Development and Application of a Multielectron-Accepting Organic Oxidant for the Catalytic Transition-Metal-Free Oxidative Homocoupling of Grignard Reagents in Air

Article abstract of DOI:10.1021/acs.orglett.5b02887

Heptafluorotolyl-substituted perfluorocyclopentene acts as a four-electron oxidant for the homocoupling of Grignard reagents. It can also be used for catalytic homocoupling with a low catalyst loading (up to 2 mol %) in the presence of atmospheric oxygen. The organocatalytic cycle involves the generation of an organic radical and a perfluorocyclopentadienyl anion.

Full text of DOI:10.1021/acs.orglett.5b02887

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Letter
pubs.acs.org/OrgLett
Development and Application of a Multielectron-Accepting Organic
Oxidant for the Catalytic Transition-Metal-Free Oxidative
Homocoupling of Grignard Reagents in Air
Toshinobu Korenaga,* Kaoru Nitatori, Hiroki Muraoka, Satoshi Ogawa, and Kazuaki Shimada
Department of Chemistry and Bioengineering, Faculty of Engineering, Iwate University, 4-3-5 Ueda, Morioka, Iwate 020-8551, Japan
S
* Supporting Information
ABSTRACT: Heptafluorotolyl-substituted perfluorocyclopen-
tene acts as a four-electron oxidant for the homocoupling of
Grignard reagents. It can also be used for catalytic
homocoupling with a low catalyst loading (up to 2 mol %) in
the presence of atmospheric oxygen. The organocatalytic cycle
involves the generation of an organic radical and a perfluoro-
cyclopentadienyl anion.
ransition-metal-free oxidizing reactions using organic
Toxidants are now widely used in organic syntheses
because of their environmental sustainability.1 Although these
organic oxidants are typically used to oxidize alcohols, they may
also be applied toward oxidative C−C coupling reactions in
certain cases.2 For instance, the transition-metal-free homo-
coupling reactions of Grignard reagents can be effectively
mediated by organic oxidants.3 The homocoupling of Grignard
reagents4 has potential value for the industrial synthesis of
symmetrical biaryls or polyaromatic conjugated compounds, as
Grignard reagents are widely used.5 However, current
transition-metal-free homocouplings require large amounts of
the organic oxidant upward of 50 mol %.3 Therefore, large-scale
applications require the development of a new reaction
methodology that utilizes a relatively smaller amount of an
organic oxidant. In terms of the electron-accepting mechanism,
a trailblazing transition-metal-free homocoupling of Grignard
reagents was reported by Knochel and Mayr.3c They used 55
mol % of a quinone derivative as an oxidant, which was
aromatized by accepting two electrons from Grignard reagents
(Figure 1a). Studer also later reported on a homocoupling
reaction that used 108 mol % of TEMPO,3e which was reduced
with one electron from a Grignard reagent (Figure 1b).6 In this
case, the catalytic reaction was performed with 14 mol % of
TEMPO through successive cycles, where each cycle consists of
a stoichiometric reaction and an in situ regeneration of the
oxidant.3e Organic halides have also been used as oxidants: 300
mol % 1,2-dibromoethane by O’Shea3f and 50 mol % 2,3-
dichloropropene by Luo.3a In the latter case, 2,3-dichloropro-
pene accepted two electrons and both the allylic and vinylic
chlorides were eliminated (Figure 1c). To apply the halide
elimination mechanism, we hypothesized that the perhalo-2-
butene unit would act as a multielectron acceptor, accepting
three or more electrons (Figure 1c, below).
Figure 1. Electron-accepting mechanism of organic oxidant.
Previously, 1a had been used as a precursor for photochromic
diarylethenes,7 which were prepared by substituting the vinylic
fluorides of 1a with ArLi or ArMgX, indicating that 1a was
attacked by Grignard reagents. We were thus able to design
novel perfluorocyclopentene derivatives with fluoroaromatic
groups (ArF) (Figure 2). By introducing strong electron-
withdrawing ArF at the vinylic position of 1a, we expected to
Figure 2. Perfluorocyclopentene derivatives as a novel organic oxidant.
