Zn-mediated synthesis of 3-substituted indoles using a three-component reaction approach

Article abstract of DOI:10.1002/ejic.201200150

The synthesis of 3-substituted indoles was investigated through a multicomponent reaction (MCR) approach by using aldehydes, indole and malononitrile as the reagents. The reaction was catalyzed by Lewis acidic Zn(salphen) complexes and their performance was compared with a number of other Zn^II structures and M(salphen)s, which showed the Zn(salphen)s to be superior. However, the complex nature of this three-component reaction (3-CR) results in substantial byproduct formation that arises from the intermediate benzylidene malononitrile species. The 3-CR was studied in detail that covered the influence of the base, solvent, reagent stoichiometry and also involved stability studies. The results led to a mechanistic proposal in which the benzylidene malononitrile intermediate plays a central role; it is one of the major species that is formed in most of the catalytic reactions studied. Furthermore, it provided a prelude for the in situ reaction with the malononitrile reagent, which most probably affords a complex mixture of N-containing heterocycles. Copyright

Full text of DOI:10.1002/ejic.201200150

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FULL PAPER
DOI: 10.1002/ejic.201200150
Zn-Mediated Synthesis of 3-Substituted Indoles Using a Three-Component
Reaction Approach
Daniele Anselmo,[a] Eduardo C. Escudero-Adán,[b] Marta Martínez Belmonte,[b] and
Arjan W. Kleij*[a,b]
Keywords: Homogeneous catalysis / Zinc / Multicomponent reactions / Nitrogen heterocycles / Salphen ligands
The synthesis of 3-substituted indoles was investigated
through a multicomponent reaction (MCR) approach by
using aldehydes, indole and malononitrile as the reagents.
The reaction was catalyzed by Lewis acidic Zn(salphen) com-
plexes and their performance was compared with a number
of other ZnII structures and M(salphen)s, which showed the
Zn(salphen)s to be superior. However, the complex nature of
this three-component reaction (3-CR) results in substantial
byproduct formation that arises from the intermediate
benzylidene malononitrile species. The 3-CR was studied in
detail that covered the influence of the base, solvent, reagent
stoichiometry and also involved stability studies. The results
led to a mechanistic proposal in which the benzylidene ma-
lononitrile intermediate plays a central role; it is one of the
major species that is formed in most of the catalytic reactions
studied. Furthermore, it provided a prelude for the in situ
reaction with the malononitrile reagent, which most probably
affords a complex mixture of N-containing heterocycles.
reaction medium. The fact that Cu(salphen) complexes are
able to catalyze this 3-CR caught our attention because we
have recently reported that Zn(salphen) complexes are ex-
cellent Lewis acid activators in the catalytic conversion of
oxiranes and carbon dioxide to afford organic carbonates.[5]
Cu(salphen)s are coordinatively saturated whereas
Zn(salphen)s show a propensity to form pentacoordinated
structures due to the high Lewis acidity that these systems
possess.[6] Therefore, we envisioned that the use of ZnII-
rather than CuII-salphen complexes would be beneficial for
effective synthesis of the 3-substituted indoles. It is worth
noting that recent work has shown that Cu- and
Zn(salen)s have a tendency to decompose under aqueous
conditions to provide access to “half-salen” type intermedi-
ates.[7] This stability issue therefore raises the question as to
whether or not water is truly the best solvent for this 3-CR
process since the organic products needed to be isolated and
purified by using organic solvents.
Introduction
Multicomponent reaction (MCR) strategies represent a
powerful tool in organic synthesis for creating diversity-ori-
ented libraries of scaffolds with potentially interesting bio-
logical activities.[1] The attractiveness of the MCR approach
is undoubtedly the simple operation by which organic struc-
tures with impressive molecular complexity can be as-
sembled into targets with, ideally, high selectivity and yield
by using minimal synthetic requirements. In this context,
indole scaffolds have achieved a prominent position as these
structures are known for their importance in the develop-
ment of new compounds of pharmaceutical interest.[2] For
the family of substituted indoles there exists a number of
MCRs that are comprised of efficient procedures towards
these structures.[3] Recent interest in this field, which fo-
cused on 3-substituted indoles, revealed that such MCR ap-
proaches may be also feasible in environmentally benign
solvents such as water.[4] Zhou and coworkers reported that
water-soluble Cu(salphen)s [salphen = N,NЈ-bis(salicylid-
ene)imine-1,2-phenylenediamine] in the presence of a suit-
able base are excellent catalysts for converting various com-
binations of aldehydes, malononitrile and indoles into the
respective 3-component reaction (3-CR) products
(Scheme 1) and provide high yields by using water as the
[a] Institute of Chemical Research of Catalonia (ICIQ),
Av. Països Catalans 16, 43007 Tarragona, Spain
Fax: +34-977-920-828
Scheme 1. A 3-CR affording 3-substituted indoles.
E-mail: akleij@iciq.es
[b] Catalan Institute for Research and Advanced Studies (ICREA),
Pg. Lluís Companys 23, 08010 Barcelona, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201200150.
Herein we report an extensive investigation into the use
of Zn(salphen) complexes as mediators for the 3-CR that
affords 3-substituted indoles. The process parameters, such
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A. W. Kleij et al.
FULL PAPER
as temperature, solvent, type of base, catalyst structure, sta- Table 1. Screening of various Zn-based catalysts in the 3-CR
towards 3-substituted indoles.[a]
bility of intermediates and the final 3-CR product, were
investigated and a comparison with previously reported
data[4] was carried out. The results show that the 3-CR ap-
proach towards 3-substituted indoles (Scheme 1) is much
more complicated than was previously reported and that
the selectivity towards the desired target is compromised
by side-product formation, which encompasses the reaction
between an intermediate 2-CR compound and malono-
nitrile.
