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Synthesis of gem-Difluoroalkenes via NickelCatalyzed Reductive C-F and C-O Bond Cleavage Zhiyang Lin, Yun Lan, and Chuan Wang ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04348 • Publication Date (Web): 21 Dec 2018 Downloaded from http://pubs.acs.org on December 22, 2018
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ACS Catalysis
Synthesis of gem-Difluoroalkenes via Nickel-Catalyzed Reductive C-F and C-O Bond Cleavage Zhiyang Lin, Yun Lan and Chuan Wang* Hefei National Laboratory for Physical Science at the Microscale, Department of Chemistry, Center for Excellence in Molecular Synthesis, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China Supporting Information Placeholder ABSTRACT: By merging C-O and C-F bond cleavage in crosselectrophile coupling we developed a method for efficient synthesis of gem-difluoroalkenes with an alkoxy-substituent on the homoallylic position using easily accessible acetals as coupling partners with α-trifluoromethyl alkenes. Remarkably, this Nicatalyzed allylic defluorinative cross-coupling reaction demonstrates high tolerance of a wide range of sensitive functional groups and proves to be applicable in late-stage functionalization of structurally complex compounds.
of this reaction lies in realizing an unprecedented merging of C-F13 and C-O14 bond cleavage in the reductive Ni-catalysis. Scheme 1. Ni-catalyzed cross-electrophile coupling involving C-F and C-O bond cleavage C-F Bond Cleavage F R1
F
F
+
OR3 3
R O
R2
Reductive Ni-Catalysis
F R
1
F
OR3 R2
C-O Bond Cleavage
Key Words: gem-Difluoroalkenes • C-F Bond Cleavage• C-O Bond Cleavage • Reductive Cross-Coupling • Acetals gem-Difluoroalkenes are a characteristic structural motif contained in a number of biologically active compounds1 and also known as stable bioisostere for metabolically susceptible keto group in drug research.2 Although organic chemists have made great efforts over the past decades in order to achieve simpler and more efficient methods for construction of this structural unit,3 the lack of methods to prepare functional-group-rich structurally complex gem-difluoroalkenes hampers the fulfilling of their potential in pharmaceutical discovery. The conventional strategies for synthesis of gem-difluoroalkenes include difluoroolefination of carbonyl or diazo compounds4,5 and organometallics- or strong base-mediated nucleophilic addition to trifluoromethyl alkenes involving β-fluoro elimination step.6 However, many of these methods suffer from narrow substrate scope concerning structure diversity or functional groups tolerance. In recent years Molander7 and Zhou8 successfully applied photocatalysis in the synthesis of gem-difluoroalkenes under mild reaction conditions. Furthermore, Ichikawa et al. reported a Ni-catalyzed alkenylation of trifluoromethyl alkenes to prepapre gem-difluoroalkenes with diene structure.9 Very recently, our group developed a Ni-catalyzed allylic defluorinative reductive coupling between trifluoromethyl alkenes and unactivated alkyl halides offering an approach to diverse gem-difluoroalkenes with high compatibility of various functional groups.10 However, gem-difluoroalkenes containing an alkoxy-substituent on the homoallylic position are not simple to access through the most of known methods mentioned above, as both organometallics and alkyl bromides or iodides bearing an αalkoxy moiety are difficult to prepare. In contrast, acetals are easily accessible and kown to serve as radical coupling partners with aryl halides in Ni-catalyzed reactions according to the seminal work of Doyle et al.11, Therefore, we envisaged that the use of acetals instead of halides in the cross-electrophile coupling with trifluoromethyl alkenes would enable the construction of gemdifluoroalkenes bearing an alkoxy-substituent on the homoallylic position in a simple and direct manner (Scheme 1).12 The challenge
For optimization of the reaction conditions, we employed αtrifluoromethyl styrene (1a) and benzaldehyde dimethyl acetal (2a) as standard substrates (Table 1). After systematic screening of all reaction parameters the optimum reaction conditions were achieved using NiI2 as catalyst, 4,4’-dimethoxy 2,2’-bipyridine (L1) as ligand, Zn-powder as reductant and trimethylsilyl chloride (TMSCl) as additive in DMA as solvent at room temperature for 24 h (entry 1). When the other pyridine-based ligands L2-4 or 1,10phenanthroline (L5) were employed, the reactions provided the product 3a in relatively low yields (entries 2-5). In the absence of ligand no desired reaction occurred (entry 6). Some other Ni-salts were also examined for this reactions and both Ni(0)- and Ni(II)complexes turned out to be able to promote the studied reaction (entries 7-10). Furthermore, the reactions performed in DMF and NMP (entries 11 and 12) proceeded with lower efficiency compared to the one in DMA. Replacing Zn by Mn as the reducing agent also led to a diminished yield (entry 13). Moreover, TMSCl proved to be a crucial additive, since its absence gave rise to the complete shut-down of this reductive cross-coupling reaction (entry 14). In addition, the temperature impact on the outcome of this reaction was also investigated (entries 15-16). Both raising and lowering the temperature resulted in lower reaction efficiency. After establishing the optimum reaction conditions, we started to evaluate the substrates spectrum of this Ni-catalyzed crosselectrophile coupling reaction. First, different dimethyl acetals 2am were reacted with α-trifluoromethyl styrene (1a) (Table 2). In the cases of both (hetero)aromatic and aliphatic aldehyde acetals as precursors the reactions all proceeded smoothly providing the corresponding gem-difluoroalkenes 3a-m in good to excellent yields. Notably, this method demonstrates good tolerance of functional groups attached on the acetal substrates, such as halide (3d and 3i), ester (3j) and olefin (3l). Moreover, diethyl and dipropyl acetals also turned out to be competitive substrates in this reaction affording the products 3n and 3o in good yields.
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Table 1. Variation of the reaction parameters of the Ni-catalyzed defluorinative reaction.a CF3
NiI2 (10 mol%), L1 (12 mol%) Zn (3 equiv), TMSCl (3 equiv)
OMe
+
Ph
Ph
MeO 1a
2a
R
R
OMe Ph
3a R R
N
N
N
N
N
N
R= H, L3 R= tBu, L4
R= OMe, L1 R= H, L2
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
F
Ph
DMA (0.4 M), r.t., 1 d
R N
F
L5
yield (%)b 88 (86c) 65 56 65 60 0 80 61 72 53 13 35 36 0 43 48
variation from standard conditions none L2 instead of L1 L3 instead of L1 L4 instead of L1 L5 instead of L1 w/o L1 NiBr2 instead of NiI2 Ni(acac)2 instead of NiI2 Ni(glyme)Br2 instead of NiI2 Ni(COD)2 instead of NiI2 DMF instead of DMA NMP instead of DMA Mn instead of Zn w/o TMSCl 50︒C instead of r.t. 0︒C instead of r.t.
mol% ligand L1, 3 equiv Zn and 3 equiv TMSCl in 1.0 mL DMA at room temperature for 24 h. b Yields of the isolated product after column chromatography. c Determined by 19F-NMR spectroscopy.
Next, we continued to investigate the substrate scope of this Nicatalyzed reaction by varying the structure of trifluoromethyl alkenes 1 (Table 3). First, we studied the effect of the substituent on the phenyl ring of aryl trifluoromethyl alkenes. To our deglight both electron-donating and -withdrawing groups were well tolerated and the corresponing prodcuts 3s-ag were furnished in good to high yields. Again, excellent compatibility of various functionalities including aryl bromide (3w), ketone (3ae), amide (3af) and nitrile (3ag) was observed. In addition, this protocol was also applicable for heteroaryl-substituted trifluoromethyl alkenes as starting materials affording the products 3ah and 3ai with good efficiency. Notably, the one-gram scale synthesis of 3ag provided a similar yield with a reduced amount of both catalyst and reductant. Scheme 2. Allylic defluorinative cross-coupling with cyclic and unsymmetric acetals
Subsequently, we tested the reaction employing the cyclic ethylene glycol acetals 2p and 2q as substrates (Scheme 2). In this case the cross-coupling reactions still afforded the products 3p and 3q with good efficiency after acidic hydrolysis to remove the in situ installed TMS-group. When the unsymmetric acetal 2q was utilized as precursor, a selective C-O bond cleavage in the pyran ring occurred furnishing the ring opening product 3r as the single product.
