FLP-catalysis meets hydrogen-bond activation

Article abstract of DOI:10.1039/d0ob01492c

The potential of two chiral amidines and three non-chiral boranes in the metal-free hydrogen activation was explored. The resulting chiral amidiunium borohydride salts were investigated in asymmetric hydrogenation reactions of ketimines, activated double bonds and dehydro amioacid esters.

Full text of DOI:10.1039/d0ob01492c

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O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
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DOI: 10.1039/D0OB01492C
ARTICLE
FLP-catalysis meets hydrogen-bond activation
a
a
b
a
Nikolai A. Sitte, Laura Köring, Peter W. Roesky and Jan Paradies*
Received 00th January 20xx,
Accepted 00th January 20xx
The potential of two chiral amidines and three non-chiral boranes in the metal-free hydrogen activation was explored. The
resulting chiral amidiunium borohydride salts were investigated in asymmetric hydrogenation reactions of ketimines,
DOI: 10.1039/x0xx00000x
activated
double
bonds
and
dehydro
amioacid
esters.
Introduction
The activation of organic molecules through hydrogen bonding
has emerged to a widely applied mode in catalysis.
Asymmetric organocatalytic processes have been developed
taking advantage of the interaction of chiral hydrogen bond
encounter complex
1
*R
R
ArF
N
BArF
*R
R*
N
+
3
B
N
R
ArF
H
donors.2 In particular, the transfer hydrogenation advanced
,3
4
NH
ArF
*R
5
–7
to a useful tool for asymmetric metal-free reductions.
Among other hydrogen (H
proved to be most versatile. Although relay catalysis may
diminish the low atom economy of Hantzsch’s ester transfer
8
9–13
*R
ArF
B
2
) surrogates, Hantzsch’s esters
hydrogen
activation
N
H
H
H2
1
4
asymmetric
hydrogenation
H
R
ArF
N
ArF
hydrogenations, the direct use of H
still underdeveloped, although highly desired.
The metal-free H -activation was realized in 2006 by the
discovery of reversible heterolytic splitting of H
2
in metal-free processes is
*R
chiral double hydride
hydrogen
bond donor
donor
2
2
by a Scheme 1 Concept of hydrogen bond donor/FLP hybrid catalysis.
1
5
borane/phosphane Lewis pair, later known as frustrated
Lewis pair (FLP).16 Subsequent transfer of the hydride and of
Results and Discussion
1
7–
the proton enables for catalytic metal-free hydrogenations.
2
4
Mostly, FLPs were modified by the interchange of the Lewis
base, probably as a result of availability, whereas the Lewis
First, we investigated the interaction of the boranes 1a-c with
34–36
the two chiral amidines 2a and 2b
(Chart 1).
2
3
acid part is usually represented by a triaryl borane.
Surprisingly, amidines have not yet been utilized as Lewis base
in the H -activation but offer the potential to act as hydrogen
bond donors for substrate activation.
an asymmetric hydrogen bond donor for substrate activation
F
F
Me
R
Me
2
B(C F )
B (
F)3
B
(
)3
6
5 3
2
5–30
Ph
N
N
Ph
(Scheme 1). Thereby,
H
F
F
1c
1a
1b
R = tBu (2a), Ph (2b)
and the hydride nucleophile are formed from molecular Chart 1 Utilised Lewis acids and Lewis bases as potential FLP-components.
hydrogen, which may give rise to asymmetric FLP-catalysed
2
2
hydrogenations using chiral Lewis bases. The general The reaction of 1a with 2a produced the Lewis pair adducts
1
1
11
feasibility of an asymmetric induction through hydrogen 1a•2a as judged by the B NMR chemical shifts of ( B) = –
1
1
1
bonding was only recently reported by utilizing chiral oxazoles 2.0, –7.5 ppm (compared to free 1a ( B) = 40 ppm). The H
as Lewis bases for the hydrogenation of ketones and NMR spectra did not provide further information of the
enones3 and in the -amination of carbonyl compounds.
