1-(isoquinolin-1-yl)urea library generation via three-component reaction of 2-alkynylbenzaldoxime, carbodiimide, with electrophile

Article abstract of DOI:10.1021/co100026y

A novel and highly efficient three-component reaction of 2-alkynylbenzaldoxime, carbodiimide, with electrophile (bromine or iodine monochloride) is disclosed, which generates 1-(4-haloisoquinolin-1-yl)ureas in good yields under mild conditions. Subsequent

Full text of DOI:10.1021/co100026y

RESEARCH ARTICLE
pubs.acs.org/acscombsci
1-(Isoquinolin-1-yl)urea Library Generation via Three-Component
Reaction of 2-Alkynylbenzaldoxime, Carbodiimide, with Electrophile
Shengqing Ye,† Huanhuan Wang,† and Jie Wu*,†,‡
†Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
S Supporting Information
b
ABSTRACT: A novel and highly efficient three-component
reaction of 2-alkynylbenzaldoxime, carbodiimide, with elec-
trophile (bromine or iodine monochloride) is disclosed, which
generates 1-(4-haloisoquinolin-1-yl)ureas in good yields under
mild conditions. Subsequent palladium-catalyzed Suzuki-
Miyaura coupling reaction is introduced, leading to the diverse
1-(isoquinolin-1-yl)ureas.
KEYWORDS: three-component reaction, 2-alkynylbenzaldoxime, carbodiimide, Suzuki-Miyaura coupling, 1-(isoquinolin-1-yl)ureas,
palladium-catalyzed
’ INTRODUCTION
access to functionalized isoquinolines. To our surprise, there are
not many examples for combinatorial synthesis of functionalized
isoquinolines.7 Most of the isoquinoline generation centered on
classical methods including the Pomeranz-Fritsch,7a,7b Bischler-
Napieralski,7c and Pictet-Spengler reactions,7d,7f which generally
suffered from either harsh conditions or tedious reaction pro-
cedures. Recently, transition metal-catalyzed isoquinoline for-
mation was developed.8 However, this method usually required
high temperature and expensive metal catalysts. For example,
Larock and co-workers8 reported the solution-phase synthesis
of a small library of isoquinoline through the palladium- and
copper-catalyzed cyclization of iminoalkynes and the palladium-
catalyzed iminoannulation of internal alkynes. The reaction pro-
ceeded at 100 °C to provide the isoquinoline compounds in low
yields. To ensure the 1-(isoquinolin-1-yl)urea library construction,
the strategy should be highly efficient with good substrate gener-
ality under mild conditions. Moreover, the starting materials
should be easily available. Herein, we wish to report our recent
efforts for diverse 1-(isoquinolin-1-yl)ureas generation via three-
component reaction of 2-alkynylbenzaldoxime, carbodiimide,
with electrophile under mild conditions. This metal-free process
with high efficiency facilitates the rapid assembly of 1-(isoquinolin-
1-yl)urea compounds.