CF3
+
Ph
NiI2 (10 mol%), L1 (12 mol%) Zn (3 equiv), TMSCl (3 equiv)
OR1 R 1O
1a
R2
F
F
2a-o
+ O
1a
R
CF3
O
+
OMe
F
F
OMe
Ph
F
Ar
F
F
OMe Cl
Ph
F
3m, 89 % dr= 1:1c a
CO2Et
4
CF3 R
1
OMe
+ MeO
R
1 F
F
F
F
OMe
F
Bn
Ph 3n, 76 %
Ph
F
DMA (0.4 M), r.t., 1 d
R1
F
F
Unless otherwise specified, reactions were performed on a 0.4 mmol scale of α-trifluoromethyl styrene (1a) using 2.0 equiv actals 2a-o, 10 mol % NiI2, 12
F
R2
F
OMe Bn
3w, 85 %
MeO OMe R
3z R= n-Nonyl, 3aa R= (CH2)5Cl, 3ab R= Ph,
74 % 75 % 71 %
OMe
F
OMe
F
F
OMe Bn
O
F
OMe
R
Bn
O 3ac, 85 %
F
F
3ad, 77 %
F
OMe
F
3ae R= Ac, 84 % 3af R= NHC=OPh, 82 % F
OMe
F
OMe
Bn
Ph NC
3o, 77 %
OMe
Br
MeO
R
OMe
On-Pr Bn
F
F
76 % 87 % 85 % 74 % F
OMe
MeO
3l, 93 % dr= 1:1c F
OEt
F
3s R= t-Bu, 3t R= Cl, 3u R= OBn, 3v R= CF3O,
OMe
MeO
Ph
Ph 3k, 93 %
F
O
OMe
OH
3s-ak
R
3h, 90 % F
Me
4
NiI2 (10 mol%), L1 (12 mol%) Zn (3 equiv), TMSCl (3 equiv)
2
Bn
Bn
F
O
Ar
2
MeO 3ag, 80 % (78 %[c])
O Me
F
F
3r, 73 %
Cl 3x R= CH2Bn, 86 % 3y R= Ph, 82 %
Ph
3g, 70 %
OMe
OMe
Ph
O
F
F
Table 3. Evaluation of the substrate scope by varying the structure of trifluoromethyl alkenes.a,b
F
F
1. NiI2 (10 mol%), L1 (12 mol%) Zn (3 equiv), TMSCl (3 equiv) DMA (0.4 M), r.t., 1 d
Ar= 3,5-(MeO)2C6H3
R2
OMe
Ph
3j, 78 %
3i, 80 %
F
F
Ph
5
F
F
F
R
2q
Bn
86 % 80 % 81 % 84 % 80 % 86 %
OH
O
3p R= Ph, 64 % 3q R= c-Hex, 78 %
2. HCl (1 N), 20 min 1a
F
Ph
2. HCl (1 N), 20 min
Ar
3a-o
3a Ar= Ph, 3b Ar= 4-FC6H4, 3c Ar= 3-ClC6H4, 3d Ar= 4-BrC6H4, 3e Ar= 3-MeOC6H4, 3f Ar= 2-F-4-MeOC6H3,
F
2p R= Ph 2q R= c-Hex
B)
OR1
Ph
DMA (0.4 M), r.t., 1 d
O
Ph
Table 2. Evaluation of the substrate scope by varying the structure of symmetric acyclic acetals.a,b CF3
1. NiI2 (10 mol%), L1 (12 mol%) Zn (3 equiv), TMSCl (3 equiv) DMA (0.4 M), r.t., 1 d
A)
a
Unless otherwise specified, reactions were performed on a 0.2 mmol scale of α-trifluoromethyl styrene (1a) using 2.0 equiv benzaldehyde dimethyl acetal (2a), 10 mol % NiI2, 12 mol% ligand L1, 3 equiv Zn and 3 equiv TMSCl in 0.5 mL DMA at room temperature for 24 h. b Yields determined by 19F-NMRspectroscopy using 4-fluoroanisole as an internal standard. c Yield of the isolated product after column chromatography.
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Bn BocN
N 3ah, 84 %
3ai, 78 %
a
Unless otherwise specified, reactions were performed on a 0.4 mmol scale of the trifuoromethyl alkenes 1 using 2.0 equiv actals 2, 10 mol % NiI2, 12 mol% ligand L1, 3 equiv Zn and 3 equiv TMSCl in 1.0 mL DMA at room temperature for 24 h. b Yields of the isolated product after column chromatography. c Reaction performed on a 1 g scale of the trifluoromethyl alkene using 5 mol% NiI2, 6 mol% ligand L1 and 2 equiv Zn.
Relying on the good fucntional group tolerance we decided to explore the application of our method in the late-stage
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ACS Catalysis functionalization of structural complex molecules. Three trifluoromethyl alkenes derived from estrone, naproxen, gemfibrozil and indometacin were subjected to Ni-catalyzed crosselectrophile coupling with phenylacetaldehyde dimethyl acetal. To our deglight all the reactions proceeded smoothly furnishing the products 3aj-am in moderately good yields (Table 4). Table 4. Late-Stage Functionalizations.a,b CF3
NiI2 (10 mol%), L1 (12 mol%) Zn (3 equiv), TMSCl (3 equiv)
OMe
+
R
MeO 1
F
OMe
F
Me
H
MeO
3ak, 66 %
F
Me Me H N 3
OMe
OMe Bn
Cl
O
O
F
H N
O
3aj, 72 %
OMe
Bn 3al-an
H
Me
OMe
R
DMA (0.4 M), r.t., 1 d
Bn
O
F
2h F
H
F
Bn
F
OMe
N Me H N
Bn MeO
O
F
F
OMe Bn
3am, 59 % O
3al, 58 %
a
Unless otherwise specified, reactions were performed on a 0.2 mmol scale of the trifuoromethyl alkenes 1 using 2.0 equiv of the actal 2h, 10 mol % NiI2, 12 mol% ligand L1, 3 equiv Zn and 3 equiv TMSCl in 0.5 mL DMA at room temperature for 24 h. b Yields of the isolated products after column chromatography.
