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doi.org/10.26434/chemrxiv.13297919.v1

Intramolecular Oxidative Coupling between Unactivated Aliphatic C-Hand Aryl C-H BondsYang Liao, Yi Zhou, Zhen Zhang, Junzhen Fan, Feng Liu, Zhangjie Shi

Submitted date: 29/11/2020 • Posted date: 01/12/2020Licence: CC BY-NC-ND 4.0Citation information: Liao, Yang; Zhou, Yi; Zhang, Zhen; Fan, Junzhen; Liu, Feng; Shi, Zhangjie (2020):Intramolecular Oxidative Coupling between Unactivated Aliphatic C-H and Aryl C-H Bonds. ChemRxiv.Preprint. https://doi.org/10.26434/chemrxiv.13297919.v1

Direct oxidative coupling of different inert C-H bonds is the most straightforward and environmentally benignmethod to construct C-C bonds. In this article, we developed a Pd-catalyzed intramolecular oxidative couplingbetween unactivated aliphatic and aryl C-H bonds. This chemistry showed great potential to build up fusedcyclic scaffolds from linear substrates through oxidative couplings. Privileged chromane and tetralin scaffoldswere constructed from readily available linear starting materials in the absence of any organohalides andorganometallic partners.

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Intramolecular Oxidative Coupling between Unactivated Aliphatic C-H and Aryl C-H Bonds

Yang Liao,† Yi Zhou,‡ Zhen Zhang,‡ Junzhen Fan,† Feng Liu,*, †, ‡ and Zhangjie Shi *, †, •

†Department of Chemistry, Fudan University. Shanghai, 200438, China. ‡School of Perfume and Aroma Technology, Shanghai Institute of Technology. Shanghai, 201418, China. §State Key Laboratory of Organometallic Chemistry, SIOC, CAS. Shanghai, 200032, China.

ABSTRACT: Direct oxidative coupling of different inert C-H bonds is the most straightforward and environmentally benign method to construct C-C bonds. In this article, we developed a Pd-catalyzed intramolecular oxidative coupling between un-activated aliphatic and aryl C-H bonds. This chemistry showed great potential to build up fused cyclic scaffolds from linear substrates through oxidative couplings. Privileged chromane and tetralin scaffolds were constructed from readily available linear starting materials in the absence of any organohalides and organometallic partners.

Chromane and tetralin are vital structural units in natural products and pharmaceutical molecules (Scheme 1a).1 In general, chromanes are synthesized through the reduction of chromanones,2 intramolecular C-O formations,3 cross-coupling of organohalides with different partners,4 as well as the Friedel-Crafts alkylations.5 While tetralins are con-structed through hydrogenation of naphthalenes,6 Friedel-Crafts cyclization of aryl derivatives,7 or C-H alkylation of alkene tethered arenes.8 Apparently, direct oxidative cou-pling between aliphatic and aromatic C-H bonds via transi-tion-metal catalysis would be a straightforward, atomic and step-economic method to construct such benzo-fused cyclic structural units from linear starting materials equipped with phenyl substituents, providing an efficient strategy to approach the fused ring systems.

Indeed, oxidative coupling of two different C-H bonds showed its great advantages in constructing C-C bonds.9 In the past decades, relatively active aliphatic C-H bonds, such as benzylic/allylic C-H bonds and C-H bonds adjacent to heteroatoms in the substrates, have been broadly ap-plied to oxidative coupling as partners, which were well-featured as cross dehydrogenative coupling reactions (CDC).9,10 Biaryl construction through oxidative couplings from two arenes have also been well investigated.11 In comparison, the investigation of oxidative coupling be-tween both unactivated aliphatic and aromatic C-H bonds is far behind, and only few examples were reported.12 In 2017, our group reported an example to construct dihy-drobenzofurans from 3-alkyloxyl-benzoic acid, in which aromatic carboxylic acid was considered as a directing group, the intramolecular cross-coupling was manipulated by tuning the reactivity with a proper ligand.12c Another elegant example reported by Loh and coworkers provided an efficient method to construct dihydroquinolinones through oxidative couplings.12e In both cases, the oxidative coupling was initiated from aromatic C-H bond activation by directing strategy with pallacycles as key intermediates. Although the directing-group-promoted unactivated ali-phatic C-H bonds functionalization with different reaction

partners were well explored,13 the oxidative coupling of unactivated C(sp3)-H with C(sp2)-H bond has never been approached by initiating from aliphatic C-H activation.

Scheme 1. The importance of Chromane/tetralin units and the straightforward strategy for synthesis.

As known, aliphatic carboxylic acid is one kind of im-portant organic compound. Direct C-H functionalization of aliphatic carboxylic acids can derive valuable compounds from readily available chemicals by using carboxylates as weakly coordinating directing groups. This chemistry has drawn much attention in the past decades, and many ele-gant progress has been made with efforts.14 In those trans-

formations, either Pd(0)/Pd(II)14a-c or Pd(II)/Pd(IV)14d catalytic cycles were proposed and the ligands showed their uniqueness in catalysis. We envisioned that, if equip-ping an aryl group at the proper position of the carboxylic acids, a coordinating pattern of palladacycles which was formed through carboxylates directed aliphatic C-H activa-tion may facilitate the intramolecular oxidative coupling (Scheme 1b). This approach might open a new channel to synthesize benzo-fused ring systems from linear aromatic substituted aliphatic carboxylates.

Table 1. Optimization of Reaction Conditionsa

Based on this hypothesis, we set out to investigate the intramolecular oxidative coupling between both unactivat-ed aliphatic and aromatic C-H bonds. 2,2-Dimethyl-3-phenoxypropanoic acid 1a was initially selected as a can-didate since the Thorpe-Ingold-effect of geminal dimethyl substituents was found essential in aliphatic C-H activa-tions.15 We first attempted to carry out the reaction with Pd(CH3CN)2Cl2 as the catalyst, KHCO3 as a base, and TBHP as an oxidant in HFIP at 60 oC, the desired product 3-methyl-chromane-3-carboxylic acid 2a was obtained in a 21% NMR yield, by using 1,3,5-trimethoxy-benzene as an internal standard (entry 1). In previous studies, ligands

were proved to be important to accelerate the rate of C-H activation and hence promote the reaction efficien-cy.12c,13,14,16 Therefore, various ligands were tested in the reaction. With previous efforts from Yu’s group, protected amino acids showed their “magic” effect in aliphatic C-H functionalization.16b,d,e As expected, with the addition of ligand L1 (Ac-Phe-OH), the yield of the desired product (2a) was somewhat improved, revealing the existence of amino acid ligands exhibited a potentially positive effect on this intramolecular oxidative coupling reaction as observed in Table 1, entry 2. On the contrary, pyridine-2-sulfonic acid L9 inhibited the reactivity (entry 3). To our delight, a 10%: 10% combination of L1 and L9 dramatically promoted this reaction, giving an utterly 1a conversion and an 80% NMR yield of 2a (entry 4). After implementing the reaction with a broad scope of ligands/co-ligands, L1/L9 was found as the most feasible combination. (Table S1, S2; Table 1, en-try 5-14). These results revealed intriguingly synergistic coordination of the L1/L9 combo. Then further investiga-tions of some other parameters, like Pd salts, temperature, reaction time, and oxidants (see the Supporting Infor-mation for details) were taken. Finally, by treating the starting material 1a with Pd(OAc)2 (5 mol%), Ac-Phe-OH (10 mol%)/ Pyridine-2-sulfonic Acid (10 mol%), KHCO3

(1.5 eq.), and tert-butyl hydrogen peroxide (TBHP, 1.5 eq., both 70% solution in water or 5.5 M in decane gave the same result) in HFIP at 45 oC for 36 h, the desired product 2a was obtained with the highest isolated yield (entry 21, 88 %).

Subsequently, we explored the substrate scope of this oxidative coupling to synthesize the diverse chromane (Table 2). A variety of para-substituted substrates on the phenyl group were examined. Both alkyl and aryl substitu-ents, for example methyl, tert-butyl, and phenyl worked well, giving the desired products in good to excellent yields (2b, 2c, and 2i). Para-methoxy, trifluoromethoxy, ben-zyloxy phenyl derived ethers were suitable substrates, affording the corresponding chromane-3-carboxylic acids 2d, 2e, and 2j in 63 %, 54 %, and 74 % yields, respectively. The halide substituents also furnished the products in good yields (2f-2h). The reactive halide substituents pro-vided another possibility for further functionalization through orthogonal cross-coupling reactions. 3,5-Dimethyl- and 2-methyl phenol ether underwent this in-tramolecular oxidative coupling smoothly, forming the anticipated 5, 7-dimethylchromane-3-carboxylic acid 2k (83 %) and 8-methylchromane-3-carboxylic acid 2l (87 %), severally. The naphthol ethers were then tested, and the coupling products were obtained in good yield (2m and 2n), no matter whether 1- or 2- naphthyl derivatives were delivered. While the latter reaction showed a unique α-regioselectivity. While the dibenzo[b,d]furan unit was in-troduced to the reaction system, the anticipated coupling proceeded to give a poly fused ring system 2o in a moder-ate yield. This result also demonstrated that the heterocy-cles survived well. Meta-substituted phenyl ether sub-strates were examined, excellent reactivity and acceptable regioselectivity were obtained, and the less steric hindered para-sp2 C-H bond functionalization product dominated the site selectivity (2p:2p’ = 1:3.3, 2q:2q’ = 1:10).

