A new approach to access difluoroalkylated diarylmethanes: Via visible-light photocatalytic cross-coupling reactions

Article abstract of DOI:10.1039/c8cc01486h

Difluoroalkylated diarylmethanes with biological and pharmacological potentials were synthesized from para-quinone methides (p-QMs) and difluoroalkylating reagents via a visible light photocatalysis strategy. Mechanism studies showed that the excited photocatalyst, ?fac-Ir(ppy)₃, was primarily quenched by p-QMs and the generated diarylmethane radical intermediates then underwent a radical-radical cross-coupling reaction with difluoroalkyl radicals. This reaction features mild conditions, high efficiency and wide functional group compatibility.

Full text of DOI:10.1039/c8cc01486h

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Y. Zhao, Y. Luo, Z.
Wang and P. Xu, Chem. Commun., 2018, DOI: 10.1039/C8CC01486H.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 5
View Article Online
DOI: 10.1039/C8CC01486H
Journal Name
COMMUNICATION
A New Approach to Access Difluoroalkylated Diarylmethanes via
Visible-Light Photocatalytic Cross-Coupling Reactions
Received 00th January 20xx,
Accepted 00th January 20xx
Yin-Na Zhao, Yong-Chun Luo, Zhu-Yin Wang and Peng-Fei Xu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Difluoroalkylated
diarylmethanes
with
biological
and triphenylmethyl radicals could be formed by treating galvinols
pharmacological potentials were synthesized from para-quinone (with structures similar to p-QMs) with a sodium amalgam in
methides (p-QMs) and difluoroalkylating reagents via a visible hydrocarbon solvents by a single electron reduction process
light photocatalysis strategy. Mechanism studies showed that the (Scheme 1b).8 However, no further research is reported.
*
excited photocatalyst fac-Ir(ppy)3 was primarily quenched by p-
OMe
OMe
QMs and the generated diarylmethane radical intermediates then
HO
OMe
underwent
a
radical-radical cross-coupling reaction with
Me
i-Pr
N
OH
OMe
i-Pr
difluoroalkyl radicals. This reaction features mild conditions, high
efficiency and wide functional group compatibility.
OMe
OH
OH
OMe
Tolterodine
(-)-latiiolin
(-)-kadangustin J
HO
OH
X
Diarylmethane scaffold widely exists in natural products and
pharmaceuticals such as podophyllotoxin,1c tolterodine,1d
latifolin,1e isochromans derivatives1f and kadangustin J,1g which
exhibit antimicrobial, antiviral, anticancer and/or antioxidant
activities (Figure 1).1 In the past decade, the synthesis of
hybrid systems with multiple biological and pharmacological
properties is attracting more and more attention.2 The
incorporation of difluoromethylene group (typically catalyzed
by transition-metal3) which can function as a bioisostere for an
oxygen atom or a carbonyl group,4a-b can significantly affect
the electronic, chemical and reaction activities of the parent
molecules.4 Considering all these, incorporation of
difluoromethylene group into diarylmethane unit to construct
the difluoroalkylated diarylmethane skeleton can increase the
diversity of diarylmethanes with new bioactivities.
H
O
O
O
H
H
O
O
MeO
OMe
N
OMe
isochromans derivatives (X = O or S)
Podophyllotoxin
Figure 1 Typical Biologically Active Molecules with the Diarylmethane Unit
(a) 1,6-conjugate addition /aromatization of p-QMs to diarylmethane scaffold5
1
OH
O
O
R'
R'
R'
R'
R'
R'
2
3
4
5
Nu
6
Nu
R
R
R
netural form
zwitterionic form
diarylmethine Scaffold
7
(b) Kurreck's group: di- and triphenylmethyl radicals generated from galvinols
para-Quinone methides (p-QMs), characterized by the
unique assembly of carbonyl and olefinic moieties, are
chemically defined as neutral and zwitterionic resonance
entities (Scheme 1a).5 Therefore, p-QMs are usually used in
1,6-conjugate addition/aromatization reactions as Michael
acceptors to access biologically active diarylmethane
compounds,6 although several other methods have been
reported.7 In 1985, Kurreck’s group found that di- and
t-Bu
O
t-Bu
OH
t-Bu
t-Bu
t-Bu
t-Bu
Na (Hg)
toluene
R
R
t-Bu
OH
t-Bu
OH
R = aryl or alkyl
(c) our design: radical-radical cross-coupling through photoredox catalysis
OH
OH
CF2R
O
Photocatalysis
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
SET
cross-coupling
+H
CF2
R
R
R
R
Scheme 1 Diarylmethane Scaffold Derivatization
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 5
View Article Online
DOI: 10.1039/C8CC01486H
COMMUNICATION
Journal Name
Photoredox catalysis has become a powerful tool for organic (entries 6, 7). After screening a series of solvents (entries 8-
synthesis in the past decade owing to its inherently mild, green 12), it was found that acetone was an ideal solvent with a yield
and highly-efficient characteristics.9 This catalysis strategy is of 72% (entry 12). With the loading of 2a increased to 2.0
well-known by its single electron transfer (SET) process.4f-g,4i equiv., the yield of the desired product 3aa was further
Inspired by Kurreck’s work, we envisioned that p-QMs (1a , E1/2 increased to 76% (entry 13). However, the yield of the desired
red = - 0.20 V vs SCE, see Supporting Information Figure S1 ) product was decreased to 65% when the loading of 2a was
could be radical precursors for generating diarylmethyl radical increased to 3.0 equiv. (entry 14). Finally, it was found that the
intermediates through
a
photocatalytic single electron yield of the reaction increased to 85% when H2O was added as
new approach an additive (entry 15). We speculated that H2O could promote
reduction process. Thus, we proposed
a
involving p-QMs and difluoroalkylating reagents to construct the protonation of the reaction process as discussed in the
difluoroalkylated diarylmethane compounds via visible light mechanism section.
