New short strategy for the snthesis of the dibenz[b,f]oxepins scaffold

Article abstract of DOI:10.3390/molecules181214797

In this report a short and efficient synthesis of the dibenz[b,f]oxepin framework through intramolecular SNAr and McMurry reactions is described. The diaryl ethers required for the McMurry reaction have been obtained in good yields under microwave-assisted conditions of the reaction of salicylaldehydes with fluorobenzaldehydes without catalysts. Application of an intramolecular McMurry reaction to the synthesized diarylethers using TiCl4/Zn in THF gave the target dibenzo[b,f]oxepin system in 53%-55% yields.

Full text of DOI:10.3390/molecules181214797

Molecules 2013, 18, 14797-14806; doi:10.3390/molecules181214797
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
New Short Strategy for the Synthesis of the
Dibenz[b,f]oxepin Scaffold
David R. R. Moreno 1, Giorgio Giorgi 2, Cristian O. Salas 1 and Ricardo A. Tapia 1,*
1
Departamento de Química Orgánica, Facultad de Química, Pontificia Universidad Católica de
Chile, Santiago 7820436, Chile; E-Mails: drmoreno@uc.cl (D.R.R.M.); cosalas@uc.cl (C.O.S.)
2
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia,
Universidad Complutense, Madrid 28040, Spain; E-Mail: giorgiogiorgi@farm.ucm.es
* Author to whom correspondence should be addressed; E-Mail: rtapia@uc.cl;
Tel.: +56-2-2354-4429; Fax: +56-2-2354-4744.
Received: 14 November 2013; in revised form: 26 November 2013 / Accepted: 26 November 2013 /
Published: 29 November 2013
Abstract: In this report a short and efficient synthesis of the dibenz[b,f]oxepin framework
through intramolecular SNAr and McMurry reactions is described. The diaryl ethers required
for the McMurry reaction have been obtained in good yields under microwave-assisted
conditions of the reaction of salicylaldehydes with fluorobenzaldehydes without catalysts.
Application of an intramolecular McMurry reaction to the synthesized diarylethers using
TiCl4/Zn in THF gave the target dibenzo[b,f]oxepin system in 53%–55% yields.
Keywords: dibenzoxepins; Wittig reaction; McMurry reaction; aromatic nucleophilic
substitution
1. Introduction
The dibenz[b,f]oxepin scaffold is an important synthetic target because a large number of
compounds having this skeleton present relevant biological activities; such as antidepressant [1],
anxiolytic [2], antipsychotic [3,4], angiotensin-II-receptor-antagonist [5], and anti-inflammatory
properties [6]. Additionally, a number of natural occurring dibenz[b,f]oxepins have been isolated from
plants of the genus Bauhinia (fam. Fabaceae) and many of them also exhibit important biological
activities [7]. For example, bauhinoxepin A isolated from Bauhinia saccocalyx Pierre (Figure 1),
shows antimycobacterial activity [8]. Pettit et al. isolated bauhiniastatin 1 from Bauhinia purpurea L.,

