Rhodium-catalyzed ketone methylation using methanol under mild conditions: Formation of α-branched products

Article abstract of DOI:10.1002/anie.201307950

The rhodium-catalyzed methylation of ketones has been accomplished using methanol as the methylating agent and the hydrogen-borrowing method. The sequence is notable for the relatively low temperatures that are required and for the ability of the reaction system to form α-branched products with ease. Doubly alkylated ketones can be prepared from methyl ketones and two different alcohols by using a sequential one-pot iridium- and rhodium-catalyzed process. Uniquely effective for making branched alkyl products from ketones (see scheme): The scope of the presented reaction includes aromatic and aliphatic ketones and consecutive one-pot double alkylation reactions to provide a convenient route to branched ketones from simple methyl ketones. A brief study into the mechanism of the reaction has given evidence for an aldol-based reaction pathway.

Full text of DOI:10.1002/anie.201307950

Angewandte
Chemie
DOI: 10.1002/anie.201307950
Ketone Alkylation
Hot Paper
Rhodium-Catalyzed Ketone Methylation Using Methanol Under Mild
Conditions: Formation of a-Branched Products**
Louis K. M. Chan, Darren L. Poole, Di Shen, Mark P. Healy, and Timothy J. Donohoe*
Abstract: The rhodium-catalyzed methylation of ketones has
been accomplished using methanol as the methylating agent
and the hydrogen-borrowing method. The sequence is notable
for the relatively low temperatures that are required and for the
ability of the reaction system to form a-branched products with
ease. Doubly alkylated ketones can be prepared from methyl
ketones and two different alcohols by using a sequential one-
pot iridium- and rhodium-catalyzed process.
H
ydrogen borrowing is a powerful method for functional-
group interconversion, which involves reversible changes in
the oxidation state of the reacting partners. In essence,
a catalyst alters the reactivity of a compound by removing two
hydrogen atoms in a formal oxidation of the substrate. This
temporarily generates a highly reactive intermediate and
permits bond formation to take place. Finally, the intermedi-
ate is reduced with the redelivery of two hydrogen atoms,
giving a product without a net change in the overall oxidation
state.[1]
Since a discovery by Grigg et al., who used alcohols as
alkylating reagents,[2] the transition-metal-catalyzed a-alky-
lation of carbonyl compounds using hydrogen borrowing has
emerged as a productive area of research. Contributions from
the groups of Cho/Shim,[3] Ishii,[4] Nishibayashi,[5] Ramꢀn/
Yus,[6] Park,[7] Uozumi,[8] Williams,[9] and others[10] have
demonstrated variations of such alkylation reactions using
different metal catalyst systems (Scheme 1A).[11] These
methods have allowed ketone alkylation with benzyl and
long-chain n-alkyl alcohols (but with surprisingly few, if any,
examples using short-chain alcohols such as methanol).
Moreover, the scope of the ketone substrates is predom-
inantly limited to methyl ketones with linear products being
obtained after monoalkylation, whereafter the reaction stops.
Scheme 1. Different alkylation methods.
The formation of a-branched products from a more-substi-
tuted carbonyl starting material is much more challenging and
restricted to a handful of examples (Scheme 1B).[2g,3,4a,c,6b,7,9c]
Our research program seeks to overcome these problems,
and we chose to investigate the possibility of performing
a methylation at the a-position to a ketone using methanol as
the alkylating reagent. We also wanted to address the
formation of branched products (i.e., cause the formation of
a stereogenic center) because a general procedure would
represent an important and useful advance.
The use of methanol in catalytic alcohol dehydrogenation
reactions is a worthwhile and challenging goal, with funda-
mental developments made by the groups of Beller[12] and
Milstein[13] and demonstrated further with methanol by the
groups of Tincado/Grꢁtzmacher[14] and Glorius.[15] However,
methods that utilize methanol as an alkylating reagent with
[*] Dr. L. K. M. Chan,[+] D. L. Poole,[+] D. Shen, Prof. T. J. Donohoe
Department of Chemistry, University of Oxford
Chemistry Research Laboratory
Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: timothy.donohoe@chem.ox.ac.uk
C C bond formation (reported on PhCH2CN[2e,16]) or as
Dr. M. P. Healy
Novartis Horsham Research Centre (UK)
[+] These authors contributed equally to this work.
