Ru-Catalyzed Selective Catalytic Methylation and Methylenation Reaction Employing Methanol as the C1 Source

Article abstract of DOI:10.1021/acs.joc.1c01185

Methanol can be employed as a green and sustainable methylating agent to form C-C and C-N bonds via borrowing hydrogen (BH) methodology. Herein we explored the activity of the acridine-derived SNS-Ru pincer for the activation of methanol to apply it as a C1 building block in different reactions. Our catalytic system shows great success toward the β-C(sp3)-methylation reaction of 2-phenylethanols to provide good to excellent yields of the methylated products. We investigated the mechanistic details, kinetic progress, and temperature-dependent product distribution, which revealed the slow and steady generation of in situ formed aldehyde, is the key factor to get the higher yield of the β-methylated product. To establish the environmental benefit of this reaction, green chemistry metrics are calculated. Furthermore, dimerization of 2-naphthol via methylene linkage and formation of N-methylation of amine are also described in this study, which offers a wide range of substrate scope with a good to excellent yield.

Full text of DOI:10.1021/acs.joc.1c01185

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Article
Ru-Catalyzed Selective Catalytic Methylation and Methylenation
Reaction Employing Methanol as the C1 Source
Nandita Biswas and Dipankar Srimani*
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ABSTRACT: Methanol can be employed as a green and
sustainable methylating agent to form C−C and C−N bonds via
borrowing hydrogen (BH) methodology. Herein we explored the
activity of the acridine-derived SNS-Ru pincer for the activation of
methanol to apply it as a C1 building block in different reactions.
Our catalytic system shows great success toward the β-C(sp3)-
methylation reaction of 2-phenylethanols to provide good to
excellent yields of the methylated products. We investigated the
mechanistic details, kinetic progress, and temperature-dependent
product distribution, which revealed the slow and steady generation of in situ formed aldehyde, is the key factor to get the higher
yield of the β-methylated product. To establish the environmental benefit of this reaction, green chemistry metrics are calculated.
Furthermore, dimerization of 2-naphthol via methylene linkage and formation of N-methylation of amine are also described in this
study, which offers a wide range of substrate scope with a good to excellent yield.
aldol condensation, and hydrogenation.12a In 2014, Beller and
INTRODUCTION
The methyl group is an important functionality found in many
■
co-workers12a first demonstrated β-methylation of 2-aryletha-
biologically active molecules1 and plays a significant role in
nols. The cooperative reactivity of Ru-MACHO and Shvo’s
regulating the pharmaceutical properties2 of a molecule. A
diruthenium complex is highly essential to afford the desired β-
methylated product in good yield. In 2019, Leitner and his
group demonstrated the selective β-methylation of 2-
arylethanols in the presence of a single Ru(II) catalyst
[RuH(CO)(BH4)(HN(C2H4PPh2)2)]. Two equivalents of
NaOMe is essential to promote the reaction at 150 °C.12b
Very recently, Fe-catalyzed β-methylation of 2-arylethanols was
reported by Renaud12c and Morrill,12d utilizing either a mixture
of bases or applying of trimethylamine N-oxide additive and
base (2 equiv). In 2020, Leitner demonstrated Mn-catalyzed β-
methylation of 2-arylethanols at higher temperatures and high
base loading.12e Heterogeneous catalysts such as Iridium
nanocluster12f and platinum on carbon12g are utilized for this
reaction. Thus, the development of a more general sustainable
protocol for methylation reaction is an area of importance.
Recently, we explored the applicability of air-stable Ru
complexes (Figure 1) in the de(hy)drogenative reactions.15
Engrossed by the salient benefit of methylation reaction using
methanol and motivated our recent work on multistep
de(hydrogenative) transformation,16 herein we demonstrated
report says that around 67% of the top-selling drugs of 2011
contain at least one methyl group that is bound to a carbon,
nitrogen, or oxygen atom.3 In particular, the installation of
methyl groups can dramatically improve IC50 values of a
specific drug.3,4 Therefore, the direct introduction of a methyl
group to such moiety in a single step and in a greener way is an
important area of scientific research. Methanol can be
renewably obtained from lignocellulosic biorefinery.5 Thus,
the applicability of methanol as a methylating agent relative to
commonly employed methylating reagents such as diazo-
methane, dimethyl sulfate, and iodomethane6 is highly
desirable as methanol is considered as a sustainable and
atom economical C1 source.7 Recently, (de)hydrogenative8
construction of C−C, C−N, and C−S bonds using renewable
alcohols has attracted enormous attention due to its atom-
efficient and environmentally benign nature. However,
methylation reactions are quite challenging over alkylation8c,9
as a large enthalpy (ΔH for methanol is +84 kJ mol−1)10 is
required to convert methanol to formaldehyde via dehydrogen-
ation. Therefore, the development of new catalytic protocols
for selective methylation is highly demanding.
Received: May 21, 2021
Published: July 15, 2021
The β-methylation of aliphatic alcohols plays an important
role in the synthesis of higher or branched alcohols, in
particular for alcohol biofuels.10b,11 The coupling of methanol
and primary alcohol12 or secondary alcohol12f,13 is highly
challenging compare to α-methylation of ketone14 as it
involves multiple reaction steps12a including dehydrogenation,
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Table 1. Optimization of the Reaction Conditions for the β-
a
Methylation of 2-Phenylethanol
Figure 1. Ruthenium pincer complexes.
MeOH
(mL)
time
(h)
yield
b
entry cat. (mol %) base (mmol)
(%)
the β-methylation of alcohols. Furthermore, the protocol
expanded toward selective mono N-methylation reaction of
amine and dimerization of 2-naphthol via methylene linkage to
present the versatility of the developed catalyst (Scheme 1).
1
2
3
4
1 (2 mol %) KOH (1)
1 (2 mol %) KOH (1)
1 (2 mol %) KOH (1)
1 (2 mol %) tBuOK (1)
1 (2 mol %) tBuOK (1)
1 (2 mol %) tBuOK (1)
1 (2 mol %) tBuOK (0.5)
1 (2 mol %) tBuOK (0.5)
1 (2 mol %) tBuONa (1)
1 (2 mol %) NaOH (1)
1 (2 mol %) K2CO3 (1)
1 (1 mol %) tBuOK (1)
1 (2 mol %)
3
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
48
48
36
48
36
24
36
48
36
36
36
48
36
36
48
36
36
36
68
98
70
99
99
70
66
70
75
50
5
Scheme 1. C-Methylation and N-Methylation Reactions
Using Methanol as the Methylating Agent
6
7
8
9
10
11
12
13
14
15
16
17
18
70
75
56
tBuOK (1)
c
1 (2 mol %) tBuOK (1)
2 (2 mol %) tBuOK (1)
3 (2 mol %) tBuOK (1)
1 (2 mol %) tBuOK (1)
d
a
Reaction conditions: alcohol (1 mmol), cat. 1 (2 mol %), base (1
b
mmol), MeOH (1 mL), 135 °C, 100 mL Ace pressure tube. NMR
c
d
yield using acetonitrile as an internal standard. 110 °C. 30 mL Ace
RESULT AND DISCUSSION
pressure tube.
■
In our initial experiments, the methylation of 2-phenylethanol
(4a) was selected as a model system to find out the optimum
reaction conditions. When 2-phenylethanol (1 mmol), MeOH
(3 mL), KOH (1 mmol) was heated at 135 °C for 48 h in a100
mL Ace pressure tube in the presence of 2 mol % catalyst 1,
68% 2-phenylpropan-1-ol (5a) was obtained (Table 1, entry
1). Interestingly, a lower amount of MeOH (1 mL) under
similar conditions improved the yield of 5a to 98% (Table 1,
entry 2). However, a lower reaction time (36 h) resulted in a
decrease of the yield of 5a (Table 1, entry 3). On the other
hand, within 36 h, quantitative conversion was observed when
tBuOK was used as a base (Table 1, entry 5). Decreasing the
substitution at the 2- and 6-positions does not hinder β-
C(sp3)-methylation. Fluoro- and chloro-substituted com-
pounds were well tolerated. However, 2-(4-bromophenyl)-
ethanol gave the corresponding product in a moderate yield
60% (5g) along with 20% (5a) dehalogenated product.
