Straightforward iron-catalyzed synthesis of nitriles by dehydration of primary amides

Article abstract of DOI:10.1002/ejoc.201100754

In the present study, the iron-catalyzed dehydration of a range of amides to the corresponding nitriles by using N-methyl-N-(trimethylsilyl) trifluoroacetamide (MSTFA) as the dehydration reagent has been explored. After investigating different reaction parameters (e.g., iron source, solvent, catalyst loading) with FeCl₂·4H₂O, an excellent and easily accessible precatalyst was found. The obtained system (5.0 mol-% [Fe], 3.0 equiv. MSTFA) was highly active and dehydrated a broad scope of amides selectively to the corresponding nitriles under mild reaction conditions (THF, 70 °C) within two hours (yields: >99 %, selectivities: >99 %).

Full text of DOI:10.1002/ejoc.201100754

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100754
Straightforward Iron-Catalyzed Synthesis of Nitriles by Dehydration of
Primary Amides
Stephan Enthaler*[a]
Keywords: Iron / Homogeneous catalysis / Dehydration / Amides / Nitriles
In the present study, the iron-catalyzed dehydration of a
range of amides to the corresponding nitriles by using N-
methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) as the
dehydration reagent has been explored. After investigating
different reaction parameters (e.g., iron source, solvent, cata-
cessible precatalyst was found. The obtained system
(5.0 mol-% [Fe], 3.0 equiv. MSTFA) was highly active and de-
hydrated a broad scope of amides selectively to the corre-
sponding nitriles under mild reaction conditions (THF, 70 °C)
within two hours (yields: Ͼ99%, selectivities: Ͼ99%).
2 2
lyst loading) with FeCl ·4H O, an excellent and easily ac-
Introduction
tem composed of FeCl ·4H O and N-methyl-N-(trimethyl-
2 2
silyl)trifluoroacetamide (MSTFA) for the dehydration of
Nitrile functionalities are one of the key structural motifs
in organic and industrial chemistry. They allow entry to the
synthesis of pharmaceuticals, agrochemicals, and poly-
[8]
primary amides under mild reaction conditions.
[
1]
mers. Over the years, diverse methodologies to produce Results and Discussion
nitriles have been accounted. For instance, one traditional
approach to nitriles is the reduction of primary amides, in-
cluding the dehydration by acidic (e.g., POCl , P O ,
Initially, as a model reaction the dehydration of 4-fluoro-
benzamide (1) with catalytic amounts of an iron source, N-
methyl-N-(trimethylsilyl)trifluoroacetamide (2, MSTFA)
was studied in toluene at 100 °C for 24 h (Table 1). In the
3
2
5
SOCl , TiCl ) and basic reagents (e.g., NaBH ) or a combi-
2
4
4
[
2]
nation of reagents. Moreover, the application of catalytic
amounts of transition metals has been demonstrated (e.g.,
Ru, Pd, Rh, W, V, Re, U, Zn, Cu). However, modern re-
search spotlights the exploration of alternatives for those
expensive and toxic metals.[ Here the utilization of abun-
Table 1. Iron-catalyzed dehydration of 4-fluorobenzamide (1).[a]
[3]
4,5]
[
6]
dant and lowly toxic biometals such as iron is desired.
More recently, the first protocol for the dehydration of or-
ganic amides with iron catalysts has been successfully pre-
sented by the group of Beller.[ They mixed primary benz-
7]
Entry
Iron source
(mol-%)
MSTFA Time
T
[°C]
Solvent Yield
[b]
amides with (EtO) MeSiH to generate the corresponding
[equiv.]
