Chemical space exploration of oxetanes

Article abstract of DOI:10.3390/ijms21218199

This paper focuses on new derivatives bearing an oxetane group to extend accessible chemical space for further identification of kinase inhibitors. The ability to modulate kinase activity represents an important therapeutic strategy for the treatment of h

Full text of DOI:10.3390/ijms21218199

International Journal of
Molecular Sciences
Article
Chemical Space Exploration of Oxetanes
Fernando Rodrigues de Sá Alves , Rafael M. Couñago 2 and Stefan Laufer 1,3,
1
*
1
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences,
Faculty of Science, Eberhard Karls University of Tübingen, 72074 Tübingen, Germany;
fernandorodriguessalves@gmail.com
2
Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG),
Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia Universidade
Estadual de Campinas (UNICAMP), Campinas 13083-875, SP, Brazil; rafaelcounago@gmail.com
Tübingen Center for Academic Drug Discovery, 72076 Tübingen, Germany
Correspondence: stefan.laufer@uni-tuebingen.de
3
*
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 7 October 2020; Accepted: 28 October 2020; Published: 2 November 2020
Abstract: This paper focuses on new derivatives bearing an oxetane group to extend accessible
chemical space for further identification of kinase inhibitors. The ability to modulate kinase activity
represents an important therapeutic strategy for the treatment of human illnesses. Known as a
nonclassical isoster of the carbonyl group, due to its high polarity and great ability to function as an
acceptor of hydrogen bond, oxetane seems to be an attractive and underexplored structural motif in
medicinal chemistry.
Keywords: oxetane; chemical space; nonclassical isosterism; Buchwald–Hartwig reaction; kinases
1
. Introduction
Oxetane is a four-membered ring having an oxygen atom with an intrinsic ring strain of
−
1
◦
◦
1
06 kJ.mol , which adopts a planar structure with a puckering angle of only 8.7 at 140 K (10.7 at 90 K).
The addition of substituents into the oxetane ring can increment unfavorable eclipsing interactions,
resulting in a more puckered conformation [1].
The strained C
to act as a good hydrogen-bond acceptor as well as donating electron density as a Lewis base. It was
also observed experimentally that oxetanes form more effective H-bonds than other cyclic ethers [ ].
Similarly, oxetanes compete as H-bond acceptors with the majority of carbonyl functional groups like
aliphatic ketones, aldehydes, and esters [ ]. These structural features are important for many of the
beneficial properties of substituted oxetanes.
−
O−
C bond angle exposes the oxygen lone pair of electrons, allowing the oxetane
2
3
Some examples of compounds bearing the oxetane are oxetanocin A, thromboxane A2,
mitrephorone A, oxetine and laureatin, as well as the marketed chemotherapy drugs Taxol and
Taxotere and a new kinase inhibitor GS-9876 (Figure 1).
In medicinal chemistry, an oxetane group is employed not only to change the conformational
preference of the main scaffold but also to influence physicochemical and biochemical properties such
as lipophilicity, aqueous solubility, and metabolic stability [
Zurich have been using oxetanes as surrogates of a carbonyl group in order to generate building
blocks providing new opportunities of molecular diversity [ ]. The group of Professor Bull from
Imperial College London has also been working extensively on the synthesis and new methodologies
for obtaining compounds bearing an oxetane [ 10]. Recently, Blomgren and co-workers have reported
4]. Carreira and co-workers from ETH
5–7
8–
the discovery of a second-generation spleen tyrosine kinase inhibitor, GS-9876 (lanraplenib), which has
human pharmacokinetic properties suitable for once-daily administration and it is used against
autoimmune diseases [11]. Known as a nonclassical isoster of the carbonyl group [12], due to its high
Int. J. Mol. Sci. 2020, 21, 8199; doi:10.3390/ijms21218199
www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2020, 21, 8199
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polarity and great ability to function as an acceptor of hydrogen bond, the oxetane still remains an
underexplored structural motif in drug discovery, especially in the kinase field, in which the oxetane
could bind the “hinge” region (Figure 2). Nevertheless, the conformational variations or the directional
hydrogen bonding differences between sp - and sp -hybridized oxygen atoms could be a benefit or a
2
3
drawback for that type of interaction.
Figure 1. Natural products and marketed drugs containing an oxetane group.
Figure 2. Schematic of the interactions of benzosuberone and oxetane analogs in the hinge region.
2
. Results and Discussion
Our main goal was to synthesize new oxetane derivatives to further extend the therapeutical
kinase space. We proposed the nonclassical isosteric replacement of the carbonyl group of some kinase
inhibitors bearing dibenzosuberone and benzophenone scaffolds by an oxetane moiety (Figure 3).
This substitution could lead to an interaction of the oxetane group with the “hinge” region. All protein
kinases contain a sequence of amino acids comprising the “hinge” between the two lobes of the
catalytic domain. The backbone atoms of the hinge region contain the critical hydrogen bond donor
and acceptor atoms anchoring ATP-binding and allowing phosphorylation of the substrate [13].

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Figure 3. Design of new oxetane derivatives.
3
,3-disubstituted oxetanes can be readily synthesized from 1,3-diols by conversion of the latter
into a halohydrin (or another good leaving group) and then by addition of a strong base to close
the ring through an intramolecular Williamson etherification reaction [14 15]. However, in the case
of 1,3-diols bearing two aryl groups, an 1,4-elimination process namely Grob fragmentation occurs
instead of a cyclization, leading to an alkene [16 18]. Thus, a different approach through a catalytic
functionalization of tertiary alcohols was used in order to obtain 3,3-diphenyloxetane derivatives
Figure 4).
,
–
(
Figure 4. Strategies used to synthesize the oxetane scaffolds.

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The ketones 1a–c reacted with dimethylsulfonium methylide in a Corey–Chaykovsky epoxidation
reaction [19], leading to the epoxide derivatives 2a–c. In the next step, the aldehydes 3a–c were
obtained through a Lewis acid catalyzed epoxide rearrangement by a 1,2-hydride shift, namely Meinwald
rearrangement [20]. Then a crossed Cannizzaro reaction was performed [21], reacting the aldehydes with
formaldehyde in concentrated basic conditions, obtaining the 1,3-diol derivatives 4a–c. For the synthesis
of the oxetanes applying strategy 1, we used the concept of hydroxyl replacement via oxyphosphonium
salts, in which phosphonium salts can also be formed by reaction of different trivalent phosphorus
compounds with oxidizing electrophiles, like the tris(dimethylamino)phosphine-carbon tetrachloride
component system. The produced phosphonium intermediates can be trapped with an alcohol to form
alkoxyphosphonium salts, which can then undergo nucleophilic displacement [22]. Based on the works
of Castro and Selve [23], the dialkyloxetanes 5a–c were obtained in good yields (Scheme 1).
Scheme 1. Reagents and Conditions: (i) (CH ) SI, NaH, DMSO, r.t. (ii) ZnI , benzene, reflux. (iii) CH O,
3
3
2
2
◦
KOH, ethylene glycol, reflux. (iv) 1. TDAP, CCl , THF, −40 C; 2. NaOMe, MeOH, reflux.
4
In the case of (5-chloro-2,3-dihydro-1H-indene-1,1-diyl)dimethanol, as the Corey–Chaykovsky
epoxidation reaction did not work, the 5-chloro-indanone was converted in compound through a
Wittig reaction [24]. Then a Brown hydroboration reaction was carried out followed by oxidation of
the borate, in which the alkene was converted into the primary alcohol , using hydrogen peroxide
in basic conditions [25 26]. The alcohol was then oxidized to the aldehyde using Dess–Martin
6
7
8
,
8
9
periodinane [27] and subsequently converted into the diol 10 and oxetane 11 employing the same
reactions mentioned before (Scheme 2).
◦
◦
Scheme 2. Reagents and Conditions: (i) 1. Ph PMeI, t-BuOK, THF, 0 C; 2. 5-chloro-indanone, 0 C
3
◦
◦
to r.t. (ii) 1. BH , THF, 0 C; 2. NaOH, H O , 0 C—r.t. (iii) Dess–Martin periodinane, CH Cl , r.t.
3
2
2
2
2
◦
(
iv) CH O, KOH, ethylene glycol, reflux. (v) 1. TDAP, CCl , THF, −40 C; 2. NaOMe, MeOH, reflux.
2
4

