Synthesis of 1,8-Dioxo-decahydroacridine Derivatives via Ru-Catalyzed Acceptorless Dehydrogenative Multicomponent Reaction

Article abstract of DOI:10.1021/acs.joc.1c01075

A Ru-catalyzed acceptorless dehydrogenative multicomponent reaction has been developed. This reaction offers a cost-effective and simple operational strategy to synthesize biologically active 1,8-dioxodecahydroacridine derivatives. The protocol provides a wide range of substrate scope and various functional groups are also well tolerated under the reaction condition. To shed light on the mechanistic and kinetic study, some controlled experiments and deuterium labeling experiments were executed. A time-dependent product distribution experiment is also presented and the reaction scale-up is performed to highlight the practical utility of this strategy.

Full text of DOI:10.1021/acs.joc.1c01075

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Synthesis of 1,8-Dioxo-decahydroacridine Derivatives via Ru-
Catalyzed Acceptorless Dehydrogenative Multicomponent Reaction
Nandita Biswas and Dipankar Srimani*
Cite This: J. Org. Chem. 2021, 86, 9733−9743
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ABSTRACT: A Ru-catalyzed acceptorless dehydrogenative multi-
component reaction has been developed. This reaction offers a
cost-effective and simple operational strategy to synthesize
biologically active 1,8-dioxodecahydroacridine derivatives. The
protocol provides a wide range of substrate scope and various
functional groups are also well tolerated under the reaction
condition. To shed light on the mechanistic and kinetic study,
some controlled experiments and deuterium labeling experiments
were executed. A time-dependent product distribution experiment
is also presented and the reaction scale-up is performed to highlight
the practical utility of this strategy.
natural sources especially from biomass.6 Hence, last decades
witnessed an extensive utilization of alcohols in organic
synthesis via “acceptorless dehydrogenation (AD)”7 or
“borrowing hydrogen (BH)” catalysis.8 Thus, the synthesis
of useful heteroaromatic compounds via acceptorless dehy-
drogenative multicomponent reactions (ADMCRs)4b,9 is
considered as a highly environmentally benign, atom
economical, and cost-effective approach. In this context,
Beller and co-workers demonstrated a unique ADMCR
approach to synthesize pyrroles via one-pot three-component
(ketones, amines, and 1,2-diols) coupling.9a,b Kempe9c and
Kirchner9d independently demonstrated the synthesis of
pyrimidines via the ADMCR strategy. The group of Milstein9e
illustrated the synthesis of N-substituted pyrroles via one-pot
synthesis of pyrroles followed by N-alkylation. Recently, we9f
and other groups9g,h have described the one-pot synthesis of
2-aminoquinoline and its successive N-alkylation with alco-
hols. 1,8-Dioxodecahydroacridines are known for their wide
spectrum of biological activities such as antitumor,10a
anticancer,10b cytotoxic,10c antifungal,10d antimicrobial,10e
antimalarial,10f and GCN5 inhibitor.10g Thus, we envisioned
that the synthesis of 1,8-dioxodecahydroacridines directly
from alcohols via the ADMCR approach (Scheme 1) would
be advantageous over the conventional approach.11
INTRODUCTION
■
Synthesis of structurally important complex organic molecules
via a green and sustainable approach is a paramount goal in
organic chemistry. In this context, multicomponent reactions
(MCRs)1 have received significant attention because of their
substantial advantages over the conventional multistep
approach. MCRs are considered as green in terms of
productivity, energy saving, and step-economy.2 Therefore,
several de novo multicomponent reaction3 strategies for the
synthesis of heterocycles via successive formation of C−C and
C−heteroatom bonds have been reported.4 The most
challenging task in the MCRs is the fine-tuning of the
reaction parameters to synthesize the targeted molecule by
suppressing the side product formation. The replacement of
toxic as well as waste generating reagents with greener and
renewable feedstock is another major aspect of green
chemistry.5 In this regard, alcohols are considered as a
greener alternative feedstock as they are obtained from various
Scheme 1. Schematic Representation of the ADMCR
Received: May 8, 2021
Published: June 25, 2021
https://doi.org/10.1021/acs.joc.1c01075
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© 2021 American Chemical Society
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Next, we looked for the scope and limitations of our
developed protocol. To demonstrate the practical applicability,
various alcohols, amines, and 1,3-diketones were investigated.
The reaction of dimedone and aniline with alcohols
containing electron-donating or electron-withdrawing func-
tional groups at various positions efficiently produced the
corresponding acridine-1,8-diones derivatives (7a−h)
(Scheme 2) in good to excellent yield (70−77%). Piperonyl
alcohol was responded well under this reaction condition and
gave a good yield, 68%, of the desired product (7h). Next,
anilines with different electron-donating or electron-with-
drawing functional groups were reacted with various alcohols.
Reaction with p-anisidine, p-toluidine, and 4-bromoaniline
afforded a good yield of 7i−l. To our delight, using a
heteroaromatic alcohol such as 2-thiophene methanol as the
substrate, compound 7m was isolated in 61% yield.
Compound 7n has antimicrobial properties,13 which can be
easily prepared by this methodology with a good yield (66%).
2-Pyridine methanol and 2-aminopyridine also under the
optimized reaction condition gave the desired product 7o and
7p in good to moderate yields. The sensitive functional group
like cyano (−CN) was also well survived under the reaction
condition and afforded a good yield of the desired product
7r−s. When methyl 4-aminobenzoate was reacted with
dimedone and alcohol, the expected product 7t was not
observed, instead 7u was formed via transesterification.14 Not
only the aniline derivative but also benzylamine reacted
smoothly to give the corresponding product 7v in good yield,
70%. 7v can be easily converted to the corresponding NH-
heterocycle via debenzylation. Of note, good selectivity existed
between amine and amide functionality, and when the
reaction was carried out with 4-aminobenzamide exclusively,
the product 7w was isolated. Unfortunately, ethanol and
secondary alcohol were not proficient of producing the
desired product (7x−z) in this protocol. Other 1,3-diketones
RESULT AND DISCUSSION
■
Thus, to find out the scope of the ADMCR approach toward
the four-component synthesis of 1,8-dioxo-decahydroacridine,
various reaction parameters were screened taking Ru-pincer
complexes12 as catalysts (Figure 1). In our initial experiment,
Figure 1. Ruthenium pincer complexes.
dimedone, benzyl alcohol, and 4-methoxyaniline were taken as
model substrates. When dimedone (1 mmol, 2 equiv), benzyl
alcohol (1.5 mmol, 3 equiv), and 4-methoxyaniline (0.5 mmol,
1 equiv) were heated at 135 °C in tamylalcohol for 36 h under
argon in the presence of 1 mol % catalyst 1 and 25 mol %
tBuOK, 15% 10-(4-methoxyphenyl)-3,3,6,6-tetramethyl-9-phe-
nyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (7a)
was obtained (Table 1, entry 1). In toluene, the yield was
not improved further (Table 1, entry 2). Interestingly, under
neat conditions, the yield of 7a was increased to 50% (Table
1, entry 3). Further enhancement of the yield of 7a was
observed when the alcohol concentration was increased to 3
mmol (6 equiv with respect to aniline), which gave 7a in 75%
yield after 36 h (Table 1, entry 5). Increase of reaction time to
48 h or the alcohol concentration did not enhance the
t
product yield (Table 1, entries 6 and 7). Bases like BuONa,
KOH, and K2CO3 gave a moderate yield compared to BuOK
(Table 1, entries 8−10). The reaction at 110 °C keeping
other reaction conditions same, furnishes a lower yield (68%)
(Table 1, entry 11). Cat 2 and cat 3 gave inferior results
under the similar condition.
t
a
Table 1. Optimization of the Reaction Conditions for the Synthesis of Hexahydroacridine-1,8-Dione
b
entry
4a (mmol)
5a(mmol)
6a (mmol)
time (h)
solvent (mL)
base
7a
1
2
3
4
5
6
7
8
9
10
1.5
1.5
1.5
3
1
1
1
1
1
1
1
1
1
1
1
1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
36
36
36
24
36
48
36
36
36
36
36
36
36
36
tamyl alcohol
toluene
neat
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuONa
KOH
K2CO3
tBuOK
tBuOK
tBuOK
tBuOK
15
13
50
60
75
76
74
35
33
20
68
50
30
35
neat
3
neat
3
neat
5
neat
3
neat
3
3
3
neat
neat
neat
c
11
d
12
3
neat
e
13
3
neat
1
f
14
3
1
neat
a
b
c
Reaction Condition: 4a (1.5−3.0 mmol), 5a (1 mmol), 6a (0.5 mmol), tBuOK (25 mol %), Cat 1 (1 mol %), 135 °C. Isolated yield. 110 °C.
d
e
f
Cat 1 (0.5 mol %). Cat 2. Cat 3.