Table 2. Substrate Scope a,b

To extend the substrate scope and examine the chemoselectivity between primary and secondary or ter-tiary C-H bonds, we introduced other alkyl groups to re-place one of the methyl group at the α-position of the car-boxylate. This intramolecular oxidative coupling reaction took place at the methyl group beyond both n-Bu (eq 1) and i-Pr (eq 2) groups, showing an excellent selectivity among different types of C(sp3)-H bonds.

For further investigating this chemistry, the “O” linker was replaced by a “C” linker of substrate analogs, which could quickly produce the tetralin core structures (Scheme 2). To our delight, tetralin-2-carboxylic acid 4 was formed with a good yield from 3 (eq 3). 2,3-dihydro-1H-indene-2-carboxylic acid 6 could also be obtained with 35% yield, showing great potential to synthesize indane derivatives (eq 4). We were happy to find that the oxidative coupling

product 8 was also produced in a moderate yield by treat-ing 2-methyl-3-phenoxypropanoic acid 7 under standard reaction conditions (eq 5). This result indicated that the Thorpe-Ingold-effect is not that essential in our system, thus providing broader application of this chemistry.

Scheme 2. Oxidative coupling of Phenyl alkyl substi-tuted isobutyric acid

Scheme 3. Oxidative coupling of Estrone derivative

We next conducted the oxidative coupling with natural product scaffold to further explore the application of this chemistry. Estrone derivative 9 was tested in this system, yielding 46 % yield of the desired compound 10 (Scheme 3). This method efficiently builds up the complexity of nat-ural and existing molecules for material chemistry and drug discovery.

To gain mechanistic insight into the reaction, we con-ducted a series of experiments to measure kinetic isotope effects (KIEs) (Scheme 4).17 Firstly, intramolecular compe-tition oxidative coupling of mono CD3 substrate 1a-d3 (eq 6) and mono-deuterated substrate 1a-d (eq 7) were carried out under standard conditions, respectively.

We observed a large primary KIE (6.87, eq 6) of the me-thyl C(sp3)-H bond, while the aryl C(sp2)-H bond KIE was 1.01 (eq 7), among the magnitude range of the typical sec-ondary KIE. Next, intermolecular one-pot competition re-actions using an equimolar mixture of 1a-d6 + 1a (eq 8) and 1a-d5 + 1a (eq 9) resulted the KIE magnitude of 5.17 and 1.14, correspondingly. Finally, we ran two pairs of intermolecular parallel experiments, the magnitude of the-se two KIEs (kH/kD = 5.03, eq 10; kH/kD = 0.98, eq 11) were very similar to the one pot competition KIEs (kH/kD = 5.17, eq 8; kH/kD = 1.14, eq 9). These experiments directly indi-cated that the unactivated C(sp3)-H bond cleavage oc-curred during the rate-determining step (RDS) of this in-tramolecular oxidative coupling reaction. In addition, the control experiment of 1a with the stoichiometric Pd(OAc)2

in the absence of TBHP did not afford any 2a at all,18 indi-cating that the Pd(II)/Pd(IV) cycle, instead of Pd(II)/Pd(0) cycle likely took place in the present case.19

Based on previous reports and the above described ex-perimental results, we proposed a plausible mechanism as shown in Figure 1. Firstly, Pd(OAc)2 combined with L1 to

generate Pd-complex int a; The β-C(sp3)H of carboxylate was activated by Pd-complex int a through the weak coor-dination of carboxylate. After the oxidation by TBHP, Cy-clic-Pd(IV) complex int b was formed. L9 then binded with the Pd-center to form a zwitterionic species with the dis-sociation of carboxylic acid,20 then to active the C(sp2)-H bond and give a 7-membered cyclic species int c. Reductive elimination of int c was expected to produce the desired product 2 and liberate int d. By the association of HOAc, int a was regenerated to fulfill this catalytic cycle by re-leasing tBuOH and H2O.

Scheme 4. Kinetic isotope effects experiments.

In conclusion, we have developed a Pd(OAc)2 catalyzed, carboxylate-directed intramolecular oxidative coupling of α-methyl-β-arenoxy (benzyl)-propanoic acid. By syner-gism employing Ac-Phe-OH L1 and pyridine-2-sulfonic acid L9 as co-ligands, the β-C(sp3)-H bond of carboxylate and the ortho-C(sp2)-H bond on aromatic ring was activat-ed and coupled to form chromane-3-carboxylic acid or tetralin derivatives under mild conditions. Kinetic studies

indicated that the aliphatic C-H cleavge was involved at the RDS. Further studies to clearly understand the mechanism and to explore its synthetic application were underway.

Figure 1. Plausible mechanism.

ASSOCIATED CONTENT

Supporting Information The Supporting Information is available free of charge on the ACS Publications website. General procedural information, characterization of new compounds, details of ECD and DFT calculations, NMR spectra (PDF)

AUTHOR INFORMATION

Corresponding Author

*[email protected] *[email protected] Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT

Dedicated to P. H. Dixneuf for his outstanding contribution to organometallic chemistry and catalysis. Dedicated to the 100th anniversary of Chemistry at Nankai Univerisity. We thank the National Nature Science Foundation of China This work was supported by NSFC (21988101, 21761132027, 22071029), Science and Technology Commission of Shanghai Municipality (19XD1400800, 18JC1411300), Shanghai Munic-ipal Education Commission (2017-01-07-00-07-E00058), Key-Area Research and Development Program of Guangdong Prov-ince (2020B010188001), and Shanghai Gaofeng & Gaoyuan Project for University Academic Program Development. We thank D. Zhai, K. Wang, C. Du, S. Xie, C. Wang, T. Liu, D. Chen, X. Lin, L. Zheng, X. Chen, H. Chen, H. Diao, W. Wang, Q. Xu, L. Ma, X. Luan, G. Yang, Z. Zhuang, H. Du, C. Bao, Y. Luo, J. Chen and Prof. B. Guan for their generous help on preparing this manu-script.

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(14) (a) Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M. Oxidative Cross-Coupling of N-(2‘-Phenylphenyl)benzene- sulfon-amides or Benzoic and Naphthoic Acids with Alkenes Using a Palladium−Copper Catalyst System under Air. J. Org. Chem. 1998, 63, 5211-5215. (b) Zhang, F.; Hong, K.; Li, T.; Park, H.; Yu, J. Func-tionalization of C (sp3)–H bonds using a transient directing group. Science 2016, 351, 252-256. (c) Liu, L.; Liu, Y.; Shi, B. Synthesis of amino acids and peptides with bulky side chains via ligand-enabled carboxylate-directed γ-C(sp3)-H arylation. Chem. Sci. 2020, 11, 290-294. (d) Zhuang, Z.; Yu, J. Lactonization as a general route to β-C(sp3)–H functionalization. Nature 2020, 577, 656-659. (e) Das, J.; Dolui, P.; Ali, W.; Biswas, J. P.; Chandrashekar, H. B.; Prakash, G.; Maiti, D. A direct route to six and seven membered lactones via γ-C(sp3)-H activation: a simple protocol to build mo-lecular complexity. Chem. Sci. 2020, 11, 9697-9702.

(15) (a) Luh, T.; Hu, Z. Thorpe–Ingold effect in organosilicon chemistry. Dalton T. 2010, 39, 9185-9192. (b) O'Neill, M. J.; Riesebeck, T.; Cornella, J. Thorpe–Ingold Effect in Branch-Selective Alkylation of Unactivated Aryl Fluorides. Angew. Chem., Int. Ed. 2018, 57, 9103-9107.

(16) (a) Muñiz, K. High-Oxidation-State Palladium Catalysis: New Reactivity for Organic Synthesis. Angew. Chem., Int. Ed. 2009, 48, 9412-9423. (b) Wang, D.; Engle, K. M.; Shi, B.; Yu, J. Ligand-Enabled Reactivity and Selectivity in a Synthetically Versatile Aryl C-H Olefination. Science 2010, 327, 315. (c) Novák, P.; Correa, A.; Gallardo-Donaire, J.; Martin, R. Synergistic Palladium-Catalyzed C(sp3)-H Activation/C(sp3)-O Bond Formation: A Direct, Step-Economical Route to Benzolactones. Angew. Chem., Int. Ed. 2011, 50, 12236-12239. (d) Chan, K. S. L.; Wasa, M.; Chu, L.; Laforteza, B. N.; Miura, M.; Yu, J. Ligand-enabled cross-coupling of C(sp3)–H bonds with arylboron reagents via Pd(II)/Pd(0) catalysis. Nat. Chem. 2014, 6, 146-150. (e) Chen, G.; Gong, W.; Zhuang, Z.; Andrä, M. S.; Chen, Y.; Hong, X.; Yang, Y.; Liu, T.; Houk, K. N.; Yu, J. Ligand-accelerated enantioselective methylene C(sp3)–H bond activation. Science 2016, 353, 1023. (f) Zhu, Y.; Chen, X.; Yuan, C.; Li, G.; Zhang, J.; Zhao, Y. Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids. Nat. Commun. 2017, 8, 14904. (g) Tong, H.; Zheng, S.; Li, X.; Deng, Z.; Wang, H.; He, G.; Peng, Q.; Chen, G. Pd(0)-Catalyzed Bidentate Auxiliary Directed Enantioselective Benzylic C-H Arylation of 3-Arylpropanamides Using the BINOL Phosphoramidite Ligand. ACS Catal. 2018, 8, 11502-11512. (h) Dolui, P.; Das, J.; Chandrashekar, H. B.; Anjana, S. S.; Maiti, D. Ligand‐Enabled Pd(II)‐Catalyzed Iter-ative γ‐C(sp3)-H Arylation of Free Aliphatic Acid. Angew. Chem., Int. Ed. 2019, 58, 13773-13777.