Combinatorial chemistry has a great impact on the drug dis-
covery process because it is well recognized as a powerful tool
for providing large collection of small molecules.1 In this field,
intense interest has been directed toward the design and synthe-
sis of natural-product-like compounds using combinatorial ap-
proaches since natural products play an important role in drug
development and drug discovery. Among the scaffolds of natural
products, isoquinoline has attracted growing interest since it is
a core structure in many natural alkaloids and pharmaceuticals
that display diverse biological and pharmacological activities.2,3
Therefore, isoquinolines are regarded as a promising class of
potentially useful pharmacologically active compounds, and their
synthesis has found widespread application so far.4 We have
involved in the development of new and practical methods for
the design and synthesis of natural-product-like compounds,5
and we are interested in undertaking the construction of small-
sized combinatorial libraries for biological screening applications
in multiple assays. Recently, we reported the 1-(isoquinolin-1-yl)urea
synthesis via a silver triflate-catalyzed tandem reaction of 2-alkynyl-
benzaldoxime with carbodiimide (Scheme 1, eq 1).6 Although
this reaction shows good generality for functional groups with
a broad substrate scope, the diversity could not be introduced in
the 4-position of isoquinoline scaffold. In addition, as we can see,
the 1-(isoquinolin-1-yl)urea products possess hydrogen bond
donor/acceptor capabilities that could confer interesting bio-
logical properties for applications in chemical biology and drug
discovery. Consequently, it is of high demand for a small library
construction of diverse 1-(isoquinolin-1-yl)ureas, with an expec-
tation to find some hits from our specific biological assays. Thus,
we initiated a program to develop efficient pathway for rapid
Among the strategies used for natural-product-like compounds
construction, multicomponent reactions are very attractive processes
with high efficiency for the generation of combinatorial libraries
based on privileged structures.9 We conceived that an electrophile
Received: October 3, 2010
Revised:
November 24, 2010
Published: December 16, 2010
r
2010 American Chemical Society
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|

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RESEARCH ARTICLE
Scheme 1. Proposed Synthetic Route for Generation of Diverse 1-(Isoquinolin-1-yl)ureas via Three-Component Reaction of
2-Alkynylbenzaldoxime, Carbodiimide, with Electrophile
Table 1. Initial Studies for Three-Component Reaction
of 2-Alkynylbenzaldoxime 1{1}, Carbodiimide 2{1},
with Bromine
To our delight, we observed the formation of compound 3{1,1}
with 28% isolated yield when the reaction was carried out in
CH2Cl2/MeCN (Table 1, entry 2). The yield was increased to
51% when DMF was utilized as a replacement (Table 1, entry 3).
Addition of base dramatically improved the reaction efficiency.
Further screening of different bases revealed that DABCO was
the best one, which furnished the corresponding product 3{1,1}
in 92% yield (Table 1, entry 11).
With the optimized conditions in hand [DABCO (1.2 equiv),
CH2Cl2/DMF, room temperature], the scope of this three-
component reaction was examined with a series of 2-alkynyl-
benzaldoximes 1 and carbodiimide 2 in the presence of bromine
or iodine monochloride. The diversity reagents of 2-alkynyl-
benzaldoximes 1 and carbodiimide 2 are shown in Figures 1 and 2,
and the results are displayed in Table 2. All reactions went to
completion in 8-10 h, which afforded the expected 1-(4-haloiso-
quinolin-1-yl)ureas in good to excellent yields under mild conditions.
All products were isolated by column chromatography on silica
gel with >97% purity.
This three-component reaction shows a broad substrate scope.
As shown in Table 2, the electron effect on the aromatic backbone
of both the substrates was invisible. In some cases, the desired
products were obtained in almost quantitative yields. Not only
bromine but also iodine monochloride was workable under the
standard conditions. For 2-alkynylbenzaldoximes 1, the groups
attached on the aromatic ring or the triple bond did not influence
the final outcome. Additionally, no difference was observed in
the reaction for alkyl or aryl substituted carbodiimides. The
possible mechanism was proposed in Scheme 2. We reasoned
that, in the presence of electrophile (bromine or iodine mono-
chloride), 4-haloisoquinoline-N-oxide would be formed from
2-alkynylbenzaldoxime 1 via 6-endo-cyclization. Subsequently,
4-haloisoquinoline-N-oxide reacted with carbodiimide 2 via [3 þ 2]
cycloaddition leading to the key intermediate A. After base-
promoted intramolecular rearrangement, the corresponding
4-halo-1-(isoquinolin-1-yl)urea would be generated. On the basis
of this hypothesis, we conceived that the substituent (R2 or R3
group) attached on the substrates would affect the final outcome.
Generally, the electrophility would be increased when R3 was an
electron-withdrawing group, while the reactivity was expected to
be decreased for carbodiimide with an electron-donating group
attached on the nitrogen. For instance, reaction of 2-alkynyl-
benzaldoxime 1{8} with 4-methoxy-N-((4-methoxyphenylimino)-
methylene)benzenamine 2{5} gave rise to the desired product
3{8,5} in 50% yield (Table 2, entry 49). A quantitative yield of
entry
base
solvent
CH2Cl2
yield (%)a
1
trace
28
51
73
77
71
75
72
65
70
92
2
CH2Cl2/MeCN
CH2Cl2/DMF
CH2Cl2/DMF
CH2Cl2/DMF
CH2Cl2/DMF
CH2Cl2/DMF
CH2Cl2/DMF
CH2Cl2/DMF
CH2Cl2/DMF
CH2Cl2/DMF
3
4
KOH
5
LiOH
6
KOAc
7
Na2CO3
NaHCO3
Cs2CO3
K3PO4
8
9
10
11
DABCO
a Isolated yield based on 2-alkynylbenzaldoxime 1{1}.
