Direct amination of secondary alcohols using ammonia

Article abstract of DOI:10.1002/anie.201002583

Hydrogen shuttle: For the first time secondary alcohols and ammonia can be directly converted into primary amines with a selectivity of up to 99% by using a simple ruthenium/phosphine catalyst (see scheme; R¹, R²= alkyl, aryl, alkenyl; M=[Ru₃(CO)₁₂]; and L=phosphine ligand).

Full text of DOI:10.1002/anie.201002583

Communications
DOI: 10.1002/anie.201002583
Amination
Direct Amination of Secondary Alcohols Using Ammonia**
Dennis Pingen, Christian Mꢀller, and Dieter Vogt*
The use of bio-based feedstocks as renewable resources
allows for “greener” and more (atom)efficient processes.
However, these bio-based feedstocks are typically highly
functionalized compounds bearing hydroxy groups, and for
many applications amine functional groups are required.
Current procedures for the conversion of alcohols into amines
produce much waste because of the protection and depro-
tection steps.[1–3] To make the conversion of alcohols into
amines industrially viable, the (atom)efficiency of the trans-
formation needs to be improved, such that there is less waste,
it is cheap, and readily available amine sources like ammonia
can be used. The direct catalytic amination of alcohols by
ammonia (Scheme 1) fulfils these requirements. In this
reaction the amine is produced with water as the only by-
product. We refer to this process as “hydrogen shuttling”,
because of the net transfer of hydrogen from the alcohol to
the amine.
and this was reported by Gunanathan and Milstein.[4] Several
primary alcohols were aminated using a Ru/PNP pincer
complex to give conversions of up to 100% and selectivity of
up to 87% for benzylalcohol (Scheme 2). The main by-
product is the secondary imine. However, it is important to
note that only primary alcohols and water-insoluble alcohols
were efficiently aminated with this catalytic system.
Scheme 2. Ru/PNP pincer complex for primary alcohol amination
reported by Gunanathan and Milstein.[4]
To date, only one example of a homogeneous catalyst is
known to catalyze the direct amination of primary alcohols,
Using the Ru/PNP complex for secondary alcohols under
identical reaction conditions yielded neither the amine nor
the corresponding ketone. Furthermore, for primary alcohols
considerable amounts of by-products such as secondary
amines and imines were formed at higher conversions.
Closely related to the direct amination of alcohols with
NH3 is the alkylation of amines with alcohols. Examples from
the early 80ꢀs are known in which amines were alkylated using
alcohols under relatively harsh conditions.[5] Recently, Beller
and co-workers reported that [Ru3(CO)12] in combination
with bulky phosphorus-based s-donor ligands give high
conversions and selectivity for secondary or tertiary amines;
they reported up to 100% conversion and 99% selectivity
under mild conditions.[6] With these systems, amines could be
alkylated by primary alcohols, even if the alcohol bears a
second, secondary alcohol.[7]
Scheme 1. Direct amination of secondary alcohols with ammonia.
Another elegant method was published by Williams and
co-workers for the alkylation of amines with alcohols in the
presence of ruthenium arene complexes.[8] Amines were
alkylated with various alcohols to give secondary and tertiary
amines with high conversions and yields. Also examples using
iridium-based catalysts in the presence of a base have been
reported by the groups of Williams,[9] Kempe,[10] Fujita,[11] and
Yamaguchi.[12] One example of an iridium-catalyzed amine
alkylation has been reported wherein no additives are
required, and it proceeds in water.[13] Williams and co-workers
refer to this process as the “borrowing hydrogen method-
ology”.[14] So far, no catalytic systems that are able to aminate
secondary alcohols with NH3 to solely form primary amines
have been described.[15]
[*] D. Pingen, Dr. C. Mꢀller, Prof. Dr. D. Vogt
Schuit Institute of Catalysis, Laboratory of Homogeneous Catalysis,
Eindhoven University of Technology
P.O. Box 513, 5600 MB, Eindhoven (The Netherlands)
Fax: (+31)40-245-5054
E-mail: D.Vogt@tue.nl
Homepage: www.catalysis.nl/homogeneous_catalysis
[**] We would like to thank Ton Staring for his technical assistance. This
research has been funded by the Netherlands Ministry of Economic
Affairs and the Netherlands Ministry of Education, Culture, and
Sciences within the framework of the CatchBio program. C. M.
thanks the Netherlands Organization for Scientific Research (NWO-
CW) for financial support.
Herein we report the first examples of a homogeneous
ruthenium-catalyzed direct amination of secondary alcohols
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002583.
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Table 1: Conversions and selectivity in the direct amination of cyclo-
hexanol using different ligands.
with NH3 to obtain primary amines with high selectivity, and
forming water as the only by-product (Scheme 3).
