BN/CC isosterism in borazaronaphthalenes towards phosphodiesterase 10A (PDE10A) inhibitors

Article abstract of DOI:10.1016/j.bmc.2015.06.019

The application of BN/CC isosterism is explored as a method of expanding the scope of core scaffolds in biologically active compounds. The viability of potential drug candidates incorporating BN-heteroaromatic moieties was investigated through the synthesis of BN-substituted analogs to known phosphodiesterase (PDE10A) inhibitors, namely MP10 and a selection of N-methylanilide analogs. These in some cases revealed unexpectedly potent and relatively stable derivatives, providing further support for the potential of BN-incorporation in medicinal chemistry.

Full text of DOI:10.1016/j.bmc.2015.06.019

Accepted Manuscript
BN/CC Isosterism in Borazaronaphthalenes towards Phosphodiesterase 10A
(PDE10A) Inhibitors
Alexandru Vlasceanu, Mikkel Jessing, John Paul Kilburn
PII:
S0968-0896(15)00513-1
DOI:
http://dx.doi.org/10.1016/j.bmc.2015.06.019
BMC 12375
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 April 2015
1 June 2015
5 June 2015
Please cite this article as: Vlasceanu, A., Jessing, M., Kilburn, J.P., BN/CC Isosterism in Borazaronaphthalenes
towards Phosphodiesterase 10A (PDE10A) Inhibitors, Bioorganic & Medicinal Chemistry (2015), doi: http://
dx.doi.org/10.1016/j.bmc.2015.06.019
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

BN/CC Isosterism in Borazaronaphthalenes towards Phosphodiesterase 10A
(PDE10A) Inhibitors
Alexandru Vlasceanu,b Mikkel Jessing,a and John Paul Kilburna*
a Discovery Chemistry and DMPK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
b Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen, Denmark
KEYWORDS: Borazaronaphthalenes, PDE10A Inhibitors, Antipsychotics
*Corresponding author. Tel:+45 30833215; e-mail: JPK@lundbeck.com
ABBREVIATIONS
cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; Boc, tert-butyloxycarbonyl; THF, tetrahydrofuran; DMF,
dimethylformamide; CPME, cyclopentyl methyl ether; TFA, trifluoroacetic acid; EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; HOBt,
hydroxybenzotriazole; TMS, trimethylsilyl; PMB, para-methoxybenzyl ether.
ABSTRACT: The application of BN/CC isosterism is explored as a method of expanding the scope of core scaffolds in biologically active com-
pounds. The viability of potential drug candidates incorporating BN-heteroaromatic moieties was investigated through the synthesis of BN-
substituted analogs to known phosphodiesterase (PDE10A) inhibitors, namely MP10 and a selection of N–methylanilide analogues. These in some
cases revealed unexpectedly potent and relatively stable derivatives, providing further support for the potential of BN-incorporation in medicinal
chemistry.
Although boron plays an important role in synthetic organic
chemistry, it is not commonly used in medicinal chemistry and
seldom found in natural products. Few chemists today appre-
ciate the unique properties and potential of boron incorpora-
tion into heterocyclic aromatic scaffolds.1
Figure 2. Two borazaronaphthalene derivatives tested by
A promising method of introducing boron in heterocycles is
Dewar in mice.4
by taking advantage of the isosteric and isoelectronic relation-
ship between the CC and BN fragments2, which has also been
Only two instances of 1,2-azaborine derivatives have been
reported to interact with biological systems thus far.5 The first
employed in the synthesis of various Hückel-aromatic scaf-
folds3a-c (Figure 1).
reported case describes the binding of both the N-ethyl- and
the parent 1,2-azaborine inside the cavity of T4 lysozyme5a
while the second demonstrates the potential of N- and B-ethyl-
1,2-azaborine to act as strong inhibitors of ethylbenzene dehy-
drogenase (EbDH)5b. With the exception of Dewar’s trials in
Figure 1. (a) 1,2-Azaborine (1,2-dihydro-1,2-azaborine)3a (b)
1964, these are to our knowledge, the only reports of
BN-indenyl analog (3a,7a-azaborindenyl anion)3b (c) 2,1-
borazaronaphthalenes exhibiting biological activity.
borazaronaphthalene (1,2-dihydrobenzo[e]-1,2-azaborine)3c.
Recent studies have shown that phosphodiesterase (PDE)
enzyme inhibition in the brain could have significant therapeu-
The investigation of borazaronaphthalenes for therapeutic
tic benefits including anti-psychotic, and pro-cognitive ef-
applications was largely abandoned following Dewar’s pio-
fects.6 In particular, PDE10A modulators have attracted par-
neering attempts in 1964. Dosing only a very limited range of
ticular attention for the treatment of Parkinson’s Disease,
BN-containing derivatives (Figure 2), these initial trials
proved immediately fatal to the lab mice.4

Huntington’s Disease, schizophrenia, and obsessive compul-
sive disorder (OCD).7
In 2009, research at Pfizer led to the identification of an N-
methylpyrazol series of which MP10 (1a), exhibited
subnanomolar PDE10A inhibition (IC50 = 0.37 nM) with
>1000-fold selectivity over other PDE’s.8a This compound has
since been used ubiquitously as the benchmark comparison
with regard to PDE10A inhibition. More recently however, an
N-methylanilide analog (1b) has also shown promising results
towards potential PDE inhibition (Figure 3).8b
Figure 4. Illustration of MP10 (1a) and N-methylanilide (1b)
binding modes in the PDE10A active site.8a,b
N
a)
b)
Studies have indicated that the PDE10A lipophilic pocket is
an important site for ligand binding and that modification of
the group occupying this space would be expected to alter the
potency of the compounds with regard to PDE10A inhibition.
Literature to date has identified the quinoline moiety as one of
the more potent variants, which has been rationalized in part
by its availability to act as an H-bond acceptor, allowing a
strong interaction with the nearby Tyr-693 residue.8a,b Alt-
hough not specifically reported, it was hypothesized that the
corresponding naphthalene-substituted analogs to these com-
pounds would present a lack of activity towards PDE10A
inhibition.
N
N
O
N
N
N
O
O
N
1a
1b
)
N-methylpyrazol MP10 (
)
N-methylanilide (
Figure 3. (a) Pfizer’s MP10 (1a)8a and (b) Lundbeck’s N-
methylanilide (1b)8b.
Key to these compounds’ activity is their ability to adopt a
favorable geometry and form strong interactions with the
binding pocket of the target enzyme. The catalytic active site
of many PDE’s was found to possess several structural fea-
tures critical to the enzyme’s function (Figure 4). In PDE10A
a flexible glutamine residue (Gln-726) can rotate to form
hydrogen bonds to either natural substrate: cAMP or cGMP.
Furthermore, a hydrophilic region containing two metal cen-
ters functions to bind the phosphate groups of the aforemen-
tioned nucleotides.8c The PDE10A active site was also found
to possess a unique lipophilic binding pocket, not normally
accessible in other PDE’s.8a,d Here, a well-positioned, nearby
tyrosine residue (Tyr-693) is able to accommodate and anchor
a guest molecule via H-bond interactions.
Borazaronaphthalenes, although isosteric and isoelectronic
with their naphthalene analogs, do present a significantly more
polarized bond, and partial protic character in the NH moiety
(Figure 5).3a With regard to their physical properties, the
borazaronaphthalenes were expected to behave more like the
naphthalene analogs in this biological system. The goal of this
investigation was to gain a better understanding of the extent
that the similarity in their physical properties would translate
to similarities in their biological interactions; such as for ex-
ample, the possibility of added interactions as a result of in-
creased polarization.
Evidence for MP10’s selectivity and affinity for PDE10A
was subsequently revealed by co-crystal structure analysis,
and could be rationalized based on the substrate’s binding
mode and structure activity relationship (SAR). These high-
lighted the critical interaction between the quinoline moiety of
MP10 and Tyr-693 in the lipophilic selectivity pocket of
PDE10A.8a Employing a similar binding mode, the recent N-
methylanilide lead compound, was also identified as an effi-
cient and selective inhibitor of PDE10A, yet considered to
lack potency compared to MP10.
a)
N
b)
N
N
O
N
H
N
H
N
R
B
O
B
O
2a
2b-f
N
N
N
O
N
R
O
O
3a
3b-f