Heterocyclic alcohol such as thiophene-substituted ethanol
was smoothly converted to the corresponding methylated
product (5h) with a high yield, 90%. The extended aromatic
system, 2-naphthylethanol, responded well under the reaction
conditions. Unfortunately, 2-phenoxyethan-1-ol (4k) failed to
give any product. When 2-(4-aminophenyl)ethanol was used as
a substrate, both β-C(sp3)-methylation and N-methylation
occurred, providing 5l in 60% isolated yield together with
some N-methylated product (5m), indicating that N-
methylation is much faster than the β-C(sp3)-methylation
reaction. 2-Phenylethanol having a −CN or −NO2 group in
the aromatic nucleus failed to give the desired product.
Methylation of 3-(4-methoxyphenyl)propan-1-ol (Scheme 2)
afforded 5p in 55% isolated yield. It is important to note that
the starting material 3-(4-methoxyphenyl)propan-1-ol was also
prepared by reacting 4-methoxybenzyl alcohol with ethanol via
BH reaction,17 employing our developed catalyst.
t
amount of BuOK (0.5 mmol) led to lower conversions of the
product even after 48 h. (Table 1, entry 8). Bases like tBuONa
and NaOH gave a moderate yield (Table 1, entries 9 and 10)
under similar reaction conditions, whereas K2CO3 failed to
give the desired product (Table 1, entry 11). Without the
presence of any base, catalyst 1 failed to activate the alcohols;
t
similarly, in the absence of catalyst 1, 1 mmol BuOK did not
give any desired 2-phenylpropan-1-ol (5a) (Table 1, entries 13
and 14). Cat. 2 and cat. 3 are incompetent toward this β-
C(sp3)-methylation reaction (Table 1, entries 16 and 17).
With optimized reaction conditions in hand (Table 1, entry
5), the scope of the Ru-catalyzed β-C(sp3)-methylation of
alcohols was explored (Scheme 2). Gratifyingly, high
conversions and good yields were observed for substituted 2-
arylethanols (Scheme 2, 5a−5m). Electron-donating substitu-
ents such as 2-(p-tolyl)ethanol (4b) and 2-(4-methoxyphenyl)-
ethanol (4c) afforded excellent yields of the corresponding
methylated products (87%, 5b; 81%, 5c). 2-(2,4,6-
Trimethoxyphenyl)propan-1-ol afforded 92% yield (5d),
indicating that the increased steric effect provided by aryl
For the preparative scale synthesis of 5a, we were able to
lower the catalyst loading (1 mol %) as well as the 4a/MeOH
ratio, and 100% conversion of 4a with a high isolated yield
(86%) of 5a was obtained. The green chemistry metrics18 of
this reaction with an E-factor of 1.34, 88% atom economy, 76%
atom efficiency, 100% carbon efficiency, and 76% reaction
mass efficiency clearly exposed the technical and environ-
mental benefits of this methodology (Scheme 3).
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of 4ad. Next, 4ae will lead to the formation of 5a via the
hydrogen-autotransfer process.
Scheme 2. Substrate Scope for β-Methylation of 2-
Phenylethanols
a
We carried out some control experiments (Scheme 5) to
shed light on the proposed mechanism. When preformed 2-
Scheme 5. Controlled Experiments
a
t
Reaction condition: alcohol (1 mmol), cat. 1 (2 mol %), BuOK (1
mmol), MeOH (1 mL), 135 °C, 100 mL Ace pressure tube.
b
t
Reaction condition: alcohol (2 mmol), cat. 1 (1 mol %), BuOK (1
mmol), EtOH (1 mL), 135 °C, 100 mL Ace pressure tube.
Scheme 3. Green Chemistry Metrics
phenylprop-2-en-1-ol 4ae was subjected to the “standard”
reaction conditions, β-C(sp3)-methylated product 5a was
formed in 87% yield. The compound 4ae was also converted
to 5a (90%) in the presence of cat. 1 and molecular H2. This
clearly indicates the involvement of compound 4ae as an
intermediate in the β-C(sp3)-methylation reaction. Intermedi-
ate 4ad under the standard reaction conditions smoothly
converted to 5a (72%), which underpins 4ad and might be
another possible intermediate. The reaction with 2-phenyl-
ethanol 4a and formaldehyde in a hydrogen atmosphere (10
bar) in toluene keeping other conditions unaltered gives β-
C(sp3)-methylated product 5a with 10% yield, supporting that
formaldehyde is another plausible intermediate. The low yield
of this experiment was possibly because of the low solubility of
formaldehyde in toluene12e and the hydrogenation reaction of
formaldehyde in the presence of a hydrogen atmosphere.
When the intermediate 4ac was subjected to the standard
reaction conditions, 5a was formed with 46% yield after 2 h.
Under standard reaction conditions, phenylacetaldehyde (4aa)
gave deoxygenative coupling19 product (6a) with 26% yield
and 2-phenylethanol 4a (35%). Thus, slow generation of
phenylacetaldehye from 4a is important to form the desired
product 5a in a high yield.
The β-C(sp3)-methylation method may likely follow a
borrowing-hydrogen mechanism12a,g (Scheme 4). First, de-
hydrogenation of 2-phenylethanol and methanol leads to the
formation of 4aa and formaldehyde, which can form
condensation product 4ab. Compound 4ab will eventually
transform to 4ae either via dehydration followed by hydro-
genation of 4ac or first hydrogenation followed by dehydration
Scheme 4. Proposed Reaction Mechanism
To gain further mechanistic insight, a deuterium-labeling
experiment with CD3OD was carried out (Scheme 6). The β-
CD3 group incorporation within alcohol yielded 76% β-CD3-
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To expand the scope of methanol activation, next, we are
interested in investigating the reactivity of methanol with β-
naphthol to synthesize 1,1′-methylene-bis(2-naphthol). These
compounds frequently occur in various biologically active
compounds20 and are used as versatile synthetic intermediates
and anion receptors.20a 1,1′-Methylene-di(2-naphthol) radio-
labeled with carbon-11 (ST1859) also used as a drug for the
treatment of Alzheimer’s disease.21 Kirchner’s group showed
the possibility (one example) of the formation of 1,1′-
methylene-bis(2-naphthol) in their work on three-component
aminomethylation reaction of 2-naphthol.22 Herein, we applied
our protocol to synthesize several important 1,1′-methylene-
bis(2-naphthol) derivatives. When 2-naphthol (1 mmol),
tBuOK (1 mmol), MeOH (1 mL), and Cat. 1 (1 mol %)
were refluxed in Ace pressure tube at 135 °C for 36 h, 1,1′-
methylenebis(naphthalen-2-ol) 8a was isolated in 81% yield
(Scheme 7). 2-Naphthol with an electron-donating group like
Scheme 6. Labeling Experiments with Deuterated Methanol
labeled 2-phenylethanol with 99.91% deuterium incorporation,
in addition to significant deuterium incorporation at the α-
(71% D) and β-(82% D) positions. This experiment confirmed
methanol acting as the methylating agent and provided the
support for the borrowing hydrogen mechanism (Scheme 6).
Next, we have studied the time-dependent product
distribution of the catalytic reaction of β-methylation of 2-
phenylethanol (Figure 2). The concentrations of the substrate
a
Scheme 7. Substrate Scope for Methylation of 2-Naphthol
Figure 2. Time-dependent product distribution in β-methylation of 2-
phenylethanol with methanol at 135 °C catalyzed by complex 1.
