Aromatization of 1, 3-cyclohexanediones mediated by bis-(Trichloromethyl) carbonate/DMF system

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Aromatization of 1,3-Cyclohexanediones
Mediated by bis-(Trichloromethyl)
Carbonate/DMF System
X. R. Liang a , F. Shi a , R. E. Chen a & W. K. Su a
a Key Laboratory of Pharmaceutical Engineering of Ministry of
Education, College of Pharmaceutical Sciences , Zhejiang University
of Technology , Hangzhou, P. R. China
Published online: 21 Jul 2010.
To cite this article: X. R. Liang , F. Shi , R. E. Chen & W. K. Su (2010) Aromatization of 1,3-
Cyclohexanediones Mediated by bis-(Trichloromethyl) Carbonate/DMF System, Organic Preparations
and Procedures International: The New Journal for Organic Synthesis, 42:4, 379-385, DOI:
10.1080/00304948.2010.495692
To link to this article: http://dx.doi.org/10.1080/00304948.2010.495692
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Organic Preparations and Procedures International, 42:379–385, 2010
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304948.2010.495692
OPPI BRIEFS
Aromatization of 1,3-Cyclohexanediones Mediated
by bis-(Trichloromethyl) Carbonate/DMF System
X. R. Liang, F. Shi, R. E. Chen, and W. K. Su
Key Laboratory of Pharmaceutical Engineering of Ministry of Education,
College of Pharmaceutical Sciences, Zhejiang University of Technology
Hangzhou, P. R. China
The synthetic potential of the versatile Vilsmeier reaction has been known for years, and
beenwidelyappliedinthepreparationofmedicinalcompounds, pesticides, dyestuffs, etc.1–3
Traditionally, Vilsmeier salts have been generated from phosphorus oxychloride (POCl3)
and N,N-dimethylformamide (DMF). Recently, the potential utilization of Vilsmeier salts
derived from the bis(trichloromethyl) carbonate (BTC)/N,N-dimethylformamide (DMF)
system has been explored extensively.4 In our previous work, new applications of the BTC
Vilsmeier reagent were developed for the preparation of a number of important pharmaceu-
tical intermediates,5–9 and we now report a new application of the same Vilsmeier reagent
for the transformation of 1,3-cyclohexanediones into polysubstituted chlorobenzaldehydes,
some of which are of great importance not only in synthesis but also in biological and indus-
trial applications.10–12 However, to our best knowledge, the synthesis of these compounds
from 1,3-cyclohexanediones has only rarely been reported.10–14
Initially we investigated for the aromatization reaction using 1,3-cyclohexanedione
(1a) as model substrate with BTC/DMF under various conditions. The aromatization of
1,3-cyclohexanediones, as reported in the literature,15–20 generally leads to the formation of
complex products.13,14 In our initial study, the results obtained when 1,3-cyclohexanedione
(1a) was used are shown in Table 1.
Table 1 indicates that the ratio of reagents affect the type of products formed.
When one equivalent of 1a was treated with one equivalent of Vilsmeier reagent (0.33
equivalent of BTC and 1.0 equivalent of DMF) in refluxing 1,2-dichloroethane for 4 h,
3-chlorocyclohex-2-enone (2) was formed in 28% yield; 2,4-dichlorobenzaldehyde (3) and
2,4-dichlorobenzene-1,3,5-tricarbaldehyde (4a) were formed in 42% and 54% yield upon
treatment with excess Vilsmeier reagent (Entries 2 and 3, Table 1). Lower yields were
Submitted January 9, 2009.
Address correspondence to W. K. Su, Key Laboratory of Pharmaceutical Engineering of Ministry
of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou
310014, P. R. China. E-mail: suweike@zjut.edu.cn
379

380
Su et al.