Results and Discussion
As part of our screening strategy, we used a number of
Zn-based structures/salts to explore their potential as cata-
lysts for the 3-CR reported in Scheme 1. By using the reac-
tion conditions reported previously for water-soluble
Cu(salphen) complexes,[4] the influence of the base, solvent
and catalyst structure was examined and the results are re-
ported in Table 1.
Firstly, we tested complexes 1 to 4 as catalyst candidates
and used benzaldehyde, malononitrile and indole as stan-
dard reagents. We selected a relatively non-nucleophilic ter-
Cat.
Base
–
Solv.
T
3-CR 2-CR PhCHO MB[%]
tiary amine (DIPEA = diisopropylethylamine) as the base
since tertiary amines have been shown to have a negligible
competing interaction with the Lewis acidic ZnII ions in
salen or salphen structures.[8]
[c]
[°C] [%][b]
[%][b]
[%][b]
–
–
1
1
DCM
25
25
25
25
25
25
40
25
25
60
60
25
25
25
25
25
25
25
0
2
0
56
28
2
57
0
Ͻ1
0
0
27
20
12
24
11
0
11
56
69
19
42
86
0
76
Ͻ 1
31
11
1
0
1
0
44
7
8
1
3
6
4
Ͻ1
7
87
58
100
86
71
88
DIPEA DCM
DCM
–
In all of the reactions that we performed we observed
the formation of several species but the major identified
components proved to be a 2-CR intermediate[9] and the 3-
CR target; the amount of each component depended highly
on the reaction conditions and the catalyst employed. The
DIPEA DCM
DIPEA DCM
DIPEA DCM
DIPEA DCM
DIPEA TCE
DIPEA ACE
DIPEA THF
DIPEA TOL
DIPEA DCM
DIPEA DCM
DIPEA DCM
1[d]
1[e]
1
58
1
1
100
0
100
Ͻ45
49
67
86
66
81
32
Ͻ69
7
1
2-CR and 3-CR products are easily recognized in the H
1[f]
1[f]
2
42
59
58
43
63
4
NMR spectra (Supporting Information) through the Ha,
Hb–Hc and NH protons (see graphic in Table 1). In the ab-
sence of base and catalyst low amounts of the 2-CR prod-
uct was already noted (Table 1, 11%) whereas the presence
of DIPEA or catalyst 1 afforded much higher levels of this
intermediate. When 1 and DIPEA were combined, the high-
est amount of the 3-CR product was observed (56%) to-
gether with low amounts of the 2-CR product (19%) and
unreacted aldehyde (11%). Hence, it would appear that
complex 1 is particularly effective for mediating the conver-
sion of the 2-CR product into the 3-CR compound. Other
Lewis acidic Zn complexes, such as 2, 3[10] and 4, were also
tested but showed inferior behaviour, that is, significantly
lower amounts of the 3-CR product were noted.
Interestingly, on examination of the mass balance (i.e.
converted aldehyde + free aldehyde against the normalized
amount of indole-based components) it was clear that some
aldehyde remains unaccountable. Despite the fact that in
some reactions this amount is rather high, no clear evidence
for other side products could be derived from the recorded
3
4
1
DBU
NEt3
TBAH DCM
PS DCM
DCM
DCM
1
57
0
1
1
23
50
1
74
[a] All of the reactions were carried out by using 0.11 mmol of
indole, 0.11 mmol of malononitrile and 0.10 mmol of benzaldehyde
and by using 5 mol-% of catalyst and 1 equiv. of base in 3.0 mL of
solvent for 24 h. Acronyms used: DIPEA = diisopropyl ethylamine,
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, TBAH = tetrabutylam-
monium hydroxide, PS = proton sponge: 1,8-bis(dimethylamino)-
naphthalene. [b] Determined by 1H NMR spectroscopy in [D6]-
DMSO and related to [3-CR] + free [indole]; the 2-CR and 3-CR
structures are provided in the scheme at the top of Table 1. [c] MB
is the mass balance based on [3-CR] + [2-CR] + free [PhCHO] vs.
total indole, i.e. normalized [3-CR] + free [indole]. [d] Using
0.5 equiv. of base. [e] Using 0.05 equiv. of base. [f] Reaction time
was 6 h.
1H NMR spectra. Since the stable 2-CR intermediate seems malononitrile) intermediate may further react with malono-
to play a key role, one can envision that it may be involved nitrile to afford a tetracyano derivative (Scheme 2, A), and,
in side reactions. A recent contribution from Chao-Guo depending on the reaction conditions, even the formation
and coworkers[11] revealed that the 2-CR (2-benzylidene- of pentasubstituted pyridines (B) should be considered.
2
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Zn-Mediated Synthesis of 3-Substituted Indoles
Scheme 2. Side-product formation starting from the 2-CR interme-
diate that results in loss of 3-CR selectivity.
The use of other bases such as DBU (1,8-diazabicyclo-
[5.4.0]undec-7-ene), NEt3, NBu4OH or proton sponge [1,8-
bis(dimethylamino)naphthalene] did not improve the selec-
tivity towards the 3-CR product. Furthermore, lower than
stoichiometric amounts of DIPEA had a detrimental effect
on the formation of the 3-CR compound. Other solvents,
including dichloroethane (DCE), THF, acetone and
MeOH, were also probed but the results were poor in terms
of the formation of the 3-CR target (Table 1) even at ele-
vated temperatures. Therefore, the next step was to investi-
gate whether or not the Zn(salphen) structure could be fur-
ther optimized by using dichloromethane (DCM) as the sol-
vent and DIPEA as the stoichiometric base additive
(Table 2 and Scheme 3). A number of differently substituted
Zn(salphen)s were prepared that comprised of electron-
withdrawing groups installed at different positions on the
salphen backbone (1 and 7–12). A comparison was made
with appropriate AlIII- and CuII-salphens (5, 6 and 13) in
order to evaluate the relative efficacies in this MCR. The
X-ray molecular structure was determined for one represen-
tative Zn(salphen) (8) (Figure 1);[12] this structure serves to
Scheme 3. M(salphen) catalyst structures 1 and 5 to 13 that were
used in this work.
