Regioselective α-Amination of Ethers Using Stable N-Chloroimides and Lithium tert-Butoxide

Article abstract of DOI:10.1021/acs.joc.9b00824

Herein we describe a metal-free regioselective α-amination of ethers mediated by N-chloroimides in ethereal solvents in the presence of lithium tert-butoxide. This reactivity of N-chloroimides leads to the synthesis of hemiaminal ethers in good to excellent yields at room temperature. This C-H functionalization is achieved without the use of a light, heat source, or external radical initiators. Initial mechanistic work indicates that the reaction proceeds through a radical pathway.

Full text of DOI:10.1021/acs.joc.9b00824

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Note
Regioselective #-Amination of Ethers Using
Stable N-Chloroimides and Lithium tert-butoxide
Makafui Gasonoo, Zachary Thom, and Sebastien Laulhe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00824 • Publication Date (Web): 06 Jun 2019
Downloaded from http://pubs.acs.org on June 6, 2019
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The Journal of Organic Chemistry
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Regioselective α-Amination of Ethers Using Stable N-Chloroimides
and Lithium tert-butoxide
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Makafui Gasonoo, Zachary W. Thom, and Sébastien Laulhé*
Indiana University-Purdue University Indianapolis (IUPUI), Department of Chemistry and Chemical Biology, Indianapolis,
Indiana, 46202, United States
Supporting Information Placeholder
3
ABSTRACT: Herein we describe
a
metal-free
More recently, direct C(sp )–H amination of ethers
has represented a more efficient approach that enables
regioselective -amination of ethers mediated by N-
chloroimides in ethereal solvents in the presence of
lithium tert-butoxide. This reactivity of N-chloroimides
leads to the synthesis of hemiaminal ethers in good to
excellent yields at room temperature.
functionalization is achieved without the use of light,
heat source, or external radical initiators. Initial
6, 7
late-stage functionalization of complex molecules.
Methods that access α-aminated ethers through such
C(sp )–H activation processes can be divided into three
main categories that depend on the nature of the
3
This C–H
aminating agent employed: i) transition-metal catalyzed
8
nitrene insertion
ii) metal-free organonitrenoid
insertion and iii) radical-based or metal-catalyzed
cross-coupling reaction of NH-amines (Figure 2).
9
10
11
mechanistic work indicates that the reaction proceeds
through a radical pathway.
i) Metal-catalyzed nitrene insertions
PhI NTs
H
O
TM (cat.)
TsHN
TfHN
O
O
1
The hemiaminal ether moiety is embedded within
+
2
TsNClNa
nitrenes
precursors
numerous natural products and pharmaceutical agents
Figure 1). The bioactivity of such compounds is wide
and ranges from anticancer (tegafur) to anti-HIV
zalcitabine and didanosine) activity, and some also
exhibits lyase and hepatitis C inhibition. Traditional
3
(
ii) Metal-free organonitrenoid insertions
(
H
O
metal-free
X = Br, I
approaches to generating hemiaminal ethers proceed via
metal-catalyzed hydroamination of enol ethers or
Tf– N– XAr
+
4
through the substitution of a leaving group in the α-
position of an ether substrate. These methods possess
limitations as enol ethers are acid-sensitive functional
groups and α-halogenated ethers are inherently unstable.
iii) Radical or metal-catalyzed coupling of NH-amines
TM (cat.)
5
R1
H
O
[
O]
R
R1
+
N
O
O
R
N
H
peroxide
This paper
R1
N
R1
N Cl
R
H
O
LiOt-Bu
+
R
dark, 1 h, r.t.
Figure 2. Different methods to generate hemiaminal ethers.
Despite the advances made towards the regioselective
3
α-amination of C(sp )–H bonds utilizing the methods
mentioned above, there still remains the challenge of
developing more environmentally friendly and atom-
economical reactions that do not require the use of
strong oxidants or external radical initiators. Herein, we
describe a novel metal-free, regioselective α-amination
Figure 1. Selected examples of natural products and
bioactive agents containing hemiaminal ether skeletons.
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of cyclic and acyclic ethers using stable N-chloroimides
counter ion appears essential for optimal reactivity since
the use of sodium or potassium tert-butoxide (Table 1,
entries 2 and 3) provided the desired product in
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as the aminating agent. Our method generates the
desired products in good yields at room temperature
without the need for transition metal catalysts, external
radical initiators, heat, or light. We found that stable N-
chloroimides can selectively aminate in the presence of
lithium tert-butoxide at room temperature (Figure 2).
significantly lower yields.
