Palladium-Catalyzed Direct Decarbonylative Phosphorylation of Benzoic Acids with P(O)–H Compounds

Article abstract of DOI:10.1002/ejoc.201901865

A direct decarbonylative phosphorylation of benzoic acids catalyzed by palladium was disclosed. Under the reaction conditions, a wide range of benzoic acids coupled readily with all the three kinds of P(O)–H compounds, i.e. secondary phosphine oxides, H-phosphinates and H-phosphonates, producing the corresponding organophosphorus compounds in good to high yields. This reaction could be conducted at a gram scale and applied in the late-stage phosphorylative modification of carboxylic acids drug molecules. These results well demonstrated the potential synthetic value of this new reaction in organic synthesis.

Full text of DOI:10.1002/ejoc.201901865

A Journal of
Accepted Article
Title: Palladium-Catalyzed Direct Decarbonylative Phosphorylation of
Benzoic Acids with P(O)–H Compounds
Authors: Ji-Shu Zhang, Tieqiao Chen, and Li-Biao Han
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901865
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901865
Supported by

10.1002/ejoc.201901865
European Journal of Organic Chemistry
COMMUNICATION
Palladium-Catalyzed Direct Decarbonylative Phosphorylation of
Benzoic Acids with P(O)–H Compounds**
Ji-Shu Zhang,[a] Tieqiao Chen,*[a,b] and Li-Biao Han*[c,d]
Abstract: A direct decarbonylative phosphorylation of benzoic acids
catalyzed by palladium was disclosed. Under the reaction conditions,
a wide range of benzoic acids coupled readily with all the three kinds
of P(O)–H compounds, i.e. secondary phosphine oxides, H-
phosphinates and H-phosphonates, producing the corresponding
organophosphorus compounds in good to high yields. This reaction
could be conducted at a gram scale and applied in the late-stage
phosphorylative modification of carboxylic acids drug molecules.
These results well demonstrated the potential synthetic value of this
new reaction in organic synthesis.
an oxidant. Despite the high reaction rate, low yields (<65%) and
narrow substrate scope were suffered. Subsequently, transition
metal-catalyzed decarbonylative phosphorylations of aromatic
carboxylate esters and amides with P(O)–H compounds were
achieved under relatively harsh conditions (>150 °C) (Scheme
1B, path 5). In the two reactions, pre-synthesis of starting
carboxylic derivatives was required, stoichiometric byproducts
Due to the novel physical and chemical properties,
organophosphorous compounds are highly valuable chemicals
that are widely used in medicinal chemistry,[1] catalysis and
organic synthesis,[2,3] coordination chemistry[4] and material
science.[5] The development of an efficient method for the
synthesis of an organophoshorus compound under mild
conditions is of current concern. A lot of organophosphorus
compounds have been prepared through transformation of
organohalides or pseudo halides, such as the nucleophilic
substitutions reactions or Michaelis-Arbusov reactions under a
rather harsh condition (Scheme 1A, paths 1 and 2).[6,7] The
Hirao-type’s coupling is also a well-employed method for
constructing C–P bonds (Scheme 1A, path 3).[8,9] An aromatic
C–H/P(O)–H cross dehydrogenation coupling was accomplished
by Yu and co-workers, despite requiring a N-heterocycle-
directing group and (or) an over-stoichiometric oxidant.[10]
Carboxylic acids are available at low cost in great structural
diversity from both natural and synthetic sources and their
application in organic synthesis has attracted much
attention.[11,12] Direct utilization of carboxylic acids instead of
organohalides to couple with P(O)–H compounds would greatly
promote the green synthesis of organophosphorus compounds.
In 2014, Xiao disclosed a Pd/Ag co-catalyzed decarboxylative
coupling of electron-deficient o-nitrobenzoic acids with H-
phosphonates (Scheme 1B, path 4).[12b] This reaction was
conducted under microwave conditions with the use of LiNO3 as
Scheme 1. Construction of aromatic sp2C–P bonds.
phenol and piperidine-2,6-dione were also generated
concomitantly.[13] Very recently, we reported a Pd-catalyzed
oxidative decarbonylative coupling of aroylhydrazides with P(O)–
H compounds under a strong acidic condition, producing the
corresponding aryl phosphorus compounds (Scheme 1B, path
6).[14]
[a]
[b]
Dr. J.-S. Zhang, Prof. Dr. T. Chen, College of Chemistry and
Chemical Engineering, Hunan University, Changsha, Hunan 410082,
China.
