Photochemical Reaction Cascade from O-Pent-4-enyl-Substituted

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Photochemical Reaction Cascade from O-Pent-4-enylsubstituted Salicylates to Complex Multifunctional Scaffolds Andreas Zech, and Thorsten Bach J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00238 • Publication Date (Web): 24 Feb 2018 Downloaded from http://pubs.acs.org on February 25, 2018

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The Journal of Organic Chemistry

Photochemical Reaction Cascade from O-Pent-4-enylsubstituted Salicylates to Complex Multifunctional Scaffolds Andreas Zech, Thorsten Bach* Department Chemie and Catalysis Research Center (CRC), Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany

Corresponding Author *

Email: [email protected]

ABSTRACT

The arene ring of the title compounds is cleaved by a reaction cascade which is initiated by an intramolecular ortho photocycloaddition reaction. Tricyclic products were obtained in a highly regio- and diastereoselective fashion via a cyclooctatriene intermediate. The facial diastereoselectivity exerted by a stereogenic center in the tether is moderate to good (d.r. = 65/35 to 82/18). Yields were acceptable (44-87%) except for a single substrate which had a geminal dimethyl substitution in the tether and which gave the respective product in only 14% yield. The reaction is stereoconvergent with regard to the olefin configuration (E or Z) in agreement with a triplet mechanism of the ortho photocycloaddition step.

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INTRODUCTION The construction of complex carbon skeletons from simple precursors is a challenging yet most rewarding task of organic synthesis.1 Certain carbon frameworks can be readily traced back to a trivial, readily available substrate once the appropriate forward transformation has been established and its scope has been studied.2 Along these lines, the 1,2,2a,2b,4a,4b-hexahydrocyclopropa[cd]pentalene skeleton is the hallmark of the meta photocycloaddition,3,4 in the course of which an arene is transformed into products of type rac-A by 1,3-addition of an olefin (Scheme 1). Cyclopropane ring opening allows to access either diquinanes (bicyclo[3.3.0]octanes)5 or bicyclo[3.2.1]octanes.6 While the meta photocycloaddition has been widely applied in natural product synthesis,7 the analogous 1,2-addition, the ortho photocycloaddition, has received less attention by the synthetic community.8 One reason for a certain reluctance to employ this transformation might be associated with the fact that the primary bicyclo[4.2.0]octa2,4-diene reaction products react further in a reaction sequence, which potentially leads to bicyclo[4.2.0]octa-2,7-dienes (rac-B).

SCHEME 1. The Hexahydrocyclopropa[cd]pentalene Skeleton (rac-A) as the Immediate Product of a meta Photocycloaddition and the Bicyclo[4.2.0]octa-2,7-diene Skeleton (rac-B) as Product of a Reaction Cascade Initiated by an ortho Photocycloaddition

Indeed, the scope of the ortho photocycloaddition reaction has not been studied to the same extent as the scope of the meta photocycloaddition and reaction cascades which unambiguously


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lead to a distinct set of defined products in a highly selective fashion are less frequent.9 Based on our interest in the photochemical construction of carbon skeletons with several options for further functionalization (exit vectors)10 we were intrigued by the intramolecular ortho photocycloaddition of O-substituted salicylic acid derivatives. There is a single study on this transformation in which the reaction of compounds 1a and 1b was described11 It was reported that the reaction proceeded in acetone (ac) as the solvent at λ = 313 nm to the products 2a and 2b. Yields were not given but it was found that the same products were also formed upon direct irradiation at λ = 254 nm in acetonitrile. The reaction was suggested to proceed via intermediates 3 and 4 with the latter being formed by a thermal disrotatory ring opening. Product formation by a photochemical disrotatory [4π] cyclization completes the cascade reaction.

SCHEME 2. Previous Work11 on the Photochemical Reaction of O-Pent-4-enyl-substituted Phenol Derivatives 1a and 1b

We have now revisited this reaction with two major objectives: (a) It was attempted to extend the substrate scope regarding the substituent X and the olefin tether. Optimal reaction conditions were to be found to achieve reliably high yields. (b) The facial diastereoselectivity was to be


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studied with chiral salicylate derivatives and the relative product configuration was to be elucidated. The results of our experiments are summarized in this account. TABLE 1. Synthesis of Various Phenyl Ethers 1, 5-7, (E)-8, 9a by a Williamson Synthesis

Ya

Base (solvent)

Tb [°C]

Br

NaH (DMF)

60

49

Br

NaH (DMF)

60

95

Br

NaH (DMF)

100

73

Br

NaH (DMF)

100

81

Br

NaOEt (EtOH)

80

50

TsO

NaH (DMF)

60

70

I

Cs2CO3 (DMF)

100

46

Cl

NaH (DMF)

25c

65

TsO

NaH (DMF)

60

95

Br

Cs2CO3 (DMF)

60

80

Product


yield [%]

4

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a

The electrophile was mostly used in excess (up to two equiv.). b The reaction was run to full completion as

indicated by TLC control. Reaction times varied between 16 and 72 hours. c The reaction was complete after 15 min.

RESULTS AND DISCUSSION The synthesis of starting materials 1 commenced with commercially available salicylic acid derivatives which underwent O-alkylation with the respective halides or pseudohalides in a Williamson ether synthesis (Table 1). Most frequently, sodium hydride was used as a base in DMF as the solvent.12 For the preparation of ethers 1a-1e, pent-4-enyl bromide was used as electrophile and the reaction temperature was adjusted to achieve complete conversion in a reasonable period of time. Since there was no formation of 1e with NaH in DMF, another wellestablished base/solvent combination (NaOEt/EtOH)13 was employed. In the synthesis of salicylate 5, the known tosylate14 was used as the electrophile but not the bromide. The neopentylic ether 6 was obtained by alkylation with the respective iodide15 in the presence of cesium carbonate as base. Ethers 7 and (E)-8 were prepared by the NaH/DMF protocol employing allyloxymethyl chloride16 in the former and (E)-hex-4-enyl tosylate17 in the latter case. Finally, the chiral ether 9a was generated by alkylation of methyl salicylate with 1-bromo-3methylpent-4-ene15 in the presence of cesium carbonate.

SCHEME 3. Synthesis of Phenyl Ethers (Z)-8, 9b, and 9c by a Mitsunobu Reaction


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For the preparation of several other ethers (Scheme 3), the Mitsunobu reaction18 turned out to be a viable, convenient alternative to the Williamson synthesis. A solution of diethyl azodicarboxylate (DEAD) was added to a mixture of methylsalicylate, triphenylphosphane and the respective alcohol19 in THF. The alcohol was used as the limiting agent and products (Z)-8, 9b, and 9c were obtained in acceptable yields (52-65%).

TABLE 2. Influence of various parameters on the reaction 1a → 2a

λa solvent [nm]

t [h]

conv.b [%]

yieldc [%]

254

MeOH

3

100

13

300

ac

4

86

19

300

ac

16

100

21

300

MeOH

4

100

74

300

MeOH

16

100

73d

350

MeOH

24

90

64

366

MeOH

24

23

5


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a

Emission maximum of the light source. Reactions were performed on a 100 µmol scale (c = 10 mM) unless

indicated otherwise. b The conversion was based on the yield of re-isolated starting material. c Yield of isolated product 2a. d The reaction was performed on a 1 mmol scale (163 mg of product).

In a first set of photochemical experiments the irradiation conditions of the transformation 1a → 2a were optimized. Under conditions which were similar to the previously reported conditions (direct irradiation at λ = 254 nm or sensitization at λ = 300 nm in acetone solution),11 the outcome was not satisfactory. At short wavelength (λ = 254 nm), the product appeared unstable and could be isolated in a yield of only 13%. Likewise, sensitized irradiation at λ = 300 nm led to notable decomposition and the yields remained low (19-21%). Upon varying the wavelength in MeOH as the solvent, we found, however, that a smooth conversion was achieved at a wavelength of λ = 300 nm.20 The result is in agreement with the fact that compound 1a exhibits an absorption maximum at λ = 294 nm (ε = 3115 M 1 cm ) in MeOH solution. The reaction was −

−1

complete after four hours and the reaction product was stable towards the irradiation conditions. For reactions on larger scale, longer irradiation times could be applied without a significant deterioration in yield. At longer wavelength (λ = 350 nm, λ = 366 nm), the reaction became sluggish which is understandable as the absorption coefficient of the substrate approaches zero at λ > 330 nm. The structure of product 2a was confirmed by extensive NMR experiments (see the Supporting Information for further details). The assignment of the relative configuration was based on NOESY spectra which established for example the proximity of the proton at C9 and one of the protons at C4 in the 2,3,4,4a,5,7a-hexyahydrocyclobuta[i]chromene skeleton of product 2a (Table 2). Intermediates 3 and 4 were not detected but our mechanistic work (vide infra) was in full agreement with the previously suggested reaction course (Scheme 2).11


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The achiral substrates 1b-e and 5-7 were subsequently subjected to the optimized reaction conditions (Scheme 4), i.e. the irradiation was performed at λ = 300 nm in MeOH for 12-16 hours. While nitrile 1b and esters 1c,d reacted smoothly and gave products 2 in yields of 53-69%, amide 1e failed to deliver any reaction products. The starting material was completely re-isolated which is likely due to the hypsochromic absorption (λ = 280 nm) of this compound relative to ester 1a. In the series 5-7, product formation was facile if the atoms in the tether were unsubstituted (O, CH2) and products 10 and 12 were obtained in yields of 87% and 77%. In stark contrast, a geminal dimethyl substitution in position C2 position of the 4-pentenyl chain led to a diminished reaction rate. The reaction was incomplete after an irradiation time of 24 h and 34% of starting material was recovered.

