Design and synthesis of novel n-tert-butyl-N- substitutedbenzoyl-N- [dihydrobenzofuran(chroman)]carbohydrazide Derivatives as Potential insect growth regulators

Article abstract of DOI:10.2174/157017809787003070

Six of new N-tert-butyl-N-substitutedbenzoyl-N-(2,4-dimethyl- 2,3-dihydrobenzofuran)-7-carbohydrazide derivatives and five of new N-tert-butyl-N-substitutedbenzoyl-N-(5-methylchroman) -8-carbohydrazide derivatives were designed and synthesized from m-cres

Full text of DOI:10.2174/157017809787003070

Letters in Organic Chemistry, 2009, 6, 29-36
29
Design and Synthesis of Novel Nꢀ-tert-butyl-Nꢀ-substitutedbenzoyl-N-
[dihydrobenzofuran(chroman)]carbohydrazide Derivatives as Potential
Insect Growth Regulators
Zhiqiang Huang, Qiqi Zhao, Runqiu Huang and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai Uni-
versity, Tianjin 300071, People’s Republic of China
Received June 25, 2008: Revised October 28, 2008: Accepted October 28, 2008
Abstract: Six of new N'-tert-butyl-N'-substitutedbenzoyl-N-(2,4-dimethyl-2,3-dihydrobenzofuran)-7-carbohydrazide
derivatives and five of new N'-tert-butyl-N'-substitutedbenzoyl-N-(5-methylchroman)-8-carbohydrazide derivatives were
designed and synthesized from m-cresol. The synthesis highlighted that some kinds of reactions were ameliorated in
methodology. An important feature is that 1-(3-allyl-2-hydroxy-4-methylphenyl)ethanone can easily be transformed into
1-(2,3-dihydro-2,4-dimethylbenzofuran-7-yl)ethanone just with concentrated sulfuric acid as catalyst. In addition, we
found that 1-(5-methyl-2H-chromen-8-yl)ethanone could not be reduced to 1-(5-methylchroman-8-yl)ethanone directly by
hydrogen with Pd/C as catalyst. It is an effective method for protecting 1-(5-methyl-2H-chromen-8-yl)ethanone with eth-
ylene glycol to obtain 5-methyl-8-(2-methyl-1,3-dioxolan-2-yl)-2H-chromene and then reducing by hydrogen with Pd/C
as catalyst to produce 1-(5-methylchroman-8-yl)ethanone in one step. Furthermore, SOCl2 can convert 2,3-dihydro-2,4-
dimethylbenzofuran-7-carboxylic acid to 2,3-dihydro-2,4-dimethylbenzofuran-7-carbonyl chloride, but it is inefficient for
transforming 5-methylchroman-8-carboxylic acid to the corresponding acyl chloride. Hence, different heterocycles on the
benzene ring of benzoheterocyle moiety have influence on the reaction property of the corresponding acid.
Kewords: Dihydrobenzofuran, chroman, benzoheterocycle, diacylhydrazine, synthesis, insect growth regulator.
INTRODUCTION
tivity to Lepidoptera, diacylhydrazines have attracted con-
siderable attention for decades [1-13]. Recently, it has been
reported that Nꢀ-benzoheterocyclecarbonyl-Nꢀ-tert-butyl-3,5-
dimethylbenzohydrazide analogs showed high insecticidal
Diacylhydrazines as a new class of insect growth regulators
(IGRs) were discovered by Rohm and Hass company in the
R'
HN
O
N
O
N
N
O
H
O
O
O
IIa~IIe
ANS-118
O
R
HN
N
N
O
N
H
O
O
O
O
JS-118
Ia~If
Fig. (1). Design of target molecules Ia~If and IIa~IIe.
mid-1980s [1-3]. Because of its unique action mechanism,
low toxicity to vertebrates and high insecticidal selec-
activities [7-13]. Among them, ANS-118 and JS-118 are the
successful examples. Nꢀ-tert-Butyl-Nꢀ-3,5-dimethylbenzoyl-
N-5-methyl-6-chromancarbohydrazide (Chromafenozide,
ANS-118, Fig. (1)) has been commercialized as insecticide
under the trade name Matric, and Nꢀ-tert-butyl-Nꢀ-3,5-
dimethylbenzoyl-N-2,7-dimethyl-2,3-dihydrobenzofuran-6-
*Address correspondence to this author at the State Key Laboratory of Ele-
mento-Organic Chemistry, Research Institute of Elemento-Organic Chemis-
try, Nankai University, Tianjin 300071, People’s Republic of China;
E-mail: wang98h@263.net; wangqm@nankai.edu.cn
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

30
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Huang et al.
Br
O
O
AlCl3
O
HO
+
O
O
O
HO
O
O
I-1
I-2
I-3
I-4
H2SO4
PhN(C2H5)2
SOCl2
Br2/NaOH
O
O
HO
O
I-7
OH
O
O
I-5
I-6
HN NH
O
R
HN
O
N
Et3N
CH2Cl2
.
