10.1002/ejoc.201901655
European Journal of Organic Chemistry
COMMUNICATION
Fast-Synthesis of α-phosphonyloxy ketones as Drug Scaffolds in
a Capillary Microreactor
Bandaru T. Ramanjaneyulu,[a] Shinde Vidyacharan,[a] Se Jun Yim,[a] and Dong-Pyo Kim*[a]
Abstract: A simple and room temperature approach for the fast
single-step synthesis of α-phosphonyloxy ketone, a drug scaffold,
has been developed which involves a highly reactive species i.e.,
1,2-dicarbonyls that combine readily with trialkyl phosphites and
formic acids in batch as well as continuous-flow. The present
approach reduced the synthesis time from hours to minutes in batch,
which was further lowered to a few seconds precisely controlled by
Not surprisingly, α-phosphonyloxy ketones are also of great
interest to serve as core structures of synthetic drugs such as
prednisolone[13] and oxaprozine drug[14] derived from benzoin,
and bupropion drug[15] derived from corresponding acyloin.
However, selective synthetic routes to α-phosphonyloxy ketones
are less prevalent over numerous reports on the synthesis of
various organophosphates.[16,17] Single-step or one-pot synthesis
for α-phosphonyloxy ketones is more attractive than two-step
approaches including extra synthetic step of intermediates
(Scheme 1).[18-21] The routes reported in the literature for the
synthesis of α-phosphonyloxy ketones require a long time up to
48 h at room temperature (RT),[18-20] 4 h to 48 h even at high
single capillary microfluidics.
A wide range of 1,2-dicarbonyl
derivatives were smoothly transformed to their corresponding
α-phosphonyloxy ketones in moderate to good yields (50-82%) in
continuous-flow with the flow rate of 3 ml/min (tR = ~4 s). Further, the
α-phosphonyloxy ketones produced can be utilized in batch process
to form benzoin, oxazole core, and α,α'-diarylated carbonyl
compounds in 82%, 50%, and 54% yields, respectively, which are
alternative key precursors/scaffolds of natural products and active
pharmaceutical ingredients (APIs).
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temperature (up to 80 C),[21-24] and also produce massive by-
products[18-20,22,24] (Scheme 1).
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Continuous-flow microreactors have recently attracted much
attention as an important technique for synthesizing organic
molecules including drug intermediates/molecules in a very short
time under mild reaction conditions.[1-4] A high surface area to
volume ratio in the microfluidic system promotes mass and heat
transfer, leading to selectivity and conversion much superior to
the levels obtainable by conventional batch processes.[2-4] Owing
to their many complex issues such as inefficient mixing, non-
uniformity in heat, and safety in the scale-up of batch process, in
recently, flow approach is more attractive and reliable in both
academia and industry.[1,2] Furthermore, high throughput
production can be achieved by simply increasing reaction
volume with larger dimension of channel, or/and by numbering
up microreactor units in parallel.[5,6] In light of the push for
continuous manufacturing of pharmaceutical products[7,8]
microreactor can be an attractive alternative to the conventional
batch process for many of the pharmaceutical products whose
world-wide consumption is of the order of tons a year. Therefore,
simple and fast continuous-flow methodologies are highly
desirable to operate at high flow rate, enabling to satisfy the
changing needs of pharmaceutical markets in a safe and
environmentally benign, cost-effective manner.
On the other hand, the organophosphate chemistry by itself is
an interesting area of organic chemistry as well as life science in
living organism such as DNA, RNA, ATP and cell membranes.[9]
Moreover, various methodologies also reported for the synthesis
of various organophosphates with applications ranging from
agrochemicals to biologically active phosphate medicines.[10-12]
Among them, α-phosphonyloxy ketones serve as key motifs[10] in
the synthesis of oligonucleotide, sugar analogues, phospholipids
and also versatile key intermediates in natural products.
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Scheme 1. Comparative approaches for the synthesis of α-phosphonyloxy
ketones between the reported work and our work.
Here, we developed a new method which involves a highly
reactive species i.e., 1,2-dicarbonyls that combine readily with
trialkyl phosphites and formic acids to produce the α-
phosphonyloxy ketones, precisely controlled by microfluidics.
The present approach reduced the synthesis time from hours to
minutes in batch, which was further lowered to a few seconds at
room temperature precisely controlled by microfluidics.
Importantly, using this approach, α-phosphonyloxy ketones
could be easily access at room temperature in fast (residence
time 3.93 s), safe, environmentally benign and compact
compared to conventional batch process. Moreover, most of the
reported methods[18-24] involves various phosphites as starting
materials known as potentially neurotoxic reagents for the
synthesis of α-phosphonyloxy ketones.
Our initial optimization studies were carried out in batch using
benzil 1 and triethyl phosphite 2 as model substrates under
various reaction conditions (Table 1). The reaction in the
absence of acid using toluene as a solvent at room temperature
didn’t give expected product i.e., α-phosphonyloxy ketone 3
(entry 1). However, in the presence of H2O the expected product
3 was obtained in 32% yield for 12 h along with the formation of
side product benzoin 4 in 10% yield. Encouraging these results,
further optimization experiments were performed by screening
different acids (entries 3–7). The yields of the product 3 were
improved to 54% yield with HCl acid (entry 3), 44% yield with
PTSA acid (entry 6), 67% yield with AcOH acid (entry 7) after
long time for 12 h. Whereas product 3 was not obtained with
strong acids such as H2SO4 & TfOH acids (entries 4 & 5) that
could be due to decreasing the reactivity of α-dicarbonyl
compounds in the presence of strong acids. Interestingly, when
the reaction was executed with HCOOH (6) as an acid source in
toluene solvent at room temperature, the desired product 3 was
isolated in 67% yield in very short time (5 min) (entry 8) along
[a] Dr. B. T. Ramanjaneyulua, Dr. S. Vidyacharana, S.-J. Yima, Prof. Dr. D.-P.
Kim*a
aCenter of Intelligent Microprocess of Pharmaceutical Synthesis,
Department of Chemical Engineering, Pohang University of Science and
Technology (POSTECH), Pohang, 37673 Korea.
*Corresponding author
Supporting information for this article is given via a link at the end of
the document.
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