Six-membered cyclic nitronates as Br?nsted bases: protonation and rearrangement into butyrolactone oximes

Article abstract of DOI:10.1016/j.mencom.2008.09.009

The protonation of six-membered cyclic nitronates (SMCNs) was studied by low-temperature NMR spectroscopy, and an efficient preparative procedure for acid-induced rearrangement of SMCNs into oximes of substituted butyrolactones was developed.

Full text of DOI:10.1016/j.mencom.2008.09.009

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 255–257
Six-membered cyclic nitronates as Brönsted bases:
protonation and rearrangement into butyrolactone oximes
Vladimir O. Smirnov, Yulia A. Khomutova and Sema L. Ioffe*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: iof@ioc.ac.ru
DOI: 10.1016/j.mencom.2008.09.009
The protonation of six-membered cyclic nitronates (SMCNs) was studied by low-temperature NMR spectroscopy, and an efficient
preparative procedure for acid-induced rearrangement of SMCNs into oximes of substituted butyrolactones was developed.
Six-membered cyclic nitronates 1 can be considered as Lewis
bases that formed ionic pairs (1–SiAlk3)+OTf– upon interaction
with powerful silyl Lewis acids such as trialkylsilyltriflates.
These oxazinium cations were studied in detail by low-tempe-
rature NMR spectroscopy.1 The cations (1–SiAlk3)+ undergo
C,C-coupling with π-nucleophiles NuC–E to give nitrosoacetals 2
(Scheme 1).1,2 However, the ability of nitronates 1 to interact
as bases with protic acids to give N-hydroxy-5,6-dihydro-4H-
1,2-oxazinium ions (1–H)+ is still unexplored.
Here we report preliminary data on the interaction of protic
acids with nitronates 1. The previously described procedure1
was applied to the generation and low-temperature NMR
monitoring of cations (1–H)+. The signals of the cation (1a–H)+
were observed after addition of 2 equiv. of TfOH to a precooled
(–40 °C) NMR sample of 1a in CD2Cl2.† For the most of signals
in 1H and 13C NMR spectra strong downfield shift accompanies
the transformation of nitronate 1a into cation (1a–H)+. The
differences of chemical shifts of analogous signals in (1a–H)+
and 1a spectra (Δd) are similar to those of previously obtained
for silylated ion (1a–SiAlk3)+ and nitronate 1a, respectively.1
In contrast to silylated cation (1a–SiAlk3)+, under incomplete
formation of (1a–H)+ (in case of TfOH deficiency) only one set
of peaks can be observed, obviously, due to rapid proton
exchange, and chemical shifts are between the chemical shifts
of nitronate 1a and cation (1a–H)+.
Pheq
Pheq
R
OTf–
R
NuC–E
NuC
– E–OTf
Me
N
O
Me
N
O
OSiAlk3
OSiAlk3
R'
R'
(1–SiAlk3)+OTf–
2a–c
Alk3SiOTf
Ph
Ph
R
O
R
OTf–
4
TfOH
3
5
6
Me
N
Me
N
O
O
OH
R'
R'
R = H,
R' = Me
(1–H)+OTf–
†
1a–c
For the calibration of NMR spectra on the solvent residual peak, the
data for chemical shifts of CH2Cl2 in CDCl3 were taken (1H: 5.30 ppm;
13C: 53.52 ppm).5
Ph
Ph
OTf–
Nitronate 1a (230 K, 10.8 mg in 0.50 ml CD2Cl2). 1H NMR (200 MHz)
d: 7.38–7.16 (m, 5H, Ph), 6.35 (d, 1H, H-3, J 2.5 Hz), 3.87–3.73 (m, 1H,
H-4), 2.04 (dd, 1H, H-5, J 13.6 and 7.7 Hz), 1.73 (t, 1H, H-5, J 13.0 Hz),
1.42 (s, 3H, Me), 1.36 (s, 3H, Me). 13C NMR (50 MHz, 230 K, CD2Cl2)
d: 139.7 (i-Ph), 128.6, 127.3, 127.2 (o,m,p-Ph), 113.0 [C(3)], 82.1 [C(6)],
38.3, 38.1 [C(4) and C(5)], 27.0, 21.6 (2Me).
