Efficient synthesis of N-protected trisubstituted oxazolidines from ketones, vinyl ethers, and fluoroalkanesulfonyl azides in mild conditions

Article abstract of DOI:10.1055/s-2005-869967

A facile one-step method has been developed for the synthesis of 2,3,5-trisubstituted oxazolidines in moderate yields by the three-component reaction of ketones, vinyl ethers, and fluoroalkanesulfonyl azides at 0 °C within five minutes. This practical syn

Full text of DOI:10.1055/s-2005-869967

PAPER
2137
Efficient Synthesis of N-Protected Trisubstituted Oxazolidines from Ketones,
Vinyl Ethers, and Fluoroalkanesulfonyl Azides in Mild Conditions
Efficient
S
ynth
i
esis of
n
N
-Protected
g
T
risubstituted Oxa
H
zolidines e,a Shizheng Zhu*a,b
a
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, P. R. China
Fax +86(21)64166128; E-mail: zhusz@mail.sioc.ac.cn
College of Chemical Environment, South China Normal University, Guangzhou 510631, P. R. China
Received 27 January 2005; revised 14 March 2005
b
perfluorinated aldehyde hemiacetal or aldehyde hydrate
(Scheme 1).
Abstract: A facile one-step method has been developed for the syn-
thesis of 2,3,5-trisubstituted oxazolidines in moderate yields by the
three-component reaction of ketones, vinyl ethers, and fluoroal-
kanesulfonyl azides at 0 °C within five minutes. This practical syn-
thetic method provides a convenient and expeditious access to N-
per(poly)fluoroalkanesulfonyl oxazolidines.
During our studies on fluoroalkanesulfonyl azides 1,9 we
found that it reacts smoothly with ketones and vinyl ethers
to afford a series of N-protected oxazolidines in good
yields. We were surprised to find that the reaction prod-
ucts were not the normal cycloaddition products 2,3,4-
trisubstituted oxazolidines but the unexpected 2,3,5-
trisubstituted isomers. This practical synthetic method
provides a convenient and expeditious access to N-
per(poly)fluoroalkanesulfonyl oxazolidines. Herein, we
wish to report these results.
Key words: fluoroalkanesulfonyl azide, ketone, vinyl ether, oxazo-
lidine, multi-component reactions
The increasing environmental consciousness of the chem-
ical community has led to the search for more efficient
and environmentally friendly methods for chemical syn-
theses.1 Among them, multi-component reactions
(MCRs), by virtue of their convergent, high productivity
and facile execution, as well as the generally high yields
of products obtained, have attracted much attention from
the vantage point of combinatorial chemistry.2 Oxazo-
lidines, usually obtained from amino acids, have found
widespread use as chiral non-racemic ligands in asymmet-
ric catalysis.3 Moreover, such oxazolidine derivatives
were assumed to have potential as pro-drug forms,4 as
they undergo conversion to the parent compound. Semen-
ov et al.5 once reported their studies on the reactions of ar-
ylsulfonyl azides, vinyl ethers, and carbonyl compounds
for the synthesis of oxazolidines but with a low yield. It is
well known that the introduction of a fluorine atom can
confer unusual chemical reactivity to organic molecules
and often exert profound effects on the physical properties
of biologically active compounds.6 Thus, fluorine-con-
taining oxazolidines should be expected to be of particular
importance. However, there exist very few methods for
the preparation of fluorine-containing oxazolidines.7 Re-
cently, Gosselin et al.8 prepared these compounds by heat-
ing chiral amino alcohol with the corresponding
Recently, we reported the results of the 1,3-dipolar cy-
cloaddition of 1 with acyclic vinyl ether.10 Reactions of
acyclic vinyl ethers with 1 at 0 °C or room temperature
failed to give the corresponding N-fluoroalkanesulfonyl
aziridines, but gave instead 1-fluoroalkanesulfonyl 1,2,3-
triazolines 3 regiospecifically; these decomposed slowly
at room temperature to give 1,4-fluoroalkanesulfonyl-2,5-
alkoxy-piperazines 4 with elimination of nitrogen gas
(Scheme 2).
RO
RfSO2
N
– N2
slow
N
SO2Rf
RfSO2
N
N
N
RfSO2N3
1
+
OR
EtO
OR
2
3
4
Scheme 2
Initially we investigated the reaction of fluoroalkane-
sulfonyl azide 1a with an equimolar amount of acetone 5a
in an excess of vinyl ether 2a at 0 °C. Nitrogen gas was re-
leased immediately. TLC analysis showed that the azide
1a disappeared within five minutes and two products were
formed, they were separated and purified by column chro-
matography using petroleum ether–diethyl ether (100:1)
as eluent. According to their NMR spectra and TLC anal-
ysis, one product obtained in 35% yield was identified as
the 1-fluoroalkanesulfonyl 1,2,3-triazolines 3a. Another
major product, obtained in 54% yield, was a five-mem-
bered trisubstituted oxazolidine, isolated as a stable color-
less oil. According to our previous results,9 we deduced
that the oxazolidine formed should be 2,3,4-trisubstituted,
however, we finally found that this was incorrect. It is
well documented in the literature that when a substituent
was placed on the 5-position of the oxazolidine ring, the
R1
R1
(a)
R1 = Et, i-Pr, i-Bu, Bn, t-Bu
OH
O
HN
H2N
R2 = CF3, CF2H, CF2CF3
R2
Scheme 1 Conditions: (a) CF3CH(OMe)OH or HCF2CH(OH)Et,
PPTS, PhCH3
SYNTHESIS 2005, No. 13, pp 2137–2142
x
x.
x
x
.
