Organocatalysis of nucleophilic substitution reactions by the combined effects of two promoters fused in a molecule: Oligoethylene glycol substituted imidazolium salts

Article abstract of DOI:10.1016/j.tet.2013.10.070

Oligoethylene glycol substituted imidazolium salts were synthesized as promoters for a range of S_N2 reactions, and their efficiency was examined. These tailor-made organic promoters enhanced the nucleophilicity of alkali metal salts significantly through the combined effects of two promoters (oligoethylene glycols and imidazolium salts) in a single molecule. The effects of the oligoethylene glycol side chain length, ionic liquid anions, nucleophiles, and substrates were investigated systematically. [hexaEGmim][OMs] and [dihexaEGim][OMs] showed the highest efficiency for S_N2 reactions using alkali metal salts. The role of the terminal hydroxyl groups of the oligoethylene glycol moiety was assessed by examining the relative S _N2 yields of chlorination and bromination. The results showed that the hydrogen bonding strength of the hydroxyl groups with the nucleophile is very important. The mechanism for the excellent promotion of S_N2 reactions by oligoEGILs was examined by quantum chemical calculations. The results showed that the oxygen atoms in the oligoethylene glycol portion and the ionic liquid anion act on the counter cation K⁺ or Na⁺ as a Lewis base, to enhance the reactivity of the metal salts significantly.

Full text of DOI:10.1016/j.tet.2013.10.070

Tetrahedron 70 (2014) 533e542
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Tetrahedron
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Organocatalysis of nucleophilic substitution reactions by the
combined effects of two promoters fused in a molecule:
oligoethylene glycol substituted imidazolium salts
Vinod H. Jadhav a 1, Ju-Young Kim b 1, Dae Yoon Chi , Sungyul Lee ,*, Dong Wook Kim
,
,
c
b
a,
*
a
Department of Chemistry, Inha University, 100 Inha-ro, Nam-gu, Incheon 402-751, Republic of Korea
Department of Applied Chemistry, Kyung Hee University, Gyeonggi 446-701, Republic of Korea
Department of Chemistry, Sogang University, 1 Shinsudong Mapogu, Seoul 121-742, Republic of Korea
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Oligoethylene glycol substituted imidazolium salts were synthesized as promoters for a range of SN2
reactions, and their efficiency was examined. These tailor-made organic promoters enhanced the nucleo-
philicity of alkali metal salts significantly through the combined effects of two promoters (oligoethylene
glycols and imidazolium salts) in a single molecule. The effects of the oligoethylene glycol side chain length,
ionic liquid anions, nucleophiles, and substrates were investigated systematically. [hexaEGmim][OMs] and
Received 22 September 2013
Received in revised form 22 October 2013
Accepted 23 October 2013
Available online 29 October 2013
[
dihexaEGim][OMs] showed the highest efficiency for S
terminal hydroxyl groups of the oligoethylene glycol moiety was assessed by examining the relative S
yields of chlorination and bromination. The results showed that the hydrogen bonding strength of the
hydroxyl groups with the nucleophile is very important. The mechanism for the excellent promotion of S
N
2 reactions using alkali metal salts. The role of the
Keywords:
Organocatalysis
S 2
N
Oligoethylene glycol
Alkali metal salts
Imidazolium salt
Ionic liquid
N
2
N
2
reactions by oligoEGILs was examined by quantum chemical calculations. The results showed that the
oxygen atoms in the oligoethylene glycol portion and the ionic liquid anion act on the counter cation K or
Na as a Lewis base, to enhance the reactivity of the metal salts significantly.
þ
þ
Ó 2013 Elsevier Ltd. All rights reserved.
1
. Introduction
system shows poor performance for metal halides due to the for-
mation of a tight ion-pair in the reaction media, and some tetra-
4
e6
Bimolecular nucleophilic substitution (S
N
2) is a fundamental
alkylammonium salts exhibit thermal instability.
Several groups have reported the effects of the solvents on the
efficiency of S 2 reactions. Polar aprotic solvents, such as acetoni-
trile, dimethyl sulfoxide (DMSO) and N,N-dimethyl formamide
(DMF), have been used as the reaction media for S 2 reactions
and well-known chemical transformation that is extremely useful
in synthetic chemistry. Although the mechanism of this process is
relatively simple, recent progress in S 2 reactions has brought new
N
developments to this very old process regarding the use and effi-
ciency of counter-ions and solvents. Alkali metal salts are very
desirable sources of the nucleophile because they are economical,
stable, and abundant. On the other hand, S
these alkali metal salts often barely proceed without the help of
a phase transfer catalyst (PTC), because of their limited solubility
and sluggish reactivity in organic solvent systems.
phase transfer agents have been developed to overcome these
problems and accelerate the reaction. Alkali metal salts/18-
crown-6 ether complexes and tetra-alkylammonium salts are
1
N
N
because they allow the selective solvation of the counter-ions
7
(metal cations). They are also considered advantageous for the
2
,3
N
2 reactions using
reaction because of a lack of protons that might retard the reaction
by forming hydrogen bonds with the nucleophile.1 Recent de-
,7
N
velopments, however, have shown that this old wisdom for S 2
1
e3
A number of
reactions does not always hold. Bulky protic solvents, such as
tert-butyl alcohol or tert-amyl alcohol, were recently reported to
increase the reactivity of alkali metal fluoride significantly by
4
5
6
8
producing a ‘flexible’ fluoride effect. In a more significant advance,
6
used frequently in a range of phase transfer protocols, but these
short-chain oligoethylene glycols (oligEG) were reported to have
two protocols have some drawbacks. For example, the 18-crown-6
spectacular promoting effects for S
N
2 reactions using alkali metal
9
fluorides (KF and CsF). Ionic liquids and molten salts may also
1
0
N
promote a range of S 2 reactions. The role of these promoting
solvents has been well established by a systematic study of the
mechanism, where functional groups in these organocatalysts act
as a Lewis base on the counter-ion to reduce the strong effects of
*
Corresponding authors. Tel.: þ82 32 860 7679; fax: þ82 32 867 5604; e-mail
addresses: sylee@khu.ac.kr (S. Lee), kimdw@inha.ac.kr (D.W. Kim).
1
These authors contributed equally to this work.
0
040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.070

534
V.H. Jadhav et al. / Tetrahedron 70 (2014) 533e542
the latter on the nucleophile. Therefore, these promoting agents
produce an MX ion-pair, in which the nucleophile X (‘flexible’
[hexaEGmim][OMs] with KOTf, NaBF
days afforded [hexaEGmim][OTf], [hexaEGmim][BF
aEGmim][PF ] in 79e83% yield, respectively.
4
or NaPF
6
in acetone for 2
ꢀ
4
] and [hex-
nucleophile) is essentially freed from the effects of the counter-ion
6
þ 8e10
M .
More recently, tailor-made hexaethylene glycolic imida-
The nucleophilic fluorination of the model compound 2 was
zolium-based ionic liquids (hexaEGILs) were reported to be highly
efficient multifunctional organic promoters designed for specific
organic reactions, such as nucleophilic fluorination using potas-
sium fluoride.11 This result prompted a study into the possible use
of various oligoethylene glycolic ionic liquids (oligoEGILs) as mul-
conducted using 3 equiv of CsF in the presence of hexaEGILs
(0.5 equiv) in acetonitrile under uniform reaction condition (80 C
for 6 h), as shown in Fig. 1. HexaEGILs ([hexaEGmim][OMs] and
[hexaEGmim][OTs]), whose anions do not contain F atoms,
exhibited significantly better promoting activity than those ([hex-
ꢁ
tifunctional organic promoters for S
salts. Bulky imidazolium cations paired with their anions, known as
room temperature ionic liquids (ILs)’, have several unique and at-
tractive properties, and have been used as eco-friendly alternative
N
2 reactions with alkali metal
aEGmim][OTf], [hexaEGmim][BF
taining F atoms in the anions. Furthermore, [hexaEGmim][PF
almost inactive as a promoter even when compared with the ionic
liquid, [bmim][PF ], which lacks the promoting effects of the oli-
goEG moiety. In particular, [hexaEGmim][PF ] could act as an in-
hibitor when compared with the same reaction in the absence of
a catalyst. The fluorine-containing anions (particularly [PF ]) are
4
] and [hexaEGmim][PF
6
]) con-
6
] was
‘
6
12
reaction media in a range of chemical science fields. In particular,
the high and straightforward tunable structural features of ILs can
allow them to be tailored to meet specific needs by conducting
6
6
13
simple structural modifications.
believed to inhibit the initial interaction by H-bonding between the
9
In the present study, the structural modification of oligo-
ethylene glycols (oligoEGs) was performed. These organocatalysts
were combined with ionic liquids to highlight the promoting effects
hexaEGIL and fluoride nucleophile, and retard the reaction with
6
these hexaEGILs (particularly [hexaEGmim][PF ]). This suggests
that mesylate [OMs] is the best among these oligoEG substituted
imidazolium salts.
N
of these two moieties for S 2 reactions. These skillfully designed
oligoEGILs exhibited the synergetic effects of oligoEGs and ILs,
significant enhancing the promoting effects compared to oligoEGs
and ILs alone. The effects of the oligoEG chain length with various IL
anions, and the relative efficiency of mono- and di-oligoEGILs were
examined. The effects of the nucleophiles and substrates were also
assessed by carrying out S
entities. The underlying mechanism for the excellent efficiency of
the oligoEGILs in the S 2 process was elucidated by quantum
chemical calculations (Mpwpw91/6-31G* for the substrate and
promoter, and IEFPCM15 for the solvent continuum), illustrating the
pre- and post-reaction complexes, transition states, and activation
barriers of the reaction.
N
2 reactions for various combinations of
1
00
N
[hexaEGmim][PF6]
no catalyst
14
80
[
bmim][PF6]
hexaEGmim][OTf]
[hexaEGmim][BF4]
6
0
[
4
0
[
hexaEGmim][OTs]
hexaEGmim][OMs]
20
2
2
. Results and discussion
[
0
.1. Influence of IL anions on S
N
2 fluorination
0
1
2
3
4
5
6
t / h
The structural modification of oligoEGILs as a promoter for nu-
Fig. 1. Influence of ionic liquid anions in nucleophilic fluorination by CsF in the
cleophilic substitutions was carried out to determine the best
structure for this purpose. First, the effects of IL anions on nucle-
ophilic fluorination were examined. 1-Hexaethylene glycolic-3-
methylimidazolium [hexaEGmim] salts with various anions, such
as mesylate [OMs], tosylate [OTs], triflate [OTf], tetrafluoroborate
presence of various [hexaEGmim][X] (X¼OMs, OTs, OTf, BF
4 6
and PF ). The quantity of
products was determined by H NMR spectroscopy. R¼naphthyl.
1
2.2. Effects of the chain length on the catalytic activity of
n-oligoEGILs
[
4 6
BF ], hexafluorophosphate [PF ], and triflate [OTf], were prepared
using a simple procedure (Scheme 1), in which 1-methylimidazole
was treated with hexaEG mesylate 1a or hexaEG tosylate 1b in
Various 1,3-dioligoethylene glycolic imidazolium mesylate salts
[dioligoEGim][OMs]) with oligoEGs of different chain lengths were
prepared (Scheme 2). The treatment of imidazole with tri-, tetra-,
(
CH
3
CN for 24 h to produce [hexaEGmim][OMs] and [hexaEGmim]
[OTs] in good yields, respectively. Further treatment of
Scheme 1. Preparation of 1-hexaethylene glycolic-3-methylimidazolium salts [hex-
aEGmim][X]. X¼OMs, OTs, OTf, BF , PF
Scheme 2. Preparation of the 1,3-dioligoethylene glycolic imidazolium mesylate salts:
[dioligoEGim][OMs].
4
6
.

V.H. Jadhav et al. / Tetrahedron 70 (2014) 533e542
535
penta-, hexa- or octaethylene glycolic bromide (4aee) in the
slower than the corresponding reaction using KBr (Fig. 3B). In-
terestingly, despite the stronger ionic bonding by KCl than by KBr,
[dihexaEGim][OMs] allowed KCl to be much more reactive than
KBr, thereby accelerating chlorination more significantly than
bromination (Fig. 3C). Because chloride ions form much stronger H-
ꢁ
presence of K
2
CO
3
at 90 C for 24 h in acetone provided the cor-
responding oligoethylene glycolic imidazoles 5aee. A range of
oligoEGILs, such as [ditriEGim][OMs], [ditetraEGim][OMs], [dipen-
taEGim][OMs], [dihexaEGim][OMs], and [dioctaEGim][OMs], were
prepared by a N-alkylation reaction of the corresponding oligo-
ethylene glycolic imidazoles 5aee with the corresponding oligo-
1
bonds with eOH than bromide, [dihexaEGim][OMs] can be as-
sumed to make ‘free’ chloride more efficiently than bromide by the
stronger initial H-bonding interactions of the two terminal hy-
droxyl groups with chloride. Therefore, the mono-hexaEG
substituted [hexaEGmim][OMs] showed better catalytic activity in
the bromination reaction, whereas [dihexaEGim][OMs] showed
much better catalytic activity in the chlorination reaction, as shown
in Fig. 3B and C. This is a good example, where an IL can be tailored
to meet the specific needs by a simple structural modification.
ꢁ
ethylene glycolic mesylate 1aee at 90 C for 48 h in acetonitrile in
8
0e85% yields.
2 fluorination was carried out with KF in the presence of
ditriEGim][OMs], [ditetraEGim][OMs], [dipentaEGim][OMs],
S
N
[
[
dihexaEGim][OMs], and [dioctaEGim][OMs], under uniform re-
ꢁ
action conditions (90 C for 2 h) in tert-amyl alcohol (Fig. 2). All
oligoEG substituted ILs exhibited much higher promoting activity
than the conventional IL [bmim][OMs] because of the additional
effects (metal chelation and initial interaction with fluoride) of the
two oligoEG moieties, among, which [dihexaEGim][OMs] showed
the best efficiency toward nucleophilic fluorination. The hexaEG
moiety proved to be optimal for chelation with metal cations to
generate ‘naked’ fluorides that enhance the reactivity and solubility
of KF. This finding is in line with a similar trend in the fluorination
reaction using oligoethylene glycol as a promoter, as reported
previously.9d
N
2.4. S 2 reactions in the presence of [dihexaEGim][OMs]
To further expand the scope of the tailor-made IL [dihexaEGim]
[OMs] as an organic promoter in diverse nucleophilic substitution
reactions (acetoxylation, thioacetoxylation, iodination, azidation,
and nitrilation) of 2-(3-methanesulfonyloxypropyl)naphthalene (2)
or 2-(3-bromopropoxy)naphthalene (7) model compounds were
ꢁ
attempted at 90 C in acetonitrile using various alkali metal salts as
nucleophile sources. Both acetoxylation using KOAc and thio-
acetoxylation using KSAc in the presence of [dihexaEGim][OMs]
proceeded almost quantitatively within 30 min, producing the
desired products 8 and 9, respectively (entries 1e4). The trans-
formation of methanesulfonate or bromide groups to an iodide
group using KI was complete within 30 min, thereby providing the
iodinated product 10 in almost quantitative yield (entries 5 and 6).
In Table 1, entries 7 and 8 show that the azide group was introduced
100
90
into the aliphatic organic compounds using NaN
3
in excellent yield
(98e99%). A cyano compound 12 was produced from the mesylate
80
N
2 or bromide 7 by a S 2 reaction using KCN in very high yield
(entries 9 and 10, 94 and 93%, respectively).
70
2
.5. S 2 reactions of the various substrates in the presence of
N
60
[dihexaEGim][OMs]
5
0
Table 2 lists the results for the halide and sulfonate substrates
using various alkali metal salts, such as KOAc, KSAc, and NaN , in
3
]
s
M
OMs]
OMs]
[
the presence of [dihexaEGim][OMs] in acetonitrile. The results
confirm that [dihexaEGim][OMs] can act as an efficient promoter
for the nucleophilic substitution of various substrates. In entries
e3 in Table 2, the acetoxyl-, thioacetoxyl-, and azido-groups were
incorporated into the benzylic site in almost quantitative yield
98e99%). Acetoxy-, thioacetoxy-, and azido-ethyl naphthalene
[
]
]
im
bmim][Oi EM Gs ]
ditr
im
Gim][O
EGim][OMs]
[
EGim][OMs]
a
a
[
1
[
ditetr
[dihexaE[dioct
dipentaEG
[
(
Fig. 2. Effects of the oligoEG chain length on the promoting activities of dioligoEGIL on
nucleophilic fluorination. The amount of products was determined by
R¼naphthyl.
1
H
NMR.
derivatives were synthesized in 98e99% yield from 1-(2-
mesyloxyethyl)naphthalene under the same reaction conditions
(entries 4e6). The nucleophilic acetoxylation, thioacetoxylation,
and azidation of a sugar-triflate or an estrone mesylate substrate in
the presence of [dihexaEGim][OMs] also proceeded quite well,
providing the corresponding products in excellent yield (entries
2
.3. Hydrogen bonding effects of oligoEGILs on nucleophilic
halogenations
7e12, 93e98%).
As shown in Fig. 3, two nucleophilic halogenation reactions
chlorination with KF and bromination with KBr) were carried out
(
2.6. Mechanistic aspects
in the presence of mono- and di-hexaEG substituted ILs ([hex-
ꢁ
aEGmim][OMs] and [dihexaEGim][OMs]) in CH
3
CN at 90 C to de-
The structures of the pre-reaction complexes, transition states,
termine the effects of hydrogen bonding between the terminal
eOH groups and the nucleophile. Standard control reactions were
also carried out in the presence of 18-crown-6 as a conventional
phase transfer catalyst. KCl was less reactive than KBr in the nu-
cleophilic displacement reactions in the presence of a conventional
phase transfer catalyst, e.g., 18-crown-6, as shown in Fig. 3A, be-
N
and post-reaction complexes for S 2 reactions were obtained using
quantum chemical methods (Mpwpw91/6-31G* for substrate and
promoter, and IEFPCM for solvent continuum) to determine the
ꢁ
reaction mechanism. The relative Gibbs energies (at 100 C) of the
pre-reaction complexes were calculated to compare their thermo-
z
dynamic stability, and the activation barriers G of the alternative
cause KCl forms tighter ion-pairs than KBr. The S
N
2 reaction using
mechanisms were evaluated to determine the most feasible re-
KCl in the presence of [hexaEGmim][OMs] also proceeded slightly
N
action pathway. Fig. 4 describes the S 2 reaction of KCl and KBr

536
V.H. Jadhav et al. / Tetrahedron 70 (2014) 533e542
(A)
18-crown-6 as a promoter
(B)
[hexaEGmim][OMs] as a promoter
(C)
[dihexaEGim][OMs] as a promoter
1
00
100
80
60
40
20
0
100
80
60
40
20
0
8
0
6
0
chlorination
bromination
chlorination
bromination
chlorination
bromination
4
0
2
0
0
0.0
1.5
3.0
time (h)
4.5
6.0
0.0
1.5
3.0
time (h)
4.5
6.0
0.0
1.5
3.0
time (h)
4.5
6.0
Fig. 3. Effects of hydrogen bonding between oligoEGILs and nucleophiles (chloride and bromide) on the displacement reactions in the presence of 18-crown-6 (A), [hexaEGmim]
1
[
OMs] (B) and [dihexaEGim][OMs] (C). The amount of products was determined by H NMR. R¼naphthyl.
