News from the 80-year-old passerini variant of the Friedel-Crafts alkylation of indole

Article abstract of DOI:10.1002/ejoc.200800841

The multi-component Friedel-Crafts alkylation reaction between indole (1), ethyl glyoxylate (2) and anilines (3a-f) gives, in analogy to the protocol of the old Passerini reaction, the expected ethyl 2-(arylamino)-2-(1H-indol-3-yl) acetates 4a-f. When the

Full text of DOI:10.1002/ejoc.200800841

FULL PAPER
DOI: 10.1002/ejoc.200800841
News from the 80-Year-Old Passerini Variant of the Friedel–Crafts Alkylation
of Indole
Giovanni Desimoni,*[a] Giuseppe Faita,[a] Mariella Mella,[a] Marco Toscanini,[a] and
Massimo Boiocchi[b]
Keywords: Friedel–Crafts alkylation / Multi-component reactions / Indole / Scandium catalysis / Rearrangements
The multi-component Friedel–Crafts alkylation reaction be-
tween indole (1), ethyl glyoxylate (2) and anilines (3a–f)
gives, in analogy to the protocol of the old Passerini reaction,
the expected ethyl 2-(arylamino)-2-(1H-indol-3-yl)acetates
4a–f. When the reactions are catalysed by 5 mol-% scandium
triflate (ScIIITf), however, or when the isolated products 4 are
treated under the same conditions, rearrangements involving
the arylamino fragments of adducts 4 take place. When the
para position of 4 is unsubstituted, ethyl 2-(2-aminoaryl)-2-
(1H-indol-3-yl) acetates 5 are obtained, and their structures
were confirmed by the X-ray crystal structure analysis of 5a.
Under milder conditions, ScIIITf gives more complicated
products, deriving from 1, 2 and 3 in the ratio of 2:2:1, and
these converted into 5. An explanation of the pathway, by
which the Passerini adducts 4, coordinated to scandium, un-
dergo the rearrangements, is proposed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
flate[14] (both in protic and ionic liquid media)[15] and cop-
per triflate.[16] The most relevant current developments are
studies on its enantioselective catalytic variant, efficiently
achieved with N-sulfonyl aldimines first with the [CuII/bis-
(oxazoline)] complex,[17] then with chiral phosphoric acid
catalysts,[18] and more recently with an organocatalyst.[19]
The negative point is sometimes the presence of a bis-
(indole) addition by-product.[17,18a]
Introduction
Multi-component reactions (MCRs)[1] are the best alter-
native to the maximization of synthetic efficiency in
multistep strategies, and in the last ten years their investiga-
tion has become increasingly popular in the syntheses of
heterocycles,[2] in the generation of libraries of new drug
candidates,[3] and in the creation of several bonds of com-
plex molecules in one operation starting from more than
two simple reagents.[4] The most attractive innovation in the
field has been the asymmetric version of the MCR, devel-
oped either with classical enantioselective catalysts,[5] or
through organocatalytic processes.[6] These contemporary
investigations occasionally involve venerable reactions, in-
cluding – in historic order – the Strecker (1850),[7] Hantzsch
(1890),[8] Biginelli (1891)[9] and Mannich reactions
(1912).[10] Catalytic enantioselective developments have also
recently been reported for the Passerini reaction, which in
its original version (1921)[11] involved an aldehyde, an acid
and an isocyanide reagent.[12] Some years later, Passerini
described a further reaction, in which indoles and Schiff
bases reacted to give (1H-indol-3-yl)benzylanilines.[13] This
reaction, which can be regarded as a Friedel–Crafts alky-
lation, was later studied with catalysis by lanthanide tri-
The enantioselective synthesis of indolyl N-tosyl α-amino
acids was an interesting application of the reaction between
N-tosylimino esters of ethyl glyoxylate (acting as Schiff
bases) and indole catalysed by the [tol-binap/CuPF6] com-
plex.[20] By this route, several new indolyl N-aryl α-amino
acids have been obtained, either in the absence of any cata-
lyst[21] or in the presence of SmI2,[22] and finally the reaction
was run with indoles, glyoxylate and amines under solvent-
free conditions,[23] according to the protocol of an MCR.
Glyoxylate and pyruvate derivatives have been found to
be useful reagents for enantioselective reactions catalysed
by the lanthanide(III) triflate complexes of (4ЈS,5ЈS)-2,6-
bis[5Ј-phenyl-4Ј-{[(triisopropylsilyl)oxy]methyl}-1Ј,3Ј-
oxazolin-2Ј-yl]pyridine (pybox): Mukaiyama aldol reac-
tions,[24] Diels–Alder/hetero-Diels–Alder cycloadditions,[25]
and Friedel–Crafts reactions between a series of substituted
indoles and methyl (E)-4-aryl-2-oxobut-3-enoates[26] have
been usefully performed. The presence of α-aldimino esters
among the reagents of the Passerini reaction discussed
above suggested testing of the effect of ScIII triflate (ScIIITf)
catalysis on the reaction between indole (1; Scheme 1), ethyl
glyoxylate (2) and o-anisidine (3a: R = OMe), with the o-
methoxy group of the last reagent suitably placed to coordi-
nate the cation.
[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.
6232
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Eur. J. Org. Chem. 2008, 6232–6238

News from the Passerini Variant of the Friedel–Crafts Alkylation of Indole
Table 2. Reactions between indole (1), ethyl glyoxylate (2) and ani-
lines (3a–f) and those of the Passerini adducts (4a–f) with scandium
triflate (5 mol-%) in CH2Cl2.
Entry Reagents Temperature Time Yield[a]
Product distribution[b]
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1 + 2 + 3a[c] room temp.
3 h
65%
–
100%
–
–
–
–
2%
14%
55%
14%
–
65%
–
–
65%
55%
–
35%
23%
–
1 + 2 + 3a[c]
4a
–50 °C
room temp.
–50 °C
30 min 92%
1 h
8 h
8 h
15 h
15 h
10 min 88%
8 h 75%
30 min 98%
3 h
5 h
100%
30%
95%
38%
30%[d]
–
100%
35%[d]
100%
–
35%[d]
7%[d]
100%
20%
–
90%
92%
73%
82%
91%
70%
3%
48%
15%
86%
–
1 + 2 + 3b[c]
1 + 2 + 3b[c] room temp.
4b
4b
–20 °C
room temp.
–50 °C
1 + 2 + 3d[c]
4d
room temp.
–50 °C
–
–
1 + 2 + 3e[c]
Scheme 1. General scheme of the uncatalysed three-component re-
actions between indole, ethyl glyoxylate and anilines to give the
corresponding Passerini adducts.
4e
4e
room temp.
