Regioselective and versatile synthesis of indoles via intramolecular Friedel-Crafts heteroannulation of enaminones

Article abstract of DOI:10.1055/s-2006-933135

A new approach is described for the synthesis of substituted indoles 5, through an intramolecular and regioselective Friedel-Crafts cyclization of enaminones 6a-h catalyzed by Lewis acids. Compounds 6 were prepared from the 2-anilinocarbonyl compounds 7, by treatment with DMFDMA under thermal or microwave (MW) irradiation conditions. An alternative and shorter one-pot two-step synthesis of indoles 5 was achieved starting from compounds 7 and promoted by MW radiation, including the elusive 2-acetylindoles 5i-m. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-933135

LETTER
749
Regioselective and Versatile Synthesis of Indoles via Intramolecular Friedel–
Crafts Heteroannulation of Enaminones
S
ynthesis of Indoles aría del Carmen Cruz,a,b Fabiola Jiménez,a Francisco Delgado,a Joaquín Tamariz*a
a
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional. Prol. Carpio y Plan de
Ayala, 11340 México, D.F., Mexico
b
Centro de Investigación en Biotecnología Aplicada, Instituto Politécnico Nacional. Km 15 Carretera Sta. Inés Tecuexcomac, Tepetitla,
90700 Tlaxcala, Mexico
Fax +52(55)53963503; E-mail: jtamariz@woodward.encb.ipn.mx
Received 21 December 2005
natural alkaloids6 as well as pharmacologically active
compounds,7 versatile synthons,8 and synthetic targets,9
we now report that this methodology provides a valuable
new route for the synthesis of this crucial framework.
Abstract: A new approach is described for the synthesis of substi-
tuted indoles 5, through an intramolecular and regioselective
Friedel–Crafts cyclization of enaminones 6a–h catalyzed by Lewis
acids. Compounds 6 were prepared from the 2-anilinocarbonyl
compounds 7, by treatment with DMFDMA under thermal or mi- Therefore, we decided to prepare 2-acyl- and 2-alkoxycar-
crowave (MW) irradiation conditions. An alternative and shorter
bonyl-indoles 5 by an intramolecular Friedel–Crafts het-
one-pot two-step synthesis of indoles 5 was achieved starting from
eroannulation of enaminones 6 (Scheme 2).
compounds 7 and promoted by MW radiation, including the elusive
2-acetylindoles 5i–m.
Me2N
Key words: indoles, enaminones, Friedel–Crafts annulations,
Lewis acid catalysis, microwaves
COR'
R
R
N
N
COR'
H
H
6, R' = Me, OMe, OEt
5, R' = Me, OMe, OEt
Enaminones have proved to be privileged Michael accep-
tors in the addition of a large variety of nucleophiles.1
Among the latter, activated aromatic rings have been effi-
cient in adding enaminones through a Friedel–Crafts reac-
tion.2 Recently, we reported a novel synthesis of 2-
methoxycarbonylbenzofurans 1 by an intramolecular
Friedel–Crafts cyclization of methyl 2-aryloxy-3-dimeth-
ylaminopropenoates 2, promoted by Lewis acid catalysis
(Scheme 1).3 The efficiency of this key synthetic step de-
pended on the presence of electron-donating groups in the
aromatic ring. Moreover, the conjugate addition in the
enaminone analogues 3-aryloxy-4-dimethylamino-3-
buten-2-ones 3, which was much faster than in substrates
2, led to the regioselective formation of 2-acylbenzo-
furans 4, which included some natural products of the ge-
nus Calea.4
Scheme 2
Although benzofurans 1 and 4 were prepared efficient-
ly,3,4 the benzene ring of precursors 2 and 3 needed strong
electron-donating groups R to achieve the cyclization
step. In the case of indoles 5, it was expected that the ami-
no group attached to the benzene ring in the precursor 6
would be a stronger activating group in the heteroannula-
tion process than the oxygen atom in the benzofuran
enaminones 2 and 3, due to the lower electronegativity
and higher polarizability of the nitrogen atom. Hence, we
evaluated the electron-demand of the aromatic ring re-
quired in this process. Consequently, we prepared the se-
ries of dimethylaminopropenoates 6b–h, whose aromatic
rings are substituted either by weak electron-donating
groups such as the methyl group (6b and 6c) or the chlo-
rine atom (6d and 6e), or by a stronger one such as the
methoxy groups (6f–h). The non-activated anilino deriva-
tive 6a was also examined.
