Synthesis of Functionalized Indolines and Dihydrobenzofurans by Iron and Copper Catalyzed Aryl C-N and C-O Bond Formation

Article abstract of DOI:10.1021/acs.joc.8b02888

A simple and effective one-pot, two-step intramolecular aryl C-N and C-O bond forming process for the preparation of a wide range of benzo-fused heterocyclic scaffolds using iron and copper catalysis is described. Activated aryl rings were subjected to a highly regioselective, iron(III) triflimide-catalyzed iodination, followed by a copper(I)-catalyzed intramolecular N-or O-arylation step leading to indolines, dihydrobenzofurans, and six-membered analogues. The general applicability and functional group tolerance of this method were exemplified by the total synthesis of the neolignan natural product, (+)-obtusafuran. DFT calculations using Fukui functions were also performed, providing a molecular orbital rationale for the highly regioselective arene iodination process.

Full text of DOI:10.1021/acs.joc.8b02888

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Article
Synthesis of Functionalized Indolines and Dihydrobenzofurans
by Iron and Copper Catalyzed Aryl C-N and C-O Bond Formation
Martyn C. Henry, Hans Martin Senn, and Andrew Sutherland
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02888 • Publication Date (Web): 06 Dec 2018
Downloaded from http://pubs.acs.org on December 7, 2018
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Synthesis of Functionalized Indolines and
Dihydrobenzofurans by Iron and Copper Catalyzed Aryl
C-N and C-O Bond Formation
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Martyn C. Henry, Hans Martin Senn and Andrew Sutherland*
WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow,
Glasgow G12 8QQ, United Kingdom.
Andrew.Sutherland@glasgow.ac.uk
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
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Table of Contents Graphic:
Fe(III) Cu(I)
n
X
H
DG
n
DG
H
30 examples
up to 93%
X
X = O or NTs
n = 0 or 1
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AcHN
Cl
MeO
MeO
O
N
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H
Ts
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HO
O
O
Ph
O
O
MeO
+)-obtusafuran
(
Abstract: A simple and effective one-pot, two-step intramolecular aryl C-N and C-O bond forming
process for the preparation of a wide range of benzo-fused heterocyclic scaffolds using iron and copper
catalysis is described. Activated aryl rings were subjected to a highly regioselective, iron(III) triflimide-
catalyzed iodination, followed by a copper(I)-catalyzed intramolecular N- or O-arylation step leading to
indolines, dihydrobenzofurans and six-membered analogues. The general applicability and functional
group tolerance of this method was exemplified by the total synthesis of the neolignan natural product,
(+)-obtusafuran. DFT calculations using Fukui functions were also performed, providing a molecular
orbital rationale for the highly regioselective arene iodination process.
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INTRODUCTION
Indoline and dihydrobenzofuran scaffolds are privileged structures, represented in a wide range of
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natural products and pharmaceutically important agents. For this reason, considerable efforts have
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focused on the discovery of efficient methods for the preparation of these heterocycles. A commonly
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used approach for the synthesis of indolines and dihydrobenzofurans is the Buchwald-Hartwig or
Ullmann-type C-N and C-O bond forming process of pre-functionalized, halogenated phenylethylamines
and phenylethylalcohols (Figure 1a).3–6 As well as 5-membered rings, this strategy is highly effective for
the preparation of 6-membered benzo-fused heterocyclic systems and has been used for the preparation
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g
5b
of a wide range of natural products such as (+)-isatisine A, corsifuran A and a number of quinoline-
containing alkaloids.3b
An alternative approach for preparing these ring systems has been developed more recently involving
transition metal-catalyzed aryl C-H activation and intramolecular cross-coupling with N-H or O-H
bonds.7–8 Pioneering work by the Yu group showed that triflimide-protected 2-phenylethylamines and
Pd(II)/Cu(I) catalysis could be used for the one-pot preparation of indolines via a tandem C-H bond
iodination-amination sequence.8a The palladium-catalyzed intramolecular aryl C(sp )-H amination
process was improved using N-chelating groups and the use of oxidizing agents such as hypervalent
iodonium salts.8-10 Among the range of N-protected amides used to direct the palladium-catalyzed
functionalization of aryl C-H bonds, the Zhao group demonstrated the highly effective use of a N,O-
bidentate oxalyl amide (Figure 1b).8g
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While this strategy has also been used to prepare dihydrobenzofurans from phenylethylalcohols, the
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oxidizing conditions can be problematic for substrates bearing primary and secondary alcohols. More
recently, Zakarian and co-workers reported a mechanistically distinct approach for the preparation of
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dihydrobenzofurans (Figure 1c). A one-pot intramolecular aryl C-O bond forming process was achieved
by formation of non-symmetrical diaryliodonium salts by oxidation of electron-rich 2-
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phenylethylalcohols, followed by a copper-catalyzed C-O bond forming process. A key feature of this
method was the room temperature conditions for copper-catalyzed cyclization.
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Figure 1. Synthesis of indolines and dihydrobenzofuran scaffolds.
While these methods provide an attractive entry to these ring systems, many of the approaches have
been specifically developed for either C-N or C-O bond formation or for the preparation of a particular
ring size. We were interested in developing a new approach for intramolecular C-N or C-O bond formation
that would avoid a pre-functionalization step, precious transition metals, strong oxidizing conditions and
could be used for the general preparation of both five- and six-membered heterocyclic systems. Herein,
we describe a one-pot intramolecular C-N and C-O bond forming process that utilizes a highly
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regioselective iron-catalyzed iodination for initial arene activation, followed by a copper-catalyzed C-N
and C-O cyclization (Figure 1d). As well as providing an electronic rationale for the high regioselectivity
of the iron-catalyzed halogenation reaction, we show the general application of this process for the
preparation of a wide range of ring systems and as the key step for the total synthesis of the natural
product, (+)-obtusafuran.
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RESULTS AND DISCUSSION
Previously, we have shown that the combination of iron(III) chloride and the inexpensive ionic liquid,
[
BMIM]NTf results in the formation of iron triflimide, which can be used as a super Lewis acid catalyst13
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to activate N-halosuccinimides for the fast and efficient regioselective halogenation of aromatic
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compounds. In this current study, this transformation was investigated for the regioselective iodination
of a new class of substrate, N-protected 2-phenylethylamines (Scheme 1). The initial aim was to evaluate
the 3-methoxy substituent as a directing group for selective para-iodination and assess if the resulting
activated aryl intermediate could undergo a copper(I)-catalyzed N-arylation reaction for the one-pot
synthesis of indolines. Using standard conditions for halogenation with iron(III) chloride (2.5 mol%) and
[
BMIM]NTf (7.5 mol%), the iodination of N-benzoyl protected 1a by N-iodosuccinimide (NIS) was
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complete in 5 hours at 40 °C.14a,15 Analysis of the crude reaction mixture by H NMR spectroscopy
showed the formation of the para-iodinated regioisomer as the sole product. The aryl ring of 1a can
undergo iodination with NIS, without the iron(III) triflimide catalyst, however, under the same conditions,
full conversion was only achieved after 22 hours giving a 10:1 mixture of para and ortho-regioisomers.
The regioselective iron(III) triflimide-catalyzed activation of 1a was then performed in combination with
a Cu(I)-catalyzed N-arylation for the one-pot synthesis of indoline 2a. Using copper iodide (10 mol%)
and DMEDA (20 mol%) during the C-N bond forming step gave N-benzoyl-protected indoline 2a in 79%
overall yield. It should be noted that when the synthesis of 2a was done by performing each step
separately, the overall yield (59%) was significantly lower than that for the one-pot process. With the
success of the one-pot synthesis of 2a, a range of N-protecting groups were explored to evaluate the most
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suitable nucleophile for the Cu(I)-catalyzed N-arylation. While N-Cbz and N-Boc carbamate protected
indolines 2c and 2d were prepared in good yields, the most efficient one-pot processes involved N-
acetamide or N-sulfonamide protected compounds. In particular, one-pot activation and cyclization of N-
tosyl phenylethylamine 1f gave indoline 2f in 93% yield.
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Scheme 1. One-Pot Activation and Cyclization of N-Protected 3-Methoxyphenylethylamines 1a
FeCl (2.5 mol%)
3
[
BMIM]NTf (7.5 mol%) MeO
2
MeO
NIS, toluene, 40 ºC, 5 h
HN
then CuI (10 mol%)
DMEDA (20 mol%)
N
PG
PG
1
2
Cs CO , water, 130 ºC, 24 h
2
3
MeO
MeO
MeO
MeO
N
N
N
COPh
Ac
Cbz
2
a, 79%
2b, 87%
2e, 73%
2c, 63%
2f, 93%
MeO
MeO
N
N
N
Boc
Ms
Ts
2
d, 56%
aIsolated yields are shown.
Having identified optimized conditions and the most efficient N-nucleophile, the scope of the one-pot
activation and cyclization process was explored for the preparation of indolines (Scheme 2). Using a range
of N-tosyl ethylamine substituted anisoles, anilines and acetanilides gave the corresponding indolines 2f–
1
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o as single regioisomers, in 43–93% yields. As expected, substrates with multiple activating groups
were converted to the indolines in shorter overall reaction times. Interestingly, phenylethylamine 1o
containing N-acetyl and chlorine substituents failed to undergo the iron(III)-catalyzed iodination even at
7
0 °C. Instead, activation was achieved by bromination using N-bromosuccinimide (NBS) at 40 °C.
