Communication Cite This: Org. Process Res. Dev. 2019, 23, 1269−1274
pubs.acs.org/OPRD
Anion Metathesis of Diaryliodonium Tosylate Salts with a SolidPhase Column Constructed from Readily Available Laboratory Consumables Rory T. Gallagher,† Thomas L. Seidl,†,⊥ Joshua Bader,‡ Charles Orella,*,§ Thomas Vickery,§ and David R. Stuart*,† †
Department of Chemistry, Portland State University, Portland, Oregon 97201, United States ExecuPharm, King of Prussia, Pennsylvania 19406, United States § Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States
Downloaded via UNIV PARIS-SUD on August 5, 2019 at 22:29:28 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
‡
S Supporting Information *
Scheme 1. Counteranion Exchange in Diaryliodonium Salts
ABSTRACT: Herein, we describe the discovery and development of a method to exchange the counteranion component of diaryliodonium salts, which is a critical step for their use in chemical synthesis. The method involves a reusable and readily available solid-phase column assembled from common laboratory consumables. This process avoids challenging product separation associated with other methods for anion metathesis of diaryliodonium salts, and selected examples demonstrate the scope of the method. Hazard analysis (differential scanning calorimetry) on all salts used in this study revealed exotherm initiation temperature in the range of 139−199 °C and exotherm magnitude of 60−845 J/g for a single peak. KEYWORDS: diaryliodonium, anion exchange, solid-phase, arylation
■
INTRODUCTION Diaryl-λ3-iodanes have emerged as useful arylation reagents under both metal-free and metal-catalyzed reaction conditions (Scheme 1a).1 These reagents are commonly referred to as diaryliodonium salts, and the “anion” component influences their stability, solubility, and reactivity. This electronegative component of the reagent is typically installed during synthesis of the salt, although relatively few anions are actually introduced in this way.2 More commonly, a subsequent salt metathesis step is performed to exchange anions, and many more anions are installed by this method.2b,m,o,3 We have become interested in a class of unsymmetrical diaryliodonium salts for selective aryl group transfer1e wherein one of the aryl groups is a 2,4,6-trimethoxyphenyl (TMP) moiety,4 and we have described the synthesis,2o,5 reactivity,2o,6 and limited salt metathesis reactions2o,6b of these reagents (Scheme 1b). On the basis of literature precedent,2b,m,o,3 we previously used a biphasic salt metathesis approach to achieve the latter; however, we observed several drawbacks of this method (Scheme 1c). Namely, in many cases, large excess of exchange salt is required for complete anion metathesis, and a second run may be required if metathesis is incomplete. In addition, liquid−liquid extraction is used to separate the diaryliodonium © 2019 American Chemical Society
salt product and the excess exchange salt, and large volumes of organic solvent and water are often required to mitigate emulsions; this is specifically problematic for large-scale operations. We were inspired to develop an alternative anion exchange reaction when one of us (T.L.S.) made an observation during a routine synthesis of an aryl(TMP)iodonium tosylate that was later to be converted to the aryl(TMP)iodonium bromide. While the diaryliodonium salt was drying in a sintered glass funnel, an aqueous solution of potassium bromide was poured over the powder, the liquid passed into the solvent trap and the solid that remained in the Received: April 18, 2019 Published: May 30, 2019 1269
DOI: 10.1021/acs.oprd.9b00163 Org. Process Res. Dev. 2019, 23, 1269−1274
Organic Process Research & Development
Communication
Figure 1. Construction of salt column. (a) Cotton plug inserted in a 60 mL plastic syringe, (b) bottom layer of sand (0.5 cm) over cotton, (c) sodium bromide, (d) top layer of sand (1 cm), and (e) reaction set up.
funnel had been converted from the aryl(TMP)iodonium tosylate to the corresponding aryl(TMP)iodonium bromide in high yield and purity. We were struck by the rapid, complete, and practical advantage of such an anion metathesis protocol. Herein, we describe the development of a solid phase anion exchange method based on this approach, wherein the columns are reusable, reaction times are short, and liquid−liquid extraction is avoided (Scheme 1d).
Chart 1. Scope of Anion Exchange
■
RESULTS AND DISCUSSION Development. Our early efforts in development focused on variations of the diaryliodonium salt or exchange salt being in the solid phase with an emphasis on a process that would be possible in many research settings. In this regard, we favored the use of readily available laboratory consumables to construct the anion exchange column. We used 2 mmol of aryl(TMP)iodonium tosylate substrate for each exchange reaction during development, which corresponds to ∼1 g of material, and we settled on a 60 mL plastic syringe as the vessel for our column. The column is constructed as shown in Figure 1: first, a cotton plug is inserted (Figure 1a), then ∼0.5 cm of sand (Figure 1b), followed by the NaX exchange salt (Figure 1c), and then another layer (∼ 1 cm) of sand (Figure 1d). The exchange column is placed above a 250 mL round-bottom flask as the receiving vessel (Figure 1e). We used columns constructed in this way to evaluate the scope of these anion metathesis reactions on 1−5 mmol (0.5−2.5 g) scale of aryl(TMP)iodonium tosylates. Scope and Recycling. A representative scope of aryl(TMP)iodonium groups and exchange anions is presented in Chart 1. The process involves pouring the aryl(TMP)iodonium tosylate 1−4-OTs (dissolved in 20 mL DCM) over the solid column of exchange salt and then washing with an additional 80 mL of DCM. The DCM (∼100 mL) is removed, and the product 1−4-X is triturated from the oily residue with tert-butyl methyl ether (TBME). We demonstrate that aryl(TMP)iodonium tosylates bearing electron-withdrawing groups (i.e., methylester), electron-donating groups (i.e., tert-butyl, phenyl), and heterocycles (i.e., pyridyl) are welltolerated in this approach. The isolated yields range from 73 to 96%, and 84% is the average over all substrates in Chart 1. Importantly, the conversion of diaryliodonium salts from tosylates to the target exchange anion is essentially quantitative (>99%); a negligible amount of remaining tosylate is observed in the 1H NMR spectrum of the products 1−4-X.
a
Conditions: aryl(TMP)iodonium tosylate (2 mmol), dichloromethane (20 mL + 80 mL wash), NaX (∼125−225 equiv; see the Experimental Section for details). Isolated yields are reported, and conversion of tosylate to target anion is reported in parentheses. b NaX was admixed with sand (see the Experimental Section for details). cRun with 1 mmol of 1-OTs. dRun with 20 mL DCM:MeOH (95:5) solution.
A large excess (>100 mol equiv) of the exchange salt, similar to the biphasic reaction, is used to construct the columns. Given that most of the exchange salt is left unreacted after a single metathesis reaction, we assessed the reusability of the columns. Table 1 demonstrates this concept for exchange from tosylate to bromide. A column constructed from NaBr was used repeatedly in 5 runs to convert 2-OTs to 2-Br in high yield (86−96%) and excellent conversion to bromide (>99%; Table 1, runs 1−5). Conceivably, more than 5 runs are possible because each run consumes only 2 mmol of sodium bromide. We also demonstrated that the same column can successfully be used for more than one iodonium group without cross contamination (Table 1, runs 6 and 7). The column was washed 3 times with dichloromethane (80 mL each) after run #5, followed by conversion of 3-OTs to 3-Br in both high yield (88%) and conversion (>99%) with no crosscontamination by residual 2-Br. We conducted a seventh run with 2-OTs and obtained the same high yield and conversion seen in runs 1−5 with no cross-contamination of 3-Br. Safety Considerations. We previously assessed the thermal stability of the reagents (methyl-4-iodobenzoate), oxidant (m-CPBA), intermediate ([hydroxyl(tosyloxy)]iodo 1270
DOI: 10.1021/acs.oprd.9b00163 Org. Process Res. Dev. 2019, 23, 1269−1274
Organic Process Research & Development
Communication
