Novel synthetic method for allylic amination of cyclic allylic ethers using chlorosulfonyl isocyanate

Article abstract of DOI:10.1016/j.tetlet.2011.02.036

The introduction of amines to allylic or benzylic position of cyclic compounds with chlorosulfonyl isocyanate is developed in high to excellent yields. This method provides a novel access to biologically active compounds including the framework of 1-amino

Full text of DOI:10.1016/j.tetlet.2011.02.036

Tetrahedron Letters 52 (2011) 1901–1904
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Tetrahedron Letters
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Novel synthetic method for allylic amination of cyclic allylic ethers using
chlorosulfonyl isocyanate
Sang Hwi Lee a, In Su Kim b, Qing Ri Li a, Guang Ri Dong a, Young Hoon Jung a,
⇑
a School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
b Department of Chemistry, University of Ulsan, Ulsan 680-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The introduction of amines to allylic or benzylic position of cyclic compounds with chlorosulfonyl isocy-
anate is developed in high to excellent yields. This method provides a novel access to biologically active
compounds including the framework of 1-aminoindanes, 1-aminotetralines, and 1-amino-2-hydroxy cyc-
lic compounds. Mechanistic evidence for the reaction pathway is also provided.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 13 December 2010
Revised 1 February 2011
Accepted 9 February 2011
Available online 13 February 2011
Keywords:
Chlorosulfonyl isocyanate
Amination
Allylic ether
Allylic carbamate
1-Aminoindane
1-Aminotetraline
Considerable effort has been devoted in the last decades toward
new methods for forming carbon–nitrogen bonds. Traditional
methods can be divided into two large categories such as nucleo-
philic substitution1 and direct amination.2 Representative exam-
ples for nucleophilic substitution include metal-catalyzed
nucleophilic substitutions,1a–c Mitsunobu reactions,1d Overmann
rearrangement,1e and Gabriel amination.1f,1g The direct amination
methods involve the nitrene addition,2a [2,2]- or [2,3]-cycloaddi-
tion reactions,2b,c and reductive amination.2d In particular, cycload-
dition reactions between alkenes and an imine moiety in
chlorosulfonyl isocyanate have found great utility in synthetic
chemistry and are now valuable tools that are employed
routinely.3 As a result, carbon–nitrogen bond formation using chlo-
rosulfonyl isocyante can often be found as common synthetic steps
in numerous total syntheses of biologically active natural and
unnatural compounds, and their synthetic derivatives.4 In contrast,
an alternative chemical reaction was found to afford allylic
carbamates from allylic ethers using chlorosulfonyl isocyante.5
Moreover, this methodology was applied to the total synthesis of
biologically active polyhydroxylated alkaloids.6 This transforma-
tion is an elegant example of avoiding prefunctionalization for
the introduction of an amine moiety, and for avoiding post-
manipulation such as protection of the amine functionality.
As a part of an ongoing research program aimed at the effective
total synthesis of biologically active cyclic natural products and
drugs, we envisioned the regioselective allylic amination of cyclic
allylic ethers to give cyclic allylic amine compounds, which can
be effectively transformed into biologically active natural and
unnatural compounds, that is, rasagiline,7 sertraline,8 abacavir,9
and acarbose,10 as shown in Figure 1.
The initial study focused on the reaction of benzyl cyclohex-2-
enyl ether (1a) with CSI by varying the solvent and temperature
to optimize the yield, and the results are summarized in Table
1.11 The reaction in methylene chloride at À78 °C and 0 °C fur-
nished the corresponding carbamate 2a in 78% and 85% yield,
respectively (Table 1, entries 1 and 2).12 However, the reaction in
a nonpolar solvent, such as toluene and hexanes, provided slightly
lower reaction rates and chemical yields (Table 1, entries 3–5).
The optimal reaction conditions established for the allylic ami-
nation of cyclic benzylic ether 1a were applied to cyclic allylic
ethers 1b–e and cyclic aliphatic ether 1f, as shown in Table 2.
Treatment of cyclopentenyl ether 1b with CSI in methylene
chloride at 0 °C afforded the corresponding carbamate 2b in 81%
yield (Table 2, entry 2). In the case of cyclohexenyl ethers 1c and
1d, the desired products 2c and 2d were generated in good yield,
regardless of the hydroxyl protection groups (Table 2, entries 1,
3, and 4). The introduction of a methyl moiety at the 3-position
decreased the reaction rate slightly (Table 2, entry 5). However,
the reaction of cyclohexyl benzyl ether 1f was ineffective, even
at an increased reaction temperature and time under otherwise
identical conditions (Table 2, entry 6). This is presumably due to
the formation of a relatively unstable secondary carbocation inter-
mediate, compared to the allylic secondary one.
⇑
Corresponding author. Tel.: +82 31 290 7711; fax: +82 31 290 7773.
E-mail address: yhjung@skku.ac.kr (Y.H. Jung).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.036

1902
S. H. Lee et al. / Tetrahedron Letters 52 (2011) 1901–1904
Next, the reaction of bicylic benzylic ethers 3a with CSI was
examined. After further optimization, 1-benzyloxy-1,2,3,4-tetrahy-
dro-naphthalene (3a) was converted to the corresponding product
4a at À78 °C for 3 h under otherwise identical conditions.
However, the reaction between compound 3a and CSI above 0 °C
afforded compound 4a in low yield (50%) and 1,2-dihydronaphtha-
lene as the eliminated byproduct in 43% yield. With the optimal
reaction condition established, the substrate scope was explored,
as shown in Table 3.
Treatment of 1-benzyloxy indane 3b and 1-methoxy indane 3c
with CSI under these standard conditions gave the desired prod-
ucts 4b and 4c, respectively, in excellent yield (Table 3, entries 2
and 3). However, when the benzyloxy group was located at the
C-2 position, the amination product 4d was not formed, even at
an increased reaction temperature and time under otherwise
identical conditions. This is presumably due to the formation of a
relatively unstable secondary carbocation intermediate, compared
to the benzylic secondary one. (Table 3, entry 4). In addition,
4-(benzyloxy)chroman 3e and 9-(benzyloxy)-9H-fluorene 3f were
converted into compound 4e (59%) and compound 4f (70%),
respectively, even though this required an increased reaction
temperature and an extended reaction time, as shown in entries
5 and 6. In addition, 1,2-anti-dibenzyloxy tetraline 3g led to the
formation of the C-1 adduct 4g with excellent regioselectivity
and anti-diastereoselectivity of 99 > 1 (Table 3, entry 7).
To gain further insight into the reaction mechanism, additional
experiments were performed using isotopically labeled allylic
ether (deuterio-1a) under different solvents. As shown in Table 4,
the incorporation of deuterium is dependent on the dielectric con-
stant of the solvent. In particular, the use of n-hexanes provided a
mixture of deuterio-product 5a and iso-deuterio-product 5b at the
interior allylic position (95%) and the exterior vinylic position (5%).
A plausible reaction mechanism appears based on isotopically
labeled experiments, as outlined in Figure 2. The initial attack by
the oxygen of benzyl ether to CSI delivers an oxonium ion (I),
HN
HN
HN
N
N
N
H2N
N
Rasagiline
Cl
OH
Abacavir
OH
Cl
HO
HO
Sertraline
H3C
H
N
O
OH
HO
HO
OH
O
O
OH
HO
OH
O
OH
O
Acarbose
HO
OH
Figure 1. Biologically active compounds containing 1-amino cycloallylic or benzo-
cylic scaffold.
Table 1
Optimization of the reaction of benzyl cyclohex-2-enyl ether (1a) with CSI
OBn
NHCOOBn
1) CSI (150 mol%), Na2CO3 (300 mol%)
2) sat. Na2SO3
2a
1a
Entry
Solvent
Temp (°C)
Time (h)
Yielda (%)
1
2
3
4
5
CH2Cl2
CH2Cl2
Toluene
Toluene
n-Hexanes
À78
0
À78
1
1
8
4
8
78
85
70
75
75
0
0
a
Isolated yield of pure materials.
Table 2
Reaction of cyclic allylic ethers 1a–e and cyclic aliphatic ether 1f with CSI
NHCOOR
OR
1) CSI (150 mol%)
Na2CO3 (300 mol%), CH2Cl2
2) sat. Na2SO3
n
n
2
1
Entry
1
Allylic ether
Product
Temp (°C)
Time (h)
1
Yielda (%)
85
OBn
NHCOOBn
0
0
0
1a
2a
OBn
NHCOOBn
2
3
1
1
81
83
1b
2b
OAllyl
NHCOOAllyl
1c
2c
OPMB
NHCOOPMB
4
5
6
0
1
70
1d
2d
OBn
NHCOOBn
0
2
70
1e
2e
OBn
NHCOOBn
rt
24
No reaction
1f
2f
a
Isolated yield of pure materials.

