Zirconium Hydroaminoalkylation. An Alternative Disconnection for the Catalytic Synthesis of α-Arylated Primary Amines

Article abstract of DOI:10.1021/jacs.9b10465

Primary amine products have been prepared using zirconium-catalyzed hydroaminoalkylation of alkenes with N-silylated benzylamine substrates. Catalysis using commercially available Zr(NMe₂)₄ affords an alternative disconnection to acc

Full text of DOI:10.1021/jacs.9b10465

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Communication
Zirconium Hydroaminoalkylation. An Alternative Disconnection
for the Catalytic Synthesis of #-Arylated Primary Amines
Ana Koperniku, Paul J. Foth, Glenn M. Sammis, and Laurel L. Schafer
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b10465 • Publication Date (Web): 13 Nov 2019
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Journal of the American Chemical Society
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Zirconium Hydroaminoalkylation. An Alternative
Disconnection for the Catalytic Synthesis of α-Arylated
Primary Amines
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Ana Koperniku,a Paul J. Foth,b Glenn M. Sammisb and Laurel L. Schafer*b
a) Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall
Vancouver, BC V6T 1Z3; b) Department of Chemistry, The University of British Columbia, 2036 Main
Mall, Vancouver, BC V6T 1Z1
Supporting Information Placeholder
a)
ABSTRACT: Primary amine products have been prepared
CF3
O
O
using zirconium catalyzed hydroaminoalkylation of alkenes
N
O
with N-silylated benzylamine substrates. Catalysis using
commercially available Zr(NMe2)4, affords an alternative
disconnection to access α-arylated primary amines upon
aqueous work-up. Substrate dependent regio- and
diastereoselectivity of the reaction is observed. Bulky
substituents on the terminal alkene exclusively generate the
linear regioisomer. This atom-economic catalytic strategy for
the synthesis of building blocks that can undergo further
synthetic elaboration is highlighted in the preparation of
trifluoroethylated-α-arylated amines.
O
HN
CF3
N
OH
H
L-733, 060
Repaglinide
b)
H
N
H
SiR3
R
H
H
H
N
N
R
R
This Work
R' = R'' = H
1921: Ni (Ra)
2018: Ru
Zr
R = Alk
Primary α-arylated amines are important building
blocks to prepare pharmaceuticals such as the
R'
R''
Substituted or Protected Amines
Precious Metals
N
antidepressant/anxiolytic
L-733-060
and
the
antidiabetic repaglinide (Scheme 1a). There are three
disconnections for the incorporation of an aryl group
onto the α-carbon of an amine (Scheme 1b).
Traditional stoichiometric transformations include
reductive aminations with ammonia surrogates for C-N
R
R' = H and R'' = H
2011-2019: Pd, Ir, Ni
c)
Zr(NMe2)4 (cat.)
aq. workup
H2N
Me3SiHN
H
bond formation,1
or nucleophilic addition of
R
R
organometallic nucleophiles to protected imine
intermediates to give α-arylated primary amines.2
These routes generate stoichiometric amounts of
waste while desirable catalytic variants offer reduced
waste generation and often improved selectivity.
Using C-N bond formation, the Mignonac reaction
delivers the primary 1-phenylethylamine via reductive
amination between acetophenone and ammonia, with
a nickel catalyst, high pressure and heating.3 More
recently ruthenium catalyzed syntheses of primary
amines were reported using carbonyl substrates.4
Alternatively, the direct introduction of the aryl group
via catalytic Csp2-Csp3 bond formation requires N-
H
bulky quaternary center
exclusively linear
Scheme 1. a. Examples of pharmaceuticals with α-arylated primary
amines b. Disconnections and catalytic routes to prepare α-arylated
primary amines c. Current work on zirconium catalyzed
hydroaminoalkylation.
