Scandium as a pre-catalyst for the deoxygenative allylation of benzylic alcohols

Article abstract of DOI:10.1039/c7ob02219k

Scandium triflate is an effective pre-catalyst for the deoxygenative allylation of benzylic alcohols with a narrow substrate window. The reaction is shown to proceed through a "hidden Br?nsted acid" mechanism. The reaction is efficient provided that the aryl group is neither too electron rich nor too electron poor. It is shown that this allows useful selectivity. The reaction also works for benzyhydryl alcohols with broader scope. The reaction may also be catalysed by Nafion.

Full text of DOI:10.1039/c7ob02219k

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Scandium as a pre-catalyst for the deoxygenative
allylation of benzylic alcohols†
Cite this: Org. Biomol. Chem., 2018,
16, 119
Ivan Šolić,a Pattarakiat Seankongsuk,b Joanna Kejun Loh,a Tirayut Vilaivanb and
a
Roderick W. Bates
*
Scandium triflate is an effective pre-catalyst for the deoxygenative allylation of benzylic alcohols with a
narrow substrate window. The reaction is shown to proceed through a “hidden Brønsted acid” mecha-
nism. The reaction is efficient provided that the aryl group is neither too electron rich nor too electron
poor. It is shown that this allows useful selectivity. The reaction also works for benzyhydryl alcohols with
broader scope. The reaction may also be catalysed by Nafion.
Received 4th September 2017,
Accepted 28th November 2017
DOI: 10.1039/c7ob02219k
rsc.li/obc
Introduction
Numerous methods have been reported for the deoxygenative
allylation of benzyl alcohols, benzhydryl alcohols and related
compounds. All of these employ Lewis acids,1 including
Brønsted acids,2 to mediate the reaction (Scheme 1). Not all of
these reactions are catalytic as some Lewis acids employed are de-
activated by the reaction conditions. Arising from our new-found
interest in the use of lanthanide ions as Lewis acid catalysts,3 we
were surprised to find no reports of their effective use in this
reaction. To the best of our knowledge, there are just a few
reports of their unsatisfactory or limited application.1c,g,r,t,2e
Scheme 2 Deoxygenative allylation of benzylic alcohols.
amount of scandium triflate4 in dichloromethane gave only
modest results, a rapid reaction ensued when we employed
acetonitrile5 as the solvent at 40 °C, giving alkene 2a in good
yield (Table 1, entry 1).
Results and discussion
Anticipating a carbocation intermediate, we selected p-methox-
ybenzyl alcohol 1a for exploratory studies (Scheme 2). While
treatment with allyltrimethylsilane and a sub-stoichiometric
As we wished for a robust synthetic method, we employed
“bench” acetonitrile, with no attempt at drying of the solvent
or the glassware. Karl Fischer titration showed that this solvent
contained approximately 130 ppm of water. Lanthanide tri-
flates have been claimed to be water tolerant Lewis acids.6 We
tested this by running the same reaction in acetonitrile to
which a small amounts of water, from 2.5 to 10% by volume,
had been added (entries 2–5). At most, only traces of the
product could be observed. To our further surprise, the reac-
tion using the 10% v/v mixture (entry 4) failed to proceed even
at 90 °C. Interestingly, when dried acetonitrile (approx.
45 ppm water) was employed (entry 5), the reaction was much
less efficient, giving only 24% yield in the same time as the
original experiment. Three true lanthanide triflate salts were
also tested, but gave much lower yields than scandium, even
with extended reaction times (entries 6–8).
Scheme 1 Deoxygenative allylation.
aDivision of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link,
Singapore 637371. E-mail: roderick@ntu.edu.sg
bOrganic Synthesis Research Unit, Department of Chemistry, Faculty of Science,
Chulalongkorn University, Phayathai Road, Patumwan, Bangkok 10330, Thailand
†Electronic supplementary information (ESI) available: General procedures;
experimental details and NMR spectra for compounds 1c, 1e, 1l, 8a–j, 2a, c, d, f,
h, j, l′, m, 4–7, 9a, b, c, d, e, f, h, i, j. See DOI: 10.1039/c7ob02219k
Spencer7 has demonstrated that the real catalyst when
many metal salts are employed as Lewis acids is actually in situ
generated H+ i.e. a “hidden Brønsted acid”.8 Following the
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Table 1 Deoxygenative allylation of p-methoxybenzyl alcohol: water
content and pre-catalysta
Table 2 Deoxygenative allylation of benzylic alcohols and ethers using
Sc(OTf)3
a
Entry
Substrate
Ar
R′
Product, yield (%)
Entry
Pre-catalyst
Solvent
Time
Yield (%)
1
2
3
4
5
1a
1b
1c
1d
1e
p-MeOC6H4
p-MeOC6H4
p-BnOC6H4
p-Allyl O C6H4
p-TBSO(CH2)3OC6H4
H
2a, 71
2a, 77
2c, 97
2d, 94
2e, 6
1
2
3
4
5
6
7
8
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
La(OTf)3
Gd(OTf)3
Lu(OTf)3
Bench CH3CNb
2.5% H2O in CH3CN
5% H2O in CH3CN
10% H2O in CH3CN
Dried CH3CNc
Bench CH3CN
Bench CH3CN
Bench CH3CN
1 h
1 h
2 h
2 h
1 h
1 h
20 h
20 h
71
Me
Me
Me
Me
Traced
—
—
24
23
2f, 51b
0
6
7
8
9
10
11
12
1g
1h
1i
1j
1k
1l
Ph
H
H
H
H
H
H
H
15
o-MeOC6H4
m-MeOC6H4
o,m-OCH2OC6H3
p-ClC6H4
2-Thiophenyl
m,p-(MeO)2
2h, 24
0
8d
2j, 10
2k, 0
a Solutions were 0.5 M in substrate, using 4 equivalents of the allyl
silane; reactions were stirred at 40 °C for the indicated time. b Water
content: 130 ppm. c Water content: 45 ppm. d Accompanied by some
decomposition.