À
À
a substrate for formal C H functionalization (such as the
work by Krische et al.[17]) are extremely rare and represent an
important area in need of development.
[**] We thank the EPSRC/Pharma Organic Synthetic Chemistry Stu-
dentships program and EPSRC, Pfizer, and Novartis for support.
Herein, we report our findings on the synthesis of a-
branched ketone products (Scheme 1C). They are significant
because 1) they provide a general solution to the problem of
ketone methylation using methanol; 2) the conditions are
mild and the catalyst commercially available; 3) the forma-
tion of a-branched products is now possible.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307950.
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KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
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Our initial reactions employed valerophenone in meth-
anol, with various transition metal catalysts and Cs2CO3 as
a base; early on we discovered the beneficial effect of
performing reactions under an atmosphere of oxygen, which
is unusual in the context of hydrogen-borrowing chemistry.
Interestingly, we also found that the alkylation of valerophe-
none by methanol was observed at temperatures as low as
658C,[18] implying that methanol dehydrogenation was taking
place under these relatively mild conditions.
Early experiments using catalytic amounts of [{Cp*IrCl2}2]
or [{Cp*RuCl2}n] gave a mixture of the desired a-methylated
ketone 2a, dimer 3a, enone 4a, and b-methoxyketone 5a
(Table 1, entries 1,2). The product distribution shows that,
and [Rh2(OAc)4] gave small amounts of the desired product
(entries 7–9). As a control experiment, the reaction was
performed in the absence of the Rh catalyst and no product
(2a) or intermediates were observed (entry 10). In reactions
that were run under argon (entry 11), the yield of 2a was
acceptable but inferior to that shown earlier (entry 3). A
further reaction with Cp*H as an additive, in the absence of
RhCl3, did not promote a reaction (entry 12).
We turned our attention to explore the substrate scope of
the methylation reaction (Table 2) and found that a ketone
with a shorter ethyl sidechain gave the product (2b) in 73%
yield. When varying the electronic properties of the aromatic
ring, good to high yields were obtained with electron-rich (2d,
2h, 2k) and electron-poor (2c, 2e, 2g, 2i, 2j) rings
and with heteroaromatic alkyl ketones (2l). We
found that electron-poor substrates required a lower
catalyst loading as well as shorter reaction times to
achieve optimal yields. For example, 2i was obtained
in 73% yield with 2.5 mol% of [{Cp*RhCl2}2] after
2 h versus in only 41% yield with 5 mol% of
[{Cp*RhCl2}2] after 4 h.[21] We think that this varia-
tion derives from 1,2-reduction of the carbonyl group
in both starting ketone and product and leads to an
undesired consumption of material. On the other
Table 1: Optimization of the a-methylation of ketone 1a (0.2m).[a]
Entry Conditions
Yield [%]
(Æ)-2a
3a
4a (Æ)-5a
hand, an electron-rich aniline substrate (2h)
required portionwise catalyst addition and a longer
reaction time to reach full conversion. Notably,
halogen-substituted substrates (2c, 2e, 2g, 2j) are
tolerated under the reaction conditions.