Figure 5. BN- and napthyl-substituted analogs to (a) Pfizer’s
MP10 (2a, 3a) and (b) Lundbeck’s N-methylanilide series (2b-
f, 3b-f). See Table 1.
Via route 1, selective Boc-protection of 4-
(methylamino)phenol allowed for successful O-alkylation and
incorporation of the trifluoroborate functionality to yield the
potassium
trifluoroborate
salt
5.
Subsequent
Thus, in an effort to probe the viability of BN-substituted
compounds in the context of biological systems, and at the
same time gain insight into PDE inhibition, the synthesis and
characterization of BN-substituted analogs of MP10 and N-
methylanilide analogs (2a-f, Figure 5) was undertaken.
borazaronaphthalene formation, followed by deprotection
furnished 6. Lastly, a standard HOBt-catalyzed amide cou-
pling led to the synthesis of compounds 2b-f. An analogous
strategy was also applied towards the synthesis of 2a (Scheme
2).
The synthesis and functionalization of borazaronaphthalene
scaffolds has been successfully achieved by several groups
including Dewar3c,4,9, Paetzold10, Ashe11, and Liu12. In a recent
development, a one-pot versatile synthesis to 1,2-disubstituted
2,1-borazaronaphthalenes without the use of metal catalysts,
under mild conditions, and using inexpensive starting materi-
als was reported by Molander13a. Together with the work pre-
sented here, rapid progress towards borazaronaphthalene func-
tionalization and derivatization confirms the emerging interest
in this field.13 Employing these techniques, optimization to-
wards the synthesis of the borazaronaphthalene targets was
achieved by two routes (Scheme 1). Route 1 presents a general
and synthetically convergent four-step protocol which led to
the facile synthesis of compound series 2b-f while route 2
supports the possibility of early derivatization via a linear
approach.
Scheme 2. Synthesis of BN-MP10 (2a).a
a
Reagents and Conditions: i) NaH, DMF, 120 °C, 1 h;
KF3BCH2Br, 120 °C, 16 h. ii) 2-aminostyrene, Et3N, SiCl4,
MeCN/CPME (3:1), 80 °C, 6 h, then 40 °C, 3 d.
For a more comprehensive analysis of results the napthyl-
substituted derivatives of compounds 2a-f were also targeted.
Similar methods were employed towards the synthesis of the
naphthyl N-methylanilide analogs 3b-f (Scheme3) and
naphthyl MP10 3a (Scheme 4).
Scheme 3. General protocol towards 3b-f.a
Scheme 1. General protocol towards 2b-f.a
a
Reagents and Conditions: ii) 2-(bromomethyl)naphthalene,
K2CO3, MeCN, 20 h. iii) TFA, CH2Cl2, 30 °C, 15 min. iv)
a
Reagents and Conditions: i) Boc anhydride, pyridine,
EDCI, HOBt, carboxylic acid b-f, Et3N, THF, 3 d.
THF/MeCN (5:1), 70 °C, 20 h. ii) NaH, DMF, 120 °C, 1 h;
KF3BCH2Br, 120 °C, 16 h. iii) 2-aminostyrene, Et3N, SiCl4,
toluene/CPME (1:1), 100 °C, 24 h; TFA, 80 °C, 5 h. iv) EDCI,
HOBt, carboxylic acid b-f, Et3N, THF, 16 h. v) Isonicotinoyl
chloride, Et3N, THF, 50 °C, 23 h. vi) 2-aminostyrene, Et3N,
SiCl4, toluene/CPME (1:1), 80 °C, 22 h.
Scheme 4. Synthesis of Naphthyl-MP10 (3a).a

a
Reagents and Conditions: i) 2-(bromomethyl)naphthalene,
1d
2d
3d
NaH, MeCN, 60 °C, 30 min.
IC50 = 24
IC50 = 1800
3 % inh.
In agreement with literature and the hypotheses proposed, in
vitro studies showed that the quinolinyl-substituted derivatives
(1a-f)8 in general exhibited the highest potencies towards
PDE10A, whereas the naphthyl analogs (3a-f) showed the
least activity. Due to the isosteric and isoelectronic relation-
ship with the naphthyl derivatives, it was hypothesized and
generally confirmed that the borazaronaphthyl analogs (2a-d)
presented similar inactivity. Compounds 2e and 2f however,
exhibited a surprisingly high affinity for PDE10A, comparable
to that of the corresponding quinolinyl compounds (Table 1).
Docking studies of compounds 2e and 2f did not provide evi-
dence for the unexpected high affinity for PDE10A.
cLogP = 4.78 cLogP = 5.38 cLogP = 6.07
Clint = 1.3
Clint = 0.34
Clint = 0.41
1e
2e
3e
IC50 = 12
IC50 = 64
4 % inh.
cLogP = 3.58 cLogP = 4.18 cLogP = 4.87
Clint = 2.1
Clint = 1.5
Clint = 1.8
1f
2f
3f
Table 1. Metabolic stability, lipophilicity, and PDE10A
potency as a function of naphthyl-, quinolinyl-, or
borazaronaphthyl-substitution.
IC50 = 170
IC50 = 330
2 % inh.
cLogP = 2.35 cLogP = 3.95 cLogP = 4.64
Clint = >17 Clint = >17 Clint = >17
a
1a (MP10)
2a
3a
Metabolic Stability as a measure of microsomal intrinsic
IC50 = 2.6
48 % inh.
25 % inh.
clearance (Clint) in L/kg/h; Lipophilicity as calculated LogP
(cLogP); PDE10A potency measured as 50 % inhibitory con-
centration (IC50) in nM or given as percent inhibition at 10
µM. Data for the quinolinyl series (1a-f) are literature values.8
cLogP = 3.84 cLogP = 4.44 cLogP = 5.13
Clint = 1.9
Clint = 2.5
Clint = 5
As good metabolic stability leads to lower clearance com-
pounds, in the search for better drug candidates, these have the
potential benefits of reducing the dose quantity and frequency.
A common strategy used to estimate and reduce clearance is
based on the empirical correlation between lower lipophilicity
and lower clearance.14 Although a subject of debate15, it was of
interest to investigate this trend, hypothesizing a decrease in
metabolic stability with 1 a-f > 2 a-f > 3 a-f.
1b
2b
3b
IC50 = 250
11 % inh.
2 % at 2 µM
cLogP = 2.85 cLogP = 3.44 cLogP = 4.14
Clint = 0.9
Clint = 6.9
Clint = 4.5
1c
2c
3c
Results however, do not show a systematic trend between
metabolic stability and lipophilicity with the compounds de-
scribed. Although the quinoline derivatives presented the
highest metabolic stabilities, borazaronaphthalenes 2d and 2e
did show metabolic stabilities comparable to their quinolinyl
analogs. This suggests that it is not only lipophilicity driving
IC50 = 31
45 % inh.
5 % inh.
cLogP = 4.17 cLogP = 4.76 cLogP = 5.45
Clint = 1.9 Clint = 4.4 Clint = 2.9
metabolism and that
a better understanding of struc-
ture‐clearance relationships for the chemotype in question may

be a more effective strategy to delivering low clearance com-
pounds.
purification. All reactions involving dry solvents or air-
sensitive agents were performed under a nitrogen or argon
atmosphere and glassware was dried prior to use. Solvents
were dried according to standard procedures. Reactions were
monitored by analytical LC-MS which was conducted on a
Waters Acquity UPLC-MS, equipped with an Acquity UPLC
BEH C18 1.7 µm; 2.1 x 50 mm column at a temperature of 60
°C. A three-component solvent system, A = H2O/TFA
(99.5:0.5) and B = MeCN/H2O/TFA (94.965:5:0.035) was
applied with a linear gradient, A:B = 90:10 to 0:100 in 1.0
min, eluting at rate of 1.2 mL/min. Compound detection and
visualization was achieved via internal PDA (254 nm) and
ELSD detectors. APPI+ was used as the ionization method.
With regard to the compounds’ ability to inhibit PDE10A,
no systematic trend is readily apparent. As expected, the naph-
thalene analogues (3a-f) show little inhibitory activity, and
although the borazaronaphthalenes (2a-d) in general fall far
below the activities of the quinoline derivatives (1a-d), their
potencies as inhibitors are marginally better than that of the
corresponding naphthalene analogues. Compounds 2e and 2f
however, were found to be relatively potent compared to the
corresponding naphthalene analogues 3e and 3f. Initial
thoughts were that these results could possibly be explained by
an interaction between the pyridine group and the water mole-
cules associated with the metal ions. This would be supported
by the diminished potency observed in 2d. However, affinity
data obtained for compounds 3e and 3f suggests that the pyri-
dine group alone is not a cause of potency gain. Furthermore,
the results also indicate that a more favorable interaction be-
tween the borazaronaphthalene moiety in 2e and 2f exists in
the lipophilic selectivity pocket of PDE10A, when compared
to that of the corresponding naphthalene analogues 3e and 3f.
Flash chromatography was performed using either
a
CombiFlash Rf System (Teledyne Isco, Inc.) on GraceResolv
columns or a Flashmaster II (Argonaut) on ISOLUTE Flash Si
II columns. Eluent systems are given in volume/volume con-
centrations. NMR spectra were recorded on a 500 MHz Bruker
Avance AV500 instrument or on a 600 MHz Bruker Avance
Ultrashield 600 plus instrument. The samples were prepared as
CDCl3 solutions using TMS/CDCl3 as internal standards, or
DMSO-d6 solutions. Chemical shifts (δ) are given in parts per
million (ppm), and coupling constants (J) are given in Hertz
(Hz). The following abbreviations are used: br = broad, s =
singlet, d = doublet, dd = doublet of doublet, ddd = doublet of
doublet of doublets, t = triplet, q = quartet, m = multiplet. The
synthesis and properties of compounds 1a-f have been report-
ed in previous litterature.8 2-Vinylaniline13a and potassium
trifluoro(phenoxymethyl)borate13f were synthesized according
to literature procedure. 4-(1-methyl-4-(pyridin-4-yl)-1H-
pyrazol-3-yl)phenol can be synthesized according to literature
procedure8a or purchased from Ambinter.
In conclusion, the potential of several borazaronaphthyl-
substituted compounds as potent, metabolically stable, and
thus biologically viable candidates for further studies is re-
vealed. These results suggest that although affinity for the
enzyme’s active site is diminished, a certain degree of interac-
tion between these compounds and the PDE10A active site
persists. Assuming a similar binding mode as for the known
analogs, the relatively high activity of compounds 2e and 2f
might be attributable to a favorable interaction between the
BN moiety and the Tyr-693 residue, in addition to interactions
between the pyridinyl moieties and the hydrophilic region of
the enzymatic active site. In view of the prevalence and im-
portance of naphthalene and quinoline moieties in medicinal
chemistry, this study further supports the potential of
borazaronaphthalenes and their use as naphthalene and
quinoline bioisosteres.
tert-Butyl(4-hydroxyphenyl)(methyl)carbamate (4)
A solution of 4-(methylamino)phenol hemisulfate (10.33 g,
30.0 mmol) in THF (250 mL), MeCN (50 mL), and pyridine
(4.75 g, 4.83 mL, 60.0 mmol) was treated with di-tert-butyl
dicarbonate (13.75 g, 63.0 mmol) and heated to 70 °C for 21 h.
The mixture was concentrated in vacuo to 1/3 the volume,
then diluted with Et2O (400 mL) and washed with sat. aq.
NH4Cl (2 x 400 mL) then brine (400 mL). The organic phase
was isolated, dried over Na2SO4, filtered, and the solvent was
EXPERIMENTAL
General Procedures and Materials.
Unless otherwise stated, all solvents and reagents were ob-
tained from commercial suppliers and used without further

