Chemoselective amide reductions by heteroleptic fluoroaryl boron Lewis acids

Article abstract of DOI:10.1039/c8cc01863d

The heteroleptic borane catalyst (C₆F₅)₂B(CH₂CH₂CH₂)BPin is found to hydrosilylatively reduce amides under mild conditions. Simple tertiary amides can be reduced using Me₂EtSiH, whereas tertiary benzamides required a more reactive secondary silane, Et₂SiH₂, for efficient reduction. The catalytic system described exhibits exceptional chemoselectivity in the reduction of oligoamides and tolerates functionalities which are prone to reduction under similar conditions.

Full text of DOI:10.1039/c8cc01863d

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: M. Peruzzi, Q.
Mei, S. Lee and M. Gagné, Chem. Commun., 2018, DOI: 10.1039/C8CC01863D.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 4
View Article Online
DOI: 10.1039/C8CC01863D
ChemComm
COMMUNICATION
Chemoselective amide reductions by heteroleptic fluoroaryl
boron Lewis acids
Michael T. Peruzzi,a Qiong Qiong Mei,a Stephen J. Lee,b and Michel R Gagnéa
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Heteroleptic borane catalyst (C6F5)2B(CH2CH2CH2)BPin is found to
hydrosilylatively reduce amides under mild conditions. Simple
tertiary amides can be reduced using Me2EtSiH, whereas tertiary
benzamides required a more reactive secondary silane, Et2SiH2, for
efficient reduction. The catalytic system described exhibits
exceptional chemoselectivity in the reduction of oligoamides and
tolerates functionalities which are prone to reduction under
similar conditions
The reduction of amides to amines is a fundamental
transformation that has traditionally been accomplished with
main-group metal hydrides (LAH, DIBAL-H, etc.). However, the
aggressive nature of these reagents can lead to poor selectivity
and functional group tolerance. Catalytic methods1,2
employing transition metal catalysts in combination with
hydrogen as the stoichiometric reductant have been
developed, however in most cases elevated temperatures and
pressures of hydrogen must be employed.3–6 Alternatively, the
catalytic, reductive hydrosilylation of amides using transition
metals (Ni,7 Rh,8,9 Ir,10 Pt,11 Zn12) can occur under milder
conditions and thus exhibit good functional group tolerance
and selectivity. In addition to transition metal catalysts is the
recent emergence of main-group Lewis acids13–16, such as
B(C6F5)3 (BCF), however, many of these systems require
elevated temperature,17,18 stoichiometric activation of the
amide,19 or activated amides.20
the
Scheme 1 Chemoselective amide reduction of natamycin derivative by heteroleptic
borane catalyst 2
enoate, lactol, or combinations thereof. In each case, other
reactive sites were not affected (epoxide, tetraene, anomeric
center, etc.). One alluring facet of the heteroleptic borane
catalyst
2 is its high modularity. By virtue of its in situ
formation from readily available starting materials ((C6F5)2BH
and the corresponding olefin22–28), catalyst variations can
quickly be assessed, akin to the variation of ligands in
transition metal catalysed reactions. To this end, we sought to
utilize this platform to develop a second generation catalyst
that might offer increased efficiency and selectivity for amide
reductions.
