Reductive Alkylation of Arenes by a Thiol-Based Multicomponent Reaction

Article abstract of DOI:10.1021/acs.orglett.5b01142

A simple and highly chemo- and regioselective method for introducing primary alkyl substituents into aromatic compounds was developed. The method is based on an electrophilic aromatic substitution of an aldehyde, promoted by a thiol, to afford 1-(alkylthio)alkylarenes, which can either be reduced in situ with triethylsilane or reacted further. This multicomponent reaction enables the direct introduction of both aromatic and linear and branched aliphatic alkyl groups into arenes. The above one-pot protocol may be performed in air and in the presence of water and is compatible with various functional groups.

Full text of DOI:10.1021/acs.orglett.5b01142

Letter
pubs.acs.org/OrgLett
Reductive Alkylation of Arenes by a Thiol-Based Multicomponent
Reaction
Regev Parnes and Doron Pappo*
Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
S
* Supporting Information
ABSTRACT: A simple and highly chemo- and regioselective
method for introducing primary alkyl substituents into aromatic
compounds was developed. The method is based on an
electrophilic aromatic substitution of an aldehyde, promoted by a
thiol, to afford 1-(alkylthio)alkylarenes, which can either be
reduced in situ with triethylsilane or reacted further. This
multicomponent reaction enables the direct introduction of both
aromatic and linear and branched aliphatic alkyl groups into arenes. The above one-pot protocol may be performed in air and in
the presence of water and is compatible with various functional groups.
he introduction of primary alkyl groups into aromatic
compounds is one of the oldest synthetic problems that still
conditions, further affect the applicability of the process. To
address the synthetic difficulties of attaching primary alkyl groups
to aromatic compounds, alternative multistep protocols have
been developed, such as Friedel−Crafts acylation and reduction,
reductive Friedel−Crafts benzylation and allylation,5 metal-
catalyzed cross-coupling,6 and metal-catalyzed C−H activation.7
Here, we disclose a practical solution to this long-standing
synthetic problem (Scheme 1, eq 2) of directly attaching the
primary alkyl group to aromatic compounds. The novel
transformation is based on the electrophilic aromatic substitution
of arenes and heteroarenes by a thionium ion, which is produced
in situ from aldehydes and thiols under mild acid-catalyzed
conditions. This efficient and highly chemo- and regioselective
Pummerer-type reaction affords 1-(alkylthio)alkylarenes, which
can either be reduced in situ to the corresponding saturated
benzyl or alkylarenes (Scheme 1, eq 2) or, alternatively, used as
synthetic intermediates. This multicomponent reaction is
suitable for both aromatic and linear and branched aliphatic
aldehydes, and it is compatible with a variety of functionalities
and reagents including alkyl halides and alcohols, which are the
substrates of the classic Friedel−Crafts reaction. Other
advantages are that the reaction is water tolerant, does not
require corrosive reagents or toxic halides, and can be applied to
the direct alkylation of important biologically active compounds.
