Iridium-Catalyzed, β-Selective C(sp3)-H Silylation of Aliphatic Amines to Form Silapyrrolidines and 1,2-Amino Alcohols

Article abstract of DOI:10.1021/jacs.8b10428

The functionalization of unactivated C(sp³)-H bonds of aliphatic amines catalyzed by transition-metal complexes is important because amine-based functionality is present in a majority of biologically active molecules and commercial pharmaceuticals. However, such reactions are underdeveloped and challenging to achieve in general because the basicity and reducing properties of alkylamines tends to interfere with potential reagents and catalysts. The functionalization of C-H bonds β to the nitrogen of aliphatic amines to form prevalent 1,2-amino functionalized structures is particularly challenging because the C-H bond β to nitrogen is stronger than the C-H bond α to nitrogen, and the nitrogen in the amine or its derivatives usually directs a catalyst to react at more distal γ- and δ-C-H bonds to form 5- or 6-membered metallacyclic intermediate. The enantioselective functionalization of a C-H bond at any position in amines also has been vexing and is currently limited to reactions of specific, sterically hindered, cyclic structures. We report iridium-catalyzed, β-selective silylations of unactivated C(sp³)-H bonds of aliphatic amines to form silapyrrolidines that are both silicon-containing analogs of common saturated nitrogen heterocycles and precursors to 1,2-amino alcohols by Tamao-Fleming oxidation. These silylations of amines are accomplished by introducing a simple methylene linker between the heteroatom and silicon that has not been used previously for the silylation of C-H bonds. The reactions occur with high enantioselectivity when catalyzed by complexes of new chiral, pyridyl imidazoline ligands, and the rates of reactions with catalysts of these highly basic ligands are particularly fast, occuring in some cases at or even below room temperature.

Full text of DOI:10.1021/jacs.8b10428

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Article
Iridium-catalyzed, #-selective C(sp3)–H silylation of aliphatic
amines to form silapyrrolidines and 1,2-amino alcohols
Bo Su, Taegyo Lee, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b10428 • Publication Date (Web): 24 Oct 2018
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Iridium-catalyzed, β-selective C(sp3)–H silylation of aliphatic amines to
form silapyrrolidines and 1,2-amino alcohols
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,‡
Bo Su†, Taegyo Lee† , and John F. Hartwig*
Department of Chemistry, University of California, Berkeley, California, 94720, CA
ABSTRACT: The functionalization of unactivated C(sp3)-H bonds of aliphatic amines catalyzed by transition-metal complexes
is an important because amine-based functionality is present in a majority of biologically active molecules and commercial
pharmaceuticals. However, such reactions are under-developed and challenging to achieve in general because the basicity
and reducing properties of alkylamines tends to interfere with potential reagents and catalysts. The functionalization of C-H
bonds β to the nitrogen of aliphatic amines to form prevalent 1,2-amino functionalized structures is a particular challenge to
achieve because the C-H bond b to nitrogen is stronger than the C-H bond α to nitrogen, and the nitrogen in the amine or its
derivatives usually directs a catalyst to react at more distal γ- and δ-C-H bonds to form 5- or 6-membered metallacyclic inter-
mediate. The enantioselective functionalization of a C-H bond at any position in amines also has been vexing and is currently
limited to reactions of specific, sterically hindered, cyclic structures. We report iridium-catalyzed, β-selective silylations of
unactivated C(sp3)-H bonds of aliphatic amines to form silapyrrolidines that are both silicon-containing analogs of common
saturated nitrogen heterocycles and precursors to 1,2-amino alcohols by Tamao-Fleming oxidation. These silylations of
amines are accomplished by introducing a simple methylene linker between the heteroatom and silicon that has not been
used previously for the silylation of C-H bonds. The reactions occur with high enantioselectivity when catalyzed by complexes
of new chiral, pyridyl imidazoline ligands, and the rates of reactions with catalysts of these highly basic ligands are particularly
fast and even occur at or even below room temperature.
can prevent the deactivation of the catalyst and the oxida-
tion of the amine, facilitate the coordination of substrate to
the catalyst, and direct the functionalization to specific sites.
