Chemo- A nd Regioselective Synthesis of Acyl-Cyclohexenes by a Tandem Acceptorless Dehydrogenation-[1,5]-Hydride Shift Cascade

Article abstract of DOI:10.1021/jacs.9b12296

An atom-economical methodology to access substituted acyl-cyclohexenes from pentamethylacetophenone and 1,5-diols is described. This process is catalyzed by an iridium(I) catalyst in conjunction with a bulky electron rich phosphine ligand (CataCXium A) which favors acceptorless dehydrogenation over conjugate reduction to the corresponding cyclohexane. The reaction produces water and hydrogen gas as the sole byproducts and a wide range of functionalized acyl-cyclohexene products can be synthesized using this method in very high yields. A series of control experiments were carried out, which revealed that the process is initiated by acceptorless dehydrogenation of the diol followed by a redox-neutral cascade process, which is independent of the iridium catalyst. Deuterium labeling studies established that the key step of this cascade involves a novel base-mediated [1,5]-hydride shift. The cyclohexenyl ketone products could readily be cleaved under mildly acidic conditions to access a range of valuable substituted cyclohexene derivatives.

Full text of DOI:10.1021/jacs.9b12296

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Chemo- and Regioselective Synthesis of Acyl-Cyclohexenes by a
Tandem Acceptorless Dehydrogenation-[1,5]-Hydride Shift Cascade
Lewis B. Smith, Roly J. Armstrong, Daniel Matheau-Raven, and Timothy J. Donohoe*
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ABSTRACT: An atom-economical methodology to access sub-
stituted acyl-cyclohexenes from pentamethylacetophenone and 1,5-
diols is described. This process is catalyzed by an iridium(I)
catalyst in conjunction with a bulky electron rich phosphine ligand
(CataCXium A) which favors acceptorless dehydrogenation over
conjugate reduction to the corresponding cyclohexane. The
reaction produces water and hydrogen gas as the sole byproducts
and a wide range of functionalized acyl-cyclohexene products can
be synthesized using this method in very high yields. A series of control experiments were carried out, which revealed that the
process is initiated by acceptorless dehydrogenation of the diol followed by a redox-neutral cascade process, which is independent of
the iridium catalyst. Deuterium labeling studies established that the key step of this cascade involves a novel base-mediated [1,5]-
hydride shift. The cyclohexenyl ketone products could readily be cleaved under mildly acidic conditions to access a range of valuable
substituted cyclohexene derivatives.
hydride. Aldol condensation with Ph*COMe would generate
an acyclic enone which could then be reduced by iridium
hydride to release a hydroxyketone intermediate and close
cycle 1. This intermediate could then enter cycle 2 in which
oxidation of the remaining alcohol, followed by condensation,
would generate a cyclic enone intermediate which could finally
undergo reduction to form the corresponding cyclohexane
product. We were intrigued by the acyl-cyclohexenes formed as
the penultimate intermediates in this sequence and speculated
that if the final reduction step in cycle 2 could be interrupted, it
might be possible to selectively isolate these compounds and
thereby develop an unprecedented intermolecular (5 + 1)
strategy for cyclohexene synthesis. However, in order to
accomplish this goal, we would have to solve the challenging
chemoselectivity issue of achieving complete reduction of the
acyclic enone intermediate in cycle 1 while fully suppressing
reduction of the cyclic enone products in cycle 2. We aimed to
achieve this goal by a combination of two approaches: (i) by
addition of a hydrogen acceptor, which could competitively
intercept and recycle iridium hydride;10 (ii) by employing α-
substituted diol starting materials to target sterically hindered
tetrasubstituted enones as the final product, which would be
less prone to over reduction.11 Here we describe how we were
ultimately able to address these challenges to develop a
remarkably general and operationally simple synthesis of acyl
1. INTRODUCTION
The synthesis of cyclohexenes in a regio- and stereocontrolled
manner is of fundamental importance in the preparation of
natural products, functional materials, and medicinally relevant
compounds.1 As a testament to this, the Diels−Alder
cycloaddition reaction remains the premier method for the
construction of the cyclohexene core (Scheme 1A).2 However,
in order to achieve high regioselectivity in intermolecular
Diels−Alder reactions, it is often necessary to rely upon
sterically or electronically biased substrates, which means only
cyclohexenes bearing certain substitution patterns can be
accessed.3 Several catalytic approaches to cyclohexene syn-
thesis have also been developed, such as ring closing
metathesis (RCM) and catalytic cyclotrimerization.4,5 How-
ever, these approaches are best expressed in intramolecular
reactions and depend on the accessibility of appropriately
substituted precursors. Intermolecular reactions used to
synthesize sterically demanding, multisubstituted cyclohexenes
are much less well documented, and therefore, new methods
for cyclohexene synthesis that complement the Diels−Alder
approach are highly desirable.
