Controlling the selectivity and efficiency of the hydrogen borrowing reaction by switching between rhodium and iridium catalysts

Article abstract of DOI:10.1039/c9dt02819f

The catalytic alkylation of ketones with alcohols via the hydrogen borrowing methodology (HB) has the potential to be a highly efficient approach for forming new carbon-carbon bonds. However, this transformation can result in more than one product being formed. The work reported here utilises bidentate triazole-carbene ligated iridium and rhodium complexes as catalysts for the selective formation of alkylated ketone or alcohol products. Switching from an iridium centre to a rhodium centre in the complex resulted in significant changes in product selectivity. Other factors-base, base loading, solvent and reaction temperature-were also investigated to tune the selectivity further. The optimised conditions were used to demonstrate the scope of the reaction across 17 ketones and 14 alcohols containing a variety of functional groups. A series of mechanistic investigations were performed to probe the reasons behind the product selectivity, including kinetic and deuterium studies.

Full text of DOI:10.1039/c9dt02819f

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DOI: 10.1039/C9DT02819F
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ARTICLE
Controlling the Selectivity and Efficiency of the
Hydrogen Borrowing Reaction by Switching
Between Rhodium and Iridium Catalysts
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Danfeng Wang, Roy T. McBurney, Indrek Pernik* and Barbara A. Messerle*
The catalytic alkylation of ketones with alcohols via the hydrogen borrowing methodology (HB) has the potential to be a
highly efficient approach for forming new carbon-carbon bonds. However, this transformation can result in more than one
product being formed. The work reported here utilises bidentate triazole-carbene ligated iridium and rhodium complexes
as catalysts for the selective formation of alkylated ketone or alcohol products. Switching from an iridium centre to a
rhodium centre in the complex resulted in significant changes in product selectivity. Other factors – base, base loading,
solvent and reaction temperature – were also investigated to tune the selectivity further. The optimised conditions were
used to demonstrate the scope of the reaction across 17 ketones and 14 alcohols containing a variety of functional groups.
A series of mechanistic investigations were performed to probe the reasons behind the product selectivity, including kinetic
and deuterium studies.
Recently, Gülcemal and co-workers reported an iridium based
system allowing for catalyst loadings as low as 0.05 mol% and
Introduction
Methodologies for promoting carbon-carbon bond formation
play a key role in the area of organic synthesis, including
pharmaceutical, agrochemical, natural product and other fine
chemical synthesis processes. While a number of methods
exist, the use of mutagenic alkyl halides as the alkylating agent
has a strong presence, leading to the formation of problematic
-1 31
TOF values of >900 h . However, a number of these
approaches still suffer from high catalyst or base loadings, high
reaction temperatures or in particular, poor product selectivity.
For this catalytic C-C bond forming transformation the
particularly challenging problems arise from the product
selectivity, as during this HB process two different products can
readily form; alkylated ketone and alkylated alcohol.7
1, 2
, 32
3-5
toxic waste, thus limiting sustainable applications.
In
alternative approaches, substantial efforts have been made to
achieve C-C bond formation in a more effective, and sustainable
manner for example C-C bond formation via catalytic cross-
6
coupling reactions. Another such C-C bond forming approach is
the hydrogen borrowing (HB) reaction which is a highly efficient,
low cost and eco-friendly approach with water being the only
side-product formed. Thanks to these aspects, HB has seen
1, 7-14
increased interest over the past decade.
This work, in particular, is concentrated on utilising the HB
approach for the alkylation of ketones with alcohols to form
new C-C bonds. The alkylation of ketones has been reported
1
5, 16
under transition metal free conditions
and also promoted
7
by a number of different metal containing catalysts, including
Scheme 1. Previous work by Messerle and co-workers indicated that the
analogous Rh and Ir catalysts can lead to different reactivity for the C-N bond
forming hydrogen borrowing reaction. This work investigates the use of Rh and Ir
complexes for product selectivity in C-C bond forming hydrogen borrowing
Mn,1 Ru, Os, Pd,
7-19
20
8
21-23
Rh,
24, 25
Fe,
26, 27
Co,
28, 29
Ni, and Ir.
30
31
– –
3 4 3 6 3 4 2
, Y = [BPh ] or [B(3,5-CF -C H ) ] . H O is formed in all cases
reaction. X = H or CF
as a side-product.
Department of Molecular Sciences, Macquarie University, North Ryde, NSW,
Australia, 2109,
E-mail: barbara.messerle@mq.edu.au, indrek.pernik@mq.edu.au † Footnotes
relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Recently we reported a HB strategy for synthesising C-N
bonds through coupling alcohols and amines (Scheme 1,
Previous work). It was found that upon comparing the
33
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catalysis results when using rhodium or iridium complexes as ketone and alcohol products during the HB transformation by
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DOI: 10.1039/C9DT02819F
the catalysts, in some instances substantially different catalytic simply changing the metal centre of the complex used as the
3
4
activity was observed. Based on these previous results, we catalyst. In addition, other aspects of the reaction set-up were
were interested to investigate whether this difference in evaluated.
activity can be advantageous in product selectivity for the C-C
bond formation and thus allow us to achieve control over the
nature of the product formed (Scheme 1, This work).
Results and Discussion
The general mechanism for the HB mediated alkylation
reaction that leads to the formation of C-C bonds relies on three
main steps (Scheme 2). In the first step the alcohol reagent is
oxidised to an aldehyde by the synergistic cooperation of metal
catalyst and base. This can be seen as the hydrogen being
captured or “borrowed” (i.e. dehydrogenation) from the alcohol
to form the corresponding aldehyde. Next via the aldol
condensation step the aldehyde forms a C−C bond with a
nucleophilic enolate generated from the ketone in the presence
of base. In the final step the unsaturated enol intermediate
undergoes the hydrogen “returning” process (i.e.
hydrogenation) resulting in the alkylated product which can be
an alcohol or a ketone.
