N-Difluoromethylation of imidazoles and pyrazoles using BrCF2PO(OEt)2 under mild condition

Article abstract of DOI:10.1016/j.tetlet.2018.06.003

A simple and efficient protocol for the direct N-difluoromethylation of imidazoles and pyrazoles has been developed. The reaction makes use of commercially available, non-ozone-depleting and easy handling BrCF₂PO(OEt)₂ as difluorocarbene precursor, and provides a cost-efficient and environmentally benign access to some difluoromethylated biologically relevant molecules.

Full text of DOI:10.1016/j.tetlet.2018.06.003

Accepted Manuscript
N-Difluoromethylation of Imidazoles and Pyrazoles Using BrCF2PO(OEt)2 un-
der Mild Condition
Ting Mao, Liang Zhao, Yang Huang, Yue-Guang Lou, Qiuli Yao, Xiao-Fei Li,
Chun-Yang He
PII:
S0040-4039(18)30733-0
https://doi.org/10.1016/j.tetlet.2018.06.003
TETL 50041
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 April 2018
25 May 2018
1 June 2018
Please cite this article as: Mao, T., Zhao, L., Huang, Y., Lou, Y-G., Yao, Q., Li, X-F., He, C-Y., N-
Difluoromethylation of Imidazoles and Pyrazoles Using BrCF2PO(OEt)2 under Mild Condition, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.06.003
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N-Difluoromethylation of Imidazoles and
Pyrazoles Using BrCF2PO(OEt)2 under Mild
Condition
Ting Mao, Liang Zhao, Yang Huang, Yue-Guang Lou, Qiuli Yao, Xiao-Fei Li,* and Chun-Yang He*
Generic Drug Research Center of Guizhou Province, School of Pharmacy, Zunyi Medical University, No. 6 West Xuefu Road, Zunyi, Guizhou, 563003,
China.

1
Tetrahedron Letters
journal homepage: www.els evier.com
N-Difluoromethylation of Imidazoles and Pyrazoles Using BrCF2PO(OEt)2 under
Mild Condition
Ting Mao, Liang Zhao, Yang Huang, Yue-Guang Lou, Qiuli Yao, Xiao-Fei Li* and Chun-Yang He*
Generic Drug Research Center of Guizhou Province, School of Pharmacy, Zunyi Medical University, No. 6 West Xuefu Road, Zunyi, Guizhou, 563003, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
A simple and efficient protocol for the direct N-difluoromethylation of imidazoles
and pyrazoles has been developed. The reaction makes use of commercially available,
non-ozone-depleting and easy handling BrCF2PO(OEt)2 as difluorocarbene precursor,
Received in revised form
Accepted
and provides a cost-efficient and environmentally benign access to some
difluoromethylated biologically relevant molecules.
Available online
Keywords:
Difluoromethylation
Difluorocarbene
Benzimidazoles
Imidazoles
2013 Elsevier Ltd. All rights reserved.
Pyrazoles
The introduction of a fluorine-containing group into organic
molecules has been well recognized as a general strategy in
structure-based pharmaceutical research and drug discovery.1
Specifically, as one of the most omnipresent fluorinated moieties,
difluoromethyl (CF2H) group has attracted much attention
because this group can act as a lipophilic hydrogen-bond donor
(CF2-H) and a weak hydrogen-bond acceptor (C-F). Moreover,
the introduced CF2H group can appreciably affect the metabolic
stability, lipophility, bioavailability, membrane permeability, and
binding affinity of pharmaceutically relevant compounds.2
Consequently, the CF2H moiety has been used as bioisostere in
drug discovery and considerable efforts have been made in order
to develop new and improved strategies for incorporating this
important group into a wide scope of compounds. 3
Until now, there are several methods to access to N-
difluoromethylated imidazole. Chlorodifluoromethane, an ozone-
depleting chlorofluorocarbon gas, is the frequently used reagent.8
Over the past few years, some impressive non-ozone-depleting
and bench-stable sources to generate difluorocarbene
intermediate have been developed (Scheme 1). 9 Hu et al., in their
recent works, used TMSCF2Br9a and N-tosyl-S-difluoromethyl-
9b
S-phenylsulfox
in the difluoromethylation of heteroatom
nucleophiles. Prakash’s group reported difluoromethylation of
imidazoles using commercial available TMSCF3 under neutral
conditions. 9c However, methods access to such structures were
still
limited.
Consequently,
an
alternative
mild
difluoromethylation procedure using commercial available
reagents is still of higher desirable.
In previous works, BrCF2PO(OEt)2 was proved to be an
efficient difluorocarbene precursor for difluoromethylation of
phenols, thiophenols 10 and tertiary amines 11. Inspired by those
works, we envisioned the N-difluoromethylation of imidazoles
and pyrazoles via this strategy would also be feasible. As part
of our ongoing study on natural compounds fluoroalkylated
modification,12 herein, we report a general method for the N-
difluoromethylation of imidazoles and pyrazoles utilizing readily
available and bench stable BrCF2PO(OEt)2 as difluorocarbene
precursor (Scheme 1). The notable features of this protocol
include their mild reaction conditions, broad substrate scope and
synthetic simplicity. Furthermore, the reaction conducted with
Figure 1. Bioactive compounds containing the difluoromethyl
group.
1:1
ratio
of
imidazoles/pyrazoles
and
diethyl
bromodifluoromethylphosphonate in high efficiency, thus
highlighting the atom economy of this protocol.
Imidazole derivatives play an important role in chemical and
biological systems.4 Recently, the introduction of fluorinated
alkyl onto the imidazole and benzimidazole nitrogen attracted
much attention, because this kind of structure can be used as
precursors for the preparation of ionic liquids,5 N-heterocyclic
carbenes 6 and as important intermediates in drug discovery. 7