1,32
33
solution structure due to severe line broadening caused by
hindered conformational changes, which could not be resolved
by variable temperature NMR experiments. Nonetheless, the
reaction mixture was pressurised with H
2
(4 bar) and heated to
a. Department of Chemistry, Paderborn University, Warburger Str.100, D-33098
Paderborn (Germany) E-mail: jan.paradies@uni-paderborn.de.
Institute of InorganicChemistry, Karlsruhe Institute of Technology (KIT)
9
0 °C over night (Scheme 2).
b.
Engesserstraße 15, D-76131Karlsruhe (Germany)
†
Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
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ARTICLE
Organic & Biomolecular Chemistry
complicates the interpretation. Therefore, we investigated the
View Article Online
DOI: 10.1039/D0OB01492C
NMR pattern of the corresponding BF
4
-salt, obtained by the
1
reaction of 2b with HBF
4
. The H NMR spectrum of [2b–H][BF
4
]
displays three sets for the phenylethyl groups (Fig. 2). One set
for the C -symmetric trans/trans and two sets for the
unsymmetrical cis/trans [2b–H] cation in solution in a ratio of
2
1
:1.1 (Fig. 2).
2
Scheme 2 H -Activation by the amidine/borane Lewis pair 2a•1a.
Me
Ph
Me
Me
Ph
Me
H
*
Me H
Me
H
1.29
6.88
H
Me H7.47
1.65
6
.32
65.9
H
7.29
164.4 5.43
3
.76
1
Ph
N
N
Ph
7.28 HN
N
4.35
H
Ph
BF
N
N
H
Ph
b•1a
N
N
Ph
H
H
H
7.38
2b
C6D6
8.95
+
H
[
4
]
Me
B(C6F5)3
1.50
[
BF
4
]
2
H
B(C F )
6.08
1a
6 5 3
trans/trans-[H-2b][BF
4
]
cis/trans-[H-2b][BF
4
]
Ph
Me
H2 (4 bar)
0 °C, C D6
9
6
HN
N
H
Ph
H–B(C F ) ]
[
6
5 3
Ph
Me
[
2b–H][H–1a]
(1a) with phenyl amidine 2b.
1
Fig. 2 H NMR spectrum of [2b–H][BF
4
] (0.04 M, C
6
D
6
, 500 MHz); red numbers
1
13
denote H and C NMR chemical shifts; green arrows denote nOe contacts.
Scheme 3 Reaction of B(C
F
6 5
)
3
All resonances were assigned by 2D NMR experiments (HSQC,
HMBC, COSY and NOESY). Particularly, the NOESY experiments
were useful to match the resonances with the two conformers.
Only one phenylethyl/phenyl nOe contact (5.43/7.29) was
found for the cis/trans conformer. The two N–H protons in the
symmetric trans/trans conformer generate a sharp resonance
*
11B NMR
1H NMR (C
D )
6 6
H
2
$
0
–10
–20
–30
*
*
11B NMR
1
H NMR (C D )
6
6
H
2
1
at ( H) = 8.95 ppm, whereas the unsymmetrical conformer
$
1
exhibits two resonances at ( H) = 7.38 and 7.28 ppm.
0
–10
–20
–30
1
Comparison of the [2b–H][BF
obtained from the H
4
] H NMR spectrum with the one
2
-splitting by 1a•2b supports the
1H NMR (C
6
6
D )
formation of the cis/trans isomer (compare Scheme 3) due to
$
1
the absence of the low field resonance ( H) = 8.95 ppm.
1
Furthermore, two resonances ( H) = 1.05 and 0.97 ppm (Fig. 1
top) are observed which indicate the presence of two
magnetically inequivalent methyl groups.