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like cyclohexane-1,3-dione and cyclopentane-1,3-dione also
responded well (7aa−7ai). When cinnamyl alcohol was
reacted with cyclohexane-1,3-dione and aniline, the hydro-
genated product 7af was isolated. Unfortunately, when acyclic
diketones like acetylacetone and ethyl acetoacetate were taken
as substrates, the desired heterocycle was not formed. In most
cases, the known 1,8-dioxo-decahydroacridine derivatives are
symmetrical. Therefore, we have tried to synthesize the
unsymmetrical 1,8-dioxo-decahydroacridine derivative using
our methodology. With little modification in our method-
ology, we are able to synthesize the unsymmetrical 1,8-dioxo-
decahydroacridine derivatives (7aj−am) and afforded a good
yield (52−67%) (Scheme 3).
Scheme 2. Substrate Scope for ADMCRs to Synthesize N-
Substituted Acridine-1,8-Dione Derivatives
a
Scheme 3. Substrate Scope for ADMCRs to Synthesize
Unsymmetrical 1,8-Dioxo-Decahydroacridine Derivatives
a
a
Reaction Condition: 1,3-dione (0.5 mmol), 6 (0.5 mmol), and 4
(3.0 mmol) stirred at 135 °C for 3 h. After that added another 1,3-
dione (0.5 mmol), tBuOK (25 mol %), and Cat 1 (1 mol %), 135 °C,
36 h, argon.
Next, we choose urea as the nitrogen source instead of
aniline to synthesize NH-acridine-1,8-dione derivatives
(Scheme 4). An important compound 8e, which is used to
Scheme 4. Substrate Scope for ADMCRs to Synthesize
a
Acridine-1,8-Dione Derivatives with Urea Source
a
a
Reaction Condition: 4 (3.0 mmol, 6 equiv), 5a (1 mmol, 2 equiv), 6
Reaction Condition: 4 (3.0 mmol), 5a (1 mmol), urea (60 mg, 1
t
t
(0.5 mmol, 1 equiv), BuOK (25 mol %), Cat 1 (1 mol %), 135 °C,
36 h, argon.
mmol), BuOK (25 mol %), Cat 1 (1 mol %), 135 °C, 15 mL Ace
pressure tube.
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treat infections caused by herpes simplex virus15a was easily
prepared in a good yield (75%). 8f was isolated in 55% yield
using heteroaromatic alcohol such as 2-thiophene methanol as
the substrate. Of note, compound 8f is used in electrostato-
graphic toners and developers.15b Our method also provides a
route to synthesize compound 8g, which is known to have
antitumor activity.15c However, aliphatic alcohols such 1-
octanol delivered the desired 8h in 45% yield.
Scheme 6. Control Experiments
Next, we proposed the mechanism of this ADMCR, which
is depicted in Scheme 5. Two possible mechanistic pathways
Scheme 5. Propose Mechanism
formed (80%) by reacting dimedone with 4-methoxybenzy-
lalcohol under the reaction. When β-enaminone D was
reacted with intermediate Bˈ under standard reaction
conditions, the desired product 7ah was isolated in 85%
yield. This indicates that pathway 3 is the most possible route
of this ADMCR process.
Next, we have studied the time-dependent product
distribution of the ADMCR of dimedone, aniline, and 4-
methoxybenzylalcohol (Figure 2). During the study of the
kinetic profile of this reaction, it was observed that the
reaction between dimedone and aniline is much faster
have been proposed. Alcohol can be dehydrogenated by the
Ru-catalyst and the formed aldehyde reacts with dimedone
and form Knoevenagel adducts A or intermediate B, which
can generate desired product 7 by reacting with aniline.
Another possibility is the quick formation of β-enaminone D,
which can react with intermediate B to furnish the desired
product 7.
To prove the favorable pathway, some controlled experi-
ments have been conducted (Scheme 6). When the reaction
of aniline, dimedone, and 4-methoxybenzyl alcohol was
stopped after 30 min, we got β-enaminone D in a quantitative
yield which discarded the possible pathway 1 and 2. The
reaction of intermediate D, with 4-methoxybenzylalcohol and
dimedone afforded the desired product 7d with 75% isolated
yield. This proves that β-enaminone is one of the
intermediates in this reaction mixture. The same reaction
with 1,3-cyclohexanedione afforded the desired product 7ah
with 65% isolated yield, which indicates that the β-enaminone
formation is not reversible in nature. Intermediate B was easily
Figure 2. Kinetic profile of the ADMCR between 4-methoxybenzyl
alcohol, dimedone, and aniline. (The yield of the product was
determined by NMR using CH3CN as the internal standard).
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compared to the dehydrogenative conversion12 of alcohol to
aldehyde. First, 0.5 mmol dimedone was consumed by 0.5
mmol aniline to form D within 1 h. After 6 h, almost 40%
product 7d formation was observed and then the concen-
tration of 7d was gradually increased with time. During the
kinetic study we have observed the aldehyde formation. At
any point of time the concentration of the formed aldehyde
was very less in the reaction mixture, which underpins the
rapid consumption of the formed aldehyde by dimedone to
form B that eventually transforms to the final product.
dehydrogenation of alcohol is the key factor which controls
the reaction path. This indicates involvement of the β-
enaminone intermediate in the process. The deuterium
labeling experiment underpins involvement of the α-C−H
bond cleavage of the alcohol in the rate-determining step.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise mentioned, all chemicals
were purchase from common commercial sources and used as-
received. RuCl2(PPh3)3 was purchased from Sigma-Aldrich. All
solvents were dried by the standard procedure.16 Catalyst preparation
was carried out under an argon atmosphere with freshly distilled dry
THF or dichloromethane. All catalytic reactions were carried out
under an argon atmosphere using dry glassware and standard
syringe/septa techniques. DRX-400 Varian and Bruker Avance III
In order to gain insight, kinetic isotope experiments (KIE)
were carried out (Scheme 7). First, a mixture of 4d/4dˈ (1:1,
Scheme 7. Labeling Experiments
1
600 and 400 spectrometers were used to record H, 13C{1H} NMR,
and 31P NMR, respectively. Chemical shifts (δ) are reported in the
ppm downfield from tetramethylsilane; spin−spin coupling constants
(J) are expressed in Hz and other data are reported as follows: s =
singlet, d = doublet, t = triplet, m = multiplet, q = quartet, and br s =
broad singlet. Column chromatography was done with SRL silica gel
100−200 mesh. Analytical thin layer chromatography (TLC) was
carried out on silica gel plates (silica gel 60 F254) that were visualized
by exposure to ultraviolet light and an aqueous solution of p-
anisaldehyde.
General Procedure for the Preparation of 1,8-Dioxo-
Decahydroacridine Derivatives. Alcohol (3 mmol), dimedone
t
(1.0 mmol), aniline (0.5 mmol), BuOK (25 mol %), and complex 1
(1 mol %) were placed in a round-bottom flask under an argon
atmosphere and then it was immersed in an oil bath at 135 °C and
stirred at this temperature for 36 h. After this, the reaction mixture
was cooled to room temperature, diluted with dichloromethane, and
filtered over a plug of celite. The solvent was evaporated under
reduced pressure and the residue obtained was purified by column
chromatography (hexane:ethylacetate = 50:50) on silica gel to afford
the desired product.
v:v) was used in a competitive experiment. The observed
product ratio of the deuterated (7dˈ) and nondeuterated
1
General Procedure for the Preparation of Unsymmetrical
1,8-Dioxo-Decahydroacridine Derivatives. Dimedone (0.5
mmol), aniline (0.5 mmol), and alcohol (3 mmol) were heated at
135 °C in a two-necked round-bottom flask under an argon
atmosphere for 3 h. After cooling to room temperature, 1,3-diketone
products (7d) was determined by H NMR, which indicates
the KIE value ∼1.58. Furthermore, the parallel reaction with
4d and 4dˈ afforded the nondeuterated and deuterated
product in 70% and 45% yield, respectively. The calculated
kH/kD value (∼1.55) is in close agreement with result from
the competitive reaction. This is indicative of the involvement
of the C−H bond cleavage in the rate-determining step. To
demonstrate the utility of this reaction the reaction was also
scaled up to afford 7a (0.690 g) in 65% yield (Scheme 8).
t
(0.5 mmol), BuOK (25 mol %), and complex 1 (1 mol %) were
added to it and heated at the same temperature for 36 h. After this,
the reaction mixture was cooled to room temperature, diluted with
dichloromethane, and filtered over a plug of celite. The solvent was
evaporated under reduced pressure and the residue obtained was
purified by column chromatography (hexane:ethylacetate = 50:50)
on silica gel to afford the desired product.
