One-pot synthesis of substituted indoles via titanium(iv) alkoxide mediated imine formation-copper-catalyzed N-arylation

Article abstract of DOI:10.1039/c3ra40389k

Readily accessible o-bromobenzylketones and primary alkyl amines and anilines were used for the construction of substituted indoles in good to excellent yields. The sequence involves a titanium-mediated reaction of ketones with amines to afford imines and subsequent intramolecular cyclization into indoles employing copper catalysis. The two-step protocol allows for the preparation of indoles bearing both N-alkyl and N-aryl groups as well as N-unsubstituted indoles without isolation of the intermediates and is tolerant of a wide range of functionality.

Full text of DOI:10.1039/c3ra40389k

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One-Pot Synthesis of Substituted Indoles via Titanium (IV) Alkoxide
Mediated Imine Formation – Copper-Catalyzed N-Arylation
Ferdinand S. Melkonyan,*‡ Daniil E. Kuznetsov, Marina A. Yurovskaya and Alexander V. Karchava*
A new efficient protocol for the synthesis of substituted indoles from o-bromobezyl ketones and primary
amines or ammonia was developed.

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ARTICLE TYPE
One-Pot Synthesis of Substituted Indoles via Titanium (IV) Alkoxide
Mediated Imine Formation – Copper-Catalyzed N-Arylation†
Ferdinand S. Melkonyan,*‡ Daniil E. Kuznetsov, Marina A. Yurovskaya and Alexander V. Karchava*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Readily accessible o-bromobenzylketones and primary alkyl amines and anilines were used for the
construction of substituted indoles in good to excellent yields. The sequence involves a titanium-mediated
reaction of ketones with amines to afford imines and subsequent intramolecular cyclization into indoles
employing copper catalysis. The two-step protocol allows for the preparation of indoles bearing both N-
10 alkyl and N-aryl groups as well as N-unsubstituted indoles without isolation of the intermediates and is
tolerant of a wide range of functionality.
Introduction
Benzo-fused five-membered heterocycles, particularly indoles,
benzothiophenes and benzofurans, are the key structural elements
15 found in a great number of natural products and developed and
marketed drugs.1 Compounds containing these heterocyclic cores
are privileged structures and their exploitation in drug discovery
programs allows to rapidly identify new high-binding ligands to
variety of biological targets.2 Due to the importance of these
20 heterocyclic structures in medicinal chemistry, numerous of
diverse approaches have been developed for preparing them,2-5
including a great number of recent routes based on the use of
transition metal-catalyzed reactions or oxidative cyclizations.6
In 2004 Willis and co-workers demonstrated that o-
25 bromobenzylketones 1 and thioketones derived from ketones 1
could be easily converted to benzofurans and benzothiophenes
respectively via a Pd2(dba)3/DPEphos-catalyzed base-promoted
cyclization.7 The same direct conversion of ketones 1 (and related
aldehydes) to substituted benzofurans can be achieved by the use
30 of a Pd-NHC-catalyst8 or by employing a low-cost copper9 or an
iron catalyst.10 The ready availability of compounds of the type 1
by various methods6a,7-10 makes this metal-catalyzed cyclization a
Scheme 1 Complementary strategies for the synthesis of indoles through
practically useful synthetic route to deliver both functionalized
benzofuran and benzothiophene from a single precursor.
50
the cyclization of in situ generated imines A
35
Following the same retrosynthetic strategy, it could be
assumed that reactions of ketones 1 with primary amines should
directly provide imines A (in equilibrium with the corresponding
enamines) which could in turn undergo a base-promoted metal-
catalyzed cyclization to supply substituted indoles 2 in a
On the other hand, a few recently developed strategies for indole
synthesis are based on an intramolecular cyclization of imines A
generated in situ without using ketones 1 (Scheme 1). In a two-
step, one-pot sequence to 2-alkylindoles presented by Doye and
55 co-workers imines A were generated employing a titanium-
catalyzed hydroamination process.14 The Willis research group
developed a cascade strategy where the same intermediates A
were provided through an initial intermolecular metal-catalyzed
amination of 2-(2-haloalkenyl)arylhalides.15 In the approach
60 disclosed by Barluenga and co-workers the indole precursors
were formed by palladium catalyzed α-arylation of imines of
enolizable ketones with 1,2-dihaloarenes under basic
40 regiodefined fashion (Scheme 1). However, compounds of the
general type 1 have rarely been used as starting materials for the
preparation of substituted indoles. Published examples are
restricted to Pd11 and Cu-catalyzed12,13 cyclizations of preformed
imines12 and hydrazones11,13 of o-haloarylacetaldehydes (1,
45 R2=H) to deliver 2-unsubstituted indoles, but there is no report on
the preparation of 2-substituted indoles starting from ketones 1.
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conditions.16
Normally,
for
the
intramolecular
N-
arylation/cyclization step these protocols use an expensive
catalyst based on palladium associated with either phosphines15,16
or N-heterocyclic carbenes14 as ligands. The Willis’ approach
was also briefly exemplified with using a copper–diamine
catalyst only for the synthesis of 2-unsubstituted 1-alkyl and 1-
arylindoles.15e
5
Despite the success of the above strategies, it would be
desirable to develop an alternative method for the generation of
Scheme 2 Initial experiments
10 ketimines A and, thus, for the synthesis of substituted indoles
employing easily accessible o-bromobenzylketones 1 and primary
amines as the starting material pool. This approach would
complement the existing syntheses of both N-alkyl and N-aryl
indoles, and in particular, a range of diversely 1,2-disubstituted
15 indoles,17 which are usually achieved through a functionalization
at the nitrogen atom of preformed NH-indoles. Furthermore, an
opportunity for three classes of five-membered benzo-fused
heterocycles to be prepared in an expeditious fashion using the
same preassembled precursors with slight modifications of the
20 reaction conditions would be of significant value for medicinal
chemistry.
