Facile assembly of 1-(4-haloisoquinolin-1-yl)ureas via a reaction of 2-alkynylbenzaldoxime, carbodiimide, and halide in water

Article abstract of DOI:10.1016/j.tet.2014.02.026

1-(4-Haloisoquinolin-1-yl)ureas are generated efficiently via a tandem reaction of 2-alkynylbenzaldoxime, carbodiimide, with halide in water. The process involves the generation of halonium ion in situ by employment of NaI/oxone or NaBr/oxone as the promoters. This green process proceeds smoothly and efficiently, accommodating a variety of substituents to generate the desired products.

Full text of DOI:10.1016/j.tet.2014.02.026

Tetrahedron 70 (2014) 2246e2250
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Facile assembly of 1-(4-haloisoquinolin-1-yl)ureas via a reaction
of 2-alkynylbenzaldoxime, carbodiimide, and halide in water
,c,
Lifang Lai a, Huanhuan Wang b, Jie Wu b
*
a School of Petrochemical Engineering, Changzhou University, Changzhou, Jiangsu 213146, China
b Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
c State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
1-(4-Haloisoquinolin-1-yl)ureas are generated efficiently via a tandem reaction of 2-alkynylbenzal
doxime, carbodiimide, with halide in water. The process involves the generation of halonium ion in
situ by employment of NaI/oxone or NaBr/oxone as the promoters. This green process proceeds smoothly
and efficiently, accommodating a variety of substituents to generate the desired products.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 29 December 2013
Received in revised form 25 January 2014
Accepted 13 February 2014
Available online 18 February 2014
Keywords:
2-Alkynylbenzaldoxime
Carbodiimide
Halide
1-(4-Haloisoquinolin-1-yl)urea
Water
1. Introduction
from commercially available materials. For example, a three-
component reaction of 2-alkynylbenzaldoxime,
a,b-unsaturated
The isoquinoline ring system has been employed as the valuable
intermediate for the synthesis of biologically active compounds
including alkaloids, natural products, and pharmaceuticals.1,2 This
essential fragment also encouraged the studies for the synthesis of
polycyclic isoquinoline derivatives. Traditional approaches in-
cluding BischlereNapieralski,3 PicteteSpengler,4 and Pomeranze-
Fritsch reactions5 generally require either harsh conditions or
tedious reaction procedures,6 which are not desirable for the con-
struction of functionalized isoquinolines. As a result, many diverse
synthetic routes for the construction of isoquinoline frameworks
were extensively exploited.7e9 While there still remains a need of
novel and efficient methodologies from readily available building
blocks for the generation of functionalized isoquinolines under
mild conditions.
carbonyl compound with bromine or iodine monochloride gave
rise to 2-(4-haloisoquinolin-1-yl)ethanol derivatives in good to
excellent yields.10d In the process, 2-alkynylbenzaldoxime experi-
enced a 6-endo cyclization in the presence of electrophile, leading
to 4-haloisoquinoline N-oxide. The following transformation could
deliver the desired product in a smooth way.