Table 1
2 reactions with various alkali metal salts (MNu) in the presence of [dihexaEGim]
Table 2
a
S
N
Nucleophilic substitutions of the various substrates
a
[OMs]]
Entry
Substrate
MNu Time (h) Temp ( C) Yield (%)b
ꢁ
1
2
3
KOAc 0.5
KSAc 0.5
90
90
90
99
98
98
NaN
3
0.5
4
5
6
KOAc 0.5
KSAc 0.5
90
90
90
99
98
99
Entry
X
MNu
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
OMs
Br
OMs
Br
OMs
Br
OMs
Br
KOAc
KOAc
KSAc
KSAc
KI
0.5
0.5
0.5
0.5
0.5
0.5
1.5
1.5
1.5
3
99
99
97
98
99
98
99
98
94
93
NaN
3
0.5
1
7
8
KOAc
KSAc
80
80
98
97
KI
NaN
NaN
KCN
KCN
3
3
1
OMs
Br
9
NaN
3
1
3
80
90
98
96
10
a
All reactions were carried out on a 1.0 mmol reaction scale of mesyloxyalkane 2
10
KOAc
KSAc
or bromoalkane 7 using 3 mmol of MNu in 4.0 mL of solvent.
b
Isolated yield. R¼naphthyl.
11
4
3
90
90
93
94
12
NaN
3
promoted by 18-crown-6 in CH
3
CN. Several notable features can be
a
Unless noted otherwise, all reactions were carried out on a 1.0 mmol scale of the
z
seen. First, the reaction barrier G in the reaction of KCl was
w2 kcal/mol larger than that for KBr, presumably because the
substrate with 3.0 equiv of MNu and 0.5 equiv of [dihexaEGim][OMs] in 4.0 mL of
CH
3
CN.
b
þ
ꢀ
þ
ꢀ
Isolated yield.
K eCl interactions are stronger than the K eBr interactions (the
dissociation energy of KCl (4.42 eV) is larger than that (3.96 eV) of
KBr), which is in excellent agreement with the higher rate constant
for KBr than KCl observed experimentally. Second, the RKx (X¼Cl,
Br) distances in the pre-reaction complexes were 3.097 and
ꢀ
3
.259 A, respectively, suggesting that KCl and KBr react as ion-pairs
under the influence of 18-crown-6. This is rather surprising because
crown ethers have long been believed to act as promoting agents
for S
N
2 reactions by ‘detaching’ the nucleophile from the counter
cation. These results suggest that 18-crown-6 acts as a Lewis base,
þ
ꢀ
ꢀ
alleviating the Coulombic influence of K on Cl and Br . Pliego
16
recently reported similar results.
Fig. 5 shows the calculated S 2 reaction mechanisms of KBr and
KCl promoted by [hexaEGmim][OMs] in CH CN. The most favorable
pathway of S 2 bromination is via a pre-reaction complex (A) with
N
Fig. 4. Pre-reaction complexes in the S 2 reaction of (A) KBr and (B) KCl promoted by
18-crown-6 in CH CN.
3
N
3
N
an activation barrier of 28.3 kcal/mol. It is worth noting that the
distance RKBr of 3.552 A renders KBr as an ion-pair in this complex.
the oligoethylene glycol portion and the ionic liquid anion acts as
ꢀ
þ
a Lewis bases in a cooperative manner on the counter cation, K or
þ
This mechanism is in line with the previously reported S
N
2 process
ethylene glycol, bis-terminal
hydroxyl polyethers,9 and ionic liquids.10d The oxygen atoms in
Na , as a Lewis base, whereas the nucleophiles react as an ion-pair.
8
a,b
8e
promoted by bulky alcohols,
For the S 2 reaction of KCl promoted by [hexaEGmim][OMs] in
N
a
CH CN (Fig. 5B and C), two mechanisms are feasible. These two
3

V.H. Jadhav et al. / Tetrahedron 70 (2014) 533e542
537
N 3
Fig. 5. Pre-reaction complexes in the S 2 reaction of KBr (A) and KCl (B and C) in [hexaEGmim][OMs]/CH CN.
þ
complexes (B and C) have similar thermodynamic stability (the
difference in Gibbs energy is only 0.1 kcal/mol). Therefore, the re-
action mechanism would be determined by the relative activation
barriers. The difference between the barriers from complexes (A)
and (B) is also quite small (w0.7 kcal/mol). Therefore, the two
mechanisms are competing. The distance in pre-reaction complex
ion-pair and promoter as a Lewis base on the counteraction K and
an ‘anchor’ to the nucleophile. Very compact pre-reaction com-
plexes that are quite favorable for S 2 reactions are formed. The
N
only exception appears to be for chlorination (reaction of KCl) in the
presence of [hexaEGmin][OMs], in which a ‘naked’ nucleophilic
mechanism appears to be competing with the ion-pair mechanism.
Further studies on the applications of this tailor-made multifunc-
tional organic promoter to the rapid F-18 labeling of radiophar-
maceuticals are currently underway.
ꢀ
ꢀ
þ
(
B) was quite large (5.085 A), suggesting that Cl and K is disso-
ciated from the ion-pair form by the influence of the promoter
hexaEGmim][OMs]. These results are summarized in Table 3. It is
[
worth noting that the activation barrier (28.3 kcal/mol) for bro-
mination is smaller than those (29.6, 28.9 kcal/mol) of the two al-
ternative pathways from (B) or (C).
4
4
. Experimental section
.1. General
Table 3
Unless otherwise noted, all reagents and solvents were com-
Relative Gibbs energies (kcal/mol) of the pre-reaction complexes and activation
barriers (kcal/mol) in S
mercially available. The reaction progress was followed by TLC on
.25 mm silica gel 60 plates containing the F-254 indicator. Visu-
alization on TLC was monitored by UV light. Flash chromatography
N
2 reactions of metal salts promoted by 18-crown-6 and
0
[hexaEGmim][OMs] in CH CN
3
ꢀ
Promotor in CH
3
CN
MF
Relative G and RMx (A) of
Activation
barrier G
1
13
was performed with 230e400 mesh silica gel. The H and C NMR
z
pre-reaction complexes
spectra were recorded on a 400 or 600 MHz spectrometer, and the
chemical shifts are reported in d units (parts per million) relative to
tetramethylsilane. Low- and high-resolution electron impact (EI,
70 eV) spectra were obtained.
1
8-crown-6
8-crown-6
KBr
KCl
KBr
KCl
d
26.8
28.9
28.3
29.6
28.9
R
d
KBr¼3.259
1
R
d
KCl¼3.097
[
HexaEGmim][OMs]
HexaEGmim][OMs]
R
KBr¼3.552
4
.2. [hexaEGmim][OMs]
[
(B) G¼0
R
KCl¼3.556
(C) G¼0.1
Hexaethylene glycolic mesylate (1d), (2.0 g, 5.5 mmol, 1 equiv)
was added dropwise to the solution of 1-methylimidazole (556 mg,
RKCl¼5.085
5
.5 mmol, 1 equiv) in CH
3
CN (25 mL). The reaction mixture was
ꢁ
stirred at 90 C for 48 h and evaporated under reduced pressure to
3
remove CH CN. The residue was washed repeatedly with diethyl
3
. Conclusion
range of structurally modified oligoethylene glycol
ether (10 mLꢂ5) and dried under high vacuum for overnight at
room temperature to afford 2.23 g (5.0 mmol, 91%) of [hexaEGmim]
A
1
[
OMs] as a pale yellow thick liquid. H NMR (600 MHz, CDCl
3
)
d
2.78
substituted, imidazolium-based ionic liquid (oligoEGILs) were
prepared as tailor-made multifunctional organic promoters
designed for S 2 reactions using alkali metal salts. Among the
N
various oligoEGILs examined, hexaEGIL paired with ‘fluorine free’
anions, such as mesylate, performed best as highly efficient pro-
moters for enhancing the reactivity of alkali metal salts. Further-
more, di-hexaEG-substituted IL [dihexaEGim][OMs] exhibited
(
2
S, 3H), 3.57 (t, J¼4.8 Hz, 2H), 3.59e3.69 (m, 18H), 3.87 (t, J¼4.8 Hz,
H), 4.01 (s, 1H), 4.52 (t, J¼4.8 Hz, 2H), 7.39 (s, 1H), 7.67 (s, 1H), 9.64
1
3
(s, 1H); C NMR (150 MHz, CDCl
3
) d 36.4, 39.7, 49.7, 61.4, 69.2, 70.2,
7
0.2, 70.3, 70.4, 70.5, 70.6, 70.7, 72.8, 122.9, 123.7, 138.1; MS (FAB)
þ
m/z 347 (M ꢀX, 100); HRMS (FAB TOF) m/z calcd for C16
31 2 6
H N O
þ
(M ꢀX) 347.2182, found 347.2179; (X¼[OMs]).
