Regioselective alkylation of heteroaromatic compounds with 3-methyl-2-quinonyl boronic acids

Article abstract of DOI:10.1021/ol1028964

Reactions of heteroaromatic compounds with 3-methyl substituted 2-quinonyl boronic acids proceeded by 1,4-addition followed by spontaneous protodeboronation, leading directly to the Friedel-Crafts alkylation products instead of the commonly observed alken

Full text of DOI:10.1021/ol1028964

ORGANIC
LETTERS
2011
Vol. 13, No. 4
656–659
Regioselective Alkylation of
Heteroaromatic Compounds with
3-Methyl-2-Quinonyl Boronic Acids
~
Marcos Veguillas, Marıa Ribagorda,* and M. Carmen Carreno*
´
´
Departamento de Quımica Organica (Modulo 01), Universidad Autonoma de Madrid,
C/Francisco Tomas y Valiente 7, Cantoblanco, 28049-Madrid, Spain
ꢀ
ꢀ
ꢀ
ꢀ
maria.ribagorda@uam.es; carmen.carrenno@uam.es
Received November 30, 2010
ABSTRACT
Reactions of heteroaromatic compounds with 3-methyl substituted 2-quinonyl boronic acids proceeded by 1,4-addition followed by spontaneous
protodeboronation, leading directly to the Friedel-Crafts alkylation products instead of the commonly observed alkenylation derivatives
resulting from quinones. The boronic acid acts as a temporary regiocontroller, making the system a highly reactive quinone equivalent and
opening a direct access to 5,5-disubstituted cyclohexene-1,4-diones.
The Lewis acid catalyzed Friedel-Crafts (FC)1,2 reaction
of aromatic systems with R,β-unsaturated carbonyl com-
pounds is one of the most powerful C-C bond-forming
processes in organic synthesis, giving rise to the alkylation
products resulting from the 1,4-conjugate addition. In sharp
contrast, the FC reactions of heterocyclic compounds, such
as indole with quinones, are a formal aromatic alkenylation,
because the initial 1,4-addition product spontaneously en-
olizes to an aryl substituted hydroquinone, which usually
undergoes in situ oxidation to the quinone, with the starting
quinone or an additional reagent acting as an oxidant
(Scheme 1).3-5 When the electrophiles are substituted ben-
zoquinones, the regioselectivity of the FC reaction is highly
dependent on the type of substituent on each double bond
(R). With dialkyl substituted (2,5- or 2,6-) quinones, the
reaction generally occurs at the unsubstituted position, to
give a quinone having a heteroaromatic substituent, after
the aromatization/oxidation steps. Despite the significance
of the FC reaction and the synthetic potential of quinones,6
the preparation of substituted 2-cyclohexene-1,4-diones by
(3) (a) Zhan, H.-B.; Liu, L.; Chen, Y.-J.; Wang, D.; Li, C.-J. Adv.
Synth. Catal. 2006, 348, 229–235. (b) Yadav, J. S.; Reddy, B. V. S.; Swamy,
T. Synthesis 2004, 106–110. (c) Yadav, J. S.; Reddy, B. V. S.; Swamy, T.
Tetrahedron Lett. 2003, 44, 9121–9124.
(4) For examples of protic acid catalyzed FC reaction, see: (a) Pirrung,
M. C.; Park, K.; Li, Z. Org. Lett. 2001, 3, 365–367. (b) Pirrung, M. C.; Deng,
L.; Li, Z.; Park, K. J. Org. Chem. 2002, 67, 8374–8388. (c) Pirrung, M. C.; Liu,
Y.; Deng, L.; Halstead, D. K.; Li, Z.; May, J. F.; Wedel, M.; Austin, D. A.; Webster,
N. J. G. J. Am. Chem. Soc. 2005, 127, 4609–4624.
(1) For general reviews of Friedel-Crafts reactions, see: (a) Organic
Synthesis; Smith, M. B., Ed.; McGraw-Hill: New York, 1994; p 1313. (b)
Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. Friedel-Crafts Alkylations.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 3, pp 293-339. (c) Heaney, H.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 2, p 733. (d) Roberts, R. M.; Khalaf, A. A.
