Multicomponent reactions of indole, ethyl glyoxylate and anilines: From friedel-crafts to aza-Diels-Alder reactions catalysed by scandium triflate

Article abstract of DOI:10.1002/ejoc.200900054

The multicomponent reaction (MCR) of indole (1), ethyl glyoxylate (2) and3,4-dimethoxy- or3,4-methylenedioxyanilines (3a,b) give, in analogy to Friedel-Crafts alkylation of indole, expected acetates 4a,b. When the reactions are catalysed by scandium trifl

Full text of DOI:10.1002/ejoc.200900054

FULL PAPER
DOI: 10.1002/ejoc.200900054
Multicomponent Reactions of Indole, Ethyl Glyoxylate and Anilines: From
Friedel–Crafts to Aza-Diels–Alder Reactions Catalysed by Scandium Triflate
Giovanni Desimoni,*[a] Giuseppe Faita,[a] Mariella Mella,[a] Marco Toscanini,[a] and
Massimo Boiocchi[b]
Keywords: Multicomponent reactions / Cycloaddition / Rearrangement / Fused-ring systems / Scandium
The multicomponent reaction (MCR) of indole (1), ethyl
glyoxylate (2) and 3,4-dimethoxy- or 3,4-methylenedioxyani-
lines (3a,b) give, in analogy to Friedel–Crafts alkylation of
and indole is the dienophile. These products, whose struc-
tures were confirmed by X-ray crystal structure analysis of
7a, are not derived from the scandium-catalysed rearrange-
indole, expected acetates 4a,b. When the reactions are cata- ment of 4a,b, because when these latter are treated with
lysed by scandium triflate, however, a completely different
reaction pathway is followed and two pairs of diastereomeric
aza-Diels–Alder adducts (7a,b and 8a,b) are isolated, which
result from the reactions in which the ethyl 2-(arylimino)ace-
tates (azomethynes of 2 with 3a,b) behave as heterodienes
Sc(OTf)3, the rearrangement produces acetates 5a,b only.
The limits of the aza-Diels–Alder reaction were investigated
by performing the MCR on substituted anilines 3f–k.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The multicomponent reaction (MCR)[1] between indole
(1), ethyl glyoxylate (2) and anilines (3),[2–6] in analogy to
the Friedel–Crafts alkylation reaction first described by
Passerini more than 80 years ago,[7] gives the expected ace-
tates 4. Copper[8] and lanthanide cations[9a–9c] have been
found to be efficient catalysts for the electrophilic alkylation
of indoles, but whereas dysprosium and ytterbium triflate
simply increase the reaction rate,[10a,10b] the use of scandium
triflate [Sc(OTf)3] gives new product 5 derived from a re-
arrangement involving the migration of the arylamino frag-
ment of 4. Even if this rearrangement is observed in the
case of unsubstituted aniline, the use of methoxy-substi-
tuted anilines favours the rearrangement and determines
the selective formation of one specific regioisomer. When
the para position to the amino group of 4 is unsubstituted,
the rearrangement involves this position to give ethyl 2-(4-
aminoaryl)-2-(1H-indol-3-yl)acetates, whereas methoxy
substituents in the ortho and para positions to the amino
group force the rearrangement to the meta position to pro-
duce ethyl 2-(5-amino-2,4-dimethoxyphenyl)-2-(1H-indol-3-
yl)acetate (Scheme 1).
Scheme 1. MCR between indole, glyoxylate and anilines and re-
arrangement of the reaction product.
To define the limits induced by the position of these sub-
stituents on the aryl group, the reaction with 3,4-dimeth-
oxy- and 3,4-methylenedioxyanilines (3a,b) were tested, in
which both the para and meta positions to the amino group
are unavailable to the rearrangement.
Results and Discussion
Preliminarily, the reactions between 1, 2 and 3a,b were
run at ambient temperature in CH2Cl2 with 5 Å molecular
sieves (MS). The reaction of 1, 2 and aniline 3a gives ex-
pected product acetate 4a as the sole product in 55% yield
(Scheme 2; Table 1, Entry 1). The analogous reaction with
3b, together with a 55% yield of 4b (R,R1 = OCH2O), gives
a further product (6b) that does not include the indole frag-
ment, with a structure similar to that of a dimer of ethyl 2-
(benzo[d][1,3]dioxol-5-ylimino)acetate, the Schiff base of 2
[a] Dipartimento di Chimica Organica dell’Università di Pavia,
Viale Taramelli 10, 27100 Pavia, Italy
Fax: +39-382-987323
E-mail: desimoni@unipv.it
[b] Centro Grandi Strumenti, dell’Università di Pavia,
Via Bassi 21, 27100 Pavia, Italy
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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G. Desimoni, G. Faita, M. Mella, M. Toscanini, M. Boiocchi
Table 1. Reactions of indole (1), ethyl glyoxylate (2) and anilines (3a,b) in CH2Cl2 with or without scandium triflate (5 mol-%) in CH2Cl2.
FULL PAPER
Entry
Reagents[a]
Sc(OTf)3
T [°C]
Time [h]
4%[b]
6%[b]
7 and 8%[c]
1
2
3
4
5
1+2+3a
1+2+3b
1+2+3a
1+2+3a
1+2+3b
–
–
r.t.
r.t.
–50
r.t.
24
3
4
0.5
1
55
55
25
–
–
15
–
–
–
–
–
5 mol-%
5 mol-%
5 mol-%
55[d]
83[e]
75[f]
–50
–
1
[a] Ratio 1/2/3, 1:1:1; in the presence of MS. [b] Isolated yields. [c] Ratio determined by H NMR spectroscopy. [d] Ratio 7a/8a, 68:32.
[e] Ratio 7a/8a, 70:30. [f] Ratio 7b/8b, 85:15.
and 3b (Table 1, Entry 2). Even if three-component aza-
Diels-Alder (DA) cycloadditions have been reported in the
literature,[11] this seems to be an example of a four-compo-
nent aza-DA reaction.
Figure 1. An ORTEP view of the crystal structure of 7a (ellipsoids
are drawn at the 30% probability level) labelled with crystallo-
graphic atom names.
isolation as pure products can be achieved by column
chromatography and fractional crystallisation (see Experi-
mental Section).
Therefore, the Sc(OTf)3-catalysed MCR of 1, 2 and 3a,b
gives two pairs of diastereomeric aza-DA adducts (i.e., 7a,b
and 8a,b).
To infer the mechanism by which the aza-DA adducts
are formed, specifically if they arise from a ScIII-catalysed
rearrangement of 4a,b, these latter were allowed to react in
the presence of Sc(OTf)3. A CH2Cl2 solution of 4a was
cooled to –50 °C in the presence of Sc(OTf)3 (5mol-%) and
Scheme 2. MCR between indole, glyoxylate and 3,4-dialkoxyani-
lines with and without Sc(OTf)3.
