FeCl2-Catalyzed Decarboxylative Radical Alkylation/Cyclization of Cinnamamides: Access to Dihydroquinolinone and Pyrrolo[1,2- a]indole Analogues

Article abstract of DOI:10.1021/acs.joc.8b00511

A simple and unified method for the synthesis of alkylated dihydroquinolinone and pyrrolo[1,2-a]indole derivatives in moderate to high yields (up to 91%) with excellent diastereoselectivity (>20:1 dr) was developed. The inexpensive FeCl₂·4H₂O works as catalyst, and easily prepared peresters (or peroxides) from aliphatic acids act as alkylating reagents and single electron oxidants. This environmentally friendly reaction proceeds via an FeCl₂-catalyzed alkyl radical cascade addition/cyclization fashion.

Full text of DOI:10.1021/acs.joc.8b00511

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FeCl2-Catalyzed Decarboxylative Radical
Alkylation/Cyclization of Cinnamamides: Access to
Dihydroquinolinone and Pyrrolo[1,2-a]indole Analogues
Zhihao Cui, and Da-Ming Du
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00511 • Publication Date (Web): 12 Apr 2018
Downloaded from http://pubs.acs.org on April 12, 2018
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FeCl2-Catalyzed Decarboxylative Radical Alkylation/Cyclization of
Cinnamamides: Access to Dihydroquinolinone and Pyrrolo[1,2-a]indole
Analogues
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Zhihao Cui and Da-Ming Du*
School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081,
People’s Republic of China
e-mail: dudm@bit.edu.cn
ABSTRACT
A simple and unified method for the synthesis of alkylated dihydroquinolinone and pyrrolo[1,2-
a]indole derivatives in moderate to high yields (up to 91%) with excellent diastereoselectivity (>20:1 dr)
was developed. The inexpensive FeCl24H2O works as catalyst, and easily-prepared peresters (or
peroxides) from aliphatic acids act as alkylating reagents and single electron oxidants. This
environmental-friendly reaction proceeds via FeCl2-catalyzed alkyl radical cascade addition/cyclization
fashion.
INTRODUCTION
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As an indispensable part, N-heterocyclic compounds invariably hold a huge proportion in the
chemical compound library, and novel methodologies for prepared efficiently N-heterocycles are always
highly sought-after.1 In the recent years, there is a growing concern over two distinctive N-heterocycles,
3,4-dihydroquinolinones2 and pyrrolo[1,2-a]indoles,3 which often serve as bioactive alkaloids scaffolds4
such as the pyrrolo[1,2-a]indole-containing anti-HIV Isatisine A5 and the psychoactive Yuremamine6 or
as the core pharmacophores in drugs (Figure 1).7 As always, high demand advances the rapid
development of technologies and many protocols have been exploited to forge such useful frameworks.
For instances, in terms of construction of dihydroquinolinone derivatives, Shi group developed a Pd-
catalyzed intramolecular arylation of inert C(sp3)-H bond in 20142b and Mai reported a Ag-catalyzed
radical addition/cyclization pattern.2c As for pyrrolo[1,2-a]indole, Shen and his coworkers achieved
success via a one-pot protocol catalyzed successively by Rh2(OAc)4 and Cu(OTf)2 in 20153b and
Lautens group developed a Pd-catalyzed dearomative indole bisfunctionalization.3c Notwithstanding
these elegant breakthroughs, drawbacks still exist such as high temperature,2b,2c complicated starting
materials3a and noble metals.2a,3b In addition, strategies of straightforward incorporation of alkyl group
into these core skeletons have been relatively little studied, particularly into 2-position of pyrrolo[1,2-a]
indoles.
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Figure 1. Representative alkaloids containing dihydroquinolinone and pyrrolo[1,2-a]indole moieties
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Construction of complicated molecule scaffolds by alkyl radical addition strategy has emerged as a
powerful tool in the past decades.8 The frequently-used precursors of alkyl radicals are alkyl halides9
and aliphatic acids.2c,10 Recently, redox-active esters as the alkyl source attract more and more attention,
because such strategies hold many outstanding advantages.11 Peresters, employed more often as
initiators and oxidants,12 represent another type of redox-active esters.13 Recently, the elaborate studies
have been performed of alkyl radical addition reactions employing peresters as alkylating reagents and
oxidants.14 Also, based on the bifunctional features of perester, we have successfully developed a
practical two-step sequence for synthesis of fused-indoline-heterocycles (Scheme1A).15 Similarly, we
envision that combination of peresters and different cinnamamides might allow convenient access to the
alkylated 3,4-dihydroquinolinone and pyrrolo[1,2-a]indole derivatives via alkyl radical
addition/annulation fashion (Scheme 1B).
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Scheme 1. Alkyl Radical Addition/Cyclization of ,-Unsaturated Amides
RESULTS AND DISCUSSION
Our investigation was initiated by employing cinnamamide 1a and perester 3a as the model substrates
(Table 1). Results of screening catalysts showed that only iron salts took effect and the inexpensive
FeCl24H2O gave the best outcome (Table 1, entries 1-6). The structure of 4aa (CCDC 1818937) was
confirmed by single-crystal X-ray diffraction analysis16 and only trans isomer was detected and
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achieved (Figure 2). In the presence of copper or nickel salts, the reaction process was completely
suppressed and only starting materials were recovered (Table 1, entries 7-9). In the absence of catalyst,
only trace amount of product 4aa was obtained and when the reaction was conducted at elevated
temperature (100 C), the yield was improved (Table 1, entries 10 and 11). However, decomposition
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temperatures measured by DSC showed that upon heating over 100 C, peresters were potentially
explosive and it would cause unsafe operation.15 The optimization of solvents displayed that DMF was
superior to other solvents such as DMSO, MeCN, toluene and dioxane (Table 1, entries 5, 12-15).
Table 1. Optimization of Reaction Conditions.a
O
Ph
O
Ph
O
OOtBu
catalyst
N
+
N
solvent, 50 oC
12 h, Ar
N
O
N
O
O
O
1a
3a
4aa
entry
1
catalyst
solvent
yield (%)b
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Fe(OTf)2
Fe(OTf)3
Fe(acac)2
Fe(acac)3
DMF
DMF
2
33
3
DMF
51
4
DMF
56
5
DMF
64
FeCl24H2O
6
Cp2Fe
DMF
38
7
DMF
n.r.
n.r.
n.r.
trace
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NiCl26H2O
CuBr
8
DMF
9
Cu(OAc)2
DMF
10
11c
12
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15
DMF


DMF
DMSO
MeCN
toluene
1,4-dioxane
n.r.
20
FeCl24H2O
FeCl24H2O
FeCl24H2O
FeCl24H2O
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aReaction conditions: 1a (0.1 mmol), 3a (0.25 mmol), catalyst (0.01 mmol), solvent (2.0 mL), 50 C, 12 h, Ar.
bIsolated yield. c100 C. n.r. = no reaction
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Figure 2. X-ray crystal structure of 4aa (displacement ellipsoids are drawn at the 50%
probability level)
Table 2. Substrate Scope for Construction of Dihydroquinolinone Derivativesa c
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aUnless note otherwise, the reaction conditions are as following: cinnamamide 1 (0.2 mmol), perester 3 (0.5 mmol),
b
c
FeCl24H2O (0.02 mmol), DMF (2.0 mL), Ar, 50 C, 12 h. Isolated yield after silica gel column chromatography. The dr
value was determined by 1H NMR. dPerester 3 (0.6 mmol), 60 C, 12 h. ePerester 3 (0.6 mmol), 60 C, 36 h. fCinnamamide 1
(0.2 mmol), diacyl peroxide 3 (0.5 mmol), FeCl24H2O (0.02 mmol), DMF (2.0 mL), Ar, 50 C, 12 h. gDiacyl peroxide 3 (0.6
mmol), 60 C, 12 h.
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a c
Table 3. Substrate Scope for Construction of Pyrrolo[1,2-a]indole Derivatives[ - ]
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aUnless note otherwise, the reaction conditions are as following: cinnamamide 2 (0.2 mmol), perester 3 (0.5 mmol),
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b
c
FeCl24H2O (0.02 mmol), DMF (2.0 mL), Ar, 50 C, 12 h. Isolated yield after silica gel column chromatography. The dr
value was determined by 1H NMR. dPerester 3 (0.6 mmol), 60 C, 12 h. ePerester 3 (0.6 mmol), 60 C, 36 h. fCinnamamide 2
(0.2 mmol), diacyl peroxide 3 (0.5 mmol), FeCl24H2O (0.02 mmol), DMF (2.0 mL), Ar, 50 C, 12 h. gDiacyl peroxide 3 (0.6
mmol), 60 C, 12 h.
