Radical arylation of triphenyl phosphite catalyzed by salicylic acid: Mechanistic investigations and synthetic applications

Article abstract of DOI:10.1021/acs.joc.0c00795

A straightforward and scalable methodology to synthesize diphenyl arylphosphonates at 20 °C within 1-2 h is reported using inexpensive SA as the catalytic promoter of the reaction. Mechanistic investigations suggest that the reaction proceeds via radical-radical coupling, consistent with the so-called persistent radical effect. The reaction tolerated a wide range of functional groups and heteroaromatic moieties. The synthetic usefulness and the unique reactivity of the obtained phosphonates were demonstrated in different one-step transformations.

Full text of DOI:10.1021/acs.joc.0c00795

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Article
Radical Arylation of Triphenyl Phosphite Catalyzed by Salicylic
Acid: Mechanistic Investigations and Synthetic Applications
Manel Estruch-Blasco, Diego Felipe-Blanco, Irene Bosque, and José C. González-Gómez
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00795 • Publication Date (Web): 18 May 2020
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Radical Arylation of Triphenyl Phosphite Catalyzed by Salicylic Acid: Mechanistic
Investigations and Synthetic Applications
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Manel Estruch-Blasco,† Diego Felipe-Blanco,† Irene Bosque, Jose C. Gonzalez-Gomez*
Instituto de Síntesis Orgánica (ISO) and Departamento de Química Orgánica, Facultad de
Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Email: josecarlos.gonzalez@ua.es
CO2H
NH2
O
P
Ar
O
P
OH
<10 mol %
SA
+
Ar +
OPh
OPh
OPh
OPh
P(OPh)3
+
t-BuONO
Ar
CH3CN [0.20 M]
Ar, 20 ºC, 12 h
29 examples
up to 94% yield
"Persistent radical effect"
 Metal free and additive free
 Availability of starting materials
 SA as very convenient catalyst  Gram-scale and operationally simple
 Short reaction times at 20 ºC  Unique reactivity of diaryl phosphonates
ABSTRACT: A straightforward and scalable methodology to synthesize diphenyl
arylphosphonates at 20 ºC within 1-2 h is reported, using inexpensive SA as the catalytic
promoter of the reaction. Mechanistic investigations suggest that the reaction proceeds via
radical-radical coupling, consistent with the so-called Persistent Radical Effect. The reaction
tolerated a wide range of functional groups and heteroaromatic moieties. The synthetic
usefulness and the unique reactivity of the obtained phosphonates were demonstrated in
different one-step transformations.
INTRODUCTION
Aryl phosphonates are privileged scaffolds among pharmaceuticals, agrochemicals, and
organic materials; as well as being versatile building blocks in organic synthesis or ligands
in transition-metal (TM) catalysis.1 Traditionally, these organophosphorus compounds were
prepared by reaction of electrophilic dialkyl chlorophosphonates with organolithium2 or
Grignard reagents.3 Since the seminal contribution of Hirao and coworkers,4 the
TM-catalyzed cross-coupling of (pseudo)haloarenes with H-phosphonates or trialkyl
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phosphites has been one of the most extensively used strategies to prepare aryl
phosphonates.5-7 Given the recent advancements in visible light photocatalysis,8 the room
temperature preparation of aryl phosphonates has also been accomplished using this
methodology. In this frame, the photoinduced reductive generation of aryl radicals trapped
by trisubstituted phosphites has been successfully implemented,9 as well as the single-
electron oxidation of arenes to obtain radical cations that easily add nucleophilic
phosphites.10 In addition, intensive efforts have been made recently in the development of
TM-free synthesis of aryl phosphonates at room temperature. In this context, one successful
approach relied on the nucleophilic addition of dialkyl phosphites to in situ generated arynes
from 2-(trimethylsilyl)aryl triflates (Kobayashi precursors, Scheme 1a).11 It has been also
recently reported that the combination of diaryliodonium salts with phosphites can form an
electron donor-acceptor complex, upon irradiation with blue light in the presence of a base,
leading to the desired aryl phosphonates (Scheme 1b).12 The photoinduced oxidation of
arylhydrazines to produce aryl radicals that were trapped with trialkyl phosphites was also
recently developed,13 using an organic photocatalyst and 1,4-diazabicyclo[2.2.2]octane
(DABCO) as additive under aerobic conditions (Scheme 1c). The visible light-driven
generation of aryl radicals from arylazo sulfones in the absence of photocatalyst, which was
trapped with triaryl phosphites, is another elegant approach recently reported (Scheme 1d).14
Furthermore, a Sandmeyer-type reaction of in situ formed diazonium salts with triaryl
phosphites promoted by stoichiometric amounts of p-toluene sulfonic acid (TsOH), has also
allowed the efficient preparation of aryl phosphonates (Scheme 1e).15 Despite these
remarkable contributions, a TM-free synthesis of aryl phosphonates at room temperature,
from readily available starting materials, without stoichiometric additives or excess of
reagents, is still desired.
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Given the high reactivity and low selectivity of aryl radicals, a sustained catalytic aryl
radical generation is a more convenient approach for a successful synthetic
transformation.16,17 We have recently demonstrated that aryl radicals can be catalytically
generated from readily available anilines that are in situ transformed into diazonium salts
with tert-butyl nitrite (TBN),18 by using salicylic acid (SA) as a catalyst at room
temperature.19 We do think that SA is a very convenient catalyst because is inexpensive, non-
toxic, and a renewable feedstock derived from natural salicin. As part of our ongoing
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program, we decided to explore these mild and environmentally benign conditions to obtain
diphenyl arylphosphonates.
Scheme 1. Context of the TM-free synthesis of diaryl phosphonates
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(a) Chen, Q., et al.: Reference 11
CsF (5 equiv)
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OTf
Cs2CO3 (1 equiv)
Ar
+
P(OR)3
CH3CN, 25 ºC, 24 h
TMS
(2 equiv)
(1 equiv)
(b) Lecroq, W., et al.: Reference 12
K2CO3 (1 equiv)
Blue LEDs, 16 h
Ar2IOTf
+
P(OR)3
(1.5 equiv)
(1 equiv)
CH3CN, 35 ºC
(c) Li, R., et al.: Reference 13
Eosin B (5 mol%)
DABCO (50 mol%)
O
P
OR
OR
+
P(OR)3
ArNHNH2
(1 equiv)
white LEDS, 45 ºC
Ar
(2 equiv)
CH3CN, open air, 6 h
(d) Qiu, D., et al.: Reference 14
Blue LEDs, 24 h
CH3CN, 35 ºC
ArN2SO2Me
(1 equiv)
+
P(OR)3
(3.5 equiv)
(e) Wang, S., et al.: Reference 15
TsOH×H2O (1.2 equiv)
P(OPh)3 (3 equiv)
0 ºC- 25 ºC, 8 h
t-BuONO (1.5 equiv)
ArNH2
CH3CN, 0 ºC, 15 min
(1 equiv)
RESULTS AND DISCUSSION
Since at 60 ºC the diazonium salts can react with CH3CN to form acetamides via N-
arenenitrilium salts (Ritter reaction),20 we carefully controlled the reaction temperature at 20
ºC. We were pleased to observe how the addition of 10 mol % of salicylic acid (SA)
significantly accelerated the formation of phosphonate 2a in CH3CN (Table 1, entries 1-2).
Importantly, the reaction was complete within 1 h without preforming of the diazonium salt,
and without requiring an excess of triphenyl phosphite (TPP) or any other additive. We have
seen that the presence of minor amounts of H2O is not critical for the success of the reaction,
but its addition to the reaction media was not beneficial neither (entry 3). The reaction
performance was worst under air atmosphere, which is in accordance with the intermediacy
of radicals, as also suggested by its complete inhibition in the presence of 2,2,6,6-
Tetramethylpiperidine 1-oxyl (TEMPO, entries 4-5). Given the precedents in the
photogeneration of aryl radicals from aryl diazonium salts,21 we carefully checked that the
ambient light was not promoting the reaction (entry 6). Importantly, no reaction was
observed using P(OEt)3 (entry 7), and the addition of TPP after the formation of the
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diazonium salt was detrimental to the reaction yield (entry 8). When stoichiometric amounts
of the more acidic p-TsOH were used to promote the reaction, in analogy to the conditions
reported by Wang and coworkers but without preforming the diazonium salt,15 only 38% of
2a was obtained (entry 9).22 We have also confirmed that with both hydroxyl groups free in
the SA, the formation of 2a is more efficient (entries 10-11). Remarkably, the reaction is
complete after only 30 min under our optimal reaction conditions (entry 12 and Figure S3),
and only 2 mol % of SA is enough to efficiently promote the reaction (Figure S4) with about
1 equivalent of TPP. These conditions represent a significant improvement over the method
shown in Scheme 1e,15 where 3 equivalents of TPP are required in a sequential procedure
(preformation of the diazonium salt) that uses stoichiometric amounts of p-TsOH and needs
about 8 h for completion.
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Table 1. Reaction optimization and control experiments.a
O
t-BuONO (1.50 equiv)
SA (10 mol %), Ar
NH2
+ P(OPh)3
P
OPh
OPh
CH3CN, 20 ºC, 1 h
Cl
Cl
1a
(TPP: 1.15 equiv)
2a
(Yield)
Entry
1
Deviation from above
Yieldb
27%
94%
88%
64%
traces
93%
0%
Without SA
none
2
3
in 3:1 CH3CN: H2O
Without an Ar atmosphere
+ TEMPO (2.0 equiv)
Protected from light
With P(OEt)3 as phosphite
4
5
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7
8c
9
TPP added to the diazonium salt
p-TsOH•H2O (1.2 equiv) instead of SA
With Methyl salicylate instead of SA
With O-Acetyl SA instead of SA
After 30 min
45%
38%
37%
48%
93%
10
11
12
aReactions with 0.30 mmol of aniline in 1.5 mL of CH3CN.
bDetermined by GC, using adamantane as the internal standard
(Figure S1). cTPP was added 30 min after the other reactants.
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To gather information about our arylation of TPP, we conducted a series of experiments.
When the isolated pure diazonium salt of 1a reacted with TPP in MeCN at 20 ºC, only 17%
of 2a was obtained, being improved to 40% in the presence of SA (Scheme 2a). This
experiment excludes a direct single-electron transfer (SET) between the diazonium salt and
TPP as the main pathway under our optimized conditions (Sandmeyer-like reaction),23 as
proposed by Wang and coworkers under the conditions shown in Scheme 1e.15 The formation
of diazo anhydrides (Ar-N=N-O-N=N-Ar)24 or triazene intermediates (ArN=N-NHAr)25 and
their radical fragmentation could explain the background reaction. The p-nitrophenyl radical
was trapped by TEMPO (Scheme 2b) and a competitive experiment in the presence of
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≈ 106 푀 ―1푠 ―1
2-propanol (kHAT
)26 allowed us to estimate the rate constant for the addition
7
of the p-chlorophenyl radical to the TPP (Scheme 2c). This very fast reaction (k ≈
2.2 푥10
―1
푀 ―1푠 )
indicates that TPP is functioning as a very efficient radical trap under our reaction
conditions, competing favorably with the other possible radical side-reactions. It has been
known for a long time that phenyl radicals react very rapidly with trimethyl phosphite to give
dimethyl phenylphosphonate, likely through a radical Arbuzov-like mechanism.27 However,
in a reaction of aryl radical with TPP, this pathway involves the cleavage of a stronger O-
C(sp2) bond to furnish the desired product and the phenyl radical. More importantly, this
phenyl radical would eventually be trapped by TPP, and we never observed the formation of
2c when we submitted anilines 1a or 1h to our reaction conditions (Scheme 2d). Trying to
identify the catalytically active species of the process, we put into reacting the diazonium salt
of 1h with SA. After careful crystallization, we only isolated the azo compound II-h in a
rather low yield (Scheme 2e).28 However, this tan azo compound was unreactive with
stoichiometric amounts of TPP, as well as in THF solution, and resulted catalytically inactive
in the studied reaction (Scheme 2f).