photocatalytic radical-radical cross-coupling reactions (Scheme
1c).
With the optimal conditions established, we next evaluated
the substrate scope of p-QMs (Scheme 2). To our delight, a
1
variety of substituented p-QMs could smoothly react to
provide the desired diarylmethane products with moderate to
excellent yields (45-85%). Both electron-donating substituents
Table 1 Optimization of the Reaction Conditionsa
OH
O
t-Bu
t-Bu
O
(
3ba-3ea) and electron-withdrawing substituents (3fa-3ma)
t-Bu
t-Bu
catalyst (1 mol%)
reductant (3.0 equiv.)
Br
OEt
+
O
were compatible in the reaction system. Notably, the nitro
group (3ja) gave a lower yield (45%), probably owing to its
strong oxidizing ability. Bis-substituted p-QMs (1o, R1 = 3,4-
solvent (0.1 M)
blue LEDs, N2, r.t.
F
F
Ph
OEt
Ph
1a (0.1 mmol)
F
F
2a (0.15 mmol)
3aa
dichloro and 1n, 3,5-dimethoxyl) and p-QM with naphthyl (1p
)
Entry
Catalyst
Reductant
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Toulene
MeOH
THF
Yieldb
65
could also take part in the reaction with good yields.
1
facꢀIr(ppy)3
iꢀPr2NEt
2
3c
4d
Ru(bpy)3Cl2▪6H2O iꢀPr2NEt
32
Eosin Y
facꢀIr(ppy)3
ꢀ
iꢀPr2NEt
iꢀPr2NEt
iꢀPr2NEt
HEf
38
NRe
trace
11
5
6
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
7
Et3N
32
8
iꢀPr2NEt
iꢀPr2NEt
iꢀPr2NEt
iꢀPr2NEt
iꢀPr2NEt
iꢀPr2NEt
iꢀPr2NEt
iꢀPr2NEt
47
9
14
10
11
12
13g
14h
15gij
40
1,4ꢀdioxane
acetone
69
72
acetone
76
acetone
65
acetone
85
aReaction conditions: 1a (0.1 mmol), 2a (1.5 equiv.), catalyst (1 mol%), reductant
(3.0 equiv.), solvent (1 mL), and blue LEDs under N2 at room temperature for 36
h. bIsolated yield. cGreen LEDs. dNo light. eNR (No Reaction). fHE (Hantzsch Ester).
g2a (2.0 equiv.). h2a (3.0 equiv.). iH2O (1.0 equiv.) as additive. jReacted for 24 h.
The study was initiated by using p-QM 1a and ethyl
bromodifluoroacetate 2a (E1/2 red = - 0.89 V vs SCE, see
Supporting Information Figure S2) as model substrates (Table
1). Fortunately, the desired diarylmethane product 3aa was
obtained in 65% yield in the presence of fac-Ir(ppy)3 (1 mol%)
and i-Pr2NEt (3.0 equiv.) in MeCN (entry 1). However, when
the catalyst was replaced by Ru(bpy)3Cl2▪6H2O or Eosin Y, the
yield of 3aa was dramatically decreased to 32% (entry 2) and
38% (entry 3), respectively. Control experiments were then
performed and the results confirmed the necessity of both
light and fac-Ir(ppy)3 (entries 4, 5). Compared with i-Pr2NEt,
neither Hantzsch ester nor Et3N was a better reductant
Scheme 2 The Scope of para-Quinone Methides (p-QMs)
Next, we explored the scope of difluoroalkylating reagents
2
to examine their applicability in our system (Scheme 3).
