Stereospecific Suzuki, Sonogashira, and Negishi coupling reactions of N-alkoxyimidoyl iodides and bromides

Article abstract of DOI:10.1021/jo400179u

A high-yielding stereospecific route to the synthesis of single geometric isomers of diaryl oxime ethers through Suzuki coupling of N-alkoxyimidoyl iodides is described. This reaction occurs with complete retention of the imidoyl halide geometry to give single E- or Z-isomers of diaryl oxime ethers. The Sonogashira coupling of N-alkoxyimidoyl iodides and bromides with a wide variety of terminal alkynes to afford single geometric isomers of aryl alkynyl oxime ethers has also been developed. Several of these reactions proceed through copper-free conditions. The Negishi coupling of N-alkoxyimidoyl halides is introduced. The E and Z configurations of nine Suzuki-coupling products and two Sonogashira-coupling products were confirmed by X-ray crystallography.

Full text of DOI:10.1021/jo400179u

Subscriber access provided by UNIVERSITÁ DEGLI STUDI DI TORINO
Article
Stereospecific Suzuki, Sonogashira, and Negishi coupling
reactions of N-alkoxyimidoyl iodides and bromides
Debra Dee Dolliver, Bijay T. Bhattarai, Arjun Pandey, Megan L. Lanier, Amber S. Bordelon, Sarju Adhikari,
Jordan A. Dinser, Patrick F. Flowers, Veronica S. Wills, Caroline L. Schneider, Kevin H. Shaughnessy,
Jane N. Moore, Steven M. Raders, Timothy S. Snowden, Artie Sean McKim, and Frank R Fronczek
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400179u • Publication Date (Web): 27 Mar 2013
Downloaded from http://pubs.acs.org on April 7, 2013
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Stereospecific Suzuki, Sonogashira, and Negishi coupling
reactions of N-alkoxyimidoyl iodides and bromides
9
Debra D. Dolliver,* Bijay T. Bhattarai, Arjun Pandey, Megan L. Lanier, Amber S. Bordelon,
Sarju Adhikari, Jordan A. Dinser, Patrick F. Flowers, Veronica S. Wills, Caroline L.
Schneider
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Department of Chemistry and Physics, Southeastern Louisiana University, SLU 10878
Hammond, LA 70402, USA
ddolliver@selu.edu
Kevin H. Shaughnessy, Jane N. Moore, Steven M. Raders, Timothy S. Snowden
Department of Chemistry, The University of Alabama, Box 870336, Tuscaloosa, AL 35487-
0336
Artie S. McKim
Gaylord Chemical Company, 106 Galaria Blvd., Slidell, LA, 70459-1209
Frank R. Fronczek
Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803
R1
O
R1
c
A
O
.
e u v
i
0 01
q
.
e u v
i
0 0
2
q
Pd
O
(
)2 (
)
N
C
N
C
- u
PH t B 3BF4
(
)
(
)
R2
B
H
O
( )
2
+
e u v
R2
K
2CO3
4
i
q
)
r
r
A
A
I
(
0
.
.
m
m
h
THF 25
H2 0 25
L
(
)
. mmo
4
l
0
.
v
i
e u
1 5
q
(
)
-
81 99
%
L
)
O
7
(
o
e
xam es
11
l
p
(
)
0 C 6
,
.
e u v
i
q
Pd l
C 2
H
N
0 05
C
3C
(
)2 (
)
R1
OR1
O
- .
v
u
e u
. e u v
I
2
i
i
C
PPh3
0 0
(
q
q
)
N
N
+
0
1
(
)
R2
am ne
m
r
r
A
X
A
i
5
L
)
(
,
80 oC 4h
R2
. mmo
0 5
e u v
q
l
2
(
i
)
-
55 95
%
p
exam es
13
(
l
)
Abstract: A high-yielding stereospecific route to the synthesis of single geometric isomers
of diaryl oxime ethers through Suzuki coupling of N-alkoxyimidoyl iodides is described. This
reaction occurs with complete retention of the imidoyl halide geometry to give single E or Z
isomers of diaryl oxime ethers. The Sonogashira coupling of N-alkoxyimidoyl iodides and
bromides with a wide variety of terminal alkynes to afford single geometric isomers of aryl
alkynyl oxime ethers has also been developed. Several of these reactions proceed through
copper-free conditions. The Negishi coupling of N-alkoxyimidoyl halides is introduced. The
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 37
1
2
3
4
5
E and Z configurations of nine Suzuki-coupling products and two Sonogashira-coupling
products were confirmed by X-ray crystallography.
6
7
8
9
Introduction:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Palladium-catalyzed coupling reactions are widely used to make new carbon-carbon
bonds under relatively mild conditions with good functional group tolerance. The vast
majority of these coupling reactions occur at the sp2 hybridized carbon atom of vinyl or aryl
halides. Coupling reactions of sp2 centers where the carbon is π-bonded to a heteroatom,
such as acid chlorides and imidoyl halides, have received less attention, however. Cross-
coupling of acyl halides with alkynes, organoboron, organotin, and other organometallic
reagents to provide ketones are well precedented.1-11 In contrast, there are few examples of
palladium-catalyzed coupling of imidoyl halides [RC(X)=N-Y] to give imines.
There are a few examples of successful palladium-catalyzed coupling reactions
between imidoyl halides/pseudohalides having either an alkyl or aryl group attached to
nitrogen [R′C(X)=NR″ or R′C(X)=NAr] and a nucleophilic coupling partner. Most of these
reactions involve Sonogashira coupling where an imidoyl halide is coupled to a terminal
alkyne.12-22 The rest are divided between Suzuki,23 Hiyama,24 Stille,25,26 and Negishi27
coupling reactions. These reactions have provided routes to pharmacologically important
compounds, including quinolines,14,22 lactams,25 and subunits of peptides.24 There are even
fewer reports in which an imidoyl halide/pseudohalide containing a heteroatom attached to
the nitrogen of the C=N bond is used in palladium-catalyzed coupling schemes. Only two of
these report coupling where the heteroatom attached to the nitrogen of the C=N bond is
sulfur or nitrogen. In 2008, Deng and Qian reported the palladium-catalyzed coupling of an
N-tosyl imidoyl chloride with a boronic acid.28 In 2009, Grimm described the palladium-
catalyzed coupling of cyclic hydrazonyl nonaflates with boronate esters and trifluoroborate
ACS Paragon Plus Environment

