Short Synthesis of 1-(3-tert-Butyl-1-phenyl-1H-pyrazol-5-yl)-3-(5-(2- morpholinoethoxy)-2H-chromen-8-yl) urea derivatives

Article abstract of DOI:10.1080/00397910902883603

A short and efficient synthesis of 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5- yl)-3-(5-(2-morpholinoethoxy)-2H-chromen-8-yl) urea derivatives (1a-c), a novel type of p38 MAPK inhibitors, is described. The Claisen thermal rearrangement of arylpropargyl ethers

Full text of DOI:10.1080/00397910902883603

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Short Synthesis of 1-(3-
tert-Butyl-1-phenyl-1H-
pyrazol-5-yl)-3-(5-(2-
morpholinoethoxy)-2H-
chromen-8-yl) Urea Derivatives
Xingzhou Li a , Xinming Zhou b , Zhibing Zheng a , Wu
Zhong a , Junhai Xiao a & Song Li a
a Department of Medicinal Chemistry , Beijing
Institute of Pharmacology and Toxicology , Beijing,
China
b School of Pharmaceutical Engineering, Shenyang
Pharmaceutical University , Shenyang, Liaoning,
China
Published online: 16 Oct 2009.
To cite this article: Xingzhou Li , Xinming Zhou , Zhibing Zheng , Wu Zhong , Junhai
Xiao & Song Li (2009) Short Synthesis of 1-(3-tert-Butyl-1-phenyl-1H-pyrazol-5-
yl)-3-(5-(2-morpholinoethoxy)-2H-chromen-8-yl) Urea Derivatives, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:22, 3999-4009, DOI: 10.1080/00397910902883603
To link to this article: http://dx.doi.org/10.1080/00397910902883603
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Synthetic Communications1, 39: 3999–4009, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902883603
Short Synthesis of 1-(3-tert-Butyl-1-phenyl-
1H-pyrazol-5-yl)-3-(5-(2-morpholinoethoxy)-
2H-chromen-8-yl) Urea Derivatives
Xingzhou Li,1 Xinming Zhou,2 Zhibing Zheng,1 Wu Zhong,1
Junhai Xiao,1 and Song Li1
1Department of Medicinal Chemistry, Beijing Institute of Pharmacology
and Toxicology, Beijing, China
2School of Pharmaceutical Engineering, Shenyang Pharmaceutical
University, Shenyang, Liaoning, China
Abstract: A short and efficient synthesis of 1-(3-tert-butyl-1-phenyl-1H-pyrazol-
5-yl)-3-(5-(2-morpholinoethoxy)-2H-chromen-8-yl) urea derivatives (1a–c), a novel
type of p38 MAPK inhibitors, is described. The Claisen thermal rearrangement of
arylpropargyl ethers was employd as a key step to synthesize the chromene
core. The solvent effect on the ratio of the resultant two isomers of Claisen
thermal rearrangement, namely 2-methylbenzofuran and 2H-chromen, was also
investigated.
Keywords: Claisen thermal rearrangement, 2H-chromene, p38 MAPK inhibitor,
unsymmetrical urea
The p38 mitogen-activated protein kinase (MAPK) plays a key role in
proinflammatory activities; therefore, inhibitors of this kinase may be
used as therapeutic agents to treat chronic inflammatory diseases.[1]
Our group had found a novel series of p38 MAPK inhibitors. The
structural characteristic of these compounds is that of an asym-
metrically substituted urea fragment connected to a chromene core
Received October 30, 2008.
Address correspondence to Song Li, Department of Medicinal Chemistry,
Beijing Institute of Pharmacology and Toxicology, Academy, Beijing 100850,
China. E-mail: lis@nic.bmi.ac.cn
3999

4000
X. Li et al.
Figure 1. Structures of compounds 1a–c.
(Fig. 1). Preliminary study showed that the TNF-a inhibition activity of
compounds 1a–c in lipopolysaccharide (LPS)-induced THP-1 cells
(human acute monocytic leukemia cell line) is comparable to that of
BIRB-796. Unfortunately, the 12-step synthetic route (shown in
Scheme 1) for the synthesis of compounds 1a–c, starting from resorcinol,
was rather ineffective (only about 0.45% overall yield), which limited the
further development of these compounds.[2–4]
The poor effectivity of the original synthetic route is mainly due to
three factors. First is the poor yield of the thermal rearrangement of
arylpropargyl ethers to construct the chromene core (step 7), mainly
Scheme 1. Synopsis of the formerly reported synthetic route of compound 1a–c.

