of 236
Supporting Information for
Barbor, Nair
,
Sharp
,
Lohrey, Dibrell,
Shah, Walsh, Reisman,
and Stoltz
1
Supporting Information for
Development of a Nickel
-
Catalyzed N
N Coupling for the Synthesis of Hydrazides
J
ay P. Barbor
,
Vaishnavi N. Nair
,
Kim
berly
R. Sharp,
Trevor D. Lohrey, Sara E. Dibrell, Tejas
K. Shah, Martin
J
. Walsh, Sarah E. Reisman, and
Brian M. Stoltz
Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering, Division
of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena,
California 91125, United States.
*reisman@caltech.edu
*stoltz@caltech.edu
Table of Contents:
Materials and Methods
................................
................................
................................
...................
2
List of Abbreviations
................................
................................
................................
......................
3
Addit
ional Optimization Data
................................
................................
................................
........
4
Preparation of Hydroxamic Esters
................................
................................
................................
7
Ni
-
Catalyzed N
N Cross
-
Coupling Reactions
................................
................................
.............
17
Examination of Ni(I) Half
-
Sandwich Catalyst
................................
................................
...........
41
Large Scale Ni
-
Catalyzed N
N Cross
-
Coupling Reactions
................................
........................
41
Iminophosphorane Capture Experiment
................................
................................
.....................
42
Crystal Structure Analysis of [Ni(Cp)(NHCi
-
Pr)(Cl)] (7a) (sample No.: V22313)
...................
43
Crystal Structure Analysis of N'
-
benzyl
-
N'
-
methylbenzohydrazide (9a) (sample No.: V23142)
................................
................................
................................
................................
.......................
54
Crystal Structure Analysis of
N'
-
methyl
-
N'
-
(oxetan
-
3
-
yl)benzohydrazide (9g) (sample No.:
V23141)
................................
................................
................................
................................
.........
63
References
................................
................................
................................
................................
.....
71
NMR and IR Spectra of New Compounds
................................
................................
..................
72
Supporting Information for
Barbor, Nair
,
Sharp
,
Lohrey, Dibrell,
Shah, Walsh, Reisman,
and Stoltz
2
Materials and Methods
Unless otherwise stated, reactions were performed in flame
-
dried glassware under a
nitrogen atmosphere using dry, deoxygenated solvents. Solvents
were dried by passage through an
activated alumina column under argon.
1
Reaction progress was monitored by thin
-
layer
chromatography (TLC)
or Agilent 1290 UHPLC
-
MS. TLC was performed using E. Merck silica
gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching,
iodine,
p
-
anisaldehyde, or KMnO
4
staining. Silicycle Silia
Flash
® P60 Academic Silica gel
(particle
size 40
63 μm) was used for
silica gel
flash chromatography.
Teledyne Isco RediSep
Gold High Performance C18 columns
w
ere
used for
reverse phase
flash chromatography.
1
H NMR
spectra were recorded on Bruker 400 MHz spectrometers and are reported relative to
residual
CHCl
3
(δ 7.26 ppm)
.
13
C NMR spectra were recorded on a Bruker 400 MHz spectrometer (10
1
MHz) and are reported relative to
residual
CHCl
3
(δ 77.16 ppm)
.
1
9
F
NMR spectra were recorded
on
a
Varian Mercury 300 MHz
spectrometer
(282 MHz)
and referenced to an external standard
(
hexafluorobenzene
;
19
F NMR (282 MHz, CDCl
3
) δ
-
161.64;
19
F NMR (282 MHz, CD
3
OD
) δ
-
165.37)
.
2
1
1
B
NMR spectra were recorded on
a Bruker
4
00 MHz
spectrometer
(128 MHz)
and
referenced to an external standard (
boron trifluoride diethyl etherate
;
11
B
NMR (
1
2
8
MHz, CDCl
3
)
δ
0.0
)
.
3
Data for
1
H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling
constant (Hz), integration). Multiplicities are reported
as follows: s = singlet, d = doublet, t =
triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet. Data for
13
C
NMR
,
1
1
B
and
19
F NMR
are reported in terms of chemical shifts (δ ppm). IR spectra were obtained
by use of a
ThermoScientific Nicolet iS50 FT
-
IR
spectrometer
, or a Perkin Elmer Spectrum BXII
spectrometer using thin films deposited on NaCl plates,
and reported in frequency of ab
sorption
(cm
1
).
High resolution mass spectra (HRMS) were obtained from the Caltech
Center for Catalysis
and Chemical Synthesis
,
using
a
n
Agilent 62
30
Series TOF
LC/MS
with an Agilent
Jet Stream
source in
electrospray
mode (ESI)
,
and the Caltech Mass Spectral Facility
,
using
a
J
EOL
J
MS
-
T2000 AccuTOF GC
-
Alpha time
-
of
-
flight
mass
spectrometer using Field Desorption (FD)
ionization
(i
ons detected are M
+
)
.
The Caltech Chemistry
Division
Mass
Spectrometry laboratory
acknowledges DOW C
hemical Company
(
DOW Next Generation Instrumentation Grant
) and the
NSF CRIF program
for providing funds that enabled the purchase of this instrumentation
.
Low
-
temperature diffraction data (
f
-
and
w
-
scans) were collected on a Bruker AXS D8
VENTURE KAPPA diffractometer coupled to a PHOTON II CPAD detector with Cu
K
a
radiation
Supporting Information for
Barbor, Nair
,
Sharp
,
Lohrey, Dibrell,
Shah, Walsh, Reisman,
and Stoltz
3
(
l
= 1.54178 Å) from an I
μ
S micro
-
source for the structure
s
of compoun
ds
V21281
,
V22396
, and
V22221
.
The structure was solved b
y direct methods using SHELXS
4
and refined against
F
2
on
all data by full
-
matrix least squares with SHELXL
-
2017
or
SHELXL
-
201
9
5
using established
refinement techniques.
6
All non
-
hydrogen atoms were refined anisotropically. All hydrogen atoms
were included
into the model at geometrically calculated positions and refined using a riding
model. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the
U
value of the atoms they are linked to (1.5 times for methyl groups).
Reagents were purchased from commercial sources and used as received unless otherwise
stated.
N
-
(benzoyloxy)
-
N
-
methylbenzamide
(
S1
),
7
N
-
(pivaloyloxy)benzamide
(
S2
),
8
N
-
acetoxybenzamide
(
S3
),
9
N
-
methoxybenzamide
(
S4
),
10
N
-
hydroxybenzamide
(
S5
),
11
3
-
phenyl
-
1
,4,2
-
dioxazol
-
5
-
one
(
S6
),
1
2
tert
-
butyl (3
-
((benzoyloxy)amino)
-
3
-
oxopropyl)(benzyl)carbamate
(
S7
),
1
3
[Ni(Cp)(IPr)(Cl)]
(
7b
),
1
4
[Ni(Cp)(IPr)]
(
7c
),
1
5
[Ni(Cp)(
SIPr)(Cl)]
(
7d
),
1
6
[Ni(Cp)(
NHC
Me,
n
-
Bu
)(Cl)]
(
7e
),
1
6
and
[Ni(Cp)(IMes)(Cl)]
(
7f
)
1
7
were prepared according to literature procedures.
List of Abbreviations
TLC
thin
-
layer chromatography,
NHC
N
-
heterocyclic carbene, Cp
cyclopentadiene
,
KHMDS
potassium (bis)trimethylsilylamine,
LDA
lithium diisopropylamide
,
EtOAc
ethyl
acetate
,
TFA
trifluoroacetic acid, THF
tetrahydrofuran
, MeCN
acetonitrile
, MeOH
methanol
Supporting Information for
Barbor, Nair
,
Sharp
,
Lohrey, Dibrell,
Shah, Walsh, Reisman,
and Stoltz
4
Additional Optimization
Data
Table S
1
.
Initial e
valuation of alternative
electrophiles
.
a
a
Yields
determined by LC/MS integration against internal standard.
Table S
2
.
Initial evaluation of NHC ligands.
a
a
Yields determined by LC/MS integration against internal standard.
b
KHMDS used instead of KO
t
-
Bu.
c
LDA used
instead of KO
t
-
Bu.
N
H
O
OR
+
NH
2
Me
N
H
O
H
N
Me
Ni(PPh
3
)
2
Cl
2
(10 mol%)
Zn dust (1 equiv)
THF (0.2 M)
23 °C, 18 h
N
H
O
OBz
N
H
O
OPiv
N
H
O
OAc
N
H
O
OMe
N
H
O
OH
N
O
O
O
1a
30% yield
N
O
OBz
S1
0% yield
Me
S2
0% yield
S3
0% yield
S4
0% yield
S5
0% yield
S6
0% yield
2
3a
N
H
O
OBz
NiCl
2
•glyme (10 mol%)
ligand
(10 mol%)
KO
t
-Bu (10 mol%)
Zn dust (1 equiv)
THF (0.2 M)
23 °C, 18 h
NH
2
+
N
H
H
N
O
Me
Me
N
N
Me
Me
Me
Me
Me
Me
Me
Me
IPr
30% yield
Cl
N
N
Me
Me
Me
Me
IMes
13% yield
Cl
Me
Me
IPent
7% yield
N
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
IPr
*
OMe
12% yield
Cl
MeO
OMe
N
N
Et
Et
Et
Et
Et
Et
Et
Et
Cl
N
N
Cl
7% yield
O
O
Me
Me
Me
Me
Me
Me
N
N
Cl
19% yield
Me
Me
Me
Me
Me
Me
Me
N
N
i
–Pr
i
–Pr
i
–Pr
i
–Pr
N
Me
Me
Me
Me
Me
Me
Me
6%
b
yield
Cl
Cl
7%
c
yield
SIPr
32% yield
1a
2
3a
N
N
Me
Me
Me
Me
Me
Me
Me
Me
Cl
N
N
Me
Me
Me
Me
14% yield
Cl
N
N
n
-Bu
n
-Bu
14% yield
Cl
Ph
Ph
Supporting Information for
Barbor, Nair
,
Sharp
,
Lohrey, Dibrell,
Shah, Walsh, Reisman,
and Stoltz
5
Table S
3
.
Evaluation of additives.
a
a
Yields determined by LC/MS integration against internal standard.
Table S
4
.
Evaluation of half
-
sandwich complexes with aryl
amines.
a
Reaction time 72 h.
N
H
O
OBz
NiCl
2
•glyme (10 mol%)
IPr•HCl(10 mol%)
KO
t
-Bu (10 mol%)
additive
THF (0.2 M)
23 °C, 18 h
NH
2
+
N
H
H
N
O
Me
Me
Entry
1
2
3
4
5
6
7
8
9
10
Additive
Zn dust
Mn dust
B
2
Pin
2
B
2
Pin
2
Et
3
SiH
Et
3
SiH
Me(OEt)
2
SiH
PMHS
PhSiH
3
PhSiH
3
Equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
5 equiv
1 equiv
1 equiv
Nucleophile
2
2
2
8b
2
8b
2
2
2
8b
Yield (%)
a
30
7
54
0
37
36
33
53
68
65
1a
2
3a
or
N
Me
8b
TMS
N
H
N
O
9a
Me
or
Deviation
SIPr instead of IPr
N
H
O
OBz
N
H
O
H
N
Me
Me
H
2
N
+
[Ni] (10 mol%)
PhSiH
3
(1.0 equiv)
THF (0.2 M), 23 °C, 24 h
Ni
Cl
N
N
R
R
R =
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
7b
16% yield
7b
41% yield
a
7a
61% yield
Ni
Cl
N
N
R
R
R =
Me
Me
Me
Me
7d
35% yield
a
Ni
Cl
N
N
R
1
R
2
R
1
= Me
R
2
=
n
-Bu
7e
52% yield
1a
2
3a
Me
Me
7f
41% yield
a
Me
Supporting Information for
Barbor, Nair
,
Sharp
,
Lohrey, Dibrell,
Shah, Walsh, Reisman,
and Stoltz
6
Table S
5
.
Evaluation of half
-
sandwich complexes with aliphatic amines.
Table S
6
.
Control studies.
Table S7.
Examination of reduced silane loadings
.
a
Yield determined by
1
H NMR integration against internal standard.
N
H
O
OBz
N
H
O
N
N
+
[Ni] (10 mol%)
PhSiH
3
(1.0 equiv)
THF (0.2 M), 23 °C, 24 h
Ni
Cl
N
N
R
R
R =
Me
Me
Me
Me
7f
44% yield
7a
49% yield
Ni
Cl
N
N
R
R
R =
Me
Me
Me
Me
7d
46% yield
1a
8b
9a
Me
Me
TMS
Me
N
H
O
OBz
N
H
O
H
N
Me
Me
H
2
N
+
[NI(Cp)(NHC
i
-Pr)(Cl)] (10 mol%)
PhSiH
3
(1.0 equiv)
DCM/THF (1:4) (0.2 M)
30 °C, 24 h
1a
2
3a
Entry
1
2
3
4
Devation
No [Ni]
No PhSiH
3
No [Ni] or PhSiH
3
under air
Yield (%)
0
24
0
54
NH
2
Me
N
H
O
OBz
N
H
O
H
N
+
[Ni]
7a
(10 mol%)
PhSiH
3
1:4 CH
2
Cl
2
/THF (0.2 M)
30 °C, 24 h
1a
2a
3a
Me
entry
PhSiH
3
(mol%)
yield (%)
1
2
3
49
a
71
81
10
20
50
Supporting Information for
Barbor, Nair
,
Sharp
,
Lohrey, Dibrell,
Shah, Walsh, Reisman,
and Stoltz
7
Preparation
of
Hydroxamic Esters
Preparation of O
-
Benzoylated Hydroxylamine HCl (1
6
)
To
N
-
Boc
-
hydroxylamine (13.3 g, 100 mmol, 1.0 equiv) and triethylamine (14 mL, 100 mmol, 1.0
equiv) in CH
2
Cl
2
(0.2 M) at 0 °C was added benzoic anhydride (22.6 g, 100 mmol, 1.0 equiv)
portionwise over five minutes. The reaction was continued at 0 °C for 2 hours, then diluted with
saturated NaHCO
3
, transferred to a separatory funnel, and extracted with dichloromet
hane three
times. The combined organics were washed with saturated NaHCO
3
and brine, dried over
anhydrous Na
2
SO
4
, filtered, and concentrated to provide crude
tert
-
butyl
-
(benzoyloxy)carbamate
.
The crude material was then dissolved in 4 M HCl in dioxane (200
mL, 8 equiv) and stirred for 1
hour. The precipitated product was filtered from solution, washed with diethyl ether, and dried
under vacuum to afford
16
(17 g, 98% yield) as a white solid;
1
H NMR (400 MHz,
CD
3
OD
) δ
8.11
8.02 (m,
2
H), 7.82
7.71 (m,
1
H)
, 7.66
7.49 (m,
2
H)
;
13
C NMR (101 MHz,
CD
3
OD
) δ
164.5,
136.
5
, 13
1.0
, 130.
4
, 126.
2
; IR (
neat
f
ilm)
1739, 1647, 1450, 1371, 1273, 1243, 1084, 1059, 907,
862, 705
cm
1
; HRMS (
ESI+)
m/z calc’d for
C
7
H
8
NO
2
[M
+
H]
+
:
138.0550
, found
138.0556
.
Preparation of Hydroxamate Starting Materials:
General Procedure
A
To a round bottom flask containing carboxylic acid (1.0 equiv) dissolved in dichloromethane (0.2
M) was added
1,1'
-
c
arbonyldiimidazole
(1.1 equiv
). The reaction mixture was stirred for 30
minutes, and then
O
-
benzoylhydroxylamine hydrochloride (
1
6
) (1.1 equiv) was added. The
reaction was continued for an additional 2 hours, or until reaction reached completion as
determined by monitoring with TLC. T
he crude mixture was diluted with water and transferred to
a separatory funnel. The organic layer was separated, and the aqueous layer was extracted three
times with ethyl acetate. The combined organics were washed with brine, dried over anhydrous
Na
2
SO
4
,
filtered, concentrated, and purified by silica gel flash chromatography to provide the
desired hydroxamic ester.
Note: all reaction yields for the preparation of hydroxamate starting materials are unoptimized.
H
2
N
OBz
•HCl
1. Bz
2
O (1 equiv)
triethylamine (1 equiv)
CH
2
Cl
2
(0.1 M), 0 °C, 2 h
2. HCl (4.0 M in dioxane)
BocHN
OH
16
H
2
N
OBz
•HCl
16
R
OH
O
+
R
N
H
O
OBz
CDI
CH
2
Cl
2
23 °C, 2 h
Supporting Information for
Barbor, Nair
,
Sharp
,
Lohrey, Dibrell,
Shah, Walsh, Reisman,
and Stoltz
8
Preparation of Hydroxamate Starting Materials
: General Procedure B
To a round bottom flask containing carboxylic acid (1.0 equiv) dissolved in dichloromethane (0.2
M) was added
1,1'
-
c
arbonyldiimidazole
(1.1 equiv). The reaction mixture was stirred for 30
minutes, and then hydroxylamine hydrochlorid
e (1.1 equiv) was added. The reaction was
continued for an additional 2 hours, or until reaction reached completion as determined by TLC.
The crude mixture was diluted with water and transferred to a separatory funnel. The organic layer
was separated, and
the aqueous layer was extracted three times with ethyl acetate. The combined
organics were washed with brine, dried over anhydrous Na
2
SO
4
, filtered, concentrated, and used
without further purification.
The crude hydroxamic acid was dissolved in dichloromet
hane (0.2 M), and triethylamine (1.0
equiv) was added. The reaction mixture was cooled to 0 °C, and benzoic anhydride (1.0 equiv)
was added portionwise over 5 minutes. The reaction continued and was allowed to slowly warm
to room temperature over 2 hours,
after which the mixture was transferred to a separatory funnel,
the organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate.
The combined organics were washed with brine, dried over anhydrous Na
2
SO
4
,
filtered,
concentrated, and purified by silica gel chromatography to provide the desired hydroxamic ester.
Note: all reaction yields for the preparation of hydroxamate starting materials are unoptimized.
Preparation of Hydroxamate Starting Materials: Gene
ral Procedure C
To a round bottom flask containing
O
-
benzoylhydroxylamine hydrochloride (
1
6
)
(1.5 equiv) and
sodium carbonate (2.0 equiv) was added water and ethyl acetate (1:1, 0.2 M). The biphasic mixture
was cooled to 0 °C, and the acid chloride (1.0
equiv) was added dropwise. The reaction continued
and was allowed to slowly warm to room temperature over 2 hours, after which the mixture was
transferred to a separatory funnel, the organic layer was separated, and the aqueous layer was
extracted three ti
mes with ethyl acetate. The combined organics were washed with brine, dried
R
OH
O
R
N
H
O
OBz
1. hydroxylamine HCl
CDI
CH
2
Cl
2
, 23 °C, 2 h
2. Bz
2
O, Et
3
N
CH
2
Cl
2
0 to 23 °C, 2 h
H
2
N
OBz
•HCl
16
R
Cl
O
+
R
N
H
O
OBz
Na
2
CO
3
H
2
O/EtOAc (1:1)
0 to 23 °C, 2 h
Supporting Information for
Barbor, Nair
,
Sharp
,
Lohrey, Dibrell,
Shah, Walsh, Reisman,
and Stoltz
9
over anhydrous Na
2
SO
4
, filtered, concentrated, and purified by silica gel chromatography to
provide the desired hydroxamic ester.
Note: all reaction yields for the preparation of h
ydroxamate starting materials are unoptimized.
Preparation of Hydroxamate Starting Materials: General Procedure D
To a round bottom flask containing hydroxylamine hydrochloride (1.5 equiv) and sodium
carbonate (2.0 equiv
) was added water and ethyl acetate (1:1, 0.2 M). The biphasic mixture was
cooled to 0 °C, and the acid chloride (1.0 equiv) was added dropwise. The reaction continued and
was allowed to slowly warm to room temperature over 2 hours, after which the mixture
was
transferred to a separatory funnel, the organic layer was separated, and the aqueous layer was
extracted three times with ethyl acetate. The combined organics were washed with brine, dried
over anhydrous Na
2
SO
4
, filtered, concentrated, and used withou
t further purification.
The crude hydroxamic acid was dissolved in dichloromethane (0.2 M), and triethylamine (1.0
equiv) was added. The reaction mixture was cooled to 0 °C, and benzoic anhydride (1.0 equiv)
was added portionwise over 5 minutes. The reacti
on continued and was allowed to slowly warm
to room temperature over 2 hours, after which the mixture was transferred to a separatory funnel,
the organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate.
The combined
organics were washed with brine, dried over anhydrous Na
2
SO
4
, filtered,
concentrated, and purified by silica gel chromatography to provide the desired hydroxamic ester.
Note: all reaction yields for the preparation of hydroxamate starting materials are uno
ptimized.
Preparation of N
-
(benzoyloxy)benzamide (1a)
To
N
-
Boc
-
hydroxylamine (26.6 g, 200 mmol, 1.0 equiv) and triethylamine (56 mL, 400 mmol, 2.0
equiv) in CH
2
Cl
2
(0.4 M) was added benzoic anhydride (90.5 g, 400 mmol, 2.0 equiv) portionwise
over five minutes. The reaction was stirred at 23 °C for 2 hours, then diluted with saturated
NaHCO
3
, transferred to a separatory funnel, and extracted with dichloromethane thre
e times. The
R
Cl
O
R
N
H
O
OBz
1. hydroxylamine HCl
H
2
O/EtOAc
0 to 23 °C, 2 h
2. Bz
2
O, Et
3
N
CH
2
Cl
2
0 to 23 °C, 2 h
Ph
N
H
O
OBz
BocHN
OH
1. Bz
2
O (2.0 equiv)
Et
3
N (2.0 equiv)
CH
2
Cl
2
(0.4 M)
2. HCl (4N in dioxane)
1a