Many products 2 were formed in good to
excellent yields, significantly extending the scope of
the reaction and showing that other primary alkyl
chains were compatible with the methylation. Fur-
thermore, the reaction was found to work well with
b-substitution on the alkyl chains: high to excellent
yields of the a-methylation products 2m,n were
1
2
5 mol% [{Cp*IrCl2}2]
10 mol% [Cp*RuCl2]
42
<2
12
19
14
23
27
39
3
5mol% [{Cp*RhCl2}2]
5 mol% [{Cp*RhCl2}2]
10 mol% RhCl3·H2O
10 mol% RhCl3·H2O, 10 mol% Cp*H
10 mol% RhCl3·H2O, 10 mol% PPh3
10 mol% [RhCl(PPh3)3]
5 mol% [Rh2(OAc)4]
no catalyst
5 mol% [{Cp*RhCl2}2], argon
10 mol% Cp*H
98
53
14
74
15
23
10
n/o n/o n/o
33 n/o n/o
4[b]
5
10
8
12
18
n/o n/o
27 44
30
6
7
8
9
10
11
12
n/o n/o n/o
21 23
<5 n/o n/o
n/o n/o
5
n/o (98)[c]
57
9
n/o (86)[c] trace n/o n/o
[a] n/o=not observed. All yields given are of isolated material. Compound 3a was obtained with KOH as a base. Unfortunately,
isolated as a 1:1 mixture of diastereomers. [b] 5 equiv of KOH instead of Cs2CO3.
[c] Yield of recovered starting material.
a stereogenic center at the b-position did not
induce diastereoselectivity under these reaction
conditions.
We also investigated the methylation of alkyl/
along with consumption of the starting material 1a, the
conjugate reduction process was interrupted by the addition
of nucleophiles to the enone 4a. Thus, in an attempt to
improve the yield of 2a, we turned to using Rh, a well-known
catalyst for 1,4-reduction.[19] When using 5 mol% of
[{Cp*RhCl2}2], a-methylation could be accomplished in
98% yield (entry 3); the use of a stronger base such as
KOH resulted in a higher amount of dimer 3a formed
(entry 4); RhCl3 gave a mixture of unreduced intermediates
(entry 5), whereas a respectable 74% yield of 2a was
achieved by using a mixture of RhCl3 and added Cp* ligand
(entry 6).[20] We were pleased to find that the reaction does
not require the use of anhydrous methanol or extra precau-
tions such as the exclusion of moisture, making this a highly
practical method when compared to the traditional lithium–
enolate alkylation methods.
alkyl ketone substrates. As alkylation does not occur on
secondary centers, site-selective alkylation was accomplished
on a-n-alkyl-a’-dialkyl ketones in 81% and 49% yields for 2s
and 2u, respectively. The lower yield obtained for 2u may be
due to the higher pKa value of the dialkylketone versus the
aryl–alkyl ketones. In this case, the slower reaction led to
decomposition of both substrate and product under the
reaction conditions. With double (a,a’) dimethylation reac-
tions we obtained 2t in 55% yield (74% yield per methyl-
ation), although no 1,3-diastereoselectivity was observed.
During our investigation, we noted that several of the
starting ketones required multi-step synthesis, usually via the
corresponding Weinreb amides. The wide commercial acces-
sibility of many methyl ketones encouraged us to examine the
double alkylation of these substrates (Scheme 2A). Ketone
2k was synthesized directly from the corresponding methyl
ketone in 56% yield (i.e., 75% yield per methylation). Direct
access to isopropyl ketones 2v and 2w from commercially
When testing other Rh complexes, we found that RhI,
RhII, and RhIII complexes such as RhCl3/PPh3, [RhCl(PPh3)3],
762
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Table 2: Scope of the a-methylation of ketones; structures of the
complex carbonyl compounds from simple methyl ketone
precursors.
It is important to expand the synthetic utility of the
products formed. All yields are of isolated material and d.r. was
1
determined from H NMR spectroscopy of the crude reaction mixture.
methylation reaction so that other alkylated carbonyl deriv-
atives can be prepared. At this point we have only inves-
tigated the methylation of ketones, however, we were able to
transform the products formed through this reaction into
ester-derived products in a single, high-yielding step. Regio-
selective Baeyer–Villiger oxidation of 2k and 2o with
mCPBA was accomplished in 98% and 92% yield, respec-
tively (Scheme 2C), thus providing access to a-branched
alkylated (and activated) esters (7k, 7o).[4d]
[a] [{Cp*RhCl2}2] (7.5 mol%) was added over 72 h in 3 portions.