Due to the highly toxicity of halogen, methods involving to af-
ford substitutes of halogen are continually developed, which ex-
perience the oxidation of bromides or iodides delivering
bromonium or iodonium ions in the procedure.11e14 The combi-
nation of bromide or iodide with oxidant was reported to be a re-
liable and efficient replacement of halogen. Several iodide sources,
such as quaternary ammonium iodides and iodobenzene were re-
ported as the precursors with some common oxidants.10e,13,14 Ad-
ditionally, these solid reactants could simplify the operation to
a certain extent. Prompted by these results, we envisioned that the
appliance of the above combination, which could promote the
hypobromite or hypoiodite instead of the direct employment of
halogen, would deliver a green protocol for the generation of
functionalized isoquinolines. Moreover, owing to the halides and
some of the oxidants are well soluble in water, we conceived that an
electrophilic cyclization of 2-alkynylbenzaldoxime with hypohalite
generated in situ and the following [3þ2] cyclization with
The fragment of 2-alkynylbenzaldoxime has drawn our atten-
tion recently. Using this versatile block, several isoquinoline de-
rivatives could be produced.10 These methods readily accommodate
a wide variety of functionality, allowing one to dramatically in-
crease molecular complexity in just a few synthetic steps starting
* Corresponding author. Tel.: þ86 21 6510 2412; fax: þ86 21 6564 1740; e-mail
address: jie_wu@fudan.edu.cn (J. Wu).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.026

L. Lai et al. / Tetrahedron 70 (2014) 2246e2250
2247
carbondiimide could be feasible in water. Herein, we describe the
Tol
N
O
Tol
Tol
H
synthesis of functionalized 1-(4-haloisoquinolin-1-yl)ureas via
a one-pot procedure starting from 2-alkynylbenzaldoxime, carbo-
diimide, and halide in water. The reaction based on the use of oxone
and halide salts as the source of hypohalite in water proceeds
smoothly and efficiently.
N
I
N C
N
base
O
2a
N
Tol
N
[3+2]
cycloaddition
Ph
Ph
A
I
B
NaI
oxone
2. Results/discussion
O
Tol
Tol
N
I
N
OH
To assess the potential of the proposed transformation as
mentioned above, we first selected the reaction of 2-(phenyl-
ethynyl)benzaldehyde oxime 1a with carbodiimide as model
studies. The reaction proceeded in the presence of sodium iodide
and oxone in water. We expected that the electrophile of iodonium
ion could be generated in situ from the combination of iodide and
oxidant. To our delight, the desired product 3a was obtained in 44%
yield (Table 1, entry 1). The presence of base would improve the
result. The corresponding 1-(4-iodoisoquinolin-1-yl)urea 3a was
generated in 92% yield when DABCO was added in the reaction as
a base (Table 1, entry 5). The reaction was also performed in organic
solvents compared with the results obtained in water. Interestingly,
only a trace amount of product was detected when the reaction
occurred in most of commonly used solvents (THF, toluene, DCM).
1,4-Dioxane and DMF displayed higher level of reactivity, delivering
the target compound 3a in 64% and 71% yields. Further in-
vestigation revealed that the addition of surfactant in the reaction
was not required. Changing the oxidant to peroxide from oxone also
resulted in poor yield of the product (data not shown in Table 1).
N
H
N
Ph
Ph
1a
3a
Scheme 1. A possible mechanism for the generation of 1-(4-iodoisoquinolin-1-yl)urea
3a via a reaction of 2-alkynylbenzaldoxime 1a, carbodiimide 2a, and iodide.
Table 2
Synthesis of 1-(4-iodoisoquinolin-1-yl)ureas
3
via
a
reaction of 2-
alkynylbenzaldoxime 1, carbodiimide 2, and sodium iodide in watera
O
N
R3
NaI (3.0 equiv)
oxone (1.5 equiv)
OH
R2
NHR3
R3
N
N
I
N
R1
+
N
C
R3
DABCO (1.5 equiv)
R1
H2O
30 ºC
R2
3
2
1
O
O
O
p-MeC6H4
p-MeC6H4
p-MeC6H4
N
NH
C6H4p-Me
N
NH
C6H4p-Me
N
I
NH
C6H4p-Me
Table 1
Cl
N
N
N
Initial studies for the reaction of 2-(phenylethynyl)benzaldehyde oxime 1a with
carbodiimide 2a in watera
Ph
MeO
Ph
Ph
O
I
I
Tol
Tol
NaI (3.0 equiv)
3a, 92% yield
3b, 93% yield
3c, 80% yield
OH
Ph
N
I
N
H
Tol
N
N
oxone (1.5 equiv)
+
N C
O
O
O
N
base (1.5 equiv)
Tol
p-MeC6H4
p-ClC6H4
p-MeC6H4
N
NH
N
NH
N
NH
H2O
30 ºC
3a
Ph
2a
1a
C6H4p-Me
C6H4p-Cl
C6H4p-Me
N
N
N
C6H4p-OMe
Ph
C6H4p-Cl
Entry
Base
Yielda (%)
I
I
I
1
2
3
4
5
d
44
59
50
55
92
3d, 70% yield
3e, 70% yield
3f, 63% yield
KOH
KOAc
K3PO4
O
O
O
Cy
p-ClC6H4
p-ClC6H4
N
NH
N
NH
C6H4p-Cl
N
NH
DABCO
Cy
Cl
F
C6H4p-Cl
a
N
N
N
Isolated yield based on 2-alkynylbenzaldoxime 1a.
