Anhydrous hydration of nitriles to amides using aldoximes as the water source

Article abstract of DOI:10.1021/ol902309z

[Chemical Equation Presented] Anhydrous hydrolysis of nitriles to amides was developed using acetaldoxime as the water source In the presence of Rh catalyst. Conversion of various nitriles to amides was performed under neutral and anhydrous conditions, and the reaction displays excellent compatibility with acid or base labile and hydrolytically labile functional groups.

Full text of DOI:10.1021/ol902309z

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5598-5601
Anhydrous Hydration of Nitriles to
Amides using Aldoximes as the Water
Source
Jinwoo Lee, Min Kim, Sukbok Chang,* and Hee-Yoon Lee*
Department of Chemistry, Korea AdVanced Institute of Science and Technology
(KAIST), Daejeon 305-701, Korea
leeheeyoon@kaist.ac.kr; sbchang@kaist.ac.kr
Received October 6, 2009
ABSTRACT
Anhydrous hydrolysis of nitriles to amides was developed using acetaldoxime as the water source in the presence of Rh catalyst. Conversion
of various nitriles to amides was performed under neutral and anhydrous conditions, and the reaction displays excellent compatibility with
acid or base labile and hydrolytically labile functional groups.
Nitrile is one of the most versatile functional groups as it
can be readily transformed into various other functional
groups or reactive intermediates. Among them, hydration of
nitriles has great synthetic significance in the preparation of
the corresponding amides for the isohypsic nature of the
transformation that is an important factor in redox-economy
in organic synthesis1 and for its broad industrial and
pharmacological applications.2 For example, hydration of
acrylonitrile produces annually more than 2 × 105 tons of
acrylamide and is the most important technology for the
production of this chemical.3 The reaction proceeds in a
sequence of distinct steps upon treatment with strong
inorganic acids or bases. Due to these harsh conditions,
carboxylic acids could form as the major byproduct, and more
importantly, acid or base labile functional groups and protective
groups cannot be tolerated.4 Although metals, especially transi-
tion metal catalyzed nitrile hydrolysis reactions, have offered
mild reaction conditions and selective formation of amides
without the formation of carboxylic acids, functional group
tolerability during the nitrile hydrolysis has not been addressed
yet.5 Therefore, the development of an efficient and mild process
for the synthesis of amides from nitriles even in the presence
of other labile functional groups would be a valuable tool in
organic synthesis.
(1) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int.
Ed. 2009, 48, 2854–2867.
(2) Books and reviews: (a) The Chemistry of Functional Groups, The
Chemistry of Cyano Group; Pappoport, Z., Patai, S., Eds.; Wiley: London,
1970. (b) Fatiadi, A. J. in The Chemistry of Functional Groups, Supplement
C, The Chemistry of Triple-Bonded Functional Groups, Part 2; Pappoport,
Z., Patai, S., Eds.; Wiley: London, 1983; pp 1057-1303. (c) Murahashi,
S.-I.; Naota, T. Bull. Chem. Soc. Jpn. 1996, 69, 1805–1824. (d) Murahashi,
S.-I.; Takaya, H. Acc. Chem. Res. 2000, 33, 225–233. (e) Kukushkin, V. Y.;
Pombeiro, A. J. L. Chem. ReV. 2002, 102, 1771–1802. (f) Kukushkin, V. Y.;
Pombeiro, A. J. L. Inorg. Chim. Acta 2005, 358, 1–21. (g) Mascharak, P. K.
Coord. Chem. ReV. 2002, 225, 201–214. (h) Harrop, T. C.; Mascharak,
P. K. Acc. Chem. Res. 2004, 37, 253–260.
Herein, we report a selective hydrolysis reaction of nitriles
to amides under essentially neutral and anhydrous conditions
(4) Kukushikin, V. Y.; Pombeiro, A. J. L. Inorg. Chim. Acta 2005, 358,
1–21, and references therein.
(5) (a) Goto, A.; Endo, K.; Saito, S. Angew. Chem., Int. Ed. 2008, 47,
3607–3609. (b) Yamaguchi, K.; Matsushita, M.; Mizuno, N. Angew. Chem.,
Int. Ed. 2004, 43, 1576–1580. (c) Crestani, M. G.; Garcia, J. J. J. Mol.
Catal. A: Chem. 2009, 299, 26–36. (d) Solhy, A.; Smahi, A.; Badaoui, H. E.;
Elaabar, B.; Amoukal, A.; Tikad, A.; Sebtia, S.; Macquarrie, D. J.
Tetrahedron Lett. 2003, 44, 4031–4033. (e) Thallaj, N. K.; Przybilla, J.;
Welter, R.; Mandon, D. J. Am. Chem. Soc. 2008, 130, 2414–2415. (f)
Ramon, R. S.; Marion, N.; Nolan, S. P. Chem.sEur. J. 2009, 15, 8695–
8697.
(3) (a) Opsahl, R. Encyclopedia of Chemical Technology; Kroschwitz,
J. I., Ed.; Wiley: New York, 1991; Vol. 2, pp 346-356. (b) Ingvosersen,
K.; Kamphuis, J. Enzyme Catalysis in Organic Synthesis; Drauz, K.,
Waldmann, H., Eds.; VCH: Weinheim, 1995; Vol. 1, pp 365-392.
10.1021/ol902309z  2009 American Chemical Society
Published on Web 11/13/2009