(17) Simmons, E. M.; Hartwig, J. F. On the Interpretation of Deu-terium Kinetic Isotope Effects in C-H Bond Functionalizations by Transition-Metal Complexes. Angew. Chem., Int. Ed. 2012, 51, 3066-3072.

(18) 1a was treated with Pd(OAc)2 (1.0 eq.), Ac-Phe-OH (2.0 eq.)/ Pyridine-2-sulfonic Acid (1.0 eq.), KHCO3 (1.5 eq.), in HFIP at 45 oC for 20 h , no desired product 2a was observed.

(19) Wei, Y.; Yoshikai, N. Oxidative Cyclization of 2-Arylphenols to Dibenzofurans under Pd(II)/Peroxybenzoate Catalysis. Org. Lett. 2011, 13, 5504-5507.

(20) (a) Zhang, Y.; Shi, B.; Yu, J. Pd(II)-Catalyzed Olefination of Electron-Deficient Arenes Using 2,6-Dialkylpyridine Ligands. J. Am. Chem. Soc. 2009, 131, 5072-5074. (b) Chen, F.; Zhao, S.; Hu, F.; Chen, K.; Zhang, Q.; Zhang, S.; Shi, B. Pd(II)-catalyzed alkoxylation of unactivated C(sp3)-H and C(sp2)-H bonds using a removable directing group: efficient synthesis of alkyl ethers. Chem. Sci. 2013, 4, 4187-4192. (c) Park, H.; Chekshin, N.; Shen, P.; Yu, J. Ligand-Enabled, Palladium-Catalyzed β-C(sp3)-H Arylation of Weinreb Amides. ACS Catal. 2018, 8, 9292-9297.

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S1

Supporting Information

Intramolecular Oxidative Coupling between Unactivated

Aliphatic C-H and Aryl C-H Bonds

Yang Liao, Yi Zhou, Zhen Zhang, Junzhen Fan, Feng Liu*, and Zhangjie Shi*

Department of Chemistry, Fudan University. Shanghai, 200438, P. R. China.

School of Perfume and Aroma Technology, Shanghai Institute of Technology.

Shanghai, 201418, P. R. China.

State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic

Chemistry, Chinese Academy of Sciences. Shanghai, 200032, Shanghai, P. R. China.

Emails: [email protected]; [email protected]

CONTENTS:

1. General Information……………………………………………………………..S2

2. General procedures for the Synthesis of starting materials (1a –1s)………….S3

3. Optimization of Reaction Conditions………………………………………….S13

4. General procedures for the Catalytic Reaction……………………………….S18

5. Kinetic Isotope Experiments………………………………………………..….S29

6. NMR Spectra……………………………………………………………………S37

mailto:[email protected]

S2

1. General Information

All commercially available reagents were used directly without further

purification. All catalytic reactions were operated in air, and all starting materials

were prepared. Solvents employed for column chromatography were purchased in

technical grade quality without distillation before use. NMR spectra were recorded on

a Bruker 400 spectrometer operating at 400 MHz for 1H NMR, 101 MHz for

13C

NMR, 162 MHz for 31

P NMR, and 376 MHz for 19

F NMR. Chemical shifts are

reported in ppm with the solvent resonance as the internal standard (CDCl3: 77.0

ppm). The coupling constants are in Hertz (Hz). The following abbreviations are used

for spin multiplicity: s = singlet, d = doublet, dd = doublet of doublet, dq = doublet of

quartet, dt = doublet of quartet, t = triplet, q = quartet, m = multiplet and brs = broad

singlet. ESI-MS analysis was performed by Analytical Instrumentation Center, Fudan

University. All reported yields are isolated yields, unless otherwise noted.

S3

2. General procedures for the Synthesis of starting materials (1a – 1s)

Under argon atmosphere, phenol derivatives (30 mmol, 1.0 equiv) and PPh3 (75

mmol, 2.5 equiv) were added into 250 mL round-bottom flask. Then anhydrous THF

(50 mL) was added at room temperature. Methyl 3-hydroxy-2,2-dimethylpropanoate

(60 mmol, 2.0 equiv) were added into the reaction mixture. At last, Diethyl

azodicarboxylate (DEAD, 66 mmol, 2.2 equiv) was added to the solution slowly.

After addition, the reaction mixture was warmed to 45 °C and stirred for 12 hours.

After the fully conversion of phenol by TLC, the reaction mixture was quenched with

H2O2 (5 mL), and stirred fiercely for 10 min. The solvent was removed under vaccum,

then mixed solvent (n-hexane: diethyl ether = 1:1, 50 mL) was added into the residue

and stirred fiercely. The mixture was filtrated by a celite pad, the filtrate was removed

by rotary evaporation, then flash chromatography of the crude product with PE/EA

from 1:0 to 20:1 afforded the intermediate products methyl ester.

The methyl ester was dissolved in mixed solvents (MeOH/THF 1:1, 30 mL), then

3.0 M NaOH (20 mL) was added. The resulting mixture was stirred for 3 hours at

room temperature. After the reaction was finished, which was monitored by TLC,

DCM (30 mL) was added and stirred for another 5 minutes. The mixture was

transferred to a separating funnel and the aq. layer was collected, 3.0 M HCl (aq.)

was added to adjust pH to 1-2. This resulting mixture was extracted with EtOAc (80

mL). Then the organic layer was dried over Na2SO4 and concentrated to obtain the

target products as white solid without further purification. The spectral data of the

products were identified as follows.

S4

2,2-dimethyl-3-phenoxypropanoic acid (1a)

White solid. Mp. 82 – 84 °C. 1H NMR (400 MHz, CDCl3): δ 11.15 (br s,

-COOH), 7.31 – 7.27 (m, 2H), 6.99 – 6.92 (m, 3H), 3.99 (s, 2H), 1.37 (s, 6H). 13

C

NMR (101 MHz, CDCl3): δ 182.84, 158.82, 129.39, 120.94, 114.64, 73.92, 43.23,

22.18. HRMS (m/z, ESI): Calcd. for C11H13O3 [M-H]-: 193.0870, Found: 193.0867.

2,2-dimethyl-3-(p-tolyloxy)propanoic acid (1b)


-COOH), 7.09 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 3.97 (s, 2H), 2.30 (s, 3H),

1.36 (s, 6H). 13

C NMR (101 MHz, CDCl3): δ 182.91, 156.78, 130.14, 129.80, 114.52,

74.19, 43.25, 22.16, 20.44. HRMS (m/z, ESI): Calcd. for C12H15O3 [M-H]-: 207.1027,

Found: 207.1016.

3-([1,1'-biphenyl]-4-yloxy)-2,2-dimethylpropanoic acid (1c)

White solid. Mp. 159 – 161 °C. 1H NMR (400 MHz, CDCl3): δ 7.56 – 7.51 (m,

4H), 7.42 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 8.7 Hz, 2H), 4.03 (s,

2H), 1.39 (s, 6H). 13

C NMR (101 MHz, CDCl3): δ 182.42, 158.39, 140.77, 134.07,

128.69, 128.10, 126.74, 126.66, 114.90, 74.11, 43.23, 22.20. HRMS (m/z, ESI): Calcd.

for C17H17O3 [M-H]-: 269.1183, Found: 269.1187.

S5

3-(4-methoxyphenoxy)-2,2-dimethylpropanoic acid (1d)


-COOH), 6.86 – 6.80 (m, 4H), 3.93 (s, 2H), 3.77 (s, 3H), 1.34 (s, 6H). 13

C NMR (101

MHz, CDCl3): δ 182.51, 153.99, 153.08, 115.71, 114.57, 74.94, 55.72, 43.29, 22.18.

HRMS (m/z, ESI): Calcd. for C12H15O4 [M-H]-: 223.0976, Found: 223.0977.

2,2-dimethyl-3-(4-(trifluoromethoxy)phenoxy)propanoic acid (1e)


-COOH), 7.13 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 3.96 (s, 2H), 1.35 (s, 6H).

13C NMR (101 MHz, CDCl3): δ 182.70, 157.30, 142.92, 122.40, 120.55 (q, J = 256

Hz), 115.38, 74.41, 43.21, 22.13. HRMS (m/z, ESI): Calcd. for C12H12F3O4 [M-H]-:

277.0693, Found: 277.0699.

