Ligand-Enabled β-C(sp3)-H Olefination of Free Carboxylic Acids

Article abstract of DOI:10.1021/jacs.8b06527

An acetyl-protected aminoethyl phenyl thioether has been developed to promote C(sp³)-H activation. Significant ligand enhancement is demonstrated by the realization of the first Pd(II)-catalyzed olefination of C(sp³)-H bonds of free carboxylic acids without using an auxiliary. Subsequent lactonization of the olefinated product via 1,4 addition provided exclusively monoselectivity in the presence of multiple β-C-H bonds. The product γ-lactone can be readily opened to give either the highly valuable β-olefinated or γ-hydroxylated aliphatic acids. Considering the challenges in developing Heck couplings using alkyl halides, this reaction offers a useful alternative.

Full text of DOI:10.1021/jacs.8b06527

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Ligand-Enabled #-C(sp)–H Olefination of Free Carboxylic Acids
Zhe Zhuang, Chang-Bin Yu, Gang Chen, Qing-Feng Wu, Yi Hsiao,
Candice L Joe, Jennifer X Qiao, Michael A Poss, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 20 Jul 2018
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Ligand-Enabled β-C(sp3)–H Olefination of Free
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Carboxylic Acids
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Zhe Zhuang,†,┴ Chang-Bin Yu,†,┴ Gang Chen,† Qing-Feng Wu,† Yi Hsiao,‡ Candice L. Joe,‡ Jennifer X.
Qiao,§ Michael A. Poss,§ and Jin-Quan Yu*,†
†Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla,
California 92037, United States
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‡Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New
Jersey 08903, United States
§Discovery Chemistry, Bristol-Myers Squibb Company, PO Box 4000, Princeton, New Jersey 08543,
United States
*yu200@scripps.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract. An acetyl-protected aminoethyl phenyl thioether has been developed to promote C(sp3)–H
activation. Significant ligand enhancement is demonstrated by the realization of the first Pd(II)-catalyzed
olefination of C(sp3)–H bonds of free carboxylic acids without using an auxiliary. Subsequent
lactonization of the olefinated product via 1,4 addition provided exclusively mono-selectivity in the
presence of multiple β-C–H bonds. The product γ-lactone can be readily opened to give either the highly
valuable β-olefinated or γ-hydroxylated aliphatic acids. Considering the challenges in developing Heck
couplings using alkyl halides, this reaction offers a useful alternative.
1. Introduction
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Carboxylic acids are readily available and highly versatile starting materials in organic synthesis.
In the past decade, a number of directed C(sp3)–H activation reactions of aliphatic acids using various
directing groups have provided unprecedented synthetic disconnections.1 For example, Pd-catalyzed
C(sp3)–H iodination,1a oxygenation,1b arylation,1c alkylation,1d–f and fluorination1g,1h have been developed
using various directing auxiliaries. However, carboxyl-directed C(sp3)–H activation reactions are rare.
K2PtCl4-catalyzed or mediated carboxyl-directed lactonization of aromatic and aliphatic acids has been
demonstrated, albeit in poor yields.2 The use of COOK salts led to the discovery of Pd-catalyzed C(sp3)–
H arylation of free carboxylic acids3 and was further improved by ligand acceleration.4,5 However, further
development of carboxyl-directed C(sp3)–H functionalization reactions have only been successful using
exogenous auxiliaries. In particular, the development of a C(sp3)–H olefination reaction protocol would
be synthetically useful considering the challenges of developing Heck couplings with alkyl halides due to
premature β-hydride elimination.6 To date, only a few precedents using auxiliaries have been reported.7
In 2010, our group has reported the first example of Pd(II)-catalyzed β-C(sp3)–H olefination of N-aryl
amide with acrylates (Scheme 1, eq 1).7a The highly electron-withdrawing perfluorinated N-arylamide
auxiliary was crucial to effect C(sp3)–H activation. In 2014, the reaction efficiency in β-C(sp3)–H
olefination of amide was dramatically improved by using a newly tricyclic quinoline ligand developed by
our group; alanine-derived amide could be successfully olefinated (Scheme 1, eq 2).7b Subsequently in
2014, the combination of a quinoline-based ligand and a weakly coordinating amide directing group also
allowed for γ-C(sp3)–H olefination of amide for the first time (Scheme 1, eq 3).7c However, these reactions
suffer from the undesired subsequent cyclization reaction with the nitrogen containing auxiliary,
preventing further synthetic elaborations. Recently, the Maiti group used a bidentate directing group to
achieve γ-C(sp3)–H olefination, albeit largely limited to substrates containing quaternary carbon centers
(Scheme 1, eq 4).7f
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Scheme 1. C(sp3)–H Olefination of Carboxylic Acid Derivatives
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Herein we report the first example of β-C(sp3)–H olefination of free carboxylic acids enabled by
an acetyl-protected aminoethyl phenyl thioether ligand (Scheme 2). Carboxylic acids containing α-
hydrogen are also compatible with this catalyst. The γ-lactone products formed by C(sp3)–H olefination
and subsequent 1,4-addition can be found in many bioactive compounds (Figure 1).8 The hydrolytic
opening of the lactones provides synthetically useful β-olefinated aliphatic acids or 1,4-dihydroxy
compounds (Scheme 2).
