Lewis-base-catalysed selective reductions of ynones with a mild hydride donor

Article abstract of DOI:10.1039/c8cc00058a

Ynones are efficiently reduced with a mild hydride donor in the presence of a catalytic amount of nucleophilic phosphines. The reactions are selective 1,2-reductions that give propargyl alcohols in yields of up to 96%. It is proposed that success in these reactions depends on the activation of ynones by a Lewis base catalyst. A protic additive plays a key role in suppressing the undesired reaction pathways and accelerating the 1,2-reductions.

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Lewis-Base-Catalysed Selective Reductions of Ynones with Mild
Hydride Donor
F. Schömberg, a Y. Zi a and I. Vilotijevica
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Ynones are efficiently reduced with a mild hydride donor in reactivity towards mild hydride donors such as pinBH (Scheme
presence of catalytic amount of nucleophilic phosphines. The 1d), and that (ii) different carbonyl compounds could be
reactions are selective 1,2-reductions that give propargyl alcohols chemoselectively reduced based on their contrasting
in yields of up to 96%. It is proposed that success in these reactivities with Lewis bases.
reactions depends on activation of ynone by a Lewis base catalyst.
Protic additive plays a key role in suppressing the undesired
reaction pathways and accelerating the 1,2-reductions.
Propargylic alcohols are a common moiety in natural products
and biologically active molecules,1 and they serve as versatile
intermediates in organic synthesis.2 Secondary propargylic
alcohols can be prepared via 1,2-reduction of ynones that are
easily accessible, i.e. via addition of alkynyl nucleophiles to
various carbonyl compounds.3 Reductions of carbonyl
compounds, including ynones, and chemoselectivity of these
reactions have been the subject of investigation for many
decades.4 Recent efforts have focused on the use of mild
reducing agents, mild hydride donors with overall goal of
developing more selective transformations.5
Easy to handle, mild hydride donors such as pinacolborane
(pinBH) is an ideal reductant for applications in small scale
preparation of compound libraries where scope and generality
are of high importance. The low reactivity of pinBH prevents
its direct use as a reducing agent and enables its use in
catalytic processes.6 The common strategies to increase the
reactivity of such mild hydride donors, illustrated in Scheme 1,
are to rely on transition metal mediated activation,7 Brønsted
or Lewis acid activation of the substrate,8 and/or activation of
Scheme 1 Catalytic reduction of carbonyl compounds with
the borane with a suitable Lewis base.9 Inspired by reductions
mild-hydride-donor boranes.
catalysed by frustrated Lewis pairs,10 and the surge of interest
in metal-free catalysts for reductions,8,11 we speculated that (i)
To test both of our hypotheses, we focused on reactions of
a suitable Lewis base may be used to activate the carbonyl
substrate, instead of activating the borane, and increase its
pinBH with ynone 5a and simple ketones (acetophenone and
cyclohexanone) in presence of a Lewis base catalyst. The
choice of catalyst and reaction solvent in the initial
experiments was governed by the intent to activate the
carbonyl compound while avoiding activation of borane
through creation of a Lewis adduct. Simple nucleophilic
phosphines were chosen as catalysts because they don’t form
stable adducts with pinBH.12 Dichloromethane, 1,2-
dichloroethane or toluene were used as solvents to avoid
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activation of pinBH through formation of Lewis adduct with as 1 mol% for tributylphosphine without effecting the yield.
solvent molecules. In the presence of catalytic amounts of Only 1.1 equivalents of pinBH were sufficient to effect
tributylphosphine (20 mol%), ynone 5a readily reacted with complete consumption of the starting ynone. In absence of
pinBH while acetophenone and cyclohexanone remained phosphine, tert-butanol doesn’t catalyse the 1,2-reduction
unaffected after prolonged exposure to the reaction reaction: reduction product 6a was not observed after 6 hours
conditions. In absence of phosphine catalyst, pinBH does not in presence of 2 equiv. of pinBH and 2 equiv. of alcohol.
reduce the ynone 5a
.
These experiments seemingly
corroborated the initial hypotheses showing (i) the A set of commercially available and easy to handle alkyl- and
effectiveness of phosphine catalysts in reductions of ynones arylphosphines was tested as Lewis base catalysts in the
with pinBH and (ii) that phosphines do not promote reduction reductions of ynones (for detailed results see Table 2, ESI
of ketones which opened the door for development of document). Triphenylphosphine and diphenylmethylphosphine
chemoselective catalytic reactions.
provided the desired product in acceptable yields but required
longer reaction times and failed to drive complete
The product mixture isolated in reaction of ynone 5a consumption of ynone after 24 hours. Trialkylphosphines
highlighted the issues with reaction regioselectivity. The well- proved to be more efficient catalysts with tributyl- and
established modes of reactivity including 1,2- and 1,4- trimethylphosphine both effecting full conversion of ynone
reduction with possible overreduction pathways, alkyne within 10 minutes with desired products isolated in high yield.
hydroboration, and dimerization or oligomerization of ynones In contrast, bulky trialkylphosphines, tri-t-butylphosphine and
could easily lead to formation of a variety of different tricyclohexylphosphine, showed decreased activity which
products. The major products in the reduction of ynone 5a
however, were the products of 1,2- and 1,4-reduction, 6a and catalyst for successful reaction outcome.
. Products of overreduction (allylic alcohol derived from
and ynone dimerization were observed in minor quantities.