60 by primary amines extremely slowly (which is probably
attributed to the steric congestion at the carbonyl group and/or
easy enolization of ketones 1) and a simple Brønsted acid (p-
TsOH) was not a suitable catalyst for the preparation of the
corresponding ketimines. Because our challenge lay in
65 developing a one-pot procedure to access substituted indoles, the
first step of our sequence must give the intermediate imines A
(Scheme 1) in reasonably high yields and proceed cleanly enough
for the next step to continue without isolation and purification of
intermediates. Therefore, we next focused our attention on the
70 use of titanium (IV) alkoxides22 as promoters for the reaction of
ketones 1 with primary amines. Titanium-based reagents are both
Lewis acids, which have a high affinity to oxygenated organic
molecules, and dehydrating reagents. The mild nature of titanium
(IV) alkoxides makes this type of reagents best suitable for our
75 needs and should provide a high degree of functional group
tolerance. The optimization of the indole synthesis was
performed on 0.5 mmol scale using a one-pot procedure (Table
1). A mixture of ketone 1a and p-anisidine as test substrates and 5
equiv of titanium (IV) alkoxides were initially heated to generate
80 the imine, then the reagents and solvent needed for the Ullmann
reaction were introduced and the cyclization step was carried out
under the same conditions as above. Using less than 5 equiv of
titanium (IV) alkoxides resulted in incomplete homogenization of
the reaction mixture even at an elevated temperature. At a
85 temperature below 140 °С, the reaction of ketone 1a with p-
anisidine in Ti(OiPr)4 did not take place and after subsequent
cyclization benzofuran 3a was obtained exclusively. Conducting
the first step at 140 °С led to the expected indole 2a (45%) along
with 2,3-dihydrobenzofuran 4a (15%) (entry 1). The formation of
90 the latter is probably due to the partial reduction of the starting
ketone 1a to the corresponding alcohol (Meerwein-Ponndorf-
Verley reaction)23 followed by a copper-catalyzed intramolecular
cyclization.24 Heating of ketone 1a with 10 equiv of Ti(OiPr)4
without adding p-anisidine after the following cyclization gave
95 dihydrobenzofuran 4a in 70% yield (entry 2). The use of titanium
(IV) tert-butoxide25 in place of Ti(OiPr)4 at 140 °С lead to the
desired indole 2a in 77% isolated yield with no trace of
benzofuran 3a (entry 3). However, reducing of the reaction
temperature and/or shortening of the reaction time in the first step
100 of the process resulted in a lower yield of indole 2a and the
formation of the undesired benzofuran 3a. Replacing DMF with
DMA in the cyclization step afforded a better yield of indole 2a
(85%, isolated, entry 4). Notably, when the scale was increased
from 0.5 to 2 mmol, the best yield of indole 2a (93%, entry 5)
105 was observed with using of 2 equiv of Ti(OtBu)4. Omitting DMA
under otherwise identical condition did not give the cyclization
product (entry 6). Attempts to reduce the requisite amount of
With this in mind we sought to extend the synthetic utility of
o-bromobenzylketones 1 to access substituted indoles 2 (Scheme
1). We aimed to develop a practical synthesis of indoles via a
25 one-pot, two-step process comprising the generation of imines
from ketones 1 and various primary amines and their subsequent
cyclization into indoles through an intramolecular N-arylation
reaction (Scheme 1). Given that imines A, though assembled
using other approaches, were explored in palladium-catalyzed
30 cyclizations before,14–16 we chose copper-catalyzed C–N coupling
conditions18 for the second step of our process. In recent years,
the field of copper-catalyzed reactions has seen a great number of
contributions and the intramolecular version of the Ullmann
coupling reaction has emerged as a powerful method for the
35 construction
of
various
heterocycles6a,d;19
including
indoles12,13,15e,20 through the formation of a carbon–heteroatom
bond.
Results and discussion
We began our study by examining p-anisidine and benzylamine
40 in the reactions with o-bromobenzylketones 1a and 1b
respectively in the presence of catalytic amount of p-
toluenesulfonic acid monohydrate in toluene at reflux in a Dean–
Stark apparatus containing 4Å molecular sieves for 20 h.21 The
crude mixtures obtained after removal of the solvent were used
45 without further purification in the cyclization step. In our initial
examination the Cu-catalyzed cyclization was carried out under
standard conditions (10 mol % of CuI, 2 equiv Cs2CO3, DMF,
100 °С, 10 h) previously reported by us for the synthesis of N-
substituted indole-3-carboxylates.12a,b To our surprise, no desired
50 indole 2a was formed when less nucleophilic p-anisidine was
utilized, while N-benzylindole 2b was obtained in only 9% yield
(based on 1H NMR) when benzylamine was employed in the
reaction with ketone 1b (Scheme 2). The major product in both
cases was identified as benzofurans 3a and 3b respectively
55 formed from o-bromobenzylketone 1a,b through a copper-
catalyzed intramolecular C–O-bond formation.9 Thus, our initial
experiments showed that ketones 1 undergo nucleophilic attack
2
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Ti(OtBu)4 from 5 to 2 equiv by partially replacing with o-xylene
or DMA were unsuccessful, as no desired product was obtained 20 optimal conditions for the formation of imines from ketone 1a
conducting the reaction at 140 °С for 10 h were selected as the
in both cases (entries 7 & 8). Titanium (IV) ethoxide as a
promoter for the in situ imine formation and other inorganic bases
(K2CO3, K3PO4) for the following cyclization step were also
examined, but in all cases the desired product 2a was obtained in
lower yield (entries 9–11).
and p-anisidine. We also found that the combination of DMA as
the solvent and Cs2CO3 as the base provided the highest yield of
indole 2a through the copper-catalyzed intramolecular cyclization
under ligandless conditions at 125 °С (Table 1, entry 4).
5
25
Table 1 Optimization of the one pot indole synthesis a
Fig. 1 o-Bromobenzyl ketones 1 used in the one-pot indole synthesis
The scope and limitations of this one-pot two-step method for
the preparation of substituted indoles (Table 2) was explored with
30
a
variety of aliphatic amines and anilines and 2-
bromobenzylketones 1a–i bearing different substituents (Fig. 1),
which were readily prepared using known methods. When the
more nucleophilic aliphatic amines were employed, the first step
of the process was performed at 60 °С. A series of primary
35 aliphatic amines with both primary and secondary alkyl groups
reacted smoothly to give the corresponding N-alkylated indoles
2b–2e, and 2g in good to high yields. A high yield of the desired
product 2h was also obtained when N,N-dimethylhydrazine was
used. However, steric effects of amines appeared to play a
40 significant role in the reaction efficiency, as exposing tert-
butylamine to the optimal reaction conditions lead only to the
formation of benzofuran 3a. Alternative reaction conditions,
namely, a prolonged heating of ketone 1a and Ti(OtBu)4 with a
large excess (~10 equiv) of tert-butylamine at 100 °С in a sealed
45 tube did not afford the desired indole 2f. Several substituted
anilines and 3-aminopyridine were found to react with ketones 1
to form N-arylated indoles in high yields. The process is tolerant
a range of aryl substituents such as methyl, methoxy, halogens,
trifluoromethyl, cyano, esters. Notably, we found that, besides
50 fluoro-, chloro-, bromo-substituted indoles, even iodo-compound
2k could be prepared in 67% yield if the cyclization step was
performed at lower temperature (90 °С) in the presence of 20 mol
% L-proline. Ortho-substituted anilines also reacted smoothly
affording the desired indoles 2j, 2l, 2p and 2r cleanly and usually
55 in high yields. In contrast, 2,4,6-trimethylaniline proved to be
more problematic substrate and gave under the optimal conditions
an inseparable mixture (~1:1) of indole 2o and benzofuran 3a. To
further examine the scope of the method o-bromobenzylketones
1f,g bearing a substituent at the benzylic position were employed
60 for the synthesis of 3-substituted indoles. While 3-methylindoles
2u and 2w were prepared in ~77% yield, 3-benzylindole 2v could
not be synthesized using this method; only the corresponding 2-
(4-methoxyphenyl)-3-benzylbenzofuran (3b) was isolated in the
latter case, presumably because the considerable steric hindrance
65 caused by the benzyl group disfavours the reaction of ketone 1g
with amines. On the contrary, ketone 1i bearing tert-butyl group
afforded the expected 2-tert-butylindole 2y without attenuation of
the yield.