Me3CNHNH2 HCl
O
O
O
O
O
Cl
I-8
I-9
Ia-If
Scheme 1.
carbohydrazide (JS-118, Fig. (1)) has been developed by the
Jiangsu Institute of Agricultural Chemical, P. R. China [9,
11]. In the structures of the two compounds, heterocycles of
chroman and dihydrobenzofuran are important parts for their
activities. Inspired by these reports, we developed an idea for
the synthesis of novel N'-tert-butyl-N'-substitutedbenzoyl-N-
(2,3-dihydro-2,4-dimethylbenzofuran)-7-carbohydrazide der-
ivatives (Ia~If) and Nꢀ-tert-butyl-Nꢀ-substitutedbenzoyl-N-
(5-methylchroman)-8-carbohydrazide derivatives (IIa~IIe)
in a research for new insect growth regulators (Fig. (1)).
chlorobenzene as solvent and polyphosphoric acid (PPA) as
catalyst [15], which is not effective for transforming 1-(3-
allyl-2-hydroxy-4-methylphenyl)ethanone (I-5) into 1-(2,3-
dihydro-2,4-dimethylbenzofuran-7-yl)ethanone (I-6). The
intermediate I-6 was oxidized by using bromine and sodium
hydroxide to 2,3-dihydro-2,4-dimethylbenzofuran-7-carbo-
xylic acid (I-7), subsequent treatment with thionyl chloride
provided the corresponding acyl chloride I-8, further reac-
tion with tert-butylhydrazine hydrochloride gave N-tert-
butyl-N'-2,3-dihydro-2,4-dimethylbenzofuran-7-carbohydra-
zide (I-9). Then the key intermediate I-9 was condensed with
various substituted benzoylchloride in dichloromethane us-
ing triethylamine as proton scavenger to obtain the target
compounds Ia~If. The physical properties and elemental
analyses or HRMS of compounds Ia~If are listed in Table 1,
and their 1H NMR is listed in Table 2.
RESULTS AND DISCUSSION
The synthetic pathway for N'-tert-butyl-N'-substituted-
benzoyl-N-(2,3-dihydro-2,4-dimethylbenzofuran)-7-carbohy-
drazide (Ia~If) is outlined in Scheme 1. m-Tolyl acetate (I-2)
and 1-(2-hydroxy-4-methylphenyl)ethanone (I-3) were syn-
thesized from m-cresol according to the literature and their
1H NMR spectra were in agreement with those reported in
the literature [14]. 1-[2-(Allyloxy)-4-methylphenyl]ethanone
(I-4) was synthesized from 1-(2-hydroxy-4-methylphenyl)
ethanone (I-3) and 3-bromoprop-1-ene under phase transfer
catalytic condition and then refluxed in N,N-diethylaniline to
give 1-(3-allyl-2-hydroxy-4-methylphenyl)ethanone (I-5).
Then we successfully got 1-(2,3-dihydro-2,4-dimethyl-
benzofuran-7-yl)ethanone (I-6) from the phenylehanone I-5
just with concentrated sulfuric acid as catalyst. The reaction
was improved with respect to the reported condition using
The process of synthesis of N'-tert-butyl-N'-substitute-
dbenzoyl-N-(5-methylchroman)-8-carbohydrazide
deriva-
tives (IIa~IIe) is shown in Scheme 2.
1-(4-Methyl-2-(prop-2-ynyloxy)phenyl]ethanone (II-1)
was obtained in excellent yield by the reaction of 1-(2-
hydroxy-4-methylphenyl)ethanone (I-3) with 3-bromoprop-
1-yne using tetrabutylammonium bromide as phase transfer
catalytic condition, and then refluxed in N,N-diethylaniline
to give 1-(5-methyl-2H-chromen-8-yl)ethanone (II-2)
through claisen rearrangement. Initially, we expected to re-
duce 1-(5-methyl-2H-chromen-8-yl)ethanone (II-2) to 1-(5-

Design and Synthesis of Novel
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
31
Table 1. Physical Properties and Elemental Analyses (HRMS) of Target Compounds Ia~If and IIa~IIe
elem anal. (%, calc)
H
Compd.
R (Rꢀ)
Yield (%)
mp (˚C)
C
N
Ia
Ib
H
3-Me
86
64
93
53
47
41
79
74
38
76
39
207-208
112-114
133-134
182-183
176-177
101-103
240-242
jelly
72.27 (72.11)
72.65 (72.60)
65.89 (65.91)
73.31 (73.07)
60.79 (60.70)
6.97 (7.15)
7.53 (7.64)
7.34 (7.36)
7.05 (7.11)
6.91 (7.10)
6.20 (6.43)
7.31 (7.42)
Ic
3-Cl
6.32 (6.29)
Id
3,5-Me2
3,5-Cl2
3,5-(NO2)2
H
7.79 (7.66)
Ie
5.74 (5.56)
If
457.1713 (457.1718)a
389.1836 (389.1836)b
412.1866 (412.1867)a
457.1050 (457.1056)b
395.2335 (395.2329)a
423.1454 (423.1446)b
IIa
IIb
IIc
IId
IIe
2-NO2
3-Cl
182-184
190-192
149-151
3,5-Me2
2,4-Cl2
aThe [M+H]+ value of HRMS.
bThe [M+Na]+ value of HRMS.
Table 2. 1H NMR Spectral Data of Target Compounds Ia~If and IIa~IIe
Compd.
