Palladium Catalyzed Carbonylative Coupling of Alkyl Boron Reagents

10 hours ago - A catalytic protocol for the preparation of α,α-difluoro-α-alkyl-β-ketoamides is developed employing a Pd-mediated carbonylative Su...
5 downloads 17 Views 560KB Size
Download PDF
Subscriber access provided by UNIVERSITY OF TOLEDO LIBRARIES

Palladium Catalyzed Carbonylative Coupling of Alkyl Boron Reagents with Bromodifluoroacetamides Hongfei Yin, Jakob Kumke, Katrine Domino, and Troels Skrydstrup ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00420 • Publication Date (Web): 29 Mar 2018 Downloaded from http://pubs.acs.org on March 29, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 7 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

ACS Catalysis

Palladium Catalyzed Carbonylative Coupling of Alkyl Boron Reagents with Bromodifluoroacetamides Hongfei Yin, Jakob J. Kumke, Katrine Domino, Troels Skrydstrup* Carbon Dioxide Activation Center (CADIAC), Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark

Supporting Information Placeholder ABSTRACT: A catalytic protocol for the preparation of α,α-difluoro-β-alkyl-β-ketoamides is developed employing a Pd-mediated carbonylative Suzuki coupling between alkylboron reagents and bromodifluoroacetamides with COgen as the CO source. The reaction reveals good functional group tolerance providing a broad selection of α,α-difluoro-β-alkyl-β-ketoamides in moderate to good yields, which represent useful precursors for further synthetic manipulation. Finally, the methodology is amenable to 13C-isotope labeling at the ketone carbon applying 13C-COgen. KEYWORDS: palladium catalysis, carbonylative Suzuki, alkyl substrates, carbon-13 isotope-labeling, fluoride Fluorine-containing compounds play a significant role in the development of new pharmaceuticals, agrochemicals and materials due to their distinctive properties.1 For example, fluorine’s high electronegativity and small atomic size provide opportunities for fine-tuning the properties of bioactive molecules by influencing their bioavailability, lipophilicity and metabolic stability.2 Numerous methods for the synthesis of fluorine-containing moieties have therefore been reported.3 Recently, the introduction of a CF2 group has drawn considerable attention because of its ability to act as bioisostere for various other functional groups, including an isopropyl or carbonyl group, as well as an oxygen atom.4 As depicted in Scheme 1, a diverse array of difluoromethylene-containing molecules have been synthesized via transition metalcatalyzed coupling reactions invoking either a difluoromethyl radical intermediate generated from a corresponding difluorohalomethyl group linked to a number of radical stabilizing functionalities, or a difluoromethyl carbanion produced from α-silyldifluoroacetates with fluoride salts (Scheme 1).5 Amongst them, two Pd-catalyzed carbonylative Suzuki transformations were recently reported providing access to α,αdifluoroacylated arenes (Scheme 2a).6 Broad reaction scopes and excellent yields were achieved, however, major focus in this work was made on the use of aryl boron reagents. The α,α-difluoro-β-alkyl-β-ketoamide substructure has been identified in bioactive molecules acting as agonists for regulating the release of virulence factors in Pseudomonas aeruginosa.7 The traditional method for preparing the main skeleton of these compounds relies on a Reformatsky reaction followed by an alcohol oxidation step (Scheme 2b), or electrophilic fluorination of β-ketoamides, both of which suffer from limited scopes.7a,8 With our strong interest in metalcatalyzed carbonylative reactions and the preparation of fluorine-containing molecules,6a,9 this prompted us to develop a successful Pd-catalyzed carbonylative method for the synthe-

sis of α,α-difluoro-β-alkyl-β-ketoamides, the results of which are discussed below. Furthermore, we demonstrate that such functionalized β-ketoamides, represent an excellent starting point for the synthesis of numerous difluoro-containing compounds including heterocycles. Scheme 1. Examples of Introduction of CF2 Moieties

