Manganese-Catalyzed Hydrogen-Autotransfer C?C Bond Formation: α-Alkylation of Ketones with Primary Alcohols

Article abstract of DOI:10.1002/anie.201607072

A novel catalytic hydrogen-autotransfer protocol for the atom-efficient α-alkylation of ketones with readily available alcohols is presented. The use of manganese complexes bearing non-innocent PNP pincer ligands enabled the functionalization of a broad range of valuable ketones, including 2-oxindole, estrone 3-methyl ether, and testosterone. Mechanistic investigations suggest the participation of an intramolecular amidate-assisted alcohol-dehydrogenation process.

Full text of DOI:10.1002/anie.201607072

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201607072
German Edition: DOI: 10.1002/ange.201607072
Borrowing Hydrogen
À
Manganese-Catalyzed Hydrogen-Autotransfer C C Bond Formation:
a-Alkylation of Ketones with Primary Alcohols
Miguel PeÇa-Lꢀpez, Patrick Piehl, Saravanakumar Elangovan, Helfried Neumann, and
Matthias Beller*
Abstract: A novel catalytic hydrogen-autotransfer protocol for
the atom-efficient a-alkylation of ketones with readily avail-
able alcohols is presented. The use of manganese complexes
bearing non-innocent PNP pincer ligands enabled the func-
tionalization of a broad range of valuable ketones, including 2-
oxindole, estrone 3-methyl ether, and testosterone. Mechanistic
investigations suggest the participation of an intramolecular
amidate-assisted alcohol-dehydrogenation process.
during the last few years.[6] Despite all this progress, the use of
manganese in dehydrogenative coupling processes is scarce,[7]
and to the best of our knowledge no catalytic hydrogen-
À
autotransfer C C bond-forming processes in the presence of
defined molecular manganese complexes have been de-
scribed previously.[8]
On the basis of our recent study on the iron-catalyzed a-
alkylation of ketones with alcohols,[5] we became interested in
the catalytic application of manganese(I) pincer complexes
for such transformations (Scheme 1). We therefore prepared
precatalysts 1–3 by the treatment of the corresponding
T
ransition-metal-catalyzed hydrogen autotransfer—also
called borrowing hydrogen—has become an important syn-
thetic strategy in organic chemistry as a result of its efficiency,
À
low cost, and versatility. It allows the formation of C N and
À
C C bonds through the reaction of non-activated alcohols
with amines or C-nucleophiles, respectively,[1] as well as the
synthesis of valuable heterocycles by domino processes.[2] The
availability of starting materials from renewable resources,
the operational simplicity, and the generation of H2O as the
only stoichiometric by-product make this process sustainable,
atom-economical, and environmentally benign.
Applications of this methodology include the formation of
new carbon–carbon bonds. More specifically, the a-function-
alization of carbonyl compounds with simple alcohols as
electrophiles provides several advantages as compared to
classical procedures involving enolates. In the latter reactions,
relevant amounts of waste are formed as a result of the use of
stoichiometric bases and halides.[3] Hydrogen autotransfer,
which is commonly performed with noble metals, such as
ruthenium and iridium, constitutes a greener alternative.[4]
Besides different reactivity, catalysis with nonprecious metals
has economic and ecological benefits. In this regard, the
report of a general iron-catalyzed a-alkylation of ketones
with Knçlker-type complexes is notable.[5]
Apart from iron, manganese is attracting increasing
interest in synthesis, since it is cheap and toxicologically
benign in comparison to most other transition metals. It is also
an abundant element on Earthꢀs crust and is capable of
existing in several oxidation states. A wide variety of
derivatives are readily available, and the number of manga-
nese-catalyzed transformations has increased considerably
Scheme 1. Manganese-catalyzed a-alkylation of ketones with alcohols.
tridentate ligands with [Mn(CO)5Br] (see the Supporting
Information for a general procedure). In accordance with the
outer-sphere mechanism established for related processes
with ruthenium-based complexes,[9] the active catalytic spe-
cies would be formed through base-mediated dehydrobromi-
nation of the precatalyst. Then, the in situ dehydrogenation of
the alcohol would afford the corresponding carbonyl com-
pound. Subsequent aldol condensation with the starting
ketone should provide the a,b-unsaturated intermediate,
which would finally be reduced by the hydrogen extracted
in the first step. Water would be formed as the only by-
product in a reaction which avoids the use of stoichiometric
reagents for both redox processes.