5-Alkoxy-2H-chromen-8-yl Ureas
4001
due to the formation of 2-methylbenzofuran isomer and carbonization.
Second is the poor output of the nonsymmetrical urea synthesis (step
12), which affects the symmetrical urea by-product generation. Third is
the tediously long and ineffective procedure for the synthesis of com-
pound I-3, which is due mainly to the poor selectivity of benzylation of
resorcinol (step 1) and the ineffective protection group manipulations
(steps 2–6).
To overcome these drawbacks, a much more efficient synthetic
method for the preparation of compounds 1a–c was developed.
RESULTS AND DISCUSSION
The improved synthetic route is described in Scheme 2. Commercially
available 2-nitro-5-fluorophenol (II-1), which is available at low cost,
reacted with propargyl bromide in dimethylformamide (DMF) in the
presence of potassium carbonate to afford compound II-2 in 85% yield.
The compound II-3 was obtained in the yield of 75% through the reaction
of II-2 with the sodium 2-morpholinoethanolate in DMF via a nucleophi-
lic aromatic displacement mechanism.
Scheme 2. Reagents and conditions: (a) propargyl bromide, K2CO3=DMF (88%);
(b) NaH=DMF=ꢀ35ꢁC (93%); (c) 189–195ꢁC=solvent; (d) crystallization from
EtOAc and hexane (35%); (e) SnCl2 ꢂ 2H2O=EtOAc and EtOH (84%); (f)
SnCl2 ꢂ 2H2O=EtOAc and EtOH (85%); (g) silica-gel chromatography (60%); (h)
DIEA=DMSO (83–88%); and (i) base=THF (85–93%).

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X. Li et al.
Although the Claisen thermal rearrangement of aryl propargyl ethers
is one of the most versatile routes for the synthesis of 2H-chromen
derivatives, this reaction usually gives rise to a mixture of 2-methylbenzo-
furan and 2H-chromen and has a reputation for erratic yields. Many
reports have appeared in literature on this rearrangement, but no detailed
reports on the rearrangement of 2-nitro-5-alkoxy substituted aryl propar-
gyl ethers have appeared so far.[4] According to the similar method
reported in the literature,[5] 2H-chromen II-4 was initially prepared by
heating the key intermediate (II-3) to 180–200ꢁC in the solvent of
N,N-diethyl aniline. Surprisingly, contrary to literature reports, the main
product of II-3 cyclization was 2-methylbenzofuran II-40 under this
condition, not the desired 2H-chromen II-4. The ratio of II-4=II-40 was
only 10=90 (determined by 1H NMR). Further investigation unexpectedly
showed that the solvents used in the cyclization had a significant effect on
the ratio of the resulting two isomers (II-4 and II-40). If dimethylsulfoxide
(DMSO) was used as the solvent for II-3 cyclization, only compound II-40
1
was obtained under reflux and no signal of II-4 was detected by H
NMR. When II-3 was heated in diphenyl ether at 190ꢁC, the two isomers
II-4 and II-40 were obtained at a ratio of 71=29 with the yield of 65%.
When decahydronaphthalene was used as the solvent, the ratio of II-4
to II-40 was raised to 83=17, but poor overall yield (30%) was obtained
because of serious carbonization. A subsequently careful literature
search revealed that the solvent effect of Claisen thermal rearrange-
ment had been touched on by some authors,[5d] but no sufficient and
explicit information was available. Our finding may provide a clue to
improve the selectivity and efficiency of Claisen thermal rearrangement
reaction.
With everything taken into consideration, reaction in diphenyl ether
was designed to prepare II-4. Although compound II-4 was the main
product of this reaction, the minor product compound II-40 was also
formed. Compounds II-4 and II-40 were very difficult to separate by
chromatography, but fractional recrystallization from a solvent mixture
of EtOAc and hexane could afford pure II-4 (20% from II-3). On the
other hand, the two isomeric compounds could also be separated in
the next step after the nitro group was reduced to amino. The nitro group
of II-4 and II-40 was reduced to amino to afford II-5 and II-50 (60%) by
using SnCl2 in ethanol (EtOH). Compound II-5 could be separated easily
from II-50 by silica-gel chromatography using EtOAc=petroleum as the
eluant (31% from II-3). Aryl amines II-6a–c were prepared from
pivaloylacetonitrile and substituted phenylhydrazine hydrochloride by a
reported method.[6]
The last step is to synthesize the unsymmetrical urea 1a–c from aryl
amino II-5 and II-6a–c. The general procedures for the synthesis of