Scheme 2. Mechanistic investigations
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N2BF4
O
P
4
5
6
7
P(OPh)3 (1.15 equiv) - N2
MeCN, 20 ºC, Ar, 2 h
BF4
P(OPh)3
Ar1
+
(a)
OPh
OPh
Ar1
Sandmeyer-like reaction
Cl
Ar1
2a (17%)
With 10 mol % of SA (40%)
1a-diazonium salt
8
9
NH2
TEMPO (2 equiv)
SA (10 mol %)
t-BuONO (1.5 equiv)
P(OPh)3 (1.15 equiv)
Me
N
Me
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O
(b)
2a
(traces)
+
Me
O2N
MeCN, 20 ºC, Ar, 1 h
NO2
Me
1h
(32%)
1h-TEMPO
NH2
SA (10 mol %)
t-BuONO (1.5 equiv)
P(OPh)3 (3.3 equiv)
P(OPh)3
(75%)
kad  2.5 x 107 M-1s-1
2a
(c)
(d)
i-PrOH (3.3 equiv)
MeCN, 20 ºC, Ar, 1 h
i-PrOH
Ar1H (3%)
Cl
1a
kHAT
SA (10 mol %)
t-BuONO (1.5 equiv)
P(OPh)3 (1.15 equiv)
Ph
O
P
O
Ar-NH2
P
OPh
Ar
OPh
OPh
OPh
MeCN, 20 ºC, Ar, 1 h
Ar
1a or 1h
2a or 2h
Ph
O
P(OPh)3
P
Radical Arbuzov-like reaction
OPh
OPh
2c (0%)
Ph
N2BF4
Ar2
CO2H
N
CO2H
N
40 min, 20 ºC
+
(e)
MeCN:H2O/ 2:1
OH
OH
II-h (18% after recryst.)
(SA)
Ar2
NO2
in THF
P(OPh)3 (1.15 equiv)
in MeCN (0.20 M)
2h (0%)
(0.20 M)
C6H5NO2 (0%)
II-h (10 mol %)
1h-diazonium
salt
O
P
NH2
t-BuONO (1.5 equiv)
OPh
OPh
P(OPh)3 (1.15 equiv)
(f)
Cl
Cl
MeCN, 20 ºC, Ar, 1 h
1a
2a (29%)
The redox potentials of TPP, P(OEt)3 and SA were measured by cyclic voltammetry (CV,
Figure S5) to examine their different reactivities (entries 2 and 7 of Table 1). Considering the
표푥
experimental values obtained, the salicyloyl radical (SA•, 푝/2 =+1.97 V vs SCE) would be
퐸
표푥
able to oxidize TPP (
= +1.85 V vs SCE) but the oxidation of P(OEt)3 is slightly
퐸푝/2
표푥
unfavored ( 푝/2 = +2.04 V vs SCE). As shown in Figure 1 (left), the onset potential of the
퐸
mixture of SA and TPP was found to be like the one of the SA alone, but higher current
density was achieved. This result suggests that after the oxidation of the SA, an electron
transfer occurs from TPP to SA•. On the contrary, when a similar experiment was conducted
with P(OEt)3, the onset potential for the oxidation of the mixture started at least 400 mV
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before than the one of SA alone (Figure 1, right). This significant difference suggests that
P(OEt)3 reacts directly with SA (not with SA•), resulting in the consumption of the SA before
the catalytic cycle starts.29
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Figure 1. Cyclic voltammograms. See SI for more details.
Based on our experimental investigations and literature precedents, we propose the
mechanism depicted in Scheme 3. The reaction of aniline 1 with TBN in the presence of SA
would form the diazonium salt I. This intermediate would lead to the azo compound II, which
is catalytically inactive, or to the aryl diazobenzoate III.30 Based on literature precedents,
acyloxydiazoaryls decompose easily to generate N2 and aryl radicals.31,32 The fragmentation
of III would lead to the aryl radicals and to the salicyloyl radical SA•, likely stabilized by an
intramolecular H-bond. We have then shown by CV measurements that the SET between
TPP and SA• is feasible, enabling the turnover of the SA and producing the phosphoniumyl
radical cation IV.33 We speculate that hydrolysis of IV would produce phenol (almost 1 equiv
of phenol in the formation of 2a, see SI) and the phosphanyl radical V, which is stabilized by
electron-donation from the two phenoxy groups and can be considered a persistent radical.
We thus propose that nucleophilic radical V serves as an efficient trap of the aryl radicals,
which are σ-sp2 radicals and therefore more electrophilic than common π-alkyl radicals
(pathway A).34 This highly selective cross-coupling is consistent with the reaction between a
transient aryl radical and a longer-lived phosphanyl radical, being both generated at equal
rates within the catalytic cycle (Persistent Radical Effect).35 Alternatively, aryl radical can
also be trapped by the radical cation IV to obtain the quaternary phosphonium intermediate
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VI, which after hydrolysis could provide the product 2, with concomitant formation of phenol
and deprotonation (pathway B).14
Scheme 3. Plausible mechanism
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O
catalytically
inactive
Ar
N
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O
P
N
OH
OH
(II)
OPh
OPh
Ar
(2)
O
N
Ar
N
O
N
CO2
OH
(III)
N
A
OH
Ar
(I)
- N2
Ar
t-BuOH
P a t h w a y
O
P
t-BuO N2Ar
O
PhO
(V)
O
OH
OPh
H
O
O
H
(SA)
H2O
SET
O
P(OPh)3
t-BuONO
(TBN)
+ H+
H+
(SA)
(IV)
P(OPh)3
H2O
PhOH
Ar
O
ArNH2 (1)
PhOH
OPh
P
H2O
P
OPh
OPh
(VI)
OPh
Ar
(2)
Ar
OPh
Pathway B
Having identified the optimal conditions for the radical arylation of TPP, we examined
the scope of the reaction with diversely substituted anilines. As shown in Scheme 4,
unsubstituted aniline and halogen-containing anilines at the ortho-, metha- or para- position,
ready for further functionalization, afforded the phosphonates (2a, 2b, 2c, 2m, 2q, 2x) in
good-to-excellent yields. Anilines bearing electron-donating groups (methyl, ethynyl,
phenyl, methoxy, N-acetyl) were also suitable substrates, leading to the expected
phosphonates (2d-2g, 2p, 2r-2s) in moderate-to-good yields. However, the yield dropped
when the electron-rich 2-methoxy aniline (1t) was used to obtain compound 2t. On the other
hand, a variety of electron-withdrawing groups in the aniline remained intact (NO2, CN, Ac,
CO2H, CO2Me, CF3), affording the corresponding products in good-to-excellent yields (2h-
2l, 2n-2o, 2u-2v). Electron-donating- and electron-withdrawing-groups could also be
successfully combined in the same aniline, as exemplified by the product 2w. More
importantly, the reaction was not restricted to anilines since heteroaryl amines were also
suitable substrates. While 8-aminoquinoline and 2-aminobenzothiazole gave the
corresponding phosphonates (2y and 2z) in rather low yields, the thiophene-derived 2aa and
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pyridine-phosphonate 2ab were obtained in moderate-to-good yields. Furthermore, the
2-(4-aminophenyl)benzothiazole (1ac), which exhibits a potent anti-breast cancer activity,36
was smoothly transformed into the phosphonate 2ac under our optimized conditions.
Scheme 4. Reaction scope
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SA (10 mol %)
P(OPh)3 (1.15 equiv)
t-BuONO (1.5 equiv)
O
P
P
NH2
OPh
OPh
Ar
Ar
CH3CN [0.20 M]
Ar, 20 ºC, 2 h
1 (0.3 mmol)
2 (Yield)
P
P
P
X
EWG
EDG
2a: X = Cl (92%)
2b: X = Br (65%)
2c: X = H (81%)
2h: EWG = NO2 (94%)
2i: EWG = CN (82%)
2j: EWG = Ac (76%)
2k: EWG = CO2H 56%)
2l: EWG = CO2Me (75%)
2d: EDG = Me (50%)
2e: EDG = C CH (65%)
2f: EDG = OMe (61%)
2g: EDG = NHAc (63%)
P
P
R
Br
NO2
P
R
P
2m: R= Cl (65%)
2n: R= NO2 (87%)
2o: R= CF3 (66%)
2q: R = Cl (67%)
2r: R = Me (63%)
2s: R = Ph (58%)
MeO
F
2w (54%)
2x (72%)
2p: R= NHAc (48%) 2t: R = OMe (37%)
2u: R = CN (69%)
P
MeO2C
2v: R = NO2 (91%)
P
P
N
S
S
P
N
Cl
N
2aa (50%)
2ab (74%)
2z (27%)
standard
conditions
2y (32%)
S
N
S
P
NH2
N
1ac: potent antitumor agent
2ac (81%)
We further carried out the preparation of phosphonates 2s, 2x and 2ac on the gram scale,
using only 2 mol % of SA (Scheme 5a). Remarkably, we obtained similar yields of isolated
pure products than in 0.30 mmol-scale, even after recrystallization (see SI for details). With
these diphenyl arylphosphonates in gram-quantities, we explored the underexploited
reactivity of this family of compounds. To overcome the limitation of this methodology to
triaryl phosphites we examined the transesterification of diphenyl phosphonates into dialkyl
phosphonates (Scheme 5b). This two-step protocol provided a convenient TM-free approach
to the calcium channel blocker compound 3,37 which is analogous to the pharmaceutical
fostedil. We also studied the transformation of diaryl phosphonates into phosphine
derivatives since they can be used as ligands in TM catalysis and their preparation usually
requires expensive and multistep procedures. It is known that the reaction of dialkyl
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phosphonates with Grignard reagents is limited by Arbuzov-like decomposition of the
starting material,38a and this limitation was recently circumvented by the use of
stoichiometric amounts of NaOTf as additive.38b In stark contrast, we have observed that
diphenyl phosphonate 2s smoothly reacted with MeMgBr at 0 ºC, in the absence of additives,
obtaining dimethyl(aryl)phosphine oxide 4 in excellent yield (Scheme 5c). Importantly,
compound 4 can be easily transformed by one-step reduction into Methyl JohnPhos, a
Buchwald-type ligand.38b Under similar conditions but using an excess of PhMgBr and
longer reaction time, compound 5 was prepared in excellent yield. It is worthy of mention
that compound 5 and some derivatives have been used as “platform molecules” for the Pd-
catalyzed R2(O)P-directed C(sp2)–H activation, introducing a wide range of functionalities
at the adjacent phenyl ring.39 Moreover, by only reducing the amount of PhMgBr and running
the reaction over 30 min at 0 ºC, we obtained the racemic phosphinate 6 in an unoptimized
but useful synthetic yield. The reaction of this compound with MeMgBr allowed the efficient
preparation of chiral, albeit racemic, tertiary phosphine oxide 7. The results shown in
Scheme 5c support diaryl phosphonates as convenient synthetic precursors for the
preparation of tertiary phosphine oxides by reaction with Grignard reagents.40 Finally, we
explored an intramolecular C-H arylation reaction with diaryl phosphonate 2x (Scheme 5d).
Using (R)-BINAP as chiral ligand and Pd(OAc)2 we obtained the P-chiral biaryl phosphonate
8. Although in an unoptimized yield and enantioselectivity, this reaction demonstrates the
straightforward access to chiral biaryl phosphonates in only two steps from readily available
starting materials.41
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Scheme 5. Scale-up and follow-up reactions
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(a) Gram-scale preparation (only 2 mol % SA used)
O
O
P
P
OPh
OPh
O
S
OPh
OPh
P
OPh
OPh
N
F
Ph
2s: 2.30 g (60%)
Br
2x: 2.85 g (70%)
2ac: 1.99 g (75%)
(b) Transformation into dialkyl phosphonates
O
P
S
N
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NaOEt (6 equiv)
2ac
OEt
EtOH
20 ºC, 2 h
OEt
3 (80%, calcium antagonist)
(c) Transformation into phosphine oxides and phosphinates
O
P
O
P
Me
Ph
Me
Me
PhMgBr (4 equiv)
THF, 0 ºC, 4 h
MeMgBr (2.6 equiv)
THF, 0 ºC, 30 min
Ph
2s
Ph
Ph
5 (80%)
4 (92%)
PhMgBr (1.2 equiv)
THF, 0 ºC, 1 h
Ref. 36b
O
P
Me
O
P
OPh
P
Ph
Ph
MeMgBr (1.5 equiv)
THF, 0 ºC, 1 h
Me
Ph
Ph
 6 (62%)
Ph
Methyl JohnPhos
 7 (87%)
(d) Intramolecular C-H arylation
H
OPh
O
OPh
O
Pd(OAc)2 (5 mol %)
(R)-BINAP (10 mol %)
O
P
O
P
AcOK (1.5 equiv.)
F
F
Br
toluene, 100 ºC, 24 h
2x
8 (31%, S:R / 61:39)
CONCLUSION
In summary, we have demonstrated that SA efficiently catalyzes the arylation of TPP,
using readily available anilines as starting materials and TBN for the in situ formation of
diazonium salts, without thermal or photochemical activation. Our mechanistic studies
supported the intermediacy of transient aryl radicals which rapidly coupled with the longer-
lived phosphanyl radical, being the SA regenerated by SET between the TPP and the SA•.
