Rhodium-catalyzed redox-neutral coupling of phenidones with alkynes

Article abstract of DOI:10.1039/c7ob01271c

A switchable synthesis of N-substituted indole derivatives from phenidones via rhodium-catalyzed redox-neutral C-H activation has been achieved. In this protocol, we firstly disclosed that the reactivity of Rh(iii) catalysis could be enhanced through employing palladium acetate as an additive. Some representative features include external oxidant-free, applicable to terminal alkynes, short reaction time and operational simplicity. The utility of this method is further showcased by the economical synthesis of potent anticancer PARP-1 inhibitors.

Full text of DOI:10.1039/c7ob01271c

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Rhodium-Catalyzed Redox-Neutral Coupling of Phenidones with
Alkynes
Received 00th January 20xx,
Accepted 00th January 20xx
a,b,†
c,†
a
a,b
a,b,c
Zhoulong Fan,
Heng Lu, Wei Li, Kaijun Geng, and Ao Zhang*
DOI: 10.1039/x0xx00000x
A switchable synthesis of N-substituted indole derivatives from phenidones via rhodium-catalyzed redox-neutral C-H
activation has been achieved. In this protocol, we firstly disclosed that the reactivity of Rh(III) catalysis could be enhanced
through employing palladium acetate as an additive. Some representative features include external oxidant-free,
applicable to terminal alkynes, short reaction time and operational simplicity. The utility of this method is further
showcased by the economical synthesis of potent anticancer PARP-1 inhibitors.
www.rsc.org/
oxidizing bonds.
Introduction
N-substituted indoles are ubiquitous scaffolds in biologically
active natural or synthetic molecules, organic dyes and
In the past decade, a broad spectrum of Rh(III)-catalyzed C-H
activation/nucleophilic substitution or oxidative coupling
reactions have been established, allowing many synthetically
1
4
pigments. As a consequence, the establishment of practical
and economical methods for synthesis of indole motifs are still
of great interest. Recently, we reported an economical
synthesis of N-substituted indoles via Rh(III)-catalyzed C-H
1
versatile building blocks to be readily assembled. One of the
most successful examples is the Rh(III)-catalyzed C-H
1
5
activation of pyrazolones without loss of the N-terminus, in
which the pyrazolone moiety was used as both intrinsic and
oxidizing DG (Scheme 1a). In addition, the Huang group also
developed an excellent Ru(II)-catalyzed redox-neutral coupling
activation/oxidative coupling of arenes with unsaturated
1
a,c
partners such as alkenes and alkynes,
among which the
directing group (DG) plays a dual role through chelating Rh(III)
to assist ortho C-H activation and participating in the oxidative
coupling to construct diversified heterocyclic products.
Recently, an additional function of DG as an internal oxidant to
16
of phenidones via N-N bond cleavage. Though it represents
an efficient and switchable approach for synthesis of N-
substituted indole derivatives from phenidones, there are still
some limitations which need to be solved: 1) longer reaction
2
avoid the use of external oxidants has been excavated. The
redox-neutral C-H activation process was firstly reported by time; 2) strict argon protection. To overcome these drawbacks,
3
4
Fagnou and Glorius using an oxidizing N-O DG. Subsequently, it is of significance to explore different catalytic systems.
5
6
other N-alkoxylbenzamides, N-oxides, N-phenoxyamides
7
8
and oximes containing N-O bonds were also used as oxidizing
9
DGs. Further, the N-N bonds in hydrazines, N-nitrosoanilines
10
1
1
and triazenes, C-N bonds in ammonium acetophenones as
12
1
3
well as N−S bonds in N-sulfinyl or sulfonyl ketamines have
also been applied recently as oxidizing DGs. Despite the
progress, the oxidizing DG strategy often suffered two major
drawbacks: 1) installation of the DG in advance; 2) low atom
economy due to loss of fragments after the cleavage of
a.
CAS Key Laboratory of Receptor Research, and the State Key Laboratory of Drug
Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of
Sciences, Shanghai 201203, China. Email: aozhang@simm.ac.cn
University of Chinese Academy of Sciences, Beijing 100049, China.
b.
c.
ShanghaiTech University, Shanghai 201210, China.
These two authors contributed equally to this work.
†
Electronic Supplementary Information (ESI) available: spectroscopic data of all
Scheme 1 Rhodium-catalyzed redox-neutral C-H activation of
compounds and X-ray for compound 3a (CCDC 1540588). See pyrazolones and phenidones.
DOI: 10.1039/x0xx00000x
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a
Table 1 Optimization of the reaction conditions
b
Yield (%)
Entry
Catalyst
Additive
.
Cu(OAc) H O
Solvent
1
2
3
4
5
6
7
8
9
[RhCp*Cl2]2
o-xylene
o-xylene
o-xylene
24
2
2
.
Cu(OAc) H O
[RuCl (p-cymene)]2
2
trace
<5
2
2
.
[IrCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
Cu(OAc) H O
2 2
.
Cu(OAc) H O
t
AmOH
28
2
2
.
Cu(OAc) H O
DCE
HFIP
DCE
DCE
DCE
DCE
DCE
DCE
65
2
2
.
Cu(OAc) H O
trace
68
2
2
Cu(OAc)2
Cu(OTf)2
Cu(TFA)2
CuI
50
76
1
1
0
1
2
88
FeCl3
12
1
a
Pd(OAc)2
96
Reaction Conditions: 1a (0.1 mmol), 2a (0.1 mmol), catalyst (2.5 mol%), additive (5 mol%),
o
b
1
Na
2
CO
3
(0.2 mmol), solvent (1 mL), 100 C, 2 h, air. Yield was determined by H NMR
Br as internal standard. Cp* = pentamethylcyclopentadiene. HFIP =
analysis using CH
2
2
hexafluoroisopropyl alcohol.
.
2 2 2 2
Herein, we established a new strategy for synthesis of N- in 24% yield when used [RhCp*Cl ] as a catalyst, Cu(OAc) H O
substituted indole derivatives via Rh(III)-catalyzed C-H as an additive and Na
activation tandem N-N bond cleavage of phenidones (Scheme structure of 3a was also confirmed by X-ray crystallography.
b). This method is a complement for the previous ruthenium Subsequently, several other catalysts were examined and no
2 3
CO as a base (Table 1, entry 1), the
1
catalysis featuring mild reaction condition, simple operations improvement was observed (entries 2-3). Investigating the
t
and short reaction time. Besides, we found that palladium alternative solvents ( AmOH, DCE or HFIP) in this reaction
acetate as an additive could improve the reactivity of Rh(III) indicated that DCE led to 65% yield (entries 4-6). Further, we
catalysis. Furthermore, the utility of this transformation was tested various Cu salts with different anions (entries 7-10), and
strengthened by the economical synthesis of potent anticancer found that employing CuI as an additive gave the product 3a in
drug candidates.
88% yield (entry 10). While altering the additive from Cu(OAc)
to Pd(OAc) , an excellent yield of 96% was achieved. Since the
promoting effect of Pd(OAc) in the Rh(III) catalysis has not
2
2
Results and discussion
2
been reported, we therefore took the reaction condition of
entry 12 as the optimal reaction condition.
Our initial investigation was carried out by using phenidone 1a
as model substrate and diphenylacetylene (2a) as the coupling
partner. It was found that the desired product 3a was obtained
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We firstly explored the scope and limitations of a variety of employed in the reaction, and only single regioisomers 3x-z
substituted phenidones (Scheme 2). Substrates with were observed in good to excellent yield, which is consistent
1
6
unsubstituted or substituted pyrazolidinone moieties were with previous Ru(II) catalysis. We suppose that the high
tested and the corresponding products 3a were obtained in regioselectivity of this reaction was controlled by the
8-95% yields. In the case of 4-(hydroxymethyl)-4-methyl-1- nucleophilic addition of Rh-C bond with alkyl-aryl acetylenes.
phenylpyrazolidinone, the product 3d was obtained in lower In addition, we have also explored several terminal alkynes, to
6% yield, we supposed that the hydroxyl may induce our delight, both the substituted phenylacetylenes and the
-c
7
4
disadvantageous coordination with rhodium catalyst and alkylacetylenes worked smoothly and gave the single
decrease the reactivity of the transformation. Subsequently, regioisomers 3aa-ad in 38-60% yields.
we surveyed the substrates with both electron-donating (Me,
i
3 2
Pr, OMe and OCF ) and electron-withdrawing (Br and NO )
R1
groups on the para position of the phenyl rings, the desired
products 3e-j were obtained in good to excellent yields. As for
the meta substituted phenidones, the reaction occurred
regioselectively on the less hindered sites and the single
R1
H
N
2.5 mol% [RhCp*Cl2]2
R2
O
5
mol% Pd(OAc)2
2 equiv Na2CO3
DCE, 100 o
N
N
R2
2
C
O
1a
3
H2N
regioisomers were observed in 62-82% yields (3k-m). It is
R1
worth mentioning that diversified ortho substituents were well
tolerated and the reaction proceeded smoothly to give the
corresponding products 3n-p in 75-81% yields.
3q, R1 = R2 = Me, 85%
R1
r, R1 = R2 = OMe, 83%
s, R1 = R2 = CF3, 83%
3
3
R2
N
N
t, R1 = R2 = Me, 87%
3u, R1 = R2 = Cl, 81%
R2
3
O
O
H2N
S
H2N
Me
nPr
N
nBu
S
nPr
Ph
N
Ph
N
N
O
O
O
O
H2N
v, 74%
H2N
3w, 76%
H2N
H2N
3y, 65%
3
3x, 85%
CO2Et
3
3
3
3
aa, R = 4-MeC6H4, 44%
ab, R = 4-CF3C6H4, 38%
Ph
R
N
N
ac, R = cyclopropyl, 42%
ad, R = tBu, 60%
O
O
3
z, 78% H2N
H2N
Scheme 3 Substrate scope of alkynes for the synthesis of 3q-ad
Isolated yields are given. Reaction Conditions: 1a (0.5 mmol),
.
2
(
(
0.5 mmol), [RhCp*Cl
2 2 2 2 3
] (2.5 mol%), Pd(OAc) (5 mol%), Na CO
o
1.0 mmol), DCE (1 mL), 100 C, 2h, air.
Scheme 2 Substrate scope of phenidones for the synthesis of
3
a-p. Isolated yields are given. Reaction Conditions:
mmol), 2a (0.5 mmol), [RhCp*Cl (2.5 mol%), Pd(OAc)
mol%), Na CO (1.0 mmol), DCE (1 mL), 100 C, 2h, air.
1
(0.5
(5
2
]
2
2
o
2
3
Next, we examined the scope of the alkyne partners. Various
aryl and alkyl, symmetrical and unsymmetrical alkynes were
tested and the results are shown in Scheme 3. Symmetrical
diphenylacetylenes bearing electron-donating or electron-
withdrawing substituents participated in the reaction smoothly
and gave the desired products 3q-u in 81-87% yields.
Interestingly, in the case of dithienylacetylene, the
transformation successfully proceeded to afford the
corresponding product 3v in 74% yield. Symmetrical alkyl-alkyl
acetylene was also investigated, and the product 3w was
obtained in 76% yield. Further, asymmetric acetylenes were
Scheme 4 Economical synthesis of PRAP-1 inhibitor 6.
To demonstrate the utility of the present method, we set up
an economical route to access the potent anticancer poly(ADP-
17
ribose) polymerase-1 (PARP-1) inhibitor
6
by using product
3y
as the key precursor. As shown in Scheme 4, the indole
scaffold 3y was conveniently prepared according to the
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present approach in 65% yield. Subsequent hydrolysis with
aqueous NaOH and intramolecular annulation furnished the
Experimental section
General information
tricyclic skeleton
5. Finally, The PARP-1 inhibitor 6 was
prepared in 79% yield via Schmitt rearrangement under All reactions were performed in flame-dried sealed tubes.
NaN /MeSO H. Compared to the traditional seven-step Liquids and solutions were transferred with syringes. All
3
3
1
7
process, this economical four-step route with 38% overall solvents and chemical reagents were obtained from
1
yield (from phenidone 1a) shows significant superiority for the commercial sources and used without further purifications. H
1
and C NMR spectra were recorded with tetramethylsilane as
3
synthesis of PARP-1 inhibitor
6
and its derivatives.
1
5,18-19
Based on the previous reports,
the mechanism for Rh(III) an internal reference. Low and high-resolution mass spectra
catalysis is proposed as shown in Scheme 5. Firstly, treatment were recorded on EI-TOF (electrospray ionization-time of
of [RhCp*Cl
RhCp*(OAc)
2
]
2
with Pd(OAc)
Subsequent
2
gave the active catalyst flight). Flash column chromatography on silica gel (200 - 300
concerted metalation– mesh). The column output was monitored by TLC on silica gel
2
.
deprotonation (CMD)-type ortho C-H bond cleavage of 1a (100 - 200 mesh) precoated on glass plates (15 x 50 mm), and
1
9-20
yielded the Rh(III) complex
I
.
Then, the alkyne 2a inserted spots were visualized by UV light at 254 nM. Starting materials
2
1
into Rh(III)-C(phenyl) bond, affording the seven-membered were synthesized according to previous literatures
or
intermediate II. The unstable Rh(III) complex II was inclined to obtained from commercial sources which were used without
transform into stable Rh(V) intermediate III via N-N bond further purification.
1
cleavage and 1,2-rhodium migration. Subsequently, Rh(III)
5
General procedure for the synthesis of indole derivatives 3a-y
(0.50 mmol) in DCE (3
(0.50 mmol), [RhCp*Cl ] (8 mg, 2.5 mol%),
complex IV was formed via reductive elimination followed by
protonation of the intermediate III. Finally, ligand exchange of To a stirred solution of phenidones
IV with CH COOH released the indole derivative 3a and mL), alkynes
regenerated the active Rh(III) catalyst for the next catalytic Pd(OAc) (6 mg, 5 mol%) and Na CO (106 mg, 1 mmol) were
1
3
2
2
2
2
2
3
o
cycle.
added. The mixture was stirred at 100 C in a sealed tube for 2
h. After cooled to room temperature, the reaction mixture was
filtered and the filtrate was concentrated. The residue was
purified on a silica gel column with petroleum ether (PE) /ethyl
acetate (EA) as the eluent to afford indole derivatives 3a-y.
3-(2,3-Diphenyl-1H-indol-1-yl)propanamide
(3a).
The
product was obtained as a white solid (PE:EA = 1:1, 160 mg,
o
1
9
=
–
1
3
4%). mp = 166 - 168 C; H NMR (300 MHz, CDCl ) δ 7.79 (d, J
7.9 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.42 – 7.35 (m, 3H), 7.34
7.24 (m, 7H), 7.17 (q, J = 6.8, 5.9 Hz, 2H), 5.47 (s, 1H), 5.17 (s,
1
3
H), 4.46 (t, J = 7.7 Hz, 2H), 2.46 (t, J = 7.7 Hz, 2H); C NMR
) δ 172.2, 137.1, 136.2, 134.8, 131.8, 131.0,
(
126 MHz, CDCl
3
1
1
29.8, 128.7, 128.4, 128.2, 127.3, 125.6, 122.5, 120.5, 119.9,
+
16.1, 109.9, 39.7, 35.6; EI-MS (m/z) 340 (M ); HRMS (EI): m/z
+
[M ] calcd for C23
H
20
N
2
O, 340.1576; found, 340.1574. Spectral
1
6
data correspond to those previously reported.
-(2,3-Diphenyl-1H-indol-1-yl)-2-methylpropanamide (3b).
The product was obtained as a white solid (PE:EA = 1:1, 168
3
Scheme 5 Proposed mechanism.
o
1
mg, 95%). mp = 160 - 162 C; H NMR (300 MHz, CDCl
3
) δ 7.78
(
d, J = 7.9 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.42 – 7.23 (m, 10H),
Conclusions
7.17 (d, J = 6.9 Hz, 2H), 5.18 (s, 1H), 4.95 (s, 1H), 4.51 (dd, J =
In conclusion, we have developed a mild and efficient 14.8, 6.7 Hz, 1H), 4.19 (dd, J = 14.8, 7.4 Hz, 1H), 2.56 (q, J = 7.1
1
rhodium-catalyzed redox-neutral coupling of phenidones with Hz, 1H), 0.92 (d, J = 6.9 Hz, 3H); C NMR (126 MHz, CDCl ) δ
3
3
alkynes for the synthesis of N-substituted indole derivatives. 175.9, 137.2, 136.7, 134.8, 132.0, 131.2, 129.8, 128.7, 128.3,
The protocol is suitable for a broad scope of substrates and 128.2, 127.1, 125.7, 122.5, 120.4, 119.8, 116.1, 110.2, 46.7,
+
+
provided diversified indole derivatives in good to excellent 40.9, 15.4; EI-MS (m/z) 354 (M ); HRMS (EI): m/z [M ] calcd for
yields. In this process, Pd(OAc) was used an the additive and C H N O, 354.1732; found, 354.1730. Spectral data
showed a promoting effect to the Rh(III) catalysis. The N-N correspond to those previously reported.
bond cleavage fulfilled the oxidation from Rh(III) to Rh(V) and
3-(2,3-Diphenyl-1H-indol-1-yl)-2,2-dimethylpropanamide
avoided the use of external oxidants. Therefore, the present (3c). The product was obtained as a white solid (PE:EA = 1:1,
2
2
4 22 2
1
6
o
1
approach is a useful complement for the previous work on 144 mg, 78%). mp = 206 - 208 C; H NMR (300 MHz, CDCl ) δ
3
account of mild reaction condition, simple operations and 7.72 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 5.2
short reaction time. Furthermore, this transformation provides Hz, 3H), 7.29 – 7.20 (m, 7H), 7.15 (q, J = 7.3 Hz, 2H), 5.38 (s,
1
an economical route for the synthesis of anticancer drug 2H), 4.55 (s, 2H), 0.90 (s, 6H); C NMR (101 MHz, CDCl ) δ
3
3
candidate and its analogues.
179.5, 137.8, 137.5, 134.9, 132.2, 131.7, 130.1, 128.6, 128.1,
4
| J. Name., 2012, 00, 1-3
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+
28.1, 127.1, 125.7, 122.3, 120.3, 119.4, 116.3, 111.6, 50.7, 424 (M ); HRMS (EI): m/z [M ] calcd for C24
+
1
H
19
F
3
N
2
O
2
,
+
4.5, 24.2; EI-MS (m/z) 368 (M ); HRMS (EI): m/z [M ] calcd for 424.1399; found, 424.1402.
+
4
C
25
H
24
N
2
O, 368.1889; found, 368.1890. Spectral data
3-(5-Bromo-2,3-diphenyl-1H-indol-1-yl)propanamide (3i).
1
6
correspond to those previously reported.
-(2,3-Diphenyl-1H-indol-1-yl)-2-(hydroxymethyl)-2-
methylpropanamide (3d). The product was obtained as a 7.70 (d, J = 1.9 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.47 – 7.43 (m,
The product was obtained as a white solid (PE:EA = 1:1, 163
o
1
3
6
mg, 78%). mp = 206 - 208 C; H NMR (400 MHz, DMSO-d ) δ
o
1
white solid (PE:EA = 1:1, 89 mg, 46%). mp = 219 - 221 C; H 3H), 7.41 – 7.34 (m, 4H), 7.31 – 7.26 (m, 2H), 7.19 (d, J = 7.4 Hz,
1
NMR (300 MHz, DMSO-d
3
6
) δ 7.76 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 3H), 6.88 (s, 1H), 4.30 – 4.24 (m, 2H), 2.40 – 2.34 (m, 2H);
C
7
6
4
.9 Hz, 1H), 7.42 (d, J = 6.3 Hz, 3H), 7.34 – 7.09 (m, 9H), 7.07 – NMR (101 MHz, DMSO-d ) δ 171.4, 138.5, 134.7, 133.9, 130.9,
6
.83 (m, 2H), 4.87 (t, J = 4.9 Hz, 1H), 4.60 (d, J = 15.1 Hz, 1H), 130.8, 129.2, 128.7, 128.6, 128.4, 128.1, 125.9, 124.4, 120.7,
+
.39 (d, J = 15.2 Hz, 1H), 3.27 (dd, J = 10.4, 5.0 Hz, 1H), 3.08 (dd, 114.1, 112.9, 112.7, 40.5, 35.3; EI-MS (m/z) 418 (M ); HRMS
1
3
+
J = 10.6, 5.0 Hz, 1H), 0.54 (s, 3H); C NMR (101 MHz, DMSO-d
6
)
2
(EI): m/z [M ] calcd for C23H19BrN O, 418.0681; found,
δ 177.2, 138.5, 137.8, 135.2, 132.3, 132.1, 130.0, 128.9, 128.6, 418.0673.
1
1
C
26.7, 126.0, 122.3, 120.5, 118.9, 115.2, 112.2, 66.5, 49.6, 46.7,
3-(5-Nitro-2,3-diphenyl-1H-indol-1-yl)propanamide
(3j).
) δ
+
+
7.8; EI-MS (m/z) 384 (M ); HRMS (EI): m/z [M ] calcd for The product was obtained as a white solid (PE:EA = 1:2, 135
o
1
25
H
24
N
2
O
2
, 384.1838; found, 384.1834.
-(5-Methyl-2,3-diphenyl-1H-indol-1-yl)propanamide (3e). 8.46 (d, J = 2.3 Hz, 1H), 8.14 (dd, J = 9.1, 2.3 Hz, 1H), 7.88 (d, J =
The product was obtained as a white solid (PE:EA = 1:1, 150 9.1 Hz, 1H), 7.51 – 7.42 (m, 5H), 7.35 (dd, J = 14.3, 6.3 Hz, 3H),
mg, 70%). mp = 134 - 136 C; H NMR (300 MHz, DMSO-d
6
3
o
1
mg, 85%). mp = 200 - 202 C; H NMR (400 MHz, DMSO-d
.51 (d, J = 8.4 Hz, 1H), 7.43 (dt, J = 6.6, 3.3 Hz, 4H), 7.38 – 7.34 (t, J = 7.5 Hz, 2H); C NMR (126 MHz, DMSO-d
m, 3H), 7.26 (t, J = 7.6 Hz, 2H), 7.20 – 7.12 (m, 3H), 7.07 (dd, J 141.0, 139.3, 133.5, 131.3, 130.6, 129.8, 129.6, 129.2, 129.1,
6
) δ 7.25 (d, J = 7.4 Hz, 3H), 6.90 (s, 1H), 4.37 (t, J = 7.4 Hz, 2H), 2.41
1
3
7
6
) δ 171.7, 141.9,
(
=
2
1
1
3
C
8.4, 1.6 Hz, 1H), 6.88 (s, 1H), 4.26 – 4.21 (m, 2H), 2.40 (s, 3H), 127.0, 126.2, 117.6, 117.3, 116.1, 112.0, 79.7, 40.9, 35.7; EI-MS
1
3
+
+
.37 (dd, J = 5.9, 3.9 Hz, 2H); C NMR (101 MHz, DMSO-d
71.5, 137.1, 134.8, 134.4, 131.5, 130.9, 129.3, 128.8, 128.5, 385.1426; found, 385.1422.
28.4, 128.2, 126.7, 125.4, 123.6, 118.3, 114.0, 110.4, 40.3, 3-(6-Methyl-2,3-diphenyl-1H-indol-1-yl)propanamide (3k).
5.4, 21.2; EI-MS (m/z) 354 (M ); HRMS (EI): m/z [M ] calcd for The product was obtained as a white solid (PE:EA = 1:1, 145
6 19 3 3
) δ (m/z) 385 (M ); HRMS (EI): m/z [M ] calcd for C23H N O ,
+
+
o
1
24
H
22
N
2
O, 354.1732; found, 354.1736.
-(5-Isopropyl-2,3-diphenyl-1H-indol-1-yl)propanamide
3f). The product was obtained as a white solid (PE:EA = 1:1, 7.25 (t, J = 7.5 Hz, 2H), 7.19 (d, J = 6.7 Hz, 2H), 7.14 (t, J = 7.1 Hz,
mg, 82%). mp = 167 - 169 C; H NMR (400 MHz, DMSO-d
6
) δ
3
7.53 (d, J = 8.1 Hz, 1H), 7.45 – 7.42 (m, 4H), 7.39 – 7.34 (m, 3H),
(
o
1
1
7
7
–
53 mg, 80%). mp = 170 - 172 C; H NMR (300 MHz, CDCl
3
) δ 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.91 (s, 1H), 4.26 – 4.21 (m, 2H),
1
3
.61 (s, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.37 – 7.30 (m, 3H), 7.30 – 2.47 (s, 3H), 2.42 – 2.37 (m, 2H); C NMR (101 MHz, DMSO-d
6
)
.23 (m, 5H), 7.21 – 7.12 (m, 2H), 5.75 (s, 1H), 5.23 (s, 1H), 4.48 δ 171.5, 136.4, 136.3, 134.8, 131.5, 131.3, 130.9, 129.1, 128.5,
4.32 (m, 2H), 3.02 (p, J = 6.9 Hz, 1H), 2.50 – 2.34 (m, 2H), 1.30 128.3, 128.2, 125.4, 124.4, 121.9, 118.6, 114.3, 110.4, 40.2,
1
3
+
+
(
d, J = 6.9 Hz, 6H); C NMR (126 MHz, CDCl
3
) δ 172.7, 141.5, 35.3, 21.6; EI-MS (m/z) 354 (M ); HRMS (EI): m/z [M ] calcd for
37.3, 135.1, 134.9, 131.9, 131.0, 129.9, 128.7, 128.3, 128.2, O, 354.1732; found, 354.1724.
27.3, 125.6, 121.6, 116.8, 115.9, 109.8, 39.8, 35.8, 34.4, 24.8; 3-(6-Bromo-2,3-diphenyl-1H-indol-1-yl)propanamide (3l).
O, The product was obtained as a white solid (PE:EA = 1:1, 130
1
1
24 22 2
C H N
+
+
EI-MS (m/z) 382 (M ); HRMS (EI): m/z [M ] calcd for C26
82.2045; found, 382.2045.
-(5-Methoxy-2,3-diphenyl-1H-indol-1-yl)propanamide
3g). The product was obtained as a white solid (PE:EA = 1:1, J = 3.6 Hz, 3H), 7.27 (dd, J = 8.3, 6.9 Hz, 3H), 7.17 (dd, J = 11.2,
26 2
H N
o
1
3
mg, 62%). mp = 201 - 203 C; H NMR (400 MHz, DMSO-d
6
) δ
3
7.92 (s, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.48 – 7.43 (m, 3H), 7.39 (t,
(
o
1
1
7
6
4
35 mg, 73%). mp = 206 - 208 C; H NMR (300 MHz, CDCl
.42 – 7.33 (m, 4H), 7.32 – 7.21 (m, 7H), 7.17 (q, J = 4.4 Hz, 1H), Hz, 2H); C NMR (101 MHz, DMSO-d
.94 (dd, J = 8.9, 2.5 Hz, 1H), 5.54 (s, 1H), 5.20 (s, 1H), 4.46 – 134.0, 130.9, 129.2, 128.7, 128.6, 128.3, 125.8, 125.4, 123.0,
3
) δ 7.7 Hz, 3H), 6.91 (s, 1H), 4.27 (t, J = 7.6 Hz, 2H), 2.37 (t, J = 7.6
1
3
6
) δ 171.4, 137.8, 136.8,
1
3
+
.35 (m, 2H), 3.83 (s, 3H), 2.48 – 2.38 (m, 2H); C NMR (151 120.5, 114.8, 114.7, 113.4, 40.4, 35.4; EI-MS (m/z) 418 (M );
+
) δ 172.3, 154.9, 137.8, 135.0, 131.8, 131.5, 130.9, HRMS (EI): m/z [M ] calcd for C23
MHz, CDCl
3
2
H19BrN O, 418.0681; found,
1
1
29.7, 128.7, 128.4, 128.3, 127.7, 125.6, 115.8, 112.6, 110.7, 418.0683.
+
01.6, 56.0, 39.9, 35.8; EI-MS (m/z) 370 (M ); HRMS (EI): m/z
3-(2,3-Diphenyl-6-(trifluoromethyl)-1H-indol-1-
+
[
M ] calcd for C24
-(2,3-Diphenyl-5-(trifluoromethoxy)-1H-indol-1-
yl)propanamide (3h). The product was obtained as a white (300 MHz, CDCl
H
22
N
2
O
2
, 370.1681; found, 370.1678.
yl)propanamide (3m). The product was obtained as a white
o
1
3
solid (PE:EA = 1:1, 130 mg, 64%). mp = 197 - 199 C; H NMR
) δ 7.84 (d, J = 8.3 Hz, 1H), 7.77 (s, 1H), 7.49 –
solid (PE:EA = 1:1, 174 mg, 82%). mp = 195 - 197 C; H NMR 7.39 (m, 4H), 7.33 (ddd, J = 5.1, 3.5, 1.7 Hz, 2H), 7.29 – 7.19 (m,
3
o
1
(
300 MHz, CDCl
3
) δ 7.61 (s, 1H), 7.47 (d, J = 8.9 Hz, 1H), 7.42 – 5H), 5.42 (s, 1H), 5.19 (s, 1H), 4.57 – 4.48 (m, 2H), 2.49 (t, J =
1
.37 (m, 3H), 7.33 – 7.26 (m, 3H), 7.25 – 7.14 (m, 5H), 5.54 (s, 7.6 Hz, 2H); C NMR (101 MHz, CDCl
3
7
3
) δ 171.7, 139.7, 135.2,
1
3
1
H), 5.21 (s, 1H), 4.49 – 4.43 (m, 2H), 2.48 – 2.41 (m, 2H);
C
134.0, 131.0, 130.8, 129.7, 129.6, 128.9, 128.3, 126.1, 125.2 (q,
NMR (126 MHz, CDCl
3
) δ 172.1, 143.7, 138.8, 134.6, 134.1, J = 272.6 Hz), 124.4 (q, J = 32.2 Hz), 120.2, 117.1 (q, J = 1.8 Hz),
+
31.3, 130.8, 129.6, 128.8, 128.7, 128.4, 127.5, 126.0, 120.8 (q, 116.4, 107.4 (q, J = 3.9 Hz), 39.8, 35.5; EI-MS (m/z) 408 (M );
1
J = 255.3 Hz), 116.4 (2), 112.4, 110.6, 39.9, 35.6; EI-MS (m/z)
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ARTICLE
Journal Name
+
+
+
HRMS (EI): m/z [M ] calcd for C24
08.1449.