Received: October 5, 2015
Accordingly, we focused on the readily available octafluoro-
cyclopentene (1a) as a potential multielectron acceptor.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02887
Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters
Letter
increase its oxidizability as an oxidant, decrease its reactivity in
substitution reactions with nucleophiles,8 and eliminate its high
volatility. Here, we report on the development of a novel
organic oxidant that can act as both a four-electron oxidant and
a catalyst in the presence of atmospheric oxygen.
In order to reduce the amount of 1f in the reaction from 25
mol %, we decided to further evaluate the catalytic oxidative
homocoupling reaction from another perspective. Studer et al.
previously attempted a TEMPO-catalyzed homocoupling of a
Grignard reagent, where 2a was reacted in the presence of 20
mol % of TEMPO with a continual bubbling of pure O2
throughout the reaction mixture to give 3a and a phenol with
61% and 24% yields, respectively.3e They then attempted
several sequential reaction cycles with 14 mol % of TEMPO.
This consisted of a stoichiometric TEMPO-mediated coupling
of 1a, an in situ regeneration of TEMPO with pure O2, and the
readdition of 1a to give 3a with an 81% yield.3e This catalytic
system relied on the oxidation of the TEMPO−MgBr complex
with pure O2 to regenerate the TEMPO catalyst. When we
originally viewed our devised system, we noticed that a
coupling reaction with 25 mol % of 1f under argon produced a
dark greenish-brown solution at the end of the reaction (Table
1, entry 8). However, this solution immediately changed into a
dark purple color upon exposure to the atmosphere. This
inspired us to consider that the residue from 1f after
homocoupling was readily oxidized with atmospheric oxygen
to give radical species. Therefore, we attempted 1f-catalyzed
homocoupling of the Grignard reagent by completely exposing
the reaction to the atmosphere (Table 2). The reaction of 2a in
The novel perfluorocyclopentene derivatives, ArF = 3,4,5-F3-
C6H2 (1c), C6F5 (1d), 3,5-(CF3)2-C6H3 (1e), and 4-CF3-C6F4
(1f) (Figure 2), were prepared in moderate to high yields from
1a with treatment of ArF-Li. All of the compounds 1 were stable
in air. The homocouplings of phenylmagnesium bromide (2a)
in the presence of 50 mol % of 1 were performed in THF at 20
°C for 0.5 h under an argon atmosphere (Table 1). The 1a-
Table 1. Homocoupling Reaction of PhMgBr (2a) Using
a
Perfluorocyclopentene Derivatives
oxidant
yield
b
LUMO
c
entry
ArF of oxidant
F (1a)
(mol %)
(%)
(eV)
1
2
3
4
5
6
50
50
50
50
50
50
50
25
10
33
0
−2.07
−2.31
−3.07
−3.09
−3.31
−3.46
Ph (1b)
3,4,5-F3-C6H2 (1c)
32
23
58
82
99
99
37
C6F5 (1d)
a
3,5-(CF3)2-C6H3 (1e)
Table 2. 1f-Catalyzed Homocoupling of 2a
4-CF3-C6F4 (1f)
d
7
de
,
1f
1f
1f
8
9
df
,
b
entry
catalyst (mol %)
temp (°C)
time (h)
yield (%)
a
All reactions were carried out using 0.50 mmol of 2a (1.0 M THF
1
2
3
10
10
10
5
25
50
50
50
60
6
84
93
96
87
76
solution, which was titrated with 1,10-phenanthroline and i-PrOH)
b
6
purchased from Aldrich, and 0.25 mmol of 1 for 30 min. Isolated
c
12
yields. LUMO energy levels were calculated at the B3LYP/6-31+g(d)
c
d
e
f
4
d
24
level. For 1 h. 0.125 mmol of 1f. 0.05 mmol of 1f.
