Efficient difluoromethylation of isoflavonoids and flavonoid under mild conditions

Article abstract of DOI:10.1080/00397911.2017.1390686

A simple and efficient protocol for difluoromethylation of isoflavones, flavonoids, and coumarins has been developed. The protocol uses readily available, non-ozone-depleting and easy handling BrCF₂PO(OEt)₂ as difluorocarbene precursor. The reaction underwent the formation of difluorocarbene under mild reaction conditions with relatively weak base therefore demonstrates high selectivity. Application of the reaction led to difluoromethylated biologically relevant molecules.

Full text of DOI:10.1080/00397911.2017.1390686

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Efficient difluoromethylation of isoflavonoids and
flavonoid under mild conditions
Yang Huang, An-Jun Wang, Jingjing Kong, Yue-Guang Lou, Xiao-Fei Li & Chun-
Yang He
To cite this article: Yang Huang, An-Jun Wang, Jingjing Kong, Yue-Guang Lou, Xiao-Fei Li
& Chun-Yang He (2018) Efficient difluoromethylation of isoflavonoids and flavonoid under mild
conditions, Synthetic Communications, 48:1, 91-96, DOI: 10.1080/00397911.2017.1390686
To link to this article: https://doi.org/10.1080/00397911.2017.1390686
View supplementary material
Published online: 14 Dec 2017.
Submit your article to this journal
Article views: 25
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [RMIT University Library]
Date: 26 December 2017, At: 07:05

SYNTHETIC COMMUNICATIONS®
2018, VOL. 48, NO. 1, 91–96
https://doi.org/10.1080/00397911.2017.1390686
Efficient difluoromethylation of isoflavonoids and flavonoid
under mild conditions
Yang Huang, An-Jun Wang, Jingjing Kong, Yue-Guang Lou, Xiao-Fei Li,
and Chun-Yang He
Generic Drug Research Center of Guizhou Province, School of Pharmacy, Zunyi Medical
University, Zunyi, China
ABSTRACT
ARTICLE HISTORY
Received 26 July 2017
A simple and efficient protocol for difluoromethylation of isoflavones,
flavonoids, and coumarins has been developed. The protocol uses
readily available, non-ozone-depleting and easy handling BrCF2PO(OEt)2
as difluorocarbene precursor. The reaction underwent the formation of
difluorocarbene under mild reaction conditions with relatively weak
base therefore demonstrates high selectivity. Application of the reaction
led to difluoromethylated biologically relevant molecules.
KEYWORDS
Coumarins; difluorocarbene;
difluoromethylation;
flavonoids; isoflavones
GRAPHICAL ABSTRACT
Introduction
Isoflavonoids and flavonoids belong to a large class of more than 4000 naturally occurring
polyphenolic compounds found mainly in fruits, vegetables, and cereals.[1–3] Various
studies have shown that these compounds exhibit a wide range of biological activity that
are beneficial to humans, including anti-inflammatory, antitumor, antioxidant, antimicro-
bial, cytotoxic, and antiallergic.[4–7] Selective introduction of fluorine-bearing motifs into
bioactive organic compounds, including the above-mentioned isoflavonoids and flavonoids
derivatives, has become a leading strategy for drug design and lead optimization.
Owing to its unique properties, fluorine is frequently used to modify biologically
relevant properties such as metabolic stability, basicity, lipophilicity, and bioavailablity.[8,9]
As one of the most omnipresent fluorinated moieties, difluoromethyl (CF2H) group has
attracted particular interest because this group can act as a lipophilic hydrogen-bond donor
and has been used in various bioisostere design.[10–14] Among those difluoromethylated
compounds, aryl difluoromethyl ethers are becoming increasingly prevalent in the
pharmaceutical, agrochemical, and materials industries, such as enzyme inhibitors,[15]
anti-HIV agents,[16] antimicrobial agents,[17] and proton-pump inhibitors.[18] As the
CONTACT Chun-Yang He
hechy2002@163.com; Xiao-Fei Li
lixiaofei@zmu.edu.cn
Generic Drug Research Center
of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi 563003, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
© 2017 Taylor & Francis