T2, ⁰C
Entry Ti(OR)4,
equiv
Base
Solvent
Ligand Product(s):
yield, %b
1
2
3
4
Ti(OiPr)4; 5 Cs2CO3
Ti(OiPr)4; 10 Cs2CO3
Ti(OtBu)4; 5 Cs2CO3
Ti(OtBu)4; 5 Cs2CO3
DMF
DMF
DMF
DMA
DMA
none
125
125
125
125
125
125
125
125
125
125
125
90
2a: 45; 4a: 15
4a: (70)c
2a: 77
2a: (85)
2a: (93)
5d Ti(OtBu)4; 2 Cs2CO3
6
7
8
9
Ti(OtBu)4; 5 Cs2CO3
Ti(OtBu)4; 2 Cs2CO3 o-xylenee
Ti(OtBu)4; 2 Cs2CO3
Ti(OEt)4; 5 Cs2CO3
DMAe
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
2a: 50
2a:70
2a: 67
2a: 73
2a: 11
10 Ti(OtBu)4; 5 K2CO3
11 Ti(OtBu)4; 5 K3PO4
12 Ti(OtBu)4; 5 Cs2CO3
13 Ti(OtBu)4; 5 Cs2CO3
14 Ti(OtBu)4; 5 Cs2CO3
15 Ti(OtBu)4; 5 Cs2CO3
16 Ti(OtBu)4; 5 Cs2CO3
90
90
90
90
2a: (75)
L1
2a: 20
L2
2a: 26
L3
2a: 43
L4
a Reaction scale: 1a (0.5 mmol, 0.25 M); p-anisidine (0.65 mmol), base (1
b
mmol, 2 equiv), under argon. NMR yields determined using CH2Br2 as
an internal standard. Isolated yields are in parentheses. cWithout
ArNH2.dReaction scale: 1a (2 mmol, 0.25 M); p-anisidine (2.6 mmol)
base (4 mmol, 2 equiv). eAdded at the beginning of the two step reaction.
L1= L-proline. L2=ethylene glycol. L3=N,N´-dimethylethylenediamine.
L4=1,10-phenantroline.
10
We also screened the effect of several commonly employed
ligands on the copper-catalyzed cyclization reaction. We
anticipated that the using of a suitable ligand would permit the
cyclization to successfully proceed at lower temperature allowing
good functional group tolerance. Among all ligands tested, L-
15 proline gave a comparable yield of indole 2a (75%) at 90 °С
(entry 13), whereas ethylene glycol, DMEDA and 1,10-
phenantroline were much less effective (entries 14–16).
Based on the above studies, Ti(OtBu)4 as the promoter and
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a
Table 2 One pot synthesis of N-substituted indoles a
Reaction scale: 1a (0.5 mmol, 0.25 M); amine (0.65 mmol), base (1
mmol, 2 equiv), under argon. Isolated yields. bReaction scale: 1a (2
mmol, 0.25 M); p-anisidine (2.6 mmol) base (4 mmol, 2 equiv).c The 1st
5 step performed at 60 oC. For the conditions, see: Tab.1, entry 13.
d
eIsolated as an inseparable mixture (~1:1) with 3a. Ti(OEt)4 was used to
f
avoid transesterification.
Scheme 3 Synthesis of N-unsubstituted indoles
10
The electronic nature of the substituent in the phenyl rings
does not affect the efficiency of the method (2a and 2x).
Finally, we were interested whether our procedure for the
preparation of N-substituted indoles could be extended to the
synthesis of N-unsubstituted indoles by employing ammonia in
15 the first step of the process. We used a commercially available
solution of ammonia in MeOH (7 M) (7–10 equiv) and Ti(OiPr)4
for the preparation of the cyclization precursors. Unfortunately,
under standard reaction conditions for the copper-catalyzed
cyclization indoles 5a and 5b were obtained only in moderate
20 yields, whereas ketone 1f bearing benzyl group gave only trace
amounts of the target product 5c.
Conclusions
In summary, we have developed an effective one-pot procedure
for the synthesis of substituted indoles through a Ti-mediated
25 imine formation/Cu-catalyzed N-arylation sequence. The protocol
allows the preparation of 2-substituted indoles from o-
bromobenzylketones and ammonia, alkyl amines with 1⁰ and 2⁰
groups, and anilines, excluding 2,6-disubstituted, in good to high
overall yields without using expensive reagents and catalysts.
30 Due to the simplicity and versatility of the proposed method, we
believe it could be an attractive and highly practical alternative to
other protocols for the synthesis of indoles, especially those
bearing substituents at both the 1 and 2 positions.
Experimental
35 General Information. All commercially available chemicals
were used without purification. Solvents were purified using
standard procedures. Column chromatography was performed in
flash conditions using silica gel (0.040–0.063 mm). Analytical
thin-layer chromatography (TLC) was carried out on silica gel 60
1
40 F254 plates that were visualized by exposure to UV light. H and
13C NMR were recorded at 400MHz/100MHz for solutions in
CDCl3 or DMSO-d6. Chemical shifts are quoted in δ (ppm) and J
values are reported in Hz and referenced against residual proton
signals of the deuterated solvents. Mass-spectra were recorded by
45 EI mode at 70 eV. All reactions were run in inert atmosphere.
Yields refer to chromatographically and spectroscopically pure
4
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compounds and represent an average of at least two independent
7.22; N, 5.28. Found: C, 81.52; H, 7.28; N, 5.24.
runs. Melting points were determined in open capillaries and are 60 1-Cyclopropyl-2-(4-methoxyphenyl)-1H-indole
(2d):
uncorrected.
