Hydrogenation of Secondary Amides using Phosphane Oxide and Frustrated Lewis Pair Catalysis

Article abstract of DOI:10.1002/chem.202100041

The metal-free catalytic hydrogenation of secondary carboxylic acid amides is developed. The reduction is realized by two new catalytic reactions. First, the amide is converted into the imidoyl chloride by triphosgene (CO(OCCl₃)₂) using novel phosphorus(V) catalysts. Second, the in situ generated imidoyl chlorides are hydrogenated in high yields by an FLP-catalyst. Mechanistic and quantum mechanical calculations support an autoinduced catalytic cycle for the hydrogenation with chloride acting as unusual Lewis base for FLP-mediated H₂-activation.

Full text of DOI:10.1002/chem.202100041

Accepted Article
Accepted Article
Title: Hydrogenation of secondary amides using phosphane oxide and
frustrated Lewis pair catalysis
Authors: Laura Köring, Nikolai A. Sitte, Markus Bursch, Stefan
Grimme, and Jan Henry Hakan Paradies
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.202100041
Link to VoR: https://doi.org/10.1002/chem.202100041
01/2020

10.1002/chem.202100041
Chemistry - A European Journal
COMMUNICATION
Hydrogenation of secondary amides using phosphane oxide and
frustrated Lewis pair catalysis
Laura Köring,[a] Nikolai A. Sitte,[a] Markus Bursch,[b]* Stefan Grimme,[b] and Jan Paradies[a]*
[a]
L. Köring, Dr. N. A. Sitte, Prof. Dr. J. Paradies
Chemistry Department
Paderborn University
Warburger Strasse 100, D-33098 Paderborn, Germany
E-mail: jan.paradies@uni-paderborn.de
M. Bursch, Prof. S. Grimme
[b]
Mulliken Center for Theoretical Chemistry, Institute of Physical and Theoretical Chemistry
Rheinische Friedrich-Wilhelms-Universität Bonn
Beringstr. 4, D-53115 Bonn, Germany
Supporting information for this article is given via a link at the end of the document.
A. Metal-free reduction of secondary amides
Abstract: The metal-free catalytic hydrogenation of secondary
carboxylic acid amides is developed. The reduction is realized by two
new catalytic reactions. First, the amide is converted into the imidoyl
chloride by triphosgene (CO(OCCl3)2) using novel phosphorus(V)
catalysts. Second, the in situ generated imidoyl chlorides are
hydrogenated in high yields by an FLP-catalyst. Mechanistic and
quantum mechanical calculations support an autoinduced catalytic
cycle for the hydrogenation with chloride acting as unusual Lewis
base for FLP-mediated H2-activation.
1.05 equiv. Tf2O
1.10 equiv. 2-fuoropyridine
O
R2
N
H
R2
R1
R1
N
1.10 equiv. H–SiEt3
1.40 equiv. Hantzsch’s ester
H
B. Catalytic hydrosilylation of secondary amides
20 mol%
(HO)2B
Br
O
S
R2
R2
R1
R1
N
H
N
H
2.4 equiv. PhSiH3
C. Phosphane oxide and FLP-catalyzed
reduction of secondary amides
(this work)
O=P(1-naphth)3 (20 mol%),
0.34 equiv. CO(OCCl3)2
O
The acylation of primary and secondary amines serves as a highly
efficient method for the construction of simple secondary and
tertiary amides, complex molecules,[1] natural products[2] and in
late stage macrocyclizations.[3] Such readily available key
intermediates are valuable starting points for the selective
synthesis of secondary and tertiary amines. Therefore, the
reduction of carboxamides is a key transformation for the
selective synthesis of symmetrical and unsymmetrical amines.[4]
The reduction can be realized using stoichiometric amounts of
strongly reducing metal hydrides but these reagents suffer from
major drawbacks such as limited functional group tolerance and
require a rigorous protection group strategy. Metal catalyzed
hydrogenations of amides are by far the most atom economic
reductions[5] but require drastic conditions.[6] Recently, milder
reaction conditions were realized,[7–11] however selectivity issues
due to C–N bond cleavage of hemiacetals[9],[12] or exhaustive
reduction of functional groups such as alkenes and alkynes are
still prevailing problems. The hydrosilylation of amides facilitates
the reduction by the removal of the oxygen atom as siloxane, but
comes at the cost of atom efficiency (Figure 1A and B).
Nonetheless, high tolerance towards hydrogenation susceptible
functionalities was achieved with inorganic[13–19] and organic[20–24]
catalysts. Recently, we reported the highly effective
hydrogenation of tertiary amides using an FLP-catalyst[25–27] and
oxalyl chloride as low molecular weight deoxygenation reagent.[28]
However, the hydrogenation of secondary amides remained a
major challenge. Thus, a new strategy for the hydrogenation of
secondary amides is required.
R2
R2
then
+ 3 CO2
R1
N
N
R1
H
H
• HCl
B(2,3,6-F3-C6H2)3 (5 mol%),
H2 (80 bar)
D. Proposed strategy
Cl
O
R2
R2
R2
R1
+ HCl
N
H
• HCl
R1
N
R1
N
H
[LB–H]
[H–BR3]
Cl2PR3
O=PR3
BR3
chlorination reagent
LB = active
Lewis
H2
phosphane oxide
catalysis
FLP-cat.
base
hydrogenation
Scheme 1. Metal-free reductions of secondary carboxamides.
reactions with particular consideration of compatible conditions.
First, we set out to investigate the efficient formation of the imidoyl
chloride which will later serve as in situ formed substrate for the
FLP-catalyzed hydrogenation. We observed that SOCl2 cleanly
converts the amide 1a into the imidoyl chloride 2a in excellent
yields under mild conditions (Table 1, entry 1).[29,30] However,
SOCl2 was incompatible with the conditions of the FLP-catalyzed
hydrogenation. The addition of (COCl)2 to the amide 1a furnished
mostly acylation products (entry 2). Alternatively, in situ generated
dichlorotriphenyl phosphorane[31–33] is
a known dehydrating
reagent.[34,35] We investigated the conversion of 1a into 2a in the
presence of 1.0 equiv. O=PPh3 and indeed, 2a was obtained in
93% yield (entry 3). The catalytic version with (COCl)2 could not
be elaborated because the acylation could not be outcompeted
by the phosphane oxide reaction (entry 4).
We envisioned a new phosphane oxide catalyzed conversion of
the sec. amide to the imidoyl chloride, which is subsequently
reduced with H2 in the presence of an FLP catalyst (Figure 1D).
This approach required the development of two new catalytic
1
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Table 1. Phosphine oxide catalyzed imidoyl chloride formation.
catalysts:
F
O
O
PPh3
P (
)
3
O
reagent, catalyst
time, temp.
Cl
3a
3b
3d
iPr
F
iPr
N
H
N
CDCl3
Br
O
O
P
1a
2a
Br
PtBu3
(
)
3
3c
entry
reagent (equiv.)
cat.
(mol%)
temp.
[°C]
time
[h]
yield[a]
[%]
1
2
SOCl2 (10)
–
70
70
70
70
70
70
70
70
70
90
3
18
110
18
18
34
18
18
42
18
>98
0[b]
(COCl)2 (1.1)
–
3
“
3a (100)
3a (20)
–
93
4
“
20[c]
<20
5
CO(OCCl3)2 (0.4)
Figure 1. Free energy diagram of the conversion of carboxamides to imidoyl
6
“
“
“
“
“
3a (20)
3b (20)
3c (20)
3d (20)
3d (20)
>98 (>98)[d][e]
80 (90)[d]
<30 (55)[d]
85
chlorides
at
the
PW6B95-D4/def2-QZVP+COSMO-RS(CHCl3)//PBEh-
3c(COSMO(CHCl3)) level of theory. All free energies in kcal/mol.
7
8
Table 2. FLP-catalyzed hydrogenation of imidoyl chloride 2b.