Importantly, a control
experiment in the absence of base did not provide the
desired product (Table 1, entry 4). Mild heating of the
reaction at 40 °C did not have a deleterious effect on
product formation (Entry 5). Extensive screening of
other inorganic (Table 1, entries 6–10) and organic
Table 1. Reaction optimization and influence of base on
reaction outcome.
(Table 1, entries 11 and 12) bases did not provide the
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desired product in satisfactory useful yields. An
important observation from our optimization study was
the deleterious effect of oxygen. Lower yields were
obtained when the reaction was performed in an open-
to-air microwave vial (Table 1, entry 13). Presumably,
in the open-to-air reactions, we surmise that atmospheric
oxygen is responsible for the quenching of the generated
radical species, leading to reduced overall yields. Also,
we hypothesize that covering the reaction flask in
aluminum foil would prevent light induced
decomposition of N-chlorophthalimide, but such path
seems to be minimal. Indeed, laboratory lighting did not
have a considerable effect on product formation (Table
Temperature Additives Yielda
Entry Base
-
80%b
1
LiOt-Bu
26 °C (r.t.)
(
86%)
44%
20%
0%
2
3
4
5
6
7
8
9
1
1
NaOt-Bu
KOt-Bu
none
r.t.
-
r.t.
-
r.t.
-
LiOt-Bu
40 °C
r.t.
-
76%
15%
0%
1
, entry 14). As such, it was not surprising that the
Cs
2
CO
3
-
optimal reaction conditions were achieved in the
absence of oxygen in an argon atmosphere. The use of
reagent grade THF (non-anhydrous and stabilized with
K
2
CO
3
r.t.
-
LiOH.H
LiOAc
LiOMe
2
O
r.t.
-
19%
0%
0
.025% butylated hydroxytoluene) also afforded the
r.t.
-
aminated THF product in only 62 % NMR yield (Table
1, entry 15), corroborating further the radical nature of
this transformation. Finally, while reactions in neat THF
0
1
r.t.
-
41%
19%
0%
Et
3
N
r.t.
-
(1 mL) were consistently optimal, the use of a 1:1 (by
12
Pyridine
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
r.t.
-
volume) mixture of dichloroethane (DCE) and THF at
50 °C also gave the desired product in 72 % NMR yield
(Table 1, entry 17).
1
1
15e
3c
4d
r.t.
air
light
-
22%
78%
62%
47%
72%
r.t.
With the established optimal conditions in hand, we
proceeded to first examine the scope of ether substrates
r.t.
1
1
6f
7f
50 °C
50 °C
CH
2
Cl
2
2
compatible with our reaction conditions. Gratifyingly,
DCE
the protocol was efficient for the α-amination of a
diverse set of ethers (Scheme 2). Cyclic ethers such as
tetrahydrofuran and tetrahydropyran were found to react
smoothly to generate the coupling products 3aa and 3ab
in good isolated yields. Linear ethers were also tolerated
and afforded the corresponding products 3ac, 3ad, 3ae
and 3af in moderate to good yields. In a previously
published article, diethyl ether 2d and methyl tert-butyl
All reactions were performed using 1 mL of anhydrous,
degassed, non-stabilized THF, 0.14 mmol of N-
chlorophthalimide and 0.14 mmol of LiOt-Bu under argon
atmosphere, constant stirring in the dark, and at room
temperature, unless stated otherwise. a. NMR yield
obtained using dibromomethane as internal standard. b.
Isolated yield. c. The reaction was performed in open
atmosphere. d. The reaction was performed without
covering the reactor in aluminium foil to allow ambient
light in the reaction flask. e. Stabilized reagent-grade THF
was used without further purification and without
degassing. f. The reaction was performed using 1:1 ratio of
THF and the additive solvent (total volume 1 mL).
ether 2f substrates failed to undergo amination due to the
10e
poor solubility of the reagents used.
This amination
reaction may therefore be complementary to existing
amination strategies. Reaction of 2-
methyltetrahydrofuran provided an interesting
regioselectivity assessment experiment. Interestingly,
the aminated product 3ag was found as a single
regioisomer favoring the less sterically hindered C–H
bond at the 4 position (3ag, Scheme 2) in 72% yield (d.r.
