Synthesis of ortho/ortho ′-substituted 1,1-diarylethylenes through cross-coupling reactions of sterically encumbered hydrazones and aryl halides

Article abstract of DOI:10.1021/jo3023268

The reactivity of sterically hindered N-tosylhydrazones 2 featuring ortho/ortho′-substituents on the aromatic ring with various ortho-, meta-, and para-substituted aryl halides 3 was investigated. To accomplish successfully this challenging coupling, fine-tuning of the reaction conditions were required. The newly established PdCl₂(MeCN)₂/Xphos/ NaO-t-Bu/F-benzene system in a sealed tube is compatible with a broad spectrum of both coupling partners, regardless of their electronic and steric nature. This protocol has been applied successfully to the synthesis of a xanthene derivative.

Full text of DOI:10.1021/jo3023268

Article
pubs.acs.org/joc
Synthesis of Ortho/Ortho′‑Substituted 1,1-Diarylethylenes through
Cross-Coupling Reactions of Sterically Encumbered Hydrazones and
Aryl Halides
Maxime Roche, Abdallah Hamze,* Olivier Provot, Jean-Daniel Brion, and Mouad Alami*
Universite
́
Paris-Sud, CNRS, BioCIS-UMR 8076, LabEx LERMIT, Laboratoire de Chimie Ther
́ ́
apeutique, Faculte de Pharmacie, rue
J.-B. Clem
́
ent, Chatenay-Malabry, F-92296, France
̂
S
* Supporting Information
ABSTRACT: The reactivity of sterically hindered N-tosylhydrazones 2 featuring ortho/ortho′-substituents on the aromatic ring
with various ortho-, meta-, and para-substituted aryl halides 3 was investigated. To accomplish successfully this challenging
coupling, fine-tuning of the reaction conditions were required. The newly established PdCl2(MeCN)2/Xphos/NaO-t-Bu/F-
benzene system in a sealed tube is compatible with a broad spectrum of both coupling partners, regardless of their electronic and
steric nature. This protocol has been applied successfully to the synthesis of a xanthene derivative.
activity.14 A structure−activity relationship (SAR) study of
INTRODUCTION
■
isoCA-4 led us to the design and synthesis of molecules of type
Transition-metal-catalyzed cross-coupling reactions have been
established as one of the most powerful tools for the
construction of C−C bonds.1 In this context, the development
of novel metal-catalyzed cross-coupling processes that do not
require stoichiometric organometallic reagents is particularly
attractive.2 Recently, Pd-catalyzed cross-coupling of diazo
compounds, pioneered by Van Vranken,3 has emerged as a
new type of cross-coupling reactions; however, diazo
compounds without an electron-withdrawing group are usually
unstable and thus difficult to handle. N-Tosylhydrazones, which
are easily prepared from aldehydes or ketones, could be used as
generally reliable precursors to diazo compounds.4 In 2007,
1 (Scheme 1).15
In continuation of our earlier work, and in order to have a
better understanding of the SAR, a further panel of compounds
of type A was designed to evaluate the steric effects of the
methoxy groups of aromatic rings and/or double-bond
substituents on biological activity. These 1,1-diarylolefin
derivatives having a di- or tetrasubstituted double bond are
characterized by the presence of ortho/ortho′-substituents on
the aromatic rings. Their synthesis was envisioned by coupling
of highly sterically hindered N-tosylhydrazones 2 with ortho-
substituted aryl halides 3 under palladium catalysis as outlined
in Scheme 2. All our attempts to prepare 4a by coupling 2a
with 3a under the standard protocol (Pd2dba3/XPhos, LiO-t-
Bu) developed by Barluenga et al.5a or using our previously
reported conditions (PdCl2(MeCN)2/dppp, Cs2CO3)15 re-
sulted in unsatisfactory yields (Table 1, entries 1 and 2). Our
attempts to increase the yield of 4a by using high catalyst
loading (up to 15 mol %) and elevated temperatures (up to 130
°C) combined with a prolonged reaction time did not lead to
any improvement. These unsuccessful results clearly demon-
strate that steric hindrance in both coupling partners plays a
́
Barluenga, Valdes, et al. demonstrated that the procedure for
generating in situ the diazo compounds from N-tosylhydra-
zones was compatible with the Pd-catalyzed cross-coupling
reaction of aryl halides.5 Since then, N-tosylhydrazones have
attracted extensive attention as a new type of versatile coupling
partners under transition-metal-catalyzed cross-coupling reac-
tions. In particular, they represent the most important metal−
carbenoid precursors capable of undergoing a range of reactions
with aryl sulfonates,6 benzyl halides,7 alkynes,8 amines,9
azoles,10 arylboronic acid,11 isocyanides,12 etc.
Our interest in the 1,1-diarylethylene unit synthesis13 led us
to identify iso-combretastatin A-4 (isoCA-4), a promising
cytotoxic agent with antitubulin and vascular targeting
Received: October 18, 2012
Published: December 17, 2012
© 2012 American Chemical Society
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Scheme 1
Scheme 2
critical role in the outcome of this reaction. To address
difficulties associated with the reactivity of highly sterically
hindered N-tosylhydrazones 2,16 we decided to reinvestigate
this challenging coupling reaction by fine-tuning of the base
source, solvent, ligand, and palladium. The results of this study
are now reported.
DavePhos (L4) was also effective, albeit furnishing 4a with
slightly diminished yield (entry 18). Changing the palladium
source from PdCl2(MeCN)2 to Pd2dba3 induced a slightly
lowering of the reaction yield (compare entries 19 and 20).
Entry 21 confirmed the crucial role of NaO-t-Bu in this
coupling, since its replacement by LiO-t-Bu led to a dramatic
decrease in the yield. The influence of the temperature was also
investigated, and it was confirmed that reactions run at 100 °C
gave the best results. Performing the reaction under
atmospheric pressure led to 4a in a similar yield (90%), but
6 h was needed to accomplish the reaction. Finally, reduction of
the catalytic loading to 2 mol % of PdCl2(MeCN)2 and 4 mol
% of L1 furnished 4a in a 90% isolated yield. As a result, the
combination of PdCl2(MeCN)2 (2 mol %), XPhos (4 mol %),
NaO-t-Bu (3 equiv), and PhF in a sealed tube at 100 °C was
fixed as optimal condition.20 A control experiment revealed that
both palladium catalyst and ligand were necessary for the
coupling to occur as no coupling product could be formed in
the absence of PdCl2(MeCN)2 or XPhos. It should be noted
that the coupling of hydrazone 2a with aryl halide 3a is not
limited to a small scale (1.25 mmol) as it could be conveniently
performed on a 2 g scale for 2a (5.29 mmol), giving rise 4a in
92% yield.
With optimal conditions in hand, we subsequently
investigated the substrate scope for the Pd-catalyzed coupling
of sterically hindered N-tosylhydrazone 2a with various aryl
halides possessing different steric and electronic properties. As
shown in Table 2, the reaction proceeded smoothly with aryl
iodides, bromides, or chlorides having ortho-, meta-, and para-
substituents on the aryl ring to give the corresponding products
4b−d in 72−97% isolated yields (entries 1−7). The reaction
displays little dependence upon electronic nature and position
of the substituent on the aromatic ring. Electron-rich and
electron-poor aryl halides all reacted completely and effectively
within 2 h (Table 2, entries 4−13). Additionally, we
successfully coupled hydrazone 2a with 4-iodo-1-methoxy-2-
(methoxymethoxy)benzene 3o and 4-bromo-2-fluoro-1-me-
thoxybenzene 3p, giving rise to olefins 4k and 4l, respectively,
which share structural similarity with isoCA-4 and isoFCA-4,
two vascular disrupting agents recently identified by us.14
Entries 17 and 18 illustrate examples of coupling reactions
between hydrazone 2a with heteroaryl halides, furnishing the
corresponding products 4n,o in good isolated yields.