Ia
1H NMR (ꢁppm)
(400MHz, CDCl3): 9.16 (brs, 1H, NH); 7.63 (d, 1H, 3JHH = 7.9 Hz, Ph);7.45-7.52 (m, 2H, Ph)；7.21 (brs, 3H, Ph); 6.69 (d, 1H, 3JHH = 8.1 Hz,
Ph); 4.99-5.14 (m, 1H, CH); 3.19-3.30 (m, 1H, CH2); 2.64-2.76 (m, 1H, CH2); 2.20 (s, 3H, PhCH3); 1.58 (s, 9H, C(CH3)3); 1.48 (d, 3H, 3JHH
6.2 Hz, CCH3)
=
(300MHz, CDCl3): 9.14 (brs, 1H, NH); 7.62-7.66 (m, 1H, Ph); 7.23-7.33 (m, 2H, Ph); 7.00-7.11 (m, 2H, Ph); 6.70 (d, 1H, 3JHH = 8.1 Hz, Ph);
4.98-5.14 (m, 1H, CH); 3.19-3.30 (m, 1H, CH2); 2.64-2.76 (m, 1H, CH2); 2.24 (d, 3H, 4JHH = 3.6 Hz, PhCH3); 2.20 (s, 3H, PhCH3); 1.57 (s,
9H, C(CH3)3); 1.46 (d, 3H, 3JHH = 6.2 Hz, CCH3)
Ib
Ic
Id
Ie
If
(300MHz, CDCl3): 9.17 (brs, 1H, NH); 7.56-7.65 (m, 1H, Ph); 7.37-7.47 (m, 2H, Ph); 7.12-7.17 (m, 2H, Ph); 6.71 (d, 1H, 3JHH = 8.0 Hz, Ph);
5.05-5.15 (m, 1H, CH); 3.22-3.30 (m, 1H, CH2); 2.66-2.77 (m, 1H, CH2); 2.21 (s, 3H, PhCH3); 1.56 (s, 9H, C(CH3)3); 1.46 (d, 3H, 3JHH = 6.1
Hz, CCH3)
(300MHz, CDCl3): 9.12 (brs, 1H, NH); 7.66 (t, 1H, 3JHH = 7.6 Hz, Ph); 7.09 (d, 2H, 4JHH = 14.0 Hz, Ph); 6.84 (s, 1H, Ph); 6.71 (d, 1H, 3JHH
=
8.1 Hz, Ph); 4.97-5.13 (m, 1H, CH); 3.19-3.30 (m, 1H, CH2); 2.65-2.77 (m, 1H, CH2); 2.21 (s, 6H, PhCH3); 1.57 (s, 9H, C(CH3)3); 1.41 (d,
3H, 3JHH = 6.1 Hz, CCH3)
(300MHz, CDCl3): 9.12 (brs, 1H, NH); 7.64 (t, 1H, 3JHH = 6.7 Hz, Ph); 7.38 (d, 2H, 3JHH = 11.3 Hz, Ph); 7.21 (s, 1H, Ph); 6.73 (d, 1H, 3JHH
=
8.1 Hz, Ph); 5.08-5.16 (m, 1H, CH); 3.23-3.32 (m, 1H, CH2); 2.69-2.79 (m, 1H, CH2); 2.23 (s, 3H, PhCH3); 1.55 (s, 9H, C(CH3)3); 1.50 (t, 3H,
3JHH = 6.4 Hz, CCH3)
(300MHz, CDCl3): 9.10 (brs, 1H, NH); 9.00 (t, 1H, 4JHH = 2.0 Hz, Ph); 8.79 (d, 2H, 4JHH = 2.0 Hz, Ph); 7.30 (d, 1H, 3JHH = 8.0 Hz, Ph); 6.67 (d,
1H, 3JHH = 8.0 Hz, Ph);4.81-4.93 (m, 1H, CH); 3.11-3.19 (m, 1H, CH2); 2.58-2.66 (m, 1H, CH2); 2.17 (s, 3H, PhCH3); 1.29 (s, 3H, CCH3);
0.95 (s, 9H, C(CH3)3)
(400MHz, CDCl3): 9.32 (s, 1H, NH); 7.65 (d, 1H, 3JHH = 8.0 Hz, Ph); 7.46-7.48 (m, 2H, Ph); 7.21-7.24 (m, 3H, Ph); 6.75 (d, 1H, 3JHH = 8.0
Hz, Ph); 4.19-4.23 (m, 2H, CH2); 2.59-2.62 (m, 2H, CH2); 2.16 (s, 3H, PhCH3); 2.01-2.04 (m, 2H, CH2); 1.57 (s, 9H, C(CH3)3)
IIa
IIb
(400MHz, CDCl3): 9.60 (s, 1H, NH); 8.04 (d, 1H, 3JHH = 8.3 Hz, Ph); 7.82-7.84 (m, 1H, Ph); 7.64 (d, 1H, 3JHH = 7.9 Hz, Ph); 7.55-7.56 (m,
1H, Ph); 7.32-7.37 (m, 1H, Ph); 6.73 (d, 1H, 3JHH = 8.0 Hz, Ph); 4.09-4.16 (m, 2H, CH2); 2.49-2.61 (m, 2H, CH2); 2.14 (s, 3H, PhCH3); 1.99-
2.04 (m, 2H, CH2); 1.60 (s, 9H, C(CH3)3)
(400MHz, CDCl3): 9.35 (s, 1H, NH); 7.67 (d, 1H, 3JHH = 8.0 Hz, Ph); 7.43 (s, 1H, Ph); 7.39 (d, 1H, 3JHH = 7.3 Hz, Ph); 7.13-7.21 (m, 2H, Ph);
6.77 (d, 1H, 3JHH = 8.1 Hz, Ph); 4.25-4.29 (m, 2H, CH2); 2.61-2.64 (m, 2H, CH2); 2.18 (s, 3H, PhCH3); 2.04-2.07 (m, 2H, CH2); 1.56 (s, 9H,
C(CH3)3)
IIc
(400MHz, CDCl3): 9.35 (s, 1H, NH); 7.61 (d, 1H, 3JHH = 7.8 Hz, Ph); 7.05 (s, 2H, Ph); 6.81 (s, 1H, Ph); 6.69 (d, 1H, 3JHH = 7.8 Hz, Ph); 4.19-
4.21 (m, 2H, CH2); 2.55-2.57 (m, 2H, CH2); 2.16 (s, 6H, PhCH3); 2.12 (s, 3H, PhCH3); 2.00-2.05 (m, 2H, CH2); 1.54 (s, 9H, C(CH3)3)
IId
IIe
(400MHz, CDCl3): 9.66 (s, 1H, NH); 7.67 (d, 1H, 3JHH = 8.0 Hz, Ph); 7.35 (d, 1H, 3JHH = 8.3 Hz, Ph); 7.24 (s, 1H, Ph); 7.10 (d, 1H, 3JHH = 8.3
Hz, Ph); 6.77 (d, 1H, 3JHH = 8.0 Hz, Ph); 4.30-4.35 (m, 2H, CH2); 2.60-2.64 (m, 2H, CH2); 2.18 (s, 3H, PhCH3); 2.02-2.08 (m, 2H, CH2); 1.56
(s, 9H, C(CH3)3)

32
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Huang et al.
