Insight into O2-promoted base-catalyzed N-alkylation of amines with alcohols

Article abstract of DOI:10.1002/ejoc.201500086

A highly efficient and practical transition-metal-free CsOH/O₂ catalyst system was developed for the N-alkylation of amines with alcohols under argon. This strategy was compatible with many alcohols and exhibits excellent functional group tolerance. More significantly, the selective formation of secondary amines was achieved in excellent yields. The detailed mechanistic study gave a clear understanding of the role of base and oxygen in the catalytic cycle.

Full text of DOI:10.1002/ejoc.201500086

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FULL PAPER
DOI: 10.1002/ejoc.201500086
Insight into O2-Promoted Base-Catalyzed N-Alkylation of Amines with
Alcohols
Chao Wang,[a] Changpeng Chen,[a] Jian Han,[a] Jingyu Zhang,[b] Yingming Yao,*[a] and
Yingsheng Zhao*[a]
Keywords: Synthetic methods / Alkylation / Alcohols / Amines / Cesium / Oxygen
A highly efficient and practical transition-metal-free CsOH/
O2 catalyst system was developed for the N-alkylation of
amines with alcohols under argon. This strategy was compat-
ible with many alcohols and exhibits excellent functional
group tolerance. More significantly, the selective formation
of secondary amines was achieved in excellent yields. The
detailed mechanistic study gave a clear understanding of the
role of base and oxygen in the catalytic cycle.
The transition-metal-catalyzed methods require the use
of precious metals, expensive ligands, or noncommercially
available catalysts, which limits their further application in
synthetic organic chemistry. In recent years, transition-
metal-free N-alkylation reactions[15] have been successfully
developed under basic conditions (Scheme 1, A). However,
these primary studies reported the use of very high tem-
peratures (Ͼ200 °C) and excess amounts of the alcohols
and bases, the need of the corresponding aldehyde for the
starting alcohol, which may not be readily available and
could be toxic, and problems of low yields and selectivities.
Herein, we report a new method for N-alkylation of amines
with alcohols by using a catalytic amount of CsOH and
catalytic amount of O2 as the initiator under mild, econ-
omic conditions (Scheme 1, B).
Introduction
Amines are versatile building blocks for a variety of bio-
logically active compounds, natural products, and other fine
chemicals.[1] The development of highly selective and envi-
ronmentally benign routes to synthesize higher amines is of
considerable interest.[2] The application of an alcohol as an
alkylating reagent has advantages with regard to atom effi-
ciency and the generation of water as the only byproduct.
In the past few years, numerous catalytic procedures for the
N-alkylation of amines with alcohols have been devel-
oped.[3] Since the early 1980s, transition-metal complexes,
particularly ruthenium[4] and iridium complexes,[5] have
been employed in versatile routes to synthesize secondary
and tertiary amines with high selectivity. Indeed, numerous
other homogeneous catalysts such as those that contain pal-
ladium,[6] rhodium,[7] copper,[8] iron,[9] platinum,[10] and os-
mium[11] have also been developed, and several protocols
are already utilized in the pharmaceutical industry.[12] The
mechanism of these transition-metal-catalyzed N-alkylation
reactions proceeds through a dehydrogenation/imination/
hydrogenation sequence. In addition, Lewis acid[13] and
heterogeneous catalysts[14] have also been intensively
studied and implemented in valuable applications.
Scheme 1. N-alkylation of amines with alcohols.
[a] Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and Materials
Science, Soochow University,
Suzhou 215123, P. R. China
Results and Discussion
E-mail: yszhao@suda.edu.cn
yaoym@suda.edu.cn
http://eng.suda.edu.cn/
http://chemistry.suda.edu.cn/en/index.aspx?lanmuid=
80&sublanmuid=636&id=181
Initially, we attempted the N-alkylation reaction by using
an iron catalyst and starting from aniline (1a) and benzyl
alcohol (2a). However, when we carried out control experi-
ments with KOH under argon at 140 °C, product 3aa was
observed by chance in 64% yield (Table 1, Entry 1). Thus,
we proposed that only an alkali hydroxide could promote
the N-alkylation of amines with alcohols under an inert at-
mosphere. Inspired by the result, we tested the reaction by
http://web.suda.edu.cn/yszhao/award.html
[b] College of Physics, Optoelectronics and Energy & Collaborative
Innovation Center of Suzhou Nano Science and Technology,
Soochow University,
Suzhou 215006, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500086.