RESULTS AND DISCUSSION
■
Initially, the reaction of 2a (1.2 equiv) with 3a (1 equiv) under
previously reported conditions (PdCl2(MeCN)2/dppp,
Cs2CO3, 1,4-dioxane, 100 °C, entry 2)15 provided 4a in a
low 28% yield (Table 1). This coupling was inefficient and
resulted in concomitant formation of the desired compound 4a
and two other byproducts: (i) the Bamford−Stevens17 alkene
5a, derived from the evolution of the diazo compound
generated from the hydrazone 2a, and (ii) sulfone 6a which
resulted from decomposition of sulfonylhydrazone. On the
basis of the results obtained in entries 2, PdCl2(MeCN)2 was
fixed as the source of palladium, then, we started screening a
variety of bases.18 We were delighted to find that the use of
alkoxide bases such as LiOMe, LiO-t-Bu or NaO-t-Bu leads to
improvement of performance of the coupling reaction with
yields up to 56% (entries 3−7). With NaO-t-Bu19 as the base,
the screening reactions with respect to the solvent revealed that
the use of fluorobenzene is superior to all other choices,
providing 4a in 70% yield (entry 12); in this case, byproduct
alkene 5a was not detected by 1H NMR analysis. Other
solvents18 such as toluene, dimethoxyethane (DME), or
cyclopentyl methyl ether (CPME) were also effective, albeit
affording 4a with slightly reduced yield. As summarized in
Table 1, screening of phosphine ligands revealed that these
latter play an important role in the outcome of this
transformation. Reactions using other bidentate ligands such
as DPEPhos (L5), Xantphos (L6), and dppf (L8) were less
efficient than dppp (L7) (compare entries 13 and 14−15).
Based on these results, we turned to the use of monodentate
biaryl phosphine (Buchwald ligands). The reaction with
CyJohnPhos (L3) gave the desired coupling product 4a in a
moderate yield (64%, entry 16), while no reaction occurred
with the bulky, electron-rich monodentate phosphine ligand
tert-butylXphos (L2) (entry 17); in the latter case, the sulfone
6a became the major product. The use of XPhos (L1) led to
the best result, and the desired product 4a was isolated in a
nearly quantitative 96% yield (entry 19). One can note that
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Table 1. Optimization Coupling Reaction of Sterically Hindered N-Tosylhydrazones 2a with 4-Iodotoluene 3a under Various
a
Conditions
b
c
entry
[Pd]
Pd2dba3
L
solvent
base
ratio 4a/5a/6a
yield (%)
d
1
2
L1
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L5
L6
L8
L3
L2
L4
L1
L1
L1
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DCE
LiO-t-Bu
Cs2CO3
30/65/5
50/40/10
55/45/0
48/52/0
50/15/35
57/43/0
65/15/20
35/30/35
63/5/32
65/5/30
72/0/28
77/0/23
60/15/25
45/45/10
64/12/24
70/15/15
0/35/65
93/7/0
15
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
Pd2dba3
28
48
40
38
50
56
29
57
61
65
70
54
37
59
64
0
3
LiOH
4
LiOMe
5
KO-t-Bu
LiO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
Na-O-tBu
NaO-t-Bu
NaO-t-Bu
LiO-t-Bu
6
7
8
9
Toluene
DME
CPME
PhF
10
11
12
13
14
15
16
17
18
19
20
21
PhF
PhF
PhF
PhF
PhF
PhF
88
e
,f
PhF
98/2/0
96
PhF
88/7/5
82
59
Pd2dba3
PhF
67/23/10
a
The reactions were carried out in a sealed tube with 2a (1.2 mmol), 3a (1 mmol), [Pd] (5 mol %), ligand (10 mol %), and base (3 equiv) at 100 °C
b
1
in 4.0 mL of solvent. Total conversion of 2a was observed in all cases. Ratio was determined by H NMR in the crude reaction mixture, see the
c
d
Supporting Information. Isolated yield of 4a. When the reaction was carried out at atmospheric pressure, 4a was isolated in a 17% yield.
e
f
Performing the reaction in the presence of PdCl2(MeCN)2 (2 mol %) and L1 (4 mol %) led to 90% of 4a. A 92% (1.38 g) yield of 4a was obtained
when the reaction was carried out on a 2.0 g scale of tosylhydrazone 2a at atmospheric pressure.
In order to gauge the performance of this catalytic system,
the substrate scope with respect to the sterically hindred N-
tosylhydrazone components has been investigated. As depicted
in Table 3, the coupling of pentamethyl-1,2,3,4-tetrahydro-
naphthalene hydrazone 2b with 4-iodoanisole 3f furnished the
expected 1,1-diarylethylene 4p in 76% yield (entry 1). One can
note that compound 4p may be regarded as an analogue of
bexarotene (Targretin), an oral antineoplastic agent indicated
for cutaneous T cell lymphoma.21 The results of entries 2 and 3
revealed that the electronic character of the N-tosylhydrazone
coupling partner did not influence the outcome of the reaction,
as component 2c also reacts successfully, providing the 1,1-
diarylethylene products 4q,r in excellent yields. It is noteworthy
that an ortho chlorine atom on the aromatic ring is tolerated,
enabling further derivatizations through metal-catalyzed cross-
coupling techniques. Interestingly, the coupling reaction is also
effective even with more challenging ortho/ortho′-substituted
substrates. Accordingly, the reaction of hydrazone 2d with 2-
iodo-1,3,5-trimethylbenzene 3u gave the expected olefin 4s in a
good 86% yield (entry 4). More interestingly, by increasing the
steric hindrance in the hydrazone component, the reaction of
2a with 3u still can be performed, giving rise in a moderate 40%
yield the 1,1-diarylolefin 4t featuring ortho/ortho′-substituents
on both of the aromatic rings (entry 5). The effectiveness of
our protocol is not restricted to N-tosylhydrazones having an
ortho-substituent on the aromatic ring. Substrates 2e−g
containing a secondary carbon atom alpha to the hydrazone
function were also successfully coupled with 4-iodoanisole 3f to
provide tetrasubstituted olefins 4w and olefins 4u−v having a
cycloalkylidene unit in good yields (entries 6−8). It should be
noted that with respect to the reaction yield, this protocol
proved to be more efficient than our previously reported
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a
Table 2. Palladium-Catalyzed Coupling of Sterically Hindered N-Tosylhydrazone 2a with Various Aryl Halides 3b−s
a
The reactions were carried out in a sealed tube with 2a (1.2 mmol), 3a (1 mmol), [Pd] (2 mol %), Ligand (4 mol %), base (3 equiv) at 100 °C in
b
c
4.0 mL of PhF. Yield of isolated product. A 94% (1.43 g) yield of 4e was obtained when the reaction was carried out on a 2.0 g scale of
tosylhydrazone 2a at atmospheric pressure.
one.15a Finally, in hope of further pushing the limit of the
degree of steric hindrance of the N-tosylhydrazone, we
examined the reaction with substrate 2h possessing both, an
ortho substituent on the aromatic ring, and a secondary carbon
atom alpha to the hydrazine function. Accordingly, we found
that if the coupling of 2h with 2-iodoanisole 3b failed due to
the strong steric hindrance of the two coupling partners (entry
9), the reaction of the same substrate 2h with 4-bromoanisole
3c proved to be highly efficient giving rise the desired product
4y in a 76% isolated yield (entry 10).
Since we had successfully succeeded in coupling N-
tosylhydrazone 2c having an ortho chorine atom, we undertake
to illustrate the potential of this reaction by achieving the
coupling of the remaining C−Cl bond through an intra-
molecular C−O bond-forming process, giving rise to 9-
methylenexanthene derivatives. Thus, reaction of 2c with 3t
under our optimized conditions furnished after removal of the
OMOM-protecting group olefin 4z in a 80% yield (Scheme 3).
