Ynamide Carbopalladation: A Flexible Route to Mono-, Bi- and Tricyclic Azacycles

Bromoenynamides represent precursors to a diversity of azacycles by a cascade sequence of carbopalladation followed by cross-coupling/electrocyclization, or reduction processes. Full details of our investigations into intramolecular ynamide carbopalladation are disclosed, which include the first examples of carbopalladation/cross-coupling reactions using potassium organotrifluoroborate salts; and an understanding of factors influencing the success of these processes, including ring size, and the nature of the coupling partner. Additional mechanistic observations are reported, such as the isolation of triene intermediates for electrocyclization. A variety of hetero-Diels–Alder reactions using the product heterocycles are also described, which provide insight into Diels–Alder regioselectivity.

where volatile bromoalkynes were prepared, some residual THF remained in the concentrate.

General procedure D: Silver-catalyzed bromination of alkynes with NBS
To a solution of terminal alkyne (1.0 equiv.) in acetone (1 mL mmol -1 ) was added AgNO 3 (2.5 mol%). After stirring for 5 min, N-bromosuccinimide (1.1 equiv.) was added, and the mixture stirred for a further 4-15 h at rt until complete as judged by tlc. The mixture was then diluted with petroleum ether and filtered through a short silica pad (petroleum ether eluent). The resulting solution was concentrated, to obtain the corresponding bromoalkyne.

General Procedure F: Stille cascade cyclisation to amidodienes
To a reaction vessel containing PdCl 2 (PPh 3 ) 2 (1 or 10 mol%) under Ar was added a degassed (Ar bubbling, 15 min) solution of the bromoenynamide (1.0 equiv.) and stannane coupling partner (1.6 equiv) in toluene (16.7 mL mmol -1 ). The reaction mixture was then heated to 95 °C under Ar until the reaction was judged complete by TLC (4-24 h). The reaction was then cooled to rt, and concentrated. Purification via flash chromatography (EtOAc / petroleum ether eluent) afforded the bicyclic dienamide product.

General Procedure G: Suzuki cascade cyclisation to amidodienes
To a reaction vessel containing Pd(PPh 3 ) 4 (5 mol%) and Cs 2 CO 3 (1.5 equiv.) under Ar was added a degassed (Ar bubbling, 15 min) solution of the bromoenynamide (1.0 equiv.) and vinylboronate (1.5 equiv.) in DME (16.7 mL.mmol -1 ). The reaction mixture heated to reflux under Ar until the reaction was judged complete by TLC. The reaction was then cooled to rt and concentrated; purification via flash chromatography afforded the bicyclic dienamide product.

General Procedure H: Reductive cyclization of bromoenynamides to pyrrolidines and piperidines (n = 1, 2)
To a degassed (Ar bubbling, 15 min) solution of bromoenynamide (1.0 equiv.) in EtOH (0.045 M) was added Pd(PPh 3 ) 4 (2.5 mol%) and Cs 2 CO 3 (1.5 equiv.). The reaction mixture was heated to 80 °C until judged complete by TLC, then it was cooled to rt and filtered through a Celite® plug (EtOAc eluent). The filtrate was concentrated, and the residue purified via column chromatography to afford the corresponding exocyclic diene product.

General Procedure I: Reductive cyclization of bromoenynamides to piperidines (n = 2) and azepanes (n = 3)
Method A: To a degassed (Ar bubbling, 15 min) solution of bromoenynamide (1.0 equiv.) in toluene / EtOH (10:1, 0.045 M) was added Pd(PPh 3 ) 4 (10 mol%) and K 2 CO 3 (1.5 equiv.). The reaction mixture was heated to 80 °C until judged complete by TLC (3 x TLC runs on the same plate in 20:1 petroleum ether / EtOAc, to give separation of SM and product). The reaction was then cooled to rt and filtered through a Celite® plug (EtOAc eluent). The filtrate was concentrated, and the residue purified via flash chromatography to afford the corresponding exocyclic diene.

Method B:
To a degassed (Ar bubbling, 15 min) solution of the appropriate bromoenynamide (1.0 equiv.) in toluene / EtOH (1:1, 0.045 M) was added Pd(PPh 3 ) 4 (2.5 mol%) and K 2 CO 3 (1.5 equiv.). The reaction mixture was heated to 80 °C until the reaction was judged complete by TLC (3 x TLC runs on the same plate in 20:1 petroleum ether / EtOAc to give separation). The reaction was tehn cooled to rt and filtered through a Celite® plug (EtOAc eluent). The filtrate was concentrated, and the residue purified via flash chromatography to afford the corresponding exocyclic diene.
General Procedure J: Molander-Suzuki cascade cyclisation to amidodienes NB. No precautions of anhydrous, degassed solvent or inert atmosphere were employed.