(inset: B NMR (160 Having the H -activation by the amidine/B(C F ) system
2 6 5 3
1
1
Fig. 1 bottom: H NMR (500 MHz) spectrum of 2b in C
NMR (500 MHz) spectrum of 2b•1a and H (4 bar) in C
, 300 K)  = –5.8 ppm; top: H NMR spectrum of the reaction of 2b•1a
6 6
D (0.16M); middle: H
11
2
D
6 6
1
MHz, C
6 6
D
1
1
established, we turned out attention to the application of the
weaker Lewis acids. The two boranes 1b and 1c display a lower
Lewis acidity of 87% and 82%, respectively, compared to
with H
2
(4 bar) at 90 °C in C
d, JB-H = 69 Hz) ppm; * solvent resonance; $ silicon grease impurity.
6 6 6 6
D (inset: B NMR (160 MHz, C D , 300 K)  = –24.3
1
(
After 18 h, only small amounts of the H
2a–H][H–1a] were detected by B NMR ( B) = –24 ppm)
with the characteristic JB-H coupling of 77 Hz. However, the
majority of the Lewis pair 2a•1a remained unreacted. The
reactivity changed by the application of the phenyl derivative
2
-activation product
3
7–
B(C
6
F
5
)
3
(100%) according to the Gutmann-Beckett-method.
This reduced Lewis acidity is a key requirement for the
tolerance of functionalized substrates, which will be used as
1
1
11
[
4
1
1
4
2,43
hydrogen bond acceptors.
Again, the phenyl-substituted
amidine 2b was reacted with the boranes 1b and 1c in order to
study the complexation properties (Scheme 4).
2
b (Scheme 3). The reaction of 2b with 1a cleanly furnished
the Lewis adduct 2b•1a with separated and sharp resonances
1
11
1
in the H and B NMR spectrum (Fig. 1 middle). The H NMR
spectrum revealed two sets of phenylethyl-groups in 2b
fragment with one set being significantly shifted to higher
field. This presumably arises from the shielding effect of the
electron-deficient pentaflurophenyl groups of 1a. This
Me
Ph
Me
Me
Ph
Me
Ph
N
H
N
Ph
Ph
N
N
Ph
2b
+
H
C D
6 6
BArF
3
BArF
3
0.04 M
1
1
11
observation and the B NMR chemical shift of ( B) = –5.8
ppm strongly supports the formation of the Lewis adduct
ArF = 2,4,6-F -C H (1b),
–1
3
6
2
K = 50 M (2b•1b)
2
,6-F2-C6H3 (1c)
–1
9
3 M (2b•1c)
2
b•1a. Subsequent reaction with 4 bar H
furnished the H -activation product [2b–H][H–1a] (Scheme 3)
as evidenced by the intense B NMR resonance at ( B) = –24
2
at 90 °C over night
Scheme 4 Equilibrium of 2b with the weaker Lewis acids 1b and 1c.
2
1
1
11
The reduced Lewis acidity resulted in the equilibration of the
free components with the corresponding Lewis adducts 2b•1b
1
1
(
JB-H = 69 Hz) ppm (see inset Fig.1 top). However, the H NMR
spectrum displayed significant line broadening, which
2
| J. Name., 2012, 00, 1-3
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ARTICLE
–
1
–1
and 2b•1c in 3:2 (K = 93 M ) and 1:1 (K = 50 M ) ratio
View Article Online
DOI: 10.1039/D0OB01492C
1
1
respectively. The B NMR spectra clearly show the presence of
free borane and B-N adduct (1b: ( B) = 60.0, –5.4 ppm); 1c:
1
1
1
1

( B) = 63.5, –4.7 ppm). Encouraged by this result we
attempted the H -activation and reacted the Lewis pairs with 4
bar H at 90 °C for 18 h. Only small amounts of the
corresponding H
3.1 ppm and [2b–H][H–1c] ( B) = –22.4 ppm) together with
significant amounts of new B-N adducts were detected (2b•1b:
20.8
2
2
0.6
0.5
2
2
1
1
TS s-trans/cis-2b•••H•••H•••1c
TS s-cis/trans-2b•••H•••H•••1c
2
-activation products ([2b–H][H–1b]: ( B) = –
d(H-H) = 0.87 Å
d(H-H) = 0.85 Å
1
1
2
1
1
11

( B) = –2.3, –4.7 ppm; 2b•1c: ( B) = –1.5, –7.5 ppm). The
9.9
.8
.1
8
7
formation of new amidine/borane adducts after heating must
be attributed to the kinetic barrier to other conformers leading
to more stable adducts. Nonetheless, the formation of the
Lewis adducts is not necessarily problematic for catalytic
applications as long as they can be thermally cleaved (compare
Scheme 2).