Next, compound 4z was subjected to Buchwald−Hartwig
coupling by using our optimized conditions; however, 9-
methylenexanthene derivative 7 formed could not be isolated as
it decomposes during the purification step.22 To circumvent
this problem, we instead considered a one-pot Buchwald−
Hartwig coupling followed by a catalytic hydrogenation of the
CC double bond. In a typical experiment, after achieving the
intramolecular coupling process, the resulting crude product
was treated with Pd/C in AcOEt under hydrogen atmosphere.
Thus, under these conditions, we were pleased to observe that
the reaction worked very well and provided the desired 3-
methoxy-9-methylxanthene 8 in a 56% overall yield (Scheme
3). One can note that in a preliminary result compound 8 could
also be synthesized from diaryl ether 9 through an intra-
molecular N-tosylhydrazone coupling with aryl bromide and
further reduction of the CC double bond in a 31% overall
yield, despite the fact that the reaction conditions had never
been optimized (Scheme 3).
CONCLUSION
■
In summary, we have succeeded in developing an efficient
catalytic system for the Pd-catalyzed cross-coupling reaction of
sterically encumbered N-tosylhydrazones containing an ortho/
orho′-substituent on the aromatic ring. This system overcomes
many of the important limitations encountered with highly
sterically N-tosylhydrazone Pd-coupling processes. The steric
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a
Table 3. Coupling of Various Sterically Hindered N-Tosylhydrazones 2a−h with Aryl Halides 3
a
The reactions were carried out in a sealed tube with 2 (1.2 mmol), 3 (1 mmol), [Pd] (2 mol %), ligand (4 mol %), and base (3 equiv) at 100 °C in
b
c
4.0 mL of PhF. Yield of isolated product. A 93% (1.75 g) yield of 4r was obtained when the reaction was carried out on a 2.0 g scale of
d
tosylhydrazone 2c at atmospheric pressure. 4u was obtained in 68% isolated yield, 4v in 80% isolated yield, and 4w in 64% isolated yield by using
our initial conditions (PdCl2(MeCN)2/dppp, Cs2CO3, 1,4-dioxane, 100 °C, entry 2, Table 1).15a No reaction is observed even when using high
e
catalyst loading of PdCl2(MeCN)2 (15 mol %), XPhos (30 mol %).
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Scheme 3. Synthesis of 3-Methoxy-9-methylxanthene Derivative 8
(2CH3), 31.9 (2CH3), 25.0 (CH3), 21.8 (CH3), 18.4 (CH3); HRMS
(ESI) (M + H)+ m/z calcd for C24H33N2O2S 413.2257, found
413.2235.
hindrance effect on the outcome of the reaction was studied
both on the aryl moiety of the N-tosylhydrazone, and on the
aryl halide partner. The catalytic system based on
PdCl2(MeCN)2/Xphos/NaO-t-Bu/F-benzene in a sealed tube
is very general with regard to both coupling partners, and
coupling occurs with good to excellent yields in most of the
studied cases.
(Z/E)-N′-(1-(2,4-Dimethoxyphenyl)ethylidene)-4-methylbenzene-
sulfonohydrazide (2d): white solid (1.60 g, 92% yield); mp 147−149
°C; TLC Rf = 0.44 (EtOAc/cyclohexane, 3/7, SiO2); IR (neat) 1596,
1506, 1468, 1209, 1186, 1161, 1033; The presence of Z/E isomers in a
ratio 2:1 complicates the NMR spectroscopic data. Data for major Z
1
isomer: H NMR (300 MHz, CDCl3) δ (ppm) 7.80 (d, J = 8.3 Hz,
2H), 7.46 (bs, 1H), 7.31 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.4 Hz, 1H),
6.52 (dd, J = 8.4, 2.3 Hz, 1H), 6.46 (d, J = 2.2 Hz, 1H), 3.81 (s, 3H),
3.64 (s, 3H), 2.43 (s, 3H), 2.13 (s, 3H); 13C NMR (75 MHz, CDCl3)
(ppm) 162.3 (C), 156.4 (C), 153.3 (C), 143.8 (C), 136.1 (C), 129.6
(CH), 129.5 (2CH), 128.0 (2CH), 115.2 (C), 106.0 (CH), 99.3
(CH), 55.7 (2CH3), 25.0 (CH3), 21.7 (CH3); HRMS (ESI) (M + H)+
m/z calcd for C17H21N2O4S 349.1222, found 349.1206.
EXPERIMENTAL SECTION
■
General Methods. Solvent peaks were used as reference values,
1
with CDCl3 at 7.26 ppm for H NMR and 77.16 ppm for 13C NMR.
Chemical shifts δ are given in ppm, and the following abbreviations are
used: singlet (s), doublet (d), doublet of doublet (dd), triplet (t),
multiplet (m), and broad singlet (bs). Reaction courses and product
mixtures were routinely monitored by TLC on silica gel, and
compounds were visualized with under a UVP Mineralight UVGL-
58 lamp (254 nm) and with phosphomolybdic acid/Δ, anisaldehyde/
Δ, or vanillin/Δ. Flash chromatography was performed using silica gel
60 (40−63 mm, 230−400 mesh) at medium pressure (200 mbar).
Fluorobenzene was used as received; dioxane, dichloromethane,
cyclohexane, and tetrahydrofuran were dried using the procedures
described in Purification of Laboratory Chemicals.23 Organic extracts
were, in general, dried over MgSO4 or Na2SO4. All products reported
(E)-N′-(Cyclohexyl(2-methoxyphenyl)methylene)-4-methylbenze-
nesulfonohydrazide (2h): white solid (1.45g, 75% yield); mp 123−
125 °C; TLC Rf = 0.48 (EtOAc/cyclohexane, 3/7, SiO2); IR (neat,
cm−1) 2928, 2853, 2364, 1597, 1490, 1451, 1382, 1341, 1290, 1242,
1
1167, 1093, 1020, 990, 908, 814; H NMR (300 MHz, CDCl3) δ
(ppm) 7.79 (d, J = 8.3 Hz, 2H), 7.41−7.28 (m, 3H), 7.14 (s, 1H), 6.98
(t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 7.5, 1.7 Hz,
1H), 3.59 (s, 3H), 2.45 (s, 3H), 2.41−2.26 (m, 1H), 1.84−1.51 (m,
4H), 1.32−1.02 (m, 6H); 13C NMR (75 MHz, CDCl3) δ (ppm) 160.2
(C), 155.6 (C), 143.7 (C), 136.0 (C), 131.1 (CH), 129.4 (2CH),
128.6 (2CH), 128.1 (2CH), 121.6 (C), 121.5 (CH), 111.5 (CH), 55.5
(CH3), 45.9 (CH3), 30.1 (2CH2), 26.1 (2CH2), 21.8 (CH3); HRMS
(ESI) (M + H)+ m/z calcd for C21H27N2O3S 387.1742, found
387.1730.
Typical Procedure for Pd-Catalyzed N-Tosylhydrazones
Coupling with Aryl Halides. N-Tosylhydrazone (1.2 mmol),
PdCl2(MeCN)2 (0.02 mmol, 2 mol %), 2-dicyclohexylphosphino-
2′,4′,6′-triisopropylbiphenyl (Xphos) (0.04 mmol, 4 mol %), and 4 mL
of PhF were mixed under argon for 5 min at rt. NaO-t-Bu (3.0 mmol)
was then added, the reaction mixture was stirred for an additional 1
min, and finally, aryl halide (1.0 mmol) was added. The resulting
mixture was stirred at 100 °C in a sealed tube for 1−2 h until
completion of reaction as judged by TLC analysis. The crude reaction
mixture was allowed to cool to room temperature. EtOAc was added
to the mixture, which was filtered through Celite. The solvents were
evaporated under reduced pressure, and the crude residue was purified
by flash chromatography on silica gel.
