Direct Photoredox-Catalyzed Reductive Difluoromethylation of Electron-Deficient Alkenes

Article abstract of DOI:10.1002/chem.201504363

Photoredox-catalyzed reductive difluoromethylation of electron-deficient alkenes was achieved in one step under tin-free, mild and neutral conditions. This protocol affords a facile method to introduce RCF₂ (R=H, Ph, Me, and CH₂N₃) groups at sites β to electron-withdrawing groups. It was found that TTMS (tris(trimethylsilyl)silane) served nicely as both the H-atom donor and the electron donor in the catalytic cycle. Experimental and DFT computational results provided evidence that RCF₂ (R=H, Ph, Me) radicals are nucleophilic in nature.

Full text of DOI:10.1002/chem.201504363

DOI: 10.1002/chem.201504363
Communication
&
Synthetic Methods
Direct Photoredox-Catalyzed Reductive Difluoromethylation of
Electron-Deficient Alkenes
[
a]
Xiao-Jun Tang, Zuxiao Zhang, and William R. Dolbier, Jr.*
this protocol was only applied to addition to alkenes bearing
Abstract: Photoredox-catalyzed reductive difluoromethy-
lation of electron-deficient alkenes was achieved in one
step under tin-free, mild and neutral conditions. This pro-
[
11]
two electron-withdrawing groups.
On the other hand, addition of radicals to electron-deficient
alkenes provides an alternative to classical Michael addition re-
actions (Scheme 1). In some such reactions, the resulting elec-
tocol affords a facile method to introduce RCF (R=H, Ph,
2
Me, and CH N ) groups at sites b to electron-withdrawing
2
3
[12]
trophilic radical intermediates dimerize, rearrange, or cyclize.
groups. It was found that TTMS (tris(trimethylsilyl)silane)
served nicely as both the H-atom donor and the electron
donor in the catalytic cycle. Experimental and DFT compu-
tational results provided evidence that RCF2 (R=H, Ph,
Me) radicals are nucleophilic in nature.
In others they are able to be reduced to anions by reductive
Methods for the introduction of fluorinated groups into organ-
ic compounds remain of considerable interest within the agro-
chemical, pharmaceutical, and material science industries, be-
cause of the unique physical and chemical effects such groups
Scheme 1. Michael-type radical addition to electron-deficient alkenes by nu-
cleophilic radicals. EWG=electron-withdrawing group.
[1]
can bestow upon compounds. In particular, the HCF group
2
[
13]
[14]
is of great interest in drug design because it can serve as a lipo-
philic hydrogen-bond donor and as a bioisostere of the SH or
reagents, such as the photocatalyst, or low-valent metals
to avoid dimerization or polymerization. Reductive perfluoroal-
kylation of electron-deficient alkenes using R I or R Br could
[
2]
OH group. Traditionally, difluoromethylated organic com-
pounds have been prepared by deoxofluorination of the corre-
F
F
also be achieved by addition of H-atom donors to reactions in-
itiated by azobisisobutyronitrile (AIBN), Et B/O , UV irradiation,
[3]
sponding aldehydes using DAST or SF4. Recently, transition-
metal-catalyzed or -mediated direct methods for introduction
3
2
or photocatalysis. However, the requirement of a large excess
of the CF H group into arene or alkene moieties by using re-
of the alkenes, harsh conditions, or low yields makes these
2
[4]
[5]
[6]
[15]
agents, such as TMSCF H, Bn SnCF H, or (HCF SO ) Zn
protocols impractical.
In reactions of a,b-unsaturated ke-
2
3
2
2
2 2
have been extensively developed. Nevertheless, methods for
tones, by use of excess of Et B, corresponding products can be
3
the direct introduction of the CF H group into aliphatic sys-
obtained with moderate yields via boron enolate intermedi-
2
[7]
[16]
tems are still limited.
ates. Without reductive reagents or added H-atom donors,
Nucleophilic difluoromethylations have been mainly focused
on additions to reactive electrophilic species such as alde-
reductive fluoroalkylation products can only be obtained,
albeit in poor yields, when the alkenes are not prone to poly-
[8]
[9]
[6a,17]
hydes, ketones, imines, or allyl halides. This can be attribut-
ed to the relative instability and “hard” nature of the HCF2
anion under those conditions where it acts as a nucleophile.
merization.
