Visible light-mediated C-H difluoromethylation of electron-rich heteroarenes

Article abstract of DOI:10.1021/ol501094z

A novel method for visible-light photoredox-catalyzed difluoromethylation of electron-rich N-, O-, and S-containingheteroarenes under mild reaction conditions is developed. Mechanistic investigation indicates that the net C-H difluoromethylation proceeds through an electrophilic radical-type pathway.

Full text of DOI:10.1021/ol501094z

Letter
pubs.acs.org/OrgLett
Visible Light-Mediated C−H Difluoromethylation of Electron-Rich
Heteroarenes
Yi-Ming Su, Yu Hou, Feng Yin, Yue-Ming Xu, Yan Li, Xiaoqi Zheng, and Xi-Sheng Wang*
Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, China
S
* Supporting Information
ABSTRACT: A novel method for visible-light photoredox-catalyzed
difluoromethylation of electron-rich N-, O-, and S-containingheter-
oarenes under mild reaction conditions is developed. Mechanistic
investigation indicates that the net C−H difluoromethylation
proceeds through an electrophilic radical-type pathway.
he difluoromethyl moiety (CF2H) is an intriguing
replacing the acidic hydrogen on HCF2 moiety with a
Tstructural motif that has special biological properties, removable electron-withdrawing group. Herein, we report a
visible light photoredox difluoromethylation of electron-rich N-,
O-, and S-containing electron-rich heteroarenes,11,12 in which
the net C−H difluoromethylation proceeds through an
electrophilic radical-type path.
such as enhancement of membrane permeability, binding
affinity, and bioavailability.1 Additionally, it can act as lipophilic
hydrogen-bond donor and a bioisostere of alcohols and thiols.2
As a result, the difluoromethyl moiety has been of extensive
interest for use in pharmaceuticals, agrochemicals, and material
sciences.3 However, although a variety of methods for
incorporating the closely related trifluoromethyl group into a
diverse array of organic compounds have been reported,4 there
remain relatively few successful examples of difluoromethyla-
tion, particularly of (hetero)arenes.
Classically, the strategy of choice for synthesizing difluor-
omethylated (hetero)arenes has been deoxofluorination of
aldehydes. However, these reactions generally suffered from
harsh reaction conditions5 and requirement of prefunctionaliza-
tion. Recently, the Amii group reported a sequential copper-
catalyzed cross-coupling/hydrolysis/decarboxylation route to
difluoromethylarenes.6 The Hartwig7 and Prakash8 groups
reported direct copper-mediated nucleophilic difluoromethyla-
tion of iodoarenes with HCF2M (M = TMS and n-Bu3Sn,
respectively). Although the difluoromethylatedarene products
were obtained in excellent yields in these cases, successful
examples of heterocycles to which this methodology was
applied were quite limited, primarily to pyridine derivatives.
Inspired by Minisci’s early research,9 Baran and co-workers
recently reported an impressive approach for direct difluor-
omethylation of electron-deficient heterocycles with zinc
difluoromethanesulfinate(DFMS) through a radical pathway,
in which a nucleophilic CF2H radical attack to an electron-
deficient reactive site was claimed, and mainly electron-deficient
heteroarenes were reported (Scheme 1).10 We envision an
electrophilic difluoromethyl radical might be triggered by
Inspired by recent advances in visible-light photoredox
catalysis,13 which avoid the use of potential hazardous radical
initiators, our study commenced with N-methylpyrrole (1a) as
the pilot substrate and PhSO2CF2I, a well-established
difluoromethylation reagent developed by Prakash and Hu,14
as a difluoromethyl resource in the presence of catalytic
Ru(bpy)3Cl2·6H2O (1 mol %) at 40 °C. To our excitement, the
desired difluoro(phenylsulfonyl)methylated product 2a was
obtained when DMF was used as the solvent, albeit in low yield
(entry 1, Table 1). A careful survey of solvents was then
performed, which revealed CH2Cl2 as optimal (entries 1−6).