Table 1
Effect of the Ratio of Reagents on Aromatization of 1aa
Ratio of
BTC : DMF : 1a
Yield
(%)b
Entry
Solvent
Conditions
Product
1
2
3
0.33 : 1 : 1
1 : 3 : 1
1.67 : 5 : 1
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
Reflux, 4h
Reflux, 4h
Reflux, 4h
2
3
4a
28
42
54
a) Two mmol of compound 1a were used.
b) Yields based on 1a.
obtained when methylene chloride, DMF and THF were used as solvents. Although 4a was
also formed (in lower yields) from similar treatment of substituted 1,3-cyclohexanediones
(Table 2, Entries 2–4), several by-products were also generated from 1e–g. Surprisingly,
2,4-dichlorobenzaldehyde (3) was the only Vilsmeier aromatization product formed in
42% yield from 1h (Table 2). Katritzky and his group13,14 have reported that 4,6-dichloro-
5-[(dimethylamino)methylene]-cyclohexa-3,6-diene-1,3-dicarbaldehyde, the tautomer of
product 4c, was formed as an intermediate in this reaction; however, only product 4c was
isolated in our work. 2,4-Dichlorobenzene-1,3,5-tricarbaldehyde (4a) was formed in all
Table 2
Synthesis of Substituted Aromatic Compounds under Vilsmeier Conditionsa
Entry
R
Product
R1
R2
Yield (%)b
1
2
3
H (1a)
C6H5CH2 (1b)
p-ClC6H4CO (1c)
4a
4a
4a
CHO
CHO
CHO
—
CHO
—
Cl
Cl
Cl
—
Cl
—
OCHO
Cl
54
22
37
30
35
28
41
26
18
38
20
15
47
17
42
p-ClC6H4CO2H
4
5
C6H5CO (1d)
4a
PhCO2H
4b
CH2CO2Et (1e)
CH2CO2Et
CH2NMe2
CHO
n-Bu
4c
4a
4d
4e
4a
4f
4a
3
Cl
6
n-Bu (1f)
OCHO
OH
Cl
OCHO
Cl
n-Bu
CHO
n-Pr
CHO
H
7
8
n-Pr (1g)
Br (1h)
Cl
a) Substrate 1 (5 mmol), BTC (8.33 mmol), DMF (25 mmol), 4.0 h. The reaction was carried out
in refluxing 1,2-dichloroethane.
b) Yield of isolated products based on 1,3-cyclohexanediones added.

Aromatization of 1,3-Cyclohexanediones
381
Cl
Cl
)
q
e
1
(
CHO
C
D
T
B
)
q
e
3
3
(
F
Cl
O
M
O
O
BTC (0.33 eq)
DMF (1 eq)
B
T
C
(
1
.
6
7
CHO
e
q
D
)
M
F
(
1a
5
2
Cl
Cl
e
q
)
CHO
CHO
4a
Scheme 1
R1
R
Cl
Cl
Cl
R2
BTC (1.67 eq)
BTC (1.67 eq)
DMF (5 eq)
O
O
DMF (5 eq)
CHO
CHO
CHO
R = Br (1b)
4a-4f
1a-1h
3
Scheme 2
reactions except for 1b. In addition to 4a, benzoic acid and 4-chlorobenzoic acid were
isolated in the case of 2-benzoyl-1,3-cyclohexanedione (1c) or 2-(4-chlorobenzoyl)-1,3-
cyclohexanedione (1d) .
Although is possible to rationalize the generation of 4a from 1a as shown in Scheme
3, the mode of formation of 4a from the other substrates remains unclear.
+
+
O
OH
-
NMe2
O
O
O
Cl
Cl
CHCl NMe2
-
DMF
-
Cl
-
HCl
+
NMe2
H
Cl
Cl
Cl
Cl
Vilsmeier
Reagent
Vilsmeier
Reagent
Cl
Cl
+
+
NMe2
NMe2
+
Me2N CHCl
+
NMe2
CHO
CHO
Cl
Cl
Cl
Cl
H2O
[O]
Cl
Cl
+
Me2N
+
-Me2NH
NMe2
CHO
CHO
CHO
CHO
4a
Scheme 3

382
Su et al.