Friedel-Crafts Alkylation Chemistry: A Century of Discovery; Marcel
Dekker: New York, 1984.
(5) For a direct FC alkenylation in water without any added catalyst,
see: Zhan, H.-B.; Liu, L.; Chen, Y.-J.; Wang, D.; Li, C.-J. Eur. J. Org.
Chem. 2006, 869–873.
(6) Thomson, R. H. Naturally Occuring Quinones IV; Blackie Aca-
demic & Professional: London, 1997.
(2) For recent reviews on asymmetric Friedel-Crafts reactions, see:
(a) Poulsen, T. B.; Jørgensen, K. A. Chem. Rev. 2008, 108, 2903–2915. (b)
Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004,
43, 550–556. (c) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38,
2190–2201.
r
10.1021/ol1028964
Published on Web 01/10/2011
2011 American Chemical Society

of the boron substituent as a temporary controller, open-
ing up a straightforward and regiocontrolled access to the
indole-substituted cyclohexenedienone adducts, not easily
accessible by other methods. A significant increase of the
electrophilic reactivity of quinone 1 at the methyl bearing
carbon was evident.
Scheme 1. FC Reaction of Indole with Benzoquinones
Table 1. Friedel-Crafts Alkylation of Indoles 4 with 1
a classic FC alkylation with quinones still remains unsolved
(Scheme 1). Substituted cyclohexene-1,4-diones and deriva-
tives are found in a variety of bioactive natural products7
and serve as excellent substrates for further synthetic elab-
oration. Recently, our group reported the synthesis and
Diels-Alder reactions of 2-quinonyl boronic acids.8 Our
study evidenced a dramatic increase of their dienophilic
reactivity when compared with other reactive quinones,9
opening an easy access to otherwise elusive adducts, after a
domino sequence of cycloaddition and protodeboronation.
Herein, we describe the Friedel-Crafts alkylation of hetero-
aromatic compounds with 3-alkyl substituted 2-quinonyl
boronic acids that enable a direct and site-selective hetero-
aromatic alkylation, to give 5-alkyl-5-heteroaryl substituted
cyclohexene 1,4-diones.
4 (1.1 equiv)
(R
¼ H)
time
(h)
yield
(%)
entry
6
5
1
2
3
4
5
6
7
8a
Indole
2
5
5a
5b
5c
5d
5e
5f
73
81
89
92
70
83
93
56
R1 = Me
R2 = Me
18
18
36
18
72
3
R4 = OMe
R5 = NHBOC
R4 = F
R4 = Br
R3 = CO2Me
5g
5h
a Heat was applied (36 °C).
We later undertook a survey to know the scope of the
reaction. We first considered the influence of indole archi-
tecture (Table 1). N-Methyl indole 4b reacted similarly with 1
(CH2Cl2, rt, 5 h) to give compound 5b (Table 1, entry 2, 81%
yield). The reaction of 7-methylindole 4c with 1 occurred
more slowly, giving the addition/protodeboronation product
5c in 89% yield (Table 1, entry 3). The incorporation of an
electron-donating methoxy group at the C-5 position of the
indole 4d allowed the isolation of 5d in 92% yield (Table 1,
entry 4). The addition of 4-N-tert-butoxycarbonylamino
indole to quinone 1 provided compound 5f in 70% yield
(Table 1, entry 5). The indole framework can also accom-
modate electron-withdrawing groups. Thus, 5-fluoro- or
5-bromoindole reacted with 1, giving compounds 5f and 5g
in 83% and 93% yield, respectively (Table 1, entries 6 and 7).
6-Methoxycarbonyl indole 4h was less reactive, and complete
evolution could only be achieved under reflux, affording 5i in
56% yield (Table 1, entry 8).
