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Feb 22, 2017 - Yichao Zhao†, Jianwen Jin†, Joshua William Boyle†, Bo Ra Lee†, David Philip ... *E-mail: [email protected], p.w.h.chan@warwi...
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Silver Catalyzed 1,3-Acyloxy Migration/Diels-Alder Reaction of 1,9-Dien-4-yne Esters to Partially Hydrogenated Isoquinolines Yichao Zhao, Jianwen Jin, Joshua William Boyle, Bo Ra Lee, David P. Day, Dewi Susanti, Guy J Clarkson, and Philip Wai Hong Chan J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00048 • Publication Date (Web): 22 Feb 2017 Downloaded from http://pubs.acs.org on February 23, 2017

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Silver Catalyzed 1,3-Acyloxy Migration/Diels-Alder Reaction of 1,9-Dien-4-yne Esters to Partially Hydrogenated Isoquinolines Yichao Zhao,† Jianwen Jin,† Joshua William Boyle,† Bo Ra Lee,† David Philip Day,‡ Dewi Susanti,§ Guy James Clarkson,‡ and Philip Wai Hong Chan†,‡* ‡



§

School of Chemistry, Monash University, Clayton 3800, Victoria, Australia

Department of Chemistry, University of Warwick, Coventry, CV4 7AL, United Kingdom

Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore [email protected] and [email protected]

RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to)

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TOC O R1

O O

R2

R5 TsN

R3 R6

R4

AgSbF6 (5 mol %) JohnPhos (5 mol %) 4 Å MS, PhMe 80 °C, 2–72 h

R1

O

R2

TsN

R5 R6 R4 R3 20 examples 34–99 % yield

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Abstract A synthetic method to prepare partially hydrogenated isoquinolines efficiently from silvermediated [3,3]-sigmatropic rearrangement/Diels-Alder reaction of 1,9-dien-4-yne esters is described. The reactions were shown to be robust with a wide variety of substitution patterns tolerated to provide the corresponding nitrogen-containing heterocyclic products in good to excellent yields. This includes examples containing a bridgehead sp3 quaternary carbon center as well as the cycloisomerization of one substrate to give the corresponding bicyclic adduct in excellent yield at the gram–scale.

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Introduction The partially hydrogenated isoquinoline motif is found in a wide range of bioactive natural products and pharmaceutically interesting compounds such as the ircinal and manzamine family of compounds shown in Figure 1.1 The nitrogen–containing heterocycle also features in many functional materials and is a useful building block in organic synthesis.2 For this reason, the establishing of efficient catalytic methods for their synthesis with selective control of substitution patterns by using readily accessible starting materials continues to be actively pursued.3,4 Figure 1. Examples of the Ircinal and Manzamine Compound Family Containing a Partially Hydrogenated Isoquinoline Core

N H

HN H

N H

H

N H H

CHO OH

N OH

N N

manzamine A

OH

N

N HN

manzamine H

ircinal A

The first reported example of a propargyl ester to undergo 1,3-acyloxy migration to give the corresponding allenic ester was achieved with Ag2CO3 as the catalyst.5 Over one and half decades later, the [2,3]-sigmatropic rearrangement of this substrate class was shown to give cyclohex-2-en1-ones in the presence of a stoichiometric amount of ZnCl2.6 In the intervening years, these seminal works have acted as the inspiration for the development of an immense number of elegant methods that exploit these two modes of reactivity to access various synthetically useful products.7–9 For instance, we recently described an efficient and convenient synthetic route to 3a,6methanoisoindole esters involving gold(I)-catalyzed Rautenstrauch rearrangement and Diels-Alder

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reaction of 1,9-dien-4-yne esters (Scheme 1a).8b Building on this initial work, we posited that if this substrate class could be prevented from undergoing the putative Nazarov cyclization step of the rearrangement, a change in the chemoselective outcome of the reaction would ensue. This might be achieved by employing a silver(I) complex instead of a gold(I) salt as the catalyst by exploiting the significantly lower propensity of the second row element to coordinate to the π-bonds of alkenes, alkynes and allenes.10–15 In doing so, we discovered the substrate to follow a reactivity pathway that was initially triggered by an 1,3–acyloxy migration to give the corresponding allenic ester. Subsequent Diels–Alder reaction of the allene motif with the allyl amine group was then found to afford the partially hydrogenated isoquinoline product.4,15,17 Herein, we disclose the details of this rearrangement chemistry that offers a facile and chemoselective synthetic route to a new member of the partially hydrogenated N–heterocyclic family in good to excellent yields under mild conditions. Included in this are two examples containing an architecturally challenging sp3 quaternary carbon center at one of the bridgehead positions of the bicyclic adduct as well as the gram–scale synthesis of one analogue. To our knowledge, there are only a limited number of synthetic methods to prepare trihydroisoquinolines in which the π-bonds are embedded along the C4-C5-C6 positions of the N-heterocycle but no known examples from a readily accessible propargyl ester.18 Added to this, while the transition metal-catalyzed and thermally driven [m + n] cycloaddition of preformed or in situ formed allenenes have been extensively explored, the analogous reactions mediated by silver catalysis have received significantly less attention.19 Thus far, synthetic approaches that have exploited the use of silver-catalyzed [3,3]-sigmatropic rearrangement of propargyl esters to rapidly increase molecular complexity and access to a variety of synthetically valuable targets have been limited to only a handful of reported works.9,10

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Scheme 1. Exploring the Distinctive Reactivities of 1,9-Dien-4-yne Esters Mediated by Au(I) and Ag(I) Catalysis (a) previous work: R1 OCO R 2 R3

[Au] +

R6

ref 8b

R4

TsN R7

R2

R1 OCO [Au] TsN

R3 R6

R7

R5

[4+2] –[Au]+

R4 R6

R1 OCO N Ts

R4 R5 I

1

R 3R 5

R2

R7

2

(b) this work: 2

R1 OCO R 2 [Ag] + R5 TsN

R3 R6

R4

1

[Ag] + R 1 R OCO • [4+2] 5 R –[Ag]+ TsN R3 R6

R4

II

R1 OCO

R2

TsN

R5 R6 R4 R3 3

Results and Discussion Our studies commenced by examining the Ag(I)–catalyzed cycloisomerizations of 1,9-dien-4yne acetate 1a to establish the reaction conditions and the results are outlined in Table 1. This initially revealed treatment of the substrate with 5 mol % of AgOTf and 4 Å molecular sieves (MS) in toluene at 80 °C for 17 h gave the trihydroisoquinoline 3a in 60% yield (entry 1). The structure of the nitrogen–containing bicyclic adduct was determined by NMR measurements and X–ray crystallographic analysis of two closely related products vide infra.20 Comparable product yields of 52–68% were obtained on repeating the reaction with AgNTf2, AgNO3, AgBF4, AgPF6 or AgSbF6 in place of AgOTf as the catalyst (entries 2–6). At 70 °C, the analogous control experiment mediated by 5 mol % of AgSbF6 and 5 mol % of PPh3 gave a product yield of 80% (entry 7). At this latter reaction temperature, control reactions with 5 mol % of AgSbF6 and 5 mol % of tBuXPhos

(tBuXPhos

=

di–tert–butyl(2',4',6'–triisopropyl–[1,1'–biphenyl]–2–yl)phosphine),

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CyJohnPhos (CyJohnPhos = (1,1'–biphenyl–2–yl)–dicyclohexylphosphine) or JohnPhos (JohnPhos = (1,1'–biphenyl–2–yl)–di–tert–butylphosphine) gave product yields of 65–94% (entries 8–10).16 Our investigations subsequently found the use of 5 mol % of AgSbF6 and 5 mol % of JohnPhos as the catalyst system at 80 °C gave the best result, furnishing a product yield of 94% after a reaction time of 2 h (entry 11). However, changing the solvent of this latter catalytic system from toluene to 1,2–dichloroethane or dichloromethane at respective temperatures of 80 and 35 °C was observed to lead to lower product yields of 87 and 50% (entries 12 and 13).

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Table 1. Optimization of Reaction Conditionsa AcO Me

OAc Me

[Ag] + (5 mol %) 4 Å MS, see Table

TsN

TsN

1a

entry

3a

catalyst

solvent

T (°C)

t (h)

yield (%)

1

AgOTf

toluene

80

17

60

2

AgNTf2

toluene

80

17

52

3

AgNO3

toluene

80

17

57

4

AgBF4

toluene

80

17

68

5

AgPF6

toluene

80

17

68

6

AgSbF6

toluene

80

17

57

7

AgSbF6/PPh3

toluene

70

17

80

8

AgSbF6/tBuXPhos

toluene

70

17

65

9

AgSbF6/CyJohnPhos

toluene

70

17

94

10

AgSbF6/JohnPhos

toluene

70

17

94

11

AgSbF6/JohnPhos

toluene

80

2

94

12

AgSbF6/JohnPhos

(CH2Cl)2

80

2

87

13

AgSbF6/JohnPhos

CH2Cl2

35

24

50

a

All experiments were conducted at the 0.3 mmol scale with 5 mol % of catalyst and 4 Å

MS (100 mg) in the solvent (3 mL), reaction temperature and time stated in the Table.

To define the generality of the methodology, we next turned our attention to the cycloisomerizations of a series of 1,9-dien-4-yne esters. As illustrated in Table 2, these experiments

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demonstrated the Ag(I)–catalyzed reaction conditions to be broad, with a variety of substituted trihydroisoquinolines 3b–t afforded in 34–99% yield. Starting esters in which the methyl group on the ester carbon center was replaced by other alkyl groups (1b,c) or cycloalkyl substituents (1d,e) were found to proceed well, producing the corresponding bicyclic adducts 3b–e in 77–99% yield with the structure of 3c confirmed by X–ray single crystal analysis.20 Reactions of substrates with a pendant methyl (1f) or cyclopentyl (1g) substituent at the proximal carbon center of the allylic amine moiety were found to afford 3f and 3g in 98 and 48% yield, respectively. Likewise, substrates containing an alkyl (1h,i), benzyl methyl ether (1j), aryl (1k–n) or thiophenyl (1o) group at the distal carbon center of the allylic amine motif gave 3h–o in 60–99% yield with the structure and relative cis-stereochemistry of 3n being established by X–ray crystallography.20 The presence of a trisubstituted allylic amine moiety, as in 1p and 1q, in the starting ester was also found to give the corresponding fused– and spiro–tricyclic adducts 3p and 3q in respective yields of 60 and 80%; in the former experiment, the allenic ester 4p was also obtained in 21% yield. However, the nature of the migrating group on the cycloisomerization of 1,9-dien-4-yne esters with an OPMB (1r), OBz (1s), or OPNB (1t) in place of an OAc moiety were found to have an influence on the outcome of the reaction. In these experiments, the product yields of 3r–t was found to decrease from 94 to 70 to 34% as the carboxylic ester changed from an electron–donating to an electron–neutral to an electron–withdrawing group. On the other hand, in all the above examples, no other products arising from further rearrangement of the penta–1,2,4–triene motif of the posited allenic ester intermediate were observed based on TLC analysis and 1H NMR spectroscopic measurements of the crude reaction mixtures. This was further corroborated by the gram–scale cycloisomerization of 1a (1.08 g) with 5 mol % of AgSbF6 and 5 mol % of JohnPhos under the present protocol giving 3a as the only product in 94% yield (1.02 g).