synthesized from ketone 1a (153 mg) and cyclopropylamine (40
mg); white solid; yield 68 % (90 mg); mp 114–116 °C. Н NMR
(CDCl3): δ 0.77–0.83 (m, 2Н), 1.04–1.10 (m, 2Н), 3.46–3.54 (m,
1Н), 3.96 (c, 3H), 6.61 (s, 1Н), 7.09 (d, J=8.8 Hz, 2H), 7.23–7.31
1
General Procedure for the Synthesis of Indoles 2. Indoles 2
(except for compound 2k) were synthesized according to the
following general procedure. An oven-dried screw-cap test tube
5
equipped with a Teflon-coated magnetic stir bar was charged 65 (m, 1Н), 7.36–7.39 (m, 1Н), 7.67 (d, J=8.8 Hz, 2H), 7.71–7.76
with a ketone 1 (0.5 mmol), an appropriate amine (0.65 mmol,
1.3 equiv) and Ti(OtBu)4 (965 µL, 2.5 mmol, 5 equiv). The tube
10 was evacuated and backfilled with argon (sequence was repeated
three times) and was placed into a preheated reaction block. After
(m, 2Н). 13C NMR (CDCl3): δ 8.8, 25.7, 55.0, 100.8, 110.6,
113.4, 119.6, 120.0, 121.0, 125.7, 127.5, 129.7, 138.4, 141.4,
158.8. MS, m/z (I, %): 263 (M+, 100), 248 (24). Anal. Calcd for
C18Н17NO: C, 82.10; H, 6.51; N, 5.32. Found: C, 82.16; H, 6.55;
stirring at 60 °C (for indoles 2c, 2d and 2h) or at 140 °C (for all 70 N, 5.27.
other indoles) for 10 h the reaction mixture was allowed to cool
to room temperature and Cs2CO3 (326 mg, 1 mmol, 2 equiv), CuI
15 (9.5 mg, 0.05 mmol, 10 mol %) and DMA (2 mL) were added.
The tube was then evacuated and backfilled with argon (sequence
1-Cyclohexyl-2-(4-methoxyphenyl)-1H-indole (2e): synthesized
from ketone 1a (153 mg) and cyclohexylamine (64 mg); white
1
solid; yield 89 % (136 mg); mp 146–148 °C. Н NMR (CDCl3):
δ 1.32–1.44 (m, 3Н), 1.75–1.85 (m, 1Н), 1.93–2.04 (m, 4Н),
was repeated three times) and was placed into a preheated 75 2.40–2.54 (m, 2Н), 3.96 (s, 3Н), 4.24–4.35 (m, 1Н), 6.52 (s, 1Н),
reaction block. After stirring at 125 °C for 10 h the mixture was
allowed to cool down and directly poured on top of a short silica
20 gel chromatography column. The crude product was eluted with a
mixture EtOAc/hexanes, 1:1. The residue after evaporation of the
7.08 (d, J=8.7 Hz, 2Н), 7.16–7.23 (m, 1Н), 7.24–7.29 (m, 1Н),
7.46 (d, J=8.7 Hz, 2Н), 7.69–7.79 (m, 2Н). 13C NMR (CDCl3): δ
25.7, 26.4, 31.6, 55.4, 56.4, 102.0, 112.7, 114.0, 119.4, 120.7,
120.8, 126.3, 129.1, 130.9, 135.8, 141.4, 159.0. MS, m/z (I, %):
solvent was purified by column chromatography on silica gel 80 305 (M+, 100), 223 (92), 208 (56), 55 (40). Anal. Calcd for
(EtOAc/hexanes, 1:10).
C21H23NO: C, 82.58; H, 7.59; N, 4.59. Found: C, 82.50; H, 7.52;
N, 4.64.
(R)-2-Phenyl-1-(1-phenylethyl)-1H-indole (2g): synthesized
from ketone 1a (153 mg) and R-(+)-1-phenylethylamine (79 mg);
1,2-bis(4-Methoxyphenyl)-1H-indole (2a): synthesized from
25 ketone 1a (153 mg) and p-anisidine (80 mg); yellow solid; yield
85 % (140 mg); mp 139–141 °C. (lit.26 mp 136–137 °C). 1Н
NMR (CDCl3): δ 3.81(s, 3Н), 3.88 (s, 3Н),6.73 (s, 1Н), 6.81 (d, 85 light-yellow solid; yield 88 % (144 mg); [α]25 = 44.5 °; mp 89–
D
1
2Н, J=8.8 Hz), 6.96 (d, 2Н, J=8.9 Hz), 7.14–7.25 (m, 7Н), 7.20–
7.65 (m, 1Н). 13C NMR (CDCl3): δ 55.2, 55.5, 102.2, 110.5,
30 113.7, 114.5, 120.2, 120.5, 121.9, 125.2, 128.2, 129.2, 130.2,
131.4, 139.2, 140.8, 158.5, 158.9. MS, m/z (I, %): 329 (M+, 56),
92 °C. Н NMR (CDCl3): δ 1.99 (d, J=7.0 Hz, 3Н), 5.91 (q,
J=6.9 Hz, 1Н), 6.72 (s, 1Н), 7.06–7.15 (m, 2Н), 7.16–7.23 (m,
1Н), 7.33–7.39 (m, 3Н), 7.39–7.46 (m, 2Н), 7.47–7.57 (m, 3Н),
7.59–7.66 (m, 2Н), 7.73–7.80 (m, 1Н). 13C NMR (CDCl3): δ
254(40), 242(56), 165 (48), 127 (72), 121 (80), 77 (48), 63 (96). 90 18.3, 53.1, 102.4, 112.7, 119.5, 120.4, 120.9, 125.9, 126.7, 127.8,
Anal. Calcd for C22H19NO2: C, 80.22; H, 5.81; N, 4.25. Found: %
C, 80.17; H, 5.87; N, 4.29. Indole 2a was also synthesized from
35 ketone 1a (610 mg, 2 mmol) and p-anisidine (321 mg,2.6 mmol)
following the general procedure and using Ti(OtBu)4 (1,54 mL,
2equiv) and DMA (8 mL) in 93 % (613 mg) yield.
128.3, 128.8, 129.1, 133.0, 135.5, 141.4, 141.7. MS, m/z (I, %):
297 (M+, 32), 193 (98), 105 (84). Anal. Calcd for C22H19N: C,
88.85; H, 6.44; N, 4.71. Found: C, 88.89; H, 6.39; N, 4.66.