H
19
F
3
N
2
O, 408.1449; found, (m/z) 400 (M ); HRMS (EI): m/z [M ] calcd for C25
400.1787; found, 400.1764.
24 2 3
H N O ,
4
3-(7-Methyl-2,3-diphenyl-1H-indol-1-yl)propanamide (3n).
3-(2,3-Bis(4-(trifluoromethyl)phenyl)-1H-indol-1-
The product was obtained as a pale yellow solid (PE:EA = 1:1, yl)propanamide (3s). The product was obtained as a white
o
33 mg, 75%). mp = 176 - 178 C; H NMR (300 MHz, CDCl
1
o
1
1
7
4
1
3
) δ solid (PE:EA = 1:2, 198 mg, 83%). mp = 160 - 162 C; H NMR
) δ 7.75 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz,
.60 (d, J = 7.5 Hz, 1H), 7.41 – 7.30 (m, 5H), 7.25 (d, J = 4.8 Hz, (300 MHz, CDCl
3
H), 7.18 (dt, J = 9.1, 4.5 Hz, 1H), 7.13 – 6.99 (m, 2H), 5.24 (s, 2H), 7.53 (d, J = 8.3 Hz, 3H), 7.44 (d, J = 8.0 Hz, 2H), 7.33 (d, J =
H), 5.00 (s, 1H), 4.68 – 4.57 (m, 2H), 2.80 (s, 3H), 2.37 – 2.27 8.3 Hz, 3H), 7.26 – 7.21 (m, 1H), 5.66 (s, 1H), 5.23 (s, 1H), 4.53
1
3
13
(
3 3
m, 2H); C NMR (126 MHz, CDCl ) δ 171.8, 138.4, 135.4, – 4.41 (m, 2H), 2.55 – 2.43 (m, 2H); C NMR (101 MHz, CDCl )
1
1
3
34.8, 131.8, 131.2, 129.9, 128.9, 128.6, 128.3, 128.1, 125.9, δ 172.0, 138.2, 136.5, 136.0, 135.0, 131.3, 130.7 (d, J = 32.8
25.7, 121.3, 120.8, 118.0, 117.4, 41.6, 36.8, 20.4; EI-MS (m/z) Hz), 129.8, 127.9 (d, J = 32.3 Hz), 127.0, 125.9 (d, J = 4.0 Hz),
+
54 (M ); HRMS (EI): m/z [M ] calcd for C24
+
H
22
N
2
O, 354.1732; 125.5 (d, J = 43.4 Hz), 125.4 (d, J = 3.9 Hz), 123.3, 122.8 (d, J =
43.4 Hz), 121.3, 119.7, 115.7, 110.2, 39.8, 35.4; EI-MS (m/z)
found, 354.1735.
-(7-Methoxy-2,3-diphenyl-1H-indol-1-yl)propanamide
3o). The product was obtained as a white solid (PE:EA = 1:2, found, 476.1320.
+
+
3
18 6 2
476 (M ); HRMS (EI): m/z [M ] calcd for C25H F N O, 476.1323;
(
o
1
1
7
4
7
22 mg, 66%). mp = 211 - 213 C; H NMR (300 MHz, CDCl
3
) δ
3-(2,3-Di-m-tolyl-1H-indol-1-yl)propanamide (3t). The
.37 (d, J = 8.1 Hz, 4H), 7.33 – 7.27 (m, 2H), 7.24 (d, J = 4.6 Hz, product was obtained as a white solid (PE:EA = 1:2, 160 mg,
o
H), 7.15 (q, J = 4.3 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.74 (d, J = 87%). mp = 149 - 151 C; H NMR (300 MHz, CDCl
1
3
) δ 7.78 (d, J
.7 Hz, 1H), 5.26 (d, J = 46.6 Hz, 2H), 4.69 – 4.59 (m, 2H), 3.99 = 7.9 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.28 – 7.21 (m, 2H), 7.19
1
3
(s, 3H), 2.58 – 2.49 (m, 2H); C NMR (101 MHz, CDCl
3
) δ 172.3, – 7.06 (m, 6H), 7.03 – 6.94 (m, 2H), 5.68 (s, 1H), 5.19 (s, 1H),
1
1
46.8, 137.7, 134.5, 131.2, 130.8, 129.4, 129.2, 128.1, 127.9, 4.41 (t, J = 7.7 Hz, 2H), 2.43 (t, J = 7.7 Hz, 2H), 2.33 (s, 3H), 2.27
1
3
3
27.6, 125.4, 125.2, 120.4, 116.0, 112.2, 103.1, 55.3, 41.9, 37.4; (s, 3H); C NMR (101 MHz, CDCl ) δ 172.6, 138.2, 137.5, 137.2,
+
+
EI-MS (m/z) 370 (M ); HRMS (EI): m/z [M ] calcd for C24
70.1681; found, 370.1685.
H
22
N
2
O
2
,
136.2, 134.8, 131.7, 131.4, 130.4, 129.2, 128.5, 128.1, 128.0,
127.4, 126.9, 126.4, 122.3, 120.4, 119.9, 115.9, 109.8, 39.7,
3
+
+
3
-(7-Fluoro-2,3-diphenyl-1H-indol-1-yl)propanamide (3p). 35.7, 21.6; EI-MS (m/z) 368 (M ); HRMS (EI): m/z [M ] calcd for
The product was obtained as a white solid (PE:EA = 1:1, 145 O, 368.1889; found, 368.1883.
3-(2,3-Bis(3-chlorophenyl)-1H-indol-1-yl)propanamide (3u).
d, J = 7.9 Hz, 1H), 7.39 – 7.33 (m, 3H), 7.29 (dd, J = 6.6, 3.2 Hz, The product was obtained as a white solid (PE:EA = 1:2, 165
25 24 2
C H N
o
1
3
mg, 81%). mp = 181 - 183 C; H NMR (300 MHz, CDCl ) δ 7.51
(
o
1
2
7
5
H), 7.23 (d, J = 3.6 Hz, 4H), 7.20 – 7.13 (m, 1H), 7.05 (td, J = mg, 81%). mp = 172 - 174 C; H NMR (300 MHz, CDCl
3
) δ 7.75
.9, 4.7 Hz, 1H), 6.94 (dd, J = 12.7, 7.8 Hz, 1H), 5.71 (s, 1H), (d, J = 7.7 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.44 – 7.28 (m, 5H),
1
.29 (s, 1H), 4.55 – 4.48 (m, 2H), 2.58 – 2.51 (m, 2H); C NMR 7.25 – 7.12 (m, 4H), 7.04 (ddd, J = 5.6, 3.7, 1.6 Hz, 1H), 5.47 (s,
3
1
3
(126 MHz, CDCl
3
) δ 172.2, 149.9 (d, J = 243.0 Hz), 138.7, 134.4, 1H), 5.22 (s, 1H), 4.52 – 4.41 (m, 2H), 2.54 – 2.44 (m, 2H);
C
3
131.4 (d, J = 5.3 Hz), 131.1, 130.9, 129.8, 128.7 (2), 128.2, NMR (101 MHz, CDCl ) δ 172.0, 136.4, 136.2, 135.8, 134.6,
126.0, 124.0 (d, J = 9.2 Hz), 120.6 (d, J = 6.7 Hz), 116.8, 115.7 (d, 134.1, 133.2, 130.7, 130.1, 129.6, 129.5, 129.2, 128.9, 127.9,
J = 3.5 Hz), 108.1 (d, J = 18.7 Hz), 42.1 (d, J = 5.3 Hz), 37.2 (d, J = 126.9, 126.0, 123.1, 121.0, 119.7, 115.3, 110.1, 39.7, 35.5; EI-
+
+
+
+
2
.9 Hz); EI-MS (m/z) 358 (M ); HRMS (EI): m/z [M ] calcd for MS (m/z) 408 (M ); HRMS (EI): m/z [M ] calcd for C23
O, 358.1481; found, 358.1486. 408.0796; found, 408.0791.
