Visible light-promoted umpolung coupling of aryl tri-/difluoroethanones with 2-alkenylpyridines

Article abstract of DOI:10.1039/c8cc06748a

Tertiary alcohols bearing a trifluoromethyl group are of considerable medicinal interest. Using an umpolung strategy, we herein report the first intermolecular reductive cross-coupling of aryl tri-/difluoroethanones with 2-alkenylpyridines with the aid of a Br?nsted acid catalyst upon visible-light irradiation. This metal-free reaction is operationally simple and performed at ambient temperature, allowing access to desired tertiary alcohols with tri-/difluoromethyl groups in moderate to excellent yields. The commercially available and easily handled Hantzsch ester effectively serves as an electron donor, as well as a hydrogen atom source.

Full text of DOI:10.1039/c8cc06748a

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: X. Xu, Q. Min, N. Li
and F. Liu, Chem. Commun., 2018, DOI: 10.1039/C8CC06748A.
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/C8CC06748A
Journal Name
COMMUNICATION
Visible light-promoted umpolung coupling of aryl tri-
/difluoroethanones with 2-alkenylpyridines
Xiao Xu,‡a Qing-Qiang Min,‡a Na Lia and Feng Liu*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Tertiary alcohols bearing
a trifluoromethyl group are of
the reaction for β-selective reductive coupling via synergistic Lewis
acid/photoredox catalysis has been achieved in a radical process
very recently (Scheme 1a).8a
considerable medicinal interest. Via an umpolung strategy, we
herein report the first intermolecular reductive cross-coupling of
aryl tri-/difluoroethanones with 2-alkenylpyridines with the aid of
a Brønsted acid catalyst upon visible-light irradiation. This metal-
free reaction is operationally simple and performed at ambient
temperature, allowing to access desired tertiary alcohols with tri-
/difluoromethyl groups in moderate to excellent yields. The
commercially available and easily handled Hantzsch ester
effectively serves as an electron donor, as well as a hydrogen
atom source.
a) Previous work:
Ru(bpy)3(PF6)2 (1 mol%)
OH R2
La(OTf)3 (20 mol%)
bpy (40 mol%)
O
Y
Z
Y
β
Ar/
Het
+
R1
Ar/
Het
Hantzsch ester (2 equiv)
Blue LEDs
Z
R1
α
R2
ref. 8a
Y, Z = CH or N
b) This study:
OH
Rf
A fluorinated moiety is often considered as a “magic” group in
pharmaceuticals, agrochemicals and materials.1 Although the direct
construction of C−F bonds and fluorinated C−C bonds with
fluorination and fluoroalkylation reagents continues to be the main
approach,2 synthesis with fluorinated building blocks/substrates is
also an attractive strategy for the incorporation of fluorine-
containing groups into target molecules.3 Notably, the fluorine or
fluoroalkyl group directly connected with the reactive site could
have significant impact on the outcome of the reaction.3 On the
other hand, pyridine with a basic nitrogen centre is ubiquitous in
agrochemicals,4 pharmaceuticals,5 and ligands in catalysis.6 As the
versatile synthons for the construction of complex molecules with
pyridine subunits,7 alkenylpyridines have electrophilic nature and
thus the reductive coupling with another electrophile is rare.8 Of
the few relevant reports, Cu-8b-c or Rh-catalysed8d reductive C−C
coupling of carbonyl or iminyl derivatives to alkenylpyridines at the
O
Hantzsch ester (2 equiv)
(PhO)2PO2H (20 mol%)
N
N
Ar/
Het
R2
Rf
R1
+
Ar/
R1
Het
395 nm LEDs
R2
Rf = CF3 or CF2H
e, H
N
OH
Rf
OH
Rf
R2
N
Ar/
Het
R1
Ar/
R1
Het
intermolecular radical addition
R2
Scheme 1 Umpolung reductive cross-coupling of aldehydes/ketones with
alkenylpyridines.
To produce ketyl radicals, the strongly negative reduction
potential of carbonyl compounds9 (E1/2 = -1.93 V vs SCE for
red
red
benzaldehyde and E1/2 = -2.11 V vs SCE for acetophenone) has to
be overcome. Fortunately, the single electron reduction of an
electrophilic carbonyl group to generate a polarity-reversed ketyl
radical via photoredox catalysis has been developed recently.10-12 In
these protocols, harsh reaction conditions and water-/air-sensitive
strong reductants that were often used in the traditional methods
are not required.13 However, these photoredox catalysis reactions
are mainly limited to intramolecular rearrangement /addition or
radical-radical coupling,10,11 and there have been only few reports
of intermolecular radical addition reactions.8a,12 Despite these
reports, it is important to note that the generation of ketyl radicals
requires very expensive Ir- or Ru-photocatalyst. Moreover, tertiary
α
-position of the vinyl moiety was first developed. Furthermore,
a.Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of
Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, 199
Ren-Ai Road, Suzhou, Jiangsu 215123, People’s Republic of China. E-mail:
fliu2@suda.edu.cn
b.Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
People’s Republic of China.
