Synthesis of Functionalized Isoindolinones: Addition of In Situ Generated Organoalanes to Acyliminium Ions

Abstract

Addition of in situ generated di- or trisubstituted alkenylalanes to N-acyliminium ions provides rapid access to functionalized isoindolinones. Subsequent ring closing metathesis leads to tricyclic products. These transformations proceed under mild conditions and allow for the convergent synthesis of biologically significant scaffolds from readily available starting materials.

1. Introduction

Isoindolinones constitute the core structures of numerous naturally occurring biologically active compounds such as magallanesine 1ⁱ and lennoxamine 2ⁱⁱ as well as many drug candidates such as pagoclone 3ⁱⁱⁱ (Figure 1). Isoindolinones demonstrate a remarkably wide array of biological activities, including anti-inflammatory,^iv antihypertensive,^v antipsychotic,^vi vasodilatory^vii and antileukemic^viii effects, which renders the development of new synthetic routes toward these heterocycles particularly attractive. While several methods have been reported for the preparation of isoindolinones,^ix some leading to the synthesis of natural products^x and compound libraries,^xi many approaches suffer from a lack of generality or functional group compatibility.

Figure 1.

Biologically active isoindolinones.

In view of the potent and diverse biological spectrum of isoindolinones, we initiated studies directed at their preparation as part of our program for the synthesis of nitrogen containing heterocycles.^xii We initially proposed combining our water-accelerated carboalumination^xiii or hydrozirconation^xiv with an intramolecular N-acyliminium ion addition in a cascade process that would generate medium-ring containing isoindolinones (Scheme 1). N-acyliminium ions are versatile synthetic intermediates^xv and have previously been employed in the formation of simple isoindolinones;^xvi however, with the exception of allylsilanes, the addition of functionalized organometallic reagents to these systems has not yet been exploited. Moreover, the intramolecular addition would potentially provide an entry toward strained medium rings containing (E)-alkenes.

Scheme 1.

Proposed intramolecular addition of alkenylalanes to N-acyliminium ions. A: Zirconium-Catalyzed, Water-Accelerated Carboalumination or Hydrozirconation/Transmetallation; B: Elimination; C: Addition/Ring Closure.

2. Results and Discussion

Our investigations began with the synthesis of methoxy-8 and phenoxy lactam 9 (Scheme 2). Alcohol 5 was obtained in 85% yield by the isomerization of the commercially available hept-3-yne-1-ol with KAPA reagent in 85% yield.^xvii Imide 6 could then be constructed by a Mitsunobu alkylation with alkynol 5, which proceeded in 82% yield. Reduction with sodium borohydride was followed by a methanol exchange to give methoxylactam 8 in 40% overall yield (Scheme 2). With the key substrate in hand, we submitted 8 to our water accelerated carboalumination conditions (AlMe₃ (3 eq), H₂O (1 eq), zirconocene dichloride (10 mol%)) which only returned starting material with no evidence for elimination of methanol or carboalumination of the alkyne moiety (Scheme 3).

Scheme 2.

Synthesis of lactam precursors.

Scheme 3.

Attempted cascade cyclization of 8 and 9.

We anticipated the need for a better leaving group and hence prepared phenoxy lactam 9, which was generated by treatment of 7 with SOCl₂ and catalytic DMF. The resulting unstable chloride intermediate was immediately treated with phenol in the presence of triethylamine to yield 9 in 34% yield.^xviii When 9 was subjected to the carboalumination conditions, only alkylated lactam 10 (10%), starting material (52%), and decomposition products were observed by NMR analysis (Scheme 3).

These experiments suggested that the functionality present in these lactam acetals was inhibiting the carboalumination step. We postulated that the lactam group was responsible for the observed inhibition, as highly Lewis basic functionality has been noted to decrease the reactivity of aluminoxanes.^xix Therefore, we performed a series of GC experiments to test this hypothesis with 1-heptyne, which is known to undergo rapid water-accelerated carboalumination. A control experiment demonstrated that the carboalumination of heptyne with AlMe₃ (3 eq), H₂O (1 eq), and Cp₂ZrCl₂ (10 mol%) proceeded to completion in less than 5 min at low temperatures (−78 °C to −25 °C) to furnish a 97:3 mixture of regioisomers by GC analysis (Scheme 4). Conducting the identical experiment in the presence of 1 equivalent of methoxylactam 8 dramatically inhibited carboalumination, with only 4.4% of heptyne undergoing conversion after 1 h at ambient temperature. Most likely, this inhibition is due to the coordination of Lewis basic functional groups to AlMe₃ oligomers, thus preventing alkyne carboalumination.

Scheme 4.

GC analysis of the water-accelerated carboalumination of heptyne in the presence and absence of 8.

Due to the lack of reactivity in the carboalumination approach, we turned to hydrozirconation, known to be quite tolerant of diverse functionality.¹⁴ When lactam 8 was treated with Cp₂ZrHCl, only the corresponding alkene was recovered (Scheme 5). Treatment of the intermediate alkenylzirconocene with AgClO₄ or trimethylaluminum also provided no desired cyclization products. Our attempts to enhance leaving group ability by using pivaloate 11 also failed to promote cyclization under any of the above conditions. Highly concentrated reaction mixtures or prolonged heating resulted only in slow methyl group addition. Possibly, the ring strain present in the desired products is too high to allow the reaction to proceed under these experimental conditions.

Scheme 5.

Attempted hydrozirconation and medium ring formation.

Because the intramolecular cyclizations proved elusive, we turned our attention toward an alternative construction of these systems starting with an intermolecular addition process. Alkenylation of N-acyliminium ions can often require harsh reaction conditions^xx or unusual anomeric leaving groups;^xxi a noteworthy exception is the mild intermolecular addition of alkenyl boronates reported by Batey et al.^xxii We first explored the hydrozirconation of terminal alkynes as a method to generate alkenyl nucleophiles (Table 1). Hydrozirconation of 1-hexyne, followed by treatment with silver perchlorate^xxiii and lactam 13 yielded only a trace of addition product after 24 h at rt (entry 1, Table 1). Transmetallation to dimethylzinc also proved unsuccessful (entry 2, Table 1). Gratifyingly, hydrozirconation-transmetallation to trimethylaluminum^xxiv generated an alkenylalane that reacted with lactam 13 in a moderate 43% yield (entry 3, Table 1). We further increased the leaving group ability by using acetate 14; however, product 17 was only formed in 30% yield while the remaining starting material was consumed (entry 4, Table 1). Attempts to perform this reaction in THF or toluene led to recovered starting material. In an effort to prevent decomposition pathways while retaining good leaving group ability, pivaloate 15 was synthesized and treated with the in situ generated alane to provide hexenyl isoindolinone 17 in 81% yield without any observed isomerization of the alkene moiety (entry 5, Table 1). Attempts to achieve this transformation under cationic conditions with silver perchlorate²⁰ led to complex mixtures, seemingly arising from alkene isomerization. The mild conditions under which the addition proceeds and the ability to utilize readily available alkynes and pivaloate iminium ion precursors encouraged us to explore this process further.

Table 1.

Reaction optimization for the addition of hexenylzirconocene to lactams 13–15.