Scheme 8. Gram Scale Synthesis
General Procedure for the Preparation of 1,8-Dioxo-
Decahydroacridine Derivatives Using Urea. Alcohol (3
t
mmol), dimedone (1.0 mmol), aniline (0.5 mmol), BuOK (25
mol %), and complex 1 (1 mol %) were placed in a 15 mL Ace
pressure tube under an argon atmosphere. The tube was sealed with
a screw cap and then it was immersed in an oil bath at 135 °C and
stirred at this temperature for 36 h. After this, the reaction mixture
was cooled to room temperature, diluted with dichloromethane, and
filtered over a plug of celite. The solvent was evaporated under
reduced pressure and the residue obtained was purified by column
chromatography (hexane:ethylacetate = 50:50 with 1% NEt3) on
silica gel to afford the desired product.
CONCLUSIONS
Kinetic Isotope Study. Competition Reaction. 4-Methoxybenzyl
■
alcohol (1.5 mmol), deuterated 4-methoxybenzyl alcohol, (1.5
In conclusion, we have developed ADMCR to synthesize 1,8-
dioxo-decahydroacridine derivatives. A broad range of alcohols
and amines bearing diverse functional groups were tolerated.
The synthesis of various biologically important medicinal
compounds was also demonstrated. In addition, mechanistic
and kinetic studies were executed to understand the reaction
sequences to achieve the targeted product. The slow
t
mmol), dimedone (1.0 mmol), aniline (0.5 mmol), BuOK (25
mol %), and complex 1 (1 mol %) were placed in a round-bottom
flask under an argon atmosphere and then it was immersed in an oil
bath at 135 °C and stirred at this temperature for 36 h. After this, the
reaction mixture was cooled to room temperature, diluted with
dichloromethane, and filtered over a plug of celite. The solvent was
evaporated under reduced pressure and the residue obtained was
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purified by column chromatography (hexane:ethylacetate = 50:50)
on silica gel to afford a mixture of 7d and 7dˈ in 50% yield.
Parallel Reaction. 4-Methoxybenzyl alcohol (3 mmol) or
deuterated 4-methoxybenzyl alcohol, (1.5 mmol), dimedone (1.0
148.4, 143.2, 139.3, 129.4, 127.5, 125.1, 114.9, 50.4, 41.9, 34.4, 32.5,
32.2, 31.5, 29.8, 27.1. HRMS (ESI) m/z: [M + H]+ calcd for
C33H40NO2:482.3059; found: 482.3061.
9-(3-Methoxyphenyl)-3,3,6,6-tetramethyl-10-phenyl-
3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (7g). It was ob-
tained as a white solid.19 Column chromatography (hexane:ethyla-
cetate = 50:50). Yield: 70%, 159.4 mg. 1H NMR (600 MHz, CDCl3)
δ 7.57−7.53 (m, 3H), 7.22 (d, J = 6.7 Hz, 3H), 7.14 (t, J = 7.8 Hz,
1H), 7.02−7.00 (m, 3H), 6.65 (dd, J = 7.9, 2.1 Hz, 2H), 5.26 (s,
1H), 3.78 (s, 3H), 2.16 (ABq, J = 17.0 Hz, 4H), 2.06 (d, J = 17.5 Hz,
2H), 1.81 (d, J = 17.5 Hz, 2H), 0.93 (s, 6H), 0.80 (s, 6H). 13C{1H}
NMR (150 MHz, CDCl3) δ 196.1, 159.4, 149.9, 147.7, 139.1, 129.5,
129.0, 120.3, 114.5, 113.6, 111.9, 55.2, 50.2, 41.9, 32.7, 32.5, 29.8,
26.9.
9-(Benzo[d][1,3]dioxol-5-yl)-10-(4-methoxyphenyl)-3,3,6,6-tetra-
methyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (7h). It
was obtained as a brown solid.20 Column chromatography
(hexane:ethylacetate = 50:50). Yield: 68%, 159.5 mg. 1H NMR
(600 MHz, CDCl3) δ 7.13−7.09 (m, 2H), 7.02 (t, J = 6.78 Hz, 2H),
6.93 (d, J = 1.7 Hz, 2H), 6.88 (dd, J = 8.0, 1.7 Hz, 1H), 6.69 (d, J =
8.0 Hz, 1H), 5.87 (s, 2H), 5.17 (s, 1H), 3.91 (s, 3H), 2.16 (ABq, J =
18.8 Hz, 4H), 2.05 (d, J = 17.5 Hz, 2H), 1.84 (dd, J = 17.5, 1.4 Hz,
2H), 0.94 (s, 6H), 0.82 (s, 6H). 13C{1H} NMR (150 MHz, CDCl3)
δ 196.1, 159.9, 150.2, 147.4, 145.7, 140.8, 131.1, 130.2, 130.2, 121.0,
115.3, 115.1, 114.8, 108.8, 108.0, 100.7, 55.7, 50.3, 41.9, 32.5, 32.5,
29.8, 27.0.
t
mmol), aniline (0.5 mmol), BuOK (25 mol %), and complex 1 (1
mol %) were placed in a round-bottom flask under an argon
atmosphere and then it was immersed in an oil bath at 135 °C and
stirred at this temperature for 36 h. After this, the reaction mixture
was cooled to room temperature, diluted with dichloromethane, and
filtered over a plug of celite. The solvent was evaporated under
reduced pressure and the residue obtained was purified by column
chromatography (hexane:ethylacetate = 50:50) on silica gel to afford
7d and 7dˈ in 70 and 45% yield, respectively.
10-(4-Methoxyphenyl)-3,3,6,6-tetramethyl-9-phenyl-
3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (7a). It was ob-
tained as a white solid.17 Column chromatography (hexane:ethyla-
cetate = 50:50). Yield: 72%, 164.0 mg. 1H NMR (600 MHz, CDCl3)
δ 7.41 (d, J = 7.3 Hz, 2H), 7.22 (t, J = 7.6 Hz, 2H), 7.13 (d, J = 8.0
Hz, 2H), 7.07 (t, J = 7.3 Hz, 1H), 7.03 (d, J = 7.1 Hz, 2H), 5.26 (s,
1H), 3.90 (s, 3H), 2.14 (ABq, J = 21.3 Hz, 4H), 2.07 (d, J = 17.6 Hz,
2H), 1.84 (d, J = 17.5 Hz, 2H), 0.93 (s, 6H), 0.78 (s, 6H). 13C{1H}
NMR (150 MHz, CDCl3) δ 195.9, 159.8, 150.4, 146.3, 131.5, 131.0,
130.1, 128.1, 127.9, 125.9, 115.3, 114.9, 114.5, 55.6, 50.2, 41.8, 32.7,
32.4, 29.8, 26.8.
3,3,6,6-Tetramethyl-9,10-diphenyl-3,4,6,7,9,10-hexahydroacri-
dine-1,8(2H,5H)-dione (7b). It was obtained as a white solid.11b
Column chromatography (hexane:ethylacetate = 50:50). Yield: 75%,
9,10-Bis(4-methoxyphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hex-
ahydroacridine-1,8(2H,5H)-dione (7i). It was obtained as a white
solid.17 Column chromatography (hexane:ethylacetate = 50:50).
1
159.3 mg. H NMR (600 MHz, CDCl3) δ 7.57−7.54 (m, 3H), 7.43
(d, J = 7.3 Hz, 2H), 7.26−7.23 (m, 4H), 7.10 (t, J = 7.3 Hz, 1H),
5.27 (s, 1H), 2.16 (ABq, J = 20.4 Hz, 4H), 2.07 (d, J = 17.4 Hz, 2H),
1.81 (d, J = 17.4 Hz, 2H), 0.93 (s, 6H), 0.79 (s, 6H). 13C{1H} NMR
(150 MHz, CDCl3) δ 196.0, 149.8, 146.2, 139.2, 129.5, 128.2, 128.0,
126.1, 114.7, 50.3, 41.9, 32.8, 32.5, 29.8, 26.9.
