S
1
Nickel
-
Catalyzed Reductive Alkylation of Redox
-
Active Heteroaryl Imines
Marco Brandstätter
‡
,
Raymond
F.
Turro
‡
,
Sarah E. Reisman
*
The Warren and Katharine Schlinger
Laboratory of Chemistry and Chemical Engineering
Division of Chemistry and Chemical Engineering, California Institute of Technology
Pasadena, California 911
2
5
*reisman@caltech.edu
Supporting Information
Table of Contents
1.
General
Information
S
2
2.
Optimization of Reaction Parameters
Procedure
S
4
3.
Electrochemistry
S
4
3.1.
Cyclic Voltammetry
S
4
3.2.
Electrochemical Alkylation Procedure
S
8
4.
Substrate Preparation
S
8
4.1.
Synthesis of Heteroaryl Imines
S
8
4.2.
Synthesis of
N
-
hydroxyphthalimide
(NHP)
Ester Substrates
S
19
5.
Nickel
-
Catalyzed
Alkyl Halide Addition to Heteroaryl Imines
S
19
5.1.
General procedure
3
: Reaction on 0.3 mmol scale
S
20
5.2.
Challenging Substrates
S
20
5.3.
Characterization of Reaction Products:
Scheme 1
S
21
6.
Mechanistic Experiments
S
44
S
2
6.1.
Independent synthesis of diamine
1a
’:
S
44
6.2.
Probing Intermediacy of Organomanganese Intermediate
S
45
6.3.
Stoichiometric Ni
0
Alkylation
S
47
7.
Electron Paramagnetic Resonance (EPR) Studies
S
47
7.1.
General EPR Details
S
47
7.2.
EPR Sample Preparation
S
47
7.3.
EPR Data
S
49
8.
Computational Details S
50
8.1.
DFT Input
Files and Coordinates
S
51
8.2.
Calculated Geometries of
5
and
5
ox
S
64
9.
Comparison of
5
/
5
ox
with redox
-
active iminopyridine Ni complexes
S
66
10.
X
-
Ray Data for
1a’
S
68
11.
Elemental Analysis of Commercial Mn
0
S
70
12.
References
S
72
13.
1
H NMR and
13
C NMR Spectra
S
73
S
3
1.
General Information
Materials and Methods
Unless otherwise stated, reactions were performed under a N
2
atmosphere using freshly dried
solvents.
All reagents were purchased from commercial suppliers (Sigma Aldrich, Combi
Blocks, TCI, Enamine, Strem) and used without further purifications unless mentioned
otherwise.
Tetrahydrofuran (THF), diethyl ether (Et
2
O), methylene chloride (CH
2
Cl
2
),
toluene
(PhMe), hexane, and benzene (C
6
H
6
) were dried by passing through activated alumina
columns. Anhydro
us
N
-
methylpyrrolidinone (NMP) were purchased from Aldrich and stored
under N
2
.
NiCl
2
·dme was purchased from Strem and stored in the glovebox.
Mangan
ese
powder (
~
325 mesh, 99.3%) was purchased from Alfa Aesar. Zinc dust (97.5%) was purchased
from Strem. Unless otherwise stated, chemicals and reagents were used as received. All
reactions were monitored by thin
-
layer chromatography using EMD/Merck silica
gel 60 F254
pre
-
coated plates (0.25 mm) and were visualized by UV,
p
-
Anisaldehyde,
Ninhydrin
, or
KMnO
4
staining. Flash column
chromatography was performed as described by Still et al. using
silica gel (230
-
400 mesh, Silicycle).
1
Purified compounds were d
ried on a high vacuum line
(0.2 torr) to remove trace solvent.
1
H and
13
C NMR spectra were recorded on a Bruker Avance
III HD with Prodigy
cryoprobe
(at 400 MHz and 101 MHz, respectively), a Varian 400 MR (at
400 MHz and 101 MHz, respectively), or a Varian
Inova 500 (at 500 MHz and 126 MHz,
respectively).
1
H and
19
F NMR spectra were also recorded on a Varian Inova 300 (at 300 MHz
and 282 MHz, respectively). NMR data is reported relative to internal CHCl
3
(
1
H, δ = 7.26)
and
CDCl
3
(
13
C, δ = 77.0)
.
Data for
1
H NMR spectra are reported as follows: chemical shift (δ
ppm) (multiplicity, coupling constant (Hz), integration). Multiplicity and qualifier
abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br
= br
oad. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are
reported in frequency of absorption (cm
–
1
). HRMS were acquired from the Caltech Mass
Spectral Facility using fast
-
atom bombardment (FAB), electrospray ionization (ESI
-
TOF), o
r
electron impact (EI).
E
lemental analysis (EA)
with ICP
-
MS
on
a
commercial manganese
sample
w
as
performed
at
the
Resnick Sustainability Institute's Water and Environment Lab at
the California Institute of Technology
.
X
-
ray diffraction
was
performed at the
Caltech X
-
ray
Crystal Facility.
The computations presented here were conducted on the Caltech High
Performance Cluster, partially supported by a grant from the Gordon and Betty Moore
Foundation.
S
4
2.
Optimization of Reaction Parameters
(
Table 1.
)
General Procedure:
To a 1
-
dram vial equipped with a stir bar was
added
2
-
imino pyridine
1a
(0.
3
mmol), benzyl bromide (0.
36
mmol,
1.2
equiv)
,
and Mn
0
(0.