2
Tetrahedron
13 c
-----
MeCN
MeCN
Nr
64
14c,d
KF (2.0)
a Reaction conditions (unless otherwise specified): 1a (0.4 mmol, 1 equiv), 2
(2.0 equiv), anhydrous solvent (3 mL) at r.t under Ar for 12 h.
b NMR yield determined by 19F NMR using fluorobenzene as an internal
standard (isolated yield in parentheses).
c 1a (0.4 mmol, 1 equiv), 2 (1.0 equiv), solvent (3 mL) at r.t for 12 h.
d The reaction was carried out under the air atmosphere.
We then investigated the generality and scope of the reaction
under the optimal reaction conditions. Various benzimidazoles
and imidazoles were subjected to our difluoromethylation
protocol to obtain their N-difluoromethylated analogues and
representative results are illustrated in Table 2. Substrates
bearing cyano (3b), hydroxyl (3c), methyl (3d), halogen (3e, 3f,
3i), phenyl (3g), methylthio- (3h), nitro (3k) were all tolerated
and afforded the corresponding products in good to excellent
yields. Moreover, when the reaction performed on a gram scale
(3b, c), comparable yields can still be obtained, which
demonstrate the synthetic utility of the protocol.
Scheme 1. N-Difluoromethylation of Benzoimidazoles and
Imidazoles
We began our investigating by treatment of benzoimidazole 1a
equiv)
(1.0
with
readily
available
diethyl
bromodifluoromethylphosphonate 2 (2.0 equiv) in the presence
of Cs2CO3 (2.0 equiv) in MeCN at room temperature. To our
delight, 26% yield of desired difluoromethylated product 3a was
detected after 12 h reaction. To improve the reaction efficiency
further, different bases were tested. Only a trace yield of 3a was
obtained when Na2CO3 was used instead. However, K3PO4,
K2CO3, and KOAc can gave better results (entries 3-5), and 73%
yield was obtained when KF was used. The reaction efficiency
was even increased when the loading of diethyl
bromodifluoromethylphosphonate 2 decreased to 1.0 equiv, and
79% yield of the desired product can be obtained (entry 7). After
a survey of the reaction medium utilized, DCE and DMSO were
not suitable for this transformation and only trace yield of the
desired product was detected. DMF and THF were less effective
compared to MeCN. (entries 8, 10). The yield decreased to 48%
when 1.0 equiv of KF was used (entry 11), and no desired
product was detected in the absence of KF. The yield decreased
to 64% when the reaction performed under the air atmosphere.
Table 2. N-difluoromethylation of Benzimidazoles and
Imidazoles.a
Table 1. Optimization of N-Difluoromethylation of
Benzoimidazole
1a
(bromodifluoromethyl)phosphonate 2. a
with
diethyl
a Reaction conditions (unless otherwise specified): 1 (0.4 mmol, 1.0 equiv), 2
(1.0 equiv), KF (2.0 equiv), anhydrous MeCN (3 mL), room temperature,
under Ar for 12 h.
Entry
1
Base (equiv)
Cs2CO3 (2.0)
Na2CO3 (2.0)
K2CO3 (2.0)
K3PO4 (2.0)
KOAc (2.0)
KF (2.0)
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
Yield (% ) b
b1 (0.4 mmol, 1.0 equiv), KF (2.0 equiv), and 2 (2.0 equiv) were used.
c1 (13 mmol, 1.0 equiv), KF(2.0 equiv), 2 (1.0 equiv) and 15 mL MeCN were
used.
26
Trace
47
2
3
As pyrazoles are also very important N-containing
heterocyclic found in numerous bioactive molecules, methods
for introducing a difluoromethylene group to these structures
are still limited. 9e Therefore, the reaction of 2 with pyrazoles
was also examined (Table 3). 1H-pyrazole and 4-bromo-1H-
pyrazole give the product in excellent yield. 60%-70% yield
were obtained when the substrate bearing hydroxyl (5c), ester
(5d), nitro (5e) and phenyl (5f). Indazole (5g) and
benzotriazole (5h) were also suitable substrates and good
yield can still be obtained.
4
64
5
55
6
73
7 c
8 c
9 c
10 c
11 c
12 c
KF (2.0)
79 (77)
65
KF (2.0)
KF (2.0)
DCE
Nr
KF (2.0)
DMF
68
KF (2.0)
DMSO
MeCN
9
KF (1.0)
48

