Nickel-Catalyzed Alkyl-Alkyl Cross-Couplings of Fluorinated Secondary Electrophiles: A General Approach to the Synthesis of Compounds having a Perfluoroalkyl Substituent

Article abstract of DOI:10.1002/anie.201503297

Fluorinated organic molecules are of interest in fields ranging from medicinal chemistry to polymer science. Described herein is a mild, convenient, and versatile method for the synthesis of compounds bearing a perfluoroalkyl group attached to a tertiary carbon atom by using an alkyl-alkyl cross-coupling. A nickel catalyst derived from NiCl₂ glyme and a pybox ligand achieves the coupling of a wide range of fluorinated alkyl halides with alkylzinc reagents at room temperature. A broad array of functional groups is compatible with the reaction conditions, and highly selective couplings can be achieved on the basis of differing levels of fluorination. A mechanistic investigation has established that the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) inhibits cross-coupling under these conditions and that a TEMPO-electrophile adduct can be isolated.

Full text of DOI:10.1002/anie.201503297

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Chemie
International Edition: DOI: 10.1002/anie.201503297
German Edition: DOI: 10.1002/ange.201503297
Homogeneous Catalysis
Hot Paper
Nickel-Catalyzed Alkyl–Alkyl Cross-Couplings of Fluorinated
Secondary Electrophiles: A General Approach to the Synthesis of
Compounds having a Perfluoroalkyl Substituent**
Yufan Liang and Gregory C. Fu*
Abstract: Fluorinated organic molecules are of interest in
fields ranging from medicinal chemistry to polymer science.
Described herein is a mild, convenient, and versatile method
for the synthesis of compounds bearing a perfluoroalkyl group
attached to a tertiary carbon atom by using an alkyl–alkyl
cross-coupling. A nickel catalyst derived from NiCl2·glyme and
a pybox ligand achieves the coupling of a wide range of
fluorinated alkyl halides with alkylzinc reagents at room
temperature. A broad array of functional groups is compatible
with the reaction conditions, and highly selective couplings can
be achieved on the basis of differing levels of fluorination. A
mechanistic investigation has established that the presence of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) inhibits cross-
coupling under these conditions and that a TEMPO–electro-
phile adduct can be isolated.
of stoichiometric cross-couplings of fluorinated nucleophiles
with alkyl electrophiles, catalyzed processes have been
limited to activated electrophiles (e.g., allylic, benzylic, and
propargylic).[8]
To the best of our knowledge, an alternative strategy in
which a secondary alkyl electrophile, which includes a per-
fluoroalkyl substituent, is cross-coupled with an alkylmetal
reagent [Eq. (1); pathway B] has not been described,[9]
perhaps because of the deleterious effect of the perfluoro-
alkyl group at one or more stages in the catalytic cycle.[10,11] In
this report, we provide a method that accomplishes this
transformation with secondary alkyl halides bearing a variety
of perfluoroalkyl substituents [Eq. (2); DMA = N,N-dime-
thylacetamide].
B
ecause fluorinated organic compounds exhibit different
properties, including different biological activities, when
compared with their nonfluorinated counterparts, interest in
the synthesis of fluorinated molecules has increased rapidly in
recent years.[1] Whereas impressive progress has been de-
scribed in the development of general strategies for the
À
preparation of fluorinated aromatic compounds (e.g., Ar F
[2,3]
À
and Ar CF3),
current approaches to the synthesis of
À
molecules which include a Csp3 RF bond (RF = a perfluoro-
Because of their ready accessibility and their high func-
tional-group compatibility, alkylzinc reagents are attractive
partners for cross-coupling processes.[12] Several years ago, we
reported a nickel/pybox-based method for coupling unacti-
vated secondary alkyl bromides with alkylzinc reagents in
good yield [Eq. (3); cod = 1,5-cyclooctadiene].[13] When we
applied these conditions to the cross-coupling of an alkyl
bromide bearing a perfluoroalkyl substituent, we obtained
a low yield of the desired product [8%; Eq. (4)]. Debromo-
defluorination (-BrF)[14] and hydrodebromination of the
electrophile were significant side reactions.
alkyl group) are generally narrow in scope.[3b, 4]
For target compounds wherein a perfluoroalkyl group is
attached to an sp3-hybridized tertiary carbon atom,[5,6] alkyl–
alkyl cross-coupling with a perfluorinated nucleophile (M-RF)
represents a potentially attractive and versatile approach
[Eq. (1); pathway A].[7] Although there are scattered reports
[*] Y. Liang, Prof. G. C. Fu
Division of Chemistry and Chemical Engineering
California Institute of Technology
Pasadena, CA 91125 (USA)
E-mail: gcfu@caltech.edu
[**] Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences: R01-GM62871)
and the Gordon and Betty Moore Foundation (Caltech Center for
Catalysis and Chemical Synthesis). We thank Dr. Nathan D. Schley
for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201503297.
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Table 1: Alkyl–alkyl cross-coupling of a fluorinated secondary electro-
Table 2: Alkyl–alkyl cross-couplings of fluorinated secondary electro-
phile: Effect of reaction parameters.[a]
philes: Scope.[a]
Entry
R1
R2
Yield [%][b]
Entry
Variation from the “standard” conditions
Yield [%][b]
1
2
CH2CH2Ph
CH2CH2Ph
74
55
1
2
3
4
5
6
7
8
none
no NaBr
79
28
75
66
61
74
59
66
27
5
LiBr, instead of NaBr
KBr, instead of NaBr
CsBr, instead of NaBr
(nBu)4NBr, instead of NaBr
NaI, instead of NaBr
NaCl, instead of NaBr
NaF, instead of NaBr
3, instead of 1
4, instead of 1
5, instead of 1
6, instead of 1
7, instead of 1
3
4
5
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
61
59
66
9
10
11
12
13
14
15
16
17
18
19
20
21
22
6
CH2CH2Ph
CH2CH2Ph
70
<1
7
7
8
77
64
17
<1
79
60
72
75
71
64
<1
49
[a] All data are the average of two experiments. [b] Yield of purified
product.
+0.1 equiv H2O
under air in a closed vial
408C, instead of RT
08C, instead of RT
1.0 equiv of organozinc reagent
5.0 mol% NiCl2·glyme, 5.5 mol% 1
no NiCl2·glyme
1 are both commercially available and can be handled in the
air.
The scope of this new alkyl–alkyl cross-coupling process is
fairly broad (Table 2).[17] Thus, functional groups such as an
ether, an acetal, an alkyne, an ester, a phosphonate, a nitrile,
and a primary alkyl chloride are compatible with the reaction
conditions. Electrophiles which bear higher order perfluoro-
alkyl substituents are also suitable coupling partners
(Table 3).
no 1
[a] All data are the average of two experiments. [b] The yields were
determined by 19F NMR spectroscopy with the aid of an internal
standard.
This method is not limited to cross-couplings of alkyl
bromides. Thus, under the same reaction conditions, the
Negishi reaction of a fluorinated alkyl iodide proceeds in
fairly good yield [Eq. (5)].[18]
Among perfluoroalkyl groups, trifluoromethyl (CF3) is
the most commonly encountered, and considerable effort has
Nevertheless, by modifying the reaction conditions, we
can achieve the desired alkyl–alkyl cross-coupling of a fluo-
rinated secondary electrophile in good yield (Table 1,
entry 1). The presence of the bromide ion is particularly
helpful, with NaBr being the most useful source among those
that we have examined (entries 1–6).[15] The addition of either
NaI or NaCl also has a substantial beneficial effect (entries 7
and 8), whereas NaF does not (entry 9). A variety of other
ligands, both tridentate and bidentate, furnish significantly
lower yields compared with that obtained with the pybox
ligand 1 (entries 10–14).[16] The optimized method is not
affected by the presence of a small amount of water (entry 15)
and is only modestly sensitive to air (entry 16). Changes in
temperature (0–408C), as well as the use of a smaller amount
of the nucleophile (1.0 equiv), lead to only a small loss in
coupling efficiency (entries 17–19). Cutting the catalyst load-
ing in half results in a moderate decrease in yield (entry 20).