As a model system, the manganese-catalyzed alkylation of
acetophenone (4a) with benzyl alcohol (5a) was optimized
(Table 1). To our delight, the use of 3 mol% of pincer
complexes 1–3 for the reaction of 4a (1 mmol) with 5a
(1.2 mmol) in the presence of Cs2CO3 (10 mol%) in 1,4-
dioxane at 1508C allowed the alkylated ketone 6a to be
obtained selectively in good yields (77–90%; Table 1,
entries 1–3). The diisopropylphosphine derivative 3 was the
most effective precatalyst, whereas [Mn(CO)5Br], the pre-
cursor in the preparation of the pincer complexes, only
[*] Dr. M. PeÇa-Lꢀpez, P. Piehl, S. Elangovan, Dr. H. Neumann,
Prof. Dr. M. Beller
Leibniz-Institut fꢁr Katalyse e.V. an der Universitꢂt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
E-mail: Matthias.Beller@catalysis.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201607072.
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Table 1: Optimization of the reaction conditions for the synthesis of 1,3-
diphenylpropan-1-one (6a).[a]
Entry Mn catalyst
Base
Solvent
T [8C] Yield [%][b]
1
2
3
4
5
Mn complex 1 Cs2CO3 1,4-dioxane
Mn complex 2 Cs2CO3 1,4-dioxane
Mn complex 3 Cs2CO3 1,4-dioxane
150
150
150
150
150
150
150
150
150
140
130
140
83
77
90
6
[Mn(CO)5Br]
Cs2CO3 1,4-dioxane
Mn complex 3 KOH
Mn complex 3 K2CO3
1,4-dioxane
1,4-dioxane
69
52
70
87
78
84
63
85
86
88
64
–
6
7
Mn complex 3 KOtBu 1,4-dioxane
Mn complex 3 Cs2CO3 1,4-dioxane
Mn complex 3 Cs2CO3 1,4-dioxane
Mn complex 3 Cs2CO3 1,4-dioxane
Mn complex 3 Cs2CO3 1,4-dioxane
Mn complex 3 Cs2CO3 toluene
8[c]
9[d]
10[c]
11[c]
12[c]
13[c]
Mn complex 3 Cs2CO3 tert-amyl alcohol 140
14[c,e] Mn complex 3 Cs2CO3 tert-amyl alcohol 140
15[c,f] Mn complex 3 Cs2CO3 tert-amyl alcohol 140
16[c]
Mn complex 3
–
tert-amyl alcohol 140
17[c,e]
–
Cs2CO3 tert-amyl alcohol 140
20
[a] Unless otherwise specified, reactions were carried out with 4a
(1 mmol), 5a (1.2 mmol), the Mn catalyst (0.03 mmol), and the base
(0.10 mmol) in 1 mL of the solvent at the indicated temperature for 22 h.
[b] Yield of the isolated product. [c] Catalyst loading: 2 mol%. [d] Cata-
lyst loading: 1 mol%. [e] Base: 5 mol%. [f] Base: 2 mol%.
afforded the desired product in 6% yield (Table 1, entry 4).
The relevance of the basic medium for both catalyst activation
and aldol condensation led us to analyze different bases. We
obtained the best result when using cesium carbonate
(Table 1, entries 5–7). For further optimization, we examined
other critical parameters, such as the catalyst loading, solvent,
base concentration, and temperature (Table 1, entries 8–15).
Finally, we selected the reaction of 4a (1 mmol), 5a
(1.2 mmol), 3 (0.02 mmol), and Cs2CO3 (0.05 mmol) in tert-
amyl alcohol at 1408C for 22 h as optimal conditions, which
gave 6a in 88% yield (Table 1, entry 14). An experiment
without a base showed no conversion, and a reaction in the
absence of a manganese complex led to the coupling product
in 20% yield (Table 1, entries 16 and 17). As reported
previously, such processes can be promoted in a basic
medium under metal-free conditions.[10] The selectivity of
the transformation is notable, since by-product formation is
completely avoided.
Having developed a reliable procedure, we analyzed the
reaction of benzyl alcohol (5a) with structurally diverse
ketones 4a–l (Scheme 2). An aryl ketone substituted with
a methoxy group was converted into 6b in excellent 92%
yield, whereas the presence of electron-withdrawing substitu-
ents, such as Br and CF3, led to a slight decrease in efficiency
(products 6c,d, 73 and 45%, respectively). This reaction could
also be carried out with 2- and 3-acetyltoluene as well as 2-
acetylnaphthalene as starting materials (products 6e–g, 70–
92%). Gratifyingly, heterocyclic ketones containing thio-
phene, furyl, pyrrole, and pyridine moieties were transformed
into the desired products 6h–k in moderate to good yields
(48–89%). A cyclic substrate with a secondary a-carbon atom
Scheme 2. Manganese-catalyzed reaction of ketones 4 with primary
alcohols 5. Yields are for the isolated product. [a] EtOH (1 mL) was
used as the solvent. The yield was determined by GC with hexadecane
as an internal standard.
was also functionalized. Thus, the reaction of benzyl alcohol
with 4l afforded the product 6l in 83% yield. Interestingly,
the aliphatic ketone 4m also showed reactivity, although in
this case the alkylated compound 6m was obtained in lower
35% yield.