9
catalyst
Cl
H2
iPr
iPr
Ph
F
N
H
10
>98
Ph
N
2b
• HCl
70 °C, CDCl3
5b
catalysts:
F
[a] determined by 1H NMR spectroscopy; [b] contaminated with >98 % of
acylation product; [c] contaminated with 5% 1a and 75% of acylation product;
[d] performed at 90 °C; [e] 18h.
F
F
F
F
F
F
F
(
)
B
F
3
)
(
)
(
B
F
B
(
B
3
)
3
(
)
B
3
3
F
F
F
F
F
F
4a
4b
98%
4c
87%
4d
82%
4e
Lewis
aciditya
We found with triphosgene (CO(CCl3)2) a selective alternative for
the conversion of O=PPh3 to PPh3Cl2 in shorter reaction times
without noticeable background reaction (Table 1, entry 6). The
catalytic conversion of 1a by CO(CCl3)2 is achieved in the
presence of all four investigated phosphane oxides (O=PPh3 (3a),
O=P(2,6-F2-C6H3)3 (3b), O=PtBu3 (3c) and O=P(1-Naphth)3 (3d),
entries 6-9). Up to >98% yield within 18h was obtained at 90 °C.
Among the investigated phosphine oxides, 3d preformed best
(entry 10) and displayed in contrast to 3a and 3b no interference
with the borane 4e in the FLP-catalyzed hydrogenation (vide
infra).[36]
100%
92%
entry
cat. (mol%)
4a (20)
4b (20)
4c (20)
4d (20)
4e (20)
4e (5)
H2 [bar]
time [h]
yield [%]b
1
2
3
4
5
6
4
90
“
traces
0
4
4
“
53
4
“
12
4
“
99
Whereas the mechanism of the phosphane oxide dichlorophos-
phorane interconversion is known,[33] the subsequent reaction
with sec. amides to the imidoyl chloride is so far unreported.
Quantum-mechanical calculations at the PW6B95-D4/def2-
80
20
99
[a] according to Gutmann-Beckett with B(C6F5)3 referenced to 100% Lewis
acidity;[47–51] [b] determined by 1H NMR spectroscopy.
QZVP+COSMO-RS(CHCl3)//PBEh-3c(COSMO
(CHCl3))[37–46]
of the amide to the phosphorane in order to form the P-O bond.
The second challenge of the amide reduction is the FLP-catalyzed
hydrogenation of the imidoyl chloride intermediate. We
investigated the catalytic hydrogenation of 2b with a series of the
five boranes 4a-e, comprising Lewis acidities between 100% and
82%. Treatment of 2b (0.16M) in chloroform with H2 (4 bar) at
70 °C in the presence of 20 mol% of the two strongest Lewis acids
4a and 4b in our study resulted in essentially no conversion as a
consequence of catalyst inhibition. However, the application of
the weaker Lewis acid 4c provided the product 5b as
hydrochloride salt in 53% yield (Table 2, entries 1-3). Further
decrease of the Lewis acidity to 82% (4d, entry 4) resulted in
inefficient H2-activation by the imidoyl chloride/borane Lewis pair
and caused the drastic decrease of the catalytic productivity.[28]
The Lewis acid 4e with an acidity between 87% and 98% provided
an even more efficient catalyst, which produced the product in
level of theory level (for details see the Supporting Information)
identify the SN2-type addition of the amide oxygen (TS1b) to the
chloro phosphonium ion as rate determining step (Figure 1) with
a reactions barrier of 27.0 kcal/mol under chloride loss and
formation of INT1b. Deprotonation of INT1b by a chloride anion
yields INT4b via TS2b (22.4 kcal/mol). Phosphane oxide 3a is
reformed via TS3b (26.7 kcal/mol), yielding 2b after chloride
addition The overall free reaction energy amounts to 6.5 kcal/mol,
indicating that the subsequent deoxygenation of the formed
phosphane oxide (not shown in Figure 1), which is known to be
strongly exergonic, is needed as driving force.31 The generally
high reaction barriers qualitatively agree with the necessity of
heating the reaction mixture and relatively slow reactions. This
observation is supported by the increased reactivity of the
fluorinated aryl phosphane 3b compared to 3a or 3c. The steric
restrictions also play a significant role due to the back-side attack
2
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10.1002/chem.202100041
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quantitative yield (entry 5). Moreover, the catalyst loading was
reduced to 5 mol% employing 80 bar H2 without yield depletion in
20 h (entry 6).