1
Yield: 76%, 184.3 mg. H NMR (600 MHz, CDCl3) δ 7.33 (d, J =
8.6 Hz, 2H), 7.11 (t, J = 9.5 Hz, 2H), 7.03 (t, J = 7.6 Hz, 2H), 6.78
(d, J = 8.6 Hz, 2H), 5.20 (s, 1H), 3.91 (s, 2H), 3.74 (s, 3H), 2.15
((ABq, J = 19.4 Hz, 4H), 2.05 (d, J = 17.0 Hz, 2H), 1.84 (d, J = 17.5
Hz, 2H), 0.94 (s, 6H), 0.80 (s, 6H). 13C{1H} NMR (150 MHz,
CDCl3) δ 196.1, 159.8, 157.7, 150.1, 138.9, 131.1, 130.2, 130.2,
128.9, 115.3, 114.9, 114.9, 113.5, 55.7, 55.2, 50.3, 41.9, 32.5, 31.9,
29.9, 26.9.
9-(4-Fluorophenyl)-3,3,6,6-tetramethyl-10-(p-tolyl)-3,4,6,7,9,10-
hexahydroacridine-1,8(2H,5H)-dione (7j). It was obtained as a white
solid.19 Column chromatography (hexane:ethylacetate = 50:50).
Yield: 65%, 148.5 mg. 1H NMR (600 MHz, CDCl3) δ 7.40−7.35 (m,
2H), 7.33 (d, J = 7.7 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H), 6.91 (t, J =
8.6 Hz, 2H), 5.23 (s, 1H), 2.47 (s, 3H), 2.14 (ABq, J = 21.8 Hz,
4H), 2.06 (d, J = 17.5 Hz, 2H), 1.82 (d, J = 17.5 Hz, 3H), 0.93 (s,
6H), 0.78 (s, 6H). 13C{1H} NMR (150 MHz, CDCl3) δ 196.0, 161.2
(d, J = 243.2 Hz), 150.2, 142.3 (d, J = 3.1 Hz), 139.7, 136.3, 130.8
(d, J = 66.2 Hz), 129.4 (d, J = 8.0 Hz), 114.8 (d, J = 21.2 Hz), 114.5,
50.3, 41.8, 32.5, 32.2, 29.8, 26.8, 21.4.
3,3,6,6-Tetramethyl-10-phenyl-9-(p-tolyl)-3,4,6,7,9,10-hexahy-
droacridine-1,8(2H,5H)-dione (7c). It was obtained as a white
solid.18 Column chromatography (hexane:ethylacetate = 50:50).
Yield: 75%, 156.0 mg. 1H NMR (600 MHz, CDCl3) δ 7.58−7.51 (m,
3H), 7.32 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.2 Hz, 2H), 7.05 (d, J =
7.7 Hz, 2H), 5.23 (s, 1H), 2.25 (s, 3H), 2.15 (ABq, J = 19.9 Hz,
4H), 2.06 (d, J = 17.4 Hz, 2H), 1.80 (d, J = 17.4 Hz, 2H), 0.93 (s,
6H), 0.80 (s, 6H). 13C{1H} NMR (150 MHz, CDCl3) δ 196.0,
149.7, 143.4, 139.3, 135.4, 129.5, 128.9, 127.9, 114.9, 50.3, 41.9, 32.5,
32.4, 29.8, 27.0, 21.2.
9-(4-Methoxyphenyl)-3,3,6,6-tetramethyl-10-phenyl-
3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (7d). It was ob-
tained as a white solid.11b Column chromatography (hexane:ethyla-
cetate = 50:50). Yield: 70%, 159.4 mg. 1H NMR (600 MHz, CDCl3)
δ 7.58−7.50 (m, 3H), 7.34 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 6.9 Hz,
2H), 6.78 (d, J = 8.6 Hz, 2H), 5.21 (s, 1H), 3.74 (s, 3H), 2.15 (ABq,
J = 19.9 Hz, 4H), 2.06 (d, J = 17.5 Hz, 2H), 1.80 (d, J = 17.4 Hz,
2H), 0.93 (s, 6H), 0.80 (s, 6H). 13C{1H} NMR (150 MHz, CDCl3)
δ 196.0, 157.8, 149.6, 149.6, 139.3, 138.9, 129.5, 128.9, 114.9, 113.6,
55.2, 50.3, 41.9, 32.5, 32.0, 29.8, 26.9.
9-(4-Chlorophenyl)-3,3,6,6-tetramethyl-10-phenyl-3,4,6,7,9,10-
hexahydroacridine-1,8(2H,5H)-dione (7e). It was obtained as a
yellow solid.11b Column chromatography (hexane:ethylacetate =
50:50). Yield: 76%, 174.8 mg. 1H NMR (600 MHz, CDCl3) δ 7.59−
7.53 (m, 3H), 7.37 (d, J = 8.4 Hz, 2H), 7.23−7.20 (m, 4H) 5.23 (s,
1H), 2.16 (ABq, J = 21.33 Hz 4H), 2.06 (d, J = 17.5 Hz, 2H), 1.80
(d, J = 17.5 Hz, 2H), 0.94 (s, 6H), 0.79 (s, 6H). 13C{1H} NMR (150
MHz, CDCl3) δ 195.9, 149.9, 144.9, 139.1, 131.6, 129.6, 129.4,
128.8, 128.4, 128.3, 114.4, 50.2, 41.9, 32.5, 32.5, 29.9, 26.9.
9-(4-(Tert-butyl)phenyl)-3,3,6,6-tetramethyl-10-phenyl-
3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (7f). It was ob-
tained as an off-white solid. Column chromatography (hexane:ethy-
lacetate = 50:50). Yield: 77%, 185.2 mg. 1H NMR (600 MHz,
CDCl3) δ 7.61−7.51 (m, 3H), 7.36 (d, J = 8.4 Hz, 2H), 7.30−7.22
(m, 4H), 5.27 (s, 1H), 2.18 (ABq, J = 17.9 Hz, 4H), 2.08 (d, J =
17.4 Hz, 2H), 1.84 (d, J = 17.4 Hz, 2H), 1.27 (s, 9H), 0.96 (s, 6H),
0.83 (s, 6H). 13C{1H} NMR (150 MHz, CDCl3) δ 196.1, 149.6,
3,3,6,6Tetramethyl-9-phenyl-10-(p-tolyl)-3,4,6,7,9,10-hexahy-
droacridine-1,8(2H,5H)-dione (7k). It was obtained as a white
solid.11b Column chromatography (hexane:ethylacetate = 50:50).
1
Yield: 72%, 169.7 mg. H NMR (600 MHz, CDCl3) δ 7.42 (d, J =
7.3 Hz, 2H), 7.33 (d, J = 7.7 Hz, 2H), 7.24 (t, J = 7.6 Hz, 2H), 7.10
(t, J = 7.3 Hz, 3H), 5.26 (s, 1H), 2.48 (s, 3H), 2.15 (ABq, J = 20.5
Hz, 4H), 2.06 (d, J = 17.5 Hz, 2H), 1.83 (d, J = 17.4 Hz, 2H), 0.94
(s, 6H), 0.79 (s, 6H). 13C{1H} NMR (150 MHz, CDCl3) δ 196.0,
150.1, 146.3, 139.6, 136.5, 128.2, 128.0, 126.0, 114.7, 50.3, 41.9, 32.8,
32.5, 29.8, 26.9, 21.4.
10-(4-Bromophenyl)-3,3,6,6-tetramethyl-9-phenyl-3,4,6,7,9,10-
hexahydroacridine-1,8(2H,5H)-dione (7l). It was obtained as a white
solid.11b Column chromatography (hexane:ethylacetate = 50:50).
Yield: 60%, 151.2 mg. 1H NMR (600 MHz, CDCl3)δ 7.70 (d, J = 8.3
Hz, 2H), 7.39 (d, J = 7.3 Hz, 2H), 7.23 (t, J = 7.6 Hz, 2H), 7.13 (d, J
= 6.8 Hz, 2H), 7.10 (t, J = 6.8 Hz, 1H), 5.26 (s, 1H), 2.16 (ABq, J =
20.6 Hz, 4H), 2.05 (d, J = 17.4 Hz, 2H), 1.81 (d, J = 17.3 Hz, 0H),
0.95 (s, 6H), 0.80 (s, 6H). 13C{1H} NMR (150 MHz, CDCl3) δ
195.9, 149.3, 149.3, 146.0, 138.3, 133.6, 131.3, 128.2, 127.9, 126.2,
123.6, 115.0, 50.2, 42.0, 32.6, 29.8, 26.9.
10-(4-Methoxyphenyl)-3,3,6,6-tetramethyl-9-(thiophen-2-yl)-
3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (7m). It was
9738
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J. Org. Chem. 2021, 86, 9733−9743

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
obtained as a yellow solid.21 Column chromatography (hexane:ethy-
lacetate = 50:50). Yield: 61%, 140.6 mg. 1H NMR (600 MHz,
CDCl3) δ 7.17 (d, J = 7.5 Hz, 1H), 7.11 (d, J = 7.1 Hz, 1H), 7.01−
6.98 (m, 4H), 6.83 (t, J = 5.0 Hz, 1H), 5.64 (s, 1H), 3.89 (s, 3H),
2.16 (ABq, J = 12.1 Hz, 4H), 2.08 (d, J = 17.6 Hz, 2H), 1.83 (d, J =
17.5 Hz, 2H), 0.94 (s, 6H), 0.85 (s, 6H). 13C{1H} NMR (150 MHz,
CDCl3) δ 195.8, 159.9, 150.7, 150.5, 131.4, 130.9, 130.5, 127.0,
124.1, 122.4, 115.4, 114.8, 114.1, 55.7, 50.3, 41.7, 32.4, 30.0, 27.3,
26.8. HRMS (ESI) m/z: [M + H]+ calcd for C28H32NO3S: 462.2103;
found 462.2103.
1H), 5.29 (s, 1H), 2.20 (ABq, J = 17.4 Hz, 4H), 2.05 (d, J = 17.4 Hz,
2H), 1.75 (d, J = 17.2 Hz, 2H), 0.99 (s, 6H), 0.84 (s, 6H). 13C{1H}
NMR (150 MHz, CDCl3) δ 195.8, 148.5, 145.6, 140.3, 133.2, 128.4,
127.9, 126.4, 117.4, 115.4, 50.2, 42.1, 32.7, 32.7, 29.8, 27.0. HRMS
(ESI) m/z: [M + H]+ calcd for C30H31N2O2: 451.2386; found:
451.2385.
Benzyl 4-(3,3,6,6-tetramethyl-1,8-dioxo-9-phenyl-1,2,3,4,5,6,7,8-
octahydroacridin-10(9H)-yl)benzoate (7u). It was obtained as a
white solid. Column chromatography (hexane:ethylacetate = 50:50).
1
Yield: 45%, 125.9 mg. H NMR (600 MHz, CDCl3) δ 8.29 (d, J =
3,3,6,6-Tetramethyl-10-phenyl-9-(thiophen-2-yl)-3,4,6,7,9,10-
hexahydroacridine-1,8(2H,5H)-dione (7n). It was obtained as a
yellow solid.13 Column chromatography (hexane:ethylacetate =
50:50). Yield: 66%, 142.2 mg. 1H NMR (600 MHz, CDCl3) δ
7.59−7.47 (m, 3H), 7.31−7.20 (m, 2H),7.04−6.98 (m, 2H), 6.85
(dd, J = 5.1, 3.5 Hz, 1H), 5.66 (s, 1H), 2.15 (ABq, J = 11.7 Hz, 5H),
2.09 (d, J = 17.5 Hz, 2H), 1.79 (d, J = 17.5 Hz, 2H), 0.95 (s, 6H),
0.85 (s, 6H). 13C{1H} NMR (150 MHz, CDCl3) δ 195.8, 150.4,
150.2, 139.0, 130.6, 130.1, 129.7, 129.5, 127.1, 124.2, 122.5, 114.2,
50.3, 41.8, 32.5, 30.0, 27.4, 26.8.
8.0 Hz, 2H), 7.52 (d, J = 7.1 Hz, 2H), 7.47−7.41 (m, 4H), 7.35 (d, J
= 8.0 Hz, 2H), 7.30−7.24 (m, 3H), 7.13 (t, J = 7.4 Hz, 1H), 5.45 (s,
2H), 5.30 (s, 1H), 2.19 (ABq, J = 18.4 Hz, 4H), 2.07 (d, J = 17.4 Hz,
2H), 1.80 (d, J = 17.3 Hz, 2H), 0.96 (s, 6H), 0.81 (s, 6H). 13C{1H}
NMR (150 MHz, CDCl3) δ 195.8, 165.3, 148.9, 146.0, 143.4, 135.6,
131.3, 128.9, 128.8, 128.7, 128.3, 128.0, 126.2, 115.1, 77.3, 77.1, 76.9,
50.3, 42.0, 32.8, 32.6, 29.8, 26.9. HRMS (ESI) m/z: [M + H]+ calcd
for C37H38NO4: 560.2801; found: 560.2803.
10-Benzyl-3,3,6,6-tetramethyl-9-phenyl-3,4,6,7,9,10-hexahy-
droacridine-1,8(2H,5H)-dione (7v). It was obtained as a white
solid.22 Column chromatography (hexane:ethylacetate = 50:50).
Yield: 70%, 153.6 mg. 1H NMR (600 MHz, CDCl3) δ 7.39 (t, J = 7.4
Hz, 2H), 7.34 (d, J = 7.1 Hz, 1H), 7.29 (d, J = 7.6 Hz, 2H), 7.21−
7.13 (m, 4H), 7.08 (d, J = 7.2 Hz, 1H), 5.34 (s, 1H), 4.90 (s, 2H),
2.49 (d, J = 16.6 Hz, 2H), 2.30 (d, J = 16.6 Hz, 2H), 2.19 (ABq, J =
9.5 Hz, 4H), 0.98 (s, 6H), 0.88 (s, 6H). 13C{1H} NMR (150 MHz,
CDCl3) δ 195.8, 150.7, 150.7, 145.9, 137.2, 129.3, 128.0, 128.0,
126.0, 125.5, 115.4, 50.1, 48.8, 40.28, 32.8, 32.2, 28.5, 28.3.
3,3,6,6-Tetramethyl-10-phenyl-9-(pyridin-2-yl)-3,4,6,7,9,10-hex-
ahydroacridine-1,8(2H,5H)-dione (7o). It was obtained as a yellow
solid.13 Column chromatography (hexane:ethylacetate = 50:50).
1
Yield: 65%, 138.4 mg. H NMR (500 MHz, CDCl3) δ 8.42 (d, J =
4.0 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.53−7.50 (m, 5H), 6.98 (t, J
= 5.4 Hz, 1H), 5.38 (s, 1H), 2.21 (d, J = 16.1 Hz, 2H), 2.14−2.03
(m, 4H), 1.83 (d, J = 17.3 Hz, 2H), 0.94 (s, 6H), 0.78 (s, 6H).
13C{1H} NMR (125 MHz, CDCl3) δ 196.2, 163.4, 151.4, 149.2,
140.0, 135.6, 130.1, 129.2, 123.7, 121.2, 113.9, 50.4, 41.8, 35.20, 32.7,
29.8, 26.7.
4-(3,3,6,6-Tetramethyl-1,8-dioxo-9-phenyl-1,2,3,4,5,6,7,8-octa-
hydroacridin-10(9H)-yl)benzamide (7w). It was obtained as a white
solid. Column chromatography (hexane:ethylacetate = 50:50). Yield:
3,3,6,6-Tetramethyl-9-phenyl-10-(pyridin-2-yl)-3,4,6,7,9,10-hex-
ahydroacridine-1,8(2H,5H)-dione (7p). It was obtained as a yellow
solid.11c Column chromatography (hexane:ethylacetate = 50:50).