3
mmol, 1.0 equiv) on the
benchtop. The vial was brought into a nitrogen
-
filled glovebox and a stock so
lution of
NiCl
2
·dme in NMP (0.
75
ml, 0.0
2
M, 0.
05
equiv [Ni]) and TMSCl (0.
6
mmol, 2.0 equiv)
was
added
. The vial w
as
sealed with a Teflon cap, removed from the glovebox, and stirred
at
ambient temperature
for 14 hours at
60
0 rpm. The resulting suspension
was diluted with
CH
2
Cl
2
(0.5 ml) and extracted 3x with 1
N HCl (0.5 ml). To the combined aqueous phases was
added K
2
CO
3
(s) until gas evolution ceased. The resulting aqueous solution was extracted 3x
with EtOAc and the combined
EtOAc layers
were concentrat
ed under reduced pressure and
analyzed by
1
H NMR
with 1,1,2,2
-
tetrachloroet
ha
ne as an analytical standard
to obtain the
reaction yield.
3.
Electrochemistry
3.1.
Cyclic Volt
a
m
metry
Cyclic voltammo
g
rams were obtained at an analyte concentration of
10.0 mM and a supporting
electrolyte concentration of 0.1 M TBAPF
6
in
DMA
. A glassy carbon working electrode,
graphite counter electrode, and a silver wire pseudo
-
reference electrode were employed, and
data
were collected using a Biologic SP
-
300 potentiostat. All cyclic voltammog
r
ams w
e
re
measured in the presence of
1 equiv of freshly
-
sublimed ferrocene and
the
r
eduction potentials
are given versus the
½ wave potential of the Fc/Fc
+
peak
.
Yields reported are
average of 2 runs
from reactions of imine with benzyl bromide according to General Procedure 3.
1
a
,
76
% yield
S
5
Figure S
1
:
Cyclic voltammogram of
1a
, at a scan rate of 200 mV/s
Figure S
2
:
Cyclic voltammogram of
1
n
, at a scan rate of 200 mV/s
Figure S
3
:
Cyclic voltammogram of
1
o
, at a scan rate of
3
00 mV/s
1n
,
59
% yield
1
o
,
7
4
% yield
S
6
Figure S
4
:
Cyclic voltammogram of
1
p
, at a scan rate of 200 mV/s
Figure S
5
:
Cyclic voltammogram of
S
1
b
, at a scan rate of 200 mV/s
1
p
,
5
2
% yield
S1b
,
29
% yield
S
7
Figure S
6
:
Cyclic voltammogram of
S
1
d
, at a scan rate of 200 mV/s
Figure S
7
:
Cyclic voltammogram of
S1f
e
at a scan rate of 200 mV/s
.
The presence of
an additional, earlier
(
–
1.65 V to
–
2.50 V)
,
irreversible reduction peak in imine
substrates that did not perform well in the imine alkylation reaction (
S1b, S1
d
,
and
S1
e
)
suggests that there may be deleterious redox reactions happening under the reaction conditions.
S
elected heteroaryl imines (
1a,
1n,
and
1o
)
perform well in the alkylation reaction that only
have the quasi
-
reve
r
sible peaks at ~2.88 V.
Further investigations into this correlation are
ongoing in our laboratory.
S1
d
,
3
3
% yield
S1
e
,
7
% yield
S
8
3.2.
Electrochemical Alkylation Procedure
On the bench
-
top, a standard 2 m
L ElectraSyn vial was charged with a stir bar, iminopyridine
1a
(44.5mg, 1.2 mmol, 1.0 equiv) and cyclohexyl iodide (378 mg, 1.8 mmol, 1.2 equiv). The
vial was brought into a N
2
-
filled glovebox and a stock
-
solution of NiCl
2
·dme in NMP (3.0 ml,
0.04 M, 0.1
equiv [Ni]) was added. The vial was sealed with a septum and brought out of the
glove box. IKA
Zn
(anode) and
RVC
(cathode) plate electrodes were connected to an
ElectraSyn vial cap. The cap was installed under N
2
-
flow and fit into the ElectraSyn and the
f
ollowing setup was employed:
New exp.
-
> Constant current
-
> 10 mA
-
> no ref. electrode
-
> no alternating polarity
-
> start.
The reaction was stirred at room temperature for 5 hours.
The resulting dark solution was diluted with CH
2
Cl
2
(2 ml) and extracted 3x with 1N HCl (2
ml). To the combined aqueous phases was added K
2
CO
3
(s) until gas evolution ceased. The
resulting aqueous
solution was extracted 3x with EtOAc and the combined organic phases
were concentrated under reduced pressure at 40 °C until most of the NMP was removed. The
crude material was purified by column chromatography (1:1 hexanes:EtOAc w/ 1% Et
3
N) to
afford the
desired product
4o
(162 mg, 0.70 mmol, 58%).
4.
Substrate Preparation
4.1.
Synthesis of Heteroaryl Imines
a. General Procedure 1: Heteroaryl Imine
Synthesis using Volatile Amines
A 1
-
dram vial equipped with a stir bar was charged with MeOH (0.7 M), heteroaryl
aldehyde
(1.0 equiv), and primary amine RNH
2
(1.2 equiv). The resulting solution was stirred at room
temperature for 2 hours, followed by concentration in vacuo. The resulting
2
-
imino
-
heteroar
ene
was obtained in pure form and used without further purification.
b. General Procedure 2: Heteroaryl Imine Synthesis using
N
on
-
volatile
A
mines
A 1
-
dram vial equipped with a stir bar was charged with CH
2
Cl
2
(0.7 M), heteroaryl aldehyde
(1.05 equiv), MgSO
4
(1.5 equiv) and primary amine RNH
2
(1.0 equiv). The resulting solution
N
O
N
N
R
RNH
2
(1.2 equiv)
MeOH, rt
Het
Het
S
9
was stirred at room temperature for 18 hours. The resulting suspension was filtered and
concentrated in vacuo. The resulting 2
-
imino
-
heteroaryl was obtained in pure
form and used
without further purification.