= 1:1.5). This result mirrors previous radical amination
To begin our study, we chose commercially available
N-chlorophthalimide 1a and tetrahydrofuran (THF) 2a
as model substrates. Optimal reaction conditions (Table
1
, entry 1) were obtained when using 1 equiv. of LiOt-
1
0e
Bu at room temperature in the dark for 1h. The lithium
strategies independently developed by the Hu group
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and the Du group.10g Other unsymmetrical substrates,
moderate yields. N-chlorosuccinimide (NCS) provided
the desired product 3ba low yield, however, N-
bromosuccinimide (NBS) and N-iodosuccinimide (NIS)
did not provide the desired product in synthetically
useful yields. Presumably, the greater reactivity of NBS
and NIS lead to premature decomposition of the
reagents. On the other hand, N-chloro-3,3-dimethyl-
glutarimide (33DMNCG, product 3ca) provided the
desired product in good yield. We surmise that the
difference in reactivity between succinimide reagents
(NCS, NBS, and NIS) and glutarimide reagents
(33DMNCG) arises from the decomposition pathways of
these reagents (Figure 4B). Indeed, under radical
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such as dimethoxyethane (DME), also provided the
expected product 3ae as single regioisomers in the
3
internal C(sp )-H bond. Dioxane and acetals were also
tolerated and provided the desired products 3ah and 3ai
in good yields. These substrates required longer
reaction times (4 h instead of 1 h) to achieve a sufficient
amount
of
the
desired
aminated
products.
Tetrahydrothiophene 3aj also reacted under the current
reaction conditions, but the transformation only
provided the product in moderate yields. An important
limitation of the current method remains the poor
reactivity of benzyl ethers. As shown in scheme 2,
compounds 3ak, and 3al, were only provided in trace
amount. This, presumably, may be due to decomposition
of the reactive intermediates into aldehydes under our
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reaction
conditions
succinimide-based
reagents
generally undergoes a radical ring opening after the
formation of the N-centered radical, while 33DMNCG is
12
reaction conditions.
a more stable N-centered radical and do not decompose
13
via ring opening.
Unfortunately, the corresponding
aminated product for 2-chloro-5-nitroisoindoline-1,3-
dione, and 2,4,5,6,7-pentachloroisoindoline-1,3-dione
were generated in only trace amounts under our reaction
conditions. The lack of product formation with these
electron withdrawing N-chloroimides was quite
surprising to us and we can only surmise at this moment
that the N-centered radical intermediates of these species
were either not generated under our reaction conditions,
are not reactive enough to perform a C–H abstraction, or
are not stable.
Figure 3. Reaction scope. All reactions were performed
under argon atmosphere in 1 mL of solvent, 1a (0.55
mmol) and LiOt-Bu (0.55 mmol), unless otherwise
specified (see Experimental Section). a. Refers to the
reaction conditions shown in Table 1, Entry 1 (General
Method). b. Reaction stirred for 4 h (See Experimental
Section). Yields reported are isolated yields.
Next, we examine the compatibility of our optimal
reaction conditions with different imide agents (1b–1h)
using THF 2a as the preferred ether substrate. As shown
in Figure 4A, the method enabled the α-amination of
THF using some of the tested N-chloroimide reagents in
Figure 4. A. Scope of imide reagents. B. Radical
decomposition pathways of N-halosuccinimide versus 3,3-
dimethyl-N-haloglutarimide.
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Of major interest, N-chlorosulfonimides also
generated the desired product 3da in good yield (Figure
). Similarly, 1-chlorobenzotriazole provided
separable mixture of two regioisomeric products
ea/3e'a in good yield as well. Similar regioisomeric
mixtures from reactive benzotriazole reagents have been
In the absence of a base, no desired product formation
was observed via NMR analysis, but GC-MS analysis of
this crude reaction mixture revealed the formation of a
chlorinated THF and phthalimide (See Supporting
Information). Similar halogenation of ethers using N-
halosuccinimide reagents is well documented in the
literature. Addition of 2,2,6,6-tetramethylpiperidine-1-
oxyl (TEMPO) as a radical trapping reagent into the
reaction mixture led to complete reaction shutdown
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a
3
10f
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reported in the literature.
Interestingly, 1-
chloroindoline-2,3-dione did not aminate THF under our
reaction conditions.
(Table 2, entries 3, 4). Importantly, neither desired
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product nor the chlorinated THF byproducts were
observed through GC-MS analysis of these crudes.
In an attempt to trap radical intermediates generated
during the reaction, we used 1,1-diphenylethylene (4) as
1
4
a reaction additive (see SI).
To our delight, we
observed the formation of products 5a, 5b, and 5c by
GC-MS (Scheme 1). This result suggests the formation
of chlorine, tert-butoxy, and phthalimide radicals.
Formation of 5a and 5c could come from homolytic
1
5
cleavage of the N–Cl bond of 1a in the ethereal
solvent. Such an initiation step is supported by the
1
2
presence of chlorinated THF in the absence of base.
Formation of 5b and 5c supports a single electron
transfer (SET) step between LiOt-Bu and 1a. Literature
Figure 5. Scope of other aminating agents.
