Tandem addition-cyclization reactions of 2-alkynylbenzenamines with isocyanates catalyzed by PdCl2

Article abstract of DOI:10.1039/b812015c

Tandem addition-cyclization reactions of 2-alkynylbenzenamines with isocyanates catalyzed by palladium chloride are described. This reaction is performed in the presence of 10 mol% of palladium chloride in THF at 80 °C, which provides an efficient and pra

Full text of DOI:10.1039/b812015c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Tandem addition-cyclization reactions of 2-alkynylbenzenamines with
isocyanates catalyzed by PdCl2†‡
Shengqing Ye,a Qiuping Ding,a Zhiyong Wang,a Haibo Zhoua and Jie Wu*a,b
Received 14th July 2008, Accepted 1st September 2008
First published as an Advance Article on the web 15th October 2008
DOI: 10.1039/b812015c
Tandem addition-cyclization reactions of 2-alkynylbenzenamines with isocyanates catalyzed by
palladium chloride are described. This reaction is performed in the presence of 10 mol% of palladium
chloride in THF at 80 ◦C, which provides an efficient and practical route for the synthesis of
1,2-disubstituted indoles.
workers reported tandem cyclization of 2-alkynylbenzenamines in
the presence of certain nucleophiles to give the nucleophile incor-
Introduction
porated indoles.7 Li described an efficient double-hydroamination
reaction of 2-alkynylbenzenamines with terminal alkynes leading
to N-alkenylindoles using gold(III) as a catalyst under neat
conditions.8
As part of a continuing effort in our laboratory toward the
development of new methods for the expeditious synthesis of bio-
logically relevant heterocyclic compounds,9 we became interested
in the possibility of developing novel and efficient method to
construct poly-substituted indoles, with a hope of finding more
active hits or leads for our particular biological assays. Herein,
we would like to disclose our recent efforts for the synthesis of
1,2-disubstituted indoles via PdCl2-catalyzed tandem reaction of
2-alkynylbenzenamine with isocyanate.
Among the strategies used for the construction of small
molecules, the design and synthesis of natural product-like com-
pounds via tandem reactions have attracted much attention, and
the development of tandem reactions has been a fertile area in
organic synthesis.10 In particular, the development of tandem
reactions for the efficient construction of small molecules is an
important goal in combinatorial chemistry from the viewpoints
of operational simplicity and assembly efficiency. In our previous
reports,9a,b,e we found that o-alkynylbenzaldehyde11 was a versatile
building block in tandem reactions for the construction of
1,2-dihydroisoquinoline skeleton. Prompted by these results, we
envisioned that 2-alkynylbenzenamine could be also utilized as
starting material due to the structural similarity for synthesis
of N-heterocycles via tandem addition-cyclization reaction. The
projected synthetic route is shown in Scheme 1. We conceived that
in the presence of suitable catalyst, 2-alkynylbenzenamine would
react with isocyanate leading to the intermediate A. Meanwhile,
the formed metal-complex renders the carbon-carbon unsaturated
bond moiety electrophilic, which triggers intramolecular attack of
the nucleophile, giving rise to the final product 3 or 4.
The increasing significance of combinatorial chemistry in phar-
maceutical and material sciences demands the development of
new strategies to synthesize a collection of analogues of inter-
esting compounds.1 Since the indole skeleton is an important
substructure in both natural products and therapeutic agents,
as well as the wide application of indoles in pharmaceutical
research,2 the development of efficient methods for indole syn-
thesis has continuously attracted the attentions of many chemists.
