Design and Synthesis of Fused Pyridine Building Blocks for Automated Library Generation

Article abstract of DOI:10.1002/cmdc.202000852

We demonstrate that a diboration-electrocyclization sequence provides access to a range of pyridine-fused, small-molecule boronic ester building blocks, and that these are amenable to high-throughput synthesis leading to biaryl and ether-linked compound libraries. Moreover, the implementation of an integrated physicochemical and ADME profiling workflow allows accelerated design of novel lead compounds for application in drug-discovery projects.

Full text of DOI:10.1002/cmdc.202000852

Accepted Article
Title: Design and Synthesis of Fused Pyridine Building Blocks for
Automated Library Generation
Authors: Joseph P.A. Harrity, Helena Mora-Radó, Werngard
Czechtizky, and María Méndez
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemMedChem 10.1002/cmdc.202000852
Link to VoR: https://doi.org/10.1002/cmdc.202000852
01/2020

10.1002/cmdc.202000852
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Design and Synthesis of Fused Pyridine Building Blocks for
Automated Library Generation
Helena Mora-Radó,[a] Werngard Czechtizky,[b,c] María Méndez,*[b] and Joseph P. A. Harrity*[a]
[a]
Dr. H. Mora-Radó, Prof. J. P. A. Harrity
Department of Chemistry, University of Sheffield
Sheffield, S3 7HF (U.K.)
E-mail: j.harrity@sheffield.ac.uk
[b]
[c]
Dr. W. Czechtizky, Dr. M. Méndez
Integrated Drug discovery, R&D, Sanofi Aventis Deutschland GmbH, Industriepark Höchst, D-65926 Frankfurt Am Main, Germany.
Present address: Respiratory, Inflammation, Autoimmunity IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
Supporting information for this article is given via a link at the end of the document.
We recently highlighted how a pyrazole trifluoroborate scaffold
can be easily elaborated to a series of tricycles that are subject to
high-throughput experimentation with rapid testing in an
integrated physicochemical and ADME profiling workflow.[6]
Isoquinolines are common motifs in pharmaceutically active
compounds,[7] and therefore broad variations of these structural
motifs could represent a valuable approach to sampling the
chemical space around this privileged scaffold thereby leading to
promising starting points for medicinal chemistry optimization
programs. In particular, 3,4-disubstituted isoquinolines and
heteroisoquinolines have been disclosed that exhibit promising
antiviral properties (Figure 1).[8] A robust access to variations of
these motifs would offer a valuable way to quickly support the
synthesis of analogs, however, there are relatively few strategies
available to prepare congested fused pyridine derivatives bearing
useful functionality.[9] We report herein the generation and
characterization of a library of 3,4-substituted isoquinolines and
related analogs by functionalization of organoboron intermediates
that were readily accessed via our previously reported sequential
Abstract: We demonstrate that
a diboration-electrocyclization
sequence provides access to a range of pyridine fused small molecule
boronic ester building blocks, and that these are amenable to high
throughput synthesis leading to biaryl and ether linked compound
libraries. Moreover, the implementation of an integrated physchem
and ADME profiling workflow allows accelerated design of novel lead
compounds for application in drug discovery projects.
Introduction
Up to the 1990s, failure of drug candidates was mostly driven by
inappropriate pharmacokinetic (PK) parameters and lack of
clinical efficacy.[1] In 2000, the attrition rate due to poor PK profiles
was significantly reduced, while failure due to lack of efficacy and
drug safety remained high.[2] One of the main reasons for this
reduction was the improvement of physicochemical and eADME
(early compound absorption, distribution, metabolism and
excretion) profiles in the course of lead optimization.[3] Indeed, it
is now common for compound optimization workflows to include
the early experimental assessment of intestinal absorption (e.g.
CaCo-2 profiling), inhibition of CYP3A4 enzyme, metabolic lability
in microsome preparations (metabolic lability), solubility and log
D.