SCHEME 4. Photochemical Reaction Cascade to Products 2, 10, 11, and 12: No Stereogenic Center in the Terminal Alkenyl Side Chain

When the diastereomeric O-hex-4-enyl-substituted methyl salicylates (Z)-8 and (E)-8 were irradiated the major product 13a was identical in both reactions (Scheme 5). Starting from (Z)-8, the tricyclic products 13 were formed in 62% yield and in a diastereomeric ratio (d.r.) of 93/7. The yield was lower for (E)-8 (48%), but the d.r. was only slightly diminished (88/12). NOESY ACS Paragon Plus Environment

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experiments confirmed the relative configuration of products 13a and 13b. The contact between the methyl group at C5 and the C9 hydrogen atom in compound 13a was most prominent. In addition, the 4J coupling (4J ≅ 3.0 Hz) of the axial hydrogen atom21 at C5 was clearly detected for 13b (R = H) but not for 13a (R1 = H).

SCHEME 5. Photochemical Reaction Cascade to Products 13: Relative Product Configuration (cis/trans) as a Result of the Relative Configuration of the Alkenyl Double Bond (Z/E)

In enone [2+2] photocycloaddition reactions a stereoconvergent reaction course as observed above for (Z)-8 and (E)-8 is taken as evidence for a triplet 1,4-diradical intermediate.22 The first stable intermediates in the formation of products 13 are the respective ortho photocycloaddition products 15 (Figure 1). The relative configuration between the stereogenic centers at C4a and C5 in products 13 is established in this step and the subsequent ring opening and [4π] cyclization do not alter the configuration. Consequently, compound 15a is the precursor of 13a and product 13b derives from ortho photocycloaddition product 15b. In intermediate 15a which is apparently formed preferably both from (Z)-8 and from (E)-8 the methyl group is in a cis relationship to the pre-existing tetrahydropyran ring and in a trans relationship to the annulated cyclohexadiene ring. The stereoconvergence and the observed diastereoselectivity can be readily explained by invoking triplet 1,4-diradical 14 as an intermediate. Free rotation around the indicated single bond is possible and leads to the loss of the stereochemical information. After intersystem


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crossing the subsequent ring closure to compounds 15 occurs in favor of the observed cis diastereoisomer.

FIGURE 1. Structure of intermediate 1,4-diradical 14 and of intermediate ortho photocycloaddition products 15 derived from substrates 8

Triplet quenching experiments were previously performed with substrates related to compounds 1 and 823 and – in agreement with our results – evidence was collected that the orthophotocycloaddition is a triplet process occurring from the respective arene 3ππ* state. In a final set of experiments the facial diastereoselectivity of the reaction cascade was studied depending on a stereogenic center at positions C1-C3 of the pent-4-enyl substituent. To this end the three chiral substrates 9 (Figure 2) were subjected to the irradiation conditions.

FIGURE 2. Chiral (racemic) ortho photocycloaddition substrates 9 with a methyl substituent at different positions of the O-pent-4-enyl chain and induced stereogenic centers (l) in intermediates 16 and final products 17

It is evident that the stereogenic center which is marked in intermediate 16 (Figure 2) results from the facial diastereoselectivity of the ortho photocycloaddition step. The stereogenic center is ACS Paragon Plus Environment

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retained in the further reaction course and determines the relative configuration of the cyclobutadiene ring in products 17. The latter control seems to be perfect based on the high diastereoselectivity observed for the previous transformations (vide supra). Consequently, any diastereoisomeric products formed from irradiation of compounds 9 should only differ in the relative configuration of the tetrahydropyran ring in 16. Indeed, it was found that the reactions of each substrate 9a and 9b produced two diastereoisomeric products (17a and 17b) with the respective major diastereoisomer depicted in Figure 3. The relative configuration was elucidated by NOESY experiments (see Supporting Information). Assuming a chair-like conformation 9’ of substrates 9, the relative configuration of the major diastereoisomer can be explained by a preferential equatorial position of the methyl group. The position of the ortho substituent (COOMe) in the phenyl ring remains unclear because the intermediate products 16 could not be isolated. Based on analogous enone [2+2] photocycloaddition reactions24 one would assume that the tetrahydropyran ring forms in a cis fashion relative to the annulated cyclobutane ring as shown. However, it cannot be completely ruled out that the methoxycarbonyl group prefers ortho position o’. Inspection of conformation 9’ reveals that a disubstitution at position C2 of the tether increases the distance between the reactive centers which may account for the low reactivity of substrate 6.

FIGURE 3. Structures of products 17a and 17b obtained by irradiation of compounds 9a and 9b in MeOH at λ = 300 nm; chair conformation 9’ of compounds 9a and 9b


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Given that the reactions of substrates 9a and 9b had followed nicely our expectations, it was surprising that irradiation of compound 9c led to a different result (Scheme 6). The typical cascade product 17c was isolated as a single diastereoisomer and its epimer epi-17c was formed in low quantities. However, a constitutional isomer of compound 17c was isolated as a byproduct. Structure 18 could eventually be assigned to this product which appears to be a regioisomer formed in the photochemical disrotatory [4π] cyclization step. The preferred conformation 9c’’ of compound 9c seems to be determined by two factors: (a) the two reactive centers are in close proximity to each other and (b) steric hindrance is minimized with the hydrogen atom at the stereogenic center C1 being in the same plane as the arene ring. Primary product 16c should thus result from the ortho photocycloaddition from which cyclooctatriene 19 is formed by pericyclic ring opening. The competing [4π] photocyclization to product 18 can be readily explained by the fact that the formation of compound 17c from 19 is associated with a significant degree of strain developing between the methyl group in the tetrahydropyran ring and the cyclobutene.

SCHEME 6. Product Composition from Irradiation of Compound 9c, Preferred Conformation 9c’’, and Proposed Intermediates 16c and 19


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CONCLUSION In summary, a reliable way for the construction of tricyclic 2,3,4,4a,5,7a-hexyahydrocyclobuta[i]chromenes from simple starting materials was established. A complex three-dimensional structure evolves in a photochemical reaction sequence from a planar arene framework. The product skeleton allows for further functionalization at the ester group in position C6 and at the cyclobutene double bond. The selectivity, reliability, and predictability of the reaction cascade suggest its usefulness for synthetic applications and warrant further studies in this area.

EXPERIMENTAL SECTION General Methods: Air and moisture sensitive reactions were carried out in oven-dried glassware sealed with rubber septa under a positive pressure of dry argon. Irradiation experiments were conducted in an photochemical reactor equipped with 16 fluorescence lamps (λmax = 300 nm).20a Dry tetrahydrofuran (THF), dichloromethane (CH2Cl2), and diethyl ether (Et2O) were obtained from a solvent purification system. Other dry solvents, e.g. methanol (MeOH), were obtained in the highest purity available stored over molecular sieves. Analytical thin layer chromatography ACS Paragon Plus Environment

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(TLC) was performed on silica gel 60 (F254) glass plates. The TLC plates were visualized by either ultraviolet (UV) light (λ = 254 nm) or treatment with KMnO4 stain followed by gentle heating. Purification of products was accomplished by either flash chromatography on silica gel 60 (230-400 mesh) or with preparative TLC on silica gel 60 (F254) glass plates. All solvents for chromatography, e.g. ethyl acetate (EtOAc), were distilled prior to use. NMR spectra were measured on either a 300, or a 400 or a 500 MHz nuclear magnetic resonance spectrometer. The 1

H NMR spectra were calibrated against the residual solvent peak of either chloroform

(7.26 ppm) or C6D6 (7.16 ppm), and the 13C{1H} NMR spectra were calibrated either against the central peak of CDCl3 (77.16 ppm) or the residual solvent peak of C6D6 (128.06 ppm). Data for 1

H NMR spectra were reported as follows: chemical shift in parts per million (ppm), peak shape

(s = singlet, d = dublet, t = triplet, q = quartet, quin = quintet, h = sextet, m = multiplet, br = broad), coupling constant in Hertz (Hz), and integration. Apparent multiplicity which occurs as a result of accidental equality of coupling constants to those of magnetically non-equivalent protons are marked as virtual (virt.). Infrared spectra were recorded by attenuated total reflection (ATR) technique and are reported as wave numbers ṽ (cm–1). Mass spectra were measured with a mass selective quadrupole detector (EI, 70 eV). HRMS data were determined at a doublefocussing magnetic sector instrument (EI, 70 eV).

Methyl 2-(pent-4-en-1-yloxy)benzoate (1a) Methyl salicylate (1.00 g, 847 µL, 6.57 mmol, 1.0 equiv) was dissolved in DMF (9 mL). NaH (315 mg, 7.89 mmol, 60 % suspension in mineral oil, 1.2 equiv) was added in a flow of argon and the mixture was stirred for 30 min. 5-Bromo-1-pentene (1.18 g, 932 µL 7.89 mmol, 1.2 equiv) was added and the solution was heated to 80 °C. After 3.5 h the resulting suspension was cooled to room temperature. The mixture was diluted with water (100 mL) and extracted with Et2O


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(50 mL). The organic layer was washed with water (2 × 50 mL) and with brine (50 mL). After drying over Na2SO4 all volatiles were removed in vacuo. Purification by flash chromatography (SiO2, pentane/EtOAc 50:1, UV) gave the product as a colorless liquid (702 mg, 3.19 mmol, 49%). TLC (CH2Cl2): Rf = 0.49 [UV, KMnO4]. 1H NMR (500 MHz, CDCl3, 300 K) δ = 1.89– 1.97 (m, 2H), 2.23–2.32 (m, 2H), 3.89 (s, 3H), 4.05 (t, 3J = 6.4 Hz, 2H), 5.00 (ddt, 2J = 1.2 Hz, 3J = 10.2 Hz, 4J = 2.1 Hz, 1H), 5.06 (virt. dq, 3J = 17.1 Hz, 2J ≅ 4J = 1.7 Hz, 1H), 5.86 (ddt, 3J = 17.1, 10.2, 6.7 Hz, 1H), 6.93–6.99 (m, 2H), 7.43 (ddd, 3J = 8.2, 7.4 Hz, 4J = 1.8 Hz, 1H), 7.78 (dd, 3J = 7.7 Hz, 4J = 1.8 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3, 300 K) δ = 28.5 (t), 30.1 (t), 52.0 (q), 68.2 (t), 113.3 (d), 115.3 (t), 120.2 (d), 120.6 (s), 131.7 (d), 133.5 (d), 137.9 (d), 158.6 (s), 167.1 (s). IR (ATR): ṽ = 3074, 2948, 1729, 1600, 1303, 1246, 1082, 752. MS (EI, 70 eV): m/z (%) = 220 (3), 152 (63), 120 (100). HRMS (EI, 70 eV): calcd for C13H16O3+ [M+] = 220.1094; found = 220.1092.