OH
OH
Br
PhN(C2H5)2
O
O
HO
O
O
O
O
O
O
II-1
II-2
I-3
II-3
COCl
H2,Pd/C
.
Me3CNHNH2 HCl
Br2/NaOH
COCl
O
O
O
O
O
OH
O
Cl
II-4
II-5
II-6
R'
HN NH
O
HN
O
N
O
Et3N/CH2Cl2
O
O
II-7
IIa-IIe
Scheme 2.
methylchroman-8-yl)ethanone (II-4) by hydrogen with Pd/C
as catalyst, but we got unexpected compound, 1-(5-
methylchroman-8-yl)ethanol (II-2', Scheme 3). Physical
Because of the influence of heterocycle pyran, 1-(5-
methyl-2H-chromen-8-yl)ethanone (II-2) can not be oxi-
dized to 1-(5-methylchroman-8-yl)ethanone (II-4). At last,
compound II-2' was protected by ethylene glycol to give 5-
methyl-8-(2-methyl-1,3-dioxolan-2-yl)-2H-chromene (II-3),
and then reduced by hydrogen with Pd/C as catalyst to suc-
cessfully afford 1-(5-methylchroman-8-yl)ethanone (II-4) in
one pot (Scheme 3).
1
properties and H NMR data of compound II-2', colorless
1
viscous liquid, H NMR (400MHz, CDCl3) ꢀ: 7.05 (d, 1H,
3
3JHH = 7.6, Ph), 6.74 (d, 1H, JHH = 7.6, Ph), 4.99-5.04 (m,
3
1H, CH), 4.20 (t, 2H, JHH = 5.1, CH2O), 2.85 (br, 1H, OH),
2.66 (t, 2H, 3JHH = 6.6, CH2), 2.22 (s, 3H, PhCH3), 2.04-2.07
(m, 2H, CH2), 1.50 (d, 3H, 3JHH = 6.5, CH3).
H2
Pd/C
[O]
X
O
O
O
O
HO
II-2'
O
II-2
II-4
OH
OH
H2
Pd/C
O
O
O
II-3
Scheme 3.

Design and Synthesis of Novel
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
33
Oxidation of 1-(5-methylchroman-8-yl)ethanone (II-4)
gave 5-methylchroman-8-carboxylic acid (II-5) by bromo-
form reaction. It is interesting that acid II-5 could not be
transformed to 5-methylchroman-8-carbonyl chloride (II-6)
by thionyl chloride, because acid II-5 was decomposed to a
black solid by SOCl2. As mentioned above, 2,3-dihydro-2,4-
dimethylbenzofuran-7-carboxylic acid (I-7) could be reacted
with SOCl2 to produce the corresponding acyl chloride I-8,
successfully. This indicated that different heterocycle on the
benzene ring of benzoheterocyle moiety can influence the
reaction of corresponding acid. 5-Methylchroman-8-
carboxylic acid (II-5) was reacted with oxalyl chloride to
successfully produce the corresponding acyl chloride II-6, its
subsequent reaction with tert-butylhydrazine hydrochloride
yielded N'-tert-butyl-N-5-methylchroman-8-carbohydrazide
(II-7). Finally, the target compounds IIa~IIe were synthe-
sized by the reaction of various substituted benzoylchloride
with intermediate II-7 in dichloromethane using triethy-
lamine as proton scavenger. The physical properties and ele-
mental analyses or HRMS of compounds IIa~IIe are listed
in Table 1, and their 1H NMR is listed in Table 2.
to obtain 5-methyl-8-(2-methyl-1,3-dioxolan-2-yl)-2H-chro-
mene and then reducing by hydrogen with Pd/C as catalyst to
produce 1-(5-methylchroman-8-yl)ethanone in one step. Fur-
thermore, we noted a new phenomena that SOCl2 can con-
vert 2,3-dihydro-2,4-dimethylbenzofuran-7-carboxylic acid
to 2,3-dihydro-2,4-dimethylbenzofuran-7-carbonyl chloride,
but it is inefficient for transforming 5-methylchroman-8-
carboxylic acid to the corresponding acyl chloride because of
its degradation. So it shows that different heterocycle on the
benzene ring of benzoheterocyle moiety have influence on
the reaction property of the corresponding acid.