addition to the major exotherm(s), we view the lowest initiation temperature and the total decomposition energy as good indicators of the overall stability of these compounds. The counteranion identity has an influence on the initiation temperatures observed, whereas aryl substitution has very little influence on initiation temperature. Overall, the OTs salts had the highest initiation temperatures (184−299 °C) followed by TFA (158−261 °C), and Br had the lowest initiation temperatures (139−256 °C). Although comparing the magnitude of the combined exotherms for the series of salts is more complicated, generally, the OTs salts had the smallest energy release (472−602 J/g) followed by the Br salts (487− 702 J/g), and the TFA salts had the largest energy release (595−1006 J/g) (Table 2). Collectively, our data suggest that the iodonium tosylates 1−4-OTs are the most thermally stable in this series. Although the salts 1−4 are in the “safe” region of a Yoshida correlation,8 the most energetic salt, 1-TFA, with the highest risk of propagating an explosion or being shock sensitive, was subjected to a drop weight test and found to be insensitive to an impact of 25 J. We strongly urge caution in the synthesis and use of these reagents, especially above 80−90 °C and when screening new counteranions and nucleophiles. In our own research on method development with aryl(TMP)iodonium salts, we have typically noted that the highest yields are obtained between 50−80 °C. We emphasize that large scale operations should be carried out with caution, although we also recognize the critical role that solvent can play in dilution and heat transfer.7 An example of the benefit is that for the metathesis reported here, we anticipate the heat of reaction to be below 20 kJ/mol.9 Given the dilution of 20 mL solvent/ gram of iodonium salt, the expected adiabatic temperature rise will be below 2 °C for the metathesis. The initiation temperature and exotherm data for a series of azido-λ3-iodanes was recently measured in the range of 90−143 °C and 1345− 1770 J/g, respectively;10 as done by Waser and coworkers, we
Table 1. Repeated Use of a Sodium Bromide Column
run
R group
yield/%
conversion/%
1 2 3 4 5 6 7
t-Bu t-Bu t-Bu t-Bu t-Bu Ph t-Bu
92 96 93 92 86 88 89
>99 >99 >99 >99 >99 >99 >99
a
Conditions: aryl(TMP)iodonium tosylate (2 mmol), dichloromethane (20 mL + 80 mL wash), and NaBr (450 mmol). Isolated yields and 1H NMR conversion of tosylate to target anion are reported.
arene), and product (1-OTs) in a large scale (50 mmol) synthesis by differential scanning calorimetry (DSC).7 Here, we expand the safety analysis to include other iodonium salts with different aryl substituents and counteranions. Table 2 lists the initiation temperature and magnitude of the exothermic event observed upon heating these reagents as neat solids in a closed crucible, and we discerned several general trends from the data. First, seven of the salts (1-TFA, Br; 2-OTs, Br; 3OTs, Br; 4-Br) had two distinct major exotherms, and five salts (1-OTs; 2-TFA; 3-TFA; 4-OTs, TFA) had one major exothermic event. The first major exotherm (or in cases where there is only one) occurs in the range of 130−200 °C, and the second occurs between 200 and 300 °C (Table 2). In general, the second major exothermic event is more energetic than the first, except in the cases of 2-OTs. While most of the DSC thermograms show one or more minor exotherms in Table 2. Safety analysis of 1−4-Xa
Conditions: DSC analysis was performed with a temperature ramp of 5 K/min from ambient to 350 °C. bA repeat scan was conducted with a ramp of 5 K/min from ambient to 450 °C. a
1271
DOI: 10.1021/acs.oprd.9b00163 Org. Process Res. Dev. 2019, 23, 1269−1274
Organic Process Research & Development
Communication
ionization (ESI) with an ion trap mass analyzer or electron impact (EI, 70 eV). Melting points are reported as uncorrected. DSC analysis was performed in a gold plated pressure crucible. General Procedure for Anion Exchange via SolidPhase Column. The column of appropriate sodium salt was constructed as shown in Figure 1 and described in the accompanying text. Aryl(TMP)iodonium tosylate (2 mmol) was weighed, transferred to an Erlenmeyer flask, and dissolved in DCM (20 mL). The aryl(TMP)iodonium tosylate solution was poured onto the column and eluted by gravity. An additional 80 mL of DCM was passed through the column to wash any remaining iodonium salt off the column. The bulk of the DCM was removed under reduced pressure on a rotary evaporator to yield an oily residue. The residue was triturated with tert-butyl methyl ether (TBME; 250 mL) to precipitate the iodonium salt product. The solid product was isolated by filtration and washed with additional TBME (20 mL). Compound 1-TFA. Prepared as described above on 2 mmol scale of 1-OTs with 250 mmol of NaTFA admixed with sand (20 g). The product was obtained as a white powder in 73% yield (0.797 g). The spectral data were consistent with those previously described.5 1H NMR (400 MHz, DMSO-d6) δ 8.12−7.72 (m, 4H), 6.18 (s, 2H), 3.90 (s, 3H), 3.87 (s, 6H), 3.86 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 167.0, 165.7, 161.4 (q, J = 34.0 Hz), 160.50, 133.7, 132.5, 132.0, 121.5, 116.6 (q, J = 295.2 Hz), 91.6, 86.0, 56.9, 56.0, 52.6. 