2-(Pent-4-en-1-yloxy)benzonitrile (1b) 2-Hydroxybenzonitrile (200 mg, 1.68 mmol, 1.0 equiv) was dissolved in DMF (4.5 mL). NaH (80.6 mg, 2.01 mmol, 60 % suspension in mineral oil, 1.2 equiv) was added in a flow of argon and the mixture was stirred for 45 min. 5-Bromo-1-pentene (375 mg, 298 µL 2.52 mmol, 1.5 equiv) was added and the solution was heated to 60 °C. After 17 h the resulting suspension was cooled to room temperature. The mixture was diluted with water (25 mL) and extracted with Et2O (25 mL). The organic layer was washed with water (2 × 25 mL). After drying over Na2SO4 all volatiles were removed in vacuo. Purification by flash chromatography (SiO2, pentane/EtOAc 10:1, UV) gave the product as a colorless liquid (298 mg, 1.59 mmol, 95%). TLC (pentane/EtOAc 10:1): Rf = 0.44 [UV, KMnO4]. 1H NMR (300 MHz, CDCl3, 300 K) δ = 1.95 (virt. quin, 3J ≅ 3J = 6.5 Hz, 2H), 2.17–2.42 (m, 2H), 4.08 (t, 3J = 6.5 Hz, 2H), 4.98–5.12 (m, 2H), ACS Paragon Plus Environment

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5.85 (ddt, 3J = 16.9, 10.1, 6.6 Hz, 1H), 6.84–7.07 (m, 2H), 7.40–7.63 (m, 2H).

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C{1H} NMR

(75 MHz, CDCl3, 300 K) δ = 28.1 (t), 30.0 (t), 68.2 (t), 102.2 (s), 112.3 (d), 115.7 (t), 116.6 (s), 120.7 (d), 133.9 (d), 134.4 (d), 137.5 (d), 160.9 (s). IR (ATR): ṽ = 3079, 2943, 2227, 1598, 1492, 1450, 1289, 1259, 754. MS (EI, 70 eV): m/z (%) = 187 (10), 119 (100), 68 (65). HRMS (EI, 70 eV): calcd for C12H13NO+ [M+] = 187.0992; found = 187.0986.

Butyl 2-(pent-4-en-1-yloxy)benzoate (1c) Butyl salicylate25 (120 mg, 618 µmol, 1.0 equiv) was dissolved in DMF (1.5 mL). NaH (27.2 mg, 680 µmol, 60 % suspension in mineral oil, 1.1 equiv) was added in a flow of argon and the mixture was stirred for 30 min. 5-Bromo-1-pentene (138 mg, 110 µL 927 µmol, 1.5 equiv) was added and the solution was heated to 100 °C. After 17 h the resulting suspension was cooled to room temperature. The mixture was diluted with water (10 mL) and extracted with Et2O (10 mL). The organic layer was washed with water (2 × 10 mL) and with brine (10 mL). After drying over Na2SO4 all volatiles were removed in vacuo. Purification by flash chromatography (SiO2, pentane/EtOAc 50:1, UV) gave the product as a colorless liquid (119 mg, 464 µmol, 73%). TLC (pentane/EtOAc 50:1): Rf = 0.20 [UV, KMnO4]. 1H NMR (300 MHz, CDCl3, 300 K) δ = 0.97 (t, 3

J = 7.3 Hz, 3H), 1.39–1.56 (m, 2H), 1.65–1.81 (m, 2H), 1.93 (tt, 3J = 6.9, 6.3 Hz, 2H), 2.20–2.36

(m, 2H), 4.04 (t, 3J = 6.3 Hz, 2H), 4.30 (t, 3J = 6.6 Hz, 2H), 4.91–5.16 (m, 2H), 5.85 (ddt, 3

J = 16.9, 10.2, 6.6 Hz, 1H), 6.86–7.04 (m, 2H), 7.36–7.51 (m, 1H), 7.72 (dd, 3J = 7.5 Hz,

4

J = 2.1 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3, 300 K) δ = 13.9 (q), 19.4 (t), 28.5 (t), 30.2 (t),

31.0 (t), 64.9 (t), 68.15 (t), 113.2 (d), 115.3 (t), 120.2 (d), 121.1, (s), 131.7 (d), 133.26 (d), 137.9 (d), 158.6 (s), 166.9 (s). IR (ATR): ṽ = 3076, 2958, 1726, 1600, 1246, 1078. MS (EI, 70 eV): m/z


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(%) = 262 (2), 194 (30), 189 (10), 120 (100), 68 (10). HRMS (EI, 70 eV): calcd for C16H22O3+ [M+] = 262.1563; found = 262.1558.

tert-Butyl 2-(pent-4-en-1-yloxy)benzoate (1d) tert-Butyl salicylate26 (120 mg, 618 µmol, 1.0 equiv) was dissolved in DMF (1.5 mL). NaH (29.7 mg, 741 µmol, 60 % suspension in mineral oil, 1.2 equiv) was added in a flow of argon and the mixture was stirred for 60 min. 5-Bromo-1-pentene (138 mg, 110 µL 927 µmol, 1.5 equiv) was added and the solution was heated to 100 °C. After 17.5 h the resulting suspension was cooled to room temperature. The mixture was diluted with water (10 mL) and was extracted with Et2O (10 mL). The organic layer was washed with water (3 × 10 mL). After drying over Na2SO4 all volatiles were removed in vacuo. Purification by flash chromatography (SiO2, pentane/EtOAc 50:1, UV) gave the product as a colorless liquid (131 mg, 499 µmol, 81%). TLC (pentane/EtOAc 10:1): Rf = 0.38 [UV, KMnO4]. 1H NMR (300 MHz, CDCl3, 300 K): δ = 1.59 (s, 9H), 1.85–2.01 (m, 2H), 2.22–2.37 (m, 2H), 4.02 (t, 3J = 6.3 Hz, 2H), 4.95–5.13 (m, 2H), 5.86 (ddt, 3J = 16.9, 10.2, 6.6 Hz, 1H), 6.86–7.00 (m, 2H), 7.38 (ddd, 3J = 8.3, 7.4 Hz, 4J = 1.8 Hz, 1H), 7.66 (dd, 3

J = 7.6, 4J = 1.8 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3, 300 K): δ = 28.3 (q), 28.5 (t), 30.1

(t), 67.9 (t), 81.0 (s), 113.0 (d), 115.2 (t), 120.0 (d), 122.9 (s), 131.0 (d), 132.4 (d), 137.8 (d), 157.9 (s), 166.26 (s). IR (ATR): ṽ = 3076, 2978, 1720, 1600, 1248, 1130, 1079. MS (EI, 70 eV): m/z (%) = 262 (3), 189 (16), 120 (100). HRMS (EI): calcd for C16H22O3+ [M+] = 262.1563; found = 262.1565.

N,N-Dimethyl-2-(pent-4-en-1-yloxy)benzamide (1e) 2-Hydroxy-N,N-dimethylbenzamide27

(110 mg, 611 µmol, 1.0 equiv) and NaOEt (41.6 mg,

611 µmol, 1.0 equiv) were dissolved in EtOH (1.5 mL) and heated to 40 °C. 5-Bromo-1-pentene


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(91.1 mg, 611 µmol, 1.0 equiv) was added and the mixture was refluxed for 27 h. After cooling to room temperature all volatiles were removed in vacuo. The crude product was partitioned between water (10 mL) and Et2O (10 mL) and the water layer was extracted with Et2O (3 × 10 mL). The combined organic layers were concentrated under reduced pressure and purification by preparative TLC (SiO2, CH2Cl2/MeOH 20:1, UV) gave the product as a colorless liquid (71.2 mg, 305 µmol, 50%). TLC (CH2Cl2/MeOH 20:1): Rf = 0.43 [UV, KMnO4]. 1H NMR (500 MHz, CDCl3, 300 K): δ = 1.82–1.90 (m, 2H), 2.19 (virt. q, 3J ≅ 3J = 6.9 Hz, 2H), 2.85 (s, 3H), 3.11 (s, 3H), 3.99 (t, 3J = 6.4 Hz, 2H), 4.99 (dd, 2J = 1.8 Hz, 3J = 10.2 Hz, 1H), 5.03 (virt. dt, 3

J = 17.1 Hz, 2J ≅ 4J = 1.7 Hz, 1H), 5.83 (ddt, 3J = 17.1, 10.2, 6.9 Hz, 1H), 6.87 (dd, 3J = 8.1 Hz,

4

J = 1.0 Hz, 1H), 6.96 (virt. td, 3J ≅ 3J = 7.7 Hz, 4J = 1.0 Hz, 1H), 7.24 (dd, 3J = 7.5 Hz, 4J = 1.7

Hz, 1H), 7.30 (ddd, 3J = 8.1, 7.7 Hz, 4J = 1.7 Hz, 1H) .13C{1H} NMR (101 MHz, CDCl3, 300 K): δ = 28.6 (t), 30.2 (t), 34.8 (q), 38.4 (q), 67.7 (t), 112.1 (d), 115.1 (t), 121.0 (d), 126.8 (s), 128.1 (d), 130.3 (d), 137.8 (d), 154.8 (s), 169.6 (s). IR (ATR): ṽ = 3072, 2929, 2875, 1631, 1600, 1450. MS (EI, 70 eV): m/z (%) = 233 (3), 189 (16), 164 (16), 121 (100). HRMS (EI): calcd for C14H19O2N+ [M+] = 233.1410; found = 233.1413.

