Direct Metal-Free C–H Functionalization of Cyclic Ethers with Schiff Bases Through an Azobisisobutyronitrile-Initiated Radical Chain Process

Article abstract of DOI:10.1002/ejoc.201701288

The radical-initiated C–H bond functionalization of cyclic ethers with imines represents an efficient way to form C–C bonds and construct 1,2-amino ethers. Despite being a net redox-neutral process, most examples require excess amounts of radical reagents or oxidants to continuously generate the radical species. Herein, we report an atom-economic protocol for the radical addition of cyclic ethers to imines without the need for any oxidant, metal salt, delicate catalyst, or UV irradiation. In the presence of small amounts of AIBN (2 mol-%), tetrahydrofuran smoothly undergoes the reaction with a variety of imines to afford 1,2-amino ethers in moderate to good yields. Preliminary mechanistic studies suggest that this transformation likely proceeds through a radical chain process with the hydrogen atom abstraction as the rate-determining step.

Full text of DOI:10.1002/ejoc.201701288

A Journal of
Accepted Article
Title: Direct Metal-free C-H Functionalization of Cyclic Ethers with
Schiff Bases through an Azobisisobutyronitrile (AIBN) Initiated
Radical Chain Process
Authors: Haipeng Zeng, Dengfu Lu, and Yuefa Gong
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701288
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European Journal of Organic Chemistry
10.1002/ejoc.201701288
FULL PAPER
Direct Metal-free C-H Functionalization of Cyclic Ethers with
Schiff Bases through an Azobisisobutyronitrile (AIBN) Initiated
Radical Chain Process
[a]
[a]
[a]
Haipeng Zeng, Dengfu Lu,* and Yuefa Gong*
Dedication ((optional))
Abstract: Radical-initiated C-H bond functionalization of cyclic
ethers with imines represents an efficient way to form C-C bonds as
well as to construct 1,2-amino ethers. Despite the fact that it’s a net
redox-neutral process, most of previous examples require an excess
amount of radical reagents or oxidants to continuously generate
radical species. Herein we report an atom-economic radical addition
reaction of cyclic ethers to imines without using any oxidant, metal
salt, delicate catalyst or UV irradiation. In the presence of small
amount of AIBN (2 mol%), tetrahydrofuran reacts smoothly with a
variety of imines to affords 1,2-amino ethers in moderate to good
yields. Preliminary mechanistic studies suggest that this
transformation likely goes through a radical chain process and the
hydrogen atom abstraction is the rate-determining step.
even an excess amount of radical initiators. Tomioka5a,5b
discovered that 3-12 equivalents of Me Zn could promote the
2
addition reaction of THF to imines in the presence of constant
air/oxygen flow. Methyl radical was proposed to implement the
C-H abstraction in these reactions. In a later study, Lewiński et
al. reported that under similar conditions, the actual initiator is
more likely to be oxygen-centered radicals.5j Another frequently-
used system described by Porta,5d Punta5g and Shi5h et al.
comprises stoichiometric amounts of titanium salts, oxidants,
and sometimes UV irradiation. Copper salts along with extra
oxidants were also reported to do similar jobs.7 All the above
methods consume at least one equivalent of oxygen-centered
radicals to generate the reactive species, making this reaction
less practical and inefficient. Recently, MacMillan’s group
2
established a delicate Ir(ppy) (dtbbpy)/thiol co-catalyzed system
for the addition of highly reactive benzyl ethers to Schiff bases,
under the irradiation of visible light. Therefore, an efficient and
Introduction
8
practical protocol for this transformation is highly desired.
The exploitation of small oxygen-containing molecules such as
ethers is of great significance to synthetic chemistry because of
their abundance and sustainability.1 sp C-H bonds in these
structures are known to be stable in polar reactions so that
ethers are widely used as solvents rather than carbon synthons.
Nonetheless, the α C-H bonds are substantially weakened
towards radical processes due to the stabilization effect of the
3
oxygen atom,2 rendering
a
feasibility of direct C-H
functionalization through radical pathways. Based on this unique
reactivity, we debuted our exploration on the activation of these
materials, intending to develop some redox-neutral and atom-
economic transformations, meanwhile minimize the production
of hazardous wastes. As its derivatives are potentially useful in
polymer science,3 and their frequent occurrence in the
frameworks of many important organic compounds,4
tetrahydrofuran (THF) was chosen as the model for our initial
study. Since imines are known to react with alkyl radicals,5 we
envisioned to establish a “green” method for the synthesis of
valuable 1,2-amino ethers via the addition of cyclic etheric
Scheme 1. Comparison of previous works and our current work.
6
radicals to imines, provided the radical species, once initiated,
From our understanding, if the nitrogen radical that formed from
the addition to imine could effectively abstract another hydrogen
atom from THF to regenerate a 2-tetrahydrofuranyl radical, the
reaction might be able to propagate in a chain manner. This
would allow us to decrease the loading of radical reagent to a
catalytic level. Herein, we disclose a simple, efficient and metal-
free method for the addition of THF and its analogues to a
series of Schiff Bases without using any oxidants or delicate
catalyst.
can be repeatedly regenerated throughout the reaction.
However, to the best of our knowledge, the vast majority of
current examples of this reaction require a stoichiometric or
[
a]
School of Chemistry and Chemical Engineering
Huazhong University of Science and Technology
1037 Luoyu Rd., Wuhan, Hubei, China, 430074
E-mail: dlu@hust.edu.cn; gongyf@hust.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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European Journal of Organic Chemistry
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FULL PAPER
Results and Discussion
mol% led to a substantial yield drop (53%, entry 9), while
lowering the loading of AIBN to 2 mol% improved the yield
significantly (76%, entry 11). When we further decrease AIBN
dosage to 1 mol%, the reaction became slower and the yield of
3a slightly dropped to 66% within the same reaction time (entry
12).
We started our work from the reaction of tetrahydrofuran 2 with
simple (E)-N,1-diphenylmethanimine 1a to seek for an optimal
initiating method. Since oxygen radicals are known for being
able to abstract hydrogen atom form ethers, a few common
oxygen-based radical initiators, such as benzoyl peroxide (BPO),
di-tert-butyl peroxide (DTBP), or tert-butyl hydroperoxide (TBHP)
were preferentially examined. The reaction was performed in
THF at 100 °C in a sealed tube. Unexpectedly, in the presence
of 10 mol% peroxides, the conversions of imine 1a were almost
negligible after being heated for 48 hours (Table 1, entries 1-3).
An N-oxyl radical, 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO)
was also tested, but no desired product was detected (entry 4).