19 1 F{ H} NMR (376 MHz, DMSO-d6) δ −75.24. Compound 1-Br. Prepared as described above on 2 mmol scale of 1-OTs with 250 mmol of NaBr. The product was obtained as a white powder in 90% yield (0.920 g). 1H NMR (400 MHz, DMSO-d6) δ 8.10−7.98 (m, 2H), 7.92−7.87 (m, 2H), 6.15 (s, 2H), 3.89 (s, 3H), 3.88 (s, 6H), 3.84 (s, 3H). 13 C{1H} NMR (101 MHz, DMSO-d6) δ 206.4, 165.8, 165.2, 159.3, 134.4, 131.5 (d, J = 17.3 Hz), 123.5, 92.0, 90.5, 64.9, 57.2, 56.0, 52.5, 48.5, 30.6, 15.1. FTIR 3077, 2846, 2841, 1724, 1578, 1451, 1340, 1281, 1188, 814 cm−1. HRMS (ESI+) calcd for C17H18IO5+ [M − Br]+, 429.01934; observed 429.01966. Melting point 157−158 °C Compound 2-TFA. Prepared as described above on 2 mmol scale of 2-OTs with 250 mmol of NaTFA admixed with sand (20 g). The product was observed as a white powder in 83% yield (0.898 g). Spectral data were consistent with those previously described.5 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 6.47 (s, 2H), 3.96 (s, 6H), 3.87 (s, 3H), 1.25 (s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 166.0, 159.4, 157.7 (q, J = 30.4 Hz), 154.5, 134.1, 128.6, 117.3 (q, J = 301.1 Hz), 112.8, 92.0, 87.2, 57.3, 56.1, 34.8 30.7. 19F{1H} NMR (376 MHz, DMSO-d6) δ −73.41. Compound 2-Br. Prepared as described above on 2 mmol scale of 2-Br with 300 mmol NaBr. The product was obtained as a white powder in 96% yield (0.973 g). 1H NMR (400 MHz, DMSO-d6) δ 7.86−7.78 (m, 2H), 7.50−7.41 (m, 2H), 6.44 (s, 2H), 3.94 (s, 6H), 3.86 (s, 3H), 1.24 (s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 206.4, 165.8, 165.22, 159.3, 134.4, 131.6, 131.4, 123.5, 92.0, 90.5, 64.9, 57.2, 56.0, 52.5, 48.5, 30.6, 15.1. FTIR 3077, 2846, 2841, 1724, 1578, 1451, 1340, 1281, 1188, 814 cm−1. HRMS (ESI+) calcd for C17H18IO5+ [M − Br]+, 429.01934; observed 429.01966. Melting point 157.5− 157.9 °C. Compound 3-TFA. Prepared as described above on 2 mmol of 1-OTs with 250 mmol of NaTFA admixed with sand
advocate other researchers to conduct and report similar test on new iodonium compounds. Trouble Shooting. We encountered several problems during the design and development phase that are worth pointing out when considering future implementation of this strategy. The most notable of these was column clogging during the reaction, which led to longer elution time and was noted specifically with sodium trifluoroacetate. To avoid this, the inorganic salt may be admixed with sand (∼0.25 g of sand per mmol NaTFA); other materials, including Celite, were also examined toward this end. The solubility of diaryliodonium salts is largely dictated by the identity of the aryl group when the anion component remains constant. Diaryliodonium tosylates typically have low solubility in nonpolar organic solvents,11 which presents a potential issue that may be encountered when moving outside the scope presented here (Chart 1). In the present work, low solubility was noted for 4OTs.11 A small amount (∼5 v/v%) of methanol was added to the eluent to fully solubilize 4-OTs, and this approach may prove useful in other settings where solubility is an issue. Limitations. Some anions do not appear to exchange well under this method; absent is conversion to triflate, tetrafluoroborate, or chloride salts. The solubility of sodium triflate or tetrafluoroborate is not significantly different from the sodium salts that do exchange under these conditions.12 Although high recovery of material (>80%) was obtained when sodium triflate, tetrafluoroborate, or chloride columns were used, the conversion from tosylate to these other anions was highly variable. Specifically, conversion to triflate ranged from 68 to 80% but could not be pushed to synthetically useful levels (>98%); the conversion to tetrafluoroborate or chloride anion was