Entry	Conditions	R (lactam acetal)	17 [%]
1	AgClO4, 24 h, rt	OMe (13)	Tracea
2	Me2Zn, 12 h, rt	OMe (13)	-
3	Me3Al, 12 h, rt	OMe (13)	43b
4	Me3Al, 4 h, rt	OAc (14)	30
5	Me3Al, 4 h, rt	OPiv (15)	81
6	AgClO4, 12 h, rt	OPiv (15)	Complex mixture

^aProduct was formed as a mixture of alkene isomers.

^bStarting material observed after 12 h.

Among the numerous methods known for the synthesis of substituted isoindolinones, only a few examples of Heck-type cyclizations install an alkenyl moiety at the 3-position.^xxv The modularity of our approach warranted further investigation, and therefore we evaluated the substrate scope of this process. As shown in Table 2, silyl ether, carbamate, and sulfonamide functionalities are well tolerated, generating functionalized isoindolinones in a high yielding, one-pot procedure.

Table 2.

Variation of alkyne substrates.

Entry	R (alkyne)	Product [%]
1	C4H9 (16)	17 [81]
2	c-C6H11 (18)	19 [79]
3	CH2CH2OTBDPS (20)	21 [71]
4	CH2CH2N(CO2Me)Ts (22)	23 [62]

To further probe the scope of this reaction, we synthesized succinimide-derived pivaloate 25 from 1-benzyl-3,3-dimethylpyrrolidine-2,5-dione (24) and subjected it to our optimized conditions (Scheme 6). Addition product 26 was isolated in 83% yield. This success bodes well for the extension of the cyclic iminium ion alkenylation methodology toward a broad class of heterocyclic electrophiles.

Scheme 6.

Addition to succinimide-derived iminium ion precursor.

We also explored the use of trisubstituted alkenes in this transformation. Although the lactam functionality had prevented an intramolecular addition, pre-forming the alkenylalane under our water-accelerated conditions, followed by addition of 15, provided isoindolinones 27 and 29 in 77% yield after only 15 minutes (Table 3). The flexibility and mild nature of these transformations are well suited for their application in the synthesis of biologically interesting target molecules and libraries.

Table 3.

Water-accelerated carboalumination – addition to lactam 15.

Entry	R	Product [%]
1	C4H9 (16)	27 [77]
2	Ph (28)	29 [77]a

^aProduct contains ~5% of a carbometallation regioisomer.

Since this strategy provided a rapid access toward alkenyl-functionalized phthalimides, we sought to revisit our initial goal of generating medium rings. As a model system, we synthesized alkyne 30 and allyl-pivaloate 31 and subjected them to our hydrozirconation-transmetallation conditions to generate 32 in 55% yield accompanied by considerable amounts of methyl addition side product (Scheme 7). It should be noted that carbometallation of 30 failed and the rate of addition for the alkenylalane generated via the transmetallation reaction was retarded due to the presence of the ether functionality. With 32 in hand, we screened conditions to form the desired 12-membered macrocycle. Although ring closing metathesis methodology²³ has been demonstrated to perform well for the synthesis of a variety of macrocycles,^xxvi rapid formation of the undesired 5-membered ring 33 was observed (Scheme 7).^xxvii Increasing dilution, change of metathesis catalyst, addition of Ti(OⁱPr)₄,^xxviii or varying solvents did not influence the reaction pathway.

Scheme 7.

Attempted medium ring formation via ring closing metathesis.

Due to the ease of formation of pyrrolizidine 33, we explored the synthesis of this compound via addition of hexyne to 31 and subsequent ring closing metathesis to provide tricycle 33 in 75% yield (Scheme 8). Extension of this approach to the synthesis of fused azepines was achieved from indolinone 37, prepared from 2-(pent-4-enyl)isoindoline-1,3-dione (35) via pivaloate 36 and 1-hexyne in 72% yield. Ring closing metathesis of 37 proved to be problematic in CH₂Cl₂ with several ruthenium catalysts, yielding only starting material or decomposition products. Addition of Ti(OⁱPr)₄ in toluene at room temperature resolved these issues and yielded 67% of 38. Possible deactivation of the metathesis intermediate by the neighboring amide carbonyl could explain the difficulty in this transformation.^xxix While not fully optimized, these reactions provide proof of concept for the conversion of our phthalimide substrates to structurally diverse tricyclic products.

Scheme 8.

Application of ring closing metathesis to generate 5- and 7-membered fused ring systems.

3. Conclusions

We have demonstrated that in situ generated alkenylalanes represent versatile nucleophiles for additions to N-acyliminium ions. While direct intramolecular cyclization strategies currently suffer from inhibition of the carboalumination reaction by Lewis basic functional groups, preforming alkenylalanes via hydrozirconation-transmetallation or carboalumination and subsequent addition to the lactam acetal substrates yield functionalized isoindolinones. This method applies easily prepared or commercially available starting materials that provide opportunities for diversification at numerous points and yields synthetically useful heterocyclic products in a one-pot transformation. Further elaboration of the alkenyl heterocycles through the use of ring closing metathesis leads to tricyclic products that are common motifs in natural products and drug-like molecules.

4. Experimental Section

4.1 General Details

All reactions were performed under an N₂ atmosphere and all glassware was dried in an oven at 140 °C for 2 h prior to use. THF and Et₂O was distilled over sodium/benzophenone ketyl, Et₃N was distilled from CaH₂, and CH₂Cl₂ and toluene were purified using an alumina filtration system. Cp₂ZrHCl,^xxx 18,^xxxi 20,^xxxii and 22²⁴ were prepared according to literature procedures and all other compounds were purchased and used as received.

Reactions were monitored by TLC analysis (EM Science pre-coated silica gel 60 F₂₅₄ plates, 250 mm layer thickness) and visualization was accomplished with a 254 nm UV light and by staining with a PMA solution (5 g of phosphomolybdic acid in 100 mL of 95% EtOH), p-anisaldehyde solution (2.5 mL of p-anisaldehyde, 2 mL of AcOH, and 3.5 mL of conc. H₂SO₄ in 100 mL of 95% EtOH), Vaughn’s reagent (4.8 g of (NH₄)₆Mo₇O₂₄•4 H₂O and 0.2 g of Ce(SO₄)₂ in 100 mL of a 3.5 N H₂SO₄ solution) or a KMnO₄ solution (1.5 g of KMnO₄ and 1.5 g of K₂CO₃ in 100 mL of a 0.1% NaOH solution). Flash chromatography on SiO₂ was used to purify the crude reaction mixtures.

Melting points were determined using a Laboratory Devices Mel-Temp II. Infrared spectra were determined on a Nicolet Avatar 360 FT-IR spectrometer. ¹H and ¹³C NMR spectra were obtained on a Bruker Avance 300 instrument in CDCl₃ unless otherwise noted. Chemical shifts were reported in parts per million with the residual solvent peak used as an internal standard. ¹H NMR spectra were run at 300 MHz and are tabulated as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet), number of protons, and coupling constant(s). ¹³C NMR spectra were run at 76 MHz using a proton-decoupled pulse sequence with a d₁ of 3 sec, and are tabulated by observed peak. Mass spectra were obtained on a Micromass Autospec double focusing instrument.

