[5 + 2]Cycloaddition reaction of 2-vinylaziridines and sulfonyl isocyanates. Synthesis of seven-membered cyclic ureas

Article abstract of DOI:10.1021/jo201959a

The [5 + 2] cycloaddition reaction of 2-vinylaziridines with sulfonyl isocyanates proceeded smoothly under mild conditions, and various cyclic ureas were isolated in high yields. The remarkable solvent effect on the reaction was observed, and the preferential formation of the seven-membered ring occurred when the reaction was carried out in CH₂Cl₂. The scope and limitation were studied, and the mechanism of this reaction was discussed. This study provides a new and simple method for the synthesis of seven-membered cyclic ureas.

Full text of DOI:10.1021/jo201959a

Article
pubs.acs.org/joc
[5 + 2] Cycloaddition Reaction of 2-Vinylaziridines and Sulfonyl
Isocyanates. Synthesis of Seven-Membered Cyclic Ureas
Eri Kanno,† Kenichi Yamanoi,† Shunsuke Koya,† Isao Azumaya,‡ Hyuma Masu,‡,§ Ryu Yamasaki,†
and Shinichi Saito*,†
†Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku, Tokyo 162-8601, Japan
‡Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Shido, Sanuki-city, Kagawa 769-2193, Japan
S
* Supporting Information
ABSTRACT: The [5 + 2] cycloaddition reaction of 2-
vinylaziridines with sulfonyl isocyanates proceeded smoothly
under mild conditions, and various cyclic ureas were isolated in
high yields. The remarkable solvent effect on the reaction was
observed, and the preferential formation of the seven-membered
ring occurred when the reaction was carried out in CH2Cl2. The
scope and limitation were studied, and the mechanism of this
reaction was discussed. This study provides a new and simple
method for the synthesis of seven-membered cyclic ureas.
(0.05 M) overnight (16 h), and a mixture of the seven-
membered cyclic urea (3a) and five-membered cyclic urea (4a)
was isolated in 28% combined yield (entry 1). The structure of
3a was confirmed by X-ray crystallographic analysis (Figure S1,
Supporting Information). It is noteworthy that the reaction
proceeded in the absence of catalyst, and the seven-membered
cyclic urea (3a) was isolated as the major product. When we
used DMF as the solvent, five-membered cyclic urea (4a) was
isolated in 51% yield, and the formation of 3a was not observed
(entry 2).11 The combined yield of the products increased to
58%, and compound 3a was isolated as the major product when
THF was used as the solvent (entry 3). When the reaction was
carried out in toluene, the total yield of compounds increased
to 62%, and compound 3a was formed in a highly selective
manner (entry 4).
Further studies disclosed that CH2Cl2 was the best solvent
for this reaction: the combined yield of the product was 64%,
and the selective formation of 3a was observed (entry 5). We
studied the effect of the concentration of the substrates on the
yields of the products. When the reaction was carried out at
higher concentration (0.1 M, or 0.2 M), the yield as well as the
selectivity of the products decreased (entries 6 and 7). It also
turned out that the reaction proceeded rapidly in CH2Cl2: the
product was isolated in comparable yield when the reaction
time was reduced from 16 h to 5 min (entry 8).
INTRODUCTION
■
2-Vinylaziridine is a strained and reactive cyclic amine, and
many reactions, which involve the cleavage of the C−N bond,
have been reported.1 The formation of seven-membered
heterocycles by the intramolecular aza-Cope rearrangement of
divinylaziridines2 and related compounds3 provided a unique
and efficient method for the synthesis of azepane derivatives,
and this reaction has been applied to the synthesis of a natural
product.4
The intermolecular [5 + 2] reaction of vinylaziridines with
unsaturated compounds is another attractive approach for the
synthesis of the azepane framework, and highly electron-
deficient compounds such as hexafluoro-2-butyne5 or dimethyl
acetylenedicarboxylate6 were employed as the C2 units.7 The
[5 + 2] reaction of unsubstituted 2-vinylaziridine with phenyl
isothiocyanate8 gave 1,3-thiazepine derivatives, and the
formation of a mixture of seven-membered cyclic urea and
five-membered heterocycles was reported in the reactions of
2-vinylaziridines with phenyl isocyanate.9
We recently reported the ring-expansion reaction ([6 + 2]
cycloaddition reaction) of vinylazetidines with electron-
deficient isocyanates.10 The study prompted us to examine
the reaction of vinylaziridines with electron-deficient isocya-
nates. In this paper, we report the [5 + 2] cycloaddition
reaction of 2-vinylaziridines and sulfonyl isocyanates.
We examined the effect of the temperature on the yield of
the products. The reaction proceeded smoothly when the
reaction was carried out at 0 °C, and the combined yield of the
products reached to 70% (entry 9). On the other hand, the yield
decreased when the temperature was set to −20 °C (entry 10).
RESULTS
■
1-Benzyl-2-vinylaziridine (1a) reacted with tosyl isocyanate
(2a) in the absence of a catalyst, and a mixture of seven-
membered and five-membered cyclic ureas was obtained. We
studied the effects of the solvent and the concentration on this
reaction, and the results are summarized in Table 1.
The cycloaddition reaction proceeded when a 1:1 mixture of
the substrates was stirred in acetonitrile at low concentration
Received: September 21, 2011
Published: January 31, 2012
© 2012 American Chemical Society
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the corresponding seven-membered cyclic urea (3b) was isolated
in 64% yield. It is noteworthy that the corresponding five-
membered cyclic urea was not isolated. On the other hand, phenyl
isocyanate (2c) was not a good substrate, and the cycloaddition
reaction did not proceed when 1a was treated with 2c for 4 h at
0 °C.12 Though the reaction of 1a with other electron-deficient
isocyanates such as trichloroacetyl isocyanate or 4-acetylphenyl
isocyanate proceeded, the yields of the products were very low
and the purification of the products was difficult.
Table 1. Screening of the Reaction Conditions for the [5 + 2]
Cycloaddition
To study the scope and limitation of this reaction, we carried
out the reaction of various vinylaziridines with sulfonyl isocy-
anates. The results of the reactions of substituted 1-benzyl-2-
vinylaziridines are summarized in Table 2.