(2-phenylethanol 4a) gradually decreased with time, and
concurrently, the concentration of product 5a increased at 135
°C. From the curve, it is clear that very slow conversion of 2-
phenylethanol happened with the optimum reaction con-
ditions, and it takes 30 h to complete the reaction.
Subsequently, we have checked the temperature-dependent
product distribution of β-methylation of 2-phenylethanol
(Figure 3). At temperatures 90, 110, and 135 °C, the reaction
a
Reaction conditions: 2-naphthol (1 mmol), cat. 1 (1 mol %), tBuOK
(1 mmol), MeOH (1 mL), 36 h, 135 °C, 100 mL Ace pressure tube.
b
0.5 mmol scale.
7-methoxynaphthalen-2-ol and 3-methoxynaphthalen-2-ol also
participated well in the reaction and produced 1,1′-
methylenebis(7-methoxynaphthalen-2-ol) 8b and 1,1′-
methylenebis(3-methoxynaphthalen-2-ol) 8c in good yields.
Electron-withdrawing groups like 6-bromo and 7-bromo
napthalen-2-ol gave moderate to good yields (8d, 55%; 8e,
79%).
Gram-scale synthesis of 1,1′-methylenebis(naphthalen-2-ol)
with catalyst loading 0.5 mol %, using MeOH 2 mL, giving
69% isolated yield. The green chemistry metrics for this
reaction with an E-factor of 2.24, 94% atom economy, 65%
atom efficiency, 100% carbon efficiency, and 65% reaction
Figure 3. Temperature-dependent product distribution in β-
methylation of 2-phenylethanol with methanol catalyzed by complex
1.
proceeded slowly and steadily, whereas, at a higher temper-
ature (160 °C), a sharp rise in product formation was
observed. Within 3 h, 55% conversion was noticed, and it took
only 15 h to complete the reaction. Therefore, the high
temperature has some salient effect on product distribution
over time.
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mass efficiency clearly exposed the synthetic utility of this
methodology (Scheme 8).
Aniline with electron-donating and electron-withdrawing
groups responded well, giving excellent yields (80−92%) of
the corresponding products (10b−10e). 2-Aminopyridine was
also well-tolerated and afforded 90% yield 10f. Benzene-1,3-
diamine and pyridine-2,6-diamine were also converted to
corresponding methylated products N1,N3-dimethylbenzene-
1,3-diamine (10g, 80%) and N2,N6-dimethylpyridine-2,6-
diamine (10h, 91%) in good yields. Furthermore, when two
−NH2 groups are para to each other in an aromatic ring, then
double methylation occurs in one amine group, and mono
methylation occurs on the other amine group, giving N1,N1,N4-
trimethylbenzene-1,4-diamine 10i (79%). Substituents at the
ortho position suppressed the product yield (10j−10l) due to
the steric effect. More sterically demanding 2,4,6-trimethylani-
line did not respond toward this reaction. Only moderate
yields of the monomethylated products were isolated (32−
35%) when aliphatic amines such as octylamine, dodecylamine,
and hexadecylamine were used as substrates. Under the
optimized reaction conditions in the presence of 1 mol % cat.
1, hexadecylamine converted to the corresponding mono-
methylated product 10o in 44% yield (35% isolated), whereas
no dimethylated product was detected. Interestingly, when 5
mol % of cat. 1 was used, 88% conversion (NMR) to the
monomethylated product was observed with a small amount
(8%) of dimethylated product. Furthermore, when mono-
methylated product 10o was separately treated with MeOH
under the optimized reaction condition in the presence of 2
mol % cat. 1 only 10% dimethylated product was formed.
When secondary amines such as 1,2,3,4-tetrahydroisoquinoline
were subjected to the methylation reaction, no methylated
tertiary amine (10u) was observed. When (2-aminophenyl)-
(phenyl)methanone and (5-chloro-2-(methylamino)phenyl)-
(phenyl)methanol were used as substrates, 10r and 10s were
obtained in 70% and 65% yields, respectively. Here, the
carbonyl group was also hydrogenated due to the presence of
excess H2 in the reaction medium. Nevertheless, when
dehydrogenative reaction conditions were employed, using
cat. 1, 10s can be easily converted to the biologically
important26 diazepam precursor (10s′) with 60% isolated
yield.
Scheme 8. Green Chemistry Metrics
Next, to check the versatility of our catalyst, the direct N-
methylation of amines17e,23,24 was investigated as this is
considered as one of the most important transformations in the
synthesis of natural products, fine chemicals, and pharmaceut-
icals.25 Thus, when a mixture of aniline (1 mmol), KOH (0.5
mmol), cat. 1 (1 mol %), and MeOH was refluxed at 135 °C in
a 100 mL Ace pressure tube for 48 h, 50% N-methylaniline
(10a) (Table S1) was formed. The reaction is selective toward
monomethylation as no N,N-dimethyl aniline was not
detected. The yield of 10a was further improved to 95%
when the base amount increased to 2 mmol (Table S1, entry
3). A quick screening of different bases (Table S1, entries 4, 5,
t
and 8−10) revealed that BuOK is a better choice over KOH.
After having the optimized reaction condition, we explored
the substrate scope of the N-methylation reaction (Scheme 9).
a
Scheme 9. Substrate Scope for Methylation of Amine
For the preparative scale synthesis of N-methylaniline, the
green chemistry metrics with an E-factor of 1.85, 86% atom
economy, 80% atom efficiency, 100% carbon efficiency, and
80% reaction mass efficiency clearly exposed the technical and
environmental benefits of this methodology (Scheme 10).
Scheme 10. Green Chemistry Metrics
In order to gain insight, kinetic isotope experiments (KIE)
were carried out (Scheme 11). First, a mixture of CD3OD/
Scheme 11. Labeling Experiments with Deuterated
Methanol
a
t
Reaction conditions: aniline (1 mmol), cat. 1 (1 mol %), BuOK (1
mmol), MeOH (1 mL), 135 °C, 36 h, 100 mL Ace pressure tube.
b
c
d
Yield in the parentheses is the NMR yield. 5 mol % catalyst. 48 h.
e
t
10p (0.5 mmol), cat. 1 (1 mol %), BuOK (5 mol %), toluene (1
mL), 135 °C, 24 h, argon.
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reaction mixture was cooled to room temperature, diluted with
dichloromethane, and filtered over a plug of Celite. The solvent was
evaporated under reduced pressure, and the residue obtained was
purified by column chromatography (hexane/ethyl acetate) on silica
gel to afford the desired product.
CH3OH (1:1, v/v) was used in a competitive experiment. In a
100 mL Ace pressure tube, a mixture of CD3OD (0.5 mL) and
CH3OH (0.5 mL) was reacted with p-toluidine under standard
conditions. The observed product ratio of the deuterated and
nondeuterated products was determined by H NMR, which
indicates the KIE value ∼1.77.
1
General Procedure for the Methylation of Amines. Aniline (1
t
mmol, 1 equiv), MeOH (1 mL), BuOK (1 mmol, 1 equiv), and
complex 1 (7.6 mg, 0.01 mmol) were placed in a 100 mL Ace pressure
tube under an argon atmosphere. The tube was sealed with a screw
cap, then it was immersed in an oil bath at 135 °C, and the mixture
was stirred at this temperature for 36 h. After that, the reaction
mixture was cooled to room temperature, diluted with dichloro-
methane, and filtered over a plug of Celite. The solvent was
evaporated under reduced pressure, and the residue obtained was
purified by column chromatography (hexane/ethyl acetate/triethyl-
amine 50:1:1) on silica gel to afford the desired product.
CONCLUSION
■
In summary, we have developed an acridine-derived air-stable
ruthenium pincer complex catalyzed β-methylation of 2-
arylethanol and N-methylation of amines using methanol as
a C1 building block via the borrowing hydrogen approach. In
addition, dehydrogenative dimerization of 2-naphthol via
methylene linkage was also illustrated. This straightforward
protocol applies to a wide range of substrates giving well to
excellent isolated yields. Kinetics and mechanistic investiga-
tions help to know the reaction pathway. A temperature-
dependent kinetic profile β-methylation of 2-phenylethanol is
also demonstrated. The technical and environmental benefit of
this methodology was revealed, which clearly shows high atom
economy and atom efficiency and 100% carbon efficiency. This
work expands the scope and builds on our previous successful
protocols on borrowing hydrogen catalysis.16
Isotopic Labeling Experiments for the N-Methylation
Reaction. Competition Reaction. Aniline (1 mmol, 1 equiv),
t
MeOH (0.5 mL), CD3OD (0.5 mL), BuOK (1 mmol, 1 equiv),
and complex 1 (7.6 mg, 0.01 mmol) were placed in a 100 mL Ace
pressure tube under an argon atmosphere. The tube was sealed with a
screw cap, then it was immersed in an oil bath at 135 °C, and the
mixture was stirred at this temperature for 36 h. After that, the
reaction mixture was cooled to room temperature, diluted with
dichloromethane, and filtered over a plug of Celite. The solvent was
evaporated under reduced pressure, and the residue obtained was
purified by column chromatography (hexane/ethyl acetate/triethyl-
amine 50:1:1) on silica gel to afford the mixture of 10b and 11b in
63% yield.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise mentioned, all chemicals
were purchase from common commercial sources and used as
received. RuCl2(PPh3)3 was purchased from Sigma-Aldrich. All
solvents were dried by standard procedures.27 Solvents such as
MeOH are typically dried by heating over iodine-activated
magnesium and storage of the methanol over 20% m/v 3 Å molecular
sieves. The catalyst preparation was carried out under an argon
atmosphere with freshly distilled dry THF or dichloromethane. All
catalytic reactions were carried out under an argon atmosphere using
dry glassware and standard syringe/septa techniques. DRX-400 Varian
and Bruker Avance III 600 and 400 spectrometers were used to record
1H and 13C{1H} NMR, respectively. Chemical shifts (δ) are reported
in ppm downfield from tetramethylsilane; spin−spin coupling
constants (J) are expressed in hertz (Hz), and other data are reported
as follows: s = singlet, d = doublet, t = triplet, m = multiplet, q =
quartet, and br s = broad singlet. Column chromatography was done
with SRL silica gel 100−200 mesh. Analytical thin-layer chromatog-
Gram-Scale Synthesis of 5a. 2-Phenylethanol (10 mmol), MeOH
t
(1 mL), BuOK (10 mmol), and complex 1 (2 mol %, 0.20 mmol)
were placed in a 100 mL Ace pressure tube under an argon
atmosphere, and the general procedure for the β-C(sp3)-methylation
of 2-phenylethanol derivatives was used. Yield: 86%, 1.04 g.
Gram-Scale Synthesis of 8a. 2-Naphthol (10 mmol), MeOH (2
t
mL), BuOK (10 mmol), and complex 1 (0.5 mol %, 0.05 mmol)
were placed in a 100 mL Ace pressure tube under an argon
atmosphere, and the general procedure for the methylation of 2-
naphthol was used. Yield: 69%, 1.03 g.
Gram-Scale Synthesis of 10a. Aniline (10 mmol), MeOH (1 mL),
tBuOK (10 mmol), and complex 1 (0.5 mol %, 0.05 mmol) were
placed in a 100 mL Ace pressure tube under an argon atmosphere and
the general procedure for the methylation of amines was used. Yield:
93%, 0.99 g.
2-Phenylpropan-1-ol (5a).12a Pale yellow oil. Column chromatog-
raphy (hexane/ethyl acetate = 50:1). Yield: 90%, 122.4 mg. 1H NMR
(600 MHz, CDCl3): δ 7.32−7.29 (m, 2H), 7.22−7.19 (m, 3H), 3.64
(d, J = 7.3 Hz, 2H), 2.94−2.86 (m, 1H), 1.95 (br s, 1H), 1.25 (d, J =
7.1 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ 143.9, 128.5
(2C), 127.5 (2C), 126.5, 68.5, 42.4, 17.6.
raphy (TLC) was carried out on silica gel plates (silica gel 60 F254
)
that were visualized by exposure to ultraviolet light and an aqueous
solution of p-anisaldehyde. Compound 4a is commercially available.
Compounds 4a, 7a, 7c, 7d, 7e, and 9a−9q were commercially
available. Compounds 4b−4n28a were known compounds synthesized
from the corresponding phenyl acetic acid derivatives according to the
literature procedure. Compounds 4ae,28b 4ac,28c 4ad,28d 7b,28e and
7f−7g28f were also synthesized following the literature procedure.
General Procedure for the β-C(sp3)-Methylation of 2-
Phenylethanol Derivatives. 2-Phenylethanol (1 mmol, 1 equiv),
MeOH (1 mL), tBuOK (1 mmol, 1 equiv), and complex 1 (15.2 mg,
0.02 mmol) were placed in a 100 mL Ace pressure tube under an
argon atmosphere. The tube was sealed with a screw cap, then it was
immersed in an oil bath at 135 °C, and the mixture was stirred at this
temperature for 36 h. After that, the reaction mixture was cooled to
room temperature, diluted with dichloromethane, and filtered over a
plug of Celite. The solvent was evaporated under reduced pressure,
and the residue obtained was purified by column chromatography
(hexane/ethyl acetate 50:1) on silica gel to afford the desired product.
General Procedure for the Methylation of 2-Naphthol. 2-
2-(p-Tolyl)propan-1-ol (5b).12d Yellow oil. Column chromatog-
raphy (hexane/ethyl acetate = 50:1). Yield: 87%, 130.5 mg. 1H NMR
(600 MHz, CDCl3): δ 7.16−7.13 (m, 4H), 3.69−3.67 (m, 2H),
2.94−2.90 (m, 2H), 2.34 (s, 3H), 1.39 (br s, 1H), 1.26 (d, J = 7.0 Hz,
3H). 13C{1H} NMR (150 MHz, CDCl3): δ 140.6, 136.3, 129.4 (2C),
127.4 (2C), 68.8, 42.1, 21.1, 17.7.
2-(4-Methoxyphenyl)propan-1-ol (5c).12a Yellow oil. Column
chromatography (hexane/ethyl acetate = 50:1). Yield: 81%, 134.5
mg. 1H NMR (600 MHz, CDCl3): δ 7.16 (d, J = 8.6 Hz, 2H), 6.87 (d,
J = 8.6 Hz, 2H), 3.79 (s, 3H), 3.66−3.64 (m, 2H), 2.92−2.88(m,
1H), 1.71 (br s, 1H), 1.24 (d, J = 7.0 Hz, 2H). 13C{1H} NMR (150
MHz, CDCl3): δ 158.4, 135.7, 128.5 (2C), 114.1 (2C), 68.9, 55.3,
41.6, 17.8.
2-(2,4,6-Trimethoxyphenyl)propan-1-ol (5d). Yellow oil. Column
chromatography (hexane/ethyl acetate = 50:1). Yield: 92%, 208.0 mg.