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Scheme 2. β-C(sp3)–H Olefination of Carboxylic Acids and Subsequent Lactonization
Figure 1. Bioactive Compounds Containing γ-Lactone and Derivatives
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2. Results and Discussion
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Our initial investigation into carboxyl-directed β-C(sp3)–H olefination employed 2,2-
dimethylbutyric acid 1b as a model substrate and benzyl acrylate 2a as an olefin coupling partner. We
have previously established that countercations, such as Na+ or K+, promote Pd(II) insertion into ortho-
or β-C–H in carboxylic acid substrates by engaging К2 coordination with the carboxylate.5 We were
pleased to observe that using Pd(OAc)2 (10 mol%) in the presence of Na2HPO4·7H2O as the base and
Ag2CO3 as the oxidant provided olefination product 3b in 16% yield (Table 1). We next tested
representative pyridine- or quinoline-based ligands (L1–L4) developed in our laboratory to exploite
ligand acceleration. To our delight, the yield was improved to 57% by using the simple monodentate 2,6-
lutidine ligand L2. Further screening of pyridone ligands (L5–L7) which were identified to enable meta-
C(sp2)–H arylation of phenyl acetic acids5e only gave inferior yields. After extensive screening of different
bases and external oxidants, the product 3b could be isolated in 70% when we used K2HPO4 as the base
and AgOAc as the oxidant in the presence of 2,6-lutidine L2 (15 mol%). However, use of this ligand is
limited to carboxylic acids containing α-quaternary centers.
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To overcome this limitation, we turned our attention to the bidentate ligands that were recently
developed to accelerate C(sp3)–H activation in our laboratory. Guided by ligand-accelerated ortho-
C(sp2)–H olefination of phenyl acetic acids5c and β-C(sp3)–H arylation of α-branched carboxylic acids,4d,4e
we tested mono-N-protected amino acid (MPAA) ligands. However, this type of ligand gave poor yields.
Other bidentate ligands (L11–L13), previously found to promote enantioselective intermolecular C(sp3)–
H activation,4a,4b gave moderate yield with substrate 1b, but displayed no reactivity with α-hydrogen
containing carboxylic acids. The essential role played by the NHAc group in the bidentate ligands (L8–
L13) prompted us to replace the quinoline and oxazoline by sulfur as a soft σ-donor.9 We prepared acetyl-
protected aminoethyl phenyl thioether ligand L14 in two steps from commercial available 2-aminoethyl
bromide. Ligand L14 afforded a dramatic increase in reactivity providing a 90% yield. The product could
be isolated in nearly quantitative yield (96%) by increasing the temperature and using Pd(TFA)2. L14, a
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bench-stable and odorless solid, was easily recycled after the reaction, demonstrating its stability in the
presence of a mild oxidant (Ag salt in this case). Efforts to introduce substitution on the ligand backbone
(L15) did not enhance the reactivity. It is worth-noting that the formation of the γ-lactone via the
intramolecular conjugate addition secured the exclusive mono-selectivity which has not been possible in
other C–H functionalizations in the presence of multiple β-C–H bonds.
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To investigate the impact of ligand structure on the reaction efficiency, systematic ligand
modification on L14 have been conducted. The protecting group of the amino group has noticeable
influence on the reactivity: Changing Ac to TFA (L16), Bz (L17), Boc (L18), or Cbz (L19) decreased
the yield considerably, which revealed that the NHAc might be involved in the C(sp3)–H cleavage step.