We focused our study on 3-methyl substituted-2-quinonyl
boronic acids 1-3, available by CAN oxidation of the
corresponding methyl-substituted 2,5-dimethoxy arylboro-
nic acids, as previously reported.8 Indole reacted with 3,5-
dimethyl benzoquinonyl boronic acid 1 without any added
catalyst, in CH2Cl2 (0.1 M) at room temperature to give, in 2
h, 6-(1H-indole-3-yl)-2,6-dimethyl-2-cyclohexene-1,4-dione
5a in a 73% isolated yield (entry 1, Table 1). The FC alkyla-
tion of 4a occurred by attack of the C3 indole to the methyl-
substituted C3 carbon of 1, generating a quaternary center,
and was followed by in situ protodeboronation of the ini-
tially formed 1,4-adduct. The product was detected directly
1
in the reaction vessel before workup by H NMR.10 FC
reactions of indole with 2,6-dialkyl substituted quinones as
electrophiles have been reported to give 2-indole-3,5-dialkyl
substituted quinones.3a,c Our result illustrates the potential
Reactions of quinonyl boronic acid 1 with other hetero-
aromatic derivatives were next explored. As shown in
Scheme 2, pyrrole was particularly reactive. When 1 and
6a were dissolved in CH2Cl2 a mixture of the 2- and 2,5-
dialkylated pyrrole derivatives 7a and 8 in a 46:54 ratio was
rapidly formed (Scheme 2). The monoalkylated product 7a
could be obtained in excellent yield (92%) using pyrrole as
solvent. 2,4-Dimethylpyrrole 6b behaves similarly, when
reacted neat over 5 min, affording product 7b in 56% yield.
Unfortunately, reactions of 1 with other heteroaromatic
compounds under similar conditions failed even at long
reaction times or high temperatures. To overcome this
limitation, we screened different Lewis acids that might
ꢀ
(7) (a) Salva, J.; Faulkner, D. J. J. Org. Chem. 1990, 55, 1941–1943.
(b) Hudlicky, T.; Cebulak, M. Cyclitols and Their Derivatives: A Handbook
of Physical, Spectral, and Synthetic Data; VCH: New York, 1993. (c)
Delgado, A. Eur. J. Org. Chem. 2008, 3893–3906. (d) Marco-Contelles, J.;
Molina, M. T.; Anjum, S. Chem. Rev. 2004, 104, 2857–2900.
(8) (a) Redondo, M. C.; Veguillas, M.; Ribagorda, M.; Carreno,
M. C. Angew. Chem., Int. Ed. 2009, 48, 370–374. (b) Veguillas, M.;
Redondo, M. C.; García, I.; Ribagorda, M.; Carreno, M. C. Chem.;Eur.
J. 2010, 16, 3707–3719.
(9) (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis,
G. Angew. Chem., Int. Ed. 2002, 41, 1668–1698. (b) Pindur, U.; Lutz, G.; Otto, C.
Chem. Rev. 1999, 93, 741–701. (c) Carreno, M. C.; Hernandez-Torres, G.;
Ribagorda, M.; Urbano, A. Chem Commun. 2009, 6129–6144.
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~
~
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(10) Water is generated from the boronic acid/boroxine equilibrium
presumably occurring in situ; see: Snyder, H. R.; Konecky, M. S.;
Lennarz, W. J. J. Am. Chem. Soc. 1958, 80, 3611–3615.
Org. Lett., Vol. 13, No. 4, 2011
657

Scheme 2. FC Alkylation of 6a and 6b with 1
Scheme 3. FC Alkylation of Naphthoquinonyl Boronic Acid 9
catalyze the Friedel-Crafts alkylation. The use of Cu(OTf)2,
ZnI2, Bi(OTf)3, ZrCl4, Yb(OTf)3, or LiClO4 was ineffective.
