Frustrated Lewis Pair Catalyzed Hydrogenation of Amides: Halides as Active Lewis Base in the Metal-Free Hydrogen Activation

Article abstract of DOI:10.1021/jacs.8b12997

A method for the metal-free reduction of carboxylic amides using oxalyl chloride as an activating agent and hydrogen as the final reductant is introduced. The reaction proceeds via the hydrogen splitting by B(2,6-F₂-C₆H₃)₃ in combination with chloride as the Lewis base. Density functional theory calculations support the unprecedented role of halides as active Lewis base components in the frustrated Lewis pair mediated hydrogen activation. The reaction displays broad substrate scope for tertiary benzoic acid amides and α-branched carboxamides.

Full text of DOI:10.1021/jacs.8b12997

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Communication
Frustrated Lewis pair catalyzed hydrogenation of amides: halides
as active Lewis base in the metal-free hydrogen activation
Nikolai Sitte, Markus Bursch, Stefan Grimme, and Jan Henry Hakan Paradies
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12997 • Publication Date (Web): 13 Dec 2018
Downloaded from http://pubs.acs.org on December 13, 2018
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Frustrated Lewis pair catalyzed hydrogenation of amides: halides as
active Lewis base in the metal-free hydrogen activation
Nikolai A. Sitte,a Markus Bursch,b Stefan Grimme,b* Jan Paradiesa*
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a University of Paderborn, Department of Chemistry, Warburger Strasse 100, D-33098 Paderborn, Germany; b University of Bonn,
Mulliken Center for Theoretical Chemistry, Beringstr. 4, D-53115 Bonn, Germany
Supporting Information Placeholder
from H213 and may serve as reduction equivalent in the metal-
ABSTRACT:
A method for the metal-free reduction of carbox-
free reduction of activated carboxamides (Scheme 1).
ylic amides using oxalyl chloride as activating agent and hy-
drogen as final reductant is introduced. The reaction proceeds
via the hydrogen splitting by B(2,6-F2-C6H3)3 in combination
with chloride as the Lewis base. Density functional theory cal-
culations support the unprecedented role of halides as active
Lewis base components in the frustrated Lewis pair mediated
hydrogen activation. The reaction displays broad substrate
scope for tertiary benzoic acid amides and a-branched car-
boxamides.
Scheme 1. Metal-free reductions of amides.
for sec. amides: R2 = H
1.05 equiv. Tf2O
ref. 11
ref. 12
1.1 equiv. 2-fluoropyridine
1.1 equiv. Et3SiH
1.4 equiv. Hantzsch's ester
for tert. amides
1.1 equiv. Tf O
2
2.5 equiv. Hantzsch's ester
O
R3
R3
R1
R1
N
N
R2
R2
for tert. amides
this
work
1.5 equiv. (COCl)2
80 bar H2, 2 mol% B(2,6-F2-C6H3)3
The reduction of carboxylic amides is one of the most im-
portant key transformations in preparative chemistry on both
the laboratory and industrial scale. The development of mild,
chemoselective and robust general methods relying on cata-
lytic reactions is of great importance for the pharmacological
industry, since this serves as a platform for the implementa-
tion of the structural diversity of amines. Most abundant re-
ductions of carboxamides require strong nucleophilic ‘ate’ hy-
dride donors, such as aluminum or boron reagents. Catalytic
processes are highly demanded because of the reduced func-
tional group tolerance, safety issues of these pyrophoric rea-
gents and byproduct separation. The most desirable reduc-
tion of carboxylic amides with molecular hydrogen1 (H2) was
reported in 1934 by the use of a heterogeneous Cu/Cr cata-
lyst and required over 990 bar at 250 °C.2 These drastic con-
ditions were improved (10-30 bar, 160 °C) by the application
of a bimetallic Pd/Re@graphite3 and a homogeneous ruthe-
nium catalyst.4 Milder amide reductions were realized using
stoichiometric hydrosilane based reduction equivalents in
combination with metals, e.g. iron,5 platinum6 or zinc7 and
Here we present the metal-free hydrogenation of carbox-
amides to amines in excellent yields under mild conditions
(50-70 °C, 80 bar), taking advantage of oxalyl chloride as acti-
vating reagent. The produced amines are furnished as hydro-
chloride salts, enabling the most convenient isolation by filtra-
tion. Mechanistic details support the unparalleled role of chlo-
ride as the Lewis base in the frustrated Lewis pair catalyzed
hydrogenation.13a, 13c, 13f, 13g, 14
We initiated our investigation using the FLP system consist-
15
1
2
ing of B(C6F5)3 ( ), B(2,4,6-F3-C6H2)3 ( ) or B(2,6-F2-
15-16
3
4
in combination with 2,6-lutidine ( ) and the
C6H3)3 ( )
5
in situ generated chloroiminium chloride from the reaction
17,18
6a
of the amide with oxalyl chloride (Table 1).