3.2
2.5
[2b–H][H–1c]
0
.0
1c + 2b + H2
TS s-trans/trans-2b•••H•••H•••1c
d(H-H) = 0.83 Å
The thermodynamics of the hydrogen activation by the FLP
2
b•1c was investigated by density functional theory (DFT) as Fig. 4 Computed free reaction and transitions state energies for the H
2
-activation by
the three amidine conformers of 2b with 1c in kcal/mol (selected hydrogen atoms were
4
4,45
implemented in the ORCA package.
optimized using PBEh-3c/def2-mSVP
Structures were omitted for clarity).
functional including
4
6–48
4
9,50
dispersion correction D3BJ
and thermochemical properties The energies for H -activation are in the same order of
2
at 90 °C were obtained from frequency calculations. magnitude as the barriers for the conformer isomerisation, so
Equilibrium geometries were confirmed by the absence of that all three conformers were considered as active Lewis
imaginary frequencies whereas transition states were bases in the H -splitting. The activation of H by the FLPs is
2
2
characterized by one imaginary frequency along the reaction endergonic by 3.9 kcal/mol to 9.9 kcal/mol, which is in
trajectory. Final energy evaluations were conducted with the agreement with the detection of traces of H -acivation
2
5
1–53,48
double hybrid functional PWP95/def2-QZVPP
using RI- products by NMR spectroscopy. The splitting of H with the
2
acceleration, D3BJ and solvation model based on density most stable conformer results in a barrier of 20.8 kcal/mol,
5
4
(
SMD) for benzene.
2
whereas the energy for the H -activation with the other two
The s-cis/trans conformer of 2b found to be 3.3 kcal/mol more conformers is by ca. 3 kcal/mol lower (17.4 kcal/mol and 18.0
stable than the s-trans/trans isomer (Fig.3).
kcal/mol). The subsequent deprotonation of the amidinium
species may result in the equilibration of the amidine isomers
of 2b, offering an alternative pathway to isomerization.
However, the computational study shows that the activation
barriers are comparable for all three isomers.
2
2.1
1
6.8
Next, the FLP-system 1c/2b was subjected to the
hydrogenation of electron-deficient double bonds with
suitable functional groups for hydrogen bond activation
3
.3
5
5
(Scheme 5).
1
.2
s-trans/trans-2b
0
.0
s-trans/cis-2b
s-cis/trans-2b
1
c/2b
x mol%)
H2 (4 bar)
(
EWG
CO Et
EWG
CO2Et
Ph
Ph
2
C D
6
6,
9
0 °C
EWG = CO Et (5a)
x = 100: 90%
20: 70%
x = 100: 95%
EWG = CO Et (4a),
2
2
1
8 h
SO Ph (4b)
2
SO Ph (5b)
Fig. 3 Free energies for three conformers of 2b and their transition state energies for
interconversion and transition state energies in kcal/mol (selected hydrogen atoms
were omitted for clarity).
2
50: 95%
Scheme 5 Hydrogenation of electron-deficient double bonds (yields determined
by NMR using silicon grease as internal standard).