Figure 1. X-ray molecular structure determined for Zn(salphen)
complex 8. H atoms and cocrystallized solvent are omitted for clar-
ity and a partial numbering scheme is provided. Selected bond
lengths [Å] and angles [°]: Zn(1)–O(1) 1.9765(8), Zn(1)–O(2)
1.9769(8), Zn(1)–N(1) 2.0948(9), Zn(1)–N(2) 2.0759(9), Zn(1)–O(7)
demonstrate that the Lewis acidic Zn ion presents axial 2.0712(9); O(1)–Zn(1)–O(2) 98.54(3), N(1)–Zn(1)–N(2) 78.34(4),
O(1)–Zn(1)–N(2) 158.64(4), O(2)–Zn(1)–N(1) 160.17(4), O(1)–
binding for potential substrates.
Zn(1)–N(1) 88.07(4), N(2)–Zn(1)–O(7) 104.63(4), O(2)–Zn(1)–O(7)
93.79(3).
Table 2. Screening of various M(salphen) catalysts in the 3-CR
towards 3-substituted indoles.[a]
The Zn(salphen)s that are equipped with NO2 and/or Br
Cat.
T [°C] 3-CR [%][b] 2-CR [%][b] PhCHO [%][b] MB [%][c]
substituents were tested as catalysts for the MCR towards
3-substituted indoles with the primary objective to increase
the selectivity for the target 3-CR product. As can be de-
duced from Table 2, Zn(salphen) 8 showed the highest selec-
tivity for the 3-CR derivative (60%) at 25 °C, a result that
could not be improved by increasing the reaction tempera-
ture (40 °C: 41%). However, complexes 1, 10 and 11 showed
similar results that indicated that the structure of the cata-
lyst does not impart a significant influence under these re-
action conditions. Water-soluble Cu(salphen)s have recently
been reported as efficient catalysts for the same MCR lead-
ing to high isolated yields of the 3-CR product.[4] Therefore,
we also tested complexes 12 (M = Zn) and 13 [M = Cu;
made in situ by transmetalation of 12 with Cu(OAc)2][13] by
using H2O as the medium at 60 °C and KH2PO4 as the
base, which are the original conditions. In our hands, we
failed to reproduce these original results; on the contrary,
1
5
6
7
8
8
9
10
11
12[d]
13[d]
25
25
25
25
25
40
25
25
25
60
60
56
5
6
19
46
75
17
10
31
40
37
29
48
34
11
7
1
0
1
6
1
8
5
86
58
84
25
71
78
66
94
86
8
60
41
25
49
52
36
9
Ͻ 1
7
Ͻ 85
50
[a] All of the reactions were carried out by using 0.11 mmol of
indole, 0.11 mmol of malononitrile and 0.10 mmol of benzaldehyde
and by using 5 mol-% of catalyst and 1 equiv. of DIPEA in 3.0 mL
of DCM. [b] Determined by 1H NMR spectroscopy in [D6]DMSO
and related to [3-CR] + free [indole]. [c] MB is the mass balance
based on [3-CR] + [2-CR] vs. total indole, i.e. normalized [3-CR]
+ free [indole]. [d] The base was KH2PO4 and the reaction time
was 6 h.
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we observed rather similar features to that of the other
In order to further evaluate the formation of both the 2-
Zn(salphen)s. Much lower amounts of the 3-CR product CR intermediate as well as the 3-CR indole product, we
were formed and concomitantly higher amounts of the 2- followed this MCR in time by using 1H NMR spectroscopy
CR product were present. In general, these results are in (CD2Cl2, Figure 2) and three different aldehyde reagents.
line with the general impression that the formation of the As for benzaldehyde, the reaction is slow (as expected) and
3-CR product is significantly compromised by side-product low levels of the 3-CR product are formed (ca. 25%) after
formation as indicated in Scheme 2.
22.5 h. Interestingly, under these conditions there is a slow
We then screened some other aldehydes and monitored decay of the 2-CR intermediate after a fast initial forma-
the formation of both the 2-CR (15–19) and 3-CR products. tion. Significantly larger amounts of the 3-CR product (50–
We found that in the case of the more electron-deficient 55%) are formed for the more reactive aldehydes (4-
reagents the amount of 3-CR product was comparable with bromobenzaldehyde and 3,5-dibromobenzaldehyde, Fig-
that noted in the case of benzaldehyde (54–55%) while ure 2), and the decay in the 2-CR intermediate is also no-
(very) low amounts of the 2-CR intermediate could be ob- tably faster. In the case of 3,5-dibromobenzaldehyde the
served. This indicates that the respective 2-CR derivatives amount of the 2-CR derivative was lowered to around 4%
16 and 17 are more prone to form the 3-CR target but are after 22.5 h.
also likely to react in situ with malononitrile to form side
products. This is in line with the mass balance data for these
substrates as lower amounts of accountable aldehyde-based
components are noted in the reactions that involve 3,5-di-
bromobenzaldehyde, 4-bromobenzaldehyde or benzalde-
hyde. To further test this hypothesis, we used the relatively
electron-rich 4-methoxy- and 4-methylbenzaldehyde as sub-
strates (Table 3); in these cases much higher amounts of the
2-CR intermediates 18 and 19 were found together with
small amounts of 3-CR products. More importantly, a
nearly closed mass balance is apparent when these sub-
strates were used.
