Solid acid-catalysed michael-type conjugate addition of indoles to electron-poor C=C bonds: Towards high atom economical semicontinuous processes

Article abstract of DOI:10.1002/adsc.200303213

In this paper a novel application of solid acid catalysts in the chemoselective Friedel-Crafts (FC) alkylation of indoles is reported. The optimal protocol allows highly functionalised indolyl compounds to be synthesised in excellent yields through conjug

Full text of DOI:10.1002/adsc.200303213

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Solid Acid-Catalysed Michael-Type Conjugate Addition of
¼
Indoles to Electron-Poor C C Bonds: Towards High Atom
Economical Semicontinuous Processes
Marco Bandini,* Matteo Fagioli, Achille Umani-Ronchi*
Dipartimento di Chimica −G. Ciamician×, Universityof Bologna, via Selmi 2, 40126 Bologna Italy
Fax: þ39 051/2099456, e-mail: marco.bandini@unibo.it, achille.umanironchi@unibo.it
Received: November 21, 2003; Accepted: March 10, 2004
Abstract: In this paper a novel application of solid
acid catalysts in the chemoselective Friedel Crafts
(FC) alkylation of indoles is reported. The optimal
protocol allows highlyfunctionalised indolly com-
pounds to be synthesised in excellent yields through
conjugate addition of indoles with a,b-unsaturated
ketones and nitro compounds. Finally, the use of
commercial Amberlyst-15 as the heterogeneous cat-
alyst for highly atom efficient continuous and semi-
continuous Friedel Crafts processes is described.
Michael-type addition of indoles to a,b-unsaturated car-
bonyls and nitro compounds.
Firstly, by selecting the batch 1,4-addition of 2-methyl-
indole (1) to 2-cyclohexen-1-one (2) as the model reac-
tion, a range of solid acids were screened as catalysts
(Scheme 1).[6]
From the data collected in Table 1 it emerges that, al-
though in the absence of promoting agent the reaction
did not occur in significant extents over 24 h reaction
time, commercial ion-exchange sulfonic resins such as
Amberlyst-15, 35, 36 and 40, employed at 20% wt, al-
lowed 3 to be isolated in high yields (61 76%). On the
contrary, montomorillonite-based catalyst (F-13 and F-
20X, entries 3, 4) provided 3 in unacceptable yields (23
35%). This finding can be rationalised byconsidering the
capacity(equiv./kg) of the solid acids utilised. In fact,
when the Amberlyst-15 dry (4.70 equiv./kg) was re-
placed bythe less acid clays F-13 and F-20X (capacity:
Keywords: Amberlyst 15; continuous process; Frie-
del Crafts alkylation; heterogeneous catalysis; in-
doles; Michael addition
Solid acid catalysis is a growing field of research as the 0.4 and 0.2 equiv./kg respectively) a remarkable drop
demand for clean and eco-friendlychemical processes
in chemical yield was observed. Moreover, the perfluori-
nated resin-sulfonic acid Nafion-H was also examined
¾
is increasing.[1] Manyorganic reactions are known to
be catalysed by clays, ion-exchange resins and zeolites as the catalyst, but in this case the desired indole com-
both in natural and modified form.[2] Among them, het- pound 3 was isolated onlyin 46% yield (entry11). It is
erogeneously catalysed Friedel Crafts alkylation reac- worthyof note that conventional Br˘nsted acid catalysis
tions are receiving a great deal of attention even for (pTSA 10 mol%) was poorlyeffective for this transfor-
large scale processes.[3]
mation, in fact, undesired polymerisation of the indole
Catalytic and stereoselective alkylation of indoles via occurred yielding 3 onlyin traces (entry2).
1,4-addition to electron-deficient double bonds is an im- Chemical outcomes can be further improved byin-
portant organic reaction that affords products that may creasing the loading of Amberlyst-15 and 35 to 50%
be transformed into valuable building blocks.[4] As a wt, in these cases 3 was isolated in 98% and 85% yield
[7]
continuation of our ongoing investigations in this respectively.
area,[5] we now describe our preliminaryresults in the
optimisation of a novel heterogeneouslycatalysed FC
Both scope and generalityof the procedure were eval-
uated byreacting several a,b-unsaturated carbonyls and
nitro compounds with 1 in the presence of Amberlyst-15
and 39 (20% wt). All the reactions provided the desired
1,4-adducts in good yields (up to 96%) by a proper
choice of the solvent (generallyreagent grade Et O
2
and CH2Cl2 afforded the highest yields) depending on
the substrates solubility(Table 2).