While most of the inorganic and organic bases were not
compatible with this reaction (Table S2, Supporting
Information), KOAc and NaOH afforded the best yields
(entry 13 and 14) as well as K2HPO4 (entry 7). To further
improve the yield, the reaction concentration was also
investigated, which indicated a higher concentration gave the
best yield while combination of CH2Cl2 as solvent (entry 15).
Lastly, control experiments demonstrated that no desired
product would be generated without light (entry 16), and the
yield would be significantly reduced (26%) without Ru-
(bpy)3Cl2·6H2O as catalyst (entry 17). To compare the
different scope of application, N-methylpyrrole (1a) was also
subjected to the standard conditions of Baran’s method,10
which showed no corresponding difluoromethylated product
generated after checking by 19F NMR (entry 18).15
With the optimized reaction conditions in hand, we
examined the substrate scope. Gratifyingly, N-free pyrroles
(2b, 2e) were found to smoothly undergo difluoromethylation,
giving the desired products in slightly reduced yields (Figure 1).
The investigation of substituents effect showed both electron-
Scheme 1. C−H Difluoromethylation of Heteroarenes
Received: April 15, 2014
Published: May 9, 2014
© 2014 American Chemical Society
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a,b
Table 1. Visible Light-Mediated Difluoromethylation of N-Methylpyrrole: Optimization of Reaction Conditions
entry
solvent
base
yield (%)
entry
solvent
base
yield (%)
1
2
3
4
5
6
7
8
9
DMF
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
NEt3
10
22
21
21
11
30
59
54
17
10
11
12
13
14
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
NaHCO3
Cs2CO3
NaOAc
KOAc
21
50
32
DMSO
MeCN
MeOH
NMP
c
67 (80 )
c
NaOH
72 (60 )
c
DCE
15
K2HPO4
K2HPO4
K2HPO4
91
0
c
c
f
,
,
d
e
CH2Cl2
CH2Cl2
CH2Cl2
16
17
18
26
0
DABCO
a
Reaction conditions: 1a (0.4 mmol, 2.0 equiv), PhSO2CF2I (1.0 equiv), Ru(bpy)3Cl2·6H2O (1 mol %), base (3.0 equiv), solvent (1.5 mL), 40 °C,
24 h. Isolated yield. Solvent (0.5 mL). No light. No catalyst. The reaction was performed under Baran’s standard conditions.10
b
c
d
e
f
Et, Ph, MeO, and SAc on the furan and thiophene rings were
also tolerated. Interestingly, 2,4-dimethylthiazole and 1,4-
dimethylpyrazole, which contain two heteroatoms in their
rings, also were found to give good yields (2t−u) but required a
higher catalyst loading (3 mol %) for the later one (2u).
To test whether this method extended to other heteroarenes,
we next examined a variety of electron-rich indoles, whose
framework has been realized as a key motif in biological and
medical chemistry. Unsurprisingly, a series of 3-substiuted
indoles were difluoromethylated smoothly, giving the desired
products in moderate to good yields (Figure 2). Additionally,
while the N-free indole gave moderate yield, changing N-
protecting group from Me to other electron-donating groups,
such as Et or Bn, has almost no effect on the yields (4c,d). All
indoles bearing primary (1°) or secondary (2°) alkyl groups or
a phenyl group at the C3 position were proven to be effective
substrates for this transformation (4e−g). A range of functional
groups on the aryl ring of indoles, including both electron-
donating groups, such as Me and OMe, and electron-
withdrawing groups, such as F, Cl, and Br, were also tolerated
(4h−o). Notably, the difluoro(phenylsulfonyl)methylation of
simple indoles without C3 substitution also proceeded in good
yields, albeit with low regioselectivities (4p−r).