General procedure for the photochemical reaction cascade: The substrate (100 µmol, 1.0 equiv) was placed in an oven dried Duran phototube (diameter: 1 cm, volume: 12 mL) under a positive pressure of argon. 10 mL of MeOH (dry, freshly distilled) were added and the solution was purged with argon (ultrasound, 15 min, argon flow). The mixture was irradiated at λ = 300 nm at room temperature until reaction control (TLC) indicated full conversion. If full conversion was not reached within 24 h irradiation was stopped at this point. All volatiles were removed under reduced pressure whereby the temperature was kept below 30 °C. Purification by


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either flash chromatography (SiO2, solvent, detection mode) or preparative TLC (SiO2, solvent, detection mode) gave the respective cascade products.

Methyl 2,3,4,4a,5,7a-hexahydrocyclobuta[i]chromene-6-carboxylate (2a) Following the general procedure for the photochemical reaction cascade, compound 1a (22.0 mg) was transformed into 2a. Purification by flash chromatography (SiO2, pentane/EtOAc 10:1, UV) gave the product as a colorless liquid (16.3 mg, 74.0 µmol, 74%). TLC (pentane/EtOAc 10:1): Rf = 0.30 [UV, KMnO4]. 1H NMR (300 MHz, CDCl3, 300 K): δ = 1.36–1.84 (m, 6H), 2.57 (dd, 2

J = 16.1 Hz, 3J = 3.1 Hz, 1H), 3.22 (virt. dt, 3J = 5.7 Hz, 3J ≅ 5J = 1.2 Hz, 1H), 3.53–3.67 (m,

1H), 3.72 (s, 3H), 3.89–3.96 (m, 1H), 6.16 (dd, 3J = 3.0, 0.9 Hz, 1H), 6.66 (d, 3J = 3.0 Hz, 1H), 6.99 (dd, 3J = 5.7 Hz, 4J = 2.8 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3, 300 K): δ = 26.8 (m), 27.8 (t), 39.5 (d), 49.5 (d), 51.9 (q), 65.4 (t), 84.4 (s), 132.2 (s), 134.6 (d), 138.4 (d), 139.0 (d), 167.4 (s). IR (ATR): ṽ = 3044, 2931, 1708, 1633, 1247, 732. MS (EI, 70 eV): m/z (%) = 220 (8), 194 (64), 161 (100). HRMS (EI): calcd for C13H16O3+ [M+] = 220.1094; found = 220.1091. In analogy, the reaction of compound 1a was performed on a larger scale (220 mg, 1.00 mmol) in ten phototubes. After an irradiation time of 16 hours and typical work-up product 2a was obtained as a colorless liquid (161 mg, 732 µmol, 73%).

2,3,4,4a,5,7a-Hexahydrocyclobuta[i]chromene-6-carbonitrile (2b) Following the general procedure for the photochemical reaction cascade compound 1b (18.7 mg) was transformed into 2b. Purification by flash chromatography (SiO2, pentane/EtOAc 10:1, UV) gave the product as a colorless liquid (10.0 mg, 53.4 µmol, 53%). TLC (pentane/EtOAc 10:1): Rf = 0.20 [UV, KMnO4]. 1H NMR (400 MHz, CDCl3, 300 K): δ = 1.33–1.48 (m, 1H), 1.56–1.69 (m, 2H), 1.69–1.91 (m, 3H), 2.20 (dd, 2J = 16.2 Hz, 3J = 3.8 Hz, 1H), 3.20 (d, 3J = 5.1 Hz, 1H), ACS Paragon Plus Environment

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3.59 (virt. td, 2J ≅ 3J = 11.8 Hz, 3J = 2.9 Hz, 1H), 3.87–3.98 (m, 1H), 6.18 (d, 3J = 2.9 Hz, 1H), 6.61–6.74 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3, 300 K): δ = 26.4 (t), 26.5 (t), 30.7 (t), 39.2 (d), 49.4 (d), 65.3 (t), 83.6 (s), 113.7 (s), 119.3 (s), 135.1 (d), 139.0 (d), 144.3 (d). IR (ATR): ṽ = 3047, 2934, 2189, 1633, 1599. MS (EI, 70 eV): m/z (%) = 187 (25), 161 (100), 135 (43). HRMS (EI): calcd for C12H13NO + [M+] = 187.0992; found = 187.0986.

Butyl 2,3,4,4a,5,7a-hexahydrocyclobuta[i]chromene-6-carboxylate (2c) Following the general procedure for the photochemical reaction cascade compound 1c (26.2 mg) was transformed into 2c. Purification by preparative TLC (SiO2, pentane/EtOAc 10:1, UV) gave the product as a colorless liquid (17.0 mg, 64.8 µmol, 65%). TLC (pentane/EtOAc 10:1): Rf = 0.38 [UV, KMnO4]. 1H NMR (300 MHz, C6D6, 300 K): δ = 0.77 (t, 3J = 7.3 Hz, 3H), 0.97–1.31 (m, 4H), 1.33–1.56 (m, 5H), 1.61–1.78 (m, 1H), 2.75 (dd, 2J = 16.4 Hz, 3J = 3.6 Hz, 1H), 3.22 (virt. dt, 3J = 5.6 Hz, 3J ≅ 5J = 1.2 Hz, 1H), 3.30 (ddd, 2J = 11.6 Hz, 3J = 12.7, 2.6 Hz, 1H), 3.71 (ddd, 2J = 11.6 Hz, 3J = 5.3, 1.6 Hz, 1H), 3.99-4.18 (m, 2H), 5.79 (dd, 3J = 3.0, 1.1 Hz, 1H), 6.33 (d, 3J = 3.0 Hz, 1H), 7.02 (dd, 3J = 5.6 Hz, 4J = 3.0 Hz, 1H).

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C{1H} NMR (75 MHz, CDCl3,

300 K): δ = 13.9 (q), 19.6 (t), 26.9 (t), 27.1 (t), 28.2 (t), 31.2 (t), 39.9 (d), 49.8 (d), 64.3 (t), 64.9 (t), 84.5 (s), 132.9 (s), 134.79 (d), 138.18 (d), 138.69 (d), 166.53 (s). IR (ATR): ṽ = 3045, 2956, 2931, 2853, 1706, 1633, 1245. MS (EI, 70 eV): m/z (%) = 262 (8), 236 (37), 161 (100), 135 (32). HRMS (EI): calcd for C16H22O3 + [M+] = 262.1563; found = 262.1561.

tert-Butyl 2,3,4,4a,5,7a-hexahydrocyclobuta[i]chromene-6-carboxylate (2d) Following the general procedure for the photochemical reaction cascade compound 1d (26.2 mg) was transformed into 2d. Purification by preparative TLC (SiO2, pentane/EtOAc 10:1, UV) gave the product as a colorless liquid (18.0 mg, 68.6 µmol, 69%). TLC (pentane/EtOAc 10:1): Rf = ACS Paragon Plus Environment

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0.48 [UV, KMnO4]. 1H NMR (400 MHz, C6D6, 300 K): δ = 1.00–1.19 (m, 2H), 1.32–1.49 (m, 3H), 1.43 (s, 9H), 1.61–1.74 (m, 1H), 2.75 (dd, 2J = 16.5 Hz, 3J = 3.6 Hz, 1H), 3.22 (virt. dt, 3J = 5.7 Hz, 3J ≅ 5J = 1.2 Hz, 1H), 3.25–3.36 (m, 1H), 3.71 (ddd, 2J = 11.7 Hz, 3J = 5.2, 3.1 Hz, 1H), 5.79 (dd, 3J = 3.0, 1.0 Hz, 1H), 6.32 (d, 3J = 3.0 Hz, 1H), 6.97 (dd, 3J = 5.7 Hz, 4J = 3.1 Hz, 1H). 13

C{1H} NMR (101 MHz, CDCl3, 300 K): δ = 26.9 (t), 27.1 (t), 28.1 (t), 28.2 (q), 40.0 (d), 49.8

(d), 64.9 (t), 79.6 (s), 84.6 (s), 134.2 (s), 134.7 (d), 137.4 (d), 138.7 (d), 165.9 (s). IR (ATR): ṽ = 3046, 2930, 1700, 1632, 1253. MS (EI, 70 eV): m/z (%) = 262 (1), 236 (15), 206 (49), 161 (100), 135 (43). HRMS (EI): calcd for C16H22O3 + [M+] = 262.1563; found = 262.1561.

