Heteroannulation of arynes with N-aryl-α-aminoketones for the synthesis of unsymmetrical N-aryl-2,3-disubstituted indoles: An aryne twist of Bischler-Moehlau indole synthesis

Article abstract of DOI:10.1039/c3cc46361c

Reaction of 2-(trimethylsilyl)aryl triflates 1 with N-aryl-α-amino ketones 2 afforded N-aryl-2,3-disubstituted indoles in good to excellent yields with complete control of the substitution patterns. This methodology allowed for the first time a one-step s

Full text of DOI:10.1039/c3cc46361c

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ARTICLE TYPE
Heteroannulation of Arynes with N-Aryl-α-Aminoketones for the
Synthesis of Unsymmetrical N-Aryl-2,3-Disubstituted Indoles: An Aryne
Twist of Bischler-Möhlau Indole Synthesis
Ala Bunescu,a Cyril Piemontesi,a Qian Wanga and Jieping Zhu*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
addition, it could provide a valuable solution to a one-step
synthesis of unsymmetrical 2,3-dialkyl (non-methyl) substituted
35 indoles, a longstanding and challenging problem in the field of
indole synthesis.11
Reaction of 2-(trimethylsilyl)aryl triflates 1 with N-aryl-α-
amino ketones 2 afforded N-aryl-2,3-disubstituted indoles in
good to excellent yields with complete control of the
10 substitution patterns. This methodology allowed for the first
time one-step synthesis of unsymmetric 2,3-dialkyl
Table 1 Optimizations of reaction conditionsa
a
substituted indoles in a regiospecific manner.
Me
OTf
Me
O
Table 1
N-arylindoles are present in a large number of biologically and
medicinally relevant compounds with proven utilities in
15 pharmacology, agrochemistry and material science.1 Despite a
large number of existing methodologies that have been developed
over the past century,2 methods allowing direct access to N-
arylindoles3 remain scarce.
+
Me
N
TMS PhHN
Me
Ph
3a
1a
2a
Entry
Additive
Solvent
T (°C)
Yielde
1
2
3
4
5
6
7
8
9
--
--
--
--
--
CH3CN
EtCN
n-PrCN
i-PrCN
t-BuCN
i-PrCN/DCE (1/4) rt
i-PrCN rt
i-PrCN/DCE (1/4) rt
65
65
65
65
65
50
61
58
62
eq 1: Benzyne twist of Bischler-Möhlau Indole Synthesis
R2
HN
B
O
R2
3
4a
7a
C(7a)-N(1)
C(4a)-C(3)
OTf
R1
FG
A
44
R1
FG'
+
A
18-C-6b
18-C-6b
18-C-6b,c
(72)f
(52)f
(65)f
71(75)f
FG
N
bonds formation
TMS
B
18-C-6b, Cs2CO3 i-PrCN/DCE (1/4) rt
d
FG'
1
2
3
a
40 All reactions were carried out under Ar using 2a (1.0 equiv), 1a (1.4
equiv), CsF (3.0 equiv), solvent (c 0.14 M); b 1.1 equiv of 18-C-6; c KF
R2
3
eq 2: Bischler-Möhlau Indole Synthesis
4a
(3.0 equiv) was used as fluoride source; d 2.0 equiv of Cs2CO3; Isolated
e
FG
yield; Yield in parenthesis is calculated based on 1H NMR spectrum
f
C(2)-N(1)
C(4a)-C(3)
R2
Br
O
R1
2
N
using CH2Br2 as an internal standard; DCE = 1,2-dichloroethane.
FG
+
H
+
bonds formation
R1
NH2
R1
FG
45
We began our investigation using 2-(trimethylsilyl)phenyl triflate
(1a)12 and 3-(phenylamino)butan-2-one (2a) as test substrates for
evaluating reaction conditions (Table 1). Performing the reaction
in acetonitrile at 65 °C in the presence of CsF afforded the
50 desired indole 3a in 50% yield accompanied by a significant
amount of 3aa (32%) and 3ab (9%, Scheme 2). Mechanistically,
nucleophilic addition of amine 2a to the in situ generated benzyne
A would lead to intermediate B from which, three different
reactions could take place leading to the observed products.
55 Indole 3a resulted from the cyclization of B followed by
dehydration of 3-hydroxyindoline C as we expected (pathway a).
