Visible light promoted deaminative difluoroalkylation of aliphatic amines with difluoroenoxysilanes

Article abstract of DOI:10.1039/d0cc05725h

A visible light promoted deaminative strategy for the difluoroalkylation reaction utilizing pyridinium-activated aliphatic primary amines and difluoroenoxysilane as substrates has been developed. This protocol is characteriazed by its mild reaction conditions and broad substrate scope, which converted a diverse array of amine-containing molecules to the alkyl-CF2COPh products. Moreover, the resulting products can be easily transformed into a vast array of structurally novel and interesting difluoro-containing moieties, therefore providing a facile route for applications in medicinal chemistry and the life sciences. This journal is

Full text of DOI:10.1039/d0cc05725h

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Visible Light Promoted Deaminative Difluoroalkylation of Aliphatic
Amines with Difluoroenoxysilanes
Yang Huang, a Jia Jia,a Qi-Ping Huang, a Liang Zhao, a Pan Wang, b Jiwei Gu c and Chun-Yang He a *
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract: A visible light promoted deaminative strategy for the into organic compounds.6 Among them, transition-metal
difluoroalkylation reaction utilizing pyridinium-activated aliphatic catalytic or photocatalytic strategies are particularly appealing
primary amines and difluoroenoxysilane as substrates have been owing to their atom economy and step economy. However,
developed. This protocol is characteriazed by its mild reaction most of these well-developed methods are focused on the
7
conditions, broad substrate scope, which converted a diverse array difluoroalkylation of (hetero)arenes or unsaturated carbon-
of amine-containing molecules to the alkyl-CF2COPh products. carbon systems 8.
Moreover, the resulting products can be easily transformed to a
Zhang's work
vast array of structurally novel and interesting difluoro-containing
CF2CONEt2
TMSCF2CONEt2
Alkyl
moieties, therefore providing a facile route for applications in
medicinal chemistry and life science.
OSO2Mes
R1
Cu
or
+
Alkyl
R1
high enantioselectivity
OTES
CF2COAr
F
Alkyl
F
Due to the unique characteristics of the fluorine atom,
fluorinated compounds played important roles in medicinal
chemistry, agrochemistry and materials sciences.1 Among the
commonly encounted fluoro-containing functional groups,
difluoromethylene (CF2) groups are intriguing structural motifs,
because they can be used as an isopolar-isosteric substitute for
an oxygen atom or a carbonyl group, and can modulate the pKa
value of neighboring groups such as hydroxy, thiol, or amine.2
In addition, CF2H group can act as a hydrogen bond donor.3
Consequently, difluoromethylene groups are playing decisive
roles as substituents in compounds with pharmacological
activities.4 Traditionally, the CF2 group is generated by
deoxyfluorination of a ketone with reagents such as N,N-
This work
NH2
Ph
Ph
BF4
O
activation
conditions
OTES
N
Ph
Ph
Ph
F
F
Ph
F
1
O
3
5
BF4
F
Ph
Versatile Building Blocks
4
2
3
Scheme 1 Methods for the difluoroalkylation of secondary Csp
.
Despite the tremendous progress on this field, the
difluoroalkylation of C(sp3) remain a challenge. To the best of
our knowledge, only a few examples with limited substrate
scope have been reported so far because of the lack of general
9
and efficient strategies. Recently, Zhang and co-workers
diethylaminosulfur
trifluoride
(DAST)
or
bis(2-
reported
a
copper-catalyzed highly enantioselective
methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor).5 In the
past 10 years, many effective and elegant difluoroalkylation
protocols have been developed to introduce difluoromethylene
difluoroalkylation of secondary propargyl sulfonates with
TMSCF2CONEt2 10 or difluoroenoxysilanes (Scheme 1).11 Despite
the significant advances, those reactions were restricted to the
propargyl positions. Given the unique properties of
difluoromethylene group in pharmaceuticals containing C(sp3)-
CF2R moieties, the development of a new mode for the
construction of C(sp3)-CF2R will be of high demanding, to the
medicinal chemistry and life science.