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The 3,3-diaryloxetane scaffold 14 was synthesized based on the works of Croft and co-workers [28
]
through the catalytic functionalization of a tertiary alcohol to construct a fully substituted carbon
center, using Li as a catalyst in a Friedel–Crafts alkylation reaction [29]. A halogen-metal exchange
reaction of BuLi and compound 12, followed by a nucleophilic addition of the organolithium to the
1
carbonyl group of the oxetan-3-one, gave rise to compound 13. The H NMR spectrum shows two
doublets related to the methylene groups of oxetane, at 4.88 and 4.91 ppm. Additionally, the OH group
could be detected as a broad singlet at 2.92 ppm. Afterwards, the tertiary alcohol 13 was reacted with
phenol, leading to the diaryloxetane 14 in a 60% yield. Compound 14 was then converted into the
triflate derivative 15 in a 62% yield [30] (Scheme 3).
◦
Scheme 3. Reagents and Conditions: (i) n-BuLi, oxetan-3-one, THF,
−
78 C. (ii) Li(NTf ), Bu NPF ,
2
4
6
◦
CHCl , 40 C. (iii) triflic anhydride, pyridine, CH Cl , r.t.
3
2
2
For the last step, the optimal experimental conditions were established for the Buchwald–Hartwig
reaction of the halide scaffolds with arylamines, using a catalyst system composed of Pd(OAc)2,
XPhos and Cs CO , in a methodology adapted from our research group for dibenzosuberone
2
3
derivatives [31]. For the coupling of the aryl triflate with arylamines, a modified method from
Buchwald’s group was employed [32 33], through a catalyst system composed of Pd(OAc) , BINAP and
Cs CO . No formation of phenol was detected. The deprotection of the benzyloxyl group was carried
,
2
2
3
out with Pd/C under H atmosphere at r.t. in a mixture of ethanol/acetonitrile, leading to the final
2
compounds in quantitative yields. The oxetane derivatives were reacted with different arylamines.
The 2,4-difluoroaniline was initially selected, based on previous works of our laboratory, where it had
demonstrated good potency for some kinase inhibitors [34]. Then other modifications were carried out
in the arylamine subunit, selecting both electron-withdrawing and donating groups. Additionally,
aniline was chosen as a non-substituted group to complete the design of new derivatives (Table 1).
In order to identify novel scaffolds for molecular recognition in kinases, we selected some
compounds to be screened in a panel of kinases using the differential scanning fluorimetry (DSF)
method [35,36] at SGC-Unicamp. This technique allows selectivity profiling of any protein kinase
without prior knowledge of either substrate or activity of the kinase under investigation. The most
promising results were obtained for the CAMK1G calcium/calmodulin dependent protein kinase I
gamma and for AAK1 AP2-associated protein kinase 1, as depicted in Figure 5, showing Tm shifts
◦
greater than 2 C. The pankinase inhibitor staurosporine (stauro) served as a positive control in
the assay.
Table 1. N-arylamine oxetanes obtained via Buchwald–Hartwig Reaction.
Entry
1
Halide/Triflate
Product
Yield (%) a
1
6a: W = H
86
73
77
86
1
1
1
6b: W = 2,4-di-F
6c: W = 2-CF3
6d: W = 4-OCH3
1
7a: W = H
92
51
82
82
1
1
1
7b: W = 2,4-di-F
7c: W = 2-CF3
7d: W = 2-OCH3
2

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Table 1. Cont.
Entry
3
Halide/Triflate
Product
Yield (%) a
1
8a: W = H
71
76
95
80
1
1
1
8b: W = 2,4-di-F
8c: W = 2-CF3
8d: W = 2-OCH3
1
9a: W = H
83
71
88
81
1
1
1
9b: W = 2,4-di-F
9c: W = 2-CF3
9d: W = 2-OCH3
4
O
2
2
0a: W = H
0b: W = 2,4-di-F
85
66
71
54
70
5 b
20c: W = 4-CF3
0d: W = 4-OCH3
20e: W = 4-CN
2
HO
N
W
H
a
Isolated yields after purification by column chromatography. b Products obtained after deprotection of benzyl
ether group.
◦ ◦
∆Tm of 5.8 C and 5.2 C at
4-(3-phenyloxetan-3-yl)phenol derivatives 20c and 20e showed a
10 µM, respectively against CAMK1G (Figure 6). These results suggest that electron-withdrawing
groups on the aryl ring are well tolerated, in which the 4-CF and 4-CN analogs showed similar values.
3
However, both an electron-donating group like 4-OCH3 (20d) and the group 2,4-difluoryl (20b) were
detrimental to CAMK1G interaction. Calcium–calmodulin dependent protein kinase I (CaMKI) is
part of a calmodulin-dependent protein kinase cascade and is implicated in various physiological
processes, being expressed in many tissues. CaMKI regulates transcriptional activator activity, the cell
cycle, cell differentiation, actin filament organization and neurite outgrowth [37]. However, the role of
CAMK1G is still mainly unclear.
◦ ◦
Compounds 20c and 19b showed a ∆Tm of 5.2 C and 4.5 C, respectively against AAK1 (Figure 7).
Adaptor-associated kinase 1 (AAK1), a member of Ark1/Prk1 family of serine/threonine kinases,
is involved in the endocytic pathway. Although AAK1 has been mostly related to the regulation
of receptor endocytosis, several studies suggested that AAK1 may be associated to psychiatric and
neurological disorders [38]. Recently, Kostich and co-workers have showed that the inhibition of AAK1
kinase could be a novel therapeutic approach for the treatment of neuropathic pain [39]. The inhibition of
AAK1 also showed to be important as an antivirus strategy, especially against HCV [40,41]. In addition
to these preliminary results, new structural modifications and experiments to measure the K and IC
d
50
will be carried out for a better understanding of the structure-activity relationship.

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Kinases
Compounds
20e 19b
16b
20b
20d
20c
17b
18b stauro DMSO
AAK1
BMP2K
BMX
2.78 2.12 0.11 5.20 2.60 4.54 2.65 1.69 8.13 0.00
0.80 0.29 0.01 1.19 0.47 0.39 0.37 0.28 7.34 0.00
-0.23 -0.36 0.00 0.47 0.23 0.13 0.18 0.56 4.26 0.00
BRAF
0.23 0.23 0.22
0.26 0.15 0.15 0.24 -0.02 0.00
CAMK1D
CAMK1G
CAMKK1
CAMKK2
CDC42BPA
CDK2
CDKL1
CHEK2
CLK1
CSNK1G1
CSNK1G3
CSNK2A1
DYRK1
DYRK2
EPHA2
GAK
-1.49 -1.62 -1.60 -1.41 -1.93 0.41 -0.38 -0.63 3.71 0.00
-0.40 1.24 1.24 5.82 5.23 1.19 1.14 0.94 4.98 0.00
-1.87 -1.69 -2.07 -1.81 -1.93 -1.56
-0.68 5.35 0.00
-0.25 -0.09 -0.22 1.82 0.33 0.56 0.54 0.06 15.90 0.00
0.29 -0.22 -0.20 -0.13 0.26 0.14 0.02 0.14 0.92 0.00
2.20 2.10 2.20 2.53 1.97 1.95 2.21 2.35 6.99 0.00
0.22 0.31 0.26 0.23 0.15 0.62 0.07 0.33 0.93 0.00
-0.06 -0.61 -0.29 0.48 -0.49 -0.26 0.29 0.11 0.87 0.00
0.21 -0.36 -0.30 2.00 -0.10 -0.37 0.01 0.19 6.36 0.00
0.63 0.60 0.74 0.44 0.46 0.37 0.22 0.62 0.23 0.00
-0.38 -0.37 -0.07 -0.07 -0.35 -0.07 0.03 -0.10 0.04 0.00
0.26 0.27 0.24 0.22 0.29 0.31 0.08 0.55 0.26 0.00
-1.06 -1.24 -0.78 -1.59 -1.14 -0.50 -0.41 -0.65 2.20 0.00
0.24 0.35 0.45 0.65 0.22 0.19 0.32 0.34 1.23 0.00
-0.21 -0.14 -0.08 0.40 -0.05 -0.42 -0.39 -0.16 1.79 0.00
-0.99 -1.21 -1.47 -1.51 -1.22 -0.82 -0.30 -0.82 3.68 0.00
0.08 0.12 -0.38 -13.16 -6.62 0.21 -0.33 0.16 4.57 0.00
-0.51 -0.33 -0.66 -0.33 -0.29 -0.46 -0.30 -0.32 -0.21 0.00
-0.13 -0.68 -1.28 -0.38 -0.82 -0.66 -0.26 -0.50 -0.63 0.00
0.50 0.03 -0.53 0.41 -0.28 -0.10 -0.31 0.23 1.14 0.00
0.34 0.94 0.84 1.72 1.37 1.16 1.30 0.76 16.68 0.00
-0.27 -0.72 -1.41 0.24 -0.41 -0.53 -0.86 -0.60 4.67 0.00
-2.48 -2.17 -1.63 -1.46 -1.50 -1.28 -1.01 -1.48 -0.01 0.00
-0.97 -0.41 -0.21 0.28 -0.30 -0.57 -0.56 0.00 0.12 0.00
-1.20 -1.21 -0.46 -1.53 -0.24 -0.39 0.05 -0.91 -0.12 0.00
-0.70 -0.96 -0.85 -2.20 -1.34 0.20 -0.14 -0.70 3.74 0.00
-3.26 -3.90 -1.70 -4.42 0.06 -2.54 -2.60 -2.75 8.94 0.00
GSG2
MAPK1
MAPK14B
MAPK3
PHKG2A
PIM1
PKMYT1A
PRPF4B
RPS6KA1A
RPS6KA5A
RPS6KA6A
SLK
-1.85 -2.98 -1.85 -0.57
-0.55 -0.92 -0.66 -0.97
-2.06 0.09 -1.74 15.03 0.00
-0.12 -0.60 -0.71 2.31 0.00
SRPK1
SRPK2
-0.77 -1.09 -0.79 -1.42 -1.08 -0.41 -0.63 -0.57 0.10 0.00
STK3
STK6
STK10
-0.24 -0.66 -0.65
0.06 0.25 -0.71 0.24
-0.11 -1.19 -0.51
-0.51 0.29 -0.47 0.09 0.67 0.00
-0.24 -0.82 0.01 11.88 0.00
-0.31 0.53 0.20 22.26 0.00
STK38
TRIB2
-0.75 -0.22 -0.26 0.69 0.25 0.53 -0.01 0.03 5.12 0.00
-0.69 -0.74 -3.36 -1.69 -0.89 -0.49 -1.46 -0.98 -0.41 0.00
TTKA
WNK3
VRK1
VRK2
-1.53 -1.12 -1.20
-0.59 -0.31 -0.25 -0.60 -0.42 -0.28 -0.25 -0.97 -0.46 0.00
0.76 -0.20 0.08 0.38 -0.34 0.41 1.43 0.58 0.00
-0.36 -1.32 -1.36 -2.29 1.17 -1.28 -0.75 0.05 0.92 0.00
-0.70 -0.76 -0.06 1.68 0.00
Figure 5. Results obtained from a kinase panel using differential scanning fluorimetry (DSF).

