Tandem Buildup of Complexity of Aromatic Molecules Through Multiple Successive Electrophile Generation in One Pot, Controlled by Varying the Reaction Temperature

While some sequential electrophilic aromatic substitution reactions, known as tandem/domino/cascade reactions, have been reported for construction of aromatic single skeletons, one of the most interesting and challenging possibilities remains the one-pot build-up of complex aromatic molecule from multiple starting components, i.e., ultimately multi-component electrophilic aromatic substitution reactions. In this work, we show how tuning of the leaving group ability of phenolate derivatives from carbamates and esters provides a way to successively generate multiple unmasked electrophiles in a controlled manner in one pot, simply by varying the temperature. Here, we demonstrate autonomous formation of up to three bonds in one pot and formation of two bonds arising from a three-component electrophilic aromatic substitution reaction. This result provides a proof-of-concept of our strategy Page 1 of 37 Organic & Biomolecular Chemistry


Introduction
Assembly of multiple functionalized aromatic structures into a single molecule is of interest both in drug design, as exemplified by the integration of multiple functionalized aromatic pharmacophores. 1 For this purpose, the idea of sequentially connecting structurally simple aromatic compounds seems an attractive approach. 2 Electrophilic aromatic substitution (S E Ar) reactions can be used for individual functionalization of several different aromatic moieties in a single molecule (Chart 1).
The conventional methodology would be convergent connection of several substituted aromatic compounds through electrophilic centers, as shown in Chart 1(a). However, this approach often requires workup/isolation processes to minimize side reactions or to remove excess reactants or by-products. For example, the reactivity of electrophiles is frequently insufficient to drive the reaction to completion, so an excess amount of  Because the substitution position of ester groups dramatically changes the C-O bond cleavage reaction rates of carbamates bearing methyl salicylates, we expected that adding another ester group into the leaving group (methyl salicylate) would increase the unmasking reaction rate. It turned out that dimethyl 4-hydroxyisophthalate (1d), containing two ester groups at the ortho-and para-positions with respect to the phenolic oxygen atom, is a better leaving group than methyl salicylate (1c). In the case of 1d, the leaving group is cleaved to form isocyanate cation even at 0°C, and the reaction is completed within 20 minutes (Figure 1(b)). Thus, at 0°C, the reaction of methyl salicylate (1c) can be differentiated from the reaction of diester 1d.
This concept is also applicable to differentiate between esters and carbamates, that is, between generation of acyl cations and isocyanate cations. Because the C-O bond strength in esters 1e is weaker than that in carbamates 1c, the C-O bond in esters is cleaved faster than the C-O bond in carbamates: this enables temperature control of the generation of acyl cation (at 0°C) and isocyanate cation (at 20°C) ( Figure 2). Thus, we can control the speed of unmasking to generate different reactive electrophiles simply by changing the temperature. a) Isolation yields, b) NMR yield.

Activation of leaving group through protonation and hydrogen bonding
We conducted kinetic studies to characterize the difference in leaving ability between the monoester leaving group (see 1b) and diester leaving group (see 1f). Figure 3 shows the dependence of the reaction profiles on the acidity of the medium. In the case of monoester leaving group (1b), as the acidity is increased, the reaction rate increases to a broad maximum, and then decreases in the strong acidity region. (methyl salicylate) and one rather unstable dicationic species (O-protonated carbamate dication). Therefore, this means that the monocationic species (TS-1b, Figure 3a) rather than the diprotonated species (TS-1b', Figure 3a)   On the other hand, in the case of diester leaving group (1f), as the acidity increased, the reaction rate increases monotonically to a broad maximum from relatively weak acidic region (-H 0 = 10) to strong acidic region (-H 0 = 14) (Figure 3b). Because ortho-monoester-substituted carbamate (1b) is diprotonated under strong acidic region (-H 0 = 14) (see TS-1b', Figure 3a), disubstituted carbamate (1f) also can be diprotonated under strong acidic region (-H 0 = 14). When the carbonyl oxygen atom of the carbamate functional group of diester-substituted carbamate (1f) is protonated (TS-1f', Figure 3), the C-O bond cleavage of this diprotonated species will be difficult because of the generation of one neutral species and one rather unstable gitonic (close) dicationic isocyanate cation species. Therefore, the C-O bond cleavage of the diprotonated species will take place through the alternative diprotonated state TS-1f rather than the dication state TS-1f' (Figure 3).