Page 3 of 37
The Journal of Organic Chemistry
1
2
salts.29 The reports of coupling reaction where the heteroatom attached to the nitrogen of
the C=N bond is oxygen will be discussed below.
3
4
5
6
7
8
9
The barrier to E/Z isomerization is relatively low (usually <25 kcal/mole) in most
imines that have either an alkyl or aryl group attached to the nitrogen of the C=N bond.30-34
In these cases, the E/Z isomers generally interconvert readily at room temperature. This is
not the case with most oxime ethers [R1C(R2)=N-OR3], however. In these cases, the barrier
to geometric isomerization is high, and they do not readily thermally isomerize.32
The common way to make oxime ethers involves a condensation reaction between a
ketone and an N-alkoxyamine, which generally results in a mixture of E and Z isomers (eq
1).35-42 When R1 and R2 are similarly sized, such as two aryl groups, the product ratio is
typically close to 50:50. These mixtures of geometric isomers, depending on the nature of
R1 and R2, can be very difficult to separate. This paper explores palladium-catalyzed routes
using diastereomerically pure (Z)-N-alkoxybenzimidoyl halides to stereospecifically
synthesize single geometric isomers of diaryl and aryl alkynyl oxime ethers.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R3
R3
O
O
O
H
H
N
N
+
1
( )
+
+
N
R3
2
2
H
2O
2
O
R1
R2
R1
R2 R1
R2
There have been three groups to report instances where N-alkoxyimidoyl halides
[R1C(X)=N-OR2, X = halogen] have been used in palladium-catalyzed coupling reactions
with an organometallic species [Met-R3] to make oxime ethers [R1C(R3)=N-OR2]. The first
reported example involved the Stille-type coupling of an N-alkoxyimidoyl bromide with an
organostannane.43 This reaction gave excellent yields and was thought to proceed with
retained stereochemistry, but no evidence was given to support this conclusion. Our group
provided the first report of Sonogashira and Suzuki coupling reactions of N-
alkoxybenzimidoyl iodides [ArC(I)=N-OR], which demonstrated the ability to target a single
geometric isomer of the oxime ether product.44-48 Subsequently Miyata, et. al., wrote a
communication reporting the Sonogashira and Suzuki coupling of N-alkoxybenzimidoyl
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 37
1
2
bromides.49 Their report indicated that the Sonogashira coupling generally gave good yields
(67-91%) of the coupling product, but the study was somewhat limited in scope. The Suzuki
coupling reaction required high catalyst (10 mol%) and ligand (20 mol%) loadings. It gave
good yields when the substituent on the aromatic ring of the boronic acid was electron
donating, but poor yields were seen with electron-deficient or sterically-demanding aryl
boronic acids. Whereas they reported generation of a single geometric isomer for the
Suzuki reaction, they failed to demonstrate that either the E or Z isomer could be made by
this technique.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
This paper reports high-yielding, stereospecific Suzuki and Sonogashira coupling
reactions of (Z)-N-alkoxybenzimidoyl halides [ArC(X)=N-OR] with a variety of coupling
partners to give diastereomerically pure oxime ether derivatives. The reported methodology
provides high-yielding Sonogashira couplings with a wide range of alkyne coupling partners
and Suzuki coupling of N-alkoxyimidoyl iodides using low catalyst/ligand loads while still
attaining excellent yields when coupled with a wide variety of boronic acids or boronic acid
derivatives. The ability of this Suzuki coupling reaction to stereospecifically produce the E
or Z isomer of the oxime ether as single diastereomers is shown. In addition, the first study
of an alternate pathway to the diaryl oxime ether product through Negishi coupling of an N-
alkoxyimidoyl halide with an organozinc coupling partner is reported.
Results and Discussion:
Our group has previously reported the first synthesis of N-alkoxyimidoyl iodides50 by
the route given in Scheme 1. Although this route is high yielding, it suffers from long
reaction times (up to a week), and it is difficult to remove unreacted N-alkoxyimidoyl bromide
starting material 2 from the product. This reaction was shown to result in only the Z-isomer
of the imidoyl iodide 3. An improved method to synthesize the iodides (Scheme 2), which
proceeds through the N-alkoxyimidoyl tosylates 4a-i, was developed. The tosylates
ACS Paragon Plus Environment

Page 5 of 37
The Journal of Organic Chemistry
1
2
themselves were synthesized by a method similar to that reported in the literature.51-53 This
route requires shorter reaction times and lower temperatures. The reaction mixture is easier
to purify in comparison to the reaction shown in Scheme 1 as the unreacted tosylate (4) is
easier to separate from the iodide product than bromide 2. This reaction also results in only
the Z-isomer of compound 3. It gives good yields in all cases except in the conversion of N-
methoxy-4-nitrobenzimidoyl tosylate 4e to the iodide 3e, where the reaction is very slow.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1: Previously reported route to synthesize N-alkoxybenzimidoyl iodides50
r
B
A
R
O
I
R
O
R
O
O
H
r
r
3
a
N I
B
PB
,
2
N
N
N
enzene
b
su o ane
lf l
r
r
A
r
A
re ux
fl
2
3
~
~
wee
k
100
1
1
oC
Scheme 2: Alternate route to the synthesis of N-alkoxybenzimidoyl iodides
s
I
R
T
R
O
O
O
R
O
O
H
a
a
N I
N H DMA
,
s
l
C
T
N
N
N
r
m n
i
t
,
r
30
t 2 h
,
su o ane
lf l
24 h
80 oC
r
r
A
A
r
A
3
4
1
Table 1: Isolated yields of N-alkoxybenzimidoyl tosylates and iodides from route
shown in Scheme 2
4
yield 4
(%)
88
86
87
72
69
84
76
3
yield 3
(%)
87
97
86
80
<20
62
93
82
entry Ar
R
4a
4b
4c
4d
4e
4f
4g
4h
4i
3a
3b
3c
3d
3e
3f
3g
3h
3i
1
2
3
4
5
6
7
8
9
Ph
4-CH3Ph
4-ClPh
CH3
CH3
CH3
4-CH3OPh CH3
4-NO2Ph
3-NO2Ph
Ph
4-CH3Ph
4-ClPh
CH3
CH3
i-Pr
i-Pr
i-Pr
77
78
93
Suzuki Coupling: Initial studies of the Suzuki coupling utilized N-alkoxyimidoyl iodides 3
with trifluoroborate salts 5′, Pd(OAc)2, and K2CO3 in methanol following a procedure in the
literature (eq 2).54,55 These conditions gave moderate to good isolated yields when using N-
alkoxybenzimidoyl iodides 3 containing electron-withdrawing groups on the aromatic ring
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 37
1
2
3
4
5
6
7
8
9
and/or electron-donating groups on the trifluoroborate salt 5′. However, under these
conditions, yields were poor when there were electron-donating groups on the aromatic ring
of 3 or electron-withdrawing groups on 5′ (Table 2). Of note, reactions run under these
conditions produced a significant amount of the benzonitrile (Y-C6H4C≡N) side product and
were therefore difficult to purify due to coelution of 6 and the benzonitrile side product.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R
O
R
O
c
.
e u v
0 01
i
q
)
Pd
A
O
N
C
BF3K
(
)2 (
N
C
H
H
C
3O
2
( )
+
I
e u v
K
4
i
2CO3
q
(
)
45 °
C
Z
Y
Y
Z
24 h
N2
5'
3
6
e u v
q
1
i
e u v
1
i
q
Table 2: Isolated yields for unoptimized Suzuki coupling of 3
6
6
(% yield)
73
entry
Y
Z
6Ee
6Ef
1
2
3
4
5
6
7
8
9
4-NO2
3-NO2
4-Cl
4-CH3
4-OCH3
H
H
H
H
H
H
57
49
42
25
0
0
35
41
6Eb
6Ed
6Ea
6Ze
6Zf
6Zb
6Zd
6Za
4-NO2
3-NO2
4-Cl
4-CH3
4-OCH3
H
H
H
H
10
64
The effects of added ligand [PPh3, P(t-Bu)3HBF4, dppf, SPhos] and different bases
[Cs2CO3, K2CO3, KOH, KF] were then assessed using the conditions shown in equation 3.
The phosphonium salt of tri-t-butylphosphine with potassium carbonate gave the best yields
(Table 3). Although the reaction using SPhos and potassium carbonate gave a similar yield
of the coupling product 6Ed, P(t-Bu)3HBF4 was thought to be a better choice as it gave less
of the 3-methylbenzonitrile byproduct.
ACS Paragon Plus Environment