Methyl 2-[(4-methylpent-4-en-1-yl)oxy]benzoate (5) Methyl salicylate (62.2 mg, 52.7 µL, 409 µmol, 1.3 equiv) was dissolved in DMF (0.8 mL). NaH (9.06 mg, 377 µmol, 60 % suspension in mineral oil, 1.2 equiv) was added in a flow of argon and the mixture was stirred for 30 min. 4-Methylpent-4-en-1-yl 4-methylbenzenesulfonate14 (80.0 mg, 315 µmol, 1.0 equiv) was added and the solution was heated to 60 °C. After 5 h the resulting suspension was cooled to room temperature. The mixture was diluted with water (10 mL) and extracted with Et2O (10 mL). The organic layer was washed with water (2 × 10 mL) and with saturated aqueous NH4Cl solution (10 mL). The combined aqueous layers were extracted with Et2O (10 mL) and the extracts were washed with water (10 mL). After drying the combined organic layers over Na2SO4 all volatiles were removed in vacuo. Purification by flash chromatography (SiO2, pentane/Et2O 50:1, UV) gave the product as a colorless liquid (51.1 mg, 218 µmol, 70%). TLC (pentane/EtOAc 10:1): Rf = 0.62 [UV, KMnO4]. 1H NMR (400 MHz, CDCl3, 300 K): δ = 1.76 (s, 3H), 1.91–2.03 (m, 2H), 2.24 (t, 3J = 6.6 Hz, 2H), 3.89 (s, 3H), 4.04 (t, 3J = 6.6 Hz, 2H), 4.70–4.77 (m, 2H), 6.91–7.03 (m, 2H), 7.43 (ddd, 3J = 8.0, 7.1 Hz, 4

J = 1.9 Hz, 1H), 7.78 (dd, 3J = 8.0 Hz, 4J = 1.9 Hz, 1H). ACS Paragon Plus Environment

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C{1H} NMR (101 MHz, CDCl3, 21


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300 K): δ = 22.6 (q), 27.3 (t), 34.1 (t), 52.0 (q), 68.4 (t), 110.6 (t), 113.4 (d), 120.2 (d), 120.7 (s), 131.8 (d), 133.5 (d), 145.1 (s), 158.7 (s), 167.2 (s). IR (ATR): ṽ = 3075, 2948, 1729, 1600, 1245, 1081, 752. MS (EI, 70 eV): m/z (%) = 234 (1), 152 (63), 120 (100), 82 (39). HRMS (EI): calcd for C14H18O3+ [M+] = 234.1250; found = 234.1249.

Methyl 2-((2,2-dimethylpent-4-en-1-yl)oxy)benzoate (6) 5-Iodo-4,4-dimethylpent-1-ene15 (200 mg, 893 µmol, 1.0 equiv) was dissolved in DMF (1.0 mL). Methyl salicylate (204 mg, 1.34 mmol, 1.5 equiv) and Cs2CO3 (465 mg, 1.43 mmol, 1.6 equiv) were added in a flow of argon and the mixture was heated to 100 °C. After 40 h the suspension was cooled to room temperature. Water (10 mL), Et2O (10 mL), and 1M HCl (1 mL) were added and the organic layer was washed with water (3 × 10 mL). The combined aqueous layers were extracted with Et2O (10 mL) and the extract was washed with water (10 mL). The combined organic layers were dried over Na2SO4 and all volatiles were removed in vacuo. Purification by flash chromatography (SiO2, pentane/Et2O 50:1, UV) gave the product as a colorless liquid (102 mg, 460 µmol, 46%). TLC (pentane/Et2O 20:1): Rf = 0.28 [UV, KMnO4]. 1H NMR (300 MHz, CDCl3, 300 K): δ = 1.04 (s, 6H), 2.19 (virt. dt, 3J = 7.6 Hz, 4J ≅ 4J = 1.1 Hz, 2H), 3.67 (s, 2H), 3.90 (s, 3H), 4.97–5.08 (m, 2H), 5.76–5.92 (m, 1H), 6.88–6.99 (m, 2H), 7.43 (ddd, 3J = 8.3, 7.4 Hz, 4J = 1.8 Hz, 1H), 7.79 (dd, 3J = 7.7 Hz, 4J = 1.8 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3, 300 K): δ = 24.5 (q), 35.0 (s), 43.6 (t), 52.0 (q), 76.6 (t), 112.9 (d), 117.7 (t), 120.0 (d), 120.4 (s), 131.9 (d), 133.5 (d), 135.0 (d), 158.8 (s), 167.4 (s). IR (ATR): ṽ = 3075, 2953, 2910, 2871, 1730, 1600, 1246, 1081, 752. MS (EI, 70 eV): m/z (%) = 248 (2), 152 (71), 120 (100), 96 (42). HRMS (EI): calcd for C15H20O3+ [M+] = 248.1407; found = 248.1403.

Methyl 2-[(allyloxy)methoxy]benzoate (7) ACS Paragon Plus Environment

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Methyl salicylate (200 mg, 169 µL, 1.31 mmol, 1.0 equiv) was dissolved in DMF (6.0 mL). NaH (57.8 mg, 1.45 mmol, 60 % suspension in mineral oil, 1.1 equiv) was added in a flow of argon and the mixture was stirred for 60 min. Allyl chloromethyl ether16 (280 mg, 2.63 mmol, 2.0 equiv) was added. After 15 min the reaction mixture was poured into a saturated aqueous Na2CO3 solution (30 mL). The suspension was extracted with Et2O (30 mL) and the organic extract was washed with water (3 ×20 mL). After drying over Na2SO4 all volatiles were removed in vacuo. Purification by flash chromatography (SiO2, pentane/EtOAc 15:1, UV) gave the product as a colorless liquid (189 mg, 850 µmol, 65%). TLC (pentane/EtOAc 10:1): Rf = 0.30 [UV, KMnO4]. 1H NMR (400 MHz, C6D6, 300 K): δ = 3.54 (s, 3H), 4.02 (virt. dt, 3J = 5.5 Hz, 4

J ≅ 4J = 1.5 Hz, 2H), 4.96 (virt. dq, 3J = 10.6 Hz, 2J ≅ 4J = 1.5 Hz, 1H), 5.00 (s, 2H), 5.14 (virt.

dq, 3J = 17.2 Hz, 2J ≅ 4J = 1.7 Hz, 1H), 5.71 (ddt, 3J = 17.2, 10.6, 5.5 Hz, 1H), 6.71 (virt. td, 3J ≅ 3

J = 7.3 Hz, 4J = 1.3 Hz, 1H), 6.99–7.11 (m, 2H), 7.81 (dd, 3J = 7.7 Hz, 4J = 1.8 Hz, 1H).

13

C{1H} NMR (101 MHz, C6D6, 300 K): δ = 51.6 (q), 69.4 (t), 93.3 (t), 116.7 (d), 117.0 (t), 121.6

(d), 122.61 (s), 131.7 (d), 133.1 (d), 134.4 (d), 157.3 (s), 166.4 (s). IR (ATR): ṽ = 3080, 2952, 1727, 1600, 1489, 1227, 1075, 960. MS (EI, 70 eV): m/z (%) = 222 (8), 165 (22), 120 (100). HRMS (EI): calcd for C12H14O4+ [M+] = 222.0887; found = 222.0886.

Methyl (E)-2-(hex-4-en-1-yloxy)benzoate [(E)-8] Methyl salicylate (180 mg, 152 µL, 1.18 mmol, 1.0 equiv) was dissolved in DMF (3.0 mL). NaH (56.8 mg, 1.42 mmol, 60 % suspension in mineral oil, 1.2 equiv) was added in a flow of argon and the mixture was stirred for 2 h. (E)-Hex-4-en-1-yl 4-methylbenzenesulfonate17 (451 mg, 1.77 mmol, 1.5 equiv) was added and the solution was heated to 60 °C. After 21 h the resulting suspension was cooled to room temperature. The mixture was diluted with water (20 mL) and extracted with Et2O (20 mL). The organic layer was washed with water (3 × 20 mL). The ACS Paragon Plus Environment

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combined aqueous phases were extracted with Et2O (20 mL) and the extracts were washed with water (10 mL). After drying the combined organic phases over Na2SO4 all volatiles were removed in vacuo. Purification by flash chromatography (SiO2, pentane/EtOAc 50:1, UV) gave the product as a colorless liquid (267 mg, 1.14 mmol, 96%). TLC (pentane/EtOAc 10:1): Rf = 0.66 [UV, KMnO4]. 1H NMR (500 MHz, CDCl3, 300 K): δ = 1.65 (d, 3J = 4.6 Hz, 3H), 1.88 (virt. quin, 3J ≅ 3J = 6.6 Hz, 2H), 2.16–2.33 (m, 2H), 3.89 (s, 3H), 4.03 (t, 3J = 6.5 Hz, 2H), 5.40– 5.53 (m, 2H), 6.92–6.98 (m, 2H), 7.41–7.46 (m, 1H), 7.77 (dd, 3J = 8.0 Hz, 4J = 1.8 Hz, 1H). 13

C{1H} NMR (101 MHz, CDCl3, 300 K): δ = 18.1 (q), 28.9 (t), 29.1 (t), 52.0 (q), 68.3 (t), 113.4

(d), 120.2 (d), 120.6 (s), 125.9 (d), 130.4 (d), 131.7 (d), 133.4 (d), 158.7 (s), 167.2 (s). IR (ATR): ṽ (cm-1) = 3021, 2947, 2880, 2854, 1730, 1600, 1582, 1453. MS (EI, 70 eV): m/z (%) = 234 (2), 203 (6), 152 (45), 120 (93), 82 (100). HRMS (EI): calcd for C14H18O3+ [M+] = 234.1250; found = 234.1252.

