of 7
Development
of
a Nickel-Catalyzed
N
N
Coupling
for
the
Synthesis
of
Hydrazides
Jay P. Barbor, Vaishnavi
N. Nair,
§
Kimberly
R. Sharp,
§
Trevor D. Lohrey, Sara E. Dibrell, Tejas K. Shah,
Martin J. Walsh, Sarah E. Reisman,
*
and Brian M. Stoltz
*
Cite
This:
J. Am. Chem.
Soc.
2023,
145,
15071−15077
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Online
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*
Supporting
Information
ABSTRACT:
A nickel-catalyzed
N
N
cross-coupling
for the synthesis
of hydrazides
is reported.
O
-Benzoylated
hydroxamates
were
efficiently
coupled
with
a broad
range
of aryl and aliphatic
amines
via nickel
catalysis
to form
hydrazides
in an up to 81%
yield.
Experimental
evidence
implicates
the intermediacy
of electrophilic
Ni-stabilized
acyl nitrenoids
and the formation
of a Ni(I)
catalyst
via silane-mediated
reduction.
This
report
constitutes
the first
example
of an intermolecular
N
N
coupling
compatible
with
secondary
aliphatic
amines.
N
itrogen
nitrogen
bonds
are prevalent
motifs
in bio-
logically
active
small
molecules
and
natural
products,
featured
prominently
in pharmaceutical
and
agricultural
compounds
(Figure
1A).
1
5
Moreover,
a variety
of druglike
heterocyclic
scaffolds
can be accessed
from
hydrazines
and
hydrazides.
2,6
The
synthesis
of N
N
containing
compounds
typically
entails
a linear,
stepwise
process
of hydrazine
protection
and derivatization,
which
hampers
rapid
access
to
highly
substituted
products.
2
Improved
methods
for the
convergent
cross-coupling
of two complex
nitrogen-containing
compounds
would
not only
simplify
the preparation
of known
hydrazines
and hydrazides
but also accelerate
access
to new
chemical
space.
For these
reasons,
new
N
N
bond
forming
reactions
are of high
value
to the
synthetic
chemistry
community.
While
several
impressive
examples
of N
N
cross-coupling
have
been
developed
to form
hydrazines
via oxidative
or
reductive
pathways,
the majority
of methods
furnish
fully
aromatic
products.
7,8
Transition-metal-catalyzed
nitrene
in-
sertion
has recently
gained
attention
as a powerful
tool for N
N coupling
(Figure
1B).
9
Both
Ag and Rh have
been
utilized
as
catalysts
for nitrene
transfer
to tertiary
amines,
although
these
methods
only
lend
access
to tailored
synthetic
frameworks.
9a,b
In 2021,
Chang
and
Chen
disclosed
the first
N
N
cross-
coupling
method
for the formation
of hydrazides
utilizing
Fe or
Ir catalysis
(Figure
1B).
9c
They
propose
the formation
of an
electrophilic
metal-bound
nitrenoid
that
is subject
to outer-
sphere
attack
by an amine
to generate
the hydrazide
product.
In a subsequent
communication,
Chen
demonstrated
the
compatibility
of this
Ir-catalyzed
transformation
with
O
-
benzoylated
hydroxamates.
9d
While
these
methods
enable
efficient
coupling
of a wide
array
of aliphatic
electrophiles
and
secondary
anilines,
other
classes
of amine
nucleophiles,
most
notably
aliphatic
amines,
remain
incompatible.
As part
of an
industrial-academic
collaboration
aimed
at developing
new
modular
approaches
for N
N
coupling,
we pursued
the
development
of a new
nitrene-mediated
N
N
cross-coupling
with
the goal
of accessing
diverse
hydrazides
from
both
aryl
and aliphatic
coupling
partners
(Figure
1C).
After
an unsuccessful
survey
of Cu and Fe catalysts,
we were
pleased
to discover
that
reaction
with
N
-(benzoyloxy)-
benzamide
1a
and
p
-toluidine
(
2a
)
in the presence
of Zn(0)
and
catalytic
Ni(PPh
3
)
2
Cl
2
resulted
in a 30%
yield
of the
desired
hydrazide
product
3a
(Table
1, entry
1). Iminophos-
phorane
4
was observed
as a side
product
of this reaction,
which
is suggestive
of the intermediacy
of a nitrenoid
species.
10
Surprisingly,
we observed
no urea
formation,
indicating
robust
stabilization
of the nitrene
intermediate
against
Lossen-type
rearrangement.
11
In the absence
of Zn,
poor
conversion
was
observed,
providing
a similar
30%
yield
of
3a
only
after
an extended
reaction
time
with
significant
unconsumed
starting
material
(entry
2). We postulate
that
Ni(II)
may
be effecting
the
desired
transformation
via an alternative
mechanism,
such
as
Lewis
acid
activation.
Use of Ni(COD)
2
yielded
no reaction,
suggesting
that a Ni(0)
species
is not involved
in the catalytic
cycle
(entry
3). Use of bidentate
ligands
dppe
or bpy resulted
in a complete
loss of reactivity
(entries
4 and 5); however,
strongly
σ
-donating
N-heterocyclic
carbene
(NHC)
SIPr
afforded
a 32%
yield
of
3a
with
no observed
nitrene
transfer
to the ligand
(entry
6). Use
of alternative
NHC
ligands
resulted
in diminished
yields
(Supporting
Information).
Given
the stark
difference
in reactivity
observed
between
mono-
dentate
and
bidentate
ligands,
we hypothesized
that
the
catalyst
must
be coordinatively
unsaturated
to enter
the
catalytic
cycle.
Received:
May
9, 2023
Published:
July 6,
2023
Communication
pubs.acs.org/JACS
© 2023
The Authors.
Published
by
American
Chemical
Society
15071
https://doi.org/10.1021/jacs.3c04834
J. Am. Chem.
Soc.
2023,
145,
15071
15077
Having
identified
a more
suitable
ligand,
we re-examined
the
role of Zn as an additive.
Previous
reports
have
demonstrated
the ability
of Ni(I)
dimer
6
to form
a bridged
Ni-nitrene;
we
considered
the possibility
that Zn-mediated
reduction
may
be
forming
a similar
species
in situ
.
12,13
Unfortunately,
examina-
tion of
6
both
with
and without
Zn resulted
in no reactivity
(entry
7, 8), leading
us to hypothesize
a mononuclear
Ni(I)
complex
as the active
catalyst.
14
While
further
exploration
of
reductants
revealed
that phenylsilane
improved
reactivity
(see
Supporting
Information),
yields
were
highly
variable
across
batches
of starting
materials
and reagents
(entry
9). Despite
an
extensive
effort
to assess
the purity
of our reagents,
we were
ultimately
unable
to identify
the cause
of irreproducibility.
Aiming
to achieve
more
consistent
results,
we explored
well-
defined
Ni complexes
and were
intrigued
by reports
of NHC-
ligated
Ni(II)
half-sandwich
catalysts,
which
have
recently
been
utilized
for catalytic
oxidative
N
N
coupling
of ammonia
to dinitrogen.
15
18
These
easily
synthesized
and
air-stable
complexes
have
been
implicated
to undergo
hydride-mediated
reduction
to Ni(I).
15,16
Additionally,
the substituent
cyclo-
pentadienyl
(Cp)
ligand
has demonstrated
surprisingly
facile
equilibration
among
η
5
,
η
3
, and
η
1
binding
modes,
which
we
hypothesized
could
satisfy
the previously
observed
require-
ment
for a coordinatively
unsaturated
catalyst.
15,17
After
evaluating
a variety
of Ni half-sandwich
catalysts,
we found
that
the use of
7a
afforded
a reproducible
61%
yield
of the
desired
product
(entry
10).
Exploration
of solvent
effects
revealed
that a 1:4 mixture
of CH
2
Cl
2
/THF
further
improved
the yield
to 80%
(entry
11).
Having
identified
optimal
conditions
for aryl
amine
nucleophiles,
we sought
to expand
the
scope
of the
transformation
to aliphatic
amines.
Reaction
with
unprotected
secondary
aliphatic
amine
8a
resulted
in significant
O
-to-
N
benzoyl
transfer
from
the hydroxamate
to the amine,
yielding
product
10
and minimal
formation
of the desired
hydrazide
(Table
2, entry
1). Surmising
that
silylation
of these
more
challenging
nucleophiles
might
serve
as a transient
protection
strategy
until
either
transmetalation
with
the catalyst
or
benzoate-mediated
desilylation,
we explored
reactivity
with
Figure
1.
Compounds
featuring
N
N
bonds
and nitrene-mediated
synthetic
strategies.
Table
1. Reaction
Optimization
of Aryl
Amines
a
a
Reactions
performed
on 0.05
mmol
scale.
b
72 h.
c
Excess
hydroxamate
1a
(1.5 equiv).
d
30
°
C.
Table
2. Reaction
Optimization
of Aliphatic
Amines
a
a
Reactions
performed
on 0.05
mmol
scale.
b
Excess
hydroxamate
1a
(1.5 equiv).
Journal
of
the
American
Chemical
Society
pubs.acs.org/JACS
Communication
https://doi.org/10.1021/jacs.3c04834
J. Am. Chem.
Soc.
2023,
145,
15071
15077
15072
silylamine
8b
.
19
To our satisfaction,
the reaction
of
8b
with
excess
1a
afforded
the desired
product
9a
in 27%
yield
(entry
2). Use of excess
amine
was found
to improve
the product
distribution,
with
1.5 equiv
of
8b
resulting
in a 57%
yield
(entries
3, 4). Gratifyingly,
the use of IPr- substituted
catalyst
7b
afforded
a 69%
yield
of the
desired
hydrazide
9a
,
Scheme
1. Substrate
Scope
a
a
Reactions
performed
on 0.2 mmol
scale.
b
Protected
as TBS
ether
for isolation.
c
72 h.
d
Silylamine
(
8b
)
used.
e
48 h.
Journal
of
the
American
Chemical
Society
pubs.acs.org/JACS
Communication
https://doi.org/10.1021/jacs.3c04834
J. Am. Chem.
Soc.
2023,
145,
15071
15077
15073
minimizing
the formation
of undesired
side-product
10
(entry
5). We posit
the
O
-to-
N
benzoyl
transfer
may
be accelerated
within
the coordination
sphere
of the catalyst
and
that
increasing
steric
hindrance
around
the metal
center
may
block
this competing
pathway.
Although
the efficiency
of these
conditions
utilizing
presilylated
amines
was satisfactory,
a more
operationally
expedient
route
was
developed
via
in situ
silylation
of amine
8a
with
MSTFA,
affording
a 59%
yield
of
product
in a single
synthetic
step (entry
6).
With
optimized
conditions
in hand,
we examined
the scope
of compatible
coupling
partners
(Scheme
1). Aniline
derivatives
with
electron-donating
substituents
at the
para-
position
provided
the desired
products
in good
yields
(
3a
and
3b
),
while
electron-deficient
amines
gave
slightly
diminished
yields
(
3c
and
3d
).
Halide
substituents
on the arene
(
3e
3h
)
were
well tolerated
under
the reaction
conditions
and showed
no signs
of protodehalogenation.
Functional
handles
for
further
derivatization,
such
as an aryl iodide
(
3h
)
and boronic
ester
(
3i
),
remained
intact
under
the reaction
conditions.
Sterically
hindered
ortho
-substituted
aniline
derivatives
afforded
products
3j
and
3k
in good
yields.
Amines
bearing
unprotected
ketone
(
3l
)
and hydroxyl
(
3m
and
3n
) moieties
were
also
found
to be compatible.
Moreover,
amino-
glutethimide,
a drug
used
in the treatment
of Cushing’s
disease,
was
efficiently
derivatized
to the
corresponding
hydrazide
(
3o
),
highlighting
the potential
of this method
for
late-stage
functionalization
of complex
molecules.
20
Although
exploration
of a secondary
aniline
in reaction
with
1a
yielded
only
trace
hydrazide
(
3p
),
we observed
an 81%
yield
of the
product
when
using
N
-(benzoyloxy)acetamide
as an electro-
phile
(
3q
).
We postulate
the difference
in reactivity
between
aryl and aliphatic
hydroxamates
with
secondary
anilines
reveals
the
stereoelectronic
constraints
of this
transformation
although
secondary
anilines
are more
nucleophilic
than
primary
anilines,
21
the increased
steric
bulk
may
bar their
reactivity
with
more
encumbered
aryl electrophiles.
Hydroxamates
with
a variety
of electron-donating
and
-withdrawing
para
-substituents
on the aryl ring furnished
the
N
N
products
with
moderate
to high
yields
(
11a
11g
).
Additionally,
primary,
secondary,
and
tertiary
aliphatic
hydroxamates
were
compatible
with
this
chemistry
(
12a
12l
).
We
were
pleased
to observe
styrenyl
and
alkenyl
functional
groups
did not
participate
in undesired
C
H
insertion,
hydroamidation,
reduction,
or aziridination
pro-
cesses,
affording
moderate
yields
of products
12e
and
12f
,
respectively.
13,22
24
Additionally,
several
saturated
heterocyclic
compounds,
such
as tetrahydropyran-,
piperidine-,
and
azetidine-derived
hydroxamates
(
12g
12i
)
afforded
products
in 52
67%
yields.
Hydroxamates
featuring
phenyl
isostere
[1.1.1]-bicyclopentane
(BCP)
derivatives
were
also compatible
in this transformation
(
12k
and
12l
).
25
Surprisingly,
a benzylic
hydroxamate
remained
inert
under
the reaction
conditions
(
12m
).
N
-Methylbenzylamine
derivatives
with
both
electron-donat-
ing and
electron-withdrawing
substituents
on the aryl
ring
afforded
modest
yields
of the desired
products
(
9a
9d)
.
Replacement
of the benzyl
group
with
a variety
of acyclic
and
cyclic
moieties
(
9e
9i
),
including
a formamide
isostere
(
9g
),
resulted
in efficient
product
formation.
26
Reaction
with
duloxetine,
an antidepressant,
yielded
the
corresponding
hydrazide
derivative
9i
in a synthetically
useful
yield.
27
Although
broadly
amenable
to reaction
with
secondary
aliphatic
amines,
primary
aliphatic
amines
remain
incompatible
with
this
transformation,
instead
yielding
undesired
amine
acylation
arising
from
O
-to-
N
benzoyl
transfer
and only
trace
amount
of product
(
9j
).
Cyclic
aliphatic
amines,
including
piperidine
(
13a
),
azepane
(
13b
),
azocane
(
13c
),
morpholine
(
13d
),
N
-Boc
piperazine
(
13e
),
tetrahydroisoquinoline
(
13f
),
(
S
)-proline
ethyl
ester
(
13g
),
and an azaspirocycle
(
13h
)
were
competent
coupling
partners
in this
chemistry,
albeit
affording
products
in
diminished
yields
due
to the greater
propensity
of these
nucleophiles
to generate
O-
to
-N
benzoyl
transfer
side products.
Cytisine,
a smoking
cessation
agent,
was able to be derivatized
to the corresponding
hydrazide
in a synthetically
useful
yield
(
13i
),
28
and we were
able to access
fully
aliphatic
hydrazides
(
14a
and
14b
),
including
saturated
heterocycle
15
resulting
from
intramolecular
bond
formation.
Lastly,
both
sets
of
conditions
were
demonstrated
to be scalable,
with
hydrazides
3a
and
8a
obtained
in near
identical
yields
on a 2 mmol
scale
(Scheme
2).
To investigate
the role
of the silane
additive,
Ni(I)
half
sandwich
7c
was independently
synthesized
and its catalytic
competence
was
examined
(Scheme
3).
17
Reaction
in the
presence
and absence
of phenylsilane
afforded
similar
product
yields
with
near-identical
reaction
times,
supporting
the notion
that the active
catalyst
is a Ni(I)
species
formed
via reduction
with
silane.
15,29
With
this
evidence
in hand,
we suggest
the following
mechanism:
phenylsilane
can reduce
7a
via the formation
of
Ni(II)
hydride
A
to Ni(I)
species
B
. Reaction
with
a
hydroxamate
starting
material
can form
Ni-nitrenoid
C
with
net loss of benzoic
acid,
which
may
be enabled
by transient
slippage
of the Cp ligand.
15,17
Ni-nitrenoid
C
can then
undergo
outer
sphere
N
N
bond
formation
with
an amine,
which
following
proton
transfer
yields
intermediate
D
. Dissociation
of
the product
regenerates
the active
catalyst
(
B
) (Figure
2).
Scheme
2. Large
Scale
Reactions
a
a
Reactions
performed
on 2 mmol
scale.
Scheme
3. Ni(I)
Catalyst
a
a
Reactions
performed
on 0.05
mmol
scale.
Journal
of
the
American
Chemical
Society
pubs.acs.org/JACS
Communication
https://doi.org/10.1021/jacs.3c04834
J. Am. Chem.
Soc.
2023,
145,
15071
15077
15074
In summary,
we have
developed
a Ni-catalyzed
N
N
cross-
coupling
enabling
the
convenient
formation
of complex
hydrazides.
This
transformation
is effected
by an easily
synthesized
and air-stable
Ni(II)
half-sandwich
precatalyst.
In
situ
silylation
allows
unprecedented
access
to secondary
aliphatic
amines
in N
N
coupling
methodology.
This
reaction
tolerates
an impressive
breadth
of functionality,
including
handles
for further
derivatization.
Preliminary
mechanistic
investigation
suggests
a mononuclear
Ni(I)
active
catalyst.
ASSOCIATED
CONTENT
*
Supporting
Information
The
Supporting
Information
is available
free
of charge
at
https://pubs.acs.org/doi/10.1021/jacs.3c04834.
Experimental
procedures,
spectroscopic
(
1
H NMR,
13
C
NMR,
IR, HRMS),
and crystallographic
data
(PDF)
Accession
Codes
CCDC
2254582
and 2255601
2255602
contain
the supple-
mentary
crystallographic
data for this paper.
These
data can be
obtained
free of charge
via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing
data_request@ccdc.cam.ac.uk,
or by
contacting
The
Cambridge
Crystallographic
Data
Centre,
12
Union
Road,
Cambridge
CB2
1EZ,
UK; fax: +44 1223
336033.
AUTHOR
INFORMATION
Corresponding
Authors
Brian M. Stoltz
The Warren
and Katharine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States;
orcid.org/0000-0001-9837-1528;
Email:
stoltz@
caltech.edu
Sarah E. Reisman
The Warren
and Katharine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States;
orcid.org/0000-0001-8244-9300;
Email:
reisman@caltech.edu
Authors
Jay P. Barbor
The Warren
and Katharine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States
Vaishnavi
N. Nair
The Warren
and Katharine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States;
orcid.org/0000-0002-2873-0596
Kimberly
R. Sharp
The Warren
and Katharine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States
Trevor D. Lohrey
The Warren
and Katharine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States
Sara E. Dibrell
The Warren
and Katharine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States
Tejas K. Shah
Corteva
Agriscience,
Indianapolis,
Indiana
46268,
United
States;
orcid.org/0000-0002-2345-4764
Martin J. Walsh
Corteva
Agriscience,
Indianapolis,
Indiana
46268,
United
States
Complete
contact
information
is available
at:
https://pubs.acs.org/10.1021/jacs.3c04834
Author
Contributions
§
V.N.N.
and K.R.S.
contributed
equally.
Notes
The authors
declare
no competing
financial
interest.
ACKNOWLEDGMENTS
The
authors
thank
Corteva
Agriscience
for funding
and
scientific
discussion,
as well
as NIH-NIGMS
(R01GM080269),
NIH-NIGMS
(R35GM145239),
NIH-
NIGMS
(R35GM118191),
Heritage
Medical
Research
Inves-
tigators
Program,
and Caltech
for the support
of our research
program.
The authors
also thank
Dr. Scott
Virgil
(Caltech)
for
assistance
with
instrumentation,
Dr.
Dave
VanderVelde
(Caltech)
for NMR
expertise,
Dr. Mona
Shahgholi
for mass
spectrometry,
and
Dr. Michael
Takase
(Caltech)
for X-ray
analysis.
ABBREVIATIONS
Cp, cyclopentadiene;
MSTFA,
N
-trimethylsilyl-
N
-methyl
tri-
fluoroacetamide;
dppe,
1,2-bis(diphenylphosphino)ethane;
bpy,
bipyridine;
NHC,
N
-heterocyclic
carbene;
IPr,
1,3-
bis(2,6-diisopropylphenyl)-1
H
-imidazol-3-ium-2-ide;
SIPr,
1,3-bis(2,6-diisopropylphenyl)-4,5-dihydro-1
H
-imidazol-3-
ium-2-ide;
COD,
1,5-cyclooctadiene;
BCP,
bicyclo[1.1.1]-
pentane;
Boc,
tert
-butyloxycarbonyl
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