Allylic and Allenylic Dearomatization of Indoles Promoted by Graphene Oxide by Covalent Grafting Activation Mode

Article abstract of DOI:10.1002/chem.202001373

The site-selective allylative and allenylative dearomatization of indoles with alcohols was performed under carbocatalytic regime in the presence of graphene oxide (GO, 10 wt percent loading) as the promoter. Metal-free conditions, absence of stoichiometric additive, environmentally friendly conditions (H₂O/CH₃CN, 55 °C, 6 h), broad substrate scope (33 examples, yield up to 92 percent) and excellent site- and stereoselectivity characterize the present methodology. Moreover, a covalent activation model exerted by GO functionalities was corroborated by spectroscopic, experimental and computational evidences. Recovering and regeneration of the GO catalyst through simple acidic treatment was also documented.

Full text of DOI:10.1002/chem.202001373

Accepted Article
Accepted Article
Title: Allylic and Allenylic Dearomatization of Indoles promoted by
Graphene Oxide via Covalent Grafting Activation Mode
Authors: Marco Bandini, Lorenzo Lombardi, Daniele Bellini, Andrea
Bottoni, Matteo Calvaresi, Magda Monari, Alessandro Kotvun,
Vincenzo Palermo, and Manuela Melucci
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202001373
Link to VoR: https://doi.org/10.1002/chem.202001373
01/2020

10.1002/chem.202001373
Chemistry - A European Journal
COMMUNICATION
Allylic and Allenylic Dearomatization of Indoles promoted by
Graphene Oxide via Covalent Grafting Activation Mode
Lorenzo Lombardi,[a] Daniele Bellini,[a] Andrea Bottoni,[a] Matteo Calvaresi,[a] Magda Monari,[a]
Alessandro Kovtun,[c] Vincenzo Palermo,[c,d] Manuela Melucci[c] and Marco Bandini*[a,b]
Abstract:
The
site-selective
allylative
and
allenylative
very elegant methodologies (Figure 1). Additionally, Pd-mediated
allylic C-H activations[4a] and site-selective insertion into C-C triple
bonds[4b] deserve particular mention as parallel methodologies in
the indole allylative dearomatization realm.
dearomatization of indoles with alcohols is performed under
carbocatalytic regime in the presence of graphene oxide (GO, 10 wt%
loading) as the promoter. Metal-free conditions, absence of
stoichiometric additive, environmentally friendly conditions
(H2O/CH3CN, 55 °C, 6 h), broad substrate scope (33 examples, yield
up to 92%) and excellent site- and stereoselectivity characterize the
present methodology. Moreover, a covalent activation model exerted
by GO functionalities was corroborated by spectroscopic,
experimental and computational evidences. Recovering and
regeneration of the GO catalyst via simple acidic treatment was also
documented.
Despite efficiency, these protocols suffer of some undoubted
limitations related to the need of noble-metal complexes,
stoichiometric acid or base additives and rigorous anhydrous
conditions. Consequently, the search for more economic and
environmentally benign 2D®3D chemical space mutations of
indoles with alcohols is ongoing.
The dearomatization reaction of indoles is receiving growing
attention in the synthetic organic chemistry scenario, providing
rapid access to complex 3D molecular architectures starting from
widely available aromatic 2D-platforms.[1] In this context, the
combination of catalytic tools and environmentally benign
substrates is an ultimate goal in order to conjugate the intrinsic
synthetic utility of dearomative protocols with crucial requirements
of nowadays organic synthetic chemistry such as sustainability.
Undoubtfully, p-alcohols represent a convenient portfolio of
substrates for arene manipulations featuring the enviable
advantage of producing water as the only stoichiometric side-
product.[2] However, their employment has proven challenging
due to the intrinsic inertness towards nucleophilic substitution-
type reactions that makes mandatory the use of harsh reaction
conditions or stoichiometric co-additives.
In this segment, pioneering works on the use of allylic alcohols
deal with the combination of transition metal-based catalysts and
acid or base additives. In particular, Tamaru ([Pd(0)]/BEt3),[3a]
Trost ([Pd(0)]/9-BBN-C6H13),[3b] You ([Ru(II)]/pTsOH),[3c] You
([Ir(I)]/Fe(OTf)2)[3d] and Bisai ([Pd(0)/BEt3/KOtBu])[3e] documented
Figure 1. State of the art (metal-catalyzed allylative dearomatization of indoles
with alcohols) and schematic representation of the present GO-assisted
metal-free dearomatization of indoles with allylic/propargylic alcohols.
[a]
L. Lombardi, D. Bellini, Prof. A. Bottoni, Prof. M. Calvaresi, Prof. M.
Monari, Prof. M. Bandini
Dipartimento di Chimica “Giacomo Ciamician”
Alma Mater Studiorum – Università di Bologna
via Selmi 2, 40126 Bologna, Italy
E-mail: marco.bandini@unibo.it
Prof. M. Bandini
In this regard, we envisioned that the emerging field of
carbocatalysis could provide a concrete hint to address these
challenges.[6] As a matter of fact, the Brønsted acidity provided
by some nanostructured functionalized carbon-based materials
could assist the selective alcohol activation and the network of
functional groups, together with the non-innocent p-matrix of the
carbon material, could synergistically contribute in fine-tuning
the arene reactivity.
