Novel synthetic method of 2-(2-oxoethyl)-1 H -indole-3-carbaldehydes

Article abstract of DOI:10.1055/s-0030-1260317

The smooth and regioselective synthesis of 2-(2-oxo-ethyl)-1H-indole-3- carbaldehydes via silver-catalyzed 6-endo-dig acetalization-cyclization reaction followed by immediate hydrolysis of the unstable 1-alkoxypyrano[4,3-b]indole intermediates is describe

Full text of DOI:10.1055/s-0030-1260317

LETTER
2529
Novel Synthetic Method of 2-(2-Oxoethyl)-1H-indole-3-carbaldehydes
S
ynthesisof 2-(2
i
t
H
a
-indole-3-carbald
B
e
hydes uksnaitiene, Inga Cikotiene*
Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, 03225 Vilnius, Lithuania
Fax +370(5)2330987; E-mail: inga.cikotiene@chf.vu.lt
Received 8 June 2011
hydes with alcohols in the presence of transition-metal
catalysts or electrophilic initiators proceed to give 6-endo-
dig cyclization products, the corresponding alkoxypyr-
anes.
Abstract: The smooth and regioselective synthesis of 2-(2-oxo-
ethyl)-1H-indole-3-carbaldehydes via silver-catalyzed 6-endo-dig
acetalization–cyclization reaction followed by immediate hydroly-
sis of the unstable 1-alkoxypyrano[4,3-b]indole intermediates is de-
scribed.
Encouraged by literature precedent and our previous re-
sults, we envisaged that cycloisomerization of all aromat-
ic and heteroaromatic compounds, bearing a triple bond
and an aldehyde moiety in close proximity to each other
would always lead to the 5-exo-dig and/or 6-endo-dig
acetalization–cyclization. However, to our surprise, we
observed the formation of different products during reac-
tions of 2-alkynylindole-3-carbaldehydes, so herein we
wish to report on these unexpected results.
Key words: 2-alkynyl-1H-indole-3-carbaldehydes, 2-(2-oxoethyl)-
1H-indole-3-carbaldehydes, acetalization, hydrolysis
Aromatic or heteroaromatic aldehydes bearing the triple
bond in close proximity to a carbonyl group are versatile
building blocks in organic synthesis for the preparation of
various carbo- and heterocyclic compounds.1 A variety of
synthetic methodologies for the creation of new dihydro-
furane and dihydropyrane rings has been developed, start-
ing from o-alkynylbenzaldehydes via tandem
acetalization–cyclization reactions (Scheme 1). Since the
pioneering work of Yamamoto,2 a variety of transition-
metal-catalyzed,3 base-,4 or electrophile-induced5 5-exo-
dig and/or 6-endo-dig acetalization–cyclization processes
of o-alkynylbenzaldehydes and their heterocyclic ana-
logues has been described.
The starting compounds 1 were synthesized by the well-
known Sonogashira reaction7 from 2-bromo-1H-indole-3-
carbaldehydes. It should be noted that 2-phenylethynyl-
1H-indole-3-carbaldehyde (1a) treated with sodium or
potassium methoxide in methanol did not undergo acetal-
ization–cyclization reactions. This result can be explained
by the fact that the triple bond is electron-rich due to the
neighboring electron-donating indole ring, so tandem cy-
clization becomes impossible. However, no changes of
the starting material were observed by TLC when we used
a catalytic amount of silver nitrate or trifluoroacetate as a
catalyst under the same reaction conditions: boiling meth-
anol and basic medium (1 equiv of sodium or potassium
methoxide). On the other hand, the reaction of 1a with
methanol only in the presence of AgNO3 or AgCF3CO2
proceeded smoothly, and formation of one major product
was observed by TLC. We were intrigued that the NMR,
IR, and microanalysis data of the isolated product did not
correspond to any of the expected structures – (3Z)-3-ben-
zylidene-3,4-dihydro-1-methoxy-1H-furo[3,4-b]indole
(3a) or 1,5-dihydro-1-methoxy-3-phenylpyrano[4,3-b]
indole (4a). The analytical data showed that during the re-
action of the starting compound with methanol in the pres-
ence of silver salts 2-(2-oxo-2-phenylethyl)-1H-indole-3-
carbaldehyde (2a) was formed as the sole product
(Scheme 2). The same reaction result was obtained from
heating of a solution of 1a in 1,2-dichloroethane in the
presence of 2 equivalents of methanol and 5 mol% of
AgCF3CO2 in a microwave oven for 15 minutes.