Methyl (Z)-2-(hex-4-en-1-yloxy)benzoate [(Z)-8] Triphenylphosphine (392 mg, 1.50 mmol, 1.5 equiv), methyl salicylate (160 mg, 136 µL, 1.05 mmol, 1.05 equiv), and (Z)-hex-4-en-1-ol19a (100 mg, 998 µmol, 1.0 equiv) were dissolved in THF (1.2 mL). DEAD (261 mg, 1.50 mmol, 2.2 M in toluene, 1.5 equiv) was added dropwise in a way that the reaction temperature did not exceed 40 °C. After 16 h all volatiles were removed in vacuo. Purification by flash chromatography (SiO2, pentane/Et2O 20:1, UV) gave the product as a colorless liquid (152 mg, 649 µmol, 65%). TLC (pentane/EtOAc 10:1): Rf = 0.56 [UV, KMnO4]. 1H NMR (500 MHz, CDCl3, 298 K): δ = 1.60 (dd, 3J = 6.7 Hz, 4J = 1.5 Hz, 3H), 1.89 (virt. quin, 3J ≅ 3J = 6.5 Hz, 2H), 2.28 (virt. q, 3J ≅ 3J = 7.3 Hz, 2H), 3.89 (s, 3H), 4.03 (t, 3J = 6.3 Hz, 2H), 5.38-5.54 (m, 2H), 6.95-7.00 (m, 2H), 7.43 (virt. td, 3J ≅ 3J = 7.9 Hz, 4J = 1.8 Hz, 1H), 7.78 (dd, 3J = 7.7 Hz, 4J = 1.8 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3, 298 K): δ = 12.8 ACS Paragon Plus Environment

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(q), 23.3 (t), 29.1 (t), 52.03 (q), 68.2 (t), 113.3 (d), 120.2 (d), 120.6 (s), 125.1 (d), 129.5 (d), 131.7 (d), 133.5 (d), 158.7 (s), 167.2 (s). IR (ATR): ṽ = 3012, 2948, 2868, 1730, 1491, 1453. MS (EI, 70 eV): m/z (%) = 234 (1), 152 (43), 120 (100), 82 (99). HRMS (EI): calcd for C14H18O3+ [M+] = 234.1250; found = 234.1246.

Methyl 2[(3-methylpent-4-en-1-yl)oxy]benzoate (9a) 5-Bromo-3-methylpent-1-ene15 (100 mg, 613 µmol, 1.0 equiv) was dissolved in DMF (700 µL). Methyl salicylate (140 mg, 920 µmol, 1.5 equiv) and Cs2CO3 (320 mg, 981 µmol, 1.6 equiv) were added in a flow of argon and the mixture was heated to 60 °C. After 19 h, the suspension was cooled to room temperature. Water (10 mL) and Et2O (20 mL) were added and the organic phase was washed with water (2 × 10 mL). The combined aqueous phases were extracted with Et2O (10 mL) and the extract was washed with water (10 mL). The combined organic phases were dried over Na2SO4 and all volatiles were removed in vacuo. Purification by flash chromatography (SiO2, pentane/Et2O 20:1, UV) gave the product as a colorless liquid (114 mg, 487 µmol, 80%). TLC (pentane/Et2O 20:1): Rf = 0.44 [UV, KMnO4]. 1H NMR (400 MHz, CDCl3, 300 K): δ = 1.07 (d, 3J = 6.8 Hz, 3H), 1.72–1.93 (m, 2H), 2.41–2.53 (m, 1H), 3.89 (s, 3H), 3.97–4.10 (m, 2H), 4.95 (ddd, 2J = 1.9 Hz, 3J = 10.3 Hz, 4J = 0.9 Hz, 1H), 5.01 (ddd, 2

J = 1.9 Hz, 3J = 17.2 Hz, 4J = 1.1 Hz, 1H), 5.72 (ddd, 3J = 17.2, 10.3, 7.7 Hz, 1H), 6.91–7.01 (m,

2H), 7.43 (virt. td, 3J ≅ 3J = 7.6 Hz, 4J = 1.9 Hz, 1H), 7.77 (dd, 3J = 8.0 Hz, 4J = 1.9 Hz, 1H). 13

C{1H} NMR (101 MHz, CDCl3, 300 K): δ = 20.5 (q), 34.7 (d), 35.8 (t), 52.0 (q), 67.1 (t), 113.4

(d), 113.6 (t), 120.2 (d), 120.6 (s), 131.7 (d), 133.4 (d), 143.8 (d), 158.7 (s), 167.1 (s). IR (ATR): ṽ = 3078, 2951, 2873, 1729, 1600, 1243, 753. MS (EI, 70 eV): m/z (%) = 234 (3), 203 (5), 152 (74), 120 (100), 82 (27). HRMS (EI): calcd for C14H18O3+ [M+] = 234.1250; found = 234.1253.


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Methyl 2-[(2-methylpent-4-en-1-yl)oxy]benzoate (9b) Triphenylphosphine (392 mg, 1.50 mmol, 1.5 equiv), methyl salicylate (160 mg, 136 µL, 1.05 mmol, 1.05 equiv), and 2-methylpent-4-en-1-ol19b (100 mg, 998 µmol, 1.0 equiv) were dissolved in THF (1.2 mL). DEAD (261 mg, 1.50 mmol, 2.2 M in toluene, 1.5 equiv) was added dropwise in a way that the reaction temperature did not exceed 40 °C. After 19 h, all volatiles were removed in vacuo. Purification by flash chromatography (SiO2, pentane/Et2O 50:1, UV) gave the product as a colorless liquid (137 mg, 585 µmol, 59%). TLC (pentane/EtOAc 10:1): Rf = 0.63 [UV, KMnO4]. 1H NMR (400 MHz, CDCl3, 300 K): δ = 1.07 (d, 3J = 6.3 Hz, 3H), 2.01–2.15 (m, 2H), 2.27–2.39 (m, 1H), 3.80–3.93 (m, 5H), 4.99–5.10 (m, 2H), 5.83 (ddt, 3

J = 17.0, 10.2, 6.9 Hz, 1H), 6.90–6.99 (m, 2H), 7.43 (ddd, 3J = 8.4, 7.4 Hz, 4J = 1.9 Hz, 1H),

7.78 (dd, 3J = 7.7 Hz, 4J = 1.9 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3, 300 K): δ = 16.8 (q), 33.3 (d), 37.8 (t), 52.0 (q), 73.2 (t), 113.2 (d), 116.6 (t), 120.1 (d), 120.6 (s), 131.8 (d), 133.5 (d), 136.6 (d), 158.7 (s), 167.3 (s). IR (ATR): ṽ = 3076, 2953, 1731, 1601, 1305, 1250, 1084, 755. MS (EI, 70 eV): m/z (%) = 234 (3), 152 (55), 120 (100), 82 (30). HRMS (EI): calcd for C14H18O3+ [M+] = 234.1250; found = 234.1251.

Methyl 2-(hex-5-en-2-yloxy)benzoate (9c) Triphenylphosphine (157 mg, 599 µmol, 1.5 equiv), methyl salicylate (63.8 mg, 54.1 µL, 419 µmol, 1.05 equiv), and hex-5-en-2-ol19c (50.0 mg, 399 µmol, 1.0 equiv) were dissolved in THF (0.5 mL). DEAD (104 mg, 599 µmol, 2.2 M in toluene, 1.5 equiv) was added dropwise in a way that the reaction temperature did not exceed 40 °C. After 19 h, all volatiles were removed in vacuo. Purification by flash chromatography (SiO2, pentane/Et2O 20:1, UV) gave the product as a colorless liquid (48.0 mg, 205 µmol, 52%). TLC (pentane/EtOAc 10:1): Rf = 0.63 [UV, KMnO4]. 1

H NMR (400 MHz, CDCl3, 300 K): δ = 1.33 (d, 3J = 6.1 Hz, 3H), 1.71 (dddd, 2J = 13.8 Hz,


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3

J = 8.9, 6.7, 5.2 Hz, 1H), 1.90 (ddt, 2J = 13.8 Hz, 3J = 8.7, 6.6 Hz, 1H), 2.13–2.31 (m, 2H), 3.77

(s, 3H), 4.44 (virt. h, 3J ≅ 3J = 6.1 Hz, 1H), 4.91–5.05 (m, 2H), 5.83 (ddt, 3J = 16.9, 10.2, 6.7 Hz, 1H), 6.90–6.98 (m, 2H), 7.41 (virt. td, 3J ≅ 3J = 8.0 Hz, 4J = 1.8 Hz, 1H), 7.74 (dd, 3J = 8.0 Hz, 4J = 1.8 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3, 300 K): δ = 19.7 (q), 29.7 (t), 35.8 (t), 52.0 (q), 74.8 (d), 115.1 (t), 115.2 (d), 120.2 (d), 121.9 (s), 131.7 (d), 133.2 (d), 138.3 (d), 157.8 (s), 167.3 (s). IR (ATR): ṽ (cm-1) = 3074, 2977, 1733, 1600, 1303, 1248, 1082. MS (EI, 70 eV): m/z (%) = 234 (2), 152 (64), 120 (100). HRMS (EI): calcd for C14H18O3+ [M+] = 234.1250; found = 234.1252.

Methyl 4a-methyl-2,3,4,4a,5,7a-hexahydrocyclobuta[i]chromene-6-carboxylate (10) Following the general procedure for the photochemical reaction cascade compound 5 (23.4 mg) was transformed into 10. Purification by flash chromatography (SiO2, pentane/EtOAc 10:1, UV) gave the product as a colorless liquid (20.4 mg, 87.1 µmol, 87%). TLC (pentane/EtOAc 10:1): Rf = 0.46 [UV, KMnO4]. 1H NMR (400 MHz, CDCl3, 300 K): δ = 0.91 (s, 3H), 1.39–1.48 (m, 1H), 1.52–1.64 (m, 2H), 1.80 (br d, 2J = 16.5 Hz, 1H), 1.97–2.14 (m, 1H), 2.45 (d, 2J = 16.5 Hz, 1H), 3.14 (d, 3J = 5.2 Hz, 1H), 3.61 (ddd, 2J = 11.7 Hz, 3J = 13.2, 3.4 Hz, 1H), 3.73 (s, 3H), 3.85– 3.93 (m, 1H), 6.17 (dd, 3J = 3.0, 0.9 Hz, 1H), 6.83 (d, 3J = 3.0 Hz, 1H), 7.06 (dd, 3J = 5.2 Hz, 4J = 3.0 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3, 300 K): δ = 16.3 (q), 22.2 (t), 32.5 (t), 33.7 (s), 35.9 (t), 48.2 (d), 51.9 (q), 64.9 (t), 86.3 (s), 129.2 (s), 136.0 (d), 138.9 (d), 139.3 (d), 167.8 (s). IR (ATR): ṽ = 3045, 2945, 2854, 1709, 1632, 1248, 1090, 735. MS (EI, 70 eV): m/z (%) = 234 (33), 208 (100), 175 (47). HRMS (EI): calcd for C14H18O3+ [M+] = 234.1250; found = 234.1248.

