SnAP Reagents

Introduction to Saturated N-heterocycle Building Blocks (SnAP)

Saturated N-heterocyclic building blocks are of growing importance but their installation has been challenging due to poor commercial availability and the often long, laborious synthetic routes needed to form these ring systems.

SnAP Reagents are an ever-expanding class of reagents, which are now available for the convenient synthesis of medium-ring (6-9 membered) saturated N-heterocycles, including bicyclic and spirocyclic structures. In collaboration with the Bode research group, many of the SnAP Reagents are now commercially available, and custom-made reagents for specific applications or targets can also be prepared from simple starting materials.

Advantages of SnAP Reagents

SnAP reagents are stable and readily available and can be coupled with widely available aromatic, heteroaromatic, aliphatic, and glyoxylic aldehydes using versatile and predictable methodology, developed within the Bode group, for the synthesis of saturated N-heterocycles. A general procedure from the review is shown below.

Procedure for Synthesis of N-Heterocycles Using SnAP Reagents

1. 1 equiv (0.50 mmol) of amino tributylstannane (SnAP Reagent) was dissolved in 2.5 mL CH₂Cl₂.
2. To this solution, 1 equiv (0.50 mmol) of the correspond aldehyde and 4Å molecular sieves (ca. 100 mg/mmol) were added. The reaction mixture was stirred at room temperature for 2 hours and filtered through a short layer of Celite (CH₂Cl₂ rinse).
3. The filtrate was concentrated under reduced pressure to afford the pure imine.
4. Separately, 1 equiv (0.50 mmol) of 2,6-lutidine, 2.0 mL of HFIP, and 1 equiv (0.50 mmol) of anhydrous Cu(OTf)₂ were stirred at room temperature for 1 hour, forming a homogeneous suspension.
5. To this homogeneous suspension, 8.0 mL CH₂Cl₂ and the imine from Step 3 was added at once and stirred at room temperature for 12 hours.
6. The reaction was quenched with 5 mL 10% aq NH₄OH and stirred vigorously for 15 minutes.
7. The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3 x 3 mL). The combined organic layers were washed with H₂O (3 x 5 mL) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated.
8. Purification by flash column chromatography affords the corresponding N-heterocycle.

References

1. Vo CT, Mikutis G, Bode JW. 2013. SnAP Reagents for the Transformation of Aldehydes into Substituted Thiomorpholines-An Alternative to Cross-Coupling with Saturated Heterocycles. Angew. Chem. Int. Ed.. 52(6):1705-1708. https://doi.org/10.1002/anie.201208064

2. Luescher MU, Vo CT, Bode JW. 2014. SnAP Reagents for the Synthesis of Piperazines and Morpholines. Org. Lett.. 16(4):1236-1239. https://doi.org/10.1021/ol500210z

3. Siau W, Bode JW. 2014. One-Step Synthesis of Saturated Spirocyclic N-Heterocycles with Stannyl Amine Protocol (SnAP) Reagents and Ketones. J. Am. Chem. Soc.. 136(51):17726-17729. https://doi.org/10.1021/ja511232b

4. Vo CT, Luescher MU, Bode JW. 2014. SnAP reagents for the one-step synthesis of medium-ring saturated N-heterocycles from aldehydes. Nature Chem. 6(4):310-314. https://doi.org/10.1038/nchem.1878

5. Geoghegan K, Bode JW. 2015. Bespoke SnAP Reagents for the Synthesis of C-Substituted Spirocyclic and Bicyclic Saturated N-Heterocycles. Org. Lett.. 17(8):1934-1937. https://doi.org/10.1021/acs.orglett.5b00618