EXPERIMENTAL
The melting points were determined on an X-4 binocular
microscope melting point apparatus (Beijing Tech Instru-
1
ments Co., Beijing, China) and were uncorrected. H NMR
spectra were recorded on a Bruker AC-P300 or Varian Mer-
cury Plus 400 spectrometer in CDCl3 with tetramethylsilane
as internal standard. Chemical shift values (ꢀ) are given in
parts per million and J values were given in Hz. Elemental
analyses were determined on a Yanaca CHN Corder MT-3
elemental analyzer. HRMS was obtained on FTICR-MS
(Ionspec 7.0T). X-ray single crystal diffraction was deter-
mined on BRUCKER SMART 1000 X-ray single crystal
diffraction analyzer. Yields were not optimized.
The intermediates I-4~I-9, II-1~II-4, II-7 and the target
compounds Ia~If and IIa~IIe are new compounds. The
structure of N-tert-butyl-N'-2,3-dihydro-2,4-dimethylbenzo-
furan-7-carbohydrazide (I-9) was also determined by X-ray
diffraction (Fig. (2)).
Synthesis of 1-[2-(allyloxy)-4-methylphenyl]ethanone (I-
4)
3-Bromoprop-1-ene (38.6 g, 318.8 mmol) was added to
the mixture of compound I-3 (39.9 g, 265.7 mmol), toluene
(200 ml), aqueous solution (30 ml) of sodium hydroxide
(12.8 g, 318.8 mmol), tetrabutyl ammonium bromide (8.6 g,
26.6 mmol) at stirring and in ice bath. After stirring for 12 h
at 50-55 ˚C, the reaction mixture was cooled and diluted
with ethyl acetate (100 ml). The separated organic layer was
washed with water (3 ꢁ 50 ml) and brine (50 ml) and then
dried over anhydrous sodium sulfate. After removal of the
solvent, the residue was recrystallized from petroleum ether
(60-90 ˚C) and ethyl acetate (5/1) to give 1-[2-(allyloxy)-4-
methylphenyl]ethanone (I-4) as a white crystal (34.2 g,
72%), m.p. 48-49 ꢀ. 1H NMR (300 MHz, CDCl3) ꢀ: 7.67 (d,
1H, 3JHH = 7.9, Ph), 6.80 (d, 1H, 3JHH = 7.9, Ph), 6.74 (s, 1H,
Fig. (2). Crystal structure of compound I-9.
3
Ph), 6.04-6.13 (m, 1H, CH2=CH), 5.43 (d, 1H, JHH = 17.3,
In conclusion, six of new N'-tert-butyl-N'-substitute-
dbenzoyl-N-(2,4-dimethyl-2,3-dihydrobenzofuran)-7-carbo-
hydrazide derivatives (Ia~If) and five of new N'-tert-butyl-
N'-substitutedbenzoyl-N-(5-methylchroman)-8-carbohydraz-
ide derivatives (IIa~IIe) were synthesized and their struc-
tures were confirmed by 1H NMR spectra, elemental analysis
or high resolution mass spectra (HRMS). The structure of N-
tert-butyl-N'-2,3-dihydro-2,4-dimethylbenzofuran-7-carbohy-
drazide was also determined by X-ray diffraction. An impor-
tant feature is that 1-(3-allyl-2-hydroxy-4-methylphenyl)
ethanone can easily transformed into 1-(2,3-dihydro-2,4-
dimethylbenzofuran-7-yl)ethanone just with concentrated
sulfuric acid as catalyst. In addition, we found that 1-(5-
methyl-2H-chromen-8-yl)ethanone could not be reduced to
1-(5-methylchroman-8-yl)ethanone directly by hydrogen
with Pd/C as catalyst. It is an effective method for protecting
1-(5-methyl-2H-chromen-8-yl)ethanone with ethylene glycol
3
CH2=CH), 5.32 (d, 1H, JHH = 10.5, CH2=CH), 4.62 (d, 2H,
3JHH = 5.3, CH2O), 2.62 (s, 3H, CH3CO), 2.36 (s, 3H,
PhCH3). Anal. Calcd for C12H14O2 (%): C 75.76, H 7.42;
found C 75.75, H 7.00.
Synthesis of 1-(3-allyl-2-hydroxy-4-methylphenyl) etha-
none (I-5)
A mixture of compound I-4 (14.7 g, 77.3 mmol), N,N-
diethylaniline (150 ml) was refluxed for 7 h. After cooling at
room temperature, the reaction mixture was neutralized with
hydrochloric acid (2 mol L-1), and then extracted with petro-
leum ether (60-90 ˚C, 3 ꢁ 200 ml). The separated organic
layer was washed successively with water (2 ꢁ 200 ml) and
brine (200 ml), and then dried over anhydrous sodium sul-
fate. The solvent was evaporated and the residue was vac-
uum distilled (b.p. 130-132 ˚C/0.5 mmHg) to give 1-(3-allyl-

34
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Huang et al.
2-hydroxy-4-methylphenyl)ethanone (I-5) as a light yellow
perature, the organic layer was separated and washed succes-
sively with water (2 ꢁ 20 ml) and brine (20 ml) then dried
over anhydrous sodium sulfate. The solvent was evaporated
and the residue was purified by silica-gel column chromatog-
raphy [petroleum ether (60-90ꢀ)/ ethyl acetate = 3/1] to
give N-tert-butyl-N'-2,3-dihydro-2,4-dimethylbenzofuran-7-
carbohydrazide (I-9) as a colorless crystal (0.6 g, 55%), m.p.