5-Alkoxy-2H-chromen-8-yl Ureas
4003
unsymmetrical urea involve the reaction of isocyanate with primary
amine. Isocyanates are usually prepared through the reaction of phos-
gene or its surrogates—for example, triphosgene—with an amine in the
presence of a tertiary base.[7] Phosgene is hazardous to handle, especially
in the laboratory. Triphosgene is relatively easy to use, but according to
Dr. Zhou’s report,[2,3] when I-6a–c is coupled with the isocyanate
produced from I-5 and triphosgene in CH2Cl2 in the presence of diisopro-
pylethylamine, unsymmetrical ureas 1a–c were obtained in only 27–37%
yield after careful chromatography. The poor yield was mainly attributed
to the formation of symmetrical urea. Addition of the unreacted I-6 (or
II-5) to the isocyanate, formed in situ by reaction of I-6 (or II-5) with tri-
phosgene, led to the formation of symmetrical urea. To overcome this
difficulty, we turned to another method for the synthesis of unsymmetri-
cal urea based on 2,2,2-trichloroethyl carbamate.[8] Compounds II-7a–c
were first prepared by reaction of II-6a–c with 2,2,2-trichloroethyl chlor-
oformate with good yield in tetrahydrofuran (THF) in the presence of
N,N-diisopropylethylamine (DIEA) or sodium bicarbonate. Then, the
desired unsymmetrical ureas (1a–c) were successfully synthesized though
the reaction of compounds II-7a–c with primary amino II-5 in DMSO
under the catalysis of DIEA at 60ꢁC. The formation of the symmetrical
urea derived from I-6 and II-5 was not detected. Pure ureas (1a–c) were
obtained in overall yields of about 13% or 18%, varied with different
methods for compound II-4 and II-4 after work up. Structures of all
1
new compounds were unambiguously characterized with H NMR and
mass spectrometry. Compounds 1a–c were also verified with
high-resolution mass spectrometry (HRMS).
In conclusion, we have developed a facile procedure for the synthesis
of 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(5-(2-morpholinoethoxy)-
2H-chromen-8-yl) urea derivatives (1a–c) (as shown in Scheme 2). This
method was more effective and straightforward when compared with
the former one (shown in Scheme 1). First, the 2-morpholinoethoxy
was introduced directly through nucleophilic aromatic displacement reac-
tion, which deprived the poorly effective protection group manipulations
of the former procedure. Second, the reaction condition for the Claisen
thermal rearrangement was studied and optimized to achieve high yields
of 2H-chromen derivatives. Third, a novel method for the synthesis of
unsymmetrical urea based on 2,2,2-trichloroethyl carbamate, featuring
no symmetrical urea by-product formation, was adopted. It took only
five steps for our improved route to give compounds 1a–c, and the overall
yield was increased to more than 13%. It is also worth mentioning that we
have found that the solvent has a significant effect on the selectivity of
the Claisen thermal rearrangement of arylpropargyl ethers. To our
knowledge, such effect has been seldom discussed in the literature.

