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Fluoroalkylation-Borylation of Alkynes: An Efficient Method to (Z)-Tri- and Tetra-Substituted Fluoroalkylated Alkenyl-boronates Wen-Hao Guo, Hai-Yang Zhao, Zhi-Ji Luo, Shu Zhang, and Xingang Zhang ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02842 • Publication Date (Web): 19 Nov 2018 Downloaded from http://pubs.acs.org on November 19, 2018
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ACS Catalysis
Fluoroalkylation-Borylation of Alkynes: An Efficient Method to (Z)Tri- and Tetra-Substituted Fluoroalkylated Alkenyl-boronates Wen-Hao Guo,†, ¶ Hai-Yang Zhao,†, ¶ Zhi-Ji Luo,† Shu Zhang,‡ and Xingang Zhang*,† †Key
Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China ‡School of Materials and Energy, University of Electronic Science and Technology of China, 2006 Xiyuan Avenue, West High-Tech Zone, Chengdu, Sichuan 611731, China ABSTRACT: Efficient methods for the synthesis of fluoroalkylated alkenylboronates are very limited, despite their importance in modern organic synthesis. Herein, we report a palladium-catalyzed trans-fluoroalkylation-borylation of alkynes with fluoroalkyl iodides and B2pin2. The reaction allows a series of difluoroalkyl iodides and perfluoroalkyl iodides and can enable coupling with a variety of alkynes, including internal and terminal alkynes, with high efficiency, high functional group compatibility and high regioand stereoselectivities. Preliminary mechanistic studies reveal that a trans-fluoroalkylated alkenyl iodide is the key intermediate, which subsequently undergoes borylation to produce the trans-fluoroalkylated alkenylboronate.
KEYWORDS: alkynes, borylation, fluoroalkylated alkenyl boronates, fluoroalkyl iodides, palladium Fluoroalkyl substituted alkenes are of great importance in life1 and materials sciences,2 owing to the unique properties of fluoroalkyl groups.3 For the synthesis of multisubstituted fluorine-containing alkenes,4 fluoroalkylated alkenylboronates are essential building blocks that can be readily used in transition-metal-catalyzed transformations, especially in Suzuki−Miyaura cross-couplings.5 However, step-economic, versatile, and stereoselective synthetic methods toward trisubstituted and tetrasubstituted fluoroalkylborylated alkenes have been extremely limited thus far. For example, in 2001, Shimizu et al. developed a lithium reagent mediated strategy that can afford CF3-containing tetrasubstituted alkenes through stepwise C−C and C−B bonds formation (Scheme 1a).6 Such a process suffers from the use of restricted CF3-containing dichlorohydins, handling with lithium reagents, and requirement of multiple steps. With regard to the efficient synthesis of versatile fluoroalkylated alkenylboronates, our efforts focus on the catalytic fluoroalkylation-borylation reaction. In the category of transition-metal catalyzed synthesis, copper-catalyzed borylation of alkynes has recently emerged as a general method to access multisubstituted alkenylboronates with regio- and stereoselectivities (Scheme 1b), in which the βborylalkenylcopper species generated from syn-addition of the borylcopper to alkynes reacts with various electrophiles to form new C−C or C−heteroatom bonds.7 However, attempts to adopt this method directly using fluoroalkyl halides (XCF2R) as electrophiles failed to afford corresponding fluoroalkylated alkenylboronates, due to the inert reactivity of XCF2R toward borylalkenylcopper species.