Reactions of such amine derivatives by coordination of the
metal to this nitrogen atom usually provide products from func-
tionalization of the C-H bonds γ or δ to the amino group by
forming a five- or six-membered metallacyclic intermediate
(Figure 1a, i). 6, 7-8 A second strategy involves the complexa-
tion of the amine to a Brønsted acid or Lewis acid. This com-
plexation deactivates the C-H bonds proximal to the nitro-
gen and directs the reaction to occur at C-H bonds more dis-
tal to this atom (Figure 1a, ii).9 A third strategy involves the
installation of a removable linker between the nitrogen of
the aliphatic amine and the functional group that is being
introduced, thereby rendering the process intramolecular
(Figure 1a, iii).10 This strategy has led to the metal-catalyzed
insertion of nitrenes into C-H bonds, most commonly into
tertiary or activated secondary C–H bonds.10a, 10b
Introduction
Aliphatic amines are important organic compounds that
are commonly found in natural products and pharmaceuti-
cals,1 including almost half of the top 200 drugs by prescrip-
tions in the US in 2016.2 Therefore, methods that enable ef-
ficient synthesis or selective functionalization of aliphatic
amines have been pursued intensively. Among various ap-
proaches to the synthesis of functionalized aliphatic amines,
site-selective functionalization of traditionally unreactive
C-H bonds catalyzed by transition metals is attractive be-
cause this process can occur with reactants that contain
fewer functional groups than those typically needed to pre-
pare products containing amino groups, and it can intro-
duce functional groups at sites that are usually unreactive
in amines.
However, the development of site-selective functionaliza-
tion of C–H bonds of aliphatic amines has been limited be-
cause of the challenges associated with this process. For ex-
ample, functionalizations of the C–H bonds in aliphatic
amines often occur at highly activated C–H bonds α to nitro-
gen,3 rather than the stronger C-H bonds more distal to ni-
trogen.4 In addition, the oxidative conditions of many C–H
functionalization processes lead to N-oxides, and amines
can bind strongly to transition metals, thereby deactivating
the catalyst.5
We considered that the silylation of C–H bonds could en-
able the selective functionalization of amines because hy-
drosilanes are reducing and would not oxidize the amine ni-
trogen.11 In addition, the oxidative addition of an Si-H bond
would likely occur in the presence of amines, render the
subsequent C-H bond silylation intramolecular, and address
both deactivation of the catalysts by free amines and over-
come the tendency of metal complexes to react at the C-H
bond α to nitrogen. Previously, our group reported metal-
catalyzed intramolecular silylations of unactivated C(sp3)-H
bonds by first forming an O-Si bond between the alcohol
and a silane.12 However, efforts to develop the silylation of
C(sp3)-H bonds in amines by first forming an N-Si bond led
to functionalizations of only activated benzylic C(sp3)-H
Various strategies have been explored to address these
challenges and achieve the site-selective functionalization
of C-H bonds in aliphatic amines (Figure 1a). One of the
most common strategies is to convert the free amine to an
amide or imine.6, 7 The installation of such auxiliary moieties
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bonds in aniline derivatives (Figure 1b, i).13 Reactions of hy-
drosilyl amines derived from aliphatic amines underwent
disproportionation and decomposition due to the instabil-
ity of the N-Si linker (Figure 1b, ii). Therefore, a different
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Figure 1. Strategies, challenges, conception, realization, and potential applications of C-H functionalization of aliphatic amines.
approach to link the nitrogen and silicon that would with-
stand the conditions of the C-H bond functionalization pro-
cess was needed for the silylation of alkylamines to occur in
high yield (Figure 1b, iii).
