Bifunctional Iron Complexes Catalyzed Alkylation of Indoles

Article abstract of DOI:10.1002/adsc.201800924

Cyclopentadienone iron carbonyl complexes have been applied in alkylation of indoles with various benzylic alcohols, aliphatic alcohols (butanol, ethanol, methanol and 2-methylpentanol) via the hydrogen autotransfer strategy in mild reaction conditions. Experimental works highlight the role of the bifunctional iron complexes and the base. These iron complexes demonstrated a broad applicability in mild conditions and extended the scope of substrates in iron catalyzed C?C bond formation. (Figure presented.).

Full text of DOI:10.1002/adsc.201800924

Title: Bifunctional Iron Complexes Catalyzed Alkylation of Indoles.
Authors: Charlotte Seck-Diouf, Mbaye Diagne Mbaye, Sylvain Gaillard,
and Jean-Luc RENAUD
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10.1002/adsc.201800924
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Bifunctional Iron Complexes Catalyzed Alkylation of Indoles.
Charlotte Seck,[a,b] Mbaye Diagne Mbaye,[a,b] Sylvain Gaillard,[a] and Jean-Luc
Renaud*[a].
a
Normandie Univ., LCMT, ENSICAEN, UNICAEN, CNRS, 6 boulevard du Maréchal Juin, 14050 Caen, France
E-mail: jean-luc.renaud@ensicaen.fr
Université Assane Seck de Ziguinchor, BP 523, Ziguinchor, Sénégal
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Cyclopentadienone iron carbonyl complexes
have been applied in alkylation of indoles with various
benzylic alcohols, aliphatic alcohols (butanol, ethanol,
methanol and 2-methylpentanol) via the hydrogen
autotransfer strategy in mild reaction conditions.
Experimental works highlight the role of the bifunctional
iron complexes and the base. These iron complexes
demonstrated a broad applicability in mild conditions and
extended the scope of substrates in iron catalyzed C-C bond
formation.
Keywords: Bifunctional complexes; Ligand-assisted
reactions; borrowing hydrogen strategy; alkylation;
catalysis
Scheme 1. Accepted mechanism for the alkylation of
The indole framework is a ubiquitous scaffold in
nucleophile via the hydrogen borrowing strategy.
pharmaceutical and natural product chemistry.[1] C3-
Alkylation of indoles traditionally involves alkyl
halides or pseudohalides derivatives in basic
conditions,[2] or via a Friedel-Craft type reaction in
Alkylation of indoles with alcohols was initially
the presence of a Lewis acid.[3] Such methods
reported by Grigg et al. in 2007 with [Cp*IrCl2]2 as
pre-catalyst.[6] However, this procedure was mainly
generate wastes as halides are prepared from alcohols
limited to benzylic alcohols. Later, Ohta and Shimizu
and involve toxic and hazardous chemicals .
demonstrated that [Pd/C], [Ru(PPh3)2Cl2] and [Pt/-
Hydrogen autotransfer or borrowing strategy is an
Al2O3-1.5 nm] were efficient catalysts for the
effective alternative strategy to the traditional
alkylation of various indoles with benzylic and
alkylation process as non toxic or hazardous alcohols
aliphatic alcohols.[7,8] Nevertheless, these works rely
(or amines) are applied as alkylating reagent and
on the use of platinum metals. Due to economic
water is the sole byproduct (Scheme 1).[4] Indeed,
pressure and sustainability concerns, the replacement
based on an accepted mechanism, the alcohol is
of platinum metals by first row-based metals is an
initially dehydrogenated in the presence of an
attractive alternative.
organometallic complex to generate a carbonyl
Beller has reported a cobalt-catalyzed reductive
intermediate and
a
metal hydride species.