Ph
Ph
Ph
I
I
I
A possible mechanism is proposed in Scheme 1. In the presence
of iodonium ion generated by oxidation of iodide, 4-
iodoisoquinoline-N-oxide A would be produced through 6-endo
cyclization of 2-alkynylbenzaldoxime 1a. A subsequent [3þ2] cy-
cloaddition of 4-iodoisoquinoline-N-oxide A with carbodiimide 2a
would happen, affording intermediate B, which would undergo
based-promoted intramolecular rearrangement to generate 4-
iodo-1-(isoquinolin-1-yl)urea 3a.
The optimized conditions developed for the one-pot tandem
reaction of 2-alkynylbenzaldoxime 1 with carbodiimide 2 were
then applied through a range of substrates. Both the NaI/oxone and
NaBr/oxone were evaluated as the halonium ion source across the
substrates, and we first focused on the NaI/oxone system (Table 2).
The process was proven to be broad in scope, tolerating a series of
electronic changes to both partners. For instance, products 3b and
3c demonstrated the ability of the 2-alkynylbenzaldoxime 1 to bear
either electron-withdrawing or -donating substituents on the
3g, 72% yield
3h, 75% yield
3i, 72% yield
a Isolated yield based on 2-alkynylbenzaldoxime 1.
aromatic ring. Alkyl-substituted 2-alkynylbenzaldoxime could also
be employed (3d, 3e). As shown in the Table, the products 3fei
were successfully delivered, which demonstrated the tolerance of
substituted carbondiimides 2 in the process. The multi-substituted
1-(4-iodoisoquinolin-1-yl) urea 3h, as an example, was obtained in
75% yield, highly proved the efficiency of chlorophenyl-substituted
carbondiimide. The formation of compound 3i demonstrated that
DCC was tolerable as well being as the cyclization partner.
We then transferred the optimized condition to the aqueous
system with brominium ion. The results are summarized in Table 3.
The demonstration gives the scope of the one-pot process and
a series of substituents prove to be tolerated. Variation of the

2248
L. Lai et al. / Tetrahedron 70 (2014) 2246e2250
Table 3
0.6 mmol) and DABCO (1.5 equiv, 0.45 mmol) were added. The
mixture was stirred under 30 ꢀC for 20 h. After completion of the
reaction, the mixture was extracted by EtOAc (2ꢁ5.0 mL) and dried
by anhydrous Na2SO4. Evaporation of the solvent followed by pu-
rification on silica gel (eluted with PE/EA¼10:1) provided the
product 3 or 4.