Page 7 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
c
.
e u v
0 01
i
q
)
Pd
A
an
O
(
)2 (
(
H
OC
.
e u v
Li
g
d 0 02
i
3
q
OCH3
)
N
BF3K
N
ase e u v
B
4
i
q
H
(
H
)
C
3O
+
3
( )
I
6h 45 oC N
,
,
2
Ed
6
9
a
5 '
3b
q
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
e u v
.
e u v
1 5 i
q
1
i
Table 3: Optimization of Conditions for the Suzuki Coupling of 3b
ligand
PPh3
base
KOH
3b (%)a 6Ed (%)a,b
0
8
29
42
17
18
52
70
1
PPh3
Cs2CO3
K2CO3
KOH
PPh3
73
0
SPhos
SPhos
Cs2CO3
K2CO3
KOH
5
SPhos
3
P(t-Bu)3HBF4
0
P(t-Bu)3HBF4 Cs2CO3
P(t-Bu)3HBF4 K2CO3
65
6
2
73
0
Dppf
Dppf
Dppf
None
None
None
KOH
Cs2CO3
K2CO3
KOH
74
72
79
1
4
2
31
35
32
Cs2CO3
K2CO3
6
6
b
aAverage GC yield of four trials using tridecane as internal standard. Remaining mass
balance composed of benzonitrile and uncharacterized side products.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 37
1
2
3
4
5
6
7
8
9
The reaction was also tried in THF and THF/H2O, and the latter was found to
increase the product yield, while decreasing formation of benzonitrile and other unidentified
byproducts. Further optimization of temperature, concentration and reaction time (using the
4-methyl-substituted imidoyl iodide 3b, and the unsubstituted trifluoroborate salt 5a′) showed
that the reaction conditions given in equation 4 gave a quantitative yield by GC analysis of
the reaction mixture at 6 hours. Of note, this reaction requires low metal (1 mol%) and
ligand (2 mol%) loading. Under the optimized conditions, boronic acid 5 afforded the same
or higher yields as trifluoroborate salt 5′. Therefore, the more widely available boronic acids
can be used in this methodology.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Under the optimized conditions given in equation 4, good to excellent (70-99%)
isolated yields of oxime ether products were obtained (Table 4). Good yields were obtained
with challenging substrates, such as when strong electron-withdrawing groups were
attached to the boron coupling partner (entries 13 and 15), when strong electron-donating
groups were attached to the N-alkoxybenzimidoyl iodide (entry 3), when the more sterically
demanding N-isopropoxyimidoyl iodide substrate was used (entries 18 and 19), or when
there was a single ortho-substituent on the boron coupling partner (entry 7). This reaction
also gave high product yield using the vinylboronic acid trans-β-styrylboronic acid (5h, entry
20), which resulted in no isomerization of the C=C or C=N bond. Coupling with 4-
styrylboronic (5i) acid gave selective Suzuki coupling without competitive Heck reaction
(entry 21). The more sterically hindered mesitylboronic acid (5j, entry 17) led to recovery of
unreacted starting material. The reaction of 4-pyridinylboronic acid 5k (entry 22) also gave
no coupling product and showed only unreacted starting material by GC at the end of 6
hours. Using N-methoxyimidoyl bromide 2a instead of the iodide 3a (entry 9 vs. 8, 43%
yield vs. 99% yield) significantly diminished the yield, suggesting that in these Suzuki
coupling reactions the N-alkoxyimidoyl iodide is a better coupling partner
ACS Paragon Plus Environment

Page 9 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A benefit of this method is its ability to predictably synthesize exclusively the E- or
the Z-oxime ether product (examples include entries 1 and 2 vs. 3, 4 and 5 vs. 6, 8 and 10
vs. 11 and 12, 13 vs. 14, 15 vs. 16, 18 vs. 19). A single diastereomer was obtained in each
case where unsymmetrical oxime ethers were synthesized as determined by GC analysis
and 1H and 13C NMR spectroscopy. In cases where both isomers were synthesized, such
as 6Za and 6Ea (entries 1 and 3), the isolated products could be distinguished by both GC
and 1H and 13C NMR spectroscopy.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R1
P
A
R1
c
.
e u v
0 0
1 i
q
)2 ( )
O
d O
O
(
N
C
N
C
- u
.
e u v
PH t B 3BF4 0 02
i
)
4
( )
q
(
)
(
R2
Y
+
e u v
K
4
.
.
o
i
L
L
R2
2CO3
r
q
m
m
r
A
A
.
X
(
)
THF 0 25
H2 0 25
(
(
)
)
mmo
.
v
i
e u
q
0 4
l
1 5
(
)
O
6
or
or
5
5'
2
3
7
0 C
6 h
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 37
1
2
3
4
5
6
7
8
9
Table 4: Isolated yields for optimized Suzuki coupling reactions of N-
alkoxybenzimidoyl halides
a
a
en r
e
i ld
y
e
i ld
y
t
en r
t
3
6
3
6
5
5
y
y
OCH3
OCH3
N
N
BF3K
a
1
2
12
13
14
15
PhB OH
(
3
88
3b
8
5
%
%
%
%
%
)
2
e
e
OM
M O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
5
a
5d'
5d
6Z
6 d
E
OCH3
N
B OH
(
B OH
(
)
2
)
2
a
3
a
Z
a
3
e
3
a
3
72
6
99
%
%
%
e
M O
O2N
NO2
e
a
e
6
Z
5
OCH3
OCH3
N
N
PhBF3K
7
9
5
7
0
3
4
3d
9
e
M O
O2N
a
5 '
a
6E
e
6E
OCH3
OCH3
N
N
BF3K
O2N
B OH
NO2
(
)
2
a
3
75
7
Cl
Cl
Cl
c
5f
5 '
6Zb
6
Zf
OCH3
N
B OH
(
O2N
)
2
a
3
a
5
5
6
7
Z
6 b
1
1
8
6
3f
96
%
%
%
c
5
6Ef
OCH3
OCH3
N
N
B OH
(
)
2
c
3
a
5 '
a
3
17
18
93
%
0
Cl
6Eb
5
j
6Z
g
- r
Oi P
OCH3
N
N
BF3K
a
3
84
%
3
g
5b'
98
%
c
6Z
5 '
g
6Zh
- r
Oi P
OCH3
N
N
BF3K
a
a
a
5 '
8
9
3
99
43
19
20
3
3
99
89
%
%
g
5b'
5b'
6Zd
6Zd
6Eh
OCH3
N
Ph
B OH
a
(
)
2
2
%
%
Ph
5h
5i
6Ei
OCH3
N
B OH
B OH
( )
2
(
)
2
a
c
a
a
10
11
3
Zd
93
21
22
3
82
0
6
%
%
5b
6Z
j
OCH3
OCH3
N
N
B OH
(
)
2
a
3
5
'
8
5
4
3
%
%
N
N
6Eb
5k
6Zb
a
so a e
l t d i ld
e
carr e ou un er e con ons n ua on
i d
diti
th ti
.
I
t
d
i E
q
y
ACS Paragon Plus Environment

Page 11 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The oxidative addition, transmetalation, and reductive elimination steps of the Suzuki
coupling are known to occur with retention of configuration in most cases.56 Based on this
precedent, the formation of the oxime ethers would be expected to occur with retention of
configuration at the imine. Several of the oxime ether products were crystalline, so X-ray
crystallography was used to confirm the E- or Z-configuration of these compounds. X-ray
crystallography was performed on nine of the compounds synthesized through the Suzuki
coupling reaction (see Supporting Information). The X-ray crystal structures of two of the
coupling reaction products run under the conditions in equation 4 are shown in Figures 1
and 2. As can be seen, the aryl group from the boron coupling partner substitutes the
iodide with retention of the geometry of the C=N bond. All other compounds that were
structurally characterized showed retention independent of the nature or position of the
substituent on the aromatic rings on either the N-alkoxybenzimidoyl iodide or the boron
coupling partner. Additionally, the nature of the R group attached to oxygen (methyl vs.
isopropyl) does not change this trend. Based on these findings, it appears that the reaction
proceeds with retention of geometric configuration, and the oxime ether moiety does not
undergo isomerization under these reaction conditions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Thermal ellipsoid plot (50% level) of the molecular structure of 6Ze formed from
3a and 5e.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 37
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Thermal ellipsoid plot (50% level) of the molecular structure of 6Ee formed from
3e and 5a.
The structure of one of the five Z Suzuki-coupled isomers determined by X-ray
crystallography is illustrated in Fig.1, and one of the four E isomers in Fig. 2. There is little
variation of the oxime ether C=N and N-O distances over all nine compounds studied. C=N
distances fall in the range 1.2857(17) - 1.2949(8) Å, with mean value 1.290 Å. N-O
distances fall in the range 1.4004(6) - 1.411(2) Å, with mean value 1.406 Å.
Sonogashira Coupling:
The study of the Sonogashira coupling of N-alkoxyimidoyl halides began using
conditions similar to those given in the literature for the Sonogashira reaction of N-
arylimidoyl chlorides.12,14 Initially, dichlorobis(chlorodi-tert-butylphosphine)palladium(II)
{PdCl2[(t-Bu)2PCl]2} was used as the precatalyst. This reaction was performed using N-
isopropylbenzimidoyl iodide 3g with phenylacetylene 7a in the presence of catalytic amounts
of PdCl2[(t-Bu)2PCl]2 (5 mol%) and CuI (7 mol%) in triethylamine to produce 8Zf in a 45%
yield as measured by GC using tridecane as an internal standard. The effect of added
ligands on the reaction was then examined by testing the ability of catalysts derived from a
triarylphosphine (PPh3), a sterically-hindered trialkylphosphine in its salt form [P(t-
ACS Paragon Plus Environment