alkylation of indoles using carboxylic acid, as
alkylating agent, under a hydrogen pressure.[9]
Alkylation of indoles via the borrowing hydrogen
strategy with Earth-abundant metals is scarcely
described in literature and has only been
demonstrated recently in the presence of a iron(II)-
phthalocyanine complex with various benzylic
alcohols.[10a] Surprisingly, in this work, the Knolker's
complex did not provide any alkylated product.[10] So,
even if these procedures paved the way to more
Condensation of the nucleophile followed by a
reduction step liberates the alkylated compound
(Scheme 1). Such catalytic alkylation with indoles, as
nucleophiles, and alcohols, as electrophiles, could
offer an environmentally benign technology for the
synthesis of 3-substituted indoles.[5]
1
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10.1002/adsc.201800924
Advanced Synthesis & Catalysis
sustainable chemistry, there are still some limitations,
such as the alkylating agents. Benzylic type alcohols
indole was then obtained in full conversion and up to
94 % yield (entries 4-10, Table 1). It is worth to
mention that an excess of benzyl alcohol (3 equiv.)
was needed in order to reach full conversion.
Alteration of these conditions led to lower yields or
no reaction (see also Table S1 in the E.S.I.). Thus, no
reaction occurred in the absence of base or iron
complex, excluding the role of the base as catalyst
10]
are mainly involved in such alkylation.[3e,
Alkylation studies with aliphatic alcohols rather
limited and methylation has been less investigated,
due to the higher enthalpy of dehydrogenation
compared to higher alcohols.[10b]
In our ongoing research on iron-catalyzed reduction
of polarized C=C and C=X bonds,[11,12] we recently
described several electron-rich cyclopentadienone
iron tricarbonyl complexes which are highly active in
alkylation of both aliphatic and aromatic ketones, and
amines (Fe1 and Fe2, Figure 1).[13] Based on DFT
(entries
11-12,
Table
1).
Finally,
other
cyclopentadienone iron tricarbonyl complexes
(Fe3[11b], Fe4[14] and Fe5,[15] Figure 1) presented
either lower reactivity (entry 14, Table 1) or no
reactivity (entries 13 and 15 , Table 1).
calculations
and
experimental
works,
we
demonstrated the crucial role of the base both in the
dehydrogenation step (decreasing the barrier of
activation) and in the reduction step.[13a] We report
herein that our complexes Fe1 and Fe2 are also
active complexes for the alkylation of indoles
derivatives in basic conditions with various benzylic
and aliphatic alcohols, including methanol.
Table 1. Cylopentadienone iron carbonyl complexes-
catalyzed benzylation of 2-methyl-1H-indole 1a.
Conv.
Base
Time
(h)
(%)b)
[Yield
(%)]c)
Entrya) [Fe]
Solventc)
(mol%)b)
Cs2CO3
(10)
Cs2CO3
(10)
Cs2CO3
(20)
Cs2CO3
(30)
Cs2CO3
(30)
Cs2CO3
(30)
Cs2CO3
(30)
Cs2CO3
(10)
K3PO4
K3PO4
K3PO4
-
K3PO4
K3PO4
K3PO4
K3PO4
1d)
Toluene
Dioxane
Toluene
t-BuOH
neat
16
24
13
Fe2
2
3
3
Fe2
Fe2
24
24
49
4
88 [73]
100 [89]
100 [94]
100 [86]
100 [82]
Fe2
Fe2
24
24
5
Figure 1. Complexes Fe1-5 evaluated in this work.
Fe1
Fe2
Fe2
6e, f)
7f)
8f)
neat
neat
16
16
As a starting point for this reaction, we chose the
alkylation of 2-methyl-1H-indole 1a (1 equiv.) with
benzylic alcohol 2a as a model reaction for the
optimization of the reaction conditions (Table S1 in
the E.S.I.). A rapid screening of the solvent, bases
and temperatures revealed that non-polar solvents
were inappropriate for this alkylation (entries 1-3,
Table 1, see also Table S1 in the E.S.I. for the
complete optimization screening). Several activation
methods can be used with these cyclopentadienone
iron carbonyl complexes: UV-A or Me3NO for
complex Fe1, and thermal activation for Fe2.