The Integrated Drug Discovery unit at Sanofi routinely uses library
synthesis to access sufficiently large compound pools to expedite
the optimization of the overall profiles in a chemical series with
respect to biological activity and physicochemical and eADME
properties.[4] In order to enable this approach, robust methods that
permit rapid access to functionalized small molecule scaffolds is
essential.[5]
Pt-catalyzed diborylation reaction and
a disrotatory 6π-
electrocyclic transformation (Scheme 1).[10] Using the powerful
chemistry of organoboron compounds,[11] these building blocks
can be transformed to a diverse product set, and assessed for
their physicochemical and eADME properties allowing a quickly
understanding of the property distribution among this chemical
class and potentially expediting future medicinal chemistry
programs.
Scheme 1. Divergent strategy to pyrazole-based tricycles.
Results and Discussion
Figure 1. Bioactive (hetero)isoquinolines.
Our first goal was to generate a series of boronic ester building
blocks using simple and scalable chemistry. Therefore, we
employed commercially available unsaturated ß-bromo
1
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Scheme 2. Library building block synthesis.
aldehydes to produce a small family of yne-ene-oxime ethers via
Sonogashira coupling and condensation with methoxylamine
hydrochloride (further details are contained within the Supporting
Information). Following diboration-electrocyclization, we were
able to rapidly generate eight 3,4-disubstituted isoquinoline and
isoquinoline-like scaffolds with three distinct cores and several
substituents in high yield. In addition, intermediates 3, 4, and 6
were oxidized with hydrogen peroxide to provide the
corresponding 3-hydroxypyridines 9-11, thereby offering an
alternative vector for further functionalization (Scheme 2).
Detailed physicochemical and ADME data for all synthesized
compounds are provided in the Supporting Information, but Table
1 highlights the data for those compounds that showed solubilities
of >10 mg/mL at pH 7.4. The approach provided a diverse set of
compounds with an attractive range of molecular weights and
logD values spanning from 0 to 5. Whereas the cell permeability
(CaCo-2 measurements) was generally good, the metabolic
lability of most analogs in human microsomes was generally high;
only 12 of the compounds shown in Table 1 exhibited values
below 40%. Not surprisingly, these 12 compounds contain mostly
polar substituents, which would be expected to increase
metabolic stability. Finally, a significant proportion of compounds
showed acceptable CYP inhibition values with IC50 values >30.0
µM, albeit boronates 2 and 5 gave rise to derivatives that were
more prone to CYP inhibition liability. The poor metabolic profile
of derivatives of 2 is likely due to the presence of the alkene
moiety, although this could be offset by employing this as a handle
for the introduction of more drug-like fragments. Generally
speaking, while the overall profile was dependent on the nature
of both coupling partners, we found that those compounds derived
from 2-pyridones xiii and xiv showed the best overall profile, with
low metabolic lability, high CaCo, no CYP3A4 inhibition and
reasonable logD values accompanied by a high solubility.
Library synthesis – Generation of structural diversity and
Compound Properties.
We next carried out the Suzuki coupling of boronates 1,2,5,7 and
8 in a parallel library synthesis approach using a selection of 43
different aryl bromides. In a first step, the reaction conditions for
the coupling were optimized; the highest yield and broadest
reagent scope was achieved using a 2nd generation S-phos
precatalyst in combination with K3PO4 in THF.[12,13] In total, we
generated >100 novel compounds that were characterized by
NMR spectroscopy and LC-MS analysis, and subsequently
subjected these to our automated physicochemical and eADME
profiling to acquire logD, solubility, CaCo, CYP inhibition and
metabolic lability data.
Table 1. Physical and ADME properties of a biaryl library
2
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Product[a]
Mol.
Wt.
Metabolic
Lability[b]
CaCo-2[c
CYP
inhibition[d]
Solubility[e] logD[f]
Product[a] Mol. Metabolic CaCo-2[c] CYP
Solubility[e] logD[f]
Wt.
