Synthesis and Anti-inflammatory Evaluation of 2-Aminobenzaldehydes via Ir(III)-Catalyzed C-H Amidation of Aldimines with Acyl Azides

Article abstract of DOI:10.1021/acs.joc.7b01280

The aldimine-directed C-H amidation of various arenes with N-acyl azides as amidation surrogates under cationic iridium(III) catalysis is described. This transformation efficiently provides a range of 2-aminobenzaldehyde derivatives with excellent site selectivity and functional group compatibility. The resulting 2-aminobenzaldehyde framework provides facile access to a range of biologically interesting heterocycles. In addition, all synthetic compounds were screened for anti-inflammatory activity against interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) with lipopolysaccharide (LPS)-induced RAW264.7 cells. Generally, a range of ortho-amidated benzaldehydes displayed promising inhibitory activity against IL-1β and TNF-α compared to dexamethasone as a positive control. Notably, compounds (3ae and 4ac) were found to exhibit potent anti-inflammatory activity stronger than that of dexamethasone.

Full text of DOI:10.1021/acs.joc.7b01280

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Article
Synthesis and Anti-inflammatory Evaluation of 2-Aminobenzaldehydes
via Ir(III)-Catalyzed C-H Amidation of Aldimines with Acyl Azides
Saegun Kim, Prashant Chakrasali, Hyo Sun Suh, Neeraj Kumar Mishra, Taeyoung
Kim, Sang Hoon Han, Hyung Sik Kim, Byung-Moo Lee, Soo Bong Han, and In Su Kim
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 Jun 2017
Downloaded from http://pubs.acs.org on June 23, 2017
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The Journal of Organic Chemistry
Synthesis and Antiꢀinflammatory Evaluation of 2ꢀAminobenzaldehydes
via Ir(III)ꢀCatalyzed C−H Amidation of Aldimines with Acyl Azides
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Saegun Kim,a,† Prashant Chakrasali,b,c,† Hyo Sun Suh,a Neeraj Kumar Mishra,a Taeyoung Kim,a
Sang Hoon Han,a Hyung Sik Kim,a Byung Mu Lee,a,* Soo Bong Han,b,c,* and In Su Kima,*
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a School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
b Division of Bio & Drug Discovery, Korea Research Institute of Chemical Technology, Daejeon 305-600,
Republic of Korea
c Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 217
Gajeongro, Yuseong, Daejeon 305-355, Republic of Korea
* Corresponding authors. Eꢀmail: bmlee@skku.edu (B.M.Lee), sbhan@krict.re.kr (S.B.Han), insukim@skku.edu
(I.S.Kim)
† These authors equally contributed.
Keywords: Acyl Azides; Amidation; Antiꢀinflammatory; C–H Functionalization; Iridium.
Abstract
The aldimineꢀdirected C–H amidation of various arenes with Nꢀacyl azides as amidation surrogates
under cationic iridium(III) catalysis is described. This transformation efficiently provides a range of 2ꢀ
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aminobenzaldehydes derivatives with excellent siteꢀselectivity and functional group compatibility. The
resulting 2ꢀaminobenzaldehyde framework provides facile access to a range of biologically interesting
heterocycles. In addition, all synthetic compounds were screened for antiꢀinflammatory activity against
interleukinꢀ1β (ILꢀ1β) and tumor necrosis factor alpha (TNFꢀα) with lipopolysaccharide (LPS)ꢀinduced
RAW264.7 cells. Generally, a range of orthoꢀamidated benzaldehydes displayed promising inhibitory
activity against ILꢀ1β and TNFꢀα compared to dexamethasone as a positive control. Notably, compounds
(3ae and 4ac) were found to exhibit potent antiꢀinflammatory activity stronger than that of
dexamethasone.
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Introduction
Transitionꢀmetalꢀcatalyzed C−N bond formation reactions via C−H bond activation have been of
great interest in organic and medicinal chemistry due to the prevalence of bioactive nitrogenꢀcontaining
heterocycles.1 In this area, various Nꢀamidation surrogates, such as Nꢀcarboxylates, Nꢀtosylates, organic
azides and dioxazolones, have been investigated as relevant sources for the C−H amidation reactions.2
Particularly, Nꢀacyl azides have been intensively studied in the direct C−N amidation reactions of sp2
C−H bonds,3 although Nꢀacyl azides can be readily converted to aryl isocyanates through the Curtius
rearrangement under thermal and photochemical conditions.4 Chang reported a pioneering example on the
C−H amidation reaction of arenes and alkenes with various Nꢀacyl azides as amidating reagents under
Ir(III) and Ru(II) catalysis.3a,b Zhu also disclosed a single example on the Cu(I)Tcꢀcatalyzed C−N bond
formation of phenylpyridine with 4ꢀmethylbenzoyl azide.3c König demonstrated the Ru(II)ꢀcatalyzed
C−H amidation of heteroarenes with Nꢀacyl azides in the presence of visible light.3d In addition, Zhou and
Li presented the Ir(III)ꢀcatalyzed C7ꢀamidation of indolines with acyl, sulfonyl and aryl azides leading to
a biologically important C7ꢀaminated indolinic scaffold.3e Moreover, Ackermann described the
inexpensive Co(III)ꢀcatalyzed C−H aminocarbonylation of unactivated (hetero)arenes and alkenes
through the Curtius rearrangement of acyl azides.3f In sharp contrast, Zhou and Li disclosed the Rh(III)ꢀ
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catalyzed synthesis of amides from aldehydes and sulfonyl/aryl azides by chelationꢀassisted aldehydic
C−H bond activation.3g
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2ꢀAminobenzaldehydes have been utilized as ubiquitous precursors for the construction of various
heterocycles such as quinolines, acridines, quinolinones, dibenzonaphthyridines, benzoxazinꢀ4ꢀones and
natural neocryptolepine.5 Furthermore, Nꢀsubstituted orthoꢀaminobenzaldehydes have been employed for
the formation of pharmaceutically relevant indoles.6 Due to the weak coordinating ability of aldehydes to
transition metals, aldimines have been recently applied as alternative directing groups to afford orthoꢀ
functionalized benzaldehydes.7 In shrap contrast, aldimines were also used as electrophilic coupling
partners in C−H activation event leading to the corresponding secondary amine adducts.8 In continuation
of our recent works on siteꢀselective C−H amidation of (hetero)arenes,9 we herein report the Cp*Ir(III)ꢀ
catalyzed direct amidation of aldimines with Nꢀacyl azides followed by inꢀsitu acidic hydrolysis affording
orthoꢀamidobenzaldehydes (Scheme 1). It is noted that the resulting orthoꢀamidated benzaldehydes are
readily converted to various biologically relevant heterocycles such as 4Hꢀ1,3ꢀbenzoxazinꢀ4ꢀones,
quinazoline and 1,2ꢀdihydroquinoline. Additionally, synthesized orthoꢀamidated benzaldehydes and 4Hꢀ
1,3ꢀbenzoxazinꢀ4ꢀones were evaluated for antiꢀinflammatory activity against interleukinꢀ1β (ILꢀ1β) and
tumor necrosis factor alpha (TNFꢀα) with lipopolysaccharideꢀinduced RAW264.7 cells, and were found
to display promising antiꢀinflammatory activity competitive with dexamethasone as a positive control.
