Selective N-monoalkylation of aromatic amines with benzylic alcohols by a hydrogen autotransfer process catalyzed by unmodified magnetite

Article abstract of DOI:10.1039/b901929d

A new catalyst for an old material: magnetite is a good catalyst for the selective N-alkylation of aromatic amines using benzylic alcohols as electrophiles. The process could be repeated up to eight times without losing effectiveness. The catalyst recycling is very easy, using a simple magnet. The catalyst is selective and could discriminate between aromatic and aliphatic amines, as well as between benzylic and aliphatic alcohols, as the reactions only take place with aromatic amines and benzylic alcohols.

Full text of DOI:10.1039/b901929d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Selective N-monoalkylation of aromatic amines with benzylic alcohols
by a hydrogen autotransfer process catalyzed by unmodified magnetite†
Ricardo Mart ´ı nez, Diego J. Ram o´ n* and Miguel Yus*
Received 29th January 2009, Accepted 5th March 2009
First published as an Advance Article on the web 2nd April 2009
DOI: 10.1039/b901929d
A new catalyst for an old material: magnetite is a good catalyst for the selective N-alkylation of aromatic
amines using benzylic alcohols as electrophiles. The process could be repeated up to eight times without
losing effectiveness. The catalyst recycling is very easy, using a simple magnet. The catalyst is selective
and could discriminate between aromatic and aliphatic amines, as well as between benzylic and
aliphatic alcohols, as the reactions only take place with aromatic amines and benzylic alcohols.
Table 1 Reaction conditions optimization
Introduction
1
Hydrogen autotransfer, also called borrowing hydrogen, is an old
2
reaction and it is currently of great interest in C–C bond formation
3
processes (Scheme 1). This interest now leans towards the use of
amines, and other nitrogenated compounds, as nucleophiles to
Catalyst
2a (mol%) (mol%)
Yield 3a Yield 4a
a b
yield the corresponding N-alkylated products. The reason for this
change takes root in the great variety of amines present in Nature,
as well as their relevant importance in the pharmaceutical and
agrochemical industries as usual building blocks. The extremely
high advantage of this N-alkylation process, compared with
Entry Solvent
1
t (d) (%)
(%)
1,4-dioxane 400
—
—
Fe
Fe
Fe
10
7
7
7
7
7
8
7
7
7
7
67
52
88
72
80
89
66
76
62
60
65
12
21
<5
13
5
<5
19
8
2
3
4
5
6
7
8
9
0
1,4-dioxane 400
1,4-dioxane 400
1,4-dioxane 400
1,4-dioxane 200
1,4-dioxane 400
1,4-dioxane 400
1,4-dioxane 400
1,4-dioxane 400
1,4-dioxane 400
3
3
3
O
O
O
4
4
4
(20)
(20)
(20)
c
4
classical protocols, is due, on the one hand, to the simplicity
of the protocol and, on the other hand, to the avoidance of using
either mutagenic alkyl halides, sulfates, etc., or difficult storable
carbonyl compounds, as well as to the reduction of wastes. Many
different complexes have been proposed as catalysts for this thrifty
Fe O (40)
3
3
3
2
4
4
4
3
Fe
Fe
Fe
O
O
O
(1)
(20)
(20)
d
7
11
19
1
FeO (20)
Fe (20)
5
6
7
process, including those derived from nickel, copper, ruthenium,
11
PhMe
400
3 4
O
8
9
10
11
rhodium, palladium, iridium and platinum.
a
Isolated yields after column chromatography (silica gel: hexane/ethyl
acetate. Yields calculated by CG analysis of crude mixture using 1,2,3-
trimethylbenzene as standard. Reaction performed using only 1 equiva-
lent of tBuOK. Reaction performed using nanopowder (20–30 nm).
b
c
d
typical heterogeneous catalyst in the selective N-monoalkylation
of aromatic amines.
Results and discussion
Scheme 1 General scheme for a hydrogen autotransfer process.
Our starting point is the known surface of the magnetite-Fe
3
O
4
(
111), which is terminated by a hexagonal oxygen layer covered by
Very recently, we have demonstrated the possible usefulness of
nano-powder magnetite as catalyst in the four-component aza-
14
one quarter monolayer of iron cations, these metallic centers on
the surface are able to act as catalysts. So, the reaction outlined
in Table 1 was used as the standard one for optimization of the
reaction conditions.
12
Sakuray reaction, which is the first example of using unprotected,
naked and commercially available magnetite as a typical soft
13
Lewis acid in organic synthesis. With this study we would like
to show that simple magnetite can be used (and re-used) as a
15
Firstly, we performed the reaction in the absence of any catalyst
in order to prove the real effect of catalyst. Thus, the reaction of
aniline (1a) with an excess of benzylic alcohol (2a, 4 equiv) in
dioxane, and in the presence of potassium tert-butoxide (2 equiv)
gave the expected amine 3a with a modest yield in seven (or even
in ten) days, with imine 4a being detected as the only by-product
Instituto de S ´ı ntesis Org a´ nica (ISO), and Departamento de Qu ´ı mica
Org a´ nica, Facultad de Ciencias, Universidad de Alicante Apdo. 99, E-03080,
Alicante, Spain. E-mail: djramon@ua.es, yus@ua.es; Fax: +35-965903549;
Tel: +35-965903548
(entries 1 and 2). The preparation of this product can only be
†
Electronic supplementary information (ESI) available: TEM images of
1 13
explained by the alcohol undergoing a dehydrogenation process
catalyzed by the base, followed by condensation with the amine
magnetite after and before being used, as well as H and C NMR for
16
compounds 3a–n. See DOI: 10.1039/b901929d
2
176 | Org. Biomol. Chem., 2009, 7, 2176–2181
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to give compound 4a. The final reduction of this compound gave
the alkylated amine 3a, with this process being produced through a
extra nitrogen atom seems to have no influence on these unbeatable
results, as well as the existence of two nitrogen atoms on the six-
membered ring of the amine (entries 12 and 13). Finally, it should
be pointed out that the reaction can be performed with electron-
rich heteroaromatic amines, such as thiazolamine derivatives and
the result was appreciably lower (entry 14), as in the case of
methoxy substituted anilines.