Whatever the initial activation, both Fe1 and Fe2
catalyzed the alkylation of indoles at 110 °C in the
presence of a base and similar yields were obtained
(entries 6, 10, 16, Table 1). So, due to easier
implementations, photolytic activation in the
presence of Fe1 and the thermal activation with Fe2
were used in the study of the scope and limitation
(vide infra). Reactions have been then carried out
either in t-BuOH with solid alcohols or neat with
liquid alcohols throughout the study. The alkylated
neat
9f)
neat
neat
neat
neat
neat
neat
neat
neat
16
16
16
16
16
16
16
16
100 [91]
100 [92]
Fe2
Fe1
-
Fe2
Fe3
Fe4
Fe5
Fe1
10e, f)
11f)
-
-
-
-
12f)
13f)
14f, g)
15f, g)
16f, g)
66 [44]
100 [91]
a)
General conditions: 2-methyl-1H-indole 1a (0.5 mmol),
pre-catalyst (2 mol%), benzyl alcohol (1.5 mmol), base (30
mol%), solvent (0.5 mL). b) Conversion was determined by
c)
d)
e)
1H-NMR spectroscopy. Isolated yield. 90 °C. Pre-
catalyst was activated under UV-A (400-315 nm)
f)
g)
irradiation for 30 min. 0.5 mL of benzyl alcohol. 2.5
mol% of Me3NO were used as additive.
Having established the optimized conditions, we
decided to explore the applicability of such iron-
2
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10.1002/adsc.201800924
Advanced Synthesis & Catalysis
complex catalyzed alkylation of indole with various
benzylic alcohols (Table 2). Both 2-methyl-1H-indole
1a and non-substituted indole underwent 3-alkylation
in moderate to high isolated yields (products 3a-10,
Table 2).
mmol), Fe2, ArCH2OH (1.5 mmol), K3PO4 (30 mol%), t-
BuOH (0.5 mL), 110 °C, 16 h. b) Isolated yield.
In all these reactions, both thermal activation
(Procedure B or C with Fe2) and photoactivation
(Procedure A with Fe1) could be applied without any
detrimental impact on the chemical yields. Both
Table 2. Fe-catalyzed benzylation of substituted indoles.a,
b)
electron-donating
and
electron-withdrawing
substituent either on the indole framework or on the
benzylic alcohol could be tolerated and alkylated
products were isolated in yields ranging from 47-98%.
Gratifyingly, heteroaromatic alcohols such as 2-
pyridyl-,
2-furanyl-,
2-thiofuranylmethanol
performed equally well in these conditions and the
corresponding alkylated indoles were obtained in 43-
91% yield (products 3d, 3g-h, 4b, 4d, Table 2). N-
Methyl indoles failed to provide any alkylated
product, demonstrating that an indole anion might be
an intermediate for such alkylation (Table 2).
Encouraged by these results, we extended this
protocol to aliphatic alcohols, including methanol and
ethanol, as alkylating agent. Compared to benzyl type
alcohols or any other higher aliphatic alcohols,
methanol is much less reactive and its use in
hydrogen
autotransfer
technology
remains
challenging.[10b] Indeed, the dehydrogenation of
methanol is more energetically demanding than the
dehydrogenation of other alcohols (as example, H =
+ 84 kJ.mol-1 for methanol vs. H = +68 kJ.mol-1 for
ethanol). But, to our delight, the 3-methylated indoles
were isolated as efficiently as other alkylated indoles
(Table 3). Methylation of various substituted indoles
was achieved in methanol using the previously
reaction conditions in moderate to high yields (47-
90%, Table 3). Both electron-donating and electron-
withdrawing substituents were tolerated on the indole
framework (compounds 12-16, Table 3). The same
procedure with ethanol or butanol furnished the
alkylated indoles in 55 to 92% yields (compounds 17-
25, Table 3). Interestingly, and to our delight, -
substituted primary alcohols could also be engaged in
this alkylation reaction. Even if the reactivity of such
alcohol may be lower in basic medium due to some
steric hindrance, or to the formation of the enol and
subsequent aldolisation side reactions, we isolated
compounds 26 and 27 by alkylation of the indoles
with 2-methylpentanol in moderate yields (45-55%,
Table 3). These examples represent the first ones in
the presence of Earth-abundant complexes. However,
secondary alcohols were not reactive in these
conditions.[16] We already demonstrated that the
dehydrogenation of secondary alcohols in basic
conditions was energetically feasible.[12a] Then, we
assumed that either the condensation step, between
the in-situ generated ketone and the indole, or the
reduction of tetrasubstituted alkene intermediate
(intermediate IV vide infra, Scheme 2) was not
possible in these conditions.
