Zinc-catalyzed chemoselective reduction of tertiary and secondary amides to amines

Article abstract of DOI:10.1002/chem.201101143

General and convenient procedures for the catalytic hydrosilylation of secondary and tertiary amides under mild conditions have been developed. In the presence of inexpensive zinc catalysts, tertiary amides are easily reduced by applying monosilanes. Key to success for the reduction of the secondary amides is the use of zinc triflate and disilanes with dual Si-H moieties. The presented hydrosilylations proceed with excellent chemoselectivity in the presence of sensitive ester, nitro, azo, nitrile, olefins, and other functional groups, thus making the method attractive for organic synthesis.

Full text of DOI:10.1002/chem.201101143

DOI: 10.1002/chem.201101143
Zinc-Catalyzed Chemoselective Reduction of Tertiary and Secondary
Amides to Amines
Shoubhik Das, Daniele Addis, Kathrin Junge, and Matthias Beller*[a]
Abstract: General and convenient pro-
cedures for the catalytic hydrosilylation
of secondary and tertiary amides under
mild conditions have been developed.
In the presence of inexpensive zinc cat-
alysts, tertiary amides are easily re-
duced by applying monosilanes. Key to
success for the reduction of the secon-
dary amides is the use of zinc triflate
The presented hydrosilylations proceed
with excellent chemoselectivity in the
presence of sensitive ester, nitro, azo,
nitrile, olefins, and other functional
groups, thus making the method attrac-
tive for organic synthesis.
À
and disilanes with dual Si H moieties.
Keywords: amides · amines · hy-
drosilanes · reduction · zinc
Introduction
reduction of tertiary amides. Catalytic reductions of func-
tionalized primary and secondary amides are only scarcely
investigated and still constitute a challenge, especially in the
presence of other reducible functional groups. For the first
time, Ito et al. and Ohta et al.[14] demonstrated the reduction
of secondary amides using a rhodium–triphenylphosphine
complex along with Ph2SiH2 as reducing agent. Later on,
Rom¼o[15] et al. published an unusual [MoO2Cl2]-catalyzed
reduction using PhSiH3. Fuchikami[16] and co-workers used
group 7–10 transition metals along with diethylamine and/or
ethyl iodide as co-catalysts in presence of triethylsilane.
Very recently, Nagashima[4,12] and co-workers reported the
reduction of secondary amides in the presence of a special
ruthenium cluster and commercially available platinum cata-
lysts such as chloroplatinic acid and Karstedtꢀs catalyst. The
latter reactions proceed under mild conditions and showed
high functional-group tolerance in the case of tertiary
amides. However, the selectivity for the reduction of secon-
dary amides in presence of other reducible functional
groups was still not fully demonstrated.
The chemoselective reduction of carboxylic amides to
amines under mild conditions is an essential transformation
in organic synthesis, which is also of significant interest for
the pharmaceutical as well as agrochemical industry.[1] High
selectivity and broad tolerance towards various functional
groups are key factors for the acceptance and application of
such a methodology. To date, most of the applied reductive
transformations of amides to amines still make use of
(over)stoichiometric amounts of aluminum and boron hy-
drides.[2,3] In spite of their utility, drawbacks of these re-
agents are their air and moisture sensitivity. In addition,
sometimes tedious purification of the products and concomi-
tant formation of salt byproducts are disadvantages of these
procedures. Due to these problems, the development of cat-
alytic reductions of amides is highly desired.[4] Despite prog-
ress in recent years, the straightforward hydrogenation of
carboxylic acid derivatives is still in its infancy.[5] On the
other hand, hydrosilanes[6] have become viable reducing
agents, which are used in industry on the ton scale for vari-
ous processes. Notably, they tolerate air and moisture but
promote the reduction of aldehydes and ketones along with
alkenes and alkynes in the presence of Brønsted[7] and
Lewis acids[8] and bases,[9] as well as transition metals.[10–13]
In the last decade, significant progress has also been
achieved for hydrosilylations of carboxamides in the pres-
ence of noble-metal-based catalysts.[4,12] More recently, Na-
gashima and co-workers as well as our group also developed
iron-based catalysts for this transformation.[13] However, so
far most of the known studies have focused on the catalytic
Based on our previous investigations on chemoselective
reductions with silanes,[17] herein we report improved zinc-
catalyzed hydrosilylations of both secondary and tertiary
amides. The reaction proceeded under mild conditions and
kept other sensitive functional groups such as esters, ethers,
double bonds, nitro, nitriles, and azo bonds intact
(Scheme 1).
Results and Discussion
Reduction of tertiary amides using methyldiethoxysilane: In
2009, we discovered a general zinc-catalyzed chemoselective
reduction of tertiary amides using triethoxysilane.[17a] Shortly
after publication we were informed about potential safety
risks of this silane.[18] Although we have never experienced
any safety problems using triethoxysilane during our studies
and it is used on an industrial scale in the silane and silicone
[a] S. Das, Dr. D. Addis, Dr. K. Junge, Prof. Dr. M. Beller
Leibniz-Institut fꢁr Katalyse e.V.
an der Universitꢂt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax : (+49)381-1281-51113
E-mail: matthias.beller@catalysis.de
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FULL PAPER
Reduction
amides using tetramethyldisil-
AHCTUNGERTGoNNUN xane (TMDS): It is well
of
secondary
known that catalytic hydroge-
nations of secondary amides
are more difficult than the re-
duction of tertiary amides.[19]
This reactivity pattern is sim-
ilar for hydrosilylations. Never-
theless, recently Nagashima
and co-workers[4,12] were able
Scheme 1. Selective reduction of amides in the presence of other reducible functional groups.
industry for the production of organofunctional coupling
agents, low-temperature-vulcanizing silicone rubbers and
elastomers, as well as specialty monomers, we looked for
safer alternatives. Among the various silanes tested for the
Zn-catalyzed reduction of N,N-dimethylbenzamide, phenyl
silane, diphenyl silane, and methyldiethoxy silane worked
excellently at 658C. Due to the cheaper price, and with re-
spect to its chemoselectivity, we thought it best to use
to achieve this challenging goal by using ruthenium and
À
platinum catalysts in the presence of silanes with dual Si H
moieties. Their elegant work encouraged us to reconsider
our zinc-catalyzed procedure by using other silanes. Initially,
we investigated N-benzylbenzamide as model substrate for
the reduction of secondary amides (Table 2). To our delight,
moderate activity (40% yield) was observed by applying the
more reactive zinc triflate and 1,1,3,3-tetramethyldisiloxane
(3 equiv) at 658C. Increasing the temperature gave im-
proved yields. Hence, at 1008C, 85% of dibenzyl amine was
obtained with full conversion of the starting material. Nota-
bly, monosilanes such as phenylsilane and diphenylsilane
were significantly less active (10% yield). Methyldiethoxysi-
lane, triethoxysilane, and triethylsilane showed only 2%
yield of the desired product, and in all of the cases we re-
covered only starting material. In contrast to the work of
Nagashimaꢀs group, 1,1,1,3,3-pentamethyldisiloxane and 1,2-
bis(dimethylsilyl)benzene also afforded the product in low
yield (Table 2, entries 10 and 11). This demonstrates that the
sterics and electronics of the disilane are crucial in enforcing
the reduction of secondary amides. It is worth noting that
the optimized catalytic system for the reduction of tertiary
amides was completely unsuccessful for secondary amides
even at higher temperature (1008C). By applying commer-
cially available 1,1,3,3-tetramethyldisiloxane, we investigated
the effect of various metal triflates and zinc sources for the
reduction of N-benzyl benzamide. Clearly, the reaction did
not proceed without any catalyst. Other metal triflates such
methylACHTUNGTRENNUNGdiethoxysilane as the silane of choice for the reduc-
tion of tertiary amides. In fact, by applying a threefold
excess amount of methyldiethoxysilane in the presence of
catalytic amounts of inexpensive zinc acetate in THF, the re-
duction of a plethora of tertiary amides took place with ex-
cellent chemoselectivity (Table 1). A variety of amides, in-
cluding aromatic and heteroaromatic amides, were hydrosi-
lylated smoothly with high yields up to 93%. Electron-with-
drawing substituents (Table 1, entries 3, 5, and 8) at the para
position gave better yields than electron-donating substitu-
ents (entry 10). Steric hindrance on the amine part of the
amide bond had a significant effect and reduced the rate of
reduction. On the other hand, the reaction proceeded well
with aliphatic groups and N-piperidinyl as well as N-cyclo-
pentyl moieties. However, no reaction was observed with
anilides. Heteroaromatic amides were also reduced in excel-
lent yields (entries 15 and 16). Here furan-based amides
were reduced in higher yields than the corresponding thio-
phene derivatives. This is in contrast to our previous reduc-
tion by applying triethoxysilane. Using halide-substituted
benzamides the reactions proceeded with excellent chemo-
selectivity and no other reductive dehalogenation was ob-
served (entries 5–7). Various other functional groups such as
double bonds, nitro, azo, nitrile, ester, and ether were satis-
factorily accepted under our reaction conditions, too (en-
tries 3, 12, 13, 17, 19, and 20). In none of these cases a re-
duction of the respective functional group except the ester
substituent was observed. Notably, the reaction also tolerat-
ed hydroxy groups as well, although it is well known that al-
cohols might react with the silane (entry 18).[6b] On the
other hand, a methylthio substituent and a keto group were
not tolerated under these conditions. In the latter case re-
duction of the ketone took place. Gratifyingly, scale up of
N,N-dimethylbenzamide reaction to 20 mmol-scale resulted
in no problem and produced 90% of the corresponding
amine.