Initial study of the benchmark reaction using Ir and Rh catalysts.
The rhodium(I) and iridium(III) triazole-carbene complexes used
in this investigation were designed based on the successful
results obtained for the C-N bond forming HB reaction via the
coupling of primary alcohols and amines (Scheme 1, Previous
33, 34
work).
The benchmark reaction for the C-C bond formation
work undertaken here was conducted with acetophenone (1a
and benzyl alcohol (2a) as the substrates (Scheme 3).
)
Scheme 3. Benchmark reaction for the hydrogen borrowing reaction using
acetophenone (1a) and benzyl alcohol (2a) as the substrates and iridium and
F
rhodium complexes (Ir-1
–
Ir-4
,
Rh-1
–
Rh-3) as catalysts. Ar
4
= 3,5-CF
3
-C
6
H
3
.
t
Toluene as solvent (1.0 mL). Substrates in 1:1 ratio (0.5 mmol). 0.5 mmol of KO Bu.
In addition water is formed as a side-product.
The benchmark reaction was probed using four iridium- and
three rhodium complexes with varied catalyst parameters
Scheme 2. General mechanistic pathway for coupling ketones with alcohols using including oxidation state, co-ligands, ligand design and counter-
the hydrogen borrowing methodology to form new ketone and alcohol products.
MPV = Meerwein-Ponndorf-Verley pathway.
ion (complexes Ir-1
– Ir-4 and Rh-1 – Rh-3, Scheme 3). All iridium
and rhodium catalysts led to 100% consumption of starting
In addition to the synergistic transition metal and base materials (1a and 2a) within the 18 h reaction but with
mediated HB processes, the formation of the alkylated ketone substantially different product selectivity (Table 1). Iridium
and alcohol products can also be promoted by the presence of catalysts displayed significant preference for the alkylated
1
5, 16
an alkali base alone.
the reaction mixture can open the Oppenauer pathway to the alkylated alcohol product 1,3-diphenylpropan-1-ol
oxidation of the alcohols to form carbonyls and the Meerwein-
3aa 4aa ratio of >7:1 for iridium(I) complexes, and 4:1 for the
Ponndorf-Verley (MPV) pathway leading to the reduction of iridium(III) complex, Table 3, Entry 1-4). Under the same
Furthermore, the presence of a base in ketone product 1,3-diphenylpropan-1-one (3aa) over the
(
4aa
)
(
:
16, 35
carbonyls to the corresponding alcohols.
reactions can significantly impact the product selectivity.
These side reaction conditions, the rhodium catalysts yielded 3aa and 4aa
36
at much lower preferences (3aa:4aa ratio of 2.6:1 for the
The development of a catalyst that can control the product rhodium(III) complex, and <1.3:1 in the case of rhodium(I)
selectivity, even with the base present in the reaction mixture, complexes, table 3, Entry 5-7). For all catalysts in addition to 3aa
is crucial. Such control could be highly significant for both, and 4aa, small quantities (<5%) of 1-phenylethan-1-ol (5a) and
environment and industry, as using the most effective catalyst very small amounts of benzaldehyde were observed during the
would substantially reduce the production cost, the waste reaction. Both of these additional species were expected to
formed and increase the overall viability of the process. form reversibly via either the HB or the MPV/Oppenauer
16, 35, 36
Therefore, within this work we investigated the extent to which pathways.
we can affect the product selectivity between the formation of
2
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When the reaction was carried out with no metal complex substantial change was observed. When the catalyst loading
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t
DOI: 10.1039/C9DT02819F
in the reaction mixture, but with base (KO Bu) still present, only was dropped to 0.5, 0.1 or even 0.05 mol%, the major product
6% of the starting materials was consumed, and the product formed during the reaction was still 3aa (for 0.05 mol% loading
ratio of 1.4:1 (3aa 4aa) was obtained, indicating only a slight of Ir-3; 82%, 1640 turnovers). Only when the catalyst loading
7
:
preference for the ketone product (Table 3, Entry 8). This was reduced to 0.005 mol%, a substantial drop in the selectivity
matches the “base only” work reported by Xu et. al. where towards the formation of 3aa resulted (59%), with 4aa as the
16
similar yield and selectivity were seen for these substrates.
major side product (38%). This product ratio was similar to that
The control reaction with no base in the mixture led to no achieved using base only (Table 1, Entry 8), indicating that the
conversion to products (Table 3, Entry 9). Similarly, no products limit of the base to catalyst ratio was breached, and the product
formed when no iridium and no base were added to the selectivity gain from the catalyst was lost. When both, the
reaction mixture (Table 3, Entry 10).
catalyst loading and the base loading were lowered (0.005 mol%
Ir-3, 0.5 mol% KO Bu), while keeping their relative ratio constant
with respect to the 1.0 mol% catalyst loading reaction
conditions, no product formed.
t
Table 1. Comparison of different rhodium and iridium complexes as catalyst for the
benchmark reaction depicted in Scheme 3.