In contrast, catalytic FeCl3 6H2O (5 mol%) provided the
desired alkylation products with full control of the regioselec-
tivity and moderate to good yields. Thus, thiophene 6c pro-
vided the 1,4-addition/protodeboronation product 7c in 4 h
The generality of the FC reaction was further extended
to the quinone partner. Thus, indole 4a reacted with
3-methyl-2-naphthoquinonyl boronic acid 9 in refluxing
CHCl3, in the absence of any added catalyst, to afford the
compound 10 in 78% yield (Scheme 3).11 Once again, a very
fast reaction (5 min) occurred between 9 and pyrrole (neat)
at -20 °C, to give 11 in 87% yield. 2-Methylfuran reacted in
3
and 69% yield in the presence of FeCl3 6H2O (Table 2,
entry 1). Under the same conditions, 2-chloro-3-methylthio-
phene 6d reacted in 48 h, leading to 7d in 72% yield (Table 2,
3
the presence of catalytic FeCl3 6H2O to afford 12 in a short
3
reaction time (5 min) and excellent yield (98%).
In the case of 3,6-dimethyl-2-benzoquinonyl boronic
acid 13, the reaction with pyrrole (neat) occurred at the
C3 position of the quinone to give the quaternary alkylated
product 14 in 74% yield (entry 1, Table 3).
Table 2. FC Reactions of 6c-g with 1 Catalyzed by
FeCl3 6H2O
3
Table 3. FC Reactions of Quinonyl Boronic Acid 13 and 20
entry 2). 2-Methyl furan 6e reacted with 1 very quickly (10
min) to afford 7e in 69% yield (Table 2, entry 3). 2,3-Dimethyl
furan 6f and benzofuran 6g reacted similarly, giving deriva-
tives 7f and 7g in 75% and 47% yields, respectively (Table 2,
entries 4 and 5). In all cases, the heteroaromatic compound
reacted, as expected, through its most electron-rich position.
a 5 mol %.
The reaction between 13 and indole in CH2Cl2 gave an
84:16 mixture of compounds 15 (major) and indole qui-
none 17, inseparable by column chromatography, in a
74% yield (entry 2, Table 3). A reaction between 13 and
(11) Previous to our work, there were two reports describing the FC
reaction of indole with 2-methyl naphthoquinone in the presence of Bi(OTf)3,
to give, under similar reaction conditions, compound 10 in very different
yields; see: Reddy, A. V.; Ravinder, K.; Goud, T. V.; Krishnaiah, P.; Raju,
T. V.;Venkateswarlu, Y. Tetrahedron Lett. 2003, 44, 6257–6260 and ref 3c. We
repeated both reactions under the conditions reported in both references to obtain a
mixture of the starting 2-methylnaphthoquinone and the 1,4-addition product 10
(minor) in an 82:18 and a 96:4 ratio, respectively.
2-methylfuran only occurred in the presence of FeCl3
6H2O (5 mol %), to afford a mixture of cyclohexenedione
3
658
Org. Lett., Vol. 13, No. 4, 2011

16and quinone 1812 thatcouldbeisolated in46%and 17%
yield, respectively (entry 3, Table 3).
gap,13 and the existence of a hydrogen bond between the
boronic acid and the C-1 carbonyl group (see 1 in scheme of
Table 1), evident in the X-ray of quinone 1.8b
The mechanism of the formation of the heteroaryl
substituted quinones 17 and 18 was not evident. An ipso-
substitution of the B(OH)2 groups seemed plausible. To
gain insight into this assumption, we synthesized an asym-
metrically substituted analogue of 13, 3-methyl-6-iso-
propyl-2-quinonyl boronic acid 20.12 Its reaction with
The results obtained suggest a domino process starting
from the conjugate addition of the heteroaromatic com-
pound to the quinone. The initial 1,4-adduct could suffer
an in situ protonation and a transfer of the boron atom
from carbon to oxygen to give a dienolate intermediate
such as A (Scheme 4). To extend this domino sequence, we
decided to trap the initially formed intermediate A by
cycloaddition with N-phenylmaleimide. Thus, a mixture
of 3,5-dimethyl-2-quinonyl boronic acid 1, indole, and N-
phenylmaleimide was dissolved in CH2Cl2. After 18 h a
57:43 mixture of 5a and the polycyclic compound 23 was
formed, from which 23 could be isolated pure in 40% yield
as a 1:1 mixture of diastereoisomers. Compound 23 re-
sulted from the domino process that embraces a Friedel-
Craftsindole alkylation atC3ofthe quinonyl boronicacid,
a [4 þ 2] cycloaddition reaction of the intermediate boron
dienolate and a protodeboronation (Scheme 4). The for-
mation of a mixture of epimers 23 must be a consequence
of the endo approach of the dienophile from both faces of
the intermediate diene A.
