Benzylamines via Iron-Catalyzed Direct Amination of Benzyl Alcohols

Article abstract of DOI:10.1021/acscatal.5b02160

Benzylamines play a prominent role in numerous pharmaceutically active compounds. Thus, the development of novel, sustainable catalytic methodologies to provide access to these privileged structural motifs is of central importance. Herein we describe a systematic study for the construction of a large variety of benzylamines using a well-defined homogeneous iron complex. The methodology consists of the direct coupling of readily available benzyl alcohols with simpler amines through the borrowing hydrogen methodology, producing a variety of substituted secondary and tertiary benzylamines in moderate to excellent yields for the first time with an iron catalyst. Notably, we explore the versatility of this methodology in the one-pot synthesis of nonsymmetric tertiary amines, sequential functionalization of diols with distinctly different amines, and the synthesis of N-benzyl piperidines via various synthetic pathways. In addition, direct conversion of the renewable building block 2,5-furan-dimethanol to pharmaceutically relevant compounds is achieved.

Full text of DOI:10.1021/acscatal.5b02160

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Article
Benzylamines via iron catalyzed direct amination of benzyl alcohols
Tao Yan, Ben L. Feringa, and Katalin Barta
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b02160 • Publication Date (Web): 03 Dec 2015
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Benzylamines via iron catalyzed direct amination of benzyl
alcohols
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Tao Yan, Ben L. Feringa, Katalin Barta*
Stratingh Institute for Chemistry, University of Groningen, 9747 AG, Groningen, The Netherlands
ABSTRACT: Benzylamines play a prominent role in numerous pharmaceutically active compounds. Thus, the develop-
ment of novel, sustainable catalytic methodologies to provide access to these privileged structural motifs is of central
importance. Herein we describe a systematic study for the construction of a large variety of benzylamines using a well-
defined homogeneous iron-complex. The methodology consists of the direct coupling of readily available benzyl alcohols
with simpler amines through the borrowing hydrogen methodology producing a variety of substituted secondary and
tertiary benzylamines in moderate to excellent yields for the first time with an iron catalyst. Notably, we explore the ver-
satility of this methodology in the one-pot synthesis of non-symmetric tertiary amines, sequential functionalization of
diols with distinctly different amines as well as the synthesis of N-benzyl piperidines via various synthetic pathways. In
addition, direct conversion of renewable building block 2,5-furan-dimethanol to pharmaceutically relevant compounds is
achieved.
KEYWORDS: iron catalysis, borrowing hydrogen, homogenous catalysis, benzylamines, alcohol to amine transformation
are shown in Scheme 2, A and B. Catalytic hydroamina-
INTRODUCTION
tion of alkenes or alkynes is an efficient way to access 1-
methyl-benzylamines.2 Alternatively, benzylation of
Benzylamines are frequently encountered motifs in bio-
amines with benzyl halides via nucleophilic substitution3
logical systems, and are highly valuable targets due to
their versatility1 (Scheme 1). Many pharmaceuticals con-
leads to the formation of stoichiometric amounts of
waste. Reductive amination4 is a catalytic and atom-
tain a benzylamine moiety. Prominent examples include
Rivastigmine1b, a cholinergic agent for treating dementia
economic alternative, however here the aldehyde reaction
due to Parkinson’s disease; Ezetimibe1c, a drug that helps
partner is usually generated by selective alcohol oxidation
reducing plasma cholesterol levels; and Emend1d, an
representing an additional reaction step, moreover, aldol-
condensation is a frequent side reaction.
aprepitant that blocks the neurokinin 1 (NK1) receptor.
Developing efficient pathways that allow for selective
synthesis of benzylamines, especially starting from readily
available substrates using sustainable catalysts based on
Among these methods, direct amination of benzyl al-
cohols is a preferred method because these substrates are
readily available and can even be obtained from renewa-
ble resources5,6, making this route a highly sustainable
alternative. However, direct nucleo-
non-toxic and inexpensive metals is an important goal2,3,4
.