4004
X. Li et al.
EXPERIMENTAL
All the reagents for synthesis were commercially available and either used
without further purification or purified by standard methods prior to use.
Melting points were determined using a RY-1 apparatus, and the therometer
1
was uncorrected. H NMR spectra were measured using a multinuclear
Fourier transform (FT)–NMR spectrometer ARX400 (Bruker). Mass spec-
tra were obtained from Micromass ZabSpec 1000 and API3000 instruments.
4-Fluoro-1-nitro-2-(prop-2-ynyloxy)benzene (II-2)
Anhydrous K2CO3 (35.22 g, 254.8 mmol) and 3-bromopropyne (18.18 g,
152.8 mmol) were successively added to a stirred solution of 5-fluoro-2-nitro-
phenol (II-l, 20 g, 127.4 mmol) in DMF (200 mL). The mixture was stirred at
room temperature for 5 h and then poured into 1000 ml ice water. A buff
deposit was separated out upon standing overnight. The solid was collected
through filtration and air dried to give the title compound (21.84 g). Yield:
1
88%; mp 50–52ꢁC; H NMR (CDCl3, 400), d 7.98 (m, 1H), 6.98 (m, 1H),
6.80 (m, 1H), 4.86 (s, 2H), 2.66 (s, 1H). MS (FAB): 196 (M þ H)þ.
4-(4-Nitro-3-(prop-2-ynyloxy)phenethyl)morpholine (II-3)
Sodium hydrogen (60%, 8.74 g, 218.4 mmol) was added in batches to a
stirred solution of 2-morpholinoethanol (21.84 g, 163.8 mmol) in anhy-
drous DMF (200 mL). The mixture was stirred at ambient temperature
until no gas was released and then cooled to ꢀ35ꢁC. To this resulting
solution, compound II-2 (21.84 g, 109.2 mmol) was added at one time.
The reaction mixture was stirred for 6 more h at ꢀ35ꢁC under nitrogen
and then poured into 1000 ml ice water. The deposit was collected,
washed with water, and air dried to give the title compound (27.82 g);
1
yield: 93%; mp 53–54ꢁC; H NMR (CDCl3, 400), d 8.01 (m, 1H), 6.73
(m, 1H), 6.59 (m, 1H), 4.85 (s, 2H), 4.19 (m, 2H), 3.75 (m, 4H), 2.84
(m, 2H), 2.59 (m, 5H). MS (ESI): 307 (M þ H)þ.
4-(2-(8-Nitro-2H-chromen-5-yloxy)ethyl)morpholine (II-4) and
4-(2-(2-Methyl-7-nitrobenzofuran-4-yloxy)ethyl) morpholine (II-40)
Reaction in Diphenyl Ether
Compound II-3 (22 g, 71.8 mmol) was dissolved in 330 mL diphenyl
ether. The reaction mixture was heated to 195ꢁC and kept at this

5-Alkoxy-2H-chromen-8-yl Ureas
4005
temperature for 3 h. After cooling to room temperature, the solvent was
distillated off under reduced pressure. The residue was dissolved in
CH2Cl2, poured onto the head of a short column packed with silica gel
(200–300 mesh), and eluted with EtOAc=PE (1=1 ! 2=1) to give a
mixture of 4-(2-(8-nitro-2H-chromen-5-yloxy)ethyl)morpholine (II-4)
and 4-(2-(2-methyl-7-nitrobenzofuran- 4-yloxy)ethyl)morpholine (II-40)
as yellow oil (13.6 g); crude yield 62%. The proportion of the two isomers
was determined by 1H NMR to be 71=29 (II-4=II-40). The crude product
was crystallized twice with EtOAc and hexane to give pure II-4 (4.75 g).
1
Yield 22%; mp 92–94ꢁC; H NMR (CDCl3, 400), d 7.86 (d, J ¼ 9.2 Hz,
1H), 6.73 (dt, J ¼ 10.0, 2.0 Hz, 1H), 6.47 (d, J ¼ 9.2 Hz, 1H), 5.86 (dt,
J ¼ 10, 3.6 Hz, 1H), 4.95 (m, 2H), 4.22 (m, 2H), 3.75 (m, 4H), 2.86 (m,
2H), 2.61 (m, 4H). MS(FAB): 307 (M þ H)þ.
Reaction in DMSO
Compound II-3 (2 g, 6.54 mmol) was dissolved in 30 mL DMSO. The
reaction mixture was heated to reflux (189ꢁC) for 2 h. After cooling to
room temperature, the solvent was poured into ice-water (300 mL). The
deposit was separated out upon standing. The deposit was collected
through filtration, dissolved in CH2Cl2, poured onto the head of a short
column packed with silica gel (200–300 mesh), and eluted with
EtOAc=PE (1=1 ! 2=1) to give nearly pure II-40 (0.62 g). Yield: 31%;
1
mp 105–107ꢁC; H NMR (CDCl3, 400), d 8.08 (d, J ¼ 9.2 Hz, 1H), 6.68
(d, J ¼ 9.2 Hz, 1H), 6.57 (s, 1H), 4.34 (m, 2H), 3.76 (m, 4H), 2.92
(m, 2H), 2.64 (m, 4H), 2.56 (s, 3 H). MS(FAB): 307 (M þ H)þ.
Reaction in N,N-Diethyl Aniline
Compound II-3 (2 g, 6.54 mmol) was dissolved in 30 mL N,N-diethyl
aniline. The reaction was heated to 195ꢁC and allowed to keep at this
temperature for 2 h. After cooling to room temperature, the solvent was
distillated off under reduced pressure. The residue was dissolved in
CH2Cl2, poured onto the head of a short column packed with silica gel
(200–300 mesh), and eluted with EtOAc=PE (1=1 ! 2=1) to give a mixture
of II-4 and II-40 as yellow oil (1.02 g), crude yield 51%. The proportion of
1
the two isomers was determined by H NMR to be 10=90 (II-4=II-40).
Reaction in Decahydronaphthalene
Compound II-3 (2 g, 6.54mmol) was suspended in 30mL decahydro-
naphthalene, and the reaction mixture was gradually warmed to 120ꢁC to