92
Y. HUANG ET AL.
Scheme 1. Difluoromethylation of formononetin and its analogues.
interest in fluorination of candidate drug increases, special interest in the construction of
aryl difluoromethyl ethers is also growing.
The original medicinal chemistry route utilized chlorodifluoromethane, a toxic and
ozone-depleting chlorofluorocarbon gas, as the source of the difluorocarbene intermediate.
This difluoromethylated reagent could not be used on scale.[19,20] Over the past few years,
some impressive non-ozone-depleting and bench-stable sources to generate difluorocar-
bene intermediate have been developed using HCF2OTf,[21] CHF3,[22] TMSCF2Br,[23]
[Cu(Phen)2][O2CCF2Cl],[24] BrCF2PO(OEt)2,[25] PhCOCF2Cl,[26] PhSO2CF2Cl,[27] as
difluorocarbene precursor to access to aryl difluoromethyl ethers. However, a large amount
strong alkaline base (6.0–20.0 equiv. of KOH or NaOH) is usually needed in those
processes. Thus restrict their application in modification of natural products, which usually
containing multifunctional groups. Although other reagents used for the difluoromethyla-
tion of phenols could proceed under nonbasic conditions, the synthesis of aryl
difluoromethyl ethers with these reagents is subjected to low yields or narrow substrate
scope.[28,29] Consequently, an alternative mild difluoromethylation procedure that amen-
able to late-stage modification of natural occurring hydroxyl containing molecules is still
of high desirable.
As part of our ongoing study on natural compounds fluoroalkylated modification,[30,31]
herein, we report a catalyst free procedure for difluoromethylation of isoflavones, flavo-
noids, and coumarins utilizing K2CO3 to generate difluorocarbene from readily available
and bench stable BrCF2PO(OEt)2, thus avoid the use of ozone-depleting, toxic and gaseous
chlorodifluoromethane in previous reported procedures (Scheme 1). The notable feature of
this protocol also include their mild reaction conditions, synthetic simplicity, and high
selectivity.
Results and discussion
We commenced our investigating by treatment of formononetin 1a (1.0 equiv.) with
readily available diethyl bromodifluoromethylphosphonate 2 (2.0 equiv.) in the presence
of K2CO3 (2.0 equiv.) in DMSO at room temperature. However, only trace amount of
desired difluoromethylated product 3a was detected. To further improve the reaction
efficiency, different reaction media were tested, non-polar solvent toluene and dioxane

SYNTHETIC COMMUNICATIONS®
93
were still not suitable for this transformation and only trace yield of the desired product
was detected. It was found that a dramatically improved yield of 3a was obtained when
the reaction was conducted in MeCN (82% by 19F NMR and 74% upon isolation, entry 3).
DMF was also a suitable reaction media and 3a can be obtained in 77% yield (entry 4). After
a survey of the base utilized, it was found that the choice of base was very critical to the
reaction efficiency. Only a trace yield of 3a was obtained when Na2CO3 was used as a base
(entry 7). Stronger base, Cs2CO3, was less effective than K2CO3 and a decreased yield of 3a
was reached (60% by 19F-NMR, entry 8). Other bases, such as K3PO4, KF, KOAc also led to
lower yield (entries 8–10). The yield decreased to 38% when 1.0 equiv. of K2CO3 was used
(entry 11), and no desired product was detected in the absence of K2CO3, thus
demonstrating that base did play an essential role for promotion of the reaction. Finally,
the optimal reaction conditions were identified using K2CO3 (2.0 equiv.) as base and MeCN
as solvent, with 74% isolated yield of 3a obtained (Table 1, entry 3).
With the optimal reaction conditions in hand, various of biologically active molecules
containing hydroxyl were subjected to our difluoromethylation protocol to obtain their
difluoromethyl ethers analogues and representative results are illustrated in Table 2.
Genistein furnished the reaction with high selectivity, and the difluoromethylation almost
occurred at the hydroxyl of more acidic, affording 3b in 55% yield when K3PO4 used as a
base. When chrysin was used as substrate, only mono-difluoromethylation was obtained
under standard reaction conditions (3c, 64% yield), and bis-difluoromethylation could be
obtained when a stronger base such as Cs2CO3 was used (3d, 72% yield). The substrates
with hydroxyl group of low acidic, such as (�)-Naringenin and (S)-30,5,7-trihydroxy-40-
methoxyflavanone, can also be difluoromethylated with high selectivity, albeit with somewhat
diminished efficiency. The yield increased a bit when the base switched to K3PO4 (3e, 3f).
Table 1. Optimization of difluoromethylation of formononetin 1a with diethyl (bromodifluoromethyl)
phosphonate 2.a
Entry
Base (equiv.)
Solvent
Yield (%)b
1
2
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
Na2CO3 (2.0)
Cs2CO3 (2.0)
K3PO4 (2.0)
KOAc (2.0)
KF (2.0)
DMSO
Toluene
MeCN
DMF
Dioxane
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Trace
Trace
82 (74)
77
3
4
5
Trace
Trace
60 (54)
53 (46)
33
6
7
8
9
10
11
12
13
32
K2CO3 (1.0)
K2CO3 (2.0)
–
38
42c
Nr
aReaction conditions (unless otherwise specified): 1a (0.4 mmol, 1 equiv.), 2a (2.0 equiv.), solvent (3 mL) at room temperature
for 48 h.
bNMR yield determined by 19F NMR using fluorobenzene as an internal standard (isolated yield in parentheses).
cThe reaction was performed in the air.

