A Selective and Functional Group Tolerant Ruthenium Catalyzed

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A Selective and Functional Group Tolerant Ruthenium Catalyzed Olefin Metathesis/Transfer Hydrogenation Tandem Sequence Using Formic Acid as Hydrogen Source Grzegorz Krzysztof Zieli#ski, Jaros#awa Majtczak, Maciej Gutowski, and Karol Grela J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02468 • Publication Date (Web): 05 Jan 2018 Downloaded from http://pubs.acs.org on January 5, 2018

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The Journal of Organic Chemistry

A Selective and Functional Group Tolerant Ruthenium Catalyzed Olefin Metathesis/Transfer Hydrogenation Tandem Sequence Using Formic Acid as Hydrogen Source Grzegorz K. Zieliński,† Jarosława Majtczak, Maciej Gutowski, Karol Grela* Institute of Organic Chemistry Polish Academy of Sciences, Kasprzaka 44/52, Warsaw, Poland KEYWORDS Tandem Catalysis, Transfer Hydrogenation, Olefin Metathesis, Formic Acid ABSTRACT: A ruthenium-catalyzed transfer hydrogenation of olefins utilizing formic acid as a hydrogen donor is described. The application of commercially available alkylidene ruthenium complexes opens an access to attractive C(sp3)C(sp3) bond formation in an olefin metathesis/transfer hydrogenation sequence under tandem catalysis conditions. High chemoselectivity of the developed methodology provides a remarkable synthetic tool for the reduction of various functionalized alkenes under mild reaction conditions. The developed methodology is applied for the formal synthesis of drugs pentoxyverine and bencyclane.

Introduction The most elemental functional group interconversions, the C-C double bond reduction methods,1 are dominated by catalytic hydrogenation using explosive hydrogen gas in the presence of noble metal-based promoters under both homo-2 and heterogeneous3 catalysis conditions. Considering safety issues, transfer hydrogenation (TH) utilizing mild and convenient hydrogen sources other than H2 provides an attractive methodology to reduce diverse unsaturated compounds. Although the conventional hydrogenation offers the highest possible atom economy, it often requires the application of high hydrogen pressures and specialized laboratory equipment. Conversely, the choice of TH hydrogen donors includes cheap, easy to handle and store, low molecular weight organic compounds, typically isopropanol, formic acid or its salts.4–7 Moreover, both the hydrogen donors and their oxidized products are non-toxic and easier to remove from reaction mixtures, as compared to reductions using moisture and air sensitive metal hydrides,8 silanes9,10 or boranes.11

Figure 1. Selected ruthenium olefin metathesis catalysts.

Transfer hydrogenation has recently gained widespread attention and numerous examples of improvements have been described in comprehensive reviews.12–15 The majori-

ty of examples in literature concerns the reduction of polarized C=O, C=N or C=C bonds.16–20 However, the TH of inactivated olefins has not been extensively explored. Among the few excellent reports, works of Vol’pin,21–23 Nolan,24 Brunel,25,26 Albrecht,27 Cazin,28 and Pees29 have been substantial contributions to the field. One-pot transformations, which include inter alia domino and tandem processes, are always followed by a single workup and feature various advantages in the economy and ecology of the process, when compared to a linear reaction sequence. Domino (cascade) catalysis encompasses a series of transformations proceeding via exclusively one mechanism.30 Literature examples of cascade reactions involving olefin metathesis were thoroughly reviewed in a comprehensive book chapter.31 Tandem catalysis, however, relies on performing multiple mechanistically disparate transformations without isolation of any intermediates. Fogg et al.32 defined and characterized illustratively three categories of tandem catalysis (orthogonal, auto, and assisted). An intriguing and particularly useful aspect of the tandem catalysis is its high efficiency and lowered waste emission. Recently, elegant examples of tandem catalysis utilizing olefin metathesis with alkylidene Ru-based complexes, exhibiting non-metathetic activity,33,34 (Figure 1.) have been reviewed.35 A sequence of olefin metathesis followed by hydrogenation under tandem catalysis conditions has been previously reported (Scheme 1). Grubbs and co-workers36 described an olefin metathesis/hydrogenation sequence under tandem conditions. Complex Ru-1 was found to be an efficient (pre)catalyst for both transformations, while upon treatment with H2, it could be converted into RuHCl(H2)(PCy3)2, a hydrogenation catalyst. However,

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The Journal of Organic Chemistry some examples required rather elevated hydrogen pressures. Importantly, Schmidt and co-workers37 have reported a successful RCM/hydrogenation tandem sequence using NaH as an trigger for efficient ruthenium hydride formation in aprotic solvents. Although the proposed conditions were mild and therefore the undesired double bond isomerization was suppressed, the reported substrate scope was narrow. Further investigation of a novel camphor-derived chiral auxillary38 revealed an unexpected tandem ring-closing metathesis/transfer hydrogenation (RCM/TH) transformation occurring in the presence of base and i-PrOH.

the acidic hydrogen in formic acid plays a major role in the TH catalytic cycle. Additionally, we confirmed that the minimal excess of formic acid that provides the reduction product exclusively is 50 equiv. under the presented conditions. Table. 1. The optimization of reaction conditions.

Entry

Cat.

Base

HCO2H [equiv.]

1/2/3

1

none

NaH

50

100/0/0

2

Ru-1

NaH

50

69/5/26

3

Ru-4

NaH

50

20/35/45

4

Ru-5

NaH

50

0/0/100

5

Ru-3

HCO2Na

50

0/0/100

6

Ru-3

NaOH

50

6/16/78

[b]

Ru-3

HCO2Na

0

34/66/0

8

Ru-3

NaH

30

1/2/97

9

Ru-3

NaH

10

8/8/84

7

Scheme 1. Reported sis/hydrogenations sequences.

olefin

metathe-

Peese et al.29 have demonstrated an RCM/TH approach applying sodium borohydride in methanol as a hydrogen donor. Nearly concurrently, we reported a similar protocol using formic acid.39 The visible interest in new, selective, and mild metathesis/hydrogenation sequences encouraged us to continue our investigation and soon we were delighted to find the studied methodology to be highly chemoselective. In addition, the protocol was extended to tandem cross-metathesis/transfer hydrogenation (CM/TH). Herein, we present the details of our study.

[a] The product ratio was determined by the analysis of 1 a H NMR spectrum of the crude reaction mixture; [b] 10 equiv. of sodium formate were used without any HCO2H; Ru-5 = RuCl2(PPh3)3.

A detailed study of the TH reaction course in an NMR experiment (Chart 1.) provided the information about the product ration in time. Naturally, the isomerization product 2 can also enter the TH catalytic cycle, thereby leading to the formation of the desired product 3. Hence, the consumption of 2 was detectable after the time of reaching the maximum contribution to the reaction mixture. Chart 1. Molar composition of the reaction mixture vs. time.

Results and Discussion In order to fully optimize the studied TH transformation, we investigated the influence of various factors on the reaction outcome. Optimization experiments relied on cyclic olefin 1 as a model substrate. Extensive reaction parameter screening and crude reaction mixture analysis (Table 1) immediately revealed that double bond isomerization always accompanies the TH reaction. Numerous commercially available Ru-based olefin metathesis catalysts were tested, among which all exhibited catalytic activity in studied reaction, though the most potent were ones bearing an NHC ligand. Encouraged by this generality, we investigated a simpler ruthenium complex Ru-5 which surprisingly served as a superior TH promoter. A control experiment in the absence of a catalyst resulted in no conversion. Moreover, both the inorganic base and formic acid were proven to be necessary in order to give product 3 in an acceptable yield. Interestingly, an experiment without HCO2H led exclusively to a mixture of 1 and 2. Undetectable amounts of 3 could suggest that

Composition [%]

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

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Additionally, as compared to a classical hydrogenation, the studied method exhibits intriguing regioselectivity. By applying our conditions, we were able to obtain 4c by the reduction of the C-C double bond present in the five-


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membered ring of diene 4a exclusively, while reduction using hydrogen and Pd-C led to a fully saturated compound 4b (Scheme 2).

Scheme 2. Classical H2/Pd-C reduction compared with regioselective reduction by Ru-3/HCO2H. Although the initial study involved an efficient reduction of simple cyclic and linear olefins with remarkable regioselectivity, the most significant feature of the developed method—the possibility of utilization in tandem catalysis—was only superficially explored. Due to the attractiveness of tandem methods involving olefin metathesis,32,35 we decided to explore this selective and possibly functional group tolerant transformation in more detail. First interesting results were noted in a RCM/TH tandem reaction, where the desired cycloalkane products were afforded in good to excellent yields (Table 2.). Importantly, the crude products often required only simple filtration though a silica pad in order to obtain spectroscopically pure compounds. The reaction of ketone 6a proceeded without undesired carbonyl group reduction (Table 2., Entry 2). When hydroxyl group-containing substrates (8a and 19b) were used, the standard protocol was followed by 30 min basic hydrolysis of the resulting formates. Table 2. Tandem RCM/TH sequence. Entry

Substrate

Product

Time [h]

[a]

[b]

Yield [%]

Reaction conditions: Diene (1 mmol), Ru-3 (2 mol%), THF, 40 °C, 30 min, then NaH (0.2 equiv.), HCO2H (50 equiv.), 80 °C, Time. [a] Time of TH reaction; [b] Yield of isolated product; [c] The RCM/TH sequence was followed by saponification using NaOH, H2O/EtOH, 30 min, RT.

