Preparation of Tributyl(iodomethyl)stannane

A. Tributyl(chloromethyl)stannane (1). An oven-dried 500-mL pear-shaped recovery flask equipped with a 34 x 16 mm, Teflon-coated, oval magnetic stir bar is charged with anhydrous THF (150 mL) (Note 2) and N,Ndiisopropylamine (10.6 mL, 7.65 g, 75.6 mmol, 1.1 equiv) (Note 3) via a syringe. The flask is fitted with a rubber septum and a nitrogen inlet needle, after which the stir rate is set to ca. 375 rpm (Figure 1A). The reaction is cooled to 0–5 °C using an ice/water bath before the dropwise addition of nBuLi (47.8 mL, 75.6 mmol, 1.1 equiv) (Note 4) via a 20 mL syringe over 25 min (Figure 1B). The resulting clear pale-yellow solution is stirred further at 0–5 °C for 30 min before tributyltin hydride (18.5 mL, 20.0 g, 68.7 mmol, 1.0 equiv) (Note 5) is added dropwise via syringe over 15 min (Figure 1C). The resulting clear yellow solution is stirred further at 0–5 °C for 30 min before paraformaldehyde (2.30 g, 76.6 mmol, 1.1 equiv) (Note 6) is weighed under air into a glass vial and charged in one portion to the reaction flask. Bu3Sn Cl Bu3SnH DIPA, n-BuLi, (CH2)nO, THF; then CH3SO2Cl

The ice/water bath is removed, and the turbid yellow suspension is stirred at 25-27 °C for 3 h during which a discoloration takes place affording a turbid pale-yellow reaction mixture ( Figure 1D).

Figure 1. Color change through the course of the reaction
The resulting turbid reaction solution is cooled in a dry ice-acetone bath for 30 min before methanesulfonyl chloride (6.40 mL, 9.47 g, 82.7 mmol, 1.2 equiv) (Note 7) is added dropwise via a syringe over 10 min ( Figure 1E). The cooling bath is removed, and the resulting pale-yellow suspension is stirred at 25-27 °C for 10 h (Note 8) ( Figure 1F). At this point water (100 mL) is added in one portion using a graduated cylinder and the mixture is stirred further for 15 min.
The contents of the reaction flask are transferred to a 500-mL separatory funnel containing hexanes (150 mL). The aqueous layer is separated and extracted with hexanes (2 x 60 mL). The combined organic layers are washed with saturated NaCl solution (2 x 50 mL), dried over anhydrous MgSO 4 (12 g), and filtered through a 150-mL sintered glass Büchner funnel (medium porosity, 66 mm diameter). The MgSO 4 is washed with hexanes (3 x 10 mL) and the combined filtrate is concentrated by rotary evaporation (40 °C, 20 mmHg) to afford ca. 26 g of a pale-yellow oil (Notes 9 and 10). This material is diluted with hexanes (15 mL) and deposited onto a column (90 mm diameter) of 550 g of silica gel (16 cm high) (Note 11) prepared as a slurry in hexanes. Elution is carried out with hexanes collecting 50-mL fractions. The desired product is obtained in fractions 25-46 (Note 12).
Mixed fractions 20-24 are collected separately and concentrated by rotary evaporation (40 °C, 20 mmHg). The resulting colorless oil is diluted with hexanes (10 mL) and loaded onto a column (60 mm diameter) of 300 g of silica gel (8.5 cm high) (Note 11) prepared as a slurry in hexanes. Elution is carried out with hexanes collecting 30-mL fractions. The desired product is obtained in fractions 16-27. All fractions containing pure product according to TLC (Note 9) are combined and concentrated by rotary evaporation (40 °C,20 mmHg). Further concentration at 23 °C under 0.1 mmHg for 2 h provides 15.8 g (68%) of chloromethyl stannane 1 as a colorless oil ( Figure  1G) (Notes 13,14,15,and 16).
B. Tributyl(iodomethyl)stannane (2). An oven-dried 500-mL pear-shaped recovery flask equipped with a 34 x 16 mm, Teflon-coated, oval magnetic stir bar is charged with acetone (125 mL) (Note 17) via a graduated cylinder and tributyl(chloromethyl)stannane (1) (10.5 g, 30.9 mmol, 1.0 equiv) (Note 13) from step A via a syringe over 10 min. The flask is fitted with a rubber septum and nitrogen inlet needle, after which the stir rate is set to ca. 375 rmp. Sodium iodide (9.50 g, 63.4 mmol, 2.0 equiv) (Note 18) is weighed in air into a glass vial and added in one portion to the reaction flask ( Figure 2A). The colorless suspension is stirred at 25-27 °C for 8 h during which the mixture turns pale yellow (Note 19) ( Figure 2B).