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previous works
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cat. [Rh], [Ru],
[Ir], [Co], [Cu]
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DG
DG
+
N3
R
H
NHR
R = Ts, Acyl,
Aryl, Alkyl
DG
NHR
DG
cat. [Rh]
+
N3
R
H
R = Ts, Aryl
O
O
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this work
H
H
H
O
O
R1
Ts
i) cat. [Ir]
N
R1
N3
R2
NH
R2
+
ii) 2 M HCl
O
Scheme 1. Transitionꢀmetalꢀcatalyzed C−H amidation reactions using organic azides.
Results and discussion
Our optimization was initiated by examining the coupling of Nꢀsulfonyl aldimine 1a and acyl azide
2a under cationic Ir(III) catalysis, as shown in Table 1. To our pleasure, the desired orthoꢀamidated
aldimine 3a was formed in 30% yield (Table 1, entry 1). However, other catalysts such as Rh(III), Ru(II)
and Co(III) were found to be unsuccessful in this transformation (Table 1, entries 2–4). Exchange of
AgSbF6 to AgNTf2 displayed the slightly increased formation of the desired product 3a in 35% yield
(Table 1, entry 5). Control experiments indicated that both Ir(III) catalyst and silver additive are highly
required for the coupling reaction between 1a and 2a (Table 1, entries 6 and 7). Interestingly, a catalytic
amount of LiOAc additive was found to display the remarkably increased reactivity to give 3a in 85%
yield (Table 1, entry 8). However, other additives, e.g., NaOAc, KOAc, CuOAc, AcOH and Li2CO3, were
less effective (Table 1, entries 9–13). In addition, various solvents were screened, and DCE solvent was
found to be most effective in this reaction (Table 1, entries 14–17). Decreasing amount of Ir(III) catalyst
to 1 mol % provided 2ꢀamido aldimine 3a in 42% yield (Table 1, entry 18). In addition, increasing
amount of acyl azide 2a was found to be comparable in this transformation to provide 3a in 83% yield
(Table 1, entry 19). Finally, it should be mentioned that the reaction temperature is quite important for the
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amidation reaction to furnish 3a in high yield (Table 1, entries 20 and 21).
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Table 1. Selected optimization of reaction conditions.a
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Entry
Catalyst (mol %)
Additive (mol %)
Solvent
Yield (%)b
1
2
[IrCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[Ru(pꢀcymene)Cl2]2 (2.5)
[CoCp*(CO)I2] (5)
[IrCp*Cl2]2 (2.5)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgNTf2 (10)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeOH
MeCN
toluene
THF
30
N.R.
N.R.
N.R.
35
3
4
5
6
[IrCp*Cl2]2 (2.5)
N.R.
N.R.
85
7
AgNTf2 (10)
8
[IrCp*Cl2]2 (2.5)
[IrCp*Cl2]2 (2.5)
[IrCp*Cl2]2 (2.5)
[IrCp*Cl2]2 (2.5)
[IrCp*Cl2]2 (2.5)
[IrCp*Cl2]2 (2.5)
[IrCp*Cl2]2 (2.5)
[IrCp*Cl2]2 (2.5)
[IrCp*Cl2]2 (2.5)
[IrCp*Cl2]2 (2.5)
[IrCp*Cl2]2 (1)
AgNTf2 (10), LiOAc (10)
AgNTf2 (10), NaOAc (10)
AgNTf2 (10), KOAc (10)
AgNTf2 (10), CuOAc (10)
AgNTf2 (10), AcOH (10)
AgNTf2 (10), Li2CO3 (10)
AgNTf2 (10), LiOAc (10)
AgNTf2 (10), LiOAc (10)
AgNTf2 (10), LiOAc (10)
AgNTf2 (10), LiOAc (10)
AgNTf2 (5), LiOAc (10)
AgNTf2 (10), LiOAc (10)
AgNTf2 (10), LiOAc (10)
AgNTf2 (5), LiOAc (10)
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42
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17
18
19c
20d
53
40
62
57
trace
N.R.
N.R.
trace
42
DCE
DCE
DCE
DCE
[IrCp*Cl2]2 (2.5)
[IrCp*Cl2]2 (2.5)
[IrCp*Cl2]2 (2.5)
83
70
21e
45
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (quantity noted), additive (quantity noted),
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solvent (1 mL) under air at 60 oC for 20 h in pressure tubes. b Isolated yield by flash column chromatography. c 2a
1
(0.6 mmol) was used. d 80 oC. e room temperature.
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Scheme 2. Inꢀsitu formation of 2ꢀamidobenzaldehyde 3aa.
Meanwhile, we envisioned the inꢀsitu formation of 2ꢀaminobenzaldehyde 3aa under acidic
hydrolysis conditions. After screening of reaction conditions, we found that treatment of reaction mixture
with 2 M HCl in THF at 60 oC for 3 h afforded 2ꢀaminobenzaldehyde 3aa in 80% yield (Scheme 2, eq. 1).
Additionally, this reaction could be applied to other Nꢀsulfonyl aldimine 1aa, which was readily coupled
with 2a to provide 3aa in 62% yield (Scheme 2, eq. 2). However, the reaction of highly electronꢀdeficient
Nꢀsulfonyl aldimine 1ab was unsuccessful to deliver 3aa under the current reaction conditions.
Table 2. Scope of aldimines.a
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H
1
i) [IrCp*Cl]2 (2.5 mol %)
O
H
H
2
3
4
5
6
7
8
O
AgNTf2 (10 mol %)
LiOAc (10 mol %)
DCE, 60 oC, 20 h
R
Ts
NH
N
N3
R
+
O
NO2
ii) 2 M HCl, THF
60 oC, 3 h
1b-1k
2a
NO2
3ab-3ak, %b
H
H
H
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O
O
O
R
NH
O2N
NH
F3C
NH
O
O
O
NO2
NO2
NO2
3ab, 76% (R = H)
3ad
3ae
, 62%
, 60%
3ac
, 79% (R = Cl)
H
Me
H
OMe H
Me
O
NH
O
O
NH
NH
O
O
O
NO2
NO2
NO2
3af
, 61%
3ah
, 56%
3ag, 41%
H
H
Cl
H
S
O
O
O
NH
NH
HO
NH
O
O
O
NO2
NO2
NO2
3aj, 38%
3ak, 30%
3ai
, 50%
a Reaction conditions: i) 1b–1k (0.2 mmol), 2a (0.3 mmol), [IrCp*Cl2]2 (2.5 mol %), AgNTf2 (10 mol %),
o
LiOAc (10 mol %), DCE (1 mL) under air at 60 C for 20 h in pressure tubes. ii) 2 M HCl (1 mL), THF (2 mL)
under air at 60 oC for 3 h. b Isolated yield by flash column chromatography.
