Pictet-Spengler heterocyclizations via microwave-assisted degradation of DMSO

Article abstract of DOI:10.1016/j.tetlet.2005.02.043

For the first time the ability of DMSO to decompose rapidly under microwaves was explored in order to perform heterocyclizations in good conditions. This modified Pictet-Spengler reaction allowed, in this case, the synthesis of rigidified melatonin analog

Full text of DOI:10.1016/j.tetlet.2005.02.043

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2465–2468
Pictet–Spengler heterocyclizations via
microwave-assisted degradation of DMSO
a
Christophe Mesangeau, Sa¨ıd Yous, Basile Peres, Daniel Lesieur and Thierry Besson
a
a
a
b,
*
´
´ `
a
´ ´
Laboratoire de Chimie Therapeutique, EA1043, Faculte des Sciences Pharmaceutiques et Biologiques, BP 83,
59006 Lille Cedex, France
bLaboratoire de Biotechnologies et Chimie Bio-organique, FRE CNRS 2766, UFR Sciences Fondamentales et Sciences
´ ˆ ´
pour l’Ingenieur, Batiment Marie Curie, Universite de La Rochelle, F-17042 La Rochelle Cedex 1, France
Received 14 January 2005; revised 7 February 2005; accepted 8 February 2005
Abstract—For the first time the ability of DMSO to decompose rapidly under microwaves was explored in order to perform het-
erocyclizations in good conditions. This modified Pictet–Spengler reaction allowed, in this case, the synthesis of rigidified melatonin
analogues.
Ó 2005 Elsevier Ltd. All rights reserved.
Microwave-assisted reactions are now well established
and have gained popularity as indicated by the large
number of papers, reviews and books published recently
on this topic.1 Using microwave heating offers the possi-
bility of reducing reaction time from hours to minutes
and improving product yield. Key advantages of mod-
ern scientific microwave apparatus is the ability to
control reaction conditions precisely, monitoring
temperature, pressure and reaction times.2 The variabil-
ity of chemical reactions pushed a lot of chemistry
groups to develop several methods, performing reac-
tions in solvent free conditions or by adsorbing reac-
tants onto various supports. If a reaction is carried out
in a solvent, the medium or reactants need to have high
dielectric constant (e) in order to benefit from micro-
wave heating. Due to this, most of the work in this area
was performed using 1-methyl-2-pyrrolidinone (NMP,
e = 32.2), DMF (e = 36.7) and DMSO (e = 46.7).
Among these solvents, DMSO appears to be quite stable
thermally but upon prolonged reflux it does decompose
slightly to dimethylsulfide, dimethyldisulfide, bis-
methylthiomethane, water and formaldehyde (Fig. 1).
Formation of these compounds was suggested via vari-
ous intermediates such as hemithioformal,3 methyl
methanesulfenate4 or methyl dimethylsulfenate.5 The
decomposition of dimethyl sulfoxide is aided by acids
and retarded by many bases.5–9 Thus, heating this sol-
vent in the presence of various catalysts such as NBS,6
PPA,7 TMSCl,8 POCl3 and SOCl2 is now an efficient
9
alternative for the use of formaldehyde in organic chem-
istry and it has been used in the transformation of ali-
phatic diols into cyclic acetals or in the formation of
methylene bis-amides from amides. Considering these
facts and in connection with our work on the use of
microwaves in organic synthesis, we decided to realize
a preliminary study of the microwave-assisted decompo-
sition of dimethylsulfoxide and we applied the defined
conditions to the synthesis of novel rigidified hetero-
cyclic analogues of melatonine.
The approach described in this letter is an interesting
alternative to the Pictet–Spengler reaction,10 a hetero-
cyclization that usually involves formaldehyde. Our goal
was to establish its feasibility and to identify standard
experimental conditions, which could be transposed to
various starting molecules.
Working on benzothiophenic derivatives of melato-
nin11–13 we observed that microwave-assisted heating
(140 W) of the benzothiophene 1 (prepared as described
in Ref. 13) in large excess of DMSO (35 mL), at reflux
for 3 h, afforded a new cyclized molecule 2 (Scheme 1)
Keywords: Microwave-assisted reactions; Dimethyl sulfoxide; Form-
aldehyde; Pictet–Spengler heterocyclization.