Enantioselective functionalizations of C-H bonds14, 15, 16 in
aliphatic amines at any site are rare, perhaps because
poorly selective catalysts can form by coordination of the
achiral amine reactants. Only one enantioselective function-
alization of a C(sp3)-H bond in an aliphatic amine has been
reported,16e and this reaction requires a cyclic secondary
amine that possesses two adjacent tertiary carbons.
1. Initial silylations of aliphatic amines. Our studies on
the silylation of C-H bonds in aliphatic amines began with
reactions of silylmethylamines. This substrate was selected
because the silylmethylamine would be more stable to hy-
drolysis and disproportionation than a silylamine, cycliza-
tion would form five-membered ring products that have
been studied as silicon-containing analogs of pyrrolidine
derivatives, and oxidation would generate a hemiaminal
that would hydrolyze to an amino alcohol. This amino alco-
hol would result from an overall hydroxylation β to the
amino group. Such hydroxylations have been limited to hy-
drazone derivatives that require over six steps to prepare
or secondary amines that contain two hindered tertiary al-
kyl groups on the nitrogen in a ring.6i, 20
We report an iridium-catalyzed, β-selective silylation of
unactivated C(sp3)-H bonds of aliphatic amines (Figure 1c).
The reaction is enabled by linking a hydrosilyl unit to the
nitrogen by a methylene group, which is easily prepared by
alkylation of the amine with a chloromethylsilane.17 The re-
action occurs enantioselectively at one of two enantiotopic
methyl groups when conducted with a pyridyl imidazoline
ligand. Such ligands have rarely been used in asymmetric
catalysis, but were evaluated because they make the metal
center more electron rich than those in complexes of more
common chiral, nitrogen-based ligands.18 The silapyrroli-
dine products are known to possess unique physical and
chemical properties for medical chemistry (Figure 1d),19
and are precursors to 1,2-amino alcohols after oxidation of
the Si-C bond.
To identify conditions for the iridium-catalyzed, β-selec-
tive silylation of the alkyl C-H bond of a silylmethylamine,
the reactions of (silylmethyl)amine 2a with various iridium
catalysts generated from [Ir(cod)OMe]2 and dinitrogen lig-
ands L1-L6 were evaluated (Table 1). The reaction con-
ducted with 4,4’-di-tert-butylbipyridine L1 as the ligand
and norbornene as the hydrogen acceptor at 100 °C formed
silapyrrolidine 3a in 46% yield (entry 1). Higher yields
were obtained from the reactions with phenanthroline lig-
ands L2-L5 than with 4,4′-di-tert-butylbipyridine L1 (entry
2-5). Among these phenanthroline ligands, sterically hin-
dered 2-substituted phenanthrolines L4 and L5, used pre-
viously for the iridium-catalyzed, intermolecular silylation
of aromatic C-H bonds,21 formed more active catalysts than
did L2 and L3. However, 2,9-disubstituted phenanthroline
Results and Discussion
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L6, which is more sterically hindered than L4 and L5, gen-
amine 2t gave silapyrrolidine 3t from silylation of the β-
C(sp3)-H bond as the major product over benzosilapiperi-
dine 3tt, which would form from silylation of the γ-C(sp2)-
H bond. Reaction of 2u, which contains primary β- and γ-
C(sp3)-H bonds and secondary β-C(sp3)-H bonds, formed
the sole product 3u from silylation of the primary β-C(sp3)-
H bond.
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erated a less active catalyst (entry 6). In the absence of any
dinitrogen ligand, the reaction gave the silylation product
3a in a very low yield (6%, entry 7), indicating that (silyl-
methyl)amine 2a itself cannot serve as a ligand to generate
an active iridium catalyst for this C-H bond functionaliza-
tion. Although we typically assembled our silylation reac-
tions in an N2-filled glovebox, a high yield of the silapyrroli-
dine product 3a was obtained from the reaction conducted
by standard air-free techniques without a glovebox (entry
8).
