Selective reduction of amides to amines by boronic acid catalyzed hydrosilylation

Article abstract of DOI:10.1002/anie.201304495

Not a 'B'ore! Benzothiophene-based boronic acids catalyze the reduction of tertiary, secondary, and primary amides in the presence of a hydrosilane. The reaction demonstrates good functional-group tolerance. Copyright

Full text of DOI:10.1002/anie.201304495

Angewandte
Chemie
DOI: 10.1002/anie.201304495
Homogeneous Catalysis
Selective Reduction of Amides to Amines by Boronic Acid Catalyzed
Hydrosilylation**
Yuehui Li, Jesffls A. Molina de La Torre, Kathleen Grabow, Ursula Bentrup, Kathrin Junge,
Shaolin Zhou, Angelika Brückner, and Matthias Beller*
Amines constitute important intermediates for the pharma-
ceutical, agrochemical, and chemical industry. Regarding
their preparation, the reduction of carboxamides constitutes
a convenient and straightforward synthetic access.[1] Conven-
tionally, amides have been reduced using aluminum or boron
hydrides,[2] but these protocols show only limited functional-
group tolerance. However, for the efficient construction of
functionalized complex molecules, achieving high chemo-
selectivity is crucial in organic synthesis. For instance, among
the top 20 drugs (based on sales) in 2010, five are amine
derivatives having additional reducible moieties, such as ester
and cyano groups.[3] In contrast to stoichiometric reductions,
catalytic routes offer the possibility to control selectivity by
modifying the catalyst metal and the surrounding ligands. In
this respect, catalytic hydrosilylation has recently become the
method of choice for chemoselective reductions of carbox-
amides. Compared to hydrogenation,[4] a variety of noble-
metal catalysts based on Rh,[5] Ru,[6] Pt,[7] Ir,[8] as well as
others[9–10] can be applied in this transformation.
lane or the Hantzsch ester as reductants.[15] Unfortunately, in
their process stoichiometric amounts of expensive triflic
anhydride has to be used for the activation of the amide.
Since the 1970s it has been well known that hydro-
silylation of carbonyl groups is also promoted by addition of
acids.[16] Based on our recent work on phosphoric acid ester
catalyzed hydrosilylation of phosphine oxides,[17] the combi-
nation of silanes and acids for reductions of amides attracted
our interest. Herein we report the first metal-free chemo-
selective hydrosilylation for the reduction of tertiary, secon-
dary, and primary amides in the presence of boronic acids
(Scheme 1).
Notable recent examples of chemoselective reductions
have been performed even in the presence of inexpensive
Fe[11] or Zn salts.[12] Nevertheless, despite the progress made
none of the known catalytic hydrosilylation methods can
directly reduce all types of amide bonds (tertiary, secondary,
and primary) in the presence of other functional groups such
as ester, nitro, and nitrile groups.[13]
Scheme 1. Direct catalytic reduction of tertiary, secondary, and primary
amides to amines using silanes.
The invention of new types of catalysts might be the key to
solving this problem. Complementary to organometallic
catalysts, metal-free catalysis may allow novel reactivity and
chemoselectivity for the synthesis of functionalized mole-
cules.[14] Interestingly, Charette and co-workers reported the
metal-free reduction of both tertiary and secondary amides
with excellent functional-group tolerance by using triethylsi-
At the start of our investigation the benchmark reduction
of N,N-dimethylbenzamide (1a) with phenylsilane was per-
formed in the presence of a variety of Brønsted acids
(5 mol%). Among the different phosphorous-, carbon-, and
sulfur-based acids, the diarylphosphate 3a and benzenesul-
fonic acid (3d) were found to be slightly active, thus giving
N,N-dimethylbenzylamine (2a) in 12 and 13% yield, respec-
tively (Table 1, entries 2 and 5). To our surprise significantly
improved yields were obtained when boronic acids (BA) were
used as the catalysts. Although these acids have been
extensively applied in modern organic synthesis,[18,19] to the
best of our knowledge their use as catalysts for hydrosilylation
reactions is not known. More than 30 boronic acids were
tested, specifically the benzothiophene-derived boronic acids
3i and 3j were efficient, thus resulting in 61% and 81% yield,
respectively, of the desired amine in the presence of PhSiH3
(Table 1, entries 7–12).[20] Although several boronic acids
showed activity, the yields varied significantly depending on
the structure. Comparison of the activity of 3i with 3j (61%
versus 81%; Table 1, entries 10 and 11), as well as that of 3i
with 3k (61% versus 34%; Table 1, entries 10 and 12),
suggests that both electronic and steric effects are important.
When using other types of silanes as the reductant, lower
[*] Dr. Y. Li, Dr. K. Grabow, Dr. U. Bentrup, Dr. K. Junge,
Prof. Dr. A. Brꢀckner, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V.
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
Homepage: http://www.catalysis.de
J. A. Molina de La Torre
IU CINQUIMA/Quꢁmica Inorgꢂnica, Facultad de Ciencias
Universidad de Valladolid, 47071 Valladolid (Spain)
Prof. Dr. S. Zhou
College of Chemistry, Central China Normal University
Luoyu Road 152, Wuhan, Hubei 430079 (China)
[**] We thank the State of Mecklenburg-Vorpommern and the BMBF for
financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304495.
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Table 1: Acid-catalyzed reduction of amides using silanes.[a]
the reaction (Scheme S4). As shown, TEMPO had no
influence on the reactivity and clearly indicates a nonradical
pathway. When using Ph2SiD2 as a reductant, the desired
deuterated product was obtained in 43% yield, as determined
by NMR spectroscopy, with a D content of greater than
99%.[20]
To get more information on the mechanism of the reaction
between 1a and PhSiH3 with the boronic acid catalyst,
simultaneous in situ ATR-FTIR and UV/Vis spectroscopic
measurements were performed (Figures S3 and S5).
Although these in situ experiments allowed real-time mon-
itoring of the reduction process, the direct mode of action of
the catalyst was not observed. Thus, further experiments were
performed to study the interaction of the boronic acid 3j with
PhSiH3 and 1a individually (see the Supporting Information).
Here, an interaction of the OH group of the boronic acid with
the carbonyl group of the amide through hydrogen bonding
was observed,[21] and might explain the possible activation
mode for the reduction process.
Entry
3
Yield[b] [%]
Entry
3
Yield[b] [%]
1
2
3
4
5
6
7
8
–
n.r.
12
n.r.
3
13
n.r.
22
11
9
10
11
12
3h
3i
3j
3k
3j
3j
3j
3j
48
61
81
34
16
2
3a
3b
3c
3d
3e
3 f
3g
Table 2: The boronic acid 3j catalyzed reduction of tertiary amides.[a]
13[c]
14[c]
15[c]
16[d]
n.r.
69
Entry
1
2
T [8C] Yield[b]
[a] Reaction conditions: 1a (0.5 mmol), 3 (0.025 mmol), silane
(1.2 mmol), toluene (2.0 mL). [b] Determined by GC methods using
n-hexadecane as an internal standard. [c] The silanes for entries 13, 14,
and 15 are Ph2SiH2, TMDS, and Et3SiH, respectively. [d] THFas solvent in
a sealed tube. n.r.=no reaction.
[%]
1
2
1a
1b
2a 110
88
75
2b 110
2c 110
yields were obtained (Table 1, entries 13–15). Notably, the
reactivity also decreased when polar solvents such as THF or
1,4-dioxane were used (Table 1, entry 16; see Table S1 in the
Supporting Information).
3
1c
80
From a mechanistic point of view it is interesting to note
that the (benzo)thiophene moiety of the catalyst significantly
contributes to the high reactivity. However, the use of
benzothiophene (4a) as the catalyst resulted in no reaction.
To prove that catalysis is promoted by the boronic acid and
not by trace amounts of transition metals, boronic acids from
different suppliers were tested and showed no difference in
reactivity (see Schemes S1 and S2). Meanwhile, NMR experi-
ments were carried out for the reduction of 1a in the presence
of 2.4 equivalents of PhSiH3 and 20 mol% of the boronic acid
3i. While the original 11B NMR signal of 3i (d = 26.2 ppm)
disappeared, two new peaks having chemical shifts of d =
19.4 ppm (major) and d = 1.6 ppm (minor) are formed during
the reduction process, thus demonstrating reaction of the
boronic acid. To further understand the role of boron,
4
1d
1e
1 f
2d 110
2e 130
2 f 130
2g 110
70
99
96
86
5
6[c]
7
1g
8
1h
1i
2h 130
2i 130
2j 110
77
82
72
compounds having
a
B(O-C)2 (4b), B(O-C)3 (4c),
9
B(O-C)2Si (4d), or B(O-Si)3 (4e) structure were tested for
reduction of 1a, and all showed no reactivity, even in the
presence of 4a (see Table S2). Hence, the possible silylated
species having a B-O-Si moiety is not likely to be responsible
for the catalysis.
10[c]
1j
[a] Reaction conditions: 1 (0.5 mmol), PhSiH3 (1.2 mmol), toluene
(2.0 mL), 110–1308C, 36 h. [b] Yield of the isolated product. [c] Yield
To exclude the possibility of radical reactions, 2,2,6,6-
tetramethyl-1-piperidinyloxy radical (TEMPO) was added to
determined by GC methods using n-hexadecane as an internal standard.