94
Y. HUANG ET AL.
Table 2. Difluoromethylation of formononetin and its analogues.a
aReaction conditions (unless otherwise specified): 1 (0.4 mmol, 1.0 equiv.), 2 (2.0 equiv.), K2CO3(2.0 equiv.), MeCN (3 mL),
room temperature, 48 h.
b1 (0.4 mmol, 1.0 equiv.), K3PO4 (2.0 equiv.) and 2 (2.0 equiv.) were used.
c1 (0.4 mmol, 1.0 equiv.), Cs2CO3 (4.0 equiv.), and 2 (4.0 equiv.) were used.
d1 (0.4 mmol, 1.0 equiv.), Cs2CO3 (2.0 equiv.), and 2 (2.0 equiv.) were used.
There is no reaction occurred when hydroxyflavones were treated under standard reaction
conditions because of the existence of intramolecular hydrogen bond, a stronger base,
Cs2CO3, enabled difluoromethylation with excellent levels of efficiency (3g, 3h). Those
results (3b–h) demonstrate high selectivity of this protocol which benefit from using weak
base in this process. As coumarins represent an important class of heterocyclic motifs found
in numerous bioactive natural molecules, umbelliferone and 4-hydroxycoumarin were also
amenable to this difluoromethyl protocol, and useful levels of efficiency are obtained (3i–l)
when treated with diethyl bromodifluoromethylphosphonate 2 under optimal reaction
conditions.
Experimental
1H NMR, 19F NMR, and 13C NMR spectra were recorded on a Agilent AM400
spectrometer. Chemical shifts (δ) are reported in ppm, and coupling constants (J) are in

SYNTHETIC COMMUNICATIONS®
95
Hertz (Hz). NMR yield was determined by 19F NMR using fluorobenzene as an internal
standard before working up the reaction. All reagents were used as received from
commercial sources, and handled in air, and then refilled with an inert atmosphere of
Ar at room temperature. DMF and DMSO were distilled under reduced pressure from
CaH2. 1,4-Dioxane was distilled from sodium and benzophenone immediately before use.
General procedure for the difluoromethylation of isoflavonoids and flavonoids under
mild conditions: To a 25 mL of Schlenk tube equipped with a Teflon septum were
added 1 (0.4 mmol, 1.0 equiv.) and K2CO3 (2.0 equiv.), after refilled with Ar three times,
2 (0.8 mmol, 2.0 equiv.), MeCN (3.0 mL) was added. The Schlenk tube was screw capped.
After stirring for 48 h, the reaction mixture was concentrated. The residue was subjected to
column chromatography on silica gel to afford the pure product.
Conclusion
In summary, we have developed a simple and efficient method for difluoromethylation of
isoflavones, flavonoids, and coumarins with a readily available, non-ozone-depleting liquid
reagent, diethyl bromodifluoromethylphosphonate. The acidic of hydroxy group plays a
crucial role in the reaction therefore demonstrate high selectivity. Applications of the
reaction led to difluoromethylated biologically relevant molecules. Further modification
and studies on biological activities of these compounds are currently underway in our
laboratory.
Funding
This work was financially supported by the Young Elite Scientists Sponsorship Program by CAST
(No. 2015-41), The National Natural Science Foundation of China (Nos. 81260488, 21702241),
The Training Programme Foundation for the Talents of the Zun Yi Science and Technology Bureau
(No. 2015-40), and Key Programs of Guizhou Province (125 Program, No. 2015-039).
ORCID
Chun-Yang He
http://orcid.org/0000-0002-0599-7335
References
[1] Gaspar, A.; Matos, M. J.; Garrido, J.; Uriarte, E.; Borges, F. Chem. Rev. 2014, 114, 4960–4992.
[2] Hussain, H.; Al-Harrasi, A.; Al-Rawahi, A.; Green, I. R.; Gibbons, S. Chem. Rev. 2014, 114,
10369–10428.
[3] Silva, L. N.; Zimmer, K. R.; Macedo, A. J.; Trentin, D. S. Chem. Rev. 2016, 116, 9162–9236.
[4] Fu, Y.; Chen, J.; Li, Y.-J.; Zheng, Y.-F.; Li, P. Food Chem. 2013, 141, 1063–1071.
[5] Cho, N.; Choi, J. H.; Yang, H.; Jeong, E. J.; Lee, K. Y.; Kim, Y. C.; Sung, S. H. Food Chem.
Toxicol. 2012, 50, 1940–1945.
[6] García-Lafuente, A.; Guillamón, E.; Villares, A.; Rostagno, M. A.; Martínez, J. A. Inflamm. Res.
2009, 58, 537–552.
[7] Imai, M.; Kikuchi, H.; Denda, T.; Ohyama, K.; Hirobe, C.; Toyoda, H. Cancer Lett. 2009, 276,
74–80.
[8] Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis Reactivity, Applications, 2nd ed.;
Wiley-VCH: Weinheim, 2013.
[9] Ojima, I., Ed. Fluorine in Medicinal Chemistry and Chemical Biology; Wiley: Chichester, 2009.
[10] Meanwell, N. A. J. Med. Chem. 2011, 54, 2529–2591.
[11] Feng, Z.; Min, Q.-Q.; Fu, X-P.; An, L.; Zhang, X. Nat. Chem. 2017, 9, 918–923.