Given the relatively broad scope of the TH reaction offering the possibility to couple it with numerous olefin metathesis transformations, we decided to study the functional group tolerance in more detail. To our delight, the method exhibited a high level of chemoselectivity, which was demonstrated in a series of RCM/TH tandem reactions (Table 3.). The model substrates were adapted from the recent Pees report29 and bear various substituents, including “problematic” groups known for their susceptibility to reductive conditions or some moieties considered catalyst poisons. The studied TH conditions tolerate aryl halides, making the methodology compatible with substrates for various Pd-catalyzed coupling reaction (Suzuki, Heck, BuchwaldHartwig, and others). Therefore, this methodology can be attractive during multistep syntheses, as it allows for C-C double bond hydrogenation without undesired hydrogenolysis of Ar-X bonds. Thioethers and sulfoxides are known metal-coordinating ligands; consequently, substrates possessing those groups are often found to be challenging in metal-catalyzed transformations. Under the studied conditions, thioether 12a and sulfoxide 13a were efficiently converted into the corresponding products. However, both required longer reaction time to reach full conversion. Amide bearing substrates selectively underwent the RCM/TH reaction leading to the formation of desired products in high yields. Interestingly, the reaction of nitroarene 16a successfully proceeded to give the RCM/TH product with a retained NO2 group.29 Table 3. Functional group tolerance examination in RCM/TH reaction sequence.

1 20

97

2 7

4

99

4 7

[c]

98

5 6

R

Loading [mol%]

Time [h]

1

Br

2

30

81

2

I

3

30

86

3

SMe

3

40

84

4

S(O)Me

3

40

92

5

NHAc

3

30

90

6

NHBz

3

30

86

7

NO2

2

20

99

8

Ac

3

30

47

9

CN

4

40

92

3

89

[a]

Entry

Yield [%]

75

[b]

Reaction conditions: Diene (1 mmol), Ru-3 (loading), THF, 40 °C 30 min, then NaH (0.2 equiv.), HCO2H (50 equiv.), Time. [a] Yield of isolated product; [b] Yield deter-


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mined by NMR.

Although we have already demonstrated high chemoselectivity of the reviewed TH reaction in the presence of numerous unsaturated ketones,39 in the case of acetophenone derivative 17a, the reaction was followed by a partial carbonyl group reduction. Nevertheless, the expected keto product 17b and corresponding alcohol (as formate ester 17c) were both efficiently obtained in moderate yield after a chromatographic separation (Scheme 3a). Analogously, an aromatic nitrile group was found to be slightly reactive under the transfer hydrogenation conditions and the reaction with compound 18a led to the corresponding formamide 18c as a minor by-product (Scheme 3b). Scheme 3. The results of RCM/TH reactions with ketone 17a and nitrile 18a.

The “one-pot” metathesis/TH protocol can be extended to more demanding cross-metathesis/transfer hydrogenation CM/TH sequences (Scheme 5), thus widening its synthetic utility. We concentrated our efforts on the examination of methyl acrylate as a challenging CM partner44 which can lead to a number of useful products in CM/TH tandem reactions (Scheme 6). The application of this methodology allows for formal conversion of terminal olefins into homologous methyl esters, and provides an elegant retrosynthetic tool in synthesis planning.45 The CM step was conducted for 2 hours at 40 °C. After that time, both sodium hydride and formic acid were added and then the reaction mixture was heated at 80 °C until full conversion was determined by GC-FID. The reaction of ethyl 5-hexenoate proceeded readily to give an unnatural homologue of dimethyl adipate in moderate yield. Although a primary alcohol, 10-undecen-1-ol, reacted in the tandem reaction sequence in good yield, the product bore the O-formyl group, installed due to the excess of formic acid. On the other hand, a phenolic type hydroxyl group present in eugenol was tolerated and preserved under the reaction conditions. Hydrocarbons, allylcyclopentane 24a and allylbenzene 25a, were also converted into desired products in good yields.

Encouraged by these results, we envisioned an application of the studied RCM/TH protocol in the synthesis of more advanced targets, such as the API substances bencyclane and pentoxyverine, known vasodilator40 and nonopioid antitussive,41 respectively. Precursors 19a and 20a for both these pharmaceuticals were derived from methyl phenylacetate in a few simple steps involving Grignard reagent addition and alkylation with allyl bromide, respectively. Having assembled the required precursors 19a and 20a, we demonstrated the utilization of the RCM/TH sequence in the formal synthesis of bencyclane and pentoxyverine. A stepwise RCM reaction followed by TH reduction confirmed that the transfer hydrogenation conditions led to saturated products 19b and 20b, the key intermediates that can be converted to bencyclane and pentoxyverine following literature procedures (Scheme 4).42,43 It should be noted that a free carboxylic acid group in 20a is well preserved during the studied RCM/TH sequence. Scheme 4. Formal synthesis of bencyclane and pentoxyverine.

Scheme. 5. Tandem CM/TH sequence utilizing methyl acrylate as a common reaction partner.

We believe both isomerization and transfer hydrogenation to be mediated by ruthenium hydrides that can be formed during the degradation of alkylidene ruthenium complexes under particular conditions.46,47 In order to understand the nature of the studied TH transformation better, we attempted a number of experiments. In a NMR experiment, Grubbs’ second-generation catalyst was sub-


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jected to HCO2H and, as a result, the formation of a ruthenium hydride complex was observed (the appearance of a singlet was observed at δ = −6.86 ppm in 1H NMR spectrum). Unfortunately, numerous attempts to isolate the ruthenium hydride complex ended in failure, thus the exact chemical structure of the hydride complex remains unknown. Nevertheless, we have not observed any catalytic activity drop in the presence of metallic mercury. Thus, we rejected the hypothesis that any ruthenium nanoparticles might be involved in the catalysis.48–50 Furthermore, we found that the ruthenium hydrides RuH-1 and RuH-2 can also mediate the model TH reaction, though they exhibited lower activity compared to Ru-3 (Scheme 6.). Given all of the above evidence, we believe that ruthenium hydride, [Ru]-H, is likely to be a homogenous promoter of TH reaction. Scheme 6. Control experiments.

Unfortunately, despite many efforts, we were unable to isolate the exact catalytic species produced upon the action of HCO2Na/HCO2H on Ru-3. Based on the NMR analysis, we suggest that the entry into the catalytic cycle starts with the conversion of Ru-3 into a Ru–hydride species, which acts as the actual hydrogenation catalyst. A similar mechanism has been suggested for other Rucatalyzed transfer hydrogenation reactions.51 The course of the reaction was proposed based on several experiments described below.

Deuterium-labeling experiments were carried out using DCO2D in the model reaction. Having observed the isomerization process accompanying the TH reaction before, we anticipated an exchange of hydrogens with the deuterium atoms. The analysis of the MS spectrum of the obtained product mixture confirmed our hypothesis, and strongly suggests that both isomerization and transfer hydrogenation processes could be mediated by the same active species (Scheme 8a). In order to understand the stereochemistry of the hydrogen addition process, we carried out the reaction with substrate 26a, unable to undergo an isomerization of the double bond. An analysis of a NOE NMR experiment revealed that the addition occurred in a syn manner, leading to the formation of endo-dideutero diastereomer (Scheme 8b). Scheme. 8. Mechanistic experiments involving deuterium-labeled formic acid.

Moreover, a separate experiment revealed that formic acid undergoes Ru-catalyzed degradation (flask A) to gaseous products in the form of carbon dioxide (absorbed in basic scrubber B) and hydrogen (detected in flask C).52 This unproductive catalytic cycle may explain the need of application of formic acid in excess (Scheme 7.). Scheme 7. Ru-catalyzed degradation of HCO2H. A plausible mechanistic pathway for transfer hydrogenation of 1 catalyzed by Ru-3 is outlined in Scheme 9. First, upon HCO2H treatment, the Ru-3 complex is converted into ruthenium hydride [Ru]-H which undergoes addition to C-C double bond leading to alkyl complex 27. The addition process is reversible and a β-hydride elimination can afford isomerization product 2 or starting olefin 1. Regardless, complex 27 can also ultimately be quenched by formic acid, liberating the reduction product 3 and generating a ruthenium formate, [Ru]-OCHO, which subsequently undergoes decarboxylation to give [Ru]-H.



Scheme 9. Proposed mechanism of TH reaction.

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of time at 80 °C. After the reaction was completed, the reaction mixture was cooled to room temperature and poured into a saturated solution of NaHCO3 (ca. 50 mL) to neutralize the excess acid. The aqueous layer was extracted with EtOAc (3 x 30 mL) and the combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated to obtain the crude product. RCM/TH Tandem Reaction (general procedure C)

In conclusion, we developed a mild and selective method for the reduction of a broad scope of alkenes via transfer hydrogenation reaction using formic acid as a hydrogen donor. The investigated conditions were proved compatible with various functional groups, allowing to obtain the desired products in a highly regio- and chemoselective manner. Since the reaction is promoted by commercially available olefin metathesis catalysts, it may be coupled with cross-metathesis or ring-closing-metathesis reaction to provide products in good to excellent yields. A mechanistic study allowed us to discern the catalytically active species and to propose the mechanism of the studied reaction. Moreover, the experiments with deuterated formic acid confirmed the syn-addition of hydrogen during the process.