[b]
[c]
[d]
Consorzio C.I.N.M.P.I.S.
via Selmi 2, 40126 Bologna, Italy
Dr. M. Melucci, Dr. A. Kovtun, Dr. V. Palermo
Istituto per la Sintesi Organica e Fotoreattività (ISOF) - CNR
via Gobetti 101, 40129 Bologna
Chalmers University of Technology, Industrial and Materials
Science, Hörsalsvägen 7A, SE-412 96 Goteborg, Sweden
In this context, graphene oxide (GO)[7] is collecting growing
credit in the area of organic transformations being effectively
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.202001373
Chemistry - A European Journal
COMMUNICATION
employed either as a catalyst or promoter (i.e. co-reagent)[8] in
numerous C-C and C-X bond forming transformations.[9]
In this article, our preliminary findings in the GO-assisted
dearomatization of indoles with allylic alcohols as well as the
covalent activation mode exerted by the GO-surface will be
presented and supported by experimental, computational and
spectroscopic evidences (Figure 1 lower).
In light of our ongoing interest in catalytic dearomatization
reactions,[10] we selected N(H)-2,3-Me2-indole (1a) and the
secondary allylic alcohol 2a as model substrates for the
optimization of the reaction conditions. Upon an extensive survey
of reaction conditions the use of 10 wt% loading of GO enabled
the selective formation of the desired C(3)-allylated dearomatized
compound 3aa in 70% yield under very mild conditions
(CH3CN:H2O 4:1, 55 °C, 6 h, entry 1, Table 1).[11]
the indolenine (E)-3aa was recorded almost exclusively in a
stereospecific manner (SN2’-like pathway).¤
The background reaction was incomparable in terms of product
realization (12% yield, 36 h, entry 2) with respect to the optimal
GO-based protocol (70%, entry 1). Additionally, the oxygenated
groups of the GO surface proved essential for the condensation
(vide infra), indeed reduced GO analogous proved inert as a
promoter (yield = 12%, entry 6).
The high GO-loading is one of the critical aspects usually
encountered
in
GO-based
carbo-catalyzed
organic
transformations. Loadings commonly fluctuate around 100-200
wt% posing serious issues in term of process scalability. In this
methodology, we were pleased to verify that 10 wt% loading of
GO was elected as the best conditions. Here, while higher
amounts (25 wt%, entry 4) did not bring any benefit at the process,
the use of 5 wt% caused a slight drop in the isolation of 3aa (59%,
entry 3). The choice of the solvent was crucial too. In particular,
the addition of water (ca. 20% v/v with CH3CN) was found to be
essential for the protocol (entry 9 vs entry 1).[12] The use of water
for this class of dearomatizations with alcohols is unprecedented
and remarkable.
Table 1. Variations from the optimal conditions in the allylic dearomatization
of indoles.
OH
Me
Me
Me
GO (10 mol%)
+
Me
N
H
CH3CN : H2O (4:1)
55 °C, 5 h
OMe
N
MeO
(+/-)-3aa
1a
(+/-)-2a
Proofs of a genuine GO catalysis were gained via dedicated
control experiments. In particular, the inefficiency of a background
Brønsted acid catalysis was empathized by running the model
reaction in the presence of AcOH (entry 13) and pTSA (Table
S1).[13] Additionally, the potential co-catalysis promoted by metal
contaminations of GO (i.e. Mn2+) was ruled out via designed
experiments with Mn(OAc)2•4H2O (entry 14) and cation-trapping
EDTA solution (entry 15). The suitability of the protocol towards a
gram scale variant was also verified in the presence of 5 mmol of
indole 1a (entry 17). In this case, notable 78% isolated yield (1.13
gr) of 3aa was obtained under model conditions.
Run[a]
Deviations from optimal
Yield (%)
3aa[b]
1
--
70
2
No GO, 36 h
12
3
5 wt% of GO
59
4
25 wt% of GO
69
5[c]
6
Pre-sonication of GO
67
with GOr (25 wt%)
12
Then, we focused on to the scope of the reaction by subjecting
several poly-substituted indoles (1b-n) to the GO-assisted
condensation with 2a (Scheme 1).
7
Dioxane instead of CH3CN, 25 wt% of GO
THF instead of CH3CN, 25 wt% of GO
CH3CN as the solvent, 24 h
H2O as the solvent, 25 wt% of GO
H2O as the solvent, 25 wt% of GO, rt, 16 h
H2O as the solvent, 25 wt% of GO, 80 °C
AcOH pH = 4
66
8
30
Scheme 1. Scope of the reaction: the indole.