Scope investigation for the reaction of 2-alkynylbenzaldoxime 1, carbodiimide 2,
and bromonium ion generated in situ in watera
O
R3
NaBr (3.0 equiv)
oxone (1.5 equiv)
OH
R2
R3
N
N
NHR3
N
R1
+
N
C
N
R3
DABCO (1.5 equiv)
R1
H2O
30 ºC
R2
4
2
1
4.1.1. 1-(4-Iodo-3-phenylisoquinolin-1-yl)-1,3-di-p-tolylurea
Br
(3a). 1H NMR (400 MHz, CDCl3)
d 2.27 (s, 3H), 2.36 (s, 3H), 7.07 (d,
J¼8.4 Hz, 2H), 7.10e7.26 (m, 5H), 7.45e7.51 (m, 5H), 7.62e7.68 (m,
O
O
O
N
3H), 7.78 (t, J¼7.2 Hz, 1H), 8.23 (d, J¼8.0 Hz, 1H), 8.29 (d, J¼8.4 Hz,
p-MeC6H4
p-MeC6H4
p-MeC6H4
1H); 13C NMR (100 MHz, CDCl3)
d 20.8, 21.1, 97.3, 119.7, 125.4, 126.0,
N
NH
N
NH
C6H4p-Me
N
NH
C6H4p-Me
Cl
C6H4p-Me F
127.9, 128.0, 128.1, 128.4, 128.8, 129.4, 129.9, 130.2, 130.3, 132.4,
135.8, 137.5, 138.5, 140.9, 143.0, 152.0, 153.7, 155.0; HRMS (ESI) calcd
for C30H24IN3O: 570.1037 (MþHþ), found: 570.1029.
N
N
Ph
Ph
Ph
Br
Br
Br
4a, 62% yield
4b, 60% yield
4c, 71% yield
4.1.2. 1-(7-Chloro-4-iodo-3-phenylisoquinolin-1-yl)-1,3-di-p-toly-
O
O
lurea (3b). 1H NMR (400 MHz, CDCl3)
d 2.31 (s, 3H), 2.39 (s, 3H),
O
p-ClC6H4
p-ClC6H4
p-ClC6H4
N
NH
N
NH
7.09e7.11 (m, 3H), 7.25e7.29 (m, 4H), 7.47e7.54 (m, 5H), 7.66e7.69
N
NH
(m, 3H), 8.23 (d, J¼9.2 Hz, 1H), 8.26 (d, J¼2.0 Hz, 1H); 13C NMR
Cl
C6H4p-Cl
F
C6H4p-Cl
C6H4p-Cl
N
N
N
(100 MHz, CDCl3)
d 20.9, 21.2, 96.6, 119.9, 124.7, 126.0, 127.9, 128.2,
Ph
Ph
Ph
128.6, 129.5, 130.2, 130.7, 133.1, 133.2, 134.9, 135.6, 138.0, 138.1,
139.4, 142.6, 152.9, 154.0, 155.9; HRMS (ESI) calcd for C30H23ClIN3O:
604.0647 (MþHþ), found: 604.0641.
Br
Br
Br
4d, 92% yield
4e, 72% yield
4f, 75% yield
O
O
Cy
p-ClC6H4
4.1.3. 1-(4-Iodo-6-methoxy-3-phenylisoquinolin-1-yl)-1,3-di-p-toly-
N
NH
Cy
N
NH
C6H4p-Cl
lurea (3c). 1H NMR (400 MHz, CDCl3)
d 2.30 (s, 3H), 2.36 (s, 3H),
F
N
N
3.99 (s, 3H), 7.08 (d, J¼8.4 Hz, 2H), 7.20e7.27 (m, 5H), 7.34 (s, 1H),
7.47e7.49 (m, 5H), 7.58 (d, J¼2.0 Hz, 1H), 7.68 (d, J¼6.8 Hz, 2H), 8.14
Ph
C6H4p-Cl
Br
Br
(d, J¼9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 20.8, 21.1, 55.8, 96.4,
4g, 63% yield
4h, 67% yield
111.6, 119.7, 120.5, 121.4, 127.6, 127.9, 128.0, 128.5, 129.4, 130.1, 130.3,
132.9, 135.8, 137.2, 138.7, 143.2, 143.3, 153.2, 153.8, 156.2, 162.8;
HRMS (ESI) calcd for C31H26IN3O2: 600.1142 (MþHþ), found:
600.1124.
a Isolated yield based on 2-alkynylbenzaldoxime 1.
aromatic-substituted 2-alkynylbenzaldoxime 1, almost had little
impact on the efficiency of the whole process, delivering moderate
yields of compounds 4. For instance, 2-alkynylbenzaldoxime 1a and
carbondiimide 2b were successfully employed, giving rise to the
corresponding product 4d in 92% yield. Cyclohexyl-substituted 1-
(4-bromoisoquinolin-1-yl)urea 4h was smoothly produced, again
demonstrating the ability of carbondiimide to tolerate alkyl group
for product modification. The use of alternative bromides KBr and
TBAB (tetrabutyl ammonium bromide) in combination with
the oxidant oxone, delivered inferior results (data not shown in
Table 3).
