Dichloroimidazolidinedione-Activated Beckmann Rearrangement of Ketoximes for Accessing Amides and Lactams

Article abstract of DOI:10.1021/acs.joc.7b02983

A novel protocol for the activation of the Beckmann rearrangement utilizing the readily available and economical geminal dichloroimidazolidinediones (DCIDs) on a substoichiometric scale (10 mol %) has been developed. A unique self-propagating mechanism for the substoichiometric dichloroimidazolidinedione-activated transformation was proposed and validated. The substrate scope of the developed protocol has been demonstrated by 23 examples with good to excellent yields (mostly 90-98%) in a short time (mostly 10-30 min), including a substrate for synthesizing the monomer of nylon-12 and a complicated steroidal substrate on a preparative scale. This research not only unveils for the first time the synthetic potential of substoichiometric amounts of dichloroimidazolidinediones in promoting chemical transformation but also offers yet another important illustration of the self-propagating cycle in the context of the Beckmann rearrangement activated by a structurally novel organic promoter.

Full text of DOI:10.1021/acs.joc.7b02983

Subscriber access provided by READING UNIV
Article
Dichloroimidazolidinedione-Activated Beckmann Rearrangement
of Ketoximes for Accessing Amides and Lactams
Yu Gao, Jingjing Liu, Zhenjiang Li, Tianfo Guo, Songquan Xu, Hui
Zhu, Fulan Wei, Siming Chen, Hailemariam Gebru, and Kai Guo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02983 • Publication Date (Web): 19 Jan 2018
Downloaded from http://pubs.acs.org on January 19, 2018
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 25
The Journal of Organic Chemistry
1
2
3
4
5
6
Dichloroimidazolidinedione-Activated Beckmann Rearrangement of
Ketoximes for Accessing Amides and Lactams
7
8
9
Yu Gao, Jingjing Liu, Zhenjiang Li, Tianfo Guo, Songquan Xu, Hui Zhu, Fulan Wei, Siming Chen,
Hailemariam Gebru, and Kai Guo*
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
State Key Laboratory of Materials-Oriented Chemical Engineering, College of Biotechnology and
Pharmaceutical Engineering, Nanjing Tech University, 30 Puzhu Road South, Nanjing 211816, China.
ABSTRACT
A novel protocol for the activation of Beckmann rearrangement utilizing the readily available
and economical geminal dichloroimidazolidinediones (DCIDs) on a substoichiometric scale (10 mol%)
has been developed.
A
unique self-propagating mechanism for substoichiometric
dichloroimidazolidinedione-activated transformation was proposed and validated. The substrate
scope of the developed protocol has been demonstrated by 23 examples with good to excellent
yields (mostly 90–98%) in a short time (mostly 10–30 min), including a substrate for synthesizing
monomer of nylon-12 and a complicated steroidal substrate on a preparative scale. This research
not only unveils for the first time the synthetic potential of substoichiometric amounts of
dichloroimidazolidinediones in promoting chemical transformation, but also offers yet another
important illustration of the self-propagating cycle in the context of the Beckmann rearrangement
activated by a structurally novel organic promoter.
INTRODUCTION
Geminal dihalides are privileged building blocks in modern synthetic organic chemistry in that
the two halogens on the same carbon nucleus could function as good leaving groups.1-3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 25
1
2
3
4
5
6
7
8
9
2,2-Dichloroimidazolidine-4,5-diones (DCIDs) (1), as a category of cyclic geminal dihalides, were
initially prepared by Stachel4 in 1959 through the condensation of carbodiimides with oxalyl chloride
and subsequently investigated by others5-10 (Figure 1). The connection of four electron-withdrawing
groups on DCIDs (1) makes the quaternary carbon nucleus at 2-position electron-deficient and thus
highly electrophilic (Figure 1). Moreover, the two chlorines on the 2-position quaternary carbon
nucleus could serve as good leaving groups (Figure 1). Besides, the N-substituents on DCIDs (1) can
be easily modified, offering opportunities to tune their electronic and physical properties (Figure 1).
However, despite possessing these intriguing and valuable characteristics, DCIDs have rarely been
applied in practical synthetic chemistry.11-13 Bielawski and co-workers leveraged
dihaloimidazolidinediones as halodehydrating agents to generate alkyl halides from their
corresponding alcohols in the stoichiometric version recently.13 To the best of our knowledge, DCIDs
have never been employed in substoichiometric amounts for promoting chemical transformations.
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. Dichloroimidazolidinediones (DCIDs).
The Beckmann rearrangement,14-20 discovered in 1886, is undoubtedly a powerful and atom
economic tool to construct amides and lactams from their corresponding oximes. A very important
application of this reaction lies in manufacturing monomers for polymerization of polyamides
nylon-6 and nylon-12 on a large scale in industrial chemistry.21,22 Traditionally, this reaction involves
harsh conditions such as strongly acidic media and high reaction temperature, which generates
considerable amounts of byproducts and precludes its compatibility with acid sensitive substrates.
Accordingly, to overcome these deficiencies, several organocatalytic methods via the activation of
the oxime hydroxyl group have been developed in recent years.23-30 Yamamoto and Ishihara
reported cyanuric chloride as the first highly efficient organocatalyst for Beckmann rearrangement
in 2005 (Scheme 1A).23 Most notably, Lambert and co-workers reported elegant studies in which
they used chlorocyclopropenium to activate Beckmann rearrangement with satisfying outcomes
(Scheme 1B).28 What’s more, they made a mechanistic distinction between authentic catalysis and
self-propagation. Their experimental results gave evidence to support the latter self-propagation
ACS Paragon Plus Environment

Page 3 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
mode, casting doubt on the mechanisms of other reported “organocatalytic” Beckmann
rearrangements.28
7
Scheme 1. Organic Promoters for Beckmann Rearrangement
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
In this context, we have become interested in developing a novel activation method for
Beckmann rearrangement by employing geminal dichloroimidazolidinediones and revisiting this
intriguing mechanistic controversy. On the basis of the intrinsic characteristic of DCIDs, we
envisioned that under the suitable conditions, DCIDs might serve as a well suited electrophilic
activator of the oxime hydroxyl group for the efficient transformation of ketoximes to amides and
lactams. In fact, we have successfully demonstrated for the first time that DCIDs can be utilized in
substoichiometric amounts for promoting the Beckmann rearrangement with extremely high
reactivity in a unique self-propagating mode. Herein, we would like to elaborate the development of
such a new DCID-activated Beckmann rearrangement method (Scheme 1C).
RESUITS AND DISCUSSION
At the onset, we chose cyclododecanone oxime as an oxime substrate to investigate the
feasibility of DCID-activated Beckmannn rearrangement. To our amazement, treatment of the oxime
with 10 mol% of 2,2-dichloro-1,3-bis(2,6-diisopropylphenyl)imidazolidine-4,5-dione (1a) in
acetonitrile (MeCN) at 80 oC for 20 min led to the corresponding ω-laurolactam, a monomer for the
manufacture of nylon-12 polymer, in 96% isolated yield (Scheme 2). Noticeably, this favorable
preliminary result demonstrates DCIDs can actually serve as a potent reagent to activate the
Beckmannn rearrangement.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 25
1
2
3
4
Scheme 2. Demonstration of DCID-Activated Beckmannn Rearrangement
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
To screen for the optimal conditions, acetophenone oxime (2a) was selected as a model
substrate to run a series of trial reactions under various conditions as compiled in Table 1. Given
that a potential equivalent of acid HCl was produced in situ by reaction of ketoxime (2a) with DCIDs
(1) at room temperature, our initial trial commenced with the addition of an equivalent of HCl at
room temperature. The result ruled out the possibility that the rearrangement was due to a
background reaction (Table 1, entry 1). When the reaction was conducted in MeCN at room
temperature, among the four different N-substituted DCIDs tested, which were readily prepared
through the condensation of commercially available carbodiimides (RN=C=NR, R = Dipp, iPr, tBu, Cy)
with oxalyl chloride, DCID 1a was found to give the rearranged product N-phenylacetamide 3a in 91%
yield (via GC analysis) after 3 h (Table 1, entry 2). DCIDs 1b and 1d gave similar results with shorter
times and comparatively higher yields than DCID 1a. Compared with the other three DCIDs, DCID 1c
showed slightly poor reactivity presumably due to the steric hindrance of the tert-butyl group (Table
1, entries 2–5). In terms of the lower cost of N,N’-dicyclohexylcarbodiimide (DCC) than
N,N’-diisopropylcarbodiimide (DIC), which are the raw materials of synthesizing the DCIDs,
2,2-dichloro-1,3-dicyclohexylimidazolidine-4,5-dione (1d) was chosen as the optimal reagent.
Satisfied with the superior reactivity of stoichiometric DCIDs at room temperature, we next
examined the performance of a substoichiometric amount of DCID at slightly elevated temperatures.
o
It was found that raising the reaction temperature from 25 to 50 C could induce rearrangement in
98% yield within 40 min by using 10 mol% of DCID 1d (Table 1, entry 7), whereas at room
temperature only 31% of the title compound 3a in 3 h was observed in the presence of 10 mol% of
o
DCID 1d (Table 1, entry 6). Moreover, further heating the reaction to 80 C gave rise to
rearrangement in quantitative yield within shorter time (20 min, entry 10). Once again, to exclude
the possibility that a potential acid HCl catalyzed rearrangement under heating conditions, we
performed control experiments as shown in Table 1, entries 8–9. As expected, neither heat nor HCl
ACS Paragon Plus Environment