1
67%, 157.0 mg. H NMR (600 MHz, CDCl3)δ 8.04 (d, J = 8.3 Hz,
2H), 7.42 (d, J = 7.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 7.24 (d, J =
7.7 Hz, 2H), 7.11 (t, J = 7.3 Hz, 1H), 5.28 (s, 1H), 2.17 (ABq, J =
20.0 Hz, 4H), 2.06 (d, J = 17.5 Hz, 2H), 1.79 (d, J = 17.4 Hz, 2H),
0.94 (s, 6H), 0.80 (s, 6H). 13C{1H} NMR (150 MHz, CDCl3) δ
196.0, 168.0, 149.2, 146.0, 142.3, 134.6, 130.2, 129.4, 128.3, 127.9,
126.2, 115.0, 50.3, 42.0, 32.6, 29.8, 26.9. HRMS (ESI) m/z: [M +
H]+ calcd for C30H33N2O3: 469.2491; found: 469.2493.
1
Yield: 40%, 84.9 mg. H NMR (500 MHz, CDCl3) δ 8.73 (s, 1H),
7.95 (t, J = 7.5 Hz, 1H), 7.55−7.42 (m, 2H), 7.32 (d, J = 7.7 Hz,
1H), 7.26−7.22 (m, 3H), 7.09 (t, J = 7.2 Hz, 1H), 5.27 (s, 1H),
2.26−2.09 (m, 6H), 1.71 (d, J = 17.3 Hz, 2H), 0.94 (s, 6H), 0.81 (s,
6H). 13C{1H} NMR (125 MHz, CDCl3) δ 195.8, 152.7, 150.4,
149.0, 146.2, 139.1, 128.2, 128.2, 126.1, 124.8, 124.6, 115.1, 50.4,
41.5, 33.1, 32.6, 29.8, 27.1.
10-(4-Bromophenyl)-9-(4-fluorophenyl)-3,3,6,6-tetramethyl-
3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (7q). It was ob-
tained as a white solid. Column chromatography (hexane:ethylace-
tate = 50:50). Yield: 40%, 104.4 mg. 1H NMR (600 MHz, CDCl3) δ
7.70 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 6.8 Hz, 2H), 7.11 (d, J = 8.0
Hz, 2H), 6.92 (t, J = 8.5 Hz, 2H), 5.23 (s, 1H), 2.16 (ABq, J = 20.9
Hz, 4H), 2.05 (d, J = 17.4 Hz, 2H), 1.81 (d, J = 17.4 Hz, 2H), 0.96
(s, 6H), 0.81 (s, 6H). 13C{1H} NMR (150 MHz, CDCl3) δ 195.9,
161.3 (d, J = 243.6 Hz), 149.3, 142.0 (d, J = 3.0 Hz), 138.1, 133.6,
129.4 (d, J = 8.0 Hz), 123.7, 115.0, 114.9 (d, J = 4.7 Hz), 50.2, 42.0,
32.6, 32.2, 29.8, 26.9. HRMS (ESI) m/z: [M + H]+ calcd for
C29H30BrFNO2: 522.1444, found: 522.1439.
9,10-Diphenyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione
(7aa). It was obtained as a yellow solid.23 Column chromatography
1
(hexane:ethylacetate = 50:50). Yield: 74%, 136.5 mg. H NMR (600
MHz, CDCl3) δ 7.57−7.52 (m, 3H), 7.44 (d, J = 7.6 Hz, 2H), 7.31−
7.24 (m, 4H), 7.15 (t, J = 7.3 Hz, 1H), 5.41 (s, 1H), 2.39 (dt, J =
16.6, 4.6 Hz, 2H), 2.32−2.16 (m, 4H), 2.08−2.00 (m, 2H), 1.89 (dt,
J = 13.6, 4.7 Hz, 2H), 1.82−1.77 (m, 2H). 13C{1H} NMR (150
MHz, CDCl3) δ 196.2, 151.6, 146.6, 139.2, 130.4, 130.0, 129.7,
129.5, 129.4, 128.3, 127.9, 126.1, 115.6, 36.9, 32.1, 28.4, 21.2.
10-(4-Methoxyphenyl)-9-phenyl-3,4,6,7,9,10-hexahydroacridine-
1,8(2H,5H)-dione (7ab). It was obtained as a yellow solid. Column
chromatography (hexane:ethylacetate = 50:50). Yield: 73%, 145.6
mg. 1H NMR (600 MHz, CDCl3) δ 7.40 (d, J = 7.5 Hz, 2H), 7.24 (t,
J = 7.6 Hz, 2H), 7.18−7.14 (m, 2H), 7.11 (t, J = 7.3 Hz, 1H), 7.00
(d, J = 8.1 Hz, 2H), 5.37 (s, 1H), 3.88 (s, 3H), 2.36 (dt, J = 16.9, 4.6
Hz, 2H), 2.28−2.14 (m, 4H), 2.06 (dt, J = 17.8, 4.6 Hz, 2H), 1.89−
1.85 (m, 2H), 1.80−1.75 (m, 2H). 13C{1H} NMR (150 MHz,
CDCl3) δ 196.3, 160.0, 152.2, 146.6, 131.6, 130.9, 130.3, 128.3,
127.8, 126.1, 115.6, 115.2, 114.8, 55.7, 36.8, 32.1, 28.4, 21.2. HRMS
(ESI) m/z: [M + H]+ calcd for C26H26NO3: 400.1913; found:
400.1919.
9-(4-Methoxyphenyl)-10-phenyl-3,4,6,7,9,10-hexahydroacridine-
1,8(2H,5H)-dione (7ac). It was obtained as a white solid.23 Column
chromatography (hexane:ethylacetate = 50:50). Yield: 78%, 155.9
mg. 1H NMR (600 MHz, CDCl3) δ 7.58−7.43 (m, 3H), 7.36 (d, J =
8.6 Hz, 2H), 7.33−7.22 (m, 2H), 6.82 (d, J = 8.7 Hz, 2H), 5.34 (s,
1H), 3.78 (s, 3H), 2.39 (dt, J = 16.6, 4.6 Hz, 2H), 2.32−2.15 (m,
4H), 2.04 (dt, J = 17.7, 4.6 Hz, 2H), 1.92−1.87 (m, 2H), 1.85−1.75
(m, 2H). 13C{1H} NMR (150 MHz, CDCl3) δ 196.3, 157.9, 151.4,
139.3, 139.2, 129.4, 128.8, 115.9, 113.7, 55.3, 36.9, 31.3, 28.4, 21.2.
3-(3,3,6,6-Tetramethyl-1,8-dioxo-10-(p-tolyl)-1,2,3,4,5,6,7,8,9,10-
decahydroacridin-9-yl)benzonitrile (7r). It was obtained as a white
solid. Column chromatography (hexane:ethylacetate = 50:50). Yield:
1
70%, 162.4 mg. H NMR (600 MHz, CDCl3) δ 7.79 (d, J = 7.7 Hz,
1H), 7.61 (s, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.38−7.32 (m, 3H),
7.13−7.05 (d, J = 6.7 Hz, 1H), 5.26 (s, 1H), 2.49 (s, 3H), 2.15
(ABq, J = 23.5 Hz, 4H), 2.06 (d, J = 17.6 Hz, 2H), 1.86 (d, J = 17.6
Hz, 2H), 0.95 (s, 6H), 0.79 (s, 6H). 13C{1H} NMR (150 MHz,
CDCl3) δ 195.9, 150.7, 147.9, 139.9, 136.1, 133.6, 131.2, 130.7,
129.9, 129.6, 128.9, 119.7, 113.8, 112.0, 50.2, 41.9, 33.3, 32.5, 29.7,
26.9, 21.4. HRMS (ESI) m/z: [M + H]+ calcd for C31H33N2O2:
465.2542; found 465.2541.
3-(3,3,6,6-Tetramethyl-1,8-dioxo-9-phenyl-1,2,3,4,5,6,7,8-octa-
hydroacridin-10(9H)-yl)benzonitrile (7s). It was obtained as a white
solid. Column chromatography (hexane:ethylacetate = 50:50). Yield:
1
65%, 146.2 mg. H NMR (600 MHz, CDCl3) δ 7.89 (d, J = 7.8 Hz,
1H), 7.76 (t, J = 7.9 Hz, 1H), 7.60 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H),
7.41 (d, J = 7.6 Hz, 2H), 7.30−7.26 (m, 2H), 7.15 (t, J = 7.3 Hz,
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J. Org. Chem. 2021, 86, 9733−9743

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Article
10-(4-Bromophenyl)-9-phenyl-3,4,6,7,9,10-hexahydroacridine-
1,8(2H,5H)-dione (7ad). It was obtained as a white solid.24 Column
chromatography (hexane:ethylacetate = 50:50). Yield: 68%, 152.3
196.1, 157.8, 151.4, 149.5, 139.2, 139.0, 129.4, 128.9, 115.9, 114.9,
113.6, 55.2, 50.3, 41.9, 36.8, 32.5, 31.7, 29.8, 28.4, 27.0, 21.2.