4.1.4. 1-(3-(4-Chlorophenyl)-4-iodoisoquinolin-1-yl)-1,3-di-p-toly-
lurea (3d). 1H NMR (400 MHz, CDCl3)
d 2.30 (s, 3H), 2.38 (s, 3H),
7.08 (s, 1H), 7.09 (d, J¼1.2 Hz, 2H), 7.23 (d, J¼8.4 Hz, 2H), 7.27 (d,
J¼8.0 Hz, 2H), 7.45 (d, J¼8.8 Hz, 2H), 7.49 (d, J¼8.4 Hz, 2H),
7.62e7.69 (m, 3H), 7.78 (t, J¼8.4 Hz, 1H), 8.27 (t, J¼8.4 Hz, 2H); 13
C
NMR (100 MHz, CDCl3)
d 20.9, 21.2, 97.2, 119.7, 125.5, 126.0, 128.0,
128.1, 129.0, 129.5, 130.5, 131.7, 132.4, 133.0, 133.1, 134.5, 135.7, 137.8,
138.3, 140.8, 141.3, 153.9, 154.0, 154.3; HRMS (ESI) calcd for
C
30H23ClIN3O: 604.0647 (MþHþ), found: 604.0633.
4.1.5. 1-(4-Iodo-3-(4-methoxyphenyl)isoquinolin-1-yl)-1,3-di-p-tol-
ylurea (3e). 1H NMR (400 MHz, CDCl3)
2.29 (s, 3H), 2.36 (s, 3H),
d
3. Conclusions
3.88 (s, 3H), 7.01 (d, J¼8.8 Hz, 2H), 7.07 (d, J¼8.0 Hz, 2H), 7.20e7.27
(m, 5H), 7.48 (d, J¼8.4 Hz, 2H), 7.66 (d, J¼8.8 Hz, 2H), 7.76 (t,
J¼6.8 Hz, 1H), 8.21 (d, J¼7.6 Hz, 1H), 8.28 (d, J¼8.4 Hz, 1H); 13C NMR
In summary, with the employment of NaI/oxone or NaBr/oxone
as the promoters of hypohalite generated in situ, we have dem-
onstrated the one-pot tandem reaction of 2-alkynylbenzaldoxime
and carbondiimide, delivering 1-(4-haloisoquinolin-1-yl)urea in
water. The green process proceeds smoothly and efficiently, ac-
commodating a variety of substituents to generate the desired
products.
(100 MHz, CDCl3)
d 20.9, 21.2, 55.4, 97.1, 113.2, 119.8, 125.2, 126.0,
127.9,128.7,129.5,130.4,131.4,131.8,132.3,133.0,135.8,137.5,138.6,
141.1, 153.6, 154.0, 155.1, 159.8; HRMS (ESI) calcd for C31H26IN3O2:
600.1142 (MþHþ), found: 600.1132.