*
Corresponding author. Tel.: +33 5 46 45 82 55; fax: +33 5 46 45 82
47; e-mail: tbesson@univ-lr.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.043

´
C. Mesangeau et al. / Tetrahedron Letters 46 (2005) 2465–2468
2466
S
OH
O
S
CH O + CH SH
CH SCH SCH
3 2 3
2
3
S
O
O
+
S
CH O + CH SCH + H
2 3 3
O
S
CH SSCH + CH SCH + H O
2 CH SH
3
3
3
3
2
3
Figure 1. Products mainly described in DMSO decomposition by heating.2–6
NHCOCH
3
Cl
Cl
N
Cl
NCOCH
3
DMSO
S
S
S
µw(140W), reflux, 3h
1
2 (62%)
3 (10%)
NCOCH
NCOCH
NCOCH
H
3
3
3
Cl
Cl
Cl
OH
H
S
S
S
Scheme 1. Proposed mechanism of formation of compound 2.
in a good yield (62%), accompanied by a small amount
of the aromatized analogue 3 (yield: 10%).
bridge (4.8 ppm) of the final product was effectively fur-
nished by DMSO.
The mechanism involved (Scheme 1) suggests a modified
Pictet–Spengler reaction in which the formaldehyde was
provided by the thermal decomposition of DMSO. The
aldehyde formed in situ reacted with the starting N-2-(5-
chloro-benzo[b]thiophen-3-yl)ethylacetamide (1) to
form a carbinolamide. This intermediate may rearrange
to form an N-acylium ion which cyclized by electrophilic
substitution affording the final 1-(6-chloro-1,2,3,4-tetra-
hydrobenzo[4,5]thieno[2,3-c]pyridin-2-yl)ethanone (2).
This hypothesis was confirmed during the reaction by
the presence of a white precipitate of paraformaldehyde
on the glassware. The same reaction was also performed
with deuterated DMSO (DMSO-d6). Comparison
The preceding hypothesis was definitively confirmed by
the synthesis of 2 by conventional heating of the starting
benzothiophene 1 with formaldehyde in the presence of
para-toluenesulfonic acid (p-TSA, 1.5 equiv), following
a process previously described by Venkov and Luka-
nov14 for the preparation of N-acyltetrahydroisoquino-
lines. In our conditions (DMSO, microwaves),
addition of p-TSA was experimented in the hope of
favouring formation of the intermediate N-acylium ion
or, more probably, to accelerate the decomposition of
DMSO into formaldehyde and then, to allow cycliza-
tion. After experimental design, we observed that a simi-
lar yield (65%) of product 2 was more rapidly obtained
(20 min instead of 3 h), confirming the crucial role of p-
TSA in the mechanism of the reaction, as previously de-
1
between the H NMRspectra of 2 and its deuterated
homologue demonstrated univocally that the methylene
Table 1. Microwave-assisted experiments for the synthesis of 2, 5 and 8a
Methodb
Starting materialc (2 mmol)
DMSO (mL)
p-TSA (equiv)
Product
Microwave irradiation
Reaction time (min) Yield (%)
A
B
C
C
C
1
1
1
4
7
35
35
7
—
2
2
2
5
8
360
20
62d
65e
69
1.5
1.5
1.5
1.5
10
10
7
40
65
7
10
a All compounds were fully characterized by spectroscopic and elemental analysis (see Ref. 17).
b See Refs. 15 and 16 for description of the procedures.
c Compounds 1, 4 and 7 were prepared as described, respectively, in Refs. 13,18,19.
d Conventional heating: reaction time: 15 h; yield: 52%.
e Conventional heating: reaction time: 70–80 min; yield: 57%.

´
C. Mesangeau et al. / Tetrahedron Letters 46 (2005) 2465–2468
2467
NHCOCH3
MeO
NCOCH3
MeO
DMSO, p-TSA (1.5 eq.)
O
O
µw(140W), reflux, 10 min
4
5
(40%)
Scheme 2.
NHCOCH
3
NHCOCH
MeO
3
MeO
MeO
NCOCH
3
b
a
(71%)
N
(65%)
N
H
N
SO Ph
SO Ph
2
2
6
8
7
b
(62%)
MeO
NCOCH
3
N
9
H
Scheme 3. Reagents and conditions: (a) (i) NaOH, (Bu)4N+IÀ, 0 °C, 15 min; (ii) PhSO2Cl, rt, 3.5 h; (b) DMSO, p-TSA (1.5 equiv), lw (140 W),
reflux, 10 min; (c) Mg, NH4Cl, CH3OH, rt, 2 h.
scribed by Venkov for isoquinolines. In the same condi-
tions of reactants, a similar ratio in the reduction of
reaction time was also observed with conventional heat-
ing (70–80 min instead of 15 h, see Table 1).
