Synthesis of Ring-Fused, N-Substituted 4-Quinolinones Using p Ka-Guided, Base-Promoted Annulations with Isatoic Anhydrides: Total Synthesis of Penicinotam

Article abstract of DOI:10.1021/acs.joc.9b02541

An anionic annulation strategy employing isatoic anhydrides and a wide assortment of enolizable partners was developed to afford over 80 novel ring-fused, N-substituted 4-quinolinones, an underrepresented privileged template. Multiple factors governing the efficiency of the transformation were determined, resulting in a reliable and tunable synthetic platform applicable for a broad range of substrates with variable deprotonation susceptibility, such as tetramic and tetronic acids, cyclic 1,3-diketones, and cycloalkanones. Application to the synthesis of bioactive, pyrrolizine-fused 4-quinolinone, penicinotam 3, resulted in the most brief and highest yielding total synthesis of the alkaloid in three steps and a 36% overall yield.

Full text of DOI:10.1021/acs.joc.9b02541

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Article
Synthesis of Ring-Fused, N-Substituted 4-Quinolinones
Using pKa-Guided, Base-Promoted Annulations with
Isatoic Anhydrides: Total Synthesis of Penicinotam
Muhammad M. Khalifa, Satish Chandra Philkhana, and Jennifer E. Golden
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02541 • Publication Date (Web): 02 Dec 2019
Downloaded from pubs.acs.org on December 3, 2019
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The Journal of Organic Chemistry
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Synthesis of Ring-Fused, N-Substituted 4-Quinolinones Using pKa-
Guided, Base-Promoted Annulations with Isatoic Anhydrides: Total
Synthesis of Penicinotam
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Muhammad M. Khalifa§, Satish Chandra Philkhana§ and Jennifer E. Golden*
§contributed equally to this work.
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Ave, Madison,
Wisconsin 53703, United States.
*Email: jennifer.golden@wisc.edu
Supporting Information Placeholder
ABSTRACT: An anionic annulation strategy employing isatoic anhydrides and a wide assortment of enolizable partners was
developed to afford over 80 novel ring-fused, N-substituted 4-quinolinones, an underrepresented privileged template. Multiple factors
governing the efficiency of the transformation were determined, resulting in a reliable and tunable synthetic platform applicable for
a broad range of substrates with variable deprotonation susceptibility, such as tetramic and tetronic acids, cyclic 1,3-diketones, and
cycloalkanones. Application to the synthesis of bioactive, pyrrolizine-fused 4-quinolinone, penicinotam 3, resulted in the most brief
and highest yielding total synthesis of the alkaloid in 3 steps and 36% overall yield.
INTRODUCTION
For instance, the quinolactacins7,8 are a Penicillium-derived, natural
product family featuring a -lactam-fused, N-methyl 4-quinolinone with
antibacterial activity, and quinolactacin A2 (1) also inhibits
The 4-quinolinone motif is a privileged heterocycle,1, 2 often imbedded
within ring-fused frameworks with diverse bioactivity (Fig. 1, shaded
blue).3 While unsubstituted, NH-4-quinolinones are recognized for
acetylcholinesterase (AChE).9 Compound 2, designed with
a
antimalarial activity4, and intermediacy to potential anti-Alzheimer6
5
recognizable 5-HT3 antagonist or “setron” pharmacophore, is a serotonin
receptor ligand.10 Penicinotam 3 is a pyrrolizinone-fused 4-quinolinone
agents, annulated N-substituted derivatives have been less explored.
Nonetheless, the emergence of ring-fused, N-substituted 4-quinolinones
in natural product alkaloids and in directed syntheses has revealed this
underrepresented template as a source of structural and medicinal value.
with potent insecticidal properties,11,
and a collection of N-benzyl
12
derivatives, represented by analog 4, are patented for antifibrotic and
immunomodulatory activity.13
Carbocycle-appended, N-substituted 4-quinolinones are also relevant,
as exemplified by the antiviral derivatives, indenone 5 and indene 6.14
O
O
N
O
O
O
O
Six-membered, annulated variants such as floxacrine15
7 and
pyranoquinolinone16 8 show antimalarial and AChE inhibitory activity,
respectively. As part of a program aimed at the efficient assembly and
application of unique, bioactive heterocycles,17, 18 we sought a general and
efficient synthetic strategy that would enable the construction of a diverse
collection of previously unknown, ring-fused, N-substituted-4-
quinolinones for biological screening. We first took note of literature
precedents leading to the construction of some of these scaffolds, starting
with lactam-fused derivatives (Fig. 2).
NH
N
N
N
N
CH3
H3C
H3C
R1
R2
H3C
N
CH3
penicinotam, , R1 = R2 = H
1
2
quinolactacin A2,
3
, R1 = F, R2 = 4-F-C6H4
4
O
O
O
O
iPr
Cl
OH
X
CH3
CH3
N
N
N
O
Members of the quinolactacin natural product family differ by
stereochemical configuration and substitution pattern of the C3-carbon of
the quinolinone-fused lactam ring (Fig. 2, 1).8 Several alkaloids in this
family have been the subject of enantioselective syntheses,19-21 inherently
requiring synthetic sophistication to selectively install the requisite
stereocenter. Of these, the shortest approach21 featured a four-step route
to (+)-quinolactacin A2 1 (see (a), Fig. 2). Employing a condensation
OH
CH3
H3C
5
6
CF3
7
8
(-)-ribalinine,
, X = CO
, X = CH2
floxacrine,
Figure 1. Bioactive N-substituted, ring-fused 4-quinolinones
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conditions appropriate for a collection of new substrates was relegated to
trial and error and promised meager outcomes.
between N-methyl isatoic anhydride 9a and isoleucine derived N-Boc -
ketoester 10, product 1 was isolated as an 8:1 ratio of C3 diastereoisomers
in 30% overall yield. While the key addition-elimination-cyclization step
involving DBU maximally occurred in 42% yield, this represented a
potential starting point for platform optimization given its brevity and
similarity to other synthetic routes for carbocyclic derivatives, discussed
below. In contrast, related pyrrolizinone-fused quinolinone, penicinotam
3, was first prepared by concomitant cyclization and methylation of
naturally sourced penicinoline 11.12 In 2017, Saito et al synthesized 3 via
1
2
3
4
5
6
7
8
(a) Werbel, 199224
O
O
O
NaH, DMF
-10-90 °C, 4 h
O
X
X
O
+
CHR1
26-43%
7 examples
CHR1
N
O
N
O
CH3
CH3
19
17
18
a
Lewis-base catalyzed tandem acyl transfer cyclization of o-
(b) Coppola, 198925
alkynoylaniline 12, followed by intramolecular lactamization (see (c),
Fig. 2.).22 The resulting NH-quinolactacide 13 was converted to 3 by N-
methylation (7 steps, 26% yield overall). Analogs of 3 have been also
made through a six-step sequence involving assembly of quinolinones 14,
generated in ~10% yield13 from substituted anilines, and subsequent
alkylation/cyclization to afford mixtures of N- and O-alkylated products
15 and 16 in 35% yield (see (d), Fig. 2.).13
O
O
9
LDA, THF
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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O
R1
R1
+
+
-50 °C, 6 h
40-49%
2 examples
N
N
R2
20
O
CH3
22
21a
(c) Reed, 194426
O
O
CO2H
240 °C, 2h
60%
Lee, 200421
(a)
NHCH3
N
O
O
O
O
1. DBU, CH2Cl2, 3Å m.s., 20 h
2. TFA, Et2O, H2O, 2 h
CH3
24a
O
OEt
+
23
21b
NH
(S)
NHBoc
N
O
O
N
(d) Deng, 201827
3
4 steps, 30% overall
C3 isomers: 8:1
O
H
CH3
H3C
Et
H3C
H3C
Et
Ru(bpy)3Cl2·6H2O,KOH, O2,
CH3CN, H2O, rt, blue LED
n
9a
10
1
N
Lin, 201012
N
(b)
n
CH3
CH3
24a-b
O
O
O
25a
25b
24a
24b
CO2H
HN
, n = 2
, n = 1
, n = 2, 65%
, n = 1, 43%
K2CO3, CH3I, rt, 12, (CH3)2CO
no yield reported
N
N
H
N
CH3
Figure 3. Select routes to cycloalkane/one-fused N-alkyl-4-quinolinones
11
3
Doi, 201722
(c)
O
O
O
7 steps
26% overall
K2CO3, CH3I
rt, 14 h
Boc
N
N
As such, we sought a high yielding strategy that offered expedient and
comprehensive access to divergently functionalized, ring-fused, N-
substituted 4-quinolinone templates. Moreover, the process needed to be
highly adaptable for use with enolizable substrates ranging broadly in
acidity, and it was desirable to utilize readily available, shelf stable
reagents and mild conditions. Based on the literature review, we
anticipated this could be accomplished with cyclic anhydrides and various
cyclic, enolizable partners if suitable conditions could be identified and
factors governing product formation could be understood and optimized
(Fig. 4). Further, a successful implementation of this strategy would
provide access to penicinotam 3 and its derivatives via the shortest route
reported to date.
(CH3)2CO
NBoc
N
H
CO2Et
12
Shao, 201813
O
13
(d)
O
OR2
O
O
K2CO3,
R2Br
CO2Et
R1
R1
+
R1
N
N
50°C,
N
H
N
R2
N
CH3CN
HN
35%
14
15
16
15
16
mix)
(
and
Figure 2. Select syntheses of lactam-fused, N-alkyl-4-quinolinones
pKa range: 3.3 to > 20.7
O
O
O
Assessment of methods leading to N-substituted 4-quinolinones fused
to cyclic ketones or carbocycles revealed a few approaches which were
all limited in scope. Nonetheless, a few examples are noteworthy (Fig.
3). The most extensive report curated seven N-methyl-4-quinolinones 19
in low yield when anhydrides 17 and 1,3-cyclohexanediones 18 were
combined in the presence of sodium hydride (see (a), Fig. 3).24 Fused
carbocyclic rings were also integrated onto the N-alkyl 4-quinolinone
core (see (b-d)). Coppola et al showed that acridines (i.e., fully
aromatized versions of 22) could be prepared by generating and then
oxidizing cyclohexene-fused-4-quinolinones 22.25 The study only
described isolation of two examples of 22 in modest yields when
cyclohexanone 21a, deprotonated with LDA, was treated with isatoic
anhydrides 20. Cycloalkane-fused quinolinones 24a-b have been
prepared by two protocols. With high thermal heating, anthranilic acid
23 was converted to cyclohexanone-fused 4-quinolinone 24a in 60%
yield (see (c)).26 More recently, LED/ruthenium catalysis converted
indoles 25a-b to 24a-b in 65% and 43% yield, respectively, though these
were the only two ring-fused examples in the report.27 Encouragingly,
this review showed that base-promoted annulations with isatoic
anhydrides generated ring-fused, N-alkyl-4-quinolinones; however,
exemplification and structural diversity were limited, overall yields were
generally modest, and in some cases, experimental procedures were
ambiguous. Taken together, the prospect of determining optimal
R1
R1
Y
or
base
O
X
O
N
R2
O
N
R2
O
0-1
R4
O
O
O
O
Y
N
R3
O
N
n
n = 0-2
Y = O,
= ring junction
NR, CR
Figure 4. Proposed general base-promoted annulation strategy to afford
new, structurally-diverse, ring-fused N-alkylquinolinones using tetramic
and tetronic acids, cyclic 1,3-diones, and cycloalkanones
RESULTS AND DISCUSSION
Given our interest in similar heterocycles,17 we initially focused on
generating the -lactam-fused, N-methyl 4-quinolinone core
representative of the quinolactacins. In our case, C3 substitution of the
lactam ring was unnecessary (c.f., C3-labeled 1, Fig. 2), thereby enabling
the use of a simplified, enolizable partner such as known28 N-Boc tetramic
acid 26a (Table 1). Employing DBU to promote the reaction between 26a
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and an anhydride was a logical starting point given its precedence in the
assembly of quinolactacin 1 from anhydride 9a and N-Boc ketoester 10
to form B (via path b), thus avoiding the intermediacy of acyliminium ion
A.
1
(see (a), Fig. 2).21 Unfortunately, experimental details for this reaction
were limited to what was depicted above the reaction arrow, so the best
estimation was made to replicate these conditions for our substrate 26a.
Under these and modified conditions involving heating (Table 1, entries
1-4), quinolinone 27a was maximally generated in 28% yield (entry 4),
although in most cases the anhydride was consumed. Control experiments
with 9a and DBU alone revealed that the anhydride was depleted readily
even in the absence of tetramic acid 26a, affording anthranilic acid after
workup. This result was consistent with Park’s report that the suboptimal
yield of 1 was due to substantial hydrolysis of 9a.21 Given these
limitations, we took note of the difference in the calculated23 pKa value of
N-Boc tetramic acid 26a (avg pKa = 3.20) at temperatures ranging from
25-85 °C compared to ketoester 10 (avg pKa = 9.46). As a result, we
employed triethylamine in place of DBU, the pKaH values of which differ
by at least one order of magnitude (e.g., at 50 °C, DBU-H+ pKaH = 10.49
2
3
4
5
6
7
8
9
Scheme 1. Proposed mechanism for the generation of lactam-fused 4-
quinolinone 27a with DBU via acyliminium ion formation (path a) or direct
ring opening by an enolate (path b).
O
O
N
T = rt - 85 °C
N
Boc +
N
+
Boc
N
N
H
N
O
DBU-H+
O
26a
26a'
DBU
pKaH = 11.30-9.55
pKa = 3.11-3.31
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
N
path a
Boc
N
O
N
O
O
DBU
N
O
N
26a
O
N
- CO2
- DBU
O
+
N
O
N
and HNEt3 pKaH = 9.48). Fortunately, the annulation proceeded with
CH3
9a
26a'
CH3
CH3
A
NEt3 in a variety of solvents, though the transformation was generally
sluggish until polar aprotic solvents and elevated temperatures were
employed, along with increased equivalency of tetramic acid 26a and
base relative to anhydride 9a. For example, at ambient temperature and
in CH2Cl2/NEt3, 27a was obtained in 50% yield, albeit with a prolonged
reaction time (Table 1, entry 5). Switching the solvent to acetonitrile
enabled heating to higher temperature and obviated the need for column
chromatography without reducing yield. A multiplexed assessment of
various bases, solvents, stoichiometry, reaction concentration, time and
temperature eventually revealed that using acetonitrile with four
equivalents of triethylamine at 85 °C resulted in an improved 75% yield
of 27a after 13 h (entry 9, Table 1). Shorter reaction times (entry 8) or
lower temperatures (entry 10) reduced product yield.
path b
O
O
N
O
O
26'
O
O
H+ xfr
Boc
N
Boc
N
Boc
N
O
- CO2
-H2O
N
N
OH
H3C
27a
H3C
CH3
B
C
Faced with NEt3-promoted conditions that worked well with 26a in
the reaction and DBU-promoted conditions that were inferior, we sought
to rationalize these results. With either DBU or NEt3, enolate 26a’
formation was expected; however, nucleophilic addition of enolate 26a’
might be less effective than a competing hydrolysis of acyliminium ion A
that might be in play exclusively when DBU was used. However, we also
noted that the lactam C3 methylene of 27a had a calculated pKa = 8.72 at
85 °C. In the presence of DBU (pKaH = 9.55, T = 85 °C), the N-Boc
products emerging from the transformation may be unstable, while these
same products might be less effected in NEt3. By 1H NMR we observed
that the C3 methylene of 27a was susceptible to deprotonation when DBU
was used, which appeared to contribute to the formation of unidentified
degradation products. However, under NEt3 conditions, the C3
methylene resonance remained undisturbed, unlike the signal broadening
and eventual loss of the resonance with DBU (see SI, Fig. S1).
Furthermore, when purified 27a was submitted to DBU-promoted
reaction conditions lacking anhydride (i.e., DBU (2 eq.), mol sieves,
CH3CN at 50 °C, 2 h), only 20% of product 27a was recovered. These
experiments showed that base choice was critical not only for
deprotonation of the enolizable partner but also for the stability of the
anhydride reagent and N-Boc 4-quinolinone product under the reaction
conditions. As such, the reaction generality was evaluated for anhydride
structural changes (Scheme 2).
Table 1. Selected annulation optimization results with 26aa
O
O
O
O
O
base, solvent
N
Boc
N
Boc
N
N
O
3 Å mol sieves
T °C, time
O
CH3
CH3
9a
26a
27a
yieldc
27a (%)
13
26a
base
T
°C
entry
time
solvent
equivb name equivb
1
2
0.8
0.9
1.5
0.5
3.0
3.0
1.0
2.5
2.5
2.5
DBU
DBU
DBU
DBU
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
0.8
0.8
1.6
2.0
4.0
2.2
4.0
4.0
4.0
4.0
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
rt
20 h
20 h
20 h
14 h
96 h
17 h
17 h
8 h
45
45
50
rt
< 25
10
3
4
28
5
50
6
85
85
85
85
50
34
For isatoic anhydrides featuring a range of aryl ring or N-substituents
at R2 (9a-p and 9q-r, respectively), the corresponding N-Boc
pyrrolidinone-fused, 4-quinolinones 27a-r were generally obtained in
good yield with a few exceptions. Anhydrides with electron withdrawing
substituents appended on the phenyl core generally resulted in better
yields and shorter reaction times than when anhydrides bearing electron
donating substituents were used, and these electronic effects were most
pronounced for substrates leading to a 6- or 8-substituted quinolinone.
The electronic contributions of substituents resulting in 5- or 7-substituted
quinolinones were more widely tolerated. For example, yields of 54% and
72% could be obtained with products 27f (R1 = 7-OCH3) and 27d (R1 =
7-CH3), respectively, while the comparably electron rich examples 27g
(R1 = 6-OCH3) and 27e (R1 = 6-CH3) could only be obtained in 18% and
45% yield, respectively. When an unprotected NH-tetramic acid (i.e.,
pyrrolidine-2,4-dione) was subjected to the reaction conditions with 9a,
only a tar-like substance was obtained that did not provide insight upon
NMR or LCMS analysis. However, deprotection of the N-Boc annulation
products proceeded smoothly with TFA to afford corresponding NH-
pyrrolidinone-fused, 4-quinolinones 28a-b, 28d-f, and 28h-r in yields of
63-96% (Scheme 2).
7
33
8
62
75d
9
13 h
10
28 h
68
b
aReactions done at 0.5 M concentration in sealed vials. Relative to 9a (1.0
equiv.). cIsolated yields; davg of three independent experiments.
We rationalized that these optimized conditions were more favorable
for 27a formation than when DBU was used for several reasons. Given
the disparity between the pKa of 26a and the pKaH of DBU, deprotonation
of 26a to form enolate 26a’ was anticipated to be strongly favored, and
the desired product could theoretically result from two related pathways
(Scheme 1, paths a or b). DBU is a well-documented acyl transfer agent.29
Accordingly, we expected that anhydride 9a might react with any excess
DBU to generate an acyliminium ion A (via path a) after ring opening and
decarboxylation. In fact, we observed a mass by LCMS consistent with
acyliminium ion formation. Nucleophilic attack on A by enolate 26a’
would liberate DBU and form diketoamide B which, upon ring closure
and dehydration through tricycle C, would afford the N-Boc protected
pyrrolidinone-fused, N-methyl-4-quinolinone 27a. Alternatively, once
26a’ is formed from an equivalent of DBU, it may react with 9a directly
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Scheme 2. Pyrrolidinone-fused, N-substituted 4-quinolinones from isatoic
anhydrides 9a-r via base promoted annulationa-b
(pKaH = 9.55 at 85 °C) would not degrade the product but would
effectively generate the enolate of 26b (26b, pKa = 6.76 at 85 °C). Further,
the N-Bn enolate of 26b would be a stronger nucleophile than the
corresponding enolate 26a’, and might more effectively compete with
potential hydrolysis of an activated acyliminium ion A generated with
DBU (c.f., Scheme 1).
