Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of Î±-Oxo-Vinylsulfones

Subscriber access provided by IDAHO STATE UNIV

Communication

Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of #-OxoVinylsulfones to Prepare C-Aryl Glycals and Acyclic Vinyl Ethers Liang Gong, Hongbao Sun, Li-Fan Deng, Xia Zhang, Jie Liu, Shengyong Yang, and Dawen Niu J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Apr 2019 Downloaded from http://pubs.acs.org on April 26, 2019

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 14 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

Journal of the American Chemical Society

Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of -Oxo-Vinylsulfones to Prepare C-Aryl Glycals and Acyclic Vinyl Ethers Liang Gong,‡ Hong-Bao Sun,‡ Li-Fan Deng, Xia Zhang, Jie Liu, Shengyong Yang, Dawen Niu* Department of Emergency, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and School of Chemical Engineering, Sichuan University, Chengdu, China 610041

Supporting Information Placeholder ABSTRACT: We demonstrate that readily available and

bench-stable -oxo-vinylsulfones are competent electrophiles in Ni-catalyzed Suzuki-Miyaura crosscoupling reactions. The C–sulfone bond in the -oxovinylsulfone motif is cleaved chemoselectively in these reactions, furnishing C-aryl glycals or acyclic vinyl ethers in high yields. These reactions proceed under mild conditions and tolerate a remarkable scope of heterocycles and functional groups. Preliminary mechanistic studies revealed the importance of an heteroatom in facilitating these transformations.

Scheme 1. Sulfones as electrophiles in cross-coupling reactions. a) Challenges of using arylsulfones as electrophiles in cross-coupling reactions Main Challenges: O O S R1 R2

- RSO2Met +

R3

R1

Met

2

1

3

I. non-trivial oxidative insertion step II. chemoselective oxidative insertion? III. desulfination process of R2SO2-

Previous work: Wenkert, Julia, Denmark, Crudden, Baran, Hu, Li, etc. b) Use of -oxo vinylsulfones as electrophiles in cross-coupling reactions (This work) O O

O S

RO

Ar

R’

Ar

BPin

– R’SO2–

O

O

O S

RO

R’

O

Ar

RO

Ni 40 to 80 °C

5

4 O

B(OH)2

or

+ OR

The Suzuki-Miyaura cross-coupling reactions have become indispensable tools in organic and medicinal chemistry by enabling the facile and robust union of molecular fragments via C–C bonds.1 The current availability and relative stability of various organoboron nucleophiles imparts great operational simplicity to these reactions. The most frequently used electrophiles for Suzuki-Miyaura couplings are organohalides and sulfonates.2 The discovery and development of alternative electrophilic partners for Suzuki-Miyaura reactions is of significance, especially in situations where the conventional ones are unreactive, unstable, or difficult to prepare. In this regard, some very recent achievements include the use of phenolates, ethers or esters,3 ammonium or pyridinium salts,4 nitro compounds,5 amides,6 acid fluorides,7 and activated C–C bonds8 as electrophiles.9 Such advances have dramatically enriched the toolboxes of synthetic chemists and enlarged the accessible chemical space. Sulfones represent a fundamental functional group in chemistry.10 The versatility and general stability of sulfones render them important intermediates that have been applied in the synthetic schemes of many complex products. However, when compared with organohalides or sulfonates, the use of sulfones as electrophiles in crosscoupling reactions (1+2 to 3, Scheme 1a) is relatively uncommon. Several factors may have contributed to

R3

OR

6

• Mild conditions • Broad substrate scope

RO

• Desulfination process suppressed OR

4

OR

7

• -Oxygen atom is critical for reactivity

this outcome. First, the oxidative insertion of the less polarized C–SO2R bonds is considered to be more difficult.11 Second, sulfones contain two C–SO2 bonds (cf. 1 in Scheme 1a), which have to be distinguished during the oxidative insertion step. Third, upon oxidative insertion, the resulting sulfinates (RSO2-) are prone to undergo desulfination to give R- which can re-enter the catalytic cycle as nucleophiles, rather than electrophiles.12 In spite of the above challenges, tremendous progress has been made in harnessing sulfones as electrophilic cross-coupling partners. The use of sulfones as the C(sp3) electrophiles was reported by the Li13a and the Denmark groups.13b Recent significant developments include those disclosed by the Crudden group14 to make tertiary or quaternary carbon-centers, and by the Baran15 and Hu groups16 to make C–C bonds from highly fluorinated species. Interestingly, although the use of vinyl or arylsulfones as C(sp2) electrophiles has a longer history, research in this realm11 has remained largely dormant since the seminal studies of the Wenkert17 and the Julia groups.18 Most of the reported methods employ Grignard reagents as nucleophiles,19 which greatly limits their synthetic utility.

ACS Paragon Plus Environment

Journal of the American Chemical Society 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

Table 1. Condition optimization for cross-coupling of 8a/b and 9.a OBn

O O

O S

R

Ni(COD)2 (10 mol%) Cy3P•HBF4 (20 mol%)

+

Ph B(OH)2

BnO OBn R = Ph, 8a

9

KOH (2 equiv) THF, 60 °C, 13 h

OBn

+ RSO2K BnO OBn

R = 4-CF3Ph, 8b

10 conversion yield of 8a of 10

entry

deviation from “standard conditions”

1

“standard conditions” with 8a Fe, Co, Pd instead of Ni(COD)2

100%

94%

2

trace

0%

3

Ni(OTf)2 instead of Ni(COD)2, 80 °C

100%

93%

4

NiCl2•glyme instead of Ni(COD)2, 80 °C

90%

81%c

5 Ni(COD)2 (5 mol%) and Cy3P•HBF4 (10 mol%) 90%

86%

6

L2 instead of Cy3P•HBF4, 80 °C

7 8 9

Ph

O

83%

81%

L3 instead of Cy3P•HBF4

26%

12%

87% 100%

71% 11%

10

NaOH instead of KOH KOtBu instead of KOH Ph-Bpin instead of Ph-B(OH)2

100%

90%

11

Ph-BF3K instead of Ph-B(OH)2

90%

0%

12

8b instead of 8a

100%

84%

13

tBuOH instead of THFb

100%

82%

14

PhMe instead of THFb

95%

92%

15

THF/H2O (3:1) used as solvent

100%

90%

16

reaction performed at 40 °C for 16 h

>95%

85%

11

Cy3P•HBF4 L1

Ph

Ph

N

N L2

iPr

iPr N

N

iPr

iPr L3

a Reactions

in this Table were performed at 0.05 mmol scale, using 2 equiv. of 9. Yield and conversion were determined by 1H NMR using 1,3,5-trimethoxybenzene as internal standard. b Reaction was performed at 80 °C using Ni(OTf) . c Isolated yield of a 2 mmol scale reaction. 2