‡ These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: Experimental details,
characterization data, and copies of 1H, 13C and 19F NMR spectra for all compounds.
See DOI: 10.1039/x0xx00000x
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/C8CC06748A
COMMUNICATION
Journal Name
alcohols bearing trifluoromethyl group are considerable of further tested the influence of light source, finding that 395
medicinal interest.14 Herein we report a novel intermolecular nm of LEDs gave the optimal yield of 3a (entry 15). Finally, we
reductive cross-coupling reaction of aryl tri-/difluoroethanones with also found that heat at reflux could promote the reaction as
2-alkenylpyridines via a visible light-driven radical process under well though the chemical yield is much lower than that upon
metal-free conditions (Scheme 1b).
light irradiation (entry 16).
Table 1 Optimization of reaction conditions a
OH
O
HE (2 equiv)
(PhO)2PO2H (20 mol%)
N
N
+
R2
Ar/
CF3
Ar/
Het
R1
CF3
Het
R1
395 nm LEDs
DCM, rt
R2
2
3
1 (1.5 equiv)
OH
O
Hantzsch ester (2 equiv)
BrØnsted acid (20 mol%)
OH
N
OH
N
OH
CF3
CF3
N
N
+
CF3
N
solvent
LEDs, rt, 12 h
CF3
CF3
R
2a
3a
1a
X
X
R = Me, 3f, 83%
X = F, 3b, 54%
X = Cl, 3c, 94%
X = Br, 3d, 70%
Yield (%)b
< 5
X = F, 3j, 95%
Entry
Solvent
DCE
Brønsted acid
−
LEDs
Blue
R = Ph, 3g, 94%
R = CN, 3h, 60%
R = CO2Me, 3i, 55%
X = Cl, 3k, 95%
1
2c
3
X = I, 3e, 99%
DCE
DCE
(PhO)2PO2H
(PhO)2PO2H
CF3CO2H
−
0
81
31
< 10
47
51
86
46
40
77
67
OH
OH
X
OH
N
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
White
MeO
MeO
N
N
CF3
CF3
CF3
DCE
4
3o, 82%
OMe
3l
X = Cl, , 33%
DCE
CH3CO2H
5
3n, 92%
X = Br 3m, 49%
OH
DCE
CH3SO3H
6
N
R
OH
OH
CF3
N
DCE
CF3SO3H
7
N
Ph
CF3
CF3
Ph
Me
DCM
MeCN
DMF
THF
(PhO)2PO2H
(PhO)2PO2H
(PhO)2PO2H
(PhO)2PO2H
(PhO)2PO2H
S
R = Me, 3r, 57%
8
3q
, 63%
3s
3p, 33%
Unsuccessful examples
R = OMe, , 72%
9
10
11
O
O
Cl
O
CF3
CF3
CF3
DCE
O2N
OMe
12
13
Cl
1aa
1ac
1ab
DCE
DCE
DCM
DCE
(PhO)2PO2H
(PhO)2PO2H
(PhO)2PO2H
(PhO)2PO2H
Red
395 nm
395 nm
−
0
Scheme 2 Scope of reductive coupling of aryl trifluoroethanones with 2-
14d
90
95
23
alkenylpyridines.
15
16e
With the optimized conditions in hand, we next aimed to define
the scope and limitations of aryl trifluoroethanones in this mild
photoredox reaction. As shown in Scheme 2, a broad range of
trifluoromethylated products were readily obtained in reasonable
yields (3b−s). This protocol could accommodate an array of para-
substituents on the phenyl ring regardless of their electronic
properties (3b−i) except the substrate 1aa. Halogen substituents
(3b−e), especially bromo and iodo atoms, did not affect the
reaction, and the reserved Br and I provide the options for further
cross-coupling. In addition, the meta-substituents show little impact
on the reaction efficiency (3j−k). However, this transformation
appears to be sensitive to ortho steric effects, giving the desired
products in lower yields (3l−m) compared to their para
counterparts (3c−d) or failing to give any desired products
(1ab−1ac). It is noteworthy that the highly electron-rich substrate
1n could furnish the corresponding product 3n in excellent yield.