4.1.6. 1,3-Bis(4-chlorophenyl)-1-(4-iodo-3-phenylisoquinolin-1-yl)
urea (3f). 1H NMR (400 MHz, CDCl3)
d
7.20 (d, J¼9.2 Hz, 2H), 7.25 (d,
4. Experimental section
J¼9.2 Hz, 2H), 7.33 (d, J¼8.8 Hz, 2H), 7.43e7.51 (m, 5H), 7.62e7.69
(m, 4H), 7.79 (t, J¼7.6 Hz, 1H), 8.07 (d, J¼8.4 Hz, 1H), 8.31 (d,
4.1. General experimental procedure for the generation of 1-
(4-haloisoquinolin-1-yl)ureas in water
J¼8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 97.8, 121.0, 124.6, 125.6,
127.8, 128.1, 128.7, 128.8, 128.9, 129.2, 129.6, 130.0, 132.8, 133.3,
136.7, 139.9, 141.2, 142.6, 152.9, 153.2, 155.4; HRMS (ESI) calcd for
2-Alkynylbenzaldoxime 1 (0.30 mmol) was added to a mixture
of sodium iodide or sodium bromide (2.0 equiv, 0.6 mmol) and
oxone (1.5 equiv, 0.45 mmol) in water (3.0 mL). The mixture was
stirred under 30 ꢀC. After 10e12 h, carbodiimide 2 (2.0 equiv,
C
28H18Cl2IN3O: 609.9944 (MþHþ), found: 609.9961.
4.1.7. 1-(7-Chloro-4-iodo-3-phenylisoquinolin-1-yl)-1,3-bis(4-
chlorophenyl)urea (3g). 1H NMR (400 MHz, CDCl3)
7.20 (d,
d

L. Lai et al. / Tetrahedron 70 (2014) 2246e2250
2249
J¼9.2 Hz, 2H), 7.26 (d, J¼9.2 Hz, 2H), 7.46e7.50 (m, 6H), 7.63e7.650
(m, 2H), 7.68 (dd, J¼2.0, 8.8 Hz, 1H), 8.08 (d, J¼1.6 Hz, 1H), 8.23 (d,
(m, 5H), 7.73e7.75 (m, 3H), 8.10 (d, J¼2.0 Hz, 1H), 8.32 (d, J¼9.2 Hz,
1H); 13C NMR (100 MHz, CDCl3)
117.6, 121.0, 124.3, 126.0, 128.1,
128.8, 128.9, 129.2, 129.8, 129.9, 130.0, 130.1, 133.1, 133.6, 135.1,
136.5, 137.0, 139.2, 139.3, 150.9, 151.1, 153.2.
d
J¼8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
97.1, 121.2, 124.2, 128.0,
128.6, 128.8, 129.0, 129.2, 129.9, 130.0, 130.1, 133.4, 133.6, 135.1,
135.3, 136.4, 139.2, 139.5, 142.2, 152.0, 153.4, 155.8; HRMS (ESI)
calcd for C28H17Cl3IN3O: 643.9555 (MþHþ), found: 609.9518.
4.1.15. 1-(4-Bromo-7-fluoro-3-phenylisoquinolin-1-yl)-1,3-bis(4-
chlorophenyl)urea (4f).10c 1H NMR (400 MHz, CDCl3)
d 7.21 (d,
4.1.8. 1,3-Bis(4-chlorophenyl)-1-(7-fluoro-4-iodo-3-phenylisoquinolin-
J¼8.8 Hz, 2H), 7.27 (d, J¼8.8 Hz, 2H), 7.37 (d, J¼8.4 Hz, 2H), 7.42 (s,
1-yl)urea (3h). 1H NMR (400 MHz, CDCl3)
d
7.20 (d, J¼8.8 Hz, 2H),
1H), 7.46e7.51 (m, 5H), 7.58 (t, J¼10.0 Hz, 1H), 7.73e7.75 (m, 3H),
7.25 (d, J¼8.8 Hz, 2H), 7.36 (d, J¼8.8 Hz, 2H), 7.44e7.54 (m, 7H),
8.41 (dd, J¼5.2, 9.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 109.2 (d,
2
7.63e7.65 (m, 2H), 7.71 (dd, J¼2.4, 9.2 Hz,1H), 8.34 (dd, J¼4.2, 9.2 Hz,
2JCF¼22.0 Hz), 117.5, 121.4, 122.7 (d, JCF¼25.0 Hz), 126.4 (d,
3JCF¼9.0 Hz), 128.1, 128.8, 128.9, 128.8, 129.1, 129.9, 130.0, 131.1 (d,
3JCF¼9.0 Hz), 133.5, 135.6, 136.5, 139.2, 139.4, 150.4, 151.3, 153.1,
161.9 (d, 1JCF¼252.0 Hz).