Page 5 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
promoted the reaction. Afterward, lowering the amount of DCID 1d to 5 mol% resulted in a similar
yield of 3a, yet three times of the duration of reaction was needed (Table 1, entry 11). In continuing
to decrease the loading to 3 mol%, it was observed that the yield of amide 3a was lowered to 77%
as well as the reaction time was prolonged to 2 h (Table 1, entry 12).
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
To investigate the solvent effect on this transformation, several aprotic solvents including
1,4-dioxane, N,N-dimethylformamide (DMF), 1,2-dichloroethane (DCE), toluene, nitromethane
(MeNO2) and tetrahydrofuran (THF) were utilized (Table 1, entry 10 vs. entries 13–18). It turned out
that the reaction efficiency was strongly dependent on the solvent. For example, the reaction in DCE
o
was nearly as efficient as in MeCN and delivered 3a in 95% yield within 20 min at 80 C, whereas in
o
other solvents it proved to be far less effective than in MeCN and DCE at 80 C, especially in
1,4-dioxane and THF, where the reaction process was almost entirely suppressed (Table 1, entries 13
and 18). In terms of safety, among MeCN and DCE, we preferred to select MeCN rather than DCE as
the optimal reaction solvent.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 25
1
2
3
4
Table 1. Optimization of the Reaction Conditionsa
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
Entry Reagent (mol %)
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
1,4-dioxane
DMF
T (°C)
25
25
25
25
25
25
50
80
80
80
80
80
80
80
80
80
80
68
time (min)
10 h
3 h
60
yield (%)b
1c
-
7
2
1a (100)
1b (100)
1c (100)
1d (100)
1d (10)
1d (10)
-
91
94
87
98
31
98
0
3
4
2 h
60
5
6
3 h
40
7
8
12 h
2 h
20
9d
10
11
12
13
14
15
16
17
18
-
5
1d (10)
1d (5)
1d (3)
1d (10)
1d (10)
1d (10)
1d (10)
1d (10)
1d (10)
99
96
77
2
60
2 h
60
20
36
95
24
23
3
DCE
20
toluene
MeNO2
THF
60
2 h
60
a The rearrangement of acetophenone oxime (0.5 mmol) was carried out in
MeCN (2 mL). b Yield (%) of N-phenylacetamide determined by GC analysis
using standard working curve method. c HCl (36–38 wt%, 1.0 equiv., 0.5 mmol)
was added. d HCl (36–38 wt%, 10 mol%) was added.
The striking high reactivity of substoichiometric DCIDs intrigued us to contemplate the
mechanism in this protocol setting. On the basis of the above experimental facts and literature
reports,28,31-33
a
putative mechanism for substoichiometric DCID-mediated Beckmann
rearrangement is proposed in Scheme 3. Initially, the heterolysis of the C–Cl bond in DCID 1 occurs
with the aid of the election donating of two amide nitrogen atoms adjacent to the quaternary
carbon nucleus, affording 2-chloro-4,5-dioxo-imidazolinium chloride salt A. Subsequently, attack of
the oxime substrate 2 by the electrophile A forms the activated protonated species B. Then, the
ACS Paragon Plus Environment

Page 7 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
corresponding intermediate C is formed after deprotonation of B. Next, the arrangement of the
oxime moiety in the intermediate C happens along with the loss of the second chlorine atom,
producing the urea D as well as nitrilium ion E (or the imidoyl chloride F). The reaction then
proceeds through a self-propagating pathway. Another molecule of the oxime substrate 2 might be
directly alkylated by the imidoyl chloride F/nitrilium ion E, affording a dimer-like cation intermediate
G, which then yields the amide product 3 via Beckmann rearrangement and retrieves F/E so that
this self-propagating pathway could continue. It is worth mentioning that this mode would
represent a special case of autocatalytic reaction, which requires the intermediate formed rather
than the final product in the rate-limiting step to accelerate the reaction rate.
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 3. Putative Mechanism for Substoichiometric DCID-Activated Beckmann Rearrangement
To confirm the catalytic role of E/F in our protocol, the N-phenylbenzimidoyl chloride 4 was
synthesized and 10 mol% loading of 4 in the presence of HCl was utilized to mimic F to promote the
rearrangement of benzophenone oxime 2m at 80 oC in MeCN. It turned out that this reagent (4+HCl;
10 mol %:10 mol %) promoted the Beckmann rearrangement of 2m at 80 °C with excellent yields
(via GC analysis) in only 30 min (Scheme 4a). Furthermore, we ran a rate comparison experiment
between DCID 1d and N-phenylbenzimidoyl chloride 4 by comparing the rate of conversion of the
oxime 2m to the amide product 3m and found that imidoyl chloride activated Beckmann
rearrangement at almost the same rate as did DCID 1d (Scheme 4b). 34 Additionally, it is noteworthy
that species D was detected via HRMS analysis in the course of rate comparison experiment (see
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 25
1
2
3
4
5
6
7
8
9
page S2 in the Supporting Information) and the presence of imidoyl chloride intermediate 4 was
detected by 1H NMR in the duration of the reaction promoted by DCID 1d in deuterated acetonitrile
at 80 °C (Scheme 5, see page S3 in the Supporting Information for full extended version).35 These
experimental results certainly suggest that under our protocol conditions DCID 1d may merely serve
as an initiator and imidoyl chloride may in fact be responsible for catalysis.
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 4. (a) Rate comparison of imidoyl chloride 4 versus DCID 1d. (b) Percent conversions of
benzophenone oxime in MeCN at 80 °C, with 10 mol% activator loading, were determined by GC
analysis, comparing DCID 1d (black squares) versus N-phenylbenimidoyl chloride and HCl (red
circles).
Scheme 5. Demonstration of the Presence of Imidoyl Chloride Intermediate by 1H NMR via
Monitoring the Reaction Promoted by DCID 1d
ACS Paragon Plus Environment

Page 9 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
With the optimized conditions being established and the tentative mechanism being proposed
and investigated, the scope and generality of this DCID-activation protocol was then probed (Table
2). Pleasantly, a broad range of aromatic and aliphatic oximes were found to be rearranged
smoothly under this protocol to afford the corresponding amides/lactams in good to excellent yields
and a functional group-tolerant fashion. The acetophenone oximes with electron-donating or
-withdrawing groups on the phenyl ring, such as methyl (2b), methoxy (2c−2e), hydroxyl (2f) or
halides (2g−2i), all delivered the corresponding acetanilides in high yields within very short time
(10–20 min). It is noteworthy that product 3f, namely Paracetamol, possesses antipyretic-analgesic
effect. Moreover, 2-acetonaphthone oxime 2j and the ketoxime with N-Boc indole ring 2k featuring
an aromatic fused ring and a heterocyclic aromatic ring respectively were amenable to the protocol
condition, which furnished their rearranged products 3j and 3k in 91% and 72% yields, respectively.
In addition to methyl, other variations in the R2 moiety of the ketoxime 2, such as phenyl (2m), ethyl
(2p), cyclopropyl (2o) and an extended aliphatic chain (R2 = MeO2C(CH2)2−, 2r) were studied and also
found to be successfully and efficiently engaged in the Beckmann rearrangement. Besides, the
symmetrical ketoxime 2n and 2q can be rapidly converted into the corresponding amides 3n and 3q
with high yields as well. When alkyl oximes including cyclohexyl, cyclododecyl and nonanone oximes
were subjected to this reaction, the results turned out to be different from each other to a great
extent. N-heptylacetamide 3t could be obtained in 87% yield, albeit with extended reaction time.
However, cyclohexyl oxime 2s was failed to give the desired ε-caprolactam 3s in acceptable yield at
80 oC using 10 mol% 1d. Gratifyingly, yield improvement was reached by switching to employing one
equivalent of 1d at room temperature. Remarkably, cyclododecyl oxime 2u was one exception.
ω-Laurolactam 3u, a monomer of nylon-12 polymer, was obtained with near quantitative yield in 10
min, with 6-fold decrease in reaction time compared to the reported23 organocatalytic method.
Furthermore, a 1.5 : 1 (E : Z) isomeric mixture of the unsymmetrical oxime
(4-hydroxyphenyl)(phenyl)methanone oxime was selected to examine the selectivity of the
migrating group. As speculated, the rearrangement of this oxime proceeded with exclusive trans
migration, giving access to an isomeric mixture of the amide products 3v and 3w in the ratio of 1.5 :
1 in an overall yield of 91%, which suggests that no oxime isomerization happens under this
protocol. Additionally, it is worth mentioning that this protocol also exhibited compatibility with
acid labile functional groups such as a Boc group and a sily ether to furnish the desired amides in
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

