Phase-transfer catalyzed carbene additions have been known since the early days of PTC in the 1970’s. We don’t see many PTC carbene reactions in the patent literature, so we are highlighting this report this month.
Other than the identity of the phase-transfer catalyst used in this patent (discussed in the PTC Catalyst of the Month below), the reaction conditions are typical of those reported for PTC carbene additions over the years. This included [1] the use of 50% NaOH as base, [2] mild reaction temperature, historically from room temperature to about 50 C and [3] chloroform used as both reagent and solvent.
Most PTC carbene additions in the early days of PTC used triethyl benzyl ammonium (TEBA) chloride as the phase-transfer catalyst. TEBA is inexpensive but it is not very stable in the presence of 50% NaOH at high temperature due to Hofmann Elimination (note the three sensitive ethyl groups). The instability of TEBA in the presence of NaOH at may be the reason that PTC carbene additions using TEBA were typically performed at 30-40 C.
Unexpectedly, the inventors of this patent used tetrabutylammonium hexafluorophosphate as the phase-transfer catalyst. The tetrabutylammonium cation almost always works well for almost all PTC reactions performed at mild temperatures, so the choice of quat is not very surprising. However, the use of the expensive hexafluorophosphate counteranion is surprising. The choice of phase-transfer catalyst is discussed in this month’s PTC Tip of the Month.
The excess 50% NaOH used in the patent was significant at 25.2 equiv. The inventors also used powdered NaOH for the carbene addition to a similar substrate (see Example 105 in which the diether was cyclic 1,3-dioxolane instead of the open chain diethoxy shown in the figure) and they reduced the excess NaOH to 10 equiv. Solid NaOH was also used for the addition of bromochlorocarbene (shown in Example 107) when using dibromochloromethane as the carbene source and solvent.
PTC carbene reactions are typically “T-Reactions” (explained in the 2-day course “Industrial Phase-Transfer Catalysis“) and as such, are sensitive to agitation more than PTC “I-Reactions.” For this reason it is not surprising to read that the inventors specified the rpm used for vigorous mixing.
If your company can benefit from reducing cost and improving process performance for strong base PTC reactions, now contact Marc Halpern of PTC Organics to integrate our highly specialized expertise in PTC-NaOH technology with your process development and process optimization goals.
