New catalytic properties of iron complexes: Dehydration of amides to nitriles

Article abstract of DOI:10.1039/b910145d

Various iron carbonyl clusters such as Fe₂(CO)₉ or [Et₃NH][HFe₃(CO)₁₁] are shown to catalyze the dehydration of amides into the corresponding nitriles in the presence of silanes in high yields; this novel protocol showed good functional group tolerance and wide substrate scope.

Full text of DOI:10.1039/b910145d

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New catalytic properties of iron complexes: dehydration of
amides to nitrilesw
Shaolin Zhou, Daniele Addis, Shoubhik Das, Kathrin Junge and Matthias Beller*
Received (in Cambridge, UK) 22nd May 2009, Accepted 25th June 2009
First published as an Advance Article on the web 13th July 2009
DOI: 10.1039/b910145d
Various iron carbonyl clusters such as Fe2(CO)9 or
[Et3NH][HFe3(CO)11] are shown to catalyze the dehydration
of amides into the corresponding nitriles in the presence of
silanes in high yields; this novel protocol showed good functional
group tolerance and wide substrate scope.
optimize critical reaction parameters. Here, (EtO)2MeSiH is
used as a comparably cheap and stable silane in toluene in the
presence of various iron catalysts (Table 1, entries 2–10). The
reaction did not occur in the absence of any catalyst (Table 1,
entry 1). However, to our delight 5 mol% of non-toxic iron(II)
acetate catalyzed the desired transformation and afforded
benzonitrile in 83% yield (Table 1, entry 2). No reaction is
observed applying 5 mol% of either Fe(CO)5, FeCl2 or FeCl3
(Table 1, entries 3, 8 and 9). On the other hand, higher
activities and good yields (83–92%) are observed in the
presence of 2–3 mol% of [CpFe(CO)2]2, Fe3(CO)12 and
[Et3NH] [HFe3(CO)11] (Table 1, entries 5, 6 and 7). Nearly
quantitative yield (97%) is obtained applying Fe2(CO)9
(Table 1, entry 4). Other iron sources, such as Fe(acac)3, also
gave reasonable yield of benzonitrile (Table 1, entry 10).
Next, we investigated the influence of different silanes. As
shown in Table 2 applying 3.0 equivalents of (EtO)2MeSiH
showed the highest reactivity (Table 2, entry 1). Among the
different solvents tested, toluene was the best choice (Table 2,
entries 1, 10, 11 and 12).
Aromatic and aliphatic nitriles are common intermediates in
the industrial production of polyamides, pharmaceuticals,
agrochemicals, dyes, pigments, and numerous fine chemicals.1
Moreover, in organic synthesis the nitrile group serves as an
important starting material for various transformations into
other functional groups, such as amines, aldehydes, ketones,
heterocycles, etc.
The dehydration of primary amides is one of the most
fundamental methods for the synthesis of nitriles.2
Traditionally, this transformation has been performed in the
presence of strongly acidic dehydrating agents, such as P2O5,3
POCl3,4 SOCl2,5 TiCl4,6 or basic reagents, e.g. sodium
borohydride.7 Recently, more sophisticated reagents such as
the combination of ethyl dichlorophosphate and DBU,8
pivaloyl chloride–pyridine9 or trichloroacetyl chloride,10
which can be used under milder conditions, have been
developed.11 However, the use of these advanced reagents
might cause severe storage and handling problems as well as
significant waste generation.12 Hence, the development of
novel catalytic reactions is of general interest.13
With respect to the reaction mechanism we believe that our
iron-catalyzed dehydration protocol proceeds similar to the
ruthenium one reported by Nagashima and co-workers.17
Reaction of the silane with the iron catalyst should generate
an activated species, which hydrosilylates the amide.20,21
Subsequent exchange of the N–H proton by another silyl
group under release of hydrogen leads to a mixture of the
bis(silyl)amide A and the N,O-bis(silyl)imidate B (Fig. 1).
For some time we have been interested in the catalytic
synthesis of benzonitriles. Based on this work,14 we started a
programme on the development of novel catalysts for
reduction15 and dehydration of nitriles. To our surprise
dehydration of carboxylic amides proceeds with PhSiH3 in
the presence of tetra-n-butylammonium fluoride.16 Notably,
Nagashima and co-workers17 reported a similar protocol for
the dehydration of aromatic and aliphatic amides applying a
ruthenium carbonyl cluster catalyst at high temperature.
Inspired by these results, we decided to explore this dehydration
reaction using iron catalysts.18 Clearly, the abundant
availability makes iron a highly attractive candidate for
catalysis and a ‘‘cheap metal for noble tasks’’.19 Herein, we
report to the best of our knowledge the first iron-catalyzed
dehydration of primary amides to nitriles.