[b] 2 equiv of Cs2CO3 was used. [c] SNAr product (2k) was also isolated in
21% yield. [d] 5 equiv of KOH was used as a base instead of Cs2CO3.
available material was achieved in 53% and 44% yields,
respectively.
To extend this concept further, we examined the con-
ditions for ketone alkylation reported by Ishii et al.[4a] and
combined them with our methylation reaction in a one-pot
procedure (Scheme 2B). This sequence further demonstrates
the orthogonal reactivity between the new system and the
existing alkylation methods which use hydrogen-borrowing
chemistry (and which do not form branched products). We
were able to perform the one-pot consecutive alkylation of
methyl ketones using tandem alcohol alkylation reactions,
firstly with a benzyl (2r, 2s, 2o) or primary alkyl alcohol (2q)
and secondly with methanol. Once the first alkylation was
complete (Ir catalysis; no over-alkylation observed), meth-
anol, oxygen, Cs2CO3, and Rh catalyst were added directly to
the reaction mixture without any solvent removal or purifi-
cation.[5] Moderate to good yields of doubly alkylated
products 2o,q,r,s were obtained in this one-pot process
(note that the overall yields are comparable to the multiples
of the individual steps). We suggest that this double alkylation
method holds considerable promise for the generation of
Scheme 2. A) Rh-catalyzed double methylation. B) One-pot sequential Ir/
Rh-catalyzed dialkylation; typical conditions: 1 mol% of [{IrCl(cod)}2],
KOH, Ph3P, 1.2–5 equiv of alcohol, 1008C, 4 h; then 5 mol% of
[{Cp*RhCl2}2], 5 equiv of Cs2CO3, MeOH, 658C, O2. In addition to the
overall yields, those of the individual steps are given. C) Baeyer–Villiger
oxidation.—See the Supporting Information for experimental details;
structures of the products shown.
To provide insight into the reaction mechanism, we
carried out a series of reactions whereby the proposed (and
in some cases observed) intermediates were resubjected to
the reaction conditions (Scheme 3). In every case but one, we
found that these compounds were converted into the meth-
ylation product 2a, providing evidence for their participation
in a reaction sequence involving an aldol reaction with
formaldehyde, elimination, and alkene reduction. However,
when we used the reaction conditions on 3a (which might
derive from the conjugate addition of an enolate to enone
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of RhIII H, thus regenerating the active catalyst in situ,
À
although other possibilities exist.[23]
Finally, it should be noted that the reactive and unhin-
dered nature of formaldehyde as an electrophile may explain
why this system is uniquely effective for making branched
alkyl products, as only this particular electrophile is able to
couple effectively with a substituted enolate under these
conditions.
In conclusion, we have reported a method for the use of
methanol as an alkylating reagent in a rhodium-catalyzed
reaction. We found that an atmosphere of oxygen is beneficial
to the yields of methylation and have shown that methanol
oxidation could be achieved under remarkably mild condi-
tions. The scope of this reaction includes aromatic and
aliphatic ketones and consecutive one-pot double alkylation
reactions provide a convenient route to branched ketones
from simple methyl ketones. A brief study into the mecha-
nism of the reaction has given evidence for an aldol-based
reaction pathway.
Scheme 3. Mechanistic experiments.
4a), we recovered only starting material, which suggests that
3a is a dead-end that does not contribute to the formation of
methylated product 2a.
At this point, we interpret our results as shown below
(Scheme 4). The key steps are methanol oxidation to form-
aldehyde, followed by an aldol reaction and elimination to
Received: September 10, 2013
Published online: November 29, 2013
Keywords: homogeneous catalysis · hydrogen borrowing ·
.
ketones · methanol
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À
from methanol as being the formation of Rh H and a proton, at
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