EXPERIMENTAL PROCEDURES Steglich esterification (general procedure A) To a stirred solution of 33 (1.17 g, 5.50 mmol) in anhydrous DCM (25 mL), DMAP (0.31 g, 2.50 mmol) and corresponding benzyl alcohol (34-42) (5.00 mmol) were added under argon atmosphere. The reaction mixture was cooled to 0 °C and EDCI (1.44 g, 7.50 mmol) was added. The reaction mixture was stirred at 0 °C for 30 min and then at room temperature until full conversion was observed. Then the reaction mixture was diluted with DCM (25 mL) and washed with saturated aqueous solution of NH4Cl (20 mL), saturated aqueous solution of NaHCO3 (20 mL) and dried over MgSO4, filtered and evaporated. The crude product was purified using column chromatography (3 → 50% EtOAc/cyclohexane) on silica gel. RCM/TH Tandem Reaction (general procedure B) A dry pressure ampoule was charged with diene (1.00 mmol) and a stirring bar. The compound was degassed and dissolved in anhydrous THF under argon atmosphere. Ru-3 (2–4 mol%) was added to the resulting solution and the ring closing metathesis reaction was carried out for 0.5 h at 40 °C. After that time, HCO2Na (17.00 mg, 0.20 mmol) and HCO2H (2.30 g, 50.00 mmol) were added and the reaction was continued for an appropriate period

A dry pressure ampoule was charged with diene (1.00 mmol) and a stirring bar. The compound was degassed and dissolved in anhydrous THF under argon atmosphere. Ru-3 (2–4 mol%) was added to the resulting solution and the ring closing metathesis reaction was carried out for 0.5 h at 40 °C. After that time, NaH (4.60 mg, 0.20 mmol) and HCO2H (2.30 g, 50.00 mmol) were added and the reaction was continued for an appropriate period of time at 80 °C. After the reaction was completed, the reaction mixture was cooled to room temperature and poured into saturated solution of NaHCO3 (ca. 50 mL) to neutralize the excess acid. The aqueous layer was extracted with EtOAc (3 x 30 mL) and the combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated to obtain the crude product. CM/TH Tandem Reaction (general procedure D) A dry pressure ampoule was charged with olefin (1.00 mmol), methyl acrylate (3 mmol) and a stirring bar. The compounds were degassed and diluted in anhydrous THF (5 mL) under argon atmosphere. Ru-3 (4 mol%) was added to the resulting solution and the cross-metathesis reaction was carried out for 2 h at 40 °C. After that time, NaH (4.60 mg, 0.20 mmol) and HCO2H (2.30 g, 50.00 mmol) were added and the reaction was continued for an appropriate period of time at 80 °C. After the reaction was completed, the reaction mixture was cooled to room temperature and poured into saturated solution of NaHCO3 (ca. 50 mL) to neutralize the excess acid. The aqueous layer was extracted with EtOAc (3 x 30 mL) and the combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated to obtain the crude product. Procedure used in control experiment comparing TH catalytic activity of ruthenium complexes. A dry pressure ampoule was charged with olefin 1 (0.21 g, 1.00 mmol), durene (approx. 20.00 mg) and a stirring bar under argon atmosphere. The compounds were degassed and diluted with anhydrous THF (5 mL). NaH (4.60 mg, 0.20 mmol) and HCO2H (2.30 g, 50.00 mmol) were added and after 5 min of stirring at room temperature, a sample (t = 0 h) was taken. Then, catalyst (2 mol%) was added and the ampoule was sealed. The reaction mixture was heated at 80 °C for 24 h. The conversion was determined by GC-FID analysis using durene as internal standard. Cyclohex-3-en-1-ylmethyl cyclopent-3-ene-1carboxylate (4a). To an ice-cooled solution of 29 (0.37 g, 3.3 mmol), 31 (0.34 g, 3.0 mmol) and DMAP (0.55 g, 4.5 mmol) in anhydrous DCM (15 mL), 1-ethyl-3-(3dimethylaminopropyl)carbodiimide (1.15 g, 6.0 mmol) was


Page 7 of 15 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


added portionwise under Ar atmosphere. The reaction mixture was stirred at 0 °C for 30 min, and then at room temperature overnight. After the reaction was completed, the mixture was diluted with DCM (50 mL). The organic solution was washed with saturated NaHCO3aq (15 mL), 1 M HClaq (15 mL), distilled water (15 mL) and brine (15 mL). The organic phase was dried over MgSO4, filtrated and evaporated to obtain a crude product. Purification using column chromatography (10% EtOAc/cyclohexane) afforded 4a (0.21 g, 1.02 mmol 34%) as a colorless oil. Analyses were in accordance with previously reported ones.39 1H NMR (400 MHz, CDCl3) δ 5.77–5.56 (m, 4H), 3.99 (d, J = 6.6 Hz, 2H), 3.20–3.04 (m, 1H), 2.72–2.58 (m, 4H), 2.18–2.03 (m, 3H), 2.00–1.90 (m, 1H), 1.84–1.71 (m, 2H), 1.37–1.23 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 176.4, 129.1, 127.2, 125.7, 68.9, 41.8, 36.4, 33.3, 28.3, 25.4, 24.6. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H18O2Na 229.1204; Found 229.1215. Cyclohexylmethyl cyclopentanecarboxylate (4b). A dry Schlenk flask was charged with diene 4a (10.30 mg, 50.00 μmol), 10% wt. Pd-C (1.0 mg) and EtOAc (1 mL) under argon atmosphere. The flask was evacuated and backfilled with hydrogen using a balloon. The reaction was carried out for 4 h at room temperature, under a hydrogen atmosphere (1 atm). After the reaction was completed, the catalyst was separated by filtration through a Celite pad. The solid was washed with a fresh portion of EtOAc (5 mL) and the filtrate was evaporated to give the spectrally pure product (10.40 mg, 49.50 μmol, 99%) as a colorless oil. Analyses were in accordance with previously reported ones.53 1H NMR (400 MHz, CDCl3) δ 3.87 (d, J = 6.5 Hz, 2H), 2.72 (p, J = 8.0 Hz, 1H), 1.87–1.54 (m, 14H), 1.30–1.10 (m, 3H), 1.03–0.91 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 177.0, 69.6, 44.1, 37.3, 30.1, 29.8, 26.5, 25.9, 25.8. Cyclohex-3-en-1-ylmethyl cyclopentanecarboxylate (4c). A dry pressure ampoule was charged with olefin 4a (20.6 mg 0.10 mmol). The compound was degassed and diluted with anhydrous THF (500 μL). Then Ru-3 (1.70 mg, 2.00 μmol, 2 mol%), HCO2Na (1.40 mg, 20.00 μmol), HCO2H (189 µL, 5.00 mmol) and durene (5.40 mg, 40.0 μmol) as internal standard. The crude product was isolated by extraction and was analyzed by GC-FID (92% GC yield). Cyclohexylmethyl cyclopentanecarboxylate (4c). Product was synthesized according to general procedure C using diene 7a (0.34 g, 1.00 mmol) and Ru-4 (17.00 mg, 0.02 mmol, 2 mol%). The transfer hydrogenation reaction was carried out for 4 h. Purification by using column chromatography afforded spectrally pure product 4c (0.21 g mg, 0.99 mmol, 99%) as a colorless oil.53 1H NMR (400 MHz, CDCl3) δ 3.87 (d, J = 6.5 Hz, 2H), 2.72 (p, J = 8.0 Hz, 1H), 1.87–1.54 (m, 14H), 1.30–1.10 (m, 3H), 1.03–0.91 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 177.0, 69.6, 44.1, 37.2, 30.2, 29.8, 26.5, 25.9, 25.8. Ethyl 1,1-diallyl-1-(phenylsulfonyl)acetate (5a). Compound was prepared according to the literature.