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Table 2. Cycloisomerization of 1b–t Catalyzed by AgSbF6/JohnPhosa O

O

R1

O

R2

AgSbF6 (5 mol %) R1 JohnPhos (5 mol %)

R5 TsN

R3

4 Å MS, PhMe 80 °C, 2–72 h

R2

O O

R2

O

R5 R 6 R 4R 3

R6

R4

4

3

OAc

R3

TsN

TsN

R6 R4 1 OAc R 2

• R5

1 +R

OAc Et

( )n TsN

TsN

TsN d, n = 1 (84%) e, n = 2 (77%) OAc Me

b, R 2 = Et (99%) c, R 2 = Bn (97%)

R5 f, R 5 = Me (98%) g, R 5 = c(C 5H 9) (48%) OAc Me

OAc Et TsN TsN

H

TsN

H

H S

R3

h, R 3 = Me (99%) i, R 3 = Et (93%) j, R 3 = CH2OBn (99%) k, R 3 = pCF 3(C 6H 4) (80%) l, R 3 = Ph (87%) m, R 3 = oMe(C 6H 4) (97%) OAc Et

Me n, (71%)

o, (60%)

O

OAc Et

O TsN

TsN

H p, (60%) b

a

Et

R7 TsN

q, (80%)

r, R 7 = OMe (94%) s, R 7 = H (70%) t, R 7 = NO 2 (34%)

All experiments were conducted at the 0.3 mmol scale with 5 mol % of AgSbF6 and 5 mol % of

JohnPhos, 4 Å MS (100 mg) in toluene (3 mL) at 80 °C for 2–72 h. Values in parentheses denote

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product yields. bAllenic acetate 4p also obtained in 21% yield.

While the isolation of 4p furnished from the reaction of 1p catalyzed by AgSbF6 and JohnPhos outlined in Table 2 was not foreseen, the result argues in favor of the possible involvement of the allene intermediate put forward in Scheme 1. This argument was further supported with the allenic acetate being obtained as the only product in 50% yield when the reaction of 1p in the presence of 5 mol % of AgSbF6 and 5 mol % of JohnPhos at 50 °C under the conditions described in Scheme 2 was examined. Further treatment of 4p to the same silver-catalyzed reaction conditions at 80 °C was then found to give the expected trihydroisoquinoline product 3p in 48% yield. The role of the silver(I) complex in assisting the [4+2]–cycloaddition step could also be shown by repeating the reaction of 4p in the absence of the metal catalyst, which gave the Diels-Alder reaction product in a lower yield of 29%. Scheme 2. Control Experiments with 1p and 4p. (a) 1H NMR Yield with CH2Br2 as the Internal Standard AcO Et

Et AgSbF6 (5 mol %) JohnPhos (5 mol %) 4 Å MS, PhMe 50 °C, 48 h

TsN

1p

AcO



TsN

TsN

4p, 50% yield

OAc Et

4 Å MS, PhMe 80 °C, 48 h

H 3p 29% yielda + AgSbF6 /JohnPhos (5 mol %): 48% yielda

A tentative mechanism for the present silver(I)-catalyzed [3,3]-sigmatropic rearrangement/DielsAlder reaction is illustrated in Scheme 3. With 1,9-dien-4-yne acetate 1a as representative example, this could involve activation of the alkyne bond in the substrate by coordination of the metal catalyst to give the organosilver complex IIIa. As a consequence, this might lead to syn-1,3migration of the acyloxy group in the metal–activated adduct to give the silver-coordinated allenic

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ester IIa via the 1,3–dioxin–1–ium species IVa.9,10 The observed decrease in product yields from 94 to 34% on going from 1r to 1t would be consistent with the nucleophilicity and thus ability of the ester functional group to undergo this 1,3-migration step decreases. At this juncture, there is the possibility of two competitive pathways in which both the thermal and silver(I)–assisted Diels– Alder reaction are in operation. In both instances, the cycloaddition of the penta–1,2,4–triene motif with the allylic amine group in the Ag(I)–activated species IIa or 1,3,4,9–tetraen–5–yl ester 4a, furnished on demetalation of the former, would provide the trihydroisoquinoline product 3a.15,17 Scheme 3. Tentative Mechanism for the Ag(I)-Mediated Rearrangement of 1,9-Dien-4-yne Esters Represented by 1a Me

Me

AcO Me [Ag] +

O

TsN

OAc Me

R2 AcO

[Ag] + AcO



R2 •

–[Ag]+ TsN

3a

[Ag] IVa

[4+2]

TsN

TsN

IIIa

[Ag] + /Δ

Me

O

[Ag] +

TsN 1a

O

O Me

TsN 4a

IIa

Conclusion In summary, we have elucidated an efficient Ag(I)-catalyzed cycloisomerization/Diels-Alder reaction process for the construction of partially hydrogenated isoquinoline derivatives from 1,9dien-4-yne esters. The reaction was shown not only to be applicable to a variety of substrates but also provided a convenient and efficient strategy to introduce a bridgehead sp3 quaternary carbon center onto the N-heterocycle that would have been challenging by conventional synthetic methods.

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The potential utility of the transformation was further demonstrated by the gram–scale synthesis of one analogue in excellent yield. Our studies revealed that the silver(I) complex was not only involved in mediating the [3,3]-sigmatropic rearrangement of the substrate but may also assist in promoting the subsequent product forming Diels-Alder reaction step. Efforts to explore the scope and synthetic applications of the present reactions are in progress and will be reported in due course. Experimental Section General Considerations. Unless specified, all reagents and starting materials were purchased from commercial sources and used as received. The 1,6-enyne precursor to substrate 1 was prepared following literature procedures.21 Solvents were purified following standard literature procedures. Analytical thin layer chromatography (TLC) was performed using pre-coated silica gel plates and visualization was achieved by UV light (254 nm). Flash chromatography was performed using silica gel and a gradient solvent system. 1H and 13C spectra were measured on 400 and 600 MHz spectrometers. Chemical shifts (ppm) were recorded with respect to TMS in CDCl3. Multiplicities are given as: s (singlet), brs (broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), ddd (doublet of doublets of doublets), or dt (doublet of triplets). The number of protons (n) for a given resonance is indicated by nH. Coupling constants are reported as a J value in Hz. Infrared spectra were recorded on a IR spectrometer. High resolution mass spectra (ESI) were obtained using a LC/HRMS TOF spectrometer fitted with an analytical electrospray source using NaI for accurate mass calibration. Mass spectral data are reported in units of mass to charge (m/z). General Experimental Procedure for the Synthesis of 1,9-Dien-4-yne Ester 1a, 1b and 1f–t. To a stirred solution of the appropriate 1,6-enyne (5 mmol) in 20 mL of THF at –78 °C was slowly added n-butyllithium (2.0 M in cyclohexane solution, 3.75 mL, 7.5 mmol). The resulting solution was stirred for 45 min and the corresponding vinyl ketone (1.5 equiv) was subsequently added in

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dropwise manner at –78 °C. After 3 h, the reaction mixture was quenched with saturated NH4Cl (15 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, concentrated under reduced pressure and purified by flash column chromatography on silica gel (eluent: n-hexane/EtOAc = 6:1) to give the enynyl alcohol which, without characterization, was directly employed to the next step. To a solution of the enynyl alcohol (1.5 mmol) in CH2Cl2 (10 mL) at 0 °C was added 4-(dimethylamino)pyridine (0.3 mmol, 37 mg), benzoyl chloride (3 mmol, 0.35 mL) or acetic anhydride (3 mmol, 0.28 mL) and triethylamine (6 mmol, 0.83 mL). The resulting solution was allowed to stir for 17 h at room temperature. Upon completion, the reaction mixture was quenched with saturated NaHCO3 solution (10 mL) and extracted with CH2Cl2 (2 x15 mL). The combined organic layer was washed with brine (10 mL), dried over MgSO4, concentrated under reduced pressure and purified by flash column chromatography on silica gel (eluent: n-hexane/EtOAc = 9:1) to give the desired substrate 1 in 50–78% yield. General Experimental Procedure for the Synthesis of 1,9-Dien-4-yne Ester 1c–e. To a stirred solution of the appropriate 1,6-enyne (5 mmol) in 20 mL of THF at –78 °C was slowly added nbutyllithium (2.0 M in cyclohexane solution, 3.75 mL, 7.5 mmol). The resulting solution was stirred for 45 min and the corresponding aldehyde (1.5 equiv) was subsequently added in dropwise manner at –78 °C. After 3 h, the reaction mixture was quenched with saturated NH4Cl (15 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, concentrated under reduced pressure and purified by flash column chromatography on silica gel (eluent: n-hexane/EtOAc = 6:1) to give the enynyl alcohol which, without characterization, was directly employed to the next step. To a stirred solution of the enynyl alcohol (3 mmol) in DMSO (20 mL) was added IBX (2.5 equiv) portionwise and the reaction mixture was stirred for 3 h at room temperature. Subsequently, water (10 mL) and EtOAc (10 mL)

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were added and the resulting solution was stirred for 15 min. After filtration through a pad of Celite, the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), brine (10 mL), dried over MgSO4 and concentrated under reduced pressure. The crude mixture was used directly without further purification. To a stirred solution containing the crude mixture was added vinylmagnesium chloride (1.6 M in THF, 5.6 mL, 9 mmol) and the reaction mixture was stirred for 1 h. Upon completion, the reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, concentrated under reduced pressure and purified by flash column chromatography on silica gel (eluent: n-hexane/EtOAc = 7:1) to give the 1,9-dien-4-yne alcohol in 50-60% yield which, without characterization, was directly employed to the next step. To a solution of the 1,9-dien-4-yne alcohol (1.5 mmol) in CH2Cl2 (10 mL) at 0 °C was added 4-(dimethylamino)pyridine (0.3 mmol, 37 mg), acetic anhydride (3 mmol, 0.28 mL) and triethylamine (6 mmol, 0.83 mL). The resulting solution was allowed to stir for 17 h at room temperature. Upon completion, the reaction mixture was quenched with saturated NaHCO3 solution (10 mL) and extracted with CH2Cl2 (2 x 15 mL). The combined organic layer was washed with brine (10 mL), dried over MgSO4, concentrated under reduced pressure and purified by flash column chromatography on silica gel (eluent: n-hexane/EtOAc = 9:1) to give the desired substrate 1 in 54-80% yield. 6-((N-Allyl-4-methylphenyl)sulfonamido)-3-methylhex-1-en-4-yn-3-yl Acetate (1a).8b White solid; (980 mg, 71% yield); 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 5.75 (ddd, J = 16.9, 12.3, 10.3 Hz, 2H), 5.38–5.28 (m, 1H), 5.28–5.17 (m, 2H), 5.09 (d, J = 10.4 Hz, 1H), 4.19 (s, 2H), 3.85 (d, J = 6.5 Hz, 2H), 2.41 (s, 3H), 1.97 (s, 3H), 1.43 (s, 3H); 13

C{1H}NMR (100 MHz, CDCl3) δ 168.6, 143.3, 138.3, 136.2, 131.9, 129.6, 127.7, 120.1, 115.2,

84.3, 79.4, 73.7, 48.9, 36.1, 28.0, 21.7, 21.5.

