Manganese-Catalyzed α-Alkylation of Ketones, Esters, and Amides Using Alcohols

Article abstract of DOI:10.1021/acscatal.8b03720

Herein we report the manganese-catalyzed C-C bond-forming reactions via α-alkylation of ketones, amides, and esters, using primary alcohols. β-Alkylation of secondary alcohols by primary alcohols to obtain α-alkylated ketones is also reported. The reactions are catalyzed by a (ⁱPr-PNP)Mn(H)(CO)₂ pincer complex under mild conditions in the presence of (catalytic) base liberating water (and H₂ in the case of secondary alcohol alkylation) as the sole byproduct.

Full text of DOI:10.1021/acscatal.8b03720

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Letter
Manganese Catalyzed #-Alkylation of
Ketones, Esters and Amides Using Alcohols
Subrata Chakraborty, Prosenjit Daw, Yehoshoa Ben-David, and David Milstein
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03720 • Publication Date (Web): 02 Oct 2018
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ACS Catalysis
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Manganese Catalyzed α-Alkylation of Ketones, Esters and Amides
Using Alcohols
Subrata Chakraborty,† Prosenjit Daw,† Yehoshoa Ben David, and David Milstein*
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Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel
ABSTRACT: Herein we report the manganese catalyzed C-C bond forming reactions via α-alkylation of ketones, amides
and esters, using primary alcohols. β-alkylation of secondary alcohols by primary alcohols to obtain α-alkylated ketones
is also reported. The reactions are catalyzed by a (iPr-PNP)Mn(H)(CO)2 pincer complex under mild conditions in the
presence of (catalytic) base liberating water (and H2 in the case of secondary alcohol alkylation) as the sole-byproduct.
KEYWORDS : alkylation, ketones, secondary alcohol, amides, esters, manganese, pincer
Carbon-Carbon bond formation represents one of the
most important synthetic methodologies in organic
chemistry. A classical route of carbon-carbon bond
formation involves nucleophilic substitution reactions
involving an organometallic reagent and an organic
electrophile. Transition-metal-catalyzed cross-coupling
reactions have made great progress in C-C bond
formation. However, traditional alkylations usually require
environmentally unfriendly organic or organometallic
coupling partners, and large amounts of bases, and
generate copious waste.1
Recent catalysis is aimed at cheaper, greener and
sustainable methodologies. Therefore development of a
practical, green, and atom-economical alkylation process
for the formation of C−C bonds is highly desirable. In
recent years, transition-metal complexes have been de-
veloped as catalysts for dehydrogenation of alcohols to
the corresponding carbonyl compounds, which subse-
quently undergo condensation with a CH-acidic com-
pound followed by hydrogen autotransfer to form α-
alkylated products.2,3 This so-called redox neutral
“hydrogen borrowing methodologyˮ has attracted
increasing attention for C-C bond formation reactions
owing to its atom-economy (Scheme 1).2,4 Only water is
released in these reactions, rendering them green or sus-
tainable.
Moreover, use of alcohols as starting materials for C-C
bond formation processes is attractive, because they are
cheap, easy to handle and store, and are renewable
alternative to petroleum-based compounds. Since the
past few years there has been a growing interest in re-
placing homogeneous catalysts based on noble metals by
earth abundant base metal complexes.5-6 This is due to
the higher cost of precious metals, lower abundance and
potential higher toxicity. In this respect application of man-
ganese complexes in (de)hydrogenation reactions is an
attractive goal;7 manganese is the third most earth-abun-
dant transition metal on earth crust after iron and tita-
nium.7b Indeed hydrogenation of ketones7h-q, nitriles8, es-
ters9, CO210 and amides11 catalyzed by manganese com-
plexes has been reported in recent years by several
groups including ours.
Substantial efforts are also made in manganese catalyzed
dehydrogenation reactions. We reported dehydrogena-
tive coupling of alcohols and amines to give imines,12a cat-
alyzed by a pincer Mn-PNP complex 2 (Figure 1). Several
other reports on Mn catalyzed dehydrogenation reactions
appeared subsequently.12b,c,13 Recently N-alkylation of
amines using alcohols,14a-c and catalytic upgrading of eth-
anol to 1-butanol14d,e via ‘borrowing hydrogen’ were re-
ported.
Figure 1. Manganese pincer complexes employed in this
work.
We reported the Mn-catalyzed N-formylation of
amines using methanol,15a and deoxygenation of
alcohols,15b catalyzed by MnPNP pincer complex 1
Scheme 1. Transition metal catalyzed C-alkylation via
borrowing hydrogen methodology.