99-100 ꢀ. 1H NMR (300 MHz, CDCl3) ꢀ: 8.84 (brs, 1H,
1
oil (14.2 g, 97%). H NMR (300 MHz, CDCl3) ꢀ: 12.69 (s,
3
1H, PhOH), 7.51 (d, 1H, JHH = 8.2, Ph), 6.71 (d, 1H, 3JHH
=
=
3
8.2, Ph), 5.86-5.99 (m, 1H, CH2=CH), 4.99 (d, 1H, JHH
11.3, CH2=CH), 4.93 (d, 1H, 3JHH = 17.1, CH2=CH), 3.44 (d,
3
2H, JHH = 5.9, CH2O), 2.59 (s, 3H, CH3CO), 2.32 (s, 3H,
PhCH3).
3
3
NH), 7.81 (d, 1H, JHH = 7.9, Ph), 6.79 (d, 1H, JHH =7.9,
Ph), 5.07-5.14 (m, 1H), 3.25-3.33 (m, 2H, NH, CH), 2.73-
Synthesis of 1-(2,3-dihydro-2,4-dimethylbenzofuran-7-
yl)ethanone (I-6)
3
2.81 (m, 1H), 2.26 (s, 3H, PhCH3), 1.52 (d, 3H, JHH = 6.2),
A mixture of compound I-5 (10.0 g, 52.3 mmol), concen-
trated sulfuric acid (1.1 g, 10.5 mmol) was heated at about
110 ꢀ for 0.5 h. The reaction mixture was resolved with
CH2Cl2 (30 ml) and then was washed successively with wa-
ter (20 ml) and brine (20 ml), and then dried over anhydrous
sodium sulfate. The solvent was evaporated and the residue
was purified by silica-gel column chromatography [petro-
leum ether ( 60-90ꢀ)/ ethyl acetate = 30/1] to give 1-(2,3-
dihydro-2,4-dimethylbenzofuran-7-yl)ethanone (I-6) as a
1.16 (s, 9H, C(CH3)3). Anal. Calcd for C15H22N2O2 (%): C
68.67, H 8.45, N 10.68; found C 68.68, H 8.47, N 10.63.
General Synthetic Procedure for N'-tert-butyl-N'-subs-
titutedbenzoyl-N-(2,3-dihydro-2,4-dimethylbenzofuran)-
7-carbohydrazide (Ia~If)
The solution of substituted benzoyl chloride (0.4 mmol)
in dichloromethane (10 ml) was added dropwise to a stirred
mixture of compound I-9 (0.1 g, 0.4 mmol), triethylamine
(0.04 g, 0.42 mmol) and dichloromethane (10 ml) in an ice
bath. After stirring the reaction mixture at room temperature
overnight. The reaction mixture was washed successively
with water (2 ꢁ 10 ml) and brine (10 ml) then dried over
anhydrous sodium sulfate. After evaporation of the solvent,
the residue was purified by recrystallization or column
chromatography on silica gel to afford compounds Ia~If.
The physical properties and elemental analyses or HRMS of
1
white crystal (4.1 g, 41%), m.p. 73-74ꢀ. H NMR (400
3
MHz, CDCl3) ꢀ: 7.61 (d, 1H, JHH = 8.1, Ph), 6.69 (d, 1H,
3JHH = 8.1, Ph), 5.02-5.10 (m, 1H), 3.22-3.28 (m, 1H), 2.69-
2.75 (m, 1H), 2.59 (s, 3H, CH3CO), 2.24 (s, 3H,
3
PhCH3),1.51(d, 3H, JHH = 6.2). Anal. Calcd for C12H14O2
(%): C 75.76, H 7.42; found C 75.66, H 7.40.
Synthesis of 2,3-dihydro-2,4-dimethylbenzofuran-7-car-
boxylic acid (I-7)
1
new compounds (Ia~If) are listed in Table 1, and their H
Bromine (2.5 g, 15.6 mmol) was added dropwise to a
stirred solution of sodium hydroxide (2.5 g, 15.6 mmol) in
water (10 ml) in an ice bath. After 2 h, compound I-6 (0.9 g,
4.7 mmol) in 1,4-dioxane (10 ml) was added with stirring
and the mixture was stirred overnight at room temperature.
The reaction mixture was extracted with diethyl ether (2 ꢁ 20
ml). The aqueous layer was acidified with hydrochloride (1
mol L-1) and extracted with dichloromethane (3 ꢁ 20 ml).
The combined organic layer was washed with water (20 ml)
and brine (20 ml), and then dried over anhydrous sodium
sulfate. After removal of the solvent, the residue was recrys-
tallized with dichloromethane to give 2,3-dihydro-2,4-
dimethylbenzofuran-7-carboxylic acid (I-7) as a white crys-
NMR is listed in Table 2.
