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The Solvent-free Michaelis-Arbuzov Rearrangement under Flow Conditions Aleksandra Jasiak, Gra#yna Mielniczak, Krzysztof Owsianik, Marek Koprowski, Dorota Krasowska, and Jozef Drabowicz J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03053 • Publication Date (Web): 30 Jan 2019 Downloaded from http://pubs.acs.org on February 3, 2019
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The Journal of Organic Chemistry
The Solvent-free Michaelis-Arbuzov Rearrangement under Flow Conditions Aleksandra Jasiak,*† Grażyna Mielniczak,† Krzysztof Owsianik,† Marek Koprowski,† Dorota Krasowska† and Józef Drabowicz*†,‡ †Division
of Organic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences,
Sienkiewicza 112, 90-363 Łódź, Poland ‡Institute
of Chemistry, Health and Food Sciences, The Faculty of Mathematics and Natural Sciences, Jan
Długosz University in Częstochowa, Armii Krajowej 13/15, Częstochowa 42-201, Poland *Corresponding Authors: E-mail:
[email protected] (J. Drabowicz) E-mail:
[email protected] (A. Jasiak)
Abstract: The first solvent- and catalyst–free procedure for the Michaelis- Arbuzov reaction under flow conditions was developed. A variety of alkylphosphonic esters could be obtained using this protocol starting from the corresponding trialkyl phosphites and even catalytic amounts of alkyl halides with very short reaction times (8.33 – 50 min.) and excellent conversions. In general, this protocol works effectively when the alkyl halide is used in catalytic amounts as low as 5% to 10% only if it concerns the synthesis of homo alkylphosphonates. One equivalent and an excess of alkyl halides should be used in the reaction with alkyl phosphite if alkyl group of the selected substrates differ. Thus, it provides a sustainable, fast alternative to the existing methods for the preparation of alkylphosphonates. The isolation of the reaction products is straightforward due to the lack of solvents, a high purity of the obtained products (conv. ≥ 99%), and notably, in the catalytic procedures there are only traces of alkyl halides formed after the reaction is complete. The reactions conducted using a glass microreactor chip with an internal volume of 250 µl allow the production of 1.6 – 1.95 g organophosphorus esters per hour.
Introduction Alkyl phosphonates can be considered as one of the basic families of organophosphorus compounds that have found a broad spectrum of useful applications in the areas of industrial, agricultural and medicinal chemistry.1 Their importance stems from their diverse biological activity, as well as their utility as synthetic intermediates2 especially in the synthesis of other organophosphorus esters and amides including also biologically active molecules.3 The Michaelis-Arbuzov (M-A) rearrangement, also known as the Arbuzov reaction relies on a double SN2 reaction between an alkyl halide and a trialkyl phosphite (Scheme 1) and is one of the most versatile methods for the preparation of phosphonates, phosphinates and phosphine oxides starting from the corresponding tricoordinated precursors.4
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The Journal of Organic Chemistry
R 1O
: P
OR1
R2 X
R 1O R1 O
OR1
R2 P OR1
R 1O R 2 + P O OR1
X
R1 X
Scheme 1. The SN2 Arbuzov reaction mechanism. Several review articles on this rearrangement have been published,5 including reviews of the M-A reaction of phosphorohalidites5c and Arbuzov rearrangements using haloacetylenes as a method for synthesizing alkynyl phosphonates and other important organophosphorus compounds.5d From a synthetic point of view the conventional Arbuzov reaction has several disadvantages. First of all, the reaction requires high temperature for an extended period of time. Secondly, extended periods of heating at higher temperatures led to the isolation of unexpected products. In addition one equivalent of alkyl halide is formed in the reaction, which can react with the phosphite under the reaction conditions to give an undesirable side-product, leading to the reduced yield. Considering these limitations it should be noted that more and more alternative and green methods described in the literature6 involve microwaves irradiations,7,8 microwaves irradiations with metallic Lewis acid,9 catalysis with either metal salts10 or the application of a non-metallic Lewis acid.11 An alcohol-version of M-A reaction is achieved by an iodide-catalyzed C–P(O) formation reaction of a wide range of alcohols with phosphites, phosphonites, and phosphinites.12 In light of the comments given above it would still be useful to develop alternative approaches to the M-A rearrangement. Therefore, we decided to be the first in examining the Arbuzov reaction under flow condition in order to develop a practical, fast and industrially relevant, procedure for the synthesis of homo and mixed alkylphosphonates (Scheme 2).6,13
Microreactor chip R1O
OR1 P R2 X + OR1 0.05-1.5 equiv.
:
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1
2
O P R1O 2 OR1 + R conv. 90 - 99% 3 T = 50-150 oC tres = 8.33-50 min.