Difluoroalkylating reagents with different functional groups
including carbonyl, esteryl, acylamino and heteroaryl groups,
proceeded well with 1a to achieve the expected products in
52% to 77% yields
(3ab-3ag). Moreover, ethyl
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 5
View Article Online
DOI: 10.1039/C8CC01486H
Journal Name
COMMUNICATION
bromofluoroacetate 2g could also be applied to this reaction (1.361 g) in the yield of 82%. p-QMs bearing 2,6-di-tert-butyl
system and afforded the product 3ag (69% yield) albeit with a groups are useful synthons because of their facile synthesis
low diastereoselectivity (dr = 1:1). Additionally, the structure and inherent stability.10 AlCl3 mediated de-tert-butylation
of 3ad was confirmed by X-ray analysis (see Supporting reaction produced the diphenolmethane derivative
moderate yield (Scheme 4b).5b,10
4 with a
Information).
To gain insight into the mechanism of this reaction, several
control experiments were performed. Stern-Volmer
fluorescence quenching experiments revealed that fac-Ir(ppy)3
was primarily quenched by p-QM 1a while ethyl
bromodifluoroacetate 2a and i-Pr2NEt showed a much less
effect (Figure 2). The radical trapping experiments were
conducted with different scavengers to capture the radical
intermediates in the system, and the products were detected
by ESI-HRMS techniques (see Supporting Information). Under
the standard conditions, TEMPO-trapped product
6 was
observed when TEMPO was used as the scavenger with no
product 3aa detected (Scheme 4c). Moreover, both product
3aa and
7
were observed when 1-(phenylsulfonyl)-2-phenyl-2-
propene
5 was added to the reaction (Scheme 4d). These
observations indicated the existence of diarylmethyl radical
and difluoroacetate radical intermediates.
1000
800
600
400
200
0
1000
800
600
400
200
0
Scheme 3 The Scope of Bromodifluoroacetates
450
500
550
600
650
450
500
550
600
650
Wavelength (nm)
Wavelength (nm)
2.0
1.8
1.6
1.4
1.2
1.0
1000
800
600
400
200
0
0.0
0.2
0.4
0.6
10-5
0.8
1.0
1.2
450
500
550
600
650
M
Wavelength (nm)
Figure 2 Stern-Volmer Fluorescence Quenching Experiments
On the basis of our findings and previous studies, a possible
mechanism is illustrated in Figure Upon visible light
3
.
*
irradiation, the excited fac-Ir(ppy)3 engages in single electron
transfer (SET) with p-QM 1a followed by a protonation process
to give the radical intermediate I as well as the oxidized fac-
IVIr(ppy)3. Then the photocatalytic cycle is closed by a SET
process between i-Pr2NEt and fac-IVIr(ppy)3, delivering the
radical intermediate II. The resultant
αꢀamino alkyl radical III
from sequential deprotonation of intermediate II, known as a
strong reducing agent,11-14 can easily reduce ethyl
bromodifluoroacetate 2a to generate radical intermediate IV
Scheme
4 Applications of Difluoroalkylation of p-QMs and Radical Trapping
Experiments
and bromide-iminium ion pair
cross-coupling of intermediates
diarylmethane product (3aa).
V. Finally, a radical–radical
To demonstrate the synthetic value of this work, the gram-
scale reaction was conducted with 1f (1.205 g) and 2a (Scheme
4a) to give the corresponding diarylmethane product 3fa
I
and IV leads to the target
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 5
View Article Online
DOI: 10.1039/C8CC01486H
COMMUNICATION
Journal Name
50, 12884; (g) J. Xie, T. Zhang, F. Chen, N. Mehrkens, F.
Rominger, M. Rudolph and A. S. K. Hashmi, Angew. Chem.
Int. Ed., 2016, 55, 2934; (h) M. Ke and Q. Song, Adv. Synth.
Catal., 2017, 359, 384; (i) T. Chatterjee, N. Iqbal, Y. You and
E. J. Cho, Acc. Chem. Res., 2016, 49, 2284; (j) D. E. Yerien, S.
Barata-Vallejo and A. Postigo, Chem. Eur. J., 2017, 23, 14676.