[
18]
Very recently, we reported the photoredox-catalyzed di-
[
12d]
fluoromethylation/cyclization of N-phenylacrylamides,
and
Thus the CF H anion inclines to 1,2-addition rather than 1,4-ad-
the chloro, difluoromethylation of electron-deficient alkenes
2
[
19]
dition when reacting with Michael acceptors, such as a,b-unsa-
using HCF SO Cl. In connection with these results, we specu-
2 2
turated carbonyl compounds. On the other hand, the stabilized
lated that a direct photoredox-catalyzed reductive difluorome-
thylation of electron-deficient alkenes carried out in the pres-
ence of a hydrogen atom donor might be possible (Scheme 1).
The results of such a study are disclosed in the present com-
munication.
“
CF R’’ anion derived upon treatment of ethyl bromodifluoro-
2
[
10]
acetate with copper is an excellent Michael nucleophile.
+
À
More recently, Ph P CF COO was reported as a two-step
3
2
equivalent of the ”CF H“ anion for Michael addition. However,
2
The results of using N-phenylacrylamide (2a) for optimiza-
tion experiments are summarized in Table 1. Based on its excel-
lent reductive ability and its generally poor observed Cl-trans-
[
a] Dr. X.-J. Tang, Z. Zhang, Prof. Dr. W. R. Dolbier, Jr.
Department of Chemistry, University of Florida
PO Box 117200, Gainesville, FL, 32611-7200 (USA)
E-mail: wrd@chem.ufl.edu
fer behavior, fac-[Ir(ppy) ] was selected as a potentially effec-
3
tive catalyst. As expected, without addition of an H-atom
donor, only the atom-transfer radical addition (ATRA) prod-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504363.
Chem. Eur. J. 2015, 21, 18961 – 18965
18961
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Table 1. Optimization of reaction conditions.
[
a]
Entry
Cat.
H-donor (equiv)
–
Yield [%]
[b]
1
2
3
4
5
6
7
8
9
fac-[Ir(ppy)
fac-[Ir(ppy)
[Ir(ppy)
3
]
]
22
78
3
(TMS)
(TMS)
(TMS)
3
3
3
SiH (2)
SiH (2)
SiH (2)
2
(dtbbpy)PF
6
]
61
75
18
<5
20
<5
<5
65
Ir[dCF (ppy)
3
2
](dtbbpy)PF
6
fac-[Ir(ppy)
fac-[Ir(ppy)
fac-[Ir(ppy)
fac-[Ir(ppy)
fac-[Ir(ppy)
fac-[Ir(ppy)
fac-[Ir(ppy)
fac-[Ir(ppy)
fac-[Ir(ppy)
3
3
3
3
3
3
3
3
3
]
Ph
Et
Bu
PO
p-TolSH (2)
2
SiH
SiH (2)
SnH (2)
/NaHCO
2
(2)
]
]
]
]
]
]
]
]
3
3
H
3
2
3
(2)
1
0
(TMS)
(TMS)
(TMS)
(TMS)
3
3
3
3
SiH (1.5)
1
1
SiH (2.5)
SiH (2)
SiH (2)
70
[
c]
1
1
2
3
85 (82 )
90
[
a] Reactions were run with 0.3 mmol (1 equiv) 2a, 0.6 mmol (2 equiv)
HCF SO Cl, and 0.0015 mmol (0.5% equiv) catalyst in MeCN (2 mL) under
2
2
visible light for 12 h, and yields were determined by using PhF as the in-
ternal standard. [b] ATRA product was obtained as the product.
[
c] 7.5 mmol (2.5 equiv) HCF
2
SO
2
Cl was used, and isolated yield was
SO Cl was used. ppy = 2-phe-
3 2
nylpyridinato-C ,N, dCF (ppy) = 3,5-difluoro-2-[5-(trifluoromethyl)-2-pyri-
based on 2a. [d] 0.9 mmol (3 equiv) HCF
2
2
2
dinyl-N]phenyl-C, dtbbpy = 4,4’-bis(1,1-dimethylethyl)-2,2’-bipyridine-N1,
N1’ .
Scheme 2. Reactions of HCF SO Cl with electron-deficient alkenes. [a] Reac-
2
2
tions were run on a 0.3 mmol scale; isolated yields based on alkenes.
1
9
[
b] F NMR yield using PhF as the internal standard; 3ah was not isolated
due to low yield.