3-(4-fluorophenoxy)-2,2-dimethylpropanoic acid (1f)

White solid. Mp. 57 – 59 °C. 1H NMR (400 MHz, CDCl3): δ 6.96 – 6.94 (m, 2H),

6.86 – 6.82 (m, 2H), 3.93 (s, 2H), 1.34 (s, 6H). 13

C NMR (101 MHz, CDCl3): δ

182.68, 157.40 (d, J = 238.4 Hz), 154.97 (d, J = 1.8 Hz), 115.74 (d, J = 23.0 Hz),

115.71 (d, J = 8.0 Hz), 74.79, 43.26, 22.15. HRMS (m/z, ESI): Calcd. for C11H12FO3

S6

[M-H]-: 211.0776, Found: 211.0776.

3-(4-chlorophenoxy)-2,2-dimethylpropanoic acid (1g)



13C NMR (101 MHz, CDCl3): δ 182.68, 157.42, 129.26, 125.86, 115.93, 74.32,

43.20, 22.14. HRMS (m/z, ESI): Calcd. for C11H12ClO3 [M-H]-: 227.0480, Found:

227.0473.

3-(4-bromophenoxy)-2,2-dimethylpropanoic acid (1h)



13C NMR (101 MHz, CDCl3): δ 182.71, 157.90, 132.19, 116.43, 113.15, 74.21,

43.18, 22.13. HRMS (m/z, ESI): Calcd. for C11H12BrO3 [M-H]-: 270.9975, Found:

270.9973.

3-(4-(tert-butyl)phenoxy)-2,2-dimethylpropanoic acid (1i)

White solid. Mp. 142 – 144 °C. 1H NMR (400 MHz, CDCl3): δ 7.30 (d, J = 8.8

Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 3.96 (s, 2H), 1.35 (s, 6H), 1.30 (s, 9H). 13

C NMR

S7

(101 MHz, CDCl3): δ 182.44, 156.55, 143.62, 126.16, 114.03, 73.95, 43.20, 34.05,

31.50, 22.19. HRMS (m/z, ESI): Calcd. for C15H21O3 [M-H]-: 249.1496, Found:

249.1498.

3-(4-(benzyloxy)phenoxy)-2,2-dimethylpropanoic acid (1j)


-COOH), 7.43 – 7.36 (m, 4H), 7.34 – 7.30 (m, 1H), 6.91 – 6.83 (m, 4H), 5.02 (s, 2H),

3.93 (s, 2H), 1.35 (s, 6H). 13

C NMR (101 MHz, CDCl3): δ 182.18, 153.30, 153.23,

137.26, 128.52, 127.85, 127.44, 115.83, 115.72, 74.92, 70.70, 43.28, 22.20. HRMS

(m/z, ESI): Calcd. for C18H19O4 [M-H]-: 299.1289, Found: 299.1279.

3-(3,5-dimethylphenoxy)-2,2-dimethylpropanoic acid (1k)

White solid. Mp. 86 – 88 °C. 1H NMR (400 MHz, CDCl3): δ 11.56 (br s, -COOH),

6.61 (s, 1H), 6.56 (s, 2H), 3.95 (s, 2H), 2.29 (s, 6H), 1.35 (s, 6H). 13

C NMR (101

MHz, CDCl3): δ 182.56, 158.85, 139.17, 122.68, 112.35, 73.80, 43.18, 22.19, 21.37.


2,2-dimethyl-3-(o-tolyloxy)propanoic acid (1l)


S8

2H), 6.88 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 3.99 (s, 2H), 2.20 (s, 3H), 1.39

(s, 6H). 13

C NMR (101 MHz, CDCl3): δ 182.83, 156.71, 130.59, 126.94, 126.71,

120.57, 110.90, 74.01, 43.39, 22.19, 16.02. HRMS (m/z, ESI): Calcd. for C12H15O3

[M-H]-: 207.1027, Found: 207.1028.

2,2-dimethyl-3-(naphthalen-1-yloxy)propanoic acid (1m)

White solid. Mp. 128 – 130 °C. 1H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 8.0

Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.49 – 7.41 (m, 3H), 7.37 (t, J = 8.0 Hz, 1H), 6.81

(d, J = 7.8 Hz, 1H), 4.17 (s, 2H), 1.47 (s, 6H). 13


182.52, 154.37, 134.44, 127.38, 126.40, 125.75, 125.57, 125.27, 121.92, 120.51,


Found: 243.1021.

2,2-dimethyl-3-(naphthalen-2-yloxy)propanoic acid (1n)


3H), 7.46 – 7.41 (m, 1H), 7.36 – 7.32 (m, 1H), 7.18 – 7.15 (m, 2H), 4.11 (s, 2H), 1.41

(s, 6H). 13

C NMR (101 MHz, CDCl3): δ 182.05, 156.76, 134.46, 129.34, 129.07,

127.61, 126.73, 126.35, 123.67, 118.87, 106.86, 74.00, 43.20, 22.27. HRMS (m/z,

ESI): Calcd. for C15H15O3 [M-H]-: 243.1027, Found: 243.1015.

3-(dibenzo[b,d]furan-1-yloxy)-2,2-dimethylpropanoic acid (1o)

S9

White solid. Mp. 178 – 180 °C. 1H NMR (400 MHz, DMSO): δ 12.51 (br s,

-COOH), 8.03 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.50 – 7.37 (m, 3H), 7.29

(d, J = 8.2 Hz, 1H), 6.98 – 6.95 (m, 1H), 4.22 (s, 2H), 1.35 (s, 6H). 13

C NMR (101

MHz, DMSO): δ 177.56, 156.92, 155.19, 155.02, 129.10, 127.14, 123.69, 123.22,

122.70, 113.01, 111.71, 105.71, 104.79, 75.35, 43.00, 22.64. HRMS (m/z, ESI): Calcd.

for C17H15O4 [M-H]-: 283.0976, Found: 283.0977.

2,2-dimethyl-3-(m-tolyloxy)propanoic acid (1p)


-COOH), 7.18 (t, J = 7.8 Hz, 1H), 6.80 – 6.73 (m, 3H), 3.98 (s, 2H), 2.35 (s, 3H), 1.37

(s, 6H). 13

C NMR (101 MHz, CDCl3): δ 182.86, 158.83, 139.43, 129.12, 121.74,


[M-H]-: 207.1027, Found: 207.1026.

3-(3-methoxyphenoxy)-2,2-dimethylpropanoic acid (1q)

White solid. Mp. 42 – 44 °C. 1H NMR (400 MHz, CDCl3): δ 7.17 (t, J = 8.1 Hz,

1H), 6.54 – 6.48 (m, 3H), 3.97 (s, 2H), 3.79 (s, 3H), 1.35 (s, 6H). 13

C NMR (101

S10

MHz, CDCl3): δ 182.71, 160.77, 160.08, 129.81, 106.77, 106.65, 101.04, 73.99,

55.26, 43.18, 22.18. HRMS (m/z, ESI): Calcd. for C12H15O4 [M-H]-: 223.0976, Found:

223.0967.

2,3-dimethyl-2-(phenoxymethyl)butanoic acid (1r)

White solid. 1H NMR (400 MHz, CDCl3): δ 7.29 – 7.25 (m, 2H), 6.95 (t, J = 7.4

Hz, 1H), 6.90 (d, J = 7.4 Hz, 2H), 4.16 (d, J = 8.6 Hz, 1H), 3.92 (d, J = 8.6 Hz, 1H),

2.24 – 2.15 (m, 1H), 1.26 (s, 3H), 0.97 (d, J = 6.9 Hz, 6H).

2-methyl-2-(phenoxymethyl)hexanoic acid (1s)

White solid. 1H NMR (400 MHz, CDCl3): δ 7.31 – 7.27 (m, 2H), 6.96 – 6.91 (m,

3H), 4.10 (d, J = 8.7 Hz, 1H), 3.92 (d, J = 8.7 Hz, 1H), 1.81 – 1.74 (m, 3H), 1.67 –

1.59 (m, 1H), 1.36 (s, 3H), 1.33 – 1.27 (m, 4H), 0.92 (t, J = 6.9 Hz, 3H). 13

C NMR

(101 MHz, CDCl3): δ 182.18, 158.87, 129.38, 120.90, 114.64, 72.48, 46.79, 35.40,

26.30, 23.09, 19.70.

2,2-dimethyl-4-phenylbutanoic acid (3)


-COOH), 7.31 – 7.28 (m, 2H), 7.22 – 7.18 (m, 3H), 2.66 – 2.62 (m, 2H), 1.92 – 1.87

(m, 2H), 1.31 (s, 6H). 13

C NMR (101 MHz, CDCl3): δ 184.77, 142.06, 128.36,


[M-H]-: 191.1078, Found: 191.1078.

S11

3-([1,1'-biphenyl]-4-yl)-2,2-dimethylpropanoic acid (5)


4H), 7.42 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 7.5 Hz, 2H), 2.95 (s,

2H), 1.25 (s, 6H). 13

C NMR (101 MHz, CDCl3): δ 140.86, 139.40, 136.62, 130.65,

128.71, 127.10, 126.97, 126.74, 45.47, 43.46, 24.71. HRMS (m/z, ESI): Calcd. for

C17H17O2 [M-H]-: 253.1234, Found: 253.1236.

