Solvent-free amination of secondary benzylic alcohols with N-nucleophiles catalyzed by FeCl3

Article abstract of DOI:10.1080/00397911.2010.488798

A general, simple, and environmentally friendly method for the direct amination of secondary benzyl alcohols with amides or 4-nitroaniline is described. This method has been applied to a variety of substrates, and the reaction proceeded smoothly at room temperature under solvent-free conditions. CbzNH₂ was proved to be very useful in the direct preparation of the benzylic amines from corresponding alcohols.

Full text of DOI:10.1080/00397911.2010.488798

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Solvent-Free Amination of Secondary
Benzylic Alcohols with N-Nucleophiles
Catalyzed by FeCl3
Jian-Jun Yu a , Li-Min Wang a , Feng-Lou Guo a , Jin-Qian Liu a , Ying
Liu a & Ning Jiao a
a Laboratory for Advanced Materials and Institute of Fine
Chemicals , East China University of Science and Technology ,
Shanghai , China
Published online: 20 Apr 2011.
To cite this article: Jian-Jun Yu , Li-Min Wang , Feng-Lou Guo , Jin-Qian Liu , Ying Liu & Ning Jiao
(2011) Solvent-Free Amination of Secondary Benzylic Alcohols with N-Nucleophiles Catalyzed by FeCl3
, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:11, 1609-1616, DOI: 10.1080/00397911.2010.488798
To link to this article: http://dx.doi.org/10.1080/00397911.2010.488798
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Synthetic Communications1, 41: 1609–1616, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.488798
SOLVENT-FREE AMINATION OF SECONDARY
BENZYLIC ALCOHOLS WITH N-NUCLEOPHILES
CATALYZED BY FeCl3
Jian-Jun Yu, Li-Min Wang, Feng-Lou Guo, Jin-Qian Liu,
Ying Liu, and Ning Jiao
Laboratory for Advanced Materials and Institute of Fine Chemicals, East
China University of Science and Technology, Shanghai, China
GRAPHICAL ABSTRACT
Abstract A general, simple, and environmentally friendly method for the direct amination of
secondary benzyl alcohols with amides or 4-nitroaniline is described. This method has been
applied to a variety of substrates, and the reaction proceeded smoothly at room temperature
under solvent-free conditions. CbzNH2 was proved to be very useful in the direct
preparation of the benzylic amines from corresponding alcohols.
Keywords Amination; benzyl alcohols; benzyl amines; FeCl3; solvent free
INTRODUCTION
Benzylic amines are of medicinal potential and are found in a number of
biologically active compounds.[1,2] CꢀN bond formation is an important reaction
for the synthesis of these kinds of amines. Generally, this transformation is carried
out using alkyl halides in the presence of a stoichiometric amount of base. Although
this method works well even on a large scale, often it is associated with significant
drawbacks including unavailability of halogenated substrate, toxicity of halogenated
substrates, the use of a strong base, and production of large amounts of salts as
by-products. Thus, benzylic alcohols and their derivatives have received considerable
Received August 30, 2009.
Address correspondence to Li-Min Wang, Laboratory for Advanced Materials and Institute of
Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai
200237, China. E-mail: wanglimin@ecust.edu.cn
1609