Methods for the synthesis of benzylamine derivatives
philic substitution of the hydroxyl
group of benzyl alcohols with amines
is an energy and cost intensive pro-
cess7,8, while, installing a good leaving
group instead of the hydroxyl func-
tionality will suffer from low atom-
efficiency. The desired, catalytic way
to perform the direct coupling of
benzyl alcohols with amines involves
the borrowing hydrogen9 strategy
(Scheme 2, C). In this case, a specific
sequence of reaction steps will occur:
dehydrogenation of alcohol to alde-
hyde (a), imine formation (b) reduc-
tion of imine (c), which maintain the
high atom-efficiency10 while requiring
much lower activation energy9c. Addi-
Scheme 1. Bio-active compounds which are based on benzylamines as building
blocks.
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Scheme 2. Comparison of synthetic pathways to access benzylamine derivatives. A Hydroamination of styrene with
amine. B Comparison of amination of benzyl alcohols, benzyl halides and benzyl aldehydes. C Catalytic amination of
alcohols through borrowing hydrogen.
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tionally, this method provides innocuous water as the
only side product.
Optimization of reaction conditions. 4-Methylbenzyl
alcohol (1a) and morpholine (2a) were selected as the
starting materials for optimization of the reaction condi-
tions for direct coupling of benzyl-alcohols with second-
ary amines (Table 1). Using our previously reported con-
ditions18 with additional assistance of molecular sieves,
Since the first examples of catalytic amination of alco-
hols through borrowing hydrogen reported by Grigg11 and
Watanabe12 in 1981, considerable progress has been made
in this area13. However, mostly precious metal catalysts
containing ruthenium14 or iridium15 were used. Bio-
relevant and abundant transition metals like iron, have
Table 1. Optimization of reaction conditions for amina-
tion of 4-methylbenzyl alcohol (1a) with morpholine
(2a).a
been only scarcely used for this transformation16,18,19
.
Recently, we reported the first example of a sustainable,
direct amination of alcohols catalyzed by a well-defined
iron17 complex through the borrowing hydrogen strate-
gy.18 This work focused on the use of diverse aromatic
amines and aliphatic alcohols and diols. Two examples
were also included using benzyl alcohol as substrate,
however, these reactions suffered from rather low yields.
Very recently, Wills and coworkers also reported on the
iron catalyzed amination of alcohols19a. Examples of ben-
zyl alcohol amination, primarily with aniline were de-
scribed, however no product formation was observed
when benzylamine was employed as the reaction partner
to benzyl alcohols. Later, Zhao and coworkers reported
iron catalyzed amination of secondary alcohols with assis-
tant of 0.4 equiv AgF19b. However, only very limited suc-
cess has been shown with use of benzyl alcohols.
Entry 1a [mmol]
1
Solvent
1 (2 equiv.) CPME
T [oC] Conversion [%]b
130
130
39
33
2
1
1
1
1
1
1
1
1
1
1
1
THF
3
Dioxane 130
30
4
DCE
CH3CN
DMF
130
130
130
>95c
<5
5
6
<5
64
7
Toluene 130
Toluene 130
Toluene 130
Toluene 130
Toluene 135
8d
9e
10f
11
12
13
<5
<5
Here, a highly versatile method for the synthesis of a
large variety of benzylamines through direct iron cata-
lyzed amination of benzyl alcohols is presented. In addi-
tion to the impressive scope, important novel aspects are
the one-pot synthesis of asymmetric tertiary amines as
well as uncovering the reactivity trends in the sequential
functionalization of benzyl alcohols. Moreover, fully sus-
tainable, two step pathways from cellulosic platform
chemicals to pharmaceutically active compounds is de-
scribed.
<5
87
CPME
135
82
2 (4 equiv.) Toluene 135
>95 (87)
aGeneral reaction conditions: General Procedure (see
Supporting information, page S2), 0.5 mmol 2a, 2 or 4
equiv. 1a, 0.04 equiv. Cat 1, 0.08 equiv. Me3NO, 2 ml sol-
vent, 18 h, 130 or 135 oC, 95 - 105 mg molecular sieves, unless
b
otherwise specified, isolated yield in parenthesis. Conver-
sion was determined by GC-FID using decane as the inter-
nal standard. cNo 3a has been observed based on GC-MS.
d4 mol% FeCl3 instead of Cat 1 and Me3NO. e2 mol%
RESULTS AND DISCUSSION
f
Fe2(CO)9 instead of Cat 1 and Me3NO. 4 mol% Iron(II)
phthalocyanine instead of Cat 1 and Me3NO.
