A highly efficient nucleophilic substitution reaction between R2P(O)H and triarylmethanols to synthesize phosphorus-substituted triarylmethanes

Article abstract of DOI:10.1039/c7ob02970e

A highly efficient and general nucleophilic substitution reaction between dialkyl H-phosphonates or diarylphosphine oxides and triarylmethanols catalyzed by HOTf (trifluoromethanesulfonic acid) has been developed. It provides an atom-economical protocol for the synthesis of various symmetrical and unsymmetrical phosphorus-substituted triarylmethanes that constitute an emerging family of potent anticancer agents in rich diversity with 40 to 96% yields. The synthetic applicability of this protocol is demonstrated by gram-scale preparations.

Full text of DOI:10.1039/c7ob02970e

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Takeharu Haino et al.
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A Highly Efficient Nucleophilic Substitution Reaction Between
R2P(O)H and Triarylmethanols to Phosphorus-Substituted
Triarylmethanes
Received 00th January 20xx,
Accepted 00th January 20xx
Long Chen,a* Xin-Yue Fanga and Yun-Xiang Zoua
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly efficient and general nucleophilic substitution reaction between dialkyl H-phosphonates or diarylphosphine oxides
and triarylmethanols catalyzed by HOTf (šŒ]Gµ}Œ}uꢀšZꢁvꢀ•µo(}v]ꢂ ꢁꢂ]ꢃ) has been developed. It provides an atom-
economical protocol for the synthesis of various symmetrical and unsymmetrical phosphorus-substituted triarylmethanes
that constitute an emerging family of potent anticancer agents in rich diversity with 40 to 96% yield. The synthetic
applicability
of
this
protocol
is
demonstrated
by
the
gram-scale
preparations.
between trialkyl- or triarylphosphite and triarylmethyl chlorides
(Scheme 1a).11 However, this transformation generally suffers from
harsh reaction conditions and the limited unavailability of
trialkylphosphites or triarylmethanols. Displacement of the
chlorines of triarylmethyl phosphonyl dichloride (prepared from
triarylmethanols and phosphorus trichloride) with alkoxides was
another choice to gain access to '-triarylsubstituted phosphonates
(Scheme 1b).10 Although the reaction condition of this method is
relatively mild, the easy hydrolysis of phosphorus trichloride and
triarylmethyl phosphonyl dichloride limits its application. Recently,
Anand and co-workers developed an attractive protocol for
accessing these compounds via NHC catalyzed 1,6-
hydrophosphonation of fuchsones (Scheme 1c).12 Nevertheless, the
substrate scope and diversity of the products are limited, and the
reaction yield is low to moderate. Therefore, the development of
highly efficient method for synthesis of phosphorus-substituted
triarylmethanes would be more attractive and highly desired.
Introduction
Triarylmethanes and related compounds have attracted significant
attention as a result of their distinctive structural and physical
properties and diverse applications as leuco dye precursors,1
fluorescent probes,2 and photochromic agents.3 In addition, they
also show powerful value in medicinal chemistry (Figure 1).4 On the
other hand, organophosphorus compounds play an important role
in organic synthesis, catalysis, biochemistry.5-9 Thus, it is suspected
that phosphorus-substituted triarylmethanes, which combine the
triarylmethyl group and P(E)R2 (E = O or lone pair) moieties together
at a tetrasubstituted carbon center, potentially have some unique
bioactivities. For instance, Hergenrother et al. has demonstrated
that triarylmethyl-containing phosphonates constituted an
emerging family of potent anticancer agents, which potently induce
death of multiple cancer cell lines in culture (Figure 1).10
Figure 1 Some biologically important triarylmethanes.
However,
the
synthesis
of
phosphorus-substituted
triarylmethanes has been scarcely investigated. The classical
approach to these compounds involves the Arbuzov reaction
a.Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province,
Sichuan Industrial Institute of Antibiotics Chengdu University, 168 Hua Guan
Road, Chengdu 610052, P. R. China;
E-mail: chenlong@cdu.edu.cn
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1 Synthetic approaches to phosphorus-substituted triarylmethanes.
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The catalytic nucleophilic substitution reaction of tertiary achieved by employing CH3CN and CH3NO2 as solvent (entries 17-
alcohols and carbon or heteroatom based nucleophiles is a versatile 18). And CH3NO2 was found to be the best solvent in terms of
method for efficient, diverse and atom-economical synthesis of fully reaction yield and time, which gave product 3a in 80% yield within
substituted carbon centers.13 Up to now, C-, O-, S- and N-based 14 h. (entry 18). We also tried raising the amount of 1a, and found
nucleophiles have be well used. But to the best of our knowledge, 85% yield could be obtained when using 1.5 equivs of 1a (entry 19).
phosphorus-containing nucleophiles have not been applied in this However, no further improvement was observed even increasing
transformation, which could provide a quite useful methodology for the equivlents of 1a to 2.0 (entry 20). Interestingly, when increasing
accessing
phosphorus-substituted
tetrasubstituted
carbon the temperature from 60 to 75 oC, the reaction could proceed
centers.14 In addition, this strategy has two important advantages: (i) completely within 10 h, giving 3a in 90% yield (entry 21). Reaction
high atom-economy,15 as only water is generated as the by-product; at 90 oC led to the formation of side products and lower yield of 3a
and (ii) excellent diversity, because different kinds of substituted (entry 22). Based on these results, the optimal reaction conditions
tertiary alcohols could readily react with phosphorus-containing were at 75 oC under air using 10 mol% of HOTf as catalyst and
nucleophiles, enabling convenient construction of phosphorus- CH3NO2 as solvent.
substituted tetrasubstituted carbon centers in sufficient structural
Table 1 Condition optimization
diversity, which could be attractive in medicinal research.
As continuous work directed at the catalytic construction of
organophosphorus compounds using easily available starting
materials,16 we envisage the acid catalyzed nucleophilic substitution
reaction between triarylmethanols and disubstituted phosphonates
or phosphine oxides17 would be a feasible protocol for synthesis of
phosphorus-substituted triarylmethanes (Scheme 1d). Herein, we
are pleased to find this reaction could proceed smoothly by using
HOTf as Brønsted acid catalyst, affording the desired products in
good to excellent yields.
tempt.
(oC)
time
(h)
yield
(%)b
entrya
catalyst
solvent
1
2
Fe(ClO4)3·6H2O
Cu(ClO4)2·6H2O
Zn(ClO4)2·6H2O
Hg(ClO4)2·6H2O
AgClO4·H2O
Ga(OTf)2
Hg(OTf)2
Sc(OTf)3
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
THF
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
75
90
24
24
24
20
24
44
18
18
44
24
18
24
24
12
24
24
24
22
14
14
14
10
10
55
50
3
44
4
63
5
43
Results and discussion
6
60
7
65
The reaction of '-triphenylmethanol 1a and diethyl H-
phosphonate 2a was selected as the model reaction for condition
optimization, and typical results were shown in Table 1. The
reaction was run out in 1,2-dichloroethane (DCE) at 60 oC. We first
screened a variety of inexpensive and easily to handle metal
perchlorate hydrates, known as powerful Lewis acid catalysts.18
FeIII-, CuII-, ZnII-, HgII- and AgI-derived perchlorates could catalyze
the reaction smoothly, furnishing the desired product 3a in
moderate yields (Table 1, entries 1-5). Among them, Hg(ClO4)2‰3H2O
proved to be the most efficient one, and afforded 3a in 63% yield
within 20 h (entry 4). And we found metal triflates19 could also
mediate the reaction. For example, under the catalysis of Ga(OTf)2
and Hg(OTf)2, product 3a was obtained in 60% and 65% yield,
respectively (Entries 6-7). However, lower yields were observed
when Sc(OTf)3 and AgOTf were used (entries 8-9). Finally, Brønsted
acids20 such as CF3CO2H, p-TsOH‰H2O, HClO4 and HOTf were
investigated, and only HClO4 and HOTf could promote the reaction
well, furnishing product 3a in 64% and 75% yield (entries 9-10).
8
51
9
AgOTf
46
9
HClO4
64
10
11
12
13
14
15
16
17
18
19c
20d
21c
22c
CF3SO3H
75
CF3SO3H
trace
30
CF3SO3H
1,4-dioxane
Ethyl acetate
Toluene
CF3SO3H
32
CF3SO3H
59
CF3SO3H
Acetone
trace
np
72
CF3SO3H
DMF
CF3SO3H
CH3CN
CF3SO3H
CH3NO2
80
CF3SO3H
CH3NO2
85
CF3SO3H
CH3NO2
86
CF3SO3H
CH3NO2
90
The catalyst screening indicated that HOTf was the optimal acid
catalyst. On this basis, we further investigated the solvent effects. It
was found that the solvent had a great effect on reaction outcome,
but there is no obvious pattern. For example, the use of
tetrahydrofuran (THF) and acetone as solvent resulted in trace
product (entries 11 and 15), and low to moderate yields were
obtained in 1,4-dioxane, ethyl acetate and toluene. (entries 12-14).
When polar and aprotic solvent N,N-dimethylformamide (DMF) was
used, no desired product was observed even raising the reaction
temperaure (entry 16). To our delight, improved yields could be
CF3SO3H
CH3NO2
79
a On a 0.30 mmol scale; b Isolated yield, np means no product 3a; 0.45
c
mmol of 1a; d 0.6 mmol of 1a.
With the best conditions in hand, we next examined the
substrate scope with respect to both triarylmethanols and R2P(O)H.