To our delight, product 3a was obtained in 63% yield when the
same amount of azobisisobutyronitrile (AIBN) was employed
With the optimized reaction condition in hand, we next explored
the compatibility of other imines that possess different functional
groups. As shown in Table 2, the substituents on the aldehyde
part apparently have an influence on the reactivity of imines
(Table 2, entries 1-8). Compared to the model substrate 1a,
imine 1b with an electron-deficient para-ester group is more
reactive and offers a slightly better yield (entries 1-2), while a
weakly electron-donating methyl group causes an opposite
effect. A strongly electron-donating para-methoxyl renders a
dramatic drop of the yield of 3d (entry 4). Halogen substituents
(
entry 5, d.r. = 1.2:1), indicating a carbon-centered radical could
be an effective initiator and this reaction probably goes through
a chain pathway as we proposed. The infertile outcome in the
absence of radical source demonstrates that it’s not a thermo-
induced process (entry 6). Nevertheless, temperature does play
a role. The reaction at 80 °C under otherwise the same condition
resulted in a slightly lower yield (55%, entry 7), and only 28%
product was isolated when the reaction was performed at 60 °C
Table 2. Substrate scope of the reaction between tetrahydrofuran and
imines.[
a]
(
entry 8). Additionally, we investigated the loadings of initiator for
this reaction. Interestingly, increasing the amount of AIBN to 20
structure
entry
substitution
product
3a
3b
3c
3d
3e
3f
Yield[b,c]
76%
82%
65%
40%
75%
78%
72%
88%
62%
47%
55%
68%
57%
83%
30%
68%
73%
78%
87%
1
1
2
3
4
5
6
7
8
9
Ar = Ph
Table 1. Initiator evaluation and condition optimization.[a]
1
Ar = 4-CO
2
MePh
1
Ar = 4-Me-Ph
1
Ar = 4-OMe-Ph
1
Ar = 4-F-Ph
Entry
Initiator
BPO
Loading
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
--
Temp[c]
100 ˚C
100 ˚C
100 ˚C
100 ˚C
100 ˚C
100 ˚C
80 ˚C
Yield of 3a[c,d]
<5%[e]
<5%[e]
<5%[e]
n.d.[e,f]
63%
1
Ar = 4-Cl-Ph
1
2
3
4
5
6
7
8
9
1
Ar = 3-Cl-Ph
3g
3h
3i
DTBP
TBHP
TEMPO
AIBN
None
AIBN
AIBN
AIBN
AIBN
AIBN
AIBN
1
Ar = 2,4-Cl
2
Ph
2
Ar = 4-Me-Ph
2
10
11
12
13
14
15
16
17
18
Ar = 4-OMe-Ph
3j
2
Ar = 4-Cl-Ph
3k
3l
n.d.[e,f]
55%
2
Ar = 3-Cl-Ph
10 mol%
10 mol%
20 mol%
5 mol%
2 mol%
1 mol%
2
Ar = 4-Br-Ph
3m
3n
3o
3p
3q
3r
60 ˚C
28%
2
Ar = 4-Me-Ph
100 ˚C
100 ˚C
100 ˚C
100 ˚C
53%
2
Ar = 2-Me-Ph
10
11
12
68%
2
Ar = 4-OMe-Ph
76%
2
Ar = 4-Cl-Ph
66%
2
Ar = 3-Cl-Ph
[
a] Reactions conditions: 0.5 mmol of
1
, initiator, 4.0 mL of THF, 48h.
2
[
b] The reaction was conducted in a sealed tube when the temperature
19
Ar = 4-Br-Ph
3s
was above 60 °C. [c] Isolated yield. [d] d.r. were mostly within 1:1 to
1
1
1
.3:1, which were determined by H NMR. [e] Determined by H NMR
[
a] Reactions were carried out using 0.5 mmol of 1, 2 mol% AIBN, in 4.0 mL
of the crude sample. [f] Not detected. BPO = benzoyl peroxide; DTBP =
di-tert-butyl peroxide; TBHP = tert-butyl hydro peroxide; TEMPO = 2,2,6,6-
tetramethylpiperidine-N-oxyl; AIBN = azobisisobutyronitrile.
of THF at 100 °C in a sealed tube for 48h. [b] Isolated yield. [c] d.r. were
mostly within 1:1 to 1.3:1, which were determined by 1H NMR, for details,
see SI. AIBN = azobisisobutyronitrile
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European Journal of Organic Chemistry
10.1002/ejoc.201701288
FULL PAPER
are perfectly tolerated that the yields of addition products 3e-3h
remain the same level (entries 5-8). Among them, the imine 1h
derived from 2,4-dichlorobenzaldehyde was converted to 3h with
the best yield (88%, entry 8). Next, we surveyed a couple of
imines prepared from benzaldehyde with different anilines, like
very low when “one-pot” procedure was applied with in-situ
9
formed imines. As H
2
O has strong O-H bonds and is less likely
to interact directly with radicals, these phenomena might be
caused by a small amount of free aldehyde or aniline hydrolyzed
from imine, which are not stable to radicals and could, therefore,
increase the chance of termination pathways. This assumption
was verified by control reactions with additional aldehyde or
aniline (eq. V). Additionally, kinetic isotope experiments were
performed in both parallel and competing fashions. The reaction
in THF-d8 only afford 8% of 3s-d8 under the same condition
after the same time (eq. VII versus entry 19 in table 2). When
the reaction was conducted in 1:1 mixture of THF/THF-d8, the
results are in good agreement (kH/kD = 11:1, eq. VIII). These
results demonstrate that the hydrogen atom transfer (HAT) from
THF may be the rate-determining step, which is different with the
previous case induced by oxygen radicals.5h Probably because
this HAT event is involved twice to afford the final product, the
KIE observed in this reaction is more significantly than a typical
one. “Tunneling effect”10 could also be an explanation since a
small hydrogen atom is involved. Furthermore, we discovered
that the reaction rate does not depend on the concentrations of
imines, (eq. VI) corroborating that the addition of THF-2-yl
radical B to imine is a faster step.
4-methyl, 4-methoxyl and 4-chloro. There is no obvious trend
observed between these imines and different substituents, most
of the reactions afford the desired product 3i-3m in moderate
yields (47% to 68%, entries 9-13).
Scheme 2. A few control experiments and Kinetic Isotope Effect Study.
Considering good results were achieved when the aldehyde part
is electron-deficient, a few substrates synthesized from 2,4-
dichlorobenzaldehyde with various anilines were thereby
inspected. To our delight, both electron-rich and electron-
2
deficient substrates (Ar ) participate the reaction smoothly and
furnish corresponding 1,2-amino ethers 3n, 3p-3s in satisfactory
yield (68%-87%, entries 14-19). A lower conversion and yield
were observed in the case of the substrate made by 2-methyl
aniline, which could probably be attributed to the steric
hindrance (3o).