1H NMR (600 MHz, CDCl3): δ 6.43 (s, 2H), 3.85 (s, 6H), 3.85 (s,
3H), 3.67−3.65 (m, 2H), 2.90−2.84 (m, 1H), 1.82 (br s, 1H), 1.24
(d, J = 7.1 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ 153.3,
139.5, 136.6, 104.2, 68.7, 60.9, 56.1, 42.9, 17.7. HRMS (ESI+): m/z
calcd. for C12H19O4: 227.1283 [M + H]+; Found: 227.1288.
t
Naphthol (1 mmol, 1 equiv), MeOH (1 mL), BuOK (1 mmol, 1
equiv), and complex 1 (7.6 mg, 0.01 mmol) were placed in a 100 mL
Ace pressure tube under an argon atmosphere. The tube was sealed
with a screw cap, then it was immersed in an oil bath at 135 °C, and
the mixture was stirred at this temperature for 36 h. After that, the
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Article
2-(4-Chlorophenyl)propan-1-ol (5e).12a Pale yellow oil. Column
chromatography (hexane/ethyl acetate = 50:1). Yield: 73%, 124.1 mg.
1H NMR (600 MHz, CDCl3): δ 7.30 (d, J = 8.4 Hz, 2H), 7.17 (d, J =
8.5 Hz, 2H), 3.87−3.39 (m, 2H), 2.96−2.90 (m, 1H), 1.46 (br s, 1H),
1.25 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ 142.3,
132.4, 128.9 (2C), 128.8 (2C), 68.6, 41.9, 17.6.
MHz, CDCl3): δ 7.34−7.31 (m, 2H), 7.28−7.17 (m, 3H), 4.05−3.86
(m, 4H), 3.07 (m, 1H), 1.94 (brs, 2H).
(E)-Prop-1-ene-1,3-diyldibenzene (6a″).34 Yellow oil. Column
chromatography (hexane/ethyl acetate = 50:1). Yield: 85%, 165.0 mg.
1H NMR (600 MHz, CDCl3): δ 7.79−7.04 (m, 10H), 6.55 (d, J =
15.8 Hz, 1H), 6.45 (dt, J = 15.8, 6.8 Hz, 1H), 3.64 (d, J = 6.8 Hz,
2H). 13C{1H} NMR (150 MHz, CDCl3): δ 140.3, 137.6, 131.2, 129.4,
128.8, 128.6 (2C),127.23, 126.31, 126.27, 39.48.
2-(4-Fluorophenyl)propan-1-ol (5f).12a Yellow oil. Column
chromatography (hexane/ethyl acetate = 50:1). Yield: 92%, 141.6
1,1′-Methylenebis(naphthalen-2-ol) (8a).35 White solid. Column
chromatography (hexane/ethyl acetate = 50:5). Yield: 81%, 121.5 mg.
1H NMR (600 MHz, CDCl3): δ 8.22 (d, J = 8.6 Hz, 2H), 7.77 (d, J =
8.0 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.45 (t, J = 8.1 Hz, 2H), 7.33
(t, J = 7.4 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.60 (br s, 2H), 4.81 (s,
2H). 13C{1H} NMR (150 MHz, CDCl3): δ 151.6 (2C), 133.5 (2C),
129.8 (2C), 129.0 (2C), 129.0 (2C), 127.0 (2C), 123.4 (2C), 123.2
(2C), 118.1 (2C), 117.3 (2C), 21.8.
1
mg. H NMR (600 MHz, CDCl3): δ 7.20−7.16 (m, 2H), 3.64−3.61
(m, 2H), 2.95−2.86 (m, 1H), 1.85 (br s, 1H), 1.24 (d, J = 7.0 Hz,
2H). 13C{1H} NMR (150 MHz, CDCl3): δ 161.6 (d, J = 244.3 Hz),
139.5 (d, J = 3.2 Hz), 128.9 (d, J = 7.8 Hz), 115.3 (d, J = 21.0 Hz),
68.6, 41.7, 17.7.
2-(4-Bromophenyl)propan-1-ol (5g).12d Yellow oil. Column
chromatography (hexane/ethyl acetate = 50:1). Yield: 60%, 129.0
mg. 1H NMR (600 MHz, CDCl3): δ 7.45 (d, J = 8.4 Hz, 2H), 7.12 (d,
J = 8.4 Hz, 2H), 3.72−3.67 (m, 2H), 2.97−2.92 (m, 1H), 1.36 (br s,
1H), 1.28 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ
142.9, 131.8, 129.3 (2C), 126.8 (2C), 68.6, 42.6, 17.6.
1,1′-Methylenebis(7-methoxynaphthalen-2-ol) (8b). White solid.
Column chromatography (hexane/ethyl acetate = 50:5). Yield: 74%,
1
133.2 mg. H NMR (600 MHz, DMSO-d6): δ 10.22 (s, 2H), 7.66−
2-(Thiophen-2-yl)propan-1-ol (5h).12d Yellow oil. Column
chromatography (hexane/ethyl acetate = 50:1). Yield: 90%, 127.8
mg. 1H NMR (600 MHz, CDCl3): δ 7.16 (d, J = 4.7 Hz, 1H), 6.97−
6.93 (m, 1H), 6.87 (d, J = 3.1 Hz, 2H), 3.64 (d, J = 6.3 Hz, 2H),
3.23−3.19 (m, 1H), 1.33 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (150
MHz, CDCl3): δ 147.5, 126.9, 124.0, 123.6, 69.1, 38.2, 18.7.
2-(Naphthalen-2-yl)propan-1-ol (5i).12a Off-white solid. Column
chromatography (hexane/ethyl acetate = 50:1). Yield: 73%, 135.8 mg.
1H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.5 Hz, 1H), 7.90 (d, J =
1.5 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.59−7.48 (m, 3H), 7.45 (d, J
= 7.0 Hz, 1H), 3.98−3.84 (m, 3H), 1.58 (br s, 1H), 1.47 (d, J = 6.8
Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 139.6, 134.1, 132.0,
129.1, 127.2, 126.1, 125.6 (2C), 123.1, 123.1, 68.2, 36.4, 17.9.
2-(o-Tolyl)propan-1-ol (5j).12a Yellow oil. Column chromatog-
7.33 (m, 6H), 7.11 (d, J = 8.7 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H), 4.64
(s, 2H), 3.69 (s, 6H). 13C{1H} NMR (150 MHz, DMSO-d6): δ 157.1
(2C), 152.5 (2C), 135.0 (2C), 129.5 (2C), 127.2 (2C), 123.7 (2C),
118.1 (2C), 114.9 (2C), 114.5 (2C), 102.8 (2C), 54.9 (2C), 20.4.
HRMS (ESI+): m/z calcd. for C23H21O4: 361.1440 [M + H]+;
Found: 361.1441.
1,1′-Methylenebis(3-methoxynaphthalen-2-ol) (8c). White solid.
Column chromatography (hexane/ethyl acetate = 50:5). Yield: 86%,
154.8 mg. 1H NMR (600 MHz, CDCl3): δ 8.17 (dd, J = 6.3, 3.4 Hz,
2H), 7.63 (dd, J = 6.2, 3.3 Hz, 2H), 7.24 (dd, J = 6.3, 3.3 Hz, 4H),
7.04 (s, 2H), 6.61 (s, 2H), 4.88 (s, 2H), 4.04 (s, 6H). 13C{1H} NMR
(150 MHz, CDCl3): δ 146.9 (2C), 143.3 (2C), 129.3 (2C), 129.1
(2C), 127.2 (2C), 124.2 (2C), 123.9 (2C), 123.6 (2C), 119.1 (2C),
104.7 (2C), 56.0 (2C), 21.8. HRMS (ESI-): m/z calcd. for C23H20O4:
359.1283 [M-H]; Found: 359.1290
1
raphy (hexane/ethyl acetate = 50:1). Yield: 65%, 97.5 mg. H NMR
1,1′-Methylenebis(6-bromonaphthalen-2-ol) (8d).36 White solid.