Synthesis of 1-[4-methyl-2-(prop-2-ynyloxy)phenyl]etha-
none (II-1)
3-Bromoprop-1-yne (14.3 g, 120.0 mmol) was added to
the mixture of compound I-3 (15.0 g, 100.0 mmol), toluene
(600 ml), aqueous solution (10 ml) of sodium hydroxide (9.6
g, 240.0 mmol), tetrabutyl ammonium bromide (3.9 g, 12.0
mmol) at stirring and in ice bath. After stirring for 5 h at
room temperature, the reaction mixture was cooled and di-
luted with ethyl acetate (50 ml). The separated organic layer
was washed with water (3 ꢁ 50 ml) and brine (50 ml) and
then dried over anhydrous sodium sulfate. After removal of
the solvent, the residue was recrystallized [petroleum ether
(60-90 ꢀ)/ethyl acetate = 10/1] to give 1-[4-methyl-2-(prop-
2-ynyloxy)phenyl]ethanone (II-1) as a white crystal (15.2 g,
81%), m.p. 69-71 ꢀ. 1H NMR (400 MHz, CDCl3) ꢀ: 7.67 (d,
1H, 3JHH = 8.2, Ph), 6.83 (s, 2H, Ph), 4.77 (d, 2H, 4JHH = 2.2,
1
tal (0.8 g, 83%), m.p. 203-205 ꢀ. H NMR (300 MHz,
3
CDCl3) ꢀ: 10.39 (brs, 1H, COOH), 7.74 (d, 1H, JHH = 8.1,
3
Ph), 6.78 (d, 1H, JHH = 8.1, Ph), 5.14-5.26 (m, 1H), 3.27-
3.36 (m, 1H), 2.75-2.83 (m, 1H), 2.28 (s, 3H, PhCH3),
3
1.57(d, 3H, JHH = 6.3). Anal. Calcd for C11H12O3 (%): C
68.74, H 6.29; found C 68.50, H 6.45.
4
CH2O), 2.60 (s, 3H, CH3CO), 2.55 (t, 1H, JHH = 2.3,
CH),2.37 (s, 3H, PhCH3). Anal. Calcd for C12H12O2 (%): C
76.57, H 6.43; found C 76.57, H 6.40.
Synthesis of 2,3-dihydro-2,4-dimethylbenzofuran-7-car-
bonyl chloride (I-8) and N'-tert-butyl-N-2,3-dihydro-2,4-
dimethylbenzofuran-7-carbohydrazide (I-9)
Synthesis of 1-(5-methyl-2H-chromen-8-yl)ethanone (II-
2)
A mixture of compound I-7 (0.8 g, 3.9 mmol) and thionyl
chloride (3 ml) was refluxed for 2 h. After the excess of
thionyl chloride was removed under reduced pressure, the
residue was dissolved in dichloromethane (5 ml). The result-
ing solution was added dropwise to a stirred mixture of tert-
butylhydrazine hydrochloride (0.6 g, 4.7 mmol), sodium
hydroxide (0.2 g, 4.7 mmol), dichloromethane (40 ml) and
water (5 ml) at -15ꢀ. After stirring overnight at room tem-
A mixture of compound II-1 (17.0 g, 90.1 mmol), N,N-
diethylaniline (150 ml) was refluxed for 5 h. After cooling at
room temperature, the reaction mixture was neutralized with
hydrochloric acid (1 mol L-1), and then extracted with di-
chloromethane (3 ꢁ 100 ml). The separated organic layer
was washed successively with water (2 ꢁ 70 ml) and brine

Design and Synthesis of Novel
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
35
(70 ml), and then dried over anhydrous sodium sulfate. The
solvent was evaporated and the residue was purified by sil-
ica-gel column chromatography [petroleum ether ( 60-90ꢀ)/
ethyl acetate = 30/1] to give 1-(5-methyl-2H-chromen-8-
sulfate. After removal of the solvent, the residue was recrys-
tallized with dichloromethane to give 5-methylchroman-8-
carboxylic acid (II-5) as a white crystal (4.0 g, 71%), m.p.
1
121-122 ꢀ. H NMR (300 MHz, CDCl3) ꢀ: 10.87 (brs, 1H,
yl)ethanone (II-2) as a white crystal (10.3 g, 61%), m.p. 51-
COOH), 7.91 (d, 1H, 3JHH = 7.9, Ph), 6.90 (d, 1H, 3JHH = 7.9,
3
3
3
53 ꢀ. 1H NMR (400 MHz, CDCl3) ꢀ: 7.49 (d, 1H, JHH
=
=
Ph), 4.40 (t, 2H, JHH = 4.8, CH2O), 2.72 (t, 2H, JHH = 6.5,
CH2), 2.27 (s, 3H, PhCH3), 2.12-2.20 (m, 2H, CH2). Anal.
Calcd for C11H12O3 (%): C 68.74, H 6.29; found C 68.55, H
6.35.
3
3
8.1, Ph), 6.73 (d, 1H, JHH = 8.1, Ph), 6.60 (d, 1H, JHH
10.0, CH=CH), 5.86-5.91 (m, 1H, CH=CH), 4.80-4.81 (m,
2H, CH2O), 2.56 (s, 3H, CH3CO), 2.28 (s, 3H, PhCH3).
Anal. Calcd for C12H12O2 (%): C 76.57, H 6.43; found C
76.52, H 6.42.
Synthesis of 5-methylchroman-8-carbonyl chloride (II-6)
and N'-tert-butyl-N-5-methylchroman-8-carbohydrazide
(II-7)
Synthesis of 5-methyl-8-(2-methyl-1,3-dioxolan-2-yl)-2H-
chromene (II-3)
A mixture of compound II-5 (0.5 g, 2.6 mmol) and oxa-
lyl chloride (3 ml) was stirred for 10 h at room temperature.
After the excess of oxalyl chloride was removed under re-
duced pressure, the residue was dissolved in dichloro-
methane (5 ml). The resulting solution was added dropwise
to a stirred mixture of tert-butylhydrazine hydrochloride (0.4
g, 3.12 mmol), sodium hydroxide (0.1 g, 3.1 mmol), di-
chloromethane (30 ml) and water (5 ml) at -15ꢀ. After stir-
ring overnight at room temperature, the organic layer was
separated and washed successively with water (2 ꢁ 15 ml)
and brine (15 ml) then dried over anhydrous sodium sulfate.