Aniline 3aa could be produced by an intramolecular proton
transfer of intermediate B (pathway b).13 This pathway, a side
reaction to be avoided in our case, has been elegantly exploited
60 for the synthesis of functionalized anilines.14 The formation of
R2
N
H
20
Scheme 1 Reaction of arynes with N-aryl-α-aminoketones to N-
arylindoles
As a continuation of our research program aiming at developing
efficient syntheses of indoles4 and indole-containing natural
25 products,5 we became interested in developing a one-step
synthesis of N-arylindoles by a new benzannulation reaction
between arynes,6,7 generated in situ from 2-(trimethylsilyl)aryl
triflates 1, and N-aryl-α-aminoketones 2 (Scheme 1, eq 1).8,9 The
advantage of the present transformation is that it should allow the
30 regiospecific synthesis of 2,3-disubstituted indoles in contrast to
the classic Bischler-Möhlau reaction, which inevitably afforded a
mixture of two regioisomeric indoles (Scheme 1, eq 2).10 In
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3ab was less evident and we assumed that it might go through the
intermediate D resulting from the nucleophilic addition of tertiary
amine C onto the benzyne A. Intramolecular proton transfer 45 without scrambling of the R1 and R2 substituents. To the best of
k). Most importantly, the unsymmetrical 2,3-dialkyl (non-methyl)
substituted indoles (3m – 3r) can be synthesized in good yields
View Article Online
DOI: 10.1039/C3CC46361C
followed by β-elimination would then afford 3ab (pathway c)15
To channel the reaction into the pathway a, an extensive survey
of reaction conditions was carried out varying the fluoride
sources (CsF, KF, TBAF), the solvents, the temperature, the
reaction time, the bases, and the additives. Some representative
results are presented in Table 1. Addition of crown ether enabled
our knowledge, this represented the first examples of one-step
synthesis of this type of indoles with complete control of
regiochemistry.17
5
Table 2 Reaction Scopea
R
R1
Me
10 the annulation to be realized at room temperature that effectively
suppressed the formation of side product 3ab. Overall, the
optimized conditions consisted of performing the reaction in a
solvent mixture (isopropionitrile/dichloroethane = 1/4) in the
presence of CsF (3.0 equiv), Cs2CO3 (2.0 equiv) and 18-C-6 (1.1
15 equiv) at room temperature (entry 9).16 Under these conditions,
the indole 3a was formed together with a variable amount of N-
phenyl-2,3-dimethyl-3-hydroxy indoline C (Scheme 2). However,
the latter readily underwent dehydration upon purification on
silica gel column chromatography to provide indole 3a in 71%
20 overall yield.
R
R1
Me
N
N
R
3b, R = p-NO2, 21% (47%)b
3c, R = p-OMe, 63%
3d, R = o-OMe, 67%
3e, R = o-Me, 75%
3t, R = Me, R1 = Ph, 68%
3u, R = OCH2O, R1 = Ph, 73%
3v, R = OMe, R1 = Ph, 68%
3w, R = F, R1 = Me, 57%
Ph
3f, R = o-Br, 80%
R
3g, R = 2, 6-dimethyl, 87%
R2
nPr
Me
N
O
R1
N
Me
N
N
3aa
3a
Ph
Ph
3x/3x' (~ 1.5 /1)
pathway
a
-H2O
OH
pathway b
R = 4-Me/7-Me, 74%d
3h, R1 = Et, R2 = Ph, 78%
3i, R1 = nPr, R2 = Ph, 81%
3j, R1= iPr, R2 = Ph, 86%
3k, R1 = Ph, R2 = Ph, 90%
3l, R1 = Ph, R2 = Bn, 83%
3m, R1 = Et, R2= nPr, 76%
3n, R1 = nPr, R2 = nBu, 69%
3o, R1 = iPr, R2 = Et, 81%
3p, R1 = iPr, R2 = cPr, 83%
3q, R1 = iBu, R2 = homoallyl, 85%
3r/3r' (~10/1), R1 = iBu
Me
Me
Me
O
-
R
2a
R1
+
A
N
Me
N
Me
N
Ph
H
Ph
C
B
+A
pathway c
Me
HO Me
OH
3y/3y' (~ 1/1)
R = 5-OMe/6-OMe, 66%d
H
+
N
-
OMe
NPh2
R
Ph
R2 = (E)/(Z)-(prop-1-en-1-yl), 79%c
Me
D
3ab
Me
Me
N
Scheme 2 Possible reaction pathways leading to 3a, 3aa and 3ab.
Me
N
Me
Me
The generality of this reaction was subsequently explored by
varying electronic and steric properties of both 1 and 2 under the
25 optimal conditions. Since the dehydration of 3-hydroxyindoline C
was not spontaneous in some cases, the crude annulation product
was first treated with silica gel in MeOH/CH2Cl2/AcOH (1/1/1,
40 °C) before purification. The results are summarized in Table 2.