Molecules 2013, 18
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which exhibits significant growth inhibition activity against several human cancer lines [9]. From the
same plant, Kittakoop et al. have described bauhinoxepin J, which shows potent antimycobacterial
and antimalarial activities, as well as tumor growth inhibitory activity, against KB cells [10].
Bulbophylol B is another interesting example isolated from Bulbophyllum kwangtungense Schlecht
(fam. Orchidaceae), which displays significant cytotoxicity against human epithelial carcinoma (HeLa)
and human erythromyeloblastoid leukemia (K562) cell lines [11].
Figure 1. Structure of some natural dibenz[b,f]oxepins.
bauhinoxepin A
bauhiniastatin 1
bauhinoxepin J
bulbophylol
Synthetic approaches to natural dibenzo[b,f]oxepins have been directed mainly to the preparation of
dihydro derivatives. For example, the total synthesis of bauhinoxepin J using an intramolecular
persulfate-mediated radical addition to a quinone was described by Krauss and Kim [12]. Furthermore,
Katoh et al. [13] have also recently described their synthesis using the reaction of an aryllithium
derivative with a phenylacetaldehyde and subsequent internal nucleophilic addition/elimination sequences
as key steps. Yao et al. have described the synthesis of bulbophylol employing Wittig, selective
reduction and intramolecular Ullmann reactions as key steps (18% overall yield over 12 steps) [14].
It is noteworthy that the synthesis of bauhinoxepin A and bauhiniastatin 1 are not reported, probably
because the described routes to dibenzo[b,f]oxepins are multi-step procedures or require the
preparation of complex starting materials [15]. Some interesting approaches have been described
recently, but they are limited to the synthesis of dibenz[b,f]oxepincarboxylic acid derivatives [16,17].
In connection with our interest on the synthesis of bioactive heterocyclic quinones [18,19], herein we
describe a convenient procedure for the preparation of the dibenzo[b,f]oxepin scaffold.
Retrosynthetic analysis of the tricyclic system I led us to consider two strategies (Scheme 1).
Approach A, is via an intramolecular Ullmann, or nucleophilic aromatic substitution (SNAr) reaction [20].
Path B, was envisaged through an intramolecular McMurry reaction, which has been used successfully
in the synthesis of natural products [21], but there are no precedents for the preparation of
dibenzo[b,f]oxepins using it, except for sulfur and selenium analogues [22].
Scheme 1. Strategies for the synthesis of dibenzo[b,f]oxepin scaffold.

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2. Results and Discussion
First, we focused our research on the synthesis of a Z-stilbene. To achieve our objective, we
planned to apply the Wittig reaction that gives high Z selectivity when both the ylide and benzaldehyde
incorporate ortho-halo and ortho-alkoxy substituents [23,24]. Thus, Wittig reaction of o-bromobenzyl-
triphenylphosphonium salt 1 [23] with 2-formylphenyl-4-methylbenzene sulfonate (2) in the presence
of potassium t-butoxide gave stilbene 3 (87%) as a single isomer. Attempts to obtain dibenzo[b,f]oxepin 5a
directly from compound 3, by applying an intramolecular palladium-catalyzed biaryl ether formation
using Pd(OAc)2 and tri(o-tolyl)phosphine as described by Harayama et al. for an aza-analog [25]
were unsuccessful. Cleavage of the p-toluenesulfonate group under standard basic conditions
(KOH/EtOH-H2O) gave phenol 4 which was directly converted to dibenzo[b,f]oxepin 5a (72%) by
treatment with cesium carbonate in DMSO at 180 °C under microwave irradiation (Scheme 2).
Scheme 2. Synthesis of dibenzoxepin 5a by intramolecular SNAr reaction.
Reagents and conditions: (a) t-BuOK, THF, 0 °C, 30 min; (b) 2, THF, 18 h, rt; (c) KOH,
EtOH-H2O, 1 h reflux; (d) DMSO, Cs2CO3, MW, 180 °C,15 min.
Considering the low synthetic efficiency of the Wittig process, we focused our attention on the
intramolecular McMurry reaction. Therefore, we concentrated our attention on the preparation of
suitable diaryl ether precursors. The synthesis of o-phenoxybenzaldehydes by Ullmann or SNAr
nucleophilic aromatic substitution reactions of salicylaldehydes with aryl halides normally requires
harsh conditions, long reaction times and often gives low yields [26–28]. Considering the successful
application of microwave irradiation to improve the nucleophilic SNAr reaction of activated aryl
halides with phenols [29], we decided to use this methodology to obtain diaryl ethers 8. Therefore,
preliminary experiments were carried out in order to determine the optimal conditions for the synthesis
of 8a using highly polar solvents such as DMSO or DMA and K2CO3 or Cs2CO3 as bases [20].
The reaction of 1.2 equivalents of 2-hydroxybenzaldehyde (6a) with 1.0 equivalent of
2-fluoro-benzaldehyde (7a) and K2CO3 (2 equiv.) in DMSO using microwave irradiation over a wide
temperature range was examined. The best result was obtained when the reaction was carried out at
120 °C (Table 1, entry 3) with a 73% yield of dialdehyde 8a and at higher temperatures a progressive
degradation of compound 8a was observed. Similar results were obtained using DMA and Cs2CO3 as
solvent and base, respectively (Table 1, entry 14). Using the optimized conditions, 2-fluoro-6-(2-
formylphenoxy)-benzaldehyde (8b) and 2-(2-formylphenoxy)-6-methoxybenzaldehyde (8c) were
obtained in 80% and 82% yield. Finally, the treatment of dialdehyde 8a with TiCl4 (3.0 equiv.) and Zn
(6.0 equiv.) in THF at reflux for 2.5 h gave compound 5a in 55% yield through an intramolecular
McMurry coupling reaction. Similarly, dialdehydes 8b and 8c underwent intramolecular McMurry
coupling to give dibenzoxepins 5b and 5c (53%–55%) (Scheme 3).

