Tf2O-Promoted Activating Strategy of Phosphate Analogues: Synthesis of Mixed Phosphates and Phosphinate

Article abstract of DOI:10.1021/acs.orglett.8b02073

A metal-, toxic chloride reagent-free activating strategy of various phosphates has been developed. This method enables the facile synthesis of functional phosphates such as alkyl phosphates, aza phosphates, thiophosphate, and mixed diaryl phosphates. A transient phosphorylpyridin-1-ium species in situ generated from phosphates with Tf₂O/pyridine readily undergoes a substitution reaction with diverse nucleophiles to form versatile phosphate compounds.

Full text of DOI:10.1021/acs.orglett.8b02073

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Tf2O‑Promoted Activating Strategy of Phosphate Analogues:
Synthesis of Mixed Phosphates and Phosphinate
Hai Huang,†,‡ Jeffrey Ash,† and Jun Yong Kang*,†
†Department of Chemistry and Biochemistry, University of Nevada Las Vegas, 4505 South Maryland Parkway, Las Vegas, Nevada
89154-4003, United States
‡Department of Applied Chemistry, College of Chemistry and Molecular Engineering, Nanjing Tech University, No. 30 Puzhu Road
(S), Nanjing 211816, People’s Republic of China
S
* Supporting Information
ABSTRACT: A metal-, toxic chloride reagent-free activating
strategy of various phosphates has been developed. This method
enables the facile synthesis of functional phosphates such as alkyl
phosphates, aza phosphates, thiophosphate, and mixed diaryl
phosphates. A transient phosphorylpyridin-1-ium species in situ
generated from phosphates with Tf2O/pyridine readily undergoes
a substitution reaction with diverse nucleophiles to form versatile
phosphate compounds.
Organophosphate analogues are ubiquitous structural motifs
widely present in pharmaceuticals and bioactive small
molecules.1 The development of an efficient method for the
synthesis of these analogues is highly desirable but challenging
in organophosphorus chemistry. Over the past decades, a
number of synthetic methods for phosphate derivatives
employing different phosphorus reagents have been developed.
Prefunctionalized P(O)−X substrates have been commonly
used for the construction of organophosphate compounds
(Scheme 1, a).2 Nevertheless, this procedure suffered from
reagents due to their chemical inertness. In 2014, Feringa and
co-workers reported an elegant activation strategy of
phosphonate substrates for the synthesis of mixed alkyl aryl
phosphonates via a copper-catalyzed direct arylation of
dialkylphosphonates with diaryliodonium salts.8 However, the
current activating strategies of chemically inert pentavalent
phosphorus species mainly rely on stepwise processes, which
involve a substitution reaction of a pregenerated alkyl
phosphorus electrophile with nucleophiles.2a,9 Thus, a direct
functionalization strategy of inertial phosphates is of great
necessity, yet it remains a challenge.10
The Tf2O-triggered activation of carbonyl compounds,11
sulfoxides,12 and phosphine oxides13 has become an important
synthetic tool in organic synthesis. Recently, we reported a
direct nucleophilic substitution reaction of dialkyl phospho-
nates with hydroxyl compounds for the synthesis of mixed
phosphonates in which a highly reactive phosphorylpyridin-1-
ium intermediate A could be in situ generated (Scheme 2, a).14
With an enduring interest in organophosphorus compounds
and as part of our continued effort to contribute to diverse
Scheme 1. Methods for the Synthesis of Phosphates
shortcomings such as stepwise synthesis, limited functional
group tolerance, and moisture-sensitive reagents. Atherton and
Todd introduced dialkyl phosphites (P(O)−H) as a
phosphorylation reagent in 1947 (Scheme 1, b).3 A highly
reactive in situ formed halogen phosphonate intermediate is
responsible for phosphorylation of alcohol and amine
nucleophiles via a substitution reaction.3,4 In addition, dialkyl
phosphates (P(O)−OH) with a chemically differentiated
−OH group on the phosphorus atom are efficiently activated
under basic conditions, and they have been subjected to
esterification,5 alkylation,6 and coupling reactions7 to give
phosphate compounds (Scheme 1, c). On the other hand,
pentavalent phosphorus species such as phosphate/phospho-
nate/phosphinate moieties are underused as phosphorylation
Scheme 2. Activation Strategies of Phosphonates/
Phosphates as P-reagents
Received: July 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02073
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
organophosphate synthesis employing the chemically stable
phosphate moieties, we hypothesized that trialkyl phosphates
could be also activated by Tf2O/pyridine to afford the
phosphorylpyridin-1-ium intermediate,15 which is then con-
verted to functional phosphates via a nucleophilic substitution
reaction (Scheme 2, b). Herein, we report a general activating
strategy of phosphate analogues for the synthesis of phosphate
derivatives and mixed phosphates.