–20 °C
75%
94%
100%
–
38%
–
45%
77%
100%
4e
1 + 2 + 3f[c]
1 + 2 + 3f[c]
4f
room temp. 15 min 93%
–50 °C
–20 °C
room temp. 10 min 95%
room temp. 1 h 95%
6 h
35%
15 min 30%
Results and Discussion
4f
–
Preliminarily, the reaction was run at ambient tempera-
ture in CH2Cl2 with molecular sieves (MS, 5 Å). The ex-
pected ethyl 2-(1H-indol-3-yl)-2-[(2-methoxyphenyl)amino]-
acetate (4a: R = OMe), the usual Passerini product, was
obtained as the sole product in 75% yield (Scheme 1,
Table 1, Entry 1).
[a] Overall reaction yield. [b] Ratio of the isolated products deter-
mined by gravimetric analysis after chromatographic separation.
[c] In the presence of MS. [d] % of recovered starting product.
Table 1. Reactions of indole (1), ethyl glyoxylate (2) and anilines
(3a–f) in CH2Cl2 at room temperature.
Entry
Reagents[a]
Time
Yield of 4[b]
1
2
3
4
5
6
1 + 2 + 3a
1 + 2 + 3b
1 + 2 + 3c
1 + 2 + 3d
1 + 2 + 3e
1 + 2 + 3f
15 h
20 h
24 h
24 h
6 h
75%
85%
75%
75%
75%
54%
6 h
[a] In the presence of MS. [b] Isolated yields.
The reaction was then performed under the same condi-
tions at ambient temperature, but in the presence of ScIIITf
(5 mol-%). Again, a single product was obtained in 65%
yield, but it was not 4a. Its molecular mass and spectro-
scopic data show significant similarities with those of 4a,
1
the fundamental difference being the H NMR spectrum,
since a proton of the anisidine fragment is lacking, and the
remaining three protons show that the phenyl ring has a
1,2,4-substitution pattern (Table 2, Entry 1).
These data suggest a rearrangement involving the 2-
methoxyaniline fragment to give ethyl 2-(4-amino-3-meth-
Scheme 2. General scheme for the ScIII-catalysed three-component
reaction between indole, ethyl glyoxylate and anilines to give the
Passerini adducts and the rearranged products.
oxyphenyl)-2-(1H-indol-3-yl)acetate (5a,
Scheme 2), the structure of which was confirmed by X-ray
R
=
OMe;
Then, a sample of 4a in CH2Cl2 was treated with ScIIITf
analysis (Figure 1). In particular, in the solid state, the 5a (5 mol-%) at ambient temperature: the mixture composition
molecule exhibits an extensive hydrogen-bond motif for the of [4a]/[5a] obtained after about 1 h was 30:70, and this ra-
particular feature of the NH2 group of the methoxyaniline tio had not changed after leaving the mixture overnight.
fragment.
The results of all the above reactions are summarized in
The formation of the new product occurs in the presence Table 2 (Entries 2 and 3).
of ScIIITf at ambient temperature. Are both factors neces-
Finally, the MCR was also run at –50 °C in the presence
sary? To test this, the catalysed reaction was run at –50 °C: of the [pybox/ScIIITf] complex (5 mol-%) and, after 30 min,
after 30 min the reaction was complete, and a 92% yield of 4a was obtained in quantitative yield, but unfortunately as
4a was obtained.
a racemate.
Eur. J. Org. Chem. 2008, 6232–6238
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G. Desimoni, G. Faita, M. Mella, M. Toscanini, M. Boiocchi
FULL PAPER
temperature, and 4b, 5b and 6b were obtained in different
yields (Table 2, Entries 4 and 5).
To explore further possibilities of the rearrangement, the
reactions of 1 and 2 with 3c–f were run first under uncata-
lysed conditions, and excellent yields of the normal Pass-
erini products 4c–f were obtained (Table 1, Entries 4–6).
The same reactions were then performed in the presence of
ScIIITf as catalyst, and the results are reported in Table 2
(Entries 8, 10 and 14).
The catalysed reaction of 1, 2 and 3c gave unsatisfactory
results because only decomposition products were obtained,
together with variable amounts of 4c. The same disappoint-
ing result was obtained when 4c was allowed to react with
ScIIITf, with no significant amount of rearranged product
being obtained.
Figure 1. ORTEP view of the crystal structure of 5a (ellipsoids are
drawn at the 50% probability level) labelled with crystallographic
atom numbering.
The reaction of 1, 2 and 3d in the presence of ScIIITf at
–50 °C gave 4d as the sole product (Table 2, Entry 8),
From the reaction involving 3a as the amine component whereas at higher temperature only decomposition products
some pieces of evidence can be pointed out: were observed. When ethyl 2-(1H-indol-3-yl)-2-[(4-meth-
(a) In the absence of ScIIITf the Passerini product 4a is oxyphenyl)amino]acetate (4d) was treated with ScIIITf at
formed.
ambient temperature, 6d was obtained in 50% yield after
(b) The ScIIITf-catalysed reaction gives the rearranged 24 h, together with unreacted 4d (26%; Table 2, Entry 9);
product 5a, the formation of which depends on the reaction its H and 13C NMR spectra suggest that it derives from 1,
1
temperature.
(c) At room temperature 4a rearranges to 5a in the pres- diastereoisomers. Since any attempt to transform 6d into
ence of ScIIITf. the analogous derivative of 5 by treatment with ScIIITf
(d) The ScIIITf catalysis in the presence of pybox does either failed (at –50 °C) or only gave decomposition prod-
not induce enantioselectivity. ucts (at higher temperatures), it is difficult to give it a defi-
Two questions deserve attention: (i) Because the re- nite structure.
2 and 3d in the ratio of 2:2:1 and consists of at least two
arrangement from 4a to 5a involves the o-anisidine residue
The reaction between 1, 2 and 3e at ambient temperature,
of the Passerini adduct, is this behaviour specific for 4a or either in the absence of catalyst or at –50 °C with ScIIITf,
can it be expected for products with different aniline resi- gave ethyl 2-[(2,4-dimethoxyphenyl)amino]-2-(1H-indol-3-
dues? (ii) What is the mechanism of this new rearrange- yl)acetate (4e) in 75% and 98% yields, respectively (Table 1,
ment?
Entry 5 and Table 2, Entry 10). When 4e was treated with
The next reaction was carried out with 1, 2 and aniline ScIIITf, after 3 h at ambient temperature, ethyl 2-(5-amino-
3b (R = H), the Passerini adduct of which (4b) had been 2,4-dimethoxyphenyl)-2-(1H-indol-3-yl)acetate (5e) was ob-
reported in the literature previously.[21,23] Compound 4b, tained in 75% yield (Table 2, Entry 11); its structure
obtained in 85% yield under uncatalysed conditions (Scheme 3) is easily derived from the presence of two aro-
(Table 1, Entry 2), was dissolved in CH2Cl2, and ScIIITf matic protons as singlets in the H NMR spectrum.