To gain insight into the possible mechanism of this
reaction, we carried out a number of experiments, some
of which are illustrated in Table 2. An important
observation from these experiments was the relationship
between the equivalents of base used and the overall
yield of the reaction. When sub-stoichiometric amounts
of LiOt-Bu (e.g., 0.5 equiv) were used the desired
product was generated in only 48% yield (Table 2, entry
16
precedents for this initiation step are documented.
1
). Similarly, super-stoichiometric amounts of base (1.5
equiv) was also detrimental to the reaction forming the
desired product in 65% yield (Table 2, entries 2).
Scheme 1. Radical trapping experiment.
On the basis of the preliminary mechanistic
investigations above and previous literature on
Table 2. Mechanistic Studies.
6
functionalization of ethers, we propose a plausible
mechanism involving both a radical step and a two-
electron substitution (Scheme 2).
Entry LiOt-Bu
Additives
Yielda
48%
65%
0%
1
2
3
4
0.5 equiv.
1.5 equiv.
1 equiv.
-
-
TEMPO (1 equiv.)
1 equiv.
TEMPO (0.5 equiv.) 0%
All reactions were performed using 1 mL of anhydrous,
degassed, non-stabilized THF, 0.14 mmol of N-
chlorophthalimide, and 0.14 mmol of LiOt-Bu under Argon
atmosphere, constant stirring in the dark, and at room
temperature, unless stated otherwise. a. NMR yield
obtained using dibromomethane as internal standard.
Scheme 2. Proposed mechanism.
Single electron transfer (SET) process between LiOt-
Bu and N-chlorophthalimide would generate tert-
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The Journal of Organic Chemistry
butoxyl radical and phthalimidyl radical A (Scheme 2).
Literature precedents for this initiation step are
Instrumentation
1
2
3
4
5
6
7
8
9
NMR Spectrometry: NMR spectra were obtained on Bruker
spectrometers operating at 400 or 500 MHz for H NMR,
16
1
documented
and in our case supported by the
13
1
generation of products 5b and 5c. Regioselective
abstraction of α-hydrogen from THF by radical
intermediate A forms a stable carbon-centered ethereal
radical B and phthalimide C. Stable imidyl radicals
and 101 or 126 MHz for C{ H} NMR. Chemical shifts (δ
ppm), multiplicity (s = singlet, d = doublet, dd = doublet of
doublets, t = triplet, q = quartet, m = multiplet), coupling
constant, (Hz), relative integral was made in reference to
NMR solvent signals.
Mass Spectrometry: Gas chromatograph-mass spectrometry
were obtained using Hewlett Packard GC System HP 6890
Series coupled with a HP 5973 Mass Selective Detector.
High-resolution mass spectra were obtained using Agilent
Technologies 6520 Accurate-Mass Q-TOF LC/MS with
electrospray ionization (ESI).
have been shown to react as good hydrogen
13a
abstractors.
In the propagation step, radical
intermediate B reacts with reagent 1a to form
chlorinated THF D and regenerates the imidyl radical A.
Similar radical chlorination mechanisms have been
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7
reported with N-chlorosulfamate esters.
Finally, the
base deprotonates phthalimide C to generate an imide
anion that subsequently reacts with D via S 2 to afford
Optimization Method
N
the desired product (Scheme 2).
General Method: On a bench top, a 10 mL microwave vial
was charged with the appropriate N-chloroimide (0.55
mmol), covered with a Kim wipe and tighten with a rubber
band. The vial was then brought into an argon filled
glovebox before adding base (0.55 mmol) and capped with
a 20 mm microwave crimp caps with septa in the glovebox.
The vial was removed from the glovebox, covered
completely with aluminum foil and 2 mL of the
corresponding ether solvent was added. The reaction was
then stirred at room temperature for 1 hour unless
otherwise stated. After completion, the reaction mixture
was prepared directly for chromatography without workup.
In summary, we have discovered a mild and metal-
free method for the formation of hemiaminal ethers.
This new approach enables the regioselective α-
amination of various cyclic and acyclic ethers with
different N-chloroimides such as phthalimides,
sulfonimides, and triazoles. Preliminary mechanistic
investigations suggest the reaction is initiated via, firstly,
a radical chlorination of the ether substrate followed by
a substitution reaction with the nucleophilic nitrogen
source to afford the desired aminated product. This
method provides rapid access to many hemiaminal
ethers that may serve as useful synthetic or biologically
active small molecule intermediates for further
functionalization.
Compounds Synthesis and Characterization
1-chloro-4,4-dimethylpiperidine-2,6-dione, 1c. A 25 mL
round bottom flask was flame dried and allowed to cool to
room temperature. The flask was then cooled to 0 C and
charged with 3,3,-dimethylglutarimide (240 mg, 1.70
mmol, 1 equiv.). 10 mL anhydrous DCM was subsequently
o
EXPERIMENTAL SECTION
General Considerations
added
to
dissolve
the
3,3,-dimethylglutarimide.