We recently reported that pentamethylphenyl (Ph*) ketones
can be directly alkylated with alcohols via hydrogen borrowing
catalysis.6,7 We subsequently showed that this approach could
be extended to an iridium catalyzed synthesis of cyclohexanes
by double alkylation of pentamethylacetophenone with 1,5-
diols (Scheme 1B).8,9 Mechanistically, it was proposed that
this process operated via two sequential hydrogen borrowing
catalytic cycles (cycles 1 and 2). The first cycle would begin
with oxidation of the 1,5-diol to the corresponding
hydroxyaldehyde along with concomitant formation of iridium
Received: November 14, 2019
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A

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a
Scheme 1. Previous Work and Strategy for Formation of
Acyl-Cyclohexenes by Interrupted Hydrogen Borrowing
Catalysis
Table 1. Optimization of Reaction Conditions
entry
1
2
3
4
5
6
7
metal precatalyst
ligand
[1] (M)
yield 3a/4a
b
c
(mol %)
(mol %)
(% )
[IrCp*Cl2]2(4)
[IrCp*Cl2]2(4)
[IrCp*Cl2]2(4)
[IrCp*Cl2]2(4)
[IrCp*Cl2]2(4)
[IrCp*Cl2]2(4)
[RhCp*Cl2]2 (4)
[Ru(Cp*)Cl2]n(4)
[Ir(cod)Cl]2(4)
[Ir(cod)Cl]2(1)
[Ir(cod)Cl]2(1)
-
-
-
-
-
-
-
-
-
4
4
2
1
0.25
0.1
0.25
0.25
0.25
0.25
0.25
0.25
0.25
7/71
51/25
16/61
36/40
54/7
35/2
52/2
18/1
65/2
67/0
75(79)/0
<5
d
8
9
PPh3(8)
PPh3(2)
10
11
12
n
PAd2 Bu (2)
-
e
n
13
[Ir(cod)Cl]2(1)
PAd2 Bu (2)
<5
a
Reaction conditions: aryl ketone 1 (1 equiv), diol 2a (2 equiv),
b
KOH (4 equiv) PhMe, 115 °C, 24 h. Loading refers to stoichiometry
of monomeric metal after dissociation of multimeric precursors. Yield
c
determined by reverse phase HPLC analysis versus durene as an
internal standard; values in parentheses indicate the yield of isolated
d
e
product. Norbornene (2 equiv) was added. Reaction carried out
with acetophenone (1 equiv) instead of pentamethylacetophenone 1.
1, entry 6). Several other catalysts reported for hydrogen
borrowing were tested but were found to be less effective
(Table 1, entries 7 and 8). However, we found that switching
to an Ir(I) precatalyst with PPh3 led to a further increase in
selectivity, providing 3 in 65% yield along with only a trace of
the corresponding over-reduced cyclohexane 4a (Table 1,
entry 9). Pleasingly, the loading of iridium could be reduced to
1 mol % (0.5 mol % dimer) with no reduction in efficiency
(Table 1, entry 10). Finally, we found that a further
improvement was obtained with bulky alkyl phosphine ligand
cyclohexenes and how a detailed study of the mechanism of
the process has led us to revise our understanding of the
annulation chemistry more generally.
2. RESULTS AND DISCUSSION
n
We commenced our study by investigating the formation of
tetrasubstituted cyclohexene 3a from pentamethylacetophe-
none (1) and 1,5-hexane diol (2a). Applying our previously
reported conditions for cyclohexane synthesis, we found that
the major product was the over-reduced cyclohexane 4a which
was formed in 71% yield along with a small amount (7% yield)
of the desired acyl-cyclohexene 3a (Table 1, entry 1). Using
this result as a benchmark, we investigated the effect of adding
norbornene which has been reported to be an effective
hydrogen acceptor in a variety of iridium and rhodium
catalyzed processes.12 We were delighted to find that addition
of 2 equiv of norbornene resulted in a dramatic improvement
and cyclohexene 3a was formed in 51% yield (Table 1, entry
2). At this point, we embarked upon an extensive program of
optimization exploring the stoichiometry of norbornene (for
full details of the optimization, see the Supporting
Information). However, ultimately, we discovered that the
beneficial result observed with norbornene was simply due to
increased dilution; in fact, the hydrogen acceptor could be
removed entirely, and by decreasing the concentration in
toluene to 0.25 M enone 3a could be obtained in up to 54%
yield (Table 1, entries 3−5). A further decrease in
concentration to 0.1 M resulted in lower conversion (Table
CataCXium A (PAd2 Bu), enabling isolation of cyclohexene 3a
in 79% yield with no over reduction observed at all (Table 1,
entry 11). Notably, 3a was formed as a single regioisomer,
which suggests that the first C−C bond formation (in cycle 1)
takes place exclusively with the primary alcohol end of the diol
rather than the secondary site. Analysis of the reaction
headspace by gas chromatography with a thermal conductivity
detector (GC-TCD) qualitatively indicated the formation of
H2 gas, which suggests that the process proceeds via
acceptorless dehydrogenation and explains why the reaction
can proceed efficiently in the absence of a hydrogen acceptor.13
This hypothesis is also in good agreement with studies by
Beller and co-workers, who have reported that CataCXium A is
particularly effective at promoting acceptorless dehydrogen-
ation processes.14 Our working hypothesis is that switching
from [Cp*IrCl2]2 to a more sterically bulky Ir(I)-CataCXium
system favors protonation of Ir−H rather than conjugate
reduction of the enone. Increased dilution is also predicted to
retard the reduction step and therefore favors formation of the
desired acyl-cyclohexene.
As expected, a control experiment conducted in the absence
of iridium catalyst returned only unreacted starting material
(Table 1, entry 12). Furthermore, when we replaced ketone 1
B
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ab
Table 2. Substrate Scope for the Synthesis of Acyl-Cyclohexenes from Diols
a
Reaction conditions: pentamethylacetophenone 1 (1 equiv), diol (2 equiv), KOH (4 equiv), [Ir(cod)Cl]2 (0.5 mol %), CataCXium A (2 mol %),
b
c
d
PhMe (0.25 M), 115 °C, 24 h. Yields refer to isolated material after column chromatography. Reaction time of 48 h. Isolated as an inseparable
e
mixture with Ph*COMe. Uncyclized compounds Ph*CO(CH2)6COCH3 and Ph*CO(CH2)6CH(OH)CH3 were isolated in yields of 19% and
f
33% respectively. Significant amounts of over reduced products were obtained (see the Supporting Information for details).
with acetophenone, we observed a complex mixture of polar
products by HPLC, with significant formation of 1,3-diphenyl-
1-butanone (Table 1, entry 13). This result highlights the key
role played by the bulky Ph* group in preventing undesired
homodimerization reactions.
With optimal conditions in hand for the synthesis of acyl-
cyclohexenes, we set out to investigate the generality of the
process (Table 2).15 All diols used were either commercially
available or readily prepared in 1−2 steps (details of diol
synthesis are provided in the Supporting Information). We first
investigated the effect of sterics on the reaction and found that
increasing the size of the α-substituent from methyl to n-propyl
or n-butyl had no detrimental effect on reactivity and the
corresponding products 3b and 3c were isolated in yields of
95% and 99% respectively. The reaction also proceeded
efficiently with branched substituents, affording isobutyl and
isopropyl substituted products 3d and 3e in high yields. We
then investigated the functional group tolerance of the reaction
and found that cyclohexenes containing ether (3f), thioether
(3g), acetal (3h), furan (3i), trifluoromethyl (3j), and benzyl
(3k) groups were all obtained in excellent yields with no
evidence of any competing side reactions. A diol substituted
with a phenyl group also underwent the desired reaction to
generate cyclic chalcone 3l in 60% yield. We next investigated
extending the methodology to multisubstituted diols aiming to
introduce substituents at each position around the newly
formed cyclohexene ring. We were pleased to find that an α,β-
dimethyl substituted diol reacted cleanly to afford 1,2,3-
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trisubstituted cyclohexane 3m in 87% yield. α,γ-disubstituted
diols also underwent the desired transformations leading 1,2,4-
trisubstituted cyclohexenes 3n−3p in excellent yields. Cyclo-
hexenes 3q and 3r featuring 1,2,5- and 1,2,6-substitution
patterns respectively were also isolated in high yields. We
found that we could also employ geminally disubstituted diols
in this chemistry enabling the synthesis of spirocyclic acyl-
cyclohexene 3s in 70% yield. Annulation with a multi-
substituted diol derived from Thujone afforded 1,2,3,4-
tetrasubstituted cyclohexene 3t in 80% yield as a single
regio- and diastereoisomer. Finally, we employed an
enantiopure α,γ-disubstituted diol and found that acyl-
cyclohexene product 3u was formed in 67% yield with no
loss of stereochemical integrity.
and acetone, and the corresponding enones 3am and 3an were
not observed. Taken in conjunction, these results imply that a
key role of the Ph* group is to sterically shield the carbonyl
against reduction. Not all of the diols we investigated
underwent the desired annulation reaction. For example,
attempts at heterocycle formation with diethylene glycol (2ao)
and N-protected diethanolamines (2ap−ar) returned only
unreacted pentamethylacetophenone.