4006
X. Li et al.
dissolve compound II-3. Then the mixture was the heated to 195ꢁC and
kept at this temperature for 2 h. After cooling to room temperature, the sol-
vent was distilled off under reduced pressure. The residue was dissolved in
CH2Cl2, poured onto the head of a short column packed with silica gel
(200–300 mesh), and eluted with EtOAc=PE (1=1 ! 2=1) to give a mixture
of II-4 and II-40 as yellow oil (0.60 g), crude yield 30%. The proportion of
the two isomers was determined by 1H NMR to be 83=17 (II-4=II-40).
4-(2-(2-Methyl-7-nitrobenzofuran-4-yloxy)ethyl)morpholine (II-5)
Method A (from Pure II-4)
SnCl2 ꢂ 2H2O (29.0 g, 40 mmol) was added in batches to a stirred solution
of pure II-4 (3.02 g, 10 mmol) dissolved in 50 mL EtOH and 50 mL EtOAc.
Then the mixture was heated at reflux for 8 h. After cooling to room tem-
perature, saturated solution of sodium bicarbonate was added untill the
mixture layered. The organic layer was separated, and the aqueous layer
was extracted with EtOAc (100 mL ꢃ 2). The combined organic layer
was washed with water (100 mL) and brine (100 mL), dried with Na2SO4,
filtered, and concentrated in vacuum to give a purple oil (2.30 g, crude yield
85%), which was pure enough to be directly used in the next step. 1H NMR
(CDCl3, 400), d 6.73 (dt, J ¼ 9.6, 2.0 Hz, 1H), 6.52 (d, J ¼ 8.8 Hz, 1H), 6.31
(d, J ¼ 8.8 Hz, 1H), 5.74 (dt, J ¼ 9.6, 3.6 Hz, 1H), 4.77 (m, 2H), 4.04 (m,
2H), 7.73 (m, 4H), 2.78 (m, 2H), 2.59 (m, 4H). MS (FAB): 277 (M þ H)þ.
Method B (from the Mixture of II-4=II-40)
A mixture of II-5=II-50 (4.96 g, 17.9 mmol, crude yield 85%) could be
obtained from the mixture of II-4=II-40 (6.46 g, 21.1 mmol), which was
prepared from II-3 in diphenyl ether, as described previously. This crude
product was separated by column chromatography on silica gel with
EtOAc=PE (3=2) as eluent, to give II-4 (oil, 2.92 g, 12.9 mmol, 50%)
1
and II-40 (oil, 0.87 g, 3.17 mmol, 15%). H NMR (CDCl3, 400), d 6.73
(dt, J ¼ 9.6, 2.0 Hz, 1H), 6.52 (d, J ¼ 8.8 Hz, 1H), 6.31 (d, J ¼ 8.8 Hz,
1H), 5.74 (dt, J ¼ 9.6, 3.6 Hz, 1H), 4.77 (m, 2H), 4.04 (m, 2H), 7.73 (m,
4H), 2.78 (m, 2H), 2.59 (m, 4H). MS (FAB): 277 (M þ H)þ.
3-tert-Butyl-1-phenyl-1H-pyrazol-5-amine derivatives (II-6a–c)
3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-amine (II-6a), 3-tert-butyl-1-m-tolyl-
1H-pyrazol-5-amine (II-6b), and 3-tert-butyl-1-(4-nitrophenyl)-1H-pyrazol-