Table 3. Screening of various aldehydes in the 3-CR towards 3-
substituted indoles[a] catalyzed by complex 8 and the influence of
reaction stoichiometry.
Figure 2. 1H NMR spectroscopy analysis ([D2]DCM, 30 °C) in
time of the 3-CR reactions catalyzed by 8 involving benzaldehyde
(filled circles), 4-bromobenzaldehyde (filled triangles) and 3,5-di-
bromobenzaldehyde (filled pentagons). Note that both the forma-
tion of the 3-CR product (top) as well as the decay of the 2-CR
intermediate was examined (below) by using normalized NMR in-
tegrals. The purple dot at t = 22.5 h indicates the reaction without
any catalyst.
Cat. T [°C]
R
3-CR [%][b] 2-CR [%][b] RCHO [%][b] MB [%][c]
8[d] 25
8[e] 25
8[f] 25
H
H
H
3,5-Br2
4-Br
H
4-Me
4-MeO
48
13
22
54
55
60
16
15
26
56
35
0
11
10
73
84
Ͻ 1
0
–
0
1
1
2
1
Ͻ 75
69
–
54
67
71
91
100
8
8
8
8
8
25
25
25
25
25
Preformed 2-benzylidenemalononitrile (15) (i.e. the 2-CR
intermediate of the reaction that involved benzaldehyde)
was then treated with indole under the catalytic conditions
to see whether or not larger amounts of product could be
formed. In 24 h, the amount of the 3-CR product was 33%,
and, remarkably, some free aldehyde (3% by integration)
was also present. The free aldehyde probably arises from
some decomposition of the 2-CR reagent rather than from
the 3-CR product as the stability of the 3-CR derivative
was confirmed by separate NMR spectroscopy studies that
showed no observable changes under similar conditions
over 24 h (Supporting Information).
[a] All of the reactions were carried out by using 0.11 mmol of
indole, 0.11 mmol of malononitrile and 0.10 mmol of benzaldehyde
and by using 5 mol-% of 8 and 1 equiv. of DIPEA in 3.0 mL of
1
DCM, unless otherwise stated. [b] Determined by H NMR spec-
troscopy in [D6]DMSO and related to [3-CR] + free [indole]. [c]
MB is the mass balance based on [3-CR] + [2-CR] vs. total indole,
i.e. normalized [3-CR] + free [indole]. [d] The ratio of indole/alde-
hyde/malonionitrile was 2:1:1. [e] The ratio of indole/aldehyde/ma-
lononitrile was 1:1:2. [f] The ratio of indole/aldehyde/malononitrile
was 1:2:1.
4
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Zn-Mediated Synthesis of 3-Substituted Indoles
Finally, the reaction of 2-benzylidenemalononitrile (15) intermediate 2-CR derivative (i.e. the benzylidenemalonon-
with one equivalent of malononitrile in dichloromethane itrile) causes significant side-product formation that is a
was carried out in order to study the possible formation probable result of in situ conversion into N-heterocyclic
of side products. After 24 h, NMR spectroscopy analysis structures. The (irreversible) side-product formation de-
showed the presence of other species (asterisks in Figure 3, pends on the type of benzaldehyde used as larger amounts
red trace). When the NMR spectrum was compared with of side products seem to be evident when electron-poor rea-
that of the 1:2:1 stoichiometry reaction (i.e. benzaldehyde/ gents are used. This work demonstrates that this MCR re-
malononitrile/indole, Table 3 and blue trace in Figure 3) action is not as straightforward as previously communi-
similar peaks at 3.5, 4.8 and 5.05 ppm were noted. Thus, it cated.[4] Further research is thus required to increase the
seems likely that the 2-CR intermediate 15 in the presence overall selectivity towards the 3-CR target, and, since the
of malononitrile can lead to side-product formation with MCR products contain a chiral centre, the development of
chemical structures that are related to those in Scheme 2. asymmetric versions also remains a highly attractive objec-
Although an excess of malononitrile was probed in this tive.
case, we have seen similar by-products in other reactions
carried out with various catalysts (although in most cases
in reduced amounts), which indicates that in the course of
3-CR product formation, the formation of these side prod-
ucts effectively lowers the selectivity for the desired product.
We also checked the stability of 15 in the presence of
DIPEA (see Supporting Information) and found that some
decomposition of the alkene intermediate 15 takes place as
several traces of other components (cf. Figure 3) were pres-
ent after 24 h. Thus, an in situ “retro” Knoevenagel con-
densation reaction of 15 followed by irreversible formation viously reported. Complexes 1,[16] 3,[10a] 5,[5b] 6,[5b] 7,[5b] 10[13] and
of side products may lead to diminished selectivity for the
Experimental Section
General: NMR spectra were recorded with a Bruker AV-400 or AV-
500 spectrometer and were referenced to the residual deuterated
solvent signals. Elemental analysis was performed by the Unidád
de Análisis Elemental at the Universidad de Santiago de Compost-
ela. Mass spectrometric analysis and X-ray diffraction studies were
performed by the Research Support Group at the ICIQ. The inter-
mediate compounds 15,[14] 16,[15] 18[14] and 19[14] have been pre-
11[13] were prepared according to previously reported procedures.
3-CR product.