Table 3
Spectral Data for Products
Cmpd.
MS (EI)
1H NMR (δ)
13C NMR (δ)
2
130 (M+, 100),
132 (M+ +
2, 33)
174 (M+, 100),
176 (M+ + 2,
67), 178
(M+ + 4, 11)
230 (M+, 100),
232 (M+ + 2,
67), 234
(M+ + 4, 11)
298 (M+, 11),
211 (100), 213
(33)
2.06–2.12 (m, 2 H, CH2), 2.40 (t, 2 H, 22.6, 33.8, 36.2,
J = 6.8 Hz, CH2), 2.69 (t, 2 H, J =
6.0 Hz, CH2), 6.22 (s, 1 H, CH)
7.37 (d, 1 H, J = 6.8 Hz, Ar H), 7.49
(s, 1 H, Ar H), 7.87 (d, 1 H, J =
8.4 Hz, Ar H), 10.42 (s, 1 H, CHO)
128.4, 158.6,
196.8
128.2, 130.5,
130.7, 131.1,
138.4, 141.3,
188.7
3
4a
4b
8.58 (s, 1 H, Ar H), 10.54 (s, 3 H,
CHO)
132.4, 132.7,
133.7, 143.0,
186.8, 187.2
1.27 (t, 3 H, J = 7.0 Hz, CH3),
4.20–4.25 (m, 2 H, CH2), 4.84
(s, 2 H, CH2), 8.61 (s, 1 H, Ar H),
10.50 (s, 1 H, CHO), 10.52 (s, 1 H,
CHO), 10.61 (s, 1 H, CHO)
10.0, 61.8, 73.3,
127.5, 129.4,
129.9, 134.7,
145.6, 164.6,
168.0, 186.8,
187.6, 187.7
45.5, 59.8, 131.5,
132.8, 133.5,
136.7, 138.3,
141.2, 188.1,
188.6
4c
259 (M+, 23),
261 (M+ + 2,
15), 263
2.32 (s, 6 H, CH3), 3.59 (s, 2 H,
CH2), 8.20 (s, 1 H, Ar H), 10.49 (s,
1 H, CHO), 10.53 (s, 1 H, CHO)
(M+ + 4, 2.5),
58 (100)
4d
268 (M+, 11),
184 (100), 186
(33)
1.01 (t, 3 H, J = 7.5 Hz, CH3),
1.47–1.55 (m, 2 H, CH2), 1.85–1.91
(m, 2 H, CH2), 4.17 (t, 2 H, J =
6.5 Hz, CH2), 8.54 (s, 1 H, Ar H),
10.36 (s, 1 H, CHO), 10.50 (s, 1 H,
CHO), 10.53 (s, 1 H, CHO)
1.02 (t, 3 H, J = 7.5 Hz, CH3),
1.52–1.57 (m, 2 H, CH2), 1.86–1.91
(m, 2 H, CH2), 4.18 (t, 2 H, J = 6.5
Hz, CH2), 7.04 (s, 1 H, Ar OH),
8.41 (s, 1 H, Ar H), 10.33 (s, 1 H,
CHO), 10.41 (s, 1 H, CHO)
13.7, 18.9, 31.8,
80.1, 128.6,
129.0, 129.2,
133.9, 144.5,
166.9, 187.0,
187.1, 187.7
13.7, 19.1, 30.7,
69.5, 114.2,
123.9, 125.8,
130.8, 144.7,
164.6, 187.7
4e
4f
240 (M+, 45),
242 (M+ + 2,
15) 183 (100)
254 (M+, 7), 184 1.07 (t, 3 H, J = 7.5 Hz, CH3),
10.2, 23.2, 81.7,
128.6, 129.0,
129.3, 133.9,
144.6, 166.8,
187.0, 187.1,
187.7
(100), 186 (33)
1.90–1.95 (m, 2 H, CH2), 4.13 (t,
2 H, J = 7.0 Hz, CH2), 8.55 (s, 1 H,
Ar H), 10.37 (s, 1 H, CHO), 10.50
(s, 1 H, CHO), 10.53 (s, 1 H, CHO)

Aromatization of 1,3-Cyclohexanediones
383
Table 4
Mps and Combustion Analyses
mp (◦C)
EA of new
Cmpd.
