I.
Nagao
*,
T.
Ishizaka
and
H.
Kawanami
*
Research Institute for Chemical Process Technology, Department of Materials and Chemistry, 4-2-1, Nigatake, Miyaginoku, Sendai 983-8551, Japan. E-mail: i.nagao@aist.go.jp; h-kawanami@aist.go.jp
First published on 25th May 2016
A high-pressure and high-temperature (HPHT) water microflow chemical process was utilized for the synthesis of benzazole derivatives. The current approach enables the extremely rapid production of various 2-arylbenzazoles including benzimidazoles, benzoxazoles, and benzthiazole in excellent yields.
It should be of significant interest to develop production methods of 2-aryl-substituted benzazole derivatives,4 since these structures are often found as a key unit in various natural compounds, biologically active agents, pharmaceuticals, and functional chemicals, etc.5 For example, Telmisartan and Pimobendan are two well known medicines, for high blood pressure (hypertension) and congestive heart failure, respectively (Fig. 1). Recently, Pittsburgh compound B (PiB), which is a positron emission tomography (PET) imaging agent for Alzheimers disease, has entered the stages of clinical trials. Functional chemicals such as polybenzoxazole (PBO) and polybenzimidazole (PBI) have long been developed for use as super engineering plastics. Another example is fluorescent 2,5-bis(benzoxazol-2-yl)thiophene, which is known to be utilized as an optical brightener for textiles. The compounds shown here are a very few selected examples of already commercialized materials. Furthermore, in the literature, incomparably great numbers of 2-arylbenzazole-based materials have been reported, potentially waiting for industrialization.5
In this contribution, it will be shown that a HPHT water process in association with a microflow reaction system allows to produce various 2-arylbenzazoles including benzimidazoles, benzoxazoles, and benzthioazoles within 10 seconds in excellent yields. To the best of our knowledge, the results shown here would be one of the best demonstrations of the acceleration of benzazole synthesis via dehydration.
A set of our investigations was initiated with the aim of developing a process for 2-arylbenzazoles as a future “green” chemical technology. For this purpose, we specifically paid attention to the condensation reaction between ortho-substituted aniline and benzoic acid derivatives (Scheme 1).6 The route principally consists two fundamental organic reactions; (i) an intramolecular N-acylation and (ii) a dehydration cyclization.4 It has been already reported by our research group that N-acylation of amine and aniline derivatives with acid anhydrides was performed efficiently in ambient-to-subcritical water using microreaction systems.3 Therefore, it is quite plausible that the intramolecular N-acylation proceeds effectively in HPHT water if utilizing benzoic anhydrides as benzoic acid derivatives. In this context, our assumptions leading to this achievement were that; (i) overall reaction completion of the condensation should be extremely fast due to the high energetic state of HPHT water; (ii) the dehydration cyclization step would be facilitated without any addition of acid or base catalysts, since HPHT water itself acts as a catalyst; (iii) the exceptional characteristics of HPHT water would ensure production of the desired benzazoles by preventing undesirable retroreactions such as hydrolysis.
Scheme 1 Production of benzazoles by a high-pressure high-temperature (HPHT) water microflow process. |
Table 1 summarizes selected results of the effects by HPHT water in intramolecular dehydration of N-phenylbenzamides 1.9 At first, N-[2-(phenylamino)phenyl]benzamide 1a was reacted at 400 °C and 30 MPa in a reactor of 0.88 cm3 volume, affording the desired product 1,2-diphenyl-1H-benzo[d]imidazole 2a in 59% yield (Table 1, entry 1). Then, maintaining a constant reaction temperature of 400 °C, pressure was gradually increased from 35 MPa up to 45 MPa. As a result, the yield of 2a was increased from 76% (35 MPa) to 94% (45 MPa). Subsequently, fixing the pressure at 45 MPa, the temperature was increased up to 445 °C, and finally the yield of 2a achieved was quantitative (entry 5). Under these conditions using the reactor of 0.88 cm3 volume, the residence time was estimated to be in the order of ca. 4–5 s. So as to prolong the residence time, a reactor of 4.99 cm3 volume was utilized instead, allowing the product to be given quantitatively under relatively ambient conditions of 400 °C and 30 MPa (entry 6). It should be noted that by-products were not observed in any of the cases above (entries 1–6); 2a was generated as the sole product, otherwise, starting substrate 1a was recovered.10
Entry | X | R. Vol.a (cm3) | Temp. (°C) | Pres. (MPa) | Yieldb (%) | Timec (s) |
---|---|---|---|---|---|---|
a Reactor volume. b GC yield. c Estimated residence time in microreactor. d 50 mM of substrate solution was processed. e 1.0 M of substrate solution was processed. | ||||||
1d | NPh (1a) | 0.88 | 400 | 30 | 59 (2a) | 3.79 |
2d | NPh (1a) | 0.88 | 400 | 35 | 76 (2a) | 5.04 |
3d | NPh (1a) | 0.88 | 400 | 40 | 87 (2a) | 5.55 |
4d | NPh (1a) | 0.88 | 400 | 45 | 94 (2a) | 5.88 |
5d | NPh (1a) | 0.88 | 445 | 45 | >99 (2a) | 3.87 |
6d | NPh (1a) | 4.9 | 400 | 30 | >99 (2a) | 21.1 |
7e | O (1b) | 0.88 | 400 | 40 | 41 (2b) | 5.55 |