We began by monitoring (1H-NMR) the initial rate of
While investigating the chemoselective reduction of
complex bioactive molecules,21 we were struck by the
reducing tertiary alkyl amide (
several novel borane catalysts (Table 1). From this short
screen, we identified a catalyst ( ), which performed the
reduction at a rate x13 of catalyst . Since boryl migration at
elevated temperatures is possible in certain cases,23 and
sterics should inhibit this in catalyst , we focused on the allyl
3) with 2.5 equiv. Me2EtSiH and
unprecedented selectivity of catalyst
2
to chemoselectively
(57%
5
and hydrosilylatively reduce the acetamide moiety of
1
2
yield, Scheme 1). Homoleptic B(ArF)3 as catalysts, by contrast,
do not reduce the amide and instead carry out reductions at
7
Bpin derived catalyst. It performed at a rate x8 faster than
2
and existed as a single major species by 19F-NMR (see
supplemental information). Notably, all catalysts in this study
out performed 2 in terms of initial rates.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
View Article Online
DOI: 10.1039/C8CC01863D
COMMUNICATION
Journal Name
Table 1: Initial rates for the reduction of 3° amide, 3, by various boron catalysts
Table 2: Reduction of alkyl tertiary amides
(C6F5)2BH (5 mol%)
(C6F5)2BH (5 mol%)
olefin (6 mol%)
O
allyl-Bpin (6 mol%)
O
Me2EtSiH (2.5 equiv)
Me2EtSiH (3.0 equiv)
Ph
Ph
R'
R'
N
N
R
N
R
N
tol-d8, rt
tol:dcm (6:5), rt, 24h
R''
R''
3
4
Ph
Ph
N
N
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
73%
98%
92%
4
13
15
7
Ph
Ph
Ph
N
Ph
N
98%
O
14
16
Ph
N
N
62%
0%
91%
0%
Ph
17
5
6
7
8
9
10
11
12
Bn
N
N
Ph
aConversion was assessed by 1H-NMR spectroscopy. Initial rates reflect the first 6
hours of reaction time.
18
19
Despite these rapid initial rates, incomplete conversion of
starting material was observed after 24 h. Preliminary studies
on the reduction of dipeptides, vide infra, required a mixed
solvent system (tol/dcm) to fully solubilize starting materials
and so further optimization studies were performed in this
solvent mixture. Increasing the amount of silane to 3 equiv.
Table 3: Reduction of tertiary benzoyl amides
(C6F5)2BH (5 mol%)
O
allyl-Bpin (6 mol%)
Et2SiH2 (2.5 equiv)
R
R
N
N
G
R
R'
R'
tol:dcm (6:5), rt, 24h
allowed for full conversion and isolation of
4 in 73% yield.
Notably, using amides of this type, the parent BCF catalyst
requires forcing conditions (130 °C, 8 eqv. Si–H20) to achieve
lesser conversions. To examine the generality of this reaction
we performed the reduction of several tertiary alkyl amides
(Table 2), which proceeded in good to excellent yield under
these conditions. While N-aryl amides were reduced in good
yield, the reduction of N-Bn amide (18) resulted in complex
mixtures of products. The reduction of 2-oxindoles did not give
the expected indoline (19).29
R=
Yield (%)
N
H (20)
20-25
G
85
93
4-OMe (21)
4-NO2 (22)
4-Br (23)
99
92
N
26
2,4-Cl (24)
2-Br (25)
NR
NR
The application of similar conditions to N-benzoyl amides
with 2.5 (or 3.5) equivalents of Me2EtSiH led to incomplete
conversion of starting material. The tertiary amine products
could be isolated in a moderate yield of 55% with long
reactions times or gentle heating (60 oC). The enhanced
reactivity of a secondary silane (Et2SiH2, 2.5 eqv) proved more
productive, and provided full conversion of starting material
and isolation in 85% yield (Table 3). Both electron donating (-
OMe) and withdrawing (-NO2, -Br) substituents in the para-
position were well tolerated under these conditions and gave
high yields of product (92-99%). Arenes containing
substituents in the ortho position (2,4-Cl, 2-Br), however, were
untouched even after extended reaction times (~72 h). Cyclic
N-benzoyl amides were also reduced in good yield (26).
Benzamide, a primary amide, is not a viable substrate under
these conditions.
74%
BCF mediated hydrosilylation conditions are known to
reduce cyclic ethers, aryl ethers, and aryl nitro groups.
Considering the lack of reduction of these groups in 21 and 22
we concluded that the bias of towards amide reduction may
,
7
provide functional group tolerance and selectivity in more
complex systems. Inspired by the Rh-catalysed reduction of
peptides by Beller et. al.9 we chose to examine these oligo-
amides. The variability of functionality and the presence of
enolizable stereocenters would showcase the potential of
a selective catalyst for amide reduction.