[h]
[%]
2
nitriles, hydrogen, and siloxanes in the presence of a cata-
lytic amount of [Et NH][HFe (CO) ]. However, problems
1
2
3
4
5
6
7
8
9
10
–-
3
3
3
3
3
3
3
3
3
3
3
2
1
3
3
24
24
24
24
24
24
24
24
24
24
24
24
24
1
100
100
100
100
100
100
70
70
70
70
70
toluene
Ͻ1
3
3
11
FeCl (5)
3
toluene Ͼ99
toluene Ͼ99
toluene Ͼ99
toluene Ͼ99
toluene Ͼ99
toluene Ͼ99
FeBr
FeCl ·4H
Fe (CO)12 (5)
Fe(ClO ·H O (5)
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl ·4H
FeCl ·4H
3
(5)
can arise in the presence of functional groups sensitive
towards reduction chemistry as a result of the reduction
abilities of the combination of catalytic amounts of metals
and hydrosilanes. As the dehydration of primary amides is
proposed to proceed via silylation, we wonder if the hydro-
2
2
O (5)
3
4
)
3
2
3
(5)
(5)
(5)
3
dioxane
82
3
THF Ͼ99
THF Ͼ99
THF Ͼ99
THF
THF
silanes can be substituted by silylation reagents without ad-
ditional reduction abilities.[
3,7]
3
(2.5)
Based on this idea we present
11
12
13
14
3
(1)
(5)
(5)
herein the usefulness of an easy-to-adopt dehydration sys-
3
70
70
70
70
52
Ͻ5
3
[
a] Technische Universität Berlin, Department of Chemistry,
Cluster of Excellence “Unifying Concepts in Catalysis”,
Straße des 17. Juni 135, 10623 Berlin, Germany
Fax: +49-30-314-29732
2
2
O (5)
O (1)
THF Ͼ99
THF 19
15
2
2
0.5
[
a] Reaction conditions: 1 (0.72 mmol), iron source (1–5 mol-%),
MSTFA (1.0–3.0 equiv.), solvent (2.0 mL), r.t. to 100 °C, 0.5–24 h.
[b] Determined by GC methods using biphenyl as an internal stan-
dard.
E-mail: stephan.enthaler@tu-berlin.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100754.
4760
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4760–4763

Fe-Catalyzed Synthesis of Nitriles by Dehydration of Primary Amides
absence of any iron precursor, no formation of 4-fluoroben- Table 2. Iron-catalyzed dehydration of various primary amides.[a]
zonitrile (1a) was observed, which was also noticed in the
absence of compound 2. However, in the presence of FeCl3
(5.0 mol-%) and MSTFA (3 equiv.) an excellent yield
(Ͼ99%) and chemoselectivity (Ͼ99%) to 1a was realized
under non-inert conditions (Table 1, Entry 2). Along with
MSTFA, also N,O-bis(trimethylsilyl)acetamide (BSA) and
hexamethyldisilazane (HMDS) have been applied as sil-
ylation reagents. In the case of BSA, similar results
(Ͼ99%) to those obtained with MSTFA were realized,
whereas for HMDS no product was observed. Moreover,
other iron sources, for example, FeBr , FeCl ·4H O,
3
2
2
Fe (CO) , and Fe(ClO ) ·H O, were tested and 1a was ob-
3
12
4 3
2
tained in excellent yields (Table 1, Entries 3–6), whereas
Brønsted acids (p-toluenesulfonic acid monohydrate)
[
9]
showed no activity. Additionally, dioxane and THF were
applied as the solvent, resulting in Ͼ99% yield (THF), and
the reaction temperature could be decreased to 70 °C
(Table 1, Entries 8 & 9).
Further on the catalyst loading was investigated, re-
sulting in excellent yields with a loading of 1.0 mol-%
Table 1, Entries 9–11). By decreasing the amount of
(
MSTFA to 2.0 and 1.0 equiv., respectively, a diminished
yield of 1a was noted (Table 1, Entries 12 & 13). Finally,
the reaction was stopped after 1 h, resulting in a turnover
–
1
frequency of 51 h . Noteworthy, 1 was completely con-
verted into the N-monosilylated intermediate within this
timeframe by applying FeCl ·4H O as a precatalyst.
2
2
With the optimized conditions in hand [FeCl ·4H O
2
2
(5 mol-%), MSTFA (3.0 equiv.), THF, 70 °C, 2 h] we ex-
plored the scope and limitation in the dehydration of a vari-
ety of primary amides to the corresponding nitriles
(Table 2). First, various substituted benzamides were inves-
tigated. In all cases excellent yields (Ͼ99%) were observed
and no difference was detected for electron-withdrawing or
electron-donating groups under the described reaction con-
ditions (Table 2, Entries 1–11). In addition, heteroaromatic
systems were tested (Table 2, Entries 14 & 15). An excellent
yield was observed for a thiophene-based amide, whereas
no transformation was observed for a pyridine-based
amide. Furthermore, alkyl amide 17 was successfully con-
verted into the corresponding nitrile (Table 2, Entry 16).
The presented method was applicable to the efficient dehy-
dration of thiobenzamide 18 (Table 2, Entry 17). Notably,
the iron/MSTFA system demonstrated excellent selectivity
in the presence of sensitive functional groups (e.g., nitro
and C=C bonds), whereas side reactions can occur for tran-
sition metal/R SiH-based systems (Table 2, Entries 11 &
3
3).[
10]
1
With respect to the reaction mechanism, we assume a
pathway similar to that reported by Nagashima (ruthe-
[
3a,7]
nium), Beller (iron), and co-workers (Scheme 1).
Ini-
tially, the iron catalyst activates the primary amide and al-
lows the transfer of the SiMe group to the NH function-
3
2
ality. This process will take place two times to obtain inter-
mediate 22 and two equivalents of 20, which was detected
by 1 F NMR spectroscopy. Noteworthy, the mono- and
[
2 2
a] Reaction conditions: amide (1.0 mmol), FeCl ·4H O (5 mol-%),
MSTFA (3.0 equiv.), THF (2.0 mL), 70 °C, 2 h. [b] Determined by
GC methods and H NMR spectroscopy. The isolated yield is given
9
1
bissilylated compounds of 1 were synthesized and reacted in parentheses.
Eur. J. Org. Chem. 2011, 4760–4763
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4761

S. Enthaler
SHORT COMMUNICATION
with a catalytic amount of FeCl ·4H O. Only in the case of Supporting Information (see footnote on the first page of this arti-
2
2
cle): General methods and characterization data.
bissilylated 1 was the corresponding nitrile observed,
whereas for the monosilylated compound no product was
detected. N,N-Bis(trimethylsilyl)amide intermediate 20 re-
arranges to N,O-bis(trimethylsilyl)imidate 23. In the pres-
Acknowledgments
ence of the catalyst, the desired nitrile and siloxane 24 are Financial support from the Cluster of Excellence “Unifying Con-
1
formed. The production of siloxane 24 was clarified by H cepts in Catalysis” (funded by the Deutsche Forschungsgemein-
2
9
and Si NMR spectroscopy. Finally, the iron catalyst is re- schaft and administered by the Technische Universität Berlin) is
gratefully acknowledged. The author thanks Dr. K. Junge, Dr. K.
covered and can react again.
Schröder and B. Wendt (Leibniz-Institut für Katalyse e.V. an der
Universität Rostock) for donation of substrates and general dis-
cussion. Furthermore, M. Weidauer, S. Hennig, and R. Skobalj
(
Technische Universität Berlin) are thanked for their support.
[
[
1] R. C. Larock, Comprehensive Organic Transformations, Wiley,
New York, 2010.
2] See for instance: a) R. E. Kent, S. M. McElvain, Org. Synth.
1945, 25, 61; b) D. T. Mowry, Chem. Rev. 1948, 42, 189–283;
c) D. B. Reisner, E. C. Horning, Org. Synth. 1950, 30, 22; d) B.
Rickborn, F. R. Jensen, J. Org. Chem. 1962, 27, 4608–4610; e)
J. A. Krynitsky, H. W. Carhart, Org. Synth. 1952, 32, 65; f) W.
Lehnert, Tetrahedron Lett. 1971, 12, 1501–1504; g) S. E. Ellzey,
C. H. Mack, W. J. Connick, J. Org. Chem. 1967, 32, 846–847;
h) N. Nakajima, M. Saito, M. Ubukata, Tetrahedron 2002, 58,
3561–3577; i) O. Sugimoto, M. Mori, K. Moriya, K.-I. Tanji,
Helv. Chim. Acta 2001, 84, 1112–1118; j) G. A. Hiegel, J. Rami-
rez, R. K. Barr, Synth. Commun. 1999, 29, 1415–1419; k) D. S.
Bose, P. R. Goud, Tetrahedron Lett. 1999, 40, 747–748; l) S.
Kim, K. Y. Yi, Tetrahedron Lett. 1986, 27, 1925–1928; m) G. A.
Olah, S. C. Narang, A. P. Fung, B. G. B. Gupta, Synthesis
1
980, 657–658; n) F. Campagna, A. Carotti, G. Casini, Tetrahe-
dron Lett. 1977, 18, 1813–1816.
[
3] For ruthenium, see: a) S. Hanada, Y. Motoyama, H. Nagshima,
Eur. J. Org. Chem. 2008, 4097–4100; b) Y. Watanabe, F. Oku-
ida, Y. Tsuji, J. Mol. Catal. 1990, 58, 87–94; for rhodium, see:
c) J. Blum, A. Fisher, Tetrahedron Lett. 1970, 11, 1963–1966;
d) J. Blum, A. Fisher, E. Greener, Tetrahedron 1973, 29, 1073–
Scheme 1. Mechanistic proposal for the dehydration of amides in
the presence of an iron catalyst.
1081; for tungtsen, see: e) J. A. Campbell, G. McDougald, H.
McNab, L. V. C. Rees, R. G. Tyas, Synthesis 2007, 3179–3184;
for palladium, see: f) S. I. Maffioli, E. Marzorati, A. Marazzi,
Org. Lett. 2005, 7, 5237–5239; for vanadium, see: g) S. Sueoka,
T. Mitsudome, T. Mizugaki, K. Jitsukawa, K. Kaneda, Chem.
Commun. 2010, 46, 8243–8245; for rhenium, see: h) K. Ishi-
hara, Y. Furuya, H. Yamamoto, Angew. Chem. 2002, 114,
Conclusions
In summary, we have demonstrated the value of a new
system for the dehydration of amides to the corresponding
nitriles composed of FeCl ·4H O and N-methyl-N-(trimeth-
ylsilyl)trifluoroacetamide (MSTFA). Excellent reactivity
and selectivity were observed in the dehydration of 14 dif-
ferent amides. Future work will be dedicated to making the
MSTFA heterogeneous to allow easy separation of second-
2
2
3109–3112; Angew. Chem. Int. Ed. 2002, 41, 2983–2986; i) Y.
Furuya, K. Ishihara, H. Yamamoto, Bull. Chem. Soc. Jpn.
2007, 80, 400–406; for uranium, see: j) S. Enthaler, Chem. Eur.
J. 2011, DOI: 10.1002/chem.201101478; for zinc, see: k) S. En-
thaler, S. Inoue, Chem. Asian J. 2011, DOI: 10.1002/
asia.201100493; l) for copper, see: S. Enthaler, M. Weidauer,
Catal. Lett. 2011, DOI: 10.1007/s10562-011-0660-9.
ary amide 20 and recharging with “SiMe ” for recycling.
3
[
4] a) P. T. Anastas, M. M. Kirchhoff, Acc. Chem. Res. 2002, 35,
6
331.
86–694; b) J. L. Tucker, Org. Process Res. Dev. 2010, 14, 328–
Experimental Section
[
5] S. Enthaler, K. Junge, M. Beller, Angew. Chem. 2008, 120,
General Procedure for the Dehydration of Amides: A pressure tube
was charged with an appropriate amount of FeCl
3363–3367; Angew. Chem. Int. Ed. 2008, 47, 3317–3321.
2
·4H
2
O
[6] For iron, see: a) R. H. Morris, Chem. Soc. Rev. 2009, 38, 2282–
2291; b) B. Plietker (Ed.), Iron Catalysis in Organic Chemistry,
Wiley-VCH, Weinheim, 2008; c) S. Gaillard, J.-L. Renaud,
ChemSusChem 2008, 1, 505–509; d) A. Correa, O. G. Man-
cheño, C. Bolm, Chem. Soc. Rev. 2008, 37, 1108–1117; e) B. D.
Sherry, A. Fürstner, Acc. Chem. Res. 2008, 41, 1500–1511; f)
R. M. Bullock, Angew. Chem. 2007, 119, 7504–7507; Angew.
Chem. Int. Ed. 2007, 46, 7360–7363; g) C. Bolm, J. Legros, J.
Le Paih, L. Zani, Chem. Rev. 2004, 104, 6217–6254; h) K.
Junge, K. Schröder, M. Beller, Chem. Commun. 2011, 47, 4849–
4859; i) E. B. Bauer, Curr. Org. Synth. 2008, 12, 1341–1369; j)
W. M. Czaplik, M. Mayer, J. Cvengros, A. Jacobi von Wange-
(0.05 mmol, 5.0 mol-%), the corresponding amide (1.0 mmol), and
MSTFA (3.0 equiv., 3.0 mmol). After addition of THF (2.0 mL),
the reaction mixture was stirred in a preheated oil bath at 70 °C for
2
h. The mixture was cooled in an ice bath and biphenyl (internal
standard) was added. The solution was diluted with dichlorometh-
ane, and an aliquot was taken for GC analysis (30 m Rxi-5ms col-
umn, 40–300 °C). The solvent was carefully removed, and the resi-
due was purified by column chromatography (n-hexane/ethyl acet-
ate, 5:1). The analytical properties of the corresponding nitriles are
in agreement with those reported in the literature.[
11–17]
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Eur. J. Org. Chem. 2011, 4760–4763

Fe-Catalyzed Synthesis of Nitriles by Dehydration of Primary Amides
lin, ChemSusChem 2009, 2, 396–417; k) B. D. Sherry, A.
Fürstner, Acc. Chem. Res. 2008, 41, 1500–1511.
7] S. Zhou, D. Addis, S. Das, K. Junge, M. Beller, Chem. Com-
mun. 2009, 4883–4885.
8] a) S. Enthaler, K. Schröder, S. Inoue, B. Eckhardt, K. Junge,
M. Beller, M. Driess, Eur. J. Org. Chem. 2010, 4893–4901; b)
S. Enthaler, ChemCatChem 2010, 2, 1411–1415; c) S. Enthaler,
for instance: S. L. Buchwald, C. Bolm, Angew. Chem. 2009,
121, 5694–5695; Angew. Chem. Int. Ed. 2009, 48, 5586–5587.
[10] K. Junge, B. Wendt, N. Shaikh, M. Beller, Chem. Commun.
2010, 46, 1769–1771.
[11] C. Yang, J. M. Williams, Org. Lett. 2004, 6, 2837–2840.
[12] S. Zhou, K. Junge, D. Addis, S. Das, M. Beller, Org. Lett. 2009,
11, 2461–2464.
[
[
ChemCatChem 2011, 3, 666–670; d) S. Enthaler, M. Haber- [13] M. Hatsuda, M. Seki, Tetrahedron 2005, 61, 9908–9917.
berger, E. Irran, Chem. Asian J. 2011, 6, 1613–1623; e) M. Ha-
berberger, E. Irran, S. Enthaler, Eur. J. Inorg. Chem. 2011,
[14] P. Y. Yeung, C. M. So, C. P. Lau, F. Y. Kwong, Org. Lett. 2011,
13, 648–651.
[15] R. Sasson, S. Rozen, Shlomo, Org. Lett. 2005, 7, 2177–2179.
[16] K. Riina, A. Leadbeater, N. E. Leadbeater, J. Org. Chem. 2003,
68, 9122–9125.
[17] D. N. Sawant, Y. S. Wagh, P. J. Tambade, K. D. Bhatte, B. M.
Bhanage, Ad. Synth. Catal. 2011, 353, 781–787.
Received: May 30, 2011
2
797–2802.
9] Cu(acac) was also applied as a precatalyst under conditions
described in Table 1, Entry 2, resulting in a yield Ͼ99% for
a. A decrease in the copper loading to 0.1 mol-% showed no
[
2
1
conversion of 1. This result indicates that the iron-catalyzed
dehydration process is based on iron as catalyst and not per-
formed by small impurities as found for other reactions. See
Published Online: July 19, 2011
Eur. J. Org. Chem. 2011, 4760–4763
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4763