8e | O (1b) | 0.88 | 445 | 45 | 57 (2b) | 3.87 |
Fig. 2 shows a graphical representation of product yields in a more extensive range of temperature and pressure. The presented data shows a tendency to reach higher yields at higher pressure and temperature. This suggests that the increased thermal energy at a higher pressure/temperature and prolonged residence time by higher pressure work in favor of affording the product. It should be noted that a local maximum of product yield was observed around at 375 °C under each pressure. This correlates very well to the fact that the ionic constants of HPHT water are maximized up to ca. 370 °C, then lower gradually at higher temperature. This might imply that catalytic function of HPHT water as an acid/base also plays a significant role in achieving a high yield of the product.11
Fig. 2 Effects of temperature and pressure on the yield of benzimidazole 2a using a microreactor tube of 0.88 cm3 volume. |
For production of 2-phenylbenzoxazole 2b, N-(2-hydroxyphenyl)benzamide 1b was subjected to HPHT conditions. For example, the reaction at 400 °C and 40 MPa using a 0.88 cm3 reactor proceeded in 41% yield (entry 7). Higher temperature/pressure (entry 8, 445 °C, 45 MPa) improved the yield up to 57%. The residence time in these reactions was estimated to be 5.55 and 3.87 s, respectively. Contrary to the case of imidazole 2a, a small amount of by-products such as 2-aminophenol and benzoic acid was observed, because of hydrolysis of 1a.10
To clarify characteristics of the current process using HPHT water, we ran the dehydration reactions under non-HPHT conditions (Table 2). For example, reactions of 1a or 1b were performed in aqueous solution under reflux (120 °C, 0.1 MPa) for 24 h (entries 1 and 2 for 1a; entries 4 and 5 for 1b). However, the desired products were hardly detected in each case. Then, acetic acid was added to the reaction mixtures; 1a was converted into 2a in quantitative yield (entry 3), on the other hand, 1b was never transformed into 2b in satisfactory yield (entry 6). These results most clearly point to the distinguishing features of the HPHT process, which completes the reactions without any additional catalyst within only a few seconds.12
Entry | X | Solvent | Recovery | Yieldb (%) | Product | Yieldb (%) |
---|---|---|---|---|---|---|
a 5 mM of 1 in solvent. b GC yield. c H2O:NMP = 9:1. d H2O:AcOH = 9:1. | ||||||
1 | NPh | H2O | 69 | (1a) | 9 | (2a) |
2 | NPh | H2O/NMPc | 87 | (1a) | 12 | (2a) |
3 | NPh | H2O/AcOHd | 0 | (1a) | >99 | (2a) |
4 | O | H2O | >99 | (1b) | trace | (2b) |
5 | O | H2O/NMPc | >99 | (1b) | trace | (2b) |
6 | O | H2O/AcOHd | 54 | (1b) | trace | (2b) |
After confirming that the intramolecular dehydration step proceeded very well under HPHT water conditions as shown above, we extended the current approach to an N-acylation/dehydration sequential process. An example is presented in Scheme 2; N-phenyl-o-phenylenediamine and benzoic anhydride (1.25 eq.) were applied to the HPHT water process, producing 2a efficiently as well.
Scheme 2 N-Acylation/dehydration condensation sequence leading to 1,2-diphenyl-1H-benzo[d]imidazole (2a). |
Finally, scope and limitations are shown in Table 3. All the benzazoles were produced by an N-acylation/dehydration sequential process. Reactions of 1a with MeO- and CF3 substituted benzoic anhydrides proceeded smoothly at 445 °C and 45 MPa, giving the corresponding 1,2-diphenyl-1H-benzo[d]imidazoles 2c and 2d, respectively, in high yields (entries 1 and 2). As a benzazole, 2-phenylbenzimidazole 2e was attainable by condensation between o-phenylenediamine and benzoic anhydride at 445 °C and 35 MPa (entry 3). In the case of 2e, conditions of 445 °C and 45 MPa achieved the most accelerated reaction completion time, 0.17 s (entry 4). Various 2-phenylbenzimidazoles with Br, F, PhCO, and NO2 substituents at the 5 position and a Me substituent at the 1 position, were obtained in excellent yields under the corresponding HPHT conditions (entries 5–9, 2f–2j). The process was also applicable to the efficient production of benzoxazoles 2b, 2k, 2l, benzthiazole 2m, and bis(benzimidazole) 2n (entries 10–14).
Entry | Product/functional groups (2) | Conditionsb (°C/MPa/s) | Yieldc (%) | |
---|---|---|---|---|
a A 50 mM NMP solution of starting substrates including o-substituted aniline (1.0 eq.) and benzoic anhydride derivative (1.25 eq.) was applied to the HTHP water process. Reactor volume = 0.88 cm3. b Process conditions: temperature (°C); pressure (MPa); residence time (s). c GC yield. d Reactor volume = 0.039 cm3. e 1.0 M NMP solution of 2-aminophenol and benzoic anhydride (1.25 eq.) was processed. | ||||
1 | R1 = OMe (2c) | 445/45/3.87 | 90 | |
2 | R1 = CF3 (2d) | 445/45/3.87 | >99 | |
3 | R2 = H (2e) | 445/35/2.26 | 98 | |
4d | 445/45/0.17 | 81 | ||
5 | R2 = Br (2f) | 400/25/1.77 | >99 | |
6 | R2 = F (2g) | 400/40/5.55 | >99 | |
7 | R2 = COPh (2h) | 445/45/3.87 | >99 | |
8 | R2 = NO2 (2i) | 340/45/7.45 | >99 | |
9 | X = NMe, R3 = H (2j) | 400/25/1.77 | >99 | |
10e | X = O, R3 = H (2b) | 445/45/3.87 | 81 | |
11 | X = O, R3 = CF3 (2k) | 445/45/3.87 | 69 | |
12 | X = O, R3 = OMe (2l) | 445/45/3.87 | 84 | |
13 | X = S, R3 = H (2m) | 400/30/3.79 | >99 | |
14 | 400/40/5.55 | 92 |
Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6gc01195k |
This journal is © The Royal Society of Chemistry 2016 |