1
(5 mol-%) was added at –50 °C. After 2 d, together with a
When the above reaction was run at –20 °C, after a few
60% yield of unreacted 4b, a new product was obtained. minutes a new product (6e) had begun to form at the ex-
The spectroscopic and mass data support a structure de- pense of 4e, which correspondingly tended to disappear.
rived from 1, 2 and 3b in a 2:2:1 ratio, with the phenyl ring The optimum conditions (Table 2, Entry 12) maximizing its
originating from 3b being para-disubstituted.
formation (61% yield), without any 5e, were reached after
From these data, 6b is ethyl 2-({4-[(ethoxycarbonyl)(1H- 5 h. The H and 13C NMR spectra strongly suggest that
indol-3-yl)methyl]phenyl}amino)-2-(1H-indol-3-yl)acetate. two different diastereoisomers are formed, deriving from 1,
When 4b was treated with ScIIITf at –20 °C for 15 h, 6b was 2 and 3e in the ratio of 2:2:1. The evidence that 6e is the
obtained as the major product (45%) together with unre- intermediate between 4e and 5e could be obtained by treat-
acted 4b (25% yield), whereas 5b was isolated in 12% yield. ment of 4e with ScIIITf at ambient temperature, stopping
This last product became the major one (78%) when the the reaction after 15 min (Table 2, Entry 13), before the re-
reaction was run at ambient temperature, and the yield of action begins to behave as in Entry 11. Chromatographic
6b was only 13% (Table 2, Entries 6 and 7; Scheme 2). To separation gave, besides a small amount of 4e, a good yield
test the possible relationship between 5b and 6b, this of 5e, and again 6e, the structure of which is therefore ethyl
latter adduct was allowed to stand with ScIIITf at ambient 2-({5-[(ethoxycarbonyl)(1H-indol-3-yl)methyl]-2,4-dimeth-
temperature overnight, and 5b was obtained in 30% oxyphenyl}amino)-2-(1H-indol-3-yl)acetate.
1
yield.
The reaction between 1, 2 and 3f at ambient temperature,
The reaction between 1, 2 and 3b was also run in the either in the absence of any catalyst or at –50 °C in the
presence of ScIIITf (5 mol-%) both at –50 °C and at ambient presence of ScIIITf, gave ethyl 2-[(2,5-dimethoxyphenyl)-
6234
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News from the Passerini Variant of the Friedel–Crafts Alkylation of Indole
Scheme 4 depicts a plausible pathway: the Passerini ad-
ducts 4, coordinated to scandium, undergo elimination of
the corresponding aniline to generate the ScIII-coordinated
ethyl 2-(1H-indol-3-yl)acetate (7). This reactive electrophile
attacks what is available in the environment, which could
be a second indole to give a bis(indolyl)methane deriva-
tive,[15a] or a second molecule of 4 (if this is suitably acti-
vated, as in the majority of the examples described) at the
most nucleophilic site, which in 4b and 4f (when R1 = H,
as reported in Scheme 4) is the para position, giving rise to
the isolated intermediates 6b and 6f. It is noteworthy that,
with the para position of the (2,4-dimethoxyphenyl)amino
group of 4e occupied by a methoxy group, the preferred
position involved in the rearrangement is not the 6-position,
ortho to the amino group, but the 5-position, which seems
to benefit from combined ortho/para activation induced by
two methoxy groups, thus giving 6e (Scheme 3).
Scheme 3. General scheme of the ScIII-catalysed three-component
reaction between indole, ethyl glyoxylate and 2,4-dimethoxyaniline
to give the Passerini adducts and the rearranged products.
amino]-2-(1H-indol-3-yl)acetate (4f) in 54% and 35%
yields, respectively (Table 1, Entry 6 and Table 2, Entry 14).
When 4f was treated with ScIIITf at ambient temperature,
ethyl 2-(4-amino-2,5-dimethoxyphenyl)-2-(1H-indol-3-yl)-
acetate (5f) was obtained in 95% yield after 2 h (Table 2,
Entry 16), its structure being easily derivable from the pres-
1
ence of two aromatic protons as singlets in its H NMR
spectrum. If the same reaction was interrupted after 10 min
(Table 2, Entry 17), the new product 6f (disappearing after
prolonged treatment with ScIIITf) was also obtained to-
gether with 5f, which could be separated by column
chromatography (Scheme 2). The 1H and 13C NMR spectra
allow it to be determined that 6f is ethyl 2-({4-[(ethoxycar-
bonyl)(1H-indol-3-yl)methyl]-2,4-dimethoxyphenyl}-
amino)-2-(1H-indol-3-yl)acetate, as a pair of diastereoiso-
mers. The products 5f and 6f, together with 4f, were ob-
tained from 1, 2 and 3f at –20 °C (Table 2, Entry 15) in the
presence of ScIIITf, again following first an MCR, and then
a cascade of reactions involving 6f to give 5f.
Conclusions
Scheme 4. Proposed mechanism for the ScIII-catalysed rearrange-
ments from 4b and 4f to 5b and 5f.
The efforts to induce enantioselective catalysis of Pass-
erini MCRs between indole, ethyl glyoxylate and anilines
through the use of a [pybox/ScIIITf] complex were unsuc-
Intermediates 6 again coordinate to scandium and un-
cessful, but the attempt has allowed the discovery of new dergo the elimination of 5b, 5e or 5f (the products of the
ScIII-catalysed rearrangements of the above reaction prod- rearrangement), giving rise again to 7, which goes on in the
ucts 4a, 4b and 4d–f (either formed “in situ” from the catalytic cycle. Obviously, the expulsion of the anilines not
MCR, or isolated beforehand), in which the arylamino only sometimes gives the observed coloured decomposition
groups migrate to give 5a, 5b, 5e and 5f. These unusual products, but it may interfere in the catalytic cycle, compet-
conversions occur through the intermediates 6 (isolated in ing in the coordination of scandium and sometimes pre-
many experiments), which develop during the courses of the venting the complete rearrangement of 4, as ScIIITf is
reactions at the expense of 4, and disappear when products 5 mol-% of the reagents.