Scheme 3. Proposed chain reaction mechanism.
Based on the obtaining results, a plausible radical chain
mechanism was proposed as depicted in scheme 3. First, the
homolysis of AIBN generates isobutyronitrile radical A, which
may then initiate the reaction in two different ways: i) H atom
was directly abstracted from THF by isobutyronitrile radical A,
resulting a THF-2-yl radical B; (eq. IX) or ii) isobutyronitrile
radicals A adds to imine 1a to generate an amine radical C,
which then abstract a H from THF to yield the same species B.
In order to gather evidences for
a mechanistic working
hypothesis of this efficient transformation, we designed and
carried out several sets of control experiments. Firstly, a small
amount of persistent radical, TEMPO, was found to inhibit the
reaction of imine 1h (eq. IV). Although no specific trapped
product was identified, this result strongly suggests the
involvement of radical intermediates. Secondly, one equivalent
of water suppresses the reaction, and the conversion was also
(
eq. X-XI) Because neither isobutyl nitrile 4, nor adduct 5 were
isolated, we currently cannot rule out any of these possibilities.
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European Journal of Organic Chemistry
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After the generation of THF-2-yl radical B, the rapid nucleophilic Experimental Section
addition to 1 furnishes the amine radical D as the major radical
species in this reaction, managing to abstract a hydrogen from
THF to propagate the chain. (eq. XII-XIII) The termination
process may happen between two radical species. When the
overall concentration of radicals is high, the chance of
termination increases, which may explain the lower yield with
high AIBN loading. As shown in equation XIV, the termination
phase may associate with radical D, radical B, trace amount of
oxygen or any other radicals.
General procedures for Initiator evaluation and condition
optimization: Imine 1a (90.5 mg, 0.5 mmol) and a corresponding initiator
(0.005 - 0.1 mmol) were added in an oven-dried sealable tube charged
with a stir bar. The tube was filled with freshly distilled tetrahydrofuran (4
mL) and sealed with a Teflon cap. The reaction was then heated-up to
the indicated temperature and kept stirring for 48 hours. After completion
of the reaction, the solvent was evaporated in vacuo, and then the
1H
residue was submitted for
NMR analysis with 1,3,5-
trimethoxybenzene as an internal standard. For those reactions with a
reasonable yield, isolated yield was obtained after purifying product 3a
through a silica gel flash column.
N-(Phenyl(tetrahydrofuran-2-yl)methyl)aniline (3a): compound 3a was
isolated through a flash column (PE: EtOAc from 20:1 to 10:1); Colorless
1
oil (Table 1, entry 11, 96 mg, 76% yield, d.r. = 1.2:1); H NMR (400 MHz,
CDCl
3
) (mixture of 2 diastereomers) δ 7.40 – 7.33 (m, 2H), 7.30 – 7.23
(m, 2H), 7.22 – 7.15 (m, 1H), 7.02 (t, J = 7.9 Hz, 2H), 6.60 (t, J = 7.3 Hz,
1
4
–
1
1
2
H), 6.50 (d, J = 7.9 Hz, 2H), 4.66 (s, 1H), 4.40 (d, J = 4.2 Hz, 0.45H),
.24 – 4.15 (m, 1H), 4.03 – 3.96 (m, 0.55H), 3.92 – 3.82 (m, 0.55H), 3.78
3.66 (m, 1.45H), 1.91 – 1.43 (m, 4H); 13C NMR (100 MHz, CDCl
) δ
3
48.0, 147.6, 141.9, 140.2, 129.1, 128.7, 128.4, 127.9, 127.5, 127.4,
17.6, 117.6, 114.0, 114.0, 83.1, 82.2, 68.9, 68.7, 62.3, 60.9, 29.0, 27.4,
+
5.9, 25.7; HRMS (ESI, m/z): calcd for C17
H
19NONa [M + Na] 276.1359,
found 276.1375.
General procedure for synthesis of compound 3b-3s: an imine (1b-
1
s) (0.5 mmol) and AIBN (1.6 mg, 0.01 mmol) were added in an
oven-dried sealable tube charged with a stir bar. The tube was
filled with freshly distilled tetrahydrofuran (4 mL) and sealed with
a Teflon cap. The sealed tube was then heated-up to 100 °C and
kept stirring for 48 hours. After completion of the reaction, the
solvent was evaporated in vacuo, and the residue was then
purified through a silica gel flash column to give the corresponding
addition product 3b-3s.
Scheme 4. Reactions of other cyclic ethers and electrophiles.
At last, we put some preliminary efforts to examine the
compatibility of other cyclic ethers and electrophiles with this
method. The results are as described in Scheme 4. 2-Methyl
THF 6 shows excellent reactivity, affording a mixture of two
regio-isomers 7 and 8 with a moderate ratio. (eq. XV) The
reaction of 1,3-dioxolane 9 suffers a low conversion and provide
the product 10 in only 30% yield. (eq. XVI) On the other hand,
beside imines, dimethyl fumarate 11 can also serve as the
electrophile, the desired product 12 was obtained in a decent
yield, (eq. XVII) corroborating that an electron-deficient
carboradical is also capable of H atom abstraction from THF,
similar to what we have mentioned in the mechanistic part. (eq.
IX)
Methyl 4-((phenylamino)(tetrahydrofuran-2-yl)methyl)benzoate (3b):
Compound 3b was prepared form 1b according to the general procedure,
and isolated through a flash column (PE: EtOAc from 15:1 to 10:1);
Colorless oil (127 mg, 82% yield, d.r. = 1:1); H NMR (400 MHz, CDCl3)
(mixture of 2 diastereomers) δ 8.03 – 7.92 (m, 2H), 7.54 – 7.43 (m, 2H),
7.10 – 6.98 (m, 2H), 6.69 – 6.58 (m, 1H), 6.49 (d, J = 8.2 Hz, 2H), 4.63 (s,
1
1
0
1
1
1
2
3
H), 4.45 (d, J = 4.4 Hz, 0.5H), 4.29 (d, J = 5.9 Hz, 0.5H), 4.27 – 4.18 (m,
.5H), 4.06 – 3.97 (m, 0.5H), 3.94 – 3.84 (m, 3.5H), 3.83 – 3.70 (m, 1.5H),
.98 – 1.46 (m, 4H); 13C NMR (100 MHz, CDCl
) δ 167.0, 167.0, 147.4,
3
47.3, 147.0, 145.8, 130.0, 129.6, 129.4, 129.3, 129.1, 129.1, 128.0,
27.3, 117.8, 113.9, 113.9, 82.6, 81.7, 68.8, 68.7, 61.9, 60.8, 52.1, 28.8,
7.5, 25.8, 25.5; HRMS (ESI, m/z): calcd for C19
34.1414, found 334.1426.
H21NO
3
Na [M + Na]+
Conclusions
N-((Tetrahydrofuran-2-yl)(p-tolyl)methyl)aniline (3c): Compound 3c
was prepared form 1c according to the general procedure, and isolated
through a flash column (PE: EtOAc from 20:1 to 10:1); Pale yellow oil (86
In summary, we have developed an efficient and practical
method for the direct functionalization of THF and other cyclic
ethers with various imines by using only 2 mol% of AIBN as the
initiator. Considering the solvent could be easily recycled by
distillation, nothing much is wasted in this reaction and no
oxidants, metal salt, delicate catalyst or any irradiation was
required. Different imines could be well tolerated, transformed
into the corresponding addition products in moderate to good
yields. According to the experimental results, the reaction is
proposed to undergo a radical chain pathway and the efficiency
of this chain is critical to the reaction outcomes. Further studies
on the synthetic applications of this method are currently
ongoing in our laboratory.
mg, 65% yield, d.r. = 1.2:1); 1H NMR (400 MHz, CDCl
diastereomers) δ 7.28 (d, J = 7.9 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 7.13 –
3
) (mixture of 2
7
8
4
.06 (m, 2H), 7.03 (t, J = 7.8 Hz, 2H), 6.60 (t, J = 7.3 Hz, 1H), 6.52 (d, J =
.0 Hz, 2H), 4.58 (s, 1H), 4.37 (d, J = 4.3 Hz, 0.55H), 4.23 – 4.13 (m, 1H),
.02 – 3.96 (m,0.55H), 3.92 – 3.85 (m, 0.55H), 3.80 – 3.69 (m, 1.45H),
2.28 (s, 1.65H), 2.28 (s, 1.35H), 1.93 – 1.49 (m, 4H); 13C NMR (100 MHz,
CDCl ) δ 148.0, 147.6, 138.7, 137.1, 137.0, 136.8, 129.4, 129.1, 129.1,
27.7, 127.2, 117.5, 114.0, 83.2, 82.2, 68.8, 68.6, 62.0, 60.7, 28.9, 27.4,
3
1
2
2
5.8, 25.7, 21.2; HRMS (ESI, m/z): calcd for C18
90.1515, found 290.1533.
H
21NONa [M + Na]+
N-((4-Methoxyphenyl)(tetrahydrofuran-2-yl)methyl)aniline
(3d):
Compound 3d was prepared form 1d according to the general procedure,
and isolated through a flash column (PE: EtOAc from 20:1 to 10:1);
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European Journal of Organic Chemistry
10.1002/ejoc.201701288
FULL PAPER
Yellow oil (56 mg, 40% yield, d.r. = 1:1); 1H NMR (400 MHz, CDCl
4-Methyl-N-(phenyl(tetrahydrofuran-2-yl)methyl)aniline
(3i):
3
)
(mixture of 2 diastereomers) δ 7.30 (dd, J = 14.0, 8.3 Hz, 2H), 7.05 (dd, J
Compound 3i was prepared form 1i according to the general procedure,
=
6
4
6
1
1
1
2
8.3, 7.3 Hz, 2H), 6.83 (t, J = 8.1 Hz, 2H), 6.62 (td, J = 7.3, 3.3 Hz, 1H),
.52 (dd, J = 8.1, 1.6 Hz, 2H), 4.67 (s, 1H), 4.36 (d, J = 4.2 Hz, 0.5H),
.21 (dd, J = 11.0, 6.7 Hz, 0.5H), 4.16 (d, J = 6.7 Hz, 0.5H), 4.00 (q, J =
.7 Hz, 0.5H), 3.90 (dd, J = 14.7, 7.0 Hz, 0.5H), 3.82 – 3.69 (m, 4.5H),
and isolated through a flash column (PE: EtOAc from 20:1 to 10:1); Pale
yellow oil (82 mg, 62% yield, d.r. = 1:1); 1H NMR (400 MHz, CDCl
3
)
(mixture of 2 diastereomers) δ 7.55 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.5
Hz, 1H), 7.46 – 7.38(m, 2H), 7.37 – 7.31 (m, 1H), 7.01 (d, J = 8.4 Hz, 2H),
6.60 (m, 2H), 4.54 (d, J = 4.3 Hz, 0.5H), 4.47 (s, 1H), 4.41 – 4.34 (m,
0.5H), 4.33 (d, J = 6.5 Hz, 0.5H), 4.17 (q, J = 6.5 Hz, 0.5H), 4.07 – 4.00
.96 – 1.48 (m, 4H); 13C NMR (100MHz, CDCl
3
) δ 158.9, 158.8, 147.8,
47.4, 133.5, 132.0, 129.0, 128.8, 128.3, 117.5, 117.5, 114.1, 114.0,
13.7, 83.1, 82.2, 68.8, 68.6, 61.7, 60.3, 55.2, 55.2, 28.8, 27.4, 25.8,
(m, 0.5H), 3.95 – 3.83 (m, 1.5H), 2.30 (s, 3H), 2.08 – 1.63 (m, 4H); 13
NMR (100 MHz, CDCl ) δ 145.5, 145.2, 141.8, 140.3, 129.6, 128.7,
128.4, 127.9, 127.4, 127.4, 127.3, 126.8, 114.3, 114.3, 83.1, 82.2, 68.9,
C
5.6; HRMS (ESI, m/z): calcd for C18
H
21NO
2
Na [M + Na]+ 306.1465,
3
found 306.1483.
6
C
8.7, 62.7, 61.3, 28.9, 27.4, 25.8, 25.7, 20.5; HRMS (ESI, m/z): calcd for
+
18
H21NONa [M + Na] 290.1515, found 290.1529.
