Lithium compound catalyzed deoxygenative hydroboration of primary, secondary and tertiary amides

Article abstract of DOI:10.1039/d1dt00364j

A selective and efficient route for the deoxygenative reduction of primary to tertiary amides to corresponding amines has been achieved with pinacolborane (HBpin) using simple and readily accessible 2,6-di-tert-butyl phenolate lithium·THF (1a) as a catalyst. Both experimental and DFT studies provide mechanistic insight. This journal is

Full text of DOI:10.1039/d1dt00364j

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Lithium compound catalyzed deoxygenative
hydroboration of primary, secondary and tertiary
amides†‡
Cite this: Dalton Trans., 2021, 50,
2354
Received 1st February 2021,
Accepted 5th February 2021
Milan Kumar Bisai,a,b Kritika Gour,a,b Tamal Das,b,c Kumar Vanka b,c and
a,b
DOI: 10.1039/d1dt00364j
Sakya S. Sen
*
rsc.li/dalton
A selective and efficient route for the deoxygenative reduction of complex for amide hydroboration under ambient conditions.5
primary to tertiary amides to corresponding amines has been Lohr and Marks reported La[N(SiMe3)2]3 catalyzed deoxygena-
achieved with pinacolborane (HBpin) using simple and readily tive reduction of secondary and tertiary amides with HBpin,6
accessible 2,6-di-tert-butyl phenolate lithium·THF (1a) as a catalyst. but reduction does not occur with the acetamide and benz-
Both experimental and DFT studies provide mechanistic insight.
amide. Nonetheless, Findlater and coworkers have recently
shown that La4O(acac)10 can hydroborate 1°, 2° and 3°
amides.7 Mandal and coworkers have also shown that the com-
bination of an abnormal N-heterocyclic carbene and a potass-
ium complex serve as an efficient cooperative catalyst for the
hydroboration of a broad range of primary amides with
HBpin.8a Likewise, Yao and coworkers reported a combined
KOtBu/BEt3 catalyst for the hydroboration of primary to tertiary
amides.8b
Lithium compounds are emerging as molecular catalysts,
thanks to significant breakthroughs that have recently
emerged from the groups of Okuda,9–11 Mulvey,12,13
Wangelin14 and others15 for the hydroboration of aldehydes,
ketones, nitriles, and other organic substrates. We have been
Reduction of amide to amine is a very important transform-
ation because (a) amides are readily available as precursors
and (b) amines are essential building blocks in the synthesis
of many pharmaceuticals, natural products, and agrochem-
icals.1 The electrophilicity of the amide carbonyl group is con-
siderably lower than that of aldehydes and ketones, which
makes the reduction of amides a challenging task. A variety of
noble and non-noble metal based catalysts have been devel-
oped for the catalytic hydrosilylation of amides to amines.2
However, dwindling noble metal reserves and their skyrocket-
ing prices have led to significant focus on the development of
compounds containing main group elements as homogeneous
catalysts driven by their high terrestrial abundances and low
cost. Meanwhile, the synthetic usefulness of hydroboration
has been demonstrated for the chemoselective reduction of
aldehydes, ketones, pyridines, alkenes, alkynes and nitriles by
compounds with main-group elements.3 However, the develop-
ment of catalytic hydroboration for the reduction of amides to
amines remains cursory and mainly limited to only secondary
and tertiary amides (Scheme 1). The reduction of primary
amides to amines groups is more difficult than that of second-
ary and tertiary amides. Sadow and coworkers reported the
catalytic reduction of amides by HBpin using a magnesium
compound.4 Panda and coworkers prepared an aluminum
aInorganic Chemistry and Catalysis Division, CSIR-National Chemical Laboratory,
Dr Homi Bhabha Road, Pashan, Pune 411008, India. E-mail: ss.sen@ncl.res.in
bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
cPhysical and Material Chemistry Division, CSIR-National Chemical Laboratory,
Dr Homi Bhabha Road, Pashan, Pune 411008, India
†Dedicated to Professor Herbert W. Roesky on the occasion of his 85th birthday.
‡Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1dt00364j
Scheme 1 Previous approaches towards the hydroboration of amides
to amines using single-site/combined catalysts involving main-group
elements/lanthanides and the development of our strategy.