Prof. Dr. T. Chen, Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, College of
Chemical Engineering and Technology, Hainan University, Haikou,
Hainan 570228, China.
[c]
[d]
Prof. Dr. L.-B. Han, Institute of Drug Discovery Technology, Ningbo
University, Ningbo, Zhejiang, 450052, China.
Prof. Dr. L.-B. Han, National Institute of Advanced Industrial Science
and Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan.
Scheme 2. Constructing chemical bonds via in situ activation of benzoic acids.
E-mail: chentieqiao@hnu.edu.cn; libiao-han@aist.go.jp
In 1990s, Prof. Yamamoto firstly introduced an in situ
activation strategy of carboxylic acids with anhydrides for
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901865
European Journal of Organic Chemistry
COMMUNICATION
oxidative addition to Pd-catalysts, achieving the hydrogenation
to aldehydes.[15a] This concept was subsequently extended to
the synthesis of ketones.[15b–f] With the strategy, decarbonylative
eliminations of fatty acids forming alkenes were also achieved
by chemists.[15g–h] The in situ activation strategy was also
employed in the decarbonylation couplings of benzoic acids with
alkenes, arylboroxines, diboroxines, aromatics bearing N-
heterocycle and hydrosilanes mediated by nickel, rhodium and
palladium (Scheme 2A).[16] We envision that if the in situ
activation strategy is applied in the cross coupling of carboxylic
We carried out the reaction by choosing 2-naphthoic acid
with diphenylphosphine oxide as the model reaction. In the
presence
of
10
mol
%
Pd(OAc)2/dppp
(1,3-
bis(diphenylphosphino)propane), a mixture of 2-naphthoic acid,
diphenylphosphine oxide, CyNMe2 and (Boc)2O was heated in
dioxane[16] at 115 °C for 18 h. To our delight, 2-
naphthylphosphine oxide 3a was obtained in 72% yield (Table 1,
entry 1). Both Pd catalyst and phosphine ligand were essential.
Without either of them, the reaction proceeded sluggishly (Table
1, entries 2 and 3). Lowering or elevating the reaction
temperature decreased the yield of 3a (Table 1, entries 4 and 5).
The choice of a suitable base was also crucial to this reaction.
The yields were low with Cy2NMe and Et3N, while almost no
reaction could be observed with DBU, K2CO3 and Cs2CO3 (Table
1, entries 6–10). The reaction also took place readily in toluene
and cyclohexane, but poorly in the strongly polar DMF, DMAc
and t-AmylOH (Table 1, entries 11–15). The phosphine ligands
were subsequently screened (Table 1, entries 16–22). When
dppb (1,4-bis(diphenylphosphino)butane) was used, 39% yield
of 3a was obtained. Other selected phosphine ligands, such as
acids
with
P(O)–H
compounds,
a
decarbonylation
phosphorylation might be realized out through transition metal
catalysis. This reaction would avoid the pre-transformation of
acids into active carboxylic derivatives and the use of oxidant
which usually leads to oxidation of P(O)–H compounds in the
oxidative couplings, thus providing an efficient method for
constructing P–C bonds. After extensive studies,[17] we achieved
such a reaction through palladium catalysis. This reaction used
Boc2O as the activating reagent and was performed under a
relatively mild reaction condition (115 oC). A wide substrate
scope for both benzoic acids and P(O)–H compounds was
demonstrated. This reaction provided a general method for
sp2C–P bonds formation (Scheme 2B). It should be noted that
Szostak and co-authors reported a similar reaction with the use
of Piv2O as an activating reagent during the submission.[18]
Compared with our catalytic system, the reaction was conducted
at a higher temperature (160 oC) and seemed to be only
applicable to H-phosphonates and Ph2PH.
dcype
(bis(diphenylphosphino)methane),
ylphosphino)ethane), dppf
(1,2-bis(dicyclohexylphosphino)ethane),
dppm
dppe
(1,2-bis(diphen-
(1,1'-bis(diphenylphosphino)-
ferrocene), dpph (1,6-bis(diphenylphosphino)hexane) and Ph3P,
all were ineffective for the decarbonylative phosphorylation.