removed in vacuo. The residue was purified by gradient col-
back to 120 °C overnight. The mixture was then cooled to RT
and quenched using sat. aq. potassium bifluoride (5 mL, 22.5
mmol, 4.5 M). The mixture was stirred for 30 min before it
was concentrated to dryness in vacuo. The crude solid was
loaded onto a filter and washed with hot acetone (200 mL).
The filtrate was concentrated in vacuo onto celite, loaded onto
a new filter, and washed with CH2Cl2 (100 mL). 5 % MeOH/
CH2Cl2 (200 mL) was then used to elute the title compound,
(11) which was isolated after solvent removal, as a pale yellow
umn chromatography (SiO2, flash, 0-100 % EtOAc/heptane) to
isolate
the
title
compound,
tert-butyl
(4-
hydroxyphenyl)(methyl)carbamate (4) after solvent removal,
1
as a white solid (4.99 g, 22.4 mmol, 75 %). H NMR (600
MHz, DMSO-d6) δ 9.38 (s, 1H), 7.03 – 7.00 (m, 2H), 6.71 –
6.68 (m, 2H), 3.08 (s, 3H), 1.35 (s, 9H). 13C NMR (151 MHz,
DMSO-d6) δ 155.04, 154.16, 135.02, 126.92, 115.05, 78.97,
37.49, 28.01. GC-MS (EI+, EtOH, m/z) found 168 [M-(t-
Bu)+H]+ calculated 168.1 [M-(t-Bu)+H]+. LC-MS (APPI+,
H2O/MeCN/TFA, m/z) found 168 [M-(t-Bu)+H]+ calculated
168.1 [M-(t-Bu)+H]+, rt (PDA) 0.59 min.
1
solid (0.334 g, 0.959 mmol, 61 %). mp = 104-110 °C. H
NMR (600 MHz, DMSO-d6) δ 8.42 (d, J = 5.7 Hz, 2H), 7.15
(d, J = 5.7 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.69 (d, J = 8.8
Hz, 2H), 3.32 (s, 3H), 2.89 – 2.83 (m, 2H). 13C NMR (151
MHz, DMSO-d6) δ 167.50, 160.92, 149.35, 144.26, 134.47,
128.28, 122.17, 114.20, 37.66. *note: B-CH2 13C signal not
observed. IR (ATR, neat) 3052, 2911, 1636, 1552, 1509, 1442,
1414, 1383, 1286, 1269, 1245, 1089, 1067, 1020, 979, 837,
756, 731, 693, 642 cm-1. LC-MS (APPI+, H2O/MeCN/TFA,
m/z) found 287 [C14H16BN2O4]+ calculated 287.1
[C14H16BN2O4]+, rt (PDA) 0.24 min. HRMS (MALDI+ FT-
ICR, dithranol): found 291.11125 [M-KF+H]+ calculated
N-(4-hydroxyphenyl)-N-methylisonicotinamide (10)
To a suspension of N-methyl-p-aminophenol sulfate (6.89 g,
20.0 mmol) and isonicotinoyl chloride hydrochloride (7.12 g,
40.0 mmol)) in THF (120 mL) at 0 °C, was added Et3N (12.14
g, 16.74 mL, 120 mmol) dropwise over 5 min. The mixture
was then heated to 50 °C for 23 h, after which it was cooled to
RT, concentrated in vacuo and the crude residue purified by
gradient column chromatography (SiO2, flash, 0-100 % (10 %
MeOH/5 % Et3N/EtOAc)/EtOAc) to yield the title compound,
N-(4-hydroxyphenyl)-N-methylisonicotinamide (10) after
solvent removal, as a pale yellow solid (1.95 g, 8.54 mmol, 43
%). 1H NMR (600 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.42 (d, J
= 5.5 Hz, 2H), 7.15 (d, J = 5.5 Hz, 2H), 7.00 (d, J = 8.5 Hz,
2H), 6.60 (d, J = 8.5 Hz, 2H), 3.30 (s, 3H). 13C NMR (151
MHz, DMSO-d6) δ 167.56, 156.29, 149.33, 144.34, 134.75,
128.72, 122.16, 115.69, 37.57. LC-MS (APPI+,
H2O/MeCN/TFA, m/z) found 229 [M+H]+ calculated 229.1
[M+H]+, rt (PDA) 0.21 min.
291.11109
[M-KF+H]+.
Elemental
Analysis
Calc.
(C14H13BF3KN2O2): C, 48.30; H, 3.76; N, 8.05; Found: C,
48.39; H, 3.83; N, 8.15.
N-(4-(benzo[e][1,2]azaborinin-2(1H)-ylmethoxy)phenyl)-
N-methylisonicotinamide (2b)
Route 2: To an oven-dried microwave vial equipped with a
stirrer bar was added potassium trifluoroborate salt (11) (0.104
g, 0.300 mmol) under Ar atmosphere. To this, dry CPME (1
mL) and toluene (1 mL) were added, followed by dry, de-
gassed 2-vinylaniline (0.043 g, 0.042 mL, 0.360 mmol),
perchlorosilane (0.051 g, 0.034 mL, 0.300 mmol), then Et3N
(0.046 g, 0.063 mL, 0.450 mmol). The vial was heated to 80
°C for 22 h on an aluminum block. The reaction mixture was
then diluted with CH2Cl2 (5 mL) and passed through a small
celite plug eluting with CH2Cl2 (50 mL). The eluent was con-
centrated in vacuo and the residue purified by gradient column
chromatography (SiO2, flash, 0-100 % (10 % MeOH/5 %
Et3N/ EtOAc)/EtOAc) to elute the title compound (2b) which
was isolated, after solvent removal, as a pale yellow solid (5.2
mg, 0.014 mmol, 5 %). mp = 143-146 °C. 1H NMR (600 MHz,
Potassium trifluoro((4-(N-methylisonicotinamido)-
phenoxy)methyl)borate (11)
To
a
solution
of
N-(4-hydroxyphenyl)-N-
methylisonicotinamide (10) (0.433 g, 1.90 mmol) in DMF (20
mL) under Ar atmosphere, was added sodium hydride (0.076
g, 1.90 mmol, 60 % dispersion in mineral oil) in one portion.
The mixture was heated to 120 °C and stirred for 1 h. Potassi-
um bromomethyltrifluoroborate (0.317 g, 1.58 mmol) was
then added in one portion at RT, and the reaction was heated

CDCl3) δ 8.45 (d, J = 5.5 Hz, 2H), 8.33 (s, 1H), 8.05 (d, J =
11.5 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.45 (ddd, J = 8.3, 7.3,
1.4 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.20 (ddd, J = 8.0, 7.1,
1.0 Hz, 1H), 7.14 (d, J = 5.5 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H),
6.93 (d, J = 8.8 Hz, 2H), 6.77 (dd, J = 11.5, 1.6 Hz, 1H), 4.27
(s, 2H), 3.48 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 168.45,
159.58, 149.75, 145.63, 143.93, 139.70, 136.37, 129.72,
128.62, 128.31, 126.17 (br), 125.66, 122.70, 121.36, 118.26,
115.26, 61.59 (br), 38.47. 11B NMR (160 MHz, CDCl3) δ
35.11 (br). IR (ATR, neat) 3390, 3306, 3043, 2880, 2825,
1641, 1615, 1595, 1565, 1508, 1437, 1378, 1291, 1265, 1243,
1207, 1171, 1147, 1133, 1107, 1067, 1022, 997, 886, 835,
803, 758, 734, 701, 680, 631 cm-1. LC-MS (APPI+,
H2O/MeCN/TFA, m/z) found 370 [M+H]+ calculated 370.2
[M+H]+, rt (PDA) 0.65 min. HRMS (ESI+, DMSO) found
370.1727 [M+H]+ calculated 370.1721 [M+H]+; found
443.2622 [M+Et2NH2]+ calculated 443.2613 [M+Et2NH2]+.
Elemental Analysis Calc. (C22H20BN3O2): C, 71.57; H, 5.46;
N, 11.38; Found: C, 71.55; H, 5.57; N, 11.20.
d6) δ 159.81, 154.22, 134.75, 126.56, 113.58, 78.91, 37.53,
28.03. *note: B-CH2 13C signal not observed. IR (ATR, neat)
2977, 2904, 2847, 1695, 1608, 1512, 1479, 1444, 1365, 1291,
1244, 1157, 1105, 1009, 976, 836, 798, 768, 745, 647, 600 cm-
1
.
LC-MS (APPI+, H2O/MeCN/TFA, m/z) found 226
[C9H13BNO5]+ calculated 226.1 [C9H13BNO5]+, rt (PDA) 0.57
min. HRMS (MALDI+ FT-ICR, dithranol): found 382.05994
[M+K]+ calculated 382.06005 [M+K]+.
4-(Benzo[e][1,2]azaborinin-2(1H)-ylmethoxy)-N-
methylaniline (6)
To an oven-dried flask equipped with a stirrer bar and reflux
condenser was added potassium trifluoroborate salt (5) (6.00
g, 17.5 mmol) under Ar atmosphere and suspended 1:1 tolu-
ene/CPME (50 mL). To this mixture were consecutively added
2-vinylaniline (2.50 g, 2.47 mL, 21.0 mmol), perchlorosilane
(2.97 g, 2.00 mL, 17.5 mmol), then Et3N (2.65 g, 3.66 mL,
26.2 mmol). The reaction was heated to 100 °C for 24 h then
cooled back down to RT. The mixture was treated with TFA
(2.99 g, 2.00 mL, 26.2 mmol) and heated to 80 °C for 3 h,
after which another two aliquots of TFA (2.99 g, 2.00 mL,
26.2 mmol) were added at 1 h intervals. The reaction was then
cooled RT, quenched with a solution of Et3N (15 mL) in
MeOH (50 mL), and the volatiles were removed in vacuo. The
crude residue was diluted with EtOAc (100 mL), washed with
sat. aq. NaHCO3 (3 x 100 mL) and finally brine (100 mL). The
organic layer was dried over anhydrous Na2SO4, filtered, and
the solvent was removed in vacuo. The residue was further
purified by gradient column chromatography (SiO2, flash, 0-
100 % EtOAc/heptane) to isolate the title compound (6), after
solvent removal, as a white powder (1.65 g, 6.24 mmol, 36
Potassium ((4-((tert-
butoxycarbonyl)(methyl)amino)phenoxy)methyl)trifluorob
orate (5)
To
a
solution
of
tert-butyl
(4-
hydroxyphenyl)(methyl)carbamate (4) (4.93 g, 22.1 mmol) in
DMF (150 mL) was added sodium hydride (0.883 g, 22.1
mmol, 60 % dispersion in mineral oil) and the mixture was
heated
to
120
°C
for
1
h.
Potassium
bromomethyltrifluoroborate (3.70 g, 18.4 mmol) was then
added in one portion at RT, and the reaction was heated back
to 120 °C overnight. The mixture was then cooled to RT,
quenched using sat. aq. potassium bifluoride (50 mL, 225
mmol, 4.5 M) and stirred for a further 30 min before it was
concentrated to dryness in vacuo. The residue was loaded onto
a filter and washed with acetone (100 mL). The filtrate was
concentrated in vacuo to approx. 10 mL, and the product was
precipitated out of solution by slow addition into heptane (400
mL). The fine suspension was then filtered and the title com-
pound (5) was isolated as a white powder (4.38 g, 12.8 mmol,
1
%). mp = 96-99 °C. H NMR (600 MHz, CDCl3) δ 8.44 (s,
1H), 8.04 (d, J = 11.5 Hz, 1H), 7.67 – 7.61 (m, 1H), 7.44 (ddd,
J = 8.3, 7.2, 1.4 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.19 (ddd, J
= 7.9, 7.2, 1.0 Hz, 1H), 7.00 – 6.96 (m, 2H), 6.79 (dd, J =
11.5, 1.7 Hz, 1H), 6.67 – 6.62 (m, 2H), 4.29 (s, 2H), 3.47 (s,
br, 1H), 2.83 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 153.22,
145.27, 143.62, 139.90, 129.62, 128.44, 126.50 (br), 125.64,
121.08, 118.29, 115.44, 113.86, 61.86 (br), 31.83. 11B NMR
(160 MHz, CDCl3) δ 35.79 (br). IR (ATR, neat) 3390, 3024,
2875, 2810, 1725, 1615, 1593, 1563, 1511, 1436, 1390, 1345,
1281, 1232, 1133, 1104, 1057, 999, 941, 882, 818, 760, 705
1
69 %). mp = 140-146 °C. H NMR (600 MHz, DMSO-d6) δ
7.06 – 7.02 (m, 2H), 6.80 – 6.76 (m, 2H), 3.09 (s, 3H), 2.93 (q,
3JFH = 5.0 Hz, 2H), 1.35 (s, 9H). 13C NMR (151 MHz, DMSO-

cm-1. LC-MS (APPI+, H2O/MeCN/TFA, m/z) found 265
[M+H]+ calculated 265.2 [M+H]+, rt (PDA) 0.58 min. HRMS
(MALDI+ FT-ICR, dithranol): found 265.15067 [M+H]+
calculated 265.15067 [M+H]+. Elemental Analysis Calc.
(C16H17BN2O): C, 72.76; H, 6.49; N, 10.61; Found: C, 72.64;
H, 6.59; N, 10.54.
159.08, 155.81, 153.63, 145.57, 139.71, 137.47, 133.81,
133.44, 129.70, 128.59, 128.20, 126.94, 126.21 (br), 125.65,
123.08, 122.76, 121.31, 118.25, 115.15, 61.53 (br), 38.93. 11B
NMR (160 MHz, CDCl3) δ 35.30 (br). IR (ATR, neat) 3388,
3302, 3056, 2878, 2823, 1632, 1615, 1594, 1564, 1507, 1436,
1391, 1368, 1291, 1240, 1206, 1171, 1155, 1146, 1132, 1106,
1067, 1020, 996, 910, 885, 865, 833, 801, 759, 730, 719, 700,
653 cm-1. LC-MS (APPI+, H2O/MeCN/TFA, m/z) found 426
[M+H]+ calculated 426.1 [M+H]+, rt (PDA) 0.82 min. HRMS
(ESI+, DMSO) found 499.2348 [M+Et2NH2]+ calculated
N-(4-(benzo[e][1,2]azaborinin-2(1H)-ylmethoxy)phenyl)-
N-methylamides (2b-f)
499.2334
[M+Et2NH2]+.
Elemental
Analysis
Calc.
Route 1: To a suspension of N-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDCI) (100 mg, 0.520
mmol) in THF (5 mL) under Ar atmosphere were added 1-
hydroxybenzotriazole (HOBt) (60 mg, 0.440 mmol) and the
corresponding carboxylic acid (b-f) (0.400 mmol). After 30
(C24H20BN3O2S): C, 67.78; H, 4.74; N, 9.88; Found: C, 67.55;
H, 4.83; N, 9.71.
N-(4-(benzo[e][1,2]azaborinin-2(1H)-ylmethoxy)phenyl)-
N-methyl-3-phenyl-1H-pyrazole-5-carboxamide (2d)
min,
4-(benzo[e][1,2]azaborinin-2(1H)-ylmethoxy)-N-
Obtained as a white solid (103 mg, 59 %). Compound crys-
tallizes with heptane upon concentration from EtOAc/heptane
methylaniline (6) (106 mg, 0.400 mmol) followed by Et3N
(121 mg, 167 µL, 1.20 mmol) were added at 0 °C and the
mixture was allowed to warm to RT overnight (16 h). The
crude mixture was then diluted with EtOAc (25 mL) and
washed with sat. aq. NH4Cl (3 x 25 mL) then brine (25 mL).
The organic phase was isolated and dried over Na2SO4, fil-
tered, and the solvent was removed in vacuo. The crude resi-
due was further purified by gradient column chromatography
(SiO2, flash, 0-100 % EtOAc/heptane) to isolate the title com-
pounds (2b-f) after solvent removal.
1
solution. mp = 186-192 °C H NMR (600 MHz, CDCl3) δ
10.99 (s, 1H), 8.44 (s, 1H), 8.08 (d, J = 11.5 Hz, 1H), 7.67 (d,
J = 7.6 Hz, 1H), 7.52 (d, J = 7.4 Hz, 2H), 7.46 (ddd, J = 8.3,
7.2, 1.4 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.32 – 7.29 (m, 2H),
7.25 – 7.21 (m, 3H), 7.20 – 7.17 (m, 2H), 6.83 (dd, J = 11.5,
1.8 Hz, 1H), 5.32 (s, 1H), 4.42 (s, 2H), 3.46 (s, 3H). 13C NMR
(151 MHz, CDCl3) δ 160.84, 145.72, 139.74, 135.72, 129.76,
129.12, 128.73, 128.68, 128.09, 126.23 (br), 125.68, 121.42,
118.31, 115.75, 104.82, 61.85 (br), 38.80. *note: 5 13C signals
not observed; EtOAc and heptane impurities present. 11B
NMR (160 MHz, CDCl3) δ 35.09 (br). IR (ATR, neat) 3279,
3062, 3025, 2922, 2360, 2021, 1964, 1737, 1626, 1616, 1567,
1508, 1438, 1396, 1292, 1245, 1194, 1170, 1155, 1133, 1107,
1074, 1042, 994, 960, 886, 833, 798, 757, 736, 695, 648, 614
cm-1. LC-MS (APPI+, H2O/MeCN/TFA, m/z) found 435
[M+H]+ calculated 435.2 [M+H]+, rt (PDA) 0.88 min. HRMS
(ESI+, DMSO) found 435.1987 [M+H]+ calculated 435.1987
[M+H]+.
N-(4-(benzo[e][1,2]azaborinin-2(1H)-ylmethoxy)phenyl)-
N-methylisonicotinamide (2b)
Route 1: Obtained as a white solid (111 mg, 75 %). Charac-
terization reported above.
N-(4-(benzo[e][1,2]azaborinin-2(1H)-ylmethoxy)phenyl)-
N-methylbenzo[d]thiazole-6-carboxamide (2c)
Obtained as a white solid (121 mg, 71 %). mp = 64-71 °C.
1H NMR (600 MHz, CDCl3) δ 8.99 (s, 1H), 8.32 (s, 1H), 8.06
– 8.05 (m, 1H), 8.03 (d, J = 11.5 Hz, 1H), 7.88 (d, J = 8.4 Hz,
1H), 7.63 (d, J = 7.6 Hz, 1H), 7.44 (ddd, J = 8.4, 7.2, 1.4 Hz,
1H), 7.39 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.19
(ddd, J = 8.0, 7.2, 1.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.91
(d, J = 8.4 Hz, 2H), 6.75 (dd, J = 11.5, 1.7 Hz, 1H), 4.25 (s,
2H), 3.52 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 170.06,
N-(4-(benzo[e][1,2]azaborinin-2(1H)-ylmethoxy)phenyl)-
N-methyl-5-(pyridin-2-yl)-1H-pyrazole-3-carboxamide (2e)
Obtained as a white solid (124 mg, 71 %). mp = 174-182
1
°C. H NMR (600 MHz, CDCl3) δ 11.39 (s, 1H), 8.55 – 8.38

(m, 2H), 8.07 (d, J = 11.5 Hz, 1H), 7.72 (s, 1H), 7.68 – 7.62
(m, 2H), 7.47 – 7.42 (m, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.25 –
7.19 (m, 3H), 7.14 (d, J = 7.7 Hz, 3H), 6.82 (dd, J = 11.5, 1.6
Hz, 1H), 5.86 (s, 1H), 4.38 (s, 2H), 3.47 (s, 3H). 13C NMR
(151 MHz, CDCl3) δ 149.54, 145.62, 139.77, 136.74, 129.72,
128.82, 128.62, 126.27 (br), 125.68, 122.83, 121.34, 120.21,
118.32, 115.69, 61.72 (br), 38.92. *note: 7 13C signals not
observed. 11B NMR (160 MHz, CDCl3) δ 35.17 (br). IR (ATR,
neat) 3390, 3233, 3052, 2925, 2875, 2360, 1615, 1594, 1565,
1508, 1432, 1395, 1360, 1282, 1243, 1207, 1170, 1147, 1133,
995, 963, 886, 837, 789, 760, 734, 650 cm-1. LC-MS (APPI+,
H2O/MeCN/TFA, m/z) found 436 [M+H]+ calculated 436.2
[M+H]+, rt (PDA) 0.69 min. HRMS (ESI+, DMSO) found
436.1950 [M+H]+ calculated 436.1939 [M+H]+; found
509.2828 [M+Et2NH2]+ calculated 509.2831 [M+Et2NH2]+.
Elemental Analysis Calc. (C25H22BN5O2): C, 68.98; H, 5.09;
N, 16.09; Found: C, 69.05; H, 5.16; N, 15.91.
Potassium
trifluoro((4-(1-methyl-4-(pyridin-4-yl)-1H-
pyrazol-3-yl)phenoxy)methyl)borate (7)
To a solution of 4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-
yl)phenol (1.00 g, 4.00 mmol) in dry, degassed DMF (50 mL)
under Ar atmosphere was added sodium hydride (0.160 g, 4.00
mmol, 60 % dispersion in mineral oil) in one portion. The
mixture was heated to 120 °C and stirred for 1 h. Potassium
bromomethyltrifluoroborate (0.669 g, 3.33 mmol) was then
added in one portion at RT, and the reaction was heated back
to 120 °C overnight. The mixture was then cooled to RT and
quenched using sat. aq. potassium bifluoride (10 mL, 45.0
mmol, 4.5 M), allowing to stir for 30 min before the mixture
was concentrated to dryness in vacuo. The crude solid was
loaded onto a filter and washed with hot acetone (200 mL).
The filtrate was concentrated in vacuo onto celite which was
then loaded onto a filter and washed with CH2Cl2 (200 mL).
5% MeOH/ CH2Cl2 (300 mL) was used to elute the title com-
pound (7), which was isolated after solvent removal, as a pale
yellow powder (0.894 g, 2.41 mmol, 72 %). mp = 124-130 °C.
1H NMR (600 MHz, DMSO-d6) δ 8.44 – 8.42 (m, 2H), 8.14 (s,
1H), 7.22 – 7.18 (m, 4H), 6.90 – 6.78 (m, 2H), 3.89 (s, 3H),
3.02 – 2.89 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ
161.98, 149.68, 148.60, 141.13, 131.81, 129.17, 123.53,
121.91, 116.34, 113.89, 38.74. *note: B-CH2 13C signal not
observed. IR (ATR, neat) 3050, 2922, 1681, 1640, 1604, 1545,
1527, 1440, 1418, 1347, 1316, 1278, 1243, 1206, 1177, 1090,
1026, 987, 972, 835, 819, 733, 702, 670, 660, 641 cm-1. LC-
MS (APPI+, H2O/MeCN/TFA, m/z) found 314 [(M-KF)+H]+
calculated 314.1 [(M-KF)+H]+, rt (PDA) 0.27 min. HRMS
(MALDI+ FT-ICR, dithranol): found 314.12746 [M-KF+H]+
calculated 314.12708 [M-KF+H]+.
N-(4-(benzo[e][1,2]azaborinin-2(1H)-ylmethoxy)phenyl)-
N-methyl-2-(pyridin-3-yl)thiazole-4-carboxamide (2f)
Obtained as a pale yellow solid (132 mg, 73 %). mp = 192-
200 °C. 1H NMR (600 MHz, CDCl3) δ 8.86 (s, 1H), 8.57 (d, J
= 3.7 Hz, 1H), 8.41 (s, 1H), 8.04 (d, J = 11.5 Hz, 1H), 7.92 (d,
J = 7.3 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.61 (s, 1H), 7.44
(ddd, J = 8.3, 7.2, 1.4 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.28 –
7.24 (m, 1H), 7.20 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H), 7.13 (d, J =
7.9 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), 6.78 (dd, J = 11.5, 1.6
Hz, 1H), 4.31 (s, 2H), 3.51 (s, 3H). 13C NMR (151 MHz,
CDCl3) δ 163.38, 163.11, 159.62, 151.65, 151.08, 147.83,
145.56, 139.76, 137.60, 133.79, 129.69, 129.23, 128.58,
128.32, 126.29 (br), 125.66, 124.47, 123.71, 121.30, 118.28,
114.94, 61.69 (br), 38.83. *note: residual EtOAc solvent impu-
rity present.11B NMR (160 MHz, CDCl3) δ 35.31 (br). IR
(ATR, neat) 3373, 2875, 2360, 2338, 1630, 1612, 1563, 1507,
1437, 1419, 1367, 1271, 1237, 1130, 1007, 978, 882, 836,
817, 806, 768, 738, 706, 640 cm-1. LC-MS (APPI+,
H2O/MeCN/TFA, m/z) found 453 [M+H]+ calculated 453.2
[M+H]+, rt (PDA) 0.74 min. HRMS (ESI+, DMSO) found
453.1544 [M+H]+ calculated 453.1551 [M+H]+; found
526.2434 [M+Et2NH2]+ calculated 526.2443 [M+Et2NH2]+.
Elemental Analysis Calc. (C25H21BN4O2S): C, 66.38; H, 4.68;
N, 12.39; Found: C, 65.92; H, 4.79; N, 12.15.
2-((4-(1-Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-
yl)phenoxy)methyl)-1,2-dihydrobenzo[e][1,2]azaborinine
(2a)
In an oven-dried microwave vial equipped with a stirrer bar,
potassium trifluoroborate salt (7) (148 mg, 0.400 mmol) was
suspended in a mixture of dry CPME (0.8 mL) and MeCN (1.6
mL) under Ar atmosphere. The mixture was solubilized by
heating to 80 °C. To this hot stirring mixture, 2-vinylaniline
(57 mg, 57 µL, 0.480 mmol), followed by Et3N (243 mg, 335
µL, 2.40 mmol) and lastly perchlorosilane (68 mg, 46 µL,

0.400 mmol) were added. After stirring for 6 h at 80 °C, addi-
tional 2-vinylaniline (29 mg, 28 µL, 0.240 mmol) was added,
followed by perchlorosilane (34 mg, 23 µL, 0.200 mmol) 1 h
later. The mixture was then stirred for 3 days at 40 °C, after
which it was quenched with a solution of Et3N (243 mg, 335
µL, 2.40 mmol) in MeOH (2 mL). The volatiles were then
removed in vacuo and the residue dissolved in EtOAc (25
mL). The organic phase was washed with 1 M NaOH (2 x 25
mL) and brine (25 mL), dried over anhydrous Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by gradi-
EtOAc/heptane). The title compound (8) was isolated, after
solvent removal, as a crystalline white solid (4.31 g, 11.9
mmol, 93 %). mp = 119-120 °C. 1H NMR (600 MHz, CDCl3)
δ 7.90 – 7.83 (m, 4H), 7.54 (dd, J = 8.4, 1.5 Hz, 1H), 7.52 –
7.47 (m, 2H), 7.20 – 7.07 (m, 2H), 6.99 – 6.95 (m, 2H), 5.22
(s, 2H), 3.22 (s, 3H), 1.44 (s, 9H). 13C NMR (151 MHz,
CDCl3) δ 156.55, 155.23, 137.29, 134.51, 133.39, 133.18,
128.54, 128.06, 127.86, 127.05, 126.46, 126.38, 126.22,
125.38, 114.99, 80.16, 70.49, 37.75, 28.49. IR (ATR, neat)
3053, 2976, 2929, 2361, 1694, 1604, 1585, 1511, 1475, 1456,
1434, 1365, 1294, 1238, 1151, 1109, 1014, 976, 894, 860,
832, 817, 747, 620, cm-1. LC-MS (APPI+, H2O/MeCN/TFA,
m/z) found 308 [M-(t-Bu)+H]+ calculated 308.1 [M-(t-
Bu)+H]+, rt (PDA) 0.99 min. HRMS (MALDI+ FT-ICR,
dithranol): found 386.17249 [M+Na]+ calculated 386.17266
[M+Na]+.
ent column chromatography (SiO2, flash, 0-100
%
EtOAc/heptane) to isolate the title compound (2a), after sol-
vent removal, as a pale beige solid (55 mg, 35 %). mp = 76-78
1
°C. H NMR (600 MHz, CDCl3) δ 8.48 (d, J = 5.5 Hz, 2H),
8.43 (s, 1H), 8.06 (d, J = 11.5 Hz, 1H), 7.65 (d, J = 7.8 Hz,
1H), 7.59 (s, 1H), 7.47 – 7.40 (m, 3H), 7.36 (d, J = 8.0 Hz,
1H), 7.22 – 7.17 (m, 3H), 7.08 (d, J = 8.5 Hz, 2H), 6.81 (d, J =
11.5 Hz, 1H), 4.37 (s, 2H), 3.99 (s, 3H). 13C NMR (151 MHz,
CDCl3) δ 160.64, 150.08, 149.66, 145.48, 141.48, 139.81,
130.64, 129.87, 129.68, 128.55, 126.37 (br), 125.67, 125.22,
N-methyl-4-(naphthalen-2-ylmethoxy)aniline (9)
To
a
solution of tert-butyl methyl(4-(naphthalen-2-
ylmethoxy)phenyl)carbamate (8) (3.64 g, 10.0 mmol) in
CH2Cl2 (100 mL) was added TFA (29.8 g, 20 mL, 261 mmol)
and the mixture was heated to 30 °C for 15 min. The volatiles
were then removed in vacuo and the residue was purified by
gradient column chromatography (SiO2, flash, 0 - 100%
EtOAc/heptane). The title compound (9) was isolated, after
solvent removal, as a white solid (2.21 g, 8.38 mmol, 84 %).
mp = 68-72 °C. 1H NMR (600 MHz, CDCl3) δ 7.89 – 7.82 (m,
4H), 7.55 (dd, J = 8.4, 1.6 Hz, 1H), 7.51 – 7.46 (m, 2H), 6.93
– 6.90 (m, 2H), 6.61 – 6.57 (m, 2H), 5.17 (s, 2H), 2.81 (s, 3H).
*note: NH 1H signal not observed. 13C NMR (151 MHz,
CDCl3) δ 151.35, 144.08, 135.26, 133.43, 133.12, 128.40,
128.07, 127.84, 126.37, 126.26, 126.05, 125.54, 116.37,
113.70, 71.19, 31.70. IR (ATR, neat) 3393, 3052, 2868, 2807,
1632, 1601, 1508, 1467, 1372, 1296, 1223, 1178, 1149, 1123,
1104, 1016, 951, 900, 854, 813, 737, 642, 621 cm-1. LC-MS
(APPI+, H2O/MeCN/TFA, m/z) found 264 [M+H]+ calculated
264.1 [M+H]+, rt (PDA) 0.55 min. HRMS (MALDI+ FT-ICR,
dithranol): found 264.13832 [M+H]+ calculated 264.13829
[M+H]+. Elemental Analysis Calc. (C18H17NO): C, 82.10; H,
6.51; N, 5.32; Found: C, 81.97; H, 6.59; N, 5.25.
122.69, 121.23, 118.32, 117.89, 114.62, 61.29 (br), 39.33. 11
B
NMR (160 MHz, CDCl3) δ 35.35 (br). IR (ATR, neat) 3389,
3252, 3029, 2939, 2874, 1601, 1564, 1525, 1498, 1438, 1417,
1345, 1302, 1280, 1264, 1240, 1177, 1155, 1146, 1133, 1109,
1087, 999, 977, 942, 885, 833, 813, 761, 737, 704, 669, 659,
627 cm-1. LC-MS (APPI+, H2O/MeCN/TFA, m/z) found 393
[M+H]+ calculated 393.2 [M+H]+, rt (PDA) 0.62 min. HRMS
(MALDI+ FT-ICR, dithranol): found 393.18787 [M+H]+
calculated 393.18812 [M+H]+.
tert-Butyl
methyl(4-(naphthalen-2-
ylmethoxy)phenyl)carbamate (8)
To
a
solution
of
tert-butyl
(4-
hydroxyphenyl)(methyl)carbamate (4) (4.36 g, 19.6 mmol)
and 2-(bromomethyl)naphthalene (2.83 g, 12.8 mmol) in
MeCN (100 mL) was added potassium carbonate (5.31 g, 38.4
mmol) and the reaction was stirred overnight (20 h). The sol-
vent was then removed in vacuo, and the residue dissolved in
EtOAc (300 mL). The organic phase was washed with H2O (2
x 200 mL) and brine (200 mL) then dried over MgSO4, fil-
tered, and concentrated in vacuo. The crude product was puri-
fied by gradient column chromatography (SiO2, flash, 0-100 %

5.14 (s, 2H), 3.50 (s, 3H). 13C NMR (151 MHz, CDCl3) δ
170.02, 157.28, 155.86, 153.65, 137.94, 134.03, 133.69,
133.46, 133.34, 133.20, 128.60, 128.23, 128.05, 127.88,
126.92, 126.51, 126.47, 126.33, 125.28, 123.08, 122.79,
115.68, 70.42, 38.90. IR (ATR, neat) 3055, 2930, 1636, 1509,
1469, 1442, 1426, 1395, 1366, 1293, 1239, 1177, 1108, 1021,
954, 909, 890, 865, 836, 816, 767, 752, 619 cm-1. LC-MS
(APPI+, H2O/MeCN/TFA, m/z) found 425 [M+H]+ calculated
425.1 [M+H]+, rt (PDA) 0.82 min. HRMS (MALDI+ FT-ICR,
dithranol): found 425.13174 [M+H]+ calculated 425.13183
[M+H]+. Elemental Analysis Calc. (C26H20N2O2S): C, 73.56;
H, 4.75; N, 6.60; Found: C, 73.66; H, 4.83; N, 6.54.
N-methyl-N-(4-(naphthalen-2-
ylmethoxy)phenyl)carboxamides (3b-f)
To
a
suspension of N-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDCI) (0.100 g, 0.520
mmol) in THF (4 mL), were added 1-hydroxybenzotriazole
(HOBt) (0.059 g, 0.440 mmol) and the corresponding carbox-
ylic acid (b-f) (0.400 mmol). After 30 min, a solution of N-
methyl-4-(naphthalen-2-ylmethoxy)aniline (9) (0.105 g, 0.400
mmol) and Et3N (0.121 g, 0.167 mL, 1.20 mmol) in THF (1
mL) was added and the mixture was stirred over 3 d. The
reaction was then diluted with CH2Cl2 (10 mL) and the result-
ing solution was concentrated in vacuo onto celite. The residue
was purified by gradient column chromatography (SiO2, flash,
0-100 % EtOAc/heptane) to isolate the title compounds (3b-f)
after solvent removal.
N-methyl-N-(4-(naphthalen-2-ylmethoxy)phenyl)-3-
phenyl-1H-pyrazole-5-carboxamide (3d)
Obtained as a white solid (94 mg, 0.217 mmol, 54 %). mp =
164-166 °C. 1H NMR (600 MHz, CDCl3) δ 10.85 (s, 1H), 7.92
(s, 1H), 7.90 – 7.83 (m, 3H), 7.57 (dd, J = 8.4, 1.6 Hz, 1H),
7.54 – 7.49 (m, 4H), 7.35 – 7.31 (m, 2H), 7.29 (d, J = 7.3 Hz,
1H), 7.23 – 7.20 (m, 2H), 7.13 – 7.10 (m, 2H), 5.31 (s, 2H),
5.29 (s, 1H), 3.43 (s, 3H). 13C NMR (151 MHz, CDCl3) δ
159.00, 133.93, 133.40, 133.27, 129.22, 128.76, 128.14,
128.07, 127.93, 126.57, 126.52, 126.43, 125.70, 125.16,
116.25, 104.79, 70.66, 38.73. *note: 6 13C signals not ob-
served. IR (ATR, neat) 3207, 3059, 2360, 2334, 1740, 1621,
1509, 1443, 1395, 1357, 1297, 1241, 1173, 1121, 1076, 1009,
988, 955, 894, 836, 816, 757, 694, 668, 622 cm-1. LC-MS
(APPI+, H2O/MeCN/TFA, m/z) found 434 [M+H]+ calculated
434.2 [M+H]+, rt (PDA) 0.88 min. HRMS (MALDI+ FT-ICR,
dithranol): found 434.18630 [M+H]+ calculated 434.18630
[M+H]+. Elemental Analysis Calc. (C28H23N3O2): C, 77.58; H,
5.35; N, 9.69; Found: C, 77.69; H, 5.30; N, 9.54.
N-methyl-N-(4-(naphthalen-2-
ylmethoxy)phenyl)isonicotinamide (3b)
Obtained as a white solid (115 mg, 0.312 mmol, 78 %). mp
= 163-165 °C. 1H NMR (600 MHz, CDCl3) δ 8.45 (d, J = 5.0
Hz, 2H), 7.88 – 7.81 (m, 4H), 7.52 – 7.47 (m, 3H), 7.12 (d, J =
5.1 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H),
5.16 (s, 2H), 3.46 (s, 3H). 13C NMR (151 MHz, CDCl3) δ
168.42, 157.80, 149.77, 143.83, 136.85, 133.90, 133.35,
133.23, 128.66, 128.36, 128.05, 127.90, 126.58, 126.52,
126.39, 125.29, 122.68, 115.79, 70.50, 38.44. IR (ATR, neat)
3051, 2935, 1645, 1598, 1552, 1509, 1466, 1430, 1408, 1376,
1300, 1287, 1240, 1176, 1108, 1067, 1022, 894, 834, 816,
755, 690, 644, 620 cm-1. LC-MS (APPI+, H2O/MeCN/TFA,
m/z) found 369 [M+H]+ calculated 369.2 [M+H]+, rt (PDA)
0.63 min. HRMS (MALDI+ FT-ICR, dithranol): found
369.15970 [M+H]+ calculated 369.15975 [M+H]+. Elemental
Analysis Calc. (C24H20N2O2): C, 78.24; H, 5.47; N, 7.60;
Found: C, 78.15; H, 5.41; N, 7.68.
N-methyl-N-(4-(naphthalen-2-ylmethoxy)phenyl)-5-
(pyridin-2-yl)-1H-pyrazole-3-carboxamide (3e)
Obtained as a white solid (78 mg, 0.180 mmol, 45 %). mp =
N-methyl-N-(4-(naphthalen-2-
1
ylmethoxy)phenyl)benzo[d]thiazole-6-carboxamide (3c)
92-96 °C. H NMR (600 MHz, CDCl3) δ 11.37 (s, 1H), 8.53
(d, J = 3.7 Hz, 1H), 7.90 (s, 1H), 7.88 – 7.82 (m, 3H), 7.69 (dt,
J = 24.5, 7.8 Hz, 2H), 7.55 (dd, J = 8.4, 1.6 Hz, 1H), 7.52 –
7.48 (m, 2H), 7.22 – 7.16 (m, 3H), 7.09 – 7.05 (m, 2H), 5.92
(s, 1H), 5.27 (s, 2H), 3.45 (s, 3H). 13C NMR (151 MHz,
Obtained as a white solid (108 mg, 0.253 mmol, 63 %). mp
1
= 56-60 °C. H NMR (600 MHz, CDCl3) δ 9.00 (s, 1H), 8.03
(s, 1H), 7.90 – 7.79 (m, 5H), 7.51 – 7.45 (m, 3H), 7.37 (d, J =
8.0 Hz, 1H), 6.98 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H),