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With the optimal conditions in hand, the effect of substituent variation on cinnamamide 1 and
peresters 3 was investigated (Table 2). Whether halogens anchoring on aniline motifs (R1) or
cinnamamide moieties (R2), remained intact in the reaction (4ba, 4da, 4ga, 4ha). Substrates containing
the electron-donating or electron-withdrawing group proceeded well, affording the cyclized products
with excellent diastereoselectivity (4ca, 4ea, 4fa). Subsequently, the scope of peresters was examined.
Peresters stemmed from primary acids were amenable to the addition/annulation process (4ac, 4ad).
Alternatively, the analogues of peresters, the alkyl diacyl peroxides, also worked well under the
conditions and delivered the desired alkylated products 4ai, 4aj, 4ak, 4ik and 4jk with good
diastereoselectivity. It is worth noting that the existence of terminal alkene of peroxide 3j did not alter
the radical addition pathway (4aj). Peresters of secondary acids displayed moderate reactivity in this
transformation (4ae, 4af, 4ag). Possibly due to the steric hindrance, employing tertiary perester would
lead to only trace amount of isolated product 4al.
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Figure 3. X-ray crystal structure of 5ba (Displacement ellipsoids are drawn at the 50%
probability level)
Then, the optimal conditions was successfully applied to construction of pyrrolo[1,2-a]indole
derivatives without any change (Table 3). Substituents such as methyl and methoxy on indoles moiety
(R1) had no big effect on the reaction results (5aa, 5ba, 5cb). The trans isomer of 5ba (CCDC 1819940)
was confirmed by single-crystal X-ray diffraction analysis (Figure 3).16 Substrates bearing CF3, MeO
and Br on R2 moiety reacted well with commercially available dilauroyl peroxide (DLP), providing the
expected product with excellent diastereoselectivity (5dk, 5ek, 5fk). Besides, peresters (or peroxides) of
primary alkyl acids could be applied to this reaction and give the tricycle products in moderate yields
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(5dc, 5dj and 5hk). Also, peresters of secondary acids proved to be suitable substrates for this reaction
(5de, 5dg, 5dh and 5gg). Unfortunately, perester of tertiary aliphatic acid was ill-suited to this protocol
(5gl).
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To showcase the scalability of this transformation, two scale-up experiments were carried out. DLP as
the alkylating reagents separately afforded the bicycle product 4ak in 84% yield and the tricycle product
5hk in 59% yield (Scheme 2).
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To probe into the mechanism, radical trapping experiments were performed. With respect to the
construction of product 4aa, neither did the addition of TEMPO, a common radical scavenger, make this
transformation run, nor did BHT. Analysis by TLC and LC-MS exhibited that only adduct 6a or 6b was
detected and no the expected product 4aa was generated (Scheme 3). Similarly, the addition of TEMPO
or BHT into the reaction for synthesis of product 5ca had the same results as well (Scheme 3) (see
Supporting Information).
Scheme 2. Scale-up experiments.
Ph
N
Ph
C11 H23
O
FeCl2 4H2O (10 mol%)
+
DLP
DMF, Ar
60 oC, 36 h
N
O
1a
4ak
, 1.185 g
, 1.642 g, 84% yield
3k
, 4.98 g
MeO
MeO
OMe
OMe
Ph
Ph
FeCl2 4H2O (10 mol%)
DLP
+
N
N
DMF, Ar
60 oC, 36 h
C11 H23
O
O
2h,
5hk
, 950 mg, 59% yield
1.149 g
3k,
2.985 g
Based on these experiments, a FeCl2-catalyzed alkyl radical addition/cyclization mechanism was
proposed (Scheme 4). Outer-sphere single-electron transfer from Fe(II) to perester leads to the O-O
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bond cleavage, generating the reactive alkyl radical I, Fe(III), CO2 and tBuO. The addition of radical I
to ,-unsaturated amide 1a delivers the relatively stable benzyl radical II. Subsequently,
intramolecular cyclization of II generates radical intermediate III, which then successively undergoes
single electron oxidation by Fe(III) and deprotonation by tBuO to give the annulated product 4aa and
Fe(II).
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Scheme 3. Preliminary Investigation of Mechanism
Scheme 4. Plausible Mechanism
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CONCLUSIONS
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In conclusion, we have developed an inexpensive and environmental-friendly FeCl24H2O-catalyzed
unified approach for highly diastereoselective synthesis of alkylated dihydroquinolinone and
pyrrolo[1,2-a]indole derivatives. This reaction is enabled by the alkyl radical addition/annulation of
different cinnamamides. Peresters (or peroxides) not only serve as alkyl source, but also as single
electron oxidizing agents. This approach demonstrates strong regio-selectivity and special
cinnamamides produce cycles with specific size.
EXPERIMENTAL SECTION
General Information: All commercial reagents were used without further purification. Solvents
were distilled according to the purification procedures. 1H NMR spectra were measured with 400 MHz
spectrometer, chemical shifts were reported in δ (ppm) units relative to tetramethylsilane (TMS) as
13
internal standard. C NMR spectra were measured at 176 MHz with 700 MHz spectrometer, chemical
shifts are reported in ppm relative to tetramethylsilane and referenced to solvent peak (CDCl3, δ C =
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77.00). Proton coupling patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet
(m), and broad (br). The ESI-HRMS spectra were obtained with Accurate-Mass-Q-TOF
MS spectrometer.
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Peresters 3a-3h, 3l and peroxides 3i, 3j were synthesized according to the following procedure A and
B. 3k (DLP) was commercially available.
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General procedures A: A solution of alkyl carboxylic acid (6 mmol), DMAP (73.2 mg, 0.6 mmol),
tBuOOH (900 mg, 7 mmol, 70% w/w solution in water) in CH2Cl2 (5 mL) was cooled to 0 oC, followed
by dropwise addition of DCC (1.44 g, 7 mmol) in CH2Cl2. After the resulting solution was stirred for 3h
at 0 C, petroleum ether (30 mL) was added. Then the resulting mixture was quickly filtered by silica
gel flash chromatography (35 cm height) with pressure pump and the chromatography was quickly
washed by 80 mL eluent (petroleum ether/AcOEt = 20:1). The filtration was concentrated under reduced
pressure to give the crude peresters 3a-3h, 3l, which would keep intact and undegraded for months at
20 oC and would be directly used in the next step without any further purification.
The simply-filtered crude perester (0.5 mmmol or 0.6 mmol), FeCl24H2O (3.98 mg, 0.02 mmol, 10
mol%), cinnamamide (0.2 mmol) were added into a Schlenk tube under Ar atmosphere, followed by the
addition of degassed DMF (2.0 mL) via syringe. The tube was immediately placed in a preheated 50 or
60 °C oil bath for 12 h under stirring. After completion, the mixture was added into 0.1 M aqueous HCl
(not for acid-sensitive substrates) and extracted with EtOAc for 3 times. The combined organic layer
was dried over anhydrous Na2SO4 and concentrated under vacuum to furnish the title product 4, which
was then purified by silica gel flash column chromatography (EtOAc/petroleum ether as eluant) to
furnish the title product.
General procedures B: a solution of alkyl carboxylic acid (6 mmol), DMAP (73.2 mg, 0.6 mmol),
o
H2O2 (245 mg, 3.5 mmol, 50% w/w solution in water) in CH2Cl2 (5 mL) was cooled to 0 C, followed
by dropwise addition of DCC (1.44 g, 7 mmol) in CH2Cl2. After the resulting solution was stirred for 3h
at 0 C, petroleum ether (30 mL) was added. Then the resulting mixture was quickly filtered by silica
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gel chromatography (35 cm height) with pressure pump and the chromatography was quickly washed
by 80 mL eluent (petroleum ether/AcOEt = 20:1). The filtration was concentrated under reduced
pressure to give the crude peroxides 3i and 3j, which would keep intact and undegraded for months at
20 oC and would be directly used in the next step without any further purification.
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The simply-filtered crude peroxide (0.5 mmol or 0.6 mmol), FeCl24H2O (3.98 mg, 0.02 mmol, 10
mol%), cinnamamide (0.2 mmol) were added into a Schlenk tube under Ar atmosphere, followed by the
addition of degassed DMF (2.0 mL) via syringe. The tube was immediately placed in a preheated 50 or
60 °C oil bath for 12 h under stirring. After completion, the mixture was added into 0.1 M aqueous HCl
(not for acid-sensitive substrates) and extracted with EtOAc for 3 times. The combined organic layer
was dried over anhydrous Na2SO4 and concentrated under vacuum to furnish the title product, which
was then purified by silica gel flash column chromatography (EtOAc/petroleum ether as eluant) to
furnish the title product 5.
2-((1-Methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)methyl)isoindoline-1,3-dione (4aa).
Following procedure A: the reaction of 1a (47.4 mg, 0.2 mmol) and 3a (138 mg, 0.5 mmol) was
performed at 50 C for 12 h. The crude product was purified by silica gel flash chromatography using
PE/EtOAc (10:1 to 4:1) to afford 4aa (51.0 mg, 64% yield) as white solid. Rf = 0.30 (PE/EtOAc 2:1). M.
p. 205-207 C. 1H NMR (400 MHz, CDCl3): δ 7.75-7.63 (m, 4H), 7.26-7.19 (m, 3H), 7.13-6.95 (m, 6H),
4.13 (d, J = 4.0 Hz, 1H), 4.04 (dd, J1 = 14.0 Hz, J2 = 8.8 Hz, 1H), 3.84 (dd, J1 = 14.0 Hz, J2 = 5.6 Hz,
1H), 3.50 (dt, J1 = 8.8 Hz, J2 = 4.8 Hz, 1H), 3.34 (s, 3H). 13C NMR (176 MHz, CDCl3): δ 168.7, 167.9,
140.5, 139.2, 133.7, 131.8, 129.4, 128.7, 128.2, 127.4, 127.0, 126.0, 123.2, 123.1, 114.8, 46.4, 45.3,
38.7, 29.6. HRMS (ESI): m/z calcd. for C25H21N2O3 [M + H]+ 397.1547, found 397.1545.
2-((1-Benzyl-6-chloro-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)methyl)isoindoline-1,3-dione
(4ba). Following procedure A: the reaction of 1b (69.4 mg, 0.2 mmol) and 3a (138 mg, 0.5 mmol) was
performed at 50 C for 12 h. The crude product was purified by silica gel flash chromatography using
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PE/EtOAc (10:1 to 4:1) to afford 4ba (51.0 mg, 50% yield) as white solid. Rf = 0.30 (PE/EtOAc 2:1). M.
p. 233-235 C. 1H NMR (400 MHz, CDCl3): δ 7.77 (s, 2H), 7.67 (d, J = 2.8 Hz, 2H), 7.24-7.18 (m, 5H),
7.16-7.11 (m, 3H), 7.07-6.99 (m, 4H), 6.92 (d, J = 8.8 Hz, 1H), 5.48 (d, J = 16.0 Hz, 1H), 4.79 (d, J =
16.4 Hz, 1H), 4.16-4.11 (m, 2H), 3.91 (dd, J1 = 14.0 Hz, J2 = 5.6 Hz, 1H), 3.70-3.68 (m, 1H). 13C NMR
(176 MHz, CDCl3): δ 168.7, 167.9, 139.5, 136.8, 136.1, 133.9, 131.8, 129.5, 128.8, 128.6, 128.1, 128.0,
127.6, 127.32, 127.26, 127.1, 123.2, 117.0, 46.2, 45.6, 45.2, 38.8. HRMS (ESI): m/z calcd. for
C31H24ClN2O3 [M + H]+ 507.1470, found 507.1477.
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2-((1-Benzyl-6-methoxy-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)methyl)isoindoline-1,3-
dione (4ca). Following procedure A: the reaction of 1c (68.6 mg, 0.2 mmol) and 3a (138 mg, 0.5 mmol)
was performed at 50 C for 12 h. The crude product was purified by silica gel flash chromatography
using PE/EtOAc (10:1 to 4:1) to afford 4ca (59.0 mg, 59% yield) as white solid. Rf = 0.20 (PE/EtOAc
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2:1). M. p. 91-92 C. H NMR (400 MHz, CDCl3): δ 7.78-7.76 (m, 2H), 7.67-7.65 (m, 2H), 7.25-7.13
(m, 8H), 7.03 (d, J = 7.6 Hz, 2H), 6.94 (d, J = 8.8 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 6.58 (s, 1H), 5.45
(d, J = 16.0 Hz, 1H), 4.81 (d, J = 16.0 Hz, 1H), 4.18-4.13 (m, 2H), 3.91 (dd, J1 = 14.0 Hz, J2 = 6.0 Hz,
1H), 3.68-3.63 (m, 4H). 13C NMR (176 MHz, CDCl3): δ 168.6, 168.0, 155.5, 140.1, 136.7, 133.8, 131.9,
131.7, 128.7, 128.5, 127.7, 127.6, 127.2, 127.1, 123.2, 116.8, 115.7, 112.7, 55.3, 46.6, 45.7, 45.6, 38.9.
HRMS (ESI): m/z calcd. for C32H27N2O4 [M + H]+ 503.1965, found 503.1975.
2-((6-Fluoro-1-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)methyl)isoindoline-1,3-
dione (4da). Following procedure A: the reaction of 1d (51 mg, 0.2 mmol) and 3a (138 mg, 0.5 mmol)
was performed at 50 C for 12 h. The crude product was purified by silica gel flash chromatography
using PE/EtOAc (10:1 to 4:1) to afford 4da (57.0 mg, 69% yield) as white solid. Rf = 0.20 (PE/EtOAc
2:1). M. p. 244-246 C. 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 3.2 Hz, 2H), 7.67 (J = 3.2 Hz, 2H),
7.26-7.21 (m, 2H), 7.14 (t, J = 7.2 Hz, 1H), 7.07 (d, J = 7.6 Hz, 2H), 6.99 (dd, J1 = 8.4 Hz, J2 = 4.8 Hz,
1H), 6.92 (t, J = 8.0 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 4.09-4.03 (m, 2H), 3.84 (dd, J1 = 14.0 Hz, J2 =
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5.6 Hz, 1H), 3.53-3.48 (m, 1H), 3.33 (s, 3H). C NMR (176 MHz, CDCl3): δ 168.4, 168.0, 158.7 (d,
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1JC-F = 243.8 Hz), 139.8, 135.6, 133.8, 131.8, 128.9, 128.4 (d, 3JC-F = 7.0 Hz), 127.5, 127.3, 123.2, 116.4
(d, 2JC-F = 23.4 Hz), 116.0 (d, 3JC-F = 7.9 Hz), 114.6 (d, 2JC-F = 22.2 Hz), 45.9, 45.5, 38.7, 29.9. HRMS
(ESI): m/z calcd. for C25H20FN2O3 [M + H]+ 415.1452, found 415.1457.
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Ethyl 1-benzyl-3-((1,3-dioxoisoindolin-2-yl)methyl)-2-oxo-4-phenyl-1,2,3,4-tetrahydro-
quinolone-6-carboxylate (4ea). Following procedure A: the reaction of 1e (77 mg, 0.2 mmol) and 3a
(138 mg, 0.5 mmol) was performed at 50 C for 12 h. The crude product was purified by silica gel flash
chromatography using PE/EtOAc (10:1 to 4:1) to afford 4ea (56.0 mg, 52% yield) as colorless liquid. Rf
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= 0.40 (PE/EtOAc 2:1). H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 6.0 Hz,
3H), 7.67 (d, J = 4.0 Hz, 2H), 7.23-7.16 (m, 6H), 7.14-7.08 (m, 3H), 7.00 (d, J = 7.6 Hz, 2H), 5.54 (d, J
= 16.0 Hz, 1H), 4.82 (d, J = 16.0 Hz, 1H), 4.32-4.27 (m, 3H), 4.09 (dd, J1 = 13.6 Hz, J2 = 9.2 Hz, 1H),
3.93 (dd, J1 = 14.0 Hz, J2 = 5.6 Hz, 1H), 3.70 (dt, J1 = 8.8 Hz, J2 = 4.0 Hz, 1H), 1.33 (t, J = 7.2 Hz, 3H).
13C NMR (176 MHz, CDCl3): δ 169.1, 167.9, 165.7, 141.8, 139.8, 136.0, 133.9, 131.8, 131.2, 130.0,
128.8, 128.5, 127.5, 127.3, 127.2, 125.7, 125.4, 123.3, 115.6, 60.8, 46.8, 45.5, 45.1, 38.8, 14.3. HRMS
(ESI): m/z calcd. for C34H29N2O5 [M + H]+ 545.2071, found 545.2075 .
2-((1-Methyl-2-oxo-4-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-
yl)methyl)isoindoline-1,3-dione (4fa). Following procedure A: the reaction of 1f (71 mg, 0.2 mmol)
and 3a (138 mg, 0.5 mmol) was performed at 50 C for 12 h. The crude product was purified by silica
gel flash chromatography using PE/EtOAc (10:1 to 4:1) to afford 4fa (70.0 mg, 75% yield) as white
solid. Rf = 0.35 (PE/EtOAc 3:1). M. p. 207-208 C. 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 2.4 Hz,
2H), 7.67 (d, J = 2.8 Hz, 2H), 7.46 (d, J = 7.6 Hz, 2H), 7.28 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 2H),
7.08 (d, J = 8.0 Hz, 1H), 7.01-6.97 (m, 2H), 4.19 (d, J = 4.0 Hz, 1H), 4.08 (dd, J1 = 14.0 Hz, J2 = 8.8 Hz,
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1H), 3.88 (dd, J1 = 14.0 Hz, J2 = 5.6 Hz, 1H), 3.53-3.48 (m, 1H), 3.35 (s, 3H). C NMR (176 MHz,
CDCl3): δ 168.3, 167.9, 144.6, 139.3, 133.9, 131.7, 129.4 (q, 2JCF = 32.6 Hz), 129.3, 128.7, 128.0, 125.7
(q, 3JCF = 3.5 Hz), 125.1, 123.9 (q, 1JCF = 271.9 Hz), 123.5, 123.2, 115.0, 46.1, 45.3, 38.7, 29.7. HRMS
(ESI): m/z calcd. for C26H20F3N2O3 [M + H]+ 465.1421, found 465.1404.
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dione (4ga). Following procedure A: the reaction of 1g (54.2 mg, 0.2 mmol) and 3a (138 mg, 0.5 mmol)
was performed at 50 C for 12 h. The crude product was purified by silica gel flash chromatography
using PE/EtOAc (10:1 to 4:1) to afford 4ga (62.0 mg, 72% yield) as white solid. Rf = 0.3 (PE/EtOAc
2:1). M. p. 215-216 C. 1H NMR (400 MHz, CDCl3): δ 7.78-7.75 (m, 2H), 7.69-7.66 (m, 2H), 7.36 (d, J
= 8.0 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.13-6.97 (m, 5H), 6.62 (d, J = 7.6 Hz, 1H), 4.62 (s, 1H), 4.04
(dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 1H), 3.91 (dd, J1 = 13.6 Hz, J2 = 5.6 Hz, 1H), 3.45-3.41 (m, 1H), 3.37 (s,
3H). 13C NMR (176 MHz, CDCl3): δ 168.2, 167.9, 140.0, 138.0, 133.8, 133.6, 131.8, 130.0, 129.9,
128.62, 128.57, 128.4, 127.2, 124.4, 123.6, 123.2, 114.8, 46.0, 42.0, 38.7, 29.7. HRMS (ESI): m/z calcd.
for C25H20ClN2O3 [M + H]+ 431.1157, found 431.1146 .
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2-((4-(4-Bromophenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)methyl)isoindoline-1,3-
dione (4ha). Following procedure A: the reaction of 1h (63 mg, 0.2 mmol) and 3a (138 mg, 0.5 mmol)
was performed at 50 C for 12 h. The crude product was purified by silica gel flash chromatography
using PE/EtOAc (10:1 to 4:1) to afford 4ha (65.0 mg, 69% yield) as white solid. Rf = 0.3 (PE/EtOAc
2:1). M. p. 217-219 C. 1H NMR (400 MHz, CDCl3): δ 7.76-7.74 (m, 2H), 7.67-7.65 (m, 2H), 7.32 (d, J
= 7.2 Hz, 2H), 7.29-7.24 (m, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.98-6.93 (m, 4H), 4.09-4.02 (m, 2H), 3.84
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(dd, J1 = 14.0 Hz, J2 = 6.0 Hz, 1H), 3.49-3.42 (m, 1H), 3.34 (s, 3H). C NMR (176 MHz, CDCl3): δ
168.4, 167.9, 139.5, 139.2, 133.9, 131.9, 131.8, 129.3, 128.5, 125.5, 123.4, 123.2, 121.0, 114.9, 46.1,
44.9, 38.7, 29.7. HRMS (ESI): m/z calcd. for C25H20BrN2O3 [M + H]+ 475.0652, found 475.0644.
1-Methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)methyl benzoate (4ab). Following
procedure A: the reaction of 1a (47.4 mg, 0.2 mmol) and 3b (124 mg, 0.5 mmol) was performed at 50
C for 12 h. The crude product was purified by silica gel flash chromatography using PE/EtOAc (10:1
to 4:1) to afford 4ab (50.0 mg, 70% yield) as colorless liquid. Rf = 0.3 (PE/EtOAc 5:1). 1H NMR (400
MHz, CDCl3): δ 7.92 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.2 Hz, 2H), 7.33-7.25 (m,
4H), 7.14 (d, J = 7.6 Hz, 2H), 7.08 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H),
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4.71 (dd, J1 = 11.2 Hz, J2 = 4.8 Hz, 1H), 4.37 (d, J = 8.4 Hz, 1H), 4.30 (dd, J1 = 11.2 Hz, J2 = 4.4 Hz,
1H), 3.45 (s, 3H), 3.28 (dt, J1 = 8.0 Hz, J2 = 4.8 Hz, 1H). 13C NMR (176 MHz, CDCl3): δ 168.3, 166.0,
140.2, 139.5, 132.9, 129.9, 129.6, 129.0, 128.9, 128.3, 128.13, 128.05, 127.6, 127.4, 123.3, 114.7, 62.8,
47.3, 44.2, 30.0. HRMS (ESI): m/z calcd. for C24H22NO3 [M + H]+ 372.1594, found 372.1582.
1-Methyl-4-phenyl-3-propyl-3,4-dihydroquinolin-2(1H)-one (4ac). Following procedure A: the
reaction of 1a (47.4 mg, 0.2 mmol) and 3c (96 mg, 0.6 mmol) was performed at 60 C for 12 h. The
crude product was purified by silica gel flash chromatography using PE/EtOAc (20:1 to 12:1) to afford
4ac (32 mg, 57% yield) as colorless liquid. Rf = 0.5 (PE/EtOAc 10:1). 1H NMR (400 MHz, CDCl3): δ
7.31 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.18 (t, J = 7.2 Hz, 1H), 7.10-7.02 (m, 5H), 4.02 (d, J
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= 3.6 Hz, 1H), 3.37 (s, 3H), 2.93-2.91 (m, 1H), 1.52-1.44 (m, 4H), 0.89 (t, J = 6.4 Hz, 3H). C NMR
(176 MHz, CDCl3): δ 171.5, 141.8, 139.7, 129.5, 128.7, 127.9, 127.4, 127.0, 126.8, 123.1, 114.6, 48.4,
46.5, 32.6, 29.5, 20.2, 13.9. HRMS (ESI): m/z calcd. for C19H22NO [M + H]+ 280.1696, found 280.1691.
3-(4-chlorobutyl)-1-methyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one (4ad). Following procedure A:
the reaction of 1a (47.4 mg, 0.2 mmol) and 3d (124.8 mg, 0.6 mmol) was performed at 60 C for 12 h.