The effect of N-aryl substituents was studied first (see 3b-g).
30 Strong (OMe) and weak (Me) electron donating groups were
tolerated in the ortho and para positions. The presence of an
ortho substituent in the N-aryl group had a positive effect on the
reaction outcome (3a vs 3e vs 3g). Weak electron withdrawing
group (Br, 3f) was well tolerated. However, strong electron-
35 withdrawing group (NO2) in para position reduced significantly
the reaction efficiency furnishing 3b in only 21% yield. The
reduced nucleophilicity of the p-nitroaniline could account for
this observation. Fortunately, by performing the reaction in EtCN
at 65 °C in the absence of 18-C-6, 3b can be isolated in 47%
40 yield. Variation of substituents at position 2 and 3 of indole was
next examined (3h-3r). It was noticed that the efficiency of the
reaction increased as the size of the R1 substituent increased (3h-
Me
Me
3z/3z' (~ 3.1 /1)
R = H/3-OMe-Ph, 70%e
3s, 65%
a
50 All reactions were carried out under Ar using N-aryl-α-aminoketone 2
(0.21 mmol, 1.0 equiv), 1 (0.29 mmol, 1.4 equiv), CsF (0.63 mmol, 3.0
equiv), Cs2CO3 (0.42 mmol, 2.0 equiv), 18-C-6 (0.23 mmol, 1.1 equiv), i-
PrCN/DCE (1/4) (1.5 mL,
c 0.14 M) at RT for 2-6 h then
MeOH/CH2Cl2/AcOH (1/1/1), silica gel, 40 °C; b EtCN (c 0.14 M), 65 °C;
c
d
55
the starting material was 2-methyl-5-(phenylamino)oct-7-en-4-one;
inseparable mixture; e the two compound were separated.
Finally, substituted 2-(trimethylsilyl)aryl triflates
examined. Electron rich and poor symmetric arynes all reacted
60 well with N-aryl α-aminoketones to furnish N-arylindoles in
moderate to good yields (3s-w). As expected, a mixture of two
regioisomers were produced (3x/3x’, 3y/3y’) when 3-methyl-2-
(trimethylsilyl)phenyl
(trimethylsilyl)phenyl triflate were used as aryne precursors.
65 However, a single regioisomer 3z was produced with 3-methoxy-
1
were
triflate,
and
4-methoxy-2-
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65
D. Pérez, E. Guitián, Angew. Chem. Int. Ed., 2006, 45, 3579-3581;
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3z (R = H) to benzyne in this case.
Bronner, A. E. Goetz, N. K. Garg, Synlett, 2011, 2599–2604; (e) S. S.
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70
75
5
Conclusions
In summary, we developed a novel heteroannulation reaction
between benzynes and N-aryl α-aminoketones for the synthesis of
N-aryl-2,3-disubstituted indoles 3 with a wide application scope.
The reaction allowed, for the first time, a one-step synthesis of
10 unsymmetrical 2,3-dialkyl (non methyl) substituted indoles with
complete control of regioseletivity.
We thank EPFL (Switzerland), Swiss National Science
Foundation (SNSF) and Swiss National Centres of Competence
in Research (NCCR) for financial supports
7
For recent selected examples: (a) A. E. Goetz, N. K. Garg, Nat.
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80
85
15 Notes and references
a Laboratory of Synthesis and Natural Products, Institute of Chemical
Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne,
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland). Fax:
+41 (0)21 693 97 40; Tel: +41 (0)21 693 97 42; E-mail:
20 jieping.zhu@epfl.ch
8
9
90
† Electronic Supplementary Information (ESI) available: Experimental
procedures and characterization data. See DOI: 10.1039/b000000x/
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35 3 Selected examples of N-arylindole synthesis: For N-arylation
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4
5
6
125
130 18 (a) H. Yoshida, H. Fukushima, T. Morishita, J. Ohshita, A. Kunai,
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135
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Scheme for TOC
View Article Online
DOI: 10.1039/C3CC46361C
R2
R2
O
OTf
CsF, Cs2CO3
R1
+
FG
FG
R1
i-PrCN/DCE (1/4)
18-C-6, RT
N
Ar
HN
TMS
Ar
1
2
3
5
A new indole synthesis was developed allowing preparation of
unsymmetrical 2,3-dialkyl substituted N-aryl indoles in one-step with
complete regio control.
4 | Journal Name, [year], [vol], 00–00
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