directing/protecting groups and subsequent reactions
to afford primary α-arylated amine products.5 An
underexplored
catalytic
disconnection
uses
benzylamine substrates and catalytic Csp3-Csp3 bond
formation α- to nitrogen. Here we show that catalytic
hydroaminoalkylation
of
alkenes
with
N-
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Journal of the American Chemical Society
silylbenzylamine enables the isolation of primary α-
Page 2 of 7
ineffective while reactivity with Ti(NMe2)4 gave a low
yield of a mixture of regioisomers in a 1:1 ratio, with
poor diastereoselectivity (2:1) for the branched
products. The observed reactivity with Ti(IV), with only
4 ligands about the metal center in contrast to the 5
ligands of the similarly sized Ta (V) metal center,
suggested that enhanced steric accessibility to the
metal center is required for realizing reactivity with the
sterically demanding silylated benzylamine substrates.
Thus, to access a more sterically accessible metal
center the larger covalent radius of Zr in Zr(NMe2)4 was
tested (Table 1, entry 6). In this case an improved
combined yield of 55% was observed with a 1:2 ratio
of linear:branched products and a dr of 3:1. Thus, as
well as offering higher yields, the Zr catalyst afforded
products with modestly improved regioselectivity and
diastereselectivity.
1
2
3
4
5
6
7
8
arylated amines upon workup (Scheme 1c).
Hydroaminoalkylation is an atom-economic, emerging
catalytic tool for the synthesis of Csp3-Csp3 bonds α- to
nitrogen in both secondary and tertiary amine
substrates.6 Early transition metal,7 late transition
metal8
and
photoredox
catalysis9
feature
mechanistically distinct hydroaminoalkylation reactions
for the assembly of selectively substituted amines and
N-heterocycles using simple alkenes as the alkylating
agent. Control of regioselective hydroaminoalkylation
remains a challenge with early transition metal
catalysts that favor branched products7f-h, 10 while late
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transition metal catalysts typically favor linear
8d, 8e, 11
products.8a,
Rovis and coworkers recently
showed that primary amines protected as
sulfonamides can be used for the
Table 1. Precatalyst screening for intermolecular HAA with N-silylbenzylamine.
hydroaminoalkylation of electron-deficient alkenes
using visible‐light photoredox catalysis.9b In early
transition metal catalysis unprotected primary
aminoalkene substrates can deliver aminated
cycloalkanes by titanium or zirconium catalyzed
linear
branched
1) catalyst - 5 or 10 mol%
C7D8 or C6D6
range: 145 oC - 160 oC
Me3SiHN
H2N
H2N
2) aq. workup
intramolecular
hydroaminoalkylation.12
However,
C6H13
C6H13
C6H13
intermolecular hydroaminoalkylation of primary amines
is unknown. Meanwhile, N-silylated amines have been
used by Buchwald and co-workers for stoichiometric
zirconium mediated C-C reductive coupling with
alkynes to deliver unprotected primary allylamines
upon workup.13 Furthermore, we showed that N-
silylated amines can be used in catalytic alkyne
hydroamination (C-N bond formation) to give primary
amine products after reduction and work-up.14 We
questioned if N-silylated amines could be used in
catalytic hydroaminoalkylation to yield primary amine
products suitable for further synthetic elaboration.
Time
Selectivity
Entry
1
Precatalysta, b
Ta(NMe2)5
Yieldc
dr
-
(h)
up to
96
L:B
-
-
O
Ta(NMe2)4
tBu
iPr
N
up to
96
-
-
-
2
iPr
up to
96
-
-
-
-
-
-
3
4
Ta(CH2SiMe3)3Cl2
[Ta(NMe2)3Cl2]2
Here we show an alternative disconnection for the
catalytic synthesis of α-arylated primary amines
featuring the hydroaminoalkylation of activated and
unactivated alkenes with N-silylated benzyl amines.
Simple commercially available Zr(NMe2)4 was found to
catalyze Csp3-Csp3 bond formation via C-H bond
activation -to nitrogen to give the desired products
upon aqueous work-up (Scheme 1b). Furthermore, in
the presence of sterically bulky vinyl substrates, the
linear product is obtained exclusively (Scheme 1c).