Figure 2. Color change through the course of the reaction
The resulting suspension is concentrated by rotary evaporation (40 °C, 40 mmHg) to afford a colorless oil containing excess sodium iodide and formed sodium chloride precipitates ( Figure 3).

Notes
1. Prior to performing each reaction, a thorough hazard analysis and risk assessment should be carried out with regard to each chemical substance and experimental operation on the scale planned and in the context of the laboratory where the procedures will be carried out. Guidelines for carrying out risk assessments and for analyzing the hazards associated with chemicals can be found in references such as Chapter 4 of "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011; the full text can be accessed free of charge at https://www.nap.edu/catalog/12654/prudentpractices-in-the-laboratory-handling-and-management-of-chemical. See also "Identifying and Evaluating Hazards in Research Laboratories" (American Chemical Society, 2015) which is available via the associated website "Hazard Assessment in Research Laboratories" at B A https://www.acs.org/content/acs/en/about/governance/committees /chemicalsafety/hazard-assessment.html. In the case of this procedure, the risk assessment should include (but not necessarily be limited to) an evaluation of the potential hazards associated with, as well as the proper procedures for tetrahydrofuran, N,N-diisopropylamine, nbutyllithium, tributyltin hydride, paraformaldehyde, methanesulfonyl chloride, hexanes, magnesium sulfate, sodium chloride, silica gel, acetone, sodium iodide, and sodium chloride. Tributyltin hydride and other tributyltin derivatives are moderately toxic. Those reagents should only be handled by individuals trained in their proper and safe use. 2. Tetrahydrofuran (low water inhibitor free HPLC grade) was purchased from Sigma-Aldrich and purified by pressure filtration through activated alumina immediately prior to use. 3. N,N-Diisopropylamine (≥99.5%) was obtained from Sigma-Aldrich and distilled from calcium hydride at 83-86 °C (760 mmHg) prior to use. 4. n-Butyllithium (1.60 M in hexanes under AcroSeal) was purchased from Sigma-Aldrich and titrated prior to use. The concentration was determined to be 1.58 M according to the reported procedure from Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165-168. 5. Tributyltin hydride (97% containing 0.05% BHT as stabilizer) was purchased from Sigma-Aldrich and used as received. 6. Paraformaldehyde (95%) was purchased from Sigma-Aldrich and used as received. 7. Methanesulfonyl chloride (98%) was purchased from Alfa Aesar and used as received. 8. The reaction progress was not monitored as the intermediate mesylate is rather unstable. 9. TLC analysis (hexanes with KMnO 4 stain visualization): Hexabutyldistannane sideproduct (Rf = 0.87) and tributyl(chloromethyl)stannane (1) (Rf = 0.74). The tributyl(chloromethyl)stannane (1) is not visible using UV 254 nm as the visualization technique. 10. The KMnO 4 stain was prepared using 1.5 g of KMnO 4 and 10 g of K 2 CO 3 dissolved in 200 mL of water and 1.25 mL of 10% w/v NaOH solution. 11. High-purity silica gel grade (9385), pore size 60 Å, 230-400 mesh particle size purchased from Sigma-Aldrich. 12. Purification is followed using TLC analysis on Silica gel (hexanes with UV 254 nm and KMnO 4 stain visualization): Hexabutyldistannane sideproduct (Rf = 0.87) and tributyl(chloromethyl)stannane (1) (Rf = 0.74). The tributyl(chloromethyl)stannane (1) is not visible using UV 254 nm as the visualization technique.
Some fractions contain minor amounts of Bu 3 SnOSnBu 3 and Bu 3 SnH as impurities; see TLC in Note 12. The second column is not necessary for synthetic purposes as the impurity (ca. 5%) does not affect the followup reaction and only slightly diminishes (≤ 5% difference) the yield in following alkylation steps. The second purification was done to meet the purity standards on the publication and improve the yield of pure material. 13. Tributyl(chloromethyl)stannane (1) 3015, 2969, 2654, 2926, 1738, 1456, 1365, 1228, 1216, 1206, 876, 692, 664, 527, 515 cm -1 ; Purity of the product was not assessed due to the instability of the product, which was quickly taken on to the second step.
16. 1 H NMR chemical shifts are expressed in parts per million (d) downfield from tetramethylsilane (with the CHCl 3 peak at 7.26 ppm used as a standard). 13 C NMR chemical shifts are expressed in parts per million (d) downfield from tetramethylsilane (with the central peak of CHCl 3 at 77.00 ppm used as a standard) and 117 / 119 Sn-13 C couplings are not reported. 17. Acetone (≥99.5% analytical reagent grade) was purchased from Fisher Scientific and used as received. 18. Sodium iodide (puriss. p. a. ≥99.0%) was purchased from Sigma-Aldrich and used as received. 19. The progress of the reaction was not monitored. 20. Tributyl(iodomethyl)stannane (2) was prepared according to a modified procedure of Seitz et al 2 . 21. A second run on the same scale provided 12.6 g (95%) of the identical product. Tributyl(iodomethyl)stannane (2) decomposes over time when stored neat at ambient temperature. This reagent should be stored as a degassed 1 M solution in hexanes at -10 °C and used within a few days for best results. 22. Tributyl(iodomethyl)stannane (2) 2871, 2848, 1739, 1456, 1375, 1365, 1228, 1217, 875, 692, 664, 588, 515, 456 cm -1 ; Purity was assessed as >95% via Q NMR using 4'nitroacetophenone as the internal standard.

