Tandem buildup of complexity of aromatic molecules through multiple successive electrophile generation in one pot, controlled by varying the reaction temperature

Article abstract of DOI:10.1039/c5ob02240a

While some sequential electrophilic aromatic substitution reactions, known as tandem/domino/cascade reactions, have been reported for the construction of aromatic single skeletons, one of the most interesting and challenging possibilities remains the one-pot build-up of a 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 the 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 applicable for the self-directed construction of complex aromatic structures from multiple simple molecules, which can be a potential avenue to realize multi-component electrophilic aromatic substitution reactions.

Full text of DOI:10.1039/c5ob02240a

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Tandem buildup of complexity of aromatic
molecules through multiple successive
electrophile generation in one pot, controlled by
varying the reaction temperature†
Cite this: DOI: 10.1039/c5ob02240a
Akinari Sumita, Yuko Otani and Tomohiko Ohwada*
While some sequential electrophilic aromatic substitution reactions, known as tandem/domino/cascade
reactions, have been reported for the construction of aromatic single skeletons, one of the most interest-
ing and challenging possibilities remains the one-pot build-up of a complex aromatic molecule from mul-
tiple 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 the 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 applicable for the
self-directed construction of complex aromatic structures from multiple simple molecules, which can be
a potential avenue to realize multi-component electrophilic aromatic substitution reactions.
Received 30th October 2015,
Accepted 16th December 2015
DOI: 10.1039/c5ob02240a
www.rsc.org/obc
tiple starting components, i.e., ultimately multi-component
electrophilic aromatic substitution reactions (Chart 1(b)). This
Introduction
The assembly of multiple functionalized aromatic structures strategy requires precise temporal control of bond formation
into a single molecule is of interest in drug design, as exempli- via multiple sequential electrophilic aromatic substitution reac-
fied by the integration of multiple functionalized aromatic tions in order to increase molecular complexity in a precisely
pharmacophores.1 For this purpose, the idea of sequentially defined manner. Several sequential electrophilic aromatic sub-
connecting structurally simple aromatic compounds seems to stitution reactions, known as tandem/domino/cascade reac-
be an attractive approach.2 Electrophilic aromatic substitution tions, have already been reported for the construction of
(SEAr) reactions can be used for individual functionalization of aromatic single skeletons such as indoles,3 indenes,4 dihy-
several different aromatic moieties in a single molecule droindenes,5 indanones,6 fluorenes,7 carbazoles,8 di- and tri-
(Chart 1). The conventional methodology would be convergent phenylmethane,9 naphthoquinones,10 and other skeletons.11
connection of several substituted aromatic compounds through However, most of these reactions are limited to only two kinds
electrophilic centers, as shown in Chart 1(a). However, this of reactions, i.e., involving the formation of two bonds, often
approach often requires workup/isolation processes to mini- via intermolecular–intramolecular or intramolecular–inter-
mize side reactions or to remove excess reactants or by-pro- molecular sequences (Chart 1(c)). The main reason for this is
ducts. For example, the reactivity of electrophiles is frequently that most of the reactions require the use of an excess amount
insufficient to drive the reaction to completion, so an excess of aromatic compound(s) to effectively promote the inter-
amount of aromatic compound(s) is often used to promote the molecular SEAr reaction, and thus the following SEAr reaction is
intermolecular SEAr reaction (vide infra). On the other hand, inevitably restricted to a kinetically favorable intramolecular
one of the most interesting and challenging possibilities is reaction (Chart 1(c-1)), or vice versa (Chart 1(c-2)). Low reactivity
one-pot build-up of a complex aromatic molecule from mul- of electrophiles is also a reason why many electrophilic reac-
tions are unsuitable for multi-component electrophilic aro-
matic substitution reactions: specifically, the second SEAr
reaction can start before the first SEAr reaction is completed,
and therefore the chemoselectivity is impaired. Thus, current
methodology in this field is commonly restricted to the for-
mation of two bonds, of which one is intramolecular.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: ohwada@mol.f.u-toko.ac.jp
†Electronic supplementary information (ESI) available: Full experimental sec-
tions, details of computation, and 1H and 13C NMR spectra. See DOI: 10.1039/
c5ob02240a
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Chart 1 (a) Conventional step-by-step build-up of aromatic molecules through electrophilic substitution. (b) Hypothetical multi-component aro-
matic electrophilic reactions in one pot. (c-1/c-2) Previous examples of two-step tandem reactions.
One way to achieve multi-component electrophilic aromatic self-directed construction of complex aromatic structures from
substitution reactions would be precise temporal control of the multiple simple molecules, which can be a potential avenue to
generation of highly reactive electrophiles, which can react realize multi-component electrophilic aromatic substitution
rapidly with the target aromatic compound even when the target reactions, as illustrated in Chart 1(b).
aromatic compound is present only in a stoichiometric amount.
An approach to the generation of such electrophiles has
been to transform masked (deactivated or latent) electrophiles
into active (unmasked) electrophiles. For example, ureas and
carbamates can be regarded as masked isocyanate cations that
Results and discussion
Tuning of leaving groups in aromatic amidation and acylation
can be activated via N–C and O–C bond cleavage.12 There have We recently have shown that methyl salicylate is a good leaving
been a few reports on the application of masked isocyanate group from carbamate (which is a stable functional group)
cations to SEAr reactions.12f–h These SEAr reactions of masked under relatively strong acid-catalyzed conditions.13 The methyl
isocyanate cations have been used for intramolecular reac- ester group, located at the ortho position with respect to the
tions, such as the construction of dihydroisoquinolones12g,h or phenolic oxygen atom, assists partial protonation of, or
isoindolin-1-one,12f,g but they are not suitable for inter- H-bonding to, the phenolic oxygen atom, which weakens the
molecular SEAr reactions due to the moderate yields, require- C–O (phenolic) bond, resulting in ready C–O bond cleavage to
ment of excess amounts of aromatic compounds, and the need generate isocyanate cations at 20 °C (20 °C for 90 minutes: 1b,
for heating. These are obstacles for application in tandem/ Fig. 1(a)).14 We have demonstrated previously that N-H and
cascade/domino reactions. To our knowledge, there are few N-alkyl or N-aryl isocyanate cations show different reactivities:
reports of sequential multiple unmasking reactions, mainly N-alkyl and N-aryl isocyanate cations are generated from the
because the unmasking reaction rate is usually dependent on carbamates more slowly than N-H isocyanate cations.13a While
the substrate structure, not on the leaving group, resulting in multiple amidations can be achieved by using isocyanate
severe limitations on suitable reactants.13a Thus, for the devel- cations with different reactivities, we found here that tuning of
opment of multi-component SEAr reactions, new chemical the leaving group ability to generate the isocyanate cations is a
species of leaving groups are required, which can control the more effective strategy to achieve multiple amidations.
unmasking reaction rates.