To understand the site-selectivity patterns of this reaction
with heterocyclic compounds that contain multiple potentially
reactive sites, we applied our catalytic C−H difluoromethyla-
tion reaction to two select heteroarenes, 5 and 7, in order to
observe the product distributions (Scheme 2). Interestingly,
compared with Baran’s previous result with dihydroquinine, in
which a nucleophilic radical addition mode was seen
Figure 1. Scope of electron-rich heteroarene substrates. (a) Reaction
(functionalization of the electron-deficient C2 position adjacent
conditions: PhSO2CF2I (0.2 mmol, 1.0 equiv), 1 (2.0 equiv),
to nitrogen atom of the pyridine ring),10 our difluoromethy-
Ru(bpy)3Cl2·6H2O (1 mol %), K2HPO4 (3.0 equiv), CH2Cl2 (0.5
lation reaction occurred at the most electron-rich C5 position
with 5. This suggests that the putative electrophilic difluoro-
(phenylsulfonyl)methyl radical generated by photoredox-
mL), 40 °C, 24 h. (b) Isolated yield. (c) 48 h. (d) Ru(bpy)3Cl2·6H2O
(3 mol %). (e) 1 (5.0 equiv). (f) 60 °C. (g) 72 h.
catalyzed reduction of PhSO2CF2I is more electrophilic than
•
the HCF2 radical implicated in Baran’s case. Futhermore, the
reaction with 4-methylthiazole (7) also predominantly gave
functionalization at the electron-rich C5 position (C5:C2 =
3.3:1), further corroborating the preference of our new
developed method for attack at the electron-rich position.
To understand the mechanism of this transformation, we
carried out a series of experiments. First, we attempted to
perform the reaction in the presence of 1.0 equiv TEMPO as a
radical scavenger, and only 4% of the desired product was
donating (2c) and electron-withdrawing groups (2d−f) on the
pyrrole ring were compatible with this method. While 3- and 4-
postion on pyrrole ring were substituted by different electron-
withdrawing and electron-donating groups respectively, this
transformation gave the difluoromethylated compounds at the
electron-rich 5-position as major product (2g). Notably, O- and
S-containing heteroarenes, such as furan and thiophene
derivatives, could also be difluoro(phenylsulfonyl)methylated
in satisfactory yields. Various substituted groups including Me,
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Scheme 3. Radical-Trapping Experiments
Scheme 4. Possible Catalytic Cycle
photocatalyst Ru(bpy)3Cl2·6H2O with visible light produced
by a 26 W light bulb gives the exited state A, which sequentially
followed a reduction of PhSO2CF2I to afford Ru(III) and an
•
Figure 2. Scope of functional indoles. (a) Reaction conditions: 3 (0.2
mmol, 1.0 equiv), PhSO2CF2I (1.4 equiv), Ru(bpy)3Cl2·6H2O (1 mol
%), K2HPO4 (3.0 equiv), CH2Cl2 (0.5 mL), 40 °C, 48 h. (b) Isolated
yield. (c) 24 h. (d) Ru(bpy)3Cl2·6H2O (3 mol %). (e) 58 h. (f) 60 °C.
(g) 3 (1.6 equiv).
electrophilic PhSO2CF2 radical B. Addition of this radical
species to the electron-rich arene results in the formation of
radical intermediate C. Radical C is then oxidized to cation D
by Ru(III) followed by base-mediated deprotonation to give
the final difluoromethylated product.
Desulfonylation of 4p mediated by Mg was found to proceed
smoothly at room temperature,16 affording the difluoromethy-
lindole 13a in 95% yield (Figure 3). While the indoles with
electron-rich (4b) or -deficient groups (4q−r) were compatible
with this method, O- (2m−n), S- (2s), and two heteroatoms
(2t,u) containing (phenylsulfonyl)difluoromethylatedhetero-
cycles were also desulfonylated smoothly to provide the desired
Scheme 2. Site-Selectivity of Difluoromethylation
obtained (eq 1, Scheme 3). This observation was consistent
with the established catalytic cycle that the photoredox catalysis
proceeds via a radical path. While we failed to capture the
coupling product of TEMPO with PhSO2CF2I (eq 1, Scheme
3), we were able to employ two kinds of radical clocks to trap
•
the PhSO2CF2 radical. The reaction of PhSO2CF2I with allyl
ether 9 under the standard reaction conditions gave the cyclized
product 10 in 86% yield (3:1 dr), and the reaction with β-
pinene 11 provided the ring-opened diene 12 (isolated as an
isomeric mixture) via rearrangement (eq 2 and 3, Scheme 3).