The bicyclic naphthalene was also accommodated with good
efficiency (3o). With respect to heteroaromatic substrates, we
found that the thienyl moiety (3p) led to much lower yields
compared to that of 3a. Moreover, we were pleased to find that
methyl and methoxy groups were tolerated on the pyridine ring,
a1a (0.30 mmol), 2a (0.20 mmol), Hantzsch ester (0.40 mmol), Brønsted acid (20
mol%), solvent (2 mL), LEDs (9 W), room temperature. bIsolated yield. cIn the
dark. d395 nm LEDs (6 W). eReflux in the dark.
Our examination and optimization of this new photoredox
reaction is given in Table 1. At first, we conducted the reaction
of 2,2,2-trifluoro-1-phenylethanone 1a with 2-vinylpyridine 2a
in 1,2-dichloroethane (DCE) by use of Hantzsch ester (HE) as a
stoichiometric reductant and diphenylphosphoric acid as a
catalyst upon irradiation with household blue LEDs, delightedly
giving the desired reductive coupling product 3a in good yield
(entry 3). Control experiments revealed that the Brønsted acid
catalyst and visible light were both essential for the success of
the reaction (entries 1−2). An evaluation of different Brønsted
acids showed that diphenylphosphoric acid was the most
effective one (entry 3 vs entries 4−7). It is of note that higher
yields of 3a were obtained when stronger acids were used.
Next, a brief screening of organic solvents revealed that DCM
was the best one in terms of chemical yield (entry 8). We
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/C8CC06748A
Journal Name
COMMUNICATION
2) though the reductive cross-coupling with aryl aldehyde was
reported8a when using 4-vinylpyridne as the ketyl radical
acceptor.
providing the desired products in good yields (3q−s). However, the
reaction of alkenes bearing more than one substituent, such as 2-
(1-methylalkenyl)pyridine, led to an inseparable complex mixture.
HE, with strongly negative excited-state oxidation potential
*Eox = -2.28 V (vs. SCE),16 could effect single electron reduction of
aryl aldehydes/ketones.9 It should be noted that the strong
O
OH
HE (2 equiv)
(PhO)2PO2H (20 mol%)
N
N
CF2H
+
inductive effect of the
α–fluoro substituent could substantially
CF2H
395 nm LEDs
DCM, rt
increase the negative reduction potentials of aryl ketones. Indeed,
the Stern-Volmer experiments showed that trifluoroacetophenone
1a quenched the photoexcited HE (HE*) effectively whereas 2-
vinylpyridine 2a did not (Figure S2).17 In addition, a series of UV-vis
absorption experiments were conducted and the data may indicate
that no electron donor-acceptor (EDA) aggregate generated
between HE and 1a and/or 2a (Figure S1).17 On the other hand,
without addition of Brønsted acid, only trace amount of the
desired product was detected (Table 1, entry 1), which could
be consistent with previous reports of ketyl radical formation
R
R
2a
5
4 (1.5 equiv)
OH
OH
OH
N
N
N
CF2H
CF2H
CF2H
Br
Ph
Me
5a, 63%
5c, 62%
5b, 60%
OH
OH
OH
N
N
MeO
MeO
N
CF2H
CF2H
CF2H
by the proton-coupled electron-transfer (PCET) mechanism.10-
Cl
OMe
5f
5d, 72%
, 60%
5e
, 65%
12
Scheme 3 Scope of reductive coupling of aryl difluoroethanones with 2-
In summary, we have developed a practical protocol for the
intermolecular umpolung reductive cross-coupling of aryl tri-
/difluoroethanones with 2-alkenylpyridines under metal-free
conditions. This visible-light-induced reaction is operational
simple and tolerant of a range of functional groups, furnishing
a variety of desired tertiary alcohols bearing vicinal tri-
/difluoromethyl groups. The Hantzsch ester serves as an
effective electron and proton donor. We also found that the
vinylpyridine.
Considering the fact that the CF2H group is often used as the
bioisostere of a carbinol moiety and as a more lipophilic hydrogen
bond donor,15 we further chose aryl difluoroethanones as the
coupling partner and the scope was explored (Scheme 3). The
reaction proceeded smoothly to achieve the desired
difluoromethylated products in satisfactory yields (5a−f, 60−72%
yield) and this transformation also showed good functional group
tolerance though the chemical yields were lower than that of the
number of the α–fluorine atoms of the arylethanones could
influence the chemical outcome.
corresponding trifluoroethanone-alkenylpyridine coupling reaction. Conflicts of interest
There are no conflicts to declare.