1
2
3
4
5
6
7
8
O
O
O
O
O
R1
R1
R1
8
8
5
a
c
O
7
R3
N-Bn
6
7
N
N
R2
N
R2
O
N
R2
7
6
5
5
8
, R3 = Boc
9a-r
27a-r
28a-r
Table 2. Selected annulation optimization results with 26b
29a-r
b
3
, R = H
O
O
CH3
8
O
O
O
O
N
O
O
O
O
base, solvent
3 Å mol sieves
9
N
R
O
N
R
R
N
Bn
N
Bn
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
sealed vial
T °C, time
N
N
O
CH3
O
CH3
CH3
CH3
CH3
9a
c
27a
28a
29a
27b
28b
29b
, R = Boc, 75%
, R = Boc, 87%
, R = H, 82%, (71%)
, R = Bn, 65%
27c
28c
29c
, R = Boc, trace
, R = H, ND
, R = Bn, 83%
26b
b
29a
b,d
, R = H, 63%, (62%)
, R = Bn, 77%
yield b
29a%
tracec
31
26b
base
T
°C
entry
time
solvent
O
O
O
O
O
O
equiv.a name equiv.a
H3CO
H3C
7
7
N
R
N
R
1
2
3
4
5
2.5
2.5
1.2
2.5
0.5
NEt3
DBU
DBU
DBU
DBU
2.5
4.0
4.0
2.0
2.0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
85
85
85
85
50
13 h
13 h
13 h
13 h
2 h
N
R
N
N
H3C
b
6
N
CH3
CH3
CH3
39
27e
28e
29e
27f
28f
29f
, R = Boc, 45%
, R = H, 85%, (38%)
, R = Bn, 73%
, R = Boc, 54%
, R = H, 96%, (54%)
, R = Bn, 76%
27d
28d
29d
, R = Boc,72%
, R = H, 71%, (55%)
, R = Bn, 74%
b
b
47
77
O
O
O
O
O
O
b
c
Cl
aRelative to 9a (1.0 equiv). Isolated yields unless otherwise noted; LCMS
7
N
R
N
R
analysis.
N
R
N
N
5
H3CO
6
N
CH3O
CH3
CH3
CH3
Our first attempts to reinstate DBU in the reaction with 26b
afforded modest yields of 29a (Table 2, entries 2-4); however, we were
encouraged that 29a was generated in 47% with fewer equivalents of
base. Reaction monitoring by TLC showed that reactions using 26b
required much less time and milder heating to reach completion compared
to reactions using 26a. Ultimately, the reaction time and temperature
could be reduced to 2 h and 50 °C, respectively, and using a two-fold
excess of anhydride afforded 29a in 77% yield (entry 5). The optimized
DBU-promoted conditions were then applied to the generation of N-
benzylpyrrolidinone-fused, 4-quinolinones 29a-r using the same
substituted isatoic anhydrides used to make quinolinones 27a-r (Scheme
2). The structural modifications of the anhydrides 9a-r were well-
tolerated under the conditions, and generally provided good yields of
corresponding lactam-fused 4-quinolinones. Notably, in some cases the
outcomes were strikingly improved when 26b was used instead of 26a
under respective conditions derived for either base. For instance,
anhydrides 9c and 9g were unproductive under NEt3-promoted conditions
with 26a, affording only trace or low yields of 4-quinolinones 27c and
27g, respectively; however, these anhydrides led to the corresponding N-
Bn ring-fused 4-quinolinones 29c (83%) and 29g (70%) in good yields
with 26b. We attribute these results to differences in enolate reactivity
and variable susceptibility of the anhydride or acyliminium ion A (the
latter in the circumstance of DBU use only) to competing hydrolysis
under a given set of reaction conditions.
27i
28i
29i
, R = Boc, 88%
, R = H, 85%, (67%)
, R = Bn, 76%
27h
28h
29h
, R = Boc, 72%
, R = H, 85%, (66%)
, R = Bn, 82%
27g
28g
29g
, R = Boc, 18%
, R = H, ND
, R = Bn, 70%
b
b
O
O
O
O
O
O
Br
N
R
7
N
R
N
R
6
Cl
N
Br
N
6
N
CH3
CH3
CH3
27k
28k
29k
27l
28l
29l
, R = Boc, 58%
, R = H, 83%, (51%)
, R = Bn, 68%
, R = Boc, 68%
, R = H, 82%, (56%)
, R = Bn, 54%
27j
28j
29j
, R = Boc, 77%
, R = H, 82%, (67%)
, R = Bn, 69%
b
b
b
O
O
O
O
F
8
O
O
F
7
N
R
N
R
N
R
N
6
F
N
N
CH3
CH3
CH3
27o
28o
29o
, R = Boc, 64%
, R = H, 67%, (47%)
, R = Bn, 70%
27n
28n
29n
, R = Boc, 79%
, R = H, 85%, (68%)
, R = Bn, 83%
27m
28m
29m
, R = Boc, 43%
, R = H, 92%, (42%)
, R = Bn, 59%
b
b
b
O
O
O
O
O
O
N
R
N
R
N R
N
N
N
5
F
CH3
Ph
Bn
27p
28p
29p
, R = Boc, 65%
, R = H, 89%, (63%)
, R = Bn, 81%
27q
28q
29q
27r
28r
29r
, R = Boc, 58%
, R = H, 79%, (45%)
, R = Bn, 49%
, R = Boc, 43%
, R = H, 91%, (39%)
, R = Bn, 76%
b
b
b
aConditions: (a) tert-butyl 2,4-dioxopyrrolidine-1-carboxylate 26a, NEt3,
CH3CN (0.5 M), 3Å mol sieves, 85 °C, sealed vial, 13 h; (b) TFA, CH2Cl2, 0
°C - rt, 30 min; (c) 1-benzylpyrrolidine-2,4-dione 26b, DBU, CH3CN (0.5 M),
3Å mol sieves, 50 °C, sealed vial, 2 h; bParenthetical value is overall yield over
two steps from 9; ND = not determined due to insufficient amount of 27 to
deprotect; c2.5 mmol scale, 56% yield of 27a. d2.8 mmol scale, 40% yield of
28a over two steps.
Seeking to expand the protocol to include other enolizable partners and
armed with the insights gained from reactions with 26a-b, the DBU
conditions were applied to several other dicarbonyl substrates with
calculated pKa values ranging from 6.33 to 7.96 (Table 3). Tetramic acids
featuring an N-phenyl, N-cyclohexyl, or a bicyclic variant30 (26c-e,
respectively) performed well under these conditions, affording the
corresponding ring-fused, 4-quinolinones 30-35 in reasonable yields.
Only 10% of -lactone-fused 33 was obtained when tetronic acid 26f was
used; however, the yield improved to 47% when using NEt3 conditions
optimized with 26a were employed (entry 4). Interestingly, in
NEt3/CH3CN, the lactone product precipitated during the reaction and
was collected by filtration, but this was not observed under DBU/CH3CN
conditions. When purified lactone 33 was resubmitted to DBU/CH3CN
conditions lacking anhydride, only 34% was recovered, indicating that
stability of 33 was compromised under these conditions, contributing to
the lower yield. Indanone 26g smoothly underwent the annulation in 67%
yield under DBU conditions (entry 5) to afford the indanone-fused, 4-
quinolinone core of a known antiviral series based on compound 5.14
Parallel experiments with isatoic anhydride 9a were carried out
using 1-benzylpyrrolidine-2,4-dione (i.e., N-benzyl tetramic acid 26b) in
place of N-Boc tetramic acid 26a. At 85 °C, a calculated23 pKa value of
6.76 was determined for 26b while the pKaH of NEt3 was 8.65 at the same
temperature. Given that the equilibrium constant is less than 2 orders of
magnitude ((Keq = 10ΔpKa = 101.9 = 79), it is likely that NEt3 would
inefficiently deprotonate 26b and potentially lead to poor product
turnover. In fact, when 26b was used with the NEt3 conditions, only a
trace amount of the corresponding N-benzylpyrrolidinone-fused, 4-
quinolinone 29a was observed by LCMS (entry 1, Table 2). A stronger
base was required, and in this case, the C3 methylene of N-Bn product
29a had a pKa value of 11.06 at 85 °C. As such, we expected that DBU
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Also, 1,3-cyclohexanedione was employed in the reaction, generating
dione 35 in 57% yield.
products bearing a broad spectrum of regional structural variations.
Notable examples included using a number of N-substituted anhydrides
which uneventfully underwent annulation to generate acridinones 24d-f.
1
2
3
4
5
6
7
8
Table 4. Selected 4-methylcyclohexanone annulation optimization
Table 3. Results of changing enolizable partner in DBU-promoted
annulation
O
O
O
O
LiHMDS,
O
CH3
O
O
O
toluene (0.5 M)
DBU, CH3CN
X
O
see
table 3
+
N
3 Å mol sieves
N
O
3Å mol sieves
50°C, 2h
N
O
CH3
CH3
CH3
N
O
CH3
9a
24c
26c-h
H3C 30-35
9a
21c
9
entry
21c equiv.a LiHMDS equiv. T °C
time
4h
yield b 24c %
51%
product yield b
reactant
ID
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry reactant
pKaa
4-quinolinone
ID
%
1
2
3
4
1.3
1.3
2.5
2.1
1.4
1.4
2.7
2.3
0-rt
0-110
0-rt
O
O
4h
56%
O
N
2h
75%
N
1
26c
26d
6.90
30
71
N
0-80
2h
84%
CH3
O
O
aRelative to anhydride 9a (1.0 equiv.). bIsolated yields; rt = room temperature
O
O
N
N
__________________________________________________________
2
6.33
6.54
31
32
75
60
N
CH3
Scheme 3. Cycloalkane/ene- and heterocycle-fused 4-quinolinones
resulting from monoketone annulation
O
O
O
O
N
N
3
26e
26f
N
O
O
CH3
O
O
O
10
O
4
6.79
7.00
7.96
33
34
35
(47)b
N
O
CH3
O
O
O
5
26g
26h
67
57
N
O
CH3
O
O
O
6
N
O
CH3
aCalculated value23 refers to enolizable proton between the two carbonyls of
26c-h at 50 °C; Using conditions optimized for 26a: NEt3 (4.0 equiv.), 26f
(2.5 equiv.), CH3CN (0.5 M), 3Å mol sieves, 85 °C, 13 h.
b
We then turned our attention to monoketones as substrates to generate
N-alkyl 4-quinolinones with fused rings lacking a carbonyl. We
recognized that NEt3 and DBU would be inadequate to deprotonate the
cycloalkanones. Historically, LDA25 or TMEDA/n-BuLi14 has been
employed (Fig. 3) with mixed results to build compounds of this type.
Seeking
a less air-sensitive, readily available base capable of
deprotonating these substrates, commercially available LiHMDS was
evaluated.31 Compared to LDA, LiHMDS32 is more sterically hindered,
rendering it less basic, a weaker nucleophile, and a milder choice for the
annulation. These were important considerations based on (a) promoting
sufficient ketone deprotonation, (b) preventing anhydride degradation,
and (c) avoiding deprotonation and degradation of annulated products.
Switching the solvent to toluene, and using 4-methylcyclohexanone as a
case study, we assessed temperatures ranging from 0 °C to 110 °C while
also modifying the stoichiometry of the base and ketone relative to the
anhydride (Table 4). By calculation,23 the pKa of the most acidic proton
of 24c at 80 °C was ~ 25 which is roughly equal to the pKaH of LiHMDS.33
As such, the deprotonation of product with this base would not be
expected to be favored. Experimentally, anhydride, ketone, activated
sieves and solvent were combined, cooled to 0 °C (LiHMDS calc’d pKaH
= 22), and then LiHMDS was added before heating the reaction mixture.
Ultimately, using the anhydride as the limiting reagent and heating at 80
°C for only 2 hours afforded N-methyl 4-quinolinone 24c in 84% (entry
4).
The optimized conditions from the test reactions with 4-
methylcyclohexanone 21c were then applied to a set of twelve anhydrides
and eleven ketones, resulting in 25 ring-fused, N-substituted 4-
quinolinones 24a-y (Scheme 3). Generally, good to excellent yields were
obtained, reaching up to 94%, and affording an array of quinolinone
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Page 6 of 17
O
X
O
O
Z
flash vacuum pyrolysis and the compound is known to readily decompose
5
8
8
Y
under basic conditions.34 Alternatively, we considered the use of
ketolactam 26e which we had already shown to be productive to afford 4-
quinolinone 32 under DBU conditions (entry 3, Table 3, 60%).
Therefore, we set out to identify oxidative conditions to oxidize the fused
pyrrolidine ring of 32.
LiHMDS
7
6
6
7
O
1
2
3
4
X
R1
R1
+
toluene, 2h
0°C-80°C
Z
N
R2
O
N
R2
24a-aa
5
Y
21a-k
9a, 9f, 9i, 9m-p, 9r-v
anhydrides
products
5
6
O
O
O
O
CH3
R
CH3
Scheme 4. Retrosynthetic analysis of penicinotam 3
7
8
9
N
R
N
N
R
O
CH3
O
O
O
O
24c
24d
24e
, R=CH3, 84%
, R=Bn, 73%
, R=p-CH3O-Bn, 74%
, R=p-CF3-Bn, 70%
24g
24h
24i
24j
, R=OCH3, 90%
, R=Cl, 65%
, R=CN, 72%
, R=F, 72%
9a
9r
9s
, R = CH3
, R = Bn
, R = p-CH3OBn
, R = p-CF3-Bn
O
N
N
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
x
O
N
N
O
9t
24f
CH3
CH3
9a
26i
O
5
O
F
O
3
penicinotam
unstable to base
6
CH3
CH3
challenge to make
O
R1
7
N
O
F
N
N
8
CH3
O
N
CH3
O
N
CH3
O
O
, R1 = C6-OCH3
, R1 = C6-Cl
, R1 = C5-F
, R1 = C6-F
, R1 = C7-F
, R1 = C8-F
, R1 = C6-CN
9f
9i
24l
, 56%
24k
, 63%
O
N
O
N
O
+
9m
O
R
O
CH3
9n
9o
9p
9u
9v
CH3
CH3
32
9a
26e
N
N
CH3 CH3
F
CH3
Commercially available ketolactam 26e was costly, so it was prepared
by a one-step, Dieckmann-like cyclization30 from racemic N-acetyl
proline methyl ester 37 in 83% yield (Scheme 5). As previously noted,
the annulation reaction between 9a and 26e proceeded in 60% yield to
give tetracycle 32. On a 2.5 mmol scale, this key step afforded 48% of 32.
Oxidation of a similar pyrrolidine ring-fused NH-4-quinolinone system
had been reported to afford related alkaloid, quinolactacide 13; however,
in that case, portion-wise addition of MnO2 over 24 h in refluxing
chloroform/DMF gave quinolactacide in only 21% yield.30 With our
substrate 32, MnO2 afforded complex mixtures. DDQ was investigated
with slightly improved results, often affording mixtures of desired and
ring-cleaved products.
24n
24o
, R = H, 78%
, R = OCH3, 80%
24m
, 69%
, R1 = C6,C7-di-OCH3
O
O
N
ketones
H3CO
H3CO
CH3
N
O
O
CH3
CH3
24q
24p
, 65%
, 32%
O
X
CH3
21b
21c
21d
, X = CH2
, X = CHCH3
, X = CHPh
21a
O
(R)
O
N
N
O
CH3
CH3 CH3
, 86%
N
24r
, 70%
O
24s
Boc
O
Scheme 5. Total synthesis of penicinotam 3
21f
21e
R
O
N
O
O
n
O
O
O
9a
, DBU
CH3CN
O
CH3
t-BuOK,
THF
N
24a
24b
24t
24u
24v
, R = H, n=1, 45%
, R = H, n=2, 74%
, R = H, n=3, 39%
, R = F, n=3, 94%
, R = OCH3, n=3, 70%
N
N
CO2CH3
N
3Å M.S
50°C, 2h,
60%
reflux,
n
CH3
N
COCH3
18h, 83%
21i
O
CH3
21g
21h
, n = 1
, n = 3
24w
, 90%
37
26e
32
O
O
chloranil
toluene
O
O
O
O
Boc
N
CH3
CH3
N
penicinotam
3 steps, 36% overall
125°C,
16h
72%
N
(R)
N
N
3
CH3
CH3
CH3
CH3
21j
21k
,
78%b
24x
24y
, 80%
aIsolated yields. b2.8 mmol scale, 64% yield.
Finally, using chloranil in refluxing toluene for 16 h gave the best results,
delivering penicinotam 3 in 72% yield. Satisfyingly, 3 was generated
from proline ester 37 in 3 steps and in 36% overall yield (2 steps, 43%
from commercial 26e). This compares favorably to the reported
synthesis of 3 by an alternative sequence in 26% yield over 7 steps (see
(c), Fig. 2).22 To our knowledge, our approach is the shortest and highest
yielding synthesis of penicinotam reported to date and is amenable to
quickly generating analogs by bidirectional diversification of the
anhydride component.
Many C5-C8 core phenyl ring substitutions were also evaluated. An
electron-donating methoxy group at the C6 position of the anhydride
afforded product 24g in 90% yield, whereas an electron withdrawing
nitrile group (24i) or halogen (24h, 24j) gave more moderate yields (65-
72%). The ketone partner in the reaction was also modified with success.
For instance, reactions with 4-pyranone (21f) and unsaturated cyclic
ketones (21a, 21i, 21k) proceeded smoothly, giving desired ring-fused
quinolinones 24q-s, including one derived from (R)-carvone to produce a
uniquely elaborated, chiral 4-quinolinone. The reactions with
cycloheptanone and cyclopentanone were more variable, a feature
attributed to tedious purification in some cases, though the reactions
appeared insensitive to ring size of the paired ketone or substitution of the
parent anhydride (see 24a-b, 24t-v). Use of 1-Boc-4-piperidone 21e with
9a afforded 4-quinolinone 24x in 78% yield, thus enabling deprotection
and further diversification at the revealed amine.
CONCLUSION
Ring-fused
N-substituted
4-quinolinones
comprise
an
underrepresented privileged structural class. While sporadic examples
populate the literature, these reports often suffer from any combination of
limited scope, harsh conditions, mediocre yields, or vague experimental
detail, thus complicating method selection and application to the
synthesis of novel and more diverse analogs. To expand and screen a
compound collection based on this motif, it was necessary to develop a
platform strategy utilizing a base-promoted condensation between isatoic
anhydrides and a wide variety of enolizable partners with a spectrum of
With a robust method in hand that delivered structurally-diverse, ring-
fused N-substituted 4-quinolinones, we turned attention to applying this
strategy to the synthesis of penicinotam 3 (Scheme 4). Ideally, annulation
of pyrrolizine-1,3-dione 26i with anhydride 9a would directly provide the
target using our protocols in one step; however, generation of 26i requires
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deprotonation susceptibility. This work resulted in the efficient assembly
for this work were synthesized by modified literature procedures
described below. Characterization matched available literature reports.
of more than 80 ring-fused, N-substituted 4-quinolinones (94% of these
are new to the literature), led to the shortest and highest yielding total
synthesis of a bioactive 4-quinolinone, penicinotam 3, and importantly,
determined several factors influencing the success of these annulations.
An obvious aspect of base selection is the requirement of sufficient base
strength to favorably deprotonate the enolizable reactant, but it was also
found that stability of the isatoic anhydride and the resulting 4-
quinolinone products in the presence of the chosen base also significantly
impacted the overall yield. For instance, we concluded that when DBU
was used, it is likely that an acyliminium ion is formed, resulting from
nucleophilic addition of DBU to the anhydride. As such, the fate of the
annulation is dependent on the pairing of this putative highly reactive
intermediate with a strongly nucleophilic enolate, thus favoring the
desired annulation, or pairing with a weakly nucleophilic enolate in which
the competing hydrolysis to the anthranilic acid predominates. In the
latter situation, mild conditions were also developed to address this issue,
thereby avoiding the formation of the acyliminium ion and resulting in a
novel series of lactam-fused 4-quinolinones in good yield. Finally, this
strategy provides a reliable roadmap to the appropriate reaction condition
selection which can be tuned based on the pKa of the reactant and the
product. Due to the broad accessibility of substituted anhydrides and the
establishment of this method to couple them to a range of enolizable
partners, the approach is efficient, divergent, and enables multiregional
scaffold diversification. The 4-quinolinones resulting from this work have
been compiled into our screening collection and are undergoing
assessment across an array of bioassays. Results of that effort will be
reported at a future date.
