br Acknowledgments br Introduction Dihydropyridines DHPs are a

Acknowledgments

Introduction
1,4-Dihydropyridines (1,4-DHPs) are a class of highly important molecular skeletons abundant in natural products. They are key intermediates of nitrogen-containing polycyclic hydrocarbons and widely used in pharmaceutical agents [1,2]. In view of their high significance, great effort has been made to develop new methods to synthesize 1,4-DHPs, among which, the Hantzsch reaction utilizing an amine, an aldehyde, and two 1,3-dicarbonyl compounds to synthesize 1,4-DHPs is the most classic approach. However, this approach has some obvious disadvantages such as harsh reaction conditions, excessive use of volatile organic solvents and high reaction temperature [3]. Later, chemists developed several alternate and efficient methods for the synthesis of 1,4-DHPs, which include the promotion of microwave [4], polymer [5], TMSCl [6], Lewis HZ-1157 Supplier [7], Brønsted acid [8], solid acid [9], base [10], biocatalysts [11] and organocatalysts [12]. Although the known methodologies have convenient protocols with good to high yields, the reported methods still suffered from drawbacks, such as prolonged reaction times, high temperature and the use of non-recyclable catalysts. Thus, it is essential to develop a simple, efficient and green method for the synthesis of 1,4-DHPs.
In the recent years, green chemistry using environment-friend reagents and conditions is one of the most fascinating developments in synthesis of widely used organic compounds. Ultrasound has been used to accelerate the chemical reactions proceed via the formation and adiabatic collapse of transient cavitation bubbles. The ultrasonic effect induces very high local pressure and temperatures inside the bubbles and enhances mass transfer and turbulent flow in the liquid [13]. Ultrasound has been utilized to accelerate a number of synthetically useful reactions, especially in heterocyclic chemistry [13].
Ionic liquids (ILs) technology has been widely used as another new and environment-friend approach toward modern synthetic chemistry and has attracting advantages such as extremely low vapor pressure, excellent thermal stability, reusability, and talent to dissolve many organic and inorganic substrates [14]. 1-Carboxymethyl-3-methylimidazolium tetrafluoroborate ([CMMIM]BF4) is a Brønsted acidic ionic liquid and has been proofed to be excellent catalysts to some organic synthesis, which clearly indicate its advantages such as benign to environment, easy to be recycled and homogeneous to reaction, such as synthesis of Fischer indole [15], synthesis of 3,4-dihydropyrimidin-2-(1H)-ones [16], Mannich reaction [17]. Besides, solvent-free organic synthesis as a green synthetic approach has received considerable attention because they are operationally simple, often involve nontoxic materials, and proceed in excellent yield with high selectivity [18]. Toward the development of clean chemical processes [19], we report a novel and environment-friend procedure for the solvent-free preparation of 4-substituted 1,4-dihydropiridine-3,5-dicarboxylates in the presence of [CMMIM]BF4 as an efficient and versatile catalyst under ultrasonic irradiation (Scheme 1).

Experimental

Results and discussion
For the solvent-free synthesis of the dimethyl 4-phenyl-1,4-dihydropiridine-3,5-dicarboxylate (4a), ultrasound promotion, ionic liquid catalyzation are the two most important parameters. To optimize, the preliminary reaction was sonicated under various sets of conditions at 25–30°C catalyzed by benzaldehyde (1a, 1mmol), methyl propiolate (2, 2mmol), ammonium carbonate (1mmol) and 5mol% [CMMIM]BF4 as catalyst (Table 1). The effect of the ultrasound power intensity on the product yield was also investigated by increasing the irradiation power from 150 to 350W. It can be seen from Table 1 that increase of ultrasonic power led to relatively higher yield and shorter reaction time, which peaked at 300W. Then the yield decreased slightly with increasing ultrasound power intensity >300W. Therefore, 300W of ultrasonic irradiation was sufficient to push the reaction forward. The best yield for 4a was obtained at 15min at room temperature with 300W ultrasonic irradiation. The possible explanation for the positive association of between yield and irradiation power is that the increase in the acoustic power could increase the number of active cavitation bubbles and the size of the individual bubbles, both of which are expected to result in higher maximum collapse temperature and accelerated respective reaction. However, when ultrasonic intensity exceeded the optimal value (>300W), excessive number of gas bubbles exist in the solution, which adversely exhibits scattering effect on the sound waves and lowers the level of energy focused on the reaction vessel. Additionally, the coalescence of the cavities in the presence of large number of cavities may promote the formation of a large cavity which collapses less violently. Consistent with previous studies, increase in the operating intensity beyond the optimum will lead to the decrease of the utilization efficiency of ultrasound and the reaction yield [21,22].