2-methyl-4-phenylbutanoic acid (7)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 9.81 (br s, -COOH), 7.33 – 7.29

(m, 2H), 7.24 – 7.21 (m, 3H), 2.70 (t, J = 7.4 Hz, 2H), 2.57 – 2.51 (m, 1H), 2.13 –

2.04 (m, 1H), 1.82 – 1.71 (m, 1H), 1.26 (dd, J = 7.0 Hz, 2.4 Hz, 3H). 13

C NMR (101

MHz, CDCl3): δ 183.23, 141.44, 128.39, 128.37, 125.93, 38.83, 35.10, 33.32, 16.90.

2,2-dimethyl-3-(((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-dec

ahydro-6H-cyclopenta[a]phenanthren-3-yl)oxy)propanoic acid (9)

White solid. Mp. 189 – 191 °C. 1H NMR (400 MHz, DMSO): δ 12.29 (br s,

-COOH), 7.15 (d, J = 8.6 Hz, 1H), 6.68 – 6.62 (m, 2H), 3.88 (s, 2H), 2.81 – 2.79 (m,

2H), 2.46 – 2.32 (m, 2H), 2.17 (br s, 1H), 2.08 – 1.91 (m, 3H), 1.75 (br d, J = 7.2 Hz,

1H), 1.58 – 1.28 (m, 6H), 1.19 (s, 6H), 0.82 (s, 3H). 13

C NMR (101 MHz, DMSO): δ

220.11, 177.54, 157.09, 137.91, 132.37, 126.65, 114.73, 112.54, 74.66, 50.54, 47.79,

43.89, 42.82, 38.34, 35.85, 31.82, 29.56, 26.52, 26.01, 22.61, 21.62, 13.99. HRMS

S12


S13

3. Optimization of Reaction Conditions

Table S1. Screening of the additivesa

Entry additive Conversion of 1a (%)b yield of 2a (%)

b

1 / 35 25

2 L9 > 95 80

3 L10 20 20

4 L11 20 17

5 L12 < 5% 0

6 L13 34 25

7 L14 30 23

8 L15 15 11

9 L16 46 40

aConditions: 1a (0.5 mmol, 1.0 equiv), Pd(CH3CN)2Cl2 (5 mol%), Ligand

(10 mol%), KHCO3 (0.75 mmol, 1.5 equiv), TBHP (1.0 mmol, 2.0 equiv),

additive (10 mol%), HFIP (4.0 mL), 60 °C, 16 hrs. bDetermined by

1H NMR

spectroscopy with 1,3,5-Trimethoxybenzene as an internal standard.

S14

Table S2. Screening of Ligandsa

Entry Ligands Conversion of 1a (%)

b yield of 2a (%)

b

1 / 10 7

2c / 23 21

3 L1 > 95 80

4 L2 71 51

5 L3 85 68

6 L4 38 36

7 L5 < 5 0

8 L6 73 58

9 L7 90 74

10 L8 42 34

aConditions: 1a (0.5 mmol, 1.0 equiv), Pd(CH3CN)2Cl2 (5 mol%), Ligand (10 mol%),

KHCO3 (0.75 mmol, 1.5 equiv), TBHP (1.0 mmol, 2.0 equiv), L9 (10 mol%), HFIP (4.0

mL), 60 °C, 16 hrs. bDetermined by

1H NMR spectroscopy with

1,3,5-Trimethoxybenzene as an internal standard. cwithout L9.

S15

Table S3. Screening of Pd saltsa

Entry Pd salts Conversion of 1a (%)b yield of 2a (%)

b

1 Pd(CH3CN)2Cl2 > 95 80

2 Pd(OAc)2 > 95 80

3c [Pd(allyl)]2 60 55

4 PdI2 < 5 0

5 Pd(PPh3)Cl2 72 58

6 Pd(PPh3)4 53 51 aConditions: 1a (0.5 mmol, 1.0 equiv), Ligand (10 mol%), KHCO3 (0.75 mmol, 1.5

equiv), TBHP (1.0 mmol, 2.0 equiv), L9 (10 mol%), HFIP (4.0 mL), 60 °C, 16 hrs. bDetermined by

1H NMR spectroscopy with 1,3,5-Trimethoxybenzene as an internal

standard. c[Pd(allyl)]2 was used only 2.5 mol%.

Table S4. Screening of Basea

Entry Base Conversion of 1a (%)b yield of 2a (%)

b

1 KHCO3 > 95 80

2 K2CO3 > 95 75

3 Cs2CO3 85 67

4 CsHCO3 84 67

5 CsOAc 12 11

6 K3PO4 92 72

7 KOAc 20 19

8 NaOAc 15 9 aConditions: 1a (0.5 mmol, 1.0 equiv), Pd(CH3CN)2Cl2 (5 mol%), Ligand (10 mol%),

TBHP (1.0 mmol, 2.0 equiv), L9 (10 mol%), HFIP (4.0 mL), 60 °C, 16 hrs. bDetermined

by 1H NMR spectroscopy with 1,3,5-Trimethoxybenzene as an internal standard.

S16

Table S5. Screening of Oxidantsa

Entry Oxidant Conversion of 1a (%)b yield of 2a (%)

b

1c Ox.1 (TBHP) > 95 80

2d Ox.1 (TBHP) > 95 78

3 Ox.2 35 32

4 Ox.3 < 5 0

5 Ox.4 15 13

6 Cu(OAc)2 < 5 0

7 PhI(OAc)2 < 5 0

8 K2S2O8 < 5 0


KHCO3 (0.75 mmol, 1.5 equiv), L9 (10 mol%), HFIP (4.0 mL), 60 °C, 16 hrs. bDetermined by

1H NMR spectroscopy with 1,3,5-Trimethoxybenzene as an internal

standard. cOx.1 (TBHP 70% solution in water) was used.

dOx.1 (TBHP ~5.5 M in

decane) was used.

Table S6. Screening of Solventsa

Entry Solvent Conversion of 1a (%)b yield of 2a (%)

b

1 HFIP > 95 80

2 DCE < 5 0

3 THF < 5 0

4 MeCN < 5 0

5 Toluene < 5 0

6 tAmylOH < 5 0



mL), 60 °C, 16 hrs. bDetermined by

1H NMR spectroscopy with

1,3,5-Trimethoxybenzene as an internal standard.

S17

Table S7. Screening of temperaturea

Entry Temperature (°C) Conversion of 1a (%)b yield of 2a (%)

b

1 25 24 23

2 40 70 68

3 50 90 77

4 60 > 95 80

5 70 > 95 70

6 80 > 95 62 aConditions: 1a (0.5 mmol, 1.0 equiv), Pd(CH3CN)2Cl2 (5 mol%), Ligand (10 mol%),


mL), 16 hrs. bDetermined by

1H NMR spectroscopy with 1,3,5-Trimethoxybenzene as an

internal standard.

Table S8. Screening of Selected Reaction Parametersa

Entry T. (°C) Pd salt Time

(hours)

Conversion of

1a (%)b

yield of

2a (%)b

1 40 Pd(CH3CN)2Cl2 12 60 57

2 40 Pd(CH3CN)2Cl2 16 70 68

3 40 Pd(CH3CN)2Cl2 24 78 74

4 45 Pd(CH3CN)2Cl2 24 83 78

5 45 Pd(CH3CN)2Cl2 36 93 79

6 45 Pd(CH3CN)2Cl2 48 > 95 80

7 45 Pd(OAc)2 12 80 76

8 45 Pd(OAc)2 24 93 87

9 45 Pd(OAc)2 36 > 95 91

10c 45 Pd(OAc)2 36 > 95 92(88)

d

11 50 Pd(OAc)2 24 > 95 82 aConditions: 1a (0.5 mmol, 1.0 equiv), Ligand (10 mol%), KHCO3 (0.75 mmol, 1.5 equiv),

TBHP (1.0 mmol, 2.0 equiv), L9 (10 mol%), HFIP (4.0 mL). bDetermined by

1H NMR

spectroscopy with 1,3,5-Trimethoxybenzene as an internal standard. cTBHP (1.5 equiv) was

used. d The data in the parentheses was isolated yield of 2a .

S18

4. General procedures for the Catalytic Reaction

To a 20 mL oven-dried glass tube with magnetic stir bar was added Pd(OAc)2

(5.6 mg, 5 mol%), L1 (10.4 mg, 10 mol%) and 2.0 mL HFIP. The tube was sealed and

the reaction mixture was stirred for 20 minutes at room temperature. Then the

substrate (1a, 97.0 mg, 0.5 mmol, 1.0 equiv), KHCO3 (75.0 mg, 1.5 equiv), L9 (8.0

mg, 10 mol%), TBHP (70% in water, 105 uL, 1.5 equiv), and 2.0 mL HFIP was added

to the reaction mixture successively, the tube was sealed and stirred at 45 °C for 36

hours.

After the reaction was completed, the reaction mixture was cooled to room

temperature and added 3 mL 2.0 M HCl solution, stirred 1 minute. After that, the

resulting mixture was extracted with DCM (3*20 mL), combined organic phase, dried

over Na2SO4. And the organic phase was evaporated under vacuum, purified by flash

column chromatography on silica gel (PE:EA from 50:1 to 5:1 with 0.2% AcOH). The

oxidative coupling product 2a was obtained in 88% yield (84.5 mg).