In the absence of NiCl2·glyme, essentially no product is
formed (entry 21), whereas, in the absence of the ligand,
cross-coupling is less efficient (entry 22). NiCl2·glyme and
Table 3: Alkyl–alkyl cross-couplings of fluorinated secondary electro-
philes: Scope with respect to the perfluoroalkyl group.[a]
Entry
RF
R
Yield [%][b]
1
2
nC3F7
nC3F7
65
54
3
nC3F7
51
4
5
nC3F7
nC4F9
69
67
6
nC4F9
54
7
8
nC4F9
69
66
nC9F19
[a] All data are the average of two experiments. [b] Yield of purified
product.
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Table 5: Alkyl–alkyl cross-couplings to generate trifluoromethyl-substi-
tuted products: Scope with respect to the electrophile.[a]
therefore been dedicated to the development of approaches
to the synthesis of various scaffolds that bear this substi-
tuent.[3b, 4] Although some progress has been described in the
generation of targets which include a trifluoromethyl group
attached to a tertiary carbon atom, there is still a need for
a general method that proceeds in good yield.[3b, 4,19] As
illustrated in Tables 4 and 5,[20] our cross-coupling conditions
Entry
R
Yield [%][b]
1
86
79
76
72
2
3
4[c]
5
83
Table 4: Alkyl–alkyl cross-couplings to generate trifluoromethyl-substi-
6[c]
7
81
80
tuted products: Scope with respect to the nucleophile.[a]
Yield [%][b]
8
86
Entry
R
1
2
3
79
78
83
[a] All data are the average of two experiments. [b] Yield of purified
product. [c] Nucleophile: BrZnCH2CH2CH2CN. Boc=tert-butoxycar-
bonyl, TBDPS=tert-butyldiphenylsilyl, Ts =4-toluenesulfonyl.
4
5
6
74
72
83
Table 6: Selective alkyl–alkyl cross-couplings based on fluorine substi-
tution.
7
8
67
83
9
89
[a] All data are the average of two experiments. [b] Yield of purified
product.
The yields and conversions were determined through analysis by
19F NMR spectroscopy and gas chromatography with the aid of internal
standards.
provide versatile access to such compounds and are compat-
ible with a wide array of functional groups (e.g., ether, acetal,
ester, alkyne, nitrile, phosphonate, primary alkyl bromide,
primary alkyl tosylate, furan, aryl iodide, carbamate, and
ketone). On a gram scale, in the presence of 5 mol%
NiCl2·glyme/5.5 mol% 1, the alkyl–alkyl Negishi coupling
depicted in entry 8 of Table 4 proceeds in 80% yield (1.22 g of
product).
We have observed that, under our standard cross-coupling
conditions, replacement of the CF3 substituent of the electro-
phile with a CF2H group leads to a significantly slower
reaction. The enhanced reactivity of the CF3-substituted
electrophile enables unusual and highly selective Negishi
reactions in the presence of less fluorinated electrophiles
(Table 6).[21]
side product of this Negishi reaction is a TEMPO-electrophile
adduct [Eq. (7)], potentially generated from the coupling of
TEMPO with an alkyl radical.[24]
In conclusion, we have developed a mild and simple
nickel-catalyzed cross-coupling method for synthesizing
a broad array of compounds which include a tertiary carbon
atom bearing a perfluoroalkyl substituent, thereby providing
For the array of nickel-catalyzed cross-couplings of alkyl
halides that we have developed, we have suggested that the
electrophile may react to furnish an alkyl radical during the
oxidative-addition step of the catalytic cycle.[22] For the
present method, we have determined that the addition of
2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO)[23] substan-
tially inhibits carbon–carbon bond formation [Eq. (6)]. A
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nina, W. W. Brennessel, J. L. Miller, D. A. Vicic, Organometallics
2008, 27, 3933 – 3938.
a general approach to the synthesis of this family of target
molecules. Awide variety of functional groups are compatible
with the reaction conditions, and the catalyst components are
commercially available. The rate of cross-coupling is remark-
ably sensitive to the level of fluorination of the electrophile,
and enables the unusual and highly selective reaction of
a substrate which bears a CF3 group in the presence of the
corresponding CF2H-substituted compound. In a mechanistic
study, we have established that the presence of TEMPO,
a radical trap, inhibits carbon–carbon bond formation, and we
have isolated a TEMPO-electrophile adduct. Additional
studies of nickel-catalyzed cross-couplings of alkyl electro-
philes are underway.