Int. J. Mol. Sci. 2020, 21, 8199
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Figure 6. ∆Tm values obtained for the CAMK1G calcium/calmodulin dependent protein kinase I gamma.
Figure 7. ∆Tm values obtained for the AAK1 AP2-associated protein kinase 1.
3
. Materials and Methods
All commercially available reagents and solvents were used without further purification.
1H and 13C nuclear magnetic resonance (NMR) spectra were determined in DMSO-d , CDCl and
6
3
1
13
Acetone-d solutions using a Bruker Avance 200 ( H = 200 MHz; C = 50 MHz) or a Bruker
6
1
13C = 100 MHz) spectrometer. The chemical shifts are given in parts
Avance 400 ( H = 400 MHz
;
per million (ppm) from solvent residual peaks and the coupling constant values (J) are given in
Hz. Signal multiplicities are represented by: s (singlet), d (doublet), dd (double doublet), t (triplet),
m (multiplet) and br (broad signal). The evaluation of spectra was performed using the MestReNova
program. Infrared spectra were obtained using a Thermo Scientific Nicolet’s Avatar iS10 spectrometer
equipped with a smart endurance diamond ATR unit for direct measurements. ESI mass spectra were
+
obtained from a TLC-MS interface CAMAG in negative mode [M
−
H ]. EI-MS mass spectra were
obtained from the Mass Spectrometry Department of the Institute of Organic Chemistry, University of
Tübingen: Finnigan MAT, TSQ 70 Tripel quadrupol; ion source temperature at 200 C; temperature of
◦
◦
evaporation: 30–300 C; ionization energy: 70 eV. The compounds were purified through column
chromatography, using silica gel as stationary phase (Geduran® Si 60, 0.063–0.200 mm). The purity of
compounds was determined by HPLC (Merck Hitachi L-6200 intelligent pump, Merck Hitachi AS-2000
auto sampler, Merck Hitachi L-4250 UV vis detector) using a ZORBAX Eclipse XDB C8 column (5 mm),
employing a gradient of 0.01 M KH PO (pH 2.3) and methanol as solvent system with a flow rate of
2
4
1
.5 mL/min and detection at 254 nm.
Kinase selectivity assay: Starting from 100
were diluted to 1 M in buffer 100 mM K HPO pH 7.5 containing 150 mM NaCl, 10% glycerol and
X dye (Applied Biosystems catalog 4461806). The protein/dye mixture was transferred column-wise
to a 384-well PCR microplate with 20 L per well. Compounds at 10 mM concentration in DMSO
from a separate plate arranged in rows) were added next, in 20 nL volume, using a liquid handling
device setup with a pin head to make a final 10 M compound in the assay plate. The final DMSO
µM protein stocks, all the kinases present in the panel
µ
2
4
1
µ
(
µ
concentration in all wells is 0.2%, including the reference with DMSO only. Thermal shift data was
measured in a qPCR instrument (Applied Biosystems QuantStudio 6) programmed to equilibrate the
◦
◦
◦
plate at 25 C for 5 min followed by ramping the temperature to 95 C at a rate of 0.05 C per second.
Data was processed on Protein Thermal shift software (Applied Biosystems) fitting experimental
curves to a Boltzmann function to calculate differential thermal shifts (dTm) referenced to protein/dye

Int. J. Mol. Sci. 2020, 21, 8199
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in 0.2% DMSO. The kinases were cloned, expressed (bacteria or insect cell expression) and purified at
the laboratory of SGC.
3
.1. General Procedure A—Corey-Chaykovsky Epoxidation
.0 eq. of NaH (60% dispersion in mineral oil) was placed in a three-necked flask under argon and
4
then DMSO (0.6 M) and the ketone were added, after which 2.25 eq. of trimethylsulfonium iodide was
also added, all at once. The reaction mixture was stirred at ambient temperature. After controlling
through TLC, the mixture was poured over ice and extracted with diethyl ether and ethyl acetate (1:1).
The extracts were combined, washed with brine and afterwards dried over Na SO . The solvent was
2
4
removed under vacuum, and the residue was used without purification for the next step. Adapted from
Winter [19].
0
1
2
-bromo-6,7,8,9-tetrahydrospiro[benzo[7]annulene-5,2 -oxirane](2a): Yellow oil. 95% yield. H-NMR (200 MHz,
CDCl3) in ppm: 1.62–1.80 (m, 2H), 1.80–2.15 (m, 2H), 2.74 (d, 1H, J = 6.0 Hz), 2.82–2.87 (m, 2H),
.98 (d, 1H, J = 6.0 Hz), 7.30 (m, 3H); C-NMR (50 MHz, CDCl3)
21.2, 126.9, 129.1, 131.8, 140.1, 143.3.
δ
13
2
1
δ
in ppm: 27.0, 28.6, 35.9, 36.0, 53.9, 60.8,
0
1
6
-bromo-3,4-dihydro-2H-spiro[naphthalene-1,2 -oxirane] (2b): Yellow solid. 90% yield. H-NMR (200 MHz,
CDCl )
7
1
δ in ppm: 1.75–1.85 (m, 2H), 2.06–2.11 (m, 2H), 2.83–2.87 (m, 2H), 2.97 (s, 2H), 6.92–6.96 (d, 2H),
3
.27–7.29 (s, 1H); 13C-NMR (50 MHz, CDCl3)
31.4, 134.9, 141.7.
δ
in ppm: 21.9, 29.6, 31.7, 56.4, 58.9, 121.5, 125.4, 129.6,
1
2
1
2
-(4-bromophenyl)-2-methyloxirane (2c): Yellow solid. 90% yield. H-NMR (200 MHz, CDCl )
δ
in ppm:
3
.70 (s, 3H), 2.74–2.77 (d, 1H), 2.97–2.99 (d, 1H), 7.22–7.26 (d, J = 8.0 Hz, 2H), 7.44–7.48 (d, J = 8.0 Hz,
H); C-NMR (50 MHz, CDCl ) δ in ppm: 21.7, 56.5, 57.1, 121.6, 127.2, 131.6, 140.4.
13
3
3
.2. General Procedure B—Meinwald Rearrangement
The crude epoxide was dissolved in benzene (0.3 M) and 0.3 eq. of ZnI was added; the reaction
2
mixture was heated at reflux under argon. After controlling through TLC, it was then diluted with
ethyl acetate and washed with water. The organic layer was dried with Na SO , and the solvent
2
4
was evaporated to afford the pure aldehyde, which was used without purification for the next step.
Adapted from Snyder et al. [20].
1
2
-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-carbaldehyde (3a): Brown oil. 98% yield. H-NMR (200 MHz,
CDCl3)
δ in ppm: 1.59–2.25 (m, 6H, CH ), 2.68 (t, 2H, CH ), 3.71 (d, 1H, CH), 6.95 (d, 1H, J = 8.0 Hz),
2 2
7.31 (m, 2H), 9.89 (s, 1H).
1
6
-bromo-1,2,3,4-tetrahydronaphthalene-1-carbaldehyde (3b): Brown oil. 95% yield. H-NMR (200 MHz,
CDCl3)
.30–7.34 (m, 2H), 9.64 (s, 1H); C-NMR (50 MHz, CDCl3)
29.9, 131.3, 132.6, 140.3, 201.4.
δ
in ppm: 1.92 (m, 2H), 2.24 (m, 2H), 2.72–2.78 (t, 2H), 3.58 (t, 1H), 6.99–7.03 (d, 1H),
13
7
1
δ in ppm: 20.2, 22.9, 29.1, 51.3, 121.2, 129.4,
1
2
3
-(4-bromophenyl)propanal(3c): Brownoil. 98%yield. H-NMR(200MHz, CDCl )
δ
inppm: 1.41–1.45(d, 3H),
in ppm:
3
.55–3.66 (q, 1H), 7.06–7.11 (d, 2H), 7.48–7.52 (d, 2H), 9.65 (s, 1H); 1 C-NMR (50 MHz, CDCl3)
3
δ
14.7, 52.5, 121.7, 130.1, 132.3, 136.8, 200.5.
3
.3. General Procedure C—Crossed Cannizzaro Reaction
A mixture of 35% formalin, KOH 50% aqueous solution and the aldehyde in ethylene glycol
0.4 M) was heated at reflux overnight. Water was added to the resulting mixture, and the organic
layer was extracted with CH Cl , washed with brine, and dried over Na SO . After concentration of
(
2
2
2
4
the solution, hexane was added immediately with vigorous stirring, and then the mixture was cooled
◦
to 0 C. White precipitate was collected, washed with hexane, and dried under air to obtain the diol.
Adapted from Sato et al. [21].

