Triflic Anhydride-Mediated Beckmann Rearrangement Reaction of β-Oximyl Amides: Access to 5-Iminooxazolines

Article abstract of DOI:10.1007/s12039-016-1085-1

Facile and efficient synthesis of 5-iminooxazolines from α,α-disubstituted β-oximyl amides mediated by triflic anhydride (Tf₂O) in the presence of 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) in dichloromethane at room temperature is developed, and

Full text of DOI:10.1007/s12039-016-1085-1

c
J. Chem. Sci. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-016-1085-1
Triflic Anhydride-Mediated Beckmann Rearrangement Reaction of
β-Oximyl Amides: Access to 5-Iminooxazolines
MANGFEI YUa, QIAN ZHANGb, JIA WANGb, PENG HUANGb, PENGFEI YANa,∗
,
RUI ZHANGb and DEWEN DONGb,∗
aSchool of Chemistry and Materials Science, Heilongjiang University, Harbin 150080, China
bKey Laboratory of Synthetic Rubber, Changchun Institute of Applied Chemistry,
Chinese Academy of Sciences, Changchun 130022, China
e-mail: yanpf@vip.sina.com; dwdong@ciac.ac.cn
MS received 19 January 2016; revised 14 March 2016; accepted 27 March 2016
Abstract. Facile and efficient synthesis of 5-iminooxazolines from α, α-disubstituted β-oximyl amides
mediated by triflic anhydride (Tf2O) in the presence of 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) in
dichloromethane at room temperature is developed, and a mechanism involving tandem Beckmann rearrange-
ment and intramolecular cyclization reaction is proposed.
Keywords. Beckmann rearrangement; cyclization; β-oximyl amides; oxazolines; triflic anhydride.
pyrazolin-5-ones (Path D)10 under varied conditions
(scheme 1). Contrary to those reported Beckmann rear-
rangement reactions mediated or catalyzed by the acti-
vation of the hydroxyl group by the p-toluenesulfonyl
or cyanuric chloride,4,11 the Beckmann rearrangement
reaction of β-oximyl amides 1 was not observed
under our tested conditions as described in scheme 1.
Very recently, we developed a facile synthesis of 2,3-
dihydrofuro[3,2-c]pyridin-4(5H)-ones by the reaction
of 1-aminopropenoyl cyclopropane-1-carboxamides in
the presence of triflic anhydride (Tf2O).12 In connec-
tion with these studies and our continuing interest in
the further synthetic potential of β-oximyl amides 1, we
investigated their reactivity toward triflic anhydride and
other organic anhydrides under different conditions. As
a result of this study, we achieved an efficient synthe-
sis of 5-iminooxazolines 2 (scheme 1, Path E) under
very mild conditions. In the present work, we wish to
report our experimental results and present a proposed
mechanism involved.
1. Introduction
The rearrangement of ketoximes to the corresponding
amides, known as the Beckmann reaction, is a classical
transformation in organic chemistry and continues to be
an active area of current research.1 In chemical indus-
try, it is successfully employed as a powerful tool for
the manufacturing ε-caprolactam.2 Unfortunately, the
conventional Beckmann rearrangement reaction usually
requires strong acid catalysts and harsh conditions, such
as high reaction temperature and dehydrating media,
which meanwhile releases quite a lot of acidic wastes.1,3
Therefore, mild and efficient organocatalysis of the
Beckmann rearrangement reaction has been developed
to overcome these drawbacks,4–6 and some Beckmann
rearrangement reactions have been realized in ionic
liquids at room temperature7 and supercritical water.8
Most reported mild conditions were still associated with
the use of rather toxic and/or expensive reagents or
solvents.1,3 The investigation of Beckmann rearrange-
ment reactions with the aim to obtain mild and efficient
conditions is still in demand.
2. Experimental
During the course our studies on the development of
synthetic methodologies for heterocycles from β-oxo
amide derivatives, we prepared a series of β-oximyl
amides 1 and investigated their reaction behavior under
different conditions, and achieved a divergent synthe-
sis of 5-chloro-1H-pyrazoles (Path A),9 5-arylamino-4-
haloethylisoxazoles (Path B and C),9,10 and spiro-fused
2.1 Reagents and Instrumentation
All reagents were purchased from commercial sources
and used without purification, unless otherwise indi-
cated. 1H NMR and 13C NMR spectra were recorded at
25◦C at 300 MHz (or 400 MHz) and 100 MHz, respec-
tively, with TMS as internal standard. IR spectra (KBr)
were recorded on FTIR-spectrophotometer in the range
∗For correspondence

Mangfei Yu et al.
61.16; H, 4.80; N, 11.88. MS calcd. m/z 234.1, found
235.1 [(M+1)+].
Colorless crystal, M = 234.68, Monoclinic, C2/c,
a = 23.827(6) Å, b = 7.4104(19) Å, c = 14.707(4)
Å, α = 90.00◦, β = 116.100(5)◦, γ = 90.00◦, V =
2332.0(11) Å3, Z = 8, T = 293, F000 = 976, R1 =
0.0553, wR2 = 0.2452.
2.3b (Z)-3-Chloro-N-(5-methyl-6-oxa-4-azaspiro[2.4]
hept-4-en-7-ylidene)aniline (2b): Colorless semi-solid;
1H NMR (400 MHz, CDCl3): δ = 1.54 (t, J = 3.5 Hz,
2H), 1.63 (d, J = 3.2, 2H), 2.18 (s, 3H), 6.98 (d, J =
8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H),
7.19 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3):
δ = 14.8, 18.9, 49.7, 121.1, 123.0, 124.3, 129.6, 134.1,
146.6, 162.0, 162.8. IR (KBr) 3145, 3021, 2938, 1702,
1617, 1488, 1406, 1253, 1038, 1012, 963, 922, 835, 684
cm−1; Anal. Calcd. (%) for C12H11ClN2O: C, 61.41; H,
4.72; N, 11.94; Found (%): C, 61.55; H, 4.75; N, 11.87.
Scheme 1. Reactions of α-Carbamoyl-α-Oximyl Cyclo-
propanes 1 under different conditions.
of 400-4000 cm−1. Melting points were uncorrected.
All reactions were monitored by TLC with GF254 sil-
ica gel-coated plates. Chromatography was carried out
on silica gel (300−400 mesh).
2.3c (Z)-2-Methyl-N-(5-methyl-6-oxa-4-azaspiro[2.4]
hept-4-en-7-ylidene)aniline(2e): Colorlessoil;1H NMR
(400 MHz, CDCl3): δ = 1.57 (t, J = 3.2 Hz, 2H), 1.64
(t, J = 3.2 Hz, 2H), 2.16 (s, 3H), 2.19 (s, 3H), 6.97-
7.04 (m, 2H), 7.15 (d, J = 7.6 Hz, 1H), 7.18 (d, J =
7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 14.9,
17.7, 18.6, 49.1, 121.1, 124.0, 126.0, 130.0, 130.1,
144.4, 161.1, 162.4; IR (KBr) 3138, 3014, 2946, 1789,
1721, 1633, 1488, 1425, 1402, 1274, 1039, 1014, 965,
926, 838, 691 cm−1; Anal. Calcd. (%) for C13H14N2O:
C, 72.87; H, 6.59; N, 13.07. Found (%): C, 73.05; H,
6.52; N, 13.02.
2.2 Typical procedure for the synthesis of 2 (2a as an
example)
To a solution of 1a (1.0 mmol) in DCM (5 mL) at room
temperature was added Tf2O (1.2 mmol) and DBU (1.2
mmol) in one portion. The mixture was stirred at room
temperature for 15 min, and then poured into brine (15
mL), which was extracted with DCM (3 × 10 mL). The
combined organic phases were washed with water (2 ×
10 mL), dried over MgSO4, filtered and concentrated in
vacuo. The crude product was purified by flash chro-
matography (silica gel, petroleum ether : ethyl acetate
= 10: 1) to give 2a as a white solid (0.208 g, 89%).
2.3d (Z)-N-(5-Phenyl-6-oxa-4-azaspiro[2.4]hept-4-en-
7-ylidene)aniline (2g): White solid, M.p. 117-119◦C;
1H NMR (400 MHz, CDCl3): δ = 1.72 (dd, J1 = 8.0
Hz, J2 = 4.4 Hz, 2H), 1.82 (dd, J1 = 8.0 Hz, J2 = 4.4
Hz, 2H), 7.17 (t, J = 7.3 Hz, 1H), 7.26 (d, J = 9.0 Hz,
2H), 7.39 (t, J = 7.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H),
2.3 Physical Data of Compounds 2 and 3
2a, 2c, 2d, 2f, 2h, 2i are known compounds, and their
analytical data are in good agreement with those in
literature [see ref. 14].
7.53 (t, J = 7.3 Hz, 1H), 7.94 (d, J = 7.3 Hz, 2H); 13
C
NMR (100 MHz, CDCl3): δ = 19.7, 19.8, 50.7, 123.1,
124.5, 126.4, 127.4, 128.7, 128.8, 132.0, 145.3, 161.2,
161.6; IR (KBr) 3136, 3018, 2964, 1797, 1712, 1641,
1488, 1422, 1400, 1269, 1039, 1016, 962, 921, 765,
692 cm−1; Anal. Calcd. (%) for C17H14N2O: C, 77.84;
H, 5.38; N, 10.68. Found (%): C, 77.64; H, 5.43; N,
10.75.
2.3a (Z)-4-Chloro-N-(5-methyl-6-oxa-4-azaspiro[2.4]
hept-4-en-7-ylidene)aniline (2a): White solid, M.p.
179-181◦C; 1H NMR (400 MHz, CDCl3): δ = 1.55 (t,
J = 3.6 Hz, 2H), 1.63 (t, J = 3.6 Hz, 2H), 2.20 (s, 3H),
7.06 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H);
13C NMR (100 MHz, CDCl3): δ = 14.9, 18.9, 49.8,
124.3, 128.8, 129.6, 143.9, 162.1, 162.4; IR (KBr)
3132, 3012, 2931, 1718, 1672, 1598, 1544, 1488, 1402, 2.3e (Z)-N-(4,4-Diallyl-2-methyloxazol-5(4H)-ylidene)
1240, 1083, 966, 918, 841, 653 cm−1; Anal. Calcd. for aniline (2j): Colorless oil; 1H NMR (400 MHz,
C12H11ClN2O: C, 61.41; H, 4.72; N, 11.94. Found: C, CDCl3): δ = 1.99 (s, 3H), 2.43-2.48 (m, 2H), 2.64-2.69

Triflic Anhydride-Mediated Beckmann Rearrangement
(m, 2H), 5.14-5.22 (m, 4H), 5.57-5.67 (m, 2H), 7.10- 3134, 3029, 2916, 1704, 1591, 1487, 1400, 1085, 871,
7.13 (m, 1H), 7.16 (d, J = 7.6 Hz, 2H), 7.33 (t, J = 840, 777, 703 cm−1; Anal. Calcd. (%) for C24H22N2O:
7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ = 11.0, C, 81.33; H, 6.26; N, 7.90. Found (%): C, 81.52; H,
40.5, 58.5, 119.7, 122.6, 124.2, 128.6, 130.9, 145.5, 6.16; N, 7.95.
162.9, 165.0; IR (KBr) 3138, 3022, 2914, 1703, 1618,
1594, 1523, 1485, 1411, 1087, 885, 843, 706 cm−1;
Anal. Calcd. (%) for C16H18N2O: C, 75.56; H, 7.13; N,
11.01. Found (%): C, 75.42; H, 7.17; N, 10.93.
2.3h 4-Benzyl-2-methyl-N-phenyloxazol-5-amine (3m):
1
White solid, M.p. 134-137◦C; H NMR (300 MHz,
CDCl3): δ = 2.16 (s, 3H), 3.65 (s, 2H), 5.72 (s, 1H),
6.93-6.99 (m, 3H), 7.16-7.21 (m, 4H), 7.28-7.36 (m,
3H); 13C NMR (100 MHz, CDCl3) δ = 9.6, 26.9, 94.1,
115.9, 120.9, 125.7, 127.2, 127.8, 128.2, 137.1, 138.9,
160.0, 160.9; IR (KBr) 3131, 3036, 2927, 1715, 1642,
1583, 1478, 1393, 1094, 868, 832, 759, 696 cm−1; Anal.
Calcd. (%) for C17H16N2O: C, 77.25; H, 6.10; N, 10.60.
Found (%): C, 77.03; H, 6.19; N, 10.49.
2.3f (Z)-N-(2-Methyl-4,4-di(prop-2-yn-1-yl)oxazol-
5(4H)-ylidene)aniline (2k): Colorless oil; H NMR
1
(400 MHz, CDCl3): δ = 2.16-2.17 (m, 5H), 2.71-2.72
(m, 4H), 7.15 (t, J = 7.2 Hz, 1H), 7.24 (d, J = 7.6 Hz,
2H), 7.36 (t, J = 7.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ = 11.3, 25.6, 57.0, 72.3, 77.0, 122.8, 124.6,
128.6, 144.9, 161.6, 163.8; IR (KBr) 3135, 3027, 2921,
1698, 1609, 1562, 1485, 1403, 1092, 876, 837, 768,
705 cm−1; Anal. Calcd. (%) for C16H14N2O: C, 76.78;
H, 5.64; N, 11.19. Found (%): C, 76.60; H, 5.70; N,
11.29.
3. Results and Discussion
The substrates, β-oximyl amides 1, were prepared
by the reaction of β-oxo amides with hydroxylamine
(NH2OH.HCl) in the presence of NaOAc in methanol
2.3g (Z)-N-(4,4-Dibenzyl-2-methyloxazol-5(4H)-
ylidene)aniline (2l): White solid, M.p. 102-103◦C; 1H at room temperature in high yields.9 We selected N-(4-
NMR (400 MHz, CDCl3): δ = 2.14 (s, 3H), 3.14 (d, chlorophenyl)-1-[1-(hydroxyimino)ethyl]cyclopropane
J = 13.6 Hz, 2H), 3.46 (d, J = 13.6 Hz, 2H), 7.13 (t, carboxamide 1a as the model compound and exam-
J = 7.2 Hz, 3H), 7.21-7.30 (m, 10H), 7.33 (t, J = ined its behavior in the presence of triflic anhydride.
8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 12.3, Upon treatment of 1a with triflic anhydride (1.2 equiv.)
43.2, 62.4, 120.0, 122.9, 124.5, 127.5, 128.6, 128.8, in dichloromethane (DCM) at room temperature for
129.4, 134.9, 136.0, 145.3, 162.8, 164.2; IR (KBr) 60 min, the reaction proceeded as indicated by TLC,
Table 1. Reaction of 1a under different conditions.a
Entry Reagent (equiv)b Base (equiv)c Solvent Temp (◦C) Time (min) Yield(%)d
1
2
3
4
5
6
7
8
Tf2O(1.2)
Tf2O(1.2)
Tf2O(1.2)
Tf2O(1.2)
Tf2O(1.2)
Tf2O(1.2)
Tf2O(1.0)
Tf2O(1.2)
Tf2O(1.2)
Tf2O(1.2)
Ac2O(1.2)
TFAA(1.2)
TfOH(1.2)
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
rt
rt
40
0
rt
rt
rt
rt
rt
rt
rt
60
15
15
15
5
60
10
10
30
30
18
20
60
58
80
89
Et3N(1.2)
DBU(1.2)
Py(1.2)
mixture
90
DBU(1.2)
DBU(1.2)
DBU(1.2)
DBU(1.0)
DBU(1.2)
DBU(1.2)
DBU(1.2)
DBU(1.2)
DBU(1.2)
67
85
81
58
62
83
9
10
11
12
13
76
n.r.e
aReagents and conditions: 1a (1.0 mmol), solvent (5.0 mL). bTFAA: trifluoroacetic
anhydride; Ac2O: acetic anhydride; TfOH: trifluoro-methanesulfonic acid. cDBU: 1,8-
diazabicyclo(5.4.0)undec-7-ene; Py: pyridine. dIsolated yield for 2a. eNo reaction.

Mangfei Yu et al.
and furnished one product after workup and purifica- reaction was even observed when 1a was subjected to
tion by silica column chromatography. The product TfOH (table 1, entry13).
was characterized as 4-chloro-N-(5-methyl-6-oxa-4-
Under the conditions as for 2a in entry 3 (table 1), a
azaspiro[2.4]hept-4-en-7-ylidene) aniline 2a based on series of reactions of α-carbamoyl-α-oximyl cyclopro-
its spectral and analytical data, (table 1, entry 1). Then, panes 1 and Tf2O and DBU were carried out, and some
we briefly examined the effect of different acidic/basic of the results are listed in table 2. It was observed that
reagents and their loaded amounts, solvents, and tem- the reactions of α-carbamoyl-α-oximyl cyclopropanes
perature on the success of the cyclization reaction to 2a. 1b-f bearing varied electron-withdrawing and electron-
It was found that the yield of 2a could reach 80% when donating aryl amide groups proceeded efficiently to
the reaction was performed with triethylamine (NEt3) afford the corresponding 5-iminooxazolines 2b-f in
(table 1, entry 2). Subjecting 1a, Tf2O (1.2 equiv.) and good to high yields (table 2, entries 2-6). The versatil-
DBU (1.2 equiv.) to DCM, the reaction could afford 2a ity of the 5-iminooxazoline synthesis was further eval-
in 89% yield (table 1, entry 3). However, a complex uated by reacting 1g bearing phenyl group R with Tf2O
mixture was formed when the reaction of 1a and Tf2O and DBU in DCM (table 2, entry 7). The structure of 2a
was conducted in pyridine (table 1, entry 4). Recently, was further elucidated by X-ray single crystal analysis
Wray and co-workers discovered that the base played a as shown in figure 1. It should be mentioned that most
key role on the reaction of a ketoximes with an adjacent recently Li and co-workers conducted the reaction of α-
amino group to selectively produce N-arylindazoles or carbamoyl-α-oximyl cyclopropanes in the presence of
benzimidazoles, and the stronger bases favoured the DAST (diethylaminosulfur trifluride), and obtained the
formation of benzimidazole products via the Beckmann same compound 2a.14
rearrangement reaction.13 Our results are consistent
The efficiency of the synthesis of 5-iminooxazolines
with their discovery. It was observed that the increase 2 was next examined by subjecting α, α-disubstituted
of reaction temperature to 40◦C had no significant β-oximyl amides 1h-l to the cyclization reaction under
influence on the yield of 2a, but did reduce the reaction identical conditions. It was found that the reactions
time (table 1, entry 5), whereas the reaction required could furnish the corresponding 5-iminooxazolines 2h-
prolonged reaction time along with lower yield when l in good to high yields (table 3, entries 1-5). To the best
performed at 0◦C (table 1, entry 6). The decrease of of our knowledge, this is the first example for the
loading of either Tf2O or DBU would result in slightly triflic anhydride-mediated Beckmann Rearrangement
lower yield of 2a (table 1, entries 7 and 8). The reaction reaction of ketoximes. In comparison to the conventio
of 1a with Tf2O could take place in THF or CH3CN, nal Beckmann rearrangement reaction of ketoximes, our
but the yields of 2a were not good in comparison to protocol is associated with very mild conditions, such
that in DCM (table 1, entries 9 and 10). The experi- as room temperature, short reaction time of less than an
ments revealed that Tf2O was most effective among hour, simple execution and no strong acid was required.
those tested anhydrides (table 1, entries 11 and 12). No
To expand the general applicability of the synthesis
of 5-iminooxazolines 2, we also carried out the reac-
tion of α-monosubstituted β-oximyl amides 1m in the
same fashion. The reaction could proceed smoothly
and furnished a product, which was characterized as
4-benzyl-2-methyl-N-phenyloxazol-5-amine 3m based
on its spectral and analytical data (scheme 2). Obvi-
ously, product 3m is the isomer of the corresponding
Table 2. Synthesis of 5-Iminooxazolines 2 from α-
Carbamoyl-α-Oximyl Cyclopropanes 1a.
Entry
1
Ar
R
2
Yield(%)b
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
4-ClC6H4
3-ClC6H4
4-MeC6H4
2,4-Me2C6H3
2-MeC6H4
Ph
Me
Me
Me
Me
Me
Me
Ph
2a
2b
2c
2d
2e
2f
89
85
83
74
75
83
66
1g
Ph
2g
aReagents and conditions: 1 (1.0 mmol), Tf2O (1.2 mmol),
DBU (1.2 mmol), DCM (5.0 mL), r.t., 15-30 min. bIsolated
yield.
Figure 1. ORTEP drawing of 2a.

Triflic Anhydride-Mediated Beckmann Rearrangement
Table 3. Synthesis of 5-iminooxazolines 2 from α, α-
Disubstituted β-Oximyl Amides 1.a
as depicted in scheme 3. In the presence of DBU,
tosylation of β-oximyl amide 1 occurs to give an inter-
mediate A,18 which undergoes the Beckmann rear-
rangement reaction to afford intermediate B,19 followed
by intramolecular cyclization to form substituted 5-
iminooxazoline of type 2.
4. Conclusions
Entry
1
Ar
R1
R2
2
Yield(%)b
In summary, a facile and efficient one-pot synthesis of
5-iminooxazolines 2 is developed via triflic anhydride-
mediated Beckmann rearrangement reaction of readily
available β-oximyl amides 1. The protocol was success-
fully expanded to the synthesis of 5-aminooxazoles 3.
The ready availability of substrates, mild reaction con-
ditions, simple execution, and synthetic potential of the
products make this novel protocol very attractive.
1
2
3
4
5
1h Ph
1i Ph
1j Ph
Me
Et
Allyl
Me
Et
Allyl
2h
2i
2j
68
91
94
88
77
1k Ph Propargyl Propargyl 2k
1l Ph Bn Bn 2l
aReagents and conditions: 1 (1.0 mmol), Tf2O (1.2 mmol),
DBU (1.2 mmol), DCM (5.0 mL), r.t., 15-30 min. bIsolated
yield.
Supplementary Information (SI)
Copies of NMR spectra for products 2 and 3 are
available at www.ias.ac.in/chemsci. CCDC deposition
number: 1063953. The crystallographic data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallogra-
phic Data Center, 12 Union Road, Cambridge CB21EZ,
UK; fax: (+44) 1223 336 033; or deposit@ccdc.cam.
ac.uk).
Scheme 2. The reaction of 1m with Tf2O in DCM.
Acknowledgements
Financial support for this research by the National
Natural Science Foundation of China (21172211 and
21542006) are greatly acknowledged.
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Scheme 3. Plausible mechanism for the reaction of 1 with
Tf2O in DCM.
5-iminooxazoline 2m. Therefore, we provided here-
with an alternative synthetic route to 5-iminooxazolines
2 and 5-aminooxazoles 3. Actually, oxazoline unit is
the core moiety present in numerous natural products
and synthetic organic compounds along with a vari-
ety of biological activities, such as melatonin recep-
tor agonist, antimycobacterial, anticancer, and elastase
inhibitor agents.15–17
On the basis of the above experimental results
together with some literature reports,18,19 a mechanism
for the synthesis of 5-Iminooxazolines 2 is proposed

Mangfei Yu et al.
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