(a) M. G. Peter, Angew. Chem. Int. Ed. Engl., 1989, 28, 555;
(b) T. Itoh, Prog. Polym. Sci., 2001, 26, 1019; (c) M. M. Toteva
and J. P. Richard, Adv. Phys. Org. Chem., 2011, 45, 39; (d) A.
5
6
Parra and M. Tortosa, ChemCatChem, 2015, 7, 1524.
(a) W.-D. Chu, L.-F. Zhang, X. Bao, X.-H. Zhao, C. Zeng, J.-Y.
Du, G.-B. Zhang, F.-X. Wang, X.-Y. Ma and C.-A. Fan, Angew.
Chem. Int. Ed., 2013, 52, 9229; (b) L. Caruana, F. Kniep, T. K.
Johansen, P. H. Poulsen and K. A. Jørgensen, J. Am. Chem.
Soc., 2014, 136, 15929; (c) B. T. Ramanjaneyulu, S. Mahesh
and R. V. Anand, Org. Lett., 2015, 17, 3952; (d) S. Mahesh, G.
Kant and R. V. Anand, RSC Adv., 2016, 6, 80718; (e) Z. Wang,
Y. F. Wong and J. Sun, Angew. Chem. Int. Ed., 2015, 54,
Figure 3 Proposed Mechanism
13711; (f) N. Dong, Z.-P. Zhang, X.-S. Xue, X. Li and J.-P.
Cheng, Angew. Chem. Int. Ed., 2016, 55, 1460; (g) Y. Shen, J.
Qi, Z. Mao and S. Cui, Org. Lett., 2016, 18, 2722; (h) C. Jarava-
Barrera, A. Parra, A. López, F. Cruz-Acosta, D. Collado-Sanz,
D. J. Cárdenas and M. Tortosa, ACS Catal., 2016, 6, 442; (i) K.
Zhao, Y. Zhi, T. Shu, A. Valkonen, K. Rissanen and D. Enders,
Angew. Chem. Int. Ed., 2016, 55, 12104; (j) S. Li, Y. Liu, B.
Huang, T. Zhou, H. Tao, Y. Xiao, L. Liu and J. Zhang, ACS Catal.,
In summary, we have developed a novel photocatalytic
radical-radical cross-coupling reaction under mild conditions to
access difluoroalkylated diarylmethane compounds with
pharmaceutical potentials, the reaction features high
efficiency and wide functional group compatibility. It is
noteworthy that the reaction was mediated by a diarylmethyl
radical intermediate generated from the single electron
reduction and protonation processes of p-QMs.
2017, 7, 2805; (k) R. Zhuge, L. Wu, M. Quan, N. Butt, G. Yang
and W. Zhang, Adv. Synth. Catal., 2017, 359, 1028; (l) T.-C.
Kang, L.-P. Wu, Q.-W. Yu and X.-Y. Wu, Chem. Eur. J., 2017,
23, 6509.
(a) T. P. Pathak and M. S. Sigman, Org. Lett., 2011, 13, 2774;
(b) S. M. Podhajsky, Y. Iwai, A. Cook-Sneathen and M. S.
Sigman, Tetrahedron, 2011, 67, 4435; (c) K. M. Gligorich, Y.
Iwai, S. A. Cummings and M. S. Sigman, Tetrahedron, 2009,
65, 5074; (d) Y. Iwai, K. M. Gligorich and M. S. Sigman,
Angew. Chem. Int. Ed., 2008, 47, 3219; (e) K. M. Gligorich, S.
We are grateful to the NSFC (21632003 and 21572087), the
key program of Gansu province (17ZD2GC011) and the “111”
program from the MOE of P. R. China for financial support.
7
Notes and references
1
(a) M. Recanatini, A. Cavalli and P. Valenti, Med. Res. Rev.,
2002, 22, 282; (b) H. A. I. Yoshihara, J. W. Apriletti, J. D.
A. Cummings and M. S. Sigman, J. Am. Chem. Soc., 2007, 129
,
14193; (f) F. Jin, Y. Zhong, X. Zhang, H. Zhang, Q. Zhao and W.
Han, Green Chem., 2016, 18, 2598; (g) E. N. Bess and M. S.
Sigman, Org. Lett., 2013, 15, 646; (h) J. Ghorai and P.
Anbarasan, J. Org. Chem., 2015, 80, 3455; (i) S. Y. Lee, A.
Villani-Gale and C. C. Eichman, Org. Lett., 2016, 18, 5034.
B. Kirste, W. Harrer and H. Kurreck, J. Am. Chem. Soc., 1985,
107, 20.
(a) C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem.
Rev., 2013, 113, 5322; (b) R. Brimioulle, D. Lenhart, M. M.