The base loading was evaluated at 1.0 mol% catalyst
loading. The use of 0.5-1.0 molar equivalents of KO Bu to
Consumption
Conversion / %
Entry
Catalyst
Base
3aa : 4aa
t
of 2a / %
3aa
4aa
5a
substrate resulted in >15:1 selectivity for the formation of 3aa
1
2
3
4
5
6
7
8
9
Ir-1
Ir-2
Ir-3
Ir-4
Rh-1
Rh-2
Rh-3
-
100
100
100
100
100
100
100
76
91
85
95
80
70
53
47
40
-
9
13
4
-
10 : 1
7 : 1
24 : 1
4 : 1
2.6 : 1
1.3 : 1
1 : 1
1.4 : 1
-
2
1
1
3
5
4
6
-
in all cases, whereas increasing the base loading to 1.5 molar
t
KO Bu
t
equivalents of KO Bu led to 10:1 selectivity towards 3aa. A series
19
27
42
49
29
-
of different bases were screened. Analogous results were
obtained when using KOH, while other bases led to lower yields
and reduced selectivity (Table S1). 100 °C was found to be
optimal for high conversions (Table S1). In addition, the reaction
time was evaluated. The kinetic studies showed that the
reaction reached completion in 6 hours.
t
KO Bu
t
KO Bu
Ir-1
-
-
-
0
10
0
-
-
-
-
t
Substrate scope for ketone formation. Using the catalyst (Ir-3)
Reaction conditions: 1a and 2a in 1:1 ratio (1.0 mmol), with 1.0 molar equivalent of KO Bu
as the base and 1.0 mol% catalyst loading. 100 °C for 18 h. Toluene as solvent (1.0 mL). and the conditions that led to high selectivity towards the
1
Conversion measured by H NMR spectral analysis
ketone product formation, the substrate scope of this reaction
was evaluated. The first set of reactions was carried out
between benzyl alcohol (2a) and a variety of ketone substrates
The best product selectivity towards the alkylated ketone
product 3aa (24:1 ratio of 3aa:4aa) was observed using the
iridium(I) complex Ir-3 as the catalyst and therefore the
(1a
-
q) (Scheme 4).
subsequent reaction condition screening for the formation of
3
aa was conducted using Ir-3 as the catalyst.
Figure 1. The effect of catalyst loading to the product ratio of 3aa and 4aa
.
Reaction conditions: 1a and 2a in 1:1 ratio (1.0 mmol), with 1.0 molar equivalent
t
of KO Bu as the base (1.0 mmol) and Ir-3 as the catalyst. 100 °C for 18 h. Toluene
as solvent (1.0 mL). The equivalent comparisons for all other catalysts are in the
Supporting Information section S1.5.
As both the transition metal catalyst and the base can
affect the product selectivity of this HB reaction, the ratio of Ir-
t
3
to KO Bu was investigated. The benchmark reaction (Scheme
3
) was conducted using Ir-3 as the catalyst at different loadings,
t
while the base (KO Bu) loading was kept at 1.0 molar equivalent
a
t
Scheme 4. Conditions:
1 (0.5 mmol), 2 (0.5 mmol), Ir-3 (1.0 mol %), KO Bu (0.5-
(
to substrate) (Figure 1). When the catalyst loading was
0
.8 equiv.), toluene (1.0 mL) at 100 °C for 6 h. Isolated yields of the ketones are
b
t
c
t
given. 0.8 equiv of KO Bu was employed 0.5 equiv of KO Bu was employed.
increased from the initial 1.0 mol% to 2.0 or 5.0 mol%, no
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d
1
Conversion measured by H NMR spectral analysis of crude product mixture using
,1,2,2-tetrachloroethane (TCE) as the internal standard.
1
Substituted benzyl alcohols were all readily con
corresponding ketones (3ab – ah) in good yields (77-88%), with
V
v
ie
e
w
rt
A
e
rt
d
icletoOn
the
line
DOI: 10.1039/C9DT02819F
The coupling between benzyl alcohol and the ketone the exception of 4-nitrobenzylalcohol 2i, which led to catalyst
substrates with electron-donating groups resulted in good to decomposition, similar to what had been observed for the other
excellent isolated yields (3aa
to 92%. The one exception was 3ga for which a lower yield to 3). Heterocycle containing substrates (2j
–
3fa and 3ka) ranging from 71% nitro-substituted reagent, 4-nitroacetophenone (cf. 1q, Scheme
2l) resulted in the
–
the ketone product was observed (63%) with the corresponding desired products in good yields (62-87%). In the case of 3ak, the
alcohol product as the main other species, and less than 5% of major side-product was the corresponding alcohol product.
the starting materials remaining. This could be attributed to the Aliphatic substrates of either cyclic (2m
– n) or non-cyclic
additional steric bulk near the reactive site. In contrast, the alcohols (2o) proved to be challenging and led to the formation
ketone substrates bearing electron-withdrawing groups at the of products in low to moderate yields (12-63%). The
para-position led to a slight drop in the yield of the ketone transformation of cyclopropylmethanol (2m) resulted in the
product (3ha
–
3ia), and in the case of meta-bromo substituted formation of a mixture of products. The best conversion to the
1
1
j
the isolated yield was only 57% (with the alkylated alcohol desired ketone (12% H NMR spectral yield) was obtained upon
t
product formed as the main side product). When the aliphatic using 0.2 molar equivalents of KO Bu, with the unreacted
ketone was used as a starting material, only traces of the starting materials remaining as the major species at the end of
product 3la were observed, whereas, the incorporation of a the reaction. In the case of 3an and 3ao, the major side-
phenyl ring to the starting material structure (1p), resulted in products were the corresponding alcohols.
slightly higher conversion to the desired ketone (3pa), with the
unreacted starting materials as the main species at the end of Catalyst and reaction conditions screening for forming alcohols. As
the reaction. Unprotected cyclohexanone 1m was double the HB protocol can lead to two different products – alkylated
alkylated in good yield. Interestingly, in this example no mono- ketones (
alkylated ketone product formation was observed. The 1- substrates are used (
3
) or alcohols (
4
) (Scheme 1) even when the same
) – we were curious to investigate
37
1
and 2
tetralone substrate 1n was successfully alkylated in excellent whether we can also selectively promote the alcohol (
4)
yield (85%), and the more conjugated ketone 1o bearing a formation over the ketone ( ). Based on the initial catalyst
3
naphthalene skeleton resulted in a 75% yield. The para-nitro- comparisons (Table 1), the best relative ratio for the formation
substituted ketone 1q led to no product formation, likely due to of the alcohol product 4aa was obtained when using the
catalyst decomposition indicated by dark particles precipitating rhodium(I) complexes Rh-2 or Rh-3 as the catalyst (ca. 1:1
during the reaction process.