Indeed, we found that when the ester group is substituted
In this paper, we report successive reaction-temperature- at the para-position with respect to the phenolic oxygen atom
controlled generation of multiple unmasked electrophiles, par- (1a, Fig. 1(a)), C–O (phenolic) bond cleavage occurs slowly
ticularly isocyanate cations and related cations, leading to even on heating (at 40 °C, 26 hours). Therefore, the change in
autonomous sequential electrophilic aromatic substitution the reaction temperature can be used to control the time of
reactions. To achieve this, we focused on control of the bond generation of even the same reactive electrophile, the isocya-
strength of the leaving groups in carbamates as a strategy to nate cation.
obtain the differential leaving ability in order to control the
Because the substitution position of the ester groups dra-
generation of multiple electrophiles. We demonstrated auto- matically changes the C–O bond cleavage reaction rates of car-
nomous formation of up to three bonds in one pot and the for- bamates bearing methyl salicylates, we expected that adding
mation of two bonds arising from
a three-component another ester group into the leaving group (methyl salicylate)
electrophilic aromatic substitution reaction. The present study would increase the unmasking reaction rate. It turned out that
provides a proof-of-concept of our strategy applicable for the dimethyl 4-hydroxyisophthalate (1d), containing two ester
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Fig. 1 Control of amide formation based on different leaving abilities.
groups at the ortho- and para-positions with respect to the phe-
This concept is also applicable to differentiate between
nolic oxygen atom, is a better leaving group than methyl salicy- esters and carbamates, that is, between the generation of acyl
late (1c). In the case of 1d, the leaving group is cleaved to form cations and isocyanate cations. Because the C–O bond strength
isocyanate cations even at 0 °C, and the reaction is completed in esters 1e is weaker than that in carbamates 1c, the C–O bond
within 20 minutes (Fig. 1(b)). Thus, at 0 °C, the reaction of in esters is cleaved faster than the C–O bond in carbamates:
methyl salicylate (1c) can be differentiated from the reaction of this enables temperature control of the generation of acyl
diester 1d.
cations (at 0 °C) and isocyanate cations (at 20 °C) (Fig. 2). Thus,
Fig. 2 Comparison of amide formation rate and ketone formation rate.
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we can control the speed of unmasking to generate different region (−H0 = 10) to a strong acidic region (−H0 = 14) (Fig. 3b).
reactive electrophiles simply by changing the temperature.
Because the ortho-monoester-substituted carbamate (1b) is
diprotonated in the strong acidic region (−H0 = 14) (see TS-1b′,
Fig. 3a), disubstituted carbamate (1f) also can be diprotonated
in the strong acidic region (−H0 = 14). When the carbonyl
oxygen atom of the carbamate functional group of diester-sub-
stituted carbamate (1f) is protonated (TS-1f′, Fig. 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′ (Fig. 3).
Activation of leaving groups through protonation and
hydrogen bonding
We conducted kinetic studies to characterize the difference in
the leaving ability between the monoester leaving group (see
1b) and diester leaving group (see 1f). Fig. 3 shows the depen-
dence 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. O,O-Diproto-
nation of salicyl carbamates (like TS-1b′, Fig. 3a) can be
observed by proton NMR spectroscopy in a strong acid (−H0 =
14). Cleavage of the C–O bond of the diprotonated species will
Computational support for leaving group activation
be difficult because of the generation of one neutral species These kinetic results are supported by the results of calcu-
(methyl salicylate) and one rather unstable dicationic species lations (Fig. 4). The calculated energy differences are shown in
(O-protonated carbamate dication). Therefore, this means that terms of ΔΔG at 25 °C (298 K), together with ΔΔH.
the monocationic species (TS-1b, Fig. 3a) rather than the
In the continuum environment of TfOH, there are several
diprotonated species (TS-1b′, Fig. 3a) is involved in the bond possible stable conformers of diester-substituted carbamate 1f
dissociation transition state.13
in protonated states, because the diester carbamate functional-
On the other hand, in the case of the diester leaving group ities have several basic sites.13a,b The ester carbonyl oxygen
(1f), as the acidity increased, the reaction rate increases mono- atom(s), the most basic sites, is mono-protonated or are di-pro-
tonically to a broad maximum from a relatively weak acidic tonated, such cationic species, 1f-SM0-H+ and 1f-SM0-2H+, are
Fig. 3 Acidity-dependence of the reaction profiles of different leaving groups (measured at 31 °C for (a), and at −6 °C for (b)).
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Fig. 4 Calculated energy diagram of C–O bond cleavage steps of 1f (CPCM-M06-2X/6-311++G(d,p)//CPCM-B3LYP/6-31+G(d)).
the most stable (Fig. 4). On the other hand, a proton can higher than that of C–O bond cleavage of the ester from the
switch the protonation site to the less basic phenolic oxygen more stable monocationic species (SM-1e), ΔΔG298
:
K
atom, and such isomeric conformers, 1f-SM-H+ and 1f- 13.1 kcal mol−1; ΔΔH: 13.7 kcal mol−1. This may be partially
SM-2H+, are destabilized as compared to the most stable con- true because the carbamate is more stable than the ester due
formers (1f-SM0-H+, 1f-SM0-2H+). Destabilization is similar in to Y-type conjugation,12h,15 and thus more energy is needed to
magnitude in both cases of the monocation and the dication, break the stable C–O bond of the carbamate. In the case of
and the energy gaps are attainable probably because of the for- ester, it is worth noting that when the intramolecular hydro-
mation of intramolecular hydrogen bonding. Through the gen bond is formed with the phenolic oxygen atom, the con-
intervention of these equilibrating species, 1f-SM-H+ and 1f- former SM-1e is more stable than the isomeric SM0-1e (Fig. 5).
