Trimolecular condensation of substituted indoles with paraformaldehyde and Meldrum's acid. Convective heating versus microwave irradiation: A comparative study

Article abstract of DOI:10.1055/s-1999-3395

Results obtained in a comparative study on the trimolecular condensation of substituted indoles 1 with paraformaldehyde and Meldrum's acid using convective heating vs. microwave irradiation are described. Both methods afforded adducts 2 together with their hydroxymethylated derivatives 3 in good yields. Although in both cases the yields are about the same, the microwave irradiation was found to be more advantageous, as this procedure makes possible to considerably reduce the reaction times and to obtain cleaner reaction mixtures.

Full text of DOI:10.1055/s-1999-3395

2
54
PAPER
Trimolecular Condensation of Substituted Indoles with Paraformaldehyde
and MeldrumÕs Acid. Convective Heating versus Microwave Irradiation:
A Comparative Study
Csaba Nemes,* Jean-Yves Laronze
UPRES A CNRS 6013, FacultŽ de Pharmacie, UniversitŽ de Reims-Champagne-Ardenne, 51, rue Cognacq-Jay, 51096 Reims CŽdex,
France
Fax +33(326)898029; E-mail: jean.levy@univ-reims.fr
Received 10 July 1998; revised 6 September 1998
the presence of the hydroxymethylated derivatives 3 in the
Abstract: Results obtained in a comparative study on the trimolec-
reaction mixtures, although they were not mentioned in
the publication describing the procedure.
ular condensation of substituted indoles 1 with paraformaldehyde
and MeldrumÕs acid using convective heating vs. microwave irradi-
2
ation are described. Both methods afforded adducts 2 together with
their hydroxymethylated derivatives 3 in good yields. Although in
both cases the yields are about the same, the microwave irradiation
hyde, therefore, we turned to the utilization of
was found to be more advantageous, as this procedure makes possi-
ble to considerably reduce the reaction times and to obtain cleaner
Owing to the problems detailed above, we found it desir-
able to avoid the use of the aqueous solution of formalde-
paraformaldehyde. The polymer form is easier to handle,
however, at ambient or slightly elevated temperatures its
depolymerization is slow and insufficient. We also ap-
plied the reactant in excess to reduce the reaction time, al-
though this excess can give rise to the formation of
secondary products. Nonetheless, our former experience
showed as well that one equivalent of paraformaldehyde
was not sufficient for the full conversion of the starting in-
dole.
reaction mixtures.
Key words: condensation, indole, MeldrumÕs acid, paraformalde-
hyde, microwave irradiation
In our laboratory, compounds 2 are key intermediates in
the synthesis of nonnatural tryptophan derivatives, which
can be used as topographical constraints in peptides and
peptidomimetics. Certain representatives of adducts 2
were reported to be obtained by following a synthetic
route utilizing the condensation of aqueous formaldehyde,
substituted indoles, and MeldrumÕs acid, although other
strategies have also been described in the literature for
their preparation. First, we attempted to apply the
former method to obtain several derivatives of com-
pounds 2. During our work, however, we encountered se-
vere problems concerning the reproducibility of this
procedure. Our difficulties started with the use of aqueous
formaldehyde, as with this reagent it proved to be prob-
1
Indoles 1aÐe bearing both electron-donor and electron-ac-
ceptor substituents in position 5 were allowed to react
with MeldrumÕs acid (1.1 equiv.) and paraformaldehyde
(
1.5 equiv.) in acetonitrile, in the presence of D,L-proline
5
as catalyst (0.05 equiv.) (Scheme 1). We found the D,L-
proline optimal for this role, as on utilizing other bases,
such as piperidine, we obtained more complex reaction
mixtures and much lower yields of 2. Because of the prob-
lematic depolymerization of paraformaldehyde, we per-
formed a comparative study by carrying out the reactions
2
3
,4
2
using both the conventional conductive heating (oil bath)
6
(
Table 1) and irradiation (microwave oven ) (Table 2).