2
0
0
5
Advanced online publication: 20.06.2005
DOI: 10.1055/s-2005-869967; Art ID: F02205SS
© Georg Thieme Verlag Stuttgart · New York

2138
P. He, S. Zhu
PAPER
signal observed in 13C NMR spectrum generally appears minutes. During the reaction process, the corresponding
at lower field than that in the 4-substituted couterpart.11 1,2,3-triazolines 3 were obtained, however the yields of 6
To determine the concrete position of the ethoxy group, varied from 61% to 75%. Varying the substituents on 2
the 13C NMR spectrum of the oxazolidine 6 was further and 5 did not have a great effect on the yields; even the cy-
investigated. The chemical shift observed at 99.7 ppm in clopentanone 5b (R as a cyclic group) could generate the
13C NMR spectrum of 6 indicated that the ethoxy group corresponding oxazolidine 6dbb in 72% yield (Table 1,
should be attached to the 5-C of the oxazolidine ring entry 16).
(Figure 1).
Table 1 Reaction Results of Fluoroalkanesulfonyl Azides, Vinyl
O
Ethers, and Ketonesa
O
RfSO2
N
N
N
O
5
Entry Azides Vinyl Ketones Products Yield Product Yield
O
O
4
ethers
(%)b
66
67
62
61
68
63
64
64
63
75
67
71
72
66
64
72
(%)b
24
22
20
25
18
20
18
20
15
15
20
18
16
15
20
17
BzO
OBz
OEt
1
2
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1d
2a
5a
5a
5b
5b
5a
5a
5b
5b
5a
5a
5b
5b
5a
5a
5b
5b
6aaa
6aba
6aab
6abb
6baa
6bba
6bab
6bbb
6caa
6cba
6cab
6cbb
6daa
6dba
6dab
6dbb
3aa
3ab
3aa
3ab
3ba
3bb
3bb
3bb
3cb
3cb
3ca
3cb
3da
3db
3da
3db
13C NMR: 83.63 ppm
13C NMR: 97.78 ppm
13C NMR: 99.7 ppm
2b
2a
Figure 1 Determination of the ethoxy position in the ring of fluori-
nated oxazolidine 6
3
4
2b
2a
5
By comparison with results for arylsulfonyl azides, all
5
these data indicated that the product should be character-
ized as 5-ethoxy-2,2-dimethyl-3-fluoroalkanesulfonylox-
azolidine 6aaa, instead of the 4-ethoxy-2,2-dimethyl-3-
fluoroalkanesulfonyloxazolidine 6aaa¢. This conclusion
was supported by a further study with trans-cinnamalde-
hyde,12 in which the major product oxazolidine was eluci-
dated by single crystal X-ray diffraction analysis.13 When
this reaction was carried out in anhydrous diethyl ether or
dichloromethane the yield of 6aaa was improved to 66%
and the amount of 3aa decreased. Furthermore, it was
found that the addition of activated MS 4Å could not cat-
alyze this reaction, which indicated that the dehydration
process was not involved in the formation of product
6aaa.
6
2b
2a
7
8
2b
2a
9
10
11
12
13
14
15
16
2b
2a
2b
2a
2b
2a
Other azides 1b–d reacted with vinyl ether 2 and ketone 5
in dichloromethane at 0 °C giving similar results. All
these results were summarized in Table 1. The MCRs
were found to be general and efficient. All the above reac-
tions proceeded smoothly and were complete within five
2b
a Reactant ratio: 1/2/5 = 1:1:1.
b Isolated yields based on 1.
H3C
CH3
N
N
N
RfSO2N
RfSO2
O
+
0 °C
EtO
3aa
RfSO2N3
OEt
6aaa
+
+
CH3COCH3
OEt
5 min
H3C
1a
2a
5a
CH3
RfSO2N
6aaa'
O
EtO
Scheme 3
R
R
N
CH2Cl2
0 °C, 5 min
RfSO2N
RfSO2N3
RfSO2N
+
+
RCOR
O
N
OR1
2a–b
+
R1O
OR1
1a–d
5a–b
6
3
Rf = IC2F4OC2F4 (a), ClC2F4OC2F4 (b), HC2F4OC2F4 (c), C4F9 (d)
1 = C2H5 (a), i-Bu (b)
R = CH3 (a), -(CH2)4- (b)
R
Scheme 4
Synthesis 2005, No. 13, 2137–2142 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of N-Protected Trisubstituted Oxazolidines
2139
Ph
CH3
N
RfSO2N
RfSO2N
N
CH2Cl2
RfSO2N3
+
O
+
PhCOCH3
+
OEt
0 °C, 5 min
EtO
OEt
1a
2a
5c
3aa
Yield: 54%
6aac
Yield: 31%
Scheme 5
However, in the case of 1-phenylethanone 5c a), though a reversible equilibrium process might exist.
(PhCOCH3), it was found the yield of 6aac decreased dra- Due to the relative stability of the competing products tri-
matically to 31% (Scheme 5). An interesting phenomenon azolines, which could not release N2 gas immediately un-
was observed that although within five minutes 1a was der the same conditions, so the correlation of the reaction
not detected in the reaction mixture, PhCOCH3 was not equilibrium constants during the process is k1,k2 >>
consumed completely and the corresponding yield of tri- k3,k4,k5. In addition, due to the p-p conjugated action in
azolidine 3 increased to 54%.
the structure of B1, B1 is one a secondary carbonium, so B1
is more stable than B2 (primary carbonium), i.e., the for-
mation of B1 is easier than the other zwitter ionic B2.14
Thus, the isomers in 6¢ could not be obtained (path b). To
rationalize this proposal, further chemical transformation
of triazolines was studied. No reaction was observed
when mixing equimolar amounts of triazoline and ketone
under the same reaction conditions, which indicated the
formation of 6 was not through the competing products
triazolines.
Moreover, in the case of cyclic vinyl ethers such as 2,3-
dihydrofuran, the expected 2,3,5-trisubstituted oxazoli-
dine was not isolated, fluoroalkanesulfonylamide
RfSO2NH2 was obtained in high yield (Scheme 6). We as-
sumed that the 2,3-dihydrofuran reacted easily with azides
affording the corresponding sulfonylimines, which were
moisture sensitive and were readily hydrolyzed to the cor-
responding g-butyrolactone and polyfluoroalkanesulfonyl
amine. Futhermore, when electron-rich alkenes such as si-
lyl ketene acetals and tetrakis(dimethylamino)ethylene In conclusion, we have demonstrated a concise and effi-
(TDAE) were employed, the expected fluoroalkanesulfo- cient synthetic protocol for the synthesis of 2,3,5-trisub-
nyl substituted oxazolidines were not obtained, but the stituted fluorinated oxazolidines via the one-pot three-
corresponding results of the reaction of fluoroalkane- component reaction of ketones, vinyl ethers, and fluoroal-
sulfonyl azides with electron-rich alkenes, i.e. the third kanesulfonyl azides under mild conditions. Further ring-
component ketone did not participate in the process.
opening chemical transformations are under investigation
in our group.
Based on the above results and a similar mechanism re-
ported by Semenov et al.,5 a possible reaction pathway for
the formation of the fluorinated oxazolidines 6 was pro-
posed (Scheme 7). A competing reaction between fluoro-
alkanesulfonyl azides 1 and vinyl ethers 2 occurred during
the initial process. We propose that products 6 should be
form through the intermediate A1 or zwitter ionic B1 (path
Melting points were measured in a Temp-Melt apparatus and were
1
uncorrected. H NMR, 13C NMR, and 19F NMR spectra were re-
corded in CDCl3 on Bruker AM-300 instruments with Me4Si and
CFCl3 as the internal and external standards, respectively. IR spec-
tra were obtained with a Nicolet AV-360 spectrophotometer. Lower
resolution mass spectra were obtained on a Finnigen MAT-8430 in-
moisture
O
RfSO2NH2
+
NSO2Rf
O
O
O
OSiMe3
OEt
OEt
RfSO2N3
+
CH3COCH3
RfSO2NH
O
N(CH3)2
N(CH3)2
TDAE
RfSO2N
Scheme 6
_
R
OR1
R
RfSO2N
RCOR RfSO2N
path a
-N2
+
N
O
6
OR1
SO2Rf
k1
B1
OR1
A1
+
1
k5
OR1
k4
-N2
R
_
N
R
RfSO2N
– N2
N
RfSO2N
RCOR
path b
RfSO2N
R1O
+
O
6'
k3
R1O
k2
R1O
B2
k1, k2 >> k3, k4, k5
Scheme 7
Synthesis 2005, No. 13, 2137–2142 © Thieme Stuttgart · New York

2140
P. He, S. Zhu
PAPER
strument using the electron impact ionization technique (70ev). El-
emental analyses were performed by this Institute. All reactions as
well as column chromatography were monitored routinely with the
aid of TLC or 19F NMR spectroscopy. All liquid ketones were dis-
tilled prior to use. All solvents were purified before use. The petro-
leum ether fraction used had a boiling range of 60–90 °C.
Fluoroalkanesulfonyl azides 1 were prepared according to the liter-
ature.15
19F NMR (282 MHz, CDCl3): d = –65.3 (d, J = 5.4 Hz, 2 F, ICF2),
–82.3 (t, J = 12.4 Hz, 2 F, CF2O), –86.0 (m, 2 F, OCF2), –114.0 (s,
2 F, CF2S).
MS (EI, 70 eV): m/z (%) = 577 (M+, 11), 548 (M+ – Et, 53), 532
+
+
(M+ – EtO, 9), 227 (IC2F4 , 14), 177 (ICF2 , 11), 170 (M+ – RfSO2,
48), 141 (M+ – RfSO2Et, 63), 96 (C6H8O+, 53), 67 (C5H7 , 48), 55
(C4H7 , 100), 41 (C3H5 , 66).
+
+
+
Anal. Calcd for C13H16F8INO5S: C, 27.04; H, 2.77; N, 2.43. Found:
C, 27.22; H, 2.72; N, 2.64.
N-Protected 2,3,5-Trisubstituted Oxazolidines; Typical Proce-
dure
2-Isobutoxy-4-[1,1,2,2-tetrafluoro-2-(1,1,2,2-tetrafluoro-2-io-
doethoxy)ethanesulfonyl]-1-oxa-4-azaspiro[4.4]nonane (6abb)
Colorless oil.
IR (KBr): 2963,1395, 1293, 1153, 1033, 914 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.22 (dd, J = 4.8 Hz, 1.8 Hz, 1 H),
3.90–3.76 (m, 2 H), 3.51 (dd, J = 9.0 Hz, 6.6 Hz, 1 H), 3.20 (dd,
J = 9.0 Hz, 6.0 Hz, 1 H), 2.39–2.35 (m, 1 H), 2.16 (br, 2 H), 1.92–
1.70 (m, 6 H), 0.93 (d, J = 7.2 Hz, 3 H, CH3), 0.92 (d, J = 6.6 Hz, 3
H, CH3).
