C-N bond formation between alcohols and amines using an iron cyclopentadienone catalyst

Article abstract of DOI:10.1021/ol503587n

An iron-tetraphenylcyclopentadienone tricarbonyl complex is demonstrated to act as a precursor of a catalyst for the formation of C-N bonds through a "hydrogen-borrowing" reaction between amines and alcohols.

Full text of DOI:10.1021/ol503587n

Letter
pubs.acs.org/OrgLett
C−N Bond Formation between Alcohols and Amines Using an Iron
Cyclopentadienone Catalyst
Andrew J. Rawlings, Louis J. Diorazio, and Martin Wills*
†
‡
,†
†
Department of Chemistry, The University of Warwick, Coventry, CV4 7AL, U.K.
‡
Pharmaceutical Development, AstraZeneca, Silk Road Business Park, Macclesfield, Cheshire SK10 2NA, U.K.
*
S Supporting Information
ABSTRACT: An iron-tetraphenylcyclopentadienone tricarbonyl
complex is demonstrated to act as a precursor of a catalyst for the
formation of C−N bonds through a “hydrogen-borrowing”
reaction between amines and alcohols.
9
he development of sustainable methods for the formation
article focused on the use of the Kno
̈
lker complex 4 (the iron
10
T
of C−N bonds represents an important challenge for
hydride formed in situ from 2) has prompted us to report our
results in this area.
11
synthetic chemistry. One of the most promising methods
involves the reaction between an amine and an alcohol, from
In initial studies, the readily available iron cyclone complex 1
showed promise as a catalyst for the formation of C−N bonds
in the reaction between benzyl alcohol 5 and aniline 6 to form
amine 7 (Table 1). Using 10 mol % of 1 in toluene, with a 2-
fold excess of benzyl alcohol, and trimethylamine-N-oxide to
activate the catalyst,
clearly be observed and assayed by gas chromatography and H
NMR spectroscopy of the reaction.
1
−3
which the only side product is a molecule of water.
This
process can be catalyzed by a number of organometallic
complexes and involves a hydrogen transfer mechanism
Scheme 1) sometimes referred to as “hydrogen borrowing”.
(
6
,12
conversion to N-benzyl aniline 7 could
1
Scheme 1. C−N Bond Formation via “Hydrogen Borrowing”
Under these conditions, the conversion for the 48 h reaction
was at least 99% provided an inert atmosphere was employed
(
entries 1 and 2). A reaction conducted in air gave <5%
conversion to product (not shown) although ca. 40% imine was
formed, indicating a significant level of aerial oxidation of the
alcohol. Increasing the number of equivalents of alcohol did not
significantly change the conversion, while reducing the alcohol
below 1.5 equiv resulted in lower conversions. The conversion
was almost complete after 24 h, and in xylene (140 °C) 98.6%
of the required product was formed in 24 h. The conversion
was significantly lower at 80 °C (5%), 90 °C (37%), and 100
°C (69%) after 48 h.
Although reactions were usually carried out in pressure tubes
after degassing, they could also be conducted under reflux,
without significant loss of yield. No coupling was observed in
the absence of catalyst, or when an attempt was made to form
Although most commonly precious metal derivatives are
employed in this process, it would be desirable to be able to4
use less expensive and/or more common metals such as iron.
Iron cyclone complexes, including 1−3 (Figure 1), have been
applied to alcohol oxidation and ketone reduction, including
5
−7
6,7
asymmetric versions.
We recently extended our studies to
the application of the same catalysts to C−N bond-formation
reactions through a hydrogen-transfer process. At the time this
work was undertaken, there was limited precedent for the use
the catalyst in situ by adding Fe(CO) , tetraphenylcyclopenta-
5
dienone, and substrate together from the outset. Only 2% of
8
of iron catalysts for this transformation; however, a recent
product was formed when Fe(CO) was employed alone as the
5
catalyst. In contrast, however, it was possible to form a complex
in situ in a separate step and then to add the amine and alcohol
to this in order to achieve successful coupling (Table 1, entry
1
7). The use of 15 mol % of catalyst did not significantly
Received: December 12, 2014
Figure 1. Iron cyclone complexes.
©
XXXX American Chemical Society
A
DOI: 10.1021/ol503587n
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Letter
Table 1. Coupling of Aniline and Benzyl Alcohol Using
Catalyst 1
Scheme 2. Coupling of Aromatic Amines with Benzylamines
Using Iron Tricarbonyl Complex 1
a
temp
(°C)
convn
(%)
imine
(%)
N or
2
Ar
entry mol % 1 equiv 5
t (h)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
15
5
2.0
2.0
2.5
3.0
5.0
1.8
1.6
1.5
1.5
1.3
1.2
1.1
1.1
1.0
2.0
2.0
2.0
2.0
2.0
1.1
1.1
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
48
48
48
48
48
48
48
48
48
48
48
48
48
48
24
24
48
48
48
48
48
99.0
99.8
99.5
99.6
99.7
99
1
Ar
N2
Ar
Ar
Ar
Ar
Ar
Ar
N2
N2
N2
Ar
N2
N2
Ar
N2
N2
N2
Ar
Ar
Ar
0.2
0.5
0.3
0.3
1
89
6
97
3
95
5
0
1
2
3
4
5
6
7
8
9
0
1
81
7
88
8
78
7
89
8
90
8
Figure 3. Products formed by coupling of aromatic amines with benzyl
alcohols; 7 in toluene, 110 °C, 48 h, 9−16 in xylene, 140 °C, 24 h.
94.4
98.6
96
0.3
0.6
2
b
140
,
bc
140
110
110
110
110
conditions were found to be efficient for the formation of the
majority of the products. The reaction appears to tolerate
changes to the benzyl alcohol, with products 9−12 all being
formed in good conversion and subsequently isolated from the
140 °C/xylene reactions in the yields shown in Figure 3.
Variation of the arylamine was investigated with attempts at
the coupling using para-methoxy-, ortho-methoxy-, para-
chloro-, and ortho-chloroaniline. In the case of para-methoxy
aniline, product 13 was obtained in 87% yield; however,
products from the other amines (Figure 4) were formed in only
98.8
90.5
52
0.2
0.4
5
2
2
21
2
a
1
.0 equiv of aniline, 1 equiv of Me NO relative to Fe complex,
3
b c
[
aniline] = 0.5 M. Conducted in xylene. Catalyst was first formed in
situ by combination of dicyclopentadiene and Fe(CO)5 and then
addition of aniline and benzylalcohol. Conversion by mass recovery
and GC ratio.
change the conversion, whereas it decreased slightly when only
5
mol % was employed, and significantly with just 2 mol %
(
Table 1, entries 18−21).
When benzylamine was employed as the amine partner, no
product formation was observed. An attempted reaction
between benzyl alcohol and aniline in the presence of 0.5
equiv of benzylamine also gave no coupling products, indicating
that the benzylamine was inhibiting the catalyst. This may be
due to the formation of a stable complex between the
benzylamine and the activated catalyst (i.e., 8, Figure 2). This
Figure 4. Substrates which worked poorly and were not isolated.
low conversions of 23%, 35%, and 4% respectively, and it was
not possible to isolate purified products from these reactions
(see Supporting Information for full details).
The reaction of aniline with hexanol gave up to 72% isolated
product 14, although a quantity of dialkylated material 15 was
also observed. Using just 1.1 equiv of hexanol, 67% of 14 was
isolated without coformation of 15. However, all attempts to
produce solely 15 by the use of excess hexanol (up to 3 equiv,
for an extended reaction time of 48 h in xylene) gave at most
Figure 2. Iron cyclone complex with benzylamine.
2
8% of conversion to 15, the majority being the monoalkylated
1
4. It is noteworthy that our findings for 14 and the other
9
is supported by the observation by Beller of deactivation of the
products match Feringa’s in this respect; use of excess alcohol
did not readily result in dialkylation. Likewise, attempts at the
alkylation of secondary amines (N-methylaniline, pyrrolidine,
cyclohexylmethylamine) were unsuccessful, yielding only traces
of products even at the higher temperature of 140 °C. Attempts
to couple aniline with α- and β-tetralol, and 1-phenylethanol,
also resulted in only low conversions to impure products,
13
corresponding Ru species by basic and unhindered amines. In
contrast, aniline is insufficiently basic to strongly inhibit the
catalysis by this mechanism.
Following optimization, we tested further combinations of
aromatic amines with aliphatic alcohols using the optimized
conditions (Scheme 2, Figure 3). The higher temperature
B
DOI: 10.1021/ol503587n
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
although the reaction with cyclohexanol did give a product, 16,
in 77% yield. Hence the reaction appears to be specific for
certain classes of substrate, with a sharp dependence on the
steric and electronic nature of the substituents on the reagents.
Traces of an imine intermediate were detected in the
reaction mixtures at high conversion, and high levels of imine
were observed at lower conversions (see Supporting
Information). This supports the proposed “hydrogen borrow-
ing” mechanism outlined in the introduction to this paper.
Feringa has likewise found support for this mechanism in his
ACKNOWLEDGMENTS
■
We thank the EPSRC and Astrazeneca Ltd. for generous
funding (to A.J.R.) via the EPSRC Industrial CASE
Programme.
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C
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