[19]
uct was detected, in 22% yield (Table 1, entry 1). We were
pleased to observe the desired reduced product, 3aa, to be
3au) in good to excellent yields. In addition, functional-group
formed in 78% yield when two equivalents of (TMS) SiH was
substituents, such as Ac, CN, Br, NO , and MeO on arenes were
3
2
added to the mixture, with no ATRA product being detected
well-tolerated in this reaction. A relatively low yield of desired
19
[20]
(
entry 2). It should be noted that considerable CF H ( F NMR:
product 3ah was obtained when using the b-substituted ac-
2
2
19
d=À143.6 ppm, t, J=50.0 Hz) was also observed by F NMR
rylamide 2h as a substrate. This indicates that steric effects at
the b-position can be important. Yields of desired products are
improved significantly when there are two electron-withdraw-
ing groups on the double bond (3ai, 3aj, and 3an). In addi-
tion, substrates bearing alkyl or halide (2p and 2q) at the a-
position resulted in lower yields of desired product than that
of the substrate bearing the electron-withdrawing group, ester
(2r). Thus, the difluoromethyl radical appeared to be more re-
active with the more electron-deficient substrates.
spectroscopy as a co-product, which was attributed to direct
abstraction of an H atom from (TMS) SiH by the difluoromethyl
3
radical intermediate in competition with its addition to 2a.
Other Ir catalysts proved less effective than fac-[Ir(ppy) ] for
3
this reaction (entries 3 and 4) and use of silanes with greater
SiÀH bond energies, such as Ph SiH or Et SiH, resulted in low
2
2
3
yields of the desired product 3aa (entries 5 and 6). Interesting-
ly, the excellent hydrogen-atom source, Bu SnH, only produced
3
3
aa in 20% yield (entry 7). Furthermore, neither H PO nor p-
Subsequently, this reaction was extended to the use of
other fluoroalkyl radical precursors. As seen in Scheme 3, reac-
tions of CH CF SO Cl with a,b-unsaturated amide, ester,
3
2
TolSH was effective in facilitating this reaction (entries 8 and 9).
Neither increasing nor decreasing the amount of (TMS) SiH in
3
3
2
2
the reaction improved the yield of 3aa (entries 10 and 11). If
ketone, or sulfone resulted in the corresponding products in
good yields.
two equivalents of (TMS) SiH are used, the yields of 3aa can
3
be improved to 85 or 90% when the amount of HCF SO Cl
When using N CH CF SO Cl, the resulting products were ob-
2
2
3
2
2
2
was increased to 2.5 or three equivalents, respectively (en-
tries 12 and 13). When considering cost and efficiency, it was
tained in lower yields, perhaps because the inductive effect of
azide may decrease the nucleophilicity of the difluoroalkyl radi-
[
21]
decided to consider two equivalents of (TMS) SiH and
cal. PhCF SO Cl is unstable at room temperature. However,
2 2
3
2
.5 equivalents of HCF SO Cl as optimal for determination of
PhCF Br can be smoothly reduced by fac-[Ir(ppy) ] at room
2 3
2
2
the scope of the reaction.
temperature due to the presence of phenyl as an activating
[
22]
Using these optimized conditions, the reaction was applied
to a large variety of electron-deficient alkenes. As seen in
Scheme 2, reactions of a series of a,b-unsaturated acrylamides,
esters, ketones, sulfones, or phosphonates with HCF SO Cl re-
group. Reactions of PhCF Br with electron-deficient alkenes
2
led to the corresponding products in good to excellent yields.
A proposed mechanism for these reactions is shown in
Scheme 4. The fluorinated radicals that are generated by re-
2
2
III
sulted in difluoromethylation–hydrogenation products (3ab–
duction of the respective difluoroalkylsulfonyl chlorides by Ir*
Chem. Eur. J. 2015, 21, 18961 – 18965
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Communication
In general, fluorinated radicals are considered to be electro-
philic. However, the results shown at Scheme 2 indicated that
the difluoromethyl radical was more reactive with the more
electron-deficient alkenes. In a study of the reactions of various
fluorinated radicals with the typical electron-deficient alkene,
acrylonitrile, it was observed that, in contrast with excellent
yields resulting from radical sources of CF H, CF CH , and
2
2
3
PhCF , the reaction of CF SO Cl with acrylonitrile produced
2
3
2
only 18% yield of the desired addition product, along with
a large amount of CF H (Scheme 5).
3
3 2 2 3 2 2 2 2
Scheme 3. Reactions of CH CF SO Cl, N CH CF SO Cl, or PhCF Br with elec-
tron-deficient alkenes. [a] Isolated yields based on electron-deficient alkenes.