a)
Procedure A: indole (0.5 mmol), Fe1 (2 mol%), hν, 2 h,
K3PO4 (30 mol%), ArCH2OH (0.5 mL) then 110 °C, 16 h;
Procedure B: indole (0.5 mmol), Fe2, ArCH2OH (0.5 mL),
K3PO4 (30 mol%), 110 °C, 16 h; Procedure C: indole (0.5
3
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10.1002/adsc.201800924
Advanced Synthesis & Catalysis
Table 3. Alkylation of substituted indoles with aliphatic
In conclusion, we have developed a general
alkylation procedure for a broad range of indoles
using benzylic type alcohols, aliphatic alcohols
(including butanol, ethanol, methanol and 2-
methylpentanol) as alkylating reagent in the presence
of a well-defined bifunctional iron complex. This
alkylation process provided indoles in high yields, in
the presence of other reducible functionalities.
alcohols.a, b)
Experimental Section
General procedure A: Fe1-catalyzed alkylation of indoles
In a 15-mL flame-dried Schlenk tube equipped with a
stirring bar, the indole (1 eq.), alcohol (0.5 ml), iron
complex Fe1 (2 mol%) and K3PO4 (30 mol%) were poured
in under an argon atmosphere. The mixture was rapidly
stirred at room temperature under UV-A for 2 hours and
then placed into a pre-heated oil bath at 110 °C and stirred
overnight. The mixture was cooled-down to room
temperature and then diluted with diethyl ether and
concentrated under reduced pressure. The conversion was
determined by 1H-NMR spectroscopy, and then, the
residue was purified by flash chromatography on silica gel
to afford the desired product.
General procedure B: Fe2-catalyzed alkylation of indoles
In a 15-mL flame-dried Schlenk tube equipped with a
stirring bar, the indole (1 eq.), alcohol (0.5 ml), iron
complex Fe2 (2 mol%) and K3PO4 (30 mol%) were poured
in under an argon atmosphere. The mixture was rapidly
stirred at room temperature for 2 min and then placed into
a pre-heated oil bath at 110 °C and stirred overnight. The
mixture was cooled-down to room temperature and then
diluted with ethyl acetate and washed with brine solution.
The organic layers were dried over MgSO4 and
concentrated under reduced pressure. The conversion was
determined by 1H-NMR spectroscopy, and then, the
residue was purified by flash chromatography on silica gel
to afford the desired product.
General procedure C: Fe2-catalyzed alkylation of indoles
In a 15-mL flame-dried Schlenk tube equipped with a
stirring bar, the indole (1 eq.), alcohol (3 eq.), iron
complex Fe2 (2 mol%), K3PO4 (30 mol%) and tert-butanol
(0.5 ml) were poured in under an argon atmosphere. The
mixture was rapidly stirred at room temperature for 2 min
and then placed into a pre-heated oil bath at 110 °C and
stirred 16 h. The mixture was cooled-down to room
temperature and then diluted with diethyl ether and
concentrated under reduced pressure. The conversion was
determined by 1H-NMR spectroscopy, and then, the
residue was purified by flash chromatography on silica gel
to afford the desired product.
a)
General conditions: indole (0.5 mmol), pre-catalyst Fe2
(2 mol%), methanol or ethanol (0.5 mL), K3PO4 (30
mol%), 110 °C. b) Isolated yield.