Analyses were in accordance with previously reported ones.54 2-Allyl-1-phenylpent-4-en-1-one (6a). Compound was prepared according to the literature. Analyses were in accordance with previously reported ones.39 Cyclohexylmethyl 2-allylpent-4-enoate (7a). Compound was prepared analogously to 4a using 28 (2.31 g, 15.0 mmol), cyclohexylmethanol (1.71 g, 15.0 mmol), DMAP (2.75 g, 22.5 mmol), DCC (6.19 g, 30 mmol) and anhydrous DCM (60 mL). The crude product was purified using column chromatography on silica gel to give 7a (1.90 g, 8.10, 54%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.73 (ddt, J = 17.1, 10.2, 7.0 Hz, 2H), 5.11–4.94 (m, 4H), 3.85 (d, J = 6.5 Hz, 2H), 2.57–2.43 (m, 1H), 2.41–2.30 (m, 2H), 2.29–2.19 (m, 2H), 1.77–1.55 (m, 6H), 1.30–1.11 (m, 3H), 1.01–0.88 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 175.1, 135.5, 117.0, 69.7, 45.23, 37.2, 36.0, 29.8, 26.5, 25.8. 4-Benzylhepta-1,6-dien-4-ol (8a). Compound was prepared analogously to 19a using methyl phenylacetate (0.45 g, 3.0 mmol), allyl bromide (3.27 g, 27.0 mmol), magnesium (1.09 g, 45.0 mmol) and anhydrous Et2O (15 mL). The title compound was isolated by extraction to give 8a (0.61 g, 2.97 mmol, 99%) as a colorless oil. Analyses were in accordance with previously reported ones.55 1 H NMR (200 MHz, CDCl3) δ 7.38–7.21 (m, 5H), 6.95–6.83 (m, 2H), 5.20–5.07 (m, 4H), 2.79 (s, 2H), 2.29–2.17 (m, 4H). 13C NMR (50 MHz, CDCl3) δ 137.1, 133.74, 130.7, 128.2, 126.5, 118.8, 73.4, 45.3, 43.4. Diethyl 2,2-di(but-3-en-1-yl)malonate (9a). Compound was prepared according to the literature. Analyses were in accordance with previously reported ones.39 Ethyl 1-(phenylsulfonyl)cyclopentanecarboxylate (5b). Product was synthesized according to general procedure B using diene 5a (0.31 g, 1.00 mmol) and Ru-4 (17.00 mg, 0.02 mmol, 2 mol%). The transfer hydrogenation reaction was carried out for 20 h. Purification by using column chromatography afforded spectrally pure product 5b (0.27 g, 0.97 mmol 97%) as a colorless solid. Analyses were in accordance with previously reported ones.39 1H NMR (400 MHz, CDCl3): δ 7.92-7.80 (m, 2H), 7.73-7.61 (m, 1H), 7.58-7.48 (m, 2H), 4.09 (q, J = 7.1 Hz, 2H), 2.53-2.32 (m, 4H), 1.92-1.78 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 169.0, 137.4, 134.0, 130.0, 128.8, 79.6, 62.5, 32.5, 25.4, 13.9. Benzoylcyclopentane (6b). Product was synthesized according to general procedure B using diene 6a (0.20 g, 1.00 mmol) and Ru-4 (17.00 mg, 0.02 mmol, 2 mol%). The transfer hydrogenation reaction was carried out for 7 h. Purification by using column chromatography afforded spectrally pure product 6b (0.16 g, 0.92 mmol, 92%) as a colorless oil. Analyses were in accordance with previously reported ones.39 1H NMR (400 MHz, CDCl3) δ 8.03-7.93 (m, 2H), 7.60-7.50 (m, 1H), 7.50-7.42 (m, 2H),3.72 (q, J = 7.88 Hz, 1H), 2.06-1.85 (m, 4H), 1.83-1.54 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 202.9, 137.0, 132.8, 128.6, 128.6, 46.5, 30.1, 26.4. 1-Benzylcyclopentan-1-ol (8b). Product was synthesized according to general procedure C using diene 8a



(0.20 g, 1.00 mmol) and Ru-4 (17.00 mg, 0.02 mmol, 2 mol%). The transfer hydrogenation reaction was carried out for 7 h. A crude ester product was diluted with EtOH (5 mL) and 20% NaOHaq (5 mL) was added. The saponification reaction was carried out for 30 min at room temperature. Spectrally pure product 8b (0.17 g, 0.99 mmol, 99%) was isolated by extraction. Analyses were in accordance with previously reported ones.56 1H NMR (400 MHz, CDCl3) δ 7.36–7.28 (m, 2H), 7.28–7.21 (m, 3H), 2.89 (s, 2H), 1.85–1.77 (m, 2H), 1.72–1.64 (m, 4H), 1.63–1.54 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 138.4, 130.3, 128.4, 126.6, 82.2, 47.2, 39.5, 23.6. Diethyl cycloheptane-1,1-dicarboxylate (9b). Product was synthesized according to general procedure C using diene 9a (0.27 g, 1.00 mmol) and Ru-4 (17.00 mg, 0.02 mmol, 2 mol%). The transfer hydrogenation reaction was carried out for 6 h. Spectrally pure product 9b (0.20 g, 0.89 mmol, 89%) was isolated by extraction. Analyses were in accordance with previously reported ones.39 1H NMR (400 MHz, CDCl3) δ = 4.14 (q, J = 7.1 Hz, 4H), 2.112.05 (m, 4H), 1.60-1.47 (m, 8H), 1.21 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 173.1, 61.2, 57.7, 33.8, 29.9, 23.9, 14.2. 1-(4-Bromobenzyl)-3-ethyl-2,2-diallylmalonate (10a). Prepared according to general procedure A using 4bromophenylmethanol (5.00 mmol, 0.94 g). The crude product was purified by column chromatography on silica gel to provide 10a (411 mg, 1.05 mmol, 21%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 5.69–5.55 (m, 2H), 5.10 (s, 4H), 5.07–5.03 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H), 2.65 (d, J = 7.4 Hz, 4H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.7, 170.6, 134.7, 132.2, 131.8, 130.1, 122.5, 119.5, 66.2, 61.5, 57.6, 37.0, 14.2. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H21BrO4Na 403.0521; Found 403.0512. Anal. Calcd for C18H21BrO4: C, 56.70; H, 5.55; Br, 20.96. Found: C, 56.72; H, 5.51; Br, 20.87. IR (film CHCl3) [cm-1] 2981, 1734, 1490, 1442.

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4.15 (q, J = 7.1 Hz, 2H), 2.67 (d, J = 7.4 Hz, 4H), 2.50 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.7, 170.6, 139.1, 132.4, 132.3, 129.1, 126.6, 119.4, 66.7, 61.5, 57.6, 36.9, 15.9, 14.2. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H24SO4Na 371.1293; Found 371.1285. Anal. Calcd for C19H24SO4: C, 65.49; H, 6.94; S, 9.20. Found: C, 65.39; H, 6.77; S, 9.38. IR (film CHCl3) [cm-1] 2980, 1732, 1440. 1-Ethyl 3-(4-methylsulfinyl-benzyl)-2,2diallylmalonate (13a). Prepared according to general procedure A using 36 (5.00 mmol, 0.85 g). The crude product was purified by column chromatography on silica gel to provide 13a (1.22 g, 3.35 mmol, 67%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 5.69–5.56 (m, 2H), 5.20 (s, 2H), 5.12–5.04 (m, 4H), 4.14 (q, J = 7.1 Hz, 2H), 2.71 (s, 3H), 2.66 (d, J = 7.4 Hz, 4H), 1.18 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.6, 170.5, 146.1, 138.9, 132.2, 129.1, 123.9, 119.5, 66.1, 61.5, 57.6, 44.2, 37.0, 14.2. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H24SO5Na 387.1242; Found 387.1232. IR (film CHCl3) [cm-1] 3078, 1732, 1053. 1-(4-Acetamidobenzyl)-3-ethyl-2,2-diallylmalonate (14a). Prepared according to general procedure A using 37 (5.00 mmol, 0.83 g). The crude product was purified by column chromatography on silica gel to provide 14a (0.86 g, 2.40 mmol, 48%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.61 (brs, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.30–7.20 (m, 2H), 5.67–5.54 (m, 2H), 5.13–4.99 (m, 6H), 4.11 (q, J = 7.1 Hz, 2H), 2.63 (d, J = 7.4 Hz, 4H), 2.15 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.8, 170.7, 168.6, 138.3, 132.2, 131.4, 129.3, 119.8, 119.4, 66.7, 61.5, 57.6, 36.9, 24.7, 14.2. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H25NO5Na 382.1630; Found 382.1630. Anal. Calcd for C20H25NO5: C, 66.83; H, 7.01; N, 3.90. Found: C, 66.73; H, 6.83; N, 3.74. IR (film CHCl3) [cm-1] 3309, 1732, 1697.

1-Ethyl-3-(4-iodobenzyl)-2,2-diallylmalonate (11a). Prepared according to general procedure A using 4iodophenyl-methanol (5.00 mmol, 1.17 g). The crude product was purified by column chromatography on silica gel to provide 11a (1.33 g, 3.10 mmol, 62%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 5.69–5.55 (m, 2H), 5.14–5.01 (m, 6H), 4.12 (q, J = 7.1 Hz, 2H), 2.65 (d, J = 7.4 Hz, 4H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.6, 170.5, 137.8, 135.3, 132.2, 130.2, 119.5, 94.1, 66.3, 61.5, 57.6, 36.9, 14.2. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H21IO4Na 451.0382; Found 451.0371. IR (film CHCl3) [cm-1] 3346, 2980, 1734, 1486.

1-(4-Benzamidobenzyl)-3-ethyl-2,2-diallylmalonate (15a). Prepared according to general procedure A using 38 (5.00 mmol, 1.14 g). The crude product was purified by column chromatography on silica gel to provide 15a (1.00 g, 2.40 mmol, 48%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.90–7.80 (m, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.56–7.49 (m, 1H), 7.49–7.40 (m, 2H), 7.30 (d, J = 8.5 Hz, 2H), 5.69–5.56 (m, 2H), 5.14–5.01 (m, 6H), 4.12 (q, J = 7.1 Hz, 2H), 2.64 (d, J = 7.4 Hz, 4H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.7, 170.7, 165.9, 138.3, 134.9, 132.3, 132.0, 131.7, 129.3, 128.9, 127.2, 120.3, 119.4, 66.7, 61.5, 57.5, 36.9, 14.2. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C25H27NO5Na 444.1787; Found 444.1786. Anal. Calcd for C25H27NO5: C, 71.24; H, 6.46; N, 3.32. Found: C, 71.13; H, 6.34; N, 3.22. IR (film CHCl3) [cm-1] 3346, 2981, 1731, 1656, 1602.