“selectivity” for 3aa:4aa). Despite the Rh-3 catalyst displaying
In the second set of the scope evaluation for the formation slightly higher selectivity towards the ketone product 3aa, the
of the ketone product, a series of alcohol substrates (2b-o) were ease of synthesis of Rh-2 compared to Rh-3 outweighs this and
investigated as starting materials in
a
reaction with further testing was carried out using Rh-2 as the catalyst.
acetophenone (1a) (Scheme 4).
Scheme 6. Hydrogen borrowing reaction with the amount of the alcohol substrate
2a varied between 1.0 and 2.0 molar equivalents. The relative amount of 1a was
fixed to 1.0 molar equivalent in both reactions. Toluene as solvent. In addition
water is formed as a side-product.
Although the rhodium complexes led to higher selectivity
towards the alcohol product than the iridium catalysts, the
selectivity was still limited (Table 1). This was rationalised by the
need for two “extra” H atoms to form the alcohol product.16 To
overcome this limitation, additional alcohol was introduced to
the system by using an excess of the alcohol substrate (two
molar equivalents of 2a, Scheme 6). This change resulted in a
substantially higher conversion to the desired alkylated alcohol
product. The direct comparison of the substrate ratio, using Rh-
2
as the catalyst, demonstrated that one molar equivalent of 2a
to 1a) resulted in 1.3 to 1 ratio of ketone to alcohol products
1 (0.5 mmol), 2
(0.5 mmol), Ir-3 (1 mol %), KO Bu (0.5-0.8 3aa and 4aa, whereas two molar equivalents of 2a led to a
(
a
t
Scheme 5. Conditions:
equiv.), toluene (1.0 mL) at 100 °C for 6 h. Isolated yields of the ketones are given.
b
t
c
t
d
0
.8 equiv of KO Bu was employed. 0.5 equiv of KO Bu was employed. 0.2 equiv significant improvement for the alcohol product selectivity with
t
e
1
of KO Bu was employed. Conversion measured by H NMR spectral analysis of the
crude product mixture using 1,1,2,2-tetrachloroethane (TCE) as the internal 1 to 13.3 ratio of 3aa to 4aa (Scheme 6).
standard.
To confirm that this selectivity towards the alcohol product
was not solely due to the increased alcohol presence (2.0
4
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Journal Name
equivalence), the iridium catalyst Ir-3 that was previously (Scheme 7, 4aa
ARTICLE
,
4ba
,
4ab and 4ag). Interestingly, the
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employed for selective ketone formation was evaluated under brominated ketone 4ia was an excepDtiOoIn: ,10.w10i3th9/Co9nDlTy0238719%F
the conditions employing the higher alcohol equivalence. When conversion seen after 18 hours. In the case of both halogenated
the iridium(III) complex Ir-3 was used as a catalyst, the alcohol species (4ia and 4ag) the main other product formed was the
product (4aa) was still formed as a major product, but the ketone product, indicating that the substrate can also have an
selectivity was lower by approximately a factor of 3, compared effect on the product selectivity. This relative preference for the
to that seen upon using the rhodium(I) complexes (Table 2, ketone product can also be seen by the good conversions
Entries 8 and 9). This result confirms the initial hypothesis that observed in Schemes 4 and 5. The biologically relevant
the difference in the catalysis activity seen when comparing piperonyl alcohol proved to be a suitable substrate leading to
34
rhodium and iridium for the C-N bond formation via HB could the formation of 4al in a 95% conversion. A relatively high
be used as a basis for achieving different product selectivity for boiling aliphatic alcohol decanol allowed for a good conversion
forming C-C bonds.
to the corresponding product, resulting in 77% conversion to
ao. In most cases, a reaction time of 6 hours was also found to
be sufficient to obtain the same conversions as seen after 18
hours (Scheme 7). In all cases no remaining traces of substrate
4
Table 2. Screening of the catalysts and reaction conditions for the selective formation of
the alcohol product 4aa.
2
a /
Base
Base
equiv
Temp
/ °C
Conversion / %
Entry
Catalyst
3aa : 4aa
equiv
3aa
4aa
42
92
90
64
84
91
92
82
84
5a
1 were observed at the end of the reaction.
t
1
2
3
4
5
6
7
8
9
Rh-2
Rh-2
Rh-2
Rh-2
Rh-2
Rh-2
Rh-2
Ir-3
1.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
KO Bu
1.0
1.0
2.0
0.8
1.0
2.0
2.0
2.0
2.0
100
100
100
100
100
100
120
100
120
53
7
5
-
1.3 : 1
1 : 13.3
1 : 9
t
KO Bu
t
KO Bu
10
36
11
6
-
t
KO Bu
-
1 : 1.8
1 : 7.6
1 : 15.2
1 : 11.5
1 : 4.6
1 : 5.3
KOH
KOH
KOH
5
3
-
8
t
KO Bu
18
16
-
Ir-3
KOH
-
Reaction conditions: 1a and 2a in 1:1 molar ratio, catalyst (1.0 mol %), base and toluene-
(0.5 mL) were placed to the 4 mL glass vial sealed with PTFE cap. Preparations were
operated under air. The reactions were stirred at 100 °C for 18 h. bDetermined by 1
d
8
H
NMR spectral analysis of crude product mixture using 1,1,2,2-tetrachloroethane (TCE) as
the internal standard.