The protocol was easily adapted for the gram-scale preparation of three diphenyl
arylphosphonates and we examined the unique reactivity of these compounds by
straightforward transformations into dialkyl phosphonates, phosphinates, phosphine oxides,
and cyclic P-chiral biaryl phosphonates.
EXPERIMENTAL SECTION
General Remarks. Most commercial chemicals were used as obtained from Sigma-
Aldrich, TCI Europe or Alfa-Aesar. However, after the long storage of TPP, it became yellow
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and it was purified by washing its solution in EtOAc with a 1 M solution of NaOH. CH3CN
(for analysis, ACS) was purchased from Panreac 99.7% pure. The preparation of starting
materials not obtained from commercial sources is detailed below. TLCs were performed on
silica gel 60 F254, using aluminum plates and visualized by exposure to ultraviolet light. Flash
chromatographies (FC) were carried out on handpacked- columns of silica gel 60 (230–400
mesh). Melting points (mp) were measured in a Riecher Thermovar heating stage microscope
and were not corrected. GC yields were determined by GC-FID (6890 Agilent, HP-5 30 m
column), using adamantane as the internal standard. LRMS were obtained using a mass
spectrometer coupled with a gas chromatographer (GC); the mobile phase was helium (2
mL·min−1); HP-1 column of 12 m was used; temperature program starts at 80 ºC for 3 min,
then up to 270 ºC at a rate of 15 ºC·min−1, and 15 min at 300 ºC (unless other conditions are
indicated). NMR spectra were recorded at 300 or 400 MHz for 1H, at 75 or 101 MHz for 13C,
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1
and at 122 or 202 MHz for P, using CDCl3 as solvent (unless otherwise stated). For H
NMR, TMS was used as an internal standard (0.00 ppm) and for 31P-NMR, H3PO4 was the
external standard used (0.00 ppm). The data are reported as (s = singlet, d = doublet, t =
triplet, m = multiplet or unresolved, brs = broad signal, coupling constant(s) in Hz,
13
1
integration). C NMR spectra were recorded with H-decoupling {1H} at 101 MHz and
referenced to CDCl3 at 77.16 ppm. Enantiomeric ratios were determined by chiral HPLC
(1100 Series Agilent Hewlett-Packard, G1311A pump, DAD G1315B detector, Chiral
column AD-H Chiralpack, Particle size: 5 µm; Dimensions: 4.6 mm x 250 mm). Exact
masses were determined by HRMS (Agilent 7200 de Quadrupole-Time of Flight (Q-TOF)).
Procedure for the synthesis of anilines 1g and 1p:42 Into an oven-dried pressure tube
was added the corresponding N-(nitrophenyl)acetamide (360.0 mg, 2 mmol) capped with a
rubber septum and the system was evacuated and filled with Ar (3 times), then MeOH
anhydrous (10 mL) was added, followed by 10% wt Pd/C (100.0 mg, 0.10 mmol) and
ammonium formate (252.22 mg, 4 mmol). After 24 h at 20 ºC (water bath), the reaction
mixture was filtered through a short plug of Celite, dried over MgSO4, filtered and
concentrated in vacuo. The corresponding pure products were obtained after FC in silica gel
from (50:50 hexane/EtOAc to 100% EtOAc).
N-(4-Aminophenyl)acetamide (1g). Compound 1g was obtained as an off-white solid
(169.1 mg, 1.12 mmol, 57 %): TLC (EtOAc 100%) Rf 0.30; 1H-NMR (300 MHz, CD3OD) δ
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7.33 – 7.25 (m, 2H), 6.78 – 6.71 (m, 1H), 4.87 (s, 2H), 2.08 (s, 3H) ppm; 13C-NMR {1H} (75
MHz, CD3OD) δ 171.6 (CO), 143.6 (C-NH2), 132.2 (C-NHAc), 123.4 (2xCH), 117.9
(2xCH), 23.8 (Me).
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N-(3-Aminophenyl)acetamide (1p). Compound 1p was obtained as a pale-yellow solid
(145.2 mg, 0.96 mmol, 48%): TLC (EtOAc 100%) Rf 0.42; 1H-NMR (300 MHz, CD3OD) δ
7.18 – 6.98 (m, 2H), 6.87 – 6.80 (m, 1H), 6.51 (ddd, J = 8.0, 2.3, 1.1 Hz, 1H), 4.90 (s, 2H),
2.12 (s, 3H) ppm; 13C-NMR (75 MHz, CD3OD) δ 13C-NMR {1H} (75 MHz) δ 171.5 (CO),
149.2 (C3-NH2), 140.5 (C1-NHAc), 130.3 (C5-H), 112.6 (C6-H), 111.2 (C4-H), 108.4 (C2-H),
23.8 (Me).
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4-(Benzo[d]thiazol-2-yl)aniline (1ac). Aniline 1ac was synthesized by minor
modifications of a reported procedure.43 Into a pressure tube equipped with a magnetic stirrer
were added 4-aminobenzoic acid (1.37 g, 10.0 mmol, 1 equiv.) and polyphosphoric acid (4
g). The reaction mixture was gently heated to obtain a homogeneous mixture, before adding
2-Aminophenol (1.04 mL, 10.0 mmol, 1 equiv.). The tube was closed with a Teflon cap and
heated at 220 ºC into a san bath for 3 h. After cooling at room temperature, the reaction
mixture was poured into aqueous ammonia (15 mL, 25%v/v). The precipitate was collected
by filtration and washed with water (50 mL). The solid product was recrystallized from EtOH
(13 mL, 60 ºC to 20 ºC) (1.358 g, 6 mmol, 60%): TLC (hexane/EtOAc 70:30) Rf 0.36; 1H-
NMR (300 MHz, CDCl3) δ 8.05 – 7.79 (m, 2H), 7.38 (dt, J = 38.0, 7.6 Hz, 1H), 6.73 (d, J =
13
7.9 Hz, 1H) ppm; C-NMR {1H} (75 MHz, CDCl3) δ 168.7 (C5), 154.3 (C10a), 149.4 (C1-
NH2), 134.7 (C6a-S), 129.3 (2xC3-H), 126.2 (C9-H), 124.66 (C8-H), 124.04 (C4), 122.6 (C6-
H), 121.5 (C10-H), 114.9 (2xC2-H) ppm.
Procedure for the synthesis of 4-chlorobenzenediazonium tetrafluoroborate (1a-
diazonium salt) and 4-nitrobenzenediazonium tetrafluoroborate (1h-diazonium salt): The
corresponding aniline (10.0 mmol) was dissolved in a 50% (w/w aqueous solution) mixture
of tetrafluoroboric acid (5 mL, 39.9 mmol, 4 equiv) and water (5 mL). After cooling near to
0 ºC, a freshly-prepared solution of sodium nitrite (700 mg, 10.1 mmol) in H2O (3 mL), was
added in portions (0.25 mL each) during 10 min. The mixture was stirred for an additional
30 min and the thick precipitate formed was collected by filtration, washed with water, and
dissolved in the minimal amount of acetone. The diazonium tetrafluoroborate was then
precipitated by the addition of Et2O. The solid was filtered out and dried under vacuum for
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several hours. The corresponding diazonium salts were employed directly without further
purification.
2-Hydroxy-5-((4-nitrophenyl)diazenyl)benzoic acid (II-h): Into and oven-dried round-
bottom flask equipped with a magnetic stirrer, 4-nitrophenyl diazonium tetrafluoroborate
(1.185 g, 5.0 mmol) and SA (690 mg, 5.0 mmol) were added. The system was evacuated and
filled with argon (three times), before adding MeCN (13.20 mL) and water (6.80 mL). Then,
the reaction mixture was protected from the light and was stirred for 45 min at 20 ºC (water
bath). After this time, the aqueous solution was extracted with Et2O (3x20 mL), the combined
organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced
pressure without heating. The residue was dissolved in Et2O and precipitated by the addition
of hexane. The solid was filtered out and dried in vacuo to give the pure product as a brick-
red solid (287.2 mg, 0.90 mmol, 18 %). The spectral data matched that reported.44
1H-NMR (500 MHz, Acetone-d6) δ 8.56 (d, J = 2.5 Hz, 1H), 8.45 (d, J = 9.0 Hz, 2H),
8.22 (dd, J = 8.9, 2.5 Hz, 1H), 8.13 (d, J = 9.0 Hz, 2H), 7.20 (d, J = 8.9 Hz, 1H), 3.42 – 3.12
(m, 1H) ppm; 13C-NMR {1H} (126 MHz, Acetone) δ 172.2, 166.2, 156.7, 149.7, 146.2, 130.0,
128.7, 125.7, 124.2, 119.5, 113.8 ppm.
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2,2,6,6-Tetramethyl-1-(4-nitrophenoxy)piperidine (1h-TEMPO). p-Nitroaniline (41.4
mg, 0.30 mmol), TEMPO (93.9 mg, 0.6 mmol), SA (4.14 mg, 0.04 mmol), TPP (90 μL, 0.345
mmol) and TBN (60 μL, 0.45 mmol), were put into reacting in acetonitrile (1.5 mL). The
reaction mixture was then diluted with EtOAc (25 mL), transferred to a round-bottom flask,
and the solvent was evaporated in-vacuo. The crude mixture was purified by flash column
chromatography on silica gel from hexane 100% to 90:10 hexane/EtOAc obtaining the
TEMPO-adduct as a white amorphous solid (26.7 mg, 0.096 mmol, 32%): TLC
(hexane/EtOAc 90:10) Rf 0.65; 1H-NMR (300 MHz, CDCl3) δ 8.14 (d, J = 9.5 Hz, 2H), 7.30
13
(br s, 2H), 1.65 – 1.56 (m, 5H), 1.45 – 1.42 (m, 1H), 1.24 (s, 6H), 0.98 (s, 6H) ppm; C-
NMR {1H} (75 MHz, CDCl3) δ 168.8 (C), 141.2 (C), 125.6 (CH), 114.2 (CH), 61.0 (C), 39.8
(CH2), 32.4 (CH3), 20.6 (CH3), 17.0 (CH2) ppm; LRMS (EI-DIP) m/z (%) 278 (M+, 11), 263
(43), 149 (20), 125 (100), 97 (40).
General Procedure (GP) for the synthesis of compounds 2: The corresponding
aromatic amine (0.30 mmol) and the salicylic acid (SA, 4,14 mg, 0,03 mmol, 10 mol%) were
added into an oven-dried Schlenck tube. The system was evacuated and filled with argon
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(three times), then acetonitrile (1.5 mL) and the TPP (90.4 μL, 0.35 mmol) were added. The
reaction mixture was stirred vigorously until a homogeneous solution was obtained. At this
point, tert-butyl nitrite (TBN, 60 μL, 0.45 mmol) was added (the solution turned orange after
some minutes) and the reaction mixture was stirred for 2 h, keeping the temperature at 20 ºC
with an external water bath. For most substrates, the reaction was complete within 1 h, but
we ran the reactions over 2 h to use uniform conditions. The mixture was diluted with EtOAc
(25 mL), concentrated in vacuo, and the residue was purified by FC.
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Diphenyl (4-chlorophenyl)phosphonate (2a). Following the general procedure, compound
2a was obtained after FC (from 98:2 hexane/EtOAc to 90:10 hexane/EtOAc) as a yellow
liquid (93.18 mg, 0.27 mmol, 92%). The spectral data matched that reported:15 TLC
1
(hexane/EtOAc 80:20) Rf 0.40; H NMR (300 MHz, CDCl3) δ 7.90 (dd, J = 13.6, 8.5 Hz,
2H), 7.48 (dd, J = 8.4, 3.8 Hz, 2H), 7.33-7.27 (m, 4H), 7.17 (m, 6H) ppm; 13C NMR {1H}
(101, CDCl3) δ 150.3 (d, 2JC-P = 7.6 Hz, 2xC1’-H), 140.1 (d, 4JC-P = 4.2 Hz, C4-Cl), 133.9 (d,
2JC-P = 11.4 Hz, 2xC2-H), 130.0 (d, 4JC-P = 5.6 Hz, 4xC3’-H), 129.3 (d, 3JC-P = 16.6 Hz, 2xC3-
H), 125.48 (d, 1JC-P = 195.8 Hz, C1-P), 125.47 (2xC4’-H), 120.7 (d, 3JC-P = 4.6 Hz, 4xC2’-H)
ppm; LRMS (EI) m/z (%) 346 (M++2, 27) 344 (M+, 100), 251 (M+-OPh, 42), 77 (100). For
the numbering of the skeleton of compounds 2 used to assign the peaks in 13C NMR, see the
structure shown for compound 2n as example
Diphenyl (4-bromophenyl)phosphonate(2b). Following the general procedure, compound
2b was obtained after FC (from 95:5 hexane/EtOAc to 80:20 hexane/EtOAc) as a brown
liquid (74.98 mg, 0.193 mmol, 65%). The spectral data matched that reported:15 TLC
(hexane/EtOAc 80:20) Rf 0.32; 1H NMR (300 MHz, CDCl3) δ 7.86–7.76 (m, 2H), 7.67–7.61
13
(m, 2H), 7.36–7.22 (m, 4H), 7.21–7.12 (m, 6H) ppm; C NMR {1H} (75 MHz, CDCl3) δ
150.3 (d, 2JC-P= 7.5 Hz, 2xC1’-H), 133.9 (d, 2JC-P = 11.2 Hz, 2xC2-H), 132.2 (d, 3JC-P = 16.4
Hz, 2xC3-H), 129.9 (4xC3’-H), 128.7 (d, 4JC-P = 4.2 Hz, C4), 126.0 (d, 1JC-P = 195.4 Hz, C1-
P), 125.4 (2xC4’-H), 120.7 (d, 3JC-P = 4.5 Hz, 4xC2’-H) ppm; LRMS (EI) m/z (%) 390 (M++2,
100), 388 (M+, 97), 297 (M++2-OPh, 40) 295 (M+-OPh, 43), 170, (28), 77 (89).
Diphenyl phenylphosphonate (2c). Following the general procedure, compound 2c was
obtained after FC (90:10 hexane/EtOAc) as a dark orange solid (75.18 mg, 0.242 mmol,
81%). The spectral data matched that reported:15 TLC (hexane/EtOAc 80:20) Rf 0.25;
1H NMR (300 MHz, CDCl3) δ 7.97 (dd, J = 14.1, 7.5 Hz, 2H), 7.65–7.55 (m, 1H), 7.49 (td,
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J = 7.5, 4.7 Hz, 2H), 7.36–7.24 (m, 4H), 7.23–7.10 (m, 6H) ppm; 13C NMR {1H} (101 MHz,
CDCl3) δ 150.5 (d, 2JC-P = 7.6 Hz) (2xC1’), 133.3 (d, 4JC-P = 3.3 Hz) (C4-H), 132.4 (d, 2JC-P
10.3 Hz) (4xC2-H), 129.8 (4xC3’-H), 128.8 (d, 3JC-P = 15.7 Hz) (2xC3-H), 127.0 (d, 1JC-P
=
=
8
9
192.9 Hz) (C-P), 125.3 (2xC4’-H), 120.7 (d, 3JC-P = 4.6 Hz) (4xC2’-H) ppm; LRMS (EI) m/z
(%) 310 (M+, 78), 309 (M+-H, 100), 217 (41), 170 (33), 77 (46).
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Diphenyl p-tolylphosphonate (2d). Following the general procedure, compound 2d was
obtained after FC (from 98:2 hexane/EtOAc to 95:5 hexane/EtOAc) as an orange liquid (49.7
mg, 0.15 mmol, 50%). The spectral data matched that reported:15 TLC (hexane/EtOAc 80:20)
Rf 0.50; 1H NMR (400 MHz, CDCl3) δ 7.91 – 7.77 (dd, J = 13.8, 8.1 Hz, 2H), 7.33 – 7.23
(m, 6H), 7.18 (dq, J = 7.8, 1.3 Hz, 4H), 7.13 (tt, J = 7.2, 1.1 Hz, 2H), 2.40 (s, 3H) ppm; 13C
NMR {1H} (101, CDCl3) δ 150.6 (d, 2JC-P = 7.5 Hz, 2xC1’-H), 144.2 (d, 4JC-P = 3.5 Hz, C4-
Me), 132.5 (d, 2JC-P = 10.8 Hz, 2xC2-H), 129.9 (4xC3’-H), 129.6 (d, 3JC-P = 16.3 Hz, 2xC3-
1
3
H), 125.2 (2xC4’-H), 123.7 (d, JC-P = 195.1 Hz, C1-P), 120.8 (d, JC-P = 4.6 Hz, 4xC2’-H),
21.9 (Me) ppm; LRMS (EI) m/z (%) 324 (M+, 81), 323 (M+-H, 100), 231 (M+-OPh, 70), 77
(45).
Diphenyl (4-ethynylphenyl)phosphonate (2e). Following the general procedure,
compound 2e was obtained after FC (from 95:10 hexane/EtOAc to 80:20 hexane/EtOAc) as
a pale brown solid (65.1 mg, 0,192 mmol, 65%). The spectral data matched that reported:15
1
TLC (hexane/EtOAc/AcOH 80:20) Rf 0.28; H NMR (300 MHz, CDCl3) δ 7.92 (dd, J =
13.8, 8.5 Hz, 1H), 7.60 (dd, J = 8.3, 4.2 Hz, 2H), 7.33 – 7.25 (m, 4H), 7.21 – 7.11 (m, 6H)
ppm; 13C NMR {1H} (75 MHz, CDCl3) δ 150.33 (d, 2JC-P = 7.5 Hz, C1’), 132.29 (d, 3JC-P
=
=
2
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16.0 Hz, 2xC3-H), 132.28 (d, JC-P = 10.7 Hz, 2xC2-H), 129.9 (4xC3’-H), 127.3 (d, JC-P
193.8 Hz, C1), 125.4 (d, 4JC-P = 1.3 Hz, 2xC4’-H), 120.7 (d, 3JC-P = 4.5 Hz, 4xC2’-H), 120.2
(d, 4JC-P = 4.8 Hz, C4), 82.5 (d, 5JC-P = 1.8 Hz, C≡CH), 80.7 (CC-H) ppm; LRMS (EI) m/z
(%) 334 (M+, 96), 333 (M+-H, 100), 241 (54), 194 (42), 77 (68).
Diphenyl (4-methoxyphenyl)phosphonate (2f). Following the general procedure,
compound 2f was obtained after FC (from 90:10 hexane/EtOAc to 70:30 hexane/EtOAc) as
a dark orange liquid (62.0 mg, 0.182 mmol, 61%). The spectral data matched that reported:15
TLC (hexane/EtOAc 80:20) Rf 0.28; 1H NMR (300 MHz, CDCl3) δ 7.97–7.86 (m, 2H), 7.35–
7.27 (m, 4H), 7.24–7.12 (m, 6H), 7.05–6.95 (m, 2H), 3.86 (s, 3H) ppm; 13C NMR {1H} (101
MHz, CDCl3) δ 163.6 (d, 4JC-P = 3.4 Hz, C4-OMe), 150.6 (d, 2JC-P = 7.4 Hz, 2xC1’), 134.5 (d,
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2JC-P = 11.9 Hz, 2xC2-H), 129.8 (4xC3’-H), 125.2 (2xC4’-H), 120.7 (d, 3JC-P = 4.6 Hz, 4xC2’-
H), 117.9 (d, 1JC-P = 200.5 Hz, C1-P), 114.3 (d, 3JC-P = 16.9 Hz, 2xC3-H), 55.5 (OCH3) ppm;
LRMS (EI) m/z (%) 340 (M+, 73), 247 (M+-OPh, 100), 200 (17), 77 (39).
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Diphenyl (4-acetamidophenyl)phosphonate(2g). Following the general procedure,
compound 2g was obtained after FC (from 50:50 hexane/EtOAc to 100% EtOAc) as an
orange sticky oil (69.0 mg, 0.19 mmol, 63%). The spectral data matched that reported:14 TLC
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(hexane/EtOAc 50:50) Rf 0.32; H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.81 (dd, J =
13.4, 8.4 Hz, 2H), 7.67 (dd, J = 8.4, 4.1 Hz, 2H), 7.32 – 7.16 (m, 4H), 7.17 – 7.05 (m, 6H),
2.07 (s, 3H) ppm; 13C NMR {1H} (101 MHz, CDCl3) δ 169.5 (CO), 150.3 (d, 2JC-P = 7.5 Hz,
C1’), 143.3 (d, 4JC-P = 3.6 Hz, C4-NH), 133.4 (d, 2JC-P = 11.4 Hz, 2xC2-H), 129.9 (4xC3’-H),
125.4 (2xC4’-H), 120.73 (d, 3JC-P = 4.5 Hz, C2’-H), 120.61 (d, 1JC-P = 198.6 Hz, C1-P), 119.3
(d, J = 16.1 Hz, 2xC3-H), 24.6 (NHCOCH3) ppm; LRMS (EI) m/z (%) 367 (M+, 100), 325
(25), 274 (64), 232 (86).
Diphenyl (4-nitrophenyl)phosphonate (2h). Following the general procedure, compound
2h was obtained after FC (from 95:5 hexane/EtOAc to 70:30 hexane/EtOAc) as an orange
liquid (100.2 mg, 0.28 mmol, 94%). The spectral data matched that reported:15 TLC
(hexane/EtOAc 80:20) Rf 0.20; 1H NMR (300 MHz, CDCl3) δ 8.37 – 8.32 (m, 2H), 8.21 –
8.12 (m, 2H), 7.36 – 7.28 (m, 4H), 7.19 (m, 6H) ppm; 13C NMR {1H} (75 MHz, CDCl3) δ
150.8 (d, 4JC-P = 4.0 Hz, C4-NO2), 150.0 (d, 2JC-P = 7.8 Hz, 2xC1’), 133.91 (d, 1JC-P = 191.8
Hz, C-P), 133.73 (d, 2JC-P = 11.1 Hz, 2xC2-H), 130.1 (4xC3’-H), 126.0 (2xC4’-H), 123.7 (d,
3JC-P = 16.1 Hz, 2xC3-H), 120.6 (d, 3JC-P = 4.5 Hz, 4xC2’-H) ppm; LRMS (EI) m/z (%) 355
(M+, 90), 354 (M+-H, 100), 308 (M+-NO2 17), 262 (M+-OPh, 15), 215 (37), 77 (89).
Diphenyl (4-cyanophenyl)phosphonate (2i). Following the general procedure, compound
2i was obtained after FC (from 85:15 to 80:20 hexane/EtOAc) as pale brown solid (82.4 mg,
0.25 mmol, 82%). The spectral data matched that reported:15TLC (hexane/EtOAc 80:20) Rf
0.18; 1H NMR (300 MHz, CDCl3) δ 8.13–8.02 (m, 2H), 7.84–7.76 (m, 2H), 7.36–7.27 (m,
4H), 7.21–7.14 (m, 6H) ppm; 13C NMR {1H} (75 MHz, CDCl3) δ 150.0 (d, 2JC-P = 7.8 Hz,
2xC1’), 132.89 (d, 2JC-P = 10.3 Hz, 2xC2-H), 132.33 (d, 3JC-P = 15.8 Hz, 2xC3-H), 132.07 (d,
1JC-P = 192.5 Hz, C1-P), 130.1 (4xC3’-H), 125.8 (d, 5JC-P = 1.4 Hz, 2xC4’-H), 120.6 (d, 3JC-P
5
4
= 4.6 Hz, 4xC2’-H), 117.7 (d, JC-P = 1.3 Hz, CN), 117.1 (d, JC-P = 3.7 Hz, C4-CN) ppm;
LRMS (EI) m/z (%) 335 (M+, 79), 334 (M+-1, 90), 242 (M+-OPh, 19), 195 (45), 77 (100).
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Diphenyl (4-acetylphenyl)phosphonate (2j). Following the general procedure, compound
2j was obtained after FC (from 85:15 to 7:3 hexane/EtOAc) as an orange liquid (79.80 mg,
0.23 mmol, 76%); The spectral data matched that reported:15 TLC (hexane/EtOAc 80:20) Rf
0.15; 1H NMR (300 MHz, CDCl3) δ 8.10 – 7.99 (m, 4H), 7.34 – 7.26 (m, 4H), 7.22 – 7.14
(m, 6H), 2.63 (s, 3H) ppm; 13C NMR {1H} (75, CDCl3) δ 197.4 (C=O), 150.2 (d, 2JC-P = 7.7
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Hz, 2xC1’), 140.5 (d, JC-P = 3.5 Hz, C4-COMe), 132.7 (d, JC-P = 10.6 Hz, 2xC2-H), 131.6
(d, 1JC-P = 191.1 Hz, C-P), 129.9 (d, 4JC-P = 1.1 Hz, 2xC3’-H), 128.3 (d, 3JC-P = 15.9 Hz, 2xC3-
H), 125.5 (d, 5JC-P = 1.3 Hz, 2xC4’-H), 120.6 (d, 3JC-P = 4.5 Hz, 4xC2’-H), 26.9 (CH3) ppm;
LRMS (EI) m/z (%) 352(M+, 100), 259 (M+-OPh, 33), 77 (82).