N
much better efficiency for S 2 bromination and chlorination than
the mono-hexaEG substituted IL [hexaEGmin][OMs] and [18]
crown-6 presumably because the nucleophiles may be ‘freed’
more efficiently from the initial strong hydrogen bonding in-
teractions between the halides and terminal eOH in hexaEG moi-
eties. This shows that IL can be tailored to meet specific needs by
a simple structural modification. The mechanistic investigation
4.3. [hexaEGmim][OTs]
The procedure for the preparation of [hexaEGmim][OMs] (see
above) was followed except that (2.0 g, 4.7 mmol) of hexaethylene
glycolic tosylate (1f) was used. 2.12 g (4.2 mmol, 89%) of [hex-
1
aEGmim][OTs] was obtained as a pale yellow thick oil. H NMR
indicated that the S
N
2 reactions examined in this study proceed
3
(600 MHz, CDCl ) d 2.18 (br s, 1H), 2.34 (s, 3H), 3.55e3.68 (m, 20H),
from pre-reaction complexes, in which the metal salt reacts as an
3.85 (t, J¼4.8 Hz, 2H), 3.99 (s, 3H), 4.51 (t, J¼4.8 Hz, 2H), 7.15

538
V.H. Jadhav et al. / Tetrahedron 70 (2014) 533e542
(
(
7
1
d, J¼7.6 Hz, 2H), 7.31 (s, 1H), 7.65 (s, 1H), 7.79 (d, J¼8.2 Hz, 2H), 9.72
s, 1H); 13C NMR (150 MHz, CDCl
21.4, 36.4, 49.7, 61.5, 69.2, 70.2,
0.2, 70.3, 70.4, 70.5; 70.7, 72.8, 122.7, 123.8, 126.0, 128.7, 138.2,
NMR (150 MHz, CDCl
3
)
d
47.2, 61.7, 70.4, 70.5, 70.9, 72.7,119.4,129.2,
þ
3
)
d
137.9; MS (FAB) m/z 201 (M þ1,100); HRMS (FAB TOF) m/z calcd for
þ
C
9
H
17
N
2
O
3
(M þ1) 201.1239, found 201.1236. Registry No. provided
þ
39.3, 143.6; MS (FAB) m/z 347 (M ꢀX, 100); HRMS (FAB TOF) m/z
by the author: 187482-77-5.
þ
calcd for C16
31
H N
2
O
6
(M ꢀX) 347.2182, found 347.2178; (X¼[OTs]).
4.9. 1-Tetraethylene glycolic imidazole (5b)
4
.4. [hexaEGmim][OTf]
Yield 654 mg (2.7 mmol, 49%) as a colorless oil; 1H NMR
KOTf (6.8 g, 36.0 mmol, 8 equiv) was added to the [hexaEGmim]
(600 MHz, CDCl
3
)
d
3.60e3.69 (m, 10H), 3.75 (t, J¼4.8 Hz, 4H), 4.11
1
C NMR
[
OMs] (2.0 g, 4.5 mmol, 1 equiv) in acetone (100 mL) and the
(t, J¼4.8 Hz, 2H), 6.94 (s, 1H), 7.01 (s, 1H), 7.76 (s, 1H); 3
ꢁ
(150 MHz, CDCl
mixture was stirred over 2 days at 25 C. The residue was dissolved
in water (100 mL) and extracted from the aqueous phase with
3
)
d
47.1, 61.4, 70.2, 70.3, 70.4, 70.5, 70.7, 73.3, 119.4,
þ
128.6, 138.2; MS (FAB) m/z 245 (M þ1, 100); HRMS (FAB TOF) m/z
þ
CH
2
Cl
2
(100 mLꢂ3). The organic layer was dried (sodium sulfate)
21
calcd for C11H N
2
O
4
(M þ1) 245.1501, found 245.1502.
and evaporated under reduced pressure. After drying under high
vacuum, 1.8 g (3.6 mmol, 81%) of [hexaEGmim][OTf] was obtained
4.10. 1-Pentaethylene glycolic imidazole (5c)
1
as a pale yellow thick oil. H NMR (600 MHz, CDCl
3
)
d
3.56 (t,
J¼4.2 Hz, 2H), 3.60e3.66 (m, 16H), 3.69 (t, J¼4.8 Hz, 2H), 3.85 (t,
Yield 795 mg (2.7 mmol, 50%) as a colorless oil; 1H NMR
(600 MHz, CDCl ) d 3.46 (br s, 1H), 3.57e3.69 (m, 14H), 3.72e3.75
3
J¼4.2 Hz, 2H), 3.97 (s, 3H), 4.42 (t, J¼4.8 Hz, 2H), 7.42 (s, 1H), 7.60 (s,
1
7
H), 9.05 (s, 1H); 13C NMR (150 MHz, CDCl
3
)
d
36.3, 49.7, 61.4, 68.8,
(m, 4H), 4.12 (t, J¼4.8 Hz, 2H), 6.99 (s, 1H), 7.03 (s, 1H), 7.58 (s, 1H);
13
0.0, 70.2, 70.2, 70.3, 70.4, 70.5, 72.5, 120.7 (q, J¼319 Hz), 123.3,
C NMR (150 MHz, CDCl
3
)
d
47.1, 61.6, 70.4, 70.6, 70.6, 70.6, 70.7,
þ
þ
123.5, 137.2; MS (FAB) m/z 347 (M ꢀX, 100); HRMS (FAB TOF) m/z
70.8, 72.8, 119.5, 129.1, 137.7; MS (FAB) m/z 289 (M þ1, 100); HRMS
þ
þ
calcd for C16
H
31
N
2
O
6
(M ꢀX) 347.2182, found 347.2182; (X¼[OTf]).
(FAB TOF) m/z calcd for C13
H
25
N
2
O
5
(M þ1) 289.1763, found
289.1762.
4
.5. [hexaEGmim][BF
4
]
4.11. 1-Hexaethylene glycolic imidazole (5d)
The procedure of [hexaEGmim][OTf] (see above) was followed
except that NaBF (4.0 g, 36.0 mmol) was used. 1.7 g (3.7 mmol,
3%) of [hexaEGmim][BF ] was obtained as a pale yellow thick oil.
3.58 (t, J¼4.2 Hz, 2H), 3.62e3.68 (m,
6H), 3.71 (t, J¼4.2 Hz, 2H), 3.89 (t, J¼4.2 Hz, 2H), 4.02 (s, 3H), 4.51
Yield 826 mg (2.5 mmol, 45%) as a colorless oil; 1H NMR
4
8
4
(600 MHz, CDCl
3
)
d
3.39e3.44 (m, 18H), 3.52 (t, J¼4.8 Hz, 2H), 3.55
1
H NMR (600 MHz, CDCl
3
)
d
(t, J¼5.4 Hz, 2H), 3.93 (t, J¼4.8 Hz, 2H), 4.28 (br s, 1H), 6.80 (s, 1H),
13
1
(
6.83 (s, 1H), 7.37 (s, 1H); C NMR (150 MHz, CDCl
3
)
d
47.0, 61.1, 69.5,
13
þ
t, J¼4.8 Hz, 2H), 7.39 (s, 1H), 7.67 (s, 1H), 9.43 (s, 1H); C NMR
70.2, 70.4, 70.5, 72.6, 119.5, 128.8, 137.5; MS (EI) m/z 332 (M þ1,
þ
(
7
150 MHz, CDCl
3
)
d
36.5, 49.8, 61.2, 68.9, 69.9, 70.1, 70.2, 70.3, 70.4,
100); HRMS (EI TOF) m/z calcd for C15
H
28
N
2
O
6
(M ) 332.1947, found
þ
2.6, 123.0,123.6,137.4; MS (FAB) m/z 347 (M ꢀX,100); HRMS (FAB
332.1942.
þ
TOF) m/z calcd for C16
X¼[BF ]).
H
31
N
2
O
6
(M ꢀX) 347.2182, found 347.2185;
(
4
4.12. 1-Octaethylene glycolic imidazole (5e)
1
4
.6. [hexaEGmim][PF
6
]
Yield 1.0 g (2.5 mmol, 46%) as a colorless oil; H NMR (600 MHz,
3
CDCl ) d 3.19 (br s, 1H), 3.59e3.63 (m, 8H), 3.64e3.68 (m, 18H),
The procedure of [hexaEGmim][OTf] (see above) was followed
except that NaPF (6.2 g, 36.0 mmol) was used. 1.8 g (3.6 mmol,
9%) of [hexaEGmim][PF ] was obtained as a white solid. Mp:
21 C; H NMR (600 MHz, MeOD 3.33 (s, 1H), 3.57 (t,
þCDCl
J¼4.8 Hz, 2H), 3.63e3.71 (m, 16H), 3.87 (t, J¼4.8 Hz, 2H), 3.92 (s,
3.73e3.76 (m, 4H), 4.13 (t, J¼4.8 Hz, 2H), 7.01 (s, 1H), 7.03 (s, 1H),
13
6
7.59 (s, 1H); C NMR (150 MHz, CDCl
3
)
d
47.1, 61.6, 70.4, 70.6, 70.6,
þ
7
1
6
70.6, 70.7, 70.8, 72.8, 119.5, 129.1, 137.7; MS (FAB) m/z 443 (M þNa,
ꢁ
1
þ
4
3
)
d
100); HRMS (FAB TOF) m/z calcd for C19
36
H N
2
O
8
Na (M þNa)
þ
443.2369, found 443.2374 (M þNa). Registry No. provided by the
13
3
H), 4.38 (t, J¼4.8 Hz, 2H), 7.46 (s, 1H), 7.54 (s, 1H), 8.65 (s, 1H);
C
author: 126078-24-8.
NMR (150 MHz, MeOD 35.2, 49.2, 60.2, 68.4, 69.0, 69.0,
4
þCDCl
3
) d
6
3
(
9.2, 69.3, 69.4, 69.5, 69.8, 71.3, 122.8, 123.3, 136.6; MS (FAB) m/z
4.13. General procedure of [dioligoEGim][OMs]
þ
47 (M ꢀX, 100); HRMS (FAB TOF) m/z calcd for C16
31 2 6
H N O
þ
M ꢀX) 347.2182, found 347.2185; (X¼[PF
6
]).
Each oligoethylene glycolic mesylate (1aee) (2.4 mmol) was
added dropwise to the solution of the corresponding oligoethylene
4
.7. General procedure of oligoethylene glycolic imidazoles
glycolic imidazole (5aee, 2.4 mmol) in CH
mixture was stirred at 90 C for 48 h and evaporated under reduced
3
CN (20 mL). The reaction
ꢁ
(
5aee, Scheme 2)
3
pressure to remove CH CN. The residue was washed repeatedly
Potassium carbonate (916 mg, 6.6 mmol) was added to the so-
with diethyl ether (10 mLꢂ7) and dried under high vacuum for
overnight at room temperature to afford the corresponding [dio-
ligoEGim][OMs].
lution of imidazole (375 mg, 5.5 mmol) and oligoethylene glycolic
ꢁ
bromide (4aee, 5.5 mmol) in acetone (30 mL) at 25 C. The residue
was dissolved in water (50 mL) and extracted from the aqueous
phase with EtOAc (50 mLꢂ3). The organic layer was dried (sodium
sulfate) and evaporated under reduced pressure. The residue was
4.14. [ditriEGim][OMs]
1
purified by flash column chromatography (10% MeOH/CH
2
Cl
2
) to
Yield 876 mg (2.0 mmol, 84%) as a pale yellow thick liquid; H
afford the corresponding oligoethylene glycolic imidazole (5aee).
NMR (600 MHz, CDCl
3
)
d
2.74 (s, 3H), 3.57 (t, J¼4.2 Hz, 4H),
3
.59e3.62 (m, 4H), 3.66e3.68 (m, 4H), 3.72 (t, J¼4.8 Hz, 4H), 3.87 (t,
4
.8. 1-Triethylene glycolic imidazole (5a)
J¼4.8 Hz, 4H), 4.47 (t, J¼4.8 Hz, 4H), 7.66 (d, J¼1.4 Hz, 2H), 9.42 (s,
13
1H); C NMR (150 MHz, CDCl
3
)
d
39.6, 49.5, 61.3, 68.9, 70.1, 70.1,
Yield 517 mg (2.6 mmol, 47%) as a colorless oil; 1H NMR
72.7, 123.1, 137.5; MS (FAB) m/z 333 (M ꢀX, 100); HRMS (FAB TOF)
þ
þ
(
4
600 MHz, CDCl
3
)
d
3.12 (br s,1H), 3.55e3.67 (m, 6H), 3.76e3.77 (m,
m/z calcd for C15
(X¼[OMs]).
H
29
N
2
O
6
(M ꢀX) 333.2026, found 333.2024;
13
H), 4.11 (t, J¼4.8 Hz, 2H), 6.98 (s, 1H), 7.04 (s, 1H), 7.58 (s, 1H);
C

V.H. Jadhav et al. / Tetrahedron 70 (2014) 533e542
539
4
.15. [ditetraEGim][OMs]
diethyl ether, and the filtrate was evaporated under reduced pres-
sure. Flash column chromatography (10% EtOAc/hexanes) of the
Yield 1.1 g (2.1 mmol, 85%) as a brown thick liquid; 1H NMR
filtrate afforded 259 mg (0.98 mmol, 98%) of 2-(3-bromopropoxy)
1
(
600 MHz, CDCl
3
)
d
2.77 (s, 3H), 3.57e3.68 (m, 20H), 3.69e3.74 (m,
naphthalene (7) as a colorless oil: H NMR (400 MHz, CDCl
3
)
4
H), 3.89 (t, J¼4.8 Hz, 4H), 4.11 (br s, 2H), 4.49 (t, J¼4.8 Hz, 4H), 7.65
d
2.36e2.43 (m, 2H), 3.67 (t, J¼6.6 Hz, 2H), 4.23 (t, J¼5.6 Hz, 2H),
13
13
(
4
d, J¼4.8 Hz, 2H), 9.50 (s, 1H); C NMR (150 MHz, CDCl
3
)
d
39.6,
7.14e7.17 (m, 2H), 7.34e7.49 (m, 2H), 7.74e7.80 (m, 3H); C NMR
(100 MHz, CDCl 30.1, 32.2, 65.2, 106.6, 118.8, 123.7, 126.4, 126.7,
127.6,128.9,129.4,134.4,156.5; MS (EI) m/z 264 (M ), 266 (M ),144
(100), 115; HRMS (EI TOF) m/z calcd for C13
found 264.0151. Registry No. provided by the author: 3245-62-3.
9.6, 61.4, 69.2, 70.2, 70.2, 70.4, 70.4, 72.6, 123.0, 137.6; MS (FAB) m/
3
) d
þ
þ
þ
z 421 (M ꢀX, 100); HRMS (FAB TOF) m/z calcd for C19
37 2 8
H N O
þ
79
þ
(
M ꢀX) 421.2550, found 421.2553; (X¼[OMs]).
13
H O Br (M ) 264.0150;
4
.16. [dipentaEGim][OMs]
4.21. Typical procedure of the chlorination (Fig. 3C)
1
Yield 1.2 g (1.9 mmol, 81%) as a pale yellow thick liquid; H NMR
(
600 MHz, CDCl
3
)
d
2.75 (s, 3H), 3.28 (br s, 2H), 3.55e3.58 (m, 4H),
KCl (224 mg, 3.0 mmol) was added to the mixture of mesylate 2
3
.60e3.70 (m, 28H), 3.90 (t, J¼4.8 Hz, 4H), 4.50 (t, J¼4.8 Hz, 4H),
(281 mg, 1.0 mmol), [dihexaEGim][OMs] (346 mg, 0.5 mmol), and
acetonitrile (4 mL) in a reaction vial. The reaction mixture was
stirred over 1.5 h at 90 C. The reaction time was determined by
checking TLC. The reaction mixture was filtered and washed with
diethyl ether, and the filtrate was evaporated under reduced pres-
sure. Flash column chromatography (10% EtOAc/hexanes) of the
13
7
4
.63 (d, J¼1.4 Hz, 2H), 9.44 (s, 1H); C NMR (150 MHz, CDCl
3
) d 39.5,
ꢁ
9.6, 61.3, 69.2, 70.2, 70.2, 70.3, 70.3, 70.5, 70.5, 72.8, 123.1, 137.4;
þ
MS (FAB) m/z 509 (M ꢀX, 100); HRMS (FAB TOF) m/z calcd for
þ
C
H
23 45
N
2
O
10 (M ꢀX) 509.3074, found 509.3077; (X¼[OMs]).
4
.17. [dihexaEGim][OMs]
filtrate afforded 213 mg (0.97 mmol, 97%) of 2-(3-chloropropoxy)
1
naphthalene (6) as a colorless oil: H NMR (600 MHz, CDCl
3
)
1
Yield 1.23 g (1.8 mmol, 80%) as a pale yellow thick liquid; H
NMR (600 MHz, CDCl
2.78 (s, 3H), 3.58 (t, J¼6.0 Hz, 4H),
.60e3.71 (m, 36H), 3.89 (t, J¼6.0 Hz, 4H), 4.52 (t, J¼6.0 Hz, 4H),
d
2.28e2.32 (m, 2H), 3.79 (t, J¼6.2 Hz, 2H), 4.23 (t, J¼6.2 Hz, 2H),
3
) d
7.12e7.15 (m, 2H), 7.34 (t, J¼6.8 Hz, 1H), 7.44 (t, J¼6.8 Hz, 1H),
13
3
3
7.72e7.77 (m, 3H); C NMR (100 MHz, CDCl ) d 32.2, 41.6, 64.2,
13
7
4
.58 (d, J¼1.4 Hz, 2H), 9.69 (s,1H); C NMR (150 MHz, CDCl
3
)
d
39.6,
106.6, 118.8, 123.7, 126.4, 126.7, 127.6, 128.9, 129.4, 134.4, 156.6; MS
þ
9.7, 61.5, 69.3, 70.3, 70.3, 70.4, 70.5, 70.6, 70.6, 72.7, 123.0, 137.7;
(EI) m/z 220 (M ), 144, 115; HRMS (EI TOF) m/z calcd for C13
H13OCl
þ
þ
MS (FAB) m/z 597 (M ꢀX, 100); HRMS (FAB TOF) m/z calcd for
(M ) 220.0655; found 220.0667. Registry No. provided by the au-
thor: 56231-42-6.
þ
C
27
H
53
O
12
N
2
(M ꢀX) 597.3599, found 597.3601; (X¼[OMs]).
4
.18. [dioctaEGim][OMs]
4.22. 2-(3-Iodopropoxy)naphthalene (10, entries 5 and 6 in
Table 1)
1
Yield 1.7 mg (2.0 mmol, 82%) as a pale yellow thick liquid; H
NMR (600 MHz, CDCl 2.79 (s, 3H), 3.59e3.68 (m, 64H), 3.72 (t,
J¼4.8 Hz, 6H), 3.89 (t, J¼4.8 Hz, 4H), 4.52 (t, J¼4.8 Hz, 4H), 7.58 (d,
3
)
d
N
Typical procedure of S 2 reaction (see above) was followed
except that potassium iodide (498 mg, 3.0 mmol) was used for
13
J¼2.0 Hz, 2H), 9.74 (s, 1H); C NMR (150 MHz, CDCl
3
)
d
39.6, 49.6,
0.5 h. 306 mg (0.98 mmol, 98%) of 2-(3-iodopropoxy)naphthalene
1
61.6, 69.3, 70.3, 70.4, 70.5, 70.6, 70.6, 70.7, 70.7, 72.7, 123.0, 137.7;
(10) was obtained as a colorless oil: H NMR (400 MHz, CDCl
3
)
þ
MS (FAB) m/z 773 (M ꢀX, 100); HRMS (FAB TOF) m/z calcd for
d
2.32e2.38 (m, 2H), 3.43 (t, J¼6.6 Hz, 2H), 4.16 (t, J¼5.8 Hz, 2H),
þ
13
C
H
35 69
N
2
O
16 (M ꢀX) 773.4647, found 773.4649; (X¼[OMs]).
7.15e7.17 (m, 2H), 7.35e7.49 (m, 2H), 7.49e7.80 (m, 3H); C NMR
(
100 MHz, CDCl
3
) 2.7, 32.8, 67.1, 106.6, 118.8, 123.6, 126.4, 126.7,
þ
4
.19. Typical procedure of the fluorination (Fig. 1)
127.6, 128.1, 129.4, 134.4, 156.5; MS (EI) m/z 312 (M ), 185, 144, 115
(
þ
100); HRMS (EI TOF) m/z calcd for C13
H
13OI (M ) 312.0011, found
CsF (456 mg, 3 mmol) was added to the mixture of mesylate 2
281 mg, 1.0 mmol), [hexaEGmim][OMs] (221 mg, 0.5 mmol), and
312.0006. Registry No. provided by the author: 380363-99-5.
4.23. General procedure for S 2 reaction
or KCN) (3.0 mmol) was added to
(
acetonitrile (4 mL) in a reaction vial. The reaction mixture was
N
ꢁ
stirred over 6 h at 80 C. The reaction time was determined by
checking TLC. The reaction mixture was filtered and washed with
diethyl ether, and the filtrate was evaporated under reduced pres-
sure. Flash column chromatography (10% EtOAc/hexanes) of the
MNu (M¼KOAc, KSAc, NaN
3
a mixture of each mesylate, triflate or bromide compound
(1.0 mmol), [dihexaEGim][OMs] (346 mg, 0.5 mmol) and acetoni-
trile (4 mL) in a reaction vial. The reaction mixture was stirred over
filtrate afforded 189 mg (0.92 mmol, 92%) of 2-(3-fluoropropoxy)
1
ꢁ
naphthalene (3) as a colorless oil. H NMR (400 MHz, CDCl
3
)
0.5e3 h at 90 C. The reaction mixture was filtered and washed
d
2.14e2.39 (m, 2H), 4.24 (t, J¼6.2 Hz, 2H), 4.72 (dt, J¼46.8, 5.8 Hz,
with diethyl ether (15 mL). The filtrate was evaporated under re-
duced pressure. Flash column chromatography (10% EtOAc/hex-
anes) of the filtrate afforded each product compound.
13
2
H), 7.16e7.22 (m, 2H), 7.34e7.53 (m, 2H), 7.76e7.83 (m, 3H);
30.4 (d, J¼20.1 Hz), 63.6 (d, J¼25.3 Hz),
0.8 (d, J¼163.9 Hz), 106.8, 118.8, 123.6, 126.4, 126.7, 127.6, 129.1,
C
3
NMR (100 MHz, CDCl ) d
8
1
þ
29.4, 134.6, 156.7; MS (EI) m/z 204 (M ); HRMS (EI TOF) m/z calcd
4.24. 2-(3-Acetoxypropoxy)naphthalene (8)
þ
for C13
H13FO(M ) 204.0950, found 204.0932. Registry No. provided
by the author: 398-53-8.
According to the general procedure for S
(281 mg, 1.0 mmol) or bromide 7 (264 mg, 1.0 mmol) with KOAC
(294 mg, 3.0 mmol) for 0.5 h. 8 (241 mg, 0.99 mmol, 99%) was
N
2 reaction of mesylate
2
4
.20. Typical procedure for the bromination (Fig. 3B)
1
3
obtained as a colorless oil: H NMR (600 MHz, CDCl ) d 2.08 (s, 3H),
KBr (357 mg, 3.0 mmol) was added to the mixture of mesylate 2
281 mg, 1.0 mmol), [hexaEGmim][OMs] (221 mg, 0.5 mmol), and
2.18e2.22 (m, 2H), 4.17 (t, J¼6.18 Hz, 2H), 4.31 (t, J¼6.18 Hz, 2H),
(
7.10e7.15 (m, 2H), 7.33 (t, J¼7.56 Hz, 1H), 7.43 (t, J¼6.90 Hz, 1H),
13
acetonitrile (4 mL) in a reaction vial. The reaction mixture was
3
7.71e7.77 (m, 3H); C NMR (150 MHz, CDCl ) d 21.1, 28.7, 61.5, 64.4,
ꢁ
stirred over 3 h at 90 C. The reaction time was determined by
106.6, 118.9, 123.7, 126.5, 126.8, 127.7, 129.0, 129.5, 134.6, 156.8,
þ
checking TLC. The reaction mixture was filtered and washed with
171.2; MS (EI) m/z 244 (M ); HRMS (EI TOF) m/z calcd for C15
H
16
O
3

540
V.H. Jadhav et al. / Tetrahedron 70 (2014) 533e542
þ
(
M ) 244.1099, found 244.1096. Registry No. provided by the au-
4.29. 2-(3-Thioacetoxypropoxy)naphthalene (9)
thor: 876485-90-4.
According to the general procedure for S
(281 mg, 1.0 mmol) or bromide 7 (264 mg, 1.0 mmol) with KSAC
343 mg, 3.0 mmol) for 0.5 h. 9 (252e255 mg 0.97e0.98 mmol,
N
2 reaction of mesylate
2
(
4
.25. 2-(Acetoxymethyl)naphthalene (entry 1 in Table 2)
1
97e98%) was obtained as a brown oil: H NMR (600 MHz, CDCl
3
)
According to the general procedure for S
N
2 reaction of
d
2.11e2.16 (m, 2H), 2.34 (s, 3H), 3.10 (t, J¼6.84 Hz, 2H), 4.13 (t,
2
-(bromomethyl)naphthalene (211 mg, 1.0 mmol) with KOAC
J¼6.18 Hz, 2H), 7.11e7.15 (m, 2H), 7.33 (t, J¼6.84 Hz, 1H), 7.44 (t,
(
(
(
7
1
294 mg, 3.0 mmol) for 0.5 h. 2-(acetoxymethyl)naphthalene
198 mg, 0.99 mmol, 99%) was obtained as a colorless oil: H NMR
600 MHz, CDCl
.79e7.85 (m, 4H); C NMR (150 MHz, CDCl
26.4, 126.4, 127.5, 127.8, 128.1, 128.5, 133.2, 133.3, 133.4, 171.0; MS
13
J¼6.90 Hz, 1H), 7.71e7.76 (m, 3H); C NMR (150 MHz, CDCl
3
) d 26.1,
1
2
1
9.3, 30.8, 66.2, 106.7, 118.9, 123.7, 126.5, 126.8, 127.7, 129.0, 129.5,
3
)
d
13
2.19 (s, 3H), 5.26 (s, 2H), 7.44e7.49 (m, 3H),
34.6, 156.8, 195.9; MS (EI) m/z 260 (M ); HRMS (EI TOF) m/z calcd
þ
3
)
d
21.2, 66.6, 126.0,
for C15
H O S (M ) 260.0871, found 260.0874.
þ
16 2
þ
þ
(
EI) m/z 200 (M ); HRMS (EI TOF) m/z calcd for C13H O (M )
12 2
4.30. 2-(Thioaetoxymethyl)naphthalene (entry 2 in Table 2)
2
3
00.0837, found 200.0839. Registry No. provided by the author:
5480-23-0.
According to the general procedure for S
N
2 reaction of 2-(bro-
momethyl)naphthalene (211 mg, 1.0 mmol) with KSAC (343 mg,
3
0
.0 mmol) for 0.5 h. 2-(Thioacetoxymethyl)naphthalene (212 mg,
.98 mmol, 98%) was obtained as a brown oil: H NMR (600 MHz,
4
.26. 1-(2-Acetoxyethyl)naphthalene (entry 4 in Table 2)
1
CDCl
3
)
d
2.35 (s, 3H), 4.28 (s, 2H), 7.37 (dd, J¼8.2 and 2.0 Hz, 1H)
According to the general procedure for S
mesyloxyethyl)naphthalene (250 mg, 1.0 mmol) with KOAC
294 mg, 3.0 mmol) for 0.5 h. 1-(2-Acetoxyethyl)naphthalene
212 mg, 0.99 mmol, 99%) was obtained as a colorless oil: H NMR
N
2 reaction of 1-(2-
13
7.42e7.47 (m, 2H), 7.73e7.81 (m, 4H); C NMR (150 MHz, CDCl
3
)
d
30.5, 33.8,126.0,126.4,126.9,127.6,127.8,127.8,128.6,132.7,133.4,
(
(
(
þ
135.1, 195.2; MS (EI) m/z 216 (M ); HRMS (EI TOF) m/z calcd for
1
þ
C
13
H12OS (M ) 216.0609, found 216.0640.
600 MHz, CDCl
3
)
d
2.04 (s, 3H), 3.41 (t, J¼7.6 Hz, 2H), 4.41 (t,
J¼7.6 Hz, 2H), 7.35e7.42 (m, 2H), 7.47e7.55 (m, 2H), 7.75 (d,
4.31. 1-(2-Thioacetoxyethyl)naphthalene (entry 5 in Table 2)
13
J¼8.2 Hz, 1H), 7.86 (d, J¼7.6 Hz, 1H), 8.09 (d, J¼8.2 Hz, 1H); C NMR
(
1
150 MHz, CDCl
3
)
d
21.1, 32.3, 64.6, 123.7, 125.6, 125.8, 126.3, 127.1,
According to the general procedure for S
mesyloxyethyl)naphthalene (250 mg, 1.0 mmol) with KSAC
N
2 reaction of 1-(2-
þ
27.6, 128.9, 132.1, 133.8, 133.9; MS (EI) m/z 214 (M ); HRMS (EI
þ
TOF) m/z calcd for C14
istry No. provided by the author: 26157-05-1.
H O (M ) 214.0994, found 214.0995. Reg-
14 2
(
(
(
343 mg, 3.0 mmol) for 0.5 h. 1-(2-Thioacetoxyethyl)naphthalene
225 mg, 0.98 mmol, 98%) was obtained as a brown oil: H NMR
600 MHz, CDCl
1
3
)
d
2.38 (s, 3H), 3.21 (t, J¼7.6 Hz, 2H), 3.33 (t,
J¼7.6 Hz, 2H), 7.34e7.42 (m, 2H), 7.47e7.57 (m, 2H), 7.75 (d,
4
.27. 1,2:3,4-Di-O-isopropylidene-6-acetoxy-6-deoxy-a-D-gal-
actopyranose (entry 7 in Table 2)
13
J¼8.2 Hz, 1H), 7.86 (d, J¼8.2 Hz, 1H), 8.19 (d, J¼8.2 Hz, 1H); C NMR
(150 MHz, CDCl
3
)
d
30.1, 30.8, 33.6, 123.8, 125.6, 125.8, 126.3, 126.7,
þ
127.5, 128.9, 131.8, 134.0, 136.2, 196.2; MS (EI) m/z 230 (M ); HRMS
According to the general procedure for S
di-O-isopropylidene-6-trifluoromethanesulfonyloxy-a-D
N
2 reaction of 1,2:3,4-
-gal-
þ
(EI TOF) m/z calcd for C14
H14OS (M ) 230.0765, found 230.0762.
actopyranose (541 mg, 1.0 mmol) with KOAC (294 mg, 3.0 mmol) at
ꢁ
4.32. 1,2:3,4-Di-O-isopropylidene-6-thioacetoxy-6-deoxy-a-D-
galactopyranose (entry 8 in Table 2)
8
0 C for 1 h. 1,2:3,4-Di-O-isopropylidene-6-acetoxy-6-deoxy-
a
-D
-
galactopyranose (297 mg, 0.98 mmol, 98%) was obtained as a col-
1
orless oil: H NMR (600 MHz, CDCl
3
)
d
1.33 (s, 3H), 1.34 (m, 3H), 1.45
According to the general procedure for S
di-O-isopropylidene-6-trifluoromethanesulfonyloxy-a-D
N
2 reaction of 1,2:3,4-
-gal-
(
s, 3H), 1.52 (s, 3H), 2.09 (s, 3H), 4.02e4.04 (m, 1H), 4.17e4.20 (m,
1
4
d
H), 4.24.4.25 (m, 1H), 4.27e4.30 (m, 1H), 4.33e4.34 (m, 1H),
13
actopyranose (541 mg, 1.0 mmol) with KSAC (343 mg, 3.0 mmol) at
.62e4.63 (m, 1H), 555 (d, J¼4.8 Hz,1H); C NMR (150 MHz, CDCl
3
)
ꢁ
8
0 C for 1 h. 1,2:3,4-Di-O-isopropylidene-6-thioacetoxy-6-deoxy-
21.0, 24.6, 25.0, 26.0, 26.1, 63.5, 66.0, 70.5, 70.7, 71.1, 96.4, 108.9,
þ
a
-D-galactopyranose (309 mg, 0.97 mmol, 97%) was obtained as
1
3
4
09.7, 171.1; HRMS (ESI TOF) m/z calcd for C14
03.1444, found 303.1448. Registry No. provided by the author:
860-78-0.
H
23
O
7
(M þH)
1
a brown oil: H NMR (600 MHz, CDCl
.46 (s, 3H), 1.48 (s, 3H), 2.34 (s, 3H), 3.02e3.05 (m, 1H), 3.15e3.18
m, 1H), 3.84e3.86 (m, 1H), 4.26e4.27 (m, 1H), 4.29e4.31 (m, 1H),
3
) d 1.32 (s, 3H), 1.35 (s, 3H),
1
(
4
CDCl
13
.60e4.62 (m, 1H), 5.51 (d, J¼4.8 Hz, 1H); C NMR (150 MHz,
4
.28. 3-O-(3-Acetoxypropyl)estrone (entry 10 in Table 2)
3
)
d
24.5, 25.1, 26.0, 29.8, 30.6, 66.9, 70.6, 71.0, 72.1, 96.6, 108.9,
þ
109.6, 196.0; HRMS (ESI TOF) m/z calcd for C14
H
23
O
6
S (M þH)
According to the general procedure for S
N
2 reaction of 3-O-(3-
319.1215, found 319.1213.
mesyloxypropyl)estrone (406 mg, 1.0 mmol) with KOAC (294 mg,
3
0
CDCl
.0 mmol) for 3 h. 3-O-(3-acetoxypropyl)estrone (355 mg,
.96 mmol, 96%) was obtained as a colorless oil: H NMR (600 MHz,
4.33. 3-O-(3-Thioacetoxypropyl)estrone (entry 11 in Table 2)
According to the general procedure for S 2 reaction of 3-O-(3-
1
3
)
d
0.91 (s, 3H), 1.40e1.65 (m, 6H), 1.94e2.03 (m, 2H), 2.05 (s,
N
3
H), 2.08e2.18 (m, 4H), 2.23e2.27 (m, 1H), 2.38e2.41 (m, 1H), 2.50
mesyloxypropyl)estrone (406 mg, 1.0 mmol) with KSAC (343 mg,
(
4
1
2
1
dd, J¼19.3, 8.2 Hz, 1H), 2.86e2.91 (m, 2H), 4.02 (t, J¼6.2 Hz, 2H),
3.0 mmol) for 4 h. 3-O-(3-Thioacetoxypropyl)estrone (359 mg,
0.93 mmol, 93%) was obtained as a brown solid: H NMR (600 MHz,
CDCl ) d 0.91 (s, 3H), 1.40e1.66 (m, 6H), 1.94e2.10 (m, 5H),
3
1
.25 (t, J¼6.2 Hz, 2H), 6.64 (d, J¼2.8 Hz, 1H), 6.71 (dd, J¼8.2, 2.8 Hz,
13
H), 7.20 (d, J¼8.2 Hz, 1H); C NMR (150 MHz, CDCl
1.7, 26.0, 26.6, 28.7, 29.7, 31.6, 35.9, 38.4, 44.0, 48.1, 50.5, 61.4, 64.3,
12.2, 114.6, 126.4, 132.3, 137.9, 156.8, 171.2, 221.1; MS (EI) m/z 370
3
)
d
13.9, 21.0,
2.11e2.17 (m, 1H), 2.25 (t, J¼10.9 Hz,1H), 2.34 (s, 3H), 2.38e2.41 (m,
1H), 2.50 (dd, J¼19.3, 8.3 Hz, 1H), 2.87e2.91 (m, 2H), 3.05 (t,
J¼6.8 Hz, 2H), 3.99 (t, J¼6.2 Hz, 2H), 6.64 (d, J¼2.8 Hz, 1H), 6.70 (dd,
þ
þ
30 4
H O (M )
(
3
1
M ), 101 (100). HRMS (EI TOF) m/z calcd for C23
70.2144, found 370.2146. Registry No. provided by the author:
042940-68-0.
1
3
J¼8.2, 2.8 Hz, 1H), 7.19 (d, J¼8.2 Hz, 1H); C NMR (150 MHz, CDCl
3
)
d 13.9, 21.7, 26.0, 26.3, 29.4, 29.7, 30.7, 31.6, 35.0, 38.4, 44.0, 48.1,

V.H. Jadhav et al. / Tetrahedron 70 (2014) 533e542
541
5
3
0.5, 66.2,112.2,114.6,126.4,132.3,137.9,156.9,195.9, 221.1; MS (EI)
d 0.91 (s, 3H), 1.42e1.66 (m, 6H), 1.92e1.96 (m, 1H), 1.99e2.08 (m,
þ
þ
86 (M ); HRMS (EI TOF) m/z calcd for C23
H
30
O
3
S (M ) 386.1916,
4H), 2.11e2.18 (m, 1H), 2.25 (t, J¼10.9 Hz, 1H), 2.38e2.41 (m, 1H),
found 386.1918.
2.50 (dd, J¼18.6, 8.3 Hz, 1H), 2.87e2.91 (m, 2H), 3.51 (t, J¼6.8 Hz,
2
H), 4.02 (t, J¼5.5 Hz, 2H), 6.65 (d, J¼2.8 Hz, 1H), 6.71 (dd, J¼8.2,
13
4
1
.34. 2-(3-Azidopropoxy)naphthalene (entry 7 and 8 in Table
)
2.8 Hz, 1H), 7.20 (d, J¼8.2 Hz, 1H); C NMR (150 MHz, CDCl
21.7, 26.0, 26.6, 28.9, 29.7, 31.6, 35.9, 38.4, 44.0, 48.1, 48.4, 50.5, 64.5,
12.2, 114.6, 126.5, 132.4, 137.9, 156.8, 221.1; HRMS (EI TOF) m/z
3
) d 13.9,
1
þ
According to the general procedure for S
N
2 reaction of mesylate
calcd for C21H N O (M ) 353.2103, found 353.2100. Registry No.
27 3 2
2
(281 mg, 1.0 mmol) or bromide 7 (264 mg, 1.0 mmol) with NaN
3
provided by the author: 1042940-70-4.
(
9
d
195 mg, 3.0 mmol) for 1.5 h. 11 (222e225 mg, 0.98e0.99 mmol,
1
8e99%) was obtained as a colorless oil; H NMR (600 MHz, CDCl
2.10e2.14 (m, 2H), 3.57 (t, J¼6.9 Hz, 2H), 4.17 (t, J¼6.2 Hz, 2H),
.13e7.16 (m, 2H), 7.32e7.35 (m, 1H), 7.42e7.45 (m, 1H), 7.71e7.77
m, 3H); 13C NMR (150 MHz, CDCl
28.9, 48.4, 64.6, 106.7, 118.8,
3
)
4.39. 2-(3-Cyanopropoxy)naphthalene (12)
7
(
According to the general procedure for S 2 reaction of mesylate
N
3
)
d
2 (281 mg, 1.0 mmol) or bromide 7 (264 mg, 1.0 mmol) with KCN
1
23.8, 126.5, 126.8, 127.7, 129.1, 129.5, 134.6, 156.7; MS (EI) m/z 227
(195 mg, 3.0 mmol) for 1.5e3 h. 12 (196e198 mg, 0.93e0.94 mmol,
þ
1
(
(
M ), 169, 143 (100), 115; HRMS (EI TOF) m/z calcd for C13
M ) 227.1059, found 227.1060. Registry No. provided by the au-
H
13
N
3
O
93e94%) was obtained as a colorless oil; H NMR (600 MHz, CDCl )
3
þ
d
2.18e2.23 (m, 2H), 2.63 (t, J¼6.90 Hz, 2H), 4.19 (t, J¼6.18 Hz, 2H),
thor: 1199811-23-8.