SM-2H+, the transition states of C–O bond dissociation can be Therefore, an ester compound bearing the methyl salicylester
obtained (Fig. 4): the activation energy from the most stable group can easily cleave its O–C bond. These calculations are
conformer 1f-SM0-2H+ through the dicationic state (1f-TS-2H+) consistent with the experimental results: the reaction of ester
(ΔΔG298 K: 18.6 kcal mol−1; ΔΔH: 19.1 kcal mol−1) is lower (1e) is dramatically faster than that of monoester-substituted
than that from 1f-SM0-H+ through the monocationic state (1f- carbamate 1b, and 1e is distinctly faster than the diester-sub-
TS-H+) (ΔΔG298 K: 22.2 kcal mol−1; ΔΔH: 22.2 kcal mol−1). stituted carbamate 1f. Other calculation levels (M06, MP2) also
Other calculation levels (M06, M06-HF, B3LYP, B3PW91, MP2) support this conclusion (ESI, Fig. SI3 and 4†) and the observed
also converged to similar results (ESI, Fig. SI1 and 2†). Thus, relationship (Fig. 2).
the observed acidity–rate relationship (Fig. 3) can be rationally
explained. Moreover, the difference in energy between the di-
Temperature control of multiple electrophile generation,
enabling two-step buildup of complexity of aromatic
molecules
cationic pathway and monocationic pathway amounts to 3 kcal
mol−1, which means that the reaction pathway of C–O bond
dissociation through the dicationic state should be dominant.
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 rele-
vant carbamate and ester (Fig. 5). From the calculation result,
the activation energy of C–O bond cleavage of the monoester-
substituted carbamate 1b from the most stable conformer
(SM0-1b) through the equilibrating minor monocationic species
(SM-1b), ΔΔG298 K: 23.0 kcal mol−1; ΔΔH: 24.5 kcal mol−1, is
Based on the above findings, we considered that temperature
control for unmasking electrophiles could be applied to build-
up aromatic molecular complexity in one-pot reactions
(Fig. 6–8 and Tables 1 and 2). First, we explored the formation
of two bonds.
Double aromatic amidations
Fig. 6 shows a representative example of the build-up of two
kinds of aromatic amide molecules. Mixing 4 and 5 in the
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Fig. 5 Calculated energy diagrams of C–O bond cleavage steps of 1b and 1e (CPCM-M06-2X/6-311++G(d,p)//CPCM-B3LYP/6-31+G(d)).
Fig. 6 Formation of two amide bonds through temperature-controlled multiple electrophile generation: (a) overall reaction (b) individual steps.
presence of TfOH produced compound 7 in 86% yield (red bond) (Fig. 6(b)). Under cooling (0 °C), the carbamate con-
(Fig. 6(a), in which the reaction temperature was changed from taining para-monosubstituted phenol did not uncage to form
0 °C to 20 °C). First, the corresponding isocyanate cation the isocyanate cation (4-cation). When the reaction mixture was
(4-cation) was generated from carbamate bearing ortho, para-dis- warmed to room temperature (20 °C), the second isocyanate
ubstituted phenol at 0 °C, and then the electron-rich aromatic cation (6-cation, red) was generated from the carbamate con-
ring (magenta) of 5 reacted with the resulting isocyanate cation taining para-monosubstituted phenol (6), and the second aro-
(blue) to form a C–C bond in the aromatic amide structure 6 matic compound (orange) reacted with the isocyanate cation
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Fig. 7 Ketone and amide bond formations through temperature control of multiple electrophile generation: (a) overall reaction (b) individual steps.
(6-cation) to form a C–C bond in the aromatic amide structure, philic aromatic substitution reactions. The average yield of
affording 7 in an intramolecular manner in this example (red each reaction ranged from 60% to 93% (Table 1).
bond) (Fig. 6(b)). The yield that is shown is over the two steps;
Sequential aromatic acylation-amidation
thus, the average yield of each reaction is larger than 93%.
The generality of this sequential dual amidation reaction
was examined and the results are shown in Table 1, which sup-
ports the feasibility of multiple intermolecular or intra-
molecular amidation reactions. Because the reaction
temperature (20 °C) is not so high, ethyl carbamate (8),12h the
ester groups (14 and 16),16 and a methoxy group (15)17 can be
tolerated; the former substituents can generate electrophile
species, and the latter substituent can be demethylated.
Examples of successive double intermolecular reactions were
also obtained (entries 4 and 5, Table 1). After the first SEAr
reaction was completed (the formation of 16 or 20), one aro-
matic molecule (17 or 21) was added and the reaction mixture
was warmed to 20 °C to produce a double amidation product
(18 and 22), respectively. Importantly, a three-component reac-
tion to create two amide bonds can be realized (entry 6,
Table 1): when TfOH was added into a mixture of three com-
ponents (14, 23, 26) at 0 °C and then at 20 °C, the product 25
was obtained, though in moderate yield (overall yield for the
two step reaction is 48%). One of the (equivalent) aromatic
rings of the substrate 23 can react with the first electrophile
(generated at 0 °C from 14), leading to the intermediate 24
smoothly, because we used stoichiometric amounts of the aro-
matic substrate (23) and the electrophile (14), to minimize side
reactions. Then, the intermediate 24 reacted with the second
electrophile, generated from 26 at 20 °C, to give compound 25.
This result demonstrates that the strategy of tuning the leaving
group ability of masked electrophiles, e.g., the phenolate
derivatives, should be valid for real multi-component electro-
Fig. 7 shows a representative example of one-pot build-up of
aromatic ketone and aromatic amide molecules. Mixing 27
and 5 in the presence of TfOH produced compound 29 in 79%
yield, by the change in the reaction temperature from 0 °C to
20 °C (Fig. 7(a)). First, the corresponding acyl cation
(27-cation) was generated from the carbamate bearing ortho-
substituted phenol at 0 °C, and then the electron-rich aromatic
ring (magenta) of 5 reacted with the resulting acyl cation (blue)
to form a C–C bond in the aromatic ketone structure 28 (red
bond; Fig. 7(b)). At 0 °C, the carbamate containing para-mono-
substituted 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 gener-
ated from the carbamate containing para-monosubstituted
phenol (28), and the second aromatic compound (orange) reacted
with the resulting isocyanate cation (28-cation) in an intra-
molecular manner to form an aromatic amide bond (red bond in
product 29) (Fig. 7(b)). Again the yield shown is the two-step
yield, and the average yield of each reaction was larger than 89%.