OR2
O
OR2
R2OH
O
O
and/
or
cat. or E+
R1
R1
R1
H(E)
(E)H
Scheme 1 Literature results overview
Recently, we have developed a novel, concise, and regio-
selective synthetic method for constructing 5,7-dihydro-
furo[3,4-d]pyrimidine and 5H-pyrano[4,3-d]pyrimidine
frameworks via acetalization–cyclization reactions of 2,4-
disubstituted
6-phenylethynylpyrimidine-5-carbalde-
hydes.6 We have also demonstrated the influence of the
substituent at the 4-position of the pyrimidine ring on sub-
strate reactivity and regioselectivity of the reaction.
Overall, from the literature results and our previous stud-
ies, it is possible to conclude that base-catalyzed transfor-
mations of aromatic or heteroaromatic aldehydes having
an o-alkynyl substituent with alcohols lead mainly to 5-
exo-dig cyclization, for example, to the formation of the
furan ring. On the other hand, reactions of acetylenic alde-
Thus, we decided to perform a more detailed study of the
reactions of 2-phenylethynyl-1H-indole-3-carbaldehyde
(1a) with alcohols. It should be noted that in all successful
cases 2-(2-oxo-2-phenylethyl)-1H-indole-3-carbaldehyde
(2a) was formed, and no formation of 5-exo-dig or 6-
endo-dig cyclization reaction products was observed. The
results are summarized in Table 1.
SYNLETT 2011, No. 17, pp 2529–2532
x
x
.x
x
.2
0
1
1
Advanced online publication: 19.09.2011
DOI: 10.1055/s-0030-1260317; Art ID: D17411ST
© Georg Thieme Verlag Stuttgart · New York

2530
R. Buksnaitiene, I. Cikotiene
LETTER
O
O
is also suitable for the synthesis of 2a (Table 1, entry 12).
On the other hand, absence of alcohol inhibited the reac-
tion, so it can be concluded that direct addition of water to
the triple bond of the starting compound does not take
place (Table 1, entry 13).
i or ii
N
N
H
Ph
H
Ph
O
1a
3a
2a
Me
Encouraged by these results we decided to perform the
synthesis of a range of 2-(2-oxoethyl)-1H-indole-3-carb-
aldehydes 2. The results are summarized in Table 2. It is
noteworthy, that the nature of the alkynyl substituent nor-
mally does not have a strong influence on the result of the
reaction. In the case of 2-arylethynyl-1H-indole-3-carbal-
dehydes and 2-alkynyl-1H-indole-3-carbaldehydes, the
formation of the dicarbonyl compounds took place
(Table 2, entries 1, 2, and 5–7). However, when the sub-
stituent on the alkynyl moiety contains a basic pyridine-
type nitrogen (compounds 1c,d, Table 2, entries 3 and 4)
no changes of the starting materials were observed under
the reaction conditions. This ‘nitrogen-effect’ can be ex-
plained by complexation of the pyridine moiety with sil-
ver ion or by the pyridine substituent acting as a base and
inhibiting the process. In the case of 2-trimethylsilylethy-
nyl-1H-indole-3-carbaldehyde (1h) and 2-ethynyl-1H-
indole-3-carbaldehyde (1g), the formation of the same
product 2-(2,2-dimethoxyethyl)-1H-indole-3-carbalde-
hyde (2h) was observed (Table 2, entries 8 and 9). Proba-
bly, the expected reaction product 3-formyl-1H-indole-2-
acetaldehyde reacted with methanol to give the dimethyl
acetal.
Me
O
O
O
O
Ph
N
N
Ph
H
H
4a
not observed
Scheme 2 Reagents and conditions: i) MeOH, AgCF3CO2 (5
mol%), reflux, 2 h; ii) MeOH (2 equiv), AgCF3CO2 (5 mol%), DCE,
MW, 600 W, 15 min.