Table 2. [5 + 2] Cycloaddition Reaction of 1-Benzyl-2-
vinylaziridines with Sulfonyl Isocyanates
a
entry
solvent
conc (M)
yield (%)
ratio (3a:4a)
1
2
3
4
5
6
7
CH3CN
DMF
0.05
0.05
0.05
0.05
0.05
0.1
28
51
58
62
64
54
51
65
70
46
10:1
<5:>95
3:1
THF
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10:1
>95:<5
10:1
0.2
5:1
b
entry
1
R1
Me
2
yield (%)
8
0.05
0.05
0.05
>95:<5
10:1
c
1
2
3
4
5
6
1b
1b
1c
1c
1d
1d
2a
2b
2a
2b
2a
2b
82 (3c)
89 (3d)
90 (3e)
52 (3f)
59 (3g)
48 (3h)
9
d
Me
10
10:1
a
1
Ph
The ratio was estimated by the H NMR spectra of the isolated
mixture of 3 and 4. The reaction was carried out for 5 min. The
reaction was carried out at 0 °C for 5 min. The reaction was carried
out at −20 °C for 5 min.
b
c
Ph
d
OTBS
OTBS
As shown in entries 1 and 2, the reaction of 1-benzyl-2-
isopropenylaziridine (1b) proceeded smoothly with sulfonyl
isocyanates, and the corresponding seven-membered ureas
were isolated in high yields. The reaction of 1-benzyl-2-
(1-phenylvinyl)aziridine (1c) with 2a also proceeded efficiently,
and the yield of the product reached to 90% (entry 3). The
yield of the product decreased when the reaction of 1c with 2b
was examined (entry 4). The cyclic ureas were isolated in
moderate yields by the reaction of vinylaziridine with OTBS
group (1d) with 2 (entries 5 and 6). It is noteworthy that the
selective formation of the seven-membered urea was observed
in these reactions, and a trace amount of five-membered urea
was occasionally detected in the crude reaction mixture.
We also examined the reaction of various N-substituted
vinylaziridines with sulfonyl isocyanates. The results are
summarized in Table 3.
Based on these results, we decided to carry out further studies
based on the reaction conditions described in entry 9.
We studied the reaction of 1a with other isocyanates and
found that the sulfonyl isocyanates were suitable substrates for
this reaction (Scheme 1). For example, the cycloaddition of 1a
with methanesulfonyl isocyanate (2b) proceeded smoothly, and
Scheme 1
The reaction of 1-(2,4-dimethoxybenzyl)-2-vinylaziridine
(1e) with 2a as well as 2b proceeded efficiently, and the
corresponding seven-membered cyclic ureas were isolated in
good to high yields (entries 1 and 2). 1-Butyl-2-propenylazir-
idine (1f) was a good substrate for this reaction, and the
reaction of 1f with 2a gave the cyclic urea (3k) in 83% yield
(entry 3). The reaction of 1f with 2b also proceeded smoothly
(entry 4). The cycloaddition reaction of 1-cyclohexyl-2-
propenylaziridine (1g) with 2a (or 2b) gave the corresponding
cyclic ureas in high yields (entries 5 and 6). It was possible to
remove the 2,4-dimethoxybenzyl (DMB) group bound to the
cyclic urea under acidic conditions: when compound 3i was
treated with TFA at 60 °C, the deprotected urea (5) was isolated
in 78% yield (Scheme 2).
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We assume that the mechanism of this reaction is similar to the
mechanism we discussed in the reaction of 2-vinylazetidines.10
A plausible mechanism of the reaction is shown in Scheme 4.
Table 3. [5 + 2] Cycloaddition Reaction of Various
Vinylaziridines with Sulfonyl Isocyanates
Scheme 4. Proposed Mechanism for the Reaction of
2-Vinylaziridine (1a) with Tosyl Isocyanate (2a)
entry
1
R1
R2
2
yield (%)
a
1
2
3
4
5
6
1e
1e
1f
DMB
DMB
n-Bu
n-Bu
H
2a
2b
2a
2b
2a
2b
90 (3i)
69 (3j)
83 (3k)
92 (3l)
92 (3m)
98 (3n)
H
Me
Me
Me
Me
1f
b
1g
1g
Cy
Cy
a
b
2,4-Dimethoxybenzyl. Cyclohexyl.
Scheme 2. Deprotection of the DMB group
Aziridine 1a is a good nucleophile and the attack of 1a
toward tosyl isocyanate (2a) would proceed to give a
zwitterionic species 10 as the key intermediate. The presence
of the sulfonyl group would accelerate this process and stabilize
the zwitterionic structure. When the intramolecular SN2′
reaction of 10 proceeded, the corresponding seven-membered
cyclic urea (3a) would be isolated. We previously reported the
formation of a small amount of the eight-membered cyclic
imine in the reaction of 2-vinylazetidines with 2a.10 However,
the formation of cyclic imine, which would be formed by the
attack of the oxygen atom (instead of the nitrogen atom) to the
vinyl group, was not observed in the reaction of 2-vinyl-
aziridines. The zwitterionic species 10 would be more sterically
crowded than the zwitterion generated from 2-vinylazetidine,
and the tosyl group might be located to the vicinity of the vinyl
group, inducing the selective formation of the urea.
Scheme 3. Cycloaddition Reaction of 1,2,3-Trisubstituted
Vinylaziridines with Tosyl Isocyanate (2a)
When the reaction was carried out in a polar solvent (DMF),
the formation of a seven-membered cyclic urea was not observed.
In this case, the ring-opening of 10 would give a linear inter-
mediate 11 (or a cationic adduct of the solvent molecule). The
five-membered cyclic urea would be formed preferentially by
the cyclization reaction of these intermediates.
Remarkable results were observed in the reactions of 1,2,
3-trisubstituted vinylaziridines with tosyl isocyanate (2a)
(Scheme 3). The reaction of the trans isomer gave, as expected,
the corresponding seven-membered cyclic urea, while the reaction
of the cis isomer was sluggish and the five-membered cyclic urea
was isolated in low yield. These results would be explained in
terms of the conformation of the vinylaziridines as well as the
structure and reactivity of the corresponding zwitterion (Scheme 5).