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 acyla-
tion–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), acyla-
tion–amidation reactions are accomplished without interference
from these functional groups. After the first SEAr reaction was com-
pleted (the formation of 36 or 39), the aromatic substrate (37 or 40)
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Fig. 8 Temperature control of multiple electrophile generation, enabling three-step buildup of complexity of aromatic molecules ((a) ketone–
amide–amide; (b) amide–amide–amide).
was added, and therefore three kinds of starting materials are com- one pot (Fig. 8). The first electrophiles (blue) are generated
bined sequentially into a single aromatic molecule (38 or 41) in one from ester (27) containing ortho-mono-substituted phenol
pot. The average yield of each reaction ranged from 77% to 89%.
(methyl salicylate) (Fig. 8(a)) or carbamate (4) (Fig. 8(b)) con-
taining 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 gener-
Formation of three bonds in a one-pot reaction
Finally, we demonstrate the formation of three inter- and intra-
molecular bonds constituting ketone/amide functionalities in
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Table 1 Two-step buildup of complexity of aromatic molecules by dual amidation
Reaction
temperature 1
Reaction temperature 2
and 3rd substrate
Entry Substrates
1
Intermediate
Final product
0 °C
20 °C
2
0 °C
20 °C
20 °C
3
4
0 °C
0 °C
5
6
0 °C
0 °C
20 °C
ated very slowly (in around half a day) from carbamates (42 or
This reaction design is, therefore, a potential avenue to
44) containing para-monosubstituted phenol at 20 °C. As realize ultimate multi-component electrophilic aromatic sub-
described above, these combined reactions enable temporally stitution reactions (as shown in Chart 1(b)).
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).
Conclusion
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 intra-
molecular and the third component (5) was added after the
first SEAr 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.
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 (unmask-
ing) simply by appropriate selection of the reaction tempera-
ture, so that the 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 elec-
trophilic 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,
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Table 2 Two-step buildup of complexity of aromatic molecules by acylation and amidation
Reaction
temperature 1
Reaction temperature 2
and 3rd substrate
Entry Substrates
1
Intermediate
Final product
0 °C
20 °C
2
0 °C
20 °C
20 °C
3
4
0 °C
0 °C
5
0 °C
we demonstrated autonomous formation of up to three bonds (HRMS). All reagents were commercially available and used
in one pot, and we realized one example of the three-com- without further purification, unless otherwise noted. Flash
ponent reaction to make two amide bonds. In order to use this column chromatography was carried out on silica gel (silica
system for practical reactions applicable to the synthesis of gel (40–63 µm)). The combustion analyses were carried out in
libraries of compounds, it will be necessary to reduce the the microanalytical laboratory of this department.
amount of acid and to design sophisticated leaving group
systems. Nevertheless, in this work, we have demonstrated the
conceptual validity of a one-pot build-up of a complex aromatic
Preparation of substrates
molecule from multiple starting components, ultimately
leading to multi-component electrophilic aromatic substi-
tution reactions (Chart 1(b)).
Preparation of dimethyl 4-((diphenylcarbamoyl)oxy)iso-
phthalate (4). To a solution of dimethyl 4-hydroxyisophthalate
(698.2 mg, 3.32 mmol) in iPr2NEt (0.65 mL), diphenylcarbamic
chloride (717.8 mg, 3.10 mmol) was added at rt. The whole
mixture was stirred for 13 hours at rt. After the reaction com-
pleted, 2 M aqueous solution of HCl (40 mL) was added and
then extracted with CH2Cl2 (40 mL × 3). The organic phase was
washed with brine (40 mL), dried over Na2SO4, and the solvent
Experimental procedure
General procedures
The melting points were determined with a Yanaco micro was evaporated under reduced pressure to give a residue,
melting point apparatus without correction. 1H- (400 MHz) which was flash column-chromatographed on silica-gel
and 13C- (100 MHz) NMR spectra were recorded on a Bruker (eluent: EtOAc/n-hexane = 1/2) to afford dimethyl 4-((diphenyl-
Avance 400. Chemical shifts were calibrated with tetramethyl- carbamoyl)oxy)isophthalate (4) (1223.8 mg, 3.02 mmol, 97%)
silane as an internal standard or with the solvent peak, and as a colorless solid. Mp. 158.9–159.7 °C (colorless needles,
are shown in ppm (δ) values, and coupling constants are recrystallized from CH2Cl2/n-hexane). 1H-NMR (CDCl3,
shown in hertz (Hz). The following abbreviations are used: s = 400 MHz) δ (ppm): 8.649 (1H, d, J = 2.0 Hz), 8.173 (1H, dd, J =
singlet, d = doublet, t = triplet, q = quartet, dd = double 8.4, 2.0 Hz), 7.448–7.352 (8H, m), 7.265–7.197 (3H, m), 3.933
doublet, dt = double triplet, dq = double quartet, h = hextet, (3H, s), 3.920 (3H, s). 13C-NMR (CDCl3, 100 MHz) δ (ppm):
m = multiplet, and brs = broad singlet. Electron spray ioniza- 166.10, 164.86, 154.82, 152.75, 142.75, 135.13, 133.67, 129.60,
tion time-of-flight mass spectra (ESI-TOF MS) were recorded 128.27, 127.23 (br), 124.67, 124.56, 52.98, 52.92. HRMS
on a Bruker micrOTOF-05 to give high-resolution mass spectra (ESI-TOF, [M + Na]+): Calcd for C23H19NNaO6 : 428.1105.
+
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Found: 428.1105. Anal. Calcd for C23H19NO6: C, 68.14; H, 4.72; Mp. 122.3–123.2 °C (colorless needles, recrystallized from
N, 3.46. Found: C, 67.79; H, 4.90; N, 3.32.