Methyl 3,3-dimethyl-2,3,4,4a,5,7a-hexahydrocyclobuta[i]chromene-6-carboxylate (11) ACS Paragon Plus Environment

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Following the general procedure for the photochemical reaction cascade compound 6 (24.8 mg) was transformed into 11. Purification by flash chromatography (SiO2, pentane/EtOAc 10:1, UV) gave the product as a colorless liquid (3.41 mg, 13.7 µmol, 14%). TLC (pentane/EtOAc 10:1): Rf = 0.44 [UV, KMnO4]. 1H NMR (500 MHz, CDCl3, 300 K): δ = 0.87 (s, 3H), 1.08 (s, 3H), 1.30 (virt. t, 2J ≅ 3J = 12.8 Hz, 1H), 1.45–1.50 (m, 1H), 1.59–1.67 (m, 1H), 1.72 (virt. tt, 3J ≅ 3J = 12.5 Hz, 3J ≅ 3J = 3.3 Hz, 1H), 2.51 (dd, 2J = 15.9 Hz, 3J = 3.3 Hz, 1H), 3.27 (virt. dt, 3J = 5.6 Hz, 3J ≅ 5

J = 1.1 Hz, 1H), 3.35 (dd, 2J = 11.5 Hz, 4J = 1.0 Hz, 1H), 3.41 (dd, 2J = 11.5 Hz, 4J = 2.3 Hz,

1H), 3.73 (s, 3H), 6.15 (dd, 3J = 2.9, 0.9 Hz, 1H), 6.65 (d, 3J = 2.9 Hz, 1H), 7.00 (dd, 3J = 5.6 Hz, 4

J = 3.0 Hz, 1H).13C{1H} NMR (126 MHz, CDCl3, 300 K): δ = 24.9 (q), 27.4 (q), 27.6 (t), 31.7

(s), 35.4 (d), 40.3 (t), 49.2 (d), 51.9 (q), 75.4 (t), 84.6 (s), 132.3 (s), 134.2 (d), 138.7 (d), 139.1 (d), 167.5 (s). IR (ATR): ṽ = 3048, 2951, 2848, 1715, 1634, 1247, 1113. MS (EI, 70 eV): m/z (%) = 248 (24), 222 (100), 189 (67). HRMS (EI): calcd for C15H20O3+ [M+] = 248.1407; found = 248.1400.

Methyl 4,4a,5,7a-tetrahydrocyclobuta[1,6]benzo[1,2-d][1,3]dioxine-6-carboxylate (12) Following the general procedure for the photochemical reaction cascade compound 7 (22.2 mg) was transformed into 12. Purification by flash chromatography (SiO2, pentane/EtOAc 10:1, UV) gave the product as a colorless liquid (17.0 mg, 77.2 µmol, 77%). TLC (pentane/EtOAc 10:1): Rf = 0.18 [UV, KMnO4]. 1H NMR (500 MHz, C6D6, 300 K): δ = 1.21–1.41 (m, 1H), 1.78–1.92 (m, 1H), 2.42 (dd, 2J = 16.3 Hz, 3J = 3.7 Hz, 1H), 3.10–3.19 (m, 2H), 3.40 (s, 3H), 3.66 (dd, 2

J = 10.8 Hz, 3J = 4.0 Hz, 1H), 4.55 (d, 2J = 6.3 Hz, 1H), 4.97 (d, 2J = 6.3 Hz, 1H), 5.69 (dd,

3

J = 2.9, 0.9 Hz, 1H), 6.17 (d, 3J = 2.9 Hz, 1H), 6.84 (dd, 3J = 5.5 Hz, 4J = 3.0 Hz, 1H).

13

C{1H} NMR (101 MHz, C6D6, 300 K): δ = 23.2 (t), 39.6 (d), 49.1 (d), 51.3 (q), 67.9 (t), 83.6

(s), 90.9 (t), 131.8 (s), 133.5 (d), 138.1 (d), 139.8 (d), 166.5 (s). IR (ATR): ṽ = 2924, 2852, 1713,


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1632, 1254, 1141, 1009. MS (EI, 70 eV): m/z (%) = 222 (1), 196 (74), 105 (100). HRMS (EI): calcd for C12H14O4+ [M+] = 222.0887; found = 222.0886.

Methyl 5-methyl-2,3,4,4a,5,7a-hexahydrocyclobuta[i]chromene-6-carboxylate (13) Following the general procedure for the photochemical reaction cascade either compound (E)-8 or compound (Z)-8 (23.4 mg) was transformed into 13. Purification by flash chromatography (SiO2, pentane/EtOAc 10:1, UV) gave the product as a colorless liquid (10.2 mg, 43.5 µmol, 44%, 13a/13b 88:12 starting from (E)-8; 14.6 mg, 62.3 µmol, 62%, 13a/13b 93:7 starting from (Z)-8). TLC (pentane/EtOAc 10:1): Rf = 0.40 [UV, KMnO4]. 1H NMR (500 MHz, CDCl3, 300 K): δ = 0.97 (d, 3J = 7.4 Hz, 3H), 1.62–1.90 (m, 5H), 2.77 (qd, 3J = 7.4, 5.2 Hz, 1H), 3.16 (d, 3

J = 5.4 Hz, 1H), 3.57–3.65 (m, 1H), 3.73 (s, 3H), 3.86–3.96 (m, 1H), 6.41 (dd, 3J = 2.8, 1.3 Hz,

1H), 6.69 (d, 3J = 2.8 Hz, 1H), 7.06 (d, 3J = 5.4 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3, 300 K): δ = 12.6 (q), 24.6 (t), 27.2 (t), 33.1 (s), 43.1 (d), 49.8 (d), 51.8 (q), 65.3 (t), 83.3 (s), 137.0 (s), 138.8 (d), 138.9 (d), 143.1 (d), 167.4 (s). IR (ATR): ṽ = 3043, 2936, 2854, 1708, 1452, 1375, 1243, 841. MS (EI, 70 eV): m/z (%) = 234 (6), 208 (22), 121 (100). HRMS (EI): calcd for C14H18O3+ [M+] = 234.1250; found = 234.1258.

Methyl 4-methyl-2,3,4,4a,5,7a-hexahydrocyclobuta[i]chromene-6-carboxylate (17a) Following the general procedure for the photochemical reaction cascade compound 9a (23.4 mg) was transformed into 17a. Purification by flash chromatography (SiO2, pentane/EtOAc 10:1, UV) gave the product as a colorless liquid (18.0 mg, 76.8 µmol, 77%, d.r. = 82:18). TLC (pentane/EtOAc 10:1): Rf = 0.36 [UV, KMnO4]. 1H NMR (400 MHz, CDCl3, 300 K): δ = 0.99 (d, 3

J = 6.2 Hz, 3H), 1.14 (ddd, 3J = 12.6, 10.6, 3.9 Hz, 1H), 1.34–1.46 (m, 1H), 1.46–1.64 (m, 3H),

2.87 (dd, 2J = 16.4 Hz, 3J = 3.9 Hz, 1H), 3.23 (d, 3J = 5.6 Hz, 1H), 3.60–3.70 (m, 1H), 3.73 (s,


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3H), 3.90 (ddd, 2J = 11.6 Hz, 3J = 5.2, 1.3 Hz, 1H), 6.14 (dd, 3J = 3.0, 1.0 Hz, 1H), 6.62 (d, 3J = 3.0 Hz, 1H), 7.00 (dd, 3J = 5.6 Hz, 4J = 3.0 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3, 300 K): δ = 19.3 (q), 24.1 (t), 31.4 (d), 35.6 (t), 45.8 (d), 49.7 (d), 51.9 (q), 65.2 (t), 84.0 (s), 132.0 (s), 135.1 (d), 138.4 (d), 139.0 (d), 167.5 (s). IR (ATR): ṽ = 3047, 2953, 1711, 1636, 1435, 1251, 1096. MS (EI, 70 eV): m/z (%) = 149 (9), 75 (100). HRMS (EI): calcd for C14H18O3+ [M+] = 234.1250; found = 234.1215.