With the optimal reaction conditions in hand, the substrate scope of aldimines was examined, as
shown in Table 2. The paraꢀsubstituted aldimines 1b–1e were found to display moderate to good
reactivity furnishing the corresponding orthoꢀamidated benzaldehydes 3ab–3ae in 60–79% yields. The
coupling reaction of metaꢀsubstituted aldimine 1f with acyl azide 2a preferentially occurred at the less
sterically congested position affording the amidated adduct 3af as a single regioisomer. In addition, orthoꢀ
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substituted aldimines 1g–1i and heterocyclic aldimine 1j showed relatively decreased reactivity under the
current reaction conditions. It should be noted that aldimines 1k having OH as a functional group was
also tolerable in this transformation to provide 3ak in 30% yield.
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Table 3. Scope of acyl azides.a
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a
Reaction conditions: 1a (0.2 mmol), 2b–2g (0.3 mmol), [IrCp*Cl2]2 (2.5 mol %), AgNTf2 (10 mol %),
o
LiOAc (10 mol %), DCE (1 mL) under air at 60 C for 20 h in pressure tubes. ii) 2 M HCl (1 mL), THF (2 mL)
under air at 60 oC for 3 h. b Isolated yield by flash column chromatography.
To further evaluate the substrate scope of this process, a range of Nꢀacyl azides was tested under the
optimal reaction conditions (Table 3). The paraꢀ and metaꢀsubstituted aroyl azides 2b–2d were found to
show good reactivity giving the corresponding orthoꢀamidated benzaldehyde derivatives 4ab–4ad in
moderate to high yields. However, acyl azide 2e containing a naphthyl moiety displayed relatively
decreased reactivity to afford 4ae in 21% yield. To our pleasure, cinnamoyl azide 2f was found to be
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highly reactive under the optimized reaction conditions to furnish the α,βꢀunsaturated amide 4af in 78%
yield. Additionally, heterocyclic Nꢀacyl azide 2g was also coupled with 1a to provide the corresponding
orthoꢀamidobenzaldehyde 4ag in moderate yield.
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Scheme 3. Synthesis of various heterocycles using orthoꢀamidated benzaldehydes.
To show the synthetic utility of Nꢀ(2ꢀformylphenyl)amide derivatives, we first performed the
CoCl2/TBHPꢀmediated intramolecular oxidative cyclization of 4ab and 4ac to deliver the corresponding
4Hꢀ1,3ꢀbenzoxazinꢀ4ꢀones 5a and 5b in 86% and 50% yields, respectively (Scheme 3, eq. 1).5f Notably,
the 4Hꢀ1,3ꢀbenzoxazinꢀ4ꢀone skeleton has been found in a number of physiologically and
pharmaceutically important molecules such as a chymotrypsin inactivator and selective inhibitors of
human leukocyte elastase and serine protease.10 To further highlight the applicability of amide products,
we exploited the formation of quinazoline and 1,2ꢀdihydroquinoline derivatives. When orthoꢀamidated
benzaldehyde 3ab was reacted with 30% ammonia in water, 2ꢀaryl quinazoline 5c was smoothly formed
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in 86% yield through the Bischler cyclization (Scheme 3, eq. 2).11 In addition, 3ab was also coupled with
an internal alkyne 6a to yield 1,2ꢀdihydroquinoline 5d via the vinyltriphenylphosphonium saltꢀmediated
intramolecular Wittig reaction (Scheme 3, eq. 3).12 However, ethyl phenylpropiolate as an unsymmetrical
acetylene did not give any coupling product under the identical reaction conditions, and most of starting
material 3ab was recovered.
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1a
HCl
3aa
[Cp*Ir(III)OAc][NTf2]
HOAc
3a
H
HOAc
N Ts
Ir
MeO
H
N
Cp*
Ts
N
Ir
I
Cp*
MeO
2a
Ar
IV
O
H
Ir
N Ts
H
MeO
Cp*
N Ts
Cp*
N3
Ir
II
MeO
Ar
O
N
Ar = (p-NO2)Ph
Ar
O
III
N2
Scheme 4. Proposed reaction pathway.
Based on previous literatures,7c,d a proposed reaction mechanism is outlined in Scheme 4. A cationic
Ir(III) complex I is generated from the reaction between aldimine 1a and [Cp*Ir(III)OAc][NTf2] via the
C–H activation process. Then coordination of acyl azide 2a and subsequent formation of iridium N–Ts
imine species III can occur in an oxidative manner to release the N2 molecule. A C–N bond can be
formed by migratory insertion of N–Ts imine to deliver an Ir(III)–amino species IV, which undergoes
protonation step to provide orthoꢀamidated adduct 3a and an active Ir(III) catalyst. Finally, the desired
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orthoꢀamidated benzaldehyde 3aa is generated via hydrolysis with HCl solution.
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Figure 1. Antiꢀinflammatory activity of synthesized compounds against ILꢀ1β and TNFꢀα.
Meanwhile, synthesized orthoꢀamidated benzaldehydes (3aa–3ak and 4ab–4ag) and 4Hꢀ1,3ꢀ
benzoxazinꢀ4ꢀones (5a and 5b) were evaluated for in vitro inhibitory activity against interleukinꢀ1β (ILꢀ
1β) and tumor necrosis factor alpha (TNFꢀα) as cell signaling cytokines involved in systemic
inflammation process (Figure 1). The antiꢀinflammatory activity was analyzed by Western blot
experiments using lipopolysaccharide (LPS)ꢀstimulated RAW264.7 cells.13 The intensity of immunoblot
signaling was quantified using Image J software,14 and represents the inhibition % values of compounds
compared with LPSꢀstimulated cells. Dexamethasone as an antiꢀinflammatory drug was chosen as a
positive control.15 A broad range of compounds (3ac–3af, 4ab–4ad and 4ag) exhibited superior
inhibitory activity to dexamethasone against ILꢀ1β. Particulary, analogues (4ad and 4ag) were found to
display most potent inhibitory activities (47% inhibition for 4ad and 55% inhibition for 4ag) about 2ꢀfold
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stronger than that of a positive control. Next, we screened the TNFꢀα inhibition activity of synthetic
compounds using lipopolysaccharide (LPS)ꢀstimulated RAW264.7 cells. Various orthoꢀamidated
benzaldehydes (3ac, 3ae–3ag, 3aj, 3ak, 4ab and 4ac) were found to induce higher inhibition activity than
that of dexamethasone. Interstingly, compounds (3ae and 4ac) showed potent inhibitory activities against
both ILꢀ1β and TNFꢀα. In this stage, we are not clear about the structureꢀactivity relationship (SAR)
between synthetic compounds (3ae and 4ac), but these results could be very useful for our future SAR
studies to discover novel antiꢀinflammatory agents.