Column chromatography (hexane/ethyl acetate = 50:5). Yield: 55%,
126.0 mg. 1H NMR (600 MHz, DMSO-d6): δ 10.47 (s, 2H), 8.08 (d,
J = 9.2 Hz, 2H), 7.93 (d, J = 2.1 Hz, 2H), 7.62 (d, J = 8.9 Hz, 2H),
7.44−7.22 (m, 4H), 4.64 (s, 2H). 13C{1H} NMR (150 MHz, DMSO-
d6): δ 152.4 (2C), 132.3 (2C), 130.0 (2C), 129.9 (2C), 128.4 (2C),
127.2 (2C), 126.1 (2.C), 119.6 (2C), 119.4 (2C), 115.31 (2C), 20.3.
1,1′-Methylenebis(7-bromonaphthalen-2-ol) (8e). White solid.
Column chromatography (hexane/ethyl acetate = 50:5). Yield: 79%,
180.9 mg. 1H NMR (600 MHz, DMSO-d6): δ 10.62 (s, 2H), 8.43 (s,
2H), 7.66−7.63 (m, 4H), 7.34 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.6
Hz, 2H), 4.59 (s, 2H). 13C{1H} NMR (150 MHz, DMSO-d6): δ
152.8 (2C), 134.9 (2C), 130.36 (2C), 127.9 (2C), 126.8 (2C), 125.9
(2C), 125.1 (2C), 119.6 (2C), 118.4 (2C), 118.2 (2C), 20.0. HRMS
(ESI-): m/z calcd. for C21H14Br2O2: 456.9262 [M-H]−; Found:
456.9268.
(600 MHz, CDCl3): δ 7.22−7.11 (m, 4H), 3.76−3.67 (m, 2H),
3.29−3.24 (m, 1H), 2.37 (s, 3H), 1.62 (br s, 1H), 1.25 (d, J = 7.0 Hz,
1H). 13C{1H} NMR (150 MHz, CDCl3): δ 141.8, 136.5, 130.6, 126.4,
126.3, 125.5, 68.1, 37.3, 19.7, 17.6.
2-(4-(Methylamino)phenyl)propan-1-ol (5l).12d Pale yellow oil.
Column chromatography (hexane/ethyl acetate = 50:1). Yield: 60%,
1
99.0 mg. H NMR (600 MHz CDCl3): δ 7.05 (d, J = 8.5 Hz, 2H),
6.60 (d, J = 8.5 Hz, 2H), 3.64−3.62 (m, 2H), 2.82 (s, 3H), 1.23 (d, J
= 7.0 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ 148.2, 132.1,
128.3 (2C), 112.82 (2C), 68.9, 41.6, 30.9, 17.8.
2-(4-(Methylamino)phenyl)ethanol (5m).29 Yellow oil. Column
chromatography (hexane/ethyl acetate = 50:1). Yield: 10%, 15.0 mg.
1H NMR (600 MHz, CDCl3): δ 7.06 (d, J = 8.4 Hz, 2H), 6.59 (d, J =
8.4 Hz, 2H), 3.80 (t, J = 6.5 Hz, 2H), 2.83 (s, 3H), 2.77 (t, J = 6.5 Hz,
2H). 13C{1H} NMR (150 MHz, CDCl3): δ 148.1, 129.9 (2C), 126.8,
112.8 (2C), 64.1, 38.3, 31.0.
3-(4-Methoxyphenyl)-2-methylpropan-1-ol (5p).30 Colorless oil.
Column chromatography (hexane/ethyl acetate = 50:1). Yield: 55%,
1,1′-Methylenebis(6-phenylnaphthalen-2-ol) (8f). White solid.
Column chromatography (hexane/ethyl acetate = 50:5). Yield: 82%,
1
1
99.0 mg. H NMR (600 MHz, CDCl3): δ 7.09 (d, J = 8.5 Hz, 2H),
92.6 mg. H NMR (600 MHz, DMSO-d6): δ 10.30 (s, 2H), 8.38−
6.83 (d, J = 8.5 Hz, 2H), 3.79 (s, 3H), 3.54−3.45 (m, 2H), 2.68 (dd, J
= 13.6, 6.4 Hz, 1H), 2.38 (dd, J = 13.6, 8.0 Hz, 1H), 1.97−1.85 (m,
1H), 0.90 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ
157.9, 132.7, 130.1, 113.8, 67.8, 55.3, 38.9, 38.0, 16.5.
8.21 (m, 2H), 7.96 (s, 2H), 7.71 (d, J = 11.0 Hz, 2H), 7.67 (d, J = 7.9
Hz, 6H), 7.51 (d, J = 8.9 Hz, 4H), 7.41 (t, J = 7.6 Hz, 6H), 7.35−7.28
(m, 4H), 4.74 (s, 2H). 13C{1H} NMR (150 MHz, DMSO-d6): δ
152.1 (2C), 140.0 (2C), 133.75 (2C), 133.0 (2C), 128.9 (4C), 128.8
(2C), 128.1 (2C), 128.1 (2C), 127.0 (2C), 126.5 (4C), 125.6 (2C),
124.5 (2C), 119.38 (2C), 118.6 (2C), 20.5. HRMS (ESI-): m/z calcd.
for C33H24O2: 451.1698 [M-H]−, Found: 451.1705.
2-Phenylprop-2-en-1-ol (4ae).31 Yellow oil. Column chromatog-
raphy (hexane/ethyl acetate = 50:1). Yield: 85%, 113.9 mg. 1H NMR
(600 MHz, CDCl3): δ 7.45 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.5 Hz,
2H), 7.31 (t, J = 7.3 Hz, 1H), 5.48 (d, J = 1.1 Hz, 1H), 5.36 (d, J = 1.4
Hz, 1H), 4.55 (s, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ 147.3,
138.5, 128.6, 128.0, 126.1, 112.7, 65.1.
1,1′-Methylenebis(6-(3,5-bis(trifluoromethyl)phenyl)-
naphthalen-2-ol) (8g). White solid. Column chromatography
(hexane/ethyl acetate = 50:5). Yield: 75%, 135.7 mg. 1H NMR
(600 MHz, DMSO-d6): δ 10.48 (s, 2H), 8.35 (s, 4H), 8.31−8.23 (m,
4H), 8.00 (s, 2H), 7.80 (d, J = 8.9 Hz, 2H), 7.71 (d, J = 9.1 Hz, 2H),
7.37 (d, J = 8.9 Hz, 2H), 4.77 (s, 2H). 13C{1H} NMR (150 MHz,
DMSO-d6): δ 153.3 (2C), 143.0 (2C), 134.2 (2C), 131.3 (q, J = 32.8
Hz) (4C), 129.0 (d, J = 9.3 Hz) (4C), 127.5 (2C), 127.4 (2C), 126.5
(2C), 125.2 (2C), 124.7 (d, J = 6.5 Hz) (2C), 122.9 (2C), 121.1
(2C), 120.7 (2C), 119.8 (2C), 119.3 (2C), 20.9. Several peaks are
2-Phenylacrylaldehyde (4ac).32 Yellow oil. Column chromatog-
1
raphy (hexane/ethyl acetate = 50:1). Yield: 50%, 66.0 mg. H NMR
(600 MHz, CDCl3): δ 9.85 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.47−
7.38 (m, 1H), 6.67 (s, 1H), 6.22 (s, 1H). 13C{1H} NMR (150 MHz,
CDCl3): δ 193.2, 148.6, 135.8, 133.8, 128.9, 128.5, 128.2.
2-Phenylpropane-1,3-diol (4ad).33 Column chromatography
1
(hexane/ethyl acetate = 50:1). Yield: 59%, 89.6 mg. H NMR (500
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Article
eclipsed. HRMS (ESI-): m/z calcd. for C37H20F12O2: 723.1193 [M-
H]−; Found: 723.1200.