Based on these results and on our previous works
on hydrogen autotransfer strategy[13] and reduction of
polarized C=X bonds,[11-12] we proposed the
following mechanism (Scheme 2). After an initial
dissociation of a ligand (thermal activation for Fe2,
or photolytic activation for Fe1), leading to
intermediate I, and coordination of potassium
alkoxyde (intermediate II), the first key step is the
dehydrogenation of the alcohol generating the
hydrido-intermediate III. Reduction of the ,-
unsaturated imine (generated by condensation
between the aldehyde and the indole), via
intermediates IV, could generate the amide-V.
Release of the indole and liberation of the unsaturated
iron species I occurs after protonation with K2HPO4.
Acknowledgements
We gratefully acknowledge financial support from the "Ministère
de la Recherche et des Nouvelles Technologies", Normandie
Université, CNRS, and the LABEX SynOrg (ANR-11-LABX-0029).
Coopération Française-Sénégal is also acknowledged for a grant
to C. S.
4
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10.1002/adsc.201800924
Advanced Synthesis & Catalysis
Scheme 2. Proposed mechanism for the alkylation of indoles via the hydrogen borrowing strategy.
[4] For reviews, see: a) M. H. S. A. Hamid, P. A. Slatford,
J. M. J. Williams, Adv. Synth. Catal. 2007, 349, 1555.
b) G. E. Dobereiner, R. H. Crabtree, Chem. Rev. 2010,
110, 681. c) G. Guillena, D. J. Ramón, M. Yus, Chem.
Rev. 2010, 110, 1611. d) F. Huang, Z. Liu, Z. Yu,
Angew. Chem. Int. Ed. 2016, 55, 862. e) G. Chelucci,
Coord. Chem. Rev. 2017, 331, 1. f) A. Corma, J. Navas,
J. Sabater, Chem. Rev. 2018, 118, 1410-1459. For
recent reviews on iron-catalyzed tandem reactions
involving hydrogenation and auto-transfer reactions,
see: g) J-L. Renaud, S. Gaillard, Synthesis 2016, 48,
3659-3683. h) A. Quintard, J. Rodriguez,
ChemSusChem 2016, 9, 28-30.
References
[1] a) S. R. Walker, E. J. Carter, B. C. Huff, J. C. Morris,
Chem. Rev. 2009, 109, 3080-3098; b) R. J. Melander,
M. J. Minvielle, C. Melander, Tetrahedron 2014, 70,
6363-6372; c) N. Netz, T. Opatz, Mar. Drugs 2015, 13,
4814-4914; d) E. Stempel, T. Gaich, Acc. Chem. Res.
2016, 49, 2390-2402.
[2] a) M. Westermaier, H. Mayr, Org. Lett. 2006, 8, 4791-
4794, and reference cited therein; b) S. Ma, S. Yu, Z. J.
Peng, J. Org. Chem. 2006, 71, 9865-9868, and
reference cited therein.
[5] For a non-catalytic C3-alkylation using activated benzyl
alcohol with an excess amount of KOH, see: R. Cano,
M. Yus, D. J. Ramón, Tetrahedron Lett. 2013, 54,
3394-3397.
[3] a) F. de Nanteuil, J. Loup, J. Waser, Org. Lett. 2013,
15, 3738-3741; b) H.-M. Ko, K. K.-Y. Kung, J.-F. Cui,
M.-K. Wong, Chem. Commun. 2013, 49, 8869-8871; c)
C. Garciá-Garciá, L. Ortiz-Rojano, S. Álvarez, R.
Álvarez, M. Ribagorda, M. C. Carreño, Org. Lett. 2016,
18, 2224-2227; d) X.-W. Wang, Y.-Z. Hua, M.-C.
Wang, J. Org. Chem. 2016, 81, 9227-9234; e) P. C.
Rao, S. Mandal, ChemCatChem 2017, 9, 1172-1176; e)
For a recent example of a Friedel-Craft type reaction
catalyzed by an iron salt, see: U. Jana, S. Maiti, S.