Zn(salen) Complex 2: A solution of (+)-(1R,2R)-1,2-diphenyleth-
ylenediamine (96 mg, 0.45 mmol), 3,5-dinitrosalicylaldehyde
(200 mg, 0.94 mmol) and Zn(OAc)2·2H2O (110 mg, 0.50 mmol) in
MeOH (35 mL) was stirred for 4 h at room temperature. The de-
sired compound was isolated by filtration and dried in vacuo to
yield an orange solid; yield 214 mg (72%). 1H NMR (400 MHz,
4
[D6]acetone): δ = 8.59 (d, JH,H = 3.1 Hz, 2 H, ArH), 8.43 (s, 2 H,
4
CH=N), 8.35 (d, JH,H = 3.1 Hz, 2 H, ArH), 7.32–7.45 (m, 10 H,
ArH), 5.54 (s, 2 H, CH-CH) ppm. 13C{1H} NMR (100 MHz, [D6]-
acetone): δ = 168.36, 166.98, 137.15, 134.95, 132.37, 129.22, 129.03,
128.55, 123.64, 121.75, 83.25, 72.61 ppm. MS (MALDI–, DCTB):
m/z = 662.2 [M]– (calcd. 662.0). C28H18N6O10Zn·H2O: calcd. C
49.32, H 2.96, N, 12.32; found C 49.42, H 2.79, N 12.23.
Ligand Precursor to 8: 3-tert-Butyl-5-nitrosalicylaldehyde (147 mg,
0.66 mmol) was dissolved in MeOH (20 mL). ortho-Phenylenedi-
amine (36 mg, 0.33 mmol) was added and the mixture was stirred
for 6 h. The orange precipitate that formed was isolated by fil-
tration and dried in vacuo; yield 118 mg (69%). 1H NMR
(400 MHz, [D6]DMSO): δ = 15.40 (s, 2 H, OH), 9.30 (s, 2 H,
4
4
CH=N), 8.61 (d, JH,H = 2.7 Hz, 2 H, ArH), 8.15 (d, JH,H
=
1
Figure 3. A comparison of the 1–5.5 ppm region of the H NMR
2.7 Hz, 2 H, ArH), 7.69 (m, 2 H, ArH), 7.56 (m, 2 H, ArH), 1.41
[s, 18 H, C(CH3)3] ppm. 13C{1H} NMR (100 MHz, [D6]DMSO): δ
= 161.52, 158.20, 155.75, 136.43, 134.67, 135.17, 124.14, 122.10,
121.05, 114.93 30.64, 24.25 ppm. HRMS (ESI–, MeOH): calcd. for
C28H30N4O6 517.2087; found 517.2093.
spectra ([D6]DMSO) of DIPEA, the 2-CR derivative 15, the reac-
tion between isolated 15 and 1 equiv. of malononitrile at 24 h, and
the 1:2:1 reaction between benzaldehyde, malononitrile and indole
after 24 h. Abbreviations used: B = base [(iPr)2NEt], S = residual
solvent signals. The asterisks denote side products.
Zn(salphen) Complex 8: Zn(OAc)2·2H2O (60 mg, 0.27 mmol) was
added to a solution of the ligand precursor (110 mg, 0.21 mmol) in
MeOH (15 mL). The reaction mixture was stirred for 6 h during
which time an orange precipitate slowly formed. Filtration and dry-
Conclusions
1
ing in vacuo gave an orange solid; yield 118 mg (97%). H NMR
In summary, the MCR between (substituted) benzalde-
hydes, malononitrile and indole catalyzed by Zn(salphen)
complexes in the presence of DIPEA as the base affords
mixtures of reaction products. Whereas the 3-CR target can
4
(400 MHz, [D6]DMSO): δ = 9.28 (s, 2 H, CH=N), 8.56 (d, JH,H
4
= 3.0 Hz, 2 H, ArH), 8.05 (d, JH,H = 3.3 Hz, 2 H, ArH), 8.02–
8.04 (m, 2 H, ArH), 7.47–7.50 (m, 2 H, ArH), 1.50 [s, 18 H,
C(CH3)3] ppm. 13C{1H} NMR (100 MHz, [D6]DMSO): δ = 176.85,
be obtained with reasonable selectivity, the reactivity of the 163.60, 143.02, 139.34, 133.87, 133.33, 128.83, 124.78, 119.02,
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A. W. Kleij et al.
FULL PAPER
117.51, 35.76, 29.48 ppm. MS (MALDI–, pyrene): m/z = 580 [M]–
(calcd. 580). C28H28N4O6Zn·H2O: calcd. C 56.06, H 5.04, N 9.34;
found C 56.19, H 5.35, N 9.04.
3
= 7.6 Hz, 1 H, ArH), 5.84 (d, JH,H = 9.3 Hz, 1 H, CH=CH), 5.21
(d, 3JH,H = 9.3 Hz, 1 H, CH=CH) ppm. 13C{1H} NMR (100 MHz,
[D6]acetone): δ = 139.68, 136.52, 129.07, 128.46, 126.34, 123.19,
122.09, 119.33, 119.00, 114.50, 114.27, 112.80, 112.11, 42.89, 29.10
ppm. HRMS (ESI+, MeOH): calcd. for C18H13N3·Na [M + Na]+
294.1007; found 294.1012.
Zn(salphen) Complex 9: A mixture of 4,5-dibromo-o-phenylenedia-
mine (40 mg, 0.15 mmol), 3-tert-butyl-5-nitrosalicylaldehyde
(70 mg, 0.31 mmol) and Zn(OAc)2·2H2O (40 mg, 0.18 mmol) in
MeOH (20 mL) was stirred for 4 h at room temperature. The
orange product was then isolated by filtration and dried; yield
NMR Spectroscopy Studies: The NMR spectroscopy studies were
conducted by following the same conditions adopted for the cataly-
sis experiments except for the use of deuterated dichloromethane
as the solvent. After initial mixing of the reagents, a sample
(0.7 mL) was withdrawn and inserted into the NMR spectrometer
1
69 mg (62%). H NMR (400 MHz, [D6]acetone): δ = 9.37 (s, 2 H,
4
CH=N), 8.49 (d, JH,H = 3.0 Hz, 2 H, ArH), 8.45 (s, 2 H, ArH),
4
8.16 (d, JH,H = 3.0 Hz, 2 H, ArH), 1.55 [s, 18 H, C(CH3)3] ppm.