Table 1 Dehydration of benzamide with (EtO)2MeSiH in the
presence of various Fe catalystsa
Catalyst (mol%)
Entry
Time/h
Yieldb (%)
1
2
3
4
5
6
7
8
None
24
5
24
20
19
2
0
83
0
97
92
83
90
0
Fe(OAc)2 (5)
Fe(CO)5 (5)
Fe2(CO)9 (3)
[CpFe(CO)2]2 (3)
Fe3(CO)12 (2)
[Et3NH][HFe3(CO)11] (2)
FeCl2 (5)
In our initial investigation the reaction of benzamide to
benzonitriles was selected as a model system to identify and
3
20
20
20
9
10
FeCl3 (5)
Fe(acac)3 (5)
0
65
Leibniz-Institut fur Katalyse e.V. an der Universitat Rostock,
¨
¨
Albert-Einstein-Straße 29a, 18059, Rostock, Germany.
E-mail: matthias.beller@catalysis.de; Fax: +49 381-1281-5000
w Electronic supplementary information (ESI) available: Experi-
mental details and characterization of compounds 2a–2r. See
DOI: 10.1039/b910145d
a
Reaction conditions: 1a (1.0 mmol), catalyst (2–5 mol%),
(EtO)2MeSiH (3.0 equiv.), toluene (2 mL), 100 1C, argon atmosphere.
Determined by GC.
b
ꢀc
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Table 3 Iron-catalyzed dehydration of primary amides to nitrilesa
Table 2 Iron-catalyzed dehydration of benzamide with different
silanesa
Catalyst/
mol%
Yieldb
(%)
Entry
1
Amide
Time/h
4
Entry Hydrosilanes/equiv. Solvent
Temp/1C Yieldb (%)
1
2
3
4
5
6
(EtO)2MeSiH (3)
PMHS (3)
PhSiH3 (3)
Ph2SiH2 (3)
Et3SiH (3)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
100
100
100
100
100
100
100
80
90
36
43
70
9
25
55
72
74
74
75
14
2
2
2b 95
2c 95
2
3
4
6
TMSOSiMeH (3)
(EtO)3SiH
7
8c
9
(EtO)2MeSiH (3)
(EtO)2MeSiH (2.5)
(EtO)2MeSiH (3)
(EtO)2MeSiH (3)
(EtO)2MeSiH (3)
2
2d 85
100
10
11
12
1,4-Dioxane 100
Bu2O
DMSO
100
100
4
5
2
2
20
2
2e 83
2f 81
a
Reaction conditions: 1a (1.0 mmol), solvent (2 mL), [Fe]
b
(0.02 mmol), argon atmosphere. Determined by GC. 8 h.
c
6
7
4
5
4
2g 93
2h 84
16
8
5
18
2i 93
9c
5
4
30
4
2j 86
Fig. 1 Proposed reaction mechanism.
10cd
2k 89
Finally, elimination of the disiloxane from B produces the
corresponding nitrile. Formation of 1,1,3,3-tetraethoxy-1,3-
dimethyldisiloxane and its monohydrolysis product is
confirmed by 13C and 29Si NMR spectroscopy as well as by
GC-MS analysis of the reaction mixture.22 However, attempts
to detect intermediates A and B via in situ 13C and 29Si NMR
spectroscopy failed due to their low concentration and/or
instability.
11c
4
4
30
3
2l 67
12cd
99e
13c
14c
5
4
30
48
2n 52
Once the optimized conditions are obtained, the scope and
limitations of the iron-catalyzed nitrile formation with
(EtO)2MeSiH as dehydrating reagent were explored.23
Notably, a variety of primary carboxylic amides, including
aromatic, heteroaromatic, and aliphatic amides, provided
smoothly the corresponding nitriles in good to excellent yields
(Table 3). Commercially available methyl-, methoxy-, and tert-
butyl-substituted benzamides gave the respective nitriles in
81–95% yield (Table 3, entries 1–5). For the dehydration of
electron-withdrawing chloride- and bromide-substituted
benzamides, 4–5 mol% of catalyst were needed for effective
conversion (Table 3, entries 6 and 7). 1- and 2-naphthalene-
carboxamide 1i–j as well as the amino-substituted benzamide
1k led to nitriles 2i–k in 86–93% yield (Table 3, entries 8–10).
Notably, substrate 1l, containing both ester and amide
groups, afforded the product 2l in 67% yield and no reduction
2o 59f
15c
16
3
4
4
2
2p 94
2q 88
n-C9H19CONH2
1q
17c
4
24
2r 99
a
Reaction conditions: amides (1.0 mmol), [Fe] (2–5 mol%), (EtO)2-
MeSiH (3.0 mmol), toluene (2 mL), 100 1C, argon atmosphere.
