Direct Synthesis of N,N-Disubstituted Formamides by Oxidation of Imines Using an HFIP/UHP System

Article abstract of DOI:10.1021/acs.joc.0c01579

The straightforward synthesis of N,N-disubstituted formamides using a combination of 1,1,1,3,3,3-hexafluoroispropanol (HFIP) and H2O2 is described. The unique features of HFIP allowed the utilization of a green oxidant such as H2O2, and the products, arising from an oxidation-rearrangement sequence, were obtained in good to high yields under smooth reaction conditions.

Full text of DOI:10.1021/acs.joc.0c01579

Subscriber access provided by Stony Brook University | University Libraries
Featured Article
DIRECT SYNTHESIS OF N,N-DISUBSTITUTED FORMAMIDES
BY OXIDATION OF IMINES USING HFIP/UHP SYSTEM
Natalia Llopis, Patricia Gisbert, and Alejandro Baeza
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01579 • Publication Date (Web): 12 Aug 2020
Downloaded from pubs.acs.org on August 13, 2020
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 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 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.
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 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
DIRECT SYNTHESIS OF N,N-DISUBSTITUTED
FORMAMIDES BY OXIDATION OF IMINES
USING HFIP/UHP SYSTEM
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Natalia Llopis, Patricia Gisbert and Alejandro Baeza*
AUTHOR ADDRESS. Departamento de Química Orgánica and Instituto de Síntesis Orgánica
(ISO), Facultad de Ciencias, Universidad de Alicante. Apdo. 99, E-03080 Alicante, Spain.
KEYWORDS: Green oxidation, Formamides, Fluorinated alcohol, Imines, Water peroxide
ABSTRACT
The straightforward synthesis of N,N-disubstituted formamides using 1,1,1,3,3,3-
hexafluoroispropanol (HFIP) and H O combination is described. The unique features of HFIP
2
2
allowed the utilization of a green oxidant such as H O and the products, arising from an
2
2
oxidation-rearrangement sequence, were obtained in good to high yields under smooth reaction
conditions.
INTRODUCTION
ACS Paragon Plus Environment
1

The Journal of Organic Chemistry
Page 2 of 23
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Formamides are considered valuable intermediates in organic synthesis which have been
extensively utilized in the synthesis of pharmaceutically relevant compounds such as
1
2
3
fluoroquinolones, substituted aryl imidazoles or 1,2-dihydroquinolines. Besides, during the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
last years, formamides have been also used as Lewis bases being employed as catalysts in
4
numerous organic transformations. Further to this, these organic compounds play an important
role as reagents in the Vilsmeir formylation reaction.5
On the other hand, imines are considered very accessible and versatile compounds. Thus, it is not
surprising that oxidation of imines has been addressed in a myriad of articles giving rise to the
6
7
corresponding oxaziridines or N-substituted amides (Scheme 1, eq. a). However, to the best of
our knowledge, there are only a couple of precedents in the literature describing the oxidative
rearrangement of imines in order to get access to N,N-disubstituted formamides (Scheme 1, eq.
8
b). In addition, in both routes, the authors use organic peroxyacids, requiring the presence of a
strong Lewis or Brønsted acid; hence generating a stoichiometric amount of non-degradable
waste in a low atom-economy process. Therefore, the development of a more environmentally
benign oxidative route for the synthesis of such formamides from readily available imines, which
can overcome such problems, would be highly desirable. In this regard, continuing with an
ongoing project about the use of fluorinated alcohols in organic transformations as solvents and
reaction mediators,9,10 we envisioned the employment of H O or the more stable form UHP
2
2
(urea-hydrogen peroxide adduct) as a green alternative oxidants to those previously described
ones in combination with 1,1,1,3,3,3-hexafluoroispropanol (HFIP) for such purpose (Scheme 1,
11
eq. c). The use of this system would considerably reduce the amount and the environmental
1
2
impact of the generated waste. The results of this research are herein reported.
Scheme 1. Imines oxidation
ACS Paragon Plus Environment
2

Page 3 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
a) Well-known procedures6,7
R2
O
O
N
R2
oxidation
R2
R1
N
R1
or
R1
N
H
b) 2 reported procedures8
O
R2
RCOOOH
R2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R1
H
N
R1
N
Lewis or
Brønsted acid
c) Our proposal
O
R2
H O or UHP
R2
2
2
R1
H
N
R1
N
R OH
F
RESULTS AND DISCUSSION
The optimization of the reaction conditions was tackled, using N-benzylideneaniline (1a) as
model substrate (Table 1). Firstly, different organic polar protic solvents (namely HFIP, H O,
2
MeOH and TFE) were tested using 2 equiv. of H O (30% v/v) as oxidizing agent at 45 ºC
2
2
(Table 1, entries 1-4). As depicted in Table 1, only HFIP gave a good conversion towards the
formation of 2a (Table 1, entry 1). It is noteworthy that, although in poor conversion, MeOH
gave rise to the formation of the regioisomer 3a (Table 1, entry 3). Other commonly employed
polar aprotic and apolar organic solvents were also essayed (DMSO, MeCN, EtOAc, THF,
acetone, CHCl , PhMe) remaining the imine unaltered or slightly hydrolysed. Attempts to
3
ameliorate the conversion of 2a were performed by increasing or lowering the amount of H O2
2
employed using HFIP as solvent (Table 1, entries 5 and 7). However, whereas the use of 3 equiv.
barely changed the result, the employment of 1.5 equiv. resulted in lower conversion. The same
experiments were performed with MeOH, trying to favor the formation of 3a (Table 1, entries 6
and 8). Unfortunately, the same trend was observed and no significant improvement was
accomplished. It is also noteworthy that, at this point, different solvent mixtures HFIP/MeOH
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 23
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and HFIP/H O were also tested without further success. Focused on the formation of compound
2
2
a, refining the reaction conditions in order to increase the conversion was next addressed. Thus,
the concentration was examined and it was observed that changing the concentration from 1 M to
.6 M improved the conversion of 2a reaching up to 91% (Table 1, compare entry 9 and 10). The
reaction at room temperature was also essayed but the conversion was not as high as at 45 ºC
Table 1, entry 11). Finally, from the presence of benzaldehyde and aniline in the GC-MS
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
(
analysis, arising from the partial hydrolysis of imine, it was decided to switch to an anhydrous
H O source in order to minimize such background reaction. In this regard, when UHP was used
2
2
instead, an excellent conversion towards the formation of 2a was achieved (Table 1, entry 12).
Further changes in concentration or temperature did not produce any substantial improvement
(Table 1, entries 13-15).
Table 1. Optimization of the reaction conditionsa
H O source
2
2
Ph
N
H
(x equiv.)
Ph
N
Ph
N
+
Ph
Ph
Ph
OHC
Solvent, Temp (º C)
H
O
15 h
1a
2a
3a
(1 M)
Conv. (2a/3a ratio)b
Entry
H O source (x equiv.)
Solvent
Temp (º C)
2
2
1
2
3
4
5
H O (2 equiv.)
HFIP
45
45
45
45
45
85% (98/2)
<10%
2
2
H O (2 equiv.)
H O
2
2
2
H O (2 equiv.)
MeOH
TFE
35% (4/96)
<15%
2
2
H O (2 equiv.)
2
2
H O (1.5 equiv.)
HFIP
77% (95/5)
2
2
ACS Paragon Plus Environment
4