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6-((N-Allyl-4-methylphenyl)sulfonamido)-3-ethylhex-1-en-4-yn-3-yl Acetate (1b). Colorless oil; (510 mg, 71% yield); 1H NMR (400 MHz, CDCl3) δ 7.70–7.63 (m, 2H), 7.26–7.19 (m, 2H), 5.63 (ddd, J = 33.2, 17.1, 10.3 Hz, 2H), 5.26 (dq, J = 17.1, 1.5 Hz, 1H), 5.22–5.03 (m, 3H), 4.14 (s, 2H), 3.79 (dt, J = 6.6, 1.3 Hz, 2H), 2.33 (s, 3H), 1.89 (s, 3H), 1.73–1.62 (m, 1H), 1.54 (dd, J = 13.5, 7.4 Hz, 1H), 0.72 (t, J = 7.4 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 168.4, 143.3, 137.1, 136.2, 131.9, 129.6, 127.5, 120.0, 116.2, 80.3, 77.7, 48.8, 36.0, 33.6, 21.5, 21.4, 8.0; IR (neat, cm-1): 3085, 2931, 1736, 1346, 1232, 1158, 1090, 1016, 814, 758; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C20H25NO4SNa 398.1402; Found 398.1396. 6-((N-Allyl-4-methylphenyl)sulfonamido)-3-benzylhex-1-en-4-yn-3-yl Acetate (1c).8b Colorless oil; (191mg, 72% yield); 1H NMR (400 MHz, CDCl3) δ 7.64–7.58 (m, 2H), 7.18 (ddd, J = 5.7, 3.6, 2.4 Hz, 3H), 7.15–7.09 (m, 2H), 7.03 (dd, J = 7.2, 2.4 Hz, 2H), 5.59 (ddd, J = 17.2, 10.3, 8.2 Hz, 2H), 5.19–5.07 (m, 2H), 5.07–4.98 (m, 2H), 4.11 (d, J = 1.4 Hz, 2H), 3.69 (ddt, J = 6.7, 4.4, 1.3 Hz, 2H), 2.93–2.81 (m, 2H), 2.28 (s, 3H), 1.86 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 143.3, 137.0, 134.7, 131.9, 131.0, 129.7, 127.8, 127.7, 127.1, 120.1, 116.6, 81.7, 77.0, 48.8, 46.7, 36.1, 21.7, 21.5. 6-((N-Allyl-4-methylphenyl)sulfonamido)-3-cyclopentylhex-1-en-4-yn-3-yl

Acetate

(1d).8b

Colorless oil; (610 mg, 82% yield); 1H NMR (400 MHz, CDCl3) δ 7.71–7.59 (m, 2H), 7.21 (dd, J = 8.7, 1.0 Hz, 2H), 5.72–5.54 (m, 2H), 5.25 (dq, J = 17.1, 1.4 Hz, 1H), 5.16 (dq, J = 10.1, 1.2 Hz, 1H), 5.13–5.00 (m, 2H), 4.15 (d, J = 1.2 Hz, 2H), 3.80 (ddt, J = 6.7, 2.4, 1.3 Hz, 2H), 2.33 (s, 3H), 2.15–2.03 (m, 1H), 1.88 (s, 3H), 1.62–1.35 (m, 6H), 1.34–1.21 (m, 1H), 1.21–1.06 (m, 1H); 13

C{1H}NMR (100 MHz, CDCl3) δ 143.3, 137.0, 131.9, 129.7, 127.5, 120.0, 116.4, 80.6, 80.4,

48.8, 48.7, 36.0, 27.6, 25.8, 25.6, 21.6, 21.5. 6-((N-Allyl-4-methylphenyl)sulfonamido)-3-cyclohexylhex-1-en-4-yn-3-yl

Acetate

(1e).8b

Colorless oil; (422 mg, 83% yield); 1H NMR (400 MHz, CDCl3) δ 7.71–7.63 (m, 2H), 7.25–7.19

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The Journal of Organic Chemistry

(m, 2H), 5.68 (ddt, J = 16.7, 10.0, 6.5 Hz, 1H), 5.54 (dd, J = 16.9, 10.8 Hz, 1H), 5.32–5.23 (m, 1H), 5.17 (dd, J = 10.1, 1.4 Hz, 1H), 5.13–5.04 (m, 2H), 4.18 (s, 2H), 3.82 (dt, J = 6.5, 1.3 Hz, 2H), 2.34 (s, 3H), 1.89 (s, 3H), 1.78–1.62 (m, 3H), 1.62–1.44 (m, 3H), 1.24–0.71 (m, 5H); 13C{1H}NMR (100 MHz, CDCl3) δ 168.3, 143.2, 136.4, 136.3, 132.0, 129.6, 127.5, 120.0, 117.0, 82.4, 81.0, 80.7, 48.7, 46.6, 36.0, 27.1, 26.8, 26.2, 26.0, 25.9, 21.6, 21.5. 3-Ethyl-6-((4-methyl-N-(2-methylallyl)phenyl)sulfonamido)hex-1-en-4-yn-3-yl

Acetate

(1f).

Colorless oil; (372 mg, 61% yield); 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.4 Hz, 2H), 7.28– 7.22 (m, 2H), 5.60 (dd, J = 17.1, 10.4 Hz, 1H), 5.20–5.04 (m, 2H), 5.04–4.90 (m, 2H), 4.15 (s, 2H), 3.75 (s, 2H), 2.37 (s, 3H), 1.93 (s, 3H), 1.74 (t, J = 1.2 Hz, 3H), 1.73–1.61 (m, 1H), 1.55 (dq, J = 13.4, 7.4 Hz, 1H), 0.73 (t, J = 7.4 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 143.2, 139.0, 137.1, 136.4, 129.6, 127.6, 116.2, 115.6, 83.2, 80.2, 77.8, 52.2, 35.7, 33.6, 21.5, 21.4, 19.6, 8.1; IR (neat, cm-1): 2980, 2307, 1739, 1644, 1596, 1348, 1153, 1066; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C21H27NO4SNa 412.1558; Found 412.1553. 6-((N-(2-Cyclopentylallyl)-4-methylphenyl)sulfonamido)-3-ethylhex-1-en-4-yn-3-yl Acetate (1g). Colorless oil; (157 mg, 68% yield); 1H NMR (400 MHz, CDCl3) δ 7.76–7.71 (m, 2H), 7.31–7.24 (m, 2H), 5.62 (dd, J = 17.1, 10.4 Hz, 1H), 5.20–5.07 (m, 2H), 5.02 (dt, J = 12.9, 1.3 Hz, 2H), 4.18 (s, 2H), 3.83 (s, 2H), 2.46 (ddd, J = 17.0, 9.3, 7.2 Hz, 1H), 2.39 (s, 3H), 1.95 (s, 3H), 1.93–1.84 (m, 1H), 1.77–1.63 (m, 3H), 1.63–1.49 (m, 3H), 1.37 (tdd, J = 8.2, 3.4, 1.9 Hz, 1H), 0.74 (t, J = 7.4 Hz, 3H);

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C{1H}NMR (100 MHz, CDCl3) δ 146.3, 143.2, 137.2, 136.3, 129.6, 127.6, 116.3, 112.4,

80.3, 77.8, 51.1, 42.8, 35.7, 33.6, 31.45, 31.42, 24.8, 21.6, 21.5, 8.1; IR (neat, cm-1): 3373, 2942, 1743, 1349, 1232, 1160, 1094, 1013, 768; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C25H33NO4SNa 466.2028; Found 466.2023. 6-((N-(But-2-en-1-yl)-4-methylphenyl)sulfonamido)-3-ethylhex-1-en-4-yn-3-yl

Acetate

(1h).8b

Colorless oil; (371 mg, 70% yield); 1H NMR (400 MHz, CDCl3) δ 7.69–7.63 (m, 2H), 7.25–7.18

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(m, 2H), 5.76–5.54 (m, 2H), 5.31 (dtd, J = 15.3, 6.9, 1.7 Hz, 1H), 5.20–4.96 (m, 2H), 4.14 (s, 2H), 3.72 (dq, J = 6.8, 1.1 Hz, 2H), 2.34 (s, 3H), 1.90 (s, 3H), 1.74–1.64 (m, 1H), 1.62 (dq, J = 6.6, 1.2 Hz, 3H), 1.58–1.49 (m, 1H), 0.72 (t, J = 7.4 Hz, 3H);

13

C{1H}NMR (100 MHz, CDCl3) δ 168.4,

143.2, 137.2, 136.4, 131.6, 129.6, 127.6, 124.5, 116.2, 80.6, 77.8, 48.2, 35.8, 33.6, 21.5, 21.4, 17.7, 8.1; IR (neat, cm-1): 3022, 2401, 1744, 1670, 1597, 1354, 1163, 1016; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C21H28NO4S 390.1739; Found 390.1732. 3-Ethyl-6-((4-methyl-N-(pent-2-en-1-yl)phenyl)sulfonamido)hex-1-en-4-yn-3-yl

Acetate

(1i).

Colorless oil; (273 mg, 57% yield); 1H NMR (400 MHz, CDCl3) δ 7.73–7.59 (m, 2H), 7.28–7.15 (m, 2H), 5.79–5.66 (m, 1H), 5.58 (dd, J = 17.1, 10.4 Hz, 1H), 5.33–5.19 (m, 1H), 5.19–5.01 (m, 2H), 4.13 (s, 2H), 3.72 (dd, J = 6.9, 1.2 Hz, 2H), 2.33 (s, 3H), 2.01–1.91 (m, 2H), 1.89 (s, 3H), 1.68 (dq, J = 13.4, 7.2 Hz, 1H), 1.58–1.47 (m, 1H), 0.88 (t, J = 7.5 Hz, 3H), 0.71 (t, J = 7.4 Hz, 3H); 13

C{1H}NMR (100 MHz, CDCl3) δ 143.2, 138.6, 137.2, 129.6, 127.6, 122.2, 116.3, 82.8, 80.6,

77.9, 48.2, 35.8, 33.6, 25.2, 21.6, 21.5, 13.3, 8.1; IR (neat, cm-1): 2971, 1719, 1340, 1233, 1157, 1090, 1107, 814; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C22H29NO4SNa 426.1715; Found 426.1711. 6-((N-(4-(Benzyloxy)but-2-en-1-yl)-4-methylphenyl)sulfonamido)-3-ethylhex-1-en-4-yn-3-yl Acetate (1j).8b Colorless oil; (330 mg, 64% yield); 1H NMR (400 MHz, CDCl3) δ 7.67–7.59 (m, 2H), 7.23 (d, J = 4.0 Hz, 4H), 7.20–7.13 (m, 3H), 5.74 (m, 1H), 5.62–5.38 (m, 2H), 5.19–4.95 (m, 2H), 4.40 (s, 2H), 4.12 (d, J = 1.2 Hz, 2H), 4.06 (dd, J = 6.4, 1.6 Hz, 2H), 3.89–3.80 (m, 2H), 2.30 (s, 3H), 1.84 (s, 3H), 1.73–1.60 (m, 1H), 1.58–1.45 (m, 1H), 0.68 (t, J = 7.4 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 168.4, 143.4, 138.2, 137.2, 136.3, 132.1, 129.7, 129.7, 128.4, 127.7, 127.6, 126.5, 116.3, 80.6, 77.7, 72.3, 65.6, 43.3, 36.2, 33.6, 21.6, 21.5, 8.2. 3-Ethyl-6-((4-methyl-N-(3-(4-(trifluoromethyl)phenyl)allyl)phenyl)sulfonamido) hex-1-en-4-yn-3yl Acetate (1k). White solid; (283mg, 75% yield); m.p. 108–110 °C; 1H NMR (400 MHz, CDCl3) δ

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The Journal of Organic Chemistry

7.78–7.71 (m, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.32–7.26 (m, 2H), 6.70 (d, J = 15.8 Hz, 1H), 6.20 (dt, J = 15.8, 6.7 Hz, 1H), 5.64 (dd, J = 17.2, 10.4 Hz, 1H), 5.18–5.08 (m, 2H), 4.24 (d, J = 1.2 Hz, 2H), 4.09–4.02 (m, 2H), 2.40 (s, 3H), 1.96 (s, 3H), 1.82–1.69 (m, 1H), 1.67–1.56 (m, 1H), 0.80 (t, J = 7.4 Hz, 3H);

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C{1H}NMR (100 MHz, CDCl3) δ 143.5, 139.8,

137.2, 136.2, 133.5, 129.7, 127.7, 126.8, 125.9, 125.5 (q, 1C, JC-F = 3.9 Hz), 116.3, 83.4, 80.3, 77.8, 48.3, 36.5, 33.7, 21.6, 21.4, 8.1; IR (neat, cm-1): 3067, 2982, 1748, 1325, 1109, 1065, 867; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C27H28F3NO4SNa 542.1588; Found 542.1583. 3-Ethyl-6-((4-methyl-N-(3-phenylallyl)phenyl)sulfonamido)hex-1-en-4-yn-3-yl

Acetate

(1l).