5-Alkoxy-2H-chromen-8-yl Ureas
4007
5-amine (II-6c) was prepared from the corresponding phenylhydrazine
hydrochloride and pivaloylacetonitrile according to the literature.[6]
2,2,2-Trichloroethyl-3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate
Derivative (II-7a–c)
2,2,2-Trichloroethyl 3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-
ylcarbamate (II-7a)
2,2,2-Trichloroethyl chlorofomate (1.3 g, 6.18 mmol) was added via
syringe to
a solution of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine
(1.00 g, 4.32 mmol) and N,N-diisopropylethyl-amine (1.2 mL) in THF
(22 mL), cooled to ꢀ10ꢁC under nitrogen gas, over 10 min. After stirring
at ꢀ10ꢁC for 3 h, EtOAc and water were added. The organic layer was
washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo.
The crude product was triturated (petroleum), filtered, and air dired
to give a slightly yellow-white solid (1.6 g, yield 85%); mp 149–151ꢁC;
1H NMR (CDCl3, 400), 7.30–7.33 (m, 4H), 6.81 (brs, exchangeable,
1H), 6.43 (s, 1H), 4.81 (s, 2H), 2.41 (s, 3H), 1.35 (s, 9H); MS (FAB):
404 (Mþ).
2,2,2-Trichloroethyl 3-tert-Butyl-1-m-tolyl-1H-pyrazol-5-
ylcarbamate (II-7b)
Compound II-7b was prepared nearly the same as II-7a except using II-6b
instead of II-6a; yield 93%; mp 109–111ꢁC. 1H NMR (CDCl3, 400),
7.22–7.41 (m, 4H), 6.82 (brs, exchangeable, 1H), 6.45 (s, 1H), 4.82 (s,
2H), 2.42 (s, 3H), 1.36 (s, 9H); MS (FAB): 404 (Mþ).
2,2,2-Trichloroethyl 3-tert-butyl-1-(4-nitrophenyl)-1H-
pyrazol-5-ylcarbamate (II-7c)
2,2,2-Trichloroethyl chlorofomate (1.01 g, 4.77 mmol) in 2 mL THF was
added via syringe to a mixture of II-6c (1.13 g, 4.34 mmol) and sodium
bicarbonate (3.9 g, 46.5 mmol) in THF (18 mL), cooled to ꢀ20ꢁC under
nitrogen gas, over 10 min. The reaction mixture was allowed to warm
to 0ꢁC and was stirred at this temperature for 15 h. Then, EtOAc
(40 mL) and water (20 mL) were added. The organic layer was washed
with brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography (EtOAc=
petroleum, 1:1), isolated as oil, and solidified in petroleum to give a