The crude product was purified by silica gel flash chromatography using PE/EtOAc (15:1 to 10:1) to
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afford 4ad (33 mg, 51% yield) as colorless liquid. Rf = 0.3 (PE/EtOAc 10:1). H NMR (400 MHz,
CDCl3): δ 7.33-7.19 (m, 4H), 7.06-7.02 (m, 5H). 4.03 (d, J = 5.2 Hz, 1H), 3.48 (t, J = 6.4 Hz, 2H), 3.38
(s, 3H), 2.93-2.88 (m, 1H), 1.76-1.69 (m, 2H), 1.61-1.55 (m, 4H). 13C NMR (176 MHz, CDCl3): δ 171.1,
141.40, 139.6, 129.4, 128.8, 128.0, 127.5, 127.1, 127.0, 123.2, 114.7, 48.1, 46.5, 44.7, 32.3, 29.6, 29.5,
24.2. HRMS (ESI): m/z calcd. for C20H23ClNO [M + H]+ 328.1463, found 328.1462.
3-Cyclobutyl-1-methyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one (4ae). Following procedure A: the
reaction of 1a (47.4 mg, 0.2 mmol) and 3e (103.2 mg, 0.6 mmol) was performed at 60 C for 36 h. The
crude product was purified by silica gel flash chromatography using PE/EtOAc (15:1 to 7:1) to afford
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CDCl3): δ 7.32 (t, J = 8.0 Hz, 1H), 7.24-7.13 (m, 4H), 7.06-7.04 (m, 2H), 6.98 (d, J = 7.2 Hz, 2H), 3.92
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(s, 1H), 3.34 (s, 3H), 2.89 (d, J = 10.8 Hz, 1H), 2.35-2.25 (m, 1H), 2.11-2.02 (m, 2H), 1.90-1.74 (m, 4H).
13C NMR (176 MHz, CDCl3): δ 169.8, 142.2, 139.7, 129.8, 128.7, 128.0, 127.0, 126.7, 126.2, 123.2,
114.7, 55.7, 44.7, 36.2, 29.3, 27.5, 26.4, 17.7. HRMS (ESI): m/z calcd. for C20H22NO [M + H]+
292.1696, found 292.1689.
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3-Cyclopentyl-1-methyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one (4af). Following procedure A: the
reaction of 1a (47.4 mg, 0.2 mmol) and 3f (111.6 mg, 0.6 mmol) was performed at 60 C for 12 h. The
crude product was purified by silica gel flash chromatography using PE/EtOAc (20:1 to 12:1) to afford
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4af (34 mg, 56% yield) as colorless liquid. Rf = 0.5 (PE/EtOAc 10:1). H NMR (400 MHz, CDCl3): δ
7.33 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.2 Hz, 3H), 7.14 (t, J = 7.2 Hz, 1H), 7.08-7.05 (m, 2H), 6.97 (d, J =
7.6 Hz, 2H), 4.13 (s, 1H), 3.35 (s, 3H), 2.70 (d, J = 10.4 Hz, 1H), 1.93-1.87 (m, 1H), 1.67-1.62 (m, 2H),
1.58-1.43 (m, 4H), 1.38-1.32 (m, 2H). 13C NMR (176 MHz, CDCl3): δ 170.8, 142.0, 140.0, 129.7, 128.7,
128.0, 127.0, 126.7, 126.4, 123.2, 114.8, 55.0, 46.5, 40.3, 31.4, 30.8, 29.4, 25.1, 24.5. HRMS (ESI): m/z
calcd. for C21H24NO [M + H]+ 306.1852, found 306.1841.
3-Cyclohexyl-1-methyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one (4ag). Following procedure A: the
reaction of 1a (47.4 mg, 0.2 mmol) and 3g (120 mg, 0.6 mmol) was performed at 60 C for 12 h. The
crude product was purified by silica gel flash chromatography using PE/EtOAc (20:1 to 12:1) to afford
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4ag (31 mg, 49% yield) as colorless liquid. Rf = 0.5 (PE/EtOAc 10:1). H NMR (400 MHz, CDCl3): δ
7.33 (t, J = 8.0 Hz, 1H), 7.23-7.12 (m, 4H), 7.07-7.04 (m, 2H), 6.96 (d, J = 8.0 Hz, 2H), 4.21 (s, 1H),
3.36 (s, 3H), 2.67 (d, J = 8.4 Hz, 1H), 1.92 (d, J = 10.4 Hz, 1H), 1.71-1.67 (m, 2H), 1.59-1.56 (m, 2H),
1.29-1.23 (m, 2H), 1.17-1.05 (m, 4H). 13C NMR (176 MHz, CDCl3): δ 170.4, 142.3, 140.1, 129.6, 128.7,
128.0, 127.1, 126.7, 126.6, 123.2, 114.8, 55.6, 44.5, 37.8, 31.4, 31.1, 29.4, 26.2, 26.1, 26.0. HRMS
(ESI): m/z calcd. for C22H26NO [M + H]+ 320.2009, found 320.2000.
3-Isobutyl-1-methyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one (4ai). Following procedure B: the
reaction of 1a (47.4 mg, 0.2 mmol) and 3i (121.2 mg, 0.6 mmol) was performed at 60 C for 12 h. The
crude product was purified by silica gel flash chromatography using PE/EtOAc (15:1 to 10:1) to afford
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4ai (42 mg, 72% yield) as colorless liquid. Rf = 0.7 (PE/EtOAc 5:1). H NMR (400 MHz, CDCl3): δ
7.32 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 7.2 Hz, 2H), 7.18 (d, J = 6.8 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.06
(d, J = 8.8 Hz, 2H), 7.01 (d, J = 7.6 Hz, 2H), 3.98 (s, 1H), 3.36 (s, 3H), 3.01 (t, J = 7.6 Hz, 1H), 1.77 (dt,
J1 = 13.2 Hz, J2 = 6.8 Hz, 1H), 1.46 (dt, J1 = 13.6 Hz, J2 = 7.2 Hz, 1H), 1.32-1.26 (m, 1H), 0.92 (d, J =
6.8 Hz, 6H). 13C NMR (176 MHz, CDCl3): δ 171.7, 142.0, 139.8, 129.7, 128.7, 128.0, 127.2, 126.8,
126.6, 123.2, 114.7, 46.79, 46.77, 39.8, 29.5, 25.6, 22.7, 22.3. HRMS (ESI): m/z calcd. for C20H24NO
[M + H]+ 294.1852, found 294.1850.
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3-(Dec-9-en-1-yl)-1-methyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one (4aj). Following procedure B:
the reaction of 1a (47.4 mg, 0.2 mmol) and 3j (219.6 mg, 0.6 mmol) was performed at 60 C for 12 h.
The crude product was purified by silica gel flash chromatography using PE/EtOAc (15:1 to 10:1) to
afford 4aj (68 mg, 91% yield) as colorless liquid. Rf = 0.7 (PE/EtOAc 5:1). 1H NMR (400 MHz, CDCl3):
δ 7.33-7.16 (m, 4H), 7.09-7.02 (m, 5H), 5.85-5.75 (m, 1H), 4.98 (d, J = 17.2 Hz, 1H), 4.92 (d, J = 10.0
Hz, 1H), 4.02 (d, J = 3.6 Hz, 1H), 3.37 (s, 3H), 2.92-2.88 (m, 1H), 2.02 (dd, J1 = 13.6 Hz, J2 = 6.4 Hz,,
2H), 1.55-1.46 (m, 2H), 1.35-1.24 (m, 12H). 13C NMR (176 MHz, CDCl3): δ 171.5, 141.8, 139.7, 139.2,
129.5, 128.7, 127.9, 127.4, 127.0, 126.8, 123.1, 114.6, 114.1, 48.6, 46.5, 33.8, 30.5, 29.5, 29.4, 29.33,
29.30, 29.0, 28.9, 26.9. HRMS (ESI): m/z calcd. for C26H34NO [M + H]+ 376.2635, found 376.2635.
1-Methyl-4-phenyl-3-undecyl-3,4-dihydroquinolin-2(1H)-one (4ak). Following procedure B: the
reaction of 1a (47.4 mg, 0.2 mmol) and 3k (199 mg, 0.5 mmol) was performed at 50 C for 12 h. The
crude product was purified by silica gel flash chromatography using PE/EtOAc (20:1 to 12:1) to afford
4ak (70.0 mg, 90% yield) as colorless liquid. Rf = 0.65 (PE/EtOAc 10:1). 1H NMR (400 MHz, CDCl3):
δ 7.33-7.18 (m, 4H), 7.09-7.02 (m, 5H), 4.03 (d, J = 4.0 Hz, 1H), 3.37 (s, 3H), 2.92-2.88 (m, 1H), 1.57-
1.48 (m, 2H), 1.23 (s, 18H), 0.88 (t, J = 7.2 Hz, 3H). 13C NMR (176 MHz, CDCl3): δ 171.6, 141.8,
139.8, 129.5, 128.7, 127.9, 127.4, 127.0, 126.8, 123.1, 114.6, 48.6, 46.5, 31.9, 30.5, 29.60, 29.58, 29.55,
29.5, 29.43, 29.38, 29.3, 27.0, 22.7, 14.11. HRMS (ESI): m/z calcd. for C27H38NO [M + H]+ 392.2948,
found 392.2946.
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4-(3,4-Dimethoxyphenyl)-1-methyl-3-undecyl-3,4-dihydroquinolin-2(1H)-one (4ik). Following
procedure B: the reaction of 1i (59.4 mg, 0.2 mmol) and 3k (199 mg, 0.5 mmol) was performed at 50 C
for 12 h. The crude product was purified by silica gel flash chromatography using PE/EtOAc (13:1 to
7:1) to afford 4ik (57 mg, 63% yield) as colorless liquid. Rf = 0.28 (PE/EtOAc 5:1). 1H NMR (400 MHz,
CDCl3): δ 7.31 (t, J = 7.6 Hz, 1H), 7.09-7.01 (m, 3H), 6.74 (d, J = 8.4 Hz, 1H), 6.60 (s, 1H ), 6.53 (d, J
= 8.4 Hz, 1H), 3.97 (d, J = 4.0 Hz, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.37 (s, 3H), 2.91-2.87 (m, 1H), 1.65-
1.60 (m, 1H), 1.54-1.49 (m, 1H), 1.23 (s, 18H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (176 MHz, CDCl3): δ
178.6, 171.8, 149.0, 147.8, 139.6, 134.2, 129.4, 127.9, 123.1, 119.5, 114.6, 111.3, 110.6, 55.82, 55.75,
48.5, 46.1, 31.9, 30.3, 29.59, 29.57, 29.56, 29.53, 29.48, 29.4, 29.3, 27.0, 22.6, 14.1. HRMS (ESI): m/z
calcd. for C29H41NO3 [M + H]+ 452.3159, found 452.3142.
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1-Phenyl-2-undecyl-1,2,6,7-tetrahydropyrido[3,2,1-ij]quinolin-3(5H)-one
(4jk).
Following
procedure B: the reaction of 1j (52.6 mg, 0.2 mmol) and 3k (199 mg, 0.5 mmol) was performed at 50
C for 12 h. The crude product was purified by silica gel flash chromatography using PE/EtOAc (13:1
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to 7:1) to afford 4jk (69 mg, 83% yield) as colorless liquid. Rf = 0.45 (PE/EtOAc 5:1). H NMR (400
MHz, CDCl3): δ 7.26-7.16 (m, 3H), 7.04 (d, J = 6.8 Hz, 3H), 6.91 (d, J = 3.6 Hz, 2H), 4.15-4.11 (m,
1H), 4.00 (d, J = 3.2 Hz, 1H), 3.63-3.57 (m, 1H), 2.89-2.82 (m, 3H), 1.96 (br s, 2H), 1.52-1.46 (m, 2H),
1.23 (s, 18H), 0.88 (t, J = 6.8 Hz, 3 H). 13C NMR (176 MHz, CDCl3): δ 170.8, 142.1, 135.2, 128.7,
128.2, 127.5, 127.4, 126.7, 126.3, 125.0, 122.7, 48.3, 46.3, 40.8, 31.9, 30.5, 29.6, 29.5, 29.44, 29.38,
29.3 27.4, 26.9, 22.7, 21.5, 14.1. HRMS (ESI): m/z calcd. for C29H39NO [M + H]+ 418.3104, found
418.3091.
2-((3-Oxo-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-2-yl)methyl)isoindoline-1,3-dione (5aa).
Following procedure A: the reaction of 2a (49.4 mg, 0.2 mmol) and 3a (138 mg, 0.5 mmol) was
performed at 50 C for 12 h. The crude product was purified by silica gel flash chromatography using
PE/EtOAc (8:1 to 4:1) to afford 5aa (35 mg, 43% yield) as white solid. Rf = 0.5 (PE/EtOAc 2:1). M. p.
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215-217 C. H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 8.0 Hz, 1H), 7.78-7.75 (m, 2H), 7.71-7.68 (m,
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2H), 7.47 (d, J = 7.6 Hz, 1H), 7.33-7.27 (m, 2H), 7.12 (s, 5H), 6.14 (s, 1H), 4.49 (d, J = 6.0 Hz, 1H),
4.33 (dd, J1 = 14.0 Hz, J2 = 6.4 Hz, 1H), 4.26 (dd, J1 = 14.0 Hz, J2 = 8.8 Hz, 1H), 3.85-3.80 (m, 1H).
13C NMR (176 MHz, CDCl3): δ 169.4, 168.1, 144.9, 139.6, 135.0, 134.1, 131.7, 130.4, 128.8, 127.5,
127.3, 124.4, 123.9, 123.3, 120.9, 114.0, 101.5, 54.3, 44.4, 38.0. HRMS (ESI): m/z calcd. for
C26H19N2O3 [M + H]+ 407.1390, found 407.1398.
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2-((7-Methyl-3-oxo-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-2-yl)methyl)isoindoline-1,3-
dione (5ba). Following procedure A: the reaction of 2b (52.2 mg, 0.2 mmol) and 3a (138 mg, 0.5 mmol)
was performed at 50 C for 12 h. The crude product was purified by silica gel flash chromatography
using PE/EtOAc (8:1 to 4:1) to afford 5ba (38 mg, 45% yield) as white solid. Rf = 0.5 (PE/EtOAc 2:1).
M. p. 154 C. 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.0 Hz, 1H), 7.78-7.75 (m, 2H), 7.70-7.68 (m,
2H), 7.26 (s, 1H), 7.11 (s, 6H), 6.06 (s, 1H), 4.47 (d, J = 5.6 Hz, 1H), 4.32 (dd, J1 = 14.0 Hz, J2 = 6.4 Hz,
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1H), 4.24 (dd, J1 = 14.0 Hz, J2 = 9.2 Hz, 1H), 3.83-3.78 (m, 1H), 2.43 (s, 3H). C NMR (176 MHz,
CDCl3): δ 169.2, 168.1, 145.0, 139.7, 135.3, 134.1, 134.0, 131.7, 128.8, 128.6, 127.5, 127.3, 125.1,
123.3, 120.9, 113.6, 101.3, 54.3, 44.4, 38.1, 21.6. HRMS (ESI): m/z calcd. for C27H21N2O3 [M + H]+
421.1547, found 421.1558.
2-((7-Methoxy-3-oxo-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-2-yl)methyl)isoindoline-1,3-
dione (5ca). Following procedure A: the reaction of 2c (55.4 mg, 0.2 mmol) and 3a (138 mg, 0.5 mmol)
was performed at 50 C for 12 h. The crude product was purified by silica gel flash chromatography
using PE/EtOAc (8:1 to 3:1) to afford 5ca (46 mg, 53% yield) as white solid. Rf = 0.2 (PE/EtOAc 5:1).
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M. p. 230-231 C. H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.8 Hz, 1H), 7.77-7.69 (m, 4H), 7.12 (s,
5H), 6.92 (d, J = 8.8 Hz, 2H), 6.07 (s, 1H), 4.47 (d, J = 5.6 Hz, 1H), 4.31 (dd, J1 = 14.0 Hz, J2 = 6.4 Hz,
1H), 4.24 (dd, J1 = 14.0 Hz, J2 = 8.8 Hz, 1H), 3.83-3.76 (m, 4H). 13C NMR (176 MHz, CDCl3): δ 169.0,
168.1, 157.1, 145.8, 139.6, 136.1, 134.0, 131.7, 128.8, 127.5, 127.3, 125.1, 123.3, 114.6, 112.2, 104.0,
101.5, 55.7, 54.3, 44.4, 38.1. HRMS (ESI): m/z calcd. for C27H21N2O4 [M + H]+ 437.1496, found
437.1505.
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7-Methoxy-3-oxo-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-2-yl)methyl benzoate (5cb).
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Following procedure A: the reaction of 2c (55.4 mg, 0.2 mmol) and 3b (124 mg, 0.5 mmol) was
performed at 50 C for 12 h. The crude product was purified by silica gel flash chromatography using
PE/EtOAc (10:1 to 5:1) to afford 5cb (25 mg, 32% yield) as white solid. Rf = 0.2 (PE/EtOAc 10:1). M.
p. 137-138 C. 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.52 (t,
J = 7.6 Hz, 1H), 7.38-7.31 (m, 7H), 7.00 (s, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.21 (s, 1H), 4.89 (dd, J1 =
11.6 Hz, J2 = 3.6 Hz, 1H), 4.80 (dd, J1 = 11.6 Hz, J2 = 4.8 Hz, 1H), 4.59 (d, J = 5.6 Hz, 1H), 3.86 (s,
3H), 3.49-3.45 (m, 1H). 13C NMR (176 MHz, CDCl3): δ 168.8, 166.2, 157.2, 145.7, 140.1, 136.3, 133.3,
129.7, 129.4, 129.1, 128.4, 127.8, 127.6, 125.2, 114.6, 112.3, 104.0, 101.9, 62.3, 56.7, 55.7, 42.9.
HRMS (ESI): m/z calcd. for C26H22NO4 [M + H]+ 412.1543, found 412.1544.
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1-(3,4-Dimethoxyphenyl)-9-methyl-2-propyl-1H-pyrrolo[1,2-a]indol-3(2H)-one (5dc). Following
procedure A: the reaction of 2d (64 mg, 0.2 mmol) and 3c (96 mg, 0.6 mmol) was performed at 60 C
for 12 h. The crude product was purified by silica gel flash chromatography using PE/EtOAc (15:1 to
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6:1) to afford 5dc (36 mg, 50% yield) as colorless liquid. Rf = 0.3 (PE/EtOAc 10:1). H NMR (400
MHz, CDCl3): δ 8.10 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.35-7.29 (m, 2H), 6.82 (s, 2H), 6.70
(s, 1H), 4.20 (d, J = 4.8 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 3.11-3.06 (m, 1H), 2.06-1.99 (m, 1H), 1.89
(s, 3H), 1.86-1.79 (m, 1H), 1.59-1.50 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H). 13C NMR (176 MHz, CDCl3): δ
172.8, 149.4, 148.2, 140.3, 136.2, 133.5, 130.1, 123.8, 123.6, 119.9, 118.8, 113.8, 111.2, 110.2, 109.7,
57.4, 56.0, 55.9, 44.9, 33.3, 20.0, 14.0, 8.0. HRMS (ESI): m/z calcd. for C23H26NO3 [M + H]+ 364.1907,
found 364.1897.
2-Cyclobutyl-1-(3,4-dimethoxyphenyl)-9-methyl-1H-pyrrolo[1,2-a]indol-3(2H)-one
(5de).
Following procedure A: the reaction of 2d (64 mg, 0.2 mmol) and 3e (103 mg, 0.6 mmol) was
performed at 60 C for 36 h. The crude product was purified by silica gel flash chromatography using
PE/EtOAc (20:1 to 13:1) to afford 5de (30 mg, 40% yield) as colorless liquid. Rf = 0.5 (PE/EtOAc 10:1).
1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.34-7.28 (m, 2H),
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6.82 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 8.4 Hz, 1H), 6.67 (s, 1H), 4.18 (d, J = 3.2 Hz, 1H), 3.88 (s, 3H),
3.81 (s, 3H), 3.08 (dd, J1 = 8.4 Hz, J2 = 4.8 Hz, 1H), 2.91-2.81 (m, 1H), 2.24-1.93 (m, 5H), 1.90 (s, 3H).
13C NMR (176 MHz, CDCl3): δ 171.9, 149.4, 148.2, 140.2, 136.2, 133.8, 130.1, 123.8, 123.6, 119.9,
118.8, 113.8, 111.3, 110.3, 109.6, 61.9, 56.0, 55.9, 43.4, 37.8, 26.8, 26.2, 18.8, 8.1. HRMS (ESI): m/z
calcd. for C24H26NO3 [M + H]+ 376.1907, found 376.1896.
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2-Cyclohexyl-1-(3,4-dimethoxyphenyl)-9-methyl-1H-pyrrolo[1,2-a]indol-3(2H)-one (5dg).
Following procedure A: the reaction of 2d (64 mg, 0.2 mmol) and 3g (120 mg, 0.6 mmol) was
performed at 60 C for 12 h. The crude product was purified by silica gel flash chromatography using
PE/EtOAc (20:1 to 10:1) to afford 5dg (42 mg, 52% yield) as white solid. Rf = 0.5 (PE/EtOAc 10:1). M.
p. 148-149 C. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.34-
7.28 (m, 2H), 6.81 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.66 (s, 1H), 4.33 (d, J = 3.6 Hz, 1H),
3.88 (s, 3H), 3.80 (s, 3H), 3.06 (t, J = 4.0 Hz, 1H), 2.13-2.07 (m, 1H), 1.90 (s, 3H), 1.77-1.72 (m, 4H),
1.43-1.21 (m, 6H). 13C NMR (176 MHz, CDCl3): δ 172.4, 149.4, 148.1, 140.8, 136.3, 134.4, 129.9,
123.8, 123.5, 119.9, 118.8, 113.9, 111.2, 110.3, 109.4, 63.3, 56.0, 55.8, 41.3, 40.0, 30.3, 28.8, 26.5, 26.2,
26.1, 8.0. HRMS (ESI): m/z calcd. for C26H30NO3 [M + H]+ 404.2220, found 404.2221.
1-(3,4-Dimethoxyphenyl)-9-methyl-2-(1-tosylpiperidin-4-yl)-1H-pyrrolo[1,2-a]indol-3(2H)-one
(5dh). Following procedure A: the reaction of 2d (64 mg, 0.2 mmol) and 3h (257 mg, 0.6 mmol) was
performed at 60 C for 12 h. The crude product was purified by silica gel flash chromatography using
PE/EtOAc (6:1 to 2:1) to afford 5dh (45 mg, 40% yield) as white solid. Rf = 0.5 (PE/EtOAc 1:1). M. p.
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205-207 C. H NMR (400 MHz, CDCl3): δ 8.06-8.04 (m, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.45-7.43 (m,
1H), 7.33 (d, J = 7.6 Hz, 4H), 6.79 (dd, J1 = 17.6 Hz, J2 = 8.4 Hz, 2H), 6.63 (s, 1H, 4.28 (d, J = 4.0 Hz,
1H), 3.88-3.80 (m, 8H), 3.11 (t, J = 4.0 Hz, 1H), 2.44 (s, 3H), 2.25 (t, J = 11.2 Hz, 2H), 2.10-2.02 (m,
1H), 1.87 (s, 3H), 1.76-1.59 (m, 4H). 13C NMR (176 MHz, CDCl3): δ 171.2, 149.5, 148.3, 143.6, 140.2,
136.3, 133.7, 133.0, 129.9, 129.6, 127.7, 124.1, 123.7, 120.1, 118.9, 113.8, 111.3, 110.08, 110.05, 61.7,
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56.0, 55.9, 46.5, 46.2, 40.8, 37.0, 29.2, 26.7, 21.5, 7.9. HRMS (ESI): m/z calcd. for C32H35N2O5S [M +
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H]+ 559.2261, found 559.2247.
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performed at 60 C for 12 h. The crude product was purified by silica gel flash chromatography using
PE/EtOAc (15:1 to 6:1) to afford 5dj (43 mg, 47% yield) as colorless liquid. Rf = 0.5 (PE/EtOAc 10:1).
1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 6.8 Hz, 1H), 7.45 (d, J = 6.8 Hz, 1H), 7.34-7.29 (m, 2H),
6.82 (s, 2H), 6.70 (s, 1H), 5.85-5.75 (m, 1H), 4.98 (d, J = 17.2 Hz, 1H), 4.92 (d, J = 10.4 Hz, 1H), 4.20
(d, J = 4.0 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 3.09-3.05 (m, 1H), 2.05-2.00 (m, 3H), 1.89-1.82 (m, 4H),
1.36-1.26 (m, 12H). 13C NMR (176 MHz, CDCl3): δ 172.7, 149.4, 148.2, 140.3, 139.2, 136.2, 133.5,
130.1, 123.8, 123.6, 119.9, 118.8, 114.1, 113.8, 111.2, 110.2, 109.7, 57.6, 56.0, 55.9, 44.8, 33.8, 31.0,
29.5, 29.34, 29.31, 29.0, 28.9, 26.6, 8.1. HRMS (ESI): m/z calcd. for C30H38NO3 [M + H]+ 460.2846,
found 460.2836.
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1-(3,4-Dimethoxyphenyl)-9-methyl-2-undecyl-1H-pyrrolo[1,2-a]indol-3(2H)-one (5dk). Following
procedure B: the reaction of 2d (64 mg, 0.2 mmol) and 3k (199 mg, 0.5 mmol) was performed at 50 C
for 12 h. The crude product was purified by silica gel flash chromatography using PE/EtOAc (20:1 to
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10:1) to afford 5dk (59 mg, 62% yield) as colorless liquid. Rf = 0.5 (PE/EtOAc 10:1). H NMR (400
MHz, CDCl3): δ 8.10 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 6.8 Hz, 1H), 7.35-7.28 (m, 2H), 6.82 (s, 2H), 6.70
(s, 1H), 4.20 (d, J = 4.8 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 3.09-3.05 (m, 1H), 2.06-1.97 (m, 1H), 1.89-
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1.80 (m, 4H), 1.29-1.24 (m, 18H), 0.88 (t, J = 6.8 Hz). C NMR (176 MHz, CDCl3): δ 172.7, 149.4,
148.2, 140.3, 136.2, 133.5, 130.1, 123.8, 123.6, 119.9, 118.8, 113.8, 111.2, 110.2, 109.6, 57.6, 56.0,
55.9, 44.8, 31.9, 31.1, 29.59, 29.58, 29.53, 29.51, 29.4, 29.3, 26.6, 22.7, 14.1, 8.1. HRMS (ESI): m/z
calcd. for C31H42NO3 [M + H]+ 476.3159, found 476.3160.
1-(4-Bromophenyl)-9-methyl-2-undecyl-1H-pyrrolo[1,2-a]indol-3(2H)-one
(5ek).
Following
procedure B: the reaction of 2e (68 mg, 0.2 mmol) and 3k (199 mg, 0.5 mmol) was performed at 50 C
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for 12 h. The crude product was purified by silica gel flash chromatography using PE/EtOAc (200:1 to
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100:1) to afford 5ek (73 mg, 74% yield) as colorless liquid. Rf = 0.5 (PE/EtOAc 0:1). H NMR (400
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MHz, CDCl3): δ 8.09 (d, J = 7.2 Hz, 1H), 7.47-7.44 (m, 3H), 7.35-7.28 (m, 2H), 7.11 (d, J = 8.0 Hz,
2H), 4.21 (d, J = 4.0 Hz, 1H), 3.05-3.00 (m, 1H), 2.05-1.97 (m, 1H), 1.88-1.79 (m, 4H), 1.24 (s, 18H),
0.88 (t, J = 7.2 Hz, 3H). 13C NMR (176 MHz, CDCl3): δ 172.3, 140.4, 139.5, 136.1, 132.1, 130.1, 129.2,
123.9, 123.8, 121.1, 118.8, 113.9, 109.9, 57.6, 44.4, 31.9, 31.2, 29.6, 29.5, 29.4, 29.34, 29.31, 26.6, 22.7,
14.1, 8.1. HRMS (ESI): m/z calcd. for C29H37BrNO [M + H]+ 494.2053, found 494.2064.
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9-Methyl-1-(4-(trifluoromethyl)phenyl)-2-undecyl-1H-pyrrolo[1,2-a]indol-3(2H)-one
(5fk).
Following procedure B: the reaction of 2f (65.8 mg, 0.2 mmol) and 3k (199 mg, 0.5 mmol) was
performed at 50 C for 12 h. The crude product was purified by silica gel flash chromatography using
PE/EtOAc (200:1 to 100:1) to afford 5fk (61 mg, 63% yield) as colorless liquid. Rf = 0.5 (PE/EtOAc
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0:1). H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 7.2 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 7.2
Hz, 1H), 7.37-7.32 (m, 4H), 4.32 (d, J = 4.4 Hz, 1H), 3.08-3.04 (m, 1H), 2.08-1.99 (m, 1H), 1.91-1.81
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(m, 4H), 1.24 (s, 18H), 0.88 (t, J = 6.8 Hz, 3H). C NMR (176 MHz, CDCl3): δ 172.1, 145.4, 139.2,
136.1, 130.1, 129.7 (q, 2JCF = 32.6 Hz), 127.9, 126.0 (q, 3JCF = 3.7 Hz), 124.00, 123.99 (q, 1JCF = 271.9
Hz), 123.9, 118.9, 113.9, 110.1, 57.6, 44.7, 31.9, 31.3, 29.6, 29.5, 29.44, 29.35, 29.3, 26.6, 22.7, 14.1,
8.1. HRMS (ESI): m/z calcd. for C30H37F3NO [M + H]+ 484.2822, found 484.2835.
2-Cyclohexyl-9-methyl-1-phenyl-1H-pyrrolo[1,2-a]indol-3(2H)-one (5gg). Following procedure A:
the reaction of 2g (52 mg, 0.2 mmol) and 3g (120 mg, 0.6 mmol) was performed at 60 C for 12 h. The
crude product was purified by silica gel flash chromatography using PE/EtOAc (200:1 to 100:1) to
1
afford 5gg (41 mg, 60% yield) as colorless liquid. Rf = 0.4 (PE/EtOAc 0:1). H NMR (400 MHz,
CDCl3): δ 8.10 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.33-7.23 (m, 5H), 7.19 (d, J = 7.6 Hz, 2H),
4.37 (d, J = 2.8 Hz, 1H), 3.06 (t, J = 3.2 Hz, 1H), 2.11 (br s, 1H), 1.88 (s, 3H), 1.79-1.72 (m, 4H), 1.41-
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1.20 (m, 6H). C NMR (176 MHz, CDCl3): δ 172.3, 142.1, 140.8, 136.3, 129.9, 128.9, 127.5, 127.1,
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123.8, 123.5, 118.7, 113.8, 109.3, 63.4, 41.5, 40.2, 30.4, 28.8, 26.4, 26.2, 26.1, 8.0. HRMS (ESI): m/z
calcd. for C24H26NO [M + H]+ 344.2009, found 344.2004.
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1-(3,4-Dimethoxyphenyl)-9-phenyl-2-undecyl-1H-pyrrolo[1,2-a]indol-3(2H)-one (5hk). Following
procedure B: the reaction of 2h (76.6 mg, 0.2 mmol) and 3k (240 mg, 0.6 mmol) was performed at 60
C for 12 h. The crude product was purified by silica gel flash chromatography using PE/EtOAc (15:1
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to 8:1) to afford 5hk (70 mg, 65% yield) as colorless liquid. Rf = 0.5 (PE/EtOAc 5:1). H NMR (400
MHz, CDCl3): δ 8.21 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.41-7.33 (m, 2H), 7.26-7.19 (m,
5H), 6.72 (s, 2H), 6.58 (s, 1H), 4.38 (d, J = 3.2 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H), 3.14-3.12 (m, 1H),
2.08-1.99 (m, 1H), 1.90-1.81 (m, 1H), 1.24 (s, 18H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (176 MHz,
CDCl3): δ 173.3, 149.2, 148.1, 140.8, 134.2, 134.0, 132.6, 130.4, 128.5, 128.3, 126.8, 124.4, 124.1,
120.0, 119.7, 115.9, 114.1, 111.2, 110.3, 57.6, 55.8, 55.8, 45.3, 31.9, 31.6, 29.6, 29.52, 29.47, 29.4, 29.3,
26.7, 22.6, 14.1. HRMS (ESI): m/z calcd. for C36H44NO3 [M + H]+ 538.3316, found 538.3307.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS Publications website.
X-ray crystallographic data of 4aa and 5ba, gram-scale preparation and mechanism study, copies of 1H
and 13C NMR spectra and cif files of 4aa and 5ba.
AUTHOR INFORMATION
Corresponding Author
dudm@bit.edu.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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We are grateful for financial support from National Natural Science Foundation of China (Grant No.
21272024). We also thank Analysis & Testing Center of Beijing Institute of Technology for the
measurement of NMR and mass spectrometry.
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