Working with Hazardous Chemicals
The procedures in Organic Syntheses are intended for use only by persons with proper training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011; the full text can be accessed free of charge at http://www.nap.edu/catalog.php?record_id=12654). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
In some articles in Organic Syntheses, chemical-specific hazards are highlighted in red "Caution Notes" within a procedure. It is important to recognize that the absence of a caution note does not imply that no significant hazards are associated with the chemicals involved in that procedure. Prior to performing a reaction, a thorough risk assessment should be carried out that includes a review of the potential hazards associated with each chemical and experimental operation on the scale that is planned for the procedure. Guidelines for carrying out a risk assessment and for analyzing the hazards associated with chemicals can be found in Chapter 4 of Prudent Practices.
The procedures described in Organic Syntheses are provided as published and are conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.

Discussion
The development of transition metal-catalyzed cross-coupling reactions has greatly influenced the manner in which the synthesis of complex organic molecules is approached. A wide variety of methods are now available for the formation of C(sp2)-C(sp2) bonds, and more recent work has focused on the use of C(sp3) electrophiles and nucleophiles. 3,4 Access to functionalized aliphatic building blocks for such potential cross-coupling efforts are sought after, and organotin reagents remain one of the best approaches. While their applications have been hampered by challenges in removing organotin residues from the final products, 5,6 organotin reagents often allow for mild processes tolerating a wide variety of functional groups. 5,6 Their popularity is also due to their air-and moisture-stable nature, 5,6 and their wide-availability.
Tributyl(iodomethyl)stannane (2) has been used as an electrophile in the preparation of a-heteroalkylstannanes nucleophiles such as atributylstannylmethyl ethers, 7 amines, 8 or sulfides, 9 as in SnAP reagents for the preparation of functionalized, unprotected N-heterocycles (Scheme 1). 10,11 Scheme 1. Preparation of an a-tributylstannanemethyl ether and its application in the synthesis of a functionalized morpholines.