Table 2. Scope of the intramolecular C-H silylation of al-
iphatic aminea
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Table 1. Evaluation of conditions for the intramolecular
C-H silylation of 2aa
aReactions were conducted on a 0.10 mmol scale in an N2-filled
glovebox, and the yields refer to 1H NMR yields using 1,3,5-tri-
b
methoxybenzene as an internal standard. Reaction was con-
ducted on a 0.25 mmol scale using a standard air-free tech-
nique outside an N2-filled glovebox.
2. Scope of the silylation of aliphatic amines. Having es-
tablished conditions for the silylation of (silylmethyl)amine
2a, we investigated the scope of the reaction (Table 2). β-
Selective silylations of amines that contain various cyclic or
acyclic alkyl groups proceeded smoothly, affording si-
lapyrrolidines 3a-3e in high yields (75-82%). A wide range
of functional groups, such as a cyclic ether (3f), ketals (3g
and 3h), cyclic and linear alkenes (3i and 3j), various aryl
halides (3k-3n), and a methoxy group (3p) were tolerated.
Fused silapyrrolidines 3q-3s also were obtained. The
unique properties for silicon-containing pyrrolidine deriva-
tives have been highlighted, but current methods for their
preparation require both enamine and ester groups en
route to silaproline derivatives,22 whereas the catalytic
method we report provides silapyrrolidine derivatives from
amines without the need for additional functionality in the
reactant.
3. Formation of 1,2-amino alcohols. 1,2-Aminoalcohols
are common substructures and precursors to natural prod-
ucts and pharmaceuticals and could be envisioned to form
by hydroxylation of aliphatic amines. Part of our design of
the silylmethylamine substructure for the silylation of C-H
bonds was based on the anticipated Tamao-Fleming oxida-
tion of the silapyrrolidine to an aminal that would hydrolyze
to the 1,2-amino alcohol. However, this process requires
conditions in which the Si-C bond oxidizes in preference to
the amine nitrogen.
To investigate the selectivity of the silylation process to-
ward β- and γ-C-H bonds, the silylation of amines 2t and 2u
containing γ-C-H bonds that are aliphatic and aromatic were
conducted. Although aromatic C-H bonds are generally
more reactive than alkyl C-H bonds toward functionaliza-
tions through organometallic intermediates, the reaction of
To identify conditions for the Tamao-Fleming oxidation of
silapyrrodine 3, we conducted reactions with various oxi-
dants and additives. These experiments showed that the ox-
idation of 3 formed amino alcohol 4 in good yields (79-
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92%), as determined by NMR spectroscopy, without oxida-
tion of the amino group in 4 when conducted with tert-butyl
hydroperoxide (TBHP), cesium hydroxide, and tetrabu-
tylammonium fluoride (TBAF) in THF at room temperature.
Page 4 of 8
amines, iridium complexes of a variety of chiral N,N-ligands
were investigated as catalysts for the silylation of amine 2a
(Table 4). An initial survey with chiral, nitrogen-based lig-
ands that are commonly used in asymmetric catalysis, such
as bis(oxazoline) ligands (e.g. L7, entry 1) and pyridyl oxa-
zoline ligands (e.g. L8, entry 2) that formed highly enanti-
oselective catalysts in our prior silylation of both C(sp2)-H
and C(sp3)-H bonds,23e, 23f showed that the reactivity and en-
antioselectivity of catalysts formed from these common
classes of chiral N,N-based structures were low.
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Examples of the formation of 1,2-amino alcohols are
shown in Table 3. Functional groups, such as a cyclic ether
(4f), a ketal (4h), an alkene (4j), and a fluoroaryl group
(4m), were tolerated under the oxidation conditions. To fa-
cilitate the isolation by silica-gel chromatography, amino al-
cohols 4 from the oxidation of silapyrrolidines 3 were con-
verted to the corresponding carbamate 5 by treatment with
di-tert-butyl carbonate and base.
9
We hypothesized that ligands containing an imidazoline
unit might generate more active catalysts than those con-
taining an oxazoline unit because the imidazoline unit is
more basic than an oxazoline.18 This greater basicity of the
imidazoline group would lead to more electron-rich cata-
lysts than those containing an oxazoline donor and to higher
reactivity toward the oxidative addition of C–H bonds.