5
2
3 days
a
All reactions were carried out using 1.0 mmol of 2a (1.0 M THF
solution, which was titrated with 1,10-phenanthroline and i-PrOH)
mediated reaction of 2a produced a homocoupled biphenyl
(3a) product (33%) and a substitution product from 1a, 1-
phenyl-perfluorocyclopentene (10%) (entry 1).8 The reaction
using the phenyl-substituted 1b did not proceed (entry 2). In
contrast, the reactions in the presence of novel organic oxidants
bearing ArF (1c−1f) afforded 3a (entries 3−6) without any
substitution products. In particular, the heptafluorotolyl-
substituted 1f exhibited a good oxidizing capacity (entry 6).
The performances of these organic oxidants 1 were roughly
proportional to their LUMO levels, which indicated that the
strong electron-withdrawing effect of ArF at the vinylic position
increased their oxidizing capabilities. The reaction of 2a with 50
mol % of 1f for 1 h proceeded almost to completion (entry 7).
After the reaction, roughly half of 1f remained in the reaction
solution.9 When the reaction was performed with 25 mol % of
1f for 1 h, the product 3a was obtained almost quantitatively
(entry 8) and 1f was not observed in the reaction solution.9 A
reaction that used 10 mol % of 1f for 1 h gave the product 3a
(entry 9) with a ca. 40% yield (37%). Based on these results, we
have concluded that 1f behaves as a novel four-electron oxidant.
To the best of our knowledge, this is the first example of an
organic four-electron oxidant. However, the experimental
results indicate that the stoichiometric amount of 1f cannot
be reduced to less than 25 mol %.
b
c
purchased from Aldrich, and 0.1 mmol of 1f. Isolated yields. 0.05
d
mmol of 1f. 0.02 mmol of 1f.
the presence of 10 mol % of 1f at 25 °C in dry air gave 3a with
an 84% yield after 6 h (entry 1). The yield of 3a increased to
93% when the reaction temperature was increased to 50 °C
(entry 2). Increasing the reaction time also slightly improved
the yield of 3a to 96% (entry 3). When the catalyst loading was
reduced to 5 mol % for 24 h or 2 mol % for 3 days, 3a was
obtained with an 87% or a 76% yield, respectively (entries 4, 5).
To the best of our knowledge, this is the first successful
example of an organocatalyzed homocoupling of a Grignard
reagent with atmospheric oxygen.
The mechanism of the redox process of 1f was considered.
After the stoichiometric homocoupling of 100 mol % 2a using
25 mol % 1f under argon, the trifluorocyclopentadienyl anion
410 was observed as the principal fluorine component in a dark
greenish brown solution by 19F NMR under argon (Figure 3,
NMR1, ○). Due to the loss of three fluorine atoms from 1f, it
is presumed that the anion 4 was produced from 1f through a
halide elimination process where the oxidant could readily
accept four electrons. A previous report11 has stated that the
−
The reactions of other Grignard reagents with 25 mol % of 1f
also proceeded smoothly under the same conditions (see the
Supporting Information).
metal salts of the perfluorocyclopentadienyl anion (C5F5 ) in
THF were unstable at temperatures that were greater than −30
°C. In contrast, the anion 4 with a Mg salt in THF at room
B
DOI: 10.1021/acs.orglett.5b02887
Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters
Letter
Figure 4. Initially, the stoichiometric homocoupling of the
Grignard reagent proceeds by four-electron oxidation with 1f,
followed by catalytic homocoupling with radical species 5
derived from 4 in the presence of atmospheric oxygen.