Ligand
Conv. [%][a]
Total amine
Primary amine
selectivity [%][c]
selectivity [%][b]
1
2
3
4
5
6
7
8
9
8.4
1.9
32.1
0
51.9
0
10.6
39.1
36.2
90.3
75.6
45.6
29.1
43.9
96.7
95.6
97.9
98.6
92.2
87.5
100
52.4
77.5
74.0
84.3
73.3
68.2
Scheme 3. Ruthenium-catalyzed direct amination of cyclohexanol with
ammonia.
In searching for an efficient catalyst for the conversion of
secondary alcohols using NH3 we chose cyclohexanol as a
model substrate. Starting from the systems reported by
Milstein[4] and Beller,[6] a number of ruthenium complexes
were tested as catalyst precursors in combination with
phosphorus ligands. The best results were obtained with the
combination of [Ru3(CO)12] and simple phosphine ligands
(Figure 1 and Table 1); cyclohexylamine was delivered with
Reaction conditions: cyclohexanol (10 mmol), [Ru3(CO)12] (0.1 mmol),
ligand (0.6 mmol), cyclohexane (6 mL), NH3 (l) (6 mL), 1408C, 21 h
([Ru3(CO)12]/L/substrate=1:6:100). [a] Conversions were determined by
GC analysis and based on the alcohol consumption and amine
production [b] S(primary + secondary amine + secondary imine), the
remainder is the intermediate ketone. [c] Percentage of the primary
amine present within the total amount of amine products.
amine, although with low activity. Consequently, one of the
cyclohexyl groups in 3 was replaced by a phenyl group, giving
rise to ligand 4 and the Buchwald ligand 5, and the
corresponding catalysts showed increased activity and good
selectivity towards the primary amine. The catalyst derived
from the pyrrole phosphine 6, successfully used by Beller for
the alkylation of amines with primary alcohols,[6] gave the best
results in terms of activity and selectivity. The results obtained
with catalysts derived from the N-alkyl derivative 8 and the
pyridine phosphine 9 demonstrated some activity, but good
selectivity.
On the basis of the results achieved with the catalyst
system Ru/6, the scope of the reaction was investigated by
subjecting a range of secondary alcohols to amination
reactions with ammonia. Table 2 shows that the conversions
are satisfying for all substrates. Conversions are slightly lower
for acyclic substrates (Table 2, entries 4–8). Aryl-substituted
and also unsaturated alcohols are converted equally well
(Table 2, entries 10–11). The primary amine selectivity is good
to excellent for all substrates and for menthol complete
selectivity is observed (Table 2, entry 12). These examples
demonstrate the potential of this new transformation.
In all cases, the corresponding secondary imine was
formed as the major by-product. For acyclic alcohols, more
intermediate ketone was observed. In general, as a result of
the higher nucleophilicity of the primary amine product,
compared to that of NH3, the secondary imine is formed. Only
very little of the secondary amine (typically below 2%) was
observed.
Remarkably, upon using longer reaction times the amount
of secondary imines decreased in favor of the primary amine
selectivity. Apparently, under the given reaction conditions,
the formation of the secondary imine seems to be reversible.
This effect was investigated by analyzing the reaction mixture
during the course of the catalytic reaction (Figure 2). It was
found that the selectivity towards the primary amines
increases over time for all secondary alcohol substrates
tested (Figure 3). In this process, the secondary imine can
Figure 1. Ligands used in the direct amination of secondary alcohols
with ammonia.
high selectivity (over 75%), even at high conversion (up to
90%). The best results were obtained when using cyclohex-
ane as the solvent at a reaction temperature of 1408C in a
stainless-steel autoclave. The ligands were systematically
varied to study and optimize the reaction. The catalysts
derived from bulky triarylphosphines 1 and 2 showed very
poor activities, although promising selectivities towards
cyclohexylamine were already observed for Ru/1. Notably, 1
gave good results in the ruthenium-catalyzed amine alkyla-
tion with primary alcohols as reported by Beller.[6] Next, the
bulky s-donating PCy3 (3) was used, and showed complete
selectivity in combination with Ru towards the primary
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Communications
Table 2: Different substrates used in the direct amination of secondary
alcohols.
Entry
Substrate
Conv.