Since aziridines generally exist as a mixture of invertomers at the
aziridine ring nitrogen, the 1,2,3-trisubstituted aziridine would
exist as a mixture of nitrogen invertomers such as A and A′. The
ratio and reactivity of the invertomers of the trans isomer would be
comparable, and two diastereomeric zwitterionic species (B, B′)
would be formed when they reacted with 2a. Since the vinyl
group and the isocyanate group are located at the cis position,
intermediate B would undergo cyclization smoothly, and the seven-
membered cyclic urea would be formed. On the other hand,
isomer B′ would not undergo cyclization and the dissociation of
the isocyanate would proceed, providing the starting material.
Finally, we studied the reaction of 1,2,3-trisubstituted
aziridines with 2a. The results are summarized in Scheme 3.
The treatment of trans-1-benzyl-2-phenyl-3-vinylaziridine (6)
with 2a at rt for 2 h gave the corresponding seven-membered
cyclic urea (7) in 92% yield. On the other hand, the reactivity
of the cis-vinylaziridine (8) was much lower: the progress of the
reaction was slow (rt, 24 h), and the five-membered cyclic urea
(9) was isolated in 10% yield; although we recovered the start-
ing material in low yield (ca. 5%), we could not isolate other
products in pure form, and the formation of the seven-membered
cyclic urea was not observed.13 It is noteworthy that the reactivity
as well as the pathway of the reaction changed dramatically when a
cis-vinylaziridine was used as the substrate.
DISCUSSION
■
In most reactions of 2-vinylaziridine with sulfonyl isocyanates,
2-vinylaziridine reacted as a five-atom unit, and seven-
membered cyclic urea was isolated as the major product.
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slowly, and the five-membered cyclic urea was isolated in low
yield. The mechanism of this reaction was discussed in detail.
The study provided a new and simple method for the synthesis
of seven-membered cyclic ureas.
Scheme 5. Proposed Mechanism for the Reaction of
Trisubstituted Aziridines with Tosyl Isocyanate (2a)
EXPERIMENTAL SECTION
■
General Information. Commercially available reagents were
purchased and used without further purification. Aziridine 1a16 was
prepared by the procedure reported for the preparation of 1e.17
Aziridines 1c18 and 1e17 as well as the isocyanate 2b19 were prepared
as reported. Chemical shifts were reported in delta units (δ) relative to
1
chloroform (7.24 ppm for H NMR and 77.0 ppm for 13C NMR) or
1
dimethyl sulfoxide (2.49 ppm for H NMR and 39.7 ppm for 13C
NMR). Multiplicity is indicated by s (singlet), d (doublet), t (triplet),
q (quartet) or m (multiplet).
Preparation of Aziridine 1b. To a mixture of methyltriphenyl-
phosphonium bromide (1.86 g, 5.2 mmol) in THF (20 mL) was
added n-BuLi (1.6 M in hexane, 3.2 mL, 5.0 mmol), and the mixture
was stirred for 30 min. To the yellow mixture was added a solution of
2-acetyl-1-benzylaziridine20 (910 mg, 3.5 mmol) in THF (5 mL). After
being stirred for an additional 21 h at room temperature, the mixture
was diluted with diethyl ether, washed with satd NH4Cl aq, and dried
over Na2SO4. The solvent was removed in vacuo, and the crude
product was purified by silica gel column chromatography (ethyl
acetate/hexane = 1:10) to yield a yellow oil (426 mg, 72%): 1H NMR
(300 MHz, CDCl3) 7.35−7.23 (m, 5 H), 4.96 (dd, J = 0.9, 1.8 Hz,
1 H), 4.83 (d, J = 1.8 Hz, 1 H), 3.63 (d, J = 13.8 Hz, 1 H), 3.35 (d, J =
13.8 Hz, 1 H), 1.98 (dd, J = 3.6, 6.4 Hz, 1 H), 1.90 (d, J = 3.6 Hz, 1
H), 1.62 (d, J = 0.9 Hz, 3 H), 1.52 (d, J = 6.4 Hz, 1 H); 13C NMR
(75 MHz, CDCl3) 143.5, 139.2, 128.2, 127.7, 126.8, 111.6, 64.6, 43.8,
33.7, 18.5; IR (neat) 3028, 2976, 2827, 1644, 1495, 1454, 1356, 1026,
889, 732, 696 cm−1; HR-MS (EI) calcd for C12H15N (M+) 173.1204,
found 173.1206.
Preparation of Aziridine 1d. Triethyamine (0.3 mL, 2.2 mmol)
was added to a solution of 2-acetyl-1-benzylaziridine20 (280 mg,
1.6 mmol) in CH2Cl2 (8 mL), and the solution was cooled to 0 °C.
TBSOTf (0.45 mL, 1.9 mmol) was added over 5 min, and the mixture
was stirred at 0 °C for 1 h. The reaction was quenched with brine and
extracted with CH2Cl2. The combined organic layer was dried over
Na2SO4, and the solvent was evaporated in vacuo. The crude product
was purified by silica gel column chromatography (ethyl acetate/
The stability of the invertomers of the cis isomer would be
quite different, and invertomer C would be the major species.
The nucleophilicity of C, however, would be very low due to
the steric hindrance of the substituents, and the reaction of C
with the isocyanate would not proceed. The minor invertomer
C′ would react with isocyanate and intermediate D′ would be
formed. The rate of the addition reaction would be slow since
the concentration of the invertomer C′ would be very low.