as scandium triflate, iron(II) triflate, ironACHTNUTRGNEUNG(III) triflate, yt-
terbium triflate, and zirconium triflate also did not show any
activity, even at 1008C (Table 3).
However, in the presence of zinc halides (chloride, bro-
mide, and iodide) some activity with up to 20% yield of the
product was observed. On the other hand, zinc fluoride, ace-
tate, and nitrate gave no conversion at all. In all these cases,
we observed only starting material after the reaction. At-
tempted lower catalyst loading of zinc triflate (5–10 mol%)
led to lower yields of the corresponding amine. Appropriate
selection of the solvent is also important in this reductive
hydrosilylation. For example, the reaction becomes sluggish
in the presence of n-butyl ether or 1,4-dioxane, and only
50% of the secondary amine was obtained. To check the in-
fluence of metal contaminants[20] in the precursor, we used
zinc triflate from different suppliers (ABCR, Sigma Aldrich,
Acros, Alfa Aesar), which all provided similar yields.
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M. Beller et al.
Table 1. Zn-catalyzed chemoselective reduction of tertiary amides.
Entry Amides[a]
Amines
Yield[b] [%]
90
Entry Amides[a]
Amines
Yield[b] [%]
89
1
11
2
70
12
91
3
4
5
75
80
92
13
14
15
75
<1
71[c]
6
7
8
93
76
91
16
17
18
60[c]
74
64
9
<1
19
20
50
70
10
70
[a] Reaction conditions: Zn
tained by distillation.
ACHTUNGTERN(NUNG OAc)2 (10 mol%), (EtO)2MeSiH (3 mmol), THF (3 mL), amide (1.0 mmol.). [b] Yield of isolated product. [c] Product ob-
In general, conventional procedures for the reduction of
carboxamides by metal hydrides involve safety problems
due to their sensitivity to air and moisture. In addition,
problems often arise during the purification of the product.
Clearly, mildly hydridic silanes are chemically stable and
easy to handle. Usually they do not require particular pre-
cautions. Indeed, our reaction protocol proceeded smoothly
also on a 10 mmol scale without special precautions. Remov-
al of the resulting siloxane concomitantly produced with the
amine is easily achieved by treatment of the reaction mix-
ture with sodium hydroxide solution followed by aqueous
work up and purification by column chromatography or dis-
tillation. Alternatively, the amine can also be purified by the
conventional acidification followed by basification and aque-
ous workup.
With optimized conditions in hand, the scope and limita-
tions of the zinc triflate-catalyzed reductive hydrosilylation
of secondary amides were explored. Again, a number of
amides including aromatic, heteroaromatic, and aliphatic
amides were smoothly reduced with high yield up to 90%.
Both electron-donating and electron-withdrawing substitu-
ents on the aromatic ring at the para or meta position had
little influence on the yield of the reaction, whereas steric
crowding on both sides of the amide bond has a significant
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Chem. Eur. J. 2011, 17, 12186 – 12192

Chemoselective Reduction
FULL PAPER
Table 2. Reduction of N-benzyl benzamide: effect of the silane.
83% yield (Table 4, entries 8–11). In none of the cases did
we observe any reductive dehalogenated product. Interest-
ingly, the zinc catalyst worked excellently in the case of het-
eroaromatic amides such as furan, thiophene, and benzodi-
hydrofuran (Table 4, entries 16 and 17; Table 5, entry 4). In
addition, araliphatic N-benzyl 3-phenylpropionamide was
reduced in good yields (86%; Table 4, entry 13).
Entry
Hydrosilane ([mmol])
Temperature
Yield[a]
[%]
[8C]
[b]
1
2
3
4
5
6
7
8
9
Me2HSiOSiHMe2 (3)
65
80
90
100
100
100
100
100
100
100
40
53
65
85
10
10
2
2
2
3
[b]
As stated in the Introduction, the chemoselectivity of a
given method is a prerequisite for its implication in organic
synthesis and natural product synthesis. In this regard, the
reduction of amides in the presence of other reducible func-
tional groups is of special importance. Thus, we evaluated
the zinc-catalyzed reduction process by grafting different
functional groups onto different parts of N-benzyl benza-
mide. By positioning these functionalities either at the aryl
or at the amine part of the amide moiety, we minimized
both steric and electronic influence of the functional group
on the reaction. To our delight, without further optimization
nitrile, azo-, double bond-, nitro-, ether-, and ester-substitut-
ed benzamides were well tolerated, thereby providing the
corresponding amines in good to excellent yield (Table 5,
entries 1–4, 6–8, 10, and 11). It should be noted that in all of
the cases no additional reduction of the functional group
was observed, thereby demonstrating the excellent chemose-
lectivity of this reduction process. However, keto and a free
amino group were not tolerated under our reaction condi-
tions. In the former case, reduction of the ketone took place
again. In general, product separation occurred in an easy
manner similar to the tertiary amides. In the case of the
ester-substituted benzamides, the resulting amine was first
converted to the ammonium salt soluble in water due to the
potential hydrolysis problem. This ammonium salt without
contamination of siloxane waste was extracted to the aque-
ous phase, from which the desired amine was easily isolated
by treatment with base.
Me2HSiOSiHMe2 (3)
[b]
Me2HSiOSiHMe2 (3)
[b]
Me2HSiOSiHMe2 (3)
PhSiH3 (2)
Ph2SiH2 (3)
ACHTUNGTRENNUNG
N
[c]
10
11
100
5
[a] GC
yield
with
hexadecane
as
an
internal
standard.
[b] Me2HSiOSiHMe2 =TMDS. [c] Me3SiOSiHMe2 =PMDSO.
Table 3. Reduction of N-benzyl benzamide: effect of different catalysts.
Entry
Catalyst
–
Catalyst loading
[mol%]
Yield[a]
[%]
AHCTUNGTRENNUNG
1
2
3
4
5
6
7
8
–
5
–
8
30
40
85
–
–
–
–
–
Zn
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Sc(OTf)2
Yb(OTf)2
(OTf)2
(OTf)3
(OTf)4
A
E
10
15
20
20
20
20
20
20
20
20
20
20
20
20
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
E
Fe
Fe
U
9
10
11
12
13
14
15
16
Zr
U
ZnF2
ZnCl2
ZnBr2
ZnI2
–
Conclusion
10
20
13
–
In conclusion, we have established the chemoselective re-
duction of tertiary and secondary amides to the correspond-
ing amines with commercially available zinc catalysts and si-
lanes. Safe and simple operational procedures, mild condi-
tions, easy purification methods, and excellent functional
group tolerance make this new method attractive. Due to
the excellent chemoselectivity including functional groups
such as ester, nitrile, ether, double-bond, and azo, we be-
lieve our protocols will be beneficial for organic synthesis
and natural product synthesis without using protecting and
deprotecting steps.
ZnACHTUNGTRENNUNG(OAc)2
ZnN(NO3)2·6H2O
–
[a] GC yield with hexadecane as an internal standard. [b] Reaction runs
for 28 h. [c] After finishing the reaction, the internal standard was added
and the mixture was diluted with THF. After one quick filtration, the
mixtures were subjected to GC.
effect on the product yield. For example, compared to N-
benzyl benzamide the reactivity decreased for N-aryl benza-
mides (Table 4, entry 18). In this case, the reaction needed
significantly longer time (three days) for completion. In
agreement with this, tert-butyl-substituted amides showed
lower reactivity too (up to 68% yield; Table 4, entries 15
and 19). Amides with alkyl substituents either in the aryl or
amine part reacted smoothly (Table 4, entries 2–4, 20, and
21). Furthermore, para-fluoro, chloro-, bromo-, and iodo-
substituted amides gave the corresponding products in 71–
Experimental Section
Typical experimental procedures of the reactions are described. Further
experimental details and spectroscopic data of the compounds are sum-
marized in the Supporting Information.