White solid; (354 mg, 65% yield); m.p. 82–84 °C; 1H NMR (400 MHz, CDCl3) δ 7.70–7.60 (m, 2H), 7.25–7.21 (m, 2H), 7.21–7.14 (m, 4H), 7.14–7.09 (m, 1H), 6.56 (d, J = 15.9 Hz, 1H), 5.98 (dt, J = 15.8, 6.9 Hz, 1H), 5.55 (dd, J = 17.2, 10.4 Hz, 1H), 5.16–4.98 (m, 2H), 4.14 (s, 2H), 3.93 (dd, J = 6.9, 1.3 Hz, 2H), 2.29 (s, 3H), 1.86 (s, 3H), 1.72–1.59 (m, 1H), 1.59–1.47 (m, 1H), 0.70 (t, J = 7.4 Hz, 3H);

13

C{1H}NMR (100 MHz, CDCl3) δ 143.4, 137.2, 136.3, 135.2, 129.7, 128.6, 128.0,

127.7, 126.6, 122.8, 116.4, 80.4, 77.8, 48.5, 36.3, 33.7, 21.7, 21.5, 8.2; IR (neat, cm-1): 3022, 2978, 1732, 1340, 1243, 1120, 978, 733, 667; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C26H29NO4SNa 474.1715; Found 474.1710. 3-Ethyl-6-((4-methyl-N-(3-(o-tolyl)allyl)phenyl)sulfonamido)hex-1-en-4-yn-3-yl

Acetate

(1m).

White solid; (167 mg, 62% yield); m.p. 82–83 °C; 1H NMR (400 MHz, CDCl3) δ 7.82–7.73 (m, 2H), 7.41–7.34 (m, 1H), 7.34–7.27 (m, 2H), 7.20–7.08 (m, 3H), 6.93–6.82 (m, 1H), 6.02–5.92 (m, 1H), 5.67 (dd, J = 17.2, 10.4 Hz, 1H), 5.24–5.10 (m, 2H), 4.27 (s, 2H), 4.06 (dd, J = 7.0, 1.3 Hz, 2H), 2.42 (s, 3H), 2.32 (s, 3H), 1.96 (s, 3H), 1.78 (dd, J = 13.5, 7.4 Hz, 1H), 1.64 (dd, J = 13.6, 7.4 Hz, 1H), 0.82 (t, J = 7.4 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 168.5, 143.4, 137.2, 136.4, 135.5, 135.4, 133.2, 130.3, 129.7, 127.9, 127.7, 126.1, 125.9, 124.2, 116.4, 83.3, 80.4, 77.8, 48.6,

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36.1, 33.7, 21.6, 21.5, 19.7, 8.2; IR (neat, cm-1): 3022, 2978, 1732, 1340, 1243, 1156, 733, 667; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C27H31NO4SNa 488.1871; Found 488.1866. 3-Methyl-6-((4-methyl-N-(3-(p-tolyl)allyl)phenyl)sulfonamido)hex-1-en-4-yn-3-yl Acetate (1n).8b White solid; (398 mg, 66% yield); 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.12 Hz. 2H), 7.23 (d, J = 8.04 Hz, 2H), 7.12 (d, J = 7.92 Hz, 2H), 6.62 (d, J = 15.8 Hz, 1H), 6.03 (dt, J = 15.8, 6.9 Hz, 1H), 5.79 (dd, J = 17.1, 10.4 Hz, 1H), 5.24 (dd, J = 17.1, 0.8 Hz, 1H), 5.10 (dd, J = 10.3, 0.8 Hz, 1H), 4.22 (s, 2H), 4.00 (dd, J = 7.0, 1.3 Hz, 2H), 2.41 (s, 3H), 2.33 (s, 3H), 1.98 (s, 3H), 1.45 (s, 3H);

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C{1H}NMR (100 MHz, CDCl3) δ 168.6, 143.4, 138.4, 137.9,

136.2, 135.1, 133.5, 129.6, 129.3, 127.8, 126.5, 121.7, 115.3, 84.4, 79.5, 77.4, 73.8, 48.6, 36.2, 28.0, 21.7, 21.5, 21.2. 3-Methyl-6-((4-methyl-N-(3-(thiophen-2-yl)allyl)phenyl)sulfonamido)hex-1-en-4-yn-3-yl Acetate (1o).8b Yellow solid; (515 mg, 67% yield); 1H NMR (400 MHz, CDCl3) δ 7.77–7.71 (m, 2H), 7.32– 7.22 (m, 2H), 7.18–7.12 (m, 1H), 6.97–6.89 (m, 2H), 6.78 (dt, J = 15.6, 1.2 Hz, 1H), 5.88 (dt, J = 15.5, 6.9 Hz, 1H), 5.77 (dd, J = 17.1, 10.4 Hz, 1H), 5.21 (dd, J = 17.1, 0.7 Hz, 1H), 5.09 (dd, J = 10.4, 0.7 Hz, 1H), 4.21 (s, 2H), 3.97 (dd, J = 6.9, 1.3 Hz, 2H), 2.40 (s, 3H), 1.97 (s, 3H), 1.44 (s, 3H);

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C{1H}NMR (100 MHz, CDCl3) δ 168.6, 143.4, 141.3, 138.3, 136.1, 129.7, 128.3, 127.7,

127.7, 127.4, 126.2, 124.8, 122.2, 115.3, 84.5, 79.4, 73.8, 48.3, 36.3, 28.0, 21.7, 21.5. 6-((N-(Cyclohex-2-en-1-yl)-4-methylphenyl)sulfonamido)-3-ethylhex-1-en-4-yn-3-yl Acetate (1p). Colorless oil; (421 mg, 71% yield); 1H NMR (400 MHz, CDCl3) δ 7.76–7.70 (m, 2H), 7.22–7.17 (m, 2H), 5.82–5.74 (m, 1H), 5.69 (ddd, J = 17.1, 10.4, 1.2 Hz, 1H), 5.37–5.24 (m, 2H), 5.11 (dt, J = 10.4, 1.4 Hz, 1H), 4.42–4.33 (m, 1H), 4.17 (dd, J = 18.4, 1.3 Hz, 1H), 3.98 (dd, J = 18.5, 1.1 Hz, 1H), 2.32 (s, 3H), 1.91 (s, 3H), 1.90–1.77 (m, 3H), 1.77–1.59 (m, 4H), 1.55–1.38 (m, 1H), 0.81 (td, J = 7.4, 1.3 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 168.4, 143.0, 138.2, 137.4, 132.9, 129.5, 127.3, 127.2, 116.4, 80.8, 78.2, 78.1, 54.8, 54.8, 33.7, 33.7, 32.8, 27.8, 24.3, 21.6, 21.6, 21.4, 8.1;

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The Journal of Organic Chemistry

IR (neat, cm-1): 3398, 2934, 1743, 1330, 1233, 1138, 1096, 1015, 814; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C23H29NO4SNa 438.1715; Found 438.1710. 6-((N-(2-Cyclopropylideneethyl)-4-methylphenyl)sulfonamido)-3-ethylhex-1-en-4-yn-3-yl Acetate (1q). Colorless oil; (265 mg, 70% yield); 1H NMR (400 MHz, CDCl3) δ 7.63–7.57 (m, 2H), 7.17– 7.11 (m, 2H), 5.60–5.48 (m, 2H), 5.15–4.95 (m, 2H), 4.06 (d, J = 1.3 Hz, 2H), 3.91–3.84 (m, 2H), 2.26 (s, 3H), 1.83 (s, 3H), 1.62 (dd, J = 13.5, 7.4 Hz, 1H), 1.44 (dd, J = 13.6, 7.4 Hz, 1H), 0.99– 0.87 (m, 4H), 0.64 (t, J = 7.4 Hz, 3H);

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C{1H}NMR (100 MHz, CDCl3) δ 166.6, 141.3, 135.4,

134.7, 127.7, 126.7, 125.6, 114.3, 110.1, 80.7, 78.9, 76.0, 45.8, 34.0, 31.7, 19.7, 19.6, 6.2; IR (neat, cm-1): 3061, 2933, 1736, 1346, 1231, 1158, 1090, 1017, 814; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C22H27NO4SNa 424.1558; Found 424.1553. 6-((N-Allyl-4-methylphenyl)sulfonamido)-3-ethylhex-1-en-4-yn-3-yl

4-Methoxybenzoate

(1r).

Colorless oil; (164 mg, 52% yield); 1H NMR (400 MHz, CDCl3) δ 7.96–7.88 (m, 2H), 7.73–7.67 (m, 2H), 7.19–7.13 (m, 2H), 6.95–6.87 (m, 2H), 5.75 (ddd, J = 17.0, 10.3, 9.4 Hz, 2H), 5.36–5.13 (m, 4H), 4.23 (d, J = 1.3 Hz, 2H), 3.89 (dt, J = 6.6, 1.3 Hz, 2H), 3.85 (s, 3H), 2.28 (s, 3H), 1.87 (dd, J = 13.6, 7.4 Hz, 1H), 1.72 (dd, J = 13.6, 7.4 Hz, 1H), 0.86 (t, J = 7.4 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 163.4, 143.3, 137.5, 131.9, 131.5, 129.6, 127.6, 120.1, 116.3, 113.6, 83.4, 80.4, 77.9, 55.5, 48.9, 36.1, 34.1, 21.4, 8.3; IR (neat, cm-1): 3387, 2934, 1719, 1605, 1348, 1253, 1160, 1092, 1024, 768; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C26H29NO5SNa 490.1664; Found 490.1659. 6-((N-Allyl-4-methylphenyl)sulfonamido)-3-ethylhex-1-en-4-yn-3-yl Benzoate (1s). Colorless oil; (145 mg, 55% yield); 1H NMR (400 MHz, CDCl3) δ 8.03–7.93 (m, 2H), 7.73–7.67 (m, 2H), 7.60– 7.52 (m, 1H), 7.50–7.40 (m, 2H), 7.20–7.10 (m, 2H), 5.75 (ddd, J = 17.0, 11.7, 10.3 Hz, 2H), 5.40– 5.25 (m, 2H), 5.25–5.13 (m, 2H), 4.23 (d, J = 0.7 Hz, 2H), 3.89 (dt, J = 6.6, 1.2 Hz, 2H), 2.25 (s, 3H), 1.90 (dd, J = 13.6, 7.4 Hz, 1H), 1.75 (dd, J = 13.6, 7.4 Hz, 1H), 0.88 (t, J = 7.4 Hz, 3H);

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C{1H}NMR (100 MHz, CDCl3) δ 143.3, 137.3, 136.2, 133.0, 131.9, 130.7, 129.6, 129.5, 128.4,

127.5, 120.1, 116.5, 80.6, 78.2, 48.9, 36.1, 34.0, 21.4, 8.3; IR (neat, cm-1): 3438, 2926, 1724, 1349, 1268, 1160, 1092, 1067, 1025, 710; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C25H27NO4SNa 460.1558; Found 460.1553. 6-((N-Allyl-4-methylphenyl)sulfonamido)-3-ethylhex-1-en-4-yn-3-yl 4-Nitrobenzoate (1t). Yellow solid; (600 mg, 79% yield); m.p. 94–96 °C; 1H NMR (400 MHz, CDCl3) δ 8.29–8.21 (m, 2H), 8.14–8.06 (m, 2H), 7.73–7.64 (m, 2H), 7.23–7.14 (m, 2H), 5.81–5.63 (m, 2H), 5.29 (dt, J = 17.1, 1.2 Hz, 2H), 5.24–5.14 (m, 2H), 4.21 (d, J = 0.9 Hz, 2H), 3.86 (dt, J = 6.6, 1.3 Hz, 2H), 2.28 (s, 3H), 1.99–1.86 (m, 1H), 1.81–1.68 (m, 1H), 0.87 (t, J = 7.4 Hz, 3H);