N,N-Dimethyl-2-phenyl-1H-indol-1-amine (2h): synthesized
95 from ketone 1e (137 mg) and N,N-dimethylhydrazine (40 mg);
white solid; yield 83 % (100 mg); mp 115–116 °C. 1Н NMR
(CDCl3): δ 3.24 (s, 6Н), 6.65 (s, 1Н), 7.25–7.31 (m, 1Н), 7.32–
7.37 (m, 1Н), 7.46–7.52 (m, 1Н), 7.54–7.60 (m, 2Н), 7.72–7.80
(m, 2Н), 7.81–7.86 (m, 2Н). 13C NMR (CDCl3): δ 44.5, 99.3,
1-Benzyl-2-(3,4-dimethoxyphenyl)-1H-indole (2b): synthesized
from ketone 1b (168 mg) and benzylamine (70 mg); white solid;
1
40 yield 78 % (135 mg); mp 132–134 °C. Н NMR (CDCl3): δ 3.60
(s, 3H), 3.93 (s, 3H), 5.39 (s, 2H), 6.66 (s, 1H), 6.84–6.94 (m,
2H), 7.03–7.34 (m, 9H), 7.66–7.77 (m, 1H). 13C NMR (CDCl3): δ 100 111.2, 119.7, 121.0, 126.9, 127.2, 127.7, 128.7, 132.4, 134.5,
47.7, 55.5, 55.9, 101.7, 110.3, 111.2, 112.3, 120.3, 120.4, 121.7,
121.8, 125.3, 125.9, 127.2, 128.3, 128.8, 138.0, 138.6, 141.8,
45 148.7, 149.0. MS, m/z (I, %): 343 (M+,100), 252 (92), 237 (40),
192 (40), 166 (47), 139 (48), 91 (88), 65 (84). Anal. Calcd for
140.2. MS, m/z (I, %): 236 (M+, 24), 165 (44), 132 (98). Anal.
Calcd for C16H16N2: C, 81.32; H, 6.82; N, 11.85.Found C, 81.28;
H, 6.77; N, 11.94.
1-(4-Chlorophenyl)-2-(4-methoxyphenyl)-1H-indole
(2i):
C23H21NO2: C, 80.44; H, 6.16; N, 4.08. Found: C, 80.39; H, 6.24; 105 synthesized from ketone 1a (153 mg) and 4-chloroaniline (83
1
N, 4.00.
mg); yellow solid; yield 75 % (125 mg); mp 134–1 36 °C. Н
NMR (CDCl3): δ 3.82 (s, 3H), 6.75 (s, 1H), 6.83 (d, 2Н, J=8.8
Hz), 7.18–7.27 (m, 7H), 7.41 (d, 2Н, J=8.8 Hz), 7.67–7.70 (m,
1H). 13C NMR (CDCl3): δ 55.3, 103.3, 110.3, 113.8, 120.5,
2-(4-Methoxyphenyl)l-1-propyl-1H-indole (2c): synthesized
50 from ketone 1a (153 mg) and propylamine (40 mg); white solid;
yield 60 % (80 mg); mp 80–81 °C. Н NMR (CDCl3): δ 0.88 (t,
1
J=7.6 Hz, 3H), 1.82 (sextet, J=7.6 Hz, 2H), 3.95 (s, 3H), 4.15– 110 120.9, 122.3, 124.7, 128.5, 129.3, 129.5, 130.2, 132.8, 137.2,
4.20 (m, 2H), 6.58 (s, 1H), 7.09 (d, J=8.8 Hz, 2Н), 7.20–7.26 (m,
1H), 7.28–7.36 (m, 1H), 7.45–7.49 (m, 1H), 7.51 (d, J=8.8 Hz,
55 2Н), 7.73 (d, J=7.8 Hz, 1Н). 13C NMR (CDCl3): δ 11.0, 23.0,
45.2, 55.0, 101.2, 109.7, 113.6, 119.3, 120.0, 120.9, 125.4, 127.9,
138.6, 140.6, 159.1. MS, m/z (I, %): 333(M+, 100), 254 (56).
Anal. Calcd for C21H16ClNO: C, 75.56; H, 4.83; N, 4.20. Found:
C, 75.61; H, 4.78; N, 4.23.
1-(2-Bromophenyl)-2-(4-methoxyphenyl)-1H-indole
(2j):
130.3, 136.9, 140.9, 159.1. MS, m/z (I, %): 265 (M+, 100), 236 115 synthesized from ketone 1a (153 mg) and 2-bromoaniline (112
(90), 205 (25), 41 (35). Anal. Calcd for C18H19NO: C, 81.48; H,
mg); light-brown solid; yield 90 % (170 mg); mp 150–153 °C. 1Н
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NMR (CDCl3): δ 3.86 (s, 3Н), 6.87–6.92 (m, 3Н), 7.06–7.11 (m,
NMR (CDCl3): δ 3.84 (s, 3Н), 6.74 (s, 1Н), 6.86 (d, J=8.8 Hz,
1Н), 7.28–7.48 (m, 7Н), 7.79–7.85 (m, 2Н). 13C NMR (CDCl3): δ 60 2Н), 6.96–7.04 (m, 2Н), 7.15 (d, J=8.7 Hz, 2Н), 7.21 (d, J=8.9
54.9, 102.2, 110.5, 113.4, 114.0, 120.1, 120.4, 121.8, 123.8,
124.6, 128.1, 129.4, 129.5, 131.1, 133.4, 137.9, 138.3, 140.8,
158.8. MS, m/z (I, %): 379, 377 (M+, 100, 100), 298 (24), 283
(40), 254 (100), 127 (56). Anal. Calcd for C21H16BrNO: C, 66.68;
H, 4.26; N, 3.70.Found: C, 66.63; H, 4.32; N, 3.74.
Hz, 2Н), 7.57–7.64 (m, 3Н). 13C NMR (CDCl3): δ 54.8, 96.6 (JC-
F=26.8 Hz), 102.7, 109.1 (JC-F=24.5 Hz), 113.5, 120.7, 120.8 (JC-
F=10.0 Hz), 124.0, 124.5, 129.0, 129.7 (2S), 132.2, 137.0, 138.3
(JC-F=12.7 Hz), 140.6 (JC-F=3.8 Hz), 158.8, 159.5 (JC-F=239 Hz).
65 MS, m/z (I, %): 397, 395 (M+, 71, 75), 272 (98), 136 (32), 84
(36). Anal. Calcd for C21H15BrFNO: C, 63.65; H, 3.82; N, 4.79.
Found: C, 63.69; H, 3.74; N, 4.76.