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only 39 % conversion was obtained (Table 1, entry 1). A
poor conversion (Table 1, entries 5 and 6). In toluene, 64
% conversion was obtained (Table 1, entry 7). When oth-
er iron sources like FeCl3, Fe2(CO)9 or Iron(II) phtalocya-
nine were applied instead of Cat 1, the conversions were
unsatisfactory (Table 1, entries 8 - 10). Using Cat1, the
conversion improved to 87 % when increasing the tem-
perature to 135 C in toluene, probably due to the acceler-
ation of imine reduction (Table 1, entry 11). Similar results
were obtained in CPME at 135 oC (82 %, Table 1, entry 12).
solvent screening showed, that etherate solvents like
tetrahydrofuran (THF) and dioxane gave low conversions
(33 % and 30 %, respectively, Table 1, entries 2 and 3).
Dichloroethane (DCE) gave full conversion but the de-
sired product (3a) was not detected presumably due to
nucleophilic substitution of the solvent (DCE) with mor-
pholine (2a) (Table 1, entry 4). More polar solvents like
acetonitrile and dimethylformamide (DMF) gave very
o
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Table 2. Amination of benzyl alcohols with secondary amines.a
Entry Substrate 1
Product 3
Yield [%]b
1
1b
3b
88
2
3
1c
3c
60
40
1d
3d
4
5
1e
1a
3e
3f
74
78
6
1f
3g
69
7
8
9
1c
1e
1a
3h
3i
90
80
65
3j
10
11
1a
1d
1g
3k
3l
91
63
69
12
3m
13
14
15
1a
1e
1h
3n
3o
3p
89
79
59
aGeneral reaction conditions: General Procedure (see Supporting information, page S2), 0.5 mmol 2, 2 mmol 1a, 0.02 –
0.03 mmol Cat 1, 0.04 - 0.06 mmol Me3NO, 2 ml solvent, 18 - 24 h, 135 oC, 95 - 105 mg molecular sieves,for specified conditions
see Supporting information, Table S2a and Table S2b. bIsolated yields.
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Increasing the loading of 1a to 2 mmol in toluene gave full
sides, was tested with 2 mmol (4 equiv) of 1c, 35 % of
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conversion and 87 % isolated yield of 3a (Table 1, entry
13).
mono N-benzylation and 55 % of 1,4-N-dibenzylation
product was obtained (Supporting information, Table
S2a, entry 11). With increasing the amount of 1c to 3 mmol
(6 equiv), the 1,4-N-dibenzylation product (3h) was ob-
tained in 90 % isolated yield (Supporting information,
Table S2a, entry 12).
Reactions of benzyl alcohols with secondary
amines. Next, under optimized reaction conditions, a
variety of secondary amines and benzyl alcohols were
tested (Table 2). Benzyl alcohol 1b with an electron-
donating –OCH3 substituent reacted smoothly with 2a
providing full conversion and 88 % isolated yield of 3b
(Table 2, entry 1). When less electron rich substrates 1c
and 1d were employed, lower reactivity was observed; 60
% of 3c and 40 % of 3d were isolated after 18 and 24 h
reaction time, respectively (Table 2, entries 2 and 3).