1
showed H and 13C NMR spectra in agreement with the assigned
structures.
General Procedure for Preparation of Hydrazones.24 To a
rapidly stirred suspension of p-toluenesulfonohydrazide (5 mmol) in
dry methanol (10 mL) at 60 °C was added the ketone (5 mmol)
dropwise. Within 5−60 min, the N-tosylhydrazone began to
precipitate. The mixture was cooled to 0 °C, and the product was
collected on a Buchner funnel, washed with petroleum ether, and then
̈
dried in vacuo to afford the pure product.
(E)-4-Methyl-N′-(1-(2,4,6-trimethoxyphenyl)ethylidene)-
benzenesulfonohydrazide (2a): white solid (1.68 g, 89% yield); mp
197−199 °C; TLC Rf = 0.26 (EtOAc/cyclohexane, 3/7, SiO2); IR
(neat, cm−1) 3190, 1606, 1583, 1496, 1456, 1415, 1382, 1337, 1186,
1156, 1126, 1049, 911; 1H NMR (300 MHz, CDCl3) δ (ppm) 7.82 (d,
J = 8.3 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 6.11 (s, 2H), 3.84 (s, 3H),
3.63 (s, 6H), 2.46 (s, 3H), 2.10 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ (ppm) 163.1 (C), 157.4 (2C), 151.4 (C), 143.5 (C), 136.4 (C),
129.4 (2CH), 128.0 (2CH), 103.2 (C), 91.0 (2CH3), 55.8 (2CH3),
55.7 (CH3), 23.9 (CH3), 21.7 (CH3); HRMS (ESI) (M + Na)+ m/z
calcd for C18H22N2NaO5S 401.1142, found 401.1137.
(E)-4-Methyl-N′-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-
naphthalen-2-yl)ethylidene)benzenesulfonohydrazide (2b): white
solid (1.67 g, 81% yield); mp 223−225 °C; TLC Rf = 0.49
(EtOAc/cyclohexane, 3/7, SiO2); IR (neat) 3196, 2961, 2362, 1497,
1380, 1340, 1168, 1092, 1060, 899, 812; 1H NMR (300 MHz, CDCl3)
δ (ppm) 7.78 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.19 (s,
1H), 7.13 (s, 1H), 6.66 (s, 1H), 2.45 (s, 3H), 2.12 (s, 3H), 1.94 (s,
3H), 1.67 (s, 4H), 1.29 (m, 6H), 1.19 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ (ppm) 156.9 (C), 146.8 (C), 144.1 (C), 144.0 (C), 135.9
(C), 131.1 (C), 130.9 (C), 129.7 (2CH), 129.3 (CH), 127.9 (2CH),
124.0 (CH), 35.0 (CH2), 35.0 (CH2), 34.4 (C), 34.2 (C), 32.0
1,3,5-Trimethoxy-2-(1-(o-tolyl)vinyl)benzene (4a). After 2 h at 100
°C in a sealed tube, compound 4a was obtained as a white solid (256
mg, 90% yield), mp 72−74 °C. A 92% (1.38 g) yield of 4a was
obtained when the reaction was carried out on a 2.0 g scale of
tosylhydrazone 2a at atmospheric pressure for 4 h: TLC Rf = 0.59
(EtOAc/cyclohexane, 2/8, SiO2); IR (neat) 1603, 1581, 1494, 1453,
1
1413, 1334, 1224, 1203, 1161, 1125, 1036, 950, 908, 811; H NMR
(300 MHz, CDCl3) δ (ppm)7.22−7.15 (m, 1H), 7.14−7.01 (m, 3H),
6.14 (s, 2H), 5.47 (d, J = 2.2 Hz, 1H), 5.41 (d, J = 2.2 Hz, 1H), 3.82
(s, 3H), 3.68 (s, 6H), 2.29 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
(ppm) 160.5 (C), 158.6 (2C), 143.3 (C), 141.6 (C), 135.3 (C), 130.2
(CH), 129.1 (CH), 126.4 (CH), 125.2 (CH), 120.6 (CH2), 114.4 (C),
450
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The Journal of Organic Chemistry
Article
91.2 (2CH), 56.0 (2CH3), 55.4 (CH3), 20.2 (CH3); HRMS (ESI) (M
+ H)+ m/z calcd for C18H21O3 285.1485, found 285.1476.
55.5 (CH3); 19F NMR (188 MHz, CDCl3) δ (ppm) −114.2; HRMS
(ESI) (M + H)+ m/z calcd for C17H18FO3 289.1234, found 289.1231.
1,3,5-Trimethoxy-2-(1-(4-(trifluoromethyl)phenyl)vinyl)benzene
(4g). After 1 h at 100 °C in a sealed tube, compound 4g was obtained
as a colorless oil (247 mg, 73% yield): TLC Rf = 0.47 (EtOAc/
cyclohexane, 2/8, SiO2); IR (neat, cm−1) 2839, 1604, 1583, 1497,
1468, 1455, 1413, 1322, 1225, 1204, 1160, 1125, 1108, 1079, 1064,
1,3,5-Trimethoxy-2-(1-(2-methoxyphenyl)vinyl)benzene (4b).
After 1 h at 100 °C in a sealed tube, compound 4b was obtained as
a white solid (279 mg, 93% yield): mp 98−100 °C; TLC Rf = 0.44
(EtOAc/cyclohexane, 2/8, SiO2); IR (neat, cm−1): 2835; 2359, 2329,
1605, 1583, 1490, 1466, 1453, 1434, 1412, 1335, 1282, 1243, 1224,
1203, 1182, 1160, 1124, 1052, 1026, 950; 1H NMR (300 MHz,
CDCl3) δ (ppm) 7.15 (td, J = 7.7, 1.7 Hz, 1H), 7.05 (dd, J = 7.6, 1.7
Hz, 1H), 6.92−6.76 (m, 2H), 6.17 (s, 2H), 6.03 (d, J = 2.4 Hz, 1H),
5.41 (d, J = 2.4 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.68 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ (ppm) 160.3 (C), 158.7 (2C), 157.5 (C),
138.1 (C), 131.2 (C), 130.0 (CH), 127.8 (CH), 120.8 (CH2), 120.4
(CH), 114.6 (C), 111.6 (CH), 91.1 (2CH), 56.1 (2CH3), 55.8 (CH3),
55.4 (CH3); HRMS (ESI) (M + Na)+ m/z calcd for C18H20NaO4
323.1254, found 323.1255.
1
1037, 1014, 950; H NMR (300 MHz, CDCl3) δ (ppm) 7.49 (d, J =
8.2 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 6.21 (s, 2H), 5.99 (d, J = 1.2 Hz,
1H), 5.32 (d, J = 1.2 Hz, 1H), 3.86 (s, 3H), 3.69 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ (ppm) 161.1 (C), 158.9 (2C), 144.9 (C), 140.2
(C), 129.0 (C, q, J = 32.1 Hz), 126.2 (2CH), 125.1 (2CH, q, J = 3.6
Hz), 124.6 (C, q, J = 271.6 Hz), 118.7 (CH2), 111.6 (C), 91.1 (2CH),
56.1 (2CH3), 55.5 (CH3); 19F NMR (188 MHz, CDCl3) δ (ppm)
−62.8; HRMS (ESI) (M + H)+ m/z calcd for C18H18F3O3 339.1203,
found 339.1193.
tert-Butyl 4-(1-(2,4,6-Trimethoxyphenyl)vinyl)benzoate (4h).