CDCl3) δ 158.66, 149.55, 136.78, 134.08, 133.39, 133.23,
128.89, 128.66, 128.08, 127.90, 126.51, 126.48, 126.34,
125.28, 122.89, 120.22, 116.21, 105.85, 70.63, 38.87. *note: 5
13C signals not observed. IR (ATR, neat) 3195, 3050, 2931,
1620, 1594, 1568, 1506, 1429, 1394, 1358, 1299, 1280, 1238,
1172, 1121, 1035, 993, 962, 893, 835, 814, 789, 735, 702,
667, 622 cm-1. LC-MS (APPI+, H2O/MeCN/TFA, m/z) found
435 [M+H]+ calculated 435.2 [M+H]+, rt (PDA) 0.67 min.
HRMS (MALDI+ FT-ICR, dithranol): found 435.18149
[M+H]+ calculated 435.18155 [M+H]+. Elemental Analysis
Calc. (C27H22N4O2): C, 74.64; H, 5.10; N, 12.89; Found: C,
74.46; H, 5.03; N, 12.72.
for 30 min. The mixture was then diluted with MeOH (10 mL)
and CH2Cl2 (10 mL) and the solution was concentrated in
vacuo onto celite. The residue was purified by gradient col-
umn chromatography (SiO2, flash, 0-100 % EtOAc /heptane)
to isolate the title compound (3a), after solvent removal, as a
beige solid (83 mg, 0.211 mmol, 34 %). mp = 144-146 °C. 1H
NMR (600 MHz, CDCl3) δ 8.49 – 8.46 (m, 2H), 7.90 (s, 1H),
7.89 – 7.84 (m, 3H), 7.58 (s, 1H), 7.56 (dd, J = 8.4, 1.6 Hz,
1H), 7.51 – 7.47 (m, 2H), 7.42 – 7.39 (m, 2H), 7.19 – 7.16 (m,
2H), 7.03 – 6.99 (m, 2H), 5.25 (s, 2H), 3.98 (s, 3H). 13C NMR
(151 MHz, CDCl3) δ 158.89, 150.06, 149.45, 141.40, 134.40,
133.40, 133.19, 130.64, 129.86, 128.54, 128.08, 127.86,
126.56, 126.39, 126.23, 125.79, 125.45, 122.68, 117.90,
115.10, 70.28, 39.32. IR (ATR, neat) 3053, 2938, 2866, 1602,
1577, 1543, 1525, 1510, 1445, 1415, 1346, 1302, 1282, 1238,
1179, 1124, 1109, 1087, 1009, 993, 978, 954, 896, 833, 815,
747, 706, 660, 620 cm-1. LC-MS (APPI+, H2O/MeCN/TFA,
m/z) found 392 [M+H]+ calculated 392.2 [M+H]+, rt (PDA)
0.63 min. HRMS (MALDI+ FT-ICR, dithranol): found
392.17567 [M+H]+ calculated 392.17574 [M+H]+.
N-methyl-N-(4-(naphthalen-2-ylmethoxy)phenyl)-2-
(pyridin-3-yl)thiazole-4-carboxamide (3f)
Obtained as a white solid (115 mg, 0.255 mmol, 64 %). mp
1
= 148-154 °C. H NMR (600 MHz, CDCl3) δ 8.86 (s, 1H),
8.60 (d, J = 3.8 Hz, 1H), 7.92 – 7.88 (m, 1H), 7.86 – 7.82 (m,
3H), 7.80 (dd, J = 5.9, 3.2 Hz, 1H), 7.59 (s, 1H), 7.52 – 7.47
(m, 3H), 7.29 – 7.24 (m, 1H), 7.10 (d, J = 7.6 Hz, 2H), 6.96 (d,
J = 8.2 Hz, 2H), 5.21 (s, 2H), 3.49 (s, 3H). 13C NMR (151
MHz, CDCl3) δ 163.34, 163.11, 157.79, 151.53, 151.08,
147.80, 138.08, 134.17, 133.76, 133.35, 133.18, 129.22,
128.59, 128.35, 128.21, 128.02, 127.88, 126.45, 126.31,
125.25, 124.53, 123.73, 115.49, 70.57, 38.79. IR (ATR, neat)
3053, 2930, 1637, 1586, 1572, 1509, 1467, 1450, 1417, 1369,
1274, 1238, 1172, 1146, 1107, 1024, 1009, 981, 954, 894,
834, 814, 748, 704, 670, 642, 619 cm-1. LC-MS (APPI+,
H2O/MeCN/TFA, m/z) found 452 [M+H]+ calculated 452.1
[M+H]+, rt (PDA) 0.72 min. HRMS (MALDI+ FT-ICR,
dithranol): found 452.14277 [M+H]+ calculated 452.14272
[M+H]+. Elemental Analysis Calc. (C27H21N3O2S): C, 71.82;
H, 4.69; N, 9.31; Found: C, 71.93; H, 4.71; N, 9.12.
ACKNOWLEDGMENT
We would like to gratefully acknowledge Professor Mogens
Brøndsted Nielsen for his support and contributions. In addi-
tion, the Molecular Pharmacology and DMPK departments at
H. Lundbeck A/S for collecting and processing the data from
both in vitro stability and affinity assays. Finally we would
like to thank H. Lundbeck A/S for financial support of this
project.
REFERENCES
(1) a) Fritsch, A. J. Borazaromatic Compounds. In The
Chemistry of Heterocyclic Compounds, Special Topics
in Heterocyclic Chemistry. Weissberger, A., Taylor, E.
C. Eds.; John Wiley & Sons, 2009, pp. 382-437. b)
Groziak, M. P. Boron Heterocycles as Platforms for
Building New Bioactive Agents. In Progress in Hetero-
cyclic Chemistry, Vol. 12: A critical review of the 1999
literature preceded by three chapters on current heter-
ocyclic topics; Gribble, G.W., Gilchrist T. L., Eds.;
Elsevier, 2000, pp. 1-21. c) Maitlis, P. M. Heterocyclic
Organic Boron Compounds. Chem. Rev., 1962, 62, pp.
223–245.
4-(1-Methyl-3-(4-(naphthalen-2-ylmethoxy)phenyl)-1H-
pyrazol-4-yl)pyridine (3a)
To a solution of 4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-
yl)phenol
(157
mg,
0.624
mmol)
and
2-
(bromomethyl)naphthalene (138 mg, 0.624 mmol) in MeCN
(3 mL) was added sodium hydride (25 mg, 0.624 mmol, 60 %
dispersion in mineral oil) and the reaction was heated to 60 °C

(2) a) Campbell, P. G.; Marwitz, A. J. V.; Liu, S. Y. Recent
Advances in Azaborine Chemistry. Angew. Chem. Int.
Ed. 2012, 51, 6074-6092; b) Bosdet, M. J. D.; Piers, W.
E. B-N as a C-C substitute in aromatic systems. Can. J.
Chem. 2009, 87, 8-29; c) Dewar, M. J. S.
Heteroaromatic boron compounds. In Progress in Bo-
ron Chemistry; Steinberg, H., McCloskey, A. L., Eds.;
Pergamon Press, 1964, pp. 235-263.
Chem. 2007, 50, 182-185; c) Chappie, T. A.; Humph-
rey, J. M.; Menniti, F.; Schmidt, C. PDE10A inhibitors:
an assessment of the current CNS drug discovery land-
scape. Curr. Opin. Drug Discovery Dev. 2009, 12, 458-
467; d) Kehler, J.; Kilburn, J. P. Patented PDE10A in-
hibitors: novel compounds since 2007. Expert Opin.
Ther. Pat. 2009, 19, 1715-1725.
(7) a) Menniti, F. S.; Chappie, T. A.; Humphrey, J. M.;
Schmidt, C. J. Phosphodiesterase 10A inhibitors: a
novel approach to the treatment of the symptoms of
schizophrenia. Curr. Opin. Invest. Drugs 2007, 8, 54-
59; b) Siuciak, J. A. The Role of Phosphodiesterases in
Schizophrenia: Therapeutic Implications. CNS Drugs
2008, 22, 983-993; c) Halene, T. B.; Siegel, S. J. PDE
inhibitors in psychiatry – future options for dementia,
depression and schizophrenia? Drug Discovery Today
2007, 12, 870-878; d) Siuciak, J. A.; Chapin, D. S.;
Harms, J. F.; Lebel, L. A.; McCarthy, S. A.; Chambers,
L.; Shrikhande, A.; Wong, S.; Menniti, F. S.; Schmidt,
(3) a) Marwitz, A.; Matus, M.; Zakharov, L.; Dixon, D.;
Liu, S. Y. A Hybrid Organic/Inorganic Benzene. Angew.
Chem. Int. Ed. 2009, 48, 973-977; b) Ashe III, A. J.;
Yang, H.; Fang, X.; Kampf, J. W. Synthesis and Coor-
dination Chemistry of 3a,7a-Azaborindenyl, a New
Isoelectronic Analogue of the Indenyl Ligand. Organ-
ometallics 2002, 21, 4578-4580; c) Dewar, M. J. S.;
Dietz, R. New heteroaromatic compounds. Part III. 2,1-
Borazaro-naphthalene
(1,2-dihydro-1-aza-2-
boranaphthalene). J. Chem. Soc. 1959, 2728-2730.
(4) Dewar, M. J. S.; Hashmall, J.; Kubba, V. P. New
Heteroaromatic Boron Compounds. XIX.1,2 Water-
Soluble Derivatives of 10,9-Borazarophenanthrene and
2,1-Borazaronaphthalene as Potential Agents for Neu-
tron Capture Therapy. J. Org. Chem. 1964, 29, 1755-
1757.
C.
J.
Inhibition
of the
striatum-enriched
phosphodiesterase PDE10A: a novel approach to the
treatment of psychosis. Neuropharmacology 2006, 51,
386-396; e) Brandon, N. J.; Rotella, D. P. Potential
CNS Applications for Phosphodiesterase Enzyme In-
hibitors. Annu. Rep. Med. Chem. 2007, 42, 3-12; f)
Siuciak, J. A.; McCarthy, S. A.; Chapin, D. S.; Fujiwa-
ra, R. A.; James, L. C.; Williams, R. D.; Stock, J. L.;
McNeish, J. D.; Strick, C. A.; Menniti, F. S.; Schmidt,
C. J. Genetic deletion of the striatum-enriched
phosphodiesterase PDE10A: Evidence for altered stria-
tal function. Neuropharmacology 2006, 51, 374-385.
(8) a) Verhoest, P. R.; Chapin, D. S.; Corman, M.; Fonseca,
K.; Harms, J. F.; Hou, X.; Marr, E. S.; Menniti, F. S.;
Nelson, F.; O’Connor, R.; Pandit, J.; Proulx-LaFrance,
C.; Schmidt, A. W.; Schmidt, C. J.; Suiciak, J. A.; Li-
(5) a) Liu, L.; Marwitz, A.; Matthews, B. W.; Liu, S. Y.
Boron Mimetics: 1,2-Dihydro-1,2-azaborines Bind in-
side a Nonpolar Cavity of T4 Lysozyme. Angew. Chem.
Int. Ed. 2009, 48, 6817-6819; b) Knack, D. H.; Mar-
shall, J. L.; Harlow, G. P.; Dudzik, A.; Szaleniec, M.;
Liu, S. Y.; Heider, J. BN/CC Isosteric Compounds as
Enzyme Inhibitors: N- and B-Ethyl-1,2-azaborine In-
hibit Ethylbenzene Hydroxylation as Nonconvertible
Substrate Analogues. Angew. Chem. Int. Ed. 2013, 52,
2599-2601.
(6) a) Kehler, J.; Ritzén, A.; Greve, D. R. The potential
therapeutic use of phosphodiesterase 10 inhibitors. Ex-
pert Opin. Ther. Pat. 2007, 17, 147-158; b) Chappie, T.
A.; Humphrey, J. M.; Allen, M. P.; Estep, K. G.; Fox,
C. B.; Lebel, L. A.; Liras, S.; Marr, E. S.; Menniti, F.
S.; Pandit, J.; Schmidt, C. J.; Tu, M.; Williams, R. D.;
Yang, F. V. Discovery of a Series of 6,7-Dimethoxy-4-
pyrrolidylquinazoline PDE10A Inhibitors. J. Med.
ras, S. Discovery of
a
Novel Class of
Phosphodiesterase 10A Inhibitors and Identification of
Clinical Candidate 2-[4-(1-Methyl-4-pyridin-4-yl-1H-
pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920)
for the Treatment of Schizophrenia. J. Med. Chem.
2009, 52, 5188-5196. b) Kilburn, J. P.; Kehler, J.;
Langgård, M.; Erichsen, M. N.; Leth-Petersen, S.;

Larsen, M.; Christoffersen, C. T.; Nielsen, J. N-
Methylanilide and N-methylbenzamide derivatives as
phosphodiesterase 10A (PDE10A) inhibitors. Bioor-
ganic & Medicinal Chemistry 2013, 21, 6053-6062. c)
Card, G. L.; England, B. P.; Suzuki, Y.; Fong, D.; Pow-
ell, B.; Lee, B.; Luu, C.; Tabrizizad, M.; Gillette, S.; Ib-
rahim, P. N.; Artis, D. R.; Bollag, G.; Milburn, M. V.;
Kim, S. H.; Schlessinger, J.; Zhang, K. Y. J. Structural
Basis for the Activity of Drugs that Inhibit
Phosphodiesterases. Structure 2004, 12, 2233-2247. d)
Manallack, D. T.; Hughes, R. A.; Thompson, P. E. The
Next Generation of Phosphodiesterase Inhibitors:
Structural Clues to Ligand and Substrate Selectivity of
Phosphodiesterases. J. Med. Chem. 2005, 48, 3449-
3462.
K. M. Reductive Cross-Coupling of 3-Bromo-2,1-
borazaronaphthalenes with Alkyl Iodides. Org. Lett.,
2014, 16, 3692-3695. d) Molander, G. A.; Wisniewski,
S. R. Accessing 2,1-Borazaronaphthols: Self-Arylation
of 1-Alkyl-2-aryl-3-bromo-2,1-borazaronaphthalenes.
J. Org. Chem., 2014, 79, 8339-8347. e) Molander, G.
A.; Wisniewski, S. R.; Amani, J. Accessing an
Azaborine Building Block: Synthesis and Substitution
Reactions of 2-Chloromethyl-2,1-borazaronaphthalene.
Org Lett., 2014,16, 5636-5639. f) Molander, G. A.;
Canturk,
B.
Preparation
of
Potassium
Alkoxymethyltrifluoroborates and Their Cross-
Coupling with Aryl Chlorides. Org. Lett., 2008, 10,
2135-2138.
(14) a) Smith, D. A.; Allerton, C.; Kalgutkar, A.; van de
Waterbeemd, H.; Walker, D. K. Role of Lipophilicity in
Drug Clearance. In Pharmacokinetics and Metabolism
in Drug Design, Third Edition. Wiley‐VCH Verlag&
Co., 2012, pp. 87-88. b) Martin, Y. C.; Hansch, C. In-
fluence of Hydrophobic Character on the Relative Rate
of Oxidation of Drugs by Rat Liver Microsomes. J.
Med. Chem., 1971, 14, 777–779.
(9) Dewar, M. J. S.; Jones, R. New Heteroaromatic Com-
pounds. XXVIII.1 Preparation and Properties of 1 0,9-
Borazaronaphthalene2. J. Am. Chem. Soc. 1968, 90,
2137-2144.
(10) a) Paetzold, P.; Stohr, G.; Maisch, H.; Lenz, H.; Die
Reaktion von Borimiden mit Phenylacetylen. Chem.
Ber. 1968, 101, 2881-2888; b) Paetzold, P.; Stanescu,
C.; Stubenrauch, J. R.; Bienmüller, M.; Englert, U. 1-
Azonia-2-boratanaphthalenes. Z. Anorg. Allg. Chem.
2004, 630, 2632-2640.
(15) Dossetter, A. G. A matched molecular pair analysis of
in vitro human microsomal metabolic stability meas-
urements for methylene substitution or replacements –
identification of those transforms more likely to have
beneficial effects. Med. Chem. Commun., 2012, 3,
1518-1525.
(11) Fang, X.; Yang, H.; Kampf, J. W.; Holl, M. M. B.; Ashe
III, A. J. Syntheses of Ring-Fused B-N Heteroaromatic
Compounds. Organometallics 2006, 25, 513-518.
(12) Rudebusch, G. E.; Zakharov, L. N.; Liu, S. Y. Rhodi-
um-Catalyzed Boron Arylation of 1,2-Azaborines.
Angew. Chem. Int. Ed. 2013, 52, 9316-9319.
(13) a) Wisniewski, S. R.; Guenther, C.; Argintaru, O. A.;
Molander, G. A. A Convergent, Modular Approach to
Functionalized 2,1-Borazaronaphthalenes from 2-
Aminostyrenes and Potassium Organotrifluoroborates.
J. Org. Chem. 2014, 79, 365-378. b) Molander, G. A.;
Wisniewski, S. R. Accessing Molecularly Complex
Azaborines: Palladium-Catalyzed Suzuki-Miyaura
Cross-Couplings
of
Brominated
and
2,1-
Borazaronaphthalenes
Potassium
Organotrifluoroborates. J. Org. Chem., 2014, 79, 6663-
6678. c) Molander, G. A.; Wisniewski, S. R.; Traister,

15