Once the catalytic activity and scope of the unmodified mag-
netite was demonstrated, we faced the re-using problem, finding
that the chemical yields were constant in a range between 83 and
93%, after 8 cycles of reaction, for the preparation of compound
3a (Fig. 1), with the magnetite being maintained inside the flask
only by the help of a magnet.
17,18
Meerwein–Ponndorf–Verley process.
The same reaction using
19
2
0 mol% of commercial powder magnetite (particle size <5 mm)
rendered the expected product 3a with a better yield and in a
lower reaction time (compare entries 2 and 3 in Table 1), with the
amount of imine 4a being negligible. This result clearly showed
that magnetite catalyzed the hydrogen autotransfer process, this
result being in concordance with the fact that glauconite [natural
silicate containing Fe(II) and Fe(III)] was able to dehydrogenate
20
different alcohols. Once the catalysis of magnetite was proved,
other parameters of the reaction were optimized. Thus, when the
amount of base or benzylic alcohol (2a) was diminished the results
were accountably lower (entries 4 and 5). Although the increase
of amount of catalyst did not have any appreciable impact on
the chemical yield; its decrease diminished significantly the yield
(
compare entries 2, 6 and 7). The use of nanoparticles of magnetite
did not improve the previous results (compare entries 3 and 8).
Other different source of heterogeneous iron, such as iron oxides,
gave lower chemical yields (entries 9 and 10). The reaction using
a less polar solvent, such as toluene, yielded a moderated result,
with the amount of by-product being at a maximum (entry 11).
After completing the optimization study, we faced the problem
of the reaction scope (Table 2), and we started by changing
the electronic nature of the substituent on benzylic alcohol 2.
The reaction using different 4-substituted benzylic alcohols gave
practically the same results (Table 2, entries 1–3), independently
of the electron-donor or withdrawing character of the substituent.
However, when different substituted anilines were used as a
nucleophile, the best result was obtained with the less nucleophilic
one, 3-chloroaniline, whereas the worst results were obtained
with the most nucleophilic ones (compare entries 1 and 4–6).
The reaction can also be performed using electron-poor het-
eroaromatic amines. For instance, the reaction with a 2-pyridyl
derivative gave a quantitative yield, practically independently of
the benzylic alcohol 2 used (entries 7–11). The position of this
Fig. 1
In order to explore the possible degradation of the naked
magnetite on the reaction conditions, the BET surface area was
2
determined at the beginning of the process (being 9.86 m /g) and
2
after 8 cycles (being 10.94 m /g), with this concordant result
showing that there is not any type of significant sinterization
process under the assayed reaction conditions. A similar result
could be extracted from the observation of TEM microscopy
images, which did not show any difference between the unmodified
magnetite and the 8-fold reused one (Fig. 2 and ESI†).
Table 2 Magnetite catalyzes the N-alkylation process
To finish the study of magnetite stability, we studied the obtained
liquid phase after a one-cycle reaction for the preparation of
compound 3a. The magnetite was isolated by a magnet and
washed with toluene; the resulting mixture without filtration
was concentrated and re-dissolved in methanol. Flame atomic
absorption spectroscopy (FAAS) showed the presence of around
0.0020 mg of iron in the methanolic solution (less than 0.003% of
initial iron added). However, if a simple filtration is done before
concentration, the FAAS did not show the presence of iron atoms,
excluding the presence of homogeneous iron species. Therefore, we
believe that the possible degradation of magnetite does not occur,
and the FAAS result only showed the capacity of the magnet used
to trap the magnetite, keeping free only a very small amount of
magnetite.
1
2
(a)
Entry
Ar
Ar
Product
Yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
Ph
Ph
Ph
4-MeOC
2-MeOC
Ph
4-MeOC
4-ClC
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
88
84
83
42
44
99
96
>99
>99
>99
>99
>99
>99
33
6
H
H
4
6
H
4
6
H
H
4
4
6
Ph
Ph
3-ClC
6
H
4
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
4-pyridyl
Ph
4-MeOC
4-MeC
4-ClC
2-MeOC
Ph
Ph
Ph
6
4
4
6
H
4
1
1
1
1
1
6
H
4
6
H
Finally, we tried to discover the possible selectivity of the
process and, for that purpose, we performed different competitive
reactions. Thus, the reaction of amine 1e with two different
alcohols 2a (4 equiv) and 5 (4 equiv) gave the benzylic amine
2-pyrimidyl
5-methylthiazol-2-yl
a
Isolated yields after column chromatography (silica gel: hexane/ethyl
3g, as the only compound detected by CG-MS analysis of crude
acetate).
mixture [equation (a) in Scheme 2].
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Scheme 2 Competitive experiments.
being negligible [equation (c) in Scheme 2]. Therefore we might
conclude that the process presented here is selective, to a certain
level, for the amine as well as for the alcohol partner.
The last part of this study deals with the study of the possible
catalytic cycle and where the catalysis takes place. Firstly, we
should mention that the reactions failed in the absence of
potassium tert-butoxide, therefore we believe that the catalytic
cycle starts with the deprotonation of benzylic alcohol. When
the reaction was performed under standard conditions but in an
open air flask, and after 3 days, the main product detected was
the imine 4a. Whereas 68% yield was obtained in the reaction
catalyzed by magnetite, only 35% yield of product 4a was achieved
in the absence of catalyst, showing the effect of the catalyst in
the oxidation step, probably rendering initially potassium hydride
for the uncatalyzed process and an iron hydride species for the
magnetite catalyzed one. Then, we study the final reduction
process, and for that purpose the imine 4a was reacted with an
excess of benzyl alcohol (2a, 3 equivalents) yielding the expected
amine 3a after two days with yields of 55% for the magnetite
catalyzed process and 35% for the uncatalyzed one. The process
probably works through a Meerwein–Ponndorf–Verley reaction,
since the reaction failed in the absence of benzyl alcohol. Finally,
the reduction process was studied by reaction of imine 4a with
NaH (4 equivalents) rendering surprisingly in this case 35% of
amine 3a only when the reaction was performed in the presence of
magnetite, with these experiments showing the possible connection
between the uncatalyzed cycle with the magnetite catalyzed one.