The reusabilityof the solid acid was also effectively
proved by recycling the catalyst (Amberlyst-15 20%
wt) for 5 runs in the addition of 2-methylindole to 4.
No margin of activityloss was observed even if a moder-
Scheme 1. Model reaction for the catalyst screening. Reac-
tion conditions: cat (20% wt), 1 (1.5 equivs.), 2, (1 equiv.).
Adv. Synth. Catal. 2004, 346, 545 548
DOI: 10.1002/adsc.200303213
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
545

Marco Bandini et al
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Table 1. Screening of heterogeneous catalysts for the conju-
gate addition of 2-methylindole (1) to 2.[a]
EntryCstataly
Capacity
Yield
[%][b]
[equiv./kg]
1
2
3
4
5
6
7
8
9
none
pTSA
traces
traces[c]
23
Grade F-13 (dry)
Grade F-20X (dry)
Amberlyst-15 dry
Amberlyst-15 dry
Amberlyst-35 wet
Amberlyst-35 wet
Amberlyst-36 wet
Amberlyst-40 wet
0.4
0.2
4.7
∫
5.2
∫
35
62
98[d]
76
85[d]
72
Figure 1. Schematic representation of the reactor for a) con-
tinuous and b) semicontinuous alkylation of 1 with 2. The re-
actor consists in a glass column (15 mm) charged with the de-
sired amount of commerciallyavailable Amberlyst-15 dry.
5.4
10
11
61
46
¾
Nafion-H
5.0
[a]
All the reactions were carried out with 0.2 mmol of 2 in
Et2O (1 mL, reagent grade Et2O was used without inert at-
mosphere technique) using 20% wt of catalyst (about
10 mol % based on the acid sites). Reaction time 24 h.
Isolated yields of 3 after flash chromatography.
The reaction was carried out in the presence of 10 mol %
of pTSA. Polymerisation of 3 occurred.
ꢀ
scale-up, the development of practical C C bond form-
ing reactions in a continuous and semicontinuous man-
ner is still a crucial task.[10]
[b]
[c]
The remarkable effectiveness of ion-exchange resins
in catalysing this class of Michael additions prompted
us to investigate the possibilityto optimise a flow reac-
tion protocol involving common laboratoryequipment.
To this aim a glass column (15 mm diameter) filled with
Amberlyst-15 was connected to a flask containing a pre-
[d]
50% wt of catalyst was used (about 25 mol % based on the
acid sites).
ate increase of the reaction time was needed for comple- formed solution of reactants via an HPLC pump respon-
tion.[8]
It is well known that easilyrecoverable and reusable
solid acid catalysts are valuable candidates for the de- was first evaluated bystudiyng the addition of
sible for controlling the flow rate (Figure 1a). The de-
pendence of the reaction outcome on the feeding rate
1
sign of highlyperforming semicontinuous and continu-
ous processes. In this context, Poliakoff et al. recentlyre-
(0.1 M) to 2 (0.1 M) in a CH2Cl2:EtOH solution (9:1)
as the solvent at room temperature with various
ported on the combined use of solid acids and supercrit- amounts of Amberlyst-15 dry (1 g, 3.5 g and 7 g).
ical fluids for selectiveFC alkylations, hydrogenation re-
The data obtained for 2 mmol of reactants are sum-
marised in Figure 2 and from the graphics two main as-
actions and dehydration of alcohols.[9]
Due to the numerous potential benefits of flow proc- pects clearlyemerged. First, at comparable feeding rates
esses namely: environmental concerns, safety and easy the lower the loading, the higher is the conversion in 3;
[a]
ꢀ
Table 2. Conjugate addition of 1 to electron-poor C C double bonds promoted byion-exchange resins.
[b]
EntrySubstrate
1
st/solvenCtataly
Product
Yield [%]
Amberlyst-15 dry/CH2Cl2
9
95
90
2
3
Amberlyst-15 dry/Et2O
Amberlyst-15 dry/Et2O
10
11
81
4
5
Amberlyst-39 wet/CH2Cl2
Amberlyst-39 wet/CH2Cl2
12
13
96
81
[a]
All the reactions were carried byusing 20% wt of catalyst.
Isolated yields after flash chromatography.