Our group is interested in the development of novel methods to make carbohydrate derivatives.20 In a project aimed at making C-aryl glycals,21 common intermediates to pharmaceutically important C-glycosides,22 we became intrigued by the possibility of using 1-sulfonyl glycals as an alternative to the corresponding 1-iodoglycals as the electrophilic cross-coupling partners (4 + 5 to 6, Scheme 1b). The reported preparation of 1-iodoglycals requires the use of t-BuLi, and, as with other oxo-vinyl halides, many 1-iodo-glycals are inherently unstable.21a-e In comparison, 1-sulfonyl glycals are readily obtained in large scale from glycosyl sulfones by -oxo elimination and show stability toward long-term storage.23 These features should render them more attractive substrates in library synthesis. We were aware, though, besides the intrinsic challenges of using sulfones as cross-coupling electrophiles mentioned above, to employ sulfonyl glycal 4 as a synthetic equivalent of 7 presents additional difficulties. First, the presence of an -oxygen atom in 4 would render the double bond more electron-rich, and might further deactivate the C–S bond toward oxidative addition. Second, a number of other functional groups, including vinyl ethers3,24 and allyl ethers, could potentially undergo oxidative addition and interfere with the reaction outcomes. These potential pitfalls notwithstanding, we established in this work that 1-sulfonyl glycals could serve as convenient electrophilic partners in the Ni-catalyzed Suzuki-Miyaura reactions, to produce various C-aryl glycals in high yields. We further established that acyclic -oxo-vinyl sulfones could function as electrophilic synthons in these reactions as well, furnishing acyclic vinyl ethers. Control experiments have shown that the -oxygen atom played critical roles to activate these substrates and facilitate the desired reactions.

Page 2 of 14

We commenced our study by using phenyl boronic acid (9) and the sulfonyl glycal 8a as model substrates (Table 1). After screening reaction parameters, we found the desired aryl glycal 10 could be formed in excellent yield when Ni(COD)2 and Cy3P•HBF4 (L1) were employed as catalyst precursors, KOH as base, and THF as solvent at 60 °C (entry 1). Under these conditions, we found potassium phenylsulfinate (11) was formed in almost quantitative yield and precipitated out of solution. The vinyl ether or allyl ether groups in 8a stayed intact under these reaction conditions. Control experiments have revealed some key factors for the success of this reaction. Among the various transition metals (Pd, Fe, Co, Ni, etc.) attempted, Ni is uniquely effective to promote this reaction (entry 2 and Table S1 in SI). Besides Ni(COD)2, other Ni(II) precatalysts could also be employed (entry 3– 4). A gram scale reaction was performed using NiCl2•glyme with standard Schlenk technique (entry 4). Lowering the catalyst loading to 5 mol% resulted in slightly diminished yield of 10 (entry 5). Switching ligand to L2 delivered 10 in decent yield, but the use of L3 dramatically lowered the reaction efficiency (entries 6– 7). The use of NaOH instead of KOH gave 71% yield of 10 (entry 8), but employing tBuOK afforded 10 in only 11% yield (entry 9). Boronic acid pinacol esters could also be used as nucleophiles, giving almost identical yields as did boronic acids (entry 10). In contrast, the use of trifluoroborates led to almost no desired product (entry 11). An electronically tuned sulfone substrate 8b, which contains a 4-trifluoromethyl substituent could also be used (entry 12). This reaction could be conducted in other solvents such as tBuOH and toluene (entry 13–14). Interestingly, water could be used as a co-solvent (entry 15). Lastly, the reaction could even proceed at 40 °C, albeit with somewhat lower yield of 10 (entry 16). With satisfactory reaction conditions established, we explored the scope of this reaction (Scheme 2). We found a large variety of boronic acid derivatives could partake in this reaction. For example, both electron-rich (13a-b, e-f, j) and electron-deficient aryl rings (13d) were tolerated. Aryl boronic acids bearing an ortho-substituent were suitable substrates (13g-i). Vinyl and allyl group could be installed as well, furnishing conjugate diene 13k and skipped diene 13l, respectively. Functional groups including nitriles (13m), esters (13n), free hydroxyls (13o), ketones (13p), amines (13b), amides (13q), and carbamates (13af) were all accommodated, attesting to the mildness of the reaction conditions. Various heteroaryls including dioxolanes (13j), thiophenes (13rs), furans (13t-v), quinolines (13x-y), indoles (13z), azaindoles (13aa), pyridines (13w, 13ab-af), and pyrimidines (13ag) could be readily incorporated, highlighting the generality and practicality of this reaction. Lastly, we showed that the aryl pinacol boronic ester derived from loratadine could be employed in this transformation, affording 13ah in 55% yield.


Page 3 of 14 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. Substrate nucleophiles.a OBn

O O

O S

Het

(HO)2B

Ph

scope

BnO

8a

KOH (2 equiv) THF or tBuOH 60 °C, 12 h

Het

PinB

OBn

organoboron


or

+

of

OBn

13a 13b 13c 13d

R

yield

OMe NMe2 F CF3

82% 74% 79% 74%

Het

O BnO OBn

13

12 R

Scheme 3. Substrate scope of the sulfones.a

F

MeO

Me

MeO

13e, 82%

13f, 75%

13g, 72%

13k, 48%b

13l, 85%b

Me O O

13h, 90%

13i, 80%

13j, 82% Me

Me NC

HO

MeOOC

13m, 70%

13n, 81%

Me2N

Me

O

O

13o, 71%

13p, 73%

13q, 45%

S S

O

13r, 83%

13s, 90%

13w, 59%

13u, 75%

13t, 86%

N

N

13v, 86%

N

N

N

Bn

N

Bn

13z, 68%

13y, 87%

13x, 89%

O

O

13aa, 86%

MeO N

F3C

N

MeO

13ab, 84%

13ac, 90%

N

13ad, 94%

N

N N

N

N

O

Boc

13ae, 89%

N

N MeO

N

13af, 80%

N

OMe

13ag, 73%

EtO

O

13ah, 55%b

a Reactions

were performed at 0.2 mmol. The reported isolated yields are average of two runs. See SI for experimental details. b Reaction was performed at 80 °C.