N1-Methylbenzene-1,2-diamine (10l).41 Pale yellow oil. Column
chromatography (hexane/ethyl acetate/triethylamine 50:1:1).
N-Methylaniline (10a).23j Pale yellow oil. Column chromatog-
raphy (hexane/ethyl acetate/triethylamine 50:1:1). Yield: 95%, 101.6
mg. 1H NMR (600 MHz, CDCl3): δ 7.23 (t, J = 8.4 Hz, 2H), 6.75 (t,
J = 7.3 Hz, 1H), 6.65 (d, J = 7.7 Hz, 2H), 3.72 (br s, 1H), 2.86 (s,
3H). 13C{1H} NMR (150 MHz, CDCl3): δ 149.4, 129.3 (2C), 117.3,
112.5 (2C), 30.8.
1
Yield:10%, 12.0 mg. H NMR (600 MHz, CDCl3): δ6.86−6.85 (m,
1H), 6.73−6.65 (m, 1H), 3.33 (s, 2H), 2.87 (s, 3H). 13C{1H}NMR
(150 MHz, CDCl3): δ 139.1, 134.1, 120.9, 118.5, 116.4, 111.0, 31.1.
N-Methyloctan-1-amine (10m).42 Pale yellow oil. Column
chromatography (DCM/MeOH/triethylamine 50:1:1). Yield: 33%,
1
47.2 mg. H NMR (600 MHz, CDCl3): δ 2.57 (t, J = 7.4 Hz, 2H),
N,4-Dimethylaniline (10b).17e Pale yellow oil. Column chroma-
tography (hexane/ethyl acetate/triethylamine 50:1:1). Yield: 89%,
107.7 mg. 1H NMR (600 MHz, CDCl3): δ 7.06 (d, J = 8.6 Hz, 2H),
6.59 (d, J = 8.4 Hz, 2H), 3.59 (br s, 1H), 2.85 (s, 3H), 2.30 (s, 3H).
13C{1H} NMR (150 MHz, CDCl3): δ 147.2, 129.7 (2C), 126.5,
112.68 (2C), 31.1, 20.4.
2.43 (s, 3H), 1.53−1.45 (m, 1H), 1.30−1.2 (m, 10H), 0.85 (t, J = 6.9
Hz, 3H). 13C NMR (150 MHz, CDCl3): δ 51.5, 35.6, 31.9, 29.5, 29.3,
28.9, 27.3, 22.7, 14.2.
N-Methyldodecan-1-amine (10n).43 White solid. Column chro-
matography (DCM/MeOH/triethylamine 50:1:1). Yield: 32%,63.7
mg. 1H NMR (600 MHz, CDCl3): δ 2.74 (t, J = 7.9 Hz, 2H), 2.54 (s,
3H), 1.67−1.65 (m, 2H), 1.41−1.09 (m, 18H), 0.84 (t, J = 7.0 Hz,
3H). 13C NMR (150 MHz, CDCl3): δ 50.4, 34.2, 32.0, 29.7, 29.6,
29.6, 29.4, 29.3, 27.4, 27.3, 27.0, 22.7, 14.2.
4-Methoxy-N-methylaniline (10c).17e Pale yellow oil. Column
chromatography (hexane/ethyl acetate/triethylamine 50:1:1). Yield:
1
92%, 126.0 mg. H NMR (600 MHz, CDCl3): δ 6.81 (d, J = 8.9 Hz,
2H), 6.60 (d, J = 8.9 Hz, 2H), 3.76 (s, 3H), 3.17 (br s, 1H), 2.81 (s,
3H). 13C{1H} NMR (150 MHz, CDCl3): δ 152.2, 143.72, 115.0
(2C), 113.8 (2C), 55.9, 31.7.
N-Methylhexadecan-1-amine (10o).44 White solid. Column
chromatography (DCM/MeOH/triethylamine 50:1:1). Yield:
1
4-Bromo-N-methylaniline (10d).17e Pale yellow oil. Column
chromatography (hexane/ethyl acetate/triethylamine 50:1:1). Yield:
35%,89.2 mg. H NMR (600 MHz, CDCl3): δ 2.54 (t, J = 7.3 Hz,
2H), 2.41 (s, 3H), 1.84 (brs, 1H), 1.48−1.42 (m, 2H), 1.33−1.13 (m,
26H), 0.86 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ 52.2,
36.5, 32.1, 30.0, 29.8, 29.8, 29.7, 29.7, 29.5, 27.4, 22.8, 14.3.
1
91%, 169.2 mg. H NMR (600 MHz, CDCl3): δ 7.24 (d, J = 8.9 Hz,
2H), 6.46 (d, J = 8.8 Hz, 2H), 3.71 (br s, 1H), 2.78 (s, 3H). 13C{1H}
NMR (150 MHz, CDCl3): δ 148.3, 131.9 (2C), 114.0 (2C), 108.8,
30.7.
N-Methyl-2-phenylethanamine (10p).45 White solid. Column
chromatography (DCM/MeOH/triethylamine 50:1:1). Yield: 48%,
64.8 mg. 1H NMR (500 MHz, CDCl3): δ 7.31−7.24 (m, 2H), 7.22−
7.16 (m, 3H), 2.97−2.95 (m, 4H), 2.53 (s, 3H). 13C NMR (125
MHz, CDCl3): δ 138.5, 128.8, 128.7, 126.7, 52.0, 34.7, 34.42.
N-(Trideuteromethyl)aniline (10q).46 Pale yellow oil. Column
chromatography (hexane/ethyl acetate/triethylamine 50:1:1). Yield:
4-Fluoro-N-methylaniline (10e).17d Pale yellow oil. Column
chromatography (hexane/ethyl acetate/triethylamine 50:1:1). Yield:
80%, 100.0 mg. 1H NMR (600 MHz, CDCl3): δ 6.93−6.90 (m, 2H),
6.56−6.54 (m, 1H), 2.81 (s, 2H). 13C{1H} NMR (150 MHz, CDCl3):
δ 155.8 (d, J = 234.4 Hz), 145.8 (d, J = 1.8 Hz), 115.7 (d, J = 22.5 Hz,
2C), 113.2 (d, J = 7.6 Hz, 2C), 31.4.
1
85%, 93.5 mg. H NMR (600 MHz, CDCl3): δ 7.23 (t, J = 7.9 Hz,
N-Methylpyridin-2-amine (10f).37 Pale yellow oil. Column
chromatography (hexane/ethyl acetate/triethylamine 50:1:1). Yield:
2H), 6.75 (t, J = 7.3 Hz, 1H), 6.65 (d, J = 7.7 Hz, 2H). 13C{1H}
NMR (150 MHz, CDCl3): δ 149.4, 129.2 (2C), 117.3, 112.5 (2C),
30.3−29.8 (m).
1
90%, 97.2 mg. H NMR (600 MHz, CDCl3): δ 8.07 (d, J = 4.8 Hz,
(2-(Methylamino)phenyl)(phenyl)methanol (10r).47 Pale yellow
oil. Column chromatography (hexane/ethyl acetate/triethylamine
1H), 7.50−7.34 (m, 1H), 6.63−6.49 (m, 1H), 6.36 (d, J = 8.4 Hz,
1H), 4.70 (br s, 1H), 2.88 (d, J = 5.3 Hz, 3H). 13C{1H} NMR (150
MHz, CDCl3): δ 159.7, 148.2, 137.5, 112.7, 106.2, 29.1.
1
50:1:1). Yield: 70%, 149.1 mg. H NMR (600 MHz, CDCl3) 7.42−
N1,N3-Dimethylbenzene-1,3-diamine (10g).38 Pale yellow oil.