We have proved that magnetite catalyzes the first oxidation step of
alcohol to aldehyde rendering either hydrogen or iron hydride
species, as well as the second reduction step either by direct
Fig. 2 TEM microscopy images of commercial magnetite (top) and the
same magnetite after being used in 8 cycles (bottom).
It should pointed out that the chemical yield is a little bit lower
than that presented in entry 7 of Table 2, but this result could
be partially explained by the smaller amount of base used with
respect to the total amount of alcohol. If the competitive assay
is performed between two amines, one aromatic 1e and another
aliphatic 6a, the only products detected were 3g, which arose from
the coupling of the aromatic amine with the benzylic alcohol,
and a small amount of the imine 4b [equation (b) in Scheme 2].
This result indicates that the reduction process of N-alkyl imines
does not take place on the magnetite catalyst, at least under
these reaction conditions. Finally, the mixture of aromatic and
aliphatic amines (1e and 6b) and two alcohols 2a and 5, only gave
coupling between both aromatic systems, with the by-product
21
2
178 | Org. Biomol. Chem., 2009, 7, 2176–2181
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addition of hydride or by a Meerwein–Ponndorf–Verley process.
It should be pointed out that the condensation process is very fast
and does not need any catalysis.
residue was purified, if needed, by flash chromatography on silica
gel (hexane/ethyl acetate) to give the corresponding product 3.
22
1
0l
-1
Benzyl(phenyl)aniline (3a). Colourless oil; IR (film, cm ):
1
3
4
2
1
421, 3071, 1607, 1512, 1323, 1239, 917; H NMR d 4.22 (s, 2H),
Conclusion
.54 (s, 1H), 6.50–6.55 (m, 2H), 6.65–6.70 (m, 1H), 7.10–7.15 (m,
H), 7.20–7.30 (m, 5H); C NMR d 48.05, 112.70 (2C), 117.35,
1
3
In conclusion, unmodified commercial magnetite has been shown
to be an active, stable and highly selective catalyst for the
selective monoalkylation of aromatic amines through a hydrogen
autotransfer process. Even working with long reaction times, this
is the first time that unmodified magnetite has been used as a
recyclable catalyst in an alkylation of amines using alcohols as the
initial source of electrophiles.
27.05, 127.35 (2C), 128.45 (2C), 129.10 (2C), 139.30, 148.00; MS
+
(
EI) m/z 184 (M +1, 13%), 183 (93), 182 (43), 181 (58), 180 (71),
106 (20), 104 (17), 91 (100), 78 (11), 77 (57), 65 (25), 63 (11), 51
(31); HRMS calcd. for C13
H
13N: 183.1048: Found 183.1040.
10j
4
-Methoxybenzyl(phenyl)amine (3b). Pale yellow oil; IR (film,
-1
1
cm ): 3421, 3054,2837, 1613, 1518, 1307, 1268, 1251; H NMR d
.50 (s, 1H), 3.68 (s, 3H), 4.15 (s, 2H), 6.50–6.55 (m, 2H), 6.65–
6.70 (m, 1H), 6.80–6.85 (m, 2H), 7.10–7.25 (m, 5H); C NMR
3
1
3
Experimental
d 47.40, 54.95, 112.60 (2C), 113.75 (2C), 117.15, 128.30, 128.50
General
+
(
2C), 129.00 (2C), 131.20, 148.00; MS (EI) m/z 213 (M , 29%),
2
C
11(20), 210 (23), 121 (100), 78 (11), 77 (22); HRMS calcd. for
Melting points were obtained with a Reichert Thermovar appa-
ratus. FT-IR spectra were obtained on a Nicolet Impact 400D
spectrophotometer. NMR spectra were recorded on a Bruker AC-
14
H
15NO: 213.1154: Found 213.1158.
10j
4
-Chlorobenzyl(phenyl)amine (3c). Pale yellow oil; IR (film,
1
13
3
00 (300 MHz for H and 75 MHz for C) using CDCl
3
as a
-1
1
cm ) n 3427, 3060, 1607, 1513, 1429, 1323, 1101; H NMR d 3.80
solvent and TMS as internal standard; chemical shifts are given
in d (parts per million) and coupling constants (J) in Hertz. Mass
spectra (EI) were obtained at 70 eV on a Shimazdu QP-5000
spectrometer, giving fragment ions in m/z with relative intensities
13
(.10–7.15 (m, 2H), 7.20–725 (m, 4H); C NMR d 47.35, 112.70
(2C), 117.57, 128.50 (2C), 128.55 (2C), 129.15 (2C), 132.60, 137.90,
+
147.70; MS (EI) m/z 219 (M +2, 19%), 218 (14), 217 (73), 216 (35),
215 (47), 214 (50), 182 (11), 127 (34), 125 (100), 106 (10), 104 (12),
89 (23), 77 (51), 75 (11), 65 (10), 63 (12), 51 (24); HRMS calcd. for
(
%) in parentheses. The high resolution mass spectroscopy was
performed by the corresponding Mass Spectrometry Service at
the University of Alicante. The chromatographic analyses (GLC)
were determined with a Hewlett Packard HP-5890 instrument
equipped with a flame ionization detector and 12 m HP-1 capillary
column (0.2 mm diam, 0.33 mm film thickness, OV-1 stationary
C H12NCl: 217.0658: Found 217.0650.