With a general method for cyclohexene synthesis in hand,
we set out to demonstrate the utility of the Ph* containing
products by carrying out a series of derivatization reactions
(Scheme 2). We were pleased to find that moderately acidic
a
Scheme 2. Derivatizations of Cyclohexene Products
We next applied the optimized conditions for cyclohexene
formation to double primary diols. Our expectation was that
we would observe a significant amount of over reduction in
these reactions as the trisubstituted enone products would be
considerably easier to reduce than tetrasubstituted enones.11
We were therefore surprised and pleased to find the reaction
remained highly selective and 1,4-disubstituted cyclohexenes
3v and 3w were isolated in yields of 75% and 84%, respectively,
with only traces of the corresponding over-reduced cyclo-
hexanes. Other diols substituted at the γ-position were also
well tolerated, leading to arylated cyclohexenes 3x−3z and
spirocycle 3aa. The annulation could also be performed on
gram scale enabling access to geminally substituted product
3ab in 94% yield. A symmetrical β,β′-disubstituted diol reacted
cleanly to afford cyclohexene 3ac in 61% yield as a mixture of
diastereoisomers. When we investigated nonsymmetrical diols
bearing a β-substituent we observed some regioselectivity in
favor of the C3-substituted products (for example 3ad and
3ae). These results imply that the initial oxidation and aldol
condensation occurs more rapidly at the least hindered alcohol
and is in good agreement with our previous studies in this
area.8b To probe this hypothesis further, we investigated a
reaction of a more sterically encumbered diol substituted with
a geminal dimethyl group at the β-position. In this case, we
were delighted to find that the corresponding cyclohexene 3af
was isolated in 75% yield as a single regioisomer. We were also
able to apply this method to natural product derived diols to
access more complex cyclohexenes 3ag and 3ah. In both cases,
these products were obtained with complete regiocontrol in
favor of initial C−C bond formation at the least hindered end
of the diol.
The annulation reaction appears to be most efficient for the
construction of cyclohexenes and we found that a 1,4-diol
reacted to afford cyclopentene 3ai in reduced yield.
Interestingly, an analogous reaction with heptane-1,6-diol did
not afford any of the desired cycloheptene product 3aj and
instead a mixture of monoalkylated intermediates was isolated
(see the Supporting Information for details). This result
implies that increasing the ring size makes the final aldol
condensation significantly less favorable. We next set out to
probe the role of the Ph* group in more detail by
systematically removing methyl substituents from the aryl
ring. Pleasingly, a mesityl ketone reacted cleanly to afford 3ak
in 86% yield. In contrast, an aryl ketone bearing a single ortho-
methyl group underwent annulation to afford 3al in
significantly reduced yield (9%) accompanied by significant
reduction of the carbonyl group (see the Supporting
Information for details). This effect was even more
pronounced with unhindered ketones such as acetophenone
a
(a) Enone (1 equiv, 0.1 mmol), 2 M HCl in HFIP (1 mL), 65 °C.
(b) 3ab (1 equiv, 0.175 mmol), H2SO4 (0.3 mL), 65 °C, then nBuOH
(1 mL), 65 °C. (c) 3ab (1 equiv), 2 M HCl in HFIP 65 °C, then
EDCI (1.5 equiv), DIPEA (5 equiv), HOBT (1.5 equiv), MeNH-
(OMe).HCl (1.5 equiv), DMF, RT. (d) 3ab (1 equiv), Me3SOI
(1.5 equiv), NaH (1.6 equiv), DMSO, 50 °C. (e) 3ab (1 equiv),
tBuOOH (5 equiv), NaOH (5 equiv), BuOH, 85 °C. (f) 3ab (1
t
equiv), Br2 (1.2 equiv), CHCl3, −17 °C to RT. (g) 3ab (1 equiv), n-
BuLi (2 equiv), pentane, RT then 2,6-di-tert-butylphenol (4 equiv), −
78 °C to RT.