Completion of the one-pot process gave indoline 2o in 43% yield. Access to other benzannulated
heterocycles was also achieved using the one-pot process. Iron(III)-catalyzed iodination and copper(I)-
catalyzed cyclization of 3-methoxyphenylacetamide (1p) gave 2-oxindole 2p in 65% yield, while an N-
tosyl propylamine substituted anisole led to the corresponding tetrahydroquinoline 2q in 85% yield.17
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Scheme 2. One-Pot Activation and Cyclization for the Synthesis of N-Heterocyclesa
FeCl (2.5 mol%)
3
[
BMIM]NTf (7.5 mol%)
2
n
n
NIS, toluene, 40 ºC, 4-5 h
R
R
HN
then CuI (10 mol%)
DMEDA (20 mol%), water
Cs CO , 130 ºC, 21-24 h
N
Ts
Ts
1
2
2
3
MeO
MeO
MeO
N
N
N
MeO
Ts
Ts
OMe Ts
2h, 75%
2f, 93%
2g, 78%
MeO
MeO
O
O
N
N
N
MeO
Ts
Ts
Ts
OMe
i, 74%
2
2j, 74%
2k, 73%
H N
2
H N
2
AcHN
N
N
N
Cl
Ts
Ts
Ts
2l, 70%
2m, 55%
MeO
2n, 64%
MeO
AcHN
Cl
O
N
N
N
H
Ts
Ts
o, 43%b
2p, 65%
2q, 85%
2
a
b
Isolated yields are shown. The one-pot process was performed via the bromide intermediate using NBS
for the activation step.
The use of palladium-catalyzed C-H activation in the presence of phenyliodonium diacetate, followed
by C-O cyclization for the synthesis of dihydrobenzofurans can be done using tertiary,11a or secondary
benzylic alcohol nucleophiles.11b However, the general use of substrates bearing primary or secondary
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hydroxy groups for this process are problematic due to competitive oxidation. Mild oxidative conditions
such as reported by the Zakarian group are required for general access to dihydrobenzofurans (Figure
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c). Following the successful application of the one-pot iron(III)-catalyzed activation and copper(I)-
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catalyzed cyclization for the synthesis of N-heterocycles, we were interested to discover whether the mild
oxidative conditions for this two-step process could also be applied for the preparation of
dihydrobenzofurans. The transformation was initially attempted using 3-methoxyphenylethan-2’-ol (3a)
for the synthesis of 2,3-dihydro-5-methoxybenzofuran (4a) (Scheme 3). While the standard iodination
conditions could be used, a slightly higher temperature (150 °C) was required for complete conversion to
the cyclized dihydrobenzofuran. This gave 4a in 65% yield. The scope of this process was then explored
using a range of substrates with various aryl activating groups and primary, secondary or tertiary alcohol
nucleophiles (3a–3i). In general, the one-pot processes were performed under the standard conditions
developed for the N-heterocycles, giving the corresponding dihydrobenzofurans as single regioisomers in
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6–72% yields. It should be noted that while other one-pot methods have had problems with over-
oxidation and the generation of benzofuran by-products, especially with electron-rich substrates,11b
analogous dihydrobenzofurans produced in this study (e.g. 4b–4d), were formed cleanly as single
products. The only limitation was found during the synthesis of natural product, corsifuran A (4g).18
Substrate 3g, which contains two activated aryl rings gave a mixture of products during the iodination
1
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step, resulting in the isolation of corsifuran A (4g) in only 29% yield. However, using secondary
benzylic alcohols with less electron-rich aryl rings (e.g. 3h and 3i) allowed selective iodination of the 3-
methoxyphenyl moiety resulting in the synthesis of dihydrobenzofurans 4h and 4i in 64% and 63% yields,
respectively. This approach was also effective for the one-pot synthesis of dihydrobenzopyrans.
Application of (3-methoxyphenyl)propan-3’-ol (3j) to the one-pot iron(III)-catalyzed activation and
copper(I)-catalyzed cyclization gave dihydrobenzopyran 4j as the sole product in 57% yield. Similar
results were also obtained for dihydrobenzopyrans 4k and 4l.
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Scheme 3. One-Pot Activation and Cyclization for the Synthesis of O-Heterocyclesa
FeCl3 (2.5 mol%)
[
BMIM]NTf (7.5 mol%)
R2
2
NIS, toluene, 40 ºC, 4-5 h
n
n
R1
R2
R1
then CuI (10 mol%)
DMEDA (20 mol%), water
OH
O
3
4
Cs CO , 130-150 ºC, 18-24 h
2
3
MeO
MeO
O
O
O
O
MeO
O
4a, 65%
4b, 72%
4c, 64%
O
O
AcHN
MeO
O
O
O
4d, 60%
4e, 56%
4f, 69%
MeO
MeO
OMe
O
O
4g, 29%
4h, 64%
MeO
Cl
O
4i, 63%
MeO
MeO
MeO
MeO
MeO
O
O
O
OMe
4l, 51%
4j, 57%
4k, 56%
aIsolated yields are shown.
To further explore the functional group tolerance of the one-pot process and illustrate its application for
natural product synthesis, the method was investigated as a key step for the total synthesis of (+)-
obtusafuran (10). The neolignan, (+)-obtusafuran was first isolated from the heartwood of Dalbergia
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retusa20 and more recently from several other Dalbergia species.21–23 As well as possessing
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1
antiplasmodial activity, (+)-obtusafuran has been shown to have anticarcinogenic activity as a potent
inducer of the carcinogen-detoxifying enzyme, quinone reductase.24 Racemic obtusafuran has been
25
prepared by a thermal rearrangement of the neoflavanoid, obtusaquinol, while the only asymmetric
synthesis of (+)-obtusafuran was reported by Chen and Weisel, who used an enantioselective
0
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hydrogenation to produce a chiral alcohol that was then subjected to an S Ar reaction to form the furan
N
26
ring. Our strategy involved the synthesis of -methyl phenyl ketone 7 (Scheme 4) and the application
of this to a Merck-type enantioselective hydrogenation involving a base-mediated dynamic kinetic
resolution process.27,28 The resulting secondary benzylic alcohol 8 would then be used in the one-pot
iron(III)-catalyzed iodination and copper(I)-catalyzed cyclization to complete the synthesis of the
dihydrobenzofuran skeleton. Initially, Weinreb amide 6 was prepared in two steps from phenylacetic acid
5
, by coupling with N,O-dimethylhydroxylamine using EDCI and HOBt, followed by TBDMS protection
of the phenol under standard conditions. Reaction of 6 with phenylmagnesium bromide and then -
alkylation with LiHMDS and methyl iodide gave key intermediate 7 in good overall yield. This was then
subjected to the Merck enantioselective hydrogenation using the commercially available Noyori-type
2
7–29
chiral catalyst, RuCl [(S)-DM-Segphos][(S)-DAIPEN].
On screening various conditions and catalyst
2
loadings, the best results were achieved by hydrogenation at 10 bar of pressure, using 2 mol% of the
Ru(II)-catalyst. This gave secondary alcohol 8 as a single diastereomer, in 95% enantiomeric excess and
3
0
64% yield. Our one-pot process was then investigated for the final key step. Activation of the aryl ring
using the iron(III)-catalyzed iodination required a slightly higher temperature (50 °C) and longer reaction
time (7 h) than the more simple substrates. Following this step, the standard conditions of the copper(I)-
catalyzed cyclization were then used to complete the one-pot process, which gave dihydrobenzofuran 9
in 63% yield. Despite using a substrate with a highly activated aryl ring and a secondary alcohol, no by-
products from over-iodination or oxidation were observed at either stage of the one-pot process. Finally,
TBAF mediated removal of the silyl protecting group completed the eight-step synthesis of (+)-
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obtusafuran (10) in 16% overall yield. The spectroscopic data and optical rotation of 10 were entirely
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consistent with literature data.20b,26
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Scheme 4. Total Synthesis of (+)-Obtusafuran (10)a
aIsolated yields are shown.
Iron(III)-catalyzed activation of the N-protected 2-phenylethylamines and phenylethan-2’-ols gave the
para-iodinated isomers as the sole product. As no reaction was observed at the other activated positions,
including the most sterically accessible ortho-position, DFT calculations were used to explore electronic
31
reasons for this reactivity. The reactivities of different sites towards electrophilic or nucleophilic attack
may be assessed using a computed descriptor such as partial (atomic) charge. In this study, the Hirshfeld
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3
2
partitioning scheme was used. The Hirshfeld charges calculated for the (unsubstituted) aromatic carbons
of N-mesyl protected 2-phenylethylamine 1e single out C-5 as the least preferred site for electrophilic
attack, but cannot distinguish which of C-2, C-4, or C-6 would be the most preferred site (Table 1, entry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
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1
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4
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4
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
). A more refined and powerful reactivity descriptor is provided by the Fukui functions.33,34 The
1
–
electrophilic Fukui function f (r) has more positive values at points in space where it is energetically
0
1
2
3
4
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7
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9
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3
4
5
6
7
8
9
0
–
favorable to remove electrons (see supporting information for background and derivations); that is, f (r)
identifies sites favored for electrophilic attack. If the reactivity is entirely controlled by the frontier
–
orbitals, f (r) is well approximated by the density of the HOMO. From Figure 2, it is evident that the most
–
positive region of f (r), and hence the most favorable site for electrophilic attack of 1e, is located around
C-6. More specifically, the p atomic orbital on C-6 makes the largest contribution to the HOMO. By
z
contracting the continuous Fukui functions to distinct sites (e.g. atoms), “condensed” Fukui reactivity
–
indices are obtained; a large (positive) electrophilicity index f indicates a favored site for electrophilic
–
attack. Using frontier-orbital terminology, f for a particular atom can be identified with the contribution
–
of that atom to the HOMO. f values for the aromatic carbons in 1e are presented in Table 1 (entries 2 and
3
). The quantitative reactivity analysis using atomic Fukui indices thus clearly identifies C-6 as the most
preferred site for electrophilic attack in this case, in agreement with experiment. C-2 and C-4 have
significantly diminished, nearly equal reactivity; C-5 is predicted to be least reactive. Further analysis can
be performed using a “dual descriptor” ∆f, which combines the separate electrophilic and nucleophilic
3
5
Fukui functions into one descriptor. More positive values of ∆f indicates sites for nucleophilic attack;
more negative values sites for electrophilic attack. As can be seen from Table 1 (entries 4 and 5), the
analysis based on ∆f values fully confirms the regioselectivity observed for activation of the substrates in
this study.
