Gold(I) or silver catalyzed synthesis of α-indolylacrylates

Article abstract of DOI:10.1021/ol401716b

Methyl 2-acetamidoacrylate reacted with various 2-substituted indoles in the presence of catalytic amounts of AgSbF₆ or AuPPh ₃NTf₂ to provide the corresponding methyl 2-(2-substituted-1H-indol-3-yl)acrylates.

Full text of DOI:10.1021/ol401716b

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Gold(I) or Silver Catalyzed Synthesis
of r‑Indolylacrylates
Valentina Pirovano, Diego Facoetti, Monica Dell’Acqua, Emanuela Della Fontana,
Giorgio Abbiati, and Elisabetta Rossi*
Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Generale e Organica
“A. Marchesini”, Via Venezian, 21, 20133 Milano, Italy
elisabetta.rossi@unimi.it
Received June 19, 2013
ABSTRACT
Methyl 2-acetamidoacrylate reacted with various 2-substituted indoles in the presence of catalytic amounts of AgSbF6 or AuPPh3NTf2 to provide
the corresponding methyl 2-(2-substituted-1H-indol-3-yl)acrylates.
The synthesis of indole derivatives through the direct
functionalization of the indole nucleus is a widespread
researchareaand hadbeenand remains anexciting topic in
organic synthesis. The C3 functionalization of the indole
nucleus through the formation of a new carbonꢀcarbon
bond has been traditionally achieved by FriedelꢀCrafts
alkylation and acylation reactions featuring the well-
recognized reactivity of this electron-rich heteroaromatic
system.1 More recently, the introduction of innovative
catalytic and organocatalytic processes widened the scope
of these reactions and, consequently, the chance to achieve
complex and intriguing architectures with high regioselec-
tivity, avoiding dimerization and polymerization reac-
tions, and in selected cases in a stereocontrolled fashion.2
Inter alias,3 Piersanti4 reported an efficient C3 alkylation
of indoles with R-amidoacrylate where the regioselectivity
(conjugate (β) vs R alkylation) was achieved by switching
from oxo- to aza-philic Lewis acids (Scheme 1). On the
other hand, Arcadi5 reported the C3 regioselective alkyla-
tionof indoles throughgold-catalyzedconjugated addition
type reactions with R,β-enones (Scheme 1).
In this work we want to report our findings about the
reaction of indole derivatives with methyl 2-acetamido-
acrylate in the presence of catalytic amounts of cationic
gold(I) complexes and silver or gold(III) salts (Scheme 1).
We started our investigations taking into account
the results obtained by Arcadi on the C3 regioselective
alkylation of indoles through gold-catalyzed conjugated
addition-type reactions with R,β-enones. These reactions,
performed in ethanol at room temperature and in the
(1) (a) Sundberg, R. J. Indoles; Academic Press: London, U.K., 1996.
(b) Brown, R. K. Indoles; Houlihan, W. J., Ed.; Wiley-Interscience: New
York, US, 1972. (c) Trofimov, B. A.; Nedolya, N. A. In Comprehensive
Heterocyclic Chemistry; Jones, G., Ramsden, C. A., Eds.; Elsevier: Oxford,
U.K., 2008; Vol. 3, pp 88ꢀ168.
(3) For selected recent examples of indole functionalizations, see:
(a) Hikawa, H.; Yokoyama, Y. RSC Adv. 2013, 3, 1061. (b) Leskinen,
M. V.; Yip, K.-T.; Valkonen, A.; Pihko, P. M. J. Am. Chem. Soc. 2012,
134, 5750. (c) Lian, Y.; Davies, H. M. L. Org. Lett. 2012, 14, 1934. (d)
Aikawa, K.; Honda, K.; Mimura, S.; Mikami, K. Tetrahedron Lett.
2011, 52, 6682. (e) Cai, Y.; Zhu, S.-F.; Wang, G.-P.; Zhou, Q.-L. Adv.
