Dehydrogenative cross-coupling of primary alcohols to form cross-esters catalyzed by a manganese pincer complex

Article abstract of DOI:10.1021/acscatal.8b04585

Base-metal-catalyzed dehydrogenative cross-coupling of primary alcohols to form cross-esters as major products, liberating hydrogen gas, is reported. The reaction is catalyzed by a pincer complex of earth-abundant manganese in the presence of catalytic base, without any hydrogen acceptor or oxidant. Mechanistic insight indicates that a dearomatized complex is the actual catalyst, and indeed this independently prepared dearomatized complex catalyzes the reaction under neutral conditions.

Full text of DOI:10.1021/acscatal.8b04585

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Letter
Dehydrogenative Cross-Coupling of Primary Alcohols to Form
Cross-Esters Catalyzed by a Manganese Pincer Complex
Uttam Kumar Das, Yehoshoa Ben-David, Gregory Leitus, Yael Diskin-Posner, and David Milstein
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04585 • Publication Date (Web): 13 Dec 2018
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ACS Catalysis
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Dehydrogenative Cross-Coupling of Primary Alcohols to Form Cross-
Esters Catalyzed by a Manganese Pincer Complex
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†
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‡
‡
†
Uttam Kumar Das, Yehoshoa Ben-David, Gregory Leitus, Yael Diskin-Posner, and David Milstein*
†
‡
Department of Organic Chemistry and Department of Chemical Research Support, Weizmann Institute of Science, Rehovot, 76100,
Israel
ABSTRACT: Base-metal-catalyzed dehydrogenative cross-coupling of primary alcohols to form cross-esters as major products, liberating hy-
drogen gas, is reported. The reaction is catalyzed by a pincer complex of earth-abundant manganese in presence of catalytic base, without any
hydrogen acceptor or oxidant. Mechanistic insight indicates that a dearomatized complex is the actual catalyst, and indeed this independently
prepared dearomatized complex catalyzes the reaction under neutral conditions.
KEYWORDS: manganese, pincer complex, dehydrogenation, primary alcohol, cross-ester, hydrogen
Esters constitute one of the most important classes of compounds in or-
ganic chemistry, and are used as bulk chemicals in commercial products
and polymer industries. The esterification process has numerous appli-
cations in the production of synthetic intermediates, biologically active
Gauvin and co-workers reported Mn-catalyzed dehydrogenative cou-
1
3
pling of alcohols to form homo-esters. We are not aware of reported
base-metal catalyzed dehydrogenative cross-coupling of two different
primary alcohols to form mainly cross-esters with evolution of H .
2
1
natural products, esters of oils and fats, polymers and pharmaceuticals.
Esters are commonly prepared by the reaction of carboxylic
acids or activated acid derivatives, e.g. acid chlorides or anhydrides, with
2
alcohols. In recent years, noble-metal based homogeneous catalysts
have been developed for the dehydrogenative transformation of alco-
3
hols to esters using oxidants or hydrogen aceptors. Heterogeneous cat-
alytic systems based on supported noble-metal nanoparticles have also
4
been developed for the transformation of alcohols to esters. Although
several catalytic procedures for esterification of alcohols to esters have
been reported so far, less attention has been paid to the dehydrogenative
cross coupling of different alcohols to form esters.
The acceptorless dehydrogenative homo-coupling of alco-
5
hols to esters catalyzed by ruthenium was reported by Shvo. We re-
ported metal–ligand cooperative ruthenium catalysts for dehydrogena-
6
tive coupling of primary alcohols, dehydrogenative cross coupling of
7
primary alcohols with secondary alcohols and transesterification of
8
symmetrical ester with secondary alcohols to form esters. The dehy-
drogenative cross coupling of two different primary alcohols to form es-
Scheme 1. Dehydrogenative cross coupling of two different alcohols to
cross esters.
ters with evolution of H is rare. Xiao reported dehydrogenative cross
2
coupling of primary alcohols to esters catalyzed by a dimeric rhodium
9
catalyst in the presence of stoichiometric base (Scheme 1).
Herein we report such a reaction to produce cross-esters from
two different primary alcohols under mild conditions. Moreover this ac-
ceptorless dehydrogenative cross-coupling reaction is catalyzed by a
new manganese pincer complex.
Despite all of these well-established methodologies, the de-
velopment of environmentally benign and cost-effective procedures for
the synthesis of cross-esters continues to attract considerable interest. In
this respect, acceptorless dehydrogenative coupling (ADC) reaction be-
tween primary alcohols appears as an environmentally friendly, oxidant-
free, and atom-efficient catalytic cross coupling process that simultane-
ously produces cross esters and hydrogen.