2-(Hept-6-ynyl)isoindoline-1,3-dione (6)

A solution of hept-6-yn-1-ol (5) (228 mg, 2.04 mmol), phthalimide 4 (302 mg, 2.04 mmol), and PPh₃ (540 mg, 2.04 mmol) in THF (20 mL) was cooled to 0 °C and treated with DIAD (403 μL, 2.04 mmol) over 5 min. The reaction mixture was warmed to rt and stirred for 6 h. The solvent was evaporated, the residue was dissolved in EtOAc/hexanes (1:1, 10 mL) and the solids were filtered off. The filtrate was concentrated and chromatographed on SiO₂ (EtOAc:hexanes, 1:5) to yield imide 6 (407 mg, 1.69 mmol, 82%) as a colorless oil: IR (neat) 3466, 3283, 2941, 2862, 2115, 1772, 1709, 1615, 1397, 1046, 720 cm⁻¹; ¹H NMR δ 7.84-7.79 (m, 2 H), 7.72-7.67 (m, 2 H), 3.67 (t, 2 H, J = 7.1 Hz), 2.17 (td, 2 H, J = 6.8, 2.6 Hz), 1.91 (t, 1 H, J = 2.6 Hz), 1.75-1.61 (m, 2 H), 1.58-1.51 (m, 2 H), 1.49-1.38 (m, 2 H); ¹³C NMR δ 168.3 (2 C), 133.8 (2 C), 132.1 (2 C), 123.1 (2 C), 84.2, 68.4, 37.7, 28.0, 27.9, 25.8, 18.2; MS (EI) m/z (rel intensity) 241 ([M]⁺, 11), 186 (6), 173 (10), 160 (100), 148 (31), 130 (29), 104 (27); HRMS (EI) m/z calcd for C₁₅H₁₅NO₂ 241.1103, found 241.1107.

2-(Hept-6-ynyl)-3-methoxyisoindolin-1-one (8)

To a 0 °C solution of imide 6 (40.0 mg, 0.166 mmol) in MeOH (4 mL) was added NaBH₄ (5.00 mg, 0.125 mmol). The reaction mixture was stirred at rt for 2.5 h, quenched with H₂O (1 mL) and the MeOH was removed in vacuo. The residue was extracted with CH₂Cl₂ (5 × 3 mL) and the combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated to provide crude hydroxylactam 7 which was immediately dissolved in MeOH (4 mL), treated with d,l-camphorsulfonic acid (3.85 mg, 0.0166 mmol) and stirred for 16 h. The solvent was removed in vacuo and the residue was partitioned between H₂O (5 mL) and CH₂Cl₂ (5 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), concentrated and chromatographed on SiO₂ (EtOAc:hexanes, 1:4) to yield methoxy lactam 8 (17.0 mg, 0.0661 mmol, 40% over two steps) as a colorless oil: IR (neat) 3298, 2925, 2854, 2115, 1702, 1466, 1412, 1059, 746 cm⁻¹; ¹H NMR δ 7.84-7.80 (m, 1 H), 7.61-7.49 (m, 3 H), 5.88 (s, 1 H), 3.79 (ddd, 1 H, J = 13.7, 8.1, 7.3 Hz), 3.24 (ddd, 1 H, J = 14.0, 8.0, 6.3 Hz), 2.87 (s, 3 H), 2.19 (td, 2 H, J = 6.7, 2.6 Hz), 1.92 (t, 1 H, J = 2.6 Hz), 1.75-1.63 (m, 2 H), 1.62-1.43 (m, 4 H); ¹³C NMR δ 167.6, 140.3, 133.2, 131.9, 129.9, 123.4 (2 C), 86.2, 84.3, 68.4, 49.1, 39.3, 28.0, 27.6, 26.0, 18.3; MS (EI) m/z (rel intensity) 257 ([M]⁺, 18), 242 (17), 226 (20), 176 (66), 146 (100), 132 (39), 117 (21); HRMS (EI) m/z calcd for C₁₆H₁₉NO₂ 257.1416, found 257.1419.

2-(Hept-6-ynyl)-3-phenoxyisoindolin-1-one (9)

A 0 °C solution of imide 6 (307 mg, 1.27 mmol) in MeOH (20 mL) was treated with NaBH₄ (36.3 mg, 0.953 mmol), warmed to rt and stirred for 1 h. The reaction mixture was quenched with H₂O (10 mL) and the MeOH was removed in vacuo. The residue was extracted with CH₂Cl₂ (6 × 10 mL) and the combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated to yield crude hydroxylactam 7 as a colorless oil. A portion of the crude hydroxylactam (101 mg, 0.416 mmol) was immediately dissolved in THF (5 mL) at rt and treated with SOCl₂ (30.3 μL, 0.416 mmol) and DMF (1 drop) and stirred for 14 h. The volatiles were removed under reduced pressure and the residue was dried in vacuo for 12 h. The unstable crude chloride was obtained as a colorless oil and immediately dissolved in THF (4.1 mL) at ambient temperature. This solution was treated with phenol (58.0 mg, 0.620 mmol) and Et₃N (288 μL, 2.07 mmol) and stirred for 2 h. The reaction mixture was quenched with H₂O (1 mL) and the THF was removed in vacuo. The residue was extracted with CH₂Cl₂ (4 × 5 mL) and the combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated. The residue was chromatographed on SiO₂ (EtOAc:hexanes, 1:3) to yield phenoxylactam 9 (45.0 mg, 1.41 mmol, 34% over two steps) as a colorless oil: IR (neat) 3296, 2936, 2115, 1707, 1588, 1491, 1415, 1222, 992, 780 cm⁻¹; ¹H NMR δ 7.85-7.79 (m, 1 H), 7.53-7.46 (m, 3 H), 7.33-7.27 (m, 2 H), 7.08-6.98 (m, 3 H), 6.42 (s, 1 H), 3.80 (dt, 1 H, J = 14.2, 7.4 Hz), 3.44 (ddd, 1 H, J = 14.0, 7.8, 6.4 Hz), 2.16 (td, 2 H, J = 6.7, 2.6 Hz), 1.91 (t, 1 H, J = 2.6 Hz), 1.78-1.61 (m, 2 H), 1.57-1.39 (m, 4 H); ¹³C NMR δ 167.4, 156.3, 141.3, 132.3, 132.0, 130.0, 129.7 (2 C), 123.5, 123.3, 123.1, 118.1 (2 C), 86.8, 84.2, 68.4, 40.0, 27.9, 27.6, 25.9, 18.2; MS (EI) m/z (rel intensity) 319 ([M]⁺, 70), 265 (28), 226 (100), 198 (8), 146 (52), 132 (65); HRMS (EI) m/z calcd for C₂₁H₂₁NO₂ 319.1572, found 319.1573.

