Metal-Free Hydrophosphoryloxylation of Ynamides: Rapid Access to Enol Phosphates

Article abstract of DOI:10.1002/ejoc.202001335

We herein report a metal-free hydrophosphoryloxylation of ynamides with phosphoric acids, which provides an expeditious route to access useful enol phosphates. The advantages of this protocol include exclusive selectivity, short reaction time, high efficiency, and broad substrate scope. Additionally, the products can serve as good partners in Suzuki-Miyaura cross-coupling.

Full text of DOI:10.1002/ejoc.202001335

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Metal-Free Hydrophosphoryloxylation of Ynamides: Rapid
Access to Enol Phosphates
Authors: Dalie An, Weinan Zhang, Bin Pan, and Yingying Zhao
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01/2020

10.1002/ejoc.202001335
European Journal of Organic Chemistry
COMMUNICATION
Metal-Free Hydrophosphoryloxylation of Ynamides: Rapid
Access to Enol Phosphates
Dalie An,[a] Weinan Zhang,[a] Bin Pan,*,[b] Yingying Zhao*,[a]
Abstract: We herein report a metal-free hydrophosphoryloxylation of
ynamides with phosphoric acids, which provides an expeditious
route to access useful enol phosphates. The advantages of this
protocol include exclusive selectivity, short reaction time, high
efficiency and broad substrate scope. Additionally, the products can
serve as good partners in Suzuki-Miyaura cross-coupling.
particular, has never been reported before, likely due to the
difficulty in controlling the regioselectivity.
Enol phosphates are an intriguing class of organophosphates
that can be found in a variety of agrochemicals and bioactive
natural products.[1] For example (Scheme 1), dimethyl 2,2-
dichlorovinylphosphate (DDVP) and monocrotophos are widely
used as insecticides in agriculture.[2] Phosphoenolpyruvate
(PEP), containing high-energy phosphate bonds, can facilitate
the transformation of adenosine diphosphate (ADP) into
adenosine triphosphate (ATP) in living organisms.[3]
Cyclophostin, isolated from Streptomyces strains, exhibits potent
inhibition against acetyl cholinesterase (AChE) from the housefly
and brown plant hopper.[4] Besides, enol phosphates are also
versatile building blocks in transition-metal-catalyzed cross-
couplings.[5] Therefore, tremendous efforts have been devoted to
the synthesis of such important frameworks over the past
decades.
Scheme 2. Hydrophosphoryloxylation of alkynes with phosphoric acids.
Ynamides are special alkynes that feature the electron-
donating nitrogen atom directly attached to the carbon-carbon
triple bond, and their high electron density can be finely
balanced by the electron-withdrawing substituent on the nitrogen
atom. Consequently, ynamides can display diverse reactivities in
organic synthesis and their chemistry has become a research
hotspot.[12] The recent years have wittnessed impressive
advances in hydrofunctionalizations of ynamides.[13] For instance,
Lam et al[14] and Bi et al[15] achieved the regioselective
hydroacyloxylation of ynamides with carboxylic acids under
palladium catalysis and metal-free conditions, respectively.
Besides, metal-free additions of hydrogen halides[16] and sulfonic
acids[17] to ynamides were also well documented. Prompted by
these precedents and our continuing interests in ynamide
chemistry[18], we envisioned that phosphoric acid might undergo
addition with ynamides to yield useful enol phosphates. Indeed,
this expected hydrophosphoryloxylation could proceed smoothly
with no need of transition-metal promoters, and notably most of
the cases could be completed within 10 minutes at room
temperature (Scheme 2b). Given that the protocol features
excellent regioselectivity, exclusive (E)-stereoselectivity, short
reaction time, mild conditions, metal-free system, and useful
products, we herein present the results of our studies.
Scheme 1. Representative bioactive molecules containing enol phosphates.