7.12e7.14 (m, 2H), 7.35 (t, J¼6.90 Hz, 1H), 7.45 (t, J¼8.22 Hz, 1H),
13
7
3
.72e7.78 (m, 3H); C NMR (150 MHz, CDCl ) d 14.4, 25.6, 65.4,
4
.35. 2-(Azidomethyl)naphthalene (entry 3 in Table 2)
106.9, 118.8, 119.3, 124.0, 126.7, 126.9, 127.7, 129.2, 129.6, 134.5,
þ
1
56.4; MS (EI) m/z 211 (M ); HRMS (EI TOF) m/z calcd for C14
H
13NO
þ
According to the general procedure for S
N
2 reaction of 2-(bro-
(195 mg,
.0 mmol) for 0.5 h. 2-(azidomethyl)naphthalene (179 mg,
(M ) 211.0997, found 211.0998. Registry No. provided by the au-
thor: 727429-81-4.
momethyl)naphthalene (211 mg, 1.0 mmol) with NaN
3
0
3
1
.98 mmol, 98%) was obtained as a colorless oil; H NMR (600 MHz,
4.49 (s, 2H), 7.42 (dd, J¼8.2 and 2.0 Hz, 1H) 7.48e7.53 (m,
Acknowledgements
3
CDCl ) d
13
2
H), 7.76 (s, 1H), 7.83e7.87 (m, 3H); C NMR (150 MHz, CDCl
3
)
This work was supported by the Nuclear Research & De-
velopment Program of the Korea Science and Engineering Foun-
dation (KOSEF) grant funded by the Korean Government (MEST)
(grant code: 2011-0030952), the Conversing Research Center Pro-
gram through the National Research Foundation of Korea (NRF)
funded by the MEST (grant code: 2011K000705), Basic Research
Program by NRF (2013030262) and Inha University Research Grant
(INHA-47397-01).
d
55.1, 16.0, 126.5, 126.6, 127.3, 127.9, 128.1, 128.9, 132.9, 133.2, 133.4;
þ
þ
MS (EI) m/z 183 (M ); HRMS (EI TOF) m/z calcd for C11
H
9
N
3
(M )
183.0796, found 183.0799.
4
.36. 1-(2-Azidoethyl)naphthalene (entry 6 in Table 2)
According to the general procedure for S
N
2 reaction of 1-(2-
mesyloxyethyl)naphthalene (250 mg, 1.0 mmol) with NaN
3
(
0
CDCl
2
7
1
1
195 mg, 3.0 mmol) for 0.5 h. 1-(2-azidoethyl)naphthalene (195 mg,
Supplementary data
1
.99 mmol, 99%) was obtained as a colorless oil; H NMR (600 MHz,
3.36 (t, J¼7.6 Hz, 2H), 3.62 (t, J¼7.6 Hz, 2H), 7.36e7.43 (m,
H), 7.48e7.56 (m, 2H), 7.77 (d, J¼7.5 Hz, 1H), 7.87 (d, J¼8.2 Hz, 1H),
3
)
d
NMR spectra for all relevant compounds, and calculation data
are available. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2013.10.070.
1
3
.99 (d, J¼8.2 Hz, 1H); C NMR (150 MHz, CDCl
3
) d 32.6, 51.8, 123.2,
25.6, 125.8, 126.4, 127.1, 127.8, 129.1, 131.8, 133.9, 134.0; MS (EI) m/z
97 (M ); HRMS (EI TOF) m/z calcd for C12
þ
þ
11 3
H N (M ) 197.0953,
References and notes
found 197.0955.
1. Smith, M. D.; March, J. Advanced Organic Chemistry, 5th ed.; Wiley-Interscience:
New York, NY, 2001; pp 462e467.
. Makosza, M.; Wojciechowski, K. Chem. Rev. 2004, 104, 2631e2666.
. (a) Gerstenberger, M. R. C.; Haas, A. Angew. Chem., Int. Ed. Engl. 1981, 20,
4
.37. 1,2:3,4-Di-O-isopropylidene-6-azido-6-deoxy-a-D-gal-
2
3
actopyranose (entry 9 in Table 2)
647e667; (b) Mascaretti, O. A. Aldrichimica Acta 1993, 26, 47e58.
4
5
. Forche, D. In Methoden der Organischen Chemie; Mueller, E., Ed.; Thieme:
Stuttgart, Germany, 1962; Vol. 5/4.
. Gokel, G. W. Crown Ethers and Cryptands; Royal Society of Chemistry: Cam-
bridge, UK, 1991.
According to the general procedure for S
di-O-isopropylidene-6-trifluoromethanesulfonyloxy-a-D
N
2 reaction of 1,2:3,4-
-gal-
3
(195 mg, 3.0 mmol) at
actopyranose (541 mg, 1.0 mmol) with NaN
ꢁ
6. (a) Dehmlow, E. V.; Dehmlow, S. S. Phase Transfer Catalysis, 3rd ed.; VCH Ltd.:
New York, NY, 1993; (b) Sun, H.; DiMingo, S. G. J. Am. Chem. Soc. 2005, 127,
050e2051.
7. (a) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry, 2nd ed.; VCH
UK) Ltd: Cambridge, UK, 1998; (b) Sowinski, A. F.; Whitesides, G. M. J. Org.
Chem. 1979, 44, 2369e2376; (c) Hutchins, R. O.; Taffer, I. M. J. Org. Chem. 1983,
8, 1360e1362.
8. (a) Kim, D. W.; Ahn, D.-S.; Oh, Y.-H.; Lee, S.; Kil, H. S.; Oh, S. J.; Lee, S. J.; Kim, J. S.;
Ryu, J.-S.; Moon, D. H.; Chi, D. Y. J. Am. Chem. Soc. 2006, 128, 16394e16397; (b)
Oh, Y.-H.; Ahn, D.-S.; Chung, S.-Y.; Jeong, J.-H.; Park, S.-W.; Lee, S.; Oh, S. J.; Kim,
D. W.; Kil, H. S.; Chi, D. Y. J. Phys. Chem. A 2007, 111, 10152e10161; (c) Kim, D. W.;
Jeong, H.-J.; Lim, S. T.; Sohn, M.-H.; Katzenellenbogen, J. A.; Chi, D. Y. J. Org.
Chem. 2008, 73, 957e962; (d) Kim, D. W.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H.
Angew. Chem., Int. Ed. 2008, 47, 8404e8406; (e) Im, S.; Jang, S.-W.; Kim, H.-R.;
Oh, Y.-H.; Park, S.-W.; Lee, S.; Chi, D. Y. J. Phys. Chem. A 2009, 113, 3685e3689.
8
0
C for 1 h. 1,2:3,4-Di-O-isopropylidene-6-azido-6-deoxy-
a-
D-
galactopyranose (280 mg, 0.98 mmol, 98%) was obtained as a col-
2
1
orless oil; H NMR (600 MHz, CDCl
3
)
d
1.34 (s, 3H), 1.35 (s, 3H), 1.46
(
(
3
(
2
(
2
s, 3H), 1.55 (s, 3H), 3.35e3.38 (m, 1H), 3.49e3.53 (m, 1H),
.90e3.93 (m, 1H), 4.19e4.21 (m, 1H), 4.33e4.35 (m, 1H), 4.62e4.64
4
13
m, 1H), 5.55 (d, J¼4.8 Hz, 1H); C NMR (150 MHz, CDCl
3
)
d
24.5,
4.9, 26.0, 26.1, 50.7, 67.1, 70.4, 70.9, 71.2, 96.4, 108.9, 109.7; HRMS
þ
ESI TOF) m/z calcd for C12
H
20
N
3
O
5
(M þH) 286.1403, found
86.1401. Registry No. provided by the author: 4711-00-6.
4
.38. 3-O-(3-Azidopropyl)estrone (entry 12 in Table 2)
9
. (a) Lee, J. W.; Yan, H.; Jang, H. B.; Kim, H. K.; Park, S.-W.; Lee, S.; Chi, D. Y.; Song,
C. E. Angew. Chem., Int. Ed. 2009, 48, 7683e7688; (b) Jadhav, V. H.; Jang, S. H.;
Jeong, H.-J.; Lim, S. T.; Sohn, M.-H.; Kim, D. W. Org. Lett. 2010, 12, 3740e3743; (c)
Jadhav, V. H.; Jang, S. H.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H.; Kim, J.-Y.; Lee, S.;
Lee, J. W.; Song, C. E.; Kim, D. W. Chem.dEur. J. 2012, 18, 3918e3924; (d) Kim, J.-
Y.; Kim, D. W.; Song, C. E.; Chi, D. Y.; Lee, S. J. Phys. Org. Chem. 2013, 26, 9e14.
According to the general procedure for S
mesyloxypropyl)estrone (406 mg, 1.0 mmol) with NaN
N
2 reaction of 3-O-(3-
(195 mg,
.0 mmol) for 3 h. 3-O-(3-Azidopropyl)estrone (332 mg, 0.94 mmol,
3
3
9
1
3
4%) was obtained as a white solid; H NMR (600 MHz, CDCl )

542
V.H. Jadhav et al. / Tetrahedron 70 (2014) 533e542
1
0. (a) Kim, D. W.; Song, C. E.; Chi, D. Y. J. Am. Chem. Soc. 2002, 124, 10278e10279;
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1. Jadhav, V. H.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H.; Kim, D. W. Org. Lett. 2011, 13,
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2
1
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