13

C{1H}NMR (100 MHz,

CDCl3) δ 150.5, 143.4, 136.5, 136.0, 131.9, 130.6, 129.6, 127.6, 123.5, 120.1, 117.4, 82.3, 81.6, 79.6, 49.0, 36.1, 33.9, 21.4, 8.3; IR (neat, cm-1): 2978, 2863, 1728, 1524, 1344, 1270, 1160, 928, 714; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C25H26N2O6SNa 505.1409; Found 505.1404. General Experimental Procedure for the Silver(I)/JohnPhos-Catalyzed Cycloisomerization and Diels-Alder Reaction of 1. To a solution of 1,9-dien-4-yne esters 1 (0.3 mmol) and 4 Å MS (100 mg) in toluene (3 mL) was added AgSbF6 (15 µmol, 5.2 mg)/JohnPhos (15 µmol, 4.5 mg) under nitrogen atmosphere. The resulting solution was heated 80 °C and the reaction was monitored by thin layer chromatography. Upon completion, the reaction mixture was cooled to room temperature, filtered through a pad of Celite, washed with EtOAc and the solvent was evaporated under reduced pressure. Purification by flash column chromatography on silica gel (nhexane/ EtOAc = 6:1 as eluent) gave the product 3. 5-Methyl-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl Acetate (3a). White solid; (102 mg, 94% yield); m.p. 114–115 °C; 1H NMR (400 MHz, CDCl3) δ 7.73–7.65 (m, 2H), 7.38–7.27 (m, 2H), 5.55 (t, J = 3.8 Hz, 1H), 4.01 (d, J = 15.7 Hz, 1H), 3.79 (ddd, J = 11.6, 5.4, 1.5 Hz, 1H), 3.30 (dd, J = 15.8, 2.8 Hz, 1H), 2.58–2.45 (m, 1H), 2.41 (s, 3H), 2.22 (dd, J = 11.7, 10.5 Hz, 1H), 2.12

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The Journal of Organic Chemistry

(s, 5H), 1.85 (q, J = 1.7 Hz, 3H), 1.77–1.66 (m, 1H), 1.20 (tdd, J = 12.8, 11.2, 6.4 Hz, 1H); 13

C{1H}NMR (100 MHz, CDCl3) δ 169.0, 143.8, 136.0, 132.8, 130.4, 129.8, 128.4, 127.7, 123.8,

48.9, 46.3, 35.3, 26.4, 25.2, 22.7, 21.5, 21.0; IR (neat, cm-1): 2927; 2863, 1755, 1343, 1194, 1139, 806; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C19H23NO4SNa 384.1245; Found 384.1240. 5-Ethyl-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl Acetate (3b). White solid; (111 mg, 99% yield); m.p. 114–116 °C; 1 H NMR (400 MHz, CDCl3) δ 7.71–7.63 (m, 2H), 7.37–7.29 (m, 2H), 5.63–5.57 (m, 1H), 3.96 (d, J = 15.7 Hz, 1H), 3.77 (ddd, J = 11.7, 5.6, 1.7 Hz, 1H), 3.44–3.33 (m, 1H), 2.48 (ddt, J = 10.3, 5.3, 2.5 Hz, 1H), 2.43 (s, 3H), 2.33–2.17 (m, 3H), 2.13 (s, 5H), 1.78–1.68 (m, 1H), 1.55 (s, 1H), 1.33–1.19 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H);

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C{1H}NMR (100 MHz,

CDCl3) δ 168.8, 143.8, 135.4, 134.7, 133.1, 129.8, 128.7, 127.7, 122.9, 77.2, 49.1, 46.4, 35.5, 28.5, 26.8, 25.3, 21.5, 21.0, 13.8; IR (neat, cm-1): 2925, 1760, 1343, 1190, 1157, 977, 839; HRMS (ESITOF) m/z: [M + Na]+ Calcd. for C20H25NO4SNa 398.1402; Found 398.1396. 5-Benzyl-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl Acetate (3c). White solid; (127 mg, 97% yield); m.p. 141–143 °C; 1H NMR (400 MHz, CDCl3) δ 7.61–7.56 (m, 2H), 7.27–7.22 (m, 2H), 7.22–7.15 (m, 2H), 7.13–7.06 (m, 1H), 6.99 (ddt, J = 7.5, 1.4, 0.7 Hz, 2H), 5.44 (t, J = 3.9 Hz, 1H), 3.86–3.76 (m, 1H), 3.72 (ddd, J = 11.7, 5.6, 1.7 Hz, 1H), 3.53 (s, 2H), 3.38–3.27 (m, 1H), 2.58– 2.46 (m, 1H), 2.36 (s, 3H), 2.26–2.20 (m, 1H), 2.20–2.09 (m, 2H), 1.69 (s, 4H), 1.27 (tdd, J = 12.8, 10.7, 6.5 Hz, 1H);

13

C{1H}NMR (100 MHz, CDCl3) δ 168.9, 143.8, 140.7, 136.3, 132.9, 132.9,

131.2, 129.8, 128.4, 128.3, 127.8, 125.8, 123.4, 77.2, 49.0, 46.4, 41.0, 35.8, 26.6, 25.5, 21.6, 20.6; IR (neat, cm-1): 2917, 1757, 1340, 1192, 1161, 1147, 808, 726; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C25H27NO4SNa 460.1558; Found 460.1553. 5-Cyclopent yl-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl Acetate (3d). Colorless oil; (105 mg, 84% yield); 1H NMR (400 MHz, CDCl3) δ 7.68–7.61 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 5.63 (t, J = 4.1 Hz, 1H), 3.91 (d, J = 15.7 Hz, 1H), 3.70 (ddd, J = 11.8, 5.6, 1.7 Hz, 1H), 3.38 (dd, J =

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15.7, 2.5 Hz, 1H), 2.72–2.59 (m, 1H), 2.40 (s, 4H), 2.31 (dd, J = 11.8, 9.7 Hz, 1H), 2.21–2.11 (m, 2H), 2.09 (s, 3H), 1.81 (dt, J = 7.6, 4.6 Hz, 1H), 1.76–1.61 (m, 3H), 1.61–1.42 (m, 3H), 1.42–1.16 (m, 2H), 1.15–0.99 (m, 1H); 13C{1H}NMR (100 MHz, CDCl3) δ 168.7, 143.8, 136.7, 135.2, 133.1, 129.8, 127.7, 125.7, 124.0, 77.3, 49.3, 46.6, 43.2, 35.5, 33.2, 32.0, 27.3, 25.1, 24.6, 24.2, 21.5, 21.0; IR (neat, cm-1): 2919, 1751, 1680, 1604, 1456, 1304, 1166, 914; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C23H29NO4SNa 438.1715; Found 438.1711. 5-Cyclohexyl-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl Acetate (3e). Colorless oil; (99 mg, 77% yield); 1H NMR (400 MHz, CDCl3) δ 7.68–7.62 (m, 2H), 7.33–7.27 (m, 2H), 5.57 (t, J = 4.0 Hz, 1H), 3.91 (dd, J = 15.7, 2.1 Hz, 1H), 3.70 (ddd, J = 11.6, 5.5, 1.7 Hz, 1H), 3.39 (dd, J = 15.7, 2.4 Hz, 1H), 2.39 (s, 4H), 2.32 (dd, J = 11.7, 9.7 Hz, 1H), 2.28–2.19 (m, 1H), 2.12 (s, 5H), 1.84– 1.60 (m, 6H), 1.36–1.02 (m, 6H), 0.93–0.76 (m, 1H);

13

C{1H}NMR (100 MHz, CDCl3) δ 168.6,

143.8, 139.0, 135.2, 133.2, 129.8, 127.7, 126.1, 123.4, 49.3, 46.6, 40.6, 35.6, 34.3, 32.8, 27.4, 27.3, 27.2, 26.5, 25.2, 21.5, 21.0; IR (neat, cm-1): 2924, 2851; 1758, 1346, 1194, 1165, 914; HRMS (ESITOF) m/z: [M + Na]+ Calcd. for C24H31NO4SNa 452.1871; Found 452.1866. 5-Ethyl-8a-methyl-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl Acetate (3f). White solid; (114 mg, 98% yield); m.p. 96–98 °C; 1H NMR (400 MHz, CDCl3) δ 7.70–7.63 (m, 2H), 7.36–7.29 (m, 2H), 5.58 (s, 1H), 3.97 (d, J = 15.3 Hz, 1H), 3.42 (dd, J = 11.2, 1.5 Hz, 1H), 3.26 (d, J = 15.3 Hz, 1H), 2.44 (s, 3H), 2.32–2.13 (m, 4H), 2.11 (s, 4H), 1.45–1.33 (m, 2H), 1.19 (s, 3H), 0.95 (t, J = 7.4 Hz, 3H);

13

C{1H}NMR (100 MHz, CDCl3) δ 168.8, 143.8, 135.1, 133.7, 132.8, 129.8, 127.7,

127.6, 126.6, 55.9, 46.7, 35.6, 32.8, 28.8, 22.5, 21.7, 21.5, 21.0, 13.7; IR (neat, cm-1): 2970, 2916, 1758, 1341, 1161, 998, 815, 708, 662; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C21H27NO4SNa 412.1558; Found 412.1553. 8a-Cyclopentyl-5-ethyl-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl Acetate (3g). Colorless oil; (64 mg, 48% yield); 1H NMR (400 MHz, CDCl3) δ 7.69–7.60 (m, 2H), 7.38–7.28 (m, 2H), 5.57

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The Journal of Organic Chemistry

(d, J = 3.9 Hz, 1H), 3.89 (d, J = 15.2 Hz, 1H), 3.67 (dd, J = 11.7, 1.1 Hz, 1H), 3.24 (d, J = 15.2 Hz, 1H), 2.43 (s, 3H), 2.37–2.15 (m, 3H), 2.12 (s, 5H), 1.90–1.24 (m, 11H), 0.96 (t, J = 7.4 Hz, 3H); 13

C{1H}NMR (100 MHz, CDCl3) δ 143.8, 135.6, 134.2, 129.8, 127.8, 127.6, 50.7, 46.4, 42.6, 39.3,

31.7, 28.8, 27.8, 26.4, 25.4, 25.3, 22.9, 21.6, 21.0, 13.6; IR (neat, cm-1): 2945, 1759, 1346, 1162, 812, 729; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C25H33NO4SNa 466.2028; Found 466.2023. 5-Ethyl-8-methyl-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl Acetate (3h). White solid; (115 mg, 99% yield); m.p. 125–128 °C; 1H NMR (400 MHz, CDCl3) δ 7.73–7.64 (m, 2H), 7.38–7.29 (m, 2H), 5.56 (t, J = 3.8 Hz, 1H), 4.01–3.81 (m, 2H), 3.36 (dd, J = 15.5, 2.5 Hz, 1H), 2.43 (s, 3H), 2.31 (dd, J = 11.7, 10.0 Hz, 1H), 2.27–2.13 (m, 3H), 2.12 (s, 3H), 1.83 (dd, J = 18.6, 10.7 Hz, 1H), 1.56 (s, 1H), 1.49 (dt, J = 11.5, 5.8 Hz, 1H), 1.06–0.88 (m, 6H); 13C{1H}NMR (100 MHz, CDCl3) δ 143.8, 135.8, 134.8, 133.1, 129.8, 128.2, 127.7, 123.3, 47.3, 46.3, 41.3, 34.9, 32.7, 28.5, 21.5, 21.0, 19.2, 13.7; IR (neat, cm-1): 2886, 1760, 1342, 1339, 1199, 1087, 974, 808; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C21H27NO4SNa 412.1558; Found 412.1553. 5,8-Diethyl-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl Acetate (3i). White solid; (112 mg, 93% yield); m.p. 130–132 °C; 1H NMR (600 MHz, CDCl3) δ 7.70–7.66 (m, 2H), 7.35–7.30 (m, 2H), 5.61–5.57 (m, 1H), 3.92 (d, J = 15.6 Hz, 1H), 3.88 (ddd, J = 11.7, 5.5, 1.7 Hz, 1H), 3.35 (dd, J = 15.6, 2.6 Hz, 1H), 2.43 (s, 3H), 2.32 (dd, J = 11.7, 10.0 Hz, 1H), 2.28–2.21 (m, 3H), 2.12 (s, 4H), 1.84–1.76 (m, 1H), 1.62–1.51 (m, 2H), 1.43–1.33 (m, 1H), 1.22–1.12 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H); 13C{1H}NMR (150 MHz, CDCl3) δ 168.8, 143.8, 135.7, 134.7, 133.1, 129.8, 128.2, 127.8, 123.5, 47.3, 46.3, 39.6, 38.3, 30.9, 28.4, 25.3, 21.5, 21.0, 13.7, 10.1; IR (neat, cm-1): 2964, 2875, 1759, 1346, 1201, 1163, 1133, 813; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C22H29NO4SNa 426.1715; Found 426.1711. 8-((Benzyloxy)methyl)-5-ethyl-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl Acetate (3j). White solid; (147 mg, 99% yield); m.p. 101–104 °C; 1H NMR (400 MHz, CDCl3) δ 7.71–7.63 (m, 2H),