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C. Wang, C. Chen, J. Han, J. Zhang, Y. Yao, Y. Zhao
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using alkali metal bases as the catalyst under various condi- which include Me, Cl, Br, OPh, OMe, and CF3, were toler-
tions (Table 1). To our delight, the reaction with KOH, ated in the transformation. Heteroatom-containing amines
which was purchased from Across in 99.999% purity based such as amino-pyridines and -pyrazine afforded the corre-
on trace metal analysis, afforded 3aa in 66% yield under sponding secondary amine derivatives in excellent yields
argon (Table 1, Entry 2) and involved no transition metals. (Table 2, Entries 9–11). Notably, 8-aminoquinoline also
Interestingly, when the reaction proceeded under air or oxy- gave the corresponding secondary amine in 57% yield
gen, imine 4aa was obtained as the major product (Table 1, (Table 2, Entry 12). However, when we tried to expand the
Entries 3 and 4), and the desired product 3aa was obtained scope of the amines to include an aliphatic amine (i.e., 1n),
in less than 10% yield, which implies that oxygen plays an product 3na was not observed, according to LC–MS analy-
inhibiting role in the transformation. The catalytic abilities sis. In addition, several secondary amines, such as N-benz-
of different bases were then examined, and CsOH·H2O was ylaniline, N-methylaniline, and morpholine were studied,
found to be the best catalyst for the reaction (Table 1, En- but no products were afforded along with the recovered
tries 5–7). When the reaction carried out in a glove box (O2, starting materials.
2.9 ppm), product 3aa was afforded in just 38% yield,
which indicates that O2 might play an important role in the
Table 2. Coupling between various amines 1 and alcohol 2a.[a]
catalytic cycle and a small amount of it is necessary to the
reaction. Further optimization of the reaction conditions
by using 2 mol-% O2 as an additive afforded 3aa in 94%
isolated yield accompanied by 4% of 4aa (Table 1, Entry 9).
A lower conversion of the aniline was observed when
Ba(OH)2, Sr(OH)2, tBuOK, and DBU (1,8-diazabicyclo-
[5.4.0]undec-7-ene) were used as the catalyst (Supporting
Information, Table s2). The temperature was also crucial
for the transformation, as 79% yield of 3aa was obtained
when the reaction was carried out at 120 °C (Table 1, En-
try 11). No reaction occurred in the absence of CsOH, and
only starting material was recovered (Table 1, Entry 12).
Table 1. Optimization of reaction conditions.[a]
[a] Reagents and conditions: 1 (1 mmol), 2a (1.2 mmol), and
CsOH·H2O (0.2 mmol) in mesitylene (0.3 mL) at 140 °C for 24 h
[a] Reagents and conditions: 1a (1 mmol), 2a (1.2 mmol), and base
under argon. O2 (0.45 mL, 2 mol-%) was added by syringe, yields
(0.2 mmol) in mesitylene (0.3 mL) for 24 h, yield was determined
are of isolated products.
by GC analysis with tridecane as the internal standard. [b] 99.999%
purity. [c] Carried out in a glove box (O2, 2.9 ppm). [d] O2
(0.45 mL, 2 mol-%) was added by syringe. [e] Isolated yield.