The chemistry of the thionium ion, also known as the
Pummerer reaction, has been applied in numerous trans-
formations and applications.8,9 Relevant to the current work,
the reactivity of aromatic thionium ions toward aromatic π-bonds
has been investigated by several groups.8,9q In those studies, the
powerful electrophile was generated from aromatic sulfoxides,9q
thioacetals (connective Pummerer),9o or dithioacetals that were
prepared in advance.9l,m,o Undesired side processes, e.g.,
Pummerer rearrangement, were usually prevented by the use
T
pose a challenge to chemists today despite the enormous
progress that has been made in organic synthesis since the
pioneering work of Charles Friedel and James M. Crafts on the
substitution of aromatic C−H bonds with alkyl halides in the
presence of AlCl3.1,2 Over the years, the classic Friedel−Crafts
reaction has seen a number of improvements, leading to the
development of novel techniques that are more selective,
nontoxic, and less harmful. Indeed, this reaction has become
the method of choice for the introduction of allyl and benzyl
groups3 and secondary and tertiary alkyl moieties.3 Nonetheless,
due to mechanistic constraints, the alkylation of primary alkyl
groups requires harsh conditions4 and is ineffective in that it
results in the formation of a mixture of rearrangement products
(Scheme 1, eq 1). Other major drawbacks, such as polyalkylation
of the aromatic core and a strict requirement for anhydrous
Scheme 1. Classic Friedel−Crafts Alkylation (eq 1), Reductive
Alkylation of Arenes (eq 2)
Received: April 18, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01142
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Organic Letters
Letter
of kinetic conditions that include stoichiometric amounts of
activators such as Ac2O, Tf2O, TMSOTf, or SnCl4, in moisture-
free solvents at reduced temperatures. Under these harsh acidic
conditions, only substrates that are unreactive toward acid or
acylating reagents are compatible, and as a result of competitive
side reactions, the chemistry has mainly been applied for
cyclization of small- and medium-sized rings.9s,10
Recently, our group has developed an attractive approach,
governed by thermodynamic considerations, to transform
aldehydes into thionium ion intermediates.11 We demonstrated,
that aldehydes and thiols react under certain conditions
[Cu(OTf)2 (5 mol %) in CH3NO2 or CF3CH2OH] to form
dithioacetals that exist in a rapid equilibrium with their thionium
ion intermediates (Scheme 1B). In the presence of ketones, a
selective cross-addition takes place, producing β-ketosulfides in a
single step via a unique mechanistic scheme.11 Encouraged by
these results, we investigated the reactivity of aromatic
compounds toward thionium ions under our mild Lewis-acid
catalyzed conditions.
We began our investigation by exploring the reactivity of
aromatic aldehydes toward anisole in the presence of ethanethiol
under a modification of previously reported conditions [Cu-
ο
(OTf)2 (2.5 mol %) in 2,2,2-trifluoroethanol, 50 C, Scheme
2].11 While the substitution of 4-anisaldehyde afforded 1-
Scheme 2. Alkylation of Arenes with Aldehydes by Thiol-
Based Multicomponent Reaction
Figure 1. Scope of the thiol-based multicomponent alkylation of arenes.
For the exact reaction conditions, see SI.
reactive arenes that we were able to react under the developed
conditions. To demonstrate the suitability of the method for
complex biologically active compounds, we successfully alkylated
N-Cbz-protected tyrosine (products 20 and 21 in 41% and 37%
yields, respectively) and an N-Ts indole (22, 98%).
(ethylthio)benzylarene 3 as a single product in moderate yield
(54%), the reaction with electron-deficient benzaldehydes (R =
Br and R = CN) exhibited higher reactivity, leading to coupling
products 4 and 5 in 74% and 90% yields, respectively. Similar to
other electrophilic aromatic substitution reactions, this trans-
formation is reversible: the 1-(ethylthio)benzylarenes can revert
back to the dithioacetal and the arene coupling partners (see
Supporting Information (SI) for further details). This reversi-
bility may explain the high para-selectivity that was observed in
the above examples. Different thiol-promoters can be used; for
example, the benzylation of benzaldehyde with electron-rich
arenes produced 1-(alkylthio)benzylarenes 8−11 (Figure 1) in
moderate to excellent yields. While ethanethiol and isopropylth-
iol exhibited similar reactivity and required prolonged heating
(4−7 h) at 50 οC to reach satisfactory conversions (products 8
and 9, 94% and 92% yields, respectively), the reaction of
benzaldehyde with 2,6-dimethylphenol, using thioacetic acid as
the promoter, reached completion within minutes at room