We have found that in all cases the adducts 2 were formed
along with their hydroxymethylated derivatives 3 in the
ratios given in Tables 1 and 2. Irrespective of the means
of heating, the yields of products 2 and 3 were found to be
practically the same in both series of experiments, the re-
action times, however, differ considerably, being much
shorter with the use of the microwave oven (Tables 1 and
2
lematic to adjust the 1:1:1 molar ratio of the three reac-
tants, due to the relatively rapid change in its
concentration. We could also observe that this method did
not give satisfactory results when working with indoles
substituted by electron-withdrawing groups, as in these
cases the yields of the corresponding adducts 2 dropped
drastically. Additionally, we were always able to detect
2
). According to our experience, the microwave irradia-
Scheme 1
Synthesis 1999, No. 2, 254Ð257 ISSN 0039-7881 © Thieme Stuttgart á New York

PAPER
Trimolecular Condensation of Substituted Indoles
255
Table 1 Condensation of Substituted Indoles 1 with Paraformal-
dehyde and MeldrumÕs Acid (Oil Bath Heating)
is also feasible for the formation of adducts 2 (Scheme 2,
Route 2). As for the formation of the hydroxymethylated
products 3, two possible ways should be considered: on
the one hand, indoles 1 can react with formaldehyde to
Indole R
Reaction Temperature Ratio 2:3a Yield (%)
time (h) (¡C)
8
give the intermediates I-3, followed by the Michael addi-
2
3
tion between the latter and the hydroxymethylated Mel-
drumÕs acid I-1 to afford derivatives 3 (Scheme 2, Route
3); while on the other hand, compounds 3 can also be
formed from the reaction of adducts 2 with formaldehyde
1
1
1
1
a
b
c
H
MeO
Br
10
9
21
24
50
50
50
50
3:1
3:1
2:3
1:4
61
59
28
15
18
19
39
53
d
CN
(Scheme 2, Route 4). On the basis of our results we are not
able to determine which mechanism is responsible for the
formation of products 3. Nevertheless, whichever of the
two mechanisms takes place, the product ratios obtained
are in full accordance with the tendency that electron ac-
ceptor groups in position 5 decrease the electron density
of the methylene group attached to the indole C-3, making
the intermediates I-3 more reactive towards the attack by
I-1. At the same time such groups increase the acidity of
the proton attached to C(β) (C-5') in adducts 2, which fa-
cilitates their nucleophilic addition on formaldehyde. In-
deed, a control experiment unambiguously revealed that
the pure adduct 2c did react with paraformaldehyde to fur-
nish the product 3c under the same reaction conditions as
applied in the trimolecular condensations in the micro-
wave oven.
1
e
20
45
9:11
32
36
a
Determined by NMR measurements on the crude reaction mix-
tures.
Table 2 Condensation of Substituted Indoles 1 with Paraformal-
dehyde and MeldrumÕs Acid (Microwave Oven)
Reaction Temperature Ratio 2:3a Yield (%)
time
Indole R
(ûC)
(min)
2
3
1
1
1
1
a
b
c
H
MeO
Br
30
30
50
60
85
85
85
85
3:1
3:1
2:3
1:4
63
61
28
15
19
18
39
55
Previously, we observed that on opening the 1,3-dioxane
cycle of adducts 2 and 3 (used as a mixture in the reac-
tions) with various alcohols to the respective hemiacid
d
CN
1
e
40
85
2:3
30
42
1
esters the latter were not contaminated with the corre-
sponding β-hydroxymethylated derivatives, thus, the hy-
droxymethyl group was removed during heating in
boiling alcohol. To gain further support for this assump-
tion, we carried out another control experiment, in which
the mixture of 2c and 3c was exposed to microwave irra-
diation in refluxing acetonitrile in the presence of triethyl-
amine to afford 2c quantitatively (Scheme 1).
a
Determined by NMR measurements on the crude reaction mix-
tures.
tion gave cleaner reaction mixtures, which could be han-
dled more easily with respect to chromatography. It is
important to note that if R was an electron-withdrawing
substituent, the formation of compounds 3 was preferen-
tial.