Lability[b]
inhibition[d]
1iii
1iv
324.4
20
36
87
5
151.8
25.3
>30.0
2.9
55
>392
187
2.03
0.84
2.41
1.07
2.09
1.35
1.48
2.02
1.81
1.73
2xx
2xxii
5i
299.4
299.4
293.4
279.4
320.4
420.5
250.4
251.3
275.4
280.4
85
98
6
285.2
152.1
137.5
127.4
183.0
92.4
>30.0
19.8
>1665
>230
>604
14
1.77
1.74
1.39
2.53
2.49
2.21
2.15
1.40
2.49
1.11
1.31
2.46
0.64
1.26
0.91
0.91
0.97
1.21
0.85
0.83
313.7
316.4
276.3
246.3
247.3
317.4
304.4
249.2
239.3
300.4
275.4
316.4
416.5
337.4
246.3
279.4
414.4
317.4
239.3
1v
291.6
280.8
330.3
414.9
437.1
337.2
365.8
190.3
292.2
139.7
194.7
134.2
194.5
243.4
162.6
64.8
>30.0
>30.0
1.3
>30.0
24.6
1xiii
1ix
>1809
50
5ii
91
98
96
96
90
83
21
44
97
5
80
77
72
33
65
97
68
89
92
94
68
82
35
23
92
79
5v
>30.0
>30.0
1.9
>1560
>1189
>1997
107
1x
10.2
>2022
>1575
>1643
>2006
>2089
37
5vi
5ix
5x
1xi
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
27.8
252.8
257.4
245.7
201.9
52.6
1xiv
1xv
15.6
5xii
5xiii
>30.0
>30.0
27.6
166
1xix
1xx
>1783
179
2.40 5xvii.TFA 418.5
2ii
59
1.79
1.79
1.52
2.41
1.43
0.40
0.72
2.42
1.21
5xx
7i
304.4
329.4
356.4
329.4
344.4
326.4
320.4
308.4
290.3
276.9
NoVal
253.4
102.8
206.9
202.4
218.4
196.7
232.5
25.8
23
2v
>1580
>1201
36
>30.0
23.9
>1518
>1403
>1518
>1452
168
2vi.TFA
2viii
2ix
>30.0
21.7
7v
68
6
7vii
7xiv
7xxi
8v
>30.0
>30.0
9.9
<1.0
34
36
62
56
36
62
2xvi
2xvii.TFA
2xviii
2xix
>30.0
16.9
>282
>1207
7
>30.0
>30.0
>30.0
>1561
>1621
54
189.4
193.1
15.3
8xiv
8xxi
20.2
>2089
[a] Products are a biaryl consisting of the heteroaromatic fragment (1, 2, 5, 7, 8) bonded to the residues i-xxii; [b] Metabolic lability in human microsomes; Total
Metabolism (%) after 30 min, no CYP inhibitor added. [c] CaCo-2; Mean; PTotal (A2B) (10-7 cm/s). [d] CYP inhibition, IC50 (INH) (M), Isoform: CYP3A4, Substrate:
Midazolam. [e] Solubility (pH 7.4; mg/mL). [f] LogD (pH 7.4), Mean. NoVal: Insufficient sample to perform the assay in this case
Our next step was to compare the physicochemical properties of
our fused pyridine cores coupled to more sp3-rich fragments
through an ether linkage. Accordingly, we alkylated phenols 9-11
with a library of alkyl bromides and our results are summarized in
Table 2, again highlighting only those compounds that had
solubilities of >10 mg/mL at pH 7.4.[13]
and 10xvi showing reasonable metabolic stability. This was
unsurprising given the number of methylene groups present in
these molecules. CaCo values were overall acceptable to good
with a few exceptions. CYP inhibition could be influenced by the
residues linked via the ether, and this appeared to have little
correlation to logD values. Finally, this library was also able to
deliver intermediates with handles for further elaboration by
incorporating epoxide (9viii) and acetal (11vii) fragments, as well
as free amines (9-11i, 11iv).
In comparison to the biaryl derivatives of the previous libraries,
the ether linked series generally provided compounds with good
solubility and lower logD. However, the metabolic lability of this
compound library was significant across the series with only 10i
3
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Table 2. Physical and ADME properties of an ether library
Product[a]
Mol. Wt.
Metabolic
Lability[b]
Caco-2[c]
CYP
inhibition[d]
Solubility[e] logD[f] Product[a] Mol. Metabolic Caco-2[c] CYP
Solubility[e] logD[f]
Wt.