CH2Cl2/n-hexane). 1H-NMR (CDCl3, 400 MHz) δ (ppm) (pres-
Preparation of methyl 4-(((2-(2,5-dimethylphenyl)-2-phenyl- ence of two amide conformers): 8.646–8.607 (1H, m), 8.186
ethyl)-carbamoyl)oxy)benzoate (5). To solution of para- (1H, dd, J = 8.6, 2.0 Hz), 7.236 (1H, d, J = 8.4 Hz), 5.413 (0.89H,
a
xylene (5 mL) in TfOH (10 mL), 2-amino-1-phenylethanol t, J = 13.2 Hz), 5.085 (0.11H, brs), 4.121 (2H, q, J = 6.8 Hz),
(1011.2 mg, 7.37 mmol) was added at 0 °C. The whole mixture 3.930 (3H, s), 3.883 (3H, s), 3.238 (0.24H, t, J = 6.4 Hz), 3.129
was warmed up from 0 °C to 20 °C, and stirred for 2 hours. (1.84H, t, J = 6.4 Hz), 2.238 (1H, tt, J = 12.1, 3.6 Hz),
After the reaction completed, the whole mixture was poured 2.051–2.017 (2H, m), 1.929–1.850 (2H, m), 1.605–1.390 (3H,
into ice-water and 2 M aqueous solution of NaOH (50 mL) was m), 1.250 (3H, t, J = 7.2 Hz), 1.015 (2H, qd, J = 13.2, 3.2 Hz).
added. This reaction mixture was extracted with CH2Cl2 13C-NMR (CDCl3, 100 MHz) δ (ppm): 176.33, 166.10, 165.05,
(30 mL × 4). The organic phase was washed with brine 154.57, 154.35, 134.99, 133.49, 127.97, 124.78, 124.65, 60.69,
(30 mL), dried over Na2SO4, and the solvent was evaporated 52.87, 52.81, 47.81, 43.72, 38.00, 30.06, 28.88, 14.70. HRMS
+
under reduced pressure to give a yellow crude (1784.3 mg). (ESI-TOF, [M + Na]+): Calcd for C21H27NNaO8 : 444.16129.
Then this crude was added to the solution of dimethyl 4,4′- Found: 444.1619. Anal. Calcd for C21H27NO8: C, 59.85; H, 6.46;
(carbonylbis(oxy))dibenzoate (2109.0 mg, 6.39 mmol) in THF N, 3.32. Found: C, 59.73; H, 6.35; N, 3.29.
(20 mL) at rt. The whole mixture was stirred for 4 hours at rt.
Preparation of methyl 2-((diphenylcarbamoyl)oxy)benzoate
After the reaction completed, 2 M aqueous solution of NaOH (26). To a solution of triphosgene (300.3 mg, 1.01 mmol) in
(40 mL) was added and then extracted with CH2Cl2 (30 mL × CH2Cl2 (3.0 mL) were added a solution of diphenylamine
4). The organic phase was washed with brine (30 mL), dried (364.4 mg, 2.15 mmol) in CH2Cl2 (4.0 mL) and dry pyridine
over Na2SO4, and the solvent was evaporated under reduced (1.0 mL) at 0 °C. The resulting mixture was stirred at 0 °C for
pressure to give a residue, which was column-chromato- 15 min and at rt for an additional 17.5 h. The reaction was
graphed on silica-gel (eluent: EtOAc/n-hexane = 2/3) to afford quenched with 2 M aqueous solution of HCl (20 mL). The reac-
methyl 4-(((2-(2,5-dimethylphenyl)-2-phenylethyl)carbamoyl)- tion mixture was extracted with CH2Cl2 (20 mL × 5). The
oxy)benzoate (5) (222.0 mg, 4.99 mmol, 68% in two steps) as a organic phase was washed with brine (20 mL), dried over
colorless amorphous material.
Na2SO4, and the solvent was evaporated to give the crude iso-
1H-NMR (CDCl3, 400 MHz) δ (ppm): 8.011 (2H, d, J = cyanate (498.9 mg). To a solution of methyl 2-hydroxybenzoate
8.4 Hz), 7.297 (2H, t, J = 7.6 Hz), 7.230–7.194 (3H, m), 7.135 (518.3 mg, 3.41 mmol), pyridine (3.0 mL) and iPr2NEt (0.5 mL,
(2H, td, J = 8.8, 2.0 Hz), 7.080–7.047 (2H, m), 6.990–6.971 (1H, 2.87 mmol),
a solution of the above crude isocyanate
m), 5.190–4.866 (1H, m), 4.419 (1H, t, J = 8.0 Hz), 3.878 (5H, (498.9 mg) in CH2Cl2 (4.0 mL) was added at rt. The whole
m), 2.333 (3H, s), 2.229 (3H, s). 13C-NMR (CDCl3, 100 MHz) mixture was stirred for 3 h at rt. The crude reaction mixture
δ (ppm): 166.92, 155.23, 154.20, 141.77, 139.50, 136.17, 134.34, was purified by column-chromatography on silica gel (eluent:
131.55, 131.45, 129.23, 128.79, 128.08, 127.54, 127.31, 121.77, EtOAc/n-hexane = 1/2) to afford methyl 2-((diphenylcarbamoyl)
52.60, 47.24, 46.00, 21.78, 19.80. HRMS (ESI-TOF, [M + Na]+): oxy)benzoate (26) (636.2 mg, 1.83 mmol, 85%) as a colorless
+
Calcd for C25H25NNaO4 : 426.1676. Found: 426.1652. Anal. solid. Mp. 82.6–84.9 °C (colorless needles, recrystallized from
Calcd for C25H25NO4 + 0.2H2O: C, 73.76; H, 6.29; N, 3.44. CH2Cl2/n-hexane). 1H-NMR (CDCl3, 400 MHz) δ (ppm): 7.976
Found: C, 73.46; H, 6.02; N, 3.25.