The reaction of a variety of symmetrical and unsymmetrical
triarylmethanols and diethyl H-phosphonate 2a were first checked
as shown in Scheme 2. The substituents on the phenyl ring greatly
influence the reaction rate and yield. For example, triarylmethanols
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that have electron-donating group such as methyl, methoxyl and phosphonates in this reaction, and products 4a-4c were obtained in
tert-butyl at the para position of the phenyl ring, afforded products 84-91% yields within 30 mins. We supposed the higher reactivity of
3b, 3c and 3d, respectively, in 80-95% yields. While triarylmethanols, diarylphosphine oxides might be ascribed to the higher
with electron-withdrawing group such as bromo, trifluomethyl, nucleophilicity of their corresponding phosphine tautomeric forms
were much less reactive and longer reaction time (31-41 h) and low compared to that of dialkyl H-phoshonates.21
yields (only 40-47%) were observed for products 3e and 3f.
Substituents on the ortho and meta position of phenyl ring also
affect the reaction results. Lower yields were obtained for products
3g and 3h compared to 3b and 3c. Interestingly, triarylmethaol that
bear two methoxyl groups on the ortho and para positon of phenyl
ring could afford 3j in 88% yield within 23 h. Other symmetrical
triarylmethanols that prepared from (4-methoxyphenyl)magnesium
bromide and the corresponding diaryl ketones could also
participate in this reaction, furnishing products 3k-3o in good to
high yields. In addition, unsymmetrical triarylmethanols were also
viable substrates under this reaction condition, thereby affording
the desired unsymmetrical triarylmethanes bearing a diethyl H-
phosphonate group 3p-3r in 83-88% yield.
Scheme 3 Substrate scope of R2P(O)H compounds.
Considering the potential utility of phosphine oxides
containing an '-triarylmethyl group, we further checked the
reaction of diphenyl phosphine oxide 2b with various
symmetrical and unsymmetrical triarylmethanols (Scheme 4).
Generally, the reaction could proceed completely in 15 mins to
18 h, and the corresponding products 4a-4q were produced in
good to high yields (up to 96%).
Scheme 2 Substrate scope of symmetrical and unsymmetrical triarylmethanols.
Triarylmethanol 1b was then selected to evaluate the scope of
phosphorus-containing nucleophiles (Scheme 3). Dialkyl H-
phosphonates with methyl, isopropyl, and n-butyl as the ester
functionality could also be tolerated and afforded products 3s-3u in
78-90% yields. We also examined the reaction of 1b and diaryl- and
dialkyl substituted phosphine oxides, which provided a convenient
route to the stable precursors of phosphine compounds containing
a
'-triarylmethyl group. Interestingly, the reactivity of
Scheme 4 Syntheis of '-triarylmethyl substituted phosphine oxides.
diarylphosphine oxides was much higher than dialkyl H-
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To demonstrate the synthetic applicability of this protocol,
Journal Name
Experimental Section
the nucleophilic substitution reaction between R2P(O)H and
triarylmethanols was carried out on a gram scale under
optimal conditions (Scheme 5). As anticipated, products 3a
and 4a were obtained in 85% and 90% yields, respectively.
General information: Reactions were monitored by thin layer
chromatography using UV light to visualize the reaction course.
Purification of reaction products was carried out by flash
chromatography on silica gel. Chemical yields refer to pure isolated
substances. 1H and 13C NMR spectra were obtained using a Bruker
DPX-400 spectrometer. The 31P NMR spectra were recorded at 162
MHz with 85% H3PO4 as external standard. All reactions were run
under an atmosphere of air. Anhydrous CH3NO2 was prepared by
first drying with anhydrous Na2SO4 and then distilling under
reduced pressure. Triarylmethanols 1 were prepared according to
the
literature
report.22
Commercially
available
HOTf
(trifluoromethanesulfonic acid) was used as received.
Scheme 5 Gram scale reaction.
General procedure for the nucleophilic substitution reaction
between R2P(O)H and triarylmethanols
Considering the fact that the electronic property of the
substituents on the phenyl ring has great impact on the
reaction efficiency (Scheme 2 and 4) and similar kinds of
literature reports,17 we proposed a plausible mechanism for
this transformation (Scheme 6). In the presence of HOTf,
To a 5-mL vial were added triarylmethanols 1 (0.45 mmol, 1.5
equivs), R2P(O)H 2 (0.3 mmol, 1.0 equiv) and 1.0 mL of anhydrous
CH3NO2. After adding HOTf (4.5 mg, 10 mol%) which was prepared
as a solution in CH3NO2, the reaction mixture was stirred at 75 oC till
almost full conversion of 2 by TLC analysis. The reaction mixture
was directly subjected to column chromatography using petrol
ether/ethyl acetate (generally 6:1 to 3:1, v:v) as the eluent to afford
the desired products 3 or 4. The representative products are listed
here.
triarylmethyl cation is generated from triarylmethanol 1, while
the equilibrium of R2PV(O)H and R2PIIIOH shifts to the more
nucleophilic form R2PIIIOH. R2PIIIOH then immediately reacts
with triarylmethyl cation to produce the product
releasing the catalyst HOTf.