Synth. Catal. 2011, 353, 2939. (f) Goto, T.; Natori, Y.; Takeda, K.;
Nambu, H.; Hashimoto, S. Tetrahedron: Asymmetry 2011, 22, 907. (g)
Campbell, A. N.; Meyer, E. B.; Stahl, S. S. Chem. Commun. 2011, 47,
10257. (h) Liu, Q.; Li, G.; Yi, H.; Wu, P.; Liu, J.; Lei, A. Chem.;Eur. J.
2011, 17, 2353. (i) Liu, H.; Du, D.-M. Eur. J. Org. Chem. 2010, 11, 2121.
(j) Blay, G.; Fernandez, I.; Munoz, M. C.; Pedro, J. R.; Vila, C. Chem.;
Eur. J. 2010, 16, 9117.
(2) For selected recent reviews and books on indole functionaliza-
tion, see: (a) Broggini, G.; Beccalli, E. M.; Fasana, A.; Gazzola, S.
Beilstein J. Org. Chem. 2012, 8, 1730. (b) Lindel, T.; Marsch, N.; Adla,
S. K. Top. Curr. Chem. 2012, 309, 67. (c) Batail, N.; Genelot, M.;
Dufaud, V.; Joucla, L.; Djakovitch, L. Catal. Today 2011, 173, 2. (d)
Bandini, M. Chem. Soc. Rev. 2011, 40, 1358. (e) Beck, E. M.; Gaunt,
M. J. Top. Curr. Chem. 2010, 292, 85. (f) Palmieri, A.; Petrini, M.;
Shaikh, R. R. Org. Biomol. Chem. 2010, 8, 1259. (g) Bartoli, G.;
Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39, 4449. (h)
Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608. (i)
Joucla, L.; Djakovitch, L. Adv. Synth. Catal. 2009, 351, 673. (j) Catalytic
Asymmetric Friedel-Crafts Alkylations; Bandini, M., Umani-Ronchi, A.,
Eds.; Wiley-VCH: Weinheim, 2009. (k) Thomas, B.; Poulsen, T. B.;
Jørgensen, K. A. Chem. Rev. 2008, 108, 2903.
(4) Angelini, E.; Balsamini, C.; Bartoccini, F.; Lucarini, S.; Piersanti,
G. J. Org. Chem. 2008, 73, 5654.
(5) Arcadi, A.; Bianchi, G.; Chiarini, M.; D’Anniballe, G.; Marinelli,
F. Synlett 2004, 944.
r
10.1021/ol401716b
XXXX American Chemical Society

Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Routes to C3 Functionalized Indoles
temp
time
3ab
entry
catalyst (mol %)
solvent
EtOH
(°C)
(h)
(%)
1
2
3
4
5
6
7
8
9
NaAuCl4 2H2O (5)
70
24
30
ꢀ
3
ꢀ
toluene 130 (mw) 6a
NaAuCl4 2H2O (4)
DCM
60
30
48
30
6
ꢀ
3
AuCl3 (4)
toluene 130
ꢀ
AuPPh3Cl/AgOTf (2)
AuPPh3Cl/AgOTf (2)
AuPPh3Cl/AgOTf (2)
AuPPh3Cl/AgOTf (2)
AuPPh3Cl/AgOTf (2)
EtOH
EtOH
DMF
70
ꢀ
100 (mw)
100 (mw)
130 (mw)
100 (mw)
100 (mw)
ꢀ
6
ꢀ
DCE
6
31
48
60
74
70
80
76
75
79
74
83
85
MeCN
CHCl3
6
10 AuPPh3Cl/AgOTf (2)
11 AuPPh3Cl/AgOTf (2)
12 AuPPh3Cl/AgOTf (2)
6
presence of 5 mol % NaAuCl4 2H2O, afforded the corre-
3
toluene 130
6
sponding alkylated indoles in good yields. However, when
we reacted the 1-methyl-2-phenylindole 1a with R-amidoa-
crylate 2 under the same reaction conditions no reaction
occurred at rt, whereas, surprisingly, at 70 °C methyl
2-(1-methyl-2-phenyl-1H-indol-3-yl)acrylate 3a was iso-
lated in 30% yield (Table 1, entry 1). The novelty of the
achieved transformation and the remarkable structure of
the obtained compound prompted us to investigate both
the catalyst/solvent system and the reaction mechanism.