In this study we have explored our previously reported man-
ganese pincer complexes
1
to (Scheme 2, a), which are very good cat-
5
1
2a, 14
alyst for (de)hydrogenation of alcohols.
For this purpose, we have
now prepared
the new manganese pincer complex
6
Br ( ). Treatment of ourpreviously reported PNN
Ph
Ph
The application of complexes of earth abundant metals (Fe,
Mn( PNN)(CO)
2
15
Co, Ni, Mn) in homogeneous catalysis has attracted much recent atten-
tion.10 Since our first report of a manganese pincer catalyst in 2016,
manganese has offered an attractive alternative to noble metal-based cat-
ligand with one equivalent of Mn(CO)
THF led to formation of complex (
two carbonyl ligands of complex
1917 cm in the IR spectrum in a 1:1 ratio, indicating a nearly 90 C-
Mn-C angle. Single crystals of complex suitable for X-ray diffraction
5
Br at room temperature in
11
6
) in 88% yield (Scheme 2, b). The
6
give rise to two bands at 1838 and
1
2
-1
o
alysts in the area of alcohol dehydrogenation chemistry. Recently
6
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ACS Catalysis
by Ph P groups resulted under the same conditions in high catalytic ac-
Page 2 of 6
were obtained by slow diffusion of pentane into a saturated solution of
dichloromethane at -30 °C. The molecular structure of exhibits an oc-
tahedral geometry with a meridional arrangement of the PNN ligand.
The CO ligands are orthogonal to each other (86.75°), in line with the
IR spectrum (Figure 1, and SI).
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tivity, perhaps due to decreased steric hindrance and higher Lewis acid-
ity of the metal center, favoring a coordinated aldehyde intermediate.
Thus, methyl benzoate was formed in 87% yield at 110 °C (Table 1, en-
try 6) and 93% at 120 °C, with 97 % benzyl alcohol conversion after 24h
Ph
(
Table 1, entry 7), as revealed by GC-MS and NMR. Analysis of the gas
phase by GC indicated formation of H . Noteworthy the reaction does
not require addition of an oxidant or hydrogen acceptor. Thus,
2
Ph
t
Mn( PNN)(CO) Br ( ) in the presence of catalytic BuOK is an effi-
6
2
cient catalyst for alcohol dehydrogenative coupling with methanol to
form methyl esters. Good yields were obtained also after 12h (Table 1,
entry 8). Using 1:5 molar ratio of benzyl alcohol andmethanol produced
56% of methyl ester in addition to benzyl benzoate as self-coupled prod-
uct (Table 1, entry 9). Unexpectedly, using methanol (2 mL) as solvent
and one equivalent of benzyl alcohol at 110 °C in a closed Schlenk tube
under the same conditions did not produce any ester product, perhaps
due to lower actual reaction temperature (Table 1, entry 10). Employing
methanol: THF (1:1) was not effective and resulted in only 43% of me-
thyl benzoate with 50 % alcohol conversion after 24h (Table 1, entry
0
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11).
Table 1. Manganese catalyzed dehydrogenative coupling of benzyl alco-
hol and methanol.
Scheme 2. (a) Manganese pincer complexes (1-5) explored in this
Ph
study. (b) Synthesis of Mn( PNN)(CO)
formation (SI) for experimental details.
2
Br (6). See Supporting In-
entry
[Mn]
solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Methanol
temp.
110
110
110
110
110
110
120
120
120
110
110
conv.(%)
25
yield(%)
16
9
a
1
2
3
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5
6
1
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6
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6
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6
a
15
45
63
25
82
97
74
99
a
30
41
17
78
93
70
a
a
a
a
7
8
b
9c
56
d
e
1
1
0
1
10
50
-
43
f
THF:CH
3
OH
Ph
Figure 1. Molecular structure of Mn( PNN)(CO)
2
Br (
6
) complex.
Reaction conditions: [a] benzyl alcohol (1 mmol), Mn-cat (0.02
t
Thermal ellipsoids are drawn at 50% probability level. Hydrogen atoms
are omitted for clarity. Selected bond lengths (Å): Mn1-Br1 =
2.5429(3), Mn1-N1 = 2.0301(12), Mn1-N2 = 2.0276(13), C24-O1 =
1.1611(18), C25-O2 = 1.188(4), Mn1-P1 = 2.2353(4). Selected bond
angles (°): N1-Mn1-N2 = 79.09(5), Br1-Mn1-C25 = 176.22(11), N1-
Mn1-P1 = 84.62(4), N2-Mn1-P1 = 163.12(4), N1-Mn1-C24 =
mmol), BuOK (0.03 mmol), methanol (10 mmol), 2 mL toluene, 24h.