Scheme 3. Control experiments defluorinative coupling. A) MeO
Ph
allylic
Ph
DMA (0.4 M), r.t., 1 d
Ph
Ni-catalyzed
OMe
Zn (3 equiv), TMSCl (3 equiv)
OMe
for
OMe 4, trace
B)
NiI2 (10 mol%), L1 (12 mol%) Zn (3 equiv), TMSCl (3 equiv)
OMe Ph
MeO
OMe Ph
Ph OMe
DMA (0.4 M), r.t., 1 d
Ph OMe
4, 63 % dr= 50:50
C)
Ni(COD)2 (1 equiv), L1 (1 equiv) TMSCl (3 equiv) X DMA (0.4 M), r.t., 1 d
OMe Ph
MeO
D)
OMe Ph
DMA (0.4 M), r.t., 1 d
Ph
Ph OMe 4
NaI (1 equiv) Zn (3 equiv), TMSCl (3 equiv)
OMe
MeO
OMe Ph
Ph OMe 4, trace
E)
CF3
OMe
+
Ar
Cl
Ph
NiI2 (10 mol%), L1 (12 mol%) Zn (3 equiv), TMSCl (3 equiv) DMA (0.4 M), r.t., 1 d
F
OMe
Ar
Ph
5 (2 equiv)
1a
F
3a, trace
Ar= 4-MeOC6H4
F) CF3 Ar
Ni(COD)2 (1 equiv) L4 (1 equiv)
Ar
DMA (0.2 M) r.t., 1 d
1h
Ar= 3,5-(MeO)2C6H3
F3C
Ni(0)L4
or
Ar (II) NiL4 F3C
putative structure
2a (2 equiv) Zn (3 equiv)
F
F
Ar
TMSCl (3 equiv)
OMe Ph
3ab, 47 %
X H2O (5 equiv) CF3 Ar
CF3
G) Ar
1 equiv CO2Et
OMe Ph
1 equiv Ar= 4-MeOC6H4
OMe
2 equiv
6
Me
NiI2 (10 mol%), L1 (12 mol%) Zn (3 equiv), TMSCl (3 equiv) DMA (0.4 M), r.t., 1 d
F
F
OMe Ph
Ar 3a, 57 %
OMe +
Ph
EtO2C 7, 20
To gain some insights into this Ni-catalyzed defluorination reaction we performed a series of control experiments (Scheme 3). It is known that acetals upon treatment with Zn in the presence of TMSCl and K2CO3 in toluene resulted in reductive homocoupling reaction.15 However, under our reaction conditions in DMA without K2CO3 only trace of homocoupling product 4 was formed (Scheme 3A). In contrast, the reaction using a catalytic amount of NiI2 gave the dimerization product 4 in a yield of 63 % (Scheme 3B). The diastereomeric ratio of 50:50 implies that the homocoupling proceeds probably in a radical pathway and an αoxy alkyl radical is consequently present in our defluorinative cross-coupling. Moreover, we performed the reactions involving TEMPO as radical scavenger resulting in complete inhibition of the dimerization reaction. This result can also serve as evidence for the existence of radicals as key intermediates in this reaction. Replacing the combination of NiI2 and Zn by Ni(COD)2 (1 equiv) led to the complete shutdown of the homocoupling reaction (Scheme 3C). This result indicates that the generation of the α-oxy alkyl radical could be attributed to an in situ produced Ni(I) species rather than a Ni(0) species. In the case of NaI as additive instead of NiI2 only trace of 4 was formed excluding the possibility of homocoupling of in situ-generated TMSI (Scheme 3D). Likely, αalkoxy chlorides may be formed in the reaction and participate in the coupling reaction. To verify this, (chloro(methoxy)methyl)benzene (5) was employed as substrate instead of the acetal. In this case only trace amount of the coupling product 3a was afforded indicating that α-alkoxy chlorides are probably not the actual species for the coupling (Scheme 3E). Previously, Ichikawa et al. discovered the formation of a nickelacyclopropane in the reaction between Ni(COD)2 and a trifluoromethylalkene using a phosphine-ligand.9,16 Furthermore, we confirmed in our previous work that the reaction between Ni(COD)2 and the trifluoromethyl alkene 1h in presence of L4 as ligand led to the formation of a Fspecies containing a CF3-group, which is likely a nickelacyclopropane or a Ni(0)-alkene complex.10 Then we conducted this stoichiometric reaction again and the subsequent addition of benzaldehyde dimethyl acetal (2a) to the reaction mixture in the presence of Zn and TMSCl furnished the product 3ab in 47 % yield (Scheme 3F). If the stoichiometric reaction was quenched by water before the addition of the acetal 2a, a full recovery of 1h was observed and the hydrogenated product 6 was not formed, revealing that the formation of the Ni(0)-alkene complex is more likely than the nickelacyclopropane under our conditions. Since Molander et al. have reported that alkyl radicals can react with trifluoromethyl alkenes in polar solvents,7 it is questionable whether the radicals favor the addition to Ni(0)-alkene complex or trifluoromethyl alkenes. Acrylates are known to be very active species to trap