Interestingly, also for 2-thiophenemethanol (1e), a high
isolated yield (74 %) of 3e was obtained (Table 2, entry
4). For other secondary amines, such as 1-methyl-
piperazine (2b), piperazine (2c) and di-n-butyl-amine
(2d), the corresponding products were also obtained in
good to excellent yields (Table 2, entries 5 - 9). Interest-
ingly, when piperazine (2c), which has two reactive -NH
Next, secondary benzylic amines, which are less basic
compared to secondary aliphatic amines20, were used as
the substrate (Table 2). N-methyl benzylamine (2e) re-
acted smoothly with 1a, 1d, 1g and the corresponding
products were obtained in good to excellent yields (Table
2, entries 10 – 12). Similarly the reaction of 1,2,3,4-
tetrahydroisoquinoline (2f) with alcohols 1a, 1e, 1h pro-
vided the corresponding products in high yields (Table 2,
entries 13 – 15). Remarkably, alcohols, which possess het-
ero-aromatic moieties such as 1e and 1h, which have the
possibility to act as chelating ligands, could also be used
as shown in various entries in Table 2, and products 3e,
3i, 3o and 3p could be obtained in good to excellent
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Table 3. Amination of benzyl alcohols with primary amines.a
Entry Substrate 1
Product 5
Yield [%]b
1
1b
5a
54
2
3
4
5
1a
1c
1g
1i
5b
5c
5d
5e
61
59
53
42
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7
1j
5f
22
1c
5g
60
8
9
1c
1f
5h
5i
61
60
10
11
1a
1a
1c
5j
5k
5l
70
66
56
12
aGeneral reaction conditions: General Procedure (see Supporting information, page S2), 0.5 mmol 2, 2 mmol 1a, 0.02 –
0.03 mmol Cat 1, 0.04 - 0.06 mmol Me3NO, 2 ml solvent, 18 - 24 h, 135 oC, 95 - 105 mg molecular sieves, for specified conditions
see Supporting information, Table S3. bIsolated yields.
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yield.21
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Scheme 3. Reactivity difference through different sub-
strates.
Reactions of benzyl alcohols with primary amines.
We recently reported the synthesis of mono-N-alkylated
benzylamines from the corresponding primary benzyla-
mines and aliphatic alcohols.18 Here we demonstrate a
new alternative route to the same products, starting from
benzyl alcohols and aliphatic amines (Table 3), which to
the best of our knowledge has not been previously report-
ed with any iron catalyst, and allows great synthetic flexi-
bility for the selection of the substrates and more insight
into the reaction mechanism.
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First, n-pentylamine (4a) was selected for the synthesis
of a variety of functionalized benzyl alcohols (Table 3,
entries 1 – 6; Supporting information, Table S3, entries 1
to 13). Selectivity towards the mono-alkylation products
was sensitive to the amount of alcohol substrate added.
For example, 2 eq. of 4-methoxybenzyl alcohol (1b) lead
to preferential formation and 54% isolated yield of 5a
(Table 3, entry 1; Supporting information, Table S3, entry
2), however further increasing 1b loading lead to more
dialkylation product (Supporting information, Table S-3,
entry 1). On the other hand, only using 1.5 eq of 1b, the
corresponding imine was detected as the major product
(Supporting information, Table S3, entry 3). The same
behavior was observed with 4-methylbenzyl alcohol (1a)
(Supporting information, Table S3, entries 4 - 6). In addi-
tion, increasing Cat 1 loading to 6 mol % provided 61 %
isolated yield of 5b (Supporting information, Table S3,
entry 2).
differences in the rate of the imine reduction step.22 It has
to be noted that the imine intermediates formed from
benzyl-alcohols will possess a double bond in conjugation
with the aromatic system (Pathway A, Scheme 3) and
those formed from benzyl amines will not (Pathway B,
Scheme 3). These reactivity differences under similar
conditions, also show that isomerization of the imine
double bond is not likely. The detailed understanding of
these mechanistic details and rate limiting steps will be
subject of future in depth-studies.
Next, a series of other primary amines were tested as
substrates (Table 3, Entry 7 - 12). Long chain amines like
n-nonylamine (4b) and 2-phenylethamine (4c) were ben-
zylated with benzyl alcohol (1c) providing 5g and 5h in
good isolated yields (Table 3, entries 7 and 8). Further-
more, primary benzylamines and anilines could be readily
applied to provide 5k and 5l (Table 3, entries 9 – 12).
Interestingly, when less electron-rich substrates such as
benzyl alcohol (1c) and 4-fluorobenzyl alcohol (1g) were
examined, less di-N-benzylation product was observed
and 59 % and 53 % of mono-N-benzylation products were
isolated, respectively (Table 3, entries 3 and 4).