We also studied the reaction of acetophenone (4a) with
differently substituted primary alcohols 5a–m (Scheme 2).
The electron-rich derivative 5b afforded ketone 7b in good
yield (76%), and the reaction with 4-(trifluoromethyl)benzyl
alcohol (5c) took place in a similar manner (65%). An
experiment with more hindered 2-methoxybenzyl alcohol
gave rise to 7d in 78% yield, and 1-naphthylmethanol reacted
with 4a to give the desired product 7e in high yield (86%).
Heteroaromatic substrates were also efficiently applied to the
alkylation of 4a, although in moderate yields (products 7 f–h,
51–64% yield). Moreover, the reaction with cinnamyl alcohol
(5i) gave the desired ketone 7i but in low 22% yield. Next, we
studied the reactivity of aliphatic alcohols. The alkylation of
acetophenone (4a) with ethanol, used as the solvent, pro-
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vided 7j in 50% yield (as determined by GC), whereas 1-
butanol afforded the corresponding ketone 7k in good 72%
yield. Cyclohexanemethanol (5l) was also used effectively as
the electrophile (79%). Interestingly, the reaction with
cyclohex-3-en-1-ylmethanol (5m) provided 7m in 85%
yield. In this case, unlike in some ruthenium-catalyzed
hydrogen-autotransfer applications,[11] reduction of the C C
À
double bond present in the starting alcohol did not take place.
To increase the versatility of this catalytic protocol, we
applied it to the functionalization of other interesting
carbonyl compounds (Scheme 3). Initially, we studied the a-
alkylation of 2-oxindole, a relevant heterocycle found in many
biologically active molecules.[12] Such compounds often pres-
Scheme 4. Plausible mechanism for the manganese-catalyzed a-alkyl-
ation of ketones with alcohols.
tially, the precatalyst 3 is activated by reaction with a base in
a dehydrobromination reaction to give species I. In agree-
ment with related complexes based on other transition
metals,[16] coordination of the deprotonated alcohol 5 then
provides an alkoxo-type complex II. At this point, a dehydro-
genation reaction might take place by b-hydride elimination,
despite the lack of free coordination sites at the metal center.
However, we do not think that this option is very probable
and instead propose that the basic medium promotes the
formation of an amidate, which undergoes abstraction of the
b-hydrogen atom, as shown in transition state III. Such an
intramolecular ligand-assisted mechanism leads to aldehyde
11 and the intermediate IV, which is protonated to form the
manganese hydride V. An aldol condensation between 11 and
the enolate resulting from the starting ketone 4 affords the
a,b-unsaturated compound 12 with the release of a molecule
of H2O. Finally, hydrogenation by species V yields the desired
ketone 6/7 and regenerates the catalytic active species I.
Previously, organometallic hydride complexes (e.g. Ru, Ir, as
well as Fe) with pincer ligands have been shown to reduce
polarized multiple bonds.[17] Thus, we assume that our
Scheme 3. Manganese-catalyzed a-alkylation of a) 2-oxindole and
b) estrone 3-methyl ether and testosterone with alcohols. Yields are for
the isolated product.
ent substituents at the 3-position, which are normally
introduced by the use of organic halides. Owing to the
presence of a free amine in this cyclic amide, carbon–carbon
bond formation by the method described herein must be
performed selectively to avoid the amination reaction.[13] The
manganese-catalyzed reaction of 2-oxindole with alcohols
bearing aryl, heteroaryl, and alkyl groups under the previ-
À
ously optimized conditions provided the C C coupled
products 8a–d in excellent yields (81–92%, Scheme 3a).
The modification of natural products allows for structure–
activity relationship (SAR) studies with the aim of exploring
their full drug potential.[14] Along this line, we applied our
catalytic strategy to the derivatization of hormones. Indeed,
estrone and testosterone derivatives could be readily func-
tionalized by using simple alcohols as starting materials
(Scheme 3b). In this way, estrone 3-methyl ether was
effectively alkylated at the carbon atom adjacent to the
carbonyl group with benzyl alcohol, 2-thiophenemethanol,
and 1-butanol to afford products 9a–c in 71–94% yield.
Despite the presence of a free secondary alcohol in the D ring
of testosterone, the a-position of the six-membered cyclic
ketone was smoothly substituted with the same alcohols. In
this case, lower product yields were observed (products 10a–
c, 29–51%) owing to the formation of two main side
products.[15]
À
reaction proceeds through Mn H hydride transfer from
complex V to the b-position in a Michael-type process
À
followed by N H proton transfer to the corresponding
enolate.[4f]
À
To confirm the participation of the N H moiety of the
pincer ligand in this transformation, we performed the
alkylation of acetophenone (4a) with benzyl alcohol (5a) in
the presence of the corresponding N-methylated manganese
complex 3’ (Scheme 5a). When the optimal conditions were
applied, ketone 6a was isolated in only 32% yield (88% yield
was observed with 3 as the catalyst). This observation
indicates the possibility of different pathways with the
prevalence of an NH-assisted outer-sphere mechanism.
