1-Amino-1-hydroxymethylcyclobutane derivatives via intramolecular amination of nonclassical cyclopropylmethyl cation

Article abstract of DOI:10.1007/s10593-017-2162-1

[Figure not available: see fulltext.] Bis(trichloroacetimidoyloxymethyl)cyclopropanes provide intramolecular amination products of intermediate cyclobutyl or cyclopropylmethyl carbenium ion when exposed to Lewis acid catalyst or thermal ionization. The ra

Full text of DOI:10.1007/s10593-017-2162-1

DOI 10.1007/s10593-017-2162-1
Chemistry of Heterocyclic Compounds 2017, 53(9), 989–996
Dedicated on the occasion of Prof. Ivars Kalvinsh 70th anniversary
1-Amino-1-hydroxymethylcyclobutane derivatives via
intramolecular amination of nonclassical cyclopropylmethyl cation
Marija Skvorcova1, Liene Grigorjeva1, Aigars Jirgensons1*
1 Latvian Institute of Organic Synthesis,
21 Aizkraukles St., Riga LV-1006, Latvia; е-mail: aigars@osi.lv
Submitted May 29, 2017
Accepted July 17, 2017
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2017, 53(9), 989–996
Bis(trichloroacetimidoyloxymethyl)cyclopropanes provide intramolecular amination products of intermediate cyclobutyl or cyclopropyl-
methyl carbenium ion when exposed to Lewis acid catalyst or thermal ionization. The ratio of the two amination products of cyclobutyl
carbenium ion depends primarily on the substituent at the alkoxymethyl group of the substrate and can be altered by the solvent used and
the ionization conditions. An oxazoline derivative forms as the major amination product in the case of unsubstituted bis(trichlo-
roacetimidoyloxymethyl)cyclopropane or if the substrate contains isopropyl or alkoxymethyl substituents. The amination of cyclobutyl
carbenium ion formed in situ proceeds with high diastereoselectivity leading to exclusive formation of trans-cyclobutane derivatives.
The latter can be transformed to N-Boc-protected cyclobutane-based amino alcohols in high yields.
Keywords: amino alcohol, carbenium ion, cyclobutane, 5-oxa-7-azaspiro[2.5]oct-6-ene, 5-oxa-7-azaspiro[3.4]oct-5-ene, 1,3-oxazine,
oxazoline, trichloroacetimidate, Lewis acid.
Cyclopropylmethyl cation, due to its nonclassical nature,
can be attacked at three possible sites leading to
homoallyl,1–11 cyclopropylmethyl,1,8,12,13 or cyclobutyl13–20
derivatives. As a part of our ongoing interest to develop the
amination reactions of carbenium ions,21–24 we have
investigated amination of the cyclopropylmethyl cation25
depending on the cyclopropane substitution pattern in bis-
(trichloroacetimidate) system 1. Based on our previous
research it could be predicted that in substrate 1, the
imidate function at the most substituted carbon will act as a
leaving group when activated with Lewis acid.21,23,26 This
would generate carbenium ion which is trapped with other
imidate moiety as N-nucleophile (Scheme 1). Depending
on the regioselectivity of the intramolecular imidate attack
on the carbenium ion the following products could be
expected: [3.4]-spirocyclic oxazoline 2 if cyclobutyl
carbenium ion A1 is aminated; [2.5]-spirocyclic dihydro-
oxazine 3 if cyclopropylmethyl carbenium ion A2 is
aminated; tetrahydrooxazepine derivative 4 if homoallylic
ion A3 is aminated. Oxazoline derivatives 2 are precursors
of cyclobutane-based β-amino alcohols and α-amino acids
with potential utility in medicinal chemistry.27 This
prompted us to investigate if this type of products can be
prepared from readily available bis(imidates) 1.
Scheme 1
0009-3122/17/53(09)-0989©2017 Springer Science+Business Media New York
989

Chemistry of Heterocyclic Compounds 2017, 53(9), 989–996
Table 2. Bis(imidate) 1b rearrangement product 2b vs oxazine 3b
Diol 7a for the synthesis of bis(imidate) 1a is com-
mercially available. The synthesis of other diols 7b–f was
started from β-ketoesters 5b–f which were alkylated with
dibromoethane to give esters of 1-acylcyclopropane
carboxylic acids 6b–f (Scheme 2). The latter were reduced
to diols 7b–f and all the diols 7a–f were transformed to bis-
(imidates) 1a–f in DBU-catalyzed reaction.
formation depending on Lewis acid and solvent used
Scheme 2
Entry
Catalyst
Solvent
Ratio 2b:3b*
(CH2Br2)2
1
2
3
BF3·OEt2
AlCl3
DCM
DCM
PhMe
1:8.4 (85%**)
1:>99
O
O
O
O
LiAlH4
K2CO3, cat. TBAB
R1O
R
R1O
R
6b f
–
DMF, rt
70–97%
THF, 0°C–rt
72–97%
AlCl3
1:>99
5b f
–
* GC-MS data.
** Yield of oxazine 3b.
Cl3CCN
R
R
cat. DBU
HN
Cl3C
O
O
NH
CCl3
coordinating Lewis acid catalysts investigated (entries 2, 3),
BF3·Et2O induced considerably improved amination
product ratio in favor to compound 2a. The efficiency of
multicoordinating Lewis acids FeCl3 and AlCl3 was
investigated in several solvents. Acetonitrile inhibited the
reaction leading to incomplete conversion of starting
material 1a (entries 4, 7). In the case of FeCl3 as a Lewis
acid, DCM was superior to Et2O for more selective
oxazoline 2a formation (entries 5, 6) while in the case of
AlCl3 oxazoline 2a formed exclusively in both solvents
(entries 8, 9). From the experiment using AlCl3 as catalyst
in Et2O, product 2a was isolated in 75% yield.
Next, bis(imidate) 1b bearing phenyl substituent was
subjected to the action of BF3·Et2O and AlCl3 as Lewis
acid catalysts (Table 2). For this substrate, both catalysts
induced preferential formation of dihydrooxazine 3b as a
product of cyclopropylmethyl carbenium ion A2 amination.
Such regioselectivity could be explained by stabilizing
effect of the phenyl substituent on the carbenium ion that
induced electron distribution in the favor to cyclopropyl-
methyl carbenium ion A2 (Scheme 1).
DCM, 0°C
71–83%
OH OH
7a–f
1a–f
1, 7 a R = H;
1, 5–7 b R = Ph, R1 = Et; c R = n-Pr, R1 = Et; d R = i-Pr, R1 = Me;
e R = CH2OMe, R1 = Me; f R = CH2OBn, R1 = Et
Bis(trichloroacetimidate) 1a derived from 1,1-bis(hydroxy-
methyl)cyclopropane (7a) was subjected to a range of acid
catalysts to induce the carbenium ion formation (Table 1).