N-((4-Fluorophenyl)(tetrahydrofuran-2-yl)methyl)aniline
(3e):
Compound 3e was prepared form 1e according to the general procedure,
and isolated through a flash column (PE: EtOAc from 20:1 to 10:1); Pale
4-Methoxy-N-(phenyl(tetrahydrofuran-2-yl)methyl)aniline
Compound 3j was prepared form 1j according to the general procedure,
(3j):
yellow oil (101 mg, 75% yield, d.r. = 1.2:1); 1H NMR (400 MHz, CDCl
3
)
(
mixture of 2 diastereomers) δ 7.37 – 7.30 (m, 2H), 7.07 – 7.03 (m, 2H),
and isolated through a flash column (PE: EtOAc from 20:1 to 10:1);
7
4
3
4
.0 – 6.94 (m, 2H), 6.65 – 6.61(m, 1H), 6.55 – 6.45 (m, 2H), 4.60 (s, 1H),
.37 (d, J = 4.2 Hz, 0.45H), 4.19 (m, 1H), 3.98 (q, J = 6.6 Hz, 0.55H),
.89 (dt, J = 13.7, 6.6 Hz, 0.55H), 3.81 – 3.70 (m, 1.45H), 1.91 – 1.43 (m,
Yellow oil (66 mg, 47% yield, d.r. = 1:1); 1H NMR (400 MHz, CDCl
3
)
(mixture of 2 diastereomers) δ 7.44 – 7.18 (m, 5H), 6.65 (d, J = 8.8 Hz,
2H), 6.48 (d, J = 8.8 Hz, 2H), 4.47 (s, 1H), 4.38 (d, J = 4.2 Hz, 0.5H),
4.26 – 4.19 (m, 0.5H), 4.12 (d, J = 6.8 Hz, 0.5H), 4.06 – 3.98 (m, 0.5H),
3.95 – 3.86 (m, 1H), 3.86 – 3.71 (m, 1.5H), 3.66 (s, 3H),1.98 – 1.52 (m,
H); 13C NMR (100 MHz, CDCl
3
) δ 163.4, 160.9, 147.6, 147.2, 136.63 (d,
J = 162.1 Hz), 136.60 (d, J = 162.1 Hz), 129.39 (d, J = 8.0 Hz),129.1,
1
1
2
29.1, 128.79 (d, J = 8.0 Hz), 117.7, 117.7, 115.53 (d, J = 21.3 Hz),
15.23 (d, J = 21.3 Hz), 114.0, 114.0, 83.0, 82.0, 68.8, 68.7, 61.5, 60.3,
4H); 13C NMR (100 MHz, CDCl
3
) δ 152.1, 152.1, 142.0, 141.8, 141.6,
140.3, 128.6, 128.3, 127.7, 127.4, 127.2, 115.3, 115.2, 114.7, 114.6,
83.0, 82.2, 68.8, 68.5, 63.3, 61.6, 55.7, 55.7, 28.8, 27.1, 25.7, 25.6;
8.8, 27.5, 25.8, 25.6; HRMS (ESI, m/z): calcd for C17
H18FNONa [M +
+
H21NO
2
Na [M + Na]+ 306.1465, found
Na] 294.1265, found 294.1273.
HRMS (ESI, m/z): calcd for C18
06.1473.
3
N-((4-Chlorophenyl)(tetrahydrofuran-2-yl)methyl)aniline
(3f):
Compound 3f was prepared form 1f according to the general procedure,
4-Chloro-N-(phenyl(tetrahydrofuran-2-yl)methyl)aniline
(3k):
and isolated through a flash column (PE: EtOAc from 20:1 to 10:1);
Compound 3k was prepared form 1k according to the general procedure,
Colorless oil (112 mg, 78% yield, d.r. = 1:1); 1H NMR (400 MHz, CDCl
and isolated through a flash column (PE: EtOAc from 20:1 to 10:1); Pale
3
)
(mixture of 2 diastereomers) δ 7.36 – 7.21 (m, 4H), 7.05 (t, J = 7.4 Hz,
yellow oil (79 mg, 55% yield, d.r. = 1:1); 1H NMR (400 MHz, CDCl
3
)
2
1
1
H), 6.63 (td, J = 7.3, 2.7 Hz, 1H), 6.48 (dd, J = 8.4, 1.9 Hz, 2H), 4.60 (s,
H), 4.36 (d, J = 4.3 Hz, 1H), 4.23 – 4.13 (m, 0.5H), 3.97 (q, J = 6.6 Hz,
H), 3.88 (dt, J = 13.6, 6.6 Hz, 0.5H), 3.80 – 3.67 (m, 1.5H), 1.94 – 1.48
(mixture of 2 diastereomers) δ 7.42 – 7.19 (m, 5H), 6.98 (d, J = 8.7 Hz,
2H), 6.43 (d, J = 8.7 Hz, 2H), 4.73 (s, 1H), 4.38 (d, J = 4.0 Hz, 0.5H),
4.27 – 4.21 (m, 0.5H), 4.15 (d, J = 6.5 Hz, 0.5H), 4.04 – 3.97 (m, 0.5H),
(
m, 4H); 13C NMR (100 MHz, CDCl
3
) δ 147.5, 147.1, 140.4, 138.8, 133.1,
3.95 – 3.88 (m, 0.5H), 3.83 – 3.70 (m, 1.5H), 1.96 – 1.49 (m, 4H); 13
NMR (100 MHz, CDCl ) δ 146.3, 146.0, 141.1, 139.5, 128.8, 128.7,
C
133.0, 129.3, 129.2, 129.1, 128.9, 128.7, 128.6, 117.8, 114.0, 82.8, 81.8,
3
6
C
8.9, 68.7, 61.5, 60.4, 28.8, 27.5, 25.8, 25.6; HRMS (ESI, m/z): calcd for
128.4, 127.8, 127.6, 127.4, 127.2, 122.1, 115.1, 115.0, 82.9, 81.9, 76.8,
+
17
H18ClNONa [M + Na] 310.0969, found 310.0984.
68.8, 68.6, 62.4, 60.9, 28.9, 27.2, 25.7, 25.5; HRMS (ESI, m/z): calcd for
+
C
17
H
18ClNONa [M + Na] 310.0969, found 310.0987.