5 are formed. To understand the mechanism of the re-
In conclusion, lanthanides are efficient catalysts of the
arrangements of 4 to 5, the role of 6, even if not always reactions between indole and imines, but whereas dyspro-
isolated and sometimes difficult to obtain at a high level of sium and ytterbium triflate simply increase the reaction ra-
purity, is therefore crucial.
tes,[15a,15b] scandium triflate is found to catalyse a new re-
Eur. J. Org. Chem. 2008, 6232–6238
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G. Desimoni, G. Faita, M. Mella, M. Toscanini, M. Boiocchi
FULL PAPER
Ethyl 2-(1H-Indol-3-yl)-2-[(4-methoxyphenyl)amino]acetate (4d):
Eluent cyclohexane/ethyl acetate (70:30), light cream-coloured crys-
tals, m.p. 66–67 °C from ethyl acetate/hexane (ref.[21] slightly yellow
oil). 1H and 13C NMR (CDCl3) data are identical to those reported
arrangement that, starting from the products of an old
MCR between indole and the imine precursors, gives rise
to a new class of indole derivatives.
in the literature.[21] IR (Nujol): ν = 3396 (NH), 3376 (NH), 1726
˜
(C=O) cm–1.
Experimental Section
Ethyl
2-[(2,4-Dimethoxyphenyl)amino]-2-(1H-indol-3-yl)acetate
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
on Merck silica gel 60 (230–400 mesh).
(4e): Eluent cyclohexane/ethyl acetate (70:30), white crystals, m.p.
114–115 °C (ethyl acetate/hexane). 1H NMR (300 MHz, CDCl3,
3
25 °C, TMS): δ = 8.23 (br. s, 1 H, NH), 7.88 (d, JH,H = 7.7 Hz, 1
3
H, indole 4-H), 7.37 (d, JH,H = 7.5 Hz, 1 H, indole 7-H), 7.28–
7.18 (m, 2 H, indole 5-H and 6-H), 7.24 (s, 1 H, indole 2-H), 6.51
3
4
(d, JH,H = 8.7 Hz, 1 H, 6-H aromatic proton), 6.49 (d, JH,H
=
=
3
4
Materials: Dichloromethane was the hydrocarbon-stabilised
Aldrich ACS grade, distilled from calcium hydride and used imme-
diately. Other solvents were purified by standard procedures. Scan-
dium triflate, indole, ethyl glyoxylate and all anilines 3a–f were
commercially available Aldrich reagents; powdered molecular
sieves (5 Å) were Aldrich reagents heated under vacuum at 300 °C
for 5 h and kept in sealed vials in a dryer.
2.6 Hz, 1 H, 3-H aromatic proton), 6.35 (dd, JH,H = 8.7, JH,H
2.6 Hz, 1 H, 5-H aromatic proton), 5.37 (s, 1 H, CH acetate), 5.0
(br. s, 1 H, NH), 4.28 (m, 1 H, CHH ethyl), 4.16 (m, 1 H, CHH
ethyl), 3.84 (s, 3 H, methoxy), 3.75 (s, 3 H, methoxy), 1.24 (t, 3JH,H
= 7.1 Hz, 3 H, CH3 ethyl) ppm. 13C NMR (75 MHz, CDCl3, 25 °C,
TMS): δ = 172.3, 151.9, 147.8, 136.0, 130.4, 125.6, 122.6, 121.9,
119.4, 119.2, 112.4, 110.8, 110.6, 103.1, 98.8, 60.9, 55.2, 55.0, 54.4,
13.7 ppm. IR (Nujol): ν = 3434 (NH), 3347 (NH), 1708 (C=O)
˜
General Procedure for the Reactions between Indole (1), Ethyl
Glyoxylate (2) and Anilines 3a–f: MS (0.10–0.15 g) were added to a
solution of indole (1, 0.234 g, 2 mmol), ethyl glyoxylate (2, 0.41 mL
solution 50% in toluene, 2 mmol) and one of the arylamines 3a–f
(2 mmol) in CH2Cl2 (5.0 mL), and stirring at ambient temperature
was continued for the time reported in Table 1, after which nearly
all reagents had disappeared. Column chromatography with the
eluent reported in each specific description gave 4a–f with the yields
reported in Table 1.
cm–1. C20H22N2O4 (354.4): calcd. C 67.78, H 6.26, N 7.90; found
C 67.59, H 6.30, N 8.01.
Ethyl 2-[(2,5-Dimethoxyphenyl)amino]-2-(1H-indol-3-yl)acetate (4f):
Eluent cyclohexane/ethyl acetate (80:20), white crystals, m.p.
1
105 °C (ethyl acetate/hexane). H NMR (300 MHz, CDCl3, 25 °C,
3
TMS): δ = 8.18 (br. s, 1 H, NH), 7.86 (d, JH,H = 7.8 Hz, 1 H,
3
indole 4-H), 7.39 (d, JH,H = 7.9 Hz, 1 H, indole 7-H), 7.28–7.15
(m, 2 H, indole 5-H and 6-H), 7.28 (s, 1 H, indole 2-H), 6.69 (d,
3JH,H = 7.8 Hz, 1 H, 3-H aromatic proton), 6.20 (d, 4JH,H = 2.6 Hz,
Ethyl 2-(1H-Indol-3-yl)-2-[(2-methoxyphenyl)amino]acetate (4a):
Eluent cyclohexane/ethyl acetate (80:20), white crystals, m.p. 104–
3
4
1 H, 6-H aromatic proton), 6.35 (dd, JH,H = 7.8, JH,H = 2.6 Hz,
1 H, 4-H aromatic proton), 5.37 (s, 1 H, CH acetate), 5.4 (br. s, 1
H, NH), 4.29 (m, 1 H, CHH ethyl), 4.16 (m, 1 H, CHH ethyl), 3.82
1
105 °C (ethyl acetate/hexane). H NMR (300 MHz, CDCl3, 25 °C,
3
TMS): δ = 8.24 (br. s, 1 H, NH), 7.90 (d, JH,H = 7.5 Hz, 1 H,
3
3
(s, 3 H, methoxy), 3.70 (s, 3 H, methoxy), 1.24 (t, JH,H = 7.1 Hz,
indole 4-H), 7.36 (d, JH,H = 7.5 Hz, 1 H, indole 7-H), 7.28–7.18
3 H, CH3 ethyl) ppm. 13C NMR (75 MHz, CDCl3, 25 °C, TMS):
δ = 172.3, 154.4, 141.7, 137.5, 136.3, 125.8, 123.0, 122.4, 119.9,
119.6, 112.5, 111.2, 110.0, 99.4, 98.7, 61.4, 55.9, 55.3, 53.9,
(m, 2 H, indole 5-H and 6-H), 7.21 (s, 1 H, indole 2-H), 6.87–6.59
(m, 4 H, aromatic protons), 5.44 (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), 3.87
3
14.0 ppm. IR (Nujol): ν = 3430 (NH), 3344 (NH), 1723 (C=O)
˜
(s, 3 H, methoxy), 1.25 (t, JH,H = 7.0 Hz, 3 H, CH3 ethyl) ppm.
cm–1. C20H22N2O4 (354.4): calcd. C 67.78, H 6.26, N 7.90; found
C 67.65, H 6.20, N 7.79.