Int. J. Mol. Sci. 2020, 21, 8199
10 of 18
(
2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5,5-diyl)dimethanol (4a): White solid. 61% yield.
−1
HPLC: 6.948 min (83%) at 254 nm. IR (ATR): 3276, 2931, 2882, 2855, 1556, 1445 cm . ESI-MS: Calculated:
2
1
7
−
1
84.0 for C H BrO . Found: 283 [M
−
H] . H-NMR (200 MHz, CDCl )
δ
in ppm: 1.26 (s, 2H, CH2),
13
17
2
3
.79 (m, 4H, CH ), 2.31 (s, 2H, CH ), 2.90 (br, 2H), 3.88 (d, 2H, J = 10 Hz), 4.04 (d, 2H, J = 12 Hz),
2
2
13
.27–7.30 (m, 3H); C-NMR (50 MHz, CDCl3) δ in ppm: 23.9, 27.3, 30.9, 35.9, 48.6, 68.5, 120.7, 129.3,
1
29.9, 134.4, 140.2, 144.8.
(
(
6-bromo-1,2,3,4-tetrahydronaphthalene-1,1-diyl)dimethanol (4b): White solid. 45% yield. HPLC: 6.950 min
−
96%). IR (ATR): 3269, 2928, 2868, 2360, 1479 cm . ESI-MS: Calculated: 270.03 for C H BrO .
12 15 2
1
−
H] . H-NMR (200 MHz, CDCl ) δ in ppm: 1.77–1.92 (m, 4H), 1.93 (s, 2H), 2.72–2.78
3
1
Found: 269 [M
(
−
13
t, 2H), 3.71–3.76 (d, 2H, J = 10 Hz), 3.87–3.92 (d, 2H, J = 10 Hz), 7.27 (s, 3H); C-NMR (50 MHz, CDCl3)
δ in ppm: 18.9, 27.7, 30.5, 43.3, 69.7, 120.6, 128.9, 129.2, 132.4, 136.9, 141.2.
(
5-chloro-2,3-dihydro-1H-indene-1,1-diyl)dimethanol (10): White solid. 30% yield. HPLC: 5.580 min (98%).
−1
IR (ATR): 3280, 2933, 2877, 2843, 1451, 1200, 824 cm . ESI-MS: Calculated: 212.0 for C H ClO .
1
1
13
2
−
1
Found: 211 [M
.72–3.87 (q, 4H), 7.12–7.25 (m, 3H); 13C-NMR (50 MHz, CDCl3)
25.4, 126.8, 133.6, 143.2, 146.8.
−
H] . H-NMR (200 MHz, CDCl )
δ
in ppm: 2.04–2.12 (m, 4H), 2.88–2.96 (t, 2H),
3
3
1
δ
in ppm: 30.2, 31.4, 54.2, 68.2, 125.2,
2
-(4-bromophenyl)-2-methylpropane-1,3-diol (4c): White solid. 67% yield. HPLC: 5.280 min (100%).
−
1
ESI-MS: Calculated: 244.01/246.01 for C H BrO . Found: 243/245 [M
CDCl3)
7
−
H] . H-NMR (200 MHz,
in ppm: 1.25 (s, 3H), 2.22 (s, 2H), 3.78–3.83 (d, 2H), 3.91–3.97 (d, 2H), 7.29–7.33 (d, 2H),
10
13
2
δ
.46–7.51 (d, 2H); 13C-NMR (50 MHz, CDCl ) δ in ppm: 20.9, 44.5, 70.0, 120.8, 128.7, 131.8, 142.3.
3
3
.4. General Procedure D—Wittig Reaction
Methyltriphenylphosphonium bromide (1.287 g, 3.601 mmol) was suspended in 15 mL of dry
◦
THF at 0 C. KOtBu (0.404 g, 3.601 mmol) was added to the suspension and a bright yellow color was
◦
observed. The mixture was stirred at 0 C for 30 min. Then 5-chloro-2,3-dihydro-1H-inden-1-one
0.200 g, 1.200 mmol) was added neat and the reaction mixture was stirred at 0 C to r.t. for 4 h
the solution turned green and then dark brown). Water was added to the mixture and the product
◦
(
(
was extracted with CH Cl and dried with Na SO , filtrated and concentrated in vacuum. The residue
2
2
2
4
was purified by column chromatography using n-hexane. Adapted from Liwosz and Chemler [24].
5
-chloro-1-methylene-2,3-dihydro-1H-indene (
7
): Incolor oil. 83% yield. HPLC: 9.720 min (99.4%).
in ppm: 2.77–2.85 (m, 2H), 2.93–3.00 (m, 2H), 5.04–5.07 (t, 1H),
.42–5.44 (t, 1H), 7.15–7.19 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.38–7.42 (d, J = 8.0 Hz, 1H); 13C-NMR (50 MHz,
CDCl ) δ in ppm: 13.1, 37.6, 119.7, 124.1, 126.3, 129.2, 130.7, 139.5, 144.8, 146.1.
1
H-NMR (200 MHz, CDCl )
5
δ
3
3
3
.5. General Procedure E—Brown Hydroboration—Oxidation
A solution of 1.6 g (9.537 mmol) of 5-chloro-1-methylene-2,3-dihydro-1H-indene in 10 mL of THF
was treated with a solution of 19.0 mL of BH -THF complex at ice-bath temperature. The reaction
3
mixture was stirred until disappearance of the alkene. It was then cooled in a water-ice bath,
and carefully treated with methanol followed by addition of 31.8 mL (95.365 mmol) of NaOH 3.0 M
and 25.3 mL (247.959 mmol) of 30% H O . The resulting mixture was stirred at room temperature,
2
2
poured into water, acidified with 10% HCl, and extracted with ether. The organic layer was dried with
Na SO and the solvent was evaporated to afford the pure alcohol after purification by column in silica
2
4
gel (20% EtOAc:n-hexane). Adapted from Zimmerman and Nesterov [26].
5-chloro-2,3-dihydro-1H-inden-1-yl)methanol ( ): Yellow oil. 80% yield. HPLC: 9.720 min (99.4%).
IR (ATR): 3323, 2940, 2866, 1598, 1471, 1067, 870 cm . H-NMR (400 MHz, CDCl3)
(
8
−1
1
δ
in ppm:
1
3
4
.62 (br s, 1H), 1.91–1.98 (sextet, 1H), 2.23–2.32 (sextet, 1H), 2.82–2.99 (m, 2H), 3.27–3.34 (quintet, 1H),
.76–3.77 (d, 2H), 7.13–7.15 (d, 1H), 7.19–7.21 (m, 2H); 13C-NMR (50 MHz, CDCl3)
7.1, 65.9, 125.1, 125.3, 126.5, 132.8, 142.5, 146.8.
δ in ppm: 28.7, 31.4,