[%][a]
Total amine
selectivity
[%][b]
Primary amine
selectivity
[%][c]
1
2
3
4
5
6
7
8
cyclohexanol
cyclopentanol
cyclooctanol
2-hexanol
2-heptanol
2-octanol
2-nonanol
3-hexanol
1-phenyl-ethanol
2-cyclohexen-1-ol
trans-3-penten-2-ol
rac-menthol
90.3
94.0
81.2
83.7
68.7
61.8
94.9
78.3
53.3
83.2
60.4
32.0
97.9
100
74.0
63.9
73.2
54.5
54.1
67.1
51.2
83.8
80.0
64.5
77.5
100
94.6
56.2
85.6
77.7
53.2
100
67.5
100
95.6
34.8
9
10
11
12
Reaction conditions: substrate (10 mmol), [Ru3(CO)12] (0.1 mmol),
ligand 6 (0.6 mmol), cyclohexane (6 mL), NH3 (l) (6 mL), 1408C, 21 h,
([Ru3(CO)12]/6/substrate=1:6:100). [a] Conversions were determined by
GC analysis, and based on the alcohol consumption and amine
production [b] S(primary + secondary amine + secondary imine), the
remainder is the intermediate ketone. [c] Percentage of the primary
amine present within the total amount of the amine products.
Figure 3. Primary amine selectivity for different substrates after 21 and
64 h. For cyclohexanol the selectivities are given after 21 and 92 h.
Reaction conditions: substrate (10 mmol), [Ru3(CO)12] (0.1 mmol),
ligand 6 (0.6 mmol), cyclohexane (6 mL), NH3(l) (6 mL), 1408C,
([Ru3(CO)12]/6/substrate 1:6:100).
Scheme 4. Most important equilibria for the reversibility in the direct
amination of secondary alcohols. The structures within the brackets
are non-observable intermediates.
Figure 2. Production distribution over time (for reaction conditions
see Table 2). &: cyclohexanol, *: cyclohexylamine, ~: dicyclohexyli-
mine, !: cyclohexanone.
The secondary imine can be reconverted into the ketone
or the imine by reaction with either water or ammonia,
respectively. Furthermore, the rates of dehydrogenation and
hydrogenation directly influence these equilibria, as cyclo-
hexanone and cyclohexylamine both participate in the
equilibria leading to the secondary imine, for which the
hydrogenation is apparently very slow. As Figure 3 suggests,
other substrates are likely to undergo these equilibria since
they exhibit similar selectivity patterns. Additional investiga-
tions are required for a complete understanding of the
reaction, as well as studies on the mechanism of the
ruthenium-catalyzed reaction.
be considered a reaction intermediate from which the primary
amine can be formed.
To gain a better understanding of this phenomenon, a
closer look was taken on the reaction intermediates and
products. A number of equilibria will be involved in the total
reaction scheme, thus involving the alcohol, the correspond-
ing ketone, ammonia, the primary amine product, corre-
sponding imines, hemiaminals, and aminals, as well as water.
Only a few of those compounds were observed in the reaction
mixture as determined by GC analysis. More compounds
were probably not observed because of the limited stability of
some of the intermediates. The most important equilibria for
cyclohexanol are shown in Scheme 4.
In conclusion, we show for the first time an atom-efficient
and very selective catalytic route for the direct synthesis of
primary amines from secondary alcohols and ammonia
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[6] a) A. Tillack, D. Hollmann, K. Mevius, D. Michalik, S. Bꢁhn, M.
without the need for protecting groups. The scope of the
reaction includes cyclic and acyclic aliphatic substrates, as
well as unsaturated and aryl-substituted alcohols. This
reaction may open up new pathways to the conversion of
bio-based feedstocks into intermediates and fine chemicals.
Mechanistic studies concerning the structure and properties
of the catalyst are underway. Furthermore, detailed inves-
tigations into the equilibria involved in this reaction are in
progress.
Beller, Eur. J. Org. Chem. 2008, 4745 – 4750; b) A. Tillack, D.
Hollmann, D. Michalik, M. Beller, Tetrahedron Lett. 2006, 47,
8881 – 8885; c) D. Hollmann, A. Tillack, D. Michalik, R.
Jackstell, M. Beller, Chem. Asian J. 2007, 2, 403 – 410.
[7] a) S. Bꢁhn, A. Tillack, S. Imm, K. Mevius, D. Michalik, D.
Hollmann, L. Neubert, M. Beller, ChemSusChem 2009, 2, 551 –
557; b) S. Bꢁhn, S. Imm, K. Mevius, L. Neubert, A. Tillack,
J. M. J. Williams, M. Beller, Chem. Eur. J. 2010, 16, 3590 – 3593.
[8] a) M. H. S. A. Hamid, J. M. J. Williams, Chem. Commun. 2007,
725 – 727; b) M. H. S. A. Hamid, C. L. Allen, G. W. Lamb, A. C.
Maxwell, H. C. Maytum, A. J. A. Watson, J. M. J. Williams, J.