Page 13 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Bu3)HBF4], a ferrocenyl diphosphine (dppf), and a Buchwald-type phosphine (SPhos) using
PdCl2(CH3CN)2 as the metal source for the coupling of 3g and 7a (eq 5). All of these
ligands improved the yield of product over the ligand-free reaction, and triphenylphosphine
gave the best yield of coupling product (Table 5).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
.
e u v
Pd l
C 2
H
N
.
0 05
i
C
3C
q
(
)2 (
e u
v
i
q
)
- r
i P
- r
i P
O
O
a
n
Li
g
d 0 10
(
)
N
N
u
.
e u v
I 0 7 i
q
)
C
5
(
( )
NEt3 70 o 4 h
+
I
C
,
,
Ph
Ph
a
7
3
g
Zf
8
e u v
q
.
e u v
1 1 i
q
1
i
Table 5: Optimization of Conditions for the Sonogashira Coupling of 3g
ligand
PPh3
3g (%)a 8Zf (%)a % othera,b
13
56
61
59
77
80
19
23
35
17
7
25
16
6
SPhos
P(t-Bu)3HBF4
dppf
None
6
aAverage of three GC runs using tridecane as an internal standard. Remaining mass
balance composed of uncharacterized side products.
b
The concentrations of catalyst/reagents and temperature were then adjusted using
bis(acetonitrile)dichloropalladium (II) [PdCl2(CH3CN)2] and triphenylphosphine ligand to give
optimal yields. The optimized conditions are given in equation 6.
R1
Pd l
C 2
H N
C 3C
)2 (
0 05
OR1
.
e u v
i
q
)
O
(
N
N
+
.
e u v
q
PPh3 0 1
i
(
)
6
( )
r
r
A
Ph
A
X
m
L
80 oC 4h
NEt3
5
(
)
or
2
3
a
8
7
Ph
,
e u v
.
mmo
l
)
2
(
i
0 5
q
)
(
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 37
1
2
3
4
5
6
7
8
9
Using these optimized conditions, the effect of the substituent on the aryl ring of the
N-alkoxybenzimidoyl halide was tested in the reaction with phenylacetylene (entries 1-5,
Table 6). While conducting this study, it was discovered that the reaction yield was actually
better in the absence of the copper co-catalyst, so all the reactions with phenylacetylene
were run under copper-free conditions. It was found that the reaction worked well for all
substituents (electron-donating to electron-withdrawing). Additionally, the effect of the
halogen of the N-alkoxyimidoyl halide was tested by comparing the reaction with 4-methyl-
N-methoxybenzimidoyl iodide 3b vs. 4-methyl-N-methoxybenzimidoyl bromide 2b (entry 2
vs. 8, 92% yield vs. 81% yield). For these reactions with phenylacetylene, it appeared that
the halogen did not make a tremendous difference with the imidoyl bromide still giving a
good yield. In addition, the effect of the alkoxy group attached to nitrogen (entries 6 & 7,
Table 6) was examined, and it was found that this too had little effect on the reaction with
the N-isopropoxyimidoyl iodides 3g and 3i also affording high yields. In all cases, products
were formed as a single diastereomer as determined by GC and NMR analysis. As with the
Suzuki coupling reactions, the geometry is retained in the Sonogashira reaction (Figure 3
and Supporting Information).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 15 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
Table 6: Isolated yields for the optimized Sonogashira coupling reactions of N-
alkoxyimidoyl halides (2 or 3) with phenylacetylene (7a).
m
o
l
y
i
id
a
en r
t
a e
h li
d
8
e
i ld
y
y
7
8
9
H
OC
3
N
a
3
1
2
3
92
%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph
a
8Z
H
OC
3
N
3b
92
%
Ph
Ph
8Zb
H
OC
3
N
c
3
89
%
c
8Z
l
C
H
OC
3
N
94
92
%
4
3d
8Zd
Ph
H
3CO
H
OC
3
N
8Z
N
5
6
e
g
2
%
e
Ph
N
O2
- r
i P
O
3
93
%
Ph
Ph
8Zf
- r
i P
O
N
3i
7
8
88
81
%
8Z
g
l
C
H
OC
3
N
2b
%
8Zb
Ph
a
so a e
I
e
carr e ou un er e con ons n ua on
.
i d
th ti
diti
6
l t d i ld
t
d
i
E
y
q
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 37
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Thermal ellipsoid plot (50% level) of the molecular structure of 8Zd formed from
3d and phenylacetylene.
The structure the Sonogashira-coupled 8Zd is illustrated in Fig. 3. The structure of 8Zi was
also determined, containing three independent molecules. Over the two structures, the
oxime ether C=N distances fall in the range 1.293(4) - 1.299(4) Å, with mean value 1.297 Å.
N-O distances fall in the range 1.392(4) - 1.401(3) Å, with mean value 1.396 Å.
The utility of this reaction was expanded using a straight-chain aliphatic alkyne, 1-
hexyne 7b, in the place of phenylacetylene 7a (eq 7). It was found that this reaction did not
work well without the copper co-catalyst (entry 1, Table 7). However, when copper(I) iodide
was included, the reaction provided a good yield of the coupling product 8Zh (entry 2, Table
7). As yields for this reaction were not quite as high as those for the coupling with
phenylacetylene, the reaction was run with a more basic amine solvent (diisopropylamine)
(entry 3, Table 7) to see if this improved the situation, but this did not significantly affect the
yield. Since the Sonogashira reaction of 4-methyl-N-methoxybenzimidoyl bromide 2b with
phenylacetylene looked to give approximately the same yield as that between 4-methyl-N-
methoxybenzimidoyl iodide 3b and phenylacetylene, the effect of the halogen on the imidoyl
halide was also examined when coupling with the more difficult hexyne substrate. In this
more difficult reaction, it can be seen that the N-methoxybenzimidoyl iodide 3a (74% yield)
outperforms the N-methoxybenzimidoyl bromide 2a (45% yield) (entries 3 & 4, Table 7)
ACS Paragon Plus Environment