After 1 h at 100 °C in a sealed tube, compound 4h was obtained as
yellow oil (192 mg, 52% yield): TLC Rf = 0.64 (EtOAc/cyclohexane,
2/8, SiO2); IR (neat, cm−1): 2360, 1704 1605, 1583, 1495, 1454, 1412,
1368, 1336, 1294, 1255, 1204, 1162, 1140, 1125, 1106, 1052, 1037,
1016, 950, 907, 864, 849, 813; 1H NMR (300 MHz, CDCl3) δ (ppm)
7.87 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 8.7 Hz, 2H), 6.20 (s, 2H), 6.00
(d, J = 1.3 Hz, 1H), 5.30 (d, J = 1.3 Hz, 1H), 3.86 (s, 3H), 3.67 (s,
6H), 1.58 (s, 9H); 13C NMR (75 MHz, CDCl3) δ (ppm) 166.0 (C),
161.0 (C), 158.9 (2C), 145.4 (C), 140.7 (C), 130.6 (C), 129.4 (2CH),
125.8 (2CH), 118.4 (CH2), 111.9 (C), 91.1 (2CH), 80.8 (C), 56.1
(2CH3), 55.5 (CH3), 28.4 (3CH3); (ESI) (M + H)+ m/z calcd for
C22H27O5 371.1858, found 371.1877.
4-(1-(2,4,6-Trimethoxyphenyl)vinyl)benzonitrile (4i). After 2 h at
100 °C in a sealed tube, compound 4i was obtained as a white solid
(165 mg, 56% yield): mp 102−104 °C; TLC Rf = 0.47 (EtOAc/
cyclohexane, 2/8, SiO2); IR (neat, cm−1) 2837, 2224, 1604, 1583,
1468, 1454, 1416, 1336, 1226, 1204, 1161, 1124, 1052, 1036, 950; 1H
NMR (300 MHz, CDCl3) δ (ppm) 7.53 (d, J = 8.2 Hz, 2H), 7.39 (d, J
= 8.2 Hz, 2H), 6.20 (s, 2H), 5.99 (d, J = 1.1 Hz, 1H), 5.37 (d, J = 1.0
Hz, 1H), 3.86 (s, 3H), 3.68 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
(ppm) 161.3 (C), 158.8 (2C), 146.1 (C), 140.0 (C), 132.1 (2CH),
126.6 (2CH), 119.8 (CH2), 119.4 (C), 110.5 (C), 91.0 (2CH), 56.0
(2CH3), 55.5 (CH3); (ESI) (M + Na)+ m/z calcd for C18H17NNaO3
318.1101, found 318.1096.
1,3,5-Trimethoxy-2-(1-(3-methoxyphenyl)vinyl)benzene (4c).
After 1 h at 100 °C in a sealed tube, compound 4c was obtained as
a colorless oil (291 mg, 97% yield): TLC Rf = 0.49 (EtOAc/
cyclohexane, 2/8, SiO2); IR (neat, cm−1) 2939, 2836, 2361, 2018,
1603, 1577, 1499, 1487, 1467, 1453, 1412; 1335, 1284, 1224, 1203,
1
1184, 1158, 1123, 1050, 1037, 950. H NMR (300 MHz, CDCl3) δ
(ppm) 7.17 (t, J = 7.9 Hz, 1H), 6.96−6.88 (m, 2H), 6.77 (dd, J = 8.1,
1.7 Hz, 1H), 6.20 (s, 2H), 5.95 (d, J = 1.4 Hz, 1H), 5.21 (d, J = 1.3 Hz,
1H), 3.85 (s, 3H), 3.77 (s, 3H), 3.70 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ (ppm) 160.8 (C), 159.6 (C), 158.9 (2C), 142.6 (C), 141.1
(2C), 129.0 (CH), 118.7 (CH), 116.7 (CH2), 112.5 (CH), 111.9
(CH), 91.1 (2CH), 56.2 (2CH3), 55.5 (CH3), 55.3 (CH3); HRMS
(ESI) (M + Na)+ m/z calcd for C18H20NaO4 323.1254, found
323.1246.
1,3,5-Trimethoxy-2-(1-(4-methoxyphenyl)vinyl)benzene (4d).
After 1 h at 100 °C in a sealed tube, compound 4d was obtained as
a white solid (261 mg, 87% yield): mp 121−123 °C; TLC Rf = 0.61
(EtOAc/cyclohexane, 2/8, SiO2); IR (neat, cm−1): 3185, 2999, 2837,
2358, 2181, 2131, 1603, 1582, 1511, 1467, 1454, 1412, 1335, 1247,
1
1225, 1204, 1181, 1160, 1123, 1052, 1033, 950; H NMR (300 MHz,
CDCl3) δ (ppm) 7.27 (d, J = 8.9 Hz, 2H), 6.79 (d, J = 8.9 Hz, 2H),
6.21 (s, 2H), 5.86 (d, J = 1.5 Hz, 1H), 5.10 (d, J = 1.5 Hz, 1H), 3.86
(s, 3H), 3.78 (s, 3H), 3.70 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
(ppm) 160.70 (C), 159.04 (C), 158.84 (2 C), 140.64 (C), 133.51 (C),
127.12 (2 CH), 114.36 (CH2), 113.5 (2CH), 112.8 (C), 91.2 (2CH),
56.2 (2CH3), 55.5 (CH3), 55.3 (CH3); HRMS (ESI) (M + Na)+ m/z
calcd for C18H20NaO4 323.1254, found 323.1244.
2-(1-(2,4-Dimethoxyphenyl)vinyl)-1,3,5-trimethoxybenzene (4j).
After 1 h at 100 °C in a sealed tube, compound 4j was obtained as
a white solid (317 mg, 96% yield): mp 115−117 °C; TLC Rf = 0.33
(EtOAc/cyclohexane, 2/8, SiO2); IR (neat, cm−1):, 2836, 2253, 2177,
2158, 2017, 1605, 1583, 1570, 1504, 1466, 1453, 1413, 1335, 1295,
2-(1-(2-Fluorophenyl)vinyl)-1,3,5-trimethoxybenzene (4e). After 2
h at 100 °C in a sealed tube, compound 4e was obtained as a white
solid (276 mg, 96% yield); mp 72−74 °C; A 94% (1.43 g) yield of 4e
was obtained when the reaction was carried out on a 2.0 g scale of
tosylhydrazone 2a at atmospheric pressure for 4 h: TLC Rf = 0.53
(EtOAc/cyclohexane, 2/8, SiO2); IR (neat) 1584, 1225, 1204, 1157,
1127, 905, 812; 1H NMR (300 MHz, CDCl3) δ (ppm) 7.21−6.83 (m,
4H), 6.18 (s, 2H), 5.97 (d, J = 1.5 Hz, 1H), 5.45 (d, J = 1.6 Hz, 1H),
3.84 (s, 3H), 3.69 (s, 6H); 13C NMR (75 MHz, CDCl3) δ (ppm)
160.7 (C), 160.6 (d, J = 258.2 Hz, C) 158.8 (2C), 135.8 (C), 130.0 (d,
J = 3.2 Hz, CH), 129.6 (d, J = 11.9 Hz, C), 128.2 (d, J = 8.4 Hz, CH),
123.6 (d, J = 3.3 Hz, CH), 121.7 (d, J = 7.4 Hz, CH2), 115.8 (d, J =
1
1259, 1225, 1205, 1160, 1125, 1076, 1035, 950; H NMR (300 MHz,
CDCl3) δ (ppm) 6.92 (d, J = 8.5 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H),
6.35 (dd, J = 8.5, 2.4 Hz, 1H), 6.17 (s, 2H), 6.03 (d, J = 2.4 Hz, 1H),
5.31 (d, J = 2.4 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 6H), 3.69 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ (ppm) 160.3 (C), 159.6 (C), 158.7 (2C),
137.7 (C), 130.5 (CH), 123.7 (C), 119.2 (CH2), 114.9 (C),
104.1(CH), 99.2 (CH), 91.1 (2CH), 56.2 (2CH3), 55.7 (CH3), 55.4
(2CH3), 55.3 (CH3); HRMS (ESI) (M + Na)+ m/z calcd for
C19H22NaO5 353.1359, found 353.1360.