All reagents and solvents were purchased and used without
further purification unless otherwise noted. All reactions
were performed under an inert atmosphere unless otherwise
stated. Room temperature refers to 26 °C.
Moisture-sensitive reactions were performed using flame-
dried glassware under an atmosphere of dry argon (Ar).
Air- and water-sensitive reactions, were setup in a Vacuum
Atmosphere GENESIS glove box held under an
atmosphere of argon gas (working pressure 2–6 mbar).
Flame-dried equipment was stored in a 130 °C oven before
use and either allowed to cool in a cabinet desiccator or
assembled hot and allowed to cool under an inert
Isocyanuric chloride (500 mg, 2.15 mmol, 1.30 equiv.) was
added in one portion and the resulting solution stirred at 0
o
C for 4 h. After this time, the reaction mixture was
prepared for flash chromatography (solid deposition)
without any workup. The desired product was isolated as a
white solid in 92 % yield. Spectra data matched reported
18
1
3
data. H NMR (400 MHz, CDCl ) δ 1.15 (s, 6 H), 2.73 (s,
13
1
4 H). C{ H} NMR (100 MHz, CDCl
167.4.
3
) δ 27.4, 29.5, 47.4,
2-(tetrahydrofuran-2-yl)isoindoline-1,3-dione,
3aa.
Using the General Method, (100 mg N-chlorophthalimide,
44 mg lithium tert-butoxide and 2 mL tetrahydrofuran),
product 3aa is isolated in 80% yield (96 mg) after column
atmosphere.
solutions were transferred via plastic or glass syringe.
Chromatographic purification of products
Air- and moisture-sensitive liquids and
chromatography (R
Spectra data matched reported data.
CDCl ) δ 1.90 – 2.07 (m, 1 H), 2.24 – 2.33 (m, 1 H), 2.35 –
.44 (m, 1 H), 2.51 – 2.59 (m, 1 H), 3.92 – 3.97 (m, 1 H),
.17 – 4.23 (m, 1 H), 6.04 (dd, J = 4.84, 4.96 Hz, 1 H),
f
= 0.39, hexane: ethyl acetate, 3:1).
was
10f 1
H NMR (400 MHz,
accomplished using flash column chromatography Silicycle
Silica flash F60 (particle size 40–63 μm, 230–400 mesh).
Thin layer chromatography was performed on EMD
Millipore silica gel 60 F254 glass-backed plates (layer
thickness 250 μm, particle size 10–12 μm, impregnated
3
2
4
7
13
1
.71 – 7.73 (m, 1 H), 7.82 – 7.85 (m, 1 H). C{ H} NMR
) δ 26.0, 29.1, 69.8, 80.9, 123.3, 132.0,
(100 MHz, CDCl
3
with a fluorescent indicator).
Visualization of the
1
34.1. 167.8.
-(tetrahydro-2H-pyran-2-yl)isoindoline-1,3-dione, 3ab.
Using the General Method, (100 mg N-chlorophthalimide,
4 mg lithium tert-butoxide and 2 mL tetrahydropyran),
developed chromatogram was accomplished by
fluorescence quenching under shortwave UV light and/or
by staining with phosphomolybdic acid, p-anisaldehyde, or
2
4
4
KMnO stains.
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product 3ab is isolated in 75% yield (96 mg) after column
chromatography (R = 0.41, hexane: ethyl acetate, 3:1).
Spectra data matched reported data.10f 1H NMR (400 MHz,
CDCl ) δ 1.55 – 1.80 (m, 4 H), 2.04 – 2.08 (m, 1 H), 2.74 –
0.4 H), 2.05 – 2.15 (m, 0.4 H), 2.20 – 2.28 (m, 1 H), 2.30 –
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
f
2.37 (m, 0.8 H), 2.43 – 2.50 (m, 0.4 H), 2.54 – 2.63 (m, 0.7
H), 4.01 – 4.07 (m, 0.3 H), 4.46 – 4.51 (m, 0.6 H), 5.90 (dd,
J = 3.76, 3.68 Hz, 0.3 H), 6.03 (dd, J = 5.80, 3.64 Hz, 0.6
3
1
3
1
2.80 (m, 1 H), 3.65 – 3.71 (m, 1 H), 4.11 – 4.15 (m, 1 H),
H), 7.63 – 7065 (m, 2 H), 7.76 – 7.78 (m, 2 H). C{ H}
5.35 (dd, J = 11.4, 2.2 Hz, 1 H), 7.34 – 7.56 (m, 2 H), 7.87
NMR (100 MHz, CDCl ) δ 20.3, 20.8, 29.6, 29.8, 32.5,
3
1
3
1
– 7.90 (m, 2 H). C{ H} NMR (100 MHz, CDCl
24.9, 27.9, 68.9, 79.4, 123.5, 131.8, 134.2, 167.4.