Page 17 of 37
The Journal of Organic Chemistry
1
2
3
4
under identical conditions. It appears that in this more challenging Sonogashira coupling
5
6
reaction, the N-alkoxyimidoyl iodide 3 would be a better starting material than the bromide 2.
7
8
9
Pd l
C 2
H
e u
v
i
q
)
N
3C
)
2
C
(
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R1
.
O
R1
O
0 05
(
N
N
7
.
e u v
( )
PPh3 0 1
i
q
+
(
)
H
H
3
C
2 3C
r
r
A
X
A
(
)
am ne
m
L
)
i
5
(
80 oC 4h
a
2
a
or
3
CH2 3CH3
)
7
e u v
q
b
i
)
Zh
8
(
,
.
mmo
l
)
2
0 5
(
(
Table 7: Isolated yields of 8Zh from the Sonogashira coupling with 1-hexyne (7b)
8Zh
(% yield)
11
entry imidoyl
halide
amine
CuI
3a
3a
3a
2a
1
2
3
4
NEt3
NEt3
none
0.15 equiv
0.15 equiv
0.15 equiv
81
74
45
NH(i-Pr)2
NH(i-Pr)2
The reaction was subsequently tested with a variety of functional groups on the
alkyne (eq 8), and it was found that the reaction worked well in most cases if copper(I)
iodide was included (Table 8) even when using the N-alkoxyimidoyl bromide 2a. The one
exception was 1-amino-2-propyne 7g, which failed to give any product under these
conditions (entries 3 & 4).
.
e u v
Pd
(
l H N
C 3C
)2(
0 05
i
C
q
)2 (
e u v
)
.
PPh3 0 1
i
R1
q
R1
(
)
O
O
u
. - . e u v
I 0 1 0 2
(
i
C
q
N
N
)
8
( )
+
R2
am ne
m
L
i
5
(
r
A
r
)
A
X
80 oC 4h
,
R2
or
7
2
3
8
e u v
i
q
)
.
mmo
2
0 5
l
(
(
)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 37
1
2
3
4
5
6
Table 8: Conditions and isolated yields of Sonogashira reaction with functionalized
alkynes
m
o
i id l
y
a
en r
t
y
8
7
u
I
C
a e
h lid
e
i ld
a
m ne
i
y
7
8
9
H
OC
3
N
H
O
a
2
1
5
8
%
- r
NH i P
.
e u v
i
q
)
0 1
(
)
2
(
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
d
Ph
8Zi
H
O
H
OC
3
N
a
2
1
2
55
%
%
NEt3
.
e u
v
i
q
)
0 2
(
e
7
Ph
8Z
j
H
OC
3
N
a
2
95
- r
NH i P
(
.
e u v
i
q
)
0 1
)
2
(
Ph
7
f
8Zk
H
OC
3
N
3
a
2
H NH
C
NEt3
2
2
.
e u v
i
q
)
0 1
0
0
(
%
Ph
Ph
7
g
H NH
2
C
8Zl
2
H
OC
3
N
H NH
C
- r
NH i P
(
2
2
.
e u v
i
q
)
0 1
%
)
2
a
(
2
2
4
5
7
g
H NH
C
2
2
8Zl
H
OC
3
N
NEt3
a
.
e u v
0 1
i
q
)
90
%
(
Ph
H
O
H
O
7i
m
8Z
a so a e
l t d i ld
e
carr e ou un er e con ons
i d
th
diti
n
i
ua on
ti
8
q
I
t
d
E
y
ACS Paragon Plus Environment

Page 19 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
Negishi Coupling Screening:
7
8
9
To extend the coupling reaction to other metal species, an investigation of the
coupling of N-alkoxyimidoyl halides with an organozinc reagent was undertaken (eq 9, Table
9). In this initial work, imidoyl iodide 3b and phenylzinc bromide were used as model
substrates. For these reactions, Pd2(dba)3 (5 mol %) was initially used as the palladium
source along with the ligands (5 mol %) indicated in entries 1-5 in Table 9, and the reaction
was run at room temperature for 1 hour. Triphenylphosphine allowed the reaction to go to
completion and provided the best product 6Eb/nitrile 9b ratio (entry 5). On switching to
PdCl2(CH3CN)2 (5 mol%) as the metal source with triphenylphosphine (5 mol %) the 6Eb/9b
ratio further improved (entry 6).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
n r
ca .
Pd
PPh3
.
PhZ B 0 5 M
(
)
H
H
OC
OC
N
C
3
3
t
N
C
N
C
9
( )
+
r
r
A
Ph
A
X
r
A
THF
or
2
3
6
9
a: r =
9
A
Ph
:
r = -
4 H Ph
C
9b A
3
Table 9: Initial screening of palladium source and ligand in the Negishi reactiona
entry imidoyl
halide
palladium
source
Pd2(dba)3
ligand
no ligand
SPhos
dppf
6 / 9 / 3 b
1
2
3
4
5
6
7
3b
3b
3b
3b
3b
3b
2a
6.0% / 94% / 0%
7.0% / 93% / 0%
12% / 88% / 0%
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
P(t-Bu)3HBF4 25% / 75% / 0%
Pd2(dba)3
PPh3
PPh3
PPh3
26% / 74% / 0%
66% / 34% / 0%
68% / 21% / 11%
PdCl2(CH3CN)2
PdCl2(CH3CN)2
aReaction conditions are described in equation 9. bDetermined by FID-GC.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 37
1
2
3
4
5
6
7
8
9
Thinking that the temperature of the reaction might affect the amount of benzonitrile
formation, the reaction was run at 0 oC, but the ratio of coupling product to benzonitrile
remained essentially unchanged. Increasing the catalyst loading to 10 mol% Pd and 20
mol% triphenylphosphine worsened the 6Eb/9b ratio to 52:48. Addition of TMEDA to
Negishi reactions has been shown to affect coupling of alkenyl halides,57 so the effect of this
additive was investigated in this reaction. Addition of TMEDA led to mostly unreacted
starting material and a lower 6Eb/9b ratio (6Eb/9b/3b = 13:10:77).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The effect of the halogen on the N-alkoxybenzimidoyl halide was also examined,
using N-alkoxybenzimidoyl bromide 2a with PdCl2(CH3CN)2 (5 mol %)/PPh3 (5 mol %) at
room temperature for 1 hour. The less reactive bromide 2a gave only 89% conversion after
one hour, but the 6 : 9a ratio improved giving a 6/9a/2a ratio of 68:21:11. This improvement
in selectivity could indicate that the ease of dissociation of the halogen plays a role in the
rate of formation of the benzonitrile. Addition of halide salts [N(Bu)4Br and LiBr] in an
attempt to dampen dissociation of the halide from the N-alkoxyimidoyl halide had no affect
on the product selectivity. Future work with this reaction will focus on optimizing conditions
for the Negishi coupling using the N-alkoxyimidoyl bromide or chloride as the coupling
partner.
Conclusions:
A high yielding, stereospecific Suzuki coupling reaction of N-alkoxyimidoyl iodides with
boronic acids or trifluoroborate salts has been established. This reaction occurs with
complete retention of the imidoyl halide geometry to give single E- or Z-isomers of diaryl
oxime ethers. The N-alkoxyimidoyl iodides and bromides also are successful substrates in
the Sonogashira coupling with terminal alkynes. High yields are achieved under copper-free
conditions in the coupling of phenylacetylene, whereas alkyl-substituted alkynes required
copper to achieve high yields. The first attempts at Negishi coupling of N-alkoxyimidoyl
ACS Paragon Plus Environment

