Copper/TEMPO catalysed synthesis of nitriles from aldehydes or alcohols using aqueous ammonia and with air as the oxidant

Article abstract of DOI:10.1039/c3cc42231c

Copper/TEMPO catalysts can be used to prepare nitriles from aldehydes or alcohols using aqueous ammonia. Readily accessible methods were developed that enable standard glassware to be used with air as the source of O₂. It was further shown that, at higher temperatures in a pressurised reactor under limiting oxygen conditions (8% O₂), catalyst loadings of 1 mol% could be employed.

Full text of DOI:10.1039/c3cc42231c

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Copper/TEMPO catalysed synthesis of nitriles from
aldehydes or alcohols using aqueous ammonia and
with air as the oxidant†‡
Cite this: DOI: 10.1039/c3cc42231c
Received 27th March 2013,
Accepted 22nd May 2013
Laura M. Dornan,a Qun Cao,a James C. A. Flanagan,ya James J. Crawford,zb
Matthew J. Cook*a and Mark J. Muldoon*a
DOI: 10.1039/c3cc42231c
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Copper/TEMPO catalysts can be used to prepare nitriles from aldehydes source and hydrogen peroxide as the oxidant, however the yields
or alcohols using aqueous ammonia. Readily accessible methods were reported for a number of substrates were low.5 From an atom
developed that enable standard glassware to be used with air as the efficiency point of view the best approach is the catalytic aerobic
source of O2. It was further shown that, at higher temperatures in a oxidation of primary imines; formed in situ by the reaction of an
pressurised reactor under limiting oxygen conditions (8% O2), catalyst aldehyde with ammonia. To date, there are very few reports of aerobic
loadings of 1 mol% could be employed.
catalytic methods that would be widely applicable to synthetic
chemists. Traditionally, this route has been implemented using
The nitrile group is an important functional group in organic heterogeneous catalysts under harsh conditions (e.g. 300 1C).6 More
chemistry; used as an intermediate in the synthesis of other recently there have been reports of heterogeneous catalysts operating
functional groups as well as being present in the structure of a at more reasonable conditions, for example 100–130 1C.7,8 None-
number of important fine chemicals and pharmaceuticals. For theless these methods still require the use of pressurised reactors.
example, aromatic nitriles are present in a number of leading
There is a need to develop chemoselective oxidation catalysts that
pharmaceuticals.1 Traditional methods for preparing nitriles utilise can be utilised by the pharmaceutical industry.9 To have catalytic
toxic/dangerous reagents and produce stoichiometric amounts of oxidation reactions carried out on scale, it would help if these
metal waste. In recent years there have been developments whereby methods were first adopted by synthetic chemists working at the
catalysts can be combined with nonmetallic cyano group sources.2 early stages of R&D. Therefore we believe that it is important that
These methods offer an improvement, but in most cases still utilise methods are developed that are readily accessible and safe. We
aryl halides as the substrates; which are not always straightforward to wanted to develop a method that did not specifically require
prepare. As such, there have been sustained efforts to develop greener specialist high pressure reactors. Additionally, we did not want to
catalytic methods. Alcohols and aldehydes are attractive starting employ a pure O2 atmosphere. The use of pure O2 is quite common
materials as these are readily accessed and easy to handle. Although in the aerobic catalysis literature, but it is a dangerous approach and
there are a number of reports that utilise aldehydes for the synthesis it is a barrier to such catalysts being widely adopted. We aimed to
of nitriles, in many cases the reagents used are not ideal for larger develop a safe, practical and scalable method. Herein, we report for
scale applications. For example, they use unstable hydroxylamine3 or the first time the use of the Cu–TEMPO–air catalytic system for the
atom inefficient oxidising agents such as trichloroisocyanuric acid.4 oxidation of aldehydes or alcohols to a range of nitriles.10–12As
Erman et al. prepared nitriles from aldehydes, using simple copper shown in Scheme 1, this catalyst system consists of a Cu salt
salts (such as CuCl and CuCl2) as the catalyst, NH3 as the nitrogen complexed with a ligand such as 2,2-bipyridine (bipy), a stable free
a School of Chemistry and Chemical Engineering, Queen’s University Belfast,
David Keir Building, Stranmillis Road, Belfast, BT9 5AG, UK.