The hydrogenation of 4a and 4b was successfully achieved in
the presence of stoichiometric amounts of 1c/2b after 18 h (4
bar H ). In the presence of substoichiometric amounts of the
2
catalyst, both reactions were efficiently promoted and the
products 5a and 5b were obtained in 70% and 95%
respectively.
The barrier for the interconversion of these to isomers by C–N
bond rotation was calculated to 16.8 kcal/mol and can be
readily achieved at 90 °C. The interconversion of s-cis/trans-2b
to the 1.2 kcal/mol less stable s-trans/cis isomer requires
substantially more energy (22.1 kcal/mol). Next we
investigated the potential of these three conformers to act as
2
Lewis bases in the H -splitting with 1c (Fig.4).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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ARTICLE
Organic & Biomolecular Chemistry
Finally, we investigated the asymmetric hydrogenation of the reduced in high yields although in racemic form,VwiewhAicrthiclemOinglihnet
ketimine 6 and the dehydro amino acid 7 with the hydrogen be a result of the conformational fleDxiObIi:li1t0y.10o3f9/tDh0eOBd0o14u9b2lCe
bond donor/borane catalyst (Scheme 6 and 7).
hydrogen bond donor.
1
c/2b
Conflicts of interest
There are no conflicts to declare.
(
25 mol%)
H2 (4 bar)
H
Ph
N
Ph
N
Ph
Ph
C D
Me
6 6,
Me
70 °C
6
18 h
8 (>95%, rac.)
Acknowledgements
Scheme 6 FLP-catalysed hydrogenation of 6.
The German science foundation (DFG) (PA 1562/16-1) and the
FCI is gratefully acknowledged for financial support and a
Kekulé-Stipendium to N. Sitte. We thank Dr. Meng He for the
preparation of 2b.
base/1c
25 mol%)
H2 (4 bar)
temp. base yield
Me
Me
(
9
0 °C
0 °C
lut
“
85%
25%
7
O
NH
O
NH
TMP 80%
C D
6
6,
PoTol 0%
3
18 h
H C
2
CO Bn
H C
3
CO Bn 90 °C
2b
55% (rac.)
2
2
“
“
“
“
“
>95% (96 h)
30% (rac.)
7
9
Notes and references
70 °C
65% (96 h)
a
90% (96 h, rac.)
‡ Epimerization of the stereocentre in 2b in the presence of 10
mol% 1c at 90 °C does not occur.
50 °C
40% (96 h, rac.)a
Scheme 7 Lewis base influence on the FLP-catalysed hydrogenation of the 1 Pihko, Petri M., Hydrogen Bonding in Organic Synthesis, Wiley-
dehydro amino acid 7 (yields determined by NMR using silicon grease as internal
VCH, Weinheim, 2009.
standard).
2
3
M. S. Taylor and E. N. Jacobsen, Angew. Chem. Int. Ed., 2006, 45,
a
2
performed with 80 bar H .
1
520–1543.
A. G. Doyle and E. N. Jacobsen, Chem. Rev., 2007, 107, 5713–
743.
5
The ketimine 6 was reduced to the secondary amine 8 in 4 D. Wang and D. Astruc, Chem. Rev., 2015, 115, 6621–6686.
5
J. Wang and Y.-G. Zhou, in Homogeneous Hydrogenation with
Non-Precious Catalysts, John Wiley & Sons, Ltd, 2019, pp. 261–
excellent yield within 18 h, however the product was obtained
in racemic form. The catalytic performance of 1c/2b in the
hydrogenation of 4a, 4b and 6 is comparable to earlier reports
using 1c as catalyst.4
2
84.
6
S. Rossi, M. Benaglia, E. Massolo and L. Raimondi, Catal. Sci.
Technol., 2014, 4, 2708–2723.
3,42,56
Next, we investigated the FLP-catalyzed hydrogenation of the 7 A. M. F. Phillips and A. J. L. Pombeiro, Org. Biomol. Chem., 2017,
1
5, 2307–2340.