could be involved in the reaction of 2-alkynylbenzaldoxime with
carbodiimide (Scheme 1, eq 2). Thus, 1-(4-haloisoquinolin-1-
yl)ureas would be formed under suitable conditions from the
above three-component reaction. After subsequent palladium-
catalyzed cross-coupling reactions, the functionalized 1-(isoquinolin-
1-yl)ureas would be generated.
’ RESULT AND DISCUSSION
At the beginning of our investigations, we examined the three-
component reaction of 2-alkynylbenzaldoxime 1{1}, N-((cyclo-
hexylimino)methylene)cyclohexanamine 2{1}, with bromine
under different conditions. Since 2-alkynylbenzaldoxime worked
the most efficiently with bromine in dichloromethane,10 the
initial attempt was performed in CH2Cl2 at room temperature.
However, only a trace amount of desired product 3{1,1} was
detected (Table 1, entry 1). In the reaction process, HBr would
be generated as a byproduct. Thus, the basic solvents were used.
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RESEARCH ARTICLE
Figure 1. Diversity reagents 1{1-10}.
Figure 2. Carbodiimide reagents 2{1-7}.
3{8,7} was isolated when 4-chloro-N-((4-chlorophenylimino)-
methylene)benzenamine 2{7} was used as a replacement in
the reaction (Table 2, entry 51). For the effect of substituent
(R2 group) attached on the triple bond of 2-alkynylbenzaldoxime 1,
we reasoned that the group with π electron would facilitate
the transformation, which would stabilize the 4-haloisoquinoline-
N-oxide intermediate. As expected, reactions proceeded well for
the 2-alkynylbenzaldoxime 1 with aryl or cyclopropyl group
attached on the triple bond, while inferior results were generated
when the R2 group was changed to n-Bu group (Table 2, entries
53-61).
Some 1-(4-bromoisoquinolin-1-yl)ureas 3 were selected for
further elaboration. Because of their easy availability, arylboronic
acid derivatives would be the starting materials of choice. Thus,
the palladium-catalyzed Suzuki-Miyaura coupling reaction11 of
1-(4-bromoisoquinolin-1-yl)ureas 3 with arylboronic acid was
tested. The selected representative of arylboronic acids was
shown in Figure 3. As expected, the diversity on the 4-position
could be easily introduced in the scaffold. The reactions pro-
ceeded efficiently in the presence of Pd(OAc)2 (5 mol %), PPh3
(10 mol %), and K3PO4 in toluene (Table 3). For most cases, the
desired products 6 were generated in excellent yields.
’ EXPERIMENTAL PROCEDURES
General Procedure for Three-Component Reactions of
2-Alkynylbenzaldoxime 1, Carbodiimide 2, with Br2 or ICl.