After the unsuccessful experiments with methanol in ba-
sic medium (Table 1, entries 1–3), it was noted that the
use of 2 equivalents of methanol, silver trifluoroacetate (5
mol%) in dichloroethane, and the heating of the reaction
mixture in a sealed tube in a domestic microwave oven
gave the best result (Table 1, entry 5). While use of silver
nitrate or ethanol provided a slightly lower yield of the de-
sired product 2a (Table 1, entries 6, 9), conventional heat-
ing of the reaction mixture in methanol, as well as the use
of catalytic amounts of CuI and Cu(OTf)2, proved to be far
less effective (Table 1, entries 4, 7–8). The formation of
2a was slower, and the conversion was not complete when
1-propanol or 1-butanol were used (Table 1, entries 10,
11). However, the use of a catalytic amount of methanol
In Scheme 3 the possible mechanism of formation of 2-(2-
oxoethyl)-1H-indole-3-carbaldehydes 2 is depicted. We
Table 1 Reaction Conditions for the Synthesis of 2-(2-Oxo-2-phenylethyl)-1H-indole-3-carbaldehyde (2a) from 2-Phenylethynyl-1H-indole-
3-carbaldehyde (1a)
Entry
1
Reaction conditions
Time
12 h
Conv. (%)
0a
Yield of 2a (%)
MeOH, reflux
0
0
2
MeOH, NaOMe (1 equiv), reflux
12 h
0a
3
MeOH, KOMe (1 equiv), reflux
12 h
0a
0
3
MeOH, KOMe (1 equiv), AgCF3CO2 (5 mol%), reflux
MeOH, AgCF3CO2 (5 mol%), reflux
12 h
0a
0
4
3 h
75
43
84
71
23
44
70
62
52
80
0
5
MeOH, AgCF3CO2 (5 mol%), DCE, MW, 600 W
MeOH, AgNO3 (5 mol%), DCE, MW, 600 W
MeOH, CuI (10 mol%), DCE, MW, 600 W
MeOH, Cu(OTf)2 (10 mol%), DCE, MW, 600 W
EtOH, AgCF3CO2 (5 mol%), DCE, MW, 600 W
PrOH, AgCF3CO2 (5 mol%), DCE, MW, 600 W
BuOH, AgCF3CO2 (5 mol%), DCE, MW, 600 W
MeOH (10 mol%), AgCF3CO2 (5 mol%), DCE, MW, 600 W
H2O, AgCF3CO2 (5 mol%), DCE, MW, 600 W
15 min
20 min
40 min
40 min
20 min
35 min
45 min
20 min
1 h
100
100
50
6
7
8
80
9
100
80
10
11
12
13
70
100
0a
a Starting material 1a was isolated.
Synlett 2011, No. 17, 2529–2532 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-(2-Oxoethyl)-1H-indole-3-carbaldehydes
2531
Table 2 Synthesis of 2-(2-Oxoethyl)-1H-indole-3-carbaldehydes 28
Entry
Starting material
Product
Yield (%)
O
O
N
R1
N
R1
R2
R2
O
1
2
1
2
3
4
5
6
7
1a R1 = H, R2 = Ph
2a R1 = H, R2 = Ph
2b R1 = H, R2 = 4-EtC6H4
–
84
1b R1 = H, R2 = 4-EtC6H4
1c R1 = H, R2 = 2-pyridyl
1d R1 = Bn, R2 = 2-pyridyl
1e R1 = H, R2 = n-Bu
77
n.r.a
n.r.a
66
–
2e R1 = H, R2 = n-Bu
2f R1 = Bn, R2 = t-Bu
2g R1 = Bn, R2 = c-Pr
1f R1 = Bn, R2 = t-Bu
67
1g R1 = Bn, R2 = c-Pr
76
O
8
9
1h R1 = H, R2 = TMS
1k R1 = R2 = H
48
78
N
H
O
O
2h
2h
a The starting material was isolated after the workup of the reaction mixture.
propose that, after the complexation of the metal with the dimethoxy-2-phenylethynylbenzene (8), after heating in
triple bond, intramolecular 6-endo-dig cyclization reac- the microwave oven with 2 equivalents of methanol in
tion takes place. The intermediate 1,5-dihydro-1-methoxy- DCE in the presence of AgCF3CO2, formed 4,5-
pyrano[4,3-b]indole 4 should be unstable due to the dimethoxy-2-(2-oxo-2-phenylethyl)benzene (9) in 89%
electron-donating indole ring and therefore undergo yield (Scheme 5). So it is possible to conclude that the
smooth hydrolytic cleavage with traces of water leading to stability of the intramolecular acetalization 6-endo-dig
the formation of final dicarbonyl compounds 2.
cyclization products strongly depends on the electron den-
sity of the 2-alkoxy-2H-pyrane moiety.