Among the synthetic strategies developed, catalytic transforma-
tions utilizing transition-metal catalysts is one of the popular ap-
proaches for forming indoles.3,4 In particular, using functionalized
2-alkynylbenzenamines as starting material is one of the most effi-
cient ways.5–8 For instance, palladium(II)-catalyzed intramolecular
cyclization of 2-alkynylbenzenamines can produce 2-substituted
indoles in high yield.5d Regioselective synthesis of 3-allylindoles via
palladium-catalyzed cyclization of o-alkynyltrifluoroacetanilides
with allyl esters was achieved by Cacchi and co-workers.6a
Polyfunctionalized indoles were generated in the presence of large
excess amount of cesium and potassium bases (such as CsO-t-Bu,
KO-t-Bu, and KH) in N-methylpyrrolidinone.6b Hiroya and co-
workers developed Cu(II)-catalyzed indole formation and applied
this method in natural product syntheses.6c,d Arcadi and coworkers
reported reactions of 2-alkynylbenzenamines to give rise to
C-3-alkylindoles catalyzed by gold catalyst.6e Yamamoto and co-
aDepartment of Chemistry, Fudan University, 220 Handan Road, Shanghai,
200433, China. E-mail: jie_wu@fudan.edu.cn; Fax: 86 21 6510 2412; Tel: 86
21 5566 4619
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai, 200032, China
† Electronic supplementary information (ESI) available: General exper-
imental information, characterization data, and copies of 1H and 13C
NMR spectra of compound 3. CCDC reference number 695031. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b812015c
‡ Crystal data and structure refinement for compound 3a. Empirical for-
mula: C21H16N2O (Molecular weight: 312.36), Crystal system: Monoclinic,
Unit cell dimensions: a = 10.974(5) A alpha = 90 deg., b = 14.927(6) A,
beta = 95.267(6) deg., c = 9.978(4) A, gamma = 90 deg. Volume:
Results and discussion
To identify suitable conditions for the proposed metal-catalyzed
tandem addition-cyclization process, reaction screening involving
2-alkynylbenzenamine 1a, phenyl isocyanate 2a, and a series of
metal catalysts was carried out at room temperature. Results of this
preliminary survey are shown in Table 1. In an initial experiment,
ˆ
1627.6(12) A3, refine_1s_shift/su_max 0.000 mean 0.000, Temperature:
ˆ
293(2) K, space group: P2(1)/c, Z, Calculated density : 4, 1.275 Mg/m3,
Reflections collected/unique: 6575/2852 [R(int) = 0.0507], Final R indices
[I>2sigma(I)]: R1 = 0.0505, wR2 = 0.1155, R indices (all data): R1 =
0.0830, wR2 = 0.1226
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Table 1 Screening of Conditions for the Reaction of 2-Alkynylbenzenamine 1a with Phenyl Isocyanate 2aa
Entry
Lewis acid
Solvent
T (◦C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
AgOTf (10 mol%)
CuI (10 mol%)
THF
THF
THF
THF
THF
THF
EtOH
EtOH
MeCN
Toluene
THF
(CH2Cl)2
CH3NO2
1,4-dioxane
THF
25
25
25
25
25
25
80
80
80
80
80
80
80
80
80
4.5
24
24
40
24
24
36
7
20
24
10
20
20
20
20
90 (5a)
95 (5a)
85 (5a)
85 (5a)
80 (5a)
15 (3a)/70 (5a)
52 (3a)
58 (3a)
64 (3a)
trace
87 (3a)
43 (3a)
35 (3a)
54 (3a)
20 (3a)
FeCl3 (10 mol%)
In(OTf)3 (10 mol%)
Bi(OTf)3 (10 mol%)
PdCl2 (10 mol%)
AgSbF6 (10 mol%)
PdCl2 (10 mol%)
PdCl2 (10 mol%)
PdCl2 (10 mol%)
PdCl2 (10 mol%)
PdCl2 (10 mol%)
PdCl2 (10 mol%)
PdCl2 (10 mol%)
PdCl2 (5 mol%)
a Reaction conditions: 2-alkynylbenzenamine 1a (0.50 mmol), phenyl isocyanate 2a (0.75 mmol, 1.5 equiv), solvent (2.0 mL). b Isolated yield based on
2-alkynylbenzenamine 1a.
Scheme 1 Proposed tandem reaction of 2-alkynylbenzenamine with
isocyanate.
only normal addition product 5a (90% yield, Table 1, entry 1) was
Fig. 1 ORTEP illustration of 1,2-disubstituted indole 3a (30% probability
generated when AgOTf (10 mol%) was employed in the reaction
at room temperature in THF. Similar results were observed when
ellipsoids).