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Conclusion
In conclusion, we described the iridium(III)ꢀcatalyzed C–H amidation reaction of various aldimines
with Nꢀacyl azides followed by hydrolysis affording orthoꢀamidated benzaldehydes. This transformation
has been applied to a wide range of substrates, and typically proceeds with excellent levels of siteꢀ
selectivity as well as with high functional group tolerance. The synthesized orthoꢀamidated
benzaldehydes were readily transformed into biologically relevant heterocycles such as 4Hꢀ1,3ꢀ
benzoxazinꢀ4ꢀones, quinazoline and 1,2ꢀdihydroquinoline. In addition, all synthetic compounds were
screened for antiꢀinflammatory property against ILꢀ1β and TNFꢀα with LPSꢀinduced RAW264.7 cells. In
general, a broad range of orthoꢀamidated benzaldehydes displayed promising inhibitory activity of ILꢀ1β
and TNFꢀα compared to dexamethasone as a positive control. Notably, compounds (3ae and 4ac) were
found to display potent antiꢀinflammatory activity stronger than that of dexamethasone.
Experimental Section
General procedure for the reaction of aldimine with acyl azide (3a): To an ovenꢀdried sealed tube
charged with (E)ꢀNꢀ(4ꢀmethoxybenzylidene)ꢀ4ꢀmethylbenzenesulfonamide (1a) (57.9 mg, 0.2 mmol, 100
mol %), [IrCp*Cl2]2 (4.0 mg, 0.005 mmol, 2.5 mol %), AgNTf2 (7.8 mg, 0.02 mmol, 10 mol %) and
LiOAc (1.3 mg, 0.02 mmol, 10 mol %) was added 4ꢀnitrobenzoyl azide (2a) (57.6 mg, 0.3 mmol, 150
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o
mol %) and DCE (1 mL) under air. The reaction mixture was allowed to stir for 20 h at 60 C. The
reaction mixture was filtered, washed with MeOH (10 mL), and dried to afford 3a (77.1 mg) in 85% yield
without purification using flash column chromatography.
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(E)ꢀNꢀ(5ꢀMethoxyꢀ2ꢀ((tosylimino)methyl)phenyl)ꢀ4ꢀnitrobenzamide (3a). 77.1 mg (85%, E:Z =
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7.8:1); yellow solid; mp = 235.0–255.6 C; H NMR (400 MHz, DMSOꢀd6) δ 11.81 (br s, 1H), 9.12 (s,
1H), 8.31 (dt, J = 9.2, 2.4 Hz, 2H), 8.07–8.00 (m, 4H), 7.82 (dt, J = 8.8, 2.4 Hz, 2H), 7.42 (d, J = 8.0 Hz,
2H), 6.99 (dd, J = 8.8, 2.8 Hz, 1H), 3.90 (s, 3H), 2.36 (s, 3H); C{1H} NMR (100 MHz, DMSOꢀd6) δ
13
170.2, 165.8, 163.9, 149.6, 144.6, 142.7, 139.3, 138.1, 135.1, 130.1, 128.7, 127.6, 123.9, 114.4, 111.2,
106.7, 56.1, 21.0; IR (KBr) υ 3266, 3124, 2834, 2359, 1711, 1685, 1626, 1587, 1530, 1462, 1425, 1344,
1318, 1268, 1156, 1086, 1034, 914, 862, 843, 808, 744 cmꢀ1; HRMS (quadrupole, EI) calcd for
C22H19N3O6S [M]+ 453.0995, found 453.0995.
Typical procedure for the reaction of aldimines with acyl azides to access the 2ꢀ
aminobenzaldehyde derivatives (3aa–3ak and 4ab–4ag): To an ovenꢀdried sealed tube charged with
(E)ꢀNꢀ(4ꢀmethoxybenzylidene)ꢀ4ꢀmethylbenzenesulfonamide (1a) (57.9 mg, 0.2 mmol, 100 mol %),
[IrCp*Cl2]2 (4.0 mg, 0.005 mmol, 2.5 mol %), AgNTf2 (7.8 mg, 0.02 mmol, 10 mol %) and LiOAc (1.3
mg, 0.02 mmol, 10 mol %) was added 4ꢀnitrobenzoyl azide (2a) (57.6 mg, 0.3 mmol, 150 mol %) and
o
DCE (1 mL) under air. The reaction mixture was allowed to stir for 20 h at 60 C, and cooled to room
temperature. Then, 2 M HCl (1 mL) and THF (2 mL) was added to the resulting reaction mixture. The
o
reaction mixture was allowed to stir for 3 h at 60 C. The reaction mixture was cooled to room
temperature, quenched with saturated NaHCO3 solution (1 mL) to reach pH 7, and extracted with EtOAc
(2 x 10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography (nꢀhexanes/EtOAc = 3:1) to afford 3aa (48.2 mg) in 80%
yield.
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Nꢀ(2ꢀFormylꢀ5ꢀmethoxyphenyl)ꢀ4ꢀnitrobenzamide (3aa). 48.2 mg (80%); light yellow solid; mp =
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208.6–209.7 C; H NMR (400 MHz, CDCl3) δ 12.55 (br s, 1H), 9.84 (s, 1H), 8.53 (d, J = 2.4 Hz, 1H),
8.37 (dt, J = 9.6, 2.4 Hz, 2H), 8.22 (dt, J = 9.2, 2.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 1H), 6.80 (dd, J = 8.4,
2.4 Hz, 1H), 3.96 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 194.1, 166.2, 164.1, 150.0, 143.1, 139.7,
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138.2, 128.7, 124.1, 116.2, 110.9, 104.2, 55.9; IR (KBr) υ 3200, 2925, 2363, 1686,1624, 3585, 1521,
1340, 1267, 1214, 1165, 1029, 856, 800, 740, 703 cmꢀ1; HRMS (quadrupole, EI) calcd for C15H12N2O5
[M]+ 300.0746, found 300.0747.
Nꢀ(2ꢀFormylphenyl)ꢀ4ꢀnitrobenzamide (3ab).16a 41.2 mg (76%); orange solid; mp = 200.3–206.5
oC; 1H NMR (400 MHz, CDCl3) δ 12.26 (br s, 1H), 10.02 (s, 1H), 8.92 (d, J = 8.4 Hz, 1H), 8.38 (dt, J =
9.2, 2.4 Hz, 2H), 8.22 (dt, J = 9.2, 2.4 Hz, 2H), 7.77 (dd, J = 7.6, 1.6 Hz, 1H), 7.74–7.70 (m, 1H), 7.34
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(td, J = 8.4, 1.0 Hz, 1H); C{1H} NMR (100 MHz, CDCl3) δ 196.2, 163.9, 150.0, 140.6, 139.8, 136.6,
136.3, 128.7, 124.1, 123.9, 122.1, 120.1; IR (KBr) υ 3005, 2365, 2358, 1715, 1667, 1602, 1587, 1513,
1418, 1363, 1322, 1222, 1095, 870, 763, 709 cmꢀ1; HRMS (quadrupole, EI) calcd for C14H10N2O4 [M]+
270.0641, found 270.0640.