Lability[b]
inhibition[d]
9i.TFA
9viii
9x
426.5
257.3
300.5
272.4
258.3
240.3
312.4
295.4
384.4
272.4
261.3
216.2
198.2
270.4
253.3
51
100
90
79
98
90
97
100
20
47
71
44
80
82
36
NoVal
6.8
17.2
13.6
>1172
>1943
>1664
>1836
>1936
>2081
192
1.03
10xvii 297.3
100
82
2.0
>30.0
4.6
137
>1161
1310
808
1.88
1.15
2.46
1.40
0.43
4.35
3.69
4.22
1.02
2.88
1.07
3.45
1.91
3.69
3.16
2.56 11i.TFA 430.5
35.8
135.1
129.3
138.1
163.3
NoVal
198.5
45.5
>30.0
>30.0
>30.0
>30.0
5.7
2.00
1.42
0.85
2.62
3.22
1.71
-0.11
0.63
0.89
-0.55
0.69
1.40
0.22
11ii
11iii
11iv
11v
318.5
302.5
374.4
303.5
303.5
100
100
88
165.1
103.1
NoVal
160.5
161.8
149.3
NoVal
182.0
116.7
172.0
174.4
2.5
4.8
9xi
>30.0
<1.0
12.5
12.9
5.8
9xii
702
9xiii
9xv
99
150
11vi
99
281
9xvi
10i.TFA
10ii
5.0
>1693
>1301
>1834
>1913
>2312
>2522
>1849
>1974
11vii 333.5
11xii 262.4
11xiii 244.3
11xiv 295.4
11xv 316.5
11xvi 299.4
11xvii 343.4
11xviii 296.4
99
139
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
12.8
98
>30.0
28.6
>30.0
5.7
935
NoVal
198.3
144.4
239.8
NoVal
170
100
99
210
10ix
10xii
10xiii
10xv
10xvi
314
100
100
100
100
299
2.0
>1670
41
>30.0
6.0
158.4
393
[a] Products consist of the heteroaromatic fragment (9-11) bonded to the residues i-xviii through an ether linkage; [b] Metabolic lability in human microsomes; Total
Metabolism (%) after 30 min, no CYP inhibitor added. [c] CaCo-2; Mean; PTotal (A2B) (10-7 cm/s). [d] CYP inhibition, IC50 (INH) (M), Isoform: CYP3A4, Substrate:
Midazolam. [e] Solubility (pH 7.4; mg/mL). [f] LogD (pH 7.4), Mean. NoVal: Insufficient sample to perform the assay in this case.
In order to better illustrate the property distribution across both
compound series, we performed the analysis depicted in Figure
2. In these graphs, the physicochemical properties (Chart 1) and
the eADME properties (Chart 2) are depicted as a function of
molecular weight and logD, and these are provided for all
synthesized compounds (including those with poorer solubilities
that are described in the Supporting Information). The various
fused pyridine scaffolds are represented by different colors and
the shape and size of the dots indicate the different properties and
their value ranges respectively. For example, for the Chart 1, the
size of the points indicates the solubility range, with larger points
indicating those with higher solubilities. On Chart 2, the size of the
points indicates the metabolic lability in human microsomes; in
this case more stable compounds are represented by larger dots.
Additionally, in this chart, the shape of the points indicates the
permeability in Caco2 cells: whereas low permeability is
represented with points, high permeability compounds are
represented with crosses.
This analysis shows that all scaffolds produced compounds within
the desirable range of logD (<3) and solubility (> 200 µM)
(Compounds within the blue square). [14] Although the number of
compounds with acceptable metabolic stability (i.e. < 40%) is
limited (larger crosses on chart 2, Figure 2), the fact that these
compounds are distributed among all scaffolds and include both
types of linkages (C and O) indicates, that by choosing the
appropriate derivatization, the physicochemical and ADME
properties of these compounds can be successfully modulated
into a region of interest from a medicinal chemistry perspective.