23.3 Hz, CH), 113.1 (C), 91.1 (2CH), 56.1 (2 CH3), 55.5 (CH3); 19
F
1,3,5-Trimethoxy-2-(1-(4-methoxy-3-(methoxymethoxy)phenyl)-
vinyl)benzene (4k). After 1 h at 100 °C in a sealed tube, compound 4k
was obtained as a colorless oil (335 mg, 93% yield): TLC Rf = 0.28
(EtOAc/cyclohexane, 2/8, SiO2); IR (neat, cm−1) 2836, 1603, 1581,
1511, 1466, 1454, 1412, 1334, 1299, 1251, 1224, 1202, 1182, 1156,
NMR (188 MHz, CDCl3) δ (ppm) −113.9; HRMS (ESI) (M + H)+
m/z calcd for C17H18FO3 289.1234, found 289.1223.
2-(1-(4-Fluorophenyl)vinyl)-1,3,5-trimethoxybenzene (4f). After 1
h at 100 °C in a sealed tube, compound 4f was obtained as a white
solid (245 mg, 85% yield): mp 61−63 °C; TLC Rf = 0.47 (EtOAc/
cyclohexane, 2/8, SiO2); IR (neat, cm−1) 2835, 2361, 2329, 1603,
1584, 1508, 1467, 1454, 1413, 1336, 1225, 1204, 1160, 1125, 1052,
950; 1H NMR (300 MHz, CDCl3) δ (ppm) 7.38−7.19 (m, 2H), 6.93
(t, J = 8.7 Hz, 2H), 6.21 (s, 2H), 5.87 (d, J = 1.0 Hz, 1H), 5.18 (d, J =
1.0 Hz, 1H), 3.86 (s, 3H), 3.70 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ (ppm) 162.2 (C, d, J = 245.7 Hz), 160.9 (C), 158.8 (2C), 140.3 (C),
137.2 (C, d, J = 3.3 Hz), 127.6 (2CH, d, J = 7.7 Hz), 116.2 (CH2),
114.9 (2CH, d, J = 21.4 Hz), 112.3 (C), 91.1 (2CH), 56.1 (2CH3),
1
1121, 1074, 1052, 1030, 982; H NMR (300 MHz, CDCl3) δ (ppm)
7.27 (d, J = 2.1 Hz, 1H), 6.85 (dd, J = 8.5, 2.1 Hz, 1H), 6.74 (d, J = 8.5
Hz, 1H), 6.20 (s, 2H), 5.86 (s, 1H), 5.19 (s, 2H), 5.10 (s, 1H), 3.85 (s,
3H), 3.84 (s, 3H), 3.70 (s, 6H), 3.49 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ (ppm) 160.7 (C), 158.8 (2C), 149.5 (C), 146.2 (C), 140.4
(C), 133.8 (C), 120.5 (CH), 114.8 (CH2), 114.7 (CH), 112.5 (C),
111.3 (CH), 95.9 (CH2), 91.1 (2CH), 56.2 (CH3), 56.1 (2CH3), 55.9
(CH3), 55.4 (CH3); HRMS (ESI) (M + Na)+ m/z calcd for
C20H24NaO6 383.1465, found 383.1462.
451
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Article
2-(1-(3-Fluoro-4-methoxyphenyl)vinyl)-1,3,5-trimethoxybenzene
(4l). After 1 h at 100 °C in a sealed tube, compound 4l was obtained as
a white solid (235 mg, 74% yield): mp 120−122 °C; TLC Rf = 0.54
(EtOAc/cyclohexane, 2/8, SiO2); IR (neat, cm−1): 812, 875, 910, 950,
1026, 1052, 1109, 1126, 1158, 1183, 1204, 1225, 1271, 1300, 1335,
1413, 1454, 1467, 1515, 1582, 1603, 1728, 2839; 1H NMR (300 MHz,
CDCl3) δ (ppm) 7.13−6.95 (m, 2H), 6.83 (t, J = 8.8 Hz, 1H), 6.20 (s,
2H), 5.85 (d, J = 1.2 Hz, 1H), 5.13 (d, J = 1.2 Hz, 1H), 3.86 (s, 3H),
3.86 (s, 3H), 3.70 (s, 6H); 13C NMR (75 MHz, CDCl3) δ (ppm)
160.9 (C), 158.8 (2C), 153.95 (C), 150.7 (C), 146.9 (C), 139.8 (C),
134.5 (C, d, J = 6.0 Hz), 121.7 (CH, d, J = 3.3 Hz), 115.6 (CH2),
113.8 (CH, d, J = 19.0 Hz), 113.0 (CH, d, J = 2.2 Hz), 91.1 (2CH),
56.4 (CH3), 56.2 (2CH3), 55.5(CH3); 19F NMR (188 MHz, CDCl3) δ
(ppm) −134.6; HRMS (ESI) (M + H)+ m/z calcd for C18H20FO4
319.1340, found 319.1331.
2-(1-(2,4,6-Trimethoxyphenyl)vinyl)naphthalene (4m). After 1 h
at 100 °C in a sealed tube, compound 4m was obtained as a white
solid (243 mg, 76% yield): mp 106−108 °C; TLC Rf = 0.38 (EtOAc/
cyclohexane, 2/8, SiO2); IR (neat, cm−1) 1604, 1583, 1498, 1466,
1453, 1413, 1335, 1225, 1203, 1159, 1126, 1051, 1037, 949; 1H NMR
(300 MHz, CDCl3) δ (ppm) 7.80−7.71 (m, 3H), 7.66−7.57 (m, 2H),
7.46−7.32 (m, 2H), 6.25 (s, 2H), 6.09 (d, J = 1.2 Hz, 1H), 5.31 (d, J =
1.2 Hz, 1H), 3.89 (s, 3H), 3.69 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ (ppm) 160.9 (C), 159.0 (2C), 141.2 (C), 138.4 (C), 133.6 (C),
133.00 (C), 128.4 (CH), 127.7 (CH), 127.6 (CH), 125.9 (CH), 125.6
(CH), 124.9 (CH), 124.4 (CH), 117.0 (CH2), 112.6 (C), 91.2 (2CH),
56.2 (2CH3), 55.5 (CH3); HRMS (ESI) (M + H)+ m/z calcd for
C21H21O3 321.1485, found 321.1479.
3-(1-(2,4,6-Trimethoxyphenyl)vinyl)pyridine (4n). After 2 h at 100
°C in a sealed tube, compound 4n was obtained as a white solid (171
mg, 63% yield): mp 74−76 °C; TLC Rf = 0.24 (EtOAc/cyclohexane,
5/5, SiO2); IR (neat, cm−1) 2839, 1604, 1583, 1497, 1468, 1455, 1413,
1322, 1225, 1204, 1160, 1125, 1108, 1079, 1064, 1037, 1014, 950; 1H
NMR (300 MHz, CDCl3) δ (ppm) 8.56 (d, J = 1.6 Hz, 1H), 8.43 (dd,
J = 4.8, 1.6 Hz, 1H), 7.58 (dt, J = 8.0, 2.0 Hz, 1H), 7.16 (ddd, J = 8.0,
4.8, 0.8 Hz, 1H), 6.19 (s, 2H), 5.95 (d, J = 1.2 Hz, 1H), 5.30 (d, J = 1.2
Hz, 1H), 3.85 (s, 3H), 3.68 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
(ppm) 161.2 (C), 158.8 (2C), 148.2 (CH), 147.8 (CH), 138.5 (C),
136.8 (C), 133.2 (CH), 123.0 (CH), 118.4 (CH2), 111.1 (C), 91.0
(2CH), 56.0 (2CH3), 55.5 (CH3); HRMS (ESI) (M + H)+ m/z calcd
for C16H18NO3 272.1281, found 272.1288.