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actively developing convenient methods for hydroboration of
aldehydes, ketones, imines.16–18 We have demonstrated the
use of readily accessible lithium compounds 2,6-di-tert-butyl
phenolate lithium·THF (1a) and 1,1′-dilithioferrocene·TMEDA
(1b) as catalysts for the reduction of aldehydes, ketones,
alkenes, and alkynes.19,20 Herein, we report single-site chemo-
selective hydroboration of 1°, 2° and 3° amides using HBpin
in the presence of 1a. However, a mixture of product formation
was observed with 1b.
A systematic study was carried out for the optimization of
the catalytic reduction using benzamide as a model substrate
with HBpin (see ESI, Table S1‡). In the absence of any solvent,
the reaction of benzamide (1 equiv., 0.25 mmol) and HBpin
(4.5 equiv., 1.12 mmol) at 60 °C for 18 h in the presence of 1a
(5 mol%) afforded 87.0% of the corresponding borylamine
(see entry 9, Table S1 in the ESI‡). Although quantitative con-
version of benzamide to the corresponding borylamine is
achievable in the presence of 5 equiv. HBpin (entry 10), we
have chosen entry 9 as the optimized condition to examine the
electronic influence of the substituents. LiOtBu, LiCl, LiOPh
and LiN(SiMe3)2 were also employed as the catalysts for com-
parison and afforded 68%, 48%, 45% and 66.5% yield, respect-
ively for the hydroboration of benzamide in 18 h (see ESI,
Scheme 2 Lithium compound catalyzed hydroboration of primary
amides. Reaction conditions: Amide (0.25 mmol), HBpin (1.12 mmol, 4.5
equiv.), 5.0 mol% catalyst, 18 h reaction at 60 °C temperature in neat.
Yields were determined by the 1H NMR integration relative to mesitylene
as an internal standard.
Table S1,‡ entries 11–14). Note that, the same reaction under yields. Conjugated amides such as acrylamide (2r) undergo
catalyst free conditions produces only 55.0% yield in 20 h (see hydroboration in both the functional groups and form the
ESI, Table S1,‡ entry 15). Subsequently, the scope of the reac- same product as obtained from 2o. However, in addition to
tion was tested with a range of aromatic and aliphatic primary amide hydroboration (45.0% yield), reduction of both cyano
amides, and the corresponding borylated products were and amide functionality was also observed for 2s, with 22.0%
obtained in good to excellent yields (Scheme 2). Some of the yield.
corresponding borylated amines were converted to the corres-
With good results in hand for the reduction of primary
ponding primary amines and isolated as their hydrochloride amides, the reactivity of secondary and tertiary amides was
salts upon hydrolysis and acidification. Smooth hydroboration studied in the presence of 1a under the optimized reaction
was observed for the different aromatic amides with electron conditions (Schemes 3 and 4). Here, N-methylbenzamide and
donating or withdrawing substituents at the o/m/p position N,N-dimethyl benzamide were employed as substrates for the
(2a–2j). Under the optimized conditions, aromatic amides optimization of secondary and tertiary amide hydroboration
bearing electron-donating functional groups (Me, OMe, Ph, respectively (see ESI, entry 6, Table S3 and entry 6, Table S5‡
and I) provide better conversion compared to electron-with- respectively). Similar to primary amide hydroboration, second-
drawing groups (F and NO2). The catalyst shows very good tol- ary amides also deoxygenated to secondary amines with sub-
erance towards the functional groups such as halogens (2f–2i), sequent release of dihydrogen in the presence of three equiva-
as well as alkoxy (2b and 2e) and nitro (2j) containing sub- lents of HBpin. Both aromatic and aliphatic N-alkyl or N-aryl
strates. Both electronic and steric influences was reflected on substituted secondary amides (3a–3h) underwent hydrobora-
the moderate conversion of 2,6-difuorobenzamide (2g), and tion smoothly and formed the corresponding borylated sec-
perfluorobenzamide (2h). No product formation was observed ondary amines in good to excellent yields. Cyclic secondary
for the pyridine containing substrate such as nicotinamide (2t) amides, such as ε-caprolactam (3g), provide the corresponding
and 3-bromo nicotinamide (2u), probably due to the coordi- borylated amine in good yield without suffering any
nation of the pyridine lone pair with HBpin.
polymerization.
It is of note here that the hydroboration of the aliphatic
The methodology works smoothly for the hydroboration of
amides is also very important, as the aliphatic amines rep- tertiary amide substrates as well. The slight excess of HBpin
resent a privileged class in drug molecules. Herein, we (4.5 equiv.) and longer reaction time (21 h) was found necess-
employed the standard reaction conditions for the aliphatic ary to obtain good conversion over the selected temperature
amides bearing aromatic moiety such as 2-(naphthalen-1-yl) range and this was also noted by the groups by Lohr and
acetamide (2k) and 2-phenylacetamide (2l), and for both the Marks.6 In comparison to primary or secondary amides, mod-
cases, almost quantitative conversion of their corresponding erate to good conversion was achieved for all five tertiary
borylated amines was observed. Furthermore, the cyclic (2m) amides (4a–4e), probably due to greater steric around the nitro-
and short to long chain aliphatic amides (2n–2q) were also gen center. It is fair to mention here that selective formation
tested and all of them afforded the desired products in good of corresponding amine products was observed for all the sub-
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10 mol% TMEDA. Formation of the corresponding borylated
amine with 73.0% yield for the benzamide substrate suggests
negligible or low influence of BH3 in catalysis (see ESI,
Scheme S4‡). Notably, although the evolution of molecular
dihydrogen was observed for the non-catalytic reaction of
benzamide and HBpin, the evolution was rapid in the pres-
ence of the catalyst and it was monitored by 1H NMR reso-
nance at δ 4.48 ppm (see ESI, Scheme S2‡).7 Furthermore, the
formation of N-borylated imine (Int-5) was detected with a
1
sharp resonance in the H NMR at δ 10.20 ppm, when hydro-
Scheme 3 Scope of hydroboration with secondary amides. Reaction
conditions: Amide (0.25 mmol), HBpin (0.75 mmol, 3.0 equiv.), 5.0 mol%
catalyst, 18 h reaction at 60 °C temperature in neat.
boration was carried out at room temperature in toluene, or
by ceasing the standard heating reaction after 1 h (see ESI,
Scheme S3‡).7
Full quantum chemical calculations were done with density
functional theory (DFT) at the dispersion corrected PBE/TZVP
level of theory in order to understand the mechanism
(Scheme 5 in the manuscript and Fig. S88 in the ESI‡) of the
primary amide hydroboration reaction in the presence of cata-
lyst 1a.
In the first step of the reaction, a weakly bound complex
(Int-1) is formed between catalyst 1a and HBpin, with one of
the oxygen atoms of HBpin approaching towards the lithium
atom of 1a and making a weak coordinate bond. The first step
of the mechanism is same as those reported for aldehyde,
alkene or alkyne hydroboration.19,20 The reaction energy (ΔE)
Scheme 4 Scope of hydroboration with tertiary amides. Reaction con-
ditions: Amide (0.25 mmol), HBpin (1.12 mmol, 4.5 equiv.), 5.0 mol%
catalyst, 21 h reaction at 60 °C temperature in neat.
strates except N,N-dimethyl benzamide (4c), which produces and the Gibbs free energy (ΔG) for this step are −11.5 kcal
both C–O and C–N bond cleavage product in 76.0% and 24.0% mol−1 and −0.7 kcal mol−1, respectively. We cannot ignore the
yield, respectively.
possibility of the binding of amide oxygen with the lithium
We have performed a series of stoichiometric reactions to atom of 1a, which would lead to the formation of Int-1′. The
gain mechanistic insight into primary amide hydroboration corresponding reaction free energy for this step is favourable
with 1a. In the stoichiometric reaction of 1a with benzamide by 12.8 kcal mol−1. Now, in the next step, either benzamide
in CDCl3, a possible formation of Int-1′ was observed at room approaches the B–H bond of Int-1 and makes a four-mem-
1
temperature, as indicated by H NMR spectroscopy. However,
monitoring the reaction between 1a and HBpin in toluene-d8
showed a new set of resonance signals in 11B NMR at
δ 4.7 ppm, indicating the formation of an intermediate
(Int-1)19,20 along with a singlet at δ 21.6 and a quintet at
−
−39.8 ppm for a trialkoxyborane and BH4 anion, respectively.
In addition, a singlet at δ 86.9 and a quartet at −25.4 ppm
were also observed, probably due to the decomposition of
HBpin and the Lewis base·BH3 adduct.21,22 Upon filtration of
a white precipitate formed after 3–4 h, the filtrate part showed
only three peaks at δ 4.7, 21.6 and −39.8 ppm in the 11B NMR
spectrum. The elimination of LiH would lead to the formation
of both trialkoxyborane and LiBH4, which was also observed
by Thomas,21,22 Clark and coworkers.23 However, due to the
very high lattice energy and poor solubility, the involvement
of LiH in the catalytic activity is very unlikely, which was also
noted by the groups of Mulvey,12 Thomas and Cowley.24
Another set of reactions involving 1a, HBpin and benzamide
in toluene-d8 showed a broad resonance at δ 3.8–3.5 ppm in
11B NMR, indicating the possible formation of Int-2 with the
Scheme 5 The catalytic cycle and reaction mechanism for the benz-
amide hydroboration by catalyst 1a, calculated at the PBE/TZVP level of
theory with density functional theory (DFT). ΔG and ΔG# represent the
evolution of molecular dihydrogen. Also, to identify whether
BH3 was involved in hidden catalysis, as it may form by the
decomposition of HBpin for the amide hydroboration,21,22 we
have carried out the same reaction in the presence of in kcal mol−1
Gibbs free energy of reaction and the barrier, respectively. All values are
.
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bered transition state TS-1 involving N⋯H⋯H⋯B atoms where setting up a platform for the HBpin to offer its B–H bond to
H2 evolution takes place leading to the formation of Int-2 with the unsaturated amide functionality.
the free energy of activation barrier 36.2 kcal mol−1, or HBpin
approaches towards the N–H bond of Int-1′ and similarly
makes
a
four-membered transition state TS-1′ involving Conflicts of interest
N⋯H⋯H⋯B atoms, where H2 extrusion occurs, leading to Int-
2. The barrier for this step was calculated to be 41.3 kcal mol−1
(shown in red in Scheme 5). During the experiments, we have
observed the bubbling of H2 gas in the initial phase of the
reaction. Therefore, from our DFT calculations, we have
excluded the H2 evolution pathway via TS-1′ due to the high
energy barrier, which cannot be achieved under the reaction
conditions. As the reaction proceeds through the TS-1 pathway,
in the next step, another molecule of HBpin comes towards
the carbonyl group of Int-2. This is the prelude to the nucleo-
philic attack by the oxygen atom of the carbonyl group to the
boron atom of HBpin, with the hydride being transferred to
the carbonyl carbon atom of Int-2. This occurs through a four-
membered transition state (TS-2) and leads to the formation of
There are no conflicts to declare.
Acknowledgements
Science and Engineering Research Board (SERB), India (CRG/
2018/000287) and Council of Scientific and Industrial
Research (YSA000726) (SSS) are acknowledged for providing
financial assistance. MKB, KG and TD thank CSIR, India for
their research fellowships. The support and the resources pro-
vided by ‘PARAM Brahma Facility’ under the National
Supercomputing Mission, Government of India at the IISER
Pune are gratefully acknowledged.
Int-3. The Gibbs free energy for this step is −12.8 kcal mol−1
,
i.e., the step is thermodynamically favourable. The activation
free energy (ΔG#) barrier corresponding to the transition state
is 32.7 kcal mol−1. Furthermore, the elimination of Bpin-
O-Bpin from Int-3 leads to the formation of the important
intermediate imine (Int-4) via a four-membered transition
state (TS-3) involving O⋯C⋯N⋯B atoms. The reaction free
energy (ΔG) and the barrier (ΔG#) for this step are 16.9 kcal
mol−1 and 21.4 kcal mol−1, respectively. In the next step of the
reaction, the imine (Int-4) reacts with a third molecule of
HBpin, where the B–H bond of HBpin approaches towards the
N–H bond of imine (Int-4), thereby making a four-membered
transition state (TS-4) and leading to the formation of Int-5 by
evolution of one equivalent of H2 gas. The reaction free energy
(ΔG) and the barrier (ΔG#) for this step are −10.1 kcal mol−1
and 29.6 kcal mol−1, respectively. In the last step of the reac-
tion, Int-5 reacts with a fourth molecule of HBpin, where the
B–H bond of HBpin approaches towards the imine double
bond of Int-5, making a four-membered transition state (TS-5)
involving C⋯H⋯B⋯N atoms, which leads to the formation of
Bpin substituted amine. In this case, both the B–H bond and
the imine double bond activation takes place. The reaction
free energy (ΔG) and the barrier (ΔG#) for this step are
−32.8 kcal mol−1 and 19.9 kcal mol−1, respectively. Further
stepwise hydrolysis leads to the formation of final product ben-
zylamine. The ΔG (−23.1 kcal mol−1) value for the slowest step
is significantly negative and the barrier corresponding to the
transition state is 36.2 kcal mol−1, which explains why the reac-
tion takes place at 60 °C.
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