(1H, d, J = 7.6 Hz), 7.519–7.340 (9H, m), 7.277–7.118 (4H, m),
Preparation of dimethyl 4-((((4-(ethoxycarbonyl)cyclohexyl)- 3.907 (3H, s). 13C-NMR (CDCl3, 100 MHz) δ (ppm): 165.51,
methyl)-carbamoyl)oxy)isophthalate (14). To
a solution of 153.24, 151.24, 142.89, 134.05, 131.97, 129.43, 127.51, 126.92,
SOCl2 (0.5 mL, 6.9 mmol) in EtOH (20 mL) was added 4-(ami- 126.16, 124.22, 124.19, 52.64. HRMS (ESI-TOF, [M + Na]+):
+
nomethyl)cyclohexane-1-carboxylic acid (847.2 mg, 5.39 mmol) Calcd for C21H17NNaO4 : 370.10498. Found: 370.10432. Anal.
at 0 °C, and the whole mixture was stirred for 30 minutes at rt, Calcd for C21H17NO4: C, 72.61; H, 4.93; N, 4.03. Found: C,
then for 1 hour at reflux. After the reaction completed, the 72.77; H, 4.82; N, 4.12.
mixture was poured into ice-water and quenched with 2 M
Preparation of methyl 2-((4-(trifluoromethyl)benzoyl)oxy)-
aqueous solution of NaOH (50 mL). Then, EtOAc (100 mL) was benzoate (27). To a solution of methyl salicylate (15 657.5 mg,
added and the mixture was washed with 2 M aqueous solution 10.3 mmol) in CH2Cl2 (20 mL) and iPr2NEt (9.0 mL), 4-(tri-
of NaOH (50 mL × 2). The organic phase was washed with fluoromethyl)benzoyl chloride (1823.9 mg, 8.74 mmol) in
brine (30 mL), dried over Na2SO4, and the solvent was evapor- CH2Cl2 (10 mL) was added at 0 °C. The whole mixture was
ated under reduced pressure to give a crude (947.6 mg). To a stirred for 40 minutes at 0 °C. The reaction mixture was puri-
solution of tetramethyl 4,4′-(carbonylbis(oxy))diisophthalate fied by column-chromatography on silica gel (eluent: EtOAc/
(1362.0 mg, 3.05 mmol) in THF (8.0 mL), the crude (947.6 mg) n-hexane
= 1/4) to afford methyl 2-((4-(trifluoromethyl)-
in THF (2.0 mL) was added at 0 °C. The whole mixture was benzoyl)oxy)benzoate (27) (1142.8 mg, 3.52 mmol, 40%) as a
stirred for 10 minutes at 0 °C. The reaction mixture was puri- colorless solid. Mp. 68.7–69.2 °C (colorless plates, recrystal-
fied by column-chromatography on silica gel (eluent: EtOAc/ lized from CH2Cl2/n-hexane). 1H-NMR (CDCl3, 400 MHz)
n-hexane = 2/3) to afford dimethyl 4-((((4-(ethoxycarbonyl)cyclo- δ (ppm): 8.339 (2H, d, J = 8.0 Hz), 8.091 (1H, dd, J = 7.8,
hexyl)methyl)carbamoyl)oxy)isophthalate (14) (947.6 mg, 1.6 Hz), 7.788 (2H, d, J = 8.0 Hz), 7.627 (1H, td, J = 7.6, 2.0 Hz),
2.25 mmol, 42% in two steps) as
a
colorless solid. 7.383 (1H, td, J = 7.8, 1.2 Hz), 7.252–7.230 (1H, m), 3.750
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(3H, s). 13C-NMR (CDCl3, 100 MHz) δ (ppm): 165.33, 164.83, 127.49, 127.03, 46.13, 40.50, 19.81, 19.58. HRMS (ESI-TOF,
151.14, 135.55 (q, J = 32 Hz), 134.60, 133.39, 132.60, 131.25, [M + Na]+): Calcd for C30H26N2NaO2 : 469.1886. Found:
+
126.98, 126.22 (q, J = 3 Hz), 124.39, 124.18 (q, J = 271 Hz), 469.1876. Anal. Calcd for C30H26N2O2 + 0.2H2O: C, 80.05; H,
123.73, 52.81. HRMS (ESI-TOF, [M
C16H11F3NaO4 : 347.0507. Found: 347.0496. Anal. Calcd for
C16H11F3O4: C, 59.27; H, 3.42. Found: C, 59.08; H, 3.58.
+
Na]+): Calcd for 5.91; N, 6.22. Found: C, 80.13; H, 6.17; N, 6.07.
+
Three-component dual amidation reactions (25) (Table 1,
entry 6). To a solution of 1,2-bis(3,4-dimethylphenyl)ethane
Preparation of methyl 2-(((4-methoxyphenethyl)carbamoyl)- 14 (120.3 mg, 0.51 mmol), dimethyl 4-((((4-(ethoxycarbonyl)-
oxy)benzoate (15). To a solution of dimethyl 2,2′-carbonyldi- cyclohexyl)methyl)carbamoyl)oxy)isophthalate 23 (210.8 mg,
benzoate (1660.9 mg, 5.03 mmol) in THF (10.0 mL), a solution 0.50 mmol) and methyl 2-((diphenylcarbamoyl)oxy)benzoate
of 2-(4-methoxyphenyl)ethan-1-amine (776.1 mg, 5.13 mmol) 26 (175.9 mg, 0.51 mmol) in CH2Cl2 (1.0 mL), TfOH (2.0 mL)
in THF (5.0 mL) was added at rt. The whole mixture was was added at 0 °C. The whole mixture was stirred for
stirred for 1 hour at rt. The reaction mixture was directly puri- 15 minutes. Then, the whole mixture was warmed up from
fied by column-chromatography on silica gel (eluent: EtOAc/ 0 °C to 20 °C, and stirred for 1 hour. After the reaction com-
n-hexane = 1/1) to afford methyl 2-(((4-methoxyphenethyl)-car- pleted, the whole mixture was poured into ice-water and 2 M
bamoyl)oxy)benzoate (15) (1630.2 mg, 4.95 mmol, 90%) as a aqueous solution of NaOH (30 mL) was added. This reaction
colorless solid.