br Acknowledgments br Introduction Dihydropyridines DHPs are a

Acknowledgments

Introduction
1,4-Dihydropyridines (1,4-DHPs) are a class of highly important molecular skeletons abundant in natural products. They are key intermediates of nitrogen-containing polycyclic hydrocarbons and widely used in pharmaceutical agents [1,2]. In view of their high significance, great effort has been made to develop new methods to synthesize 1,4-DHPs, among which, the Hantzsch reaction utilizing an amine, an aldehyde, and two 1,3-dicarbonyl compounds to synthesize 1,4-DHPs is the most classic approach. However, this approach has some obvious disadvantages such as harsh reaction conditions, excessive use of volatile organic solvents and high reaction temperature [3]. Later, chemists developed several alternate and efficient methods for the synthesis of 1,4-DHPs, which include the promotion of microwave [4], polymer [5], TMSCl [6], Lewis HZ-1157 Supplier [7], Brønsted acid [8], solid acid [9], base [10], biocatalysts [11] and organocatalysts [12]. Although the known methodologies have convenient protocols with good to high yields, the reported methods still suffered from drawbacks, such as prolonged reaction times, high temperature and the use of non-recyclable catalysts. Thus, it is essential to develop a simple, efficient and green method for the synthesis of 1,4-DHPs.
In the recent years, green chemistry using environment-friend reagents and conditions is one of the most fascinating developments in synthesis of widely used organic compounds. Ultrasound has been used to accelerate the chemical reactions proceed via the formation and adiabatic collapse of transient cavitation bubbles. The ultrasonic effect induces very high local pressure and temperatures inside the bubbles and enhances mass transfer and turbulent flow in the liquid [13]. Ultrasound has been utilized to accelerate a number of synthetically useful reactions, especially in heterocyclic chemistry [13].
Ionic liquids (ILs) technology has been widely used as another new and environment-friend approach toward modern synthetic chemistry and has attracting advantages such as extremely low vapor pressure, excellent thermal stability, reusability, and talent to dissolve many organic and inorganic substrates [14]. 1-Carboxymethyl-3-methylimidazolium tetrafluoroborate ([CMMIM]BF4) is a Brønsted acidic ionic liquid and has been proofed to be excellent catalysts to some organic synthesis, which clearly indicate its advantages such as benign to environment, easy to be recycled and homogeneous to reaction, such as synthesis of Fischer indole [15], synthesis of 3,4-dihydropyrimidin-2-(1H)-ones [16], Mannich reaction [17]. Besides, solvent-free organic synthesis as a green synthetic approach has received considerable attention because they are operationally simple, often involve nontoxic materials, and proceed in excellent yield with high selectivity [18]. Toward the development of clean chemical processes [19], we report a novel and environment-friend procedure for the solvent-free preparation of 4-substituted 1,4-dihydropiridine-3,5-dicarboxylates in the presence of [CMMIM]BF4 as an efficient and versatile catalyst under ultrasonic irradiation (Scheme 1).

Experimental

Results and discussion
For the solvent-free synthesis of the dimethyl 4-phenyl-1,4-dihydropiridine-3,5-dicarboxylate (4a), ultrasound promotion, ionic liquid catalyzation are the two most important parameters. To optimize, the preliminary reaction was sonicated under various sets of conditions at 25–30°C catalyzed by benzaldehyde (1a, 1mmol), methyl propiolate (2, 2mmol), ammonium carbonate (1mmol) and 5mol% [CMMIM]BF4 as catalyst (Table 1). The effect of the ultrasound power intensity on the product yield was also investigated by increasing the irradiation power from 150 to 350W. It can be seen from Table 1 that increase of ultrasonic power led to relatively higher yield and shorter reaction time, which peaked at 300W. Then the yield decreased slightly with increasing ultrasound power intensity >300W. Therefore, 300W of ultrasonic irradiation was sufficient to push the reaction forward. The best yield for 4a was obtained at 15min at room temperature with 300W ultrasonic irradiation. The possible explanation for the positive association of between yield and irradiation power is that the increase in the acoustic power could increase the number of active cavitation bubbles and the size of the individual bubbles, both of which are expected to result in higher maximum collapse temperature and accelerated respective reaction. However, when ultrasonic intensity exceeded the optimal value (>300W), excessive number of gas bubbles exist in the solution, which adversely exhibits scattering effect on the sound waves and lowers the level of energy focused on the reaction vessel. Additionally, the coalescence of the cavities in the presence of large number of cavities may promote the formation of a large cavity which collapses less violently. Consistent with previous studies, increase in the operating intensity beyond the optimum will lead to the decrease of the utilization efficiency of ultrasound and the reaction yield [21,22].