Previous work: a) Synthesis of trifluoromethylated alkenylboronates Bpin F3C Ar
OH
RLi
Cl
F3C
O
Ar
Cl
B2pin2
R
or Bpin-SiMe2Ph
R
Li R
CF3 Ar or CF3
Bpin
Ar
b) Cu-catalyzed three-component borylation reaction
R1
R2
Cu-B syn-addition
CuL
R3
R3-X
Bpin
R1
X = Br, I
R2
R
Bpin
1
R2 R3 = aryl, alkyl
This work: c) Pd-Catalyzed tandem fluoroalkylation-borylation reaction R1
Ar + ICF2R
[Pd0] anti-addition
LnPdIII Ar
R1 CF2R
Bpin
B2pin2 Ar
R1 CF2R
R1 = H, aryl, alkyl
Scheme 1. Strategies for the Synthesis of Borylated Alkenes Inspired by our recent work on palladium-catalyzed fluoroalkylations of alkenes with fluoroalkyl halides,8 in which a fluoroalkyl radical intermediate is involved (Scheme 2a), we envisioned the feasibility of a similar radical to trigger a tandem fluoroalkylation-borylation with alkynes; that is, as shown in Scheme 2b, a fluoroalkyl radical initiated by a palladium species is traped with the alkyne to form a vinyl radical, which subsequently generates an alkenylpalladium species, followed by cross-coupling with the borate9 to produce desired fluoroalkylated alkenylboronate. Here, we report a a palladiumcatalyzed trans-fluoroalkylation-borylation of alkynes with fluoroalkyl iodides and B2pin2 (Scheme 1c).
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ACS Catalysis a)
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Zhang, 2015, ref 8 R
1
aReaction
[PdI] +
[Pd0]
+
R1
LnPdIII
[Pd0]
+
Ar
ICF2R
CF2R
R1 CF2R
CF2R
Ar
Base
R1
R1
Br(I)CF2R
b)
LnPdIIX
R1
0
[Pd ]
Bpin
B2pin2
R1
Ar
CF2R
CF2R R1 = H, aryl, alkyl
[PdI]
[Pd0] [PdI] + CHF2R
Ar
R
1
Ar
R1 CF2R
Scheme 2. Hypothesis for the Pd-Catalyzed Tandem Fluoroalkylation-Borylation On the basis of the above hypothesis, we chose 1-phenyl-1propyne 1a, ethyl iododifluoroacetate 2a and bis(pinacolato)diboron (B2pin2) 3 as the model substrates to test this palladium-catalyzed fluoroalkylation-borylation reaction (Table 1). Initially, instead of the desired product difluoroacetylated alkenylboronate 4a, a large amount of side product vinyl iodide 4a (98% yield) was provided when the reaction was carried out with Pd(PPh3)2Cl2 (5 mol%) as the catalyst, dppb (5 mol%) as the ligand and KOAc as the base in DCE at 80 oC (entry 1). Switching KOAc to K3PO4 or K2CO3 showed almost no improvement (entries 2 and 3), while the use of CsOAc benefited the reaction efficiency, and provided the trans-difluoroacetylated alkenylboronate 4a in 40% yield, albeit formation of 43% yield of difluoroacetylated alkene 4a (entry 4). The formation of side product 4a is probably because of the proton transfer from solvent DCE to vinyl radical. To our delight, when Cs2CO3 was used, the yield of 4a could be improved to 84% along with small amount of 4a (7% yield, entry 5). Table 1. Representative Results for Optimization of Palladium-Catalyzed Fluoroalkylation-Borylation of 1Phenyl-1-propyne 1a with Iododifluoroacetate 2a and B2pin2 3a Me + ICF2CO2Et
Ph 1a
+
B2pin2
2a
3
Pd(PPh3)2Cl2 (5 mol%) dppb (5 mol%) Base (3.0 equiv) DCE, 80 C
R Me
Ph
CF2CO2Et 4a, R = Bpin 4a', R = H 4a'', R = I
Entry
[Pd]
Base
Yield (%)b 4a/4a′/4a′′
1
Pd(PPh3)2Cl2
KOAc
trace / 0 / 98
2
Pd(PPh3)2Cl2
K3PO4
5 / 2 / 89
3
Pd(PPh3)2Cl2
K2CO3
0 / 1 / 95
4
Pd(PPh3)2Cl2
CsOAc
40 / 43 / 0
5
Pd(PPh3)2Cl2
Cs2CO3
84 / 7 / 0
6c
Pd(PPh3)2Cl2
Cs2CO3
40 / 12 / 0
7
Pd(PPh3)4
Cs2CO3
80 / 8 / 0
8
Pd(OAc)2
Cs2CO3
71 / 11 / 0
9
Pd(PhCN)2Cl2
Cs2CO3
73 / 0 / 0
10d
Pd(PPh3)2Cl2
Cs2CO3
95(86) / 5 / 0
conditions (unless otherwise specified): 1a (0.3 mmol, 1.0 equiv), 2a (0.6 mmol, 2.0 equiv), 3 (0.6 mmol, 2.0 equiv), DCE (3.0 mL), 24 h. bThe yield was determined by 19F NMR using fluorobenzene as an internal standard; values in parentheses are the isolated yields. cToluene (3 mL) was used. d5 equiv of H2O was used as an additive.