2-Benzyl-3-oxoisoindolin-1-yl pivaloate (15)

To a solution of benzyl phtalimide (8.89 g, 37.5 mmol) in MeOH (130 mL) was added sodium borohydride (1.42 g, 37.5 mmol) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 2 h and carefully quenched with H₂O. The aqueous layer was extracted with EtOAc (2×) and the organic layer was separated, dried (MgSO₄) and concentrated. The residue was dried to yield a white solid which was carried on to the next step without further purification. To a solution of the crude reduced phthalamide (1.00 g, 4.20 mmol) in THF (30 mL) was added Et₃N (1.17 mL, 8.40 mmol) and pivaloyl chloride (621 μL, 5.04 mmol) at 0 °C and the reaction mixture was allowed to warm to rt and stirred at this temperature for 4 h. The mixture was quenched with sat. aq. NaHCO₃, extracted with EtOAc (2×), dried (MgSO₄) and concentrated. The residue was purified by chromatography on SiO₂ (EtOAc:hexanes, 3:7) to yield 1.09 g (80% over 2 steps) of 15 as a colorless solid: mp 88.1 – 89.0 °C (CH₂Cl₂); IR (neat) 3419, 3062, 3031, 2973, 2934, 2872, 1717, 1408, 1276, 1122, 959, 751 cm⁻¹; ¹H NMR δ 7.92-7.84 (m, 1 H), 7.61-7.53 (m, 2 H), 7.50-7.43 (m, 1 H), 7.38-7.22 (m, 5 H), 6.89 (s, 1 H), 5.01 (d, 1 H, J = 15 Hz), 4.44 (d, 1 H, J = 15 Hz), 1.13 (s, 9 H); ¹³C NMR δ 178.4, 167.9, 141.3, 136.8, 132.5, 131.9, 130.2, 128.7, 128.1, 127.7, 123.7, 123.7, 81.0, 44.2, 39.0, 26.8; MS (EI) m/z (rel intensity) 323 ([M]⁺, 35), 221 (100), 133 (65), 91 (100); HRMS (EI) m/z calcd for C₂₁H₂₃NO 323.1521, found 323.1515.

(E)-2-Benzyl-3-(hex-1-enyl)isoindolin-1-one (17). General Protocol A

To a solution of 1-hexyne (16) (60.5 μL, 0.526 mmol) in CH₂Cl₂ (1.5 mL) was added zirconocene hydrochloride (156 mg, 0.605 mmol) and the resulting suspension was stirred at rt for 10 min. The resulting yellow solution was cooled to 0 °C and Me₃Al (1.0 M in CH₂Cl₂, 0.605 mL, 0.605 mmol) and 15 (85.0 mg, 0.263 mmol) were added. The mixture was warmed to rt and stirred at this temperature for 1 h, quenched with sat. aq. NH₄Cl, and extracted with CH₂Cl₂. The organic layers were separated, dried (MgSO₄) and concentrated. The residue was purified by chromatography on SiO₂ (EtOAc:hexanes, 3:7) to yield 65.1 mg (81%) of 17 as a colorless oil: IR (neat) 3479, 3031, 2927, 2857, 1694, 1615, 1400, 972 cm⁻¹; ¹H NMR δ 7.91-7.86 (m, 1 H), 7.56-7.42 (m, 2 H), 7.36-7.21 (m, 6 H), 5.90 (dt, 1 H, J = 15.0, 6.8 Hz), 5.30 (d, 1 H, J = 14.8 Hz), 5.09 (dd, 1 H, J = 15.2, 9.2 Hz), 4.70 (d, 1 H, J = 9.2 Hz), 4.17 (d, 1 H, J = 14.9 Hz), 2.13 (app q, 2 H, J = 6.7 Hz), 1.50-1.30 (m, 4 H), 0.94 (t, 3 H, J = 7.2 Hz); ¹³C NMR δ 167.9, 145.1, 138.3, 137.5, 131.8, 131.5, 128.6, 128.3, 127.3, 126.1, 123.6, 123.0, 62.7, 43.8, 31.8, 31.1, 22.1, 13.8; MS (EI) m/z (rel intensity) 305 ([M]⁺, 100), 248 (40), 237 (70), 214 (40); HRMS (EI) m/z calcd for C₂₁H₂₃NO 305.1780, found 305.1785.

(E)-2-Benzyl-3-(2-cyclohexylvinyl)isoindolin-1-one (19)

According to general protocol A, alkyne 18 (66.9 mg, 0.618 mmol), CH₂Cl₂ (1.5 mL), zirconocene hydrochloride (183 mg, 0.711 mmol), Me₃Al (1.0 M in CH₂Cl₂, 0.711 mL, 0.711 mmol) and 15 (100 mg, 0.309 mmol) afforded 80.8 mg (79%) of 19 as a colorless oil after purification on SiO₂ (EtOAc:hexanes, 3:7): IR (neat) 3375, 3030, 2921, 2851, 2243, 1220, 1200, 1097, 844 cm⁻¹; ¹H NMR δ 7.92-7.86 (m, 1 H), 7.54-7.41 (m, 2 H), 7.35-7.20 (m, 6 H), 5.85 (dd, 1 H, J = 15.3, 6.6 Hz), 5.28 (d, 1 H, J = 14.8 Hz), 5.02 (ddd, 1 H, J = 15.3, 9.2, 1.2 Hz), 4.67 (d, 1 H, J = 9.2 Hz), 4.18 (d, 1H, J = 14.8 Hz), 2.14-1.96 (m, 1 H), 1.85-1.60 (m, 4 H), 1.42-1.00 (m, 6 H); ¹³C NMR δ 167.9, 145.1, 144.1, 137.4, 131.8, 131.4, 128.5, 128.3, 128.2, 127.3, 123.6, 122.9, 62.8, 43.8, 40.3, 32.6, 26.0, 25.8; MS (EI) m/z (rel intensity) 331 ([M]⁺, 86), 248 (40), 237 (100); HRMS (EI) m/z calcd for C₂₃H₂₅NO 331.1936, found 331.1951.

(E)-2-Benzyl-3-(4-(tert-butyldiphenylsilyloxy)but-1-enyl)isoindolin-1-one (21)

According to general protocol A, alkyne 20 (94.4 mg, 0.306 mmol), CH₂Cl₂ (1 mL), zirconocene hydrochloride (78.9 mg, 0.306 mmol), Me₃Al (1.0 M in CH₂Cl₂, 0.306 mL, 0.306 mmol) and 15 (50.0 mg, 0.153) afforded 57.6 mg (71%) of 21 as a colorless oil after purification on SiO₂ (EtOAc:hexanes, 2:8): IR (neat) 3450, 2930, 2857, 1692, 1428, 1111, 735, 701 cm⁻¹; ¹H NMR δ 7.92-7.86 (m, 1 H), 7.72-7.65 (m, 4 H), 7.53-7.35 (m, 9 H), 7.32-7.21 (m, 5 H), 5.96 (dt, 1 H, J = 15.3, 6.8 Hz), 5.27 (d, 1 H, J = 14.9 Hz), 5.16 (dddd, 1 H, J = 15.3, 9.1, 1.2, 1.2 Hz), 4.71 (d, 1 H, J = 9.1 Hz), 4.16 (d, 1 H, J = 14.9 Hz), 3.77 (dt, 2 H, J = 6.3, 1.2 Hz), 2.37 (app q, 2 H, J = 6.6 Hz), 1.08 (s, 9 H); ¹³C NMR δ 168.0, 144.9, 137.5, 135.6, 134.8, 133.8, 131.9, 131.5, 129.7, 128.6, 128.4, 128.2, 127.7, 127.4, 123.6, 123.1, 63.2, 62.6, 43.9, 35.6, 26.9, 19.2; MS (EI) m/z (rel intensity) 532 ([M]⁺, 35), 488 (100), 474 (45), 306 (65), 252 (75); HRMS (EI) m/z calcd for C₃₅H₃₇NO₂Si 532.2664, found 532.2664.