Molecules 2013, 18
Table 1. Optimization of microwave-induced synthesis of 2,2'-oxybis(benzaldehyde) 8a.
14800
6a
7a
8a
Entry Temp. (°C)
Base
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMA
Time (min)
Yields (%)
48%
1
2
100 °C
110 °C
120 °C
130 °C
140 °C
160 °C
100 °C
110 °C
120 °C
130 °C
140 °C
160 °C
120 °C
120 °C
120 °C
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
30
30
30
30
30
30
30
30
30
30
30
30
30
30
24 h
67%
3
73%
4
72%
5
55%
6
3% a
50%
7
8
65%
9
73%
10
11
12
13
14
15
70%
45%
0% a
72%
DMA
DMA
73%
71% b
DMA
a The decomposition of the product was observed; b Reaction performed without microwave irradiation.
Scheme 3. Synthesis of dibenzo[b,f]oxepin scaffold via McMurry reaction.
6a R1 = H
6a R1 = H
6b R1 = OMe
7a R2 = H
7b R2 = F
7a R2 = H
8a R1 = R2 = H (73%)
8b R1 = H, R2 = F (80%)
8c R1 = OMe, R2 = H (82%)
5a R1 = R2 = H (55%)
5b R1 = H, R2 = F (53%)
5c R1 = OMe, R2 = H (55%)
Reagents and conditions: (a) DMSO, MW, 120 °C 30 min; (b) Zn, TiCl4, THF, 12 h rt.
The mechanism of the McMurry reaction is still under debate, but new evidences suggest
participation of a metallopinacol intermediate formed by dimerization of ketyl radicals [30–33]. A
possible mechanism for our route is shown in Scheme 4.
Scheme 4. Possible mechanism for the McMurry reaction formation of dibenzo[b,f]oxepins.
[Ti]
[Ti]
O
O
O
O
[Ti]
O
O
O

