1H), 8.55 (t, J = 1.8 Hz, 1H), 8.39–8.37
(m, 1H), 8.07 (d, J = 6.6 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H); 13C NMR (150
MHz, CDCl3): δ 170.3, 148.6, 134.6, 133.2, 130.2, 126.4, 122.9; MS
(EI) m/z (%) = 184.0 ([M (35Cl)]+, 100.0%), 186.0 ([M (37Cl)]+, 32.1%);
HRMS (EI) calcd for C7H5N2O2Cl: [M (35Cl)]+: 184.0040; found:
184.0047 (100%); [M (37Cl)]+: 186.0010; found: 186.0022 (31.8%).
3-Nitrobenzonitrile (2o′): Pale yellow solid; m.p. 115.3–117.0 °C
(lit. 14 116 °C); 1H NMR (600 MHz, CDCl3): δ 8.56 (s, 1H), 8.51–8.50
(m, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.78–7.76 (t, J = 8.4Hz, 1H);
13C NMR (150 MHz, CDCl3): δ 148.3, 137.6, 130.7, 127.5, 127.2,
116.5, 114.2; MS (EI) m/z = 148.0 [M]+ (lit. MS (EI) m/z = 148.0
[M]+).
4-Cyanobenzalchloroimine (2p): Colourless oil; 1H NMR
(500 MHz, CDCl3): δ 8.87 (s, 1H), 7.82 (d, J = 10.5 Hz, 2H), 7.77 (d,
J = 10.5 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 170.9, 136.7, 132.7,
128.4, 117.9, 115.4; HRMS (EI) calcd for C8H5N2Cl: [M (35Cl)]+:
164.0141; found: 164.0148 (100%); [M (37Cl)]+: 166.0112; found:
166.0110 (32.0%).
Terephthalonitrile (2p′): White solid; m.p. 222.5–223.6 °C (lit.15
224 °C); 1H NMR (500 MHz, DMSO): δ 8.10 (s, 4H); 13C NMR (125
MHz, DMSO): δ 133.2, 117.5, 115.7; MS (EI) m/z = 128.0 [M]+ (lit.15
MS (EI) m/z = 128.0 [M]+).
Synthesis of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-
5-carboxylate (2q′)
A solution of 1q (1.00 g, 3.4 mmol) and NH4OAc (0.54 g, 6.8 mmol)
in ethanol (15 mL) was stirred for 30 min at 50 °C. NaClO2 (80%,
0.62 g, 5.4 mmol) was then added and the mixture was stirred for 2
h under nitrogen (TLC control, petroleum ether [boiling range:
60–90 °C)/EtOAc (3:1, v/v)]. After cooling, the filtrate was rotary-
evaporated to dryness and the residues were purified by column
chromatography on silica gel (ethyl acetate/n-hexane, 1:8) to afford
2q′ [yield 0.69 g (70%)].
Ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate
(2q′): Pale yellow solid; m.p. 184.5–185.5 °C (lit.11 184.7–185.4 °C);
1H NMR (600 MHz, DMSO): δ 11.89 (s, 1H), 8.15 (d, J = 2.4 Hz, 1H),
8.05 (dd, J1 = 2.4 Hz, J2 = 4.2 Hz, 1H), 7.11–7.09 (m, 1H), 4.27 (q, J =
7.2 Hz, 2H), 2.63 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz,
DMSO): δ 167.5, 162.9, 161.7, 160.5, 133.3, 131.9, 124.3, 121.3, 117.4,
116.4, 100.3, 61.6, 17.6, 14.6; MS (ESI): 289.1 [M + H]+ (lit.11 MS (ESI):
286.9 [M – H]–).
2-Nitrobenzalchloroimine (2j): Pale yellow oil; 1H NMR
(500 MHz, CDCl3): δ 9.38 (s, 1H), 8.17 (dd, J1 = 1.0 Hz, J2 = 3.2 Hz,
1H), 7.98–7.97 (dd, J1 = 3.0 Hz, J2 = 1.5 Hz, 1H), 7.78–7.74 (td, J1 =
0.8 Hz, J2 = 3.0 Hz, 1H), 7.72–7.69 (m, 1H); 13C NMR (125 MHz,
CDCl3): δ 169.4, 147.5, 134.1, 132.2, 129.7, 128.3, 124.9; MS (EI) m/z
(%) = 184.0 ([M (35Cl)]+, 100.0%), 186.0 ([M (37Cl)]+, 32.0%); HRMS
(EI) calcd for C7H5N2O2Cl: [M (35Cl)]+: 184.0040; found: 184.0033
(100.0%); [M (37Cl)]+: 186.0010; found: 185.9986 (29.5%).
