Protecting group-free use of alcohols as carbon electrophiles in atom efficient aluminium triflate-catalysed dehydrative nucleophilic displacement reactions

Article abstract of DOI:10.1039/c7ra08784e

Benzylic and allylic alcohols are rendered electrophilic without chemical modification by the use of aluminium triflate as catalyst. The reaction succeeds with alcohol, thiol, carbon and nitrogen nucleophiles. When phenols are employed as nucleophiles, C-alkylation ensues. An advanced application of the method is demonstrated in the synthesis of 2H-chromenes and their N and S analogues.

Full text of DOI:10.1039/c7ra08784e

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Protecting group-free use of alcohols as carbon
electrophiles in atom efficient aluminium triflate-
Cite this: RSC Adv., 2017, 7, 42168
catalysed dehydrative nucleophilic displacement
reactions†
ab
Adam Cullen,a Alfred J. Mullera and D. Bradley G. Williams
*
Received 9th August 2017
Accepted 14th August 2017
Benzylic and allylic alcohols are rendered electrophilic without chemical modification by the use of
aluminium triflate as catalyst. The reaction succeeds with alcohol, thiol, carbon and nitrogen
nucleophiles. When phenols are employed as nucleophiles, C-alkylation ensues. An advanced application
of the method is demonstrated in the synthesis of 2H-chromenes and their N and S analogues.
DOI: 10.1039/c7ra08784e
rsc.li/rsc-advances
Introduction
Many of the problems relating to regio- or chemoselective
synthesis have not yet been solved.1 As such, organic synthesis
usually requires protecting group strategies to deliver selec-
tivity. In multistep syntheses protection–deprotection strategies
are not only critical to the success of the synthesis, they oen
comprise a signicant proportion of the steps involved.1
Because of these deciencies, atom economic chemistry
remains a touchstone by which the efficiency of synthetic
organic chemistry is measured. Alcohols have been used for
decades as a source of electrophiles once they have been con-
verted into halides or other leaving groups such as tosylates or
triates.2 Alternatively, it is known that propargylic and benzyl
alcohols can form stabilised carbocations under appropriate
conditions, usually in the presence of aluminium- and gallium
triates, respectively.3 Aluminium triate has been shown to be
a highly active yet selective catalyst for a range of reactions,
including some highly atom economic processes where 100% of
the atoms are incorporated into the products.4–7 Aluminium
triate is believed to exert its function in many cases as a Lewis
acid-assisted Brønsted acid.8–10 It is also useful as a co-catalyst in
the Pd-catalysed hydromethoxycarbonylation reaction, where it
takes the place of traditional Brønsted acids.6,7 Importantly, it
tolerates protic conditions and so can be readily recycled by
simply extracting it into water and recovered by subsequent
removal of the water.11
Scheme 1 Conversion of (S)-1-phenethyl alcohol into di(1-phenyl-
ethyl) ether.
When investigating epoxide ring-opening reactions,12,13 we
became interested in the possibility of employing chiral alco-
hols as nucleophiles by which to potentially desymmetrise the
epoxides. During that study, we employed (S)-1-phenylethanol
(1) as the nucleophile and obtained the S,R (meso) and S,S
diastereomers 2 of di(1-phenylethyl) ether as the major prod-
ucts.13 The scrambling of the stereogenic centre implied that
a benzylic carbocation had formed in the process, under the
action of Al(OTf)3, and could be captured by a nucleophile
present in the reaction mixture (Scheme 1). This manuscript
details the direct use of benzylic and allylic alcohols as elec-
trophiles in high yielding C–O, C–S, C–N and C–C bond-forming
reactions, where water is the by-product, in intramolecular and
intermolecular reactions.
Results and discussion
Benzhydrol 3 was subjected to reaction with a range of nucle-
ophiles in the presence of Al(OTf)3 in nitroethane solvent at
70 ꢀC, affording the corresponding elaborated products in very
high yields (Table 1) [nitroethane demonstrates low toxicity to
a range of organisms, does not bioaccumulate and readily
biodegrades14]. Notably, the reaction is successful with O, C, N
and S nucleophiles, requires no manipulation of the hetero-
atoms and it can be performed solvent-free without loss of yield
or selectivity (Table 1, entries 7 and 11). Furthermore, reactions
involving phenols yield C-alkylated aromatics as products
aResearch Centre for Synthesis and Catalysis, University of Johannesburg, P.O. Box
564, Auckland Park, 2006, South Africa
bSchool of Mathematical and Physical Sciences, University of Technology Sydney, P.O.
