Regio- and enantioselective Friedel-Crafts reactions of indoles to epoxides catalyzed by graphene oxide: A green approach

Article abstract of DOI:10.1002/cssc.201402770

Graphene oxide efficiently promotes high regio- and enantioselective ring opening reactions of aromatic epoxides by indoles addition, in solvent- and metal-free conditions. The Friedel-Crafts products were obtained with enantioselectivity up to 99% ee. Th

Full text of DOI:10.1002/cssc.201402770

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DOI: 10.1002/cssc.201402770
Regio- and Enantioselective Friedel–Crafts Reactions of
Indoles to Epoxides Catalyzed by Graphene Oxide:
A Green Approach
Maria Rosaria Acocella,* Marco Mauro, and Gaetano Guerra*[a]
Graphene oxide efficiently promotes high regio- and enantio-
selective ring opening reactions of aromatic epoxides by in-
doles addition, in solvent- and metal-free conditions. The Frie-
del–Crafts products were obtained with enantioselectivity up
to 99% ee. The complete inversion of stereochemistry indicates
the occurrence of SN2-type reaction, which assures high level
of enantioselectivity.
Although ring-opening of epoxides with nitrogen-, oxygen-,
and sulfur-based nucleophiles has been extensively studied,
the subject of regio- and stereoselective reactions with carbon
nucleophiles to give new CÀC bonds has been relatively unex-
plored.[18–21] Carbon-alkylated indoles are important synthetic
intermediates owing to the presence of the indole core unit,
which is characteristic of various natural products and biologi-
cally active molecules.[22,23] Much attention has been devoted
to the study of regio- and stereoselective pathways, but very
few procedures with ecofriendly conditions have been report-
ed. Only in the last years, Friedel–Crafts alkylation of indole
with epoxide was reported to occur in presence of nanocrystal-
line titanium(IV) oxide[24] and, more recently, catalyzed by mag-
netic Fe3O4 and CuFe2O4 nanomaterials.[25]
Meeting the need for sustainable catalytic processes is an im-
portant task of modern synthetic chemistry, and has stimulated
the development of new heterogeneous catalysts because
they offer ease of handling, simple work-up, and, most impor-
tantly, reusability. Combining these benefits with the opportu-
nity to avoid dangerous and expensive organic solvents,
mainly by working in solvent-free conditions, realizes the possi-
bility of green and economical procedures and the redesign of
current organic chemistry processes by using environmentally
benign alternatives.
In this Communication, we report the first highly regio- and
enantioselective ring-opening of aromatic epoxides by addi-
tion of indoles in the presence of catalytic amounts of eGO in
solvent- and metal-free conditions (Scheme 1). To the best of
our knowledge, ring-opening reactions of epoxides with in-
doles catalyzed by graphene oxide have not been reported
before.
Recently, carbon materials have emerged as cheap and
metal-free catalysts and have attracted much attention,[1–3]
mainly regarding the use of graphite oxide (GO) and exfoliated
graphite oxide (eGO) in oxidation reactions,[4–7] Friedel–Crafts
reactions,[8] aza-Michael additions,[9] Mukaiyama–Michael addi-
tions,[10] polymerizations,[11] and epoxide ring-opening reac-
tions.[12] In particular, GO is an efficient catalyst for the Friedel–
Crafts addition of indoles to a,b-unsaturated ketones,[8] giving
3-alkylindoles which are useful precursor structures for the syn-
thesis of different drugs. Epoxides, however, are well-known
carbon electrophiles and are susceptible, under appropriate
conditions, to ring-opening reactions. Generally, high-pressure
conditions[13] and SiO2,[14] lanthanide triflate,[15] and some other
Lewis acids[16,17] have been reported as mild catalysts to facili-
tate this reaction, while there are limited reports on ecofriendly
conditions and heterogeneous catalysts. Only recently was an
efficient procedure for room-temperature ring-opening of ep-
oxides with methanol using GO reported, but a very large
amount of nucleophile is required to obtain the product with
high conversion.[12]
Scheme 1. Regioselective ring opening reaction of styrene oxide.
