Chlorotrifluoromethylation of Terminal Olefins by Atom Transfer-Type Radical Reaction Catalyzed by Cobalt Complexes

Article abstract of DOI:10.1002/ejoc.201900834

A cobalt porphyrin-catalyzed chlorotrifluoromethylation reaction of olefins is described. The use of CF₃SO₂Cl as the CF₃ radical source and a cobalt catalyst enabled the selective addition of CF₃ radicals under thermal conditions. Various functional groups such as esters and Ar–X moieties, which can be reactive with low valent transition metal catalysts, were well-tolerated in this catalytic process. A highly functionalized alkaloid derivative was also tolerated as a substrate. As a demonstration of the bio-inspired catalytic system, catalytic usage of vitamin B₁₂, which is the commercially available form of the natural cobalt porphyrinoid, was employed, and diastereoselective chlorotrifluoromethylation of the alkaloid molecule was achieved.

Full text of DOI:10.1002/ejoc.201900834

A Journal of
Accepted Article
Title: Chlorotrifluoromethylation of Terminal Olefins via Atom Transfer-
Type Radical Reaction Catalyzed by Cobalt Complexes
Authors: Kazuki Maeda, Takuya Kurahashi, and Seijiro Matsubara
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900834
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10.1002/ejoc.201900834
European Journal of Organic Chemistry
COMMUNICATION
Chlorotrifluoromethylation of Terminal Olefins via Atom Transfer-
Type Radical Reaction Catalyzed by Cobalt Complexes
Kazuki Maeda, Takuya Kurahashi,* and Seijiro Matsubara*
Dedicated to Professor Armin de Meijere on the occasion of his 80th birthday.
Abstract: A cobalt porphyrin-catalyzed chlorotrifluoromethylation
reaction of olefins is described. The use of CF3SO2Cl as the CF3
radical source and a cobalt catalyst enabled the selective addition of
CF3 radicals under thermal conditions. Various functional groups
such as esters and Ar-X moieties, which can be reactive with low
valent transition metal catalysts, were well-tolerated in this catalytic
for the thermal atom transfer radical trifluoromethylation reaction.
Highly coordinated square-planar cobalt(II) complexes, such as
cobalt(II) porphyrins or salens, are generally known to have
unpaired electron in the dz2 orbital. If the singly occupied orbital
of the paramagnetic low-spin cobalt center can interact with the
low-lying LUMO of the CF3-containing substrate, selective
generation of the CF3 radical might be achieved (Scheme
1(b)).[6] Even more advantageously, such a cobalt catalyst does
not possess reactive orbitals for side reactions, therefore,
generation and addition of the CF3 radical might proceed in a
chemoselective manner.
process.
A highly functionalized alkaloid derivative was also
tolerated as a substrate. As a demonstration of the bio-inspired
catalytic system, catalytic usage of vitamin B12, which is the
commercially available form of the natural cobalt porphyrinoid, was
employed, and diastereoselective chlorotrifluoromethylation of the
alkaloid molecule was achieved.
Introduction
Trifluoromethyl (CF3) groups are generally accepted as essential
functionality in pharmaceutical chemistry because of their
excellent anti-metabolic nature, electron negativity, membrane-
permeability, and other expedient characteristics.[1] For these
reasons, various methodologies which enable the introduction of
CF3 groups have been well established.[2] Among them,
utilization of CF3 radicals has been recognized as a powerful
strategy for trifluoromethylation reactions. For example,
MacMillan and co-workers demonstrated an elegant application
of
their
photoredox
technique
in
the
electrophilic
trifluoromethylation of electron-rich arenes.[3] After their
pioneering results, photo-induced generation of the CF3 free
radical has become common methodology for mild and
functional group-tolerant trifluoromethylative functionalization.[4]
In contrast, utilization of perfluoroalkyl radicals under thermal
conditions using olefins and perfluoroalkyl halides is an old yet
powerful methodology, and easier to apply in classical laboratory
and industrial processes. Both early and late low valent
transition metals are able to catalyze this type of
perfluoroalkylation reaction, known as an atom transfer radical
addition.[5] However, the low valent transition metal complexes
are potentially reactive toward various functional groups,
including the resulting carbon–halogen bond and the hydrogen
atom at the β-position (Scheme 1(a)). This could result in a lack
of chemoselectivity and could be problematic in the late stage
trifluoromethylation reaction.
Scheme 1. (a) Early transition metal-catalyzed atom transfer CF3 radical
addition, (b) Co(II) metalloradical for generation of CF3 radicals, and (c) the
envisaged catalytic cycle for the chlorotrifluoromethylation of olefins.
Results and Discussion
In the course of our trial, trifluoromethanesulfonyl chloride
(CF3SO2Cl), which was previously used for the Ru(II) catalyzed
chlorotrifluoromethylation of olefins,[7] was chosen as the highly
electron-deficient CF3 radical source. If the cobalt metalloradical
can interact with the low-lying LUMO of CF3SO2Cl, homolytic
abstraction of Cl might occur, and the CF3 radical should be
generated after the pyrolytic release of SO2 gas (Scheme 1(c)).
Pleasingly, when 5 mol % of cobalt(II) porphyrin, CoTPP (TPP:
5,10,15,20-tetraphenylporphyrinato), was used as the catalyst in
the presence of olefin 1a and CF3SO2Cl, the desired
chlorotrifluoromethylated product 2a was obtained in 77% yield
(Table 1, entry 1). The use of the Jacobsen-type cobalt salen
Considering the above issues, we supposed that some types
of cobalt(II) complexes could be robust and selective catalysts
[*]
K. Maeda, Prof. Dr. T. Kurahashi, Prof. Dr. S. Matsubara
Department of Material Chemistry
Graduate School of Engineering, Kyoto University
Kyoto 615-8510, Japan
E-mail: maeda.kazuki.62x@st.kyoto-u.ac.jp,
kurahashi.takuya.2c@kyoto-u.ac.jp,
matsubara.seijiro.2e@kyoto-u.ac.jp
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900834
European Journal of Organic Chemistry
COMMUNICATION
the presence of CF3SO2Na, though some decomposition of the
Co salen complex under the reaction conditions diminished the
yield (entry 5). This clearly reflects the importance of having a
robust catalyst in this transformation. Co(acac)3 was not
effective for this reaction (entry 6). Some copper salts known to
be important for atom transfer radical addition reactions[9] and
other trifluoromethylative reactions[10] were also tested, however,
none of these gave better results (entry 7-9). It is noteworthy
that some by-products, likely derived from uncontrolled addition
of the CF3SO2 radical intermediates, were detected in the
reaction mixture of these copper-catalyzed reactions. This
emphasizes the efficient catalytic ability of the Co porphyrin in
controlling the generation and reactivity of the CF3 radicals. The
paramagnetic copper(II) porphyrin, CuTPP, afforded 2a in only
31% yield (entry 10). This indicates the importance of the redox
viability of the cobalt porphyrin catalyst in this reaction.[11] The
combination of CoClTPP and CF3SO2Na was found to be a fairly
effective catalytic system to furnish the product in 92% isolated
yield even with only 1 mol % catalyst loading, although a
somewhat longer reaction time was needed (entry 11). Thus, the
combination of CoClTPP and CF3SO2Na was chosen as the
best catalyst.Additionally, vitamin B12 (commercially available
cyanocobalamin form) was tested as a Co(III) porphyrinoid
catalyst, and cleanly gave 2a in 70% yield (entry 12). The
catalytic use of cobalamin is well known in single-electron
catalysis,[12] however, preactivation of the catalysts to the Co(I)
species was commonly needed. In this transformation, no such
highly reductive condition was required. Thus, this result might
expand the utility of the cobalamins as environmentally friendly
catalysts.