Scheme 3. Scope of Nucleophiles
To test our hypothesis, we used triethyl phosphate 1a and
phenol 2a as model substrates to optimize the reaction
conditions (Table 1). When our previous optimized reaction
a
Table 1. Optimization of the Reaction Conditions
b
entry
base
X/Y/Z
yield (%)
1
2
3
4
5
6
7
8
9
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
lutidine
DMAP
DABCO
DBU
1.5/2.0/2.5
1.5/2.0/2.0
1.5/2.0/1.5
2.0/2.0/2.0
1.5/1.1/2.0
1.5/1.5/2.0
1.5/2.0/2.0
1.5/2.0/2.0
1.5/2.0/2.0
1.5/2.0/2.0
96
99 (92)
c
43
92
80
70
d
d
d
d
10
a
Reaction conditions: 1a (0.2 mmol), Tf2O (X equiv), base (Y equiv)
b
in DCM (1.0 mL) for 10 min, then 2a (Z equiv) for 30 min. Yield
was determined by H NMR on the crude reaction mixture using
1,3,5-trimethylbenzene as an internal standard. Isolated yield. Major
a
Reaction conditions: 1 (0.2 mmol), Tf2O (0.3 mmol), pyridine (0.4
mmol) in DCM (1.0 mL) for 10 min, then 2 (0.4 mmol) for 30 min;
1
c
d
b
isolated yields are given. A gram-scale experiment with 6.0 mmol of
product was PhOTf.
1a.
conditions for mixed phosphonate were employed, the desired
phenyl phosphate 3a was generated in 96% yield by NMR
(Table 1, entry 1). Further control experiments revealed that
the optimized reaction conditions need 2 equiv of phenol 2a,
providing the target compound with 92% isolated yield (Table
1, entries 2−6). Evaluation of other bases such as lutidine,
DMAP, DABCO, and DBU provided no target products
(Table 1, entries 7−10).
With the optimized reaction conditions in hand, the scope of
this reaction was explored with phosphates 1 and diverse
arenol nucleophiles 2 to synthesize phosphate derivatives 3
(Scheme 3). To demonstrate scalability of this reaction, we
first performed a gram-scale reaction of 1a (1.09 g, 6.0 mmol)
with 2a, which afforded the target phosphonate product 3a
(1.24 g) in 90% yield (Scheme 3, 3a). Generally, the electronic
effects of substituents on the phenyl ring have a negligible
effect on this transformation. The reaction tolerates various
phenols with diverse substituents (Me, MeO, Br, I, NO2, Ph)
and polycyclic aromatic alcohols such as 1-naphthol and 2-
naphthol, providing the desired aryl phosphates in 71−91%
yields (Scheme 3, 3b−k). However, a bulky nucleophile such
as 2,6-diisopropyl phenol reduced the reactivity and provided
the target product 3m in 53% yield due to steric hindrance. On
the other hand, a sterically bulky phosphate electrophile,
triisopropyl phosphate 1b, afforded the corresponding
diisopropyl phosphate 3n in 73% yield (Scheme 3, 3n).
Next, we investigated the late-stage phosphorylation of various
natural products. The phosphorylation of quinol, coumarin,
sesamol, and ferulate demonstrated good functional group
tolerance (e.g., carbonate, ester, ether, and acrylate), yielding
the corresponding products in high yields (Scheme 3, 3o−r).
Importantly, the reaction of 1a with a cholesterol-derived
phenol provided a phosphorylated cholesteryl ester 3s with a
biologically important phosphate moiety in 76% yield (Scheme
3, 3s). Furthermore, we evaluated the reactivity of other
nucleophiles under the standard reaction conditions (Scheme
3, 3t−aa). Both primary and secondary aliphatic alcohols were
also efficiently coupled with phosphate 1a to yield alkyl
phosphates 3t−v in 49−87% yields. Finally, we demonstrated
that amine and thiol nucleophiles can be employed in this
transformation to provide the aza phosphates 3w−z and
thiophosphate 3aa in acceptable to moderate yields. However,
amine and thiol nucleophiles could also undergo a substitution
reaction directly with Tf2O to form amine triflates and thiol
triflate, respectively, due to their strong nucleophilicity.