When 5 mol% Pd(OAc)2 was loaded, the yield decreased to 62%
(Table 1, entry 23). Zero valent Pd catalyst like Pd2(dba)3 could
also mediate the coupling reaction (Table 1, entry 24). Finally,
anhydride (PivO)2O was used instead of (Boc)2O, a relatively low
yield was afforded (Table 1, entry 25).[16]
Table 1. Optimization of reaction conditions [a]
With the optimal conditions in hand, we then investigated
the substrate scope. As shown in Table 2, this reaction was a
rather general method, since various carboxylic acids including
some drugs were readily decarbonylatively phosphorylated,
producing the corresponding aryl phosphorus compounds in
moderate to high yields. Thus, both 1-naphthoic and 2-naphthoic
acids coupled with Ph2P(O)H, furnishing the expected coupling
products 3a–3c in good yields. Polycyclic carboxylic acids
served well under the reaction conditions (3d–3f). Good yields
were also obtained with the heterocyclic substrates (3g–3k). By
slightly tuning the reaction conditions, both electron-rich and
electron-deficient benzoic acids including those bearing
functional
groups
at
the
ortho-position
underwent
decarbonylative phosphorylation with Ph2P(O)H, delivering the
corresponding products 3l–3w in moderate to good yields.
Functional groups such as Me, Ph, PhO, MeO, CF3O, acetal,
ester, carbonyl, methylsulfonyl and even chloro groups all
[a] Reaction conditions: a mixture of 1a (0.12 mmol), Ph2P(O)H (0.1 mmol), 10
Scheme 3. Gram-scale reaction.
mol % Pd catalyst, phosphine ligand (Pd/P =1:2), 1.4 equiv (Boc)2O, 2.0 equiv
[b]
base was heated in 1 mL solvent at the indicated temperature for 18 h. 31P
NMR yield using methyldiphenylphine oxide as an internal standard. [c] 5 mol%
Pd2(dba)3. [d] 5 mol % Pd(OAc)2. [e] (PivO)2O was used instead of (Boc)2O.
survived well under the current reaction conditions. The
carboxylic acid drugs such as Probenecid, Flavonoid,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901865
European Journal of Organic Chemistry
COMMUNICATION
Bexarotene and Adpalene also proved to be good coupling
partners (3x–3aa). However, under the reaction conditions,
cinnamic acid showed poor reactivity (3ab), while no reaction
took place with 3-phenylpropanoic acid (3ac).
other aromatic secondary phosphine oxides including the bulky
di(2-naphthyl)2P(O)H all produced the expected phosphine
oxides in moderate to good yields under similar reaction
conditions (3ad–3ag). Similarly, the present Pd-catalyzed
decarbonylative phosphorylation also took place smoothly with
All the three kinds of hydrogen phosphoryl compounds were
applicable to this reaction (Table 2B). In addition to Ph2P(O)H,
Table 2. Substrate scope [a]
[a]
Reaction conditions: a mixture of 1 (0.48 mmol), Ph2P(O)H (0.4 mmol), 10 mol % Pd(OAc)2/dppp, 1.4 equiv (Boc)2O, 2.0 equiv CyNMe2 was heated at
115 °C in 3 mL dioxane for 18 h; isolated yield. [b] 1.5 equiv (Boc)2O, 2.5 equiv CyNMe2. [c] 105 °C. [d] 130 °C. [e] 1.5 equiv (Boc)2O, 3 equiv CyNMe2, 90 °C. [f]
Names of starting carboxylic acid drugs.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901865
European Journal of Organic Chemistry
COMMUNICATION
aliphatic secondary phosphine oxide, hydrogen phosphinate and
hydrogen phosphonates (3ah–3an). Worth noting is that the
phosphorylated products from drugs with hydrogen phosphinate
and hydrogen phosphonates could be easily hydrolyzed to the
corresponding phosphinic acid and phosphonic acids, which
might efficiently adjust the bioactivity of drugs.[19] This reaction
provided an efficient method for phosphorylative modification of
carboxylic acid drugs through decarbonylative C–C(O)/P(O)–H
coupling. Diphenylphosphine showed a low reactivity and gave
the coupling product triphenylphosphine in 25% GC yield (3ao).
carboxylic derivatives and the use of stoichiometric oxidant.
Under the reaction conditions, a variety of aryl phosphorus
compounds were produced in moderate to excellent yields. The
gram-scale experiments and further applications in the
phosphorylative modification of drugs like Probenecid, Flavonoid,
Bexarotene, Adapalene and Telmisartan well demonstrated the
potential synthetic value of this new reaction in organic synthesis.