9-(4-Bromophenyl)-3,3-dimethyl-10-phenyl-3,4,6,7,9,10-hexahy-
droacridine-1,8(2H,5H)-dione (7ak). It was obtained as a white
solid.26 Column chromatography (hexane:ethylacetate = 50:50).
1
mg. H NMR (600 MHz, CDCl3) δ 7.67 (d, J = 8.6 Hz, 2H), 7.38
(d, J = 7.2 Hz, 2H), 7.26 (d, J = 5.9 Hz, 2H), 7.15 (d, J = 8.5 Hz,
2H), 7.13 (t, J = 7.4 Hz, 1H), 5.37 (s, 1H), 2.38 (dt, J = 16.6, 4.6
Hz, 2H), 2.29−2.11 (m, 4H), 2.03 (dt, J = 17.7, 4.6 Hz, 2H), 1.93−
1.87 (m, 2H), 1.83−1.74 (m, 2H). 13C{1H} NMR (150 MHz,
CDCl3) δ 196.1, 151.0, 146.4, 138.2, 128.4, 127.8, 126.2, 123.6,
116.0, 36.8, 32.1, 28.5, 21.2. HRMS (ESI) m/z: [M + H]+ calcd for
C25H23BrNO2: 448.0912, found: 448.0911.
1
Yield: 57%, 135.6 mg. H NMR (600 MHz, , CDCl3) δ 7.56 (t, J =
7.5 Hz, 3H), 7.39 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.25
(d, J = 7.6 Hz, 2H), 5.30 (s, 1H), 2.42−2.00 (m, 6H), 1.96−1.78 (m,
4H), 0.97 (s, 3H), 0.84 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3)
δ 196.1, 195.9, 151.83, 149.9, 145.6, 139.1, 131.3, 129.8, 129.6,
119.9, 115.3, 114.4, 50.3, 41.9, 36.8, 32.5, 32.3, 29.8, 28.5, 27.0, 21.3.
3,3-Dimethyl-9,10-diphenyl-3,4,6,7,9,10-hexahydroacridine-1,8-
(2H,5H)-dione (7al). It was obtained as a white solid.27 Column
chromatography (hexane:ethylacetate = 50:50). Yield: 52%, 103.2
mg. 1H NMR (600 MHz, CDCl3) δ 7.56−7.51 (m, 3H), 7.43 (d, J =
7.6 Hz, 2H), 7.26−7.24 (m, 4H), 7.12 (t, J = 7.6 Hz, 1H), 5.34 (s,
1H), 2.37−2.00 (m, 8H), 1.89−1.75 (m, 2H), 0.94 (s, 3H), 0.82 (s,
3H). 13C{1H} NMR (150 MHz, CDCl3) δ 196.1, 196.0, 151.6,
149.7, 146.5, 139.3, 129.5, 128.3, 127.9, 126.1, 115.7, 114.8, 50.4,
41.9, 36.9, 32.5, 32.5, 29.8, 28.5, 27.0, 21.2.
9-(4-Chlorophenyl)-10-(4-methoxyphenyl)-3,4,6,7,9,10-hexahy-
droacridine-1,8(2H,5H)-dione (7ae). It was obtained as a white
solid.25 Column chromatography (hexane:ethylacetate = 50:50).
1
Yield: 64%, 138.5 mg. H NMR (600 MHz, CDCl3) δ 7.33 (d, J =
8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.17−7.11 (m, 2H), 7.01 (d, J
= 8.2 Hz, 2H), 5.32 (s, 1H), 3.88 (s, 3H), 2.35 (dt, J = 16.6, 4.6 Hz,
2H), 2.29−2.14 (m, 2H), 2.06 (dt, J = 17.2, 4.1 Hz, 2H), 1.91−1.87
(m, 2H), 1.82−1.71 (m, 2H). 13C{1H} NMR (150 MHz, CDCl3) δ
196.3, 160.0, 152.4, 145.2, 131.7, 131.5, 130.8, 130.2, 129.3, 128.4,
115.3, 55.8, 36.8, 31.8, 28.4, 21.2.
4-(4-Methoxyphenyl)-6,6-dimethyl-9-phenyl-2,3,5,6,7,9-hexahy-
dro-1H-cyclopenta[b]quinoline-1,8(4H)-dione (7am). It was ob-
tained as a white solid. Column chromatography (hexane:ethylace-
9-Phenethyl-10-phenyl-3,4,6,7,9,10-hexahydroacridine-1,8-
(2H,5H)-dione (7af). It was obtained as a white solid. Column
chromatography (hexane:ethylacetate = 50:50). Yield: 62%, 123.0
1
tate = 50:50). Yield: 67%, 138.4 mg. H NMR (600 MHz, CDCl3) δ
1
7.40 (d, J = 7.6 Hz, 2H), 7.28 (d, J = 3.7 Hz, 2H), 7.26−7.18 (m,
2H), 7.15 (t, J = 7.0 Hz, 1H), 7.05 (t, J = 6.2 Hz, 2H), 5.06 (s, 1H),
3.92 (s, 2H), 2.33−2.04(m, 8H), 1.00 (s, 3H), 0.94 (s, 3H). 13C{1H}
NMR (150 MHz, CDCl3) δ 202.3, 195.9, 164.9, 160.1, 150.9, 145.5,
130.6, 130.10, 130.0, 128.3, 127.9, 126.4, 120.4, 115.3, 115.2, 115.1,
55.7, 50.4, 41.3, 34.3, 34.0, 32.5, 29.5, 27.3, 25.8. HRMS (ESI) m/z:
[M + H]+ calcd for C27H28NO3: 414.2069; found: 414.2071.
3,3,6,6-Tetramethyl-9-phenyl-3,4,6,7,9,10-hexahydroacridine-
1,8(2H,5H)-dione (8a). It was obtained as a white solid.28 Column
chromatography (hexane:ethylacetate = 50:50 with 1% NEt3). Yield:
mg. H NMR (600 MHz, CDCl3) δ 7.50−7.48 (m, 3H), 7.23 (t, J =
7.6 Hz, 2H), 7.20 (d, J = 6.6 Hz, 2H), 7.17−7.11 (m, 3H), 4.40 (t, J
= 5.5 Hz, 1H), 2.64−2.57 (m, 2H), 2.44 (dt, J = 16.5, 4.4 Hz, 2H),
2.30−2.08 (m, 4H), 1.95 (dt, J = 17.6, 4.4 Hz, 2H), 1.91−1.87 (m,
2H), 1.80−1.70 (m, 4H). 13C{1H} NMR (150 MHz, CDCl3) δ
196.7, 152.7, 143.1, 139.3, 129.4, 128.4, 128.3, 125.6, 115.0, 37.8,
37.0, 31.8, 28.4, 26.2, 21.4. HRMS (ESI) m/z: [M + H]+ calcd for
C27H28NO2: 398.2120; found: 398.2121.
10-Butyl-9-(p-tolyl)-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-
dione (7ag). It was obtained as a white solid. Column
chromatography (hexane:ethylacetate = 50:50). Yield: 45%, 81.6
1
60%, 104.7 mg. H NMR (500 MHz, CDCl3) δ 7.30 (d, J = 7.1 Hz,
2H), 7.15 (t, J = 7.6 Hz, 2H), 7.03 (t, J = 7.5 Hz, 1H), 5.06 (s, 1H),
2.36−2.00 (m, 8H), 1.04 (s, 6H), 0.93 (s, 6H). 13C{1H} NMR (125
MHz, CDCl3) δ 195.4, 147.9, 146.6, 128.2, 128.1, 126.1, 113.9, 51.0,
41.3, 33.8, 32.8, 29.6, 27.3.