Instead of the cyclization, the simple cleavage of the C−N bond
of D′ would proceed and a linear intermediate E′ would be
generated.14 The five-membered cyclic urea would be formed
by the cyclization of E′.15
1
hexane = 1:20) to yield a colorless oil (305 mg, 66%): H NMR
(300 MHz, CDCl3) 7.36−7.22 (m, 5 H), 4.33 (s, 1 H), 4.15 (s, 1 H),
3.47 (s, 2 H), 1.92 (dd, J = 3.4, 6.0 Hz, 1 H), 1.89 (d, J = 3.4 Hz, 1 H),
1.47 (d, J = 6.0 Hz, 1 H), 0.90 (s, 9 H), 0.13 (s, 6 H); 13C NMR (75
MHz, CDCl3) 156.8, 139.1, 128.2, 127.8, 126.8, 91.2, 64.4, 41.4, 34.0,
25.7, 18.1, −4.67, −4.72; IR (neat) 2930, 2857, 1636, 1472, 1361, 1294,
1251, 1028, 838, 781, 731, 696 cm−1. Anal. Calcd for C17H27NOSi: C,
70.53; H, 9.40; N, 4.84. Found: C, 70.25; H, 9.49; N, 4.80.
Preparation of Aziridine 1f. To a solution of 1,2-dibromobutan-
3-one21 (3.4 g, 15 mmol) in THF (50 mL) was added n-butylamine
(1.63 mL, 16.5 mmol) at 0 °C. After 5 min, DBU (4.5 mL, 30 mmol)
was added and the mixture was stirred at ambient temperature for
overnight. The salt was filtered off and the solid was rinsed with
diethyl ether. The combined filtrate was evaporated and purified by
silica gel column chromatography (ethyl acetate/hexane = 1:5) to
CONCLUSION
1
■
afford 2-acetyl-1-n-butylaziridine (1.44 g, 69%) as a brown oil: H
The [5 + 2] cycloaddition reaction of 2-vinylaziridines with
sulfonyl isocyanates proceeded in the absence of catalyst, and
the seven-membered cyclic ureas were isolated in good to high
yields. Various 2-vinylaziridines turned out to be suitable
substrates for this reaction. The use of reactive sulfonyl
isocyanates and the choice of CH2Cl2 as the solvent are critical
for the progress of the reaction. As for the reaction of 1,2,3-
trisubstituted aziridines, different products were isolated
depending on the structure of the aziridine. The trans isomer
gave the corresponding seven-membered cyclic urea in high
yield. Meanwhile, the reaction of the cis isomer proceeded
NMR (600 MHz, CDCl3) 2.31−2.36 (m, 1 H), 2.20−2.24 (m, 1 H),
2.07 (m, 1 H), 2.00 (s, 3 H), 1.99 (m, 1 H), 1.59 (d, J = 6.4 Hz, 1 H),
1.49−1.54 (m, 2 H), 1.32−1.36 (m, 2 H), 0.89 (t, J = 7.2 Hz, 3 H);
13C NMR (125 MHz, CDCl3) 207.7, 60.6, 45.3, 35.0, 31.6, 24.9, 20.4,
14.0; IR (neat) 3394, 3047, 2954, 2931, 2870, 1705, 1466, 1427, 1358,
1257, 1211, 1173, 1088, 1026, 972, 918, 787, 517 cm−1; HR-MS (EI)
calcd for C8H14NO ([M + H]+) 140.1070, found 140.1075.
To a solution of methyltriphenylphosphonium bromide (5.5 g,
15.4 mmol) in THF (40 mL) was added n-BuLi (1.6 M in hexanes, 9.7 mL,
15.4 mmol) at 0 °C, and the mixture was stirred for 30 min. A solution
of 2-acetyl-1-butylaziridine (1.45 g, 10.3 mmol) in THF (10 mL) was
added, and the mixture was warmed to room temperature and stirred
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for 13 h. The reaction mixture was diluted with diethyl ether, washed
with satd NH4Cl aq, and dried over Na2SO4. The solvent was removed
in vacuo, and the residue was purified by silica gel column
chromatography (ethyl acetate/hexane = 1:10). The product 1f was
obtained as a colorless oil (730 mg, 50%): 1H NMR (300 MHz,
CDCl3) 4.94 (s, 1 H), 4.81(m, 1 H), 2.43(m, 1 H), 2.08 (m, 1 H),
1.77 (m, 1 H), 1.63 (m, 2 H), 1.58−0.87 (m, 10 H); 13C NMR
(150 MHz, CDCl3) 144.0, 111.3, 61.4, 43.7, 33.6, 31.9, 20.5,
18.7, 14.1; IR (neat) 2959, 2931, 2811, 1644, 1455, 1376, 1236,
1084, 882 cm−1; HR-MS (EI+) calcd for C9H16N ([M − H]+) 138.1283,
found 138.1284.
Preparation of Aziridine 1g. To the solution of 1,2-
dibromobutan-3-one21 (3.4 g, 15 mmol) in THF (50 mL) was
added cyclohexylamine (1.9 mL, 16.5 mmol) at 0 °C. After 5 min,
DBU (4.5 mL, 30 mmol) was added, and the mixture was stirred at
ambient temperature overnight. The salt was filtered off and washed
with diethyl ether. The solvent was removed in vacuo, and the crude
product was purified by silica gel column chromatography (ethyl
acetate/hexane = 1:5) to afford 2-acetyl-1-cyclohexylaziridine (1.68 g,
66%) as a pale brown oil: 1H NMR (600 MHz, CDCl3) 2.03 (m, 1 H),
2.01 (s, 3 H), 1.73 (m, 4 H), 1.61 (d, J = 6.8 Hz, 1 H), 1.54 (m, 1 H),
1.32−1.40 (m, 2 H), 1.12−1.20 (m, 4 H); 13C NMR (125 MHz,
CDCl3) 207.8, 68.7, 44.2, 33.8, 32.5, 32.4, 26.0, 25.2, 24.51, 24.45; IR
(neat) 3047, 2978, 2931, 2854, 1705, 1450, 1358, 1257, 1219, 1165,
1088, 1034, 980 cm−1; HR-MS (EI) calcd for C10H17NO (M+)
167.1310, found 167.1306.
To a mixture of methyltriphenylphosphonium bromide (5.4 g, 15.1
mmol) in THF (50 mL) was added n-BuLi (1.6 M in hexane, 9.1 mL,
15.1 mmol) at 0 °C. To the solution was added 2-acetyl-1-
cyclohexylaziridine (1.68 g, 10.0 mmol) in THF (10 mL), and the
mixture was stirred for 5 h at room temperature. The solution was
diluted with diethyl ether, washed with satd NH4Cl aq, and dried over
Na2SO4. The solvent was removed in vacuo, and the crude product
was purified by silica gel column chromatography (ethyl acetate/
hexane = 1:10) to afford 1g as a colorless oil (1.31 g, 79%): 1H NMR
(300 MHz, CDCl3) 4.91 (m, 1 H), 4.80 (m, 1 H), 1.81−1.06 (m, 17
H); 13C NMR (75 MHz, CDCl3) 144.1, 111.2, 69.5, 42.4, 32.9, 32.23,
32.18, 26.1, 24.82, 24.79, 19.3; IR (neat) 2972, 2928, 2854, 1643,
1450, 1368, 1226, 1167, 881, 829 cm−1; HR-MS (EI) calcd for
C11H19N (M+) 165.1517, found 165.1513.
General Procedure for the Cycloaddition of Vinylaziridines
and Sulfonyl Isocyanates. To a solution of sulfonyl isocyanate
(0.5 mmol) in CH2Cl2 (9 mL) was added vinylaziridine (0.5 mmol) in
CH2Cl2 (1 mL) and the solution stirred at the designated temperature.
The progress of the reaction was monitored by TLC and/or GC−MS.
After the consumption of vinylaziridine, the solvent was removed in
vacuo, and the residue was purified by silica gel column
chromatography (hexane/ethyl acetate) to give the product.
3a: colorless solid; mp 227.5−231.2 °C; 1H NMR (300 MHz,
CDCl3) 7.98−7.20 (m, 9 H), 5.71 (m, 1 H), 5.66 (m, 1 H), 4.54 (s,
2 H), 4.09 (s, 2 H), 3.89 (s, 2 H), 2.42 (s, 3 H); 13C NMR (150 MHz,
CDCl3) 157.7, 144.1, 136.0, 135.8, 129.3, 128.71, 128.69, 127.70,
127.68, 126.1, 124.9, 52.6, 46.9, 45.5, 21.6; IR (KBr) 3035, 1698, 1472,
1455, 1431, 1348, 1239, 1159, 1095, 876, 819, 735, 666, 589, 539
cm−1. Anal. Calcd for C19H20N2O3S: C, 64.02; H, 5.66; N, 7.86.
Found: C, 63.84; H, 5.73; N, 7.82.
542 cm−1. Anal. Calcd for C20H22N2O3S: C, 64.84; H, 5.99; N, 7.56.
Found: C, 64.55; H, 5.99; N, 7.44.
3d: colorless solid; mp 122.0−123.5 °C; 1H NMR (300 MHz,
CDCl3) 7.35−7.22 (m, 5 H), 5.47 (m, 1 H), 4.55 (s, 2 H), 4.02 (m, 2
H), 3.80 (m, 2 H), 3.27 (m, 3 H), 1.67 (d, J = 1.1 Hz, 3 H); 13C NMR
(75 MHz, CDCl3) 158.0, 135.9, 133.8, 128.8, 127.8, 127.7, 119.5, 52.4,
50.1, 45.3, 39.7, 21.0; IR (KBr) 3005, 2925, 1681, 1605, 1476, 1455,
1424, 1335, 1262, 1149, 1109, 1062, 1003, 963, 929, 795, 773, 729,
696, 517 cm−1. Anal. Calcd for C14H18N2O3S: C, 57.12; H, 6.16; N,
9.52. Found: C, 57.18, H, 6.35, N, 9.35.
1
3e: colorless amorphous; H NMR (300 MHz, CDCl3) 8.02−7.19
(m, 14 H), 5.82 (m, 1 H), 4.58 (s, 2 H), 4.39 (d, J = 2.1 Hz, 2 H), 4.04
(m, 2 H), 2.42 (s, 3 H); 13C NMR (75 MHz, CDCl3) 157.6, 144.2,
139.1, 138.0, 136.1, 135.9, 129.4, 128.8, 127.77, 128.76, 128.6, 128.2,
127.8, 126.2, 122.6, 52.5, 49.2, 45.9, 21.6; IR (neat) 3735, 3648, 1698,
1472, 1351, 1228, 1163, 1099, 741, 698, 659, 598, 574 cm−1. Anal.
Calcd for C25H24N2O3S: C, 69.42; H, 5.59; N, 6.48. Found: C, 69.17;
H, 5.89; N, 6.34.
3f: colorless solid; mp 131−132.3 °C; 1H NMR (300 MHz, CDCl3)
7.37−7.20 (m, 10 H), 5.85 (tt, J = 5.5, 1.7 Hz, 1 H), 4.62 (s, 2 H), 4.50
(q, J = 2.1 Hz, 2 H), 4.02 (dt, J = 5.5, 2.1 Hz, 2 H), 3.32 (s, 3 H); 13C
NMR (75 MHz, CDCl3) 187.1, 138.8, 137.8, 135.9, 128.8, 128.7,
128.4, 127.9, 127.8, 126.2, 122.4, 52.6, 49.0, 46.0, 40.0; IR (KBr) 3026,
2924, 2360, 1698, 1468, 1335, 1159, 966, 765, 696, 497 cm−1; HR-MS
(ESI) calcd for C19H20N2O3S ([M + Na]+) 379.1087, found 379.1099.
3g: colorless solid; mp 127.8−130.0 °C; 1H NMR (300 MHz,
CDCl3) 7.96 (d, J = 8.4 Hz, 2H), 7.34−7.21 (m, 7 H), 4.89 (t, J = 6.0
Hz, 1 H), 4.53 (s, 2 H), 3.86 (d, J = 1.5 Hz, 2 H), 3.82 (d, 6.0 Hz, 2
H), 2.42 (s, 3 H), 0.86 (s, 9 H), 0.06 (s, 6 H); 13C NMR (150 MHz,
CDCl3) 156.9, 149.5, 144.1, 136.1, 135.8, 129.4, 128.73, 128.70, 127.8,
127.7, 101.6, 52.3, 48.8, 43.3, 25.5, 21.6, 17.9, −4.7; IR (KBr) 3648,
2929, 1696, 1464, 1350, 1244, 1210, 1166, 1099, 884, 830, 733, 664,
592, 546, 507 cm−1. Anal. Calcd for C25H34N2O4SSi: C, 61.69; H,
7.04; N, 5.76. Found: C, 61.66; H, 7.16; N, 5.61.