2l, tracec
2m, 15c
1m
a Solutions were 0.5 M in substrate, using 4 equivalents of the allyl
silane; reactions were stirred at 40 °C for the indicated time.
b Desilylated product. c Oligomerisation was also observed: see
Scheme 5.
work of Spencer, we tested for this by addition of di-t-butyl-4-
methylpyridine which, for steric reasons, is capable of seques-
tering a proton, but not a Lewis acid.9 In the presence of this
additive, two equivalents relative to scandium, the reaction did
not proceed at 40 °C. Even at 90 °C only a 60% conversion was
observed after 22 hours. This experiment indicates that the
reaction is actually catalysed by a Brønsted acid (Scheme 3),
likely to have formed by hydrolysis of the scandium salt8b and
that, in the absence of a proton source, substantially more
forcing conditions are required. Scandium triflate is, therefore,
As would be expected from the mechanism, the corres-
ponding methyl ether 1b performed equally well (Table 2,
entry 2). In contrast, various other benzyl alcohols performed
very poorly. No product could be obtained when benzyl
alcohol 1g (entry 6), m-methoxybenzyl alcohol 1i (entry 8) and
p-chlorobenzyl alcohol 1k (entry 10) were employed; low yields
were obtained with o-methoxybenzyl alcohol 1h (entry 7) and
piperonyl alcohol 1i (entry 9). These examples would be
expected to be less electron rich or less effective at stabilising a
benzylic cation. The lower reactivity is, therefore, to be
expected. Such selectivity is, of course, valuable: when p-benzy-
loxybenzyl methyl ether 1c was employed as the substrate
(entry 3), selective allylation at only the more electron rich
benzylic position was observed. p-Allyloxybenzyl methyl ether
1d also underwent efficient deoxygenative allylation. A sub-
strate 1e with a TBS group, however, did not survive the reac-
tion conditions, predominantly yielding the corresponding
allylated compound 1f with a free alcohol group.10 In addition,
the dimethoxy acetal of p-methoxybenzaldehyde 3 underwent
diallylation, giving diene 4a, contaminated by some of the
mono-allylated product 4b in a 3.2 : 1 ratio (Scheme 4).
a
pre-catalyst unless those more forcing conditions are
applied. Catalysis of this reaction by Brønsted acids is well
documented.2 Indeed, the reaction was also catalysed by triflic
acid giving 75% conversion in 2 hours. Given that triflic acid
was a less effective catalyst than scandium triflate it seems
that, although a hidden Brønsted acid mechanism operates,
there is a modest synergistic effect due to the scandium. The
addition of water, of course, inhibits the reaction by diluting
the acid, while concentrations of water that are too low prevent
the formation of a sufficient Brønsted acid concentration.
Consistent with the need to form a strong Brønsted acid by
hydrolysis to catalyse the reaction, no reaction was observed
when scandium acetate was employed.
Thiophenylmethanol 1l (entry 11) gave a trace of the volatile
allylation product 2l, accompanied by oligomerisation pro-
ducts, amongst which the pseudodimer 2l′ could be isolated
(Scheme 5). We were interested to find what would happen
with an aryl group bearing more electron donating groups.
Veratryl alcohol 1m reacted rapidly under these conditions,
but gave a mixture of products. The expected allylation
product 2m was obtained in 15% yield (entry 12), but the
pseudo-dimer 5, isolated in 29% yield, proved to be the major
product. We were also able to isolate the pseudo-trimer 6 and
pseudo-tetramer
7
in
4
and 5% yields respectively.
Scheme 3 The “hidden Brønsted acid mechanism”.
120 | Org. Biomol. Chem., 2018, 16, 119–123
Dimerisation, oligomerisation and polymerisation have been
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Table 3 Deoxygenative allylation of benzhydryl alcohols using Sc
a
(OTf)3
Scheme 4 Use of an acetal as the substrate.