Since β-hydride elimination has been recognized as a common side reaction in Pd-mediated transformations with alkyl reagents, considerable efforts have been devoted to identifying suitable solutions for this variation of coupling reactions.10 As seen from the diagram in Table 1, our plan to prepare the desired product was initiated by implementing a similar catalytic system as from our previous work with aryl boronic acid substrates as the nucleophilic coupling partner.6a As such, Xantphos and Pd(PPh3)4 were chosen as the ligand and Pd source, and K2CO3 was used as the base together with CuI as the co-catalyst. The carbonylation reaction was tested applying the two-chamber reactor, COware,9,11 at 100 oC with 2.0 equivalents of the bromodifluoroacetamide 1, 1.0 equivalent of n-octyl–B(OH)2 (2), and 3 equivalents of CO generated from COgen. Unfortunately, under these conditions no desired product could be detected according to the analysis of the crude reaction mixture by 19F-NMR spectroscopy, which

1 ACS Paragon Plus Environment

ACS Catalysis 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

Scheme 2. Previous and Proposed Strategies for the Synthesis of α,α-Difluoro-β β-ketoamides6–8

Page 2 of 7

Table 1. Optimization of the Preparation of α,α-Difluoroβ-alkyl-β β -ketoamidesa

a) Previous Carbonylative Version (Only with Aryl Boron Reagents) O R'RN/RO

CF 2Br

+

Pd/CO

ArBX2

O

O C

F

F

R'RN/RO

Ar

b) Traditional Synthetic Method O O CF 2Br

EtO

c)

R

O

O

[O] EtO

+ OHC

OH

Zn R F

F

EtO

R F

F

This Work O R'RN/RO

CF 2Br + Alkyl-9-BBN

Pd/CO

O

O C

F

F

R'RN/RO

Alkyl

revealed extensive decomposition. Replacing n-octyl–B(OH)2 with the corresponding n-octyl trifluoroboronate salt proved unsuccessful as well (See Supporting Information). On the other hand, Suzuki and coworkers have previously demonstrated the successful use of alkyl–9-BBN derivatives in the Pd-catalyzed carbonylative synthesis of simple aliphatic ketones.12 When n-octyl–9-BBN was used in our system, pleasingly and after some initial optimization, a 52% yield could be achieved (entry 1). Still, major side-reactions in these cases included debromination to the difluoroacetamide even up to approx. 50% in certain cases, and the solvent adduct (up to ≈ 20%) from the radical addition to toluene as previously observed in our work with aryl boronic acid derivatives (See Supporting Information).6a The presence of CuI provided up to 20% higher coupling yield in comparison to its absence. Whether the presence of this copper salt facilitates the transmetalation step or the dissociation of one of the phosphine ligands on Pd is not known.13 A further screening of the reaction conditions was undertaken with a selection of different bases. Both Na2CO3 and K3PO4 led to inferior results compared to K2CO3 with a 17% and a 27% yield decrease, respectively (entries 2 and 3). tBuOK shut down the reaction totally, while with KF a 10% yield reduction was observed compared to K2CO3 (entries 4 and 5). The reaction was then carried out in various solvent systems, and an anisole-water mixture provided a comparable result to the previous toluene-water system. Poorer yields were obtained with DMF-water or dioxane-water (entries 6–8). Not surprisingly, water was essential for catalytic turnover (entry 9), but increasing the amount of water was also detrimental for product formation (entry 10). Increasing the addition of CuI to 0.5 equivalents gave only trace amounts of product, while either decreasing the amount of CuI or K2CO3 resulted in an approximate 10% drop in yield (entries 11–13). Testing other Pd sources either gave lower conversion or poor selectivities between the desired ketone and the side product from simple debromination of the bromodifluoroacetamide (see Supporting Information). Increasing the internal pressure of the reactor using 6.0 equivalents of CO yielded no better outcome (entry 14). To our delight, we could isolate the desired product in a 60% yield after column chromatography when the bromodifluoroamide was employed as the limiting reagent at 50 oC (entry 16).