temperature, affording product 12 in 98% yield. High chemo-
selectivity was observed, and polar functional groups, such as
−OH (products 11−13 and 15), −CO2H (14), −CN (16,17),
and −NMe2 (19), were left untouched under the reaction
conditions. Mesitylene (16) and thioanisole (17) are the least
Next, the alkylation of arenes with aliphatic aldehydes was
examined. The tendency of enolizable aldehydes to undergo self-
coupling under acidic conditions precludes their application in
SEAr reactions. Indeed, the reaction of 2-naphthol (1b) with an
excess of isobutyraldehyde (2d) under our general conditions, in
the absence of thiol, produced a complex reaction mixture (see
SI). This picture changed completely when the reaction was
performed in the presence of ethanethiol (Scheme 2); the
aliphatic aldehyde was protected as dithioacetal, which trans-
formed to an active thionium ion species. This ion, in turn,
reacted with naphthols 1b or 1c, affording benzylsulfides 6 or 7 in
excellent isolated yields of 87% and 98%, respectively. Both linear
and branched aliphatic aldehydes are suitable reactants for this
reaction, including sensitive aldehydes (product 29), and
afforded 1-(ethylthio)alkylarene derivatives 23−28 and 30−33
in high yields (Figure 1). Side processes, such as rearrangement,
polyalkylation of the aromatic ring, or cationic reactions on the
benzylsulfide group, were not observed.10a The reaction of 1,3,5-
trimethoxybenzene (1d) with trimethyl orthoformate provided a
B
DOI: 10.1021/acs.orglett.5b01142
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Letter
direct entry to masked aldehyde 30 in 85% yield. Notably,
primary and tertiary alkyl halides and tertiary alcohols, which are
common substrates in the classical Friedel−Crafts reaction, were
stable under the mild acidic conditions (products: 31, 77%; 32,
70%; 33, 71%).
Contrary to the classic Friedel−Crafts alkylation, which
requires anhydrous conditions, the reversibility of this process
endows it with tolerance to water, as exemplified in the coupling
of an arene 1d with glutaraldehyde (2e, 25% v/v in H2O, Scheme
3). This aldehyde is probably transformed into the thionium ion I
before reacting with the arene to afford the dithioacetal 34 in a
moderate 58% yield.
Scheme 3. Electrophilic Aromatic Substitution of
Glutaraldehyde in Water
Figure 2. Scope of the reductive alkylation reaction. For the exact
reaction conditions, see SI.
To successfully address the historical problem of direct
rearrangement-free alkylation of arenes with primary alkyl
groups, it was essential to find a suitable desulfurization agent
that would be (1) compatible with the reaction’s mild acidic
conditions [Cu(OTf)2 (2.5 mol %) in CF3CH2OH] and with
water residues and protic functionalities, (2) highly chemo-
selective, and (3) sustainable and economically acceptable.
Although many reducing reagents are suitable for conducting this
transformation,12 including SmI2 that was successfully applied by
Procter,9k−p,12c triethylsilane (Et3SiH), which has the ability to
deliver hydride ions under acid-catalyzed conditions and meet
the above requirements, was examined. Indeed, when compound
34 was treated with Et3SiH (1.5 equiv) under our general
reaction conditions, selective reduction of the benzylic sulfide
group took place (without affecting the dithioacetal function-
ality), affording the desired masked aldehyde 35 in 70% yield
(Scheme 3). We speculate that the reduction step involves an
intermolecular hydrogen transfer to an ion-pair framework of the
activated complex II (Scheme 3),13 which liberates both the
reduced product and GC-MS detectable EtS−SiEt3.
The compatibility of triethylsilane with our mild acid-catalyzed
conditions enables a one-pot reductive alkylation reaction that
begins with the substitution of the aldehyde to the arene in the
presence of an ethanethiol promoter. Upon completion of the
coupling step, as indicated by TLC, the sulfide group is
selectively reduced by the addition of Et3SiH to the reaction
mixture. The generality of the protocol was examined, and the
results are shown in Figure 2. The method is efficient for
introducing linear and branched primary alkyl substituents. Alkyl
groups, such as methyl (product 36, 51% yield), ethyl (37, 81%),
isobutyl (38, 73%; 41, 87%; 42, 78%), isopentyl (40, 78%),
neopentyl (43, 70%), and nonanyl (44, 62%), were attached to
various aromatic compounds in a single synthetic step with high
chemo- and regioselectivity. Importantly, functional groups that
are incompatible with other alkylation methods and/or are
sensitive to reduction, such as tertiary alcohols (46, 77%), tertiary
alkyl chlorides (47, 90%), and alkenes (48, 85%), were not
affected, thereby offering additional synthetic possibilities.