1
2
3
4
5
6
7
8
General Procedure A. Synthesis of tert-Butyl 4-substituted-1,9-dioxo-
1,3,4,9-tetrahydro-2H-pyrrolo[3,4-b]quinolone-2-carboxylates (27a-r).
To an oven dry screw cap vial with heat-activated, inert-atmosphere-
cooled 3Å molecular sieves (3 beads, 4-8 mesh) was added the
corresponding isatoic anhydride 9 (0.25 mmol, 1.0 equiv.) and N-Boc
tetramic acid 26a (0.63 mmol, 2.5 equiv.). The vial was evacuated and
backfilled with N2 before adding dry CH3CN (0.5 mL) followed by Et3N
(0.15 mL, 1.08 mmol, 4.3 equiv.). The reaction tube was transferred to a
preheated sand bath at 85°C and stirred 8-18 h (monitored by TLC for
consumption of the anhydride). A gentle reflux was observed in the
screw-capped vial which were tall enough to permit air-cooled
condensation at roughly the half-way point in the vial. Upon completion
of the reaction, or at the conclusion 18 h, the reaction was cooled to rt and
then poured into ice water (7 mL) and stirred 30 min. Unless otherwise
indicated, the precipitate was then collected by filtration to give the
desired product 27.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
tert-Butyl
4-methyl-1,9-dioxo-1,3,4,9-tetrahydro-2H-pyrrolo[3,4-
b]quinoline-2-carboxylate (27a). 9a (44.3 mg, 0.25 mmol) was subjected
to procedure A to give 27a (74.3 mg, 95% yield) as an amorphous off-
white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (dd, J = 8.0, 1.5 Hz,
1H), 7.92 – 7.80 (m, 2H), 7.52 (ddd, J = 8.0, 6.6, 1.4 Hz, 1H), 4.88 (s,
2H), 3.75 (s, 3H), 1.52 (s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6) δ
171.5, 163.0, 160.7, 149.4, 140.7, 133.0, 127.8, 126.1, 124.9, 116.9,
108.1, 81.7, 46.6, 34.9, 27.8. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd
for C17H19N2O4+ 315.1339; Found: 315.1327.
tert-Butyl
4-methyl-1,11-dioxo-1,3,4,11-tetrahydro-2H-
benzo[g]pyrrolo[3,4-b]quinoline-2-carboxylate (27b). 9b (56.4 mg, 0.25
mmol) was subjected to procedure A to give 27b (78.7 mg, 87% yield) as
an off-white amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s,
1H), 8.40 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.70
(t, J = 7.1 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 4.91 (s, 2H), 3.84 (s, 3H),
1.53 (s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 172.3, 163.0, 162.1,
149.4, 137.6, 134.7, 129.3, 129.2, 128.8, 127.7, 127.1, 126.4, 114.3,
106.1, 81.7, 46.8, 35.1, 27.9. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd
for C21H21N2O4+ 365.1496; Found: 365.1496.
EXPERIMENTAL SECTION
General Information. Commercial reagents and solvents were used as
received. All thin layer chromatography was performed using precoated
silica gel 60 F254 plates (EMD Millipore). Flash chromatography
separations were carried out using a Teledyne Isco CombiFlash Rf 200
purification system (MPLC) with silica gel columns. Purity of all final
compounds was confirmed by HPLC/MS analysis and determined to be
≥ 95% AUC at 254nm. Melting points were measured on OptiMelt
MPA100 Automated Melting Point System. 1H, 19F, and 13C nuclear
magnetic resonance (NMR) spectra were recorded on a Varian Unity-
Inova 400 MHz NMR Spectrometer (operating at 400, 376, and 101 MHz,
respectively) or a Varian Unity-Inova 500 MHz NMR Spectrometer
(operating at 500, 470, and 126 MHz, respectively) or Bruker Ascend 400
MHz Spectrometer (operating at 400, 376, and 101 MHz, respectively) in
CDCl3 or DMSO-d6. The chemical shifts (δ) reported are given in parts
per million (ppm). The Signal splitting patterns were described as s =
singlet, d = doublet, t = triplet, q = quartet, p = pentuplet, dd = doublet of
doublet, dt = doublet of triplet, td = triplet of doublet, tt = triplet of triplet,
ddd = doublet of doublet of doublet, br = broad and m = multiplet, with
coupling constants (J) in hertz (Hz). The LC-MS analysis was performed
on an Agilent 1290 Infinity II HPLC system with 1290 Infinity II Diode
Array Detector and an Agilent 6120 Quadrupole LC-MS system. The
analytical chromatography method utilized the following parameters:
Poroshell 120 EC-C18, 1.9 μm column, UV detection wavelength = 254
nm, Flow rate = 1.0 mL/min, Gradient = 5-100% LC-MS grade Methanol
over 4 min; The organic mobile phase and aqueous mobile phase
contained 0.1% LC-MS grade formic acid. The mass spectrometer
utilized the following parameters: an Agilent multimode source that
simultaneously acquires ESI+/APCI+. High resolution mass spectra
(HRMS) were performed by the Analytical Instrument Center at the
School of Pharmacy on a Bruker MaXis 4G mass spectrometer. Chemical
nomenclature was generated using ChemBioDraw Ultra version 14.0.
Calculated pKa values were obtained using MarvinSketch version 18.25,
ChemAxon: Budapest, Hungary, 2018.
tert-Butyl
4,7-dimethyl-1,9-dioxo-1,3,4,9-tetrahydro-2H-pyrrolo[3,4-
b]quinoline-2-carboxylate (27d). 9d (47.5 mg, 0.25 mmol) was subjected
to procedure A to give 27d (62.4 mg, 77% yield) as an off-white
amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 2.0 Hz,
1H), 7.77 (d, J = 8.7 Hz, 1H), 7.66 (dd, J = 8.7, 2.1 Hz, 1H), 4.85 (s, 2H),
3.73 (s, 3H), 2.45 (s, 3H), 1.52 (s, 9H).13C{1H} NMR (101 MHz, DMSO-
d6) δ 171.4, 163.1, 160.1, 149.4, 138.7, 134.4, 134.1, 127.7, 125.6, 116.9,
107.8, 81.7, 46.5, 34.9, 27.8, 20.4. HRMS (ESI-QTOF) m/z: [M + H]+
Calcd for C18H21N2O4+ 329.1496; Found: 329.1491.
tert-Butyl
4,6-dimethyl-1,9-dioxo-1,3,4,9-tetrahydro-2H-pyrrolo[3,4-
b]quinoline-2-carboxylate (27e). 9e (47.0 mg, 0.25 mmol) was subjected
to procedure A to give 27e (35.6 mg, 44% yield) as an off-white
amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 8.1 Hz,
1H), 7.69 (s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 4.86 (s, 2H), 3.73 (s, 3H), 2.51
(s, 3H), 1.52 (s, 9H).13C{1H} NMR (101 MHz, DMSO-d6) δ 171.4, 163.0,
160.5, 149.4, 143.6, 140.8, 126.2, 126.0, 125.7, 116.7, 107.9, 81.7, 46.6,
34.8, 27.8, 21.5. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C18H21N2O4+ 329.1496; Found: 329.1479.
tert-Butyl
7-methoxy-4-methyl-1,9-dioxo-1,3,4,9-tetrahydro-2H-
pyrrolo[3,4-b]quinoline-2-carboxylate (27f). 9f (42.7 mg, 0.21 mmol)
was subjected to procedure A to give 27f (39.5 mg, 56% yield) as an off-
white amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 9.3
Hz, 1H), 7.68 (d, J = 3.1 Hz, 1H), 7.44 (dd, J = 9.2, 3.1 Hz, 1H), 4.86 (s,
2H), 3.88 (s, 3H), 3.74 (s, 3H), 1.52 (s, 9H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 170.9, 163.1, 159.2, 156.6, 149.5, 135.0, 129.1, 121.9,
118.7, 107.2, 106.6, 81.7, 55.6, 46.4, 35.0, 27.8. HRMS (ESI-QTOF) m/z:
[M + H]+ Calcd for C18H21N2O5+ 345.1445; Found: 345.1430.
Starting materials 9a, 21a-d, 21f-k, 26c, and 26f-h were purchased and
used as received. Known compounds (26a,28 26b,17 26d,17 26e,30 and
21e35) were synthesized according to literature procedures;
characterization matched previous reports. With the exception of 9u,
various syntheses of anhydrides 9b-v have been reported. Materials used
tert-Butyl
6-methoxy-4-methyl-1,9-dioxo-1,3,4,9-tetrahydro-2H-
pyrrolo[3,4-b]quinoline-2-carboxylate (27g). 9g (49.3 mg, 0.24 mmol)
was subjected to procedure A to give 27g (14.6 mg, 18% yield) as an off-
white amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 8.8
Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 7.11 (dd, J = 8.8, 2.2 Hz, 1H), 4.85 (s,
2H), 3.96 (s, 3H), 3.72 (s, 3H), 1.53 (s, 9H). 13C{1H} NMR (101 MHz,
7
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The Journal of Organic Chemistry
Page 8 of 17
DMSO-d6) δ 163.0, 160.8, 149.4, 142.6, 140.5, 127.9, 121.7, 121.2,
tert-Butyl
6-fluoro-4-methyl-1,9-dioxo-1,3,4,9-tetrahydro-2H-
113.2, 108.0, 100.0, 81.6, 56.0, 46.6, 35.0, 27.8. HRMS (ESI-QTOF) m/z:
pyrrolo[3,4-b]quinoline-2-carboxylate (27o). 9o (42.1 mg, 0.22 mmol)
was subjected to procedure A to give 27o (41.9 mg, 58% yield) as an
amorphous off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (ddd,
J = 9.0, 6.7, 2.5 Hz, 1H), 7.77 (dd, J = 11.4, 2.4 Hz, 1H), 7.37 (td, J = 8.6,
7.3, 4.1 Hz, 1H), 4.86 (s, 2H), 3.72 (s, 3H), 1.51 (s, 9H). 13C{1H} NMR
(101 MHz, DMSO-d6) δ 170.7, 164.70 (d, J = 249.3 Hz), 162.8, 161.4,
149.3, 142.5 (d, J = 11.9 Hz), 129.2 (d, J = 11.0 Hz), 124.7, 113.0 (d, J =
23.1 Hz), 108.4, 103.8 (d, J = 27.2 Hz), 81.8, 46.6, 35.2, 27.8. 19F{1H}
NMR (376 MHz, DMSO-d6) δ -104.88. HRMS (ESI-QTOF) m/z: [M +
H]+ Calcd for C17H18FN2O4+ 333.1245; Found: 333.1244.
1
2
3
4
5
6
7
8
[M + H]+ Calcd for C18H21N2O5+ 345.1445; Found: 345.1445.
tert-Butyl
5-methoxy-4-methyl-1,9-dioxo-1,3,4,9-tetrahydro-2H-
pyrrolo[3,4-b]quinoline-2-carboxylate (27h). 9h (51.0 mg, 0.25 mmol)
was subjected to procedure A to give 27h (66.4 mg, 78% yield) as an off-
white amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ 7.86 (dd, J =
7.4, 2.0 Hz, 1H), 7.47 – 7.40 (m, 2H), 4.84 (s, 2H), 3.95 (s, 3H), 3.94 (s,
3H), 1.52 (s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 170.9, 162.8,
161.7, 150.8, 149.4, 131.5, 130.4, 125.5, 118.0, 116.3, 108.0, 81.7, 56.1,
47.0, 27.8. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C18H21N2O5
+
9
345.1445; Found: 345.1449.
tert-Butyl
5-fluoro-4-methyl-1,9-dioxo-1,3,4,9-tetrahydro-2H-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
pyrrolo[3,4-b]quinoline-2-carboxylate (27p). 9p (43.8 mg, 0.22 mmol)
was subjected to procedure A to give 27p (43.1 mg, 58% yield) as an
amorphous off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.10 (dd, J
= 8.1, 1.5 Hz, 1H), 7.71 (ddd, J = 15.0, 7.9, 1.6 Hz, 1H), 7.48 (td, J = 8.0,
4.1 Hz, 1H), 4.87 (s, 2H), 3.89 (d, J = 7.5 Hz, 3H), 1.52 (s, 9H). 13C{1H}
NMR (101 MHz, DMSO-d6) δ 189.4, 170.2 (d, J = 2.5 Hz), 162.6, 161.9,
152.3 (d, J = 248.8 Hz), 149.2, 130.7, 129.9, 125.5 (d, J = 8.4 Hz), 122.2
(d, J = 3.3 Hz), 120.5 (d, J = 23.5 Hz), 108.3, 81.9, 46.9, 27.8. 19F{1H}
NMR (376 MHz, DMSO-d6) δ -119.85. HRMS (ESI-QTOF) m/z: [M +
H]+ Calcd for C17H18FN2O4+ 333.1245; Found: 333.1247.
tert-Butyl
7-chloro-4-methyl-1,9-dioxo-1,3,4,9-tetrahydro-2H-
pyrrolo[3,4-b]quinoline-2-carboxylate (27i). 9i (53.0 mg, 0.25 mmol)
was subjected to procedure A to give 27i (68.7 mg, 79% yield) as an off-
white amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 2.5
Hz, 1H), 8.01 – 7.81 (m, 2H), 4.88 (s, 2H), 3.76 (s, 3H), 1.52 (s, 9H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 170.2, 162.7, 161.0, 149.3, 139.4,
132.8, 129.9, 129.0, 125.0, 119.6, 108.4, 81.8, 46.7, 35.2, 27.8. HRMS
(ESI-QTOF) m/z: [M + H]+ Calcd for C17H18ClN2O4+ 349.0950; Found:
349.0950.
tert-Butyl
6-chloro-4-methyl-1,9-dioxo-1,3,4,9-tetrahydro-2H-
tert-Butyl
1,9-dioxo-4-phenyl-1,3,4,9-tetrahydro-2H-pyrrolo[3,4-
pyrrolo[3,4-b]quinoline-2-carboxylate (27j). 9j (39.2 mg, 0.19 mmol)
was subjected to procedure A to give 27j (53.0 mg, 82% yield) as an off-
white amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ 8.23 (dd, J =
8.6, 2.4 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 8.3Hz, 1H), 4.86
(s, 2H), 3.74 (s, 3H), 1.52 (s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6)
δ 170.8, 162.7, 161.3, 149.3, 141.6, 138.0, 128.0, 126.5, 125.1, 116.9,
108.6, 81.8, 46.7, 35.2, 27.8. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd
for C17H18ClN2O4+ 349.0950; Found: 349.0934.
b]quinoline-2-carboxylate (27q). 9q (57.0 mg, 0.24 mmol) was subjected
to procedure A to give 27q (42.9 mg, 48% yield) as an amorphous off-
white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 7.1 Hz, 1H),
7.79 – 7.61 (m, 6H), 7.52 (d, J = 8.9 Hz, 1H), 6.85 (d, J = 7.2 Hz, 1H),
4.28 (s, 2H), 1.43 (s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 171.7,
162.7, 160.5, 149.4, 141.6, 135.8, 133.1, 130.8, 130.7, 128.3, 127.4,
126.0, 125.0, 117.6, 108.4, 81.8, 46.5, 27.7. HRMS (ESI-QTOF) m/z: [M
+ H]+ Calcd for C22H21N2O4+ 377.1496; Found: 377.1482.
tert-Butyl
7-bromo-4-methyl-1,9-dioxo-1,3,4,9-tetrahydro-2H-
tert-Butyl
4-benzyl-1,9-dioxo-1,3,4,9-tetrahydro-2H-pyrrolo[3,4-
pyrrolo[3,4-b]quinoline-2-carboxylate (27k). 9k (64.2 mg, 0.25 mmol)
was subjected to procedure A to give 27k (51.8 mg, 53% yield) as an
amorphous off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J =
2.5 Hz, 1H), 7.97 (dd, J = 9.0, 2.5 Hz, 1H), 7.85 (d, J = 9.1 Hz, 1H), 4.85
(s, 2H), 3.74 (s, 3H), 1.52 (s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6)
δ 170.1, 162.70, 161.0, 149.3, 139.8, 135.5, 129.3, 128.1, 119.8, 118.0,
108.5, 81.8, 46.7, 35.1, 27.8. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd
for C17H18BrN2O4+ 393.0445; Found: 393.0442.
b]quinoline-2-carboxylate (27r). 9r (61.6 mg, 0.24 mmol) was subjected
to procedure A to give 27r (40.7 mg, 43% yield) as an amorphous off-
white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.28 (dd, J = 8.0, 1.5 Hz,
1H), 7.70 – 7.66 (m, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.35 – 7.26 (m, 5H),
5.58 (s, 2H), 4.85 (s, 2H), 1.49 (s, 9H).13C{1H} NMR (101 MHz, DMSO-
d6) δ 171.6, 162.9, 160.8, 149.3, 139.9, 134.9, 133.0, 129.0, 128.2, 127.7,
126.2, 126.1, 124.9, 117.6, 108.7, 81.7, 50.3, 46.8, 27.8. HRMS (ESI-
+
QTOF) m/z: [M + H]+ Calcd for C23H23N2O4 391.1652; Found:
tert-Butyl
6-bromo-4-methyl-1,9-dioxo-1,3,4,9-tetrahydro-2H-
391.1633.
pyrrolo[3,4-b]quinoline-2-carboxylate (27l). 9l (61.9 mg, 0.24 mmol)
was subjected to procedure A to give 27l (64.2 mg, 68% yield) as an
amorphous off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.16 – 8.13
(m, 2H), 7.68 (dd, J = 8.5, 1.6 Hz, 1H), 4.87 (s, 2H), 3.75 (s, 3H), 1.52 (s,
9H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 170.9, 161.3, 149.3, 141.7,
128.1, 128.0, 127.0, 126.8, 119.8, 108.6, 81.8, 46.7, 35.2, 27.8. HRMS
(ESI-QTOF) m/z: [M + H]+ Calcd for C17H18BrN2O4+ 393.0445; Found:
393.0446.
4-Methylfuro[3,4-b]quinoline-1,9(3H,4H)-dione (33). 9a (42.0 mg, 0.237
mmol) was treated analogously as in procedure A but using tetronic acid
26f (77.2 mg, 0.77 mmol) to give 33 (25.6 mg, 50% yield) as an
amorphous white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 7.9
Hz, 1H), 7.88 (d, J = 3.9 Hz, 2H), 7.55 (dt, J = 8.1, 4.1 Hz, 1H), 5.39 (s,
2H), 3.72 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 171.5, 167.6,
166.4, 140.9, 133.3, 127.8, 126.1, 125.2, 117.0, 102.3, 65.1, 35.2. HRMS
+
(ESI-QTOF) m/z: [M + H]+ Calcd for C12H10NO3 216.0655; Found:
tert-Butyl
8-fluoro-9-hydroxy-4-methyl-1-oxo-1,4-dihydro-2H-
216.0657.
pyrrolo[3,4-b]quinoline-2-carboxylate (27m). 9m (47.8 mg, 0.25 mmol)
was subjected to procedure A to give 27m (37.2 mg, 46% yield) as an
amorphous off-white solid. This compound is observed exclusively as the
enol tautomer by 1H NMR (400 MHz, DMSO-d6) δ 14.40 (s, 1H), 7.70 (t,
J = 8.3 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 4.91
(s, 2H), 3.73 (s, 3H), 1.53 (s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6)
δ 178.2, 163.1, 162.5, 161.6, 149.7, 142.1, 135.6, 113.9, 111.8, 107.4,
106.4, 82.4, 47.3, 36.2, 28.3. 19F{1H} NMR (376 MHz, DMSO-d6) δ -
107.81, -112.37. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C17H18FN2O4+ 333.1245; Found: 333.1244.