α-alkoxy carbon radicals without coordination to Ni-center17 and thus the use of an acrylate as additive is expected to inhibit our defluorinative coupling. Then we performed the reaction using ethyl acrylate as a competitive substrate (Scheme 3G). In this case the defluorinative product 3a still was provided as the major product supporting the activation of trifluoromethyl substituted C−C double bond by a Ni-species. However, in this stage we do not have clear-cut evidence to rule out the direct addition to trifluoromethyl alkenes. Based on the experimental results aforementioned and the previous reports we propose the following plausible mechanism for the studied Ni-catalyzed reaction (Scheme 4). In the reaction mixture a Ni(I)-species I is generated under reductive conditions and subsequently mediates the formation of an α-alkoxy alkyl radical II from the acetal 2 in assitance of TMSCl. The resulting αalkoxy alkyl radical II can then undergo two possible pathways. In the pathway A the direct addition to trifluoromethyl alkenes 1 occurs affording a CF3-neighboured relatively electron-deficient Ccentered radical III, which performs the subsequent oxidative addition to a Ni(0) species. Alternatively, the α-alkoxy alkyl radical
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II can interact with the Ni(0)-alkene complex IV via sequential oxidative addition and migratory insertion. In both cases a Ni(I)intermediate V is produced and the subsequent β-fluoro elimination affords the product 3 and a Ni(I) species. Scheme 4. Proposed Mechanism for the Ni-Catalyzed Allylic Defluorinative Cross-Coupling. OR3
ZnFCl
LnNi(I)X (I)
3
R O
R2
+ TMSCl
CF3 R1
(A) Zn
LnNi(II)ClOR3
TMSX +
CF3 OR3
1 R
1
OR3 (II)
R2
Ni(0)Ln
Ni(0)Ln R1 F3C (IV)
R2
(III)
CF3 OR3
Ln(I)Ni R
(B)
R2
1
(V) LnNi(I)F F R
F
1
3
OR3 R2
In summary, we demonstrate an unprecedented merging of C-F and C-O bond activation in the Ni-catalyzed cross-electrophile coupling. This allylic defluorinative reaction using easily accessible acetals as coupling partners with α-trifluoromethyl alkenes provides an efficient entry to diverse gem-difluoroalkenes bearing an alkoxy-substituent on the homoallylic position. This new method feautures broad substrate scope and high tolerance of a wide range of sensitive functional moieties enabling its application in the late-stage functionalization of structurally complex molecules.
ASSOCIATED CONTENT Supporting Information Representative experimental procedures and necessary characterization data for all new compounds are provided. This material is available free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION Corresponding Author
[email protected] Notes The authors declare no competing financial interest.
ACKNOWLEDGMENT This work is supported by “1000-Youth Talents Plan” starting up funding, National Natural Science Foundation of China (Grant No. 21772183), the Fundamental Research Funds for the Central Universities (WK2060190086), as well as by the University of Science and Technology of China.
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Thrombin Inhibitor. Bioorg. Med. Chem. 2004, 12, 1713-1730. (d) Messaoudi, S.; Tréguier, B.; Hamze, A.; Provot, O.; Peyrat, J.-F.; De Losada, J. R.; Liu, J.-M.; Bignon ,J.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.-D.; Alami, M. Isocombretastatins A versus Combretastatins A: The Forgotten isoCA-4 Isomer as a Highly Promising Cytotoxic and Antitubulin Agen. J. Med. Chem. 2009, 52, 4538-4542. (2) (a) Meanwell, N. A. Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design. J. Med. Chem. 2011, 54, 2529-2591. (b) Magueur, G.; Crousse, B.; Ourévitch, M.; Bonnet-Delpon, D.; Bégué, J.-P. Fluoro-artemisinins: When a gem-Difluoroethylene Replaces a Carbonyl Group J. Fluorine Chem. 2006, 127, 637-642. (c) Leriche, C.; He, X.; Chang, C.-w.; Liu, H.