The scope of 1-sulfonyl glycals was also investigated (Scheme 3a). The 1-sulfonyl glycals 15 were prepared by base induced -elimination from the corresponding glycosyl sulfones 14. Substrates derived from glucose (16a-b), galactose (16c), fucose (16d), rhamnose (16e), arabinose (16f), and xylose (16g) could be employed. Both alkyl ether and silyl ether protecting groups (16a-b) were well tolerated by the reaction conditions. Even sulfones made from disaccharides such as maltose (16h) were competent reaction partners, affording the corresponding aryl glycals in excellent yield. In addition to the cyclic -oxo-vinyl sulfones listed above, acyclic variants also could be employed in our reactions (Scheme 3b). Acyclic -oxo-vinyl sulfones 19 could be prepared in one step from the condensation between aldehydes 17 and sulfone 18. Their subsequent coupling with tolyl boronic acid (20) afforded the corresponding vinyl ethers (21a-d) in good yields as a mixture of E/Z isomers. Further hydrolysis afforded the corresponding ketone 22. Compared with conventional 1,2-addition/oxidation sequence that converts aldehydes to ketones, the method outlined in Scheme 3b affords ketones that are further extended by one methylene unit.

To further demonstrate the potential utility of this reaction, we employed it to synthesize known pharmaceutical agents and modified amino esters (Scheme 4). We established that the cross-coupling between sulfone 23 and boronate 24 proceeded smoothly to afford 25 in 88% yield. Aryl glycal 25 could then be converted to ipragliflozin (26a) by a sequence of hydroboration/oxidation/deprotection reactions. Alternative treatment of 25 by a hydrogenation/deprotection process led to 2-deoxy ipragliflozin (26b). Transition metal catalyzed C–H borylation is a robust method to prepare aryl boronates from complex molecules.25 Combining this C–H borylation reaction with our cross-coupling reaction with 8a, a carbohydrate moiety could be readily installed onto a tryptophan derivative 27 to furnish 29 via the intermediacy of 28. Lastly, the cross-coupling between vinyl sulfone 30 (derived from 4-fluorobenzaldehyde) and vinyl boronic acid pinacol ester (31) afforded electron-rich diene 32 in high yield as a mixture of E/Z isomers. Both isomers underwent smooth Diels–Alder reaction with diethyl fumarate to give a pair of diastereomers, which then converge to the same ketone 33 upon hydrolysis.26 Ketone 33 was used as a key intermediate in the synthesis of 34, a potent human NK1



Page 4 of 14

Scheme 4. Synthetic applications.a

Scheme 5. Mechanistic studies.a

receptor antagonist. With other arylaldehydes used as starting materials, analogues of 34 could be made by this route (See Scheme S1 in SI for another example). The facility with which our cross-coupling proceeds is surprising. We performed some preliminary studies to probe into the mechanism of this reaction. We first prepared a pair of substrates 35a and 35b that differ only by O atom vs. a CH2 group, respectively (Scheme 5a). When subjecting these two substrates to our standard conditions, we found that 35a was cleanly converted to 36a, while the all-carbon analog 35b remained inert. Thus, instead of deactivating vinyl sulfones, the presence of an -oxygen atom appears to activate these substrates. This result led us to propose that the -oxygen atom in 35a might facilitate the oxidative insertion step by precoordinating with the Ni catalyst.27 This hypothesis could also explain the high regioselectivity of the oxidative insertion step: the C–S bond adjacent to the oxygen atom is cleaved selectively. To further corroborate this hypothesis, we then prepared and compared the reactivity of sulfones 37a-c. Among these substrates, 37a, which possess a coordinating -nitrogen atom, underwent smooth coupling with tolyl boronic acid (20). Sulfone 37b also contains a nitrogen atom in the aromatic ring, but it is para to the sulfone moiety. Accordingly, both 38b and the all-carbon analog 38c

provided only low quantities of the arylated products under identical conditions. In another experiment, we subjected sulfone 8a to a THF solution containing a stoichiometric amount of Ni(COD)2 and PCy3 at 45 °C but without a boronic acid component, and found phenylated product 10 was formed in 76% yield (Scheme 5b). This result suggests that both the oxidative insertion of 8a by Ni(0) and the desulfination of the resulting phenyl sulfinate (cf. 41 in Scheme 5c) are viable and facile processes. With the above information, we proposed a plausible reaction mechanism as depicted in Scheme 5c. Substrate 39 first undergoes an regioselective C–S bond insertion by Ni(0) to afford 41, presumably facilitated by the transient formation of 40. Vinyl nickel species 41 could either undergo a desulfination/reductive elimination sequence to give 42, or a transmetallation step to furnish 43 followed by reductive elimination to give 44 as product. The success of our reaction suggests that the transmetallation process could outcompete the desulfination step. In summary, we have shown that -oxo-vinylsulfones are competent electrophilic partners in the Ni-catalyzed Suzuki-Miyaura cross-coupling reactions, and developed general methods to prepare pharmaceutically relevant


Page 5 of 14 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


aryl glycals and synthetically important acyclic vinyl ethers. These reactions employ readily available starting materials and reagents, proceed under mild conditions, and tolerate a remarkable scope of functional groups and heterocycles. Mechanistic studies provide insights into the reaction pathway, and suggest the presence of an heteroatom in -oxo-vinylsulfones was critical for their reactivities in these cross-coupling reactions. ASSOCIATED CONTENT

Supporting Information. The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures and characterization data (file type, i.e., PDF) AUTHOR INFORMATION Corresponding Author

[email protected] Author Contributions

‡These authors contributed equally. Funding Sources

No competing financial interests have been declared. This work is supported by funding from National Natural Science Foundation (Nos. 21772125 and 21602145), and start-up funding from Sichuan University. ACKNOWLEDGMENT

