Iridium-catalyzed reduction of secondary amides to secondary amines and imines by diethylsilane

Article abstract of DOI:10.1021/ja304547s

Catalytic reduction of secondary amides to imines and secondary amines has been achieved using readily available iridium catalysts such as [Ir(COE) ₂Cl]₂ with diethylsilane as reductant. The stepwise reduction to secondary amine proceeds through an imine intermediate that can be isolated when only 2 equiv of silane is used. This system requires low catalyst loading and shows high efficiency (up to 1000 turnovers at room temperature with 99% conversion have been attained) and an appreciable level of functional group tolerance.

Full text of DOI:10.1021/ja304547s

Communication
pubs.acs.org/JACS
Iridium-Catalyzed Reduction of Secondary Amides to Secondary
Amines and Imines by Diethylsilane
Chen Cheng and Maurice Brookhart*
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
S
* Supporting Information
Table 1. Catalyst Screening Experiments for Reduction of 1a
ABSTRACT: Catalytic reduction of secondary amides to
imines and secondary amines has been achieved using
readily available iridium catalysts such as [Ir(COE)2Cl]2
with diethylsilane as reductant. The stepwise reduction to
secondary amine proceeds through an imine intermediate
that can be isolated when only 2 equiv of silane is used.
This system requires low catalyst loading and shows high
efficiency (up to 1000 turnovers at room temperature with
99% conversion have been attained) and an appreciable
level of functional group tolerance.
silane
a
entry
catalyst (mol%)
(equiv)
solvent time (h) yield (%)
1
2
3
4
5
6
7
8
9
[Ir(COE)2Cl]2 (0.5)
[Ir(COE)2Cl]2 (0.5)
[Ir(COE)2Cl]2 (1)
[Ir(COE)2Cl]2 (0.5)
Et2SiH2 (4) C6D6
12
11
22
7
98
98
80
98
85
99
33
Et2SiH2 (4) CD2Cl2
Et2SiH2 (4) THF-d8
b
Et2SiH2 (4)
−
[Ir(COD)(OMe)]2 (0.5) Et2SiH2 (4) C6D6
14
12
9
[Ir(COD)Cl]2 (1)
[Rh(COE)2Cl]2 (1)
[Ir(COE)2Cl]2 (0.5)
[Ir(COE)2Cl]2 (0.5)
Et2SiH2 (4) C6D6
Et2SiH2 (4) C6D6
Et3SiH (4) C6D6
eduction of carboxamides is an attractive route to amines.1
R
Although amides are the least reactive species among
carbonyl compounds toward hydride addition, reduction of
amides to amines can be achieved using stoichiometric metal
hydride reducing agents such as LiAlH4.2 However, these
reagents suffer from drawbacks such as limited functional group
tolerance and air and moisture sensitivity.3 Alternative methods
include metal-free reduction of tertiary and secondary amides
with high chemoselectivity using triflic anhydride as the
activating reagent and both triethylsilane and Hantzsch ester
as hydride sources.4 Catalytic reduction of tertiary amides has
been achieved using various metal catalysts and hydrosilanes as
the reductant.5 Catalytic reduction of secondary amides to
secondary amines, however, has not been extensively explored.6
For example, Nagashima reported a ruthenium cluster catalyst
that produces either secondary or tertiary amines depending on
the silane used.6c Beller has described a method using readily
available zinc catalysts at high catalyst loading (20 mol%).6d
Ohta also reported reduction of a limited number of secondary
amides with Rh(I) catalysts to give a mixture of amines and
imines in moderate yields.6a Recently we reported a highly
efficient iridium pincer catalyst for reduction of tertiary
amides,5i but the same system cannot be applied to secondary
amides. Here we report catalytic reduction of secondary amides
to either imines or secondary amines with high efficiency using
a commercially available iridium complex, [Ir(COE)2Cl]2.
Since several group 8 and 9 metal complexes are known to
catalyze addition of hydrosilanes across CO double
bonds,5a,6a,c,7 we investigated the catalytic reactivity of some
simple rhodium and iridium complexes with respect to hydro-
silylation of N-methylbenzamide (1a). Using Et2SiH2 (4 equiv)
and [Ir(COE)2Cl]2 (0.5 mol %) at room temperature in nonpolar
solvents such as C6D6 or CD2Cl2, 1a was converted to imine 2a in
5 min and subsequently to amine 3a within 12 h (Table 1, entries
1 and 2). Hydrogen evolution was observed upon mixing the
c
34
48
−
d
c
TMDS (2) C6D6
−
Reaction conditions: catalyst in 0.35 mL of solvent with 0.1 mmol of
N-methylbenzamide and silane. Reactions were run at room
a
b
temperature. Yield of 3a determined by 1H NMR. Run in neat
c
d
silane. Unidentified product. Tetramethyldisiloxane.
reagents and confirmed by GC analysis. Coordinating solvents
such as THF inhibit the reaction (entry 3). Other iridium(I) bis-
olefin complexes showed similar or lower reactivities (entries 5
and 6). One rhodium analogue was screened but proved
ineffective (entry 7). Using tertiary silanes such as Et3SiH or tetra-
methyldisiloxane led to an unidentified product (entries 8 and 9).
Although most secondary amides have limited solubility in
Et2SiH2, rapid conversion to the much more soluble imines
allows running the reaction in neat silane (Table 1, entry 4).
Applying this condition to various secondary amides gave the
corresponding N-silyl amines (Table 2). Aqueous HCl workup
followed by neutralization afforded secondary amines 4 in good
to excellent yields. This method is compatible with substrates
bearing various functionalities including aryl halides, alkyl
halides, ethers, heterocycles, azo and amino groups, and alkenes.
High catalytic efficiencies were achieved; for example, turnovers up
to 1000 at room temperature with 99% conversion were recorded
for 1b (entry 2). This system is not compatible with nitro groups
and the catalytic rate is severely retarded by nitrile groups.
Reaction with nitro-substituted 1i led to unidentified products,
whereas reaction with nitrile-containing 1h resulted in full
conversion to the imine but only low conversion (24%) to the
amine after 50 h.8 Reduction of amide 1s bearing a bulky tert-butyl
Received: February 5, 2012
Published: July 6, 2012
© 2012 American Chemical Society
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Communication
substrates bearing heteroatoms, the reactions were slow at
room temperature probably due to the coordinating effect of O,
N, S, and halides, and the reactions were run at 80 °C to
achieve rapid conversion.
Table 2. Reduction of Secondary Amides to Secondary
Amines
To investigate the resting state of the catalyst, [Ir(COE)2Cl]2
was treated with ∼100 equiv of Et2SiH2 in C6D6. Immediately
after mixing of the reagents at room temperature, a major
hydride signal at −12.98 ppm was observed, together with two
low-field signals at 131.86 and 130.27 ppm in the 29Si NMR
spectrum, suggestive of a silylene-bridged iridium dimer 6
formed via intermediate 5 (Scheme 1).10 In contrast to our pre-
Scheme 1. Formation of the Proposed Catalyst Resting State
vious report in which [Ir(COE)2Cl]2 was reacted with Et3SiH,
the chloride-bridged dimer 5 was not observed in this case.10
With time, the major hydride signal at −12.98 ppm decreased
in intensity and multiple hydride signals in the −11 to −14 ppm
region appeared, which is likely caused by silane scrambling
catalyzed by 6 (Scheme 1).10 Although a single crystal of 6 could
not be obtained, a model complex, 6′,11 derived from (tBu)2SiH2
was characterized by X-ray crystallography (Figure 1). While the
Figure 1. ORTEP drawing of 6′ at the 50% probability level. The
molecule lies on a center of symmetry. Selected bond lengths (Å) and
angles (deg): Ir(1)−Si(1) 2.408, Ir(1)−Ir(1′) 2.896, Ir(1)−Si(2)
2.410; Si(1)−Ir(1)−Si(2) 133.4, Ir(1)−Si(2)−Ir(1′) 73.2, Si(2)−
Ir(1)−Si(2′) 106.7. Hydrogen atoms were omitted for clarity.
Reaction conditions: amide (1.0 mmol) with 4.5 mg (5.0 μmol) of
[Ir(COE)2Cl]2 in 350 mg (4.0 mmol) of Et2SiH2. Reactions were run at
a
b
1
room temperature or 80 °C. Determined by H NMR. Yields of 3
determined by 1H NMR. Numbers in parentheses are isolated yields of
4. Reaction run on a 5.0 mmol substrate scale with 2.5 μmol (0.05
mol%) of catalyst (0.1 mol% Ir). Reaction run on a 0.1 mmol
c
d
substrate scale in 0.35 mL of C6D6 in the presence of 0.1 mmol of
benzyl bromide. At the end of the reaction benzyl bromide remained
iridium hydrides in Scheme 1 are shown as terminal hydrides
they could not be located by X-ray diffraction, so bridging
hydride structures cannot be ruled out, nor can binding of the
terminal silanes in an η2-fashion.12 The short Ir−Ir distance
(2.896 Å) suggests significant Ir−Ir interaction.13
We propose that 6 catalyzes reduction of amides by con-
secutive hydrosilylations across the CO and CN bonds
(Scheme 2).14 Following the first hydrosilylation of the CO bond
that yields the hemiaminal, elimination of silanol gives the imine.15
e
f
unreacted. C6H6 (0.5 g) was added as cosolvent. Reaction run on a
g
0.1 mmol substrate scale in 0.35 mL of C6D6. Unidentified products.
h
i
j
Product is somewhat volatile. Product isolated as the HCl salt. 6 mg
(0.6 mol%) of Et3NH+BArF− was added at 3 h.
group requires a catalytic amount of an acid, Et3NH+BArF−
9
−
(BArF− = B[3,5-(CF3)2C6H3]4 ), as additive. For some
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Journal of the American Chemical Society
Communication
In summary, we report a highly efficient method for catalytic
reduction of secondary amides to imines and secondary amines
using diethylsilane as reductant. Side products are minimal and
high efficiencies have been achieved. The simple preparation of
the catalysts, mild reaction conditions, simple product isolation,
and tolerance toward many functional groups render this system
an attractive route for accessing secondary amines, imines, and
aldehydes from secondary amides.
Scheme 2. Proposed Mechanism for Iridium-Catalyzed
Reduction of Secondary Amides to N-Silylamines
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, product characterization, and crys-
tallographic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
Complex 6 then catalyzes the addition of a second equivalent of
silane across the imine CN bond to give the N-silyl amine. In
both steps the hydrosilylation is proposed to proceed by
electrophilic addition of “Et2SiH+ ” followed by hydride attack
at carbonyl carbon, supported by competition experiments
showing that the electron-deficient substrate 1g reacts much
slower than 1b (see Supporting Information). Following
hydrosilylations, oxidative addition of Et2SiH2 to the iridium
center regenerates the iridium silyl hydride moiety.
Because of the stepwise nature of the amide reduction and
the large rate difference between the two hydrosilylations, imines
can also be directly accessed by using 0.1 mol% of [Ir(COE)2Cl]2
and exactly 2 equiv of Et2SiH2 at room temperature (Table 3).16
AUTHOR INFORMATION
■
Corresponding Author
mbrookhart@unc.edu
Notes
The authors have submitted a provisional patent on this work.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support of the NSF as
part of the Center for Enabling New Technologies through
Catalysis (CENTC, Grant No. CHE-0650456).
REFERENCES
■
Table 3. Reduction of Secondary Amides to Imines
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[Ir(COE)2Cl]2 (1.0 μmol) and Et2SiH2 (2.0 mmol). Reactions were
a
1
run at room temperature. Determined by H NMR. Numbers in
b
parentheses are isolated yields of 2. Reaction run on a 0.1 mmol
substrate scale in 0.35 mL of C6D6.
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Journal of the American Chemical Society
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(9) Without the acid co-catalyst, the reduction stopped at the imine
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t
(11) Prepared by treating [Ir(COE)2Cl]2 with 15 equiv of Bu2SiH2
in C6D6. 6′ is poorly soluble in pentane, C6D6, CD2Cl2, or THF and
readily precipitates out of solution as red crystals.
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which suggests an η1 Ir−Si bond in 6′. See: (a) Rappoli, B. J.; Janik,
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(14) Complex 6 is stable for hours at room temperature but degrades
to unknown complexes upon warming. We have assumed that 6 is the
resting state, but it is quite possible that a further reaction product of 6
is the true active hydrosilylation catalyst, especially in reactions run at
80 °C.
(15) Since H2 is formed, it appears that the iridium complex catalyzes
the reaction of the silanol with silane to produce siloxane (an observed
product) and H2. These products could also result from transfer of
“Et2SiH+ ” to the hemiaminal, promoting the loss of silanol and
forming siloxane and an iminium ion which reacts with the resultant
[IrH]− to form H2 and imine.
(16) A small fraction of over-reduction to the amines can occur for
some substrates and appears to be caused by further reduction of the
imines by the byproduct of the amide reduction, (Et2HSi)2O.
Optimization of the reaction time and catalyst loading can avoid or
minimize over-reduction.
(17) Adding additional Et2SiH2 resulted in hydrosilylation of both
the imine and ester.
NOTE ADDED AFTER ASAP PUBLICATION
■
After this paper was published ASAP on July 6, 2012, the note
in the Author Information section was amended. The corrected
version was posted July 18, 2012.
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