13C{1H} NMR (100 MHz, [D6]acetone): δ = 164.49, 143.50,
141.34, 139.72, 134.69, 132.63, 125.05, 123.30, 122.04, 118.33,
39.84, 35.46 ppm. MS (MALDI–, DCTB): m/z = 739.7 [M]– (calcd.
739.9). C28H26Br2N4O6Zn·3.5H2O: calcd. C 41.43, H 4.22, N 6.90;
found C 41.83, H 3.61, N 6.72.
1
for analysis. The NMR sample was examined over 24 h and a H
NMR spectrum was acquired every 30 min at 30 °C.
Synthesis of Intermediate Alkenes 15–19: The (substituted) benzyl-
idene malononitriles were prepared by a standard method. In a
typical example, malononitrile (444.3 mg, 6.73 mmol) was dis-
solved in EtOH (10 mL), benzaldehyde was added (713.9 mg,
6.73 mmol) followed by piperidine (2 drops), and the reaction mix-
ture was refluxed for a brief period of time. The precipitate that
formed upon cooling of the reaction mixture to room temperature
was isolated by filtration and dried in vacuo, following analysis by
NMR spectroscopy. A second fraction (cf. 15) was obtained by
cooling the mother liquor to –30 °C; yield 729.3 mg (4.73 mmol,
70%). Note that compounds 15, 16, 18 and 19 are literature-known
(see general remarks above).
Zn(salphen) Complex 12: To a solution of sodium 3-formyl-4-hy-
droxybenzenesulfonate (0.63 g, 2.38 mmol) in H2O (10 mL) was
added o-phenylenediamine (0.13 g, 1.20 mmol) dissolved in MeOH
(15 mL). The initial suspension quickly turned into a clear solution,
after which Zn(OAc)2·2H2O (0.28 g, 1.28 mmol) dissolved in H2O
(10 mL) was added. Instantaneously a suspension was obtained
that was filtered after 1 h to give 253.9 mg of product. A second
crop of product (164.0 mg) was obtained from the mother liquor
after dilution by acetone; yield 417.9 mg (60% based on the di-
amine reagent). 1H NMR (400 MHz, [D6]DMSO/[D5]pyridine =
2-Benzylidenemalononitrile (15): Yield 0.73 g (70%). 1H NMR
(300 MHz, [D6]DMSO): δ = 8.55 (s, 1 H, CH=C), 7.94–7.97 (m, 2
H, ArH), 7.62–7.72 (m, 3 H, ArH) ppm. 13C{1H} NMR (100 MHz,
[D6]DMSO): δ = 162.05, 134.85, 131.78, 130.97, 130.00, 114.69,
113.70, 82.09 ppm.
4
9:1 v/v): δ = 8.95 (s, 2 H, CH=N), 7.82 (d, JH,H = 2.4 Hz, 2 H,
ArH), 7.77–7.80 (m, 2 H, ArH), 7.59 (d, JH,H = 8.9, JH,H
2.4 Hz, 2 H, ArH), 7.34–7.36 (m, 2 H, ArH), 6.78 (d, JH,H
3
4
=
=
3
8.9 Hz, 2 H, ArH) ppm. 13C{1H} NMR (100 MHz, [D6]DMSO/
[D5]pyridine = 7:3 v/v): δ = 173.11, 163.50, 139.89, 134.41, 134.38,
132.98, 127.83, 123.01, 118.10, 117.03 ppm. MS (ESI–, MeOH):
m/z = 559.0 [M – Na]– (calcd. 558.9). HRMS (ESI–, MeOH): calcd.
For C20H12N2O8S2Zn [M – 2Na]2– 267.9669; found 267.9654.
2-(4-Bromobenzylidene)malononitrile (16): Yield 0.94 g (84%). 1H
NMR (400 MHz, [D6]DMSO): δ = 8.54 (s, 1 H, CH=C), 7.87 (m, 4
H, ArH) ppm. 13C{1H} NMR (100 MHz, [D6]DMSO): δ = 160.75,
133.15, 132.60, 130.86, 128.79, 114.55, 113.48, 82.78 ppm.
Catalytic Reactions: In
a
typical procedure, the catalyst
(0.005 mmol), indole (0.11 mmol) and malononitrile (0.11 mmol)
were dissolved in dichloromethane (3 mL). The aldehyde
(0.1 mmol) and DIPEA (0.1 mmol) were then added to the solu-
tion. The resulting mixture was stirred at 40 °C for 24 h and then
cooled to room temperature. Sampling after appropriate time inter-
vals was done by taking aliquots, concentration and NMR spec-
troscopy analysis in [D6]DMSO. Identification of the reaction com-
ponents was done by comparison with authentic samples. For the
isolation of pure 3-CR product, the reaction mixture was dried with
Na2SO4 and the solvent was removed under reduced pressure. The
residue was purified by silica gel flash column chromatography
(hexane/AcOEt: 8:1 to 4:1)[4] to give the desired product. See below
for a typical example.
2-(3,5-Dibromobenzylidene)malononitrile (17): Yield 1.15 g (74%).
1H NMR (500 MHz, [D6]DMSO): δ = 8.49 (s, 1 H, CH=C), 8.20
(d, 4JH,H = 2.2 Hz, 1 H, Ar-H), 8.10 (d, 4JH,H = 1.9 Hz, 2 H, Ar-H)
ppm. 13C{1H} NMR (125 MHz, [D6]DMSO): δ = 158.75, 138.47,
135.20, 132.02, 123.65, 114.02, 112.94, 85.75 ppm. HRMS (APCI+,
MeOH): calcd. for C11H9N2OBr2 [M + MeOH + H]+ 342.9082;
found 342.9091. C10H4Br2N2: calcd. C 38.50, H 1.29, N 8.98; found
C 38.39, H 1.12, N 8.80.
2-(4-Methoxybenzylidene)malononitrile (18): Yield 0.82 g (88%). 1H
NMR (500 MHz, [D6]DMSO): δ = 8.44 (s, 1 H, CH=C), 7.85 (d,
JH,H = 8.2 Hz, 2 H, ArH), 7.41 (d, JH,H = 8.2 Hz, 2 H, ArH), 2.40
(s, 3 H, Me) ppm. 13C{1H} NMR (125 MHz, [D6]DMSO): δ =
164.82, 160.84, 133.83, 124.58, 115.63, 115.25, 114.34, 77.27, 56.36
ppm.
2-[(1H-Indol-3-yl)(phenyl)methyl]malononitrile: Zn-(salphen) com-
plex 1 (25 mg, 0.05 mmol), indole (129 mg, 1.1 mmol) and malono-
nitrile (73 mg, 0.11 mmol) were added to dichloromethane
(6.0 mL). Salicylaldehyde (106 mg, 1.0 mmol) and DIPEA (129 mg,
1.0 mmol) were then added to the solution. The resulting mixture
was stirred at 40 °C for 24 h and then cooled to room temperature.
The solution was dried with Na2SO4 and the solvent was removed
under reduced pressure. The residue was purified by silica gel flash
column chromatography (hexane/AcOEt: gradient from 8:1 to 4:1
2-(4-Methylbenzylidene)malononitrile (19): Yield 0.84 g (87%). 1H
NMR (500 MHz, [D6]DMSO): δ = 8.36 (s, 1 H, CH=C), 7.96 (d,
JH,H = 8.9 Hz, 2 H, ArH), 7.16 (d, JH,H = 8.9 Hz, 2 H, ArH), 3.98
(s, 3 H, OMe) ppm. 13C{1H} NMR (125 MHz, [D6]DMSO): δ =
161.68, 146.13, 131.16, 130.59, 129.20, 114.84, 113.87, 80.32, 21.92
ppm.
X-ray Crystallography: The measured crystals of complex 8 were
stable under atmospheric conditions. Nevertheless, they were
treated under inert conditions and were immersed in perfluoropoly-
ether as the protecting oil for manipulation. Measurements were
v/v) to give the desired product; yield 72.5 mg (30%). 1H NMR
4
(400 MHz, [D6]acetone): δ = 11.21 (s, 1 H, NH), 7.55 (d, JH,H
=
3
2.3 Hz, 1 H, ArH), 7.51 (d, JH,H = 7.1 Hz, 2H, ArH), 7.47 (d,
3JH,H = 8.1 Hz, 1 H, ArH), 7.34–7.39 (m, 3 H, ArH), 7.26–7.30 made with a Bruker–Nonius diffractometer that was equipped with
3
3
(m, 1 H, ArH), 7.08 (t, JH,H = 7.5 Hz, 1 H, ArH), 6.95 (t, JH,H an APPEX 2 4K CCD area detector, a FR591 rotating anode with
6
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Job/Unit: I20150
/KAP1
Date: 02-05-12 17:04:55
Pages: 8
Zn-Mediated Synthesis of 3-Substituted Indoles
2009, 48, 7892; d) S. Shirakawa, S. Kobayashi, Org. Lett. 2006,
Mo-Kα radiation, Montel mirrors and a Kryoflex low-temperature
device (T = –173 °C). Full-sphere data collection was used with ω
and φ scans. The program that was used for data collection was
Apex2 v. 2011-3 (Bruker–Nonius, 2008), for data reduction was
Saint+ version 7.60A (Bruker AXS 2008) and for absorption cor-
rection was SADABS v. 2008-1. The structure was solved with
SHELXTL version 6.10 (Sheldrick, 2000).[17] Structure refinement
was achieved with SHELXTL-97 for UNIX .
8, 4939.
[4] Y. Qu, F. Ke, L. Zhou, Z. Li, H. Xiang, D. Wua, X. Zhou,
Chem. Commun. 2011, 47, 3912.
[5] a) A. Decortes, M. Martínez Belmonte, J. Benet-Buchholz,
A. W. Kleij, Chem. Commun. 2010, 46, 4580; b) A. Decortes,
A. W. Kleij, ChemCatChem 2011, 3, 831.
[6] For some contributions, see: a) A. W. Kleij, Dalton Trans. 2009,
4635; b) A. W. Kleij, Chem. Eur. J. 2008, 14, 10520; c) E. C.
Escudero-Adán, J. Benet-Buchholz, A. W. Kleij, Chem. Eur. J.
2009, 15, 4233; d) S. J. Wezenberg, G. Salassa, E. C. Escudero-
Adán, J. Benet-Buchholz, A. W. Kleij, Angew. Chem. Int. Ed.
2011, 50, 713.
[7] E. Delahaye, M. Diop, R. Welter, M. Boero, C. Massobrio, P.
Rabu, G. Rogez, Eur. J. Inorg. Chem. 2010, 4450.
[8] A. Dalla Cort, L. Mandolini, C. Pasquini, K. Rissanen, L.
Russo, L. Schiaffino, New J. Chem. 2007, 31, 1633.
[9] In fact, the 2-CR constitutes the product of a well-known base-
assisted Knoevenagel condensation.
CCDC-865459 (for 8) contains the supplementary crystallographic
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): Experimental data, copies of relevant MS and NMR spectra
of known and new compounds.
[10] Complex 3 represents the “basic zinc acetate” structure that
has been known for decades. For its preparation, see: a) A. C.
Poshkus, Ind. Eng. Chem. Prod. Res. Dev. 1983, 22, 381.