Encouraged by this result, a survey of a series of reaction parameters, such as solvent and palladium sources, was performed to improve the reaction efficiency further (for details, see the Supporting Information, SI). Polar solvents, such as DMF, THF, DME and dioxane, led to low yields. The non-polar solvent, toluene, showed better compatibility, but was inferior to DCE (entry 6). The reaction was not sensitive to the nature of palladium salts, and comparable yields of 4a could be obtained with different palladium catalyst precursors (entries 7-9 and SI). Finally, an optimal yield of 4a with high Z/E ratio (Z/E = 65:1, determined by LC-MS before purification) was provided by using 5.0 equiv of H2O as an additive and Pd(PPh3)2Cl2 as the catalyst (entry 10). The role of H2O is to facilitate the transmetalation step between alkenylpalladium species and B2pin2.10 No 4a was obtained in the absence of palladium catalyst or base (SI), demonstrating the essential roles of palladium and base in promotion of the reaction. Upon the identification of viable reaction conditions, the substrate scope of the reaction was examined by using ICF2CO2Et 2a as the fluorine source and aryl-alkyl internal alkynes as substrates (Table 2). Overall, moderate to high yields of trans-fluoroalkylated alkenylborates 4 were obtained with the difluoroacetyl group addition to the -position of the alkyne relative to the aryl terminal. Aromatic substrates bearing electron-donating groups or electron-withdrawing groups did not interfere with the reaction efficiency and trans-selectivity (4a-4m). For some moderate yields obtained in the reaction is because defluorination side reactions occured during the process. Furthermore, the internal alkynes bearing different aliphatic substituents also underwent the current palladiumcatalyzed process smoothly (4n-4x). Importantly, most of the important functional groups (including chloride, silyl, ester, formyl, amide, nitro and ketone moiety) all showed excellent tolerance to the reaction (4c-4f, 4l-4p, 4t-4v). Most remarkably, substrates bearing an alcohol or an azide moiety were also competent coupling partners (4q-4s), providing good opportunities for downstreamed transformations. The substrates bearing a S-containing heteroaryl group (4h and 4w) or an amino acid residue (4x) in the aliphatic chain were also applicable to the current process with slightly decreased Z/E slectivities. Unfortunately, the aryl-alkyl alkynes bearing a secondary alkyl group or a tertiary alkyl group led to poor yields or no desired products. The reaction was not restricted to the aryl-alkyl internal alkynes, as the diaryl internal alkyne was amenable to the reaction and provided corresponding product in a moderate yield with trans-selectivity (4y). However, the Ncontaining heteroaryl and dialkyl substituted alkynes are not suitable substrates, in which oct-4-yne only provided the corresponding product in 10% yield. Table 2. Palladium-Catalyzed Fluoroalkylation-Borylation of Internal Alkynes 1 with Iododifluoroacetate 2a and B2pin2 3a