The catalytic homocoupling reactions of other Grignard
reagents were also performed (Table 3). The reactions of
a
Table 3. 1f-Catalyzed Homocoupling of 2
Figure 3. NMR study of redox process of 1f.
temperature showed stability under argon; however, it was very
unstable in air. As above-mentioned, the dark greenish brown
solution containing anion 4 immediately changed to a dark
purple color when it was exposed to the atmosphere. A 19F
NMR spectrum of the dark purple solution verified that 4 was
not present, based on the presence of broad signals, which
suggested that a radical species must be present within the
solution (NMR2). The presence of the organic radical species
was further confirmed by an ESR spectrum of the dark purple
solution under an argon atmosphere.12 When 50 mol % of 4-
tolyl-MgBr (2b) was added to the dark purple solution under
an argon atmosphere, the color turned dark brown and
produced a biaryl compound 3b with a 49% yield (12.3 mol
%).9 This indicated that the radical species oxidized 2b by
acting as a one-electron oxidant. In the dark brown solution, a
19F NMR spectrum showed that the anion 4 was present along
with an unknown species (NMR3). Based on these results, we
propose that the most viable candidate for the active catalytic
species is an organic radical species 5 (see Figure 4).13 The
unknown structure in NMR3 can be narrowed down to two
possible species: (1) an inactive species formed through the
breakdown of the active catalytic species or (2) another active
catalytic species such as an oligomeric derivative.
a
All reactions were carried out using 1.0 mmol of RMgX (2) THF
solution, which was titrated with 1,10-phenanthroline and i-PrOH, and
0.1 mmol of 1f for 6 h. Isolated yields. For 9 h. For 12 h. Et2O
solution of Grignard reagent was used.
b
c
d
e
ArMgX (2b−2g) or phenylvinylmagnesium bromide (2h) in
the presence of 10 mol % of 1f gave C(sp2)−C(sp2) coupled
products (3b−3h) in high yields (89%−92%, entries 1−7). The
reaction of BnMgBr (2i) also gave a C(sp3)−C(sp3) coupled
product (3i) with a high yield (91%, entry 8).
In the 1f-catalyzed homocoupling reactions, atmospheric
oxygen was used as an inexpensive and environmentally
friendly source to renew the catalytic species. Therefore, the
additional co-oxidant, which was typically used in TEMPO-
mediated oxidation reactions,1a was not required. Even for
transition-metal-catalyzed homocoupling of Grignard reagents,
there have not been many examples using atmospheric
oxygen,4l−q and many reactions required a stoichiometric
amount of a terminal organic oxidant.4a−k Furthermore, there is
still a great demand for other catalytic systems that employ
atmospheric oxygen, since catalytic aerobic-oxidation systems
can provide environmentally sustainable benefits.14 Therefore,
the design of a viable system that allows for organocatalyzed
C−C coupling reactions under atmospheric oxygen is highly
valuable for the scientific community.
Based on our results, a plausible mechanism for the redox
process of 1f through catalytic homocoupling is shown in
Figure 4. Plausible reaction pathway of the catalytic homocoupling
using 1f.
C
DOI: 10.1021/acs.orglett.5b02887
Org. Lett. XXXX, XXX, XXX−XXX

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(i) Kiefer, G.; Jeanbourquin, L.; Severin, K. Angew. Chem., Int. Ed.
2013, 52, 6302. Diaziridinone as an oxidant: (j) Zhu, Y.; Xiong, T.;
Han, W.; Shi, Y. Org. Lett. 2014, 16, 6144. Pure O2 as an oxidant:
(k) Hua, S.-K.; Hu, Q.-P.; Ren, J.; Zeng, B.-B. Synthesis 2013, 45, 518.
Atmospheric oxygen as an oxidant: (l) Cahiez, G.; Moyeux, A.;
Buendia, J.; Duplais, C. J. Am. Chem. Soc. 2007, 129, 13788. (m) Liu,
W.; Lei, A. Tetrahedron Lett. 2008, 49, 610. (n) Mayer, M.; Czaplik, W.