The sample of GO used in this study was obtained by
Hummers oxidation[26] of graphite followed by ball-milling ex-
foliation. Figure 1A shows an X-ray diffraction (XRD) patterns
of the high-surface-area graphite before oxidation. The XRD
patterns of the oxidized samples, graphite oxide (GO) and ex-
foliated graphite oxide (eGO) (Figure 1B and C, respectively),
show that the 100 and 110 reflections are maintained while
the periodicity perpendicular to the graphite layers (002 and
004 reflections) disappears. These reflections are mainly re-
placed by a broad reflection with spacing d=0.84 nm and cor-
relation length Dꢀ4.5 nm (Figure 1B), corresponding to the
001 reflection of a disordered GO.[27–30] The same reflections,
for the milled graphite oxide sample of Figure 1C, are mainly
replaced by a very broad intense halo, centered at d=0.37 nm
with a correlation length of about 1 nm, indicating the pres-
ence of a large fraction of essentially exfoliated GO.[31] The
[a] Dr. M. R. Acocella, M. Mauro, G. Guerra
Department of Chemistry and Biology, University of Salerno
Via Giovanni Paolo II, 132, 84080 Fisciano (Sa) (Italy)
E-mail: rosyaco@hotmail.it
gguerra@unisa.it
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201402770.
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Table 1. Ring-opening reaction of styrene oxide with indole.
Entry Catalyst (%wt) Amount
[wt%]
t
T
Yield 3[a] Regioselectivity[b]
[h] [8C] [%]
(3/4)
1
2
3
4
5
6
7
GO
GO
GO
eGO
eGO in H2O
HSAG[c]
carbon black
10
3
3
3
3
48 RT 20
72 100 55
120 RT 80
96 RT 80
96 RT 30
96 RT 25
96:4
70:30
98:2
98:2
67:33
97:3
–
3
3
96 RT
–
[a] All the yields refer to the pure isolated product. [b] The regioselectivity
was determined by 1H NMR analysis (400 MHz) on the crude products.
[c] High-surface-area graphite.
Figure 1. X-ray diffraction patterns (CuKa) of (A) the high-surface-area
graphite, (B) the derived GO, and (C) eGO, obtained by ball-milling of GO.
B) GO sample exhibiting a 001 reflection (d001 =0.84 nm) with half-height
width larger than for the 100 reflection (b001 =28 and b100 =0.58), and hence
higher correlation length parallel (D100 =30 nm) than perpendicular to the
graphitic layers (D001 =4.5 nm). C) Exfoliated graphite oxide (eGO) maintain-
ing essentially only the order parallel to the graphitic layers (D100 =30 nm).
(eGO) to verify such improvements. The reaction was per-
formed in the same conditions with 3 wt% of eGO and the
product was obtained with the same efficiency and regioselec-
tivity but in shorter time. (Table 1, entry 4 vs entry 3). The reac-
tion was also explored in water, but a strong decrease of the
yield was observed (entry 5).
weak reflection with d=0.76 nm and Dꢀ2.5 nm can be inter-
preted as 001 reflection of nonexfoliated GO, present in an
amount lower than 10 wt%. Our GO and eGO samples present
similar C/O ratios (nearly 1.7, according to elemental analysis)
and largely different surface areas (according to Brunauer–
Emmett–Teller (BET) measurements): 0.8 and 4.6 m2 gÀ1, respec-
tively. These surface area values agree well with those reported
in the literature for GO samples,[32,33] while they are definitely
lower than the value of the graphite starting material
(308 m2 gÀ1).
We also investigated the possible catalytic activity of high-
surface-area graphite as well as carbon black (with C/O ratios
nearly equal to 30) towards the reaction. Both catalysts are
active diastereoselective catalysts for Mukaiyama–Michael addi-
tions,[10] possibly because of p-stacking of the aromatic sub-
strate with graphite. The notably reduced and negligible yields
observed for the high-surface-graphite of Figure 1A (Table 1,
entry 6) and carbon black (entry 7), respectively, suggest that
the catalytic activity of GO samples is due to their carboxylic
and hydroxyl groups. To assess the scope of the reaction,
a range of indoles variously substituted was reacted with sty-
rene oxide under the conditions previously reported
(Scheme 3).
The activities of GO and eGO as acid catalysts were tested
for the ring-opening reaction of styrene epoxide with indole,
chosen as representative substrate, in solvent-free conditions.
(Scheme 2). The possibility to perform the reaction with graph-
Scheme 3. General scope of the reaction.
Scheme 2. Catalyst screening for the regioselective ring-opening reaction of
styrene oxide with indole.
Table 2 shows that the corresponding alcohols can be ob-
tained in moderate to good yields from the tested indoles
with aromatic epoxy electrophiles. The decreased yield ob-
served for substituted indoles is not strictly dependent on the
electron-donating or -withdrawing nature of the substituents,
while according to the expected trend, ethyl 3-phenylglycidate
(mixture of trans and cis) afforded the product 3j in 35% yield.
Furthermore, the reaction of indole with epicholoroidrine did
not proceed at all because of the (commonly observed) lower
reactivity of aliphatic epoxides compared to aryl epoxides.
The reusability of eGO was investigated by using the addi-
tion of indole 1a to styrene oxide 2a as model reaction. The
solid eGO, recovered after extraction from the aqueous solu-
tion and dried at 608C overnight, was used without any further
ite oxide was explored by changing the catalyst loading and
the temperature conditions. As reported in Table 1, the best re-
sults for yield and regioselectivity were obtained when using
only 3 wt% of graphite oxide at room temperature in solvent-
free conditions (entry 3). An attempt to reduce the reaction
time by increasing the temperature failed as it led to a de-
creased control over regioselectivity (entry 2).
Notably, even in Friedel–Crafts reaction conditions, aromatic
epoxides could rearrange to isomeric carbonyls as only the ad-
dition adducts 3 and 4 were observed and no side products
were detected. In heterogeneous catalysis, the use of catalysts
with smaller-size particles and higher surface areas can im-
prove the catalytic performance, so we tested graphene oxide
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Table 2. General scope of the ring-opening reaction of styrene oxide
with indoles variously substituted.
Entry
1
2
t [days] Product Yield[a]
[%]
1
2
3
1a
1b
1c
2a
2a
2a
4
4
5
3a
3b
3c
80
78
61
Scheme 4. Regio- and enantioselective ring opening reaction.
ral products, and a direct synthesis of optically active indolyl
derivatives is desired. Because enantioenriched epoxides are
readily available, an enantioselective version of our approach
could be realized and become a new and very attractive as
tool in the synthesis of optically active aromatic compounds.
In Friedel–Crafts reaction conditions, aromatic optically
active epoxides can not only rearrange to isomeric carbonyl
compounds but also racemize. Herein, we report the first ex-
ample of enantioselective Friedel–Crafts reaction catalyzed by
graphene oxide in solvent-free conditions, proceeding in good
yield and high enantioselectivity without side products and
with high regioselectivity.
4
5
1d
1e
2a
2a
4
4
3d
3e
54
69
6
7
1 f
2a
2a
4
4
3 f
25
68
1g
3g
The absolute configuration of the products obtained by the
attack of indole to (S)-styrene oxide were assigned by compari-
son by chiral HPLC analysis, previously reported in literature
for compounds 3a–g.[36] The generality of the procedure with
a chiral epoxide in the presence of graphene oxide is summar-
ized by the data reported in Table 4. The reaction proceeded
efficiently with various substituted indoles with high enantio-
selectivities. In agreement with the nucleophilicity scale report-
ed by Mayr,[36] the competitive racemization gave a slight re-
duction of enantioselectivity only for indole, 5-Br-indole, and
N-Me-indole (entries 1, 3, and 4).
8
1a
1a
1a
2b
2c
2d
4
5
5
3h
3i
75
–
9
10
3j
35
[a] All the yields refer to pure, isolated product.
treatment. The reaction conditions (RT and 96 h) were kept the
same in all cycles. As shown in Table 3, both the yield of the re-
action (a reduction from 80 to 75%) as well as the regioselec-
tivity remained almost unchanged after five recycling steps
(Scheme 4).
In fact, the presence of different acidic functionalities on the
carbocatalyst surface activates the epoxide ring-opening and
forms an incipient carbocation ready to react with the nucleo-
philic carbon of the indole before the occurrence of fast race-
mization usually associated to carbocation intermediates. So,
as reported in literature,[16,36] partial racemization, coming from
a competitive SN1 pathway, possibly occurs in presence of a re-
duced nucleophilicity. In every case the high stereoselectivities
observed, with complete inversion of stereochemistry, indicate
the occurrence of SN2-type reaction even if the nucleophilic
attack takes place regioselectively at the benzylic position, usu-
ally favored in SN1- type processes
Table 3. Recycling test of eGO catalyst.