13
10l
-1
Benzyl(4-methoxyphenyl)amine (3d). Brown oil; IR (film, cm )
-
1
1
3
1
2
1
1
377, 3026, 1507, 1451, 1239, 1045, 906 cm ; H NMR d 3.30 (s,
H), 3.65 (s, 3H), 4.20 (s, 2H), 6.50–6.55 (m, 2H), 6.70–6.75 (m,
1
3
H), 7.20–7.30 (m, 5H); C NMR d 48.95, 55.50, 114.00 (2C),
phase), using nitrogen (2 mL/min) as a carrier gas, Tinjector
=
◦
◦
◦
◦
14.65 (2C), 126.75, 126.95, 127.35 (2C), 128.35 (2C), 142.25,
2
75 C, Tdetector = 300 C, Tcolumn = 60 C (3 min) and 60–270 C
+
◦
51.90; MS (EI) m/z 214 (M +1, 13%), 213 (84), 212 (21), 211
(
15 C/min), P = 40 kPa. Surface areas were determined by the
(
(
2
86), 210 (18), 198 (10), 97 (16), 196 (100), 167 (29), 122 (56), 92
11), 91 (50), 77 (12), 65 (13), 63 (12); HRMS calcd. for C14
13.1154: Found 213.1157.
application of the BET equation to the N
2
adsorption isotherm at
H
15NO:
7
7K. Adsorption data were obtained from a QUANTACHROME
AUTOSORB-6 equipment. TEM images were obtained with
a JEOL JEM-2010 Electron Microscope. FAAS analyses were
carried out using a Varian SpectrAA 10 plus Atomic Absorption
Spectrometer.
10l
Benzyl(2-methoxyphenyl)amine (3e). Colourless oil; IR (film,
-1
1
cm ) 3444, 3077, 1607, 1512, 1468, 1423, 1251; H NMR d 3.77
s, 3H), 4.29 (s, 2H), 4.60 (s, 1H), 6.50–6.55 (m, 1H), 6.60–6.65 (m,
H), 6.70–6.75 (m, 1H), 6.80–6.85 (m, 1H), 7.20–7.35 (m, 5H);
(
1
Thin layer chromatography (TLC) was carried out on Schleicher
&
Schuell F1400/LS 254 plates coated with a 0.2 mm layer of
silica gel; detection by UV254 light, staining with phosphomolybdic
acid [25 g phosphomolybdic acid, 10 g Ce(SO O, 60 ml of
·4H
concentrated H SO and 940 ml H O]. Column chromatography
13
C NMR d 47.85, 55.20, 109.25, 109.95, 116.50, 121.15, 126.95,
27.35 (2C), 128.45 (2C), 138.00, 139.45, 146.65; MS (EI) m/z 214
1
4
)
2
2
+
(
(
M +1, 15%), 213 (100), 212 (24), 211 (26), 198 (33),196 (12), 180
12), 167 (11), 120 (21), 104 (11), 94 (13), 92 (19), 91 (84), 77 (17),
2
4
2
was performed using silica gel 60 of 35–70 mesh. All reagents were
commercially available (Acros, Aldrich, Strem) and were used as
received.
65 (29), 63 (10), 51 (13); HRMS calcd. for C14
H15NO: 213.1154:
Found 213.1147.
10l
Benzyl(3-chlorophenyl)amine (3f). Colourless oil; IR (film,
-
1
-1
1
General procedure for the N-monoalkylation of amines using
alcohols catalyzed by magnetite
cm ) 3416, 3032, 1596, 1490, 1323 cm ; H NMR d 4.05 (s, 1H),
4.25 (s, 2H), 6.40–6.45 (m, 1H), 6.55–6.65 (m, 2H), 7.00–7.05 (m,
1
3
1
H), 7.20–7.35 (m, 5H); C NMR d 48.00, 111.05, 112.40, 117.30,
To a mixture of Fe
3
4
O (< 5 mm, 0.093 g) and potassium tert-
1
27.35, 127.40 (2C), 128.65 (2C), 130.15, 134.95, 138.65, 149.15;
butoxide (0.473 g, 4 mmol) in dry 1,4-dioxane (5 mL) were added
the arylamine derivative (1, 2.0 mmol) and the corresponding
alcohol (2, 8 mmol) under an argon atmosphere. The reaction
+
MS (EI) m/z 219 (M +2, 15%), 218 (11), 217 (51), 216 (25), 215
(26), 214 (30), 111 (19), 91 (100), 77 (12), 75 (18), 65 (14), 63 (11),
5
1 (12); HRMS calcd. for C13 12NCl: 217.0658: Found 217.0653.
H
◦
mixture was heated at 90 C in sealed vessel and stirred for 7 days.
10l
◦
Then, the reaction mixture was filtered off through Celite and
the solvent was removed under reduced pressure. The resulting
Benzyl(2-pyridyl)amine (3g). Colourless solid; mp 105–107 C;
-
1
-1
IR (KBr, cm ) 3225, 3022, 1604, 1567, 1510, 1448, 1334 cm ;
This journal is © The Royal Society of Chemistry 2009
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1
1
H NMR d 4.40 (s, 2H), 5.25 (s, 1H), 6.29 (d, J = 8.4 Hz, 1H),
H NMR d 4.61 (d, J = 5.8 Hz, 2H), 6.42 (t, J = 4.8 Hz, 1H), 6.70
1
3
13
6
.50–6.55 (m, 1H), 7.20–7.35 (m, 6H), 7.95–8.00 (m, 1H);
C
(s, 1H), 7.20–7.40 (m, 4H), 8.05 (s, 2H); C NMR d 45.35, 110.35,
NMR d 46.05, 106.50, 112.85, 126.75, 127.15 (2C), 128.45 (2C),
127.10 (2C), 127.55, 128.45 (2C), 139.05, 157.85 (2C), 162.20; MS
(EI) m/z 186 (M +1, 13%), 185 (100), 184 (71), 108 (13), 106 (54),
91 (30), 80 (19), 79 (20), 77 (11), 64 (14), 53 (11); HRMS calcd. for
+
+
137.45, 138.95, 147.75, 158.50; MS (EI) m/z 185 (M +1, 13%),
184 (100), 183 (52), 182 (10), 181 (21), 107 (17), 106 (69), 91 (36),
79 (47), 78 (29), 77 (11), 65 (17), 52 (13), 51 (19); HRMS calcd. for
C
11
H
11
N
3
: 185.0953: Found 185.0962.
C
12
H
12
N
2
: 184.1000: Found 184.1002.
Benzyl(5-methyl-1,3-thiazol-2-yl)amine (3n). White solid; mp
10l
◦
-1
4
-Methoxybenzyl(2-pyridyl)amine (3h). Colourless solid; mp
89–91 C; IR (KBr, cm ) n 3177, 3127, 2915, 1691, 1579, 1501,
1 1
◦
-1
-
8
1
6
7
1
1
1
5–87 C; IR (KBr, cm ) 3438, 3065, 1607, 1513, 1440, 1268,
1451, 1345, 1318, 1218, 1173, 1089 cm ; H NMR d 2.20 (s, 3H),
-
1
1
13
251 cm ; H NMR d 3.75 (s, 3H), 4.40 (s, 2H), 4.50 (s, 1H),
.50–6.55 (m, 1H), 6.80–6.90 (m, 2H), 7.25 (d, J = 8.6 Hz, 2H),
4.38 (s, 2H), 6.50 (s, 1H), 6.55 (s 1H), 7.25–7.35 (m, 5H); C NMR
d 11.85, 49.60, 120.70, 127.40, 127.60 (2C), 128.50 (2C), 135.30,
1
3
+
.35–7.45 (m, 1H), 7.85–7.90 (m, 1H); C NMR d 45.95, 55.65,
137.90, 169.00; MS (EI) m/z 204 (M , 58%), 203 (20), 159 (12),
09.70, 113.35, 114.75, 114.85 (2C), 129.60 (2C), 132.85, 138.80,
47.90, 160.25; MS (EI) m/z 214 (M , 51%), 213 (11), 136 (22),
21 (100), 79 (23), 78 (22); HRMS calcd. for C13
91 (100), 65 (13); HRMS calcd. for C H N : 204.0721: Found
1
1
12
2
+
204.0719.
H
14
2
N O: 214.1106:
Found 214.1098.
Acknowledgements
10l
4
-Methylbenzyl(2-pyridyl)amine (3i). White solid; mp 73–
◦
-1
We are grateful to the Spanish Ministerio de Educaci o´ n y
Ciencia (Consolider Ingenio 2010 CSD2007–00006, CTQ2007–
7
1
6
2
1
1
1
1
5 C, IR (KBr, cm ) 3438, 3054, 2976, 1607, 1573, 1507, 1445,
-
1 1
418, 1273 cm ; H NMR d 2.30 (s, 3H), 4.40 (s, 2H), 5.36 (s, 1H),
.30 (d, J = 8.4 Hz, 1H), 6.50–6.55 (m 1H), 7.10 (d, J = 7.9 Hz,
H), 7.20 (d, J = 7.9 Hz, 2H), 7.30–7.35 (m, 1H), 8.00–8.05 (m,
6
5218/BQU) for the financial support. We thank Dr. Juan Mora
Pastor of the Analytic Chemistry Department of the University
of Alicante for the flame atomic absorption spectroscopy (FAAS)
studies. R. M. thanks Generalitat Valenciana for a predoctoral
grant.
1
3
H); C NMR d 20.85, 45.85, 106.45, 112.65, 127.15 (2C), 128.90,
+
29.10 (2C), 135.80, 137.50, 147.60, 158.50; MS (EI) m/z 199 (M ,
4%), 198 (100), 197 (46), 196 (13), 195 (26), 183 (16), 120 (79),
05 (57), 103 (10), 91 (14), 79 (65), 78 (29), 77 (17); HRMS calcd.
for C13
H
14
N
2
: 198.1157: Found 198.1152.
Notes and References
1
0l
4
-Chlorobenzyl(2-pyridyl)amine (3j). Colourless solid; mp 98–
1 (a) G. Guillena, D. J. Ram o´ n and M. Yus, Angew. Chem. Int. Ed., 2007,
46, 2358–2364; (b) M. H. S. A. Hamid, P. A. Slatford and J. M. J.
Williams, Adv. Synth. Catal., 2007, 349, 1555–1575; (c) T. D. Nixon,
M. K. Whittlesey and J. M. J. Williams, Dalton Trans., 2009, 753–762.
2 M. C. R. Guerbet, C. R. Chim., 1908, 146, 298–300.
3 (a) For recent examples from our laboratory, see: R. Mart ´ı nez, G. J.
Brand, D. J. Ram o´ n and M. Yus, Tetrahedron Lett., 2005, 46, 3683–
◦
-1
1
1
8
1
1
00 C; IR (KBr, cm ) 3444, 3071, 1613, 1568, 1496, 1329,
-
1
1
268 cm ; H NMR d 4.40 (s, 2H), 5.35 (s, 1H), 6.30 (d, J =
.4 Hz, 1H), 6.50–6.55 (m, 1H), 7.20–7.25 (m, 4H), 7.30–7.35 (m,
1
3
H), 8.00–8.05 (m, 1H); C NMR d 45.30, 76.65, 106.65, 113.05,
28.45 (2C), 128.50 (2C), 137.45, 137.70, 147.90, 158.35; MS (EI)
m/z 220 (M +1, 25%), 219 (21), 218 (80), 217 (35), 215 (12), 142
30), 140 (93), 127 (17), 125 (45), 107 (12), 89 (21), 80 (11), 79 (100),
3
6
686; (b) R. Mart ´ı nez, D. J. Ram o´ n and M. Yus, Tetrahedron, 2006,
2, 8982–8987; (c) R. Mart ´ı nez, D. J. Ram o´ n and M. Yus, Tetrahedron,
+
(
7
2006, 62, 8988–9001.