-w. Reversal of the Apparent Regiospecificity of NAD(P)H-Dependent Hydride Transfer: The Properties of the Difluoromethylene Group, A Carbonyl Mimic. J. Am. Chem. Soc. 2003, 125, 6348-6349. (3) For reviews on synthesis of gem-difluoroalkenes and their applications in organic synthesis, see: (a) Ichikawa, J. gem-Difluoroolefin Synthesis: General Methods via Thermostable Difluorovinylmetals Starting from 2,2,2-Trifluoroethanol Derivatives. J. Fluorine Chem. 2000, 105, 257-263; (b) Chelucci, G. Synthesis and Metal-Catalyzed Reactions of gemDihalovinyl Systems. Chem. Rev. 2012, 112, 1344-1462. (c) Zhang, X.; Cao, S. Recent Advances in the Synthesis and C-F Functionalization of gem-Difluoroalkenes. Tetrahedron Lett. 2017, 58, 375-392. (4) For recent examples on gem-difluoroolefination of carbonyl compounds, see: (a) Nowak, R.; Robins, M. J. New Methodology for the Deoxygenative Difluoromethylenation of Aldehydes and Ketones; Unexpected Formation of Tetrafluorocyclopropanes. Org. Lett. 2005, 7, 721-724. (b) Zhao, Y.; Huang, W.; Zhu, L.; Hu, J. Difluoromethyl 2-Pyridyl Sulfone: A New gem-Difluoroolefination Reagent for Aldehydes and Ketones. Org. Lett. 2010, 12, 1444-1447. (c) Zheng, J.; Lin, J.-H.; Cai, J.; Xiao, J.-C. Conversion between Difluorocarbene and Difluoromethylene Ylide. Chem. Eur. J. 2013, 19, 15261-15266. (d) Zheng, J.; Cai, J.; Lin, J.H.; Guo, Y.; Xiao, J.-C. Synthesis and Decarboxylative Wittig Reaction of Difluoromethylene Phosphobetaine. Chem. Commun. 2013, 49, 7513-7515. (e) Thomson, C. S.; Martinez, H.; Dolbier Jr., W. R. The Use of Methyl 2,2difluoro-2-(fluorosulfonyl)acetate as the Difluorocarbene Source to Generate an in situ Source of Difluoromethylene Triphenylphosphonium Ylide. J. Fluorine Chem. 2013, 150, 53-59. (f) Li, Q.; Lin, J.-H.; Deng, Z. Y.; Zheng, J.; Cai, J.; Xiao, J.-C. Wittig gem-Difluoroolefination of Aldehydes with Difluoromethyltriphenylphosphonium Bromide. J. Fluorine Chem. 2014, 163, 38-41. (g) Gao, B.; Zhao, Y.; Hu, M.; Ni, C.; Hu, J. gem‐Difluoroolefination of Diaryl Ketones and Enolizable Aldehydes with Difluoromethyl 2‐Pyridyl Sulfone: New Insights into the Julia–Kocienski Reaction. Chem. Eur. J. 2014, 20, 7803-7810. (h) Wang, X.-P.; Lin, J.-H.; Xiao, J.-C.; Zheng, X. Decarboxylative Julia–Kocienski gem-Difluoro-Olefination of 2-Pyridinyl Sulfonyldifluoroacetate. Eur. J. Org. Chem. 2014, 2014, 928-932. (i) Aikawa, K.; Toga, W.; Nakamura, Y.; Mikami, K. Development of (Trifluoromethyl)zinc Reagent as Trifluoromethyl Anion and Difluorocarbene Sources. Org. Lett. 2015, 17, 4996-4999. (j) Gao, B.; Zhao, Y.; Hu, J.; Hu, J. Difluoromethyl 2-Pyridyl Sulfone: a Versatile Carbonyl gem-Difluoroolefination Reagent. Org. Chem. Front. 2015, 2, 163-168. (k) Krishnamoorthy, S.; Kothandaraman, J.; Saldana, J.; Prakash, G. K. S. Direct Difluoromethylenation of Carbonyl Compounds by Using TMSCF3: The Right Conditions. Eur. J. Org. Chem. 2016, 2016, 4965-4969. (5) For selected examples on gem-difluoroolefination of diazo compounds, see: (a) Hu, M.; He, Z.; Gao, B.; Li, L.; Ni, C.; Hu, J. CopperCatalyzed gem-Difluoroolefination of Diazo Compounds with TMSCF3 via C–F Bond Cleavage. J. Am. Chem. Soc. 2013, 135, 17302-17305. (b) Hu, M.; Ni, C.; Li, L.; Han, Y.; Hu, J. gem-Difluoroolefination of Diazo Compounds with TMSCF3 or TMSCF2Br: Transition-Metal-Free CrossCoupling of Two Carbene Precursor. J. Am. Chem. Soc. 2015, 137, 1449614501. (c) Zheng, J.; Lin, J.-H.; Yu, L.-Y.; Wei, Y.; Zheng, X.; Xiao, J.-C. Cross-Coupling between Difluorocarbene and Carbene-Derived Intermediates Generated from Diazocompounds for the Synthesis of gemDifluoroolefins. Org. Lett. 2015, 17, 6150-6153. (d) Zhang, Z.; Yu, W.; Wu, C.; Wang, C.; Zhang, Y.; Wang, J. Reaction of Diazo Compounds with Difluorocarbene: An Efficient Approach towards 1,1‐Difluoroolefins. Angew. Chem. Int. Ed. 2016, 55, 273-277. (6) For selected examples on synthesis of gem-difluoroalkenes via organometallics- or strong base-mediated nucleophilic addition to trifluoromethyl alkenes involving β–F elimination, see: (a) Hiyama, T.; Obayashi, M.; Sawahata, M. Preparation and Carbonyl Addition of γ,γDifluoroallylsilanes. Tetrahedron Lett. 1983, 24, 4113-4116. (b) Fuchikami, T.; Shibata, Y.; Suzuki, Y. Facile Syntheses of Fluorine-Containing α,βUnsaturated Acids and Esters from 2-Trifluoromethylacrylic Acid.