These primary amine products can be used as building
blocks in further functionalization reactions relevant to
medicinal chemistry, as demonstrated in the synthesis
of N-trifluoroethylated α-arylated amine small
molecules.
up to
96
5
6
Ti(NMe2)4
Zr(NMe2)4
72
72
28
55
1:1
2:1
2:1
3:1
Reactions performed at a 0.5 mmol scale. Amine:alkene mmol ratio 1:1.5 for
tantalum HAA; 1:1.8 for titanium and zirconium HAA. aHomoleptic complexes:
10% of precatalyst loading, solvent: C6D6 for Ti and C7D8 for Ta; Non-
homoleptic complexes: 5% of precatalyst loading, solvent C7D8. bFor tantalum
HAA: up to 160 oC; for titanium and zirconium HAA: reactivity at 145 oC. c
Isolated yield of mixture of regio- and diastereomers.
Next a series of alkenes (1-9) were evaluated for
zirconium catalyzed hydroaminoalkylation with N-
silylated benzylamine (Table 2). Results demonstrate
the favored formation of the branched product when
there is little steric bulk incorporated into the alkene
Results and Discussion
(Entries 1-3).
As the terminal alkene becomes
Initial tests focused on attempts to use N-silylated
benzylamine as a substrate for hydroaminoalkylation
increasingly sterically demanding, such as with
vinylcyclohexane (Entry 4) the formation of the linear
product is favored (linear:branched 3:1) and the even
more sterically demanding 2-methylstyrene (Entry 5,
Table 2) generated mostly linear product (17:1
with
reported
tantalum
and
titanium
hydroaminoalkylation catalysts (Table 1, entries 1 -
7h, 10b, 15
5).7f,
Known Ta catalysts were completely
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Journal of the American Chemical Society
linear:branched). The ratio of diastereomers formed for
Me3Si
9
240
68
1:7
3:1
1
all products with alkyl substituents, regardless of steric
bulk, was 3:1, while for 2-methylstyrene the ratio was
7:1, as determined by 1H NMR spectroscopy (See SI).
Further examination of the effect of steric bulk showed
that incorporation of a sterically demanding quaternary
center on the alkene affords exclusively the linear
product (Entry 6). Notably, this is the first example of
catalytic hydroaminoalkylation with such a sterically
demanding unactivated substrate. This tolerance to
steric bulk suggests that activated vinylsilanes could be
used in these reactions, while offering functionality
suitable for further synthetic elaboration. As shown in
Entries 7 & 8, only linear products are observed as
noted by an apparent triplet at 3.76 and 3.79 ppm in
the benzylic region of the 1H NMR spectra for products
7a and 8a, respectively (See SI). Vinyl silanes afford
improved reactivity, in addition to complete
regioselectivity. Notably, allyltrimethylsilane (Entry 9),
the next homologue, affords the product with almost
the opposite regioselectivity (1:7 linear:branched),
once again illustrating profound substrate controlled
regioselectivity. This simple catalyst cannot promote
the hydroaminoalkylation of internal alkenes.
2
3
4
5
6
7
8
9
Reactions performed at a 0.5 mmol scale. Amine:alkene mmol ratio 1:1.8.
Catalyst loading: 10 mol%. aIsolated yields of mixtures of regio- and
diastereoisomers. bRegio- and diastereoselectivity ratios calculated based on
the relative integrations of the benzylic peaks of the 1H NMR spectra of the
isolated mixtures of regio- and diastereoisomers (see SI).