Characterization Data for the products.

3-methylchromane-3-carboxylic acid (2a)

2a was obtained as a white solid (84.6 mg, 88% yield), Mp. 158 – 160 °C. 1H

NMR (400 MHz, CDCl3): δ 9.68 (br s, -COOH), 7.12 – 7.10 (m, 1H), 7.07 (d, J = 7.6

S19

Hz, 1H), 6.89 (td, J = 7.6 Hz, 1.1 Hz, 1H), 6.85 (dd, J = 7.6 Hz, 1.1 Hz, 1H), 4.32 (dd,

J = 10.8 Hz, 1.4 Hz, 1H), 3.96 (dd, J = 10.8 Hz, 1.4 Hz, 1H), 3.28 (d, J = 16.4 Hz,

1H), 2.70 (d, J = 16.4 Hz, 1H), 1.35 (s, 3H). 13

C NMR (101 MHz, CDCl3): δ 181.42,

153.27, 129.79, 127.49, 120.97, 119.93, 116.61, 70.77, 40.64, 34.21, 20.97. HRMS


3,6-dimethylchromane-3-carboxylic acid (2b)

2b was obtained as a white solid (76.2 mg, 74% yield), Mp. 116 – 118 °C. 1H

NMR (400 MHz, CDCl3): δ 10.77 (br s, -COOH), 6.92 (d, J = 8.3 Hz, 1H), 6.88 (s,

1H), 6.73 (d, J = 8.3 Hz, 1H), 4.29 (dd, J = 10.8 Hz, 1.3 Hz, 1H), 3.92 (dd, J = 10.8

Hz, 1.3 Hz, 1H), 3.23 (d, J = 16.4 Hz, 1H), 2.66 (d, J = 16.4 Hz, 1H), 2.26 (s, 3H),

1.34 (s, 3H). 13

C NMR (101 MHz, CDCl3): δ 181.57, 151.07, 130.19, 130.06, 128.15,


C12H13O3 [M-H]-: 205.0870, Found: 205.0867.

3-methyl-6-phenylchromane-3-carboxylic acid (2c)

2c was obtained as a white solid (117.1 mg, 87% yield), Mp. 168 – 170 °C. 1H

NMR (400 MHz, CDCl3): δ 7.55 – 7.53 (m, 2H), 7.44 – 7.30 (m, 5H), 6.92 (d, J =

8.4 Hz, 1H), 4.37 (dd, J = 10.8 Hz, 1.2 Hz, 1H), 3.99 (d, J = 10.8 Hz, 1H), 3.35 (d, J =

16.4 Hz, 1H), 2.77 (d, J = 16.4 Hz, 1H), 1.38 (s, 3H). 13

C NMR (101 MHz, CDCl3):

δ 181.17, 152.91, 140.70, 134.15, 128.67, 128.39, 126.69, 126.34, 120.19, 116.98,


Found: 267.1016.

S20

6-methoxy-3-methylchromane-3-carboxylic acid (2d)

2d was obtained as a white solid (69.7 mg, 63% yield), Mp. 112 – 114 °C. 1H

NMR (400 MHz, CDCl3): δ 9.58 (br s, -COOH), 6.77 (d, J = 8.9 Hz, 1H), 6.69 (dd, J

= 8.9 Hz, 3.0 Hz, 1H), 6.60 (d, J = 3.0 Hz, 1H), 4.27 (dd, J = 10.7 Hz, 1.4 Hz, 1H),

3.89 (dd, J = 10.8 Hz, 0.9 Hz, 1H), 3.75 (s, 3H), 3.25 (d, J = 16.5 Hz, 1H), 2.67 (d, J

= 16.5 Hz, 1H), 1.33 (s, 3H). 13

C NMR (101 MHz, CDCl3): δ 181.38, 153.73, 147.30,

120.61, 117.21, 114.04, 113.61, 70.90, 55.62, 40.74, 34.46, 20.98. HRMS (m/z, ESI):

Calcd. for C12H13O4 [M-H]-: 221.0819, Found: 221.0820.

3-methyl-6-(trifluoromethoxy)chromane-3-carboxylic acid (2e)

2e was obtained as a white solid (74.3 mg, 54% yield), Mp. 74 – 76 °C. 1H

NMR (400 MHz, CDCl3): δ 10.77 (br s, -COOH), 6.98 – 6.93 (m, 2H), 6.82 (d, J =

8.8 Hz, 1H), 4.33 (dd, J = 10.9 Hz, 1.5 Hz, 1H), 3.93 (dd, J = 10.9 Hz, 1.5 Hz, 1H),

3.27 (d, J = 16.6 Hz, 1H), 2.69 (d, J = 16.4 Hz, 1H), 1.34 (s, 3H). 13

C NMR (101

MHz, CDCl3): δ 180.90, 151.86, 142.79, 122.26, 121.20, 120.60, 120.52 (q, J =

256.3 Hz, -OCF3), 117.58, 71.04, 40.46, 34.14, 21.01. HRMS (m/z, ESI): Calcd. for

C12H10F3O4 [M-H]-: 275.0537, Found: 275.0536.

6-fluoro-3-methylchromane-3-carboxylic acid (2f)

2f was obtained as a white solid (74.0 mg, 70% yield), Mp. 117 – 119 °C. 1H

S21

NMR (400 MHz, CDCl3): δ 10.54 (br s, -COOH), 6.83 – 6.75 (m, 3H), 4.30 (dd, J =

10.8 Hz, 1.5 Hz, 1H), 3.90 (dd, J = 10.8 Hz, 1.5 Hz, 1H), 3.25 (d, J = 16.7 Hz, 1H),

2.66 (d, J = 16.7 Hz, 1H), 2.26 (s, 3H), 1.33 (s, 3H). 13


181.27, 157.12 (d, J = 238.9 Hz), 149.30, 121.21 (d, J = 7.8 Hz), 117.54 (d, J = 8.1

Hz), 115.51 (d, J = 23.0 Hz), 114.29 (d, J = 23.3 Hz), 71.00, 40.56, 34.24, 20.99.

HRMS (m/z, ESI): Calcd. for C11H10FO3 [M-H]-: 209.0619, Found: 209.0608.

6-chloro-3-methylchromane-3-carboxylic acid (2g)

2g was obtained as a white solid (73.3 mg, 65% yield), Mp. 126 – 128 °C. 1H

NMR (400 MHz, CDCl3): δ 9.62 (br s, -COOH), 7.07 – 7.04 (m, 2H), 6.76 (d, J = 8.4

Hz, 1H), 4.31 (dd, J = 10.9 Hz, 1.5 Hz, 1H), 3.91 (dd, J = 10.9 Hz, 0.8 Hz, 1H), 3.23

(d, J = 16.6 Hz, 1H), 2.65 (d, J = 16.6 Hz, 1H), 1.33 (s, 3H). 13

C NMR (101 MHz,

CDCl3): δ 180.99, 151.98, 129.30, 127.58, 125.73, 121.64, 118.00, 71.03, 40.51,

34.08, 21.02. HRMS (m/z, ESI): Calcd. for C11H10ClO3 [M-H]-: 225.0342, Found:

225.0347.

6-bromo-3-methylchromane-3-carboxylic acid (2h)

2h was obtained as a white solid (94.3 mg, 70% yield), Mp. 135 – 137 °C. 1H

NMR (400 MHz, CDCl3): δ 7.20 – 7.18 (m, 2H), 6.71 (d, J = 9.3 Hz, 1H), 4.31 (dd, J

= 10.9 Hz, 1.1 Hz, 1H), 3.91 (d, J = 10.9 Hz, 1H), 3.23 (d, J = 16.6 Hz, 1H), 2.66 (d, J

= 16.6 Hz, 1H), 1.33 (s, 3H). 13

C NMR (101 MHz, CDCl3): δ 180.56, 152.49, 132.22,

130.45, 122.19, 118.44, 113.02, 70.97, 40.43, 34.00, 20.98. HRMS (m/z, ESI): Calcd.

for C11H10BrO3 [M-H]-: 268.9819, Found: 268.9812.

S22

6-(tert-butyl)-3-methylchromane-3-carboxylic acid (2i)

2i was obtained as a white solid (107.5 mg, 86% yield), Mp. 152 – 154 °C. 1H

NMR (400 MHz, CDCl3): δ 7.14 (dd, J = 8.6 Hz, 2.4 Hz, 1H), 7.05 (d, J = 2.4 Hz,

1H), 6.78 (d, J = 8.6 Hz, 1H), 4.29 (dd, J = 10.8 Hz, 1.1 Hz, 1H), 3.93 (dd, J = 10.8

Hz, 0.8 Hz, 1H), 3.27 (d, J = 16.4 Hz, 1H), 2.69 (d, J = 16.4 Hz, 1H), 1.35 (s, 3H),

1.29 (s, 9H). 13

C NMR (101 MHz, CDCl3): δ 181.40, 151.05, 143.72, 126.45, 124.62,

119.14, 116.08, 70.81, 40.83, 34.50, 34.07, 31.53, 21.11. HRMS (m/z, ESI): Calcd. for

C15H19O3 [M-H]-: 247.1340, Found: 247.1339.