2-Alkynylbenzaldoxime 1 (0.2 mmol) was added to a solution
of Br2 or ICl in DCM (0.4 mmol/mL, 0.5 mL), and the solution
was stirred at room temperature in air for 10 min. Then DABCO
(1.2 equiv) was added, and the solution was stirred at room tem-
perature in air for another 10 min. Subsequently, DMF (2.0 mL)
and carbodiimide 2 (1.5 equiv) were added, and the mixture was
stirred at room temperature in air for 12 h. After completion of
reaction as indicated by TLC, the reaction was quenched by
addition of saturated aqueous NH4Cl (5.0 mL), and the mixture
was extracted with EtOAc (4.0 mLꢀ3). The combined organic
layer was dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel to
provide the desired product 3 or 4. Data of selected examples:
1-(4-Bromo-3-phenylisoquinolin-1-yl)-1,3-dicyclohexylurea
(3{1,1}): 1H NMR (400 MHz, CDCl3) δ 0.76 (q, J = 12.4 Hz,
2H), 0.84-1.00 (m, 2H), 1.20-1.60 (m, 10H), 1.70-1.76
(m, 4H), 1.98-1.99 (m, 2H), 3.59-3.66 (m, 1H), 3.72 (d, J =
7.7 Hz, 1H), 4.49-4.58 (m, 1H), 7.44-7.53 (m, 3H), 7.66 (t, J =
8.0 Hz, 1H), 7.79 (d, J = 7.0 Hz, 2H), 7.84 (t, J = 7.7 Hz, 1H),
8.12 (d, J = 8.8 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 24.8, 25.4, 25.5, 26.0, 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; HRMS (ESI) calcd for
C28H32BrN3O 528.1626 (M þ Naþ), found 528.1606. 1-(4-
Bromo-3-phenylisoquinolin-1-yl)-1,3-diisopropylurea (3{1,2}):
1H NMR (400 MHz, CDCl3) δ 0.92 (d, J = 6.6 Hz, 6H), 1.25 (d,
J = 6.6 Hz, 6H), 3.69 (d, J = 7.7 Hz, 1H), 3.95-4.01 (m, 1H),
4.92-4.98 (m, 1H), 7.44-7.53 (m, 3H), 7.67 (t, J = 8.1 Hz, 1H),
7.80 (d, J = 8.3 Hz, 2H), 7.85 (t, J = 7.7 Hz, 1H), 8.09 (d, J = 8.3 Hz,
1H), 8.40 (d, J = 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 21.5, 23.0, 42.5, 49.4, 117.7, 126.0, 127.0, 127.5, 127.9, 128.4,
’ CONCLUSION
In summary, we have described a novel and highly efficient
three-component reaction of 2-alkynylbenzaldoxime, carbodi-
imide, with electrophile, leading to 1-(4-haloisoquinolin-1-yl)-
ureas in good yields under mild conditions. The scaffold could be
further decorated to introduce more diversity through sub-
sequent palladium-catalyzed Suzuki-Miyaura coupling reaction.
The facile assembly of 1-(isoquinolin-1-yl)urea library could
be expected becaue of the high efficiency, good substrate general-
ity, mild conditions, and the easily availability of the starting
materials.
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RESEARCH ARTICLE
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
1{8}
1{8}
1{8}
1{8}
1{8}
1{8}
1{8}
1{8}
1{9}
1{9}
1{9}
1{9}
1{9}
1{9}
1{9}
1{9}
1{10}
2{1}
2{2}
2{3}
2{4}
2{5}
2{6}
2{7}
2{1}
2{1}
2{2}
2{3}
2{4}
2{5}
2{6}
2{7}
2{1}
2{2}
3{8,1}
3{8,2}
3{8,3}
3{8,4}
3{8,5}
3{8,6}
3{8,7}
4{8,1}
3{9,1}
3{9,2}
3{9,3}
3{9,4}
3{9,5}
3{9,6}
3{9,7}
4{9,1}
3{10,2}
97
96
95
88
50
96
99
97
88
80
60
53
51
53
58
77
75
Table 2. Three-Component Reaction of 2-Alkynylbenzal-
doxime 1, Carbodiimide 2, with Electrophile
entry 2-alkynylbenzaldoxime 1 carbodiimide 2 product yield (%)a
1
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{2}
1{2}
1{2}
1{2}
1{2}
1{2}
1{2}
1{2}
1{3}
1{3}
1{3}
1{3}
1{3}
1{3}
1{3}
1{3}
1{4}
1{4}
1{4}
1{4}
1{4}
1{4}
1{4}
1{4}
1{5}
1{5}
1{5}
1{5}
1{5}
1{5}
1{5}
1{5}
1{6}
1{6}
1{7}
1{7}
2{1}
2{2}
2{3}
2{4}
2{5}
2{6}
2{7}
2{1}
2{1}
2{2}
2{3}
2{4}
2{5}
2{6}
2{7}
2{1}
2{1}
2{2}
2{3}
2{4}
2{5}
2{6}
2{7}
2{1}
2{1}
2{2}
2{3}
2{4}
2{5}
2{6}
2{7}
2{1}
2{1}
2{2}
2{3}
2{4}
2{5}
2{6}
2{7}
2{1}
2{2}
2{1}
2{1}
2{2}
3{1,1}
3{1,2}
3{1,3}
3{1,4}
3{1,5}
3{1,6}
3{1,7}
4{1,1}
3{2,1}
3{2,2}
3{2,3}
3{2,4}
3{2,5}
3{2,6}
3{2,7}
4{2,1}
3{3,1}
3{3,2}
3{3,3}
3{3,4}
3{3,5}
3{3,6}
3{3,7}
4{3,1}
3{4,1}
3{4,2}
3{4,3}
3{4,4}
3{4,5}
3{4,6}
3{4,7}
4{4,1}
3{5,1}
3{5,2}
3{5,3}
3{5,4}
3{5,5}
3{5,6}
3{5,7}
4{5,1}
3{6,2}
4{6,1}
3{7,1}
3{7,2}
92
85
97
91
95
97
98
83
88
78
90
88
94
93
92
93
95
84
81
75
83
60
96
80
98
86
98
92
99
97
99
83
91
87
93
91
86
98
90
82
84
78
93
92
2
3
4
a Isolated yield based on 2-alkynylbenzaldoxime 1.
