Organic Letters
Letter
boronates (6a, 7a) as byproducts judged by GC-MS (see also
Scheme 3. Flow System for Optimizing the Conditions
(Temperature = T2, Residence Time = τ2) of the 1,2-
Scheme 2). The undesired overhomologation can occur when
Aniotropic Rearrangement by Determining the Yield of the
a
Second Homologation Product 6a
Scheme 1. Concept of the (Iterative) Matteson
Homologation and Possible Side Reactions
Scheme 2. Comparison of Mixer Systems for the Model
Reaction (3a → 5a−7a) (Yields Determined by GC-MS);
the Graphic Presentation of the Mixer Is Also Shown;
Internal Cross-section of the 3D Model and Enlarged
Kenics Mixer Module of 180° Clockwise and 180°
Counterclockwise Spiral Structure
a
Details on the second homologation are found in Scheme 4 and the
SI; yields determined by GC-MS.
microtube (V = 0.1 mL, ID = 1 mm). Downstream of the
outlet, the reaction solution was passed into a glass flask where
the 1,2-aniotropic rearrangement took place at elevated
temperature over a period of 30 min (Scheme 2). First
experiments showed that residence times greater than 1 s are
not practical, presumably due to the low stability of the
lithiated species 2 (Scheme 1). Thus, residence times between
1 s and 100 ms and a temperature range of −78 °C and −
30 °C were chosen for optimization. The best yields were
found for residence times of 200 to 300 ms and temperatures
between −40 and 30 °C. Under these conditions, the yield for
the homologation product 5a was found to be 83% with 11%
of starting boronate 3a and 5% of doubly homologated product
6a.
The per-homologation could not be suppressed by lowering
the temperature. We also observed the formation of the Wurtz
product from the excess of bromochloromethane (1), as
determined by GC MS analysis. One reason for these
unsatisfactory results may be insufficient mixing; initial
indications of this were already provided by the batch
experiments. Therefore, we planned to replace the specified
T-piece.
Since the flow in microflow systems is mostly laminar, which
drastically reduces efficient mixing, two approaches can be
taken to overcome this problem. Either one can reduce the
inner diameter of the T-piece as well as the tubing. However,
this would lead to a sharp increase in pressure, which we tried
to avoid. Alternatively, static or dynamic mixers can be used.
We decided to use a Kenics mixing module to eliminate per-
homologation and Wurtz coupling. The static mixer used here
contains eight helical mixing elements, rotated alternately left
and right, which divide the flow into thin layers to increase
mixing speed and efficiency.16 The mixer was designed using a
CAD program and 3D printed from 1.4404 stainless steel using
the SLM (selective laser melting) process (Scheme 2).
The performance of this static mixer was compared with T-
mixers (ID = 750 mm and 250 mm) for the model reaction
(Scheme 2), and it proved to be clearly superior to the T-
mixers. The homologation product 5a was obtained in 96%
the first homologation product 5a reacts with a second
equivalent of (chloromethyl)lithium (2), followed by rear-
rangement.
Engineered devices such as micromixers, as well as
controlling reaction times by adjusting flow rates, are powerful
tools for controlling ultrafast reactions under very mild
conditions Thus, we started with 30 s as a guideline from
above for developing a flow protocol. The optimization of the
continuous Matteson reaction was divided into two separate
steps: (a) the generation of the carbanion with the formation
of the boronate complex and (b) then the 1,2-aniotropic
rearrangement of the ate complex in a flask located at the
outlet of the flow reactor. To prevent precipitation of lithium
salts the solvent had to be changed from Et2O to THF. The
premixed solution containing boronate 3 and chloromethyl
bromide (1) in THF and the nBuLi solution were transferred
into two precooled loop reactors (V = 1 mL, ID = 1 mm),
using a syringe pump. From there, the two cooled streams were
mixed in a T piece (ID = 750 μm) and then fed into a
4301
Org. Lett. 2021, 23, 4300−4304