Analysis of the proposed mechanism for early
transition metal catalyzed hydroaminoalkylation
presented in Scheme 2,6a, 7f, 16 provides a rationale for
the change in regioselectivity and preferred
diastereomer formation when using the sterically
silylbenzylamine
Transamination of the amido groups of complex A with
N-silylamine leads to complex B, which upon hydrogen
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demanding
substrate.
abstraction
leads
to
catalytically
active
zirconaaziridine C. Zirconaaziridine C, with its phenyl
substituent, undergoes alkene insertion into the more
reactive C-C bond and forms the zirconapyrrolidine
intermediate D or E, where the steric bulk of the alkene
affects the regioselectivity of the reaction. In the
formation of intermediate D two diastereomers can
result (D and D’), with the trans-orientation of the
metallacyclic intermediates giving the major
diastereomer.17 This is consistent with computational
Table 2. Alkene scope for the zirconium catalyzed HAA.
investigations of early transition metal catalyzed
18
hydroaminoalkylation7b,
which propose that
H2N
polarized, activated alkenes, such as vinyl silanes,
offer enhanced reactivity and modified regioselectivity
due to substrate and catalyst dependent electronic
control. For example, a bulky Ti complex affords the
linear product with dimethylphenylvinylsilane7e while
Ta hydroaminoalkylation catalysts offer mixtures of
regioisomers with vinylsilane substrates.7g, 15
Me3SiHN
1) Zr(NMe2)4 10 mol%
C6D6, 145 oC, 24-240 h
R
1a-9a
2) aq. workup
H2N
H2N
R
1-9
R
R
1b-5b, 9b
1c-5c, 9c
Ph
Time
(h)
Yield %
Selectivity
dr
NMe2
Entry
Alkene (1-9)
[Zr]
(a+b+c)a
[a:(b+c)]b
b/cb
HN
2
NMe2
SiMe3
A
Ph
1
2
3
48
78
55
82
1:3
3:1
3:1
3:1
-2 HNMe2
Ph
2
R
Ph
R
N
SiMe3
Ph
H
Ph
HN
SiMe3
[Zr]
72
72
1:2
1:2
C6H13
Ph
N
N
1,2-insertion
branched
Ph
Me3Si
SiMe3
1,2-insertion
[Zr]
B
Ph
Ph
HN
N
SiMe3
HN
[Zr]
SiMe3
SiMe3
R
Ph
R
2,1-insertion
2,1-insertion
R
linear
N
SiMe3
4
5
72
48
66
56
3:1
3:1
[Zr]
C
alkene
insertion
C-H
activation
R
17:1
7:1
-
R
Ph
R
Ph
disfavored
Ph
Ph
H
or
SiMe3
N
[Zr]
N
N
N
SiMe3
SiMe3
Me3Si
[Zr]
[Zr]
6
7
8
240
24
47
52
58
99:1
99:1
99:1
Me3C
Me3Si
D
D'
F or F'
1,2-insertion
or
or
Ph
Ph
Ph
N
N
[Zr]
R
SiMe3
protonolysis
Ph
R
SiMe3
N
Me3Si
[Zr]
E
2,1-insertion
G
24
-
PhMe2Si
HN
SiMe3
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Journal of the American Chemical Society
Page 4 of 7
molecules.20 Consequently, a recently developed
strategy for the efficient installation of trifluoroethylated
substituents onto primary amines21 was exploited to
further functionalize the unprotected products obtained
from hydroaminoalkylation. Thus, amines 7a, 17, 19
and 20 were trifluoroethylated using sulfuryl fluoride
and 2,2,2-trifluoroethanol to give new α-arylated-
fluorinated secondary amine derivatives in yields
ranging from 36-56% (Scheme 3b). This sequential
transformation highlights the modular, catalytic
approach for the facile assembly of unprotected small
molecules ready to be used in further synthesis.
Scheme 2. Proposed mechanism, including regioselective and
diastereoselective reactivity, in the hydroaminoalkylation of alkenes with N-
silylamines.