[8] a) T. Kitazume, N. Ishikawa, J. Am. Chem. Soc. 1985, 107, 5186 –
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[9] Indeed, we are not aware of any previous reports of metal-
catalyzed alkyl–alkyl cross-couplings of electrophiles (primary,
secondary, or tertiary) which include a perfluoroalkyl substitu-
ent. Successful reactions to date have been limited to couplings
of aryl, alkenyl, and alkynyl nucleophiles with primary alkyl
electrophiles that bear a CF3 group (specifically, trifluoroethyl
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L. Qing, Organometallics 2012, 31, 1578 – 1582.
Keywords: cross-coupling · fluorine · homogeneous catalysis ·
nickel · zinc
How to cite: Angew. Chem. Int. Ed. 2015, 54, 9047–9051
Angew. Chem. 2015, 127, 9175–9179
[1] For examples of recent monographs which include leading
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À
[2] For Ar F, see: a) D. A. Watson, M. Su, G. Teverovskiy, Y.
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À
[3] For Ar CF3, see: a) E. J. Cho, T. D. Senecal, T. Kinzel, Y. Zhang,
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b) C. Alonso, E. Martínez de Marigorta, G. Rubiales, F. Palacios,
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[17] Notes: a) Under our standard reaction conditions, the cross-
À
coupling product is stable (e.g., no C F bond cleavage is
observed), and a secondary alkylzinc reagent (cyclopentyl-
ZnBr) was not a suitable coupling partner; b) The cross-coupling
illustrated in entry 3 of Table 2 proceeds with 28% ee.
[18] Under our standard reaction conditions, the corresponding
secondary alkyl chloride and secondary alkyl tosylate are not
suitable substrates.
pounds which contain a perfluoroalkyl group, see: E. Prchalovµ,
ˇ
˘
ˇ
O. Stepµnek, S. Smrcek, M. Kotora, Future Med. Chem. 2014, 6,
1201 – 1229.
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40 mol% 3,4,7,8-tetramethyl-1,10-phenanthroline, 3 equiv AgF,
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G. C. Fu, J. Am. Chem. Soc. 2014, 136, 16588 – 16593.
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[24] Notes: a) After the TEMPO (15 mol%) has been consumed,
cross-coupling resumes; b) In the absence of NiCl2·glyme or of
the organozinc reagent, the adduct of TEMPO with the electro-
phile was not observed; c) Addition of the TEMPO-electrophile
adduct to a cross-coupling reaction does not inhibit carbon–
carbon bond formation; d) The TEMPO-electrophile adduct is
stable to the cross-coupling conditions.
[20] Under our standard reaction conditions: a) For the reaction
illustrated in entry 1 of Table 4, the corresponding alkyl iodide
couples in 57% yield, whereas the chloride and the tosylate are
ineffective cross-coupling partners; b) Debromodefluorination
is the predominant side reaction; c) An allylic, benzylic,
propargylic, and hindered (alkyl = Cy) electrophile, as well as
a secondary alkylzinc (cyclopentyl-ZnBr) and a perfluoroalkyl-
zinc reagent, were not suitable coupling partners; d) The cross-
coupling illustrated in entry 5 of Table 4 proceeds in 20% ee.
[21] Nevertheless, the cross-coupling of the difluoromethyl-substi-
tuted electrophile which is illustrated in Table 6 can be achieved
in good yield (70%) under related conditions (10 mol%
NiCl2·glyme, 11 mol% 1, 1 equiv KBr, DMA/DMF, RT). For
Received: April 11, 2015
Revised: May 3, 2015
Published online: June 12, 2015
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