4
(a) For reviews on the synthesis of amines, see: J. R. Malpass,
Comprehensive Organic Chemistry, Vol. 2, Eds.: D. Barton, W. D. Ollis,
Pergamon, Oxford, 1979, pp. 3–59; (b) J. M. Z. Gladych, D. Hartley,
Comprehensive Organic Chemistry, Vol. 2, Eds.: D. Barton, W. D. Ollis,
Pergamon, Oxford, 1979, pp. 61–130; (c) R. J. Lindsay, Comprehensive
Organic Chemistry, Vol. 2, Eds.: D. Barton, W. D. Ollis, Pergamon,
Oxford, 1979, pp. 131–184; (d) O. Mitsunobu, Comprehensive Organic
Synthesis, Vol. 6, Eds.: B. M. Trost, I. Fleming, Pergamon Press,
Oxford, 1991, pp. 65–101; (e) T. L. Gilchrist, Comprehensive Organic
Synthesis, Vol. 8, Eds.: B. M. Trost, I. Fleming, Pergamon Press, Oxford,
1991, pp. 381–402; (f) R. N. Salvatore, C. H. Yoon and K. W. Jung,
Tetrahedron, 2001, 57, 7785–7811; (g) B. Schlummer and U. Scholz, Adv.
Synth. Catal., 2004, 346, 1599–1626; (h) K. Mu n˜ iz, C. H. H o¨ velmann,
J. Streuff and E. Campos-G o´ mez, Pure Appl. Chem., 2008, 80, 1089–
8 (35); HRMS calcd. for C12
H
11
N
2
Cl: 218.0611: Found 218.0615.
10l
2
-Methoxybenzyl(2-pyridyl)amine (3k). Colourless solid; mp
8–60 C; IR (KBr, cm ) 3438, 3054, 2843, 1607, 1574, 1496, 1440,
◦
-1
5
1
5
-
1 1
268, 1240 cm ; H NMR d 3.75 (s, 3H), 4.45 (d, J = 5.8 Hz, 2H),
.50 (s, 1H), 6.30 (d, J = 8.4 Hz, 1H), 6.40–6.45 (m, 1H), 6.80–6.85
(
m, 2H), 7.15–7.20 (m, 1H), 7.25–7.30 (m, 2H), 8.00–8.05 (m, 1H);
1
3
C NMR d 41.10, 54.75, 106.30, 109.75, 112.20, 120.05, 126.80,
27.85, 128.20, 136.95, 147.65, 157.00, 158.65; MS (EI) m/z 215
M +1, 11%), 214 (72), 213 (15), 199 (26), 184 (15), 183 (99), 182
12), 181 (48), 180 (12), 136 (47), 121 (36), 107 (20), 105 (17), 92
10), 91 (100), 79 (44), 78 (52), 77 (15), 65 (21), 52 (14), 51 (18);
1
+
(
(
(
1
096; (i) T. E. M u¨ ller, K. C. Hultzsch, M. Yus, F. Foubelo and M. Tada,
Chem. Rev., 2008, 108, 3795–3892; (j) J. F. H. Hartwig, Acc. Chem. Res.,
008, 41, 1534–1544.
HRMS calcd. for C13
H
14
N O: 214.1106: Found 214.1099.
2
2
23
◦
Benzyl(4-pyridyl)amine (3l).
White solid; mp 88–90 C; IR
5 (a) C. F. Winans and H. Adkins, J. Am. Chem. Soc., 1932, 54, 306–312;
(b) R. G. Rice and E. J. Kohn, J. Am. Chem. Soc., 1955, 77, 4052–4054;
-
1
-1
1
(
KBr, cm ) 3465, 3125, 1615, 1522, 1448, 1348, 1228 cm ; H
NMR d 4.30 (d, J = 5.6 Hz, 2H), 5.65 (s, 1H), 6.40 (d, J =
.4 Hz, 2H), 7.20–7.35 (m, 5H), 8.05 (d, J = 5.4 Hz, 2H);
NMR d 46.40, 107.50, 126.95 (2C), 127.20, 128.50 (2C), 137.90,
49.35, 153.40; MS (EI) m/z 185 (M +1, 10%), 184 (81), 183 (21),
1 (100), 78 (10), 65 (11); HRMS calcd. for C12
(
c) C. Ainsworth, J. Am. Chem. Soc., 1956, 78, 1635–1636; (d) R. G.
Rice, E. J. Kohn and L. W. Daasch, J. Org. Chem., 1958, 23, 1352–1354;
e) M. Botta, F. De Angelis and R. Nicoletti, Synthesis, 1977, 722–723;
1
3
6
C
(
(f) F. De Angelis, G. Ferretti, M. Botta, I. Grgurina and R. Nicoletti,
+
Gazz. Chim. Ital., 1982, 112, 267–271.
1
9
6
(a) E. J. Schwoegler and H. Adkins, J. Am. Chem. Soc., 1939, 61, 3499–
H
12
N
2
: 184.1000:
3
(
502; (b) A. Baiker and W. Richarz, Tetrahedron Lett., 1977, 1937–1938;
Found 184.1002.
c) A. Balker, W. Caprez and W. L. Holstein, Ind. Eng. Prod. Res. Dev.,
1
1
983, 22, 217–225; (d) R. B. C. Pillari, J. Mol. Catal., 1993, 84, 125–
29; (e) T. Yamakawa, I. Tsuchiya, D. Mitsuzuka and T. Ogawa, Catal.