The reaction conditions to promote the alcohol production
as the main product were further screened using Rh-2 as the
t
catalyst (Table 2, Entries 3-7). By changing the base (KO Bu) Scheme 7. Scope study of coupling various methylene ketones (
1
) with primary
a
alcohols (2) for alkylated alcohols (4). Conditions: 1 (0.5 mmol), 2 (1 mmol), Rh-2
loading from 1.0 to 2.0 molar equivalents relative to 1a, a small (1 mol %), KOH (2.0 equiv), toluene (1.0 mL) at 120 °C for 18 h. Conversions based
4aa product ratio of 1:9), 18 h. Conversions measured by H NMR spectral analysis of crude product
whereas when the base loading was dropped to the level spectral data after 6h : 4aa (94%), 4ba (85%), 4ia (36%), 4ab (97%), 4ag (63%), 4al
1
b
1
on H NMR spectral data are given. Isolated yields of the alcohols are given after
c
drop in selectivity was observed (3aa
:
1
mixture using 1,1,2,2-tetrachloroethane (TCE) as the internal standard. H NMR
a
(
93%) and 4ao (84%).
suitable for ketone formation (0.8 molar equivalents relative to
1
a
), product selectivity dropped to a 3aa
:4aa product ratio of
1
:1.8. Similarly to what had been observed during the ketone
Mechanistic investigations
formation screening results, KOH was also found to be a suitable
base for these transformations. With one equivalent of KOH
added, a product ratio of 1 to 7.6 (3aa
upon comparing KO Bu and KOH a different trend was observed
and the increase of the base loading to two equivalents of KOH
led to increased selectivity towards the alcohol product (1:15.2
of 3aa:4aa). In both cases when using KOH as the base, small
amounts of 1-phenylethan-1-ol (5a) (≤5 %) formed. The use of
KOH did allow for simpler reaction work-up and H NMR spectra
interpretation.
The mechanistic investigation was conducted based on our
3
3
previous HB work on the C-N bond formation and the recently
reported fundamental computational studies using density
:
4aa) was seen. However,
t
38-40
functional theory (DFT).
In particular, the following aspects
were probed: (1) understanding the origin of the selectivity
between the formation of alkylated ketone and alcohol
products, (2) understanding the roles of the base and the metal
catalyst in the catalytic process, and (3) understanding the
formation and the fate of the reaction intermediates during the
1
1
catalysis. To this end, an NMR study was conducted using H
The substrate scope study for the formation of the alcohol
2
NMR, H NMR and in situ NMR spectroscopy.
product (
of the substrates
4
) was carried out using Rh-2 as the catalyst, 1:2 ratio
and
1
2
, 2.0 molar equivalents of KOH, 120 °C Kinetic study. The reaction between 1a and 2a was monitored
and toluene as the solvent. For assessing the scope of the over time to probe the relative product ratios at different time
reaction, a representative set of ketone and alcohol substrates points. This was carried out using three different reaction set-
was used. Typical electron-donating and electron-withdrawing ups: a) no transition metal catalyst, b) a rhodium catalyst (Rh-2
groups of both substrates resulted in moderate to good yields and c) an iridium catalyst (Ir-3) present in the reaction mixture.
)
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Journal Name
In all cases the substrates 1a and 2a were used in 1:2 ratio to conversion of 3aa to 4aa (see Supporting Information, section
View Article Online
DOI: 10.1039/C9DT02819F
promote the formation of both products (3aa and 4aa), one S1.6).
molar equivalent of KO Bu in toluene at 100 °C (Figure 2).
t
As the presence of base can lead to the interchange of the
Under all three reaction conditions (Figure 2a-c) the same formed products 3aa and 4aa (cf. MPV-O reactions), and we saw
three main products (3aa 4aa and 5a) formed during the changes in the product ratios during the HB reaction (Figure 2),
,
catalytic transformation, however, some clear trends were we were intrigued to understand the stability of the alkylated
observed. While the reaction with no transition metal catalyst products once they formed. For this 3aa was used as the
in the mixture gradually led to the production of both coupling starting material under three sets of reaction conditions; i) Ir-3
,
products (3aa and 4aa), both transition metal containing ii) Rh-2 and iii) no transition metal catalyst present in the
reactions resulted in the fast initial formation of 3aa (within the reaction mixture. All three reaction conditions were tested
t
first 30 minutes), which was consumed over time – presumably using both bases KO Bu and KOH, and the alcohol substrate
converted to 4aa. Interestingly, during the 6 hour reaction, Rh- quantity was modified (no 2a vs. one molar equivalent of 2a
led to the full consumption of 3aa, whereas Ir-3 resulted in Table 3).
,
2
the formation of a mixture of both products. In addition to the
formation of the two coupling products, the reversible
formation of the secondary alcohol 5a was also observed in all
cases. After 6 hours, the reaction was effectively complete, with
no significant change in the product ratios seen after 24 hours.
In addition to the mentioned species forming, traces of benzyl
Table 3 Cross experiments of reactions using 3aa as the starting material.
1
Conversion to 4aa / %
aldehyde were observed in the H NMR spectra.
Ir-3a
36
n.r.
62
Rh-2b
62
n.r.
61
N/Ac
13
n.r.
29
t
KO Bu
t
KO Bu (no 2a)
KOH
KOH (no 2a)
n.r.
n.r.
n.r.