The solvent was evaporated and the residue was purified by
silica-gel column chromatography [petroleum ether (60-
90ꢀ)/ ethyl acetate = 2/1] to give N'-tert-butyl-N-5-
methylchroman-8-carbohydrazide (II-7) as a light yellow
The mixture of compound II-2 (10.3 g, 54.6 mmol), tolu-
ene (30 ml), ethylene glycol (4.1g, 65.5 mmol), p-
toluenesulfonic acid (0.2 g, 1.1 mmol) was refluxed for
about 3 h until there is no water separated from the reaction
mixture using water segregator. The reaction mixture was
washed successively with saturated sodium bicarbonate solu-
tion (20 ml), water (20 ml) and then dried over anhydrous
sodium sulfate. After removal of the solvent, the residue was
purified by silica-gel column chromatography [petroleum
ether ( 60-90ꢀ)/ ethyl acetate = 30/1] to give 5-methyl-8-(2-
methyl-1,3-dioxolan-2-yl)-2H-chromene (II-3) as a light
yellow oil (5.5 g, 43%). 1H NMR (300 MHz, CDCl3) ꢀ: 7.23
3
(d, 1H, 3JHH = 7.9, Ph), 6.70 (d, 1H, JHH = 7.9, Ph), 6.62 (d,
1H, 3JHH = 10.0, CH=CH), 5.86-5.91 (m, 1H, CH=CH), 4.76-
4.77 (m, 2H, CH2O), 4.02-4.06 (m, 2H, CH2O), 3.82-3.877
(m, 2H, CH2O), 2.28 (s, 3H, CH3), 1.78 (s, 3H, PhCH3).
Anal. Calcd for C14H16O3 (%): C 72.39, H 6.94; found C
72.29, H 6.91.
1
ropy liquid (0.3 g, 41%). H NMR (400 MHz, CDCl3) ꢀ:
9.11 (brs, 1H, NH), 7.91 (d, 1H, 3JHH = 8.1, Ph), 6.85 (d, 1H,
3
3JHH = 7.9, Ph), 4.26 (t, 2H, JHH = 5.2, CH2O), 2.74 (t, 2H,
3JHH = 6.4, CH2), 2.45 (brs, 1H, NH), 2.31 (s, 3H, PhCH3),
2.06-2.12 (m, 2H, CH2), 1.14 (s, 9H, C(CH3)3).
Synthesis of 1-(5-methylchroman-8-yl)ethanone (II-4)
General Synthetic Procedure for N'-tert-butyl-N'-subs-
titutedbenzoyl-N-(5-methylchroman)-8-carbohydrazide
Derivatives (IIa~IIe)
A mixture of compound II-3 (5.5 g, 23.6 mmol), ethanol
(30 ml) and 10% palladium on activated carbon (0.9 g, 50%
in water) was vigorously stirred under 1 atm of hydrogen at
room temperature for 5 h. The reaction mixture was filtered.
After removal of the solvent, the residue was purified by
silica-gel column chromatography [petroleum ether (60-90
ꢀ)/ ethyl acetate = 30/1] to give1-(5-methylchroman-8-
yl)ethanone (II-4) as a white crystal (3.2 g, 72%), m.p. 62-63
The solution of substituted benzoyl chloride (0.7 mmol)
in dichloromethane (10 ml) was added dropwise to a stirred
mixture of compound II-7 (0.2 g, 0.7 mmol), triethylamine
(0.07 g, 0.72 mmol) and dichloromethane (10 ml) in an ice
bath. After stirring the reaction mixture at room temperature
overnight, the reaction mixture was washed successively
with water (2 ꢁ 10 ml) and brine (10 ml) and then dried over
anhydrous sodium sulfate. After evaporation of the solvent,
the residue was purified by recrystallization or column
chromatography on silica gel to afford compounds IIa~IIe.
The physical properties and elemental analyses or HRMS of
3
ꢀ. 1H NMR (400 MHz, CDCl3) ꢀ: 7.49 (d, 1H, JHH = 7.9,
3
3
Ph), 6.75 (d, 1H, JHH = 7.9, Ph), 4.23 (t, 2H, JHH = 5.1,
3
CH2O), 2.67 (t, 2H, JHH = 6.6, CH2), 2.57 (s, 3H, CH3CO),
2.22 (s, 3H, PhCH3), 2.04-2.10 (m, 2H, CH2). Anal. Calcd
for C12H14O2 (%): C 75.76, H 7.42; found C 76.00, H 7.44.
1
new compounds (IIa~IIe) are listed in Table 1, and their H
Synthesis of 5-methylchroman-8-carboxylic Acid (II-5)
NMR is listed in Table 2.
Bromine (15.6 g, 97.4 mmol) was added dropwise to a
stirred solution of sodium hydroxide (15.6 g, 389.7 mmol) in
water (63 ml) in an ice bath. After 2 h, compound II-4 (5.6
g, 29.5 mmol) in 1,4-dioxane (63 ml) was added with stirring
and the mixture was stirred overnight at room temperature.
The reaction mixture was extracted with diethyl ether (2 ꢁ 40
ml). The aqueous layer was acidified with hydrochloride (1
mol L-1) and extracted with dichloromethane (3 ꢁ 40 ml).
The combined organic layer was washed with water (20 ml)
and brine (20 ml), and then dried over anhydrous sodium
ACKNOWLEDGEMENT
This work was supported by the National Natural Science
Foundation of China (20672064).
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