Me2N
ZnCl2
CH2Cl2
COR'
R
R
O
O
COR'
Starting from anilines 8a–h, the preparation of the series
of compounds 6a–h was achieved in a two-step synthetic
sequence, via the corresponding a-anilino esters 7a–h
(Scheme 3). Thus, in the first step, the reaction of anilines
8a–e with methyl bromoacetate (9) took place smoothly in
the presence of K2CO3 in refluxing acetone for 12 hours,
to give compounds 7a–e in high yields (83–86%).10 Ethyl
esters 7f–h were obtained in similar yields (78–81%) by
reacting the respective anilines 8f–h with ethyl bromo-
acetate (10). This methodology was successfully extended
to the preparation of a-anilinoacetones 7i–o, carrying out
the reaction between anilines 8a,b,d–h and a-chloro-
acetone (11) to furnish the desired products 7i–o, respec-
2, R' = OMe
3, R' = Me
1, R' = OMe
4, R' = Me
Scheme 1
Encouraged by success in the synthesis of benzofurans,
we investigated the potential of this methodology in the
preparation of other heterocycles. Owing to the impor-
tance of indoles5 because of their widespread presence as
SYNLETT 2006, No. 5, pp 0749–0755
Advanced online publication: 09.03.2006
DOI: 10.1055/s-2006-933135; Art ID: S12505ST
© Georg Thieme Verlag Stuttgart · New York
1
7.
0
3.
2
0
0
6

750
M. C. Cruz et al.
LETTER
tively, in good yields (68–86%). In the second step, (Table 2, entries 2–5).12 This is in contrast with similar an-
compounds 7a–h were treated with N,N-dimethylform- alogues in the benzofuran series, whose corresponding
amide dimethyl acetal (DMFDMA) under thermal condi- aminopropenoates 2 and 3 were not reactive enough to
tions, to provide dimethylaminopropenoates 6a–h in good give the heterocyclic framework.3,4
yields (Table 1, entries 1–8).11 Interestingly, it was found
Therefore, and in agreement with the initial hypothesis, it
that microwave (MW) radiation could promote the same
appears that the electron-donating effect of the nitrogen
transformation with shorter reaction times, although the
atom on the aromatic ring in precursors 6a–e contributes
significantly to the reactivity of the cyclization process to
yields were slightly lower (Table 1, entries 9–16). In all
these products, the Z-configuration was found for the ste-
provide indoles 5. This is evident when we compare the
reochemistry of the double bond, as revealed by NOE ex-
reaction efficiency observed for the para-isomers 6c and
6e (Table 2, entries 2 and 4). Even though the methyl
group, or the chlorine atom, does not directly activate the
periments (an enhancement of the aromatic signals was
observed when the broad singlet attributed to the N,N-
dimethyl groups was irradiated). The E-isomer was not
ring-closure at the proper position, the cyclization pro-
1
observed from the H NMR analysis of the crude mix-
ceeds in fairly good yield. As opposed to the activation of
tures. The same stereoselectivity was found in the forma-
the aryl ring, the double bond might be deactivated by a
resonance effect from the lone pairs of the anilino nitro-
gen atom. The X-ray diffraction of compound 6a shows
tion of benzofuran precursors 2 and 3.3,4 A more efficient
resonance of the enaminone system in the Z- than in the E-
isomer might account for this preference.
that the anilino group is completely out of the plane of the
p
CC of the double bond (Figure 1).13 Consequently, the de-
Me2N
activating resonance effect between the lone pairs of the
nitrogen atom and the pCC of the double bond could be in-
hibited by a conformational restriction, and by a favorable
delocalization of the electronic density of the nitrogen
atom through the aryl ring. A similar behavior has been
observed for many analogous captodative olefins we have
studied.14
b
a
R
R
R
NH2
N
COR'
N
H
COR'
H
8
7, R' = OMe, OEt, Me
6, R' = OMe, OEt, Me
c
COR'
R
N
H
5, R' = OMe, OEt, Me
Scheme 3 Reagents and conditions: a) XCH2COR¢ (9, X = Br,
R¢ = OMe; 10, X = Br, R¢ = OEt; 11, X = Cl, R = Me), K2CO3, ace-
tone, 60 °C, 12 h; b) DMFDMA, 90 °C, 2–5 h, or DMFDMA, MW
(600 W), 100 °C, 10 min; c) AlCl3, CH2Cl2, 20 °C, 24 h, or ZnCl2,
CH2Cl2, 20 °C, 24 h.
Unlike enaminones 3, which were prepared in high yields
and found to be stable under the purification process (col-
umn chromatography over silica gel), anilino compounds
6i–o were found to be unstable during this process. Enam-
inones 6k–m were isolated in low yields, and character-
ized by spectroscopy (Table 1, entries 19–21), while the
remaining compounds of the series were only identified
by 1H NMR of the crude mixtures. For this reason, we de-
cided to use compounds 6i–o in the cyclization reaction
without previous purification (vide infra).