Reaction conditions: Only other product in the mixtures is the starting 3aa (and 2a when
a
added). n.r. = no reaction. 1.0 equiv. of 3aa, 1.0 equiv. of 2a, 1.0 mol% Ir-3, 0.8 equiv.
t
o
b
of KO Bu/2.0 equiv. of KOH, 100 C, 18 h, 1.0 equiv. of 3aa, 1.0 equiv. of 2a, 1.0 mol%
t
o
c
t
o
Rh-2, 0.8 equiv. of KO Bu/2.0 equiv. of KOH, 120 C, 18 h. for KO Bu at 100 C 18 h, for
KOH, 120 C, 18 h. 1,1,2,2-tetrachloroethane (TCE) was used as the internal standard.
o
When 2a was present in the mixture, 36-62% conversion
from 3aa to the alkylated alcohol (4aa) was observed in the
presence of transition metal catalysts, and 13-29% conversion
under the “base only” conditions, demonstrating that the
exchange between alcohols and carbonyls does not simply
proceed via MPV-O processes. However, the lack of 2a in the
reaction mixture completely halted the conversion of 3aa to 4aa
under all reaction conditions. Evidently, excess alcohol plays an
important role in the formation of the alkylated alcohol
products. This means that any excess alcohol substrate in the
Figure 2. Time course of the hydrogen borrowing reaction using 1a and 2a as the
t
substrates in 1:2 ratio, KO Bu (1 molar equivalent), toluene (1.0 mL) at 100 °C), a)
no transition metal catalyst, b) Rh-2 (1.0 mol %), c) Ir-3 (1.0 mol %). In addition
catalytic mixture can significantly reduce the selectivity for 3aa
while the excess of the alcohol substrate does aid the formation
of 4aa
,
water is formed as a side-product.
.
Besides the different product ratios, a clear difference in the
reaction rates was observed. Both metals promote faster
product formation than the base only, with Ir-3 resulting in
particularly fast initial rate. While this fast initial rate can shed
some light on the difference in product selectivity when
Isotopic labelling experiments. To probe the product selectivity
further, deuterium was introduced to the reaction mixture at
the beginning of the reaction. In particular, we were interested
compared to the base only reaction, we don’t think that the in comparing the outcome of the incorporation of deuterium
enhanced product selectivity is simply due to the transition atoms to understand whether the reaction undergoes two
metal catalyst outrunning the base catalysed reaction, as even mechanisms in parallel – transition metal catalysis and base-
at very low catalyst loading (0.05 mol%) significant product dictated catalysis, or whether a mechanism involving both the
selectivity was still observed (cf. Figure 1).
transition metal catalyst and the base simultaneously was
occurring.
When the reagent ratio was changed to a 1:1 ratio of the
substrates 1a and 2a, reversible formation of 5a was still
observed, however, no conversion of 3aa to other products was
detected, indicating that the limited availability of substrate 2a
(i.e. 1 vs 2 equivalents) in the reaction mixture inhibits the
6
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ARTICLE
Upon reacting benzyl alcohol 2a-Cd
2
and 1a, the iridium and
View Article Online
DOI: 10.1039/C9DT02819F
rhodium catalysts (Ir-3 and Rh-2) led to the formation of the
ketone product 3aa with the deuterium atom mostly
incorporated on the α-carbon regardless of the substrate ratio
used. In the case of the alcohol product (4aa) both reaction
conditions led to the deuterium mainly being incorporated at
the β-carbon and at the tertiary carbon. Small amounts of
deuterium also ended up on the α-carbon, likely due to
2
interactions with the H O in the mixture. When no transition
metal catalyst was present in the reaction mixture, the reaction
did not go to completion after 18 hours, and for both products
2
Scheme 8. Deuterium incorporation from D O into the alcohol product (4aa) and
into the alcohol substrate (2a) with and without the presence Rh-2. The ratio of
1
:2 of 1a to 2a was used. In addition water is formed as a side-product.
As the first test, a very simple reaction was designed –
(3aa and 4aa) the deuterium ended up in the β-position.
deuterated water was added to the reaction mixture. D
2
O can
By changing the alcohol reagent from 2a-Cd to 2a-Od the
opposite trend was observed. Only deuterium scrambling to the
β-carbon of the ketone product 3aa was observed under the
2
1
OD and KOD,4
1,
promote the formation of C H CH OD, C H CD
6 5 2 6 5 2
42
which in turn would allow for the deuterium incorporation
into the reaction products. In addition, the control reaction of ketone formation condition (1a and 2a-Od
adding 25.0 molar equivalents of H
O to the reaction mixture When the higher ratio of 2a-Od was employed (2.0
was tested and this had no effect on the reaction outcome. equivalents), both, Ir-3 and Rh-2 led to the deuterium ending up
Therefore, 25.0 equivalents of D
O was added to different on the α-carbon of the alcohol product 4aa. In addition,
reaction mixtures and the deuterium incorporations were deuterium migration to the CH unit of 2a-Od was observed,
indicating that reversible hydrogen borrowing occurred. These
Information, section S1.7.1). In the case of 1a and 2a as the trends in the deuterium allocations when using 2a-Od as a
substrates in 1:2 ratio and Rh-2 as the catalyst, deuterium was substrate were analogous to the D O addition experiments,
incorporated onto the tertiary carbon of the alcohol product, indicating that in the D O addition experiments, the H/D-
consistent with the HB process (Scheme 1, reversible hydrogen scrambling into the OH group was much faster than into the CH
1
at the ratio of 1:1).
2
1
2
2
1
1
2
inspected by H and H NMR spectroscopy (see Supporting
1
2
2
2
borrowing; Scheme 8, top). Presumably the deuteration of the unit of benzyl alcohol starting substrate. Under the base only
alcohol unit also occurred, but we were not able to observe the conditions, deuterium incorporation was only observed at the
1
2
β-carbon of 3aa when the substrate ratio was 1:1.
OH/D peaks by H or H NMR spectra, likely due to the
interaction with the base in the reaction mixture. When the
Overall, these deuterium reactions once again suggest that
same reaction was carried out without Rh-2, no H/D scrambling the role of the base is significantly altered when there is a
occurred. This verifies the presence of a different mechanism transition metal catalyst (rhodium or iridium) present in the
when a transition metal is present in the reaction mixture. The reaction mixture during the HB transformation.
control reactions with no ketone (1a) in the reaction mixture
resulted in analogous results, with H/D scrambling occurring in Reaction mechanism. Based on the catalysis results, the
the alcohol substrate 2a when Rh-2 was included into the deuterium incorporation and the reported mechanistic studies,
reaction mixture, but no scrambling when no Rh-2 was added we postulated a mechanism to explain the formation of each
(
Scheme 8, bottom).