2
4
◦
Benzyl(2-pyrimidyl)amine (3m). White solid; mp 74–76 C; IR
-
1
-1
(
KBr, cm ) 449, 3104, 1596, 1574, 1518, 1457, 1401, 1362 cm ;
180 | Org. Biomol. Chem., 2009, 7, 2176–2181
Commun., 2004, 5, 291–295.
2
This journal is © The Royal Society of Chemistry 2009

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7
(a) For leading examples, see: Y. Shvo and R. M. Laine, J. Chem.
Soc. Chem. Commun., 1980, 753–754; (b) A. Arcelli, B.-T. Khai and
G. Porzi, J. Organomet. Chem., 1982, 235, 93–96; (c) S.-i. Murahashi,
K. Kondo and T. Hakata, Tetrahedron Lett., 1982, 23, 229–232; (d) Y.
Watanabe, T. Tsuji, H. Ige, Y. Ohsugi and T. Ohta, J. Org. Chem., 1984,
12 R. Mart ´ı nez, D. J. Ram o´ n and M. Yus, Adv. Synth. Catal., 2008, 350,
1235–1240.
13 (a) For instance, see: Y. Deng, W. Yang, C. Wang and S. Fu, Adv. Mater.,
2003, 15, 1729–1732; (b) A.-H. Lu, W. Schmidt, N. Matoussevitch, H.
B o¨ nnemann, B. Spliethoff, B. Tesche, E. Bill, W. Kiefer and F. Sch u¨ th,
Angew. Chem. Int. Ed., 2004, 43, 4303–4306; (c) Y. Ding, Y. Hu, X.
Jiang, L. Zhang and C. Yang, Angew. Chem. Int. Ed., 2004, 43, 6369–
6372; (d) D.-J. Kim, Y.-K. Lyu, H. N. Choi, I.-H. Min and W.-Y. Lee,
Chem. Commun., 2005, 2966–2968; (e) A. Hu, G. T. Yee and W. Lin, J.
Am. Chem. Soc., 2005, 127, 12486–12487; (f) A.-H. Lu, E. L. Salabas
and F. Sch u¨ th, Angew. Chem. Int. Ed., 2007, 46, 1222–1244; (g) S.
Laurent, D. Forge, M. Port, A. Roch, C. Robic, L. Vander Elst and R.
N. Muller, Chem. Rev., 2008, 108, 2064–2110; (h) Y. Jiang, J. Jiang, Q.
Gao, M. Ruan, H. Yu and L. Qi, Nanotechnology, 2008, 19, 075714
(6pp).
14 (a) Y. Joseph, W. Ranke and W. Weiss, J. Phys. Chem. B, 2000, 104,
3224–3236; (b) Y. Joseph, M. W u¨ hn, A. Niklewski, W. Ranke, W. Weiss,
C. W o¨ ll and R. Schl o¨ gl, Phys. Chem. Chem. Phys., 2000, 2, 5314–5319.
15 (a) For examples of alkylation processes in the absence of transition-
metal catalysts, see: S. Miyano, Chem. Pharm. Bull., 1965, 13, 1135–
1137; (b) S. Miyano, A. Uno and N. Abe, Chem. Pharm. Bull., 1967,
15, 515–517; (c) S. Miyano, N. Abe and A. Abe, Chem. Pharm. Bull.,
1970, 18, 511–514; (d) S. Miyano and M. Nakao, Chem. Pharm. Bull.,
1972, 20, 1328–1331; (e) Y. Horikawa, Y. Uchino and T. Sako, Chem.
Lett., 2003, 32, 232–233.
4
9, 3359–3363; (e) J. A. Marsella, J. Org. Chem., 1987, 52, 467–468;
(
(
f) S. Ganguly and D. M. Roundhill, Polyhedron, 1990, 9, 2517–2526;
g) Y. Watanabe, Y. Morisaki, T. Kondo and T.-a. Mitsudo, J. Org.
Chem., 1996, 61, 4214–4218; (h) R. A. T. M. Abbenhuis, J. Boersma
and G. van Koten, J. Org. Chem., 1998, 63, 4282–4290; (i) C. S. Cho, J.
H. Kim, T.-J. Kim and S. C. Shim, Tetrahedron, 2001, 57, 3321–3329;
(
j) A. Del Zotto, W. Baratta, M. Sandri, G. Verardo and P. Rigo, Eur. J.
Inorg. Chem., 2004, 524–529; (k) A. Tillack, D. Hollmann, D. Michalik
and M. Beller, Tetrahedron Lett., 2006, 47, 8881–8885; (l) M. H. S. A.
Hamid and J. M. J. Williams, Chem. Commun., 2007, 725–727; (m) D.
Hollmann, S. B a¨ hn, A. Tillack and M. Beller, Angew. Chem. Int. Ed.,
2
007, 46, 8291–8294; (n) M. H. S. A. Hamid and J. M. J. Williams,
Tetrahedron Lett., 2007, 48, 8263–8265; (o) D. Hollman, S. B a¨ hn, A.
Tillack and M. Beller, Chem. Commun., 2008, 3199–3201; (p) S. B a¨ hn,
D. Hollmann, A. Tillack and M. Beller, Adv. Synth. Catal., 2008, 350,
2
099–2103; (q) A. Tillack, D. Hollmann, K. Mevius, D. Michalik, S.
B a¨ hn and M. Beller, Eur. J. Org. Chem., 2008, 4745–4750.
8
9
R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit and N. Tongpenyai, J.
Chem. Soc. Chem. Commun., 1981, 611–612.