Deuterium-labeling experiments were also carried out with
[a,a-D2]benzyl alcohol (5a’). In this case, the aprotic solvent
toluene was used instead of tert-amyl alcohol to avoid
additional H/D exchange. An experiment with the N-Me
complex 3’ provided the desired ketone 6a’ in low yield
Finally, we propose a plausible mechanism depicted in
Scheme 4 for this manganese-catalyzed transformation. Ini-
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Scheme 5. Control experiments. Yields are for the isolated product.
(12%) with 9% deuteration at the a-position and 60% at the
b-position (Scheme 5b). The lower yield is caused by the
absence of an alcoholic solvent (alkoxide formation in basic
medium) or the different reactivity of 5a’. Alternatively, the
À
reaction of 4a with 5a’ under the catalysis of the N H
complex 3 led to 6a’ in 84% yield with deuterium atoms
equally distributed in the C2 and C3 positions (36 and 33% D,
respectively, Scheme 5c). Deuterium incorporation at the a-
position of 6a’ implies the formation of “D+” from deuterated
benzyl alcohol. As shown in Scheme 4, the amidate-assisted
À
pathway offers the possibility of transforming the C D bonds
in the benzyloxy intermediate II to give an N-deuterated
complex IV, which acts as a source of “D+”. On the other
hand, with complex 3’ such transition state cannot be formed,
thereby explaining the high incorporation of H+ at the a-
position in this experiment (91%). Notably, the observed H/
D ratios in both reactions suggest the possibility of alternative
pathways for this manganese-catalyzed transformation.
In conclusion, we have developed the first manganese-
catalyzed alkylation of ketones and related compounds with
primary alcohols. This straightforward transformation takes
place with an air- and water-stable manganese(I) PNP pincer
precatalyst. A low base concentration and broad applicability
are notable features of this hydrogen-autotransfer method-
ology.
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Acknowledgements
We thank the state of Mecklenburg-Vorpommern and the
Bundesministerium fꢁr Bildung und Forschung (BMBF) for
financial support. We also thank Dr. Elisabetta Alberico, Dr.
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À
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Keywords: alcohols · atom economy · hydrogen transfer ·
ketones · manganese catalysis
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alcohols, see: a) A. E. Putra, Y. Oe, T. Ohta, Eur. J. Org. Chem.
2015, 7799 – 7805; b) C. Chaudhari, S. M. A. H. Siddiki, K. Kon,
A. Tomita, Y. Tai, K.-I. Shimizu, Catal. Sci. Technol. 2014, 4,
1064 – 1069; c) T. Jensen, R. Madsen, J. Org. Chem. 2009, 74,
3990 – 3992; d) R. Grigg, S. Whitney, V. Sridharan, A. Keep, A.
Derrick, Tetrahedron 2009, 65, 4375 – 4383.
[17] a) R. Xu, S. Chakraborty, S. M. Bellows, H. Yuan, T. R. Cundari,
W. D. Jones, ACS Catal. 2016, 6, 2127 – 2135; b) C. Bornschein, S.
Werkmeister, B. Wendt, H. Jiao, E. Alberico, W. Baumann, H.
Junge, K. Junge, M. Beller, Nat. Commun. 2014, 5, 4111; c) D.
Spasyuk, S. Smith, D. G. Gusev, Angew. Chem. Int. Ed. 2012, 51,
2772 – 2775; Angew. Chem. 2012, 124, 2826 – 2829; d) E. Balara-
man, B. Gnanaprakasam, L. J. W. Shimon, D. Milstein, J. Am.
Chem. Soc. 2010, 132, 16756 – 16758.
Received: July 21, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Borrowing Hydrogen
M. PeÇa-Lꢁpez, P. Piehl, S. Elangovan,
H. Neumann, M. Beller*
&&&& — &&&&
Manganese-Catalyzed Hydrogen-
À
Autotransfer C C Bond Formation: a-
Alkylation of Ketones with Primary
Alcohols
Something borrowed, something new: A
hydrogen-autotransfer reaction catalyzed
by manganese(I) PNP pincer complexes
was developed for the a-alkylation of
ketones with alcohols (see scheme).
Structurally diverse primary alcohols were
used to functionalize a wide range of
ketones, including 2-oxindole, estrone 3-
methyl ether, and testosterone, by this
straightforward method.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!