Under these conditions, the formation of two main
amination products – spirocyclic oxazoline 2a and dihydro-
oxazine 3a, was observed by NMR spectroscopy while
tetrahydrooxazepine derivative 4 was no detected.
The ratio of oxazoline 2a and dihydrooxazine 3a varied
depending on the acid catalyst and the solvent used.
Brønsted acid catalyst (TsOH) provided products 2a and 3a
in equal ratio (Table 1, entry 1). Out of the two mono-
Table 1. Bis(imidate) 1a rearrangement product 2a vs
oxazine 3a formation depending on acid catalyst and solvent
When bis(imidate) 1c bearing n-propyl substituent
was treated with the catalysts, such as TMSOTf,
Cu(OTf)2·C6H6, the desired oxazoline 2c formed as the
minor product (Table 3, entries 1, 2). Surprisingly, in the
case of AlCl3 the ratio of products 2c and 3c was found to
be highly favorable to oxazoline 2c (entry 3). However, the
isolated yield of product 2c was low (37%) which
prompted us to investigate the reaction more carefully.
When the reaction was performed at lower temperature
(–50°C, 2 h) in the presence of AlCl3, the ratio of products
2c and 3c was 1:1 and NMR yield of oxazoline 2c was 45%
(using 1,4-bis(trichloromethyl)benzene as an internal
standard). Increasing the temperature (rt, 3 h) led to
selective formation of oxazoline 2c (product ratio 2c/3c
>99:1) with the same NMR yield – 45%. This implies that
dihydrooxazine 3c slowly decomposes under the reaction
conditions resulting in the increased content of oxazoline
2c. The performance of several Lewis acid catalysts was
also investigated in diethyl ether as a solvent. In the case of
TMSOTf, almost exclusive formation of dihydrooxazine 3c
was observed (entry 4), while nonselective reaction took
Catalyst (10 mol %)
+
O
HN
N
NH
O
N
O
O
Solvent, 4 A MS, rt
Cl3C
CCl3
CCl3
CCl3
1a
2a
3a
Ratio
Entry Catalyst Solvent Time, h Conversion, %*
2a:
3a***
1
2
3
4
5
6
7
8
9
p-TsOH
TMSOTf
BF3·OEt2
FeCl3
DCM
DCM
DCM
MeCN
Et2O
24
1.5
24
24
24
24
24
24
0.1
>99
>99
1:1
1.7:1
6.6:1
43:1
3:1
>99
~50
FeCl3
>99
FeCl3
DCM
MeCN
Et2O
>99
5.6:1
26:1
AlCl3
50
AlCl3
>99 (75**)
>99
>99:1
>99:1
AlCl3
DCM
* TLC and GC-MS data.
** Isolated yield of compound 2a.
*** GC-MS data.
.
place in the case of FeCl3 and BF3 Et2O (entries 5, 6).
990

Chemistry of Heterocyclic Compounds 2017, 53(9), 989–996
Table 3. Bis(imidate) 1c rearrangement product 2c vs
Table 4. Bis(imidate) 1d rearrangement product 2d vs
dihydroxazine 3d formation depending
on the reaction conditions
oxazine 3c formation depending
on the reaction conditions
Ratio
NMR yield
Entry Catalyst
Solvent
Time
Entry
Catalyst
Solvent
Time
Ratio 2c:3c*
2d:3d* of compound 2d**, %
1
2
3
4
5
6
7
8
9
TMSOTf
Cu(OTf)2·C6H6
AlCl3
DCM
DCM
DCM
Et2O
Et2O
Et2O
Et2O
THF
10 min
10 min
1.5 h
1:3.8
1:5.7
1
2
3
4
5
6
7
8
TMSOTf
BF3·OEt2
AlCl3
PhMe
PhMe
PhMe
DCM
3 min
3 min
3 min
3 min
4 min
2 min
3 h
2.9:1
9.1:1
4.6:1
1.9:1
2.3:1
3.0:1
7:1
66
67 (70***)
40:1** (37%***)
1:>99
70
TMSOTf
FeCl3
1.5 h
TMSOTf
BF3·Et2O
AlCl3
67
5.5 h
1.4:1
DCM
73
76
BF3·OEt2
–*4
–*4
3 min
3 days
20 h
1.4:1
DCM
1.7:1 (59%*5)
1:2 (26%*5)
2:1 (64%*5)
–4*
PhMe
Dioxane
89 (88***)
60
–4*
3.5 h
2:1
–*4
PhMe
30 min
* GC-MS data.
* GC-MS data.
** Determined using 1,4-bis(trichloromethyl)benzene as an internal standard.
*** Isolated yield of compound 2d.
** Dihydrooxazine 3c decomposes during the reaction.
*** Isolated yield of oxazoline 2c.
4* Refluxing.
*4 Refluxing.
5
*
NMR yield determined using 1,4-bis(trichloromethyl)benzene as an
internal standard.
cyclization (entries 2 and 4). Comparing both the ratio of
cyclization products 2e,f and 3e,f and the NMR yields, it
was observed that thermally induced reaction leads to
higher yields of oxazolines 2e,f. This was confirmed by
high isolated yields of these compounds. It is an interesting
to note that oxymethyl group-containing bis(imidates) 1e,f
give higher yield of oxazolines 2e,f compared to propyl-
substituted bis(imidate) 2c. This could be explained by
destabilizing (–I) effect of oxygen on carbenium ion which
shifts the electron density in favor to cyclobutyl carbenium
ion A1.
Bis(imidate) 1c was also subjected to thermal ionization
conditions by refluxing in the selected solvents (entries 7–9).
The reactions in Et2O and THF required long reaction time
to achieve full conversion of starting material 1c, while the
reaction proceeded in acceptable time in toluene. Thermal
reaction conditions induced the formation of both
oxazoline 2c and dihydrooxazine 3c with little preference
for the rearrangement product 2c in Et2O and toluene as the
solvents. The NMR yields of oxazoline 2c were determined
in crude reaction mixtures which were in accordance with
the ratio of compounds 2c and 3c.
Table 5. Bis(imidate) 1e,f rearrangement product 2e,f vs
dihydroxazine 3e,f formation depending
on the reaction conditions
Bis(imidate) 1d bearing bulky isopropyl substituent
gave the mixture of products 2d and 3d with preference for
oxazoline 2d formation in Lewis acid-catalyzed (TMSOTf,
BF3·Et2O, AlCl3) reaction (Table 4). The NMR yields of
product 2d were determined in the crude reaction mixture.