S. H. Lee et al. / Tetrahedron Letters 52 (2011) 1901–1904
1903
Table 3
Reaction of bicylic benzylic ethers 3a–g with CSI
NHCOOR
OR
1) CSI (150 mol%)
Na2CO3 (300 mol%), CH2Cl2
2) sat. Na2SO3
n
n
4
3
Entry
1
Allylic ether
Product
Temp (°C)
À78
Time (h)
3
Yielda (%)
OBn
NHCOOBn
82
90
4a
NHCOOBn
4b
3a
OBn
3b
OMe
2
À78
1
NHCOOMe
3
4
À78
1
86
3c
4c
NHCOOBn
4d
OBn
3d
rt
24
No reaction
OBn
NHCOOBn
5
rt
12
59
4e
O
3e
O
OMe
NHCOOMe
6
7
rt
12
24
70
68
4f
3f
OBn
NHCOOBn
OBn
OBn
À40
4g
3g
a
Isolated yield of pure materials.
Table 4
Isotopically labeled experiments
OBn
NHCOOBn
D
NHCOOBn
1) CSI (150 mol%)
D
Na2CO3 (300 mol%)
+
2) sat. Na2SO3
D
5a
5b
1a
deuterio -
Entry
Solvent
Dielectric constant (°C)
Time (h)
Yielda (%)
Ratiob (5a:5b)
1
2
3
CH3NO2
CH2Cl2
n-Hexanes
35.87 (30)
9.14 (20)
1.90 (20)
1
1
10
80
79
80
81:19
91:9
95:5
a
Isolated yield of pure materials.
Ratio was determined by 1H NMR and 2H NMR analysis.
b
which can be converted to the deuterio-product 5a as a major com-
pound through a 4-centered transition structure (IIa) according to
a SNi mechanism. This is consistent with the results of isotopic
labeling under nonpolar n-hexanes solvent, compared to relatively
polar nitromethane and dichloromethane solvents. Another plausi-
ble SN1 mechanism can be in competition with the SNi mechanism.
However, this reaction may be partially proceed via SN1 mecha-
nism due to the incomplete orbital overlap between p orbital of
the double bond and p orbital of cyclic allylic sp2 carbocation in
the reaction intermediate (IIb).
at the allylic and benzylic positions with chlorosulfonyl isocyanate
in high yield. These aminations are believed to proceed through a
SNi mechanism. This synthetic methodology can be applied easily
to the preparation of various biologically active natural products
and drugs containing a cyclic amine moiety.
Acknowledgments
This research was supported by a National Research Foundation
Grant (NRF-2009-0074658) and the Ministry of Knowledge Econ-
omy for the Regional Innovation System program in 2010 (No.
B0012306).
In conclusion, we have reported the introduction of protected
amines to the ring system by a treatment of various alkyl ethers

1904
S. H. Lee et al. / Tetrahedron Letters 52 (2011) 1901–1904
tight ion pair
Solvent shell surrounds the ions
O
Bn
ClO2S
SNi
major
O
N
D
O
HN OBn
D
ΙΙa
O
ClO2S
Bn
D
Bn
D
N
O
O
ClO2S N C O
5a
O
ClO2S
Bn
I
N
O
deuterio-1a
D
D
O
SN1
BnO
N
H
minor
delocalized pi bond
5b
solvent separated
loose ion pair
ΙΙb
Figure 2. Proposed reaction pathway (SNi vs SN1).
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.02.036.
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12. Selected characterization (2a): Rf = 0.14 (n-hexanes/EtOAc = 10/1); mp 66.2 °C;
IR (KBr)
m ;
3313, 3034, 2936, 1685, 1531, 1306, 1241, 1036 cmÀ1 1H NMR
(300 MHz, CDCl3) d 1.49–1.68 (m, 3H), 1.88–2.02 (m, 3H), 4.21–4.23 (m, 1H),
4.70–4.72 (m, 1H), 5.10 (s, 2H), 5.59–5.64 (m, 1H), 5.80–5.86 (m, 1H), 7.28–
7.43 (m, 5H); 13C NMR (75 MHz, CDCl3) d 19.51, 24.67, 29.64, 46.27, 66.49,
127.64, 127.99, 128.05, 128.43, 130.74, 136.54, 155.57; HRMS (EI) Calcd for
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C
14H17NO2 [M]+ 231.1259, found 231.1259.