1-Ethyl-3-(4-methylthiobenzyl)-2,2-diallylmalonate (12a). Prepared according to general procedure A using 4methylthio-phenylmethanol (5.00 mmol, 0.77 g). The crude product was purified by column chromatography on silica gel to provide 12a (1.24 g, 3.05 mmol, 71%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.31–7.22 (m, 4H), 5.65 (ddt, J = 13.6, 9.5, 7.4 Hz, 2H), 5.17–5.04 (m, 6H),

1-Ethyl-3-(4-nitrobenzyl)-2,2-diallylmalonate (16a). Prepared according to general procedure A using 4nitrophenylmethanol (5.00 mmol, 0.77 g). The crude product was purified by column chromatography on silica gel to provide 16a (1.62 g, 4.90 mmol, 93%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.26–8.12 (m, 2H), 7.53– 7.42 (m, 2H), 5.70–5.54 (m, 2H), 5.23 (s, 2H), 5.14–4.99 (m,


Page 9 of 15 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


4H), 4.19–4.08 (m, 2H), 2.70–2.59 (m, 4H), 1.23–1.12 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 170.4, 170.3, 147.8, 142.8, 132.0, 128.5, 123.8, 119.5, 65.4, 61.5, 57.6, 37.0, 14.2. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H21NO6Na 370.1267; Found 370.1258. Anal. Calcd for C18H21NO6: C, 62.24; H, 6.09; N, 4.03. Found: C, 62.19; H, 6.12; N, 3.90. IR (film CHCl3) [cm-1] 2982, 1734, 1524, 1348, 1322. 1-(4-Acetylbenzyl)-3-ethyl-2,2-diallylmalonate (17a). Prepared according to general procedure A using 35 (5.00 mmol, 0.75 g). The crude product was purified by column chromatography on silica gel to provide 17a (0.89 g, 2,60 mmol, 52%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 5.64 (ddt, J = 20.2, 9.6, 7.4 Hz, 2H), 5.20 (s, 2H), 5.13–5.05 (m, 4H), 4.15 (q, J = 7.1 Hz, 2H), 2.67 (d, J = 7.4 Hz, 4H), 2.60 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 197.7, 170.6 (2C), 140.9, 137.1, 132.2, 128.7, 128.1, 119.5, 66.2, 61.6, 57.6, 37.0, 26.8, 14.2. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H24O5Na 367.1521; Found 367.1514. Anal. Calcd for C20H24O5: C, 69.75; H, 7.02. Found: C, 69.74; H, 7.07. IR (film CHCl3) [cm-1] 2981, 1733, 1686, 1642. 1-(4-Cyanobenzyl)-3-ethyl-2,2-diallylmalonate (18a). Prepared according to general procedure A using 4hydroxymethyl-benzonitrile (5.00 mmol, 0.67 g). The crude product was purified by column chromatography on silica gel to provide 18a (1.25 g, 3.90 mmol, 76%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 5.70–5.55 (m, 2H), 5.19 (s, 2H), 5.13–5.02 (m, 4H), 4.14 (q, J = 7.1 Hz, 2H), 2.66 (d, J = 7.4 Hz, 4H), 1.18 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.5, 170.4, 140.9, 132.5, 132.1, 128.5, 119.6, 118.6, 112.3, 65.8, 61.6, 57.6, 37.0, 14.2. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H21NO4Na 350.1368; Found 350.1362. Anal. Calcd for C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C, 69.70; H, 6.34; N, 4.39. IR (film CHCl3) [cm-1] 2981, 2230, 1733, 1642. 1-(4-Bromobenzyl)-1-ethyl-cyclopentane-1,1dicarboxylate (10b). The product was synthesized according to general procedure B using diene 10a (0.19 g, 0.50 mmol) and Ru-3 (8.49 mg, 0.01 mmol, 2 mol%). The transfer hydrogenation reaction was carried out for 30 h. Purification by using column chromatography afforded spectrally pure product 10b (144 mg, 0.41 mmol, 81%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 5.10 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.23–2.12 (m, 4H), 1.74–1.62 (m, 4H), 1.15 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 172.5 (2C), 135.0, 131.8, 129.9, 122.4, 66.2, 61.5, 60.6, 34.7, 25.6, 14.1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C16H19BrO4Na 377.0364; Found 377.0363. Anal. Calcd for C16H19BrO4: C, 54.10; H, 5.39; Br, 22.49. Found: C, 54.31; H, 5.54; Br, 22.65. IR (film CHCl3) [cm-1] 2960, 1731. 1-Ethyl 1-(4-iodobenzyl) cyclopentane-1,1dicarboxylate (11b). The product was synthesized according to general procedure B using diene 11a (0.21 g, 0.50 mmol) and Ru-3 (12.73 mg, 0.015 mmol, 3 mol%). The transfer hydrogenation reaction was carried out for 40 h. Purification by using column chromatography afforded

spectrally pure product 11b (0.17 g, 0.83 mmol, 86%) as a red oil. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 5.09 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.24–2.12 (m, 4H), 1.73–1.62 (m, 4H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 172.5 (2C), 137.8, 135.6, 130.0, 94.0, 66.3, 61.5, 60.6, 34.7, 25.6, 14.1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C16H19IO4Na 425.0226; Found 425.0229. IR (film CHCl3) [cm-1] 1730, 1486. 1-Ethyl-1-(4-methylthiobenzyl)-cyclopentane-1,1dicarboxylate (12b). The product was synthesized according to general procedure B using diene 12a (0.17 g, 0.50 mmol) and Ru-3 (12.73 mg, 0.015 mmol, 3 mol%). The transfer hydrogenation reaction was carried out for 40 h. Purification by using column chromatography afforded spectrally pure product 12b (0.14 g, 0.42 mmol, 84%) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 1.7 Hz, 4H), 5.11 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.48 (s, 3H), 2.24–2.14 (m, 4H), 1.72–1.63 (m, 4H), 1.15 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 172.6 (2C), 138.9, 132.7, 128.9, 126.7, 66.6, 61.5, 60.6, 34.7, 25.6, 15.9, 14.1. HRMS (ESITOF) m/z: [M + Na]+ Calcd for C17H22SO4Na 345.1136; Found 345.1134. Anal. Calcd for C17H22SO4: C, 63.33; H, 6.88; S, 9.95. Found: C, 63.54; H, 6.91; S, 9.94. IR (film CHCl3) [cm-1] 1730, 1496. 1-Ethyl-1-(4-(methylsulfinyl)-benzyl)-cyclopentane1,1-dicarboxylate (13b). The product was synthesized according to general procedure B using diene 13a (0.18 g, 0.50 mmol) and Ru-3 (12.73 mg, 0.015 mmol, 3 mol%). The transfer hydrogenation reaction was carried out for 30 h. Purification by using column chromatography afforded spectrally pure product 13b (0.16 g, 0.46 mmol, 93%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 5.19 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.70 (s, 3H), 2.27–2.02 (m, 4H), 1.77–1.53 (m, 4H), 1.15 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 172.5, 172.4, 145.9, 139.2, 128.8, 123.9, 66.0, 61.5, 60.5, 44.1, 34.7, 25.5, 14.1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C17H22SO5Na 361.1086; Found 361.1079. Anal. Calcd for C17H22SO5: C, 60.33; H, 6.55; S, 9.47. Found: C, 60.22; H, 6.36; S, 9.43. IR (film CHCl3) [cm-1] 3464, 1730, 1452, 1409. 1-(4-Acetamidobenzyl) 1-ethyl cyclopentane-1,1dicarboxylate (14b). The product was synthesized according to general procedure B using diene 14a (0.17 g, 0.50 mmol) and Ru-3 (12.73 mg, 0.015 mmol, 3 mol%). The transfer hydrogenation reaction was carried out for 30 h. Purification by using column chromatography afforded spectrally pure product 14b (0.15 g, 0.46 mmol, 91%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 7.21 (br, 1H), 5.11 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.24–2.11 (m, 7H), 1.73–1.59 (m, 4H), 1.15 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 172.7 (2C), 168.4, 138.0, 131.7, 129.1, 119.8, 66.6, 61.5, 60.5, 34.6, 25.6, 24.8, 14.1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H23NO5Na 356.1474; Found 356.1474. Anal. Calcd for C18H23NO5: C, 64.85; H, 6.95; N, 4.20. Found: C, 64.62; H, 7.12; N, 4.02. IR (film CHCl3) [cm-1] 3311, 1730, 1671, 1537, 1451.