We acknowledge Prof. Jason C. Chruma for proofreading this manuscript and helpful suggestions. REFERENCES (1) (a) Suzuki, A. Cross-Coupling Reactions of Organoboranes: An Easy Way to Construct C–C Bonds (Nobel Lecture). Angew. Chem. Int. Ed. 2011, 50, 6722–6737. (b) Brown, D. G.; Boström, J. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone? J. Med. Chem. 2016, 59, 4443–4458. (2) (a) Smith, M. J.; Lawler, M. J.; Kopp, N.; Mcleod, D. D.; Davulcu, A. H.; Lin, D.; Katipally, K.; Sfouggatakis, C. Development of a Concise Multikilogram Synthesis of LPA-1 Antagonist BMS986020 via a Tandem Borylation–Suzuki Procedure. Org. Process Rec. Dev. 2017, 21, 1859–1863. (b) Seo, J. H.; Liu, P.; Weinreb, S. M. Evolution of a Strategy for Total Synthesis of the Marine Fungal Alkaloid (±)-Communesin F. J. Org. Chem. 2010, 75, 2667–2680. (c) Wang, Z.; Fan, R.; Wu, J. Palladium-Catalyzed Regioselective CrossCoupling Reactions of 3-Bromo-4-tosyloxyquinolin-2(1H)-one with Arylboronic Acids. A Facile and Convenient Route to 3,4Disubstituted Quinolin-2(1H)-ones. Adv. Synth. Catal. 2007, 349, 1943–1948. (3) For reviews, see: (a) Zhang, Y.-F.; Shi, Z.-J. Upgrading CrossCoupling Reactions for Biaryl Syntheses. Acc. Chem. Res. 2019, 52, 161−169. (b) Zeng, H.; Qiu, Z.; Domínguez-Huerta, A.; Hearne, Z.; Chen, Z.; Li, C.-J., An Adventure in Sustainable Cross-Coupling of Phenols and Derivatives via Carbon–Oxygen Bond Cleavage. ACS Catalysis 2016, 7, 510-519. (c) Zarate, C.; van Gemmeren, M.; Somerville, R. J.; Martin, R., Phenol Derivatives: Modern

Electrophiles in Cross-Coupling Reactions. Adv. Organomet. Chem. 2016, 66, 143–222. (d) Tobisu, M.; Chatani, N., Cross-Couplings Using Aryl Ethers via C-O Bond Activation Enabled by Nickel Catalysts. Acc. Chem. Res. 2015, 48, 1717–1726. (e) Tollefson, E. J.; Hanna, L. E.; Jarvo, E. R. Stereospecific nickel-catalyzed crosscoupling reactions of benzylic ethers and esters. Acc. Chem. Res. 2015, 48, 2344–2353. (f) Su, B.; Cao, Z. C.; Shi, Z.-J. Exploration of earthabundant transition metals (Fe, Co, and Ni) as catalysts in unreactive chemical bond activations. Acc. Chem. Res. 2015, 48, 886–896. (g) 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. (h) Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Exploration of New C−O Electrophiles in Cross-Coupling Reactions. Acc. Chem. Res. 2010, 43, 1486–1495. (i) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita, A.-M.; Garg, N. K.; Percec, V. Nickel-Catalyzed Cross-Couplings Involving Carbon-Oxygen Bonds. Chem. Rev. 2011, 111, 1346–1416. (4) Yadav, M. R.; Nagaoka, M.; Kashihara, M.; Zhong, R. L.; Miyazaki, T.; Sakaki, S.; Nakao, Y. The Suzuki-Miyaura Coupling of Nitroarenes. J. Am. Chem. Soc. 2017, 139, 9423−9426. (5) (a) Blakey, S. B.; MacMillan, D. W. C. The First Suzuki CrossCouplings of Aryltrimethylammonium Salts. J. Am. Chem. Soc. 2003, 125, 6046–6047. (b) Maity, P.; Shacklady-McAtee, D. M.; Yap, G. P. A.; Sirianni, E. R.; Watson, M. P. Nickel-Catalyzed Cross Couplings of Benzylic Ammonium Salts and Boronic Acids: Stereospecific Formation of Diarylethanes via C−N Bond Activation. J. Am. Chem. Soc. 2013, 135, 280–285. (c) Buszek, K. R.; Brown, N. NVinylpyridinium and ammonium Tetrafluoroborate Salts: New Electrophilic Coupling Partners for Pd(0)-Catalyzed Suzuki CrossCoupling Reactions. Org. Lett. 2007, 9, 707−710. (d) Basch, C. H.; Liao, J.; Xu, J.; Piane, J. J.; Watson, M. P. Harnessing Alkyl Amines as Electrophiles for Nickel-Catalyzed Cross Couplings via C−N Bond Activation. J. Am. Chem. Soc. 2017, 139, 5313–5316. (e) Plunkett, S.; Basch, C. H.; Santana, S. O.; Watson, M. P. Harnessing Alkylpyridinium Salts as Electrophiles in Deaminative Alkyl–Alkyl Cross-Couplings. J. Am. Chem. Soc. 2019, 141, 2257−2262. (6) For recent reviews, see: (a) Dander, J. E.; Garg, N. K. Breaking Amides using Nickel Catalysis. ACS Catal. 2017, 7, 1413−1423. (b) Takise, R.; Muto, K.; Yamaguchi, J. Cross-coupling of aromatic esters and amides. Chem. Soc. Rev. 2017, 46, 5864–5888. (c) Szostak, M.; Meng, G.; Shi, S. Cross-Coupling of Amides by N–C Bond Activation. Synlett 2016, 27, 2530−2540. (d) Hie, L.; Fine Nathel, N. F.; Shah, T. K.; Baker, E. L.; Hong, X.; Yang, Y. F.; Liu, P.; Houk, K. N.; Garg, N. K. Conversion of amides to esters by the nickel-catalysed activation of amide C-N bonds. Nature 2015, 524, 79−83. (e) Weires, N. A.; Baker, E. L.; Garg, N. K. Nickel-catalysed Suzuki-Miyaura coupling of amides. Nat Chem. 2016, 8, 75−79. (7) Malapit, C. A.; Bour, J. R.; Brigham, C. E.; Sanford, M. S. Basefree Nickel-Catalysed Decarbonylative Suzuki–Miyaura Coupling of Acid Fluorides. Nature 2018, 563, 100–104. (8) (a) Matsuda, T.; Makino, M.; Murakami, M. Rhodium-Catalyzed Addition/Ring-Opening Reaction of Arylboronic Acids with Cyclobutanones. Org. Lett. 2004, 6, 1257−1259. (b) Yu, D.-G.; Yu, M.; Guan, B.-T.; Li, B.-J.; Zheng, Y.; Wu, Z.-H.; Shi, Z.-J. Carbon–Carbon Formation via Ni-Catalyzed Suzuki–Miyaura Coupling through C–CN Bond Cleavage of Aryl Nitrile. Org. Lett. 2009, 11, 3374–3377. (c) Wang, J.; Chen, W.; Zuo, S.; Liu, L.; Zhang, X.; Wang, J. Direct exchange of a ketone methyl or aryl group to another aryl group through C-C bond activation assisted by rhodium chelation. Angew. Chem. Int. Ed. 2012, 51, 12334−12338. (d) Dennis, J. M.; Compagner, C. T.; Dorn, S. K.; Johnson, J. B., Rhodium-Catalyzed Interconversion of Quinolinyl Ketones with Boronic Acids via C-C Bond Activation. Org. Lett. 2016, 18, 3334−3337. (e) Xia, Y.; Wang, J.; Dong, G. Suzuki−Miyaura Coupling of Simple Ketones via Activation of Unstrained Carbon−Carbon Bonds. J. Am. Chem. Soc. 2018, 140, 5347–5351. (9) For other examples, see: (a) Schaub, T.; Backes, M.; Radius, U. Catalytic C−C Bond Formation Accomplished by Selective C−F Activation of Perfluorinated Arenes. J. Am. Chem. Soc. 2006, 128, 15964−15965. (b) Tobisu, M.; Xu, T.; Shimasaki, T.; Chatani, N.



Nickel-Catalyzed Suzuki–Miyaura Reaction of Aryl Fluorides. J. Am. Chem. Soc. 2011, 133, 19505−19511. (c) Muto, K.; Yamaguchi, J.; Musaev, D. G.; Itami, K. Decarbonylative organoboron cross-coupling of esters by nickel catalysis. Nat. Commun. 2015, 6, 1–8. (d) Wang, J.; Qin, T.; Chen, T. G.; Wimmer, L.; Edwards, J. T.; Cornella, J.; Vokits, B.; Shaw, S. A.; Baran, P. S. Nickel-Catalyzed Cross-Coupling of Redox-Active Esters with Boronic Acids. Angew. Chem., Int. Ed. 2016, 55, 9676–9679. (e) Wu, K.; Doyle, A. G. “Parameterization of phosphine ligands demonstrates enhancement of nickel catalysis via remote steric effects” Nature Chem. 2017, 9, 779–784. (10) (a) Meadows, D. C.; Gervay-Hague, J. Vinyl Sulfones: Synthetic Preparations and Medicinal Chemistry Applications. Med. Res. Rev. 2006, 26,793–814. (b) Patai, S.; Rappoport, Z.; Stirling, C. J. M. The Chemistry of Sulphones and Sulphoxides; Wiley: New York, 1988. (11) (a) Dubbaka, S. R.; Vogel, P. Organosulfur Compounds: Electrophilic Reagents in Transition-Metal-Catalyzed Carbon–Carbon Bond-Forming Reactions. Angew. Chem. Int. Ed. 2005, 44, 7674–7684. (b) Wang, L.; He, W.; Yu, Z. Transition-metal mediated carbon–sulfur bond activation and transformations. Chem. Soc. Rev. 2013, 42, 599– 621. (c) Modha, S. G.; Mehta, V. P.; Van der Eycken, E. V. Transition metal-catalyzed C–C bond formation via C–S bond cleavage: an overview. Chem. Soc. Rev. 2013, 42, 5042–5055. (d) Pan, F.; Shi, Z.-J. Recent Advances in Transition-Metal-Catalyzed C−S Activation: From Thioester to (Hetero)aryl Thioether. ACS Catal. 2014, 4, 280–288. (12) (a) Markovic, T.; Murray, P. R. D.; Rocke, B. N.; Shavnya, A.; Blakemore, D. C.; Willis, M. C. Heterocyclic allylsulfones as latent heteroaryl nucleophiles in palladium-catalyzed cross-coupling reactions. J. Am. Chem. Soc. 2018, 15916–15923. (b) Markovic, T.; Rocke, B. N.; Blakemore,D. C.; Mascitti, V.; Willis, M. C. Catalyst selection facilitates the use of heterocyclic sulfinates as general nucleophilic coupling partners in palladium-catalyzed coupling reactions. Org. Lett. 2017, 19, 6033–6035. (c) Markovic, T.; Rocke, B. N.; Blakemore, D. C.; Mascitti, V.; Willis, M. C. Pyridine sulfinates as general nucleophilic coupling partners in palladium-catalyzed crosscoupling reactions with aryl halides. Chem. Sci. 2017, 8, 4437–4442. (d) Takahashi, F.; Nogi, K.; Yorimitsu, H. Intramolecular Desulfitative Coupling: Nickel-Catalyzed Transformation of Diaryl Sulfones into Biaryls via Extrusion of SO2. Org. Lett. 2018, 20, 6601−6605. (e) Zhao, F.; Tan, Q.; Xiao, F.; Zhang, S.; Deng, G.-J. Palladium-Catalyzed Desulfitative Cross-Coupling Reaction of Sodium Sulfinates with Benzyl Chlorides. Org. Lett., 2013, 15,1520–1523. (f) Zhou, C.; Liu, Q.; Li, Y.; Zhang, R.; Fu, X.; Duan, C. Palladium-catalyzed desulfitative arylation by C-O bond cleavage of aryl triflates with sodium arylsulfinates. J. Org. Chem. 2012, 77, 10468–10472. For a review, see: (g) Ortgies, D. H.; Hassanpour, A.; Chen, F.; Woo, S.; Forgione, P. Desulfination as an Emerging Strategy in PalladiumCatalyzed C-C Coupling Reactions. Eur. J. Org. Chem. 2016, 2016, 408–425. (13) (a) Wu, J.-C.; Gong, L.-B.; Xia, Y.; Song, R.-J.; Xie, Y.-X.; Li, J.-H. Nickel-Catalyzed Kumada Reaction of Tosylalkanes with Grignard Reagents to Produce Alkenes and Modified Arylketones. Angew. Chem. Int. Ed. 2012, 51, 9909–9913. (b) Denmark, S. E.; Cresswell, A. J. Iron-Catalyzed Cross-Coupling of Unactivated Secondary Alkyl Thio Ethers and Sulfones with Aryl Grignard Reagents. J. Org. Chem. 2013, 78, 12593–12628. (14) (a) Ariki, Z. T.; Maekawa, Y.; Nambo, M.; Crudden, C. M. Preparation of Quaternary Centers via Nickel-Catalyzed Suzuki−Miyaura Cross-Coupling of Tertiary Sulfones. J. Am. Chem. Soc. 2018, 140, 78–81. (b) Yim, J. C.; Nambo, M.; Crudden, C. M. PdCatalyzed Desulfonative Cross-Coupling of Benzylic Sulfone Derivatives with 1,3-Oxazoles. Org. Lett. 2017, 19, 3715–3718. (c) Nambo, M.; Keske, E. C.; Rygus, J. P. G.; Yim, J. C. H.; Crudden, C. M. Development of Versatile Sulfone Electrophiles for Suzuki– Miyaura Cross-Coupling Reactions. ACS Catalysis 2017, 7, 1108– 1112. (e) Nambo, M.; Crudden, C. M., Recent Advances in the Synthesis of Triarylmethanes by Transition Metal Catalysis. ACS Catalysis 2015, 5, 4734–4742. (f) Nambo, M.; Crudden, C. M. Modular synthesis of triarylmethanes through palladium-catalyzed sequential