other metal catalysts such as CuI, FeCl3, In(OTf)3, and Bi(OTf)3
were utilized (Table 1, entries 2–5). To our delight, we observed
the formation of the desired product 3a (15% yield) when the
reaction was performed in THF catalyzed by PdCl2 (10 mol%)
(Table 1, entry 6) although 70% of compound 5a was obtained
meanwhile. The structure of 3a was verified by 1H and 13C NMR,
mass spectroscopy, as well as X-ray diffraction analysis (Fig. 1,
also see Supporting Information). We also found that indole 3a
could be produced in the presence of AgSbF6 as catalyst in EtOH at
80 ◦C(52% yield, Table 1, entry 7), while 58% yield of compound 3a
was generated when the reaction was catalyzed by PdCl2 (Table 1,
entry 8). Further screening of solvents revealed that the yield could
be dramatically improved when THF was utilized in the reaction
(87% yield, Table 1, entry 11). Inferior results were displayed when
other solvents were used. When the catalytic amount of PdCl2 was
decreased to 5 mol%, the desired product was afforded in only
20% yield (Table 1, entry 15).
Subsequently, to investigate the scope of this reaction, vari-
ous 2-alkynylbenzenamines 1 were treated with isocycanates 2
under the optimized conditions [PdCl2 (10 mol%), THF, 80 ◦C]
(Table 2). With respect to the aryl isocycanates, as expected
both electron-rich and electron-poor aryl isocycanates are suit-
able partners in this process due to their high electrophilicity.
The expected 1,2-disubstituted indoles resulting from reactions
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Table 2 Tandem Reaction of 2-Alkynylbenzenamine 1 with Isocyanate 2 Catalyzed by Palladium Chloride
Entry
1
R1/R2
R3
Indole 3
Yield (%)a
H/C6H5 (1a)
C6H5 (2a)
87 (3a)
2
3
H/4-MeOC6H4 (1b)
4-CF3/C6H5 (1c)
C6H5 (2a)
C6H5 (2a)
53 (3b)
46 (3c)
4
4-CH3/C6H5 (1d)
C6H5 (2a)
74 (3d)
5
6
7
8
H/Cyclopropyl (1e)
H/C6H5 (1a)
C6H5 (2a)
90 (3e)
75 (3f)
65 (3g)
60 (3h)
4-FC6H4 (2b)
4-FC6H4 (2b)
4-FC6H4 (2b)
H/4-MeOC6H4 (1b)
4-CF3/C6H5 (1c)
9
4-CH3/C6H5 (1d)
4-FC6H4 (2b)
4-FC6H4 (2b)
72 (3i)
72 (3j)
10
H/Cyclopropyl (1e)
11
12
H/C6H5 (1a)
4-MeO C6H4 (2c)
4-MeO C6H4 (2c)
86 (3k)
73 (3l)
H/4-MeOC6H4 (1b)
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Table 2 (Contd.)
Entry
13
R1/R2
R3
Indole 3
Yield (%)a
4-CF3/C6H5 (1c)
4-MeO C6H4 (2c)
43 (3m)
14
15
4-CH3/C6H5 (1d)
4-MeO C6H4 (2c)
4-MeO C6H4 (2c)
83 (3n)
88 (3o)
H/Cyclopropyl (1e)
a Isolated yield based on 2-alkynylbenzenamine 1.
of 2-alkynylbenzenamine 1 could be obtained and isolated in
moderate to good yields. Better results were obtained when 2-
alkynylbenzenamine substituted with an electron-rich substituent
on the aromatic ring was employed. For instance, trifluoromethyl-
substituted 2-alkynylbenzenamine 1c reacted with phenyl isocy-
canate 2a led to the desired product 3c in 46% yield (Table 2,
entry 3), while 74% yield of indole 3d was afforded when
methyl-substituted 2-alkynylbenzenamine 1d was utilized in the
reaction (Table 2, entry 4). Similar results were observed when 4-
fluorophenyl isocycanate 2b and 4-methoxyphenyl isocycanate 2c
reacted with 2-alkynylbenzenamine 1c or 1d (Table 2, entries 8, 9,
13, 14). When R2 was changed to cyclopropyl group, the reactions
also occurred smoothly to generate the corresponding products 3
in good yields. For example, reaction of 2-alkynylbenzenamine
1e with phenyl isocycanate 2a gave rise to the indole 3e in
90% yield (Table 2, entry 5). 88% yield of compound 3o was
generated when 4-methoxyphenyl isocycanate 2c was used as a
replacement (Table 2, entry 15), whereas product 3j was afforded
in 72% yield for the reaction of 4-fluorophenyl isocycanate 2b
(Table 2, entry 10). From the results shown in Table 2, the
reactions showed very high regioselectivity. We reasoned that in
the reaction process, it may presumably involve the formation of p-
complex via coordination of the alkynyl moiety of 1 to Pd(II), thus
activating the triple bond for regioselective nucleophilic attack
by the amino group in endo mode. Although factors affecting
the above regioselectivity are not yet very clear, generally in the
presence of palladium, 5-endo-cyclization is favorable.13
and biological screening of these small molecules are under
investigation in our laboratory, and the results will be reported
in due course.
Experimental Section
All reactions were performed in test tubes under nitrogen at-
mosphere. Flash column chromatography was performed using
˚
silica gel (60-A pore size, 32–63 mm, standard grade). Analytical
thin–layer chromatography was performed using glass plates pre-
coated with 0.25 mm 230–400 mesh silica gel impregnated with
a fluorescent indicator (254 nm). Thin layer chromatography
plates were visualized by exposure to ultraviolet light. Organic
solutions were concentrat◦ed on rotary evaporators at ~20 Torr
(house vacuum) at 25–35 C. Commercial reagents and solvents
were used as received.
General procedure for reaction of 2-alkynylbenzenamine 1 with
isocyanate 2 catalyzed by palladium chloride
A solution of 2-alkynylbenzenamine 112 (0.50 mmol) and iso-
cyanate 2 (0.75 mmol, 1.5 equiv) in THF (2.0 mL) was stirred
at 80 ◦C for 3 h. Then PdCl2 (10 mol%) was added to the mixture.
After completion of reaction as indicated by TLC, the solvent was
evaporated and the residue was quenched with water (10 mL),
extracted with EtOAc (2 ¥ 10 mL), dried by anhydrate Na2SO4.
Evaporation of the solvent followed by purification on silica gel
provided the corresponding product 3.
Conclusions
N,2-Diphenyl-1H-indole-1-carboxamide 3a
In summary, we have described a novel and efficient method
for the synthesis of 1,2-disubstituted indoles via PdCl2-catalyzed
tandem addition-cyclization reactions of 2-alkynylbenzenamines
with isocyanates. The efficiency of this method combined with the
operational simplicity of the present process makes it potential
attractive for library construction. Construction of a small library
Colorless oil, yield: 87%; IR (KBr): vmax/cm-1 3298 (NH),
=
1670 (CO), 1598, 1532, 1440 (C C); UV: lmax = 204.0 nm, l =
1
293.0 nm, l = 253.0 nm; H NMR (400 MHz, CDCl3) d6.69 (s,
1H), 6.72 (br, 1H), 7.04–7.08 (m, 3H), 7.20–7.27 (m, 3H), 7.33
(dt, J = 1.5, 7.82 Hz, 1H), 7.42–7.47 (m, 3H), 7.54–7.56 (m, 2H),
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7.59 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 8.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 109.1, 114.3, 119.6, 120.6, 122.7,124.4, 124.6,
128.6, 128.8, 128.9, 129.1, 132.0, 136.7, 137.6, 137.9, 149.4; MS
(ESI) m/z 313 (M++H); HRMS calcd for C21H16N2O (M++H):
313.1341; Found: 313.1370.
292.0 nm, l = 250.0 nm, l = 230.0 nm; H NMR (400 MHz,
CDCl3) d 6.69 (br, 1H), 6.70 (s, 1H), 6.91 (t, J = 8.7 Hz, 2H), 6.98–
7.02 (m, 2H), 7.24–7.28 (m, 1H), 7.34 (dt, J = 1.5, 8.3 Hz, 1H),
7.44–7.49 (m, 3H), 7.54–7.57 (m, 2H), 7.59 (d, J = 7.8 Hz, 1H),
8.19 (d, J = 8.3 Hz, 1H);13C NMR (100 MHz, CDCl3) d 109.3,
114.4, 115.6 (d, 2JCF = 22.9 Hz), 120.6, 121.4 (d, 3JCF = 7.6 Hz),
122.8, 124.6, 128.6, 128.9, 129.0, 129.1, 132.0, 132.7 (d, 4JCF = 2.8
Hz), 137.5, 137.9, 149.5, 159.6 (d, 1JCF = 243.1 Hz); MS (ESI) m/z
331 (M++H); HRMS calcd for C21H15FN2O (M++H): 331.1247;
Found: 331.1271.
1
2-(4-Methoxyphenyl)-N-phenyl-1H-indole-1-carboxamide 3b
Colorless oil, yield: 53%; IR (KBr): vmax/cm-1 3257 (NH),
=
1680 (CO), 1593, 1542, 1491, 1445 (C C); UV: lmax = 202.0 nm,
l = 295.0 nm, l = 242.0 nm; 1H NMR (400 MHz, CDCl3) d 3.85 (s,
3H), 6.64 (s, 1H), 6.82 (br, 1H), 6.99 (d, J = 8.8 Hz, 2H), 7.06–7.13
(m, 3H), 7.23–7.27 (m, 3H), 7.33 (t, J = 7.3 Hz, 1H), 7.50 (d, J =
8.8 Hz, 2H), 7.58 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 55.4, 108.6, 114.5, 114.6, 119.7,
120.4, 122.7, 124.2, 124.3, 124.6, 128.7, 129.0, 130.3, 136.8, 137.4,
137.8, 149.5, 160.2; MS (ESI) m/z 343 (M++H); HRMS calcd for
C22H18N2O2 (M++H): 343.1447; Found: 343.1470.
N-(4-Fluorophenyl)-2-(4-methoxyphenyl)-1H-indole-1-
carboxamide 3g
Colorless oil, yield: 65%; IR (KBr): vmax/cm-1 3283 (NH),
1665 (CO), 1609, 1552, 1496, 1450 (C C), 840; UV: lmax
=
=
204.0 nm, l = 294.0 nm, l = 241.0 nm; 1H NMR(400 MHz,CDCl3)
d 3.86 (s, 3H), 6.64 (s, 1H), 6.81 (br, 1H), 6.94 (t, J = 8.3 Hz, 2H),
7.00 (d, J = 8.8 Hz, 2H), 7.05–7.09 (m, 2H), 7.25 (dt, J = 1.5,
8.3 Hz, 1H), 7.33 (dt, J = 1.5, 8.3 Hz, 1H), 7.49 (d, J = 8.8 Hz,
2H), 7.58 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 8.3 Hz, 1H);13C
NMR (100 MHz, CDCl3) d 55.4, 108.7, 114.4, 114.6, 115.6 (d,
N,2-Diphenyl-5-(trifluoromethyl)-1H-indole-1-carboxamide 3c
Colorless oil, yield: 46%; IR (KBr): vmax/cm-1 3288 (NH),
1690 (CO), 810; UV: lmax = 230.0 nm, l = 292.0 nm, l = 248.0 nm;
1H NMR (400 MHz, CDCl3) d 6.75 (br, 1H), 6.77 (s, 1H), 7.04–
7.12 (m, 3H), 7.23–7.27 (m, 2H), 7.49–7.51 (m, 3H), 7.56–7.59 (m,
3H), 7.89 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H); 13C NMR (100 MHz,
2JCF = 22.9 Hz), 120.4, 121.5 (d, JCF = 8.6 Hz), 122.7, 124.1,
3
1
124.3, 128.7, 130.3, 132.8, 137.3, 137.8, 149.7, 159.6 (d, JCF
=
242.1 Hz), 160.2; MS (ESI) m/z 383 (M++Na); HRMS calcd for
C22H17FN2O2 (M++Na): 383.1172; Found: 383.1200.
3
CDCl3) d 108.9, 114.9, 118.1 (q, JCF = 3.8 Hz), 119.7, 121.1 (q,
3JCF = 3.8 Hz), 124.8 (q, 1JCF = 270.8 Hz), 124.9, 125.0 (q, 2JCF
=
N-(4-Fluorophenyl)-2-phenyl-5-(trifluoromethyl)-1H-indole-1-
carboxamide 3h
31.5 Hz), 128.2, 129.0, 129.1, 129.3, 129.5, 131.3, 136.4, 139.3,
148.9; MS (ESI) m/z 381 (M++H); HRMS calcd for C22H15F3N2O
(M++H): 381.1215; Found: 381.1241.
Colorless oil, yield: 60%; IR (KBr): vmax/cm-1 3421 (NH),
=
1711 (CO), 1537, 1511 (C C); UV: lmax = 200.0 nm, l = 290.0 nm,
5-Methyl-N,2-diphenyl-1H-indole-1-carboxamide 3d
l = 247.0 nm, l = 231.0 nm; 1H NMR (400 MHz, CDCl3) d 6.70
(br, 1H), 6.77 (s, 1H), 6.91–7.00 (m, 4H), 7.50–7.52 (m, 3H), 7.56–
7.58 (m, 3H), 7.89 (s, 1H), 8.28 (d, J = 8.8 Hz, 1H);13C NMR
(100 MHz, CDCl3) d 109.0, 114.8, 115.8 (d, 2JCF = 22.9 Hz), 118.1
Colorless oil, yield: 74%; IR (KBr): vmax/cm-1 3334 (NH),
=
1670 (CO), 1598, 1521, 1440 (C C); UV: lmax = 203.0 nm, l =
1
296.0 nm, l = 255.0 nm, l = 230.0 nm; H NMR (400 MHz,
3
3
3
(q, JCF = 3.8 Hz), 121.1 (q, JCF = 3.1 Hz), 121.6 (d, JCF
=
CDCl3) d 2.45 (s, 3H), 6.62 (s, 1H), 6.70 (br, 1H), 7.04–7.06 (m,
3H), 7.15 (d, J = 8.3 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 7.37 (s, 1H),
7.42–7.48 (m, 3H), 7.54–7.56 (m, 2H), 8.10 (d, J = 8.3 Hz, 1H);13C
NMR (100 MHz, CDCl3) d 21.3, 109.1, 114.2, 119.6, 120.4, 124.5,
126.0, 128.9, 129.0, 129.1, 132.1, 132.2, 136.2, 136.8, 137.6, 149.5;
MS (ESI) m/z 327 (M++H); HRMS calcd for C22H18N2O (M++H):
327.1497; Found: 327.1527.
1
2
7.6 Hz), 124.7 (q, JCF = 270.2 Hz), 125.2 (q, JCF = 32.1 Hz),
128.1, 129.1, 129.4, 129.6, 131.3, 132.3, 139.1, 139.2, 149.0, 159.8
(d, JCF = 243.4 Hz); MS (ESI) m/z 399 (M++H); HRMS calcd
1
for C22H14F4N2O (M++H): 399.1121; Found: 399.1150.
N-(4-Fluorophenyl)-5-methyl-2-phenyl-1H-indole-1-
carboxamide 3i
2-Cyclopropyl-N-phenyl-1H-indole-1-carboxamide 3e
Colorless oil, yield: 72%; IR (KBr): vmax/cm-1 3304 (NH),
=
Colorless oil, yield: 90%; IR (KBr): vmax/cm-1 3293 (NH),
1690 (CO), 1511 (C C); UV: lmax = 206.0 nm, l = 293.0 nm,
l = 254.0 nm, l = 229.0 nm; 1H NMR (400 MHz, CDCl3) d 2.45
(s, 3H), 6.62 (s, 1H), 6.68 (br, 1H), 6.90 (t, J = 8.8 Hz, 2H), 6.98–
7.01 (m, 2H), 7.15 (d, J = 8.3 Hz, 1H), 7.37 (s, 1H), 7.42–7.48
(m, 3H), 7.52–7.55 (m, 2H), 8.07 (d, J = 8.3 Hz, 1H);13C NMR
(100 MHz, CDCl3) d 21.4, 109.3, 114.2, 115.7 (d, 2JCF = 21.9 Hz),
120.5, 121.6 (d, 3JCF = 7.6 Hz), 126.2, 129.0, 129.2, 132.3, 132.4,
132.9 (d, 4JCF = 2.8 Hz), 136.3, 137.6, 149.8, 159.7 (d, 1JCF = 243.1
Hz); MS (ESI) m/z 345 (M++H); HRMS calcd for C22H17FN2O
(M++H): 345.1403; Found: 345.1432.
=
1690 (CO), 1598, 1537, 1455 (C C); UV: lmax = 203.0 nm, l =
261.0 nm; 1H NMR (400 MHz, CDCl3) d 1.71–1.75 (m, 2H), 1.87–
1.91 (m, 2H), 2.90–3.00 (m, 1H), 7.03 (s, 1H), 7.89–7.93 (m, 2H),
7.96–8.00 (m, 1H), 8.13 (t, J = 8.3 Hz, 2H), 8.20 (d, J = 8.3 Hz,
1H), 8.32 (d, J = 8.3 Hz, 2H), 8.83 (d, J = 8.3 Hz, 1H), 9.05
(br, 1H);13C NMR (100 MHz, CDCl3) d 8.2, 10.3, 105.4, 114.1,
119.6, 120.1, 122.3, 123.6, 124.5, 128.4, 129.2, 137.0, 137.3, 140.0,
149.8; MS (ESI) m/z 277 (M++H); HRMS calcd for C18H16N2O
(M++H): 277.1341; Found: 277.1358.
N-(4-Fluorophenyl)-2-phenyl-1H-indole-1-carboxamide 3f
2-Cyclopropyl-N-(4-fluorophenyl)-1H-indole-1-carboxamide 3j
Colorless oil, yield: 75%; IR (KBr): vmax/cm-1 3288 (NH),
Colorless oil, yield: 72%; IR (KBr): vmax/cm-1 3293 (NH),
=
=
1675 (CO), 1547, 1506 (C C), 846; UV: lmax = 201.0 nm, l =
1680 (CO), 1608, 1542, 1506, 1445 (C C); UV: lmax = 204.0 nm,
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l = 259.0 nm; 1H NMR (400 MHz, CDCl3) d 0.97–1.01 (m, 2H),
1.12–1.17 (m, 2H), 2.15–2.24 (m, 1H), 6.30 (s, 1H), 7.08 (t, J =
7.3 Hz, 2H), 7.18 (dt, J = 1.3, 7.8 Hz, 1H), 7.25 (dt, J = 1.5,
8.6 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.52–7.55 (m, 2H), 8.08
(d, J = 8.3 Hz, 1H), 8.33 (br, 1H); 13C NMR (100 MHz, CDCl3)
2H), 6.97 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.1 Hz, 1H), 7.36 (s,
1H), 7.41–7.46 (m, 3H), 7.51–7.55 (m, 2H), 8.06 (d, J = 8.3 Hz,
1H);13C NMR (100 MHz, CDCl3) d 21.3, 55.4, 108.8, 114.0, 114.1,
120.3, 121.6, 125.9, 128.7, 128.8, 129.0, 129.8, 132.0, 132.2, 136.2,
137.6, 149.7, 156.6; MS (ESI) m/z 357 (M++H); HRMS calcd for
C23H20N2O2 (M++H): 357.1603; Found: 357.1629.
2
d 8.2, 10.4, 105.7, 114.4, 115.9 (d, JCF = 21.9 Hz), 120.1, 121.4
3
4
(d, JCF = 8.6 Hz), 122.4, 123.7, 128.4, 133.3 (d, JCF = 2.8 Hz),
1
137.0, 139.9, 150.0, 159.5 (d, JCF = 242.1 Hz); MS (ESI) m/z
2-Cyclopropyl-N-(4-methoxyphenyl)-1H-indole-1-carboxamide 3o
317 (M++Na); HRMS calcd for C18H15FN2O (M++Na): 317.1066;
Found: 317.1092.
Colorless oil, yield: 88%; IR (KBr): vmax/cm-1 3298 (NH),
=
1675 (CO), 1593, 1521, 1450 (C C); UV: lmax = 202.0 nm, l =
265.0 nm; 1H NMR (400 MHz, CDCl3) d 0.94–0.98 (m, 2H), 1.10–
1.05 (m, 2H), 2.16–2.24 (m, 1H), 3.80 (s, 3H), 6.27 (s, 1H), 6.91
(d, J = 9.3 Hz, 2H), 7.16 (t, J = 7.3 Hz, 1H), 7.23 (t, J = 7.8 Hz,
1H), 7.46 (t, J = 8.8 Hz, 3H), 8.07 (d, J = 8.3, 1H), 8.17 (br,
1H);13C NMR (100 MHz, CDCl3) d 8.2, 10.3, 55.5, 105.2, 114.0,
114.4, 120.0, 121.6, 122.2, 123.5, 128.4, 130.3, 137.0, 140.1, 150.1,
156.7; MS (ESI) m/z 307 (M++H); HRMS calcd for C19H18N2O2
(M++H): 307.1447; Found: 307.1473.