1-(4-Benzamidobenzyl)-1-ethyl-cyclopentane-1,1dicarboxylate (15b). The product was synthesized according to general procedure B using diene 15a (0.21 g, 0.50 mmol) and Ru-3 (12.73 mg, 0.015 mmol, 3 mol%). The transfer hydrogenation reaction was carried out for 30 h. Purification by using column chromatography afforded spectrally pure product 15b (0.17 g, 0.43 mmol, 86%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.96 (br, 1H), 7.89–7.82 (m, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.57–7.51 (m, 1H), 7.51–7.43 (m, 2H), 7.32 (d, J = 8.5 Hz, 2H), 5.13 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.21–2.17 (m, 4H), 1.74–1.59 (m, 4H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 172.6 (2C), 165.9, 138.1, 135.0 (2C), 132.0, 129.2, 128.9, 127.2, 120.2, 66.6, 61.5, 60.6, 34.7, 25.6, 14.1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C23H25NO5Na 418.1630; Found 418.1631. Anal. Calcd for C23H25NO5: C, 69.86; H, 6.37; N, 3.54. Found: C, 69.98; H, 6.33; N, 3.40. IR (film CHCl3) [cm-1] 3347, 1729, 1603, 1528, 1448. 1-Ethyl-1-(4-nitrobenzyl)-cyclopentane-1,1dicarboxylate (16b). The product was synthesized according to general procedure B using diene 16a (0.17 g, 0.50 mmol) and Ru-3 (8.49 mg, 0.01 mmol, 2 mol%). The transfer hydrogenation reaction was carried out for 20 h. Purification by using column chromatography afforded spectrally pure product 16b (0.16 g, 0.5 mmol, 99%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 5.24 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 2.21 (ddd, J = 6.4, 4.6, 3.1 Hz, 4H), 1.78–1.62 (m, 4H), 1.18 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 172.4, 172.3, 147.9, 143.2, 128.3, 123.9, 65.5, 61.6, 60.5, 34.8, 25.6, 14.2. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C16H19NO6Na 344.1110; Found 344.1107. Anal. Calcd for C16H19NO6: C, 59.81; H, 5.96; N, 4.36. Found: C, 59.64; H, 6.04; N, 4.34. IR (film CHCl3) [cm-1] 1732, 1606, 1524, 1452, 1348, 1320. 1-(4-Acetylbenzyl)-1-ethyl-cyclopentane-1,1dicarboxylate (17b). The product was synthesized according to general procedure B using diene 17a (0.17 g, 0.50 mmol) and Ru-3 (12.73 mg, 0.015 mmol, 3 mol%). The transfer hydrogenation reaction was carried out for 30 h. Purification by using column chromatography afforded spectrally pure product 17b (0.08 g, 0.23 mmol, 47%) and 17c (0.07 mg, 0.20 mmol, 41%) as an orange oils. Analyses of 17b: 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 5.21 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 2.60 (s, 3H), 2.27–2.15 (m, 4H), 1.74–1.65 (m, 4H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 197.7, 172.5 (2C), 141.2, 137.0, 128.7, 127.8, 66.2, 61.5, 60.6, 34.7, 26.8, 25.6, 14.2. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H22O5Na 341.1365; Found 341.1367. Anal. Calcd for C18H22O5: C, 67.91; H, 6.97. Found: C, 67.99; H, 6.99. IR (film CHCl3) [cm-1] 1731, 1686, 1611, 1450. Analysis for 17c: 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.36–7.30 (m, 4H), 6.00 (q, J = 6.6 Hz, 1H), 5.15 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.28–2.12 (m, 4H), 1.74–1.62 (m, 4H), 1.57 (d, J = 6.6 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 172.6 (2C), 160.4, 141.1, 135.9, 128.4, 126.4, 72.0, 66.6, 61.5, 60.5, 34.7, 25.6, 22.3, 14.1.

Page 10 of 15

HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H24O6Na 371.1471; Found 371.1472. Anal. Calcd for C19H24O6: C, 65.50; H, 6.94. Found: C, 65.77; H, 7.10. IR (film CHCl3) [cm-1] 2980, 2960, 1728. 18b and 18c product mixture was synthesized according to general procedure B using diene 18a (0.16 g, 0.50 mmol) and Ru-3 (16.98 mg, 0.02 mmol, 4 mol%). The transfer hydrogenation reaction was carried out for 40 h. Purification by using column chromatography afforded mixture of 18b and 18c products as an orange oil (0.13 g). 5-Benzylnona-1,8-dien-5-ol (19a). To an ice-cooled solution of methyl phenylacetate (1.80 g, 12.0 mmol) in anhydrous Et2O (40 mL), an ethereal solution of but-3-en-1ylmagnesium bromide (0.80 M, 32.0 mmol, 40 mL) was added dropwise. The resulting mixture was allowed to reach the room temperature and then the reaction was heated at reflux. GC-FID analysis indicated full conversion after 6 h and the reaction mixture was allowed to cool to the room temperature. Next the reaction mixture was poured into a saturated aqueous solution of NH4Claq (200 mL) and the aqueous layer was extracted with Et2O (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, filtrated and evaporated to give a crude product. Purification using column chromatography (EtOAc/cyclohexane 10% → 20%) on silica gel afforded 19a (1.37 g, 5.88 mmol, 49%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.43–7.20 (m, 5H), 5.86 (ddt, J = 16.8, 10.2, 6.5 Hz, 2H), 5.17–4.93 (m, 4H), 2.81 (s, 2H), 2.31–2.14 (m, 4H), 1.64–1.49 (m, 4H), 1.36 (s, 1H). 13 C NMR (101 MHz, CDCl3) δ 138.8, 137.2, 130.7, 128.4, 126.7, 114.6, 74.1, 45.7, 37.9, 28.3. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C16H22ONa 253.1568; Found 253.1566. Anal. Calcd for C16H22O: C, 83.43; H, 9.63. Found: C 83.40. H 9.43. IR (film CHCl3) cm-1 3559, 3463, 1640, 1495. 1-Benzylcycloheptan-1-ol (19b). Product was synthesized according to general procedure C using diene 19a (46.07 mg, 0.20 mmol) and Ru-3 (3.39 mg, 4.00 μmol, 2 mol%). The transfer hydrogenation reaction was carried out for 48 h. A crude ester product was diluted with EtOH (1 mL) and 20% NaOHaq (1 mL) was added. The saponification reaction was carried out for 30 min at the room temperature. Purification by using column chromatography afforded spectrally pure product 19b (29.00 mg, 0.14 mmol, 71%) as a colorless oil. Analyses were in accordance with previously reported ones.56 1H NMR (400 MHz, CDCl3) δ 7.39–7.22 (m, 5H), 2.79 (s, 2H), 1.80–1.37 (m, 12H). 13C NMR (101 MHz, CDCl3) δ 137.7, 130.9, 128.3, 126.5, 75.3, 49.4, 41.1, 29.9, 22.4. 2-Allyl-2-phenylpent-4-enoic acid (20a). To a solution of 32 (2.30 g, 10.0 mmol) in EtOH/H2O (2:1) mixture (40 mL), solid NaOH (6.40 g, 160.0 mmol) was added in one portion. The resulting mixture was heated overnight at 90 °C. After reaction was completed, the mixture was cooled to room temperature and diluted with distilled water (100 mL). The aqueous layer was extracted with Et2O (20 mL) to remove neutral residues. The remaining aqueous phase was acidified to pH = 2 with 5 M HClaq and extracted with DCM (3 x 40 mL). The combined DCM


Page 11 of 15 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


layers were washed with brine (20 mL), dried over MgSO4, filtered and evaporated to obtain spectrally pure 20a (2.01 g, 9.30 mmol, 93%) as a colorless solid. Analyses were in accordance with previously reported ones.57 1H NMR (400 MHz, CDCl3) δ 11.69 (brs, 1H), 7.48–7.24 (m, 5H), 5.69–5.52 (m, 2H), 5.20–5.04 (m, 4H), 2.98–2.71 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 181.4, 141.1, 133.2, 128.6, 127.3, 126.7, 119.0, 53.6, 38.7. 1-Phenylcyclopentane-1-carboxylic acid (20b). The product was synthesized according to general procedure C using diene 20a (43.26 mg, 0.20 mmol) and Ru-3 (5.08 mg, 6.00 μmol, 3 mol%). The transfer hydrogenation reaction was carried out for 24 h. Spectrally pure product 20b (37.00 mg, 0.20 mmol, 97%)was isolated by extraction. Analyses were in accordance with previously reported ones.58 1H NMR (400 MHz, CDCl3) δ 11.68 (s, 1H), 7.42– 7.07 (m, 5H), 2.80–2.45 (m, 2H), 2.04–1.86 (m, 2H), 1.84– 1.66 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 182.5, 142.9, 128.5, 127.2, 127.1, 59.0, 36.1, 23.7. Dimethyl heptanedioate (21b). The product was synthesized according to general procedure D using methyl 5-hexenoate (0.13 g, 1.00 mmol) as a starting olefin. The transfer hydrogenation reaction was carried out for 48 h. Purification by using column chromatography afforded spectrally pure product 21b (0.07 g, 0.38 mmol, 38%) as a colorless oil. Analyses were in accordance with previously reported ones.59 1H NMR (400 MHz, CDCl3) δ 3.66 (s, 6H), 2.29 (t, J = 7.5 Hz, 4H), 1.70–1.57 (m, 4H), 1.39–1.20 (m, 2H). 13C NMR (101 MHz. CDCl3) δ 174.1, 51.6, 34.0, 28.7, 24.7. Methyl 11-(formyloxy)undecanoate (22b). The product was synthesized according to general procedure D using 10-undecenol (0.17 g, 1.00 mmol) as a starting olefin. The transfer hydrogenation reaction was carried out for 90 h. Purification by using column chromatography afforded spectrally pure product 22b (0.16 g, 0.62 mmol, 62%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 4.15 (t, J = 6.7 Hz, 2H), 3.66 (s, 3H), 2.29 (t, J = 7.5 Hz, 2H), 1.71–1.51 (m, 4H), 1.47–1.14 (m, 14H). 13C NMR (101 MHz, CDCl3) δ 174.4, 161.3, 64.2, 51.5, 34.2, 29.6, 29.5, 29.3, 29.3, 29.3 (2C), 28.6, 25.9, 25.1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H26O4Na 281.1729 found; 281.1720. Anal. Calcd for C14H26O4: C, 65.09; H, 10.14. Found: C 65.36, H 9.92. IR (film CHCl3) [cm-1] 2927, 2855, 1728. Methyl 4-(4-hydroxy-3-methoxyphenyl)butanoate (23b). The product was synthesized according to general procedure D using eugenol (0.16 g, 1.00 mmol) as a starting olefin. The transfer hydrogenation reaction was carried out for 24 h. Purification by using column chromatography afforded spectrally pure product 23b (0.16 g, 0.73 mmol, 73%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.83 (d, J = 7.8 Hz, 1H), 6.71–6.64 (m, 2H), 5.47 (s, 1H), 3.88 (s, 3H), 3.67 (s, 3H), 2.63–2.53 (m, 2H), 2.38–2.29 (m, 3H), 1.98–1.88 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 174.1, 146.6, 144.0, 133.4, 121.2, 114.4, 111.2, 56.0, 51.6, 35.0, 33.5, 26.9. HRMS (ESI-TOF) m/z: [M - H]+ Calcd for C12H15O4 223.0970;. found 223.0969. Anal. Calcd for