Nꢀ(5ꢀChloroꢀ2ꢀformylphenyl)ꢀ4ꢀnitrobenzamide (3ac). 48.4 mg (79%); yellow solid; mp = 167.4–
170.1 oC; 1H NMR (400 MHz, CDCl3) δ 12.31 (br s, 1H), 9.97 (s, 1H), 9.01 (s, 1H), 8.39 (dt, J = 9.2, 2.4
Hz, 2H), 8.22 (dt, J = 9.2, 2.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.30 (dd, J = 8.4, 2.0 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 195.0, 163.9, 150.1, 143.4, 141.4, 139.3, 137.1, 128.7, 124.2, 124.1, 120.4,
120.3; IR (KBr) υ 3273, 3106, 2918, 2850, 2358, 1684, 1660, 1600, 1579, 1516, 1460, 1424, 1400, 1350,
1308, 1268, 1201, 1137, 1098, 1080, 1014, 924, 902, 870, 856, 819, 794, 739, 701 cmꢀ1; HRMS
(quadrupole, EI) calcd for C14H9ClN2O4 [M]+ 304.0251, found 304.0249.
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Nꢀ(2ꢀFormylꢀ5ꢀnitrophenyl)ꢀ4ꢀnitrobenzamide (3ad). 39.1 mg (62%); yellow solid; mp = 104.6–
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107.2 C; H NMR (400 MHz, CDCl3) δ 12.28 (br s, 1H), 10.17 (s, 1H), 9.81 (d, J = 2.0 Hz, 1H), 8.42
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(dt, J = 9.2, 2.4 Hz, 2H), 8.24 (dt, J = 9.2, 2.0 Hz, 2H), 8.14 (dd, J = 8.4, 2.4 Hz, 1H), 7.99 (d, J = 8.4 Hz,
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1H); C{1H} NMR (100 MHz, CDCl3) δ 195.2, 164.0, 152.2, 150.4, 141.6, 138.8, 136.9, 128.8, 124.9,
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124.3, 118.0, 115.5; IR (KBr) υ 3105, 2926, 2852, 2358, 1702, 1597, 1582, 1508, 1342, 1267, 1196, 1169,
1106, 1007, 860, 813, 730, 703 cmꢀ1; HRMS (quadrupole, EI) calcd for C14H9N3O6 [M]+ 315.0491, found
315.0491.
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Nꢀ(2ꢀFormylꢀ5ꢀ(trifluoromethyl)phenyl)ꢀ4ꢀnitrobenzamide (3ae). 40.7 mg (60%); brown solid;
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mp = 110.1–113.4 C; H NMR (400 MHz, CDCl3) δ 12.26 (br s, 1H), 10.11 (s, 1H), 9.27 (s, 1H), 8.40
(dt, J = 9.2, 2.4 Hz, 2H), 8.22 (dt, J = 9.2, 2.4 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 195.6, 164.0, 150.2, 140.9, 139.1, 137.4 (q, JCꢀF = 33.3 Hz), 136.5,
128.7, 125.74 (q, JCꢀF = 273.9 Hz), 124.2, 123.6, 120.3 (q, JCꢀF = 3.9 Hz), 117.3 (q, JCꢀF = 4.0 Hz); IR
(KBr) υ 3356, 3261, 2361, 2342, 1671, 1626, 1600, 1544, 1492, 1439, 1399, 1331, 1303, 1270, 1252,
1161, 1129, 1111, 1073, 930, 902, 840, 815, 798, 740, 709 cmꢀ1; HRMS (quadrupole, EI) calcd for
C15H9F3N2O4 [M]+ 338.0514, found 338.0516.
Nꢀ(2ꢀFormylꢀ4ꢀmethylphenyl)ꢀ4ꢀnitrobenzamide (3af). 34.9 mg (61%); brown solid; mp = 188.7–
191.5 oC; 1H NMR (400 MHz, CDCl3) δ 12.15 (br s, 1H), 9.97 (s, 1H), 8.80 (d, J = 8.4 Hz, 1H), 8.37 (dt,
J = 9.2, 2.4 Hz, 2H), 8.21 (dt, J = 9.2, 2.0 Hz, 2H), 7.56–7.51 (m, 2H), 2.44 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 196.3, 163.7, 149.9, 139.9, 138.2, 137.3, 136.5, 133.7, 128.6, 124.1, 122.1, 120.1, 20.6;
IR (KBr) υ 2923, 2852, 2361, 1684, 1657, 1600, 1540, 1555, 1469, 1391, 1345, 1321, 1260, 1242, 1157,
1109, 937, 864, 853, 833, 775, 751, 707 cmꢀ1; HRMS (quadrupole, EI) calcd for C15H12N2O4 [M]+
284.0797, found 284.0796.
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Nꢀ(2ꢀFormylꢀ3ꢀmethoxyphenyl)ꢀ4ꢀnitrobenzamide (3ag). 24.9 mg (41%); brown solid; mp =
160.2–163.1 oC; 1H NMR (400 MHz, CDCl3) δ 12.83 (br s, 1H), 10.58 (s, 1H), 8.47 (d, J = 8.8 Hz, 1H),
8.36 (dt, J = 9.2, 2.0 Hz, 2H), 8.24 (dt, J = 9.2, 2.0 Hz, 2H), 7.62 (t, J = 8.4 Hz, 1H), 6.75 (d, J = 8.0 Hz,
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1H), 3.96 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 194.1, 164.1, 163.5, 152.7, 142.1, 140.0, 138.4,
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128.7, 124.1, 112.2, 111.3, 106.1, 56.0; IR (KBr) υ 3250, 2921, 2850, 2370, 1677, 1654, 1611, 1600,
1582, 1513, 1474, 1439, 1404, 1348, 1325, 1301, 1271, 1195, 1127, 1112, 1071, 950, 871, 817, 791, 738,
705 cmꢀ1; HRMS (quadrupole, EI) calcd for C15H12N2O5 [M]+ 300.0746, found 300.0743.