Scheme 5. Reactions of HCF
yields were determined by F NMR using PhF as the internal standard; 3ax,
2
9
SO
2
Cl with electron-deficient alkenes. [a] All
1
3
bx, and 3ex were not isolated due to their low boing points. [b] Isolated
yield.
In an attempt to rationalize these results, transition states
TS) of reactions of fluorinated radicals with acrylonitrile were
(
[
24,25]
calculated using the DFT methodology.
The methyl radical
is generally considered to be a weak to moderately nucleophil-
[
26]
ic species. However, as shown in Table 2, all of the difluoroal-
kylated radicals form more favorable charge-transfer transition
states (donating more electron density to acrylonitrile) when
compared to the addition of a methyl radical to acrylonitrile.
Only the trifluoromethyl radical appears to be more electro-
philic than the methyl radical. Therefore, it appears that all of
these difluoroalkyl radicals should be considered to be nucleo-
philic radicals, which thus can react faster with more electron-
deficient alkenes due to transition-state polarization effects,
Scheme 4. Proposed reaction mechanism.
add to the electron-deficient alkene to produce another, elec-
trophilic radical intermediate. Due to their polar effects, these
intermediates can readily abstract H from TTMS, which results
in the formation of the desired product along with the silyl
III
radical. Ir is then regenerated by oxidation of the silyl radical
IV
[23]
by Ir , converting the radical into a siliconium ion. Results of
an experiment carried out by alternating light and dark on the
reaction of HCF SO Cl with acrylonitrile are shown in Figure 1.
2
2
It indicates that conversion to the desired product is depen-
Table 2. Computational results of fluorinated radicals with acrylonitrile
and propene.
III
[a]
dent on photoexcitation of Ir* . The results from this experi-
ment are highly supportive of the proposed photoredox mech-
anism, although the chain radical process cannot be entirely
ruled out.
Entry Radical Alkene
Barrier and enthalpy
Charge transfer
in TS
À1
[b]
[kJmol
]
NBO
Mulliken
1
2
3
4
5
6
7
8
CF
CH
PhCF
CF
CH
2
H
acrylonitrile 9.96, À128.42
acrylonitrile 7.80, À136.68
acrylonitrile 21.90, À81.10
acrylonitrile 8.05, À145.65
acrylonitrile 19.50, À115.30
+0.049 +0.040
+0.063 +0.056
+0.087 +0.081
+0.013 +0.010
+0.037 +0.028
À0.005 À0.018
À0.044 À0.049
À0.019 À0.034
3
CF
2
2
3
3
CF
CF
CH
2
H
propene
propene
propene
20.12, À102.45
6.21, À123.87
34.36, À80.03
3
3
[a] Energies were calculated at UB3-LYP/6-311G +(3df, 2p)//6-31G(d)
theory level, and ZPVEs calculated from UB3-LYP/6-31G(d) theory level
were scaled by 0.9806. [b] Charge transfer between radicals and alkenes
in TS was calculated at UB3-LYP/6-31G(d) theory level.
Figure 1. Alternating light and dark experiments
Chem. Eur. J. 2015, 21, 18961 – 18965
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Communication
+
À
where CT configurations RCF2 /[CH =CHCN] will lower the
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3
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1
9
[20] The F NMR spectrum of the desired product 3ah: d=À124.0 (ddd,
J=277, 57, 13.3 Hz, 1F), À126.2 ppm (ddd, J=277, 57, 16.0 Hz, 1F).
1
9
3] For pioneering work, see a) W. J. Middleton, J. Org. Chem. 1975, 40,
[21] PhCF
2
SO
2
Cl ( FNMR: d=À95.1 ppm (s)) was prepared by chlorination
5
1
74–578; b) W. R. Hasek, W. C. Smith, V. A. Engelhardt, J. Am. Chem. Soc.
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of PhCF
2
SO
2
Na at À308C. However, it decomposed slowly to PhCF
at RT.
2
Cl
1
9
( FNMR: d=À48.3 ppm (s)) with extrusion of SO
2
Chem. Eur. J. 2015, 21, 18961 – 18965
www.chemeurj.org
18964
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[
[
[
22] The reduction of PhCF
2
Cl by fac-[Ir(ppy)
3
] was very slow in the standard
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Received: October 30, 2015
Published online on November 17, 2015
Chem. Eur. J. 2015, 21, 18961 – 18965
www.chemeurj.org
18965
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim