Nickel-Catalyzed Reductive Cross-Coupling of (Hetero)Aryl Iodides with Fluorinated Secondary Alkyl Bromides

Article abstract of DOI:10.1021/acs.orglett.5b02716

A mild and efficient nickel-catalyzed reductive cross-coupling between fluorinated secondary alkyl bromides and (hetero)aryl iodides is described. The use of FeBr₂ as an additive successfully overcomes the hydrodebromination and β-fluorine elim

Full text of DOI:10.1021/acs.orglett.5b02716

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Reductive Cross-Coupling of (Hetero)Aryl Iodides
with Fluorinated Secondary Alkyl Bromides
Xuefei Li,† Zhang Feng,‡ Zhong-Xing Jiang,*,† and Xingang Zhang*,‡
†School of Pharmaceutical Sciences, Wuhan University, 189 Donghu Lu, Wuhan 430071, China
‡Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A mild and efficient nickel-catalyzed reductive
cross-coupling between fluorinated secondary alkyl bromides
and (hetero)aryl iodides is described. The use of FeBr2 as an
additive successfully overcomes the hydrodebromination and
β-fluorine elimination of fluorinated substrates and allows the
efficient synthesis of a wide range of trifluoromethyl and difluoroalkyl containing aliphatic compounds with a fluoroalkyl
substituted tertiary carbon center. The notable features of this protocol are the synthetic and operational simplicity without
preparation of moisture sensitive organometallic reagents and excellent functional group compatibility, even toward active proton
containing substrates.
ransition-metal-catalyzed cross-couplings represent one of
synthesis of fluorinated compounds,10 we herein describe an
1
Tthe fundamental transformations in C−C bond formation. efficient and mild nickel-catalyzed reductive cross-coupling
between (hetero)aryl iodides and readily available trifluorome-
thylated secondary alkyl bromides [CF3(Alkyl)CHBr].11
Efficient catalytic systems for a wide range of substrates are
widely utilized in the production of pharmaceuticals, fine
chemicals, and functional materials. Recently, nickel-catalyzed
reductive cross-couplings between two electrophiles have
emerged as direct methods for the construction of C(sp2)−
C(sp3)2 and C(sp3)−C(sp3)3 bonds because such a strategy
omits the preparation of air- and moisture-sensitive organo-
metallics from the corresponding organic halides.4 Although
important progress in this field has been made, the use of
fluorinated secondary alkyl halides [Rf(Alkyl)CHX, Rf =
fluoroalkyl, X = halides] as a coupling partner has not been
reported thus far; this still poses a synthesis challenge due to the
difficulties in suppressing the hydrodehalogenation and β-
fluorine elimination of fluorinated substrates.5
The trifluoromethyl group (CF3) is of paramount importance
in the discovery of new bioactive molecules and advanced
functional materials owning to its strong electron-withdrawing
ability, high lipophilicity, bulky steric effect, etc.6 Over the past
few years, great endeavors have been devoted to the synthesis of
trifluoromethylated aromatic compounds.7 In contrast, less
attention has been paid to the development of efficient and
general methods for trifluoromethylated aliphatic compounds
with a CF3 substituted tertiary carbon center.7b,e,8 Therefore, it is
of great interest to develop general and efficient strategies for
such compounds. During our manuscript preparation, an
efficient nickel catalyzed Negishi cross-coupling between
fluorinated secondary alkyl electrophiles with aryl- and alkylzincs
were reported.9 Despite the importance of this method in
trifluoromethylated aliphatic compounds, the use of organozinc
reagents less sensitive to moisture is accompanied by extra
synthetic steps and special operations. As part of our systematic
study on transition-metal-catalyzed reactions for the efficient
Our initial studies focused on the nickel-catalyzed reductive
cross-coupling between trifluoromethylated secondary alkyl
bromide 1a with phenyl iodide 2a (Table 1). However, no
desired product 3a was observed when the reaction was carried
out with 1a (1.0 equiv), 2a (1.1 equiv), NiCl2·DME (10 mol %),
bpy (12 mol %), and Mn0 (3.0 equiv) in DMF at room
temperature. A higher reaction temperature promoted the
reaction and led to 3a in a 19% yield (entry 1). However, both
hydrodebrominated and β-fluorine eliminated byproducts 5a
and 6a were produced in 36% and 7% yield, respectively. Further
optimization of the reaction conditions by examining a range of
bipyridine-based ligands and nickel catalysts showed the
combination of bpy and NiCl2·DME was still the best choice
(entries 2−4, for details; see the Supporting Information). No
improvement in the reaction efficiency was observed by adding
iodide ion (i.e., Bu4NI, NaI) or acids (i.e., Et3N·HCl, CF3CO2H)
to activate the reaction medium12,13 (entries 5−8). It has been
demonstrated that, for the nickel-catalyzed reductive cross-
coupling, a radical pathway is involved in the oxidative addition of
alkyl halides to the nickel(I) complex.14 We reasoned that the
formation of byproducts 5a and 6a is probably because an active
trifluoromethyl containing alkyl radical species was generated in
the reaction process, which results in a series of byproducts.
Accordingly, iron salts were examined to improve the yield of
3a (entries 9−13), as low valent iron species could be produced
by the reduction of manganese metal with FeII or FeIII, which may
have a beneficial effect on the catalytic cycle.15 To our delight, a
Received: September 18, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02716
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Organic Letters
Letter
thus demonstrating the essential role of these three factors in the
reaction (entries 15−19).
Upon the establishment of viable reaction conditions, a wide
range of aryl iodides were employed as substrates in this
transformation (Scheme 1). Overall, good to high yields of 3
Table 1. Representative Results for Optimization of Ni-
Catalyzed Reductive Cross-Coupling between 1a and 2a
a
Scheme 1. Ni-Catalyzed Reductive Cross-Coupling between
a
1a and a Variety of Aryl Iodides 2
b
bpy
(y)
Mn0
(m)
yield (%)
entry
1
[Ni] (x)
additive (z)
3a/5a/6a
NiCl2·DME
(10)
12
12
12
12
12
12
12
12
12
12
12
12
6
−
−
−
−
3
3
3
3
3
3
3
3
3
3
3
3
2
19/36/7
2
NiBr2·DME
(10)
0/0/0
3
NiCl2(PPh3)2
(10)
0/27/13
0/0/0
4
Ni(COD)2
(10)
5
NiCl2·DME
(10)
Bu4NI (0.5)
NaI (0.5)
13/24/9
0/2/0
6
NiCl2·DME
(10)
7
NiCl2·DME
(10)
Et3N·HCl (0.5)
CF3CO2H(0.5)
FeBr2 (0.5)
FeBr3 (0.5)
FeCl2 (0.5)
FeCl3 (0.5)
FeBr2 (0.4)
15/34/4
18/28/10
43/13/6
41/5/7
8
NiCl2·DME
(10)
9
NiCl2·DME
(10)
10
11
12
NiCl2·DME
(10)
NiCl2·DME
(10)
37/13/8
32/11/8
86(78)/1/10
NiCl2·DME
(10)
c
13
NiCl2·DME
(5)
c
14
NiCl2 (5)
6
6
6
−
6
FeBr2 (0.4)
FeBr2 (0.4)
FeBr2 (0.05)
FeBr2 (0.4)
−
2
2
2
2
2
18/16/18
nd/7/6
nd/5/2
nd/4/6
3/9/0
c
15
−
−
−
a
c
Reaction conditions (unless otherwise specified): 1a (0.4 mmol, 1.0
16
equiv), 2 (1.3 equiv), DMA (4 mL), 24 h. All reported yields are
c
17
b
c
isolated yields. Reaction ran at 50 °C for 48 h. Aryl iodide (2.0
c
18
NiCl2·DME
(5)
d
e
equiv), 36 h. NiCl2·DME (8 mol %), bpy (9.6 mol %). 5-
f
Bromonicotinonitrile was used. Reaction ran for 36 h.
c
19
NiCl2·DME
(5)
−
FeBr2 (0.4)
2
0/4/3
a
Reaction conditions (unless otherwise specified): 1a (0.2 mmol, 1.0
were obtained, and the electronic nature of the substituents on
aryl iodides showed no bias toward the reaction efficiency. A
variety of versatile functional groups, including base or
organometallic reagent-sensitive functionalities, such as ester,
enolizable ketone, formyl, and nitrile were quite well-tolerated
(3g−3j and 3q). Remarkably, the free proton containing
substrates, such as phenol, aniline, and alcohol underwent the
reaction smoothly and provided 3k−3m in moderate to good
yields. This is in sharp contrast to the previous results,9 in which
the organozinc reagents are very sensitive to such functional
groups, as a result of additional protection and deprotection steps
were required. Thus, the current reaction features the advantage
of synthetic and operational simplicity. Most importantly, the
aryl bromide and aryl boronic ester showed good tolerance (3n
and 3o), which provided good opportunities for the synthesis of
complex molecules. This is distinct from the classic transition-
metal-catalyzed cross-coupling, in which aryl bromides and aryl
boronic esters are good coupling partners. Heteroaromatics are a
prominent moiety found in numerous pharmaceuticals and
agrochemicals. Synthesis of fluorinated compounds bearing
heteroaromatic rings is highly relevant for drug discovery and
development. To our delight, thiophene, pyridine, and quinoline
containing substrates are competent coupling partners and
b
equiv), 2a (1.1 equiv), DMF (2 mL), 60 °C, 6 h. Determined by 19
NMR using fluorobenzene as an internal standard, and number in
parentheses is isolated yield. 1a (1.0 equiv), 2a (1.3 equiv), DMA (2
mL), rt, 24 h.
F
c
43% yield of 3a was afforded, albeit with some byproducts, when
FeBr2 (0.5 equiv) was used (entry 9). Other iron salts also
benefited the reaction, but showed less activity (entries 10−12).
However, the exact role of iron species remains elusive at this
stage and will be addressed in the future. Finally, the optimized
reaction conditions were identified by evaluation of the solvents,
reaction temperature, and the loading amount of nickel catalyst
and additive, providing 3a in 78% yield upon isolation (entry 13).