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3
.6. General Procedure F—Dess–Martin Reaction
To a solution of 0.470 g (2.573 mmol) of (5-chloro-2,3-dihydro-1H-inden-1-yl)methanol in 20 mL of
CH Cl (0.13 M) 1.6 g (3.860 mmol) of Dess–Martin periodate was added. The reaction was allowed to
2
2
stir at room temperature for 3 h. TLC and HPLC analysis showed formation of the desired product.
The solution was diluted with CH Cl and a 10% Na S O solution to consume the excess Dess–Martin
2
2
2
2
3
reagent was added. The mixture was stirred until the two layers separated. The CH Cl layer was
2
2
collected, washed with saturated Na CO solution and dried with Na SO , filtered and evaporated
2
3
2
4
to give the crude aldehyde, which was used in the next step without purification. Adapted from
Thongsornkleeb and Danheiser [27].
1
5
-chloro-2,3-dihydro-1H-indene-1-carbaldehyde (
9
): Yellow oil. 98% yield. H-NMR (200 MHz, CDCl )
δ
in
3
13
ppm: 2.36–2.45 (m, 2H), 2.95–3.03 (t, 2H), 3.88–3.95 (t, 1H), 7.20 (s, 3H), 9.64 (s, 1H); C-NMR (50 MHz,
CDCl ) δ in ppm: 25.8, 31.7, 57.3, 125.5, 126.0, 127.1, 134.0, 137.0, 146.8, 200.2.
3
3
.7. General Procedure G—Nucleophilic Addition to the Carbonyl Group
Compound was synthesized according to General Procedure H: 2,6 mL (6.513 mmol) of n-BuLi
was added dropwise over 5 min to a solution of 1.71 g (6.513 mmol) of 1-(benzyloxy)-4-bromobenzene
9
◦
◦
in 20 mL of THF at
−
78 C. The reaction mixture was stirred at
−
78 C for a further 30 min.
Then, 0.36 g (5.010 mmol) of oxetan-3-one was added dropwise to the reaction mixture. After a
◦
further 45 min at −78 C the reaction mixture was warmed to room temperature then quenched with
water. The layers were separated and the aqueous portion extracted with diethylether. The organic
extracts were combined, washed with brine, dried over Na SO , filtered and concentrated in vacuum.
2
4
Purification by column chromatography (40% EtOAc:n-hexane) afforded the product. Adapted from
Croft et al. [28].
1
3
-(4-(benzyloxy)phenyl)oxetan-3-ol (13): White solid. 70% yield. HPLC: 6.898 min (98%). H-NMR (400 MHz,
CDCl3)
(
δ
in ppm: 2.92 (br, 1H), 4.86–4.91 (m, 4H), 5.09 (s, 2H), 7.00–7.02 (d, 2H, J = 8.0 Hz), 7.33–7.35
d, 2H, J = 8.0 Hz), 7.38–7.45 (m, 4H), 7.47–7.49 (d,2H, J = 8.0 Hz); 13C-NMR (100 MHz, CDCl3)
δ
in ppm:
70.2, 75.8, 85.7, 115.2, 126.1, 127.6, 128.2, 128.8, 134.9, 136.9, 158.6.
3
.8. General Procedure H—Oxetane Formation via Williamson Etherification
The diol was dissolved in THF (0.1 M) and then 4 eq. of CCl was added. The solution was cooled
4
◦
to
−
48 C and then 1.1 eq. of Tris(dimethylamino)phosphine in 1 mL of THF was added slowly to this
solution during 5 min. The solution turned slightly turbid. The flask was transferred to an ice-bath
and then agitated until it reached room temperature. After controlling using HPLC, the solvent was
evaporated and then methanol was added followed by 4 eq. of a 5.4 M solution of sodium methoxide.
◦
The mixture was refluxed at 90 C during 1 h. The reaction was then diluted with ethyl acetate and
washed with water. The organic layer was dried with Na SO and the solvent was evaporated to
2
4
afford a product after purification by column in silica gel (5% EtOAc: n-hexane). Adapted from
Castro and Selve [23].
0
2
(
-bromo-6,7,8,9-tetrahydrospiro[benzo[7]annulene-5,3 -oxetane] (5a): Yellow oil. 47% yield. HPLC: 8.497 min
+
•
1
93%). EI-MS: Calculated 266.03 for C H BrO. Found: 235.9 [M-CH O] . H-NMR (200 MHz,
13
15
2
CDCl3)
(
δ in ppm: 1.53–1.59 (t, 2H), 1.99–2.01 (t, 2H), 2.12–2.15 (d, 2H), 2.4–2.45 (d, 2H), 4.70–4.73
d, J = 6.0 Hz, 2H), 4.97–5.00 (d, J = 6.0 Hz, 2H), 6.92–6.96 (d, 1H), 7.21–7.33 (m, 2H). 13C-NMR (50 MHz,
CDCl ) δ in ppm: 26.4, 26.9, 34.9, 36.5, 47.9, 80.4, 120.0, 129.2, 132.5, 143.4, 144.4.
3
0
6
(
-bromo-3,4-dihydro-2H-spiro[naphthalene-1,3 -oxetane] (5b): Yellow oil. 48% yield. HPLC: 8.230 min
+
•
1
98%). EI-MS: Calculated 252.01 for C H BrO. Found: 221.9 [M-CH O] . H-NMR (200 MHz,
12
13
2
CDCl3) δ in ppm: 1.65–1.77 (m, 2H), 2.14–2.20 (t, 2H), 2.69–2.75 (t, 2H), 4.62–4.65 (d, J = 6.0 Hz, 2H),
4
.75–4.78 (d, J = 6.0 Hz, 2H), 7.21–7.22 (s, 1H), 7.38–7.43 (d, 1H), 7.77–7.81 (d, 1H). 13C-NMR (50 MHz,
CDCl ) δ in ppm: 20.0, 29.9, 35.3, 42.2, 85.4, 120.4, 128.4, 129.9, 131.7, 138.7, 139.2.
3

Int. J. Mol. Sci. 2020, 21, 8199
12 of 18
0
-chloro-2,3-dihydrospiro[indene-1,3 -oxetane] (11): Yellow oil. 47% yield. HPLC: 7.664 min (97%).
5
+
•
1
EI-MS: Calculated 194.0 for C H ClO. Found: 163.9 [M-CH O] . H-NMR (200 MHz, CDCl )
δ
in
ppm: 2.43–2.50 (t, J = 6.0 Hz, 2H), 2.83–2.90 (t, J = 6.0 Hz, 2H), 4.80 (s, 4H), 7.17 (s, 1H), 7.18–7.29 (d, 1H),
.56–7.60 (d, 1H). 13C-NMR (50 MHz, CDCl3)
in ppm: 30.4, 37.9, 50.9, 84.2, 123.8, 124.8, 127.4, 133.4,
44.7, 145.4.
11
11
2
3
7
1
δ
3
2
4
-(4-bromophenyl)-3-methyloxetane (5c): Yellow solid. 35% yield. HPLC: 7.390 min (98%). EI-MS: Calculated
+•
1
26.00 for C H BrO. Found: 195.9 [M-CH O] . H-NMR (200 MHz, CDCl ) δ in ppm: 1.71 (s, 3H),
1
0
11
2
3
13
.62–4.64 (d, 2H), 4.90–4.93 (d, 2H), 7.07–7.11 (d, J = 8.0 Hz, 2H), 7.46–7.50 (d, J = 8.0 Hz, 2H). C-NMR
(
50 MHz, CDCl ) δ in ppm: 27.7, 43.3, 83.64, 120.3, 127.0, 131.8, 145.6.
3
3
.9. General Procedure I—Oxetane Formation via Friedel-Crafts Reaction
Quantities of 0.008 g (0.028 mmol) of lithium bis(trifluoromethanesulfonimide) and 0.006 g
(
(
0.014 mmol) of tetrabutylammonium hexafluorophosphate were added to a solution of 0.066 g
0.258 mmol) of 3-(4-(benzyloxy)phenyl)oxetan-3-ol and 0.12 g (1.288 mmol) of phenol in 0.5 mL of
◦
chloroform. The reaction mixture was stirred at 40 C for 1 h then quenched with sat. aq. NaHCO .
3
CH Cl2 was added and the layers were separated. The organic extracts were combined,
2
dried over Na SO , filtered and concentrated in vacuum. Purification by column chromatography
2
4
(30% EtOAc:n-hexane) afforded the oxetane. Adapted from Croft et al. [28].
4
-(3-(4-(benzyloxy)phenyl)oxetan-3-yl)phenol (14): White solid. 60% yield. HPLC: 8.286 min (93%).
−
H] . H-NMR (200 MHz, CDCl ) δ in
3
1
ESI-MS: Calculated: 332.14 for C H O . Found: 331.1 [M
−
22
20
3
ppm: 5.06 (s, 2H), 5.21 (s, 4H), 6.78–6.82 (d, J = 8.0 Hz, 2H), 6.94–6.98 (d, J = 8.0 Hz, 2H), 7.05–7.15
m, 4H), 7.36–7.42 (m, 5H); 13C-NMR (50 MHz, CDCl3)
in ppm: 50.5, 70.2, 85.2, 114.9, 115.5, 127.6,
27.8, 127.9, 128.2, 128.8, 137.1, 138.3, 138.5, 154.4, 157.6.
(
1
δ
3
.10. General Procedure J—Triflate Formation
First, 0.2 mL (2.708 mmol) of pyridine, then 0.3 mL (2.031 mmol) of triflic anhydride were added
to a solution of 4-(3-(4-(benzyloxy)phenyl)oxetan-3-yl)phenol in 3.0 mL of CH Cl . The reaction
2
2
mixture was stirred at room temperature. After controlling through TLC and HPLC, the work-up
was done adding water followed by CH Cl . The layers were separated and the aqueous portion
2
2
was extracted with CH Cl . The organic extracts were combined, dried over Na SO , filtered and
2
2
2
4
concentrated in vacuum. Purification by column chromatography (20% EtOAc:n-hexane) afforded the
triflate. Adapted from Thompson et al. [30].
4
-(3-(4-(benzyloxy)phenyl)oxetan-3-yl)phenyl trifluoromethanesulfonate (15): White solid. 90% yield.
−
HPLC: 10.332 min (100%). ESI-MS: Calculated: 464.09 for C H F O S. Found: 463.0 [M
−
H] .
23
19
3
5
1
H-NMR (200 MHz, CDCl3)
δ in ppm: 5.06 (s, 2H), 5.21 (s, 4H), 6.78–6.82 (d, J = 8.0 Hz, 2H), 6.94–6.98
(d, J = 8.0 Hz, 2H),7.05–7.15 (m, 4H), 7.36–7.42 (m, 5H).
3
.11. General Procedure K—Buchwald-Hartwig Reaction via Halides
A mixture of 1.0 eq. of aryl halide, 1.0 eq. of amine, 3.0 eq. of Cs CO as the base, 0.5 eq. of X-Phos
2
3
as the ligand and 0.1 eq. of Pd(OAc) as the catalyst in dry 1,4-dioxane and absolute tert-butanol (4:1)
2
(
0.05 M) was stirred at reflux under atmosphere of argon. After controlling through TLC and HPLC,
the mixture was allowed to cool to room temperature. It was diluted with water and subsequently
extracted with ethyl acetate. The extracts were combined, washed with brine and afterwards dried
over Na SO . The solvent was removed under vacuum, and the residue was purified by column
2
4
chromatography, affording the desired product. Adapted from Martz et al. [31].
0
N-phenyl-6,7,8,9-tetrahydrospiro[benzo[7]annulene-5,3 -oxetan]-2-amine (16a): Brown solid. 86% yield.
−
1
HPLC: 9.015 min (96%). ESI-MS: Calculated: 279.1 for C H NO. Found: 278.0 [M
400 MHz, CDCl3) δ in ppm: 1.59 (m, 2H, CH ), 2.01 (m, 2H, CH ), 2.18 (t, 2H, J = 8.0 Hz, CH ),
−
H] . H-NMR
19
21
(
2
2
2