To a 10 mL round-bottom flask containing vinyl ether 2a (144 mg,
0.19 mL, 2.0 mmol) and ketone 5a (116 mg, 0.15 mL, 2.0 mmol),
in CH2Cl2 (2 mL) was added slowly fluoroalkanesulfonyl azides 1a
(898 mg, 2.0 mmol) at 0 °C over 2 min. TLC analysis showed the
reaction finished within 5 min. Then the solvent was evaporated un-
der reduced pressure and the residue was chromatographed on a sil-
ica column (petroleum ether–Et2O, 100:1) to give 6aaa (732 mg,
66%) as colorless oil. The second product fluoroalkanesulfonyl
amide 3aa (250 mg, 24%) was also obtained as colorless oil.
19F NMR (282 MHz, CDCl3): d = –65.2 (CF2, d, J = 6.2 Hz), –82.2
(CF2, d, J = 7.3 Hz), –85.9 (CF2, s), –114.0 (CF2, s).
5-Ethoxy-3-[1,1,2,2-tetrafluoro-2-(1,1,2,2-tetrafluoro-2-iodo-
ethoxy)ethanesulfonyl]-2,2-dimethyloxazolidine (6aaa)
Colorless oil.
IR (KBr): 2984, 1384, 1293, 1200, 1156, 1045, 915 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.21 (dd, J = 4.2 Hz, 1.5 Hz, 1 H),
3.83–3.71 (m, 3 H), 3.53–3.45 (m, 1 H), 1.72 (s, 3 H, CH3), 1.61 (s,
3 H, CH3), 1.19 (t, J = 6.9 Hz, 3 H, CH3).
MS (EI, 70 eV): m/z (%) = 605 (M+, 10), 576 (M+ – Et, 16), 532
(M+ – i-BuO, 9), 198 (M+ – RfSO2, 15), 142 (M+ – RfSO2-i-Bu, 24),
+
96 (C6H8O+, 32), 57 (i-Bu+, 100), 41 (C3H5 , 48).
Anal. Calcd for C15H20F8INO5S: C, 29.75; H, 3.31; N, 2.31. Found:
C, 29.89; H, 3.25; N, 2.60.
19F NMR (282 MHz, CDCl3): d = –65.5 (s, 2 F, ICF2), –82.4 (d, J =
7.3 Hz, 2 F, CF2O), –86.2 (t, J = 6.5 Hz, 2 F, OCF2), –114.9 (br, 2
F, CF2S).
5-Ethoxy-3-[2-(2-chloro-1,1,2,2-tetrafluoroethoxy)-1,1,2,2-tet-
rafluoroethanesulfonyl]-2,2-dimethyloxazolidine (6baa)
Colorless oil.
IR (KBr): 2984, 1385, 1306, 1174, 1046, 969 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.24 (dd, J = 4.2 Hz, 1.5 Hz, 1 H),
3.86–3.75 (m, 3 H), 3.51 (dq, J = 7.2 Hz, 9.6 Hz, 1 H), 1.75 (s, 3 H,
CH3), 1.65 (s, 3 H, CH3), 1.22 (t, J = 7.2 Hz, 3 H, CH3).
MS (EI, 70 eV): m/z (%) = 536 (M+ – Me, 9), 506 (M+ – EtO, 2),
+
+
227 (IC2F4 , 9), 177 (ICF2 , 7), 129 (M+ – RfSO2NH, 100), 70(M+ –
+
RfSO2NHC3H6O, 89), 43 (C3H7 , 76). Anal. Calcd for
C11H14F8INO5S: C, 23.96; H, 2.54; N, 2.54. Found: C, 24.14; H,
2.45; N, 2.69.
13C NMR (75 MHz, CDCl3): d = 99.7, 63.1, 54.0, 29.1, 27.9, 14.5.
19F NMR (282 MHz, CDCl3): d = –74.2 (s, 2 F, ClCF2,), –82.2 (s, 2
F, CF2O), –87.2 (t, J = 13.4 Hz, 2 F, OCF2,), –114.7 (br, 2 F, CF2S).
5-Isobutoxy-3-[1,1,2,2-tetrafluoro-2-(1,1,2,2-tetrafluoro-2-io-
doethoxy)ethanesulfonyl]-2,2-dimethyloxazolidine (6aba)
Colorless oil.
IR (KBr): 2962, 1384, 1293, 1200, 1156, 1032, 915 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.22 (dd, J = 3.9 Hz, 1.8 Hz, 1 H),
3.87–3.78 (m, 2 H), 3.53 (dd, J = 9.0 Hz, 6.6 Hz, 1 H), 3.20 (dd,
J = 9.0 Hz, 6.0 Hz, 1 H), 1.92–1.81 (m, 1 H), 1.75 (s, 3 H, CH3),
1.65 (s, 3 H, CH3), 0.924 (d, J = 6.6 Hz, 3 H, CH3), 0.917 (d, J =
6.6 Hz, 3 H, CH3).
19F NMR (282 MHz, CDCl3): d = –65.2 (d, J = 2.2 Hz, 2 F, ICF2),
–82.2 (s, 2 F, CF2O), –85.9 (d, J = 11.6 Hz, 2 F, OCF2), –114.5 (br,
2 F, CF2S).
MS (EI, 70 eV): m/z (%) = 446/444 (M+ – Me, 21/57), 416/414
(M+ – EtO, 10/27), 129 (M+ – RfSO2NH, 84), 70 (M+ – RfSO2NH-
+
C3H6O, 100), 43 (C3H7 , 64).