Figure 1 X-ray structure of 6a (ellipsoids with 30% probability).
In contrast with the efficient cyclization of 3-dimethyl-
aminopropenoates 6b–h to 2-alkoxycarbonylindoles 5b–
h, the preparation of 2-acetylindoles 5i–o was particularly
difficult, due to the partial or total decomposition of the
reaction mixtures of the in situ preparation of 4-dimethyl-
amino-3-buten-2-ones 6i–o when they were treated with
the Lewis acid (ZnCl2). Thus, under these conditions, only
indole 5k was obtained in a low yield (28%).
The heteroannulation of dimethylaminopropenoates 6a–h
to give the corresponding indoles 5a–h was assisted by
Lewis acid catalysis. The choice of the catalyst depended
on the substituents in the aromatic ring of the starting ma-
terials. For derivatives 6a–e, the best catalyst was AlCl3,
while ZnCl2 was more efficient for the precursors 6f–h,
which contain methoxy groups in the benzene ring
(Table 2, entries 1–8). Although the unsubstituted ana-
logue 6a provided the corresponding indole 5a in a low
yield under more severe reaction conditions, it is worth
noting that for derivatives 6b–e, whose aromatic ring is
substituted by fairly strong activating groups, the cycliza-
tion proceeded satisfactorily to give indoles 5b–e
As with benzofurans, we investigated the preparation of
indoles 5 by a one-step tandem reaction, starting from the
a-anilino acetic esters 7 with DMFDMA under thermal
conditions, followed by a Lewis acid-catalyzed cycliza-
tion promoted by MW radiation (Scheme 4). Unlike with
benzofurans, where the use of MW radiation provided low
yields of the heterocycles, in the case of the indoles the
Synlett 2006, No. 5, 749–755 © Thieme Stuttgart · New York

LETTER
Synthesis of Indoles
751
Table 1 Preparation of Enaminones 6 from Compounds 7a
Entry
1
7 [R]
R¢
Conditions
Thermal
Thermal
Thermal
Thermal
Thermal
Thermal
Thermal
Thermal
MWc
Temp (°C)
90
Time
5 h
6
Yield (%)b
7a [H]
OMe
OMe
OMe
OMe
OMe
OEt
OEt
OEt
OMe
OMe
OMe
OMe
OMe
OEt
OEt
OEt
Me
6a
6b
6c
6d
6e
6f
75
79
80
76
72
70
72
71
74
75
72
68
70
65
66
2
7b [3-Me]
7c [4-Me]
7d [3-Cl]
90
5 h
3
90
5 h
4
90
5 h
5
7e [4-Cl]
90
5 h
6
7f [3-OMe]
7g [3,4-(OMe)2]
7h [3,5-(OMe)2]
7a [H]
90
5 h
7
90
5 h
6g
6h
6a
6b
6c
6d
6e
6f
8
90
5 h
9
100
100
100
100
100
100
100
100
90
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
2 h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
7b [3-Me]
7c [4-Me]
7d [3-Cl]
MWc
MWc
MWc
7e [4-Cl]
MWc
7f [3-OMe]
7g [3,4-(OMe)2]
7h [3,5-(OMe)2]
7i [H]
MWc
MWc
6g
6h
6i
MWc
62
d
Thermal
Thermal
Thermal
Thermal
Thermal
Thermal
Thermal
d
7j [3-Me]
Me
90
2 h
6j
7k [3-Cl]
Me
90
2 h
6k
6l
28
40
7l [4-Cl]
Me
90
2 h
7m [3-OMe]
7n [3,4-(OMe)2]
7o [3,5-(OMe)2]
Me
90
2 h
6m
6n
6o
22
d
Me
90
2 h
d
Me
90
2 h
a In the presence of 1.5 mol equiv of DMFDMA for anilinoacetates 7a–h, and 1.1 mol equiv for anilinoketones 7i–o.
b After column chromatography and recrystallization.
c 600 W.
d Decomposition.
process was much more efficient, providing indoles mol equiv) in acetonitrile (20 mL), the desired indoles 5i
5b,d,f–h in fairly good yields (Table 2, entries 9–13). In and 5j were obtained in moderate yields (Table 2, entries
addition to the fact that the yields were slightly higher 14 and 15). Under these conditions, the preparation of in-
than the overall yields for the two-step process (i.e., acetic doles 5k–m was unsuccessful. It was found that by using
esters 7 to the isolated dimethylaminopropenoates 6, then ZnCl2 in CH2Cl2 (20 mL) and carrying out the reaction at
to the indoles 5; Table 1 and Table 2), the reaction time room temperature for 24 hours, the heterocycles were fur-
was significantly reduced. Interestingly, the methyl ester nished in moderate yields (Table 2, entries 16–18). We
of indole 5g has been previously used as an intermediate tried, albeit unsuccessfully, to improve the reaction by us-
in the total synthesis of natural b-carboline reharmine.15
ing MW radiation as done with the methoxycarbonyl in-
doles.