The deuteration study was extended to using more catalyst.39, 40, 43-45
sophisticated reagents instead of D O – two deuterated
versions of the alcohol substrate 2a: C CH OD (2a-Od ) and
CD OH (2a-Cd ) (Scheme 9). The catalysis reactions were
carried out using the two different transition metal catalysts (Ir-
and Rh-2) and under the ketone and alcohol promoting
product via the HB methodology using Ir-3 or Rh-2 as the
2
6
H
5
2
1
C
H
6 5
2
2
3
reaction conditions (1:1 vs 1:2 substrate ratio of 1a and 2a) to
investigate the fate of the deuterium atoms in both products
(3aa and 4aa). In addition, the transition metal free conditions
under the same sets of substrate ratios were conducted (see
Supporting Information, section S1.7.2).
Scheme 9. Deuterium labelled substrates in hydrogen borrowing reactions. In
addition water is formed as a side-product.
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metal complexes can promote either pathway, but clear
View Article Online
DOI: 10.1039/C9DT02819F
preferences were observed.
The coordination of the C=C double bond (favoured by Ir-3
Scheme 10, green pathway) leads to the formation of the
intermediate , and sequentially the formation of via the 1,2-
migratory insertion. The intermediate then reacts with
another equivalent of 2a regenerating the metal-alkoxide
intermediate and the ketone product 3aa is formed upon
picking up” the H-atom abstracted by the base during the first
step.
,
F
G
G
B
“
Scheme 10. Proposed reaction mechanism of Ir-3 catalysed C-C bond formation of
alcohols with ketones via hydrogen borrowing. In addition, conversion from 3 to 4 can
occur (cf. Table 3). It is proposed that throughout the catalytic cycle the iridium centre
remains as Ir(III), and the +1 charge of the complex is retained.
We propose that the first half of the catalytic cycle (Scheme
1
0 and 11, black arrows) is very similar for both metals, and
33
analogous to the one reported for C-N bond formation via HB.
For both Ir-3 (Scheme 10) and Rh-2 (Scheme 11), the first step
is the coordination of the alkoxide to , with the help of the
base, forming the metal-alkoxido complex . This is followed by
the β-hydride elimination of a hydrogen from the benzylic CH
leading to the metal-hydride intermediate . Both of these
A
B
Scheme 11. Proposed reaction mechanism of Rh-2 catalysed C-C bond formation of
alcohols with ketones via hydrogen borrowing. In addition, conversion from 3 to 4 can
occur (cf. Table 3). It is proposed that throughout the catalytic cycle the rhodium centre
remains as Rh(I), and the +1 charge of the complex is retained.
2
,
D
steps are aided by the de-coordination of the nitrogen arm of
the ligand. In addition to opening up a coordination site, the
dissociation of the nitrogen arm could provide an additional
As discussed above, Int-1 can also coordinate to the metal
centre via the C=O bond (favoured by Rh-2, Scheme 11, pink
46
benefit through interactions with the substrate. The reaction
proceeds by the release of the benzaldehyde, to form the metal-
47
pathway). This coordination results in the formation of F’
hydride intermediate
E as previously demonstrated for the
which undergoes 1,2-migratiory insertion, with the H-atom
33
1
analogous C-N bond formation reaction mechanism. In situ H
NMR spectroscopy indicated that once formed, the
benzaldehyde was rapidly consumed even when higher
quantities (2.0 molar equivalents) of the starting alcohol
substrate (2a) were used. This was expected, as the formed
aldehyde undergoes aldol condensation with acetophenone
ending up on the carbonyl-carbon, forming G’ (cf.
G, where the
H-atom migrated to the α-position). ’ then reacts with another
G
equivalent of 2a leading to the formation of Int-2. No build-up
of the concentration of Int-2 was observed, indicating that once
formed the intermediate readily coordinates to the hydrido-
complex
concentration of 2a. This coordination is now limited to the C=C
bond, hence the formation of occurs (analogously to the
formation of ). Once again via 1,2-migratory insertion the H-
atom is delivered to the double bond. Interestingly, based on
the H/D-scrambling data, this migration step ( to ) has
different selectivity compared to that of to . The migration
to the β-position occurs, (cf. migration to α-position for to ).
E, availability of which is also linked to the relative
(1a) in the presence of the base to form the enone (Int-1) and
one molar equivalent of water.
H
Once formed, the enone (Int-1) enters the catalytic cycle
F
through the coordination to the metal hydride
E. This
coordination opens up two different reaction pathways,
dependant on whether the coordination of the C=C or C=O bond
occurs (depicted as a green and a pink pathway, respectively, in
Schemes 10 and 11). This coordination strongly influences
whether the formation of 3aa or 4aa will be favoured. Both
H
J
F
G
F
G
This is likely due to the changed coordination of the substrate
to the metal; carbonyl vs alcohol. With the assistance of the
base,
J
releases 4aa as the product and the catalyst is returned
8
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Page 9 of 11
Pleas De ad l too nn oT tr aa nd sj au cs t ti omn sa rgins
Journal Name
for the next cycle through formation of
ARTICLE
Upon comparing the resulting product ratios oVifew3aAratictleoO4nlainae
B. In addition, as
demonstrated in Table 3, the formation of 4aa can also occur when using Int-1 as the substrate, toDtOhIe: 10r.a10ti3o9s/C9frDoTm028t1h9eF
from 3aa, as long as some 2a is present in the reaction mixture. reactions using 1a and 2a as substrates, significant differences
As water is formed during the HB reaction, we are unsure of were observed. For the reactions starting with Int-1
,
the reversibility of the individual steps during the catalytic cycle, substantially lower product selectivity was observed. However,
as any H/D-scrambling that could stem from reversible steps, once again, these results demonstrate that low concentrations
could also arise from interactions with water.