(E)-Methyl 4-(2-benzyl-3-oxoisoindolin-1-yl)but-3-enyl(tosyl)carbamate (23)

According to general protocol A, alkyne 22 (174 mg, 0.618 mmol), CH₂Cl₂ (1.5 mL), zirconocene hydrochloride (183 mg, 0.711 mmol), Me₃Al (1.0 M in CH₂Cl₂, 0.711 mL, 0.711 mmol) and 15 (100 mg, 0.309) afforded 95.1 mg (62%) of 23 as a colorless oil after purification on SiO₂ (acetone:CH₂Cl₂, 0.3:9.7): IR (neat) 3467, 3032, 2957, 2245, 1735, 1686, 1359, 1168, 733 cm⁻¹; ¹H NMR δ 7.92-7.78 (m, 3 H), 7.56-7.41 (m, 2 H), 7.39-7.18 (m, 9 H), 5.93 (dt, 1 H, J = 15.2, 7.0 Hz), 5.26 (d, 1 H, J = 14.9 Hz), 5.21 (dd, 1 H, J = 15.1, 9.1 Hz), 4.73 (d, 1 H, J = 9.0), 4.18 (d, 1 H, J = 14.9 Hz), 3.95 (t, 2 H, J = 7.0 Hz), 3.69 (s, 3 H), 2.58 (app q, 2 H, J = 7.0 Hz), 2.43 (s, 3 H); ¹³C NMR δ 168.0, 152.8, 144.8, 144.6, 137.4, 136.5, 133.0, 131.7, 131.6, 129.7, 129.4, 128.6, 128.3, 128.3, 127.4, 123.6, 123.2, 62.3, 53.8, 46.5, 43.8, 32.9, 21.6; MS (EI) m/z (rel intensity) 504 ([M]⁺, 50), 262 (40), 155 (100); HRMS (EI) m/z calcd for C₂₈H₂₈N₂O₅S 504.1719, found 504.1724.

1-Benzyl-3,3-dimethylpyrrolidine-2,5-dione (24)

A mixture of 2,2-dimethylsuccinic anhydride (710 mg, 5.55 mmol) and benzyl amine (712 mg, 6.66 mmol, 1.2 eq) was heated over a bunsen burner for ~ 1 min. The cooled mixture was purified by chromatography on SiO₂ (EtOAc:hexanes, 1:1) to furnish 1.14 g (95%) of 24 as a colorless oil: IR (neat) 2969, 2933, 1777, 1702, 1344, 1142, 709 cm⁻¹; ¹H NMR δ 7.29-7.21 (m, 5 H), 4.57 (s, 2 H), 2.47 (s, 2 H), 1.22 (s, 6 H); ¹³C NMR δ 182.5, 175.1, 135.8, 128.3, 128.1, 127.5, 43.2, 42.0, 39.7, 25.1; MS (EI) m/z (rel intensity) 217 ([M]⁺, 100), 174 (33), 133 (22); HRMS (EI) m/z calcd for C₁₃H₁₅NO₂ 217.1103, found 217.1104.

1-Benzyl-4,4-dimethyl-5-oxopyrrolidin-2-yl pivaloate (25)

A solution of imide 24 (1.14 g, 5.25 mmol) in MeOH (53 mL) was treated with NaBH₄ (200 mg, 2.62 mmol) at ambient temperature. After 6 h, the reaction mixture was concentrated, the residue dissolved in CH₂Cl₂ (50 mL) and treated with sat. aq. NH₄Cl. The aqueous layer was separated and washed with CH₂Cl₂ (2×) and the combined organic layers were dried (MgSO₄), filtered, concentrated and the resulting oil used without further purification. A solution of the crude oil in CH₂Cl₂ (50 mL) was treated sequentially with Et₃N (2.19 mL, 15.7 mmol, 3 eq), DMAP (128 mg, 1.05 mmol, 20 mol %) and pivaloyl chloride (1.29 mL, 10.5 mmol, 2 eq) at ambient temperature. After 6 h, the reaction mixture was quenched with 3 M HCl and the aqueous layer washed with CH₂Cl₂ (3×). The combined organic layers were washed with H₂O, dried (MgSO₄), filtered, and concentrated. The residue was purified by chromatography on SiO₂ (EtOAc:hexanes, 1:2) to yield 398 mg (25%) of 25 as a colorless oil: IR (neat) 2971, 1710, 1419, 1125, 707 cm⁻¹; ¹H NMR δ 7.33-7.21 (m, 5 H), 5.99 (d, 1 H, J = 6.3 Hz), 4.74 (d, 1 H, J = 14.7 Hz), 4.15 (d, 1 H, J = 14.7 Hz), 2.14 (dd, 1 H, J = 14.1, 6.3 Hz), 1.87 (d, 1 H, J = 14.4 Hz), 1.32 (s, 3 H), 1.22 (s, 3 H), 1.10 (s, 9 H); ¹³C NMR δ 180.6, 177.9, 136.6, 128.7, 128.2, 127.6, 82.1, 44.8, 41.5, 39.3, 38.7, 26.8, 26.5, 25.6; MS (EI) m/z (rel intensity) 303 ([M]⁺, 36), 275 (15), 202 (85), 158 (46); HRMS (EI) m/z calcd for C₁₈H₂₅NO₃ 303.1834, found 303.1827.

(E)-1-Benzyl-5-(hex-1-enyl)-3,3-dimethylpyrrolidin-2-one (26)

According to general protocol A, hexyne (16) (9.77 mg, 0.119 mmol), CH₂Cl₂ (1 mL), zirconocene hydrochloride (30.7 mg, 0.119 mmol), Me₃Al (1.0 M in CH₂Cl₂, 0.119 mL, 0.119 mmol) and 25 (18.0 mg, 0.0593 mmol) afforded 14.0 mg (83%) of 26 as a colorless oil after purification on SiO₂ (EtOAc:hexanes, 2.5:7.5): IR (neat) 2958, 2928, 2868, 1692, 1411, 1262, 972, 752 cm⁻¹; ¹H NMR δ 7.35-7.23 (m, 3 H), 7.21-7.13 (m, 2 H), 5.53 (dt, 1 H, J = 15.0, 6.6 Hz), 5.16 (dd, 1 H, J = 15.3, 9.0 Hz), 4.94 (d, 1 H, J = 14.4 Hz), 3.88 (d, 1 H, J = 14.4 Hz), 3.73 (app q, 1 H, J = 7.8 Hz), 2.10-1.98 (m, 2 H), 1.99 (dd, 1 H, J = 12.9, 7.2 Hz), 1.58 (dd, 1 H, J = 12.9, 8.1 Hz), 1.42-1.28 (m, 4 H), 1.24 (s, 3 H), 1.11 (s, 3 H), 0.92 (t, 3 H, J = 6.9 Hz); ¹³C NMR δ 179.6, 137.2, 135.8, 129.8, 128.4, 128.3, 127.2, 56.9, 44.2, 42.0, 40.3, 31.8, 31.2, 25.5, 24.7, 22.2, 13.9; MS (EI) m/z (rel intensity) 285 ([M]⁺, 20), 228 (20), 175 (30), 91 (100); HRMS (EI) m/z calcd for C₁₉H₂₇NO 285.2093, found 285.2090.