C12H16O4: C, 64.27; H, 7.19. Found: C, 64.40; H, 7.13. IR (film CHCl3) [cm-1] 3449, 3001, 2950, 1734, 1604 1433. Methyl 4-cyclopentylbutanoate (24b). Product was synthesized according to general procedure D using allylcyclopentane (0.11 g, 1.00 mmol) as a starting olefin. The transfer hydrogenation reaction was carried out for 48 h. Purification by using column chromatography afforded spectrally pure product 24b (0.05 g, 0.48 mmol, 48%) as a colorless oil. Analyses were in accordance with previously reported ones.60 1H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 2.30 (t, J = 7.5 Hz, 2H), 1.75 (ddd, J = 9.6, 5.9, 4.0 Hz, 3H), 1.68–1.45 (m, 6H), 1.35–1.24 (m, 3H), 1.12–1.03 (m, 2H); 13C NMR (101 MHz. CDCl3) δ 174.4, 51.5, 40.0, 35.8, 34.5, 32.7, 25.3, 24.3. Methyl 4-phenylbutanoate (25b). Product was synthesized according to general procedure D using allylbenzene (0.12 g, 1.00 mmol) as a starting olefin. The transfer hydrogenation reaction was carried out for 48 h. Purification by using column chromatography afforded spectrally pure product 25b (0.09 g, 0.52 mmol, 52%) as a colorless oil. Analyses were in accordance with previously reported ones.61 1H NMR (400 MHz, CDCl3) δ 7.32–7.26 (m, 2H), 7.24–7.15 (m, 3H), 3.67 (s, 3H), 2.71–2.61 (m, 2H), 2.34 (t, J = 7.5 Hz, 2H), 2.03–1.91 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 174.0, 141.5, 128.6, 128.5, 126.1, 51.6, 35.3, 33.55, 26.6. Dimethyl bicyclo[2.2.1]-endo-5,6-dideuteroheptaneendo-2,3-dicarboxylate (26b). A dry pressure ampoule was charged with dimethyl cis-5-norbornene-endo-2,3dicarboxylate (0.21 g, 1.0 mmol) under argon atmosphere. The compound was degassed and diluted with anhydrous THF (5 mL). DCO2D (2.40 g, 50.0 mmol) and NaH (4.60 mg, 0.2 mmol) were added and the reaction mixture was stirred for 5 min. Then, Ru-3 (17.00 mg, 20.0 μmol, 2.0 mol%) was added in one portion. The reaction mixture was heated at 80 °C for 24 h. After the reaction was completed, the reaction mixture was cooled to room temperature and poured into a saturated solution of NaHCO3 (ca. 30 mL) to neutralize the excess acid. The aqueous layer was extracted with EtOAc (3 x 30 mL), the combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated to obtain crude product. Purification by bulb-to-bulb distillation afforded 26b (0.12 g, 0.53 mmol, 53%). 1H NMR (600 MHz, CDCl3) δ 3.60 (s, 6H), 2.94–2.93 (m, 2H), 2.51–2.50 (m, 2H), 1.70 (s, 2H), 1.40–1.39 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 172.94, 51.25, 46.65, 40.16, 39.75, 23.51 (t, J = 20.0 Hz). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C11H14D2O4Na 237.1072; Found 237.1070. 2,2-Diallylmalonic acid (27). To commercially available diethyl diallylmalonate (4.81 g, 20 mmol) placed in a flask, 40% aqueous solution of KOH (10 mL) and EtOH (5 mL) were added. The reaction mixture was heated under reflux for 4 h. After reaction was completed, the solvent was removed under reduced pressure to dryness. The residue was diluted in distilled water and extracted with n-hexane. The alkaline layer was acidified with cold 10% HClaq to reach pH = 2 and extracted with ether (3 x 35



mL). The combined ethereal phases were dried over MgSO4, filtered and evaporated. The residue solidified slowly and crystallization from cyclohexane afforded pure acid 27 (2.60 g, 14 mmol, 70%). Analyses were in accordance with previously reported ones.39 1H NMR (400 MHz, CD3OD) δ 5.71 (ddt, J = 17.5, 10.2, 7.4 Hz, 2H), 5.19–5.06 (m, 4H), 2.67–2.56 (m, 4H). 13C NMR (101 MHz, CD3OD) δ 174.3, 134.0, 119.2, 58.4, 37.8. 2-Allylpent-4-enoic acid (28). Acid 27 (2.12 g ,11.5 mmol) was placed in a flask and reaction was performed at 140 °C neat under microwave irradiation for 3 h under argon atmosphere. The crude product was purified by distillation under reduced pressure (69–71 °C, 0.4 mBar) to give a spectrally pure acid 28 (1.53 g, 10.92 mmol, 95%) as a colorless oil. Analyses were in accordance with previously reported ones.39 1H NMR (400 MHz, CDCl3) δ 11.82 (br, 1H), 5.89–5.68 (m, 2H), 5.22–4.92 (m, 4H), 2.66–2.47 (m, 1H), 2.47–2.34 (m, 2H), 2.34–2.21 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 181.7, 135.0, 117.5, 45.0, 35.0. Cyclopent-3-ene-1-carboxylic acid (29). Acid 28 (0.41 g, 3.0 mmol) was placed in a dry Schlenk flask, degassed and dissolved in anhydrous DCM (15 mL). Ru-3 (12.7 mg, 0.5 mol%, 15 μmol) was added as a solid and the reaction mixture was stirred at 40 °C for 1 h. After that time the solvent was removed to give spectrally pure 29 (0.33 g, 2.94 mmol, 98%) which was used in next step without further purification.62 1H NMR (200 MHz, CDCl3) δ 11.64 (brs, 1H), 6.06–5.76 (m, 2H), 3.50–3.23 (m, 1H), 3.01–2.74 (m, 4H). 13C NMR (50 MHz, CDCl3) δ 183.0, 129.0, 41.5, 36.3. Methyl cyclohex-3-ene-1-carboxylate (30). The compound was prepared according to the literature report63 using sulfolene (4.00 g, 33.9 mmol), methyl acrylate (1.95 g, 2.08 mL, 22.6 mmol), hydroquinone (50.0 mg, 2 mol%, 45.2 μmol) and PhCH3 (50 mL). The crude product was purified using column chromatography (10% EtOAc/cyclohexane) on silica gel to give 30 (2.01 g, 14.24 mmol 63%) as a colorless oil. Analyses were in accordance with previously reported ones.63 1H NMR (400 MHz, CDCl3) δ 5.74–5.59 (m, 2H), 3.67 (s, 3H), 2.60–2.46 (m, 1H), 2.30–2.17 (m, 2H), 2.12–2.03 (m, 2H), 2.02–1.91 (m, 1H), 1.75–1.57 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 176.4, 126.8, 125.3, 51.7, 39.4, 27.6, 25.2, 24.6. Cyclohex-3-en-1-ylmethanol (31). To a stirred suspension of lithium aluminium hydride (1.67 g, 44.0 mmol) in anhydrous Et2O (50 mL), a solution of ester 30 (1.54 g, 11.0 mmol) in anhydrous Et2O (10 mL) was added dropwise at 0 °C. The reaction mixture was allowed to reach room temperature and the stirring was continued for 2 h. After full consumption of the substrate (TLC monitoring, 20% EtOAc/cyclohexane), a saturated solution of Na2SO4aq (30 mL) was carefully added dropwise to the ice-cooled reaction mixture. A granular white solid was formed after 10 min of stirring and was filtered off. The solid was rinsed with fresh portion of Et2O (100 mL) and the filtrate was washed with brine (15 mL), dried over MgSO4, filtered and evaporated to give crude product. Purification using column chromatography afforded alcohol 31 (0.61 g, 4.95