mixture was extracted with CH2Cl2 (40 mL × 3). The organic
Mp. 61.2–61.5 °C (colorless cube, recrystallized from phase was washed with brine (40 mL), dried over Na2SO4, and
CH2Cl2/n-hexane). 1H-NMR (CDCl3, 400 MHz) δ (ppm) (pres- the solvent was evaporated under reduced pressure to give a
ence of two amide conformers): 7.954 (1H, dd, J = 8.0, 1.2 Hz), residue, which was column-chromatographed on silica-gel
7.519 (1H, td, J = 7.8, 1.6 Hz), 7.268 (1H, t, J = 7.2 Hz), (eluent: EtOAc/n-hexane = 1/2) to afford ethyl 4-((2-(2-(diphenyl-
7.192–7.128 (3H, m), 5.196 (0.93H, brs), 4.828 (0.14H, brs), carbamoyl)-4,5-dimethylphenethyl)-4,5-dimethylbenzamido)-
3.845 (3H, s), 3.792 (3H, s), 3.495 (2H, q, 6.8 Hz), 2.839 (3H, t, methyl)cyclohexane-1-carboxylate 25 (155.3 mg, 0.24 mmol,
J = 7.2 Hz). 13C-NMR (CDCl3, 100 MHz) δ (ppm): 165.89, 48%) as a colorless oil. 1H-NMR (CDCl3, 400 MHz) δ (ppm)
158.94, 154.94, 151.21, 134.06, 132.01, 131.22, 130.35, 126.11, (presence of two amide conformers): 7.181–6.792 (14H, m),
124.67, 124.55, 114.70, 55.84, 52.64, 43.32, 35.68. HRMS 6.101–6.032 (1H, m), 4.028 (2H, q, J = 7.2 Hz), 3.103 (2H, t, J =
(ESI-TOF, [M + Na]+): Calcd for C19H18NNaO5 : 352.1152. 6.4 Hz), 2.994–2.865 (5H, m), 2.157–2.122 (6H, m), 2.053 (3H,
+
Found: 352.1165. Anal. Calcd for C19H18NO5: C, 65.64; H, 5.82; s), 1.954 (3H, m), 1.873–1.692 (5H, m), 1.411–1.337 (1H, m),
N, 4.25. Found: C, 65.32; H, 5.79; N, 4.11.
1.267 (2H, qd, J = 13.2, 3.2 Hz), 1.162 (3H, t, J = 7.2 Hz), 0.856
(2H, qd, J = 12.8, 3.6 Hz). 13C-NMR (CDCl3, 100 MHz) δ (ppm):
175.96, 175.88, 171.14, 171.10, 170.84, 170.34, 143.44, 143.34,
138.38, 138.03, 137.86, 137.80, 137.47, 137.25, 136.92, 135.70,
Multiple successive electrophile substitution reactions in one
pot
Dual amidation in one pot (7) (Table 1, entry 1). To TfOH 134.68, 134.33, 134.25, 133.55, 133.52, 133.33, 133.25, 132.55,
(2.0 mL), methyl 4-(((2-(2,5-dimethylphenyl)-2-phenylethyl)-car- 131.52, 131.06, 130.88, 130.13, 129.35, 129.05, 128.92, 128.53,
bamoyl)oxy)benzoate 5 (222.5 mg, 0.50 mmol) in CH2Cl2 127.42, 126.90, 126.75, 126.31, 126.28, 60.39, 60.13, 53.45,
(0.5 mL) was added at 0 °C. Then, dimethyl 4-((diphenylcarba- 45.66, 45.45, 43.32, 43.28, 37.36, 37.18, 35.24, 34.99, 34.93,
moyl)oxy)isophthalate 4 (202.9 mg, 0.50 mmol) in CH2Cl2 34.78, 29.97, 29.86, 28.49, 28.44, 21.04, 19.90, 19.64, 19.57,
(1.0 mL) was added at 0 °C. The whole mixture was warmed up 19.19, 19.03, 16.51, 14.25. HRMS (ESI-TOF, [M + Na]+): Calcd
+
from 0 °C to 20 °C, and stirred for 12 hours. After the reaction for C40H37N3NaO3 : 630.2727. Found: 630.2731. Anal. Calcd
was completed, the whole mixture was poured into ice-water. for C40H37N3O3 + 0.6 CH2Cl2: C, 74.03; H, 5.85; N, 6.38. Found:
2 M aqueous solution of NaOH (50 mL) was added, and this C, 74.06; H, 6.07; N, 6.18.
reaction mixture was extracted with CH2Cl2 (40 mL × 3). The
Sequential aromatic acylation–amidation reaction 29
organic phase was washed with brine (40 mL), dried over (Table 2, entry 1). To a mixture of TfOH (2.0 mL), methyl
Na2SO4, and the solvent was evaporated under reduced 4-(((2-(2,5-dimethylphenyl)-2-phenylethyl)carbamoyl)oxy)ben-
pressure to give a residue, which was column-chromato- zoate 5 (441.8 mg, 1.1 mmol) in CH2Cl2 (2.0 mL) was slowly
graphed on silica-gel (eluent: acetone/n-hexane = 4/3) to afford added at 0 °C. Then, methyl 2-((4-(trifluoromethyl)benzoyl)oxy)-
2,5-dimethyl-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)-N,N- benzoate 27 (359.4 mg, 1.11 mmol) was added at 0 °C. The
diphenyl-benzamide (7) (191.7 mg, 0.43 mmol, 86%) as a whole mixture was warmed up from 0 °C to 20 °C, and stirred
colorless solid. Mp. 240.7–241.3 °C (colorless plates, recrystal- for 15 hours. After the reaction was completed, the whole
lized from CH2Cl2/n-hexane). 1H-NMR (CDCl3, 400 MHz) mixture was poured into ice-water. This reaction mixture was
δ (ppm): 8.133 (1H, dd, J = 9.2, 3.6 Hz), 7.394–6.969 (16H, m), extracted with CH2Cl2 (30 mL × 4). The organic phase was
6.831–6.796 (2H, m), 6.760 (1H, s), 5.617 (1H, t, J = 6.0 Hz), washed with brine (40 mL), dried over Na2SO4, and the solvent
4.550 (1H, t, J = 7.2 Hz), 3.634 (2H, dd, J = 7.8, 2.8 Hz), 3.485 was evaporated under reduced pressure to give a residue,
(2H, q, J = 6.4 Hz), 2.749 (2H, t, J = 6.8 Hz), 2.413 (3H, s), 2.342 which was column-chromatographed on silica-gel (eluent:
(3H, s), 2.220 (3H, s). 13C-NMR (CDCl3, 100 MHz) δ (ppm): EtOAc/n-hexane = 1/1) to afford 4-(2,5-dimethyl-4-(4-(trifluoro-
171.33, 166.81, 143.51, 141.94, 139.49, 136.06, 133.96, 133.79, methyl)benzoyl)-phenyl)-3,4-dihydroisoquinolin-1(2H)-one
132.91, 130.88, 130.66, 129.63, 129.45, 128.58, 127.89, 127.74, (29) (367.5 mg, 0.87 mmol, 79%) as a colorless solid.