4-(Diphenoxyphosphoryl)benzoic acid (2k). Following the general procedure, compound
2k was obtained after FC (from 89:10:1 to 69:30:1 hexane/EtOAc/AcOH) as a pale yellow
solid (59.54 mg, 0,17 mmol, 56%): TLC (hexane/EtOAc/AcOH 79:20:1) Rf 0.32; 1H NMR
(300 MHz, Acetone-d6) δ 8.25 – 8.09 (m, 4H), 7.42 – 7.32 (m, 4H), 7.29 – 7.15 (m, 6H) ppm;
13C NMR {1H} (75 MHz, Acetone-d6) δ 166.7 (CO2H), 151.24 (d, 2JC-P= 7.3 Hz, C1’), 135.8
(d, 4JC-P = 3.3 Hz, C4), 133.4 (d, 2JC-P= 10.7 Hz, 2xC2-H), 132.4 (d, 1JC-P= 189.4 Hz, C1-P),
130.74 (4xC3’-H), 130.56 (d, 3JC-P = 15.8 Hz, 2xC3-H), 126.22 (d, 4JC-P = 1.2 Hz, 2xC4’-H),
121.42 (d, J = 4.6 Hz, 4xC2’-H) ppm; 31P-NMR (202 MHz, Acetone-d6) δ 11.40 ppm; LRMS
(EI) m/z (%) 279 (M+-Ph, 18),167 (25), 149 (100); HRMS (EI-TOF) m/z calculated for
C19H15O5P 354.0657, found 354.0652.
Methyl 4-(diphenoxyphosphoryl)benzoate (2l). Following the general procedure,
compound 2l was obtained after FC (from 90:10 hexane/EtOAc to 80:20 hexane/EtOAc) as
an orange solid (83.14 mg, 0.226 mmol, 75%): TLC (hexane/EtOAc 80:20) Rf 0.18; 1H NMR
(300 MHz, CDCl3) δ 8.20–8.13 (m, 2H), 8.09–7.98 (m, 2H), 7.34–7.24 (m, 4H), 7.21–7.12
(m, 6H), 3.95 (s, 3H) ppm; 13C NMR {1H} (75 MHz, CDCl3) δ 166.1 (CO), 150.2 (d, 2JC-P
=
7.8 Hz, 2xC1’), 134.5 (d, JC-P = 3.2 Hz, C4), 132.4 (d, JC-P = 10.6 Hz, 2xC2-H), 131.5 (d,
1JC-P = 191.4 Hz, C1-P), 130.0 (4xC3’-H), 129.7 (d, 3JC-P = 16.0 Hz, 2xC3-H), 125.6 (2xC4’-
H), 120.7 (d, 2JC-P = 4.6 Hz, C2’-H), 52.7 (CH3-O) ppm; 31P-NMR (162 MHz, CDCl3) δ 10.04
ppm; LRMS (EI) m/z (%) 368 (M+, 82), 367 (M+-H, 100), 337 (M+-OMe, 11), 275 (M+-OPh,
29), 228 (25), 77 (50); HRMS (EI-TOF) m/z calculated for C20H17O5P 368.0814, found
368.0798.
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Diphenyl (3-chlorophenyl)phosphonate (2m). Following the general procedure compound
2m was obtained after FC (from 90:10 to 70:30 hexane/EtOAc) as an orange solid (66.87
mg, 0.194 mmol, 65%): TLC (hexane/EtOAc 80:20) Rf 0.30; 1H NMR (300 MHz, CDCl3) δ
7.96 (dt, J = 14.5, 1.6 Hz, 1H), 7.84 (ddt, J = 13.6, 7.5, 1.3 Hz, 1H), 7.59–7.54 (m, 1H), 7.44
13
(td, J = 7.8, 5.2 Hz, 1H), 7.35–7.10 (m, 10H) ppm; C NMR {1H} (101 MHz, CDCl3) δ
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150.2 (d, 2JC-P = 7.7 Hz, 2xC1’), 135.2 (d, 3JC-P = 21.4 Hz, C3-Cl), 133.5 (d, 4JC-P = 3.2 Hz,
C4-H), 132.2 (d, 2J = 11.2 Hz, C2-H), 130.41 (d, 2JC-P = 9.8 Hz, C6-H), 130.23 (d, 3JC-P = 17.3
1
Hz, C5-H), 129.9 (4xC3’-H), 127.0 (d, JC-P = 254.9 Hz, C1-P), 125.5 (2xC4’-H), 120.7 (d,
3JC-P = 4.6 Hz, 4xC2’-H) ppm; LRMS (EI) m/z (%) 346 (M++2H, 34), 344 (M+, 100), 309
(M+-Cl, 10), 251 (M+-OPh, 32), 77 (72); 31P-NMR (162 MHz, CDCl3) δ 9.30 ppm; HRMS
(EI-TOF) m/z calculated for C18H14O3P (M+-Cl) 309.0681, found 309.0675.
Diphenyl (3-nitrophenyl)phosphonate (2n).
Following the general procedure compound 2n was obtained after
O
OPh
2
3
O2N
P
O
FC (from 90:10 to 80:20 hexane/EtOAc) as an orange solid (92.3
1
6
1'
4
2' mg, 0.260 mmol, 87%). The spectral data matched that reported:14
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TLC (hexane/EtOAc 80:20) Rf 0.15; 1H NMR (300 MHz, CDCl3) δ
3'
4'
8.87–8.77 (m, 1H), 8.53–8.41 (m, 1H), 8.29 (ddt, J = 13.1, 7.6, 1.3 Hz, 1H), 7.73 (ddd, J =
8.6, 7.6, 4.5 Hz, 1H), 7.36–7.28 (m, 4H), 7.23–7.15 (m, 6H) ppm; 13C NMR {1H} (101 MHz,
CDCl3) δ 150.0 (d, 2JC-P = 7.7 Hz, 2xC1’), 148.2 (d, 3JC-P = 19.2 Hz, C3-NO2), 138.0 (d, 2JC-
P = 10.3 Hz, C6-H), 130.23 (d, 3J = 16.3 Hz, C5-H), 130.08 (4xC3’-H), 129.6 (d, 1JC-P = 196.6
Hz, C1-P), 127.9 (d, 4JC-P = 3.0 Hz, C4-H), 127.2 (d, 2JC-P = 12.0 Hz, C2-H), 125.8 (2xC4’-H),
120.6 (d, 3JC-P = 4.6 Hz, 4xC2’-H) ppm; LRMS (EI-DIP) m/z (%) 355 (M+, 100), 308 (37),
262 (M+-OPh 17), 207 (24), 77 (64).
Diphenyl (3-(trifluoromethyl)phenyl)phosphonate (2o). Following the general procedure,
compound 2o was obtained after FC (90:10 hexane/EtOAc) as an orange liquid (75.10 mg,
1
0.198/ mmol, 66 %): TLC (hexane/EtOAc 80:20) Rf 0.32; H NMR (300 MHz, CDCl3) δ
8.23 (d, J = 14.3 Hz 1H), 8.16 (dd, J = 13.6, 7.6 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.65 (tdt,
13
J = 7.8, 4.3, 0.8 Hz, 1H), 7.36–7.14 (m, 10H) ppm; C NMR {1H} (101 MHz, CDCl3) δ
150.2 (d, 2JC-P = 7.8 Hz, 2xC1’), 135.6 (dd, 2JC-P, 5JC-F = 10.0,1 Hz, C6-H), 131.4 (dq, 2JC-F,
3
3JC-P = 32, 16.5 Hz, C3-CF3), 130.01 (4xC3’-H), 129.97 (q, JC-F = 3.6 Hz, C4-H)129.4 (d,
3JC-P = 15.9 Hz, C5-H), 129.3 (dq, 4JC-P, 3JC-F = 8.6, 3.8 Hz, C2-H), 126.7 (d, 1J = 186.2 Hz,
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C1-P), 125.6 (d, 5JC-P = 1.4 Hz ,2xC4’-H), 123.5 (qd, 1JC-F, 4JC-P = 272, 3 Hz, CF3), 120.7 (d,
31
3JC-P = 4.5 Hz, 4xC2’-H) ppm; P-NMR (122 MHz, CDCl3) δ 8.10 ppm; LRMS (EI) m/z
(%) 378 (M+, 100), 377 (M+-H, 98), 285 (28), 238 (45), 77 (85); HRMS (EI-TOF) m/z
calculated for C19H14F3O3P 378.0633, found 378.0615.
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Diphenyl (3-acetamidophenyl)phosphonate (2p). Following the general procedure,
compound 2p was obtained after FC (from 50:50 hexane/EtOAc to 100% EtOAc) as an
orange sticky oil (53.0 mg, 0.144 mmol, 48 %). The spectral data matched that reported:15
TLC (hexane/EtOAc 50:50): Rf 0.45; 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.42 – 8.35
(m, 1H), 7.91 (dt, J = 16.0, 1.8 Hz, 1H), 7.60 (ddt, J = 13.4, 7.6, 1.3 Hz, 1H), 7.47 (td, J =
7.9, 5.6 Hz, 1H), 7.35 – 7.20 (m, 4H), 7.17 – 7.01 (m, 6H), 1.86 (s, 3H) ppm; 13C NMR {1H}
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3
(101 MHz, CDCl3) δ 169.5 (CONHAr), 150.2 (d, JC-P = 7.7 Hz, 2xC2’), 139.7 (d, JC-P
20.2 Hz, C3-NHAc), 129.9 (4xC3’-H), 128.6 (d, 1JC-P = 227.0 Hz, C1-P), 126.5 (d, 2JC-P = 8.8
Hz, C6-H), 125.6 (2xC4’-H), 124.6 (C4-H), 123.3 (d, 3JC-P = 13.5 Hz, C5-H), 120.8 (d, 3JC-P
=
=
4.3 Hz, 4xC2’-H), 24.2 (NHCOCH3) ppm; LRMS (EI) m/z (%) 367 (M+, 48), 325 (100), 232
(15).
Diphenyl (2-chlorophenyl)phosphonate (2q). Following the general procedure, compound
2q was obtained after FC (from 95:5 to 80:20 hexane/EtOAc) as an orange liquid (69,1 mg,
0.20 mmol, 67%). The spectral data matched that reported:15 TLC (hexane/EtOAc 80:20) Rf
0.28; 1H NMR (400 MHz, CDCl3) δ 8.20 – 8.09 (m, 1H), 7.57 – 7.47 (m, 2H), 7.41 – 7.32
(m, 1H), 7.34 – 7.21 (m, 8H), 7.19 – 7.11 (m, 2H) ppm; 13C NMR {1H} (101 MHz, CDCl3)
δ 150.3 (d, 2JC-P = 7.6 Hz, C1’), 137.1 (d, 2JC-P = 2.9 Hz, C2-Cl), 137.0 (d, 3JC-P = 8.9 Hz, C3-
H), 134.7 (d, 4JC-P = 2.7 Hz, C4-H), 131.2 (d, 2JC-P = 10.8 Hz, C6-H), 129.8 (4xC3’-H), 126.8
(d, 3JC-P = 14.7 Hz, C5-H), 125.9 (d, 1JC-P = 196.5 Hz, C1-P), 125.4 (2xC4’-H), 120.7 (d, 2JC-
P = 4.7 Hz, 4xC2’-H) ppm; LRMS (EI-DIP) m/z (%) 346 (M++2, 21), 344 (M+, 86), 309 (M+-
Cl, 72), 215 (82), 77 (100).