Alterman and Hallberg, where DMF was degraded
under microwaves.20 This work confirms that working
under focused microwave irradiation needs special
attention. Even controlling the ratio between the quan-
tity of the material and the solvent is very important
(e.g., for scale up experiments). The stability of the reac-
tants (e.g., the solvent) should be carefully checked,
especially for a solvent, like DMSO, which is commonly
used in microwave experiments, because of its interest-
ing property to be rapidly heated. The experimental
microwave conditions described in this letter are now
well established and controlled and can be safely and
beneficially reproduced. The preparation and the biolog-
ical evaluation of various analogues are under develop-
ment and will be described later.
The influence of the quantity of DMSO on yields of 2
and reaction times were also studied. Various experi-
ments were performed with the same quantity of starting
material and we observed that changing the volume of
DMSO (between 7 mL and 70 mL) did not really affect
the good yield of the reaction. The shorter reaction time
was observed with 7 mL of DMSO (see Table 1, method
C) allowing the use of concentrated mixtures and exten-
sion of the process to 1 g of the starting molecules.
Extension of such a reaction to various heterocyclic
rings (e.g., benzofurane and indole) was studied accord-
ing to the conditions described above for the benzothio-
phenic derivative. The benzofuranic analogue of
melatonin (4)18 gave the expected product (5) in a 40%
yield (Scheme 2).
Acknowledgements
´
We thank the Comite de Charente-Maritime de la Ligue
Nationale contre le cancer, Les Laboratoires Servier and
CEM Corporation (USA) for financial support.
Transformation of melatonin (6) itself was also ex-
plored. Since degradation of the starting material 6
was rapidly observed, protection of the nitrogen atom
in the indole ring was performed as previously
described.19 The heterocyclization of the N-protected
product 7 was successfully realized in good yield
(65%), affording the tricyclic compound 8 which was
easily deprotected applying a known method19 to give
the 1,3,4,9-tetrahydro-b-carboline 9 in a good yield
(62%) (Scheme 3).
References and notes
1. For a recent review in the area see: (a) Kappe, C. O.
Angew. Chem., Int. Ed. 2004, 43, 6250–6284; For the most
cited book on microwaves in chemistry see: (b) Micro-
waves in Organic Synthesis; Loupy, A., Ed.; Wiley-VCH
Verlag Gmbh & Co. KGaA: Weinhein, 2002.
2. (a) Detailed descriptions of single-mode microwave reac-
tors with integrated robotics were recently published: (a)
For CEM corp: Ferguson, J. D. Mol. Diversity 2003, 7,
281–286; For Milestone srl: (b) Favretto, L. Mol. Diversity
2003, 7, 287–291; For Biotage (Personal Chemistry AB):
(c) Schanche, J.-S. Mol. Diversity 2003, 7, 293–300.
In conclusion, we described for the first time the rapid
microwave-assisted decomposition of DMSO in order
to perform rapid Pictet–Spengler heterocyclization and
to allow, in this case, the synthesis of novel rigidified
melatonin analogues. The results described in this note
may be compared with data previously published by
3. (a) Head, D. L.; McCarty, C. G. Tetrahedron Lett. 1973,
16, 1405–1408; (b) Barnard-Smith, D. G.; Ford, J. F.
Chem. Commun. 1965, 7, 120–121; (c) Traynelis, V. J.;

´
C. Mesangeau et al. / Tetrahedron Letters 46 (2005) 2465–2468
2468
Hergenrother, W. L. J. Org. Chem. 1964, 29, 221–222; (d)
(completion of the reaction monitored by TLC). After
cooling, the reaction mixture was poured into water and
extracted with ethyl acetate. The organic layer was washed
with water, dried (MgSO4) and evaporated under reduced
pressure. Recrystallization from toluene–cyclohexane
afforded the expected product.
Szmant, H. In Dimethyl Sulfoxide; Jacob, S. W., Rosen-
baum, E. E., Wood, D. C., Eds.; Marcel Dekker: New
York, 1971; Vol. 1, p 1.
4. (a) Carruthers, W.; Entwistle, I. D.; Johnstone, R. A. W.;
Millard, B. J. Chem. Ind. 1966, 342–343; (b) Carlsen, L.;
Egsgaard, H. J. Chem. Soc., Perkin Trans. 2 1981, 1166–
1170.