3 along with
Diethyl tritylphosphonate (3a).10 White solid, 102.6 mg, 90% yield;
1H NMR (400 MHz, CDCl3): d = 7.34-7.25 (m, 15H), 4.06-3.96 (m, 2H),
3.87-3.77 (m, 2H), 1.09 (t, J = 7.2 Hz, 6H); 13C{1H} NMR (100 MHz,
CDCl3): d = 141.6 (d, JC-P= 5.0 Hz), 130.7 (d, JC-P = 6.0 Hz), 127.8,
126.8 (d, JC-P = 1.0 Hz), 63.3(d, JC-P = 8.0 Hz), 63.0 (d, JC-P = 135.0 Hz),
16.2, 16.1; 31P{1H} NMR (162 MHz, CDCl3•W w = 25.9.
Diethyl (diphenyl(p-tolyl)methyl)phosphonate (3b). White solid,
108.7 mg, 92% yield; Mp: 126-128 oC; 1H NMR (400 MHz, CDCl3): d =
7.37-7.35 (m, 4H), 7.32-7.27 (m, 6H), 7.24-7.22 (m, 2H), 7.12-7.10
(m, 2H), 4.08-3.98 (m, 2H), 3.89-3.79 (m, 2H), 2.36 (s, 3H), 1.11 (t, J
= 7.2 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): d = 141.6, 138.4, 136.4,
130.6 (d, JC-P = 4.0 Hz), 130.5 (d, JC-P = 4.0 Hz), 128.5, 127.7, 126.8,
63.3 (d, JC-P = 5.0 Hz), 62.5 (d, JC-P = 90.0 Hz), 20.9, 16.2, 16.1; 31P{1H}
NMR (162 MHz, CDCl3): w = 26.2; IR (neat): 3756, 2920, 1493, 1241,
1046, 954, 700, 624 cm-1; HRMS (ESI): Exact mass calcd for
C24H27O3P [M+H]+: 395.1771, Found: 395.1769.
Scheme 6 Plausible mechanism.
Conclusions
In summary, we have reported in this article an atom-economical
and highly efficient nucleophilic substitution reaction between
R2P(O)H and triarylmethanols for efficient and diverse synthesis of
((4-Methoxyphenyl)diphenylmethyl)diphenylphosphine oxide (4a).
1
White powder, 129.4 mg, 91% yield; Mp: 181-183 oC; H NMR (400
MHz, CDCl3): d = 7.42-7.39 (m, 2H), 7.28-7.21 (m, 16 H), 7.14-7.11
(m, 4H), 6.77-6.76 (m, 2H), 3.81 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): d = 158.5, 133.5 (d, JC-P = 5.0 Hz), 132.9, 132.7, 132.1, 131.7,
131.4, 127.9, 127.8, 127.7, 127.1, 113.0, 64.0 (d, JC-P = 42.0 Hz), 55.2;
31P{1H} NMR (162 MHz, CDCl3): w = 35.0; IR (neat): 3068, 2838, 1607,
1508, 1436, 1251, 1104, 1031, 932, 712 cm-1; HRMS (ESI): Exact
mass calcd for C32H27O2P [M+H]+: 475.1821, Found: 475.1820.
symmetrical
and
unsymmetrical
phosphorus-substituted
triarylmethanes in good to excellent yields. This is the first example
that demonstrates that phosphorus-containing nucleophiles could
participate in the functionalization of tertiary alcohols to generate
phosphorus-containing fully substituted carbon centres. The
exploration of potential applications of the obtained products in
medicinal research and the extension of this protocol in the
construction of other useful phosphorus-containing compounds are
now in progress in our laboratory.
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16 L. Chen, Y.-X. Zou, X.-Y. Fang and X. Yin, Phosphorus, Sulfur, and
Silicon and the Related Elements, 2017, DOI:
10.1080/10426507.2017.1393424.
Conflicts of interest
There are no conflicts to declare.
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The financial support from Chengdu University New Faculty
Start-up Funding (No. 2081916045) and the Open Project
Program of Antibiotics Research and Re-evaluation Key
Laboratory of Sichuan Province (No. ARRLKF16-03) is highly
appreciated.
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Organic & Biomolecular Chemistry
Page 6 of 6
View Article Online
DOI: 10.1039/C7OB02970E
A highly efficient nucleophilic substitution reaction between R2P(O)H and triarylmethanols was reported,
which provides phosphorous-substituted triarylmethanes in rich diversity with 40-96% yield .