In comparison, it should be noted that 2-phenylethynyl-3-
quinolinecarbaldehyde (5), with an electron-withdrawing In conclusion, we have presented a short and efficient syn-
quinoline core, under the same reaction conditions thesis of 2-(2-oxoethyl)-1H-indole-3-carbaldehydes via a
[MeOH (2 equiv), AgCF3CO2 (5 mol%), DCE, MW, 600 tandem 6-endo-dig cyclization process followed by
W, 15 min] formed 1-methoxy-3-phenyl-1H-pyrano[4,3- smooth hydrolysis. Taking into account that 1,5-dicarbo-
b]quinoline (6) in 95% yield. The latter compound is rel- nyl compounds can be used as useful intermediates in or-
atively stable and underwent hydrolytic pyran ring open- ganic synthesis, this method can be used for preparation of
ing only after prolonged heating of 6 in aqueous acid. The various important precursors.
product of hydrolysis 2-[(Z)-2-hydroxy-2-phenylethe-
nyl]-3-quinolinecarboxaldehyde (7) can be obtained by
direct addition of water to the electron-poor triple bond of
the starting 2-phenylethynyl-3-quinolinecarbaldehyde (5,
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.9
Scheme 4). On the other hand, electron-rich 4,5-
MeOH
O
6-endo-dig
O
O
cyclization
hydrolysis
MeOH
O
R2
N
R1
1
N
R1
R2
N
R1
R2
O
Ag
2
4
Scheme 3 Possible mechanism of formation of 2-(2-oxoethyl)-1H-indole-3-carbaldehydes 2
Synlett 2011, No. 17, 2529–2532 © Thieme Stuttgart · New York

2532
R. Buksnaitiene, I. Cikotiene
LETTER
(5) (a) Yue, D.; Della Ca, N.; Larock, R. C. Org. Lett. 2004, 6,
1581. (b) Yue, D.; Della Ca, N.; Larock, R. C. J. Org. Chem.
2005, 70, 3381. (c) Barluenga, J.; Vazquez-Villa, H.;
Ballesteros, A.; Gonzalez, J. M. J. Am. Chem. Soc. 2003,
125, 9028. (d) Yue, D.; Della Ca, N.; Larock, R. C. J. Org.
Chem. 2006, 71, 3381.
OMe
O
i
O
Ph
N
N
Ph
6
5
(6) (a) Cikotiene, I.; Morkunas, M.; Motiejaitis, D.; Rudys, S.;
Brukstus, A. Synlett 2008, 1693. (b) Cikotiene, I.;
Buksnaitiene, R.; Rudys, S.; Morkunas, M.; Motiejaitis, D.
Tetrahedron 2010, 66, 251.
ii
iii
O
O
(7) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
N
N
1975, 16, 4467.
(8) Typical Procedure for the Synthesis of 2-(2-Oxoethyl)-
1H-indole-3-carbaldehydes 2
O
Ph
HO
Ph
7
A solution of the requisite 2-alkynyl-1H-indole-3-
carbaldehyde 1 (0.3 mmol), MeOH (0.0192 g, 0.6 mmol),
AgCF3CO2 (3.3 mg, 0.015 mmol) in DCE (3 mL) was
irradiated in a closed 15 mL vessel in domestic microwave
oven (model DAEWOO KOR6305A) at 600 W for 10–15
min. After heating, the solution was cooled to r.t., filtered
through a silica gel pad, the solvent evaporated, and the solid
residue purified by column chromatography to give 2a–h.
Typical analytical data are given for compounds 2a,f,h.
2-(2-Oxo-2-phenylethyl)-1H-indole-3-carbaldehyde (2a)
Yield 84%; mp 156 °C. IR (KBr): nmax = 3313 (NH), 1680,
1645 (C=O) cm–1. 1H NMR (300 MHz, CDCl3): d = 5.02 (2
H, s, CH2CO), 7.30–7.34 (2 H, m, ArH), 7.45–7.47 (1 H, m,
ArH), 7.53–7.59 (2 H, m, ArH), 7.65–7.70 (1 H, m, ArH),
8.14–8.17 (3 H, m, ArH), 10.20 (1 H, br s, NH), 10.41 (1 H,
s, CHO) ppm. 13C NMR (75 Hz, CDCl3): d = 34.9, 111.6,
119.1, 122.6, 123.5, 126.4, 128.6, 128.8, 128.9, 129.1,
134.3, 135.2, 135.8, 184.7, 196.7 ppm. Anal. Calcd for
C17H13NO2: C, 77.55; H, 4.98; N, 5.32. Found: C, 77.62; H,
5.03; N, 5.18.
Scheme 4 Reagents and conditions: i) MeOH (2 equiv), AgCF3CO2
(5 mol%), DCE, MW, 600 W, 15 min; ii) HCl, H2O, reflux, 8 h; iii)
H2O, dioxane, AgCF3CO2 (5 mol%), reflux, 1 h.