1
2
3
4
5
6
7
8
Finally, the five-membered intermediates D, D’ or E
undergo protonolysis with an incoming equivalent of
amine to give rise to zirconium complex F, F’ or G
which in turn, upon hydrogen abstraction leads to
reformation of zirconaaziridine C with concomitant
liberation of the desired α-arylated amine products.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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35
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With substrate controlled regioselectivity in hand, we
synthesized a series of N-silylated benzylamines from
commercially available starting materials (see SI). This
catalytic approach allows for the facile synthesis of
variously substituted α-aryl primary amines using this
alternative disconnection (Scheme 3a). With the meta-
and para-substituted N-silylated benzylamines, either
electron-withdrawing or electron-donating groups
afford reactivity leading to primary amines in low to
moderate yields (36-67%). We were pleased to note
that heteroaromatic substrates (20) could also be
accommodated.
Conclusions
To summarize, we have developed the first example of
intermolecular zirconium catalyzed hydroaminoalkyla-
tion for primary amines. The increased steric
accessibility of this 4-coordinate early transition metal
has allowed for the use of the sterically demanding N-
silylbenzylamine substrates in hydroaminoalkylation to
access primary α-arylated amines directly. This
approach featuring readily modified benzyl amine
substrates and simple alkenes offers a complementary
catalytic Csp3-Csp3 disconnection strategy to prepare
these small molecules that may be building blocks for
the assembly of biologically active products. The use
of zirconium, combined with steric substrate control,
offers selective access to the linear regioisomer.
Finally, this catalytic preparation of unprotected
primary amines can be isolated, purified and subjected
to further modification to obtain fluorinated secondary
amine building blocks. Future work includes reaction
sequence development to access amino acid
derivatives, as well as catalyst development to improve
catalytic activity and regio- and stereoselectivity of this
synthetic approach.
a)
1) Zr(NMe2)4 10-20 mol%
C6D6, 145 oC, 24 h
R
R
Me3SiHN
10-15
H2N
SiMe3
2) aq. workup
SiMe3
7
SiMe3
NH2
SiMe3
SiMe3
NH2
NH2
17
16
7a
53%
F
H3CO
67%
59%
SiMe3
NH2
SiMe3
NH2
20
64%
SiMe3
NH2
F
18
48%
N
19
36%
Cl
F
Supporting Information
b)
O
O
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Full experimental procedures and spectroscopic data
S
SiMe3
NH2
SiMe3
NHCH2CF3
F3C
O
F
DIPEA
DMF, silica, 40 °C, 2 h
Ar
Ar
7a
17
19
20
, Ar: benzene
, Ar: 4-fluorobenzene
: Ar: 3,5-difluorobenzene
: Ar: 3-pyridine
21
22
23
24
: Ar: benzene, 56%
, Ar: 4-fluorobenzene, (46%)
: Ar: 3,5-difluorobenzene (42%)
: Ar: 3-pyridine, (36%)
AUTHOR INFORMATION
Corresponding Author
schaferl@mail.ubc.ca
Scheme 3. a. Amine scope. Reactions performed at a 0.5 mmol scale.
Amine:vinylsilane mmol ratio 1:1.8. Catalyst loading: 10 mol% for amines 7a,
18-23; 20 mol% for amine 24. b. Trifluoroethylation of the linear primary
amines. Isolated yields are reported with 19F NMR yields in parentheses.
Author Contributions
All authors contributed equally.
ACKNOWLEDGMENT
Ready access to a family of α-arylated primary amine
building blocks offered the opportunity to pursue further
substitution to make small molecules that may be
suitable for application in medicinal chemistry. The
pharmaceutical value of 2,2,2-trifluoroethylated
amines lies in the modified amine basicity, which in turn
We gratefully thank NSERC and the CREATE SusSyn
program. AK thanks Dr Sorin Rosca for guidance and UBC
for a Four Year Fellowship. This research was supported in
part by the Canada Research Chairs program. The authors
declare no competing financial interests.
defines
the
targeted
delivery
of
potential
pharmaceuticals.19 Furthermore, the incorporation of
fluorinated substituents is known to increase the
lipophilicity and bioavailability of the resulting
REFERENCES
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Journal of the American Chemical Society
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For selected examples see: (a) Tomioka, K.;
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