Copper(I)-catalyzed stereoselective defluoroborylation of aliphatic gem-difluoroalkenes

Article abstract of DOI:10.1246/cl.180656

This study reports a method for the stereoselective copper(I)catalyzed defluoroborylation of aliphatic gem-difluoroalkenes to afford (Z)-monofluoro-substituted borylalkenes. Gem-difluoro-alkenes bearing a variety of functional groups were efficiently borylated with high stereoselectivity. A theoretical study of the reaction mechanism is also described.

Full text of DOI:10.1246/cl.180656

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Copper(I)-Catalyzed Stereoselective Defluoroborylation of Aliphatic Gem-Difluoroalkenes
Hajime Ito,* Tamae Seo, Ryoto Kojima, and Koji Kubota
Advance Publication on the web August 22, 2018
doi:10.1246/cl.180656
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1
Copper(I)-Catalyzed Stereoselective Defluoroborylation of Aliphatic Gem-Difluoroalkenes
Hajime Ito*, Tamae Seo, Ryoto Kojima, and Koji Kubota
1Division of Applied Chemistry and Frontier Chemistry Center, Faculty of Engineering,
Hokkaido University, Sapporo, Hokkaido 060-8628
E-mail: hajito@eng.hokudai.ac.jp
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7
This study reports a method for the stereoselective
50
copper(I)-catalyzed defluoroborylation of aliphatic gem-
difluoroalkenes to afford (Z)-monofluoro-substituted
borylalkenes. Gem-difluoroalkenes bearing a variety of
functional groups were efficiently borylated with high
stereoselectivity.
A theoretical study of the reaction
mechanism is also described.
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9
Keywords: Copper, Fluoroalkene, Borylation
10
Fluorine has distinctive properties, with the introduction
11 of a fluorine atom able to greatly alter the properties of
12 bioactive compounds.1–5 Of the many existing fluorinated
13 motifs, monofluoroalkenes are of particular interest,
14 especially in medicinal chemistry, because they have the
15 potential to act as amide bond isosteres and enol mimics.6
16 Therefore, the development of efficient and stereoselective
17 synthetic methods for preparing such organofluorine
18 compounds is highly desirable.
19
Organoboron compounds are widely recognized as
20 powerful building blocks in synthetic chemistry because they
21 can be readily applied to stereospecific functionalization.7–9
22 Consequently, monofluoro-substituted borylalkenes have
23 received considerable attention as useful intermediates for the
24 preparation of various monofluoroalkene derivatives through
25 a stereospecific boron functionalization process.10–12 In 2017,
26 Cao and coworkers reported the copper(I)-catalyzed
27 stereoselective synthesis of (Z)-monofluoro-substituted
28 borylalkenes using a diboron compound and aromatic gem-
29 difluoroalkenes via a -fluoroelimination process (Scheme
30 1a).10 Subsequently, Niwa, Ogoshi, and Hosoya reported the
31 copper(I)-catalyzed defluoroborylation of aromatic gem-
32 difluoroalkenes and its application to the synthesis of a
33 fluoroalkene mimic of an antihyperlipidemic drug (Scheme
34 1b).11 More recently, Wang and Gao developed a similar
35 defluoroborylation of aromatic gem-difluoroalkenes (Scheme
36 1c).12 As for the borylation of aliphatic gem-difluoroalkenes,
37 only one example has been reported, by Gao and Wang in
38 2018, where the defluoroborylation of a gem-difluoro-
39 substituted allyl benzene proceeded in the presence of a
40 copper(I) catalyst to give the corresponding borylation
41 product in moderate yield (Scheme 1d).12 However, the scope
42 of aliphatic alkenes has yet to be investigated. Herein, we
43 report the stereoselective defluoroborylation of various
44 aliphatic gem-difluoroalkenes using a diboron compound in
45 the presence of a copper(I)/Xantphos complex catalyst
46 (Scheme 1e). Gem-difluoroalkenes bearing various
47 functional groups were efficiently borylated with high
51
52
53
54
Scheme 1. Copper(I)-catalyzed defluoroborylation of
gem-difluoroalkenes.
55
We have previously reported that a copper(I)/Xantphos
56 complex efficiently catalyzed the formal hydrodefluorination
57 of aromatic gem-difluoroalkenes using a diboron reagent.13,14
58 This reaction presumably proceeds through borylcupration of
59 the alkene, followed by -fluoroelimination to form (Z)-
60 monofluoro-substituted borylalkenes as a key intermediate.
61 Therefore, we wondered whether this catalytic system could
62 be used for the stereoselective defluoroborylation of aliphatic
63 gem-difluoroalkenes. Pleasingly, we found that the reaction
64 of gem-difluoroalkene 1a with 2.4 equivalent of
65 bis(pinacolato)diboron (2) in the presence of 5 mol% CuCl,
66 5 mol% Xantphos as ligand, 2.0 equivalent of K(O-t-Bu), and
67 2.0 equivalent of MeOH15 in THF afforded the desired (Z)-
68 monofluoro-substituted borylalkene 3a in good yield with
69 excellent stereoselectivity (64%, >95:5 Z/E, Table 1, entry 1).
70 Other
71 bis(diphenylphosphino)benzene
72 (diphenylphosphino)phenyl] ester (DPEphos) were also
73 investigated, but gave poor results (entries 26). No product
74 was
75 diisopropylphenyl)imidazolium chloride (IPrHCl) was used
phosphine
ligands,
such
as
1,2-
bis[2-
(dppbz)
and
48 stereoselectivity.
A theoretical study of the reaction
obtained
when
1,3-bis(2,6-
49 mechanism is also described.