Experimental Section
Of note, this reaction could be conducted at a gram scale
without decrease of the reaction efficiency, demonstrating its
potential synthetic value in organic synthesis (Scheme 3). For
A general procedure: in a glove box, 0.48 mmol 2-naphthoic acid, 0.52
mmol HP(O)Ph2, 10 mol % Pd(OAc)2/dppp, 1.4 equiv (Boc)2O, 2.0 equiv
CyNMe2, and 3 mL dioxane were charged into a 25 mL glass tube, the
mixture was stirred at 115 °C for 18 h. After removal of the volatiles in
vacuum, the residues were passed through a short silica column using
petroleum ether/ethyl acetate as eluent to afford analytically pure product
3a in 72% yield.
instance,
a
mixture of Flavonoid (6.0 mmol, 1.68 g),
diphenylphosphine oxide (5.0 mmol, 1.01 g), Pd(OAc)2 (10
mol %, 112.0 mg), dppp (10 mol %, 206.2 mg), (Boc)2O (1.4
equiv, 1.6 mL), and CyNMe2 (2.0 equiv, 1.5 mL) was heated in
20 mL dioxane at 115 °C for 18 h. After removal of the volatiles
in vacuum, the residues were passed through a short silica
column (eluent: petroleum ether/ethyl acetate) to give the
analytically pure product 3y in 62% isolated yield.
Acknowledgements
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (21573064 and 21403062)
and the Fundamental Research Funds for the Central
Universities (Hunan University).
The reaction mechanism is not thoroughly clear at present.
On the basis of previous literatures, we proposed a plausible
catalytic circle as shown in Scheme 4.[16a,l–n,17,20–22] Pd(OAc)2 is
first reduced to generate an active Pd(0) species A, which
oxidatively adds to a mixing anhydride B generated in situ from
(Boc)2O and the starting carboxylic acids,[16m] yielding an
complex C. The resulting C undergoes decarbonylation,[13a,14,20]
followed by ligand exchange to give intermediate E.[17,21,22]
Keywords: Palladium catalysis • C–P bond-forming reaction •
Decarbonylative coupling • Benzoic acids • In-situ activation
Reductive elimination of intermediate
phosphorylated product and regenerates the active Pd(0)
catalyst,[23] thereby completing the catalytic circle.
E
produces the
[1]
(a) W.-S. Huang, S. Liu, D. Zou, M. Thomas, Y. Wang, T. Zhou, J.
Romero, A. Kohlmann, F. Li, J. Qi, L. Cai, T. A. Dwight, Y. Xu, R. Xu, R.
Dodd, A. Toms, L. Parillon, X. Lu, R. Anjum, S. Zhang, F. Wang, J.
Keats, S. D. Wardwell, Y. Ning, Q. Xu, L. E. Moran, Q. K. Mohemmad,
H. G. Jang, T. Clackson, N. I. Narasimhan, V. M. Rivera, X. Zhu, D.
Dalgarno, W. C. Shakespeare, J. Med. Chem. 2016, 59, 4948; (b) X.
Chen, D. J. Kopecky, J. Mihalic, S. Jeffries, X. Min, J. Heath, J.
Deignan, S. Lai, Z. Fu, C. Guimaraes, S. Shen, S. Li, S. Johnstone, S.
Thibault, H. Xu, M. Cardozo, W. Shen, N. Walker, F. Kayser, Z. Wang,
J. Med. Chem. 2012, 55, 3837; (c) Q. Dang, Y. Liu, D. K. Cashion, S. R.
Kasibhatla, T. Jiang, F. Taplin, J. D. Jacintho, H. Li, Z. Sun, Y. Fan, J.
DaRe, F. Tian, W. Li, T. Gibson, R. Lemus, P. D. van Poelje, S. C.
Potter, M. D. Erion, J. Med. Chem. 2011, 54, 153.
[2]
[3]
H. Ni, W. L. Chan, Y. Lu, Chem. Rev. 2018, 118, 9344.
For selected reviews, see: (a) M. Oestreich, F. Tappe, V. Trepohl,
Synthesis 2010, 2010, 3037; (b) J.-L. Montchamp, Acc. Chem. Res.
2014, 47, 77; (c) B.-G. Cai, J. Xuan, W.-J. Xiao, Science Bulletin 2019,
64, 337; (d) J.-S. Zhang, L. Liu, T. Chen, L.-B. Han, Chem. Asian J.
2018, 13, 2277; (e) T. Chen, J.-S. Zhang, L.-B. Han, Dalton Trans.
2016, 45, 1843; For selected examples, see: (f) M. Yoshida, K. Saito, H.
Kato, S. Tsukamoto, T. Doi, Angew. Chem. Int. Ed. 2018, 57, 5147;
Angew. Chem. 2018, 130, 5241; (g) J.-S. Zhang, J.-Q. Zhang, T. Chen,
L.-B. Han, Org. Biomol. Chem. 2017, 15, 5462; (h) J. Q. Zhang, T.
Chen, J. S. Zhang, L. B. Han, Org. Lett. 2017, 19, 4692; (i) J.-S. Zhang,
T. Chen, Y. Zhou, S.-F. Yin, L.-B. Han, Org. Lett. 2018, 20, 6746.
For reviews on phosphorus compounds as ligands and directing groups,
see: (a) Y. N. Ma, S.-X. Li, S.-D. Yang, Acc. Chem. Res. 2017, 50,
1480–1492; (b) Z. Zhang, P. H. Dixneuf, J.-F. Soulé, Chem. Commun.
2018, 54, 7265; For selected recent examples, see: (c) K. Fukuda, N.
Iwasawa, J. Takaya, Angew. Chem. Int. Ed. 2019, 58, 2850; Angew.
Chem. 2019, 131, 2876; (d) J. Wen, D. Wang, J. Qian, D. Wang, C.
Zhu, Y. Zhao, Z. Shi, Angew. Chem. Int. Ed. 2019, 58, 2078; Angew.
Chem. 2019, 131, 2100.
[4]
Scheme 4. Proposed reaction mechanism.
In summarize, we disclosed
a
Pd-catalyzed direct
decarbonylative coupling of benzoic acids with P(O)–H
compounds. The reaction utilized (Boc)2O to activate carboxylic
acids in situ, avoiding pre-conversion of them into the active
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901865
European Journal of Organic Chemistry
COMMUNICATION
[5]
(a) For selected reviews on P-containing materials, see: (a) T.
Baumgartner, R. Réau, Chem. Rev. 2006, 106, 4681; (b) C. Queffelec,
M. Petit, P. Janvier, D. A. Knight, B. Bujoli, Chem. Rev. 2012, 112,
3777; (c) T. Baumgartner, Acc. Chem. Res. 2014, 47, 1613; (d) R.
Szucs, P. A. Bouit, L. Nyulaszi, M. Hissler, ChemPhysChem 2017, 18,
2618; For selected examples, see: (e) C. Han, Z. Zhang, H. Xu, J. Li, G.
Xie, R. Chen, Y. Zhao, W. Huang, Angew. Chem. Int. Ed. 2012, 51,
10104; Angew. Chem. 2012, 124, 10251; (f) L. Qiu, W. Hu, D. Wu, Z.
Duan, F. Mathey, Org. Lett. 2018, 20, 7821.
[13] (a) C. Liu, M. Szostak, Angew. Chem. Int. Ed. 2017, 56, 12718; Angew.
Chem. 2017, 129, 12892; (b) R. Isshiki, K. Muto, J. Yamaguchi, Org.
Lett. 2018, 20, 1150.
[14] J. Dong, L. Liu, X. Ji, Q. Shang, L. Liu, L. Su, B. Chen, R. Kan, Y. Zhou,
S.-F. Yin, L.-B. Han, Org. Lett. 2019, 21, 3198.
[15] For a pioneering work, see: (a) K. Nagayama, I. Shimizu, A. Yamamoto,
Chem. Lett. 1998, 27, 1143; Synthesis of ketones with the strategy, see:
(b) L. J. Gooßen, K. Ghosh, Eur. J. Org. Chem. 2002, 2002, 3254; (c) R.
Kakino, S. Yasumi, I. Shimizu, A. Yamamoto Bull. Chem. Soc. Jpn.
2002, 75, 137; (d) R. Kakino, H. Narahashi, I. Shimizu, A. Yamamoto
Bull. Chem. Soc. Jpn. 2002, 75, 1333; (e) H. Yin, C. Zhao, H. You, K.
Lin, H. Gong, Chem. Commun. 2012, 48, 7034; (f) X. Jia, X. Zhang, Q.
Qian, H. Gong, Chem. Commun. 2015, 51, 10302; For decarbonylation
elimination of alkyl carboxylic acids forming alkenes, see: (g) S.
Maetani, T. Fukuyama, N. Suzuki, D. Ishihara, I. Ryu, Chem. Commun.
2012, 48, 2552. (h) X. Zhang, F. Jordan, M. Szostak, Organ. Chem.
Front. 2018, 5, 2515.
[6]
For selected examples on nucleophilic substitutions reactions, see: (a)
C. P. Casey, E. L. Paulsen, E. W. Beuttenmueller, B. R. Proft, L. M.
Petrovich, B. A. Matter, D. R. Powell, J. Am. Chem. Soc. 1997, 119
i ne e - o ente a tolo , L. A.
Oro, Synthesis 2009, 2009, 1916.
[7]
[8]
(a) A. K. Bhattachary, G. Thyarajan, Chem. Rev. 1981, 81, 415; (b) W.
P. Almeida, C. R. D. Correia, Tetrahedron lett. 1994, 35, 1367; (c) G.
Yang, C. Shen, L. Zhang, W. Zhang, Tetrahedron Lett. 2011, 52, 5032;
(d) R. S. Shaikh, S. J. S. Düsel, B. König, ACS Catal. 2016, 6, 8410.
(a) T. Hirao, T. Masunaga, Y. Ohshiro, T. Agawa, Tetrahedron Lett.
1980, 21, 35958; (b) T. Hirao, T. Masunaga, N. Yamada, Y. Ohshiro, T.
Agawa, Bull. Chem. Soc. Jpn 1982, 55, 909; For selected examples of
Ar–X as coupling partners, see: (c) L. J. Dmitri Gelman, Stephen L.
Buchwald, Org. Lett. 2003, 5, 2315; (d) W. C. Fu, C. M. So, F. Y.
Kwong, Org. Lett. 2015, 17, 5906; (e) L. L. Liao, Y. Y. Gui, X. B. Zhang,
G. Shen, H. D. Liu, W. J. Zhou,. J. Li, D. G. Yu, Org. Lett. 2017, 19,
3735.
[16] The strategy that carboxylic acids activated in situ coupled with
nucleophiles with CO release (decarbonylation coupling) has attracted
chemists’ attention. For a related reviews, see: (a) J. Buchspies, M.
Szostak, Catalysts 2019, 9, 53. For Rh-catalyzed examples, see: (b) L.
J. Gooßen, J. Paetzold, Adv. Synth. Catal. 2004, 346, 1665; (c) F. Pan,
Z. Q. Lei, H. Wang, H. Li, J. Sun, Z. J. Shi, Angew. Chem. Int. Ed. 2013,
52, 2063; Angew. Chem. 2013, 125, 2117; (d) L. Zhang, X. Xue, C. Xu,
Y. Pan, G. Zhang, L. Xu, H. Li, Z. Shi, ChemCatChem 2014, 6, 3069; (e)
L. Zhang, R. Qiu, X. Xue, Y. Pan, C. Xu, D. Wang, X. Wang, L. Xu, H.
Li, Chem. Commun. 2014, 50, 12385; (f) R. Qiu, L. Zhang, C. Xu, Y.
Pan, H. Pang, L. Xu, H. Li, Adv. Synth. Catal. 2015, 357, 1229; (g) J.
Xu, C. Chen, H. Zhao, C. Xu, Y. Pan, X. Xu, H. Li, L. Xu, B. Fan, Organ.
Chem. Front. 2018, 5, 734; (h) X. Qiu, P. Wang, D. Wang, M. Wang, Y.
Yuan, Z. Shi, Angew. Chem. Int. Ed. 2019, 58, 1504; Angew. Chem.
2019, 131, 1518; (i) H. Zhao, X. Xu, Z. Luo, L. Cao, B. Li, H. Li, L. Xu,
Q. Fan, P. J. Walsh, Chem. Sci. 2019, 10, 10089; For Ni-catalyzed
examples, see: (j) C. A. Malapit, J. R. Bour, S. R. Laursen, M. S.
Sanford, J. Am. Chem. Soc. 2019, 141, 17322; (k) C. A. Malapit, J. R.
Bour, C. E. Brigham, M. S. Sanford, Nature 2018, 563, 100; For Pd-
catalyzed examples, see: (l) L. J. Gooßen, J. Paetzold L. Winkel,
Synlett 2002, 2002, 1721; (m) C. Liu, C. L. Ji, X. Hong, M. Szostak,
Angew. Chem. Int. Ed. 2018, 57, 16721; Angew. Chem. 2018, 130,
16963; (n) C. Liu, Z. X. Qin, C. L. Ji, X. Hong, M. Szostak, Chem. Sci.
2019, 10, 5736; (o) C. Liu, C. L. Ji, Z. X. Qin, X. Hong, M. Szostak,
iScience 2019, 19, 749.
[9]
For more recently on Hirao-type coupling forming C–P bonds through
C– C−O C–CN C−S C−N and C−Si cleavage see: a) G. Hu, W.
Chen, T. Fu, Z. Peng, H. Qiao, Y. Gao, Y. Zhao, Org. Lett. 2013, 15,
5362; (b) Zhuang, R.; J. Xu, Z. Cai, G. Tang, M. Fang, Y. Zhao, Org.
Lett. 2011, 13, 2110; (c) Y.- L. Zhao, G.- J. Wu, F.-S. Han, Chem.
Commun. 2012, 48, 5868; (d) J. Yang, T. Chen, L.-B. Han, J. Am.
Chem. Soc. 2015, 137, 1782; (e) J.-S. Zhang, T. Chen, J. Yang, L.- B.
Han, Chem. Commun. 2015, 51, 7540; (f) J. Yang, J. Xiao, T. Chen, S.-
F. Yin, L.-B. Han, Chem. Commun. 2016, 52, 12233; (g) W. Xu, G. Hu,
P. Xu, Y. Gao, Y. Yin, Y. Zhao, Adv. Synth. Catal. 2014, 356, 2948; (h)
B. Yang, Z. X. Wang, J. Org. Chem. 2019, 84, 1500; (i) H. Luo, H. Liu,
X. Chen, K. Wang, X. Luo, K. Wang, Chem. Commun. 2017, 53, 956.
[10] For oxidative C–H/P(O)–H cross dehydrogenation coupling, see: (a) Y.
H. Budnikova, O. G. Sinyashin, Russ. Chem. Rev. 2015, 84, 917; (b)
C.-G. Feng, M. Ye, K. J. Xiao, S. Li, J.-Q. Yu, J. Am. Chem. Soc. 2013,
135, 9322; (c) C. Li, T. Yano, N. Ishida, M. Murakami, Angew. Chem.
Int. Ed. 2013, 52, 9801; Angew. Chem. 2013, 125, 9983.
[17] Due to the strong coordination between P(O)–H compounds to
transition metals, it is difficult to directly extend the established catalytic
coupling system to the synthesis of organophosphorus compounds
using P(O)–H compounds. For selected examples on R1R2P(O)H as
ligands, see: (a) G. Y. Li, Angew. Chem. Int. Ed. 2001, 40, 1513;
Angew. Chem. 2001, 113, 1561; (b) J. Bigeault, L. Giordano, G. Buono,
Angew. Chem. Int. Ed. 2005, 44, 4753; Angew. Chem. 2005, 117, 4831;
(c) L. Ackermann, R. Born, J. H. Spatz, D. Meyer, Angew. Chem. Int.
Ed. 2005, 44, 7216; Angew. Chem. 2005, 117, 7382; (d) I. Cano, A. M.
Chapman, A. Urakawa, P. W. van Leeuwen, J. Am. Chem. Soc. 2014,
136, 2520; (e) I. Cano, M. A. Huertos, A. M. Chapman, G. Buntkowsky,
T. Gutmann, P. B. Groszewicz, P. W. van Leeuwen, J. Am. Chem. Soc.
2015, 137, 7718.
[11] Carboxylic acids has been widely used for constructing chemical bonds,
for selected reviews, see: (a) S. M. Bonesi, M. Fagnoni, Chem. Eur. J.
2010, 16, 13572; (b) N. Rodriguez, L. J. Goossen, Chem. Soc. Rev.
2011, 40, 5030; (c) W. I. Dzik, P. P. Lange, L. J. Gooßen, Chem. Sci.
2012, 3, 2671; (d) T. Patra, D. Maiti, Chem. Eur.J. 2017, 23, 7382;
Carboxylic derivatives have also been widely applied in organic
synthesis, for selected reviews, see: (e) A. Dermenci, G. Dong, Sci.