It is noteworthy that under the optimized reactions only 5 mol %
of NiCl2·DME was used and the reaction can be conducted at
room temperature (entry 13). A high concentration of Ni catalyst
and iron species still provided comparable yields of 3a, but
increased homocoupling of 2a was observed when a high loading
of Ni catalyst was used16 (for details, see the Supporting
Information). However, the use of NiCl2 led to a poor yield of 3a
(entry 14). Either no or a trace amount of product was observed
in the absence of nickel catalyst, bipyridine ligand, or iron species,
B
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Organic Letters
Letter
provided 3p−3r in good yields, thus highlighting the generality
of the current process.
Notably, the reaction can also be extended to difluoroacety-
lated secondary alkyl bromide 8. As shown in Scheme 3,
In addition to demonstrating the scope of this reaction, a
variety of trifluoromethylated secondary alkyl bromides were
examined (Scheme 2). Generally, good to high yields of 4 were
Scheme 3. Ni-Catalyzed Reductive Cross-Coupling between
Two Electrophiles
Scheme 2. Ni-Catalyzed Reductive Cross-Coupling between 1
a
and 2
treatment of 8 with aryl iodides 2 still afforded the corresponding
products 9 with high efficiency.19 Previous work required aryl
magnesium reagents as a coupling partner, which are
incompatible with enolizable ketone and formyl group, thus
further demonstrating the advantages of the current method.5d
To probe whether an alkyl radical existed in the reaction,
radical inhibition experiments were conducted (Scheme 4a).
Scheme 4. Radical Inhibition and Radical-Clock Experiments
a
Reaction conditions (unless otherwise specified): 1 (0.4 mmol, 1.0
equiv), 2 (1.3 equiv), DMA (4 mL), 24 h. All reported yields are
b
c
isolated yields. Aryl iodide (2.0 equiv), 36 h. Reaction ran for 36 h.
d
e
NiCl2·DME (8 mol %), bpy (9.6 mol %). Reaction ran at 50 °C for
48 h.
Dramatically decreased yields of 3d were observed with the
addition of an ET scavenger 1,4-dinitrobenzene20 or a radical
inhibitor hydroquinone to the reaction of 1a with 2d in the
presence of NiCl2·DME (5 mol %), bpy (6 mol %), FeBr2 (0.4
equiv), and Mn0 (2.0 equiv) in DMA. Thus, these results suggest
an alkyl radical may be involved in the catalytic cycle. To confirm
that a free alkyl radical was generated during the reaction, a
radical-clock experiment was conducted (Scheme 4b). When
compound 1021 was treated with 1a in the presence of aryl iodide
2d under standard reaction conditions, a ring-expanded product
11 was generated (8% yield, determined by 19F NMR) along with
a 23% yield of 3d. This finding demonstrates that a free radical is
generated in the reaction process.
In conclusion, we have demonstrated a mild and efficient
nickel-catalyzed reductive cross-coupling between fluorinated
secondary alkyl bromides and (hetero)aryl iodides. The additive
FeBr2 plays an essential role in the promotion of the reaction and
allows a broad substrate scope with high efficiency under mild
reaction conditions. A deep understanding of the exact role of
iron species in the current process would be a subject for future
work. The significant features of this protocol are the use of
bench stable and abundant organic halides without preparation
of moisture-sensitive organometallic reagents and excellent
functional group compatibility, even toward free proton-
also obtained. Again, excellent functional group compatibility
were observed for the current reaction. In particular, N-
heteroaromatics and nucleophile-sensitive phenols, alcohols,
and active proton-containing amides still furnished the
corresponding products with high efficiency (4c−4g, 4j and
4m). Importantly, thiazole, an important structural motif in
natural products and biologically active molecules, underwent
the reaction smoothly (4k). An even higher yield of 4l was
obtained when the thiazole containing alkyl bromide was treated
with 3-iodothiophene. The ferrocenyl group also showed good
tolerance, leading to 4j in moderate yield. Moreover, the amino
acid containing alkyl bromide did not affect the reaction
efficiency and provide 4m in 72% yield. This is noteworthy, as
the fluorinated amino acids and their derivatives have important
applications in the design of biologically active peptides and
protein engineering.17 Remarkably, the sterically hindered
piperidine containing alkyl bromide was a competent coupling
partner and afforded 4n−4p with high efficiency, thus further
demonstrating the broad substrate of this method. The
trifluoromethylated tertiary alkyl bromides were not applicable
to the current reaction.18
C
DOI: 10.1021/acs.orglett.5b02716
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02716.
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Detailed experimental procedures, and characterization
data for new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: zxjiang@whu.edu.cn.
*E-mail: xgzhang@mail.sioc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Basic
Research Program of China (973 Program) (Nos.
2012CB821600 and 2015CB931900), the NSFC (21425208,
21332010, 21372181, and 21572168), and SIOC.
(11) The trifluoromethylated secondary alkyl bromides [CF3(Alkyl)
CHBr] can be easily synthesized from TMSCF3 and aldehydes; see
Supporting Information p S13.
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