5
2-(4-Methoxyphenyl)-1-[2-(trifluoromethyl)phenyl]-1H-indole
(2l): synthesized from ketone 1a (153 mg) and 2-
10 (trifluoromethyl)aniline (81 mg); yellow oil; yield 85 % (156
mg). Н NMR (CDCl3): δ 3.77 (s, 3Н), 6.78 (d, J=8.9 Hz, 2Н),
1-(2-Methoxyphenyl)-2-phenyl-1H-indole (2r): synthesized
from ketone 1e (137 mg) and o-anisidine (80 mg); colourless oil;
1
6.80 (c, 1Н), 6.87–6.91 (m, 1Н), 7.13–7.20 (m, 2Н), 7.23 (d, 70 yield 86 % (129 mg). 1Н NMR (CDCl3): δ 3.54 (s, 3Н), 6.82 (s,
J=8.8 Hz, 2H), 7.36 (m, 1Н), 7.57–7.61 (m, 1Н), 7.63–7.67 (m,
1Н), 7.67–7.70 (m, 1Н), 7.83–7.85 (m, 1Н). 13C NMR (CDCl3): δ
15 54.7, 102.5, 110.4, 113.3, 119.8, 120.2, 121.6, 122.4 (JC-F=274
Hz), 124.5, 127.3 (JC-F=5 Hz), 127.8, 128.5, 129.3, 130.5 (JC-
1Н), 6.97–7.07 (m, 2Н), 7.09–7.13 (m, 1Н), 7.15–7.20 (m, 2Н),
7.23–7.34 (m, 6Н), 7.36–7.41 (m, 1Н), 7.67–7.72 (m, 1Н). 13C
NMR (CDCl3): δ 55.1, 102.3, 110.5, 112.2, 120.1, 120.2, 120.6,
121.8, 126.9, 127.7, 127.8, 127.9, 128.1, 129.0, 129.8, 132.9,
F=33 Hz), 132.2, 132.5, 136.6, 140.0, 141.4, 158.6. MS, m/z (I, 75 138.8, 141.3, 155.3. MS, m/z (I, %): 299 (M+, 100), 127 (32), 77
%): 367 (M+, 100), 352 (96), 283 (30), 254 (99), 184 (99), 142
(80), 127 (97), 75 (30), 63 (30). Anal. Cacld for C22H16F3NO: C,
20 71.93; H, 4.39; N, 3.81.Found: C, 71.99; H, 4.35; N, 3.86.
(24), 51 (24). Anal. Calcd for C21H17NO: C, 84.25; H, 5.72; N,
4.68. Found: C, 84.21; H, 5.78; N, 4.65.
5-Methoxy-2-(4-methoxyphenyl)-1-(4-methylphenyl)-1H-
indole (2s): synthesized from ketone 1c (168 mg) and p-anisidine
3-[2-(4-Methoxyphenyl)-1H-indol-1-yl]benzonitrile
(2m):
synthesized from ketone 1a (153 mg) and 3-aminobenzonitrile 80 (80 mg); light-yellow oil; yield 88 % (158 mg). 1Н NMR
1
(77 mg); white solid; yield 89 % (144 mg); mp 200–203 °C. Н
NMR (CDCl3): δ 3.84 (s, 3H), 6.79 (s, 1H), 6.85 (d, J=8.8 Hz,
25 2Н), 7.17 (d, J=8.8 Hz, 2Н), 7.21–7.31 (m, 3H), 7.47–7.51 (m,
1H), 7.53–7.58 (m, 1H), 7.64–7.68 (m, 1H), 7.69–7.74 (m, 1H).
(CDCl3): δ 2.44 (s, 3H), 3.82 (s, 3H), 3.93 (s, 3Н), 6.70 (s, 1Н),
6.79–7.89 (m, 3Н), 7.14–7.29 (m, 8Н). 13C NMR (CDCl3): δ
21.2, 55.2, 56.0, 102.0, 102.3, 111.4, 112.0, 113.7, 125.3, 127.8,
128.7, 129.9, 130.1, 134.4, 136.2, 136.9, 141.2, 154.8, 158.9. MS,
13C NMR (CDCl3): δ 54.9, 103.8, 109.5, 113.1, 113.6, 117.6, 85 m/z (I, %): 343 (M+, 100), 328 (23), 300 (30), 91 (28). Anal.
120.3, 121.0, 122.3, 123.7, 128.2, 129.9, 130.2, 130.7, 132.1,
137.9, 139.3, 140.0, 159.0. MS, m/z (I, %): 324 (M+, 100), 309
30 (30), 279 (30). Anal. Calcd for C22H16N2O: C, 81.47; H, 4.97; N,
8.64. Found: C, 81.42; H, 4.98; N, 8.61.
Calcd for C23H21NO2: C, 80.44; H, 6.16; N, 4.08. Found: C,
80.38; H, 6.26; N, 4.10.
2-(3,4-Dimethoxyphenyl)-1-[3-(trifluoromethyl)phenyl]-1H-
indole (2t): synthesized from ketone 1b (168 mg) and 3-
4-[2-(4-Methoxyphenyl)-1H-indol-1-yl]benzonitrile
synthesized from ketone 1a (153 mg) and 3-aminobenzonitrile
(77 mg); white solid; yield 87 % (141 mg), mp 176–178 °C. Н
(2n): 90 (trifluoromethyl)aniline (81 mg); light-yellow solid; yield 77%
1
(153 mg); mp 144–146 °C. Н NMR (CDCl3): δ 3.69 (s, 3Н),
3.91 (s, 3Н), 6.73 (d, 2Н, J=1.9 Hz), 6.81–6.88 (m, 2Н), 6.93 (m,
1Н), 7.24–7.29 (m, 2Н), 7.30–7.35 (m, 1Н), 7.39–7.44 (m, 1Н),
7.56 (t, J=7.8 Hz, 1Н), 7.66–7.77 (m, 3Н). 13C NMR (CDCl3): δ
1
35 NMR (CDCl3): δ 3.86 (s, 3H), 6.82 (s, 1H), 6.88 (d, J=8.5 Hz,
2Н), 7.20 (d, J=8.6 Hz, 2Н), 7.22–7.31 (m, 2H), 7.32–7.41 (m,
3H), 7.67–7.78 (m, 3H). 13C NMR (CDCl3): δ 55.3, 104.7, 110.1, 95 55.2, 55.4, 103.3, 109.7, 110.8, 111.8, 120.2, 120.8, 121.3, 122.2,
110.4, 114.1, 118.4, 120.8, 121.6, 122.8, 124.3, 128.4, 128.9,
130.3, 133.3, 138.1, 140.3, 142.7, 159.4. MS, m/z (I, %): 324
40 (M+, 100), 309 (30), 279 (30). Anal. Calcd for C22H16N2O: C,
81.46; H, 4.97; N, 8.64. Found: C, 81.49; H, 4.92; N, 8.60.