The Journal of Organic Chemistry
Page 10 of 25
1
2
3
4
5
6
7
8
9
satisfactory yields (3k and 3l). Finally, we leveraged our DCID activation strategy to examine its
validity in the context of a complex molecule. The oxime of pregnenolone acetate 2x was prepared
and subjected to our protocol conditions. Gratifyingly, after 1 h, the steroidal amide 3x could be
isolated in 90% yield.
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
Table 2. The Substrate Generality of the Beckmann Rearrangement Activated by DCIDa,b
a
Reaction conditions: ketoxime substrate 2 (1 mmol), 1d (10 mol%), 5.0 mL of anhydrous MeCN as
ACS Paragon Plus Environment

Page 11 of 25
The Journal of Organic Chemistry
1
2
3
solvent, 80 oC. b Isolated yields based on 2. c Performed using 1.0 equiv. of 1d at room temperature.
4
5
The favorable results found in mmol-scale substrate scope studies prompted us to further
6
7
8
9
examine the scalability of this protocol. As evidently illustrated in Scheme 6, the arrangement of
cyclododecyl oxime 2u and 3β-acetoxypregnenone oxime 2x were conducted on one gram scale,
furnishing the amide products 3u in 97% yield on a 0.97 gram scale and 3x in 86% yield on a 0.86
gram scale, respectively.
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 6. The 1-Gram Scale Beckmannn Rearrangement of the Oxime 2u and 2x
CONCLUSION
In conclusion, this work has demonstrated for the first time the synthetic potential of
substoichiometric amounts of dichloroimidazolidinediones in promoting Beckmann rearrangement.
The new promoter can be easily prepared from commercially available and economical starting
materials in a one step process. This novel method of activation features rapid access to amides and
lactams of chemical, industrial and medicinal importance in good to excellent yields, exhibits good
functional group tolerance, and could be amenable to scale-up. The mechanistic study offers yet
another important illustration of the self-propagating cycle in the context of a structurally novel
organic promoter, as profound and complementary to Lambert’s pioneering mechanistic insights
into Beckmann rearrangement28. Ongoing research including the potential synthetic applications of
dichloroimidazolidinediones in the catalytic version is underway in our laboratory.
EXPERIMENTAL SECTION
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 25
1
2
3
4
5
6
7
8
9
General Information. Reactions, unless otherwise stated, were carried out with magnetic stirring
under argon atmosphere in oven-dried glassware. Reagents were used as received without further
purification, unless otherwise noted. All reaction solvents prior to use were distilled according to
standard laboratory methods. Analytical thin layer chromatograph (TLC) was performed on 0.2 mm
coated silica gel plates (HSGF 254) and visualized using a UV light (254 nm or 365 nm). Flash column
chromatography was performed employing silica gel (200 – 300 mesh) at increased pressure.
1H and 13C NMR spectra were recorded on a Bruker Avance 400 & 100 MHz NMR spectrometer in
CDCl3 or as stated deuterated solvents. Chemical shifts δ are reported in part per million (ppm)
relative to residual undeuterated solvent as an internal reference (1H: δ 7.26 for CDCl3, δ 2.50 for
DMSO-d6, δ 1.94 for CD3CN; 13C: δ 77.16 for CDCl3, δ 39.52 for DMSO-d6). The following
abbreviations were used to explain NMR peak multiplicities: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, brs = broad signal. High resolution mass spectra (HRMS) were performed on
Agilent Acrrurate-Mass Q-TOF LC/MS 6520 mass spectrometer with electron spray ionization (ESI)
mode. Gas chromatograms were obtained using an Agilent 7890A gas chromatograph equipped
with a G4513A injector and an Agilent DB-WAXETR column (30 m × 0.320 mm × 0.25 μm). Melting
points were recorded in degrees Celsius (°C) using a Shanghai Precision & Scientific capillary melting
point apparatus and are reported uncorrected. Infrared spectra were obtained on a Thermo Nicolet
iS10 FT-IR spectrometer using KBr salt plates. Optical rotations were measured on a Rudolph
Research Analytical Autopol II automatic polarimeter.
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
Representative Procedure for the Synthesis of 2,2-Dichloro-imidazolidine-4,5-dione 1. Example
for synthesis of 1a: In a 100 mL Schlenk flask, N,N'-bis(2,6-diisopropylphenyl)carbodiimide (1 g, 2.76
mmol, 1.0 equiv.) was dissolved in 15 mL dry DCM. The resultant solution was cooled to 0 oC. Oxalyl
chloride (0.35 mL, 0.53 g, 4.14 mmol, 1.5 equiv.) was added dropwise at 0 oC. Then the reaction was
allowed to stir at room temperature for 4 h. Solvent and excess oxalyl chloride were removed under
reduced pressure. The residue was washed by dry hexane (×3) and dried under reduced pressure,
affording 2,2-dichloro-1,3-bis(2,6-diisopropylphenyl)imidazolidine-4,5-dione (1a).36 A colorless solid;
1.28 g, 95% yield; mp 201.3−202.8 °C; 1H NMR (400 MHz, CDCl3) δ 7.55 (t, J = 7.8 Hz, 2H), 7.38 (d, J =
13
8.0 Hz, 4H), 3.09 – 3.06 (m, 4H), 1.38 (d, J = 6.4 Hz, 12H), 1.18 (d, J = 6.8 Hz, 12H); C NMR (100
MHz, CDCl3) δ 155.3, 149.2, 131.5, 125.6, 125.1, 104.9, 30.6, 26.3, 22.7.
2,2-dichloro-1,3-diisopropylimidazolidine-4,5-dione (1b).4,11 Prepared according to the
ACS Paragon Plus Environment