This one-pot two-step reaction procedure was also inves-
tigated to prepare the elusive indoles 5i–m (Scheme 4). The annulation reaction for enaminones 6b and 6d, whose
Thus, when a mixture of the respective compound 7j or 7k aryl rings are substituted in the meta-position, was not
and DMFDMA (1.1 mol equiv) was heated to 90 °C for completely regioselective, because a mixture of the corre-
five hours, followed by addition of anhydrous AlCl3 (3.0 sponding indoles 5b and 5d and their isomers 12a and 12b
Synlett 2006, No. 5, 749–755 © Thieme Stuttgart · New York

752
M. C. Cruz et al.
LETTER
In summary, a new synthesis of indoles has been devel-
oped, by taking advantage of the enaminones that undergo
conjugate nucleophilic addition. This regioselective
methodology provided functionalized indoles 5 that were
not only limited to the methoxy groups, as we previously
observed in the preparation of benzofurans. It was also es-
tablished that the amino group that bonds to the aromatic
ring significantly facilitates the heteroannulation of enam-
inones 6. An alternative method was also described by us-
ing MW radiation to promote the cascade process: the in
situ formation of intermediates 6 from the anilino com-
pounds 7 in the presence of DMFDMA, and their intramo-
lecular cyclization to indoles 5. This shortened the
synthetic pathway and the reaction times, and improved
the overall yields.
Me2N
a
R
R
N
COR'
N
H
COR'
H
7, R' = OMe, OEt, Me
6, R' = OMe, OEt, Me
R
COR'
N
H
5, R' = OMe, OEt, Me
Scheme 4 Reagents and conditions: for indoles 5b and 5d: a) i)
DMFDMA, 90 °C, 5 h; ii) AlCl3, toluene, MW (600 W), 120 °C, 10
min. For indoles 5f–h: a) i) DMFDMA, 90 °C, 5 h; ii) ZnCl2, toluene,
MW (600 W), 120 °C, 10 min. For indoles 5i and 5j: a) i) DMFDMA,
90 °C, 5 h; ii) AlCl3, CH3CN, 20 °C, 24 h. For indoles 5k–m: a) i)
DMFDMA, 90 °C, 5 h; ii) ZnCl2, CH2Cl2, 20 °C, 24 h.
Acknowledgement
were isolated (Scheme 5). A slightly lower regioselectiv-
ity was also found in the process of the intermediates 4-
dimethylamino-3-buten-2-ones 6j and 6k (formed in situ
from aniline ketones 7j and 7k, respectively), which pro-
vided a mixture of the corresponding indoles 5i and 5j and
their ortho-isomers 12c and 12d (Scheme 5). This is in
contrast with the highly regioselective cyclization of
enaminones 6f and 6g (also for the alternative route from
precursors 7f and 7g), which furnished the expected in-
doles 5f and 5g exclusively. A similar behavior was
shown for the transformation of anilinoketones 7m and 7n
into their corresponding indoles 5k and 5l, in which the
We are grateful to Dr. Hugo A. Jiménez-Vázquez for assisting with
the X-ray data collection. We thank Fernando Labarrios for his help
in spectrometric measurements. J.T. gratefully acknowledges Coor-
dinación General de Posgrado e Investigación del Instituto Politéc-
nico Nacional (Grants 20030147. 20040123, and 20050151), and
CONACYT (Grant 43508-Q) for financial support. C.C. and F.J.
thank CONACYT for graduate scholarships, and the Ludwig K.
Hellweg Foundation for a partial scholarship. J.T. and F.D. are fel-
lows of the EDI-IPN and COFAA-IPN programs.
References and Notes
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1
ortho-isomers 12 were not detected by H NMR in the
crude mixtures. This was rather surprising, since the anili-
no rings of enaminones 6f and 6g are much more activated
with the presence of methoxy groups, and, consequently,
a lower regioselectivity might be predicted. A steric repul-
sion may be involved between the meta-methoxy group of
the aryl ring and the bulky dimethylamino group attached
to the reaction center during the ortho approach to give
isomers 12. The methoxy group in the meta-position in
precursors 6f and 6g is relatively bulkier than the methyl
group in 6b and even more so than the chlorine atom in
6d. The lower proportion of the ortho-regioisomer 12c
with respect to isomer 12d might be in agreement with
such steric control.