(a) N. Yoshimura, I. Moritani, T. Shimamura and S.-I. Murahashi,
J. Am, Chem. Soc., 1973, 95, 3038–3039; (b) S.-i. Murahashi, T.
Shimamura and I. Moritani, J. Chem. Soc. Chem. Commun., 1974,
16 (a) For dehydrogenation of alcohols to the corresponding carbonyl
compounds, see: H. Niiyama and E. Echigoya, Bull. Chem. Soc. Jpn.,
1971, 44, 1739–1742; (b) K. Hashimoto and N. Toukai, J. Mol. Catal.
A: Chem., 1999, 145, 273–280; (c) W. Zhang, M. Liu, H. Wu, J. Ding
and J. Cheng, Tetrahedron Lett., 2008, 49, 5336–5338.
9
31–932.
0 (a) K.-i. Fujita, K. Yamamoto and R. Yamaguchi, Org. Lett., 2002,
, 2691–2694; (b) K.-i. Fujita, Z. Li, N. Ozeki and R. Yamaguchi,
1
4
Tetrahedron Lett., 2003, 44, 2687–2690; (c) G. Cami-Kobeci and J.
M. J. Williams, Chem. Commun., 2004, 1072–1073; (d) K. i. Fujita, T.
Fujii and R. Yamaguchi, Org. Lett., 2004, 6, 3525–2528; (e) G. Cami-
Kobeci, P. A. Slatford, M. K. Whittlesey and J. M. J. Williams, Bioorg.
Med. Chem. Lett., 2005, 15, 535–537; (f) K.-i. Fujita, Y. Enoki and
R. Yamaguchi, Org. Synth., 2006, 83, 217–221; (g) C. T. Eary and D.
Clausen, Tetrahedron Lett., 2006, 47, 6899–6902; (h) L. U. Nordstrøm
and R. Madsen, Chem. Commun., 2007, 5034–5036; (i) R. Yamaguchi,
S. Kawagoe, C. Asai and K.-i. Fujita, Org. Lett., 2008, 10, 181–184;
17 (a) For reviews, see: G. Zassinovich, G. Mestroni and S. Gladiali, Chem.
Rev., 1992, 92, 1051–1069; (b) S. Gladiali and E. Alberico, Chem.
Soc. Rev., 2006, 35, 226–236; (c) J. S. M. Samec, J.-E. B a¨ ckvall, P. G.
Andersson and P. Brandt, Chem. Soc. Rev., 2006, 35, 237–248; (d) G.
K. Chuah, S. Jaenicke, Y. Z. Zhu and S. H. Liu, Curr. Org. Chem., 2006,
10, 1639–1654; (e) J. R. Ru ´ı z and C. Jim e´ nez-Sanchidrian, Curr. Org.
Chem., 2007, 11, 1113–1125.
18 (a) For recent examples from our research group, see: R. Mart ´ı nez, D.
J. Ram o´ n and M. Yus, Eur. J. Org. Chem., 2007, 1599–1605; (b) R.
Mart ´ı nez, L. Zoli, P. G. Cozzi, D. J. Ram o´ n and M. Yus, Tetrahedron:
Asymmetry, 2008, 19, 2600–2607.
(
j) K.-i. Fujita, Y. Enoki and R. Yamaguchi, Tetrahedron, 2008, 64,
943–1954; (k) A. P. Da Costa, M. Viciano, M. San a´ u, S. Merino, J.
Tejeda, E. Peris and B. Royo, Organometallics, 2008, 27, 1305–1309;
l) B. Blank, M. Madalska and R. Kempe, Adv. Synth. Catal., 2008,
50, 749–758; (m) D. Balcells, A. Nova, E. Clot, D. Gnanamgari, R. H.
1
2 3
19 For the only example using metallic oxide catalyst (Al O ), see: F. Valot,
(
3
F. Fache, R. Jacquot, M. Spagnol and M. Lemaire, Tetrahedron Lett.,
1999, 40, 3689–3592.
Crabtree and O. Eisenstein, Organometallics, 2008, 27, 2529–2535.
1 (a) S.-i. Nishimoto, B. Ohtani, T. Yoshikawa and T. Kagiya, J. Am.
Chem. Soc., 1983, 105, 7180–7182; (b) Y. Tsuji, J. Shida, R. Takeuchi
and Y. Watanabe, Chem. Lett., 1984, 889–890; (c) Y. Tsuji, R. Takeuchi,
H. Ogawa and Y. Watanabe, Chem. Lett., 1986, 293–294; (d) B. Ohtani,
O. Haruyoshi, S. Nishimoto and T. Kagiya, Tetrahedron Lett., 1986, 27,
20 F. C. M. J. M. van Delf, A. J. den Hartog, D. J. W. Ijdo, V. Ponec, G. H.
Vurrens and A. M. van der Kraan, J. Mol. Catal., 1990, 60, 109–125.
21 For a recent example of this process in absence of transition-metal
catalyst, see: R. Mart ´ı nez, D. J. Ram o´ n and M. Yus, J. Org. Chem.,
2008, 73, 9778–9780.
22 R. Mart ´ı nez, D. J. Ram o´ n and M. Yus, Tetrahedron Lett., 2005, 46,
8471–8474 .
1
2
019–2022; (e) B. Ohtani, O. Haruyoshi, S. Nishimoto and T. Kagiya,
J. Am. Chem. Soc., 1986, 108, 308–310; (f) B. Ohtani, O. Haruyoshi,
S. Nishimoto and T. Kagiya, Chem. Lett., 1986, 1917–1920; (g) A.
Miyazawa, K. Saitou, K. Tanaka, T. M. G a¨ dda, M. Tashiro, G. K. S.
Prakash and G. A. Olah, Teterahedron Lett., 2006, 47, 1437–1439.
23 G. R. Srinivasa, S. N. Narendra Babu, C. Lakshmi and D. C. Gowda,
Synth. Commun., 2004, 34, 1831–1837.
24 D. S. Ermolat’ev, E. V. Babaev and E. V. van der Eycken, Org. Lett.,
2006, 8, 5781–5784.
This journal is © The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 2176–2181 | 2181