In this regard, the synthesized compounds provide potentially
interesting starting points for medicinal chemistry optimization
programs in the future, which could quickly expand this chemical
space by using the synthetic workflow established in this study.[15]
4
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It is also important to note, that the heteroaromatic pyrazolo[3,4-
c]pyridine core bearing this substitution pattern is
underrepresented in the patent literature and a robust access to
this drug-like core and its derivatization using this methodology
could provide a competitive advantage for the generation of IP.
5
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Figure 2. Representation of property distribution for all synthesized compounds according to series. Chart 1: Solubility [µM]; Chart 2:
Metabolic lability [human, % metabolized] and Caco-2 Permeability [Ptotal, [*10-7 cm/sec].
General procedure B: Electrocyclization reaction of diborylalkenes.
A
sealed tube containing a solution of diborylalkene in 1,2-
dichlorobenzene (0.1 M) was stirred at 200 °C for 16 h. The reaction
mixture was allowed to cool to room temperature and was filtered through
silica gel. The residue was purified by flash column chromatography on
silica gel eluting with petroleum ether (40/60) and ethyl acetate to afford
the corresponding isoquinolines.
Conclusion
In conclusion, we have successfully established an efficient
access to broadly modifiable fused pyridine boronates from easily
accessible starting materials. Using automated parallel library
synthesis, we have demonstrated the potential of these
heterocyclic boronate building blocks to rapidly generate diverse
compound libraries. Using Sanofi´s internal compound profiling
workflow, we have identified points for diversification in these
compound series which give access to improved physicochemical
and eADME properties.
General procedure C: Oxidation of boronic esters. To a stirred solution
of the aromatic boronate in dichloromethane (0.1 M) was slowly added a
30% (w/v) aqueous solution of hydrogen peroxide (1.5 equiv). The reaction
was then stirred at room temperature over 24 h. Water was added and the
organic layer was extracted with dichloromethane. The organic phase was
dried over anhydrous MgSO4, filtered and the solvent was removed in
vacuo. The residue was purified by flash column chromatography on silica
gel eluting with petroleum ether (40/60) and ethyl acetate to afford the
desired products.
Experimental Section
3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline
(3). Following general procedure A, E-2-(prop-1-yn-1-yl)benzaldehyde O-
methyl oxime (4.2 g, 24.3 mmol), B2Pin2 (6.8 g, 26.7 mmol) and Pt(PPh3)4
(754 mg, 0.6 mmol) in toluene (250 mL) afforded the desired product as
an dark brown foam (10.3 g, 99%).1H NMR (400 MHz, CDCl3): δ 8.13 (s,
1H), 7.87 (dd, J = 8.0, 1.5 Hz, 1H), 7.29 (td, J = 7.5, 1.5 Hz, 1H), 7.20 (td,
J = 7.5, 1.0 Hz, 1H), 7.03 (dd, J = 8.0, 1.0 Hz, 1H), 3.94 (s, 3H), 1.53 (s,
General. Characterization and synthetic procedures for compounds 1, 2,
5, 7, 8 are reported elsewhere.[10(b),(c)]
General procedure A: Pt-catalyzed diborylation of alkynes. B2Pin2 (1.1
equiv) was added to a stirred solution of alkyne (1.0 equiv) in toluene (0.1
M). Pt(PPh3)4 (10 mol%) was added and the reaction was heated at 120 °C
for 30 min. The reaction mixture was allowed to cool to room temperature
and the solvent was evaporated. The residue was purified by flash column
chromatography on florisil eluting with petroleum ether (40/60) and ethyl
acetate to afford the corresponding boronic esters.
3H), 1.33 (s, J = 7.8 Hz, 12H), 1.20 (s, J = 1.0 Hz, 6H), 1.20 (s, 6H); 13
C
NMR (101 MHz, CDCl3): δ 148.1, 142.1, 129.4, 129.3, 128.8, 126.4, 125.2,
83.8, 83.7, 61.8, 24.9 (x2 C), 24.8, 24.6 (x2 C); 11B NMR (128 MHz,
CDCl3): δ 30.1 (br); FTIR: νmax 2978 (m), 1517 (w), 1473 (m), 1332 (s),
6
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1271 (s), 1144 (s), 1054 (m); HRMS calculated for C23H3511B2NO5 (MH+):
428.2774. Found: 428.2782. Following general procedure B, using E-2-
(1,2-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-1-yl)
benzaldehyde O-methyl oxime (10.8 g, 25.3 mmol) in 1,2-dichlorobenzene
(250 mL) afforded the desired product as a dark orange foam (6.1 g, 90%).