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Mp. 237.2–237.9 °C (colorless needles, recrystallized from tations21 of the transition structures verified the reactants,
EtOAc). 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.002–7.888 intermediates, and products on the potential energy surface
(6H, m), 7.458 (2H, td, J = 24.5, 7.2 Hz), 7.276 (1H, s), 6.973 (PES). Bulk solvation effects (self-consistent reaction field,
(1H, d, J = 7.2 Hz), 6.779 (1H, s), 4.619 (1H, t, J = 6.0 Hz), SCRF) were simulated by the CPCM method22 in trifluoro-
3.699–3.524 (2H, m), 2.394 (3H, s), 2.102 (3H, s). 13C-NMR methanesulfonic acid as a solvent (eps = 77.4,23 rsolv =
(DMSO-d6, 100 MHz) δ (ppm): 196.52, 164.35, 142.46, 141.00, 2.5985274,23 density = 1.696,24 epsinf = 1.882384 (the value of
140.68, 135.64, 134.06, 133.65, 132.53 (q, J = 32 Hz), 132.20, acetic acid was employed)). Single point energies were calcu-
131.02, 130.81, 130.32, 129.86, 127.46, 127.27, 127.23, 125.79 lated with CPCM-M06-2X/6-311++G(d,p) (and some other cal-
(q, J = 4 Hz), 123.76 (q, J = 271 Hz), 44.44, 39.16, 19.43, 18.68. culation levels) on the basis of the optimized structures.25 The
+
HRMS (ESI-TOF, [M + Na]+): Calcd for C25H20F3NNaO2 : zero-point vibrational energy corrections were done without
446.1338. Found: 446.1334. Anal. Calcd for C25H20F3NO2 + 0.8 scaling.
H2O: C, 68.58; H, 4.97; N, 3.20. Found: C, 68.74; H, 5.04; N,
3.09.
Formation of three bonds in a one-pot reaction 43 (Fig. 8,
reaction (a)). To TfOH (2.0 mL), methyl 2-(((4-methoxyphe-
Acknowledgements
nethyl)carbamoyl)oxy)benzoate 15 (166.1 mg, 0.50 mmol) was This work was supported by the University of Tokyo. The com-
added at 0 °C. Then, methyl 2-((4-(trifluoromethyl)benzoyl)oxy)- putations were performed at the Research Center for Compu-
benzoate 27 (164.0 mg, 0.51 mmol) was added at 0 °C. The tational Science, Okazaki, Japan. We thank the computational
whole mixture was stirred for 15 minutes. Then, methyl 4-(((2- facility for generous allotments of computer time.
(2,5-dimethylphenyl)-2-phenylethyl)carbamoyl)oxy)benzoate
5
(230.3 mg, 0.52 mmol) in CH2Cl2 (2.0 mL) was added at 0 °C.
The whole mixture was warmed up from 0 °C to 20 °C, and
stirred for 15 hours. After the reaction was completed, the
whole mixture was poured into ice-water and 2 M aqueous
solution of NaOH (30 mL) was added. This reaction mixture
was extracted with CH2Cl2 (40 mL × 3). The organic phase was
washed with brine (40 mL), dried over Na2SO4, and the solvent
was evaporated under reduced pressure to give a residue,
which was column-chromatographed on silica-gel (eluent:
EtOAc) to afford N-(4-methoxy-3-(4-(trifluoromethyl)benzoyl)
phenethyl)-2,5-dimethyl-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-
4-yl)benzamide 43 (172.7 mg, 0.29 mmol, 56%) as an amor-
Notes and references
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phous material. 1H-NMR (CDCl3, 400 MHz)
δ (ppm):
8.143–8.120 (1H, m), 7.869 (2H, d, J = 8.0 Hz), 7.673 (2H, d, J =
8.4 Hz), 7.424–7.373 (3H, m), 7.301 (1H, d, J = 2.4 Hz), 7.183
(1H, s), 6.961 (1H, d, J = 8.4 Hz), 6.818–6.796 (1H, m), 6.747
(1H, s), 6.608 (1H, brs), 5.956 (1H, t, J = 6.0 Hz), 4.546 (1H, t,
J = 7.6 Hz), 3.725–3.630 (7H, m), 2.934 (2H, t, J = 7.6 Hz), 2.327
(3H, s), 2.232 (3H, s). 13C-NMR (CDCl3, 100 MHz) δ (ppm):
195.93, 170.41, 166.80, 156.86, 141.69, 141.30, 140.66, 135.88,
134.54 (q, J = 28 Hz), 134.37, 134.31, 133.62, 133.15, 131.79,
131.52, 131.02, 130.70, 130.35, 129.73, 128.72, 128.56, 127.97,
127.84, 125.79 (q, J = 3 Hz), 124.24 (q, J = 271 Hz), 112.43,
56.20, 46.31, 41.38, 40.56, 35.25, 19.94, 19.67. HRMS (ESI-TOF,
+
[M + Na]+): Calcd for C35H31F3N2NaO4 : 623.2128. Found:
623.2128. Anal. Calcd for C35H31F3N2O4 + 0.5 CH2Cl2: C, 66.30;
H, 5.02; N, 4.36. Found: C, 66.05; H, 5.33; N, 4.35.
Computational methods
We carried out computational studies by using the Gaussian
09 suites of programs.19 The geometries of the reactants (SM),
transition states (TS), and products (PM) for dissociation steps
were fully optimized using the CPCM (Complete Polarizable
Continuum Model)-B3LYP/6-31+G(d) level.20 Harmonic
vibrational frequency computations characterized the opti-
mized structures. Intrinsic reaction coordinate (IRC) compu-
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