1610
J.-J. YU ET AL.
attention as carbon electrophiles capable of reacting with various carbon, oxygen,
and sulfur nucleophiles.[3] However, there are a very limited number of examples
known with less nucleophilic nitrogen nucleophiles such as amides and electron-
deficient aromatic amines.
To the best of our knowledge, only a few Lewis acid–catalyzed amidation reac-
tions of alcohols with primary amides have been described in the literature using
NaAuCl4,[4] H-montmorillonite,[5] MoCl5,[6] NbCl5,[7] FeCl3,[8] and Bi(OTf)3=
[9]
KPF6 among others.[10] More important, the solvents used for these reactions
mainly were CH2Cl2,[4,6] CH3NO2,[8] CH3CN,[9] and 1,4-dioxane,[5,9] which are too
expensive and toxic for practical utility of these methods in the large-scale synthesis
of differently substituted benzylic amides or amines.
Over the past few years, a significant amount of research has been directed
toward the progress of new technologies for environmentally benign processes,
and the development of new, general, efficient, ecofriendly catalytic procedures for
amination reactions is desirable. Environmental concerns about solvent-based chem-
istry have stimulated a renewed interest in the study of chemical reactions under
solvent-free conditions.[11]
In this context, we report herein that FeCl3 is an efficient catalyst for the ami-
nation reactions of secondary benzylic alcohols with nitrogen nucleophiles under
solvent-free conditions.
RESULTS AND DISCUSSION
The amidation reaction of 1-phenylethanol (2a) with 4-methylbenzenesulfona-
mide (1a) was chosen as model reaction to find the best reaction conditions
(Scheme 1). First, different kinds of catalyst were tested in this reaction, and the
results are summarized in Table 1 (entries 1–7). Brønsted acid and p-methylbenzene-
sulfonic acid were examined and only traces of benzylic amine (3a) were afforded
(Table 1, entry 1). Except for FeCl3 (Table 1, entry 7), other Lewis acids, such as
Yb(OTf)3, YbCl3, AlCl3, TiCl4, InCl3, and FeCl3 ꢁ 6H2O all had poor results
(Table 1, entries 2–6). Thus, FeCl3 was the best choice for this reaction. Using FeCl3
as catalyst, different reaction times were tested, and the results showed that 4 h was
enough for this reaction (Table 1, entries 7–9). Meanwhile, the temperature was also
examined, and the high temperature was proved to be fit for the formation of
by-product 4a (Table 1, entries 7 and 10–13). The reactions were carried out at room
Scheme 1. Amidation reaction of 1-phenylethanol with Ts-NH2.

SOLVENT-FREE AMINATION OF BENZYLIC ALCOHOLS
1611
Table 1. Optimization of the amination reaction
Entrya,b
Catalyst
Catalyst loading (mol%)
Time (h)
Temp (ꢂC)
Yieldc (%)
1
2
TsOH
Yb(OTf)3
YbCl3
TiCl4
20
20
20
20
20
20
20
20
20
20
20
20
20
1
4
4
4
4
4
4
4
1
8
4
4
4
4
4
4
4
4
4
rt
rt
Trace
Trace
Trace
Trace
Trace
Trace
85
3
rt
4
rt
5
InCl3
rt
6
FeCl3 ꢁ H2O
FeCl3
FeCl3
rt
7
rt
8
rt
60
85
9
FeCl3
FeCl3
rt
10
11
12
13
14
15
16
17
18
40
60
80
100
rt
80
50
FeCl3
FeCl3
Trace
Trace
Trace
Trace
Trace
20
FeCl3
FeCl3
FeCl3
FeCl3
2
rt
5
rt
FeCl3
FeCl3
10
30
rt
rt
80
aReaction condition: 4-methylbenzenesulfonamide (1.2 mmol), 1-phenylethanol (1 mmol).
b4-Methylbenzenesulfonamide was ground before use.
cIsolated yield.
temperature for 4 h, with different amounts of catalyst, and the most suitable
catalyst=substrate ratio seems to be 0.2 (Table 1, entries 7 and 14–18).
Having established the reaction conditions, we further explored the generality
and efficiency of the FeCl3-catalyzed direct amination of various nucleophiles such
as p-toluenesulfonamide, benzamide, benzyl carbamate, and 4-nitroaniline with
benzylic alcohols (Scheme 2). In general, the reaction proceeded smoothly for all
cases in good to excellent yields within a very short period of time with complete
selectivity. The results are summarized in Table 2.
First, p-toluenesulfonamide was treated with different benzylic alcohols
(Scheme 3), and the yields of the products were associated with the stability of the
carbon cations formed in this reaction (Table 2, entries 1–5).
As a first example, benzylic alcohol 2b was treated with p-toluenesulfonamide
in the presence of a catalytic amount of FeCl3 (20 mol%) at room temperature to give
the corresponding amidated product 3b in 80% yield within 4 h (Table 2, entry 1).
Scheme 2. Solvent-free amination of the benzylic alcohols with different N-nucleophiles catalyzed by
FeCl3.