[b]
546
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Adv. Synth. Catal. 2004, 346, 545 548

¼
Michael-Type Conjugate Addition of Indoles to Electron-Poor C C Bonds
COMMUNICATIONS
tire reaction course without appreciable loss in catalytic
activity(Figure 3).
The high impact of organic solvents in environmental
and economical assessments of organic transformations
is widelyrecognised/estimated [12] and the recycle of the
reaction media could contribute to develop environ-
mentallymore benign processes. The present catalytic
system can address this issue, in fact, by modifying the
apparatus employed for the continuous reaction with a
cold trap connected to the collecting product flask (Fig-
ure 1b), 5 cycles of semicontinuous addition of 2-meth-
ylindole to 2-cycloexen-1-one (0.1 M, 0.90 mL/min
flow rate) were carried out with high conversions (90
94%), always recovering and recycling the reaction sol-
vent (CH2Cl2 :EtOH, 9:1) as well as the washing solvent
(CH2Cl2 :EtOH, 9:1).
Figure 2. Monitoring the dependence of the conversion of the
reaction in 3 on the feeding rate of the reactants as well as the
catalyst loading. The WHSV values at the highest conver-
sions for 7 g, 3.5 g and 1 g loading were 0.13 hꢀ1, 0.33 hꢀ1
and 1.22 hꢀ1, respectively.
In conclusion, a novel procedure for ion-exchange res-
in catalysed Michael-type addition of indoles to elec-
ꢀ
tron-deficient C C double bonds is described. Exam-
ples of practical continuous and highlyatom economic
semicontinuous versions are presented byusing com-
mon laboratoryequipments and mild experimental con-
ditions. These preliminaryresults, in principle, afford an
attractive alternative to scale-up batch Michael-type al-
kylation of indoles and studies addressed towards the
ꢀ
extension of this protocol to other C C bond forming
flow reactions are actuallyunder investigation.
Experimental Section
Figure 3. In the probe continuous Michael-type addition of 2-
methylindole to 2 the conversion in 3 was found nearlycon-
stant (84 91%) over 10 h reaction time.
Typical FC-Type Michael Addition
A sample vial containing 1 mL of reagent grade Et2O was
charged with 0.2 mmol of a,b-unsaturated compound,
0.3 mmol of indole and 4 mg of Amberlyst-15 (20% wt, corre-
sponding to ꢁ10 mol % acid sites content). The mixture was
stirred for 24 h with a basic orbital mixer then the catalyst
was recovered byfiltration. Evaporation of the solvent and
subsequent purification byflash chromatographyfurnished
the desired indolyl compound.
this findingcan be easilyrationalised taking into account
the competitive polymerisation of the reagents promot-
ed bythe acidic sites of the resin. Second, the lower the
loading of catalyst employed, the higher is the optimal
feeding rate of the process. In particular, 0.90 mL/min,
0.85 mL/min and 0.67 mL/min provided the highest con-
versions in 3 (94%, 89% and 87%) for 1 g, 3.5 g and 7 g of
Amb-15 respectively.
The b-indolyl compounds 3,[5b] 9,[5b] 12[5a] and 13[5a] have been
previouslycharacterised.
1-[4-(i-Propyl)phenyl]-3-(1H-2-methylindol-3-yl)-
butan-1-one (10)
The aforementioned studycan be also described in
[11]
terms of WHSV (weight hourlyspace velocity).
In
Brown viscous oil. Yield: 90%; Rf ¼0.35 (c-Hex/Et2O, 85:15);
this context, the respective WHSV values at the highest
conversions were 0.13 hꢀ1 (7 g), 0.33 hꢀ1 (3.5 g) and
1.22 hꢀ1 (1 g).