Entry Substrate Ar1
Ar2
Ph
Product, yield (%)
observed previously.1a,t In this case and that of the thiophenyl
substrate, it appears that the aromatic ring of the allylation
product is sufficiently nucleophilic to compete with the silane.
We attempted to drive the selectivity by changing to allyl tri-n-
butylstannane, a more reactive (but less green) nucleophile.11
Surprisingly, no product was obtained and starting material
1m was recovered. We suspect that this is due to destruction of
Brønsted acids in the medium by reaction with the stannane.
Indeed, when allyl tri-n-butylstannane was added to scandium
triflate in d3-acetonitrile in an NMR tube, effervescence could
be observed and the 1H NMR signals corresponding to
propene could be identified.
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8f
Ph
9a, 96
9b, 94
9c, 95
9d, 84
9e, 93
9f, 52
0 (dec.)
9h, 48b
9i, 94
p-MeOC6H4 Ph
p-MeC6H4 Ph
p-MeOC6H4 p-FC6H4
Ph
Ph
Ph
Ph
Ferrocenyl
2-Thiophenyl
2-Furyl
8g
8h
8i
Cyclopropyl
p-MeOC6H4 m-Br
10
8jc
p-MeOC6H4 m-MeO2CC6H4 9j, 96
a Solutions were 0.5 M in substrate, using 4 equivalents of the allyl
silane; reactions were stirred at 40 °C for the indicated time. b A small
amount of ring opened product was also isolated. c The corresponding
methyl ether was used as the substrate, rather than the alcohol.
The dexoygenative allylation has been widely used with benz-
hydryl alcohols.12 Indeed, under our conditions, a range of benz-
hydryl alcohols 8 underwent deoxygenative allylation, giving the
products 9 in good yields (Table 3). Notably, a ferrocenyl group
could be one of the aromatic groups (entry 5). One exception was
phenyl 2-furyl carbinol 8g (entry 7). We suspect this is due to the
well-known acid sensitivity of furans. Thiophenes are regarded as
more stable and phenyl 2-thiophenyl carbinol 8f did give a better
yield (entry 6). Phenyl cyclopropyl carbinol 8h gave a modest
yield of the allylated product 9h (entry 8). A small amount of
4-phenylbut-3-en-1-ol (4%) was also isolated. This appears to be a
Julia product13 arising from cyclopropane ring opening during
return of water to the carbocation intermediate.
Table 4 Deoxygenative allylation of benzhydryl alcohols using Nafion
Entry
Substratea
Ar1
Ar2
Product, yield (%)
1
2
3
4
5
8a
8a
8b
8c
8f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
9a, 42
0b
9b, 74
9c, 57
9f, 51
p-MeOC6H4
p-MeC6H4
2-Thiophenyl
a 0.5 M in substrate using 125 mg of Nafion per mmol. b Nafion sup-
ported Sc3+ was used.
Returning to the concept of Brønsted acid catalysis, we won-
dered whether we could employ a solid supported catalyst.
Scheme 5 Oligomerisation reactions.
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This modification would simplify the work-up procedure and
be of future use in flow chemistry. Given that we were using
the triflate of scandium, we employed Nafion, a perfluorinated
sulfonic acid resin (Table 4).14 Pleasingly, under these con-
ditions, benzhydryl alcohol 8a was converted to its allylated
derivative 9a in 42% yield (entry 1). A number of other benz-
hydryl alcohols could also be allylated (entries 3–5). In contrast,
no reaction was observed when Nafion-supported scandium(III)15
was used (entry 2), indicating that this polymer does not undergo
significant hydrolysis under these conditions.
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Conclusions
Scandium triflate is an effective catalyst for the deoxygenative
allylation of benzhydryl alcohols, and displays significant and
potentially useful selectivity in the same reaction with benzyl
alcohols. The reaction proceeds through a hidden Brønsted
acid mechanism. Scandium triflate is, therefore, better con-
sidered as a pre-catalyst! Claims in the literature that this ally-
lation (and other) reactions are Lewis acid catalysed should be
viewed with caution if no appropriate test has been carried
out.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank the Agency for Science Technology and Research
(A-Star) for financial support of this work (PSF grant number
1321202095) and the Graduate School, Chulalongkorn
University (Overseas Research Experience Scholarship for
Graduate Student, to PS). We thank Professor Richard Webster
and Sher Li Gan for assistance with the Karl Fischer titration.
3 I. Šolić, D. Reich, J. Lim and R. W. Bates, Asian J. Org.
Chem., 2017, 6, 658.
4 S. Kobayashi, Eur. J. Org. Chem., 1999, 15. Scandium may
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Chem. Rev., 2002, 102, 2227.
7 T. C. Wabnitz, J.-Q. Yu and J. B. Spencer, Chem. – Eur. J.,
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