Diphenyl o-tolylphosphonate (2r). Following the general procedure, compound 2r was
obtained after FC (from 95:5 to 85:15 hexane/EtOAc) as an orange liquid. (60.8 mg, 0.19
mmol, 63%). The spectral data matched that reported:15 TLC (hexane/EtOAc 80:20) Rf 0.28:
1H NMR (300 MHz, CDCl3) δ 8.08 (ddd, J = 15.2, 7.7, 1.3 Hz, 1H), 7.51 – 7.44 (m, 1H),
13
7.35 – 7.09 (m, 13H), 2.76 (d, J = 1.8 Hz, 3H) ppm; C NMR {1H} (75 MHz, CDCl3) δ
150.5 (d, 2JC-P = 7.8 Hz, 2xC1’), 142.2 (d, 2JC-P = 10.6 Hz, C2-Me), 134.5 (d, 2JC-P = 11.1 Hz,
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C6-H), 133.4 (d, JC-P = 3.1 Hz, C4-H), 131.6 (d, JC-P = 15.8 Hz, C3-H), 129.8 (4xC3’-H),
125.79 (d, JC-P = 15.8 Hz, C5-H), 125.73 (d, JC-P = 188.6 Hz, C-P), 125.1 (d, JC-P = 1.2
Hz, 2xC4’-H), 120.5 (d, 3JC-P = 4.6 Hz, 4xC2’-H), 21.6 (d, 3JC-P = 3.6 Hz, CH3) ppm; LRMS
(EI) m/z (%) 324 (M+, 100), 288 (18), 231 (25), 212 (30), 77 (54).
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Diphenyl [1,1'-biphenyl]-2-ylphosphonate (2s). Following the general procedure,
compound 2s was obtained after FC (from 95:5 to 80:20 hexane/EtOAc) and further purified
by recrystallization from i-PrOH as an orange crystalline solid (67.2 mg, 0.174 mmol, 58%):
TLC (hexane/EtOAc 80:20) Rf 0.30; mp (i-PrOH) 93-95 ºC; 1H NMR (300 MHz, CDCl3) δ
8.36 – 8.27 (m, 1H), 7.65 (tt, J = 7.6, 1.6 Hz, 1H), 7.54 (dtd, J = 7.6, 3.8, 1.4 Hz, 1H), 7.51
– 7.46 (m, 2H), 7.45 – 7.38 (m, 4H), 7.25 – 7.17 (m, 4H), 7.13 – 7.05 (m, 2H), 6.93 – 6.86
(m, 4H); 13C NMR {1H} (75 MHz, CDCl3) δ 150.5 (d, 2JC-P = 8.4 Hz, 2xC1’), 146.6 (d, 2JC-P
= 10.0 Hz, C2), 141.2 (d, 3JC-P = 4.2 Hz, C7), 134.6 (d, 2J = 10.8 Hz, C6-H), 133.0 (d, 4JC-P
=
3.1 Hz, C4-H), 131.9 (d, 3JC-P = 14.9 Hz, C5-H), 129.7 (2xC9-H), 129.6 (4xC3’-H), 127.8 (C10-
H), 127.8 (2xC8-H), 127.2 (d, 3JC-P= 15.6 Hz, C3-H), 125. 9 (d, 1JC-P = 192.4 Hz, C1-P ), 124.9
(d, 5JC-P = 1.2 Hz, 2xC4’-H), 120.5 (d, 2JC-P = 4.8 Hz, 4xC2’-H) ppm; 31P-NMR (122 MHz,
CDCl3) δ 11.43 ppm; LRMS (EI-DIP) m/z (%) 386 (M+, 42), 293 (M+-OPh), 199 (100);
HRMS (ESI-TOF) m/z calculated for C24H19O3P 386.1072, found 386.1071.
Diphenyl (2-methoxyphenyl)phosphonate (2t). Following the general procedure,
compound 2t was obtained after FC (from 75:25 to 65:35 hexane/EtOAc) as a brown liquid
(37.1 mg, 0.11 mmol, 37%). The spectral data matched that reported:44 TLC (hexane/EtOAc
1
80:20) Rf 0.13; H NMR (300 MHz, CDCl3) δ 7.96 (ddd, J = 15.7, 7.6, 1.8 Hz, 1H), 7.54
(dddd, J = 8.4, 7.4, 1.8, 0.9 Hz, 1H), 7.33 – 7.26 (m, 11H), 7.26 – 7.14 (m, 1H), 7.06 – 6.89
(m, 1H), 3.87 (s, 3H) ppm; 13C NMR {1H} (75 MHz, CDCl3) δ 161.5 (d, 2JC-P = 2.5 Hz, C2-
OMe), 150.8 (d, 2JC-P = 7.5 Hz, 2xC1’), 135.9 (d, 3JC-P = 7.9 Hz, C3-H), 135.5 (d, 2JC-P = 2.2
Hz, C6-H), 129.7 (d, 3JC-P = 1.0 Hz, 4xC3’-H), 125.0 (d, 4JC-P = 1.3 Hz, 2xC4’-H), 120.8 (d,
2JC-P = 4.6 Hz, 4xC2’-H), 120.55 (C4-H), 115.0 (d, 1JC-P = 192.2 Hz, C1-P), 111.4 (d, 3JC-P
=
9.9 Hz, C5-H), 55.9 (OCH3) ppm; LRMS (EI-DIP) m/z (%) 340 (M+, 27), 309 (M+-OMe, 11),
247 (M+-OPh, 100), 215 (49), 77 (42).
Diphenyl (2-cyanophenyl)phosphonate (2u). Following the general procedure, compound
2u was obtained after FC (80:20 hexane/EtOAc) as a pale orange solid (69.5 mg, 0.207 mmol,
1
69%). The spectral data matched that reported:14 TLC (hexane/EtOAc 80:20) Rf 0.15; H
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NMR (300 MHz, CDCl3) δ 8.31–8.21 (m, 1H), 7.91–7.84 (m, 1H), 7.78–7.66 (m, 2H), 7.39–
7.23 (m, 8H), 7.21–7.09 (m, 2H) ppm; 13C NMR {1H} (101 MHz, CDCl3) δ 150.1 (d, 2JC-P
= 8.1 Hz, 2xC1’), 135.7 (d, 2JC-P = 9.5 Hz, C6-H), 134.8 (d, 3JC-P = 11.4 Hz, C3-H), 133.5 (d,
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4JC-P = 2.7 Hz, C4-H), 132.6 (d, JC-P = 14.9 Hz, C5-H), 130.0 (d, JC-P = 193.1 Hz, C1-P),
129.9 (4xC3’-H), 125.6 (2xC4’-H), 120.6 (d, JC-P = 4.6 Hz, 4xC2’-H), 117.1 (d, JC-P = 5.9
Hz, CN), 115.0 (d, 2JC-P = 4.7 Hz, C2-CN) ppm; LRMS (EI-DIP) m/z (%) 335 (M+, 100), 242
(M+-OPh, 33), 195 (55), 170 (17), 77 (51).
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Diphenyl (2-nitrophenyl)phosphonate (2v). Following the general procedure, compound
2v was obtained after FC (from 98:2 to 50:50 hexane/EtOAc) as a brown solid (96.9 mg,
1
0.273 mmol, 91%): TLC (hexane/EtOAc 80:20) Rf 0.18; H NMR (300 MHz, CDCl3) δ
8.35–8.23 (m, 1H), 8.02 (ddd, J = 7.5, 6.2, 1.6 Hz, 1H), 7.82–7.68 (m, 2H), 7.35–7.12 (m,
10H) ppm; C NMR {1H} (101 MHz, CDCl3) δ 151.9 (C2-NO2), 150.3 (d, 2JC-P = 8.3 Hz,
13
2xC1’), 136.3 (d, 2JC-P = 6.6 Hz, C6-H), 134.3 (d, 4JC-P = 2.7 Hz, C4-H), 132.8 (d, 3JC-P = 13.9
Hz, C5-H), 129.9 (4xC3’-H), 125.6 (2xC4’-H), 124.9 (d, 3JC-P = 8.9 Hz, C3-H), 121.9 (d, 1JC-P
= 196.9 Hz, C1-P), 120.7 (d, 3JC-P = 4.6 Hz, 4xC2’-H) ppm; 31P-NMR (162 MHz, CDCl3) δ
4.70 ppm; LRMS (EI-DIP) m/z (%) 355 (M+, 6), 262 (M+-OPh, 100), 232 (64), 207 (36);
HRMS (EI-TOF) m/z calculated for C18H14NO5P 355.0610, found 355.0619.
Diphenyl (4-methoxy-2-nitrophenyl)phosphonate (2w). Following the general procedure,
compound 2w was obtained after FC (from 90:10 to 70:30 hexane/EtOAc) as a pale orange
oil (62.4 mg, 0,162 mmol, 54%): TLC (hexane/EtOAc/AcOH 80:20) Rf 0.20; 1H NMR (300
MHz, CDCl3) δ 8.18 (dd, J = 14.7, 8.7 Hz, 1H), 7.50 (dd, J = 5.3, 2.5 Hz, 1H), 7.33 – 7.25
(m, 4H), 7.24 – 7.07 (m, 7H), 3.91 (s, 3H) ppm; 13C NMR {1H} (75 MHz, CDCl3) δ 163.8
(d, JC-P = 3.0 Hz, C4-OMe), 153.3 (d, JC-P = 3.9 Hz, C2-NO2), 150.3 (d, JC-P = 8.1 Hz,
2xC1’), 138.0 (d, 3JC-P = 7.8 Hz, C3-H), 129.8 (d, 4JC-P = 1.0 Hz, 4xC3’-H), 125.4 (d, 5JC-P
1.4 Hz, 2xC4’-H), 120.6 (d, 3JC-P = 4.7 Hz, 4xC2’-H), 117.4 (d, 3JC-P = 14.8 Hz, C5-H), 112.5
4
2
2
=
(d, JC-P = 204.3 Hz, C1-P), 111.2 (d, JC-P = 9.9 Hz, C6-H), 56.3 (OCH3); P-NMR (162
MHz, CDCl3) δ 5.55 ppm; LRMS (EI) m/z (%) 385 (M+, 3), 355 (M+-OMe, 7), 292 (M+-
OPh, 100), 262 (24); HRMS (ESI-TOF) m/z calculated for C19H16NO6P 385.0715, found
385.0716.
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2
31
Diphenyl (2-bromo-5-fluorophenyl)phosphonate (2x). Following the general procedure,
compound 2x was obtained after FC (from 90:10 to 80:20 hexane/EtOAc) as a pale orange
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crystalline solid. (87.5 mg, 0.216 mmol, 72%): TLC (hexane/EtOAc 80:20) Rf 0.20; mp (i-
1
PrOH/hexane 3:1) 64-66 ºC; H NMR (400 MHz, CDCl3) δ 7.89 (ddd, J = 16.1, 8.4, 3.2 Hz,
1H), 7.69 (ddd, J = 8.7, 6.5, 4.7 Hz, 1H), 7.36 – 7.23 (m, 8H), 7.21 – 7.10 (m, 3H); 13C NMR
{1H} (101 MHz, CDCl3) δ 161.4 (dd, J = 250.9, 20.7 Hz, C5-F), 150.2 (d, J = 7.6 Hz, 2xC1’),
136.4 (dd, J = 14.0, 7.3 Hz, C3-H), 130.2 (dd, J = 197.7, 6.2 Hz, C1-P), 129.9 (4xC3’-H),
125.6 (2xC4’-H), 124.5 (dd, J = 24.6, 9.9 Hz, C6-H), 121.9 (dd, J = 22.2, 3.1 Hz, C4-H), 120.6
(d, J = 4.7 Hz, 4xC2’-H), 119.6 (t, J = 3.5 Hz, C2-Br) ppm; 31P-NMR (202 MHz, CDCl3) δ
6.11 (d, J = 7.1 Hz) ppm; LRMS (EI) m/z (%) 408 (M++2 ,56), 406 (M+, 58), 327 (M+-Br,
50), 233 (46), 77 (100); HRMS (EI-TOF) m/z calculated for C18H13BrFO3P 405.977, found
405.9773.
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Diphenyl quinolin-8-ylphosphonate (2y). Following the general procedure, compound 2y
was obtained after FC (from 90:10 to 70:30 hexane/EtOAc) as a dark brown solid (34.7 mg,
0.096 mmol, 32%): TLC (hexane/EtOAc/AcOH 80:20) Rf 0.12; 1H NMR (300 MHz, CDCl3)
δ 9.15 (dd, J = 4.3, 1.7 Hz, 1H), 8.54 (ddd, J = 16.9, 7.1, 1.5 Hz, 1H), 8.24 (dt, J = 8.3, 2.1
Hz, 1H), 8.07 (dt, J = 8.2, 1.5 Hz, 1H), 7.62 (ddd, J = 8.2, 7.1, 3.9 Hz, 1H), 7.53 (dd, J = 8.3,
13
4.2 Hz, 1H), 7.25 (d, J = 4.4 Hz, 8H), 7.10 (tdd, J = 6.4, 3.2, 1.8 Hz, 2H) ppm; C NMR
{1H} (75 MHz, CDCl3) δ 151.4 (C2-H), 150.9 (d, 2JC-P = 7.5 Hz, 2xC1’), 148.0 (d, J = 1.2 Hz,
C8a), 146.5 (d, J = 205.0 Hz, C8), 138.3 (d, J = 8.5 Hz, C4-H), 134.1 (d, J = 3.4 Hz, C5-H),
129.6 (C3’), 128.4 (d, 2JC-P = 11.3 Hz, C7-H), 127.5 (C4a), 125.9 (d, J = 17.1 Hz, C6-H), 125.0
(d, J = 1.4 Hz, C4’-H), 122.1 (C3-H), 121.0 (d, J = 4.6 Hz, C2’-H) ppm; 31P-NMR (122 MHz,
CDCl3) δ 10.7 ppm; LRMS (EI-DIP) m/z (%) 361 (M+, 6), 268 (M+-OPh, 100), 192 (12);
HRMS (EI-TOF) m/z calculated for C21H16NO3P 361.0868, found 361.0854.