1H NMR (CDCl3, TMS, 200 MHz): d¼1.25 (3H, d, J
¼
7.0 Hz), 1.50 (3H, d, J¼7.0 Hz), 1.55 (3H d, J¼7.0 Hz), 2.42
(3H, s), 2.87 3.01 (1H, m), 3.39 (2H, dd, J¼7.4, 16.2 Hz),
3.72 3.82 (1H, m), 7.07 7.14 (3H, m), 7.23 7.27 (2H, m),
7.68 7.72 (2H, m), 7.82 7.86 (2H, m); 13C NMR (CDCl3,
TMS, 50 MHz): d¼12.1, 21.0, 23.7, 27.4, 34.2, 45.6, 110.4,
115.6, 118.9, 119.0, 120.6, 126.4, 127.1, 128.2, 130.2, 135.2,
135.4, 154.1, 199.5; GC-MS: m/z¼51 (1), 77 (4), 91 (6), 115
(5), 130 (5), 143 (11), 147 (11), 158 (100), 319 (13); IR (nujol):
Then, the synthesis of 3 was conduced at room temper-
ature in the continuous mode (PFR type: plug flow reac-
tor) bymaintaining a flow rate of 0.90 mL/min (WHSV
1.22 hꢀ1) of a 1:1 mixture of 1 and 2 (0.1 M) in CH2
Cl2:EtOH through the reactor (Amberlyst-15, 1 g, reac-
1
tion time 10 h). Periodical checks by H NMR showed
nearlyconstant conversions in 3 (84 91%) along the en- n¼738 (m), 824 (w), 1056 (w), 1182 (w), 1209 (w), 1282 (w),
Adv. Synth. Catal. 2004, 346, 545 548
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¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Marco Bandini et al
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1368 (w), 1600 (w), 1680 (m), 3039 (w), 3357 (m) cmꢀ1; anal.
calcd. for C22H25NO: C 82.72, H 7.89, N 4.38; found: C 82.74,
H 7.83, N 4.38.
[2] P. Espeel, R. Parton, H. Toufar, J. Martens, W. Hˆlder-
ich, P. Jacobs, Zeolite Effects in Organic Catalysis, In:
A. Vaccari, Applied Clay Science 1999, 14, 161 198.
[3] K. Tanabe, W. F. Hˆlderich, Appl. Catal. A: Gen. 1999,
181, 399 434.
[4] a) M. Bandini, M. Fagioli, P. Melchiorre, M. Melloni, A.
Umani-Ronchi, Tetrahedron Lett. 2003, 44, 5843 5846;
b) D. A. Evans, K. A. Scheidt, K. R. Fandrick, H. Wai
Lam, J. Wu, J. Am. Chem. Soc. 2003, 125, 10780
10781; c) M. Bandini, A. Melloni, S. Tommasi, A. Uma-
ni-Ronchi, Helv. Chim. Acta 2003, 86, 3753 3763; d) M.
Bandini, M. Melloni, A. Umani-Ronchi, Angew. Chem.
2004, 116, 560 566; Angew. Chem. Int. Ed. 2004, 43,
550 556, and references cited therein.
[5] a) M. Bandini, P. Melchiorre, A. Melloni, A. Umani-
Ronchi, Synthesis 2002, 1110 1114; b) M. Bandini,
P. G. Cozzi, M. Giacomini, P. Melchiorre, S. Selva, A.
Umani-Ronchi, J. Org. Chem. 2002, 67, 3700 3704;
c) M. Bandini, M. Fagioli, A. Melloni, A. Umani-Ronchi,
Synthesis 2003, 397 402; d) M. Agnusdei, M. Bandini, A.
Melloni, A. Umani-Ronchi, J. Org. Chem. 2003, 68,
7126 7129.
1-(4-Chlorophenyl)-3-(1H-2-methylindol-3-yl)-butan-
1-one (11)
Brown viscous oil. Yield: 81%; Rf ¼0.35 (c-Hex/Et2O, 85:15);
1H NMR (CDCl3, TMS, 200 MHz): d¼1.51 (3H, d, J¼
7.0 Hz), 2.38 (3H, s), 3.30 (1H, dd, J¼7.4, 16.0 Hz), 3.54 (1H,
dd, J¼6.6, 16.2 Hz), 3.73 (1H, pq, J¼7.0 Hz), 7.06 7.14 (2H,
m), 7.23 7.28 (2H, m), 7.33 (2H, dd, J¼1.8, 8.4 Hz), 7.65
7.69 (1H, m), 7.79 (2H, dd, J¼1.8, 8.4 Hz); 13C NMR (CDCl3,
TMS, 75 MHz): d¼11.9, 21.0, 27.4, 45.5, 110.5, 115.1, 118.9,
118.9, 120.6, 127.0, 128.6, 129.4, 130.4, 135.5, 139.1, 160.2,
198.9; GC-MS: m/z¼51 (3), 75 (6), 91 (5), 111 (10), 130 (13),
139 (16), 158 (100), 191 (10), 207 (71), 253 (5), 281 (9), 311
(10); IR (nujol): n¼742 (m), 825 (m), 1012 (m), 1091 (s),
1283 (m), 1399 (m), 1437 (m), 1457 (s), 1588 (s), 1696 (s),
2853 (m), 2963 (m), 3055 (w), 3398 (br) cmꢀ1; anal. calcd. for
C19H18ClNO: C 73.19, H 5.82, N 4.49; found: C 73.16, H 5.78,
N, 4.48.