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ACS Catalysis + ICF2CO2Et
Ar 1
R
B2pin2
+
4a, R = H, 96% (86%), 65:1 Bpin 4b, R = p-OMe, 86% (74%), >30:1 4c, R = p-Cl, 88% (81%), >30:1 4d, R = p-TMS, 98% (90%), nd CF2CO2Et 4e, R = m-CO2Et, 74% (70%), >30:1 4f, R = m-CHO, 66% (62%), >30:1 Bpin
Bpin CF2CO2Et
Bpin
O
S
O 4g, 81% (75%), 25:1
3
COOMe
Ph
n
3
4o, 75% (66%), 25:1
Bpin NO2
3
Ph
Bpin CF2CO2Et
Ph
CF2CO2Et
S
4w, 71% (63%), 11:1
N
Ph
COMe
4v, 83% (76%), 50:1
Bpin
O
O O
2
4u, 79% (73%), 30:1 O
2
OTBS
CF2CO2Et
CF2CO2Et 4t,49% (43%), 25:1
4s, 76% (70%), 30:1
Bpin 3
3
Bpin
O 2
CF2CO2Et
Ph
O NHBoc
4x, 65% (60%), 16:1
Ph
Bpin
4ab,89% (82%), 25:1
Ph Ph
O
4ac, 70% (58%), 25:1
Bpin
CnF2n+1 n = 4, 4ad, 61% (54%)b, >30:1 n=6, 4ae, 40% (35%)b, >30:1
Bpin
Bpin Ph
CF2CO2Et
CF2CO2Et
t-Bu
4af, 85% (32%)c, 20:1
N3
CF2CO2Et
n=3, 4q, 69% (65%), 40:1 n=5, 4r, 63% (58%), >30:1
4p, 75% (70%), 25:1
Bpin
Ph
CF2CO2Et
CF2CO2Et O
F
O
Bpin
Bpin OH
4
H N
F
N F
O
CF2CO2Et
Bpin N
Ph
CF2CO2Et
Ph
F
N F
TMS
O
Bpin
Cl
Ph
F
CF2R
Bpin Ph
O
Ph
4n, 50% (43%), 30:1
Bpin
3
R1
Ar
Cs2CO3 (3.0 equiv) H2O (5.0 equiv) DCE, 80 C
Bpin
Bpin
4aa, 83% (72%), 20:1
Bpin
B2pin2
2
Ph
4h, 80% (71%), 50:1
4i, 86% (78%), 30:1
Ph
CF2CO2Et
+
ICF2R
1
CF2CO2Et
4j, R = H, 75% (74%), 30:1 4k, R = CF3, 56% (52%), >30:1 4l, R = TMS, 75% (66%), >30:1 4m, R = Cl, 56% (48%), 40:1
CF2CO2Et
R
CF2CO2Et 4
Bpin
+
Ar
Bpin
Pd(PPh3)2Cl2 (5 mol%) dppb (5 mol%)
R1
R1
Ar
Cs2CO3 (3.0 equiv) H2O (5.0 equiv) DCE, 80 C
3
2a
Bpin
Pd(PPh3)2Cl2 (5 mol%) dppb (5 mol%)
R1
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
CF2CO2Et
Br
4ag, 75% (50%)c, 25:1
CF2CO2Et
4ah, 60% (15%)c, 13:1
4ai, (46%), 25:1
aReaction
conditions (unless otherwise specified): 1 (0.3 mmol, 1.0 equiv), 2 (2.0 equiv), 3 (2.0 equiv), DCE (3.0 mL), 80 oC, 24 h. The yield was determined by 19F NMR using fluorobenzene as an internal standard; values in parentheses are the isolated yields. Values of the ratio are the ratio of Z/E-4, which were determined by LC-MS prior to purification. b20.0 equiv of H2O was used. c1 (0.4 mmol, 1.0 equiv), 2 (2.0 equiv), 3 (2.0 equiv), DCE (4.0 mL), 55 oC, 24 h.
CF2CO2Et 4y, 50% (45%), 30:1
aReaction
conditions (unless otherwise specified): 1 (0.3 mmol, 1.0 equiv), 2a (2.0 equiv), 3 (2.0 equiv), DCE (3.0 mL), 24 h. The yield was determined by 19F NMR using fluorobenzene as an internal standard; values in parentheses are the isolated yields. Values of the ratio are the ratio of Z/E-4, which were determined by LC-MS prior to purification; nd, E-4 was not detected.
To demonstrate the generality of this palladium-catalyzed process further, a series of fluoroalkyl iodides were examined (Table 3). Generally, moderate to good yields of transfluoroalkylated alkenylboronates 4 still could be obtained with high trans-selectivities. The iododifluoroacetamides furnished corresponding products efficiently (4aa-4ac); even the amide bond bearing a free proton still could provide 4ac in good yield. Perfluoroalkyl iodides were also applicable to the reaction with 20 equiv of H2O as additve (4ad and 4ae). Furthermore, the terminal aromatic alkynes were also suitable substrates without requirement of H2O, providing anti-trisubstituted fluoroalkylated alkenylboronates with good yields (determined by 19F NMR) under relatively mild reaction conditions (55 oC) (4af-4ah), suggesting that terminal alkynes are more reactive than internal alkynes. Unfortunately, these resulting trisubstituted alkenylboronates are sensitive to the silica gel chromatography and are prone to attatching to the silica gel column. Although low to moderateisolated yields of 4af-4ah are obtained, this palladium-catalyzed process provides a new way to access this kind of structure. Additionally, aliphatic terminal alkynes were also applicable to the reaction, as 46% yield of 4ai was obtained when propynylbenzene was examined. Table 3. Palladium-Catalyzed Fluoroalkylation-Borylation of Alkynes 1 with Fluoroalkyl Iodides 2 and B2pin2 3a
In view of the synthetic versatility of alkenylboronates as well as important applications of fluorinated compounds in pharmaceuticals, agrochemicals and materials science, a series of transformations of the resulting fluoroalkylated alkenylboronate were conducted (Scheme 3). Palladiumcatalyzed Suzuki−Miyaura cross-coupling between Ncontaining heteroaryl iodide 5 and 4a afforded corresponding tetra-substituted alkene 6 in an excellent yield (96%). The couplings of 4a with vinyl bromide 7 or alkenyl bromide 9 also proceeded smoothly. In light of the importance of dienes and enynes in modern organic synthesis,11 such transformations provide facile routes in the synthesis of fluorinated complex molecules. Most importantly, the fluoroalkylated alkenylboronates 4a can also be used to modify the bioactive compounds. For example, the coupling of 4a with estrone derived triflate 11 stereoselectively produced corresponding product 12 with high efficiency, thus demonstrating the utility of fluoroalkylated alkenylboronates further. I N
CF3
Ph
CF2CO2Et
F3C
Br
N 5
7 i)
i)
Ph
CF2CO2Et
8, 86%
6, 96%
Bpin Ph O
CF2COOEt 4a
5
i) Ph
CF2CO2Et Br
10, 78%
i) n-Octyl
9
H EtO2CF2C ArOTf (derived from estrone) 11
H
H
Ph 12, 98%
Scheme 3. Transformations of Compound 4a. Reaction conditions: i) Pd(PPh3)4 (5 mol%), Cs2CO3 (3.0 equiv), toluene (2.0 mL), H2O (7 equiv), 80 oC, 24 h.
To gain insights into reaction mechanism, several experiments were performed. Firstly, as previously demonstrated, a fluoroalkyl radical RCF2 •can be generated by reaction of fluoroalkyl iodide 2 (ICF2R) with [Pd0Ln] via a single electron transfer (SET) pathway,8, 12 we carried out radical clock and radical inhibition experiments to identify whether a fluoroalkyl radical RCF2 • is involved in the current
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reaction. We found that when a mixture of 1a, 2a and 3 was treated with -cyclopropyl styrene 13 under standard reaction conditions, a ring-expanded product 14 was obtained in 35% yield (Scheme 4a). Treatment of the mixture with ET inhibitor1,4-dinitrobenzene almost inhibits the reaction (Scheme 4b). These results demonstrate that a RCF2• exists in the reaction, which was further confirmed by an electron paramagnetic resonace (EPR) study with phenyl tert-butyl nitrone (PBN) as a spin-trapping agent (Scheme 4c and Figure S4).
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a)
Et Ph
+ 1i
ICF2CO2Et 2a
I
reaction conditions
B2pin2
Et
Et
standard
Bpin CF2CO2Et
3
4i
4i''
Reaction Time
4'' (yield %)
CF2CO2Et Ph
Ph
4i (yield %)
1 min
5
5 min
10
0 0
10 min
16