The catalytic effect of Sc(OTf)3 on the MCR of 1 and 2 the reaction was monitored by TLC. After a few minutes
with 3a was first studied at –50 °C and, after 4 h, unreacted two new products began to form at the expense of 4a. Inter-
4a (29% yield) was again isolated, together with two new mediate product 9a, after reaching a maximum concentra-
products (7a and 8a) in up to 60% yield in a 68:32 ratio tion after about 1 h, was then transformed into product 5a,
(Table 1, Entry 3). Compounds 7a and 8a could be purified which is the final product of the transformation. Both prod-
by fractional crystallisation, and the structure of 7a was ucts were isolated by chromatography, and the final product
determined by X-ray analysis (Figure 1; Scheme 2). From was 5a, whereas the intermediate product, which can be
1
the comparison of the H NMR spectra of 7a and 8a, the converted into 5a by treatment with Sc(OTf)3 at ambient
relative configuration (6S*,6aS*,11aR*) can be attributed temperature, was 9a (Scheme 3; Table 2, Entries 1 and 2).
to diastereoisomer 8a. The same reaction, run at ambient The isolation of 9a and its conversion into 5a was already
temperature, gave only the DA products, and a mixture of observed in the same MCR involving different anilines.[2]
diastereoisomers 7a and 8a was obtained in up to 73% yield
in a 70:30 ratio (Table 1, Entry 4).
The reaction of 4b was run at 0 °C and, after 1 h, the
starting product disappeared to give 5b (Scheme 3; Table 2,
The scandium-catalysed reaction of 1, 2 and 3b at –50 °C Entry 3).
is complete after 20 min. The aza-DA was the only reaction
All attempts to obtain 7 and 8 from 4a,b failed, which
pathway, and the diastereoisomeric mixture 7b/8b (85:15) allowed the latter products to be excluded as the intermedi-
was obtained in up to 75% yield (Table 1, Entry 5). Their ates of the aza-DA products. To rationalise the formation
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2627–2634

Multicomponent Reactions of Indole, Ethyl Glyoxylate and Anilines
Scheme 3. The Sc(OTf)3-catalysed rearrangement of adducts 4a,b.
Table 2. Reactions of adducts 4a,b with scandium triflate (5 mol-
%) in CH2Cl2.
Entry Reagents T [°C] Time [h] % Yield[a] 4%[b]
5%[b]
9%[b]
1
2
3
4a
4a
4b
–50
r.t.
0
1
1
2
65
81
76
22[c]
–
–
56
81
76
9
–
–
Scheme 4. Sc(OTf)3-catalysed MCR between indole, glyoxylate and
anilines.
[a] Overall reaction yield. [b] Isolated yields. [c] Percent of reco-
vered starting product.
poor yields, which is not comparable with those of 3a,b
of the aza-DA adducts, the effect of the substituents on the (Table 1), in a 7h/8h ratio of 78:22 (Table 3, Entry 6).
aromatic ring of the starting aniline was further investi-
To explore the type of 3,4-disubstituted aniline required
gated.
to induce the aza-DA reaction, 4-chloro-3-methyl and 3,4-
In the previous report, no aza-DA products were evi- dichloroanilines (3j,k) were tested. Both reactions run at –
denced in the reactions with 2-methoxy, 4-methoxy- and 50 °C within one night, and only products 4j,k were ob-
2,4-dimethoxy-substituted anilines 3c–e (Table 3, Entries 1– tained in excellent yields (Scheme 4; Table 3, Entries 7 and
3).[2] Now the reactions of 1 and 2 with 3-methoxyaniline 8).
(3f), 2,3-dimethoxyaniline (3g) and 3,5-dimethoxyaniline
(3h) were tested (Scheme 4; Table 3, Entries 4–6).
Conclusions
The reactivity of 3f (R = OMe) is poor and, at ambient
temperature, a low yield (22%) of 5f was obtained, evi-
The research started with the aim to define the effect
dently derived from the primary reaction product 4f that induced by the position of a methoxy group on the regiose-
underwent the ScIII-catalysed rearrangement in the position lectivity of the scandium-catalysed rearrangement of prod-
para to the amino group (Table 3, Entry 4). On the con- ucts 4 obtained from the MCR between indole, ethyl glyox-
trary, 3g (R and R2 = OMe) is very reactive at –50 °C, but ylate and anilines.[2] The rearrangement occurs on products
no aza-DA products were isolated and only a good yield of of 3a,b (Table 2 and Scheme 3) and involves different posi-
product 4g was obtained (Table 3, Entry 5).
tions, which always correspond to the most nucleophilic
Even if the reaction of 1, 2 and 3h (R and R3 = OMe) and also the less hindered site of 4.
was influenced by a serious decomposition of the starting
A further interesting result was observed: when the MCR
amine, only aza-DA products 7h and 8h were isolated in between 1, 2, and 3a,b,h was catalysed by Sc(OTf)3, the re-
Table 3. Reactions of indole (1), ethyl glyoxylate (2) and anilines (3c–k)[a] with scandium triflate (5 mol-%) in CH2Cl2.
n
Reagents
R1
T [°C]
Time [h]
4%[b]
5%[b]
7 and 8%[c]
R
R2
R3
1[d]
2[d]
3[d]
4
5
6
3c
3d
3e
3f
H
H
H
OMe
OMe
OMe
Me
Cl
H
OMe
OMe
H
H
H
OMe
H
OMe
H
OMe
H
H
H
H
H
H
H
OMe
H
H
–50
–50
–50
r.t.
–50
–50
–50
–50
0.5
0.2
0.5
72
12
12
92
88
98
–
73
–
–
–
–
22
–
–
–
–
–
–
–
3g
3h
3j
14[e]
–
7
8
Cl
Cl
12
12
83
93
–
–
3k
H
–
1
[a] Ratio 1/2/3, 1:1:1; in the presence of MS. [b] Isolated yields. [c] Ratio determined by H NMR spectroscopy. [d] Data taken from ref.[2]
[e] Ratio 7h/8h, 78:22.
