Synthesis and Utilization of Nitroalkyne Equivalents in Batch and Continuous Flow

Abstract We report a method for overcoming the low stability of nitroalkynes through the development of nitrated vinyl silyltriflate equivalents. Because of their instability, nitroalkynes have only rarely been utilized in synthesis. The reactivity of these silyltriflates, which are prepared in situ, is exemplified by dipolar cycloaddition reactions with nitrones to give highly substituted 4‐nitro‐4‐isoxazolines in high yields. This approach has proven general for several different alkyl and aryl substituted alkynes. In order to minimize the accumulation of potentially hazardous reaction intermediates, we have also developed a continuous flow variant of this method that is capable of carrying out the entire reaction sequence in a good yield and a short residence time.

1-Nitroalkynes (nitroalkynes) are af amily of molecules whose structure and high reactivity give them the potential to serve as versatile synthetic intermediates,e specially for the rapid construction of nitrated heterocycles which are prevalent in anti-microbial agents and next-generation antibiotics. [1] Reports on the preparation of nitroalkynes are sparse, [2] with the first successful synthesis being achieved in 1969 by Viehe and co-workers,w hen 1 was prepared by an additionelimination sequence (Figure 1). [3] Then itration of alkynyl stannanes with nitronium tetrafluoroborate (NO 2 BF 4 )a nd hexafluorophosphate (NO 2 PF 6 )c an be used to access alkylsubstituted nitroalkynes 2-4 in moderate yields,t hough they are noted to rapidly decompose. [2,4] Physical data has been recorded for 1-nitro-2-phenylacetylene 5,b ut ay ield for its preparation (4.5 %) has only been recorded once by Kashin et al. [5] Later, Schmitt and co-workers showed that bis-silyl substituted alkynes can also be treated with NO 2 BF 4 or NO 2 PF 6 to prepare silyl-substituted nitroalkynes,which have proven to be uniquely stable members of this class. [6] In one report, the parent 1-nitroacetylene was prepared in a2 0% yield using similar conditions and was characterized in situ, as purification was not attempted due to safety considerations. [7] Because of our interest in nitroalkynes as building blocks for constructing biologically active heterocycles,w eh ave set out to develop an improved, high yielding,s trategy for accessing members of this class bearing av ariety of substituents,b oth alkyl and aryl, which overcomes previous limitations caused by their instability.L ow molecular weight nitroalkynes are presumed to be explosive, [2] organo-tin reagents are known to be toxic, [8] and NO 2 BF 4 is considered hazardous due to its propensity to release hydrofluoric acid upon contact with water. [9] These are issues we have also sought to address in this research.
Continuous flow reactors are an attractive alternative to batch reactors in transformations that involve reactive and unstable intermediates.B ecause only small quantities of starting materials are subjected to reaction conditions at once, safety risks associated with hazardous materials can be minimized. [10] Therefore,a nother major goal of this project has been to develop ac ontinuous flow system in which any highly reactive species can be generated and rapidly consumed in-line.A na dditional goal has been to utilize safer sources of nitronium ions that can also be generated in-line, giving in total athree-step telescoped reaction sequence.
We have found through aseries of NMR experiments that nitronium triflate (NO 2 OTf), which is generated in situ from the reaction of triflic anhydride (Tf 2 O) and tetrabutylammonium nitrate (Bu 4 NNO 3 ), [11] adds across 1-trimethylsilylpropyne 6 to generate silyltriflate 7,w hich is stable at or below 0 8 8C ( Figure 2). Key pieces of evidence for this assignment include 13 CNMR peaks at 149.8 and 149.2 ppm, diagnostic of an itro-olefin. We were also able to observe HMBC crosspeaks between these 13 CNMR peaks and 1 HNMR peaks corresponding to at rimethylsilyl group and vinyl methyl group.T his species exists as am ixture of E and Z isomers, which give distinct signals and indicate that the addition is stepwise in nature.Isolation of 7 was not attempted.
Silyltriflates have served as valuable masked equivalents of other classes of strained or unstable alkynes,s uch as arynes, [12] heteroarynes, [13] cyclic alkynes, [14] and allenes. [15] Revealing the appropriate alkyne via elimination in the presence of ar eaction partner often gives the desired products in high yields.H aving imagined that as imilar strategy would be possible using 7,w ew ere pleased to find that the addition of 3.0 equivalents of nitrone 9 resulted in the rapid formation of the desired 4-nitro-4-isoxazoline 10 in ah igh yield ( Table 1, entry 1). No product formation was observed when 1.0 equivalents of the nitrone were used (entry 2). Allowing the reaction to warm to room temper-ature resulted in decreased yields,a sd id the use of 1.0 equivalents of NO 2 OTf( entries 3a nd 4). Theu se of sulfolane as as olvent has also proven critical for obtaining high yields (entry 5). DCM was required as ac o-solvent in order to solubilize the alkyne starting materials.Sulfolane has previously been observed to be uniquely effective for enabling challenging nitration reactions of sensitive substrates. [16] No product formation was observed when using nitronium trifluoroacetate (NO 2 TFA) (entry 6).