9
25
10
11
12
13
14[d]
15[e]
16
17[f]
62
OH
’R
R’
X
GO (10 mol%)
X
47
+
R
R
N
H
CH3CN : H2O (4:1)
55 °C
OMe
N
MeO
62
(+/-)-3
1
(+/-)-2a
44
OMe
’R
N
Me
Mn(OAc)2•4H2O and no GO
EDTA as an additive
traces
68
Me
OMe
Et
OMe
N
3fa, yield = 68%
3ba, R’ = Et, yield = 68%
3ca, R’ = nBu, yield = 61%
3da, R’ = Bn, yield = 47%
N
Under N2 and degassed solvents
Gram scale (5 mmol of 1a)
69
3ea, R’ = CH2CO2Et, yield = 57%
3ga, yield = 35%
78
OMe
Me
X
Me
N
[a] All the reactions were carried out with reagent grade solvents, unless
otherwise specified (1a/2a = 1/2 on 0.15 mmol of 1a, 0.1 M). [b] Determined
after flash chromatography. [c] Sonication for 2 min, in probe sinicator. [d]
[Mn]: 1.8 mol%. [e] EDTA: 200 µL of 43 mM water solution. [f] GO (10 wt%)
3aa: 1.13 gr (16 h).
OMe
3ja, X = 5-F, yield = 92%
3ka, X = 5-Cl, yield = 77%
3la, X = 5-Br, yield = 75%
3ma, X = 5-Me, yield = 60%
3na, X = 6-Br, yield = 70%
n
N
3ha
3ha, n = 1, yield = 75%
3ia, n = 2, yield = 58%
Remarkably, while the potentially competitive N(1)- and
C(5)-allylation products were observed only sporadically (traces),
This article is protected by copyright. All rights reserved.

10.1002/chem.202001373
Chemistry - A European Journal
COMMUNICATION
In terms of indole substitutions, different aliphatic as well as
aromatic groups could be accommodated at C(2) and C(3)-
positions (Et, nBu, Bn, CH2CO2Et) leaving almost untouched the
catalytic performances of the present methodology (yield up to
70%). Interestingly, tetrahydrocarbazole 1h and 7-membered-ring
analogous 1i worked smoothly in the allylic dearomative process,
delivering the corresponding indolenines 3ha and 3ia in 75% and
58% yield, respectively.[14]
Intrigued by these results, we focused on elucidating the
mechanism of the process. On the other hand, the use of multi-
functionalized nanocarbon promoters/catalysts poses several
issues in terms of mechanistic elucidation, since multiple reaction
channels can be envisioned.
At first, significative structural modifications of the GO-surface
functionalization were observed via XPS analysis (Figures 2a-e).
In particular, the treatments of GO in the reaction media alone
(Figure 2b) did not affect significantly the O:C content (pristine GO
0.32:1, GO after solvent 0.32:1). On the contrary, while the
treatment of GO with 1a decreased slightly the O:C ratio (0.28:1,
Figure 2c), marked O:C ratio variations were observed for GO/2a
treatment (0.22:1, Figure 2d) and GO/1a+2a treatment (0.24:1,
Figure 2e).
Finally, tolerance of the protocol towards electronic
perturbation of the benzene ring was assessed with indoles 1j-o.
Remarkably, good to excellent yields (up to 92%) were recorded
regardless the electronic properties of the substituents (F, Cl, Br,
Me) and their position (C(5) and C(6)).
The extendibility of the process to different allylic alcohols was
then elaborated. A series of secondary (2b-m) and tertiary (2n-p)
alcohols was treated with the 2,3-Me2-indole 1a and the
corresponding outcomes are collected in the Scheme 2. In all
cases, excellent regio- (both indole and alcohol sites) and
stereoselectivity was recorded, delivering the desired all-carbon
C(3) quaternary stereogenic center indolenines in up to 84% yield.
In particular, the chemical structure of GO changes
significantly after heating in the presence of 2a. Here, the epoxy
content decreases from 38.3% to 17.9% and hydroxyl groups
increase from 3.2% to 9.0% (See fit of C 1s in Figure 2). This
structure modification is compatible with a partial ring-opening of
the epoxide units during the reaction course.[15]
A key feature for the success of the protocol was the presence
of electron-donating groups on the aromatic system or electron-
rich heteroarenes (i.e. thiophene, benzothiophene). Contrarily,
unsubstituted arenes or benzenes carrying electron-withdrawing
groups did not react even under harsh conditions (120 °C, 6 h). In
these cases, substantial isomerization of 2d towards the linear
cinnamyl isomer occurred exclusively (vide infra for mechanistic
interpretation). Interestingly, also tertiary alcohols 2n-p did react
in a satisfactory manner with 1a furnishing the corresponding
dearomatized heterocycles in excellent yields (72-84%) via SN2’-
type machinery.
In addition, a significant drop in carboxylic content of the GO
surface, upon treatment via alcohols 2a or 1a+2a (6 h, 55 °C),
was observed (Figure 2a vs Figures 2d/e). In particular, the
carboxylic groups decrease from 1.6% to 0 and 0.6%, respectively.
This behavior can be ascribed to the esterification of the
carboxylic group present and subsequent decomposition also via
decarboxylative events.[9g,n,16]
Therefore, we combined all spectroscopic and experimental
information with the QM/MM study to elucidate in detail the
reaction mechanism that results in a two-step process (see Figure
3a).[10,17]
In step 1 a covalent grafting of the allylic alcohol on the GO
surface is observed. The protonation of the epoxide ring on the
GO surface leads to an unstable oxonium unit that opens
barrierless (Rx).[18] Ring opening of the epoxide groups relieves
ring strain and forms a highly stabilized α-carbocation, as already
observed by Chen et al.[19] Then, the resulting α-carbocation
undergoes a facile nucleophilic attack by the allylic alcohol
(transition state Ts1).
Scheme 2. Scope of the reaction: the alcohol.
R
OH
Me
Me
Me
R
GO (10 wt%)
+
Ar
Ar
Me
N
H
CH3CN : H2O (4:1)
55 °C
N
(+/-)-3
1a
(+/-)-2
The key role of electron-donating groups on the aromatic
system (i.e. 2a) is in agreement with the current mechanistic
hypothesis. The comparison of the energetic reaction profiles for
the GO grafting of different allylic alcohols showed that a
significantly higher barrier is observed for 2d (unsubstituted
benzene) compared to 2a (25.5 vs 10.9 kcal mol-1, Figure S12).
The presence of electron-donating groups on the aromatic system
contributes to stabilize the positive charges delocalized on the GO
surface via strong p-p interactions between GO and the aromatic
moiety of the alcohol.
Me
Me
N
Me
N
O
O
X
Me
Me
3aj, yield = 66%
Me
N
X
3ag, X = 2-OMe, yield = 40%
3ab, X = OBn, yield = 65%
3ac, X = OTBDMS, yield = 66%a
3ad, X = H, yield = NRb
3ah, X = 3,4-(OMe)2, yield = 76%
3ai, X = 2,4,5-(OMe)3, yield = 81%d
3ae, X = SMe, yield = 51%c
3af, X = O(CH2)5N3, yield = 76%
Me
Me
Me
S
S
Fe
Me
N
Me
3am, yield = 61%
Me
N
N
3al, yield = 53%a,c
3ak, yield = 63%a
R
Me
S
Me
Me
OMe
N
3an, R = Me, yield = 72%e
3ao, R = nBu, yield = 80%e
3ap, yield = 84%d
Me
N
a 10% of C(3)/C(5)-diallylated product was formed. b 120 °C. c 70 °C. d RT. NR
= no reaction (branched/linear isomerization of 2d occurred). c The absolute
configuration E of the C=C was determined via 1H-NoE experiments, see SI.
This article is protected by copyright. All rights reserved.

10.1002/chem.202001373
Chemistry - A European Journal
COMMUNICATION
an ideal geometry for a SN2 attack, since it is orthogonal to the
graphene sheet and parallel to the electrophilic site. In contrast, if
the attack is carried out by N(1), a strong deviation from optimal
reaction geometry of the indole ring is necessary in order to
minimize the steric repulsion between the methyl group and GO.
As a consequence, Ts2 C(3) is significantly more stable than Ts2
N(1) (8.1 kcal mol-1), in perfect agreement with the experimental
stereospecificity.
As observed in Step 1, also in Step 2 the presence of electron-
donating groups on the aromatic system (better leaving groups)
favors the reaction and a higher barrier is observed for the C(3)
allylic alkylation of 2d compared to 2a (28.0 vs 21.4 kcal mol-1,
Figure S12).
Interestingly, at the end of the reaction the alcoholic O–H
group remains grafted on the GO surface (Pd) explaining the
overall increase of alcoholic moieties versus the oxirane ones
spectroscopically observed by XPS analysis before and after the
catalysis.
The covalent “grafting” activation model was further supported
by means of FT-IR analysis (Figure S2). In particular, the allylic
alcohol 2f bearing an azide group was reacted with GO in
CH3CN:H2O 4:1 at 55 °C (6 h) mimicking reaction conditions. The
recovered GO was then analysed via FT-IR and compared to GO
stirred with 2f (MeCN/H2O) at 0 °C for 30 min. In the former case,
FT-IR displayed the diagnostic N3 stretching at 2100 cm-1 (Figure
4a). Contrarily, a significantly weaker signal was observed in the
GO sample treated with 2f at 0 °C (Figure S2).
Figure 2. XPS C 1s signal of a) pristine GO; b) GO after ACN:H2O 4:1 at 55 °C ;
c) GO after 1a; d) GO after 2a; e) GO after 1a+2a. f) composition of C-O groups
obtained from fit (a-e). More details on fit procedure in SI.
In step 2, the obtained protonated allyl ether undergoes a SN2’-
type attack by indole derivatives leading to the observed C(3)-
allylated dearomatized compound. Step 2 follows a concerted
mechanism where either C(3) or N(1)-atom of the 2,3-Me2-indole
attacks the allylic position (Ts2), causing an overall reorganization
of the π-system. The C(3)-carbon selectivity emerges clearly from
the calculated Ts2 and it is dictated by the GO catalyst.
Figure 3. (a) Schematic representation of the reaction mechanism. The
energies of the identified critical points in square bracket (kcal mol-1); 3D
representation of the identified transition states for the C(3) (b) and (N1) (c)
attack of the indoles.
In particular, the influence of GO on the regioselective attack
by indole is determined by the following factors: i) in the C(3)-
dearomatization a stabilizing interaction between the indole N(1)-
H atom and the GO π-system is established (Figure 3b). On the
Similar trend was recorded also via XPS N 1s analysis that
confirmed univocally the N3 presence by the characteristic double
peak of azides: 404.1 eV, N=N=N and 401.1 for N=N=N (Figure
4c).[21] Contrarily, both pristine GO and the GO stirred with 2f
(MeCN/H2O) at 0 °C, presented only residual amounts of amino
groups in the region 402-399 eV (Figure 4b).
contrary, the attack involving the N(1)-position, causes
a
destabilizing interaction (steric clash) due to steric reasons
between the C(3)-methyl group and the graphene sheet (Figure
3c).[20] ii) The above discussed interactions have also important
effects on the structure of the indole ring during the SN2 attack:
when the reaction is carried out by the C(3), the indole ring shows
This article is protected by copyright. All rights reserved.

10.1002/chem.202001373
Chemistry - A European Journal
COMMUNICATION
Scheme 3. GO-assisted dearomative allenylaton of indoles.a
The remarkable drop in catalytic performance of the
recovered GO upon the first run (12% yield of 3aa in 36 h) agrees
with the disclosed mechanistic pathway in which both epoxides
and carboxylic acids of the GO surface are involved.
a Reaction time: see SI. dr determined on the reaction crude.
Delightly, sonication of the recovered GO under acidic
conditions (HCl 1 M, 1 h, Figure 5a) enabled the simultaneous
restoring of the acidity profile and part of the epoxydic content of
the pristine GO. As testified by the XPS analysis, the epoxy group
increased from 24% to 30% upon acid treatment (Figures S7).[19]
Once again, the feedback gained from catalysis was in agreement
with the structural characterization. As a matter of fact, the
regenerated GO worked similarly to the pristine one when tested
in the model reaction (3aa, yield = 63%, 36 h, Figure 5b).
Figure 4. (a) Violet: alcohol 2f. Red: GO + 2f after 6 h in CH3CN:H2O 4:1 at
55 °C. XPS N 1s signal of pristine GO (b) and GO + 2f after 6 h in CH3CN:H2O
4:1 at 55 °C (c).
HO
HO
O
O
O
O
O
O
O
HO
HO
H+
a)
HO
HO
- H2O
O
O
The evidences for a grafting activation mode exerted by the
GO-surface on the alcoholic moiety, prompted us to investigate
also the reactivity of propargylic alcohols in the dearomatization
process.[2f] In particular, the covalent binding of the carbynol unit
on the GO should leave exposed to the approaching indole only
the “external” acetylenic carbon (Scheme 3 inset), enabling an
unprecedented regioselective allenylative dearomatization of
indoles to occur.
O
O
OH
OH
Recovered-GO
Regenerated-GO
GO
Recovered-GO
Yield 3aa (12%)
Me
+
Me
GO (10 wt%)
2a
b)
CH3CN : H2O (4:1)
55 °C, 36 h
N
H
Regenerated-GO
Yield 3aa (63%)
1a
Interestingly, we were pleased to verify that the optimal
reaction conditions adopted for the allylic alcohols 2 (i.e.
CH3CN:H2O 4:1, 55 °C)[22] proved competent also in the
nucleophilic substitution with secondary and tertiary propargylic
derivatives 4a-e. The corresponding allenyl-indolines 5 were
delivered in good yields (40-94%) and diastereoisomeric ratio up
to 80:20 (Scheme 3). It is worth mentioning that this approach
represents the first example of indole dearomatization with
concomitant site-selective installation of bi-, tri-, and tetra-
substituted allenyl units.[23,24]
Figure 5. (a) Schematic representation of acidic regeneration GO; (b)
Comparing the effectiveness of recovered- and regenerated-GO in the model
reaction.
In conclusion,
a
graphene oxide mediated allylic
dearomatization of 2,3-di-substituted indoles with alcohols is
presented. The protocol does not require noble-metal catalysis,
stoichiometric additives, rigorous anhydrous conditions and
comprises facile regeneration of the carbo-nano-material via
acidic treatment. From a mechanistic view-point, a synergistic
action of the functional groups decorating the graphene surface
was discovered providing insight towards a covalent activation-
mode. Studies towards the exploitation of this efficient GO-
mediated electrophilic activation of p-alcohols in other chemical
transformations are currently underway in our laboratories
Additionally, to further explore the synthetic utility of the
present methodology, the regeneration of GO was investigated.
Acknowledgements
This article is protected by copyright. All rights reserved.

10.1002/chem.202001373
Chemistry - A European Journal
COMMUNICATION
Kumar, K. Rama Rao, Tetrahedron Lett. 2011, 52, 5188-5191; c) H.-P.
Jia, D.R. Dreyer C.W. Bielawski, Adv. Synth. Catal. 2011, 353, 528-532;
d) D.R. Dreyer, H.-P. Jia, A.D. Todd, J. Geng, C.W. Bielawski, Org.
Biomol. Chem. 2011, 9, 7292-7295; e) H.-P. Jia, D.R. Dreyer, C.W.
Bielawski, Tetrahedron 2011, 67, 4431-4434; b) D.R. Dreyer, C.W.
Bielawski, Adv. Funct. Mat. 2012, 22, 3247-3253; f) M.R. Acocella, M.
Mauro, G. Guerra, ChemSusChem 2014, 7, 3279; g) F. Hu, M. Patel, F.
Luo, C. Flach, R. Mendelsohn, E. Garfunkel, H. He, M. Szostak, J. Am.
Chem. Soc. 2015, 137, 14473-14480; h) C. Su, R. Tandiana, J.
Balapanuru, W. Tang, K. Pareek, C.T. Nai, T. Hayashi, K.P. Loh, J. Am.
Chem. Soc. 2015, 137, 685-690; i) Y. Gao, P. Tang, H. Zhou, W. Zhang,
H. Yang, N. Yan, G. Hu, D. Mei, J. Wang, D. Ma, Angew. Chem. Int. Ed.,
2016, 55, 3124-3128; j) M.R. Acocella, L. D’Urso, M. Maggio, and G.
Guerra, ChemCatChem 2016, 8, 1915; k) Y.R. Girish, S. Pandit, S.
Pandit, M. De, Chem. Asian J. 2017, 12, 2393-2398; l) H. Wu, C. Su, R.
Tandiana, C. Liu, C. Qiu, Y. Bao, J. Wu, Y. Xu, J. Lu, D. Fan, K.P. Loh,
Angew. Chem. Int. Ed. 2018, 57, 10848-10853; m) L. Favaretto, J. An,
M. Sambo, A. De Nisi, C. Bettini, M. Melucci, A. Kovtun, A. Liscio, V.
Palermo, A. Bottoni, F. Zerbetto, M. Calvaresi, M. Bandini, Org. Lett.
2018, 20, 3705-3792; n) G. Meng, M. Patel, F. Luo, Q. Li, C. Flach, R.
Mendelsohn, E. Garfunkel, H. He, M. Szostak, Chem. Commun. 2019,
55, 5379-5382; o) M. Karthik, P. Suresh, ACS Sust.Chem.Eng. 2019, 7,
9028-9034; p) H. Wu, C. Qiu, Z. Zhang, B. Zhang, S. Zhang, Y. Xu, H.
Zhou, C. Su, K.P. Loh, DOI:10.1002/adsc.201901224.
Acknowledgements are made to University of Bologna for
financial support. PRIN-2017 project 2017W8KNZW was kindly
acknowledged. The research leading to these results has
received funding from the European Union's Horizon 2020
research and innovation programme under GrapheneCore2
785219 – Graphene Flagship.
Keywords: Alcohols • Carbocatalysis • Graphene oxide •
Dearomatization • Indole
[1]
a) S.P. Roche, J.A. Porco, Angew. Chem. Int. Ed. 2011, 50, 4068-4093;
b) C.-X. Zhuo, W. Zhang, S.-L. You, Angew. Chem. Int. Ed. 2012, 51,
12662-12686; c) C.-X. Zhuo, C. Zheng, S.-L. You, Acc. Chem. Soc. 2014,
47, 2558-2573; d) C. Zheng, S.-L. You, Chem. 2016, 1, 830-857; e)
Asymmetric Dearomatization Reactions (Ed. You, S.-L.), Wiley-VCH,
2016; f) W.-T. Wu, L. Zhang, S.L. You, Chem. Soc. Rev. 2016, 45, 1570-
1580; g) X.-W. Liang, C. Zheng, S.-L. You, Chem. Eur. J. 2016, 22,
11918-11933; h) S. Park, S. Chang, Angew. Chem. Int. Ed. 2017, 56,
7720-7738; i) J. An, M. Bandini, CHIMIA 2018, 72, 610-613; j) V.
Pirovano, Eur. J. Org. Chem. 2018, 1925-1945; j) J. Bariwal, L.G.
Voskressensky, E.V. Van der Eycken, Chem. Soc. Rev. 2018, 47, 3831-
3848; k) C. Zheng, S.-L. You, Nat. Prod. Rep. 2019, 36, 1589-1605.
For general reviews on the use of allylic/propargylic alcohols in organic
synthesis see: a) M. Bandini, M. Tragni, Org. Biomol. Chem., 2009,7,
1501-1507; b) M. Bandini, Angew. Chem. Int. Ed., 2011, 50, 994995; c)
M. Bandini; G. Cera; M. Chiarucci, Synthesis, 2012, 44, 504-512; d) B.
Sundararaju, M. Achard, C. Bruneau, Chem. Soc. Rev. 2012, 41, 4467-
4483; e) H. Li, C. Mazet, 2016, 49, 1232-1241; f) J. Zhang, J. Liao, Y.-F.
Wei, G. Cheng, R. Luo, Mini Rev.Org. Chem. 2018, 15, 476-487; f) H.
Qian, D. Huang, Y. Bi, G. Yan, Adv. Synth. Catal. 2019, 361, 3240-3280.
a) M. Kimura, M. Futamata, R. Mukai, Y. Tamaru, J. Am. Chem. Soc.
2005, 127, 4592-4593; b) B. M. Trost, J. Quancard, J. Am. Chem. Soc.
2006, 128, 6314-6315; c) X. Zhang, Z.-P. Yang, C. Liu, S.-L. You, Chem.
Sci. 2013, 4, 3239-3243; d) X. Zhang, L. Han, S.-L. You, Chem. Sci. 2014,
5, 1059-1063; e) N. Kumar, A. Maity, V.P. Gavit, A. Bisai, Chem.
Commun. 2018, 54, 9083-9086.
[2]
[10] a) G. Cera, M. Chiarucci, A. Mazzanti, M. Mancinelli, M. Bandini, Org.
Lett. 2012, 14, 1350-1353; b) C. Romano, M. Jia, M. Monari, E. Manoni,
M. Bandini, Angew. Chem. Int. Ed. 2014, 53, 13854-13857; c) L.
Rocchigiani, M. Jia, M. Bandini, A. Macchioni, ACS Catal. 2015, 5, 3911-
3915; d) R. Ocello, A. De Nisi, M. Jia, Q.-Q. Yang, P. Giacinto, A. Bottoni,
G.P. Miscione, M. Bandini, Chem. Eur. J. 2015, 21, 18445-18453; e) J.
An, A. Parodi, M. Monari, M. Castiñeira Reis, C. Silva Lopez, M. Bandini,
Chem. Eur. J. 2017, 23, 2442-2449; f) P. Giacinto, A. Bottoni, A. Garelli,
G.P. Miscione, M. Bandini, ChemCatChem. 2018, 10, 2442-2449; g) J.
An, L. Lombardi, S. Grilli, M. Bandini, Org. Lett. 2018, 20, 7380-7383; h)
A. Cerveri, O. Nieto Faza, C. Silva Lopez, S. Grilli, M. Monari, M. Bandini,
J. Org. Chem. 2019, 84, 6347-6355.
[3]
[11] In addition of 3aa, C(3) and C(5)-diallylated compound was observed in
the reaction crude (ca. 10%).
[4]
[5]
a) H. Zhang, R.-B. Hu, N. Liu, S.-X. Li, S.-D. Yang, Org. Lett. 2016, 18,
28-31; b) S. Gao, Z. Wu, X. Fang, A. Lin, H. Yao, Org. Lett. 2016, 18,
3906-3909.
[12] Although the role of water is not fully understood at the present, the
following aspects could be highlighted: 1) improving the solubilization of
GO in the reaction media; 2) acting as proton shuttle during the whole
reaction process; 3) increasing acidic sited of the GO via partial
interconversion of tertiary alcohol into highly enolizable ketones: A.
Dimiev, D.V. Kosynkin, L.B. Alemany, P. Chaguine, J.M. Tour, J. Am.
Chem. Soc. 2012, 134, 2815-2822.
For some representative very recent examples see: a) M. Zhu, C. Zheng,
X. Zhang, S.-L. You, J. Am. Chem. Soc. 2019, 141, 2636-2644; b) Y.-Z.
Cheng, Q.-R. Zhao, Q.-R. Zhao, X. Zhang, S.-L. You, Angew. Chem. Int.
Ed. 2019, 58, 18069-18074; c) J. Wu, Y. Dou, R. Guillot, C. Kouklovsky,
G. Vincent, J. Am. Chem. Soc. 2019, 141, 2832-2837; d) G.-J. Mei, X.
Tang, Y. Tasdan, Y. Lu, Angew. Chem. Int. Ed. 2020, 59, 648-652.
General reviews on carbocatalysis: a) D. R. Dreyer, C. W. Bielawski,
Chem. Sci. 2011, 2, 1233-1240; b); C.K. Chua, M. Pumera, Chem. Eur.
J. 2015, 21, 12550-12562; c) D. S. Su, G. Wen, S. Wu, F. Peng, R.
Schløgl, Angew. Chem. Int. Ed. 2017, 56, 936-964; d) X. Duan, H. Sun,
S. Wang, Acc. Chem. Res. 2018, 51, 678-687; e) P. Veerakumar, P.
Thanasekaran, T. Subburj, K.-C. Lin, C, 2018, 4, 54; f) M. Antonietti, N.
Lopez-Salas, A. Primo, Adv. Mat. 2019, 31, 1805719; g) C. Campisciano,
M. Gruttadauria, F. Giacalone, Chem.Cat.Chem. 2019, 11, 90-113.
A selection of comprehensive articles regarding the use of GO in organic
synthesis: a) D. R. Dreyer, S. Park, C. W. Bielawski, R. S. Ruoff, Chem.
Soc. Rev. 2010, 39, 228-240; b) J. Pyun, Angew. Chem. Int. Ed, 2011,
50, 46-48; c) D.R. Dreyer, A.D. Todd, C.W. Bielawski, Chem. Soc. Rev.