13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 172.2, 146.6, 136.1,
136.0, 125.4, 122.7, 121.9, 120.6, 119.4, 119.1, 116.9, 112.0, 110.9,
110.1, 109.2, 61.0, 54.9, 53.7, 13.7 ppm. IR (Nujol): ν = 3405 (NH),
General Procedure for the ScIIITf-Catalysed Reactions Between In-
dole (1), Ethyl Glyoxylate (2) and Anilines 3a–f: MS (0.07–0.10 g)
were added to a solution of indole (1, 0.117 g, 1 mmol), ethyl glyox-
ylate (2, 0.204 mL 50% solution in toluene, 1 mmol) and one of
the arylamines 3a–f (1 mmol) in CH2Cl2 (1.5 mL). The mixture, in
a rubber-sealed vial, was cooled to the temperature reported in
Table 2, ScIIITf (0.025 g, 0.05 mmol) was then added, and stirring
was continued for the time reported in Table 2, after which nearly
all reagents had disappeared. The reaction was quenched with
water, the mixture was extracted with CH2Cl2, the organic layer
was dried, and the residue was column-chromatographed. When 4
was the sole reaction product, the conditions were those reported
above in each specific product. For the reaction described in
Table 2, Entry 1, 5a was separated with cyclohexane/ethyl acetate
(70:30) as eluent, whereas for the reactions described in Entries 4
and 5, compounds 4b, 6b and 5b were eluted in that order on a
column (60 cmϫ1.5 cm), and the eluent used was cyclohexane/
ethyl acetate (70:30).
˜
3374 (NH), 1717 (C=O) cm–1. C19H20N2O3 (324.4): calcd. C 70.35,
H 6.21, N 8.64; found C 70.42, H 6.28, N 8.81.
Ethyl 2-(1H-Indol-3-yl)-2-(phenylamino)acetate (4b): Eluent cyclo-
hexane/ethyl acetate (85:15), white crystals, m.p. 94–95 °C from
ethyl acetate/hexane (ref.[21,23] slightly yellow oil). 1H and 13C NMR
(CDCl3) data are identical to those reported in the literature.[21] IR
(Nujol): ν = 3422 (NH), 3346 (NH), 1705 (C=O) cm–1.
˜
Ethyl 2-[(4-Chlorophenyl)amino]-2-(1H-indol-3-yl)acetate (4c): Elu-
ent cyclohexane/ethyl acetate (85:215), white crystals, m.p. 90–
91 °C (ethyl acetate/hexane). 1H NMR (300 MHz, CDCl3, 25 °C,
3
TMS): δ = 8.27 (br. s, 1 H, NH), 7.87 (d, JH,H = 7.6 Hz, 1 H,
3
indole 4-H), 7.37 (d, JH,H = 7.6 Hz, 1 H, indole 7-H), 7.31–7.12
(m, 2 H, indole 5-H and 6-H), 7.20 (s, 1 H, indole 2-H), 6.59
(pseudo-d, 4 H, aromatic protons), 5.40 (s, 1 H, CH acetate), 4.86
(br. s, 1 H, NH), 4.34 (m, 1 H, CHH ethyl), 4.18 (m, 1 H, CHH
3
ethyl), 1.26 (t, JH,H = 7.0 Hz, 3 H, CH3 ethyl) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C, TMS): δ = 172.0, 144.6, 136.0, 131.5,
128.6, 125.2, 122.7, 122.2, 119.7, 119.0, 114.5, 114.1, 111.5, 111.1,
General Procedure for the ScIIITf-Catalysed Reactions of the Pass-
erini Products 4a, 4b, 4d–f: ScIIITf (0.005 g, 0.01 mmol) was added
to a CH2Cl2 (1.0 mL) solution of compound 4 (0.2 mmol) in a rub-
ber-sealed vial cooled to the temperature reported in Table 2, and
61.3, 53.9, 53.7, 13.7 ppm. IR (Nujol): ν = 3419 (NH), 3350 (NH),
˜
1706 (C=O) cm–1. C18H17ClN2O2 (328.8): calcd. C 65.75, H 5.21,
N 8.52; found C 65.87, H 5.08, N 8.69.
6236
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6232–6238

News from the Passerini Variant of the Friedel–Crafts Alkylation of Indole
stirring was continued for the time reported. The reaction was
quenched with water, the mixture was extracted with CH2Cl2, the
organic layer was dried, and the residue was column-chromato-
graphed to separate the different products with the eluents reported
below in the specific description of each product.
H), 7.35 (d, 3JH,H = 8.1 Hz, 1 H, indole 7-H), 7.19 (dt, 3JH,H = 8.2,
3
4JH,H = 1.5 Hz, 1 H, indole proton), 7.14 (d, JH,H = 2.4 Hz, 1 H,
3
4
indole 2-H), 7.08 (dt, JH,H = 8.1, JH,H = 0.9 Hz, 1 H, indole
proton), 6.60 (s, 1 H, 6-H aromatic proton), 6.52 (s, 1 H, 3-H aro-
matic proton), 5.52 (s, 1 H, CH acetate), 4.20 (m, 2 H, OCH2), 3.86
(s, 6 H, 2ϫmethoxy), 3.5 (br. s, 2 H, NH2), 1.27 (t, 3JH,H = 7.1 Hz,
3 H, CH3 ethyl) ppm. 13C NMR (75 MHz, CDCl3, 25 °C, TMS):
δ = 173.6 149.9, 147.0, 136.2, 129.2, 126.9, 123.1, 122.0, 119.7,
119.5, 119.3, 116.3, 113.4, 111.0, 96.9, 60.7, 56.8, 55.6, 41.4,
Ethyl 2-(4-Amino-3-methoxyphenyl)-2-(1H-indol-3-yl)acetate (5a):
Eluent cyclohexane/ethyl acetate (70:30), white crystals, m.p.
1
105 °C (ethyl acetate/hexane). H NMR (300 MHz, CDCl3, 25 °C,
3
TMS): δ = 8.16 (br. s, 1 H, NH), 7.51 (d, JH,H = 7.9 Hz, 1 H,
14.2 ppm. IR (Nujol): ν = 3406, 3370 (NH ), 3180 (NH), 1719
˜
2
3
indole 4-H), 7.34 (d, JH,H = 8.0 Hz, 1 H, indole 7-H), 7.20 (dt,
(C=O) cm–1. C20H22N2O4 (354.4): calcd. C 67.78, H 6.26, N 7.90;
4
3
3JH,H = 7.1, JH,H = 1.0 Hz, 1 H, indole proton), 7.14 (d, JH,H
=
found C 67.95, H 6.38, N 7.77.