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mmol, 45%) as a colorless oil. Analyses were in accordance with previously reported ones.64 1H NMR (400 MHz, CDCl3) δ 5.78–5.58 (m, 2H), 3.64–3.45 (m, 2H), 2.20–2.04 (m, 3H), 1.91–1.71 (m, 3H), 1.54–1.38 (m, 1H), 1.37–1.24 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 127.3, 126.0, 68.0, 36.5, 28.2, 25.4, 24.8. Methyl 2-allyl-2-phenylpent-4-enoate (32). Compound was prepared according to the literature65 using methyl phenylacetate (1.42 g, 10.0 mmol), sodium iodide (0.15 g, 1.0 mmol), allyl bromide (4.84 g, 3.46 mL, 40.0 mmol) and sodium hydride (0.96 g, 25.0 mmol) in THF (25 mL). The crude product was purified via column chromatography (10% EtOAc/cyclohexane) on silica gel, yielding 32 (1.91 g, 8.31 mmol, 83%) as a colorless oil. Analyses were in accordance with previously reported ones.65 1H NMR (400 MHz, CDCl3) δ 7.42–7.32 (m, 2H), 7.32–7.24 (m, 3H), 5.66–5.49 (m, 2H), 5.10 (ddd, J = 9.1, 6.4, 3.6 Hz, 4H), 3.68 (s, 3H), 2.90–2.74 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 175.6, 141.9, 133.5, 128.5, 127.0, 126.5, 118.7, 53.8, 52.1, 39.1. 2-Allyl-2-ethoxycarbonyl-pent-4-enoic acid (33). Diethyl 2,2-diallylmalonate (14.40 g, 60 mmol) was added dropwise to a solution of KOH (3.30 g, 50 mmol) in ethanol (200 mL). The mixture was stirred for 6 h at room temperature and then the reaction was carefully poured into a saturated solution of NaHCO3 (100 mL). The resulting mixture was extracted with diethyl ether (3 x 50 mL) to remove unreacted staring material. Next, the aqueous layer was acidified using 10% HClaq to obtain neutral pH and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated to give crude product. Purification using column chromatography on silica gel (10 → 20% EtOAc/cyclohexane) afforded 33 (2.92 g, 13.80 mmol, 23%) as colorless oil. The starting diethyl 2,2-diallylmalonate was recovered from ethereal extracts (10.37 g, 43.20 mmol, 72% recovered). 1H NMR (400 MHz, CDCl3) δ 11.24 (brs, 1H), 5.67 (ddt, J = 17.5, 10.2, 7.4 Hz, 2H), 5.19–5.12 (m, 2H), 5.11 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 2.66 (qd, J = 14.1, 7.4 Hz, 4H), 1.32–1.23 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 175.3, 172.1, 132.0, 119.7, 62.1, 57.7, 38.3, 14.2. HRMS (ESITOF) m/z: [M + Na]+ Calcd C11H16O4Na 235.0946; Found 235.0945. Anal. Calcd for C11H16O4: C, 62.25; H, 7.60. Found: C, 62.18; H, 7.72. IR (film CHCl3) [cm-1] 3081, 2983, 2936, 1712, 1642, 1443. 4-Acetylbenzyl bromide (34). 4-Methylacetophenone (4.0 mL, 30.00 mmol), N-bromosuccinimide (6.41 g, 36 mmol) and dibenzoyl peroxide (0.05 g, 0.20 mmol) were dissolved in tetrachloromethane (50 mL). The reaction mixture was stirred at 80 °C for 24 h. A solid that was formed was filtered off and washed with a fresh portion of tetrachloromethane (10 mL). The filtrate was washed with distilled water (25 mL) and a saturated solution of NaHCO3aq (25 mL). Organic layer was dried over MgSO4, filtered and evaporated under reduced pressure to obtain crude product that was purified by distillation under reduced pressure (110-113 °C, 0.6 mBar) to afford 43 (3.60 g, 16.8 mmol, 56%) as a yellow oil. Analyses were in accordance with previously reported ones.66 1H NMR (400


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MHz, CDCl3) δ 7.92 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 4.49 (s, 2H), 2.59 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 197.4, 142.9, 137.0, 129.3, 128.9, 32.2, 26.8. 4-Acetylbenzyl alcohol (35). Calcium carbonate (8.70 g, 86.4 mmol) was suspended in a solution of 34 (3.41 g, 16 mmol) dissolved in 1:1 mixture of H2O/1,4-dioxane (100 mL). The reaction mixture was vigorously stirred at reflux for 15 h. The resulting mixture was allowed to cool to room temperature and DCM (70 mL) was added. The excess of CaCO3 was neutralized using 10% HClaq to obtain a clear solution. The organic layer was separated and washed with a saturated solution of Na2CO3 (70 mL), dried over MgSO4, filtered and evaporated to give crude product. The product was purified by crystallization from diethyl ether/n-pentane to give 34 (1.52 g, 10.08 mmol, 63%) as pale yellow solid. Analyses were in accordance with previously reported ones.67 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 4.80 (d, J = 5.6 Hz, 2H), 2.62 (s, 3H), 1.90 (t, J = 5.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 198.0, 146.4, 136.5, 128.7, 126.8, 64.7, 26.7. 4-Methylsulfinyl-benzyl alcohol (36). To a suspension of 4-methylthiobenzyl alcohol (1.54 g, 10 mmol,) in distilled water (100 mL), a 70% aqueous solution of tertbutyl hydroperoxide (8.3 mL, 60 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. After that time, sodium chloride (approx. 2.00 g) was added and the resulting solution was extracted with DCM (7 x 50 mL). The organic layers were combined, dried over Na2SO4, filtered and evaporated. The crude product was purified using column chromatography on silica gel (50% → 60% EtOAc/cyclohexane), yielding 36 (1.19 g, 7.00 mmol, 70%) as a colorless oil. Analyses were in accordance with previously reported ones.68 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 4.75 (s, 2H), 2.70 (s, 3H), 2.44 (brs, 1H). 13C NMR (101 MHz, CDCl3) δ 144.7, 144.6, 127.8, 123.9, 64.6, 44.0. N-4-Hydroxymethyl-phenyl acetamide (37). To an ice-cooled solution of 4-aminobenzyl alcohol (1.85 g, 15 mmol) in anhydrous THF (100 mL), triethylamine (4.2 mL, 30 mmol) and acetic anhydride (1.4 mL, 15 mmol) were added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. Then reaction mixture was diluted with water (60 mL) and acidified to reach pH = 1 using 1 M HClaq. The aqueous layer was extracted with EtOAc (3 x 75 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The crude product was purified by crystallization from acetone to afford 37 (1.50 g, 9.00 mmol, 60%) as yellow solid. Analyses were in accordance with previously reported ones.69 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 5.07 (t, J = 5.7 Hz, 1H), 4.45 (d, J = 5.7 Hz, 2H), 2.05 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.0, 137.9, 137.0, 126.8, 118.7, 62.6, 23.9. N-4-Hydroxymethyl-phenyl benzamide (38). To an ice-cooled solution of 4-aminobenzyl alcohol (1.85 g, 15 mmol) in anhydrous tetrahydrofuran (100 mL), triethyla-

mine (4.2 mL, 30 mmol) and benzoyl chloride (15 mmol, 1.7 mL) were added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred overnight. Then reaction mixture was diluted with water (60 mL) and acidified to reach pH = 1 using 1 M HClaq. The aqueous layer was extracted with EtOAc (3 x 75 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The crude product was purified by crystallization from ethanol/water mixture to give 38 (1.90 g, 8.40 mmol, 56%) as yellow solid. Analyses were in accordance with previously reported ones.70 1H NMR (400 MHz, CD3OD) δ 7.95–7.90 (m, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.61–7.55 (m, 1H), 7.54–7.47 (m, 2H), 7.36 (d, J = 8.6 Hz, 2H), 4.59 (s, 2H). 13C NMR (101 MHz, CD3OD) δ 168.9, 139.0, 136.3, 132.8, 129.6, 128.6, 128.6, 122.2, 64.9. Carbonyl(dihydrido)tris(triphenylphosphine)ruthenium(II) (RuH-1). The complex RuH-1 was prepared according to the literature procedure71 using Ru-5 (1.25 g, 1.30 mmol), KOH (0.22 g, 3.90 mmol) and EtOH (50 mL). Analyses were in accordance with previously reported ones.71 1H NMR (400 MHz, CDCl3) δ 7.28–6.94 (m, 45H), –6.82 (tdd, J = 30.5, 15.2, 6.3 Hz, 1H), –8.79 (dtd, J = 73.9, 28.3, 6.2 Hz, 1H). Carbonylhydridobis(triphenylphosphineruthenium(II) acetate (RuH2). The complex RuH-2 was prepared according to the literature procedure72 using RuH-1 (055 g, 0.60 mmol), acetic acid (0.40 g, 6.60 mmol) and 2-methoxyethanol (10 mL). Analyses were in accordance with previously reported ones.72 1H NMR (400 MHz, CDCl3) δ 3.80–3.64 (m, 12H), 3.59–3.46 (m, 18H), 3.22 (s, 3H), –20.34 (t, J = 20.2 Hz, 1H). ASSOCIATED CONTENT

Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Analytical data of obtained compounds and copies of NMR spectra.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]; http://www.karolgrela.eu/; Fax: +48-22-632-66-81 Present Addresses † Selvita Services Sp. z o. o., Bobrzyńskiego 14, 30-348, ,Cracow, Poland; www.selvita.com.

Author Contributions All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENT The authors are grateful to the National Science Centre (Poland) for the NCN Opus grant no. UMO2013/09/B/ST5/03535.



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A Selective and Functional Group Tolerant Ruthenium Catalyzed

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