The reaction of 3-chlorobenzyl alcohol (1i) and 3-
trifluoromethylbenzyl alcohol (1j) with n-pentylamine
(4a) (Supporting information, Table S3, entries 9 - 13) was
examined as comparison with our previous approach18
that used 3-chloro and 3-trifluoromethyl substituted ben-
zylamines. In the present case, both reactions provided
preferentially imine products (Supporting information,
Table S3, entry 9 and 12, 13). Increasing the catalyst load-
ing to 6 mol % and reaction time to 24 h, provided more
amine product 5e (Supporting information, Table S3,
entry 10) but still rather low amounts of desired amine 5f
(31%, Supporting information, Table S3, entry 13) were
obtained. Increasing the reaction temperature to 140 oC in
order to facilitate imine reduction resulted in catalyst
decomposition (Supporting information, Table S3, entry
11).
In our previous study18, electron-deficient benzylamines
were more reactive towards mono-alkylation than their
electron rich analogues. The results shown here, however,
conclude that N-alkylated benzylamines are more readily
obtained starting from electron-rich benzyl alcohols than
from electron poor benzyl-alcohols (Scheme 3). The rea-
son for this reactivity difference can likely be attributed to
Scheme 4. One pot synthesis of asymmetric benzylic
tertiary amines.a
aGeneral reaction conditions: General Procedure (see
Supporting information, page S2), 0.5 mmol 4a, 1 or 2
mmol 1, 1 or 1.5 mmol 8, 0.03 mmol Cat 1, 0.06 mmol
o
Me3NO, 2 ml solvent, 24 h, 135 C, 195 - 205 mg molecular
sieves,for specified conditions, see Supporting information,
Table S-4. Isolated yields are shown for each products.
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Scheme 5. Sequential functionalization of diols.a
of
1
A one-pot method for the preparation of non-
sis
2
3
4
5
6
7
8
9
symmetric tertiary amines. Taking advantage of the
differences in reactivity between aliphatic and benzyl
alcohols, we have developed a straightforward approach
for the direct one pot synthesis of non-symmetric ben-
zylic tertiary amines (Scheme 4). To this end, a method
using benzyl alcohol (1c), n-pentylamine (4a) and n-
butanol (8a) was implemented with 6 mol % Cat 1 load-
other
non-
symmet-
ric ter-
tiary
amines
9b and
9c (Sup-
porting
infor-
mation,
Table
S4, en-
tries 4 –
6).
o
aCondition a: General Procedure (see page S2), 0.5 mmol
2a, 1.5 mmol 12a, 0.02 mmol Cat 1, 0.04 mmol Me3NO, 135 oC,
2 ml toluene, 18 h, 95 - 105 mg molecular sieves. 63 % of 13a
was isolated. Condition b: General Procedure (see page
S2), 0.5 mmol 2e, 1 mmol 13a, 0.03 mmol Cat 1, 0.06 mmol
Me3NO, 135 oC, 2 ml toluene, 18 h, 95 - 105 mg molecular
sieves. 30 % of 14 was isolated.
ing, at 135 C. Gratifyingly, the desired non-symmetric N-
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n-butyl-N-n-pentylbenzylamine (9a) was predominant in
the reaction mixture that also contained smaller amounts
of the expected di-N-benzyl-n-pentylamine (10a), and di-
N-n-butyl-n-pentylamine (11a) (Supporting information,
Table S4, entry 1). The desired tertiary amine with three
distinctly different alkyl moieties 9a was isolated in 51 %
yield. The one-pot procedure was extended to the synthe-
Scheme 6. Retro-synthetic analysis and diverse approaches for synthesizing N-benzyl piperidines.a
aA. Retro-synthesis analysis of N-benzyl piperidines. B. Diverse approaches for synthesizing N-benzyl piperidines. General
reaction conditions: General Procedure (see Supporting information, page S2), 0.5 or 1 mmol 15, 0.5 or 2 mmol 1, 0.02 mmol
Cat 1, 0.04 mmol Me3NO, 135 oC, 2 ml toluene, 18 or 24 h, 95 - 105 mg molecular sieves, for specified conditions see Supporting
information, Table S5. Isolated yields are shown for each products.
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Scheme 7. Synthesis of key intermediate to muscarinic agonist, N-[5-([l'-substituted-acetoxy)methyl]-2-
furfurylldialkylamines.