These were similar for all the reaction conditions
investigated, however the ratio of products 2d and 3d was
different. This indicates the difference in stability of
dihydrooxazine 3d depending on Lewis acid, as it was
observed in the case of analog 3c. Using BF3·Et2O as a
catalyst, the best ratio of products 2d and 3d was obtained
and in this case, the product 2d was isolated in the yield
which matched the NMR yield (entry 2). Thermal bis-
(imidate) 1d cyclization in two solvents was also per-
formed (entries 7, 8). The reaction in toluene provided
products 2d and 3d with high preference for the desired
oxazoline 2d which was isolated in high yield.
Reaction
conditions
Entry
R2
Ratio 2e(f):3e(f)*
Yield, %**
1
2
3
4
Me
Me
Bn
Bn
BF3·OEt2, rt
3.9:1
9:1
55
PhMe, 115°C
BF3·OEt2, rt
PhMe, 115°C
68 (80***)
49
3.2:1
7.1:1
70 (85***)
* GC-MS data.
Oxymethyl group-containing imidates 1e,f were
subjected to both Lewis acid-catalyzed (BF3·Et2O) (Table 5,
entries 1 and 3) and thermally induced (toluene at reflux)
** Summary yield of compounds 2 and 3 determined by NMR spectro-
scopy, using 1,4-bis(trichloromethyl)benzene as an internal standard.
*** Isolated yield of mixture of products 2e,f and 3e,f.
991

Chemistry of Heterocyclic Compounds 2017, 53(9), 989–996
Scheme 3. Stereoinduction model for the formation
of oxazolines 2c–f as trans-isomers
Experimental
NOE
1H and 13C NMR spectra were recorded on a Varian
Mercury spectrometer (400 and 100 MHz, respectively)
using the residual chloroform signal as internal standard.
LC/ESI-MS were performed on a Waters 2695 Alliance
instrument, column: Phenomenex, Gemini 5u C18 11OA,
50 × 2 mm, 5 µm; mobile phase: acetonitrile – 0.1% aq
HCOOH. Flash chromatography was carried out using
Merck Kieselgel (230–400 mesh). Elemental analyses were
R
Cl3C
NH
H
H
H
NOE
H
O
1c–f
H
C
N
O
R
A1
CCl3
2c–f
performed using
a
Carlo-Erba EA1108 Elemental
Table 6. Hydrolysis of oxazolines 2a,c–f
to 1-aminocyclobutylcarbinols 8a,c–f
Analyzer. Thin-layer chromatography was performed on
silica gel and was visualized by staining with KMnO4. All
reactions were carried out under argon atmosphere.
Solvents were purified and dried by standard procedures
prior to use; petroleum ether of boiling range 60–80°C was
used. Reagents and starting materials were obtained from
commercial sources and used as received.
Ethyl
1-benzoylcyclopropanecarboxylate
(6b).28
K2CO3 (6.910 g, 50.0 mmol) followed by 1,2-dibromo-
ethane (2.25 ml, 26.0 mmol) and TBAB (0.032 g,
0.1 mmol) were added to a solution of β-oxoester 5b (3.844 g,
20.0 mmol) in DMF (12 ml). The mixture was stirred at
room temperature for 20 h till the full consumption of
starting material (TLC control: eluent petroleum ether –
EtOAc, 10:1). To the reaction mixture, EtOAc (25 ml) and
H2O (35 ml) were added and the organic phase was separated.
The aqeuous phase was washed with EtOAc (3 × 25 ml)
and the combined organic phases were washed with
saturated aqeuous NaCl (2×30 ml). Combined organic
phase was dried over Na2SO4, filtered, and concentrated
under reduced pressure. Yield 4.250 g (97%). Colorless oil.
Compound 6b was used for the next step without additional
Entry
Product
R
Yield, %
1
2
3
4
5
8a*
8c
H
59
89
70
73
69
n-Pr
i-Pr
8d
8e
CH2OMe
CH2OBn
8f
* Commercially available.
It is noteworthy that bis(imidates) 1c–f provided
oxazolines 2c–f as a single diastereomers with trans confi-
guration. The configuration of these products was con-
firmed by 2D NMR NOESY experiments (see Scheme 3
for diagnostic interactions). Such a stereochemical outcome
could be explained by stereoinduction model where the
amination takes place from the sterically less hindered face
of close-to-planar cyclobutyl carbenium ion A1.
In order to demonstrate the utility of oxazolines, these
were transformed to Boc-protected cyclobutane-based
amino alcohols 8a,c–f in moderate to good yields (Table 6).
For this purpose, oxazolines 2a,c–f were hydrolyzed in
acidic conditions and the resulting amino alcohols were
treated with Boc2O in weakly basic conditions.
Bis(trichloroacetimidoyloxymethyl)cyclopropanes provide
an intramolecular amination products of intermediate
cyclobutyl carbenium ion or cyclopropylmethyl carbenium
ion when exposed to acid catalysis or thermal ionization.
The ratio of the two amination products depends primarily
on the substituent at the oxymethyl group of the substrate
and can be altered by the solvent and the ionization
conditions. Amination product of cyclobutyl carbenium ion –
oxazoline, forms as a major product in the case of
unsubstituted bis(trichloroacetimidoyloxymethyl)cyclopro-
pane or if the substrate contains isopropyl or oxymethyl
substituent. The amination of in situ formed cyclobutyl
carbenium ion proceeds with high diastereoselectivity
leading to exclusive formation of trans-cyclobutane-
containing oxazolines. These can be transformed to N-Boc-
protected cyclobutane-based amino alcohols in high yields.
1
purification. H NMR spectrum, δ, ppm (J, Hz): 0.95 (3H,
t, J = 7.0, OCH2CH3); 1.51–1.55 (2H, m, CH2CH2); 1.59–
1.62 (2H, m, CH2CH2); 4.04 (2H, q, J = 7.0, OCH2CH3);
7.42–7.46 (2H, m, H Ph); 7.53–7.56 (1H, m, H Ph); 7.89–
7.91 (2H, m, H Ph).
Ethyl 1-butyrylcyclopropanecarboxylate (6c) was
prepared analogously to compound 6b from β-oxoester 5c
(3.704 g, 20.0 mmol), K2CO3 (6.910 g, 50.0 mmol),
(CH2)2Br2 (2.25 ml, 26.0 mmol), TBAB (0.032 g,
0.1 mmol), DMF (15 ml). Yield 2.865 g (80%). Colorless
oil. 1H NMR spectrum, δ, ppm (J, Hz): 0.91 (3H, t, J = 7.3,
CH2CH2CH3); 1.28 (3H, t, J = 7.1, OCH2CH3); 1.42 (4H, s,
CH2CH2); 1.58–1.66 (2H, m, CH2CH2CH3); 2.81 (2H, t,
J = 7.3, CH2CH2CH3); 4.20 (2H, q, J = 7.1, OCH2CH3).