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Nꢀ(2ꢀFormylꢀ3ꢀmethylphenyl)ꢀ4ꢀnitrobenzamide (3ah).16b 32.2 mg (56%); yellow solid; mp =
o
209.6–211.1 C; 1H NMR (400 MHz, CDCl3) δ 12.74 (br s, 1H), 10.54 (s, 1H), 8.79 (d, J = 8.4 Hz, 1H),
8.38 (dt, J = 9.2, 2.4 Hz, 2H), 8.23 (dt, J = 9.2, 2.4 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 7.2 Hz,
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1H), 2.74 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 195.1, 164.0, 149.9, 143.7, 141.5, 140.1, 136.9,
128.7, 126.8, 124.1, 119.7, 118.6, 19.2; IR (KBr) υ 3112, 2924, 2357, 1681, 1644, 1601, 1578, 1541,
1520, 1466, 1396, 1345, 1304, 1276, 1200, 1174, 1111, 865, 853, 824, 790, 740, 700 cmꢀ1; HRMS
(quadrupole, EI) calcd for C15H12N2O4 [M]+ 284.0797, found 284.0796.
Nꢀ(3ꢀChloroꢀ2ꢀformylphenyl)ꢀ4ꢀnitrobenzamide (3ai). 30.6 mg (50%); yellow solid; mp = 165.3–
o
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169.5 C; H NMR (400 MHz, CDCl3) δ 12.65 (br s, 1H), 10.64 (s, 1H), 8.84 (d, J = 8.4 Hz, 1H), 8.37
(dt, J = 9.2, 2.4 Hz, 2H), 8.21 (dt, J = 9.2, 2.4 Hz, 2H), 7.59 (t, J = 8.0 Hz, 1H), 7.24 (dd, J = 8.0, 1.0 Hz,
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1H); C{1H} NMR (100 MHz, CDCl3) δ 195.0, 163.9, 150.1, 142.7, 140.5, 139.5, 137.2, 128.7, 125.5,
124.1, 119.1, 117.9; IR (KBr) υ 3113, 2364, 1686, 1654, 1604, 1579, 1530, 1489, 1450, 1397, 1346,
1267, 1197, 1102, 865, 852, 795, 741, 705 cmꢀ1; HRMS (quadrupole, EI) calcd for C14H9ClN2O4 [M]+
304.0251, found 304.0250.
Nꢀ(2ꢀFormylthiophenꢀ3ꢀyl)ꢀ4ꢀnitrobenzamide (3aj). 21.3 mg (38%); brown solid; mp = 204.8–
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207.3 oC; 1H NMR (400 MHz, CDCl3) δ 11.76 (br s, 1H), 9.81 (s, 1H), 8.38 (dt, J = 8.8, 2.0 Hz, 2H), 8.32
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(d, J = 5.6 Hz, 1H), 8.18 (dt, J = 8.8, 2.0 Hz, 2H), 7.81 (d, J = 5.2 Hz, 1H); C{1H} NMR (100 MHz,
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8
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CDCl3) δ 184.9, 162.6, 150.2, 144.5, 138.6, 136.8, 128.8, 124.2, 123.1, 123.0; IR (KBr) υ 3258, 3058,
2925, 2851, 2358, 2337, 1684, 1625, 1600, 1572, 1517, 1438, 1404, 1374, 1345, 1251, 1179, 1111, 1073,
1006, 900, 866, 857, 801, 760, 740, 707 cmꢀ1; HRMS (quadrupole, EI) calcd for C12H8N2O4S [M]+
276.0205, found 276.0202.
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Nꢀ(2ꢀFormylꢀ5ꢀhydroxyphenyl)ꢀ4ꢀnitrobenzamide (3ak). 17.2 mg (30%); yellow solid; mp =
211.7–213.9 oC; 1H NMR (400 MHz, CD3OD) δ 13.27 (br s, 1H), 10.45 (s, 1H), 9.26–9.23 (m, 2H), 9.00–
8.97 (m, 2H), 8.76 (s, 1H), 8.44 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H); 13C{1H} NMR (100 MHz,
CD3OD) δ 201.3, 172.8, 158.9, 151.9, 149.4, 148.1, 138.1, 133.7, 122.8, 116.7, 112.2, 108.1; IR (KBr) υ
3261, 2361, 2332, 1634, 1601, 1557, 1524, 1473, 1452, 1399, 1323, 1269, 1159, 1109, 865, 810, 743, 709
cmꢀ1; HRMS (quadrupole, EI) calcd for C14H10N2O5 [M]+ 286.0590, found 286.0587.
Nꢀ(2ꢀFormylꢀ5ꢀmethoxyphenyl)ꢀ4ꢀmethoxybenzamide (4ab). 31.1 mg (54%); white solid; mp =
o
1
128.8–135.3 C; H NMR (400 MHz, CDCl3) δ 12.32 (br s, 1H), 9.82 (s, 1H), 8.59 (d, J = 2.4 Hz, 1H),
8.04 (dt, J = 10.0, 3.2 Hz, 2H), 7.58 (d, J = 8.8 Hz, 1H), 7.01 (dt, J = 9.6, 2.8 Hz, 2H), 6.72 (dd, J = 8.8,
13
2.4 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 193.8, 166.1, 166.0, 162.8,
144.1, 137.9, 129.5, 126.5, 115.9, 114.1, 110.4, 103.4, 55.8, 55.5; IR (KBr) υ 3283, 3132, 2921, 2851,
2777, 2671, 1710, 1683, 1650, 1622, 1606, 1579, 1535, 1508, 1439, 1409, 1336, 1298, 1255, 1224, 1195,
1173, 1145, 1119, 1091, 1031, 951, 903, 869, 814, 756 cmꢀ1; HRMS (quadrupole, EI) calcd for
C16H15NO4 [M]+ 285.1001, found 285.1003.
Nꢀ(2ꢀFormylꢀ5ꢀmethoxyphenyl)ꢀ4ꢀ(trifluoromethyl)benzamide (4ac). 44.8 mg (69%); white
solid; mp = 108.6ꢀ111.6 oC; 1H NMR (400 MHz, CDCl3) δ 12.49 (br s, 1H), 9.83 (s, 1H), 8.56 (d, J = 2.4
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Hz, 1H), 8.18 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.8 Hz, 1H), 6.78 (dd, J = 8.4, 2.4
Hz, 1H), 3.96 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.0, 166.2, 164.9, 143.3, 138.1, 137.5,
134.0, 133.7, 127.9, 125.9 (q, JCꢀF = 4.0 Hz), 116.2, 110.8, 104.0, 55.9; IR (KBr) υ 3231, 2845, 2359,
2340, 1687, 1655, 1616, 1579, 1531, 1463, 1430, 1403, 1323, 1294, 1267, 1240, 1209, 1168, 1126, 1086,
1064, 1030, 1015, 970, 903, 857, 811, 766, 742 cmꢀ1; HRMS (quadrupole, EI) calcd for C16H12F3NO3
[M]+ 323.0769, found 323.0770.