2 M HCl in hexafluoroisopropanol (HFIP) was sufficient to
cleave the Ph* group to the corresponding carboxylic acid via a
retro-Friedel−Crafts acylation (details of the optimization of
this process are provided in the Supporting Information). We
applied these conditions to cleave a representative series of
Ph* containing acyl-cyclohexenes to the corresponding
cyclohexenecarboxylic acid derivatives 6-11 which were
formed in uniformly excellent yields (Scheme 2A).16 In
D
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a
addition to carboxylic acid synthesis, we were able to cleave
enone 3ab to ester 12 by Fisher esterification (Scheme 2B).
Weinreb amide 13 was synthesized in 75% yield by a pseudo
one-pot procedure involving Ph* hydrolysis followed by amide
coupling. In addition to the versatile Ph* group, all of the
products 3a-3al contain an enone motif which leads to many
opportunities for further functionalization. For example, we
found that 3ab could undergo Corey−Chaykovsky cyclo-
propanation to afford bicyclic ketone 14 in 70% yield or
Weitz−Scheffer epoxidation to generate epoxy ketone 15 in
87% yield. Treatment of 3ab with bromine resulted in an
unexpected allylic bromination reaction to form 16 in 91%
yield.17 Finally, we investigated conjugate addition of carbon
nucleophiles to the enone. Typically, this would necessitate
preparation of organocuprate reagents to avoid competing 1,2-
addition, but remarkably we found that when the Ph*
containing enones were treated with n-BuLi we observed
completely regioselective 1,4-addition. This is presumably a
consequence of the bulky (and twisted) Ph* group which
shields the enone carbonyl group from direct addition. By
quenching the resulting lithium enolate with a bulky proton
source (2,6-di-tert-butylphenol) we isolated the contra-
thermodynamic cis-diastereoisomer 17 in 87% yield and
80:20 d.r. This method is complementary to our previously
reported synthesis of cyclohexanes which selectively produces
the thermodynamic trans-diastereoisomer.8
Scheme 3. Reaction Profile for Cyclohexene Synthesis
Having developed an efficient method to access substituted
acyl-cyclohexenes, we set out to study the mechanism of the
process. We began by monitoring the course of the iridium-
catalyzed annulation of 2w over the first 7 h by analyzing a
series of aliquots by reverse phase HPLC (Scheme 3). As
expected, we observed steady consumption of Ph*COMe (1)
along with buildup of the acyl-cyclohexene product 3w. We
also observed another species, which we identified as pyran 21
which formed in approximately 10% yield over the first hour
and then was gradually consumed. We also measured the
volume of hydrogen gas that was released from the reaction
and found that H2 was steadily released throughout the first
seven hours. Overall, this picture is consistent with a
mechanistic scenario in which the iridium catalyst dehydrogen-
ates 2w, slowly releasing the corresponding hydroxyaldehyde
18 which likely exists in equilibrium with the corresponding
lactol 19 (vide infra). Condensation with Ph*COMe would
then generate acyclic enone 20 which is not observed as it is
reversibly converted to pyran 21, which is an off-cycle
intermediate. According to our originally conceived mecha-
nism, the next step would involve reduction of acyclic enone
20 by iridium hydride to from ketone 22. However, despite
several attempts, we were unable to observe or isolate
intermediate 22, which was surprising. As discussed previously,
this mechanism also does not fully account for the fact that
acyclic enone 20 would have to be fully reduced by iridium
hydride, whereas the cyclic enone product 3w is barely reduced
at all. Taken in conjunction, these results led us to consider an
alternative mechanistic pathway in which acyclic enone 20 is
directly converted to the corresponding cyclohexene product
in the absence of iridium catalyst.
a
(a) Reaction conditions: 1 (1 equiv), 2w (2 equiv), KOH (4 equiv),
[Ir(cod)Cl]2 (0.5 mol %), CataCXium A (2 mol %), PhMe (0.25 M),
115 °C, 24 h. Yields of 1, 21, and 3w were determined by analyzing
aliquots by reverse phase HPLC vs hexamethylbenzene. H2 evolution
was measured volumetrically and converted to absolute concentration
using the ideal gas law assuming a temperature of 298 K.
Scheme 4. Resubjection Experiments in the Absence of
Iridium Catalyst
a
a
(a) Reaction conditions: 1 (1 equiv), 19 (2 equiv), KOH (4 equiv),
PhMe (0.25 M), 115 °C, 24 h. (b) 1 (1 equiv), 23 (1 equiv), KOH
(4 equiv), PhMe (0.25 M), 115 °C, 24 h. (c) Products were isolated
1
as an inseparable mixture, and ratios were determined by H NMR
spectroscopy (see the Supporting Information).