that allow other functional groups to remain intact. During
the development of mild reaction conditions for the Rh-
catalyzed transformation of aldoximes into amides,6 we
observed an interesting additive effect. Development of
the anhydrous hydration reaction of nitriles to amides was
based on mechanistic insight from our recent report of
the Rh-catalyzed rearrangement of aldoximes into amides
(Scheme 1).7
aldoximes.7 This result could imply that aliphatic nitriles
would bind to the catalyst less tightly than aromatic nitriles,
implying that aliphatic nitriles may not effectively participate
in the rearrangement of aldoximes into amides. This observa-
tion led us to speculate a possibility of utilizing aliphatic
aldoxime as the water source for the “anhydrous” hydration
of nitriles. If an aliphatic aldoxime was used as the hydrating
agent for nitriles, aromatic nitriles could be hydrated ef-
fectively by the rhodium catalyst while utilizing aliphatic
aldoximes as the hydrating species since the in situ generated
aliphatic nitriles during the reaction course would not
compete with aromatic nitriles for the subsequent hydration.
The anhydrous hydration of nitriles was first examined
with 4-methoxybenzonitrile as a test substrate using propi-
onaldoxime as a stoichiometric hydrating species (Table 1).
Scheme 1
.
Mechanistic Proposal for the Nitrile-Mediated Amide
Formation
Table 1. Screen of Reaction Conditionsa
entry
catalyst
additive
temp (°C) convn (%)b
1
2
3
4
5
6
7
RhCl(IMes)(cod) pTsOH/H2O
RhCl(IMes)(cod) pTsOH/H2O
80
110
110
80
110
110
110
48
72
78
57
87c
80
89c
RhCl(IMes)(cod)
RhCl(IMes)(cod)
RhCl(IMes)(cod)
RhCl(PPh3)3
-
-
-
-
-
RhCl(PPh3)3
a Reaction conditions: a solution of 4-methoxybenzonitrile (0.5 mmol),
propionaldoxime (1.5 mmol), Rh catalyst (1.0 mol %), and additive (10
mol %) in toluene (0.125 mL) was stirred for 6 h in a reaction vial (1 mL).
b Measured from 1H NMR spectra of the crude products. c 2.5 mmol of
propionaldoxime was used. IMes ) N,N-bis(2,4,6-trimethylphenyl)imidazole
ligand.
In our previous report, we found out that Rh-catalyzed
rearrangement of aldoximes to amides was accelerated by
the nitrile additives. It was proposed that the added nitriles
cooperatively catalyze the dehydration reaction of aldoximes
into the corresponding nitriles, while the hydroxyl group of
aldoximes is taken up by the nitriles to form amides. In fact,
it was observed that the total concentration of nitriles
remained constant throughout the reaction course.7 This
mechanistic feature that required the formation of the
aldoxime-nitrile-metal complex such as II prompted us to
conceive an idea that aldoximes could serve as the water
source for the hydration of nitriles, thus excluding water from
the hydration reaction completely.8
The reaction was first tested under reaction conditions
similar to those used in the rearrangement of aldoximes into
amides (entry 1).7 Quite contrary to our expectation based
on the mechanistic speculation,8a it turned out that the
conversion of nitriles to amides was much slower than the
rearrangement of aldoximes into amides. Higher reaction
temperatures were required to accelerate the hydration
reaction (entry 2). To our surprise, p-toluensulfonic acid that
accelerated the rearrangement of aldoximes into amides7 did
not affect the hydration reaction efficiency (compare entries
2 and 3). This result strongly implies that the role of
p-toluensulfonic acid during the rearrangement of aldoximes
into amides might have been helping a competitive coordina-
tion of a nitrile to the catalyst,8a in addition to the activation
of the catalyst.7 In consequence, the existence of a large
amount of a nitrile seemed to abolish the effect of the
During the Rh-catalyzed rearrangement of aldoximes to
amides, aliphatic aldoximes were found to be not as much
influenced by the added corresponding nitriles as aryl
(6) (a) Yang, S. H.; Chang, S. Org. Lett. 2001, 3, 4209. (b) Choi, E.;
Lee, C.; Na, Y.; Chang, S. Org. Lett. 2002, 4, 2369. (c) Park, S.; Choi,
Y.-a.; Han, H.; Yang, S. H.; Chang, S. Chem. Commun. 2003, 1936.
(7) Kim, M.; Lee, J.; Lee, H.-Y.; Chang, S. AdV. Synth. Catal. 2009,
351, 1807–1812.
(8) For detailed mechanistic and kinetic study in support of the
intermediate II with Pd and application to the hydration of nitriles, see: (a)
Leusink, A. J.; Meerbeek, T. G.; Noltes, J. G. Recl. TraV. Chim. Pays-Bas.
1976, 95, 142–145. (b) Kim, E. S.; Kim, H. S.; Kim, J. N. Tetrahedron
Lett. 2009, 50, 2973–2975.
Org. Lett., Vol. 11, No. 24, 2009
5599

p-toluensulfonic acid additive. This unanticipated result
ensures the neutrality as well as the anhydrous nature of the
reaction.
Table 3. Hydration of Various Nitriles Using Acetaldoximea
When the amount of propionaldoxime was increased,
conversion of the hydration reaction was consequently
improved (entry 5). Since propionitrile generated from the
dehydration process of propionaldoxime could compete with
4-methoxybenzonitrile, an extra amount of aldoxime was
required to improve the conversion and the reaction rate.
Contrary to the Rh-catalyzed rearrangement of aldoximes
to amides,7 commercially available Wilkinson’s catalyst
worked as well as Rh(NHC) catalyst (entries 6 and 7).
The effect of aldoxime substituents on the hydration
reaction was next explored with the expectation that the
bulkiness of the substituent could affect reaction rate of the
hydration reaction as it could alter the rate of the dehydration
reaction of aldoximes and the rate of hydration of nitriles
produced from aldoximes (Table 2).
Table 2. Substituent Effect on Hydration Reactionsa
entry
R
aldoxime (equiv)
time (h)
convn (%)b
1
2
3
4
5
6
7
Me
Me
Me
Me
t-Bu
t-Bu
t-Bu
1.0
3.0
5.0
5.0
1.5
1.5
2.0
6.0
6.0
0.5
1.5
1.0
2.0
2.0
46
83
93
93
77
88
95
a Reaction conditions: a solution of 4-methoxybenzonitrile (0.5 mmol),
aldoxime, and Rh catalyst (1.0 mol %) in toluene (0.125 mL) was stirred
in a reaction vial (1 mL). b Measured from the 1H NMR spectra of the
crude products.
While acetaldoxime showed a result similar to propional-
doxime (entry 1), higher concentration of acetaldoxime not
only improved the conversion but also accelerated the
hydration reaction substantially (entry 2). No significant
improvement of the conversion even after an extended
reaction time (entry 3) indicated that the conversion of
acetonitrile into acetamide becomes the dominant reaction
pathway when most nitrile substrate was consumed.
When sterically encumbered pivalaldoxime was used as
a hydrating agent, the conversion rate was similar to other
cases (entry 4), and extended reaction time further improved
the conversion (entry 5). When 2.0 equiv of pivalaldoxime
was used, the hydration reaction was completed in 2 h (entry
6). This result indicates that the bulky aldoxime may play a
role as a better hydrating agent as the bulkiness might prevent
hydration of the corresponding nitrile in situ generated from
the aldoxime.
a Reaction conditions: a solution of nitrile (0.5 mmol), acetaldoxime
(2.5 mmol), and Rh catalyst (1.0 mol %) in toluene (0.125 mL) was stirred
in a reaction vial (1 mL) for 4-5 h. b Isolated yield. c Pivalaldoxime (2.0
equiv) was used.
practical reasons. Acetaldoxime was commercially available
and made the purification of the hydration product simple
as acetamide byproduct was readily soluble in water.
Although bulky aldoxime has an advantage as a hydrating
agent, we chose acetaldoxime as the hydrating reagent for
5600
Org. Lett., Vol. 11, No. 24, 2009