N-(4-Methoxyphenyl)-2-phenyl-1H-indole-1-carboxamide 3k
Colorless oil, yield: 86%; IR (KBr): vmax/cm-1 3304 (NH),
=
1696 (CO), 1603, 1516, 1450 (C C); UV: lmax = 203.0 nm, l =
1
292.0 nm, l = 255.0 nm; H NMR (400 MHz, CDCl3) d 3.73 (s,
1H), 6.61 (br, 1H), 6.69 (s, 1H), 6.75 (d, J = 8.8 Hz, 2H), 6.97
(d, J = 8.3 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 7.32 (dt, J = 1.5,
8.3 Hz, 1H), 7.42–7.47 (m, 3H), 7.54–7.60 (m, 3H), 8.18 (d, J =
8.3 Hz, 1H);13C NMR (100 MHz, CDCl3) d 55.4, 108.8, 114.1,
114.2, 120.6, 121.7, 122.6, 124.4, 128.6, 128.8, 129.0, 129.7, 132.0,
137.6, 137.9, 149.6, 156.7; MS (ESI) m/z 343 (M++H); HRMS
calcd for C22H18N2O2 (M++H): 343.1477; Found: 343.1487.
Acknowledgements
We thank Dr. Renhua Fan for his invaluable advice during the
course of this research. Financial support from National Natural
Science Foundation of China (20772018), Shanghai Pujiang
Program, and Program for New Century Excellent Talents in
University (NCET-07-0208) is gratefully acknowledged.
N,2-Bis(4-methoxyphenyl)-1H-indole-1-carboxamide 3l
Colorless oil, yield: 73%; IR (KBr): vmax/cm-1 3283 (NH),
=
1665 (CO), 1593, 1542, 1506, 1445 (C C); UV: lmax = 204.0 nm,
l = 293.0 nm, l = 256.0 nm; 1H NMR (400 MHz, CDCl3) d 3.75
(s, 3H), 3.85 (s, 3H), 6.62 (s, 1H), 6.70 (br, 1H), 6.78 (d, J = 8.8 Hz,
2H), 6.99 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), 7.24 (d,
J = 7.3 Hz, 1H), 7.31 (dt, J = 1.0, 8.3 Hz, 1H), 7.49 (d, J = 8.3 Hz,
2H), 7.57 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 8.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 55.4, 108.3, 114.1, 114.4, 114.5, 120.3, 121.7,
122.6, 124.1, 124.2, 128.7, 129.8, 130.2, 137.5, 137.8, 149.8, 156.7,
160.1; MS (ESI) m/z 373 (M++H); HRMS calcd for C23H20N2O3
(M++H): 373.1552; Found: 373.1579.
Notes and references
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N-(4-Methoxyphenyl)-2-phenyl-5-(trifluoromethyl)-1H-indole-1-
carboxamide 3m
Colorless oil, yield: 43%; IR (KBr): vmax/cm-1 3349 (NH),
=
1685 (CO), 1598, 1511 (C C); UV: lmax = 200.0 nm, l = 291.0 nm,
l = 251.0 nm, l = 231.0 nm; 1H NMR (400 MHz, CDCl3) d 3.76
(s, 3H), 6.62 (br, 1H), 6.76–6.79 (m, 3H), 6.98 (d, J = 7.3 Hz, 2H),
7.49–7.51 (m, 3H), 7.55–7.58 (m, 3H), 7.89 (s, 1H), 7.28 (d, J =
8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 55.5, 108.8, 114.3,
3
3
114.8, 118.2 (q, JCF = 4.7 Hz), 121.1 (q, JCF = 2.9 Hz), 121.9,
124.9 (q, 1JCF = 269.8 Hz), 125.1 (q, 2JCF = 31.5 Hz), 128.2, 129.1,
129.5, 129.7, 131.5, 139.3, 139.4, 149.3, 157.1; MS (ESI) m/z 433
(M++Na); HRMS calcd for C23H17F3N2O2 (M++Na): 433.1140;
Found: 433.1163.
N-(4-Methoxyphenyl)-5-methyl-2-phenyl-1H-indole-1-
carboxamide 3n
Colorless oil, yield: 83%; IR (KBr): vmax/cm-1 3329 (NH),
=
1675 (CO), 1598, 1511, 1465 (C C); UV: lmax = 206.0 nm, l =
1
293.0 nm, l = 257.0 nm; H NMR (400 MHz, CDCl3) d 2.44 (s,
3H), 3.73 (s, 3H), 6.60 (br, 1H), 6.61 (s, 1H), 6.75 (d, J = 8.8 Hz,
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