The most commonly used protocol relies on the reaction of
carbonyl compounds, such as enolization/phosphorylation,[6]
Perkow reaction,[7] and O-phosphorylation of unsaturated
ketones.[8] Notably, hydrophosphoryloxylation of alkynes
represents another efficient strategy. In 2010, Lee and Kim et al
developed an elegant gold-catalyzed addition of disubstituted
phosphates with terminal alkynes, enabling a facile synthesis of
enol phosphates (Scheme 2a).[9] Later, the similar results were
observed by Nolan and co-workers.[10] Besides, haloalkynes
could also participate in this addition with high regioselectivity
2a).[11]
Nevertheless,
metal-free
At the outset, ynamide 1a and diphenyl phosphate 2a were
selected as the model substrates to test our hypothesis (Figure
1). To our delight, when a solution of 1a and 2a in DCM was
stirred at room temperature for 10 min, the expected
hydrophosphoryloxylation could occur spontaneously without
any catalyst, producing enol phosphate 3a in a good yield with
an exclusive regioselectivity. The effect of other solvents was
further surveyed. The reactions in THF and MeCN gave inferior
outcomes, while a higher yield of 3a was obtained in non-polar
solvent toluene. The strong polar solvent DMSO totally
suppressed the transformation. It is noted that the yield still
remained high when the reaction was conducted under air.
(Scheme
hydrophosphoryloxylation of alkynes, internal alkynes in
[a]
[b]
D. An, W. Zhang, Dr. Y. Y. Zhao
Liaoning Normal University, 850 Huanghe Road, Dalian 116029,
China
E-mail: yyzhao@lnnu.edu.cn
Dr. B. Pan
Shandong
Peninsula
Engineering
Research
Center
of
Comprehensive Brine Utilization, Weifang University of Science and
Technology, Shouguang, China.
Email: bpan@wfust.edu.cn
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.202001335
European Journal of Organic Chemistry
COMMUNICATION
Figure 1. Solvent effects on the reaction. Conditions: 1a (0.1 mmol), 2a (0.11
mmol), solvent (1.0 mL), RT for 10 min. Yield of 3a was determined by HPLC
using naphthalene as the internal standard.
With the optimized conditions in hand, we then examined the
scope with respect to ynamides (Scheme 3). The
hydrophosphoryloxylation of model substrate 1a led to the
expected enol phosphate 3a in 94% isolated yield. The ortho-Me
group at phenyl ring of R1 was well tolerated (3b), whereas
varying to strong electron-donating group -OMe led to a
decreased yield due to the facile formation of side hydrolyzed
product (3c). The electron-withdrawing halides -F and -Br were
compatible with the process as well, leading to the
corresponding products 3d and 3e in 87% and 91% yield,
respectively. The meta-F and para-Cl substituted aryl ynamides
could be transformed into the desired enol phosphates in high
yields (3f, 3g). Submitting butyl-derived ynamide to the standard
conditions delivered 3h in 90% yield. Gratifyingly, chloro-
substituted ynamide also worked well and product 3i was
afforded in 89% yield. Terminal ynamide proved to be a suitable
substrate as well (3j). A range of sulfonyl groups on the nitrogen
atom were further tested. The substituents on the phenylsulfonyl
group exerted negeligible effect on the reaction outcome (3k, 3l,
3n). The reaction of bulky 2-naphthylsulfonyl derived ynamide
also took place efficiently (3m). Furthermore, N-alkylsulfonyl
ynamides could participate in this transformation, providing the
corresponding products in good yields (3o, 3p). N-Me substrate
underwent hydrophosphoryloxylation smoothly to furnish adduct
3q in 96% yield. Notably, 2-thienyl derived ynamides bearing
different substituents on the benzyl group were also amenable to
the protocol, resulting in the formation of the target products in
67‒94% yields (3r–3u). When large 1-naphthylmethyl was
attached to the nitrogen atom, the reaction also proceeded well
to generate adduct 3v in an excellent yield.
Scheme 3. Substrate scope with respect to ynamides. Conditions: 1 (0.15
mmol), 2a (0.165 mmol), toluene (1.5 mL), RT for 10 min. Isolated yields are
reported. [a]1 h.
Subsequently, a range of phosphoric acids were scrutinized
for the hydrophosphoryloxylation of ynamide 1a (Table 1). It is
found that an elevated temperature was required to promote the
conversion of dialkyl phosphates. For example, diethyl
phosphate 2b could particpate in the transformation readily at 80
oC, affording adduct 3ab in 76% yield. In the case of dibutyl
phosphate 2c, 81% yield of enol phosphate 3ac was achieved
under the optimized conditions. Pleasingly, the protocol could be
successfully extended to BINOL-derived phosphoric acid 2d,
resulting in the formation of 3ad in 98% yield. Furthermore, a
treatment of diphenylphosphinic acid 2e with ynamide 1a in
toluene also generated the desired product 3ae in a good
yield.[19]
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10.1002/ejoc.202001335
European Journal of Organic Chemistry
COMMUNICATION
Table 1. Addition of other phosphoric acids with ynamide.
envisioned that if a smaller nucleophile such as chloride anion
was involved in the process, the addition between chloride anion
and keteniminium ion should take place predomintantly.