To further examine the CsOH-promoted N-alkylation of
amines with alcohols, various substituted benzyl alcohols
Once we identified the optimal conditions for the N-alk- were employed in the reaction with aniline under the opti-
ylation of amines with alcohols, we then studied the sub- mized conditions (Table 3). Gratifyingly, benzyl alcohols
strate scope of the amines (Table 2). Overall, secondary with either electron-withdrawing and electron-donating
amines were generated in fair to good yields (i.e, 3ba–3ia) groups gave good to excellent yields (Table 3, Entries 1–5).
for a range of substituted anilines, and a variety of groups, The 2-pyridinemethanol and 2-thiophenemethanol sub-
2
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O2-Promoted Base-Catalyzed N-Alkylation of Amines with Alcohols
strates gave the N-alkylation products in good yields alcohols and primary amines, only secondary amines were
(Table 3, Entries 6 and 7). Interestingly, benzhydrol could formed, with no over-alkylated tertiary amine. Thus, the se-
also be transformed into the desired secondary amine in lective synthesis of a secondary amine could be achieved by
excellent yields (Table 3, Entry 9).
this newly developed catalyst system. To our delight, amino
alcohol 2s was coupled with aniline to give the correspond-
ing secondary amine in excellent yield (Table 4, Entry 9). To
further evaluate the efficiency of this protocol, a 10 g scale
reaction was also examined, which afforded the correspond-
ing product in good yield (Supporting Information).
Table 3. Coupling between amine 1a and benzyl alcohols 2.[a]
Table 4. Coupling between 1a and aliphatic alcohols 2.[a]
[a] Reagents and conditions: 1a (1 mmol), 2 (1.2 mmol), and
CsOH·H2O (0.2 mmol) in mesitylene (0.3 mL) at 140 °C for 24 h
under argon. O2 (0.45 mL, 2 mol-%) was added by syringe, yields
are of isolated products.
[a] Reagents and conditions: 1 (1 mmol), 2a (1.2 mmol), and
CsOH·H2O (0.2 mmol) in mesitylene (0.3 mL) at 180 °C for 24 h
under argon. O2 (0.45 mL, 2 mol-%) was added by syringe, yields
are of isolated products.
This method was then expanded to include aliphatic
alcohols as substrates, which at a higher temperature pro-
vided the coupling products in good yields (Table 4, En-
tries 1–9). Because of the low reactivity of secondary
alcohols, only acceptable yields of the aminated products
were obtained under the standard reaction conditions
Imines derivatives are important versatile synthetic pre-
(Table 4, Entries 3, 4, and 8). We proceeded to explore the cursors in the synthesis of nitrogen heterocycles, fine chemi-
selectivity of the reaction for primary/secondary alcohols cals, and pharmaceuticals.[16,17] A catalytic amount of
by employing 1-phenyl-1,2-ethanediol and found that 3ap CsOH can also promote the synthesis of imines from benzyl
was produced as the major product in 51% yield (Table 4, alcohols and aromatic or aliphatic amines. This reaction
Entry 6). The 1,3-diols could also be monoaminated in 62% had a broad substrate scope and provided good to excellent
yield (Table 4, Entry 7). Although only few reports describe yields under air in toluene at 70 °C for 18 h (Table 5). It is
the transition-metal-catalyzed N-alkylation reaction of 2,3- noteworthy that the aliphatic amines were well-tolerated
butanediol, it was also monoaminated in moderate yield and afforded good yields of the imine products (Table 5,
(Table 3, Entry 8). Throughout all of the reactions between Entries 5–7).
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C. Wang, C. Chen, J. Han, J. Zhang, Y. Yao, Y. Zhao
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Table 5. Synthesis of imines.[a]
Figure 1. Oxygen influence on N-alkylation of aniline with benzyl
alcohol.
[a] Reagents and conditions:
CsOH·H2O (0.2 mmol) in toluene (0.3 mL) at 70 °C for 18 h under
air, yields are of isolated products.
2 (1 mmol), 1 (1.2 mmol), and
Scheme 2. Base-promoted alcohol oxidation.