Page 6 of 14

arylation of methyl phenyl sulfone. Angew. Chem. Int. Ed. 2014, 53, 742–746. (15) Merchant, R. R.; Edwards, J. T.; Qin, T.; Kruszyk, M. M.; Bi, C.; Che, G.; Bao, D.-H.; Qiao, W.; Sun, L.; Collins, M. R.; Fadeyi, O. O.; Gallego, G. M.; Mousseau , J. J.; Nuhant, P.; Baran, P. S. Modular radical cross-coupling with sulfones enables access to sp3-rich (fluoro)alkylated scaffolds. Science, 2018, 360, 75–80. (16) Miao, W.; Zhao, Y.; Ni, C.; Gao, B.; Zhang, W.; Hu, J. IronCatalyzed Difluoromethylation of Arylzincs with Difluoromethyl 2Pyridyl Sulfone. J. Am. Chem. Soc. 2018, 140, 880–883. (17) Wenkert, E.; Ferreira, T. W.; Michelotti, E. L. Nickel-induced Conversion of Carbon–Sulphur into Carbon-Carbon Bonds. One-step Transformations of Enol Sulphides into Olefins and Benzenethiol Derivatives into Alkylarenes and Biaryls. J. Chem. Soc. Chem. Commun. 1979, 637– 638. (18) (a) Fabre, J.-L.; Julia, M.; Verpeaux, J.-N. Couplage mixte entre sulfones vinyliques et réactifs de grignard en présence de sels de métal de transition: synthèse stéréosélective d'oléfines trisubstituées. Tetrahedron Lett. 1982, 23, 2469–2472. (b) Clayden, J.; Julia, M. ortho-Substituted Unsymmetrical Biaryls from Aryl tert-Butyl Sulfones. J. Chem. Soc., Chem. Commun. 1993, 1682–1683. (c) Clayden, J.; Cooney, J. J. A.; Julia, M. Nickel-catalysed Substitutions of Aryl tert-Butyl Sulfones with Organometallic Reagents: Synthesis of ortho-Substituted Unsymmetrical Biaryls. J. Chem. Soc. Perkin Trans. 1 1995, 7−14. (19) Someya, C. I.; Weidauer, M.; Enthaler, S. Nickel-catalyzed C(sp2)–C(sp2) Cross Coupling Reactions of Sulfur-Functionalities and Grignard Reagents. Catal. Lett. 2013, 143, 424−431. (20) (a) Li, R.-Z.; Tang, H.; Wan, L. Q.; Zhang, X.; Fu, Z.; Liu, J.; Yang, S.; Niu, D. Site-Divergent Delivery of Terminal Propargyls to Carbohydrates by Synergistic Catalysis. Chem. 2017, 3, 1–12. (b) Li, R.-Z.; Tang, H.; Yang, K. R.; Wan, L. Q.; Zhang, X.; Liu, J.; Fu, Z.; Niu, D. Enantioselective Propargylation of Polyols and Desymmetrization of meso 1,2-Diols by Copper/Borinic Acid Dual Catalysis. Angew. Chem. Int. Ed. 2017, 56, 7213–7217. (c) Shang, W.; Mou, Z. D.; Tang, H.; Zhang, X.; Liu, J.; Fu, Z.; Niu, D. Site-Selective O-Arylation of Glycosides. Angew. Chem. Int. Ed. 2018, 57, 314–318. (21) (a) Potuzak, J. S.; Tan, D. S. Synthesis of C1-alkyl- and acylglycals from glycals using a B-alkyl Suzuki–Miyaura cross coupling approach. Tetrahedron Lett. 2004, 45, 1797–1801. (b) Friesen, R. W.; Loo, R. W. Preparation of C-Aryl Glucals via the Palladium-Catalyzed Coupling of Metalated Aromatics with 1-Iodo3,4,6-tri-O-(triisopropylsilyl)-D-glucal. J. Org. Chem. 1991, 56, 4821– 4823. (c) Tius, M. A.; Gomez-Galeno, J.; Gu, X.; Zaidi, J. H. CGlycosylanthraquinone Synthesis: Total Synthesis of Vineomycinone B2 Methyl Ester. J. Am. Chem. Soc. 1991, 113, 5775–5783. (d) Kaelin, D. E.; Lopez, O. D.; Martin, S. F. J. Am. Chem. Soc. 2001, 123, 6937– 6938. (e) Procko, K. J. Functionalization of C-Aryl Glycals and Studies Toward the Total Synthesis of 5-Hydroxyaloin A. The University of Texas at Austin, Austin, 2009. For other methods of making aryl glycals, see: (f) Koester, D. C.; Kriemen, E.; Werz, D. B. Flexible Synthesis of 2-Deoxy-C-Glycosides and (1→2)-, (1→3)-, and (1→4)-Linked C-Glycosides. Angew. Chem., Int. Ed. 2013, 52, 2985−2989. (g) Parkan, K.; Pohl, R.; Kotora, M. Cross-Coupling Reaction of Saccharide-Based Alkenyl Boronic Acids with Aryl Halides: The Synthesis of Bergenin. Chem. Eur. J. 2014, 20, 4414−4419. (h) Liu, M.; Niu, Y.; Wu, Y.-F.; Ye, X. Ligand-Controlled Monoselective C-Aryl Glycoside Synthesis via Palladium-Catalyzed C−H Functionalization of N-Quinolyl Benzamides with 1-Iodoglycals. Org. Lett. 2016, 18, 1836–1839. Palladium-catalyzed Heck-type reactions gave double-bond migrated products. For references, see: (i) Xiong, D.-C.; Zhang, L.-H.; Ye, X.-S. Oxidant-Controlled Heck-Type C-Glycosylation of Glycals with Arylboronic Acids: Stereoselective Synthesis of Aryl 2-Deoxy-C-glycosides. Org. Lett. 2009, 11, 1709−1712. (j) Singh, A. K.; Kandasamy, J. Palladium catalyzed stereocontrolled synthesis of C-aryl glycosides using glycals and arenediazonium salts at room temperature. Org. Biomol. Chem. 2018, 16, 5107–5112. (k) Mabit, T.; Siard, A.; Legros, F.; Guillarme, S.; Martel, A.; Lebreton, J.; Carreaux, F.; Dujardin, G.; Collet, S. Stereospecific C-glycosylation via Mizoroki-Heck reaction, a powerful


Page 7 of 14 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


and easy-to-set-up synthetic tool to access α and β aryl-C-glycosides. Chem. Eur. J. 2018, 24, 14069–14074. (l) Bai, Y.; Kim, L. M. H.; Liao, H.; Liu, X.-W. Oxidative Heck Reaction of Glycals and Aryl Hydrazines: a Palladium-Catalyzed C-glycosylation. J. Org. Chem. 2013, 78, 8821–8825. (m) Liu, C.-F.; Xiong, D.-C.; Ye, X.-S. “Ring Opening–Ring Closure” Strategy for the Synthesis of Aryl-Cglycosides. Chem. Eur. J. 2014, 79, 4676–4686. (n) Lehmann, U.; Awasthi, S.; Minehan, T. Palladium-Catalyzed Cross-Coupling Reactions between Dihydropyranylindium Reagents and Aryl Halides. Synthesis of C-Aryl Glycals. Org. Lett. 2003, 5, 2405–2408. (22) For an excellent review, see: Yang, Y.; Yu, B. Recent Advances in the Chemical Synthesis of C-Glycosides. Chem. Rev. 2017, 117, 12281–12356. (23) Qiu, D.; Schmidt, R. R. A Convenient Synthesis of Pyranoid Ene Lactones from Phenyl Glycosyl Sulfones. Synthesis, 1990, 875–877. (24) Shimasaki, T.; Konno, Y.; Tobisu, M.; Chatani, N. NickelCatalyzed Cross-Coupling Reaction of Alkenyl Methyl Ethers with Aryl Boronic Esters. Org. Lett. 2009, 11, 4890–4892. (25) (a) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. C−H Activation for the Construction of C−B Bonds.

Chem. Rev. 2010, 110, 890–931. (b) Hartwig, J. F. Regioselectivity of the borylation of alkanes and arenes. Chem. Soc. Rev. 2011, 40, 1992– 2002. (26) Kassick, A. J.; Jiang, J.; Bunda, J.; Wilson, D.; Bao, J.; Lu, H.; Lin, P.; Ball, R. G.; Doss, G. A.; Tong, X.; Tsao, K. C.; Wang, H.; Chicchi, G.; Karanam, B.; Tschirret-Guth, R.; Samuel, K.; Hora, D. F.; Kumar, S.; Madeira, M.; Eng, W.; Hargreaves, R.; Purcell, M.; Gantert, L.; Cook, J.; DeVita, R. J.; Mills, S. G. 2-[(3aR,4R,5S,7aS)-5-{(1S)-1[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one: A Potent Human NK1 Receptor Antagonist with Multiple Clearance Pathways. J. Med. Chem. 2013, 56, 5940−5948. An analogue of 34 has also been synthesized by this route. See SI for details. (27) (a) Hooper, J. F.; Young, R. D.; Pernik, I.; Weller, A. S.; Willis, M. C. Carbon–carbon bond construction using boronic acids and aryl methyl sulfides: orthogonal reactivity in Suzuki-type couplings. Chem. Sci. 2013, 4, 1568–1572. (b) Wang, J.-R.; Manabe, K. High Ortho Preference in Ni-Catalyzed Cross-Coupling of Halophenols with Alkyl Grignard Reagents. Org. Lett. 2009, 11, 741–743.



Page 8 of 14

For Table of Contents Only

O O

O S

RO

Ph

Ar

Ni(COD)2 Cy3P•HBF4

B(OH)2

or

+ Ar

OR

BPin

O

Ar

RO

+

KOH, 40–80 °C

PhSO2K

OR

> 50 examples 18 heteroaryls

cyclic or acyclic Ar =

CO2Me MeO

F3C

N

N

N

N N Boc

N

N

N MeO

NHBoc

N

N

OMe

EtO

TIPS O


8

Page 9 of 14 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


a) Challenges of using arylsulfones as electrophiles in cross-coupling reactions Main Challenges: O O S R1 R2

- RSO2Met +

R3

1

R1

Met

R3

3

2

I. non-trivial oxidative insertion step II. chemoselective oxidative insertion? III. desulfination process of R2SO2-

Previous work: Wenkert, Julia, Denmark, Crudden, Baran, Hu, Li, etc. b) Use of α-oxo vinylsulfones as electrophiles in cross-coupling reactions (This work) O O

O S

RO

R’

Ar

or

+ Ar

OR

O RO

BPin

– R’SO2–

O

O S

R’

O

Ar

RO

Ni 40 to 80 °C

5

4 O

B(OH)2

OR

6

• Mild conditions • Broad substrate scope

RO

• Desulfination process suppressed OR

4

OR

7

• α-Oxygen atom is critical for reactivity



OBn

O O

O S

Het

(HO)2B

Ph


or

+

BnO OBn

8a

KOH (2 equiv) THF or tBuOH 60 °C, 12 h

Het

PinB

Page 10 of 14

OBn

BnO OBn

13

12 R

13a 13b 13c 13d

R

yield

F

MeO

82% 74% 79% 74%

OMe NMe2 F CF3

Het

O

Me

MeO

13e, 82%

13f, 75%

13g, 72%

13k, 48%b

13l, 85%b

Me O O

13h, 90%

13i, 80%

13j, 82% Me

Me NC

HO

MeOOC

13m, 70%

13n, 81%

Me2N

Me

O

O

13o, 71%

13p, 73%

13q, 45%

S S

O

13r, 83%

13t, 86%

13s, 90%

N

N

13w, 59%

13u, 75%

13v, 86%

N

N

N

Bn

N

Bn

13z, 68%

13y, 87%

13x, 89%

O

O

13aa, 86%

MeO N

13ab, 84%

N

F3C

N

MeO

13ac, 90%

13ad, 94%

N

N N

N

N

O

Boc

13ae, 89%

N

N MeO

N

13af, 80%

N

OMe

13ag, 73%

a Reactions

EtO

O

13ah, 55%b

were performed at 0.2 mmol. The reported isolated yields are average of two runs. See SI for experimental details. b Reaction was performed at 80 °C.