Table 1.
Reactivity
Descriptors
Computed
for
the
Aromatic
Carbons
of
Methoxyphenylethylamine 1e.a
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2
MeO
3
1
1
2
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5
6
7
8
9
4
6
HN
Ms
5
1
e
entry reactivity descriptors
C-2
C-4
C-5
C-6
1
2
3
4
5
q
H
/ e
f–(q
f–(HOMO)
–0.065 –0.071 –0.042 –0.065
H
)
0.082
12
0.078
10
0.065
8
0.140
22
1
1
1
1
1
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9
0
∆f(q
H
)
0.045
7
0.019
4
0.068 –0.088
∆f(HOMO)
12
–15
–
q is the Hirshfeld charge (in units of the elementary charge, e); f (q ) and ∆f(q ) are the condensed
H
H
H
electrophilic Fukui function and the condensed “dual descriptor”, respectively, calculated from Hirshfeld
–
charges; f (HOMO) and ∆f(HOMO) are the same descriptors but calculated from Hirshfeld-atomic
a
contributions to the HOMO (expressed in %). M06-2X/def2-TZVP/PCM(toluene).
A
B
–
Figure 2. Isosurface plots of: (A) the HOMO and (B) the electrophilic Fukui function f (r) for 1e.
The aminoalkyl part is omitted as its contribution to either function is negligible. Positive values are
–
colored in orange, negative values in purple. Isosurface values: 0.006 a.u. for f (r), 0.1 a.u. for the HOMO.
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5
5
6
CONCLUSIONS
In summary, a one-pot, two-step method involving iron(III)-catalyzed aryl ring activation and copper(I)-
catalyzed C-N or C-O bond forming cyclization has been developed for the general synthesis of valuable
N- and O-heterocyclic scaffolds. Following DFT calculations, that showed the molecular orbital basis for
the highly regioselective halogenation step, the novel, one-pot method was applied to the efficient
synthesis of indolines and dihydrobenzofurans, as well as six-membered analogues. This one-pot
approach does not require pre-functionalization of the substrate as with the traditional Buchwald-Hartwig
and Ullmann-type intramolecular couplings and unlike the established palladium-catalyzed
dehydrogenative processes, this method has no issues with over-iodination or oxidation and could be
applied to substrates with highly activated aryl ring systems and with primary and secondary alcohols.
This was exemplified by the use of this one-pot process as the key step for the total synthesis of the
neolignan natural product, (+)-obtusafuran. We expect this simple and effective approach to find
utilization in the preparation of other heterocyclic scaffolds and for application in the synthesis of natural
products and medicinal chemistry targets. Investigation of further applications of the one-pot process is
currently underway.
0
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EXPERIMENTAL SECTION
All reagents and starting materials were obtained from commercial sources and used as received unless
otherwise stated. Dry solvents were purified using a solvent purification system. Brine refers to a saturated
solution of sodium chloride. All reactions were performed in oven-dried glassware under an atmosphere
of argon unless otherwise stated. Flash column chromatography was carried out using silica gel (40–63
μm) and neutral aluminium oxide (50–200 μm). Aluminium-backed plates pre-coated with silica gel 60
(
UV ) were used for thin layer chromatography and were visualized under ultraviolet light and by
254
1
staining with KMnO or ninhydrin. H NMR spectra were recorded on an NMR spectrometer at 400 or
4
5
00 MHz and data are reported as follows: chemical shift in ppm relative to tetramethylsilane or the
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solvent as the internal standard (CDCl , δ 7.26 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q =
3
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
1
3
1
quartet, m = multiplet or overlap of nonequivalent resonances, integration). C{ H} NMR spectra were
recorded on an NMR spectrometer at 101 or 126 MHz and data are reported as follows: chemical shift in
ppm relative to tetramethylsilane or the solvent as internal standard (CDCl , δ 77.0 ppm), multiplicity
3
with respect to hydrogen (deduced from DEPT experiments, C, CH, CH or CH ). IR spectra were
2
3
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
–
1
recorded on a FTIR spectrometer; wavenumbers are indicated in cm . Mass spectra were recorded using
electron impact or electrospray techniques. HRMS spectra were recorded using a dual-focusing magnetic
analyzer mass spectrometer. Melting points are uncorrected. Optical rotations were determined as
solutions irradiating with the sodium D line (λ = 589 nm) using a polarimeter. [α] values are given in
D
−
1
2
−1
units 10 deg cm g . Chiral HPLC methods were calibrated with the corresponding racemic mixtures.
36
3
-Methoxy-1-[(E)-2’-nitrovinyl]benzene. To a solution of m-anisaldehyde (0.890 mL, 7.30 mmol)
in toluene (30 mL) was added nitromethane (2.00 mL, 37.0 mmol) and ammonium acetate (0.560 g, 7.30
mmol). The resulting solution was heated under reflux for 18 h. The reaction mixture was washed with
water (2 × 30 mL), followed by brine (2 × 30 mL). Purification by flash column chromatography
(dichloromethane) gave 3-methoxy-1-[(E)-2’-nitrovinyl]benzene (1.21 g, 97%) as a yellow solid. Mp 91–
3
6
1
9
2 °C (lit. 89–91 °C); H NMR (400 MHz, CDCl ) δ 3.85 (s, 3H), 7.02–7.08 (m, 2H), 7.14 (d, J = 7.6
3
1
3
Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 13.6 Hz, 1H), 7.97 (d, J = 13.6 Hz, 1H); C NMR (101
MHz, CDCl ) δ 55.4 (CH ), 114.0 (CH), 118.0 (CH), 121.7 (CH), 130.4 (CH), 131.4 (C), 137.4 (CH),
3
3
+
1
39.0 (CH), 160.2 (C); MS (EI) m/z 179 (M . 100), 136 (82), 135 (72), 84 (86), 77 (50).
,4-Dimethoxy-1-[(E)-2’-nitrovinyl]benzene.37 3,4-Dimethoxy-1-[(E)-2’-nitrovinyl]benzene was
synthesized as described for 3-methoxy-1-[(E)-2’-nitrovinyl]benzene using 3,4-dimethoxybenzaldehyde
1.00 g, 6.00 mmol). Purification by flash column chromatography (dichloromethane) gave 3,4-
3
(
3
7
dimethoxy-1-[(E)-2’-nitrovinyl]benzene (1.04 g, 83%) as a yellow solid. Mp 134–136 °C (lit. 135–137
1
°C); H NMR (400 MHz, CDCl ) δ 3.93 (s, 3H), 3.95 (s, 3H), 6.91 (d, J = 8.3 Hz, 1H), 7.01 (d, J = 1.7
3
13
Hz, 1H), 7.18 (dd, J = 8.3, 1.7 Hz, 1H), 7.53 (d, J = 13.6 Hz, 1H), 7.96 (d, J = 13.6 Hz, 1H); C NMR
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(
101 MHz, CDCl ) δ 56.0 (CH ), 56.1 (CH ), 110.3 (CH), 111.4 (CH), 122.8 (C), 124.6 (CH), 135.2 (CH),
3 3 3
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
+
1
39.3 (CH), 149.6 (C), 152.9 (C); MS (ESI) m/z 232 (M+Na . 100).
,5-Dimethoxy-1-[(E)-2’-nitrovinyl]benzene.38 3,5-Dimethoxy-1-[(E)-2’-nitrovinyl]benzene was
synthesized as described for 3-methoxy-1-[(E)-2’-nitrovinyl]benzene using 3,5-dimethoxybenzaldehyde
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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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
(0.350 g, 2.10 mmol). The residue was recrystallized from diethyl ether which gave 3,5-dimethoxy-1-
3
8
1
[(E)-2’-nitrovinyl]benzene (0.357 g, 81%) as a yellow solid. Mp 81–83 °C (lit. 78 °C); H NMR (400
MHz, CDCl ) δ 3.83 (s, 6H), 6.59 (t, J = 2.2 Hz, 1H), 6.66 (d, J = 2.2 Hz, 2H), 7.54 (d, J = 13.6 Hz, 1H),
3
13
7
.92 (d, J = 13.6 Hz, 1H); C NMR (101 MHz, CDCl ) δ 55.5 (CH ), 55.6 (CH ), 102.8 (CH), 104.2
3
3
3
+
(CH), 107.0 (CH), 107.6 (CH), 133.4 (CH), 139.2 (C), 160.7 (C), 161.3 (C); MS (EI) m/z 209 (M . 100),
189 (48), 165 (90), 135 (34), 84 (98).
1-[(E)-2’-Nitrovinyl]-3,4,5-trimethoxybenzene.37
1-[(E)-2’-Nitrovinyl]-3,4,5-trimethoxybenzene
was synthesized as described for 3-methoxy-1-[(E)-2’-nitrovinyl]benzene using 3,4,5-
trimethoxybenzaldehyde (1.00 g, 6.00 mmol). The residue was recrystallized from hexane, which gave 1-
3
7
[(E)-2’-nitrovinyl]-3,4,5-trimethoxybenzene (1.14 g, 94%) as a yellow solid. Mp 119–121 °C (lit. 122–
1
1
7
1
24 °C); H NMR (400 MHz, CDCl ) δ 3.91 (s, 6H), 3.92 (s, 3H), 6.76 (s, 2H), 7.52 (d, J = 13.6 Hz, 1H),
3
1
3
.94 (d, J = 13.6 Hz, 1H); C NMR (101 MHz, CDCl ) δ 56.3 (2 × CH ), 61.1 (CH ), 106.5 (2 × CH),
3
3
3
+
25.3 (C), 136.4 (CH), 139.3 (CH), 141.8 (C), 153.7 (2 × C); MS (ESI) m/z 262 (M+Na . 100).