1
3h: colorless solid; mp 79−82 °C; H NMR (300 MHz, CDCl3)
7.34−7.26 (m, 5 H), 4.91 (t, J = 5.5 Hz, 1 H), 4.57 (s, 2 H), 3.97 (s, 2
H), 3.80 (d, J = 5.7 Hz, 2 H), 3.27 (s, 3 H), 0.88 (s, 9 H), 0.08 (s, 6
H); 13C NMR (75 MHz, CDCl3) 157.5, 149.3, 135.9, 128.8, 127.8,
127.7, 101.4, 52.3, 48.8, 43.4, 39.8, 25.4, 17.9, −4.7; IR (KBr) 3029,
2931, 2858, 1687, 1469, 1427, 1342, 1283, 1247, 1198, 1130, 1097,
1079, 1050, 1008, 965, 934, 886, 843, 777, 737, 698, 639, 590, 556,
515, 490 cm−1; HR-MS (ESI) calcd for C19H30N2O4SSi ([M + Na]+)
433.1588, found 433.1583.
3i: colorless solid; mp 143−144.5 °C; 1H NMR (300 MHz, CDCl3)
7.96 (d, J = 8.3 Hz, 2 H), 7.30 (d, J = 8.1 Hz, 2 H), 7.11 (d, J = 8.1 Hz,
1 H), 6.40 (m, 2 H), 5.66 (m, 1 H), 5.56 (m, 1 H), 4.47 (s, 2 H), 4.02
(m, 2 H), 3.91 (m, 2 H), 3.77 (s, 3 H), 3.73 (s, 3 H), 2.41 (s, 3 H);
13C NMR (75 MHz, CDCl3) 160.6, 158.5, 157.2, 143.9, 136.0, 130.4,
129.3, 128.7, 125.8, 125.2, 116.7, 104.1, 98.4, 55.3, 55.2, 47.2, 46.9,
45.3, 21.6; IR (KBr) 2935, 1695, 1614, 1508, 1465, 1417, 1349, 1290,
1209, 1162, 1124, 1092, 1035, 876, 815, 739, 665, 588, 549 cm−1. Anal.
Calcd for C21H24N2O5S: C, 60.56; H, 5.81; N, 6.73. Found: C, 60.39;
H, 5.91; N, 6.68.
3j: colorless oil; 1H NMR (300 MHz, CDCl3) 7.13 (d, J = 7.9, 1 H)
6.45−6.41 (m, 2 H), 5.69−5.65 (m, 1 H), 5.59−5.56 (m, 1 H), 4.50
(s, 2 H), 4.12 (s, 2 H), 3.90 (s, 2 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 3.24
(s, 3 H); 13C NMR (75 MHz, CDCl3) 160.0, 158.5, 157.7, 130.6,
125.5, 125.2, 116.5, 104.1, 98.4, 55.4, 55.3, 47.5, 46.7, 45.4, 39.7; IR
(KBr) 3628, 2936, 2839, 1696, 1613, 1508, 1340, 1160, 1085, 1035,
966, 878, 835, 761, 735, 703, 645, 568, 535, 512 cm−1; HR-MS (ESI)
calcd for C15H20N2O5S ([M + Na]+) 363.0985, found 363.0974.
3k: colorless solid; mp 147.5−149.8 °C; 1H NMR (300 MHz,
CDCl3) 7.94 (d, J = 8.2 Hz, 2 H), 7.30 (d, J = 8.2 Hz, 2 H), 5.60 (m,
1 H), 3.90 (d, J = 4.3 Hz, 1 H), 3.83 (s, 3 H), 3.30 (t, J = 7.5 Hz, 2 H),
2.41 (s, 3 H), 1.65 (s, 3 H), 1.51−0.84 (m, 7 H); 13C NMR (150
MHz, CDCl3) 156.5, 143.9, 135.8, 134.1, 129.3, 128.7, 119.8, 50.2,
49.1, 45.6, 30.0, 21.6, 21.0, 19.9, 13.8; IR (KBr) 2963, 2859, 1698,
1473, 1340, 1238, 1159, 1103, 1035, 832, 746, 657, 580, 542, 513
cm−1. Anal. Calcd for C17H24N2O3S: C, 60.69; H, 7.19; N, 8.33.
Found: C, 60.55; H, 7.17; N, 8.22.
3b: colorless oil; 1H NMR (300 MHz, CDCl3) 7.34−7.23 (m, 5 H),
5.74−5.71 (m, 1 H), 5.69−5.66 (m, 1 H), 4.57 (s, 2 H), 4.20−4.18
(m, 2 H), 3.88−3.86 (m, 2 H), 3.26 (s, 3 H); 13C NMR(75 MHz,
CDCl3) 158.3, 135.9, 128.8, 127.8, 127.7, 126.0, 124.9, 52.8, 46.7, 45.7,
39.8; IR (KBr) 3626, 3033, 2930, 1691, 1496, 1471, 1421, 1343, 1239,
1159, 1092, 1029, 965, 933, 878, 762, 700, 557, 514, 468 cm−1; HR-
MS (ESI) calcd for C13H16N2O3SNa ([M + Na]+) 303.0774, found
303.0765.
3c: colorless solid; mp 165−166 °C; 1H NMR (300 MHz, CDCl3)
7.99−7.20 (m 9 H), 5.46 (d, J = 1.5 Hz, 1 H), 4.52 (s, 2 H), 3.90 (s, 2
H), 3.82 (d, J = 4.3 Hz, 2 H), 2.42 (s, 3 H), 1.64 (s, 3 H); 13C NMR
(150 MHz, CDCl3) 157.5, 144.1, 136.1, 135.8, 133.9, 129.4, 128.8,
128.7, 127.69, 127.66, 119.6, 52.3, 50.2, 45.1, 21.6, 21.0; IR (KBr)
2913, 1683, 1473, 1449, 1428, 1347, 1231, 1161, 748, 733, 704, 689,
2146
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Article
1
3l: colorless oil; H NMR (300 MHz, CDCl3) 5.60 (m, 1 H), 3.95
139.6, 132.6, 128.3, 128.2, 127.6, 126.9, 126.7, 126.1, 120.5, 56.7, 50.2,
49.2; IR (KBr) 3032, 2985, 2846, 1951, 1882, 1736, 1604, 1496, 1450,
1358, 1242, 1103, 1026, 987, 918, 810, 733, 694, 609, 532, 463 cm−1.