Anal. Calcd for C11H14ClF8NO5S: C, 28.73; H, 3.05; N, 3.05.
Found: C, 29.03; H, 3.11; N, 3.36.
5-Isobutoxy-3-[2-(2-chloro-1,1,2,2-tetrafluoroethoxy)-1,1,2,2-
tetrafluoroethanesulfonyl]-2,2-dimethyloxazolidine (6bba)
Colorless oil.
IR (KBr): 2962, 1385, 1203, 1200, 1174, 1033, 969 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.22 (dd, J = 3.9 Hz, 1.8 Hz, 1 H),
3.87–3.79 (m, 2 H), 3.53 (dd, J = 9.3 Hz, 6.9 Hz, 1 H), 3.20 (dd,
J = 9.3 Hz, 6.9 Hz, 1 H), 1.92–1.81 (m, 1 H), 1.75 (s, 3 H, CH3),
1.65 (s, 3 H, CH3), 0.924 (d, J = 6.9 Hz, 3 H, CH3), 0.918 (d, J = 6.9
Hz, 3 H, CH3).
MS (EI, 70 eV): m/z (%) = 564 (M+ – Me, 26), 506 (M+ – i-BuO,
+
+
22), 227 (IC2F4 , 3), 177 (ICF2 , 3), 70 (M+ – RfSO2NHC3H6O, 73),
57 (i-Bu+, 100), 43 (C3H7 , 71).
+
Anal. Calcd for C13H18F8INO5S: C, 26.94; H, 3.11; N, 2.42. Found:
C, 27.11; H, 3.12; N, 2.62.
19F NMR (282 MHz, CDCl3): d = –74.1 (s, 2 F, ClCF2,), –82.2 (d,
J = 9.9Hz, 2 F, CF2O), –87.2 (t, J = 13.3Hz, 2 F, OCF2), –114.5 (br,
2 F, CF2S).
2-Ethoxy-4-[1,1,2,2-tetrafluoro-2-(1,1,2,2-tetrafluoro-2-iodo-
ethoxy)ethanesulfonyl]-1-oxa-4-azaspiro[4.4]nonane (6aab)
Colorless oil.
IR (KBr): 2978, 1395, 1293, 1153, 1095, 915 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.24 (dd, J = 4.8 Hz, 2.1 Hz, 1 H),
3.88–3.72 (m, 3 H), 3.51 (dq, J = 7.2 Hz, 9.3 Hz, 1 H), 2.39–2.34
(m, 1 H), 2.16 (br, 2 H), 1.85–1.64 (m, 5 H), 1.22 (t, J = 7.1 Hz, 3
H, CH3).
MS (EI, 70 eV): m/z (%) = 474/472 (M+ – Me, 18/47), 416/414
(M+ – i-BuO, 51/100), 70 (M+ – RfSO2NHC3H6O, 93), 57 (i -Bu+,
+
77), 43 (C3H7 , 38).
Anal. Calcd for C13H18ClF8NO5S: C, 32.00; H, 3.69; N, 2.87.
Found: C, 32.20; H, 3.95; N, 3.26.
Synthesis 2005, No. 13, 2137–2142 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of N-Protected Trisubstituted Oxazolidines
2141
2-Ethoxy-4-[2-(2-chloro-1,1,2,2-tetrafluoroethoxy)-1,1,2,2-tet-
rafluoroethanesulfonyl]-1-oxa-4-azaspiro[4.4]nonane (6bab)
Colorless oil.
19F NMR (282 MHz, CDCl3): d = –81.8 (s, 2 F, CF2O), –88.9 (s, 2
F, OCF2), –114.8 (br, 2 F, CF2S), –137.8 (dt, J = 53.6 Hz, 5.0 Hz,
HCF2).
IR (KBr): 2979, 1396, 1305, 1204, 1174, 1047, 970 cm–1.
MS (EI, 70 eV): m/z (%) = 438 (M+ – Me, 29), 380 (M+ – i-BuO,
+
81), 70 (M+ – RfSO2NHC3H6O, 88), 57 (i-Bu+, 100), 43 (C3H7 , 61).
1H NMR (300 MHz, CDCl3): d = 5.25 (dd, J = 5.1 Hz, 1.8 Hz, 1 H),
3.90–3.73 (m, 3 H), 3.52 (dq, J = 7.2 Hz, 9.6 Hz, 1 H), 2.39–2.32
(m, 1 H), 2.16 (br, 2 H), 1.86–1.67 (m, 5 H), 1.23 (t, J = 7.2 Hz, 3
H, CH3).
Anal. Calcd for C13H19F8NO5S: C, 34.44; H, 4.19; N, 3.09. Found:
C, 34.77; H, 4.30; N, 3.38.
2-Ethoxy-4-[1,1,2,2-tetrafluoro-2-(1,1,2,2-tetrafluoroeth-
oxy)ethanesulfonyl]-1-oxa-4-azaspiro[4.4]nonane (6cab)
Colorless oil.