(E)-2-Benzyl-3-(2-methylhex-1-enyl)isoindolin-1-one (27)

General Protocol B

To a −30 °C solution of AlMe₃ (89.0 mg, 1.24 mmol) and Cp₂ZrCl₂ (9.00 mg, 0.0309 mmol) in CH₂Cl₂ (1.5 mL) was added H₂O (11.1 mg, 0.619 mmol) dropwise. The reaction mixture was warmed to ambient temperature, cooled to 0 °C, treated with 1-hexyne (16) (71.0 μL, 0.619 mmol), stirred for 30 min and treated with 15 (100 mg, 0.309 mmol). The reaction mixture was warmed to rt and stirred at this temperature for 1 h, quenched with sat. aq. NH₄Cl, and extracted with CH₂Cl₂. The organic layers were separated, dried (MgSO₄) and concentrated. The residue was purified by chromatography on SiO₂ (EtOAc:hexanes, 3:7) to yield 76.0 mg (77%) of 27 as a colorless oil: IR (neat) 2956, 2929, 2858, 1694, 1468, 1401, 749, 703 cm⁻¹; ¹H NMR δ 7.89-7.50 (m, 1 H), 7.53-7.40 (m, 2 H), 7.35-7.20 (m, 6 H), 5.31 (d, 1 H, J = 14.9 Hz), 5.06 (d, 1 H, J = 9.8), 4.81 (dq, 1 H, J = 9.8, 1.2 Hz), 4.09 (d, 1 H, J = 14.9 Hz), 2.07 (t, 2 H, J = 7.1 Hz), 1.67 (d, 3 H, J = 1.3 Hz), 1.50-1.22 (m, 4 H), 0.91 (t, 3 H, J = 7.2 Hz); ¹³C NMR δ 168.1, 145.7, 143.4, 137.5, 132.0, 131.4, 128.5, 128.2, 128.0, 127.3, 123.6, 122.8, 120.6, 57.9, 43.9, 39.3, 29.8, 22.2, 16.5, 13.8; MS (EI) m/z (rel intensity) 319 ([M]⁺, 100), 221 (40); HRMS (EI) m/z calcd for C₂₂H₂₅NO 319.1936, found 319.1921.

(E)-2-Benzyl-3-(2-phenylprop-1-enyl)isoindolin-1-one (29)

According to general protocol B, alkyne 28 (68.0 μL, 0.619 mmol), AlMe₃ (89.0 mg, 1.24 mmol), Cp₂ZrCl₂ (9.00 mg, 0.0309 mmol), CH₂Cl₂ (1.5 mL), H₂O (11.1 mg, 0.619 mmol) and 15 (100 mg, 0.309 mmol) afforded 81.0 mg (77%) of 29 as a colorless oil and a 95:5 mixture of regioisomers after purification on SiO₂ (EtOAc:hexanes, 1:3): Major isomer: IR (neat) 3030, 2918, 1693, 1602, 1432, 1400, 1250, 749 cm⁻¹; ¹H NMR δ 7.93 (dd, 1 H, J = 6.3, 2.1 Hz), 7.54-7.46 (m, 2 H), 7.35-7.26 (m, 11 H), 5.41 (dd, 1 H, J = 9.6, 0.9 Hz), 5.35 (d, 1 H, J = 15.0 Hz), 5.27 (d, 1 H, J = 9.9 Hz), 4.21 (d, 1 H, J = 15.0 Hz), 2.12 (d, 3 H, J = 0.9 Hz); ¹³C NMR δ 168.1, 145.0, 142.0, 141.3, 137.4, 132.0, 131.6, 128.6, 128.3, 127.8, 127.5, 125.8, 123.8, 123.7, 122.9, 58.2, 44.3, 16.3; MS (EI) m/z (rel intensity) 339 ([M]⁺, 41), 248 (47), 234 (77), 91 (100); HRMS (EI) m/z calcd for C₂₄H₂₁NO 339.1623, found 339.1631. Minor isomer (characteristic peaks): ¹H NMR δ 1.44 (d, 3 H, J = 6.9 Hz); ¹³C NMR δ 128.0, 121.9, 18.0;

(E)-(3-(Pent-4-ynyloxy)prop-1-enyl)benzene (30)

To a solution of 4-pentyn-1-ol (4.03 mL, 43.3 mmol) in hexanes (75 mL) was added 50% NaOH (75 mL), TBAI (801 mg, 2.17 mmol) and cinnamyl bromide (8.97 g, 45.5 mmol). The reaction mixture was rapidly stirred for 10 h. The organic layer was separated, dried (MgSO₄) and concentrated. The residue was purified by chromatography on SiO₂ (EtOAc:hexanes, 1:9) to yield 9.00 g (69%) of 30 as a colorless oil: IR (neat) 3298, 3027, 2951, 2854, 2117, 1478, 1365, 1111, 967 cm⁻¹; ¹H NMR δ 7.44-7.37 (m, 2 H), 7.37-7.27 (m, 2 H), 7.27-7.21 (m, 1 H), 6.62 (d, 1 H, J = 15.9 Hz), 6.30 (dt, 1 H, J = 15.9, 6.0), 4.15 (dd, 2 H, J = 6.0, 0.9 Hz), 3.60 (t, 2 H, J = 6.3 Hz), 2.34 (dt, 2 H, J = 7.2, 2.7 Hz), 1.96 (t, 1 H, J = 2.7 Hz), 1.85 (app p, 2 H, J = 6.6 Hz); ¹³C NMR δ 136.5, 131.8, 128.3, 127.4, 126.2, 126.0, 83.7, 71.2, 68.5, 68.3, 28.5, 15.1; MS (EI) m/z (rel intensity) 199 ([M]⁺, 100), 186 (35), 173 (35), 131 (100); HRMS (EI) m/z calcd for C₁₄H₁₆O 199.1123, found 199.1126.