Table 1. Optimization of the chlorotrifluoromethylation of 1a.[a]
entry
1
catalyst (loading)
time
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
12 h
conv.[b]
95%
64%
28%
90%
66%
22%
69%
31%
84%
39%
>99%
yield[b]
77%
48%
21%
85%
63%
28%
39%
28%
48%
31%
CoTPP (5 mol %)
2
(R,R)-Cosalen* (5 mol %)
Co(acac)2 (5 mol %)
CoClTPP (5 mol %)[c]
(R,R)-CoClsalen* (5 mol %)[c]
Co(acac)3 (5 mol %)[c]
CuI (5 mol %)[c]
3
4
5
6
7
8
[Cu(bathophen)2]Cl (5 mol %)[c]
CuCl2 (5 mol %)[c]
9
10
11
CuTPP (5 mol %)[c]
CoClTPP (1 mol %)[c]
92%
(92%)
12
vitamin B12 (5 mol %)[c]
4 h
80%
70%
[a] The reactions were conducted with 1a (0.1 mmol), CF3SO2Cl (0.4
mmol), CF3SO2Na (10 µmol), and catalyst (1 or 5 µmol) in MeCN (1 mL) at
100 °C for the indicated time under a N2 gas atmosphere. [b] Determined
by 1H NMR using Bn2O as an internal standard. Differences between the
conversion and the yield might be due to an analytical error. The isolated
yield is shown in parenthesis. [c] 10 µmol (10 mol % to 1a) of CF3SO2Na
was used as an additive. TPP = 5,10,15,20-tetraphenylporphyrinato, salen*
= (1R,2R)-N,N-bis(3,5-di-tert-butylsalicylidene)cyclohexanediamine, acac =
pentane-2,4-dionato, bathophen = 2,9-diphenyl-1,10-phenanthroline
complex in place of the porphyrin also succeeded, though the
yield was lower (48%, entry 2). The acetylacetonate salt of Co(II)
and other cobalt salts failed to achieve good yields (entry 3; see
Supporting Information for details). Further modification of the
reaction conditions revealed that the combination of the Co(III)
porphyrin, which can be easily prepared by air-oxidation of Co(II)
complexes, and CF3SO2Na (Langlois’ salts) as catalysts gave
better yields (85%, entry 4).[8] Note these reactions proceeded
well in the absence of light (see Supporting Information),
indicating that the catalysis proceeds via a fully thermal reaction
pathway. The Co(III) salen complex also gives the products in
Scheme 2. Catalytic chlorotrifluoromethylation of terminal olefins catalyzed
by Co(III) porphyrin.[a] [a] The reactions were conducted with 1a (1 eq),
CF3SO2Cl (4 eq), CF3SO2Na (10 mol %), and catalyst in MeCN (0.1 M) at
100 °C under a N2 gas atmosphere. The isolated yield is shown. The NMR
yield, determined by using Bn2O as an internal standard, is shown in
parentheses. [b] Catalyst (1 mol %), 12 h. [c] Catalyst (5 mol %), 6 h. [d]
Catalyst (5 mol %), 24 h. [e] Catalyst (5 mol %), in 1,2-dichloroethane, 36 h
[f] The diastereomeric ratio was determined by 19F NMR.
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10.1002/ejoc.201900834
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COMMUNICATION
To exemplify the usability of this cobalt-catalyzed protocol,
functional group tolerance of the trifluoromethylation reaction
was briefly tested (Scheme 2). A fully aliphatic olefin, 1b,
quantitatively gave product 2b, and olefin 1c was transformed to
desired product 2c.[13] A protected allyl phenol derivative, which
is easily and readily accessible from substituted phenol, could
also be used in the reaction, and 2d was obtained in good yields.
The reaction with protected allyl alcohol 1e smoothly afforded 2e.
Despite the fact that this reaction might occur via electrophilic
addition of the CF3 radical equivalents to the olefins, electron
deficient olefins and styrene type substrates 1f and 1g could be
used in this transformation with extended reaction time (6-12 h).
Importantly, no substitution product at the Ar–Br moiety, which
could be produced in a reaction with the poorly coordinated low
valent transition metal catalysts,[10] was observed in this cobalt
porphyrin-catalyzed system with 1g. A substrate which contains
an amine moiety was pleasingly compatible and gave 2h in 72%
yield. As a demonstration of the utility of this catalysis, complex
molecules directly relevant to bioactive compounds were also
examined, and cinchona alkaloid-derived 1i could be converted
to 2i in satisfying yields.
the outer sphere of the catalyst. This might open opportunities
for establishing regio-, stereo-, and position-selective atom
transfer-type transformations.