Me2N
R
OMe
R
R
N
H
R'
O
R'
O
+
O
O
N
N
6b, R = Me
6d, R = Cl
R
H
H
5b, R = Me, R' = OMe 85:15 12a, R = Me, R' = OMe
5d, R = Cl, R' = OMe 80:20 12b, R = Cl, R' = OMe
5i, R = R' = Me
5j, R = Cl, R' = Me
78:22 12c, R = R' = Me
N
H
61:39 12d, R = Cl, R' = Me
7j, R = Me
7k, R = Cl
Scheme 5
Synlett 2006, No. 5, 749–755 © Thieme Stuttgart · New York

LETTER
Synthesis of Indoles
753
Table 2 Preparation of Indoles 5a–m from Compounds 6 and 7a
Entry
1
6 [R]
R¢
Conditions
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
ZnCl2
ZnCl2
ZnCl2
MWc
Solvent
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Toluene
Toluene
Toluene
Temp (°C)
80
Temp
5
Yield (%)b
14
6a [H]
OMe
OMe
OMe
OMe
OMe
OEt
OEt
OEt
OMe
OMe
OEt
OEt
OEt
Me
96 h
5a
5b
5c
5d
5e
5f
2
6b [3-Me]
20
24 h
76
3
6c [4-Me]
20
24 h
65
4
6d [3-Cl]
20
24 h
72
5
6e [4-Cl]
20
24 h
61
6
6f [3-OMe]
6g [3,4-(OMe)2]
6h [3,5-(OMe)2]
7b [3-Me]
20
24 h
68
7
20
24 h
5g
5h
5b
5d
5f
71
8
20
24 h
65
9
120
120
120
120
10 min
10 min
10 min
10 min
68
10
11
12
13
14
15
16
17
18
7d [3-Cl]
MWc
61
7f [3-OMe]
7g [3,4-(OMe)2]
7h [3,5-(OMe)2]
7j [3-Me]
MWd
60
MWd
5g
5h
5i
59
MWd
Toluene
120
10 min
63
AlCl3
32f
27g
29
e
e
e
e
e
e
h
h
h
e
h
h
h
e
h
h
h
7k [3-Cl]
Me
AlCl3
5j
h
7m [3-OMe]
7n [3,4-(OMe)2]
7o [3,5-(OMe)2]
Me
ZnCl2
5k
5l
h
Me
ZnCl2
32
h
Me
ZnCl2
5m
34
a In the presence of 3.0 mol equiv of Lewis acid. For the reactions starting from compounds 7b,d,f–h, 1.5 mol equiv of DMFDMA were used,
while for 7i–m, 1.1 mol equiv of DMFDMA were used.
b After column chromatography or recrystallization.
c i) DMFDMA, 90 °C, 5 h; ii) AlCl3, toluene, MW (600 W), 120 °C, 10 min.
d i) DMFDMA, 90 °C, 5 h; ii) ZnCl2, toluene, MW (600 W), 120 °C, 10 min.
e i) DMFDMA, 90 °C, 5 h; ii) AlCl3, MeCN, 20 °C, 24 h.
f An inseparable mixture of 5i/12a (78:22), as shown by 1H NMR and GCMS.
g An inseparable mixture of 5j/12b (61:39), as shown by 1H NMR and GCMS.
h i) DMFDMA, 90 °C, 5 h; ii) ZnCl2, CH2Cl2, 20 °C, 24 h.
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Perkin Trans. 1 2000, 1045. (b) Scott, T. L.; Söderberg, B.
C. G. Tetrahedron Lett. 2002, 43, 1621. (c) Witulski, B.;
Alayrac, C.; Tevzadze-Saeftel, L. Angew. Chem. Int. Ed.
2003, 42, 4257. (d) Walkington, A.; Gray, M.; Hossner, F.;
Kitteringham, J.; Voyle, M. Synth. Commun. 2003, 33,
(7) (a) Bunker, A. M.; Edmunds, J. J.; Berryman, K. A.; Walker,
D. M.; Flynn, M. A.; Welch, K. M.; Doherty, A. M. Bioorg.
Med. Chem. Lett. 1996, 6, 1061. (b) Sechi, M.; Derudas, M.;
Dallachio, R.; Dessi, A.; Bacchi, A.; Sannia, L.; Carta, F.;
Palomba, M.; Ragab, O.; Chan, C.; Shoemaker, R.; Sei, S.;
Dayam, R.; Neamati, N. J. Med. Chem. 2004, 47, 5298.
(c) Heinrich, T.; Böttcher, H. Bioorg. Med. Chem. Lett.
2004, 14, 2681. (d) Riendeau, D.; Aspiotis, R.; Ethier, D.;
Gareau, Y.; Grimm, E. L.; Guay, J.; Guiral, S.; Juteau, H.;
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M. C. Cruz et al.