Base

Yield [b] (%)

Xantphos (10%)

K2CO3

52

Xantphos (10%)

Na2CO3

35

Toluene/H2O

Xantphos (10%)

K3PO4

25

Entry

Solvent

Ligand (mol%)

1

Toluene/H2O

2

Toluene/H2O

3 4

Toluene/H2O

Xantphos (10%)

tBuOK

0

5

Toluene/H2O

Xantphos (10%)

KF

43

6

Anisole/H2O

Xantphos (10%)

K2CO3

48

7

DMF/H2O

Xantphos (10%)

K2CO3

0

8

Dioxane/H2O

Xantphos (10%)

K2CO3

19

9

Toluene

Xantphos (10%)

K2CO3

0

10c

Toluene/H2O

Xantphos (10%)

K2CO3

4

11d

Toluene/H2O

Xantphos (10%)

K2CO3

trace

12

e

Toluene/H2O

Xantphos (10%)

K2CO3

39

13f

Toluene/H2O

Xantphos (10%)

K2CO3

32

14g

Toluene/H2O

Xantphos (10%)

K2CO3

47

15h

Toluene/H2O

Xantphos (10%)

K2CO3

60

16i

Toluene/H2O

Xantphos (10%)

K2CO3

65(60)

a

Reactions were carried out in a two-chamber system. Chamber A: 1 (0.50 mmol), 2 (0.25 mmol), Pd(PPh3)4 (5.0 mol%), Xantphos (10.0 mol%), K2CO3 (1.0 mmol), CuI (5.0 mol%) in toluene (1 mL) and water (0.1 mL). Chamber B: COgen (0.75 mmol), Pd2(dba)3 (0.0075 mmol), HBF4tBu3P (0.0075 mmol), Cy2NMe (1.5 mmol, 0.32 mL) and toluene (3 mL). bNMR yield with α,α,α-trifluorotoluene as internal standard. Isolated yield in brackets. cToluene (0.5 mL) and H2O (0.5 mL) was used. d50 mol% CuI was used instead of 5 mol%. eNo CuI was used. f2.0 equiv of K2CO3 was used instead of 4.0 equiv. g6.0 equiv of CO was used instead of 3.0 equiv. hReaction was carried out at 50 oC instead of 100 oC. i2.0 equiv of octyl–9-BBN and 1.0 equiv of bromide were used at 50 oC.

With the optimal conditions at hand, the scope and limitations of the reaction were explored as depicted in Schemes 3 and 4. Generally, both secondary and tertiary amides showed compatibilities under the optimal conditions, giving rise to the desired α,α-difluoro-β-alkyl-β-ketoamides in moderate to good yields (Scheme 3). The secondary amide bearing a tertbutyl group was converted to the corresponding ketone 4 in a 41% yield. The products 5 and 6, carrying a benzyl amide and phenyl ethyl amide, were prepared in 50% and 46% yields, respectively. At an elevated temperature, the N-cyclooctyland N-hexylamides 7 and 8 were formed in acceptable yields. α-Bromo-α,α-difluoroamides 9 and 10 displaying substituted aniline moieties proved to be viable coupling partners for this carbonylative tranformation. Moving from secondary amides to tertiary amides gave similar results. Hence, amides 11–15 derived from piperidine, pyrrolidine, morpholine and diethylamine were well tolerated under the optimal conditions, giving yields from 50% to 75%. It is noted that the 13C-labeled

2 ACS Paragon Plus Environment

Page 3 of 7 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

ACS Catalysis Scheme 3. Carbonylative Coupling Reactions between Octyl–9-BBN and Bromodifluoroacetamidesa

butylthiopropene allowing for the formation of 26–28 in yields from 36% to 65%. Unfortunately, when internal alkenes (e.g. cyclohexene, 2-octene) were used under the optimal conditions, only the debrominated side product could be isolated. Recently, the reductive elimination rates of Pd(II) species carrying an α-fluoroacyl moiety and an aryl group were reported by the Hartwig group.14 Monofluoroacetates were found to reductively eliminate 40 times faster than the difluoro-counterpart, and 8 times faster than the N-morpholinyl difluoroacetamide. When ethyl α-fluoroacetate was tested under our optimal conditions, ketone 29 was isolated in a 60% yield as a colorless oil. However, attempts to couple this αfluoroacetate with other more elaborate olefins proved Scheme 4. Carbonylative Coupling Reactions with Various Alkyl–9-BBN Reagentsa

a Chamber A: Bromide (0.25 mmol), C8H18–9-BBN (0.5 mmol), Pd(PPh3)4 (5.0 mol%), Xantphos (10.0 mol%), K2CO3 (1.0 mmol), CuI (5.0 mol%) in toluene (1 mL) and water (0.1 mL). Chamber B: COgen (0.75 mmol), Pd2(dba)3 (0.0075 mmol), HBF4tBu3P (0.0075 mmol), Cy2NMe (1.5 mmol, 0.32 mL) and toluene (3 mL). bReaction was carried out at 60 oC.