4008
X. Li et al.
1
slightly yellow-white solid (1.63 g, yield 86%); mp 161–163ꢁC; H NMR
(DMSO-d6, 400), d: 10.28 (s, NH), 8.37 (d, J ¼ 8.8 Hz, 2H), 7.78 (d, J ¼
8.8 Hz, 2H), 6.47 (s, 1H), 4.88 (s, 2H), 1.29 (s, 9H). MS (FAB): 435 (Mþ).
1-(3-tert-Butyl-1-phenyl-1H-pyrazol-5-yl)-3-(5-(2-morpholinoethoxy)-
2H-chromen-8-yl) Urea Derivatives (1a–c)
1-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-(2-morpholinoethoxy)-
2H-chromen-8-yl) Urea (1a)
A solution of II-7a (2.0 g, 5.9 mmol), II-5 (1 g, 3.62 mmol), and N,N-
diisopropylethylamine (0.8 mL) in DMSO (20 mL) was heated at 60ꢁC
for 3 h. After cooling to room temperature, the reaction mixture was
poured into 50 mL ice water and extracted with EtOAc (50 mL ꢃ 3).
The organic layer was washed with brine, dried with Na2SO4, filtered,
and concentrated in vacuo. The crude product was purified by chromato-
graphy on silica gel eluting with EtOAc=petroleum (3=2 ! 4=1) to give
the title compound as a white solid (1.6 g, yield 83%); mp 196–198ꢁC;
1H NMR (CDCl3, 400 MHz) d: 7.74 (d, 1H, J ¼ 8.8 Hz), 7.33 (d, 2H,
J ¼ 8.4 Hz), 7.21 (d, 2H, J ¼ 8.0 Hz), 7.13 (s, 1H), 6.72–6.74 (dd, 1H,
J ¼ 8.4 Hz, 1.6 Hz), 6.39 (d, 1H, J ¼ 9.2 Hz), 6.35 (s, 1H), 6.34 (s, 1H),
5.72 (m, 1H), 4.71 (t, 2H, J ¼ 2.0 Hz), 4.11 (t, 2H), 3.74 (t, 4H), 2.82 (t,
2H), 2.60 (t, 4H), 2.36 (s, 3H), 1.35 (s, 9H). HRMS (ESI) calcd. for
C30H38N5O4 (M þ H)þ: 532.29183; found: 532.29217.
1-(3-tert-Butyl-1-m-tolyl-1H-pyrazol-5-yl)-3-(5-(2-morpholinoethoxy)-
2H-chromen-8-yl) Urea (1b) and 1-(3-tert-Butyl-1-(4-nitrophenyl)-
1H-pyrazol-5-yl)-3-(5-(2-morpholinoethoxy)-2H-chromen-8-yl) Urea (1c)
Compound 1b or 1c can be prepared nearly the same as 1a except using
II-7b or II-7c instead of II-7a.
Compound 1b: yield 88%; mp 126–128ꢁC, 1H NMR (CDCl3,
400 MHz) d: 7.22 (d, 1H, J ¼ 8.8 Hz), 7.26–7.29 (m, 3H), 7.15 (d, 2H),
6.73 (d, 1H, J ¼ 10.0 Hz), 6.58 (s, 1H), 6.38 (d, 1H, J ¼ 9.6 Hz), 6.36 (s,
1H), 5.72 (m, 1H), 4.71 (t, 2H, J ¼ 1.6 Hz), 4.12 (t, 2H), 3.76 (t, 4H),
2.84 (t, 2H), 2.63 (t, 4H), 2.36 (s, 3H), 1.36 (s, 9H). HRMS (ESI) calcd.
for C30H38N5O4 (M þ H)þ: 532.29183; found: 532.29233.
Compound 1c: yield 88%; mp 189–191ꢁC, 1H NMR (CDCl3,
400 MHz) d: 8.18 (d, 2H, J ¼ 9.2 Hz), 7.74 (d, 2H, J ¼ 8.8 Hz), 7.55 (d,
1H), 7.30 (s, 1H), 6.71 (d, 1H, J ¼ 10.0 Hz), 6.39 (s, 1H), 6.34 (d, 1H,
J ¼ 9.2 Hz), 5.70 (m, 1H), 4.68 (t, 2H, J ¼ 1.6 Hz), 4.09 (t, 2H, J ¼ 6.0 Hz),

5-Alkoxy-2H-chromen-8-yl Ureas
4009
3.74 (t, 4H, J ¼ 4.4 Hz), 2.81 (t, 2H, J ¼ 6.0 Hz), 2.60 (t, 4H), 1.34 (s, 9H).
HRMS (ESI) calcd. for C29H35N6O6 (M þ H)þ: 563.26126; found:
563.26162.
ACKNOWLEDGMENT
This work was financially supported by the National Natural Science
Foundation of China (No. 30873135).
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