Methyl 3-methyl-2,3,4,4a,5,7a-hexahydrocyclobuta[i]chromene-6-carboxylate (17b) Following the general procedure for the photochemical reaction cascade compound 9b (23.4 mg) was transformed into 17b. Purification by flash chromatography (SiO2, pentane/EtOAc 10:1, UV) gave the product as a colorless liquid as a mixture of diastereoisomers (16.0 mg, 68.3 µmol, 68%, d.r. = 65:35) with 17b being the major diastereoisomer. TLC (pentane/EtOAc 10:1): Rf = 0.36 [UV, KMnO4]. 1H NMR (500 MHz, CDCl3, 300 K): δ = 0.84 (d, 3J = 6.6 Hz, 1.95H), 1.09 (virt. q, 2J ≅ 3J ≅ 3J = 12.2 Hz, 0.65H), 1.15 (d, 3J = 7.2 Hz, 1.05H), 1.49–1.58 (m, 1.00H), 1.61–1.70 (m, 1.35H), 1.72–1.81 (m, 1.00H), 1.81–1.91 (m, 1.00H), 2.50 (dd, 2J = 16.2 Hz, 3J = 3.5 Hz, 0.35H), 2.56 (dd, 2J = 16.3 Hz, 3J = 3.6 Hz, 0.65H), 3.17 (virt. t, 2J ≅ 3J = 11.5 Hz, 0.65H), 3.22– 3.26 (m, 1.00H), 3.61 (dd, 2J = 11.6 Hz, 3J = 2.2 Hz, 0.35H), 3.73 (s, 3H), 3.76–3.83 (m, 1.00H), 6.12–6.17 (m, 1.00H), 6.62 (d, 3J = 3.0 Hz, 0.65H), 6.67 (d, 3J = 3.0 Hz, 0.35H), 6.97–7.01 (m, 1.00H). 13C{1H} NMR (101 MHz, CDCl3, 300 K): δ = 17.1 (q), 18.1 (q), 27.6 (t), 27.7 (t), 29.2 (d), 31.9 (d), 32.8 (t), 33.8 (d), 35.5 (t), 39.4 (d), 49.3 (d), 49.4 (d), 51.9 (q), 70.2 (t), 71.6 (t), 84.0 (s), 84.8 (s), 132.2 (s), 132.4 (s), 134.4 (d), 134.5 (d), 138.5 (d), 138.6 (d), 139.0 (d), 139.1 (d), 167.4 (s). IR (ATR): ṽ = 3046, 2951, 1711, 1633, 1244. MS (EI, 70 eV): m/z (%) = 234 (13), 208 (99), 175 (100), 149 (37). HRMS (EI): calcd for C14H18O3+ [M+] = 234.1250; found = 234.1249. ACS Paragon Plus Environment

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Methyl 2-methyl-2,3,4,4a,5,7a-hexahydrocyclobuta[i]chromene-6-carboxylate (17c) and Methyl 2-methyl-3,4,4a,7a-tetrahydro-2H-cyclobuta[g]chromene-5a(5H)-carboxylate (18) Following the general procedure for the photochemical reaction cascade compound 9c (23.4 mg) was transformed into a mixture of 17c and 18. Purification by flash chromatography (SiO2, pentane/EtOAc 10:1, UV) gave 17c as a colorless liquid (10.3 mg, 43.9 µmol, 44%) and 18 as a colorless liquid (4.2 mg, 17.9 µmol, 18%). Analytical data for 17c: TLC (pentane/EtOAc 10:1): Rf = 0.28 [UV, KMnO4]. 1H NMR (500 MHz, C6D6, 300 K): δ = 1.05 (d, 3J = 6.8 Hz, 3H), 1.13– 1.36 (m, 3H), 1.37–1.48 (m, 1H), 1.50–1.59 (m, 1H), 1.66–1.74 (m, 1H), 2.75 (dd, 2J = 16.3 Hz, 3

J = 3.7 Hz, 1H), 3.24 (d, 3J = 5.6 Hz, 1H), 3.44 (s, 3H), 4.05 (qdd, 3J = 6.8, 5.1, 3.9 Hz, 1H),

5.64 (dd, 3J = 2.9, 1.2 Hz, 1H), 6.07 (d, 3J = 2.9 Hz, 1H), 6.97 (dd, 3J = 5.6, 3.0 Hz, 1H). 13

C{1H} NMR (101 MHz, C6D6, 300 K): δ = 21.9 (q), 22.7 (t), 28.1 (t), 30.5 (t), 39.1 (d), 51.2

(d), 51.7 (q), 69.7 (d), 83.0 (s), 132.6 (s), 136.2 (d), 138.8 (d), 139.6 (d), 166.9 (s). IR (ATR): ṽ = 3046, 2932, 2860, 1713, 1633, 1252, 1103. MS (EI, 70 eV): m/z (%) = 234 (22), 208 (62), 175 (100). HRMS (EI): calcd for C14H18O3+ [M+] = 234.1250; found = 234.1226. Analytical data for 18: TLC (pentane/EtOAc 10:1): Rf = 0.51 [UV, KMnO4]. 1H NMR (500 MHz, C6D6, 300 K): δ = 1.04 (d, 3J = 6.4 Hz, 3H), 1.07–1.35 (m, 3H), 1.45–1.54 (m, 1H), 1.76 (dd, 2J = 13.2 Hz, 3

J = 11.9 Hz, 1H), 1.92 (dd, 2J = 13.2 Hz, 3J = 4.6 Hz, 1H), 1.95–2.05 (m, 1H), 3.36 (s, 3H), 3.67

(d, 3J = 6.2 Hz, 1H), 3.88 (virt. h, 3J ≅ 3J ≅ 3J = 6.1 Hz, 1H), 5.23 (dd, 3J = 6.2, 4J = 2.6 Hz, 1H), 5.87 (dd, 3J = 2.8, 1.0 Hz, 1H), 6.01 (d, 3J = 2.8 Hz, 1H). 13C{1H} NMR (126 MHz, C6D6, 300 K): δ = 20.3 (q), 23.6 (t), 28.8 (d), 29.2 (t), 36.8 (t), 45.9 (d), 51.5 (q), 55.1 (s), 70.6 (d), 100.8 (d), 134.7 (d), 140.0 (d), 155.4 (s), 174.8 (s). IR (ATR): ṽ = 3034, 2972, 2947, 1727, 1654, 1435, 1248, 1162, 790. MS (EI, 70 eV): m/z (%) = 234 (52), 175 (100). HRMS (EI): calcd for C14H18O3+ [M+] = 234.1250; found = 234.1247. ACS Paragon Plus Environment

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ACKNOWLEDGEMENT This work was supported by the Fonds der Chemischen Industrie and the TUM Graduate School.

SUPPORTING INFORMATION 1

H and 13C{1H} NMR spectra for all compounds, configuration assignment by NOESY studies,

UV/Vis spectra of compounds 1a, 1b, and 1e

REFERENCES 1

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Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, Wiley: New York, 1995.

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Org. Biomol. Chem. 2006, 4, 4409-4430. (b) Cornelisse, J. Chem. Rev. 1993, 93, 615-669. (c) Wender, P. A.; Siggel, L.; Nuss, J. M. Org. Photochem. 1989, 10, 357-473. 4

For reviews covering both the meta and the ortho photocycloaddition, see: (a) Remy, R.;

Bochet, C. G. Chem. Rev. 2016, 116, 9816-9849. (b) Hoffmann, N. Photochem. Photobiol. Sci. 2012, 11, 1613-1641. (c) Streit, U.; Bochet, C. G. Beilstein J. Org. Chem. 2011, 7, 525-542. (d) Streit, U.; Bochet, C. G. Chimia 2008, 62, 962-966. (e) Mattay, J. Angew. Chem. Int. Ed. Engl. 2007, 46, 663-665. (f) Hoffmann, N. Synthesis 2004, 481-495. 5

Selected examples: (a) Wender, P. A.; Howbert, J. J. Tetrahedron Lett. 1982, 23, 3983-3986.

(b) Wender, P. A.; von Geldern, T. W.; Levine, B. H. J. Am. Chem. Soc. 1988, 110, 4858-4860. (c) Baralotto, C.; Chanon, M.; Julliard, M. J. Org. Chem. 1996, 61, 3576-3577. (d) Wender, P. ACS Paragon Plus Environment

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A.; Dore, T. M. Tetrahedron Lett. 1998, 39, 8589-8592. (e) Gaich, T.; Mulzer, J. J. Am. Chem. Soc. 2009, 131, 452-453. (f) Gaich, T.; Mulzer, J. Org. Lett. 2010, 12, 272-275 and refs. cited therein. 6

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Byrne, P. W.; Penkett, C. S. Org. Lett. 1999, 1, 2073-2075. (c) Boyd, J. W.; Greaves, M.; Kettle, J.; Russell, A. T.; Steed, J. W. Angew. Chem. Int. Ed. 2005, 44, 944-946. (d) Wegmann, M.; Bach, T. J. Org. Chem. 2015, 80, 2017-2023. (e) Westphal, J.; Schumacher, C. E.; Schmalz, H.G. Synthesis 2017, 49, 218-224. 7

Reviews: (a) Kärkäs, M. D.; Porco, Jr., J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683-

9747. (b) Bach, T.; Hehn. J. P. Angew. Chem. Int. Ed. 2011, 50, 1000-1045. (c) Hoffmann, N. Chem. Rev. 2008, 108, 1052-1103. 8

For reviews exclusively on ortho photocycloaddition reactions, see: (a) Cornelisse, J., de Haan,

R. ortho-Photocycloaddition of Alkenes and Alkynes to the Benzene Ring in Molecular and Supramolecular Photochemistry, Vol. 8, Ramamurthy, V.; Schanze, K. S. Eds.; Dekker: New York, 2001; pp 1-126. (b) Wagner, P. J. Acc. Chem. Res. 2001, 34, 1-8. 9

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116, 10827-10828. (b) Nuss, J. M.; Chinn, J. P.; Murphy, M. M. J. Am. Chem. Soc. 1995, 117, 6801-6802. (c) Saeyens, W.; Busson, R.; Van der Eycken, J.; Herdewijn, P.; De Keukeleire, D. Chem. Commun. 1997, 817-818. (d) Hoffmann, N.; Pete, J.-P. J. Org. Chem. 1997, 62, 69526960. (e) Hoffmann, N.; Pete, J.-P. Tetrahedron Lett. 1998, 39, 5027-5030. (f) Hoffmann, N.; Pete, J.-P. Synthesis 2001, 1236-1242. 10

(a) Fort, D. A.; Woltering, T. J.; Nettekoven, M.; Knust, H.; Bach, T. Angew. Chem. Int. Ed.

2012, 51, 10169-10172. (b) Fort, D. A.; Woltering, T. J.; Alker, A. M.; Bach, T. J. Org. Chem. 2014, 79, 7152-7161 and refs. cited therein. ACS Paragon Plus Environment

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11

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Photochemical Reaction Cascade from O-Pent-4-enyl-Substituted

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