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3. Experimental
3.1. General
Melting points were measured on a Stuart Scientific SMP3 apparatus (Stuart Scientific, Manchester, UK)
and are uncorrected. Infrared (IR) spectra ( ෤ max) were recorded on a Bruker Model Vector 22
1
13
spectrophotometer (Bruker Optik GmbH, Bremen, Germany). H- (400 MHz) and C-NMR (100 MHz)
spectra were obtained on a Bruker AM-400 instrument (Bruker BioSpin GmbH, Rheinstetten,
Germany), using tetramethylsilane as internal reference. Column chromatography was performed on
silica gel Merck 60 (70–230 mesh) (Merck, Darmstadt, Germany). High-resolution mass spectrum was
obtained using a Thermo Finnigan mass spectrometer Model MAT 95XP (Thermo Finnigan,
San Jose, CA, USA). Microwave-assisted reactions were carried out in an Anton Paar Monowave
300 Microwave Synthesis Reactor (Anton Paar GmbH, Graz, Austria) in 30 mL sealed vials. THF was
freshly distilled over sodium. DMSO and DMA were dried over 4 Å molecular sieves prior to use.
Cs2CO3 and K2CO3 were dried overnight at 200 °C prior to use. All other reagents were used without
further purification.
(Z)-2-(2-Bromostyryl)phenyl 4-methylbenzenesulfonate (3). t-BuOK (157 mg, 1.4 mmol) was added to
a suspension of phosphonium salt 1 (615 mg, 1.2 mmol) in THF (15 mL), at 0 °C and under a nitrogen
atmosphere. The mixture was stirred at 0 °C for 30 min and a solution of aldehyde 2 (276.3 mg,
1.0 mmol) in THF (10 mL) was added via syringe. The reaction mixture was allowed to warm to room
temperature and stirred for 18 h. The cooled reaction mixture was poured into water (30 mL) and
extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried with
MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash
chromatography (CH2Cl2-hexane, 1:9) to give stilbene 3 (375 mg, 87%) as colorless oil. IR (KBr):
෤
max 3061, 1597, 1444, 1366, 1262, 1025, 810, 722, 671 cm−1. 1H-NMR (CDCl3): δ 2.39 (s, 3H), 6.56
(d, J = 12 Hz, 1H), 6.61 (d, J = 12 Hz, 1H), 6.75 (d, J = 8 Hz, 1H), 6.90–7.10 (m, 6H), 7.29 (d,
13
J = 8 Hz, 2H), 7.54 (d, J = 8 Hz, 1H), 7.80 (d, J = 8 Hz, 2H). C-NMR (acetone-d6): δ 22.1, 124.0,
124.8, 126.7, 128.0, 128.4, 130.0 (2C), 130.3, 130.6, 131.4 (2C), 131.7, 131.9, 132.1, 132.6, 133.9,
134.2, 138.3, 147.3, 149.0. HRMS (EI): m/z [M+] calcd for C21H17BrO3S: 428.0082; found: 428.0077.
Dibenz[b,f]oxepin (5a). Stilbene 3 (215 mg, 0.5 mmol) was added to a solution of KOH (900 mg,
16 mmol) in a mixture of EtOH (15 mL) and H2O (15 mL) and the suspension was heated under reflux
for 1 h. After cooling, the reaction mixture was acidified with aqueous HCl (10%) to pH 4 and
extracted with CH2Cl2 (3 × 25 mL). The combined organic extracts were washed with saturated
aqueous NaHCO3, dried, and filtered through a short column of silica gel. After the removal of the
solvent, the residue was dissolved in DMSO (5.0 mL) and Cs2CO3 (651.6 mg, 2.0 mmol) was added.
The reaction mixture was heated in a microwave reactor at 180 °C for 15 min. After cooling, the
solvent was evaporated under reduced pressure and the crude product was purified by flash column
chromatography (silica gel, EtOAc-hexanes; 1:9) to afford 5a (70 mg, 72%), mp 108.5–109.5 °C
(Lit. 106–108 °C [34], 110–111 °C [35]). IR (KBr): ෤
3069, 3044, 1483, 798 cm−1.
max
1H-NMR (acetone-d6) δ 6.82 (s, 2H), 7,19 (t, J = 7,8 Hz, 2H), 7.25 (d, J = 7.8 Hz, 2H), 7.30 (d, J = 7.8 Hz,
2H), 7.38 (t, J = 7.8 Hz, 2H). 13C-NMR (acetone-d6) δ 122.9, 126.6, 131.1, 131.6, 131.7, 132.3, 159.1.