LETTER
2229. (e) Yue, D.; Larock, R. C. Org. Lett. 2004, 6, 1037.
(f) Shen, M.; Li, G.; Lu, B. Z.; Hossain, A.; Roschangar, F.;
Farina, V.; Senanayake, C. H. Org. Lett. 2004, 6, 4129.
(g) Nazaré, M.; Schneider, C.; Lindenschmidt, A.; Will, D.
W. Angew. Chem. Int. Ed. 2004, 43, 4526. (h) Siu, J.;
Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2004, 2,
160. (i) Amjad, M.; Knight, D. W. Tetrahedron Lett. 2004,
45, 539. (j) Ackermann, L.; Born, R. Tetrahedron Lett.
2004, 45, 9541. (k) Arcadi, A.; Bianchi, G.; Marinelli, F.
Synthesis 2004, 610. (l) Hiroya, K.; Itoh, S.; Sakamoto, T. J.
Org. Chem. 2004, 69, 1126. (m) Cacchi, S.; Fabrizi, G.
Chem. Rev. 2005, 105, 2873. (n) Barluenga, J.; Vázquez-
Villa, H.; Ballesteros, A.; González, J. M. Adv. Synth. Catal.
2005, 347, 526. (o) Söderberg, B. C. G.; Hubbard, J. W.;
Rector, S. R.; O’Neil, S. N. Tetrahedron 2005, 61, 3637.
(p) Ackermann, L. Org. Lett. 2005, 7, 439. (q) Arcadi, A.;
Cacchi, S.; Fabrizi, G.; Marinelli, F.; Parisi, L. M. J. Org.
Chem. 2005, 70, 6213.
(CO2CH3), 98.6 (NC=), 113.4 (C-2), 117.9 (C-4), 129.0
(C-3), 146.3 (HC=), 149.1 (C-1), 169.6 (CO2CH3).
Compound 6c: 1H NMR (300 MHz, CDCl3): d = 2.22 (s, 3
H, CH3Ar), 3.01 [s, 6 H, N(CH3)2], 3.60 (s, 3 H, CO2CH3),
4.52 (br s, 1 H, NH), 6.51–6.57 (m, 2 H, H-2), 6.93–7.00 (m,
2 H, H-3), 7.36 (s, 1 H, HC=). 13C NMR (75.4 MHz, CDCl3):
d = 20.3 (CH3Ar), 41.6 [N(CH3)2], 51.1 (CO2CH3), 99.1
(NC=), 113.4 (C-2), 127.1 (C-4), 129.5 (C-3), 146.1 (HC=),
146.8 (C-1), 169.6 (CO2CH3).
Compound 6h: 1H NMR (300 MHz, CDCl3): d = 1.20 (t,
J = 7.2 Hz, 3 H, CH3CH2O), 3.03 [s, 6 H, N(CH3)2], 3.73 (s,
6 H, OMe), 4.10 (q, J = 7.2 Hz, 2 H, CH3CH2O), 4.70 (br s,
1 H, NH), 5.84 (d, J = 2.1 Hz, 2 H, H-2, H-6), 5.89 (t, J = 2.1
Hz, 1 H, H-4), 7.36 (s, 1 H, HC=). 13C NMR (75.4 MHz,
CDCl3): d = 14.6 (CH3CH2O), 41.8 [N(CH3)2], 55.05 (OMe),
55.08 (OMe), 59.7 (CO2CH2CH3), 90.3 (C-4), 92.4 (C-2, C-
6), 98.8 (NC=), 146.0 (HC=), 151.5 (C-1), 161.5 (C-3, C-5),
169.0 (CO2Et).
(10) Typical Procedure for Preparation of 7b.
(12) Typical Procedure for Preparation of 5b.
Under an N2 atmosphere, a mixture of 8b (1.0 g, 9.33 mmol)
and anhyd K2CO3 (1.93 g, 14.0 mmol) in dry acetone (10
mL) was heated to 60 °C for 1 h. Methyl bromoacetate (9,
1.57 g, 10.26 mmol) was added dropwise and the mixture
was stirred at 60 °C for 12 h. The mixture was filtered and
the solvent was removed under vacuum. The residue was
purified by column chromatography over silica gel (20 g/g of
sample, hexane–EtOAc, 95:5), to give 1.44 g (86%) of 7b as
a brownish solid.