N-((3-Chlorophenyl)(tetrahydrofuran-2-yl)methyl)aniline
(3g):
Compound 3g was prepared form 1g according to the general procedure,
3-Chloro-N-(phenyl(tetrahydrofuran-2-yl)methyl)aniline
(3l):
and isolated through a flash column (PE: EtOAc from 20:1 to 10:1); Pale
Compound 3l was prepared form 1l according to the general procedure,
yellow oil (103 mg, 72% yield, d.r. = 1:1); 1H NMR (400 MHz, CDCl
and isolated through a flash column (PE: EtOAc from 20:1 to 10:1);
3
)
1
(
(
(
mixture of 2 diastereomers) δ 7.41 (s, 0.5H), 7.38 (s, 0.5H), 7.32 – 7.25
m, 1H), 7.25 – 7.19 (m, 2H), 7.08 (dd, J = 8.4, 7.5 Hz, 2H), 6.72 – 6.60
m, 1H), 6.55 – 6.47 (m, 2H), 4.72 (s, 1H), 4.37 (d, J = 4.3 Hz, 0.5H),
Colorless oil (97 mg, 68% yield, d.r. = 1.1:1); H NMR (400 MHz, CDCl
3
)
(mixture of 2 diastereomers) δ 7.41 – 7.20 (m, 5H), 6.93 (t, J = 8.0 Hz,
1H), 6.58 (d, J = 7.8 Hz, 1H), 6.52 – 6.49 (m, 1H), 6.40 – 6.35 (m, 1H),
4.79 (s, 1H), 4.38 (d, J = 4.1 Hz, 0.47H), 4.27 – 4.20 (m, 0.47H), 4.18 (d,
J = 6.3 Hz, 0.53H), 4.04 – 3.97 (m, 0.53H), 3.95 – 3.88 (m, 0.53H), 3.83
4
3
1
1
6
.21 (m, 1H), 4.01 (q, J = 6.6 Hz, 0.5H), 3.91 (dd, J = 14.5, 7.0 Hz, 0.5H),
.85 – 3.71 (m, 1.5H), 1.99 – 1.55 (m, 4H); 13C NMR (100 MHz, CDCl
3
) δ
47.3, 146.9, 144.0, 142.5, 134.6, 134.3, 129.9, 129.6, 129.1, 129.1,
27.9, 127.7, 127.6, 127.4, 126.1, 125.5, 117.9, 113.9, 82.7, 81.8, 68.9,
– 3.67 (m, 1.47H), 1.99 – 1.46 (m, 4H); 13C NMR (100 MHz, CDCl
3
) δ
149.0, 148.6, 141.1, 139.4, 134.7, 130.0, 128.8, 128.4, 127.8, 127.6,
127.5, 127.1, 117.4, 113.7, 112.0, 82.9, 81.8, 68.8, 68.7, 62.0, 60.7, 28.9,
8.7, 61.7, 60.6, 28.8, 27.5, 25.8, 25.6; HRMS (ESI, m/z): calcd for
+
H
18ClNONa [M + Na]+
C
17
H
18ClNONa [M + Na] 310.0969, found 310.0986.
27.3, 25.7, 25.5; HRMS (ESI, m/z): calcd for C17
10.0969, found 310.0983.
3
N-((2,4-Dichlorophenyl)(tetrahydrofuran-2-yl)methyl)aniline
(3h):
Compound 3h was prepared form 1h according to the general procedure,
4-Bromo-N-(phenyl(tetrahydrofuran-2-yl)methyl)aniline
(3m):
and isolated through a flash column (PE: EtOAc from 20:1 to 10:1);
Compound 3m was prepared form 1m according to the general
procedure, and isolated through a flash column (PE: EtOAc from 20:1 to
10:1); Yellow oil (94 mg, 57% yield, d.r. = 1.2:1); 1H NMR (400 MHz,
1
Colorless oil (141 mg, 88% yield, d.r. = 1.4:1); H NMR (400 MHz, CDCl
3
)
(mixture of 2 diastereomers) δ 7.47 – 7.34 (m, 2H), 7.15 – 7.11 (m, 1H),
7.10 – 7.04 (m, 2H), 6.66 – 6.62 (m, 1H), 6.47 (d, J = 7.8 Hz, 2H), 4.96 (d,
3
CDCl ) (mixture of 2 diastereomers) δ 7.40 – 7.19 (m, 5H), 7.11 (d, J =
J = 4.1 Hz, 0.6H), 4.82 (d, J = 4.3 Hz, 0.42H), 4.64 (s, 1H), 4.32 – 4.28
m, 0.6H), 4.08 – 4.04(m, 0.42H), 4.00 – 3.94 (m, 0.42H), 3.80 – 3.69 (m,
8.7 Hz, 2H), 6.39 (d, J = 8.7 Hz, 2H), 4.74 (s, 1H), 4.37 (d, J = 4.0 Hz,
0.45H), 4.26 – 4.20 (m, 0.45H), 4.15 (d, J = 6.5 Hz, 0.55H), 4.03-3.97 (m,
0.55H), 3.94 – 3.88 (m, 0.55H), 3.83 – 3.70 (m, 1.45H), 1.99 – 1.46 (m,
(
1
1
1
6
.6H), 2.02 – 1.53 (m, 4H); 13C NMR (100 MHz, CDCl
) δ 146.7, 146.5,
3
37.9, 136.2, 134.7, 133.7, 133.5, 133.5, 130.5, 129.5, 129.3, 129.3,
29.2, 129.0, 127.7, 127.5, 118.0, 117.9, 113.6, 113.5, 81.7, 80.6, 69.0,
4H); 13C NMR (100 MHz, CDCl
3
) δ 146.7, 146.4, 141.0, 139.4, 131.7,
128.7, 128.4, 127.8, 127.6, 127.2, 115.6, 109.2, 82.9, 81.8, 68.8, 68.6,
8.7, 56.0, 28.5, 27.5, 25.9, 25.8; HRMS (ESI, m/z): calcd for
62.3, 60.8, 28.9, 27.2, 25.7, 25.5; HRMS (ESI, m/z): calcd for
+
+
17
C H17Cl
2
NONa [M + Na] 344.0579, found 344.0582.
C
17
H
18BrNONa [M + Na] 354.0464, found 354.0479.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701288
FULL PAPER
N-((2,4-Dichlorophenyl)(tetrahydrofuran-2-yl)methyl)-4-methylaniline
117.7, 113.5, 113.4, 111.4, 81.5, 80.4, 68.9, 68.7, 55.8, 55.7, 28.5, 27.4,
25.8; HRMS (ESI, m/z):calcd for C17
found 378.0206.
(
3n): Compound 3n was prepared form 1n according to the general
H16Cl
3
NONa [M + Na]+ 378.0190,
procedure, and isolated through a flash column (PE: EtOAc from 20:1 to
1
10:1); Pale yellow oil (139 mg, 83% yield, d.r. = 1:1); H NMR (400 MHz,
CDCl
3
) (mixture of 2 diastereomers) δ 7.59 – 7.43 (m, 2H), 7.28 – 7.22 m,
4
(
-Bromo-N-((2,4-dichlorophenyl)(tetrahydrofuran-2-yl)methyl)aniline
3s) : Compound 3s was prepared form 1s according to the general
procedure, and isolated through a flash column (PE: EtOAc from 20:1 to
0:1); Yellow oil (173 mg, 87% yield, d.r. = 1.3:1); 1H NMR (400 MHz,
CDCl ) (mixture of 2 diastereomers) δ 7.40 – 7.31 (m, 2H), 7.17 – 7.10
m, 3H), 6.37 – 6.30 (m, 2H), 4.91 (d, J = 3.9 Hz, 0.57H), 4.77 (d, J = 4.4
Hz, 0.43H), 4.35 – 4.25 (m, 0.57H), 4.07 – 4.00(m, 0.43H), 3.99 – 3.90(m,
.43H), 3.79 – 3.65 (m, 1.57H), 2.01 – 1.51 (m, 4H); 13C NMR (100 MHz,
CDCl ) δ 145.8, 145.6, 137.3, 135.6, 134.7, 133.7, 133.6, 132.0, 131.9,
30.3, 129.4, 129.4, 129.0, 127.8, 127.6, 115.1, 115.1, 109.6, 109.5,
1
0
–
1
1
1
8
H), 7.03 – 6.98 (m, 1H), 6.53 (d, J = 7.8 Hz, 2H), 5.07 (d, J = 3.5 Hz,
.5H), 4.93 (d, J = 3.8 Hz, 0.5H), 4.52 (s, 1H), 4.45 – 4.36 (m, 0.5H), 4.20
4.15(m, 0.5H), 4.10 – 4.06 (m, 0.5H), 3.88 – 3.84 (m, 1.5H), 2.29 (s,
.5H), 2.28 (s, 1.5H), 2.13 –1.73 (m, 4H); 13C NMR (100 MHz, CDCl
44.5, 144.3, 138.1, 136.4, 134.7, 133.8, 133.5, 133.4, 130.5, 129.8,
29.8, 129.6, 129.3, 129.0, 127.7, 127.6, 127.1, 127.0, 113.8, 113.7,
1.8, 80.7, 68.9, 68.8, 56.3, 28.5, 27.5, 25.9, 25.9, 20.5; HRMS (ESI,
1
3
) δ
3
(
0
+
m/z): calcd for C18
H19Cl
2
NONa [M + Na] 358.0736, found 358.0754.