intermediates [2b–H][H–4e] and [6b–H][Cl–4e] were detected by
NMR spectroscopy. The preferred splitting of H2 by Cl–/4e in
contrast to 2b/4e is supported by the difference of the pKa of the
conjugate acids (pKa ([H–2b]+) = 5, pKa (HCl) = 10.3)[28] as a
measure for the activation potency.[57–59] A second, autoinduced,
catalytic cycle is opened up with a lower barrier for the H2
activation (vide infra) as a result of the slow increase of Cl–. The
autocatalysis is supported by the drastic rate increase when 20
mol% of the product 2b•HCl is added at the beginning of the
reaction (Figure S1). In contrast to the FLP-catalyzed imine
hydrogenation,[58] the imidoyl chloride hydrogenation displays
saturation kinetic and follows zeroth-rate order after equal
amounts of the product compared to the borane are generated
(Figure S2). This indicates that the chloride anion is reversibly
bound to the borane, which is in concert with the observed
broadening in the 11B and 19F NMR spectra (see Supporting
Information). Free energy calculations reveal that the heterolytic
splitting of H2 by the FLP 2b/4e to the chloro iminium hydroborate
[2b–H][H–4e] is endergonic by 9.7 kcal/mol over a barrier of 25.5
kcal/mol (TS4b, simple catalytic cycle, scheme 2 and figure 2 left).
Finally, we successfully merged both catalytic processes in a one-
pot hydrogenation of sec. amides. The carboxylic amide was
reacted with 0.34 equiv. CO(COCl3)2 in the presence of 20 mol%
3d at 90 °C for 0.5-15h. Then, 5 mol% 4e dissolved in chloroform
was added and the reaction was pressurized with H2 (80 bar) for
18 h at 70 °C.[52] A series of benzamides bearing aliphatic,
benzylic and aromatic N-substituents were hydrogenated in good
to excellent yields (Table 3, 58-95%).
Table 3. Catalytic hydrogenation of secondary amides.[a]
(20 mol%),
0.34 equiv. CO(OCCl3)2,
90 °C, 0.5-15 h
O
P
(
)
3
3d
then
F
F
(5 mol%), H2 (80 bar),
90 °C, 20 h
(
)
3
B
O
R2
R2
4e
F
R1
R1
N
H
N
H
[H–4e]
[2b–H]
CHCl3
1a-l
5a-l
[H–4e]
H2 + Cl
H
N
Products
[H–BR3]
+
Cl–H
2b
+ H2
Ph
iPr
iPr
iPr
Me
N
H
N
H
Et
2b
Ph
N
H
Cl
[H–BR3]
Ph
N
H
N
H
Br
Cl
5b, 76%[d]
5c, 62%
5d, 71%
Me
Ph
5a, 81%
iPr
Slow
Fast
[6b–H]
[H–4e]
[Cl–BR3]
H
H
Bn
Ph
iPr
simple
cat. cycle
autoinduced
cat. cycle
BR3
4e
Ph
N
Ph
N
Ph
N
iPr
N
H
Ph
N
H
iPr
[H–BR3]
H
H
Cl
5e, 64%
5g, 80%
5h, 73%
(96% ee)
5f, 61%[b][c]
H2
[2b–H]
[H–4e]
iPr
H
N
H
H
N
O
Ph
Ph
N
Ph
iPr
Ph
N
H
iPr
H
O
[Cl–BR3]
[H–BR ]
H
[6b–H]
[Cl–4e]
iPr
5j, 58%[b][c][d]
3
H2
5i, 89%
Ph
Ph
Cl
N
H2
+ H–Cl
[6b–H]
[Cl–4e]
iPr
iPr
N
H
N
H
5b•HCl
5l, 86%[b][e]
MeO
O2N
5k, 95%
Scheme 2. Proposed catalytic cycle of the FLP-catalyzed hydrogenation of
imidoyl chlorides.
[a] Reactions were typically performed with 1 equiv. of 1 in CDCl3 (0.83 M), 0.34
equiv. CO(OCCl3)2, 20 mol% 3d at 90 C °C for 0.5-15 h, followed by the addition
of 5 mol% 4e in CHCl3 giving a 0.17M solution, H2 (80 bar), 90 °C for 20 h; [b]
10 mol% 4e; [c] 1.0 equiv. 2,6-Lutidine added, [d] performed at 70 °C; e 40h.
The reaction displayed excellent functional group tolerance,
resulting in the high yielding hydrogenation of bromide 5a, ester
5j, ether 5k and even the nitro compound 5l. Notably, a,b-
unsaturated esters and alkynes remained fully intact. The chiral
amide 1h was reduced in 73% yield with full conservation of the
stereochemical purity. N-phenyl substitution of the benzoic amide
(1f) required the application of 2,6-lutidine as auxiliary Lewis base
and the product 5f was obtained in 61% yield. Furthermore,
amines with small N-substituent (5c, 5d) were accessible in high
yields, which is so far unprecedented in FLP-catalyzed imine
hydrogenation.[53–56]
Finally, we investigated the hydrogenation mechanism by kinetic
and quantum mechanical experiments. The reaction profile of the
catalytic hydrogenation of 2b with 10 mol% 4e in CDCl3 (0.16M)
and 4 bar H2 displayed an induction period (Figure S1). This
increase of the reaction rate over the first three hours suggests
the slow activation of H2 by the FLP consisting of 4e and 2b
(compare Scheme 2, simple catalytic cycle). The imidoyl chloride
salt [2b–H][H–4e] collapses to the corresponding iminium salt
[6b–H][Cl–4e], which is hydrogenated by the Cl–/4e FLP to yield
5b•HCl salt as uncompetitive Lewis base for H2-activation. These
last two steps can be considered as fast, since neither 6b nor the
Figure 2. Simplified free energy diagrams of the H2-activation by the FLPs 2b/4e
and Cl–/4e at the PW6B95-D4/def2-QZVP+COSMO-RS(CHCl3)//PBEh-
3c(COSMO(CHCl3)) level of theory. All free energies in kcal/mol.
3
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In contrast, the splitting of H2 by Cl–/4e (TS6) requires 0.7 kcal/mol
less energy than TS4b rendering this step kinetically more
favorable. The comparison of the H–H bond lengths in TS4b and
TS6 indicates an early transition state for the H2-activation for the
Cl–/4e FLP. In case of the simple catalytic cycle the formed
Chloride ions also increasingly form Cl–/4e (-2.5 kcal/mol) thus
further disadvantaging the H2-splitting via TS4.
In summary, we developed the FLP-catalyzed hydrogenation of
amides to yield secondary amines. The in situ formed imidoyl
chloride intermediate was generated by the new developed
phosphane oxide catalysis and triphosgene as oxygen scavenger.
The final hydrogenation of the intermediate proceeds through two
catalytic cycles as revealed by DFT-calculations, incorporating
H2-activation by the imidoyl chloride and by chloride as active
Lewis base. The reaction displays high functional group tolerance
towards Lewis basic sites and hydrogenation susceptible groups
and provides the secondary amines in high yields under mild
conditions.
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10.1002/chem.202100041
Chemistry - A European Journal
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The hydrogenation of secondary carboxylic acid amides by combined phosphane oxide and frustrated Lewis pair catalysis is
described. The reaction proceeds under mild conditions and displays excellent functional group tolerance. Kinetic and quantum-
chemical experiments support the autoinduced catalytic cycle with chloride as active Lewis base for the hydrogen activation.
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