version of compounds 8 and 13 could easily be prepared with comparable yields by using 13C-COgen. Next our attention was turned to exploring the scope of various alkyl boron species (Scheme 4). These boron reagents were prepared from the hydroboration of terminal alkenes with the 9-BBN dimer. Firstly, a selection of substituted styrenes were explored under optimal conditions, generating the corresponding difluoroketoamides in yields ranging from 50% to 70%. Styrenes carrying alkyl substituents (e.g. 3-methyl and 4-t-Bu) on the phenyl ring were converted to compounds 16 and 17 in 50% and 66% yield, respectively. Similar substrates bearing a chloride and bromide substituent were also tolerant under the optimal conditions, giving rise to compounds 18 and 19 in identical yields. Difluoroketoamide 20 bearing a 3-trifluoromethyl group was prepared in a 70% yield. Biphenyl and naphthalene could also be incorporated in moderate yields (21 and 22). Furthermore, with an ortho-methyl substituted styrene, the desired product was obtained 23 in a 50% yield. α-Methylstyrene and 1,1-diphenylethylene were shown to be suitable substrates for the transformation, furnishing the desired products 24 and 25 (Scheme 4). Finally, an alkyl–9-BBN bearing a longer carbon chain were examined as demonstrated with 3-phenyl-1-propene, safrole and even 3-t-

a

Chamber A: Bromide (0.25 mmol), alkyl–9-BBN (0.5 mmol), Pd(PPh3)4 (5.0 mol%), Xantphos (10.0 mol%), K2CO3 (1.0 mmol), CuI (5.0 mol%), in toluene (1 mL) and water (0.1 mL). Chamber B: COgen (0.75 mmol), Pd2(dba)3 (0.0075 mmol), HBF4tBu3P (0.0075 mmol), Cy2NMe (1.5 mmol, 0.32 mL) and toluene (3 mL). bReaction was carried out at RT.

3 ACS Paragon Plus Environment

ACS Catalysis 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

unrewarding. Nonetheless, the carbonylative coupling of the corresponding amide with safrole provided the α-fluoro-βketoamide 30, albeit in a low yield. Finally, difluorobromotoluene was also examined, but none of the expected product was obtained from its carbonylative coupling with n-octyl–9BBN. Having demonstrated the scope of this methodology, we explored the utility of the difluoroketoamide structure as precursor for chemical synthesis of other valuable fluorinecontaining molecules (Scheme 5). Upon applying different reduction conditions, the difluoroketoamides including their 13 C-labeled versions could be reduced to an α,α-difluoro-βalkyl-β-hydroxylamide (as for 31), 2,2-difluoro-1,3-diols (35a and 35c) and a difluorohydroxylamine (34). Switching to NaBD4, the M+3 version of 35a was achieved as with 35b, and the corresponding M+4, as with 35d could also be prepared. The difluoroketoamides were also shown to be versatile precursors for the formation of fluorine-containing heterocycles. When compound 13 was subjected to hydrazine, 4,4difluoro-5-octyl-2,4-dihydro-3H-pyrazol-3-one (33) could be prepared in a 50% yield. Moreover, a 3,3-difluoroazetidin-2one (32a) and its isotopically labeled versions (32b–d) were successfully prepared applying a Mitsunobu reaction.

Page 4 of 7

radical B with a CO coordinated Pd(I) species D.16 Instead of the CO insertion step, a direct transmetalation may occur on E, providing H. Concomitant β-H elimination would form a hydride-ligated Pd(II) species I, which undergoes reductive elimination. This pathway could explain the formation of the main side product J. There is, nevertheless, the possibility that J is formed from a hydrogen abstraction event involving the intermediate radical B and toluene. However, comparison of the 1H-NMR spectra of the debrominated products obtained in a carbonylative coupling in toluene and toluene-d8, did not reveal any deuterium incorporation, suggesting this pathway is not taking place.