Primary amines are one of the most predominant functional
groups found in a large number of organic molecules ranging
from simple industrial raw materials to complex natural
products, the development of new strategies for the
construction of C(sp3)-CF2R through deaminative processes is of
aKey Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province,
Generic Drug Research Center of Guizhou Province. School of Pharmacy.
Zunyi Medical University, Zunyi, Guizhou, P.R. China
E-mail: hechy2002@163.com;
b Department of Nuclear Medicine. Affiliated Hospital of Zunyi Medical University,
Zunyi, Guizhou, P. R. China.
Zunyi Medical University, Zunyi, Guizhou, P.R. China
cSchool of Medicine，Washington University in St. Louis，St. Louis, Missouri,
United States
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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high importance. Katritzky salts are air and moisture stable tested, and an improved yield of 5a was provided when DMA
View Article Online
DOI: 10.1039/D0CC05725H
reagents, which can be easily prepared in a single step via and ether solvents were used as co-solvent (Table 1, entries 4-
condensation of primary amines with 2,4,6-triphenylpyrylium 6), and 85% yield was obtained when the reaction was
tetrafluoroborate. Very recently, a variety of deaminative performed in a co-solvent system of DMA/DME (1:1) or
protocols employing Katritzky salts have been realized and DMA/THF (1:1). After adjust the ratio of those co-solvent
allow selective transformations of abundant amino groups.12 (DMA/DME or DMA/THF), the system DMA/DME (1:3) was
Here, we describe the first example of visible light promoted proved to the best one, and 97% yield was provided (Table 1,
deaminative difluoroalkylation chemistry,13 the resulting entry 7, for details, see ESI). Other photocatalysts such as
products can be further transformed to a diverse array of Ru(bpy)3Cl2, Ir(ppy)3 or [Ir(ppy)2(bpy)]PF6 were also
structurally novel and interesting difluoro-containing moieties, investigated, but failed to give satisfactory results (Table 1,
therefore providing a facile route for applications in medicinal entry 8, for details, see ESI). Finally, the effort of the reaction
chemistry and life science.
temperature was also examined, decreasing the reaction
o
Table 1. Representative Results for the Optimization of the temperature to 35 C deminished the reaction efficiency, and
Visible Light Promoted Deaminative Difluoroalkylation of 75% yield was obtained (Table 1, entry 9). Control experiments
Amines. a b
demonstrated that both photocatalyst and visible light are
essential for this transformation (Table 1, entries 10-11). When
the reaction performed at 0.2 mmol scale, a comparable yield
could be afforded (Table 1, entry 12).
Ph
Ph
F
Solvent (0.1M)
P.C. (2.0 mol%)
Blue LEDs 24 W
50 oC, 24 h
F
F
F
OTES
Ph
N
+
BF4
O
Ph
3a
4
5a
With the optimized reaction conditions in hand, the scope of
this photochemical deaminative difluoroalkylation reaction was
explored. Various pyridinium salts derived from primary amines
were successfully difluoroalkylated in satisfactory yields (Table
2). First, the reactivity of different sizes of aliphatic rings were
examined, five-membered rings were less reactive, only
moderate yield were obtained (5b-c). Other aliphatic rings, such
as seven, eight or twelve- membered rings were suitable
substrates, providing the desirable products in good yields (5d-
f). The existence of difluoromethylene (CF2) group on the ring
does not interfere this protocol (5g). Interestingly, protected
amino was also compatible with the reaction system (5h).
Substrate derived from piperidine, the most prevalent nitrogen
ring system found in medicinal chemistry, could
difluoroalkylated smoothly in 81% yield (5i). In comparison,
pyridinium salt of pyrrolidine was less effective, and only 45%
yield was provided (5j). 60% yield was obtained when oxygen-
containing saturated heterocycle was treated (5k). Then,
straight-chain primary amines were tested, pyridinium salts
from 2-amino-4-phenylbutane worked well to afford the
corresponding products in 66% yield (5l). Amino acids, an
important class of primary amines, are also common structural
motifs found in life science and pharmaceuticals. Therefore,
difluoroalkylation of those compounds were also conducted.