Replacing the sulfur atom with σ-donor oxygen (L20) or nitrogen (L21) led to the loss of reactivity. Alkyl
protected (L22) or Ac protected (L23) thio-ligands also proved inactive indicating the importance of PhS
moiety. The rate profile of the ligand L14 with substrate 1b (see Supporting Information) also indicated
the dual role of thioether ligand in the olefination: (1) the initial rate of the reaction is accelerated by a
factor of twenty; (2) Pd catalyst is more stable over reaction time affording higher turnover numbers.
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Table 1. Ligand Development for β-C(sp3)–H Olefinationa,b
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aConditions A: 1b (0.1 mmol), 2a (2.0 eq), Pd(OAc)2 (10 mol%), ligand (10 mol% for bidentate ligands (L8–L23) or 20
mol% for monodentate ligands (L1–L7)), Na2HPO4·7H2O (1.0 eq), Ag2CO3 (1.0 eq), HFIP (1.0 mL), 90 oC, 12 h. bThe
yields were determined by 1H NMR analysis of the crude product using CH2Br2 as the internal standard. cConditions B:
1b (0.1 mmol), 2a (2.0 eq), Pd(OAc)2 (10 mol%), L2 (15 mol%), K2HPO4 (2.0 eq), AgOAc (2.0 eq), HFIP (1.0 mL),
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100 C, 24 h. Isolated yield. Conditions C: 1b (0.1 mmol), 2a (2.0 eq), Pd(TFA)2 (10 mol%), L14 (10 mol%),
Na2HPO4·7H2O (1.0 eq), Ag2CO3 (1.0 eq), HFIP (1.0 mL), 120 oC, 12 h. Isolated yield.
With the optimal ligand and reaction conditions in hand, the scope of aliphatic carboxylic acid
substrates was evaluated (Table 2). For aliphatic acids bearing α-quaternary centers, both 2,6-lutidine L2
and the thioether ligand L14 are effective with the latter being superior (3a–3h). Various α-dialkyl
substituted propionic acids were olefinated to give the desired γ-lactones in good to excellent yields (3a–
3d). Phenyl groups at the β- or γ-positions of the carboxyl group were well tolerated (3e, 3f, and 3m) and
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remained intact despite the potentially reactive ortho-C(sp2)–H bonds. Substrates containing a
coordinative heteroatom such as oxygen (1g, 1h, 1s, and 1x) or nitrogen (1p) were also compatible with
the β-C(sp3)–H olefination conditions. Gemfibrozil (1g), which is an oral drug used to lower lipid levels,10
was converted to the corresponding γ-lactone 3g in 81% yield. The use of the newly developed ligand
L14 has rendered a broad range of α-hydrogen containing carboxylic acids (1i–1q) reactive under the
standard conditions. These substrates are typically challenging due to the lack of a favorable Thorpe-
Ingold effect as well as the interfering acidic α-C–H bond. The olefination of N-phthaloyl alanine substrate
1p is particularly interesting considering the importance of α-amino lactones. This protocol was also
successfully extended to the olefination of cyclopropyl and cyclobutyl C–H bonds (3q-3x), affording
highly strained fused bicyclic lactones. The presence of hydroxyl (3s) and halogen (3t) groups in those
lactones offers a synthetic handle for further elaboration.
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Table 2. Substrate Scope for β-C(sp3)–H Olefinationa,b
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aConditions A: 1 (0.1 mmol), 2a (2.0 eq), Pd(TFA)2 (10 mol%), L14 (10 mol%), Na2HPO4·7H2O (1.0 eq), Ag2CO3 (1.0
eq), HFIP (1.0 mL), 120 oC, 12 h. bIsolated yields. cConditions B: 1 (0.1 mmol), 2a (2.0 eq), Pd(OAc)2 (10 mol%), L2
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(15 mol%), K2HPO4 (2.0 eq), Ag2CO3 (2.0 eq), HFIP (1.0 mL), 100 oC, 24 h. dConditions C: 1p (0.1 mmol), 2a (2.0 eq),
Pd(OAc)2 (10 mol%), L12 (10 mol%), CsOAc (1.0 eq), Ag2CO3 (1.0 eq), HFIP (1.0 mL), 100 oC, 24 h.