2-Allyl-3-oxoisoindolin-1-yl pivaloate (31)

To a solution of 2-allylisoindoline-1,3-dione (3.64 g, 19.4 mmol) in MeOH (100 mL) was added sodium borohydride (734 mg, 19.4 mmol) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 2 h and carefully quenched with H₂O. The aqueous layer was extracted with EtOAc (2×) and the organic layer was separated, dried (MgSO₄) and concentrated. The residue was dried to yield a white solid which was carried on to the next step without further purification. To a solution of the crude reduced phthalamide (3.60 g, 19.0 mmol) in THF (100 mL) was added Et₃N (7.90 mL, 57.0 mmol) and pivaloyl chloride (2.81 mL, 22.8 mmol) at 0 °C and the reaction mixture was allowed to warm to rt and stirred at this temperature for 4 h. The mixture was quenched with sat. aq. NaHCO₃, extracted with EtOAc (2×), dried (MgSO₄) and concentrated. The residue was purified by chromatography on SiO₂ (EtOAc:hexanes, 2.5:7.5) to yield 4.40 g (83% over 2 steps) of 31 as a colorless oil: IR (neat) 2976, 1716, 1405, 1135, 753; ¹H NMR δ 7.88-7.80 (m, 1 H), 7.62-7.46 (m, 3 H), 6.99 (s, 1 H), 5.94-5.77 (m, 1 H), 5.29-5.15 (m, 2 H), 4.44 (dd, 1 H, J = 15.9, 5.1 Hz), 3.88 (dd, 1 H, J = 15.3, 6.6 Hz), 1.23 (s, 9 H) cm^{−1; 13}C NMR δ 178.3, 167.5, 141.2, 132.4, 132.4, 131.8, 130.0, 123.6, 123.5, 118.0, 80.9, 42.8, 39.0, 26.9; MS (EI) m/z (rel intensity) 273 ([M]⁺, 60), 172 (100; HRMS (EI) m/z calcd for C₁₆H₁₉NO₃ 273.1365, found 273.1358.

2-Allyl-3-((E)-5-(cinnamyloxy)pent-1-enyl)isoindolin-1-one (32)

According to general protocol A, alkyne 30 (733 mg, 3.66 mmol), CH₂Cl₂ (10 mL), zirconocene hydrochloride (944 mg, 3.66 mmol), Me₃Al (1.0 M in CH₂Cl₂, 3.66 mL, 3.66 mmol) and 31 (500 mg, 1.83 mmol) (reaction time increased to 12 h) afforded 376 mg (55%) of 32 as a colorless oil after purification on SiO₂ (Acetone:CH₂Cl₂, 0.7:9.3): IR (neat) 2924, 2853, 1694, 1468, 1289, 1098, 968, 746 cm⁻¹; ¹H NMR δ 7.85 (d, 1 H, J = 6.6 Hz), 7.57-7.20 (m, 8 H), 6.61 (d, 1 H, J = 15.9 Hz), 6.29 (dt, 1 H, J = 15.9, 6.0 Hz), 6.02 (dt, 1 H, J = 13.8, 6.9 Hz), 5.90-5.73 (m, 1 H), 5.25-5.07 (m, 3 H), 4.87 (d, 1 H, J = 9.0 Hz), 4.60 (ddd, 1 H, J = 15.6, 4.5, 2.7 Hz), 4.15 (dd, 2 H, J = 6.0, 1.2 Hz), 3.70 (dd, 1 H, J = 15.3, 7.2 Hz), 3.53 (t, 2 H, J = 6.3 Hz), 2.25 (app q, 2 H, J = 6.9 Hz), 1.77 (app p, 2 H, J = 7.8 Hz); ¹³C NMR δ 167.7, 144.9, 137.2, 136.6, 133.2, 132.3, 131.8, 131.4, 128.5, 128.3, 127.6, 126.7, 126.4, 126.1, 123.5, 122.9, 117.5, 71.5, 69.4, 62.9, 42.5, 29.2, 28.9; MS (ESI) m/z (rel intensity) 396 ([M+Na]⁺, 100), 307 (20), 297 (20); HRMS (ESI) m/z calcd for C₂₅H₂₇NO₂Na 396.1939, found 396.1928.

3H-Pyrrolo[2,1-a]isoindol-5(9bH)-one (33)

To a solution of 32 (41.7 mg, 0.112 mmol) in CH₂Cl₂ (6 mL) was added Grubbs 2^nd generation catalyst (4.75 mg, 5.60 μmol) and the red solution was heated at 50 °C for 1 h, cooled to rt and concentrated. The residue was purified by chromatography on SiO₂ (Acetone:CH₂Cl₂, 0.4:9.6) to yield 11.7 mg (61%) of 33 as a colorless oil: IR (neat) 2872, 1614, 1468, 1395, 1366, 1080, 746 cm⁻¹; ¹H NMR (acetone-d₆) δ 7.74-7.66 (m, 2 H), 7.66-7.58 (m, 1 H), 7.54-7.45 (m, 1 H), 6.28-6.20 (m, 1 H), 6.08-5.99 (m, 1 H), 5.53 (app d, 1 H, J = 1.8 Hz), 4.57-4.43 (m, 1 H), 3.98-3.83 (m, 1 H); ¹³C NMR (acetone-d₆) δ 175.4, 148.4, 133.6, 133.1, 131.9, 129.4, 129.2, 124.6, 124.0, 71.1, 52.0; MS (EI) m/z (rel intensity) 171 ([M]⁺, 60), 160 (70), 130 (55), 105 (60), 83 (100); HRMS (EI) m/z calcd for C₁₁H₉NO 171.0684, found 171.0676.

(E)-2-Allyl-3-(hex-1-enyl)isoindolin-1-one (34)

According to general protocol A, 1-hexyne (16) (420 μL, 3.66 mmol), CH₂Cl₂ (10 mL), zirconocene hydrochloride (944 mg, 3.66 mmol), Me₃Al (1.0 M in CH₂Cl₂, 3.66 mL, 3.66 mmol) and 31 (500 mg, 1.83 mmol) afforded 341 mg (73%) of 34 as a colorless oil after purification on SiO₂ (EtOAc:hexanes, 3:7): IR (neat) 2957, 2926, 1697, 1468, 1396, 971, 748 cm⁻¹; ¹H NMR δ 7.83 (d, 1 H, J = 7.2 Hz), 7.57-7.38 (m, 2 H), 7.33 (d, 1 H, J = 7.5 Hz), 5.97 (dt, 1 H, J = 15.0, 6.9 Hz), 5.88-5.71 (m, 1 H), 5.22-4.97 (m, 3 H), 4.85 (d, 1 H, J = 9.3 Hz), 4.59 (dd, 1 H, J = 15.6, 4.5 Hz), 3.69 (dd, 1 H, J = 15.3, 7.2 Hz), 2.12 (app q, 2 H, J = 6.6 Hz), 1.48-1.28 (m, 4 H), 0.91 (t, 3 H, J = 6.9 Hz); ¹³C NMR δ 167.7, 145.0, 138.2, 133.1, 131.7, 131.4, 128.2, 126.0, 123.4, 122.9, 117.4, 62.9, 42.5, 31.8, 31.1, 27.0, 22.0, 13.8; MS (EI) m/z (rel intensity) 255 ([M]⁺, 30), 198 (100), 172 (55); HRMS (EI) m/z calcd for C₁₇H₂₁NO 255.1623, found 255.1627.