1H NMR (400 MHz, CDCl3): δ 9.15 (s, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.88
(d, J = 8.0 Hz, 1H), 7.64 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 7.49 (t, J = 7.5 Hz,
1H), 2.83 (s, 3H), 1.47 (s, 12H); 13C NMR (101 MHz, CDCl3): δ 156.9,
153.3, 139.7, 130.5, 128.1, 126.6, 126.1, 126.0, 84.3, 25.0, 24.6; 11B NMR
(128 MHz, CDCl3): δ 32.3 (br); FTIR: νmax 2976 (m), 1574 (m), 1454 (m),
1324 (m), 1133 (s); HRMS calculated for C16H2011BNO2 (MH+): 270.1659.
Found: 270.1665.
CDCl3): δ 8.83 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H),
7.70 – 7.65 (m, 1H), 7.58 – 7.53 (m, 1H), 2.67 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ 146.1, 141.5, 133.5, 130.4, 128.4, 128.2, 127.4, 127.1, 120.9,
17.3; FTIR: νmax 3190 (br), 2530 (br), 1542 (m), 1412 (m), 1377 (m), 1088
(s); HRMS calculated for C10H9NO (MH+): 160.0757. Found: 160.0757.
3-n-butyl-5,6,7,8-tetrahydroisoquinolin-4-ol (11). Following general
procedure C, 3-n-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
5,6,7,8-tetrahydroisoquinoline (3.4 g, 10.8 mmol) and H2O2 (550 mg, 16.2
mmol) in dichloromethane (110 mL) afforded the desired product as a pale
orange foam (1.5 g, 68%). 1H NMR (400 MHz, CDCl3): δ 7.82 (s, 1H), 2.76
– 2.72 (m, 2H), 2.71 – 2.63 (m, 4H), 1.84 – 1.71 (m, 4H), 1.62 (tt, J = 8.0,
6.5 Hz, 2H), 1.38 – 1.28 (m, 2H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR (101
MHz, CDCl3): δ 150.4, 146.3, 138.3, 135.3, 131.9, 31.6, 31.1, 26.2, 24.9,
24.6, 23.4, 22.8, 13.9; FTIR: νmax 2931 (w), 2507 (br), 1595 (m), 1358 (m),
1207 (s), 1100 (s); HRMS calculated for C13H19NO (MH+): 206.1539.
Found: 206.1543.
3-n-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline
(4). Following general procedure A, E-2-(hex-1-yn-1-yl)benzaldehyde O-
methyl oxime (2.2 g, 10.2 mmol), B2Pin2 (2.91 g, 11.2 mmol) and Pt(PPh3)4
(635 mg, 0.51 mmol) in toluene (100 mL) afforded the desired product as
a dark orange oil (4.63 g, 97%).1H NMR (400 MHz, CDCl3): δ 8.15 (s, 1H),
7.85 (dd, J = 8.0, 1.5 Hz, 1H), 7.28 (dt, J = 7.5, 1.5 Hz, 2H), 7.19 (td, J =
7.5, 1.0 Hz, 1H), 7.01 (dd, J = 8.0, 1.0 Hz, 1H), 3.93 (s, 3H), 1.97 – 1.88
(m, 2H), 1.34 (s, 12H), 1.24 – 1.20 (m, 2H), 1.19 (s, 12H), 1.13 – 1.07 (m,
2H), 0.71 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 148.3, 142.3,
129.5, 129.2, 129.1, 126.3, 125.0, 83.7 (x2 C), 61.7, 32.8, 31.0, 25.0 (x2
C), 24.7 (x2 C), 24.6 (x2 C), 22.8 (x2 C), 13.8; 11B NMR (128 MHz, CDCl3):
δ 31.9 (br); FTIR: νmax 2977 (m), 1599 (w), 1467 (m), 1307 (s), 1146 (s),
1055 (s); HRMS calculated for C26H4111B2NO5 (MH+): 470.3244. Found:
470.3259. Following general procedure B, using E-2-(1,2-bis(4,4,5,5-
Acknowledgements
We are grateful for support from Sanofi Aventis, and the FP7
Marie Curie Actions of the European Commission (via the ITN
COSSHNET network).