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Table 3. 1,2-amino alcohols derived from C-H silylation
productsa
To test this hypothesis, pyridyl imidazoline L9 was syn-
thesized. Indeed, the silylation of 2a with L9 occurred in a
higher yield and a higher enantioselectivity than that with
pyridyl oxazoline L8 (entry 2 and 3). The enantioselective
silylation of the C-H bond occurred even at room tempera-
ture to give 3a in a higher yield (85%) and a higher e.r. (15
: 85) than those from the analogous reaction at 80 °C (entry
4). This reactivity of the catalyst derived from the new
pyridyl imidazoline ligand L9 was higher than that of any
prior metal-catalyzed silylation of a C-H bond.
Table 4. Evaluation of asymmetric C-H silylation of 2aa
To demonstrate the applicability of the combined C-H
bond silylation and C-Si bond oxidation to the functionaliza-
tion of more complex amines, the hydroxylation of a deriv-
ative of propranolon, one of the top 200 drugs by prescrip-
tion in 2016 in US, was conducted (Figure 2). Under our con-
ditions for the β-selective silylation of C(sp3)-H bonds of al-
iphatic amines, silapyrrolidine 7 was obtained in 90% yield.
Oxidation of silapyrrolidine 7 formed amino alcohol 8,
which was then transformed to carbamate 9 in 54% yield
over 2 steps.
Figure 2. Modification of pharmaceutical molecule via C-H si-
lylation and C-Si oxidation.
4. Enantioselective silylation of aliphatic amines. To
develop a catalyst for the site-selective and enantioselective
silylation11d, 23 of unactivated C(sp3)-H bonds of aliphatic
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Table 5. Scope of the asymmetric C-H silylation of aliphatic
aminesa
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Having identified conditions for the site- and enantiose-
lective silylation of the aliphatic C-H bonds in 2a, the enan-
tioselectivity of the reactions of other aliphatic amines was
examined (Table 5). (Silylmethyl)amines containing a cy-
clohexyl group (2a), a cyclopentyl group (2b), and a cyclo-
heptyl group (2c) were converted to the corresponding si-
lapyrrolidines (S)-3a-3c with high enantioselectivity (89 :
11 to 91.5 : 8.5 e.r.) in good yields. In addition, the reaction
of amine 2f, bearing an oxygen-containing six-membered
ring, and amine 2m, containing a less sterically bulky 2,6-
difluorobenzyl group, gave the chiral, silapyrrolidines (S)-
3f and (S)-3m in high yields with good enantioselectivity.
Thus, the reaction can tolerate a saturated heteroaryl ring,
does not require a secondary alkyl group on nitrogen, and
can be conducted with a removable group (2,6-difluoroben-
zyl group) from the nitrogen to generate a chiral, cyclic sec-
ondary silapyrrolidine poised for further modifications at
nitrogen.