However, surprisingly, when a mixture of ynamide 1a, diphenyl
phosphate 2a (0.5 eq) and LiCl (2.0 eq) in toluene was stirred at
room temperature for 10 min, both adducts enol phosphate 3a
and vinyl chloride 3a’ were isolated with 2:1 molar ratio. This
result suggests that the nucleophilic attack of phosphate anion
preferably proceeds through an intimate ion-pair pathway.
Phosphoric
Yield
(%)
Ynamide
Enol phosphate
acid
76[a]
Based on this experimental observation and the precedents
on the hydrofunctionalizations of ynamide,12,13
a plausible
81[a]
mechanism is depicted in Scheme 5. Ynamide 1a is first
protonated by phosphoric acid 2a to furnish contact
keteniminium/phosphate ion-pair Int-1. In this step, owing to the
partial charge transfer from the lone pair on the nitrogen atom
into carbon-carbon triple bond, the electron density of Cβ in
ynamide is significantly higher than that of Cα, so Cβ should be
protonated preferentially (Int-1). This selective protonation then
leads to the following exclusive α-addition regioselectivity. The
upper face of keteniminium intermediate Int-1 is sterically
hindered by the phenyl group. Thus, the nucleophile phosphate
anion favors syn attack from the H side to Cα of Int-1, resulting in
the formation of α-adduct 3a with exclusive (E)-stereoselectivity.
98[b]
78[b]
Conditions: [a]1a (0.15 mmol), 2 (0.165 mmol), toluene (1.5 mL), 80 oC
for 4 h. [b]1a (0.165 mmol), 2 (0.15 mmol), toluene (1.5 mL), RT for 24
h. Isolated yields are reported.
To illustrate the practicality of this approach, a gram-scale
reaction was carried out (Scheme 4). When the addition of
ynamide 1a and diphenyl phosphate 2a was amplified to 1.8
mmol, this transformation could also be completed within 10 min
to give enol phosphate 3a in 88% yield (1.0 g). Besides, the
synthetic transformation of the resulting product was further
investigated (Scheme 4). We were glad to find that enol
phosphate 3a and phenylboronic acid could undergo Suzuki-
Miyaura cross-coupling at room temperature, delivering the
expected product 4a in 80% yield. Moreover, when terminal enol
phosphate 3j was employed as the partner, the coupling also
proceeded in high efficiency (4j, 88%) and the reaction time
could be shortened to 2 h.
Scheme 5. Competitive experiment and proposed mechanism.
In
hydrophosphoryloxylation of ynamides with phosphoric acids.
This strategy enables facile formation of useful enol
summary,
we
have
described
a
metal-free
a
phosphates with exclusive regio- and stereoselectivity. Other
salient advantages include short reaction time, high yields, mild
conditions, broad substrate scope, and good synthetic utility.
This protocol will not only enrich the hydrofunctionalization of
ynamides but also provide some guidance into designing new
cross couplings for the synthesis of multi-substituted alkenes.
Acknowledgements
The work was funded by the startup research fund of Liaoning
Normal University and the Department of Science and
Technology of Liaoning Province (no. 2019-BS151). Dr. Pan
acknowledges the National Natural Science Foundation of China
(no. 81973540) and the startup research fund of Weifang
University of Science and Technology (no. KJRC2019005 and
no. KJRC2020002).
Scheme 4. Gram-scale reaction and synthetic transformation.
Keywords: metal-free
• phosphoric acids • ynamides •
To gain deeper insight into the reaction mechanism, a
competitive experiment was conducted (Scheme 5). We
regioselectivity • enol phosphates
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10.1002/ejoc.202001335
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[1]
[2]
F. W. Lichtenthaler, Chem. Rev. 1961, 61, 607.
Compain, K. Jouvin, A. Martin-Mingot, C. Bachmann, J. Marrot, G.
Evano, S. Thibaudeau, J. Org. Chem. 2015, 80, 3397; c) X. J. Zeng, Z.
C. Lu, S. W. Liu, G. B. Hammond, B. Xu, J. Org. Chem. 2017, 82,
13179; d) W. Cao, P. Chen, L. Wang, H. Wen, Y. Liu, W. Wang, Y.
Tang, Org. Lett. 2018, 20, 4507.
a) A. M. Mattson, J. T. Spillane, G. W. Pearce, J. Agric. Food. Chem.
1955, 3, 319; b) C. Fest, K.-J. Schmidt, The chemistry of
organophosphorus pesticides, Springer Science & Business Media,
2012.
[3]
[4]
a) C. T. Walsh, T. E. Benson, D. H. Kim, W. J. Lees, Chem. Biol. 1996,
3, 83; b) P. M. Krizkova, S. Prechelmacher, A. Roller, F.
Hammerschmidt, J. Org. Chem. 2017, 82, 10310.
[17] L. Wang, C. R. Lu, Y. N. Yue, C. Feng, Org. Lett. 2019, 21, 3514.
[18] a) Y. Y. Zhao, Y. C. Hu, X. C. Li, B. S. Wan, Org. Biomol. Chem. 2017,
15, 3413; b) Y. Y. Zhao, Y. C. Hu, C. X. Wang, X. C. Li, B. S. Wan, J.
Org. Chem. 2017, 82, 3935; c) Y. Y. Zhao, C. X. Wang, Y. C. Hu, B. S.
Wan, Chem. Commun. 2018, 54, 3963.
a) T. Kurokawa, K. Suzuki, T. Hayaoka, T. Nakagawa, T. Izawa, M.
Kobayashi, N. Harada, J. Antibiot. 1993, 46, 1315; b) A. Madani, J. N.
Ridenour, B. P. Martin, R. R. Paudel, A. Abdul Basir, V. Le Moigne, J.-L.
Herrmann, S. Audebert, L. Camoin, L. Kremer, C. D. Spilling, S.
Canaan, J.-F. Cavalier, ACS Infect. Dis. 2019, 5, 1597.
[19] We also conducted the reaction of ynamide with hypophosphorous
acid (H3PO2). However, because commercially available H3PO2 is
an aqueous solution, only the adduct of ynamide with water was
afforded (compound 3af in page S10).
[5]
[6]
a) K. C. Nicolaou, R. Yu, L. Shi, Q. Cai, M. Lu, P. Heretsch, Org. Lett.
2013, 15, 1994; b) V. Kotek, H. Dvořáková, T. Tobrman, Org. Lett. 2015,
17, 608; c) D. Fiorito, S. Folliet, Y. Liu, C. Mazet, ACS Catal. 2018, 8,
1392; d) M. Čubiňák, T. Tobrman, J. Org. Chem. 2020, 85, 10728.
a) H. Nakatsuji, Y. Ashida, H. Hori, Y. Sato, A. Honda, M. Taira, Y.
Tanabe, Org. Biomol. Chem. 2015, 13, 8205; b) W. J. Kerr, D. M.
Lindsay, V. K. Patel, M. Rajamanickam, Org. Biomol. Chem. 2015, 13,
10131; c) H. T. Li, Y. Q. Zhu, D. F. Lu, Y. F. Gong, Org. Biomol. Chem.
2018, 16, 5907.
[7]
[8]
a) I. J. Borowitz, Firstenb.S, E. W. R. Casper, R. K. Crouch, J. Org.
Chem. 1971, 36, 3282; b) Y. Cao, Z. Gao, J. Li, X. Bi, L. Yuan, C. Pei,
Y. Guo, E. Shi, RSC Adv. 2020, 10, 29493.
a) X.-Y. Zhu, J.-R. Chen, L.-Q. Lu, W.-J. Xiao, Tetrahedron 2012, 68,
6032; b) S. Opekar, R. Pohl, V. Eigner, P. Beier, J. Org. Chem. 2013,
78, 4573; c) L. Huang, Z. Zhu, T. H. Cao, X. Y. Lei, J. H. Gong, S. M.
Guo, H. Cai, Chin. J. Org. Chem. 2017, 37, 1571.
[9]
P. H. Lee, S. Kim, A. Park, B. C. Chary, S. Kim, Angew. Chem. Int. Ed.
2010, 49, 6806.
[10] P. Nun, J. D. Egbert, M.-J. Oliva-Madrid, S. P. Nolan, Chem. Eur. J.
2012, 18, 1064.
[11] B. C. Chary, S. Kim, D. Shin, P. H. Lee, Chem. Commun. 2011, 47,
7851.
[12] a) K. A. DeKorver, H. Y. Li, A. G. Lohse, R. Hayashi, Z. J. Lu, Y. Zhang,
R. P. Hsung, Chem. Rev. 2010, 110, 5064; b) G. Evano, A. Coste, K.
Jouvin, Angew. Chem. Int. Ed. 2010, 49, 2840; c) X. N. Wang, H. S.