[b] Reaction time 12h. [c] 5 mmol CH
3
OH used. [d] Rest of product
was benzyl benzoate. [e] Benzyl alcohol (1 mmol), methanol (2 mL),
6
t
(0.02 mmol), BuOK (0.03 mmol), [f] Benzyl alcohol (1 mmol), (0.02
6
t
mmol), BuOK (0.03 mmol), 2 mL 1:1 THF and methanol as solvent.
1
All yields and conversions are calculated using GC-MS and H NMR
1
78.13(6), N1-Mn1-C25 = 94.94(11), Mn1-C24-O1 = 176.51(13),
with mesitylene as internal standard.
Mn1-C25-O2 =175.9(3), C24-Mn1-C25 =86.75(12). See Supporting
Information (SI) for crystallography details.
The scope of this base-metal-catalyzed cross-coupling of pri-
6
mary alcohols with methanol using complex was probed with different
In optimization studies, the coupling of benzyl alcohol with
methanol was chosen as a model reaction. Reaction of benzyl alcohol (1
aromatic and aliphatic alcohols. As shown in Table 2, benzylic alcohols
with electron donating or electron withdrawing groups were converted
to the methyl esters in good to excellent yields. The para substituted
mmol), methanol (10 mmol), complex
or complex (2 mol %) in
1 2
t
presence of 3 mol % of potassium tert-butoxide ( BuOK) in 2 mL of tol-
uene at 110 °C in a closed Schlenk tube resulted after 24 h in formation
of methyl benzoate in poor yield with a very small amount of benzyl ben-
zoate (Table 1, entries 1 and 2). Under the same reaction conditions
benzyl alcohols (p-Me, p-Et, p-Ph, p-halo, p-CF , p-OMe ) dehydro-
3
genatively coupled with methanol to give methyl esters in excellent
yields. Dehydrogenative coupling of m-substituted benzyl alcohols (m-
OMe, m-N(CH ) ) with methanol also proceeded well. The methyl es-
3
2
using complex
benzyl alcohol were observed (Table 1, entry 3). Using complex
alyst, the alcohol conversion increased to 63%, giving 41% yield of the
methyl ester product (Table 1, entry 4). Complex was not an effective
catalyst, leading to only 17% of methyl benzoate (Table 1, entry 5). In-
3
as catalyst 30% methyl benzoate and 45% conversion of
ter formation was tested also with primary aliphatic alcohols. Methyl es-
ters of 1-hexanol and 1-ocatanol were formed in 85% and 80% yields,
respectively, using a 1:20 molar ratio of alcohol and methanol. In a sim-
ilar way, 2-phenyl ethanol and 3-phenyl propanol were also converted to
the corresponding methyl esters in 75% and 71% yields, respectively
(Table 2).
4
as cat-
5
t
terestingly, using complex
6
, in which the Bu P groups of are replaced
5
2
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ACS Catalysis
Table 2. Manganese catalyzed dehydrogenative coupling of primary al-
cohols with methanol.a
Table 3. Manganese catalyzed dehydrogenative cross-coupling of ben-
zylic alcohols with different aliphatic alcohols.a
1
2
3
4
5
6
7
8
9
Yield (%)b
82(78%)c
entry
1
A
B
x:y
1:10
Ethanol
2
3
4
5
6
Ethanol
Ethanol
1:5
1:10
1:10
1:5
67
85
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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9
0
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2
3
4
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9
0
Ethanol
80
78(75)c
1-Propanol
1-Propanol
1-Butanol
1:5
81
67
7
8
9
1:1
1:1.75
1:1
d
80
1-Butanol
1-Butanol
73
10
1:1
75
[
a] Reaction conditions: alcohol (1 mmol), CH
3
OH (10 mmol),
6
t
(
0.02 mmol), BuOK (0.03 mmol), toluene (2 mL), 120°C, 24 hrs. All
yields are calculated using GC-MS and H NMR with mesitylene as in-
ternal standard. [b] Isolated yields. [c] 20 mmol CH OH were used.