M.; von Wangelin, A. J. Synlett 2009, 2009, 2919. (o) Aparna, P. I.;
Bhat, B. R. J. Mol. Catal. A: Chem. 2012, 358, 73. (p) Bhat, A. P. I.;
Inam, F.; Bhat, B. R. Eur. J. Org. Chem. 2013, 2013, 7139. (q) Bhat, A.
P. I.; Inam, F.; Bhat, B. R. RSC Adv. 2013, 3, 22191.
In summary, we have developed a novel organic oxidant 1f
that acts as a four-electron oxidant for the homocoupling of
Grignard reagents. A low catalyst loading of up to 2 mol % of 1f
can also be used for catalytic homocoupling reactions in air to
give the desired coupled products in high yields. We envision
that 1f will be highly utilized in the future toward a variety of
oxidative C−C coupling reactions or the oxidation of organic
substrates with atmospheric oxygen.
ASSOCIATED CONTENT
* Supporting Information
■
(5) Recent reviews: (a) Cahiez, G.; Moyeux, A.; Cossy, J. Adv. Synth.
Catal. 2015, 357, 1983. (b) Li-Yuan Bao, R.; Zhao, R.; Shi, L. Chem.
Commun. 2015, 51, 6884. (c) Knappke, C.E. I.; von Wangelin, A. J.
Chem. Soc. Rev. 2011, 40, 4948.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02887.
(6) Detailed mechanistic studies: Murarka, S.; Mobus, J.; Erker, G.;
̈
Muck-Lichtenfeld, C.; Studer, A. Org. Biomol. Chem. 2015, 13, 2762.
(7) Irie, M. Chem. Rev. 2000, 100, 1685.
̈
Representative experimental procedure, spectroscopic
data for novel oxidants 1c, 1d, 1e, 1f and coupling
products 3; Tables for stoichiometric homocoupling
reactions using 1f; Cartesian coordinates of 1, 4, and 5;
Consideration of the structures of 4 and 5 using 19F
NMR and GIAO calculations (PDF)
(8) Reactivity of 1a with Grignard reagents: Yamada, S.; Konno, T.;
Ishihara, T.; Yamanaka, H. J. Fluorine Chem. 2005, 126, 125.
(9) GC analysis.
(10) The structure of 4 was identified by comparison of calculated
19F chemical shifts at the GIAO/B3LYP/6-31+G(2d,p) level and
observed chemical shift. See the Supporting Information.
(11) Paprott, G.; Seppelt, K. J. Am. Chem. Soc. 1984, 106, 4060.
(12) In the ESR spectrum, a broad singlet peak at the position of g =
2.00309 was observed at room temperature, which is evidence of the
presence of a radical in the THF solution. The radical can be expected
to be the cyclopentadienyl radical 5 generated by one-electron
oxidation of the cyclopentadienyl anion 4, considering the g-value is in
good agreement with those of the cyclopentadienyl radical species
reported previously. See references: (a) Sitzmann, H.; Boese, R.
Angew. Chem., Int. Ed. Engl. 1991, 30, 971. (b) Tian, Y.; Uchida, K.;
Kurata, H.; Hirao, Y.; Nishiuchi, T.; Kubo, T. J. Am. Chem. Soc. 2014,
136, 12784.
(13) The present structure 5 was also predicted by comparison of
calculated 19F chemical shifts (NMR2, ●) at the GIAO/uB3LYP/6-
31+G(2d,p) level and observed chemical shift. See the Supporting
Information.
(14) (a) Stahl, S. S. Science 2005, 309, 1824. (b) McCann, S. D.;
Stahl, S. S. Acc. Chem. Res. 2015, 48, 1756 and references cited therein.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: korenaga@iwate-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from MEXT, Japan and
the Asahi Glass Foundation. We thank Zeon Corporation for
providing 1a and CPME.
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DOI: 10.1021/acs.orglett.5b02887
Org. Lett. XXXX, XXX, XXX−XXX