NaHCO3
4
5
3
2
Me
Me
Me
Me
NHOH
NOH
O
O
(3a–H)+OTf–
3a
a R = H, R' = Me
b R = R' = Me
c R = H, R' = OMe
1a with 2.0 equiv. TfOH. 1H NMR (200 MHz, 230 K, CD2Cl2) d: 13.05
(br. s, 2H, TfOH + NOH), 7.83 (br. s, 1H, H-3), 7.46–7.33 (m, 3H, Ph),
7.29–7.18 (m, 2H, Ph), 4.29–4.14 (m, 1H, H-4), 2.31 (dd, 1H, H-5, J 14.2
and 7.4 Hz), 2.03 (t, 1H, H-5, J 13.1 Hz), 1.55 (s, 6H, 2×Me). 13C NMR
(50 MHz, 230 K, CD2Cl2) d: 139.9 [C(3)], 133.6 (i-Ph), 129.3, 128.7,
128.2 (o,m,p-Ph), 119.7 (q, CF3, J 318 Hz), 92.3 [C(6)], 38.4, 35.7 [C(4)
and C(5)], 26.1, 21.3 (2Me).
1a with 5.0 equiv. TfOH. 1H NMR (200 MHz, 230 K, CD2Cl2) d: 12.1
(br. s, 5H, TfOH + NOH), 7.90 (br. s, 1H, H-3), 7.48–7.36 (m, 3H, Ph),
7.29–7.16 (m, 2H, Ph), 4.31–4.14 (m, 1H, H-4), 2.38 (dd, 1H, H-5, J 14.5
and 7.3 Hz), 2.09 (t, 1H, H-5, J 12.9 Hz), 1.59 (s, 3H, Me), 1.55 (s, 3H,
Me). 13C NMR (50 MHz, 230 K, CD2Cl2) d: 139.6 [C(3)], 132.8 (i-Ph),
129.5, 129.1, 127.7 (o,m,p-Ph), 117.8 (q, CF3, J 317 Hz), 94.2 [C(6)],
38.5, 35.5 [C(4) and C(5)], 25.9, 21.3 (2Me).
(3a–H)+OTf–. 1H NMR (300 MHz, 298 K, CD2Cl2) d: 11.65 and 9.82
(2br. s, 2×1H, NH, OH), 7.51–7.43 (m, 3H, Ph), 7.31–7.24 (m, 2H, Ph),
4.75 (dd, 1H, H-3, J 11.9 and 9.0 Hz), 2.87 (dd, 1H, H-4, J 13.2 and
9.2 Hz), 2.51 (t, 1H, H-4, J 12.5 Hz), 1.85 and 1.70 (2s, 2×3H, 2Me).
13C NMR (75 MHz, 298 K, CD2Cl2) d: 177.0 [C(2)], 130.9, 130.4, 128.4
118.2 (Ph), 118.6 (q, CF3, J 317 Hz), 104.3 [C(5)], 49.5 [C(3)], 44.5
[C(4)], 27.9, 25.8 (2Me).
Tf = SO2CF3
Scheme 1
®
Consequently, the rate of exchange for the 1a + TfOH
¬
+
–
®
(1a–H) OTf system is much greater than that for the
1a + TfOSiAlk3 (1a–SiAlk ) OTf system. The dependence of
Δd (for characteristic peaks) on the ratio 1a:TfOH indicates that
the equilibrium 1a + TfOH (1a–H) OTf is shifted completely
¬
+
–
®
¬
3
+
–
®
¬
to the right even in the presence of 2 equiv. of TfOH. Indeed,
the increase of TfOH excess does not affect Δd values noticeably
(Figure 1).
Upon heating of (1a–H)+OTf– to room temperature, the cation
undergoes quantitative rearrangment to protonated butyrolactone
oxime (3a–H)+OTf–. The structure of the latter was confirmed,
along with spectral characteristics, with preparative isolation
of parent oxime 3a, after treatment of the NMR sample with an
aqueous solution of NaHCO3. Note that, in contrast to (1a–H)+
cation, separate peaks of NH, OH and TfOH protons are observed
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© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 255–257
Table 1 Characteristic NMR peaks for nitronates 1a–c and respective cations (1–H)+.