1612
J.-J. YU ET AL.
Table 2. Amination of secondary benzylic alcohols with N-nucleophiles catalyzed by FeCl3 under
solvent-free conditions
Entrya
R1
Alcohols (2)
Temp. (ꢂC)
Product(3)
Yield (%)b
1
2
Ts (1a)
Ts (1a)
Ts (1a)
2b
2c
2d
2e
2f
rt
60c
rt
3b
3c
3d
3e
3f
80
90
3
70
51
4
Ts (1a)
Ts (1a)
rt
5
rt
52
80
6
Benzoyl (1b)
Benzoyl (1b)
Benzoyl (1b)
Cbz (1c)
2b
2c
2d
2b
2c
2d
2a
2b
2c
2d
2f
60c
60c
rt
3g
3h
3i
7
90
65
8
9
60c
60c
rt
3j
80
96
10
11
12
13
14
15
16
17
18
19
Cbz (1c)
Cbz (1c)
3k
3l
90
46
4-Nitrophenyl (1d)
4-Nitrophenyl (1d)
4-Nitrophenyl (1d)
4-Nitrophenyl (1d)
4-Nitrophenyl (1d)
Boc (1e)
rt
3m
3n
30
3p
3q
3r
3s
3t
60c
60c
rt
75
80
91
40
rt
2c
2c
2g
60c
rt
Trace
Trace
Trace
Ph (1f)
Ts (1a)
rt
aReaction condition: nucleophile (1.2 mmol), benzylic alcohols (1 mmol), FeCl3 (20 mol%), room tem-
perature.
bIsolated yield.
cWhen the reactants were both solid, they were ground together and warmed to 60 ꢂC.
The reaction of 1a with other benzylic alcohols was also successful (Table 2, entries
2–5). With this success, we were interested in testing the nucleophilic substitution
reaction with benzamide. Thus, the reaction of benzylic alcohols with benzamide
in the presence of 20 mol% FeCl3 proceeded easily to provide the corresponding
amides with a yield of up to 90% (Table 2, entries 6–8). Similarly, the catalytic system
was also effective for the amidation of 2c with benzyl carbamate, which provided the
corresponding Cbz-protected amines up to 96% yield (Table 2, entries 9–11). Finally,
other N-nucleophiles, such as 4-nitroaniline, were also successfully tested, allowing
the introduction of aniline-based moieties at the benzylic position (Table 2, entries
12–16). When t-butyl carbamate (BocNH2) and aniline were introduced, traces of
products were afforded (Table 2, entries 17 and 18). When the less reactive benzylic
Scheme 3. Chemical structure of the benzylic alcohols used in amination reactions.

SOLVENT-FREE AMINATION OF BENZYLIC ALCOHOLS
1613
Scheme 4. Direct access to benzylic amines.
Table 3. Two-steps methods to the synthesis of benzyl amines
Entry
Alcohol (2)
Compound (4)
Yield(%)a two steps
1
2
3
2b
2c
2d
4b
4c
4d
78
94
88
aIsolated yield.
alcohol 2g was tested with 1a, almost no reaction was carried out in the model
conditions (Table 2, entry 19).
However, when two components of the reactants were both solid particles, the
reaction must be carried out at a higher temperature to get excellent yield, which
might due to the homogeneous mixing after the melting of the two components
(Table 2, entries 2, 6, 7, 10, 13, and 14).
Direct access to benzylic amines is also valuable in the context of the synthesis
of bioactive products (Scheme 4). The purification of crude product over column
chromatography, followed by the reduction of the Cbz-protected intermediates using
Pd=C and H2, afforded the desired methylamines in nearly quantitative yields. Thus,
various benzylic amines have been successfully prepared using H2 as the reducing
agent in 78% to 94% yields, and the results are gathered in Table 3.
EXPERIMENTAL
Melting points were determined with an X-4 apparatus and are uncorrected.
1H (400-MHz) and 13C (100-MHz) NMR spectra were recorded on a Bruker Avance
400 spectrometer in CDCl3 using tetramethylsilane (TMS) as internal reference.
Mass (EI) spectra were recorded on a Micromass GCTTM mass spectrometer.
All chemicals used were reagent grade and were used as received without further
purification.
Representative Procedure for the Synthesis of Compound 3j
A mixture of (4-methoxyphenyl) (phenyl) methanol (2b, 1.0 mmol) and benzyl
carbamate (1c, 1.2 mmol) was heated to 60 ꢂC for 5 min until the reactant melted.
Anhydrous FeCl3 (30 mg, 20 mol%) was added in a single portion, and the reaction
was continued until the reaction mixture solidified. The mixture was loaded onto a
silica-gel column and chromatographed with petroleum ether=ethyl acetate (4:1) to