To increase the enantioselectivity of the site-selective si-
lylation of amine 2a further, we prepared various pyridyl
imidazoline ligands (L10-L16, L18) and a quinolinyl imid-
azoline ligand L17 and studied the reactivity and enantiose-
lectivity of the catalysts derived from those ligands. Investi-
gation of the effect of substituents on the imidazoline frag-
ment of the ligand (L10-L13) showed that the enantioselec-
tivity of the reaction with L10 as ligand was a higher 89.5 :
10.5 (entry 5-8). Modification of the pyridine fragment of
the ligand (entry 9-12, L14-L17) showed that the reaction
with the quinolinyl imidazoline L17 formed the product
with high enantioselectivity, but in only 29% yield (entry
12). However, the reaction catalyzed by the complex gener-
ated from the N-alkyl imidazoline L18 occurred with both
high reactivity and selectivity (entry 13). The reaction cata-
lyzed by this complex occurred in a good yield (76%), even
below room temperature, to provide the silylation product
in a high e.r. (89.5 :10.5) (entries 14-15). The yield of 3a in-
creased to 82% from 76% without decrease of the enanti-
oselectivity by using [Ir(cod)Cl]2 as the source of iridium,
rather than [Ir(cod)OMe]2 (entry 16). These results repre-
sent the first examples in which pyridyl imidazoline ligands
have been used for a catalytic reaction with a high enanti-
oselectivity.24
Conclusions
Prior studies on the functionalization of aliphatic amines
required the amines to be very sterically hindered or to be
transformed to amides or imines. A series of features of the
substrate and catalyst in the current work have overcome
these limitations and enabled regioselective functionaliza-
tion of an alkylamine by a hydrosilyl unit with unusual se-
lectivity for the C-H bond located β to nitrogen. First, the in-
corporation of a methylene linker between the nitrogen of
the amine and the silyl group using a chloromethylsilane as
reagent addresses the instability of the N-Si bond observed
during prior studies of the silylation of amines and leads to
a rare β-selectivity for the functionalization of C-H bonds in
aliphatic amines due to the size of the intermediate metal-
lacycle. Second, the use of a silane as the functionalizing re-
agent avoids metal binding or oxidation at the electron pair
of nitrogen that usually occurs at C-H functionalization of
amines under oxidative conditions, and oxidation of the C-
Si bonds in the presence of the amine unit allows the 1,2-
amino alcohol to be generated, representing a formal β-hy-
droxylation of alkylamines. Third, linking of silicon to the
nitrogen atom avoids deactivation of the catalyst by the
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(5)
Smalley, A. P.; Gaunt, M. J., Mechanistic Insights into the
amines and prevents reaction at the weaker α C-H bond be-
cause reaction at this position would form a strained, four-
membered azasiletidine. Finally, the design of modular, chi-
ral, imidazoline ligands led to highly enantioselective cata-
lysts that are highly reactive, thereby enabling reactions to
occur at or below room temperature and enhancing stere-
oselectivity. Further applications of these principles and
these new ligands for catalytic enantioselective reactions
are ongoing in our laboratory.
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Supporting Information. Experimental procedures, charac-
terization data, NMR spectra for new compounds (PDF), and
this material is available free of charge via the Internet at
http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
* jhartwig@berkeley.edu
Present Addresses
‡Chemical Research and Development, Pfizer Worldwide Re-
search and Development, Groton Laboratories, Eastern Point
Road, Groton, Connecticut 06340, United States
Author Contributions
†These authors contributed equally.
Funding Sources
We thank the NIH GM115812 for support of this work
(7)
(a) Nadres, Enrico T. Daugulis, Olafs Nadres, E. T.;
Daugulis, O., Heterocycle Synthesis via Direct C-H/N-H Coupling J.
Am. Chem. Soc. 2012, 134, 7; (b) Chuentragool, P.; Parasram, M.;
Shi, Y.; Gevorgyan, V., General, Mild, and Selective Method for
Desaturation of Aliphatic Amines J. Am. Chem. Soc. 2018, 140, 2465.
(8)
Xu, Y.; Dong, G., sp3 C–H activation via exo-type directing
groups Chem. Sci. 2018, 9, 1424.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
T.L. thanks the Samsung Scholarship for a graduate fellowship
and Dr. Ala Bunescu, Dr. Matthew A. Larsen, Dr. Sarah Y. Lee
and Yumeng Xi for insightful discussions.
(9)
(a) Lee, M.; Sanford, M. S., Platinum-Catalyzed, Terminal-
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Zhang, Y.-F.; Shi, Z.-J., Palladium catalyzed C(sp3)-H acetoxylation
of aliphatic primary amines to r-amino alcohol derivatives Org.
Chem. Front. 2017, 4, 2097.
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rare, β-selective C-H activation of amines;
access to silapyrrolidines & 1,2-amino alcohols;
a new pyridyl imidazoline ligand for asymmetric C(sp3)-H silylation
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