Key words
alkenes functionalization - microreactor technology - flow electrosynthesis - oxyamination
- cyclic ureas
Flow electrochemistry has begun to add to the ever increasing arsenal of techniques
available to the synthetic chemist.[1] Flow electrosynthesis performed in microreactors offers a number of benefits, allowing
reactions to be performed in a more convenient and safer manner,[2] and even allow electrochemical reactions to take place without a supporting electrolyte
due to a very short interelectrode distance[3] that results in the two diffusion layers of the electrodes becoming ‘coupled’, allowing
ions to be electrogenerated and play the role of the electrolyte. Continuous-flow
electrochemistry has the potential to act as a new enabling technology to replace
some aspects of conventional batch electrochemical processes.[4]
Electrochemical functionalization of double bonds is an important and environmentally
benign method for introducing complexity into molecules.[5] While batch electrochemical protocols have been available for some time, flow electrochemistry
methods have only recently appeared as useful additions to the synthetic portfolio.[6] We have contributed to this development by reporting an electrochemical microreactor
with a very small inter-electrode gap, which is useful for the synthesis of thiazolidines
(Scheme [1], Eq. (1)).[7]
Scheme 1 Electrochemical 1,2-difunctionalization of double bonds.
Recently, we have investigated urea derivatives that allow the generation of N-centered radicals under electrochemical reaction conditions in an undivided cell.
These nitrogen radicals react with alkenes and the resulting carbon radicals can be
trapped with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) resulting in the addition
of a nitrogen and an oxygen atom to the double bond. In this way, we have synthesized
various cyclic ureas derivatives in a batch electrochemical process (Scheme [1], Eq. (2)).[8] However, to facilitate access to these cyclic ureas, we decided to apply flow conditions,
by replacing the inorganic base Na2CO3 with the organic base Triton B. Herein, we report a method for the electrochemical
cyclization of N-allyl substituted ureas in combination with TEMPO, using an undivided electrochemical
flow cell, as shown in Scheme [1], Eq. (3).
The allyl-substituted urea derivatives 3 as substrates for such electrochemical cyclizations were obtained in a straightforward
route from mono-allyl anilines 1 and isocyanates 2, as has been described earlier.[8]
Scheme 2 Synthesis of urea derivatives 3
The flow reaction was performed in our recently developed flow electrochemistry system[7] and an ion electrochemical reactor (IER).[9] It was found that the flow rates could be varied and, with flow rates up to 0.2
mL min–1, full conversion at room temperature was observed. A schematic setup of the flow
system is shown in Scheme [3].
Scheme 3 Flow electrochemical synthesis of cyclic ureas
The substrates 3 are dissolved in a 19:1 mixture of acetonitrile and water together with TEMPO (1.5
equiv) and benzyltrimethylammonium hydroxide (1.1 equiv) and electrolysed using a
graphite anode and platinum cathode with 3 F in a flow electrochemical microreactor.[7]
N-Allyl ureas 3a–h, with different aryl substituents on the monosubstituted urea nitrogen, were cyclized
under optimized reaction conditions to the cyclic ureas 4. The cyclic urea products could be isolated in excellent yields (89–95%, Figure [1]). The reaction proceeded smoothly with a range of substituents on the aryl moiety
although, in the case of naphthyl substituted urea substrate 3h, the reaction gave low yield (37%).
Figure 1 Substrate scope for the electrochemical cyclization of N-allyl ureas. a Batch electrosynthesis of cyclic ureas has been reported.[8]
The proposed mechanism for the amination of the N-allyl urea derivatives 3 is shown in Scheme [4]. A radical generated at the urea amide nitrogen atom subsequently undergoes cyclization
and reacts with TEMPO to give the cyclic urea products 4. The electrolysis process originates from anodic oxidation of TEMPO to the oxoammonium
ion and cathodic reduction of water (H2O) to hydroxide (OH–) and H2. Then deprotonation of the urea by electrogenerated hydroxide, or with Triton B,
leads to an amidyl nitrogen anion. Single-electron transfer between the anionic urea
and the oxoammonium ion affords the amidyl nitrogen radical and regenerates the TEMPO
radical molecule. The amidyl nitrogen radical intermediate can then cyclise onto the
cyclic urea group to give another radical at the terminal carbon that is trapped by
the TEMPO radical molecule to form the difunctionalized oxyamination product of the
cyclic urea.
Scheme 4 Proposed mechanism for the synthesis of cyclic ureas end up with alkene difunctionalization
of oxoamination
In conclusion, we have demonstrated that cyclic ureas can be synthesized in an electrochemical
reaction. The use of an electrochemical flow reactor enables the easy synthesis of
compounds in a straightforward way with high yields at room temperature as compared
to batch electrosynthesis.[8] Compared with previous procedures,[10]
[11]
[12]
[13] this inexpensive, metal-free and environmentally friendly method[14] provides high yields under mild reaction conditions.