1
mg. H NMR (600 MHz, CDCl3) δ 7.14 (d, J = 7.9 Hz, 2H), 7.00
(d, J = 7.7 Hz, 2H), 5.30 (s, 1H), 3.66 (t, J = 7.8 Hz, 2H), 2.76 (dt, J
= 16.9, 5.1 Hz, 2H), 2.58−2.50 (m, 2H), 2.41 (dt, J = 16.4, 4.9 Hz,
2H), 2.33−2.27 (m, 2H), 2.25 (s, 3H), 2.11−1.94 (m, 4H), 1.67−
1.59 (m, 2H), 1.42−1.34 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H). 13C{1H}
NMR (150 MHz, CDCl3) δ 196.0, 151.9, 143.3, 135.3, 128.8, 127.5,
116.6, 45.1, 36.6, 33.2, 31.1, 26.7, 21.4, 21.1, 20.0, 13.8. HRMS (ESI)
m/z: [M + H]+ calcd for C24H30NO2: 364.2277; found: 364.2272.
9-Heptyl-10-(p-tolyl)-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-
dione (7ah). It was obtained as a white solid. Column
chromatography (hexane:ethylacetate = 50:50). Yield: 35%, 70.8
9-(4-Methoxyphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahy-
droacridine-1,8(2H,5H)-dione (8b). It was obtained as a white
solid.28 Column chromatography (hexane:ethylacetate = 50:50 with
1
1% NEt3). Yield: 65%, 123.1 mg. H NMR (600 MHz, CDCl3) δ
7.24 (d, J = 8.7 Hz, 2H), 6.72 (d, J = 8.7 Hz, 2H), 6.34 (brs, 1H),
5.02 (s, 1H), 3.70 (s, 3H), 2.33 (d, J = 16.6 Hz, 2H), 2.25−2.12 (m,
6H), 1.07 (s, 6H), 0.96 (s, 6H). 13C{1H} NMR (150 MHz, CDCl3)
δ 195.6, 157.7, 147.4, 139.0, 129.1, 114.1, 113.4, 55.2, 50.8, 41.3,
32.9, 32.8, 29.6, 27.3.
1
mg. H NMR (600 MHz, CDCl3) δ 7.28 (d, J = 8.1 Hz, 2H), 7.05
(d, J = 8.9 Hz, 2H), 4.26 (s, 1H), 2.47−2.39 (m, 5H, -CH3, -CH2-),
2.29−2.05 (m, 4H), 1.97 (dt, J = 17.7, 4.5 Hz, 2H), 1.91−1.86 (m,
2H), 1.82−1.74 (m, 2H), 1.39−1.33 (m, 2H), 1.29−123 (m, 10H),
0.86 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3) δ 196.8,
152.8, 139.4, 136.7, 115.1, 37.1, 36.1, 32.1, 30.0, 29.6, 28.4, 26.0,
25.1, 22.8, 21.4, 21.3, 14.3. HRMS (ESI) m/z: [M + H]+ calcd for
C27H36NO2: 406.2746; found: 406.2745.
9-(4-Chlorophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahy-
droacridine-1,8(2H,5H)-dione (8c). It was obtained as a yellow
solid.28 Column chromatography (hexane:ethylacetate = 50:50 with
1
1% NEt3). Yield: 54%, 103.4 mg. H NMR (500 MHz, CDCl3) δ
7.27 (d, J = 7.5 Hz, 2H), 7.15 (d, J = 7.5 Hz, 2H), 5.05 (s, 1H),
2.40−2.12 (m, 8H), 1.08 (s, 6H), 0.96 (s, 6H). 13C{1H} NMR (125
MHz, CDCl3) δ 195.3, 147.8, 145.1, 131.7, 129.6, 128.2, 113.6, 50.9,
41.4, 33.5, 32.8, 29.6, 27.3.
4,8-Diphenyl-2,3,5,6-tetrahydrodicyclopenta[b,e]pyridine-1,7-
(4H,8H)-dione (7ai). It was obtained as a yellow solid. Column
chromatography (hexane:ethylacetate = 50:50). Yield: 76%, 141.0
9-(4-Bromophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahy-
droacridine-1,8(2H,5H)-dione (8d). It was obtained as a white
solid.28 Column chromatography (hexane:ethylacetate = 50:50 with
1
mg. H NMR (600 MHz, CDCl3) δ 7.57−7.53 (m, 3H), 7.36−7.33
1
(m, 2H), 7.28 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 8.3 Hz, 2H), 4.82 (s,
1H), 3.76 (s, 3H), 2.48−2.30 (m, 8H). 13C{1H} NMR (150 MHz,
CDCl3) δ 202.1, 165.5, 158.3, 137.1, 135.8, 130.3, 130.1, 129.9,
129.1, 128.6, 128.2, 121.4, 113.8, 55.3, 34.4, 33.6, 25.0. HRMS (ESI)
m/z: [M + H]+ calcd for C24H22NO3: 372.1600; found: 372.1600.
9-(4-Methoxyphenyl)-3,3-dimethyl-10-phenyl-3,4,6,7,9,10-hexa-
hydroacridine-1,8(2H,5H)-dione (7aj). It was obtained as a white
solid.26 Column chromatography (hexane:ethylacetate = 50:50).
Yield: 65%, 138.7 mg. 1H NMR (600 MHz, CDCl3) δ 7.65−7.53 (m,
3H), 7.36 (d, J = 8.7 Hz, 2H), 7.28−7.26 (m, 2H), 6.82 (d, J = 8.7
Hz, 2H), 5.29 (s, 1H), 2.38−2.02 (m, 7H), 1.90−1.79 (m, 3H), 0.96
(s, 3H), 0.84 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3) δ 196.3,
1% NEt3). Yield: 59%, 126.2 mg. H NMR (500 MHz, CDCl3) δ
7.30 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.71 (brs, 1H),
5.04 (s, 1H), 2.38−2.12 (m, 8H), 1.08 (s, 6H), 0.96 (s, 6H).
13C{1H} NMR (125 MHz, CDCl3) δ 195.4, 148.0, 145.7, 131.1,
130.1, 119.9, 113.5, 77.4, 77.1, 76.9, 50.9, 41.3, 33.6, 32.8, 29.6, 27.3.
3,3,6,6-Tetramethyl-9-(3-phenoxyphenyl)-3,4,6,7,9,10-hexahy-
droacridine-1,8(2H,5H)-dione (8e). It was obtained as a yellow
solid.15a Column chromatography (hexane:ethylacetate = 50:50 with
1
1% NEt3). Yield: 75%, 154.8 mg. H NMR (600 MHz, CDCl3) δ
7.24 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.15 (t, J = 7.8
Hz, 1H), 7.01 (t, J = 7.3 Hz, 1H), 6.92 (s, 1H), 6.88 (d, J = 8.0 Hz,
3H), 6.77 (brs, 1H), 6.70 (d, J = 7.9 Hz, 1H), 5.08 (s, 1H), 2.32 (d,
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Article
J = 16.7 Hz, 2H), 2.26−2.10 (m, 6H), 1.06 (s, 6H), 0.94 (s, 6H).
13C{1H} NMR (150 MHz, CDCl3) δ 195.6, 157.8, 156.8, 148.6,
148.1, 129.6, 129.2, 124.1, 122.7, 118.7, 118.4, 117.0, 113.4, 50.8,
41.1, 33.6, 32.7, 29.6, 27.2.
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7.8 Hz, 1H), 5.08 (s, 1H), 2.39 (d, J = 16.7 Hz, 2H), 2.32−2.21 (m,
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= 5.0 Hz, 1H), 2.35−2.18 (m, 8H), 1.43−1.42 (m, 2H), 1.29−1.09
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01075.
1
Copies of the H NMR and 13C NMR spectra of all the
compounds, HRMS data, and mechanistic details
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
Dipankar Srimani − Department of Chemistry, Indian
Institute of Technology Guwahati, Guwahati, Assam
781039, India; orcid.org/0000-0001-8826-9773;
Phone: (+91)-361-258-3312; Email: dsrimani@iitg.ac.in;
Fax: (+91)-361-258-2349
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Dehydrogenation and Related Transformations in Chemical Syn-
thesis. Science 2013, 341, No. 1229712.
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functional pincer ligands. Chem. Rev. 2019, 119, 2681−2751.
Author
Nandita Biswas − Department of Chemistry, Indian Institute
of Technology Guwahati, Guwahati, Assam 781039, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01075
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank SERB, DST (ECR/2016/000108) for
the financial support. We are also thankful to the CIF and the
Department of Chemistry, IIT-Guwahati, for the instrumental
facilities, infrastructural support, and start-up grant. N. B.
thanks the institute for her fellowship.
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