Box 123, Broadway, Sydney, NSW 2007, Australia. E-mail: Bradley.williams@uts.edu.
au
† Electronic supplementary information (ESI) available: Experimental and
analytical data; NMR spectra. See DOI: 10.1039/c7ra08784e
42168 | RSC Adv., 2017, 7, 42168–42171
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phenols.15 PdCl2 (10 mol%) as catalyst in dichloroethane also
affords O-alkylated aromatics from benzhydrol.16 Usefully,
ribose derivative 4k can be selectively deprotected of the
diphenylmethane group in high yield (90%) by a simple reac-
tion involving Al(OTf)3 and 2 equivalents of EtOH. This
compares favourably to PdCl2-catalysed (10 mol%) deprotection
of monosaccharides with EtOH (10 equivalents) in
dichloroethane.
Table
1 Al(OTf)3-catalysed nucleophilic substitution reactions of
benzhydrol with various nucleophilesa
trans-1,3-Diphenylprop-2-en-1-ol (7) was subjected to
a similar set of reactions (Table 2). Once again, high yields of
products were obtained and the reaction also tolerated a range
of nucleophiles, including O, C, N and S nucleophiles (Table 2).
As was the case with benzhydrol, phenols and indole underwent
C-alkylation while thiophenol underwent S-alkylation in other-
wise smooth transformations. The reactions were performed at
ambient temperature, affording very high yields of products
across the range of nucleophiles employed.
Reactions with benzhydrol or trans-1,3-diphenylprop-2-en-1-
ol did not proceed with unprotected anilines, acetanilide or
their p-tosylamide analogues. This is consistent with other
work17 with electron-decient amines, where higher catalyst
loadings (1–5 mol%) and (oen) microwave heating were
required before successful substitution reactions were
observed. However, successful N-alkylation could be achieved in
the present instance when using p-toluenesulphonyl amide
(Scheme 3), with which the C–N bond formation proceeded
quite readily to produce the N-alkylated products in quantitative
(>98%) yields. Nitroethane remained the solvent of choice.
We next turned our attention to the synthesis of chromenes
via intramolecular cyclisation reactions. The chromene sub-
structure is present in a wide range of physiologically active
molecules which demonstrate anti-HIV,18 antitumour,19 anti-
bacterial20 and antiprotozoal21 activity. Signicant efforts have
been made towards the synthesis of the 2H-chromene motif,22
including sugar-derived chiral systems.23 In addition, there has
Entry
Nucleophile
Product
Yield
1
2
3
4
Ethanol
Allyl alcohol
Propargyl alcohol
Acetyl acetone
Ethyl acetoacetate
Thiophenol
L-Menthol
Phenol
2-Naphthol
Indole
4a
4b
4c
4d
4e
4f
4g
4h
4i
98%
94%
>98%
96%
87%
98%
85%
84%
98%
80%
68%
5
6
7a
8
9
10
4j
4k
11a
Methyl 2,3-isopropyl-idene-b-D-riboside
a
Solvent free, 40 ꢀC, performed under vacuum (5 mm Hg).
(Table 1, entries 8 and 9). It is possible that the reaction initially
yields the analogous O-alkylated product which converts into
the C-alkylated thermodynamic product. To test this hypoth-
esis, analogues 5 (Scheme 2) of the putative benzyl ether inter-
mediates were subjected to reaction with Al(OTf)3 under
identical reaction conditions, affording the C-alkylated prod-
ucts in quantitative (>98%) yield. This result supports the
notion that a kinetically produced intermediate converts into
the thermodynamically preferred C-alkylated product. Inter-
estingly, the ortho product was the exclusive product for both
substrates (Scheme 2) in this reaction. While this is expected for
the p-cresol-derived ether 5b, it was somewhat unexpected for
the phenol-derived substrate 5a. In contrast, the product of the
reaction of phenol and benzhydrol is the para product 4h
(Table 1, entry 8). The difference in outcome may be accounted
for by the relative stability of the diphenylmethyl carbocation
that forms (compared to benzyl cation), allowing it to migrate to
the less hindered para position of the phenol ring. This is in
contrast to O-diphenylmethyl trichloroacetimidate which
affords O-alkylated aromatics from 2-naphthol and several
Table 2 Al(OTf)3-catalysed nucleophilic substitution reactions of 7
with various nucleophiles
Entry
Nucleophile
Product
Yield
1
2
3
4
5
6
7
8
9
Ethanol
8a
8b
8c
8d
8e
8f
8g
8h
8i
85%
84%
96%
98%
98%
86%
82%
81%
87%
Allyl alcohol
Propargyl alcohol
Acetyl acetone
Ethyl acetoacetate
Thiophenol
Phenol
2-Naphthol
Indole
Scheme 2 Conversion of benzyl ethers into C-alkylated products.