C. Zhu, K. Saito, M. Yamanaka and T. Akiyama, Acc. Chem. Res.,
015, 48, 388–398.
dehydro amino acid 7. Since such substrates have not yet been
reduced by FLP-catalysts, we first evaluated the 1c/2,6-lutidine
lut) system at 90 °C. The hydrogenation of 7 to N-acetyl
8
9
2
(
S. G. Ouellet, A. M. Walji and D. W. C. Macmillan, Acc. Chem. Res.,
2007, 40, 1327–1339.
alaninylbenzoate 9 proceeded smoothly in 85% yield. The yield
decreased to 25% when the reaction was performed at 70 °C. 10 D. Kampen, C. M. Reisinger and B. List, in Asymmetric
Organocatalysis, ed. B. List, Springer, Berlin, Heidelberg, 2009,
However, the yield was improved to 80% by using 2,2,6,6-
tetramethylpiperidine (TMP) at the same temperature. When
b was employed as Lewis base, the reaction proceeded in
pp. 1–37.
1
1 M. Rueping, J. Dufour and F. R. Schoepke, Green Chem., 2011,
2
1
3, 1084–1105.
comparable yields to the 2,6-lutidine system (55% and 30% 12 C. Zheng and S.-L. You, Chem. Soc. Rev., 2012, 41, 2498–2518.
after 18h and >95% and 65% after 96h at 90 °C and 70 °C 13 Z.-L. Xia, Q.-F. Xu-Xu, C. Zheng and S.-L. You, Chem. Soc. Rev.,
2
020, 49, 286–300.
respectively). The product 9 was isolated as racemic material.
The pressure increase to 80 bar H led only to slightly
improved yields (90%, 80 bar H versus 65%, 4bar H ) but
1
1
4 F. Shi and L.-Z. Gong, Angew. Chem. Int. Ed., 2012, 51, 11423–
2
1
1425.
2
2
5 G. C. Welch, R. R. S. Juan, J. D. Masuda and D. W. Stephan,
allowed us to perform the reaction at 50 °C. However, the
Science, 2006, 314, 1124–1126.
‡
products were obtained as racemic material. The observed 16 D. W. Stephan, Org. Biomol. Chem., 2008, 6, 1535–1539.
1
7 D. W. Stephan and G. Erker, Angew. Chem. Int. Ed., 2010, 49,
marginal change in the reaction speed suggests that not the
-activation is the rate determining step but the
hydride/proton transfer.
4
6–76.
H
2
1
1
2
2
8 J. Paradies, Synlett, 2013, 24, 777–780.
9 J. Paradies, Angew. Chem. Int. Ed., 2014, 53, 3552–3557.
0 D. W. Stephan, J. Am. Chem. Soc., 2015, 137, 10018–10032.
1 D. W. Stephan and G. Erker, Angew. Chem. Int. Ed., 2015, 54,
6400–6441.
Conclusions
2
2 J. Lam, K. M. Szkop, E. Mosaferi and D. W. Stephan, Chem. Soc.
Rev., 2019, 48, 3592–3612.
In conclusion, we have shown for the first time that amidines
are active Lewis bases in the heterolytic splitting of molecular 23 J. Paradies, Coord. Chem. Rev., 2019, 380, 170–183.
2
2
2
4 J. Paradies, Eur. J. Org. Chem., 2019, 2019, 283–294.
hydrogen in the presence of electrophilic triaryl boranes. The
FLPs are active hydrogenation catalysts for the reduction of
electron-deficient double bonds. Prochiral substrates were
5 T. Ishikawa and T. Isobe, Chem. – Eur. J., 2002, 8, 552–557.
6 B. M. Nugent, R. A. Yoder and J. N. Johnston, J. Am. Chem. Soc.,
2
004, 126, 3418–3419.
4
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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB01492C