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aGeneral Procedure (see page S2), 0.5 mmol 2e, 2 mmol 12b, 0.02 mmol Cat 1, 0.04 mmol Me3NO, 135 oC, 2 ml toluene, 24 h,
95 - 105 mg molecular sieves. 60 % of 13b was isolated.
Sequential functionalization of diols to obtain di-
verse diamines. Sequential functionalization of diols is
undoubtedly a valuable synthetic tool to obtain com-
pounds with great diversity. Here we present, for the first
time, a selective iron catalysed method that allows for the
preparation a non-symmetric functionalized diamines.
This reaction sequence was demonstrated for the prepara-
tion of compound 14 whereby diol 12a was selectively
monoalkylated with 2a forming 13a. This was followed by
amination of 13a with 2e to provide 14. (Scheme 5)
compounds possessing potential antimuscarinic activity.
Pharmaceutical studies have especially focused on sys-
tematic modifications of the ester- and amine side
chains.25 Here we show an efficient and fully sustainable
synthetic strategy towards obtaining key intermediate
13b. This compound can be prepared directly from benzyl
amine derivative 2e and diol 12b using our iron catalysed
methodology. Diol 12b used in this reaction can be ob-
tained in high yield from 5-(hydroxymethyl)furfural
(HMF, 17), via a sustainable pathway we have recently
reported26. In this procedure, HMF, which is one of the
most important cellulose derived platform chemicals
undergoes catalytic hydrogenation using robust, CuZn
alloy nanopowder catalysts26b. This novel combination of
methods allows for the easy, waste free synthesis of key
bioactive intermediate 13b from renewable resources,
using sustainable catalysis.
Diverse approaches to N-benzyl piperidines. N-
hetercycles are compounds of major interest due to their
prominent role in bio-active compounds e.g. pharmaceu-
ticals and agrochemicals.23 Our previous study showed
the direct synthesis of benzyl-protected five, six, and
seven membered-heterocycles from benzylamines and
diols.18
Here, we have investigated versatile synthesis routes for
the preparation of N-benyzl piperidine as representative
example for benzyl protected N-heterocycles (illustrated
in Scheme 6). The same N-benyzl piperidine 16 can be
obtained via three distinct routes, starting from different
substrates (Scheme 6). For example, 16 can be synthe-
sized from three sets of substrates through four pathways
(Scheme 6, A). 16 can be obtained from benzyl alcohol (1)
and piperidine (15a) through the formation of bond a
(Scheme 6, A, Pathway 1). Alternatively, 16 can be ob-
tained from 1 and 5-amino-1-pentanol (15b) through the
sequential formation of bonds a and b (Scheme 6, A,
Pathway 2a), or b and a (Scheme 6, A, Pathway 2b). Also,
16 can be synthesized starting from 1,5-pentanediol (15c’)
and 1c’ during which bonds b and c are formed (Scheme
6, A, Pathway 3). These substrate variations allow for
choosing the most suitable pathway24 taking into account
optimal balance of reactivity, selectivity and substrate
abundance. In order to show the power of this method,
16a, 16b, 16c, and 16d were synthesized through different
pathways, with good to excellent yields (Scheme 6, B).
CONCLUSION
In conclusion, we have established, for the first time, a
general methodology for the catalytic formation of value-
added benzylamines through amination of benzylalcohols
using a well-defined iron catalyst that operates through a
hydrogen borrowing mechanism. Many synthetically
challenging routes were systematically explored starting
from readily accessible substrates that do not require
prior alcohol activation by stoichiometric methods. This
included the one-pot synthesis of asymmetric tertiary
amines, the sequential functionalization of diols as well as
the synthesis of important synthons, for example, N-
benzyl-piperidines through diverse synthetic pathways. In
addition, direct conversion of renewable building block
2,5 furan dimethanol to pharmaceutically relevant com-
pounds was achieved with unprecedented simplicity.
Future work focuses on elucidating mechanistic questions
and the design of new catalyst structures.
EXPERIMENTAL SECTION
Reagents and Characterization Methods Reagents
were of commercial grade and used as received, unless
stated otherwise. Complex Cat 1 was synthetized accord-
ing to literature procedures27. Chromatography: Merck
From cellulose derived platform chemicals to
pharmaceutically active molecules. It was reported
that furanic compounds of the general structure (18)
shown on Scheme 7 are a class of pharmaceutically active
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macother. 2000, 20, 1-12. (c) Sniezek, M.; Stecko, S.; Panfil, I.;
silica gel type 9385 230-400 mesh or Merck Al2O3 90 ac-
tive neutral, TLC: Merck silica gel 60, 0.25 mm or Al2O3 60
F254 neutral. Components were visualized by UV, Ninhy-
drin or I2 staining. 1H- and 13C NMR spectra were recorded
on a Varian AMX400 (400 and 100.59 MHz, respectively)
using CDCl3, CD3OD, or CD2Cl2 as solvent. Chemical shift
values are reported in ppm with the solvent resonance as
Furman, B.; Chmielewski, M. J. Org. Chem. 2013, 78, 7048. (d)
Brands, K. M. J.; Payack, J. F.; Rosen, J. D.; Nelson, T. D.; Cande-
lario, A.; Huffman, M. A.; Zhao, M. M.; Li, J.; Craig, B.; Song, Z. J.;
Tschaen, D. M.; Hansen, K.; Devine, P. N.; Pye, P. J.; Rossen, K.;
Dormer, P. G.; Reamer, R. A.; Welch, C. J.; Mathre, D. J.; Tsou, N.
N.; McNamara, J. M.; Reider, P. J. J. Am. Chem. Soc. 2003, 125,
2129-2135.
(2) (a) Shi, S.-L.; Buchwald, S. L. Nature Chem. 2015, 7, 38-44. (b)
Zhu, S.; Niljianskul, N.; Buchwald, S. L. J. Am. Chem. Soc., 2013,
135, 15746-15749. (c) Miki, Y.; Hirano, K.; Satoh, T.; Miura, M.
Angew. Chem. Int. Ed. 2013, 52, 10830-10834. (d) Muller, T. E.;
Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008,
108, 3795-3892. (e) Severin, R.; Doye, S. Chem. Soc. Rev. 2007, 36,
1407-1420.
1
the internal standard (CDCl3: 7.26 for H, 77.00 for 13C;
CD3OD: 3.31 for 1H, 49.00 for 13C; CD2Cl2: 5.32 for 1H, 53.84
for 13C). Data are reported as follows: chemical shifts,
multiplicity (s = singlet, d = doublet, t = triplet, q = quar-
tet, br. = broad, m = multiplet), coupling constants (Hz),
and integration.
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Representative Procedures Procedure of amination
of 4-methoxybenzyl alcohol (1b) with morpholine (2a)
provides 3b: An oven-dried 20 ml Schlenk tube, equipped
with stirring bar, was charged with 4-methoxybenzyl
alcohol (2 mmol, 0.276 g), iron complex Cat 1 (4 mol %, 8
mg) and Me3NO (8 mol %, 3 mg) under air. Then the
Schlenk tube was subsequently connected to an argon
line and a vacuum-argon exchange was performed three
times. Morpholine (0.5 mmol, 0.044 g), and toluene (sol-
vent, 2 ml) were charged under an argon stream followed
by addition of 95 – 105 mg activated molecular sieves 4A.
The Schlenk tube was capped and the mixture was rapidly
stirred at room temperature for 1 min, then was placed
(3) Smith, M. B., March, J. March’s advanced organic chemistry:
reactions, mechanisms, and structure; chapter 10, 6th ed., John
Wiley & Sons, Inc.: Hoboken, New Jersey, 2007.
(4) (a) Pisiewicz, S.; Stemmler, T.; Surkus, A.-E.; Junge, K.; Beller,
M. ChemCatChem 2015, 7, 62-64. (b) Kolesnikov, P. N.; Yagafa-
rov, N. Z.; Usanov, D. L.; Maleev, V. I.; Chusov, D. Org. Lett.
2015, 17, 173-175. (c) Guyon, C.; Da Silva, E.; Lafon, R.; Metay, E.;
Lemaire, M. RSC Adv. 2015, 5, 2292-2298. (d) Zhou, S.; Fleischer,
S.; Jiao, H.; Junge, K.; Beller, M. Adv. Synth. Catal. 2014, 356, 3451-
3455. (e) Chusov, D.; List, B. Angew. Chem. Int. Ed. 2014, 53, 5199-
5201. (f) Pagnoux-Ozherelyeva, A.; Pannetier, N.; Mbaye, M. D.;
Gaillard, S.; Renaud, J.-L. Angew. Chem. Int. Ed. 2012, 51, 4976-
4980.