To test this hypothesis, we independently synthesized lactol
19 by DIBAL-H reduction of the corresponding lactone and
treated it with pentamethylacetophenone 1 and KOH in the
absence of iridium catalyst (Scheme 4A). We were excited to
find that under these conditions cyclohexene 3w was isolated
in 84% yield confirming that an alternative iridium-free
pathway is indeed operative. We also carried out a related
experiment in which methyl substituted pyran 21 was treated
with KOH along with an isobutyl substituted lactol 23, which
resulted in formation of a mixture of methyl and isobutyl
substituted cyclohexenes 3w and 3v in yields of 44% and 11%
E
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respectively (Scheme 4B). From this experiment we drew two
conclusions: (i) pyran 21 is a competent precursor for the
metal-free annulation process, most likely via equilibration with
acyclic enone 20 under the basic reaction conditions; (ii) the
formation of crossover product 3v suggests that the initial aldol
condensation is partially reversible.
In an attempt to study this metal-free annulation process in
more detail, we repeated the iridium-free reaction of
pentamethylacetophenone with lactol 19 and followed the
course of the reaction by reverse phase HPLC (Scheme 5). We
hexene product 3w. The concept of forming a reactive
nucleophile−electrophile pair by hydrogen transfer from an
alcohol to alkene bears some similarity to elegant chemistry
developed by Krische and co-workers.18
These experiments strongly implicated a mechanism
involving transition-metal-free hydride transfer, but we were
uncertain if this process occurred via an intramolecular or
intermolecular pathway. In order to probe this experimentally,
we set out to perform a double label crossover experiment. To
this end, lactol d3-23 was synthesized and subjected to iridium-
free annulation conditions with an equimolar amount of
nondeuterated lactol 19 (Scheme 6A). This experiment
a
Scheme 5. Reaction Profile for Cyclohexene Synthesis
a
Scheme 6. Double Label Crossover Experiments
a
The extent of deuterium labelling was determined by separating
enone products d3-3v and 3w by preparative TLC followed by
analysis employing a combination of 1H, 2H, and 13C NMR
spectroscopy (see the Supporting Information for details). For all
compounds, the percentage of D incorporation indicated refers to the
amount of D present at each site. (a) Reaction conditions: 1
(1 equiv), d3-23 (1 equiv), 19 (1 equiv), KOH (4 equiv), PhMe
(0.25 M), 115 °C, 24 h. (b) Reaction conditions: 1 (1 equiv), d4-2v
(1 equiv), 2w (1 equiv), KOH (4 equiv), [Ir(cod)Cl]2 (0.5 mol %),
CataCXium A (2 mol %), PhMe (0.25 M), 115 °C, 24 h.
produced isobutyl and methyl substituted cyclohexene
products d3-3v and 3w in yields of 32% and 48%, respectively.
These cyclohexenes were then separated by preparative TLC,
and the degree of deuteration was analyzed by a combination
a
(a) Reaction conditions: 1 (1 equiv), 19 (2 equiv), KOH (4 equiv),
PhMe (0.25 M), 115 °C, 24 h. Yields of 1, 21, and 3w were
determined by analyzing aliquots by reverse phase HPLC vs
hexamethylbenzene.
of H, H, and 13C NMR spectroscopy (see the Supporting
Information for details). This revealed >95% deuterium
incorporation at both the C2 and C6 positions of cyclohexene
d3-3v and <5% deuterium incorporation at the analogous
positions in 3w. The absence of any crossover of the deuterium
label between these products led us to the unambiguous
conclusion that the key step proceeds via an intramolecular
hydride shift.
1
2
discovered that, within the first 30 min of the reaction,
pentamethylacetophenone 1 is rapidly consumed and con-
verted to pyran 21. This intermediate is then itself gradually
consumed along with concomitant formation of the corre-
sponding cyclic enone product 3w. In this case, we observed
no evolution of H2 gas which suggests that the process is
overall redox-neutral and confirms the key role played by the
iridium catalyst in promoting acceptorless dehydrogenation of
the diol. Overall, this data led us to propose a mechanism in
which lactol 19 opens to form hydroxyaldehyde 18 and then
undergoes rapid (and reversible) aldol condensation to form
acyclic enone 20. This species is then reversibly captured via
oxa-Michael addition to form pyran 21 which is observed as an
isolable intermediate. The key step would be a hydride transfer
to form intermediate 25, which would undergo facile
intramolecular aldol condensation to afford the acyl-cyclo-
In order to confirm our hypothesis that the same process
occurs in the iridium catalyzed formation of cyclohexenes from
diols, we synthesized tetra-deuterated diol d4-2v and carried
out an analogous crossover experiment with a stoichiometric
quantity of unlabeled diol 2w (Scheme 6B). Under our
standard conditions for iridium catalyzed annulation, we
isolated a mixture of cyclohexenes d3-3v and 3w in yields of
26% and 51%, respectively. Separation and analysis of these
products again revealed that d3-3v was fully deuterated at the
C2 and C6 positions (>95%) and 3w contained no deuterium.