-(2,3-Di-p-tolyl-1H-indol-1-yl)propanamide (3q). The 3-(2,3-Di(thiophen-2-yl)-1H-indol-1-yl)propanamide (3v).
product was obtained as a white solid (PE:EA = 1:2, 156 mg, The product was obtained as a pale white solid (PE:EA = 1:2,
2 2
H18Cl N O,
23 2
C H19FN
3
o
1
o
1
8
5%). mp = 145 - 147 C; H NMR (300 MHz, CDCl
3 3
) δ 7.76 (d, J 130 mg, 74%). mp = 122 - 124 C; H NMR (300 MHz, CDCl ) δ
=
7.9 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.33 – 7.24 (m, 2H), 7.17 7.92 (d, J = 7.9 Hz, 1H), 7.55 – 7.50 (m, 1H), 7.47 (d, J = 8.2 Hz,
(d, J = 8.4 Hz, 6H), 7.07 (d, J = 7.8 Hz, 2H), 5.36 (s, 1H), 5.14 (s, 1H), 7.32 (t, J = 7.0 Hz, 1H), 7.22 (s, 1H), 7.20 – 7.14 (m, 3H),
1
2
1
1
H), 4.48 – 4.40 (m, 2H), 2.45 (d, J = 5.0 Hz, 2H), 2.38 (s, 3H), 7.05 – 6.98 (m, 2H), 5.41 (s, 1H), 5.26 (s, 1H), 4.51 – 4.40 (m,
1
3
13
3 3
.31 (s, 3H); C NMR (101 MHz, CDCl ) δ 172.4, 138.1, 137.0, 2H), 2.63 – 2.53 (m, 2H); C NMR (101 MHz, CDCl ) δ 172.2,
36.1, 135.1, 131.9, 130.8, 129.6, 129.4, 128.9, 128.8, 127.4, 136.4, 136.2, 131.3, 130.9, 129.3, 128.7, 127.6, 126.9, 126.5,
22.3, 120.3, 119.8, 115.7, 109.8, 39.6, 35.7, 21.4, 21.2; EI-MS 125.1, 124.0, 123.3, 120.9, 120.3, 112.0, 109.9, 39.9, 36.1; EI-
+
+
+
+
(
m/z) 368 (M ); HRMS (EI): m/z [M ] calcd for C25
68.1889; found, 368.1886.
-(2,3-bis(4-Methoxyphenyl)-1H-indol-1-yl)propanamide
3r). The product was obtained as a white solid (PE:EA = 1:2, product was obtained as a white solid (PE:EA = 1:2, 103 mg,
H
24
N
2
O, MS (m/z) 352 (M ); HRMS (EI): m/z [M ] calcd for C19
H
16
N
2
OS
2
,
3
352.0704; found, 352.0705.
3
3-(2,3-Dipropyl-1H-indol-1-yl)propanamide
(3w).
The
(
o
1
o
1
1
7
6
5
–
1
1
3 3
66 mg, 83%). mp = 160 - 162 C; H NMR (300 MHz, CDCl ) δ 76%). mp = 69 - 72 C; H NMR (300 MHz, CDCl ) δ 7.52 (d, J =
.74 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.29 – 7.16 (m, 7.2 Hz, 1H), 7.26 (d, J = 8.6 Hz, 1H), 7.16 – 7.04 (m, 2H), 5.61 (s,
H), 6.91 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 5.40 (s, 1H), 1H), 5.27 (s, 1H), 4.45 – 4.36 (m, 2H), 2.75 – 2.56 (m, 6H), 1.61
1
3
C
.17 (s, 1H), 4.49 – 4.39 (m, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 2.52 (dq, J = 15.6, 7.6 Hz, 4H), 0.98 (dt, J = 12.4, 7.3 Hz, 6H);
1
3
3 3
2.42 (m, 2H); C NMR (126 MHz, CDCl ) δ 171.9, 159.0, 157.1, NMR (126 MHz, CDCl ) δ 172.9, 136.6, 135.5, 128.5, 120.7,
36.1, 135.6, 131.7, 130.3, 127.0, 126.9, 123.5, 121.7, 119.8, 118.9, 118.7, 112.3, 108.8, 39.1, 35.8, 26.7, 26.4, 24.3, 23.9,
19.2, 114.9, 113.7, 113.2, 109.3, 54.8, 54.7, 39.2, 35.2; EI-MS
6
| J. Name., 2012, 00, 1-3
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ARTICLE
+
4.4, 14.2; EI-MS (m/z) 272 (M ); HRMS (EI): m/z [M ] calcd for
+
1
3-(2-Cyclopropyl-1H-indol-1-yl)propanamide (3ac). The
C
17
H
24
N
2
O, 272.1889; found, 272.1892.
product was obtained as pale yellow oil (PE:EA = 1:2, 48 mg,
1
-(3-Butyl-2-phenyl-1H-indol-1-yl)propanamide (3x). The 42%). H NMR (300 MHz, CDCl
3
3
) δ 7.50 (d, J = 8.0 Hz, 1H), 7.30
product was obtained as a white solid (PE:EA = 1:2, 136 mg, (d, J = 8.1 Hz, 1H), 7.15 (t, J = 7.7 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H),
o
5%). mp = 103 - 105 C; H NMR (300 MHz, CDCl
1
8
=
7
3
) δ 7.62 (d, J 6.10 (s, 1H), 5.34 (d, J = 35.0 Hz, 2H), 4.61 (t, J = 7.2 Hz, 2H),
7.8 Hz, 1H), 7.52 – 7.39 (m, 4H), 7.36 (dd, J = 6.4, 4.6 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 1.92 (td, J = 8.4, 4.3 Hz, 1H), 1.00 (dt, J =
1
.21 (d, J = 7.1 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 5.28 (s, 1H), 5.06 8.5, 3.1 Hz, 2H), 0.80 – 0.65 (m, 2H); C NMR (126 MHz, CDCl )
3
3
(
s, 1H), 4.38 – 4.31 (m, 2H), 2.66 – 2.60 (m, 2H), 2.42 – 2.35 (m, δ 172.6, 143.0, 136.4, 128.0, 120.9, 120.2, 119.6, 108.7, 97.7,
+
H), 1.59 – 1.51 (m, 2H), 1.27 – 1.21 (m, 2H), 0.80 (t, J = 7.3 Hz, 39.3, 35.9, 7.2, 6.8; EI-MS (m/z) 228 (M ); HRMS (EI): m/z [M ]
+
2
3
1
3
1
3
H); C NMR (101 MHz, CDCl
3
) δ 195.0, 172.7, 137.0, 136.1, calcd for C14
3-(2-(Tert-butyl)-1H-indol-1-yl)propanamide (3ad). The
9.7, 35.7, 33.3, 24.2, 22.7, 13.9; EI-MS (m/z) 320 (M ); HRMS product was obtained as a white solid (PE:EA = 1:2, 73 mg,
16 2
H N O, 228.1263; found, 228.1255.
32.1, 130.6, 128.6, 128.3, 128.1, 121.8, 119.4, 114.9, 109.6,
+
+
o
1
(
EI): m/z [M ] calcd for C21
Spectral data correspond to those previously reported.
-(3-Methyl-2-phenyl-1H-indol-1-yl)propanamide (3y). The 7.07 (t, J = 7.3 Hz, 1H), 6.29 (s, 1H), 5.64 (s, 1H), 5.43 (s, 1H),
H
24
N
2
O, 320.1889; found, 320.1891. 60%). mp = 127 - 129 C; H NMR (300 MHz, CDCl
3
) δ 7.53 (d, J
1
6
= 7.7 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H),
3
1
3
product was obtained as a white solid (PE:EA = 1:2, 90 mg, 4.72 – 4.60 (m, 2H), 2.76 – 2.64 (m, 2H), 1.47 (s, 9H); C NMR
o
5%). mp = 135 - 137 C; H NMR (300 MHz, CDCl
1
6
=
=
2
3 3
) δ 7.57 (d, J (126 MHz, CDCl ) δ 172.5, 148.7, 137.4, 127.7, 121.1, 120.3,
+
7.8 Hz, 1H), 7.46 – 7.33 (m, 5H), 7.26 – 7.18 (m, 1H), 7.13 (t, J 119.6, 109.0, 98.8, 40.8, 35.2, 32.5, 30.6; EI-MS (m/z) 244 (M );
+
20 2
7.4 Hz, 1H), 5.72 (s, 1H), 5.17 (s, 1H), 4.35 (t, J = 7.6 Hz, 2H), HRMS (EI): m/z [M ] calcd for C15H N O, 244.1576; found,
1
3
.33 (t, J = 7.7 Hz, 2H), 2.21 (s, 3H); C NMR (101 MHz, CDCl
3
)
244.1580.
δ 172.9, 137.0, 136.2, 132.0, 130.5, 128.9, 128.7, 128.2, 122.0,
19.5, 119.1, 109.7, 109.6, 39.8, 35.7, 9.3; EI-MS (m/z) 278
Synthesis of acid 4
1
+
M ); HRMS (EI): m/z [M ] calcd for C18
+
(
18 2
H N O, 278.1419; To a stirred solution of compound 3y (139 mg, 0.50 mmol) in
found, 278.1421. Spectral data correspond to those previously dioxane (10 mL), 20% NaOH aqueous solution (4 mL) was
1
6
reported.
added. The mixture was stirred for 5 h, then HCl aqueous
Ethyl
1-(3-amino-3-oxopropyl)-2-phenyl-1H-indole-3- solution was added until pH = 3-4. The mixture was extracted
carboxylate (3z). The product was obtained as a pale yellow with DCM, the combined organic phase was washed with brine,
o
1
solid (PE:EA = 1:2, 131 mg, 78%). mp = 154 - 156 C; H NMR dried over anhydrous Na
2
SO
4
and concentrated. The residue
silica gel column with
H), 7.35 – 7.24 (m, 4H), 5.53 (s, 2H), 4.38 – 4.24 (m, 2H), 4.13 chloroform/methanol/acetic acid (50/1/0.1) as the eluent to
as a white solid (116 mg, 83%).
(
300 MHz, CDCl
3
) δ 8.24 (dd, J = 6.6, 2.8 Hz, 1H), 7.49 – 7.35 (m, was
purified
on
a
4
(
q, J = 7.1 Hz, 2H), 2.42 (t, J = 7.7 Hz, 2H), 1.12 (t, J = 7.1 Hz, 3H); afford the acid
4
1
3
C NMR (126 MHz, CDCl
3
) δ 171.9, 165.1, 146.3, 135.7, 131.5,
Synthesis of tricyclic intermediate 5
1
5
29.9, 129.1, 128.3, 126.8, 123.1, 122.3, 122.0, 110.1, 105.9,
+
9.4, 39.7, 35.3, 14.0; EI-MS (m/z) 336 (M ); HRMS (EI): m/z A 25 mL round-bottom flask was charged with compound
4
(84
+
[
M ] calcd for C20
-(2-(p-Tolyl)-1H-indol-1-yl)propanamide
product was obtained as a pale yellow solid (PE:EA = 1:2, 61 into 50 mL ice water, 10% NaOH aqueous solution was added,
H
20
N
2
O
3
, 336.1474; found, 336.1470.
mg, 0.30 mmol) and polyphosphoric acid (5 mL), the mixture
o
3
(3aa).
The was heated at 130 C for 3 h. Then the solution was poured
o
1
mg, 44%). mp = 157 - 159 C; H NMR (300 MHz, CDCl
d, J = 7.8 Hz, 1H), 7.39 (dd, J = 15.5, 8.1 Hz, 3H), 7.30 (d, J = 9.2 phase was washed with brine, dried over anhydrous Na
Hz, 2H), 7.21 (d, J = 6.9 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.50 (s, and concentrated. The residue was purified on a silica gel
H), 5.39 (s, 1H), 5.15 (s, 1H), 4.59 – 4.45 (m, 2H), 2.52 – 2.45 column with petroleum ether/ethyl acetate (2/1) as the eluent
3
) δ 7.61 the mixture was extracted with DCM. The combined organic
(
2
SO
4
1
1
3
(m, 2H), 2.42 (s, 3H); C NMR (126 MHz, CDCl
3
) δ 172.4, 141.1, to afford the compound
5
as a pale white solid (69 mg, 88%).
1
1
38.2, 137.1, 129.8, 129.4, 129.2, 128.4, 121.8, 120.6, 120.1,
+
09.9, 102.7, 39.8, 35.6, 21.3; EI-MS (m/z) 278 (M ); HRMS (EI):
22
Synthesis of PARP-1 inhibitor 6
+
m/z [M ] calcd for C18
Spectral data correspond to those previously reported.
-(2-(4-(Trifluoromethyl)phenyl)-1H-indol-1-
yl)propanamide (3ab). The product was obtained as a pale The NaHCO
18 2 3
H N O, 278.1419; found, 278.1420. The compound 5 (78 mg, 0.30 mmol) was dissolved in MeSO H
1
6
o
(5 mL) and cooled to 0 C, then NaN
added. The mixture was stirred at room temperature for 12 h.
saturated solution was added, the mixture was
yellow solid (PE:EA = 1:2, 63 mg, 38%). mp = 177 - 179 C; H extracted with DCM, the combined organic phase was washed
NMR (300 MHz, CDCl ) δ 7.74 (d, J = 8.1 Hz, 2H), 7.63 (t, J = 9.1 with brine, dried over anhydrous Na SO and concentrated.
3
(29 mg, 0.45 mmol) was
3
3
o
1
3
2
4
Hz, 3H), 7.45 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 7.1 Hz, 1H), 7.17 (t, The residue was purified on a silica gel column with petroleum
J = 7.4 Hz, 1H), 6.60 (s, 1H), 5.24 (d, J = 45.7 Hz, 2H), 4.61 – ether/ ethyl acetate (1/1) as the eluent to afford the
1
3
4
1
1
.51 (m, 2H), 2.53 – 2.46 (m, 2H); C NMR (126 MHz, CDCl
71.8, 139.4, 137.5, 136.3, 129.4, 128.3, 125.7 (q, J = 14.5 Hz),
22.6, 121.0, 120.5, 110.1, 104.2, 39.9, 35.3; EI-MS (m/z) 332 = 141 - 143 C; H NMR (300 MHz, CDCl
3
) δ compound
6 as a pale yellow solid (65 mg, 79%).
3-(3-Methyl-2-phenyl-1H-indol-1-yl)propanoic acid (4). mp
o
1
3
) δ 7.60 (d, J = 8.1 Hz,
+
+
(
M ); HRMS (EI): m/z [M ] calcd for C18
H
15
F
3
N
2
O, 332.1136; 1H), 7.52 – 7.41 (m, 3H), 7.40 – 7.34 (m, 3H), 7.24 (d, J = 8.6 Hz,
1H), 7.19 – 7.12 (m, 1H), 4.40 – 4.32 (m, 2H), 2.61 – 2.52 (m,
found, 332.1130.
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1
H), 2.23 (s, 3H); C NMR (126 MHz, CDCl
3
2
1
1
3
) δ 176.6, 136.9,
4
5
S. Rakshit, C. Grohmann, T. Besset and F. Glorius, J. Am.
Chem. Soc., 2011, 133, 2350.
36.1, 131.9, 130.5, 128.9, 128.6, 128.2, 122.0, 119.5, 119.1,
+
09.9, 109.3, 39.1, 34.2, 9.2; EI-MS (m/z) 279 (M ); HRMS (EI):
a) H. Wang and F. Glorius, Angew. Chem. Int. Ed., 2012, 51
7
,
318; b) H. Wang, C. Grohmann, C. Nimphius and F. Glorius,
+
m/z [M ] calcd for C18
H17NO
2
, 279.1259; found, 279.1261.
J. Am. Chem. Soc., 2012, 134, 19592; c) J. R. Huckins, E. A.
Bercot, O. R. Thiel, T. L. Hwang and M. M. Bio, J. Am. Chem.
Soc., 2013, 135, 14492; d) T. K. Hyster, K. E. Ruhl and T.
Rovis, J. Am. Chem. Soc., 2013, 135, 5364; e) X. Wu, B. Wang,
Y. Zhou and H. Liu, Org. Lett., 2017, 19, 1294.
a) X. Huang, J. Huang, C. Du, X. Zhang, F. Song and J. You,
Angew. Chem. Int. Ed., 2013, 52, 12970; b) U. Sharma, Y. Park
and S. Chang, J. Org. Chem., 2014, 79, 9899; c) X. Zhang, Z. Qi
and X. Li, Angew. Chem. Int. Ed., 2014, 53, 10794; d) R. B.
Dateer and S. Chang, J. Am. Chem. Soc., 2015, 137, 4908; e)
B. Zhou, Z. Chen, Y. Yang, W. Ai, H. Tang, Y. Wu, W. Zhu and
Y. Li, Angew. Chem. Int. Ed., 2015, 54, 12121; f) Z. Zhou, G.
Liu, Y. Chen and X. Lu, Adv. Synth. Catal., 2015, 357, 2944.
a) G. Liu, Y. Shen, Z. Zhou and X. Lu, Angew. Chem. Int. Ed.,
2013, 52, 6033; b) Y. Shen, G. Liu, Z. Zhou and X. Lu, Org.
Lett., 2013, 15, 3366; c) Y. Chen, D. Wang, P. Duan, R. Ben, L.
Dai, X. Shao, M. Hong, J. Zhao and Y. Huang, Nat. Commun.,
1
-Methyl-2-phenyl-4,5-dihydro-6H-pyrrolo[3,2,1-
o
1
ij]quinolin-6-one (5). mp = 115 - 117 C; H NMR (300 MHz,
CDCl ) δ 7.80 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.55 –
.49 (m, 2H), 7.45 (d, J = 6.7 Hz, 3H), 7.22 (t, J = 7.7 Hz, 1H),
3
7
4
6
7
1
3
.26 (t, J = 6.9 Hz, 2H), 3.07 (t, J = 6.9 Hz, 2H), 2.35 (s, 3H);
) δ 193.2, 140.3, 137.9, 130.9, 130.0,
28.9, 128.7, 128.2, 125.2, 119.9, 118.7, 117.8, 110.6, 42.6,
C
NMR (126 MHz, CDCl
3
1
3
+
+
8.4, 9.5; EI-MS (m/z) 261 (M ); HRMS (EI): m/z [M ] calcd for
C
18
H15NO, 261.1154; found, 261.1146.
7
-Methyl-6-phenyl-3,4-dihydro-[1,4]diazepino[6,7,1-
o
1
hi]indol-1(2H)-one (6). mp = 286 - 288 C; H NMR (300 MHz,
DMSO-d ) δ 8.34 (t, J = 5.7 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.77
d, J = 7.7 Hz, 1H), 7.60 – 7.43 (m, 5H), 7.18 (t, J = 7.6 Hz, 1H),
6
(
1
3
4
.20 – 4.08 (m, 2H), 3.48 (d, J = 6.9 Hz, 2H), 2.24 (s, 3H);
) δ 168.9, 138.2, 132.7, 131.3, 131.0,
30.0, 129.0, 128.6, 126.0, 123.1, 118.9, 117.4, 108.4, 50.5,
C
2
014, 5, 4610; d) F. Hu, Y. Xia, F. Ye, Z. Liu, C. Ma, Y. Zhang
NMR (126 MHz, DMSO-d
6
and J. Wang, Angew. Chem. Int. Ed., 2014, 53, 1364; e) H.
Zhang, K. Wang, B. Wang, H. Yi, F. Hu, C. Li, Y. Zhang and J.
Wang, Angew. Chem. Int. Ed., 2014, 53, 13234; f) Z. Zhou, G.
Liu, Y. Chen and X. Lu, Org. Lett., 2015, 17, 5874; g) Z. Hu, X.
Tong and G. Liu, Org. Lett., 2016, 18, 1702.
1
4
+
+
1.1, 9.7; EI-MS (m/z) 276 (M ); HRMS (EI): m/z [M ] calcd for
O, 276.1263; found, 276.1271. Spectral data
18 16 2
C H N
1
7
correspond to those previously reported.
8
a) K. Parthasarathy, M. Jeganmohan and C.-H. Cheng, Org.
Lett., 2008, 10, 325; b) P. K. and C.-H. Cheng, J. Org. Chem.,
2
009, 74, 9359; c) P. C. Too, Y.-F. Wang and S. Chiba, Org.
Acknowledgements
Lett., 2010, 12, 5688; d) T. K. Hyster and T. Rovis, Chem.
Commun., 2011, 47, 11846; e) P. C. Too, S. H. Chua, S. H.
Wong and S. Chiba, J. Org. Chem., 2011, 76, 6159; f) X.
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This work was supported by grants from Chinese NSF
81373277, 81430080). Supporting from the National Program
(
on Key Basic Research Project of China (2015CB910603), the
International Cooperative Program (GJHZ1622) and Key
Program of the Frontier Science (160621) of the Chinese
Academy of Sciences, the Shanghai Commission of Science and
Technology (16XD1404600, 14431905300, 14431900400), as
well as grant from CAS Key Laboratory of Receptor Research of
SIMM (SIMM1606YKF-08, SIMM1606YZZ-06) are also highly
appreciated.
Zhao, F. Lied and F. Glorius, Chem. Sci., 2014, 5, 2869.
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a) S.-C. Chuang, P. Gandeepan and C.-H. Cheng, Org. Lett.,
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Notes and references
5
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