7 as
Given the diverse silane effects in Tables 2 and 3, we
performed a screen to optimize conditions for the reduction of
aspartame derived dipeptide 27 (Table 4). In all cases,
reduction of the acetamide was the major product with no
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 4
View Article Online
DOI: 10.1039/C8CC01863D
Journal Name
COMMUNICATION
evidence for reactivity at the internal amide. This result is increase in the number of equivalents aided in achieving full
consistent with the
conversion of starting material and allowed for isolation of 28
in 85% yield. Given the high yield of this system coupled with
the lack of observable diastereomers (1H-NMR), we reasoned
that epimerization of the enolizable stereocenters is not
problematic under these conditions.
Table 4: Silane screen for dipeptide reduction
To examine the breadth of functional groups that may be
applicable to selective reduction of dipeptides, N-Acetyl
proline was coupled to several amino acids and subjected to
the optimized reaction conditions (Table 5). In all cases
7
selectively reduced the proline acetamide over the internal
secondary amide in good to excellent yield (70-99%). Methyl
and benzyl esters are well tolerated by the reaction conditions
as are TBDMS-ethers, thioethers, and indoles. The reduction of
33’s parent amide required additional equivalents of silane to
achieve satisfactory yields as partial dehydrogenative silylation
of the phenol moiety occurs, which required a deprotection
step prior to chromatography. Triamide 35, which contains
two tertiary amides, is still selectively reduced at the
acetamide.
Silane
Et3Si-H
Yield (%)
Me2EtSiH equiv
Yield (%)
87
79
87
69
78
60
25
2.1
2.5
3.0
Me2EtSi-H
Et2SiH2
93 (85)
96 (87)
MePhSiH2
TMDS
PhSiH3
aYields were assessed by 1H-NMR using 1,3,5-trimethoxybenzene as internal
standard. Isolated yields are given in parenthesis.
To gain further insight into the selectivity and efficiency of
7
in complex environments, we examined the reduction of 1
Table 5: N-Acetyl Proline dipeptide reductions
(Equation 1). We found that the acetamide is selectively
reduced in 75% yield, a significant improvement over the
(C6F5)2BH (5 mol%)
2
(57% yield).21 Furthermore, the
O
R
O
R
previously reported catalyst
allyl-Bpin (6 mol%)
silane (2.5 equiv)
OR
OR
results indicate that TES-ethers, epoxides, olefins, enoates, and
acetals are tolerated under these reaction conditions.
N
N
H
H
N
O
N
O
tol:dcm (6:5), rt, 24h
O
N
OTBDMS
O
O
O
Ph
O
O
O
N
N
Bn
29
30
H
H
O
O
O
N
O
90%
91%
NH
S
O
O
O
O
O
N
N
H
H
31
32
N
N
N
O
OH
95%
99%
In summary, we have developed a readily synthesized
heteroleptic boron catalyst that is capable of reducing alkyl
tertiary amides and benzamides in excellent yield. This catalyst
exhibits good functional group tolerance and high fidelity in
functionally rich environments.
N
H
O
N
33
34
H
O
N
76%
70%
We thank the Army Research Office (ARO) for support
(W911NF-15-2-0119). The mass spectrometer used in these
studies was purchased with the support of the National
Science Foundation under Grant No. (CHE-1726291). We thank
the University of North Carolina’s Department of Chemistry
Mass Spectrometry Core Laboratory, especially Dr. Brandie
Ehrmann for her assistance with mass spectrometry analysis.
O
N
N
H
35
N
O
96%
observation that
7 is sensitive to sterically encumbered
amides. Tertiary silanes gave the highest yield of the desired
product followed by secondary and primary silanes. A slight
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
View Article Online
DOI: 10.1039/C8CC01863D
COMMUNICATION
Journal Name
Ed., 2010, 49, 9475–9478.
Y. Liu and H. Du, J. Am. Chem. Soc., 2013, 135, 12968–
Conflicts of interest
25
26
27
28
29
There are no conflicts to declare
12971.
S. Wei and H. Du, J. Am. Chem. Soc., 2014, 136, 12261–
12264.
Notes and references
X. Ren, G. Li, S. Wei and H. Du, Org. Lett., 2015, 17, 990–
993.