2-methylfuran in the presence of FeCl3 6H2O (5 mol %)
3
was completed in 2 h to give a mixture of compounds 21
and 22, from which both were isolated pure in 46% and
14% yield, respectively (entry 4, Table 3). The formation of
22 supported the ipso-substitution process. Therefore, the
heteroaromatic substituted benzoquinones 17, 18 (see
Table 3 and Scheme 4) should arise also from the direct
substitution of the boronic acid by the heteroaromatic
compound through an addition/elimination mechanism,
favored by the presence of the vicinal carbonyl group.
Scheme 4. Domino FC/Diels-Alder Reaction/Protodeborona-
tion between Indole 4a, 1, and N-Phenylmaleimide
In summary, we have reported that 3-methyl substituted
2-quinonyl boronic acids are excellent electrophiles for
Friedel-Crafts alkylation reactions of heteroaromatic
compounds. The quinonyl boronic acids behave as highly
reactive synthetic equivalents of quinones and allow direct
access to the otherwise elusive HetArH 1,4-addition prod-
ucts to a methyl-substituted quinone double bond. The
synthesis of 5-methyl-5-heteroaryl substituted cyclohexe-
nediones was achieved in one step and good to excellent
yields through a 1,4-addition reaction at C-3 and a spon-
taneous protodeboronation process. Our method allows
an efficient and regioselective FC alkylation which is
complementary to the typical quinone FC alkenylation.
An initial synthetic extension of this method comprises a
domino process including an FC alkylation/Diels-Alder
reaction/protodeboronation.
The most general FC reaction of heteroaryl aromatic
derivatives with our 3-methyl substituted 2-quinonyl boronic
acids 1, 9, 13, and 20 proceeded by nucleophilic attack of the
heterocyclic compound at the C3 methyl substituted carbon.
The boronic acid seems to be essential to trigger the process,
since no reaction was observed between the pinacol ester
derived from boronic acid 18 and indole 4a (CH2Cl2, rt, 5 d),
under the conditions where the free boronic acid 1 reacted in
2 h. Moreover, the boron lacking 2,6-dimethylbenzoquinone
was recovered unchanged when treated with indole 4a under
the same reaction conditions after long reaction times. These
observations suggested that the enhanced electrophilicity of
the quinonyl boronic acid must be a combination of the
electron-withdrawing effect of the B(OH)2 group, which
decreases the LUMO energy of the C(2)dC(3) quinonic
double bond, thus decreasing the HOMO-LUMO energy
Acknowledgment. Dedicated to the memory of Prof.
ꢀ
Dr. Jose Manuel Concellon. This work was supported by
Ministerio de Ciencia e Innovacion (MICINN, Grant
ꢀ
ꢀ
CTQ2008-04691/BQU) and Comunidad de Madrid and
EuropeanSocial Fund (Grant SOLGEMAC-S2009/ENE-
1617). M.V. thanks MEC for an FPI fellowship.
Supporting Information Available. Experimental proce-
dures, spectroscopic data, and copies of 1H and 13C NMR
spectra for all new compounds. This material is available
free of charge via Internet at http://pubs.acs.org.
(12) See Supporting Information for details.
(13) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: New York, 1976.
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