To clearly understand the mechanism of this transforma-
tion, several reactions were performed, and the results are
shown in Figure 1 and Schemes 2, 3, and 4. The reaction of
aniline and benzyl alcohol with different amounts of oxygen
at 140 °C for 8 h under argon afforded the corresponding
products 3aa and 4aa. The yield of 3aa increased rapidly
with an increased catalyst loading of O2. When too much
O2 was added, the total conversion increased, but a lower
yield of 3aa was observed along with an increase to the
yield of 4aa. On the basis of the two opposing effects of
oxygen on the catalytic cycle, a catalytic loading of 2–5 mol-
% was found to be best for the transformation, which is
consistent with the data shown in Entry 9 of Table 1. These
results were also consistent with reports of Tang and co-
workers, which describe the synthesis of imines from
alcohols and amines with the assistance of an alkali hydrox-
ide under air.[18]
Scheme 3. Transfer hydrogenation of imine by alcohol.
the cesium hydroxide, both benzaldehyde and benzoic acid
We reasoned that the oxygen may oxidize alcohol 2 into were detected in less than 5% (Scheme 2). These results sug-
a small amount of the corresponding aldehyde under the gest that a trace amount oxygen with the assistance of
assistance of cesium hydroxide. Then, the amine would cesium hydroxide affords an aldehyde, which then provides
quickly undergo a reaction with the aldehyde to yield the the key imine intermediate for the next catalytic cycle under
imine. To confirm our hypothesis, we treated benzyl alcohol argon.
with cesium hydroxide in mesitylene under oxygen. Benz-
To understand the temperature effect on these base-pro-
aldehyde 5 was obtained in an NMR yield of 13%, which moted N-alkylation reactions, the reaction between imine
was further confirmed by LC–MS, along with 32% of the 4aa and benzyl alcohol with a catalytic amount of
recovered benzyl alcohol. The over-oxidized product CsOH·H2O (20 mol-%) was carried out at different tem-
benzoic acid 6 was also isolated in 47% yield.[19] Without peratures for 24 h (Scheme 3, A). The results imply that the
4
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O2-Promoted Base-Catalyzed N-Alkylation of Amines with Alcohols
tant role in the catalyst system, that is, oxygen is required
to achieve and facilitate the oxidation of the alcohol, but
too much oxygen might inhibit the transfer hydrogenation
step during the catalytic cycle. As a result, an argon atmo-
sphere and a catalytic amount of O2 were needed for this
reaction. Although the mechanism we propose is analogous
to previous reports,[15a] the scope of the substrates and the
simple reaction conditions make this new protocol greener
and much more practical.
Scheme 4. Deuterium-labeling experiments.
transfer hydrogenation under the assistance of CsOH·H2O
requires a high temperature (140 °C) under argon, which
explains why the N-alkylation was carried out at a higher
temperature than that for the imine formation. However,
the yield of 3aa was observed in only in 6% yield when
the reaction was carried out under air, which indicates that
oxygen might interact with the hydride in the catalytic cycle
of the transfer hydrogenation and prevent the hydrogen
transformation (Scheme 3, A). When 1 equiv. of CsOH·H2O
was used in the hydrogen autotransformation, quantitative
yields of 3aa and 5 were achieved (Supporting Information,
Table S4). When we treated 4na and 2a with CsOH under
argon at 140 °C or a higher temperature, product 3na and
benzaldehyde were not observed by either LC–MS or GC–
MS analyses, which elucidates why aliphatic amines cannot
be employed in the N-alkylation promoted by CsOH
(Scheme 3, B). Furthermore, we also examined a series of
metal bases in the transfer hydrogenation of 4aa with 2a
(Supporting Information, Table S5). CsOH was found to be
the best catalyst as shown in Table 1.
Scheme 5. Reaction mechanism.
Conclusions
In summary, we have developed a highly efficient and
practical CsOH/O2 catalyst system for the N-alkylation of
alcohols with amines under argon. A wide range of alcohols
and amines were tolerated in this reaction system. The
mechanistic study provided a clear understanding of the
role of the base and oxygen in the catalytic cycle. This newly
developed protocol represents a green and economic
method for N-alkylation reactions. More synthetic applica-
tions of this catalyst system are currently under investiga-
tion.