Pleasingly, amino acids that have fluoro, chloro, tert-butoxy,
protected amino, methylthio groups as substituents reacted
with 4 very well, to afford the desirable products in 64-94%
yields (5m-u). Moreover, substrates derived from diverse
Yield
Entry
Catalyst
Solvent
(5a %)b
1
2
[Ir(dtbbpy)(ppy)2]PF6
[Ir(dtbbpy)(ppy)2]PF6
[Ir(dtbbpy)(ppy)2]PF6
[Ir(dtbbpy)(ppy)2]PF6
[Ir(dtbbpy)(ppy)2]PF6
[Ir(dtbbpy)(ppy)2]PF6
[Ir(dtbbpy)(ppy)2]PF6
Ir(ppy)3
DMA
DMF
DME
68
36
3
11
4
DMA:1,4-Dioxane (1:1)
DMA : DME (1:1)
DMA : THF (1:1)
DMA : DME (1:3)
DMA : DME (1:3)
DMA : DME (1:3)
DMA : DME (1:3)
DMA : DME (1:3)
DMA : DME (1:3)
73
5
85
6
85
7
97
8
19
9c
10d
11
[Ir(dtbbpy)(ppy)2]PF6
[Ir(dtbbpy)(ppy)2]PF6
----
75
----
----
97 (92)
12e
[Ir(dtbbpy)(ppy)2]PF6
a
Reaction conditions (unless otherwise specified): 1a (0.1
mmol, 1.0 equiv.), 2 (0.2 mmol, 2.0 equiv.), P.C. (2.0 mol%),
Solvent (1.0 mL), Blue LEDs 24 W, 50 C, 24 h, under argon
atmosphere. NMR yield determined by 19F NMR using p-
o
b
c
Fluorotoluene as internal standard.
The reaction was
performed at 35 oC. d The reaction was performed in the dark. e
Reaction performed on a 0.2 mmol scale, 36 h, yield of isolated
product given in parentheses.
Accordingly, we began this study by choosing Katritzky salts 3a
and difluoroenoxytriethylsilane 4 as the model substrate. (Table
1). Initially, a 68% of the desired product 5a was obtained when
the reaction of 3a (0.1 mmol, 1.0 equiv) with 4 (2.0 equiv) was
carried out under the irradiated of 24 W blue LEDs in DMA
utilizing [Ir(dtbbpy)(ppy)2]PF6 (2 mol%) as photocatalyst at 50 oC
for 24 h (Table 1, entry 1). Then, different reaction mediums
were screened. Among the tested solvents, other amide
solvents such as NMP and DMF were less effective (Table 1,
entry 2，for details, see ESI). Poor yields were obtained when
the reaction was conducted in DMSO or MeCN (for details, see
ESI). Ethers (THF, 1,4-dioxane and DME) were also not effective
solvents (Table 1, entry 3, for details, see ESI). To improve the
reaction efficiency further, some co-solvent systems were
primary
benzylic
amines
were
also
successfully
difluoroalkylated and provide the desired products in 41-77%
yield (5v-5af). 3-(Aminomethyl)pyridine was also compatible
with the reaction system, affording 5ag in 65% yield. The
reaction was less reactive when the steric hindrance of the
group adjacent to amino group was increased (5ah). Pyridinium
salt linked with primary carbons were not suitable substrates
because of unstable radical intermediate (5ai). To demonstrate
the synthetic application of this methodology further, gram
scale reactions for the synthesis of compounds 5e, 5i or 5t) were
conducted, and comparable yields were still obtained.