In conclusion, our comparative study on the trimolecular
condensation of substituted indoles 1 with paraformalde-
hyde and MeldrumÕs acid clearly shows that, although the
microwave irradiation does not affect the course of the re-
action, this method offers the possibility to considerably
decrease the reaction times compared to those necessary
The trimolecular condensation studied involves the par-
ticipation of several intermediates. It can proceed through
the Knoevenagel-type product I-2 (methylene MeldrumÕs
7
acid ) (Scheme 2, Route 1), although another mechanism
Scheme 2
Synthesis 1999, No. 2, 254–257 ISSN 0039-7881 © Thieme Stuttgart · New York

2
56
C. Nemes, J.-Y. Laronze
PAPER
Table 3 Characteristic Physical and Spectroscopic Data of Products 2 and 3
Pro-
duct
mp (¡C)
[Lit. mp (¡C)] n (cm )
IR (Film)
1H NMR (DMSO-d6)
d, J (Hz)
13C NMR (DMSO-d6)
d
MS m/z
(%)
a
Ð1
+
2
a
107Ð108 3414,
1.53, 1.80 [2 s, 6 H, (CH ) C], 3.47 (d, 2 21.7 (CH ), 26.6 (CH ), 27.9 273 (M , 74),
3 2 2 3
2
(106Ð108 )
1778, 1743 H, J = 2.9, CH ), 4.79 (t, 1 H, J = 2.9, (CH ), 47.4 (C-5«), 104.9 (C-2«), 216 (11), 187
2
3
CH), 6.97Ð7.16 (m, 3 Harom), 7.36 (d, 1 110.6, 111.4, 118.6, 119.1, 121.2, (39), 171 (53),
H, J = 8.0, 7-H), 7.64 (d, 1 H, J = 7.9, 4- 123.9, 127.5, 135.9, 166.4 (CO)
H), 10.90 (br s, 1 H, NH)
143 (73), 130
(100)
+
2
b
137Ð138
3410,
1.53, 1.79 [2 s, 6 H, (CH ) C], 3.42 (d, 2 21.9 (CH ), 26.7 (CH ), 27.9 303 (M , 41),
3
2
2
3
2
(135Ð136 )
1778, 1743 H, J = 3.0, CH ), 3.78 (s, 3 H, OCH ), (CH ), 47.3 (C-5«), 55.5 (OCH ), 217 (11), 201
2 3 3 3
4
.77 (t, 1 H, J = 3.0, CH), 6.75 (d, 1 H, 101.0, 105.0 (C-2«), 110.3, 111.3, (71), 173 (32),
J = 7.9, 6-H), 7.02 (br s, 1 H, 2-H), 7.12 112.0, 124.6, 127.9, 131.1, 153.2, 160 (100)
br s, 1 H, 4-H), 7.25 (d, 1 H, J = 7.9, 7- 166.4 (CO)
H), 10.75 (br s, 1 H, NH)
(
+
2
2
c
148Ð149
134Ð135
3435,
1
1.57, 1.82 [2 s, 6 H, (CH ) C], 3.42 (d, 2 21.4 (CH ), 26.5 (CH ), 27.9 351 (M , 53),
3 2 2 3
779, 1744 H, J = 2.9, CH ), 4.79 (t, 1 H, J = 2.9, (CH ), 47.4 (C-5«), 105.0 (C-2«), 294 (12), 265
2
3
CH), 7.13Ð7.22 (m, 2 Harom), 7.32 (d, 1 110.4, 111.3, 113.4, 121.5, 123.6, (35), 249 (58),
H, J = 8.0, 7-H), 7.80 (br s, 1 H, 4-H), 125.8, 129.4, 134.5, 166.3 (CO)
1.10 (br s, 1 H, NH)
221 (65), 208
(100)
1
+
d
3353,
1.58, 1.81 [2 s, 6 H, (CH ) C], 3.45 (d, 2 21.1 (CH ), 26.4 (CH ), 28.0 298 (M , 22),
3
2
2
3
2
1
220,
780, 1742 CH), 7.29 (br s, 1 H, 2-H), 7.38 (d, 1 H, J (C-2'), 112.0, 112.8, 121.2, 123.8, (45), 196 (29),
8.0, 6-H), 7.50 (d, 1 H, J = 8.0, 7-H), 125.2, 126.9, 127.5, 137.7, 166.2 168 (49), 155
.16 (br s, 1 H, 4-H), 11.50 (br s, 1 H, (CO) (100)
H, J = 3.1, CH ), 4.85 (t, 1 H, J = 3.1, (CH ), 47.4 (C-5'), 100.7, 105.1 241 (6), 212
2
3
=
8
NH)
2
e
151Ð152
3396,
1.56, 1.78 [2 s, 6 H, (CH ) C], 3.39 (d, 2 21.5 (CH ), 26.5 (CH ), 27.9 348 (7), 289
3 2 2 3
1
1
769,
H, J = 3.0, CH ), 4.73 (t, 1 H, J = 3.0, (CH ), 41.80 (NCH ), 47.3 (C-5'), (14), 276 (17),
2
3
2
746, 1709 CH), 4.86 (s, 2 H, NCH ), 7.03Ð7.10 (m, 104.9 (C-2'), 110.7, 111.5, 118.4, 219 (11), 192
2
2
Harom), 7.30 (d, 1 H, J = 8.1, 7-H), 7.59 121.3, 123.3, 124.4, 126.9, 127.5, (20), 174 (100),