Anal. Calcd for C17H17N: C, 86.77; H, 7.28; N, 5.95. Found: C, 86.62;
H, 7.30; N, 6.10.
(d, J = 0.9 Hz, 2 H), 3.86 (m, 2 H), 3.34 (t, J = 7.2 Hz, 2 H), 3.22
(s, 3 H), 1.68 (d, J = 1.1 Hz, 3 H), 1.48 (m, 2 H), 1.32 (m, 2 H), 0.90
(t, J = 7.2 Hz, 3 H); 13C NMR (75 MHz, CDCl3) 157.2, 133.9, 119.7,
50.1, 49.0, 45.6, 39.5, 30.0, 21.0, 19.9, 13.8; IR (KBr) 3386, 2931,
2870, 1689, 1473, 1427, 1342, 1234, 1157, 1118, 1034, 1003, 964, 833,
764, 555, 517 cm−1. Anal. Calcd for C11H20N2O3S: C, 50.75; H, 7.74;
N, 10.76. Found: C, 50.95, H, 7.72, N, 10.80.
8: yield 47%; pale yellow oil; 1H NMR (300 MHz, CDCl3) 7.97 (m,
10 H), 5.26−5.43 (m, 2 H), 5.04−5.08 (m, 1 H), 3.86 (d, J = 13.6 Hz,
1 H), 3.62 (d, J = 13.6 Hz, 1 H), 2.89 (d, J = 6.4 Hz, 1 H), 2.41 (t, J =
7.2 Hz, 1 H); 13C NMR (125 MHz, CDCl3) 139.0, 137.0, 134.6, 128.3,
127.9, 127.8, 127.7, 126.9, 126.7, 118.1, 64.2, 48.9, 48.0; IR (KBr)
3062, 3032, 2985, 2954, 2924, 2823, 1635, 1604, 1496, 1450, 1389,
1358, 1304, 1250, 1196, 1165, 1103, 1072, 1026, 987, 918, 841, 741,
702, 602, 463 cm−1. Anal. Calcd for C17H17N: C, 86.77; H, 7.26; N,
5.95. Found: C, 86.52; H, 7.26; N, 5.82.
1
3m: colorless solid; mp 227.5−231.2 °C; H NMR (300 MHz,
CDCl3) 7.94 (d, J = 8.2 Hz, 2 H), 7.30 (d, J = 8.2 Hz, 2 H), 5.57 (br,
1 H), 4.02 (br, 1 H), 3.84 (br, 4 H), 2.41 (s, 3 H), 1.74−1.01 (br, 13
H); 13C NMR (75 MHz, CDCl3) 156.7, 143.9, 135.8, 134.0, 129.2,
128.8, 120.5, 55.2, 50.4, 39.4, 30.5, 25.5, 25.3, 21.6, 21.0; IR (KBr)
2929, 2857, 1684, 1471, 1342, 1243, 1162, 1032, 894, 818, 741, 657,
582, 545 cm−1. Anal. Calcd for C19H26N2O3S: C, 62.96; H, 7.23; N,
7.73. Found: C, 62.83; H, 7.31; N, 7.58.
7: colorless amorphous solid; 1H NMR (300 MHz, CDCl3) 7.88 (d,
J = 8.3 Hz, 2 H), 7.36−7.20 (m, 12 H), 6.00−5.79 (m, 1 H), 5.86−
5.79 (m, 1 H), 5.14 (d, J = 15.1 Hz, 1 H), 4.83 (d, J = 6.6 Hz, 1 H),
4.48 (dd, J = 17.1, 6.0 Hz, 1 H), 4.12 (d, J = 15.4 Hz, 1 H), 3.93 (dq, J =
17.3, 2.4 Hz, 1 H), 2.40 (s, 3 H); 13C NMR (75 MHz, CDCl3) 157.9,
144.1, 138.5, 136.5, 136.2, 129.3, 129.0, 128.8, 128.7, 128.6, 128.2, 128.0,
127.7, 126.5, 125.1, 61.6, 52.7, 45.9, 21.6; IR (KBr) 3033, 1685, 1598,
1439, 1357, 1306, 1244, 1167, 1096, 1031, 872, 819, 733, 665, 592, 545,
509, 457 cm−1; HR-MS (ESI) calcd for C25H24N2O3SNa ([M + Na]+)
455.1400, found 455.1403.
3n: colorless oil; 1H NMR (300 MHz, CDCl3) 5.59−5.55 (m, 1 H),
4.09−4.00 (m, 1 H), 3.95 (d, J = 0.8 Hz, 2 H), 3.80 (dd, J = 5.7,
1.1 Hz, 2 H), 3.22 (s, 3 H), 1.75−1.03 (m, 13 H); 13C NMR (75
MHz, CDCl3) 157.2, 133.9, 120.4, 55.4, 50.2, 39.5, 39.4, 30.5, 25.4,
25.3, 20.9; IR(KBr) 3410, 2932, 2857, 1683, 1470, 1345, 1243, 1156,
1057, 1037, 1006, 967, 897, 759, 692, 650, 563, 522; HR-MS (ESI)
calcd for C13H22N2O3SNa ([M + Na]+) 309.1243, found 309.1244.