(5) Benzyl alcohol is produced naturally by many plants, see: The
Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologi-
cals, 11th ed., Merck, 1989, ISBN 091191028X, 1138.
o
into a pre-heated oil bath at 135 C and stirred for 18 h.
The reaction mixture was cooled down to room tempera-
ture and the crude mixture was filtered through celite,
eluted with ethyl acetate, and concentrated in vacuo. The
residue was purified by flash column chromatography
(SiO2, CH2Cl2/EtOAc 80:20 to 50:50) to provide the pure
amine product 3b (0.091 g, 88 % isolated yield). For char-
acterization data, see the Supporting information.
(6) Benzyl alcohols may be produced by hydrogenation of benzyl
aldehydes which derivate from oxidative depolymerization of
lignin. See: (a) Rahimi, A.; Azarpira, A.; Kim, H.; Ralph, J.; Stahl,
S. S. J. Am. Chem. Soc. 2013, 135, 6415-6418. (b) Deuss, P. J.; Barta,
K.; de Vries, J. G. Catal. Sci. Technol. 2014, 4, 1174-1196.
(7) Industrial production of amines mostly based nucleophilic
substitution mechanism. For example, methylamines can be
o
produced under 350-500 C and 15-30 bar pressure using alumi-
num-based heterogeneous catalyst from ammonia and metha-
nol. See: Weissermel, K.; Arpe, H.-J. Industrial Organic Chemis-
try, Fourth Completely Revised Edition, Wiley-VCH: Weinheim,
2003, p. 51.
ASSOCIATED CONTENT
Supporting Information.
Experimental details and NMR spectra (1H, 13C), HRMS, of all
reaction products are include in the supporting information.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(8) One promising example shown the direct amination of alco-
hols catalyzed by iron-amino acid through nucleophilic substitu-
o
tion pathway with relative milder condition (160 – 200 C). See:
Zhao, Y.; Foo, S. W.; Saito, S. Angew. Chem. Int. Ed. 2011, 50,
3006-3009.
AUTHOR INFORMATION
Corresponding Author
(9) (a) Hamid, M. H. S. A.; Slatford, P. A.; Williams, J. M. J. Adv.
Synth. Catal. 2007, 349, 1555-1575. (b) Nixon, T. D.; Whittlesey,
M. K.; Williams, J. M. J. Dalton Trans., 2009, 753-762. (c) Wat-
son, A. J. A.; Williams, J. M. J. Science 2010, 329, 635-636. (d)
Guillena, G.; Ramon, D. J.; Yus, M. Chem. Rev. 2010, 110, 1611-1641.
(e) Bahn, S.; Imm, S.; Neubert, L.; Zhang, M.; Neumann, H.;
Beller, M. ChemCatChem 2011, 3, 1853-1864. (f) Dobereiner, G. E.;
Crabtree, R. H. Chem. Rev. 2010, 110, 681-703. (g) Gunanathan, C.;
Milstein, D. Science 2013, 341, 1229712.
(10) (a) Trost, B. M. Science 1983, 219, 245-250. (b) Trost, B. M.
Science 1991, 254, 1471-1477.
(11) Grigg, R., Mitchell, T. R. B., Sutthivaiyakit, S.; Tongpenyai, N.
J. Chem. Soc., Chem. Commun. 1981, 611-612.
k.barta@rug.nl
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors thank the Ministry of Education, Culture and
Science (Gravitation Program 024.001.035) for financial sup-
port. T.Y. would like to thank Dr. Giovanni Bottari for syn-
thesizing 2,5-bis(hydroxymethyl)furan (12a), and thank Dr.
Peter Deuss for helpful discussions during manuscript prepa-
ration (both from University of Groningen).
(12) Watanabe, Y.; Tsuji, Y.; Ohsugi, Y. Tetrahedron Lett. 1981, 22,
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(13) Selected examples: (a) Fujita, K.-i.; Yamamoto, K.; Yamagu-
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