Yeom, L. C. Fang, S. H. He, Z. X. Ma, B. L. Kedrowski, R. P. Hsung,
Acc. Chem. Res. 2014, 47, 560; d) B. Zhou, T. D. Tan, X. Q. Zhu, M. Z.
Shang, L. W. Ye, ACS Catal. 2019, 9, 6393; e) X. Tian, L. Song, K.
Farshadfar, M. Rudolph, F. Rominger, T. Oeser, A. Ariafard, A. S. K.
Hashmi, Angew. Chem. Int. Ed. 2020, 59, 471; f) X.-Q. Zhu, Z.-S. Wang,
B.-S. Hou, H.-W. Zhang, C. Deng, L.-W. Ye, Angew. Chem. Int. Ed.
2020, 59, 1666.
[13] a) A. Hentz, P. Retailleau, V. Gandon, K. Cariou, R. H. Dodd, Angew.
Chem. Int. Ed. 2014, 53, 8333; b) M. Takimoto, S. S. Gholap, Z. M. Hou,
Chem. Eur. J. 2015, 21, 15218; c) G. K. He, S. N. Qiu, H. Huang, G. H.
Zhu, D. M. Zhang, R. Zhang, H. J. Zhu, Org. Lett. 2016, 18, 1856; d) L.
Hu, S. L. Xu, Z. G. Zhao, Y. Yang, Z. Y. Peng, M. Yang, C. L. Wang, J.
F. Zhao, J. Am. Chem. Soc. 2016, 138, 13135; e) H. Huang, L. N. Tang,
Q. Liu, Y. Xi, G. K. He, H. J. Zhu, Chem. Commun. 2016, 52, 5605; f) B.
Prabagar, S. Nayak, R. K. Mallick, R. Prasad, A. K. Sahoo, Org. Chem.
Front. 2016, 3, 110; g) B. Huang, L. W. Zeng, Y. Y. Shen, S. L. Cui,
Angew. Chem. Int. Ed. 2017, 56, 4565; h) S. W. Kim, T.-W. Um, S. Shin,
Chem. Commun. 2017, 53, 2733; i) K. de la Vega-Hernandez, E.
Romain, A. Coffinet, K. Bijouard, G. Gontard, F. Chemla, F. Ferreira, O.
Jackowski, A. Perez-Luna, J. Am. Chem. Soc. 2018, 140, 17632; j) H.
Huang, H. J. Zhu, J. Y. Kang, Org. Lett. 2018, 20, 2778; k) Y. Y. Shen,
C. R. Wang, W. Chen, S. L. Cui, Org. Chem. Front. 2018, 5, 3574; l) P.
Wagner, M. Donnard, N. Girard, Org. Lett. 2019, 21, 8861; m)Z. Peng,
Z. Zhang, X. Zeng, Y. Tu, J. Zhao, Adv. Synth. Catal. 2019, 361, 4489;
n) C. Yao, J. Yang, X. Lu, S. Zhang, J. Zhao, Org. Lett. 2020, 22, 6628.
[14] D. L. Smith, W. R. F. Goundry, H. W. Lam, Chem. Commun. 2012, 48,
1505.
[15] a) S. J. Xu, J. Q. Liu, D. H. Hu, X. H. Bi, Green Chem. 2015, 17, 184; A
detailed study was also conducted by Zhao's group: b) L. Hu, S. Xu, Z.
Zhao, Y. Yang, Z. Peng, M. Yang, C. Wang, J. Zhao, J. Am. Chem. Soc.
2016, 138, 13135.
[16] a) G. Compain, K. Jouvin, A. Martin-Mingot, G. Evano, J. Marrot, S.
Thibaudeau, Chem. Commun. 2012, 48, 5196; b) B. Metayer, G.
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Entry for the Table of Contents (Please choose one layout)
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Dalie An, Weinan Zhang, Bin Pan,*
Yingying Zhao*
Page No. – Page No.
Metal-Free Hydrophosphoryloxylation
of Ynamides: Rapid Access to Enol
Phosphates
An addition between phosphoric acids and ynamides is developed for the synthesis
of amino-derived enol phosphates. The protocol features metal-free conditions,
exclusive selectivity, short reaction time and easy scale-up. Notably, the resulting
products could easily undergo Suzuki-Miyaura cross-coupling at room temperature.
This article is protected by copyright. All rights reserved.