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With good results in hand for the reduction of our
benchmark substrate dimethylbenzamide, the reactivity of
other tertiary amides was studied in the presence of 3j under
the optimized reaction conditions (Table 2). When aromatic
amides were used, the desired products were obtained in 70–
99% yield (Table 2, entries 1–7). Especially high reactivity is
observed when the aryl group is substituted with electron-
donating groups, thus giving the corresponding products in
70–99% yield (Table 2, entries 4 and 5). Though the reactivity
was strongly diminished for sterically hindered substrates
under our standard reaction conditions, excellent yields were
obtained when the temperature was simply increased to
1308C (Table 2, entries 5 and 6). Notably, aliphatic N-acyl
amino esters and a lactam were also hydrosilylated in good
yields (Table 2, entries 8–10). From a synthetic point of view it
is interesting to note that other reducible groups such as nitro,
cyano, and ester moieties are well tolerated, something which
is not possible for reductions employing organometallic
hydrides.
Next, the reduction of less-reactive secondary amides was
investigated. To our delight, good yields of the corresponding
amines were obtained by increasing the catalyst loading to
20 mol% at 1308C (Table 3). Similar to the reduction of
tertiary amides, aromatic and aliphatic secondary amides, as
well as heterocyclic substrates were hydrosilylated with good
to excellent selectivity.
Finally, we were interested in the hydrosilylation of the
more challenging primary amides. Unlike tertiary and secon-
dary amides, the arylboronic acid 3i proved to be a better
catalyst for the direct reduction. Nevertheless, in the presence
of 20 mol% of 3j the reduction of benzamide gave only 17%
resulted from a known dehydration process.[22] However,
benzamide is reduced to benzylamine in 39% yield with 51%
benzonitrile in the presence of 20 mol% of 3i. Gratifyingly,
even better selectivity is achieved when 30 mol% of 3i was
used. Here, full conversion and mediocre to good yields for
aromatic amines were obtained for different aromatic sub-
strates (Scheme 2).[23]
Scheme 2. The boronic acid 3i catalyzed transformation of primary
amides into primary amines.
In conclusion, we have developed a general organocata-
lytic hydrosilylation of amides. For the first time, catalytic
reduction of tertiary, secondary, and primary amides to the
corresponding amines is possible without any metal present.
By applying a commercially available and air- and moisture-
tolerant boronic acid as the catalyst, this convenient method-
ology allows a clean and straightforward synthesis of amines
with good functional-group tolerance.
yield of desired benzyl amine and 70% of benzonitrile, which Experimental Section
General procedure for catalytic hydrosilylation: A 30 mL
dried sealable tube containing a stirring bar was charged
with 3j (6.4 mg, 0.025 mmol) and the corresponding amide
(0.5 mmol). Under an Ar flow, dry toluene (2 mL) and
PhSiH3 (150 mL, 1.2 mmol) were added, and the mixture
was stirred at 110 or 1308C for 24–40 h. The yield is
determined by GC using n-hexadecane as an internal
standard without workup. To obtain the yield of the
isolated product, 2n NaOH (aq, 3 mL) was slowly added to
the reaction mixture followed by vigorous stirring for 3 h at
room temperature. The mixture was then extracted using
ethyl acetate and the organic phase was dried by Na2SO4
and concentrated. The residue was purified by silica gel
column chromatography (for aromatic amines, it is eluted
with n-pentane/EtOAc from 100:0 to 50:50; for aliphatic
amine products, silica gel was neutralized by 5% of Et3N in
pentane, eluting with n-pentane/EtOAc from 100:0 to
70:30).
Table 3: The boronic acid 3j catalyzed reduction of secondary amides to secondary
amines.[a]
Entry
1
2
Yield[b]
[%]
1[c]
1k
1l
2k
2l
84
67
2[c]
3
4
1m
1n
2m
2n
89
52
Received: May 24, 2013
Revised: August 9, 2013
Published online: && &&, &&&&
5
1o
1p
2o
2p
60
41
Keywords: amides · boron · homogeneous catalysis ·
.
6[c]
organocatalysis · reduction
[a] Reaction conditions: 1 (0.5 mmol), 3j (0.1 mmol), PhSiH3 (1.2 mmol), toluene
(2.0 mL) at 1308C; reaction time for entries 1 and 2 is 24 h and for entries 3–6 is
40 h. [b] Yield of the isolated product. [c] Yield determined by GC methods using
n-hexadecane as an internal standard.
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Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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4
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Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Homogeneous Catalysis
Not a ‘B’ore! Benzothiophene-based
boronic acids catalyze the reduction of
tertiary, secondary, and primary amides in
the presence of a hydrosilane. The reac-
tion demonstrates good functional-group
tolerance.
Y. Li, J. A. Molina de La Torre, K. Grabow,
U. Bentrup, K. Junge, S. Zhou,
A. Brꢁckner, M. Beller*
&&&& — &&&&
Selective Reduction of Amides to Amines
by Boronic Acid Catalyzed Hydrosilylation
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!