Table 1. One-pot activation and FLP-catalyzed hydrogenation of
amide 6a.
X equiv. (COCl)2
cat.
BArF3/additive
Cl
8
9
H
1
main group Lewis acids, like boronic acids , B(C6F5)3 ( ) and
electrophilic phosphonium cations.10 Triflic anhydride
proved to be a useful, but difficult to handle, carbonyl activa-
tion agent for the direct reduction with Hantzsch’s esters11 or
silanes,12 with the significant drawback of producing stoichio-
metric amounts of byproducts. In this light, frustrated Lewis
pairs (FLP) offer a unique catalytic access to borohydrides
O
(1:1)
N
Ph
N
Ph
+ HCl
N
Ph
H2,
Cl
Cl
7a
70 °C, CDCl3
– CO
– CO2
6a
5
in situ
entry cat.
add. 4 equiv.
/mol% /mol% (COCl)2 /bar /h
H2
time
yield
/%
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H2/D2
1
1
2
3
4
5
6
7
8
20 ( ) 20
1.0
1.0
1.0
1.0
1.0
1.2
1.5
1.5
4
4
4
4
18
18
16
18
18
48
28
22
0
X = Cl, Y = PPh4 (8)
NBu4 (9)
Y = BMIM X = Cl (10)
Br (11)
I (12)
[3–H/D]Y + H/D–X
+
3
Y X
1
2
3
4
5
6
7
8
2
20 ( ) 20
40
90
0
–HD
CDCl3
3
20 ( ) 20
0
20
-
3
20 ( )
4
4
12
80
85
90
90
99
HD was unmistakably identified by its 1H NMR resonance at
4.43 ppm with the characteristic coupling constant of JHD
43 Hz. The three chloride sources , and featured identi-
cal performance in the H/D exchange supporting the role of
the chloride as active Lewis base. Importantly, the BMIM bro-
1
3
10 ( )
-
-
-
=
3
5 ( )
8 9
10
3
2 ( )
a
3
4
6a
conditions: 2-20 mol% , 0-20 mol% , 0.1 mmol in CDCl3
9
11
12
mide and iodide salts and also displayed activity in the
(0.16 M), 1 to 1.5 equiv. oxalyl chloride (in 0.2 ml CDCl3), 4 - 80
bar H2.
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H/D scrambling, however elevated temperatures were re-
11
12
quired ( : 70 °C; : 120 °C). Quantum-chemical investiga-
tions at the PW6B95-D3(BJ, ATM) + COSMO-RS (CHCl3)
/ def2-QZVP // PBEh-3c + COSMO(CHCl3)24 level of the-
ory (see SI for further details) strongly support the activity of
halides as active Lewis base in the heterolytic splitting of H2 in
6a
The hydrogenation of with the FLP
1/4
was not observed
1
because was inhibited by the chloride (entry 1) as evidenced
by the 11B NMR resonance at 6.53 ppm (see SI for details).
2 4 3 4
However, in the presence of 20 mol% / or
/
the hydro-
7a
chloride salt of N-benzyl piperidine ( ) was obtained within
18 h in 40% and 90% yield respectively (entry 2 and 3). These
results are surprising, since the base is protonated under the
reaction conditions and should no longer engage in the H2-
activation event. Control experiments clearly revealed that
the borane is necessary for the hydrogenation (entry 4)
3
3
combination with . The reaction of with dihydrogen and a
halide cation pair [Me4N]X was investigated in chloroform at
50 °C for X = Cl–, Br– and I–. For all three halides transition
TS(X)
3
states ( ) for a H2 splitting with were identified in a
thermally accessible energy range (Figure 1).
4
whereas the Lewis base 2,6-lutidine ( ) had essentially no im-
pact on the reaction (entry 5). The catalyst loading could be
reduced to 2 mol% using 1.5 equiv. oxalyl chloride and 80 bar
H2 at 70 °C in the absence of a supporting base (entries 6-8).