Int. J. Mol. Sci. 2020, 21, 8199
13 of 18
2
7
3
.42 (t, 2H, J = 8.0 Hz, CH ), 4.73 (d, 2H), 5.04 (d, 2H), 5.78 (br, 1H), 6.82 (s, 1H), 6.91–7.00 (m, 3H),
.08 (d, 2H, J = 8.0 Hz),7.27 (t, 2H, J = 8.0 Hz); C-NMR (100 MHz, CDCl3) δ in ppm: 26.5, 27.3, 35.5,
7.1, 47.7, 80.7, 115.1, 117.9, 119.4, 121.0,126.2, 129.5, 137.1, 141.8, 143.4.
2
13
0
N-(2,4-difluorophenyl)-6,7,8,9-tetrahydrospiro[benzo[7]annulene-5,3 -oxetan]-2-amine (16b): Brown solid.
−
7
3% yield. HPLC: 8.542 min (98%). ESI-MS: Calculated: 315.1 for C H F NO. Found: 314.2 [M − H]
.
19
19 2
1
H-NMR (400 MHz, CDCl3) δ in ppm: 1.49 (m, 2H), 1.91 (m, 2H), 2.08 (t, 2H), 2.31 (t, 2H), 4.63–4.64
(
d, 2H, J = 4.0 Hz), 4.93–4.94 (d, 2H, J = 4.0 Hz), 5.46 (br, 1H), 6.66 (s, 1H), 6.70–6.82 (m, 3H), 6.89 (d, 1H,
J = 8.0 Hz), 7.18 (s, 1H); 13C-NMR (100 MHz, CDCl3)
in ppm: 26.5, 27.3, 37.1, 47.7, 80.7, 104.1
dd, J = 23.6 Hz, J = 23.7 Hz), 110.9 (dd, J = 3.64 Hz, J = 3.71 Hz), 114.9, 119.3, 119.5 (dd, J = 2.28 Hz,
δ
(
1
2
1
2
1
J = 3.17 Hz), 126.4, 127.9 (dd, J = 2.35 Hz, J = 2.36 Hz), 137.6, 141.4, 143.6.
2
1
2
0
N-(2-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydrospiro[benzo[7]annulene-5,3 -oxetan]-2-amine(16c): Yellow solid.
−
7
7% yield. HPLC: 10.008 min (96%). ESI-MS: Calculated: 347.1 for C H F NO. Found: 346.1 [M
−
H] .
20
20 3
1
H-NMR (400 MHz, CDCl3)
δ
in ppm: 1.58 (m, 2H), 1.99 (m, 2H), 2.17 (t, 2H), 2.42 (t, 2H), 4.73 (d, 2H)
,
5
7
.02 (d, 2H), 6.02 (br, 1H), 6.84 (s, 1H), 6.90–6.96 (m, 2H), 7.01 (d, 1H, J = 8.0 Hz), 7.32–7.39 (m, 2H),
13
.54 (d, 1H, J = 8.0 Hz)
;
C-NMR (100 MHz, CDCl3) δ in ppm: 26.5, 27.2, 35.4, 36.9, 47.8, 80.7, 117.2, 117.5,
117.7 (d, J = 10.6 Hz), 119.6, 122.0, 123.6, 126.4, 127.0 (dd, J = 5.5 Hz, J = 5.4 Hz), 132.8, 139.0, 140.1,
1 2
142.5, 143.7.
0
N-(4-methoxyphenyl)-6,7,8,9-tetrahydrospiro[benzo[7]annulene-5,3 -oxetan]-2-amine (16d): Yellow solid.
−
8
6% yield. HPLC: 7.976 min (98%). ESI-MS: Calculated: 309.1 for C H NO . Found: 308.0 [M − H]
.
20
23
2
1
H-NMR (200 MHz, CDCl3)
δ
in ppm: 1.58 (m, 2H), 1.98 (m, 2H), 2.17 (t, 2H), 2.43 (t, 2H), 3.80 (s, 3H),
4
7
.67 (d, 2H, J = 6.0 Hz), 4.99 (d, 2H, J = 6.0 Hz), 5.45 (br, 1H), 6.63–6.74 (m, 3H), 6.84–6.93 (m, 3H),
13
.04 (t, 2H)
;
C-NMR (100 MHz, CDCl3)
δ
in ppm: 26.6, 27.3, 35.6, 37.2, 47.9, 55.7, 112.8, 114.8, 117.3,
1
22.2, 126.2, 135.6, 136.0, 143.3, 143.9, 155.4.
0
N-phenyl-3,4-dihydro-2H-spiro[naphthalene-1,3 -oxetan]-6-amine (17a): Brown solid. 92% yield. HPLC:
−
1
7
.967 min (97%). ESI-MS: Calculated: 265.1 for C H NO. Found: 264.0 [M
−
H] . H-NMR (200 MHz,
18
19
CDCl3)
δ in ppm: 1.75–1.84 (m, 2H), 2.24 (t, 2H, J = 6.0 Hz), 2.75 (t, 2H, J = 6.0 Hz), 4.66 (d, 2H,
J = 6.0 Hz), 4.87 (d, 2H, J = 6.0 Hz), 6.84 (s, 1H), 6.94–7.10 (m, 4H), 7.33 (t, 2H), 7.83 (d, 2H, J = 8.0 Hz);
1
3
C-NMR (50 MHz, CDCl3)
32.1, 138.1, 141.7, 143.2.
δ
in ppm: 20.3, 30.4, 35.9, 42.1, 85.8, 116.8, 117.4, 117.9, 121.1, 127.7, 129.5,
1
0
N-(2,4-difluorophenyl)-3,4-dihydro-2H-spiro[naphthalene-1,3 -oxetan]-6-amine(17b): Brown solid. 51% yield.
−
1
HPLC: 8.586 min (98%). ESI-MS: Calculated: 301.1 for C H F NO. Found: 299.9 [M
−
H] . H-NMR
1
8
17 2
(
200 MHz, CDCl3)
J = 6.0 Hz), 4.80 (d, 2H, J = 6.0 Hz), 6.70–6.99 (m, 4H), 7.19–7.31 (m, 1H), 7.79 (d, 2H, J = 10 Hz); C-NMR
50 MHz, CDCl3) in ppm: 20.3, 30.4, 35.8, 42.1, 85.8, 103.9 (dd, J = 23.5 Hz, J = 23.5 Hz), 110.8 (dd,
J1 = 3.76 Hz, J = 3.79 Hz), 116.5, 117.3, 119.6 (dd, J = 3.22 Hz, J = 3.30 Hz), 127.9, 132.7, 138.3, 141.3,
δ in ppm: 1.70–1.79 (m, 2H), 2.19 (t, 2H, J = 6.0 Hz), 2.70 (t, 2H, J = 6.0 Hz), 4.61 (d, 2H,
13
(
δ
1
2
2
1
2
151.0 (d, J = 11.8 Hz), 154.5 (d, J = 11.1 Hz), 155.9 (d, J = 11.8 Hz), 159.3 (d, J = 11.3 Hz).
0
N-(2-(trifluoromethyl)phenyl)-3,4-dihydro-2H-spiro[naphthalene-1,3 -oxetan]-6-amine (17c): White solid.
−
8
2% yield. HPLC: 9.943 min (98%). ESI-MS: Calculated: 333.1 for C H F NO. Found: 332.2 [M − H]
.
19
18 3
1
H-NMR (200 MHz, CDCl3)
δ in ppm: 1.71–1.74 (m, 2H), 2.20 (t, 2H, J = 6.0 Hz), 2.72 (t, 2H, J = 6.0 Hz),
4
.63 (d, 2H, J = 6.0 Hz), 4.82 (d, 2H, J = 6.0 Hz), 6.03 (br, 1H), 6.83 (s, 1H), 6.94 (t, 1H, J = 8.0 Hz), 7.06 (d, 1H,
13
J = 8.0 Hz), 7.32–7.43 (m, 2H), 7.54 (d, 1H, J = 8.0 Hz), 7.84 (d, 1H, J = 8.0 Hz); C-NMR (50 MHz,
CDCl3) in ppm: 20.3, 30.3, 35.8, 42.2, 85.8, 117.3, 117.9, 118.0, 118.9, 119.8, 120.1, 126.9 (dd, J = 5.5 Hz,
J2 = 5.5 Hz), 127.9, 132.7, 134.1, 138.3, 140.1, 142.2.
δ
1
0
N-(2-methoxyphenyl)-3,4-dihydro-2H-spiro[naphthalene-1,3 -oxetan]-6-amine (17d): Yellow solid. 82% yield.
−
1
HPLC: 9.221 min (95%). ESI-MS: Calculated: 295.1 for C H NO . Found: 294.4 [M
−
H] . H-NMR
in ppm: 1.72–1.83 (m, 2H), 2.24 (t, 2H, J = 6.0 Hz), 2.76 (t, 2H, J = 6.0 Hz), 3.93 (s,
H), 4.66 (d, 2H, J = 6.0 Hz), 4.87 (d, 2H, J = 6.0 Hz), 6.92 (m, 4H), 7.13 (d, 1H), 7.32 (m, 1H), 7.84 (d, 1H,
19
21
2
(
200 MHz, CDCl3) δ
3