3
) δ 23.6,
33.9, 80.3, 80.7, 123.3, 132.0, 134.1, 168.0.
2-(1,4-dioxan-2-yl)isoindoline-1,3-dione, 3ah. Using the
General Method and stirring for 4 h, (100 mg N-
chlorophthalimide, 44 mg lithium tert-butoxide and 2 mL
1,4-dioxane), product 3ah is isolated in 61% yield (78 mg)
f
2-(1-butoxybutyl)isoindoline-1,3-dione, 3ac. Using the
General Method, (100 mg N-chlorophthalimide, 44 mg
lithium tert-butoxide and 2 mL dibutyl ether), product 3ac
is isolated in 65% yield (99 mg) after column
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
after column chromatography (R = 0.26, hexane: ethyl
1
0d
1
chromatography (R
Spectra data matched reported data.
CDCl ) δ 0.87 (t, J = 7.36 Hz, 3 H), 0.96 (t, J = 7.40 Hz, 3
H),1.21 – 1.59 (m, 3 H), 1.41 – 1.50 (m, 1 H), 1.51 – 1.59
m, 1 H), 2.10 – 2.15 (m, 1 H), 2.22 – 2.31 (m, 1 H), 3.41 –
f
= 0.28, hexane: ethyl acetate, 3:1).
acetate, 3:1). Spectra data matched reported data.
H
1
0f 1
H NMR (400 MHz,
NMR (400 MHz, CDCl ) δ 3.78 – 3.82 (m, 3 H), 3.97 –
3
3
4.00 (m, 2 H), 4.62 (dd, J = 10.2, 10.2 Hz, 1 H), 5.57 (dd, J
= 2.84, 2.84 Hz, 1 H), 7.77 – 7.80 (m, 2 H), 7.89 – 7.92 (m,
1
3
1
(
2 H). C{ H} NMR (100 MHz, CDCl ) δ 65.8, 66.4, 67.5,
3
3
.51 (m, 2 H), 5.38 (t, J = 7.04 Hz, 1 H), 7.74 – 7.78 (m, 2
76.2, 123.7, 131.6, 134.5, 167.1.
1
3
1
H), 7.86 – 7.89 (m, 2 H).
C{ H} NMR (100 MHz,
2-(1,3-dioxolan-2-yl)isoindoline-1,3-dione, 3ai. Using
the General Method and stirring for 4 h, (100 mg N-
chlorophthalimide, 44 mg lithium tert-butoxide and 2 mL
1,3-dioxolane), product 3ai is isolated in 42% yield (51 mg)
CDCl
23.5, 131.7, 134.2, 168.1.
-(1-ethoxyethyl)isoindoline-1,3-dione, 3ad. Using the
3
) δ 13.6, 13.7, 18.8, 19.2, 31.4, 34.6, 68.8, 82.0,
1
2
General Method, (100 mg N-chlorophthalimide, 44 mg
lithium tert-butoxide and 2 mL diethyl ether), product 3ad
is isolated in 70% yield (85 mg) after column
after column chromatography (R = 0.40, hexane: ethyl
f
10f
1
acetate, 3:1). Spectra data matched reported data.
H
NMR (400 MHz, CDCl ) δ 4.09 – 4.13 (m, 2 H), 4.46 –
3
chromatography (R
Spectra data matched reported data.
CDCl ) δ 1.15 (t, J = 7.04 Hz, 3 H), 1.76 (d, J = 6.32 Hz, 3
H), 3.46 – 3.52 (m, 2 H), 5.56 (q, J = 6.32 Hz, 1 H), 7.71 –
f
= 0.50, hexane: ethyl acetate, 3:1) and.
4.49 (m, 2 H), 6.80 (s, 1 H), 7.75 – 7.77 (m, 2 H), 7.87 –
10f
1
13
1
H NMR (400 MHz,
7.89 (m, 2 H). C{ H} NMR (100 MHz, CDCl ) δ 66.6,
3
3
100.7, 123.6, 131.9, 134.4, 166.8.
2-(tetrahydrothiophen-2-yl)isoindoline-1,3-dione, 3aj.
Using the General Method, (100 mg N-chlorophthalimide,
1
3
1
7.74 (m, 2 H), 7.83 – 7.85 (m, 2 H). C{ H} NMR (100
MHz, CDCl
168.9.