3
9
3-Methoxy-4-methylbenzaldehyde. To a stirred solution of lithium aluminium hydride (0.425 g,
1
1.1 mmol) in dry tetrahydrofuran (20 mL) was added a solution of methyl 3-methoxy-4-methylbenzoate
(1.00 g, 5.55 mmol) in dry tetrahydrofuran (10 mL) dropwise at 0 °C. The resulting suspension was
warmed to room temperature and stirred for 4 h after which, the solution was cooled to 0 °C and diluted
with tetrahydrofuran (20 mL). Water (0.5 mL) was added slowly followed by 15% aqueous sodium
hydroxide solution (0.5 mL) and water (1.5 mL). The resulting solution was warmed to room temperature,
magnesium sulfate (0.50 g) was added and stirred for 0.5 h. The suspension was filtered and the filtrate
was concentrated in vacuo to give 3-methoxy-4-methylbenzyl alcohol (0.767 g, 91%) as a colorless oil
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which was used without further purification. To a stirred solution of 3-methoxy-4-methylbenzyl alcohol
0.737 g, 4.85 mmol) in chloroform (25 mL) was added manganese dioxide (4.22 g, 48.5 mmol). The
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
(
resulting suspension was stirred at room temperature for 18 h. The crude reaction mixture was filtered
through Celite® and concentrated in vacuo to give 3-methoxy-4-methylbenzaldehyde (0.621 g, 75%) as
3
9
1
a white solid. Mp 34–36 °C (lit. 39–40 °C); H NMR (400 MHz, CDCl ) δ 2.29 (s, 3H), 3.90 (s, 3H),
3
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
1
3
7
.29 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 1.4 Hz, 1H), 7.36 (dd, J = 7.5, 1.4 Hz, 1H), 9.93 (s, 1H); C NMR
(
101 MHz, CDCl ) δ 16.9 (CH ), 55.5 (CH ), 107.9 (CH), 124.5 (CH), 130.9 (C), 134.9 (CH), 135.9 (C),
3
3
3
+
1
58.3 (C), 192.0 (CH); MS (EI) m/z 150 (M . 100), 121 (19), 91 (28), 84 (21).
3
-Methoxy-4-methyl-1-[(E)-2’-nitrovinyl]benzene.
3-Methoxy-4-methyl-1-[(E)-2’-
nitrovinyl]benzene was synthesized as described for 3-methoxy-1-[(E)-2’-nitrovinyl]benzene using 3-
methoxy-4-methylbenzaldehyde (0.624 g, 4.16 mmol). The residue was recrystallized from hexane which
gave 3-methoxy-4-methyl-1-[(E)-2’-nitrovinyl]benzene (0.585 g, 73%) as a yellow solid. Mp 142–143
−
1
°
C; IR (neat) 3119, 2945, 1629, 1602, 1573, 1494, 1414, 1343, 1328, 1248, 1159, 1035, 976, 814 cm ;
1
H NMR (400 MHz, CDCl ) δ 2.26 (s, 3H), 3.87 (s, 3H), 6.92 (s, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.19 (d, J
3
13
=
7.6 Hz, 1H), 7.57 (d, J = 13.6 Hz, 1H), 7.97 (d, J = 13.6 Hz, 1H); C NMR (101 MHz, CDCl ) δ 16.6
3
(
CH ), 55.4 (CH ), 109.3 (CH), 122.2 (CH), 128.8 (C), 131.4 (CH), 132.4 (C), 136.3 (CH), 139.6 (CH),
3
3
+
+
158.3 (C); MS (ESI) m/z 216 (M+Na . 100); HRMS (ESI) calcd for C H NNaO (M+Na ) 216.0631,
1
0
11
3
found 216.0626.
,4-Methylenedioxy-1-[(E)-2’-nitrovinyl]benzene.40
3
3,4-Methylenedioxy-1-[(E)-2’-
nitrovinyl]benzene was synthesized as described for 3-methoxy-1-[(E)-2’-nitrovinyl]benzene using
piperonal (1.00 g, 6.00 mmol). The residue was recrystallized from hexane which gave 3,4-
40
methylenedioxy-1-[(E)-2’-nitrovinyl]benzene (1.03 g, 80%) as a yellow solid. Mp 142–143 °C (lit. 148
1
°
C); H NMR (400 MHz, CDCl ) δ 6.06 (s, 2H), 6.87 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 1.8 Hz, 1H), 7.08
3
1
3
(dd, J = 8.0, 1.8 Hz, 1H), 7.47 (d, J = 13.6 Hz, 1H), 7.92 (d, J = 13.6 Hz, 1H); C NMR (101 MHz,
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CDCl ) δ 102.1 (CH ), 107.0 (CH), 109.1 (CH), 124.2 (CH), 126.6 (CH), 135.5 (C), 139.1 (CH), 148.8
3
2
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
+
(
C), 151.4 (C); MS (EI) m/z 193 (M . 100), 146 (98), 89 (65), 84 (51), 63 (44).
3
-Nitro-1-[(E)-2’-nitrovinyl]benzene.41 3-Nitro-1-[(E)-2’-nitrovinyl]benzene was synthesized as
described for 3-methoxy-1-[(E)-2’-nitrovinyl]benzene using 3-nitrobenzaldehyde (1.00 g, 6.00 mmol).
Purification by flash column chromatography (petroleum ether/ethyl acetate, 9:1) gave 3-nitro-1-[(E)-2’-
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
4
1
1
nitrovinyl]benzene (0.420 g, 31%) as a yellow solid. Mp 119–121 °C (lit. 125–126 °C); H NMR (400
MHz, CDCl ) δ 7.68 (d, J = 13.7 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.88 (dt, J = 8.0, 1.6 Hz, 1H), 8.05 (d,
3
13
J = 13.7 Hz, 1H), 8.35 (dt, J = 8.0, 1.6 Hz, 1H), 8.43 (t, J = 1.6 Hz, 1H); C NMR (101 MHz, CDCl ) δ
3
1
23.5 (CH), 126.2 (CH), 130.6 (CH), 131.9 (C), 134.4 (CH), 136.2 (CH), 139.3 (CH), 148.9 (C); MS (EI)
+
m/z 194 (M . 100), 147 (48), 118 (38), 102 (100), 84 (82), 76 (36).
4-Chloro-3-nitro-1-[(E)-2’-nitrovinyl]benzene. 4-Chloro-3-nitro-1-[(E)-2’-nitrovinyl]benzene was
synthesized as described for 3-methoxy-1-[(E)-2’-nitrovinyl]benzene using 4-chloro-3-
nitrobenzaldehyde (1.00 g, 6.00 mmol). Purification by flash column chromatography (petroleum
ether/ethyl acetate, 7:3) gave 4-chloro-3-nitro-1-[(E)-2’-nitrovinyl]benzene (0.620 g, 26%) as a yellow
−1
1
solid. Mp 142–143 °C; IR (neat) 3109, 2945, 2361, 1605, 1540, 1342, 1049, 833 cm ; H NMR (400
MHz, CDCl ) δ 7.61 (d, J = 13.7 Hz, 1H), 7.66–7.72 (m, 2H), 7.96 (d, J = 13.7 Hz, 1H), 8.06 (d, J = 1.2
3
1
3
Hz, 1H); C NMR (101 MHz, CDCl ) δ 125.6 (CH), 130.1 (C), 130.4 (C), 132.6 (CH), 133.2 (CH), 133.8
3
+
(
C), 135.1 (CH), 139.4 (CH); MS (EI) m/z 228 (M . 40), 181 (100), 152 (38), 136 (95), 115 (38), 101
3
5
+
(
48), 89 (41), 75 (54); HRMS (EI) calcd for C H ClN O (M ) 227.9938, found 227.9929.
8
5
2
4
42
1
’-(3-Methoxyphenyl)ethyl-2’-amine. To a suspension of sodium borohydride (0.180 g, 4.80 mmol)
in dry tetrahydrofuran (10 mL) was added boron trifluoride diethyl etherate (0.750 mL, 6.00 mmol)
dropwise at 0 °C and the contents were stirred at room temperature for 0.25 h. A solution of 3-methoxy-
1
-[(E)-2’-nitrovinyl]benzene in tetrahydrofuran (3.0 mL) was added dropwise into the reaction mixture
which was then heated under reflux for 6.5 h. After cooling to room temperature, the reaction was
quenched by the slow addition of ice water (12 mL). The reaction mixture was acidified with 1 M aqueous
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hydrochloric acid (12 mL) and heated to 85 °C for 2 h. The reaction mixture was cooled to room
temperature, washed with dichloromethane (2 × 10 mL), then 1 M aqueous sodium hydroxide was added
until basic (ca. pH 12). The aqueous layer was extracted with dichloromethane (3 × 20 mL), dried
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
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
MgSO ) and concentrated in vacuo to give 1’-(3-methoxyphenyl)ethyl-2’-amine (0.140 g, 92%) as a
4
yellow oil which was used without further purification. Spectroscopic data were consistent with the
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
literature.42 1H NMR (400 MHz, CDCl ) δ 1.99 (br s, 2H), 2.72 (t, J = 6.8 Hz, 2H), 2.96 (t, J = 6.8 Hz,
3
1
3
2
H), 3.78 (s, 3H), 6.73–6.80 (m, 3H), 7.21 (t, J = 7.6 Hz, 1H); C NMR (101 MHz, CDCl ) δ 39.0 (CH ),
3 2
4
3.0 (CH ), 55.2 (CH ), 111.6 (CH), 114.6 (CH), 121.2 (CH), 129.5 (CH), 140.9 (C), 159.8 (C); MS (ESI)
2
3
+
m/z 152 (M+H . 100).