2
1
2
3
4
5
6
7
8
9
as a ligand (entry 7). We found that the choice of reaction
solvent significantly affected the reactivity (entries 814).
Using toluene afforded desired product (Z)-3a and protonated
byproduct (Z)-4a in 28% and 18% yields, respectively (entry
8), while using 1,2-dimethoxyethane (DME) improved the
product yield (75%, entry 10). Interestingly, highly polar
solvents, such as 1,3-dimethyl-2-imidazolidinone (DMI),
provided protonated product (Z)-4a as the major product
(entry 12). Finally, we found that using a mixed solvent
31
32
33
34
35
Scheme 2. Isolation of the borylation product.
With the optimized reaction conditions in hand, we
10 (THF/DMF = 1:1, v/v) afforded the highest product yield with
11 excellent stereoselectivity (85%, >95:5 Z/E, entry 14). While
12 the minor E isomer was produced under the conditions used
13 by Wang and Gao, our reaction showed near-perfect
14 stereoselectivity (>95:5 Z/E).
36 proceeded to investigate the substrate scope (Table 2). Simple
37 aliphatic substrates 1a1d were efficiently borylated to
38 afford corresponding trifluoroborates (Z)-5a5d in good to
39 high yields. Gem-difluoroalkenes bearing acetal 1e,
40 benzoxazole 1f, Boc-protected amine 1g and furan 1h
41 moieties were tolerate and provided the desired borylation
42 products (Z)-5e5h in good yields. Notably, no E isomers
43 were produced under these reaction conditions.
15
16
17
Table 1. Optimization of reaction conditions for the copper(I)-
catalyzed defluoroborylation of aliphatic gem-difluoroalkenes.a
44
45 Table 2. Substrate scope for the copper(I)-catalyzed defluoroborylation
46
of aliphatic gem-difluoroalkenes.a,b
18
Entry
Ligand
Solvent
Yield of
Yield
of 4a
[%]b
<5
Z/E of
3a [%]b
3ab
1c
2
Xantphos
dppbz
THF
THF
64
<5
29
<5
<5
<5
<5
28
43
75
46
25
46
>95:5

80:20



<5
3
DPEphos
dppp
THF
<5
4
THF
<5
5
PPh3
THF
<5
6
PCy3
THF
<5
7
IPr・HCl
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
THF
<5

8
toluene
Et2O
18
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
9
<5
10
11
12
13
DME
DMF
<5
<5
DMI
32
DME/DMF
(1:1)
<5
14
Xantphos
THF/DMF
(1:1)
85
<5
>95:5
47
48 aConditions: 1 (0.5 mmol), CuCl (0.025 mmol), Xantphos (0.025 mmol),
49 bis(pinacolato)diboron 2 (1.2 mmol), K(O-t-Bu) (1.0 mmol), and MeOH
50 (1.0 mmol) in THF/DMF (1:1, 1.0 mL). bYields of (Z)-3 were determined
19
20 aConditions: 1a (0.5 mmol), CuCl (0.025 mmol), ligand (0.025 mmol),
21 bis(pinacolato)diboron 2 (1.2 mmol), K(O-t-Bu) (1.0 mmol), and MeOH
22 (1.0 mmol) in solvent (1.0 mL). bDetermined by NMR analysis with an
23 internal standard.
1
51 by H NMR analysis using an internal standard and are shown in
52 parentheses.
53
This reaction presumably proceeds through an
pathway.10-12
However, the
54 additionelimination
24
55 regioselectivity of addition of the borylcopper(I) active
56 species to aliphatic gem-difluoroalkenes has not been
57 studied.11,17 Therefore, preliminary density functional theory
58 (DFT) calculations using gem-difluoropropene as a model
59 substrate were conducted to determine the regioselectivity of
60 the reaction (Scheme 3). All calculations were conducted at
61 the B97X-D/def2-SVP level of theory (see SI for
25
Next, we attempted to isolate the (Z)-monofluoro-
26 substituted borylalkenes, which tend to be partially
27 decomposed by silica gel column chromatography. The
28 borylation product (Z)-3a could be purified and isolated by
29 converting into the corresponding trifluoroborate (Z)-5a16
30 through treatment with KHF2 (Scheme 2).