Isolated yield. 1,4-Dioxane as solvent. (EtO)2MeSiH (4.0 mmol).
b
c
d
e
f
Cinnamonitrile : 3-phenylpropionitrile = 1 : 2. NMR yield.
ꢀc
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of the carbonyl group is observed (Table 3, entry 11).
However, 4-nitrobenzamide gave no desired product under
these conditions. Moreover, the a,b-unsaturated trans-
cinnamamide 1m was examined. Here, full conversion is
obtained, however partial reduction of the double bond takes
place (Table 3, entry 12). Dehydration of heterocyclic systems
such as benzo[b]-thiophene-2-carboxamide and furan-2-
carboxamide (Table 3, entries 13 and 14) gave the corresponding
nitriles 2n and 2o in 52% and 59% yield, respectively.
Unfortunately, nicotinamide did not react under these
conditions. Finally, the reaction was adapted to araliphatic
and aliphatic amides (Table 3, entries 15–17). Here, benzyl
cyanide 2p, decanonitrile 2q, and 1-adamantanecarbonitrile 2r
are obtained in 94%, 88% and 99% yield, respectively.
M. Beller, J. Organomet. Chem., 2003, 684, 50; (f) M. Sundermeier,
A. Zapf, M. Sateesh and M. Beller, Chem.–Eur. J., 2003, 9, 1828;
(g) T. Schareina, A. Zapf and M. Beller, Chem. Commun., 2004,
1388; (h) T. Schareina, A. Zapf and M. Beller, J. Organomet.
Chem., 2004, 689, 4576; (i) T. Schareina, A. Zapf, W. Magerlein,
¨
(j) T. Schareina, A. Zapf, W. Magerlein, N. Muller and
¨
N. Muller and M. Beller, Chem.–Eur. J., 2007, 13, 6249;
¨
¨
M. Beller, Synlett, 2007, 555; (k) T. Schareina, A. Zapf and
M. Beller, Tetrahedron Lett., 2005, 46, 2585; (l) T. Schareina,
A. Zapf, W. Magerlein, N. Muller and M. Beller, Tetrahedron
¨
¨
Lett., 2007, 48, 1087; (m) T. Schareina, R. Jackstell, T. Schulz,
A. Zapf, A. Cotte, M. Gotta and M. Beller, Adv. Synth. Catal.,
2009, 351, 643.
´
15 (a) S. Enthaler, K. Junge, D. Addis, G. Erre and M. Beller,
ChemSusChem, 2008, 1, 1006; (b) S. Enthaler, D. Addis,
K. Junge, G. Erre and M. Beller, Chem.–Eur. J., 2008, 14, 9491.
16 S. L Zhou, K. Junge, A. Addis, S. Das and M. Beller, Org. Lett.,
2009, 11, 2461.
In summary, the first iron-catalyzed dehydrations of
primary amides to give nitriles with (EtO)2MeSiH as
dehydrating agents have been developed. The general
applicability of the method and functional group tolerance
of the presented catalyst system are shown in the dehydration
of 18 different aromatic, heteroaromatic and aliphatic amides.
The authors thank Dr W. Baumann, Dr C. Fischer,
S. Buchholz, S. Schareina, A. Kammer, A. Koch, and
17 S. Hanada, Y. Motoyama and H. Nagashima, Eur. J. Org. Chem.,
2008, 24, 4097.
18 Recent examples from our group: (a) B. Bitterlich, K. Schroder,
¨
M. K. Tse and M. Beller, Eur. J. Org. Chem., 2008, 4867; (b) F. Shi,
M. K. Tse, M.-M. Pohl, A. Bruckner, S. Zhang and M. Beller,
¨
J. Mol. Catal. A: Chem., 2008, 292, 28; (c) F. Shi, M. K. Tse, Z. Li
and M. Beller, Chem.–Eur. J., 2008, 14, 8793; (d) S. Enthaler,
B. Spilker, G. Erre, M. K. Tse, K. Junge and M. Beller,
Tetrahedron, 2008, 64, 3867; (e) D. Li, K. Schroder, B. Bitterlich,
¨
M. K. Tse, F. Shi and M. Beller, Tetrahedron Lett., 2008, 49, 5976;
(f) F. Shi, M. K. Tse, S. Zhou, M.-M. Pohl, J. Radnik, S. Hubner,
¨
¨
¨
K. Jahnisch, A. Bruckner and M. Beller, J. Am. Chem. Soc., 2009,
S. Rossmeisel (all at the Leibniz-Institut fur Katalyse e.V.)
¨
for excellent analytical and technical support.
131, 1775; (g) S. Prateeptongkum, I. Jovel, R. Jackstell, N. Vogl,
C. Weckbecker and M. Beller, Chem. Commun., 2009, 1990.
19 For reviews see: (a) C. Bolm, J. Legros, J. Lepaih and L. Zani,
Chem. Rev., 2004, 104, 6217; (b) S. Enthaler, K. Junge and
M. Beller, Angew. Chem., Int. Ed., 2008, 47, 3317.
20 For Fe-catalyzed hydrosilylations see: (a) N. S. Shaikh,
S. Enthaler, K. Junge and M. Beller, Angew. Chem., Int. Ed.,
2008, 47, 2497; (b) N. S. Shaikh, K. Junge and M. Beller, Org.
Lett., 2007, 9, 5429; (c) A. M. Tondreau, E. Lobkovsky and
P. J. Chirik, Org. Lett., 2008, 10, 2789; (d) H. Nishiyama and
A. Furuta, Chem. Commun., 2007, 760; (e) D. V. Gutsulyak,
L. G. Kuzmina, J. A. K. Howard, S. F. Vyboishchikov and
G. I. Nikonov, J. Am. Chem. Soc., 2008, 130, 3732;
(f) B. K. Langlotz, H. Wadepohl and L. H. Gade, Angew. Chem.,
Int. Ed., 2008, 47, 4670.
Notes and references
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Verlag, Stuttgart, 4th edn, 1985, vol. E5, p 1313.
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(b) D. T. Mowry, Chem. Rev., 1948, 42, 189.
3 D. B. Reisner and E. C. Horning, Org. Synth., 1963, Coll. IV, 144.
4 B. Rickborn and F. R. Jensen, J. Org. Chem., 1962, 27, 4608.
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7 S. E. Ellzey, C. H. Mack and W. J. Connick, J. Org. Chem., 1967,
32, 846.
21 For stoichiometric dehydration of amides at high temperature see:
(a) W. E. Dennis, J. Org. Chem., 1970, 35, 3253; (b) J. F. Klebe,
J. Am. Chem. Soc., 1968, 90, 5246.
8 C.-W. Kuo, J.-L. Zhu, J.-D. Wu, C.-M. Chu, C.-F. Yao and
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11 Other recent examples of dehydration of amides: (a) J. A. Campbell,
G. McDouglad, H. McNab, L. V. C. Rees and R. G. Tyas,
Synthesis, 2007, 3179; (b) D. Vaccari, P. Davoli, M. Bucciarelli,
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14 For reviews see: (a) M. Sundermeier, A. Zapf and M. Beller, Eur. J.
22 Spectral data and MS of 1,1,3,3-tetraethoxy-1,3-dimethyldisiloxane
were consistent with literature values: T. Gunji, A. Setogawa,
K. Asakura and Y. Abe, Bull. Chem. Soc. Jpn., 1998, 71, 2967.
23 General procedure for the dehydration of primary amides to
nitriles: a 25 mL oven dried schlenk tube containing a stir bar was
charged with primary amides (1.0 mmol), and [Et3NH][HFe3(CO)11]
(0.02–0.05 mmol). (EtO)2MeSiH (3.0 mmol; for amides 1k and 1m,
4.0 mmol) and dry toluene or 1,4-dioxane (2 mL) were added,
respectively, after purging the schlenk tube with argon. The
mixture was stirred for the time indicated in Table 3 at 100 1C.
The cooled reaction mixture was diluted with diethyl ether (5 mL)
and quenched by addition of 2 M HCl (5 mL). The reaction
mixture was vigorously stirred for 3 h at room temperature and
extracted with diethyl ether (3 Â 20 mL). For amide 1k, 5 M
NaOH (2 mL) was used to adjust the pH value to 7 before
extracting. The combined organic layers were washed with brine
(10 mL), dried with anhydrous Na2SO4, filtered and concentrated
under reduced pressure (900 mbar, 40 1C). The residue was purified
by silica gel column chromatography and gave the corresponding
nitriles.
Inorg. Chem., 2003, 3513; (b) T. Schareina, A. Zapf, A. Cotte,
´
N. Muller and M. Beller, Synthesis, 2008, 3351; selected examples
¨
from our group; (c) M. Sundermeier, A. Zapf, M. Beller and
J. Sans, Tetrahedron Lett., 2001, 42, 6707; (d) M. Sundermeier,
A. Zapf and M. Beller, Angew. Chem., Int. Ed., 2003, 42, 1661;
(e) M. Sundermeier, S. Mutyala, A. Zapf, A. Spannenberg and
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 4883–4885 | 4885