3
Table 3. N-Difluoromethylation of Pyrazoles.a
Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A.
E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114,
2432. (c) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J.
L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Chem. Rev. 2016, 116,
422. (d) Preshlock, S.; Tredwell, M.; Gouverneur, V. Chem. Rev.
2016, 116, 719.
2. (a) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305. (b) Prakash,
G. K. S.; Chacko, S. Curr. Opin. Drug Discovery Dev. 2008, 11,
793.
3. (a)Meanwell, N. A. J. Med. Chem. 2011, 54, 2529-2591.; (b) Feng,
Z.; Min, Q.-Q.; Fu, X-P.; An, L.; Zhang, X., Nature Chem. 2017, 9
918-923. (c) Ge, S.; Chaladaj, W.; Hartwig, J. F., J. Am. Chem. Soc.
2014, 136, 4149-4152. (d) Feng, Z. Min, Q.-Q.; Zhang, X., Org.
Lett., 2016, 18, 44-47. (e) Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.;
Berliner, A.; Amir, D.; Marciano, D.; Gershonov, E.; Saphier, S.; J.
Med. Chem. 2017, 60, 797-804. (f) Feng, Z.; Chen, F.; Zhang, X.
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L.; Zhang, B.; Zhang, X. Angew. Chem., Int. Ed. 2014, 53, 1669-
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Y.; Lin, Q.-Y.; Xu, X.-H.; Qing, F.-L. J. Org. Chem. 2016, 81,
7001-7007.
a Reaction conditions (unless otherwise specified): 4 (0.4 mmol, 1.0 equiv), 2
(1.0 equiv), KF (2.0 equiv), anhydrous MeCN (3 mL), room temperature,
under Ar for 12 h.
b F-NMR yield
c 4 (0.4 mmol, 1.0 equiv), KF (2.0 equiv), and 2 (2.0 equiv) were used.
4. For reviews see: (a) Bando, T.; Sugiyama, H.; Acc. Chem. Res.
2006, 39, 935-944. (b) Breslow, R. Acc. Chem. Res. 1991, 24, 317-
324. (c) Townsend, L. B.; Chem. Rev., 1967, 67, 533–563. (d) Palui,
G.; Aldeek, F.; Wang, W.; Mattoussi, H. Chem. Soc. Rev., 2015, 44,
193-227.
11
On the basis of previous reports,
together with the
discovery of intermediate 6 which was demonstrated by NMR
(see supporting information). a plausible reaction mechanism
is proposed in Scheme 2. KF directly attacks the diethyl
5. Abate, A.; Petrozza, A.; Cavallo, G.; Lanzani, G.; Matteucci, F.;
Bruce, D. W.; Houbenov, N.; Metrangolo, P.; Resnati, G. J. Mater.
Chem. A. 2013, 1, 6572.
bromodifluoromethylphosphonate
(2)
to
generate
difluorocarbene intermediate. Then, difluorocarbene react
with imidazoles to afford the desired products.
6.
(a) Rivera, G.; Elizalde, O.; Roa, G.; Montiel, I.; Bernes, S. J. Org.
Met. Chem. 2012, 699, 82. (b) Liu, T.; Zhao, X.; Shen, Q.; Lu, L.
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7. (a) Hodyna, D.; Kovalishyn, V.; Rogalsky, S.; Blagodatnyi, V.;