3
4
2.3 Hz, 1 H, indole 2-H), 7.09 (dt, JH,H = 8.0, JH,H = 1.0 Hz, 1
H, indole proton), 6.93 (d, 4JH,H = 1.7 Hz, 1 H, 2-H aromatic pro-
Ethyl 2-({5-[(Ethoxycarbonyl)(1H-indol-3-yl)methyl]-2,4-dimethoxy-
phenyl}amino)-2-(1H-indol-3-yl)acetate (6e): Pale yellow oil (when
one stereoisomer makes up at least 80% of the mixture, the product
3
4
ton), 6.88 (dd, JH,H = 7.9, JH,H = 1.7 Hz, 1 H, 6-H aromatic
proton), 6.67 (d, JH,H = 7.8 Hz, 1 H, 5-H aromatic proton), 5.16
3
1
(s, 1 H, CH acetate), 4.24 (m, 2 H, OCH2), 3.80 (s, 3 H, methoxy),
3.7 (br. s, 2 H, NH2), 1.29 (t, 3JH,H = 7.1 Hz, 3 H, CH3 ethyl) ppm.
13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 173.4, 147.2, 136.2,
135.1, 128.6, 126.6, 123.0, 122.0, 120.9, 119.5, 119.0, 114.7, 114.4,
becomes a solid with m.p. 83–85 °C). H NMR (CDCl3): δ = 7.8
(8.06) (br. s + br. s, 1 H, NH), 7.58 (7.7) (br. s + br. s, 1 H, NH),
3
7.74 (7.69) [d, JH,H = 7.8 (7.7) Hz, 1 H, indole 4-H], 7.40 (7.50)
[d, 3JH,H = 7.8 (7.7) Hz, 1 H, indole 4-H], 7.4–7.0 (m, 3 H, remain-
4
111.1, 110.6, 60.9, 55.4, 48.6, 14.2 ppm. IR (Nujol): ν = 3404, 3332
˜
ing indole protons), 6.66 (6.91) [d + d, JH,H = 2.4 (2.4) Hz, 1 H,
(NH2), 3179 (NH), 1710 (C=O) cm–1. C19H20N2O3 (324.4): calcd.
C 70.35, H 6.21, N 8.64; found C 70.53, H 6.18, N 8.77.
4
indole 2-H], 6.49 (6.73) [d + d, JH,H = 2.4 (2.4) Hz, 1 H, indole
2-H], 6.49 (6,52) (s + s, 1 H, 6-H aromatic proton), 6.42 (6.36) (s
+ s, 1 H, 3-H aromatic proton), 5.46 (5.44) (s + s, 1 H, CH acetate),
5.14 (5.06) (s + s, 1 H, CH acetate), 4.05–4.25 (m, 4 H, 2ϫOCH2),
3.86 (3.85) (s + s, 3 H, methoxy), 3.81 (3.83) (s + s, 3 H, methoxy),
Ethyl 2-(4-Aminophenyl)-2-(1H-indol-3-yl)acetate (5b): For the re-
action described in Table 2, Entry 6, 4b, 6b and 5b were eluted in
that order on a column (60 cmϫ1.5 cm), and the eluent used was
cyclohexane/ethyl acetate (70:30). White crystals, m.p. 123–124 °C
3
1.26 (1.18) (t + t, JH,H = 7.1 Hz, 3 H, CH3 ethyl), 1.17 (1.03) (t +
3
t, JH,H = 7.1 Hz, 3 H, CH3 ethyl) ppm. 13C NMR [pair of dia-
1
(ethyl acetate/hexane). H NMR (300 MHz, CDCl3, 25 °C, TMS):
stereoisomers (the signal of the second stereoisomer, when detect-
able, is reported in parentheses), 75 MHz, CDCl3, 25 °C, TMS]: δ
= 173.6 (173.8), 172.2 (172.3), 149.0 (149.2), 147.0, 136.27 (136.32),
135.9 (136.0), 130.14 (130.06), 126.9, 125.6 (125.9), 123.8 (123.4),
123.3 (123.4), 121.7 (121.9), 121.6 (121.8), 119.7 (119.8), 119.5
(119.6), 119.2 (119.3), 119.1 (119.2), 119.0 (118.9), 113.2 (112.8),
113.1 (112.5), 112.2 (112.7), 111.0, 110.9 (111.0), 96.8 (96.6), 61.3
(61.1), 60.62 (60.55), 57.0 (56.8), 55.7 (55.6), 54.6 (54.5), 40.9 (41.5),
3
δ = 8.11 (br. s, 1 H, NH), 7.48 (d, JH,H = 7.7 Hz, 1 H, indole 4-
3
3
H), 7.36 (d, JH,H = 8.1 Hz, 1 H, indole 7-H), 7.23 (d, JH,H
=
=
3
8.5 Hz, 2 H, 2-H and 6-H aromatic protons), 7.19 (d, JH,H
2.3 Hz, 1 H, indole 2-H), 7.18 (dt, JH,H = 7.0, JH,H = 1.0 Hz, 1
3
4
3
4
H, indole 6-H), 7.08 (dt, JH,H = 7.0, JH,H = 0.9 Hz, 1 H, indole
5-H), 6.65 (d, 3JH,H = 8.5 Hz, 2 H, 3-H and 5-H aromatic protons),
5.15 (s, 1 H, CH acetate), 4.23 (m, 2 H, OCH2), 3.6 (br. s, 2 H,
NH2), 1.28 (t, JH,H = 7.1 Hz, 3 H, CH3 ethyl) ppm. 13C NMR
3
15.0 (14.1), 14.0 (13.8) ppm. IR (Nujol): ν = 3404 (NH), 1720
˜
(75 MHz, CDCl3, 25 °C, TMS): δ = 172.9, 144.9, 135.8, 128.8,
128.2, 126.2, 122.5, 121.7, 119.1, 118.6, 114.7, 113.9, 110.6, 60.4,
(C=O) cm–1.
55.4, 47.7, 13.7 ppm. IR (Nujol): ν = 3402, 3330 (NH ), 3171 (NH),
˜
2
Ethyl
2-(4-Amino-2,5-dimethoxyphenyl)-2-(1H-indol-3-yl)acetate
1724 (C=O) cm–1. C18H18N2O2 (294.4): calcd. C 73.45, H 6.16, N
(5f): Eluent cyclohexane/ethyl acetate (75:25), light cream-coloured
9.52; found C 73.68, H 6.28, N 9.43.
crystals m.p. 81–83 °C (ethyl acetate/hexane). 1H NMR (300 MHz,
3
CDCl3, 25 °C, TMS): δ = 8.15 (br. s, 1 H, NH), 7.58 (d, JH,H
=
Ethyl 2-({4-[(Ethoxycarbonyl)(1H-indol-3-yl)methyl]phenyl}amino)-
2-(1H-indol-3-yl)acetate (6b): White crystals, m.p. 81–83 °C (ethyl
acetate/hexane). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ =
8.19 (br. s, 1 H, NH), 8.08 (br. s, 1 H, NH), 7.84 (d, 3JH,H = 7.4 Hz,
3
8.0 Hz, 1 H, indole 4-H), 7.35 (d, JH,H = 8.1 Hz, 1 H, indole 7-
H), 7.19 (dt, JH,H = 8.1, 4JH,H = 1.1 Hz, 1 H, indole proton), 7.13
3
3
3
4
(d, JH,H = 2.4 Hz, 1 H, indole 2-H), 7.09 (dt, JH,H = 8.0, JH,H
= 1.1 Hz, 1 H, indole proton), 6.76 (s, 1 H, 6-H aromatic proton),
6.39 (s, 1 H, 3-H aromatic proton), 5.54 (s, 1 H, CH acetate), 4.20
(m, 2 H, OCH2), 3.81 (s, 3 H, methoxy), 3.7 (br. s, 2 H, NH2), 3.62
3
1 H, indole 4-H), 7.49 (d, JH,H = 7.9 Hz, 1 H, indole 4-H), 7.32
3
3
(d, JH,H = 7.8 Hz, 1 H, indole 7-H), 7.29 (d, JH,H = 8.7 Hz, 1 H,
indole 7-H), 7.22 (d, 2 H, 2-H and 6-H aromatic protons), 7.24–
7.05 (m, 6 H, indole protons), 6.59 (d, 2 H, 3-H and 5-H aromatic
protons), 5.37 (s, 1 H, CH acetate), 5.14 (s, 1 H, CH acetate), 4.79
3
(s, 3 H, methoxy), 1.28 (t, JH,H = 7.1 Hz, 3 H, CH3 ethyl) ppm.
13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 173.8 151.3, 141.1,
3
136.2, 135.8, 126.8, 123.0, 122.0, 119.4, 116.5, 113.8, 112.5, 111.0,
(br. s, 1 H, NH), 4.21 (m, 4 H, 2ϫOCH2),1.26 (t, JH,H = 6.9 Hz,
3 H, CH3 ethyl), 1.22 (t, JH,H = 6.9 Hz, 3 H, CH3 ethyl) ppm. 13
C
3
99.6, 60.7, 56.3, 56.1, 41.5, 14.2 ppm. IR (Nujol): ν = 3464, 3376
˜
(NH2), 3160 (NH), 1711 (C=O) cm–1. C20H22N2O4 (354.4): calcd.
C 67.78, H 6.26, N 7.90; found C 67.68, H 6.31, N 8.02.
NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 173.1, 172.1, 145.2,
136.0, 135.8, 128.8, 127.5, 126.1, 125.2, 122.72, 122.69, 121.9,
121.6, 119.4, 119.02, 118.99, 118.6, 113.8, 112.9, 111.8, 110.9,
Ethyl 2-({4-[(Ethoxycarbonyl)(1H-indol-3-yl)methyl]-2,4-dimethoxy-
phenyl}amino)-2-(1H-indol-3-yl)acetate (6f): For the reaction de-
scribed in Table 2, Entry 15, 6f, and 5f were eluted in that order
with cyclohexane/ethyl acetate (68:32) as eluent. Pale yellow oils.
1H NMR [pair of diastereoisomers (the signal of the second stereo-
isomer, when detectable, is reported in parentheses), 300 MHz,
CDCl3, 25 °C, TMS]: δ = 8.20 (br. s, 1 H, NH), 8.07 (br. s, 1 H,
110.7, 61.1, 60.5, 53.8, 47.7, 13.7, 13.8 ppm. IR (Nujol): ν = 3406
˜
(NH), 1720 (C=O) cm–1. C30H29N3O4 (495.6): calcd. C 72.71, H
5.90, N 8.48; found C 72.58, H 6.03, N 8.61.
Ethyl
2-(5-Amino-2,4-dimethoxyphenyl)-2-(1H-indol-3-yl)acetate
(5e): For the reaction described in Table 2, Entry 13, 4e, 6e and 5e
were eluted in that order with cyclohexane/ethyl acetate (68:32) as
1
3
3
eluent. Pale yellow oil. H NMR (300 MHz, CDCl3, 25 °C, TMS):
NH), 7.86 (d, JH,H = 7.6 Hz, 1 H, indole 4-H), 7.56 (d, JH,H
7.9 Hz, 1 H, indole 4-H), 7.40–7.05 (m, 8 H, indole protons), 6.76
=
3
δ = 8.21 (br. s, 1 H, NH), 7.55 (d, JH,H = 7.9 Hz, 1 H, indole 4-
Eur. J. Org. Chem. 2008, 6232–6238
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6237

G. Desimoni, G. Faita, M. Mella, M. Toscanini, M. Boiocchi
FULL PAPER
[3] H. Bienaymé, C. Hulme, G. Oddon, P. Schmitt, Chem. Eur. J.
2000, 6, 3321–3329.
[4] A. J. von Wangelin, H. Neumann, D. Gördes, S. Klaus, D.
Strübing, M. Beller, Chem. Eur. J. 2003, 9, 4286–4294.
[5] D. J. Ramón, M. Yus, Angew. Chem. Int. Ed. 2005, 44, 1602–
1634.
[6] G. Guillena, D. J. Ramón, M. Yus, Tetrahedron: Asymmetry
2007, 18, 693–700.
[7] A. Strecker, Justus Liebigs Ann. Chem. 1850, 75, 27.
(6.74) (s + s, 1 H, 3-H aromatic proton), 6.250 (6.245) (s + s, 1 H,
6-H aromatic proton), 5.52 (s, 1 H, CH acetate), 5.39 (s, 1 H, CH
acetate), 5.3 (br. s, 1 H, NH), 4.22 (m, 4 H, 2ϫOCH2), 3.70 (3.69)
(s + s, 3 H, methoxy), 3.63 (3.61) (s + s, 3 H, methoxy), 1.255,
3
1.245, (1.240, 1.299) (t + t + t + t, JH,H = 7.5 Hz, 6 H, 2ϫCH3
ethyl) ppm. 13C NMR [pair of diastereoisomers (the signal of the
second stereoisomer, when detectable, is reported in parentheses),
75 MHz, CDCl3, 25 °C, TMS]: δ = 173.4, 172.0, 151, 140.7 (140.6),
136.01 (135.98), 135.88, 135.80 (135.77), 126.5, 125.4, 122.6, 122.5, [8] A. Hantzsch, Ber. Dtsch. Chem. Ges. 1890, 23, 1474–1476.
[9] P. Biginelli, Ber. Dtsch. Chem. Ges. 1891, 24, 2962–2967; P. Bi-
ginelli, Gazz. Chim. Ital. 1893, 23, 360–416.