Molecules 2013, 18
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3.2. General Procedure for the Preparation of Diarylethers 8
A mixture of hydroxybenzaldehyde 6a (1.2 mmol), fluorobenzaldehyde 7 (1.0 mmol), cesium
carbonate (1.30 g, 4.0 mmol) and DMSO (4.0 mL) in a 30 mL microwave vial was irradiated at 120 °C
for 30 min under nitrogen. The reaction mixture was diluted with dichloromethane (20 mL), washed
with brine (3 × 10 mL), dried (MgSO4) and evaporated. The residue was purified by flash column
chromatography (EtOAc-hexanes, 1:9).
2,2'-Oxybis(benzaldehyde) (8a). Following general procedure, from 2-hydroxybenzaldehyde (146.5 mg,
1.2 mmol) and 2-fluorobenzaldehyde (124.1 mg, 1.0 mmol) compound 8a was obtained (168 mg,
74%), mp 76–77 °C (Lit. 74 °C [36], 77.0–77.5 °C [37]). IR (KBr): ෤max 1686, 1574, 1473, 1454, 1393,
1301, 1224, 760 cm−1. 1H-NMR (acetone-d6): δ 7.11 (d, J = 8.3 Hz, 2H), 7.39 (t, J = 7.7 Hz, 2H), 7.72
13
(m, 2H), 7.96 (dd, J = 7.7, 1.5 Hz, 2H), 10.53 (s, 2H), C-NMR (acetone-d6): δ 121.6, 126.7, 129.6,
131.0, 138.4, 161.2, 190.9.
2-Fluoro-6-(2-formylphenoxy)benzaldehyde (8b). Following the general procedure, from
2-hydroxybenzaldehyde (146.5 mg, 1.2 mmol) and 2,6-difluorobenzaldehyde (142.1 mg, 1.0 mmol)
compound 8b was obtained (196 mg, 80%), mp 80–81 °C. IR (KBr): ෤
1685, 1611, 1598, 1577,
max
1396, 787 cm−1. 1H-NMR (CDCl3) δ 6.73 (d, J = 8.3 Hz, 1H), 6.99 (m, 2H), 7.33 (t, J = 7.5 Hz, 1H),
7.54 (m, 1H), 7.62 (ddd, J = 8.3, 7.5, 1.5 Hz, 1H), 7.99 (dd, J = 7.5, 1.5 Hz, 1H), 10.44 (s, 1H),
13
10.51 (s, 1H), 10.43 (s, 1H). C-NMR (CDCl3) δ 112.5, 112.7, 115.0, 115.1, 119.7, 125.3, 127.7,
129.8, 136.4, 136.5, 158.5, 159.0, 186.2, 188.9. HRMS (EI): m/z [M+] calcd for C14H9FO3: 244.0536;
found: 244.0532.
2-Hydroxy-6-methoxybenzaldehyde (6b). A solution of 2,6-dimethoxybenzaldehyde (2.0 g, 12 mmol)
in CH2Cl2 (20 mL) was added dropwise to a stirred suspension of AlCl3 (2.4 g, 18 mmol) in CH2Cl2
(30 mL) at −20 °C. The reaction mixture was allowed to warm to room temperature and then stirred
for 6 h. After the addition of 6 M HCl (20 mL) the biphasic mixture was stirred vigorously for 12 h
and the aqueous solution was extracted with CH2Cl2 (3 × 20 mL) The combined organic extracts were
washed with water, brine, dried (MgSO4) and evaporated under reduced pressure. Purification of the
residue by flash chromatography on silica gel (EtOAc-hexanes; 1:9) gave compound 6b (1.7 g, 93%),
mp 72–74 °C (Lit. 73–75 °C [38]).
2-(2-Formylphenoxy)-6-methoxybenzaldehyde (8c). Following general procedure, from 2-hydroxy-6-
methoxybenzaldehyde (182.6 mg, 1.2 mmol) and 2-fluorobenzaldehyde (124.1 mg, 1.0 mmol)
compound 8a was obtained (210 mg, 82%), mp 116–117 °C. IR (KBr): ෤ 2914, 2862, 2762, 1687,
max
1
1600, 1279, 1236, 758, 737 cm−1. H-NMR (CDCl3) δ 3.97 (s, 3H), 6.54 (d, J = 8.4 Hz, 1H), 6.83 (d,
J = 8.4 Hz, 1H), 6.86 (dd, J = 8.4, 1.8 Hz, 1H), 7.22 (tt, J = 7.8, 1.8 Hz, 1H), 7.48 (t,
J = 8.4 Hz, 1H), 7,52 (ddd, J = 8.4, 7.8, 1.8 Hz, 1H), 7.95 (dd, J = 7.8, 1.8 Hz, 1H), 10.48 (s, 1H),
10.52 (s, 1H). 13C-NMR (CDCl3) δ 56.7, 108.0, 112.5, 117.4, 118.8, 124.3, 127.4, 129.1, 136.1,
136.2, 158.3, 159.7, 163.1, 188.4, 189.5. HRMS (EI): m/z [M+] calcd for C15H12O4: 256.0736;
found: 256.0733.