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M. Beller et al.
Table 4. Zinc-catalyzed reduction of secondary amides.
Entry Amides[a]
Amines
Yield[b]
[%]
Entry Amides[a]
Amines
Yield[b]
[%]
1
80
12
85
2
3
65c
13
14
86
85
60[c]
4
73
15
68
5
80
50
54
83
72
71
80
16
17
18
19
20
21
76[c]
75[c]
70
6
7
8
60
9
72
10
11
56
[a] Reaction conditions: ZnACTHNUTRGNE(UNG OTf)2 (20 mol%), TMDS (3 mmol), toluene (3 mL), amide (1 mmol). [b] Yield of isolated product. [c] Product obtained by
distillation. Bn=Benzyl.
The combined organic layers were dried over anhydrous Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by silica gel column
chromatography by using ethyl acetate/hexane/triethylamine (1%) to
afford the pure desired product.
General procedure for the reduction of tertiary amides: A 10 mL oven-
dried Schlenk tube that contained a stir bar was charged with zinc acetate
(0.1 mmol). Dry THF (2 mL) and methyldiethoxysilane (3 mmol) were
added respectively after purging the Schlenk tube with argon. The result-
ing mixture was stirred for 30 min at 658C. After that, the respective
amide (1 mmol) in dry THF (1 mL) was transferred to the solution under
argon. The mixture was stirred at 658C for 20–30 h and monitored by
TLC. After complete disappearance of the substrates, the reaction mix-
ture was vigorously stirred with NaOH solution (5 mL, 2m) in a 25 mL
conical flask overnight and then extracted with ethyl acetate (3ꢄ5 mL).
General procedure for the reduction of secondary amides: A 25 mL
oven-dried Schlenk tube that contained a stir bar was charged with zinc
triflate (0.2 mmol) and the corresponding amide (1 mmol). Dry toluene
(3 mL) and tetramethyldisiloxane (TMDS) (3 mmol) were added respec-
tively after purging the Schlenk tube with argon. The resulting mixture
was monitored by TLC and stirred at 1008C until the substrates com-
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Chemoselective Reduction
FULL PAPER
Table 5. Zinc-catalyzed reduction of secondary amides: functional group tolerance.
real solution of hydrogen chloride (0.1m, 10 mL; prepared
from commercially available 1m HCl/ether (1 mL) and ether
(9 mL)). The ammonium salt was precipitated as
a white
powder. The supernatant was separated by decantation or cen-
trifugation. This was followed by washing of the residue with
ether to afford silicone residues without contamination. That
was then treated with an excess amount of sodium carbonate
in wet THF at 08C for 0.5–1 h. The solid materials were fil-
tered off, and the desired amine was obtained by concentration
of the filtrate.
Entry Amides[a]
Amines
Yield[b]
[%]
1
75
82
Acknowledgements
2
This work has been funded by the State of Mecklenburg-West-
ern Pomerania, the BMBF, and the DFG (Leibniz Prize). We
thank Ms. Bianca Wendt for excellent technical assistance and
Dr. W. Baumann, Dr. C. Fischer, and Mrs. S. Buchholz (all
LIKAT) for their analytical support.
3
4
5
72
83
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10
11
89
80
[a] Reaction conditions: ZnACTHNUTRGNEUNG(OTf)2 (20 mol%), TMDS (3 mmol), toluene (3 mL),
amide (1.0 mmol). [b] Yield of isolated product. Bn=Benzyl.
pletely went away. After complete disappearance of the substrates, the
reaction mixture was vigorously stirred with NaOH (13 mL, 2m) or KOH
(5 mL, 25%) in MeOH solution in a 50 mL conical flask overnight. It
was then extracted with ethyl acetate (3ꢄ20 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel column chromatography
using ethyl acetate/hexane/triethylamine (1%) to afford the pure desired
product.
Purification method for the amine having ester functional group:[17] After
complete consumption of the starting material, the reaction mixture was
filtered through a pad of florisil, and the filtrate was poured into an ethe-
pp. 111–143.
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Received: April 13, 2011
Revised: July 27, 2011
Published online: September 13, 2011
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