The synthesis of mixed diaryl phosphates from aryl
dialkylphosphates is a challenging synthetic transformation in
organophosphate chemistry since it requires exquisite control
of reactivity and chemoselectivity to prevent dual substitution
reaction of the two alkoxy groups.16 Hence, we explored a
selective synthesis of mixed diaryl phosphates from the aryl
dialkylphosphates shown in Scheme 4. Phenyl phosphate 3a
was used as a starting material, and it was efficiently coupled
with arenols bearing different substituents such as methyl, halo,
CN, CF3, and aryl groups to afford the corresponding mixed
diarylphosphates 4a−g in 74−88% yields. 1-Naphthol and 2-
B
DOI: 10.1021/acs.orglett.8b02073
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Synthesis of Mixed Phosphates
Scheme 6. Continuous-Flow System for Phosphate
Synthesis
a
Reaction conditions: 3a (0.2 mmol), Tf2O (0.3 mmol), pyridine (0.4
mmol) in DCM (1.0 mL) for 10 min, then 2 (0.4 mmol) for 30 min;
isolated yields are given.
Scheme 7. Proposed Mechanistic Pathway
naphthol were also proven to be suitable substrates under the
standard reaction conditions, providing the mixed diary-
lphosphates 4h and 4i in 73% and 85% yields, respectively.
In addition, a natural compound sesamol also furnished the
corresponding mixed diaryl phosphate 4j in 81% yield.
Furthermore, this reaction tolerates an azo functional group
on a phenyl ring, which generated the desired product 4k in
high yield (87%).
Finally, this synthetic protocol has been successfully applied
for the conversion of an alkylphosphinate to an arylphosphi-
nate,17 demonstrating a general activating procedure of all
three different oxygen-containing pentavalent phosphorus
compounds (phosphate, phosphonate,14a and phosphinate).
When diphenyl ethylphosphinate 1c was treated with p-cresol,
the target arylphosphinate 5a was obtained in 74% yield
(Scheme 5).
transformed to the phosphates 3 via a substitution reaction
with different nucleophiles.
In summary, we have developed a new synthetic strategy for
the activation of pentavalent organophosphorus compounds
(phosphate, phosphinate) in which a phosphorylpyridin-1-ium
intermediate is generated in situ from a phosphate with Tf2O/
pyridine. This electrophilic P-species efficiently undergoes a
nucleophilic substitution reaction with various nucleophiles
(aliphatic alcohols, arenols, amines, and thiol) to provide
functional phosphate compounds under metal-free reaction
conditions. The synthetic utility of this phosphorylation has
been demonstrated by late-stage phosphorylation of natural
compounds. In addition, a continuous-flow system for the
synthesis of phosphates has been demonstrated. Further
studies on the development of an efficient synthesis of
functional phosphorus compounds based on the in situ
generated P-species, especially for improving the product
yields of aza phosphates and thio phosphates, are underway.
Scheme 5. Direct Arylation of Alkyl Phosphinate
With the potential application of this versatile synthetic
transformation (short reaction time, high tolerance of
functional groups, and mild reaction conditions) to the
chemical enterprise, we explored the development of a
continuous-flow synthesis system to further demonstrate the
synthetic utility of this method.5a,18 While enzymatic synthesis
of phosphorylated compounds via continuous-flow reactor has
been reported,19 chemical synthesis of phosphorus compounds
using flow chemistry is underdeveloped. Hence, an arylox-
ylation reaction was conducted to test amenability in a
continuous-flow reactor as described in Scheme 6. This
continuous-flow procedure efficiently furnished the desired
aryl phosphate 3a in 78% yield (see the Supporting
Information for the details). In addition, a natural compound
sesamol can also afford the corresponding phosphate 3q in
moderate yield (42% yield) under this continuous-flow system.
Based on our previous work,14 we propose a plausible
mechanism for the formation of phosphates 3 (Scheme 7).
Phosphate 1a reacts with Tf2O to give a phosphonium
intermediate I. Next, TfO-substituted phosphonate II and
ethyl triflate byproduct are generated from the intermediate I
via an SN1-type mechanism.8 Then pyridine attacks the
intermediate II to form a highly reactive electrophilic
phosphorylpyridin-1-ium III. Finally, this intermediate III is
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02073.
Experimental details (PDF)
Spectral data of all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: junyong.kang@unlv.edu.
ORCID
Jun Yong Kang: 0000-0002-7178-2981
C
DOI: 10.1021/acs.orglett.8b02073
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2999−3000. (d) Elson, K. E.; Jenkins, I. D.; Loughlin, W. A. Org.
Biomol. Chem. 2003, 1, 2958−2965.
(14) (a) Huang, H.; Denne, J.; Yang, C.-H.; Wang, H.; Kang, J. Y.
Angew. Chem., Int. Ed. 2018, 57, 6624−6628. (b) Huang, H.; Denne,
J.; Yang, C.-H.; Wang, H.; Kang, J. Y. Angew. Chem. 2018, 130, 6734−
6738.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the University of Nevada Las
Vegas. Maciej Kukula at SCAAC is acknowledged for mass
spectral data.
(15) (a) Ladame, S.; Claustre, S.; Willson, M. Phosphorus, Sulfur
Silicon Relat. Elem. 2001, 174, 37−47. (b) Li, S.-Z.; Ahmar, M.;
̀
Queneau, Y.; Soulere, L. Tetrahedron Lett. 2015, 56, 4694−4696.
(16) (a) Takeuchi, Y.; Demachi, Y.; Yoshii, E. Tetrahedron Lett.
1979, 20, 1231−1232. (b) Blackburn, G. M.; Ingleson, D. J. Chem.
Soc., Perkin Trans. 1 1980, 1150−1153. (c) Chowdhury, S.; Muni, N.
J.; Greenwood, N. P.; Pepperberg, D. R.; Standaert, R. F. Bioorg. Med.
Chem. Lett. 2007, 17, 3745−3748. (d) Koster, W. H.; Zahler, R.;
Chang, H. W.; Cimarusti, C. M.; Jacobs, G. A.; Perri, M. J. Am. Chem.
Soc. 1983, 105, 3743−3745. (e) Blackburn, G. M.; Ingleson, D. J.
Chem. Soc., Chem. Commun. 1978, 870−871. (f) Cooke, V. F. G.;
Gerrard, W. J. Chem. Soc. 1955, 1978−1982. (g) Sevrain, C. M.;
REFERENCES
■
́
(1) (a) Kozak, W.; Rachon, J.; Dasko, M.; Demkowicz, S. Asian J.
Org. Chem. 2018, 7, 314−323. (b) Schultz, C. Bioorg. Med. Chem.
2003, 11, 885−898. (c) Korhonen, H. J.; Conway, L. P.; Hodgson, D.
R. W. Curr. Opin. Chem. Biol. 2014, 21, 63−72. (d) Chen, X.;
Kopecky, D. J.; Mihalic, J.; Jeffries, S.; Min, X.; Heath, J.; Deignan, J.;
Lai, S.; Fu, Z.; Guimaraes, C.; Shen, S.; Li, S.; Johnstone, S.; Thibault,
S.; Xu, H.; Cardozo, M.; Shen, W.; Walker, N.; Kayser, F.; Wang, Z. J.
Med. Chem. 2012, 55, 3837−3851. (e) Han, Z. S.; Goyal, N.;
Herbage, M. A.; Sieber, J. D.; Qu, B.; Xu, Y.; Li, Z.; Reeves, J. T.;
Desrosiers, J.-N.; Ma, S.; Grinberg, N.; Lee, H.; Mangunuru, H. P. R.;
Zhang, Y.; Krishnamurthy, D.; Lu, B. Z.; Song, J. J.; Wang, G.;
Senanayake, C. H. J. Am. Chem. Soc. 2013, 135, 2474−2477. (f) Chan,
L. Y.; Cheong, L.; Kim, S. Org. Lett. 2013, 15, 2186−2189. (g) Zhao,
D.; Nimphius, C.; Lindale, M.; Glorius, F. Org. Lett. 2013, 15, 4504−
4507. (h) Fiorito, D.; Folliet, S.; Liu, Y.; Mazet, C. ACS Catal. 2018,
8, 1392−1398. (i) Protti, S.; Fagnoni, M. Chem. Commun. 2008,
3611−3621. (j) McLaughlin, M. Org. Lett. 2005, 7, 4875−4878.
(2) (a) Panmand, D. S.; Tiwari, A. D.; Panda, S. S.; Monbaliu, J.-C.
M.; Beagle, L. K.; Asiri, A. M.; Stevens, C. V.; Steel, P. J.; Hall, C. D.;
Katritzky, A. R. Tetrahedron Lett. 2014, 55, 5898−5901. (b) Jones, S.;
Selitsianos, D. Org. Lett. 2002, 4, 3671−3673. (c) Jones, S.;
Selitsianos, D.; Thompson, K. J.; Toms, S. M. J. Org. Chem. 2003,
68, 5211−5216. (d) Jones, S.; Smanmoo, C. Org. Lett. 2005, 7, 3271−
3274. (e) Jones, S.; Smanmoo, C. Tetrahedron Lett. 2004, 45, 1585−
1588. (f) Liu, C. Y.; Pawar, V. D.; Kao, J. Q.; Chen, C. T. Adv. Synth.