Rf = 0.45 (hexane–EtOAc, 8:2); mp 44–45 °C (hexane–
EtOAc, 8:2) [lit.16 40 °C]. IR (KBr): 3393, 1741, 1608, 1513,
1439, 1213, 1180, 772 cm–1. 1H NMR (300 MHz, CDCl3):
d = 2.33 (s, 3 H, CH3Ar), 3.81 (s, 3 H, CO2Me), 3.93 (s, 2 H,
CH2N), 4.24 (br s, 1 H, NH), 6.43–6.49 (m, 2 H, H-2, H-6),
6.63 (br d, J = 7.5 Hz, 1 H, H-4), 7.13 (t, J = 7.5 Hz, 1 H, H-
5). 13C NMR (75.4 MHz, CDCl3): d = 21.4 (CH3Ar), 45.4
(CH2N), 51.9 (CO2CH3), 109.8 (C-6), 113.6 (C-2), 118.9 (C-
4), 129.0 (C-5), 138.8 (C-3), 146.8 (C-1), 171.5 (CO2Me).
MS (70 eV): m/z (%) = 179 (65) [M+], 136 (7), 122 (34), 121
(100), 93 (3), 63 (5).
Anhyd AlCl3 (0.057 g, 0.43 mmol) was added to a solution
of 6b (0.10 g, 0.43 mmol) in dry CH2Cl2 (100 mL) at r.t. The
mixture was stirred at r.t. for 24 h and filtered. The filtrate
was washed with H2O (3 × 25 mL), the organic layer was
dried (Na2SO4), and the solvent was removed under vacuum.
The residue was purified by column chromatography over
silica gel (10 g, hexane–EtOAc, 95:5), to give 0.061 g (76%)
of 5b as a white solid.
Rf = 0.33 (hexane–EtOAc, 8:2); mp 97–98 °C (hexane–
EtOAc, 7:3) [lit.17 128–129 °C]. IR (KBr): 3324, 1697, 1527,
1441, 1333, 1262, 1211, 764 cm–1. 1H NMR (300 MHz,
CDCl3): d = 2.47 (s, 3 H, CH3Ar), 3.94 (s, 3 H, CO2Me), 6.99
(dd, J = 8.1, 0.9 Hz, 1 H, H-5), 7.18 (dd, J = 2.1, 0.9 Hz, 1
H, H-3), 7.20 (br s, 1 H, H-7), 7.56 (d, J = 8.1 Hz, 1 H, H-4),
8.85 (br s, 1 H, NH). 13C NMR (75.4 MHz, CDCl3): d = 22.0
(CH3Ar), 51.9 (CO2CH3), 108.8 (C-3), 111.5 (C-7), 122.2
(C-4), 123.0 (C-5), 125.3 (ArC), 126.5 (ArC), 135.7 (ArC),
157.3 (C-7a), 162.5 (CO2CH3). MS (70 eV):
m/z (%) = 189 (24) [M+], 175 (17), 157 (87), 129 (91), 103
(80), 102 (100), 77 (69), 51 (69).
(11) Typical Procedure for Preparation of 6b.
NMR spectral data of representative examples.
A mixture of 7b (0.20 g, 1.12 mmol) and DMFDMA (0.20
g, 1.68 mmol) was heated to 90 °C for 5 h, under an N2
atmosphere. The crude mixture was evaporated under
vacuum and the residue was purified by column
Compound 5a: 1H NMR (300 MHz, CDCl3): d = 3.95 (s, 3
H, CO2CH3), 7.16 (ddd, J = 8.1, 6.8, 1.0 Hz, 2 H, H-5), 7.23
(dd, J = 2.3, 1.0 Hz, 1 H, H-3), 7.33 (ddd, J = 8.4, 6.8, 1.0
Hz, 1 H, H-6), 7.58 (ddd, J = 8.4, 1.0, 0.9 Hz, 1 H, H-7), 7.70
chromatography over silica gel (20 g/g of sample, hexane–
EtOAc, 8:2), to give 0.21 g (79%) of 6b as an orange solid.
Rf = 0.25 (hexane–EtOAc, 8:2); mp 65–72 °C (decomp.,
hexane–EtOAc, 8:2). IR (KBr): 3318, 3025, 1735, 1645,
1607, 1488, 1435, 1227, 777 cm–1. 1H NMR (300 MHz,
CDCl3): d = 2.26 (s, 3 H, CH3Ar), 3.02 [s, 6 H, N(CH3)2],
3.61 (s, 3 H, CO2CH3), 4.62 (br s, 1 H, NH), 6.40–6.47 (m,
2 H, ArH), 6.54 (br d, J = 7.8 Hz, 1 H, H-4), 7.04 (dd,
J = 7.8, 7.2 Hz, 1 H, H-5), 7.39 (s, 1 H, HC=). 13C NMR
(75.4 MHz, CDCl3): d = 21.5 (CH3Ar), 41.6 [N(CH3)2], 51.1
(CO2CH3), 98.6 (NC=), 110.4 (C-6), 114.1 (C-2), 118.9 (C-
4), 128.8 (C-5), 138.7 (C-3), 146.3 (HC=), 149.1 (C-1),
169.6 (CO2CH3). MS (70 eV): m/z (%) = 234 (4) [M+], 203
(3), 132 (6), 118 (14), 91 (36), 83 (18), 65 (16), 57 (66), 42
(100). Anal. Calcd for C13H18N2O2: C, 66.64; H, 7.74; N,
11.96. Found: C, 66.47; H, 7.64; N, 11.74.
(dd, J = 8.1, 0.9 Hz, 1 H, H-4), 8.98 (br s, 1 H, NH). 13
C
NMR (75.4 MHz, CDCl3): d = 52.0 (CO2CH3), 108.8 (C-3),
111.9 (C-7), 120.8 (C-5), 122.6 (C-4), 125.4 (C-6), 127.1 (C-
2), 127.4 (C-3a), 136.8 (C-7a), 162.4 (CO2CH3).
Compound 5c: 1H NMR (300 MHz, CDCl3): d = 2.43 (s, 3
H, CH3Ar), 3.94 (s, 3 H, CO2CH3), 7.14 (br s, 1 H, H-3), 7.15
(dd, J = 8.4, 1.5 Hz, 1 H, H-6), 7.31 (br d, J = 8.4 Hz, 1 H,
H-7), 7.45 (br s, 1 H, H-4), 9.11 (br s, 1 H, NH). 13C NMR
(75.4 MHz, CDCl3): d = 21.4 (CH3Ar), 51.9 (CO2CH3),
108.2 (C-3), 111.6 (C-7), 121.8 (C-4), 127.0 (C-2), 127.4
(C-6), 127.7 (C-5), 130.1 (C-3a), 135.3 (C-7a), 162.6
(CO2CH3).
Compound 5h: 1H NMR (300 MHz, CDCl3): d = 1.39 (t,
J = 7.0 Hz, 3 H, CH3CH2O), 3.83 (s, 3 H, OMe), 3.90 (s, 3
H, OMe), 4.38 (q, J = 7.0 Hz, 2 H, CH3CH2O), 6.18 (d,
J = 1.5 Hz, 2 H, H-2, H-5), 6.43 (dd, J = 1.5, 0.9 Hz, 1 H, H-
7), 7.27 (dd, J = 2.3, 0.9 Hz, 1 H, H-3), 9.10 (br s, 1 H, NH).
13C NMR (75.4 MHz, CDCl3): d = 14.4 (CH3CH2O), 55.3
(OMe), 55.5 (OMe), 60.7 (CO2CH2CH3), 86.1 (C-7), 92.6
(C-5), 106.7 (C-3), 113.7 (C-3a), 124.8 (C-2), 138.6 (C-7a),
155.0 (C-4), 160.1 (C-6), 162.1 (CO2Et).
NMR spectral data of representative examples.
Compound 6a: 1H NMR (300 MHz, CDCl3): d = 3.01 [s, 6
H, N(CH3)2], 3.62 (s, 3 H, CO2CH3), 4.66 (br s, 1 H, NH),
6.62 (br d, J = 7.5 Hz, 2 H, H-2), 6.72 (t, J = 7.5 Hz, 1 H, H-
4), 7.15 (br t, J = 7.5 Hz, 1 H, H-3), 7.40 (s, 1 H, HC=).
13C NMR (75.4 MHz, CDCl3): d = 41.6 [N(CH3)2], 51.1
Synlett 2006, No. 5, 749–755 © Thieme Stuttgart · New York

LETTER
Synthesis of Indoles
755
(13) CCDC-292937 contains all crystallographic details of this
publication and is available free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK, fax: +44(1223)336033; or
(14) (a) Jiménez-Vázquez, H. A.; Ochoa, M. E.; Zepeda, G.;
Modelli, A.; Jones, D.; Mendoza, J. A.; Tamariz, J. J. Phys.
Chem. A 1997, 101, 10082. (b) Herrera, R.; Jiménez-
Vázquez, H. A.; Modelli, A.; Jones, D.; Söderberg, B. C.;
Tamariz, J. Eur. J. Org. Chem. 2001, 4657. (c) Mendoza, J.
A.; Jiménez-Vázquez, H. A.; Herrera, R.; Liu, J.; Tamariz, J.
Rev. Soc. Quím. Méx. 2003, 47, 108.
deposit@ccdc.cam.ac.uk.
(15) Reddy, M. S.; Cook, J. M. Tetrahedron Lett. 1994, 35, 5413.
(16) Ellis, F.; Naylor, A.; Wallis, C. J.; Waterhouse, I. EP
388,165, 1990; Chem. Abstr. 1991, 114, 81891.
(17) Knittel, D. Synthesis 1985, 186.
Synlett 2006, No. 5, 749–755 © Thieme Stuttgart · New York