Scheme 5. Functionalization of α,α-Difluoro-β β -alkyl-β βketoamides

Figure 1. Plausible Catalytic Cycle for the Formation of α,α-Difluoro-β β -alkyl-β β -ketoamides (Ligand omitted for clarity) a) NaBH4 (4.0 equiv), methanol, 0 oC–RT. b) From 13, NaBH4 or NaBD4 (4.0 equiv), 1-propanol, 80 oC. c) BH3·THF (5.0 equiv), THF, 0–80 oC. d) From 13, hydrazine (1.0 equiv), ethanol, RT–80 oC. e) 1. NaBH4 (4.0 equiv), methanol, 0 oC–RT. 2. PPh3 (1.5 equiv), DIAD (1.5 equiv), THF, RT.

Based on previous studies, a single electron transfer pathway would most likely be involved for this carbonylative coupling,5c,6,9c,15 and hence, a tentative mechanism is proposed in Figure 1. An initial halide abstraction step involving Pd(0) generates the carbon-centered radical B together with a Pd(I) complex C. Subsequent, combination of radical B with C under a CO atmosphere forms a CO ligated complex E, which then converts to the acyl Pd(II) complex F. Subsequent transmetalation with alkyl–9-BBN provides the Pd(II) complex G, which upon reductive elimination provides the desired difluoroketoamide. An alternative pathway to complex F could also be envisaged through the direct combination of the

In conclusion, we have provided a direct route for the preparation of α,α-difluoro-β-alkyl-β-ketoamides via a Pdcatalyzed carbonylative coupling between bromodifluoroacetamides and alkyl boron reagents. Various amides and esters containing fluoroalkylated chains have been successfully synthesized by employing this method. Moreover, difluorosubstituted heterocycles have been achieved from the modification of the products. Finally, 13C-labeled α,α-difluoro-βalkyl-β-ketoamides, diols and heterocycles can be achieved by employing 13C-COgen.

ASSOCIATED CONTENT Supporting Information Experimental details and spectroscopic data. This material is available free of charge via the Internet at http://pubs.acs.org.

4 ACS Paragon Plus Environment

Page 5 of 7 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

ACS Catalysis

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected].

Notes Troels Skrydstrup is a co-owner of SyTracks a/s, which commercializes COgen and the two-chamber technology.

ACKNOWLEDGMENT We are deeply appreciative of the generous financial support from the Danish National Research Foundation (Grant No. DNRF118) and Aarhus University for generous financial support.

REFERENCES (1) a) Gouverneur, V.; Seppelt, K. Introduction: Fluorine Chemistry. Chem. Rev. 2015, 115, 563–565. b) Wang, J.; SanchezRosello, M.; Acena, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001–2011). Chem. Rev. 2014, 114, 2432–2506. c) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J. Organic Fluorine Compounds: A Great Opportunity For Enhanced Materials Properties. Chem. Soc. Rev. 2011, 40, 3496–3508. (2) a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in Medicinal Chemistry. Chem. Soc. Rev. 2008, 37, 320–330. b) Isanbor, C.; O’Hagan, D. Fluorine In Medicinal Chemistry: A Review Of Anti-Cancer Agents. J. Fluorine Chem. 2006, 127, 303– 319. c) Cametti, M.; Crousse, B.; Metrangolo, P.; Milani, R.; Resnati, G. The Fluorous Effect in Biomolecular Applications. Chem. Soc. Rev. 2012, 41, 31–42. (3) a) Schimler, S. D.; Cismesia, M. A.; Hanley, P. S.; Froese, R. D.; Jansma, M. J.; Bland, D. C.; Sanford, M. S. Nucleophilic Deoxyfluorination of Phenols Via Aryl Fluorosulfonate Intermediates. J. Am. Chem. Soc. 2017, 139, 1452–1455. b) Sanford, M. S.; Scott, P. J. Moving Metal-Mediated 18F-Fluorination from Concept to Clinic. ACS Cent. Sci. 2016, 2, 128–130. c) Furuya, T.; Kamlet, A. S.; Ritter, T. Catalysis for Fluorination and Trifluoromethylation, Nature 2011, 473, 470–477. d) Neumann, C. N.; Hooker, J. M.; Ritter, T. Concerted Nucleophilic Aromatic Substitution with 19F− and 18F−. Nature 2016, 534, 369-373. e) Neumann, C. N.; Ritter, T. Facile C–F Bond Formation Through a Concerted Nucleophilic Aromatic Substitution Mediated by the Phenofluor Reagent. Acc. Chem. Res. 2017, 50, 2822–2833. f) Liang, T.; Neumann, C. N.; Ritter, T. Introduction of Fluorine and Fluorine-Containing Functional Groups. Angew. Chem. Int. Ed. 2013, 52, 8214–8264. (4) Meanwell, N. A. Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design. J. Med. Chem. 2011, 54, 2529–2591. (5) a) Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii, H. A New Method for Aromatic Difluoromethylation: Copper-Catalyzed CrossCoupling and Decarboxylation Sequence from Aryl Iodides. Org. Lett. 2011, 13, 5560–5563. b) Guo, C.; Wang, R.-W.; Qing, F.-L. Palladium Catalyzed Direct α-Arylation of α,α-Difluoroketones with Aryl Bromides. J. Fluorine Chem. 2012, 143, 135–142. c) Feng, Z.; Min, Q. Q.; Xiao, Y. L.; Zhang, B.; Zhang, X. Palladium-Catalyzed Difluoroalkylation of Aryl Boronic Acids: A New Method for the Synthesis of Aryldifluoromethylated Phosphonates and Carboxylic Acid Derivatives. Angew. Chem. Int. Ed. 2014, 53, 1669–1673. d) Ge, S.; Arlow, S. I.; Mormino, M. G.; Hartwig, J. F. Pd-Catalyzed αArylation of Trimethylsilyl Enolates of α,α-Difluoroacetamides. J. Am. Chem. Soc. 2014, 136, 14401–14404. e) Ge, S.; Chaladaj, W.; Hartwig, J. F. Pd-Catalyzed α-Arylation of α,α-Difluoroketones with Aryl Bromides and Chlorides. A Route to Difluoromethylarenes. J. Am. Chem. Soc. 2014, 136, 4149–4152. f) Min, Q. Q.; Yin, Z.; Feng, Z.; Guo, W. H.; Zhang, X. Highly Selective Gem-Difluoroallylation