Petko, K.; Metelytsia, L. Chem. Biol. Drug. Des. 2016. 88, 422-433.
(b) Moore, C. L.; Zivkovic, A.; Engels, J. W.; Kuchta, R. D.
Biochemistry. 2004, 43, 12367-12374.
8. Lyga, J. W.; Patera, R. M. J. Fluorine Chem. 1998, 92, 141-145.
9.
(a) Li, L.; Wang, F.; Ni, C.; Hu, J. Angew. Chem., Int. Ed. 2013,
52, 12390-12394. (b) Zhang, W.; Wang, F.; Hu, J. Org. Lett. 2009,
11, 2109-2112. (c) Prakash, G. K. S.; Krishnamoorthy, S.; Ganesh,
S. K.; Kulkarni, A.; Haiges, R.; Olah, G. A. Org. Lett. 2014, 16,
54-57. (d) Mehta, V. P.; Greaney, M. F. Org. Lett. 2013, 15, 5036-
5039. (e) Deng, X-Y.; L, J-H.; Zheng, J.; Xiao, J-C. Chem.
Commun. 2015, 51, 8805-8808. (f) Wang, F.; Zhang, L.; Zheng, J.;
Hu, J. J. Fluorine Chem. 2011, 132, 521-528. (g) Zheng, J.; Li, Y.;
Zhang, L.; Hu, J.; Meuzelaarb, G. J.; Federselb, H.-J. Chem.
Commun. 2007, 48, 5149-5151.
Scheme 2. Proposed Reaction Mechanism for the Reaction
of Imidazoles with Bromodifluoromethylphosphonate 2.
In conclusion, we have developed a simple and efficient
method for N-Difluoromethylation of imidazoles and
pyrazoles with a readily available, non-ozone-depleting liquid
reagent, diethyl bromodifluoromethylphosphonate. The
reaction underwent the formation of difluorocarbene under
very mild reaction conditions and very high atom economy is
achieved in this process.
10. (a)Yossi, Z.; Gali, S-M.; Yoffi, S. Tetrahedron. 2009, 65, 5278-
5283. (b) Huang, Y.; Wang, A-J.; Kong, J.; Lou, Y-G.; Li, X.-F.;
He, C-Y. Synth. Comm. 2018, 48, 91-96.
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Karton-Lifshin, N.; Gershonov. E. J. Org. Chem. 2016, 81, 9180-
9187.
12. (a) He, C-Y.; Kong, J.; Li, X.; Li, X.; Yao, Q.; Yuan, F-M. J. Org.
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1754.
Acknowledgments
This work was financially supported by the Young Elite
Scientists Sponsorship Program by Cast of the China Association
for Science and Technology (No. 2015-41), the National Natural
Science Foundation of China (No. 81760624, 21702241), Key
Programs of Guizhou Province (2018-1427).
Supplementary Material
Detailed experimental procedures, and characterization data
for new compounds.
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References and notes
1. (a) Ojima, I. Fluorine in Medicinal Chmeistry and Chemical
Biology; Wiley-Blackwell: Oxford, U.K., 2009. (b) Wang, J.;

4
Tetrahedron
Highlights
Readily available starting materials
Broad functional groups tolerance
Operationally simple and proceeds under mild
reaction conditions.