Diphenyl benzo[d]thiazol-2-ylphosphonate (2z). Following the general procedure,
compound 2z was obtained after FC (from 90:10 to 70:30 hexane/EtOAc) as a pale pale
1
yellow oil (29.7 mg, 0,081 mmol, 27%): TLC (hexane/EtOAc/AcOH 80:20) Rf 0.21; H
NMR (400 MHz, CDCl3) δ 8.31 (dd, J = 8.4, 1.0 Hz, 1H), 8.01 (ddd, J = 7.9, 1.4, 0.8 Hz,
13
1H), 7.66 – 7.52 (m, 2H), 7.37 – 7.27 (m, 8H), 7.23 – 7.14 (m, 2H) ppm; C NMR {1H}
(101 MHz, CDCl3) δ 157.9 (d,1JC-P = 251.2 Hz, C2), 154.6 (d, 3JC-P = 30.6 Hz, C3a-N), 150.0
(d, 2JC-P = 7.6 Hz, C1’), 136.9 (C7a), 130.0 (4xC3’-H), 127.6 (C5-H), 127.3 (C6-H), 125.9 (C7-
H), 125.5 (C4-H), 122.2 (d, 5JC-P = 1.9 Hz, 2xC4’-H), 120.9 (d, 4JC-P= 4.6 Hz, 4xC2’-H) ppm;
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31P-NMR (122 MHz, CDCl3) δ -10.28 ppm; LRMS (EI-DIP) m/z (%) 367 (M+, 8), 303 (21),
207 (100); HRMS (EI-TOF) m/z calculated for C19H14NO3PS 367.0432, found 367.0407.
Methyl 3-(diphenoxyphosphoryl)tiophene-2-carboxylate (2aa). Following the general
procedure, compound 2aa was obtained after FC (from 90:10 to 70:30 hexane/EtOAc) as an
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orange liquid (56.2 mg, 0.15 mmol, 50%): TLC (hexane/EtOAc 80:20) Rf 0.10; H NMR
(300 MHz, CDCl3) δ 7.66 (t, J = 5.0 Hz, 1H), 7.57 (dd, J = 5.0, 3.4 Hz, 1H), 7.34–7.25 (m,
13
4H), 7.25–7.19 (m, 4H), 7.18–7.10 (m, 2H), 3.90 (s, 3H) ppm; C NMR {1H} (75 MHz,
CDCl3) δ 160.8 (CO2Me), 150.6 (d, 2JC-P = 8.0 Hz, 2xC1’-H), 140.3 (d, 2JC-P = 15.0 Hz, C2),
134.7 (d, 2JC-P = 15.4 Hz, C4-H), 132.2 (d, 1JC-P = 201.4 Hz, C2-P), 130.9 (d, 3JC-P = 20.8 Hz,
C5-H), 129.8 (4xC3’-H), 125.3 (2xC4’-H), 120.7 (d, 3JC-P = 4.7 Hz, 4xC2’-H), 53.0 (O-CH3)
ppm; 31P-NMR (162 MHz, CDCl3) δ 11.40 ppm; LRMS (EI) m/z (%) 374 (M+,1), 343 (M+-
OMe, 4), 281 (M+-OPh, 100), 77 (6); HRMS (EI-TOF) m/z calculated for C17H12O4PS
343.0194 (M+-OMe), found 343.0164.
Diphenyl (2-chloropyridin-3-yl)phosphonate (2ab). Following the general procedure,
compound 2ab was obtained after FC (from 95:5 to 70:30 hexane/EtOAc) as an orange liquid
(76.75 mg, 0.22 mmol, 74 %). The spectral data matched that reported:14 TLC
(hexane/EtOAc 80:20) Rf 0.10; 1H NMR (300 MHz, CDCl3) δ 8.57 (dt, J = 4.6, 2.2 Hz, 1H),
13
8.44 (ddd, J = 14.7, 7.6, 2.1 Hz, 1H), 7.38 – 7.22 (m, 9H), 7.19 – 7.12 (m, 2H) ppm; C
NMR {1H} (75 MHz, CDCl3) δ 153.6 (C6), 153.1 (d, 2JC-P = 5.8 Hz, C2-H), 150.0 (d, 2JC-P
=
7.7 Hz, C1’), 146.1 (d, 2JC-P = 8.6 Hz, C4-H), 129.9 (4xC3’-H), 125.7 (d, 4JC-P = 1.4 Hz, 2xC4’-
H), 123.5 (d, 1JC-P = 186.7 Hz, C3-P), 122.2 (d, 3JC-P = 10.9 Hz, C5-H), 120.6 (d, 2JC-P = 4.7
Hz, C2’-H); LRMS (EI-DIP) m/z (%) 347 (M++2, 21), 345 (M+, 82), 310 (M+-Cl, 62), 169
(100).
Diphenyl (4-(benzo[d]thiazol-2-yl)phenyl)phosphonate (2ac). Following the general
procedure, compound 2ac was obtained after FC (from 90:10 to 80:20 hexane/EtOAc) as a
crystalline pale yellow solid (107.6 mg, 0.24 mmol, 81 %): TLC (hexane/EtOAc 80:20) Rf
1
0.36; mp (hexane/EtOAc 4:1) 133-135 ºC; H NMR (300 MHz, CDCl3) δ 8.24 – 8.19 (m,
2H), 8.14 – 8.04 (m, 3H), 7.92 (dt, J = 7.9, 0.9 Hz, 1H), 7.53 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H),
7.43 (ddd, J = 8.3, 7.2, 1.2 Hz, 1H), 7.35 – 7.27 (m, 4H), 7.25 – 7.11 (m, 6H) ppm; 13C NMR
{1H} (75 MHz, CDCl3) δ 166.3 (C5), 154.1 (C10a-N), 150.3 (d, 2JC-P = 7.5 Hz, 2xC1’), 137.8
(d, 2JC-P = 3.5 Hz, C4), 135.3 (C6a-S), 133.1 (d, 2JC-P = 10.6 Hz, 2xC2-H), 129.93 (4xC3’-H),
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129.24 (d, 2JC-P = 192.9 Hz, C1), 127.6 (d, 2JC-P = 16.0 Hz, 2xC3-H), 126.8 (C8-H), 126.0 (C9-
2
H), 125.4 (2xC4’-H), 123.7 (C7-H), 121.9 (C10-H), 120.7 (d, JC-P = 4.4 Hz, 4xC2’-H) ppm;
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31P-NMR (162 MHz, CDCl3) δ 10.32 ppm; LRMS (EI-DIP) m/z (%) 443 (M+, 98), 350 (M+-
OPh, 100), 77; HRMS (EI-TOF) m/z calculated for C25H18NO3PS 443.0745, found 443.074.
Diethyl (4-(benzo[d]thiazol-2-yl)phenyl)phosphonate (3). The phosphonate 2ac (443.5
mg, 1.00 mmol) was added into a flame-dried round bottom flask, and the system was
evacuated and filled with argon (three times). EtOH (3 mL, 99.9 %) was then added and the
mixture was stirred until a homogeneous solution was obtained. Then, freshly prepared
NaOEt (3 mL, 2 M, 6 equiv) was added dropwise, while stirring at 20 ºC (external water
bath). After 2 h, NaOH (40 mL, 1 M) was added to the reaction mixture and it was extracted
with Et2O (3x20 mL). The combined organic layers were dried over MgSO4, filtered and
evaporated in vacuo. The residue was purified by FC on silica gel (from 90:10 to 70:30
hexane/EtOAc), to obtain the pure product as a pale yellow solid (277.5 mg, 0.80 mmol,
80%). The spectral data matched that reported.45
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TLC (hexane/EtOAc 80:20) Rf 0.24; 1H-NMR (300 MHz, CDCl3)
7
3
2
6a
O
8
9
S
5
4
1
δ 8.22 – 8.15 (m, 2H), 8.11 (ddd, J = 8.2, 1.3, 0.6 Hz, 1H), 7.98
– 7.88 (m, 3H), 7.52 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.42 (ddd, J
P OEt
OEt
10a N
10
= 8.3, 7.3, 1.2 Hz, 1H), 4.26 – 4.01 (m, 4H), 1.34 (td, J = 7.1, 0.6 Hz, 6H); 13C-NMR {1H}
(75 MHz, CDCl3) δ 166.7 (C5), 153.9 (C10a-N), 137.0 (C4), 135.2 (C6a-S), 132.6 (d, 2JC-P
=
1
3
10.1 Hz, 2xC2-H), 131.1 (d, JC-P = 188.3 Hz, C1-P), 127.6 (d, JC-P = 15.2 Hz, 2xC3-H),
126.8 (C8-H), 125.92 (C9-H), 123.6 (C7-H), 121.9 (C10-H), 62.5 (d, 2JC-P = 5.5 Hz, O-CH2),
16.5 (d, 3JC-P = 6.5 Hz, CH3).
[1,1'-Biphenyl]-2-yldimethylphosphine oxide (4). Phosphonate 2s (115.92 mg, 0.30
mmol) was added into a flame-dried round bottom flask equipped with a magnetic stirrer and
capped with a rubber septum. The system was evacuated and filled with argon (three times),
before adding dry THF (3 mL) and then cooled to 0 ºC with an external ice-water bath. Once
the temperature was reached, MeMgBr (400 µL, 2.4 M, 2.6 equiv.) was added dropwise over
5 min, letting the drop fall down the walls of the flask to cool the MeMgBr solution. The
reaction was stirred for an additional 30 min, before being quenched with H2SO4 (0.5 mL,
0.10 M), while keeping the cooling bath. The reaction mixture was extracted with CH2Cl2
(3x10 mL), the combined organic layers were dried over MgSO4, filtered and the solvent was
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removed in vacuo. The residue was purified by FC on silica gel (from 100% EtOAc to 80:20
EtOAc/MeOH) giving the pure product as a white solid (63.0 mg, 0.28 mmol, 92 %). The
spectral data matched that reported.38b
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TLC (EtOAc/MeOH 90:10) Rf 0.18; 1H-NMR (400 MHz, CDCl3) δ 8.16 –
10
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8.06 (m, 1H), 7.50 (p, J = 7.4 Hz, 2H), 7.42 – 7.37 (m, 3H), 7.35 – 7.31 (m,
8
O
7
2
2H), 7.28 – 7.24 (m, 1H), 1.37 (d, J = 13.1 Hz, 6H) ppm; 13C-NMR {1H} (101
Me
P
Me
3
4
1
6
2
3
MHz, CDCl3) δ 144.5 (d, JC-P = 9.9 Hz, C2), 141.2 (d, JC-P = 3.3 Hz, C7),
5
132.8 (d, 1JC-P = 94.7 Hz, C1-P), 132.1 (d, J = 8.3 Hz, C6-H), 131.3 (d, 4JC-P = 2.3 Hz, C4-H),
131.1 (d, JC-P = 9.9 Hz, C3-H), 129.7 (2xC9-H), 128.2 (C10-H), 128.2 (2xC8-H), 127.5 (d,
3
3JC-P = 10.7 Hz, C5-H), 19.0 (d, 1JC-P = 71.5 Hz, 2xMe-P) ppm; 31P-NMR (202 MHz, CDCl3)
δ 36.19 ppm; LRMS (EI): m/z (%) 230 (M+, 12), 229 (M+-H, 100), 215 (M+-Me, 8), 152 (10).