1
2
3
A. Chardon, E. Morisset, J. Rouden and J. Blanchet,
Synthesis, 2018, 984–997.
D. Chen, V. Leich, F. Pan and J. Klankermayer, Chem. - A
Eur. J., 2012, 18, 5184–5187.
A. Volkov, F. Tinnis, T. Slagbrand, P. Trillo and H. Adolfsson,
Chem. Soc. Rev., 2016, 45, 6685–6697.
Reduction of the parent amide of 19, gave N-Me indole as
the sole product (94%). This product likely arises from
elimination of the intermediate O-silyl hemiaminal.
J. Coetzee, D. L. Dodds, J. Klankermayer, S. Brosinski, W.
Leitner, A. M. Z. Slawin and D. J. Cole-Hamilton, Chem. - A
Eur. J., 2013, 19, 11039–11050.
4
5
J. R. Cabrero-Antonino, E. Alberico, K. Junge, H. Junge and
M. Beller, Chem. Sci., 2016, 7, 3432–3442.
T. Mitsudome, K. Miyagawa, Z. Maeno, T. Mizugaki, K.
Jitsukawa, J. Yamasaki, Y. Kitagawa and K. Kaneda, Angew.
Chemie Int. Ed., 2017, 56, 9381–9385.
6
7
8
9
S. Werkmeister, K. Junge and M. Beller, Org. Process Res.
Dev., 2014, 18, 289–302.
B. J. Simmons, M. Hoffmann, J. Hwang, M. K. Jackl and N. K.
Garg, Org. Lett., 2017, 19, 1910–1913.
S. Das, Y. Li, L. Q. Lu, K. Junge and M. Beller, Chem. - A Eur.
J., 2016, 22, 7050–7053.
S. Das, Y. Li, C. Bornschein, S. Pisiewicz, K. Kiersch, D.
Michalik, F. Gallou, K. Junge and M. Beller, Angew. Chemie
Int. Ed., 2015, 54, 12389–12393.
10
11
12
13
14
15
C. Cheng and M. Brookhart, J. Am. Chem. Soc., 2012, 134,
11304–11307.
S. Hanada, E. Tsutsumi, Y. Motoyama and H. Nagashima, J.
Am. Chem. Soc., 2009, 131, 15032–15040.
S. Das, D. Addis, S. Zhou, K. Junge and M. Beller, J. Am.
Chem. Soc., 2010, 132, 1770–1771.
M. Oestreich, J. Hermeke and J. Mohr, Chem. Soc. Rev.,
2015, 44, 2202–2220.
D. Mukherjee, S. Shirase, K. Mashima and J. Okuda, Angew.
Chemie Int. Ed., 2016, 55, 13326–13329.
Y. Li, J. A. Molina de La Torre, K. Grabow, U. Bentrup, K.
Junge, S. Zhou, A. Brückner and M. Beller, Angew. Chemie
Int. Ed., 2013, 52, 11577–11580.
16
17
18
19
20
21
22
23
24
A. Augurusa, M. Mehta, M. Perez, J. Zhu and D. W.
Stephan, Chem. Commun., 2016, 52, 12195–12198.
M. Tan and Y. Zhang, Tetrahedron Lett., 2009, 50, 4912–
4915.
E. Blondiaux and T. Cantat, Chem. Commun., 2014, 50,
9349–9352.
P. Q. Huang, Q. W. Lang and Y. R. Wang, J. Org. Chem.,
2016, 81, 4235–4243.
R. C. Chadwick, V. Kardelis, P. Lim and A. Adronov, J. Org.
Chem., 2014, 79, 7728–7733.
T. A. Bender, P. R. Payne and M. R. Gagné, Nat. Chem.,
2017, 10, 85–90.
D. J. Parks, W. E. Piers and G. P. Yap, Organometallics,
1998, 17, 5492–5503.
D. J. Parks, R. E. Rupert and W. E. Piers, Angew. Chemie Int.
Ed., 1995, 34, 809–811.
D. Chen, Y. Wang and J. Klankermayer, Angew. Chemie Int.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins