Note pubs.acs.org/joc
Synthesis of Aminobenzopyranoxanthenes with NitrogenContaining Fused Rings Natsumi Fukino,† Shinichiro Kamino,*,†,‡ Minami Takahashi,† and Daisuke Sawada*,†,‡ †
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama-shi, Okayama 700-8530, Japan Next-generation Imaging Team, RIKEN-CLST, Kobe-shi, Hyogo 650-0047, Japan
‡
S Supporting Information *
ABSTRACT: An efficient and practical method for the synthesis of a variety of aminobenzopyranoxanthenes (ABPXs) with different nitrogencontaining fused rings was developed. On the basis of the mechanistic studies of the formation of the xanthene framework, the presented methodology was developed to facilitate access to previously inaccessible asymmetric ABPXs.
O
issues owing to the formation of byproducts, as seen in the classical synthetic method of rhodamines and fluoresceins utilized for industrial applications. In addition, very little is known about the mechanistic details of the formation of xanthene frameworks, since it involves the use of strong acids at high temperatures.9 As a part of our ongoing research regarding the practical uses of ABPXs, we report the development of a synthetic method for ABPXs based on mechanistic studies, efficient synthesis of new derivatives with different nitrogencontaining rings, and their spectral characteristics. To develop a synthetic method for ABPXs with nitrogencontaining rings, an ABPX derivative with amino groups on the pyrrolidine rings was used as the model substrate. According to the classical method, the initial reaction between benzophenone derivative 1a and resorcinol 2 was performed in CH3SO3H for 4, 6, and 10 h at 110 °C (Scheme 1, Scheme S1 and Table S1). Although these reaction conditions afforded the desired ABPXPYR (4) in low yields, 20% of Rhodol-PYR (5) was obtained
ver the past century, xanthene-based organic dyes, including rhodamines and fluoresceins, have been studied extensively owing to their diverse applications in the medical and life sciences as biological probes,1 molecular sensors,2 photosensitizers,3 photocatalysts,4 and components of optoelectronic devices.5 A number of synthetic approaches toward xanthene scaffolds, based on organometallic coupling reactions, have been developed.6 Although these attractive reactions allow for the flexible derivatization of such scaffolds, they are not amenable to industrial applications due to the use of flammable reagents, multistep reactions, and complex synthetic and purification steps. A new class of rhodamines, aminobenzopyranoxanthenes (ABPXs), have recently garnered considerable attention as color materials and in chemical sensing because of their outstanding photophysical properties (Figure 1).7,8 Specifically,
Scheme 1. Classical Synthetic Approach Toward ABPX-PYR (4) and Rhodol-PYR (5) via Monocationic Intermediate (3) from the Acid-Catalyzed Thermal Reaction of Resorcinol with a Benzophenone Derivative
Figure 1. Chemical structures of rhodamines and aminobenzopyranoxanthenes (ABPXs).
ABPXs exhibit a two-step color change depending on the presence and amount of external stimuli such as acids, phenols, or metal ions; this is extraordinary because traditional xanthenes typically only display one color. In this respect, the development of high yielding synthetic methods with a few steps is highly desirable in order to explore the functionality and potential applications of ABPXs. Conventionally, ABPXs are synthesized from the acidcatalyzed thermal reaction of resorcinol with benzophenone derivatives. However, this synthetic methodology has some drawbacks such as a low production yield and purification © 2017 American Chemical Society
Received: September 11, 2017 Published: November 15, 2017 13626
DOI: 10.1021/acs.joc.7b02290 J. Org. Chem. 2017, 82, 13626−13631
Note
The Journal of Organic Chemistry Scheme 2. Proposed Reaction Mechanism for the Formation of ABPX-PYR (4++)
distances in the catechol moiety were calculated to be 1.33 and 1.35 Å. These symmetric bond lengths can be attributed to the cross-conjugated resonance structure 7 shown in pathway 1. Overall, the mechanistic studies suggested that the regulation of the cyclization reaction pathway could be exploited to improve the yields of ABPXs. A possible rationale for the low yield of 4 under the classical conditions is that the cyclization reaction occurs via multiple intermediates shown in pathway 1, which is consistent with the observation of the production of multiple colored compounds. In contrast, pathway 2 involves an accessible cyclization route to 4 ++. Therefore, we hypothesize that the alkylation of resorcinol may alter the cyclization pathway from 1 to 2 to give higher yields of ABPXs. To validate this hypothesis, we assessed the reaction between 1,3-dimethoybenzene (15) and 