13C NMR spectrum, δ, ppm: 13.9; 14.3; 17.8; 18.5; 35.0;
44.0; 61.4; 171.3; 205.5. Found, m/z: 185.1197 [M+H]+.
C10H17O3. Calculated, m/z: 185.1178.
Methyl 1-isobutyrylcyclopropanecarboxylate (6d)
was prepared analogously to compound 6b from β-oxoester
5d (4.040 g, 28.00 mmol), K2CO3 (9.682 g, 70.00 mmol),
(CH2)2Br2 (3.15 ml, 36.40 mmol), TBAB (0.045 g,
0.14 mmol), DMF (20 ml). Yield 3.425 g (73%). Yellow
1
oil. H NMR spectrum, δ, ppm (J, Hz): 1.10–1.12 (6H, m,
CH(CH3)2); 1.41–1.44 (4H, m, CH2CH2); 3.38 (1H, septet,
J = 6.8, CH(CH3)2); 3.74 (3H, s, OCH3). 13C NMR
spectrum, δ, ppm: 18.2; 19.2; 33.9; 39.3; 52.5; 171.9;
992

Chemistry of Heterocyclic Compounds 2017, 53(9), 989–996
209.4. Found, m/z: 171.1015 [M+H]+. C9H15O. Calculated,
CH(CH3)2); 2.44 (1H, br. s, OH); 2.50 (1H, d, J = 9.6,
CHOH); 2.95 (1H, d, J =11.4) and 4.26 (1H, d, J = 11.4,
CH2OH).
m/z: 171.1021.
Methyl 1-(2-methoxyacetyl)cyclopropanecarboxylate
(6e) was prepared in analogy to compound 6b from
β-oxoester 5e (1.470 g, 10.00 mmol), K2CO3 (3.470 g,
25.11 mmol), (CH2)2Br2 (1.57 ml, 13.00 mmol), TBAB
(0.016 g, 0.05 mmol), DMF (15 ml). Yield 1.198 g (75%).
Colorless oil. 1H NMR spectrum, δ, ppm (J, Hz): 1.51–1.58
(4H, m, CH2CH2); 3.41 (3H, s, CH2OCH3); 3.73 (3H, s,
OCH3); 4.50 (2H, s, CH2OCH3). 13C NMR spectrum, δ, ppm:
19.6; 32.9; 52.3; 59.3; 77.8; 171.0; 202.7. No ionization in
HRMS or GC/MS.
Ethyl 1-[2-(benzyloxy)acetyl]cyclopropanecarboxylate
(6f) was prepared analogously to compound 6b from
β-oxoester 5f (1.000 g, 4.23 mmol), K2CO3 (1.46 g,
10.58 mmol), (CH2)2Br2 (0.66 ml, 5.50 mmol), TBAB
(0.01 g, 0.02 mmol), DMF (10 ml). Yield 0.776 g (70%).
Colorless oil. 1H NMR spectrum, δ, ppm (J, Hz): 1.21 (3H,
t, J = 7.2, OCH2CH3); 1.48–1.54 (4H, m, CH2CH2); 4.14 (2H,
q, J = 7.2, OCH2CH3); 4.57 (4H, s, OCH2Ph, OCH2C(=O));
7.27–7.35 (5H, m, H Ph). 13C NMR spectrum, δ, ppm: 4.0;
19.3; 33.3; 61.3; 73.5; 75.3; 127.9 (2C); 128.5; 137.5;
170.6; 202.9. Found, m/z: 285.1103 [M+Na]+. C15H18O4Na.
Calculated, m/z: 285.1103.
1-[1-(Hydroxymethyl)cyclopropyl]-2-methoxyethanol
(7e) was prepared analogously to compound 7b from
β-oxoester 6e (1.07 g, 6.21 mmol), LiAlH4 (0.94 g,
2.49 mmol), THF (35 ml). Yield 0.69 g (74%). Colorless
1
oil. H NMR spectrum, δ, ppm (J, Hz): 0.45–0.52 (2H, m,
CH2CH2); 0.59–0.66 (2H, m, CH2CH2); 2.68 (1H, d,
J = 3.6, OH); 2.84 (1H, dd, J = 6.3, J = 5.0, OH); 3.25 (1H,
dt, J = 7.2, J = 3.5, CHAOCH3); 3.37–3.43 (4H, m,
CHBOCH3); 3.53–3.67 (3H, m, CH2OH, CHCH2OCH3).
13C NMR spectrum, δ, ppm: 7.7; 10.7; 24.5; 59.2; 67.1;
75.2; 76.6. Found, m/z: 169.0875 [M+Na]+. C7H14NaO3.
Calculated, m/z: 169.0841.
2-(Benzyloxy)-1-[1-(hydroxymethyl)cyclopropyl]ethanol
(7f) was prepared analogously to compound 7b from
β-oxoester 6f (0.430 g, 1.64 mmol), LiAlH4 (0.249 g,
6.56 mmol, 4 equiv), THF (15 ml). Yield 0.340 g (93%).
1
Crystaline white solid. Mp 69–70°C. H NMR spectrum,
δ, ppm (J, Hz): 0.42–0.49 (2H, m, CH2CH2); 0.56–0.63
(2H, m, CH2CH2); 3.06 (2H, s, CH2OH); 3.30 (2H, br. s,
2OH); 3.62–3.70 (3H, m, OCH2CHOH); 4.58 (2H, d,
J = 2.0, OCH2Ph); 7.27–7.37 (5H, m, H Ph). 13C NMR
spectrum, δ, ppm: 7.7; 10.7; 24.3; 67.3; 72.8; 73.7; 76.7;
127.9; 128.0; 128.6; 137.7. Found, %: C 70.29; H 8.20.
C13H18O3. Calculated, %: C 70.24, H 8.16.
[1-(Hydroxymethyl)cyclopropyl](phenyl)methanol (7b).29
A solution of β-oxoester 6b (1.000 g, 4.58 mmol) in THF
(20 ml) was cooled in an ice bath, and LiAlH4 (0.696 g,
18.33 mmol) was added in small portions. The reaction
mixture was warmed to room temperature and stirred for
~0.5 h until full consumption of the starting material (TLC
control, eluent EtOAc). The reaction mixture was cooled in
an ice bath and quenched with saturated aqueous Segnet's
salt (20 ml). The mixture was extracted with Et2O (3×30 ml).
The combined organic phase was dried over Na2SO4 and
evaporated under reduced pressure to give product 7b.