1H NMR, d
(1–H)+OTf–
13C NMR, d
(1–H)+OTf–
Nitronate/
cation
1
1
1a
1b
1c
6.35 (d, H-3, J 2.5 Hz)
7.83 (br. s, H-3)
113.0 [C(3)]
82.1 [C(6)]
139.9 [C(3)]
92.3 [C(6)]
3.87–3.73 (m, H-4)
4.29–4.14 (m, H-4)
2.04 (dd, H-5eq, J 13.6 and 7.7 Hz)
1.73 (t, H-5ax, J 13.0 Hz)
2.31 (dd, H-5eq, J 14.2 and 7.4 Hz)
2.03 (t, H-5ax, J 13.1 Hz)
1.73 [s, C(3)Me]
2.17 [s, C(3)Me]
123.7 [C(3)]
82.0 [C(6)]
153.8 [C(3)]
89.9 [C(6)]
3.67 (dd, H-4, J 10.9 and 8.0 Hz)
2.06 (dd, H-5eq, J 13.8 and 7.8 Hz)
1.85 (t, H-5ax, J 12.6 Hz)
4.07 (dd, H-4, J 11.0 and 7.5 Hz)
2.32 (dd, H-5eq, J 14.6 and 7.5 Hz)
2.15 (dd, H-5ax, J 14.3 and 11.0)
6.33 (d, H-3, J 3.0 Hz)
7.85 (d, H-3, J 1.5 Hz)
4.40–4.26 (m, H-4)
2.49 (dd, H-5eq, J 14.5 and 7.5 Hz)
2.12 (dd, H-5ax, J 11.8 and 14.5 Hz)
113.9 [C(3)]
104.3 [C(6)]
140.8 [C(3)]
113.7 [C(6)]
3.96 (ddd, H-4, J 12.5, 7.0 and 3.0 Hz)
2.25 (dd, H-5eq, J 13.5 and 7.0 Hz)
1.79 (t, H-5ax, J 13.0 Hz)
in the spectra of the (3a–H)+OTf– + TfOH system even at room
temperature.
Upon treatment of NMR samples of nitronates 1b,c with an
excess of TfOH according to a described procedure,1 the corre-
sponding cations (1b–H)+ or (1c–H)+ were obtained (Scheme 1).
Their characteristic peaks are listed in Table 1. The dominant
conformations of nitronates 1a–c and respective cations (1–H)+
were similar since the vicinal coupling constants of both species
have close values.
Upon heating to room temperature, ionic intermediates
(1b,c–H)+TfO– decompose to a complex mixture of unidentified
products. Obviously, the presence of acetal moiety at C(6), as
well as the absence of a proton at C(3), makes impossible the
rearrangement of (1–H)+ into (3–H)+.
At the same time, other nitronates 1, that meet the above
restrictions, can be smoothly converted into the corresponding
oximes 3 after treatment with triflic acid using a convenient
procedure (Scheme 2).§ A possible pathway of rearrangement is
shown in Scheme 2.
Quantitative generation of the ionic species (1–H)+OTf– from
nitronates 1 is the crucial point for successful proton-induced
rearrangement of nitronate 1 into 3. The addition of only a catalytic
The kinetic investigation of the rearrangement (1a–H)+OTf– ®
® (3a–H)+OTf– was studied at 252–281 K according to a pre-
viously described procedure,1 following (1a–H)+OTf– concen-
tration. It was shown that the decrease of the amount of (1a–H)+
corresponds to the increase of the amount of (3a–H)+, and no
other intermediates were observed in proton spectra during the
rearangement. This reaction follows first-order rate law [based
on (1a–H)+]. After processing of kinetic data according to the
Eyring equation, the activation parameters for the rearrange-
¹
¹
ment were determined as ΔH = 74.8 2.8 kJ mol–1 and ΔS
=
= –26.5 10.6 J mol–1 K–1. From these data, the stability of 1a–H+
(in terms of half-life period) is estimated as 11 h at –30 °C,
36 min at –10 °C, 3 min at 10 °C and 21 s at 30 °C.
The addition of 3.5 equiv. of weaker trifluoroacetic acid (TFA)
(procedure1) to the NMR sample of nitronate 1a also leads to a
downfield shift of nitronate signals, but to less extent than with
the use of TfOH.‡ As for TfOH, further addition of TFA does
not lead to any substantial changes of chemical shifts (Figure 1).
However, upon heating of the resulting NMR sample to room
temperature only a complex mixture of unidentified products
forms, that contains no traces of (3a–H)+CF3CO2–. These facts
allow us to assume that the treatment of TFA with nitronate 1a
does not give rise to (1a–H)+CF3CO2–. Probably, other species,
for example complex 1a·TFA or 1,3-adduct 1a with TFA, are
formed in this interaction.
§
General procedure for the preparation of butyrolactone oximes 3a,d,e.