2-(Pent-4-enyl)isoindoline-1,3-dione (35)

A solution of 4-penten-1-ol (3.51 mL, 34.0 mmol), phthalimide 4 (5.00 mg, 34.0 mmol), and PPh₃ (8.92 g, 34.0 mmol) in THF (220 mL) was cooled to 0 °C and treated with DIAD (6.69 mL, 34.0 mmol) over 5 min. The reaction mixture was warmed to rt and stirred for 6 h. The solvent was evaporated, the residue was dissolved in EtOAc/hexanes (1:1, 100 mL) and the solids were filtered off. The filtrate was concentrated and chromatographed on SiO₂ (EtOAc:hexanes, 1:5) to yield 6.44 g (88%) of imide 35 as a colorless oil: IR (neat) 3466, 3077, 2939, 1773, 1641, 1397, 995, 720 cm⁻¹; ¹H NMR δ 7.88-7.81 (m, 2 H), 7.76-7.67 (m, 2 H), 5.90-5.73 (m, 1 H), 5.12-4.94 (m, 2 H), 3.70 (dt, 2 H, J = 7.5, 4.5 Hz), 2.20-2.07 (m, 2 H), 1.87-1.73 (m, 2 H); ¹³C NMR δ 168.1, 137.1, 133.7, 131.9, 122.9, 115.1, 37.3, 30.8, 27.4; MS (EI) m/z (rel intensity) 215 ([M]⁺, 45), 173 (70), 160 (100), 148 (80), 130 (80), 104 (90); HRMS (EI) m/z calcd for C₁₃H₁₃NO₂ 215.0946, found 215.0946.

3-Oxo-2-(pent-4-enyl)isoindolin-1-yl pivalate (36)

To a solution of imide 35 (4.42 g, 20.5 mmol) in MeOH (100 mL) was added sodium borohydride (776 mg, 20.5 mmol) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 2 h and carefully quenched with H₂O. The aqueous layer was extracted with EtOAc (2×) and the organic layer was separated, dried (MgSO₄) and concentrated. The residue was dried to yield a white solid which was carried on to the next step without further purification. To a solution of the crude reduced phthalamide (4.23 g, 19.5 mmol) in THF (100 mL) was added Et₃N (8.15 mL, 58.5 mmol), pivaloyl chloride (3.61 mL, 29.3 mmol) and DMAP (119 mg, 0.975 mmol) at 0 °C and the reaction mixture was allowed to warm to rt and stirred at this temperature for 8 h. The mixture was quenched with sat. aq. NaHCO₃, extracted with EtOAc (2×), dried (MgSO₄) and concentrated. The residue was purified by chromatography on SiO₂ (EtOAc:hexanes, 1:5) to yield 4.70 g (76% over 2 steps) of 36 as a colorless oil: IR (neat) 3077, 2974, 2873, 1739, 1641, 1618, 1369, 1208, 1141, 959, 751 cm⁻¹; ¹H NMR δ 7.67 (d, 1 H, J = 6.0 Hz), 7.49-7.32 (m, 3 H), 6.89 (s, 1 H), 5.79-5.58 (m, 1 H), 4.91 (d, 1 H, J = 17.1 Hz), 4.84 (d, 1 H, J = 10.5 Hz), 3.73-3.55 (m, 1 H), 3.27-3.09 (m, 1 H), 2.07-1.93 (m, 2 H), 1.77-1.50 (m, 2 H), 1.11 (s, 9 H); ¹³C NMR δ 178.2, 167.4, 140.9, 137.1, 132.0, 131.8, 129.8, 123.2, 123.1, 114.9, 80.8, 39.5, 38.7, 30.7, 27.1, 26.6; MS (EI) m/z (rel intensity) 301 ([M]⁺, 15), 246 (45), 216 (65), 200 (85), 146 (85), 133 (65); HRMS (EI) m/z calcd for C₁₈H₂₃NO₃ 301.1678, found 301.1681.

(E)-3-(Hex-1-enyl)-2-(pent-4-enyl)isoindolin-1-one (37)

According to general protocol A, hexyne (16) (420 μL, 3.66 mmol), CH₂Cl₂ (10 mL), zirconocene hydrochloride (944 mg, 3.66 mmol), Me₃Al (1.0 M in CH₂Cl₂, 3.66 mL, 3.66 mmol) and 36 (552 mg, 1.83 mmol) afforded 368 mg (72%) of 37 as a colorless oil after purification on SiO₂ (EtOAc:hexanes, 3:7): IR (neat) 3076, 2967, 2928, 2860, 1693, 1468, 1404, 972, 749 cm⁻¹; ¹H NMR δ 7.72 (d, 1 H, J = 7.5 Hz), 7.44-7.28 (m, 2 H), 7.23 (d, 1 H, J = 7.2 Hz), 5.94 (dt, 1 H, J = 14.4, 6.6 Hz), 5.80-5.63 (m, 1 H), 5.03-4.82 (m, 3 H), 4.75 (d, 1 H, J = 9.0 Hz), 3.83-3.65 (m, 1 H), 3.23-3.07 (m, 1 H), 2.13-1.93 (m, 4 H), 1.75-1.51 (m, 2 H), 1.42-1.19 (m, 4 H), 0.83 (t, 3 H, J = 6.9 Hz); ¹³C NMR δ 167.6, 144.6, 137.5, 137.3, 131.7, 131.0, 127.9, 126.2, 122.9, 122.6, 114.7, 63.2, 39.4, 31.5, 30.8, 30.7, 27.3, 26.9, 21.8, 13.5; MS (EI) m/z (rel intensity) 283 ([M]⁺, 20), 228 (70), 160 (100), 146 (50), 76 (50); HRMS (EI) m/z calcd for C₁₉H₂₅NO 283.1936, found 283.1934.

(Z)-7,8,9,11a-Tetrahydro-5H-azepino[2,1-a]isoindol-5-one (38)

To a solution of 37 (150 mg, 0.529 mmol) in toluene (100 mL) was added Ti(OⁱPr)₄ (157 μL, 0.529 mmol) and Grubbs 2^nd generation catalyst (22.5 mg, 0.0265 mmol) and the red solution was stirred at rt for 12 h and concentrated. The residue was purified by chromatography on SiO₂ (Acetone:CH₂Cl₂, 0.4:9.6) to yield 70.7 mg (67%) of 38 as a colorless oil: IR (neat) 3024, 2926, 1680, 1469, 1419, 1298, 938, 709 cm⁻¹; ¹H NMR (CD₂Cl₂) δ 7.76 (dd, 1 H, J = 6.9, 1.2 Hz), 7.58-7.51 (m, 1 H), 7.46 (app t, 2 H, 7.2 Hz), 6.13-6.02 (m, 1 H), 6.02-5.91 (m, 1 H), 4.49 (dd, 1 H, J = 11.4, 2.1 Hz), 4.26 (ddd, 1 H, J = 13.5, 6.6, 3.0 Hz), 3.22 (ddd, 1 H, J = 12.6, 9.6, 2.7 Hz), 2.81 (app ddd, 1 H, J = 15.9, 7.8, 2.4 Hz), 2.53-2.26 (m, 2 H), 2.25-2.09 (m, 1 H); ¹³C NMR (CD₂Cl₂) δ 167.5, 145.9, 133.0, 132.7, 131.6, 128.8, 128.5, 123.5, 122.4, 60.6, 41.6, 35.2, 28.2; MS (EI) m/z (rel intensity) 199 ([M]⁺, 45), 145 (100), 117 (40), 90 (35); HRMS (EI) m/z calcd for C₁₃H₁₃NO 199.0997, found 199.0991.