Solution-phase parallel synthesis of a diverse library of 1,2-dihydroisoquinolines

Article abstract of DOI:10.1021/co1000794

Synthesis of a 105 membered library of 1,2-dihydroisoquinolines is described. The 1,2-dihydroisoquinoline compounds have been prepared in good yields using a Lewis acid and organocatalyst-cocatalyzed multicomponent reaction of 2-(1-alkynyl)benzaldehydes,

Full text of DOI:10.1021/co1000794

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Solution-Phase Parallel Synthesis of a Diverse Library
of 1,2-Dihydroisoquinolines
Nataliya A. Markina,† Raffaella Mancuso,‡ Benjamin Neuenswander,§ Gerald H. Lushington,§ and
Richard C. Larock*,†
†Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
‡Dipartimento di Chimica, Universitꢀa della Calabria, 87036 Arcavacata di Rende (CS), Italy
§NIH Center of Excellence in Chemical Methodologies and Library Development, University of Kansas, Lawrence,
Kansas 66047, United States
S Supporting Information
b
ABSTRACT: Synthesis of a 105 membered library of
1,2-dihydroisoquinolines is described. The 1,2-dihydroisoquinoline
compounds have been prepared in good yields using a Lewis
acid and organocatalyst-cocatalyzed multicomponent reaction
of 2-(1-alkynyl)benzaldehydes, amines, and ketones. Various
indoles have also been employed as pronucleophiles, furnishing
1-(3-indolyl)-1,2-dihydroisoquinolines. The halogen function-
ality present in some of the synthesized compounds allows for
further diversification by palladium-catalyzed SuzukiꢁMiyaura
and Sonogashira cross-couplings to give more diversified
1,2-dihydroisoquinoline derivatives.
KEYWORDS: solution-phase, parallel synthesis, diverse library of 1,2-dihydroisoquinolines
’ INTRODUCTION
has been evaluated computationally for its drug-like properties
on the basis of Lipinski’s “rule of five”10 (Scheme 1).
Structures containing a 1,2-dihydroisoquinoline fragment are
valuable intermediates for the synthesis of biologically active
compounds, for example, alkaloids and pharmaceuticals.1 For
example, cribrostatin 4 and acetoneberbine IK-2 have been
shown to possess cytotoxicity against some human cancer cells
(Figure 1).2,3 The hydrochloride salt of the tetrahydroisoquino-
line quinapril (sold under the brand name Accupril) is used for
the treatment of congestive heart failure and hypertension.4
Among the numerous methods developed for synthesis of the
1,2-dihydroisoquinoline core, the most common strategies include
functionalization of preformed isoquinoline units using various
nucleophiles5 or ring-forming reactions of 2-(1-alkynyl)
arenecarboxaldehyde imines through transition metal-catalyzed
processes.6 The latter processes have also been extended to one-
pot procedures that employ 2-(1-alkynyl)arenecarboxaldehydes
and amines to preform the required imines in situ.7
The solution-phase parallel synthesis of libraries of low
molecular weight compounds is increasingly important in mod-
ern medicinal chemistry.8 This approach facilitates the high
throughput screening of larger and more diverse sets of com-
pounds with less time spent on optimization of the reaction
conditions. In continuation of our work in adapting proven
methods for the synthesis of heterocycles to a high throughput
synthesis format,9 we herein report the solution phase synthesis
of a library of 1,2-dihydroisoquinolines.
Calculations have been performed based on the commercial
availability of aldehydes 4 (Scheme 1), terminal alkynes 5 and 10,
ketones 6, anilines 7, indoles 9, and boronic acids 11 (Figurezs 2
and 4). This data has been used to populate a virtual library of all
theoretically possible products, giving 24,888 [(8 ꢀ 2 ꢀ 6 ꢀ 40)
þ (8 ꢀ 50 ꢀ 6 ꢀ 3) þ (8 ꢀ 50 ꢀ 6) þ (8 ꢀ 53 ꢀ 9 ꢀ 3)] unique
potential compounds. A small subset of this virtual library,
namely, 239 compounds, was shown to follow Lipinski’s rules
with e1 violation. The library synthesis of 1,2-dihydroisoquino-
lines described herein was primarily focused on the preparation
of compounds that fall within these 239 examples.
’ RESULTS AND DISCUSSION
To study a wide variety of multisubstituted 1,2-dihydroiso-
quinolines, we developed the strategy described in Scheme 1.
The 1,2-dihydroisoquinolines 1 can be prepared directly from
the corresponding 2-(1-alkynyl)benzaldehydes 3 through reac-
tion with anilines 7 and either ketones 6 or indoles 9. More highly
substituted 1,2-dihydroisoquinolines can be prepared via palla-
dium-catalyzed couplings of the corresponding halogen-contain-
ing 1,2-dihydroisoquinolines 2, prepared through the same
three-component coupling reaction.
Received: November 30, 2010
To synthesize a library with greater chances for biological
activity, the multisubstituted 1,2-dihydroisoquinoline template 1
Revised:
Published: March 16, 2011
February 4, 2011
r
2011 American Chemical Society
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|

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RESEARCH ARTICLE
The 2-(1-Alkynyl)benzaldehydes 3 are easily prepared by
palladium/copper-catalyzed Sonogashira coupling11 of the cor-
responding o-bromobenzaldehydes 4 (1.0 equiv of 4, 1.05 equiv
of terminal alkyne 5, 2 mol % of PdCl2(PPh3)2, 2 mol % of CuI,
and Et3N at 50 °C for 6 h) (Scheme 1). The yields of this process
range from 65 to 100%, and this procedure readily accommo-
dates various functional groups (Table 1).
For the synthesis of the 1,2-dihydroisoquinoline core, we
utilized the procedure described by Ding et al.7a (Scheme 2,
eq 1). The advantages of this three-component AgOTf and L-
proline cocatalyzed process include the commercially availability
of ketones 6 and amines 7, three independent points of diversi-
fication, and formation of the desired products in one step.
Additionally, we are able to replace ketones with indoles in this
process, which allows one to isolate 1-(3-indolyl)-1,2-dihydroi-
soquinolines in a single one-pot process (Scheme 2, eq 2). Since
the start of this work, Yamamoto and Wu have independently
reported the use of indoles in the same type of process under
slightly modified reaction conditions.12 By employing the reac-
tion conditions optimized for ketones using a sublibrary of
indoles 9, we have been able to isolate 1-(3-indolyl)-1,2-dihy-
droisoquinolines in moderate to good yields in most cases,
broadening the scope of the previously reported 1,2-dihydroiso-
quinoline synthesis.
The sublibraries of ketones, anilines, and indoles used for
the synthesis of 1,2-dihydroisoquinolines 8 are presented in
Figure 2.
The data for the 1,2-dihydroisoquinolines 8{1ꢁ30} prepared,
but not subjected to further diversification, is shown in Table 2.
1,2-Dihydroisoquinolines 8{31ꢁ51}, containing halogen
atoms that can be further subjected to palladium-catalyzed
couplings, have been isolated and purified by column chroma-
tography. All of the 1,2-dihydroisoquinolines 8{31ꢁ51}, except
8{39} and 8{45}, which were used crude in the next step, were
1
fully characterized using HRMS, as well as H and 13C NMR
spectroscopy (see the Supporting Information for the experi-
mental details). In most cases, moderate to good yields of the 1,2-
dihydroisoquinolines 8{31ꢁ51} have been obtained. The results
are summarized in Figure 3.
As can be seen from both Table 2 and Figure 3, this process is
generally functional group tolerant and allows one to obtain
diversely substituted 1,2-dihydroisoquinolines in 9ꢁ98% yields.
The major limitation of this procedure is that it does not tolerate
Figure 1. Examples of biologically active 1,2-dihydro- and tetrahydro-
isoquinolines.
Figure 2. Ketone 6{1ꢁ5}, aniline 7{1ꢁ4}, and indole 9{1ꢁ6}
sublibraries.
Scheme 1. Library Outline and Preparation of 2-(1-Alkynyl)benzaldehydes 3
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ACS Combinatorial Science
RESEARCH ARTICLE
strong electron-withdrawing groups in the alkyne portion of the
2-(1-alkynyl)benzaldehydes 3. For example, in the reactions of
compound 3{7}, bearing a nitro group, compounds 8{8} and
8{9} were not detected in the crude reaction mixtures, and
compound 8{39} was obtained in only an 11% yield. By employ-
ing indoles 9 instead of ketones 6 in this process, good yields
from the unsubstituted indole 9{1} have been obtained. This
process exhibits good tolerance of various functional groups in
positions 1 and 5 of the indole; thus, compounds 8{20}, 8{50},
and 8{51} were obtained in 63, 46, and 75% yields, respectively.
The presence of functional groups in position 2 of the indole
significantly lowered the yields of the corresponding products;
thus, compounds 8{4} and 8{7} were obtained in only 9 and
29% yields, respectively.
Sonogashira coupling of the 1,2-dihydroisoquinolines
8{31ꢁ51} with various terminal alkynes 10 nicely provides the
corresponding alkyne products 12a{1ꢁ22} using Et3N as the
solvent under microwave irradiation for 40 min at 60 °C
(Scheme 3). The SuzukiꢁMiyaura coupling of the 1,2-
Table 2. Library Data for Compounds 8{1ꢁ30}
product
3
6 or 9
7
yield (%)a
purity (%)c
8{1}
3{1}
6{4}
9{1}
6{1}
9{4}
6{5}
9{1}
9{3}
6{3}
9{5}
6{1}
6{1}
6{2}
6{4}
6{5}
9{1}
6{1}
6{1}
6{2}
6{4}
9{2}
9{1}
6{2}
6{1}
6{1}
6{2}
6{4}
6{1}
6{1}
6{2}
6{4}
7{1}
7{1}
7{1}
7{1}
7{2}
7{2}
7{2}
7{1}
7{2}
7{1}
7{3}
7{1}
7{1}
7{2}
7{1}
7{1}
7{3}
7{1}
7{1}
7{1}
7{1}
7{1}
7{1}
7{3}
7{1}
7{1}
7{1}
7{3}
7{1}
7{1}
33
69
43
9
96
98
8{2}
3{1}
8{3}
3{2}
99
8{4}
3{2}
88
8{5}
3{3}
15
76
29
0
100
95
Finally, the 1,2-dihydroisoquinolines 8{31ꢁ51} can be
further elaborated using well-known palladium-mediated pro-
cesses, such as SuzukiꢁMiyaura13 and Sonogashira11 couplings
(Scheme 3).
8{6}
3{5}
8{7}
3{6}
100
8{8}
3{7}
8{9}
3{7}
0
8{10}
8{11}
8{12}
8{13}
8{14}
8{15}
8{16}
8{17}
8{18}
8{19}
8{20}
8{21}
8{22}
8{23}
8{24}
8{25}
8{26}
8{27}
8{28}
8{29}
8{30}
3{8}
56
56
56
72
15 b
24
56
66
72
60
63
72
77
59
98
77
44
78
98
74
53
96
99
Table 1. Data for Compounds 3{1ꢁ15}
3{8}
3{8}
93
3{8}
42
3{11}
3{11}
3{12}
3{12}
3{12}
3{12}
3{12}
3{12}
3{13}
3{14}
3{14}
3{14}
3{14}
3{15}
3{15}
3{15}
3{15}
100
100
96
98
100
94
98
98
82
97
98
100
31
95
100
100
13
a Isolated yields after column chromatography. All compounds 3 were
1
characterized by H NMR spectroscopy. Those not described in the
literature were additionally characterized by 13C NMR and HRMS.
b Prepared from the corresponding methyl benzoate (1. LAH; 2. PCC).
c This reaction used different reaction conditions: 3% PdCl2(PPh3)2, 2%
CuI, iPr2NH (4 equiv.), DMF, 70 °C, 2 h.
a Isolated yield after column chromatography. b Isolated yield after
preparative HPLC. c UV purity determined at 214 nm after
preparative HPLC.
Scheme 2. Synthesis of 1,2-Dihydroisoquinolines and 1-(3-Indolyl)-1,2-dihydroisoquinolines 8
267
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RESEARCH ARTICLE
Figure 3. Halogen-containing 1,2-dihydroisoquinolines 8{31ꢁ51}.
dihydroisoquinolines 8{31ꢁ51} with various arylboronic acids 11
proceeded smoothly to give the desired products 12b{1ꢁ53}.
The reactions were carried out ina 1:1 ethanol/DMF mixturewith
the addition of 1 M aqueous Cs2CO3 solution at 120 °C under
microwave irradiation for 20 min. The sublibraries of commer-
cially available terminal alkynes 10 and boronic acids 11, contain-
ing heterocycles and polar functionality to incorporate drug-like
moieties into the resulting coupling products were chosen based
on their commercial availability and the Lipinski compliance
calculations mentioned above (Figure 4). Fluorine atom-contain-
ing 2-(1-alkynyl)benzaldehydes 3{6}, 3{10}, 3{15}, aniline 7{3},
and arylboronic acid 11{7} have been chosen because the
resulting fluorine-containing 1,2-dihydroisoquinolines and Suzu-
kiꢁMiyaura coupling products are of considerable interest
because of the many versatile applications of fluorine-containing
compounds in industry and medicine.14 The results for the
Sonogashira and SuzukiꢁMiyaura couplings performed on the
1,2-dihydroisoquinolines 8{31ꢁ51} are summarized in Table 3.
Under our reaction conditions, microwave irradiation has been
shown not only to dramatically reduce the reaction times, but to
provide higher yields of both the desired alkyne products 12a-
{1ꢁ22} and the SuzukiꢁMiyaura coupling products 12b{1ꢁ53}
when compared to conventional heating methods. These pro-
cesses have been performed in parallel on approximately a
∼35ꢁ60 mg scale, starting from 1,2-dihydroisoquinolines
8{31ꢁ51}. All of the crude products 12a and 12b were isolated
by either column chromatography or preparative HPLC. The
purity of the reaction mixtures has been analyzed by thin layer
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RESEARCH ARTICLE
Scheme 3. Diversification of 1,2-Dihydroisoquinolines 8{31ꢁ51}a
a Method A (Sonogashira coupling): 3 mol % PdCl2(PPh3)2, 3 mol % CuI, Et3N, alkyne 10 (1.2 equiv.), 60 °C, 40 min under microwave irradiation.
Method B (SuzukiꢁMiyaura coupling): 5 mol % Pd(PPh3)4, 1 M Cs2CO3 (2 equiv.), boronic acid 11 (1.2 equiv), 1:1 EtOH/DMF, 120 °C, 20 min
under microwave irradiation.
(HPLC). We have used Lipinski’s rule of five10 as a general guide
for bioavailability, because compounds with poor bioavailability
face more of a challenge in becoming successful clinical candi-
dates. According to Lipinski’s rules, the favorable drug candidates
should have a molecular weight less than 500, clogP less than 5,
the number of hydrogen bond donors less than 5 and acceptors
less than 10, and the number of rotatable bonds less than 10.
These parameters were calculated for each of the library members
using the SYBYL15 program. The majority of the 105 1,2-
dihydroisoquinolines 8{1ꢁ30}, 12a{1ꢁ22} and 12b{1ꢁ53}
synthesized satisfy these requirements.
In summary, a simple and efficient method for the parallel
synthesis of multisubstituted 1,2-dihydroisoquinolines 8 and 12
has been developed employing a one-pot, three-component
AgOTf and L-proline-cocatalyzed reaction of 2-(1-alky-
nyl)benzaldehydes, amines, and ketones or indoles. Palladium-
catalyzed couplings, such as SuzukiꢁMiyaura and Sonogashira
cross-couplings have been used to further diversify the 1,2-
dihydroisoquinolines 8, providing pure 5þ mg samples of each
library compound. The average purity of the 105 members of this
library is 94.1%, and the average yield is 55.7%. The elaborated,
multisubstituted 1,2-dihydroisoquinolines 8{1ꢁ30}, 12a-
{1ꢁ22} and 12b{1ꢁ53} have been added to the collection of
Figure 4. Terminal alkyne 10{1ꢁ5} and boronic acid 11{1ꢁ11}
the Kansas University NIH Center for Chemical Methodologies
sublibraries.
and Library Development (KU CMLD) and will be submitted to
the National Institutes of Health Molecular Library Screening
Center Network (MLSCN) for evaluation by a broad range of
assays.
chromatography (TLC), liquid chromatography-mass spectro-
metry (LC-MS), and high performance liquid chromatography
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RESEARCH ARTICLE
Table 3. Library Data for Compounds 12a{1ꢁ22}and 12b{1ꢁ53}
product
8
10 or 11
yield (%)a
purity (%)c
product
8
10 or 11
yield (%)a
purity (%)c
12a{1}
8{33}
8{34}
8{35}
8{35}
8{35}
8{36}
8{36}
8{36}
8{37}
8{37}
8{37}
8{40}
8{42}
8{43}
8{46}
8{46}
8{49}
8{49}
8{49}
8{50}
8{50}
8{51}
8{31}
8{32}
8{32}
8{32}
8{33}
8{33}
8{34}
8{35}
8{35}
8{35}
8{36}
8{36}
8{36}
8{37}
8{37}
8{37}
10{1}
10{1}
10{2}
10{3}
10{1}
10{1}
10{2}
10{3}
10{3}
10{1}
10{2}
10{1}
10{1}
10{1}
10{3}
10{4}
10{5}
10{1}
10{4}
10{1}
10{5}
10{1}
11{5}
11{10}
11{7}
11{5}
11{2}
11{6}
11{2}
11{2}
11{6}
11{7}
11{2}
11{6}
11{10}
11{2}
11{4}
11{10}
65
99
100
100
12b{17}
12b{18}
12b{19}
12b{20}
12b{21}
12b{22}
12b{23}
12b{24}
12b{25}
12b{26}
12b{27}
12b{28}
12b{29}
12b{30}
12b{31}
12b{32}
12b{33}
12b{34}
12b{35}
12b{36}
12b{37}
12b{38}
12b{39}
12b{40}
12b{41}
12b{42}
12b{43}
12b{44}
12b{45}
12b{46}
12b{47}
12b{48}
12b{49}
12b{50}
12b{51}
12b{52}
12b{53}
8{38}
8{38}
8{38}
8{38}
8{39}
8{40}
8{40}
8{40}
8{40}
8{40}
8{40}
8{41}
8{41}
8{42}
8{42}
8{42}
8{43}
8{43}
8{43}
8{44}
8{44}
8{44}
8{44}
8{44}
8{44}
8{45}
8{45}
8{45}
8{46}
8{46}
8{46}
8{47}
8{48}
8{49}
8{50}
8{50}
8{51}
11{1}
11{2}
11{3}
11{8}
11{3}
11{2}
11{3}
11{4}
11{6}
11{10}
11{11}
11{1}
11{2}
11{1}
11{3}
11{10}
11{3}
11{8}
11{11}
11{2}
11{4}
11{5}
11{7}
11{9}
11{10}
11{1}
11{3}
11{8}
11{1}
11{3}
11{8}
11{4}
11{4}
11{4}
11{6}
11{7}
11{10}
15 b
38 b
34 b
66
100
100
100
100
98
12a{2}
12a{3}
69
12a{4}
96
100
100
100
100
99
12a{5}
84
45
12a{6}
89
86
96
12a{7}
54
68
100
97
12a{8}
75
31 b
76
12a{9}
100
100
100
98
75
100
98
12a{10}
12a{11}
12a{12}
12a{13}
12a{14}
12a{15}
12a{16}
12a{17}
12a{18}
12a{19}
12a{20}
12a{21}
12a{22}
12b{1}
12b{2}
12b{3}
12b{4}
12b{5}
12b{6}
12b{7}
12b{8}
12b{9}
12b{10}
12b{11}
12b{12}
12b{13}
12b{14}
12b{15}
12b{16}
62
52
58
20
100
99
84
41
69
98
84
26 b
94
75
100
100
100
98
100
98
94
64
77
48 b
58
42 b
100
100
100
-
100
12 b
25
21 b
100
11 b
70
28 b
16 b
91
100
93
0
100
100
100
95
36 b
69
92
98
71
98
13 b
16 b
27 b
21 b
43 b
16 b
63
99
98
95
93
92
99
100
100
>99
100
100
100
96
100
63
49 b
100
100
97
89
100
100
100
100
99
75
58 b
91
48
50
77
77
94
100
100
42 b
55
93
100
100
100
85
99
36 b
18 b
40
100
100
100
22 b
a Isolated yield after column chromatography. b Isolated yield after preparative HPLC. c UV purity determined at 214 nm after preparative HPLC.
’ ASSOCIATED CONTENT
Kansas University Chemical Methodologies and Library Develop-
ment Center of Excellence (GM069663) for support of this research
S
Supporting Information. Synthetic methods, spectral
b
assignments, and H and 13C NMR spectra for all previously
1
’ ACKNOWLEDGMENT
unreported starting materials, intermediate compounds, and 21
representative library members. This material is available free of
charge via the Internet at http://pubs.acs.org.
We thank Johnson Matthey, Inc. and Kawaken Fine Chemi-
cals Co. Ltd. for donations of palladium catalysts; and Frontier
Scientific and Synthonix for donations of boronic acids; and Dr.
Akhilesh Verma for the preparation and characterization of 2-(1-
alkynyl)benzaldehydes 3{12}-3{15}.
’ AUTHOR INFORMATION
Corresponding Author
*Phone: (515) 294-4660. E-mail: larock@iastate.edu.
’ REFERENCES
Funding Sources
We thank the National Institute of General Medical Sciences
(GM070620 and GM079593) and the National Institutes of Health
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