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ACS Catalysis Tetrahedron Lett. 1986, 27, 3173-3176. (c) Bégué, J.-P.; Bonnet-Delpon, D.; Rock, M. H. A Concise Synthesis of Functionalised gemDifluoroalkenes, via the Addition of Organolithium Reagents to αTrifluoromethylstyrene. Tetrahedron Lett. 1995, 36, 5003-5006. (d) Bégué, J.-P.; Bonnet-Delpon, D.; Rock, M. H. Addition of Organolithium Reagents to α-(Trifluoromethyl)styrene: Concise Synthesis of Functionalised gemDifluoroalkenes. J. Chem. Soc., Perkin Trans. 1. 1996, 1409-1413. (e) Ichikawa, J.; Fukui, H.; Ishibashi, Y. 1-Trifluoromethylvinylsilane as a CF2=C-−CH2+ Synthon: Synthesis of Functionalized 1,1-Difluoro-1alkenes via Isolable 2,2-Difluorovinylsilanes. J. Org. Chem. 2003, 68, 7800-7805. (f) Ichikawa, J.; Ishibashi, Y.; Fukui, H. A Novel Synthesis of Functionalized 1,1-Difluoro-1-alkenes via Isolable 2,2Difluorovinylsilanes. Tetrahedron Lett. 2003, 44, 707-710. (g) Ichikawa, J.; Mori, T.; Iwai, Y. A New Class of Substrates for the Nucleophilic 5-endotrig Cyclization, 1-Trifluoromethylvinyl Compounds: Syntheses of Indoline and Pyrrolidine Derivatives. Chem. Lett. 2004, 33, 1354-1355. (h) Miura, T.; Ito, Y.; Murakami, M. Synthesis of gem-Difluoroalkenes via βFluoride Elimination of Organorhodium(I). Chem. Lett. 2008, 37, 10061007. (i) Ichikawa, J.; Iwai, Y.; Nadano, R.; Mori, T.; Ikeda, M. A New Class of Substrates for Nucleophilic 5‐endo‐trig Cyclization, 2‐Trifluoromethyl‐1‐alkenes: Synthesis of Five‐Membered Hetero‐ and Carbocycles That Bear Fluorinated One‐Carbon Units. Chem. Asian J. 2008, 3, 393-406. (j) Fuchibe, K.; Takahashi, M.; Ichikawa, J. Substitution of Two Fluorine Atoms in a Trifluoromethyl Group: Regioselective Synthesis of 3‐Fluoropyrazoles. Angew. Chem. Int. Ed. 2012, 51, 1205912062. (k) Hayashi, T.; Huang, Y. H. Rhodium-Catalyzed Asymmetric Arylation/Defluorination of 1-(Trifluoromethyl)alkenes Forming Enantioenriched 1,1-Difluoroalkenes. J. Am. Chem. Soc. 2016, 138, 1234012343. (l) Yang, J.; Zhou, X.; Zeng, Y.; Huang, C.; Xiao, Y.; Zhang, J. Divergent Synthesis from Reactions of 2-Trifluoromethyl-1,3-conjugated Enynes with N-Acetylated 2-Aminomalonates. Org. Biomol. Chem. 2017, 15, 2253-2258. (m) Dai, W.; Lin, Y.; Wan, Y.; Cao, S. Cu-Catalyzed Tertiary Alkylation of α-(Trifluoromethyl)styrenes with Tertiary Alkylmagnesium Reagents. Org. Chem. Front. 2018, 5, 55-58. (n) Wu, X.; Xie, F.; Gridnev, I. D.; Zhang, W. A Copper-Catalyzed Reductive Defluorination of β-Trifluoromethylated Enones via Oxidative Homocoupling of Grignard Reagents. Org. Lett. 2018, 20, 1638-1642. (o) Wang, P.; Pu, X.; Zhao, Y.; Wang, P.; Li, Z.; Zhu, C.; Shi, Z. Enantioselective Copper-Catalyzed Defluoroalkylation Using Arylboronate-Activated Alkyl Grignard Reagents. J. Am. Chem. Soc. 2018, 140, 9061-9065. (7) Lang, S.; Wiles, R. J.; Kelly, C. B.; Molander, G. A. Photoredox Generation of Carbon-Centered Radicals Enables the Construction of 1,1Difluoroalkene Carbonyl Mimic. Angew. Chem. Int. Ed. 2017, 56, 1507315077. (8) Xiao, T.; Li, L.; Zhou, L. Synthesis of Functionalized gemDifluoroalkenes via a Photocatalytic Decarboxylative/Defluorinative Reaction. J. Org. Chem. 2016, 81, 7908-7916. (9) The nickelacyclopropanation of trifluoromethyl alkenes with Ni(COD)2 has been reported.: Ichitsuka, T.; Fujita, T.; Ichikawa, J. NickelCatalyzed Allylic C(sp3)–F Bond Activation of Trifluoromethyl Groups via β-Fluorine Elimination: Synthesis of Difluoro-1,4-dienes. ACS Catal. 