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G. Desimoni, G. Faita, M. Mella, M. Toscanini, M. Boiocchi
FULL PAPER
Figure 2. The molecular structures of ScCl3 complexes with five methyl 2-(arylimino) acetates (10) optimised at the B3LYP/6-31G* level
and the respective values of the dihedral angle between the aryl group and the C=N bond.
action followed a different pathway, and two pairs of dia- of a methoxy group on the distortion can be evaluated. A
stereomeric aza-DA adducts (i.e., 7a,b,h and 8a,b,h) were comparison between 10c and 10d shows that an ortho meth-
isolated.
oxy group increases the distortion between the C=N bond
The reasons of this behaviour cannot be easily rational- and the aryl group as a result of the steric interactions of
ised, but some experimental evidence have to be taken into the ortho methoxy group with the scandium ligands,
account: (i) The aza-DA reaction is an independent path- whereas the same group in the para position lowers the dis-
way that does not involve 4 as an intermediate (Table 2, tortion (36.3 vs. 21.3°). The negative and positive effects in
Entries 1–3), and therefore, it occurs in competition with the above systems are balanced in 10e, as its dihedral angle
the Friedel–Crafts reaction (Table 1, Entry 3 vs. 4). (ii) No is similar to that in A (26.3 vs. 28.6°).
aza-DA products are obtained from the scandium-catalysed
In conclusion, the best compromise requires an aromatic
process involving anilines with only one methoxy group, re- ring with two methoxy groups, one of them being in the
gardless of its placement in the aromatic ring; hence, at least para position, and unsubstituted ortho positions. The result
two methoxy groups are required. (iii) Aza-DA products are is that 10a has the smallest dihedral angle between the aryl
not obtained with 2,4- and 2,5-dimethoxyaniline[2] or with group and the C=N bond (α = 18.9°), which results in a
the 2,3-disubstituted isomer (3g); hence, a 2-methoxy group “planar” structure suitable for a DA reaction.
inhibits this pathway. (iv) The aza-DA cycloaddition is re-
gioselective, as products 7a,b and 8a,b are derived from the
indole approach to the less-hindered ortho position of the
Experimental Section
coordinated Schiff base.
General: Melting points were determined by the capillary method
and are uncorrected. 1H and 13C NMR spectra were recorded at
300 and 75 MHz, respectively. IR spectra were registered with a
Perkin–Elmer RX I spectrophotometer. Separation and purifica-
tion of the products was carried out by column chromatography
by using Merck silica gel 60 (230–400 mesh).
Substrates giving the highest yields of the aza-DA prod-
ucts are those with two substituents on the aromatic ring in
the 3,4-positions (i.e., 3a,b), and these substituents cannot
be anything else than methoxy groups, because 3j,k induce
a different behaviour. Methoxy groups in the 3,5-positions
(3h) give an analogous result, but the reaction yield is lower.
If a comparison between these results does not allow elec-
tronic effects to be excluded, the steric effect induced by an
ortho-methoxy substituent is the key factor that inhibits the
aza-DA pathway.
To react in accordance to a DA reaction, a reasonable
coplanarity between the aryl group and the C=N bond of
the azadiene is required; this is not conceivable with an or-
tho-substituted phenyl group, but only with disubstituted
3,4- (or 3,5-) anilines. Mechanistic investigations support
this scenario. Models of ScIII complex of 3a,c–e, (10a, 10c,
10d and 10e) versus that with the unsubstituted phenyl ring
(A) were optimised with DFT calculations[12] performed by
using the GAUSSIAN98 program package[13] at the
B3LYP/6-31G* level (the methyl ester and ScCl3 were used
for sake of simplicity, scandium was assumed with a penta-
valent coordination, Figure 2).
Materials: Dichloromethane was hydrocarbon-stabilised Aldrich
ACS grade, distilled from calcium hydride and used immediately.
Other solvents were purified according to standard procedures.
Scandium triflate, indole, ethyl glyoxylate and anilines 3a,b were
commercially available Aldrich reagents; powdered 5 Å molecular
sieves were Aldrich reagents heated under vacuum at 300 °C for
5 h and kept in sealed vials in a dryer.
General Procedure for the Reaction Between Indole (1), Methyl
Glyoxylate (2) and Anilines (3a,b): To a solution of indole (1; 2 or
10 mmol), ethyl glyoxylate (2; 50% solution in toluene, 0.41 mL,
2 mmol) and arylamine 3a,b (2 mmol) in CH2Cl2 (5.0 mL) was
added MS (0.10–0.15 g) and stirring at ambient temperature was
continued for the time reported in Table 1. Column chromatog-
raphy with the eluent reported in each specific description gave 4a,b
(together with possible side products) with the yields reported in
Table 1.
Compound 4a: Eluent: cyclohexane/ethyl acetate (70:30). Light
cream-coloured needles, m.p. 137–138 °C (ethyl acetate/hexane). 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.28 (br. s, 1 H, NH),
Taking A as the reference (the dihedral angle between
the phenyl group and the C=N bond is 28.6°), the effect 7.86 [d, 3J(H,H) = 7.7 Hz, 1 H, indole H4], 7.38 [d, 3J(H,H) =
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Multicomponent Reactions of Indole, Ethyl Glyoxylate and Anilines
7.8 Hz, 1 H, indole H7], 7.28–7.17 (m, 2 H, indole H5 and H6),
Compound 7a: Light cream-coloured needles, m.p. 140–141 °C
(ethyl acetate/hexane). H NMR (300 MHz, CDCl3, 25 °C, TMS):
3
1
7.25 (s, 1 H, indole H2), 6.73 [d, J(H,H) = 8.6 Hz, 1 H, aromatic
H5], 6.34 [d, 4J(H,H) = 2.4 Hz, 1 H, aromatic H2], 6.19 [dd, δ = 7.23 [d, 3J(H,H) = 7.5 Hz, 1 H, H10], 7.10 [dt, 3J(H,H) =
4
3J(H,H) = 8.6 Hz, J(H,H) = 2.4 Hz, 1 H, aromatic H6], 5.37 (s, 1
H, CH acetate), 4.53 (bb, 1 H, NH), 4.29 (m, 1 H, CHH ethyl),
4.16 (m, 1 H, CHH ethyl), 3.80 (s, 3 H, methoxy), 3.79 (s, 3 H,
7.8 Hz, 4J(H,H) = 0.9 Hz, 1 H, H8], 6.80 [dt, 3J(H,H) = 7.5 Hz,
3
4J(H,H) = 1.2 Hz, 1 H, H9], 6.71 (s, 1 H, H1), 6.70 [d, J(H,H) =
3
7.8 Hz, 1 H, H7], 6.28 (s, 1 H, H4), 4.82 [d, J(H,H) = 8.1 Hz, 1
methoxy), 1.24 [t, 3J(H,H) = 7.1 Hz, 3 H, CH3 ethyl] ppm. 13C H, H11a], 4.26 [q, 3J(H,H) = 7.2 Hz, 2 H, CH2], 4.0 (bb, 2 H,
NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 172.3, 149.4, 141.5, 2NH), 3.97 [d, 3J(H,H) = 8.1 Hz, 1 H, H6], 3.86 (s, 3 H, OMe),
3
141.0, 135.9, 125.4, 122.5, 122.0, 119.5, 119.0, 112.5, 112.2, 110.9,
3.83 (s, 3 H, OMe), 3.74 [t, J(H,H) = 8.1 Hz, 1 H, H6a], 1.30 [t,
3J(H,H) = 7.2 Hz, 3 H, CH3] ppm. 13C NMR (75 MHz, CDCl3,
25 °C, TMS): δ = 172.2, 149.9, 149.4, 142.9, 137.1, 129.0, 128.3,
125.2, 119.1, 113.6, 112.1, 110.2, 100.4, 61.4, 57.8, 56.5, 55.7
103.6, 99.2, 61.0, 56.1, 55.2, 54.5, 13.7 ppm. IR (nujol): ν = 3376
˜
(NH), 3337 (NH), 1727 (C=O) cm–1. C20H22N2O4 (354.4): calcd.
C 67.78, H 6.26, N 7.90; found C 67.59, H 6.31, N 7.98.
(2OMe), 42.4, 14.1 ppm. IR (nujol): ν = 3360 (NH), 1723 (C=O)
˜
Compound 4b: Eluent: cyclohexane/ethyl acetate (85:15). Light
cream-coloured needles, m.p.92 °C (ethyl acetate/hexane). 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.31 (br. s, 1 H, NH),
7.85 [d, 3J(H,H) = 7.7 Hz, 1 H, indole H4], 7.36 [d, 3J(H,H) =
7.6 Hz, 1 H, indole H7], 7.22–7.16 (m, 2 H, indole H5 and H6),
cm–1. C20H22N2O4 (354.4): calcd. C 67.78, H 6.26, N 7.90; found
C 67.69, H 6.31, N 7.79.
Compound 8a: Whitish crystals, m.p. 170–172 °C (ethyl acetate/hex-
ane). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.02 [t,
3
3
3J(H,H) = 7.6 Hz, 1 H, H8], 6.90 [d, J(H,H) = 7.5 Hz, 1 H, H10],
7.17 (s, 1 H, indole H2), 6.66 [d, J(H,H) = 8.3 Hz, 1 H, aromatic
H5], 6.32 [d, 4J(H,H) = 2.3 Hz, 1 H, aromatic H2], 6.12 [dd,
6.72 [t, 3J(H,H) = 7.5 Hz, 1 H, H9], 6.68 (s, 1 H, H1), 6.60 [d,
4
3J(H,H) = 8.3 Hz, J(H,H) = 2.3 Hz, 1 H, aromatic H6], 5.86 (s, 2
3
3J(H,H) = 7.7 Hz, 1 H, H7], 6.19 (s, 1 H, H4), 5.00 [d, J(H,H) =
9.0 Hz, 1 H, H11a], 4.37 [q, 3J(H,H) = 7.1 Hz, 2 H, CH2], 4.33 [dd,
3J(H,H) = 9.0, 3.3 Hz, 1 H, H6a], 4.2 (bb, 2 H, 2NH), 4.12 [d,
3J(H,H) = 3.3 Hz, 1 H, H6], 3.85 (s, 3 H, OMe), 3.78 (s, 3 H,
OMe), 1.36 [t, 3J(H,H) = 7.1 Hz, 3 H, CH3] ppm. 13C NMR
(75 MHz, CDCl3, 25 °C, TMS): δ = 171.0, 150.6, 148.7, 142.8,
138.1, 127.6, 126.0, 123.4, 118.8, 115.9, 111.0, 110.2, 100.0, 61.1,
H, OCH2O), 5.34 (s, 1 H, CH acetate), 4.6 (bb, 1 H, NH), 4.24 (m,
1 H, CHH ethyl), 4.17 (m, 1 H, CHH ethyl), 1.24 [t, 3J(H,H) =
7.1 Hz, 3 H, CH3 ethyl] ppm. 13C NMR (75 MHz, CDCl3, 25 °C,
TMS): δ = 172.2, 147.8, 141.8, 139.6, 136.0, 125.3, 122.6, 122.0,
119.5, 119.0, 112.0, 110.9, 108.1, 104.7, 100.1, 96.2, 61.1, 54.7,
13.6 ppm. IR (nujol):
ν =
˜
3397 (NH), 1727 (C=O) cm–1.
C19H18N2O4 (338.4): calcd. C 67.44, H 5.36, N 8.28; found C 67.58,
H 5.31, N 8.17.
58.4, 56.2, 55.4, 55.2, 44.4, 13.6 ppm. IR (nujol): ν = 3360 (NH),
˜
1728 (C=O) cm–1. C20H22N2O4 (354.4): calcd. C 67.78, H 6.26, N
7.90; found C 68.02, H 6.41, N 7.75.
Compound 6b: Elution with cyclohexane/ethyl acetate (85:15) gave
as a second fraction, partly overlapped to 4b, product 6b as soft
white needles, m.p. 138 °C (ethyl acetate/hexane). 1H NMR
(300 MHz, CDCl3, 25 °C, TMS): δ = 6.78 (s, 1 H, H4), 6.66 [d,
Reaction between 1, 2 and 3b (Table 1, Entry 5): Chromatographic
separation on a column 60 cm lengthϫ1.5 cm diameter with cyclo-
hexane/ethyl acetate (85:15) gave a mixture of 7b and 8b with the
first fraction enriched with the latter product and the last fraction
with 7b nearly pure. These pure products were obtained by careful
fractional crystallisation.
4
3J(H,H) = 8.3 Hz, 1 H, aromatic H7Ј], 6.62 [d, J(H,H) = 2.3 Hz,
1 H, aromatic H4Ј], 6.54 [dd, 3J(H,H) = 8.3 Hz, 4J(H,H) = 2.3 Hz,
1 H, aromatic H6Ј], 6.35 (s, 1 H, H9), 5.91 (s, 4 H, 2OCH2O), 5.58
(s, 1 H, H6), 4.88 (s, 1 H, H8), 4.63 (bb, 1 H, NH), 4.28–4.16 (m,
3
4 H, 2CH2 ethyl), 1.29 [t, J(H,H) = 7.1 Hz, 3 H, CH3 ethyl], 1.20
Compound 7b: Soft white needles, m.p. 120–121 °C (ethyl acetate/
hexane). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.21 [d,
[t, 3J(H,H) = 7.1 Hz, 3 H, CH3 ethyl] ppm. 13C NMR (75 MHz,
CDCl3, 25 °C, TMS): δ = 171.3, 169.0, 147.4, 143.5, 141.4, 141.2,
136.0, 114.8, 109.5, 107.7, 107.5, 106.5, 103.9, 100.6, 100.4, 98.1,
3
4
3J(H,H) = 7.4 Hz, 1 H, H10], 7.10 [dt, J(H,H) = 7.7 Hz, J(H,H)
3
4
= 0.9 Hz, 1 H, H8], 6.79 [dt, J(H,H) = 7.4 Hz, J(H,H) = 0.9 Hz,
3
67.7, 63.3, 61.3, 61.0, 13.7, 13.6 ppm. IR (nujol): ν = 3395 (NH),
˜
1 H, H9], 6.69 [d, J(H,H) = 7.8 Hz, 1 H, H7], 6.65 (s, 1 H, H1),
1726 (C=O) cm–1. C22H22N2O8 (442.4): calcd. C 59.73, H 5.01, N
6.33; found C 59.58, H 5.12, N 6.39.