tetramethyl-1,3,2-dioxaborolan-2-yl)hex-1-en-1-yl)
benzaldehyde
O-
Keywords: ADME • boron • compound libraries •
physicochemical • pyridines
methyl oxime (4.3 g, 9.2 mmol) in 1,2-dichlorobenzene (90 mL) afforded
the desired product as a dark orange oil (2.32 g, 81%). 1H NMR (400 MHz,
CDCl3): δ 9.18 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H),
7.66 – 7.60 (m, 1H), 7.48 (t, J = 7.5 Hz, 1H), 3.10 – 3.04 (m, 2H), 1.81 –
1.71 (m, 2H), 1.46 (s, 12H), 1.45 – 1.38 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H);
13C NMR (101 MHz, CDCl3): δ 160.8, 153.3, 139.8, 130.5, 128.1, 126.7,
126.1 (x 2C), 84.3, 38.5, 33.8, 25.0, 23.0, 14.1; 11B NMR (128 MHz,
CDCl3): δ 32.3 (br); FTIR: νmax 2976 (m), 1574 (m), 1454 (m), 1324 (m),
1133 (s); HRMS calculated for C19H2611BNO2 (MH+): 312.2129. Found:
312.2136.
[1]
[2]
[3]
[4]
R. A. Prentis, Y. Lis, S. R. Walker, Br. J. Clin. Pharmac. 1988, 25, 387.
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L. Di, E. H. Kerns, Curr. Opin. Drug Discov. Devel. 2005, 8, 495.
For an introduction to ADME Profiling see Chapter 13 in Small Molecule
Medicinal Chemistry: Strategies and Technologies, K. Mertsch; M. Will;
W. Czechtitzky, N. Griesang, A. Marker, J. Olsen, John Wiley & Sons,Inc.,
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[5]
For an overview on the impact of enabling technologies on medicinal
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Wang, S.W. Djuric, Progress in Medicinal Chemistry, 2017, 56, 1.
P. Fricero, L. Bialy, W. Czechtizky, M. Méndez, J. P. A. Harrity,
ChemMedChem 2020, 15, 1634.
A search of the SciFinder® database revealed that there are more than
100 patents published containing the term ‘isoquinoline’ or
‘dihydroisoquinoline’ and their uses as therapeutics or pesticides.
(a) S. Ayesa, J. Bylund, K. Ersmark, L. Salvador Oden, F. Sehgelmeble,
WO2018038667; (b) S. Babu, M. Belema, J. A. Bender, C. Iwuagwu, J.
F. Dadow, S. Kumaravel, P. Nagalaskshmi, B. N. Naidu, M. Patel, K. M.
Peese, R. Rajamani, M. Saulnier, A. X. Wang, WO 2018203235.
(a) H. Wang, C. Grohmann, C. Nimphius, F. Glorius, J. Am. Chem. Soc.
2012, 134, 19592; (b) S. P. J. T. Bachollet, J. F. Vivat, D. C. Cocker, H.
Adams, J. P. A. Harrity, Chem. Eur. J. 2014, 20, 12889; (c) B. Su, J. F.
Hartwig, Angew. Chem. Int. Ed. 2018, 57, 10163.