Page 21 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
iodides and bromides have shown good product formation but suffer from a competing
elimination reaction that forms benzonitrile. Work is currently underway to slow the
elimination process responsible for the undesirable formation of benzonitrile.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental:
General Procedures. All reagents were purchased from commercial sources except for
PdCl2(CH3CN)2 which was prepared by a literature procedure.58 Phenylzinc bromide was
purchased as a 1M solution in THF and stored in a glovebox. All reaction vessels were
either loaded in a nitrogen atmosphere or were purged with nitrogen prior to heating. All
solvents were sparged with nitrogen. H and 13C NMR spectra were recorded either on a
1
360 or 500 MHz NMR spectrometer. High resolution mass spectra were acquired in positive
mode using electron impact ionization and a magnetic sector mass analyzer.
Typical procedure for the synthesis of N-alkoxybenzimidoyl tosylates (4). O-
Alkyarylhydroxamate 1 (10 mmol) was placed in an oven-dried 100 mL round-bottomed
flask. Anhydrous DMA (20 mL) was transferred to the flask with a syringe. Sodium hydride
(60% dispersion in mineral oil) (13 mmol) was added, and the solution stirred at room
temperature for approximately 30 minutes. After vigorous gas evolution had ceased, a
septum was placed on the flask. The p-toluenesulfonyl chloride (13 mmol) was added in
one portion, and the resulting solution stirred for 1 hour at room temperature. Water (25 mL)
was added, and the solution was cooled on ice. The resulting precipitate was collected by
suction filtration. This residue was purified by recrystallization in hexane:EtOAc or by flash
chromatography (hexane:EtOAc, gradient elution).
(Z)-N-Methoxybenzimidic 4-methylbenzenesulfonic anhydride (4a). Starting from
hydroxamate 1a (1.51 g, 10 mmol), 4a was obtained as a white crystalline solid (2.69 g,
88%, recrystallized in hexane:EtOAc). m.p 74.5-75.6 oC; IR (Nujol mull ν cm -1) 1606, 1596,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 37
1
2
3
4
1
1463, 1372, 1291, 1179, 1054, 1034, 1014, 934; H NMR (500 MHz, CDCl3) δ 7.85 (d, J =
5
6
7
8
8.3 Hz, 2H), 7.70-7.68 (m, 2H), 7.42-7.32 (m, 5H), 3.85 (s, 3H), 2.46 (s, 3H), 2.36 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 145.3, 144.9, 134.1, 130.7, 129.4, 129.2, 128.4, 128.3,
126.6, 62.8, 21.6; Anal. calcd. for C15H15NO4S: C, 59.00; H, 4.95; N, 4.59; S, 10.50. found:
C, 59.05; H, 4.99; N, 4.67; S, 10.35.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(Z)-N-Methoxy-4-methylbenzimidic 4-methylbenzenesulfonic anhydride (4b).
Starting from hydroxamate 1b (1.65 g, 10 mmol), 4b was obtained as a white crystalline
solid (2.75 g, 86%, recrystallized in hexane:EtOAc). mp 94.8-95.9 oC; IR (Nujol mull ν cm -1)
1596, 1462, 1376, 12919, 1187, 1170, 1054, 1028, 1010, 935; 1H NMR (300 MHz, CDCl3) δ
7.86 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.0
Hz, 2H), 3.83 (s, 3H), 2.47 (s, 3H), 2.36 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 145.2, 145.1,
141.1, 134.3, 129.4, 129.2, 128.3, 126.6, 126.4, 62.7, 21.7, 21.4; Anal. calcd. for
C16H17NO4S: C, 60.17; H, 5.37; N, 4.39; S, 10.04. found: C, 60.47; H, 5.49; N, 4.50; S,
9.92.
(Z)-4-Chloro-N-methoxybenzimidic 4-methylbenzenesulfonic anhydride (4c).
Starting from hydroxamate 1c (1.86 g, 10 mmol), 4c was obtained as a white crystalline
solid (2.96 g, 87%, recrystallized in hexane:EtOAc); mp 94.5-95.3 oC; IR (Nujol mull ν cm -1)
1603, 1594, 1456, 1381, 1306, 1180, 1061, 1036, 1010, 940; 1H NMR (360 MHz , CDCl3) δ
7.85 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 7.36-7.26 (m, 4H), 3.84 (s, 3H), 2.48 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 145.5. 144.1, 136.9, 134.0, 129.5, 128.8, 128.3, 127.9,
127.9, 62.9, 21.7; Anal. calcd for C15H14ClNO4S: C, 53.02; H, 4.15; N, 4.12; S, 9.44; Cl,
10.43. found: C, 52.93; H, 4.21; N, 4.16; S, 9.16; Cl, 10.23.
(Z)-N,4-Dimethoxybenzimidic 4-methylbenzenesulfonic anhydride (4d). Starting
from hydroxamate 1d (1.81 g, 10 mmol), 4d was obtained as a white crystalline solid (2.41
g, 72%, recrystallized in hexane:EtOAc). mp 105.9-107.0 oC; IR (Nujol mull ν cm -1) 1605,
ACS Paragon Plus Environment

Page 23 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1511, 1464, 1369, 1302, 1259, 1189, 1179, 1061, 1034, 931; 1H NMR (360 MHz, CDCl3) δ
7.86 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 9.1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 9.0
Hz, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 2.47 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 161.6, 145.2,
144.8, 134.2, 129.4, 128.3, 128.3, 121.6, 113.9, 62.6, 55.3, 21.6; Anal. calcd for
C16H17NO5S: C, 57.30; H, 5.11; N, 4.18; S, 9.56. found: C, 57.37; H, 5.37; N, 4.19; S,
9.39.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(Z)-N-Methoxy-4-nitrobenzimidic 4-methylbenzenesulfonic anhydride (4e). Starting
from hydroxamate 1e (1.96 g, 10 mmol), 4e was obtained as a yellowish crystalline solid
(2.42 g, 69%, recrystallized in hexane:EtOAc). mp 103.0-104.0 oC; IR (Nujol mull ν cm -1)
1589, 1519, 1454, 1364, 1343, 1297, 1172, 1031, 944; 1H NMR (500 MHz , CDCl3) δ 7.85
(d, J = 8.4 Hz, 2H), 7.63 ( d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.8 Hz,
2H), 3.84 (s, 3H), 2.47 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 145.5, 144.1, 136.9, 134.0,
129.5, 128.8, 128.3, 127.9, 127.9, 62.9, 21.7; Anal. calcd. for C15H14N2O6S: C, 51.42; H,
4.03; N, 8.00; S, 9.15. found: C, 51.23; H, 3.99; N, 7.98; S, 9.08.
(Z)-N-Methoxy-3-nitrobenzimidic 4-methylbenzenesulfonic anhydride (4f). Starting
from hydroxamate 1f (1.96 g, 10 mmol), 4f was obtained as a yellowish crystalline solid
(2.94 g, 84%, recrystallized in hexane:EtOAc). mp 108.2-109.0 oC; IR (Nujol mull ν cm -1)
1526, 1463, 1377, 1351, 1308, 1192, 1180, 1057, 1028, 946; 1H NMR (CDCl3, 500 MHz) δ
8.44 (t, J = 1.0 Hz, 1H), 8.25 (d, J = 4.8 Hz, 1H), 8.07 (d, J = 5.1 Hz, 1H), 7.87 (d, J = 5.1
Hz, 2H), 7.56 (t, J = 4.8 Hz, 1H), 7.38 (d, J = 4.8 Hz, 2 H), 3.92 (s, 3H), 2.49 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 148.3, 146.0, 143.0, 133.7, 132.1, 131.3, 129.7, 129.7, 128.3,
125.0, 121.5, 63.4, 21.7; HRMS m/z calcd for C15H14N2O6S, 350.0573; found 350.0573.
(Z)-N-Isopropoxybenzimidic 4-methylbenzenesulfonic anhydride (4g). Starting from
hydroxamate 1g (1.79 g, 10 mmol), 4g was obtained as a white crystalline solid (2.53 g,
76%, recrystallized in hexane:EtOAc). mp 82.5-82.7 oC; IR (Nujol mull ν cm -1) 1594, 1463,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 37
1
2
3
4
5
6
7
8
9
1366, 1287, 1190, 1014, 991; 1H NMR (CDCl3, 300 MHz) δ 7.89 (d, J = 8.4 Hz, 2H), 7.75-
7.72 (m, 2H), 7.41-7.32 (m, 5 H), 4.33 (m, J = 6.3 Hz, 1H), 2.47 (s, 3H), 1.16 (d, J = 6.3 Hz,
6H); 13C NMR (CDCl3, 125 MHz) δ 145.1, 144.0, 134.6, 130.4, 129.9, 129.4, 128.4, 128.3,
126.6, 77.4, 21.7, 21.1; HRMS m/z calcd for C17H19NO4S, 333.1035; found, 333.1042.
(Z)-N-Isopropoxy-4-methylbenzimidic 4-methylbenzenesulfonic anhydride (4h).
Starting from hydroxamate 1h (1.92 g, 10 mmol), 4h was obtained as a whitish crystalline
solid (2.68 g, 77%, recrystallized in hexane:EtOAc). mp 102.0-103.1 oC; IR (KBr pellet ν cm
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-1) 1612, 1595, 989; 1H NMR (CDCl3, 360 MHz) δ 7.88 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.3
Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 4.31 (m, J = 6.3 Hz, 1H), 2.46 (s,
3H), 2.36 (s, 3H), 1.14 (d, J = 6.3 Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ 145.0, 144.2,
140.7, 134.6, 129.4, 129.2, 128.3, 127.1, 126.5, 21.6, 21.4, 21.2 (OCH peak did not resolve
in CDCl3); 13C NMR (d6-DMSO, 125 MHz) δ 145.6, 143.5, 140.9, 133.4, 129.9, 129.4, 127.9,
126.4, 126.0, 76.8, 21.1, 20.9, 20.8. HRMS m/z calcd for C18H21NO4S, 347.1191; found
347.1198.
(Z)-4-Chloro-N-isopropoxybenzimidic 4-methylbenzenesulfonic anhydride (4i).
Starting from hydroxamate 1i (2.13 g, 10 mmol), 4i was obtained as a yellowish crystalline
solid (2.87 g, 78%, recrystallized in hexane:EtOAc). mp 126.7-127.6 oC; IR (Nujol mull ν cm
-1) 1594, 1461, 1365, 1292, 1191, 1090, 1029, 988; 1H NMR (CDCl3, 3500 MHz) δ 7.88 (d, J
= 8.4 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2 H), 7.34-7.31 (m, 4H), 4.32 (m, J = 6.3 Hz, 1 H), 2.46 (s,
3H), 1.14 (d, J = 6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 145,3, 143.2, 136.5, 134.3,
129.5, 128.7, 128.5, 128.3, 127.8, 77.6, 21.6, 21.1; GC/MS: 305 (4.1), 303 (11.5), 198 (1.6),
196 (4.8), 155 (30.9), 141 (27.6), 139 (100), 113 (3.3), 111 (10.2), 91 (26.4); Anal. calcd. for
C17H18ClNO4S: C, 55.51; H, 4.93; Cl, 9.64, N, 3.81; S, 8.72. found: C, 55.45; H, 4.99; Cl,
9.62; N, 3.82; S, 8.52.
ACS Paragon Plus Environment

Page 25 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Typical procedure for the synthesis of N-alkoxybenzimidoyl iodides (3) from
tosylates (4). N-Alkoxybenzimidoyl tosylate 4 (3.5 mmol ), NaI (35 mmol) and sulfolane (20
mL) were placed in a septum-sealed vial. The mixture was stirred in an 80 °C oil bath for 24
hours. The reaction mixture was poured into 100 mL of distilled water and extracted with
hexanes (3 × 100 mL). The extract was then washed with saturated aqueous NaHCO3
solution (100 mL). The organic layer was dried with MgSO4, and the solvent was removed
under reduced pressure. The product was purified by flash silica gel chromatography using
hexane:EtOA (gradient elution).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(Z)-N-Methoxy-3-nitrobenzimidoyl iodide (3f). Starting from tosylate 4f (1.23 g, 3.5
mmol), compound 3f was isolated as a yellow crystalline solid (664 mg, 62%). mp 67.7-68.7
oC; 1H NMR (CDCl3, 360 MHz) δ 8.64 (t, J = 1.9 Hz, 1H), 8.27-8.24 (m, 1H), 8.13-8.10 (m,
1H), 7.57 (t, J = 7.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 148.0, 137.7, 134.9, 129.3,
124.6, 124.1, 113.4, 63.0; HRMS m/z calcd for C8H7IN2O3, 305.9501; found 305.9502.
(Z)-N-Isopropoxy-4-methylbenzimidoyl iodide (3h). Starting from tosylate 4h (1.22 g,
3.5 mmol), compound 3h was isolated as a low-melting yellow crystalline solid (870 mg,
82%). mp 30.9-32.1 oC; 1H NMR (CDCl3, 360 MHz) δ 7.65 (d, J = 8.2 Hz, 2H), 7.13 (d, J =
8.0 Hz, 2 H), 4.66 (m, J = 6.3 Hz, 1H), 2.35 (s, 3H), 1.39 (d, J = 6.3 Hz, 6H); 13C NMR
(CDCl3, 125 MHz) δ 140.4, 134.1, 129.4, 129.0, 116.2, 77.3, 21.8, 21.2; HRMS m/z calcd
for C11H14INO, 303.0120; found 303.0123.
General Procedure for Suzuki Coupling Reactions. Tri-t-butylphosphonium
tetrafluoroborate (2.3 mg, 0.008 mmol), anhydrous potassium carbonate (221 mg, 1.6
mmol), and either trifluoroborate salt 5′ (0.6 mmol) or boronic acid 5 (0.6 mmol) were
weighed into a 3 mL vial in a glovebox and sealed with a septum. N-alkoxyimidoyl iodide 3
(0.4 mmol) and a solution of palladium acetate in anhydrous THF (0.016 M, 0.25 mL) were
added sequentially by syringe. Nitrogen-sparged deionized water (0.25 mL) was added with
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 37
1
2
a syringe. The mixture was stirred in a 70 oC oil bath for 6 hours. The reaction mixture was
poured into 50 mL of ethyl acetate, dried with MgSO4, and the solvent was removed under
reduced pressure. The product was purified by flash silica gel chromatography using
hexane:EtOAc (gradient elution).
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(Z)-4-Methoxybenzophenone O-methyl oxime (6Za). Starting with compound 3a (107
mg, 0.410 mmol) and compound 5d' (128 mg, 0.598 mmol), compound 6Za was obtained as
a colorless oil (87 mg, 88%). 1H NMR (CDCl3, 360 MHz) δ 7.49-7.46 (m, 2H), 7.35-7.31 (m,
5H), 6.93 (d, J = 8.9, 2H), 3.98 (s, 3H), 3.82 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 159.9,
156.4, 136.9, 131.1, 129.2, 128.2, 128.1, 125.4, 113.4, 62.3, 55.2; GC/MS: 241 (M,
100.0%), 210 (77.1), 167 (9.7), 77 (36.5); HRMS m/z calcd for C15H15NO2, 241.1103; found
241.1094.
Alternatively, compound 3a (116 mg, 0.445 mmol) and 5d (94.3 mg, 0.621 mmol) were
coupled to provide compound 6Za as a colorless oil (106 mg, 99 %).
(E)-4-Methoxybenzophenone O-methyl oxime (6Ea). Starting with compound 3d (119
mg, 0.409 mmol) and compound 5a' (115 mg, 0.625 mmol), compound 6Ea was obtained as
a reddish oil that slowly crystallized (78 mg, 79%). mp 75.8-76.6 oC; 1H NMR (CDCl3, 360
MHz) δ 7.45-7.31 (m, 7H), 6.84 (d, J = 9.0, 2H), 3.94 (s, 3H), 3.79 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 160.6, 156.4, 133.6, 129.1, 129.1, 129.0, 128.6, 128.0, 113.6, 62.2, 55.2;
GC/MS: 241 (M, 100.0%), 210 (74.5), 167 (10.1), 77 (34.4); HRMS m/z calcd for
C15H15NO2, 241.1103; found 241.1102.
(Z)-4-Chlorobenzophenone O-methyl oxime (6Zb). Starting with compound 3a (111
mg, 0.425 mmol) and compound 5c' (133 mg, 0.607 mmol), compound 6Zb was obtained as
a white crystal solid (78 mg, 75%). m.p 62.8-63.8 oC; 1H NMR (CDCl3, 360 MHz) δ 7.47-
7.28 (m, 9H), 3.98 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 155.6, 136.0, 134.8, 131.6, 130.7,
ACS Paragon Plus Environment

Page 27 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
129.4, 128.4, 128.3, 127.8, 62.4; GC/MS: 245 (M, 100.0%), 214 (67.3), 111 (14.4), 77
(55.7); HRMS m/z calcd for C14H12ClNO, 245.0607; found 245.0615.
7
8
9
Alternatively, compound 3a (107 mg, 0.410 mmol) and 5c (94.2 mg, 0.602 mmol) were
coupled to provide compound 6Zb as a white crystalline solid (82 mg, 81%).
(E)-4-Chlorobenzophenone O-methyl oxime (6Eb). Starting with compound 3c (123
mg, 0.417 mmol) and compound 5a′ (112 mg, 0.609 mmol), compound 6Eb was obtained
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
as a light yellow oil (95 mg, 93%). H NMR (CDCl3, 360 MHz) δ 7.46-7.40 (m, 5H), 7.33-
7.27 (m, 4H), 3.97 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 155.6, 135.3, 134.9, 132.8, 129.1,
129.0, 129.0, 128.4, 128.2, 62.5; GC/MS: 245 (M, 100.0%), 214 (52.5), 111 (7.2), 77 (22.1);
HRMS m/z calcd for C14H12ClNO, 245.0607; found 245.0610.
(Z)-2-Methylbenzophenone O-methyl oxime (6Zc). Starting with compound 3a (106
mg, 0.406 mmol) and compound 5g′ (119 mg, 0.601 mmol) compound 6Zc was obtained as
white crystals (76 mg, 84%). mp 111.5-112.6 oC; 1H NMR (CDCl3, 360 MHz) δ 7.48-7.45 (m,
2H), 7.35-7.22 (m, 6H), 7.07 (bd, J = 7.4 Hz, 1H), 3.96 (s, 3H), 2.16 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 156.6, 135.9, 135.6, 133.9, 129.9, 129.3, 128.5, 128.3, 127.9, 126.9,
125.6, 62.4, 19.6; GC/MS: 225 (M, 41.5%), 194 (100.0), 116 (16.0); HRMS m/z calcd for
C15H15NO, 225.1154; found 225.1154.
(Z)-4-Methylbenzophenone O-methyl oxime (6Zd). Starting with compound 3a (108
mg, 0.414 mmol) and compound 5b′ (120 mg, 0.606 mmol), compound 6Zd was obtained as
white crystals (92 mg, 99%). mp 69.9-70.8 oC; 1H NMR (CDCl3, 360 MHz) δ 7.49-7.47 (m,
2H), 7.33-7.21 (m, 7H), 3.97 (s, 3H), 2.39 (s, 3H); 13 C NMR (CDCl3, 125 MHz) δ 156.7,
138.8, 136.6, 130.3, 129.2, 129.1, 128.8, 128.1, 127.9, 62.3, 21.4; GC/MS: 225 (M,
100.0%), 194 (69.2), 91 (24.6), 77 (23.2); HRMS m/z calcd for C15H15NO, 225.1154; found
225.1161.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 37
1
2
3
4
5
6
Alternatively, compound 3a (109 mg, 0.418 mmol) and 5b (81.6 mg, 0.600 mmol) were
coupled to provide compound 6Zd as a white crystals (88 mg, 93 %).
7
8
9
(E)-4-Methylbenzophenone O-methyl oxime (6Ed). Starting with compound 3b (119
mg, 0.433 mmol) and compound 5a′ (112 mg, 0.609 mmol), compound 6Ed was obtained
as a colorless oil (83 mg, 85%). 1H NMR (CDCl3, 360 MHz) δ 7.42-7.32 (m, 7H), 7.12 (d, J
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
= 8.0 Hz, 2H), 3.96 (s, 3H), 2.34 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 156.7, 139.3, 133.6,
133.5, 129.2, 128.9, 128.7, 128.0, 127.7, 62.3, 21.3; GC/MS: 225 (M, 100.0%), 194 (67.4),
91 (30.0), 77 (25.1); HRMS m/z calcd for C15H15NO, 225.1154; found 225.1151.
Alternatively, compound 3b (103 mg, 0.420 mmol) and 5a (7302 mg, 0.600 mmol) were
coupled to provide compound 6Ed as a colorless oil (80 mg, 85 %).
(Z)-4-Nitrobenzophenone O-methyl oxime (6Ze). Starting with compound 3a (116 mg,
0.444 mmol) and compound 5e (73.2 mg, 0.600 mmol), compound 6Ze was obtained as
reddish crystals (82 mg, 72%). mp 92.2-93.0 oC; 1H NMR (CDCl3, 500 MHz) δ 8.29 (d, J =
8.9 Hz, 2H), 7.52 (d, J = 8.9 Hz, 2H), 7.45-7.33 (m, 5H), 3.99 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 154.7, 147.8, 139.9, 135.1, 130.3, 129.8, 128.5, 127.5, 123.4, 62.7; GC/MS: 256
(M, 100.0%), 225 (37.7), 179 (59.0), 77 (32.8); HRMS m/z calcd for C14H12N2O3, 256.0848;
found 256.0840.
(E)-4-Nitrobenzophenone O-methyl oxime (6Ee). Starting with compound 3e (127
mg, 0.415 mmol) and compound 5a (75 mg, 0.615 mmol), compound 6Ee was obtained as
a tan solid (102 mg, 97%). mp 96.6-97.6 oC; 1H NMR (CDCl3, 360 MHz) δ 8.16 (d, J = 9.0
Hz, 2H), 7.66 (d, J = 9.0 Hz, 2H), 7.47-7.44 (m, 3H), 7.33-7.30 (m, 2H), 4.02 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 154.7, 148.1, 142.4, 132.0, 129.3, 128.9, 128.4, 128.4, 123.4,
62.9; GC/MS: 256 (M, 100.0%), 225 (45.8), 179 (66.0), 77 (36.8); HRMS m/z calcd for
C14H12N2O3, 256.0848; found 256.0848.
ACS Paragon Plus Environment

Page 29 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
(Z)-3-Nitrobenzophenone O-methyl oxime (6Zf). Starting with compound 3a (117 mg,
0.448 mmol) and compound 5f (137 mg, 0.598 mmol), compound 6Zf was obtained as a tan
solid (80 mg, 70%). mp 78.7-79.8 oC; 1H NMR (CDCl3, 360 MHz) δ 8.29-8.24 (m, 2H), 7.69-
9
7.59 (m, 2H), 7.46-7.32 (m, 5H), 3.99 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 154.3, 148.1,
135.3, 135.2, 134.8, 129.8, 129.1, 128.5, 127.6, 124.4, 123.6, 62.6; GC/MS: 256 (M,
100.0%), 225 (51.4), 179 (71.0), 77 (39.2); HRMS m/z calcd for C14H12N2O3, 256.0848;
found 256.0844.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-3-Nitrobenzophenone O-methyl oxime (6Ef). Starting with compound 3f (133 mg,
0.435 mmol) and compound 5a (78 mg, 0.640 mmol), compound 6Ef was obtained as a tan
solid (107 mg, 96%). mp 71.5-72.3 oC; 1H NMR (CDCl3, 500 MHz) δ 8.38 (t, J = 1.9 Hz, 1H),
8.20-8.17 (m, 1H), 7.78 (dt, J = 7.8, J = 1.1 Hz, 1H), 7.49-7.43 (m, 4H), 7.34-7.32 (m, 2H),
4.01 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 154.4, 148.3, 138.2, 133.4, 131.9, 129.4, 129.1,
128.9, 128.4, 123.7, 122.4, 62.7; GC/MS: 256 (M, 100.0%), 225 (45.2), 179 (55.5), 77
(27.6); HRMS m/z calcd for C14H12N2O3, 256.0848; found 256.0846.
(Z)-4-Methylbenzophenone O-isopropyl oxime (6Zh). Starting with compound 3g
(129 mg, 0.426 mmol) and compound 5b′ (119 mg, 0.601 mmol), compound 6Zh was
obtained as white crystals (106 mg, 98%). mp 50.8-51.4 oC; 1H NMR (CDCl3, 360 MHz) δ
7.49-7.46 (m, 2H), 7.36-7.28 (m, 5H), 7.21 (d, J = 7.9 Hz, 2H), 4.49 (m, J = 6.2 Hz, 1H), 2.39
(s, 3H), 1.28 (d, J = 6.3 Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ 155.6, 138.5, 137.5, 130.6,
129.7, 128.8, 128.5, 128.1, 128.1, 76.1, 21.6, 21.4; GC/MS: 253 (M, 100.0%), 211 (51.9),
194 (81.6), 165 (16.6), 91 (20.0), 77 (21.7); HRMS m/z calcd for C17H19NO, 253.1467; found
253.1465.
(E)-4-Methylbenzophenone O-isopropyl oxime (6Eh). Starting with compound 3h
(129 mg, 0.426 mmol) and compound 5a′ (110 mg, 0.598 mmol), compound 6Eh was
obtained as tan crystals (107 mg, 99%). mp 55.0-55.9 oC; 1H NMR (CDCl3, 360 MHz) δ
ACS Paragon Plus Environment