5
6
7
128.5, 130.1, 132.1, 138.0, 139.8, 151.1, 151.3, 155.7; HRMS (ESI)
calcd for C22H24BrN3O 448.1000 (M þ Naþ), found 448.0992.
1,3-Dicyclohexyl-1-(4-iodo-3-phenylisoquinolin-1-yl)urea (4{1,1}):
1H NMR (400 MHz, CDCl3) δ 0.77 (q, J = 12.4 Hz, 2H),
0.86-1.98 (m, 2H), 1.18-1.58 (m, 10H), 1.69-1.76 (m, 4H),
1.98 (s, 2H), 3.61-3.65 (m, 1H), 3.74 (d, J = 7.7 Hz, 1H),
4.50-4.55 (m, 1H), 7.43-7.52 (m, 3H), 7.63-7.69 (m, 3H),
7.81 (t, J = 7.7 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.29 (d, J =
8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 24.8, 25.3, 25.5,
26.0, 31.9, 33.4, 49.4, 57.2, 97.7, 126.2, 126.7, 127.8, 128.4, 128.6,
130.0, 132.5, 132.8, 140.5, 142.7, 152.4, 155.6, 155.8; HRMS
(ESI) calcd for C28H32IN3O 576.1488 (M þ Naþ), found
576.1460.
General Procedure for Palladium-Catalyzed Cross-Couplings
of Compound 3 with Arylboronic Acids. Compound 3
(0.2 mmol) was added to a mixture of arylboronic acids (0.3 mmol,
1.5 equiv), Pd(OAc)2 (0.01 mmol, 0.05 equiv), PPh3 (0.02 mmol,
0.1 equiv), and K3PO4 (0.4 mmol, 2equiv) in toluene (2.0 mL).