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7.38–7.21 (m, 7H), 5.50 (t, J = 4.1 Hz, 1H), 4.49–4.33 (m, 2H), 3.88 (dd, J = 15.6, 2.1 Hz, 1H), 3.69–3.60 (m, 1H), 3.57 (dd, J = 9.6, 5.7 Hz, 1H), 3.40 (dd, J = 15.7, 2.1 Hz, 1H), 3.28 (dd, J = 9.6, 7.2 Hz, 1H), 2.94–2.80 (m, 2H), 2.43 (s, 3H), 2.40–2.29 (m, 2H), 2.22 (dtd, J = 7.2, 4.5, 3.4, 1.7 Hz, 2H), 2.15 (s, 4H), 0.97 (t, J = 7.4 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 143.8, 137.0, 134.9, 132.8, 129.8, 128.3, 127.8, 127.5, 127.4, 126.5, 120.5, 73.0, 69.9, 46.9, 46.9, 38.4, 35.7, 29.8, 28.4, 21.6, 21.0, 13.8; IR (neat, cm-1): 2872, 1759, 1341, 1191, 1158, 1106; 1021; 816; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C28H34NO5S 496.2157; Found 496.2152. 5-Ethyl-2-tosyl-8-(4-(trifluoromethyl)phenyl)-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl

Acetate

(3k). White solid; (124 mg, 80% yield); m.p. 197–199 °C; 1H NMR (400 MHz, CDCl3) δ 7.63–7.58 (m, 2H), 7.52–7.47 (m, 2H), 7.30–7.24 (m, 4H), 5.66 (dd, J = 5.3, 2.5 Hz, 1H), 3.95 (d, J = 16.0 Hz, 1H), 3.40 (dd, J = 16.0, 2.5 Hz, 1H), 3.28 (ddd, J = 12.3, 5.4, 1.6 Hz, 1H), 2.78 (tdt, J = 9.7, 5.1, 2.6 Hz, 1H), 2.66 (td, J = 11.7, 11.3, 5.7 Hz, 1H), 2.41 (s, 3H), 2.39–2.17 (m, 4H), 2.16 (s, 4H), 1.00 (t, J = 7.3 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 168.8, 147.1, 143.9, 137.1, 135.1, 133.1, 129.8, 127.7 (d, 1C, JC-F = 9.4 Hz), 127.4, 125.9 (d, 1C, JC-F = 3.7 Hz), 122.7, 77.2, 47.5, 46.4, 45.0, 39.5, 35.2, 28.5, 21.5, 21.0, 13.7; IR (neat, cm-1): 2828, 1762, 1322, 1160, 1119, 1067, 819; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C27H28F3NO4SNa 542.1588; Found 542.1583. 5-Ethyl-8-phenyl-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl Acetate (3l). White solid; (117 mg, 87% yield); m.p. 155–158 °C; 1H NMR (400 MHz, CDCl3) δ 7.55–7.43 (m, 2H), 7.37–7.30 (m, 2H), 7.30–7.23 (m, 4H), 7.18–7.11 (m, 2H), 5.67 (d, J = 3.3 Hz, 1H), 3.96 (d, J = 15.9 Hz, 1H), 3.37 (dd, J = 15.9, 2.7 Hz, 1H), 3.32 (ddd, J = 12.4, 5.5, 1.7 Hz, 1H), 2.72 (ddd, J = 9.6, 4.9, 2.6 Hz, 1H), 2.55 (td, J = 11.2, 5.9 Hz, 1H), 2.41 (s, 3H), 2.39–2.25 (m, 3H), 2.24–2.09 (m, 5H), 1.00 (t, J = 7.3 Hz, 3H);

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C{1H}NMR (100 MHz, CDCl3) δ 168.8, 143.7, 142.9, 136.6, 134.7, 133.1,

129.7, 128.9, 128.1, 127.7, 127.3, 127.0, 123.1, 77.2, 47.8, 46.5, 45.2, 39.7, 35.3, 28.5, 21.5, 21.0,

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The Journal of Organic Chemistry

13.8; IR (neat, cm-1): 2969, 1760, 1348, 1203, 1165, 813; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C26H29NO4SNa 474.1715; Found 474.1710. 5-Ethyl-8-(o-tolyl)-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl Acetate (3m). White solid; (135 mg, 97% yield); m.p. 168–169 °C; 1H NMR (400 MHz, CDCl3) δ 7.48–7.41 (m, 2H), 7.22– 7.12 (m, 3H), 7.12–7.02 (m, 3H), 5.59 (t, J = 3.8 Hz, 1H), 3.91 (d, J = 16.1 Hz, 1H), 3.43–3.27 (m, 2H), 2.80 (dd, J = 11.2, 5.5 Hz, 1H), 2.76–2.64 (m, 1H), 2.34 (s, 3H), 2.31–2.21 (m, 2H), 2.13 (d, J = 36.3 Hz, 9H), 0.93 (t, J = 7.3 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 168.8, 143.7, 136.7, 135.7, 134.8, 133.4, 129.7, 128.1, 127.6, 127.0, 126.4, 123.2, 77.2, 47.1, 46.4, 28.5, 21.5, 21.0, 19.8, 13.8; IR (neat, cm-1): 2927, 1760, 1347, 1202, 1164, 814; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C27H31NO4SNa 488.1871; Found 488.1866. 5-Methyl-8-(p-tolyl)-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl Acetate (3n). White solid; (96 mg, 71% yield); m.p. 152–154 °C; 1H NMR (400 MHz, CDCl3) δ 7.58–7.44 (m, 2H), 7.30– 7.23 (m, 4H), 7.17–7.11 (m, 2H), 7.04–6.98 (m, 2H), 5.62 (s, 1H), 3.99 (d, J = 16.0 Hz, 1H), 3.41– 3.27 (m, 2H), 2.78–2.66 (m, 1H), 2.51–2.43 (m, 1H), 2.42 (s, 3H), 2.36 (s, 3H), 2.28 (d, J = 8.8 Hz, 2H), 2.15 (s, 3H), 2.14–2.11 (m, 1H), 1.90 (q, J = 1.8 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 169.0, 143.7, 139.7, 137.1, 136.6, 133.2, 130.0, 129.7, 129.6, 128.4, 127.7, 127.1, 124.2, 47.6, 46.3, 44.4, 39.6, 35.3, 22.8, 21.5, 21.1; IR (neat, cm-1): 2989, 1760, 1346, 1203, 1162, 812; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C26H29NO4SNa 474.1715; Found 474.1710. 5-Methyl-8-(thiophen-2-yl)-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl Acetate (3o). Yellow gum; (80 mg, 60% yield); 1H NMR (400 MHz, CDCl3) δ 7.59–7.52 (m, 2H), 7.32–7.26 (m, 2H), 7.21 (ddd, J = 5.0, 1.2, 0.6 Hz, 1H), 6.96 (dd, J = 5.1, 3.5 Hz, 1H), 6.82–6.78 (m, 1H), 5.60 (tt, J = 3.0, 1.5 Hz, 1H), 4.03–3.94 (m, 1H), 3.45 (ddd, J = 12.2, 5.4, 1.6 Hz, 1H), 3.34 (dd, J = 16.1, 2.8 Hz, 1H), 2.88 (td, J = 11.3, 5.6 Hz, 1H), 2.67–2.57 (m, 1H), 2.42 (s, 5H), 2.24 (dd, J = 12.3, 10.3 Hz, 1H), 2.15 (s, 3H), 1.89 (dt, J = 3.0, 1.5 Hz, 3H);

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C{1H}NMR (150 MHz, CDCl3) δ 169.0,

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146.2, 137.5, 133.1, 129.7, 128.8, 127.7, 126.8, 124.4, 123.9, 123.8, 47.6, 46.4, 41.2, 40.0, 36.2, 22.6, 21.5, 21.1; IR (neat, cm-1): 2904, 1760, 1348, 1205, 1165, 812; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C23H25NO4S2Na 466.1122; Found 466.1117. 4-Ethyl-1-tosyl-2,3a1,6,6a,7,8,9,9a-octahydro-1H-benzo[de]quinolin-3-yl Acetate (3p). Colorless oil; (74 mg, 60% yield); 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.3 Hz, 2H), 7.32–7.23 (m, 2H), 5.54–5.46 (m, 1H), 4.10 (dt, J = 17.2, 1.9 Hz, 1H), 3.93 (dt, J = 12.1, 4.6 Hz, 1H), 3.78–3.65 (m, 1H), 2.65 (s, 1H), 2.41 (s, 3H), 2.27–2.10 (m, 5H), 1.93–1.63 (m, 4H), 1.38–1.09 (m, 6H), 0.97 (t, J = 7.3 Hz, 3H);

13

C{1H}NMR (100 MHz, CDCl3) δ 169.3, 143.3, 137.4, 136.6, 133.3, 129.7,

127.1, 126.9, 119.0, 54.1, 42.5, 39.1, 34.7, 31.8, 28.8, 26.3, 24.5, 23.8, 21.5, 21.0, 14.2; IR (neat, cm-1): 2930, 1707, 1228, 1156, 1089, 909, 812; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C23H29NO4SNa 438.1715; Found 438.1710. 5'-Ethyl-2'-tosyl-1',3',7',8a'-tetrahydro-2'H-spiro[cyclopropane-1,8'-isoquinolin]-4'-yl

Acetate

(3q). Colorless oil; (96 mg, 80% yield); 1H NMR (400 MHz, CDCl3) δ 7.68–7.61 (m, 2H), 7.35– 7.27 (m, 2H), 5.63–5.56 (m, 1H), 3.89–3.80 (m, 1H), 3.46–3.33 (m, 2H), 2.86–2.78 (m, 1H), 2.66– 2.56 (m, 1H), 2.42 (s, 3H), 2.36–2.04 (m, 6H), 1.67–1.54 (m, 1H), 1.37 (ddt, J = 18.4, 5.2, 1.5 Hz, 1H), 0.96 (t, J = 7.4 Hz, 3H), 0.62 (dt, J = 9.5, 5.3 Hz, 1H), 0.56–0.46 (m, 1H), 0.30 (dt, J = 9.3, 5.4 Hz, 1H), 0.10 (dt, J = 9.4, 5.2 Hz, 1H); 13C{1H}NMR (100 MHz, CDCl3) δ 168.8, 143.8, 136.3, 135.7, 133.1, 129.8, 127.9, 127.7, 123.0, 46.4, 43.9, 38.6, 37.4, 28.4, 21.5, 21.0, 19.0, 13.7, 8.4, 8.3; IR (neat, cm-1): 2933, 1736, 1346, 1231, 1156, 1090, 814; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C22H27NO4SNa 424.1558; Found 424.1553. 5-Ethyl-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl 4-Methoxybenzoate (3r). White gum; (131 mg, 94% yield); 1H NMR (400 MHz, CDCl3) δ 8.04–7.95 (m, 2H), 7.73–7.63 (m, 2H), 7.36– 7.28 (m, 2H), 6.99–6.89 (m, 2H), 5.58 (t, J = 4.0 Hz, 1H), 4.06 (d, J = 15.6 Hz, 1H), 3.88 (s, 3H), 3.83 (ddd, J = 11.7, 5.6, 1.7 Hz, 3H), 3.45 (dd, J = 15.7, 2.7 Hz, 1H), 2.65–2.52 (m, 1H), 2.43 (s,

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3H), 2.38–1.99 (m, 5H), 1.83–1.72 (m, 1H), 1.40–1.20 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13

C{1H}NMR (100 MHz, CDCl3) δ 164.2, 164.0, 143.8, 135.5, 134.9, 133.0, 132.2, 129.8, 128.5,

127.8, 123.2, 121.4, 114.0, 55.5, 49.3, 46.7, 35.7, 28.8, 26.9, 25.3, 21.5, 13.9; IR (neat, cm-1): 2932, 1719, 1603, 1341, 1253, 1159, 1020, 812; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C26H29NO5SNa 490.1664; Found 490.1659. 5-Ethyl-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl Benzoate (3s). White solid; (92 mg, 70% yield); m.p. 111–112 °C; 1H NMR (400 MHz, CDCl3) δ 8.07–8.02 (m, 2H), 7.71–7.65 (m, 2H), 7.64–7.57 (m, 1H), 7.52–7.44 (m, 2H), 7.35–7.27 (m, 2H), 5.59 (t, J = 3.9 Hz, 1H), 4.12–4.03 (m, 1H), 3.84 (ddd, J = 11.7, 5.6, 1.7 Hz, 1H), 3.55–3.40 (m, 1H), 2.58 (tdt, J = 9.7, 5.1, 2.4 Hz, 1H), 2.43 (s, 3H), 2.34 (dd, J = 11.8, 10.3 Hz, 1H), 2.29–1.99 (m, 4H), 1.84–1.73 (m, 1H), 1.70–1.46 (m, 1H), 1.44–1.10 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H);

13

C{1H}NMR (100 MHz, CDCl3) δ 164.4,

143.8, 135.4, 134.8, 133.8, 133.0, 130.1, 129.8, 129.1, 128.7, 128.7, 127.8, 123.4, 77.2, 49.2, 46.6, 35.7, 28.8, 26.9, 25.3, 21.5, 13.8; IR (neat, cm-1): 2915, 1729, 1336, 1264, 1159, 1058, 813; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C25H27NO4SNa 460.1558; Found 460.1553. 5-Ethyl-2-tosyl-1,2,3,7,8,8a-hexahydroisoquinolin-4-yl 4-Nitrobenzoate (3t). Yellow solid; (50 mg, 34% yield); m.p. 79–81 °C; 1H NMR (400 MHz, CDCl3) δ 8.35–8.30 (m, 2H), 8.24–8.20 (m, 2H), 7.70–7.65 (m, 2H), 7.35–7.30 (m, 2H), 5.63 (t, J = 3.7 Hz, 1H), 4.10 (d, J = 15.7 Hz, 1H), 3.84 (ddd, J = 11.8, 5.6, 1.7 Hz, 1H), 3.47 (dd, J = 15.8, 2.7 Hz, 1H), 2.58 (dt, J = 5.5, 3.0 Hz, 1H), 2.43 (s, 3H), 2.39–2.28 (m, 1H), 2.27–2.12 (m, 3H), 2.12–1.95 (m, 1H), 1.80 (dd, J = 12.4, 3.4 Hz, 1H), 1.32 (tdd, J = 12.9, 10.7, 6.7 Hz, 1H), 0.91 (t, J = 7.3 Hz, 3H);

13

C{1H}NMR (100 MHz,

CDCl3) δ 162.6, 151.0, 144.0, 135.1, 134.4, 134.3, 133.0, 131.2, 129.9, 129.5, 127.7, 123.9, 123.8, 49.2, 46.4, 35.7, 28.7, 26.8, 25.3, 21.5, 13.8; IR (neat, cm-1): 2917, 1735, 1527, 1342, 1160, 1136, 1086, 813; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C25H26N2O6SNa 505.1409; Found 505.1404.

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Experimental Procedure for the Silver(I)/JohnPhos-Catalyzed Reaction of 1p to 4p. To a solution of 1,9-dien-4-yne ester 1p (0.3 mmol) and 4 Å MS (100 mg) in toluene (3 mL) was added AgSbF6 (15 µmol, 5.2 mg)/JohnPhos (15 µmol, 4.5 mg) under nitrogen atmosphere. The reaction mixture was stirred at 50 °C for 48 h. The solution was filtered through Celite, washed with EtOAc, the solvent was removed under reduced pressure. Purification by flash column chromatography on silica gel (n-hexane/ EtOAc = 8:1 as eluent) furnished 4p in 50% yield. 1-((N-(Cyclohex-2-en-1-yl)-4-methylphenyl)sulfonamido)-4-ethylhexa-2,3,5-trien-2-yl

Acetate

(4p). Colorless oil; (0.48 mmol scale; 100 mg, 50% yield); 1H NMR (400 MHz, CDCl3) δ 7.68– 7.61 (m, 2H), 7.25–7.16 (m, 2H), 6.23 (dd, J = 17.6, 10.7 Hz, 1H), 5.70 (ddt, J = 9.6, 4.5, 1.9 Hz, 1H), 5.31 (dd, J = 17.6, 1.0 Hz, 1H), 5.12 (dd, J = 10.8, 1.0 Hz, 1H), 5.07–4.97 (m, 1H), 4.34 (ddd, J = 8.4, 4.5, 1.8 Hz, 1H), 3.96 (d, J = 16.5 Hz, 1H), 3.77 (d, J = 16.4 Hz, 1H), 2.34 (s, 3H), 2.23 (qd, J = 7.4, 2.7 Hz, 2H), 2.07 (s, 3H), 1.95–1.40 (m, 7H), 1.19 (s, 1H), 1.07 (t, J = 7.4 Hz, 3H); 13

C{1H}NMR (100 MHz, CDCl3) δ 197.1, 168.8, 143.1, 138.1, 133.7, 132.5, 129.6, 127.3, 127.2,

121.5, 119.0, 115.9, 77.2, 55.4, 44.3, 28.4, 24.4, 22.4, 21.8, 21.5, 21.0, 12.0; IR (neat, cm-1): 2933, 1753, 1340, 1207, 1154, 1092, 1036, 913, 865, 813; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C23H30NO4S 416.1895; Found 416.1875. Experimental Procedure for the Thermal Diels-Alder Reaction of 4p to 3p. A solution of 2,3,5-trien-2-yl acetate 4p (0.096 mmol, 39.7 mg) and 4 Å MS (50 mg) in toluene (1 mL) was heated at 80 °C for 48 hours under nitrogen atmosphere. The reaction mixture then cooled to room temperature and the solvent was removed under reduced pressure. The crude 1H NMR was taken without further purification and 3p was furnished in 29% yield based on 1H NMR measurements with CH2Br2 as the internal standard. Experimental Procedure for the Thermal Diels-Alder Reaction of 4p to 3p in the presence of the AgSbF6/JohnPhos Catalyst System. To a solution of 2,3,5-trien-2-yl acetate 4p (0.11

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mmol, 46 mg) and 4 Å MS (50 mg) in toluene (1 mL) was added AgSbF6 (5.5 µmol, 1.9 mg)/JohnPhos (5.5 µmol, 1.6 mg) under nitrogen atmosphere. The resulting solution was heated at 80 °C for 48 hours. The reaction mixture then cooled to room temperature and the solvent was removed under reduced pressure. The crude 1H NMR was taken without further purification and 3p was furnished in 48% yield based on 1H NMR measurements with CH2Br2 as the internal standard. AUTHOR INFORMATION Corresponding Author * [email protected]; [email protected] Notes The authors declare no competing financial interests. ACKNOWLEDGMENTS This work is supported by a Discovery Project Grant (DP160101682) from the Australian Research Council. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Characterization data and 1H and 13C NMR spectra for all starting materials and products (PDF) CIF files of 3c and 3n (cif) REFERENCES 1. Selected reviews: (a) Tang, G.-L.; Tang, M.-C.; Song, L.-Q.; Zhang, Y. Curr. Top. Med. Chem. 2016, 16, 1717. (b) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307. (c) Wu, Y.-J. Heterocycles and Medicine: A Survey of the Heterocyclic Drugs Approved by the U.S. FDA from 2000 to Present In Progress in Heterocyclic Chemistry; Elsevier 2012, 24, 1. (d) Bhadra, K.; Kumar, G. S. Med. Res. Rev. 2011, 31, 821. (e)

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Cabedo, N.; Berenguer, I.; Figadere, B.; Cortes, D. Curr. Med. Chem. 2009, 16, 2441. (f) Kumar, S; Bawa, S.; Gupta, H. Mini. Rev. Med. Chem. 2009, 9, 1648. (g) Magnier, E.; Langlois, Y. Tetrahedron 1998, 54, 6201. 2. Selected recent examples: (a) Ramanivas, T.; Gayatri, G.; Priyanka, D.; Nayak, V. L.; Singarupu, K. K.; Srivastava, A. K. RSC Adv. 2015, 5, 73373. (b) Zhang, L.; Liu, H.; Qiao, G.; Hou, Z.; Liu, Y.; Xiao, Y.; Guo, H. J. Am. Chem. Soc. 2015, 137, 4316. (c) Androvic, L.; Drabina, P.; Panov, I.; Harmand, L.; Padelkova, Z.; Sedlak, M. Heterocycles 2014, 89, 1844. (d) Karabuga, S.; Karakaya, I.; Ulukanli, S. Tetrahedron:Asymmetry 2014, 25, 851. (e) Macleod, P. D.; Reckling, A. M.; Li, C.-J. Heterocycles 2010, 80, 1319. 3. Selected recent examples: (a) Gao, Y.-N.; Shi, F.-C.; Xu, Q.; Shi, M. Chem.–Eur. J. 2016, 22, 6803. (b) Zhao, C.; He, R.; Chen, H.; Wang, C. Angew. Chem. Int. Ed. 2016, 55, 5268. (c) Dhanasekaran, S.; Suneja, A.; Bisai, V.; Singh, V. K. Org. Lett. 2016, 18, 634. (d) Liu, W.; Yu, Q., Hu, L.; Chen, Z.; Huang, J. Chem. Sci. 2015, 6, 5768. (e) Nayak, S.; Ghosh, N.; Prabagar, B.; Sahoo, A. K. Org. Lett. 2015, 17, 5662. (f) Feng, X.; Wang, J.-J.; Xun, J.; Zhang, J.-J.; Huang, Z.B.; Shi, D.-Q. Chem. Commun. 2015, 51, 1528. (g) Zhang, L.; Qureshi, Z.; Sonaglia, L.; Lautens, M. Angew. Chem. Int. Ed. 2014, 53, 13850. 4. Selected examples of partially hydrogenated isoquinoline synthesis via a Diels-Alder reaction: (a) Fershtat, L. L.; Larin, A. A.; Epishina, M. A.; Ovchinnikov, I. V.; Kulikov, A. S.; Ananyev, I. V.; Makhova, N. N. RSC Adv. 2016, 6, 31526. (b) Feng, W.; Jiang, D.; Kee, C. W.; Liu, H.; Tan, C. H. Chem.–Asian J. 2016, 11, 390. (c) Castillo, J.-C.; Quiroga, J.; Abonia, R.; Rodriguez, J.; Coquerel, Y. J. Org. Chem. 2015, 80, 9767. (d) Slauson, S. R.; Pemberton, R.; Ghosh, P.; Tantillo, D. J.; Aube, J. J. Org. Chem. 2015, 80, 5260. (e) Mihara, Y.; Matsumura, T.; Terauchi, Y.; Akiba, M.; Arai, S.; Nishida, A. Bull. Chem. Soc. Jpn. 2009, 82, 1520. (f) Kotha, S.; Banerjee, S. Synthesis 2007, 1015. (g) Brummond, K.; You, L. Tetrahedron 2005, 61, 6180. (h) Katritzky, A. R.; Nair, S.