1614
J.-J. YU ET AL.
1
afford product 3j as a white solid (273 mg, 0.80 mmol, 80%), mp 103–105 ꢂC H
NMR (CDCl3, 400 MHz): d ¼ 7.42–7.32 (m, 6H), 7.32–7.24 (m, 4H), 7.17 (d,
J ¼ 8.4 Hz, 2H), 6.87 (d, J ¼ 8.8 Hz, 2H), 5.96 (d, J ¼ 6.0 Hz, 1H), 5.40 (Br s, 1H),
5.14 (s, 2H), 3.80 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): d ¼ 159.0 155.6,
141.9, 136.4, 133.9, 128.6, 128.5, 128.2, 127.4, 127.1, 114.1, 67.0, 58.4, 55.3 ppm;
HRMS (EI): m=z calcd. for C22H21NO3 (Mþ): 347.1521; found: 347.1506.
Representative Procedure for the Synthesis of Compound 4b
Pd-C 7%, (40 mg) was added to a solution of compound 3j (173 mg, 0.5 mmol)
in MeOH (10 mL). The mixture was stirred under a hydrogen atmosphere (1 bar) for
1.5 h, the catalyst was filtered off, and the filtrate was evaporated to dryness. The
residue was redissolved in CH2Cl2 (15 mL) and dried over Na2SO4. The solvent
was removed under vacuum to give pure product (4-methoxyphenyl)(phenyl)metha-
1
namine (4b) as a colorless oil (110 mg, quant yield). H NMR (400 MHz, CDCl3):
d ¼ 7.39 (d, J ¼ 7.6 Hz, 2H), 7.30–7.35 (m, 4H), 7.24 (t, J ¼ 7.2 Hz, 1H), 6.88 (d,
J ¼ 8.8 Hz, 2H), 5.18 (s, 1H), 3.98 (s, 3H), 2.08 (s, 2H) ppm. 13C NMR (100 MHz,
CDCl3): d ¼ 158.6, 145.8, 137.7, 128.4, 128.0, 126.9, 126.8, 113.8, 59.1, 55.2 ppm.
HRMS (EI): m=z calcd. for C14H15NO (Mþ): 213.1154; found: 213.1153.
Selected Data
Benzyl (4-methoxyphenyl)(phenyl)methylcarbamate (3l). White solid;
1
mp 83–85 ꢂC; yield 224 mg (90%). H NMR (CDCl3, 400 MHz): d ¼ 7.42–7.30 (m,
5H), 7.25 (d, J ¼ 8.0 Hz, 2H), 6.88 (d, J ¼ 8.4 Hz, 2H), 5.06–5.17 (m, 2H), 5.00 (Br
s, 1H), 4.83 (m, 1H), 3.81 (s, 3H),1.48 (d, J ¼ 6.4 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3): d ¼ 158.8, 155.8, 136.5, 128.5, 128.2, 128.1, 127.2, 127.1, 114.0,
66.7, 58.3, 55.3, 22.3 ppm. HRMS (EI) m=z calcd. for C17H19NO3 (Mþ): 285.1365;
found 285.1368.
N-(1-(4-methoxyphenyl)ethyl)-4-nitroaniline (3p). Milk-white solid; mp
125–127 ꢂC; yield 246 mg (91%). 1H NMR (400 MHz, CDCl3): d ¼ 8.01 (d,
J ¼ 8.8 Hz, 2H), 7.25 (d, J ¼ 8.8 Hz, 2H), 6.89 (d, J ¼ 8.8 Hz, 2H), 6.47 (d, J ¼ 9.2 Hz,
Hz, 2H), 4.95 (br s, 1H), 4.57 (m, 1H), 3.80 (s, 3H), 1.56 (d, J ¼ 6.8 Hz, 3H) ppm; 13
C
NMR (100 MHz, CDCl3): d ¼ 158.9, 152.4, 138.0, 135.2, 126.7, 126.2, 114.3, 111.8,
55.3, 52.7, 24.5 ppm. HRMS (EI): m=z calcd. for C15H16N2O3 (Mþ): 272.1161;
found: 273.1162.
CONCLUSION
In conclusion, we have developed an efficient procedure to obtain benzylic
amines starting from the corresponding alcohols under solvent-free conditions. This
methodology tolerates various benzylic alcohols bearing electron-donating but also
mild electron-withdrawing groups. Several catalytic systems were compared, evi-
dencing the higher selectivity of FeCl3 over others. Among the nitrogen-based
nucleophiles used, CbzNH2 proved useful as an intermediate in the amidation–
reduction sequence leading to the direct preparation of benzylic amines.

SOLVENT-FREE AMINATION OF BENZYLIC ALCOHOLS
1615
ACKNOWLEDGMENT
This work was financially supported by the Natural Science Foundation of
China (No. 20672035).
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