6.27 (s, 1 H, H4), 5.88 (AB system, 2 H, OCH2O), 4.79 [d, 3J(H,H)
3
= 8.0 Hz, 1 H, H11a], 4.26 [q, J(H,H) = 7.1 Hz, 2 H, CH2], 4.10
(bb, 2 H, 2NH), 3.96 [d, 3J(H,H) = 7.6 Hz, 1 H, H6], 3.74 [t,
3J(H,H) = 7.8 Hz, 1 H, H6a], 1.30 [t, 3J(H,H) = 7.1 Hz, 3 H, CH3]
ppm. 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 171.8, 149.5,
147.2, 140.8, 137.7, 128.5, 127.9, 124.8, 118.6, 114.0, 109.7, 107.6,
General Procedure for the Reaction Between Indole (1), Methyl
Glyoxylate (2) and Anilines (3a,b,f–k) Catalysed by Sc(OTf)3: To a
solution of indole (1; 0.117 g, 1 mmol), ethyl glyoxylate (2; 50%
solution in toluene, 0.204 mL, 1 mmol) and arylamine 3a,b,f–k
(1 mmol) in CH2Cl2 (1.5 mL) was added MS (0.07–0.10 g). To the
mixture, in a rubber-sealed vial, cooled to the temperature reported
in Tables 1 and 3 was added Sc(OTf)3 (0.025 g, 0.05 mmol) and
stirring was continued for the time reported in Tables 1 and 3. The
reaction was quenched with water, the mixture was extracted with
CH2Cl2, the organic layer was dried and the residue was column
chromatographed. Eluent and products separation are reported be-
low.
100.3, 97.4, 61.0, 57.8, 55.4, 42.2, 13.7 ppm. IR (nujol): ν = 3323
˜
(NH), 1737 (C=O) cm–1. C19H18N2O4 (338.4): calcd. C 67.44, H
5.36, N 8.28; found C 67.62, H 5.41, N 8.33.
Compound 8b: White needles, m.p. 183 °C (ethyl acetate/hexane).
3
1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.02 [t, J(H,H) =
3
7.7 Hz, 1 H, H8], 6.89 [d, J(H,H) = 7.5 Hz, 1 H, H10], 6.72 [dt,
4
3J(H,H) = 7.5 Hz, J(H,H) = 0.9 Hz, 1 H, H9], 6.63 (s, 1 H, H1),
3
6.59 [d, J(H,H) = 7.7 Hz, 1 H, H7], 6.18 (s, 1 H, H4), 5.85 (AB
Reaction between 1, 2 and 3a (Table 1, Entries 3 and 4): Chromato-
graphic separation on a column 60 cm lengthϫ1.5 cm diameter
with cyclohexane/ethyl acetate (80:20), after the eventual elution of
4a (Entry 3), a mixture of 6a and 7a was eluted with the first frac-
tion enriched with the latter product and the last fraction with 6a
nearly pure. These pure products were obtained by careful frac-
tional crystallisation.
system, 2 H, OCH2O), 4.97 [d, 3J(H,H) = 9.1 Hz, 1 H, H11a], 4.38
3
3
[q, J(H,H) = 7.1 Hz, 2 H, CH2], 4.32 [dd, J(H,H) = 9.1, 3.1 Hz,
1 H, H6a], 4.21 [d, 3J(H,H) = 3.1 Hz, 1 H, H6], 4.15 (bb, 1 H,
NH), 3.92 (bb, 1 H, NH), 1.37 [t, 3J(H,H) = 7.1 Hz, 3 H, CH3]
ppm. 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 170.9, 150.6,
146.9, 141.0, 139.0, 127.7, 125.9, 123.4, 118.8, 116.8, 110.1, 106.8,
100.3, 97.4, 61.1, 58.7, 55.6, 44.3, 13.6 ppm. IR (nujol): ν = 3383
˜
Eur. J. Org. Chem. 2009, 2627–2634
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2631

G. Desimoni, G. Faita, M. Mella, M. Toscanini, M. Boiocchi
FULL PAPER
(NH), 3341 (NH),1712 (C=O) cm–1. C19H18N2O4 (338.4): C 67.44,
H 5.36, N 8.28; found C 67.32, H 5.53, N 8.30.
cm–1. C20H22N2O4 (354.4): calcd. C 67.78, H 6.26, N 7.90; found
C 67.75, H 6.32, N 7.83.
Compound 8h: White crystals, m.p. 182 °C (ethyl acetate/hexane).
Reaction between 1, 2 and 3f (Table 3, Entry 4): Chromatographic
separation of the reaction mixture with several impurities and small
amounts of side products was performed on a column 30 cm
lengthϫ1.5 cm diameter with cyclohexane/ethyl acetate (70:30),
and 5f was the only significant product separated in about 22%
yield.
3
1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.02 [t, J(H,H) =
7.5 Hz, 1 H, H8], 6.90 [d, 3J(H,H) = 7.6 Hz, 1 H, H10], 6.71 [t,
3
3J(H,H) = 7.4 Hz, 1 H, H9], 6.64 [d, J(H,H) = 7.4 Hz, 1 H, H7],
4
4
5.94 [d, J(H,H) = 2.2 Hz, 1 H, aromatic proton], 5.79 [d, J(H,H)
3
= 2.2 Hz, 1 H, aromatic proton], 5.12 [d, J(H,H) = 8.5 Hz, 1 H,
3
3
H11a], 4.34 [q, J(H,H) = 7.1 Hz, 2 H, OCH2], 4.29 [dd, J(H,H)
= 8.5, 3.3 Hz, 1 H, H6a], 4.26 [d, 3J(H,H) = 3.3 Hz, 1 H, H6], 3.86
(s, 3 H, OMe), 3.72 (s, 3 H, OMe), 3.6 (bb, 2 H, 2NH), 1.32 [t,
3J(H,H) = 7.1 Hz, 3 H, CH3] ppm. 13C NMR (75 MHz, CDCl3,
25 °C, TMS): δ = 171.4, 160.3, 159.4, 150.4, 145.9, 127.9, 123.7,
119.0, 110.7, 92.3, 89.8, 61.6, 56.2, 55.3, 55.1, 54.6, 43.7, 14.0 ppm.
Compound 5f: Eluent: cyclohexane/ethyl acetate (70:30). Light
cream-coloured crystals, m.p. 114–115 °C (ethyl acetate/hexane).