Page 13 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
representative procedure with the following exception: N,N'-diisopropylmethanediimine (1 mL, 815
mg, 6.46 mmol, 1.0 equiv.), Oxalyl chloride (0.66 mL, 984 mg, 7.75 mmol, 1.2 equiv.). A colorless
solid; 1.47 g, 90% yield; mp 172.5−175.7 °C; 1H NMR (400 MHz, CDCl3) δ 4.19 – 4.12 (m, 2H), 1.57 (d,
J = 6.8 Hz, 12H); 13C NMR (100 MHz, CDCl3) δ 154.6, 103.0, 49.5, 19.2.
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
1,3-di-tert-butyl-2,2-dichloroimidazolidine-4,5-dione (1c).37 Prepared according to the
representative procedure with the following exception: N,N'-di-tert-butylmethanediimine (800 mg,
5.19 mmol, 1.0 equiv.), Oxalyl chloride (0.50 mL, 0.53 g, 5.70 mmol, 1.1 equiv.). A colorless solid;
1.34 g, 92% yield; mp 129.1−130.7 °C; 1H NMR (400 MHz, CDCl3) δ 1.78 (s, 18H); 13C NMR (100 MHz,
CDCl3) δ 155.2, 102.0, 62.5, 28.3.
2,2-dichloro-1,3-dicyclohexylimidazolidine-4,5-dione (1d).13 Prepared according to the
representative procedure with the following exception: N,N'-dicyclohexylmethanediimine (2 g, 9.69
mmol, 1.0 equiv.), Oxalyl chloride (0.90 mL, 1.29 g, 10.18 mmol, 1.1 equiv.), 25 mL DCM and a
1
reaction time of 1 h. A colorless solid; 3.07 g, 95% yield; mp 176.0−178.1 °C; H NMR (400 MHz,
CDCl3) δ 3.73 (tt, J = 12.0, 3.6 Hz, 2H), 2.30 – 2.20 (m, 4H), 1.94 – 1.89 (m, 8H), 1.71 – 1.68 (m, 2H),
1.42 – 1.26 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 154.4, 103.2, 57.0, 28.6, 25.9, 24.8.
Note：Compounds 1a – 1d were found to be moisture sensitive, especially 1b. We failed to obtain
spectra of pure 1b in that it is high sensitive to moisture and inevitably partially forms
1,3-diisopropylimidazolidine-2,4,5-trione (1’b) upon exposure to even trace water. When 1b was
open to the ambient atmosphere for one day, it completely converted into 1’b. Thus, it is
recommended that 1a – 1d be stored under an inert atmosphere.
General Procedure for the Preparation of Oxime Substrates 2. In a 50 mL round-bottom flask
equipped with a condenser, aromatic or aliphatic ketones (10 mmol, 1.0 equiv.) were dissolved in
the mixture of EtOH/H2O (v/v = 4:1, 25 mL). Then, hydroxylamine hydrochloride (16 mmol, 1.6
equiv.) and AcONa (20 mmol, 2.0 equiv.) was added in one portion. The reaction mixture was stirred
at 80 oC until the consumption of the starting material was observed by TLC. After that, the reaction
was cooled to room temperature, diluted with water (55 mL), extracted with ethyl acetate (80 mL ×
3), dried with anhydrous Na2SO4 and concentrated. The residue was purified by recrystallization or
flash column chromatograph on silica gel to afford the desired products 2a – 2x.
(E)-1-phenylethan-1-one oxime (2a).28 A colorless solid after purification by flash column
chromatography (petroleum ether (PE)/ethyl acetate (EA) = 30/1); 1.22 g, 90% yield; Rf = 0.42
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 25
1
2
3
4
5
6
7
1
(hexane/EtOAc, 5/1); mp 56.9−58.7 °C; H NMR (400 MHz, CDCl3) δ 9.89 (brs, 1H), 7.67 – 7.65 (m,
2H), 7.42 – 7.41 (m, 3H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.1, 136.6, 129.4, 128.7, 126.2,
12.5.
8
9
(E)-1-(p-tolyl)ethan-1-one oxime (2b).28 A colorless solid after purification by flash column
chromatography (PE/EA = 30/1); 1.28 g, 86% yield; Rf = 0.40 (hexane/EtOAc, 5/1); mp 85.2−86.1 °C;
1H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 2.39 (s, 3H),
2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.0, 139.4, 133.8, 129.4, 126.1, 21.4, 12.5.
(E)-1-(2-methoxyphenyl)ethan-1-one oxime (2c). 23 A colorless crystal after recrystallization from
EA/PE; 1.01 g, 61% yield; mp 85.8−86.4 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.36 – 7.32
(m, 1H), 7.21 (dd, J = 7.6, 2.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.95 – 6.91 (m, 1H), 3.78 (s, 3H), 2.06
(s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 157.1, 154.2, 129.9, 129.2, 127.4, 120.2, 111.5, 55.4, 15.4.
(E)-1-(3-methoxyphenyl)ethan-1-one oxime (2d).28 A colorless oil after purification by flash
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
column chromatography (PE/EA = 10/1); 1.55 g, 94% yield; Rf = 0.38 (hexane/EtOAc, 2/1); H NMR
(400 MHz, CDCl3) δ 10.18 (brs, 1H), 7.24 – 7.15 (m, 3H), 6.88 – 6.86 (m, 1H), 3.72 (s, 3H), 2.25 (s, 3H);
13C NMR (100 MHz, DMSO-d6) δ 159.2, 152.8, 138.5, 129.5, 118.1, 114.3, 110.8, 55.0, 11.6.
(E)-1-(4-methoxyphenyl)ethan-1-one oxime (2e).30 A colorless solid after purification by flash
column chromatography (PE/EA = 8/1); 1.52 g, 92% yield; Rf = 0.57 (hexane/EtOAc, 2/1); mp
86.2−87.5 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.60 – 7.58 (m, 2H), 6.94 – 6.92 (m, 2H),
13
3.76 (s, 3H), 2.12 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 159.7, 152.4, 129.5, 126.9, 113.8, 55.1,
11.5.
(E)-1-(4-hydroxyphenyl)ethan-1-one oxime (2f).38,39 A colorless solid after purification by flash
column chromatography (PE/EA = 10/1); 1.28 g, 85% yield; Rf = 0.45 (hexane/EtOAc, 5/1); mp
146.2−147.3 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.62 (s, 1H), 7.49 – 7.46 (m, 2H), 6.77
– 6.75(m, 2H), 2.09 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 158.0, 152.6, 127.9, 126.9, 115.1, 11.5.
(E)-1-(4-fluorophenyl)ethan-1-one oxime (2g).30 A colorless solid after purification by flash
column chromatography (5% EA/PE to 10% EA/PE); 1.41 g, 92% yield; Rf = 0.50 (hexane/EtOAc, 5/1);
mp 75.6−76.3 °C; 1H NMR (400 MHz, CDCl3) δ 8.76 (brs, 1H), 7.63 – 7.59 (m, 2H), 7.10 – 7.05 (m, 2H),
13
1
4
2.29 (s, 3H); C NMR (100 MHz, CDCl3) δ 163.6 (d, JCF = 247.6 Hz), 155.3, 132.7 (d, JCF = 3.3 Hz),
128.0 (d, 3JCF = 8.2 Hz), 115.6 (d, 2JCF = 21.6 Hz), 12.6.
(E)-1-(4-chlorophenyl)ethan-1-one oxime (2h).38,40 A colorless solid after purification by flash
ACS Paragon Plus Environment

Page 15 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
column chromatography (5% EA/PE to 10% EA/PE); 1.58 g, 93% yield; Rf = 0.48 (hexane/EtOAc, 5/1);
mp 97.2−98.5 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 7.67 – 7.65 (m, 2H), 7.44 – 7.42 (m,
2H), 2.13 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 152.0, 135.8, 133.3, 128.4, 127.3, 11.4.
(E)-1-(4-bromophenyl)ethan-1-one oxime (2i).28 A colorless solid after purification by flash
column chromatography (PE/EA = 10/1); 1.99 g, 93% yield; Rf = 0.51 (hexane/EtOAc, 5/1); mp
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
13
128.0−129.1 °C; H NMR (400 MHz, CDCl3) δ 9.36 (brs, 1H), 7.53 – 7.48 (m, 4H), 2.28 (s, 3H); C
NMR (100 MHz, CDCl3) δ 155.4, 135.4, 131.8, 127.7, 123.7, 12.3.
(E)-1-(naphthalen-2-yl)ethan-1-one oxime (2j).41 A colorless solid after purification by flash
column chromatography (PE/EA = 10/1); 1.67 g, 90% yield; Rf = 0.52 (hexane/EtOAc, 3/1); mp
143.4−144.7 °C; 1H NMR (400 MHz, CDCl3) δ 9.57 (brs, 1H), 8.05 (s, 1H), 7.89 – 7.85 (m, 4H), 7.54 –
13
7.52 (m, 2H), 2.46 (s, 3H); C NMR (100 MHz, CDCl3) δ 156.1, 133.9, 133.8, 133.2, 128.6, 128.4,
127.8, 126.8, 126.6, 126.1, 123.4, 12.3.
tert-butyl (E)-3-(1-(hydroxyimino)ethyl)-1H-indole-1-carboxylate (2k). A colorless solid after
purification by flash column chromatography (5% EA/PE to 10% EA/PE); 1.48 g, 54% yield; Rf = 0.41
(hexane/EtOAc, 6/1); mp 121.5−123.2 °C; IR (KBr) νmax 3275, 3004, 2984, 1739, 1560, 1453, 1370,
1281, 1243, 1151, 1062 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H),
8.08 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 2.20 (s, 3H), 1.65
(s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 150.0, 148.9, 135.3, 127.1, 125.6, 124.9, 123.4, 123.2, 118.3,
114.6, 84.3, 27.7, 12.0; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H18N2O3H 275.1390; Found
275.1381.
(E)-1-(3-((tert-butyldimethylsilyl)oxy)phenyl)ethan-1-one oxime (2l). A viscous light yellow liquid
after purification by flash column chromatography (PE/EA = 15/1); 2.26 g, 85% yield; Rf = 0.45
(hexane/EtOAc, 10/1); IR (KBr) νmax 3251, 2930, 2858, 1598, 1579, 1391, 1365, 1313, 1228, 1164,
1094, 1005, 910, 783, 693 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.28 (brs, 1H), 7.18 – 7.14 (m, 2H), 7.03
– 7.02 (m, 1H), 6.80 – 6.77 (m, 1H), 2.20 (s, 3H), 0.92 (s, 9H), 0.14 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ 155.91, 155.90, 138.0, 129.6, 121.2, 119.3, 117.8, 25.8, 18.4, 12.5, −4.3; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C14H23NO2SiH 266.1571; Found 266.1578.
diphenylmethanone oxime (2m).30 A colorless solid after purification by flash column
chromatography (PE/EA = 10/1); 1.85 g, 94% yield; Rf = 0.59 (hexane/EtOAc, 5/1); mp
1
140.4−141.3 °C; H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 7.46 – 7.34 (m, 8H), 7.30 – 7.28 (m,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 25
1
2
3
13
2H); C NMR (100 MHz, DMSO-d6) δ 155.2, 136.8, 133.6, 128.92, 128.86, 128.40, 128.36, 128.2,
4
5
6
127.0.
7
bis(4-methoxyphenyl)methanone oxime (2n).30 A colorless crystal after recrystallization from
8
9
1
EA/PE; 2.08 g, 81% yield; mp 54.9−56.3 °C; H NMR (400 MHz, CDCl3) δ 9.51 (brs, 1H), 7.42 (dd, 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
13
8.8, 6.8 Hz, 4H), 6.99 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H), 3.82 (s, 3H); C NMR
(100 MHz, CDCl3) δ 160.7, 160.1, 157.2, 131.2, 129.6, 129.3, 125.1, 113.8, 113.6, 55.42, 55.39.
cyclopropyl(phenyl)methanone oxime (2o).28 A colorless solid after recrystallization from EA/PE
1
as a mixture of (E) and (Z)-isomers; 1.32 g, 82% yield; H NMR (400 MHz, DMSO-d6) δ 11.01 (s,
0.76H), 10.52 (s, 0.19H), 7.44 – 7.33 (m, 5H), 2.19 – 2.14 (m, 0.79H), 1.74 – 1.67(m, 0.20H), 0.89 –
13
0.84 (m, 1.64H), 0.75 – 0.72 (m, 0.42H), 0.69 – 0.67 (m, 0.41H), 0.52 – 0.45 (m, 1.58H); C NMR
(100 MHz, DMSO-d6) δ 158.4, 155.7, 135.1, 134.4, 128.2, 128.0, 127.93, 127.88, 15.2, 8.8, 5.5, 5.2;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C10H11NOH 162.0913; Found 162.0928.
(E)-1-phenylpropan-1-one oxime (2p).41 A colorless solid after purification by flash column
chromatography (PE/EA = 5/1); 1.37 g, 92% yield; Rf = 0.50 (hexane/EtOAc, 6/1); mp 50.3−51.6 °C;
1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 7.64 – 7.62 (m, 2H), 7.43 – 7.40 (m, 3H), 2.84 (q, J = 7.6 Hz,
13
2H), 1.19 (t, J = 7.6 Hz, 3H); C NMR (100 MHz, CDCl3) δ 160.9, 135.6, 129.3, 128.7, 126.4, 19.9,
11.0.
1,3-diphenylpropan-2-one oxime (2q).28 A colorless solid after purification by flash column
chromatography (PE/EA = 15/1); 2.03 g, 90% yield; Rf = 0.55 (hexane/EtOAc, 3/1); mp
121.4−122.7 °C; 1H NMR (400 MHz, CDCl3) δ 8.47 (brs, 1H), 7.25 – 7.09 (m, 10H), 3.58 (s, 2H), 3.37 (s,
13
2H); C NMR (100 MHz, CDCl3) δ 159.2, 136.7, 136.5, 129.4, 129.3, 128.7, 126.9, 126.6, 39.7, 32.7;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C15H15NONa 248.1046; Found 248.1056.
methyl (E)-4-(hydroxyimino)-4-phenylbutanoate (2r).23 A colorless oil after purification by flash
1
column chromatography (PE/EA = 15/1 – 6/1); 1.20 g, 58% yield; Rf = 0.52 (hexane/EtOAc, 2/1); H
NMR (400 MHz, CDCl3) δ 9.23 (brs, 1H), 7.62 – 7.59 (m, 2H), 7.40 – 7.38 (m, 3H), 3.66 (s, 3H), 3.15 –
13
3.11 (m, 2H), 2.67 – 2.60 (m, 2H); C NMR (100 MHz, CDCl3) δ 173.3, 158.0, 135.1, 129.6, 128.8,
126.4, 51.9, 30.5, 22.2; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C11H13NO3Na 230.0788; Found
230.0785.
cyclohexanone oxime (2s).28 An off-white solid after purification by flash column
chromatography (PE/EA = 20/1); 0.84 g, 74% yield; Rf = 0.54 (hexane/EtOAc, 5/1); mp 89.1−90.5 °C;
ACS Paragon Plus Environment