This result strongly suggests that the intramolecular hydride
shift is also a key step of the iridium mediated annulation
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process. The lack of crossover of the deuterium label also
implies that under these conditions oxidation of the diol to the
hydroxyaldehyde is an irreversible process.
Dimethyl substituted cyclohexane d3-26 was isolated with
1.75:0.25 D/H at the C6-position whereas the C2 position
contained much more deuterium (1.05:0.95 D/H). On the
basis of these results, we concluded that the hydride-shift
cascade process is the predominant mechanism in the
reductive annulation reaction.19 To support this result, we
independently synthesized triply deuterated enone d3-3af,
which is the proposed intermediate following the hydride shift
and resubjected it to identical conditions with a mixture of d4-
2af and 2as (Scheme 7B). Under these conditions, clean
transfer hydrogenation was observed to form cyclohexane d3-
26 in 92% yield. The pattern of deuterium incorporation was
very similar to that observed in the hydrogen borrowing
reaction, which supports the hypothesis that acyl-cyclohexene
d3-3af is the key intermediate involved in the hydrogen
borrowing crossover experiment.
These results led us to question whether this newly
identified intramolecular hydride shift-aldol cascade mecha-
nism could also be operative in related hydrogen borrowing
annulations reported by our group8a−c and others8d for the
synthesis of cyclohexanes. To test this theory, we carried out a
related double label crossover experiment with unsymmetrical
diols d4-2af and 2as, but this time at higher concentration and
in the presence of 2 mol % [Cp*IrCl2]2(conditions from Table
1, entry 1). As anticipated, under these originally published
and more reducing conditions, no cyclohexene products were
observed and the only products isolated were cyclohexanes d3-
26 and 27 in yields of 35% and 52%, respectively (Scheme
7A). To understand the mechanism of the process, we studied
Overall, these mechanistic experiments have led us to a
unified mechanistic picture for both cyclohexene and cyclo-
hexane forming annulation processes, which is summarized in
Scheme 8. Both reactions are initiated by iridium mediated
Scheme 7. Double Label Crossover Experiment to
Investigate Cyclohexane Formation with [Cp*IrCl2]2
a
Scheme 8. Revised Unified Mechanism for Iridium
Mediated Synthesis of Cyclohexenes and Cyclohexanes
a
a
The extent of deuterium labelling was determined by separating
cyclohexane products d3-26 and 27 by column chromatography
followed by analysis employing a combination of H, H, and 13C
NMR spectroscopy (see the Supporting Information for details). For
starting materials d4-2af and d3-3af, the percentage of D incorporation
indicated refers to the amount of D present at each site; for the
products each site is listed individually. (a) Reaction conditions: 1
(1 equiv), d4-2af (1 equiv), 2as (1 equiv), KOH (4 equiv),
[Cp*IrCl2]2 (2 mol %), PhMe (4 M), 115 °C, 24 h. (b) Reaction
conditions: d3-3af (1 equiv), d4-2af (1 equiv), 2as (1 equiv), KOH (4
equiv), [Cp*IrCl2]2 (2 mol %), PhMe (4 M), 115 °C, 24 h.
1
2
a
AD = acceptorless dehydrogenation.
oxidation of the diol starting material to the corresponding
hydroxyaldehyde which then undergoes aldol condensation
with Ph*COMe to form an alkoxy enone. This intermediate
then undergoes a novel cascade involving an intramolecular
[1,5]-hydride shift followed by aldol condensation to form the
corresponding cyclohexene. Although [1,5]-hydride shifts
involving alkoxide C−H donors are rare,20 analogous shifts
from the corresponding ethers and amines to enones have
been reported by several groups.21 In the presence of an Ir(III)
catalyst, the cyclohexene can be reduced to the corresponding
cyclohexane product regenerating the active iridium catalyst
(Scheme 8, green). Alternatively, with an Ir(I) catalyst along
with a bulky CataCXium ligand, iridium hydride is recycled by
protonation, releasing H2 and enabling the isolation of the
valuable acyl cyclohexene products (Scheme 8, blue).
the deuterium incorporation pattern in these reduced products.