123.1 (JC-F= 272.6 Hz), 123.4 (JC-F=3.5 Hz), 124.2, 124.4 (JC-
F=3.8 Hz), 128.2, 129.6, 131.2, 131.4 (JC-F= 33.0 Hz), 138.2,
139.1, 140.2, 148.2, 148.4. MS, m/z (I, %): 397 (M+,100) 322
(15), 241 (15). Anal. Calcd for C23H18F3NO2: C, 69.52; H, 4.57;
Ethyl 2-[2-(4-methoxyphenyl)-1H-indol-1-yl]benzoate (2p): 100 N, 3.52 Found: C, 69.56; H, 4.52; N, 3.56.
synthesised following the general procedure from ketone 1a (153
mg) and ethyl 2-aminobenzoate (83 mg) using Ti(OEt)4 (525 µL,
45 2.5 mmol, 5 equiv) instead of Ti(OtBu)4; light-yellow solid; yield
1,2-bis(4-Methoxyphenyl)-3-methyl-1H-indole
synthesized from ketone 1f (160 mg) and p-anisidine (80 mg);
yellow solid; yield 78 % (134 mg); mp 158–160 °С. Н NMR
(CDCl3): δ 2.41 (s, 3H), 3.82 (s, 3H), 3.84 (s, 3H), 6.85 (d, J=8.8
(2u):
1
1
58 % (108 mg); mp 139–141°C. Н NMR (CDCl3): δ 0.79 (m,
3H), 3.81 (s, 3H), 3.88–4.00 (m, 2H), 6.78 (s, 1H), 6.81 (d, J=8.9 105 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 7.12 (d, J=9.0 Hz, 2H), 7.16 (d,
Hz, 2H), 7.04–7.09 (m, 1H), 7.13–7.20 (m, 2H), 7.25 (d, J=8.9
Hz, 2H), 7.31–7.34 (m, 1H), 7.47–7.54 (m, 1H), 7.56–7.62 (m,
50 1H), 7.68–7.72 (m, 1H), 7.98–8.04 (m, 1Н). 13C NMR (CDCl3): δ
13.0, 54.7, 60.8, 102.0, 109.6, 113.3, 119.8, 120.0, 121.6, 124.5,
J=8.8 Hz, 2H), 7.18–7.28 (m, 3H), 7.63–7.70 (m, 1H). 13C NMR
(CDCl3): δ 9.7, 55.2, 55.4, 109.6, 110.3, 113.5, 114.3, 118.7,
119.9, 122.1, 124.5, 128.9, 129.1, 131.6, 131.8, 137.1, 137.9,
158.1, 158.7. MS, m/z (I, %): 343 (М+, 100), 107 (18). Anal.
127.5, 128.0, 129.6, 130.2, 130.5, 130.8, 132.2, 137.5, 138.7, 110 Calcd for C23H21NO2: C, 80.44; H, 6.16; N, 4.08. Found: C,
140.6, 158.6, 165.7. MS, m/z (I, %): 371 (M+, 100), 298 (30), 254
(32). Anal. Calcd for C24H21NO3: C, 77.61; H, 5.70; N, 3.77.
55 Found: C, 77.65; H, 5.65; N, 3.75.
80.40; H, 6.22; N, 4.11.
2-(4-Methoxyphenyl)-3-methyl-1-pyridin-3-yl-1H-indole (2w):
synthesized from ketone 1f (160 mg) and 3-aminopyridine (61
mg); yellow solid; yield 77 % (121 mg); mp 168–170°С. 1Н
1-(4-Bromophenyl)-6-fluoro-2-(4-methoxyphenyl)-1H-indole
(2q): synthesized from ketone 1d (162 mg) and 3-bromoaniline 115 NMR (CDCl3): δ 2.43 (s, 3H), 3.82 (s, 3H), 6.87 (d, J=8.8 Hz,
(112 mg); light-yellow amorphous solid; yield 74 % (147 mg). 1Н
2H), 7.15 (d, J=9.0 Hz, 2H), 7.23–7.36 (m, 4H), 7.46–7.52 (m,
6
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1H), 7.18–7.28 (m, 1H), 8.51–8.59 (m, 2H). 13C NMR (CDCl3): δ
9.5, 55.2, 109.8, 111.3, 113.9, 119.0, 120.7, 122.8, 123.7, 129.5, 60 times. The mixture was stirred at 140 °C for 10 h. Then the
evacuated and backfilled with argon; sequence was repeated three
131.9, 134.9, 136.6, 137.4, 147.5, 148.9, 150.0. MS, m/z (I, %):
314 (М+, 100), 269 (19), 255 (15), 207 (28). Found, %: C, 80.27;
H, 5.82; N, 8.95. C21H18N2O. Calculated, %: C, 80.23; H, 5.77;
N, 8.91.
reaction mixture was cooled to room temperature and Cs2CO3
(326 mg, 1 mmol, 2 equiv) and CuI (9.5 mg, 0,05 mmol, 10 mol
%), and DMA (4 ml) were added. The tube was evacuated and
backfilled with argon; sequence was repeated three times. The
65 resulting mixture was stirred at 125 C° for 10 h. The mixture was
allowed to cool to room temperature, DMA was removed under
reduced pressure and the residue was purified by column
chromatography (EtOAc/hexanes, 1:5) to afford 80 mg (70 %) of
5
2-(2-Fluorophenyl)-1-(4-methylphenyl)-1H-pyrrolo[2,3-
c]pyridine (2x): synthesized from ketone 1h (147 mg) and p-
1
anisidine (80 mg); yellow oil, yield 83 % (132 mg). Н NMR
10 (CDCl3): δ 2.39 (s, 3H), 6.81 (s, 1H), 7.03 (m, 1H), 7.09 (m, 1H),
7.14 (d, J=8.3 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 7.25–7.29 (m,
1
4a as white solid; mp 65–66 °C. (lit.29 mp 51–52 °C) Н NMR
1H), 7.29–7.34 (m, 1H), 7.59 (m, 1H), 8.29–8.38 (br. s, 1H), 70 (CDCl3): δ 3.21 (dd, J=15.3, 8,2 Hz, 1Н), 3.57 (dd, J=15.5, 9.4
8.65–8.78 (br. s, 1H). 13C NMR (CDCl3): δ 24.1, 107.2, 117.8,
118.9 (JC-F=21.9 Hz), 122.7 (JC-F=14.9 Hz), 126.9 (JC-F=3.0 Hz)
15 129.9, 132.9, 133.5 (JC-F=8.2 Hz), 134.9, 135.6, 136.9, 137.4,
140.7, 141.0, 142.4, 162.7 (JC-F=250.3 Hz). MS, m/z (I, %): 302
Hz, 1Н), 3.80 (c, 3Н), 5.70 (t, J=9.2 Hz, Н), 6.82–6.93 (m, 4Н),
7.11–7.21 (m, 2Н), 7.33 (d, J=8.6 Hz, 2Н). MS, m/z (I, %): 226
(M+, 100), 211(25), 165 (38).