1 in neat CH3SO3H at 110 °C. Notably, the yield of 4 increased dramatically to 73% (Table 1, entry 2) relative to that under the classical conditions (Table 1, entry 1). The cyclization reaction proceeded via pathway 2 under these conditions, since nonlabeled ABPX-PYR was obtained in the highest percentage (92%, m/z 662), as evidenced by tracer studies of 18O-labeled 15. Next, we screened various 1,3-dialkoxybenzenes (Table 1). These studies demonstrated that 1,3-diisopropoxybenzene (16) was the best substrate (Table 1, entry 5). In contrast, the cyclization reaction did not go to completion, and some intermediates such as acetals were obtained (Figure S4), as a result of the longer alkyl group. With respect to the condensed-ring xanthene structure, the scope of this method was evaluated by reacting 16 with 9-(2carboxybenzoyl)-8-hydroxyjulolidine (1b)7e in CH3SO3H at 110 °C. In this case, the yield of ABPX-JUR (17) improved slightly (37%, Table 2, entry 5) compared to that under the classical conditions (29%), and Rhodol-JUR (18) was obtained in 11% yield. Therefore, we further optimized the reaction conditions of ABPX-JUR by using the benzophenone derivative 1b. We attempted the reaction at low temperatures, because the
and multiple colored compounds were obtained, as confirmed by silica gel thin-layer chromatography. In order to gain insight into the reaction mechanism under the classical conditions, 5 and 1a were reacted in CH3SO3H at 110 °C. A substantial amount of unreacted 1a was recovered, indicating that 4 was not formed through the formation of 5. Subsequently, isotopic studies of oxygen-18 (18O)-labeled 2 with 1a were performed to investigate the cyclization of the xanthene ring.10 Following the thermal reaction of 18O-enriched 2 with 1a in CH3SO3H, several ABPX-PYR products were obtained in yields of 56% (m/z 666), 33% (m/z 664), and 11% (m/z 662). Enriched 18O Rhodol-PYR was also obtained. (Scheme S1 and Figures S1 and S2 show the results of these studies.) The large amount of 18O contained in 4 and 5 indicated that the oxygen atom of the xanthene ring was mainly derived from resorcinol. Based on the mechanistic studies, a proposed mechanism for the formation of 4 and 5 is shown in Schemes 1 and 2. Compounds 4 and 5 are competitively formed from the monocationic intermediate (3) via a Friedel−Crafts-type reaction of 2 with 1a in CH3SO3H. Intermediate 3 then reacts with 1a to give the dicationic intermediate (6) (Scheme 2); two possible cyclization pathways could give 4++. In pathway 1, 6 is stabilized by the pyrrolidinyl phenol moiety, and the stepwise ring closures involve nucleophilic attacks of hydroxyl groups on the catechol moiety of 8, 10, and 11 on the ipso-carbon atoms (C6 and C10). In contrast, nucleophilic attacks of hydroxyl oxygen in the aminophenol moiety of 6 to C7 and C9 positions afford ABPX-PYR in pathway 2. The stability of resonance forms of 6 directs which pathway is taken. Mechanistic studies using 18O-labeled 2 revealed that pathway 1 is preferred over pathway 2 under the classical conditions. Next, we confirmed the geometry of the resonance form of 6 using density functional theory (DFT) calculations (Figure S3). The C−N bond lengths in the planar pyrrolidinyl phenol moieties were calculated to be 1.34 Å. The C−O bond 13627
DOI: 10.1021/acs.joc.7b02290 J. Org. Chem. 2017, 82, 13626−13631
Note
The Journal of Organic Chemistry
Scheme 3. (Schemes S2 and S3 show the synthesis of benzophenone derivatives 1c−d.) In all cases, a dramatic
Table 1. Effect of Alkylation of Resorcinol on the Yields of ABPX-PYR (4) and Rhodol-PYR (5′)
Scheme 3. Substrate Scope for ABPXs with NitrogenContaining Fused Ringsa
yield (%) entry
R
4
5′
1a 2 3 4 5 6 7 8
H Me Et n Pr i Pr n Bu i Bu n Octyl
36 73 56 34 74 43 37 32
20 19 15 20 11 20 11 7
a
Reaction time of 6 h. Compound 5′ contains compound 5 and alkylated Rhodol-PYR.
Table 2. Optimization of the Reaction Conditions for the Formation of ABPX-JUR (17) a
The percentage in parentheses shows the yield under the classical conditions.
improvement in the yield was observed as compared to the classical conditions. Notably, ABPX-TMJUR (20), which is difficult to prepare under the classical conditions, was obtained in 68% yield by using 4 molar equiv of 1d to 16. Encouraged by these results, we designed a new method to synthesize an asymmetric ABPX based on the formation of a diphenyl isobenzofuranone derivative, followed by condensation with a different benzophenone (Scheme 4). Upon addition
yield (%) entry temp (°C) 1 2 3 4 5 6 7 8 9 10 11 12 13
rt rt→110 rt→110 rt→110 110 rt→110 rt→110 rt→110 rt→110 rt→110 rt→110 rt→110 rt→110
time (h) 48 12→12 20→24 48→6 24 48→6 48→6 48→6 48→6 48→6 48→6 48→6 48→6
solventa
CH3SO3H (vol %)
17
18
26 56 60 64 37 0 0 55 62 53 69 74 70