4
3
N-[(3-Methoxyphenyl)ethyl]benzamide (1a). 1’-(3-Methoxyphenyl)ethyl-2’-amine (0.050 g, 0.33
mmol) was dissolved in dry dichloromethane (5 mL) and triethylamine (0.070 mL, 0.50 mmol) was added.
The reaction mixture was cooled to 0 °C and benzoyl chloride (0.039 mL, 0.33 mmol) was added
dropwise. The reaction mixture was stirred at 0 °C for 0.5 h, warmed to room temperature and stirred for
20 h. The reaction mixture was diluted with dichloromethane (10 mL), washed with 1 M aqueous
hydrochloric acid (10 mL) then brine (10 mL), dried (MgSO ) and concentrated in vacuo. Purification by
4
flash
column
chromatography
(petroleum
ether/ethyl
acetate,
7:3)
gave
N-[(3-
4
3
methoxyphenyl)ethyl]benzamide (1a) (0.077 g, 91% yield) as a white solid. Mp 64–66 °C (lit. 67 °C);
1
H NMR (400 MHz, CDCl ) δ 2.91 (t, J = 6.9 Hz, 2H), 3.71 (q, J = 6.9 Hz, 2H), 3.78 (s, 3H), 6.24 (br s,
3
1
H), 6.76–6.84 (m, 3H), 7.20–7.26 (m, 1H), 7.36–7.42 (m, 2H), 7.44–7.50 (m, 1H), 7.67–7.72 (m, 2H);
1
3
C NMR (101 MHz, CDCl ) δ 35.8 (CH ), 41.1 (CH ), 55.2 (CH ), 112.1 (CH), 114.4 (CH), 121.1 (CH),
3
2
2
3
1
26.8 (2 × CH), 128.6 (2 × CH), 129.7 (CH), 131.4 (CH), 134.7 (C), 140.5 (C), 159.9 (C), 167.5 (C); MS
+
(
EI) m/z 255 (M . 25), 134 (100), 105 (62), 77 (25).
4
4
N-[(3-Methoxyphenyl)ethyl]acetamide (1b). 1’-(3-Methoxyphenyl)ethyl-2’-amine (0.050 g, 0.33
mmol) was dissolved in dry dichloromethane (10 mL) and acetic anhydride (0.038 mL, 0.40 mmol) was
added while stirring. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture
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was diluted with dichloromethane (15 mL), washed with 1 M aqueous sodium carbonate (15 mL), then
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
brine (15 mL), dried (MgSO ) and concentrated in vacuo to give N-[(3-methoxyphenyl)ethyl]acetamide
4
(1b) (0.060 g, 94%) as a yellow oil which was used without further purification. Spectroscopic data were
consistent with the literature.44 1H NMR (400 MHz, CDCl ) δ 1.94 (s, 3H), 2.79 (t, J = 6.8 Hz, 2H), 3.51
3
1
3
(
(
(
q, J = 6.8 Hz, 2H), 3.80 (s, 3H), 5.44 (br s, 1H), 6.72–6.82 (m, 3H), 7.23 (t, J = 7.9 Hz, 1H); C NMR
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
101 MHz, CDCl ) δ 23.4 (CH ), 35.7 (CH ), 40.5 (CH ), 50.2 (CH ), 111.9 (CH), 114.5 (CH), 121.1
3
3
2
2
3
+
CH), 129.7 (CH), 140.5 (C), 159.9 (C), 170.0 (C); MS (ESI) m/z 216 (M+Na . 100).
45
Benzyl N-[(3-methoxyphenyl)ethyl]carbamate (1c). 1’-(3-Methoxyphenyl)ethyl-2’-amine (0.100
g, 0.660 mmol) was dissolved in dry dichloromethane (10 mL) and triethylamine (0.142 mL, 1.00 mmol)
was added while stirring. The reaction mixture was cooled to 0 °C and benzyl chloroformate (0.114 mL,
0
.800 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 0.5 h, warmed to room
temperature and stirred for 5 h. The reaction mixture was diluted with dichloromethane (15 mL), washed
with 1 M aqueous hydrochloric acid (15 mL), then brine (15 mL), dried (MgSO ) and concentrated in
4
vacuo. Purification by flash column chromatography (petroleum ether/ethyl acetate, 4:1) gave benzyl N-
[(3-methoxyphenyl)ethyl]carbamate (1c) (0.134 g, 72%) as a colorless oil. Spectroscopic data were
consistent with the literature.45 1H NMR (400 MHz, CDCl ) δ 2.79 (t, J = 6.6 Hz, 2H), 3.45 (q, J = 6.6
3
Hz, 2H), 3.78 (s, 3H), 4.76 (br s, 1H), 5.09 (s, 2H), 6.69–6.81 (m, 3H), 7.21 (t, J = 7.9 Hz, 1H), 7.28–7.38
13
(
m, 5H); C NMR (101 MHz, CDCl ) δ 36.1 (CH ), 42.1 (CH ), 55.2 (CH ), 66.7 (CH ), 111.9 (CH),
3
2
2
3
2
1
14.5 (CH), 121.1 (CH), 128.1 (2 × CH), 128.5 (2 × CH), 128.6 (CH), 129.6 (CH), 136.6 (C), 140.3 (C),
+
156.3 (C), 159.8 (C); MS (ESI) m/z 308 (M+Na . 100).
tert-Butyl-N-[(3-methoxyphenyl)ethyl]carbamate (1d).46 1’-(3-Methoxyphenyl)ethyl-2’-amine
(0.200 g, 1.32 mmol) was dissolved in dry dichloromethane (10 mL) and triethylamine (0.370 mL, 2.64
mmol) was added with stirring. Di-tert-butyl dicarbonate (0.870 g, 3.97 mmol) was added and the
resulting solution was stirred at room temperature for 16 h. The reaction mixture was concentrated in
vacuo and the residue was purified by column chromatography (petroleum ether/ethyl acetate, 4:1) to give
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tert-butyl-N-[(3-methoxyphenyl)ethyl]carbamate (1d) (0.253 g, 76%) as a yellow oil. Spectroscopic data
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
were consistent with the literature.46 1H NMR (400 MHz, CHCl ) δ 1.44 (s, 9H), 2.77 (t, J = 6.9 Hz, 2H),
3
1
3
3.38 (q, J = 6.9 Hz, 2H), 3.80 (s, 3H), 4.55 (br s, 1H), 6.72–6.89 (m, 3H), 7.22 (t, J = 7.9 Hz, 1H); C
NMR (101 MHz, CHCl ) δ 28.4 (3 × CH ), 36.3 (CH ), 41.7 (CH ), 55.2 (CH ), 79.2 (C), 111.8 (CH),
3
3
2
2
3
+
1
14.5 (CH), 121.1 (CH), 129.6 (CH), 140.6 (C), 155.9 (C), 159.8 (C); MS (EI) m/z 251 (M . 12), 195
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
(32), 134 (100), 121 (48), 91 (24).
N-[(3-Methoxyphenyl)ethyl]methanesulfonamide (1e). 1’-(3-Methoxyphenyl)ethyl-2’-amine (0.198
g, 1.32 mmol) was dissolved in dry dichloromethane (10 mL) and triethylamine (0.370 mL, 2.64 mmol)
was added with stirring. The reaction mixture was cooled to 0 °C and methanesulfonyl chloride (0.120
mL, 1.59 mmol) was added. The reaction mixture was stirred at 0 °C for 0.5 h, warmed to room
temperature and stirred for 4 h. The reaction mixture was diluted with dichloromethane (15 mL), washed
with 1 M aqueous hydrochloric acid (15 mL), brine (15 mL), dried (MgSO ) and concentrated in vacuo.
4
Purification by flash column chromatography (petroleum ether/ethyl acetate, 1:1) gave N-[(3-
methoxyphenyl)ethyl]methanesulfonamide (1e) (0.184 g, 60%) as a yellow oil. IR (neat) 3287, 2936,
−1
1
1
586, 1489, 1312, 1258, 1146, 783 cm ; H NMR (500 MHz, CDCl ) δ 2.83–2.88 (m, 5H), 3.41 (q, J =
3
1
3
6
.4 Hz, 2H), 3.81 (s, 3H), 4.24 (br s, 1H), 6.74–6.82 (m, 3H), 7.25 (t, J = 7.9 Hz, 1H); C NMR (126
MHz, CDCl ) δ 36.5 (CH ), 40.4 (CH ), 44.3 (CH ), 55.2 (CH ), 112.2 (CH), 114.7 (CH), 121.1 (CH),
3
2
3
2
3
+
1
29.9 (CH), 139.3 (C), 160.0 (C); MS (EI) m/z 229 (M . 35), 134 (100), 122 (76), 108 (62), 91 (25);
+
HRMS (EI) calcd for C H NO S (M ) 229.0773, found 229.0780.