Conclusions
In summary, the cobalt porphyrin catalyst enabled chloro-
trifluoromethylation of variously substituted olefins via a fully
thermal process. This functional group-tolerant atom transfer
radical reaction was achieved by use of a higher valent cobalt
catalyst. Additionally, the preliminary trials suggest the possibility
of stereoselective trifluoromethylation, which is especially
essential for pharmaceutical applications. Development of other
trifluoromethylative functionalization utilizing this catalytic system
is ongoing in our laboratory.
Acknowledgements
This work was supported by ACT-C from the JST (Japan) and
Grants-in-Aid for Scientific Research (Nos. 18H04253,
17KT0006, 15H05845 and 15H03809) from MEXT (Japan). T.K.
acknowledges the Asahi Glass Foundation. K.M. acknowledges
the Council of Human Resources Fostering Program in
Chemistry, Japan Chemical Industry Association (JCIA).
Table 2. Diastereoselective chlorotrifluoromethylation of 1i.[a]
Keywords: atom transfer • cobalt catalysis • trifluoromethylation
[1]
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V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320–330; b) W. K.
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[2]
[3]
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entry
1[c]
2
catalyst (loading)
time
48 h
24 h
24 h
48 h
dr[b]
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Soc. 2009, 131, 10875–10877; b) D. A. Nagib, D. W. C. MacMillan,
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CoClTPP (5 mol %)
1.4:1
1.8:1
1.4:1
6.4:1
(R,R)-CoClsalen* (10 mol %)
(S,S)-CoClsalen* (10 mol %)
vitamin B12 (5 mol %)
[4]
For selected reports for utilization of CF3 radical with photo-redox
catalysts, see: a) C.-J. Wallentin, J. D. Nguyen, P. Finkbeiner, C. R. J.
Stephenson, J. Am. Chem. Soc. 2012, 134, 8875–8884; b) X.-J. Tang,
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7108. e) Y. Cheng, C. Mück-Lichtenfeld, A. Sturder, J. Am. Chem.
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CF3 radicals, see; A. Studer, Angew. Chem., Int. Ed. 2012, 51, 8950–
8958.
3
4
[a] The reactions were conducted with 1h (0.05 mmol), CF3SO2Cl (0.5 mmol),
CF3SO2Na (5 µmol), and catalyst (5 µmol) in MeCN (0.5 mL) at 100 °C for the
indicated time under a N2 gas atmosphere. [b] Determined by NMR. [c] An
identical result is shown in Table 1, entry 12.
Considering the result obtained with vitamin B12 catalysis
(Table 1, entry 12), the possibility of stereoselective chloro-
trifluoromethylation was examined (Table 2). Generally, dual
functionalization of olefins by the atom transfer radical reaction
have faced poor stereoselectivity because of the difficulty in
controlling the reactivity around the catalytically active center.[14]
Indeed, when 1i was used as the substrate, both the Co(III)
porphyrin and salen complexes resulted in low selectivity
(entries 1-3). A greater selectivity, 6.4:1, was observed when
vitamin B12 was used as the catalyst (entry 4). This sharp
contrast clearly supports the possibility of the cobalt center
contributing to C–Cl bond forming events and the existence of a
secondary electrostatic interaction between the substrate and
[5]
[6]
For selected examples, see: a) T. Fuchikami, I. Ojima, Tetrahedron Lett.
1984, 25, 303–306; b) Q.-Y. Chen, Z.-Y. Yang, C.-X. Zhao, Z.-M. Qiu, J.
Chem. Soc., Perkin Trans. 1 1988, 563–567.
For selected recent examples of utilization of the radical reactivity of
Co(II) in catalysis, see: a) Y. Xiong, G. Zhang, J. Am. Chem. Soc. 2018,
140, 2735−2738. b) J. L. M. Matos, S. Vásquez-Céspedes, J. Gu, T.
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[7]
Under thermal conditions: a) N. Kamigata, T. Fukushima, M. Yoshida, J.
Chem. Soc., Chem. Commun. 1989, 1559–1560. b) N. Kamigata, T.
Fukushima, Y. Terakawa, M. Yoshida, H. Sawada, J. Chem. Soc.,
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Fluorine Chem. 2018, 215, 25–31. With photo-redox catalysts: d) S. H.
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European Journal of Organic Chemistry
COMMUNICATION
Oh, Y. R. Malpani, N. Ha, Y-S. Jung, S. B. Han, Org. Lett. 2014, 16,
1310–1313. e) H. S. Han, Y. J. Lee, Y. S. Jung, S. B. Han, Org. Lett.
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Angew. Chem. 2011, 123, 7797–7801.
[12] Experimental values for the first oxidation potential of some types of the
cobalt porphyrin and the copper porphyrin were 0.111 V and 0.463 V
(vs ferrocene/ferrocenium redox potential), respectively, as determined
by differential pulse voltammetry. Additionally, in the case of the cobalt
porphyrins, oxidation occurs at the cobalt center (generating Co(III)
porphyrin). The first oxidation of the copper porphyrin, in contrast,
occurs at the porphyrin ligand.
[8]
[9]
B. R. Langlois, E. Laurent, N. Roidot, Tetrahedron. Lett. 1991, 32
7525–7528.
The improved results obtained by the use of the Co(III) complex and
CF3SO2Na were possibly due to better solubility of the Co complex in
MeCN. In fact, CoTPP and CoClTPP are sparsely soluble in MeCN
even at elevated temperature. In contrast, the sulfinate complex
Co(SO2CF3)TPP is fairly soluble in MeCN at room temperature (CCDC
1905720, 1905721). This might help the reaction proceed efficiently.
The polar solvent MeCN was required for chemoselective formation of
the chlorotrifluoromethylated products. It should be noted that no
products via intermolecular reaction between the olefin substrates and
Co(SO2CF3)TPP were observed. Therefore, the catalytically active
species might be in situ generated Co(II) porphyrins (see Supporting
Information).
[13] For selected reviews on cobalamin catalysis, see: a) R. Scheffold, S.
Abrecht, R. Orlinski, H.-R. Ruf, P. Stamouli, O. Tinembart, L. Walder, C.
Weymuth, Pure & AppI. Chem. 1987, 59, 363–372; b) M. Giedyk, K.
Goliszewska, D. Gryko, Chem. Soc. Rev., 2015, 44, 3391–3404; c) H.
Shimakoshi, Y. Hisaeda, ChemPlusChem 2017, 82, 18–29; d) K.
Tahara, L. Pan, T. Ono, Y. Hisaeda, Beilstein J. Org. Chem. 2018, 14,
2553–2567. Very recently, cobalamin-mediated CF3 radical transfer
was also described: T. Ono, K. Wakiya, Md. J. Hossain, H. Shimakoshi,
Y. Hisaeda. Chem. Lett. 2018, 47, 979–981.
[14] The yields determined from the amount of the isolated products were
lower due to the high volatility of the products. Product 2c in particular
might be even evaporate during the work-up process.
[10] For selected reviews on atom transfer radical polymerization catalyzed
by copper(I), see: a) T. Pintauer, K. Matyjaszewski, Chem. Soc. Rev.
2008, 37, 1087–1097; b) N.V. Tsarevsky, Isr. J. Chem. 2012, 52, 276–
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Ready, Angew. Chem. Int. Ed. 2017, 56, 8780–8784; Angew. Chem.
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION (Chlorotrifluoromethylation)
Kazuki Maeda, Takuya Kurahashi,* and
Seijiro Matsubara*
Page No. – Page No.
Chlorotrifluoromethylation of
Terminal Olefins via Atom Transfer-
Type Radical Reaction Catalyzed by
Cobalt Complexes
A
cobalt porphyrin-catalyzed chlorotrifluoromethylation reaction of olefins is
described. The use of CF3SO2Cl as the CF3 radical source and a cobalt catalyst
enabled the selective addition of CF3 radicals under thermal conditions.
This article is protected by copyright. All rights reserved.