5. Munavu, R. M. J. Org. Chem. 1980, 45, 3341–3343.
6. Hanessian, S.; Yang-Chung, G.; Lavalle, P.; Pernet, A. G.
J. Am. Chem. Soc. 1972, 94, 8929–8931.
7. Sato, T.; Saito, Y.; Kainosho, M.; Hata, K. Bull. Chem.
Soc. Jpn. 1967, 40, 391–394.
8. (a) Bal, B. S.; Pinnick, H. W. J. Org. Chem. 1979, 44,
3727–3728; (b) Qieiroz, E. F.; Silva, E. L. M.; Roblot, F.;
17. Data for new compounds 2, 3, 5, 8 and 9.
1-(6-Chloro-1,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c]pyr-
idin-2-yl)ethanone (2): white solid; mp 120–122 °C (tolu-
ene–cyclohexane, 2/1); IR(KBr) m 1646 cmÀ1 1H NMR
;
(300 MHz, DMSO-d6) d 2.10, 2.14 (s, s, 3H); 2.77, 2.89 (m,
m, 2H); 3.79 (m, 2H); 4.77, 4.81 (s, s, 2H); 7.35 (d,
J = 8.6 Hz, 1H); 7.73 (d, J = 1.9 Hz, 1H); 7.97, 7.99 (d, d,
J = 8.6 Hz, 1H); 1H NMR(300 MHz, DMSO- d6, 75 °C) d
2.14 (s, 3H); 2.89 (m, 2H); 3.82 (m, 2H); 4.79 (s, 2H); 7.35
(dd, J = 8.6 and 1.9 Hz, 1H); 7.73 (d, J = 1.9 Hz, 1H); 7.95
(d, d, J = 8.6 Hz, 1H); MS (EI) m/z = 267 (37ClÀM+); 265
(35ClÀM+). Found: C, 58.73; H, 4.55; N, 5.27.
C13H12ClNOS requires: C, 58.75; H, 4.55; N, 5.27.
`
Hocquemiller, R.; Figadere, B. Tetrahedron Lett. 1999, 40,
697–700.
9. Guiso, M.; Procaccio, C.; Fizzano, M. R.; Piccioni, F.
Tetrahedron Lett. 1997, 38, 4291–4294.
10. For a representative review of the Pictet–Spengler reac-
tion, see: Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95,
1797–1842.
6-Chlorobenzo[4,5]thieno[2,3-c]pyridine (3): white solid;
mp 138–142 °C (column chromatography (silica gel), with
ethyl acetate–petroleum ether, 3/7 as eluant); IR(KBr) m
11. Beaurain, N.; Mesangeau, C.; Chavatte, P.; Ferry, G.;
2921 cmÀ1 1H NMR(300 MHz, CDCl 3) d 7.58 (dd,
;
´
Audinot, V.; Boutin, J. A.; Delagrange, P.; Bennejean, C.;
Yous, S. J. Enzyme Inhib. Med. Chem. 2002, 17, 409–
414.
J = 8.4 and 1.9 Hz, 1H); 7.87 (d, J = 8.4 Hz, 2H); 7.98 (dd,
J = 5.5, 1.1 Hz, 1H); 8.22 (d, J = 1.9 Hz, 1H); 8.68 (d,
J = 5.5 Hz, 1H); 9.18 (m, 1H); MS (EI) m/z = 221
(37ClÀM+); 219 (35ClÀM+).
´
12. Mesangeau, C.; Yous, S.; Chavatte, P.; Boutin, J. A.;
Bennejean, C.; Delagrange, P.; Renard, P.; Lesieur, D.
J. Enzyme Inhib. Med. Chem. 2003, 18, 119–125.
13. Leclerc, V.; Beaurain, N.; Depreux, P.; Bennejean, C.;
Delagrange, P.; Boutin, J.; Lesieur, D. Pharm. Pharmacol.
Commun. 2000, 6(2), 61–66.
1-(6-Methoxy-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3,c]pyr-
idin-2-yl)-ethanone (5): white solid; mp 128–131 °C (col-
umn chromatography (silica gel), with ethyl acetate–
petroleum ether, 4/6 as eluant); IR(KBr)
;
m 1636
cmÀ1 1H NMR (300 MHz, DMSO-d6, 75 °C) d 2.14 (s,
14. Venkov, A. P.; Lukanov, L. K. Synth. Commun. 1992, 22,
3235–3242.
3H); 2.72 (m, 2H); 3.79 (t, J = 5.6 Hz, 2H); 3.81 (s, 3H); 4.65
(s, 2H); 6.86 (dd, J = 8.4 and 2.6 Hz, 1H); 7.05 (d, J =
2.6 Hz, 1H); 7.41 (d, J = 8.4 Hz, 1H). MS (EI) m/z = 245
(M+). Found: C, 68.33; H, 6.21; N, 5.66. C14H15NO3
requires: C, 68.56; H, 6.16; N, 5.71. 1-(9-Benzenesulfonyl-6-
methoxy-1,2,3,4-tetrahydrobenzo[4,5]pyrro[2,3-c]pyridin-
2-yl) ethanone (8): white solid; mp 187–190 °C (toluene–
15. Microwave experiments were carried out at atmospheric
pressure using a focused microwave reactor (CEM Dis-
coverTM). The instrument consists of a continuous focused
microwave power output from 0 W to 300 W. Reactions
were performed in a glass vessel prolonged by a condenser;
it is also possible to work under dry atmosphere, in vacuo,
or under pressure (0–20 bar, tubes of 10 mL, sealed with a
septum) if necessary (warning: the use of decomposing
solvent in sealed vessel may be dangerous even with
pressure and temperature control). The temperature con-
tent of a vessel is monitored using calibrated infrared
sensor mounted under the vessel. All the experiments were
performed using stirring option whereby the contents of a
vessel are stirred by means of a rotating plate located
below the floor of the microwave cavity and a Teflon-
coated magnetic stir bar in the vessel. In all experiments a
target temperature of 190 °C (DMSO bp: 189 °C) was
selected together with a power of 140 W. The target
temperature was reached with a ramp of 2 min and the
microwave power stay constant to hold the mixture at this
temperature. The time of the reaction does not include the
ramp period.
cyclohexane, 2/1); IR(KBr) m 1644 cmÀ1 1H NMR
;
(300 MHz, DMSO-d6, 75 °C) d 2.13 (s, 3H); 2.70 (m,
2H); 3.76 (t, J = 5.9 Hz, 2H); 3.79 (s, 3H); 4.93 (s, 2H);
6.93 (dd, J = 9.0 and 2.2 Hz, 1H); 6.97 (d, J = 2.2 Hz, 1H);
7.53–7.83 (m, 5H); 7.88 (d, J = 9.0 Hz, 1H). MS (EI)
m/z = 384 (M+). Found: C, 62.01; H, 5.23; N, 7.29.
C20H20N2O4S requires: C, 62.48; H, 5.24; N, 7.29.
1-(6-Methoxy-1,3,4,9-tetrahydro-b-carbolin-2-yl)ethanone
(9): white solid; mp 188–192 °C (toluene–cyclohexane, 2/
1); IR(KBr) m 3283, 1629 cmÀ1 1H NMR(300 MHz,
;
DMSO-d6, 75 °C) d 2.12 (s, 3H); 2.73 (m, 2H); 3.71–3.81
(m, 5H); 4.65 (s, 2H); 6.70 (dd, J = 8.8 and 2.4 Hz, 1H);
6.90 (d, J = 2.4 Hz, 1H); 7.20 (d, J = 8.8 Hz, 1H); 10.44 (br
s, 1H). MS (EI) m/z = 244 (M+). Found: C, 68.43; H, 6.57;
N, 11.10. C14H16N2O2 requires: C, 68.83; H, 6.60; N,
11.47.
18. Depreux, P.; Lesieur, D.; A¨ıt-Mansour, H.; Morgan, P.;
Howell, H.; Renard, P.; Caignard, D. H.; Pfeifer, B.;
Delagrange, P.; Guardiola, B.; Yous, S.; Demarque, A.;
Adam, G.; Andrieux, J. J. Med. Chem. 1994, 37, 3231–
3239.
19. Leclerc, V.; Yous, S.; Delagrange, P.; Boutin, J. A.;
Renard, P.; Lesieur, D. J. Med. Chem. 2002, 45, 1853–
1859.
16. Typical microwave procedures for the synthesis of com-
pound 2: Method A, is the same procedure as in method C
without p-TSA and with a longer reaction time (6 h).
Method B, is the same process as in Method C in 35 mL of
DMSO with a longer reaction time (20 min). Method C: a
solution of N-[2-(5-chloro-benzo[b]thiophen-3-yl)ethyl]-
acetamide 1 (1 g, 4 mmol)and p-toluenesulfonic acid
monohydrate (p-TSA, 1.14 g, 6 mmol) in DMSO (7 mL)
was irradiated at reflux (power input 140 W) for 10 min.
20. Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984–
7989, also see comments in Ref. 1.