•
Both results implicated the involvement of PhSO2CF2 radical
in this progress.
Figure 3. Reductive desulfonylation. (a) Reaction conditions: 2 or 4
(0.2 mmol, 1.0 equiv), Mg (4.7 mmol), buffer solution (2.0 mL), DMF
(2.0 mL), rt. (b) Isolated yield. (c) Values in parentheses were yields
of the one-pot process.
On the basis of these observations and the reported results
on photoredox catalysis,13 a plausible photoredox catalytic cycle
was depicted in Scheme 4. Initially, the excitation of
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Letter
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excitement, it was found that the one-pot process, in which only
removal of solvent was required after difluoro(phenylsulfonyl)-
methylation, worked pretty well with only slightly reduced yield
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difluoromethylate melatonin, a natural product with free indole
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Scheme 5. Difluoromethylation of Melatonin
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by desulfonylation with excess Mg (51% yield for one-pot
process).
In summary, we have developed a novel method for visible
light photoredox difluoromethylation of electron-rich hetero-
arenes under mild conditions, in which the net C−H
difluoromethylation proceeds through an electrophilic radical-
type path. N-, O-, and S-containing heteroarenes were found to
be compatible with this new transformation. Further
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data (1H NMR,
13C NMR, HRMS). This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
(12) For Pd-mediated Heck-type couplings of PhSO2CF2Br and
heteroarenes, see: Surapanich, N.; Kuhakarn, C.; Pohmakotr, M.;
Reutrakul, V. Eur. J. Org. Chem. 2012, 5943.
*E-mail: xswang77@ustc.edu.cn.
Notes
(13) Forselected reviews of visible light photoredox catalysis, see:
(a) Zeitler, K. Angew. Chem., Int. Ed. 2009, 48, 9785. (b) Yoon, T. P.;
Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527. (c) Narayanam, J. M. R.;
Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102. (d) Xuan, J.; Xiao,
W.-J. Angew. Chem., Int. Ed. 2012, 51, 6828. (e) Wallentin, C.-J.;
Nguyen, J. D.; Stephenson, C. R. J. Chimia 2012, 66, 394. (f) Shi, L.;
Xia, W. Chem. Soc. Rev. 2012, 41, 7687. (g) Prier, C. K.; Rankic, D. A.;
MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322. For photoredox-
catalyzed C−H trifluoromethylation of heteroarenes, see: (h) Nagib,
D. A.; MacMillan, D. W. C. Nature 2011, 480, 224. (i) Iqbal, N.; Choi,
S.; Ko, E.; Cho, E. J. Tetrahedron Lett. 2012, 53, 2005.
(14) For selected reviews, see: (a) Prakash, G. K. S.; Hu, J. Acc. Chem.
Res. 2007, 40, 921. (b) Hu, J.; Zhang, W.; Wang, F. Chem. Commun.
2009, 7465. (c) Hu, J. J. Fluorine Chem. 2009, 130, 1130. (d) Ni, C.;
Hu, J. Synlett 2011, 6, 770. (e) Zhang, W.; Ni, C.; Hu, J. Top. Curr.
Chem. 2012, 308, 25.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge NSFC (21102138, 21372209,
J1030412), the Chinese Academy of Sciences, and the Ministry
of Education (SRFDP 20123402110040) for financial support.
Y.-M.X. is a visiting student from Anhui University.
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