O
OH
R
HE (2 equiv)
(PhO)2PO2H (20 mol%)
N
N
R
+
(1)
Acknowledgements
395 nm LEDs
DCM, rt
Ph
Ph
R = H,
R = Me,
R = CH2F,
2a
6 (1.5 equiv)
6a
R = Me,
R = CH2F,
7
Financial support from the National Natural Science
Foundation of China (Grant No. 21302134).
7a
7b
(60%)
R = H,
(19%)
7c
6b
6c
6b
(18%),
(68%)
Ph
HO CF3
OH
References
F3C
1
For selected examples, see: (a) J. Wang, M. Sánchez-Roselló,
J. L. Aceña, C. del Pozo, A. E. Sorochinsky, S. Fustero, V. A.
Soloshonok and H. Liu, Chem. Rev., 2014, 114, 2432; (b) D.
O’Hagan, Chem. Soc. Rev., 2008, 37, 308; (c) S. Purser, P. R.
Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev.,
2008, 37, 320; (d) K. Müller, C. Faeh and F. Diederich,
Science, 2007, 317, 1881; (e) K. L. Kirk, Org. Process Res.
Dev., 2008, 12, 305.
Ph
O
9
, 32%
+
HE (2 equiv)
(PhO)2PO2H (20 mol%)
N
(2)
CF3
+
395 nm LEDs
DCM, rt
OH
Ph
8
1g (1.5 equiv)
CF3
N
Ph
10
, not detected
Scheme 4 Further experiments.
2
For selected recent reviews, see: (a) Q. Liu, C. Ni and J. Hu,
Natl. Sci. Rev., 2017, 4, 303; (b) Fluorine Chemistry, Chem.
Rev., 2015, 115, 566-1306 (special issue).
J. Nie, H.-C. Guo, D. Cahard and J.-A. Ma, Chem. Rev., 2011,
111, 455.
A.-Y. Guan, C.-L. Liu, X.-F. Sun, Y. Xie and M.-A. Wang, Bioorg.
Med. Chem., 2016, 24, 342.
E. Vitaku, D. T. Smith and J. T. Njardarson, J. Med. Chem.,
2014, 57, 10257.
M. N. Zafar, A. H. Atif, M. F. Nazar, S. H. Sumrra, Gul-E-Saba,
R. Paracha, Russ. J. Coord. Chem., 2016, 42, 1.
For selected examples, see: (a) S. Wang, X. Li, H. Liu, L. Xu, J.
Zhuang, J. Li, H. Li and W. Wang, J. Am. Chem. Soc., 2015, 137
We then extended this protocol to other carbonyl
compounds (Scheme 4, eq 1). As might be expected, the
reaction of aldehyde 6a gave the desired reductive cross-
coupling product 7a in reasonable yield. However, for ketones
6b and 6c, the reaction proceeded slowly, providing much
lower chemical yields of 7b and 7c. In addition, we found the
formation of 6b as the reductive defluorination product. To
3
4
5
6
7
our surprise, only reductive dimerization product 9 was
obtained under our optimal reaction conditions (Scheme 4, eq
,
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/C8CC06748A
COMMUNICATION
Journal Name
2303; (b) J. Chen, J. Li, J. Wang, H. Li, W. Wang and Y. Guo,
Org. Lett., 2015, 17, 2214; (c) M. Qi, A. Gross, G. Jeschke, A.
Godt and M. Drescher, J. Am. Chem. Soc., 2014, 136, 15366;
(d) D. Best and H. W. Lam, J. Org. Chem., 2014, 79, 831; (e) L.
Rupnicki, A. Saxena and H. W. Lam, J. Am. Chem. Soc., 2009,
131, 10386.
8
9
(a) K. N. Lee, Z. Lei and M.-Y. Ngai, J. Am. Chem. Soc., 2017,
139, 5003; (b) B. Choi, A. Saxena, J. J. Smith, G. H. Churchill
and H. W. Lam, Synlett, 2015, 26, 350; (c) A. Saxena, B. Choi
and H. W. Lam, J. Am. Chem. Soc., 2012, 134, 8428; (d) V.
Komanduri, C. D. Grant and M. J. Krische, J. Am. Chem. Soc.,
2008, 130, 12592.
H. G. Roth, N. A. Romero and D. A. Nicewicz, Synlett, 2016,
27, 714.