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC05725H
Table 2. Scope of the Visible Light Promoted Deaminative Difluoroalkylations. a b
Ph
Ph
Blue LEDs 24 W
F F
F
F
OTES
Ph
[Ir(dtbbpy)(ppy)2]PF6 (2.0 mol%)
Ph
N
+
DMA:DME (1:3, 0.1M)
50 oC, 36 h
BF4
O
Ph
3
5
4
CF
2COPh
CF
2COPh
CF2COPh
CF
2COPh
CF
2COPh
CF
2COPh
c
5a
5b
5c
5d
, 92% (74%)
, 55%
, 63%
, 86%
CF2COPh
5e
5f
5l
, 78%
CF
, 80%
CF
CF
2COPh
2COPh
CF
2COPh
CF
2COPh
2COPh
BocN
F
O
BocN
5i
BocHN
F
c
5g
5h
5j
5k
, 60%
, 69%
, 50%
, 45%
, 66%
, 81% (61%)
O
O
O
CF
MeOOC
2COPh
5n
O
O
2COPh
, 87%
CF
2COPh
O
CF
2COPh
CF
2COPh
MeO
5t
MeO
MeO
MeO
CF
2COPh
MeO
OMe
MeO
R=H,
5o
R=Cl, , 80%
R=F,
R=Ot-Bu, , 64%
, 81%
3
CF
NHBoc
, 69% (66%)
O
R
SMe
5p
, 85%
5q
Ph
c
5r
5u
5s
, 67%
, 71%
5m
, 94%
CF
2COPh
CF
2COPh
F3C
CF
2COPh
CF
2COPh
CF
CF
2COPh
2COPh
R
5z
R=F,
, 55%
5aa
R
N
N
R=Cl,
R=Br,
R=CN,
, 54%
5ab
5v
R=H,
R=Br,
, 77%
, 60%
5ac
5w
, 71%
5x
5af
, 75%
5ag
5ah
5ai
, 0%
, 65%
, 44%
, 61%
R=CF3,
, 61%
R=Me, , 56%
5ad
R=COOMe,
5ae
, 76%
5y
R=Me,
41%
a Reaction conditions (unless otherwise specified): 3 (0.2 mmol, 1.0 equiv.), 4 (0.4 mmol, 2.0 equiv.), [Ir(dtbbpy)(ppy)2]PF6 (0.004
mmol, 2.0 mol%), DMA/DME (2.0 mL, v/v=1:3), Blue LEDs 24 W, 50 oC, 36 h, under argon atmosphere. bYield of isolated product. c
3 (4.0 mmol, 1.0 equiv.), 4 (8.0 mmol, 2.0 equiv.), [Ir(dtbbpy)(ppy)2]PF6 (0.08 mmol, 2.0 mol%), DMA/DME (16.0 mL, v/v=1:3), 50
oC, Blue LEDs 24 W, 72 h.
Having established suitable reaction conditions for the
preparation of compounds 5, the utility of this reaction can also
Me
CF2H
CF2H
CF2H
be demonstrated by the further transformations. As shown in
Scheme 2, compounds 5 can serve as versatile building blocks
for the diversity-oriented synthesis. For instance, upon
treatment with t-BuOK, the phenyl acyl (C6H5CO) can be easily
removed to access difluoromethylated analogies in good yields
which provide an alternative method for deoxyfluorination of
aldehydes. The tetrafluoroethylene bridge (-CF2CF2-), which has
many applications in both material and agrochemical, can be
easily prepared by fluorination of the carbonyl group with DAST
in moderate yields. The ketone could react with VinylMgBr, and
versatile building blocks 8 could be provided in good yields. The
compounds could also be converted to alcohols via reduction
with high yields.
CF2H
N
N
Boc
Boc
6i, 81%
6j, 71%
6l, 63%
6e, 65%
Boc
Boc
N
t-BuOK (4.0 equiv.)
N
F
OH
F
t-BuOH, 100 o
C
Ph
Ph
F
F
F
F
F
F
Ph
7i, 55%
8i, 60%
DAST (20 equiv.)
DME, 80 o
VinylMgBr (5.0 equiv.)
THF, 0 o
C
O
C
5
Me
OH
Ph
F
F
NaBH4 (3.0 equiv.)
EtOH, r.t.
F
F
F
F
8e, 82%
7l, 56%
Boc
OH
Me OH
N
OH
Ph
F
F
F
F
F
F
To shed light on the mechanism of this transformation, a
series of experiments were conducted. The reaction was totally
suppressed by the addition of a radical scavenger TEMPO (100
mol%), which suggests that the involvement of radical
intermediates is likely during the reaction (for details, see ESI).
A radical clock experiment employing Katritzky salts 10 as a
substrate produced the ring opening product 11 in 14% yield
(for details, see ESI). Finally, the calculated quantum yield value
of Φ = 0.15, indicating the involvement of radical chain progress
is unlikely.
9e, 88%
9i, 94%
9l, 97% (dr=1.1:1)
Scheme 2 Transformation of Compounds 5.