Int. J. Mol. Sci. 2020, 21, 8199
14 of 18
J = 8.0 Hz); 13C-NMR (50 MHz, CDCl3)
δ
in ppm: 20.4, 30.4, 35.9, 42.1, 55.7, 85.8, 110.7, 114.9, 117.5,
1
18.2, 120.0, 120.9, 127.7, 132.3, 133.0, 138.0, 141.3, 148.4.
0
N-phenyl-2,3-dihydrospiro[indene-1,3 -oxetan]-5-amine (18a): Brown solid. 71% yield. HPLC: 8.231 min
−
H] . H-NMR (200 MHz, CDCl )
3
1
(
95%). ESI-MS: Calculated: 251.1 for C H NO. Found: 250.1 [M
−
17
17
δ
5
8
in ppm: 2.52 (t, 2H, J = 8.0 Hz), 2.89 (d, 2H, J = 8.0 Hz), 4.83–4.92 (m, 4H), 5.82 (br, 1H), 6.94–7.12 (m,
H), 7.28–7.36 (m, 2H), 7.57 (d, 2H, J = 8.0 Hz); 13C-NMR (50 MHz, CDCl3)
δ in ppm: 30.6, 38.4, 50.9,
4.6, 113.8, 117.4, 177.9, 121.1, 123.6, 129.5, 138.8, 143.0, 143.5, 144.9.
0
N-(2,4-difluorophenyl)-2,3-dihydrospiro[indene-1,3 -oxetan]-5-amine (18b): Brown solid. 76% yield. HPLC:
−
1
8
.670 min (100%). ESI-MS: Calculated: 287.1 for C H F NO. Found: 286.1 [M
−
H] . H-NMR
in ppm: 2.47 (t, 2H, J = 6.0 Hz), 2.89 (d, 2H, J = 6.0 Hz), 4.79–4.87 (m, 4H), 6.76–6.98
m, 4H), 7.17–7.29 (m, 1H), 7.53 (d, 2H, J = 8.0 Hz); 13C-NMR (100 MHz, CDCl3)
in ppm: 30.6,
8.3, 50.9, 84.6, 103.9, 104.4 (J = 2.87 Hz), 110.8 (J = 3.83, J = 3.97 Hz), 113.6, 117.3, 119.6 (J = 2.86,
17
15 2
(
200 MHz, CDCl3) δ
(
δ
3
1
2
1
J2 = 3.34 Hz), 123.7, 139.3, 142.7, 145.1.
0
N-(2-(trifluoromethyl)phenyl)-2,3-dihydrospiro[indene-1,3 -oxetan]-5-amine (18c): White solid. 95% yield.
−
1
HPLC: 9.588 min (100%). ESI-MS: Calculated: 319.1 for C H F NO. Found: 318.1 [M
200 MHz, CDCl3) δ in ppm: 2.49 (t, 2H, J = 8.0 Hz), 2.86 (d, 2H, J = 8.0 Hz), 4.80–4.88 (m, 4H), 6.06 (br,
H), 6.90–6.97 (m, 2H), 7.04 (d, 2H, J = 8.0 Hz), 7.29–7.41 (m, 2H), 7.58 (t, 2H, J = 8.0 Hz); C-NMR
−
H] . H-NMR
18
16 3
(
13
1
(50 MHz, CDCl3)
δ
in ppm: 30.6, 38.2, 50.9, 84.5, 116.5, 117.9, 119.8, 123.7, 127.1, 132.8, 140.7, 141.4,
1
42.5, 145.1.
0
N-(2-methoxyphenyl)-2,3-dihydrospiro[indene-1,3 -oxetan]-5-amine (18d): Yellow solid. 80% yield. HPLC:
−
1
8
.718 min (98%). ESI-MS: Calculated: 281.1 for C H NO . Found: 280.1 [M
−
H] . H-NMR
in ppm: 2.48 (t, 2H, J = 8.0 Hz), 2.86 (d, 2H, J = 8.0 Hz), 3.89 (s, 3H), 4.79–4.89 (m,
H), 6.15 (br, 1H), 6.85–6.91 (m, 3H), 7.02 (s, 1H), 7.07 (d, 1H), 7.28 (m, 1H), 7.54 (d, 2H, J = 8.0 Hz);
18
19
2
(
200 MHz, CDCl3) δ
4
13
C-NMR (50 MHz, CDCl3) δ in ppm: 30.6, 38.4, 50.9, 55.7, 84.6, 110.6, 114.5, 114.8, 118.1, 119.9, 120.9,
1
23.5, 133.3, 138.9, 142.6, 144.8, 148.3.
4
-(3-methyloxetan-3-yl)-N-phenylaniline (19a): Brown solid. 83% yield. HPLC: 7.967 min (96%). ESI-MS:
−
H] . H-NMR (400 MHz, CDCl ) δ in ppm: 1.75 (s,
3
1
Calculated: 239.1 for C H NO. Found: 238.0 [M
3
−
1
6
17
H, CH ), 4.65–4.66 (d, 2H, J = 4.0 Hz, CH ), 4.98–4.99 (d, 2H, J = 4.0 Hz, CH ), 5.76 (br, 1H), 6.94–6.97
3 2 2
13
(
(
t, 1H, J = 8.0 Hz), 7.08–7.11 (m, 4H), 7.16–7.18 (d, 2H, J = 8.0 Hz), 7.28–7.36 (t, 2H, J = 8.0 Hz); C-NMR
100 MHz, CDCl ) δ in ppm: 27.7, 43.0, 84.2, 117.8, 118.2, 121.1, 126.2, 129.5, 139.1, 141.6, 143.4.
3
2
,4-difluoro-N-(4-(3-methyloxetan-3-yl)phenyl)aniline (19b): Brown solid. 71% yield. HPLC: 7.689 min
−
1
(100%). ESI-MS: Calculated: 275.1 for C H F NO. Found: 274.0 [M
−
H] . H-NMR (200 MHz,
δ in ppm: 1.73 (s, 3H), 4.62 (d, 2H, J = 6.0 Hz), 4.94 (d, 2H, J = 6.0 Hz), 6.75–6.95 (m, 2H),
16
15 2
CDCl3)
6
13
.99 (d, 2H, J = 10 Hz), 7.14 (d, 2H, J = 8.0 Hz), 7.23–7.28 (d, 1H); C-NMR (50 MHz, CDCl3)
δ in ppm:
2
7.7, 42.9, 84.1, 103.9 (dd, J = 23.5 Hz, J = 23.5 Hz), 110.8 (dd, J = 3.8 Hz, J = 3.8 Hz), 117.9, 119.3 (dd,
1
2
1
2
J = 3.4 Hz, J = 3.3 Hz), 126.3, 127.8 (dd, J = 3.4 Hz, J = 3.1 Hz), 139.6, 141.2, 150.9 (d, J = 11.9 Hz),
1
2
1
2
1
54.5 (d, J = 11.1 Hz), 155.8 (d, J = 11.7 Hz), 159.3 (d, J = 11.1 Hz).
N-(4-(3-methyloxetan-3-yl)phenyl)-2-(trifluoromethyl)aniline (19c): White solid. 88% yield. HPLC:
−
1
9
.306 min (100%). ESI-MS: Calculated: 307.1 for C H F NO. Found: 306.0 [M
−
H] . H-NMR
17
16 3
(400 MHz, CDCl3)
δ in ppm: 1.78 (s, 3H, CH ), 4.67–4.70 (d, 2H, J = 6.0 Hz, CH ), 4.99–5.02 (d, 2H,
3
2
J = 6.0 Hz, CH ), 6.10 (br, 1H), 6.94–7.02 (t, 1H, J = 8.0 Hz), 7.13–7.25 (q, 4H), 7.30–7.41 (m, 2H), 7.59–7.63
2
(
d, 2H, J = 8.0 Hz); 13C-NMR (100 MHz, CDCl3)
δ in ppm: 27.7, 43.1, 84.0, 114.3, 117.7, 119.8, 120.7,
1
26.4, 127.1, 132.8, 140.0, 140.7, 141.1, 142.4.
2
-methoxy-N-(4-(3-methyloxetan-3-yl)phenyl)aniline (19d): Yellow solid. 81% yield. HPLC: 8.251 min
1
(98%). EI-MS: Calculated: 269.1 for C H NO . Found: 269.1. H-NMR (400 MHz, CDCl )
δ
in ppm:
17
19
2
3
1
.73 (s, 3H, CH ), 3.90 (s, 3H, OCH ), 4.62–4.64 (d, 2H, J = 8.0 Hz, CH ), 4.96–4.97 (d, 2H, J = 4.0 Hz,
3 3 2

