Organic Letters
Letter
similar to flash chemistry reactions involving lithium reagents,
the challenging generation and utilization of halomethyl
magnesium intermediates could be harnessed using continuous
flow technology. Indeed, improvements in the selectivity of
other transformations involving several organomagnesium
reagents have been described in the literature.16 Notably, to
the best of our knowledge, the continuous generation of highly
reactive C1 magnesium carbenoids has not been reported to
date. Herein we describe a continuous procedure for the
generation of chloromethylmagnesium chloride at noncryo-
genic temperatures. The reactive intermediate has been reacted
in situ with aldehydes and ketones. Depending on the use of an
acidic or a basic quench, chlorohydrins and epoxides were
obtained.
Halogen−magnesium exchange in halomethanes is known to
proceed at low temperatures with isopropylmagnesium
chloride and with its lithium chloride complex.15 Lithium
chloride can considerably accelerate the halogen−magnesium
exchange,17 and thus the “turbo Grignard” iPrMgCl·LiCl was
expected to be particularly suitable for the generation of
unstable carbenoids at higher temperatures. Our preliminary
batch experiments employing either CH2I2 or CH2ICl18 and
benzaldehyde as a model electrophile demonstrated that
halogen−magnesium exchange takes place in under 2 min at
−80 °C. In these experiments (Figure 2), iPrMgCl·LiCl in
for details). Excellent conversion and selectivity were obtained
with 1.2 equiv of iPrMgCl·LiCl and 1.5 equiv of CH2ICl, and
importantly, the temperature could be increased from −80 °C
to −60 °C without any decrease in reaction efficiency. Under
these conditions, a 97% GC-FID yield was achieved after a 1
min residence time for the carbenoid generation, plus 2 min for
its reaction with benzaldehyde.
We anticipated that further increase of the reaction
temperature would lead to very short reaction times, most
probably in the range of 1−2 s. Such rapid reactions can be
difficult to handle due to mass transfer limitations using simple
T-mixers, particularly in combination with low flow rates (<2
mL/min).19 To further evaluate this issue, a Villermaux−
Dushman protocol20 was employed to determine the mixing
times of >1 s were obtained for the T-mixer during the
experiment when a flow rate of less than 2 mL/min was
utilized (Figure S5). As expected, higher flow rates decreased
the mixing time, but a flow rate of >6 mL/min was required to
achieve a mixing time below 0.5 s. On the other hand, a plate-
based micromixer (FlowPlate Lab microreactor, LL-mixer,
Hastelloy, 0.24 mL volume)21 showed a much better mixing
performance at low flow rates (e.g., 0.5 s vs 1.3 s for the
FlowPlate vs T-mixer at 1.4 mL/min flow rate), in agreement
with previous studies,22 and therefore this system was selected
for further optimizations at higher temperatures.
The plate-based reactor system comprised three input feeds
and an output line (Figure 3A) (for a detailed view of the
experimental setup, see Figure S6 in the Supporting
Information). Thus, two solutions containing the halomethane
Figure 2. Preliminary batch experiments for the generation of
hamomethylmagnesium chlorides and their reaction with benzalde-
hyde 1a. Yields of ca. 95% (GC-FID) were achieved on 1 mmol scale
at −80 °C for the three examples.
THF was slowly added to a vigorously stirred solution
containing either of the two halomethanes in THF. After 2
min, a solution of benzaldehyde (1a) in THF was added. The
reaction outcome could be readily tuned by simply selecting an
acidic or a basic quench for the reaction mixture. When the
reaction mixture was quenched with an aqueous 2 M solution
of NH4Cl, the expected chlorohydrin 2a or iodohydrin 2a′
(with CH2ICl and CH2I2, respectively) were obtained (Figure
2). When an aqueous 1 M NaOH solution was used as quench
instead, the corresponding epoxide 3a was observed. Under
these conditions, yields of ca. 95% (GC-FID) were obtained.
However, batch experiments could be only performed on very
small scale, and when the temperature was raised to −60 °C no
conversion of benzaldehyde was observed. This indicates the
low stability of the halomethylmagnesium intermediate even at
−60 °C. Other major side products observed in these batch
experiments were the reduction of the carbonyl group and
nucleophilic addition of the Grignard reagent (see Figure S1
for details).
Continuous flow experiments were initially carried out using
a setup made of PTFE tubing (0.5 mm i.d.) and PEEK T-
mixers (0.5 mm thru hole). Reagent stoichiometries and the
concentration of the Grignard reagent were optimized, using
the reaction of benzaldehyde (1a) with CH2ICl18 as a model
Figure 3. (A) Schematic view of the continuous flow setup utilized for
the generation and utilization of chloromethylmagnesium chloride
and (B) contour plot representing the effect of the temperature and
the residence time for the carbenoid generation on the final yield.
B
Org. Lett. XXXX, XXX, XXX−XXX