10 For a review, see: (a) K. N. Lee and M.-Y. Ngai, Chem.
Commun., 2017, 53, 13093; The use of ketyl radicals via
photoredox
rearrangement/addition reactions, see: (b) A. G. Amador, E.
M. Sherbrook and T. P. Yoon, J. Am. Chem. Soc., 2016, 138
catalysis
in
intramolecular
,
4722; (c) L. J. Rono, H. G. Yayla, D. Y. Wang, M. F. Armstrong
and R. R. Knowles, J. Am. Chem. Soc., 2013, 135, 17735; (d) K.
T. Tarantino, P. Liu and R. R. Knowles, J. Am. Chem. Soc.,
2013, 135, 10022; (e) M. H. Larraufie, R. Pellet, L.
Fensterbank, J. P. Goddard, E. Lacôte, M. Malacria and C.
Ollivier, Angew. Chem. Int. Ed., 2011, 50, 4463.
11 The use of ketyl or
α-aminoalkyl radicals via photoredox
catalysis in radical-radical coupling reactions, see: (a) E. Fava,
A. Millet, M. Nakajima, S. Loescher and M. Rueping, Angew.
Chem. Int. Ed., 2016, 55, 6776; (b) C. Y. Wang, J. Qin, X. D.
Shen, R. Riedel, K. Harms and E. Meggers, Angew. Chem. Int.
Ed., 2016, 55, 685; (c) D. Uraguchi, N. Kinoshita, T. Kizu and
T. Ooi, J. Am. Chem. Soc., 2015, 137, 13768; (d) J. L. Jeffrey, F.
R.
Petronijević and D. W. C. MacMillan, J. Am. Chem. Soc., 2015,
137, 8404; (e) M. Nakajima, E. Fava, S. Loescher, Z. Jiang and
M. Rueping, Angew. Chem. Int. Ed., 2015, 54, 8828; (f) F. R.
Petronijević, M. Nappi and D. W. C. MacMillan, J. Am. Chem.
Soc., 2013, 135, 18323.
12 L. Qi and Y. Chen, Angew. Chem. Int. Ed., 2016, 55, 13312.
13 (a) C. H. Yeh, R. P. Korivi and C. H. Cheng, Adv. Synth. Catal.,
2013, 355, 1338; (b) M. Szostak and D. J. Procter, Angew.
Chem. Int. Ed., 2012, 51, 9238; (c) K. C. Nicolaou, S. P. Ellery
and J. S. Chen, Angew. Chem. Int. Ed., 2009, 48, 7140; (d) A.
Chatterjee and N. N. Joshi, Tetrahedron, 2006, 62, 12137.
14 (a) I. K. Sebhat, C. Franklin, M. M.-C. Lo, D. Chen, J. P. Jewell,
R. Miller, J. Pang, O. Palyha, Y. Kan, T. M. Kelly, X.-M. Guan,
D. J. Marsh, J. A. Kosinski, J. M. Metzger, K. Lyons, J.
Dragovic, P. R. Guzzo, A. J. Henderson, M. L. Reitman, R. P.
Narund, M. J. Wyvratt and L. S. Lin, ACS Med. Chem. Lett.,
2011, 2, 43; (b) J. J. Song, J. Xu, Z. Tan, J. T. Reeves, N.
Grinberg, H. Lee, K. Kuzmich, X. Feng, N. K. Yee and C. H.
Senanayake, Org. Process Res. Dev., 2007, 11, 534.
15 J. Hu, W. Zhang and F. Wang, Chem. Commun., 2009, 45
7465.
,
16 J. Jung, J. Kim, G. Park, Y. You and E. J. Cho, Adv. Synth.
Catal., 2016, 358, 74.
17 See Supporting Information.
18 For a review on photoreactions via EDA complexes, see: C. G.
S. Lima, T. de M. Lima, M. Duarte, I. D. Jurberg and M. W.
Paixão, ACS Catal., 2016, 6, 1389.
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/C8CC06748A
OH
Rf
O
Hantzsch ester (2 equiv)
(PhO)2PO2H (20 mol%)
N
N
Ar/
Het
R2
R1
Rf
+
Ar/
Het
R1
395 nm LEDs
R2
up to 95% yield
metal-free
polarity-reversed
quaternary carbon formation
o
o
o
Rf = CF3 or CF2H
A metal-free, mild, and simple protocol is developed for the synthesis of tertiary alcohols bearing
tri-/difluoromethyl groups upon visible-light irradiation.