China Chem. 2013, 56, 685; For recent developments, see: f) L. Guo,
M. Rueping, Acc. Chem. Res. 2018, 5, 1185; (g) L. Guo, M. Rueping,
Chem. Eur.J. 2018, 24, 7794.
[12] Cross coupling of carboxylic acids with P(O)–H compounds has been
achieved; however, those reactions were performed under oxidative
reaction conditions with CO2 release (decarboxylation coupling) and
usually suffered from oxidation of P(O)–H compounds to the
corresponding acids. For a review, see: (a) A. Hosseinian, F. A.
Hosseini Nasab, S. Ahmadi, Z. Rahmani, E. Vessally, RSC Adv. 2018,
8, 26383. For transformation of o-nitro benzoic acids, see: (b) J. Li, X.
Bi, H. Wang, J. Xiao, Asian J. Org. Chem. 2014, 3, 1113. For
transformations of alkyl or alkenyl carboxylic acids, see: (c) J. Hu, N.
Zhao, B. Yang, G. Wang, L. N. Guo, Y. M. Liang, S.-D. Yang, Chem.-
Eur. J. 2011, 17, 5516; (d) Y. Wu, L. Liu, K. Yan, P. Xu, Y. Gao, Y.
Zhao, J. Org. Chem. 2014, 79, 8118; (e) L. Tang, L. Wen, T. Sun, D.
Zhang, Z. Yang, C. Feng, Z. Wang, Asian J. Org. Chem. 2017, 6, 1683;
(f) L. Liu, D. Zhou, J. Dong, Y. Zhou, S.-F. Yin, L.-B. Han, J. Org. Chem.
2018, 83, 4190.
[18] C. Liu, C. L. Ji, T. Zhou, X. Hong, M. Szostak, Org. Lett. 2019, 21, 9256.
[19] Phosphonic and phosphinic acids in lieu of carboxylic acids in
bioisostere can hugely reform its intrinsic drug activity, see: (a) C.
Ballatore, D. M. Huryn, A. B. Smith, ChemMedChem 2013, 8, 385; (b)
P. Lassalas, B. Gay, C. Lasfargeas, M. J. James, V. Tran, K. G.
Vijayendran, K. R. Brunden, M. C. Kozlowski, C. J. Thomas, A. B.
Smith, D. M. Huryn, C. Ballatore, J. Med. Chem. 2016, 59, 3183.
[20] G. Meng, M. Szostak, Angew. Chem. Int. Ed. 2015, 54, 14518; Angew.
Chem. 2015, 127,14726.
[21] T. Chen, C.-Q. Zhao, L.-B. Han, J. Am. Chem. Soc. 2018, 140, 3139.
[22] Ligand exchange takes place prior to decarbonylation could not be
excluded at present. Meanwhile, it is also unknown when the possible
decomposition of carbonate derivatives upon heating to generate CO2
occurs.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901865
European Journal of Organic Chemistry
COMMUNICATION
[23] Stockland et al. have investigated the reductive elimination step using
C− d− O co plexes. (a) M. C. Kohler, T. V. Grimes, X. Wang, T. R.
Cundari, R. A. Stockland, Organometallics 2009, 28, 1193; (b) M. C.
Kohler, R. A. Stockland, N. P. Rath, Organometallics 2006, 25, 5746; (c)
A. M. Levine, R. A. Stockland, R. Clark, I. Guzei, Organometallics 2002,
21, 3278. The reaction has also been studied by calculation, see: (d) T.
Wang, S. Sang, L. Liu, H. Qiao, Y. Gao, Y. Zhao, J. Org. Chem. 2014,
79, 608.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901865
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
A direct decarbonylative
Ji-Shu Zhang, Tieqiao Chen,* Li-Biao
Han*
phosphorylation of benzoic acids
catalyzed by palladium was disclosed.
Under the reaction conditions, a wide
range of carboxylic acids coupled
readily with all the three kinds of
P(O)–H compounds, i.e. secondary
phosphine oxides, H-phosphinates
and H-phosphonates, producing the
corresponding organophosphorus
compounds in good to high yields.
This reaction could be conducted at a
gram scale and applied in the late-
stage phosphorylative modification of
carboxylic acids drug molecules.
These results well demonstrated the
potential synthetic value of this new
reaction in organic synthesis.
Page No. – Page No.
Palladium-Catalyzed Direct
Decarbonylative Phosphorylation of
Carboxylic Acids with P(O)–H
Compounds
This article is protected by copyright. All rights reserved.