Page 17 of 25
The Journal of Organic Chemistry
1
2
3
4
5
1H NMR (300 MHz, CDCl3) δ 9.43 (brs, 1H), 2.51 (t, J = 5.7 Hz, 2H), 2.22 (t, J = 5.7 Hz, 2H), 1.69 – 1.61
(m, 6H); 13C NMR (75 MHz, CDCl3) δ 160.8, 32.2, 27.0, 25.9, 25.7, 24.6.
6
7
8
9
nonan-2-one oxime (2t).42 A clear colorless oil after purification by flash column
chromatography (PE/EA = 5/1) as a 2.7:1 mixture of (E) and (Z)-isomers; 1.46 g, 93% yield; Rf = 0.50
(hexane/EtOAc, 5/1); 1H NMR (400 MHz, CDCl3) δ 8.96 (brs, 1H), 2.36 (t, J = 7.6 Hz, 0.53H), 2.17 (t, J
= 7.6 Hz, 1.49H), 1.87 (s, 2.14H), 1.85 (s, 0.78H), 1.51 – 1.47 (m, 2H), 1.31 – 1.27 (m, 8H), 0.87 (t, J =
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.2 (C), 158.8 (C), 35.9 (CH2), 31.9 (CH2), 29.8 (CH2), 29.3
(CH2), 29.2 (CH2), 29.2 (CH2), 28.8 (CH2), 26.4 (CH2), 25.6 (CH2), 22.8 (CH2), 20.0 (CH3), 14.2 (CH3),
13.5 (CH3); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C9H19NONa 180.1359; Found 180.1348.
cyclododecanone oxime (2u).28 A colorless solid after purification by flash column
chromatography (PE/EA = 20/1); 1.76 g, 89% yield; Rf = 0.55 (hexane/EtOAc, 6/1); mp
131.9−132.8 °C; 1H NMR (400 MHz, CDCl3) δ 9.19 (brs, 1H), 2.42 (t, J = 6.8 Hz, 2H), 2.27 (t, J = 6.4 Hz,
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
13
2H), 1.66 – 1.57 (m, 4H), 1.38 – 1.32 (m, 14H); C NMR (100 MHz, CDCl3) δ 160.6, 30.4, 26.3, 25.6,
25.2, 24.9, 24.1, 23.6, 23.4, 23.32, 23.28, 22.8.
(4-hydroxyphenyl)(phenyl)methanone oxime (2v). A colorless solid after purification by flash
column chromatography (10% EA/PE to 50% EA/PE) as a 1.5:1 mixture of (E) and (Z)-isomers; 1.83 g,
86% yield; Rf = 0.52 (hexane/EtOAc, 2/1); IR (KBr) νmax 3412, 3201, 3052, 2922, 1608, 1514, 1326,
1271, 1195, 1160, 995, 914, 838 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 11.21 (brs, 0.39H), 10.98 (brs,
0.57H), 9.88 (brs, 1H), 7.43 – 7.35 (m, 4H), 7.24 – 7.13 (m, 3H), 6.84 (d, J = 8.0 Hz, 1H), 6.76 (d, J =
13
8.4 Hz, 1H); C NMR (100 MHz, DMSO-d6) δ 158.3, 157.6, 155.1, 155.0, 137.6, 134.0, 130.9, 128.9,
128.7, 128.4, 128.24, 128.17, 128.1, 127.6, 127.4, 123.7, 115.2, 114.8; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C13H11NO2Na 236.0682; Found 236.0681.
3β-Acetoxypregn-5-en-20-one Oxime (2x).28 A colorless solid after purification by flash column
chromatography (PE/EA = 10/1); 3.18 g, 85% yield; Rf = 0.48 (hexane/EtOAc, 5/1); mp
183.2−185.5 °C; [α]D20 = −45 (c 0.2, C2H5OH); IR (KBr) νmax 3271, 2937, 2854, 1731, 1654, 1440, 1368,
1250, 1040, 900 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.98 (brs, 1H), 5.40 (d, J = 4.8 Hz, 1H), 4.67 – 4.59
(m, 1H), 2.36 – 2.34 (m, 2H), 2.28 – 2.24 (m, 1H), 2.16 – 2.11 (m, 1H), 2.06 (s, 3H), 1.95 – 1.88 (m,
6H), 1.75 – 1.20 (m, 12H), 1.05 (s, 3H), 1.03 – 1.00 (m, 1H), 0.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.7, 158.8, 139.8, 122.5, 74.0, 56.9, 56.2, 50.2, 43.9, 38.7, 38.2, 37.1, 36.7, 32.1, 31.8, 27.8, 24.3,
23.2, 21.6, 21.1, 19.4, 15.3, 13.2; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C23H35NO3Na 396.2509;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 25
1
2
3
4
Found 396.2530.
5
6
7
8
Synthesis of N-Phenylbenzimidoyl chloride. Prepared according to the procedure reported in
the literature.43 A mixture of SOCl2 (1.4 mL) and N-phenyl benzamide (220 mg, 1.12 mmol) was
heated to 65 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated
under reduced pressure. The residue was then stirred in n-hexane (2.0 mL) at 50 °C for 1 h, filtered,
and concentrated to afford the title compound as an off-white solid (241.6 mg, 90% yield). Mp
38.9−40.3 °C; 1H NMR (400 MHz, CDCl3) δ 8.19 – 8.17 (m, 2H), 7.58 – 7.40 (m, 5H), 7.22 (t, J = 7.6 Hz,
1H), 7.04 – 7.02 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 147.8, 143.4, 135.6, 132.2, 129.6, 129.0, 128.6,
125.2, 120.5.
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
General Procedure for the Synthesis of Amides/Lactams 3. In a 10 mL dry Schlenk tube, DCID
1d (33.33 mg, 0.1 mmol, 0.1 equiv.), the oxime substrates 2a – 2x (1 mmol, 1.0 equiv.) and dry
MeCN (5.0 mL) were sequentially added under argon atmosphere. Then the reaction was heated to
o
80 C and stirred until the completion of the reaction as indicated by TLC. The organic solvent was
removed in vacuum, and the crude material was purified by silica gel column to afford the desired
products 3a – 3x.
N-phenylacetamide (3a).44 Prepared from the oxime 2a (135 mg, 1 mmol) following the general
procedure. Reaction time: 20 min. Purification by flash column chromatography (PE/EA = 5/1 – 1/1)
furnished 3a (132.3 mg, 98% yield) as a colorless solid. Rf = 0.38 (hexane/EtOAc, 1/1); mp
113.2−114.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.22 (brs, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.19 (t, J = 7.6 Hz,
13
2H), 6.99 (t, J = 7.2 Hz, 1H), 2.04 (s, 3H); C NMR (100 MHz, CDCl3) δ 169.2, 138.1, 128.9, 124.3,
120.3, 24.4.
N-(p-tolyl)acetamide (3b).44 Prepared from the oxime 2b (149.2 mg, 1 mmol) following the
general procedure. Reaction time: 15 min. Purification by flash column chromatography (PE/EA =
8/1 – 2/1) furnished 3b (143.2 mg, 96% yield) as a colorless solid. Rf = 0.35 (hexane/EtOAc, 1/1); mp
150.5−152.6 °C; 1H NMR (400 MHz, CDCl3) δ 7.71 (brs, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.0 Hz,
13
2H), 2.30 (s, 3H), 2.13 (s, 3H); C NMR (100 MHz, CDCl3) δ 168.7, 135.5, 134.0, 129.5, 120.3, 24.5,
21.0.
N-(2-methoxyphenyl)acetamide (3c).23 Prepared from the oxime 2c (165.2 mg, 1 mmol)
following the general procedure. Reaction time: 15 min. Purification by flash column
chromatography (PE/EA = 10/1 – 2/1) furnished 3c (155.3 mg, 94% yield) as a colorless solid. Rf =
ACS Paragon Plus Environment

Page 19 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
0.47 (hexane/EtOAc, 1/1); mp 86.6−88.0 °C; 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.0 Hz, 1H), 7.76
(brs, 1H), 7.04 (t, J = 8.0 Hz, 1H), 6.96 (t, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 3.88 (s, 3H), 2.20 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 168.3, 147.7, 127.8, 123.7, 121.1, 119.8, 109.9, 55.7, 25.0.
N-(3-methoxyphenyl)acetamide (3d).28 Prepared from the oxime 2d (165.2 mg, 1 mmol)
following the general procedure. Reaction time: 10 min. Purification by flash column
chromatography (PE/EA = 8/1 – 1/1) furnished 3d (153.6 mg, 93% yield) as a yellow solid. Rf = 0.38
(hexane/EtOAc, 1/1); mp 102.5−103.8 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.90 (brs, 1H), 7.27 (t, J =
2.0 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 6.60 (dd, J = 8.4, 2.0 Hz, 1H), 3.71 (s, 3H),
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
13
2.02 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 168.4, 159.5, 140.5, 129.5, 111.3, 108.3, 104.9, 54.9,
24.1.
N-(4-methoxyphenyl)acetamide (3e).44 Prepared from the oxime 2e (165.2 mg, 1 mmol)
following the general procedure. Reaction time: 10 min. Purification by flash column
chromatography (PE/EA = 10/1 – 1/1) furnished 3e (161.9 mg, 98% yield) as a colorless solid. Rf =
0.30 (hexane/EtOAc, 1/1); mp 129.7−131.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.92 (brs, 1H), 7.37 (d, J =
13
8.4 Hz, 2H), 6.81 (d, J = 8.0 Hz, 2H), 3.76 (s, 3H), 2.10 (s, 3H); C NMR (100 MHz, CDCl3) δ 168.8,
156.4, 131.2, 122.2, 114.1, 55.5, 24.2.
N-(4-hydroxyphenyl)acetamide (3f).44 Prepared from the oxime 2f (151.2 mg, 1 mmol) following
the general procedure. Reaction time: 20 min. Purification by flash column chromatography (PE/EA
= 10/1 – 1/1) furnished 3f (143.6 mg, 95% yield) as a colorless solid. Rf = 0.44 (hexane/EtOAc, 1/4);
1
mp 170.2−170.6 °C; H NMR (400 MHz, DMSO-d6) δ 9.65 (brs, 1H), 9.14 (s, 1H), 7.34 (d, J = 9.2 Hz,
2H), 6.68 (d, J = 8.8 Hz, 2H), 1.98 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 167.6, 153.2, 131.1, 120.9,
115.1, 23.8.
N-(4-fluorophenyl)acetamide (3g).44 Prepared from the oxime 2g (153.2 mg, 1 mmol) following
the general procedure. Reaction time: 10 min. Purification by flash column chromatography (PE/EA
= 8/1 – 1/1) furnished 3g (148.6 mg, 97% yield) as a light yellow solid. Rf = 0.42 (hexane/EtOAc,
1
1/1.5); mp 154.0−154.8 °C; H NMR (400 MHz, DMSO-d6) δ 9.98 (brs, 1H), 7.59 (dd, J = 9.2, 5.2 Hz,
2H), 7.12 (t, J = 8.8 Hz, 2H), 2.03 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 168.2, 157.8 (d, 1JCF = 237.9
Hz), 135.8 (d, 4JCF = 2.0 Hz), 120.7 (d, 3JCF = 8.0 Hz), 115.2 (d, 2JCF = 22.0 Hz), 23.9.
N-(4-chlorophenyl)acetamide (3h).44 Prepared from the oxime 2h (169.6 mg, 1 mmol) following
the general procedure. Reaction time: 10 min. Purification by flash column chromatography (PE/EA
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 25
1
2
3
4
5
6
= 8/1 – 1/1) furnished 3h (156.0 mg, 92% yield) as a light yellow solid. Rf = 0.49 (hexane/EtOAc,
1
1/1.5); mp 177.4−179.1 °C; H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H),
13
7
7.33 (d, J = 8.8 Hz, 2H), 2.04 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 168.4, 138.3, 128.6, 126.5,
8
9
120.5, 24.0.
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-(4-bromophenyl)acetamide (3i).44 Prepared from the oxime 2i (214.1 mg, 1 mmol) following
the general procedure. Reaction time: 10 min. Purification by flash column chromatography (PE/EA
= 10/1 – 1/1) furnished 3i (205.5 mg, 96% yield) as a light yellow solid. Rf = 0.46 (hexane/EtOAc,
1
1/1.5); mp 166.2−167.6 °C; H NMR (400 MHz, DMSO-d6) δ 10.06 (brs, 1H), 7.55 (d, J = 8.8 Hz, 2H),
13
7.45 (d, J = 8.8 Hz, 2H), 2.04 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 168.5, 138.7, 131.5, 120.9,
114.5, 24.0.
N-(naphthalen-2-yl)acetamide (3j).27 Prepared from the oxime 2j (185.2 mg, 1 mmol) following
the general procedure. Reaction time: 20 min. Purification by flash column chromatography (PE/EA
= 10/1 – 2/1) furnished 3j (168.5 mg, 91% yield) as a colorless solid. Rf = 0.37 (hexane/EtOAc, 1/1);
mp 132.6−133.7 °C; 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.97 (brs, 1H), 7.77 – 7.72 (m, 3H), 7.48
13
– 7.39 (m, 3H), 2.20 (s, 3H); C NMR (100 MHz, CDCl3) δ 169.0, 135.5, 133.9, 130.7, 128.8, 127.7,
127.6, 126.6, 125.1, 120.1, 116.9, 24.7.
tert-butyl 3-acetamido-1H-indole-1-carboxylate (3k). Prepared from the oxime 2k (274.3 mg, 1
mmol) following the general procedure. Reaction time: 20 min. Purification by flash column
chromatography (PE/EA = 10/1 – 1/1) furnished 3k (197.5 mg, 72% yield) as a light yellow solid. Rf =
0.46 (hexane/EtOAc, 1/1); mp 164.0−165.7 °C; IR (KBr) νmax 3269, 3078, 2979, 1724, 1658, 1581,
1556, 1454, 1377, 1284, 1160, 1097, 864, 748, 536 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 10.11 (brs,
1H), 8.07 – 8.06 (m, 2H), 7.95 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 2.15
(s, 3H), 1.62 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 168.0, 149.2, 132.5, 125.0, 124.0, 122.3, 119.7,
118.6, 114.7, 113.3, 83.4, 27.7, 23.1; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C15H18N2O3Na
297.1210; Found 297.1210.
N-(3-((tert-butyldimethylsilyl)oxy)phenyl)acetamide (3l). Prepared from the oxime 2l (265.4 mg,
1 mmol) following the general procedure. Reaction time: 40 min. Purification by flash column
chromatography (PE/EA = 10/1 – 1/1) furnished 3l (220.3 mg, 83% yield) as a colorless solid. Rf =
0.58 (hexane/EtOAc, 1/1); mp 49.0−50.6 °C; IR (KBr) νmax 3283, 3208, 3086, 1668, 1589, 1563, 1471,
1396, 1282, 858, 816, 747 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.22 (brs, 1H), 7.17 – 7.12 (m, 2H), 7.00
ACS Paragon Plus Environment

Page 21 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
13
(d, J = 8.0 Hz, 1H), 6.60 – 6.56 (m, 1H), 2.16 (s, 3H), 0.97 (s, 9H), 0.20 (s, 6H); C NMR (100 MHz,
CDCl3) δ 168.6, 156.3, 139.1, 129.7, 116.1, 112.8, 111.9, 25.8, 24.8, 18.3, −4.3; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C14H23NO2SiNa 288.1390; Found 288.1388.
8
9
N-phenylbenzamide (3m).44 Prepared from the oxime 2m (197.2 mg, 1 mmol) following the
general procedure. Reaction time: 20 min. Purification by flash column chromatography (PE/EA =
5/1) furnished 3m (189.3 mg, 96% yield) as a colorless solid. Rf = 0.52 (hexane/EtOAc, 3/1); mp
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
161.2−163.0 °C; H NMR (400 MHz, CDCl3) δ 7.94 (brs, 1H), 7.87 – 7.85 (m, 2H), 7.64 (d, J = 7.6 Hz,
13
2H), 7.56 – 7.52 (m, 1H), 7.46 (t, J = 7.4 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.15 (t, J = 7.6 Hz, 1H); C
NMR (100 MHz, CDCl3) δ 165.9, 138.1, 135.1, 132.0, 129.2, 128.9, 127.2, 124.7, 120.4.
4-methoxy-N-(4-methoxyphenyl)benzamide (3n).28 Prepared from the oxime 2n (257.3 mg, 1
mmol) following the general procedure. Reaction time: 10 min. Purification by flash column
chromatography (PE/EA = 5/1) furnished 3n (241.9 mg, 94% yield) as a colorless solid. Rf = 0.59
(hexane/EtOAc, 1/1); mp 201.3−202.8 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.98 (brs, 1H), 7.95 (d, J =
8.8 Hz, 2H), 7.67 (d, J = 9.2 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H), 3.74
(s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 164.5, 161.8, 155.4, 132.4, 129.5, 127.1, 122.0, 113.7, 113.6,
55.4, 55.2.
N-phenylcyclopropanecarboxamide (3o).28 Prepared from the oxime 2o (161.2 mg, 1 mmol)
following the general procedure. Reaction time: 10 min. Purification by flash column
chromatography (PE/EA = 10/1 – 5/1) furnished 3o (143.5 mg, 89% yield) as a colorless solid. Rf =
0.38 (hexane/EtOAc, 3/1); mp 107.8−109.0 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.17 (brs, 1H), 7.58
(d, J = 8.0 Hz, 2H), 7.28 (t, J = 7.9 Hz, 2H), 7.01 (t, J = 7.2 Hz, 1H), 1.79 – 1.74 (m, 1H), 0.80 – 0.77 (m,
13
4H); C NMR (100 MHz, DMSO-d6) δ 172.0, 139.8, 129.1, 123.3, 119.4, 15.0, 7.6; HRMS (ESI-TOF)
m/z: [M+Na]+ Calcd for C10H11NONa 184.0733; Found 184.0729.
N-phenylpropionamide (3p).27 Prepared from the oxime 2p (149.2 mg, 1 mmol) following the
general procedure. Reaction time: 15 min. Purification by flash column chromatography (PE/EA =
10/1 – 3/1) furnished 3p (144.7 mg, 97% yield) as a yellow solid. Rf = 0.60 (hexane/EtOAc, 1/1); mp
102.8−104.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.65 (brs, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 8.0 Hz,
2H), 7.08 (t, J = 7.2 Hz, 1H), 2.38 (q, J = 7.2 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 172.4, 138.2, 129.0, 124.2, 120.0, 30.8, 9.8.
N-benzyl-2-phenylacetamide (3q).28,45 Prepared from the oxime 2q (225.3 mg, 1 mmol)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 25
1
2
3
4
5
6
7
8
9
following the general procedure. Reaction time: 20 min. Purification by flash column
chromatography (PE/EA = 10/1 – 3/1) furnished 3q (209.5 mg, 93% yield) as a colorless solid. Rf =
0.53 (hexane/EtOAc, 1/1); mp 121.5−122.6 °C; 1H NMR (400 MHz, CDCl3) δ 7.27 – 7.15 (m, 8H), 7.09
– 7.08 (m, 2H), 5.82 (brs, 1H), 4.30 (d, J = 6.0 Hz, 2H), 3.51 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 171.0,
138.2, 134.9, 129.5, 129.1, 128.7, 127.6, 127.5, 127.4, 43.8, 43.6; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C15H15NONa 248.1046; Found 248.1047.
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
methyl 4-oxo-4-(phenylamino)butanoate (3r).23 Prepared from the oxime 2r (207.2 mg, 1 mmol)
following the general procedure. Reaction time: 15 min. Purification by flash column
chromatography (PE/EA = 10/1 – 1/1) furnished 3r (198.9 mg, 96% yield) as a colorless solid. Rf =
1
0.48 (hexane/EtOAc, 1/1); mp 94.5−95.3 °C; H NMR (400 MHz, CDCl3) δ 7.67 (brs, 1H), 7.50 (d, J =
8.0 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.09 (t, J = 7.2 Hz, 1H), 3.71 (s, 3H), 2.76 (t, J = 6.4 Hz, 2H), 2.67 (t,
J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 173.8, 169.9, 138.0, 129.0, 124.3, 119.9, 52.1, 32.0, 29.3;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C11H13NO3Na 230.0788; Found 230.0787.
ε-caprolactam (3s).44 Prepared from the oxime 2s (113.2 mg, 1 mmol) following the general
procedure with the following exception: the reaction performed using 1.0 equiv. of 1d at room
temperature. Reaction time: 3 h. Purification by flash column chromatography (PE/EA = 10/1 – 1/1)
furnished 3s (90.56 mg, 80% yield) as an off-white solid. Rf = 0.30 (hexane/EtOAc, 3/1); mp
1
68.1−69.3 °C; H NMR (400 MHz, CDCl3) δ 6.93 (brs, 1H), 3.23 – 3.19 (m, 2H), 2.47 – 2.45 (m, 2H),
1.79 – 1.62(m, 6H); 13C NMR (100 MHz, CDCl3) δ 179.5, 42.7, 36.8, 30.6, 29.7, 23.2.
N-heptylacetamide (3t).46 Prepared from the oxime 2t (157.3 mg, 1 mmol) following the general
procedure. Reaction time: 5 h. Purification by flash column chromatography (PE/EA = 3/1 – 2/3)
furnished 3t (136.9 mg, 87% yield) as a yellow oil. Rf = 0.41 (hexane/EtOAc, 1/5); 1H NMR (400 MHz,
CDCl3) δ 6.07 (brs, 1H), 3.16 (q, J = 7.2 Hz, 2H), 1.92 (s, 3H), 1.46 – 1.42 (m, 2H), 1.27 – 1.22 (m, 8H),
13
0.82 (t, J = 6.6 Hz, 3H); C NMR (100 MHz, CDCl3) δ 170.3, 39.7, 31.8, 29.6, 29.0, 26.9, 23.3, 22.6,
14.1; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C9H19NONa 180.1359; Found 180.1348.
ω-Laurolactam (3u).28 Prepared from the oxime 2u (197.3 mg, 1 mmol) following the general
procedure. Reaction time: 10 min. Purification by flash column chromatography (PE/EA = 8/1 – 1/1)
furnished 3u (193.4 mg, 98% yield) as a colorless solid. Rf = 0.43 (hexane/EtOAc, 1/2); mp
1
150.7−153.5 °C; H NMR (400 MHz, CDCl3) δ 5.80 (brs, 1H), 3.27 (q, J = 5.6 Hz, 2H), 2.19 – 2.16 (m,
13
2H), 1.67 – 1.64 (m, 2H), 1.50 – 1.46 (m, 2H), 1.37 – 1.28 (m, 14H); C NMR (100 MHz, CDCl3) δ
ACS Paragon Plus Environment

Page 23 of 25
The Journal of Organic Chemistry
1
2
3
4
173.6, 39.1, 37.0, 28.4, 26.8, 26.4, 26.3, 25.8, 25.4, 25.0, 24.7, 24.0.
N-(4-hydroxyphenyl)benzamide and 4-hydroxy-N-phenylbenzamide (3v and 3w).47,48 Prepared
from the oxime 2v (213.2 mg, 1 mmol) following the general procedure. Reaction time: 15 min.
Purification by flash column chromatography (PE/EA = 10/1 – 2/1) furnished a 1.5:1 isomeric
mixture of 3v and 3w (194.0 mg, 91% overall yield) as a yellow solid. Rf = 0.41 (hexane/EtOAc, 1/1);
1H NMR (400 MHz, DMSO-d6) δ 10.11 (brs, 1H), 10.03 (s, 1H), 9.99 (s, 1H), 9.27 (brs, 1H), 7.92 (d, J =
7.2 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 7.6 Hz, 2H), 7.56 – 7.49 (m, 5H), 7.32 (t, J = 8.0 Hz,
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
13
2H), 7.06 (t, J = 7.2 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H); C NMR (100 MHz,
DMSO-d6) δ 165.2, 165.0, 160.6, 153.8, 139.5, 135.2, 131.3, 130.8, 129.8, 128.6, 128.4, 127.6, 125.5,
123.3, 122.4, 120.3, 115.04, 114.97; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C13H11NO2Na 236.0682;
Found 236.0682.
3β-acetoxy-5-androstene-17β-acetamide (3x).28,49 Prepared from the oxime 2x (373.5 mg, 1
mmol) following the general procedure. Reaction time: 1 h. Purification by flash column
chromatography (PE/EA = 4/1 – 3/2) furnished 3x (336.2 mg, 90% yield) as a colorless solid. Rf = 0.38
20
(hexane/EtOAc, 1/3); mp 188.6−191.5 °C; [α]D = −116 (c 1.0, C2H5OH); IR (KBr) νmax 2937, 2902,
1733, 1652, 1370, 1254, 1038 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.37 (m, 1H), 5.30 (d, J = 9.2 Hz, 1H),
4.62 – 4.55 (m, 1H), 3.88 (q, J = 9.2 Hz, 1H), 2.36 – 2.32 (m, 2H), 2.15 – 2.08 (m, 1H), 2.02 (s, 3H),
1.98 (s, 3H), 1.85 (d, J = 10.0 Hz, 2H), 1.72 – 1.10 (m, 13H), 1.01 (s, 3H), 0.99 – 0.95 (m, 1H), 0.69 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 170.6, 170.0, 139.8, 122.4, 74.0, 58.9, 52.8, 50.1, 42.8, 38.2, 37.0,
36.8, 36.7, 32.1, 31.6, 28.7, 27.8, 23.74, 23.68, 21.5, 20.6, 19.4, 12.0; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C23H35NO3Na 396.2509; Found 396.2507.
ASSOCIATED CONTENT
Supporting Information
1
13
Copies of H and C NMR spectra for all synthesized compounds and details of mechanistic study.
The Supporting Information is available free of charge on the ACS Publications website at DOI:
AUTHOR INFORMATION
Corresponding Author
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 25
1
2
3
4
*E-mail: guok@njtech.edu.cn.
5
6
Notes
7
The authors declare no competing finacial interest.
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
ACKNOWLEDGEMENTS
Support of this work by the National Natural Science Foundation of China (U1463201,
21522604), the National Key Research and Development Program of China (2017YFC1104802),
Natural Science Foundation of Jiangsu Province, China (BK20150031), Jiangsu National Synergetic
Innovation Center for Advanced Materials (SICAM), the Priority Academic Program Development of
Jiangsu Higher Education Institutions (PAPD) and the Top-notch Academic Programs Project of
Jiangsu Higher Education Institutions (TAPP) is gratefully acknowledged.
REFERENCES
(1) Fedorynski, M. Chem. Rev. 2003, 103, 1099.
(2) Banwell, M. G.; Beck, D. A. S.; Stanislawski, P. C.; Sydnes, M. O.; Taylor, R. M. Curr. Org. Chem.
2005, 9, 1589.
(3) Chelucci, G. Chem. Rev. 2012, 112, 1344.
(4) Stachel, H. D. Angew. Chem. 1959, 71, 246.
(5) Ulrich, H.; Sayigh, A. A. R. J. Org. Chem. 1965, 30, 2781.
(6) Zinner, G.; Vollrath, R. Chem. Ber. 1970, 103, 766.
(7) Gross, H.; Zinner, G. Chem. Ber. 1973, 106, 2315.
(8) Richter, R.; Barsa, E. A. J. Org. Chem. 1986, 51, 417.
(9) Ried, W.; Nenninger, H. Chem. Zeit. 1987, 111, 113.
(10)Ried, W.; Nenninger, H. Chem. Zeit. 1988, 112, 382.
(11)Zhao, F.; Wang, Y.; Zhang, W.-X.; Xi, Z. Org. Biomol. Chem. 2012, 10, 6266.
(12)Zhao, F.; Li, Y.; Wang, Y.; Zhang, W.-X.; Xi, Z. Org. Biomol. Chem. 2014, 12, 3336.
(13)Moerdyk, J. P.; Bielawski, C. W. Chem. - Eur. J. 2014, 20, 13487.
(14)Beckmann, E. Ber. Dtsch. Chem. Ges. 1886, 19, 988.
(15)Blatt, A. H. Chem. Rev. 1933, 12, 215.
(16)Jones, B. Chem. Rev. 1944, 35, 335.
(17)Jones, B. Nature 1946, 157, 519.
(18)Gawley, R. E. Org. React. 1988, 35, 14.
(19)Nguyen, M. T.; Raspoet, G.; Vanquickenborne, L. G. J. Am. Chem. Soc. 1997, 119, 2552.
(20)Chandrasekhar, S. In Comprehensive Organic Synthesis II, 2nd ed.; Elsevier: Amsterdam, 2014;
Vol. 7, pp 770–800.
(21)Weissermel, K.; Arpe, H.-J. In Industrial Organic Chemistry, 4th ed.; Wiley-VCH Verlag GmbH:
Weinheim, 2003; pp 239–266.
ACS Paragon Plus Environment

Page 25 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(22)You, K.; Mao, L.; Yin, D.; Liu, P.; Luo, H. a. Catal. Commun. 2008, 9, 1521.
(23)Furuya, Y.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 11240.
(24)Zhu, M.; Cha, C.; Deng, W.-P.; Shi, X.-X. Tetrahedron Lett. 2006, 47, 4861.
(25)Hashimoto, M.; Obora, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2008, 73, 2894.
(26)Pi, H.-J.; Dong, J.-D.; An, N.; Du, W.; Deng, W.-P. Tetrahedron 2009, 65, 7790.
(27)Srivastava, V. P.; Patel, R.; Garima; Yadav, L. D. S. Chem. Commun. 2010, 46, 5808.
(28)Vanos, C. M.; Lambert, T. H. Chem. Sci. 2010, 1, 705.
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
(29) Augustine, J. K.; Kumar, R.; Bombrun, A.; Mandal, A. B. Tetrahedron Lett. 2011, 52, 1074.
(30)Xie, F.; Du, C.; Pang, Y.; Lian, X.; Xue, C.; Chen, Y.; Wang, X.; Cheng, M.; Guo, C.; Lin, B.; Liu, Y.
Tetrahedron Lett. 2016, 57, 5820.
(31)Chapman, A. W. J. Chem. Soc. 1935, 1223.
(32)An, N.; Tian, B.-X.; Pi, H.-J.; Eriksson, L. A.; Deng, W.-P. J. Org. Chem. 2013, 78, 4297.
(33)Tian, B.-X.; An, N.; Deng, W.-P.; Eriksson, L. A. J. Org. Chem. 2013, 78, 6782.
(34)See page S2 in the Supporting Information for more details.
(35)See pages S2–4 in the Supporting Information for more details.
(36) Zhao, F.; Wang, Y.; Xu, L.; Zhang, W.-X.; Xi, Z. Tetrahedron Lett. 2014, 55, 4597.
(37)Moerdyk, J. P.; Bielawski, C. W. Chem. Commun. 2014, 50, 4551.
(38)Zhang, G.; Wen, X.; Wang, Y.; Mo, W.; Ding, C. J. Org. Chem. 2011, 76, 4665.
(39) Baleizão, C.; Corma, A.; García, H.; Leyva, A. J. Org. Chem. 2004, 69, 439.
(40) Prateeptongkum, S.; Jovel, I.; Jackstell, R.; Vogl, N.; Weckbecker, C.; Beller, M. Chem. Commun.
2009, 1990.
(41) Zhao, H.; Vandenbossche, C. P.; Koenig, S. G.; Singh, S. P.; Bakale, R. P. Org. Lett. 2008, 10, 505.
(42) Moran, J.; Pfeiffer, J. Y.; Gorelsky, S. I.; Beauchemin, A. M. Org. Lett. 2009, 11, 1895.
(43) Ram, R. N.; Kumar, N.; Singh, N. J. Org. Chem. 2010, 75, 7408.
(44) Mahajan, P. S.; Humne, V. T.; Tanpure, S. D.; Mhaske, S. B. Org. Lett. 2016, 18, 3450.
(45)Morimoto, H.; Fujiwara, R.; Shimizu, Y.; Morisaki, K.; Ohshima, T. Org. Lett. 2014, 16, 2018.
(46)Briggs, J. R.; Klosin, J.; Whiteker, G. T. Org. Lett. 2005, 7, 4795.
(47)Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 13001.
(48)Ma, F.; Xie, X.; Zhang, L.; Peng, Z.; Ding, L.; Fu, L.; Zhang, Z. J. Org. Chem. 2012, 77, 5279.
(49) Fousteris, M. A.; Koutsourea, A. I.; Lagonikakos, N. P.; Arsenou, E. S.; Spyridonidou, C.;
Mourelatos, D.; Nikolaropoulos, S. S. Med. Chem. 2006, 2, 569.
ACS Paragon Plus Environment