Maturi and T. Bach, Angew. Chem. Int. Ed., 2015, 54, 3872;
(c) K. L. Skubi, T. R. Blum and T. P. Yoon, Chem. Rev., 2016,
116, 10035; (d) N. A. Romero and D. A. Nicewicz, Chem. Rev.,
2016, 116, 10075; (e) M. H. Shaw, J. Twilton and D. W. C.
MacMillan, J. Org. Chem., 2016, 81, 6898.
Baxterb and T. S. Scanlan, Bioor. Med. Chem. Lett., 2001, 11
,
2821; (c) C. Canela, R. M. Moraesb, F. E. Dayana and D.
Ferreira, Phytochemistry, 2000, 54, 115; (d) P. Abrams, R.
Freeman, C. Anderström and A. Mattiasson, British J. Urol.,
1998, 81, 801; (e) R.-B. An, G.-S. Jeong and Y.-C. Kim, Chem.
Pharm. Bull., 2008, 56, 1722; (f) J. Liu, E. T. Birzin, W. Chan, Y.
T. Yang, L.-Y. Pai, C. DaSilva, E. C. Hayes, R. T. Mosley, F.
DiNinno, S. P. Rohrer, J. M. Schaeffer and M. L. Hammond,
Bioorg. Med. Chem. Lett., 2005, 15, 715; (g) S. J. Davidson
and D. Barker, Tetrahedron Lett., 2015, 56, 4549.
8
9
2
3
(a) J. A. M. Christiaans and H. Timmerman, Eur. J. Pharm. Sci.,
1996, 4, 1; (b) G. Mehta and V. Singh, Chem. Soc. Rev., 2002,
31, 324; (c) L. F. Tietze, H. P. Bell and S. Chandrasekhar,
Angew. Chem. Int. Ed., 2003, 42, 3996; (d) M. Decker, Curr.
Med. Chem., 2011, 18, 1464.
Transition-metal catalysis has been one of the attractive
strategies to access difluoroalkylated compounds: (a) Z. Feng,
F. Chen and X. Zhang, Org. Lett., 2012, 14, 1938; (b) Y.-L. Xiao,
W.-H. Guo, G.-Z. He, Q. Pan and X. Zhang, Angew. Chem. Int.
Ed., 2014, 53, 9909; (c) Z. Feng, Q.-Q. Min, X.-P. Fu, L. An and
10 S. A. Saleh and H. I. Tashtoush, Tetrahedron, 1998, 54
14157.
11 (a) K. Bhattacharyya and P. K. Das, J. Phys. Chem., 1986, 90
,
,
3987; (b) D. D. M. Wayner, D. J. McPhee and D. Griller, J. Am.
Chem. Soc., 1988, 110, 132; (c) M. Jonsson, D. D. M. Wayner
and J. Lusztyk, J. Phys. Chem., 1996, 100, 17539.
12 A. Bahamonde and P. Melchiorre, J. Am. Chem. Soc., 2016,
138, 8019.
13 H. Ismaili, S. P. Pitre and J. C. Scaiano, Catal. Sci. Technol.,
2013, 3, 935.
14 D. B. Freeman, L. Furst, A. G. Condie and C. R. J. Stephenson,
Org. Lett., 2012, 14, 94.
X. Zhang, Nat. Chem., 2017, 9, 918.
4
(a) C. M. Blackburn, D. A. England and F. Kolkmann, J. Chem.
Soc. Chem. Commun., 1981, 930; (b) A. K. Yudin, G. K. S.
Prakash, D. Deffieux, M. Bradley, R. Bau and G. A. Olah, J.
Am. Chem. Soc., 1997, 119, 1572; (c) Y. Fujiwara, J. A. Dixon,
R. A. Rodriguez, R. D. Baxter, D. D. Dixon, M. R. Collins, D. G.
Blackmond and P. S. Baran, J. Am. Chem. Soc., 2012, 134
,
1494; (d) Z. Feng, Q. Q. Min, Y.-L. Xiao, B. Zhang and X.
Zhang, Angew. Chem. Int. Ed., 2014, 53, 1669; (e) S.-L. Shi
and S. L. Buchwald, Angew. Chem. Int. Ed., 2015, 54, 1646; (f)
C. Yu, N. Iqbal, S. Park and E. J. Cho, Chem. Commun., 2014,
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
ChemComm
View Article Online
DOI: 10.1039/C8CC01486H
A para-quinone methides and difluoroalkylating reagents involved radicals cross-coupling reaction
was described, through the photocatalytic generated diarylmethane radical intermediates.