To a stirred solution of nitronate 1 in dry CH2Cl2 (3.0 ml mmol–1), TfOH
(1.1 equiv.) was added at –78 °C. The cooling bath was removed after
5 min, and the reaction mixture was allowed to reach ambient temperature.
After additional 5 min, a saturated aqueous sodium bicarbonate solution
(3.0 ml mmol–1) was added to the reaction mixture. The aqueous layer
was separated and washed with an equal volume of CH2Cl2. Combined
organic layers were washed with brine, dried over sodium sulfate and
evaporated. Crystalline residue was recrystallised from toluene.
3a: yield 93%, colourless crystals, mp 148–152 °C. 1H NMR (300 MHz,
298 K, CDCl3) d: 7.37–7.21 (m, 5H, Ph), 6.87 (br. s, 1H, OH), 4.20 (dd,
1H, CHPh, J 11.3 and 8.6 Hz), 2.44 (dd, 1H, H–C–H', J 12.5 and 8.5 Hz),
2.14 (t, 1H, H'–C–H, J 12.0 Hz), 1.57 (s, 3H, Me), 1.48 (s, 3H, Me).
13C NMR (75 MHz, 298 K, CDCl3) d: 161.0 (C=N), 138.5 (i-Ph), 128.9,
128.1 (o,m-Ph), 127.5 (p-Ph), 86.4 (Me2CO), 46.3 (CH2), 45.9 (CHPh)
28.5, 27.1 (2Me). Found (%): C, 70.12; H, 7.55; N, 6.85. Calc. for
C12H15NO2 (%): C, 70.22; H, 7.37; N, 6.82.
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
2.0 equiv. TfOH
5.0 equiv. TfOH
3.5 equiv. TFA
7.0 equiv. TFA
30
25
20
15
10
5
0
H-3 H-4 H-5eq H-5ax Me
C-3 C-6
Figure 1 Difference of chemical shifts (Δd) for characteristic peaks in 1H
and 13C NMR spectra of a mixture of nitronate 1a with TfOH or TFA.
3d: yield 79%, colourless crystals, mp 168–170 °C. 1H NMR (300 MHz,
298 K, CDCl3) d: 7.82 (br. s, 1H, OH), 7.40–7.25 (m, 5H, Ph), 7.24–7.05
(m, 6H, Ph), 6.95–6.65 (m, 4H, Ph), 5.87 (d, 1H, O–CHPh, J 7.2 Hz),
4.33 [d, 1H, N=C(O)CHPh, J 7.6 Hz], 3.87 (t, 1H, CHPh, J 7.3 Hz).
13C NMR (75 MHz, 298 K, CDCl3) d: 160.0 (C=N), 137.9, 135.35, 135.28
(3×i-Ph), 129.0, 128.8, 128.6 (3×o,m-Ph), 128.5 (p-Ph), 128.2, 128.1
(2×o,m-Ph), 127.4, 127.2 (2×p-Ph), 125.8 (o,m-Ph), 86.2 (PhCH–O),
57.3 (CHPh), 50.9 (CHPh). Found (%): C, 80.52; H, 5.91; N, 4.12. Calc.
for C22H19NO2 (%): C, 80.22; H, 5.81; N, 4.25.
3e, yield 83%, colourless crystals, mp 126–128 °C. 1H NMR (300 MHz,
298 K, CDCl3) d: 7.82 (br. s, 1H, OH), 7.36–7.15 (m, 5H, Ph), 4.60
(q, 1H, HCO, J 5.3 Hz), 3.80 (d, 1H, CHPh, J 6.4 Hz), 2.38 (m, 1H,
HCCHPh), 1.94–1.30 [m, 8H, (CH2)4]. 13C NMR (75 MHz, 298 K, CDCl3)
d: 160.9 (C=N), 138.0 (i-Ph), 128.7, 127.9 (o,m-Ph), 127.2 (p-Ph), 80.1
(HCO), 50.0, 44.7 (2×CH), 28.3, 25.7, 22.0, 21.2 (4CH2). Found (%):
C, 73.00; H, 7.57; N, 5.89. Calc. for C14H17NO2 (%): C, 72.70; H, 7.41;
N, 6.06.
‡
1a with 3.5 equiv. TFA. 1H NMR (200 MHz, 230 K, CD2Cl2) d: 11.52
(s, 3.5H, AcFOH, NOH), 7.42–7.30 (m, 3H, Ph), 7.22 (d, 2H, o-Ph,
J 6.4 Hz), 7.17 (s, 1H, H-3), 4.05–3.90 (m, 1H, H-4), 2.18 (dd, 1H, H-5,
J 14.2 and 7.3 Hz), 1.88 (t, 1H, H-5, J 13.0 Hz), 1.44 (s, 6H, 2Me).