3
1
N-((2,4-Dichlorophenyl)(tetrahydrofuran-2-yl)methyl)-2-methylaniline
3o): Compound 3o was prepared form 1o according to the general
procedure, and isolated through a flash column (PE: EtOAc from 20:1 to
0:1); Pale yellow oil (50 mg, 30% yield, d.r. = 1:1); 1H NMR (400 MHz,
CDCl ) (mixture of 2 diastereomers) δ 7.35 – 7.24 (m ,2H), 7.09 – 7.02
m, 1H), 6.95 (t, J = 7.8 Hz, 1H), 6.86 (t, J = 7.7 Hz, 1H), 6.57 – 6.48 (m,
81.6, 80.4, 68.9, 68.7, 56.1, 55.9, 28.5, 27.4, 25.8, 25.8; HRMS (ESI,
+
(
m/z): calcd for C17H16BrCl
2
NONa [M + Na] 421.9685, found 421.9692.
1
Reaction of 2-methyl-tetrahydrofuran with imine: Imine 1s (0.5 mmol)
and AIBN (1.6 mg, 0.01 mmol) were added in an oven-dried sealable
tube charged with a stir bar. The tube was then filled with freshly distilled
3
(
1H), 6.18 – 6.08 (m, 1H), 4.92 (d, J = 4.0 Hz, 0.5H), 4.54 (s, 1H), 4.77 (d,
2-methyl tetrahydrofuran (4 mL) and sealed with a Teflon cap. The
J = 4.0 Hz, 0.5H), 4.34 – 4.23 (m, 0.5H), 4.08 – 4.01 (m, 0.5H), 3.95 –
reaction was then heated-up to 100 °C and kept stirring for 48 hours.
After completion of the reaction, the solvent was evaporated in vacuo to
afford the crude products. Compounds 7 and 8 were isolated through a
silica gel flash column (PE: EtOAc from 20:1 to 10:1) as a mixture of
regio-isomers and diastereomers. Colorless oil (187 mg, 90% overall
3
–
1
1
6
.87 (m, 0.5H), 3.78 – 3.62 (m, 1.5H), 2.17 (s, 1.5H), 2.16 (s, 1.5H), 1.97
1.50 (m, 4H); 13C NMR (100 MHz, CDCl
3
) δ 143.5, 143.4, 136.8, 135.1,
33.5, 132.6, 132.4, 132.3, 129.2, 129.0, 129.0, 128.2, 127.9, 126.6,
26.4, 126.1, 126.0, 121.3, 121.3, 116.5, 116.4, 109.9, 109.7, 80.7, 79.6,
8.0, 67.7, 54.9, 54.9, 27.6, 26.3, 25.0, 24.8, 16.5; HRMS (ESI, m/z):
1
yield) and the ratio was assigned by H NMR analysis. As region-isomers
+
2
calcd for C18H19Cl NONa [M + Na] 358.0736, found 358.0752.
7
and 8 (each as a pair of diastereomers) are inseparable on column, so
the characterization data are reported in a mixture form. HRMS (ESI,
+
N-((2,4-Dichlorophenyl)(tetrahydrofuran-2-yl)methyl)-4-
m/z): calcd for C18H19BrCl
2
NO
5
Na [M + H] 414.0022, found 414.0020.
methoxyaniline (3p) : Compound 3p was prepared form 1p according to
the general procedure, and isolated through a flash column (PE: EtOAc
from 20:1 to 10:1); Yellow oil (119 mg, 68% yield, d.r. = 1:1); 1H NMR
For details of NMR data and analysis, see supporting information.
Reaction of 1,3-Dioxolane with Imine: Imine 1h (0.5 mmol) and AIBN
(
7
400 MHz, CDCl
.23 – 7.10 (m, 1H), 6.70 – 6.64 (m, 2H), 6.42 (d, J = 8.9 Hz, 2H), 4.91 (d,
J = 4.1 Hz, 0.5H), 4.75 (d, J = 4.8 Hz, 0.5H), 4.32 – 4.22 (m, 0.5H), 4.07
3
) (mixture of 2 diastereomers) δ 7.45 – 7.35 (m, 2H),
(
1.6 mg, 0.01 mmol) were added in an oven-dried sealable tube charged
with a stir bar. The tube was then filled with freshly distilled 1,3-dioxolane
4 mL) and sealed with a Teflon cap. The reaction was then heated-up to
00 °C and kept stirring. After even 48 hours, 1h was not consumed, the
(
1
–
1
1
1
6
3.93 (m, 0.5H), 3.99 – 3.92 (m, 0.5H), 3.80 – 3.70 (m, 1.5H), 3.66 (s,
.5H), 3.65 (s, 1.5H), 2.04 – 1.55 (m, 4H); 13C NMR (100 MHz, CDCl
3
) δ
reaction was stopped and the solvent was evaporated in vacuo to afford
the crude product 10 as a single regio-isomer.