Cyclopropane-1,1-diyldimethanediyl bis(2,2,2-trichloro-
ethanimidoate) (1a). Molecular sieves (4 Å) and DBU
(25 ml, 0.17 mmol) were added to a solution of diol 7a
(0.086 g, 0.84 mmol) in DCM (5 ml). The resulting
mixture was cooled in an ice bath and trichloracetonitrile
(0.34 ml, 3.36 mmol) was added. The reaction was stirred
while cooling in an ice bath for 4 h until complete
consumtion of the starting material (TLC control, eluent
EtOAc–hexane, 1:10). The reaction mixture was filtered
through a short pad of Celite and the filtrate was evapo-
rated. The residue was purified by flash chromatography on
silica gel column (eluent EtOAc – petroleum ether, 1:20) to
give product 1a. Yield 0.270 g (82%). Colorless oil.
1H NMR spectrum, δ, ppm: 0.76 (4H, s, CH2CH2); 4.27
(4H, s, 2CH2OC(=NH)); 8.25 (2H, s, 2NH). 13C NMR
spectrum, δ, ppm: 9.2; 19.7; 72.5; 91.6; 163.1. The product
is unstable in the HRMS conditions.
1
Yield 0.794 g (97%). Colorless oil. H NMR spectrum,
δ, ppm (J, Hz): 0.50–0.56 (1H, m), 0.63–0.69 (2H, m), and
0.70–0.75 (1H, m, CH2CH2); 2.20 (1H, t, J = 4.9, CH2OH);
3.06 (1H, d, J = 4.4, CHOH); 3.23 (1H, dd, J = 11.4,
J = 4.4) and 3.76 (1H, dd, J = 11.4, J = 4.4, CH2OH); 4.50
(1H, d, J = 3.8, CHOH); 7.27–7.42 (5H, m, H Ph).
1-[1-(Hydroxymethyl)cyclopropyl]butan-1-ol (7c) was
prepared analogously to compound 7b from β-oxoester 6c
(2.86 g, 15.5 mmol), LiAlH4 (1.76 g, 46.5 mmol), THF
1
(40 ml). Yield 2.030 g (92%). Yellowish oil. H NMR
[Phenyl(1-{[(2,2,2-trichloroethanimidoyl)oxy]methyl}-
cyclopropyl)methyl 2,2,2-trichloroethanimidoate (1b)
was prepared analogously to compound 1a from diol 7b
(0.190 g, 1.07 mmol), DBU (32 ml, 0.213 mmol), CCl3CN
(0.33 ml, 3.20 mol), DCM (7 ml). Yield 0.354 g (71%).
spectrum, δ, ppm (J, Hz): 0.33–0.39 (2H, m, CH2CH2);
0.52–0.59 (2H, m, CH2CH2); 0.90 (3H, t, J = 7.2,
CH2CH3); 1.28–1.68 (4H, m, CH2CH2CH3); 3.02 (2H, dd,
J = 11.6, J = 5.1, CH2OH ); 3.33–3.56 (2H, br. s, 2OH);
4.06 (1H, d, J = 12.0, CHOH). 13C NMR spectrum, δ, ppm:
8.1; 10.5; 14.2; 19.6; 26.1; 36.8; 67.7; 78.8. Found, m/z:
167.1090 [M+Na]+. C10H17O3. Calculated, m/z: 167.1048.
1-[1-(Hydroxymethyl)cyclopropyl]-2-methylpropan-
1-ol (7d)30 was prepared analogously to compound 7b from
β-oxoester 6d (1.300 g, 7.64 mmol), LiAlH4 (1.159 g,
30.55 mmol), THF (20 ml). Yield 0.722 g (72%). Colorless
1
Yellow oil. H NMR spectrum, δ, ppm (J, Hz): 0.67–0.81
(3H, m) and 0.92–0.96 (1H, m, CH2CH2); 4.02 (1H, d,
J = 11.6) and 4.34 (1H, d, J = 11.6, CH2OC(=NH)); 6.11
(1H, s, CHPh); 7.27–7.42 (5H, m, H Ph); 8.21 (1H, s, NH);
8.27 (1H, s, NH). 13C NMR spectrum, δ, ppm: 7.6; 8.4;
24.1; 73.2; 80.8; 91.6; 91.8; 126.9; 128.3; 128.4; 137.3;
161.4; 163.0. The product is unstable in the HRMS conditions.
(1-{1-[(2,2,2-Trichloroethanimidoyl)oxy]butyl}cyclo-
propyl)methyl 2,2,2-trichloroethanimidoate (1c) was
prepared analogously to compound 1a from diol 7c (1.72 g,
1
oil. H NMR spectrum, δ, ppm (J, Hz): 0.47–0.61 (4H, m,
CH2CH2); 0.94 (3H, d, J = 6.9) and 1.06 (3H, d, J = 6.4,
CH(CH3)2); 1.60 (1H, br. s, OH); 2.00–2.09 (1H, m,
993

Chemistry of Heterocyclic Compounds 2017, 53(9), 989–996
11.91 mmol), DBU (0.36 ml, 2.38 mmol), CCl3CN (4.81 ml,
temperature until full consumption of the starting material.
(TLC control, eluent EtOAc–hexane, 1:8). The reaction
mixture was filtered through the short Celite column, and
the filtrate was evaporated. The residue was purified by
flash chromatography on silica gel column (eluent EtOAc –
petroleum ether, 1:8) to give products 2 and/or 3.
47.64 mmol), DCM (35 ml). Yield 4.20 g (82%). Yellowish
oil. 1H NMR spectrum, δ, ppm (J, Hz): 0.62–0.67 (1H, m),
0.71–0.76 (1H, m), and 0.77–0.82 (1H, m, CH2CH2); 0.88–
0.95 (4H, m, CH2CH3, CH2CH2); 1.40–1.52 (2H, m,
CH2CH2CH3); 1.80–1.98 (2H, m, CH2CHOC(=NH)); 3.96
(1H, d, J = 12.0) and 4.65 (1H, d, J = 12.0, CH2OC(=NH));
4.74 (1H, dd, J = 8.5, J = 5.0, CH2CHOC(=NH)); 8.24 (2H,
s, 2NH). 13C NMR spectrum, δ, ppm: 8.7; 10.7 14.1; 19.3;
22.9; 35.1; 72.9; 83.3; 91.6; 92.1; 162.9; 163.1. The
product is unstable under the HRMS conditions.
(General method B). Bis(imidate) 1 (1.00 mmol) was
dissolved in the selected solvent (10 ml) under argon
atmosphere; 4 Å molecular sieves were added to this
solution. The reaction mixture was set to reflux until
complete consumption of the starting material (TLC
control, eluent EtOAc–hexane, 1:8). The reaction mixture
was filtered through the short Celite column, and the
filtrate was evaporated. The residue was purified by flash
chromatography on silica gel column (eluent EtOAc –
petroleum ether, 1:8) to give products 2 and/or 3.
2-Methyl-1-(1-{[(2,2,2-trichloroethanimidoyl)oxy]me-
thyl}cyclopropyl)propyl 2,2,2-trichloroethanimidoate (1d)
was prepared analogously to compound 1a from diol 7d
(2.04 g, 14.1 mmol), DBU (2.10 ml, 14.1 mmol), CCl3CN
(2.84 ml, 28.3 mmol), DCM (30 ml). Yield 4.34 g (71%).
Colorless oil. 1H NMR spectrum, δ, ppm (J, Hz): 0.52–0.57
(1H, m), 0.76–0.82 (1H, m), 0.83–0.88 (1H, m), and 0.90–
0.97 (1H, m, CH2CH2); 0.99 (3H, d, J = 7.2, CHCH3); 1.10
(3H, d, J = 7.2, CHCH3); 2.24–2.39 (1H, m, CH(CH3)2); 3.84
(1H, d, J = 12.1, CHAOC(=NH)); 4.47 (1H, d, J = 9.8,
CHOC(=NH)); 4.71 (1H, dd, J = 12.1, J = 1.2, CHBOC(=NH));
8.23 (2H, s, 2NH). 13C NMR spectrum, δ, ppm: 9.8; 9.9;
19.6; 20.0; 21.8; 32.3; 73.1; 88.7; 91.6; 92.2; 163.1; 163.3.
The product is unstable under the HRMS conditions.
6-(Trichloromethyl)-7-oxa-5-azaspiro[3.4]oct-5-ene (2a)
was prepared using general method A from bis(imidate) 1a
1
(See Table 1). Colorless oil. H NMR spectrum, δ, ppm:
1.74–1.86 (1H, m) and 2.06–2.22 (3H, m, CH2CH2CH2);
2.47–2.55 (2H, m, CH2CH2CH2); 4.56 (2H, s, CH2O).
13C NMR spectrum, δ, ppm: 14.9; 34.9; 72.8; 82.1; 86.9;
161.5. Found, m/z: 227.9747 [M+H]+. C7H9Cl3NO.
Calculated, m/z: 227.9750.
6-(Trichloromethyl)-5-oxa-7-azaspiro[2.5]oct-6-ene (3a)
was isolated as by-product using general method A from
(1-{2-Methoxy-1-[(2,2,2-trichloroethanimidoyl)oxy]-
ethyl}cyclopropyl)methyl 2,2,2-trichloroethanimidoate
(1e) was prepared analogously to compound 1a from diol
7e (0.400 g, 2.74 mmol), DBU (82 ml, 0.55 mmol),
CCl3CN (0.82 ml, 8.21 mmol), DCM (10 ml). Yield 0.952 g
1
bis(imidate) 1a (see Table 1). Colorless oil. H NMR
spectrum, δ, ppm: 0.67–0.68 (4H, m, CH2CH2); 3.46 (2H,
s, CH2O); 4.10 (2H, s, CH2N).
8-Phenyl-6-(trichloromethyl)-5-oxa-7-azaspiro[2.5]oct-
6-ene (3b) was prepared using general method A from bis-
(imidate) 1b. Yield 0.062 g (85%) (see Table 2). Yellow
1
(80%). Colorless oil. H NMR spectrum, δ, ppm (J, Hz):
0.64–0.69 (1H, m), 0.77–0.84 (2H, m) and 0.97–1.02 (1H,
m, CH2CH2); 3.35 (3H, s, OCH3); 3.80–3.82 (2H, m), 3.89
(1H, d, J = 12.1), and 4.65 (1H, dd, J = 11.9, J = 1.0,
2CH2); 4.97 (1H, dd, J = 4.2, J = 7.0, CHOC(=NH)); 8.26
(1H, s, NH); 8.34 (1H, s, NH). 13C NMR spectrum, δ, ppm:
8.7; 10.6; 21.4; 59.3; 72.9; 73.8; 81.7; 91.5; 92.0; 162.9
(2C). Found, m/z: 454.9072 [M+Na]+. C11H14Cl6N2NaO3.
Calculated, m/z: 454.9033.
1
oil. H NMR spectrum, δ, ppm (J, Hz): 0.48–0.53 (1H, m)
and 0.63–0.73 (3H, m, CH2CH2); 4.00 (1H, dd, J = 10.9,
J = 1.0) and 4.22 (1H, d, J = 10.9, CH2O); 4.49 (1H, s,
CHPh); 7.15–7.38 (5H, m, H Ph). 13C NMR spectrum,
δ, ppm: 6.8; 10.2; 19.5; 62.3; 72.8; 92.6; 127.7 (2C); 128.4;
139.6; 155.0. Found, m/z: 304.0102 [M+H]+. C13H13Cl3NO.
Calculated, m/z: 304.0063.
(1-{2-(Benzyloxy)-1-[(2,2,2-trichloroethanimidoyl)oxy]-
ethyl}cyclopropyl)methyl 2,2,2-trichloroethanimidoate
(1f) was prepared analogously to compound 1a from diol
7f (0.291 g, 1.31 mmol), DBU (39 ml, 0.26 mmol),
CCl3CN (0.4 ml, 3.93 mmol), DCM (10 ml). Yield 0.550 g
1-Propyl-6-(trichloromethyl)-7-oxa-5-azaspiro[3.4]oct-
5-ene (2c) was prepared using general method A from bis-
1
(imidate) 1c (see Table 3). H NMR spectrum, δ, ppm
(J, Hz): 0.90 (3H, t, J = 7.2, CH3); 1.18–1.48 (5H, m,
CHCH2CH2CH3); 1.95–2.01 (1H, m) and 2.05–2.13 (1H,
m, CH2CH2CH); 2.50–2.57 (1H, m) and 2.67–2.75 (1H, m,
CH2CH2CH); 4.36 (1H, d, J = 9.0) and 4.85 (1H, d, J = 9.0,
CH2O). 13C NMR spectrum, δ, ppm: 14.2; 20.0; 22.5; 32.4;
33.0; 44.0; 75.0; 76.9; 86.8; 161.1. Found, m/z: 270.0259
[M+H]+. C10H15Cl3NO. Calculated, m/z: 270.0219.
1
(83%). Yellowish oil. H NMR spectrum, δ, ppm (J, Hz):
0.64–0.69 (1H, m), 0.76–0.84 (2H, m), and 1.02–1.07 (1H,
m, CH2CH2); 3.85 (1H, d, J = 11.3), 3.89–3.94 (2H, m),
4.54–4.61 (2H, m), and 4.66 (1H, dd, J = 11.3, J = 0.9,
3CH2); 5.04 (1H, dd, J = 7.4, J = 4.4, OCH2CHOC(=NH));
7.23–7.33 (5H, m, H Ph); 8.23 (1H, s, NH); 8.38 (1H, s,
NH). 13C NMR spectrum, δ, ppm: 8.6; 10.8; 21.4; 71.3;
72.9; 73.3; 82.1; 91.4; 92.0; 127.6; 127.7; 128.4; 138.3;
162.8 (2C). Found, m/z: 530.9393 [M+Na]+. C17H18N2NaO3.
Calculated, m/z: 530.9346.
8-Propyl-6-(trichloromethyl)-5-oxa-7-azaspiro[2.5]oct-
6-ene (3c) was isolated as by-product using general method
1
A from bis(imidate) 1c (see Table 3). Colorless oil. H NMR
spectrum, δ, ppm (J, Hz): 0.56–0.72 (3H, m) and 0.68–0.75
(1H, m, CH2CH2); 0.93–0.97 (3H, m, CH2CH2CH3); 1.44–
1.68 (4H, m, CH2CH2CH3); 3.03–3.06 (1H, m, CHN); 3.67
(1H, dd, J = 10.8, J = 1.7) and 4.43 (1H, dd, J = 10.8, J = 1.2,
CH2O). 13C NMR spectrum, δ, ppm: 6.4; 11.6; 14.4; 18.1;
19.8; 37.0; 59.5; 72.3; 152.7. Found, m/z: 270.0259 [M+H]+.
C10H15Cl3NO. Calculated, m/z: 270.0219.
Cyclization of bis(imidate) 1 (General method A). Bis-
(imidate) 1 (1.00 mmol) was dissolved in the selected
solvent (10 ml) under argon atmosphere. To this solution,
4 Å molecular sieves were added followed by Lewis acid
(0.10 mmol, 10 mol %). The mixture was stirred at room
994

Chemistry of Heterocyclic Compounds 2017, 53(9), 989–996
1-Isopropyl-6-(trichloromethyl)-7-oxa-5-azaspiro[3.4]oct-
graphy on silica gel (eluent EtOAc – light petroleum ether,
gradient from 1:4 to 1:1). Yield 0.130 g (89%). Colorless
5-ene (2d) was prepared using general method A or B from
1
1
bis(imidate) 1d (see Table 4). Colorless oil. H NMR
solid, mp 58–61°C. H NMR spectrum, δ, ppm (J, Hz):
spectrum, δ, ppm (J, Hz): 0.79 (3H, d, J = 6.5, CHCH3); 0.84
(3H, d, J = 6.5, CHCH3); 1.22–1.32 (1H, m, CH2CH2CH);
1.54–1.64 (1H, m, CH(CH3)2); 1.87–1.92 (1H, m) and 1.97–
2.04 (1H, m, CH2CH2CH); 2.30–2.38 (1H, m) and 2.51–
2.59 (1H, m, CH2CH2CH); 4.37 (1H, d, J = 9.0) and 4.91
(1H, d, J = 9.0, CH2O). 13C NMR spectrum, δ, ppm: 19.5;
19.7; 21.6; 29.9; 32.2; 51.9; 74.7; 86.8; 160.9. Found, m/z:
270.0253 [M+H]+. C10H15Cl3NO. Calculated, m/z: 270.0219.
8-Isopropyl-6-(trichloromethyl)-5-oxa-7-azaspiro[2.5]-
oct-6-ene (3d) was isolated as by-product using general
method A or B from bis(imidate) 1d (see Table 4).
Colorless oil. 1H NMR spectrum, δ, ppm (J, Hz): 0.46–0.51
(1H, m) and 0.55–0.60 (1H, m, CH2CH2); 0.68–0.73 (1H,
m) and 0.85–0.91 (1H, m, CH2CH2); 1.05–1.09 (6H, d, J = 7.0,
CH(CH3)2); 1.81–1.89 (1H, m, CH(CH3)2); 2.65 (1H, dd,
J = 8.0, J = 2.2, CHN); 3.51 (1H, dd, J = 10.7, J = 2.2), and
4.61 (1H, dd, J = 10.7, J = 2.2, CH2O). 13C NMR spectrum,
δ, ppm: 7.5; 11.8; 17.1; 20.1; 20.6; 34.3; 65.7; 72.6; 77.4;
152.4. Found, m/z: 270.0240 [M+H]+. C10H15Cl3NO.
Calculated, m/z: 270.0219.
0.87 (3H, t, J = 7.2, CH2CH2CH3); 1.12–1.30 (3H, m,
CH2CH2CH3); 1.35–1.48 (10H, m, C(CH3)3, CH2CH2CH2);
1.51–1.58 (1H, m, CHCH2CH2); 1.88–2.03 (2H, m,
CHCH2CH2); 2.14–2.19 (1H, m) and 2.29–2.37 (1H, m,
CHCH2CH2); 3.53–3.65 (1H, br. s, OH); 3.77–3.85 (2H, m,
CH2OH); 4.87–4.95 (1H, br. s, NH). 13C NMR spectrum,
δ, ppm: 14.3; 20.9; 21.6; 28.5; 28.6; 32.2; 45.3; 59.4; 65.1;
80.1; 156.2. Found, %: N 5.80; C 64.20; H 10.40.
C13H25NO3. Calculated, %: N 5.76; C 64.16; H 10.36.
tert-Butyl-[1-(hydroxymethyl)cyclobutyl] carbamate (8a)
was prepared in analogy to compound 8c from oxazoline
2a (0.228 g, 1.00 mmol), EtOH (2 ml), 6 M HCl aqueous
solution (2 ml), di-tert-butyl dicarbonate (0.437 g,
2.00 mmol), and EtOAc (10 ml). Yield 0.119 g (59%).
Compound physical and chemical data are consistent with
commercially available sample.
tert-Butyl-1-(hydroxymethyl)-2-isopropylcyclobutyl
carbamate (8d) was prepared in analogy to compound 8c
from oxazoline 2d (0.100 g, 0.41 mmol), EtOH (2 ml), 6 M
HCl aqueous solution (2 ml), di-tert-butyl dicarbonate
(0.179 g, 2.00 mmol), and EtOAc (10 ml). Yield 0.063 g
1-Methoxymethyl-6-(trichloromethyl)-7-oxa-5-azaspiro-
[3.4]oct-5-ene (2e) was prepared using general method B
1
(70%). Colorless solid, mp 61–63°C. H NMR spectrum,
1
from bis(imidate) 1e (see Table 5). H NMR spectrum,
δ, ppm (J, Hz): 0.72 (3H, d, J = 6.4) and 0.86 (3H, d,
J = 6.4, CH(CH3)2); 1.34–1.45 (10H, m, OC(CH3)3, CH(CH3)
3); 1.51–1.61 (1H, m) and 1.83–1.97 (3H, m, CH2CH2CH);
2.20–2.34 (1H, m, CH2CH2CH); 3.82 (2H, s, CH2OH);
4.12 (1H, br. s, OH); 4.95 (1H, br. s, NH). 13C NMR
spectrum, δ, ppm: 20.0; 20.5; 22.1; 27.8; 28.5; 28.7; 53.4;
59.5; 64.8; 80.1; 156.4. Found, %: N 5.79; C 64.19;
H 10.39. C13H25NO3. Calculated, %: N 5.76; C 64.16;
H 10.36.
δ, ppm (J, Hz): 1.61–1.70 (1H, m), 2.07–2.20 (2H, m), and
2.40–2.49 (1H, m, CH2CH2CH); 2.85–2.92 (1H, m,
CH2CH2CH); 3.33 (3H, s, OCH3); 3.42–3.50 (2H, m,
CH2OMe); 4.37 (1H, d, J = 9.2) and 4.82 (1H, d, J = 9.2,
CH2OC(=N)). 13C NMR spectrum, δ, ppm: 18.2; 33.3;
43.6; 59.0; 71.9; 74.4; 77.9; 86.9; 161.3. Product 2e is
unstable in the HRMS conditions.
1-Benzyloxymethyl-6-(trichloromethyl)-7-oxa-5-aza-
spiro[3.4]oct-5-ene (2f) was prepared using general
tert-Butyl-1-(hydroxymethyl)-2-(methoxymethyl)cyclo-
butyl carbamate (8e) was prepared in analogy to
compound 8c from oxazoline 2e (0.198 g, 0.73 mmol),
EtOH (2 ml), 6 M HCl aqueous solution (2 ml), di-tert-
butyl dicarbonate (0.319 g, 1.46 mmol), and EtOAc
(10 ml). Yield 0.130 g (73%). Colorless solid, mp 70–73°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.37–1.45 (11H, m,
C(CH3)3, CH2CH2CH); 1.77–1.83 (1H, m) and 1.88–1.97
(1H, m, CH2CH2CH); 2.36–2.50 (1H, m, CH2CH2CH);
2.95 (1H, br. s, OH); 3.32 (3H, s, OCH3); 3.41–3.50 (2H,
m, CH2OMe); 3.54–3.59 (1H, m) and 3.81 (1H, d, J = 10.2,
CH2OH); 5.14 (1H, br. s, NH). 13C NMR spectrum, δ, ppm:
17.3; 27.1; 28.5; 42.1; 58.9 (2C); 64.5; 72.9; 79.4; 155.3.
Found, %: N 5.76; C 58.75; H 9.49. C12H23NO4.
Calculated, %: N 5.71; C 58.75; H 9.45.
tert-Butyl-2-(benzyloxymethyl)-1-(hydroxymethyl)cyclo-
butyl carbamate (8f) was prepared in analogy to
compound 8c from oxazoline 2f (0.172 g, 0.49 mmol),
EtOH (2 ml), 6 M HCl aqueous solution (2 ml), di-tert-
butyl dicarbonate (0.214 g, 0.98 mmol), and EtOAc
(10 ml). Yield 0.110 g (69%). Colorless solid, mp 96–97°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.41–1.51 (10H, m,
C(CH3)3, CH2CH2CH); 1.81–1.87 (2H, m, CH2CH2CH);
1.91–1.99 (1H, m, CH2CH2CH); 2.41–2.50 (1H, m,
CH2CH2CH); 3.00 (1H, br. s, OH); 3.56–3.61 (3H, m,
1
method B from bis(imidate) 1f (see Table 5). H NMR
spectrum, δ, ppm (J, Hz): 1.68–1.72 (1H, m), 2.13–2.19
(2H, m), and 2.42–2.50 (1H, m, CH2CH2CH); 2.91–2.98
(1H, m, CH2CH2CH); 3.50–3.60 (2H, m, CHCH2OCH2);
4.37 (1H, d, J = 9.4, CHAOC(=N)); 4.46–4.56 (2H, m,
OCH2Ph); 4.84 (1H, d, J = 9.4, CHBOC(=N)); 7.27–7.37
(5H, m, H Ph). 13C NMR spectrum, δ, ppm: 18.1; 33.2;
43.5; 69.2; 73.2; 74.3; 77.9; 86.9; 127.5; 127.8; 128.5;
138.1; 161.4. Found, m/z: 348.0325 [M+H]+. C10H17O3.
Calculated, m/z: 348.0346.
tert-Butyl-1-(hydroxymethyl)-2-propylcyclobutyl
carbamate (8c). 6 M aqueous HCl (2 ml) was added to a
solution of oxazoline 2c (0.158 g, 0.58 mmol) in EtOH
(2 ml), and the mixture was stirred for 1 h at room
temperature, then it was refluxed for 7 h. The solvents were
removed in vacuo, and saturated aq NaHCO3 solution
(10 ml) was added to the residue followed by di-tert-butyl
dicarbonate (0.275 g, 2.00 mmol) solution in EtOAc
(10 ml). The reaction mixture was stirred for 12 h at room
temprature. The organic phase was separated, and the
aquoeus phase was extracted with EtOAc (3 × 10 ml). The
combined, organic phases were washed with saturated aq
NaCl (10 ml) and dried over Na2SO4. The extract was
evaporated and the residue was purified by flash chromato-
995

Chemistry of Heterocyclic Compounds 2017, 53(9), 989–996
13. Caserio, M. C.; Graham, W. H.; Roberts, J. D. Tetrahedron
CH2OCH2, CHAOH); 3.86 (1H, d, J = 8.8, CHBOH); 4.52
1960, 11, 171.
(2H, s, OCH2Ph); 5.12 (1H, br. s, NH); 7.26–7.38 (5H, m,
H Ph). 13C NMR spectrum, δ, ppm: 17.3; 27.1; 28.5; 42.2;
59.0; 64.6; 70.3; 73.4; 79.5; 128.0; 128.1; 128.7; 137.5;
155.4. Found, %: N 4.40; C 67.29; H 8.51. C18H27NO4.
Calculated, %: N 4.36; C 67.26; H 8.47.
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Financial support from the Latvian Council of Science
(grant 593/2014) is gratefully acknowledged.
18. Shi, M.; Tian, G.-Q. Tetrahedron Lett. 2006, 47, 8059.
20. Chen, A.; Lin, R.; Liu, Q.; Jiao, N. Chem. Commun. 2009,
6842.
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