(
E
)
-
N
-
isopropyl
-
1
-
(pyridin
-
2
-
yl)methanimine (
1a
)
Prepared from 2
-
pyridine carboxaldehyde (
2.30 g
,
21.5
mmol)
and
isopropylamine (1.59 g, 26.8 mmol)
following General Procedure 1. After
concentration in vacuo,
1a
(
2.68
g,
18.1
mmol,
84
%) was obtained as a
yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ 8.63 (d,
J
= 3.1 Hz, 1H), 8.39 (s, 1H), 7.98 (d,
J
= 7.9 Hz,
1H), 7.73 (td,
J
= 7.9, 2.2 Hz, 1H), 7.29 (ddd
,
J
= 7.5, 4.8, 1.2 Hz, 1H), 3.69
–
3.60 (m, 1H),
1.29 (d,
J
= 6.3 Hz, 6H).
13
C NMR (126 MHz, CDCl
3
):
δ 159.5, 155.0, 149.6, 136.7, 124.8, 121.6, 61.7, 24.2.
FTIR (NaCl, thin film, cm
-
1
):
3056, 2968, 2929, 2865, 1647, 1588, 1568, 1466, 1437, 1362,
1316, 11
39, 993, 973, 945, 775, 744, 615.
HRMS (FAB, m/z):
calc’d for C
9
H
11
N
2
[M+H]
+
–
H
2
: 147.0922; found 147.0922.
(
E
)
-
N
-
butyl
-
1
-
(pyridin
-
2
-
yl)methanimine (
1b
)
Prepared fro
m
2
-
pyridine carboxaldehyde (
1.07
g,
10.0
mmol)
and
n
-
butylamine (878 mg, 12.0
mmol)
following General Procedure 1. After
concentration in vacuo,
1b
(
1.30
g,
8.00
mmol,
80
%) was obtained as
a yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ
8.64 (d,
J
= 4.8 Hz, 1H), 8.37 (s, 1H), 7.97 (d,
J
= 7.9 Hz,
1H), 7.73 (td,
J
= 7.7, 1.7 Hz, 1H), 7.30
(dd,
J
= 7.5, 4.8 Hz, 1H), 3.68 (t,
J
= 6.8 Hz, 2H), 1.71
(p,
J
= 7.1 Hz, 2H), 1.40 (h,
J
= 7.4 Hz, 2H), 0.95 (t,
J
= 7.4 Hz, 3H).
13
C NMR (126 MHz, CDCl
3
):
δ
161.9, 154.8, 149.6, 136.8, 124.8, 121.4, 61.5, 33.0, 20.6,
14.1.
FTIR (NaCl, thin film, cm
-
1
):
3053, 3009, 2958, 293
8
, 2872, 1649, 1587, 1567, 1468, 1436,
1377, 1332, 1292, 1227, 1145, 1117, 1066, 1044, 992, 978, 939, 898, 864, 775, 743, 654, 617.
HRMS (
FAB
, m/z):
calc’d for C
10
H
15
N
2
[M+H]
+
: 16
3
.
1235
; found 16
3
.
1256
.
(
E
)
-
N
-
tert
-
butyl
-
1
-
(pyridin
-
2
-
yl)methanimine (
1c
)
N
N
Me
N
N
Me
Me
S
10
Prepared from 2
-
pyridine carboxaldehyde (
225
mg,
2.10
mmol)
and
tert
-
butlyamine (185 mg, 2.52 mmol)
following General Procedure 1. After
concentration in vacuo,
1c
(
398
mg,
2.0
mmol,
95
%) was obtained as a
yellow oi
l.
1
H NMR (500 MHz, CDCl
3
):
δ
8.66
–
8.58 (m, 1H), 8.35 (s, 1H), 8.01 (dt,
J
= 7.9, 1.1 Hz,
1H), 7.76
–
7.67 (m, 1H), 7.28 (ddd,
J
= 7.5, 4.9, 1.3 Hz, 1H), 1.31 (s, 9H).
13
C NMR (126 MHz, CDCl
3
):
δ
156.6, 155.7, 149.5, 136.7, 124.6, 121.2, 58.0,
29.8.
FTIR (NaCl, thin film, cm
-
1
):
3056, 2969, 2931, 1646, 1588, 1568,
1467, 1436, 1228, 1209,
1044, 994, 972, 908, 860, 775, 744, 616.
HRMS (ESI
-
TOF, m/z):
calc’d for C
10
H
15
N
2
[M+H]
+
: 1
63
.
1235
; found 16
3.1210
.
(
E
)
-
N
-
cyclopropyl
-
1
-
(pyridin
-
2
-
yl)methanim
ine (
1d
)
Prepared from 2
-
pyridine carboxaldehyde (
225
mg,
2.10
mmol)
and
cyclopropylamine (144 mg, 2.52 mmol
following General Procedure 1. After
concentration in vacuo,
1d
(
200
mg,
1.37
mmol,
65
%) was obtained as a
yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ
7.88 (d,
J
= 9.0 Hz, 1H), 7.71 (td,
J
= 7.7, 1.7 Hz, 1H), 7.31
–
7.24 (m, 1H), 3.13 (hept,
J
= 6.8, 3.4 Hz, 1H), 1.09
–
1.04 (m, 2H), 1.03
–
0.97 (m, 2H).
13
C NMR (126 MHz, CDCl
3
):
δ
159.3, 154.8, 149.6, 136.6, 124.4, 121.3, 42.2, 9.5.
FTIR (NaCl, thin
film, cm
-
1
):
3420, 3055, 3010, 2962, 2878, 1635, 1583, 1568, 1470, 1436,
1381, 1320, 1174, 1146, 1090, 1042, 956, 887, 812, 773, 743, 612.
HRMS (
FAB
, m/z):
calc’d for C
9
H
11
N
2
[M+H]
+
: 147.0922; found 147.0922.
(
E
)
-
N
-
cyclobutyl
-
1
-
(pyridin
-
2
-
yl)methanimine (
1e
)
Prepared from 2
-
pyridine carboxaldehyde (
225
mg,
2.10
mmol)
and
cyclobutylamine (179 mg, 2.52 mmol)
following General Procedure 1. After
concentration in vacuo,
1e
(
243
mg,
1.51
mmol,
72
%) was obtained as a
yel
low oil.
1
H NMR (500 MHz, CDCl
3
):
δ
8.6 (d,
J
= 4.8 Hz, 1H), 8.3 (d,
J
= 1.7 Hz, 1H), 8.0 (d,
J
= 7.9
Hz, 1H), 7.7 (td,
J
= 7.7, 1.7 Hz, 1H), 7.3 (dd,
J
= 6.4, 4.8 Hz, 1H), 4.3
–
4.2 (m, 1H), 2.4
–
2.3
(m, 2H), 2.3
–
2.1 (m, 2H), 1.9
–
1.8 (m, 2H).
13
C NMR (126 MHz, CDCl
3
):
δ
159.4, 154.9, 149.6, 136.7, 124.8, 121.4, 62.9, 30.5, 15.8.
N
N
Me
Me
Me
N
N
N
N
S
11
FTIR (NaCl, thin film, cm
-
1
):
3055, 2980, 2939, 2868, 1642, 1589, 1567,
1469, 1436, 1374,
1319, 1228, 1140, 1080, 1042, 992, 972, 861, 773, 743.
HRMS (
FAB
, m/z):
calc’d for C
10
H
13
N
2
[M+H]
+
: 16
1
.
1079
; found 16
1
.
1086
.
(
R
,
E
)
-
N
-
(1
-
phenylethyl)
-
1
-
(pyridin
-
2
-
yl)methanimine (
1f
)
Prepared from 2
-
pyridine
carboxaldehyde (
176
mg,
1.65
mmol)
and (R)
-
(+)
-
1
-
phenethylamine (190 mg, 1.57 mmol)
following General Procedure
2
.
After concentration in vacuo,
1f
(
82.4
mg,
0.39
mmol,
25
%) was obtained
as
tan solid
.
1
H NMR (500 MHz, CDCl
3
):
δ
8.64 (ddd,
J
= 4.9, 1.7, 0.9 Hz, 1H), 8.47 (s, 1H), 8.10 (dt,
J
= 7.9, 1.1 Hz, 1H), 7.78
–
7.67 (m, 1H), 7.46
–
7.41 (m, 2H), 7.38
–
7.32 (m, 2H), 7.30 (ddd,
J
= 7.5, 4.8, 1.2 Hz, 1H), 7.28
–
7.22 (m, 1H), 4.65 (q,
J
= 6.4 Hz, 1H), 1.61 (d,
J
= 6.7 Hz, 3H).
13
C NMR
(126 MHz, CDCl
3
):
δ
160.6, 155.0, 149.5, 144.8, 136.7, 128.7, 127.2, 126.9, 124.9,
121.7, 69.8, 24.8.
FTIR (NaCl, thin film, cm
-
1
):
3059, 3027, 2972, 2927,
2861, 1646, 1586, 1568, 1491, 1466,
1456, 1436, 1373, 1338, 1304, 1080, 993, 973, 908, 763, 700.
HRM
S (
FAB
, m/z):
calc’d for C
14
H
15
N
2
[M+H]
+
:
211
.
1235
; found
211
.
1217
.
(
E
)
-
N
-
isopropyl
-
1
-
(pyridin
-
2
-
yl)ethan
-
1
-
imine
(
1g
)
Prepared from 2
-
acetylpyridine
(
162
mg,
1.34
mmol)
and isopropylamine
(95.2 mg, 1.61 mmol
following
General Procedure 1
modified to allow the
reaction to run for 48 hours
. After concentration in vacuo,
1g
(
126
mg,
0.78
mmol,
58
%) was obtained as a yellow oil.
1
H NMR (
400
MHz,
CD
2
Cl
2
):
δ
8.46 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 7.98 (dt, J = 8.0, 1.1 Hz,
1H), 7.60 (ddd, J = 8.
0, 7.4, 1.8 Hz, 1H), 7.18 (ddd, J = 7.4, 4.8, 1.3 Hz, 1H), 3.83 (hept, J =
6.3 Hz, 1H), 2.25 (s, 3H), 1.11 (d, J = 6.2 Hz, 6H).
13
C NMR (101 MHz, CD
2
Cl
2
):
δ
163.19, 158.28, 148.07, 135.98, 123.76, 120.63, 51.46,
23.20, 12.98.