Indeed, 2-(1H-indol-3-yl)acrylates are scarcely described
in the literature and were prepared mainly by addition/
elimination sequences.6 Therefore, using 1a and 2 in a
model reaction, a comprehensive review of reaction con-
ditions we tested for the synthesis of 3a is summarized in
Table 1.
The reaction failed in the absence of catalysts, in the
presence of sodium tetrachloroaurate in dichloromethane
or of gold(III) chloride in toluene (entries 2ꢀ4). The
cationic gold(I) complex AuPPh3OTf, generated in situ
from triphenylphosphine gold(I) chloride and silver tri-
flate, gave scarce results in ethanol under conventional
heating (70 °C), under microwave irradiation (100 °C) and
in dimethylformamide (entries 5ꢀ7). Moderate yields of
the desired compound 3a were obtained with the same
catalyst in 1,2-dichloroethane, acetonitrile, and chloro-
form (entries 8ꢀ10), whereas better results were achieved
in toluene under conventional heating (screw cap tube,
130 °C), under microwave irradiation (130 °C), or by
doubling the catalyst loading, giving rise to compound
3a in 74%, 70%, and 80% yield, respectively (entries
11ꢀ13). The presence of cationic N-heterocyclic carbene
gold(I) species slightly affected the reaction course
(entry 14). Silver free catalysts, triphenylphosphinegold(I)
triflate7 and gold(I) bis(trifluoromethanesulfonyl)imide,
toluene 130 (mw)
6
13 AuPPh3Cl/AgOTf (4) toluene 130
6
14 Au(IPr)Cl/AgOTf (4)
15 AuPPh3OTf (4)7
16 AuPPh3NTf2 (4)
17 AgOTf (4)
toluene 130
toluene 130
toluene 130
toluene 130
toluene 130
toluene 130
6
6
6
6
18 AgSbF6 (4)
3
19 AgNTf2 (4)
3
a Reaction conditions: dry solvent (5 mL), 1a (0.5 mmol), and 2
(0.55 mmol). b Isolated yield.
afforded 3a in comparable yields (entries 15ꢀ16). On the
other hand, also silver salts (silver triflate, silver hexafluo-
roantimonate, and silver bis(trifluoromethanesulfonyl)-
imide) very efficiently catalyzed the reaction, although
slightly better yields of 3a and shorter reaction times were
observed using AgSbF6 and AgNTf2 (entries 17ꢀ19).
Finally, in all reported examples, the counterion structure
appeared to exert a minor effect on the reaction course.
Therefore, the conditions reported in entries 13 and 16, for
the cationic gold(I)-catalyzed reactions, and in entry 18,
for the silver-catalyzed reactions, were chosen as standard
conditions to survey the generality of the reaction with
various substituted indoles (Table 2). Dielectric heating
was discharged because it was unnecessary for the purpose,
and cheap AgSbF6 was preferred over the more expensive
AgNTf2. Entry 1 reports the results obtained in the model
reaction with the best performing catalysts. The reaction
worked well also with N-unsubstituted indole 1b even if in
this case cationic gold(I) catalysts seemed to be superior
to the silver salt, entry 2. Since AuPPh3NTf2 gave better
results than AuPPh3Cl/AgOTf, it was employed in the
succeeding experiments. Good results were obtained
with 2-phenylindoles bearing both electron-withdrawing
or -donating substituents in position 5 or 6 at the indole
nucleus (entries 3ꢀ6) or on the aryl moiety (entries 7ꢀ8).