[1,1'-Biphenyl]-2-yldiphenylphosphine oxide (5). Phosphonate 2s (193.2 mg, 0.50 mmol)
was added into a flame-dried round bottom flask equipped with a magnetic stirrer and capped
with a rubber septum. The system was evacuated and filled with argon (three times), before
adding dry THF (3 mL) and then cooled to 0 ºC with an external ice-water bath. Once the
temperature was reached, PhMgBr (910 µL, 2.2 M, 4 equiv.) was added dropwise over 5 min,
letting the drop fall down the walls of the flask to cool the PhMgBr solution. The reaction
was stirred for an additional 4 h, before being quenched with H2SO4 (0.5 mL, 0.10 M), while
keeping the cooling bath. The reaction mixture was extracted with CH2Cl2 (3x10 mL), the
combined organic layers were dried over MgSO4, filtered and the solvent was removed in
vacuo. The residue was purified by FC on silica gel (from 50:50 hexane/EtOAc to 100%
EtOAc), giving the pure product as a white solid (141.80 mg, 0.40 mmol, 80 %). The spectral
data matched that reported:46
TLC (hexane/EtOAc 50:50) Rf = 0.30; 1H-NMR (400 MHz, CDCl3) δ
10
9
7.61 – 7.50 (m, 5H), 7.45 – 7.24 (m, 9H), 7.23 – 7.19 (m, 2H), 7.08 – 6.99
2'
3'
8
3
4
O
P
7
(m, 3H) ppm; 13C-NMR {1H} (101 MHz, CDCl3) δ 147.6 (d, 2JC-P = 8.5
Hz, C2), 140.2 (d, 3 JC-P = 4.1 Hz, C7), 134.0 (d, 3 JC-P = 12.2 Hz, C3-H),
132.9 (d, 1JC-P = 104.6 Hz, 2xC1’-P), 131.9 (d, 2JC-P = 9.8 Hz, C6-H), 131.7
1'
2
1
4'
Ph
6
5
(d, 4JC-P = 2.5 Hz, C4-H), 131.52 (d, 3JC-P = 9.3 Hz, 4xC3’-H), 131.50 (d, 1JC-P = 96.8 Hz, C1-
4
2
P), 131.1 (d, JC-P = 2.8 Hz, C4’-H), 130.1 (2xC9-H), 128.0 (d, JC-P = 12.0 Hz, 4xC2’-H),
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127.1 (2xC8-H), 127.06 (C10-H), 126.5 (d, J = 12.4 Hz, C5-H) ppm; P-NMR (162 MHz,
CDCl3) δ 32.60 ppm; LRMS (EI) m/z (%) 353 (M+, 43), 277 (100), 199 (27).
6
Phenyl [1,1'-biphenyl]-2-yl(phenyl)phosphinate (6). Phosphonate 2s (193.2 mg, 0.50
mmol) was added into a flame-dried round bottom flask equipped with a magnetic stirrer and
capped with a rubber septum. The system was evacuated and filled with argon (three times),
before adding dry THF (3 mL) and then cooled to 0 ºC with an external ice-water bath. Once
the temperature was reached, PhMgBr (273 µL, 2.2 M, 1.2 equiv.) was added dropwise over
5 min, letting the drop fall down the walls of the flask to cool the PhMgBr solution. The
reaction was stirred for an additional 1 h, before being quenched with H2SO4 (0.5 mL, 0.10
M), while keeping the cooling bath. The reaction mixture was extracted with CH2Cl2 (3x10
mL), the combined organic layers were dried over MgSO4, filtered and the solvent was
removed in vacuo. The residue was purified by FC on silica gel (from 70:30 to 50:50
hexane/EtOAc) giving the pure product as a white solid (113 mg, 0.31 mmol, 62%).
7
8
9
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34
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
TLC (hexane/EtOAc 50:50) Rf 0.50; 1H-NMR (400 MHz, CDCl3) δ
10
9
8.25 (ddd, J = 13.2, 7.6, 1.5 Hz, 1H), 7.58 (tt, J = 7.6, 1.5 Hz, 1H), 7.50
2'
3'
8
3
4
O
P
7
1'
2
(tdd, J = 7.6, 2.9, 1.4 Hz, 1H), 7.42 – 7.32 (m, 3H), 7.30 – 7.10 (m, 10H),
7.02 (tt, J = 6.6, 1.1 Hz, 3H) ppm; 13C-NMR {1H} (101 MHz, CDCl3) δ
1
4'
O
A
6
B
C
5
2
2
150.9 (d, JC-P = 8.0 Hz, CA), 146.7 (d, JC-P = 12.1 Hz, C2), 140.4 (d,
D
3JC-P = 4.4 Hz, C7), 133.0 (d, 2JC-P = 8.8 Hz, C6-H), 132.2 (d, 4JC-P = 2.7
Hz, C4-H), 131.82 (d, 3JC-P = 10.5 Hz, 2xC3’-H), 131.80 (C4’-H), 131.6 (d, 3JC-P = 12.4 Hz,
C3-H), 131.5 (d, 1JC-P = 120.9 Hz, C1-P), 131.3 (d, 1JC-P = 118.7 Hz, C1’-P), 129.9 (2xCC-H),
129.5 (C9-H), 128.0 (d, 2JC-P = 13.6 Hz, 2xC2’-H), 127.5 (2xC8-H), 127.40 (C10-H), 127.0 (d,
3JC-P = 12.6 Hz, C5-H), 124.4 (CD-H), 120.7 (d, 3JC-P = 4.8 Hz, 2xCB-H) ppm; 31P-NMR (162
MHz, CDCl3) δ 30.87 ppm; LRMS (EI) m/z (%) 370 (M+, 49), 293 (M+-Ph, 64), 277 (M+,
100), 199 (85); HRMS (EI-TOF) m/z calculated for C24H19O2P 370.1123, found 370.1113.
[1,1'-Biphenyl]-2-yl(methyl)(phenyl)phosphine oxide (7). Phosphonate 6 (115.92 mg,
0.30 mmol) was added into a flame-dried round bottom flask equipped with a magnetic stirrer
and capped with a rubber septum. The system was evacuated and filled with argon (three
times), before adding dry THF (3 mL) and then cooled to 0 ºC with an external ice-water
bath. Once the temperature was reached, MeMgBr (18 µL, 2.4 M, 1.5 equiv.) was added
dropwise over 5 min, letting the drop fall down the walls of the flask to cool the MeMgBr
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solution. The reaction was stirred for an additional 1 h, before being quenched with H2SO4
(0.5 mL, 0.1 M), while keeping the cooling bath. The reaction mixture was extracted with
CH2Cl2 (3x10 mL), the combined organic layers were dried over MgSO4, filtered and the
solvent was removed in vacuo. The residue was purified by flash FC on silica gel (from 100%
EtOAc to 95:05 EtOAc/MeOH) giving the pure product as a white solid (76.0 mg, 0.26 mmol,
87%).
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60
1
TLC (100% EtOAc) Rf 0.50; H-NMR (400 MHz, CDCl3) δ 7.92
10
9
(ddd, J = 13.2, 7.7, 1.1 Hz, 1H), 7.55 (tt, J = 7.5, 1.4 Hz, 1H), 7.49 –
2'
3'
8
3
4
O
P
7
1'
2
7.35 (m, 4H), 7.35 – 7.24 (m, 4H), 7.21 (ddd, J = 8.4, 7.1, 1.2 Hz, 2H),
7.11 (dt, J = 6.9, 1.4 Hz, 2H), 1.59 (d, J = 13.4 Hz, 3H); 13C-NMR {1H}
(101 MHz, CDCl3) δ 146.1 (d, 2JC-P = 9.5 Hz, C2), 140.7 (d, J = 3.9 Hz,
1
4'
Me
6
5
C7), 134.7 (d, J = 102.4 Hz (C1’-P), 132.70 (d, J = 9.7 Hz, C6-H), 131.71 (d, J = 2.8 Hz, C-
H), 131.54 (d, J = 9.9 Hz, C3-H), 131.36 (d, J = 2.8 Hz, C-H), 130.5 (d, J = 9.9 Hz,2xC3’-H),
129.9 (2xC9-H), 128.4 (d, J = 12.1 Hz, 2xC2’-H), 127.83 (2xC8-H), 127.78 (C10-H), 127.17
31
(d, J = 11.5 Hz, C5-H), 16.72 (d, J = 74.1 Hz, CH3); P-NMR (162 MHz, CDCl3) δ 28.52
ppm; LRMS (EI) m/z (%) 292 (M+, 21), 291 (M+-H, 68), 215 (M+-Ph, 100), 199 (17); HRMS
(EI-TOF) m/z calculated for C19H17OP 292.1017, found 292.0993.
8-Fluoro-6-phenoxydibenzo[c,e][1,2]oxaphosphinine 6-oxide (8). Following a previously
reported procedure,47 the phosphonate 2x was added into a flame dried pressure tube (81.43,
0.20 mmol), followed by KOAc (29 mg, 0.30 mmol, 1.5 equiv.), (Ra)-BINAP (12.45 mg,
0.02 mmol, 10 mol-%) and Pd(OAc)2 (11.25 mg, 0.01 mmol, 5 mol-%). The tube was capped
with a rubber septum, and the system was evacuated and filled with argon (three times). Then,
dry toluene (1 mL) was added under Ar and the pressure tube was finally capped with a
pressure cap. The resulting mixture was stirred at 100 ºC (sand bath) for 24 h. After this time,
the tube was cooled to room temperature, and the solvent was removed in vacuo. The residue
was directly purified by FC on silica gel (from 70:30 to 60:40 hexane/EtOAc), affording the
desired product as a white solid (20.0 mg, 0.06 mmol, 31%). The enantiomeric ratio was
determined by chiral HPLC: Chiralpak AD-H, 25 ºC, flow rate: 1 mL/min, hexane/i-PrOH:
60:40, 254 nm, 8.6 min (S), 9.3 min (R). The absolute configuration was assigned by analogy
with compounds shown in the literature.47 The authentic racemic mixture to determine the
enantiomeric ratio by HPLC (see the traces in SI) was obtained with similar yield, using
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almost identical conditions, but in the absence of phosphine ligands. The spectral data
matched that reported:48
1
TLC (hexane/EtOAc 70:30) Rf 0.24; H-NMR (400
3
7
2
4
8
9
4a
MHz, CDCl3) δ 7.99 (ddd, J = 8.9, 7.4, 4.6 Hz, 1H), 7.90
(dd, J = 7.9, 1.6 Hz, 1H), 7.69 (ddd, J = 16.0, 7.4, 2.8 Hz,
1H), 7.48 – 7.38 (m, 2H), 7.34 – 7.21 (m, 4H), 7.18 – 7.12
O 5
O
P
O
1
10b
10a
OPh
PhO
6 P
10
11
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15
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6a
10
O
7
9
8
(R)-
8
(S)-
8
F
F
13
(m, 1H), 7.04 (dt, J = 8.4, 1.3 Hz, 2H) ppm; C-NMR
{1H} (101 MHz, CDCl3) δ 162.1 (dd, 1JC-F = 252.8, 3JC-P = 22.3 Hz, C8-F), 149.6 (2xd, 2JC-P
= 7.8 Hz, C1’ and C4a), 133.5 (dd, 2JC-P = 6.4, 4JC-F 3.4 Hz, C10a), 130.7 (C3-H), 129.9 (2xC3’-
H), 126.9 (dd, 3JC-P = 14.6, 3JC-F 7.6 Hz, C10-H), 125.6 (C1-H), 125.33 (C2-H), 125.29 (C4’-
H), 123.8 (dd, 1JC-P = 182.6, 3JC-F = 6.8 Hz, C6a), 122.1 (d, 3JC-P = 11.8 Hz, C10b), 121.6 (dd,
2JC-F = 22.0, 4JC-P = 3.0 Hz, C9-H), 120.7 (d, 3JC-P = 4.4 Hz, 2xC2’-H), 120.4 (d, 3JC-P = 7.1
Hz, C4-H), 117.4 (dd, 2JC-F = 23.1, 2JC-P = 9.9 Hz, C7-H) ppm; 31P-NMR (162 MHz, CDCl3)
δ 5.04 (d, 4JP-F = 8.0 Hz); LRMS (EI) m/z (%) 326 (M+, 78), 233 (100), 186 (45); HRMS (EI-
TOF) m/z calculated for C18H12FO3P 326.0508, found 326.0511.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
GC-calibrations, mechanistic experiments, gram-scale preparations, HPLC traces of chiral
compound 8, and spectroscopy data (PDF).
AUTHOR INFORMATION
Corresponding Author
* E-mail: josecarlos.gonzalez@ua.es
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was generously supported by the Spanish Ministerio de Ciencia, Innovación y
Universidades (MICIU; grant no. CTQ2017-88171-P) and the University of Alicante (grant
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