2
1H); 13C NMR (100 MHz, DMSO-d6)
d
97.7, 109.5 (d, JCF¼23.0 Hz),
2
3
122.1, 123.5 (d, JCF¼25.0 Hz), 125.8 (d, JCF¼9.0 Hz), 127.1, 128.3,
3
128.4, 128.8, 129.6, 130.3, 130.6, 136.5 (d, JCF¼9.0 Hz), 138.3, 133.8,
141.6, 143.2, 153.0, 153.1, 154.5, 155.7, 161.8 (d, 1JCF¼248.0 Hz); HRMS
(ESI) calcd for C28H17Cl2FIN3O: 627.9850 (MþHþ), found: 627.9797.
4.1.16. 1-(4-Bromo-3-(4-chlorophenyl)-7-fluoroisoquinolin-1-yl)-
1,3-bis(4-chlorophenyl)urea (4g). 1H NMR (400 MHz, CDCl3)
4.1.9. 1,3-Dicyclohexyl-1-(4-iodo-3-phenylisoquinolin-1-yl)urea
d
7.19e7.28 (m, 5H), 7.39 (d, J¼8.8 Hz, 2H), 7.44e7.48 (m, 4H),
(3i).10c 1H NMR (400 MHz, CDCl3)
d
0.71e0.78 (m, 2H), 0.93e0.97
7.57e7.62 (m, 1H), 7.67 (d, J¼8.4 Hz, 2H), 7.75 (dd, J¼2.4, 9.2 Hz,1H),
(m, 2H), 1.22e1.37 (m, 6H), 1.48e1.58 (m, 4H), 1.68e1.75 (m, 4H),
1.85e1.98 (m, 2H), 3.60e3.66 (m, 1H), 3.72 (d, J¼8.0 Hz, 1H),
4.49e4.55 (m, 1H), 7.45e7.52 (m, 3H), 7.63e7.69 (m, 3H), 7.81 (dt,
8.41 (dd, J¼4.8, 9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 109.2 (d,
2JCF¼23.0 Hz), 117.6, 121.0, 121.6, 122.8 (d, JCF¼25.0 Hz), 128.3,
2
3
129.0, 129.2, 130.1, 131.1 (d, JCF¼9.0 Hz), 131.5, 133.8, 134.9, 135.2,
J¼1.2, 7.2 Hz, 1H), 8.07 (d, J¼7.6 Hz, 1H), 8.30 (d, J¼8.4 Hz, 1H); 13
C
136.4,137.4, 139.0,149.2, 150.4,151.4 (d, 4JCF¼6.0 Hz),153.1, 162.0 (d,
1JCF¼252.0 Hz); HRMS (ESI) calcd for C28H16BrCl3FN3O: 613.9599
(MþHþ), found: 613.9677.
NMR (100 MHz, CDCl3)
d 25.0, 25.5, 25.7, 26.1, 32.1, 33.5, 49.5, 57.4,
97.8, 126.3, 126.9, 128.0, 128.6, 128.7, 130.2, 132.7, 132.9, 140.6, 142.9,
152.6, 155.8, 156.0.
