NaH mediated isomerisation-allylation reaction of 1,3-substituted propenols

Article abstract of DOI:10.1039/c3ob41857j

A base mediated isomerisation-allylation protocol of 1,3-disubstituted propenols has been established. The use of diaryl and aryl-silyl substrates is reported alongside the use of substituted allyl bromides. Mechanistic experiments have also been conducted to elucidate the reaction pathway. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob41857j

Organic &
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NaH mediated isomerisation–allylation reaction of
1,3-substituted propenols†
Cite this: Org. Biomol. Chem., 2013, 11,
7662
Adam J. S. Johnston, Mark G. McLaughlin, Jolene P. Reid and Matthew J. Cook*
Received 11th September 2013,
Accepted 3rd October 2013
DOI: 10.1039/c3ob41857j
www.rsc.org/obc
A base mediated isomerisation–allylation protocol of 1,3-disubsti- labelling studies they proposed that following initial deproto-
tuted propenols has been established. The use of diaryl and aryl- nation of the alcohol, a competing [1,2] or [1,3]-hydride shift
silyl substrates is reported alongside the use of substituted allyl occurs as deuterium is observed at both of these positions in
bromides. Mechanistic experiments have also been conducted to the product. 2-Pyridyl substituted allylic alcohols have also
elucidate the reaction pathway.
been shown to isomerise both thermally and under sodium
hydride mediated conditions.10,11 To our knowledge there have
been no reports of base mediated isomerisations of 1,3-disub-
stituted allylic alcohols followed by electrophilic trapping.
Herein we describe the base mediated isomerisation of 1,3-
diaryl and 1-aryl-3-silyl propen-1-ols and subsequent trapping
with an allylic bromide (eqn (3)).
The isomerisation of allylic alcohols to ketones and aldehydes
can be a useful transformation that avoids the use of both oxi-
dants and reductants.1 The most common strategy to achieve
this operation is to utilise a transition metal catalyst that
isomerises the alkene moiety into an enol (or enolate) which
upon tautomerisation (or workup) affords the corresponding
carbonyl functionality.2 In most cases, the reaction is driven by
a thermodynamic preference for the enol (or enolate) over the
allylic alcohol (or alkoxide) with up to 25 kcal mol−1 difference
between the two.3
Many of these processes have also been rendered enantio-
selective.4 The allyl amine variant is generally superior produ-
cing significantly higher levels of enantiomeric enrichment.5
Motherwell also demonstrated that enolates derived from
rhodium or nickel catalysed isomerisations of allylic alkoxides
could be intercepted by electrophiles such as aldehydes or
allylic bromides to form α-branched products (eqn (1)).6
Although known for over 100 years, base mediated variants
of this reaction are much less common with relatively few
reported examples.7 Dimmel demonstrated the use of butyl
lithium and Na/K to isomerise phenyl substituted allylic alco-
hols which was proposed to proceed via a double anion with
both the alcohol and the allylic C–H being deprotonated fol-
lowed by reprotonation to form the more conjugated product.8
Borschberg reported an analogous isomerisation of a diaryl-
substituted allylic alcohol under much milder reaction con-
ditions using t-BuOK as base (eqn (2)).9 Following deuterium
ð1Þ
ð2Þ
ð3Þ
We discovered an unusual product during the course of an
allylation reaction of silyl allylic alcohol 1 (Table 1).12,13 When
allylic alcohol was treated with sodium hydride and allyl
bromide 2 in THF with heating the major product observed
was not the expected allyl ether but ketone 3.14 The mass
balance of the reaction was made up of unallylated ketone
product and the expected bis-allyl ether. This was further opti-
mised and found that lowering the equivalents of NaH
increased the yield to 57%. When the sodium hydride content
was lowered further, a reaction was still observed (at 1.05
equivalents) however O-allylation was the major product. Other
bases such as t-BuOK gave decomposition and a solvent screen
School of Chemistry and Chemical Engineering, Queen’s University Belfast, Belfast,
Northern Ireland, UK. E-mail: m.cook@qub.ac.uk; Fax: +44 (0)28 90976524;
Tel: +44 (0)28 90974682
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob41857j
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Table 1 Optimisation studies
Table 2 Biaryl substrate scope
Entry
Base
Solvent
Equiv. 2
Additive
Yielda (%)
1
2
3
4
5
6
7
8
NaH
NaH
NaH
KOt-Bu
NaH
NaH
NaH
NaH
THF
THF
THF
THF
DMSO
DMFb
THF
THF
3
—
—
—
—
—
—
15-c-5
HMPA
48
57
22
Dec.
40
0c
1.5
1.05
1.5
1.5
1.5
1.5
1.5
0d
43
a Isolated yield of 3. b Reaction performed at 25 °C. c Only O-allylated
product observed. d Only isomerised, unallylated product observed.
Scheme 1 Vinyl silane substrate scope.
showed that THF was the optimal solvent. Interestingly, when
DMF was used as solvent no ketone was observed with only
O-allylation being observed. Finally, the use of additives
was explored with 15-crown-5 giving no ketone and HMPA
affording a slightly reduced yield with several unidentified by-
products being formed.
With the optimised conditions in hand, we then probed the
substrate scope (Scheme 1). The reaction proceeded with both
phenyl and naphthyl to afford α-allylated ketones 3a and 3b.
When substitution was present on the aryl ring the reactivity
was compromised with both electron withdrawing and donat-
ing groups. 3-Fluoro substituent 1c afforded allylated product
3c in low yield and 4-methoxy substituent 1d afforded no iso-
merisation–allylation product with the majority of the mass
balance made up of O-allylated product.
a Isolated yields. b Reaction conditions: 1.5 equiv. NaH, 1.5 equiv. allyl
bromide, THF, 60 °C, 12 hours.
As the substrate scope of the vinyl silanes was limited, with
only three examples providing any ketone product, we next
turned our attention to 1,3-diaryl propen-1-ols 4 which are
readily available using a number of methods (Table 2).15 We
first looked at commercially available 1,3-diphenyl propen-1-ol
4a and found the same type of reaction occurred to afford
ketone 5a in a moderate yield.
We next examined the effect of changing the electronic
nature of the aryl group at the 1-position. Adding electron
withdrawing substituents such as 4-fluoro or 3,5-bis(trifluoro-
methyl) did increase the yield of the reaction affording 5b and
5c respectively. Heterocycles could be incorporated at the
1-position with little effect on reactivity. Both furyl 5d and
pyridyl 5e proceeded in a similar manner to the parent phenyl
compound.
We also probed the effect the 3-aryl group had on reactivity
and found that changing this showed a much larger effect
than the 1-position. 2-Naphthyl substituent 4f gave much
improved reactivity affording 5f in 50% yield. This could be
further improved by the installation of a 4-trifluoromethyl
group giving 5g in good yield. Other substituents including
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4-trifluoromethoxy 4h, 4-methyl 4i and 4-fluoro 4j also pro-
vided isomerised-allylated products 5h–j in around 50% yield.
The installation of electron donating groups in the form of a
4-methoxy group 4k resulted in a similar yield to the phenyl
group and a pyridyl group could be tolerated in the 3-position
forming 5l in 42% yield. When no anion stabilising groups
were present, such as alkyl substituents, no isomerisation was
observed and only O-allylation was obtained.
ð8Þ
ð9Þ
Next we examined other substituted allyl bromides. When
crotyl bromide was used a similar reaction was observed with
the α-crotylated product 6 being produced in 44% yield in the
same E : Z ratio as the electrophilic component (eqn (4)). This
was further extended to 2,3-dimethylallyl bromide and again
α-allylation was observed to form 7, albeit in reduced yields
(eqn (5)).
With the mechanistic data in hand we have proposed a
mechanism that accounts for all observations (Scheme 2).
Firstly the OH of allylic alcohol 4 is deprotonated to form the
corresponding alkoxide 12. This alkoxide can undergo a
second deprotonation to form allylic anion 13. The allylic
anion 13 can deprotonate a second equivalent of alkoxide 12
to afford an enolate 14 incorporating deuterium in the 3-posi-
tion and regenerating allylic anion 13. Finally the enolate 14 is
then allylated to afford the observed isomerisation allylation
product 5. As only 40%-deuterium incorporation is observed
the deprotonation of 12 must be performed by both 13 and
NaH at comparable rates. This indicates that the isomerisation
is catalytic with respect to 13 and complete double deprotona-
tion is not necessary before isomerisation can occur. In all
cases no bis-allylated product was observed, a significant by-
product in many of the other isomerisation–allylation proto-
cols that have been reported. The position of the methyl
ð4Þ
ð5Þ
Several experiments were performed to probe the mechan- groups when a substituted allyl bromide is used, SN2 type sub-
ism of these reactions. Firstly, in the absence of an electro- stitution, also rules out possibility of an O-allylation-Claisen
phile, the allylic alcohol isomerises to the corresponding pathway.
ketone 8 in excellent yield with no observed by-products (eqn
Sodium hydride has been shown to isomerise N-acyl allylic
(6)). Secondly, when deuterated compound 9 is used, the amines to their corresponding enamines with high levels of
deuterium atom is removed from the 1-position by the base E/Z control. Clayden demonstrated the use of allylic ureas in
and this was observed at the 3-position in approximately 40% this pathway17 and Smith used allylic acrylamides.18,19 Both of
D-incorporation (eqn (7)). The majority of the product in this these reactions give the corresponding enamine as a single Z
reaction was simple O-allylation product. When enantio-
enriched compound (S)-4a was used,16 the corresponding ally-
lated product 5a was produced as a racemic mixture thus
indicating the intermediacy of a planar achiral intermediate
(eqn (8)). Finally we took the allyl ether 11 and subjected this
to the reaction conditions and no reaction was observed thus
ruling out the intermediacy of allyl ether 11 (eqn (9)).
ð6Þ
ð7Þ
Scheme 2 Proposed mechanism.
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isomer and they both propose a sodium chelate analogous to
13. As deuterium is only observed at the 3-position, we can
eliminate the possibility that a competing [1,2] and [1,3] shift
is in operation as proposed by Borschberg.9
( j) N. Ahlsten, A. B. Gómez and B. Martín-Matute, Angew.
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K. J. Laider, Can. J. Chem., 1960, 38, 2367.
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see: (a) K. Tani, Pure Appl. Chem., 1985, 57, 1845;
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G. C. Fu, J. Am. Chem. Soc., 2000, 122, 9870; (c) K. Tanaka
and G. C. Fu, J. Org. Chem., 2001, 66, 8177; (d) M. Ito,
S. Kitahara and T. Ikariya, J. Am. Chem. Soc., 2005, 127,
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C. Mazet, Angew. Chem., Int. Ed., 2009, 48, 5143; (f) N. Arai,
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Conclusions
In conclusion, we have discovered and investigated the
NaH catalyzed isomerization of allylic alcohols and α-allylation
of the resultant enolate to form α-allylated ketones. We
have discovered that both silyl and aryl substitution is
tolerated at the γ-position. Several mechanistic probes and
control reactions has shed light on the mechanism of this
reaction.
We thank Queen’s University Belfast for support. We are
also grateful to the Department of Employment and Learning,
Northern Ireland for a studentship (MGM). GlaxoSmithKline
and AstraZeneca are also thanked for their generous
donation of laboratory equipment. We also thank Professor
Andrew Smith, University of St. Andrews for useful
discussions.
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19 Organolithium and lithium amide bases have also been
utilised for similar reactions: (a) J. E. Resek and P. Beak,
Tetrahedron Lett., 1993, 34, 3043; (b) P. Ribéreau,
M. Delamare, S. Célanire and G. Quéguiner, Tetrahedron
Lett., 2001, 42, 3571. For review of organolithium
chemistry see:
(c) J. Clayden, Tetrahedron Organic
Chemistry, in Organlithiums: Selectivity for Synthesis,
Pergamon, 2002.
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