1
0
15
3
4
7
N-[(3-Methoxyphenyl)ethyl]-4’’-methylbenzenesulfonamide (1f). 1’-(3-Methoxyphenyl)ethyl-2’-
amine (0.200 g, 1.32 mmol) was dissolved in dry dichloromethane (10 mL) and triethylamine (0.280 mL,
1
.98 mmol) was added with stirring. The reaction mixture was cooled to 0 °C and p-toluenesulfonyl
chloride (0.302 g, 1.58 mmol) was added. The reaction mixture was stirred at 0 °C for 0.5 h, warmed to
room temperature and stirred for 6 h. The reaction mixture was diluted with dichloromethane (15 mL),
washed with 1 M aqueous hydrochloric acid (15 mL), brine (15 mL), dried (MgSO ) and concentrated in
4
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vacuo. Purification by flash column chromatography (petroleum ether/ethyl acetate, 4:1) gave N-[(1-
methoxyphenyl)ethyl]-4’’-methylbenzenesulfonamide (1f) (0.327 g, 81%) as a yellow oil. Spectroscopic
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
data were consistent with the literature.47 1H NMR (400 MHz, CDCl ) δ 2.45 (s, 3H), 2.75 (t, J = 6.9 Hz,
3
2
H), 3.23 (q, J = 6.9 Hz, 2H), 3.79 (s, 3H), 4.54 (br s, 1H), 6.63 (br s, 1H), 6.69 (br d, J = 7.9 Hz, 1H),
.78 (dd, J = 7.9, 2.5 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H);
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
1
3
C NMR (101 MHz, CDCl ) δ 21.5 (CH ), 35.8 (CH ), 44.1 (CH ), 55.1 (CH ), 112.1 (CH), 114.4 (CH),
3
3
2
2
3
1
21.0 (CH), 127.1 (2 × CH), 129.7 (2 × CH), 129.8 (CH), 136.9 (C), 139.2 (C), 143.4 (C), 159.9 (C); MS
+
(
ESI) m/z 328 (M+Na . 100).
4
8
N-[(3,4-Dimethoxyphenyl)ethyl]-4’’-methylbenzenesulfonamide (1g). To a suspension of sodium
borohydride (0.817 g, 21.6 mmol) in dry tetrahydrofuran (50 mL) was added boron trifluoride diethyl
etherate (3.37 mL, 27.3 mmol) dropwise at 0 °C and the mixture was stirred at room temperature for 0.25
h. A solution of 3,4-dimethoxy-1-[(E)-2’-nitrovinyl]benzene (0.950 g, 4.55 mmol) in tetrahydrofuran (15
mL) was added dropwise into the reaction mixture which was then heated under reflux for 6.5 h. After
cooling to room temperature, the reaction was quenched by the slow addition of ice water (30 mL). The
reaction mixture was acidified with 1 M aqueous hydrochloric acid (30 mL) and heated to 85 °C for 2 h.
The reaction mixture was cooled to room temperature, washed with dichloromethane (2 × 40 mL), then 1
M aqueous sodium hydroxide was added until basic (ca. pH 12). The aqueous layer was extracted with
dichloromethane (3 × 40 mL), dried (MgSO ) and concentrated in vacuo to give 1’-(3,4-
4
dimethoxyphenyl)ethyl-2’-amine (0.582 g, 71%) as a yellow oil which was used without further
purification. 1’-(3,4-Dimethoxyphenyl)ethyl-2’-amine (0.509 g, 2.81 mmol) was dissolved in dry
dichloromethane (20 mL) and triethylamine (0.588 mL, 4.22 mmol) was added while stirring. The
reaction mixture was cooled to 0 °C and p-toluenesulfonyl chloride (0.643 g, 3.37 mmol) was added. The
reaction mixture was stirred at 0 °C for 0.5 h, warmed to room temperature and stirred for 6 h. The reaction
mixture was diluted with dichloromethane (30 mL), washed with 1 M aqueous hydrochloric acid (30 mL),
brine (30 mL), dried (MgSO ) and concentrated in vacuo. Purification by flash column chromatography
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(
petroleum ether/ethyl acetate, 7:3) gave N-[(3,4-dimethoxyphenyl)ethyl]-4’’-methylbenzenesulfonamide
1g) (0.716 g, 76%) as a yellow oil. Spectroscopic data were consistent with the literature.48 1H NMR
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
(
(400 MHz, CDCl ) δ 2.42 (s, 3H), 2.71 (t, J = 6.8 Hz, 2H), 3.19 (q, J = 6.8 Hz, 2H), 3.81 (s, 3H), 3.86 (s,
3
3
1
H), 4.31 (t, J = 6.8 Hz, 1H), 6.55 (d, J = 2.0 Hz, 1H), 6.62 (dd, J = 8.1, 2.0 Hz, 1H), 6.76 (d, J = 8.1 Hz,
1
3
H), 7.28 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H); C NMR (101 MHz, CDCl ) δ 21.5 (CH ), 35.3
3
3
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
(
(
(
CH ), 44.3 (CH ), 55.8 (CH ), 56.0 (CH ), 111.5 (CH), 111.8 (CH), 120.8 (CH), 127.1 (2 × CH), 129.7
2 2 3 3
+
2 × CH), 130.1 (C), 136.9 (C), 143.4 (C), 148.0 (C), 149.2 (C); MS (EI) m/z 335 (M . 60), 184 (17), 164
38), 151 (100), 107 (17), 91 (48).
N-[(3,5-Dimethoxyphenyl)ethyl]-4’’-methylbenzenesulfonamide
Dimethoxyphenyl)ethyl]-4’’-methylbenzenesulfonamide (1h) was synthesized as described for N-[(3,4-
dimethoxyphenyl)ethyl]-4’’-methylbenzenesulfonamide (1g) using 3,5-dimethoxy-1-[(E)-2’-
(1h).49
N-[(3,5-
nitrovinyl]benzene. Reduction of 3,5-dimethoxy-1-[(E)-2’-nitrovinyl]benzene (0.330 g, 1.58 mmol) using
sodium borohydride (0.285 g, 7.51 mmol) and boron trifluoride diethyl etherate (1.17 mL, 9.48 mmol)
gave 1’-(3,5-dimethoxyphenyl)ethyl-2’-amine (0.165 g, 58%) which was used without further
purification. The N-protection step was carried out at room temperature for 18 h. Purification by flash
column chromatography (petroleum ether/ethyl acetate, 4:1) gave N-[(3,5-dimethoxyphenyl)ethyl]-4’’-
methylbenzenesulfonamide (1h) (0.150 g, 50%) as a colorless oil. Spectroscopic data were consistent
with the literature.49 1H NMR (400 MHz, CDCl ) δ 2.42 (s, 3H), 2.69 (t, J = 6.9 Hz, 2H), 3.19 (q, J = 6.9
3
Hz, 2H), 3.74 (s, 6H), 4.48 (t, J = 6.9 Hz, 1H), 6.21 (d, J = 2.2 Hz, 2H), 6.31 (t, J = 2.2 Hz, 1H), 7.27 (d,
1
3
J = 8.2 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H); C NMR (126 MHz, CDCl ) δ 21.5 (CH ), 36.0 (CH ), 44.0
3
3
2
(CH ), 55.3 (2 × CH ), 98.7 (CH), 106.7 (2 × CH), 127.1 (2 × CH), 129.7 (2 × CH), 136.9 (C), 140.0 (C),
2 3
+
1
43.4 (C), 161.1 (2 × C); MS (ESI) m/z 358 (M+Na . 100).
’’-Methyl-N-[(3,4,5-trimethoxyphenyl)ethyl]benzenesulfonamide (1i).50 4’’-Methyl-N-[(3,4,5-
trimethoxyphenyl)ethyl]benzenesulfonamide (1i) was synthesized as described for N-[(3,4-
dimethoxyphenyl)ethyl]-4’’-methylbenzenesulfonamide (1g) using 1-[(E)-2’-nitrovinyl]-3,4,5-
4
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trimethoxybenzene. Reduction of 1-[(E)-2’-nitrovinyl]-3,4,5-trimethoxybenzene (1.09 g, 4.56 mmol)
using sodium borohydride (0.821 g, 21.7 mmol) and boron trifluoride diethyl etherate (3.90 mL, 27.4
mmol) gave 1’-(3,4,5-trimethoxyphenyl)ethyl-2’-amine (0.748 g, 78%) which was used without further
purification. The N-protection step was carried out at room temperature for 6 h. Purification by flash
column chromatography (petroleum ether/ethyl acetate, 3:2) gave 4’’-methyl-N-[(3,4,5-
trimethoxyphenyl)ethyl]benzenesulfonamide (1i) (0.903 g, 71%) as a yellow oil. Spectroscopic data were
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
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
consistent with the literature.50 1H NMR (400 MHz, CDCl ) δ 2.42 (s, 3H), 2.71 (t, J = 6.8 Hz, 2H), 3.21
3
(q, J = 6.8 Hz, 2H), 3.80 (s, 6H), 3.81 (s, 3H), 4.48 (t, J = 6.8 Hz, 1H), 6.28 (s, 2H), 7.28 (d, J = 8.3 Hz,
1
3
2
H), 7.69 (d, J = 8.3 Hz, 2H); C NMR (101 MHz, CDCl ) δ 21.5 (CH ), 36.1 (CH ), 44.2 (CH ), 56.1
3 3 2 2
(2 × CH ), 60.8 (CH ), 105.7 (2 × CH), 127.1 (2 × CH), 129.7 (2 × CH), 133.3 (C), 136.9 (C), 137.0 (C),
3
3
+
1
43.5 (C), 153.4 (2 × C); MS (ESI) m/z 388 (M+Na . 100).