3-n-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-
tetrahydroisoquinoline (6). Following general procedure A, E-2-(hex-1-
yn-1-yl)-1-cyclohexenecarboxaldehyde O-methyl oxime (3.9 g, 17.6 mmol),
B2Pin2 (5.0 g, 19.4 mmol) and Pt(PPh3)4 (658 mg, 0.53 mmol) in toluene
(170 mL) directly afforded the title product as a pale orange oil (4.5 g,
81%).1H NMR (400 MHz, CDCl3): δ 8.17 (s, 1H), 2.80 – 2.71 (m, 4H), 2.66
(br, 2H), 1.79 – 1.73 (m, 4H), 1.67 – 1.60 (m, 2H), 1.41 – 1.35 (m, 14H),
0.91 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 161.9, 150.5, 150.1,
129.0, 84.1, 38.5, 33.4, 29.0, 26.5, 25.0, 23.0, 22.8, 22.5, 14.1; 11B NMR
(128 MHz, CDCl3): δ 32.2 (br); FTIR: νmax 2930 (w), 1560 (m), 1475 (w),
1303 (m), 1138 (s); HRMS calculated for C19H3011BNO2 (MH+): 316.2442.
Found: 316.2452.
[6]
[7]
[8]
[9]
3-n-butylisoquinolin-4-ol (9). Following general procedure C, 3-n-butyl-
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (2.8 g, 9.0
mmol) and H2O2 (377 mg, 11.1 mmol) in dichloromethane (90 mL) afforded
the desired product as a pale yellow foam (1.1 g, 62%). 1H NMR (400 MHz,
CDCl3): δ 8.78 (s, 1H), 8.28 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H),
7.65 (dd, J = 8.0 Hz, 1H), 7.54 (dd, J = 8.0 Hz, 1H), 2.99 – 2.94 (m, 2H),
1.72 – 1.63 (m, 2H), 1.30 – 1.20 (m, 2H), 0.78 (t, J = 7.5 Hz, 3H); 13C NMR
(101 MHz, CDCl3): δ 146.8, 141.0, 139.1, 129.9, 129.4, 128.4, 127.3,
126.9, 121.5, 31.4, 31.3, 22.7, 13.9; FTIR: νmax 2917 (m), 1586 (m), 1493
(m), 1359 (s), 1104 (s); HRMS calculated for C13H15NO (MH+): 202.1226.
Found: 202.1230.
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J. P. A. Harrity, Org. Lett. 2019, 21, 6821; (b) H. Mora-Radó, L. Sotorrios,
M. P. Ball-Jones, L. Bialy, W. Czechtizky, M. Mendez, E. Gomez-Bengoa,
J. P. A. Harrity, Chem. Eur. J. 2018, 24, 9530; (c) H. Mora-Radó, L. Bialy,
W. Czechtizky, M. Mendez, J. P. A. Harrity, Angew. Chem. Int. Ed. 2016,
55, 5834.
[11] Boronic Acids: Preparation and Applications in Organic Synthesis,
Medicine and Materials, 2nd ed.; D. G. Hall, WILEY-VCH, Weinheim,
2011; Vol. 1.
[12] T. Kinzel, Y. Zhang, S. L. Buchwald, J. Am. Chem. Soc. 2010, 132, 14073.
[13] Reaction yields are provided in the Supporting Information. Reactions
carried out in parallel were not optimized individually (for example
reaction time). Instead, we employed a general method that allows the
generation of the most diverse set of compounds. Individual optimization
3-methylisoquinolin-4-ol (10). Following general procedure C, 3-methyl-
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (6.0 g, 22.3
mmol) and H2O2 (1.1 g, 33.4 mmol) in dichloromethane (225 mL) afforded
the desired product as a brown foam (2.3 g, 63%). 1H NMR (400 MHz,
7
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10.1002/cmdc.202000852
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is carried out at a later stage if the compounds obtained are moved
forward to the next stage of the program.
[14] For a perspective on drug and lead likeness see C.A. Lipinski; Drug
Discovery Today:Technologies, 2004, 1, 337 and references therein.
[15] Lead Optimization for Medicinal Chemist, Pharmacokinetic Properties of
Functional Groups and Organic Compounds, Z.Dorwalsd, WILEY-VCH,
Weinheim, 2012.
8
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ChemMedChem
FULL PAPER
Entry for the Table of Contents
Multiple choice! Pyridine fused boronic ester building blocks are accessible on multigram scale through a diboration-
electrocyclization sequence. These are amenable to the high throughput synthesis of biaryl and ether linked compound libraries
bearing a broad range of physicochemical and eADME properties.
9
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