1-Methyl-5-(1-(2,4,6-trimethoxyphenyl)vinyl)-1H-indole (4o).
After 2 h at 100 °C in a sealed tube, compound 4o was obtained as
a white solid (233 mg, 72% yield); mp 105−107 °C; TLC Rf = 0.43
(EtOAc/cyclohexane, 2/8, SiO2); IR (neat, cm−1): 2836, 1603, 1582,
1467, 1453, 1411, 1334, 1245, 1224, 1203, 1183, 1156, 1051, 1036,
950; 1H NMR (300 MHz, CDCl3) δ (ppm) 7.50 (d, J = 1.4 Hz, 1H),
7.39 (dd, J = 8.6, 1.7 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 6.98 (d, J = 3.1
Hz, 1H), 6.41 (d, J = 3.1 Hz, 1H), 6.26 (s, 2H), 5.96 (d, J = 1.5 Hz,
1H), 5.15 (d, J = 1.5 Hz, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.71 (s, 6H);
13C NMR (75 MHz, CDCl3) δ (ppm) 160.6 (C), 158.9 (2C), 142.2
oil (238 mg, 87% yield): TLC Rf = 0.73 (EtOAc/cyclohexane, 2/8,
SiO2); IR (neat) 1605, 1573, 1503, 1466, 1435, 1300, 1262, 1208,
1
1165, 1082; H NMR (300 MHz, CDCl3) δ (ppm) 7.40−7.15 (m,
4H), 7.06 (d, J = 8.6 Hz, 1H), 6.45 (m, 2H), 5.79 (s, 1H), 5.39 (s,
1H), 3.81 (s, 3H), 3.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm)
160.5 (C), 158.4 (C), 144.6 (C), 142.3 (C), 132.7 (C), 131.2 (CH),
131.1 (CH), 129.6 (CH), 128.2 (CH), 126.4 (CH), 123.0 (C), 119.1
(CH2), 104.4 (CH), 99.2 (CH), 55.7 (CH3), 55.4 (CH3); HRMS
(ESI) (M + H)+ m/z calcd for C16H16ClO2 275.0833, found 275.0834.
1-(1-(2-Chlorophenyl)vinyl)-4-methoxy-2-(methoxymethoxy)-
benzene (4r). After 1 h at 100 °C in a sealed tube, compound 4r was
obtained as pale yellow oil (303 mg, 93% yield). A 93% (1.75 g) yield
of 4r was obtained when the reaction was carried out on a 2.0 g scale
of tosylhydrazone 2c at atmospheric pressure for 4 h: TLC Rf = 0.69
(EtOAc/cyclohexane, 2/8, SiO2); IR (neat, cm−1): 3198, 2177, 2116,
1607, 1573, 1503, 1471, 1432, 1298, 1217, 1153, 1120, 1071, 1007,
923; 1H NMR (300 MHz, CDCl3) δ (ppm) 7.39−7.10 (m, 5H), 6.64
(d, J = 2.5 Hz, 1H), 6.53 (dd, J = 8.5, 2.5 Hz, 1H), 5.71 (d, J = 1.7 Hz,
1H), 5.40 (d, J = 1.7 Hz, 1H), 4.95 (s, 2H), 3.80 (s, 3H), 3.21 (s, 3H);
13C NMR (75 MHz, CDCl3) δ (ppm) 160.5 (C), 155.5 (C), 144.9
(C), 142.2 (C), 132.7 (C), 131.2 (CH), 131.1 (CH), 129.7 (CH),
128.1 (CH), 126.4 (CH), 124.0 (C), 119.3 (CH2), 106.5 (CH), 101.8
(CH), 94.4 (CH2), 55.9 (CH3), 55.5 (CH3); HRMS (ESI) (M + Na)+
m/z calcd for C17H17ClNaO3 327.0758, found 327.0740.
2-(1-(2,4-Dimethoxyphenyl)vinyl)-1,3,5-trimethylbenzene (4s).
After 2 h at 100 °C in a sealed tube, compound 4s was obtained as
a yellow oil (243 mg, 86% yield): TLC Rf = 0.68 (EtOAc/cyclohexane,
2/8, SiO2); IR (neat, cm−1) 1605, 1571, 1503, 1291, 1257, 1209, 1160,
1112, 1069, 1033, 902; 1H NMR (300 MHz, CDCl3) δ (ppm) 6.89 (s,
2H), 6.76 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.33 (dd, J =
8.6, 2.4 Hz, 1H), 6.13 (d, J = 2.4 Hz, 1H), 5.19 (d, J = 2.4 Hz, 1H),
3.83 (s, 3H), 3.79 (s, 3H), 2.31 (s, 3H), 2.15 (s, 6H); 13C NMR (75
MHz, CDCl3) δ (ppm) 159.9 (C), 159.2 (C), 143.2 (C), 140.5 (C),
136.2 (2C), 136.0 (C), 130.7 (CH), 128.2 (2CH), 121.9 (C), 117.9
(CH2), 104.2 (CH), 99.4 (CH), 55.6 (CH3), 55.4 (CH3), 21.2 (CH3),
20.2 (2CH3); HRMS (ESI) (M + H)+ m/z calcd for C19H23O2
283.1693, found 283.1684.
2-(1-Mesitylvinyl)-1,3,5-trimethoxybenzene (4t). After 2 h at 100
°C in a sealed tube, compound 4t was obtained as a colorless solid
(125 mg, 40% yield): mp 84−85 °C; TLC Rf = 0.68 (EtOAc/
cyclohexane, 2/8, SiO2); IR (neat, cm−1) 2835, 1604, 1580, 1453,
1
1412, 1333, 1224, 1204, 1158, 1128, 1054, 952, 907; H NMR (300
MHz, CDCl3) δ (ppm) 6.78 (s, 2H), 6.11 (s, 2H), 5.57 (d, J = 2.5 Hz,
1H), 5.32 (d, J = 2.5 Hz, 1H), 3.79 (s, 3H), 3.61 (s, 6H), 2.24 (s, 3H),
2.18 (s, 6H); 13C NMR (75 MHz, CDCl3) δ (ppm) 160.2 (C), 159.0
(2C), 140.4 (C), 139.1 (C), 136.4 (2C), 135.0 (C), 128.2 (2CH),
122.3 (CH2), 91.4 (2CH), 55.9 (2CH3), 55.4 (CH3), 21.1 (CH3), 20.4
(2CH3); HRMS (ESI) (M + H)+ m/z calcd for C20H25O3 313.1798,
found 313.1784.
5-(Cyclopentylidene(4-methoxyphenyl)methyl)-1,2,3-trimethoxy-
benzene (4u).15a After 2 h at 100 °C in a sealed tube, compound 4u
was obtained as a colorless oil (322 mg, 91% yield): Rf = 0.42
(cyclohexane/EtOAc, 8/2, SiO2); 1H NMR (300 MHz, CDCl3) δ
(ppm) 7.13 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.39 (s, 2H),
3.85 (s, 3H), 3.80 (s, 3H), 3.79 (s, 6H), 2.49−2.24 (m, 4H), 1.80−
1.59 (m, 4H); 13C NMR (75 MHz, CDCl3) δ (ppm) 157.7 (C), 152.7
(2C), 142.6 (2C), 139.4 (C), 135.6 (C), 132.5 (C), 130.0 (2CH),
113.2 (2CH), 106.4 (2CH), 60.8 (CH3), 56.0 (2CH3), 55.1 (CH3),
33.4 (CH2), 33.3 (CH2), 26.9 (CH2), 26.8 (CH2); MS (APCI) (M +
H)+ m/z 355.5.