1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.26 (br. s, 1 H,
3
3
NH), 7.56 [d, J(H,H) = 7.9 Hz, 1 H, indole H4], 7.33 [d, J(H,H)
3
= 8.0 Hz, 1 H, indole H7], 7.19 [t, J(H,H) = 7.9 Hz, 1 H, indole
proton], 7.09 [t, 3J(H,H) = 7.9 Hz, J(H,H) = 0.9, 1 H, indole pro-
4
IR (nujol): ν = 3380 (NH), 1734 (C=O) cm–1. C H N O (354.4):
˜
20 22
2
4
ton], 7.08 (s, 1 H, indole H2), 6.93 [d, 3J(H,H) = 8.1 Hz, 1 H,
calcd. C 67.78, H 6.26, N 7.90; found C 68.04, H 6.11, N 8.09.
aromatic proton], 6.27 [d, 4J(H,H) = 2.1 Hz, 1 H, aromatic proton],
3
4
Reaction between 1, 2 and 3j (Table 3, Entry 7): Chromatographic
separation was performed on a column 30 cm lengthϫ1.5 cm dia-
meter with cyclohexane/ethyl acetate (80:20).
6.16 [dd, J(H,H) = 8.1 Hz, J(H,H) = 2.1 Hz, 1 H, aromatic pro-
ton], 5.48 (s, 1 H, CH acetate), 4.21 (m, 2 H, OCH2), 3.83 (s, 3 H,
3
methoxy), 3.6 (bb, 1 H, NH), 1.7 (bb, 1 H, NH), 1.27 [t, J(H,H)
= 7.1 Hz, 3 H, CH3 ethyl] ppm. 13C NMR (75 MHz, CDCl3, 25 °C,
TMS): δ = 173.6, 157.2, 146.3, 135.9, 129.5, 126.5, 122.9, 121.5,
119.0, 117.3, 112.7 110.7, 106.5, 97.9, 60.3, 54.9, 41.4, 26.4,
Compound 4j: Soft-white needles, m.p. 88–89 °C (ethyl acetate/
1
hexane). H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.2 (br. s,
1 H, NH), 7.85 [d, 3J(H,H) = 7.9 Hz, 1 H, indole H4], 7.38 [d,
3J(H,H) = 8.1 Hz, 1 H, indole H7], 7.29–7.18 (m, 3 H, indole pro-
tons), 7.11 [d, 3J(H,H) = 8.5 Hz, 1 H, aromatic proton], 6.55 [d,
4J(H,H) = 2.6 Hz, 1 H, aromatic proton], 6.43 [dd, 3J(H,H) =
8.5 Hz, 4J(H,H) = 2.6 Hz, 1 H, aromatic proton], 5.38 (s, 1 H, CH
acetate), 4.7 (bb, 1 H, NH), 4.31 (m, 1 H, CHH ethyl), 4.17 (m, 1 H,
CHH ethyl), 2.29 (s, 3 H, methyl), 3.89, 1.25 [t, 3J(H,H) = 7.1 Hz, 3
H, CH3 ethyl] ppm. 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ
= 172.0, 144.7, 136.1, 136.0, 129.0, 125.2, 122.7, 122.6, 122.1, 119.6,
119.0, 115.4, 111.8, 111.5, 111.0, 61.2, 53.8, 19.8, 13.7 ppm. IR (nu-
13.8 ppm. IR (nujol): ν = 3395 and 3300 (NH and NH ), 1732
˜
2
(C=O) cm–1. C19H20N2O3 (324.4): calcd. C 70.35, H 6.21, N 8.64;
found C 70.19, H 6.28, N 8.68.
Reaction between 1, 2 and 3g (Table 3, Entry 5): Chromatographic
separation was performed on a column 30 cm lengthϫ1.5 cm dia-
meter with cyclohexane/ethyl acetate (80:20).
Compound 4g: Colourless prisms, m.p. 94 °C (ethyl acetate/hexane).
1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.54 (br. s, 1 H,
NH), 7.92 [d, 3J(H,H) = 7.3 Hz, 1 H, indole H4], 7.35 [dd, 3J(H,H)
jol): ν = 3344 (NH), 1707 (C=O) cm–1. C H ClN O (342.8):
˜
19 19
2
2
4
= 6.8 Hz, J(H,H) = 1.1 Hz, 1 H, indole H7], 7.28–7.18 (m, 3 H,
calcd. C 66.57, H 5.59, N 8.17; found C 66.39, H 5.68, N 8.09.
3
indole protons), 6.93 [t, J(H,H) = 8.3 Hz, 1 H, aromatic proton],
6.40 [t, 3J(H,H) = 8.3 Hz, 2 H, aromatic protons], 5.48 (s, 1 H, CH
acetate), 5.4 (bb, 1 H, NH), 4.30 (m, 1 H, CHH ethyl), 4.18 (m, 1
H, CHH ethyl), 3.90 (s, 3 H, methoxy), 3.89 (s, 3 H, methoxy), 1.26
[t, 3J(H,H) = 7.1 Hz, 3 H, CH3 ethyl] ppm. 13C NMR (75 MHz,
CDCl3, 25 °C, TMS): δ = 172.2, 152.2, 141.5, 140.5, 136.1, 135.3,
125.3, 124.0, 122.9, 121.9, 119.4, 119.0, 111.7, 111.1, 104.6, 101.7,
Reaction Between 1, 2 and 3k (Table 3, Entry 8): Chromatographic
separation was performed on a column 30 cm lengthϫ1.5 cm dia-
meter with cyclohexane/ethyl acetate (80:20).
Compound 4k: White crystals, m.p. 80 °C (ethyl acetate/hexane). 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.54 (br. s, 1 H, NH),
7.92 [d, 3J(H,H) = 7.3 Hz, 1 H, indole H4], 7.35 [dd, 3J(H,H) =
6.8 Hz, 4J(H,H) = 1.1 Hz, 1 H, indole H7], 7.28–7.18 (m, 3 H,
61.0, 59.6, 55.3, 54.0, 13.7 ppm. IR (nujol): ν = 3395 (NH), 1731
˜
(C=O) cm–1. C20H22N2O4 (354.4): calcd. C 67.78, H 6.26, N 7.90;
found C 67.59, H 6.35, N 8.01.
3
indole protons), 6.93 [t, J(H,H) = 8.3 Hz, 1 H, aromatic proton],
6.40 [t, 3J(H,H) = 8.3 Hz, 2 H, aromatic protons], 5.48 (s, 1 H, CH
acetate), 5.4 (br. s, 1 H, NH), 4.30 (m, 1 H, CHH ethyl), 4.18 (m,
1 H, CHH ethyl), 3.90 (s, 3 H, methoxy), 3.89 (s, 3 H, methoxy),
1.26 [t, 3J(H,H) = 7.1 Hz, 3 H, CH3 ethyl] ppm. 13C NMR
(75 MHz, CDCl3, 25 °C, TMS): δ = 172.2, 152.2, 141.5, 140.5,
136.1, 135.3, 125.3, 124.0, 122.9, 121.9, 119.4, 119.0, 111.7, 111.1,
Reaction between 1, 2 and 3h (Table 3, Entry 6): Chromatographic
separation on a column 30 cm lengthϫ1.5 cm diameter with cyclo-
hexane/ethyl acetate (78:22), after unreacted indole, gave a mixture
of 7h and 8h. Fractional crystallisation with ethyl acetate/hexane
allowed the separation of pure 7h, addition of hexane to the mother
liquors gave pure 8h.
104.6, 101.7, 61.0, 59.6, 55.3, 54.0, 13.7 ppm. IR (nujol): ν = 3356
˜
(NH), 1703 (C=O) cm–1. C18H16Cl2N2O2 (363.2): C 59.52, H 4.44,
N 7.71; found C 59.37, H 4.39, N 7.85.
Compound 7h: White needles, m.p. 110–111 °C (ethyl acetate/hex-
ane). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.20 [d,
General Procedure for the Reaction of Products 4a,b Catalysed by
Sc(OTf)3: To a CH2Cl2 (1.0 mL) solution of 4 (0.2 mmol) in a rub-
ber sealed vial cooled to the temperature reported in Table 2 was
added Sc(OTf)3 (0.005 g, 0.01 mmol) and stirring was continued for
the time reported hereto. The reaction was quenched with water,
the mixture was extracted with CH2Cl2, the organic layer was dried
and the residue was column chromatographed to separate the dif-
ferent products with the eluent reported below in the specific de-
scription of each product.
3
3J(H,H) = 7.4 Hz, 1 H, H10], 7.10 [t, J(H,H) = 7.6 Hz, 1 H, H8],
3
3
6.75 [t, J(H,H) = 7.4 Hz, 1 H, H9], 6.70 [d, J(H,H) = 7.7 Hz, 1
4
H, H7], 5.98 [d, 1 H, J(H,H) = 2.0 Hz, aromatic proton], 5.90 [d,
4J(H,H) = 2.0 Hz, 1 H, aromatic proton], 4.91 [d, 3J(H,H) =
3
7.8 Hz, 1 H, H11a], 4.3 (bb, 1 H, NH), 4.28 [q, J(H,H) = 7.1 Hz,
2 H, OCH2], 3.93 [d, 3J(H,H) = 8.7 Hz, 1 H, H6], 3.86 (s, 3 H,
3
OMe), 3.77 (s, 3 H, OMe), 3.58 [t, J(H,H) = 8.3 Hz, 1 H, H6a],
1.32 [t, 3J(H,H) = 7.1 Hz, 3 H, CH3] ppm. 13C NMR (75 MHz,
CDCl3, 25 °C, TMS): δ = 172.1, 160.5, 159.8, 150.4, 144.6, 128.3,
125.7, 118.3, 109.7, 103.2, 92.2, 89.7, 61.3, 55.3, 55.1, 54.8, 54.7,
Compound 5a: From the reaction described in Table 2, Entry 1, un-
42.2, 14.1 ppm. IR (nujol): ν = 3384 and 3325 (NH), 1734 (C=O) reacted 4a, 5a and 9a were eluted in the order on a column 40 cm
˜
2632
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2627–2634

Multicomponent Reactions of Indole, Ethyl Glyoxylate and Anilines
lengthϫ1.5 cm diameter and the eluent was cyclohexane/ethyl ace-
tate (70:30). For the reaction described in Table 2, Entry 2, only 5a
2); a = 7.399(1) Å, b = 10.363(2) Å, c = 12.234(4) Å; α = 84.21(3)°,
β = 77.69(2)°, γ = 77.49(2)°; V = 893.30(45) Å3; Z = 2; ρcalcd.
=
was easily separated. Glassy solid. 1H NMR (300 MHz, CDCl3, 1.318; F(000) = 376; µ = 0.092 mm–1; 2θmax = 50°; 4059 measured
3
25 °C, TMS): δ = 8.27 (br. s, 1 H, NH), 7.44 [d, J(H,H) = 7.9 Hz, reflections; 3168 independent reflections (Rint = 0.017); 1840 strong
3
1 H, indole H4], 7.35 [d, J(H,H) = 8.1 Hz, 1 H, indole H7], 7.19
reflections [I0Ͼ 2σ(I0)]; 244 refined parameters; R1 = 0.0517 (strong
data) and 0.1065 (all data); wR2 = 0.1133 (strong data) and 0.1369
(all data); GOF = 1.009; 0.13 and –0.18 max. and min. residual
electron density. Data reduction (including intensity integration,
background, Lorentz and polarisation corrections) was performed
with the WinGX package.[14] Absorption effects were evaluated by
3
3
[d, J(H,H) = 2.4 Hz, 1 H, indole H2] 7.18 [dt, J(H,H) = 8.1 Hz,
4J(H,H) = 1.0 Hz, 1 H, indole proton], 7.08 [dt, 3J(H,H) = 7.9 Hz,
4J(H,H) = 0.9, 1 H, indole proton], 6.83 (s, 1 H, aromatic proton),
6.33 (s, 1 H, aromatic proton), 5.24 (s, 1 H, CH acetate), 4.28 (m,
2 H, OCH2), 3.84 (s, 3 H, methoxy), 3.72 (s, 3 H, methoxy), 3.7
3
(bb, 1 H, NH), 1.7 (br. s, 1 H, NH), 1.31 [t, J(H,H) = 7.1 Hz, 3 the psi-scan method[15] and absorption correction was applied to
H, CH3 ethyl] ppm. 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ
= 172.4, 148.6, 141.6, 138.1, 135.9, 128.3, 126.2, 123.1, 121.8, 119.2,
118.6, 114.2, 113.2, 111.7, 110.7, 101.3, 60.7, 56.1, 55.3, 44.1,
the data (min./max. transmission factors were 0.873/0.987). Crystal
structure was solved by direct methods (SIR 97)[16] and refined by
full-matrix least-square procedures on F2 by using all reflections
(SHELXL 97).[17] Anisotropic displacement parameters were re-
fined for all non-hydrogen atoms. Hydrogen atoms bonded to car-
bon atoms were placed at calculated positions with the appropriate
AFIX instructions and refined by using a riding model; hydrogen
bonded to N atoms were located in the ∆F map and refined re-
straining the N–H distance to be 0.96Ϯ0.01 Å.
13.8 ppm. IR (nujol): ν = 3363 (bb, NH ), 1719 (C=O) cm–1.
˜
2
C20H22N2O4 (354.4): C 67.78, H 6.26, N 7.90; found C 67.99, H
6.39, N 8.08.
Compound 9a: From the reaction described in Table 2, Entry 1, 9a
1
was obtained as a pale-yellow oil. H NMR [pair of diastereoiso-
mers (the signal of the second stereoisomer, when detectable, is re-
ported in parenthesis)] (300 MHz, CDCl3, 25 °C, TMS): δ = 8.15
(br. s, 1 H, NH), 8.09 (8.06) (br. s + br. s, 1 H, NH), 7.73 (7.70) [d
+ d, 3J(H,H) = 8.5 Hz, 1 H, indole H4], 7.56 [d, 3J(H,H) = 7.9 Hz,
1 H, indole H4], 7.37–6.84 (m, 8 H, indole protons), 6.88 (6.87) (s
+ s, 1 H, H3 aromatic proton), 6.33 (6.29) (s + s, 1 H, H6 aromatic
proton), 5.39 (5.38) (s + s, 1 H, CH acetate), 5.36 (5.34) (s + s, 1
H, CH acetate), 5.17 (br. s, 1 H, NH), 5.11 (bb, 1 H, NH), 4.25–
4.05 (m, 4 H, 2 OCH2), 3.70, 3.695, 3.69 (s + s + s, 6 H, 2 methoxy),
CCDC-705354 (for 7a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra for compounds 4a,b,g,j,k; 5b,f; 6a,b;
7a,b,e; 8a,b,e; 9a.
3
1.28, 1.27 (1.20, 1.18) [t + t + t + t, J(H,H) = 7.1 Hz, 6 H, 2 CH3
ethyl] ppm. 13C NMR [pair of diastereoisomers (the signal of the
second stereoisomer, when detectable, is reported in parenthesis)]
(75 MHz, CDCl3, 25 °C, TMS): δ = 172.81 (172.76), 172.56
(172.52), 148.84 (148.78), 141.33 (141.25), 138.9 (138.8), 136.30
(136.25), 136.18 (136.15), 126.7 (126.6), 125.77 (125.75), 123.8,
122.8 (122.7), 122.26 (122.23), 122.1 (122.0), 119.8, 119.54 (119.50),
119.4 (119.2), 119.17 (119.12), 115.5 (115.3), 114.3 (114.2), 112.6
(112.4), 112.1.(111.9), 111.18 (111.14), 111.06 (111.0), 98.68
(98.58), 61.29 (61.24), 61.15 (61.09), 56.59 (56.53), 55.54, 54.86
Acknowledgments
Authors thanks Prof. Paolo Quadrelli (University of Pavia) for
helpful discussions. This work was supported by the Ministero Istu-
zione Università Ricerca (MIUR) and the University of Pavia.
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(54.83), 44.8 (44.5), 14.09 (14.05), 14.05 (13.95) ppm. IR (nujol): ν
˜
= 3404 (NH), 1718 (C=O) cm–1.
Compound 5b: For the reaction described in Table 2, Entry 3, 5b
was separated by column chromatography with cyclohexane/ethyl
acetate (7525) as eluent. Cream-coloured crystals, m.p. 151–152 °C
1
(ethyl acetate/hexane). H NMR (300 MHz, CDCl3, 25 °C, TMS):
3
δ = 8.13 (br. s, 1 H, NH), 7.42 [d, J(H,H) = 7.9 Hz, 1 H, indole
[7] M. Passerini, M. Bonciani, Gazz. Chim. Ital. 1933, 63, 138–
144; M. Passerini, F. Albani, Gazz. Chim. Ital. 1935, 65, 933–
938.
3
3
H4], 7.39 [d, J(H,H) = 8.1 Hz, 1 H, indole H7], 7.40 [d, J(H,H)
3
4
= 2.0 Hz, 1 H, indole H2], 7.21 [dt, J(H,H) = 7.0 Hz, J(H,H) =
1.0 Hz, 1 H, indole], 7.08 [dt, 3J(H,H) = 7.0 Hz, 4J(H,H) = 1.0 Hz,
1 H, indole], 6.70 (s, 1 H, aromatic proton), 6.33 (s, 1 H, aromatic
proton), 5.84 (AB system, 2 H, OCH2O), 5.25 (s, 1 H, CH acetate),
[8] T. B. Poulsen, K. A. Jørgensen, Chem. Rev. 2008, 108, 2903–
2915.
[9] a) D. A. Evans, K. R. Fandrick, H. Song, J. Am. Chem. Soc.
2005, 127, 8942–8943; b) D. A. Evans, H. Song, K. R. Fand-
rick, Org. Lett. 2006, 8, 3351–3354; c) D. A. Evans, K. R. Fan-
drick, H. Song, K. A. Scheidt, R. Xu, J. Am. Chem. Soc. 2007,
129, 10029–10041.
[10] a) W. Xie, K. M. Blomfield, Y. Jin, N. Y. Dolney, P. G. Wang,
Synlett 1999, 498–500; b) X. Mi, S. Luo, J. He, J. P. Cheng,
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[11] a) P. A. Grieco, A. Bahas, Tetrahedron Lett. 1988, 29, 5855–
5858; b) E. Borrione, M. Prato, G. Scorrano, M. Stivanello, V.
Lucchini, J. Heterocycl. Chem. 1988, 25, 1831–1835; c) ; L.
Shao, M. Shi, Adv. Synth. Catal. 2003, 345, 963–966; d) V. V.
Kouznetsov, A. R. Romero, A. A. Saavedra, R. Fierro Medina,
Mol. Diversity 2006, 10, 29–37; e) Z. Zhou, F. Xu, X. Han, J.
Zhou, Q. Shen, Eur. J. Org. Chem. 2007, 5265–5269.
3
4.26 [q, J(H,H) = 7.1 Hz, 2 H, OCH2], 3.74 (bb, 1 H, NH), 1.31
[t, 3J(H,H) = 7.1 Hz, 3 H, CH3 ethyl] ppm. 13C NMR (75 MHz,
CDCl3, 25 °C, TMS): δ = 172.5, 147.1, 140.7, 139.1, 136.2, 126.6,
123.4, 122.3, 119.7, 118.9, 115.7, 112.2, 111.0, 109.0, 100.6, 98.6,
61.1, 44.2, 14.1 ppm. IR (nujol): ν = 3396, 3332 (NH and NH),
˜
2
1717 (C=O) cm–1. C19H18N2O4 (338.4): calcd. C 67.44, H 5.36, N
8.28; found C 67.32, H 5.29, N 8.20.
X-ray Crystallographic Study: Diffraction data for a single crystal
of 7a were collected with an Enraf–Nonius CAD4 diffractometer,
working with graphite-monochromated Mo-Kα X-radiation (λ =
0.71073 Å). Crystal data for 7a: C20H22N2O4; Mr = 354.40; T =
¯
293 K; crystal dimensions 0.51ϫ0.30ϫ0.14 mm; triclinic; P1 (No.
Eur. J. Org. Chem. 2009, 2627–2634
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2633

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Received: January 19, 2009
Published Online: April 14, 2009
2634
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2627–2634