Column chromatography (hexane/ethyl acetate/triethylamine
50:1:1). Yield: 80%, 108.8 mg. 1H NMR (600 MHz, CDCl3): δ
7.05−7.00 (m, 1H), 6.08−6.01 (m, 2H), 5.89 (d, J = 2.3 Hz, 1H),
3.61 (br s, 2H), 2.83 (s, 6H). 13C{1H} NMR (150 MHz, CDCl3): δ
150.6 (2C), 129.9, 102.6 (2C), 96.4, 30.9 (2C).
7.28 (m, 6H), 6.97 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 7.3 Hz, 2H), 5.84
(s, 1H), 2.80 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ 147.7,
141.9, 129.3, 128.6, 128.5 (2C), 127.6, 126.9, 126.6 (2C), 116.6,
110.9, 75.1, 30.6.
(5-Chloro-2-(methylamino)phenyl)(phenyl)methanol (10s).48
Pale yellow oil. Column chromatography (hexane/ethyl acetate/
N2,N6-Dimethylpyridine-2,6-diamine (10h).38 Pale yellow oil.
Column chromatography (hexane/ethyl acetate/triethylamine
50:1:1). Yield: 91%, 124.6 mg. 1H NMR (600 MHz, CDCl3): δ
7.28 (t, J = 7.9 Hz, 1H), 5.73 (d, J = 7.9 Hz, 2H), 2.84 (d, J = 5.2 Hz,
6H). 13C{1H} NMR (150 MHz, CDCl3): δ 159.2 (2C), 139.2, 94.1
(2C), 29.3 (2C).
1
triethylamine 50:1:1). Yield: 65%, 160.5 mg. H NMR (600 MHz,
CDCl3): δ 7.45−7.30 (m, 5H), 7.18 (dd, J = 8.6, 2.6 Hz, 1H), 6.95
(d, J = 2.6 Hz, 1H), 6.57 (d, J = 8.6 Hz, 1H), 5.75 (s, 1H), 4.53 (brs,
1H), 2.74 (d, J = 4.2 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ
146.2, 141.2, 128.8, 128.7 (2C), 128.3, 128.2, 128.1, 126.7 (2C),
121.4, 112.0, 74.6, 30.7.
N1,N1,N4-Trimethylbenzene-1,4-diamine (10i).39 Pale yellow oil.
Column chromatography (hexane/ethyl acetate/triethylamine
50:1:1). Yield: 79%, 118.5 mg. 1H NMR (600 MHz, CDCl3): δ
6.78 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 8.8 Hz, 2H), 3.38 (br s, 1H),
2.83 (s, 6H), 2.81 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ
144.2, 142.2, 116.1 (2C), 114.0 (2C), 42.5 (2C), 31.8.
(5-Chloro-2-(methylamino)phenyl)(phenyl)methanone (10s′).49
Yellow solid. Column chromatography (hexane/ethyl acetate/triethyl-
amine 50:1:1). Yield: 60%, 147.0 mg. 1H NMR (600 MHz, CDCl3): δ
8.50 (s, 1H), 7.61 (d, J = 7.3 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.49−
7.42 (m, 3H), 7.37 (dd, J = 9.0, 2.5 Hz, 1H), 6.73 (d, J = 9.0 Hz, 1H),
2.98 (d, J = 5.1 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ 198.4,
151.3, 139.9, 135.0, 134.1, 131.2, 129.1 (2C), 128.3 (2C), 118.3,
118.0, 112.85, 29.74.
2-Bromo-N-methylaniline (10j).40 Pale yellow oil. Column
chromatography (hexane/ethyl acetate/triethylamine 50:1:1). Yield:
1
50%, 93.0 mg. H NMR (600 MHz, CDCl3): δ 7.46 (d, J = 7.9 Hz,
1H), 7.25 (t, J = 7.7 Hz, 2H), 6.66 (d, J = 9.1 Hz, 1H), 6.61 (t, J = 8.3
Hz, 1H), 4.39 (br s, 1H), 2.93 (d, J = 5.2 Hz, 3H). 13C{1H} NMR
(150 MHz, CDCl3): δ 146.0, 132.3, 128.6, 117.7, 110.8, 109.7, 30.7.
2-Ethyl-N-methylaniline (10k).17e Pale yellow oil. Column
chromatography (hexane/ethyl acetate/triethylamine 50:1:1). Yield:
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01185.
1
60%, 81.0 mg. H NMR (600 MHz, CDCl3): δ 7.18 (t, J = 7.7 Hz,
1H), 7.09 (m, 1H), 6.73 (t, J = 7.4 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H),
3.68 (br s, 1H), 2.90 (s, 3H), 2.49 (q, J = 7.5 Hz, 2H), 1.26 (t, J = 7.5
Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ 146.7, 127.7, 127.6,
127.1, 117.1, 109.5, 30.9, 23.8, 12.9.
1
Copies of the H NMR and 13C NMR spectra of all the
compounds (PDF)
10551
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J. Org. Chem. 2021, 86, 10544−10554

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pubs.acs.org/joc
Article
reactions using alcohols with hydrogen borrowing methodologies.
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First-row transition metal (de) hydrogenation catalysis based on
functional pincer ligands. Chem. Rev. 2019, 119, 2681−2751.
(e) Irrgang, T.; Kempe, R. 3d-Metal catalyzed N-and C-alkylation
reactions via borrowing hydrogen or hydrogen autotransfer. Chem.
Rev. 2019, 119, 2524−2549.
(9) (a) Fujita, K.-I.; Asai, C.; Yamaguchi, T.; Hanasaka, F.;
Yamaguchi, R. Direct β-alkylation of secondary alcohols with primary
alcohols catalyzed by a Cp* Ir complex. Org. Lett. 2005, 7, 4017−
4019. (b) Chakrabarti, K.; Paul, B.; Maji, M.; Roy, B. C.; Shee, S.;
Kundu, S. Bifunctional Ru (ii) complex catalysed carbon-carbon bond
formation: an eco-friendly hydrogen borrowing strategy. Org. Biomol.
Chem. 2016, 14, 10988−10997. (c) Zhang, M.-J.; Li, H.-X.; Young, D.
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AUTHOR INFORMATION
Corresponding Author
Dipankar Srimani − Department of Chemistry, Indian
Institute of Technology Guwahati, Assam 781039, India;
orcid.org/0000-0001-8826-9773; Phone: (+91)-361-
258-3312; Email: dsrimani@iitg.ac.in; Fax: (+91)-361-
258-2349
■
Author
Nandita Biswas − Department of Chemistry, Indian Institute
of Technology Guwahati, Assam 781039, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01185
Notes
The authors declare no competing financial interest.
(10) (a) Polidano, K.; Allen, B. D.; Williams, J. M.; Morrill, L. C.
Iron-catalyzed methylation using the borrowing hydrogen approach.
ACS Catal. 2018, 8, 6440−6445. (b) Wingad, L. R.; Bergström, J. E.
E.; Everett, M.; Pellow, J. K.; Wass, F. D. Catalytic conversion of
methanol/ethanol to isobutanol -a highly selective route to an
advanced biofuel. Chem. Commun. 2016, 52, 5202−5204.
(11) Aitchison, H.; Wingad, R. L.; Wass, D. F. Homogeneous
Ethanol to Butanol Catalysis-Guerbet Renewed. ACS Catal. 2016, 6,
7125−7132.
ACKNOWLEDGMENTS
■
We would like to thank SERB, DST (ECR/2016/000108) for
the financial support. We are also thankful to the CIF and the
Department of Chemistry, IIT-Guwahati, for the instrumental
facilities, infrastructural support, and startup grant. N.B. thank
the institute for her fellowship.
(12) (a) Li, Y.; Li, H.; Junge, H.; Beller, M. Selective ruthenium-
catalyzed methylation of 2-arylethanols using methanol as C1
feedstock. Chem. Commun. 2014, 50, 14991−14994. (b) Kaithal, A.;
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