E-mail: m.j.muldoon@qub.ac.uk, m.cook@qub.ac.uk
b Department of Medicinal Chemistry, AstraZeneca R & D, Charnwood, Bakewell Rd,
Loughborough, LE11 5RH, UK
† Dedicated to Professor David J. Cole-Hamilton on the occasion of his retirement
and for his outstanding contributions to transition metal catalysis.
‡ Electronic supplementary information (ESI) available: Further details of experi-
mental procedures and 1H and 13C NMR spectra. See DOI: 10.1039/c3cc42231c
§ Current address: Department of Chemistry, Stanford University, Stanford,
CA 94305, USA.
¶ Current address: Genentech, Inc.,
CA 94080, USA.
1 DNA Way, South San Francisco,
Scheme 1 Synthesis of nitriles using Cu/TEMPO.
c
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Table 1 Optimisation study
Table 2 Substrate scope
Entry CuX2
NH3 addition rate (mL hÀ1
)
Time (h) Yield (%) Entry
Staring material
Product
Yielda (%)
1
2
3
4
5
6
CuBr2
CuCl2
Cu(OTf)2
Cu(OTf)2 0.5
Cu(OTf)2 1.5
1
1
1
6
6
6
6
6
0a
6a
54a
21a
32a
95b
1
2
3
4
5
6
95
Cu(OTf)2
1
16
a
b
GC yield. Isolated yield.
72, (95)b
radical such as TEMPO (2,2,6,6-tetramethylpiperidinyloxy), and
dioxygen (from air) as the terminal oxidant.
The catalyst has been well studied for the aerobic oxidation of
alcohols to aldehydes, and we were attracted to this catalyst system as
it possesses a number of attributes that make it very desirable.13,14 It
utilises an inexpensive, abundant metal of low toxicity. It can operate
under mild conditions, demonstrates high chemoselectivity and is
tolerant of a wide range of functional groups and heteroatoms. The
use of this catalyst for the oxidation of alcohols to aldehydes is well
established13,14 therefore we have mainly focused on examining its
new application; the synthesis of nitriles from aldehydes. Some initial
optimisation experiments are shown in Table 1. It was found that
Cu(OTf)2 was the most active catalyst and was able to afford a high
isolated yield of benzonitrile at 25 1C. Cu(OTf)2 was therefore selected
as the choice of Cu(II) species when studying a wider range of
substrates (Table 2). The ‘‘open flask’’ approach means that continual
addition of NH3(aq) is required to replace NH3 that evaporates over
time. However, if the concentration of NH3 is too high it slows down
the rate of the reaction. Reactions were faster when NaOH was added,
however still proceeded readily in its absence.
Once the optimisation had been performed, we examined the
substrate scope. As Table 2 demonstrates, good to excellent yields
can be obtained for a range of substrates. We have obtained
isolated yields for all the products reported in Table 2, although
in some cases we have also reported yields determined by GC. In
these cases, we attribute the discrepancy in yields to the volatility of
the products which led to some loss of the mass balance during
product isolation. The reaction is tolerant of a wide range of
aromatic functional groups including aryl halides (1b–d), nitro
groups (1e–f), electron donating groups such as methoxy (1g) and
enals such as cinnamaldehyde (1h).
93
90
96
95
7
8
9
70
75
78, (90)b
76, (93)b
10
11
The catalyst is also tolerant of molecules containing heteroatoms
such as oxygen, sulfur and nitrogen. In the case of the case of 1j and
1l, the nitrile was obtained in good yield, but small quantities of the
corresponding primary amide were also obtained. In these cases, if
reaction times were prolonged, the nitrile was converted slowly to
the amide under the reaction conditions. Mizuno and co-workers
reported that primary amides could be produced selectively from
oxidation of alcohols or aldehydes in the presence of aqueous
ammonia using a heterogeneous Mn catalyst.15 For the majority of
substrates, the Cu–TEMPO system is selective to nitriles and amide
by-products were not observed.