Deuterium-labeling experiments (Scheme 4, A) revealed
that proton shifting occurred, which was clear evidence of
the transfer hydrogenation of the imine by the alcohol. An
equivalent amount of 4aa, 2b, and cesium hydroxide were
combined in mesitylene at 140 °C under argon to afford a
mixture of 3aa, 3ab, and 4ab (Scheme 4, B). The results
reveal an equilibrium, that is, the imine decomposes into
the corresponding aldehyde and amine, as the condensation
of aldehyde and amine affords the intermediate imine,
which can be seen from the results shown in Scheme 4.
In the light of observed experimental results and pioneer-
ing reports,[9,20] we proposed a mechanism for present
transformation (Scheme 5). Initially, a small amount of the
alcohol is oxidized into the corresponding aldehyde under
the assistance of CsOH and O2. Then, the aldehyde un-
dergoes a reaction with the amine to afford the key imine
Experimental Section
General Methods: Unless otherwise noted, all reagents were pur-
chased from commercial suppliers and used without further purifi-
cation. Column chromatography was performed by using silica gel
(300–400 mesh). The NMR spectroscopic data were recorded with
Varian Inova (400 MHz), Inova (300 MHz), Bruker DRX-400, or
a Bruker DRX-500 instrument and calibrated by using the residual
solvent peaks as an internal reference.
General Procedures for N-Alkylation Reaction: A mixture of amine
1 (1 mmol), alcohol 2 (1.2 mmol), CsOH·H2O (33.6 mg, 0.2 mmol),
and mesitylene (0.3 mL) in a 20 mL glass vial was purged with Ar
(3ϫ) and then sealed with a Teflon septum. O2 (0.45 mL, 2 mol-
%) was then added by syringe to the vial, and the reaction system
was heated in an oil bath for 24 h. The reaction mixture was cooled
intermediate. Finally, the imine is transformed into the N- to room temp. and concentrated in vacuo. The resulting residue
was purified by column chromatography on silica gel (ethyl acetate
and petroleum ether) to give product 3.
alkylation product through a transfer hydrogenation by the
alcohol with a catalytic amount of CsOH under argon, and
the alcohol is transformed into an aldehyde to form a cata-
General Procedures for Imine-Forming Reaction: A mixture of
lytic cycle. It should be noted that oxygen plays an impor- alcohol 2 (1 mmol), amine 1 (1.2 mmol), CsOH·H2O (33.6 mg,
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Acknowledgments
The authors gratefully acknowledge financial support from the
Natural Science Foundation of Jiangsu Province of China (grant
number BK20130294), and the Young National Natural Science
Foundation of China (grant number 21402133) for support of this
work. The Priority Academic Program Development of Jiangsu
Higher Education Institution (PAPD) and the Qing Lan Project
are also gratefully acknowledged for support.
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Chin. J. Chem. 2012, 30, 2322.
Received: January 19, 2015
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50086
/KAP1
Date: 12-03-15 12:36:03
Pages: 7
O2-Promoted Base-Catalyzed N-Alkylation of Amines with Alcohols
N-Alkylation of Amines
A highly efficient and practical transition-
metal-free CsOH/O2 catalyst system was
developed for the N-alkylation of amines
with alcohols under argon. This strategy
has excellent functional group tolerance
and is compatible with a wide scope of sub-
strates. The mechanistic study revealed the
necessity of a catalytic amount of O2 and
the role of the base in the hydrogen auto-
transformation.
C. Wang, C. Chen, J. Han, J. Zhang,
Y. Yao,* Y. Zhao* ............................ 1–7
Insight into O2-Promoted Base-Catalyzed
N-Alkylation of Amines with Alcohols
Keywords: Synthetic methods / Alkylation /
Alcohols / Amines / Cesium / Oxygen
Eur. J. Org. Chem. 0000, 0–0
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