O
O
O
O
i
O
O
Ph
O
Ph
8
9
Scheme 5 Reagents and conditions: i) MeOH (2 equiv), AgCF3CO2
(5 mol%), DCE, MW, 600 W, 15 min.
Acknowledgment
We thank Lithuanian Research Council for the financial support
(Global Grant No. VP1-3.1-MM-07-K-01-002).
1-Benzyl-2-(3,3-dimethyl-2-oxobutyl)-1H-indole-3-
carbaldehyde (2f)
References
Yield 67%; mp 131–131.5 °C. IR (KBr): nmax = 1709, 1651
(C=O) cm–1. 1H NMR (300 MHz, CDCl3): d = 1.28 [9 H, s,
C(CH3)3], 4.44 (2 H, s, CH2CO), 5.35 (2 H, s, NCH2), 6.99–
7.03 (2 H, m, ArH), 7.30–7.34 (6 H, m, ArH), 8.19–8.22 (1
H, m, ArH), 10.25 (1 H, s, CHO) ppm. 13C NMR (75 Hz,
CDCl3): d = 26.4, 33.8, 44.8, 47.1, 110.3, 114.7, 119.5,
122.9, 123.5, 125.9, 126.5, 127.9, 129.1, 135.7, 137.0,
143.1, 184.1, 209.9 ppm. Anal. Calcd for C22H23NO2: C,
79.25; H, 6.95; N, 4.20. Found: C, 79.40; H, 7.02; N, 4.33.
2-(2,2-Dimethoxyethyl)-1H-indole-3-carbaldehyde (2h)
Yield 78%(from 1k); mp 145–146 °C. IR (KBr):
(1) (a) Modern Acetylene Chemistry; Stang, P. J.; Diederich, F.,
Eds.; VCH: Weinheim, 1995. (b) Chemistry of Triple-
Bonded Functional Groups; Patai, S., Ed.; Wiley: New
York, 1994.
(2) (a) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y.
J. Am. Chem. Soc. 2002, 124, 764. (b) Nakamura, H.;
Ohtaka, M.; Yamamoto, Y. Tetrahedron Lett. 2002, 7631.
(3) (a) Patil, N. T.; Yamamoto, Y. J. Org. Chem. 2004, 69,
5193. (b) Godet, T.; Vaxelaire, C.; Michel, C.; Milet, A.;
Belmont, P. Chem. Eur. J. 2007, 13, 5632. (c) Liu, L.-P.;
Hammond, G. B. Org. Lett. 2010, 12, 4640. (d) Yu, X.;
Ding, Q.; Wang, W.; Wu, J. Tetrahedron Lett. 2008, 49,
4390. (e) Parker, E.; Leconte, N.; Godet, T.; Belmont, P.
Chem. Commun. 2011, 47, 343.
(4) (a) Godet, T.; Bosson, J.; Belmont, P. Synlett 2005, 2786.
(b) Kanazawa, C.; Ito, A.; Terada, M. Synlett 2009, 638.
(c) Dell’Acqua, M.; Facoetti, D.; Abbiati, G.; Rossi, E.
Synthesis 2010, 2367. (d) Wei, L.-L.; Wei, L.-M.; Pan,
W.-B.; Wu, M.-J. Synlett 2004, 1497. (e) Dell’Acqua, M.;
Facoetti, D.; Abbiati, G.; Rossi, E. Tetrahedron 2011, 67,
1552.
n
max = 3185 (NH), 1628 (C=O) cm–1. 1H NMR (300 MHz,
CDCl3): d = 3.47 (2 H, d, J = 4.8 Hz, CH2CH),3.48 [6 H, s,
CH(OCH3)2], 4.71 [1 H, t, J = 4.8 Hz, CH(OCH3)2], 7.27–
7.30 (2 H, m, ArH), 7.40–7.43 (1 H, m, ArH), 8.25–8.28 (1
H, m, ArH), 9.57 (1 H, br s, NH), 10.23 (1 H, s, CHO) ppm.
13C NMR (75 Hz, CDCl3): d = 29.9, 54.4, 103.5, 111.2,
114.9, 120.6, 122.6, 123.5, 125.8, 135.2, 145.1, 184.5 ppm.
Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00.
Found: C, 67.00; H, 6.38; N, 6.05.
(9) The Supporting Information contains experimental
procedures and characterization data for compounds 1a–k,
2b,e,g, 5–9.
Synlett 2011, No. 17, 2529–2532 © Thieme Stuttgart · New York

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