Molecules 2013, 18
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3.3. General Procedure for the McMurry Reaction
To a stirred suspension of zinc powder (98.1 mg, 3.0 mmol) in anhydrous THF (40 mL) cooled to
−5 °C under an argon atmosphere, TiCl4 (284.5 mg, 1.5 mmol) was slowly added via syringe keeping
the temperature under 0 °C. The reaction mixture was allowed to warm to room temperature and then
heated at reflux for 2.5 h. The reaction was quenched with saturated NH4Cl solution and extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried (MgSO4) and concentrated. The crude
material was purified by flash chromatography (hexanes) to give the desired product.
Dibenzo[b,f]oxepin (5a). Following the general procedure, from 2,2'-oxybis(benzaldehyde) (8a)
(226.2 mg, 1.0 mmol) compound 5a was obtained (107 mg, 55%), mp 108.5–109.5 °C.
1-Fluorodibenzo[b,f]oxepin (5b). Following general procedure, from 2-fluoro-6-(2-formylphenoxy)-
benzaldehyde (8b) (244.2 mg, 1.0 mmol) compound 5a was obtained (115 mg, 54%), mp 40.5–41.5 °C.
1
IR (KBr): ෤
3051, 1613, 1571, 1442, 1259, 1007, 774 cm−1. H-NMR (acetone-d6) δ 6.93 (d,
max
J = 11.5 Hz, 1H), 6.97 (d, J = 11.5 Hz, 1H), 7.03 (ddd, J = 9.6, 8.4, 1.2 Hz, 1H), 7.13 (dt, J = 8.4, 1.2 Hz,
13
1H), 7.23 (dd, J = 7.6, 1.2 Hz, 1H), 7.35 (dd, J = 7.6, 1.7 Hz, 1H). C-NMR (acetone-d6) δ 112.3,
117.4, 120.0, 121.8, 122.6, 126.6, 129.9, 130.4, 130.5, 130.9, 131.4, 157.7, 159.5, 161.5. HRMS (EI):
m/z [M+] calcd for C14H9FO: 212.0637; found: 212.0640.
1-methoxydibenzo[b,f]oxepin (5c). Following general procedure, from 2-(2-formylphenoxy)-6-
methoxybenzaldehyde (8c) (256.3 mg, 1.0 mmol) compound 5c was obtained (124 mg, 55%),
1
mp 63–64 °C. IR (KBr): ෤ 1599, 1570, 1464, 1075, 778 cm−1. H-NMR (acetone-d6) δ 3.90 (s, 3H),
max
6.84 (d, J = 11.6 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 11.6 Hz, 1H), 7.20 (td, J = 7.4, 1.6 Hz,
1H), 7.24 (m, 1H), 7.30 (dd, J = 7.6, 1.6 Hz, 2H), 7.35 (t, J = 8.4 Hz, 1H), 7.38 (ddd, J = 8.4, 7.4, 1.6 Hz,
13
1H). C-NMR (CDCl3) δ 56.2, 107.3, 114.1, 120.1, 121.6, 125.1, 125.2, 129.4, 129.5, 129.9, 130.3,
131.5, 157.5, 157.8, 159.53. HRMS (EI): m/z [M+] calcd for C15H12O2: 224.0837; found: 224.0831.
4. Conclusions
In conclusion, we have developed a short synthesis of dibenzo[b,f]oxepin derivatives using SNAr
and intramolecular McMurry reactions. An efficient process to obtain diarylethers through SNAr
reaction of salicylaldehydes with fluorobenzaldehydes using microwave irradiation is described.
McMurry reaction of diarylethers using TiCl4 and Zn in THF afforded the target tricyclic system in
reasonable yields (53%–55%). Further work on the synthesis of natural and pharmacologically active
dibenzo[b,f]oxepins are under way.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/18/12/14797/s1.
Acknowledgments
Financial support from FONDECYT (Research Grant 1110749), and Millenium Nucleus CILIS,
ICM-P10-003-F is gratefully acknowledged. D.M. is also grateful to CONICYT for a PhD fellowship

Molecules 2013, 18
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and Research Grant AT-24121514. G. G. thanks to Latin American Scholarship Santander Universities
Program, for a young researcher scholarship.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of all compounds are available from the authors.
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