(br s, 1 H, 4-H), 7.83Ð7.93 (m, 4 Harom), 131.8, 134.6, 135.3, 166.2 (CO), 160 (22), 148
1
0.88 (br s, 1 H, NH)
167.9 (NCO)
(42), 130 (25)
Ð
3
3
a
Colorless oil
129Ð130
3416,
0.80, 1.58 [2 s, 6 H, (CH ) C], 3.27 (s, 2 28.2 (CH ), 29.5 (CH ), 30.7
3
2
3
3
1
765, 1726 H, CH ), 4.05 (br s, 2 H, CH OH), 5.86 (CH ), 59.7 (C-5'), 67.9 (CH OH),
2 2 2 2
(
br s, 1 H, CH OH), 6.95Ð7.13 (m, 3 105.6 (C-2'), 107.4, 111.6, 118.6,
2
Harom), 7.36 (d, 1 H, J = 7.7, 7-H), 7.45 (d, 119.0, 121.4, 124.7, 128.8, 136.0,
H, J = 7.6, 4-H), 11.05 (br s, 1 H, NH) 169.3 (CO)
1
b
3416,
0.80, 1.58 [2 s, 6 H, (CH ) C], 3.22 (s, 2 28.2 (CH ), 29.5 (CH ), 30.7
Ð
3
2
3
3
1
765, 1726 H, CH ), 3.75 (s, 3 H, OCH ), 4.04 (d, 2 (CH ), 55.4 (OCH ), 59.6 (C-5«),
2 3 2 3
H, J = 2.8, CH OH), 5.84 (br s, 1 H, 68.0 (CH OH), 100.8, 105.6 (C-
2
2
CH OH), 6.73 (d, 1 H, J = 7.9, 6-H), 2'), 107.2, 111.6, 112.2, 125.5,
2
6
.91Ð6.99 (m, 2 Harom), 7.24 (d, 1 H, J = 127.2, 131.2, 153.3, 169.3 (CO)
7
.9, 7-H), 10.88 (br s, 1 H, NH)
a
Satisfactory microanalysis found: C ± 0.36; H ± 0.37; N ± 0.10.
when using conventional conductive heating. Another re- Bruker AC 300 spectrometer using TMS as internal standard. Mass
spectra were recorded with a VG Autospec apparatus. All solvents
were purified by following standard literature methods. Chroma-
tography was performed on silica gel 60 (Merck) with hexane iso-
mers/acetone (8:2 v/v) as eluent. Reactions were monitored using
Merck TLC aluminium sheets (Kieselgel 60F254). Satisfactory mi-
croanalyses were obtained for all the compounds prepared.
markable advantage of the method is that it gives cleaner
reaction mixtures, which makes the chromatographic sep-
aration of the products easier. Even though in every reac-
tion besides compounds 2 the corresponding hydroxy-
methylated derivatives 3 were formed as well, with micro-
wave irradiation the latter can be quantitatively trans-
formed to the former, which allows the preparation of the Condensation of Substituted Indoles 1 with Paraformaldehyde
desired products in good yields.
and MeldrumÕs Acid Using Oil Bath Heating; General Proce-
dure
The mixture of the substituted indole 1 (2.55Ð4.27 mmol),
paraformaldehyde (1.5 equiv.), and MeldrumÕs acid (1.1 equiv.) in
MeCN (50 mL) was heated at 45Ð50¡C in the presence of D,L-pro-
line (0.05 equiv.) for 9Ð24 h. The progress of the reaction was mon-
itored by TLC until complete consumption of indole 1. The solvent
was evaporated under reduced pressure and the residue was submit-
Microwave irradiations were carried out in a Normalab Analis Nor-
matron 112 oven. Melting points were determined on a Reichert
Thermovar hot-stage apparatus and are uncorrected. IR (film) spec-
1
tra were measured with a Bomem FTIR instrument. H NMR
1
3
(
300 MHz) and C NMR (75 MHz) spectra were acquired on a
Synthesis 1999, No. 2, 254–257 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Trimolecular Condensation of Substituted Indoles
257
ted to column chromatography using hexane isomers/acetone Acknowledgement
8:2 v/v) as eluent to yield products 2 and 3 (see Table 1).
(
This work was Þnanced by the French Ministry of Education (Edu-
cation Nationale) and the ADIR Company (Laboratoires Servier),
for which our gratitude is expressed.
Condensation of Substituted Indoles 1 with Paraformaldehyde
and MeldrumÕs Acid Using Microwave Irradiation; General
Procedure
The mixture of the substituted indole 1 (2.55Ð4.27 mmol),
paraformaldehyde (1.5 equiv.), and MeldrumÕs acid (1.1 equiv.) in
MeCN (50 mL) was heated at 85¡C in the presence of D,L-proline
References
(1) Jeannin, L.; Nagy, T.; Vassileva, E.; Sapi, J.; Laronze, J.-Y.
Tetrahedron Lett. 1995, 36, 2057.
(0.05 equiv.) for 30Ð60 min. The progress of the reaction was mon-
itored by TLC until complete consumption of indole 1. The solvent
was evaporated under reduced pressure and the residue was submit-
ted to column chromatography using hexane isomers/acetone
(2) Farlow, D.S.; Flaugh, M.E.; Horvath, S.D.; Lavagnino, E.R.;
Pranc, P. Org. Prep. Proced. Int. 1981, 13, 39.
Flaugh, M.E.; Mullen, D.L.; Fuller, R.W.; Mason, N.R. J. Med.
Chem. 1988, 31, 1746.
(8:2 v/v) as eluent to yield products 2 and 3 (see Table 2).
(3) Wright, A.D.; Haslego, M.L.; Smith, F.X. Tetrahedron Lett.
Transformation of 2c to 3c with Paraformaldehyde Using Mi-
crowave Irradiation
The mixture of product 2c (100 mg, 0.284 mmol) and paraformal-
dehyde (1.0 equiv.) in MeCN (50 mL) was heated at 85¡C in the
presence of D,L-proline (0.05 equiv.) for 60 min. After this period,
NMR measurements revealed the presence of compounds 2c and 3c
in a ratio of 2:3.
1979, 2325.
(4) Zia-Ebrahimi, M.; Huffman, G. Synthesis 1996, 215.
(5) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Tetrahedron Lett.
1978, 1759.
(6) For reviews, see: Giguere, R.J. Organic Synthesis. Theory and
Applications 1989, 1, 103.
Caddick, S. Tetrahedron 1995, 51, 10403.
Strauss, C.R.; Trainor, R.W. Aust. J. Chem. 1995, 48, 1665.
Langa, F.; De La Cruz, P.; De La Hoz, A.; D’az-Ortiz, A.;
D’ez-Barra, E. Contemporary Organic Synthesis, 1997, 4, 373.
Transformation of 3c to 2c Using Microwave Irradiation
The solution of product 3c (100 mg, 0.262 mmol) in a mixture of
(
7) McNab, H. Chem. Soc. Rev. 1978, 7, 345.
Chen, B-C. Heterocycles 1991, 32, 529.
8) Remers, W.A. In The Chemistry Of Heterocyclic Compounds,
Weissberger, A.; Taylor E.C., Eds.; Vol 25, Indoles Part 1,
Houlihan, W.J., Ed.; Wiley-Interscience: New York, 1972;
p 202.
MeCN (40 mL) and Et N (20 mL) was exposed to microwave irra-
3
diation at 85¡C for 60 min. The solvent was evaporated under re-
duced pressure, the residue was dissolved in EtOAc (10 mL) and
extracted with 5% citric acid solution (2 × 10 mL). The organic
phase was dried (Na SO ), the drying agent was filtered off, and the
(
2
4
solvent was evaporated in vacuo to afford 2c in a quantitative yield.
Synthesis 1999, No. 2, 254–257 ISSN 0039-7881 © Thieme Stuttgart · New York