Derivatization of the sex hormone 17β-estradiol was possible
with both aromatic (50, 85%) and aliphatic (51, 67%) aldehydes,
offering new opportunities in medicinal chemistry. An isotope-
labeled alkyl group was attached by using Et3SiD as the reducing
agent, affording 39-d1 in 71% yield. Finally, this multicomponent
reaction can be carried out with improved atom economy,14 as
demonstrated by the alkylation of arene 1d (1 equiv) with
benzaldehyde 2f (1 equiv) and ethanethiol promoter (1.2 equiv),
followed by in situ reduction with Et3SiH (1.2 equiv). Under
these optimized conditions, diarylmethane 52 was isolated in
80% yield (Scheme 4, eq 1).
The attachment of secondary alkyl substituents to aromatic
compounds is also facilitated by using our simple strategy, as
exemplified by the coupling of arene 1d with isobutyraldehyde
(2d) followed by in situ selective oxidation (H2O2 at 0 °C)15 to
furnish sulfoxide 53 in 55% yield (Scheme 4, eq 2). The latter
sulfoxide is a good leaving group under our reaction conditions,
and nucleophilic substitution with allyltrimethylsilane afforded
secondary alkyl substituted arene 54 in 78% yield. In a similar
manner, selective oxidation of sulfide 3 followed by reaction with
1d or a TMSN3 (eq 3) provided a direct entry to triarylmethane
55 (89% yield) and benzylazide 56 (87%).16 These examples
further highlight the applicability of this novel chemistry to
produce complex structures in a direct metal-free fashion.
In conclusion, a simple means to introduce primary alkyl
groups onto aromatic compounds was developed. The multi-
component reaction is based on aromatic electrophilic
substitution of aldehydes in the presence of thiol promoter,
followed by either reduction or functionalization of the obtained
benzylsulfide intermediates. This reductive alkylation reaction is
general, extremely simple, highly chemo- and regioselective, and
C
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Scheme 4. Preparation of Diarylmethane 52 under Improved
Atom Economy Conditions (eq 1) and Nucleophilic
Substitution of Benzylsulfoxides under Our General Reaction
Conditions (eq 2 and 3)
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does not produce toxic waste. It can be carried out in air and in
the presence of water and functional groups that are reactive
toward the classic Friedel−Crafts conditions. We are certain that
this method will find many uses in academic research and
industrial applications, as it offers a practical solution that meets
the challenge facing modern chemistry to solve one of the oldest
synthetic problems in organic chemistry, the introduction of
primary alkyl groups into aromatic compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
́
Baudoin-Dehoux, C.; Andre, C.; Blonski, C.; Hoffmann, P. Tetrahedron
Experimental procedures, characterization data, and NMR
spectra. The Supporting Information is available free of charge
on the ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01142.
Lett. 2008, 49, 5449−5451.
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AUTHOR INFORMATION
Corresponding Author
■
Karinthi, C.; Riche, C.; Chiaroni, A.; Desmaele, D. Eur. J. Org. Chem.
̈
2001, 2001, 3631−3640. (f) Horiguchi, Y.; Ogawa, K.; Saitoh, T.; Sano,
*E-mail: pappod@bgu.ac.il.
Notes
T. Chem. Pharm. Bull. 2004, 52, 214−220.
(11) Parnes, R.; Narute, S.; Pappo, D. Org. Lett. 2014, 16, 5922−5925.
(12) (a) Kuehm-Cauber
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e, C.; Guilmart, A.; Adach-Becker, S.; Fort, Y.;
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We acknowledge the financial support of the Israel Ministry of
Science, Technology and Space (MOST grant No. 3-10855).
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