6-(benzyloxy)-3-methylchromane-3-carboxylic acid (2j)

2j was obtained as a white solid (107.5 mg, 86% yield), Mp. 142 – 144 °C. 1H

NMR (400 MHz, CDCl3): δ 7.44 – 7.32 (m, 5H), 6.77 (s, 2H), 6.69 (s, 1H), 4.99 (s,

2H), 4.28 (d, J = 10.8 Hz, 1H), 3.90 (d, J = 10.8 Hz, 1H), 3.25 (d, J = 16.5 Hz, 1H),

2.66 (d, J = 16.5 Hz, 1H), 1.34 (s, 3H). 13

C NMR (101 MHz, CDCl3): δ 181.09,

153.04, 147.54, 137.22, 128.53, 127.88, 127.48, 120.67, 117.23, 115.31, 114.55,

70.93, 70.59, 40.74, 34.49, 20.99. HRMS (m/z, ESI): Calcd. for C18H17O4 [M-H]-:

297.1132, Found: 297.1128.

3,5,7-trimethylchromane-3-carboxylic acid (2k)

2k was obtained as a white solid (91.5 mg, 83% yield), Mp. 171 – 173 °C. 1H

S23

NMR (400 MHz, CDCl3): δ 11.64 (brs, -COOH), 6.63 (s, 1H), 6.56 (s, 1H), 4.27 (dd,

J = 10.7 Hz, 0.9 Hz, 1H), 3.90 (d, J = 10.7 Hz, 1H), 3.12 (d, J = 16.6 Hz, 1H), 2.50 (d,

J = 16.6 Hz, 1H), 2.26 (s, 3H), 2.20 (s, 3H), 1.36 (s, 3H). 13

C NMR (101 MHz,

CDCl3): δ 181.87, 153.33, 137.42, 136.78, 123.58, 115.80, 114.82, 70.34, 40.96,


Found: 219.1029.

3,8-dimethylchromane-3-carboxylic acid (2l)

2l was obtained as a white solid (89.4 mg, 87% yield), Mp. 157 – 159 °C. 1H

NMR (400 MHz, CDCl3): δ 6.97 (d, J = 7.2 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 6.79 (t,

J = 7.2 Hz, 1H), 4.32 (d, J = 10.8 Hz, 1H), 3.98 (d, J = 10.8 Hz, 1H), 3.27 (d, J = 16.4

Hz, 1H), 2.69 (d, J = 16.4 Hz, 1H), 2.19 (s, 3H), 1.34 (s, 3H). 13

C NMR (101 MHz,

CDCl3): δ 181.53, 151.52, 128.66, 127.33, 125.87, 120.33, 119.32, 70.79, 40.59,

34.37, 20.92, 15.95. HRMS (m/z, ESI): Calcd. for C12H13O3 [M-H]-: 205.0870, Found:

205.0859.

3-methyl-3,4-dihydro-2H-benzo[h]chromene-3-carboxylic acid (2m)

2m was obtained as a white solid (70.9 mg, 59% yield), Mp. 187 – 189 °C. 1H

NMR (400 MHz, CDCl3): δ 8.17 – 8.15 (m, 1H), 7.77 – 7.74 (m, 1H), 7.47 – 7.42 (m,

2H), 7.38 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 4.48 (dd, J = 10.7 Hz, 1.3 Hz,

1H), 4.13 (dd, J = 10.7 Hz, 1.1 Hz, 1H), 3.39 (d, J = 16.5 Hz, 1H), 2.80 (d, J = 16.5

Hz, 1H), 1.40 (s, 3H). 13

C NMR (101 MHz, CDCl3): δ 181.22, 148.35, 133.22,

S24

127.56, 127.39, 125.84, 125.36, 124.83, 121.52, 120.39, 113.75, 71.02, 40.68, 34.43,

21.04. HRMS (m/z, ESI): Calcd. for C15H13O3 [M-H]-: 241.0870, Found: 241.0869.

2-methyl-2,3-dihydro-1H-benzo[f]chromene-2-carboxylic acid (2n)

2n was obtained as a white solid (92.3 mg, 76% yield), Mp. 175 – 177 °C. 1H

NMR (400 MHz, CDCl3): δ 11.60 (br s, -COOH), 7.82 (d, J = 8.5 Hz, 1H), 7.78 (d, J

= 8.0 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.54 – 7.49 (m, 1H), 7.40 – 7.36 (m, 1H),

7.09 (d, J = 8.9 Hz, 1H), 4.39 (dd, J = 10.7 Hz, 1.0 Hz, 1H), 4.04 (dd, J = 10.7 Hz, 0.7

Hz, 1H), 3.57 (d, J = 16.6 Hz, 1H), 2.96 (d, J = 16.6 Hz, 1H), 1.44 (s, 3H). 13

C NMR

(101 MHz, CDCl3): δ 181.63, 150.99, 132.87, 129.23, 128.43, 128.00, 126.54,

123.59, 121.69, 118.55, 111.85, 70.54, 40.71, 31.09, 21.38. HRMS (m/z, ESI): Calcd.

for C15H13O3 [M-H]-: 241.0870, Found: 241.0870.

3-methyl-3,4-dihydro-2H-benzofuro[2,3-h]chromene-3-carboxylic acid (2o)

2o was obtained as a white solid (64.9 mg, 46% yield), Mp. 181 – 183 °C. 1H

NMR (400 MHz, DMSO): δ 12.68 (br s, -COOH), 8.01 (d, J = 7.1 Hz, 1H), 7.64 (d,

J = 8.2 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.25 – 7.18 (m, 2H),

4.51 (d, J = 10.6 Hz, 1H), 4.17 (d, J = 10.6 Hz, 0.7 Hz, 1H), 3.25 (d, J = 15.9 Hz, 1H),

2.79 (d, J = 15.9 Hz, 1H), 1.28 (s, 3H). 13

C NMR (101 MHz, DMSO): δ 176.36,

155.52, 155.42, 149.32, 129.53, 127.07, 123.56, 123.04, 122.85, 115.32, 112.14,


S25

[M-H]-: 281.0819, Found: 281.0815.

3,7-dimethylchromane-3-carboxylic acid (2p’)

2p’ and 2p were obtained with r.r. = 3.3:1 (84.5 mg, 82% total yield). 1H NMR

(400 MHz, CDCl3): δ 10.60 (br s, -COOH), 6.95 (d, J = 7.7 Hz, 1H), 6.72 (d, J = 7.7

Hz, 1H), 6.67 (s, 1H), 4.30 (dd, J = 10.8 Hz, 1.4 Hz, 1H), 3.93 (dd, J = 10.8 Hz, 1.4

Hz, 1H), 3.23 (d, J = 16.3 Hz, 1H), 2.66 (d, J = 16.3 Hz, 1H), 2.28 (s, 3H), 1.34 (s,

3H). HRMS (m/z, ESI): Calcd. for C12H13O3 [M-H]-: 205.0870, Found: 205.0867.

7-methoxy-3-methylchromane-3-carboxylic acid (2q’)

2q’ and 2q were obtained with r.r. = 10:1 (87.7 mg, 79% total yield). 1H NMR

(400 MHz, CDCl3): δ 11.50 (br s, -COOH), 6.95 (d, J = 8.4 Hz, 1H), 6.49 (dd, J = 8.4

Hz, 2.5 Hz, 1H), 6.41 (d, J = 2.5 Hz, 1H), 4.30 (dd, J = 10.8 Hz, 1.3 Hz, 1H), 3.92 (dd,

J = 10.8 Hz, 1.3 Hz, 1H), 3.75 (s, 3H), 3.20 (d, J = 16.0 Hz, 1H), 2.63 (d, J = 16.0 Hz,

1H), 1.33 (s, 3H). 13

C NMR (101 MHz, CDCl3): δ 181.58, 159.12, 153.97, 130.20,

111.94, 107.97, 101.36, 70.80, 55.24, 40.69, 33.60, 20.98. HRMS (m/z, ESI): Calcd.

for C12H13O4 [M-H]-: 221.0819, Found: 221.0811.

3-isopropylchromane-3-carboxylic acid (2r)

2r was obtained as a white solid (39.8 mg, 42% yield). 1H NMR (400 MHz,

S26

CDCl3): δ 9.68 (br s, -COOH), 7.11 – 7.08 (m, 2H), 6.88 (t, J = 7.0 Hz, 1H), 6.82 (d,

J = 8.1 Hz, 1H), 4.43 (dd, J = 10.8 Hz, 1.9 Hz, 1H), 3.99 (d, J = 10.8 Hz, 1H), 3.19 (d,

J = 16.1 Hz, 1H), 2.81 (d, J = 16.1 Hz, 1H), 2.09 – 1.99 (m, 1H), 1.03 (d, J = 6.9 Hz,

3H), 1.01 (d, J = 6.9 Hz, 3H). 13

C NMR (101 MHz, CDCl3): δ 179.89, 153.91,

129.81, 127.24, 120.93, 120.62, 116.55, 69.69, 48.14, 31.99, 29.42, 17.85, 17.16.