General Procedure B. Synthesis of 4-substituted-2,3-Dihydro-1H-
pyrrolo[3,4-b]quinolone-1,9(4H)-diones (28a-r). To a screw cap vial was
added 27 (0.10 mmol, 1.0 equiv.) and CH2Cl2 (0.5 mL). The solution was
cooled to 0°C in an ice bath before adding trifluoroacetic acid (0.10 mL,
1.30 mmol, 13 equiv.). The reaction mixture was then shaken at r.t. (550
rpm) with a mini plate shaker for 30 min. The reaction mixture was
concentrated, triturated with H2O (1 mL) and sonicated 30 sec. The
resulting precipitate was collected by filtration to give the desired product
28.
tert-Butyl
7-fluoro-4-methyl-1,9-dioxo-1,3,4,9-tetrahydro-2H-
pyrrolo[3,4-b]quinoline-2-carboxylate (27n). 9n (51.2 mg, 0.26 mmol)
was subjected to procedure A to give 27n (67.7 mg, 78% yield) as an
amorphous off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (dd, J
= 9.4, 4.3 Hz, 1H), 7.90 (dd, J = 8.9, 3.1 Hz, 1H), 7.74 (dd, J = 8.0, 3.1
Hz, 1H), 4.86 (s, 2H), 3.76 (s, 3H), 1.52 (s, 9H).13C{1H} NMR (101 MHz,
DMSO-d6) δ 171.0, 163.3, 161.0, 159.7 (d, J = 244.9 Hz), 149.8, 137.8,
130.0 (d, J = 6.5 Hz), 121.5 (d, J = 24.3 Hz), 120.5 (d, J = 8.3 Hz), 111.1
(d, J = 22.9 Hz), 108.1, 82.3, 47.1, 35.8, 28.3. 19F{1H} NMR (376 MHz,
DMSO-d6) δ -116.57. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C17H18FN2O4+ 333.1245; Found: 333.1238.
4-Methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-dione (28a).
27a (31.9 mg, 0.10 mmol) was subjected to procedure B to give 28a (13.4
mg, 62% yield) as an amorphous off-white solid. 1H NMR (400 MHz,
DMSO-d6) δ 8.27 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.87 – 7.76 (m, 2H),
7.48 (t, J = 7.5 Hz, 1H), 4.49 (s, 2H), 3.72 (s, 3H). 13C{1H} NMR (101
MHz, DMSO-d6) δ 172.0, 169.4, 163.4, 141.2, 132.9, 128.5, 126.5, 124.6,
117.1, 109.9, 43.7, 35.0. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C12H11N2O2+ 215.0815; Found: 215.0814.
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The Journal of Organic Chemistry
4-Methyl-2,3-dihydro-1H-benzo[g]pyrrolo[3,4-b]quinoline-1,11(4H)-
13C{1H} NMR (101 MHz, DMSO-d6) δ 171.0, 168.6, 163.5, 141.8, 128.1,
127.2, 127.0, 126.4, 119.4, 110.0, 43.4, 34.8. HRMS (ESI-QTOF) m/z:
[M + H]+ Calcd for C12H10BrN2O2+ 292.9920; Found: 292.9914.
dione (28b). 27b (35.8 mg, 0.10 mmol) was subjected to procedure B to
give 28b (21.4 mg, 82% yield) as an amorphous off-white solid. 1H NMR
(400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.34 (s, 1H), 8.21 (d, J = 8.3 Hz,
1H), 8.11 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.57
(t, J = 7.5 Hz, 1H), 4.53 (s, 2H), 3.80 (s, 3H). Solubility precluded 13C
1
2
3
4
5
6
7
8
8-Fluoro-9-hydroxy-4-methyl-2,4-dihydro-1H-pyrrolo[3,4-b]quinoline-
1,9(4H)-dione (28m). 27m (26.7 mg, 0.08 mmol) was subjected to
procedure B to give 28m (17.0 mg, 92% yield) as an amorphous off-white
solid. This compound is observed exclusively as the enol tautomer by 1H
NMR (400 MHz, DMSO-d6) δ 14.78 (s, 1H), 8.09 (s, 1H), 7.65 (t, J = 8.3
Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 4.52 (s, 2H),
3.68 (s, 3H). Solubility precluded 13C NMR. 19F{1H} NMR (376 MHz,
DMSO-d6) δ -73.48, -112.64. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd
for C12H10FN2O2+ 233.0721; Found: 233.0720.
NMR. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C16H13N2O2
265.0972; Found: 265.0968.
+
4,7-Dimethyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-dione
(28d). 27d (36.9 mg, 0.10 mmol) was subjected to procedure B to give
28d (16.1 mg, 71% yield) as an amorphous off-white solid. 1H NMR (400
MHz, DMSO-d6) δ 8.05 (d, J = 1.6 Hz, 1H), 7.89 (s, 1H), 7.72 (d, J = 8.7
Hz, 1H), 7.62 (dd, J = 8.7, 2.2 Hz, 1H), 4.46 (s, 2H), 3.69 (s, 3H), 2.44 (s,
3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 171.6, 169.2, 162.5, 138.9,
133.68, 133.67, 127.9, 125.6, 116.6, 109.2, 43.2, 34.6, 20.5. HRMS (ESI-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7-Fluoro-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-
dione (28n). 27n (32.8 mg, 0.10 mmol) was subjected to procedure B to
give 28n (19.5 mg, 85% yield) as an amorphous off-white solid. 1H NMR
(400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.96 – 7.85 (m, 2H), 7.71 (ddd, J =
9.5, 7.8, 3.2 Hz, 1H), 4.48 (s, 2H), 3.72 (s, 3H).13C{1H} NMR (101 MHz,
DMSO-d6) δ 170.6, 168.7, 162.9, 158.9 (d, J = 243.7 Hz), 137.5, 129.6
(d, J = 6.2 Hz), 120.5 (d, J = 24.6 Hz), 119.6 (d, J = 8.1 Hz), 110.5 (d, J
= 22.8 Hz), 109.0, 43.3, 34.9. 19F{1H} NMR (376 MHz, DMSO-d6) δ -
QTOF) m/z: [M + H]+ Calcd for C13H13N2O2 229.0972; Found:
+
229.0977.
4,6-Dimethyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-dione
(28e). 27e (29.3 mg, 0.09 mmol) was subjected to procedure B to give
28e (17.3 mg, 85% yield) as an amorphous off-white solid. 1H NMR (400
MHz, DMSO-d6) δ 8.14 (d, J = 8.1 Hz, 1H), 7.89 (s, 1H), 7.63 (s, 1H),
7.29 (dd, J = 8.3, 1.4 Hz, 1H), 4.46 (s, 2H), 3.69 (s, 3H). 13C{1H} NMR
(101 MHz, DMSO-d6) δ 171.5, 169.1, 162.8, 142.9, 140.9, 126.0, 125.9,
125.5, 116.3, 109.3, 43.2, 34.5, 21.5. HRMS (ESI-QTOF) m/z: [M + H]+
Calcd for C13H13N2O2+ 229.0972; Found: 229.0967.
117.65. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C12H10FN2O2
+
233.0721; Found: 233.0722.
6-Fluoro-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-
dione (28o). 27o (36.4 mg, 0.11 mmol) was subjected to procedure B to
give 28o (17.0 mg, 67% yield) as an amorphous off-white solid. 1H NMR
(400 MHz, DMSO-d6) δ 8.31 (ddd, J = 8.8, 6.6, 2.0 Hz, 1H), 7.98 (s, 1H),
7.72 (dt, J = 11.4, 2.2 Hz, 1H), 7.33 (tt, J = 8.6, 2.0 Hz, 1H), 4.48 (s, 2H),
3.69 (d, J = 2.0 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 171.0,
168.8, 164.5 (d, J = 248.3 Hz), 163.8, 142.7, 129.2 (d, J = 10.6 Hz), 124.9,
112.4 (d, J = 23.2 Hz), 109.9, 103.4 (d, J = 26.9 Hz), 43.3, 35.0. 19F{1H}
NMR (376 MHz, DMSO-d6) δ -105.91. HRMS (ESI-QTOF) m/z: [M +
H]+ Calcd for C12H10FN2O2+ 233.0721; Found: 233.0717.
7-Methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-
dione (28f). 27f (33.8 mg, 0.10 mmol) was subjected to procedure B to
give 28f (22.9 mg, 96% yield) as an amorphous off-white solid. 1H NMR
(400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.69 (d, J
= 3.1 Hz, 1H), 7.42 (dd, J = 9.2, 3.1 Hz, 1H), 4.46 (s, 2H), 3.88 (s, 3H),
3.71 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 171.0, 169.1, 161.6,
156.1, 135.2, 129.3, 121.5, 118.4, 108.5, 106.4, 55.5, 43.1, 34.7. HRMS
+
(ESI-QTOF) m/z: [M + H]+ Calcd for C13H13N2O3 245.0921; Found:
5-Fluoro-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-
dione (28p). 27p (33.5 mg, 0.10 mmol) was subjected to procedure B to
give 28p (20.9 mg, 89% yield) as an amorphous off-white solid. 1H NMR
(400 MHz, DMSO-d6) δ 8.10 (dd, J = 8.0, 1.5 Hz, 1H), 8.03 (s, 1H), 7.67
(ddd, J = 15.1, 7.9, 1.6 Hz, 1H), 7.43 (td, J = 8.0, 4.2 Hz, 1H), 4.48 (s,
2H), 3.86 (d, J = 7.5 Hz, 3H). Solubility precluded 13C NMR. 19F{1H}
NMR (376 MHz, DMSO-d6) δ -120.62. HRMS (ESI-QTOF) m/z: [M +
H]+ Calcd for C12H10FN2O2+ 233.0721; Found: 233.0714.
245.0929.
5-Methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-
dione (28h). 27h (34.1 mg, 0.10 mmol) was subjected to procedure B to
give 28h (20.6 mg, 85% yield) as an amorphous off-white solid. 1H NMR
(400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.88 (dd, J = 7.5, 1.9 Hz, 1H), 7.49
– 7.26 (m, 2H), 4.45 (s, 2H), 3.94 (s, 3H), 3.93 (s, 3H). Solubility
precluded 13C NMR. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C13H13N2O3+ 245.0921; Found: 245.0914.
4-Phenyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-dione (28q).
27q (39.9 mg, 0.11 mmol) was subjected to procedure B to give 28q (23.2
mg, 79% yield) as an amorphous off-white solid. 1H NMR (400 MHz,
DMSO-d6) δ 8.31 (dd, J = 8.0, 1.6 Hz, 1H), 7.87 (s, 1H), 7.76 – 7.53 (m,
6H), 7.46 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 3.91 (s, 2H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 172.0, 168.8, 162.7, 141.8, 136.4,
132.6, 130.8, 130.5, 128.4, 127.6, 126.1, 124.4, 117.3, 109.7, 43.4.
7-Chloro-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-
dione (28i). 27i (34.2 mg, 0.10 mmol) was subjected to procedure B above
to give 28i (20.7 mg, 85% yield) as an amorphous off-white solid. 1H
NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 2.5 Hz, 1H), 8.00 (s, 1H), 7.88
(d, J = 9.1 Hz, 1H), 7.83 (dd, J = 9.1, 2.5 Hz, 1H), 4.48 (s, 2H), 3.71 (s,
3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 170.3, 168.6, 163.3, 139.5,
132.3, 129.2, 129.1, 125.0, 119.3, 109.8, 43.3, 34.8. HRMS (ESI-QTOF)
m/z: [M + H]+ Calcd for C12H10ClN2O2+ 249.0425; Found: 249.0429.
+
HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C17H13N2O2 277.0972;
Found: 277.0961.
6-Chloro-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-
dione (28j). 27j (35.3 mg, 0.10 mmol) was subjected to procedure B to
give 28j (20.6 mg, 82% yield) as an amorphous off-white solid. 1H NMR
(400 MHz, DMSO-d6) δ 8.23 (d, J = 8.6 Hz, 1H), 7.99 (s, 1H), 7.94 (d, J
= 1.9 Hz, 1H), 7.49 (dd, J = 8.6, 1.9 Hz, 1H), 4.47 (s, 2H), 3.70 (s, 3H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 170.9, 168.6, 163.6, 141.7, 137.4,
128.1, 126.7, 124.4, 116.5, 110.0, 43.4, 34.8. HRMS (ESI-QTOF) m/z:
[M + H]+ Calcd for C12H10ClN2O2+ 249.0425; Found: 249.0414.
4-Benzyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-dione (28r).
27r (18.2 mg, 0.05 mmol) was subjected to procedure B to give 28r (12.0
mg, 88% yield) as an amorphous off-white solid. 1H NMR (400 MHz,
DMSO-d6) δ 8.29 (dd, J = 8.0, 1.4 Hz, 1H), 7.98 (s, 1H), 7.70 – 7.60 (m,
2H), 7.43 (ddd, J = 7.9, 6.3, 1.5 Hz, 1H), 7.37 – 7.25 (m, 3H), 7.18 (d, J
= 7.0 Hz, 2H), 5.53 (s, 2H), 4.46 (s, 2H). 13C{1H} NMR (101 MHz,
DMSO) δ 171.7, 168.8, 163.0, 140.1, 135.2, 132.5, 129.0, 127.7, 126.3,
126.0, 124.3, 117.2, 109.9, 99.5, 50.0, 43.4. HRMS (ESI-QTOF) m/z: [M
+ H]+ Calcd for C18H15N2O2+ 291.1128; Found: 291.1122.
7-Bromo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-
dione (28k). 27k (38.8 mg, 0.10 mmol) was subjected to procedure B to
give 28k (24.1 mg, 83% yield) as an amorphous off-white solid. 1H NMR
(400 MHz, DMSO-d6) δ 8.31 (d, J = 2.3 Hz, 1H), 8.01 (s, 1H), 7.95 (dd,
J = 9.0, 2.4 Hz, 1H), 7.82 (dd, J = 9.1, 1.9 Hz, 1H), 4.48 (s, 2H), 3.70 (s,
3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 170.4, 168.8, 163.5, 134.0,
135.4, 135.2, 128.2, 119.6, 117.4, 109.9, 43.5, 35.0. HRMS (ESI-QTOF)
m/z: [M + H]+ Calcd for C12H10BrN2O2+ 292.9920; Found: 292.9916.
General Procedure C. Synthesis of 2-benzyl 4-substituted-2,3-dihydro-
1H-pyrrolo[3,4-b]quinolone-1,9(4H)-diones (29a-r). To a 4 mL screw
cap vial was added the corresponding isatoic anhydride 9 (2.0 equiv.) and
N-benzyl tetramic acid 26b before the addition of anhydrous acetonitrile
(0.5 M) under Argon(g). The vial was then charged with 3Å molecular
sieves followed by addition of DBU (2.0 equiv.). The vial was then stirred
at 50°C for 2 h. Reaction progress was monitored through thin layer
chromatography. The reaction mixture was then cooled to room
temperature and was added with 1:1 saturated aqueous NH4Cl solution
and water. The contents were transferred to a separating funnel and
extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were
washed with saturated brine (5 mL), dried over anhydrous Na2SO4 and
6-Bromo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-
dione (28l). 27l (21.1 mg, 0.05 mmol) was subjected to procedure B to
give 28l (12.9 mg, 82% yield) as an amorphous off-white solid. 1H NMR
(400 MHz, DMSO-d6) δ 8.15 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 1.7 Hz, 1H),
7.99 (s, 1H), 7.63 (dd, J = 8.5, 1.7 Hz, 1H), 4.47 (s, 2H), 3.70 (s, 3H).
9
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The Journal of Organic Chemistry
Page 10 of 17
concentrated to give the crude material, which was purified by column
2-Benzyl-6-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-
chromatography (MPLC, Solvents: MeOH/CH2Cl2 or EtOAc/CH2Cl2; 4
g silica column; Flow rate:12 mL/min) to obtain the desired product 29.
1,9(4H)-dione (29g) Following procedure C, 26b (35 mg, 0.18 mmol)
was treated with 9g (76 mg, 0.37 mmol) to obtain 29g after column
chromatography (2.5-3% MeOH/CH2Cl2) as an amorphous pale-yellow
solid (43 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J =
8.9 Hz, 1H), 7.39 – 7.27 (m, 5H), 7.13 – 7.06 (m, 2H), 4.62 (s, 2H), 4.48
(s, 2H), 3.94 (s, 3H), 3.65 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6)
δ 171.3, 166.8, 163.1, 161.4, 142.9, 138.2, 129.1 (2C), 128.3, 128.1 (2C),
127.7, 122.4, 113.2, 109.3, 100.0, 56.3, 47.9, 44.9, 35.4. HRMS (ESI-
1
2
3
4
5
6
7
8
2-Benzyl-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-
dione (29a). Following procedure C, 26b (35 mg, 0.18 mmol) was treated
with 9a (65 mg, 0.37 mmol) to obtain 29a after column chromatography
(3.6% MeOH/CH2Cl2) as an amorphous off-white solid (43 mg, 77%
yield). 1H NMR (400 MHz, DMSO-d6) δ 8.35 – 8.32 (m, 1H), 7.88 – 7.82
(m, 2H), 7.55 – 7.51 (m, 1H), 7.44 – 7.40 (m, 2H), 7.37 – 7.32 (m, 3H),
4.68 (s, 2H), 4.56 (s, 2H), 3.73 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-
d6) δ 171.7, 166.7, 161.4, 141.1, 138.2, 133.0, 129.1 (2C), 128.5, 128.1
(2C), 127.7, 126.5, 124.7, 117.1, 109.5, 47.9, 44.9, 35.3. HRMS (ESI-
QTOF) m/z: [M + H]+ Calcd for C19H17N2O2+ 305.1285; Found 305.1289.
QTOF) m/z: [M + H]+ Calcd for C20H19N2O3 335.1390; Found
+
335.1390.
9
2-Benzyl-5-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-
1,9(4H)-dione (29h). Following procedure C, 26b (35 mg, 0.18 mmol)
was treated with 9h (76 mg, 0.37 mmol) to obtain 29h after column
chromatography (3-3.1% MeOH/CH2Cl2) as an amorphous off-white
solid (51 mg, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.90 (dd, J =
6.9, 2.6 Hz, 1H), 7.42 – 7.27 (m, 7H), 4.62 (s, 2H), 4.47 (s, 2H), 3.93 (s,
3H), 3.89 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 171.0, 166.5,
162.5, 151.1, 138.1, 132.1, 131.1, 129.1 (2C), 128.1 (2C), 127.7, 125.3,
118.5, 116.2, 109.4, 57.3, 48.5, 44.9, 40.6. HRMS (ESI-QTOF) m/z: [M
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Benzyl-4-methyl-2,3-dihydro-1H-benzo[g]pyrrolo[3,4-b]quinoline-
1,11(4H)-dione (29b). Following general procedure C, 26b (35 mg, 0.18
mmol) was treated with 9b (84 mg, 0.37 mmol) to obtain 29b after
column chromatography (2-5% MeOH/CH2Cl2) as an amorphous yellow
solid (42 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H),
8.31 (s, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.68 –
7.63 (m, 1H), 7.58 – 7.43 (m, 1H), 7.40 – 7.28 (m, 5H), 4.64 (s, 2H), 4.54
(s, 2H), 3.76 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 172.4, 166.8,
162.9, 138.3, 138.2, 135.0, 129.6, 129.5, 129.1 (2C), 128.9, 128.1 (2C),
128.0, 127.7, 127.4, 127.2, 126.5, 114.3, 107.4, 48.2, 44.9, 35.5. HRMS
+ H]+ Calcd for C20H19N2O3 335.1390; found 335.1390.
+
2-Benzyl-7-chloro-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-
1,9(4H)-dione (29i). Following procedure C, 26b (35 mg, 0.18 mmol)
was treated with 9i (79 mg, 0.37 mmol) to obtain 29i after column
chromatography (4-5% MeOH/CH2Cl2) as an amorphous pale-yellow
solid (53 mg, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J =
2.4 Hz, 1H), 7.91 – 7.82 (m, 2H), 7.39 – 7.28 (m, 5H), 4.63 (s, 2H), 4.52
(s, 2H), 3.69 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 170.4, 166.4,
161.8, 139.8, 138.1, 132.8, 129.8, 129.1 (2C), 128.9, 128.1 (2C), 127.7,
125.4, 119.8, 109.8, 48.1, 44.9, 35.6. HRMS (ESI-QTOF) m/z: [M + H]+
Calcd for C19H16ClN2O2+ 339.0895; Found 339.0892.
(ESI-QTOF) m/z: [M + H]+ Calcd for C23H19N2O2 355.1441; Found
+
355.1438.