4.1.17. 1-(4-Bromo-3-phenylisoquinolin-1-yl)-1,3-dicyclohexylurea
(4h).10c 1H NMR (400 MHz, CDCl3) 0.74e0.77 (m, 2H), 0.91e0.98
(m, 2H), 1.22e1.29 (m, 2H), 1.35e1.38 (m, 4H), 1.48e1.51 (m, 4H),
1.70e1.75 (m, 4H), 1.97e1.98 (m, 2H), 3.62e3.63 (m, 1H), 3.71 (d,
J¼8.0 Hz, 1H), 4.49e4.51 (m, 1H), 7.43e7.53 (m, 3H), 7.66 (t,
J¼7.2 Hz, 1H), 7.78e7.86 (m, 3H), 8.11 (d, J¼8.4 Hz, 1H), 8.38 (d,
4.1.10. 1-(4-Bromo-3-phenylisoquinolin-1-yl)-1,3-di-p-tolylurea
(4a).10c 1H NMR (400 MHz, CDCl3)
d 2.29 (s, 3H), 2.36 (s, 3H), 7.07
(d, J¼8.4 Hz, 2H), 7.15 (s, 1H), 7.22 (d, J¼8.4 Hz, 2H), 7.26 (d,
J¼8.4 Hz, 2H), 7.45e7.52 (m, 5H), 7.65 (t, J¼7.6 Hz, 1H), 7.76e7.82
(m, 3H), 8.29 (d, J¼8.4 Hz, 1H), 8.37 (d, J¼8.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3)
d
20.8, 21.2, 117.6, 119.8, 125.9, 127.7, 127.9, 128.5,
J¼8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 24.8, 25.4, 25.5, 26.0,
128.7, 129.5, 130.3, 130.4, 132.0, 133.1, 135.7, 137.7, 138.3, 138.4,
140.0, 150.8, 152.5, 154.0.
31.9, 33.4, 49.4, 57.2, 117.8, 126.1, 127.2, 127.4, 127.8, 128.4, 128.5,
130.1, 132.1, 137.9, 139.8, 151.1, 151.4, 155.6.
4.1.11. 1-(4-Bromo-7-chloro-3-phenylisoquinolin-1-yl)-1,3-di-p-toly-
Acknowledgements
lurea (4b).10c 1H NMR (400 MHz, CDCl3)
d 2.30 (s, 3H), 2.39 (s, 3H),
7.00 (s, 1H), 7.08 (d, J¼8.0 Hz, 2H), 7.26 (d, J¼7.6 Hz, 4H), 7.44e7.53
Financial support from National Natural Science Foundation of
China (Nos. 21032007, 21172038) is gratefully acknowledged.
(m, 5H), 7.71e7.76 (m, 3H), 8.25 (d, J¼2.0 Hz, 1H), 8.31 (d, J¼9.2 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d 20.8, 21.2, 117.1, 119.7, 124.7, 126.6,
127.9, 128.2, 128.6, 129.4, 129.5, 130.2, 130.6, 132.8, 133.2, 134.8,
135.5, 136.7, 137.9, 138.2, 139.7, 151.1, 151.7, 153.9.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.02.026.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
4.1.12. 1-(4-Bromo-7-fluoro-3-phenylisoquinolin-1-yl)-1,3-di-p-toly-
lurea (4c).10c 1H NMR (400 MHz, CDCl3)
d 2.30 (s, 3H), 2.38 (s, 3H),
7.06e7.09 (m, 3H), 7.24e7.27 (m, 4H), 7.44e7.58 (m, 6H), 7.75 (dd,
J¼2.0, 8.4 Hz, 2H), 7.89 (dd, J¼2.4, 9.2 Hz, 1H), 8.39 (dd, J¼4.8,
9.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 20.8, 21.2, 109.6 (d,
References and notes
2
2JCF¼23.0 Hz), 117.2, 119.8, 122.3 (d, JCF¼25.0 Hz), 126.9 (d,
3JCF¼9.2 Hz), 127.9, 128.1, 128.6, 129.5, 130.2, 130.6, 130.8 (d,
3JCF¼9.0 Hz), 133.2, 135.4, 135.5, 137.9, 138.0, 139.8, 150.4, 152.1 (d,
4JCF¼5.0 Hz), 153.9, 161.9 (d, 1JCF¼251.0 Hz).
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chlorophenyl)urea (4e).10c 1H NMR (400 MHz, CDCl3)
d
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