5-(Cyclobutylidene(4-methoxyphenyl)methyl)-1,2,3-trimethoxy-
benzene (4v).15a After 2 h at 100 °C in a sealed tube, compound 4v
was obtained as a colorless oil (292 mg, 86% yield): Rf = 0.39
(cyclohexane/EtOAc, 8/2, SiO2); 1H NMR (300 MHz, CDCl3) δ
(ppm) 7.12 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.39 (s, 2H),
3.86 (s, 3H), 3.81 (s, 3H), 3.78 (s, 6H), 2.93 (t, J = 7.7 Hz, 4H), 2.05
(p, J = 7.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ (ppm) 157.9 (C),
152.7 (2C), 139.6 (2C), 136.4 (C), 132.8 (C), 132.4 (C), 129.8
(2CH), 113.3 (2CH), 106.0 (2CH), 60.8 (CH3), 55.9 (2CH3), 55.1
(C), 138.5 (C), 132.4 (C), 1289.0 (CH), 128.5 (C), 120.2 (CH),
118.6 (CH), 114.0 (CH2), 113.8 (C), 108.8 (CH), 102.5 (CH), 91.2
(2CH), 56.3 (2CH3), 55.5 (CH3), 32.9 (CH3); HRMS (ESI) (M +
H)+ m/z calcd for C20H22NO3 324.1594, found 324.1583.
6-(1-(4-Methoxyphenyl)vinyl)-1,1,4,4,7-pentamethyl-1,2,3,4-tet-
rahydronaphthalene (4p). After 2 h at 100 °C in a sealed tube,
compound 4p was obtained as a white solid (254 mg, 76% yield): mp
80−82 °C; TLC Rf = 0.69 (EtOAc/cyclohexane, 1/9, SiO2) ; IR (neat)
1
1608, 1511, 1248, 1177, 1036, 897; H NMR (300 MHz, CDCl3) δ
(ppm)7.00 (d, J = 8.9 Hz, 2H), 6.92 (s, 1H), 6.86 (s, 1H), 6.61 (d, J =
8.9 Hz, 2H), 5.42 (d, J = 1.6 Hz, 1H), 4.88 (d, J = 1.6 Hz, 1H), 3.58 (s,
3H), 1.77 (s, 3H), 1.49 (s, 4H), 1.09 (s, 6H), 1.06 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ (ppm)159.2 (C), 149.3 (C), 144.0 (C), 142.2
(C), 139.1 (C), 133.8 (C), 133.0 (C), 128.1 (CH), 128.0 (CH), 127.9
(2CH), 113.7 (2CH), 112.9 (CH2), 55.4 (CH3), 35.4 (2CH2), 34.1
(C), 34.0 (C), 32.1 (4CH3), 20.0 (CH3); HRMS (ESI) (M + H)+ m/z
calcd for C24H31O 335.2369, found 335.2350.
1-(1-(2-Chlorophenyl)vinyl)-2,4-dimethoxybenzene (4q). After 1 h
at 100 °C in a sealed tube, compound 4q was obtained as pale yellow
452
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The Journal of Organic Chemistry
Article
(CH3), 32.3 (CH2), 32.2 (CH2), 26.8 (CH2); MS (ESI) (M + Na)+
m/z 363.4.
Notes
The authors declare no competing financial interest.
1,2,3-Trimethoxy-5-(1-(4-methoxyphenyl)-2-methylprop-1-en-1-
yl)benzene (4w).15a After 2 h at 100 °C in a sealed tube, compound
4w was obtained as a colorless oil (276 mg, 84% yield): Rf = 0.37
(cyclohexane/EtOAc, 8/2, SiO2); 1H NMR (300 MHz, CDCl3) δ
(ppm) 7.07 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.33 (s, 2H),
3.84 (s, 3H), 3.80 (s, 3H), 3.79 (s, 6H), 1.80 (bs, 6H); 13C NMR (75
MHz, CDCl3) δ (ppm) 157.8 (C), 152.6 (2C), 139.2 (C), 136.6 (C),
136.2 (C), 135.3 (C), 130.6 (2CH), 130.4 (C), 113.1 (2CH), 106.9
(2CH), 60.8 (CH3), 56.0 (2CH3), 55.1 (CH3), 22.7 (CH3), 22.4
(CH3); MS (APCI) (M + H)+ m/z 329.2.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support of this project by CNRS
and University Paris 11. M.R. thanks the French Ministry of
Research for a Ph.D. fellowship. Our laboratory Biocis UMR
8076 is a member of the laboratory of excellence LERMIT
supported by a grant from ANR (ANR-10-LABX-33).
1-(Cyclohexylidene(4-methoxyphenyl)methyl)-2-methoxyben-
zene (4y). After 2 h at 100 °C in a sealed tube, compound 4y was
obtained as a yellow oil (234 mg, 76% yield): TLC Rf = 0.74 (EtOAc/
cyclohexane, 2/8, SiO2); IR (neat, cm−1) 2929, 2833, 1607, 1576,
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1507, 1488, 1463, 1433, 1282, 1237, 1176, 1029, 993; H NMR (300
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6.96−6.72 (m, 4H), 3.77 (s, 3H), 3.71 (s, 3H), 2.39−1.96 (m, 4H),
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1,3,5-Trimethoxy-2-vinylbenzene (side product 5a):25 colorless
oil; TLC Rf = 0.60 (EtOAc/cyclohexane, 2/8, SiO2); IR (neat, cm−1)
1603, 1579, 1454, 1404, 1334, 1230, 1206, 1193, 1155, 1125, 1064,
1
1039, 1004, 952; H NMR (300 MHz, CDCl3) δ ppm 6.90 (dd, J =
18.0, 12.2 Hz, 1H), 6.14 (s, 2H), 5.95 (dd, J = 18.0, 2.9 Hz, 1H), 5.31
(dd, J = 12.2, 2.9 Hz, 1H), 3.83 (s, 6H), 3.82 (s, 3H); MS (ESI) (M +
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colorless oil; TLC Rf = 0.31 (EtOAc/cyclohexane, 2/8, SiO2); IR
(neat, cm−1): 1608, 1587, 1494, 1418, 1285, 1227, 1206, 1121, 1087,
1066, 1037, 950, 918; 1H NMR (300 MHz, CDCl3) δ ppm 7.54 (d, J =
8.2 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 6.02 (d, J = 2.0 Hz, 1H), 5.94
(d, J = 2.0 Hz, 1H), 5.00 (q, J = 7.3 Hz, 1H), 3.77 (s, 3H), 3.55 (s,
3H), 3.52 (s, 3H), 2.38 (s, 3H), 1.79 (d, J = 7.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ (ppm) 161.7 (C), 161.3 (C), 159.4 (C), 143.5
(C), 136.8 (C), 129.2 (2CH), 128.8 (2CH), 103.5 (C), 91.3 (2CH),
90.4 (CH), 58.0 (CH3), 55.8 (CH3), 55.4 (CH3), 21.6 (CH3), 13.0
(CH3); MS (ESI) (M + Na)+ m/z 373.2.
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SiO2); IR (neat, cm−1) 2935, 1506, 1431, 1033, 958; H NMR (300
́
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(m, 2H), 6.70 (dd, J = 8.4, 2.6 Hz, 1H), 6.64 (d, J = 2.5 Hz, 1H), 4.09
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ASSOCIATED CONTENT
■
S
* Supporting Information
Details for experiments conditions; copies of 1H and 13C NMR
spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
■
Corresponding Author
*Tel: (+33) 1 4683-5498. Fax: (+33) 1 4683-5827. E-mail:
(A.H.) abdallah.hamze@u-psud.fr, (M.A.) mouad.alami@u-
psud.fr.
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