2014, 43, 5288-5301; d) S. Navalon, A. Dhakshinamoorthy, M. Alvaro, H.
Garcia, Chem. Rev. 2014, 114, 6179-6212; e) D. Haag, H.H. Kung, Top.
Catal. 2014, 57, 762-773; f) S. Gupta, R. Banu, C Ameta, R. Ameta, P.
B. Punjabi, Top. Curr. Chem. 2019, 377, 13.
[13] See SI for a complete list of conditions screening.
[14] The use of skatole led to the formation of C(2)-allylated compound,
exclusively.
[6]
[15] A. Kovtun, D. Jones, S. Dell’Elce, A. Liscio, V. Palermo, Carbon 2019,
143, 268-275.
[16] D.R. Dreyer, S. Murali, Y. Zhu, R.S. Ruoff, and C.W. Bielawski, J. Mat.
Chem. 2011, 21, 3443-3447.
[17] a) P. Giacinto, A. Bottoni, M. Calvaresi, F. Zerbetto, F. J. Phys. Chem. C
2014, 118, 5032-5040; b) K. Spyrou, M. Calvaresi, E. K. Diamanti, T.
Tsoufis, D. Gournis, P. Rudolf, F. Zerbetto, Adv. Funct. Mater. 2015, 25,
263-269; c) P. Giacinto, F. Zerbetto, A. Bottoni, M. Calvaresi, J. Chem.
Theory Comput. 2016, 12, 4082-4092; d) T. D. Marforio, A. Bottoni, P.
Giacinto, F. Zerbetto, M. Calvaresi, J. Phys. Chem. C 2017, 121, 27674-
27682.
[7]
[18] R. Ramírez-Jiménez, M. Franco, E. Rodrigo, R. Sainz, R. Ferrito, A.M.
Lamsabhi, J.L. Aceña, M. Belén Cid, J. Mater. Chem. A. 2018, 6, 12637-
12646.
[19] V. D. Ebajo Jr., C. R. L. Santos, G. V. Alea, Y. A. Lin, C.-H. Chen, Scient.
Reports 2019, 9, 15579.
[8]
[9]
S. Presolski, M. Pumera, Angew. Chem. Int. Ed. 2018, 57, 16713-16715.
For representative examples see a) D.R. Dreyer, H.-P. Jia, and C.W.
Bielawski, Angew. Chem. Int. Ed. 2010, 49, 6813-6816; b) A. Vijay
[20] As a partial support, when 1,2,3-trimethyl-indole was utilized in the
process, the reaction was completely inhibited.
This article is protected by copyright. All rights reserved.

10.1002/chem.202001373
Chemistry - A European Journal
COMMUNICATION
[21] R.A. Zangmeister, T. A. Morris, M.J. Tarlov, Langmuir 2013, 29, 8619-
8628.
Gohain, P. García-García, M.A. Fernández-Rodríguez, E. Álvarez, F.
Rodríguez, Eur. J. Org. Chem. 2010, 7027-7039; c) X. Zhang, W. Teng,
T. Sally, P. Wai, H. Chan, J. Org. Chem., 2010, 75, 6290-6293; d) L.
Zhang, Y. Zhu, G. Yin, P. Lu, Y. Wang, J. Org. Chem. 2012, 77, 9510-
9520; e) S. Gujarathi, H. P. Hendrickson, G. Zheng, Tetrahedron Lett.,
2013, 54, 3550-3553; f) K. Selvaraj, S. Debnath, K. C. Kumura Swamy,
Org. Lett. 2019, 21, 5447-5451;
[22] The use of stoichiometric amounts of pTSA or AcOH in the reaction of
1a and 4a resulted in a complete polymerization of the starting materials
or delivered 5aa only in traces, respectively.
[23] For some representative examples of condensations of indoles and
propargylic alcohols see: a) J. S. Yadav, B. V. Subba Reddy, K. V.
Raghavendra Rao, G. G. K. S. Narayana Kumar, Tetrahedron Lett., 2007,
48, 5573-5576; b) H. Matsuzawa, K. Kanao, Y. Miyake, Y. Nishibayashi,
Org. Lett. 2007, 9, 5561-5564; c) R. Sanz, D. Miguel, A. Martínez, M.
[24] R. Roy, S. Saha, RSC Adv. 2018, 8, 31129-31193.
This article is protected by copyright. All rights reserved.

10.1002/chem.202001373
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Graft-on. The covalent
L. Lombardi, D. Bellini, A. Bottoni,
M. Calvaresi, M. Monari, A.
Kovtun, V. Palermo, M. Melucci,
M. Bandini*
“catalysis“ exerted by graphene
oxide on the site-selective
dearomatization of indoles with
allylic/propargylic alcohols is
presented under metal-,
Page No. – Page No.
additive- and anhydrous-free
conditions (see scheme).
Allylic and Allenylic
Dearomatization of Indoles
promoted by Graphene Oxide
via Covalent Grafting
Activation Mode
This article is protected by copyright. All rights reserved.