FTIR (NaCl, thin film, cm
-
1
):
3050
, 2967, 2929, 2869, 1638, 1585, 1565, 1464, 1433, 1368,
1297, 1134, 1098, 1043, 991, 783, 743.
HRMS (
FAB
, m/z):
calc’d for C
10
H
15
N
2
[M+H]
+
:
163.1235; fo
und: 163.1231.
(E)
-
N
-
isopropyl
-
1
-
(6
-
methylpyridin
-
2
-
yl)methanimine
(
1h
)
N
N
Me
Ph
N
Me
N
Me
Me
S
12
Prepared from
6
-
methylpicolinaldehyde
(
200
mg,
1.65
mmol)
and
isopropylamine (117 mg, 1.98 mmol)
following General Procedure 1.
After concentration in vacuo,
1h
(
174
mg,
1.07
mmol,
65
%) was
obtained as a yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ
8.37 (s, 1H), 7.81 (d,
J
= 7.7 Hz, 1H), 7.61 (t,
J
= 7.7 Hz, 1H),
7.16 (d,
J
= 7.6 Hz, 1H), 3.62 (hept,
J
= 6
.3 Hz, 1H), 2.59 (s, 3H), 1.28 (d,
J
= 6.3 Hz, 6H).
13
C NMR (126 MHz, CDCl
3
):
δ
159.9, 158.2, 154.5, 137.0, 124.4, 118.5, 61.6, 24.6, 24.2.
FTIR (NaCl, thin film, cm
-
1
):
3061, 2968, 2927, 2863, 1646, 1591, 1574, 1455, 1378, 1361,
1308, 1250, 1224, 1141, 1086, 990, 967, 948, 9191, 863, 792, 762, 738, 636.
HRMS (
FAB
, m/z):
calc’d for
C
10
H
15
N
2
[M+H]
+
: 163.1235; found 163.12
36
.
(E)
-
N
-
isopropyl
-
1
-
(
4
-
methylpyridin
-
2
-
yl)methanimine (
1i
)
Prepared from
6
-
methylpicolinaldehyde
(
200
mg,
1.65
mmol)
and
isopropylamine (117 mg, 1.98 mmol)
following General Procedure 1. After
concentration in vacuo,
1i
(
268
mg,
1.37
mmol,
83
%) was obtained as a
yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ
8.48 (d,
J
= 5.0 Hz, 1H), 8.37 (s, 1H), 7.82
(s, 1H), 7.12 (d,
J
= 3.2 Hz, 1H), 3.63 (hept,
J
= 6.3 Hz, 1H), 2.38 (s, 3H), 1.29 (d,
J
= 6.3 Hz,
6H).
13
C NMR (126 MHz, CDCl
3
):
δ
159.8, 154.7, 149.4, 148.0, 125.8, 122.1, 61.7,
24.2, 21.2.
FTIR (NaCl, thin film, cm
-
1
):
2968, 2925, 2864, 1647, 1602, 1558, 1466, 1380, 1362, 1315,
1155, 994, 945, 850, 826, 768, 650.
HRMS (
FAB
, m/z):
calc’d for C
10
H
15
N
2
[M+H]
+
: 1
63
.
1235
; found 16
3
.
1257
.
(E)
-
N
-
isopropyl
-
1
-
(5
-
methoxypyridin
-
2
-
yl)met
hanimine (
1j
)
Prepared from
5
-
methoxypicolinaldehyde
(
250
mg,
1.82
mmol)
and
isopropylamine (129 mg, 2.19 mmol)
following General Procedure 1.
After concentration in vacuo,
1j
(
195
mg,
1.09
mmol,
60
%) was
obtained as a yellow oil.
1
H NMR (500 MHz,
CDCl
3
):
δ
8.34 (s, 1H), 8.30 (d,
J
= 2.9 Hz, 1H), 7.93 (d,
J
= 8.7 Hz,
1H), 7.22 (dd,
J
= 8.7, 2.9 Hz, 1H), 3.89 (s, 3H), 3.60 (hept,
J
= 6.3 Hz, 1H), 1.27 (d,
J
= 6.3
Hz, 6H).
N
N
Me
Me
Me
N
N
Me
Me
Me
N
N
Me
Me
MeO
S
13
13
C NMR (126 MHz, CDCl
3
):
δ
158.8, 156.7, 147.9, 137.2, 122.4, 120.9, 61.6, 55.
9, 24.3.
FTIR (NaCl, thin film, cm
-
1
):
2967, 2867, 1644, 1588, 1571, 1491, 1379, 1363, 1302, 1278,
1251, 1217, 1142, 1030, 1142, 1030, 972, 886, 838.
HRMS (
FAB
, m/z):
calc’d for C
10
H
15
N
2
O [M+H]
+
: 179.1184; found 179.118
7
.
(E)
-
N
-
isopropyl
-
1
-
(4
-
methoxypyridin
-
2
-
yl)methanimine (
1k
)
Prepared from
4
-
methoxypicolinaldehyde
(
250
mg,
1.82
mmol)
and
isopropylamine (129 mg, 2.19 mmol)
following General Procedure 1. After
concentration in vacuo,
1k
(
310
mg,
1.73
mmol,
95
%) was obtained a
s a
yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ
8.41 (d,
J
= 5.8 Hz, 1H), 8.33 (s, 1H), 7.49
(s, 1H), 6.81 (d,
J
= 5.9 Hz, 1H), 3.88 (s, 3H), 3.62 (hept,
J
= 6.5 Hz, 1H), 1.27 (d,
J
= 4.9 Hz,
6H).
13
C NMR (126 MHz, CDCl
3
):
δ
166.4, 159.4, 156.9, 150.6,
112.1, 106.1, 61.5, 55.5, 24.1.
FTIR (NaCl, thin film, cm
-
1
):
2968, 2866, 1648, 1592, 1560, 1477, 1364, 1303, 1252, 1142,
1037, 993, 969, 944, 850, 767.
HRMS (
FAB
, m/z):
calc’d for C
10
H
15
N
2
O [M+H]
+
: 1
79
.
1184
; found 1
79
.
1181
.
(
E
)
-
1
-
(4
-
chloropyridin
-
2
-
yl)
-
N
-
isopropylmethanimine (
1l
)
Prepared from
4
-
chloropicolinaldehyde
(
200
mg,
1.41
mmol)
and
is
o
propylamine (91.9 mg, 1.55 mmol)
following General Procedure 1. After
concentration in vacuo,
1l
(
224
mg,
1.22
mmol,
87
%) was obtained
as a
yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ
8.51 (d,
J
= 7.0 Hz, 1H), 8.35 (s, 1H), 8.02
(s, 1H), 7.30 (d,
J
= 5.4 Hz, 1H), 3.65 (hept,
J
= 6.2 Hz, 1H), 1.28 (d,
J
= 5.7 Hz, 6H).
13
C NMR (126 MHz, CDCl
3
):
δ
158.3, 156.5, 150.4, 145.1, 125.0, 121.7,
61.6, 24.1.
FTIR (NaCl, thin film, cm
-
1
):
2969, 2924, 2864, 1648, 1575, 1553, 1458, 1398, 1362, 1313,
1264, 1230, 1145, 1090, 945, 827, 709.
HRMS (
FAB
, m/z):
calc’d for C
9
H
12
N
2
Cl
[M+H]
+
: 1
83
.0
689
; found 1
83
.0
662
.
(
E
)
-
1
-
(6
-
fluoropyridin
-
2
-
yl)
-
N
-
isopropylmethanimine (
1m
)
N
N
Me
Me
OMe
N
N
Me
Me
Cl
S
14
Prepared from
6
-
fluoropicolinaldehyde
(
177
mg,
1.41
mmol)
and
ispropylamine (91.9 mg, 1.55 mmol)
following General Procedure 1.
After concentration in vacuo,
1m
(
202
mg,
1.21
mmol,
86
%) was
obtained
as a yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ 8.25 (s, 1H), 7.88 (d,
J
= 7.3 Hz, 1H), 7.85
–
7.78 (m, 1H),
6.95 (d,
J
= 8.0 Hz, 1H), 3.63 (hept,
J
= 6.3 Hz, 1H), 1.27 (d,
J
= 6.4 Hz, 6H).
13
C NMR (126 MHz, CDCl
3
):
δ 163.4 (d,
J
= 240.1 Hz), 158.0, 153.7 (d,
J
= 12.5 Hz), 141.6
(d,
J
= 7.4 Hz), 118.6 (d,
J
= 4.1 Hz), 110.7 (d,
J
= 36.9 Hz), 61.6, 24.1.
FTIR (NaCl, thin film, cm
-
1
):
2970, 2930, 2868, 1650, 1598, 1578, 1455, 1380, 1362, 1309,
1262, 1228, 1139, 1071, 994, 974, 937, 865, 804, 771, 731, 630.
HRMS
(FAB, m/z):
calc’d for C
9
H
12
N
2
F [M+H]
+
: 167.0985; found 167.0963.
(
E
)
-
1
-
(5
-
fluoropyridin
-
2
-
yl)
-
N
-
isopropylmethanimine (
1n
)
Prepared from
5
-
fluoropicolinaldehyde
(
177
mg,
1.41
mmol)
and
is
o
propylamine (91.9 mg, 1.55 mmol)
following General Procedure 1.
After concentration in vacuo,
1n
(
162
mg,
0.98
mmol,
69
%) was obtained
as a yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ
8.46 (s, 1H), 8.35 (s, 1H), 8.02 (dd,
J
= 8.5, 4.9 Hz, 1H), 7.43
(t,
J
= 8.4 Hz, 1H), 3.62 (hept,
J
= 7.1 Hz,
1H), 1.27 (d,
J
= 6.5 Hz, 6H).
13
C NMR (126 MHz, CDCl
3
):
δ
160.2 (d,
J
= 259.2 Hz), 158.0, 151.5 (d,
J
= 3.9 Hz), 137.8
(d,
J
= 24.1 Hz), 123.6 (d,
J
= 18.5 Hz), 122.8 (d,
J
= 5.0 Hz), 61.6, 24.2.
FTIR (NaCl, thin film, cm
-
1
):
2970, 2933, 2865, 1647, 1593
, 1579, 1478, 1380, 1363, 1312,
1253, 1232, 1143, 1281, 1232, 1143, 1019, 961, 886, 841.
HRMS (
FAB
, m/z):
calc’d for C
9
H
12
FN
2
[M+H]
+
:
167
.
0985
; found 16
7
.
0980
.
(E)
-
N
-
isopropyl
-
1
-
(1
-
methyl
-
1H
-
benzo[d]imidazol
-
2
-
yl)methanimine (
1o
)
Prepared from
1
-
methyl
-
1H
-
benzo[d]imidazole
-
2
-
carbaldehyde
(
200
mg,
1.25
mmol)
and isopropylamine (81.2 mg, 1.37 mmol)
following
General Procedure 1. After concentration in vacuo,
1o
(
227
mg
,
1.13
mmol,
91
%) was obtained as a yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ 8.53 (s, 1H), 7.80 (d,
J
= 8.0 Hz, 1H), 7.40 (d,
J
= 8.0 Hz,
1H), 7.38
–
7.32 (m, 1H), 7.29 (t,
J
= 7.5 Hz, 1H), 4.18 (s, 3H), 3.65
–
3.56 (m, 1H), 1.30 (d,
J
= 8.1 Hz, 6H).
N
N
Me
Me
F
N
N
Me
Me
F
N
Me
Me
N
N
Me
S
15
13
C NMR (126 MHz, CDCl
3
):
δ 151.6, 147.8, 142.6, 137.0, 124.2, 122.7, 120.6, 109.8, 62.4,
31.9, 24.1.
FTIR (NaCl, thin film, cm
-
1
):
2968, 2861, 1471, 1405, 1359, 1336, 1143, 931,
882, 748.
HRMS (ESI
-
TOF, m/z):
calc’d for C
12
H
16
N
3
[M+H]
+
: 202.1344; found 202.1315.
(E)
-
N
-
isopropyl
-
1
-
(thiazol
-
2
-
yl)methanimine (
1p
)
Prepared from
thiazole
-
2
-
carbaldehyde
(
200
mg,
1.77
mmol)
and
isopropylamine (115 mg, 1.94 mmol)
following General Procedure 1. After
concentration in vacuo,
1p
(
251
mg,
1.63
mmol,
92
%) was obtained as a
yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ 8.46 (s, 1H), 7.89 (d,
J
= 3.5 Hz, 1H), 7.38 (s, 1H), 3.65 (hept,
J
= 6.4 Hz, 1H), 1.28 (d,
J
= 6.3 Hz, 6H).
13
C NMR (126 MHz, CDCl
3
):
δ 167.7, 152.6, 144.0, 121.4, 61.4, 23.9.
FTIR (NaCl, thin film, cm
-
1
):
3080, 2969, 2966, 1636, 1507, 1490, 1458, 1418, 1362, 1294,
1235, 1132, 1058, 945, 853, 775, 733, 691, 629.
HRMS (FAB, m/z):
calc’d for C
7
H
11
N
2
S [M+H]
+
: 155.
0643; found 155.0652.
(E)
-
N
-
isopropyl
-
1
-
(pyrimidin
-
2
-
yl)methanimine (
1q
)
Prepared from
pyrimidine
-
2
-
carbaldehyde
(
120
mg,
1.11
mmol)
and
isopropylamine (72.2 mg, 1.22 mmol)
following General Procedure 1. After
concentration in vacuo,
1q
(
75.1
mg,
0.50
mmol,
45
%) was obtained as a
yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ
8.84 (d,
J
= 4.9 Hz, 1H), 8.43 (s, 1H), 7.29 (t,
J
= 5.4 Hz, 1H),
3.72 (hept,
J
= 6.4 Hz, 1H), 1.33 (d,
J
=
6.9 Hz, 6H).
13
C NMR (126 MHz, CDCl
3
):
δ
162.3, 158.3, 157.8, 121.2, 62.0, 24.0.
FTIR (NaCl, thin film, cm
-
1
):
3041, 2969, 3938, 3867, 1651, 1561, 1423, 1382, 1365, 1319,
1246, 1144, 994, 964, 944, 898, 818, 793, 634.
HRMS (
FAB
, m/z):
calc’d for C
8
H
12
N
3
[M+H]
+
: 1
50
.
1031
; found 1
50
.
1043
.
(E)
-
N
-
isopropyl
-
1
-
(quinolin
-
2
-
yl)methanimine (
1r
)
N
N
N
Me
Me
N
Me
Me
S
N
S
16
Prepared from
quinoline
-
2
-
carbaldehyde
(
250
mg,
1.59
mmol)
and
isopropylamine (113 mg, 1.91 mmol)
following General Procedure 1.
After concentration in vacuo,
1r
(
296
mg,
1.50
mmol,
94
%) was
obtained as a yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ
8.56 (s, 1H), 8.17 (s, 2H)
, 8.12 (d,
J
= 8.5 Hz, 1H), 7.83 (d,
J
= 8.1 Hz, 1H), 7.73 (t,
J
= 7.7 Hz, 1H), 7.57 (t,
J
= 7.6 Hz, 1H), 3.73 (hept,
J
= 6.2 Hz, 1H),
1.33 (d,
J
= 6.4 Hz, 6H).
13
C NMR (126 MHz, CDCl
3
):
δ
160.1, 155.3, 148.0, 136.7, 130.0, 129.7, 128.9, 127.9, 127.5,
118.
7, 61.7, 24.2.
FTIR (NaCl, thin film, cm
-
1
):
3061, 2968, 2929, 2865, 1716, 1939, 1596, 1559, 1540, 1505,
1457, 1363, 1338, 1302, 1142, 966, 893, 833, 752, 620.
HRMS (
FAB
, m/z):
calc’d for C
13
H
15
N
12
[M+H]
+
: 199.1235; found 199.1210.
(
E
)
-
N
-
isopropyl
-
1
-
phenylmethanimine (
7
)
Prepared from
benzaldehyde
(
157
mg,
1.48
mmol)
and isopropylamine (105
mg, 1.77 mmol)
following General Procedure 1. After concentration in
vacuo,
7
(
215
mg,
1.46
mmol,
99
%) was obtained as a yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ 8.31 (s, 1H), 7.77
–
7.69 (m, 2H), 7.40 (t,
J
= 3.9 Hz, 3H), 3.55 (hept,
J
= 6.3 Hz, 1H), 1.28 (d,
J
= 6.3 Hz, 6H).
13
C NMR (126 MHz, CDCl
3
):
δ 158.5, 136.7, 130.6, 128.7, 128.2, 61.9, 24.4.
FTIR (NaCl, thin film, cm
-
1
):
3061, 3026, 2967, 2931, 2836, 16
47, 1581, 1450, 1382, 1306,
1159, 1141, 967, 881, 755, 693.
HRMS (
FAB
, m/z):
calc’d for
C
10
H
13
N
[M+H]
+
:
148.1126
; found
148
.
1125
(
E
)
-
N
-
isopropyl
-
1
-
(pyridin
-
3
-
yl)methanimine
(
8
)
Prepared from
nicotinaldehyde
(151
mg,
1.41
mmol)
and
isopropylamine
(91.9 mg, 1.55 mmol)
following General Procedure 1. After concentration
in vacuo,
8
(
199
mg,
1.34
mmol,
95
%) was obtained as a yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ
8
.83 (s, 1H), 8.62 (d,
J
= 4.7 Hz, 1H), 8.33
(s, 1H), 8.11 (d,
J
= 5.9 Hz, 1H), 7.36
–
7.29 (m, 1H), 3.57 (hept,
J
= 12.6, 6.3 Hz, 1H), 1.27
(d,
J
= 6.4 Hz, 6H).
13
C NMR (126 MHz, CDCl
3
):
δ
155.6, 151.5, 150.4, 134.6, 132.2, 123.8, 24.2.
N
N
Me
Me
N
N
Me
Me
N
Me
Me
S
17
FTIR (NaCl, thin film, cm
-
1
):
2969, 2931, 2864, 1646
, 1591, 1575, 1558, 1419, 1385
, 1315,
1188, 1142, 1026, 975, 944, 882, 806, 708.
HRMS (
FAB
, m/z):
calc’d for C
9
H
13
N
2
[M+H]
+
: 1
49
.
1079
; found 1
49
.
1086
.
(
(E)
-
N
-
isopropyl
-
1
-
(6
-
methoxypyridin
-
2
-
yl)methanimine (
S1a
)
Prepared from
6
-
methoxypicolinaldehyde
(
250
mg,
1.82
mmol)
and
isopropylamine (129 mg, 2.19 mmol)
following General Procedure 1.
After concentration in vacuo,
S1a
(
246
mg,
1.38
mmol,
76
%) was
obtained as a yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ 8.28 (s, 1H), 7.64
–
7.56 (m, 2H), 6.75 (dd,
J
= 6.0, 3.0 Hz,
1H), 3.97 (s, 3H), 3.62 (p,
J
= 6.3 Hz, 1H), 1.28 (d,
J
= 6.3 Hz, 6H).
13
C NMR (126 MHz, CDCl
3
):
δ 164.0, 159.7, 152.7, 139.1, 114.1, 112.0, 61.6, 53.6, 24.2.
FTIR (NaCl, thin film, cm
-
1
):
2968, 2862, 1648, 1592, 1574, 1469, 1434, 1414, 1362, 1324,
1305, 1266, 1139, 1073, 1034, 988, 966, 866, 805, 765, 734, 631.
HRMS (FAB, m/z):
calc’d for C
10
H
15
N
2
O
[M+H]
+
: 179.1184; found 179.1155.
Methyl (E)
-
6
-
((isopropylimino)methyl)nicotinate (
S1b
)
Prepared from
methyl
-
6
-
formylnicotinate
(
237
mg,
1.43
mmol)
and
isopropylamine (127 mg, 2.15 mmol)
following General Procedure
1. After concentration in vacuo,
S1b
(
294
mg,
1.43
mmol,
99
%) was
obtained as a
brown solid
.
1
H NMR (500 MHz, CDCl
3
):
δ 9.22 (s, 1H), 8.43 (s, 1H), 8.32 (d,
J
= 8.2 Hz, 1H), 8.08 (d,
J
= 9.7 Hz, 1H), 3.97 (s, 3H), 3.68 (hept,
J
= 6.4 Hz, 1H), 1.30 (d,
J
= 6.4 Hz, 6H).
13
C NMR (126 MHz,
CDCl
3
):
δ 165.8, 158.7, 158.2, 150.8, 137.8, 126.6, 121.1, 61.9, 52.7,
24.1.
FTIR (NaCl, thin film, cm
-
1
):
2968, 2863, 1721, 1596, 1456, 1388, 1360, 1287, 1194, 1112,
1021, 965, 862, 776.
HRMS (FAB, m/z):
calc’d for C
11
H
15
N
2
O
2
[M+H]
+
: 207.1134; found 207.
1131.
(
E
)
-
1
-
(5
-
bromopyridin
-
2
-
yl)
-
N
-
isopropylmethanimine (
S1c
)
N
N
Me
Me
MeO
N
N
Me
Me
MeO
2
C