N-[(3-Methoxy-4-methylphenyl)ethyl]-4’’-methylbenzenesulfonamide (1j). N-[(3-Methoxy-4-
methylphenyl)ethyl]-4’’-methylbenzenesulfonamide (1j) was synthesized as described for N-[(3,4-
dimethoxyphenyl)ethyl]-4’’-methylbenzenesulfonamide (1g) using 3-methoxy-4-methyl-1-[(E)-2’-
nitrovinyl]benzene. Reduction of 3-methoxy-4-methyl-1-[(E)-2’-nitrovinyl]benzene (0.585 g, 3.03
mmol) using sodium borohydride (0.757 g, 20.5 mmol) and boron trifluoride diethyl etherate (3.42 mL,
26.5 mmol) gave 1’-(3-methoxy-4-methylphenyl)ethyl-2’-amine (0.356 g, 71%) which was used without
further purification. The N-protection step was carried out at room temperature for 24 h. Purification by
flash column chromatography (petroleum ether/ethyl acetate, 4:1) gave N-[(3-methoxy-4-
methylphenyl)ethyl]-4’’-methylbenzenesulfonamide (1j) (0.278 g, 45%) as a yellow oil. IR (neat) 3264,
−1
1
2
3
6
924, 1586, 1512, 1464, 1414, 1323, 1256, 1155, 1094, 814 cm ; H NMR (400 MHz, CDCl ) δ 2.17 (s,
3
H), 2.42 (s, 3H), 2.72 (t, J = 6.8 Hz, 2H), 3.20 (q, J = 6.8 Hz, 2H), 3.76 (s, 3H), 4.34 (t, J = 6.8 Hz, 1H),
.51 (d, J = 1.4 Hz, 1H), 6.51 (dd, J = 7.5, 1.4 Hz, 1H), 7.01 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H),
1
3
7.67 (d, J = 8.2 Hz, 2H); C NMR (101 MHz, CDCl ) δ 15.8 (CH ), 21.5 (CH ), 35.7 (CH ), 44.2 (CH ),
3
3
3
2
2
5
5.2 (CH ), 110.4 (CH), 120.4 (CH), 125.2 (C), 127.1 (2 × CH), 129.7 (2 × CH), 130.8 (CH), 136.3 (C),
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+
1
37.0 (C), 143.4 (C), 158.0 (C); MS (ESI) m/z 342 (M+Na . 100); HRMS (ESI) calcd for C H NNaO S
1
7
21
3
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
+
(
M+Na ) 342.1134, found 342.1125.
4
’’-Methyl-N-[(3,4-methylenedioxyphenyl)ethyl]benzenesulfonamide (1k).51 4’’-Methyl-N-[(3,4-
methylenedioxyphenyl)ethyl]benzenesulfonamide (1k) was synthesized as described for N-[(3,4-
dimethoxyphenyl)ethyl]-4’’-methylbenzenesulfonamide (1g) using 3,4-methylenedioxy-1-[(E)-2’-
nitrovinyl]benzene. Reduction of 3,4-methylenedioxy-1-[(E)-2’-nitrovinyl]benzene (1.03 g, 5.32 mmol)
using sodium borohydride (0.957 g, 25.3 mmol) and boron trifluoride diethyl etherate (3.90 mL, 31.9
mmol) gave 1’-(3,4-methylenedioxyphenyl)ethyl-2’-amine (0.587 g, 66%) which was used without
further purification. The N-protection step was carried out at room temperature for 6 h. Purification by
flash column chromatography (petroleum ether/ethyl acetate, 4:1) gave 4’’-methyl-N-[(3,4-
methylenedioxyphenyl)ethyl]benzenesulfonamide (1k) (0.679 g, 76%) as a white solid. Mp 86–88 °C
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
5
1
1
(
lit. 89–90 °C); H NMR (400 MHz, CDCl ) δ 2.43 (s, 3H), 2.67 (t, J = 6.8 Hz, 2H), 3.16 (q, J = 6.8 Hz,
3
2
H), 4.34 (br s, 1H), 5.92 (s, 2H), 6.49–6.54 (m, 2H), 6.70 (dd, J = 7.1, 1.3 Hz, 1H), 7.29 (d, J = 8.4 Hz,
1
3
2H), 7.69 (d, J = 8.4 Hz, 2H); C NMR (101 MHz, CDCl ) δ 21.5 (CH ), 35.5 (CH ), 44.3 (CH ), 101.0
3
3
2
2
(
CH ), 108.5 (CH), 109.0 (CH), 121.8 (CH), 127.1 (2 × CH), 129.7 (2 × CH), 131.3 (C), 137.0 (C), 143.5
2
+
(
C), 146.5 (C), 147.9 (C); MS (ESI) m/z 342 (M+Na . 100).
4
’’-Methyl-N-[(3-nitrophenyl)ethyl]benzenesulfonamide.
4’’-Methyl-N-[(3-
described for N-[(3,4-
nitrophenyl)ethyl]benzenesulfonamide was synthesized
as
dimethoxyphenyl)ethyl]-4’’-methylbenzenesulfonamide (1g) using 3-nitro-1-[(E)-2’-nitrovinyl]benzene.
Reduction of 3-nitro-1-[(E)-2’-nitrovinyl]benzene (0.281 g, 1.45 mmol) using sodium borohydride (0.363
g, 9.78 mmol) and boron trifluoride diethyl etherate (1.59 mL, 12.3 mmol) gave 1’-(3-nitrophenyl)ethyl-
2
’-amine (0.186 g, 77%) which was used without further purification. The N-protection step was carried
out at room temperature for 6 h. Purification by flash column chromatography (petroleum ether/ethyl
acetate, 1:1) gave 4’’-methyl-N-[(3-nitrophenyl)ethyl]benzenesulfonamide (0.142 g, 82%) as a yellow oil.
−1
1
IR (neat) 3285, 1597, 1526, 1348, 1325, 1155, 1094, 814 cm ; H NMR (400 MHz, CDCl ) δ 2.42 (s,
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H), 2.88 (t, J = 7.0 Hz, 2H), 3.25 (q, J = 7.0 Hz, 2H), 5.03 (br s, 1H), 7.27 (d, J = 7.9 Hz, 2H), 7.42 (t, J
7.8 Hz, 1H), 7.47 (dt, J = 7.8, 1.5 Hz, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.90 (t, J = 1.5 Hz, 1H), 8.03 (dt, J
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
=
1
3
= 7.8, 1.5 Hz, 1H); C NMR (101 MHz, CDCl ) δ 21.5 (CH ), 35.5 (CH ), 43.8 (CH ), 121.8 (CH), 123.6
3
3
2
2
(CH), 127.0 (2 × CH), 129.5 (CH), 129.8 (2 × CH), 135.2 (CH), 136.7 (C), 140.0 (C), 143.7 (C), 148.3
+
+
(C); MS (ESI) m/z 343 (M+Na . 100); HRMS (ESI) calcd for C H N NaO S (M+Na ) 343.0723, found
15 16 2 4
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
3
43.0712.
N-[(4-Chloro-3-nitrophenyl)ethyl]-4’’-methylbenzenesulfonamide.
nitrophenyl)ethyl]-4’’-methylbenzenesulfonamide was synthesized as described for N-[(3,4-
dimethoxyphenyl)ethyl]-4’’-methylbenzenesulfonamide (1g) using 4-chloro-3-nitro-1-[(E)-2’-
N-[(4-Chloro-3-
nitrovinyl]benzene. Reduction of 4-chloro-3-nitro-1-[(E)-2’-nitrovinyl]benzene (0.255 g, 1.12 mmol)
using sodium borohydride (0.280 g, 7.55 mmol) and boron trifluoride diethyl etherate (1.23 mL, 9.52
mmol) gave 1’-(4-chloro-3-nitrophenyl)ethyl-2’-amine (0.174 g, 78%) which was used without further
purification. The N-protection step was carried out at room temperature for 6 h. Purification by flash
column chromatography (petroleum ether/ethyl acetate, 7:3) gave N-[(4-chloro-3-nitrophenyl)ethyl]-4’’-
methylbenzenesulfonamide (0.238 g, 79%) as a yellow solid. Mp 84–86 °C; IR (neat) 3271, 2922, 2361,
−
1 1
1
532, 1327, 1157, 1088, 810 cm ; H NMR (400 MHz, CDCl ) δ 2.43 (s, 3H), 2.82 (t, J = 6.8 Hz, 2H),
3
3.22 (q, J = 6.8 Hz, 2H), 5.13 (t, J = 6.8 Hz, 1H), 7.24–7.30 (m, 3H, 6-H), 7.38 (d, J = 8.2 Hz, 1H), 7.55
13
(d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.2 Hz, 2H); C NMR (101 MHz, CDCl ) δ 21.6 (CH ), 34.9 (CH ), 43.6
3
3
2
(CH ), 125.2 (C), 125.8 (CH), 127.0 (2 × CH), 129.8 (2 × CH), 131.9 (CH), 133.8 (CH), 136.5 (C), 138.6
2
+
35
(C), 143.9 (C), 147.7 (C); MS (ESI) m/z 377 (M+Na . 100); HRMS (ESI) calcd for C H ClN NaO S
1
5
15
2
4
+
(M+Na ) 377.0333, found 377.0326.
N-[(3-Aminophenyl)ethyl]-4’’-methylbenzenesulfonamide (1l). To a stirred solution of 4’’-methyl-
N-[(3-nitrophenyl)ethyl]benzenesulfonamide (0.142 g, 0.40 mmol) in ethanol (20 mL) was added tin(II)
dichloride dihydrate (0.758 g, 3.36 mmol) and the resulting solution was heated under reflux for 18 h.
After cooling to room temperature, the reaction mixture was diluted with saturated aqueous sodium
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hydrogen carbonate solution (20 mL) and extracted with dichloromethane (4 × 50 mL). The combined
1
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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
extracts were washed with brine (2 × 200 mL), dried (MgSO ) and concentrated in vacuo. Purification by
4
flash column chromatography (petroleum ether/ethyl acetate, 1:1) gave N-[(3-aminophenyl)ethyl]-4’’-
methylbenzenesulfonamide (1l) (0.102 g, 79%) as a white solid. Mp 80–82 °C; IR (neat) 3268, 2922,
−
1 1
1
6
601, 1495, 1460, 1319, 1153, 1093, 814 cm ; H NMR (400 MHz, CDCl ) δ 2.42 (s, 3H), 2.66 (t, J =
3
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
.8 Hz, 2H), 3.17 (q, J = 6.8 Hz, 2H), 3.62 (br s, 2H), 4.38 (br s, 1H), 6.39 (t, J = 1.7 Hz, 1H), 6.42–6.48
(m, 1H), 6.53 (dd, J = 7.6, 1.7 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 7.9 Hz, 2H), 7.69 (d, J = 7.9
1
3
Hz, 2H); C NMR (101 MHz, CDCl ) δ 21.5 (CH ), 35.7 (CH ), 44.1 (CH ), 113.6 (CH), 115.3 (CH),
3
3
2
2
1
18.8 (CH), 127.1 (2 × CH), 129.7 (2 × CH), 129.8 (CH), 137.0 (C), 138.8 (C), 143.4 (C), 146.8 (C); MS
+
+
(ESI) m/z 313 (M+Na . 100); HRMS (ESI) calcd for C H N NaO S (M+Na ) 313.0981, found
1
5
18
2
2
3
13.0984.
N-[(3-Amino-4-chlorophenyl)ethyl]-4’’-methylbenzenesulfonamide
chlorophenyl)ethyl]-4’’-methylbenzenesulfonamide (1m) was synthesized as described for N-[(3-
aminophenyl)ethyl]-4’’-methylbenzenesulfonamide (1l) using 4’’-methyl-N-[(3-nitro-4-
(1m).
N-[(3-Amino-4-
chlorophenyl)ethyl]benzenesulfonamide (0.278 g, 0.790 mmol). Purification by flash column
chromatography (petroleum ether/ethyl acetate, 7:3) gave N-[(3-amino-4-chlorophenyl)ethyl]-4’’-
methylbenzenesulfonamide (1m) (0.226 g, 89%) as a colorless oil. IR (neat) 3372, 3279, 2924, 2361,
−1
1
1
6
620, 1497, 1435, 1319, 1156, 1088, 810 cm ; H NMR (400 MHz, CDCl ) δ 2.41 (s, 3H), 2.62 (t, J =
3
.8 Hz, 2H), 3.13 (q, J = 6.8 Hz, 2H), 4.00 (br s, 2H), 4.88 (t, J = 6.8 Hz, 1H), 6.36 (dd, J = 8.1, 2.0 Hz,
1H), 6.49 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H);
13
C NMR (101 MHz, CDCl ) δ 21.6 (CH ), 35.3 (CH ), 44.0 (CH ), 116.1 (CH), 117.7 (C), 119.2 (CH),
3
3
2
2
1
27.1 (2 × CH), 129.6 (CH), 129.7 (2 × CH), 136.8 (C), 137.5 (C), 143.0 (C), 143.5 (C); MS (ESI) m/z
+
35
+
3
47 (M+Na . 100); HRMS (ESI) calcd for C H ClN NaO S (M+Na ) 347.0591, found 347.0582.
15 17
2
2
N-[(3-Acetamidophenyl)ethyl]-4’’-methylbenzenesulfonamide (1n). Acetic anhydride (0.110 mL,
.17 mmol) was added to a stirred solution of N-[(3-aminophenyl)ethyl]-4’’-methylbenzenesulfonamide
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(
1l) (0.225 g, 0.780 mmol) in dry dichloromethane (10 mL) and stirred at room temperature for 16 h. The
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
reaction mixture was washed with saturated sodium carbonate (15 mL) and brine (15 mL). The organic
layer was dried (MgSO ) and concentrated in vacuo. Purification by flash column chromatography
4
(petroleum ether/ethyl acetate, 3:7) gave N-[(3-acetamidophenyl)ethyl]-4’’-methylbenzenesulfonamide
(1n) (0.245 g, 95%) as a colorless oil. IR (neat) 3282, 2921, 1669, 1613, 1595, 1549, 1489, 1440, 1319,
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
−
1 1
1
3
7
153, 1094, 814 cm ; H NMR (400 MHz, CDCl ) δ 2.14 (s, 3H), 2.42 (s, 3H), 2.72 (t, J = 6.8 Hz, 2H),
3
.18 (q, J = 6.8 Hz, 2H), 4.69 (t, J = 6.8 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.25–
1
3
.30 (m, 3H), 7.39 (d, J = 7.5 Hz, 1H), 7.46 (br s, 1H), 7.69 (d, J = 7.9 Hz, 2H); C NMR (101 MHz,
CDCl ) δ 21.5 (CH ), 24.6 (CH ), 35.8 (CH ), 44.1 (CH ), 118.3 (CH), 120.2 (CH), 124.5 (CH), 127.1 (2
3
3
3
2
2
× CH), 129.3 (CH), 129.8 (2 × CH), 136.8 (C), 138.3 (C), 138.8 (C), 143.5 (C), 168.6 (C); MS (ESI) m/z
+
+
3
55 (M+Na . 100); HRMS (ESI) calcd for C H N NaO S (M+Na ) 355.1087, found 355.1080.
17 20 2 3
N-[(3-Acetamido-4-chlorophenyl)ethyl]-4’’-methylbenzenesulfonamide (1o). N-[(3-Acetamido-4-
chlorophenyl)ethyl]-4’’-methylbenzenesulfonamide (1o) was synthesized as described for N-[(3-
acetamidophenyl)ethyl]-4’’-methylbenzenesulfonamide (1n) using N-[(3-amino-4-chlorophenyl)ethyl]-
4
’’-methylbenzenesulfonamide (1m) (0.109 g, 0.340 mmol). Purification by flash column
chromatography (petroleum ether/ethyl acetate, 1:1) gave N-[(3-acetamido-4-chlorophenyl)ethyl]-4’’-
methylbenzenesulfonamide (1o) (0.121 g, 99%) as a colorless oil. IR (neat) 3279, 2932, 2361, 1674, 1582,
−1
1
1
6
528, 1427, 1319, 1157, 1096 cm ; H NMR (400 MHz, CDCl ) δ 2.22 (s, 3H), 2.42 (s, 3H), 2.72 (t, J =
3
.9 Hz, 2H), 3.19 (q, J = 6.9 Hz, 2H), 4.73 (t, J = 6.9 Hz, 1H), 6.78 (dd, J = 8.2, 1.7 Hz, 1H), 7.23 (d, J =
1
3
8.2 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.59 (br s, 1H), 7.69 (d, J = 8.2 Hz, 2H), 8.11 (br s, 1H); C NMR
(101 MHz, CDCl ) δ 21.5 (CH ), 24.9 (CH ), 35.6 (CH ), 44.0 (CH ), 121.0 (C), 121.8 (CH), 125.1 (CH),
3 3 3 2 2
1
27.1 (2 × CH), 129.0 (CH), 129.7 (2 × CH), 134.6 (C), 136.9 (C), 137.9 (C), 143.4 (C), 168.4 (C); MS
+
35
+
(ESI) m/z 389 (M+Na . 100); HRMS (ESI) calcd for C H ClN NaO S (M+Na ) 389.0697, found
17 19 2 3
389.0685.
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Page 29 of 67
The Journal of Organic Chemistry
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-Methoxyphenylacetamide (1p). To a stirred solution of 3-methoxyphenylacetic acid (0.500 g, 3.00
1
2
mmol) in dry dichloromethane (15 mL) was added thionyl chloride (2.63 mL, 63.0 mmol) at 0 °C. The
reaction mixture was heated under reflux for 2.5 h after which the solvent was removed in vacuo. The
residue was dissolved in tetrahydrofuran (20 mL) and 25% aqueous ammonium hydroxide (4 mL) was
added slowly at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. The mixture
was concentrated in vacuo and water (15 mL) was added. The solution was heated for 0.5 h. The
suspension was cooled to 0 °C and the resulting white powder was collected by vacuum filtration and
washed with ice-water to give 3-methoxyphenylacetamide (1p) (0.209 g, 42%) as a white solid. Mp 139–
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
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
5
2
1
1
41 °C (lit. 137–139 °C); H NMR (400 MHz, CDCl ) δ 3.56 (s, 2H), 3.81 (s, 3H), 5.41 (br s, 1H), 5.52
3
1
3
(br s, 1H), 6.80–6.88 (m, 3H), 7.28 (t, J = 7.8 Hz, 1H); C NMR (101 MHz, CDCl ) δ 43.4 (CH ), 55.2
3
2
(
CH ), 113.0 (CH), 115.0 (CH), 121.6 (CH), 130.1 (CH), 136.3 (C), 160.1 (C), 173.2 (C); MS (ESI) m/z
3
+
1
86 (M+Na . 100).
5
3
1
’-(3-Methoxyphenyl)acrylonitrile. To a solution of m-anisaldehyde (1.79 mL, 14.7 mmol) in dry
dichloromethane (25 mL) was added cyanomethylene triphenylphosphorane (4.88 g, 16.2 mmol) and the
resulting mixture was stirred at room temperature for 16 h. After this time, the reaction mixture was
concentrated in vacuo and the residue was purified by flash column chromatography (petroleum
ether/ethyl acetate, 9:1) to give 1’-(3-methoxyphenyl)acrylonitrile (3:1 ratio of E to Z isomers) (1.81 g,
7
9%) as a colorless oil. Spectroscopic data is reported for the major E isomer. Spectroscopic data were
consistent with the literature.53 1H NMR (400 MHz, CDCl ) δ 3.84 (s, 3H), 5.87 (t, J = 16.6 Hz, 1H),
3
1
3
6.93–7.05 (m, 3H), 7.30–7.43 (m, 2H); C NMR (101 MHz, CDCl ) δ 55.4 (CH ), 96.7 (CH), 112.5
3
3
(CH), 116.9 (CH), 117.1 (C), 120.0 (CH), 130.2 (CH), 134.8 (C), 150.5 (CH), 160.0 (C); MS (EI) m/z
+
1
59 (M . 100), 116 (20), 89 (20).
N-[(1-Methoxyphenyl)propyl]-4’’-methylbenzenesulfonamide (1q).54 To a solution of 1’-(3-
methoxyphenyl)acrylonitrile (1.00 mL, 6.29 mmol) in ethanol (25 mL) was added 37% aqueous
hydrochloric acid (3 mL) and 10% palladium on charcoal (0.073 g). The reaction mixture was
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