1
1
1
1
2
3
1-Butanol
1:1
1:1.75
1:1
73
84
65
1
d
3
1-Butanol
1-Hexanol
To evaluate the scope of the reaction, different aliphatic alco-
hols other than methanol were tested using this methodology. Reaction
between benzyl alcohol and ethanol in 1:10 molar ratio, respectively, re-
sulted in 82% yield of ethyl benzoate (Table 3, entry 1). As expected,
lowering the amount of primary alcohol relative to benzyl alcohol re-
sulted in a mixture of esters. Reaction between benzyl alcohol and etha-
nol in 1:5 molar ratio resulted in 67% of ethyl benzoate and 10% benzyl
benzoate (Table 3, entry 2). p-OMe and p-Cl benzyl alcohols produced
85% and 80% of the corresponding ethyl benzoates when a 1:10 molar
excess of ethanol was used (Table 3, entry 3 and 4). In a similar way pro-
pionic esters of different benzylic alcohols were synthesized in good
yields using 1:5 molar ratio of benzylic alcohols and 1-propanol, respec-
tively (Table 3, entry 4 and 5).
14
1:1.75
63e
[a] Reaction conditions: benzyl alcohol (1 mmol), aliphatic alcohol (y
t
mmol), (0.02 mmol), BuOK (0.03 mmol), toluene (2 mL), 120°C, 24
6
1
hrs. [b] All yields are calculated using GC and H NMR with mesitylene
as internal standard. [c] Isolated yield. [d] Butyl butyrate formed as side
product. [e] Hexyl hexanoate formed as side product.
In experiments using just benzyl alcohols or long chain pri-
mary aliphatic alcohols under the above-mentioned reaction conditions
self-coupled esters were formed (Scheme 3, a). However, we did not ob-
serve methyl formate or ethyl acetate formation using methanol or eth-
anol, likely due to volatility. Reaction of benzyl benzoate (1 mmol),
methanol (10 mmol), complex (2 mol %) in presence of 3 mol % of
6
t
potassium tert-butoxide ( BuOK) in 2 mL of toluene at 120 °C in a
closed Schlenk tube resulted 70% methyl benzoate and 6% of benzyl al-
cohol after 24 h (Scheme 3, b).
Next, the longer chain alcohols 1-butanol and 1-hexanol were
explored. Interestingly, using a 1:1 molar ratio of 1-butanol and benzyl
alcohol resulted in formation of n-butyl benzoate in 67% yield as cross-
ester product. Only small amounts of the homo-coupled esters benzyl
benzoate and butyl butyrate were formed as side products (5-10% each,
see SI).The relatively selective formation of n-butyl benzoate may be
due to faster dehydrogenation of benzyl alcohol to the aldehyde as com-
pared with formation of the aliphatic aldehyde. As expected, increasing
the amount of 1-butanol, resulted in higher yield of the cross-ester.
Thus, reaction of 1.75 mmol of 1-butanol with one mmol of benzyl alco-
hol produced butyl benzoate in 80% yield (Table 3, entry 7 and 8). As
shown in Table 3, benzyl alcohols bearing various electron-donating or
electron-withdrawing substituents at the para position (p-OMe, p-Cl, p-
F, p-CF3) dehydrogenatively coupled with 1-butanol to give selectivity
the corresponding butyl benzoates (Table 3, entries 9−13). Formation
of butyl butyrate was observed as the only homo coupled ester when ex-
cess 1-butanol was used. Coupling of one mmol of 1-hexanol with one
mmol benzyl alcohol gave mixtures of esters in both closed and open
systems (See SI); at 1:1.75 molar ratio of benzyl alcohol:1-hexanol, 63%
of hexyl benzoate and 22% of hexyl hexanoate were obtained (Table 3,
entry 14).
Scheme 3. (a) Manganese catalyzed dehydrogenative self-coupling of
alcohols and (b) coupling of benzyl benzoate with methanol. (c) alkoxy
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8 6
formation from complex and (d) coupling of benzyl alcohol
Page 4 of 6
complex
with methanol catalyzed by complex .
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Scheme 4. Plausible mechanism of manganese catalyzed dehydrogena-
tive cross coupling of alcohols.
Ph
Figure 2. Molecular structure of Mn( PNN)(OCH
2
Ph)(CO)
(8)
2
complex. Thermal ellipsoids are drawn at 50% probability level. Hydro-
gen atoms are omitted for clarity. Selected bond lengths (Å): Mn1-O1
= 2.0021(14), Mn1-N1 = 2.0349(17), Mn1-N2 = 2.0345(17), Mn1-P1
= 2.2359(6), O2-C24 = 1.168(3), O3-C25 = 1.173(2), Mn1-C24 =
.780(2), Mn1-C25 = 1.761(2). Selected bond angles (°): N1-Mn1-N2
78.66(7), O1-Mn1-C25 = 174.82(8), N1-Mn1-P1 = 160.90(5), N2-
Mn1-P1 = 82.86(5), N1-Mn1-C24 = 100.22(6), N1-Mn1-C25 =
3.86(11), Mn1-C24-O2 = 176.7(2), Mn1-C25-O3 =176.67(19), C24-
Based on the above observations, a plausible catalytic cycle
for the Mn-catalyzed cross ester formation from two different primary
alcohols is presented in Scheme 4. Reaction of the pre-catalyst with the
base generates the dearomatized complex , which adds the alcohol via
MLC to form the alkoxy complex . Then β-H elimination (perhaps in-
6
7
1
=
8
volving a non-classical alkoxide dissociation, assisted by the hydrogen
bonded alcohol molecule, followed by hydride elimination from the dis-
sociated alkoxide, as invoked for similar coordinatively saturated Mn-
9
Mn1-C25 =87.37(9), Mn1-O1-C26 = 126.67(13). See Supporting In-
formation (SI) for crystallography details.