Am. Chem. Soc. 2009, 131, 1766 – 1774.
[9] O. Saidi, A. J. Blacker, M. M. Farah, S. P. Marsden, J. M. J.
Williams, Angew. Chem. 2009, 121, 7511 – 7514; Angew. Chem.
Int. Ed. 2009, 48, 7375 – 7378; Angew. Chem. 2009, 121, 7511 –
7514.
[10] a) B. Blank, S. Michalik, R. Kempe, Chem. Eur. J. 2009, 15,
3790 – 3799; b) B. Blank, S. Michalik, R. Kempe, Adv. Synth.
Catal. 2009, 351, 2903 – 2911; c) B. Blank, M. Madalska, R.
Kempe, Adv. Synth. Catal. 2008, 350, 749 – 758.
Experimental Section
General procedure for the direct amination of secondary alcohols:
[Ru3(CO)12] (0.1 mmol), ligand (0.6 mmol), cyclohexane (6 mL), and
secondary alcohol (10 mmol) were consecutively added to an Ar-
purged Schlenk tube. The reaction mixture was then transferred to an
Ar-purged 75 mL stainless-steel autoclave. The autoclave was
charged with liquid ammonia (6 mL) by means of a mass flow
controller (MFC) for liquid NH3 (Liquiflow) and heated to 1408C for
the appropriate time.
[11] a) R. Yamaguchi, S. Kawagoe, C. Asai, K.-i. Fujita, Org. Lett.
2008, 10, 181 – 184; b) R. Yamaguchi, Z. Mingwen, S. Kawagoe,
C. Asai, K.-i. Fujita, Synthesis 2009, 1220 – 1223.
Received: April 29, 2010
Published online: July 29, 2010
[12] a) K.-i. Fujita, Z. Li, N. Ozeki, R. Yamaguchi, Tetrahedron Lett.
2003, 44, 2687 – 2690; b) K.-i. Fujita, T. Fujii, R. Yamaguchi, Org.
Lett. 2004, 6, 3525 – 3528; c) K.-i. Fujita, Y. Enoki, R. Yamagu-
chi, Tetrahedron 2008, 64, 1943 – 1954.
[13] O. Saidi, A. J. Blacker, M. M. Farah, S. P. Marsden, J. M. J.
Williams, Chem. Commun. 2010, 46, 1541 – 1543.
[14] a) M. H. S. A. Hamid, P. A. Slatford, J. M. J. Williams, Adv.
Synth. Catal. 2007, 349, 1555 – 1575; b) G. W. Lamb, J. M. J.
Williams, Chim. Oggi 2008, 26, 17 – 19; c) T. D. Nixon, M. K.
Whittlesey, J. M. J. Williams, Dalton Trans. 2009, 753 – 762;
d) G. E. Dobereiner, R. H. Crabtree, Chem. Rev. 2010, 110,
681 – 703.
Keywords: alcohols · amination · ammonia · hydrogen ·
.
ruthenium
[1] W. Sun, J. C. Pelletier, Tetrahedron Lett. 2007, 48, 7745 – 7746.
[2] E. Fabiano, B. T. Golding, M. M. Sadeghi, Synthesis 1987, 190 –
192.
[3] G. V. S. Reddy, G. V. Rao, R. V. K. Subramanyam, D. S. Iyengar,
Synth. Commun. 2000, 30, 2233 – 2237.
[4] C. Gunanathan, D. Milstein, Angew. Chem. 2008, 120, 8789 –
8792; Angew. Chem. Int. Ed. 2008, 47, 8661 – 8664.
[15] During the preparation of this manuscript we were informed by
Prof. Dr. Matthias Beller, Leibniz-Institut fꢂr Katalyse an der
Universitꢁt Rostock, that he and his co-workers developed a
similar procedure parallel to our research (S. Imm, S. Bꢁhn, L.
Neubert, H. Neumann, M. Beller, Angew. Chem. 2010, 122,
8303 – 8306; Angew. Chem. Int. Ed. 2010, 49, 8126 – 8129). We
gratefully thank Prof. Beller for this information and the
valuable comments on this subject.
[5] a) Y. Watanabe, Y. Tsuji, Y. Ohsugi, Tetrahedron Lett. 1981, 22,
2667 – 2670; b) R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit, N.
Tongpenyi, J. Chem. Soc. Chem. Commun. 1981, 611 – 612;
c) S. I. Murahashi, K. Kondo, T. Hakata, Tetrahedron Lett. 1982,
23, 229 – 232; d) Y. Watanabe, Y. Tsuji, H. Ige, Y. Ohsugi, T.
Ohta, J. Org. Chem. 1984, 49, 3359 – 3363.
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