3
) δ 14.9, 19.3, 64.2, 78.0, 123.4, 131.7, 134.2,
44
mg
lithium
tert-butoxide
and
2
mL
tetrahydrothiophene), product 3aj is isolated in 53% yield
2-(1,2-dimethoxyethyl)isoindoline-1,3-dione, 3ae. Using
the General Method, (100 mg N-chlorophthalimide, 44 mg.
lithium tert-butoxide and 2 mL 1,2-dimethoxyethane),
product 3ae is isolated in 73% yield (95 mg) after column
(68 mg) after column chromatography (R = 0.57 , hexane:
f
1
ethyl acetate, 3:1). H NMR (400 MHz, CDCl ) δ 1.93 –
3
2.02 (m, 1 H), 2.22 – 2.29 (m, 1 H), 2.39 – 2.53 (m, 2 H),
2.86 – 2.91 (m, 1 H), 3.29 – 3.35 (m, 1 H), 5.99 (dd, J =
chromatography (R
Spectra data matched reported data.10f 1H NMR (400 MHz,
CDCl ) δ 3.31 (s, 3 H), 3.33 (s, 3 H), 3.88 – 3.98 (m, 2 H),
.39 (t, J = 6.52 Hz, 1 H), 7.67 – 7.69 (m, 2 H), 7.78 – 7.81
f
= 0.35, hexane: ethyl acetate, 3:1).
5.52, 5.68 Hz, 1 H), 7.63 – 7.65 (m, 2 H), 7.45 – 7.77 (m,
13
1
2 H).
3
C{ H} NMR (100 MHz, CDCl ) δ 31.9, 34.36,
3
34.47, 57.5, 123.8, 132.0, 134.1, 167.4. Low resolution MS
(EI): 233 (M+), 200, 186, 174, 158, 149, 130, 117, 104, 86,
76, 59, 50. HRMS (ESI) for C H NNaO S [M+Na]+:
5
1
3
1
(
m, 2 H). C{ H} NMR (100 MHz, CDCl
0.9, 81.4, 123.6, 131.7, 134.3, 168.0.
-(tert-butoxymethyl)isoindoline-1,3-dione, 3af. Using
3
) δ 56.9, 59.2,
1
2
12
2
7
calcd 256.0403, found 256.0414.
1-(tetrahydrofuran-2-yl)pyrrolidine-2,5-dione,
2
3ba.
the General Method, (100 mg N-chlorophthalimide, 44 mg
lithium tert-butoxide and 2 mL methyl tert-butyl ether),
product 3af is isolated in 60% yield (77 mg) after column
Using the General Method, (73.6 mg N-chlorosuccinimide,
44 mg lithium tert-butoxide and 2 mL tetrahydrofuran),
product 3ba is isolated in 20% yield (19 mg) after column
f
chromatography (R
Spectra data matched reported data.10f 1H NMR (400 MHz,
CDCl ) δ 1.22 (s, 9 H), 5.04 (s, 2 H), 7.65 – 772 (m, 2 H),
f
= 0.43, hexane: ethyl acetate, 3:1).
chromatography (R = 0.41, hexane: ethyl acetate, 1:1).
10f
1
Spectra data matched reported data.
H NMR (400 MHz,
3
CDCl ) δ 1.86 – 1.97 (m, 1 H), 2.06 – 2.15 (m, 1 H), 2.20
3
7
2
.80 – 7.84 (m, 2 H). 13C{ H} NMR (100 MHz, CDCl
7.8, 61.3, 123.9, 134.2, 134.7, 167.6.
2-(5-methyltetrahydrofuran-2-yl)isoindoline-1,3-dione,
3ag. Using the General Method, (100 mg N-
1
3
) δ
– 2.27 (m, 1 H), 2.31 – 2.38 (m, 1 H), 2.60 (s, 4 H), 3.81 –
3.87 (m, 1 H), 4.08 (q, J = 6.80 Hz, 1 H), 5.80 (dd, J = 5.0,
1
3
1
5.0 Hz, 1 H). C{ H} NMR (100 MHz, CDCl ) δ 26.1,
3
28.2, 28.5, 70.2, 81.6, 176.7.
chlorophthalimide, 44 mg lithium tert-butoxide and 2 mL
2-methyltetrahydrofuran), product 3ag is isolated in 72%
yield (92 mg) as a mixture of diastereoisomers after column
4,4-dimethyl-1-(tetrahydrofuran-2-yl)piperidine-2,6-
dione, 3ca. Using the General Method, (100 mg 1-chloro-
4,4-dimethylpiperidine-2,6-dione, 44 mg lithium tert-
butoxide and 2 mL tetrahydrofuran), product 3ca is isolated
chromatography (R
1:1.5). Spectra data matched reported data.10f H NMR
400 MHz, CDCl ) δ 1.20 (d, J = 6.08 Hz, 1.9 H), 1.29 (d, J
6.0 Hz, 1.2 Hz), 1.50 – 1.58 (m, 0.8 H), 1.94 – 2.02 (m,
f
= 0.52, hexane: ethyl acetate, 3:1, d.r.