As the formation of Int-1 is the same for both metals, and ketone formation conditions, strongly inhibit the formation of
Int-1 is the intermediate for the formation of both 3aa and 4aa the alkylated alcohol product 4aa. Therefore it is not surprising
of the alcohol substrate 2a, as would be the case under the
,
we probed the mechanism further by using Int-1 as the starting that the product ratios change when starting from Int-1 vs 1a
material instead of 1a and 2a. Once again, the reactions were and 2a. This is valuable knowledge for designing the alkylated
carried out under three different reaction conditions; a) Ir-3, b) ketone reaction conditions, as any excess of the alcohol has a
Rh-2 and c) no transition metal catalyst present in the reaction deleterious effect on the desired selectivity. Also, the results
mixture. Additionally, the amount of 2a added to the reaction showed that the combination of the base and transition metal
mixture was varied from 1 molar equivalent of 2a added to no is key. The highest relative amount of 3aa was formed from Int-
t
2
a
being added (Table 4).
1
when the combination of Ir-3 and KO Bu was used, while the
highest amount of 4aa was observed when Rh-2 and KOH were
used, corresponding well with the optimised conditions used in
the scope study.
Table 4 Product selectivity (3aa vs 4aa) when using Int-1 as the starting material.
Clearly, the mechanism is highly nuanced and it is extremely
hard to discern the processes occurring at any given moment.
However, the combination of the mechanistic studies and
catalysis results presented in this work provide a solid ground
for determining how C-C bond formation via the HB
methodology is affected by different aspects, such as the choice
of transition metal catalyst, the base, and the relative loadings
of substrates and catalysts. In turn, this knowledge is important
for considering how to improve the catalytic approaches to
advance this high potential HB methodology.
Ir-3a
Rh-2b
N/Ac
Conversion to: / %
Conversion to: / %
Conversion to: / %
3
aa
4aa
0
3aa
13
4aa
0
3aa
6
4aa
0
t
KO Bu (no 2a)
7
t
KO Bu
41
17
59
12
0
21
26
26
0
61
19
20
67
35
0
33
KOH (no 2a)
100
39
KOH
Conclusions
Conditions: a 1.0 equiv. of Int-1, 1.0 equiv. of 2a, 1.0 mol% Ir-3, 0.8 equiv. of
t
o
b
KO Bu/2.0 equiv. of KOH, 100 C, 18 h, 1.0 equiv. of Int-1, 1.0 equiv. of 2a, 1.0
t
o
c
t
mol% Rh-2, 0.8 equiv. of KO Bu/2.0 equiv. of KOH, 120 C, 18 h. for KO Bu at 100
In this work, we were able to carry out the alkylation of ketones with
alcohols via the hydrogen borrowing (HB) methodology using
triazole-carbene ligated on rhodium(I) and iridium(III) complexes. It
was demonstrated that the nature of the products that form from
these HB reactions was strongly affected by the reaction conditions.
In addition to the reaction conditions (choice of base, relative
amounts of reagents and base, and reaction temperature), the
choice of the transition metal catalyst can play a significant role in
tuning the product selectivity between alkylated ketone and alcohol
products. Being able to select the product outcomes enables this
highly useful HB reaction to become even more viable as an approach
for new C-C bond formation for the selective synthesis of alkylated
ketones and alcohols.
The scope studies showed that this methodology could be used
for a range of substrates to selectively lead to either the ketone
products, or the alcohol products in moderate to excellent yield. The
catalyst screening, time course and deuterium studies showed that
although a number of different processes could occur during the
catalytic transformation, leading to different product ratios, it is
ultimately the transition metal catalyst that determines the product
selectivity.
o
o
C, 18 h, for KOH, 120 C, 18 h. 1,1,2,2-tetrachloroethane (TCE) was used as the
internal standard. In addition water is formed as a side-product (top).
When no 2a was added, in all cases, mixtures of the starting
Int-1 and the methylated ketone product (3aa) were observed,
however, no formation of the methylated alcohol product (4aa
was seen. This matches well with the results observed when
attempting to convert 3aa to 4aa without the presence of 2a
Table 3). These results indicate that the presence of the alcohol
substrate is important as a hydrogen source for the reduction
of the carbonyl group. This means that the ’ to Int-2 step as
depicted in the reaction mechanisms (Scheme 10 and 11) occurs
only if enough 2a is present in the reaction mixture. However,
the presence of 2a is not crucial for the reduction of the C=C
double bond. Particularly impressive activity was seen when
using Rh-2 and KOH to reduce Int-1 to 3aa. Under those
conditions quantitative conversion to 3aa was observed, while
the same reaction using Ir-3/KOH or just KOH resulted in <20%
conversion to 3aa. While not crucial, the presence of 2a did
improve the reduction of the double bond, seen in the lower
amounts of starting Int-1 remaining at the end of the reaction,
matching well with our proposed catalytic cycle.
)
(
G
Conflicts of interest
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Journal Name
There are no conflicts to declare.
27.
A. Quintard, T. Constantieux and J. Rodriguez, Angew.
View Article Online
Chem. Int. Ed., 2013, 52, 12883-128D8O7I:. 10.1039/C9DT02819F
2
2
3
3
8.
9.
0.
1.
G. Zhang, J. Wu, H. Zeng, S. Zhang, Z. Yin and S. Zheng,
Org. Lett., 2017, 19, 1080-1083.
N. Deibl and R. Kempe, J. Am. Chem. Soc., 2016, 138,
Acknowledgements
DF acknowledges Macquarie University Research Training
Pathway Scholarship.
10786-10789.
J. Das and D. Banerjee, J. Org. Chem., 2018, 83, 3378-
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Dalton Transactions
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DOI: 10.1039/C9DT02819F
Fundamental insights into rhodium and iridium catalysed hydrogen borrowing reactions have
enabled strategies for controlling product selectivity.