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Nꢀ(2ꢀFormylꢀ5ꢀmethoxyphenyl)ꢀ3ꢀnitrobenzamide (4ad). 48.3 mg (80%); yellow solid; mp =
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158.1–161.4 C; H NMR (400 MHz, CDCl3) δ 12.60 (br s, 1H), 9.85 (s, 1H), 8.96 (t, J = 2.0 Hz, 1H),
8.53 (d, J = 2.4 Hz, 1H), 8.44–8.42 (m, 1H), 8.37 (dt, J = 8.0, 1.6 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.64
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(d, J = 8.8 Hz, 1H), 6.80 (dd, J = 8.4, 2.4 Hz, 1H), 3.97 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ
194.1, 166.2, 163.8, 148.7, 143.2, 138.1, 136.1, 132.8, 130.1, 126.7, 123.1, 116.2, 110.9, 104.2, 55.9; IR
(KBr) υ 3056, 2923, 2849, 2358, 1675, 1652, 1625, 1585, 1529, 1476, 1348, 1267, 1212, 1174, 1104,
1021, 929, 857, 811, 740 cmꢀ1; HRMS (quadrupole, EI) calcd for C15H12N2O5 [M]+ 300.0746, found
300.0741.
Nꢀ(2ꢀFormylꢀ5ꢀmethoxyphenyl)ꢀ2ꢀnaphthamide (4ae). 12.9 mg (21%); brown solid; mp = 180.4–
183.1 oC; 1H NMR (500 MHz, CDCl3) δ 12.56 (br s, 1H), 9.87 (s, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.62 (s,
1H), 8.13 (dd, J = 8.5, 1.5 Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.0 Hz,
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1H), 7.62 (d, J = 8.5 Hz, 1H), 7.61–7.56 (m, 2H), 6.77 (dd, J = 8.5, 2.0 Hz, 1H), 3.98 (s, 3H); C{1H}
NMR (125 MHz, CDCl3) δ 193.9, 166.5, 166.2, 143.9, 138.0, 135.2, 132.8, 131.5, 129.5, 128.8, 128.7,
128.1, 127.8, 126.9, 123.6, 116.2, 110.6, 103.8, 55.9; IR (KBr) υ 3235, 2922, 2848, 2758, 2363, 1681,
1655, 1617, 1579, 1529, 1457, 143, 1401, 1335, 1294, 1238, 1207, 1171, 1140, 1118, 1078, 1030, 970,
912, 862, 815, 772, 741 cmꢀ1; HRMS (quadrupole, EI) calcd for C19H15NO3 [M]+ 305.1052, found
305.1053.
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(E)ꢀNꢀ(2ꢀFormylꢀ5ꢀmethoxyphenyl)ꢀ3ꢀ(4ꢀnitrophenyl)acrylamide (4af). 51.1 (78%); yellow solid;
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mp = 206.3–209.7 C; H NMR (500 MHz, DMSOꢀd6) δ 11.39 (br s, 1H), 9.89 (s, 1H), 8.27 (d, J = 8.5
Hz, 2H), 8.17 (s, 1H), 8.04 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 16.0 Hz, 1H), 7.17
(d, J = 15.5 Hz, 1H), 6.92 (dd, J = 8.5, 2.0 Hz, 1H), 3.88 (s, 3H); 13C{1H} NMR (125 MHz, DMSOꢀd6) δ
193.6, 164.8, 163.9, 147.9, 141.8, 140.8, 139.4, 137.7, 129.3, 126.1, 123.9, 117.1, 109.5, 105.4, 55.8; IR
(KBr) υ 3248, 3114, 2842, 2357, 1659, 1618, 1582, 1514, 1462, 1435, 1344, 1295, 1268, 1236, 1207,
1183, 1131, 1110, 1033, 982, 859, 839, 805, 740 cmꢀ1; HRMS (quadrupole, EI) calcd for C17H14N2O5
[M]+ 326.0903, found 326.0904.
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Nꢀ(2ꢀFormylꢀ5ꢀmethoxyphenyl)thiopheneꢀ2ꢀcarboxamide (4ag). 25.2 mg (48%); yellow solid;
o
mp = 155.2–158.0 C; 1H NMR (400 MHz, CDCl3) δ 12.35 (br s, 1H), 9.80 (s, 1H), 8.46 (d, J = 2.4 Hz,
1H), 7.83 (dd, J = 3.6, 1.2 Hz, 1H), 7.59 (dd, J = 4.8, 1.2 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.16 (dd, J =
5.2, 4.0 Hz, 1H), 6.72 (dd, J = 8.4, 2.4 Hz, 1H), 3.92 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.8,
166.0, 161.1, 143.6, 139.8, 137.9, 131.9, 128.9, 128.1, 115.7, 110.7, 103.4, 55.8; IR (KBr) υ 3227, 3121,
2995, 2840, 2361, 1670, 1650, 1619, 1583, 1537, 1455, 1435, 1415, 1403, 1354, 1294, 1274, 1228, 1201,
1175, 1151, 1094, 1042, 1031, 947, 885, 862, 808, 785, 718 cmꢀ1; HRMS (quadrupole, EI) calcd for
C13H11NO3S [M]+ 261.0460, found 261.0462.
Experimental procedure and characterization data for the synthesis of 5a and 5b: To an ovenꢀ
dried sealed tube charged with Nꢀ(2ꢀformylꢀ5ꢀmethoxyphenyl)ꢀ4ꢀmethoxybenzamide (4ab) (57.0 mg, 0.2
mmol, 100 mol %) in DCE (1 mL) was added CoCl2 (2.6 mg, 0.02 mmol, 10 mol %) and TBHP (77.2 mg,
0.6 mmol, 300 mol%, 70% in H2O) under air. The reaction mixture was stirred at 80 °C for 5 h. The
resulting mixture was cooled, diluted with EtOAc (3 mL) and concentrated in vacuo. The residue was
purified by flash column chromatography (nꢀhexanes/EtOAc = 4:1) to afford 5a (48.8 mg) in 86% yield.
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7ꢀMethoxyꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ4Hꢀbenzo[d][1,3]oxazinꢀ4ꢀone (5a). 48.8 mg (86%); white solid;
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mp = 152.0–155.4 C; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.8 Hz, 2H), 8.11 (d, J = 8.8 Hz, 1H),
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7.17 (d, J = 2.4 Hz, 1H), 7.04–7.00 (m, 3H), 3.95 (s, 3H), 3.90 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 166.4, 163.7, 158.9, 158.6, 149.0, 130.7, 130.3, 121.9, 117.2, 114.3, 109.2, 108.2, 55.9, 55.6; IR (KBr)
υ 3059, 2921, 2850, 1763, 1606, 1569, 1491, 1446, 1411, 1352, 1322, 1283, 1246, 1204, 1169, 1125,
1109, 1071, 1028, 999, 853, 774, 738 cmꢀ1; HRMS (quadrupole, EI) calcd for C16H13NO4 [M]+ 283.0845,
found 283.0844.