3
1
2
3
4
5
6
7
8
9
computational details and references). As shown in Scheme
3, the activation free energy for path A, where a boron atom
connects with a gem-difluoro-substituted carbon atom, was
lower than that of path B, where a copper connects with a
gem-difluoro-substituted carbon atom, by 5.5 kcal/mol. In the
transition state in path B, a transient five-coordinated
geometry with highly congested environment between a
boryl group and the methyl group causes destabilization of
the transition state.18 This can explain the transition state in
32 copper(I)/Xantphos complex-catalyzed defluoroborylation of
33 aliphatic gem-difluoroalkenes with a diboron compound
34 proceeded efficiently to give the borylation products with
35 excellent stereoselectivity. The products can be isolated by
36 conversion into the corresponding trifluoroborates in good
37 yields. A theoretical study was conducted to elucidate the
38 regioselectivity of the reaction. We believe that the newly
39 synthesized fluorine-containing borylalkenes will have wide
40 applications in medicinal chemistry and drug discovery.
10 path A having a lower barrier than that in path B.
41
42 Acknowledgments
43 This work was financially supported by the Japan Society for
44 the Promotion of Science via KAKENHI grants
45 (JP18H03907).
46 References and Notes
47
48
49
50
51
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53
54
55
56
57
58
59
60
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1
2
3
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4
5
6
7
11
12 aRelative G value (kcal/mol) at 298 K, 1.0 atm, gas phase.
13
14
Scheme 3. DFT calculations (B97X-D/def2-SVP) on the
regioselectivity of the reaction.
8
9
15
62 10 J. Zhang, W. Dai, S. Cao, Org. Lett. 2017, 19, 3283.
16
On the basis of this theoretical study, we have
63 11 H. Sakaguchi, Y. Uetake, M. Ohashi, T. Niwa, S. Ogoshi, T.
17 proposed a mechanism for this process, as shown in Scheme
18 4. Copper(I) alkoxide A is formed by the reaction of CuCl,
19 ligand, and K(O-t-Bu) mixture initially reacts with diboron
20 compound 2 to form borylcopper(I) intermediate B. The
21 regioselective addition of borylcopper(I) to the gem-
22 difluoroalkene forms alkylcopper(I) species C. Subsequent
64
Hosoya, J. Am. Chem. Soc. 2017, 139, 12855.
65 12 D. -H. Tan, E. Lin, W. -W. Ji, Y. -F. Zeng, W. -X. Fan, Q. Li, H.
66
Gao, H. Wang, Adv. Synth. Catal. 2018, 360, 1032.
67 13 R. Kojima, K. Kubota, H. Ito., Chem. Commun. 2017, 53, 10688.
68 14 Formal hydrodefluorination through defluoroborylation reaction
69
70
71
with a copper(I) catalyst was also reported by Shi and coworkers:
J. Hu, X. Han, Y. Yuan, Z. Shi, Angew. Chem. Int. Ed. 2017, 56,
13342.
23 -fluoro-elimination
affords
the
corresponding
72 15 The reproducibility of this reaction was significantly improved by
24 defluoroborylation product (Z)-3 and copper fluoride D.
25 Finally, copper fluoride D reacts with K(O-t-Bu), followed
26 by transmetallation with diboron 2 to form borylcopper(I)
27 active species B.19
73
74
adding MeOH. We are now currently investigating the effect of
this additive.
75 16 G. A. Molander, C. R. Bernardi, J. Org. Chem. 2002, 67, 8424.
76 17 A theoretical study on the regioselectivity of borylcopper(I)-
77
78
addition to aromatic difluoroalkenes has already been carried out
by Wang, Cao, and coworkers, see ref. 12.
79 18 Similar DFT calculations on the addition of borylcopper(I)
80
81
82
intermediate to unactivated terminal alkenes have also been
conducted by our group: K. Kubota, E. Yamamoto, H. Ito, J. Am.
Chem. Soc. 2013, 135, 2635.
83 19 The defluoroborylation of 1a with catalytic amount of K(O-t-Bu)
84
85
86
87
88
(5 mol % and 50 mol %) did not reach full conversion (trace and
31% yields, respectively), suggesting that the borylcopper(I)
species B could not generate directly from copper(I) fluoride D via
transmetallation with diboron 2.
28
29
Scheme 4. Possible mechanism based on the DFT study.
30
31
In summary, we have demonstrated that the