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Scheme 3 Reactions of activated alcohols with p-toluenesulphonyl
amide.
Scheme 6 Synthesis of dihydroquinoline in an Al(OTf)3-catalysed
dehydrative cyclisation.
been continuing interest in heteroatom analogues of chro-
menes such as dihydroquinolines24 and thiochromenes,25
which are also associated with biological activity. To set up the
intramolecular cyclisation that would build the chromene motif
in our case, it was necessary to synthesise phenylpropenols 10,
which was accomplished in four steps in good yields (see ESI for
details†). Propenols 10 were subjected to the action of 1 mole
percent Al(OTf)3 in nitroethane at ambient temperature in an
effort to produce the corresponding 2H-chromenes (Scheme 4).
Upon addition of the Al(OTf)3 to the solution of the propenols in
presence of 5 mole percent of a (t-Bu)2P(2-C6H4-Ph)-AuCl/AgOTf
catalyst at elevated temperatures has been noted.26 The Au
catalyst tolerates some functional groups but fails outright in
some instances.
Finally, propenol 13 could also be made to undergo Al(OTf)3-
catalysed dehydrative cyclisation, to afford the desired dihy-
droquinoline 14 in a pleasing yield of 94% (Scheme 6), using
only 0.05 mol% of the catalyst. While the use of DCM is less
desirable, the overall high yields on the one hand, and the fact
that this method enables alcohols to be used directly in nucle-
ophilic displacement reactions, cannot be overlooked. Further
investigations will most likely unveil other benign solvents
which are compatible with this chemistry.
nitroethane
a deep purple colour ensued immediately,
presumably the consequence of carbocation formation, and the
starting alcohol was fully consumed (by tlc analysis) within
a few minutes. Al(OTf)3 is known to produce carbocations in
solution from retinyl acetate, for example, which has been used
to probe the likely mechanism by which Al(OTf)3 functions.8
Unfortunately, the propenol reaction produced an intractable
mixture of products. To tame the reactivity of the system, the
reaction was performed in dichloromethane, which allowed the
desired 2H-chromenes to be prepared in acceptable to good
yields in a dehydrative endo cyclisation step (Scheme 4). 2H-
Chromene 11a could also be prepared from 12 (Scheme 5; see
ESI† for details on the synthesis of 12), a regioisomer of 10a,
under the same conditions in comparable yield for the endo-
cyclisation step of its regioisomer of 10a. This anticipated
ability of the reaction to proceed as desired regardless of the
position of the leaving OH group imparts signicant exibility
in the synthesis protocols that might lead to the functionalised
diphenylpropenol substrates. In a previous study, this type of
intramolecular cyclisation reaction of phenylpropenols in the
Conclusions
Al(OTf)3 catalyses the direct nucleophilic displacement of OH
groups in ‘activated’ systems with various O, N, S and C nucle-
ophiles. This efficient process allows the ready synthesis of
a wide range of product types in very high yields with water as
the by-product. Furthermore, the displacement reaction is
usefully employed in the synthesis of 2H-chromenes and dihy-
droquinolines in endo cyclisation reactions. This facile and high
yielding dehydrative procedure is expected to be useful in the
synthesis of a wide range of organic materials and biologically
active molecules. We are currently investigating the applica-
tions of this innovation to other ring structures.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We gratefully acknowledge Sasol Ltd (South Africa), NRF,
THRIP, the University of Johannesburg and University of
Technology Sydney for generous funding.
Scheme 4 Synthesis of 2H-chromenes in Al(OTf)3-catalysed cyclisa-
tion reactions.
Notes and references
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Scheme 5 Synthesis of 2H-chromene from an isomeric substrate.
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