Acknowledgements
We are grateful to the National Natural Science Foundation
of China (21606202) and the Collaborative Innovation Centre
of Yangtze River Delta Region Green Pharmaceuticals for
financial help.
4-Nitrobenzalchloroimine
(2k):
Pale
yellow oil;
1H NMR (500 MHz, CDCl3): δ 8.93 (s, 1H), 8.33 (d, J = 11.3 Hz, 2H),
7.91–7.89 (d, J = 10.5 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 170.5,
149.7, 138.3, 128.8, 124.2; MS (EI) m/z (%) = 184.0 ([M (35Cl)]+,
100.0%), 186.0 ([M (37Cl)]+, 31.7%); HRMS (EI) calcd for C7H4N2O2:
[M – HCl]+: 148.0273; found: 148.0276.
Received 23 March 2018; accepted 18 August 2018
Paper 1805338
https://doi.org/10.3184/174751918X15403084696731
Published online: 29 October 2018
2-Cyanobenzalchloroimine (2l): Pale yellow oil; 1H NMR
(500 MHz, CDCl3): δ 8.77 (s, 1H), 7.90–7.86 (m, 2H), 7.68–7.64 (m,
2H); 13C NMR (125 MHz, CDCl3): δ 159.5, 147.1, 138.5, 132.5, 132.4,
124.5, 124.0, 122.5; HRMS (EI) calcd for C8H5N2Cl; [M (35Cl)]+:
164.0141; found: 164.0150 (100.0%); [M (37Cl)]+: 166.0112; found:
166.0103 (32.2%).
4-Trifluoromethylbenzalchloroimine (2m): Pale yellow oil;
1H NMR (600 MHz, CDCl3): δ 8.89 (s, 1H), 7.83 (d, J = 7.8 Hz, 2H),
7.74–7.72 (d, J = 8.4 Hz, 2H); 13C NMR (150 MHz, CDCl3): δ 171.3,
References
1
2
R. Kupfer and U.H. Brinker, J. Org. Chem., 1996, 61, 4185.
S. Gaspa, A. Porcheddu, A. Valentoni, S. Garroni, S. Enzo and L.D. Luca,
Eur. J. Org. Chem., 2017, 37, 5519.
3
J.W. Lemaistre, A.E. Rainsford and C.R. Hauser, J. Org. Chem., 1939, 4, 106.

JOURNAL OF CHEMICAL RESEARCH 2018 551
4
5
D. Sun, Z. Wang, Y. Di, J.C. Jaen, M. Labelle, J. Ma, S. Miao, A. Sudom,
L. Tang, C.S. Tomooka, H. Tu, S. Ursu, N. Walker, X. Yan, Q. Ye and J.P.
Powers, Bioorg. Med. Chem. Lett., 2008, 18, 3513.
O. Okamoto, K. Kobayashi, H. Kawamoto, S. Ito, T. Yoshizumi, I.
Yamamoto, M. Hashimoto, A. Shimizu, H. Takahashi, Y. Ishii, S. Ozaki
and H. Ohta, Bioorg. Med. Chem. Lett., 2008, 18, 3282.
J. Liu, J. Xu, J. Ren and B.B. Zeng, Chem. Lett., 2014, 43, 190.
X. Xiong, X. Xu, Y. Zhou and C. Weng, Russ. J. Gen. Chem., 2013, 83,
2402.
9
Y. Kawagoe, K. Moriyama and H. Togo, Eur. J. Org. Chem., 2014, 19, 4115.
10 M. Hasegawa, Heterocycles, 1998, 47, 857.
11 X.L. Li, R. Qiu, W.L. Wan, X. Cheng, L. Hai and Y. Wu, Lett. Org. Chem.,
2015, 12, 217.
12 J.L. Zhang, Gaodeng Xuexiao Huaxue Xuebao, 1987, 8, 246; Chem. Abstr.,
1988, 108, 37295
13 C.R. Hauser, M.L. Hauser and A. Gillaspie, J. Am. Chem. Soc., 1930, 52,
4158.
14 M.V. Roux, P. Jiménez, J.Z. Dávalos, M. Temprado and J.F. Liebman, J.
Chem. Thermodyn., 2003, 35, 803.
6
7
8
J. Liu, H.-X. Zheng, C.-Z. Yao, B.-F. Sun and Y.-B. Kang, J. Am. Chem.
Soc., 2016, 138, 3294.
15 R.J. Abraham and M. Reid, Magn. Reson. Chem., 2000, 38, 570.