Further studies support chloride operating as a weak Lewis
base in the transient19 FLP-mediated H2-activation. In con-
trast to , the boranes and show dynamic 11B NMR spectra
in the temperature range of 20 °C to 60 °C in the presence of
a chloride source which assures the availability of free Lewis
acid in solution.20 Halides have not yet been considered as
Lewis base in borane-mediated H2 activation probably due to
two obvious reasons. Firstly, the halide, particularly, chloride
and fluoride, forms an irreversible adduct with strong Lewis
acids. Secondly, the basicity of the halide decreases dramati-
cally going from fluoride to iodide. However, very weak Lewis
bases e.g. fluorinated phosphanes or ethers have been re-
ported as active component in the FLP-catalyzed hydrogena-
tion of olefins19 and in the reduction of carbonyls.21 System-
atic studies focusing on the FLP-reactivity in dependence on
the pKa of the conjugate Brønsted acid15a, 16a, 19a support that
chloride should be able to activate H2 (pKa (MeCN): 10.30)22
provided that it does not deactivate the Lewis acid (vide su-
pra). We were able to exclude the amide and the chloroimine,
which may arise from nucleophilic ring opening23 as active
Lewis bases in the H2 splitting (see SI). Instead we observed
1
2
3
Figure 1.
Relative Gibbs energy diagram of the H2 splitting reac-
tions. All energies given are in kcal/mol relative to the corre-
sponding separated reactants. A = Me4N+; R = 2,6-F2-C6H3; X =
Cl– (green), Br– (red), I– (purple).
All investigated reactions are endergonic giving rise to the ob-
served transient formation of a borohydride upon H2 splitting
at the given reaction conditions as evidenced by the NMR ex-
periments. The observed trend of energetically higher lying
transition states in the row Cl < Br < I is reflected by the in-
creased demand of heating upon using Br and I salts. The
bond length of the split hydrogen molecule in the TS in-
creases from Cl, Br to I as bases. The value computed for the
most active system of about 0.8 Å is similar to that observed
in typical P...B FLP systems and points to an early TS.25
3
the fast isotope scrambling of a H2/D2 mixture by in the
8 9
10
presence of the chloride sources , and at 70 °C (Scheme
2).
Scheme 2. H2/D2-scrambling using B(2,6-F2-C6H3)3 (3) and
halides.
The substrate scope of the metal-free hydrogenation of am-
ides was explored (Table 2).
Table 2. Substrate scope for the FLP-catalyzed reduction of amides.a
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1.5 equiv. (COCl)2
2 mol% B(2,6-F2-C6H3)3
O
H
corresponding chloro imines were not susceptible to FLP-
R2
R2
R1
Cl
catalyzed hydrogenation.26 Nonetheless, the protocol enables
the reduction of amides derived from aliphatic carbonic acids
1
2
3
4
5
6
7
8
N
R3
N
R3
R1
+ HCl
H2 (80 bar), CHCl3
40-70 °C
– CO, – CO2
6a-ao
7a-an
6q 6aa
). The acetyl derivatives
7q
7r
(
-
and were obtained in
-
Products
low yields.27 However, the formyl and branched amides
were converted to the corresponding N-methyl amines
from benzoyl derivatives
6s 6aa
7s-v
n =
5 (7a), 99%
4 (7b), 90%
6 (7c), 97%
N
Ph
N
Ph
Me2N
Ph
(CH2)n
O
7w-7aa
and a-branched amines
in high to excellent yields.
7d, 97%
7e, 95%
nHex
cHex
Ph
Ph
Furthermore, we investigated the functional group tolerance
of the reaction. Esters, ethers, nitro, cyano or thiophenyl
7ab-ag
groups were well tolerated ( , 67-99%). Amides bearing
6ai
reactive multiple bonds as in the acrylate , the allyl amine
N
N
Ph
N
R
Ph
N
Ph
R
Me
9
R = Me (7f), 90%
nHex (7g), 83%
7h, 81% R = Me (7i), 73%b
Et (7j), 85%b
10
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7m, 81%
iPr, (7k), 73%b
Ph (7l), 15%b
6aj 6ak
7aj-ak
or in the alkyne
remained unchanged and the amines
were isolated in high to excellent yields. Even substrates
bearing acid-sensitive groups were reduced in good yields.
7al
Me
N
N
Ph
N
Ph
7o, 65%c
7n, 0%
7p, 78%
The proline derivative
was obtained in 65% yield in the
from acetyl derivatives
from cyclohexyl and pivaloyl derivatives
Me
presence of 1.0 equiv. of 2,6-di-tbu-pyridine with marginally
diminished enantiomeric purity of 93% ee (without base 76%,
69% ee). The TBDPS- and even the Boc group were stable
under the reaction conditions and enabled the reduction of si-
nHex
N
7w, 82%
N
Me
N
N
Me
Me
nHex
7x, 45%
7q, 33%c,d
7r, 26%c,d
from formyl derivatives
Me
Me
Me
Et
Me
Bn
Me
N
N
N
N
6am
lyl ether
respectively.
6an
in 65% and 70% yield
and of the carbamate
Me Me
7y, 71%
Et Me
7z, 76%
Me
Me
7t, 94%
7s, 92%
iPr
Me
Me
N
N
In summary, we developed the FLP-catalyzed hydrogenation
of carboxylic amides with the aid of oxalyl chloride as a deox-
ygenating agent. Mechanistic and quantum-mechanical inves-
tigations strongly support the role of halides in the FLP-
mediated H2-activation. The reaction displays broad general-
ity and high functional group tolerance, providing access to
tertiary amines in the presence of hydride sensitive functional
groups.
N
Me
iPr
Me
Me
7u, 87%
7v, 94%
7aa, 76%
functionalized derivatives
R
EtO
N
N
N
Ph
O
N
Me
OMe
R
R = NO2 (7ae), 99%
CN (7af), 99%
R = H (7ac), 91%
OMe (7ad), 95%
7ab, 67%c
N
Ph
Ph
O
N
Ph
S
Cl
O
Et
7ag, 96%
7ai, 84%
7ah, 89%
ASSOCIATED CONTENT
N
N
Ph
The Supporting Information is available free of charge on the
ACS Publications website: synthetic procedures, NMR-
spectroscopic data, quantum-mechanical details and structures
as coordinates.xyz.
Me
7aj, 87%b
7ak, 97%
Ph
acid sensitive groups
MeO2C
N
Ph
TBDPSO
N
Ph
tBuO
N
O
N
Ph
Et
AUTHOR INFORMATION
Corresponding Author
7am, 65%
7an, 70%e
7al, 76% (69% ee)b
62% (93% ee)b,e
a
reactions were typically performed with 1 equiv. amide in
CHCl3 (0.16 M), 2 mol% , 1.5 equiv .(COCl)2, 80 bar at 40-70
°C for 22h; 5 mol% ; 20 mol% ; performed on NMR-scale;
7al
in the presence of 1.0 equiv. 2,6-di-tBu-pyridine ( ) or 2,6-
jan.paradies@uni-paderborn.de
grimme@thch.uni-bonn.de
3
b
c
d
3
3
Funding Sources
e
German Science Foundation (DFG) and Gottfried Wilhelm
Leibniz prize to SG.
Notes
7an 7ao
); • denotes former position of the carbonyl
lutidine (
group.
,
Benzoic amides bearing cyclic and acyclic alkyl chains, heter-
ocycles or aromatic substituents were hydrogenated in excel-
7a k
lent yields ( - ). Notably, small N-Me substituted amides as
The authors declare no competing financial interest.
ACKNOWLEDGMENT
6m
well as amides bearing steric encumbrance in a-position (
were reduced in excellent yields. Highly reactive aromatic
compounds, e.g. the diphenylamine and the indole , de-
composed under the reaction conditions. However, electron
rich compounds such as indoline , or the lactam cleanly
underwent reduction in high yields. Benzoic amides derived
from primary amides were cleanly activated but the
)
The German science foundation (DFG) and the Fonds der
Chemischen Industrie (FCI) are gratefully acknowledged for fi-
nancial support (PA 1562/6-1 and Gottfried Wilhelm Leibniz
prize to SG) and for a stipend to N. Sitte.
6l
6n
6o
6p
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9.92 (exptl. 10.3, see SI for details). The chloro imin is not active as
Lewis base in the H2-splitting with
27. Result of the high propensity of enamine formation of the
corresponding chloro iminium chlorides and subsequent
polymerization. Accordingly, aliphatic carboxamindes and lactones
were not compatible with the reaction conditions.
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25. Grimme, S.; Kruse, H.; Goerigk, L.; Erker, G., The Mechanism of
Dihydrogen Activation by Frustrated Lewis Pairs Revisited. Angew.
Chem. Int. Ed. 2010, 49, 1402-1405.
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26. The corresponding chloroimine is not protonated under the reaction
conditions so that it remains unreactive to hydride addition. The
calculated pKa of a chloro imine is ca. 5, whereas the pKa of of HCl is
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1.5 equiv. (COCl)2
80 bar H2
2 mol% B(2,6-F2-C6H3)3
O
R1
R1
R3
N
R3
• HCl
N
50-70 °C
CHCl3
– CO
R2
R2
39 examples
up to 99% yield
– CO2
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