A 3-thiophenyl substituent at C2 was tolerated as well as
a methyl substituent (entries 9ꢀ11). In general, N-methyl
indoles gave comparable results to N-unsusbstituted
(6) (a) Conchon, E.; Anizon, F.; Aboab, B.; Golsteyn, R. M.; Leonce,
S.; Pfeiffer, B.; Prudhomme, M. Eur. J. Med. Chem. 2008, 43, 282. (b)
Ballini, R.; Gabrielli, S.; Palmieri, A.; Petrini, M. Tetrahedron 2008, 64,
5435. (c) Sundberg, R. J.; Hong, J.; Smith, S. Q.; Sabat, M.; Tabakovic,
I. Tetrahedron 1998, 54, 6259.
B
Org. Lett., Vol. XX, No. XX, XXXX

indoles (i.e., cfr. entries 1, 3, and 10with entries2, 4, and 11,
respectively). Nevertheless, the reaction outcome was
proven to be completely altered when 2-unsubstituted-N-
methylindole 1l was chosen as substrate (Scheme 2). Thus,
under gold catalysis at 130 °C, methyl 2,2-bis(1-methyl-
1H-indol-3-yl)propanoate 4 was isolated as the main
reaction product besides unreacted 1l and a mixture of
unidentified tarry compounds, whereas at 80 °C 4 was
obtained in 59% yield besides unreacted 1l. Similar results
were also obtained using a silver catalyst.
Scheme 2. Behaviour of 2-Unsubstituted Indoles
the indole nucleus and the R-carbon of the dehydroamino
acid. Moreover, considering a plausible reaction mecha-
nism we could reasonably disregard a mechanism involving
a heterocyclic Csp2ꢀH activation step. Indeed, under gold-
(I) catalysis, Csp2ꢀH bond activation has been demon-
strated to be consistent only for non-electron-rich
substrates.8 Moreover, 3-benzofuranyl and 3-indolylgold-
(I) derivatives have been isolated and characterized by
Hashmi as a quite stable intermediate in gold(I)-catalyzed
hydrooxylation and hydroamination reactions of ortho-
alkynylphenols and anilines,9 but they easily undergo a
deauration reaction and cannot be directly prepared from
the corresponding benzofuran or indole derivatives and
gold(I). Besides, in the presence of hard or soft Lewis acids,
σ-activation by interaction, respectively, with amide carbo-
nyl oxygen or amide nitrogen of 2 has been invoked,
evidenced by 1H NMR experiments, to explain the R versus
β selectivity observed in the addition of indoles to
dehydroalanine.4,10 Analogous 1H NMR experiments per-
formed in benzene-d6 with 2 in the presence of an equimo-
lecular amount of cationic gold(I) or Ag species did not show
any significant chemical shift variation or broadening in the
signals with respect to pure 2 thus discounting the forma-
tion of an electrophilic N-acylimine intermediate (Scheme 3).
Most probably, we could regard the reactions involving
2-substituted indoles 1aꢀk as involving the simultaneous
addition of an electrophile (the metal) and a nucleophile
(the indole) to the CdC double bond of 2 to give inter-
mediate I, followed by fast thermal and proton assisted
elimination of acetamide (intermediate II), rearomatiza-
tion of the heterocyclic nucleus, and regeneration of the
catalyst (Scheme 3). The intermediacy of conjugated
structures like II has been reported for the reaction of
indoles with carbonyl compounds.11 However, considering
that the reaction medium is somewhat acidic, protonation
of the acetamido moiety prior to elimination cannot be
excluded. In order to shed light on this point we performed
several control experiments by reacting 1a with 2 in the
Table 2. Scope of the Reactiona
a Reaction conditions: dry toluene (5 mL), catalyst (4 mol %),
1 (0.5 mmol), and 2 (0.55 mmol). b Isolated yield.
(8) (a) de Haro, T.; Nevado, C. Synthesis 2011, 2530. (b) Lu, P.;
Boorman, T. C.; Slawin, A. M.; Larrosa, I. J. Am. Chem. Soc. 2010, 132,
5580. (c) Gaillard, S.; Slawin, A. M. Z.; Nolan, S. P. Chem. Commun.