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ACS Catalysis
were employed under similar reaction conditions giving
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(Figure 1). Very recently we demonstrated Mn-catalyzed
synthesis of N-substituted hydrazones by
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decent yields of propiophenone (NaOEt, 80%; KH, 97%,
NaOH, 92%, Na2CO3, 52%) (Table 1, entries 5-8). Our
previously reported dearomatized Mn-PNPtBu complex 2
and the deprotonated Mn-PNN complex 3 (Figure 1) were
then screened, affording 1,3-diphenylpropan-1-one in 92
and 90% yields, respectively (Table 1, entries 11 and 12).
Decreasing the reaction time to 5 h resulted in only a slight
drop in conversion of the alcohol (92%) forming the corre-
sponding ketone product in 80% yield (Table 1, entry 10).
Temperature does not play crucial role, as lowering the
temperature to 110°C yielded 90% of the corresponding
product (Table 1, entry 9).
dehydrogenative coupling of alcohols and hydrazines
catalyzed by a MnPNN pincer complex,16 as well as
dehydrogenative coupling of alcohols and amines to form
amides,17 and that of diols and amines to form cyclic
imides using complex 3.18 We also reported the
unprecedented α- olefination of nitriles using alcohols
catalyzed by the manganese complex 1.19
Mn-pincer complex catalyzed α-alkylation reactions of ke-
tones was reported by Beller20 using primary alcohols
(140 °C, 2 mol% catalyst, 5 mol% base). Very recently,
while this paper was in preparation, Maji reported a limited
scope α-alkylation of arylketones by benzyl alcohol deriv-
atives under similar conditions,
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Under the optimized reaction conditions (toluene, 125°C,
t
3 mol% BuOK and 1 mol% 1), the scope of the
manganese- catalysed C-alkylation of ketones was
explored. As shown in Table 2, reactions of benzyl
alcohols bearing electron-donating substituents, including
4-methoxybenzyl alcohol, 4-methylbenzyl alcohol, 3-N,N-
dimethylbenzyl alcohol, 2-methoxybenzyl alcohol, and
Table 1. Optimization of the reaction conditions for the
C-alkylation of acetophenone using benzyl alcohol cata-
lyzed by 1-3.
En- Cat Solvent
trya
Base
Time
(h)
Tem
p
Conv
(%)b
Yield
(%)b
(mol%)
(°C)
125
Scheme 2. Base metal catalyzed C-C bond forming reac-
tions by α and β alkylation.
1
1
THF
THF
tBuOK(3)
-
20
95
75
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1
1
1
1
1
1
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20
125
125
125
125
125
125
125
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dioxane tBuOK (3)
toluene tBuOK (3)
98
96
98
97
80
92
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catalyzed by an undefined Mn complex generated in
situ.21 We now report that complex 1 is an effective
catalyst for α-alkylation of ketones, non-activated amides,
and esters by primary alcohols. Complex 1 also catalyzes
β-alkylation of secondary alcohols by primary alcohols to
obtain α-alkylated ketones.(Scheme 2)
To the best of our knowledge α-alkylation of activated22
and non-activated23 esters and of activated24 and unacti-
vated25 amides was reported using Ir and Ru complexes.
The only base metal catalyzed C-alkylation of esters and
non-activated amides was reported by Kempe using a Co
complex.26
At the outset we explored the reaction of acetophenone
and benzyl alcohol as model substrates. Reaction of ben-
zyl alcohol (1 mmol) with acetophenone (1 mmol) using
tBuOK (3 mol%) and the Mn complex 1 (1 mol%) in THF
in a closed system resulted in the formation of 1,3-
diphenylpropan-1-one in 75% yield at 125 °C after 20 h
(Table 1, entry 1). However, in the absence of base, only
8% yield of the corresponding product was obtained (Ta-
ble 1, entry 2). Changing the solvent to 1,4-dioxane or tol-
uene furnished the desired product in excellent yields (96
and 98%, respectively; Table 1, entries 3 and 4). Explor-
ing the effect of bases, NaOEt, KH, NaOH, and Na2CO3
>99
>99
97
toluene
toluene
toluene
KH(3)
NaOEt(3)
NaOH(3)
95
toluene Na2CO3(3)
toluene tBuOK(3)
97
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125
125
125
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80
92
90
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12
toluene tBuOK (3)
toluene tBuOK (3)
toluene tBuOK (3)
20
20
aConditions: benzyl alcohol (1 mmol), acetophenone (1
mmol), cat (0.01 mmol), base (3 mol%) and solvent (2 mL),
heated in 25 mL schlenk tube for given time at 125 °C. byields
and conversions determined by GC-MS analysis using m-xy-
lene as internal standard.
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Table 2. C-alkylation of ketones with alcohols catalyzed by
1.a
the optimized condition, whereas cyclohexanone was
completely inactive towards alkylation with alcohols.