2015, 5, 5947-5950. (10) Lan, Y.; Yang, F.; Wang, C. Synthesis of gem-Difluoroalkenes via Nickel-Catalyzed Allylic Defluorinative Reductive Cross-Coupling. ACS Catal. 2018, 8, 9245-9251. (11) Arendt, K. M.; Doyle, A. G. Dialkyl Ether Formation by NickelCatalyzed Cross-Coupling of Acetals and Aryl Iodides. Angew. Chem. Int. Ed. 2015, 54, 9876-9880. (12) For reviews on reductive cross-couplings, see: (a) Everson, D. A.; Weix, D. J. Cross-Electrophile Coupling: Principles of Reactivity and Selectivity. J. Org. Chem. 2014, 79, 4793-4798. (b) Moragas, T.; Correa, A.; Martin, R. Metal‐Catalyzed Reductive Coupling Reactions of Organic Halides with Carbonyl‐Type Compounds. Chem. Eur. J. 2014, 20, 82428258. (c) Gu, J.; Wang, X.; Xue, W.; Gong, H. Nickel-Catalyzed Reductive Coupling of Alkyl Halides with Other Electrophiles: Concept and Mechanistic Considerations. Org. Chem. Front. 2015, 2, 1411-1421. (d) Weix, D. J. Methods and Mechanisms for Cross-Electrophile Coupling of Csp2 Halides with Alkyl Electrophiles. Acc. Chem. Res. 2015, 48, 17671775. (e) Richmond, E.; Moran, J. Recent Advances in Nickel Catalysis Enabled by Stoichiometric Metallic Reducing Agents. Synthesis. 2018, 50, 499-513.
(13) For reviews on C-F bond cleavage in organic synthesis, see: (a) Burdeniuc, J.; Jedlicka, B.; Crabtree, R. H. Recent Advances in C–F Bond Activation. Chem. Ber. 1997, 130, 145-154. (b) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119-2183. (c) Ahrens, T.; Kohlmann, J.; Ahrens, M.; Braun, T. C−F Bond Activation in Organic Synthesis. Functionalization of Fluorinated Molecules by Transition-Metal-Mediated C–F Bond Activation To Access Fluorinated Building Blocks. Chem. Rev. 2015, 115, 931-972. (d) Fujita, T.; Fuchibe, K.; Ichikawa, J. Transition Metal‐Mediated and ‐Catalyzed C‐F Bond Activation via Fluorine Elimination. Angew. Chem. Int. Ed. 2018, 57, doi: 10.1002/anie.201805292. (14) For a review on C-O bond cleavage in cross-coupling reactions, see: Cornella, J.; Zarate, C.; Martin, R. Metal-Catalyzed Activation of Ethers via C-O Bond Cleavage: a New Strategy for Molecular Diversity. Chem. Soc. Rev. 2014, 43, 8081-8097. (15) Hatano, B.; Nagahashi, K.; Habaue, S. Reductive Coupling of Aromatic Dialkyl Acetals Using the Combination of Zinc and Chlorotrimethylsilane in the Presence of Potassium Carbonate. Chem. Lett. 2007, 36, 1418-1419. (16) Ichitsuka, T.; Fujita, T.; Arita, T.; Ichikawa, J. Double C-F Bond Activation through β-Fluorine Elimination: Nickel-Mediated [3+2] Cycloaddition of 2-Trifluoromethyl-1-alkenes with Alkynes. Angew. Chem. Int. Ed. 2014, 53, 7564-7568. (17) Gong, H.; Andrews, R. S.; Zuccarello, J. L.; Lee, S. J.; Gagné, M. R. Sn-Free Ni-Catalyzed Reductive Coupling of Glycosyl Bromides with Activated Alkenes.
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SYNOPSIS TOC C-F Bond Cleavage F R1
F
F
+
OR3 3
R O
Reductive Ni-Catalysis
R2
C-O Bond Cleavage
39 Examples
F R1
F
OR3 R2
up to 93 % yield
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