52.3, 152.3, 141.0, 140.7, 138.1, 136.4, 134.7, 133.8, 133.4, 133.4,
30.4, 129.6, 129.3, 129.0, 127.7, 127.5, 114.9, 114.8, 114.6, 81.9, 80.6,
8.9, 68.7, 56.8, 56.7, 55.7, 55.7, 28.4, 27.3, 25.9, 25.8; HRMS (ESI,
N-((2,4-Dichlorophenyl)(1,3-dioxolan-2-yl)methyl)aniline
Compound 10 was isolated through a flash column (PE: EtOAc from 20:1
to 10:1); Colorless oil (48 mg, 30% yield); 1H NMR (400 MHz, CDCl
) δ
.45 – 7.39 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 7.21 – 7.05 (m, 2H), 6.67 (t,
J = 7.4 Hz, 1H), 6.49 (d, J = 7.8 Hz, 2H), 5.16 (m, 2H), 4.49 (s, 1H), 4.04
(10):
+
m/z): calcd for C18
H19Cl
2
NONa [M + Na] 374.0685, found 374.0697.
3
4
(
-Chloro-N-((2,4-dichlorophenyl)(tetrahydrofuran-2-yl)methyl)aniline
3q) : Compound 3q was prepared form 1q according to the general
procedure, and isolated through a flash column (PE: EtOAc from 20:1 to
0:1); Colorless oil (129 mg, 73% yield, d.r. = 1.2:1); 1H NMR (400 MHz,
CDCl ) (mixture of 2 diastereomers) δ 7.36 – 7.26 (m, 2H), 7.12 – 7.05
m, 1H), 6.97 – 6.91(m, 2H), 6.33 (d, J = 8.5 Hz, 2H), 4.85 (d, J = 3.8 Hz,
7
3.81 (m, 4H); 13C NMR (100 MHz, CDCl
–
1
3
) δ 146.2, 134.9, 134.5, 133.9,
30.0, 129.3, 129.3, 127.5, 118.2, 113.5, 103.8, 65.6, 65.4, 55.6; HRMS
Na]+ 346.0372, found
NO Na [M
1
3
(ESI, m/z): calcd for
C
16
H15Cl
2
2
+
(
3
46.0387.
0.55H), 4.70 (d, J = 4.3 Hz, 0.45H), 4.28 – 4.21 (m, 0.55H), 4.03 – 3.95
(
(
1
1
m, 0.45H), 3.94 – 3.87 (m, 0.45H), 3.76 – 3.61 (m, 1.55H), 1.98 – 1.45
m, 4H); 13C NMR (100 MHz, CDCl
) δ 145.1, 144.9, 137.2, 135.5, 134.7,
33.7, 133.7, 130.3, 129.4, 129.3, 129.1, 129.0, 127.7, 127.6, 122.7,
Reaction of tetrahydrofuran to dimethyl fumarate: Dimethyl fumarate
1 (0.5 mmol) and AIBN (1.6 mg, 0.01 mmol) were added in an oven-
3
1
dried sealable tube charged with a stir bar. The tube was then filled with
freshly distilled tetrahydrofuran (4 mL) and sealed with a Teflon cap. The
reaction was then heated-up to 100 °C and kept stirring for 48 hours.
After completion of the reaction, the solvent was evaporated in vacuo to
afford the crude product 12 as a pair of diastereomers.
14.8, 114.7, 81.6, 80.4, 68.9, 68.7, 56.3, 56.1, 28.4, 27.3, 25.8, 25.7;
+
HRMS (ESI, m/z): calcd for C17
3
H16Cl
3
NONa [M + Na] 378.0190, found
78.0202.
3-Chloro-N-((2,4-dichlorophenyl)(tetrahydrofuran-2-yl)methyl)aniline
(
3r) : Compound 3r was prepared form 1r according to the general
procedure, and isolated through a flash column (PE: EtOAc from 20:1 to
0:1); Pale yellow oil (138 mg, 78% yield, d.r. = 1.2:1); 1H NMR (400
MHz, CDCl ) (mixture of 2 diastereomers) δ 7.35 – 7.24 (m, 2H), 7.11 –
.05 (m, 1H), 6.93 – 6.84 (m, 1H), 6.56 – 6.48 (m, 1H), 6.42 – 6.38 (m,
H), 6.23 (d, J = 8.2 Hz, 1H), 4.85 (d, J = 3.9 Hz, 0.55H), 4.71 (d, J = 4.2
Dimethyl 2-(tetrahydrofuran-2-yl)succinate (12): Compound 12 was
prepared with the standard procedure and isolated through a flash
column (PE: EtOAc from 20:1 to 10:1); Colorless oil (48 mg, 56% yield,
1
3
d.r. = 1.5:1); 1H NMR (400 MHz, CDCl
3
) (mixture of 2 diastereomers) δ
.06 – 3.85 (m, 1H), 3.86 – 3.55 (m, 8H), 3.01 (m, 0.4H), 2.84 (m, 0.6H),
.78 – 2.58 (m, 0.6H), 2.41 (dd, J = 16.6, 4.3 Hz, 0.4H), 2.01 – 1.48 (m,
H); 13C NMR (100 MHz, CDCl
) δ 173.3, 173.3, 172.6, 172.2, 78.8, 78.7,
8.4, 68.1, 52.0, 51.8, 51.8, 46.6, 46.0, 33.2, 32.5, 29.6, 28.6, 25.6, 25.6;
Na [M + Na]+ 239.0890, found
7
1
4
2
5
6
Hz, 0.45H), 4.22 (m, 0.55H), 4.00 – 3.93 (m, 0.45H), 3.93 – 3.86 (m,
.45H), 3.72 – 3.59 (m, 1.55H), 1.95 – 1.46 (m, 4H); 13C NMR (100 MHz,
CDCl ) δ 148.0, 147.7, 137.3, 135.5, 134.9, 134.9, 134.7, 133.8, 133.7,
33.6, 130.3, 130.3, 130.2, 129.4, 129.3, 129.0, 127.7, 127.6, 117.8,
3
0
3
HRMS (ESI, m/z): calcd for C10
16 5
H O
1
239.0801.
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European Journal of Organic Chemistry
10.1002/ejoc.201701288
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For more detailed information about mechanistic control experiments,
kinetic isotope effect study and NMR spectra, see supporting information.
W.-B. Hu, Y.-G. Luan, S. Dong, J.-J. Zhang, Y.-P. Bai, RSC Adv. 2017,
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European Journal of Organic Chemistry
10.1002/ejoc.201701288
FULL PAPER
Layout 2:
FULL PAPER
Radical Addition*
Haipeng Zeng, Dengfu Lu,* and Yuefa
Gong*
Page No. – Page No.
Direct Metal-free C-H
Here we present an efficient and practical method to functionalize cyclic ethers with
imines for the synthesis of 1,2-amino ethers. Different with previous works, this
reaction goes through a radical chain process thus no stoichiometric amount of
radical reagent or oxidant was required.
Functionalization of Cyclic Ethers
with Schiff Bases through an
Azobisisobutyronitrile (AIBN) Initiated
Radical Chain Process
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