Page 5 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
6
7
8
9
H O (1.5 equiv.)
MeOH
HFIP
45
45
45
45
45
25
45
45
45
25
<15%
2
2
H O (3 equiv.)
82% (98/2)
39% (4/96)
91% (>99/1)
68% (95/5)
86% (99/1)
97% (>99/1)
92% (>99/1)
87% (>99/1)
93% (>99/1)
2
2
H O (3 equiv.)
MeOH
HFIPc
HFIPd
HFIPc
HFIP
HFIPc
HFIPd
HFIP
2
2
H O (2 equiv.)
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
0
1
2
3
4
5
H O (2 equiv.)
2 2
1
1
1
1
1
H O (2 equiv.)
2 2
UHP (2 equiv.)
UHP (2 equiv.)
UHP (2 equiv.)
UHP (2 equiv.)
a
Reaction conditions: all the reactions were carried out using 0.15 mmol of imine 1a and the
corresponding amount of oxidant in 150 µL of the solvent at the given temperature for 15 h.
Conversion and 2a/ 3a ratio, determined by GC-MS. 250 µL of HFIP were used (0.6 M).
0 µL of HFIP were used (3 M).
b
c
d
5
Once the optimal reaction conditions were selected, the scope of the methodology was performed
by using different imines (Table 2). As previously commented, imine 1a produced the
corresponding N,N-diphenylformamide (2a) in high yield (Table 2, entry 1). Good yield was also
achieved when imine 1b was tested (Table 2, entry 2). However, imine derived from para-
anisidine 1c gave only decomposition and hydrolysis products regardless the reaction conditions
employed, probably due to its more basic character, which makes the substrate more prone to be
protonated by HFIP and hence more easily hydrolysed (Table 2, entry 3). Aldimine 1d bearing
an electron-withdrawing group in the aniline moiety, produced the desired product in a 62%
yield (Table 2, entry 4). Next, aldimines synthesized from different para-substituted
benzaldehydes were essayed, obtaining high yields in the corresponding disubstituted
formamides regardless the electronic nature of such substituent (Table 2, entries 5-8). It is worth
mentioning that in the case of imine 1h bearing an electron-withdrawing group (CF ) produced a
3
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 23
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
substantial 10% of the corresponding isomer 3h arising from the benzylic oxidation (Table 2,
entry 8). Imine derived from salicylaldehyde was also explored but unfortunately turned out to
be unreactive, probably due to an internal hydrogen bond, and low conversion towards the
desired product was detected even when increasing the amount of UHP (Table 2, entry 9). This
assumption was further reinforced in view of the good yield achieved for the product 2j when o-
anisaldehyde imine derivative 1j was essayed (Table 2, entry 10). Imine 1k bearing para-methyl
substituents in both aromatic rings produced formamide 2k in good yield (Table 2, entry 11).
Next, heteroaromatic aldehyde imine derivatives were employed and different behaviors were
observed depending on the electronic properties of the aromatic ring. Thus, whereas imine 1l
containing an electron-rich heteroaromatic ring such as furan, gave rise to decomposition and
hydrolysis products, imine 1m bearing a pyridine ring, considered as electron poor aromatic ring,
produced compound 3m in good yield as main product (Table 2, entries 12 and 13). Imines
derived from aliphatic amines were next evaluated. When imine 1n was the substrate of choice,
the formation of a mixture of both N-butylbenzamide (3n) and the corresponding formamide 2n
was observed in moderate yield (Table 2, entry 14). However, the reaction with imine 1o bearing
a cyclohexane ring resulted in the formation of the oxaziridine 4o (Table 2, entry 15).
Unexpectedly, N,N-diphenylformamide 2a was obtained in high yield when benzylamine imine
derivative 1p was employed (Table 2, entry 16). Next, imines derived from
cyclohexanecarbaldehyde were examined. Good results were obtained with imine 1q (Table 2,
entry 17). Contrariwise, oxaziridine 4r was obtained in excellent yields from imine 1r (Table 2,
entry 18). Finally, cinnamaldehyde derivative imine 1s was also tested and to our surprise a
complex mixture of products was obtained (Table 2, entry 19). We were able to distinguish (by
GC-MS) among them benzaldehyde and formamide 2a as major products (together with lower
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment
6