The new protocol of anhydrous hydration was subse-
quently applied to various aromatic nitriles and aliphatic
nitriles. A complete conversion of nitriles to amides took
place within 4-5 h at 110 °C in toluene using 1 mol % of
Wilkinson’s catalyst and 5 equiv of acetaldoxime. Aromatic
nitriles were smoothly hydrated to give the corresponding
amides in excellent yields under the employed reaction
conditions. The hydration proceeded effectively for various
benzonitriles substituted with either electron-withdrawing or
electron-donating groups (entries 1-4, Table 3). Ortho-
substituted benzonitriles also showed high reactivity provid-
ing excellent yield (entry 5). Then, we examined hydration
reaction with derivatives of benzonitriles containing ketone
or ester groups. In both cases, nitriles were hydrated
effectively without any side products derived from potential
reactions of those carbonyl groups (entries 6 and 7). We were
pleasantly surprised by the observation that, in addition to
aryl nitriles, aliphatic substrates were also hydrated with
excellent efficiency (entries 8-10). Use of 5 equiv of
acetaldoxime appeared not only to facilitae the reaction rate
but also to provide enough reagent for aliphatic nitriles to
overcome competing hydration of acetonitrile generated from
acetaldoxime. Results from entries 7, 8, and 9 clearly
demonstrate that the reaction is not only anhydrous but also
neutral, and the reaction can be applied to various compounds
with sensitive functional groups or protecting groups which
are easily deprotected under acidic or basic media (entries
11-15). In addition to that, no racemization during the
reaction was observed.9
In summary, we have developed a new “anhydrous” and
“neutral” protocol for the hydration of nitriles to amides in
good yield using commercially available acetaldoxime and
Wilkinson’s catalyst. Under the new protocol, compounds
with acid or base sensitive functional and protecting groups
along with other sensitive compounds such as acrylonitrile
or heterocyclic nitriles that were reported to be converted
into amides in the previous reports7,8b could be tolerated,
thus giving a wide opportunity that the developed synthetic
method can find numerous applications in organic synthesis
and process chemistry.
Acknowledgment. This research was supported by grants
from the Marine Biotechnology Program funded by the
Ministry of Land, Transport and Maritime Affairs of Korea.
Supporting Information Available: Experimental details
1
and H and 13C NMR spectra of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL902309Z
(9) Stereochemical integrity of the product in the entry 15 was confirmed
through Mosher ester formation as no isomeric compound was observed.
Org. Lett., Vol. 11, No. 24, 2009
5601