4a: colorless solid; mp 91.4−93.1 °C; 1H NMR (300 MHz, CDCl3)
7.94−7.11 (m, 9 H), 5.76 (ddd, J = 7.9, 10.2, 17.0 Hz, 1 H), 5.35 (d,
J = 17.0 Hz, 1 H), 5.23 (d, J = 10.2 Hz, 1 H), 4.70 (m, 1 H), 4.34 (d,
J = 14.9 Hz, 1 H), 4.27 (d, J = 14.9 Hz, 1 H), 3.45 (dd, J = 4.5, 9.1 Hz,
1 H), 2.90 (dd, J = 3.6, 9.1 Hz, 1 H), 2.42 (s, 3 H); 13C NMR (75
MHz, CDCl3) 153.5, 144.4, 136.2, 135.19, 135.17, 129.3, 128.7, 128.3,
128.0, 127.8, 118.6, 56.3, 47.8, 47.5, 21.5; IR (KBr) 2926, 1723, 1493,
1420, 1363, 1174, 1092, 942, 813, 758, 705, 663, 584, 547 cm−1. Anal.
Calcd for C19H20N2O3S: C, 64.02; H, 5.66; N, 7.86. Found: C, 64.30;
H, 5.76; N, 7.83.
9: colorless amorphous solid; 1H NMR (300 MHz, CDCl3) 7.53 (d,
J = 8.3, 2 H), 7.30−7.12 (m, 10 H), 7.02 (d, J = 7.2 Hz, 2 H), 5.30 (d,
J = 8.7 Hz, 1 H), 5.16 (dd, J = 9.6, 1.1 Hz, 1 H), 5.11 (d, J = 2.3 Hz, 1
H), 4.94 (dt, J = 16.4, 9.4 Hz, 1 H), 4.77 (d, J = 14.9 Hz, 1 H), 4.25
(t, J = 8.9 Hz, 1 H), 3.88 (d, J = 15.1 Hz, 1 H), 2.40 (s, 3 H); 13C
NMR (75 MHz, CDCl3) 156.9, 144.3, 136.0, 135.5, 135.0, 132.2,
129.0, 128.7, 128.6, 128.5, 128.4, 128.3, 127.9, 127.8, 122.8, 61.9, 61.3,
45.4 21.6; IR (KBr) 3425, 1720, 1496, 1458, 1412, 1358, 1288, 1250,
1211, 1273, 1134, 1095, 1026, 810, 756, 702, 663, 579, 540 cm−1; HR-
MS (ESI) calcd for C25H24N2O3SNa ([M + Na]+) 455.1400, found
455.1418.
Synthesis of 5 by the Deprotection of 3j. Compound 3j
(208 mg, 0.50 mmol) was dissolved with TFA (5 mL), and the mixture
was stirred for 40 min at 60 °C. The reaction was quenched by
addition of saturated NaHCO3 aq, and the mixture was extracted with
CH2Cl2. The combined organic layer was washed with brine, dried
over MgSO4, and evaporated. The residue was purified by silica gel
column chromatography (ethyl acetate/hexane = 1:2) to afford 5 as
ASSOCIATED CONTENT
* Supporting Information
■
S
X-ray crystallographic data for 3a (CIF). Crystal structure of 3a
and NMR spectra (1H, 13C) for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
colorless solid (102 mg, 78%): mp 160.5−163 °C; H NMR (300
MHz, CDCl3) 7.93 (d, J = 8.3 Hz, 2 H), 7.30 (d, J = 7.9 Hz, 2 H), 5.75
(m, 2 H), 5.18 (brs, 1 H), 4.10 (d, J = 2.4 Hz, 2 H), 3.85 (t, J = 4.1 Hz,
2 H), 2.41 (s, 3 H); 13C NMR (75 MHz, CDCl3) 195.8, 158.8, 144.2,
129.4, 128.7, 125.5, 125.4, 46.1, 41.0, 21.6; IR (KBr) 3304, 1714, 1666,
1462, 1347, 1162, 1115, 1091, 909, 812, 674, 623, 571, 536, 450, 408
cm−1. Anal. Calcd for C12H14N2O3S: C, 54.12; H, 5.30; N, 10.52.
Found: C, 54.41; H, 5.25; N, 10.43.
AUTHOR INFORMATION
Corresponding Author
*Tel: +81-3-5228-8715. E-mail: ssaito@rs.kagu.tus.ac.jp.
■
Present Address
§Chemical Analysis Center, Chiba University, 1-33 Yayoi-cho,
Inage-ku, Chiba-shi, Chiba 263-8522, Japan.
Preparation of 6 and 8. General Procedure. DIBAL-H (1.04 M
in hexane, 20.2 mL, 21 mmol) was added dropwise to a stirred
solution of cis(or trans)-1-benzyl-2-methoxycarbonyl-3-phenylaziri-
dine21 (3.04 g, 14 mmol) in CH2Cl2 (42 mL) at −78 °C. After 100
min, Na2SO4·10H2O (5 g) was added and the reaction mixture
allowed to reach rt. The inorganic precipitate was filtered off and
washed with ethyl acetate. The filtrate was dried (Na2SO4) and the
solvent removed in vacuo. The crude aldehyde was unstable, and it was
used for the next step without further purification. To a mixture of
methyltriphenylphosphonium bromide (7.5 g, 21 mmol) in THF
(75 mL) was added n-BuLi (1.6 M in hexane, 12.7 mL, 21 mmol) at
0 °C, and the mixture was stirred for 30 min. A solution of aldehyde
(2.2 mmol) in THF (3 mL) was added. The mixture was warmed to
room temperature and stirred for additional 15 h. The solution was
diluted with ethyl ether, and the combined organic layer was washed
with water and dried over Na2SO4. The solvent was removed in vacuo,
and the residue was purified by silica gel column chromatography
(ethyl acetate/hexane).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Mr. Yasuo Fujisawa for his assistance. This work was
supported by Nagase Science and Technology Foundation.
■
REFERENCES
■
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2147
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Article
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2005, 127, 1354−1355 This compound was prepared by a similar
procedure we reported in this paper for the preparation of 2-acetyl-1-
butylaziridine.
(21) Heasley, V. L.; Shellhamer, D. F.; Carter, T. L.; Gipe, D. E.; Gipe,
R. K.; Green, R. C.; Hordeen, J.; Rempel, T. D.; Spaite, D. H.; Heasley, G. E.
Tetrahedron Lett. 1981, 22, 2467−2470. This compound was unstable and
should be used for the reaction immediately as it was prepared.
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