2,3-Dibromoprop-1-ene
The procedure of Lespieau and Bourgeul was used for this reaction. [6] To a round bottomed flask, connected to efficient distillation equipment, was added 1,2,3-tribromopropane (419 g, 1.49 mol, 1.0 equiv.), water (22 mL) and NaOH pellets (104 g, 2.61 mol, 1.75 equiv.). An exotherm was observed, then the mixture was heated further using a heat gun, with stirring, until vigorous ebullition occurs, whereupon spontaneous distillation of the product took place; the heat source was immediately removed. When the reaction subsided, the flask was heated as before and the mass became solid as the volatile components were removed. Once all volatile components were removed, the distillate was isolated and washed with water (150 mL). The lower (organic) layer was then distilled in vacuo to yield 2,3-dibromopropene as a colorless oil (203 g, 1.19 mmol, 80%); bp 68 °C at 75 mbar; R f 0.54 (petroleum ether / EtOAc (10:1)); IR (thin film) ν max / cm -

3-Bromobut-3-en-1-aminium acetate, 11, and 3-bromobut-3-en-1-amine, S4
The procedure of Pillai was used for this reaction. [11] Hydrogen sulfide was bubbled through a solution of azide S3 (1.94 g, 11.0 mmol) in pyridine / water (40 mL, 1:1). After 2 h, 2N acetic acid was added until the reaction was neutralized, and the mixture was then concentrated in vacuo, then azeotroped several times with EtOH. The resulting brown oil was dissolved in water, filtered, and concentrated in vacuo, co-evaporating several times with toluene, to give the amine salt 11 as a brown oil (1.79 [11] For subsequent reactions of the free amine (vide infra), 11 was partitioned between sat. aq. NaOH and CH 2 Cl 2 , and the organic layers combined, dried (MgSO 4 ) and concentrated in vacuo to afford the amine S4;  [12] Br N 3 Br AcO -H 3 N + Br NH 2 Preparation of amide derivatives 9a-h:

Br
Preparation by General Procedure D: Synthesised from oct-1-yne (15.0 mL, 102 mmol). The resulting crude material was purified by column chromatography (petroleum ether) to give 13a as a colorless oil (18.4 g, 97.5 mmol, 96%); Data in accordance with the above.
After 10 min, the reaction was quenched with brine (50 mL), concentrated in vacuo* to remove the THF, then extracted with Et 2 O (50 mL). The mixture was concentrated in vacuo* and the product was triturated with petroleum ether (30 mL), again concentrated in vacuo*, and then purified by column chromatography

KHMDS
OBn Br dried (Na 2 SO 4 ), filtered and concentrated in vacuo (20 °C) to obtain the crude aldehyde S11, which was used immediately to prevent racemisation (assumed quantitative). To a mixture of [Ph 3 PCHBr 2 ]Br (4.95 g, 9.61 mmol) in THF (30 mL) at rt was added KOt-Bu (1.03 g, 9.18 mmol), and the mixture was stirred for 20 min. To the generated ylide was added crude (R)-3-(benzyloxy)-2-methylpropanal S11 (856 mg, 4.80 mmol). The mixture was stirred for 10 min at rt, then diluted with petroleum ether (100 mL), and the precipitate removed by filtration, washing with petroleum ether (100 mL). Following concentration, rapid purification through a pad of silica (petroleum ether / Et 2 O, 19:1 eluent) gave the vinyl dibromide S12 as a colorless oil (615 mg), which was used directly in the subsequent step.
To a solution of crude vinyl dibromide S12 (524 mg, 1.57 mmol) in THF (7 mL) -78 °C was added KHMDS  The characterization of ynamides 3a-m has been reported in our earlier communications. [16,23] For ynamides 3n-q, problems encountered using these copper-catalyzed methods necessitated ynamide synthesis using the Witulski method of alkynyl iodonium triflate salts; [24] characterization data for these compounds has also been described previously. [16,23]

Stannane Synthesis
All stannanes employed in this work are known compounds. These were prepared according to the following procedures: Tributylpropenylstannane (19a): Prepared according to the procedure of Moloney et al. [25] Tributylstyrenylstannane (19b): Prepared as 19a. 19a Br Tributylvinylstannane (19c): Prepared according to the procedure of Seyferth and Stone. [26] Tributyl(3,4-dihydro-2H-pyran-6-yl)stannane (19e): Prepared according to the procedure of Quayle et al. [27]   The stereochemistry of 20 was proven by nOe enhancement between protons H2 and H3; the assignment of structure was made on the basis of 1 H NMR chemical shifts for these protons and the associated methyl group, and by analogy to trienes prepared and isolated in earlier work from our group.
This triene was then subjected to a further VT NMR experiment, which confirmed complete conversion to the dienamide 4a, in the absence of catalyst. Notably, consumption of this intermediate was also observed in all standard VT NMR reactions (i.e. in the presence of the catalyst), according to our optimization experiments and as shown in Figure 2 of the paper.

Ynamide carbopalladation / Stille coupling / electrocyclization cascades
These were carried out using General Procedure F.
After addition, the reaction was warmed to rt and stirred for 3 h before being diluted with CH 2 Cl 2 . The organic layer was separated and washed with HCl (1M, aq.
The resulting crude material was purified by column chromatography (petroleum ether / EtOAc, 5:1) to give The assignment of regio-and stereochemistry of the cycloaddition is supported by this compound; 1 H-1 H NMR J values imply the following conformation due to large axial-axial coupling around H4-H6:
The assignment of these characteristic peaks is as follows: 1