Synthesis of NH-Indoles 5. An oven-dried screw-cap test tube
(М+, 100), 180 (20), 157 (25), 143 (30). Anal. Calcd for 75 equipped with a Teflon-coated magnetic stir bar was charged
C20H15FN2: C, 79.45; H, 5.00; N, 9.27. Found: C, 79.51; H, 5.07;
N, 9.35.
with ketone 1 (0.5 mmol) and Ti(OiPr)4 (740 µL, 2.5 mmol, 5
equiv). To the ice-cooled resulting suspension NH3–MeOH (714
µL, 5 mmol, 10 equiv, 7N) was added slowly via syringe. The
resulting mixture was stirred at 50 °C for 10 h, after which time
20 2-tert-Butyl-1-(4-methoxyphenyl)-1H-pyrrolo[2,3-c]pyridine
(2y): synthesized from ketone 1i (128 mg) and p-anisidine (80
mg); yellow solid; yield 85 % (119 mg); mp 149–151 °C. 1Н 80 reaction mixture was allowed to cool to room temperature and
NMR (CDCl3): δ 1.29 (s, 9H), 3.92 (s, 3H), 6.46 (s, 1H), 7.03 (d,
J=8.9 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.45 (d, J=5.5 Hz, 1H),
25 8.00–8.12 (br. s, 1H), 8.18–8.28 (br. s, 1H). 13C NMR (CDCl3): δ
33.7, 36.4, 58.5, 101.5, 116.9, 117.2, 134.1, 134.2, 134.5, 136.2,
MeOH was distilled off under reduced pressure. DMA (2mL),
Cs2CO3 (326 mg, 1 mmol, 2 equiv), CuI (9.5 mg, 10 mol %) were
added to the residue. The tube was evacuated and backfilled with
argon (sequence was repeated three times) and was placed into a
142.0, 157.5, 162.8. MS, m/z (I, %): 280 (М+, 72), 265 (100), 250 85 preheated reaction block. After stirring at 100 °C for 10 h the
(20), 219 (30). Anal. Calcd for C18H20N2O: C, 77.11; H, 7.19; N,
9.99. Found: C, 77.15; H, 7.30; N, 9.95.
30 1-(4-Iodophenyl)-2-(4-methoxyphenyl)-1H-indole (2k). An
oven-dried screw-cap test tube equipped with a Teflon-coated
mixture was allowed to cool to room temperature, DMA was
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel (EtOAc/hexanes, 1:5).
2-(4-Methoxyphenyl)-1H-indole (5a):28 synthesized from
magnetic stir bar was charged with ketone 1a (153 mg, 0.5 90 ketone 1a (153 mg); yellow solid; yield 61% (68 mg); mp 225–
1
mmol), 4-iodoaniline (142 mg, 0.65 mmol) and Ti(OtBu)4 (965
µL, 2.5 mmol, 5 equiv). The tube was evacuated and backfilled
35 with argon (sequence was repeated three times) and was placed
into a preheated reaction block. After stirring at 140 °C for 10 h
227 °C. (lit.29 mp 227–231 °C). NMR Н (DMSO-d6): δ 3.81 (s,
3H), 6.76 (d, J=1.4 Hz, 1H), 6.96–7.12 (m, 4H), 7.41 (d, J=8.2
Hz, 1H), 7.81 (d, J=8.9 Hz, 2H),11.40–11.46 (br. s, 1H). 13C
NMR (DMSO-d6): δ 60.0, 102.1, 115.9, 119.1, 124.0, 124.5,
the reaction mixture was allowed to cool to room temperature and 95 125.8, 129.7, 131.2, 133.7, 141.7, 142.6, 163.6.
Cs2CO3 (326 mg, 1 mmol, 2 equiv), CuI (9.5 mg, 0.05 mmol, 10
mol %), L-proline (11.5 mg, 0.1 mmol, 20 mol %), and DMA (2
40 mL) were added. The tube was evacuated and backfilled with
argon (sequence was repeated three times) and was placed into a
2-Phenyl-1H-indole (5b):28 synthesized from ketone 1b (137
mg); yellow solid; yield 57% (55 mg); mp 186–188 °C. (lit.29 mp
1
186–189 °C). Н NMR (DMSO-d6): δ 6.88 (d, J=1.6 Hz, 1H),
7.00 (t, J=7.0 Hz, 1H), 7.11 (t, J=7.0 Hz, 1H), 7.30 (t, J=7.4 Hz,
preheated reaction block (90 °C). After stirring at this 100 1H), 7.41–7.46 (m, 3H), 7.54 (d, J=7.8 Hz, 1H), 7.87 (d, J=8.4
temperature for 10 h, the reaction mixture was allowed to cool to
room temperature. DMA was evaporated under reduced pressure.
45 The residue was purified by column chromatography on silica gel
(EtOAc/hexanes, 1:10). Yield 67 % (142 mg); light-brown solid;
Hz, 2H). 11.51–11.54 (br. s, 1H). 13C NMR (DMSO-d6): δ 102.0,
114.7, 122.7, 123.4, 124.9, 128.3, 130.7, 131.6, 132.2, 135.6,
140.5, 141.0.
1
mp 110–115 °C. Н NMR (CDCl3): δ 3.83 (s, 3Н), 6.74 (s, 1Н),
6.84 (d, J=8.7 Hz, 2Н), 7.02 (d, J=8.5 Hz, 2Н), 7.15–7.24 (m,
4Н), 7.26–7.32 (m, 1H), 7.64–7.32 (m, 1H), 7.75 (d, J=8.4 Hz,
50 2Н). 13C NMR (CDCl3): δ 54.9, 91.7, 103.0, 109.9, 113.4, 120.1,
120.5, 121.9, 124.3, 128.1, 129.4, 129.8, 138.0, 140.1, 158.7. MS,
m/z (I, %): 425 (M+, 70), 298 (22), 254 (95), 127 (40). Anal.
Calcd for C21H16INO: C, 59.31; H, 3.79; N, 3.29. Found: C,
59.37; H, 3.72; N, 3.23.
105 Notes and references
Department of Chemistry, Moscow State University, Moscow 119992,
Russia. Fax: +7 495 932 8846; Tel: +7 495 932 5376; E-mail:
karchava@org.chem.msu.ru
† Electronic Supplementary Information (ESI) available: Experimental
110 procedures, analitical and spectral characterization data for starting
materials; additional optimization data and copies of 1H and 13C NMR
spectra for all new compounds.
‡ Present address: Department of Chemistry, University of Illinois at
Chicago, 845 W. Taylor St., Chicago, IL, 60607 USA. E-mail:
115 fmelkon@uic.edu
55 2-(4-Methoxyphenyl)-2,3-dihydro-1-benzofuran (4a).27 An
oven-dried screw-cap test tube equipped with a Teflon-coated
magnetic stir bar was charged with ketone 1a (152 mg, 0.5 mmol)
and Ti(OiPr)4 (1450 µL, 5 mmol, 10 equiv). The tube was
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