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7ꢀMethoxyꢀ2ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀ4Hꢀbenzo[d][1,3]oxazinꢀ4ꢀone (5b). 32.2 mg (50%);
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white solid; mp = 215.8–218.0 C; H NMR (500 MHz, CDCl3) δ 8.42 (d, J = 8.0 Hz, 2H), 8.16 (d, J =
8.5 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 2.5 Hz, 1H), 7.10 (dd, J = 8.5, 2.0 Hz, 1H), 3.97 (s,
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3H); C{1H} NMR (125 MHz, CDCl3) δ 166.5, 158.7, 156.6, 149.0, 134.0 (q, JCꢀF = 32.4 Hz), 133.7,
130.4, 128.7, 125.7 (q, JCꢀF = 3.6 Hz), 123.7 (q, JCꢀF = 271.4 Hz), 117.8, 109.9, 109.4, 55.9; IR (KBr) υ
3053, 2924, 2954, 1756, 1671, 1601, 1567, 1510, 1488, 1443, 1279, 1265, 1203, 1168, 1104, 1027, 839,
741 cmꢀ1; HRMS (quadrupole, EI) calcd for C16H10F3NO3 [M]+ 321.0613, found 321.0614.
Experimental procedure and characterization data for the synthesis of 5c: To an ovenꢀdried
sealed tube charged with Nꢀ(2ꢀformylphenyl)ꢀ4ꢀnitrobenzamide (3ab) (54.0 mg, 0.2 mmol, 100 mol %) in
H2O (1.0 mL) was added 30 % aqueous solution of ammonia (1 mL). The reaction mixture was stirred at
100 °C for 12 h. The resulting mixture was cooled to room temperature and extracted with EtOAc (2 x 2
mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography (nꢀhexanes/EtOAc = 3:1) to afford 5c (43.5 mg) in 86% yield.
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2ꢀ(4ꢀNitrophenyl)quinazoline (5c). 43.5 mg (86%); white solid; mp = 215.8–218.3 C; H NMR
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(400 MHz, CDCl3) δ 9.53 (s, 1H), 8.84–8.81 (m, 2H), 8.38–8.35 (m, 2H), 8.17 (d, J = 8.4 Hz, 1H), 7.99
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(d, J = 7.6 Hz, 2H), 7.71 (td, J = 7.2, 1.0 Hz, 1H); C{1H} NMR (100 MHz, CDCl3) δ 160.7, 158.5,
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150.5, 149.3, 143.4, 143.3, 134.9, 129.5, 128.8, 128.5, 127.3, 123.8; IR (KBr) υ 3725, 2917, 2849, 2359,
1677, 1658, 1605, 1553, 1514, 1456, 1339, 1260, 1174, 846, 764, 707 cmꢀ1; HRMS (quadrupole, EI)
calcd for C14H9N3O2 [M]+ 251.0695, found 251.0697.
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Experimental procedure and characterization data for the synthesis of 5d: To a stirred solution
of Nꢀ(2ꢀformylphenyl)ꢀ4ꢀnitrobenzamide (3ab) (54.0 mg, 0.2 mmol, 100 mol %) and triphenylphosphine
(52.5 mg, 0.2 mmol, 100 mol %) in CH2Cl2 (1 mL) was added dropwise a mixture of diethyl
acetylenedicarboxylate (6a) (34.0 mg, 0.2 mmol, 100 mol %) and CH2Cl2 (1 mL) at 0 °C for 10 min. The
reaction mixture was stirred for 24 h at room temperature. The resulting mixture was diluted with EtOAc
(1 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (nꢀ
hexanes/EtOAc = 6:1) to afford 5d (56.2 mg) in 66% yield.
Diethyl 1ꢀ(4ꢀnitrobenzoyl)ꢀ1,2ꢀdihydroquinolineꢀ2,3ꢀdicarboxylate (5d). 56.2 mg (66%); yellow
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oil; H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.8 Hz, 2H), 7.67 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.35
(dd, J = 7.6, 1.6 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.03 (br s, 1H), 6.65 (br s, 1H), 6.42 (br s, 1H), 4.43–
4.30 (m, 2H), 4.18–4.10 (m, 1H), 4.07–3.99 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 168.1, 167.3, 164.3, 148.9, 140.4, 136.2, 133.6, 130.1, 129.9, 129.1,
127.2, 127.1, 125.9, 125.3, 125.0, 123.6, 62.1, 61.5, 14.3, 13.9; IR (KBr) υ 3106, 3067, 2981, 2926, 2853,
1741, 1708, 1661, 1602, 1523, 1485, 1457, 1370, 1334, 1288, 1223, 1200, 1154, 1015, 863, 760, 735, 716
cmꢀ1; HRMS (quadrupole, EI) calcd for C22H20N2O7 [M]+ 424.1271, found 424.1272.
Cell culture and cell viability assay: Murine RAW 264.7 macrophage cell line was obtained from
American Type Culture Collection (ATCC) and cultured in Dulbecco’s modified Eagle’s medium
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(DMEM) supplemented with 10% fetal bovine serum, 1% penicillinꢀstreptomycin at 37 C in a
humidified atmosphere containing 5% CO2. Cell viability was determined by 3ꢀ[4,5ꢀdimethylthiazolꢀ2ꢀ
yl]ꢀ2,5 diphenyl tetrazolium bromide (MTT) reduction assay. In brief, RAW264.7 cells were preincubated
overnight in 96ꢀwell plates at a density of 1 х 104 cells per well. After 24 h, cells were treated with
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various concentrations of synthetic compounds for another 24 h. The mediums then were removed, and
MTT was then added to each well at a final concentration of 0.5 mg/mL. The cells were incubated for 4 h
at 37 oC, supernatants were removed, and dimethyl sulfoxide was added to each well. The optical density
was measured at 540 nm using a microplate reader.
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Western blot analysis: After pretreatment with synthetic compounds, RAW 264.7 cells were
stimulated with LPS (1 ꢁg/mL) for 24 h. After treatment, cells were harvested on ice, washed twice using
iceꢀcold PBS, and suspended in lysis buffer supplemented with protease inhibitor. After incubating on ice
for 25 min, cell extracts were subjected to centrifugation (12,000 rpm) at 4 oC for 5 min to get cell protein
and quantified using a BCA protein assay. Protein samples were separated by SDSꢀpolyacrylamide gel
(PAGE) and electroꢀtransferred to polyvinylidene difluoride (PVDF) membranes, then hybridized with
the specific antibodies. Blots were normalized by use of βꢀactin to correct for differences in loading of the
proteins. Intensity of protein bands were quantified with densitometry using Image J software.
Acknowledgment
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the
Korea government (MSIP) (Nos. 2016R1A4A1011189 and 2017R1A2B2004786).
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Supporting Information Available: Western blot analysis data and 1H and C NMR copies of all
products. This material is available free of charge via the internet at http://pubs.acs.org.
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References and notes
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(g) Vecchione, M. K.; Sun, A. X.; Seidel, D. Chem. Sci. 2011, 2, 2178.
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