(lit. mp.)
Compounds (found)
2
3
dense yellow oil23
yellow crystal
71–72
—
—
(68–7013)
4a
4b
yellow crystal
104−105
—
(104−10613,14
white crystal
127.5–128.7
)
C, 52.28 (52.26); H, 3.71 (3.76)
4c
4d
4e
4f
dense yellow oil24
dense yellow oil
dense yellow oil
dense yellow oil
—
C, 58.11 (58.02); H, 4.88 (4.96)
C, 59.88 (59.73); H, 5.44 (5.53)
C, 56.59 (56.49); H, 4.35 (4.42)
In conclusion, although the yields of 3 from 1h and of 4a from 1a are moderate, these
compounds are obtained in one step from simple starting materials instead of the several
steps that might be required to prepare them otherwise.
Experimental Section
Melting points were obtained on a Bu¨chi B-540 melting point apparatus and uncorrected.
Infrared spectra were recorded on a Thermo Nicolet Avatar 370 spectrophotometer. The
NMR spectra were measured with a Bruker Advance III 500 or Varian Mercury plus-400
spectrometer in CDCl3 using TMS as internal standard. Chemical shifts (δ) are expressed
in ppm and coupling constants J are given in Hz. Mass spectra were obtained on a Finnigan
Trace DSQ mass spectrometer. Elemental analysis was determined on a Carlo-Erba 1108
instrument. The starting materials 1,3-cyclohexanediones 1 were prepared according to the
literature 21,22. Organic solvents were obtained from commercial sources.
Preparation of 3-Chlorocyclohex-2-enone (2)
A solution of 1,3-cyclohexanedione 1a (0.56 g, 5 mmol) in 1,2-dichloroethane (10 mL) was
added dropwise to an ice-cooled magnetically stirred mixture of Vilsmeier reagent prepared
from BTC (0.50 g, 1.67 mmol) and DMF (0.36 g, 5 mmol;) in 1,2-dichloroethane (20 mL).
The reaction mixture was gradually allowed to attain room temperature, and the mixture
was heated at reflux for 4 h. The residual solution was poured into crushed ice, stirred
for 1 h, and extracted with ethyl acetate (3 × 30 mL), The organic layer was separated,
washed with water, saturated NaHCO3 and dried over Na2SO4. Evaporation of the solvent,

384
Su et al.
followed by purification of the residue by silica gel column chromatography (petroleum
ether/AcOEt 10:1) gave the product.
The preparation of 2,4-dichlorobenzaldehyde (3) was performed following the proce-
dure described above but with BTC (1.49 g, 5 mmol) and DMF (1.09 g, 15 mmol).
Preparation of Compound 4a. Typical Procedure
A solution of 1,3-cyclohexanedione (1a) (0.56 g, 5 mmol) in 1,2-dichloroethane (20 mL)
was added dropwise to an ice-cooled magnetically stirred mixture of Vilsmeier reagent
prepared from BTC (2.50 g, 8.33 mmol) and DMF (1.82 g, 25 mmol) in 1,2-dichloroethane
(30 mL). The reaction mixture was gradually allowed to attain room temperature and the
mixture was heated at reflux for 4 h. The cooled solution was then poured into crushed ice,
stirred for 1 h, extracted with CHCl3 (3 × 30 mL), concentrated, and chromatographed
on silica gel (petroleum ether/EtOAc 8:1) to give the corresponding products (Tables 2
and 3).
Acknowledgement
We are grateful to National Natural Science Foundation of China (No. 20676123) for
financial support.
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