The mixture was then stirred at 80 °C. After completion of
reaction as indicated by TLC, the solvent was evaporated and the
residue was purified by column chromatography on silica gel to
provide the product 6. Data of selected examples: 1,3-Dicyclo-
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
1
hexyl-1-(3,4-diphenylisoquinolin-1-yl)urea 6{1,1,1}: H NMR
(400 MHz, CDCl3) δ 0.81 (q, J = 11.7 Hz, 2H), 0.93-1.05 (m,
2H), 1.20-1.60 (m, 10H), 1.73-1.80 (m, 4H), 2.05-2.07 (m,
2H), 3.64-3.70 (m, 1H), 3.82 (d, J = 7.7 Hz, 1H), 4.54-4.61
(m, 1H), 7.20-7.24 (m, 3H), 7.29-7.31 (m, 2H), 7.37-7.43
(m, 5H), 7.55-7.63 (m, 2H), 7.69 (d, J = 7.7 Hz, 1H), 8.15 (d,
J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 24.9, 25.5,
25.7, 26.2, 32.1, 33.5, 49.4, 57.4, 125.7, 125.9, 126.1, 127.3, 127.6,
127.7, 128.4, 130.3, 130.6, 130.8, 131.2, 136.9, 138.3, 139.9, 149.3,
151.6, 156.1; HRMS (ESI) calcd for C34H37N3O 526.2834 (M þ
Naþ), found 526.2812. 1,3-Dicyclohexyl-1-(7-methyl-3-phenyl-
1
4-p-tolylisoquinolin-1-yl)urea 6{2,1,2}: H NMR (400 MHz,
CDCl3) δ 0.78-1.08 (m, 4H), 1.20-1.62 (m, 10H), 1.77-1.82
(m, 4H), 2.04-2.06 (m, 2H), 2.41 (s, 3H), 2.51 (s, 3H),
3.64-3.72 (m, 1H), 3.82 (d, J = 8.1 Hz, 1H), 4.56-4.62 (m,
1H), 7.15-7.24 (m, 7H), 7.38-7.43 (m, 3H), 7.60 (d, J =
8.0 Hz, 1H), 7.90 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.3,
21.7, 24.9, 25.5, 25.7, 26.2, 32.0, 33.4, 49.3, 57.2, 124.3, 125.9,
126.0, 127.1, 127.6, 129.1, 130.3, 130.7, 131.0, 132.7, 133.9,
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RESEARCH ARTICLE
Figure 3. Boronic acid 5 {1-4}.
Scheme 2. Possible Mechanism for the Three-Component Reaction of 2-Alkynylbenzaldoxime 1, Carbodiimide 2,
with Electrophile
Table 3. Palladium-Catalyzed Suzuki-Miyaura Reaction
of 1-(4-Bromoisoquinolin-1-yl)urea 3 with Arylboronic
Acid 5
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: jie_wu@fudan.edu.cn.
Author Contributions
J.W. and S.Y. conceived and designed the experiments, S.Y. and
H.W. performed the experiments, S.Y. and J.W. co-wrote the
manuscript and Supporting Information.
Funding Sources
Financial support from the National Natural Science Foundation
of China (No. 20972030) and the Science & Technology
Commission of Shanghai Municipality (09JC1404902) is grate-
fully acknowledged.
entry
compound 3
boronic acid 4
product
yield (%)a
1
3{1,1}
3{1,1}
3{1,1}
3{1,1}
3{2,1}
3{3,1}
3{4,1}
3{7,1}
3{8,1}
3{8,2}
5{1}
5{2}
5{3}
5{4}
5{2}
5{2}
5{2}
5{2}
5{2}
5{2}
6{1,1,1}
6{1,1,2}
6{1,1,3}
6{1,1,4}
6{2,1,2}
6{3,1,2}
6{4,1,2}
6{7,1,2}
6{8,1,2}
6{8,2,2}
71
93
88
55
94
82
91
97
98
96
2
3
’ REFERENCES
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K. W.; Cushman, M.; Ioanoviciu, A.; Staker, B. L.; Burgin, A. B.; Stewart, L.;
Pommier, Y. A Novel Norindenoisoquinoline Structure Reveals a Common
Interfacial Inhibitor Paradigm for Ternary Trapping of the Topoisomerase
I-DNA Covalent Complex. Mol. Cancer Ther. 2006, 5, 287–295.
(4) For selected examples, see: (a) Balasubramanian, M.; Keay, J. G.
Isoquinoline Synthesis. In Comprehensive Heterocyclic Chemistry II; McKillop,
A. E., Katrizky, A. R., Rees, C. W., Scrivem, E. F. V., Eds.; Elsevier: Oxford,
1996; Vol. 5, pp 245-300.(b) For a review on the synthesis of
4
5
6
7
8
9
10
a Isolated yield based on 1-(4-bromoisoquinolin-1-yl)urea 3.
136.8, 137.2, 137.4, 140.1, 148.5, 150.6, 156.1; HRMS (ESI)
calcd for C36H41N3O 554.3147 (M þ Naþ), found 554.3131.
For details, please see Supporting Information.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures,
b
characterization data, and 1H and 13C NMR spectra of all prod-
ucts. This material is available free of charge via the Internet at
http://pubs.acs.org.
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ACS Combinatorial Science
RESEARCH ARTICLE
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::
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::
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