Page 7 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
amounts of N-phenylformamide). At this point we speculate about a possible hydrolysis and
retroaldol reaction, which would form benzaldehyde and aniline, hence the in situ formation of
imine 1a (see Scheme 2) which would lead to the formation of 2a. Finally, a few ketimines were
also tested. Firstly, imine derived from acetophenone (1t) was essayed, but unfortunately only
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
0% conversion towards the formation of the corresponding N,N-diphenylacetamide 2t (Table 2,
entry 20) was observed. Imine derived from cyclohexyl methyl ketone 1u underwent hydrolysis
under the reaction conditions (Table 2, entry 21). Finally, all alkylic ketimine 1v produced the
corresponding oxaziridine 4v in excellent yields (Table 2, entry 22).
Table 2. Scope of the reactiona
R3
O
O
UHP (2 equiv.)
HFIP, 45 ºC
R2
R1
R2
+
R1
R1
N
R3
N
R2
N
H
15 h
1
2
2
3
1
3
R and R = Aryl, Alkyl
when R = H
3
R = H, Alkyl
b
c
Entry
Imine
Product
Yield (2/3 ratio)
O
H
Ph
Ph
H
N
1
89 (>99/1)
82 (>99/1)
Ph
H
N
a
Ph
a
1
2
O
H
N
2
Ph
N
Ph
1
b
2
b
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 23
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
H
PMP
3
4
―
―
Ph
H
N
1c
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
62 (>99/1)
H
N
Ph
N
1d
Ph
2
d
O
H
PMP
Ph
H
N
5
6
87 (>99/1)
80 (>99/1)
PMP
N
Ph
e
1e
2
H
O
Ph
N
H
N
Ph
b
1f
2
Cl
H
O
Ph
N
7
8
9
H
N
88 (96/4)
91 (90/10)
<20% conv.d
Ph
Cl
1g
2
g
CF3
H
O
Ph
N
H
N
Ph
F3C
1h
2
h
H
O
Ph
N
H
N
Ph OH
OH
2
i
1
i
H
O
Ph
N
H
N
1
0
90 (98/2)
Ph OMe
OMe
2
j
1
j
ACS Paragon Plus Environment
8

Page 9 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
O
H
H
N
N
1
1
79 (>99/1)
2
k
1k
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
O
Ph
Ph
1
1
2
3
N
―
―
1l
H
O
Ph
N
N
72 (15/85)
H
N
N
1m
3m
O
H
Bu
Bu
Ph
N
H
n
57 (35/65)e
1
4
Ph
N
1n
3
O
Ph
N
H
15
98
Ph
N
1
o
4o
O
H
Ph
H
N
1
6
83 (>99/1)
84 (>99/1)
Ph
N
1
Ph
Ph
Ph
a
p
2
H
O
N
H
N
17
Ph
2q
1q
O
N
H
N
1
8
95
1r
4r
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 23
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
H
Ph
>95% conv.d
~20% conv.d
―
19
Complex Mixture
Ph
N
1
s
O
Ph
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ph
2
0
Ph
N
t
Ph
t
1
2
Ph
N
21
22
―
1u
95
N
O
N
1v
4v
a
Reaction conditions: all the reactions were carried out using 0.15 mmol of imine 1 and 2
equiv. of UHP in 150 µL of HFIP (1 M) at 45 ºC for 15 h. Isolated yield of 2 or the 2/3
b
c
mixture after preparative TLC or chromatography column. 2/3 ratio determined by GC-MS
d
e
from the crude mixture. Determined by GC-MS. Not purely isolated; yield determined by
1
H NMR from the crude.
After the scope of the reaction was tested, we decided to explore the one-pot imine formation-
oxidative rearrangement sequence (Scheme 2). Thus, onto in situ formed benzylideneaniline 1a,
synthesised by mixing benzaldehyde and aniline for 20 minutes in the absence of solvent, UHP
(
2 equiv.) and HFIP was added in one portion. After 15 hours and subsequent purification the
formamide 2a was obtained in 81% yield. It is also worth mentioning that when this one-pot was
implemented in a larger scale reaction (5 mmol), the corresponding formamide 2a was obtained
in a notable 73% yield. In addition, since benzylidene amine it is not a very stable compound, we
decided to perform the same one-pot sequence reaction but using ammonium hydroxide. Using a
slightly modified procedure (longer reaction time to form the imine and 5 equiv. of both
ACS Paragon Plus Environment
1
0

Page 11 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
ammonium hydroxide and UHP) we were able to isolate benzamide 3w in a good 59% yield,
being in addition, the only regioisomer observed.
Scheme 2. One-pot imine formation-oxidation sequence.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1) NH (aq.), (5 equiv.)
1) PhNH (1 equiv.)
3
2
Ph
NH2
30 min.
20 min.
Ph
Ph
N
PhCHO
O
CHO
2
) UHP (5 equiv.)
HFIP, 45 ºC
15 h
2) UHP (2 equiv.)
HFIP, 45 ºC
15 h
3w
2a
81% yield
5
9% yield
73% yield, 720 mg
using 5 mmol scale reaction
Finally, based on experimental evidences, a possible reaction mechanism was proposed as
depicted in Scheme 3. Firstly, the corresponding oxaziridine B would be formed thanks to the
1
3
electrophilic activation of hydrogen peroxide by HFIP which allows the nucleophilic attack of
the iminic nitrogen and subsequent oxaziridine formation from the oxime derivative A. The
formation of intermediate B is seemingly plausible from the fact that this kind of products have
been isolated, for example in compound 4o, 4r and 4v. From this intermediate, a Meinwald-type
rearrangement mediated by HFIP could occur rendering the expected amide. Although less
probable, a Beckmann-type rearrangement from intermediate A cannot be ruled out.
Scheme 3. Proposed reaction mechanism.
R3
R2
R1
H
N
R1
N
R3
R3
R3
-
H+
R1
H+
R1
R3
Meinwald
R2
R2
R2
R2
R1
H
N
N
N
Rearrangement
O
O
H
O O
+
O
H
O
- H
OH
B
A
F
F
CF3
F
CONCLUSIONS
ACS Paragon Plus Environment
1
1

The Journal of Organic Chemistry
Page 12 of 23
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In summary, we have developed an efficient and environmentally benign methodology for the
synthesis of formamides by means of the oxidation of aldimines using UHP as green oxidant.
The use of this safe and non-toxic oxidant in absence of any Lewis acid has been possible
because the presence of HFIP as solvent and reaction mediator. The peculiar properties of such
fluorinated alcohols allow the electrophilic activation of hydrogen peroxide which is crucial for
the reaction to proceed. The corresponding formamides 2 were obtained generally in good yields
under smooth reaction conditions. However, the formation of the corresponding aryl amides 3 or
oxaziridines 4 was also observed for imines derived from electron-poor aldehydes or
cyclohexanamine, respectively. The one-pot imine formation-oxidative rearrangement sequence
has been also described obtaining good results even when a big-scale reaction was performed. In
this regard this one-pot sequence allowed the synthesis of benzamide in good yields using
benzaldehyde and aqueous ammonia which to the best of our knowledge represents the first
example of this transformation in absence of metal or Lewis acid catalysts. Finally, the
mechanism was proposed to proceed via formation of the corresponding oxaziridine and
subsequent rearrangement.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EXPERIMENTAL SECTION
General Remarks:
All reagents and solvents were obtained commercially and used without further purification.
Substrates that were not commercially available were synthesized according to known literature
procedures.
NMR spectra were performed on a Bruker AV-300 or Bruker AV-400 (Bruker Corporation)
using CDCl as solvent and TMS as internal standard unless otherwise stated.
3
ACS Paragon Plus Environment
1
2

Page 13 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Low resolution mass spectra (MS) were recorded in the electron impact mode (EI, 70 eV, He as
carrier phase) using an Agilent GC/MS 5973 Network Mass Selective Detector spectrometer
apparatus equipped with a HP-5MS column (Agilent technologies, 30 m × 0.25 mm) and giving
fragment ions in m/z with relative intensities (%) in parentheses.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Analytical TLC was performed on Merck silica gel plates and the spots visualized with UV light
at 254 nm. Flash chromatography employed Merck silica gel 60 (0.040-0.063 mm). Silica gel 60
F254 containing gypsum was employed for preparative layer chromatography.
General Procedure for the Oxidation Reaction of Imines
In a capped tube, onto the corresponding imine (0.15 mmol), HFIP (150 L) and UHP (2.0
equiv.) were added in one portion. The reaction was then stirred at 45 ºC in a sand bath for 15
hours, until the reaction was judged to be completed by GC-MS. After this time, the reaction
mixture was filtered over silica/celite plug and then the solvent was evaporated and the crude
material was directly purified by flash chromatography or preparative TLC using hexane/ethyl
acetate mixtures.
Spectroscopic and analytical data for isolated compounds are given below:
N,N-Diphenylformamide (2a):14 Slightly yellow solid; purification by preparative TLC
1
(
hexane/ethyl acetate 8.0/2.0), 29.0 mg, 89% yield; H NMR (400 MHz, CDCl ): δ = 8.69 (s,
3
H
1
3
1H), 7.46 – 7.39 (m, 4H), 7.37 – 7.27 (m, 4H), 7.23 – 7.16 (m, 2H) ppm; C{H} NMR (101
MHz, CDCl ): δ = 161.8, 141.7, 139.6, 129.7, 129.2, 127.1, 126.9, 126.1, 125.1 ppm; MS (EI):
3
C
+
m/z 197 (M , 100%), 169 (58), 168 (79), 167 (45), 104 (12), 77 (17), 66 (19), 51 (13).
ACS Paragon Plus Environment
1
3

The Journal of Organic Chemistry
Page 14 of 23
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
N-Phenyl-N-(p-tolyl)formamide (2b):15 Dark orange oil; purification by preparative TLC
1
(
hexane/ethyl acetate 8.0/2.0), 25.3 mg, 82% yield, mixture of rotamers; H NMR (300 MHz,
CDCl ): δ = 8.69 (s, 1H), 8.64 (s, 1H), 7.47 – 7.35 (m, 5H), 7.35 – 7.26 (m, 5H), 7.24 (s, 2H),
3
H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
7
.20 – 7.14 (m, 4H), 7.13 – 7.05 (m, 2H), 2.39 (s, 3H), 2.37 (s, 3H) ppm; C{H} NMR (75
MHz, CDCl ): δ = 161.8, 141.9, 139.8, 139.2, 137.2, 136.9, 130.3, 129.8, 129.6, 129.1, 126.8,
3
C
+
1
1
26.6, 126.2, 125.8, 125.3, 124.7, 29.7, 21.1, 20.9 ppm; MS (EI): m/z 211 (M , 100%), 183 (68),
82 (75), 180 (14), 168 (11), 167 (38), 108 (13), 91 (18), 80 (13), 77 (17).
N-(4-Acetylphenyl)-N-phenylformamide (2d):16 White solid; purification by preparative TLC
1
(
hexane/ethyl acetate 8.5/1.5), 22.2 mg, 62% yield; mixture of rotamers; H NMR (400 MHz,
CDCl ): δ = 8.83 (s, 1H), 8.66 (s, 1H), 8.17 – 8.09 (m, 2H), 8.06 – 7.94 (m, 7H), 7.95 – 7.86 (m,
3
H
2
7
1
H), 7.80 (d, J = 8.8 Hz, 1H), 7.60 (ddd, J = 8.8, 5.0, 1.6 Hz, 1H), 7.56 – 7.35 (m, 11H), 7.25 –
1
3
.20 (m, 4H), 2.62 (s, 4H), 2.61 (s, 4H) ppm; C{H} NMR (101 MHz, CDCl ): δ = 161.8,
3
C
61.3, 132.3, 130.0, 129.9, 129.8, 129.5, 129.4, 129.3, 128.9, 128.4, 127.9, 127.7, 127.1, 126.8,
+
126.1, 124.9, 123.4, 123.2, 119.3, 26.8, 26.6 ppm; MS (EI): m/z 239 (M , 100%), 196 (72), 167
(58), 121 (23), 77 (12).
1
6
N-(4-Methoxyphenyl)-N-phenylformamide (2e): Dark yellow solid; purification by preparative
1
TLC (hexane/ethyl acetate 8.5/1.5), 36.1 mg, 87% yield, mixture of rotamers; H NMR (400
MHz, CDCl ): δ = 8.69 (s, 1H), 8.59 (s, 1H), 7.46 – 7.35 (m, 4H), 7.34 – 7.30 (m, 3H), 7.26 –
3
H
7
.19 (m, 3H), 7.19 – 7.12 (m, 4H), 6.95 (dd, J = 8.9, 1.3 Hz, 4H), 6.79 (d, J = 1.0 Hz, 1H), 3.85
1
3
(
s, 3H), 3.83 (s, 3H) ppm; C{H} NMR (101 MHz, CDCl ): δ = 161.9, 161.9, 129.6, 129.1,
3 C
127.7, 127.2, 126.7, 126.5, 125.4, 124.4, 114.9, 114.5, 55.5, 55.4 ppm; MS (EI): m/z 277 (M+,
1
00%), 206 (32), 199 (17), 184 (76), 154 (20), 124 (13), 76 (11).
ACS Paragon Plus Environment
1
4

Page 15 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
N-(4-Chlorophenyl)-N-phenylformamide (2g):17 Brown solid; 30.4 mg, 88% yield (without
1
further purification); H NMR (400 MHz, CDCl ): δ = 8.65 (d, J = 2.6 Hz, 1H), 7.49 – 7.36 (m,
3
H
1
3
5H), 7.30 – 7.24 (m, 2H), 7.19 (dd, J = 5.3, 3.3 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H) ppm; C{H}
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (101 MHz, CDCl ): δ = 161.8, 161.5, 141.2, 140.3, 139.2, 138.1, 132.9, 132.4, 129.9,
3
C
+
1
29.4, 129.3, 127.5, 127.3, 127.2, 126.1, 126.1, 125.3 ppm; MS (EI): m/z 231 (M , 100%), 205
(20), 204 (11), 203 (60), 168 (49), 167 (84), 166 (17), 77 (11), 66 (12).
N-Phenyl-N-[4-(trifluoromethyl)phenyl]formamide (2h): white sticky solid; purification by
preparative TLC (hexane/ethyl acetate 8.0/2.0), 36.1 mg, 91% yield, mixture of rotamers (and
1
regioisomer 3h);only the signals for the major isomer 2h are given: H NMR (400 MHz, CDCl ):
3
δH = 8.78 (s, 1H), 8.66 (s, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.66 (dd, J =
1
1.1, 8.7 Hz, 8H), 7.51 – 7.35 (m, 15H), 7.27 (dd, J = 7.6, 3.9 Hz, 5H), 7.21 (d, J = 7.6 Hz, 5H)
1
3
ppm; C{H} NMR (101 MHz, CDCl ): δ = 164.4, 161.7, 161.2, 144.9, 142.8, 140.8, 138.7,
3
C
1
38.3, 137.6, 133.6, 130.0, 129.5, 129.1, 128.5, 128.1, 127.9, 127.7, 127.6, 126.9, 126.8, 126.7,
126.2, 126.2, 125.9, 125.8, 125.7, 125.4, 124.9, 124.0, 122.5, 120.4 ppm; MS (EI): m/z 265 (M+,
1
00%), 237 (73), 236 (34), 216 (17), 168 (16), 167 (42), 77 (11), 66 (13); HRMS (GC/MS-EI/Q-
TOF): m/z calcd. for C H F NO 265.0714, found 265.0717.
1
4
10 3
N-(2-Methoxyphenyl)-N-phenylformamide (2j): Dark orange oil; purification by preparative TLC
1
(
hexane/ethyl acetate 8.0/2.0), 31.1 mg, 90% yield, mixture of rotamers; H NMR (400 MHz,
CDCl ): δ = 8.57 (s, 1H), 8.26 (s, 1H), 7.31 – 7.21 (m, 4H), 7.17 – 7.01 (m, 6H), 6.93 (d, J =
3
H
1
3
8.3 Hz, 3H), 3.69 (s, 3H.), 3.69 (s, 3H) ppm; C{H} NMR (101 MHz, CDCl ): δ = 163.42,
3
C
1
1
62.41, 155.6, 155.1, 141.6, 140.0, 129.9, 129.8, 129.7, 129.6, 129.5, 129.4, 128.8, 127.5, 126.4,
26.2, 124.8, 123.1, 121.2, 112.5, 112.4, 55.7 ppm; MS (EI): m/z 227 (M+, 53%), 200 (11), 199
ACS Paragon Plus Environment
1
5

The Journal of Organic Chemistry
Page 16 of 23
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
71), 185 (14), 184 (100), 183 (23), 167 (16), 166 (14), 156 (24), 129 (25), 128 (17), 77 (15), 51
11); HRMS (GC/MS-EI/Q-TOF): m/z calcd. for C H NO 227.0946; found 227.0939.
(
1
4
13
2
N,N-Di-p-tolylformamide (2k):18 Slightly orange solid; purification by preparative TLC
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
(hexane/ethyl acetate 8.0/2.0), 26.8 mg, 79% yield; H NMR (400 MHz, CDCl ): δ = 8.63 (s,
3
H
1
3
1
H), 7.21 (t, J = 5.5 Hz, 6H), 7.07 (d, J = 8.3 Hz, 2H), 2.39 (s, 3H), 2.37 (s, 3H) ppm; C{H}
NMR (101 MHz, CDCl ): δ = 161.8, 139.4, 137.2, 136.9, 136.7, 130.2, 129.7, 125.8, 124.9,
3
C
+
2
1.0, 20.9 ppm; MS (EI): m/z 225 (M , 100%), 197 (65), 196 (69), 181 (23), 180 (29), 108 (20),
9
1 (19), 80 (20), 65 (13).
1
9
N-Phenyl-3-pyridinecarboxamide (3m): Dark orange solid; purification by preparative TLC
(hexane/ethyl acetate 8.0/2.0), 20.5 mg, 72% yield (90:10 isomeric mixture), only the major
1
isomer signals are given; H NMR (400 MHz, CDCl ): δ = 9.10 (s, 1H), 8.75 (d, J = 3.6 Hz,
3
H
1
H), 8.39 (s, 1H), 8.23 (dt, J = 7.9, 1.8 Hz, 1H), 7.66 (d, J = 7.9 Hz, 2H), 7.47 – 7.35 (m, 3H),
1
3
7
.19 (t, J = 7.4 Hz, 1H) ppm; C{H} NMR (101 MHz, CDCl ): δ = 163.9, 152.2, 147.8, 137.5,
3
C
+
135.6, 130.9, 129.2, 125.1, 123.7, 120.5 ppm; MS (EI): m/z 198 (M , 61%), 197 (16), 106 (100),
7
8 (54), 51 (17).
2
0
N-Butylbenzamide (3n): White solid; purification by preparative TLC (hexane/ethyl acetate
1
8.0/2.0), 15.5 mg, 57% yield (not pure isolated); H NMR (400 MHz, CDCl ): δ = 7.81 – 7.73
3
H
(m, 2H), 7.50 (dd, J = 5.0, 3.7 Hz, 1H), 7.47 – 7.42 (m, 2H), 6.10 (s, 1H), 3.54 – 3.44 (m, 2H),
1
.71 – 1.58 (m, 2H), 1.45 (dd, J = 15.1, 7.4 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H) ppm; MS (EI): m/z
+
177 (M , 11%), 135 (20), 134 (19), 105 (100), 77 (33).
2
-Cyclohexyl-3-phenyl-1,2-oxaziridine (4o):21 White solid; purification by preparative TLC
1
(hexane/ethyl acetate 8.5/1.5), 26.8 mg, 98% yield; H NMR (400 MHz, CDCl ): δ = 7.47 –
3
H
ACS Paragon Plus Environment
1
6