On the basis of these preliminary results and previous reports,
a plausible mechanism was proposed in Scheme 3 for this
transformation. Firstly, irradiation with visible light excites
[Ir(dtbbpy)(ppy)2][PF6] into a strong reductive species (i.e.,
*[Ir(dtbbpy)(ppy)2][PF6] that performs a single electron transfer
(SET) process to generate alkyl radical from Katritzky salt (3).
Subsequent regioselective addition of alkyl radical to (4) lead to
the carbon-radical intermediate (IV), which are further oxidized
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to cation species (V) via a SET process with strong oxidant [Ir(IV)].
Finally, the desiliconisation of (V) could afford the
corresponding difluoroalkylated product (5).
6. For selected reviews, see (a) T. Chatterjee, N. Iqbal, Y. You and
View Article Online
E. J. Cho, Acc. Chem. Res., 2016, 49, 2284. (b) Z. Feng, Y.-L. Xiao,
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Li, T. Wang, F. Fei, Y.-M. Su, Y. Li, Q. Lan and X.-S. Wang, Angew.
Chem., Int. Ed., 2016, 55, 3491.
Ph
Ph
Ph
Ph
N
N
II
Ph
I
Ph
OTES
Ph
Ph
7. For selected papers, see (a) Y.-B. Wu, G.-P. Lu, B.-J. Zhou, M.-J.
Bu, L. Wan and C. Cai, Chem. Commun., 2016, 52, 5965. (b) Y.-L.
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and X. Zhang, Angew. Chem., Int. Ed., 2014, 53, 1669. (e) Y. Guo
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W.-H. Guo, G.-Z. He, Q. Pan and X. Zhang, Angew. Chem., Int.
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S. Li and C. Zhu, Angew. Chem., Int. Ed., 2016, 55, 2939. (h) T.
Mao, M.-J. Ma, L. Zhao, D.-P. Xue, Y. Yu, J. Gu and C.-Y. He,
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F
N
F
BF4
alkyl radical III
Ph
4
3
SET
OTES
IrIV
F
F
*IrIII
IV
Ir
SET
O
OTES
- TES
F
F
F
F
IrIII
5
V
[Ir(dtbbpy)(ppy)2](PF6)
Blue LEDs
Scheme 3 Proposed Plausible Reaction Mechanism.
In summary, a simple method for the visible light promoted
deaminative difluoroalkylation reaction was developed. This
protocol is characteriazed by mild reaction conditions and
broad substrate scope, which converted a diverse array of
amine-containing molecules to the alkyl-CF2COPh products.
Moreover, the resulting products can serve as versatile building
blocks for the diversity-oriented synthesis, and a variety of
structurally novel and interesting difluoro-containing moieties
can be easily obtained by further transformations, therefore
providing a facile route for applications in medicinal chemistry,
life science and agrochemical.
9. For selected papers, (a) H. Jiang, M. Xu, W. Lu, W. Tian, W. Wan,
Y. Chen, H. Deng, S. Wu and J. Hao, Chem. Commun., 2015, 51,
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Org. Chem., 1999, 64, 6717. (c) W. Li, X. Zhu, H. Mao, Z. Tang, Y.
Cheng and C. Zhu, Chem. Commun., 2014, 50, 7521.
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Ed., 2018, 57, 3187.
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2019, 5, 2987.
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 21702241, 81760624,
21762053), Programs of Guizhou Province (No. 2018-1427), the
Innovation Talent Team of GuiZhou Science and Technology
Department (20205007), the Innovation Talent Team of Zunyi
(No. 2019-01). We thank Dr Jiwei Gu from Washington
University for his linguistic assistance.
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Conflicts of interest
There are no conflicts to declare.
Notes and references
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DOI: 10.1039/D0CC05725H
Ph
R1
Ph
F
F
R1
CF2H
R1
Ph
N
R2
F
F
F
BF4
R2 OH
Blue LEDs
P.C.
R1
R2 Ph
+
Ph
Transformations
R2
O
F
F
F
Ph
R3
R1
R1
Ph
OTES
F
F
F
R2
R2 OH
11 examples
F
Ph
Versatile Building Blocks
35 examples