Run[a]
Yield 3[a]
[%]
Regioselectivity (3/4)[b]
1
2
3
4
5
80
78
75
79
76
98:2
98:2
97:3
96:4
97:3
In conclusion, we show that graphene oxide is an effective
catalyst for epoxide ring-opening reactions by indole addition,
giving synthetic intermediates that are important for many
pharmacologically and biologically active compounds. The
eGO catalyst can operate in solvent-free conditions at a loading
of 3 wt% with high regioselectivity and, for the first time, high
stereoselectivity, ensuring that products are obtained in high
enantioselectivity. Being a heterogeneous catalyst, the catalyst
can be recycled and reused without loss of efficiency or regio-
selectivity. The metal- and solvent-free procedure is effective
and more economically and environmentally convenient than
catalysts presently described in the literature.
[a] Conditions as mentioned in the text. [b] All the yields refer to pure,
isolated product. [c] The regioselectivity was determined by H NMR anal-
ysis (400 MHz) on the crude products.
1
The procedure described is simple, metal-, and solvent-free
and represents the first carbocatalyzed ring-opening reaction
with indole compounds. Moreover, the catalyst loading is only
3 wt% with respect to the styrene epoxide, and the catalyst
can be recycled and reused without losing efficiency or regio-
selectivity. Indole is a key motif in many pharmacologically[34]
and biologically active compounds[35] as well as in many natu-
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flask immersed into an ice bath and 5 g of graphite were added,
under nitrogen, with a magnetic stirring. After obtaining an uni-
form dispersion of graphite powders, 15 g of potassium permanga-
nate were added very slowly to minimize the risk of explosion. The
reaction mixture was thus heated to 358C and stirred for 24 h. The
resulting dark green slurry was firstly poured into a copious
amount of deionized water, and then centrifuged at 10000 rpm for
15 min with a Hermle Z 323 K centrifuge. The isolated GO powder
was washed twice with 100 mL of a 5 wt% HCl aqueous solution
and subsequently with deionized water. Finally, it was dried at
608C for 12 h.
Exfoliation of graphite oxide by ball-milling: Graphite oxide pow-
ders were introduced in 125 mL ceramic jars (inner diameter of
75 mm) together with stainless steel balls (10 mm in diameter) and
were dry-milled in a planetary ball mill (Retsch GmbH 5657 Haan)
for 2 h with a milling speed of 500 rpm and a ball-to-powder mass
ratio of 10 to 1.
Table 4. Enantioselective ring opening reactions of (S)-styrene oxide with
indoles variously substituted.
Entry
1
Indole
t
Product
Yield
[%][a]
ee[b]
[%]
[days]
1a
4
4
5
3a
3b
3c
80
78
61
91
2
3
1b
1c
98.5
87
General procedure for Friedel–Crafts addition of indole to epox-
ide: The reaction was carried out in
a vial. Styrene oxide
(120.2 mg, 1.0 mmol) and indole (140.6 mg, 1.2 mmol) were added
to the GO catalyst (3 wt%) at room temperature. The reaction mix-
ture was stirred at the same temperature for the time indicated
The reaction mixture was extracted with AcOEt and the combined
organic phase was dried (MgSO4) and concentrated. The residue
was purified by column chromatography on silica gel in gradient
elution with Petroleum Ether/AcOEt to obtain the pure product.
4
5
1d
1e
4
4
3d
3e
54
69
94
97
6
7
1 f
4
4
3 f
25
68
99
99
Acknowledgements
Ministero dell’ Istruzione, dell’ Universitꢀ e della Ricerca“ and
INSTM are gratefully acknowledged.
1g
3g
Keywords: carbocatalysis
graphene oxide · indoles
· enantioselectivity · epoxides ·
[a] All the yields refer to pure, isolated product.[b] Enantiomeric excess
was evaluated by HPLC analysis with chiral column. The absolute configu-
rations match those reported in literature.
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Received: July 29, 2014
Published online on && &&, 0000
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M. R. Acocella,* M. Mauro, G. Guerra*
&& – &&
Regio- and Enantioselective Friedel–
Crafts Reactions of Indoles to
Epoxides Catalyzed by Graphene
Oxide:
A Green Approach
Do not pass GO: Graphene oxide effi-
ciently promotes highly regio- and
obtained with enantioselectivity up to
99% ee. The complete inversion of ste-
reochemistry indicates the occurrence
of SN2-type reactions, which assures
high level of enantioselectivity.
enantioselective ring opening reactions
of aromatic epoxides by addition of in-
doles, in solvent- and metal-free condi-
tions. The Friedel–Crafts products were
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