Page 17 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7
1
.43 (m, 1H), 7.42 – 7.38 (m, 1H), 4.55 (s, 1H), 2.16 – 2.05 (m, 1H), 1.90 – 1.80 (m, 1H), 1.78 –
.72 (m, 1H), 1.70 – 1.56 (m, 1H), 1.47 (ddd, J = 23.0, 12.2, 3.8 Hz, 1H), 1.39 – 1.21 (m, 2H)
1
3
ppm; C{H} NMR (101 MHz, CDCl ): δ = 135.3, 129.9, 128.5, 127.4, 79.8, 70.2, 31.6, 29.2,
3
C
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
2
5.7, 24.6, 24.1 ppm; MS (EI): m/z 203 (M , 40%), 122 (78), 105 (100), 77 (42).
N-Cyclohexyl-N-phenylformamide (2q):16 Orange oil; purification by preparative TLC
1
(hexane/ethyl acetate 8.5/1.5), 25.9 mg, 84% yield; H NMR (400 MHz, CDCl ): δ = 8.17 (s,
3
H
1
1
1
H), 7.51 – 7.36 (m, 3H), 7.23 – 7.12 (m, 2H), 4.54 – 4.27 (m, 1H), 1.88 (d, J = 12.2 Hz, 2H),
.78 (d, J = 13.8 Hz, 2H), 1.66 – 1.57 (m, 1H), 1.47 – 1.25 (m, 5H), 1.01 (qt, J = 12.9, 3.7 Hz,
1
3
H) ppm; C{H} NMR (101 MHz, CDCl ): δ = 162.6, 138.6, 129.3, 129.1, 128.2, 53.7, 31.4,
3
C
+
25.7, 25.3 ppm; MS (EI): m/z 203 (M , 15%), 160 (16), 132 (17), 122 (13), 121 (100), 93 (34),
7
7 (15).
2
,3-Dicyclohexyl-1,2-oxaziridine (4r): White solid; purification by preparative TLC
1
(hexane/ethyl acetate 8.0/2.0), 28.5 mg, 95% yield; m.p. 48-49 ºC; H NMR (400 MHz, CDCl ):
3
δH = 3.48 (d, J = 6.6 Hz, 1H), 1.99 (d, J = 13.4 Hz, 1H), 1.86 – 1.71 (m, 8H), 1.71 – 1.57 (m,
1
3
4
2
H), 1.35 – 1.12 (m, 8H) ppm; C{H} NMR (101 MHz, CDCl ): δ = 85.3, 69.3, 40.2, 31.6,
3 C
+
90, 27.7, 27.5, 26.3, 25.7, 25.2, 24.5, 23.9 ppm; MS (EI): m/z 209 (M , 30%), 192 (19), 154
(
23), 150 (18), 138 (42), 128 (98), 127 (18), 126 (48), 125 (44), 110 (42), 98 (18), 95 (28), 84
22), 83 (79), 82 (33), 81 (18), 68 (14), 67 (52), 56 (39), 55 (100), 54 (55); HRMS (GC/MS-
(
EI/Q-TOF): m/z calcd. for C H NO 209.1780, found 209.1778.
13 23
2-Cyclohexyl-1-oxa-2-azaspiro[2.5]octane (4v): Slightly yellow oil; purification by flash
chromatography (hexane/ethyl acetate 8.0/2.0), 25.7 mg, 95% estimated yield (not pure isolated);
1
H NMR (300 MHz, CDCl ): δ = 2.55 – 2.27 (m, 1H), 1.97 – 1.77 (m, 4H), 1.75 – 1.55 (m, 6H),
3
H
1
3
1.54 – 1.38 (m, 3H), 1.34 – 1.16 (m, 6H) ppm; C{H} NMR (75 MHz, CDCl ): δ = 85.1, 60.2,
3
C
ACS Paragon Plus Environment
1
7

The Journal of Organic Chemistry
Page 18 of 23
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
3
1
6.6, 31.9, 29.7, 29.2, 27.8, 25.7, 25.5, 25.4, 24.9, 24.4, 24.2 ppm; MS (EI): m/z 195 (M , 15%),
79 (20), 178 (34), 152 (15), 138 (12), 136 (25), 114 (100), 113 (11), 98 (47), 97 (12), 96 (20),
83 (16), 82 (15), 81 (21), 69 (18), 67 (24), 56 (13), 55 (52), 54 (20); HRMS (GC/MS-EI/Q-TOF):
m/z calcd. for C H NO 195.1623, found 195.1625.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
21
2
2
Benzamide (3w): White solid; purification by preparative TLC (hexane/ethyl acetate 9.0/1.0),
1
1
2
2.3 mg, 59% yield; H NMR (400 MHz, DMSO-d ): δ = 7.99 (s, 1H), 7.88 (dd, J = 5.3, 3.4 Hz,
6
H
1
3
H), 7.51 (ddd, J = 6.3, 3.7, 1.3 Hz, 1H), 7.48 – 7.41 (m, 2H), 7.38 (s, 1H) ppm; C{H} NMR
+
(
101 MHz, DMSO-d ): δ = 168.4, 134.7, 131.7, 128.6, 127.9 ppm; MS (EI): m/z 121 (M ,
6
C
8
4%), 105 (100), 77 (83), 51 (25).
ASSOCIATED CONTENT
Supporting Information.
The following files are available free of charge.
Copies of NMR spectra for all isolated compounds.
AUTHOR INFORMATION
Corresponding Author
*E-mail: alex.baeza@ua.es.
ORCID: 0000-0002-6230-1162.
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
ACS Paragon Plus Environment
1
8

Page 19 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
We would like to thank the Spanish Ministerio de Economía, Industria y Competitividad
(CTQ2015-66624-P and CTQ2017-88171-P) and Spanish Ministerio de Ciencia, Innovación y
Universidades (PGC2018-096616-B-I00) and the University of Alicante (VIGROB-316/19,
UADIF19-106) for the financial support.
REFERENCES
(1)
Jackson, A.; Meth-Cohn, O. A New Short and Efficient Strategy for the Synthesis of
Quinolone Antibiotics. J. Chem. Soc., Chem. Commun. 1995, 1319-1320.
(2)
Chen, B. C.; Bednarz, M. S.; Zhao, R.; Sundeen, J. E.; Chen, P.; Shen, Z.; Skoumbourdis,
A. P.; Barrish, J. C. A New Facile Method for the Synthesis of 1-Arylimidazole-5-carboxylates.
Tetrahedron Lett. 2000, 41, 5453-5456.
(3)
Kobayashi, K.; Nagato, S.; Kawakita, M.; Morikawa, O.; Konishi, H. Synthesis of 1-
Formyl-1,2-dihydroquinoline Derivatives by a Lewis Acid-Catalyzed Cyclization of o-(1-
Hydroxy-2-alkenyl)phenyl Isocyanides. Chem. Lett. 1995, 575-576.
(4)
(a) Kobayashi, S.; Nishio, K. Facile and Highly Stereoselective Synthesis of Homoallylic
Alcohols Using Organosilicon Intermediates. J. Org. Chem. 1994, 59, 6620-6628. (b)
Kobayashi, S.; Yasuda, M.; Hachiya, I. Trichlorosilane-Dimethylformamide (Cl SiH-DMF) as
3
an Efficient Reducing Agent. Reduction of Aldehydes and Imines and Reductive Amination of
Aldehydes under Mild Conditions Using Hypervalent Hydridosilicates. Chem. Lett. 1996, 407-
4
08.
(5)
Downie, I. M.; Earle, M. J.; Heaney, H.; Shuhaibar, K. F. Vilsmeier Formylation and
Glyoxylation Reactions of Nucleophilic Aromatic Compounds Using Pyrophosphoryl Chloride.
Tetrahedron. 1993, 49, 4015-4034.
ACS Paragon Plus Environment
1
9

The Journal of Organic Chemistry
Page 20 of 23
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
6)
(a) Tanaka, N.; Tsutsumi, R.; Uraguchi, D.; Ooi, T. N-Sulfonyl α-Imino Ester-Derived
Chiral Oxaziridines: Catalytic Asymmetric Synthesis and Application as a Modular Chiral
Organic Oxidant. Chem. Commun. 2017, 53, 6999-7002. (b) Ji, N.; Yuan, J.; Xue, S.; Zhang, J.;
He, W. Novel Chiral Thiourea Organocatalysts for the Catalytic Asymmetric Oxaziridination.
Tetrahedron. 2016, 72, 512-517. (c) Kraïem, J.; Ghedira, D.; Ollevier, T. Hydrogen
Peroxide/Dimethyl Carbonate: a Green System for Epoxidation of N-Alkylimines and N-
Sulfonylimines. One-pot Synthesis of N-Alkyloxaziridines from N-Alkylamines and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Hetero)aromatic Aldehydes. Green Chem. 2016, 18, 4859-4864. (d) Jin, Y.; Zhang, T.; Zhang,
W.; Chang, S.; Feng, B. Enantioselective Organocatalytic Oxaziridination of N‐Tosyl Aldimine
Catalyzed by Cinchona Alkaloid‐Ester Derivatives. Chirality, 2014, 26, 150-154. (e) Tsutsumi,
R.; Kim, S.; Uraguchi, D.; Ooi, T. The Practical Preparation of Chiral N-Sulfonyl Oxaziridines
via Catalytic Asymmetric Payne Oxidation. Synthesis. 2014, 46, 871-878. (f) Zhang, T.; He, W.;
Zhao, X.; Jin, Y. Asymmetric Oxaziridination Catalyzed by Cinchona Alkaloid Derivatives
Containing Sulfide. Tetrahedron. 2013, 69, 7416-7422. (g) Uraguchi, D.; Tsutsumi, R.; Ooi, T.
Catalytic Asymmetric Oxidation of N-Sulfonyl Imines with Hydrogen Peroxide–
Trichloroacetonitrile System. J. Am. Chem. Soc. 2013, 135, 8161-8164 and references cited
therein.
(7)
(a) De Souza, G. F. P.; von Zuben, T. W.; Salles Jr, A. G. “On Water” Metal-Catalyst-
Free Oxidative Coupling–Amidation of Amines To Access Imines and Amides. ACS Sustainable
Chem. Eng. 2017, 5, 8439-8446. (b) Rostamnia, S.; Doustkhah, E.; Golchin-Hosseini, H.;
Zeynizadeh, B.; Xin, H.; Luque, R. Efficient Tandem Aqueous Room Temperature Oxidative
Amidations Catalysed by Supported Pd Nanoparticles on Graphene Oxide. Catal. Sci. Technol.
2
016, 6, 4124-4133. (c) Liang, J.; Lv, J.; Shang, Z.-C. Metal-Free Synthesis of Amides by
Oxidative Amidation of Aldehydes with Amines in PEG/Oxidant System. Tetrahedron. 2011,
7, 8532-8535. (d) Mohamed, M. A.; Yamada, K.-I.; Tomioka, K. Accessing the Amide
Functionality by the Mild and Low-Cost Oxidation of Imine. Tetrahedron Lett. 2009, 50, 3436-
438. (e) Leung, C. H.; Voutchkova, A. M.; Crabtree, R. H.; Balcells, D.; Eisenstein, O. Atom
6
3
Economic Synthesis of Amides via Transition Metal Catalyzed Rearrangement of Oxaziridines.
Green Chem. 2007, 9, 976-979. (f) Larsen, J.; Jørgensen, K. A.; Christensen, D. Duality of the
Permanganate Ion in the Oxidation of Imines. Oxidation of Imines to Amides J. Chem. Soc.,
Perkin Trans. 1, 1991, 5, 1187-1190.
ACS Paragon Plus Environment
2
0

Page 21 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(
8)
(a) An, G.-I.; Kim, M.; Kim. J. Y.; Rhee. H. Oxidation of Aldimines to Amides by m-
CPBA and BF ·OEt . Tetrahedron Lett. 2003, 44, 2183-2186. (b) Nongkunsarn, P.; Ramsden. C.
3
2
A. Oxidative Rearrangement of Imines to Formamides Using Sodium Perborate. Tetrahedron.
997, 53, 3805-3830. (c) Nongkunsarn, P.; Ramsden. C. A. An Oxidative Rearrangement of
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
C,N-Diarylaldimines to Formamides Using Sodium Perborate. Tetrahedron Lett. 1993, 34, 6773-
6776.
(
9)
Metal-Free Allylation of Silyl Enol Ethers with Allylic Alcohols. Asian J. Org. Chem. 2017, 6,
440-1444. (b) Trillo, P.; Baeza, A.; Nájera, C. Fluorinated Alcohols As Promoters for the
(a) Pérez, J. M.; Maquilón, C.; Ramón, D. J.; Baeza, A. Hexafluoroisopropanol-Promoted
1
Metal-Free Direct Substitution Reaction of Allylic Alcohols with Nitrogenated, Silylated, and
Carbon Nucleophiles. J. Org. Chem. 2012, 77, 7344-7354.
(10) For selected reviews about the use of fluorinated alcohols as promoters in organic
transformations, see: (a) An, X.-D.; Xiao, J. Fluorinated Alcohols: Magic Reaction Medium and
Promoters for Organic Synthesis. Chem. Rec. 2019, 19, 142-161. (b) Colomer, I.; Chamberlain,
A. E. R.; Haughey, M. B.; Donohoe, T. J. Hexafluoroisopropanol as a Highly Versatile Solvent.
Nat. Rev. Chem. 2017, 1, 0088. (c) Bégué, J.-P. ; Bonnet-Delpon, D.; Crousse, B. Fluorinated
Alcohols: A New Medium for Selective and Clean Reaction. Synlett 2004, 18-29.
(11) Llopis, N.; Baeza, A. Oxidation of Electron-Rich Arenes Using HFIP-UHP System. J.
Org. Chem. 2020, 85, 6159-6164.
(12) Berkessel, A. “Catalytic Oxidations with Hydrogen Peroxide in Fluorinated Alcohol
Solvents” Modern Oxidation Methods; Bäckvall, J.-E., Ed; Wiley-VCH: Weinheim, 2010, p 117.
(13) (a) Neimann, K.; Neumann, R. Electrophilic Activation of Hydrogen Peroxide: Selective
Oxidation Reactions in Perfluorinated Alcohol Solvents. Org. Lett. 2000, 2, 2861-2863. (b)
Berkessel, A.; Adrio, J. A. Dramatic Acceleration of Olefin Epoxidation in Fluorinated Alcohols:
Activation of Hydrogen Peroxide by Multiple H-Bond Networks. J. Am. Chem. Soc. 2006, 128,
1
3412-13420. (c) Berkessel,A.; Adrio, J. A.; Hüttenhain, D.; Neudörfl, J. M. Unveiling the
“
Booster Effect” of Fluorinated Alcohol Solvents: Aggregation-Induced Conformational
Changes and Cooperatively Enhanced H-Bonding. J. Am. Chem. Soc. 2006, 128, 8421-8426.
ACS Paragon Plus Environment
2
1

The Journal of Organic Chemistry
Page 22 of 23
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
14) Pathare, S. P.; Jain, A. K. H.; Akamanchi, K. G. Sulfated Tungstate: a Highly Efficient
Catalyst for Transamidation of Carboxamides with Amines. RSC Adv. 2013, 3, 7697-7703.
(15) Nongkunsarn, P.; Ramsden, C. A. Oxidative Rearrangement of Imines to Formamides
using Sodium Perborate. Tetrahedron 1997, 53, 3805-3830.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
16) Jiang, L. Copper/N,N-Dimethylglycine Catalyzed Goldberg Reactions Between Aryl
Bromides and Amides, Aryl Iodides and Secondary Acyclic Amides. Molecules 2014, 19,
3448-13460.
1
(17) Phillips, D. P.; Zhu, X. – F. Lau, T. L.; He, X.; Yang, K.; Liu, H. Copper-Catalyzed C–N
Coupling of Amides and Nitrogen-Containing Heterocycles in the Presence of Cesium Fluoride.
Tetrahedron 2009, 50, 7293-7296.
(18) Yang, S.; Li, P.; Wang, Z.; Wang, L. Photoinduced Oxidative Formylation of N,N-
Dimethylanilines with Molecular Oxygen without External Photocatalyst. Org. Lett. 2017, 19,
3386-3389.
(19) Martinelli, J. R.; Clark, T. P.; Watson, D. A.; Munday, R. H.; Buchwald, S. L. Palladium-
Catalyzed Aminocarbonylation of Aryl Chlorides at Atmospheric Pressure: The Dual Role of
Sodium Phenoxide. Angew. Chem. Int. Ed. 2007, 46, 8460 –8463.
(20) Sureshbabu, P.; Azeez, S.; Chaudharya; P.; Kandasamy, J. tert-Butyl Nitrite Promoted
Transamidation of Secondary Amides Under Metal and Catalyst Free Conditions. Org. Biomol.
Chem. 2019, 17, 845-850.
(21)
Singhal, S.; Jain, S. L.; Prasad, V. V. D. N.; Sain, B. An Environmentally Friendly
Oxidation System for the Selective Oxygenation of Aldimines to Oxaziridines with Anhydrous
TBHP and Alumina-Supported MoO as a Recyclable Heterogeneous Catalyst. Eur. J. Org.
3
Chem. 2007, 2051–2054.
(22) Chen, J.; Xia, Y.; Lee, S. Transamidation for the Synthesis of Primary Amides at Room
Temperature. Org. Lett. 2020, 22, 3504–3508.
ACS Paragon Plus Environment
2
2

Page 23 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment
2
3