Furthermore, Mashima and coworkers have recently reported
numerous catalytic applications for this Lewis acidic Zn4 struc-
ture. See, for instance: b) T. Ohshima, T. Iwasaki, Y. Maegawa,
A. Yoshiyama, K. Mashima, J. Am. Chem. Soc. 2008, 130,
2944; c) T. Ohshima, T. Iwasaki, K. Mashima, Chem. Commun.
2006, 2711.
Acknowledgments
This work was financially supported by the Ministerio de Ciencia
e Innovación (MICINN) (project number CTQ2011-27385), by Ca-
talan Institute for Research and Advanced Studies (ICREA) and
by the Institute of Chemical Research of Catalonia (ICIQ) (pre-
doctoral FPU fellowship to D. A.). We thank Dr. N. Cabello, A.
Gonzalez and S. Arnal for the mass spectrometry analyses and in-
terpretation. We also thank Prof. Dr. Paolo Melchiorre for fruitful
discussions.
[11] C. Jiao, M. Zhen, Y. Chao-Guo, Chem. Res. Chin. Univ. 2010,
26, 937.
[12] Crystallographic data for complex 8. Formula: C32H37N5O7Zn,
Fw = 669.04 gmol–1, crystal system: monoclinic, space group:
P21/c, a = 10.6855(5) Å, b = 16.6868(7) Å, c = 17.9841(8) Å, α
= 90°, β = 103.532(2)°, γ = 90°, V = 3117.7(2) Å3, Z = 4, ρcalcd.
= 1.425 Mg/m3, crystal size: 0.20ϫ0.10ϫ0.02 mm3, F(000) =
1400, μ = 0.844 mm–1, θ range: 1.69–28.41°, R1(R all data) =
0.0240 (0.0267), wR2 = 0.0686 (0.0704), reflections collected:
49495, independent reflections: 7822 [Rint = 0.0249], data/re-
straints/parameters: 7822/4/445, goodness-of-fit on F2: 1.053,
largest diff. peak (hole): 0.428 (–0.306) eÅ–3.
[13] We recently reported a versatile procedure for the in situ trans-
metalation of Zn(salphen) complexes, see: E. C. Escudero-
Adán, J. Benet-Buchholz, A. W. Kleij, Inorg. Chem. 2007, 46,
7265.
[14] C. Yue, A. Mao, Y. Wei, M. Lu, Catal. Commun. 2008, 9, 1571.
[15] U. R. Pratap, D. V. Jawale, R. A. Waghmare, D. L. Lingam-
palle, R. A. Mane, New J. Chem. 2011, 35, 49.
[16] A. W. Kleij, D. M. Tooke, M. Kuil, M. Lutz, A. L. Spek,
J. N. H. Reek, Chem. Eur. J. 2005, 11, 4743.
[17] G. M. Sheldrick, SHELXTL Crystallographic System, version
5.10, Bruker AXS, Inc., Madison, Wisconsin, 1998.
Received: February 14, 2012
[1] For reviews and seminal contributions, see: a) I. Ugi, A.
Dömling, B. J. Werner, Heterocycl. Chem. 2000, 37, 647; b) I.
Ugi, R. Meyr, U. Fetzer, C. Steinbrueckner, Angew. Chem.
1959, 71, 386; c) O. Kappe, Acc. Chem. Res. 2000, 33, 879; d)
A. Dömling, I. Ugi, Angew. Chem. 2000, 112, 3300; Angew.
Chem. Int. Ed. 2000, 39, 3168; e) R. V. A. Orru, M. de Greef,
Synthesis 2003, 1471; f) T. Ngouansavanh, J. Zhu, Angew.
Chem. 2006, 118, 3575; Angew. Chem. Int. Ed. 2006, 45, 3495;
g) A. Dömling, Chem. Rev. 2006, 106, 17; h) D. Tejedor, F.
Garcia-Tellado, Chem. Soc. Rev. 2007, 36, 484.
[2] See, for instance: a) M. Somei, F. Yamada, Nat. Prod. Rep.
2005, 22, 73; b) A. C. Kinsman, M. A. Kerr, J. Am. Chem. Soc.
2003, 125, 14120; c) F. J. Chang, J. B. Rangisetty, M. Dukat, V.
Setola, T. Raffay, B. Roth, R. A. Glennon, Bioorg. Med. Chem.
Lett. 2004, 14, 1961.
[3] a) K. Diker, M. Döé de Maindreville, D. Royer, F. Le Provost,
J. Lévy, Tetrahedron Lett. 1999, 40, 7463; b) G. W. Zhang, L.
Wang, J. Nie, J. A. Ma, Adv. Synth. Catal. 2008, 350, 1457; c)
P. Galzerano, F. Pesciaioli, A. Mazzanti, G. Bartoli, P. Mel-
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Published Online: ᭿
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7

Job/Unit: I20150
/KAP1
Date: 02-05-12 17:04:55
Pages: 8
A. W. Kleij et al.
FULL PAPER
Multicomponent Reactions
The Zn(salphen)-mediated synthesis of 3-
substituted indoles by using a multicom-
ponent reaction approach is reported. The
reaction parameters were investigated and
the selectivity for the 3-CR product was
examined under various conditions. Selec-
tivity for the target compound is signifi-
cantly compromised by side-product for-
mation due to in situ reaction of the inter-
mediate species with malononitrile, which
affords N-heterocyclic structures.
D. Anselmo, E. C. Escudero-Adán,
M. Martínez Belmonte,
A. W. Kleij* ...................................... 1–8
Zn-Mediated Synthesis of 3-Substituted
Indoles Using a Three-Component Reac-
tion Approach
Keywords: Homogeneous catalysis / Zinc /
Multicomponent reactions
heterocycles / Salphen ligands
/
Nitrogen
8
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