of Organoborons with Bromodifluoromethylated Alkenes Catalyzed by Palladium. J. Am. Chem. Soc. 2014, 136, 1230–1233. g) Xiao, Y. L.; Guo, W. H.; He, G. Z.; Pan, Q.; Zhang, X. Nickel-Catalyzed Cross-Coupling of Functionalized Difluoromethyl Bromides and Chlorides with Aryl Boronic Acids: A General Method for Difluoroalkylated Arenes. Angew. Chem. Int. Ed. 2014, 53, 9909– 9913. h) Arlow, S. I.; Hartwig, J. F. Synthesis of Aryldifluoroamides by Copper-Catalyzed Cross-Coupling. Angew. Chem. Int. Ed. 2016, 55, 4567–4572. i) Feng, Z.; Xiao, Y.-L.; Zhang, X. PalladiumCatalyzed Phosphonyldifluoromethylation of Alkenes with Bromodifluoromethylphosphonate. Org. Chem. Front. 2016, 3, 466– 469. j) Gu, J. W.; Min, Q. Q.; Yu, L. C.; Zhang, X. Tandem Difluoroalkylation-Arylation of Enamides Catalyzed by Nickel. Angew. Chem. Int. Ed. 2016, 55, 12270–12274. k) Guo, W.-H.; Luo, Z.-J.; Zeng, W.; Zhang, X. Access to Difluoromethylene-Skipped 1,4-Diynes with Gem-Difluoropropargyl Bromide. ACS Catal. 2016, 7, 896–901. l) Tarui, A.; Shinohara, S.; Sato, K.; Omote, M.; Ando, A. Nickel-Catalyzed Negishi Cross-Coupling of Bromodifluoroacetamides. Org. Lett. 2016, 18, 1128–1131. m) Xiao, Y. L.; Min, Q. Q.; Xu, C.; Wang, R. W.; Zhang, X. Nickel-Catalyzed Difluoroalkylation of (Hetero)Arylborons with Unactivated 1-Bromo1,1-Difluoroalkanes. Angew. Chem. Int. Ed. 2016, 55, 5837–5841. n) An, L.; Xu, C.; Zhang, X. Highly Selective Nickel-Catalyzed GemDifluoropropargylation of Unactivated Alkylzinc Reagents. Nat. Commun. 2017, 8, 1460. o) Feng, Z.; Min, Q. Q.; Fu, X. P.; An, L.; Zhang, X. Chlorodifluoromethane-Triggered Formation of Difluoromethylated Arenes Catalysed by Palladium. Nat. Chem. 2017, 9, 918–923. (6) a) Andersen, T. L.; Frederiksen, M. W.; Domino, K.; Skrydstrup, T. Direct Access to α,α-Difluoroacylated Arenes by Palladium-Catalyzed Carbonylation of (Hetero)Aryl Boronic Acid Derivatives. Angew. Chem. Int. Ed. 2016, 55, 10396–10400. b) Zhao, H. Y.; Feng, Z.; Luo, Z.; Zhang, X. Carbonylation of Difluoroalkyl Bromides Catalyzed by Palladium. Angew. Chem. Int. Ed. 2016, 55, 10401–10405. (7) a) Kline, T.; Bowman, J.; Iglewski, B. H.; de Kievit, T.; Kakai, Y.; Passador, L. Novel Synthetic Analogs of the Pseudomonas Autoinducer. Bioorg. Med. Chem. Lett. 1999, 9, 3447–3452. b) Welch, M.; Dutton, J. M.; Glansdorp, F. G.; Thomas, G. L.; Smith, D. S.; Coulthurst, S. J.; Barnard, A. M.; Salmond, G. P.; Spring, D. R. Structure–Activity Relationships of Erwinia carotovora Quorum Sensing Signaling Molecules. Bioorg. Med. Chem. Lett. 2005, 15, 4235–4238. (8) a) Zhang, Z.; Bi, J.; Liu, Q.; Zhang, G. The Synthesis of α,αDifluoroacetamides via Electrophilic Fluorination in the MixedSolvent of Water and PEG-400. J. Fluorine Chem. 2013, 151, 45–49. b) Davis, F. A.; Han, W.; Murphy, C. K. Selective, Electrophilic Fluorinations Using N-Fluoro-O-Benzenedisulfonimide. J. Org. Chem. 1995, 60, 4730–4737. c) Glansdorp, F. G.; Thomas, G. L.; Lee, J. K.; Dutton, J. M.; Salmond, G. P.; Welch, M.; Spring, D. R. Synthesis and Stability of Small Molecule Probes for Pseudomonas aeruginosa Quorum Sensing Modulation. Org. Biomol. Chem. 2004, 2, 3329–3336. (9) a) Friis, S. D.; Lindhardt, A. T.; Skrydstrup, T. The Development and Application of Two-Chamber Reactors and Carbon Monoxide Precursors for Safe Carbonylation Reactions. Acc. Chem. Res. 2016, 49, 594–605. b) Yin, H.; Skrydstrup, T. Access To Perfluoroalkyl-Substituted Enones and Indolin-2-ones via Multicomponent Pd-Catalyzed Carbonylative Reactions. J. Org. Chem. 2017, 82, 6474–6481. c) Andersen, T. L.; Kramer, S.; Overgaard, J.; Skrydstrup, T. Evidence for Single-Electron Pathways in the Reaction Between Palladium(II) Dialkyl Complexes and Alkyl Bromides under Thermal and Photoinduced Conditions. Organometallics, 2017, 36, 2058–2066. (10) a) Kambe, N.; Iwasaki, T.; Terao, J. Pd-Catalyzed CrossCoupling Reactions of Alkyl Halides, Chem. Soc. Rev. 2011, 40, 4937–4947. b) Miyaura, N.; Ishiyama, T.; Ishikawa, M.; Suzuki, A.