14d
alkoxy complexes) generates the intermediate , bearing a coordi-
9
16
nated aldehyde. Nucleophilic attack by the another alcohol on the al-
dehyde gives hemiacetal coordinated intermediate 10, which upon β-H
elimination forms the dihydride intermediate 11, with liberation of ester
molecule. Finally, dihydrogen loss from intermediate 11 regenerates the
To gain the insight into the mechanism of the manganese cat-
alyzed dehydrogenative cross coupling of alcohols, complex
6
was re-
t
acted with 1.1 equivalent of BuOK in THF at room temperature to form
active catalyst
7
and completes the catalytic cycle. Formation of inter-
Ph
the dearomatized complex Mn( PNN*)(CO)
Complex was characterized by IR and NMR spectroscopy (see SI).
Employing the freshly prepared (3 mol %) as a catalyst in the dehydro-
2
(
7) (Scheme 3, c).
mediate with coordinated benzaldehyde, and perhaps also the nucleo-
9
7
philic attack on it by the aliphatic alcohols are likely preferred due to the
electron-withdrawing nature of the phenyl ring, resulting in the ob-
served selectivity.
7
genative coupling of benzyl alcohol and methanol at 120° C resulted in
methyl benzoate in 82% yield after 24 hours in the absence of any added
In conclusion, we have demonstrated experimental condi-
tions for the formation of cross-esters as major products using different
primary alcohols. Moreover, this acceptorless dehydrogenative coupling
reaction is catalyzed by a base metal catalyst. The reaction proceeds un-
base (Scheme 3, d). Reaction of complex and 1.5 equivalent of benzyl
7
alcohol in THF (or toluene) at room temperature resulted in formation
Ph
of the alkoxy complex Mn( PNN)(OCH
2
Ph)(CO)
(8) by O-H acti-
2
vation through metal-ligand cooperation (MLC), as we observed previ-
der homogeneous reaction conditions and is catalyzed by the new pincer
ously in case of a similar Mn-PNN complex (Scheme 3, c).1 The alkoxy
4d
Ph
catalyst Mn( PNN)(CO)
2
Br (
6
) in presence of catalytic base, or in ab-
. A plausible mechanism
is provided, supported by control experiments and the observation of in-
termediates and formed by metal-ligand cooperation.
complex
8
was also characterized by IR, NMR and single crystallography
showed a neutral octahedral
sence of base using the dearomatized complex
7
(
see SI). Crystal stucture of complex
8
manganese complex bearing a PNN pincer ligand, two mutually cis CO
7
8
ligands (C24-Mn1-C25 =87.37°) and an alkoxy group (Figure 2, see SI).
3
1
Heating complex
8
( P = 91 ppm) at 120 °C in toluene-d resulted in
8
ASSOCIATED CONTENT
Supporting Information
Experimental details, crystallographic data, NMR and IR spectra of com-
plexes. This material is available free of charge via the Internet at
http://pubs.acs.org.
observation of benzyl benzoate by GC-MS (indicating some benzyl al-
cohol dissociation from at that temperature) and two new peaks ap-
8
31
1
peared in the P{ H} NMR at 98 ppm and 115 ppm, suggesting Mn-H
complex formation. The formation of Mn-H complex (complex 11) was
confirmed by H NMR spectroscopy ( H NMR = -2.6 ppm, see SI) and
by comparison with a separate reaction of complex with an equimolar
amount of NaBHEt (See SI). We believe that complexes and 8 are
actual intermediates in the catalytic cycle.
1
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6
AUTHOR INFORMATION
Corresponding Author
3
7
*E-mail: david.milstein@weizmann.ac.il.
ORCID
David Milstein: 0000-0002-2320-0262
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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This research was supported by the European Research Council (ERC
(10) Reviews on catalysis by Fe, Ni, and Co complexes: (a) Bullock, R. M.
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doctoral Fellowship.
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