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K.; Khokhlova, T.; Akhmedov, N. G. J. Org. Chem. 2003, 68, 5724. (i) Casamitjana, N.; Amat, M.; Llor, N.; Carreras, M.; Pujol, X.; Fernandez, M. M.; Lopez, V.; Molins, E.; Miravitlles, C.; Bosch, J. Tetrahedron:Asymmetry 2003, 14, 2033. 5. Saucy, G.; Marbet, R.; Lindlar, H.; Isler O. Helv. Chim. Acta 1959, 42, 1945. 6. Strickler, H.; Davis, J. B.; Ohloff, G. Helv. Chim. Acta 1976, 59, 1328. 7. Selected recent reviews: (a) Asiria, A. M.; Hashmi, A. S. K. Chem. Soc. Rev. 2016, 45, 4471. (b) Day, D. P.; Chan, P. W. H. Adv. Synth. Catal. 2016, 358, 1368. (c) Petrovic, M.; Occhiato, E. G. Chem.–Asian J. 2016, 11, 642. (d) Dorel, R.; Echavarren, A. M. Chem. Rev. 2015, 115, 9028. (e) Ayers, B. J.; Chan, P. W. H. Synlett 2015, 26, 1305. (f) Jones, A. C.; May, J. A.; Sarpong, R.; Stoltz, B. M. Angew. Chem. Int. Ed. 2014, 53, 2556. (g) Fensterbank, L.; Malacria, M. Acc. Chem. Res. 2014, 47, 953. (h) Shiroodi, R. K.; Gevorgyan, V. Chem. Soc. Rev. 2013, 42, 4991. (i) Shu, X. Z.; Shu, D.; Schienerbeck, C. M.; Tang, W. Chem. Soc. Rev. 2012, 41, 7698. 8. Selected examples of 1,2- and 1,3-acyloxy rearrangement of propargyl esters catalyzed by a transition metal complex: (a) Rao, W. D.; Susanti, D.; Ayers, B. J.; Chan, P. W. H. J. Am. Chem. Soc. 2015, 137, 6350. (b) Susanti, D.; Liu, L.-J.; Rao, W. D.; Lin, S.; Ma, D. L.; Leung, C. H.; Chan, P. W. H. Chem.–Eur. J. 2015, 21, 9111. (c) Rao, W. D.; Koh, M. J.; Li, D.; Hirao, H.; Chan, P. W. H. J. Am. Chem. Soc. 2013, 135, 7926. (d) Shu, D. X.; Li, X. X.; Zhang, M.; Robichaux, P. J.; Tang, W. P. Angew. Chem. Int. Ed. 2011, 50, 1346. (e) Teng, T. M.; Liu, R. S. J. Am. Chem. Soc. 2010, 132, 9298. (f) Bray, C. V. L.; Derien, S.; Dixneuf, P. H. Angew. Chem. Int. Ed. 2009, 48, 1439. (g) Barluenga, J.; Riesgo, L.; Vicente, R.; Lopez, L. A.; Tomas, M. J. Am. Chem. Soc. 2008, 130, 13528. 9. Schlossarczyk, H.; Sieber, W.; Hesse, M.; Hansen, H. J.; Schmid, H. Helv. Chim. Acta 1973, 56, 875.

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10. Examples of silver(I)-catalyzed cycloisomerization of propargyl esters initiated by a [3,3]sigmatropic rearrangement: (a) Su, Y.; Zhang, Y.; Akhmedov, N. G.; Peterson, J. L.; Shi, X. Org. Lett. 2014, 16, 2478. (b) Zhang, D.-H.; Zhang, Z.; Shi, M. Chem. Commun. 2012, 48, 10271. (c) Yang, J.-M.; Zhang, Z.; Wei, Y.; Shi. M. Tetrahedron Lett. 2012, 53, 6137. (d) Zhang, Z.; Shi, M. Chem.–Eur. J. 2012, 18, 3654. (e) Schwier, T.; Sromek, A. W.; Yap, D. M. L.; Chernyak, D.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 9869. (f) Zhan, J.; Hughes, C. O.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 7436. (g) Sromek, A. W.; Kel’in, A. V.; Gevorgyan, V. Angew. Chem. Int. Ed. 2004, 43, 2280. (h) Oelberg, D. G.; Schiavelli, M. D. J. Org. Chem. 1977, 42, 1804. 11. Bach, R. D.; Henneike, H. F. J. Am. Chem. Soc. 1970, 92, 5589. 12. Selected reviews on silver catalysis: (a) Zheng, Q.-Z.; Jiao, N. Chem. Soc. Rev. 2016, 45, 4590. (b) Fang, G.; Bi, X. Chem. Soc. Rev. 2015, 44, 8124. (c) Harmata, M. Ed.; Silver in Organic Chemistry, Wiley-VCH, Weinheim, Germany, 2010. (d) Belmont, P.; Parker, E. Eur. J. Org. Chem. 2009, 6075. (e) Patel, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (f) Yamamoto, Y. Chem. Rev. 2008, 108, 3199. (g) Álvarez-Corral, M.; Muñoz-Dorado, M.; Rodírguez-García, I. Chem. Rev. 2008, 108, 3174. (h) Weibel, J.-M.; Blanc, A.; Pale, P. Chem. Rev. 2008, 108, 3149. (i) Naodovic, M.; Yamamoto, H. Chem. Rev. 2008, 108, 3132. 13. Selected recent examples of silver-catalyzed reactions of alkynes: (a) Wang, X. N.; Ma, Z. X.; Deng, J.; Hsung, R. P. Tetrahedron Lett. 2015, 56, 3463. (b) Hack, D.; Chauhan, P.; Deckers, K.; Hermann, G. N.; Mertens, L.; Raabe, G.; Enders, D. Org. Lett. 2014, 16, 5188. (c) Terada, M.; Li, F.; Toda, Y. Angew. Chem. Int. Ed. 2014, 53, 235. (d) Cabrera-Pardo, J. R.; Chai, D. I.; Kozmin, S. A. Adv. Synth. Catal. 2013, 355, 2495. (e) Zheng, D. Q.; Li, S. Y.; Wu, J. Chem. Commun. 2012, 48, 8568. (f) Turkmen, Y. E.; Montavon, T. J.; Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 2012, 134, 9062. (g) Schafer, C.; Miesch, M.; Miesch, L. Chem.–Eur. J. 2012, 18, 8028.

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14. (a) Chan, P. W. H.; Teo, W. T.; Koh, S. W. Y.; Lee, B. R.; Ayers, B. J.; Ma, D.-L.; Leung, C.-H. Eur. J. Org. Chem. 2015, 4447. (b) Mothe, S. R.; Novianti, M. L.; Ayers, B. J.; Chan, P. W. H. Org. Lett. 2014, 16, 4110. (c) Susanti, D.; Koh, F.; Kusuma, J. A.; Kothandaraman, P.; Chan, P. W. H. J. Org. Chem. 2012, 77, 7166. (d) Mothe, S. R.; Kothandaraman, P.; Lauw, S. J. L.; Chin, S. M. W.; Chan, P. W. H. Chem.–Eur. J. 2012, 18, 6133. 15. Selected recent examples of silver(I)-assisted Diels-Alder reactions: (a) Krishna, N. H.; Saraswati, A. P.; Sathish, M.; Shankaraiah, N.; Kamal, A. Chem. Commun. 2016, 52, 4581. (b) Grirrane, A.; Alvarez, E.; Garcia, H.; Corma, A. Chem.–Eur. J. 2016, 22, 340. (c) Zou, X. D.; Yang, L. Z.; Liu, X. L.; Sun, H.; Lu, H. J. Adv. Synth. Catal. 2015, 357, 3040. (d) Liu, B.; Liu, T. Y.; Luo, S. W.; Gong, L. Z. Org. Lett. 2014, 16, 6164. (e) Fernandez-Garcia, J. M.; FernandezRodriguez, M. A.; Aguilar, E. Org. Lett. 2011, 13, 5172. 16. (a) Perez-Galan, P.; Delpont, N.; Herrero-Gomez, E.; Maseras, F.; Echavarren, A. M. Chem.– Eur. J. 2010, 16, 5324. (b) Porcel, S.; Echavarren, A. M. Angew. Chem. Int. Ed. 2007, 46, 2672. 17. Selected examples of vinyl allenes participating in intramolecular Diels-Alder reactions: (a) Cheng, G. S.; He, X.; Tian, L. M.; Chen, J. W.; Li, C. J.; Jia, X. S.; Li, J. J. Org. Chem. 2015, 80, 11100. (b) Lam, J. K.; Schmidt, Y.; Vanderwal, C. D. Org. Lett. 2012, 14, 5566. (c) Gidloef, R.; Johansson, M.; Sterner, O. Org. Lett. 2010, 12, 5100. (d) Hayashi, R.; Feltenberger, J. B.; Hsung, R. P. Org. Lett. 2010, 12, 1152. (e) Regas, D.; Afonso, M. M.; Palenzuela, J. A. Synthesis 2004, 757. (f) Regas, D.; Ruiz, J. M.; Afonso, M. M.; Galindo, A.; Palenzuela, J. A. Tetrahedron Lett. 2003, 44, 8471. 18. Examples of 1,2,3,7,8,8a-hexahydroisoquinoline

synthesis: (a) Mojtahedi, M. M.; Pourabdi,

L.; Abaee, M. S.; Jami, H.; Dini, M.; Halvagar, M. R. Tetrahedron 2016, 72, 1699. (b) Zhang, X. P.; Yu, F. J.; Ding, X. W.; He, X. M.; Zou, D. H. Russ. J. Gen. Chem. 2016, 86, 1430. (c) Wang, X.-S.; Wu, J.-R.; Li, Q.; Zhang, M.-M. J. Heterocyclic Chem. 2009, 46, 1355. (d) Wang, X.-S.;

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Wu, J.-R.; Zhou, J.; Tu, S.-J. J. Comb. Chem. 2009, 11, 1011. (e) Chou, S.-S. P.; Chen, P.-W. Tetrahedron 2008, 64, 1879. (f) Srinivasan, M.; Perumal, S. Tetrahedron 2007, 63, 2865. (g) Padwa, A.; Regerm T. S. Can. J. Chem. 2000, 78, 749. (h) Schultz, A. G.; Lucci, R. D.; Napier, J. J.; Kinoshita, H.; Ravichandran, R.; Shannon, P.; Yee, Y. K. J. Org. Chem. 1985, 50, 217. 19. Selected recent examples of transition metal-catalyzed and thermally-promoted [m + n] cycloadditions of preformed and in situ formed allenenes, see ref 17f and: (a) Nada, T.; Yoneshige, Y.; Ii, Y.; Matsumoto, T.; Fujioka, H.; Shuto, S.; Arisawa, M. ACS Catal. 2016, 6, 3168. (b) Newton, C. G.; Drew, S. L.; Lawrence, A. L.; Willis, A. C.; Sherburn, M. S. Nat. Chem. 2015, 7, 82. (c) Aillard, P.; Retaileau, P.; Voituriez, A.; Marinetti, A. Chem.–Eur. J. 2015, 21, 11989. (d) Suárez-Pantiga, S.; Hernández-Díaz, C.; Rubio, E.; González, J. M. Angew. Chem. Int. Ed. 2012, 51, 11552. (e) Rao, W.; Susanti, D.; Chan, P. W. H. J. Am. Chem. Soc. 2011, 133, 15248. (f) Cergol, K. M.; Newton, C. G.; Lawrence, A. L.; Willis, A. C.; Sherburn, M. S. Angew. Chem. Int. Ed. 2011, 50, 10425. (g) Gulias, M.; Collado, A.; Trillo, B.; López, F.; Onate, E.; Esteruelas, M. A.; Mascarenas, J. L. J. Am. Chem. Soc. 2011, 133, 7660. 20. CCDC 1526148 (3c) and CCDC 1526149 (3n) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. 21. For the synthesis of 1,6 enynes leading to substrates 1a–1e, 1h–1o and 1r–1t, see: (a) Rao, W.; Koh, M. J.; Kothandaraman, P.; Chan, P. W. H. J. Am. Chem. Soc. 2012, 134, 1081. For the synthesis of 1,6 enynes leading to substrates 1f and 1g, see: (b) Benedetti, E.; Simonneau, A.; Hours, A.; Amouri, H.; Penoni, A.; Palmisano, G.; Malacria, M.; Goddard, J. P.; Fensterbank, L. Adv. Synth. Catal. 2011, 353, 1908. For the synthesis of the 1,6 enyne leading to substrate 1p, see: (c) Monnier, F.; Vovard-Le Bray, C.; Castillo, D.; Aubert, V.; Derien, S.; Dixneuf, P. H.; Toupet,

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L.; Ienco, A.; Mealli, C. J. Am. Chem. Soc. 2007, 129, 6037. For the synthesis of the 1,6 enyne leading to substrate 1q, see: (d) Kim, S.; Chung, Y. K. Org. Lett. 2014, 16, 4352.

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