We have previously established that, under identical reaction
conditions, deuterium is extensively “washed out” by exchange
of Ir−D with protic species in the reaction mixture, such that
the amount of deuterium introduced at the β-position during
iridium catalyzed reduction is typically very small.8b Con-
sequently, a mechanism involving two separate cycles of
hydrogen borrowing would be expected to introduce one
hydrogen at the C6 position and one hydrogen at the C2
position. Conversely, if the hydride shift cascade pathway is
operative, only one final reduction by Ir−H would be involved
and we would therefore anticipate no H incorporation at the
C6 position and incorporation of one H at the C2 position.
When we analyzed the distribution of deuterium in the
cyclohexane products, we found that, as expected, substituted
cyclohexane 27 contained essentially no deuterium label.
3. CONCLUSIONS
Synthesis of the cyclohexyl motif is of paramount importance
in the preparation of naturally occurring and biologically
relevant molecules. We have developed a new intermolecular
(5 + 1) strategy for cyclohexene synthesis utilizing readily
accessible and commercially available 1,5-diols along with
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pentamethylacetophenone. This method provides straightfor-
ward access to a wide range of highly functionalized
cyclohexenes with high levels of regiocontrol. It was also
demonstrated that enantiopure γ-substituted diols can undergo
annulation to afford C4-substituted cyclohexenes with no loss
of stereochemical integrity. The Ph* containing acyl-cyclo-
hexene products can be diversified into a wide range of
carbonyl derivatives under mildly acidic conditions. Based on a
series of mechanistic experiments, it was found that the
reaction proceeded via catalyst controlled acceptorless
dehydrogenation followed by an intramolecular cascade
involving a sequential [1,5]-hydride shift followed by aldol
condensation. Moreover, we have discovered that a similar
intramolecular [1,5]-hydride shift is embedded within our
previously reported cyclohexane synthesis, leading us to revise
our originally proposed mechanistic hypothesis. We anticipate
that this chemistry will find widespread application in the
synthesis of valuable acyl-cyclohexenes.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.9b12296.
■
sı
Detailed experimental procedures and characterization
data for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
Timothy J. Donohoe − Chemistry Research Laboratory,
University of Oxford, Oxford OX1 3TA, United Kingdom;
orcid.org/0000-0001-7088-6626;
́
■
(6) (a) Frost, J. R.; Cheong, C. B.; Akhtar, W. M.; Caputo, D. F. J.;
Stevenson, N. G.; Donohoe, T. J. Strategic Application and
Transformation of Ortho-Disubstituted Phenyl and Cyclopropyl
Ketones To Expand the Scope of Hydrogen Borrowing Catalysis. J.
Am. Chem. Soc. 2015, 137 (50), 15664−15667. (b) Akhtar, W. M.;
Cheong, C. B.; Frost, J. R.; Christensen, K. E.; Stevenson, N. G.;
Donohoe, T. J. Hydrogen Borrowing Catalysis with Secondary
Alcohols: A New Route for the Generation of β-Branched Carbonyl
Compounds. J. Am. Chem. Soc. 2017, 139 (7), 2577−2580.
Email: timothy.donohoe@chem.ox.ac.uk
Authors
Lewis B. Smith − Chemistry Research Laboratory, University of
Oxford, Oxford OX1 3TA, United Kingdom
Roly J. Armstrong − Chemistry Research Laboratory, University
of Oxford, Oxford OX1 3TA, United Kingdom; orcid.org/
0000-0002-3759-061X
Daniel Matheau-Raven − Chemistry Research Laboratory,
University of Oxford, Oxford OX1 3TA, United Kingdom
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Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.9b12296
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
L.B.S. and D.M.-R. are grateful to the EPSRC Centre for
Doctoral Training in Synthesis for Biology and Medicine (EP/
L015838/1) for a studentship, generously supported by
AstraZeneca, Diamond Light Source, Defence Science and
Technology Laboratory, Evotec, GlaxoSmithKline, Janssen,
Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex. We
thank the EPSRC [R.J.A., and T.J.D., Established Career
Fellowship (EP/L023121/1)] for financial support. R.J.A is
also grateful to University College, Oxford for a Junior
Research Fellowship. We are grateful to Dr. Tugce Ayvali, Dr.
Jianwei Zheng, and Prof. Edman Tsang for help with GC-TCD
measurements. We also thank Prof. Tim Claridge and Dr.
Nader Amin (University of Oxford) and Dr. Alex Smith
(Syngenta) for helpful discussions.
H
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acid 11.
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