[6] Although extensive efforts have been devoted to the het-
erogenously catalysed synthesis of bis- and tris(indolyl)-
methanes, see: M. Chakrabarty, S. Sarkar, Tetrahedron
Lett. 2002, 43, 4075 4078; C. Ramesh, J. Banerjee, R.
Pal, B. Das, Adv. Synth. Catal. 2003, 345, 557 559; G.
Panieres-Carrillo, J. G. GarcÌa-Estrada, J. L. GutÌerrez-
RamÌrez, C. Alvarez-Toledano, Green. Chem. 2003, 5,
337 339, onlyfew examples of solid acids promoted
1,4-additions were reported, see: M. Chakrabarty, R. Ba-
sak, N. Ghosh, Tetrahedron Lett. 2001, 42, 3913 3915;
G. Bartoli; M. Bartolacci; M. Bosco; G. Foglia; A. Giulia-
ni; E. Marcantoni; L. Sambri; E. Torregiani; J. Org.
Chem. 2003, 68, 4594 4597.
Typical Experimental Semicontinuous Procedure
A preformed 0.1 M solution of 1 (2 mmol) and 2 (2 mmol) was
continuouslyintroduced in a glass column (15 mm diameter)
charged with 1 g of commerciallyavailable Amberlyst-15 dry.
When all the reactants solution was passed through the reactor
(0.9 mL/min), the reaction mixture was collected in a separate
flask and the solvent was recovered byevaporation and recy-
cled in the reactant-containing unit. Then, to guarantee a com-
plete recovering of the products, the reactor was washed with
20 mL of CH2Cl2 :EtOH (9:1) followed byrecycling the wash-
ing solvent as well. 1H NMR analysis of the crude residues af-
forded the conversions in 3: I cycle: 94%, II cycle: 90%, III cy-
cle: 89%, IV cycle: 90%, V cycle: 93%.
[7] Good yields were also obtained in the addition of differ-
ent indoles to 2: 1-methylindole (80%), 1,2-dimethylin-
dole (55%).
[8] Reaction times to complete conversion: I cycle 18 h, II
cycle 22 h, III cycle 26 h, IV cycle 28 h, V cycle 30 h.
[9] Recent examples of continuous solid acid-catalysed reac-
tions, see [hydrogenation]: M. G. Hitzler, M. Poliakoff,
Chem. Commun. 1997, 1667 1668; [FC]: M. G. Hitzler,
F. R. Smail, S. K. Ross, M. Poliakoff, Chem. Commun.
1998, 359 360; [dehydration of alcohols]: W. K. Gray,
F. R. Smail, M. G. Hitzler, S. K. Ross, M. Poliakoff, J.
Am. Chem. Soc. 1999, 121, 10711 10718.
[10] a) P. Tundo, Continuous Flow Methods in Organic Syn-
thesis, Prentice Hall PTR: Upper Side River, New
York, 1992; b) N. G. Anderson, Org. Process Res. Dev.
2001, 5, 613 621.
Acknowledgements
Acknowledgements are made to FIRB (™Progettazione, prepar-
azione e valutazione biologica e farmacologica di nuove molec-
ole organiche quali potenziali farmaci innovativi∫), CINMPIS
(Bari) and M. U. R. S. T. (Progetto Nazionale ™Stereoselezione
in Sintesi Organica: Metodologie ed Applicazioni∫) and Bolo-
gna University (funds for selected research topics) for the finan-
cial support of these research projects. M. F. thanks Consorzio
Spinner for a fellowship. Great Lakes Italia s.r.l. is acknowl-
edged for the generous gift of clays and ion exchange resins.
[11] Mass flow rate of reactant for mass of catalyst utilised in
the reactor.
[12] For an elegant studyon the environmental assessment of
organic reactions, see: M. Eissen, J. O. Metzger, Chem.
Eur. J. 2002, 8, 3580 3585.
References and Notes
[1] a) K. Wilson, J. H. Clark, Pure Appl. Chem. 2000, 72,
1313 1319; b) T. Okuhara, Chem. Rev. 2002, 102, 3641
3666; c) J. H. Clark, Acc. Chem. Res. 2002, 35, 791 797.
548
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Adv. Synth. Catal. 2004, 346, 545 548