Biswas, Tetrahedron Lett. 2007, 48, 7160-7163.
[6] For iridium-catalyzed alkylation of indoles, see: a) S.
Whitney, R. Grigg, A. Derrick, A. Keep, Org. Lett.
2007, 9, 3299-3302. b) S. Koller, M. Blazejak, L.
Hintermann, Eur. J. Org. Chem. 2018, 1624-1633.
[7] For ruthenium-catalyzed alkylation of indoles, see: A.
E. Putra, K. Takigawa, H. Tanaka, Y. Ito, Y. Oe, T.
Ohta, Eur. J. Org. Chem. 2013, 6344-6354.
5
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10.1002/adsc.201800924
Advanced Synthesis & Catalysis
[8] For platinum-catalyzed alkylation of indoles, see: S. M.
A. H. Siddiki, K. Kon, K.-i. Shimizu, Chem. Eur. J.
2013, 19, 14416-14419.
[12] a) A. Lator, S. Gaillard, A. Poater, J-L. Renaud, Chem.
Eur. J. 2018, 24, 5770-5774; b) T.-T. Thai, D. S. Mérel,
A. Poater, S Gaillard, J-L. Renaud, Chem. Eur. J. 2015,
21, 7066-7070.
[9] For a cobalt-catalyzed reductive alkylation of indoles,
see: J. R. Cabrero-Antonino, R. Adam, K. Junge, M.
Beller, Chem. Sci. 2017, 8, 6439-6450.
[13] a) C. Seck, M. D. Mbaye, S. Coufourier, A. Lator, J.-F.
Lohier, A. Poater, T. R. Ward, S. Gaillard, J.-L.
Renaud, ChemCatChem 2017, 9, 4410-4416. b) A.
Lator, S. Gaillard, A. Poater, J.-L. Renaud, Org. Lett.
2018, 20, doi: 10.1021/acs.orglett.8b02080.
[10] For iron-catalyzed alkylation of indoles, see: a) G. Di
Gregorio, M. Mari, F. Bartoccini, G. Piersanti, J. Org.
Chem. 2017, 82, 8769-8775; b) during the preparation
of this manuscript, Morrill reported methylation of
ketones, indoles, oxindoles and amines catalyzed by the
iron tricarbonyl Knölker’s complex: K. Polidano, B. D.
W. Allen, J. M. J. Williams, L. C. Morrill, ACS Catal.
2018, 8, 6440-6445.
[14] a) W. Reppe, H. Vetter, Liebigs. Ann. Chem. 1953,
582, 133-161; b) G. N. Schrauzer, J. Am. Chem. Soc.
1959, 81, 5307-5310.
[15] a) H.-J. Knölker, J. Heber, C. H. Mahler, Synlett 1992,
1002-1004; b) H.-J. Knölker, J. Heber, Synlett 1993,
924-926; c) H.-J. Knölker, E. Baum, J. Heber,
Tetrahedron Lett. 1995, 42, 7647-7650.
[11] a) A. Pagnoux-Ozherelyeva, N. Pannetier, D. M.
Mbaye, S. Gaillard, J.-L. Renaud, Angew. Chem. Int.
Ed. 2012, 51, 4976-4980. b) S. Moulin, H. Dentel, A.
Pagnoux-Ozherelyeva, S. Gaillard, A. Poater, L.
Cavallo, J.-F. Lohier, J-L. Renaud, Chem. Eur. J. 2013,
19, 17881-17890.
[16] In order to avoid any Friedel-Craft type reaction (see
ref. [3e]), a secondary aliphatic was used.
6
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10.1002/adsc.201800924
Advanced Synthesis & Catalysis
UPDATE
Bifunctional Iron Complexes Catalyzed
Alkylation of Indoles.
Adv. Synth. Catal. Year, Volume, Page – Page
Charlotte Seck, Mbaye Diagne Mbaye, Sylvain
Gaillard, Jean-Luc Renaud*
7
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