3-butylchromane-3-carboxylic acid (2s)

2s was obtained as a white solid (20.1 mg, 43% yield). 1H NMR (400 MHz,

CDCl3): δ 7.12 – 7.06 (m, 2H), 6.88 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 4.31

(d, J = 10.9 Hz, 1H), 4.00 (d, J = 10.9 Hz, 1H), 3.26 (d, J = 16.4 Hz, 1H), 2.72 (d, J =

16.4 Hz, 1H), 1.75 – 1.69 (m, 1H), 1.58 – 1.50 (m, 4H), 0.90 (t, J = 6.9 Hz, 3H). 13

C

NMR (101 MHz, CDCl3): δ 180.10, 153.70, 129.82, 127.37, 120.96, 120.17, 116.59,


C14H17O3 [M-H]-: 233.1183, Found: 233.1182.

2-methyl-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (4)

4 was obtained as a white solid (50.4 mg, 53% yield). 1H NMR (400 MHz,

CDCl3): δ 10.73 (br s, -COOH), 7.15 – 7.09 (m, 4H), 3.26 (d, J = 16.5 Hz, 1H), 2.95

– 2.82 (m, 2H), 2.69 (d, J = 16.5 Hz, 1H), 2.23 – 2.16 (m, 1H), 1.84 – 1.78 (m, 1H),

1.34 (s, 3H). 13

C NMR (101 MHz, CDCl3): δ 184.23, 134.92, 134.58, 129.19, 128.74,

125.84, 125.78, 41.52, 38.23, 31.54, 26.06, 24.17.

S27

2-methyl-5-phenyl-2,3-dihydro-1H-indene-2-carboxylic acid (6)


CDCl3): δ 7.58 – 7.56 (m, 2H), 7.44 – 7.39 (m, 4H), 7.34 – 7.30 (m, 1H), 7.27 – 7.25

(m, 1H), 3.60 – 3.54 (m, 2H), 2.93 – 2.87 (m, 2H), 1.45 (s, 3H).

1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (8)


CDCl3): δ 7.20 – 7.12 (m, 4H), 3.09 – 2.99 (m, 2H), 2.95 – 2.87 (m, 2H), 2.84 – 2.78

(m, 1H), 2.28 – 2.24 (m, 1H), 1.96 – 1.85 (m, 1H). 13


181.01, 135.56, 134.55, 129.07, 128.87, 126.00, 125.87, 39.69, 31.30, 28.36, 25.65.


(3aS,3bR,11bS,13aS)-9,13a-dimethyl-1-oxo-1,2,3,3a,3b,4,5,8,9,10,11b,12,13,13a-te

tradecahydrocyclopenta[5,6]naphtho[1,2-g]chromene-9-carboxylic acid (10)

10 was obtained as a white solid (84.6 mg, 46% total yield with dr = 1:1). 1H

NMR (400 MHz, CDCl3): δ 9.48 (br s, -COOH), 6.58 (s, 1H), 6.97 (s, 1H), 4.27 (t, J

= 10.9 Hz, 1H), 3.89 (dd, J = 10.3 Hz, 8.3 Hz, 1H), 3.22 (dd, J = 16.3, 4.7 Hz, 1H),

2.85 – 2.82 (m, 2H), 2.64 (dd, J = 16.3 Hz, 7.1 Hz, 1H), 2.54 – 2.47 (m, 1H), 2.38 –

2.35 (m, 1H), 2.22 – 1.93 (m, 5H), 1.64 – 1.40 (m, 6H), 1.33 (d, J = 3.1 Hz, 3H), 0.91

S28

(s, 3H). 13

C NMR (101 MHz, CDCl3): δ 221.32, 180.86, 151.22, 135.91, 132.45,

117.34, 116.23, 70.89, 60.41, 50.35, 47.96, 43.90, 40.80, 38.22, 35.82, 34.13, 31.47,

29.05, 26.50, 21.52, 21.11, 14.12. HRMS (m/z, ESI): Calcd. for C23H27O4 [M-H]-:

367.1915, Found: 367.1912.

S29

5. Kinetic Isotope Experiments

Following the already described General procedures for the Catalytic Reaction,

kinetic isotope experiments were performed. Firstly, the mono CD3 substrate 1a-d3

and mono-deuterated substrate 1a-d were applied into the intramolecular competition

oxidative coupling reaction under the standard condition. The crude reaction mixture

obtained was tested 1H NMR for the measurement of the KIE (Figure S1 and S2).

Figure S1. The crude 1H NMR for the reaction mixture of mono CD3 substrate 1a-d3.

S30

Figure S2. The crude 1H NMR for the reaction mixture of mono-deuterated substrate 1a-d1.

S31

Next, intermolecular one-pot competition reactions were also carried out using

an equimolar mixture of 1a-d6 + 1a (Figure S3) and 1a-d5 + 1a (Figure S4). To avoid

high conversion, we quenched the two runs after 4.0 h with 25.1% yield and 4.0 h

with 33.9% yield. We also tested the 1H NMR spectra of the crude mixture for the

measurement of the KIE values.

Figure S3. The crude 1H NMR for the reaction mixture of an equimolar mixture of 1a-d6 + 1a.

S32

Figure S4. The crude 1H NMR for the reaction mixture of an equimolar mixture of 1a-d5 + 1a.

S33

Finally, two pairs of intermolecular competition experiments were run to

measure the initial rate of the reaction. As showed in the following figures, in the

three runs, under standard condition, reaction mixture (20 uL) was tested 1H NMR

every 20 minutes for drawing the yield-time curve. And according the yield-time

curve, matched the liner relation. So, the KIE value can be calculated as kH/kD = 5.03

and kH/kD = 0.98, respectively (Figure S5 – S7).

Figure S5. The reaction rate as monitored by 1H NMR spectrum from 1a to 2a.

S34

Figure S6. The reaction rate as monitored by 1H NMR spectrum from 1a-d6 to 2a-d5.

Figure S7. The reaction rate as monitored by 1H NMR spectrum from 1a-d5 to 2a-d4.

Characterization Data for 1a-d and 2a-d.

2,2-dimethyl-3-(phenoxy-2-d)propanoic acid (1a-d1)

White solid. D% > 99%. 1H NMR (400 MHz, CDCl3): δ 11.23 (br s, -COOH),

7.31 – 7.28 (m, 2H), 6.97 (t, J = 7.4 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 4.00 (s, 2H),

1.38 (s, 6H). HRMS (m/z, ESI): Calcd. for C11H12DO3 [M-H]-: 194.0933, Found:

194.0937.

S35

2,2-dimethyl-3-(phenoxy-d5)propanoic acid (1a-d5)

White solid. D% > 99%. 1H NMR (400 MHz, CDCl3): δ 3.98 (s, 2H), 1.35 (s,

6H). 13

C NMR (101 MHz, CDCl3): δ 181.58, 74.10, 43.18, 22.36, 22.25. HRMS (m/z,

ESI): Calcd. for C11H8D5O3 [M-H]-: 198.1184, Found: 198.1181.

2-methyl-2-(phenoxymethyl)propanoic-3,3,3-d3 acid (1a-d3)

White solid. D% > 99%. 1H NMR (400 MHz, CDCl3): δ 7.30 – 7.26 (m, 2H),

6.97 – 6.90 (m, 3H), 3.98 (s, 2H), 1.35 (s, 3H). HRMS (m/z, ESI): Calcd. for

C11H10D3O3 [M-H]-: 196.1058, Found: 196.1060.

2-(methyl-d3)-2-(phenoxymethyl)propanoic-3,3,3-d3 acid (1a-d6)

White solid. D% > 99%. 1H NMR (400 MHz, CDCl3): δ 7.30 – 7.26 (m, 2H),

6.97 – 6.90 (m, 3H), 3.97 (s, 2H). 13

C NMR (101 MHz, CDCl3): δ 181.97, 158.82,

129.40, 120.97, 114.64, 73.87, 42.78. HRMS (m/z, ESI): Calcd. for C11H7D6O3

[M-H]-: 199.1247, Found: 199.1249.

3-methylchromane-3-carboxylic-5,6,7,8-d4 acid (2a-d4)

S36

White solid. 1H NMR (400 MHz, CDCl3): δ 4.31 (dd, J = 10.8 Hz, 1.4 Hz, 1H),

3.95 (dd, J = 10.8 Hz, 1.4 Hz, 1H), 3.27 (dd, J = 16.4 Hz, 1.4 Hz, 1H), 2.70 (dd, J =

16.4 Hz, 1.4 Hz, 1H), 1.34 (s, 3H). HRMS (m/z, ESI): Calcd. for C11H7D4O3 [M-H]-:

195.0965, Found: 195.0958.

3-(methyl-d3)chromane-3-carboxylic-4,4-d2 acid (2a-d5)

White solid. 1H NMR (400 MHz, CDCl3): δ 7.11 (ddd, J = 8.2 Hz, 7.3 Hz, 1.7

Hz, 1H), 7.06 (dd, J = 7.6 Hz, 1.7 Hz, 1H), 6.88 (td, J = 7.4 Hz, 1.2 Hz, 1H), 6.83 (dd,

J = 8.2 Hz, 1.0 Hz, 1H), 4.31 (d, J = 10.8 Hz, 1H), 3.95 (d, J = 10.8 Hz, 1H). HRMS

(m/z, ESI): Calcd. for C11H6D5O3 [M-H]-: 196.1028, Found: 196.1017.

S37

6. NMR Spectra

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