2-Benzyl-4,8-dimethyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-
1,9(4H)-dione (29c). Following procedure C, 26b (35 mg, 0.18 mmol)
was treated with 9c (71 mg, 0.37 mmol) to obtain 29c after column
chromatography (5-6% MeOH/CH2Cl2) as an amorphous light brown
solid (49 mg, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.62 – 7.61
(m, 2H), 7.38 – 7.35 (m, 2H), 7.30 – 7.27 (m, 3H), 7.20 – 7.18 (m, 1H),
4.62 (s, 2H), 4.46 (s, 2H), 3.62 (s, 3H), 2.86 (s, 3H). 13C{1H} NMR (101
MHz, DMSO-d6) δ 174.6, 166.9, 160.3, 142.8, 141.3, 138.3, 131.9, 129.1
(2C), 128.0 (2C), 127.9, 127.7, 126.7, 115.2, 110.4, 47.6, 44.9, 35.9, 24.2.
2-Benzyl-6-chloro-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-
1,9(4H)-dione (29j). Following procedure C, 26b (35 mg, 0.18 mmol)
was treated with 9j (79 mg, 0.37 mmol) to obtain 29j after column
chromatography (1-1.2% MeOH/CH2Cl2) as an amorphous pale-yellow
solid (43 mg, 69% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J =
8.6 Hz, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.52 (dd, J = 8.6, 1.8 Hz, 1H), 7.37
– 7.29 (m, 5H), 4.63 (s, 2H), 4.51 (s, 2H), 3.68 (s, 3H). 13C{1H} NMR
(101 MHz, DMSO-d6) δ 171.0, 166.4, 162.1, 142.0, 138.1, 137.9, 129.1
(2C), 128.5, 128.1 (2C), 127.7, 127.2, 125.0, 117.1, 110.0, 48.1, 44.9,
+
HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C20H19N2O2 319.1441;
Found 319.1440.
2-Benzyl-4,7-dimethyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-
1,9(4H)-dione (29d). Following procedure C, 26b (35 mg, 0.18 mmol)
was treated with 9d (71 mg, 0.37 mmol) to obtain 29d after column
chromatography (5-6% MeOH/CH2Cl2) as an amorphous off-white solid
+
35.6. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C19H16ClN2O2
1
(44 mg, 74% yield). H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 2.3
339.0895; Found 339.0891.
Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.62 (dd, J = 8.7, 2.2 Hz, 1H), 7.39 –
7.36 (m, 2H), 7.31 – 7.27 (m, 3H), 4.62 (s, 2H), 4.49 (s, 2H), 3.66 (s, 3H),
2.46 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 171.5, 166.8, 160.8,
139.1, 138.2, 134.2, 134.1, 129.1 (2C), 128.4, 128.1 (2C), 127.7, 126.0,
117.0, 109.2, 47.9, 44.9, 35.3, 20.9. HRMS (ESI-QTOF) m/z: [M + H]+
Calcd for C20H19N2O2+ 319.1441; Found 319.1438.
2-Benzyl-7-bromo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-
1,9(4H)-dione (29k). Following procedure C, 26b (35 mg, 0.18 mmol)
was treated with 9k (95 mg, 0.37 mmol) to obtain 29k after column
chromatography (1-2% MeOH/CH2Cl2) as an amorphous yellow solid (48
1
mg, 68% yield). H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 2.5 Hz,
1H), 7.96 (dd, J = 9.0, 2.5 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.42 – 7.27
(m, 5H), 4.63 (s, 2H), 4.51 (s, 2H), 3.68 (s, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 170.3, 166.3, 161.8, 140.2, 138.0, 135.5, 130.0, 129.1 (2C),
128.6, 128.1 (2C), 127.7, 119.9, 117.8, 109.9, 48.1, 44.9, 35.6. HRMS
2-Benzyl-4,6-dimethyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-
1,9(4H)-dione (29e). Following general procedure C, 26b (35 mg, 0.18
mmol) was treated with 9e (71 mg, 0.37 mmol) to obtain 29e after column
chromatography (2.5-2.6% MeOH/CH2Cl2) as an amorphous off-white
solid (43 mg, 73% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J =
8.1 Hz, 1H), 7.63 (s, 1H), 7.39 – 7.27 (m, 6H), 4.62 (s, 2H), 4.49 (s, 2H),
3.66 (s, 3H), 2.50 (s overlapped, 3H). 13C{1H} NMR (101 MHz, DMSO-
d6) δ 171.6, 166.8, 161.2, 143.5, 141.2, 138.2, 129.1 (2C), 128.1 (2C),
127.7, 126.4, 126.4, 126.1, 116.8, 109.3, 47.9, 44.9, 35.3, 22.0. HRMS
+
(ESI-QTOF) m/z: [M + H]+ Calcd for C19H16BrN2O2 383.0390; Found
383.0386.
2-Benzyl-6-bromo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-
1,9(4H)-dione (29l). Following procedure C, 26b (35 mg, 0.18 mmol)
was treated with 9l (95 mg, 0.37 mmol) to obtain 29l after column
chromatography (3-5% MeOH/CH2Cl2) as an amorphous yellow solid (38
+
(ESI-QTOF) m/z: [M + H]+ Calcd for C20H19N2O2 319.1441; Found
1
319.1440.
mg, 54% yield). H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 8.5 Hz,
1H), 8.07 (d, J = 1.6 Hz, 1H), 7.65 (dd, J = 8.5, 1.6 Hz, 1H), 7.39 – 7.28
(m, 5H), 4.63 (s, 2H), 4.52 (s, 2H), 3.68 (s, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 170.6, 165.9, 161.5, 141.6, 137.6, 128.6, 128.1, 127.6,
127.4, 127.3, 127.0, 126.4, 119.5, 109.6, 47.6, 44.4, 35.1. HRMS (ESI-
2-Benzyl-7-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-
1,9(4H)-dione (29f). Following procedure C, 26b (35 mg, 0.18 mmol)
was treated with 9f (76 mg, 0.37 mmol) to obtain 29f after column
chromatography (3.8-4% MeOH/CH2Cl2) as an amorphous off-white
solid (47 mg, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J =
9.3 Hz, 1H), 7.71 (d, J = 3.1 Hz, 1H), 7.44 – 7.34 (m, 3H), 7.31 – 7.27
(m, 3H), 4.63 (s, 2H), 4.49 (s, 2H), 3.89 (s, 3H), 3.69 (s, 3H). 13C{1H}
NMR (101 MHz, DMSO-d6) δ 171.1, 166.8, 160.0, 156.7, 138.2, 135.5,
129.8, 129.1 (2C), 128.1 (2C), 127.7, 122.0, 118.9, 108.6, 106.9, 56.0,
47.8, 44.9, 35.5. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C20H19N2O3+ 335.1390; Found 335.1389.
+
QTOF) m/z: [M + H]+ Calcd for C19H16BrN2O2 383.0390; Found
383.0386.
2-Benzyl-8-fluoro-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-
1,9(4H)-dione (29m). Following procedure C, 26b (35 mg, 0.18 mmol)
was treated with 9m (72 mg, 0.37 mmol) to obtain 29m after column
chromatography (2.5-3.2% MeOH/CH2Cl2) as an amorphous yellow solid
1
(35 mg, 59% yield). H NMR (400 MHz, DMSO-d6) δ 7.78 – 7.73 (m,
1H), 7.60 (d, J = 8.7 Hz, 1H), 7.39 – 7.35 (m, 2H), 7.31 – 7.26 (m, 3H),
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The Journal of Organic Chemistry
7.22 – 7.16 (m, 1H), 4.62 (s, 2H), 4.48 (s, 2H), 3.64 (s, 3H). 13C{1H}
with 9a (70 mg, 0.41 mmol) to obtain 30 after column chromatography
(3-5% MeOH/CH2Cl2) as an amorphous yellow solid (41 mg, 71%). 1H
NMR (400 MHz, DMSO-d6) δ 8.31 (dd, J = 7.9, 1.5 Hz, 1H), 7.90 – 7.82
(m, 4H), 7.54 – 7.50 (m, 1H), 7.46 – 7.40 (m, 2H), 7.15 – 7.11 (m, 1H),
5.11 (s, 2H), 3.84 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 171.7,
165.6, 160.8, 141.1, 139.9, 133.2, 129.4 (2C), 128.5, 126.5, 124.9, 123.6,
118.9 (2C), 117.3, 109.9, 48.7, 35.4. HRMS (ESI-QTOF) m/z: [M + H]+
NMR (101 MHz, DMSO-d6) δ 170.7, 166.4, 162.1 (d, J = 260.5 Hz),
161.1, 143.2 (d, J = 3.7 Hz), 138.1, 134.0 (d, J = 11.3 Hz), 129.1 (2C),
128.1 (2C), 127.7, 118.0 (d, J = 7.4 Hz), 113.2 (d, J = 4.0 Hz), 111.7 (d,
J = 21.0 Hz), 110.6, 47.8, 44.9, 36.2. 19F{1H} NMR (376 MHz, DMSO-
1
2
3
4
5
6
7
8
d6) δ -112.56. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C19H16FN2O2
+
323.1190; Found 323.1188.
+
Calcd for C18H15N2O2 291.1128; Found 291.1129.
2-Benzyl-7-fluoro-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-
1,9(4H)-dione (29n). Following procedure C, 1-benzylpyrrolidine-2,4-
dione (26b) (35 mg, 0.18 mmol) was treated with compound (9n) (72 mg,
0.37 mmol) to obtain 29n after column chromatography (2.8-3%
MeOH/CH2Cl2) as an amorphous light brown solid (50 mg, 83% yield).
1H NMR (400 MHz, DMSO-d6) δ 7.94 – 7.91 (m, 2H), 7.74 – 7.69 (m,
1H), 7.39 – 7.35 (m, 2H), 7.31 – 7.27 (m, 3H), 4.63 (s, 2H), 4.51 (s, 2H),
3.70 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 170.7 (d, J = 2.4
Hz), 166.5, 161.4, 159.5 (d, J = 244.0 Hz), 138.1, 137.8, 130.2 (d, J = 6.6
Hz), 129.1 (2C), 128.1 (2C), 127.7, 121.1 (d, J = 24.3 Hz), 120.2 (d, J =
8.1 Hz), 111.0 (d, J = 22.6 Hz), 109.0, 48.0, 44.9, 35.8. 19F{1H} NMR
(376 MHz, DMSO-d6) δ -117.39. HRMS (ESI-QTOF) m/z: [M + H]+
Calcd for C19H16FN2O2+ 323.1190; Found 323.1187.
2-Cyclohexyl-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-
1,9(4H)-dione (31). Following procedure C, 26d (35 mg, 0.19 mmol) was
treated with 9a (69 mg, 0.41 mmol) to obtain 31 after column
chromatography (3-4% MeOH/CH2Cl2) as an amorphous pale-yellow
solid (43 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ 8.27 (dd, J = 8.0,
1.4 Hz, 1H), 7.86 – 7.77 (m, 2H), 7.50 – 7.46 (m, 1H), 4.57 (s, 2H), 3.98
– 3.90 (m, 1H), 3.75 (s, 3H), 1.84 – 1.79 (m, 2H), 1.73 – 1.65 (m, 3H),
1.57 – 1.47 (m, 2H), 1.43 – 1.32 (m, 2H), 1.19 – 1.08 (m, 1H). 13C{1H}
NMR (101 MHz, DMSO-d6) δ 171.6, 165.9, 161.5, 141.1, 132.9, 128.5,
126.5, 124.6, 117.0, 110.2, 49.6, 44.8, 35.2, 31.1 (2C), 25.7 (2C), 25.6.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C18H21N2O2 297.1598;
+
Found 297.1596.
2-Benzyl-6-fluoro-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-
1,9(4H)-dione (29o). Following procedure C, 1-benzylpyrrolidine-2,4-
dione (26b) (35 mg, 0.18 mmol) was treated with compound (9o) (72 mg,
0.37 mmol) to obtain 29o after column chromatography (45-50%
4-Methyl-1,2,3,3a-tetrahydro-9H-pyrrolizino[1,2-b]quinoline-9,10(4H)-
dione (32). Following procedure C, 26e (123 mg, 0.88 mmol) was treated
with 9a (313 mg, 1.77 mmol) to obtain 32 after column chromatography
(4.8-5% MeOH/CH2Cl2) as an amorphous off-white solid (134 mg, 60%).
1H NMR (400 MHz, DMSO-d6) δ 8.28 – 8.25 (m, 1H), 7.87 – 7.76 (m,
2H), 7.51 – 7.47 (m, 1H), 4.89 (dd, J = 9.8, 6.5 Hz, 1H), 3.82 (s, 3H), 3.54
– 3.47 (m, 1H), 3.18 – 3.12 (m, 1H), 2.49 – 2.44 (m, 1H), 2.23 – 2.15 (m,
2H), 1.54 – 1.44 (m, 1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 172.1,
171.3, 165.3, 141.2, 133.1, 128.7, 126.5, 124.9, 117.4, 109.4, 62.0, 43.0,
36.1, 28.7, 28.6. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C15H15N2O2+ 255.1128; Found 255.1127.
1
EtOAc/CH2Cl2) as an amorphous light brown solid (19 mg, 70%). H
NMR (400 MHz, DMSO-d6) δ 8.32 (dd, J = 8.9, 6.6 Hz, 1H), 7.72 (dd, J
= 11.4, 2.3 Hz, 1H), 7.39 – 7.27 (m, 6H), 4.63 (s, 2H), 4.51 (s, 2H), 3.66
(s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 171.0, 166.5, 164.9 (d, J
= 248.2 Hz), 162.2, 142.9 (d, J = 12.0 Hz), 138.1, 129.6 (d, J = 11.0 Hz),
129.1, 128.9, 128.1, 127.7, 125.4 (d, J = 1.5 Hz), 113.0 (d, J = 23.1 Hz),
109.9, 103.8 (d, J = 27.2 Hz), 48.0, 44.9, 35.7. 19F{1H} NMR (376 MHz,
DMSO-d6) δ -105.79. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C19H16FN2O2+ 323.1190; Found 323.1183.
5-Methyl-5H-indeno[1,2-b]quinoline-10,11-dione
(34).
Following
procedure C, 26g (35 mg, 0.24 mmol) was treated with 9a (85 mg, 0.48
mmol) to obtain 34 (40 mg, 67%) as an amorphous indigo purple solid.
1H NMR (400 MHz, DMSO-d6) δ 8.27 (dd, J = 7.9, 1.6 Hz, 1H), 8.20 (d,
J = 7.4 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.83 (ddd, J = 8.7, 7.0, 1.7 Hz,
1H), 7.74 – 7.61 (m, 3H), 7.54 (t, J = 7.5 Hz, 1H), 4.30 (s, 3H). 13C{1H}
NMR (101 MHz, DMSO-d6) δ 187.6, 170.7, 163.2, 141.7, 135.3, 135.2,
133.5, 132.9, 132.7, 129.9, 126.5, 126.1, 125.8, 122.6, 118.5, 110.6, 37.7.
2-Benzyl-5-fluoro-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-
1,9(4H)-dione (29p). Following procedure C, 26b (35 mg, 0.18 mmol)
was treated with 9p (72 mg, 0.37 mmol) to obtain 29p after column
chromatography (3.5-3.7% MeOH/CH2Cl2) as an amorphous off-white
solid (48 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ 8.12 (dd, J = 8.0,
1.5 Hz, 1H), 7.66 (ddd, J = 15.0, 7.9, 1.6 Hz, 1H), 7.47 – 7.42 (m, 1H),
7.41 – 7.35 (m, 2H), 7.31 – 7.27 (m, 3H), 4.63 (s, 2H), 4.50 (s, 2H), 3.83
(d, J = 7.6 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 170.4 (d, J =
2.4 Hz), 166.3, 162.7, 152.7 (d, J = 248.5 Hz), 138.0, 131.5, 130.4 (d, J
= 6.5 Hz), 129.1 (2C), 128.1 (2C), 127.8, 125.3 (d, J = 8.3 Hz), 122.7 (d,
J = 3.5 Hz), 120.3 (d, J = 23.1 Hz), 109.7, 48.3, 44.9. 19F{1H} NMR (376
MHz, DMSO-d6) δ -120.48. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd
+
HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C17H12NO2 262.0863;
Found: 262.0851.
10-Methyl-3,4-dihydroacridine-1,9(2H,10H)-dione (35). Following
procedure C, 26h (35 mg, 0.31 mmol) was treated with 9a (110 mg, 0.62
mmol) to obtain 35 after column chromatography (.8-5% MeOH/CH2Cl2)
as an amorphous pale-yellow solid (40 mg, 57%). 1H NMR (400 MHz,
DMSO-d6) δ 8.20 (dd, J = 7.9, 1.7 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.77
–7.73 (m, 1H), 7.45 – 7.41 (m, 1H), 3.80 (s, 3H), 3.13 (t, J = 6.2 Hz, 2H),
2.39 – 2.36 (m, 2H), 2.01 (p, J = 6.3 Hz, 2H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 193.7, 173.6, 163.1, 141.0, 133.1, 128.2, 126.5, 124.8,
117.6, 115.6, 38.5, 35.7, 29.2, 20.9. HRMS (ESI-QTOF) m/z: [M + H]+
Calcd for C14H14NO2+ 228.1019; Found 228.1021.
+
for C19H16FN2O2 323.1190; Found 323.1188.
2-Benzyl-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-
dione (29q). Following procedure C, 26b (35 mg, 0.18 mmol) was treated
with 9q (88 mg, 0.37 mmol) to obtain 29q after column chromatography
(2.5-4% MeOH/CH2Cl2) as an amorphous yellow solid (33 mg, 49%). 1H
NMR (400 MHz, DMSO-d6) δ 8.33 (dd, J = 8.0, 1.5 Hz, 1H), 7.72 – 7.62
(m, 6H), 7.47 (t, J = 7.5 Hz, 1H), 7.33 – 7.22 (m, 5H), 6.82 (d, J = 8.5 Hz,
1H), 4.54 (s, 2H), 3.94 (s, 2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ
172.0, 166.5, 161.1, 142.1, 138.1, 136.8, 133.0, 131.2 (2C), 130.9, 129.0
(2C), 128.8 (2C), 128.1 (2C), 127.7 (2C), 126.4, 124.9, 117.8, 109.8,
4-Methyl-9H-pyrrolizino[1,2-b]quinoline-9,10(4H)-dione (3). A 4 mL
vial was charged with 32 (20 mg, 0.08 mmol) and commercially available
2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione (Chloranil) (78 mg,
0.31 mmol). It was then flushed with Argon(g) followed by addition of
anhydrous toluene (2 mL). The vial was sealed and heated to 125 °C for
16 h. The reaction mixture was then cooled to room temperature and
toluene was removed under reduced pressure to obtain a crude mixture
which was directly purified by column chromatography (MPLC) to obtain
penicinotam, 3 after column chromatography (0.9-1.1% MeOH/CH2Cl2)
as an amorphous bright yellow solid (14 mg, 72%). 1H NMR (400 MHz,
DMSO-d6) δ 8.20 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.79 (t, J
= 7.8 Hz, 1H), 7.51 – 7.48 (m, 2H), 7.11 (d, J = 3.3 Hz, 1H), 6.44 (d, J =
3.2 Hz, 1H), 3.99 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 169.9,
159.5, 153.7, 140.4, 132.7, 128.7, 125.9, 125.6, 125.5, 120.2, 117.8,
116.6, 116.6, 104.2, 36.7 HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C15H11N2O2+ 251.0815; Found 251.0815..
+
47.9, 44.8. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C24H19N2O2
367.1441; Found 367.1437.
2,4-Dibenzyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-dione
(29r). Following procedure C, 26b (35 mg, 0.18 mmol) was treated with
9r (94 mg, 0.37 mmol) to obtain 29r after column chromatography (1-3%
1
MeOH/CH2Cl2) as an amorphous pale-yellow solid (53 mg, 76%). H
NMR (400 MHz, DMSO-d6) δ 8.32 (dd, J = 8.1, 1.5 Hz, 1H), 7.71 – 7.62
(m, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.37 – 7.25 (m, 8H), 7.18 – 7.14 (m,
2H), 5.52 (s, 2H), 4.62 (s, 2H), 4.50 (s, 2H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 171.8, 166.6, 161.5, 140.4, 138.1, 135.5, 133.1, 129.4 (2C),
129.1 (2C), 128.9, 128.8, 128.1 (2C), 127.7, 126.7, 126.3 (2C), 124.9,
117.7, 109.9, 50.7, 48.1, 44.9. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd
for C25H21N2O2+ 381.1598; Found 381.1597.