br Materials and methods br

Materials and methods

Results

Discussion
Our investigation supports the HZ-1157 Supplier that there are considerable differences in the source–receptor relationships between the three most important tree pollen types in England. Firstly, on all peak days, for Alnus the air masses originated from a westerly direction, while for Quercus and Betula the air masses originated from mainly westerly and easterly directions. Secondly, Fig. S1 suggests that Long Distance Transport from the European continent to England is much more relevant for Quercus and Betula than it is for Alnus – despite similar aerodynamic properties for all three pollen types. Thirdly, the source maps (Fig. 2a–c) show a very uneven distribution of the three pollen types across England, Wales and Scotland. Certain hotspots for Alnus (Wales), Betula (Wales and central England) and Quercus (Wales and central England) have affected the pollen load in Worcester. Hotspots in South-East England have previously been identified as an important area for London (Skjøth et al., 2009) but have limited effect on the pollen concentrations in Worcester (Fig. S3). Instead, the smaller woodlands (e.g. birch) located 30–50km to the north east of Worcester appear to have contributed more to high pollen concentrations. Overall these observations support our hypothesis that the atmospheric concentrations of pollen grains from these three tree types are very diverse over England and that the observed concentrations in England in many cases will relate to trees from small woodlands. Our investigation also suggests that day-to-day concentrations of these pollen types are mainly determined by atmospheric transport from specific source areas, where each area mainly affect certain regions of England (e.g. the impact on London from the birch trees in southern England). Finally, our investigation shows that the relevant spatial scales vary between the genera, which is exemplified by Long Distance Transport. This highlights that there is a clear difference in the source–receptor relationships between the pollen grains from the three tree genera, which will affect daily and seasonal pollen load in England.
The observations show that the mean pollen index is a factor of 2–3 times greater for Betula and Quercus compared to Alnus (1574; 770-2344), which stands in contrast to the difference in genus coverage. The source maps and the forestry statistics suggest that Quercus and Betula are more abundant than Alnus by up to a factor of 17. Furthermore, the weather conditions during the Birch and Quercus seasons should favour higher pollen concentrations than the weather during the Alnus season as this period has fever daytime hours with sun-shine and lower temperatures than the later birch and oak seasons, which are considered the primary factors for high pollen concentrations (Clot, 2001). Considering this, simple scaling would suggest that Betula and Quercus pollen should be present in quantities much higher than just a factor of three, maybe by a factor of 20 or more, when compared with Alnus. In Northern Europe it has been estimated that on average a single birch tree produces from 1000 to 10000 pollen grains daily, thus a factor of 10 (Ranta et al., 2008). Furthermore, Betula is considered among the tree genera as the highest pollen producer , with about a factor of ten higher productivity compared HZ-1157 Supplier to other species such as Corylus, Fraxinus sp. and Ulmus sp. (Brostrom et al., 2008), and Betula and Quercus seem to have a higher potential for Long Distance Transport (Fig. S1). However, there are regional variations in pollen production even at the same latitude, probably due to local growing conditions. In southern Sweden Betula is estimated to produce twice the amount of pollen compared to Alnus, while in Estonia Alnus is estimated to have a three times higher production than Betula (Brostrom et al., 2008). Overall this clearly shows that there is no linear relationship between genus abundance and overall pollen concentration. The most likely cause to this non-linearity is a combination of uneven source distribution and differences in weather conditions (e.g. temperature, wind gust, relative humidity) during the pollen season, causing a difference in the source–receptor relationships between Alnus and Betula or Quercus.