R1 X 4
Scheme 2. Continuous flow, solvent-free Michaelis-Arbuzov reaction. We expected that with the flow solventless process one can avoid wasteful work-up operation as products are isolated by simple evaporation traces of the alkyl halide, and the scale-up should be effortless. Moreover, because of the small internal volume, as well rapid heat transfer associated with the microreactor chip and the effective removal of heat generated in the exothermic reaction, the flow process offers the utmost scale-independent safety level.14
Results and Discussion In an effort to develop a facile and fast method for Arbuzov reaction, we started with the studies on the optimization of this transformation under flow conditions. All reactions were performed solventless in a microreactor (Syrris Asia 120) with an internal volume of 250 µl. In the first series of experiments, the optimal conditions for the Arbuzov reaction between both phosphite 1 and alkyl halide 2 having the same alkyl groups (R1 = R2) were elaborated. Residence time (tres), temperature, and stoichiometric ratio were optimized evaluating the conversion by 1H and 31P NMR (Table 1 and 2).
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Table 1. Optimization of the solvent-free Arbuzov rearrangement between trimetyl phosphite 1a and catalytic amount of methyl iodide 2a.
MeO
:
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The Journal of Organic Chemistry
OMe
P OMe 1a
MeI (2a) (0.02-0.1 equiv.) tres, T, neat
O MeO
P OMe Me 3a
Entry
2a (equiv.)
T (°C)
tres [a] (min.)
Conversion[b] (%)
1
0.02
100
25
66
2
0.05
50
25
5
3
0.05
60
25
9
4
0.05
70
25
20
5
0.05
80
25
49
6
0.05
90
25
83
7
0.05
100
8.33
≥99
8
0.05
100
5
97
9
0.1
100
batch, 7h[c]
80
[a] tres– residence time. [b] estimated on the basis of 1H and 31P NMR. [c] reaction time. To evaluate the optimal amount of halogen, residence time and temperature, the reaction of trimethyl phosphite (1a) with methyl iodide (2a) was chosen as the model reaction. As shown in Table 1 (entry 1), the reaction with 0.02 equiv. of methyl iodide (2a) at 100 °C was initially carried out. Unfortunately, the expected dimethyl methylphosphonate (3a) was obtained only in good conversion (66%) after residence time of 25 minutes. From this experiment, it was clear that 0.02 equiv. of alkyl halide 2a was insufficient, and we employed in the next attempts a quantity of 5 mol % of methyl iodide. Next, we screened the temperature of the reaction as it was reasonable to examine how this reaction rate depends on the temperature at constant residence time (Table 1, entries 2-7). At the temperatures in the range 50-80 °C (Table 1, entries 2-5) the reaction proceeded with 5% or more conversion. Increase in the reaction temperature up to 90 °C allow the conversion to raise to 83% maintaining a residence time of 25 minutes (Table 1, entry 6). Excellent conversion (≥ 99%) and short residence time (8.33 min.) was obtained for a ratio of 2a/1a of 0.05 at 100 °C (Table 1, entry 7). To our delight, these results confirm the excellent heat transfer into reaction mixture using the flow system during this rearrangement. Raising the temperature in the microchip by 20 degrees (from 80 °C to 100 °C) increased the conversion of the reaction by 50 percent (Figure 1).
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99 Conversion (%)
100
83
80
49
60 40 20
9
5
20
0 50
60 70 80 Temperature (°C)
90
100
Figure 1. Conversion of trimethyl phosphite 1a versus temperature under flow conditions and tres = 25 min. (Table 1, entry 2-7). Furthermore, to make the conditions even more cost-effective and less time-consuming, we decided to decrease a residence time to as low as 5 minutes to give 97% conversion of 2a (Table 1, entry 8). The same reaction carried out under batch conditions at 100°C required higher amounts of methyl iodide (0.1 equiv.), a much longer time (7h) and gave the product in only 80% conversion (Table 1, entry 9). Vaporization of the reagents into the headspace of the batch system decreases the concentration in solution, therefore, reactions with low-boiling point reagents such as MeI consistently proceed more efficiently in pressurized flow reactors.14 Process scale-up has been demonstrated to be facile and rapid while the quantities of alkyl halide are strongly reduced. As a result it allows for the safe production of 11.74 g of dimethyl methylphosphonate (3a) in 6 hours. Table 2. Optimization of the solvent-free Arbuzov reaction between trialkyl phosphites 1b, c and alkyl halides 2b, c, f with the same alkyl substituents. RO
:
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OR
P OR
1b R = Et 1c R = Bn
R X 0.05-0.15 equiv. tres, T, neat 2b R = Et, X = I 2c R = Bn, X = Br 2f R = Et, X = Br
O P RO OR + R X R 3b R = Et 3c R = Bn
Entry
1
2
2 (equiv.)
T (°C)
tres [a] (min.)
Prod. 3
Conversion[b] (%)
1
(EtO)3P (1b)
EtI (2b)
0.05
100
25
3b