General Procedure D. Annulation using monoketones 21a-k. A two-
neck round bottom flask equipped with a reflux condenser was charged
with the corresponding isatoic anhydride 9 (1.0 equiv.) and ketone 21 (2.1
4-Methyl-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-1,9(4H)-
dione (30). Following procedure C, 26c (35 mg, 0.20 mmol) was treated
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27.7, 21.3. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C22H24NO2
+
equiv.). The contents were dissolved in anhydrous toluene under
Argon(g) and cooled to 0°C before addition of LiHMDS (2.3 equiv., 1M
in toluene) dropwise. The resulting mixture was heated to 80°C and
stirred for 2 h. The progress of the reaction was monitored by thin layer
chromatography. The reaction mixture was then cooled to room
temperature and was added with saturated aqueous NH4Cl solution
followed by extraction with ethyl acetate (3 x 5 mL). The combined
organic layers were washed with brine solution (1 x 5 mL) and
concentrated in vacuo to obtain a crude mixture which was purified by
column chromatography (MPLC, Solvents: MeOH/CH2Cl2 or
EtOAc/CH2Cl2; 4 g silica column; Flow rate:12 mL/min) to obtain the
desired product 24.
334.1802; Found 334.1801.
1
2
3
4
5
6
7
8
2-Methyl-10-(4-(trifluoromethyl)benzyl)-1,3,4,10-tetrahydroacridin-
9(2H)-one (24f). Following procedure D, 9t (50 mg, 0.15 mmol) was
treated with 21c (37 mg, 0.33 mmol) to obtain 24f after column
chromatography (25-29% EtOAc/CH2Cl2) as an amorphous yellow solid
(40 mg, 70% yield). 1H NMR (400 MHz, CDCl3) δ 8.51 (dd, J = 8.1, 1.7
Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.52 – 7.46 (m, 1H), 7.31 (t, J = 7.5
Hz, 1H), 7.19 – 7.15 (m, 3H), 5.47 (s, 2H), 3.18 – 2.97 (m, 1H), 2.74 (br.
s, 2H), 2.19 (dd, J = 17.2, 10.2 Hz, 1H), 1.97 – 1.88 (m, 1H), 1.83 – 1.76
(m overlapped, 1H), 1.48 – 1.35 (m, 1H), 1.11 (d, J = 6.5 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 177.1, 147.6, 140.7, 140.1, 132.0,
130.3 (q, J = 32.7 Hz), 127.1, 126.3 (q, J = 3.8 Hz), 125.7, 124.8, 123.2
(q, J = 271.7 Hz), 123.0, 119.3, 115.2, 49.0, 31.0, 30.7, 27.9, 27.6, 21.3.
19F{1H} NMR (376 MHz, CDCl3) δ -62.65. HRMS (ESI-QTOF) m/z: [M
+ H]+ Calcd for C22H21F3NO+ 372.1570; Found 372.1556.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Methyl-1,2,3,4-tetrahydro-9H-cyclopenta[b]quinolin-9-one
(24a).
Following procedure D, 9a (100 mg, 0.56 mmol) was treated with 21g
(100 mg, 1.19 mmol) to obtain title compound 24a after column
chromatography (1-1.5% MeOH/CH2Cl2) as an amorphous off white
solid (50 mg, 45% yield). 1H NMR (400 MHz, CDCl3) δ 8.49 (dd, J = 8.0,
1.7 Hz, 1H), 7.64 – 7.59 (m, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.37 – 7.33
(m, 1H), 3.72 (s, 3H), 3.11 – 3.07 (m, 2H), 2.99 – 2.95 (m, 2H), 2.16 –
2.08 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 175.1, 155.4, 141.3,
131.2, 126.8, 126.7, 122.9, 121.8, 114.7, 35.6, 33.8, 28.4, 21.2. HRMS
(ESI-QTOF) m/z: [M + H]+ Calcd for C13H14NO+ 200.1070; Found
200.1075.
7-Methoxy-2,10-dimethyl-1,3,4,10-tetrahydroacridin-9(2H)-one (24g).
Following procedure D, 9f (50 mg, 0.24 mmol) was treated with 21c (57
mg, 0.51 mmol) to obtain 24g after column chromatography (3.5-3.8%
MeOH/CH2Cl2) as an amorphous white solid (56 mg, 90% yield). 1H
NMR (500 MHz, CDCl3) δ 7.88 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.23 (d,
J = 9.4 Hz, 1H), 3.92 (s, 3H), 3.70 (s, 3H), 3.02 (dd, J = 17.0, 5.0 Hz, 1H),
2.92 – 2.71 (m, 2H), 2.16 – 2.10 (m, 1H), 2.03 – 1.97 (m, 1H), 1.76 (br.
s, 1H), 1.47 – 1.39 (m, 1H), 1.11 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (126
MHz, CDCl3) δ 176.0, 155.4, 147.1, 135.9, 125.6, 122.2, 117.8, 116.6,
105.5, 55.8, 33.6, 31.3, 30.8, 28.5, 27.6, 21.4. HRMS (ESI-QTOF) m/z:
[M + H]+ Calcd for C16H20NO2+ 258.1489; Found 258.1479.
10-Methyl-1,3,4,10-tetrahydroacridin-9(2H)-one (24b). Following
procedure D, 9a (100 mg, 0.56 mmol) was treated with 21b (116 mg, 1.19
mmol) to obtain 24b after column chromatography (40-43%
1
EtOAc/CH2Cl2) as an amorphous yellow solid (88 mg, 74% yield). H
NMR (500 MHz, CDCl3) δ 8.45 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 7.8 Hz,
1H), 7.41 (d, J = 8.7 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 3.65 (s, 3H), 2.70
(dt, J = 27.8, 6.5 Hz, 4H), 1.86 (p, J = 5.9 Hz, 2H), 1.71 (p, J = 6.1 Hz,
2H). 13C{1H} NMR (126 MHz, CDCl3) δ 176.8, 148.3, 141.1, 131.5,
126.7, 124.6, 122.5, 119.2, 114.9, 33.4, 28.6, 22.9, 22.9, 21.4. HRMS
(ESI-QTOF) m/z: [M + H]+ Calcd for C14H16NO+ 214.1226; Found
214.1225.
7-Chloro-2,10-dimethyl-1,3,4,10-tetrahydroacridin-9(2H)-one
(24h).
Following procedure D, 9i (50 mg, 0.24 mmol) was treated with 21c (56
mg, 0.50 mmol) to obtain 24h after column chromatography (16-20%
EtOAc/CH2Cl2) as an amorphous off white solid (40 mg, 65% yield). 1H
NMR (400 MHz, CDCl3) δ 8.40 (d, J = 2.6 Hz, 1H), 7.50 (dd, J = 9.1, 2.6
Hz, 1H), 7.37 (d, J = 9.1 Hz, 1H), 3.69 (s, 3H), 3.03 – 2.70 (m, 3H), 2.15
– 1.96 (m, 2H), 1.72 (br.s, overlapped, 1H), 1.50 – 1.35 (m, 1H), 1.11 (d,
J = 6.6 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 175.6, 148.2, 139.4,
131.6, 128.6, 125.9, 125.5, 119.2, 116.7, 33.7, 31.1, 30.7, 28.6, 27.4, 21.3.
HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C15H17ClNO+ 262.0993;
Found 262.0985.
2,10-Dimethyl-1,3,4,10-tetrahydroacridin-9(2H)-one (24c). Following
procedure D, 9a (100 mg, 0.56 mmol) was treated with 21c (132 mg, 1.19
mmol) to obtain 24c after column chromatography (24-30%
EtOAc/CH2Cl2) as an amorphous light yellow solid (108 mg, 84% yield).
1H NMR (400 MHz, CDCl3) δ 8.47 (dd, J = 8.0, 1.7 Hz, 1H), 7.62 – 7.58
(m, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 3.69 (s, 3H),
3.04 – 2.97 (m, 1H), 2.90 – 2.71 (m, 2H), 2.18 – 2.07 (m, 1H), 2.03 – 1.94
(m, 1H), 1.79 – 1.67 (m, 1H), 1.49 – 1.36 (m, 1H), 1.11 (d, J = 6.5 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 176.8, 147.9, 141.1, 131.5,
126.8, 124.6, 122.5, 118.8, 114.8, 33.5, 31.1, 30.8, 28.6, 27.5, 21.3.
HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C15H18NO+ 228.1383;
Found 228.1375.
7,10-Dimethyl-9-oxo-5,6,7,8,9,10-hexahydroacridine-2-carbonitrile
(24i). Following procedure D, 9u (50 mg, 0.24 mmol) was treated with
21c (59 mg, 0.52 mmol) to obtain 24i after column chromatography
1
(EtOAc/CH2Cl2) as an amorphous white solid (45 mg, 72% yield). H
NMR (500 MHz, CDCl3) δ 8.75 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.52 (d,
J = 8.9 Hz, 1H), 3.75 (s, 3H), 3.04 – 2.72 (m, 3H), 2.14 – 2.00 (m, 2H),
1.72 (s overlapped, 1H), 1.49-1.41 (m, 1H), 1.12 (d, J = 6.5 Hz, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 175.5, 149.1, 142.9, 133.2, 132.4,
124.2, 120.9, 118.7, 116.3, 105.7, 33.9, 31.0, 30.6, 28.8, 27.3, 21.3.
HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C16H17N2O+ 253.1335;
Found 253.1326.
10-Benzyl-2-methyl-1,3,4,10-tetrahydroacridin-9(2H)-one
(24d).
Following procedure D, 9r (50 mg, 0.19 mmol) was treated with 21c (46
mg, 0.41 mmol) to obtain title compound 24d after column
chromatography (17-19% EtOAc/CH2Cl2) as an amorphous off white
solid (44 mg, 73% yield). 1H NMR (400 MHz, CDCl3) δ 8.51 (dd, J =
8.0, 1.7 Hz, 1H), 7.50 – 7.45 (m, 1H), 7.37 – 7.28 (m, 5H), 7.03 (d, J =
7.2 Hz, 2H), 5.43 (s, 2H), 3.17 – 3.00 (m, 1H), 2.79 (br. s, 2H), 2.20 (dd,
J = 17.0, 10.2 Hz, 1H), 1.96 J = 6.7 Hz 1.87 (m, 1H), 1.83 – 1.71 (m, 1H),
1.49 – 1.37 (m, 1H), 1.11 (d, J = 6.5 Hz, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 177.1, 148.1, 140.9, 135.9, 131.8, 129.3(2C), 127.8, 126.8,
125.3(2C), 124.9, 122.8, 118.9, 115.7, 49.4, 31.2, 30.8, 27.9 27.7, 21.4.
HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C21H22NO+ 304.1696;
Found 304.1685.
7-Fluoro-2,10-dimethyl-1,3,4,10-tetrahydroacridin-9(2H)-one
Following procedure D, 9n (50 mg, 0.25 mmol) was treated with 21c (60
mg, 0.54 mmol) to obtain 24j after column chromatography (15-22%
(24j).
1
EtOAc/CH2Cl2) as an amorphous yellow solid (45 mg, 72% yield). H
NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 9.0, 3.1 Hz, 1H), 7.45 (dd, J =
9.4, 4.1 Hz, 1H), 7.35 – 7.30 (m, 1H), 3.72 (s, 3H), 3.02 – 2.73 (m, 3H),
2.15 – 1.97 (m, 2H), 1.73 (br.s, overlapped, 1H), 1.49 – 1.38 (m, 1H),
1.11 (d, J = 6.6 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 176.0 (d, J
= 2.7 Hz), 158.5 (d, J = 243.9 Hz), 148.0, 137.7 (d, J = 1.0 Hz), 125.9 (d,
J = 6.8 Hz), 120.0 (d, J = 25.0 Hz), 118.3, 117.0 (d, J = 7.6 Hz), 111.0 (d,
J = 22.2 Hz), 33.8, 31.1, 30.7, 28.6, 27.5, 21.3. 19F{1H} NMR (376 MHz,
CDCl3) δ -119.63. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C15H17FNO+ 246.12889; Found 246.1280.
10-(4-Methoxybenzyl)-2-methyl-1,3,4,10-tetrahydroacridin-9(2H)-one
(24e). Following procedure D, 9s (50 mg, 0.18 mmol) was treated with
21c (42 mg, 0.37 mmol) to obtain 24e after column chromatography (50-
60% EtOAc/Hexanes) as an amorphous off white solid (43 mg, 74%
yield). 1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J = 8.2, 1.7 Hz, 1H), 7.48
(ddd, J = 8.8, 6.9, 1.8 Hz, 1H), 7.33 – 7.28 (m, 2H), 6.95 – 6.91 (m, 2H),
6.88 – 6.84 (m, 2H), 5.36 (s, 2H), 3.77 (s, 3H), 3.09 – 3.04 (m, 1H), 2.80
– 2.77 (m, 2H), 2.25 – 2.11 (m, 1H), 1.97 – 1.87 (m, 1H), 1.82 – 1.73 (m,
1H), 1.48 – 1.36 (m, 1H), 1.11 (d, J = 6.6 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 177.0, 159.1, 148.0, 140.9, 131.7, 127.6, 126.8, 126.4
(2C), 124.8, 122.7, 118.9, 115.66, 114.6 (2C), 55.3, 48.8, 31.1, 30.7, 27.8,
8-Fluoro-2,10-dimethyl-1,3,4,10-tetrahydroacridin-9(2H)-one
(24k).
Following procedure D, 9m (50 mg, 0.25 mmol) was treated with 21c (60
mg, 0.54 mmol) to obtain 24k after column chromatography (35-45%
EtOAc/CH2Cl2) as an amorphous off white solid (40 mg, 63% yield). 1H
NMR (400 MHz, CDCl3) δ 7.52 – 7.46 (m, 1H), 7.21 (d, J = 8.8 Hz, 1H),
6.94 – 6.89 (m, 1H), 3.67 (s, 3H), 2.96 (dd, J = 17.3, 5.1 Hz, 1H), 2.89 –
2.67 (m, 2H), 2.10 – 1.90 (m, 2H), 1.77 – 1.68 (m, 1H), 1.47 – 1.35 (m,
1H), 1.10 (d, J = 6.6 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 175.8
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Page 13 of 17
The Journal of Organic Chemistry
(d, J = 1.4 Hz), 162.2 (d, J = 262.7 Hz), 147.0, 143.3 (d, J = 4.0 Hz),
1H), 7.47 (d, J = 8.7 Hz, 1H), 7.35 – 7.31 (m, 1H), 6.66 – 6.60 (m, 2H),
3.77 (s, 3H), 2.91 – 2.86 (m, 2H), 2.34 – 2.29 (m, 2H). 13C{1H} NMR
(101 MHz, CDCl3) δ 175.8, 144.4, 140.7, 139.8, 131.5, 126.8, 125.9,
122.9, 120.4, 116.1, 115.2, 34.5, 22.3, 19.3. HRMS (ESI-QTOF) m/z: [M
+ H]+ Calcd for C14H14NO+ 212.1070; Found 212.1069.
131.4 (d, J = 11.3 Hz), 120.6, 114.8 (d, J = 7.5 Hz), 110.5 (d, J = 4.6 Hz),
109.0 (d, J = 21.7 Hz), 34.3, 30.74, 30.71, 28.6, 27.5, 21.3. 19F{1H} NMR
(376 MHz, CDCl3) δ -111.71. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd
for C15H17FNO+ 246.1290; Found 246.1280.
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2
3
4
5
6
7
8
9
6-Fluoro-2,10-dimethyl-1,3,4,10-tetrahydroacridin-9(2H)-one
(24l).
12-Methyl-6,12-dihydrobenzo[c]acridin-7(5H)-one (24r). Following
procedure D, 9a (50 mg, 0.28 mmol) was treated with 21i (86 mg, 0.59
mmol) to obtain 24r after column chromatography (20-24%
Following procedure D, 9o (40 mg, 0.20 mmol) was treated with 21c (48
mg, 0.43 mmol) to obtain 24l after column chromatography (45-50%
EtOAc/CH2Cl2) as an amorphous off white solid (28 mg, 56% yield). 1H
NMR (400 MHz, CDCl3) δ 8.46 (dd, J = 8.9, 6.8 Hz, 1H), 7.11 – 7.00 (m,
2H), 3.64 (s, 3H), 3.02 – 2.93 (m, 1H), 2.92 – 2.71 (m, 2H), 2.14 – 2.06
(m, 1H), 2.02 – 1.96 (m, 1H), 1.79 – 1.65 (m, 1H), 1.49 – 1.38 (m, 1H),
1.11 (d, J = 6.6 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 176.2, 164.8
(d, J = 249.5 Hz), 148.2 (d, J = 1.5 Hz), 142.5 (d, J = 11.2 Hz), 129.7 (d,
J = 10.6 Hz), 121.4 (d, J = 1.5 Hz), 119.1, 111.2 (d, J = 23.0 Hz), 100.9
(d, J = 26.7 Hz), 33.7, 30.9, 30.7, 28.6, 27.5, 21.3. 19F{1H} NMR (376
MHz, CDCl3) δ -106.38. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C15H17FNO+ 246.12890; Found 246.1279.
1
EtOAc/CH2Cl2) as an amorphous yellow solid (52 mg, 70% yield). H
NMR (500 MHz, CDCl3) 8.50 (dd, J = 8.0, 1.6 Hz, 1H), 7.68 (ddd, J =
8.5, 6.8, 1.7 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.52 – 7.45 (m, 1H), 7.40
– 7.32 (m, 4H), 3.95 (s, 3H), 2.89 – 2.86 (m, 2H), 2.82 – 2.78 (m, 2H).
13C{1H} NMR (126 MHz, CDCl3) δ 176.3, 148.2, 143.3, 141.9, 131.9,
130.0, 129.6, 128.5, 128.2, 126.7, 126.1, 125.5, 123.1, 122.5, 116.4, 40.9,
29.0, 21.3. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C18H16NO+
262.1226; Found 262.1225.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(R)-4,10-Dimethyl-1-(prop-1-en-2-yl)-1,10-dihydroacridin-9(2H)-one
(24s). Following procedure D, 9a (100 mg, 0.56 mmol) was treated with
21k (178 mg, 1.19 mmol) to obtain 24s after column chromatography (18-
5-Fluoro-2,10-dimethyl-1,3,4,10-tetrahydroacridin-9(2H)-one (24m).
Following procedure D, 9p (50 mg, 0.25 mmol) was treated with 21c (60
mg, 0.54 mmol) to obtain 24m after column chromatography (35-45%
EtOAc/CH2Cl2) as an amorphous off white solid (43 mg, 69% yield). 1H
NMR (400 MHz, CDCl3) δ 8.26 – 8.21 (m, 1H), 7.33 – 7.29 (m, 1H), 7.18
– 7.23 (m, 1H), 3.86 (d, J = 6.7 Hz, 3H), 3.07 – 2.95 (m, 1H), 2.89 – 2.67
(m, 2H), 2.13 – 1.95 (m, 2H), 1.82 – 1.70 (m, 1H), 1.48 – 1.36 (m, 1H),
1.11 (d, J = 6.5 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 175.9 (d, J
= 2.4 Hz), 152.0 (d, J = 247.5 Hz), 149.9, 131.6 (d, J = 5.7 Hz), 127.6,
122.6 (d, J = 8.2 Hz), 122.4 (d, J = 3.6 Hz), 119.2, 118.2 (d, J = 23.4 Hz),
37.8 (d, J = 17.7 Hz), 30.9, 30.7, 28.5, 27.5, 21.4. 19F{1H} NMR (376
MHz, CDCl3) δ -119.02. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C15H17FNO+ 246.12890; Found 246.1283.
1
22% EtOAc/CH2Cl2) as a brownish-red gummy oil (130 mg, 86%). H
NMR (500 MHz, CDCl3) δ 8.42 (dd, J = 8.0, 1.7 Hz, 1H), 7.62 (ddd, J =
8.6, 7.0, 1.7 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.32 (ddd, J = 8.0, 6.9, 1.0
Hz, 1H), 6.21 – 6.18 (m, 1H), 4.70 (s, 1H), 4.43 (s, 1H), 3.92 (d, J = 7.6
Hz, 1H), 3.76 (s, 3H), 2.55 – 2.37 (m, 2H), 2.17 (s, 3H), 1.82 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 175.8, 150.4, 142.9, 142.8, 135.3,
131.7, 128.8, 126.8, 125.7, 122.9, 121.9, 115.9, 110.8, 40.4, 37.6, 27.0,
21.9, 21.0. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C18H20NO+
266.1539; Found 266.1537.
5-Methyl-5,6,7,8,9,10-hexahydro-11H-cyclohepta[b]quinolin-11-one
(24t). Following procedure D, 9a (100 mg, 0.56 mmol) was treated with
21h (133 mg, 1.19 mmol) to obtain 24t after column chromatography (42-
60% EtOAc/CH2Cl2) as an amorphous white solid (50 mg, 39% yield).
1H NMR (500 MHz, CDCl3) δ 8.49 (dd, J = 8.0, 1.7 Hz, 1H), 7.60 (ddd,
J = 8.7, 6.9, 1.7 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.32 (ddd, J = 8.0, 6.9,
1.0 Hz, 1H), 3.79 (s, 3H), 3.04 – 2.99 (m, 4H), 1.90 – 1.85 (m, 2H), 1.75
– 1.72 (m, 2H), 1.67 – 1.58 (m, 2H). 13C{1H} NMR (126 MHz, CDCl3) δ
175.5, 155.1, 141.1, 131.3, 127.0, 125.4, 124.1, 122.7, 115.6, 35.4, 31.7,
30.9, 26.9, 24.7, 23.9. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C15H18NO+ 228.1383; Found 228.1382.
4,10-Dimethyl-1,3,4,10-tetrahydroacridin-9(2H)-one (24n). Following
procedure D, 9a (100 mg, 0.56 mmol) was treated with 21j (133 mg, 1.19
mmol) to obtain 24n after column chromatography (5-7%
1
MeOH/CH2Cl2) as an amorphous white solid (99 mg, 78% yield). H
NMR (500 MHz, CDCl3) δ 8.48 (dd, J = 8.0, 1.7 Hz, 1H), 7.63 (ddd, J =
8.7, 6.9, 1.7 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.33 (ddd, J = 7.9, 6.8, 0.9
Hz, 1H), 3.78 (s, 3H), 3.22 – 3.16 (m, 1H), 2.97 – 2.92 (m, 1H), 2.56 –
2.49 (m, 1H), 1.92 – 1.83 (m, 3H), 1.81 – 1.71 (m, 1H), 1.33 (d, J = 7.0
Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 177.3, 152.3, 141.5, 131.6,
126.6, 124.5, 122.6, 118.0, 115.2, 33.6, 30.1, 30.1, 22.9, 20.4, 16.4.
HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C15H18NO+ 228.1383;
Found 228.1378.
2-Fluoro-5-methyl-5,6,7,8,9,10-hexahydro-11H-cyclohepta[b]quinolin-
11-one (24u). Following procedure D, 9o (50 mg, 0.26 mmol) was treated
with 21h (61 mg, 0.54 mmol) to obtain 24u after column chromatography
(18-23% EtOAc/CH2Cl2) as an amorphous yellow solid (59 mg, 94%
yield). 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 9.3 Hz, 1H), 7.46 – 7.44
(m, 1H), 7.32 – 7.29 (m, 1H), 3.79 (s, 3H), 3.02 – 2.96 (m, 4H), 1.95 –
1.84 (m, 2H), 1.74 – 1.71 (m, 2H), 1.62 – 1.60 (m, 2H). 13C{1H} NMR
(126 MHz, CDCl3) δ 174.7 (d, J = 3.0 Hz), 158.7 (d, J = 244.1 Hz), 155.3,
137.8, 126.9 (d, J = 6.7 Hz), 123.7, 119.8 (d, J = 25.0 Hz), 117.8 (d, J =
7.7 Hz), 111.54 (d, J = 22.1 Hz), 35.8, 31.7, 31.0, 27.0, 24.7, 24.0.
19F{1H} NMR (376 MHz, CDCl3) δ -119.31. HRMS (ESI-QTOF) m/z:
[M + H]+ Calcd for C15H17FNO+ 246.1301; Found 246.1284.
7-Methoxy-4,10-dimethyl-1,3,4,10-tetrahydroacridin-9(2H)-one (24o).
Following general procedure D, 9f (50 mg, 0.24 mmol) was treated with
21j (57 mg, 0.51 mmol) to obtain 24o after column chromatography (28%
1
EtOAc/CH2Cl2) as an amorphous yellow solid (43 mg, 80% yield). H
NMR (400 MHz, CDCl3) δ 7.88 (d, J = 2.8 Hz, 1H), 7.46 (d, J = 9.3 Hz,
1H), 7.25 (d, J = 7.7 Hz, 1H), 3.92 (s, 3H), 3.78 (s, 3H), 3.18 (m, 1H),
2.96 (dd, J = 17.6, 5.9 Hz, 1H), 2.53 (ddd, J = 17.7, 11.3, 6.5 Hz, 1H),
1.89-1.59 (m, 4H), 1.33 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 176.7, 155.6, 151.6, 136.4, 125.7, 122.5, 117.3, 117.1, 105.6,
55.9, 33.8, 30.23, 30.20, 23.1, 20.5, 16.6. HRMS (ESI-QTOF) m/z: [M +
H]+ Calcd for C16H20NO2+ 258.1489; Found 258.1496.
2-Methoxy-5-methyl-5,6,7,8,9,10-hexahydro-11H-
cyclohepta[b]quinolin-11-one (24v). Following procedure D, 9f (50 mg,
0.24 mmol) was treated with 21h (57 mg, 0.51 mmol) to obtain 24v after
column chromatography (3.1% EtOAc/CH2Cl2) as an amorphous orange-
red solid (43 mg, 70% yield). 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J =
3.2 Hz, 1H), 7.42 (d, J = 9.2 Hz, 1H), 7.24 – 7.20 (m, 1H), 3.92 (s, 3H),
3.79 (s, 3H), 3.03 – 3.00 (m, 4H), 1.89 – 1.84 (m, 2H), 1.74 – 1.70 (m,
2H), 1.65 – 1.60 (m, 2H). 13C{1H} NMR (126 MHz, CDCl3) δ 174.9,
155.6, 154.2, 135.9, 126.6, 123.3, 122.0, 117.3, 106.2, 55.8, 35.5, 31.8,
30.9, 27.1, 24.9, 24.1. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C16H20NO2+ 258.1489; Found 258.1483.
6,7-Dimethoxy-2,10-dimethyl-1,3,4,10-tetrahydroacridin-9(2H)-one
(24p). Following procedure D, 9v (50 mg, 0.21 mmol) was treated with
21c (50 mg, 0.44 mmol) to obtain 24p after column chromatography (4-
5% MeOH/CH2Cl2) as an amorphous off white solid (19 mg, 32% yield).
1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 6.78 (s, 1H), 4.01 (s, 3H),
4.00 (s, 3H), 3.70 (s, 3H), 3.05 – 2.98 (m, 1H), 2.95 – 2.68 (m, 2H), 2.19
– 2.08 (m, 1H), 2.05 – 1.94 (m, 1H), 1.72 (br.s, overlapped, 1H), 1.50 –
1.38 (m, 1H), 1.12 (d, J = 6.6 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 175.6, 152.9, 146.5, 146.2, 136.8, 118.9, 118.1, 106.1, 96.5, 56.2, 56.1,
33.7, 31.2, 30.9, 28.6, 27.6, 21.4. HRMS (ESI-QTOF) m/z: [M + H]+
Calcd for C17H22NO3+ 288.1594; Found 288.1584.
5-Methyl-1,3,4,5-tetrahydro-10H-pyrano[4,3-b]quinolin-10-one (24w).
Following general procedure D, 9a (80 mg, 0.45 mmol) was treated with
21f (95 mg, 0.95 mmol) to obtain 24w after column chromatography
(10% MeOH/CH2Cl2) as an amorphous off white solid (88 mg, 90%
yield). 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 8.0 Hz, 1H), 7.64 (t, J
= 7.9 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 4.75 (s,
2H), 4.01 – 3.98 (m, 2H), 3.69 (s, 3H), 2.83 – 2.80 (m, 2H). 13C{1H} NMR
(101 MHz, CDCl3) δ 174.9, 145.4, 141.0, 131.9, 126.4, 124.9, 123.1,
10-Methyl-1,10-dihydroacridin-9(2H)-one (24q). Following general
procedure D, 9a (100 mg, 0.56 mmol) was treated with 21a (114 mg, 1.19
mmol) to obtain 24q after column chromatography (1.5-2%
MeOH/CH2Cl2) as an amorphous yellow solid (77 mg, 65% yield). 1H
NMR (400 MHz, CDCl3) δ 8.48 (dd, J = 7.9, 1.6 Hz, 1H), 7.63 – 7.58 (m,
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116.8, 115.0, 64.4, 63.8, 33.1, 27.4. HRMS (ESI-QTOF) m/z: [M + H]+
6-Methoxy-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
(9f).
Calcd for C13H14NO2+ 216.1019; Found 216.1019.
Commercially available 2-amino-5-methoxybenzoic acid (Ark Pharm,
159.9 mg, 0.96 mmol) was subjected to procedure E to give 9f (140.7 mg,
71% yield) as an amorphous mauve purple solid. 1H NMR (400 MHz, d6-
DMSO): δ 7.48-7.39 (m, 3H), 3.84 (s, 3H), 3.45 (s, 3H). Characterization
matched previous report.38
1
2
3
4
5
6
7
8
tert-Butyl-5-methyl-10-oxo-3,4,5,10-
tetrahydrobenzo[b][1,6]naphthyridine-2(1H)-carboxylate
(24x).
Following general procedure D, 9a (100 mg, 0.56 mmol) was treated with
21e (236 mg, 1.19 mmol) to obtain title compound 24x after column
chromatography (35-40% EtOAc/CH2Cl2) as an amorphous off white
solid (137 mg, 78% yield). 1H NMR (500 MHz, CDCl3) δ 8.47 (d, J =
8.0 Hz, 1H), 7.68 – 7.65 (m, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.38 – 7.35
(m, 1H), 4.52 (s, 2H), 3.74 (s, 3H), 3.75 –3.73 (m, overlapped 2H), 2.90
– 2.87 (m, 2H), 1.50 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3) δ 175.4,
154.9, 146.5, 141.2, 132.1, 126.4, 124.8, 123.1, 116.0, 115.1, 80.3, 41.7,
39.5, 33.6, 28.5(3C), 27.9. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C18H23N2O3+ 315.1703; Found 315.1702.
7-Methoxy-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
(9g).
Commercially available 2-amino-4-methoxybenzoic acid (Chem-Impex,
151.3 mg, 0.91 mmol) was subjected to procedure E to give 9g (112.6
mg, 60% yield) as an amorphous off-white solid. 1H NMR (400 MHz, d6-
DMSO): δ 7.93 (d, J = 8.8 Hz, 1H), 6.92 (dd, J = 8.5, 2.2 Hz, 1H), 6.85
(d, J = 2.2 Hz, 1H), 3.94 (s, 3H), 3.46 (s, 3H). Characterization matched
previous report.39
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8-Methoxy-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
(9h).
10-Methyl-2-phenyl-1,3,4,10-tetrahydroacridin-9(2H)-one
(24y).
Commercially available 2-amino-3-methoxybenzoic acid (Acros
Following general procedure D, 9a (50 mg, 0.28 mmol) was treated with
21d (103 mg, 0.59 mmol) to obtain 24y after column chromatography
(21-25% EtOAc/CH2Cl2) as an amorphous white solid (66 mg, 80%
yield). 1H NMR (500 MHz, CDCl3) δ δ 8.50 (dd, J = 8.0, 1.7 Hz, 1H),
7.64 (ddd, J = 8.7, 7.0, 1.7 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.37 – 7.28
(m, 5H), 7.25 – 7.21 (m, 1H), 3.74 (s, 3H), 3.29 – 3.20 (m, 1H), 2.99 –
2.87 (m, 3H), 2.7. – 2.65 (m, 1H), 2.32 – 2.22 (m, 1H), 2.03 – 1.95 (m,
1H). 13C{1H} NMR (126 MHz, CDCl3) δ 176.7, 147.8, 145.4, 141.2,
131.7, 128.5(2C), 126.9(2C), 126.8, 126.4, 124.7, 122.7, 118.7, 114.9,
38.5, 33.6, 30.3, 29.7, 28.9. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C20H20NO+ 290.1539; Found 290.1530.
Organics, 154.3 mg, 0.93 mmol) was subjected to procedure E to give 9h
1
(125.4 mg, 65% yield) as an amorphous off-white solid. H NMR (400
MHz, d6-DMSO): δ 7.59 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H),
7.30 (t, J = 8.0 Hz, 1H), 3.89 (s, 3H), 3.63 (s, 3H). Characterization
matched previous reports.39, 40
6-Chloro-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
(9i).
Commercially available 2-amino-5-chlorobenzoic acid (Chem-Impex,
171.2 mg, 1.00 mmol) was subjected to procedure E to give 9i (120.7 mg,
1
57% yield) as an amorphous off-white solid. H NMR (400 MHz, d6-
DMSO): δ 7.97 (d, J = 2.5 Hz, 1H), 7.90 (dd, J = 8.9, 2.6 Hz, 1H), 7.48
(d, J = 8.9 Hz, 1H), 3.46 (s, 3H). Characterization matched previous
report.38
General Procedure E. Synthesis of N-substituted isatoic anhdyrides (9b-
v). 1H-Benzo[d][1,3]oxazine-2,4-dione. To
a
solution of the
7-Chloro-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
(9j).
corresponding 2-amino benzoic acid (2 mmol) in dry THF (10 mL) under
Ar(g) at room temperature in an oven dry 25 mL round bottom flask
equipped with stir bar was added a 15 wt% solution of phosgene in
toluene (1.5 mL, 2.10 mmol, 1.2 equiv.) dropwise. The mixture was
stirred at r.t. for 24 h before diluting with hexanes (15 mL). The resulting
precipitate was collected by filtration to give the corresponding N-H
isatoic anhydride (1H-benzo[d][1,3]oxazine-2,4-dione), which was dried
under high vacuum. The solid was then added (1 mmol) to an oven dried
round bottom flask equipped with stir bar and dissolved with dry DMF (2
mL) before cooling to 0°C with an ice bath. To the reaction was then
added iPr2NEt (0.4 mL, 2.3 mmol, 2.3 equiv.) and alkyl halide (3.2 mmol,
3.2 equiv.) before allowing the reaction to warm to r.t and stirring for 24h.
After pouring the reaction over crushed ice (20 mL), the resulting
precipitate was collected by filtration, furnishing the desired N-
substituted isatoic anhydride 9.
Commercially available 2-amino-4-chlorobenzoic acid (Alfa-Aesar,
170.6 mg, 1.0 mmol) was subjected to procedure E to give 9j (176.1 mg,
1
83% yield) as an amorphous off-white solid. H NMR (400 MHz, d6-
DMSO): δ 8.00 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 1.8 Hz, 1H), 7.39 (dd, J
= 8.4, 1.8 Hz, 1H), 3.46 (s, 3H). Characterization matched previous
report.38
6-Bromo-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
(9k).
Commercially available 6-bromo-2H-benzo[d][1,3]oxazine-2,4(1H)-
dione (Matrix Scientific, 234.0 mg, 0.97 mmol) was methylated
according to procedure E to give 9k (222.4 mg, 90% yield) as an
amorphous off-white solid. 1H NMR (400 MHz, d6-DMSO): δ 8.07 (d, J
= 2.5 Hz, 1H), 8.01 (dd, J = 8.9, 2.5 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H),
3.45 (s, 3H). Characterization matched previous report.38
7-Bromo-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
(9l).
Commercially available 2-amino-4-bromobenzoic acid (Ark Pharm,
1-Methyl-2H-naphtho[2,3-d][1,3]oxazine-2,4(1H)-dione
(9b).
207.5 mg, 0.96 mmol) was subjected to procedure E to give 9l (234.4 mg,
Commercially available 3-amino-2-napthoic acid (Chem Cruz, 181 mg,
0.97 mmol) was subjected to procedure E to give 9b (210.5 mg, 96%
yield) as an amorphous off-white solid. 1H NMR (400 MHz, d6-DMSO):
δ 8.80 (s, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.85 (s,
1H), 7.72 (ddd, J = 8.2, 6.7, 1.2 Hz, 1H), 7.56 (ddd, J = 8.2, 6.9, 1.2 Hz,
1H), 3.57 (s, 3H). Characterization matched previous report.36
1
95% yield) as an amorphous off-white solid. H NMR (400 MHz, d6-
DMSO): δ 7.90 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 1.7 Hz, 1H), 7.52 (dd, J
= 8.3, 1.5 Hz, 1H), 3.46 (s, 3H). Characterization matched previous
report.41
5-Fluoro-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
(9m).
Commercially available 2-amino-6-fluorobenzoic acid (Oakwood, 148.7
mg, 0.96 mmol) was subjected to procedure E to give 9m (151.5 mg, 81%
yield) as an amorphous off-white solid. 1H NMR (400 MHz, d6-DMSO):
δ 7.85 (td, J = 8.4, 5.9 Hz, 1H), 7.26 (d, J = 8.6 Hz, 1H), 7.17 (dd, J =
10.5, 8.4 Hz, 1H), 3.46 (s, 3H). 19F NMR (376 MHz, d6-DMSO): δ -
109.65. Characterization matched previous reports.42
1,5-Dimethyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
Commercially available 2-amino-6-methylbenzoic acid (Chem-Impex,
(9c).
144 mg, 0.95 mmol) was subjected to procedure E to give 9c (152.4 mg,
1
84% yield) as an amorphous off-white solid. H NMR (400 MHz, d6-
DMSO): δ 7.70 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.18 (d, J =
7.5 Hz, 1H), 3.44 (s, 3H), 2.64 (s, 3H). Characterization matched previous
report.37
6-Fluoro-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
(9n).
Commercially available 2-amino-5-fluorobenzoic acid (Oakwood, 154.0
mg, 0.99 mmol) was subjected to procedure E to give 9n (173.4 mg, 90%
yield) as an amorphous off-white solid. 1H NMR (400 MHz, d6-DMSO):
δ 7.80-7.75 (m, 2H), 7.50 (dd, J = 8.8, 4.1 Hz, 1H), 3.47 (s, 3H). 19F NMR
(376 MHz, d6-DMSO): δ -119.32. Characterization matched previous
reports.38
1,6-Dimethyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
Commercially available 2-amino-5-methylbenzoic acid (Chem-Impex,
(9d).
152 mg, 1.0 mmol) was subjected to procedure E to give 9d (174.4 mg,
1
91% yield) as an amorphous off-white solid. H NMR (400 MHz, d6-
DMSO): δ 7.82 (d, J = 2.1 Hz, 1H), 7.68 (dd, J = 8.5, 2.1 Hz, 1H), 7.35
(d, J = 8.5 Hz, 1H), 3.45 (s, 3H), 2.37 (s, 3H). Characterization matched
previous report.38
7-Fluoro-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
(9o).
Commercially available 2-amino-4-fluorobenzoic acid (Ark Pharm,
151.5 mg, 0.98 mmol) was subjected to procedure E to give 9o (167.5
mg, 88% yield) as an amorphous off-white/tan solid. 1H NMR (400 MHz,
d6-DMSO): δ 8.08 (dd, J = 8.8, 6.2 Hz, 1H), 7.40 (dd, J = 11.4, 2.3 Hz,
1H), 7.19 (td, J = 8.6, 2.3 Hz, 1H), 3.44 (s, 3H). 19F NMR (376 MHz, d6-
DMSO): δ -98.92. Characterization matched previous report.38
1,7-Dimethyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
Commercially available 2-amino-4-methylbenzoic acid (Ark Pharm,
(9e).
150.5 mg, 1.0 mmol) was subjected to procedure E to give 9e (138.0 mg,
1
72% yield) as an amorphous off-white solid. H NMR (400 MHz, d6-
DMSO): δ 7.90 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H),
3.46 (s, 3H), 2.47 (s, 3H). Characterization matched previous report.38
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The Journal of Organic Chemistry
8-Fluoro-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
(9p).
1.00 mmol) was treated as described in procedure E but using NaH as the
Commercially available 2-amino-3-fluorobenzoic acid (Ark Pharm,
154.4 mg, 1.0 mmol) was subjected to procedure E to give 9p (147.2 mg,
75% yield) as an amorphous white solid. 1H NMR (400 MHz, d6-DMSO):
δ 7.85 (dd, J = 8.0 Hz, 1H), 7.75 (ddd, J = 14.3, 8.2, 1.6 Hz, 1H), 7.33 (td,
J = 8.0, 4.1 Hz, 1H), 3.61 (s, 3H). 19F NMR (376 MHz, d6-DMSO): δ -
122.37. Characterization matched previous report. 38
base instead of iPr2EtN, to give 9v (212 mg, 89% yield) as an amorphous
off-white solid. 1H NMR (400 MHz, d6-DMSO): δ 7.34 (s, 1H), 6.88 (s,
1H), 3.98 (s, 3H), 3.83 (s, 3H), 3.50 (s, 3H). Characterization matched
previous report.38
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4
5
6
7
8
9
1-Phenyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (9q). To an oven dried
flask under Ar(g) was added commercially available 2-
(phenylamino)benzoic acid (Acros Organics, 425.1 mg, 1.99 mmol, 1.0
equiv.) and dry THF (DrySolv, 10 mL). A 15 wt% solution of phosgene
in toluene (1.5 mL, 2.10 mmol, 1.2 equiv.) was added dropwise, followed
by dropwise addition of triethylamine (0.25 mL, 1.80 mmol, NOTE:
Rapid gas evolution occurs). The reaction was stirred at r.t. for 24 h before
diluting with hexanes (15 mL). The resulting precipitate was collected by
filtration. The collected solid was then triturated with H2O (15 mL) to
remove triethylamine salts, and then the desired product was collected by
filtration to give 9q (358.7 mg, 75% yield) as an amorphous off-white
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
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NMR spectra for all new compounds (9u, 24c-p, 24r-s, 24u-y, 27a-b,
27d-r, 28a-b, 28d-f, 28h-r, 29a-r, 30-31, 33-35) and previously reported
compounds synthesized by the methods described herein (3, 9b-t,
9v, 24a-b, 24q, 24t, 32). Additional results in the optimization of
annulation between 9a and 26a-b, 21c. NMR experiments regarding
DBU-induced degradation of 27a.
1
solid. H NMR (400 MHz, d6-DMSO): δ 8.06 (dd, J = 7.9 Hz, 1.6 Hz,
1H), 7.68-7.57 (m, 4H), 7.50 (d, J = 6.9 Hz, 2H), 7.32 (t, J = 7.6 Hz, 1H),
6.41 (d, J = 8.4Hz, 1H). Characterization matched previous report.43
1-Benzyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (9r). To commercially
available 2H-benzo[d][1,3]oxazine-2,4(1H)-dione (OxChem, 645.8 mg,
3.96 mmol, 1.0 equiv.) in DMAc (3.5 mL) was added iPr2NEt (1.4 mL,
8.04 mmol, 2 equiv.). Benzyl bromide (0.5 mL, 4.21 mmol, 1.1 equiv.)
was added, and the reaction was heated to 80 °C while stirring for 3 h.
The reaction was then cooled to rt and poured over crushed ice (80 mL).
The resulting precipitate was collected by filtration to give 9r (959.8 mg,
AUTHOR INFORMATION
Corresponding Author
Email: jennifer.golden@wisc.edu
Author Contributions
1
96% yield) as an amorphous off-white solid. H NMR (400 MHz, d6-
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
DMSO): δ 8.04 (dd, J = 7.9, 1.6 Hz, 1H), 7.73 (td, J = 7.5, 1.2 Hz, 1H),
7.41 (d, J = 7.0 Hz, 2H), 7.36-7.23 (m, 5H), 5.29 (s, 2H). Characterization
matched previous reports.38, 44
1-(4-Methoxybenzyl)-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
(9s).
Notes
Commercially available 2H-benzo[d][1,3]oxazine-2,4(1H)-dione
The authors declare no competing financial interest.
(OxChem, 162.9 mg, 1.00 mmol, 1.0 equiv.) was added to DMF (2 mL),
and the solution was cooled to 0°C before adding iPr2NEt (0.40 mL, 2.30
mmol, 2.3 equiv.). To this mixture was added 4-methoxybenzyl bromide
(0.30 mL, 2.10 mmol, 2.1 equiv.), and the reaction was allowed to warm
to rt while stirring for 14 h. The reaction was then poured over crushed
ice (20 mL). The resulting precipitate was collected by filtration and then
purified by column chromatography (4g column, CH2Cl2, 10 mL/min) to
ACKNOWLEDGMENT
J.E.G. acknowledges institutional support from the Office of the Vice
Chancellor for Research and Graduate Education at the University of
Wisconsin-Madison with funding from the Wisconsin Alumni Research
Foundation (WARF): UW2020 infrastructure grant (JEG, PI). This work
made use of the instrumentation at the UW − Madison Medicinal
Chemistry Center, funded by the UW School of Pharmacy. MMK
gratefully acknowledges support from the National Science Foundation
Graduate Research Fellowship Program (DGE-1256259) and the
American Foundation for Pharmaceutical Education Pre-Doctoral
Fellowship in Pharmaceutical Sciences Program.
1
give 9s (251.4 mg, 89% yield) as an amorphous white solid. H NMR
(400 MHz, d6-DMSO): δ 8.02 (dd, J = 7.8, 1.5 Hz, 1H), 7.74 (tt, J = 8.5,
1.3 Hz, 1H), 7.36-7.28 (m, 4H), 6.89 (d, J = 8.4 Hz, 2H), 5.22 (s, 2H),
3.72 (s, 3H). Characterization matched previous report.45
1-(4-(Trifluoromethyl)benzyl)-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
(9t). Commercially available 2H-benzo[d][1,3]oxazine-2,4(1H)-dione
(OxChem, 150 mg, 0.92 mmol, 1 equiv.) in DMF (2 mL) was cooled to 0
°C before adding NaH (26 mg, 1.10 mmol, 1.2 equiv.). To this mixture
was added 4-(trifluoromethyl)benzyl bromide (262 mg, 1.10 mmol, 1.2
equiv.), and the reaction was allowed to warm to rt and stirred 14 h. After
the reaction was poured over crushed ice (20 mL), the resulting precipitate
was collected by filtration, the filter cake was washed with cold water (1
x 10 mL) and then hexanes (1 x 10 mL) before drying under high vacuum
to give 9s (243 mg, 82% yield) as an amorphous off-white solid. 1H NMR
(400 MHz, d6-DMSO): δ 8.05 (dd, J = 7.8, 1.6 Hz, 1H), 7.76-7.64 (m,
REFERENCES
1. Vitaku, E.; Smith, D. T.; Njardarson, J. T., Analysis of the structural
diversity, substitution patterns, and frequency of nitrogen
heterocycles among U.S. FDA approved pharmaceuticals. J. Med.
Chem. 2014, 57, 10257-10274.
2. Taylor, R. D.; MacCoss, M.; Lawson, A. D. G., Rings in drugs. J.
Med. Chem. 2014, 57, 5845-5859.
5H), 7.32 (t, J = 7.54 Hz, 1H), 7.21 (d, J = 8.49 Hz, 1H), 5.39 (s, 2H). 19
F
NMR (376 MHz, d6-DMSO): δ -60.98. Characterization matched
3. Michael, J. P., Quinoline, quinazoline and acridone alkaloids. Nat.
Prod. Rep. 2003, 20, 476-93.
previous report.45
1-Methyl-2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-
4. Beteck, R. M.; Smit, F. J.; Haynes, R. K.; N'Da, D. D., Recent
progress in the development of anti-malarial quinolones. Malaria J.
2014, 13, 339.
carbonitrile (9u). Commercially available 2-amino-5-cyanobenzoic acid
(Ark Pharm, 159.1 mg, 0.98 mmol, 1.0 equiv.) was subjected to procedure
E to give 9u (179.7 mg, 91% yield) as an amorphous pale yellow solid.
1H NMR (400 MHz, d6-DMSO): δ 8.45 (d, J = 2.1 Hz, 1H), 8.26 (dd, J =
8.8, 2.0 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 3.49 (s, 3H). 13C NMR (101
MHz, d6-DMSO): δ 157.7, 147.4, 145.3, 139.8, 133.8, 117.6, 116.2,
112.8, 106.0, 32.1. HRMS (ESI-QTOF) m/z: [M + Na]+ Calcd for
C10H6N2O3Na+ 225.0271; Found 225.0271.
5. Capper, M. J.; O’Neill, P. M.; Fisher, N.; Strange, R. W.; Moss, D.;
Ward, S. A.; Berry, N. G.; Lawrenson, A. S.; Hasnain, S. S.; Biagini,
G. A.; Antonyuk, S. V., Antimalarial 4(1H)-pyridones bind to the Qi
site of cytochrome bc1. Proc. Natl. Acad. Sci. USA 2015, 112, 755-
760.
6. Cen, J.; Guo, H.; Hong, C.; Lv, J.; Yang, Y.; Wang, T.; Fang, D.;
Luo, W.; Wang, C., Development of tacrine-bifendate conjugates
6,7-Dimethoxy-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (9v).
Commercially available 2-amino-4,5-dimethoxybenzoic acid (197 mg,
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with improved cholinesterase inhibitory and pro-cognitive efficacy
substituted-3,4-dihydro-1,9(2H,10H)-acridinediones and related
and reduced hepatotoxicity. Eur. J. Med. Chem. 2018, 144, 128-136.
structures. J. Med. Chem. 1992, 35, 3429-3447.
1
7. Takahashi, S.; Kakinuma, N.; Iwai, H.; Yanagisawa, T.; Nagai, K.;
Suzuki, K.; Tokunaga, T.; Nakagawa, A., Quinolactacins A, B and
C: novel quinolone compounds from Penicillium sp. EPF-6. II.
Physico-chemical properties and structure elucidation. J. Antibiot.
(Tokyo) 2000, 53, 1252-1256.
25. Coppola, G. M.; Schuster, H. F., The chemistry of 2H-3,1-
benzoxazine-2,4(1H)-dione (isatoic anhydride). 21. a mild process
for the preparation of 10-alkyl-9-acridanones and it's application to
the synthesis of acridone alkaloids. J. Het. Chem. 1989, 26, 957-964.
2
3
4
5
6
7
8
9
26. Reed, R. A., 115. Hydroacridones. Synthesis and dehydrogenation.
8. Clark, B.; Capon, R. J.; Lacey, E.; Tennant, S.; Gill, J. H.,
Quinolactacins revisited: from lactams to imide and beyond. Org.
Biomol. Chem. 2006, 4, 1512-1519.
J. Chem. Soc. 1944, 425-426.
27. Ji, X.; Li, D.; Wang, Z.; Tan, M.; Huang, H.; Deng, G.-J., Visible
light-induced aerobic oxidation of indoles: One-pot formation of 4-
quinolones at room temperature. Asian J. Org. Chem. 2018, 7, 711-
714.
9. Kim, W.-G.; Song, N.-K.; Yoo, I.-D., Quinolactacins A1 and A2,
new acetylcholinesterase inhibitors from Penicillium citrinum. J.
Antibiot. 2001, 54, 831-835.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
28. Myrtle, J. D.; Beekman, A. M.; Barrow, R. A., Ravynic acid, an
antibiotic polyeneyne tetramic acid from Penicillium sp. elucidated
through synthesis. Org. Biomol. Chem. 2016, 14, 8253-8260.
10. Cappelli, A.; Anzini, M.; Vomero, S.; Mennuni, L.; Makovec, F.;
Doucet, E.; Hamon, M.; Menziani, M. C.; De Benedetti, P. G.;
Giorgi, G.; Ghelardini, C.; Collina, S., Novel potent 5-HT3 receptor
ligands based on the pyrrolidone structure: synthesis, biological
evaluation, and computational rationalization of the ligand–receptor
interaction modalities. Bioorg. Med. Chem. 2002, 10, 779-801.
29. Taylor, J. E.; Bull, S. D.; Williams, J. M. J., Amidines, isothioureas,
and guanidines as nucleophilic catalysts. Chem. Soc. Rev. 2012, 41,
2109-2121.
30. Abe, M.; Imai, T.; Ishii, N.; Usui, M., Synthesis of quinolactacide via
an acyl migration reaction and dehydrogenation with manganese
dioxide, and its insecticidal activities. Biosci. Biotechnol. Biochem.
2006, 70, 303-306.
11. Gao, H.; Zhang, L.; Zhu, T.; Gu, Q.; Li, D., Unusual pyrrolyl 4-
quinolinone alkaloids from the marine-derived fungus Penicillium
sp. Ghq208. Chem. Pharm. Bull. 2012, 60, 1458-1460.
12. Shao, C.-L.; Wang, C.-Y.; Gu, Y.-C.; Wei, M.-Y.; Pan, J.-H.; Deng,
D.-S.; She, Z.-G.; Lin, Y.-C., Penicinoline, a new pyrrolyl 4-
quinolinone alkaloid with an unprecedented ring system from an
endophytic fungus Penicillium sp. Bioorg. Med. Chem. Lett. 2010,
20, 3284-3286.
31. NaHMDS and KHMDS were also surveyed for the pilot reaction but
gave inferior yields compared to LiHMDS.
32. Fuchs, P. L., In Reagents for Silicon-Mediated Organic Synthesis.
John Wiley & Sons, 2011.
33. Fraser, R. R.; Mansour, T. S.; Savard, S., Acidity measurements on
pyridines in tetrahydrofuran using lithiated silylamines. J. Org.
Chem. 1985, 50, 3232-3234.
13. Shao, C.; Wei, M.; Jiang, Y. Panicinotam derivative, and preparation
method therefor and uses thereof. WO Patent WO2018171740, 2018.
14. Tamura, T.; Kuriyama, H.; Agoh, M.; Agoh, Y.; Soga, M.; Mori, T.
1,2-disubstituted 1,4-dihydro-4-oxoquinoline compounds. Eur Patent
Appl. EP1380575A1, 2000.
34. McNab, H.; Montgomery, J.; Parsons, S.; Tredgett, D. G.,
Pyrrolizine-1,3-dione. Org. Biomol. Chem. 2010, 8, 4383-4387.
35. Zhao, B.; Burgess, K., Click-addressable cassette for photoaffinity
15. Schmidt, L. H., Antimalarial properties of floxacrine,
a
labeling. ACS Med. Chem. Lett. 2018, 9, 155-158.
dihydroacridinedione derivative. Antimicrob. Agents Chemother.
1979, 16, 475-485.
36. Unangst, P. C.; Brown, R. E.; Fabian, A.; Fontseré, F., 2-Indolyl
ketone synthesis. J. Het. Chem. 1979, 16, 661-666.
16. Rahman, A.-u.; Khalid, A.; Sultana, N.; Ghayur, M. N.; Mesaik, M.
A.; Khan, M. R.; Gilani, A. H.; Choudhary, M. I., New natural
cholinesterase inhibiting and calcium channel blocking quinoline
alkaloids. J. Enzyme Inhib. Med. Chem. 2006, 21, 703-710.
37. Costil, R.; Lefebvre, Q.; Clayden, J., Medium-sized-ring analogues
of dibenzodiazepines by a conformationally induced Smiles ring
expansion. Angew. Chem., Int. Ed. 2017, 56, 14602-14606.
38. Guan, Z.-H.; Chen, M.; Ren, Z.-H., Palladium-catalyzed
regioselective carbonylation of C–H Bonds of N-alkyl anilines for
synthesis of isatoic anhydrides. J. Am. Chem. Soc. 2012, 134, 17490-
17493.
17. Yan, G.; Golden, J. E., Palladium-catalyzed cyclocarbonylation of
pyridinylated vinylogous amides and ureas to generate ring-fused
pyridopyrimidinones. Org. Lett. 2018, 20, 4393-4396.
18. Jaffett, V. A.; Nerurkar, A.; Cao, X.; Guzei, I. A.; Golden, J. E.,
39. D’Souza, A. M.; Spiccia, N.; Basutto, J.; Jokisz, P.; Wong, L. S. M.;
Meyer, A. G.; Holmes, A. B.; White, J. M.; Ryan, J. H., 1,3-Dipolar
cycloaddition−decarboxylation reactions of an azomethine ylide with
isatoic anhydrides: Formation of novel benzodiazepinones. Org. Lett.
2011, 13, 486-489.
Regiospecific synthesis of elusive C3-functionalized (E)-
arylamidines using
a
telescoped, multicomponent, dual
rearrangement strategy. Org. Biomol. Chem. 2019, 17, 3118-3128.
19. Zhang, X.; Jiang, W.; Sui, Z., Concise enantioselective syntheses of
quinolactacins A and B through alternative Winterfeldt oxidation. J.
Org. Chem. 2003, 68, 4523-4526.
40. Coppola, G. M., The chemistry of 2H-3,1-benzoxazine-2,4(1H)-
dione (isatoic anhydride). 10. Reactions with ester enolates.
Synthesis of 4-hydroxy-1-methyl-3-prenyl-2(1H)-quinolinones,
crucial intermediates in the synthesis of quinoline alkaloids. J. Het.
Chem. 1983, 20, 1217-1221.
20. Shankaraiah, N.; da Silva, W. A.; Andrade, C. K. Z.; Santos, L. S.,
Enantioselective total synthesis of (S)-(−)-quinolactacin B.
Tetrahedron Lett. 2008, 49, 4289-4291.
21. Park, S.-J.; Cho, K.-N.; Kim, W.-G.; Lee, K.-I., An expedient
synthesis of (+)-quinolactacin A2. Tetrahedron Lett. 2004, 45, 8793-
8795.
41. Lee, A.; Zhu, J. L.; Feoktistova, T.; Brueckner, A. C.; Cheong, P. H.-
Y.; Scheidt, K. A., Carbene-catalyzed enantioselective
decarboxylative annulations to access dihydrobenzoxazinones and
quinolones. Angew. Chem., Int. Ed. 2019, 131, 6002-6006.
22. Saito, K.; Yoshida, M.; Uekusa, H.; Doi, T., Facile synthesis of
pyrrolyl 4-quinolinone alkaloid quinolactacide by 9-AJ-catalyzed
tandem acyl transfer–cyclization of o-alkynoylaniline derivatives.
ACS Omega 2017, 2, 4370-4381.
42. Dong, G.; Wang, S.; Miao, Z.; Yao, J.; Zhang, Y.; Guo, Z.; Zhang,
W.; Sheng, C., New tricks for an old natural product: Discovery of
highly potent evodiamine derivatives as novel antitumor agents by
systemic structure–activity relationship analysis and biological
evaluations. J. Med. Chem. 2012, 55, 7593-7613.
23. Calculated pKa values at the appropriate temperature were obtained
using MarvinSketch, version 18.25, ChemAxon: Budapest, Hungary,
2018.
43. Tang, Q.; Zhai, X.; Tu, Y.; Wang, P.; Wang, L.; Wu, C.; Wang, W.;
Xie, H.; Gong, P.; Zheng, P., Synthesis and antiproliferative activity
of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-
oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety. Bioorg.
Med. Chem. Lett. 2016, 26, 1794-1798.
24. Kesten, S. J.; Degnan, M. J.; Hung, J.; McNamara, D. J.; Ortwine, D.
F.; Uhlendorf, S. E.; Werbel, L. M., Antimalarial drugs. 64. Synthesis
and antimalarial properties of 1-imino derivatives of 7-chloro-3-
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44. Wang, Z.-X.; Xiang, J.-C.; Wang, M.; Ma, J.-T.; Wu, Y.-D.; Wu, A.-
45. Zhang, W.-Z.; Zhang, N.; Sun, Y.-Q.; Ding, Y.-W.; Lu, X.-B.,
Palladium-catalyzed cyclization reaction of o-iodoanilines, CO2, and
CO: Access to isatoic anhydrides. ACS Cat. 2017, 7, 8072-8076.
X., One-pot total synthesis of evodiamine and its analogues through
a continuous biscyclization reaction. Org. Lett. 2018, 20, 6380-6383.
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