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We next evaluated the scope of the olefin coupling partners by using pivalic acid 1a as the pilot
acid substrate (Table 3). The olefination with various acrylate derivatives proceeded in excellent yields
(4a–4c). Other electron-withdrawing groups attached to the olefins including amide (2d), ketone (2e),
nitrile (2f), sulfone (2g), and phosphonate (2h), were all compatible with the olefination conditions,
providing the desired γ-lactones in excellent yields. N-Aryl or alkyl maleimides (2i–2k) were also found
to be suitable coupling partners under the optimized conditions, providing diverse spirocyclic pyrrolidines
in moderate to excellent yields.
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Table 3. Olefin Scope for β-C(sp3)–H Olefinationa,b
aConditions A: 1a (0.1 mmol), 2 (2.0 eq), Pd(TFA)2 (10 mol%), L14 (10 mol%), Na2HPO4·7H2O (1.0 eq), Ag2CO3 (1.0
eq), HFIP, 120 oC, 12 h. bIsolated yields. cConditions B: 1a (0.1 mmol), 2 (2.0 eq), Pd(OAc)2 (10 mol%), L14 (10 mol%),
Ag2CO3 (1.0 eq), HFIP, 120 oC, 12 h.
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Coupling of an alkyl fragment with an olefin is highly valuable due to the lack of success of
analogous Heck couplings. To demonstrate the synthetic utility of these C(sp3)–H olefination products,
we performed the olefination of pivalic acid 1a with benzyl acrylate 2a on gram scale to obtain the γ-
lactone 3a in 93% isolated yield (Scheme 3). The γ-lactone was then successfully transformed into three
structurally distinct synthons: (1) selective hydrolysis of the ester under the acidic conditions gave the γ-
lactone 5a which can be further elaborated to other compounds by decarboxylative coupling;11 (2)
hydrolysis in the presence of sodium hydroxide generated adipic acid derivative 5b which is widely used
in the polymer chemistry industry; (3) reduction of the lactone and ester afforded the 1,4,6-triol 5c.
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Scheme 3. Gram-Scale Experiment and Synthetic Applications
aConditions A: 1a (12.0 mmol), 2a (2.0 eq), Pd(TFA)2 (10 mol%), L14 (10 mol%), Na2HPO4.7H2O (1.0 eq), Ag2CO3
(1.0 eq), HFIP, 120 oC, 12 h. bConditions B: 3a (0.2 mmol), 6N HCl, 80 oC, overnight. cConditions C: 3a (1.0 mmol),
NaOH (4.0 eq), EtOH/H2O, reflux. dConditions D: 3a (0.2 mmol), LAH (4.0 eq), THF, rt.
3. Conclusion
In conclusion, we have developed a new thioether based bidentate ligand L14 that effectively
promotes β-C(sp3)–H olefination of a broad range of free carboxylic acids. The unique synthetic utility of
olefination is demonstrated by the synthesis of γ-lactones, β-vinylated acids, and γ-hydroxylated acids,
which has not been possible using an auxiliary approach. This transformation provides a highly desirable
synthetic disconnection considering the challenges in developing analogous Heck couplings due to
premature β-hydride elimination.
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4. Experimental Section
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General procedure for β-C(sp3)–H olefination. In the control tube, Pd(TFA)2 (10 mol%), ligand L14
(10 mol%), Na2HPO4.7H2O (1.0 eq), Ag2CO3 (1.0 eq), and carboxylic acid 1 (0.1 mmol) in order were
weighed in air and placed with a magnetic stir bar. Then HFIP (1.0 mL) and olefin 2 (2.0 eq) were added.
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The reaction mixture was stirred at rt for 10 min, and then heated to 120 C for 12 h (300 rpm). After
being allowed to cool to room temperature, the mixture was diluted with DCM, and filtered through a pad
of celite. The filtrate was concentrated in vacuo, and the resulting mixture purified by column
chromatography or pTLC using hexane/EA (2/1) as the eluent to afford desired products. Full
experimental details and characterization of new compounds can be found in the Supporting Information.
Corresponding author. *yu200@scripps.edu
Author Contributions. ┴Z.Z. and C.-B.Y. contributed equally to this work.
Notes. The authors declare no competing financial interest.
Acknowledgements. We gratefully acknowledge The Scripps Research Institute and Bristol-Myers
Squibb for financial support. This work was supported by NIH (NIGMS, 2R01 GM084019). This
communication is dedicated to Professor Dale Boger on the occasion of his 60th birthday.
Supporting Information Available. Full experimental details and characterization of new compounds.
This material is available free of charge via the internet at http://pubs.acs.org.
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