2010, 46, 2742. (d) Boogaerts, I. I. F.; Nolan, S. P. J. Am. Chem. Soc.
2010, 132, 8858.
(9) Hashmi, A. S. K.; Ramamurthi, T. D.; Rominger, F. Adv. Synth.
Catal. 2010, 352, 971.
(10) Avenoza, A.; Busto, J. H.; Canal, N.; Peregrina, J. M.; Perez-
Fernandez, M. Org. Lett. 2005, 7, 3597.
(11) Jones, R. A. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon: Oxford, U.K., 1984; Vol. 4, pp 205ꢀ242.
The reported reactions are regiospecific, and the new
carbonꢀcarbon bond is formed solely between the C3 of
(7) The catalyst was prepared by mixing an equimolecular amount of
AuPPh3Cl and AgOTf in dry toluene. The obtained suspension was
filtered through a syringe fitted with a Whatman Anotop 10 IC filter to
remove the AgCl precipitate. The solution was then charged with the
reactants as reported in Table 1.
Org. Lett., Vol. XX, No. XX, XXXX
C

first step of the reaction and to be easily released from
intermediate II under thermal conditions. Moreover, sole
HNTf2 in a stoichiometric amount was a poor promoter
for the reaction of 1a with 2 at rt (B), whereas at 130 °C it
promoted the formation of compound 5 which has been
isolated and characterized along with a mixture of tarry
side products (A). Finally, 5 was again the main reaction
product running the reaction under standard conditions
but in the presence of 1 equiv of HNTf2 (D). Accordingly
with the obtained results, we can reasonably rule out a
mechanism involving pure protic catalysis for the forma-
tion of 3. Moreover, 5 was formed probably via proton
catalyzed addition of a second molecule of 2 to 3 followed
by electrophilic aromatic substitution on C-4 of the indole
nucleus and loss of acetamide (Scheme 5).
Scheme 3. Proposed Reaction Mechanism for Compounds
3aꢀk
Scheme 5. Proposed Reaction Mechanism for Compound 5
presence of 1 equiv of HNTf2 in toluene at 130 °C and at rt
(Scheme 4, conditions A and B), and under the standard
conditions reported in Table 1 entry 16 in the presence of
0.1 and 1 equiv of HNTf2 (Scheme 5, conditions C and D).
Triflimide was chosen as an acidic promoter in order to
avoid modification in the counterion structure.
The reaction mechanism reported in Scheme 4 also accounts
for the behavior of 2-unsubstituted indole 1l (Scheme 2).
The formation of 4 from 1l may likely take place through
conjugate addition of a second molecule of 1l to an inter-
mediate like II. A similar mechanism has been previously
suggested starting from indole itself and 2 under silica-
supported Lewis acid catalysis.12 An analogous behavior is
not allowed for 2-substituted indole, as the elimination
pathway is probably favored by steric hindrance and by the
high reaction temperature involved.
Scheme 4. Reaction of 1a and 2 under Modified Conditions
In conclusion, this chemistry highlights new aspects of
gold and silver catalysis and, more importantly, this ap-
proach is amenable to a convenient access to quite unknown
compounds which could represent viable starting materials
for the achievement of a more complex structure by, i.e.,
cycloaddition or addition reactions eventually included in
multicomponent or cascade processes.
Supporting Information Available. Experimental pro-
cedures and spectral data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The use of HNTf2 as a cocatalyst, at a concentration of
0.1 equiv, did not alter the reaction outcome (C), suggest-
ing the elimination of the acetamido moiety from inter-
mediate I did not benefit from the presence of excess acid
and the reaction outcome is most probably related to the
intrinsic electrophilic properties of Auþ and Agþ species
able to promote the addition of the nucleophile to 2 in the
ꢀ
(12) de la Hoz, A.; Dıaz-Ortiz, A.; Gomez, M. V.; Mayoral, J. A.;
´
ꢀ
ꢀ
ꢀ
Moreno, A.; Sanchez-Migallon, A. M.; Vasquez, E. Tetrahedron 2001,
57, 5421.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX