Gold Activation of Nitriles: Catalytic Hydration to Amides

Article abstract of DOI:10.1002/chem.200901231

A gold-based catalytic system that efficiently mediates the hydration of a broad spectrum of nitriles, including aromatic, heteroaromatic and aliphatic examples and efficiently catalyze the hydration of a range of organonitriles has been reported. Nitriles are considered inert in the context gold catalysis and have only been used as reaction solvent or as throw-away ligands in well-defined cationic gold catalysis. The obtained product was purified by flash chromatography using a gradient of pentane/ethyl acetate and compound 1 was isolated as a colorless solid. Aromatic substrates bearing two nitrile groups as in rn-benzenedinitrile and p-benzenedinitrile underwent double nitrile hydration and afforded excellent yields in the corresponding diamides. There is high relevance for the use of cationic gold complexes bearing such ligands and should have important implications in catalysis.

Full text of DOI:10.1002/chem.200901231

COMMUNICATION
DOI: 10.1002/chem.200901231
Gold Activation of Nitriles: Catalytic Hydration to Amides
[
a, b]
[a, c]
[a, b]
Rubꢀn S. Ramꢁn,
Nicolas Marion,
and Steven P. Nolan*
In the last few years, homogeneous gold catalysis has
[1]
become a field of intense activity. This is due in part to the
high versatility of gold(I/III) catalysts that can act both as s-
AHCTUNGTRENNUNG
and p-Lewis acids, which has notably permitted the activa-
tion of a wide diversity of functional groups (Scheme 1,
top). Typically, carbon-based unsaturated systems (i.e., al-
kenes, allenes, and alkynes) are activated via p-coordination,
whereas heteroatom-based systems (i.e., ethers, epoxides,
[1,2]
carbonyls, aziridines, and imines) favor s-coordination.
Despite this remarkable versatility in activating unsaturated
CꢀX bonds (X=C, N, O), no report, as far as we are
[3]
aware, has appeared on the activation of nitriles by gold.
To date, nitriles have been considered inert in the context of
gold catalysis and have only been used as reaction solvent
[
4]
(
e.g., acetonitrile) or as throw-away ligands in well-defined
Scheme 1. Gold-catalyzed nitrile hydration: two remaining challenges.
[5]
cationic gold catalysts.
The conversion of nitriles into their corresponding amides
i.e., the nitrile hydration reaction) is arguably one of the
(
and fills the void left by gold in LTM-mediated nitrile hy-
dration.
[6]
most important applications of nitriles in catalysis. The hy-
[7]
dration of nitriles has been achieved using enzymes as well
Relying on our previous results in [(NHC)Au]-cata-
[6]
[19]
[20]
as a broad spectrum of late transition metals (LTM). Strik-
lyzed hydration-type chemistry, the optimization study
was initiated with benzonitrile as a model substrate using a
1:1 mixture of water/dioxane at 1008C and resulted in a
promising 66% conversion. Next, several parameters were
examined, including temperature, concentration, solvent,
amount of water, as well as the nature of the gold(I) com-
plex and the NHC ligand (see Supporting Information for
details). The final optimized conditions, making use of a
[8–18]
ingly, among the twelve LTMs of Groups 8 to 11,
only
gold has not proven active yet in this reaction (Scheme 1,
I
bottom). Herein, we report that [(NHC)Au ] complexes effi-
ciently catalyze the hydration of a range of organonitriles.
This study constitutes, to the best of our knowledge, the first
example of nitrile activation in gold homogeneous catalysis
I
well-defined cationic [(NHC)Au ] catalyst, are depicted in
Equation (1).
[
a] R. S. Ramꢀn, Dr. N. Marion, Prof. Dr. S. P. Nolan
Institute of Chemical Research of Catalonia (ICIQ)
Av. Paꢁsos Catalans 16, 43007 Tarragona (Spain)
[
b] R. S. Ramꢀn, Prof. Dr. S. P. Nolan
Present address: School of Chemistry
University of St Andrews, St Andrews KY16 9ST (UK)
Fax : (+44)1334-463808
E-mail: sn17@st-andrews.ac.uk
[
c] Dr. N. Marion
Present address: Department of Chemistry
Massachusetts Institute of Technology, Cambridge, MA 02139 (USA)
The scope of this transformation was next explored. First,
we focused on a wide array of functionalized benzonitriles
(Scheme 2). Overall, benzonitriles with electron-withdraw-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901231.
Chem. Eur. J. 2009, 15, 8695 – 8697
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8695

ing substituents (2–9) afforded good to excellent yields,
while substrates bearing electron-donating groups (10–15)
exhibited slightly lower conversions. It should be noted that
the present catalytic system is compatible with different
functional groups such as aromatic nitro, bromo, chloro, and
fluoro functionalities as well as methyl ketone and methyl
ether. Aromatic substrates bearing two nitrile groups as in
m-benzenedinitrile (16) and p-benzenedinitrile (17) under-
went double nitrile hydration and afforded excellent yields
in the corresponding diamides. Of note, o-substituted nitriles
generally required 5 mol% catalyst loading and prolonged
reaction time, regardless of the nature of the substituent.
Taken together with the low yield obtained for 2,6-dimethyl-
benzamide (13), we assume that steric hindrance greatly re-
duces the catalytic activity.
[
a,b]
Scheme 3. Hydration of heteroaromatic and aliphatic nitriles.
(IPr)Au(NTf )] (2 mol%), nitrile (1 mmol), water (0.5 mL), THF
0.5 mL), MW 1408C, 2 h. [b] Isolated yield, average of two runs. [c]
(IPr)Au(NTf )] (5 mol%), 6 h. [d] [(IPr)Au(NTf )] (4 mol%).
[a]
[
A
H
U
G
R
N
U
G
2
(
[
A
H
U
G
R
N
U
G
2
A
H
U
G
R
N
U
G
2
hydrations we previously observed for dicyano aromatic
substrates (Scheme 2, 16–17). However, the selective hydra-
tion of only one nitrile group leads to the desymmetrization
of fumaronitrile and is attractive for subsequent derivatiza-
tion. Good to excellent yields were also obtained from ben-
zylic and homobenzylic nitriles (26–27). It should be noted
that these examples can already be considered as “non-acti-
vated” since, in the amide product, the carbonyl bond is not
conjugated with a p-system. To fully determine the scope of
the present catalytic system, we examined the reactivity of
aliphatic nitriles (28–29). Satisfyingly, we observed the for-
mation of cyclopentyl- and cyclohexylcarboxamide in 91 and
[21]
7
0% yield, respectively.
In terms of mechanism, three hypotheses can be postulat-
ed at this point. Intermolecular trapping by water of the nas-
cent carbocation generated by s- or p-coordination of the
gold center to the CꢁN bond (Scheme 4, A and B) can be
[22]
envisaged. Alternatively, in line with our recent proposal
[
a,b]
Scheme 2. Hydration of functionalized benzonitriles.
(NTf )] (2 mol%), nitrile (1 mmol), water (0.5 mL), THF (0.5 mL), MW
408C, 2 h. [b] Isolated yield, average of two runs. [c] [(IPr)Au(NTf )] (5
mol%), 6 h. [d] [(IPr)Au(NTf )] (4 mol%).
[a] [(IPr)Au-
[20a]
for the conversion of propargyl acetates into enones,
an
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
in situ formed hydroxo-gold species could “deliver” the OH
1
A
H
U
G
R
N
U
G
2
[23]
moiety to the nitrile (Scheme 4, C).
Further studies are
A
T
N
T
E
N
N
2
currently ongoing in our laboratories to shed light on the
actual mechanism(s) at play in this reaction.
Heteroaromatic nitriles were also found to participate in
this reaction (Scheme 3). An excellent yield was obtained in
the case of furan-2-carbonitrile (18). Moderate to good
yields were observed with nitrogen-containing heteroaro-
matics (19–22), probably due to N coordination to the gold
In conclusion, we have developed a gold-based catalytic
system that efficiently mediates the hydration of a broad
spectrum of nitriles, including aromatic, heteroaromatic and
aliphatic examples. To the best of our knowledge, this study
[5a]
center.
To extend the reaction scope, several non-aromatic sub-
strates were also tested. Hence, cinnamamide (23) and cy-
clohexenecarboxamide (24) were obtained in good yields.
Noteworthy, fumaronitrile (25) only afforded the monohy-
drated product, which is in sharp contrast with the double
Scheme 4. Possible intermediates for gold-mediated nitrile hydration.
8696
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Chem. Eur. J. 2009, 15, 8695 – 8697

Gold Activation of Nitriles
COMMUNICATION
constitutes the first nitrile hydration catalyzed by gold, the
only missing late transition metal of Groups 8 to 11 for this
transformation. Most importantly, it represents the first ni-
trile activation in gold homogeneous catalysis. This possibili-
ty is of high relevance for the use of cationic gold complexes
bearing such ligands and should have important implications
in catalysis.
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A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
[(IPr)Au
mL microwave vial. Benzonitrile (1 mmol) was added, followed by
demineralized H O (500 mL). The vial was sealed and heated in the mi-
2
ACHTUNGTRENNUNG( NTf )] (20 mmol, 2 mol%) was added to THF (500 mL) in a
2
2
007, 400–411.
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196–7204.
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2
[
[
crowave for 2 h at 1408C (7 bar). After the reaction mixture cooled down
to room temperature, volatile compounds were evaporated under re-
duced pressure and the product was purified by flash chromatography
using a gradient of pentane/ethyl acetate (7:3 ! 0:1). Compound 1
7
2
2
000, 41, 4845–4849; b) A. Goto, K. Endo, S. Saito, Angew. Chem.
008, 120, 3663–3665; Angew. Chem. Int. Ed. 2008, 47, 3607–3609.
(
120 mg, 99%) was isolated as a colorless solid.
[
[
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Acknowledgements
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We thank the ICREA, PRF administered by the ACS, ERC (FUNCAT),
the ICIQ Foundation and the Ministerio de Educaciꢀn y Ciencia (Spain)
for financial support. N.M. (2007FI_A 01466) and R.S.R. (2008FI 01047)
thank the AGAUR for a fellowship. N.M. thanks Umicore for a Ph.D.
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Keywords: amides
carbenes · nitriles
· gold · hydration · N-heterocyclic
[
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1
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[
1] For the most recent general reviews on gold catalysis, see: a) D. J.
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[21] Of note, a primary and a tertiary alkylnitrile, namely hexanenitrile
and tert-butylnitrile, did not react under these reaction conditions.
While we assume that steric hindrance of the tert-butyl group pre-
vented coordination of gold and subsequent hydration, the reasons
for the lack of reactivity of simple primary alkylnitriles are still un-
clear.
[
[
2] For an excellent review on s/p-electrophilic Lewis acid catalysis,
see: Y. Yamamoto, J. Org. Chem. 2007, 72, 7817–7831.
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neous catalysis. Nevertheless, in both reports the nitrile moiety acts
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2
155; b) J. Barluenga, M. A. Fernꢄndez-Rodrꢃguez, P. Garcꢃa-
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[22] A related inner-sphere mechanism, where both the nitrile and water
are coordinated to the gold center and would react in an intramolec-
ular manner, could also be considered. Nevertheless, the propensity
of gold(I) to form linear dicoordinated species seems to rule out this
possibility.
[
[
[
3
9, 2285–2288; see also ref. [1].
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J. Organomet. Chem. 2009, 694, 551–560; b) C. H. M. Amijs, V.
Lꢀpez-Carrillo, M. Raducan, P. Pꢅrez-Galꢄn, C. Ferrer, A. M. Echa-
varren, J. Org. Chem. 2008, 73, 7721–7730.
6] For an excellent review on nitrile hydration, see: a) V. Y. Kukushkin,
A. J. L. Pombeiro, Inorg. Chim. Acta 2005, 358, 1–21; see also:
[23] A related dinuclear mechanism, involving the reaction of a [Auꢀ
OH] with a [Au--NꢁCꢀR] species, should also be considered. For a
relevant discussion on the different nitrile hydration mechanisms,
see reference [6a].
Received: May 8, 2009
Published online: July 21, 2009
Chem. Eur. J. 2009, 15, 8695 – 8697
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8697