Int. J. Mol. Sci. 2020, 21, 8199
15 of 18
CH ), 6.85–6.90 (m, 3H), 7.15 (s, 4H), 7.27–7.29 (d, 1H); 13C-NMR (100 MHz, CDCl3)
δ
in ppm: 27.7,
2
4
3.0, 55.7, 84.2, 110.7, 114.7, 118.9, 120.0, 120.9, 126.1, 133.2, 139.2, 141.2, 148.4.
3
.12. General Procedure L—Buchwald–Hartwig Reaction via Triflates—Benzyl Ether Deprotection
A mixture of aryl triflate, amine, Cs CO as the base, BINAP as the ligand and Pd(OAc) as
2
3
2
◦
the catalyst in dry 1,4-dioxane and absolute tert-butanol (4:1) (0.03 M) was stirred at 110 C under
an atmosphere of argon. After controlling through TLC and HPLC, the mixture was allowed to
cool to room temperature. It was diluted with water and subsequently extracted with ethyl acetate.
The extracts were combined, washed with brine and afterwards dried over Na SO . The solvent was
2
4
removed under vacuum, and the residue was purified by column chromatography, affording the
product. Adapted from Åhman and Buchwald [33].
Then the benzyl ether deprotection was performed as follows: 0.6 eq. of palladium on carbon
(
10% w/w) was added to a solution of oxetane in ethanol/acetonitrile. The reaction mixture was
◦
stirred under an atmosphere of hydrogen at 25 C until HPLC analysis indicated the end of reaction.
The reaction mixture was filtered through celite, washed through with ethanol and then concentrated
in vacuum to afford the final oxetane. Adapted from Croft et al. [28].
4
-(3-(4-(phenylamino)phenyl)oxetan-3-yl)phenol (20a): White solid. 85% yield. HPLC: 7.618 min (96%).
−
1
ESI-MS: Calculated: 317.1 for C H NO . Found: 316.2 [M
δ
−
H] . H-NMR (400 MHz, d-acetone)
21
19
2
13
in ppm: 5.13 (s, 4H), 6.82–6.85 (t, 3H), 7.10–7.17 (m, 8H), 7.20–7.24 (t, 2H), 7.41 (br, 1H); C-NMR
(
100 MHz, d-acetone) in ppm: 51.3, 84.9, 116.1, 117.9, 118.1, 120.9, 128.0, 129.9, 138.5, 139.5, 142.9,
δ
1
44.7, 156.7.
4
-(3-(4-((2,4-difluorophenyl)amino)phenyl)oxetan-3-yl)phenol (20b): Brown solid. 66% yield. HPLC:
−
1
7
.930 min (98%). ESI-MS: Calculated: 353.1 for C H F NO . Found: 352.0 [M
−
H] . H-NMR
in ppm: 5.12 (s, 4H), 6.81–6.83 (d, 2H, J = 8.0 Hz), 6.90–6.95 (t, 1H), 7.0–7.02
d, 2H, J = 8.0 Hz), 7.11–7.13 (d, 2H, J = 8.0 Hz), 7.15–7.17 (d, 2H, J = 8.0 Hz), 7.32–7.38 (m, 1H),
.29 (br, 1H); 13C-NMR (100 MHz, d-acetone)
in ppm: 51.6, 85.0, 104.9, 105.1 (d, J = 3.0 Hz), 105.4,
21
17
2
2
(
(
400 MHz, d-acetone) δ
8
δ
1
1
11.9 (d, J = 4.0 Hz), 112.1 (d, J = 4.0 Hz), 116.3, 117.9, 122.1 (d, J = 3.0 Hz), 122.2 (d, J = 3.0 Hz), 128.3,
28.5, 138.7, 140.0, 143.3, 156.9.
4
7
-(3-(4-((4-(trifluoromethyl)phenyl)amino)phenyl)oxetan-3-yl)phenol (20c): White solid. 71% yield. HPLC:
−
1
.967 min (96%). ESI-MS: Calculated: 385.1 for C H F NO . Found: 383.9 [M
−
H] . H-NMR
22
18
3
2
(
(
200 MHz, d-acetone)
d, 2H, J = 8.0 Hz), 7.93 (br, 1H), 8.34 (br, 1H); C-NMR (50 MHz, d-acetone)
δ in ppm: 5.15 (s, 4H), 6.82–6.86 (d, 2H, J = 8.0 Hz), 7.11–7.29 (m, 8H), 7.49–7.53
13
δ
in ppm: 51.5, 84.8, 115.7,
1
16.1, 120.5, 121.0, 127.3, 127.4, 128.2, 128.4, 138.3, 140.9, 141.8, 148.8, 156.8.
4
7
-(3-(4-((4-methoxyphenyl)amino)phenyl)oxetan-3-yl)phenol (20d): Yellow solid. 54% yield. HPLC:
−
1
.159 min (99%). ESI-MS: Calculated: 347.1 for C H NO . Found: 345.9 [M
−
H] . H-NMR
in ppm: 3.75 (s, 3H), 5.11 (s, 4H), 6.80–6.89 (t, 4H), 6.93–6.97 (d, 2H, J = 8.0 Hz),
.07–7.13 (m, 7H); 13C-NMR (100 MHz, d-acetone)
in ppm: 27.7, 43.0, 84.2, 117.8, 118.2, 121.1, 126.2,
22
21
3
(
400 MHz, d-acetone) δ
7
δ
1
29.5, 139.1, 141.6, 143.4.
4
6
-((4-(3-(4-hydroxyphenyl)oxetan-3-yl)phenyl)amino)benzonitrile (20e): Yellow solid. 70% yield. HPLC:
−
1
.883 min (96%). ESI-MS: Calculated: 342.1 for C H N O . Found: 341.1 [M
−
H] . H-NMR
in ppm: 5.15 (s, 4H), 6.81–6.86 (d, 2H, J = 10 Hz), 7.11–7.16 (d, 2H, J = 10 Hz),
.20–7.31 (dd, 4H, J = 10 Hz, J = 8.0 Hz), 7.52–7.56 (d, 2H, J = 8.0 Hz), 8.12 (br, 1H), 8.32 (br, 1H);
22
18
2
2
(200 MHz, d-acetone) δ
7
13
C-NMR (50 MHz, d-acetone) δ in ppm: 51.6, 84.8, 101.5, 115.7, 116.2, 120.4, 121.5, 128.4, 128.5, 134.5,
1
38.3, 140.1, 142.7, 149.7, 156.9.
4
. Conclusions
We successfully synthesized the spiro and the methyl-phenyl oxetane scaffolds in good and
reproducible yields. The hydroxyl replacement via oxyphosphonium salts proved to be a winning

Int. J. Mol. Sci. 2020, 21, 8199
16 of 18
strategy for the synthesis of oxetanes from the aryl-alkyl diols through a cyclization reaction.
Additionally, the reaction of phenol with a functionalized oxetan-3-ol was pivotal to obtain the
3,3-diaryloxetanes. Five scaffolds and novel compounds possessing different electronic properties
were synthesized using the Buchwald–Hartwig reaction, which worked well for all halides and
triflate derivatives.
We succeeded in finding three new hits against the CAMK1G and AAK1 through a screening in
a kinase panel using the DSF method. The results indicate that it is possible to explore compounds
bearing the oxetane motif in medicinal chemistry, aiming at the discovery of novel kinase inhibitor
prototypes. However, some results demonstrated that the oxetane group is probably not interacting in
the hinge region, which could be associated to conformational variations or to directional hydrogen
bonding differences between sp - and sp -hybridized oxygen atoms.
2
3
As a perspective, new experiments could be carried out to determine the K and IC50 of the hit
d
compounds. Furthermore, it is also possible to extensively expand the chemical space of oxetanes
using other palladium-catalyzed coupling reactions, such as Sonogashira, Suzuki and Heck.
In addition to these preliminary results, new structural modifications and experiments to measure
the K and IC will be carried out for a better understanding of the structure-activity relationship.
d
50
Author Contributions: Conceptualization, F.R.d.S.A. and S.L.; methodology, F.R.d.S.A. and R.M.C.;
writing—original draft preparation, F.R.d.S.A. and S.L. All authors have read and agreed to the published
version of the manuscript.
Funding: This research was funded by the Brazilian agencies FAPESP (Fundaç
de S o Paulo) (2013/50724-5 and 2014/50897-0) and CNPq (Conselho Nacional de Desenvolvimento Cient
Tecnológico) (465651/2014-3) and the University of Tübingen.
ã
o de Amparo
à
Pesquisa do Estado
ã
í
fico e
Acknowledgments: The present work was possible with financial support of the Brazilian National Council for
Scientific and Technological Development (CNPq) and of the University of Tübingen. The authors also thank
Gerd Helms for some NMR experiments and Paulo Godoi for the Kinase experiments at the Structural Genomics
Consortium—SGC (Campinas, Brazil). The authors thank Kristine Schmidt for proof-reading (language) of
the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
TDAP
ATP
BINAP
Tris(dimethylamino)phosphine
Adenosine triphosphate
2,2 -bis(diphenylphosphino)-1,1 -binaphthyl
Tetrabutylammonium hexafluorophosphate
Trimethylsulfonium iodide
0
0
Bu NPF
4
6
(
CH ) SI
3 3
Li(NTf2)
Lithium bis(trifluoromethanesulfonimide)
Methyltriphenylphosphonium iodide
0 0 0
2-Dicyclohexylphosphino-2 ,4 ,6 -triisopropylbiphenyl
Ph PMeI
3
XPhos
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