Page 11 of 14 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


a) Scope of 1-sulfonyl glycals Ph B(OH)2

9 + O

SO2Ph


O

LDA

SO2Ph

RO

RO

RO

KOH (2 equiv) THF, 60–80 °C, 12 h

OR

16

14

15

O

TBSO

O

O tBu Si

TBSO

tBu

OTBS

(from glucose) 16a, 82%b

BnO

O

O

Me

BnO OTIPS

BnO OBn

(from galactose) 16c, 72%

(from glucose) 16b, 60%

O

O

BnO

O

BnO

(from fucose) 16d, 70%

OBn

(from rhamnose) 16e, 86%

Bn

BnO

O

BnO

BnO

OBn

O O

O OBn

OBn

(from xylose) 16g, 83%

(from arabinose) 16f, 77%b

O

OBn

BnO Me

Ph

O

OBn

(from maltose) 16h, 92%

b) Scope of acyclic α-oxo vinyl sulfones Tol MeO

SO2Ph P(=O)(OEt)2

O R

18

B(OH)2

20 + MeO

LDA

SO2Ph

Ni(COD)2 (10 mol%) MeO Cy3P•HBF4 (20 mol%) KOH (2 equiv) THF, 60 °C, 8 h

Tol

R

R

21

22

19c

R=

Me

21a 83%, 1:1.2 E/Z

Tol

O

R

17

Ph

H3O+

Me

TIPSO

Me

Me

21b 70%, 1:1.3 E/Z

21c 90%, 1:1 E/Z

a Reported

Me

21d 78%, 1:1.7 E/Z

isolated yields are average of two runs. E/Z ratios were determined by 1H NMR analysis of the crude reaction mixture after extractive workup. Reactions in Scheme 3a were run at 0.1–0.15 mmol; reactions in Scheme 3b were run at 0.3 mmol. b tBuOH was used as solvent. See SI for experimental details.



Page 12 of 14

a) Synthesis of ipragliflozin and 2-deoxy ipragliflozin O

TBSO

SO2Ph

+

TBSO

S

PinB

OTBS

24

23

O

Ni(COD)2 (10 mol%) TBSO Cy3P•HBF4 (20 mol%)

F

Ar

TBSO

KOH, THF, 80 °C, 12 h

OTBS

25 (88%)

= Ar F

Conditions A

O

HO

or Conditions B

S R

HO OH

26a, R = OH, ipragliflozin 26b, R = H, 2-deoxy ipragliflozin

b) C–H borylation/Suzuki-Miyaura coupling sequence CO2Me NHBoc

+

8a

N

R

TIPS

27, R = H

KOH tBuOH, 60 °C, 12 h

NHBoc O

BnO

N TIPS

BnO

Conditions C

28, R = BPin

CO2Me


OBn

29 (45%)

c) Formal synthesis of a human NK1 antagonist CO2Et

SO2Ph MeO

+

Ni(COD)2 (10 mol%) MeO Cy 3P•HBF4 (20 mol%) BPin

F

31

30

CO2Et

O

KOH tBuOH, 80 °C, 6 h

F

32 80%, E/Z 1:1b

HO

ref. 26

Conditions D

F

33

N

F3C

O

O

a potent human NK1 receptor antagonist

CF3 F

34 a Unless otherwise noted, isolated yields are reported. See SI for experimental details. b Yield and E/Z ratio were determined by 1H NMR analysis. Conditions A: (1) BH3•THF; (2) 30% H2O2, 3 M NaOH; (3) TBAF. Overall yield = 49%. Conditions B: (1) Pd/C, H2 (balloon); (2) TBAF. Overall yield = 85%. Conditions C: [Ir(COD)(OMe)]2, 1,10-phenanthroline, B2Pin2, HBPin, 78% (An 8:1 ratio of C6- to C5position functionalized product is formed.). Conditions D: (1) diethyl fumarate, m-xylene; (2) 6 N HCl, CH3CN. Overall yield = 68%. ACS Paragon Plus Environment

Page 13 of 14 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


a) The significance of α-heteroatom in the cross-coupling of sulfones. B(OH)2 Ni(COD) (10 mol%) 2 X

+

X

36

B(OH)2 SO2Ph

+

KOH (2 equiv) tBuOH, 60 °C, 12 h

X

Me


Me

37a/b/c

yield

36a O 76% 36b CH2 trace

20

Y

X


Me

35a/b X

Me

Cy3P•HBF4 (20 mol%)

SO2Ph

Y yield

38a N CH 70%b 38b CH N 29% 38c CH CH trace

X Y

38

20

b) Facile oxidative insertion and desulfination of 8a by Ni(0). OBn

O O

O

OBn

Ni(COD)2 (100 mol%) PCy3 (200 mol%)

S

O

THF, 45 °C, 12 h w/o aryl boronic acids

BnO OBn

BnO OBn

8a

10, 76%

c) A plausible reaction pathway.c SO2R

O

Ni(0) SO2R

O

39 40

Ni(0) Ar

O

O

44

Ni

O

R

SO2R

41

42

ArB(OH)2 + KOH O

Ni

43

Ar

RSO2K

a

Unless otherwise noted, yields are determined by 1H NMR using 1,3,5-trimethoxybenzene as internal standard. b Isolated yield. c For the sake of simplicity, ligands on Ni are omitted and all steps are drawn as irreversible.



OBn

O O

O S

R

OBn


+

Ph B(OH)2

BnO

9

OBn R = Ph, 8a


+ RSO2K BnO OBn

10 conversion yield of 8a of 10

entry

deviation from “standard conditions”

1

100%

94%

2

“standard conditions” with 8a Fe, Co, Pd instead of Ni(COD)2

trace

0%

3

Ni(OTf)2 instead of Ni(COD)2, 80 °C

100%

93%

4

NiCl2•glyme instead of Ni(COD)2, 80 °C

90%

81%c

5 Ni(COD)2 (5 mol%) and Cy3P•HBF4 (10 mol%) 90%

86%

L2 instead of Cy3P•HBF4, 80 °C

7 8 9

Ph

O

R = 4-CF3Ph, 8b

6

Page 14 of 14

83%

81%

L3 instead of Cy3P•HBF4

26%

12%

87% 100%

71% 11%

10

NaOH instead of KOH KOtBu instead of KOH Ph-Bpin instead of Ph-B(OH)2

100%

90%

11

Ph-BF3K instead of Ph-B(OH)2

90%

0%

12

8b instead of 8a

100%

84%

13

tBuOH instead of THFb

100%

82%

14

PhMe instead of THFb

95%

92%

15

THF/H2O (3:1) used as solvent

100%

90%

16

reaction performed at 40 °C for 16 h

>95%

85%

a Reactions

11

Cy3P•HBF4 L1

Ph

Ph

N

N L2

iPr

iPr N

N

iPr

iPr L3

in this Table were performed at 0.05 mmol scale, using 2 equiv. of 9. Yield and conversion were determined by 1H NMR using 1,3,5-trimethoxybenzene as internal standard. b Reaction was performed at 80 °C using Ni(OTf) . c Isolated yield of a 2 mmol scale reaction. 2


Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of Î±-Oxo-Vinylsulfones

Recommend Documents