Interestingly, it is possible to employ a secondary alcohol
instead of a ketone. Thus, reaction of 1-phenyl ethanol (1
mmol) and benzyl alcohol (1 mmol) in the presence of 1
mol% cat 1 and 3 mol% tBuOK at 125°C resulted in the
corresponding ketone product in
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Scheme 3. Direct synthesis of ketones by dehydrogenative
coupling of secondary alcohol with primary alcohol.
86% yield (Scheme 3) with the liberation of water and di-
hydrogen. Analysis of the gas phase by gas chromatog-
raphy shown the formation of H2 (See Figure S1 in SI).
Reaction of 4-Methyl-, 4-chloro-, and 3-N,N-dimethyla-
mino- benzyl alcohols provide 66%, 72%, 70% of the cor-
responding α-alkylated ketones as the major product with
hydrogenated alcohol are the other product. 3-Pyridine-
methanol as substrate formed 78% of the corresponding
ketone product under the optimized conditions. β-alkyla-
tion of secondary alcohols to give α-alkylated ketones was
previously reported using Ir, Ru and Cu complexes.27 Re-
cently β-alkylation of secondary alcohols to give β-alkyl-
ated alcohols catalyzed by Mn was reported.28
aConditions: ketone (1 mmol), alcohol (1mmol), 1 (0.01
mmol), tBuOK (3 equiv. relative to 1), and 2 ml toluene
heated in a 25 mL schlenk tube at 125 °C in a closed system.
Isolated yield in parentheses. yields are based on NMR or
GC.
b
3,4-dimethoxy benzyl alcohol with acetophenone,
produced
substituted
1,3-diphenylpropan-1-one
derivatives in excellent yields (Table 2, entries A-E).
Under similar conditions, benzyl alcohols bearing electron
withdrawing substituents at the para
positions,
including
4-fluorobenzyl
alcohol,
4-
trifluoromethyl benzyl alcohol and 4-bromobenzyl alcohol
also afforded selectively the corresponding C-alkylated
products with good to moderate yields. (Table 2, entries
F-H). 4-cyanobenzyl alcohol afforded 68% of
corresponding product in addition to a minute amount the
α,β-unsaturated carbonyl product ; no products of
hydrogenation of the cyano group were observed (Table
2, entry I). Hex-5-en-1-ol as substrate afforded 61% of the
target prodcut without any hydrogenation of the olefin
functionalty (Table 2 entry J). 2-Naphthalenemethanol
was also used as alkylating substrate with acetophenone
yielding the corresponding product in 88% yield (entry K).
The scope of the reaction was further probed by
employing the heterocyclic ketones 2-acetylpyridine and
2-acetylthiophene with benyzl alcohol, furnishing the
corresponding product in moderate 42% and 50% yields,
respectively (entries L and M). Aliphatic alcohols were
also used under the optimized reaction conditions. 2-
phenylethanol, 2-phenyl-1-propanol, 1-hexanol and 3-
methyl-1-pentanol dehydrogenatively coupled with an
equivalent amount of acetophenone, affording the
corresponding C-alkylated product in good to moderated
yields (entries N-P). C-alkylation of the activated amide 2-
oxindole with benzyl alcohol yielded 78% of the deisred
product (entry Q). Employing the low- boiling methanol
and ethanol resulted in poor yields of the targeted α-alkyl-
ated product (see details in SI). The branched carbonyl
substrate propiophenone also afforded poor yield under
Carboxylic acid derivatives, such as esters and amides,
are valuable intermediates and products in industry and
academia. A useful approach to modify amides and esters
is α-alkylation by alcohols. However, alkylations of these
compounds have proved to be challenging. Amides have
a relatively low CH-acidic nature due to resonance stabi-
lization, while esters are amenable to side reactions. Tak-
ing note of the good performance of the Mn catalysts for
C-alkylation of acetophenone, we explored the possibility
to use an ester as the coupling partner (Table 3). The re-
action between benzyl alcohol and tert-butyl acetate was
investigated to find suitable reaction conditions. We found
out that in order to obtain optimum product yields, the
amount of t-butyl acetate needed to be increased to four
t
equiv. at 125°C using 1.5 equiv of BuOK and complex 1
(5 mol%). The reactions were carried out in tBuOH as sol-
vent in order to shift the equilibrium towards the product.
Thus, dehydrogenative coupling of benzyl- and 4-methylben-
zyl alcohol with t-butylacetate gave the corresponding ester
alkylation products in 65% and 95% yields, respectively (Ta-
ble 3, entries1 and 2). However, in the former case formation
of the α,β-unsaturated t-butylcinnamate was also observed.