1
=
in 55% yield (62 mg) after column chromatography (R =
f
(
3
0.29, hexane: ethyl acetate, 3:1). Spectra data matched
reported data. 1H NMR (400 MHz, CDCl3) δ 1.00 (s, 6
1
0f
=
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The Journal of Organic Chemistry
H)),1.85-1.90 (m, 1 H), 2.04 – 2.12 (m, 1 H), 2.17 – 2.25
m, 1 H), 2.42 (s, 4 H), 3.79 (td, J = 4.60 Hz, 4.14 Hz, 1 H),
Funding Sources
1
2
3
4
5
6
7
8
9
(
This publication was made possible, in part, with support
from the Indiana Clinical and Translational Sciences
Institute funded, in part by Grant Number UL1TR002529
from the National Institutes of Health, National Center for
Advancing Translational Sciences, Clinical and
Translational Sciences Award. The content is solely the
responsibility of the authors and does not necessarily
represent the official views of the National Institutes of
Health. Start-up funding from Indiana University–Purdue
University Indianapolis (IUPUI) was also used to support
this research. The authors declare no competing financial
interest.
4
.14 (q, J =7.12 Hz, 1 H), 6.35 (dd, J = 4.64, 3.09 Hz, 1 H).
C{ H} NMR (100 MHz, CDCl3) δ 26.4, 27.6, 28.9, 29.0.
1
3
1
29.6, 47.3, 70.0, 83.0. 172.0
2-(tetrahydrofuran-2-yl)benzo[d]isothiazol-3(2H)-one
1,1-dioxide, 3da. Using the General Method, (100 mg N-
chlorosaccharin, 44 mg lithium tert-butoxide and 2 mL
tetrahydrofuran), product 3da is isolated in 63% yield (73
mg) after column chromatography (R
acetate, 3:1). Spectra data matched reported data.
NMR (400 MHz, CDCl3) δ 2.02 – 2.09 (m, 1 H), 2.30 –
f
= 0.31, hexane: ethyl
6
1
H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
7
.43 (m, 1 H), 2.69 – 2.76 (m, 1 H), 3.98 – 4.03 (m ,1 H),
.25 – 4.31 (m, 1 H), 6.11 (dd, J = 3.68, 3.36 Hz, 1 H),
1
3
1
.81 – 7.90 (m, 3 H), 8.03 (d, J = 7.16 Hz, 1 H). C{ H}
ACKNOWLEDGMENT
NMR (100 MHz, CDCl3) δ 24.6, 30.3, 70.1, 85.8, 120.7,
25.1, 126.8, 134.2, 135.0, 138.4, 159.2.
-(tetrahydrofuran-2-yl)-1H-benzo[d][1,2,3]triazole, 3ea
and 2-(tetrahydrofuran-2-yl)-2H-benzo[d][1,2,3]triazole,
e'a. Using the General Method, (100 mg 1-
We gratefully acknowledge IUPUI for financial support.
Z.W.T. is also grateful for financial support from the
Center for Research and Learning (CRL) at IUPUI
(Undergraduate Research Opportunities; MURI Projects).
Prof. J.L. Roizen of Duke University and Prof. M.H. Nantz
of the University of Louisville are thanked for their
insights. The authors also acknowledge J.T. Floreancig for
his help in completing the project.
1
1
3
chlorobenzotriazole, 44 mg lithium tert-butoxide and 2 mL
tetrahydrofuran), products are isolated in 69% yield (85
mg, combined) after column chromatography. Spectra data
19
1
matched reported data.
3ea (47% yield, 58 mg).
H
NMR (400 MHz, CDCl3) δ 2.05 – 2.16 (m, 1 H), 2.26 –
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3
Hz, 1 H), 8.00 (d, J = 8.82 Hz, 1 H). C NMR (100 MHz,
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(±)-Limaspermidine
and
(±)-1-
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(
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Corresponding Author
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Functionalization of Alkyl Ethers to Construct Hemiaminal Ether
Skeletons (HESs). Org. Biomol. Chem., 2018, 16, 4384–4398.
*
E-mail: slaulhe@iupui.edu
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LiOt-Bu (1 equiv)
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N Cl +
R
dark, 1h, r.t.
up to 80% yield
Metal-free, Initiator-free, Oxidant-free
Mild reaction conditions
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