Computational support for leaving group activation
These kinetic results are supported by the results of calculations ( Figure 4). The calculated energy differences are shown in terms of ∆∆G at 25°C (298K), together with the ∆∆H.
In the continuum environment of TfOH, there are several possible stable conformers of diester-substitued carbamate 1f in protonated states, because the diester carbamate functionalities have several basic sites. 13a,b The ester carbonyl oxygen atom(s), the most basic sites, is mono-protonated or are di-protonated, such cationic species, The reaction rate of ester (1e) could not be measured due to the very rapid unmasking rate; however, the calculation results support a marked difference in reaction rates between the relevant carbamate and ester ( Figure 5). From the calculation result, the activation energy of C-O bond cleavage of the monoester-substituted carbamate 1b from the most stable conformer (SM 0 -1b) through the equilibrating minor monocationic species (SM-1b), ∆∆G 298K : 23.0 kcal/mol; ∆∆H: 24.5 kcal/mol, is higher than that of C-O bond cleavage of the ester from the more stable monocationic species (SM-1e), ∆∆G 298K : 13.1 kcal/mol; ∆∆H: 13.7 kcal/mol. This may be partially because the carbamate is more stable than the ester due to Y-type conjugation, 11i, 15 and thus more energy is needed to break the stable C-O bond of the carbamate. In the case of ester, it is worthwhile to note that when the intramolecular hydrongen bonding is formed to the phenolic oxygen atom, the conformer SM-1e is the more stable than the isomeric SM o -1e ( Figure 5).
Therefore, an ester compound bearing methyl salicylester group can be easily cleavage its O-C bond. These calculations are consistent with the experimental results: the reaction of ester (1e) is dramatically faster than that of monoester-substituted carbamate 1b, and 1e is distinctly faster than diester-substituted carbamate 1f. Other calculation levels (M06, MP2) also support this conclusion (Supporting Information, Figure SI -3, 4) and the observed relationship ( Figure 2). Based on the above findings, we considered that temperature control of unmasking of electrophiles could be applied to build-up aromatic molecular complexity in one-pot reactions (Figures 6-8 and Tables 1-3)). First, we explored formation of two bonds. First, the corresponding isocyanate cation (4-cation) was generated from carbamate bearing ortho, para-disubstituted phenol at 0°C, and then the electron-rich aromatic ring (magenta) of 5 reacted with the resulting isocyanate cation (blue) to form a C-C bond in the aromatic amide structure 6 (red bond) ( Figure 6(b)). Under cooling (0°C), the carbamate containing para-monosubstituted phenol did not uncage to form the isocyanate cation (4-cation). When the reaction mixture was warmed to room temperature (20°C), the second isocyanate cation (6-cation, red) was generated from the carbamate containing para-monosubstituted phenol (6), and the second aromatic compound (orange) reacted with the isocyanate cation (6-cation) to form a C-C bond in the aromatic amide structure, affording 7 in an intramolecular manner in this example (red bond) ( Figure 6(b)). The yield shown is that over the two steps; thus, the average yield of each reaction is larger than 93%.  Table 1

. Two-step buildup of complexity of aromatic molecules by dual amidation
The generality of this sequential dual amidation reaction was examined and the results are shown in Table 1, which supports the feasibility of multiple intermolecular or intramolecular amidation reactions. Because the reaction temperature (20°C) is not so high, ethyl carbamate (8), 12i ester groups (14 and 16), 16 and a methoxy group (15) (Table 1). to form a C-C bond in the aromatic ketone structure 28 (red bond) (Figure 7(b)). At 0°C, the carbamate containing para-monosubstituted phenol did not decompose to isocyanate cation. However, on warming the reaction mixture to room temperature (20°C), the second isocyanate cation (28-cation, red) was generated from the carbamate containing para-monosubstituted phenol (28), and the second aromatic compound (orange) reacted with the resulting isocyanate cation (28-cation) in an intramolecular manner to form an aromatic amide bond (red bond in product 29) ( Figure 7(b)). Again the yield shown is the two-step yield, and the average yield of each reaction was larger than 89%.  Table 2