̀
Berchel, M.; Couthon, H.; Jaffres, P.-A. Beilstein J. Org. Chem. 2017,
13, 2186−2213.
(17) (a) Kiss, N.; Keglevich, G. Curr. Org. Chem. 2014, 18, 2673−
2690. (b) Virieux, D.; Volle, J.-N.; Bakalara, N.; Pirat, J.-L. Top. Curr.
Chem. 2014, 360, 39−114.
(18) (a) Whitesides, G. M. Nature 2006, 442, 368. (b) Dudukovic,
M. P.; Larachi, F.; Mills, P. L. Chem. Eng. Sci. 1999, 54, 1975−1995.
(19) (a) Babich, L.; Peralta, J. L. V. M; Hartog, A. F.; Wever, R. Int.
J. Chem. 2013, DOI: 10.5539/ijc.v5n3p87. (b) Babich, L.; Hartog, A.
F.; van der Horst, M. A.; Wever, R. Chem. - Eur. J. 2012, 18, 6604−
6609.
́
Catal. 2010, 352, 188−194. (g) Guzman, A.; Diaz, E. Synth. Commun.
1997, 27, 3035−3038.
(3) Atherton, F. R.; Todd, A. R. J. Chem. Soc. 1947, 674−678.
(4) (a) Dhineshkumar, J.; Prabhu, K. R. Org. Lett. 2013, 15, 6062−
6065. (b) Wang, G.; Shen, R.; Xu, Q.; Goto, M.; Zhao, Y.; Han, L.-B.
J. Org. Chem. 2010, 75, 3890−3892.
(5) (a) Xiong, B.; Feng, X.; Zhu, L.; Chen, T.; Zhou, Y.; Au, C.-T.;
Yin, S.-F. ACS Catal. 2015, 5, 537−543. (b) Xiong, B.; Zeng, K.;
Zhang, S.; Zhou, Y.; Au, C.-T.; Yin, S.-F. Tetrahedron 2015, 71,
9293−9298. (c) Keglevich, G.; Kiss, N. Z.; Mucsi, Z.; Kortvelyesi, T.
Org. Biomol. Chem. 2012, 10, 2011−2018.
(6) Zeng, K.; Chen, L.; Xiong, B.; Zhou, Y.; Au, C.-T.; Yin, S.-F.
Tetrahedron Lett. 2016, 57, 2222−2226.
(7) Song, H.; Kerman, K.; Kraatz, H.-B. Chem. Commun. 2008, 502−
504.
́
(8) Fananas-Mastral, M.; Feringa, B. L. J. Am. Chem. Soc. 2014, 136,
̃
9894−9897.
(9) (a) Bera, M.; Sahoo, S. K.; Maiti, D. ACS Catal. 2016, 6, 3575−
3579. (b) Foust, B. J.; Poe, M. M.; Lentini, N. A.; Hsiao, C.-H. C.;
Wiemer, A. J.; Wiemer, D. F. ACS Med. Chem. Lett. 2017, 8, 914−918.
(10) Kaboudin, B.; Mostafalu, R. Phosphorus, Sulfur Silicon Relat.
Elem. 2012, 187, 776−780.
(11) (a) Baraznenok, I. L.; Nenajdenko, V. G.; Balenkova, E. S.
Tetrahedron 2000, 56, 3077−3119. (b) Chassaing, S.; Specklin, S.;
Weibel, J.-M.; Pale, P. Tetrahedron 2012, 68, 7245−7273. (c) Kaiser,
D.; Maulide, N. J. Org. Chem. 2016, 81, 4421−4428.
(12) (a) Shang, L.; Chang, Y.; Luo, F.; He, J.-N.; Huang, X.; Zhang,
L.; Kong, L.; Li, K.; Peng, B. J. Am. Chem. Soc. 2017, 139, 4211−4217.
(b) Eberhart, A. J.; Procter, D. J. Angew. Chem., Int. Ed. 2013, 52,
4008−4011. (c) Kobatake, T.; Yoshida, S.; Yorimitsu, H.; Oshima, K.
Angew. Chem., Int. Ed. 2010, 49, 2340−2343.
(13) (a) Unoh, Y.; Hirano, K.; Miura, M. J. Am. Chem. Soc. 2017,
139, 6106−6109. (b) Yuan, T.; Huang, S.; Cai, C.; Lu, G.-p. Org.
Biomol. Chem. 2018, 16, 30−33. (c) McCauley, J. I. Synlett 2012, 23,
D
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