76, (95)b
63, (92)b
12
a
b
Isolated yield; GC yield.
c
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As some of these substrates were slow to react at room tempera-
ture, this led us to explore the temperature limits of this open flask
approach. Therefore, in some cases, in order to reduce the reaction
times we employed temperatures of 40 or 70 1C.16 Above 70 1C the
rate of NH3 evaporation is too great and very little product is
obtained. With regards to the choice of radical, although TEMPO
(1)
Although not fully optimised, it was once again found that
(4a) is an effective co-catalyst, we found it difficult to separate from such aliphatic substrates could be converted with lower catalyst
many of the nitrile products using chromatography. In contrast, loadings when the reactions were carried out in a reactor.
4-hydroxy-TEMPO (4b) could be more readily separated from the
In summary, we have shown that copper/TEMPO can be
product. In most cases we utilised 4-sulfonatooxy-TEMPO (4c),16,17 as used to prepare nitriles from aldehydes or alcohols using
this derivative can be easily separated from the product by aqueous aqueous ammonia with air as the oxidant. The use of standard
extraction, allowing many of the pure products to be isolated without glassware along with air means that these methods offer a safe
the need for chromatography. Furthermore, 4c was found to be and readily accessible approach to making nitriles using an
more thermally stable than 4b.
aerobic catalyst.
As discussed earlier, initial optimisation was carried out at
We thank the Nuffield Foundation and the Department of
25 1C, however we later re-examined the use of CuCl2. We found that Education in Northern Ireland for funding.
the use of this less expensive salt becomes viable at higher tempera-
tures. For example, we were able to obtain an 88% isolated yield of
the nitrile from 4-chlorobenzaldehyde with the open air method at
Notes and references
1 Review of nitrile containing pharmaceuticals: F. F. Fleming, L. Yao,
70 1C. If these reactions were scaled up, it would likely be carried out
in a pressurised system, utilising limiting oxygen concentrations
(LOC), to avoid explosive gas mixtures. The use of reactors has the
advantage that higher temperatures can be used as evaporation of
ammonia is no longer an issue. Some preliminary tests indicate that
at higher temperatures (e.g. 120 1C) in a pressurised reactor (with
40 bar of 8% O2 in N2), not only can CuCl2 be utilised but the
loading of CuCl2 and 4c can be reduced to 1 mol%. Under these
conditions we could obtain 83% isolated yield using 4-chloro-
benzaldehyde. Such low catalyst loadings demonstrate the excellent
potential for the industrial utilisation of this catalyst system. The
results compare favourably to other catalytic methods. For example,
the recent work by Mizuno and co-workers, required 10 mol% of
ruthenium hydroxide on alumina at 120 1C.7a
In the case of aliphatic aldehydes, we found that we had a
problem with undesired, uncatalysed side reactions. It is known
that such aldehydes can react with ammonia and produce a range
of products via aldol type reactions.18,19 We found that such
substrates could be converted successfully if we modified our
method. Side reactions were reduced by removing NaOH from
the system. As might be expected, aliphatic substrates are less
reactive than their aromatic counterparts, therefore we employed
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anilines to prepare imines and azo compounds. During these
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12 While this manuscript was under review, two other independent
studies were published describing the use of copper/TEMPO cata-
lysis for the oxidative synthesis of nitriles. In both cases these
studies utilised pure O2 atmospheres, something that we have
avoided: (a) C. Tao, F. Liu, Y. Zhu, W. Liu and Z. Cao, Org. Biomol.
Chem., 2013, 11, 3349; (b) W. Yin, C. Wang and Y. Huang, Org. Lett.,
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under such conditions.14e,g The improved reactivity is not
sustained in aqueous solvent mixtures, therefore we could not
continually add ammonia as we had previously. Consequently we
added just 2.5 equivalents of NH3 (to ensure low levels of water)
and instead of an ‘‘open flask’’ we attached a balloon containing
air to our condenser. The conditions are summarised in eqn (1).
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17 V. Strehmel, H. Rexhausen and P. Strauch, Tetrahedron Lett., 2008,
temperature of 50 1C was used. As might be expected, this Cu(I)
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18 H. H. Strain, J. Am. Chem. Soc., 1932, 54, 1221.
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c
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