96
Y. HUANG ET AL.
[12] Ge, S.; Chaladaj, W.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 4149–4152.
[13] Feng, Z.; Min, Q.-Q.; Zhang, X. Org. Lett. 2016, 18, 44–47.
[14] Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.; Marciano, D.; Gershonov,
E.; Saphier, S. J. Med. Chem. 2017, 60, 797–804.
[15] Chauret, N.; Guay, D.; Li, C.; Day, S.; Silva, J.; Blouin, M.; Ducharme, Y.; Yergey, J. A.;
Nicoll-Griffith, D. A. Bioorg. Med. Chem. Lett. 2002, 12, 2149–2152.
[16] Ohmine, F. T.; Katsube, T.; Tsuzaki, Y.; Kazui, M.; Kobayashi, N.; Komai, T.; Hagihara, M.;
Nishigaki, T.; Iwamoto, A.; Kimura, T.; Kashiwase, H.; Yamashita, M. Bioorg. Med. Chem. Lett.
2002, 12, 739–742.
[17] Takahata, M.; Mitsuyama, J.; Yamashiro, Y.; Yonezawa, M.; Araki, H.; Todo, Y.; Minami, S.;
Watanabe, Y.; Narita, H. Antimicrob. Agents Chemother. 1999, 43, 1077–1084.
[18] Cheer, S. M.; Prakash, A.; Faulds, D.; Lamb, H. M. Drugs 2003, 63, 101–132.
[19] Meng, W.-D.; Zhang, Z.-H.; Qing, F.-L.; Li, Q.; Zhang, Y.-Y.; Wang, H.-S. Pharmazie 2006,
61, 648–649.
[20] Fu, X.-H.; Wang, L.; Zhao, H.; Xiang, H.-L.; Cao, J.-G. Bioorg. Med. Chem. Lett. 2008,
18, 513–517.
[21] Fier, P. S.; Hartwig J. F. Angew. Chem. Int. Ed. 2013, 52, 2092–2095.
[22] Thomoson, C. S.; Dolbier Jr., W. R. J. Org. Chem. 2013, 78, 8904–8908.
[23] Li, L.; Wang, F.; Ni, C.; Hu, J. Angew. Chem. Int. Ed. 2013, 52, 12390–12394.
[24] Lin, X.; Hou, C.; Li, H.; Weng, Z. Chem. Eur. J. 2016, 22, 2075–2084.
[25] Yossi, Z.; Gali, S-M.; Yoffi, S. Tetrahedron 2009, 65, 5278–5283.
[26] Zhang, J.; Zheng, J.; Hu, J. J. Org. Chem. 2006, 71, 9845–9848.
[27] Zheng, J.; Li, Y.; Zhang, L.; Hu, J.; Meuzelaar, G. J.; Federsel, H.-J. Chem. Commun. 2007,
5149–5151.
[28] Chen, Q.-Y.; Wu, S.-W. J. Org. Chem. 1989, 54, 3023–3027.
[29] Chen, Q.-Y.; Wu, S.-W. J. Fluorine Chem. 1989, 44, 433–440.
[30] He, C.-Y.; Kong, J.; Li, X.; Li, X.; Yao, Q.; Yuan, F.-M. J. Org. Chem. 2017, 82, 910–917.
[31] Zhang, B-H.; Kong, J.; Huang, Y.; Lou, Y-G.; Li, X.; He, C-Y. Chin. Chem. Lett. 2017,
28, 1751–1754.