5 ACS Paragon Plus Environment

ACS Catalysis 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

Page 6 of 7

Palladium-Catalyzed Cross-Coupling Reactions of B-Alkyl-9-BBN or Trialkylboranes with Aryl and 1-Alkenyl Halides. Tetrahedron Lett. 1986, 27, 6369–6372. c) Miyaura, N.; Suzuki, A. PalladiumCatalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457–2483. d) Martin, R.; Buchwald, S. L. Palladium-Catalyzed Suzuki−Miyaura Cross-Coupling Reactions Employing Dialkylbiaryl Phosphine Ligands. Acc. Chem. Res. 2008, 41, 1461–1473. e) Zhou, J.; Fu, G. C. Palladium-Catalyzed Negishi Cross-Coupling Reactions of Unactivated Alkyl Iodides, Bromides, Chlorides, and Tosylates. J. Am. Chem. Soc. 2003, 125, 12527– 12530. f) Kirchhoff, J. H.; Dai, C.; Fu, G. C. A Method For Palladium-Catalyzed Cross-Couplings of Simple Alkyl Chlorides: Suzuki Reactions Catalyzed by [Pd2(dba)3]/PCy3. Angew. Chem. Int. Ed. 2002, 41, 1945–1947. g) Netherton, M. R.; Fu, G. C. Suzuki Cross-Couplings of Alkyl Tosylates that Possess Β Hydrogen Atoms: Synthetic and Mechanistic Studies. Angew. Chem. Int. Ed. 2002, 41, 3910–3912. h) Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C. Boronic Acids:  New Coupling Partners in Room-Temperature Suzuki Reactions of Alkyl Bromides. Crystallographic Characterization of an Oxidative-Addition Adduct Generated Under Remarkably Mild Conditions. J. Am. Chem. Soc. 2002, 124, 13662– 13663. i) Lee, J. Y.; Fu, G. C. Room-Temperature Hiyama CrossCouplings of Arylsilanes with Alkyl Bromides and Iodides. J. Am. Chem. Soc. 2003, 125, 5616–5617. j) Eckhardt, M.; Fu, G. C. The First Applications of Carbene Ligands in Cross-Couplings of Alkyl Electrophiles:  Sonogashira Reactions of Unactivated Alkyl Bromides And Iodides. J. Am. Chem. Soc. 2003, 125, 13642–13643. k) Wiskur, S. L.; Korte, A.; Fu, G. C. Cross-Couplings of Alkyl Electrophiles Under “Ligandless” Conditions:  Negishi Reactions of Organozirconium Reagents. J. Am. Chem. Soc. 2004, 126, 82–83. l) Choi, J.; Fu, G. C. Transition Metal–Catalyzed Alkyl-Alkyl Bond Formation: Another Dimension in Cross-Coupling Chemistry. Science 2017, 356, eaaf7230. m) Dreher, S. D.; Lim, S. E.; Sandrock, D. L.; Molander, G. A. Suzuki−Miyaura Cross-Coupling Reactions of Primary Alkyltrifluoroborates with Aryl Chlorides. J. Org. Chem. 2009, 74, 3626–3631. (11) Hermange, P.; Lindhardt, A. T.; Taaning, R. H.; Bjerglund, K.; Lupp, D.; Skrydstrup, T. Ex Situ Generation of Stoichiometric and Substoichiometric 12CO And 13CO and its Efficient Incorporation in Palladium Catalyzed Aminocarbonylations. J. Am. Chem. Soc. 2011, 133, 6061–6071. (12) Ishiyama, T.; Miyaura, N.; Suzuki, A. Palladium-Catalyzed Carbonylative Cross-Coupling Reaction of Iodoalkanes with 9-Alkyl9-BBN Derivatives. A Direct and Selective Synthesis of Ketones. Tetrahedron Lett. 1991, 32, 6923–6926. (13) Mee, S. P. H., Lee, V.; Baldwin, J. E. Significant Enhancement of the Stille Reaction with a New Combination of Reagents– Copper(I) Iodide with Cesium Fluoride. Chem. Eur. J. 2005, 11, 2394–3308. (14) Arlow, S. I.; Hartwig, J. F. Synthesis, Characterization, and Reactivity of Palladium Fluoroenolate Complexes. J. Am. Chem. Soc. 2017, 139, 16088–16091. (15) Yang, Z. Y.; Burton, D. J. A Novel and Practical Preparation of a,a-Difluoro Functionalized Phosphonates from Iododifluoromethylphosphonate. J. Org. Chem. 1992, 57, 4676–4683. (16) Sumino, S.; Fusano, A.; Fukuyama, T.; Ryu, I. Carbonylation Reactions of Alkyl Iodides Through the Interplay of Carbon Radicals and Pd Catalysts. Acc. Chem. Res. 2014, 47, 1563–1574.

6 ACS Paragon Plus Environment

Page 7 of 7 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

ACS Catalysis

Graphical Abstract

7 ACS Paragon Plus Environment