IR (KBr): 2979, 1394, 1284, 1142, 1046 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.87 (tt, J = 52.8 Hz, 3.0 Hz, 1 H,
HCF2), 5.25 (dd, J = 4.8 Hz, 1.8 Hz, 1 H), 3.90–3.73 (m, 3 H), 3.52
(dq, J = 6.6 Hz, 9.6 Hz, 1 H), 2.39–2.32 (m, 1 H), 2.16 (br, 2 H),
1.86–1.64 (m, 5 H), 1.23 (t, J = 7.1 Hz, 3 H, CH3). 19F NMR (282
MHz, CDCl3): d = –81.8 (t, J = 12.1 Hz, 2 F, CF2O), –88.8 (d, J =
8.2 Hz, 2 F, OCF2), –114.2 (br, 2 F, CF2S), –137.7 (dt, J = 56 Hz,
5.1 Hz, 2 F, HCF2).
19F NMR (282 MHz, CDCl3): d = –74.1 (s, 2 F, ClCF2), –82.2 (t,
J = 13 Hz, 2 F, CF2O), –87.2 (t, J = 12.3 Hz, 2 F, OCF2), –114.1 (s,
2 F, CF2S).
MS (EI, 70 eV): m/z (%) = 487/485 (M+, 11/27), 458/456 (M+ – Et,
37/96), 442/440 (M+ – EtO, 13/35), 170 (M+ – RfSO2, 63), 141
+
+
(M+ – RfSO2Et, 99), 96 (C6H8O+, 80), 67 (C5H7 , 54), 55 (C4H7 ,
100), 41(C3H5 , 58).
+
Anal. Calcd for C13H16ClF8NO5S: C, 32.13; H, 3.30; N, 2.88.
Found: C, 32.45; H, 3.13; N, 3.23.
2-Isobutoxy-4-[2-(2-chloro-1,1,2,2-tetrafluoroethoxy)-1,1,2,2-
tetrafluoroethanesulfonyl]-1-oxa-4-azaspiro[4.4]nonane (6bbb)
Colorless oil.
IR (KBr): 2963, 1397, 1205, 1174, 1041, 970 cm–1.
MS (EI, 70 eV): m/z (%) = 451 (M+, 32), 422 (M+ – Et, 100), 406
(M+ – EtO, 43), 170 (M+ – RfSO2, 53), 141 (M+ – RfSO2Et, 81), 96
+
+
+
(C6H8O+, 70), 67 (C5H7 , 46), 55 (C4H7 , 85), 41 (C3H5 , 50).
Anal. Calcd for C13H17F8NO5S: C, 34.59; H, 3.77; N, 3.10. Found:
C, 34.99; H, 3.80; N, 3.50.
1H NMR (300 MHz, CDCl3): d = 5.22 (dd, J = 5.1 Hz, 1.5 Hz, 1 H,),
3.88 (dd, J = 10.2 Hz, 5.1 Hz, 1 H), 3.78 (dd, J = 10.2 Hz, 6.0 Hz,
1 H), 3.51 (dd, J = 9.0 Hz, 6.6 Hz, 1 H), 3.20 (dd, J = 9.0 Hz, 6.0
Hz, 1 H), 2.39–2.34 (m, 1 H), 2.16 (br, 2 H), 1.92–1.67 (m, 6 H),
0.93 (d, J = 6.9 Hz, 3 H, CH3), 0.92 (d, J = 6.6 Hz, 3 H, CH3).
19F NMR (282 MHz, CDCl3): d = –74.1 (s, 2 F, ClCF2), –82.2 (t,
J = 12.8 Hz, 2 F, CF2O), –87.1 (t, J = 12.7 Hz, 2 F, OCF2), –114.2
(s, 2 F, CF2S).
2-Isobutoxy-4-[1,1,2,2-tetrafluoro-2-(1,1,2,2-tetrafluoroeth-
oxy)ethanesulfonyl]-1-oxa-4-azaspiro[4.4]nonane (6cbb)
Colorless oil.
IR (KBr): 2963, 1395, 1284, 1143, 1034 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.86 (tt, J = 52.5 Hz, 3.0 Hz, 1 H,
HCF2), 5.22 (dd, J = 4.8 Hz, 1.5 Hz, 1 H), 3.87 (dd, J = 10.2 Hz, 5.1
Hz, 1 H), 3.77 (dd, J = 10.5 Hz, 1.8 Hz, 1 H), 3.51 (dd, J = 9.3 Hz,
6.9 Hz, 1 H), 3.20 (dd, J = 9.3 Hz, 6.3 Hz, 1 H), 2.38–2.32 (m, 1 H),
2.15 (br, 2 H), 1.92–1.69 (m, 6 H), 0.926 (d, J = 6.6 Hz, 3 H, CH3),
0.919 (d, J = 6.9Hz, 3 H, CH3).
MS (EI, 70 eV): m/z (%) = 515/513 (M+, 3/8), 486/484 (M+ – Et, 5/
13), 442/440 (M+ – i-BuO, 5/14), 198 (M+ –RfSO2, 11), 142 (M+ –
+
RfSO2-i-Bu, 29), 96 (C6H8O+, 30), 57 (i-Bu+, 100), 41 (C3H5 , 40).
Anal. Calcd for C15H20ClF8NO5S: C, 35.05; H, 3.89; N, 2.73.
Found: C, 35.27; H, 4.07; N, 2.80.
13C NMR (75 MHz, CDCl3): d = 99.7, 74.6, 54.3, 28.3, 22.6, 22.1,
27.9, 19.1, 18.8.
5-Ethoxy-3-[1,1,2,2-tetrafluoro-2-(1,1,2,2-tetrafluoroeth-
oxy)ethanesulfonyl]-2,2-dimethyloxazolidine (6caa)
Colorless oil.
IR (KBr): 2985, 1384, 1284, 1163, 1046, 1000 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.86 (tt, J = 52.5 Hz, 3.0 Hz, 1 H,
HCF2), 5.24 (dd, J = 4.5 Hz, 1.8 Hz, 1 H), 3.86–3.75 (m, 3 H), 3.52
(dq, J = 7.2 Hz, 9.3 Hz, 1 H), 1.75 (s, 3 H, CH3), 1.64 (s, 3 H, CH3),
1.23 (t, J = 7.0 Hz, 3 H, CH3).
19F NMR (282 MHz, CDCl3): d = –81.8 (t, J = 11.0 Hz, 2 F, CF2O),
–88.9 (m, 2 F, OCF2), –114.6 (br, 2 F, CF2S), –137.8 (dt, J = 54 Hz,
5.5 Hz, 2 F, HCF2).
19F NMR (282 MHz, CDCl3): d = –81.8 (t, J = 13.1 Hz, 2 F, CF2O),
–88.8 (d, J = 9.0 Hz, 2 F, OCF2), –114.3 (br, 2 F, CF2S), –137.8 (dt,
J = 53.9 Hz, 5.1 Hz, HCF2).
MS (EI, 70 eV): m/z (%) = 479 (M+, 11), 450 (M+ – Et, 20), 406 (M+
– i-BuO, 18), 198 (M+ – RfSO2, 12), 142 (M+ –RfSO2-i-Bu, 31), 96
(C6H8O+, 31), 57 (i-Bu+, 100), 41 (C3H5 , 43).
+
Anal. Calcd for C15H21F8NO5S: C, 37.58; H, 4.38; N, 2.92. Found:
C, 37.74; H, 4.64; N, 2.96.
5-Ethoxy-3-(nonafluorobutane-1-sulfonyl)-2,2-dimethyloxazo-
lidine (6daa)
Colorless oil.
IR (KBr): 2985, 1385, 1238, 1140, 1046, 1005 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.25 (dd, J = 4.2 Hz, 1.8 Hz, 1 H),
3.87–3.75 (m, 3 H), 3.51 (dq, J = 7.2 Hz, 9.6 Hz, 1 H), 1.76 (s, 3 H,
CH3), 1.65 (s, 3 H, CH3), 1.24 (t, J = 6.3 Hz, 3 H, CH3).
19F NMR (282 MHz, CDCl3): d = –81.3 (m, 3 F, CF3), –111.3 (br, 2
F, CF2S), –121.5 (s, 2 F, CF2), –126.4 (m, 2 F, CF2).
MS (EI, 70 eV): m/z (%) = 410 (M+ – Me, 100), 380 (M+ – EtO, 30),
129 (M+ – RfSO2NH, 62), 70 (M+ – RfSO2NH-C3H6O, 39).
Anal. Calcd for C11H15F8NO5S: C, 31.06; H, 3.53; N, 3.29. Found:
C, 31.01; H, 3.82; N, 3.35.
5-Isobutoxy-3-[1,1,2,2-tetrafluoro-2-(1,1,2,2-tetrafluoroeth-
oxy)ethanesulfony]-2,2-dimethyloxazolidine (6cba)
Colorless oil.
IR (KBr): 2963, 1384, 1196, 1162, 1032 cm–1.
MS (EI, 70 eV): m/z (%) = 412 (M+ – Me, 91), 382 (M+ – EtO, 31),
129 (M+ – RfSO2NH, 84), 70 (M+ – RfSO2NHC3H6O, 100), 43
1H NMR (300 MHz, CDCl3): d = 5.87 (tt, J = 52.2 Hz, 3.0 Hz, 1 H,
HCF2), 5.22 (dd, J = 4.5 Hz, 1.8 Hz, 1 H), 3.87–3.78 (m, 2 H), 3.53
(dd, J = 9.0 Hz, 6.3 Hz, 1 H), 3.19 (dd, J = 9.0 Hz, 6.3 Hz, 1 H),
1.92–1.81 (m, 1 H), 1.75 (s, 3 H, CH3), 1.65 (s, 3 H, CH3), 0.923 (d,
J = 6.6 Hz, 3 H, CH3), 0.916 (d, J = 6.6 Hz, 3 H, CH3).
+
(C3H7 , 60).
Anal. Calcd for C11H14F9NO4S: C, 30.91; H, 3.28; N, 3.28. Found:
C, 30.75; H, 3.59; N, 3.35.
Synthesis 2005, No. 13, 2137–2142 © Thieme Stuttgart · New York

2142
P. He, S. Zhu
PAPER
5-Isobutoxy-3-(nonafluorobutane-1-sulfonyl)-2,2-dimethylox-
azolidine (6dba)
Colorless oil.
19F NMR (282 MHz, CDCl3): d = –65.2 (t, J = 5.6 Hz, 2 F, ICF2),
–82.1 (d, J = 13.0 Hz, 2 F, CF2O), –85.8 (m, 2 F, OCF2), –113.5 (m,
2 F, CF2S).
IR (KBr): 2962, 1385, 1238, 1154, 1034 cm–1.
MS (EI, 70 eV): m/z (%) = 598 (M+ – CH3, 22), 536 (M+ – Ph, 32),
+
+
227 (IC2F4 , 8), 177 (ICF2 , 6), 191 (M+ – RfSO2CH3, 30), 91
1H NMR (300 MHz, CDCl3): d = 5.22 (dd, J = 3.6 Hz, 2.0 Hz, 1 H),
3.86–3.82 (m, 2 H), 3.53 (dd, J = 9.0 Hz, 6.9 Hz, 1 H), 3.20 (dd,
J = 9.0 Hz, 6.3 Hz, 1 H), 1.92–1.81 (m, 1 H), 1.76 (s, 3 H, CH3),
1.65 (s, 3 H, CH3), 0.921 (d, J = 7.2 Hz, 3 H, CH3), 0.914 (d, J = 6.0
Hz, 3 H, CH3).
+
(C7H7 , 100).
Anal. Calcd for C16H16F8INO5S: C, 31.32; H, 2.61; N, 2.28. Found:
C, 31.65; H, 2.70; N, 2.32.
13C NMR (75 MHz, CDCl3): d = 99.9, 74.6, 54.1, 28.5, 28.2, 18.9,
18.8.
Acknowledgment
This work supported by the National Science Foundation of China
(Nos. 20372077 and 20472106).
19F NMR (282 MHz, CDCl3): d = –81.2 (t, J = 9.6 Hz, 3 F, CF3),
–111.3 (br, 2 F, CF2S), –121.5 (s, 2 F, CF2), –126.3 (m, 2 F, CF2).
MS (EI, 70 eV): m/z (%) = 440 (M+ – Me, 28), 382 (M+ – i-BuO,
+
29), 70 (M+ – RfSO2NHC3H6O, 57), 57 (i-Bu+, 100), 43 (C3H7 , 47).
References
Anal. Calcd for C13H18F9NO4S: C, 34.29; H, 3.96; N, 3.08. Found:
C, 34.51; H, 3.94; N, 3.21.
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2-Ethoxy-4-(nonafluorobutane-1-sulfonyl)-1-oxa-4-aza-
spiro[4.4]nonane (6dab)
Colorless oil.
IR (KBr): 2979, 1397, 1239, 1195, 1142, 1046 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.25 (dd, J = 5.1 Hz, 1.5 Hz, 1 H),
3.92–3.74 (m, 3 H), 3.53 (dq, J = 7.2 Hz, 9.6 Hz, 1 H), 2.40–2.32
(m, 1 H), 2.17 (br, 2 H), 1.87–1.65 (m, 5 H), 1.23 (t, J = 7.2 Hz, 3
H, CH3).
19F NMR (282 MHz, CDCl3): d = –81.1 (m, 3 F, CF3), –110.6 (br, 2
F, CF2S), –121.5 (s, 2 F, CF2), –126.2 (m, 2 F, CF2).
MS (EI, 70 eV): m/z (%) = 453 (M+, 35), 424 (M+ – Et, 100), 408
(M+ – EtO, 58), 170 (M+ – RfSO2, 58), 141 (M+ – RfSO2Et, 86), 96
(C6H8O+, 77), 67 (C5H7 , 51), 55 (C4H7 , 85), 41 (C3H5 , 55).
+
+
+
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Anal. Calcd for C13H16F9NO4S: C, 34.44; H, 3.53; N, 3.09. Found:
C, 34.51; H, 3.52; N, 3.21.
2-Isobutoxy-4-(nonafluorobutane-1-sulfonyl)-1-oxa-4-aza-
spiro[4.4]nonane (6dbb)
Colorless oil.
IR (KBr): 2963, 1397, 1238, 1142, 1034 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.22 (dd, J = 4.5 Hz, 1.5 Hz, 1 H),
3.90–3.78 (m, 2 H), 3.51 (dd, J = 9.0 Hz, 6.9 Hz, 1 H), 3.21 (dd,
J = 9.0 Hz, 6.0 Hz, 1 H), 2.39–2.32 (m, 1 H), 2.16 (br, 2 H), 1.94–
1.68 (m, 6 H), 0.926 (d, J = 6.6 Hz, 3 H, CH3), 0.919 (d, J = 6.6 Hz,
3 H, CH3).
19F NMR (282 MHz, CDCl3): d = –81.1 (m, 3 F, CF3), –110.9 (br, 2
F, CF2S), –121.4 (s, 2 F, CF2), –126.2 (m, 2 F, CF2).
MS (EI, 70 eV): m/z (%) = 481 (M+, 16), 452 (M+ – Et, 21), 408
(M+ – i-BuO, 43), 198 (M+ – RfSO2, 15), 142 (M+ – RfSO2-i-Bu, 29),
+
96 (C6H8O+, 36), 57 (i-Bu+, 100), 41 (C3H5 , 45).
Anal. Calcd for C15H20F9NO4S: C, 37.42; H, 4.16; N, 2.91. Found:
C, 37.30; H, 4.16; N, 3.17.
5-Ethoxy-3-[1,1,2,2-tetrafluoro-2-(1,1,2,2-tetrafluoro-2-iodo-
ethoxy)ethanesulfonyl]-2-methyl-2-phenyloxazolidine (6aac)
Colorless oil.
IR (KBr): 2980, 1398, 1292, 1151, 915 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.59–7.33 (m, 5 H, ArH), 5.36 (t,
J = 4.8 Hz, 1 H), 4.13 (dd, J = 5.7 Hz, 11.4 Hz, 1 H), 3.71 (t, J = 7.2
Hz, 1 H), 3.56–3.45 (m, 2 H), 1.99 (s, 3 H, CH3), 1.01 (t, J = 7.2 Hz,
3 H, CH3).
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Synthesis 2005, No. 13, 2137–2142 © Thieme Stuttgart · New York