The use of the electron-deficient 4-chloro- and 4-trifluorome-
thyl benzyl alcohols furnished the corresponding products in
moderate yields with the formation of α,β-unsaturated esters
as major products (Table 3, entries 3 and 4). Moreover, we
also explored the possibility of C-alkylation of non-acti-
vated amides with alcohols.
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coupling of amines and methanol,15a as well as on deoxy-
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Table 3. C-alkylation of esters and amides derivatives
with alcohols catalyzed by 1.a
genation of primary alcohols catalyzed by 1,15b we pro-
pose the plausible catalytic cycle depicted in Scheme 4.
Dihydrogen liberation from complex 1 leads to the amido
complex A, which undergoes intramolecular C−H activa-
tion to form the thermodynamically more stable C-meta-
lated complex A’.15a O−H activation of the alcohol by com-
plex A or A′ via proton transfer, to either the amido nitro-
gen or benzylic carbon, results in the formation of the
alkoxo complex B. The following β-hydride elimination
step29 releases the aldehyde. Nucleophilic attack of the
deprotonated methyl group of the carbonyl functionality
(ketone, ester and amide) on the released aldehyde fol-
lowed by water elimination leads to the α,β-unsaturated
compound. The deprotonation of the methyl groups re-
quires catalytic (for ketones) or stoichiometric base (for
amides and esters). It should be mentioned at this stage
that we previously reported that the same catalyst 1 is ac-
tive for the dehydrogenative coupling of alcohols with ni-
triles in the absence of base to give substituted acryloni-
triles, in which the formed olefinic double bond is com-
pletely inert towards hydrogenation by the evolved hydro-
gen.19 However, in the current case the intermediate α,β-
unsaturated ketones (or esters, amides) undergo hydro-
genation by the evolved hydrogen generating the final C-
alkylated product. The hydrogenation is most likely medi-
ated by some Mn species assisted by base although it is
not clear how this hydrogenation occurs.
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En-
try
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Alcohol
Product
Conv
(%)b
99
Yield
(%)b
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aConditions: for esters: alcohol (1 mmol), t-butyl acetate (4
mmol), 1 (0.05 mmol), tBuOK (1.5 equiv. relative to alcohol),
and tert-butanol (2 mL), heated in 25 mL Schlenk tube. For
Amides: alcohol (1 mmol), N,N-dimethylacetamide (2 mmol),
1 (0.05 mmol), tBuOK (1.5 equiv. relative to alcohol), and tol-
uene (2 mL), heated in 25 mL Schlenk tube. bconv. and yields
determined by GC and difference between conversion and
yield indicate formation of α,β-unsaturated products.
Scheme 4. Plausible mechanism for the α-alkylation reac-
tions with primary alcohols catalyzed by manganese.
The reaction between benzyl alcohol and N,N-dimethyla-
cetamide to give the C-alkylation of amide product was
optimized in toluene at 125°C using 1.5 equiv of BuOK,
In conclusion, we have developed a manganese pincer
catalyst for the efficient -alkylation of ketones using
primary alcohols, generating water, via a hydrogen
borrowing strategy Formation of -alkylated ketones by
dehydrogenative coupling of secondary alcohols with
primary alcohols was also achieved.. Moreover,
manganes catalyzed C-alkylations of non-activated am-
ides and esters was achieved for the first time.
t
two equiv of N,N-dimethylacetamide, benzyl alcohol de-
rivatives (1 equiv.) and complex 1 (5 mol%). Benzyl alco-
hol, 4-methylbenzyl alcohol and 4-methoxybenzyl alcohol
afforded the corresponding C-alkylated products with very
good yields (86, 92, 96%, respectively) (entries 5-7). The
dehydrogenative coupling of the electron deficient 4-tri-
fluoromethylbenzyl alcohol with N,N dimethyacetamide
gave the desired product in 20% yield only (Table 3, entry
8). However, employing 4-acetylmorpholine afforded 94%
of the C-alkylated product upon treatment with benzyl al-
cohol under the optimized condition. (Table 3, entry 9).
Based on our experimental findings, and on recent mech-
anistic investigations of Mn-catalyzed dehydrogenative
ASSOCIATED CONTENT
Supporting Information. Experimental procedure, GCMS
and NMR data of products “This material is available free of
charge via the Internet at http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
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Author Contributions
†These authors contributed equally.
ORCID:
David Milstein: 0000-0002-2320-0262
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
9
This research was supported by the European Research
Council (ERC AdG 692775), and by the Israel Science
Foundation. D.M. holds the Israel Matz Professorial Chair.
P.D. thanks the Planning and Budgeting Committee
(PBC) for a postdoctoral fellowship.
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