An otable difference between this methodology and similar transformations involving silyltriflates is that the reaction proceeds in the absence of an activating reagent such as afluoride source or exogenous base. [18] Nitrones have been reported to interact appreciably with Lewis acids, [19] and since multiple equivalents are required we propose that the first is used sacrificially to induce the desired elimination. [20] This would reveal the putative nitroalkyne intermediate, which we propose rapidly undergoes the observed [3+ +2] cycloaddition ( Figure 1). In one previous case 1-nitropropyne (8)has been directly observed by mass spectroscopy, [6] but to the best of our knowledge no yield for its direct preparation has been recorded.
With optimized conditions in hand we then explored the scope of nitrone partners ( Table 2). Avariety of N-tert-butyl alkynes bearing alkyl, aromatic,and heteroaromatic substituents gave products 10-17 in good yields.5 ,5-Dimethyl-1pyrroline N-oxide (DMPO) and an N-benzyl protected nitrone also gave the desired heterocycles 18 and 19.
We subsequently investigated the scope of the reaction with regard to the alkyne component (Table 3). Alkynes bearing larger alkyl substituents gave higher yields of the  1s tandard conditions9 1 21 .0 equiv of 9 instead of 3.0 equiv 9 < 5 30 8 8Ct oRT, 1hinstead of 0 8 8C, 1h 45 41 .0 equiv NO 2 OTfinstead of 1.5 equiv NO 2 OTf3 4 51 :1 MeNO 2 :DCM instead of 4:1sulfolane:DCM 37 61 .5 equiv NO 2 TFA instead of 1.5 equiv NO 2 OTf < 5 [a] Yields were determined by 1 HNMR analysis using 1,3,5-trimethoxybenzene as an internal standard. [a] Reactionsc onducted on 1.0 mmol scale, yields reported are an average of two isolated yields. [b] Diastereoselectivity determined by crude 1 HNMR, major diastereomer assigned by X-ray crystallography. [17] desired products 20-22 when reaction times were extended to two hours and allowed to warm to room temperature. Additionally,a nX -ray crystal structure of 22 was obtained which was able to unambiguously confirm the identity and regiochemistry of the product. [21] Aryl substituted alkynes were viable substrates as well (23-26). Many nitroalkynes are presumed to be explosive in nature,asare many sources of nitronium ions. [22] We therefore designed acontinuous flow reactor that would be able to carry out the entire reaction sequence in order to minimize the quantity of hazardous compounds being accumulated (Figure 3). Our initial reactor design consisted of three reservoirs containing stock solutions of NO 2 OTf, alkyne 6, and nitrone 9.These were connected to areactor constructed from two T-mixers,p erfluoralkoxyalkane (PFA) tubing, ab ack pressure regulator (BPR), and cooling bath. When attempting to minimize the residence time for this sequence, we found that ay ield of 60 %o f10 could be obtained with atotal residence time of 8.4 minutes.Hypothesizing that this decrease was due to poor or incomplete mixing, we introduced ah elical static mixer immediately after the first Tmixer, which was found to improve the overall yield to 72 %in the same residence time.
As econd reactor was then designed that allowed for the in-line preparation of NO 2 OTf. Issues with clogging were initially observed, but quickly solved by moving from aT -to aY -mixer, though yields were again low.W hile preparing solutions of NO 2 OTffor batch reactions,wehad qualitatively observed that initially Tf 2 Ow as immiscible with sulfolane, and would remain as as eparate phase unless vigorously shaken. We hypothesized that this was the cause of the decreased yields and might also be solved by enhanced mixing. In this case,s tatic mixers were not sufficient. Submerging the reactor in as onication bath, which we propose aids dissolution by breaking up aggregates of Tf 2 O, improved the yield of 10 to 70 %. This three-step flow sequence possesses an overall average residence time of only 20.9 minutes,g enerates both NO 2 OTfa nd silyltriflate 7 in limited quantities that are used immediately,and provides the desired product in ag ood overall yield.
In conclusion, we have developed ag eneral method for the preparation and utilization of novel silyltriflates that serve as equivalents of nitroalkynes.T he use of this intermediate overcomes the minimal stability of nitroalkynes,a nd has allowed for the construction of ac ollection of diverse, functionalized heterocycles in good to high yields.S everal alkyne substituents,such as methyl and functionalized phenyl rings,w hich have not been previously accessible,a re now accessible with this methodology.W eh ave addressed safety issues associated with the potentially explosive nature of multiple reaction intermediates by developing flow reactors in which both NO 2 OTfa nd silyltriflates are generated and consumed in small quantities.W ork is currently underway to expand the scope of reaction partners in order to prepare other classes of medicinally relevant heterocycles and carbocycles,a sw ell as gain further insight into the mechanism of the reaction. [a] Reactionsc onducted on 1.0 mmol scale, yields reported are an average of two isolated yields. [b] Step 1kept at 0 8 8C, 1hreaction time.