[10] C. Mannich, W. Krosche, Arch. Pharm. 1912, 250, 647–667.
[11] M. Passerini, Gazz. Chim. Ital. 1921, 51, 126–129.
[12] P. R. Andreana, C. C. Liu, S. L. Schreiber, Org. Lett. 2004, 6,
4231–4233; S. X. Wang, M. X. Wang, D. X. Wang, J. Zhu, An-
gew. Chem. Int. Ed. 2008, 47, 388–391.
[13] M. Passerini, M. Bonciani, Gazz. Chim. Ital. 1933, 63, 138–
144; M. Passerini, F. Albani, Gazz. Chim. Ital. 1935, 65, 933–
938.
[14] 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.
Fandrick, Org. Lett. 2006, 8, 3351–3354; c) D. A. Evans, K. R.
Fandrick, H. Song, K. A. Scheidt, R. Xu, J. Am. Chem. Soc.
2007, 129, 10029–10041.
[15] 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,
Tetrahedron Lett. 2004, 45, 4567–4570.
[16] J. Esquivias, R. Gómez Arrayás, J. C. Carretero, Angew. Chem.
Int. Ed. 2006, 45, 629–633.
[17] Y. X. Jia, J. H. Xie, H. F. Duan, L. X. Wang, Q. L. Zhou, Org.
Lett. 2006, 8, 1621–1624.
[18] a) G. B. Rowland, E. B. Rowland, Y. Liang, J. A. Perman, J. C.
Antilla, Org. Lett. 2007, 9, 2609–2611; b) Q. Kang, Z. A. Zhao,
S. L. You, J. Am. Chem. Soc. 2007, 129, 1484–1485; c) M. Ter-
ada, S. Yokoyama, K. Sorimachi, D. Uraguchi, Adv. Synth. Ca-
tal. 2007, 349, 1863–1867; d) Q. Kang, X. J. Zheng, S. L. You,
Chem. Eur. J. 2008, 14, 3539–3542.
[19] Y. Q. Wang, J. Song, R. Hong, H. Li, L. Deng, J. Am. Chem.
Soc. 2006, 128, 8156–8157.
[20] M. Johannsen, Chem. Commun. 1999, 2233–2234.
[21] B. Jiang, Z. G. Huang, Synthesis 2005, 2198–2204.
[22] M. Soueidan, J. Collin, R. Gil, Tetrahedron Lett. 2006, 47,
5467–5470.
122.0, 121.6, 119.5, 119.0, 118.9, 114.6 (114.5), 113.71 (113.65),
112.23 (112.17) 111.1, 110.8, 110.5, 95.86 (95.78), 61.0, 60.2, 55.02
(55.95), 55.89 (55.55), 53.8, 40.97 (40.88), 13.75, 13.69 ppm. IR
(Nujol): ν = 3404 (NH), 1718 (C=O) cm–1.
˜
X-ray Crystallographic Study: Diffraction data for a crystal of 5a
were collected with a Bruker-Axs Smart-Apex CCD-based dif-
fractometer, working with graphite-monochromatized Mo-Kα radi-
ation (λ = 0.71073 Å). Crystal data for 5a: C19H20N2O3; Mr
=
324.37; T = 293 K; crystal dimensions 0.50ϫ0.45ϫ0.05 mm; tri-
¯
clinic; P1 (No. 2); a = 8.9027(6), b = 9.5400(7), c = 11.4684(8) Å;
α = 70.058(1), β = 70.685(1), γ = 86.011(1)°; V = 863.06(10) Å3; Z
= 2; ρcalcd. = 1.248; F(000) = 344; µ = 0.085 mm–1; 2θmax = 60°;
16719 measured reflections; 5060 independent reflections (Rint
=
0.022); 3751 strong reflections [Io Ͼ2σ(Io)]; 228 refined parameters;
R1 = 0.0533 (strong data) and 0.0691 (all data); wR2 = 0.1439
(strong data) and 0.1561 (all data); GOF = 1.040; 0.33 and –0.17
max. and min. residual electron density. Data reduction (including
intensity integration, background, Lorentz and polarization correc-
tions) was performed with the SAINT software.[27] Absorption ef-
fects were empirically evaluated by use of the SADABS software,[28]
and absorption correction was applied to the data (min./max.
transmission factors were 0.891/0.993). The crystal structure was
solved by direct methods (SIR97)[29] and refined by full-matrix, le-
ast-squares procedures on F2 with use of all reflections
(SHELXL97).[30] 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 with a riding model; H atoms
bonded to N atoms were located in the ∆F map and refined with
restraint of the N–H distance to 0.96Ϯ0.01 Å. CCDC-693250 con-
tains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[23] J. L. Zhao, L. Liu, H. B. Zhang, Y. C. Wu, D. Wang, Y. J. Chen,
Synlett 2006, 96–100.
[24] G. Desimoni, G. Faita, F. Piccinini, M. Toscanini, Eur. J. Org.
Chem. 2006, 5228–5230.
[25] G. Desimoni, G. Faita, M. Mella, F. Piccinini, M. Toscanini,
Eur. J. Org. Chem. 2007, 1529–1534; G. Desimoni, G. Faita,
M. Toscanini, M. Baiocchi, Chem. Eur. J. 2007, 13, 9478–9485.
[26] G. Desimoni, G. Faita, M. Toscanini, M. Baiocchi, Chem. Eur.
J. 2008, 14, 3630–3636.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of products obtained from thermal
and ScIII-catalysed reactions.
[27] SAINT-NT, Software Reference Manual, version 6, Bruker
AXS, Inc., Madison, Wisconsin, USA, 2003.
Acknowledgments
[28] G. M. Sheldrick, SADABS, Siemens Area Detector Absorption
Correction Program, University of Göttingen, Germany, 1996.
[29] A. Altomare, M. C. Burla, M. Camalli, G. L. Cascarano, C.
Giacovazzo, A. Guagliardi, A. G. G. Moliterni, G. Polidori, R.
Spagna, J. Appl. Crystallogr. 1999, 32, 115–119.
[30] G. M. Sheldrick, SHELX97, Programs for Crystal Structure
Analysis, University of Göttingen, Germany, 1997.
Received: September 2, 2008
This work was supported by the Ministero Istruzione Università
Ricerca (MIUR) and the University of Pavia.
[1] Multicomponent Reactions (Eds.: J. Zhu, H. Bienaymé), Wiley-
VCH, Weinheim, 2005.
[2] For a recent review see: D. M. D’Souza, J. J. Miller, Chem. Soc.
Rev. 2007, 36, 1095–1108.
Published Online: November 12, 2008
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Eur. J. Org. Chem. 2008, 6232–6238