. Two-step buildup of complexity of aromatic molecules by acylation and amidation
The generality of this sequential acylation-amidation reaction was examined and the results are shown in Table 2, which supports the feasibility of multiple intermolecular or intramolecular acylation-amidation reactions. Substrates bearing a trifluoromethyl group (27) 18 or an ester group (30) 15 can produce electrophile species, but because of the low temperature (0°C to 20 °C), acylation-amidation reactions are accomplished without interference from these functional groups. After the first S E Ar reaction was completed (the formation of 36 or 39), the aromatic substrate (37 or 40) was added, and therefore three kinds of starting materials are combined sequentially into a single aromatic molecule (38 or 41) in one pot. The average yield of each reaction ranged from 77% to 89%.

Formation of three bonds in a one-pot reaction
Finally, we demonstrate the formation of three inter-and intramolecular bonds constituting ketone/amide functionalities in one pot (Figure 8).
The first electrophiles (blue) are generated from ester (27) containing ortho-mono-substituted phenol (methyl salicylate) (Figure 8(a)) or carbamate (4) (Figure 8(b)) containing ortho, para-disubstituted phenol at 0°C, followed by generation of the second electrophiles (red) from carbamate (36 or 20) containing ortho-monosubstituted phenol at 20°C for around 30 min. The third electrophiles (green) are generated very slowly (in around half a day) from carbamates (42 or 44) containing para-monosubstituted phenol at 20°C. As described above, these combined reactions enable temporally controlled generation of highly reactive electrophiles (blue, red, and green), which react rapidly with one equivalent of the target aromatic compounds (pink, orange, and brown).

Page 20 of 37 Organic & Biomolecular Chemistry
The desired compounds were obtained in relatively good yields (43: 56%; 45: 53%) (these yields are three-step yields, so the average yield in reaction (a) is 82% and that in reaction (b) is 81%, respectively). Thus, we can control the unmasking reaction rates and the time of generation of highly reactive electrophiles.
Although the third electrophilic reaction was intramolecular and the third component (5) was added after the first S E Ar reaction between the first and second components was completed, three components were combined into a single aromatic molecule in one pot with high regioselective formation of three bonds.
This reaction design is, therefore, a potential avenue to realize ultimate multi-component electrophilic aromatic substitution reactions (as shown in Chart 1(b)).

Conclusion
Tuning of the leaving group ability of phenolate derivatives from carbamates (1a-1d) and ester (1e) enables temporal control of the generation of multiple electrophiles (unmasking) simply by appropriate selection of the reaction temperature, so that autonomous sequential electrophilic aromatic substitution reactions can proceed in one pot. This chemistry thus allows individual functionalization of several different aromatic moieties in one molecule by means of multiple electrophilic aromatic substitution reactions, affording complex aromatic assemblies in one pot. While the number of bonds that can be formed is unlimited in theory, in the present work, we demonstrated autonomous formation of up to three bonds in one pot, and we realized one example of three-component reaction to make two amide bonds. In order to use this system for practical reactions applicable to synthesis of libraries of compounds, it will be necessary to reduce the amount of acid and to design sophisticated leaving group systems. Nevertheless, in this work, we have demonstrated the conceptual validity of one-pot build-up of complex aromatic molecule from multiple starting components, ultimately leading to multi-component electrophilic aromatic substitution reactions (Chart 1(b)).

Formation of three bonds in a one-pot reaction 43 (Figure 8, Reaction (a))
To TfOH (
Single point energies were calculated with CPCM-M06-2X/6-311++G(d,p) (and some other calculation levels) on the basis of the optimized structures. [25] The zero-point vibrational energy corrections were done without scaling. The unmasking reaction rates and the time of generation of highly reactive electrophiles can be controlled. This reaction system demonstrates the conceptual validity of one-pot build-up of complex aromatic molecule from multiple starting components.