,
highlighted the importance of nucleophilicity of the phosphine
1
1)
Upon optimizing the reaction conditions for reduction of 5a
substrate scope for the 1,2-reductions of ynones was
Effects of additives on reaction selectivity and evaluated with special attention to the identity of the α’ and γ
,
Table 1
isolated yield of the 1,2-reduction product.
substituents in the ynones. Urgency to evaluate various
combinations of alkyl and aryl substituents was brought on by
the previous reports which map an extremely divergent
reactivity network in phosphine catalysed reaction of ynones
or ynoates under similar reactions conditions.13
Gratifyingly, substrates with either alkyl and aryl groups in α’
and γ positions were equally reactive as 5a, all providing the
products of 1,2-reductions in good yields (Scheme 2,
Entry
Additive (1.5 eq.)
AcOH
Time
120 min
16 h
Yield of 6a (%)a
1
2
3
4
5
6
7
8
9
(trace)
0
(18)
(trace)
86 (86)
61
64
94
87 (89)
compounds 6a, 6b, 6d, 6e and 6f). Similar reactivity was
DABCO
NEt3
t-BuOK
H2O
MeOH
EtOH
observed even when a tertiary carbon centre was present in α’
or γ positions of the ynone. However, quaternary carbon
centres in these positions significantly decrease the rates of
the reduction reactions making them less practical (Scheme 2,
compounds 6c and 6g).
16 h
10 min
10 min
60 min
60 min
10 min
10 min
i-PrOH
t-BuOH
Further inspection of the substrate scope has shown that both
electron rich and electron poor ynones are efficiently reduced
a
Isolated yield of 6a. Numbers in brackets designate yield determined
1H NMR spectroscopy of crude product mixtures after quench
designated time point using triphenylmethane as standard.
under the optimized conditions (6h, 6i, 6j and 6k). A selection
of substrates containing various heterocycles such as furan,
thiophene, both protected and non-protected indole and
protected aniline all tolerated the mild reaction conditions well
and produced the corresponding propargyl alcohols in good
Further optimization of the reaction conditions revealed that
protic additives suppress the major side reactions: 1,4-
reduction and dimerization/oligomerization of ynone. The
increase in selectivity and isolated yields of propargylic alcohol
6a correlates to the increased amount of tert-butanol in the
reaction milieu (Table 1, ESI document). When 1.5 equivalents
of tert-butanol were present in the mixture, products of 1,4-
reduction and dimerization/oligomerization were not observed
and the propargylic alcohol 6a was the only product isolated
upon aqueous work up. Furthermore, in presence of tert-
butanol additive, catalyst loading could be reduced to as low
yields (Scheme 2, compounds 6j
under optimized conditions, acetophenone
cyclohexanone ( ) do not react even after longer periods of
-
6o). It is worth noting that
(3)
and
8
time similar to our initial experiments. Other reducible groups
are also not affected under optimized conditions as illustrated
by substrates 6h, 6j, 6k, 6o, 6p and 6q which contain nitro,
carbamate, amide, ester and nitrile groups respectively.
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acceleration is also a consequence of higher rate of 1,4-
addition of the phosphine catalyst to ynones. In presence of
protic additives, resulting zwitterionic intermediate would get
protonated to produce the corresponding vinylphosphonium
salts.14 Quenching of the enolate intermediate initially
produced by conjugate addition of phosphine is believed to
play a key role in suppressing the oligomerization of ynones
which happens rapidly in absence of the additive or borane
and suppressing the 1,4-reduction pathways.
After establishing that a tertiary carbon centre in α’ position
does not deter the reactivity of ynones (Scheme 2, entries 6b
and 6d), diastereoselectivity of the reductions was briefly
examined with ynones 5r,
5s and 5t (Scheme 3).15 The
reactions of 5r produced the 1:1.8 mixture of diastereomers
6ra and 6rb with combined yield of 96%. Diastereoselectivity in
reductions of 5s and 5t which feature a phenyl and benzyl
ether substituent in α’ positions respectively, also proceeded
with moderate diastereoselectivity producing a 1.5:1 mixture
of 6sa and 6sb and a 1:2.1 mixture of 6ta and 6tb (anti
diastereomer favoured in both cases). The observed low
diastereoselectivity in these reactions may be a consequence
of low selectivity in formation of
E and Z-vinylphosphonium
intermediates and suggests that coordination of borane
followed by intramolecular hydride delivery is not the
dominant pathway.
Scheme 3 Substrate control of diastereoselectivity in the
phosphine catalysed 1,2-reductions of ynones.
Scheme 2 Reaction scope for the phosphine catalysed ynone
Finally, the scalability of the developed transformation was
tested. Reductions of 5a on gram-scale proceed efficiently
without deterioration of the isolated yield.
reduction with pinacolborane.
Closer inspection of the substrate scope clearly matched the
expectations arising from our initial hypothesis. The substrates
with electron withdrawing substituents, that should render the
ynone more electrophilic were reduced significantly faster
than the corresponding substrates that carry electron donor
groups. (i.e. compound 6h vs. 6a vs. 6i, Scheme 2). These
observations are consistent with simple hydride delivery to
In conclusion, we have developed a phosphine catalysed
chemoselective 1,2-reduction of ynones using pinBH as a mild
hydride donor. The key control element in these reactions is
the presence of protic additive, tert-butanol, which plays a role
in suppressing 1,4-reduction and ynone dimerization pathways
and increasing the reaction rates of the 1,2-reduction
presumably through activation of pinBH. The efficiency of this
transformation has been demonstrated on a number of
carbonyl. Knowing that phosphine does not react with tert
-
butanol or pinBH,12 we propose that the observed rate
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