13C NMR (50 MHz, 230 K, CD2Cl2) d: 158.7 (q, COTFA, J 41.6 Hz)
136.6 (i-Ph), 129.0, 128.0, 127.5 (o,m,p-Ph), 126.9 [C(3)], 114.1 (q, CF3,
J 285.7 Hz), 86.5 [C(6)], 38.2, 37.0 [C(4), C(5)], 26.5, 21.5 (2Me).
1a with 7.0 equiv. TFA. 1H NMR (200 MHz, 230 K, CD2Cl2) d: 11.64
(s, 7H, AcFOH, NOH), 7.43–7.31 (m, 3H, Ph), 7.29–7.19 (m, 3H, o-Ph,
H-3), 4.11–3.92 (m, 1H, H-4), 2.20 (dd, 1H, H-5, J 14.6 and 6.0 Hz),
1.90 (t, 1H, H-5, J 12.4 Hz), 1.45 (s, 6H, 2Me). 13C NMR (50 MHz,
230 K, CD2Cl2) d: 160.0 (q, COTFA, J 42.5 Hz), 136.3 (i-Ph), 129.0,
128.1, 127.5 (o,m,p-Ph), 128.3 [C(3)], 113.9 (q, CF3, J 285.0 Hz), 87.1
[C(6)], 38.2, 36.8 [C(4), C(5)], 26.5, 21.4 (2Me).
– 256 –

Mendeleev Commun., 2008, 18, 255–257
Ph
O
R
R1
R
i, 1.1 equiv. TfOH, CH2Cl2,
–78 20 °C
ii, NaHCO3
R
Ph
R
R1
R2
O
R2
R3
R'
MeNO2
O
R'
N
NOH
O
O
R3
O
R''
R''
1a,d,e
3a, 93%
3d, 79%
3e, 83%
R2, R3 = OAlk
a R = H, R' = R'' = Me
d R = R'' = Ph, R' = H
e R + R' = (CH2)4, R'' = H
i
R
ii
R1
R
Ph
R1
R2
R
Ph
NHOH
TfOH
R
R2
R3
N
NOH
R'
O
O
O
R'
N
R3
O
OH
O
R''
R''
(1–H)+
Scheme 3
(3–H)+
This work was supported by the Russian Foundation for
Basic Research (grant nos. 02-03-33350 and 03-03-04001) and
Deutsche Forschungsgemeinschaft (MA 673/19).
Ph
Ph
R
Ph
NO
R
R
R'
References
R'
R'
N
O
N
O
1 Yu. A. Khomutova, V. O. Smirnov, H. Mayr and S. L. Ioffe, J. Org.
Chem., 2007, 72, 9134.
O
O
H
O
H
R''
R''
R''
H
2 V. O. Smirnov, S. L. Ioffe, A. A. Tishkov, Yu. A. Khomutova, I. D.
Nesterov, M. Yu. Antipin, W. A. Smit and V. A. Tartakovsky, J. Org.
Chem., 2004, 69, 8485.
Scheme 2
3 S. E. Denmark, M. S. Dappen and C. J. Cramer, J. Am. Chem. Soc.,
1986, 108, 1306.
4 S. E. Denmark, Y.-C. Moon, C. J. Cramer, M. S. Dappen and C. B. W.
Senanayake, Tetrahedron, 1990, 46, 7373.
5 H. E. Gottlieb, V. Kotlyar and A. Nudelman, J. Org. Chem., 1997, 62,
7512.
amount of triflic acid (5%) to the solution of 1a leads to a
complex mixture of products, which contains the target oxime
only in trace amounts (detection by TLC).
Previously,3,4 it was shown with several examples that the above
mentioned nitronates can be converted into target oximes in
modest yields upon treatment with potassium tert-alcoholates.
The effective procedure for deoximation of 3 into substituted
butyrolactones was described.3,4 The above procedure for the
rearrangement of 1 into 3 upon treatment with triflic acid seems
more convenient and effective.
The acid-induced rearrangement of 1 to 3 can be used as a
new convenient strategy of the stereocontrolled assembly of sub-
stituted butyrolactones from very simple precursors (Scheme 3).
Received: 12th March 2008; Com. 08/3099
– 257 –